N-Phenyl-1,2,3,4-tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β-Hydroxysteroid Dehydrogenase 1 Inhibitors

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N-Phenyl-1,2,3,4-tetrahydroisoquinoline: An Alternative

Scaffold for the Design of 17β-Hydroxysteroid

Dehydrogenase 1 Inhibitors

Marco Mottinelli,^{[b, d]}Maša Sinreih,^[c]Tea L. Rižner,^[c]Mathew P. Leese,^[b]and

Barry V. L. Potter*^{[a, b]}

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17β-Hydroxysteroid dehydrogenases catalyse interconversion at

the C17 position between oxidized and reduced forms of

steroidal nuclear receptor ligands. The type 1 enzyme, ex-

pressed in malignant cells, catalyses reduction of the less-active

estrone to estradiol, and inhibitors have therapeutic potential in

estrogen-dependent diseases such as breast and ovarian

cancers and in endometriosis. Synthetic decoration of the

nonsteroidal N-phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ)

template was pursued by using Pomeranz-Fritsch-Bobbitt,

Pictet-Spengler and Bischler-Napieralski approaches to explore

the viability of this scaffold as a steroid mimic. Derivatives were

evaluated biologically in vitro as type 1 enzyme inhibitors in a

bacterial cell homogenate as source of recombinant protein.

Structure-activity relationships are discussed. THIQs possessing

a 6-hydroxy group, lipophilic substitutions at the 1- or 4-

positions in combination with N-4’-chlorophenyl substitution

were most favourable for activity. Of these, one compound had

an IC₅₀of ca. 350 nM as a racemate, testifying to the

applicability of this novel approach.

Introduction

pausal women estrogens are locally produced in many periph-

eral tissues.^[4]Hence, the main treatment strategy for breast

cancer in premenopausal women, apart from surgery and

radiotherapy, is the use of selective ER modulators (SERMs) such

as tamoxifen to block the stimulant effect on an ER+ tumour.

Conversely, in postmenopausal women, the peripheral biosyn-

thesis of estrogens can be targeted by using an aromatase

inhibitor such as anastrozole and this is becoming the first line

approach.^[5]Recently, targeting other enzymes involved in the

peripheral biosynthesis of estrogens, such as steroid sulfatase

Breast cancer is the leading cause of death in women. Despite

enormous progress in its diagnosis and treatment over recent

years, more than 2 million new diagnoses and over 626679

deaths worldwide occurred in 2018 in both men and women.^[1]

Multiple studies have highlighted an increment in estrogen

receptor positive (ER+) breast cancer cases over estrogen

receptor negative (ERÀ ) ones.^[2]ERÀ status is usually associated

with poorer prognosis, whereas ER+ status allows exploitation

of drugs targeting estrogen receptors to shrink tumour mass

before surgical removal and to reduce recurrence post-

removal.^[3]ER-targeting therapies differ between women in pre-

and postmenopausal stages. In premenopausal women, estro-

gens are mainly produced in the ovaries and then distributed

through the body by the bloodstream, whereas in postmeno-

and 17β-hydroxysteroid dehydrogenase

1 (HSD17B1), has

garnered increasing interest.^[4b,6]

HSD17Bs are a class of enzymes belonging to the short-

chain dehydrogenase/reductase (SDR) family comprising

15 subtypes. The HSD17B enzymes are involved in the reduc-

tion and oxidation of hormones, fatty acids and bile acids.

HSD17B subtypes differ in terms of substrate specificity, tissue

distribution and regulation mechanisms, and they can be

arbitrarily divided into androgenic or estrogenic, and oxidative

or reductive. The oxidative HSDs depend on NAD⁺/NADH and

the reductive HSDs on NADP⁺/NADPH. Due to higher cellular

levels of NADPH and NAD⁺, NAD⁺/NADH-dependent enzymes

act as oxidases and NADP⁺/NADPH dependent enzymes as

reductases.^[7]HSD17B1 (EC 1.1.1.62) was originally isolated from

human placenta in the 1950s and is a reducing enzyme which

catalyses the NADPH dependent conversion of estrone (E1) into

the more estrogenic estradiol (E2).^[7a,8]Although HSD17B1 is

capable of converting E2 into E1 in vitro, this function in vivo is

carried out exclusively by HSD17B2. This is due to the high

intracellular concentration of the preferred cofactor NADPH

versus NADP⁺, which drives the reductive process.

[a] Prof. Dr. B. V. L. Potter

Drug Discovery & Medicinal Chemistry

Department of Pharmacology, University of Oxford

Mansfield Road, Oxford, OX1 3QT (UK)

E-mail: barry.potter@pharm.ox.ac.uk

[b] Dr. M. Mottinelli, Dr. M. P. Leese, Prof. Dr. B. V. L. Potter

Wolfson Laboratory of Medicinal Chemistry

Department of Pharmacy and Pharmacology, University of Bath

Claverton Down, BA2 7AY Bath (UK)

[c] Dr. M. Sinreih, Dr. T. L. Rižner

Institute of Biochemistry

Faculty of Medicine, University of Ljubljana

Vrazov trg 2, 1000, Ljubljana (Slovenia)

[d] Dr. M. Mottinelli

Present address:

Department of Medicinal Chemistry

School of Pharmacy, University of Florida

1345 Center Dr., Gainesville, FL 32611 (USA)

HSD17B1 is upregulated in breast cancer cells and is

Supporting information for this article is available on the WWW under

https://doi.org/10.1002/cmdc.202000762

involved in maintaining high E2 intratumoural levels.^[9]In

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addition, HSD17B1 expression has been associated with poorer Results and Discussion

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prognoses in breast cancer patients.^[10]Accordingly, HSD17B1 is

a promising target for ER+ breast cancer.

Chemistry

Known inhibitors of HSD17B1 are based on, for example,

modified steroids, biphenyl compounds, flavonoids, coumarins,

benzothiazoles or thiophene.^[7a,11]Non-estrogenic, selective,

steroidal HSD17B1 inhibitors such as the 2,16-disubstituted

estrone derivative STX1040 have demonstrated potent inhib-

ition of E1-stimulated breast tumour growth using a murine

model.^[11g,12]STX1040 was observed to inhibit E1-stimulated

proliferation of T47D cells in vitro and significantly decrease

tumour volumes and plasma E2 levels in vivo.^[13]In addition,

designed multi-functional ligands targeting both HSD17B1 and

estrogen receptors or HSD17B1 and the steroid sulfatase

enzyme have been reported.^[14]However, no HSD17B1 inhibitor

has yet reached human clinical trials.

The nonsteroidal N-phenyl-1,2,3,4-tetrahydroisoquinoline

scaffold (THIQ) has structural similarities with steroidal E1

(Figure 1), the natural substrate of HSD17B1. Compounds based

on a similar 1,2,3,4-tetrahydroisoquinoline scaffold have been

reported in the literature as being steroidomimetic.^[6g,15]In

addition, this THIQ framework allows for a wide range of

substitutions that can be accessed in a rapid and convenient

fashion. Thus, the THIQ core represents an interesting scaffold

for constructing novel inhibitors of HSD17B1 as a potential ER+

breast cancer treatment. Moreover, the presence of a mildly

basic nitrogen atom in the THIQ core allows for the formation

of salts to aid solubility.

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With the objective of introducing simple substituents at each

possible position of the selected THIQ scaffold, synthetic

approaches were designed around three well-established

synthetic methodologies, namely the Pomeranz-Fritsch-Bobbitt,

Pictet-Spengler and Bischler-Napieralski approaches (Fig-

ure 2).^[16]These three robust and reliable key reactions delivered

the desired final compounds in a short number of steps and

starting from inexpensive, commercially available, compounds

such as anilines and benzaldehydes.

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The first step of the Pomeranz-Fritsch-Bobbitt approach

involves a double reductive amination (Scheme 1), followed by

cyclization with standard or modified conditions (6 M HCl or

70% HClO₄, respectively) as dictated by the substitution pattern

(Scheme 2), as per literature precedent.^[17]Cyclization of 3e

(Scheme 2) yielded a mixture of two regioisomers 8a and 9a,

which could be directly separated. Similarly, the two regioisom-

ers 8b and 9b were simultaneously obtained during the

cyclization of 3g (Scheme 2). Alternatively, the synthesis could

be telescoped by reductive dehydroxylation of the crude

mixture of 8a and 9a followed by purification to deliver 10a

and 11a (Scheme 2). In general, the 4-hydroxy-THIQ intermedi-

ates (4a–d, h–n, 6a–b, and the mixture of 8a and 9a) were

subjected to a reductive dehydroxylation (Scheme 2) under

conditions that were dictated by those controlling the cycliza-

tion step. The reduction could be achieved with NaBH₄as a

reducing agent in the presence of TFA where at least one

electron-donating group was directly activating the position 4

of the THIQ ring (6a and b, 8a and 9a). If this was not the case,

the NaBH₄conditions proved ineffective and the desired THIQs

5a–d, h–n were instead accessed via an ionic hydrogenation

reaction with Et₃SiH in presence of BF₃·Et₂O as a Lewis acid

(Scheme 2).

Herein we report the synthesis of a series of fully decorated

THIQs and their biological activities as candidate HSD17B1

inhibitors. We identify a tractable THIQ derivative of nanomolar

potency for further optimization.

Due to their low nucleophilicity, 2- and 3-chloroaniline

failed to deliver the double reductive amination products of

Scheme 1 (data not shown), and instead only yielded mono-

Figure 1. Structural analogies between E1 and the THIQ template.

Figure 2. Different synthetic approaches were used to explore substitution

at R¹(Bischler-Napieralski), R²and R³(Pictet-Spengler) and at R⁴and R⁵

(Pomeranz-Fritsch-Bobbitt) positions.

Scheme 1. Double reductive amination. a) i) NaBH(OAc)₃, CHCl₃, RT, 1 h; ii)

2,2-dimethoxyacetaldehyde, RT, 8 h (54–99%).

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(Scheme 3) were obtained in an approximately 10:1 ratio (ratio

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of isolated yields). Compound 15a was isolated in only a 23%

yield, but its expected regioisomer 16a was not successfully

isolated. This could be attributed to the very small amount

formed on the scale at which the reaction was performed

(Scheme 3). Thus, through the Pictet-Spengler approach, it was

possible to obtain compounds 15a–c that proved inaccessible

through the Pomeranz-Fritsch-Bobbitt approach (Scheme 3). In

addition, the respective regioisomers 16b, c could be isolated

from the same reaction (Scheme 3).

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The Pictet-Spengler approach allowed direct access to 3-

and 4-substituted THIQs devoid of substitution at the 1-position

(Scheme 4). The introduction of substituents in position 3 of the

final THIQs progressed through a Weinreb ketone synthesis

followed by a reductive amination and Pictet-Spengler cycliza-

tion. The synthesis of the initial Weinreb amide 17 through

coupling with acid chloride progressed with only 48% yield

(data not shown), possibly due to the lower nucleophilicity of

N,O-dimethylamine. However, pretreating the amine with PCl₃

to form a more reactive triaminophosphine intermediate that

was then coupled directly with the acid 12 afforded the desired

Weinreb amide 17 in a 64% yield (Scheme 4). Amide 17 was

then alkylated with various Grignard reagents to yield, after

acidic workup, the desired ketones (Scheme 4). Notably, upon

treatment of 17 with iPrMgBr, a poorly nucleophilic Grignard

reagent, none of the desired product could be recovered and

only partial N-demethoxylation was observed. Ketones 18a–d

(Scheme 4) were subjected to reductive amination conditions

to give amines 19a, b, d; however, ketone 18c proved

unreactive under these conditions and no desired product

could be isolated. Compounds 19a, b, d (Scheme 4) were

subjected to the Pictet-Spengler conditions but only compound

19b afforded the two regioisomers 20b and 21b (20b/21b

10:1), whereas 19a yielded only the 6-methoxy-THIQ 20a with

no detectable amount of the respective 8-methoxy derivative

observed. In contrast to compounds 19a and 19b, the benzyl

derivative 19d proved unreactive in the experimental con-

ditions used and none of the desired THIQs could be obtained

(Scheme 4).

To obtain 4-substituted THIQs, acid 12 was converted by

classic Fischer esterification into the respective methyl ester 23

(Scheme 4), which was then alkylated (LDA/requisite haloal-

kanes) to give compounds 24a–e. Substituted amides 25a–e

(Scheme 4) were obtained directly from the corresponding ester

by treating 4-chloroaniline first with bis(trimethylaluminum)-

1,4-diazabicyclo-[2.2.2]octane adduct (DABAL-Me₃), a non-pyro-

phoric analogue of trimethylaluminum, followed by the appro-

priate esters 24a–e. This reaction progressed cleanly and the

amides 25a–e (Scheme 4) were reduced without purification

with LiAlH₄to give the desired amines 26a–e, which in turn

were cyclized under Pictet-Spengler conditions to afford the

desired 6-methoxy-THIQs 27a–e in moderate yields (Scheme 4).

Once more, the respective 8-methoxy regioisomers were

relatively inaccessible with only 28d being delivered in small

amounts (Scheme 4).

Scheme 2. Pomeranz-Fritsch-Bobbitt reaction and reductive dehydroxylation.

a) 70% HClO₄, RT, 1 h, 26–67%; b) Et₃SiH, BF₃·Et₂O, CH₂Cl₂, reflux, 18 h, 11–

76%; c) 6M HCl, RT, 1 h, 31–82%; d) NaBH₄, TFA, CH₂Cl₂, RT, 6 h, 11–85%.

alkylated anilines. A Pictet-Spengler approach using phenyl-

acetic acid starting material was adopted when the Pomeranz-

Fritsch-Bobbitt approach proved impractical. In this case, the

formation of amides 13a–c from the commercial acid 12 via the

acid chloride (Scheme 3) proceeded with decent yields. The

resultant amides 13a–c, were then be reduced with LiAlH₄to

the corresponding amines 14a–c (Scheme 3).

Similarly to observations for the cyclization of compounds

3e, g (Scheme 2), both regioisomers 15b, c and 16b, c

Scheme 3. Synthesis of THIQs from chloroanilines by Pictet-Spengler cycliza-

tion. a) i) SOCl₂, CH₂Cl₂, RT, 1 h; ii) appropriately substituted aniline, Na₂CO₃,

°

toluene, reflux, 12–16 h, 66–80% b) LiAlH₄,THF, 80 C, 4–6 h, 74–97% c)

paraformaldehyde, PTSA, toluene, reflux, 12–18 h 23–57% (15a–c) and 4%

(16b, c).

The introduction of a substituent at position 1 of the desired

THIQ could be easily achieved by

a

Bischler-Napieralski

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Scheme 4. Synthesis of 3- and 4-substituted THIQs by Pictet-Spengler cyclization. a) i: N,O-dimethylamine, PCl₃, DIPEA, Et₂O, 0 C, 1 h then RT, 12 h; ii: 12,

°

toluene, 60 C; b) appropriately substituted Grignard reagent, THF, RT, 1 h; c) 4-chloroaniline, NaBH(OAc)₃, DCE, AcOH, RT, 6–12 h; d) paraformaldehyde, PTSA,

°

toluene, reflux, 12–18 h; e) conc. H₂SO₄, MeOH, reflux, 72 h; f) LDA, THF, À 78 C, 1 h then appropriately substituted haloalkane, RT, 4–6 h; g) i: 4-chloroaniline,

DABAL-Me₃, THF, 40 C, 1 h; ii: 24a–f, 12 h, reflux; h) LiAlH₄, THF, 80 C, 6–12 h.^[a]Compound 25e was not purified by flash column chromatography and used

°

as such.

cyclization approach. The synthesis proceeded as previously

seen for the synthesis of 1-unsubstituted THIQs that were not

accessible through the Pomeranz-Fritsch-Bobbitt approach

(Scheme 3). The synthesis commenced with conversion of the

acid 12 into the corresponding amides 13d–f (Scheme 5), which

were in turn reduced to the respective amines 14d–f in the

presence of LiAlH₄. Amines 14d–f (Scheme 5) were acylated

with the appropriate acyl chloride to give the amides 29a–i.

The Bischler-Napieralski conditions traditionally involve secon-

dary amides and yield 1,2-unsaturated THIQs.^[18]In comparison,

cyclization of the tertiary amides 29a–i (Scheme 5) led to the

formation of an iminium ion unstable to aqueous work up.

Hence, after Bischler-Napieralski cyclization of amides 29a–i

(Scheme 5) with POCl₃in anhydrous toluene, a solvent switch

from toluene to MeOH was performed followed by direct

reduction of the product with NaBH₄. This eliminated the small

excess of POCl₃and allowed direct access to the desired final

THIQs 30a–c, e–I (Scheme 5). As before (Scheme 3 and 4), the

corresponding 8-methoxy THIQs 31b, c, f, h, i (Scheme 5) were

isolable in some cases, albeit in low yield. However, the very

sterically hindered 29d showed very low reactivity under the

experimental conditions used and no quantifiable amounts of

the desired THIQ product could be identified in the reaction

mixture.

c, e–i could be cyclized under Bischler-Napieralski conditions to

give the 1- mono substituted THIQs 30a–c, e–i and 31b, c, f, h,

I (Scheme 5). 1,4-Disubstituted THIQs 33a, b, d (Scheme 5)

could be obtained by merging the two approaches for the

synthesis of 1- and 4-monosubstituted THIQs. The synthesis

started with the acylation of 26a, b, d to give amides 32a, b, d

(Scheme 5), followed by the tandem Bischler-Napieralski cycliza-

tion and NaBH₄reduction. Once more, a small amount of the 8-

methoxy regioisomers was formed and compounds 34b, d

could also be successfully isolated (Scheme 5).

Lastly, despite the hydroxy- derivatives being directly

accessible through the Pomeranz-Fritsch-Bobbitt pathway, from

a synthetic point of view, it proved expedient to derive them

from their methoxy counterparts by O-demethylation with BBr₃,

affording the final compounds as the hydrobromide salts

(Scheme 6). Naturally, compounds bearing both hydroxy and

methoxy groups, such as 5h (Scheme 2), were accessed by the

Pomeranz-Fritsch-Bobbitt approach.

Introduction of substituents in positions 1, 2 or 3 of the final

THIQs generated a chiral centre and led to the formation of a

racemic mixture, considering that all the reactions presented in

this work are expected to be non-stereoselective. Resolution of

the enantiomeric mixture was not considered to be of value at

this early stage of the work and thus the compounds were

biologically evaluated as their racemates. Consequently, the

generation of a second chiral centre during the cyclization of

32a, b, d (Scheme 5) was expected to generate two diastereo-

Branched amines 26a, b, d were cyclized under Pictet-

Spengler conditions to afford the 4-mono substituted THIQs

27a–e and 28d (Scheme 4), while the more linear amines 29a–

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Scheme 5. Synthesis of 1-substituted and 1,4-disubstituted THIQs by Bischler-Napieralski cyclization. a) i: SOCl₂, CH₂Cl₂, RT, 1 h; ii: appropriately substituted

°

aniline, Na₂CO₃, toluene, reflux, 12–16 h; b) LiAlH₄, THF, 80 C, 4–6 h; c) appropriately substituted acyl chloride, pyridine, CH₂Cl₂, RT, 12–18 h; d) i: POCl₃,

toluene, reflux, 12–18 h; ii: NaBH₄, MeOH, RT, 6 h.

meric pairs of enantiomers, 1,4-cis and 1,4-trans derivatives for

the 6-methoxy and 8-methoxy regioisomers, 33a, b, d and 34b,

d, respectively.

Primarily, H⁶showed interaction with H^3a, which in turn

correlated with H⁴. However, no direct or extended interaction

could be identified between H⁵or H⁶and H⁷or H⁸, clearly

leading to the interpretation that only enantiomers of the trans

diastereoisomers were present. The presence of only two such

The two regioisomers (33a, b, d and 34a, b, d, respectively)

were easily separated by flash chromatography, but attempts to

elucidate the diastereomeric composition of the two mixtures

1

enantiomers was also confirmed by chiral HPLC and by H and

1

by H,¹H NOESY NMR analysis were unsuccessful at this stage.

¹H,¹³C HSQC experiments with the chiral shift reagent Europium

(III) tris[3-(heptafluoropropyl-hydroxymethylene)-d-camphorate]

(see the Supporting Information for the relevant spectra).

Previous reports in the literature illustrated the stereoinduction

of substituents in position 3 of the THIQ during the reduction of

the 1,2-unsaturated bond.^[18]The relative stereochemistry

depended also on the reducing agents and the 1,3-cis-

analogue was obtained using NaBH₄while the 1,3-trans- one

formed in presence of LiAlH₄. Consequently, it is plausible to

expect that the same factors would induce the formation of 1,4-

trans isomers in the experimental conditions described in

Scheme 5. In fact, due to the conformational constraints

induced by the substituent in position 4 in the intermediate

iminium ion, the hydrogen on the same carbon, and not the

substituent itself, shields the face from which the corresponding

nucleophilic attack would yield the cis-1,4 isomer (see p. 206 of

the Supporting Information).

However, the same experiment performed on the hydroxy

derivative 43b (Figure 3), revealed that the compound was

diastereomerically pure and that thus only an enantiomeric pair

of a trans diastereomer was present.

The protonation on the nitrogen probably increased the

rigidity of the system and allowed more marked spatial

interactions on the ¹H,¹H NOESY NMR timescale (Figure 3).

Biology

Of the complete 73 compound library set only a fraction could

be evaluated for their potential to inhibit HSD17B1 activity

in vitro (Table 1). Compounds were thus selected based on

Figure 3. ¹H,¹H NOESY NMR interactions of compound trans-43b. Only the

(1R,4R)-43b enantiomer is represented for simplicity. Please refer to the

Supporting Information for complete spectra.

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°

Scheme 6. Conversion of methoxy derivatives into the corresponding hydroxy compounds. a) BBr₃, CH₂Cl₂, À 79 C to RT, 2 h or aq. 48% HBr, 120 C, 3 h.

substituent variety and compound availability, so that the

viability of the THIQ scaffold for HSD17B1 inhibitor design could

be assessed. Compounds were screened at an initial concen-

tration of 6.0 μM, with active compounds (>70% inhibition)

being re-evaluated at 0.6 μM. Finally, the most promising

compound was selected for IC₅₀quantification.

differences at 6.0 μM. This may reflect a predomination of

electronic effects on the inhibition activity over the steric

effects.

The 6-hydroxy compounds were generally more active than

their 6-methoxy analogues, whereas relocation of the hydroxy

substitution from position 6 to position 5 or 7 only led to a loss

of inhibition, as is visible by comparing compounds 35d, 38b

and 39b (Table 1). Substitution of the 4’-chloro motif by a

second hydroxy group (35k) led to loss of inhibition, but

shifting the second hydroxy group into position 3’ (35l) some-

what increased the activity compared to compound 35d

(Table 1). However, introduction of a second and/or a third

hydroxy group(s) to compound 35k, giving compounds 37a

and 37b respectively, led to drastic reduction or complete

abolition of inhibitory activity (Table 1). In addition, these very

electron-rich systems showed significant chemical stability

issues, being prone to oxidation and would thus have

eventually likely presented only a poor hit candidate. A separate

observation can be made for compounds bearing a 4-hydroxy

group. While the 4-hydroxy-substituted series in general had

only modest activity, as is evident from compounds 4g–35d,

Within the 6-methoxy series, derivative 5d that features an

apolar electron-withdrawing 4’-chloro substituent showed the

highest activity while 5k that features an electron-donating 4’-

methoxy substituent proved least active (Table 1). A similar

trend could be observed among the 6-hydroxy series with

compound 35d showing 64% inhibition at 6.0 μM. The

contribution of the chlorine atom at the 4’-position is also

evident from comparison of 6-H, 4’-H THIQ 5a with the

corresponding 4’-chloro derivative 5n, with a fourfold increase

in activity at 6.0 μM being observed (Table 1). In addition,

mono-substitution at position 4’ appears preferred over the

corresponding 2’ and 3’ derivatives (15b and 15a respectively)

that showed somewhat lower inhibition. The 3’- and 4’-chloro

substituted derivatives within the 6-hydroxy series (36a and

35d respectively, Table 1) did not show enzyme inhibition

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Table 1. In vitro inhibition of HSD17B1 for selected THIQs.^[a]

1

2

3

4

5

6

7

Cmpd.

R¹

R²

R³

R⁴

R⁵

R⁶

R⁷

R⁸

% inh.

[6.0 μM]^[b]

[0.6 μM]^[b]

8

9

4g^[c]

4n^[c]

5a

5c

5d

5h

5i

5k

H

Me

H

OH

H

OH

H

OH

H

Me

Et

i-Pr

Bn

Me₂

H

Br

H

OH

H

OH

H

OH

H

4-Cl

H

22.3

15.7

9.3

NT

28.3

NT

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

MeO

OH

MeO

H

MeO

H

27.0

38.0

12.7

27.0

13.0

40.9

12.6

25.4

12.9

47.1

33.5

25.3

45.0

64.0

38.0

42.0

76.2

65.5

0.0

21.1

47.1

45.4

54.0

77.2

91.5

100.0

84.3

80.9

44.1

40.7

73.1

90.1

81.0

74.8

73.7

68.8

69.8

95.1

58.6

4-Cl

4-MeO

4-Me

4-MeO

4-Cl

4-MeO

H

5n

H

6a^[c]

7a

MeO

Br

H

OH

H

8b^[c]

9b^[c]

15a

15b

35c

H

MeO

OH

H

3-Cl

2-Cl

H

35d

35i

35k

35l

4-Cl

4-Me

4-OH

3-OH

3-Cl

4-OH

4-Cl

H

36a

37a

37b

38b

39b

40a^[c]

41a^[c]

41b^[c]

41c^[c]

41d^[c]

41e

42a^[c]

42b^[c]

42c^[c]

42e^[c]

42f^[c]

42g^[c]

42h^[c]

42i^[c]

43a^[c]

43b^[c]

43d^[c]

H

NT

OH

19.9

45.9

60.3

0.0

39.6

NT

Me

Et

i-Pr

Ph

Bn

(CH₂)₂Ph

Bn

NT

10.8

4.7

0.0

11.0

10.6

24.1

23.5

52.7

NT

H

Me

Et

Bn

4-OH

4-Cl

H

[a] Cmpd.=compound; NT=not tested (<70% inhibition at 6.0 μM); [b] Values generated from a single experiment carried out in duplicate; [c] Compound

was tested as a racemic mixture.

4n–5n, and 6a–7a (Table 1), introduction of a lipophilic

electron-withdrawing bromine atom on the THIQ had

inhibition value than the 4-iPr derivative 41c (Table 1). The 1,4-

disubstituted compound 41e showed a twofold greater inhib-

ition at 0.6 μM relative to 4-monosubstituted 41a (Table 1). It

may well be that one of the two enantiomers of 41e is more

active than the other but we have not had the opportunity to

resolve the racemic mixture and test each enantiomer sepa-

rately to date. Whereas substituents at position 4 had drastic

effects on the inhibitory activity of the compounds, a methyl

substituent at position 3 (40a) had only a mildly detrimental

effect and this may possibly be due to the imposed change in

dihedral angle between the tetrahydroisoquinoline and the

phenyl rings (Table 1). A series of substitutions at position 1

(42a–c, e) showed a size-dependent effect on inhibition values,

a

dramatic, positive, effect on activity. The 7-bromo derivative 8b

had comparable activity to the unsubstituted THIQ 5a, whereas

the 5-bromo compound 9b showed a fourfold increased

activity that was only marginally lower than that of compound

35d (Table 1).

Although a polar and hydrogen-bond-donor hydroxy group

was not tolerated in position 4, lipophilic substitutions at the

same position showed markedly positive effects that were size

dependent (41a<41b<41c, Table 1). However, the 4-benzyl

group in compound 41d appears too large to be accommo-

dated in the lipophilic binding pocket, leading to a lower

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though with lower impact compared to the same substitutions

in position 4 (41a–c; Table 1). Activity plateaued with the

phenyl group (42e) and somewhat decreased progressively

with the benzyl (42f) and phenethyl (42g) groups (Table 1).

Attempts to optimize compound 42f by either removing the 4’-

chloro substituent (42h) or replacing it with a 4’-hydroxy group

(42i) did not produce very significant changes (Table 1).

However, the same changes on the 1-unsubstituted THIQ (35d)

had more marked effects indicating that compound 42f may

bind in a different pose than the more simply substituted 35d

(Table 1).

Finally, further efforts to optimize compound 42f by

introducing substituents in position 4 (43a, b, d) produced

significant effects, which were however less marked than in

absence of the 1-benzyl substituent. In fact, the 1-benzyl-4-

ethyl-THIQ 43b was only comparable for activity with 41c

(52.7% and 60.3% at 0.6 μM respectively), despite the large

increase in molecular weight (Table 1).

Compound 41c (60% inhibition at 0.6 μM) possessed a

marginally better enzyme inhibitory profile than 43b (53%

inhibition at 0.6 μM) making it the first choice candidate for an

IC₅₀determination In terms of their clogP parameters 41c and

43b exhibited values of 5.3 and 6.4 respectively (ChemDraw,

Cambridge Soft) and 41c was a preference. Compound 41c

showed an IC₅₀=349.9�34.7 nM (Table 1 and SI), making it an

attractive candidate for further optimization. To assess suit-

candidate from this study for further progression. Clearly, (�)-

41c is a racemate and thus a very important next step would

be to resolve the two enantiomers and evaluate their individual

biological properties. It may well be that one is more highly

favoured as an inhibitor and its IC₅₀could be lower than

349.9 nM.

1

2

3

4

5

6

7

8

9

Three selected compounds, 35d, 35k and 42c, possessing

incremental structural changes, were tested in the DiscoverX

PathHunter® assay against estrogen receptor α (ERα) at a

concentration of 100 μM. Interestingly, changing the 4’-hydroxy

group (35k) into a 4’-chloro (35d) drastically decreases the

agonist activity at ERα while somewhat increasing inhibitory

activity at HSD17B1 (Table 2). Addition of a 1-iPr group to

compound 35d gave 42c, which showed further reduction in

agonist activity at ERα accompanied by good inhibitory activity

at ERα and a significant increase in inhibitory activity at

HSD17B1 (Table 2). Altogether, even though these data cannot

be directly correlated to our selected compound 41c, it is still

possible to infer that the core THIQ structure is indeed

steroidomimetic and that simple substitution changes will

modulate not only HSD17B1 activity but also agonist and

antagonist activity at ERα. This gives considerable confidence

that later-stage optimization will be able to fine-tune the

desired activities.

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ability for potential future development and optimisation we Conclusions

also wished to compute physicochemical descriptors as well as

predict outline ADME and pharmacokinetic properties, druglike

nature and medicinal chemistry friendliness for our two best

leads 41c and 43b. Thus, they were both evaluated computa-

tionally for druglikeness using the Swiss ADME programme.^[19]

Six physicochemical properties were considered: lipophilicity,

size, polarity, solubility, flexibility and saturation. To be consid-

ered druglike these six properties of a molecule have to fall

entirely within the pink area of the “bioavailability radar” plot

shown (Figure 5b). While this was entirely the case for 41c, 43b

was borderline less favourable (see the Supporting information).

Moreover, 41c has a lower molecular weight, a consensus logP

of 4.11, TPSA 23.47 Å and has predictions of moderate solubility

and high GI absorption. We thus propose 41c as the best

The literature shows that HSD17B1 is clearly involved in certain

types of hormone-dependent cancers, as well as in endome-

triosis, and that it is an interesting and seemingly druggable

target. At present, HSD17B1 inhibitors based on multiple

chemical scaffolds, including steroidal, nonsteroidal and natural

product templates have been reported, but no compound has

yet reached the clinical trial stage. The present work reports

exploration of the N-phenyl-1,2,3,4-tetrahydroisoquinoline

(THIQ) template as a core steroidomimetic structure for the

generation of new HSD17B1 inhibitors.

The three complementary synthetic approaches explored

allowed generation of a series of fully decorated THIQ-based

inhibitory candidates that could be substituted with a variety of

Table 2. Agonist and antagonist activity of compounds 35d, 35k and 42c at ERα.^[a]

Cmpd.

HSD17B1 [% inhibition]

ERα

6.0 μM

Agonist mode

[% activity]

[100 μM]

60.7

114.7

10.7

Antagonist mode

[% inhibition]

[100 μM]

35d

35k

42c

64.0

42.0

73.1

NT

10.8

À 53.4^[b]

À 18.1^[b]

86.5

[a] Cmpd.=compound; NT=not tested (<70% inhibition at 6.0 μM). [b] Negative values in antagonist mode describe an agonist.

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23

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Figure 4. Summary of SAR results.

groups in most positions rendering this chosen new scaffold

ideal for a structure–activity relationship investigation.

A selection of the synthesised compounds was evaluated

for in vitro inhibition of HSD17B1. These data allowed us to

draw some initial structure-activity relationship (SAR) conclu-

sions (Figure 4) and revealed how simple substitutions to the

core structure could have important effects on biological

activity. Initial results demonstrated how a hydroxy group in

position 6, a chlorine in position 4’ of the N-phenyl group, and

lipophilic substitutions in either position 1 or 4 of the THIQ core

had the most marked effect. Compounds 35d, 35k and 42c

were also tested for agonist and antagonist activity at ERα,

showing how also the activity at this receptor can be easily

modulated by simple substitutions and further proving the

steroidomimetic potential of the THIQ scaffold. Among the

synthesised series of compounds, compound 41c stood out for

its relative simplicity, good druglike properties and promising

activity (IC₅₀of 349.9�34.7 nM), making it a good starting point

for further optimization ideally to the low-nanomolar inhibitory

level, as already achieved for the steroid-based inhibitor

STX1040 and other nonsteroidal thiophene and naphthalene

based inhibitors and proving the scaffold as a viable alternative

to those already reported in the literature.^{[11g,12,13,20]}

Figure 5. a) Structure of lead inhibitor (�)-41c and b) its druglike parameters

as assessed by the “bioavailability radar” of the SwissADME programme.^[19]

Product(s) and starting material(s) were detected by either TLC

and/or LC-MS. Flash column chromatography was performed on

RediSep® prepacked columns (normal phase and reversed phase)

with an Isco CombiFlash® Rf. NMR (400 MHz or 500 MHz) spectra

were recorded with Bruker AMX systems and chemical shifts are

reported in parts per million (ppm). HPLC and low-resolution mass

spectra analyses were obtained on

a Waters Micromass ZQ

equipped with a Waters 996 PDA detector using either a Waters

Radialpack C₁₈reversed-phase column (8×100 mm), or a Symmetry

C₁₈reversed-phase column (4.6×150 mm) eluting with the solvent

system specified at 1.0 mL/min. High-resolution mass spectra

(HRMS) were recorded at the Mass Spectrometry Service Centre,

University of Bath, on a Bruker microTOF. Melting points were

determined using an Optimelt block and are uncorrected.

General method for the double reductive amination reaction:

Benzaldehyde (1.0 mL, 10 mmol) and aniline (1.1 mL, 12 mmol)

were dissolved in CHCl₃(60 mL) then treated with NaBH₄(OAc)₃

(3.3 g, 15 mmol). After stirring the mixture for 1 h at RT, 2,2-

dimethoxyacetaldehyde (30 mmol) was introduced followed by

NaBH(OAc)₃(3.3 g, 15.0 mmol). After stirring for 8 h at RT the

mixture was quenched with a saturated aqueous solution of K₂CO₃.

The aqueous layer was extracted with CHCl₃(30 mL). The combined

Experimental Section

Chemistry

All chemicals were purchased from Aldrich Chemical Co. or Alfa

Aesar. Organic solvents of A. R. grade were supplied by Fisher

Scientific. Thin-layer chromatography (TLC) was performed on

precoated plates (Merck TLC aluminium sheets silica gel 60 F254).

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organics were dried with MgSO₄, filtered and evaporated to give a

pale yellow oil (3.87 g).

(400 MHz, CDCl₃): δ=3.48 (6H, s, CHOCH₃), 3.65 (2H, d, J=5.1 Hz,

NCH₂CH), 3.84 (3H, s, ArOCH₃), 4.66–4.75 (3H, m, ArCH₂, CH(OR)₂),

6.67–6.92 (6H, m, ArH) and 7.21–7.35 (3H, m, ArH) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ=53.9 (NCH₂CH), 54.6 (CH(OCH₃)₂), 54.9 (Ar-

OCH₃), 55.3 (ArCH₂N), 103.4 (CH(OR)₂), 112.0 (ArCH), 112.3 (ArCH),

112.4 (ArCH), 116.7 (ArCH), 118.9 (ArCH), 129.3 (ArCH), 129.7 (ArCH),

140.8 (ArCCH₂), 148.6 (ArCN) and 160.0 (ArCOCH₃) ppm. LC/MS (ES⁺)

t_R=2.51 min (98%), m/z 302.2 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES+) calcd. for C₁₈H₂₄NO₃[M⁺+H] 302.1751; found:

302.1739.

1

2

3

4

5

6

7

8

9

N-Benzyl-N-(2,2-dimethoxyethyl)aniline (3a): The crude com-

pound was purified by column chromatography (eluent: from 0 to

30% EtOAc in pet. ether) to give a colorless oil (2.92 g, 99%) which

showed as previously reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=

3.41 (6H, s, OCH₃), 3.58 (2H, d, J=5.1 Hz, NCH₂CH), 4.63 (1H, t, J=

5.1 Hz, CH(OR)₂), 4.67 (2H, s, CH₂Ar), 6.70 (1H, tt, J=0.9, 7.4 Hz, ArH),

6.74 (2H, dd, J=0.9, 8.9 Hz, ArH), 7.16–7.25 (5H, m, ArH) and 7.27–

7.34 (2H, m, ArH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=53.9 (CH₂CH),

54.6 (CH₃), 54.9 (ArCH₂), 103.5 (CH(OR)₂), 112.3 (ArCH), 116.7 (ArCH),

126.6 (ArCH), 126.8 (ArCH), 128.7 (ArCH), 129.4 (ArCH), 138.9

(ArCCH₂) and 148.7 (ArCN) ppm. LC/MS (ES+) t_R=1.81 min (87%),

m/z 226.0 [M⁺+H]; HRMS (ES+) calcd. for C₁₇H₂₂NO₂[M⁺+H]

272,16451; found: 272.1651.

4-Chloro-N-(2,2-dimethoxyethyl)-N-(4-methoxybenzyl)aniline (3f):

The crude compound was purified by column chromatography

(eluent: from 0 to 20% EtOAc in pet. ether) to give the product as a

10

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40

41

42

43

44

45

46

47

48

49

50

51

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54

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1

yellow oil (9.16 g, 91%) which showed: H NMR (500 MHz, CDCl₃):

δ=3.39 (6H, s, CH(OCH₃)₂), 3.52 (2H, d, J=5.1 Hz, CHCH₂), 3.78 (3H,

s, ArOCH₃), 4.55 (1H, t, J=5.1 Hz, CH₂CH), 4.56 (2H, s, ArCH₂N), 6.65

(2H, d, J=9.2 Hz, ArH, aniline), 6.84 (2H, d, J=8.7 Hz, ArH, benzyl),

7.09 (2H, d, J=8.7 Hz, ArH, benzyl) and 7.11 (2H, d, J=9.2 Hz, ArH,

aniline) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=54.0 (CHCH₂), 54.5

(ArCH₂), 54.7 (CH(OCH₃)₂), 55.4 (ArOCH₃), 103.3 (CH₂CH), 113.7 (2×

ArCH, aniline), 114.2 (2×ArCH, benzyl), 121.5 (ArCCl), 127.8 (ArCH,

benzyl), 129.1 (ArCH, aniline), 130.1 (ArCCH2), 147.4 (ArCN) and

158.7 (ArCO) ppm. LC/MS (ES+) t_R=2.98 min (85%), m/z 336.1 [M⁺

+H]. HRMS (ES+) calcd. for C₁₈H₂₃³⁵ClNO₃[M⁺+H] 336.1361; found:

336.1346; calcd. for C₁₈H₂₃³⁷ClNO₃[M⁺+H] 338.1331; found:

338.1346.

N-Benzyl-N-(2,2-dimethoxyethyl)-3-methoxyaniline (3b): The

crude compound was purified by column chromatography (eluent:

from 0 to 10% EtOAc in pet. ether) to give a colorless oil (2.21 g,

73%) which showed as previously reported:^{[17] 1}H NMR (500 MHz,

CDCl₃): δ=3.40 (6H, s, CH(OCH₃)₂), 3.55 (2H, d, J=5.1 Hz, CH₂CH),

3.74 (3H, s, ArOCH₃), 4.62 (1H, t, J=5.1 Hz, CH(OR)₂), 4.65 (2H, s,

ArCH₂), 6.28 (1H, ddd, J=0.6, 2.5, 8.2 Hz, ArH), 6.30 (1H, t, J=2.5 Hz,

ArH), 6.36 (1H, ddd, J=0.6, 2.5, 8.2 Hz, ArH), 7.10 (1H, t, J=8.2 Hz,

ArH), 7.19–7.23 (3H, m, ArH) and 7.27–7.32 (2H, m, ArH) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=53.9 (CH₂CH), 54.7 (CH(OCH₃)₂), 55.0

(ArCH₂), 55.2 (ArOCH₃), 99.0 (ArCH), 101.5 (ArCH), 103.5 (CH(OR)₂),

105.5 (ArCH), 126.6 (ArCH), 126.8 (ArCH), 128.7 (ArCH), 130.1 (ArCH),

138.8 (ArCCH₂), 150.2 (ArCN) and 160.9 (ArCOCH₃) ppm. LC/MS (ES⁺)

t_R=2.48 min (96%), m/z 301.5 [M⁺]; (RP, Isocratic, 90% MeOH).

HRMS (ES+) calcd. for C₁₈H₂₄NO₃[M⁺+H] 302.1751; found:

302.1738.

4-Chloro-N-(2,2-dimethoxyethyl)-N-(3-methoxybenzyl)aniline

(3g): The crude compound was purified by column chromatogra-

phy (eluent: from 0 to 20% EtOAc in pet. ether) to give the product

as a pale yellow oil (9.08 g, 90%) which showed as previously

reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=3.40 (6H, s, CH(OCH₃)₂),

3.54 (2H, d, J=5.1 Hz, CHCH₂), 3.76 (3H, s, ArOCH₃), 4.58 (1H, t, J=

5.1 Hz, CHCH₂), 4.60 (2H, s, ArCH₂N), 6.63 (2H, d, J=9.2 Hz, ArH,

aniline), 6.71–6.74 (1H, m, ArH, benzyl), 6.74–6.80 (2H, m, ArH,

benzyl), 7.10 (2H, d, J=9.2 Hz, ArH, aniline) and 7.22 (1H, t, J=

7.9 Hz, ArH, benzyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=54.2

(CHCH₂), 54.7 (CH(OCH₃)₂), 55.1 (ArCH₂N), 55.3(ArOCH₃₎, 103.3 (CH

(OCH₃)₂), 112.0 (ArCH, benzyl), 112.4 (ArCH, benzyl), 113.6 (ArCH,

aniline), 118.8 (ArCH, benzyl), 121.6 (ArCCl), 129.1 (ArCH, aniline),

129.8 (ArCH, benzyl), 140.2 (ArCCH₂), 147.2 (ArCN) and 160.1 (ArCO)

ppm. LC/MS (ES⁺) t_R=2.91 min (98%), m/z 336.0 [M⁺+H]; (RP,

Isocratic, 90% MeOH). HRMS (ES⁺) calcd. C₁₈H₂₃³⁵ClNO₃[M⁺+H]

336.1361; found: 336.1353; calcd. C₁₈H₂₃³⁷ClNO₃[M⁺+H] 338.1331;

found: 338.1353.

N-(2,2-Dimethoxyethyl)-N-(4-methoxybenzyl)aniline (3c): The

crude compound was purified by column chromatography (from 0

to 10% EtOAc in pet. ether) to give the product as a yellowish oil

(2.09 g, 69%) which showed as previously reported:^{[17] 1}H NMR

(400 MHz, CDCl₃): δ=3.41 (6H, s, CHOCH₃), 3.56 (2H, d, J=5.0 Hz,

NCH₂CH), 3.79 (3H, s, ArOCH₃), 4.60–4.65 (3H, m, CH(OR)₂, ArCH₂),

6.61–6.73 (1H, m, ArH), 6.76 (2H, d, J=8.3 Hz, ArH), 6.85 (2H, d, J=

8.3 Hz, ArH), 7.14 (2H, d, J=8.4 Hz, ArH) and 7.20 (2H, t, J=7.8 Hz,

ArH) ppm. ¹³C NMR (101 MHz, CDCl₃): δ=53.7 (NCH₂CH), 54.3

(ArOCH₃), 54.6 (CH(OCH₃)₂), 55.4 (ArCH2), 103.4 (CH(OR)₂), 112.4

(ArCH), 114.1 (ArCH), 116.6 (ArCH), 127.8 (ArCH), 129.3 (ArCH), 130.7

(ArCCH₂), 148.7 (ArCN) and 158.6 (ArCOCH₃) ppm. LC/MS (ES+) t_R=

2.46 min ( 70%), m/z 302.2 [M⁺+H]; HRMS (ES+) calcd. for

C₁₈H₂₄NO₃[M⁺+H] 302.1751; found: 302.1761.

4-(((2,2-Dimethoxyethyl)(phenyl)amino)methyl)phenol (3h): The

crude compound was purified by column chromatography (eluent:

from 0 to 30% of EtOAc in pet. ether) to give the product as a

N-(2,2-Dimethoxyethyl)-N-(3-methoxybenzyl)aniline (3d): The

crude product was purified by column chromatography (from 0 to

1

colourless oil (2.5 g, 90%) which showed: H NMR (500 MHz, CDCl₃):

°

10% EtOAc in pet. ether 40–60 C) to give the product as a pale

δ=3.40 (6H, s, CH₃), 3.54 (2H, d, J=5.1 Hz, CH₂CH), 4.58 (2H, s,

ArCH₂), 4.61 (1H, t, J=5.1 Hz, CH(OR)₂), 5.01 (1H, bs, OH), 6.70 (1H, t,

J=7.2 Hz, ArH), 6.74 (2H, d, J=8.7 Hz, ArH) 6.74 (2H, d, J=8.6 Hz,

ArH), 7.06 (2H, d, J=8.6 Hz, ArH) and 7.19 (2H, dd, J=7.2, 8.7 Hz,

ArH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=53.6 (CH₂CH), 54.3 (ArCH₂),

54.7 (CH₃), 103.5 (CH(OR)₂), 112.4 (ArCH), 115.5 (ArCH), 116.7 (ArCH),

128.0 (ArCH), 129.4 (ArCCH₂), 148.7 (ArCN) and 154.5 (ArCOH) ppm.

LC/MS (ES⁺) t_R=2.91 min (65%), m/z 287.5 [M⁺]; (RP, Isocratic, 80%

MeOH). HRMS (ES+) calcd. for C₁₇H₂₂NO₃[M⁺+H] 288.1600; found:

288.1595; calcd. for C₁₇H₂₁NNaO₃[M⁺+Na] 310.1419; found:

310.1421.

yellow oil (3.56 g, 79%) which showed as previously reported:^{[17] 1}H

NMR (400 MHz, CDCl₃): δ=3.48 (6H, s, CHOCH₃), 3.65 (2H, d, J=

5.1 Hz, NCH₂CH), 3.84 (3H, s, ArOCH₃), 4.66–4.75 (3H, m, ArCH₂, CH

(OR)₂), 6.67–6.92 (6H, m, ArH) and 7.21–7.35 (3H, m, ArH) ppm. ¹³C

NMR (101 MHz, CDCl₃): δ=53.86 (NCH₂CH), 54.60 (CH(OCH₃)₂), 54.93

(ArOCH₃), 55.27 (ArCH₂N), 103.38 (CH(OR)₂), 112.0 (ArCH), 112.3

(ArCH), 112.4 (ArCH), 116.7 (ArCH), 118.9 (ArCH), 129.3 (ArCH), 129.7

(ArCH), 140.8 (ArCCH₂), 148.6 (ArCN) and 160.0 (ArCOCH₃) ppm. LC/

MS (ES⁺) t_R=2.51 min (98%), m/z 302.2 [M⁺+H]; (RP, Isocratic, 90%

MeOH). HRMS (ES+) calcd. for C₁₈H₂₄NO₃[M⁺+H] 302.1751; found:

302.1739.

4-(((2,2-Dimethoxyethyl)(p-tolyl)amino)methyl)phenol (3i): The

crude compound was purified by column chromatography (eluent:

from 0 to 30% EtOAc in pet. ether) to give the product as a

colourless oil (2.83 g, 94%) which showed as previously reported:^[17]

¹H NMR (500 MHz, CDCl₃): δ=2.24 (3H, s, ArCH₃), 3.40 (6H, s, CH

N-(3-Bromobenzyl)-N-(2,2-dimethoxyethyl)aniline (3e): The crude

compound was purified by column chromatography (eluent: 0 to

10% EtOAc in pet. ether) to give the product as a colourless oil

(1.9 g, 54%) which showed as previously reported:^{[17] 1}H NMR

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(OCH₃)₂), 3.51 (2H, d, J=5.1 Hz, CH₂CH), 4.54 (2H, s, ArCH₂), 4.59 (1H,

t, J=5.1 Hz, CH(OR)₂), 5.10 (1H, bs, OH), 6.66 (2H, d, J=8.6 Hz, ArH),

6.74 (2H, d, J=8.7 Hz, ArH), 7.00 (2H, d, J=8.6 Hz, ArH) and 7.06

(2H, d, J=8.7 Hz, ArH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=20.1

(ArCH₃), 53.7 (CH₂CH), 54.4 (ArCH₂), 54.5 (CH(OCH₃)₂), 103.4 (CH

(OR)₂), 112.5 (ArCH), 115.3 (ArCH), 125.7 (ArCCH₃), 127.9 (ArCH),

129.7 (ArCH), 130.8 (ArCCH₂), 146.5 (ArCN) and 154.4 (ArCOH) ppm.

LC/MS (ES⁺) t_R=1.92 min (>99%), m/z 301.5 [M⁺]; (RP, Isocratic,

90% MeOH). HRMS (ES+) calcd. for C₁₈H₂₄NO₃[M⁺+H] 302.1751;

found: 302.1757.

benzyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=15.9 (CH₂CH₃), 27.8

(CH₂CH₃), 53.9 (CHCH₂), 54.5 (ArCH₂N), 54.6 (CH(OCH₃)₂), 55.4

(ArOCH₃), 103.5 (CHCH₂), 112.5 (ArCH, aniline), 114.0 (ArCH, benzyl),

127.9 (ArCH, benzyl), 128.7 (ArCH, aniline), 131.0 (ArCCH₂N), 132.3

(ArCEt), 146.9 (ArCN) and 158.6 (ArCO) ppm. LC/MS (ES⁺) t_R=

3.42 min (85%), m/z 330.2 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES⁺) calcd. C₂₀H₂₈NO₃[M⁺+H] 330.2064; found: 330.2053.

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N-(2,2-Dimethoxyethyl)-4-methoxy-N-(4-methoxybenzyl)-aniline

(3n): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 20% EtOAc in pet. ether) to give the

product as a yellow oil (9.65 g, 97%) which showed: ¹H NMR

(500 MHz, CDCl₃): δ=3.38 (6H, s, CH(OCH₃)₂), 3.47 (2H, d, J=5.1 Hz,

CH₂CH), 3.74 (3H, s, ArOCH₃), 3.78 (3H, s, ArOCH₃), 4.51 (2H, s,

ArCH₂), 4.55 (1H, t, J=5.1 Hz, CHCH₂), 6.72 (2H, d, J=9.2 Hz, ArH,

aniline), 6.79 (2H, d, J=9.2 Hz, ArH, aniline), 6.83 (2H, d, J=8.7 Hz,

ArH, benzyl) and 7.13 (2H, d, J=8.7 Hz, ArH, benzyl) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=54.4 (CHCH₂), 54.5 (CH(OCH₃)₂), 55.2 (ArCH₂),

55.4 (ArOCH₃), 55.9 (ArOCH₃), 103.6 (CHCH₂), 114.0 (ArCH, benzyl),

114.5 (ArCH, aniline), 114.9 (ArCH, aniline), 128.1 (ArCH, benzyl),

131.1 (ArCCH₂), 143.5 (ArCN), 151.7 (ArCO, aniline) and 158.6 (ArCO,

benzyl) ppm. LC/MS (ES+) t_R=1.99 min (92%), m/z 332.2 [M⁺+H].

HRMS (ES+) calcd. for C₁₉H₂₆NO₄[M⁺+H] 332.1856; found:

332.1859.

4-(((4-Chlorophenyl)(2,2-dimethoxyethyl)amino)methyl)-phenol

(3j): The crude compound was purified by column chromatography

(eluent: from 0 to 30% EtOAc in pet. ether) to give the product as a

colourless oil (2.12 g, 66%) which showed as previously reported:^[17]

¹H NMR (500 MHz, CDCl₃): δ=3.39 (6H, s, CH₃), 3.51 (2H, d, J=

5.1 Hz, CH₂CH), 4.54 (2H, s, ArCH₂), 4.56 (1H, t, J=5.1 Hz, CH(OR)₂),

5.02 (1H, bs, OH), 6.64 (2H, d, J=9.2 Hz, ArH), 6.76 (2H, d, J=8.6 Hz,

ArH), 7.03 (2H, d, J=8.6 Hz, ArH) and 7.10 (2H, d, J=9.1 Hz, ArH)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=53.8 (CH₂CH), 54.4 (ArCH₂), 54.6

(CH₃), 103.2 (CH(OR)₂), 113.6 (ArCH), 115.4 (ArCH), 121.4 (ArCCl),

127.8 (ArCH), 128.9 (ArCH), 129.1 (ArCCH₂), 147.2 (ArCN) and 154.5

(ArCOH) ppm. LC/MS (ES⁺) t_R=4.19 min (74%), m/z 321.6 [M⁺]; (RP,

Isocratic, 80% MeOH). HRMS (ES+) calcd. for C₁₇H₂₁ClNO₃[M⁺+H]

322.1210; found: 322.1201; calcd. for C₁₇H₂₀ClNNaO₃[M⁺+Na]

344.1029; found: 344.1043.

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N-(2,2-Dimethoxyethyl)-3-methoxy-N-(4-methoxybenzyl)-aniline

(3o): As described in the general method A except that after

stirring for 12 h at RT the mixture was concentrated in vacuo into a

slurry and stirred for further 6 h. The crude compound was purified

by column chromatography (eluent: from 0 to 10% EtOAc in pet.

ether) to give the product as an orange oil (5.93 g, 89%) which

4-(((2,2-Dimethoxyethyl)(4-methoxyphenyl)amino)methyl)-

phenol (3k): The crude compound was purified by column

chromatography (eluent 0 to 40% EtOAc in pet. ether) to give the

product as

a colourless oil (2.87 g, 90%) which showed as

previously reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=3.38 (6H, s, CH

(OCH₃)₂), 3.46 (2H, d, J=5.1 Hz, CH₂CH)), 3.74 (3H, s, ArOCH₃), 4.48

(2H, s, ArCH₂), 4.55 (1H, t, J=5.1 Hz, CH(OR)₂), 5.12 (1H, bs, OH), 6.71

(2H, d, J=9.1 Hz, ArH), 6.74 (2H, d, J=8.6 Hz, ArH), 6.79 (2H, d, J=

9.1 Hz, ArH) and 7.07 (2H, d, J=8.6 Hz, ArH) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=54.4 (CH₂CH), 54.5 (CH(OCH₃)₂), 55.3 (ArCH₂),

55.9 (ArOCH₃), 103.6 (CH(OR)₂), 114.6 (ArCH), 114.9 (ArCH), 115.4

(ArCH), 128.3 (ArCH), 131.0 (ArCCH₂), 143.5 (ArCN), 151.7 (ArCOCH₃)

and 154.6 (ArCOH) ppm. LC/MS (ES⁺) t_R=1.56 min (97%), m/z 317.5

[M⁺]; (RP, Isocratic, 90% MeOH). HRMS (ES+) calcd. for C₁₈H₂₄NO₄

[M⁺+H] 318.1700; found: 318.1698.

showed: H NMR (500 MHz, CDCl₃): δ=3.39 (6H, s, CH(OCH₃)₂), 3.52

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(2H, d, J=5.1 Hz, CHCH₂), 3.74 (3H, s, OCH₃, benzyl), 3.78 (3H, s,

OCH₃, aniline), 4.58 (2H, s, ArCH₂N), 4.60 (1H, t, J=5.1 Hz, CHCH₂),

6.27 (1H, ddd, J=0.9, 2.5, 8.2 Hz, ArH, aniline), 6.30 (1H, t, J=2.5 Hz,

ArH, aniline), 6.36 (1H, ddd, J=0.9, 2.5, 8.2 Hz, ArH aniline), 6.83 (2H,

d, J=8.9 Hz, ArH, benzyl), 7.09 (1H, t, J=8.2 Hz, ArH, aniline) and

7.11 (2H, d, J=8.9 Hz, ArH, benzyl) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ=53.8 (CHCH₂), 54.4 (ArCH₂N), 54.7 (CH(OCH₃)₂), 55.2 (ArOCH₃,

benzyl), 55.4 (ArOCH₃, aniline), 99.1 (ArCH, aniline), 101.5 (ArCH,

aniline), 103.5 (CH(OCH₃)₂), 105.6 (ArCH, aniline), 114.1 (ArCH,

benzyl), 127.8 (ArCH, benzyl), 130.0 (ArCH, aniline), 130.7 (ArCCH₂),

150.2 (ArCN), 158.6 (ArCO, aniline) and 160.9 (ArCO, benzyl) ppm.

LC/MS (ES⁺) t_R=2.30 min (96%), m/z 332.1 [M⁺+H]; (RP, Isocratic,

90% MeOH). HRMS (ES⁺) calcd. C₁₉H₂₆NO₄[M⁺+H] 332.1856; found:

332.1840.

N-(2,2-Dimethoxyethyl)-N-(4-methoxybenzyl)-4-methylaniline

(3l): The crude compound was purified by column chromatography

(eluent: from 0 to 20% EtOAc in pet. ether) to give the product as a

yellow oil (8.6 g, 91%) which showed: ¹H NMR (500 MHz, CDCl₃):

δ=2.23 (3H, s, ArCH₃), 3.39 (6H, s, CH(OCH₃)₂)), 3.51 (2H, d, J=

5.1 Hz, CH₂CH), 3.78 (3H, s, ArOCH₃), 4.56 (2H, s, ArCH₂), 4.58 (1H, t,

J=5.1 Hz, CHCH₂), 6.66 (2H, d, J=8.7 Hz, ArH, aniline), 6.83 (2H, d,

J=8.7 Hz, ArH, benzyl), 7.00 (2H, d, J=8.7 Hz, ArH, aniline) and 7.12

(2H, d, J=8.7 Hz, ArH, benzyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=

20.3 (ArCH₃), 53.9 (CHCH₂), 54.5 (ArCH₂), 54.6 (CH(OCH₃)₂), 55.4

(ArOCH₃), 103.5 (CHCH₂), 112.6 (ArCH, aniline), 114.2 (ArCH, benzyl),

125.9 (ArCCH₃), 128.0 (ArCH, benzyl), 130.0 (ArCH, aniline), 131.0

(ArCCH₂), 146.7 (ArCN) and 158.6 (ArCO) ppm. LC/MS (ES+) t_R=

2.83 min (92%), m/z 316.2 [M⁺+H]. HRMS (ES+) calcd. for

C₁₉H₂₆NO₃[M⁺+H] 316.1907; found: 316.1916.

N-(2,2-Dimethoxyethyl)-2-methoxy-N-(4-methoxybenzyl)-aniline

(3p): As described in the general method except that after stirring

for 12 h at RT the mixture was concentrated in vacuo into a slurry

and stirred for further 6 h. The crude compound was purified by

column chromatography (eluent: from 0 to 10% EtOAc in pet.

ether) to give the product as a yellow oil (5.34 g, 81%) which

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showed: H NMR (500 MHz, CDCl₃): δ=3.25 (6H, s, CH(OCH₃)₂), 3.26

(2H, d, J=5.2 Hz, CHCH₂), 3.77 (3H, s, OCH₃, benzyl), 3.88 (3H, s,

OCH₃, aniline), 4.33 (2H, s, ArCH₂N), 4.44 (1H, t, J=5.2 Hz, CHCH₂),

6.80 (2H, d, J=8.8 Hz, ArH, benzyl), 6.83 (1H, dd, J=1.6, 8.0 Hz, ArH,

aniline), 6.87 (1H, dd, J=1.4, 7.9 Hz, ArH, aniline), 6.91–6.96 (2H, m,

ArH, aniline) and 7.21 (2H, d, J=8.8 Hz, ArH, benzyl) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=53.2 (CHCH₂), 53.7 (CH(OCH₃)₂), 55.4 (ArOCH₃,

aniline), 55.7 (ArOCH₃, benzyl), 56.9 (ArCH₂N), 103.8 (CH(OCH₃)₂),

112.2 (ArCH, aniline), 113.6 (ArCH, benzyl), 120.9 (ArCH, aniline),

122.1 (ArCH, aniline), 122.6 (ArCH, aniline), 129.7 (ArCH, benzyl),

131.4 (ArCCH₂), 140.0 (ArCN), 153.4 (ArCO, benzyl) and 158.6 (ArCO,

aniline) ppm. LC/MS (ES⁺) t_R=1.87 min (99%), m/z 332.1 [M⁺+H];

(RP, Isocratic, 90% MeOH). HRMS (ES⁺) calcd. C₁₉H₂₆NO₄[M⁺+H]

332.1856; found: 332.1863.

N-(2,2-Dimethoxyethyl)-4-ethyl-N-(4-methoxybenzyl)aniline (3m):

The crude compound was purified by column chromatography

(eluent: from 0 to 10% EtOAc in pet. ether) to give the product as a

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yellow oil (3.42 g, 52%) which showed: H NMR (500 MHz, CDCl₃):

δ=1.19 (3H, t, J=7.6 Hz, CH₂CH₃), 2.54 (2H, q, J=7.6 Hz, CH₂CH₃),

3.39 (6H, s, CH(OCH₃)₂), 3.52 (2H, d, J=5.1 Hz, CHCH₂), 3.78 (3H, s,

ArOCH₃), 4.56 (2H, s, ArCH₂N), 4.59 (1H, t, J=5.1 Hz, CHCH₂), 6.68

(2H, d, J=8.7 Hz, ArH, aniline), 6.83 (2H, d, J=8.7 Hz, ArH, benzyl),

7.02 (2H, d, J=8.7 Hz, ArH, aniline) and 7.13 (2H, d, J=8.7 Hz, ArH,

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N-(3,4-Dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-4-methoxy-ani-

line (3q): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 40% EtOAc in pet. ether) to give the

product as an orange oil (6.58 g, 91%) which showed as previously

reported:^{[17] 1}H NMR (400 MHz, CDCl₃): δ=3.37 (6H, s), 3.45 (2H, t,

J=4.7 Hz), 3.73 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 4.48 (2H, s), 4.56

(1H, bs) and 6.69–6.82 (7H, m) ppm. HRMS (ES⁺) calcd. C₂₀H₂₈NO₅

[M⁺+H] 362.1962; found: 362.1976.

2.3 Hz), 6.69 (1H, dd, J=2.3, 8.2 Hz), 7.17–7.20 (1H, m), 7.23 (1H, t,

J=8.2 Hz), 7.28–7.32 (2H, m) and 7.45–7.53 (1H, m) ppm. LC/MS

(ES⁺) t_R=1.78 min (87%), m/z 256.1 [M⁺+H]; (RP, Isocratic, 90%

MeOH).

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6-Methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (4c):

A

sample of crude compound was purified by column chromatog-

raphy (eluent: from 0 to 30% EtOAc in pet. ether) to give a yellow

oil which showed as previously reported:^{[17] 1}H NMR (500 MHz,

CDCl₃): δ=2.54 (1H, bs, OH), 3.37 (1H, dd, J=2.6, 12.6 Hz, H₃À THIQ),

3.83 (3H, s, ArOCH₃), 3.84 (4H, ddd, J=1.1, 3.8, 12.6 Hz, H₃À THIQ),

4.14 (1H, d, J=14.9 Hz, H₁À THIQ), 4.43 (1H, d, J=14.9 Hz, H₁À THIQ),

4.74 (1H, bs, H₄À THIQ), 6.88 (1H, dd, J=2.7, 8.4 Hz, H₇À THIQ), 6.91

(1H, tt, J=0.8, 7.4 Hz, ArH, phenyl), 7.01 (1H, d, J=2.7 Hz, H₅À THIQ),

7.07 (2H, dd, J=0.8, 8.7 Hz, ArH, phenyl), 7.10 (1H, d, J=8.4 Hz,

H₈À THIQ) and 7.32 (2H, dd, J=7.3, 8.7 Hz, ArH, phenyl) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=50.9 (C₁À THIQ), 55.5 (ArOCH₃), 55.5

(C₃À THIQ), 67.6 (C₄À THIQ), 113.1 (C₅À THIQ), 115.3 (C₇À THIQ), 116.6

(ArCH, phenyl), 120.2 (ArCH, phenyl), 126.4 (C₁CC₈À THIQ), 127.6

(C₈À THIQ), 129.4 (ArCH, phenyl), 137.8 (C₄CC₅À THIQ), 151.2 (ArCN)

and 158.7 (C₆À THIQ) ppm. LC/MS (ES+) t_R=1.77 min (56%), m/z

255.9 [M⁺+H]. HRMS (ES+) calcd. for C₁₆H₁₈NO₂[M⁺+H] 256.1332;

found: 256.1326.

N-(2,2-Dimethoxyethyl)-4-methoxy-N-(3,4,5-trimethoxybenzyl)

aniline (3r): The crude compound was purified by column

chromatography (eluent: from 0 to 50% EtOAc in pet. ether) to give

the product as an orange oil (7.71 g, 98%) which showed as

previously reported:^{[17] 1}H NMR (400 MHz, CDCl₃): δ=3.37 (6H, s),

3.47 (2H, d, J=5.1 Hz), 3.74 (3H, s), 3.78 (6H, s), 3.81 (3H, s), 4.47 (2H,

s), 4.56 (1H, t, J=5.1 Hz), 6.46 (2H, s), 6.72 (2H, d, J=9.2 Hz) and

6.79 (2H, d, J=9.2 Hz) ppm. HRMS (ES⁺) calcd. C₂₁H₃₀NO₆[M⁺+H]

392.2068; found: 392.2081.

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4-Chloro-N-(2,2-dimethoxyethyl)-N-benzyl-aniline (3s): The crude

compound was purified by column chromatography (eluent: from 0

to 20% EtOAc in pet. ether) to give the product as a colourless oil

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(3.74 g, 82%) which solidified upon standing and showed: H NMR

(500 MHz, CDCl₃): δ=3.40 (6H, s, CH(OCH₃)₂), 3.55 (2H, d, J=5.1 Hz,

CHCH₂), 4.58 (1H, t, J=5.1 Hz, CHCH₂), 4.63 (2H, s, ArCH₂N), 6.64 (2H,

d, J=9.2 Hz, ArH, aniline), 7.11 (2H, d, J=9.2 Hz, ArH, aniline), 7.17

(2H, d, J=7.0 Hz, ArH, benzyl), 7.23 (1H, t, J=7.3 Hz, ArH, benzyl)

and 7.30 (1H, t, J=7.4 Hz, ArH, benzyl) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=54.2 (CHCH₂), 54.7 (CH(OCH₃)₂), 55.1 (ArCH₂N), 103.3

(CHCH₂), 113.6 (ArCH, aniline), 121.5 (ArCCl), 126.5 (ArCH, benzyl),

127.0 (ArCH, benzyl), 128.8 (ArCH, benzyl), 129.1 (ArCH, aniline),

138.3 (ArCCH₂) and 147.3 (ArCN) ppm. LC/MS (ES⁺) t_R=3.08 min

(96%), m/z 305.9 [M⁺+H]; (RP, Isocratic, 90% MeOH). HRMS (ES⁺)

2-(4-Chlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-4-ol

(4d): A sample of crude compound was purified by column

chromatography (eluent: from 0 to 30% EtOAc in pet. ether) to give

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a yellow oil which showed: H NMR (500 MHz, CDCl₃): δ=2.45 (1H,

bs, OH), 3.36 (1H, dd, J=2.7, 12.6 Hz, H₃À THIQ), 3.77 (1H, ddd, J=

0.9, 3.9, 12.6 Hz, H₃À THIQ), 3.83 (3H, s, ArOCH₃), 4.11 (1H, d, J=

14.8 Hz, H₁À THIQ), 4.38 (1H, d, J=14.8 Hz, H₁À THIQ), 4.74 (1H, bs,

H₄À THIQ), 6.88 (1H, dd, J=2.7, 8.5 Hz, H₇À THIQ), 6.97 (2H, d, J=

9.0 Hz, ArH, phenyl), 7.00 (1H, d, J=2.6 Hz„ H₅À THIQ), 7.09 (1H, d,

J=8.5 Hz, H₈À THIQ) and 7.25 (2H, d, J=9.0 Hz, ArH, phenyl) ppm.

¹³C NMR (126 MHz, CDCl₃): δ=50.8 (C₁À THIQ), 55.5 (C₃À THIQ), 55.5

(ArOCH₃), 67.5 (C₄À THIQ), 113.15 (C₅À THIQ), 115.45 (C₇À THIQ), 117.7

(ArCH, phenyl), 125.0 (ArCCl), 126.0 (C₁CC₈), 127.65 (C₈À THIQ), 129.2

(ArCH, phenyl), 137.6 (C₄CC₅), 149.8 (ArCN) and 158.85 (C₆À THIQ)

ppm. LC/MS (ES⁺) t_R=2.08 min (58%), m/z 290.1 [M⁺+H]; (RP,

Isocratic, 90% MeOH). HRMS (ES⁺) calcd. for C₁₆H₁₅NO₂³⁵Cl [M⁺+H]

288.0786; found: 288.0776. calcd. for C₁₆H₁₅NO₂³⁷Cl [M⁺+H]

290.0756; found: 290.0769.

calcd. C₁₇H₂₁³⁵ClNO₂[M⁺+H] 306.1255; found: 306.1244; calcd.

+

C₁₇H₂₁³⁷ClNO₂[M +H] 308.1226; found: 308.1244. Mp 61–63 C

(pet. ether).

°

General method for the Pomeranz-Fritsch-Bobbit cyclisation with

HClO₄: Compound 3a (3.0 g, 11.1 mmol) was dissolved in 70%

HClO₄(33 mL) and stirred for 1 h at RT. The mixture was then

diluted with water (30 mL) and basified with Na₂CO₃. The aqueous

layer was then extracted with EtOAc (3×30 mL). The combined

organics were dried with MgSO₄, filtered and evaporated to give a

brown foam (2.97 g).

2-Phenyl-1,2,3,4-tetrahydroisoquinoline-4,6-diol (4e): The crude

compound was obtained as a brown-yellow solid (2.15 g) which

showed: ¹H NMR (400 MHz, CDCl₃): δ=3.42 (1H, ddd, J=0.6, 2.9,

12.7 Hz), 3.85 (1H, ddd, J=1.0, 4.0, 12.7 Hz), 4.17 (1H, d, J=14.3 Hz),

4.46 (1H, d, J=14.2 Hz), 4.76 (1H, s), 6.84 (1H, dd, J=2.7, 8.4 Hz),

6.92–7.05 (2H, m), 7.08–7.13 (3H, m) and 7.31–7.39 (3H, m) ppm. LC/

MS (ES⁺) t_R=1.22 min (81%), m/z 242.1 [M⁺+H]; (RP, Isocratic, 90%

MeOH).

2-Phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (4a):

A sample of

crude compound was purified by column chromatography (eluent:

from 0 to 10% EtOAc in pet. ether) to give a yellow oil which

showed as previously reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=

2.65 (1H, bs, OH), 3.39 (1H, dd, J=2.6, 12.6 Hz, H₃À THIQ), 3.86 (1H,

ddd, J=1.1, 3.8, 12.6 Hz, H₃À THIQ), 4.20 (1H, d, J=15.4 Hz,

H₁À THIQ), 4.49 (1H, d, J=15.4 Hz, H₁À THIQ), 4.79 (1H, bs, H₄À THIQ),

6.94 (1H, tt, J=1.1, 7.4 Hz, ArH, phenyl), 7.09 (2H, dd, J=1.0, 8.8 Hz,

ArH, phenyl), 7.17–7.23 (1H, m), 7.29–7.32 (2H, m, H₆,H₇À THIQ), 7.34

(2H, dd, J=7.3, 8.8 Hz, ArH, phenyl) and 7.47–7.51 (1H, m) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=51.4 (C₁À THIQ), 55.6 (C₃À THIQ), 67.3

(C₄À THIQ), 116.6 (ArCH, phenyl), 120.2 (ArCH, phenyl), 126.5, 127.2,

128.2, 129.3, 129.4 (ArCH, phenyl), 136.7, 134.3 and 151.1 (ArCN)

ppm. LC/MS (ES⁺) t_R=1.75 min (66%), m/z 226.0 [M⁺+H]; (RP,

Isocratic, 90% MeOH). HRMS (ES⁺) calcd. for C₁₅H₁₆NO [M⁺+H]

226.1226; found: 226.1234.

2-p-Tolyl-1,2,3,4-tetrahydroisoquinoline-4,6-diol (4f): The crude

compound was obtained as a brown-yellow solid (2.05 g) which

showed as previously reported:^{[17] 1}H NMR (400 MHz, CDCl₃): δ=

3.31 (1H, dd, J=2.5, 12.2 Hz), 3.76 (1H, dd, J=3.5, 12.2 Hz), 4.07 (1H,

d, J=14.9 Hz), 4.36 (1H, d, J=14.9 Hz), 4.69 (1H, s), 6.64 (1H, d, J=

8.7 Hz), 6.71–6.83 (2H, m) and 6.89–7.17 (4H, m) ppm. LC/MS (ES⁺)

t_R=1.52 min (70%), m/z 256.1 [M⁺+H]; (RP, Isocratic, 90% MeOH).

2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-4,6-diol (4g):

The crude compound was purified by column chromatography

(eluent: 10% MeOH in CH₂Cl₂) to give a yellow-brown solid (1.88 g,

95%) which showed as previously reported:^{[17] 1}H NMR (500 MHz,

CDCl₃): δ=2.63 (1H, bs, C₄OH), 3.37 (1H, dd, J=2.2, 12.6 Hz,

H₃À THIQ), 3.76 (1H, dd, J=3.6, 12.6 Hz, H₃À THIQ), 4.11 (1H, d, J=

14.8 Hz, H₁À THIQ), 4.38 (1H, d, J=14.8 Hz, H₁À THIQ), 4.72 (1H, s,

H₄À THIQ), 5.30 (1H, bs, C₆OH), 6.81 (1H, dd, J=2.3, 8.3 Hz, H₇À THIQ),

2-(3-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-4-ol (4b): The

crude compound was obtained as a yellow oil (1.73 g) which

showed as previously reported:^{[17] 1}H NMR (400 MHz, CDCl₃): δ=

2.46 (1H, bs), 3.40 (1H, dd, J=2.7, 12.6 Hz), 3.83 (3H, s), 3.85 (1H,

ddd, J=0.7, 3.9, 12.6 Hz), 4.21 (1H, d, J=15.5 Hz), 4.50 (1H, d, J=

15.5 Hz), 4.79 (1H, s), 6.47 (1H, dd, J=2.3, 8.2 Hz), 6.61 (1H, t, J=

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6.96 (1H, d, J=2.2 Hz, H₅À THIQ), 6.99 (2H, d, J=8.7 Hz, 2×ArCH,

phenyl), 7.05 (1H, d, J=8.3 Hz, H₇À THIQ) and 7.27 (2H, d, J=8.7 Hz,

2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=50.8

(C₁À THIQ), 55.3 (C₃À THIQ), 67.1 (C₄À THIQ), 115.1 (C₅À THIQ), 115.9

(C₇À THIQ), 117.6 (2×ArCH, phenyl), 125.0 (ArCCl), 125.9

(C₁CC₈À THIQ), 127.7 (C₈À THIQ), 129.1 (2×ArCH, phenyl), 137.6

(C₄CC₅À THIQ), 149.6 (ArCN) and 154.6 (C₆À THIQ) ppm. LC/MS (ES⁺)

t_R=1.65 min (72%), m/z 276.1 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES^À) calcd. for C₁₅H₁₃ClNO₂[M^ÀÀ H] 274.0640; found:

1.52 min (83%), m/z 286.0 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES⁺) calcd. for C₁₇H₂₀NO₃[M⁺+H] 286.1438; found:

286.1445.

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6-Methoxy-2-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-4-

ol (4l): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 50% EtOAc in pet. ether) to give a yellow

1

oil (1.9 g, 36%) which showed: H NMR (500 MHz, CDCl₃): δ=2.48

(1H, d, J=10.5 Hz, OH), 3.38 (1H, dd, J=2.6, 12.6 Hz, H₃À THIQ), 3.83

(3H, s, OCH₃, THIQ), 3.83 (1H, ddd, J=1.0, 3.9, 12.6 Hz, H₃À THIQ),

3.83 (3H, s, OCH3, phenyl), 4.14 (1H, d, J=14.9 Hz, H₁À THIQ), 4.43

(1H, d, J=14.9 Hz, H₁À THIQ), 4.74 (1H, dt, J=3.1, 10.5 Hz, H₄À THIQ),

6.47 (1H, ddd, J=0.5, 2.3, 8.2 Hz, ArH, phenyl), 6.60 (1H, t, J=2.3 Hz,

ArH, phenyl), 6.68 (1H, ddd, J=0.5, 2.3, 8.2 Hz, ArH, phenyl), 6.88

(1H, dd, J=2.7, 8.5 Hz, H₇À THIQ), 7.01 (1H, d, J=2.6 Hz, H₅À THIQ),

7.10 (1H, d, J=8.5 Hz, H₈À THIQ) and 7.23 (1H, t, J=8.2 Hz, ArH,

phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=50.8 (C₁À THIQ), 55.3

(C₃À THIQ), 55.4 (OCH₃, THIQ), 55.5 (OCH₃, phenyl), 67.6 (C₄À THIQ),

102.9 (ArCH, phenyl), 104.9 (ArCH, phenyl), 109.2 (ArCH, phenyl),

113.0 (C₅À THIQ), 115.3 (C₇À THIQ), 126.3 (C₁CC₈À THIQ), 127.6

(C₈À THIQ), 130.1 (ArCH, phenyl), 137.8 (C₄CC₅À THIQ), 152.6 (ArCN),

158.7 (ArCO) and 160.8 (C₆À THIQ) ppm. LC/MS (ES⁺) t_R=1.75 min

(94%), m/z 286.0 [M⁺+H]; (RP, Isocratic, 90% MeOH). HRMS (ES⁺)

calcd. C₁₇H₂₀NO₃[M⁺+H] 286.1438; found: 286.1428.

°

274.0629. Mp 168–171 C.

2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-4,6-diol (4h):

The crude compound was obtained as a brown-yellow solid (2.17 g)

which showed as previously reported:^{[17] 1}H NMR (400 MHz, CDCl₃):

δ=3.26 (1H, dd, J=2.5, 12.4 Hz), 3.62 (1H, ddd, J=1.1, 3.7, 12.2 Hz),

3.78 (3H, s), 4.00 (1H, d, J=14.6 Hz), 4.25 (1H, d, J=14.6 Hz), 4.66

(1H, t, J=3.0 Hz), 6.77 (1H, dd, J=2.7, 8.3 Hz), 6.87 (2H, d, J=

9.0 Hz), 6.90 (1H, d, J=2.7 Hz), 6.99 (1H, d, J=8.3 Hz) and 7.02 (2H,

d, J=9.0 Hz) ppm. LC/MS (ES⁺) t_R=1.35 min (98%), m/z 271.8 [M⁺

+H]; (RP, Isocratic, 90% MeOH).

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6-Methoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-4-ol (4i):

A

sample of crude compound was purified by column chromatog-

raphy (eluent: from 0 to 30% EtOAc in pet. ether) to give a yellow

1

oil which showed: H NMR (500 MHz, CDCl₃): δ=2.30 (3H, s, ArCH₃),

2.64 (1H, bs, OH), 3.31 (1H, dd,=2.6, 12.5 Hz, H₃À THIQ), 3.77 (1H,

ddd, J=1.1, 3.8, 12.5 Hz, H₃À THIQ), 3.83 (3H, s, ArOCH₃), 4.08 (1H, d,

J=14.9 Hz, H₁À THIQ), 4.37 (1H, d, J=14.8 Hz, H₁À THIQ), 4.72 (1H,

bs, H₄À THIQ), 6.87 (1H, dd, J=2.7, 8.5 Hz, H₇À THIQ), 6.98 (2H, d, J=

8.6 Hz, ArH, phenyl), 7.00 (1H, d, J=2.7 Hz, H₅À THIQ), 7.09 (1H, d,

J=8.5 Hz, H₈À THIQ) and 7.13 (2H, d, J=8.6 Hz, ArH, phenyl) ppm.

¹³C NMR (126 MHz, CDCl₃): δ=20.6 (ArCH₃), 51.6 (C₁À THIQ), 55.5

(ArOCH₃), 56.2 (C₃À THIQ), 67.6 (C₄À THIQ), 113.1 (C₅À THIQ), 115.3

(C₇À THIQ), 117.1 (ArCH, phenyl), 126.6 (C₁CC₈), 127.6 (C₈À THIQ),

129.9 (ArCH, ArCCH₃, phenyl), 137.9 (C₄CC₅), 149.1 (ArCN) and 158.7

(C₆À THIQ) ppm. LC/MS (ES⁺) t_R=1.82 min (70%), m/z 270.2 [M⁺+

H]; (RP, Isocratic, 90% MeOH).

6-Methoxy-2-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-4-

ol (4m): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 50% EtOAc in pet. ether) to give a yellow

1

oil (1.4 g, 26%) which showed: H NMR (500 MHz, CDCl₃): δ=3.17

(1H, dd, J=2.5, 12.3 Hz, H₃À THIQ), 3.49 (1H, d, J=10.1 Hz, OH), 3.68

(1H, dd, J=2.9, 12.1 Hz, H₃À THIQ), 3.83 (3H, s, OCH₃, THIQ), 3.88 (3H,

s, OCH₃, phenyl), 4.12–4.25 (2H, m„ H₁À THIQ), 4.67 (1H, dt, J=2.7,

9.9 Hz, H₄À THIQ), 6.85 (1H, dd, J=2.8, 8.4 Hz, H₇À THIQ), 6.91 (1H,

dd, J=1.3, 8.0 Hz, ArH, phenyl), 6.97 (1H, td, J=1.4, 7.6 Hz, ArH,

phenyl), 7.01 (1H, d, J=2.7 Hz, H₅À THIQ) and 7.04–7.11 (3H, m,

H₈À THIQ, 2×ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=52.4

(C₁À THIQ), 55.5 (OCH₃, THIQ), 55.5 (OCH₃, phenyl), 57.1 (C₃À THIQ),

67.9 (C₄À THIQ), 111.3 (ArCH, phenyl), 113.5 (C₅À THIQ), 114.9

(C₇À THIQ), 119.4 (ArCH, phenyl), 121.1 (ArCH, phenyl), 123.6 (ArCH,

phenyl), 127.1 (C₁CC₈À THIQ), 127.4 (C₈À THIQ), 138.2 (C₄CC₅À THIQ),

140.9 (ArCN), 152.7 (ArCO, phenyl) and 158.6 (C₆À THIQ) ppm. LC/MS

(ES⁺) t_R=1.59 min (68%), m/z 285.9 [M⁺+H]; (RP, Isocratic, 90%

MeOH). HRMS (ES⁺) calcd. C₁₇H₂₀NO₃[M⁺+H] 286.1438; found:

286.1443.

6-Methoxy-2-(4-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-4-ol

(4j): The crude compound was purified by column chromatography

(eluent: from 0 to 20% EtOAc in pet. ether) to give the product as

1

an orange wax (900 mg, 31%) which showed: H NMR (500 MHz,

CDCl₃): δ=1.23 (1H, t, J=7.6 Hz, CH₂CH₃), 2.56 (1H, d, J=10.8 Hz,

OH), 2.61 (1H, q, J=7.6 Hz, CH₂CH₃), 3.32 (1H, dd, J=2.5, 12.5 Hz,

H₃À THIQ), 3.81 (1H, ddd, J=1.0, 3.7, 12.5 Hz, H₃À THIQ), 3.83 (1H, s,

OCH₃), 4.09 (1H, d, J=14.8 Hz, H₁À THIQ), 4.40 (1H, d, J=14.8 Hz,

H₁À THIQ), 4.73 (1H, dt, J=3.1, 10.8 Hz, H₄À THIQ), 6.87 (1H, dd, J=

2.7, 8.5 Hz, H₇À THIQ), 7.00 (1H, d, J=2.4 Hz, H₅À THIQ), 7.02 (1H, d,

J=8.8 Hz), 7.10 (1H, d, J=8.5 Hz, H₈À THIQ) and 7.16 (1H, d, J=

8.6 Hz) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=15.8 (CH₂CH₃), 28.0

(CH₂CH₃), 51.3 (C₁À THIQ), 55.4 (OCH₃), 55.9 (C₃À THIQ), 67.5

(C₄À THIQ), 113.0 (C₅À THIQ), 115.1 (C₇À THIQ), 116.9 (ArCH, phenyl),

126.4 (C₁CC₈À THIQ), 127.5 (C₈À THIQ), 128.6 (ArCH, phenyl), 136.3

(ArCEt), 137.7 (C₄CC₆À THIQ), 149.1 (ArCN) and 158.5 (C₆À THIQ) ppm.

LC/MS (ES⁺) t_R=2.19 min (48%), m/z 284.2 [M⁺+H]; (RP, Isocratic,

90% MeOH). HRMS (ES⁺) calcd. C₁₈H₂₂NO₂[M⁺+H] 284.1645; found:

284.1636.

2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-4-ol (4n): The

crude compound was purified by column chromatography (eluent:

from 0 to 30% EtOAc in pet. ether) to give a white solid (1.9 g,

61%). The compound was recrystallised from Et₂O/pet. ether to

give a white solid which showed: ¹H NMR (500 MHz, CDCl₃): δ=2.43

(1H, d, J=9.9 Hz, OH), 3.37 (1H, dd, J=2.4, 12.6 Hz, H₃À THIQ), 3.81

(1H, ddd, J=1.2, 3.7, 12.6 Hz, H₃À THIQ), 4.18 (1H, d, J=15.3 Hz,

H₁À THIQ), 4.45 (1H, d, J=15.3 Hz, H₁À THIQ), 4.75–4.84 (1H, m,

H₄À THIQ), 6.99 (2H, d, J=9.0 Hz, ArH, phenyl), 7.17–7.21 (1H, m,

H₅À THIQ), 7.26 (2H, d, J=9.0 Hz, ArH, phenyl), 7.31 (2H, t, J=3.5 Hz,

H₆,H₇À THIQ) and 7.46–7.50 (1H, m, H₈À THIQ) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=51.3 (C₁À THIQ), 55.6 (C₃À THIQ), 67.3

(C₄À THIQ), 117.7 (ArCH, phenyl), 125.1 (ArCCl), 126.5 (CÀ THIQ), 127.3

(CÀ THIQ), 128.4 (CÀ THIQ), 129.3 (ArCH, phenyl), 129.3 (C₇,C₆À THIQ),

134.0 (C₁CC₈À THIQ), 136.5 (C₄CC₅À THIQ) and 149.7 (ArCN) ppm. LC/

MS (ES⁺) t_R=2.01 min (99%), m/z 259.9 [M⁺+H]; (RP, Isocratic, 90%

MeOH). HRMS (ES⁺) calcd. C₁₅H₁₅ClNO [M⁺+H] (³⁵Cl) 260.0837;

found: 260.0830; calcd. C₁₅H₁₅ClNO [M⁺+H] (³⁷Cl) 262.0807; found:

6-Methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-4-

ol (4k): A sample of crude compound was purified by column

chromatography (eluent: from 0 to 30% EtOAc in pet. ether) to give

a yellow oil which showed: 1H NMR (400 MHz, CDCl₃): δ=3.28 (1H,

dd, J=2.6, 12.2 Hz, H₃À THIQ), 3.75 (1H, dd, J=4.5, 12.2 Hz), 3.79

(3H, s, OMe), 3.83 (3H, s, OMe), 4.04 (1H, d, J=14.7 Hz, H₁À THIQ),

4.29 (1H, d, J=14.7 Hz, H₁À THIQ), 4.71 (1H, m, H₄À THIQ), 6.86 (1H,

dd, J=2.5, 8.4 Hz, H₇À THIQ), 6.89 (2H, d, J=9.0 Hz, 2×ArH, phenyl),

7.01 (1H, d, J=2.5 Hz, H₅À THIQ), 7.03 (2H, d, J=9.0 Hz, 2×ArH,

phenyl) and 7.07 (1H, d, J=8.4 Hz, H₈À THIQ) ppm. LC/MS (ES⁺) t_R=

°

262.0830. Mp 98–100 C (Et₂O/Pet). Anal. calcd. for C₁₅H₁₄ClNO: C

69.4, H 5.43, N 5.39% found C 69.4, H 5.43, N 5.28%.

General method for the reductive dihydroxylation with Et₃SiH:

The crude compound 4a (2.77 g) was dissolved in CH₂Cl₂(60 mL)

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and Et₃SiH (6.0 mL, 36.9 mmol) and BF₃·Et₂O (9.8 mL, 36.9 mmol)

were introduced in the order. After refluxing for 18 h, the mixture

was cooled to RT and quenched with a saturated aqueous solution

of Na₂CO₃(50 mL). The aqueous layer was then extracted with

EtOAc (2×50 mL). The combined organics were dried with MgSO₄,

filtered and evaporated to give a green oil (2.03 g).

(C₇À THIQ), 113.4 (C₅À THIQ), 116.3 (ArCH, phenyl), 123.4 (ArCCl),

126.4 (C₁CC₈À THIQ), 127.6 (C₈À THIQ), 129.1 (ArCH, phenyl), 136.0

(C₅CC₆À THIQ), 149.3 (ArCN) and 158.3 (C₆À THIQ) ppm. LC/MS (ES⁺)

t_R=3.56 min (96%), m/z 274.0 [M⁺+H] (³⁵Cl), 276.0 [M⁺+H] (³⁷Cl);

(RP, Isocratic, 90% MeOH). HRMS (ES+) calcd. for C₁₆H₁₇³⁵ClNO [M⁺

+H] 274.0993; found: 274.0980; calcd. for C₁₆H₁₇³⁷ClNO [M⁺+H]

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276.0964; found: 274.0980. Mp 99–100 C (pet. ether).

2-Phenyl-1,2,3,4-tetrahydroisoquinoline (5a): The crude product

was purified by column chromatography (eluent: pet. ether) to yield

the product as a pale yellow oil (1.72 g, 67%) which solidified upon

standing and which showed:^{[21] 1}H NMR (500 MHz, CDCl₃): δ=3.00

(2H, t, J=5.8 Hz, H₄À THIQ), 3.57 (2H, t, J=5.8 Hz, H₃À THIQ), 4.42

(2H, s, H₁À THIQ), 6.83 (1H, t, J=7.3 Hz, ArH, phenyl), 6.99 (2H, d, J=

8.7 Hz, ArH, phenyl), 7.14–7.21 (4H, m, H₅,H₆,H₇,H₈À THIQ) and 7.30

(2H, dd, J=7.3, 8.7 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ=29.27 (C₄À THIQ), 46.67 (C₃À THIQ), 50.89 (C₁À THIQ), 115.29 (ArCH,

phenyl), 118.8 (ArCH, phenyl), 126.2 (ArCH, THIQ), 126.5 (ArCH,

THIQ), 126.7 (ArCH, THIQ), 128.7 (ArCH, THIQ), 129.4 (ArCH, phenyl),

134.6 (C₁CC₈À THIQ), 135.0 (C₅CC₆À THIQ) and 150.7 (ArCN) ppm. LC/

MS (ES⁺) t_R=2.79 min (97%), m/z 209.9 [M⁺+H]; (RP, Isocratic, 90%

MeOH). HRMS (ES⁺) calcd. for C₁₅H₁₆N [M⁺+H] 210.1277; found:

2-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-ol (5h): The

crude compound was purified by reversed phase column chroma-

tography (eluent: from 5 to 100% MeOH in water) to get the

1

compound as a yellow oil (503 mg, 20%) which showed: H NMR

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(500 MHz, CDCl₃): δ=2.93 (2H, t, J=5.9 Hz, ArCH₂CH₂), 3.42 (2H, t,

J=5.9 Hz, ArCH₂CH₂), 3.78 (3H, s, ArOCH₃), 4.22 (2H, s, ArCH₂N), 6.62

(1H, d, J=2.5 Hz, ArH), 6.67 (1H, dd, J=2.5, 8.2 Hz, ArH), 6.86 (2H, d,

J=9.1 Hz, ArH), 6.97 (2H, d, J=9.1 Hz, ArH) and 7.00 (1H, d, J=

8.2 Hz, ArH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=29.1 (ArCH₂CH₂),

48.4 (NCH₂CH₂), 52.2 (ArCH₂N), 55.6 (ArOCH₃), 113.4 (ArCH), 114.6

(ArCH), 114.9 (ArCH), 118.1 (ArCH), 126.7 (ArCCH₂N), 127.6 (ArCH),

131.0 (Ar CCH₂CH₂), 145.5 (ArCN), 153.5 (ArCOCH₃) and 154.0

(ArCOH) ppm. LC/MS (ES⁺) t_R=1.17 min (96%), m/z 255.7 [M⁺+H];

(RP, Isocratic, 90% MeOH). HRMS (ES+) calcd. for C₁₆H₁₈NO₂[M⁺+

°

210.1284. Mp 44–45 C (pet. ether).

°

H] 256.1332; found: 256.1336. Mp 192–194 C (hydrochloride from

MeOH/Et₂O).

2-(3-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (5b): The

crude product was purified by column chromatography (eluent 0 to

30% EtOAc in pet. ether) to yield the product as a dark yellow oil

(152 mg, 11%) which showed:^{[21] 1}H NMR (500 MHz, CDCl₃): δ=2.99

(2H, t, J=5.9 Hz, ArCH₂CH₂), 3.56 (2H, t, J=5.9 Hz, NCH₂CH₂), 3.82

(3H, s, ArOCH₃), 4.41 (2H, s, ArCH₂N), 6.39 (1H, dd, J=2.4, 8.1 Hz,

ArH), 6.52 (1H, t, J=2.4 Hz, ArH), 6.60 (1H, dd, J=2.4, 8.1 Hz, ArH)

and 7.14–7.22 (5H, m, ArH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=29.3

(ArCH₂CH₂), 46.5 (NCH₂CH₂), 50.8 (ArCH₂N), 55.3 (ArOCH₃), 101.6

(ArCH), 103.4 (ArCH), 108.0 (ArCH), 126.2 (ArCH), 126.5 (ArCH) 126.7

(ArCH), 128.6 (ArCH), 130.0 (ArCH), 134.6 (ArCCH₂N), 135.1

(ArCCH₂CH₂), 152.0 (ArCN) and 160.9 (ArCOCH₃) ppm. LC/MS (ES⁺)

t_R=2.84 min (84%), m/z 240.0 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES+) calcd. for C₁₆H₁₈NO [M⁺+H] 240.1383; found:

240.1373.

6-Methoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (5i): The

crude product was purified by column chromatography (eluent:

from 0 to 10% EtOAc in pet. ether) to yield the product as a white

solid (1.65 g, 25%) which showed: ¹H NMR (500 MHz, CDCl₃): δ=

2.28 (3H, s, ArCH₃), 2.95 (2H, t, J=5.8 Hz, H₄À THIQ), 3.49 (2H, t, J=

5.8 Hz, H₃À THIQ), 3.79 (3H, s, ArOCH₃), 4.30 (2H, s, H₁À THIQ), 6.69

(1H, d, J=2.6 Hz, H₅À THIQ), 6.76 (1H, dd, J=2.6, 8.4 Hz, H₇À THIQ),

6.91 (2H, d, J=8.6 Hz, ArH, phenyl), 7.06 (1H, d, J=8.4 Hz, H₈À THIQ)

and 7.09 (2H, d, J=8.6 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=20.5 (ArCH₃), 29.5 (C₄À THIQ), 47.4 (C₃À THIQ), 51.1

(C₁À THIQ), 55.4 (ArOCH₃), 112.5 (C₇À THIQ), 113.4 (C₅À THIQ), 116.0

(ArCH, phenyl), 126.9 (C₁CC₈À THIQ), 127.6 (C₈À THIQ), 128.5 (ArCCH₃),

129.8 (ArCH, phenyl), 136.1 (C₅CC₆À THIQ), 148.8 (ArCN) and 158.2

(C₆À THIQ) ppm. LC/MS (ES⁺) t_R=2.62 min (97%), m/z 254.0 [M⁺+

H]; (RP, Isocratic, 90% MeOH). HRMS (ES+) calcd. for C₁₇H₂₀NO [M⁺

6-Methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (5c): The

crude product was purified by column chromatography (eluent:

from 0 to 0.5% EtOAc in pet. ether) to yield the product as a

°

+H] 254.1539; found: 254.1535. Mp 69–70 C (pet. ether). Anal.

calcd. for C₁₇H₁₉NO: C 80.6, H 7.56, N 5.53. Found: C 80.4, H 7.55, N

5.44%.

1

colourless oil (1.3 g, 25%) which showed: H NMR (500 MHz, CDCl₃):

δ=2.96 (2H, t, J=5.8 Hz, H₄À THIQ), 3.55 (2H, t, J=5.8 Hz, H₃À THIQ),

3.80 (3H, s, ArOCH₃), 4.36 (2H, s, H₁À THIQ), 6.70 (1H, d, J=2.6 Hz,

H₅À THIQ), 6.77 (1H, dd, J=2.6, 8.4 Hz, H₇À THIQ), 6.83 (1H, tt, J=1.0,

7.3 Hz, ArH, phenyl), 6.98 (2H, dd, J=1.0, 8.8 Hz, ArH, phenyl), 7.08

(1H, d, J=8.4 Hz, H₈À THIQ) and 7.29 (2H, dd, J=7.3, 8.8 Hz, ArH,

phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=29.6 (C₄À THIQ), 46.6

(C₃À THIQ), 50.3 (C₁À THIQ), 55.4 (ArOCH₃), 112.5 (C₇À THIQ), 113.4

(C₅À THIQ), 115.3 (ArCH, phenyl), 118.8 (ArCH, phenyl), 126.8

(C₁CC₈À THIQ), 127.6 (C₈À THIQ), 129.3 (ArCH, phenyl), 136.2

(C₅CC₆À THIQ), 150.7 (ArCN) and 158.2 (C₆À THIQ) ppm. LC/MS (ES⁺)

t_R=2.48 min (97%), m/z 239.9 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES+) calcd. for C₁₆H₁₈NO [M⁺+H] 240.1383; found:

2-(4-Ethylphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (5j):

The crude compound was purified by column chromatography

(eluent: from 0 to 20% EtOAc in pet. ether) to get the product as a

yellow solid (409 mg, 51%) which was recrystallised from pet. ether

1

and showed: H NMR (500 MHz, CDCl₃): δ=1.22 (3H, t, J=7.6 Hz,

CH₂CH₃), 2.59 (2H, q, J=7.6 Hz, CH₂CH₃), 2.97 (2H, t, J=5.8 Hz,

H₄À THIQ), 3.51 (2H, t, J=5.8 Hz, H₃À THIQ), 3.80 (3H, s, OCH₃), 4.32

(2H, s, H₁À THIQ), 6.70 (1H, d, J=2.5 Hz, H₅À THIQ), 6.77 (1H, dd, J=

2.5, 8.4 Hz, H₇À THIQ), 6.96 (2H, d, J=8.3 Hz, 2×ArCH, phenyl), 7.07

(1H, d, J=8.4 Hz, H₈À THIQ) and 7.13 (2H, d, J=8.6 Hz, 2×ArCH,

phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=15.8 (CH₂CH₃), 27.9

(CH₂CH₃), 29.3 (C₄À THIQ), 47.2 (C₃À THIQ), 50.9 (C₁À THIQ), 55.3

(OCH₃), 112.3 (C₇À THIQ), 113.2 (C₅À THIQ), 115.8 (2×ArCH, phenyl),

126.6 (C₁CC₈À THIQ), 127.5 (C₈À THIQ), 128.5 (2×ArCH, phenyl), 135.0

(ArCCH₂CH₃), 135.8 (C₄CC₅À THIQ), 148.6 (ArCN), 158.0 (C₆À THIQ)

ppm. HRMS (ES⁺) calcd. C₁₈H₂₂NO [M⁺+H] 268.1696; found:

°

240.1372. Mp 72–73 C (pet. ether). Anal. calcd. for C₁₆H₁₇NO: C 80.3,

H 7.16, N 5.85. Found: C 80.2, H 7.16, N 5.73%.

2-(4-Chlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

(5d): The crude product was purified by column chromatography

(eluent: from 0 to 30% EtOAc in pet. ether) to yield the product as

a white solid (1.41 g, 20%) which showed:^{[22] 1}H NMR (500 MHz,

CDCl₃): δ=2.95 (2H, t, J=5.8 Hz, H₄À THIQ), 3.51 (2H, t, J=5.9 Hz,

H₃À THIQ), 3.80 (3H, s, ArOCH₃), 4.31 (2H, s, H₁À THIQ), 6.70 (1H, d, J=

2.6 Hz, H₅À THIQ), 6.77 (1H, dd, J=2.7, 8.4 Hz, H₇À THIQ), 6.87 (2H, d,

J=9.1 Hz, ArH, phenyl), 7.06 (1H, d, J=8.4 Hz, H₈À THIQ) and 7.21

(2H, d, J=9.1 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=

29.4 (C₄À THIQ), 46.6 (C₃À THIQ), 50.3 (C₁À THIQ), 55.5 (ArOCH₃), 112.6

°

268.1694. Mp 78–80 C (pet. ether). Anal. calcd. for C₁₈H₂₁NO: C

80.86, H 7.92, N 5.24%. Found: C 80.91, H 8.00, N 5.14%.

6-Methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline

(5k): The crude product was purified by column chromatography

(eluent: from 0 to 15% EtOAc in pet. ether) to yield the product as

a white solid (1.395 g, 21%) which showed:^{[23] 1}H NMR (500 MHz,

CDCl₃): δ=2.96 (2H, t, J=5.8 Hz, H₄À THIQ), 3.43 (2H, t, J=5.8 Hz,

ChemMedChem 2020, 15, 1–34

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Full Papers

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°

H₃À THIQ), 3.78 (3H, s, ArOCH₃), 3.79 (3H, s, ArOCH₃), 4.24 (2H, s,

H₁À THIQ), 6.68 (1H, d, J=2.6 Hz, H₅À THIQ), 6.75 (1H, dd, J=2.6,

8.4 Hz, H₇À THIQ), 6.86 (2H, d, J=9.1 Hz, ArH, phenyl), 6.97 (2H, d,

J=9.1 Hz, ArH, phenyl) and 7.04 (1H, d, J=8.4 Hz, H₈À THIQ) ppm.

¹³C NMR (126 MHz, CDCl₃): δ=29.5 (C₄À THIQ), 48.5 (C₃À THIQ), 52.3

(C₁À THIQ), 55.4 (ArOCH₃), 55.8 (ArOCH₃), 112.5 (C₇À THIQ), 113.4

(C₅À THIQ), 114.7 (ArCH, phenyl), 118.2 (ArCH, phenyl), 127.0

(C₁CC₈À THIQ), 127.6 (C₈À THIQ), 135.9 (C₅CC₆À THIQ), 145.6 (ArCN),

153.6 (ArCO, phenyl) and 158.2 (C₆À THIQ) ppm. LC/MS (ES⁺) t_R=

1.47 min (90%), m/z 270.0 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES+) calcd. for C₁₇H₂₀NO₂[M⁺+H] 270.1489; found:

turned red. The reaction mixture was cooled to 0 C and then

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quenched slowly with aq. 3 N NaOH (10 mL) (a white suspension

with a yellow precipitate formed) and extracted with EtOAc

(20 mL). The organic layer was dried with MgSO₄, filtered and

evaporated to give a yellow-brown oil (445 mg).

6,7-Dimethoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquino-

lin-4-ol (6a): The crude compound was purified by column

chromatography (eluent: from 0 to 50% EtOAc in pet. ether) to give

the product as a white solid (3.54 g, 62%) which showed as

previously reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=2.67 (1H, bs,

OH), 3.23 (1H, dd, J=2.3, 12.3 Hz, H₃À THIQ), 3.71 (1H, dd, J=3.1,

12.3 Hz, H₃À THIQ), 3.79 (3H, s, OCH₃, phenyl), 3.88 (3H, s,

C₆OCH₃À THIQ), 3.90 (3H, s, C₇OCH₃À THIQ), 4.01 (1H, d, J=14.8 Hz,

H₁À THIQ), 4.27 (1H, d, J=14.8 Hz, H₁À THIQ), 4.67 (1H, bs, H₄À THIQ),

6.62 (1H, s, H₈À THIQ), 6.89 (2H, d, J=9.0 Hz, 2×ArCH, phenyl), 6.96

(1H, s, H₅À THIQ) and 7.03 (2H, d, J=8.9 Hz, 2×ArCH, phenyl) ppm.

¹³C NMR (126 MHz, CDCl₃): δ=52.7 (C₁À THIQ), 55.6 (OCH₃, phenyl),

55.9 (2×OCH₃, THIQ), 57.2 (C₃À THIQ), 67.2 (C₄À THIQ), 108.6

(C₈À THIQ), 111.6 (C₅À THIQ), 114.5 (2×ArCH, phenyl), 118.9 (2×

ArCH, phenyl), 126.8 (C₁CC₈À THIQ), 128.6 (C₄CC₅À THIQ), 145.3

(ArCN), 148.1 (C₇À THIQ), 148.9 (C₆À THIQ) and 154.2 (ArCO, phenyl)

ppm. HRMS (ES⁺) calcd. C₁₈H₂₂NO₄[M⁺+H] 316.1543; found:

°

270.1477. Mp 124–125 C (pet. ether). Anal. calcd. for C₁₇H₁₉NO: C

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75.81, H 7.11, N 5.20. Found: C 75.5, H 7.16, N 5.10%.

6-Methoxy-2-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline

(5l): The crude compound was purified by column chromatography

(eluent: from 0 to 20% EtOAc in pet. ether) to get the compound as

a yellow oil (761 mg, 44%) which showed: ¹H NMR (500 MHz,

CDCl₃): δ=2.95 (2H, t, J=5.9 Hz, H₄À THIQ), 3.54 (2H, t, J=5.9 Hz,

H₃À THIQ), 3.80 (3H, s, ArOCH₃, THIQ), 3.81 (3H, s, ArOCH₃, phenyl),

4.35 (2H, s, H₁À THIQ), 6.39 (1H, ddd, J=0.9, 2.5, 8.4 Hz, ArH, phenyl),

6.50 (1H, t, J=2.5 Hz, ArH, phenyl), 6.59 (1H, ddd, J=0.9, 2.5, 8.4 Hz,

ArH, phenyl), 6.70 (1H, d, J=2.6 Hz, H₅À THIQ), 6.76 (1H, dd, J=2.7,

8.4 Hz, H₇À THIQ), 7.07 (1H, d, J=8.4 Hz, H₈À THIQ) and 7.19 (1H, t,

J=8.4 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=29.5

(C₄À THIQ), 46.4 (C₃À THIQ), 50.2 (C₁À THIQ), 55.3 (OCH₃, phenyl), 55.4

(OCH₃, THIQ), 101.6 (ArCH, phenyl), 103.4 (ArCH, phenyl), 108.0

(ArCH, phenyl), 112.5 (C₇À THIQ), 113.3 (C₅À THIQ), 126.7

(C₁CC₈À THIQ), 127.6 (C₈À THIQ), 130.0 (ArCH, phenyl), 136.2

(C₄CC₅À THIQ), 152.0 (ArCN), 158.2 (C₆À THIQ) and 160.8 (ArCO,

phenyl) ppm. HRMS (ES⁺) calcd. C₁₇H₂₀NO₂[M⁺+H] 270.1489;

°

316.1543. Mp 136–137 C (CH₂Cl₂/Et₂O).

5,6,7-Trimethoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoqui-

nolin-4-ol (6b): The crude compound was purified by column

chromatography (eluent: from 0 to 100% EtOAc in pet. ether) to

give the product as a dark brown solid (5.49 g, 82%) which showed

as previously reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=2.90 (1H, bs,

OH), 3.18 (1H, dd, J=2.7, 12.4 Hz, H₃À THIQ), 3.70 (1H, dd, J=3.5,

12.6 Hz, H₃À THIQ), 3.79 (3H, s, OCH₃, phenyl), 3.86 (3H, s,

C₆OCH₃À THIQ), 3.87 (3H, s, C₇OCH₃À THIQ), 3.98 (1H, d, J=15.1 Hz,

H₁À THIQ), 4.02 (3H, s, C₅OCH₃À THIQ), 4.29 (1H, d, J=15.0 Hz,

H₁À THIQ), 4.98 (1H, bs, H₄À THIQ), 6.45 (1H, s, H₈À THIQ), 6.88 (2H, d,

J=9.0 Hz, 2×ArCH, phenyl) and 7.04 (2H, d, J=9.0 Hz, 2×ArCH,

phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=53.2 (C₁À THIQ), 55.6

(OCH₃, phenyl), 56.0 (C₆OCH₃À THIQ), 56.9 (C₃À THIQ), 60.9

(C₇OCH₃À THIQ), 61.5(C₅OCH₃À THIQ), 62.7 (C₄À THIQ), 104.6

(C₈À THIQ), 114.5 (2×ArCH, phenyl), 119.1 (2×ArCH, phenyl), 123.0

(C₁CC₈À THIQ), 130.5 (C₄CC₅À THIQ), 140.6 (C₇À THIQ), 145.3 (ArCN),

152.2 (C₅À THIQ), 153.5 (C₆À THIQ) and 154.3 (ArCO, phenyl) ppm.

HRMS (ES⁺) calcd. C₁₉H₂₄NO₅[M⁺+H] 346.1649; found: 346.1638.

°

found: 270.1479. Mp 119–120 C (pet. ether).

6-Methoxy-2-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline

(5m): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 20% EtOAc in pet. ether) to get the

1

product as a colourless oil (143 mg, 38%) which showed: H NMR

(500 MHz, CDCl₃): δ=2.95 (2H, t, J=5.8 Hz, H₄À THIQ), 3.39 (2H, t,

J=5.9 Hz, H₃À THIQ), 3.79 (3H, s, H₁À THIQ), 3.89 (3H, s, OCH₃), 4.23

(2H, s, OCH₃), 6.67 (1H, d, J=2.3 Hz, H₅À THIQ), 6.74 (1H, dd, J=2.6,

8.4 Hz, H₇À THIQ), 6.88–6.94 (2H, m, 2×ArH, phenyl) and 6.98–7.05

(3H, m, H₈À THIQ and 2×ArH, phenyl) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=29.1 (C₄À THIQ), 48.8 (C₃À THIQ), 52.5 (C₁À THIQ), 55.2

(CH₃OÀ ), 55.4 (CH₃OÀ ), 111.2 (ArCH, phenyl), 112.1 (C₇À THIQ), 113.4

(C₅À THIQ), 118.9 (ArCH, phenyl), 120.9 (ArCH, phenyl), 122.9 (ArCH,

phenyl), 127.3 (C₆À THIQ), 127.4 (C₁CC₈À THIQ), 135.7 (C₄CC₅À THIQ),

141.1 (ArCN), 152.5 (COCH₃) and 157.9 (COCH₃) ppm. HRMS (ES⁺)

calcd. C₁₇H₂₀NO₂[M⁺+H] 270.1489; found: 270.1499. Mp 199–

General method for the reductive dehydroxylation with NaBH₄:

NaBH₄(1.53 g, 39.7 mmol) was added to a stirring solution of 6a

(2.50 g, 7.93 mmol) in CH₂Cl₂(30 mL) followed by the dropwise

addition of TFA (3.1 mL) and the mixture was stirred at RT for 3 h.

The mixture was then diluted with CH₂Cl₂(30 mL) and washed with

a sat. aq. solution of Na₂CO₃(2×60 mL) and dried with MgSO4,

filtered and evaporated to give a pale yellow solid (2.45 g).

°

200 C (as hydrochloride from Et₂O).

2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinoline (5n): The crude

compound was purified by column chromatography (eluent: from 0

to 20% EtOAc in pet. ether) to get the product as a white solid

which was recrystallised from pet. ether (1.14 g, 76%) and

showed:^{[24] 1}H NMR (500 MHz, CDCl₃): δ=2.98 (2H, t, J=5.9 Hz,

H₄À THIQ), 3.53 (2H, t, J=5.9 Hz, H₃À THIQ), 4.38 (2H, s, H₁À THIQ),

6.89 (2H, d, J=9.1 Hz, ArH, phenyl), 7.12–7.21 (4H, m,

H₅,H₆,H₇,H₈À THIQ) and 7.22 (2H, d, J=9.1 Hz, ArH, phenyl) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=29.1 (C₄À THIQ), 46.7 (C₃À THIQ), 50.8

(C₁À THIQ), 116.3 (ArCH, phenyl), 123.5, 126.3 (C₈À THIQ), 126.6

(ArCHÀ THIQ), 126.7 (ArCHÀ THIQ), 128.7 (C₅À THIQ), 129.2 (ArCH,

phenyl), 134.2 (C₁CC₈À THIQ), 134.8 (C₄CC₅À THIQ) and 149.2 (ArCN)

ppm. HRMS (ES⁺) calcd. C₁₅H₁₅³⁵ClN [M⁺+H] 244.0888; found:

244.0896; calcd. C₁₅H₁₅³⁷ClN [M⁺+H] 246.0858; found: 246.0866.

6,7-Dimethoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquino-

line (7a): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 60% EtOAc in pet. ether) to give the

product as a yellow solid (698 mg, 29%) which showed:^{[25] 1}H NMR

(500 MHz, CDCl₃): δ=2.89 (2H, t, J=5.7 Hz, H₄À THIQ), 3.43 (2H, t,

J=5.7 Hz, H₃À THIQ), 3.78 (3H, s, OCH₃, phenyl), 3.86 (3H, s,

OCH₃À THIQ), 3.87 (3H, s, OCH₃À THIQ), 4.22 (2H, s, H₁À THIQ), 6.62

(1H, s), 6.63 (1H, s), 6.86 (2H, d, J=9.0 Hz, 2×ArCH, phenyl) and 6.98

(2H, d, J=9.0 Hz, 2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ=28.5 (C₄À THIQ), 48.6 (C₃À THIQ), 52.4 (C₁À THIQ), 55.6 (OCH₃,

phenyl), 55.9 (OCH₃À THIQ), 56.0 (OCH₃À THIQ), 109.3 (C_yÀ THIQ),

111.4 (C_yÀ THIQ), 114.5 (2×ArCH, phenyl), 118.1 (2×ArCH, phenyl),

126.3 (C₁CC₈À THIQ), 126.4 (C₄CC₅À THIQ), 145.3 (ArCN), 147.4

(CÀ THIQ), 147.6 (CÀ THIQ) and 153.5 (ArCO, phenyl) ppm. HRMS

(ES⁺) calcd. C₁₈H₂₂NO₃[M⁺+H] 300.1594; found: 300.1581. Mp 138–

General method for the Pomeranz-Fritsch-Bobbit cyclisation with

HCl: Compound 3e (500 mg, 1.66 mmol) was dissolved in conc. HCl

(2 ml) and stirred at RT for 1 h during which time the mixture

°

140 C (CH₂Cl₂/Et₂O).

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5,6,7-Trimethoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoqui-

noline (7b): The crude compound was purified by column

chromatography (eluent: form 0 to 70% EtOAc in pet. ether) to give

0.9, 7.2 Hz, ArH), 7.03 (2H, dd, J=0.9, 8.7 Hz, ArH), 7.29–7.35 (4H, m,

ArH) and 7.39 (1H, dd, J=2.0, 8.2 Hz, ArH) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=51.0 (ArCH₂), 55.5 (CH₂CH), 66.6 (CHOH), 116.7 (ArCH),

120.6 (ArCH), 121.9 (ArCBr), 129.3 (ArCH), 129.4 (ArCH), 130.3 (ArCH),

131.0 (ArCH), 135.7 (ArCCH), 136.5 (ArCCH₂) and 150.7 (ArCN) ppm.

LC/MS (ES⁺) t_R=2.20 min (86%), m/z 303.4 [M⁺+H] (⁷⁹Br), 305.4

[M⁺+H] (⁸¹Br); (RP, Isocratic, 90% MeOH). HRMS (ES+) calcd. for

C₁₅H₁₅⁷⁹BrNO [M⁺+H] 304.0332; found: 304.0321; calcd. for

C₁₅H₁₅⁸¹BrNO [M⁺+H] 306.0311; found: 306.0320.

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the product as a white solid (1.13 g, 49%) which showed: H NMR

(500 MHz, CDCl₃): δ=2.86 (2H, t, J=5.9 Hz, H₄À THIQ), 3.39 (2H, t,

J=5.9 Hz, H₃À THIQ), 3.78 (3H, s, OCH₃, phenyl), 3.85 (3H, s, C₅OCH₃),

3.86 (3H, s, C₇OCH₃), 3.87 (3H, s, C₆OCH₃), 4.20 (2H, s, H₁À THIQ), 6.45

(1H, s, H₈À THIQ), 6.86 (2H, d, J=9.1 Hz, 2×ArCH, phenyl) and 6.98

(2H, d, J=9.0 Hz, 2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ=23.3 (C₄À THIQ), 48.5 (C₃À THIQ), 52.9 (C₁À THIQ), 55.6 (OCH₃,

phenyl), 56.0 (C₅OCH₃), 60.5 (C₇OCH₃), 60.9 (C₆OCH₃), 105.2

(C₈À THIQ), 114.5 (2×ArCH, phenyl), 118.4 (2×ArCH, phenyl), 120.7

(C₄CC₅À THIQ), 130.1 (C₁CC₈À THIQ), 140.5 (C₇À THIQ), 145.4 (ArCN),

151.2 (C₆À THIQ), 151.9 (C₅À THIQ) and 153.7 (ArCO, phenyl) ppm.

HRMS (ES⁺) calcd. C₁₉H₂₄NO₄[M⁺+H] 330.1700; found: 330.1697.

2-(4-Chlorophenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

(10a): Synthesised according to the general method for the

reductive dehydroxylation with NaBH₄. The crude compound was

purified by column chromatography (eluent: from 0 to 30% EtOAc

in pet. ether) to get the product as a white solid (1.1 g, 51%) which

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was recrystallised from pet. ether and showed: H NMR (500 MHz,

°

Mp 103–104 C (CH₂Cl₂/Et₂O). Anal. calcd. for C₁₉H₂₃NO₄: C 69.28, H

CDCl₃): δ=2.90 (2H, t, J=5.9 Hz, H₄À THIQ), 3.52 (2H, t, J=5.9 Hz,

H₃À THIQ), 3.80 (3H, s, OCH₃), 4.35 (2H, s, H₁À THIQ), 6.70 (1H, d, J=

2.6 Hz, H₈À THIQ), 6.76 (1H, dd, J=2.6, 8.4 Hz, H₇À THIQ), 6.88 (2H, d,

J=9.1 Hz, ArH, phenyl), 7.07 (1H, d, J=8.4 Hz, H₅À THIQ) and 7.22

(2H, d, J=9.1 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=

28.1 (C₄À THIQ), 47.0 (C₃À THIQ), 51.0 (C₁À THIQ), 55.5 (OCH₃), 111.4

(C₈À THIQ), 112.8 (C₆À THIQ), 116.4 (ArCH, phenyl), 123.5 (ArCCl),

126.9 (C₅CC₆À THIQ), 129.1 (ArCH, phenyl), 129.6 (C₅À THIQ), 135.2

(C₁CC₈À THIQ), 149.2 (ArCN) and 158.1 (C₇À THIQ) ppm. LC/MS (ES⁺)

t_R=3.49 min (99%), m/z 273.9 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES⁺) calcd. C₁₆H₁₇³⁵ClNO [M⁺+H] 274.0993; found: 274.0987;

calcd. C₁₆H₁₇³⁷ClNO [M⁺+H] 276.0964; found: 276.0987. Mp 79–

7.04, N 4.25. Found: C 69.36, H 6.95, N 4.13%.

2-(4-Clorophenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-4-ol

(8a): Synthesised according to the general method for the

Pomeranz-Fritsch-Bobbit cyclisation with HCl. The crude compound

was purified by column chromatography (eluent: from 0 to 40%

EtOAc in pet. ether) to give a dark yellow wax (2.39 g, 31%) which

showed as previously reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=

2.36 (1H, d, J=8.6 Hz, OH), 3.32 (2H, dd, J=2.5, 12.6 Hz, H₃À THIQ),

3.82 (3H, s, OCH₃), 3.82 (5H, ddd, J=1.3, 3.5, 12.8 Hz, H₃À THIQ), 4.13

(2H, d, J=15.3 Hz, H₁À THIQ), 4.42 (2H, d, J=15.3 Hz, H₁À THIQ), 4.74

(1H, bs, H₄À THIQ), 6.69 (1H, d, J=2.6 Hz, H₈À THIQ), 6.85 (1H, dd, J=

2.6, 8.5 Hz, H₆À THIQ), 6.98 (3H, d, J=9.0 Hz, ArH, phenyl), 7.25 (4H,

d, J=9.0 Hz, ArH, phenyl) and 7.39 (1H, d, J=8.5 Hz, H₅À THIQ) ppm.

¹³C NMR (126 MHz, CDCl₃): δ=51.3 (C₁À THIQ), 55.3 (OCH₃), 55.7

(C₃À THIQ), 66.7 (C₄À THIQ), 110.9 (C₈À THIQ), 113.4 (C₆À THIQ), 117.6

(ArCH, phenyl), 124.9 (ArCCl), 129.0 (C₅CC₆À THIQ), 129.1 (ArCH,

phenyl), 130.5 (C₅À THIQ), 135.3 (C₁CC₈À THIQ), 149.6 (ArCN) and

159.4 (C₇À THIQ) ppm. LC/MS (ES⁺) t_R=1.95 min (92%), m/z 290.0

[M⁺+H]; (RP, Isocratic, 90% MeOH). HRMS (ES⁺) calcd. for

C₁₆H₁₇³⁵ClNO₂[M⁺+H] 290.0942; found: 290.0935; calcd.

C₁₆H₁₇³⁷ClNO₂[M⁺+H] 292.0913; found: 292.0935.

°

80 C (pet. ether).

2-(4-Chlorophenyl)-5-methoxy-1,2,3,4-tetrahydroisoquinoline

(11a): Synthesised according to the general method for the

reductive dehydroxylation with NaBH₄. The crude compound was

purified by column chromatography (eluent: from 0 to 30% EtOAc

in pet. ether) to get the product as a white solid (230 mg, 11%)

which was recrystallised from pet. ether and showed: ¹H NMR

(500 MHz, CDCl₃): δ=2.87 (2H, t, J=6.0 Hz, H₄À THIQ), 3.52 (2H, t,

J=6.0 Hz, H₃À THIQ), 3.83 (3H, s, OCH₃), 4.35 (2H, s, H₁À THIQ), 6.72

(1H, d, J=8.1 Hz, H₆À THIQ), 6.77 (1H, d, J=7.7 Hz, H₈À THIQ), 6.91

(2H, d, J=9.0 Hz, ArH, phenyl), 7.17 (1H, t, J=8.0 Hz, H₇À THIQ) and

7.21 (2H, d, J=9.0 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ=23.0 (C₄À THIQ), 46.8 (C₃À THIQ), 51.0 (C₁À THIQ), 55.5 (OCH₃),

107.8 (C₆À THIQ), 116.8 (ArCH, phenyl), 118.8 (C₈À THIQ), 123.6

(C₅CC₆À THIQ), 123.7 (ArCCl), 126.8 (C₇À THIQ), 129.1 (ArCH, phenyl),

135.5 (C₁CC₈À THIQ), 149.4 (ArCN) and 157.2 (C₅À THIQ) ppm. HRMS

(ES⁺) calcd. C₁₆H₁₇³⁵ClNO [M⁺+H] 274.0993; found: 274.1015; Mp

7-Bromo-2-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (8b): Syn-

thesised according to the general method for the Pomeranz-

Fritsch-Bobbit cyclisation with HClO₄. The crude compound was

purified by column chromatography (eluant: from 0 to 30% EtOAc

in pet. ether) to give a pale yellow oil (250 mg, 48%) which showed

as previously reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=3.19 (1H,

dd, J=2.1, 12.9 Hz, CH₂CH), 4.07 (1H, ddd, J=1.6, 2.4, 12.9 Hz,

CH₂CH), 4.11 (1H, d, J=15.2 Hz, ArCH₂), 4.54 (1H, d, J=15.5 Hz,

ArCH₂), 5.03 (1H, t, J=2.3 Hz, CHOH), 6.95 (1H, tt, J=0.9, 7.4 Hz,

ArH), 7.10 (2H, dd, J=0.9, 8.7 Hz, ArH), 7.16 (1H, d, J=2.0 Hz, ArH),

7.17 (1H, d, J=7.2 Hz, ArH), 7.34 (2H, dd, J=7.4, 8.7 Hz, ArH) and

7.52 (1H, dd, J=2.0, 7.2 Hz, ArH) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ=51.5 (ArCH₂), 55.7 (CH₂CH), 66.7 (CHOH), 116.8 (ArCH), 117.0

(ArCH), 120.8 (ArCH), 125.8 (ArCBr), 126.0 (ArCH), 129.4 (ArCH), 131.4

(ArCH), 135.6 (ArCCH), 137.1 (ArCCH₂) and 150.9 (ArCN) ppm. LC/MS

(ES⁺) t_R=1.97 min (61%), m/z 303.4 [M⁺+H] (⁷⁹Br), 305.4 [M⁺+H]

(⁸¹Br); (RP, Isocratic, 90% MeOH). HRMS (ES⁺) calcd. for C₁₅H₁₅BrNO

[M⁺+H] (⁷⁹Br) 304.0332; found: 304.0335; calcd. for C₁₅H₁₅BrNO [M⁺

+H] (⁸¹Br) 306.0311; found: 306.0323.

°

75–78 C (pet. ether).

General method for the synthesis of amides 13a–c: SOCl₂

(14.6 mL, 200 mmol) was added to a stirring solution of 3-meth-

oxyphenylacetic acid (3.39 g, 20.0 mmol) in anhydrous CH₂Cl₂

(40 mL) and the mixture was stirred at RT for 4 h. The mixture was

then evaporated and the residue was dissolved in anhydrous

toluene

(40 mL)

and

N,N-diisopropylethylamine

(7.0 mL,

40.0 mmol), aniline (2.7 mL, 30.0 mmol) and a catalytic amount of

DMAP were introduced in the order. The mixture was refluxed

under inert atmosphere overnight and the solvent was then

evaporated. The residue was dissolved in EtOAc (150 mL) and

washed with 1 N HCl (3×100 mL), 1 N NaOH (3×100 mL) and brine

(2×100 mL) then dried with MgSO₄, filtered and evaporated to give

a yellow solid (2.73 g).

5-Bromo-2-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (9b): Syn-

thesised according to the general method for the Pomeranz-

Fritsch-Bobbit cyclisation with HClO4. The crude compound was

purified by column chromatography (eluant: from 0 to 30% EtOAc

in pet. ether) to give a pale yellow oil (50 mg, 10%) which showed

as previously reported:^{[17] 1}H NMR (500 MHz, CDCl₃): δ=3.35 (1H,

dd, J=2.7, 12.7 Hz, CH₂CH), 3.77 (1H, ddd, J=1.0, 3.9, 12.7 Hz,

CH₂CH), 3.89 (1H, bs, OH), 4.13 (1H, d, J=15.6 Hz, ArCH₂), 4.37 (1H,

d, J=15.6 Hz, ArCH₂), 4.72 (1H, t, J=3.3 Hz, CHOH), 6.93 (1H, tt, J=

N-(3-chlorophenyl)-2-(3-methoxyphenyl)acetamide (13a): A sam-

ple of the crude compound (100 mg) was recrystallised from

EtOAc/pet. ether and showed:^{[26] 1}H NMR (500 MHz, CDCl₃): δ=3.70

(2H, s, ArCH₂), 3.82 (3H, s, ArOCH₃), 6.84–6.86 (1H, m, ArCH, benzyl),

6.87–6.93 (2H, m, 2×ArCH, benzyl), 7.05 (1H, dd, J=1.7, 8.1 Hz,

ArCH, aniline), 7.16 (1H, bs, NH), 7.19 (1H, t, J=8.1 Hz, ArCH, aniline),

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7.27 (1H, dd, J=1.7, 8.1 Hz, ArCH, aniline), 7.32 (1H, t, J=8.0 Hz,

ArCH, benzyl) and 7.52 (1H, t, J=1.7 Hz, ArCH, aniline) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=44.9 (ArCH₂), 55.3 (ArOCH₃), 113.2 (ArCH,

benzyl), 115.2 (ArCH, benzyl), 117.7 (ArCH, aniline), 119.8 (ArCH,

aniline), 121.6 (ArCH, benzyl), 124.4 (ArCH, benzyl), 129.9 (ArCH,

aniline), 130.4 (ArCH, aniline), 134.6 (ArCCl), 135.5 (ArCCH₂), 138.7

(ArCN), 160.2 (ArCO) and 168.9 (CH₂CONH) ppm. HRMS (ES⁺) calcd.

for C₁₅H₁₄³⁵ClNNaO₂[M⁺+Na] 298.0605; found: 298.0600. Calcd. for

(2H, s), 3.82 (3H, s), 6.81–6.89 (2H, m), 6.91 (1H, d, J=7.5 Hz), 7.08

(1H, dd, J=4.2, 10.5 Hz), 7.14 (1H, bs), 7.26–7.35 (2H, m) and 7.41

(2H, dd, J=1.0, 8.5 Hz) ppm. HRMS (ES⁺) calcd. C₁₅H₁₆NO₂[M⁺+H]

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°

242.1176; found: 242.1184. Mp 109–110 C (as hydrochloride from

Et₂O).

2-(3-Methoxyphenyl)-N-(4-methoxyphenyl)acetamide (13f): The

crude compound was purified by column chromatography (eluent:

from 0 to 80% EtOAc in pet. ether) to give the product as a pale

yellow solid (2.77 g, 51%) which showed:^{[29] 1}H NMR (400 MHz,

CDCl₃): δ=3.69 (2H, s), 3.76 (3H, s), 3.81 (3H, s), 6.81 (2H, d, J=

9.0 Hz), 6.84–6.89 (2H, m), 6.91 (1H, d, J=7.5 Hz), 7.07 (1H, bs) and

7.27–7.35 (3H, m) ppm. HRMS (ES⁺) calcd. C₁₆H₁₈NO₃[M⁺+H]

37

+

°

C₁₅H₁₄ClNNaO₂[M +Na] 300.0576; found: 300.0589. Mp 93–94 C

(EtOAc/pet. ether).

N-(2-Chlorophenyl)-2-(3-methoxyphenyl)acetamide (13b): The

crude compound was obtained as a white solid (3.65 g, 66%) which

showed:^{[27] 1}H NMR (500 MHz, CDCl₃): δ=3.77 (2H, s, CH₂CO), 3.83

(3H, s, CH₃O), 6.88–6.92 (2H, m, phenyl), 6.95 (1H, d, J=7.5 Hz,

ArCH, phenyl), 7.00 (1H, td, J=1.5, 7.9 Hz, aniline), 7.24 (1H, dd, J=

0.9, 8.2 Hz, aniline), 7.28 (1H, dd, J=1.4, 8.0 Hz, aniline), 7.34 (1H,

dd, J=7.5, 9.0 Hz, ArCH, phenyl), 7.72 (1H, bs, NH), 8.36 (1H, d, J=

7.5 Hz, ArCH, aniline) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=45.4

(CCO), 55.4 (CH₃O), 113.7 (ArCH, phenyl), 115.2 (ArCH, phenyl), 121.4

(ArCH, aniline), 122.0 (ArCH, phenyl), 122.9 (ArCCl), 124.8 (ArCH,

aniline), 127.8 (ArCH, aniline), 129.1 (ArCH, aniline), 130.6 (ArCH,

phenyl), 134.6 (ArCN), 135.5 (ArCCH₂), 160.4 (COCH₃) and 169.1

(NCO) ppm. LC/MS (ES⁺) t_R=1.66 min (95%), m/z 276.1 [M⁺+H];

(RP, Isocratic, 90% MeOH) HRMS (ES⁺) calcd. for C₁₅H₁₄³⁵ClNaNO₂

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°

272.1281; found: 272.1277. Mp 102–103 C (as hydrochloride from

Et₂O).

General method for the reduction of the amides 13a–f: A solution

of 13e (2.0 g, 8.29 mmol) in anhydrous THF (41 mL) was added to a

stirring suspension of LiAlH₄(521 mg, 12.4 mmol) in THF (10 mL)

°

under inert atmosphere and the mixture was stirred at 80 C for 4 h

during which time the mixture turned green. The mixture was then

°

cooled to 0 C, diluted with Et₂O (50 mL) and carefully quenched

with water (0.6 mL) under inert atmosphere. The mixture was

stirred for 15 min, during which time a black precipitate formed.

15% NaOH (0.6 mL) was introduced and the mixture was stirred for

15 min, during which time the precipitate turned white. Water

(1.2 mL) was added and after stirring for 15 min the mixture was

dried with MgSO₄, filtered and evaporated to give a brown oil

(1.7 g).

[M⁺+Na] 298.0605; found: 298.0599. Calcd. for C₁₅H₁₄³⁷ClNaNO₂

+

°

[M +Na] 300.0575; found: 300.0590. Mp 109–110 C (EtOAc/pet.

ether).

N-(3,4-Dichlorophenyl)-2-(3-methoxyphenyl)acetamide (13c): The

crude compound was obtained as a white solid (4.7 g, 76%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=3.71 (2H, s, CH₂CO), 3.83 (3H,

s, CH₃O), 6.85 (1H, t, J=2.1 Hz, ArH, phenyl), 6.89 (2H, dd, J=2.1,

8.0 Hz, ArH, phenyl), 7.08 (1H, bs, NH), 7.25 (1H, dd, J=2.4, 9.0 Hz,

ArH, aniline), 7.32 (1H, d, J=9.0 Hz, ArH, aniline), 7.33 (1H, t, J=

8.0 Hz, ArH, phenyl) and 7.64 (1H, d, J=2.4 Hz, ArH, aniline) ppm.

¹³C NMR (126 MHz, CDCl₃): δ=44.8 (CH₂CO), 55.3 (CH₃O), 113.3

(ArCH, phenyl), 115.2 (ArCH, phenyl), 118.9 (ArCH, aniline), 121.4

(ArCH, aniline), 121.6 (ArCH, phenyl), 127.6 (ArCN), 130.4 (ArCH,

phenyl), 130.5 (ArCH, aniline), 132.7 (ArCCl), 135.3 (ArCCH₂), 137.0

(ArCCl), 160.3 (ArCO) and 168.9 (NCO) ppm. LC/MS (ES⁺) t_R=

2.10 min (92%), m/z (not ionised) [M⁺+H]; (RP, Isocratic, 90%

MeOH). HRMS (ES⁺) calcd. for C₁₅H₁₃³⁵Cl₂NaNO₂[M⁺+Na] 332.0216;

found: 332.0219. Calcd. for C₁₅H₁₃³⁵Cl³⁷ClNaNO₂[M⁺+Na] 334.0238;

3-Chloro-N-(3-methoxyphenethyl)aniline (14a): The crude com-

pound was purified by column chromatography (from 0 to 20%

EtOAc in pet. ether) to give the product as a yellow oil (1.32 g,

1

66%) which showed: H NMR (500 MHz, CDCl₃): δ=2.89 (2H, t, J=

6.9 Hz, ArCH₂CH₂), 3.38 (2H, t, J=6.9 Hz, CH₂CH₂N), 3.76 (1H, bs, NH),

3.80 (3H, s, ArOCH₃), 6.46 (1H, ddd, J=0.8, 2.1, 8.0 Hz, ArCH, aniline),

6.58 (1H, t, J=2.1 Hz, ArCH, aniline), 6.66 (1H, ddd, J=0.8, 2.1,

8.0 Hz, ArCH, aniline), 6.73–6.77 (1H, m, ArCH, phenethyl), 6.77–6.83

(2H, m, ArCH, phenethyl), 7.07 (1H, t, J=8.0 Hz, ArCH, aniline) and

7.24 (1H, t, J=7.9 Hz, ArCH, phenethyl) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=35.3 (ArCH₂CH₂), 44.6 (ArCH₂CH₂), 55.2 (ArOCH₃), 111.3

(ArCH, aniline), 111.8 (ArCH, phenethyl), 112.5 (ArCH, aniline), 114.6

(ArCH, phenethyl), 117.2 (ArCH, aniline), 121.1 (ArCH, phenethyl),

129.7 (ArCH, phenethyl), 130.2 (ArCH, aniline), 135.0 (ArCCl), 140.5

(ArCCH₂), 149.1 (ArCN) and 159.8 (ArCO) ppm. HRMS (ES⁺) calcd. for

C₁₅H₁₇³⁵ClNO [M⁺+H] 262.0993; found: 262.0988. Calcd. for

°

found: 334.0235. Mp 121–122 C (EtOAc/pet. ether).

37

+

°

N-(4-Chlorophenyl)-2-(3-methoxyphenyl)acetamide (13d): The

crude compound was recrystallised from EtOAc/pet. ether to give a

white solid (2.51 g, 46%) showed:^{[22] 1}H NMR (500 MHz, CDCl₃): δ=

3.77 (2H, s, CH₂CO), 3.83 (3H, s, CH₃O), 6.88–6.92 (2H, m, phenyl),

6.95 (1H, d, J=7.5 Hz, ArCH, phenyl), 7.00 (1H, td, J=1.5, 7.9 Hz,

aniline), 7.24 (1H, dd, J=0.9, 8.2 Hz, aniline), 7.28 (1H, dd, J=1.4,

8.0 Hz, aniline), 7.34 (1H, dd, J=7.5, 9.0 Hz, ArCH, phenyl), 7.72 (1H,

bs, NH) and 8.36 (1H, d, J=7.5 Hz, ArCH, aniline) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=45.4 (CCO), 55.4 (CH₃O), 113.7 (ArCH, phenyl),

115.2 (ArCH, phenyl), 121.4 (ArCH, aniline), 122.0 (ArCH, phenyl),

122.9 (ArCCl), 124.8 (ArCH, aniline), 127.8 (ArCH, aniline), 129.1

(ArCH, aniline), 130.6 (ArCH, phenyl), 134.6 (ArCN), 135.5 (ArCCH₂),

160.4 (COCH₃) and 169.1 (NCO) ppm. LC/MS (ES⁺) t_R=1.66 min

(95%), m/z 276.1 [M⁺+H]; (RP, Isocratic, 90% MeOH). HRMS (ES⁺)

calcd. for C₁₅H₁₄³⁵ClNaNO₂[M⁺+Na] 298.0605; found: 298.0599.

Calcd. for C₁₅H₁₄³⁷ClNaNO₂[M⁺+Na] 300.0575; found: 300.0590. Mp

C₁₅H₁₇ClNO [M +H] 264.0964; found: 264.0966. Mp 136–138 C

(as hydrochloride from Et₂O).

2-Chloro-N-(3-methoxyphenethyl)aniline (14b): The filtrate was

evaporated to give a yellow oil (1.5 g, 93%) which showed:^{[30] 1}H

NMR (500 MHz, CDCl₃): δ=2.93 (2H, t, J=7.1 Hz, ArCH₂), 3.44 (2H, t,

J=7.1 Hz, CH₂N), 3.81 (3H, s), 4.38 (1H, bs, NH), 6.63 (1H, td, J=1.5,

7.6 Hz, ArH, aniline), 6.70 (1H, dd, J=1.3, 8.2 Hz, ArH, aniline), 6.76–

6.78 (1H, m, ArH, benzyl), 6.80 (1H, ddd, J=0.7, 2.5, 8.2 Hz, ArH,

benzyl), 6.81–6.85 (1H, m, ArH, benzyl), 7.12–7.18 (1H, m, ArH,

aniline) and 7.25 (2H, td, J=1.3, 7.8 Hz, ArH, aniline and ArH,

benzyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=35.4 (ArCH₂), 44.8

(CH₂N), 55.2 (OCH₃), 111.2 (ArCH, aniline), 111.9 (ArCH, benzyl),

114.4 (ArCH, benzyl), 117.2 (ArCH, aniline), 119.3 (ArCCl), 121.1

(ArCH, benzyl), 127.8 (ArCH, aniline), 129.2 (ArCH, aniline), 129.6

(ArCH, benzyl), 140.6 (ArCCH₂), 143.7 (ArCN) and 159.8 (ArCO) ppm.

LC/MS (ES⁺) t_R=3.12 min (85%), m/z 262.1 [M⁺+H]; (RP, Isocratic,

90% MeOH). HRMS (ES⁺) calcd. for C₁₅H₁₇³⁵ClNO [M⁺+H] 262.0993;

found: 262.0990. Calcd. for C₁₅H₁₇³⁷Cl NO [M⁺+H] 264.0964; found:

°

224–225 C (EtOAc/pet. ether).

2-(3-Methoxyphenyl)-N-phenylacetamide (13e): The crude com-

pound was purified by column chromatography (eluent: from 0 to

80% EtOAc in pet. ether) to give the product as a pale yellow solid

(2.20 g, 46%) which showed:^{[28] 1}H NMR (400 MHz, CDCl₃): δ=3.71

°

264.0976. Mp 127–129 C (as hydrochloride from Et₂O).

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3,4-Dichloro-N-(3-methoxyphenethyl)aniline (14c): The crude

compound was purified by column chromatography (eluent: from 0

to 30% EtOAc in pet. ether) to get the product as a yellow oil

washed with 1 N NaOH (20 mL) then dried with MgSO₄, filtered and

evaporated to give a yellow oil (996 mg).

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2-(3-Chlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

(15a): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 20% EtOAc in pet. ether) to get the

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(1.6 g, 75%) which showed: H NMR (500 MHz, CDCl₃): δ=2.88 (2H,

t, J=6.9 Hz, ArCH₂CH₂), 3.36 (2H, t, J=6.9 Hz, CH₂CH₂N), 3.80 (3H, s,

OCH₃), 6.42 (1H, dd, J=2.7, 8.7 Hz, ArCH, aniline), 6.66 (1H, d, J=

2.7 Hz, ArCH, aniline), 6.75 (1H, t, J=2.1, ArCH, phenethyl), 6.80 (2H,

dd, J=2.1, 7.9 Hz, 2×ArCH, phenethyl), 7.17 (1H, d, J=8.7 Hz, ArCH,

aniline) and 7.25 (1H, t, J=7.9 Hz, ArCH, phenethyl) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=35.2 (ArCH₂CH₂), 44.7 (CH₂CH₂N), 55.2 (OCH₃),

111.8 (ArCH, phenethyl), 112.7 (ArCH, aniline), 113.9 (ArCH, aniline),

114.6 (ArCH, phenethyl), 119.8 (ArCCl), 121.0 (ArCH, phenethyl),

129.7 (ArCH, phenethyl), 130.6 (ArCH, aniline), 132.8 (ArCCl), 140.3

(ArCCH₂), 147.4 (ArCN) and 159.9 (ArCO) ppm. LC/MS (ES⁺) t_R=

3.09 min (89%), m/z 296.1 [M⁺+H] (³⁵Cl), m/z 298.0 [M⁺+H] (³⁷Cl);

(RP, Isocratic, 90% MeOH) HRMS (ES⁺) calcd. for C₁₅H₁₆³⁵Cl₂NO [M⁺

+H] 296.0609; found: 296.0597; calcd. for C₁₅H₁₆³⁵Cl³⁷ClNO [M⁺+H]

1

product as a colourless oil (247 mg, 52%) which showed: H NMR

(500 MHz, CDCl₃): δ=2.95 (1H, t, J=5.8 Hz, H₄À THIQ), 3.54 (1H, t,

J=5.8 Hz, H₃À THIQ), 3.80 (1H, s, OCH₃), 4.35 (1H, s, H₁À THIQ), 6.71

(1H, d, J=2.5 Hz, H₅À THIQ), 6.76 (1H, ddd, J=0.9, 2.2, 8.1 Hz, ArH,

phenyl), 6.77 (1H, dd, J=2.5, 8.4 Hz, H₇À THIQ), 6.81 (1H, ddd, J=0.9,

2.2, 8.1 Hz, ArH, phenyl), 6.90 (1H, t, J=2.2 Hz, ArH, phenyl), 7.08

(1H, d, J=8.4 Hz, H₈À THIQ) and 7.17 (1H, t, J=8.1 Hz, ArH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=29.4 (C₄À THIQ), 46.0 (C₃À THIQ),

49.7 (C₁À THIQ), 55.5 (OCH₃), 112.6 (C₇À THIQ), 112.7 (ArCH, phenyl),

113.3 (C₅À THIQ), 114.5 (ArCH, phenyl), 118.1 (ArCH, phenyl), 126.3

(C₁CC₈À THIQ), 127.6 (C₈À THIQ), 130.2 (ArCH, phenyl), 135.2 (ArCCl),

136.1 (C₅CC₆À THIQ), 151.5 (ArCN) and 158.4 (C₆À THIQ). LC/MS (ES⁺)

t_R=3.84 min (95%), m/z 273.9 [M⁺+H]; (RP, Isocratic, 90% MeOH).

HRMS (ES⁺) calcd. C₁₆H₁₇³⁵ClNO [M⁺+H] 274.0993; found: 274.0981;

calcd. C₁₆H₁₇³⁷ClNO [M⁺+H] 276.0964; found: 276.0974. Mp 112–

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°

298.0580; found: 298.0592. Mp 134–136 C (as hydrochloride from

Et₂O).

4-Chloro-N-(3-methoxyphenethyl)aniline (14d): The compound

was precipitate as hydrochloride from Et₂O to give a pale yellow

solid (1.38 g, 64%) which showed:^{[22] 1}H NMR (400 MHz, CDCl₃): δ=

2.87 (2H, t, J=6.9 Hz), 3.36 (2H, t, J=6.9 Hz), 3.79 (3H, s), 6.52 (2H,

d, J=8.8 Hz), 6.74 (1H, s), 6.76–6.82 (2H, m), 7.11 (2H, d, J=8.8 Hz)

and 7.23 (3H, t, J=7.9 Hz) ppm. HRMS (ES⁺) calcd. C₁₅H₁₇ClNO [M⁺

°

114 C (as hydrochloride from Et₂O).

2-(2-Chlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

(15b): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 10% EtOAc in pet. ether) to give a

colourless oil (600 mg, 57%) which was crystallised as

hydrochloride from Et₂O and showed (¹H and ¹³C NMR data refer to

°

+H] 262.0993; found: 262.1000. Mp 149–151 C (EtOAc/pet. ether).

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N-(3-Methoxyphenethyl)aniline (14e): The crude compound was

purified by column chromatography (eluent: from 0 to 40% EtOAc

in pet. ether) to give the product as a colourless oil (1.21 g, 64%)

which showed:^{[31] 1}H NMR (500 MHz, CDCl₃): δ=2.91 (2H, t, J=

7.1 Hz, CH₂CH₂N), 3.41 (2H, t, J=7.1 Hz, CH₂CH₂N), 3.80 (3H, s,

ArOCH₃), 6.67 (2H, d, J=7.8 Hz, 2×ArCH, aniline), 6.74 (1H, t, J=

7.8 Hz, ArCH, aniline), 6.76–6.80 (2H, m, 2×ArCH, phenethyl), 6.82

(1H, d, J=7.5 Hz, ArCH, phenethyl), 7.20 (2H, t, J=7.8 Hz, 2×ArCH,

aniline) and 7.24 (1H, t, J=7.9 Hz, ArCH, phenethyl) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=35.3 (CH₂CH₂N), 45.3 (CH₂CH₂N), 55.2 (ArOCH₃),

111.7 (ArCH, phenethyl), 113.4 (2×ArCH, aniline), 114.5 (ArCH,

phenethyl), 118.0 (ArCH, aniline), 121.1 (ArCH, phenethyl), 129.3 (2×

ArCH, aniline), 129.6 (ArCH, phenethyl), 140.7 (ArCCH₂), 147.4 (ArCN)

and 159.7 (ArCO) ppm. HRMS (ES⁺) calcd. C₁₅H₁₇NNaO [M⁺+Na]

the free base). H NMR (500 MHz, CDCl₃): δ=3.00 (2H, t, J=5.8 Hz,

H₄À THIQ), 3.38 (2H, t, J=5.8 Hz, H₃À THIQ), 3.80 (3H, s, OCH₃), 4.22

(2H, s, H₁À THIQ), 6.71 (1H, d, J=2.6 Hz, H₅À THIQ), 6.75 (1H, dd, J=

2.6, 8.4 Hz, H₇À THIQ), 6.98 (1H, ddd, J=1.5, 7.4, 7.8 Hz, ArH, phenyl),

7.02 (1H, d, J=8.4 Hz, H₈À THIQ), 7.12 (1H, dd, J=1.5, 8.0 Hz, ArH,

phenyl), 7.22 (1H, ddd, J=1.5, 7.4, 8.0 Hz, ArH, phenyl) and 7.39 (1H,

dd, J=1.5, 7.8 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=

29.4 (C₄À THIQ), 49.8 (C₃À THIQ), 52.7 (C₂À THIQ), 55.3 (CH₃O), 112.2

(C₇À THIQ), 113.5 (C₅À THIQ), 120.6, 123.5, 126.9 (C₁CC₈À THIQ), 127.3,

127.5, 128.8 (ArCCl), 130.7, 135.7 (C₄CC₅À THIQ), 149.1 (ArCN), 158.1

(C₆À THIQ) ppm. HRMS (ES⁺) calcd. for C₁₆H₁₇³⁵ClNO [M⁺+H]

274.0993; found: 274.0980; Calcd. for C₁₆H₁₇³⁷ClNO [M⁺+H]

°

276.0964; found: 276.0974. Mp 59–61 C (pet. ether).

2-(3,4-Dichlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

(15c): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 20% EtOAc in pet. ether) to give yellow

°

250.1208; found: 250.1201. Mp 98–100 C (as hydrochloride from

Et₂O).

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4-Methoxy-N-(3-methoxyphenethyl)aniline (14f): The crude com-

pound was purified by column chromatography (eluent: from 0 to

40% EtOAc in pet. ether) to give the product as a yellow oil (1.39 g,

59%) which showed:^{[32] 1}H NMR (500 MHz, CDCl₃): δ=2.89 (2H, t,

J=7.0 Hz, CH₂CH₂N), 3.36 (2H, t, J=7.0 Hz, CH₂CH₂N), 3.75 (3H, s,

ArOCH₃, aniline), 3.80 (3H, s, ArOCH₃, phenethyl), 6.63 (2H, d, J=

8.8 Hz, 2×ArCH, aniline), 6.74–6.83 (5H, m, 3×ArCH, phenethyl, 2×

ArCH, aniline) and 7.23 (1H, t, J=7.8 Hz, ArCH, phenethyl) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=35.4 (CH₂CH₂N), 46.2 (CH₂CH₂N), 55.2

(ArOCH₃, phenethyl), 55.8 (ArOCH₃, aniline), 111.7 (ArCH, phenethyl),

114.5 (ArCH, phenethyl), 114.8 (2×ArCH, aniline), 114.9 (2×ArCH,

aniline), 121.1 (ArCH, phenethyl), 129.6 (ArCH, phenethyl), 140.8

(ArCCH₂), 141.6 (ArCN), 152.4 (ArCO, aniline) and 159.7 (ArCO,

phenethyl) ppm. HRMS (ES⁺) calcd. C₁₆H₁₉NNaO₂[M⁺+Na]

solid (631 mg, 55%) which showed: H NMR (500 MHz, CDCl₃): δ=

2.94 (2H, t, J=5.9 Hz, H₄À THIQ), 3.51 (2H, t, J=5.9 Hz, H₃À THIQ),

3.80 (3H, s, OCH₃), 4.32 (2H, s, H₁À THIQ), 6.70 (1H, d, J=2.5 Hz), 6.75

(1H, dd, J=2.9, 8.9 Hz), 6.77 (1H, dd, J=2.3, 8.1 Hz), 6.97 (1H, d, J=

2.9 Hz), 7.07 (1H, d, J=8.4 Hz) and 7.27 (1H, d, J=8.9 Hz) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=29.1, 45.8, 49.5, 55.3, 112.5, 113.2, 113.9,

115.7, 120.6, 125.8, 127.5, 130.4, 132.8, 135.8 and 158.3 ppm. HRMS

(ES⁺) calcd. for C₁₆H₁₇³⁵Cl₂NO [M⁺+H] 306.0447; found: 306.0406.

Calcd. for C₁₆H₁₇³⁷Cl₂NO [M⁺+H] 310.0388; found: 310.0394. Calcd.

for C₁₆H₁₇³⁵Cl³⁷ClNO [M⁺+H] 308.0417; found: 308.0390. Mp 81–

°

82 C (pet. ether).

2-(2-Chlorophenyl)-8-methoxy-1,2,3,4-tetrahydroisoquinoline

(16b): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 10% EtOAc in pet. ether) to give a pale

yellow oil (46 mg, 4%) which showed: ¹H NMR (400 MHz, CDCl₃):

δ=3.01 (2H, t, J=5.7 Hz), 3.36 (2H, t, J=5.7 Hz), 3.82 (3H, s), 4.21

(2H, s), 6.70 (1H, d, J=8.1 Hz), 6.78 (1H, d, J=7.6 Hz), 6.94–7.00 (1H,

m), 7.15 (1H, t, J=7.9 Hz), 7.18–7.23 (2H, m) and 7.38 (1H, dd, J=

1.5, 7.9 Hz) ppm. LC/MS (ES⁺) t_R=4.13 min (82%), m/z 274.1 [M⁺+

H]; (RP, Isocratic, 90% MeOH)

°

280.1308; found: 280.1312. Mp 108–111 C (as hydrochloride from

Et₂O).

General method for the Pictet-Spengler cyclisation: Compound

14b (1.0 g, 3.82 mmol) was dissolved in toluene (18 mL) and

treated with paraformaldehyde (573 mg, 19.1 mmol) and PTSA

°

(32 mg, 0.191 mmol). After stirring at 90 C for 18 h, the mixture

was cooled to RT and filtered. The solvent was evaporated and the

residue was dissolved in CH₂Cl₂(30 mL). The organic layer was

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2-(3,4-Dichlorophenyl)-8-methoxy-1,2,3,4-tetrahydroisoquinoline

(16c): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 20% EtOAc in pet. ether) to give pale

yellow oil (36 mg, 4%) which showed: ¹H NMR (500 MHz, CDCl₃):

δ=2.95 (2H, t, J=5.8 Hz, H₄À THIQ), 3.50 (2H, t, J=5.8 Hz, H₃À THIQ),

3.87 (3H, s, OCH₃), 4.28 (2H, s, H₁À THIQ), 6.73 (1H, d, J=8.1 Hz,

H₇À THIQ), 6.78 (1H, d, J=7.6 Hz, H₅À THIQ), 6.82 (1H, dd, J=2.9,

9.0 Hz, ArCH, phenyl), 7.04 (1H, d, J=2.9 Hz, ArCH, phenyl), 7.17

(1H, t, J=7.9 Hz, H₆À THIQ) and 7.28 (1H, d, J=9.0 Hz, ArCH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=29.1, 45.6, 45.7, 55.4, 107.5,

114.3, 116.1, 120.8, 122.5, 127.2, 130.6, 132.9, 135.9, 150.2 and

156.2 ppm. LC/MS (ES⁺) t_R=6.12 min (12%), m/z 308.1 [M⁺+H];

(RP, Isocratic, 90% MeOH).

6.80 (1H, d, J=8.2 Hz, ArCH, methoxyphenyl), 6.82 (1H, s, ArCH,

methoxyphenyl), 6.86 (1H, d, J=7.5 Hz, ArCH, methoxyphenyl), 7.24

(1H, t, J=8.0 Hz, ArCH, methoxyphenyl), 7.46 (2H, t, J=7.7 Hz, 2×

ArCH, phenyl), 7.56 (1H, t, J=7.7 Hz, ArCH, phenyl) and 8.01 (2H, d,

J=7.7 Hz, 2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=

45.6 (CH₂), 55.2 (ArOCH₃), 112.4 (ArCH, methoxyphenyl), 115.1

(ArCH, methoxyphenyl), 121.8 (ArCH, methoxyphenyl), 128.6 (4×

ArCH, phenyl), 129.6 (ArCH, methoxyphenyl), 133.2 (ArCH, phenyl),

136.0 (ArCCH₂), 136.6 (ArCCO), 159.8 (ArCO) and 197.5 (CH₂CO)

ppm. HRMS (ES⁺) calcd. C₁₅H₁₅O₂[M⁺+H] 227.1072; found:

227.1082; calcd. C₁₅H₁₄NaO₂[M⁺+Na] 249.0891; found: 249.0901.

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1-(3-Methoxyphenyl)-3-phenylpropan-2-one (18d): The crude

compound was purified by column chromatography (eluent: pet.

ether) to give the product as a colourless oil (160 mg, 28%) which

showed:^{[36] 1}H NMR (500 MHz, CDCl₃): δ=3.69 (2H, s, CH₂, meth-

oxyphenyl), 3.72 (2H, s, CH₂, phenyl), 3.78 (3H, s, ArOCH₃), 6.69 (1H,

s, ArCH, methoxyphenyl), 6.75 (1H, d, J=7.5 Hz, ArCH, meth-

oxyphenyl), 6.81 (1H, dd, J=1.9, 7.9 Hz, ArCH, methoxyphenyl), 7.15

(2H, d, J=7.4 Hz, 2×ArCH, phenyl), 7.24 (1H, t, J=7.9 Hz, ArCH,

methoxyphenyl), 7.26–7.29 (1H, m, ArCH, phenyl) and 7.32 (2H, t,

J=7.4 Hz, 2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=

49.0 (CH₂, phenyl), 49.2 (CH₂, methoxyphenyl), 55.2 (ArOCH₃), 112.7

(ArCH, methoxyphenyl), 115.0 (ArCH, methoxyphenyl), 121.8 (ArCH,

methoxyphenyl), 127.0 (ArCH, phenyl), 128.7 (2×ArCH, phenyl),

129.5 (2×ArCH, phenyl), 129.7 (ArCH, methoxyphenyl), 134.0

(ArCCH₂, phenyl), 135.4 (ArCCH₂, methoxyphenyl), 159.8 (ArCO) and

205.6 (CH₂CO) ppm.

N-Methoxy-2-(3-methoxyphenyl)-N-methylacetamide (17): A solu-

tion of PCl₃(3.5 mL, 40.0 mmol) in anhydrous toluene (50 mL) was

added to a stirring suspension of N,O-dimethylhydroxylamine

hydrochloride (12.3 g, 124.0 mmol) and Et₃N (39 mL, 280 mmol) at

°

0 C under inert atmosphere and the mixture was stirred at RT

overnight. 3-Methoxyphenylacetic acid (13.7 g, 80.0 mmol) was

°

added and the mixture was stirred overnight at 120 C under inert

atmosphere. The mixture was evaporated and the residue was

dissolved with EtOAc (150 mL). The organic layer was washed with

1 N HCl (3×100 mL) and brine (3×100 mL), then dried with MgSO₄,

filtered and evaporated to give a brown oil (6.40 g). The crude

compound was purified by column chromatography (eluent: from 0

to 40% EtOAc in pet. ether) to give the product as a yellow oil

(5.50 g, 21%) which showed:^{[33] 1}H NMR (400 MHz, CDCl₃): δ=3.19

(3H, s), 3.60 (3H, s), 3.74 (2H, s), 3.79 (3H, s), 6.78 (1H, dd, J=2.3,

8.2 Hz), 6.83–6.91 (2H, m) and 7.22 (1H, t, J=7.8 Hz) ppm. HRMS

(ES⁺) calcd. C₁₁H₁₆NO₃[M⁺+H] 210.1125; found: 210.1125.

4-Chloro-N-(1-(3-methoxyphenyl)propan-2-yl)aniline (19a): NaBH

(OAc)₃(306 mg, 1.37 mmol) was added to a stirring solution of 18a

(105 mg, 0.914 mmol) and 4-chloroaniline (117 mg, 0.914 mmol) in

CHCl₃(5 mL) and the mixture was stirred at RT for 6 h. The mixture

was diluted with CHCl₃(15 mL) and washed with sat. aq. Na₂CO₃

(3×10 mL), then dried with MgSO₄, filtered and evaporated to give

a yellow oil (205 mg). The crude compound was purified by column

chromatography (eluent: from 0 to 30% EtOAc in pet. ether) to get

General method for the Weinreb reaction: 1.4 M solution of

MeMgBr (1.2 mL, 1.67 mmol) in toluene/THF (3:1) was added to a

stirring solution of 17 (290 mg, 1.39 mmol) in anhydrous THF

(14 mL) under inert atmosphere and the mixture was stirred at RT

for 1 h. The mixture was quenched with 1 N HCl (3 mL) and

extracted with EtOAc (3×30 mL). The combined organics were

dried with MgSO₄, filtered and evaporated to give the product as a

yellow oil (211 mg, 93%).

1

the product as a yellow oil (53 mg, 21%) which showed: H NMR

(500 MHz, CDCl₃): δ=1.16 (3H, d, J=6.4 Hz, CHCH₃), 2.70 (1H, dd,

J=7.4, 13.4 Hz, CH₂CH), 2.91 (1H, dd, J=4.7, 13.4 Hz, CH₂CH), 3.67–

3.75 (1H, m, CHCH₃), 3.79 (3H, s, OCH₃), 6.61 (2H, d, J=8.5 Hz, 2×

ArCH, aniline), 6.70 (1H, s, ArCH, phenyl), 6.73–6.81 (2H, m, 2×ArCH,

phenyl), 7.14 (2H, d, J=8.7 Hz, 2×ArCH, aniline) and 7.22 (1H, t, J=

7.9 Hz, ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=19.8

(CHCH₃), 41.9 (CH₂CH), 50.2 (CHCH₃), 55.1 (OCH₃), 111.5 (ArCH,

phenyl), 115.2 (2×ArCH, aniline), 115.3 (ArCH, phenyl), 121.8 (ArCH,

phenyl), 122.5 (ArCCl), 129.2 (2×ArCH, aniline), 129.3 (ArCH,

phenyl), 139.6 (ArCCH₂), 144.9 (ArCN) and 159.6 (ArCO) ppm.

1-(3-Methoxyphenyl)propan-2-one (18a): The product was ob-

tained as a yellow oil (211 mg, 93%) which showed:^{[34] 1}H NMR

(500 MHz, CDCl₃): δ=2.15 (3H, s, CH₃CO), 3.66 (2H, s, CH₂CO), 3.80

(3H, s, ArOCH₃), 6.73–6.76 (1H, m, ArCH), 6.77–6.80 (1H, m, ArCH),

6.80–6.84 (1H, m, ArCH) and 7.25 (1H, t, J=7.9 Hz, ArCH) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=29.2 (CH₃CO), 51.1 (CH₂CO), 55.2

(ArOCH₃), 112.5 (ArCH), 115.0 (ArCH), 121.7 (ArCH), 129.8 (ArCH),

135.7 (ArCCH₂), 159.8 (ArCO) and 206.3 (CH₂CO) ppm. HRMS (ES⁺)

calcd. C₁₀H₁₃O₂[M⁺+H] 165.0910; found: 165.0923; calcd.

C₁₀H₁₂NaO₂[M⁺+Na] 187.0730; found: 187.0737.

4-Chloro-N-(1-(3-methoxyphenyl)butan-2-yl)aniline (19b): NaBH

(OAc)₃(445 mg, 2.10 mmol) was added to a stirring solution of 18b

(250 mg, 1.40 mmol) and 4-chloroaniline (268 mg, 2.10 mmol) in

CHCl₃(15 mL) and the mixture was stirred at RT overnight. The

mixture was diluted with CHCl₃(15 mL) and washed with sat. aq.

Na₂CO₃(2×30 mL) then dried with MgSO₄, filtered and evaporated

to give a yellow oil (383 mg). the crude compound was purified by

column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a colourless oil (67 mg, 19%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=0.99 (3H, t, J=7.4 Hz,

CH₂CH₃), 1.35–1.51 (1H, m, CH₂CH₃), 1.57–1.71 (1H, m, CH₂CH₃),

2.74–2.90 (2H, m, ArCH₂), 3.47–3.60 (1H, m, CHN), 3.80 (3H, s, OCH₃),

6.57 (2H, d, J=8.7 Hz, 2×ArCH, aniline), 6.72 (1H, s, ArCH, phenyl),

6.77 (1H, d, J=8.7 Hz, ArCH, phenyl), 6.79 (1H, d, J=8.7 Hz, ArCH,

phenyl), 7.14 (2H, d, J=8.7 Hz, ArCH, phenyl) and 7.23 (1H, t, J=

7.9 Hz) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=10.4 (CH₂CH₃), 26.6

(CH₂CH₃), 39.6 (ArCH₂), 55.1 (OCH₃), 55.5 (CHN), 111.4 (ArCH, phenyl),

114.5 (2×ArCH, aniline), 115.4 (ArCH, phenyl), 121.8 (ArCCl), 121.9

(ArCH, phenyl), 129.2 (2×ArCH, aniline), 129.3 (ArCH, phenyl), 139.8

1-(3-Methoxyphenyl)butan-2-one (18b): The crude compound was

purified by column chromatography (eluent: from 0 to 15% EtOAc

in pet. ether) to give a colourless oil (257 mg, 50%) which

showed:^{[35] 1}H NMR (500 MHz, CDCl₃): δ=1.02 (3H, t, J=7.3 Hz,

CH₂CH₃), 2.47 (2H, q, J=7.3 Hz, CH₂CH₃), 3.65 (2H, s, ArCH₂), 3.80

(3H, s, OCH₃), 6.73–6.77 (1H, m, ArCH), 6.77–6.84 (2H, m, 2×ArCH)

and 7.24 (1H, t, J=8.0 Hz, ArCH) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ=7.8 (CH₂CH₃), 35.1 (CH₂CH₃), 49.9 (ArCH₂), 55.2 (OCH₃), 112.4

(ArCH), 115.0 (ArCH), 121.7 (ArCH), 129.7 (ArCH), 135.9 (ArCCH₂),

159.8 (ArCO) and 208.9 (CH₂CO) ppm. HRMS (ES⁺) calcd. C₁₁H₁₅O₂

[M⁺+H] 179.1067; found: 179.1075.

2-(3-Methoxyphenyl)-1-phenylethanone (18c): The crude com-

pound was purified by column chromatography (eluent: pet. ether)

to give the product as a yellow oil (356 mg, 66%) which showed: ¹H

NMR (500 MHz, CDCl₃): δ=3.79 (3H, s ArOCH₃), 4.26 (2H, s, CH₂),

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(ArCCH₂), 145.9 (ArCN) and 159.6 (ArCO) ppm. HRMS (ES^À) calcd.

C₁₇H₁₉³⁵ClNO [M^ÀÀ H] 288.1161; found: 288.1159; calcd. C₁₇H₁₉³⁷ClNO

[M^ÀÀ H] 290.1131; found: 290.1119.

(1H, d, J=15.9 Hz, H₄À THIQ), 3.13 (1H, dd, J=5.4, 15.9 Hz, H₄À THIQ),

3.87 (3H, s, OCH₃), 3.99–4.06 (1H, m, H₃À THIQ), 4.09 (1H, d, J=

17.4 Hz, H₁À THIQ), 4.37 (1H, d, J=16.8 Hz, H₁À THIQ), 6.73 (1H, d, J=

7.9 Hz, H₇À THIQ), 6.76 (1H, d, J=7.9 Hz, H₅À THIQ), 6.88 (2H, d, J=

9.1 Hz, 2×ArCH, phenyl), 7.17 (1H, t, J=7.9 Hz, H₆À THIQ) and 7.20

(2H, d, J=9.1 Hz, 2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ=11.5 (CH₂CH₃), 22.6 (CH₂CH₃), 32.0 (C₄À THIQ), 41.5 (C₁À THIQ),

54.5 (C₃À THIQ), 55.2 (OCH₃), 107.2 (C₇À THIQ), 115.3 (2×ArCH,

phenyl), 121.3 (C₅À THIQ), 121.9 (ArCCl), 122.0 (C₁CC₈À THIQ), 126.9

(C₆À THIQ), 128.9 (2×ArCH, phenyl), 134.2 (C₄CC₅À THIQ), 148.6

(ArCN) and 155.7 (C₈À THIQ) ppm.

Methyl 2-(3-methoxyphenyl)acetate (23): Conc. H₂SO₄(1.2 mL) was

added dropwise to a stirring solution of 3-methoxyphenylacetic

acid (6.78 g, 40.0 mmol) in MeOH (80 mL) and the mixture was

refluxed for 3 days. Product did not form according to TLC. The

mixture was then stirred for 3 h under reflux and inert atmosphere

using a Soxhlet extractor containing CaH₂as dehydrating agent.

The mixture was then neutralised with Na₂CO₃, filtered and

evaporated. The residue was dissolved in EtOAc (100 mL) and

washed with 1 N NaOH (3×100 mL) and brine (100 mL) then dried

with MgSO₄, filtered and evaporated to give the product as a

colourless oil (6.36 g, 88%) which showed: ¹H NMR (400 MHz,

CDCl₃): δ=3.60 (2H, s), 3.69 (3H, s), 3.80 (3H, s), 6.79–6.84 (2H, m),

6.86 (1H, d, J=7.6 Hz) and 7.24 (1H, t, J=7.8 Hz) ppm.

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6

7

8

9

4-Chloro-N-(1-(3-methoxyphenyl)-3-phenylpropan-2-yl)aniline

(19d): NaBH(OAc)₃(393 mg, 1.76 mmol) was added to a stirring

solution of 18d (280 mg, 1.17 mmol) and 4-chloroaniline (149 mg,

1.17 mmol) in dichloroethane (3.0 mL). Glacial acetic acid (67 μL,

1.17 mmol) was introduced and the mixture was stirred at RT

overnight during which time the suspension turned into a solution.

The mixture was diluted with CH₂Cl₂(10 mL) and washed with 1 N

NaOH (1×10 mL) then dried with MgSO₄, filtered and evaporated

to give a yellow oil (305 mg). The crude compound was purified by

column chromatography (eluent: from 0 to 40% EtOAc in pet.

ether) to give the product as a yellow oil (116 mg, 28%) which

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14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

1

showed: H NMR (400 MHz, CDCl₃): δ=2.64–2.95 (4H,z m), 3.77 (3H,

m), 3.85–4.01 (1H, m), 6.51 (2H, d, J=8.9 Hz), 6.69–6.72 (1H, m),

6.73–6.79 (2H, m), 7.09 (2H, d, J=8.9 Hz), 7.15–7.19 (2H, m), 7.22

(2H, dd, J=2.1, 7.7 Hz) and 7.26–7.30 (2H, m) ppm. HRMS (ES⁺)

calcd. C₂₂H₂₁³⁵ClNO [M^ÀÀ H] 350.1317; found: 350.1328; calcd.

C₂₂H₂₁³⁷ClNO [M^ÀÀ H] 352.1288; found: 352.1301.

2-(4-Chlorophenyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoqui-

noline (20a): Synthesised according to the general method for the

Pictet-Spengler cyclisation. The crude compound was purified by

column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a white solid (120 mg, 28%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=1.04 (3H, d, J=6.6 Hz,

CHCH₃), 2.66 (1H, dd, J=2.0, 15.6 Hz, H₄À THIQ), 3.23 (1H, dd, J=5.4,

15.6 Hz, H₄À THIQ), 3.81 (3H, s, OCH₃), 4.17 (1H, d, J=15.0 Hz,

H₁À THIQ), 4.24–4.32 (1H, m, H₃À THIQ), 4.35 (1H, d, J=15.0 Hz,

H₁À THIQ), 6.72 (1H, d, J=2.6 Hz, H₅À THIQ), 6.79 (1H, dd, J=2.6,

8.4 Hz, H₇À THIQ), 6.85 (2H, d, J=9.0 Hz, 2×ArCH, phenyl), 7.09 (1H,

d, J=8.4 Hz, H₈À THIQ) and 7.23 (2H, d, J=9.0 Hz, 2×ArCH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=15.5 (CHCH₃), 35.7 (C₄À THIQ),

45.7 (C₁À THIQ), 48.8 (C₃À THIQ), 55.2 (OCH₃), 112.2 (C₇À THIQ), 113.8

(C₅À THIQ), 115.4 (2×ArCH, phenyl), 122.4 (ArCCl), 125.3

(C₁CC₈À THIQ), 127.3 (C₈À THIQ), 129.0 (2×ArCH, phenyl), 134.3

(C₄CC₅À THIQ), 147.9 (ArCN) and 158.3 (C₆À THIQ) ppm. HRMS (ES⁺)

calcd. C₁₇H₁₉³⁵ClNO [M⁺+H] 288.1150; found: 288.1156. Mp 86–

General method for the alkylation of the ester 23: 2.0 M LDA

(3.3 mL, 6.66 mmol) was added to a stirring solution of 23 (1.0 g,

°

5.55 mmol) in anhydrous THF (50 mL) at À 78 C under inert

atmosphere and the mixture was stirred for 1 h. Methyl iodide

(384 μL, 6.11 mmol) was added and the mixture was stirred for 1 h

°

at À 78 C then let reach RT and stirred for further 4 h. The mixture

°

was cooled to 0 C and carefully quenched with 1 N HCl (10 mL)

then the organic solvent was evaporated. The aqueous layer was

extracted with EtOAc (3×50 mL) and the combined organics were

washed with 1 N HCl (3×50 mL) and brine (3×50 mL) then dried

with MgSO₄, filtered and evaporated to give a brown oil (1.11 g).

Methyl 2-(3-methoxyphenyl)propanoate (24a): The crude com-

1

pound was not purified and showed: H NMR (500 MHz, CDCl₃): δ=

1.49 (3H, d, J=7.1 Hz, CHCH₃), 3.66 (3H, s, COOCH₃), 3.70 (1H, q, J=

7.1 Hz, CHCH₃), 3.80 (3H, s, ArOCH₃), 6.80 (1H, dd, J=2.3, 8.2 Hz,

ArCH), 6.84 (1H, t, J=2.3 Hz, ArCH), 6.88 (1H, dd, J=2.3, 8.2 Hz,

ArCH) and 7.24 (1H, t, J=8.0 Hz, ArCH) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=18.5 (CHCH₃), 45.4 (CHCH₃), 52.0 (COOCH₃), 55.2

(ArOCH₃), 112.4 (ArCH), 113.2 (ArCH), 119.8 (ArCH), 129.6 (ArCH),

142.0 (ArCCH), 159.7 (ArCO) and 174.8 (COO) ppm. HRMS (ES⁺)

calcd. C₁₁H₁₅O₃[M⁺+H] 195.1021; found: 195.1014; calcd.

C₁₁H₁₄NaO₃[M⁺+H] 217.0841; found: 217.0831.

°

90 C (pet. ether).

2-(4-Chlorophenyl)-3-ethyl-6-methoxy-1,2,3,4-tetrahydroisoqui-

noline (20b): Synthesised according to the general method for the

Pictet-Spengler cyclisation. The crude compound was purified by

column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a colourless oil (92 mg, 44%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=0.87 (3H, t, J=7.4 Hz,

CH₂CH₃), 1.27–1.37 (1H, m, CH₂CH₃), 1.49–1.60 (1H, m, CH₂CH₃), 2.78

(1H, dd, J=1.5, 15.8 Hz, H₄À THIQ), 3.11 (1H, dd, J=5.4, 15.7 Hz,

H₄À THIQ), 3.81 (3H, s, OCH₃), 3.95–4.03 (1H, m, H₃À THIQ), 4.20 (1H,

d, J=15.2 Hz, H₁À THIQ), 4.35 (1H, d, J=15.1 Hz, H₁À THIQ), 6.70 (1H,

d, J=2.2 Hz, H₅À THIQ), 6.78 (1H, dd, J=2.5, 8.4 Hz, H₇À THIQ), 6.81

(2H, d, J=9.0 Hz, 2×ArCH, phenyl), 7.08 (1H, d, J=8.4 Hz, H₈À THIQ)

and 7.20 (2H, d, J=9.0 Hz, 2×ArCH, phenyl) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=11.4 (CH₂CH₃), 23.2 (CH₂CH₃), 32.3 (C₄À THIQ),

45.7 (C₁À THIQ), 55.1 (C₃À THIQ), 55.2 (OCH₃), 112.1 (C₇À THIQ), 113.9

(C₅À THIQ), 115.0 (2×ArCH, phenyl), 121.9 (ArCCl), 125.6

(C₁CC₈À THIQ), 127.2 (C₈À THIQ), 129.0 (2×ArCH, phenyl), 134.5

(C₄CC₅À THIQ), 148.3 (ArCN) and 158.2 (C₆À THIQ) ppm.

Methyl 2-(3-methoxyphenyl)butanoate (24b): The crude com-

1

pound was not purified and showed: H NMR (500 MHz, CDCl₃): δ=

0.89 (3H, t, J=7.4 Hz, CH₂CH₃), 1.72–1.86 (1H, m, CHCH₂), 2.03–2.14

(1H, m, CHCH₂), 3.42 (1H, t, J=7.7 Hz, CHCH₂), 3.66 (3H, s, COOCH₃),

3.80 (3H, s, ArOCH₃), 6.80 (1H, ddd, J=0.6, 2.5, 7.9 Hz, ArCH), 6.83–

6.86 (1H, m, ArCH), 6.88 (1H, d, J=7.9 Hz, ArCH) and 7.23 (1H, t, J=

7.9 Hz, ArCH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=12.1 (CH₂CH₃),

26.7 (CHCH₂), 51.9 (COOCH₃), 53.4 (CHCH₂), 55.2 (ArOCH₃), 112.5

(ArCH), 113.6 (ArCH), 120.4 (ArCH), 129.5 (ArCH), 140.6 (ArCCH),

159.7 (ArCO) and 174.4 (COO) ppm. HRMS (ES⁺) calcd. C₁₂H₁₇O₃[M⁺

+H] 209.1178; found: 209.1163; calcd. C₁₂H₁₆NaO₃[M⁺+H]

231.0997; found: 231.0980.

2-(4-Chlorophenyl)-3-ethyl-8-methoxy-1,2,3,4-tetrahydroisoqui-

noline (21b): Synthesised according to the general method for the

Pictet-Spengler cyclisation. The crude compound was purified by

column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a colourless oil (8 mg, 4%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=0.85 (3H, t, J=7.4 Hz,

CH₂CH₃), 1.27–1.42 (1H, m, CH₂CH₃), 1.47–1.59 (1H, m, CH₂CH₃), 2.79

Methyl 2-(3-methoxyphenyl)-3-methylbutanoate (24c): The crude

compound was purified by column chromatography (eluent: from 0

to 20% EtOAc in pet. ether) to give the product as a yellow oil

1

(243 mg, 20%) which showed: H NMR (500 MHz, CDCl₃): δ=0.71

(3H, d, J=6.7 Hz, (CH₃)₂CH), 1.02 (3H, d, J=6.5 Hz, (CH₃)₂CH), 2.24–

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2.41 (1H, m, (CH₃)₂CH), 3.12 (1H, d, J=10.6 Hz, (CH₃)₂CHCH), 3.65

(3H, s, COOCH₃), 3.80 (3H, s, ArOCH₃), 6.80 (1H, dd, J=1.7, 8.2 Hz,

ArCH), 6.90 (2H, d, J=7.8 Hz, 2×ArCH) and 7.22 (1H, t, J=7.8 Hz,

ArCH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=20.2 ((CH₃)₂CH), 21.5

((CH₃)₂CH), 31.9 ((CH₃)₂CH), 51.7 (COOCH₃), 55.2 (ArOCH₃), 60.0

((CH₃)₂CHCH), 112.5 (ArCH), 114.1 (ArCH), 121.0 (ArCH), 129.3 (ArCH),

139.9 (ArCCH), 159.6 (ArCO) and 174.3 (COO) ppm. HRMS (ES⁺)

calcd. C₁₃H₁₉O₃[M⁺+H] 223.1334; found: 223.1325; calcd.

C₁₃H₁₈NaO₃[M⁺+H] 245.1153; found: 245.1133.

N-(4-Chlorophenyl)-2-(3-methoxyphenyl)butanamide (25b): The

crude compound was purified by column chromatography (eluent:

from 0 to 40% EtOAc in pet. ether) to give the product as a yellow

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2

3

4

5

6

7

8

9

1

solid (400 mg, 24%) which showed: H NMR (500 MHz, CDCl₃): δ=

0.92 (3H, t, J=7.4 Hz, CH₂CH₃), 1.77–1.96 (1H, m, CHCH₂), 2.16–2.35

(1H, m, CHCH₂), 3.35 (1H, t, J=7.5 Hz, CHCH₂), 3.81 (3H, s OCH₃),

6.84 (1H, dd, J=2.1, 8.2 Hz, ArCH, phenacetyl), 6.87–6.90 (1H, m,

ArCH, phenacetyl), 6.92 (1H, d, J=7.6 Hz, ArCH, phenacetyl), 7.08

(1H, bs, NH), 7.23 (2H, d, J=8.8 Hz, ArCH, aniline), 7.29 (1H, t, J=

7.9 Hz, ArCH, phenacetyl) and 7.38 (2H, d, J=8.8 Hz, ArCH, aniline)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=12.3 (CH₂CH₃), 26.2 (CHCH₂),

55.2 (OCH₃), 56.1 (CHCH₂), 112.8 (ArCH, phenacetyl), 113.8 (ArCH,

phenacetyl), 120.3 (ArCH, phenacetyl), 120.9 (2×ArCH, aniline),

128.9 (2×ArCH, aniline), 129.2 (ArCCl), 130.1 (ArCH, phenacetyl),

136.4 (ArCN), 140.8 (ArCCH), 160.1 (ArCO) and 171.5 (CON) ppm.

HRMS (ES⁺) calcd. C₁₇H₁₉³⁵ClNO₂[M⁺+H] 304.1099; found:

304.1116; calcd. C₁₇H₁₉³⁷ClNO₂[M⁺+H] 306.1069; found: 306.1098.

Methyl 2-(3-methoxyphenyl)-3-phenylpropanoate (24d): The

crude compound was purified by column chromatography (eluent:

from 0 to 10% EtOAc in pet. ether) to give the product as a

colourless oil (1.29 g, 86%) which showed: ¹H NMR (500 MHz,

CDCl₃): δ=3.02 (1H, dd, J=6.7, 13.7 Hz, CH₂CH), 3.41 (1H, dd, J=

8.8, 13.7 Hz, CH₂CH), 3.61 (3H, s, COOCH₃), 3.79 (3H, s, ArOCH₃), 3.83

(1H, dd, J=6.7, 8.8 Hz, CH₂CH), 6.81 (1H, dd, J=2.4, 8.2 Hz, ArCH,

methoxyphenyl), 6.84–6.88 (1H, m, ArCH, methoxyphenyl), 6.89 (1H,

d, J=7.7 Hz, ArCH, methoxyphenyl), 7.13 (2H, d, J=7.1 Hz, 2×ArCH,

phenyl) and 7.16–7.26 (4H, m, 3×ArCH, phenyl, ArCH, meth-

oxyphenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=39.7 (CH₂CH), 52.0

(COOCH₃), 53.6 (CH₂CH), 55.2 (ArOCH₃), 112.8 (ArCH, meth-

oxyphenyl), 113.6 (ArCH, methoxyphenyl), 120.3 (ArCH, meth-

oxyphenyl), 126.4 (ArCH, phenyl), 128.3 (2×ArCH, phenyl), 128.9

(2×ArCH, phenyl), 129.6 (ArCH, methoxyphenyl), 139.0 (ArCCH₂),

140.1 (ArCCH), 159.7 (ArCO) and 173.7 (COO) ppm. HRMS (ES⁺)

calcd. C₁₇H₁₉O₃[M⁺+H] 271.1334; found: 271.1320; calcd.

C₁₇H₁₈NaO₃[M⁺+H] 293.1154; found: 293.1149.

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N-(4-Chlorophenyl)-2-(3-methoxyphenyl)-3-methylbutanamide

(25c): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 20% EtOAc in pet. ether) to give the

product as a yellow oil (212 mg, 42%) which showed: ¹H NMR

(500 MHz, CDCl₃): δ=0.76 (3H, d, J=6.6 Hz, (CH₃)₂CH), 1.09 (3H, d,

J=6.5 Hz, (CH₃)₂CH), 2.40–2.56 (1H, m„ (CH₃)₂CH), 2.95 (1H, d, J=

10.0 Hz, (CH₃)₂CHCH), 3.80 (3H, s, OCH₃), 6.81 (1H, dd, J=1.9, 8.2 Hz,

ArCH, phenacetyl), 6.87–6.96 (2H, m, 2×ArCH, phenacetyl), 7.18 (1H,

bs, NH), 7.20–7.25 (3H, m, 2×ArCH, aniline, ArCH, phenacetyl) and

7.42 (2H, d, J=8.7 Hz m, 2×ArCH, aniline) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=20.3 ((CH₃)₂CH), 21.7 ((CH₃)₂CH), 31.5 ((CH₃)₂CH), 55.2

(OCH₃), 62.8 ((CH₃)₂CHCH), 112.7 (ArCH, phenacetyl), 113.9 (ArCH,

phenacetyl), 120.7 (ArCH, phenacetyl), 121.0 (2×ArCH, aniline),

128.9 (2×ArCH, aniline), 129.2 (ArCCl), 129.7 (ArCH, phenacetyl),

136.4 (ArCN), 140.2 (ArCCH), 159.8 (ArCO) and 171.4 (CON) ppm.

Methyl 2-(3-methoxyphenyl)-2-methylpropanoate (24e): The

crude compound was not purified and showed:^{[36] 1}H NMR

(500 MHz, CDCl₃): δ=1.57 (6H, s, C(CH₃)₂), 3.65 (3H, s, COOCH₃), 3.80

(3H, s, ArOCH₃), 6.78 (1H, dd, J=2.2, 7.9 Hz, ArCH), 6.88 (1H, t, J=

2.2 Hz, ArCH), 6.92 (1H, dd, J=2.2, 7.9 Hz, ArCH) and 7.25 (1H, t, J=

7.9 Hz, ArCH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=26.5 (C(CH₃)₂),

46.5 (C(CH₃)₂), 52.2 (COOCH₃), 55.2 (ArOCH₃), 111.4 (ArCH), 112.1

(ArCH), 118.0 (ArCH), 129.3 (ArCH), 146.3 (ArCC(CH₃)₂), 159.5 (ArCO)

and 177.1 (COO) ppm. HRMS (ES⁺) calcd. C₁₂H₁₆NaO₃[M⁺+H]

231.0997; found: 231.0990.

N-(4-Chlorophenyl)-2-(3-methoxyphenyl)-3-phenylpropanamide

(25d): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 40% EtOAc in pet. ether) to give the

product as a yellow oil (145 mg, 9%) which showed: ¹H NMR

(500 MHz, CDCl₃): δ=3.04 (1H, dd, J=7.4, 13.6 Hz, CHCH₂), 3.60 (1H,

dd, J=7.4, 13.6 Hz, CHCH₂), 3.69 (1H, t, J=7.4 Hz, CHCH₂), 3.78 (3H,

s, OCH₃), 6.82 (1H, dd, J=2.2, 8.2 Hz, ArCH, methoxyphenyl), 6.84–

6.88 (1H, m, ArCH, methoxyphenyl), 6.90 (1H, d, J=7.6 Hz, ArCH,

methoxyphenyl) 6.98 (1H, bs, NH), 7.13 (2H, d, J=7.3 Hz, 2×ArCH,

phenyl), 7.17 (1H, t, J=7.3 Hz, ArCH, phenyl), 7.21 (3H, d, J=8.8 Hz,

2×ArCH, aniline), 7.23 (2H, d, J=7.3 Hz, ArCH, phenyl), 7.26 (1H, d,

J=7.8 Hz, ArCH, methoxyphenyl) and 7.32 (2H, d, J=8.7 Hz, ArCH,

aniline) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=39.5 (CHCH₂), 55.3

(OCH₃), 56.5 (CHCH₂), 113.1 (ArCH, methoxyphenyl), 113.8 (ArCH,

methoxyphenyl), 120.4 (ArCH, methoxyphenyl), 121.1 (2×ArCH,

aniline), 126.4 (ArCH, phenyl), 128.4 (2×ArCH, aniline), 128.9 (2×

ArCH, phenyl), 129.0 (2×ArCH, aniline), 129.3 (ArCCl), 130.0 (ArCH,

methoxyphenyl), 136.2 (ArCN), 139.3 (ArCCH₂), 140.4 (ArCCH), 160.0

(ArCO) and 170.7 (CON) ppm. HRMS (ES⁺) calcd. C₂₂H₂₁³⁵ClNO₂[M⁺

+H] 366.1255; found: 366.1274; calcd. C₂₂H₂₁³⁷ClNO₂[M⁺+H]

368.1226; found: 368.1250.

General method for the direct conversion of ester into amide: 4-

Chloroaniline (1.10 g, 8.49 mmol) was added to a stirring solution of

bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane

adduct

(2.20 g, 8.49 mmol) in anhydrous THF (15 mL) under inert atmos-

°

phere and the mixture was stirred at 40 C for 1 h. A solution of 24a

(1.10 g, 5.66 mmol) in anhydrous THF (3 mL) was added and the

mixture was refluxed overnight. The mixture was then evaporated

and the residue was dissolved in EtOAc (50 mL). The organic layer

was then washed with 1 N HCl (3×50 mL) and brine (50 mL) then

dried with MgSO₄, filtered and evaporated to give a brown oil

(1.10 g).

N-(4-Chlorophenyl)-2-(3-methoxyphenyl)propanamide (25a): The

crude compound was purified by column chromatography (eluent:

from 0 to 40% EtOAc in pet. ether) to give the product as a yellow

oil (418 mg, 25%) which showed: ¹H NMR (500 MHz, CDCl₃): δ=

1.58 (3H, d, J=7.1 Hz, CHCH₃), 3.68 (1H, q, J=7.1 Hz, CHCH₃), 3.81

(3H, s, OCH₃), 6.85 (1H, dd, J=2.3, 7.9 Hz, ArCH, phenacetyl), 6.87–

6.90 (1H, m, ArCH, phenacetyl), 6.93 (1H, d, J=7.9 Hz, ArCH,

phenacetyl), 7.08 (1H, bs, NH), 7.22 (2H, d, J=8.8 Hz, ArCH, aniline),

7.30 (1H, t, J=7.9 Hz, ArCH, phenacetyl) and 7.36 (2H, d, J=8.8 Hz,

ArCH, aniline) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=18.3 (CHCH₃),

48.1 (CHCH₃), 55.3 (OCH₃), 112.9 (ArCH, phenacetyl), 113.5 (ArCH,

phenacetyl), 119.9 (ArCH, phenacetyl), 120.9 (2×ArCH, aniline),

128.9 (2×ArCH, aniline), 129.2 (ArCCl), 130.3 (ArCH, phenacetyl),

136.4 (ArCN), 142.2 (ArCCH), 160.2 (ArCO) and 172.1 (CON) ppm.

HRMS (ES⁺) calcd. C₁₆H₁₇³⁵ClNO₂[M⁺+H] 290.0942; found:

290.0954; calcd. C₁₆H₁₇³⁷ClNO₂[M⁺+H] 292.0913; found: 292.0961.

N-(4-Chlorophenyl)-2-(3-methoxyphenyl)-2-methylpropanamide

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(25e): The crude compound was not purified and showed: H NMR

(500 MHz, CDCl₃): δ=1.64 (6H, s, (CH₃)₂C), 3.82 (3H, s, OCH₃), 6.81

(1H, bs, NH), 6.86 (1H, dd, J=2.1, 7.9 Hz, ArCH, phenacetyl), 6.96

(1H, t, J=2.1 Hz, ArCH, phenacetyl), 7.01 (1H, dd, J=2.1, 7.9 Hz,

ArCH, phenacetyl), 7.21 (2H, d, J=8.8 Hz, 2×ArCH, aniline), 7.31

(2H, d, J=8.8 Hz, 2×ArCH, aniline) and 7.33 (2H, t, J=7.9 Hz, ArCH,

phenacetyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=26.9 ((CH₃)₂C), 48.1

((CH₃)₂C), 55.3 (OCH₃), 112.2 (ArCH, phenacetyl), 112.9 (ArCH,

phenacetyl), 118.8 (ArCH, phenacetyl), 120.9 (2×ArCH, aniline),

128.8 (2×ArCH, aniline), 129.1 (ArCCl), 130.1 (ArCH, phenacetyl),

136.5 (ArCN), 146.0 (ArC(CH₃)₂), 160.0 (ArCO) and 175.5 (CON) ppm.

ChemMedChem 2020, 15, 1–34

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HRMS (ES⁺) calcd. C₁₈H₂₁³⁵ClNO₂[M⁺+H] 334.1204; found:

334.1215; calcd. C₁₈H₂₁³⁷ClNO₂[M⁺+H] 336.1175; found: 336.1190.

J=8.7 Hz, 2×ArCH, aniline) and 7.20 (1H, t, J=8.0 Hz, ArCH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=27.2 ((CH₃)₂C), 38.8 ((CH₃)₂C),

55.2 (OCH₃), 57.9 (CH₂N), 111.0 (ArCH, phenyl), 112.9 (ArCH, phenyl),

116.3 (2×ArCH, aniline), 118.4 (ArCH, phenyl), 124.2 (ArCCl), 129.1

(2×ArCH, aniline), 129.6 (ArCH, phenyl), 147.4 (ArCN), 147.7 (ArCC

(CH₃)₂) and 159.8 (ArCO). HRMS (ES⁺) calcd. C₁₇H₂₁³⁵ClNO [M⁺+H]

290.1306; found: 290.1320.

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4-Chloro-N-(2-(3-methoxyphenyl)butyl)aniline (26b): Synthesised

according to the general method for the reduction of the amides

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13a–f. The crude compound was not purified and showed: H NMR

(500 MHz, CDCl₃): δ=0.83 (3H, t, J=7.4 Hz, CH₂CH₃), 1.56–1.67 (1H,

m, CH₂CH₃), 1.73–1.85 (1H, m, CH₂CH₃), 2.70–2.83 (1H, m, CHCH₂CH₃),

3.18 (1H, dd, J=9.1, 12.3 Hz, CH₂N), 3.41 (1H, dd, J=5.6, 12.4 Hz,

CH₂N), 3.80 (3H, s, OCH₃), 6.56 (2H, d, J=8.8 Hz, 2×ArCH, aniline),

6.69–6.72 (1H, m, ArCH, phenyl), 6.76 (1H, d, J=8.0 Hz, ArCH,

phenyl), 6.78 (1H, dd, J=2.4, 8.0 Hz, ArCH, phenyl), 7.10 (2H, d, J=

8.8 Hz, 2×ArCH, aniline) and 7.24 (1H, t, J=8.0 Hz, ArCH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=12.0 (CH₂CH₃), 27.0 (CH₂CH₃),

46.8 (CHCH₂CH₃), 50.4 (CH₂N), 55.2 (OCH₃), 111.7 (ArCH, phenyl),

113.9 (ArCH, phenyl), 115.2 (2×ArCH, aniline), 120.2 (ArCH, phenyl),

123.2 (ArCCl), 129.1 (2×ArCH, aniline), 129.7 (ArCH, phenyl), 144.1

(ArCCH), 145.2 (ArCN) and 159.9 (ArCO) ppm. HRMS (ES⁺) calcd.

C₁₇H₂₁³⁵ClNO₂[M⁺+H] 290.1306; found: 290.1322; calcd.

C₁₇H₂₁³⁷ClNO₂[M⁺+H] 292.1277; found: 292.1268.

2-(4-Chlorophenyl)-6-methoxy-4-methyl-1,2,3,4-tetrahydroisoqui-

noline (27a): Synthesised according to the general method for the

Pictet-Spengler cyclisation. The crude compound was purified by

column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a white solid (302 mg, 58%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=1.29 (3H, d, J=6.9 Hz,

CHCH₃), 2.96–3.06 (1H, m, H₄À THIQ), 3.19 (1H, dd, J=6.2, 12.0 Hz,

H₃À THIQ), 3.40 (1H, dd, J=4.3, 12.0 Hz, H₃À THIQ), 3.74 (3H, s, OCH₃),

4.18 (1H, d, J=14.7 Hz, H₁À THIQ), 4.27 (1H, d, J=14.7 Hz, H₁À THIQ),

6.69 (1H, dd, J=2.6, 8.3 Hz, H₇À THIQ), 6.72 (1H, d, J=2.6 Hz,

H₅À THIQ), 6.78 (2H, d, J=9.0 Hz, 2×ArCH, phenyl), 7.00 (1H, d, J=

8.3 Hz, H₈À THIQ) and 7.14 (2H, d, J=9.0 Hz, 2×ArCH, phenyl) ppm.

¹³C NMR (126 MHz, CDCl₃): δ=19.6 (CHCH₃), 33.5 (C₄À THIQ), 50.0

(C₁À THIQ), 53.4 (C₃À THIQ), 55.3 (OCH₃), 112.0 (C₅À THIQ), 112.3

(C₇À THIQ), 115.7 (2×ArCH, phenyl), 122.9 (ArCCl), 125.8

(C₁CC₈À THIQ), 127.4 (C₈À THIQ), 129.0 (2×ArCH, phenyl), 141.2

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4-Chloro-N-(2-(3-methoxyphenyl)-3-methylbutyl)aniline

(26c):

Synthesised according to the general method for the reduction of

the amides 13a–f. The crude compound was not purified and

showed: ¹H NMR (500 MHz, CDCl₃): δ=0.77 (3H, d, J=6.7 Hz, CH

(CH₃)₂), 1.05 (3H, d, J=6.6 Hz, CH(CH₃)₂), 1.84–1.99 (1H, m, CH(CH₃)₂),

2.55 (1H, ddd, J=4.4, 8.4, 10.5 Hz, CHCH₂), 3.16 (1H, dd, J=10.7,

11.8 Hz, CHCH₂), 3.37 (1H, bs, NH), 3.56 (1H, dd, J=4.2, 11.9 Hz,

CHCH₂), 3.79 (3H, s, OCH₃), 6.44 (2H, d, J=8.9 Hz, 2×ArCH, aniline),

6.68–6.70 (1H, m, ArCH, phenethyl), 6.72–6.76 (1H, m, ArCH,

phenethyl), 6.79 (1H, ddd, J=0.8, 2.6, 8.2 Hz, ArCH, phenethyl), 7.07

(2H, d, J=8.9 Hz, 2×ArCH, aniline) and 7.20–7.26 (1H, m, ArCH,

phenethyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=21.1(CH(CH₃)₂),

21.2(CH(CH₃)₂), 31.9 (CH(CH₃)₂), 47.0 (CHCH₂), 52.6 (CHCH₂), 55.3

(OCH₃), 111.8 (ArCH, phenethyl), 114.3 (2×ArCH, aniline), 114.7

(ArCH, phenethyl), 121.0 (ArCH, phenethyl), 121.9 (ArCCl), 129.1 (2×

ArCH, aniline), 129.6 (ArCH, phenethyl), 143.8 (ArCCH₂), 147.0 (ArCN)

and 159.9 (ArCO) ppm. HRMS (ES⁺) calcd. C₁₈H₂₃³⁵ClNO₂[M⁺+H]

304.1463; found: 304.1465; calcd. C₁₈H₂₃³⁷ClNO₂[M⁺+H] 306.1433;

found: 306.1465.

°

(C₄CC₅À THIQ), 149.3 (ArCN) and 158.4 (C₆À THIQ) ppm. Mp 72–75 C

(pet. ether).

2-(4-Chlorophenyl)-4-ethyl-6-methoxy-1,2,3,4-tetrahydroisoqui-

noline (27b): Synthesised according to the general method for the

Pictet-Spengler cyclisation. The crude compound was purified by

column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a yellow oil (384 mg, 74%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=0.97 (3H, t, J=7.4 Hz,

CH₂CH₃), 1.59–1.72 (2H, m, CH₂CH₃), 2.67–2.75 (1H, m, H₄À THIQ),

3.24 (1H, dd, J=3.8, 12.1 Hz, H₃À THIQ), 3.53 (1H, dd, J=4.1, 12.1 Hz,

H₃À THIQ), 3.74 (3H, s, OCH₃), 4.10 (1H, d, J=14.6 Hz, H₁À THIQ), 4.32

(1H, d, J=14.7 Hz, H₁À THIQ), 6.68 (1H, d, J=2.4 Hz, H₅À THIQ), 6.70

(1H, dd, J=2.6, 8.3 Hz, H₇À THIQ), 6.77 (2H, d, J=9.0 Hz, 2×ArCH,

phenyl), 7.00 (1H, d, J=8.3 Hz, H₈À THIQ) and 7.15 (2H, d, J=9.0 Hz,

2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=12.3 (CH₂CH₃),

27.2 (CH₂CH₃), 41.0 (C₄À THIQ), 49.5 (C₃À THIQ), 49.7(C₁À THIQ), 55.3

(OCH₃), 112.2 (C₇À THIQ), 113.1(C₅À THIQ), 115.2 (2×ArCH, phenyl),

122.6 (ArCCl), 125.7 (C₁CC₈À THIQ), 127.5(C₈À THIQ), 129.0 (2×ArCH,

phenyl), 140.3 (C₄CC₅À THIQ), 149.4 (ArCN) and 158.1 (C₆À THIQ)

ppm.

4-Chloro-N-(2-(3-methoxyphenyl)-3-phenylpropyl)aniline (26d):

Synthesised according to the general method for the reduction of

the amides 13a–f. The crude compound was not purified and

showed: ¹H NMR (500 MHz, CDCl₃): δ=2.97 (2H, d, J=7.3 Hz, ArCH₂,

phenyl), 3.13–3.20 (1H, m, CHCH₂), 3.23 (1H, dd, J=8.9, 12.2 Hz,

CH₂N), 3.41 (1H, dd, J=4.9, 12.2 Hz, CH₂N), 3.77 (3H, s, OCH₃), 6.43

(2H, d, J=8.8 Hz, 2×ArCH, aniline), 6.67–6.71 (1H, m, ArCH, meth-

oxyphenyl), 6.74–6.80 (2H, m, 2×ArCH, methoxyphenyl), 7.06 (2H,

d, J=8.8 Hz, 2×ArCH, aniline), 7.09 (2H, d, J=7.1 Hz, 2×ArCH,

phenyl) and 7.18–7.26 (4H, m, 3×ArCH, phenyl, ArCH, meth-

oxyphenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=40.8 (ArCH₂,

phenyl), 46.6 (CHCH₂), 49.3 (CH₂N), 55.2 (OCH₃), 112.0 (ArCH,

methoxyphenyl), 113.8 (ArCH, methoxyphenyl), 115.0 (2×ArCH,

aniline), 120.0 (ArCH, methoxyphenyl), 123.1 (ArCCl), 126.3 (ArCH,

phenyl), 127.7, 128.3 (2×ArCH, phenyl), 129.0 (2×ArCH, phenyl),

129.1 (2×ArCH, aniline), 129.7 (ArCH, methoxyphenyl), 139.5

(ArCCH₂), 143.8 (ArCCH), 145.3 (ArCN) and 159.8 (ArCO) ppm. HRMS

(ES⁺) calcd. C₂₂H₂₂³⁵ClNO [M^ÀÀ H] 350.1317; found: 350.1330; calcd.

C₂₂H₂₃³⁷ClNO [M^ÀÀ H] 352.1288; found: 352.1275.

2-(4-Chlorophenyl)-4-isopropyl-6-methoxy-1,2,3,4-tetrahydroiso-

quinoline (27c): Synthesised according to the general method for

the Pictet-Spengler cyclisation. The crude compound was purified

by column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a colourless oil (53 mg, 36%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=0.94 (3H, d, J=6.8 Hz,

(CH₃)₂CH), 0.98 (3H, d, J=6.8 Hz, (CH₃)₂CH), 1.93–2.04 (1H, m,

(CH₃)₂CH), 2.61 (1H, dt, J=3.6, 7.2 Hz, H₄À THIQ), 3.23 (1H, dd, J=3.6,

12.1 Hz, H₃À THIQ), 3.79 (1H, dd, J=3.6, 12.1 Hz, H₃À THIQ), 3.81 (3H,

s, OCH₃), 4.16 (1H, d, J=14.6 Hz, H₁À THIQ), 4.44 (1H, d, J=14.6 Hz,

H₁À THIQ), 6.73 (1H, d, J=2.6 Hz, H₅À THIQ), 6.79 (1H, dd, J=2.6,

8.4 Hz, H₇À THIQ), 6.81 (2H, d, J=9.1 Hz, 2×ArCH, phenyl), 7.08 (1H,

d, J=8.4 Hz, H₈À THIQ) and 7.22 (2H, d, J=9.0 Hz, 2×ArCH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=20.1 ((CH₃)₂CH), 21.5 ((CH₃)₂CH),

30.7 ((CH₃)₂CH), 46.2 (C₄À THIQ), 46.4 (C₃À THIQ), 49.4 (C₁À THIQ), 55.3

(OCH₃), 112.1 (C₇À THIQ), 114.0 (C₅À THIQ), 114.3 (2×ArCH, phenyl),

122.0 (ArCCl), 125.9 (C₁CC₈À THIQ), 127.6 (C₈À THIQ), 128.8, 129.0 (2×

ArCH, phenyl), 139.5 (C₄CC₅À THIQ), 148.7 (ArCN) and 157.8

(C₆À THIQ) ppm.

4-Chloro-N-(2-(3-methoxyphenyl)-2-methylpropyl)aniline (26e):

Synthesised according to the general method for the reduction of

the amides 13a–f. The crude compound was not purified and

showed: ¹H NMR (500 MHz, CDCl₃): δ=1.32 (6H, s, (CH₃)₂C), 3.15

(2H, s, CH₂N), 3.74 (3H, s, OCH₃), 6.40 (2H, d, J=8.7 Hz, 2×ArCH,

aniline), 6.71 (1H, dd, J=2.4, 8.0 Hz, ArCH, phenyl), 6.83–6.87 (1H,

m, ArCH, phenyl), 6.89 (1H, d, J=8.0 Hz, ArCH, phenyl), 6.99 (2H, d,

4-Benzyl-2-(4-chlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoqui-

noline (27d): Synthesised according to the general method for the

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Pictet-Spengler cyclisation. The crude compound was purified by

column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a white solid (327 mg, 63%) which

showed: ¹H NMR (500 MHz, CDCl₃): δ=2.86 (1H, dd, J=10.1,

13.7 Hz, ArCH₂CH), 2.97 (1H, dd, J=5.3, 13.7 Hz, ArCH₂CH), 3.03 (1H,

dd, J=3.4, 12.2 Hz, H₃À THIQ), 3.06–3.12 (1H, m, H₄À THIQ), 3.48 (1H,

dd, J=3.0, 12.2 Hz, H₃À THIQ), 3.68 (3H, s, OCH₃), 4.07 (1H, d, J=

14.8 Hz, H₁À THIQ), 4.44 (1H, d, J=14.7 Hz, H₁À THIQ), 6.57 (1H, d, J=

2.5 Hz, H₅À THIQ), 6.70 (2H, d, J=9.0 Hz, 2×ArCH, N-phenyl), 6.73

(1H, dd, J=2.6, 8.5 Hz, H₇À THIQ), 7.03 (1H, d, J=8.4 Hz, H₈À THIQ),

7.08–7.15 (4H, m, 2×ArCH, N-phenyl, 2×ArCH, C₄-phenyl), 7.17–7.19

(1H, m, ArCH, C₄-phenyl) and 7.25 (2H, t, J=7.3 Hz, 2×ArCH, C₄-

phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=41.3 (ArCH₂CH), 41.6

(C₄À THIQ), 48.5 (C₃À THIQ), 49.9 (C₁À THIQ), 55.3 (OCH₃), 112.9

(C₇À THIQ), 113.0 (C₅À THIQ), 115.4 (2×ArCH, N-phenyl), 122.9

(ArCCl), 125.5 (C₁CC₈À THIQ), 126.4 (ArCH, C₄-phenyl), 127.6

(C₈À THIQ), 128.5 (2×ArCH, C₄-phenyl), 128.9 (2×ArCH), 129.4 (2×

ArCH), 139.4 (C₄CC₅À THIQ), 140.1 (ArCCH₂, C₄-phenyl), 149.3 (ArCN)

phenethyl), 6.74 (2H, d, J=8.3 Hz, 2×ArCH, phenethyl), 6.98 (2H, d,

J=8.5 Hz, 2×ArCH, aniline), 7.17 (1H, t, J=7.8 Hz, ArCH, phenethyl)

and 7.36 (2H, d, J=8.5 Hz, 2×ArCH, aniline) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=22.9 (NCOCH₃), 34.0 (ArCH₂CH₂), 50.6

(CH₂CH₂N), 55.2 (ArOCH₃), 112.0 (ArCH, phenethyl), 114.3 (ArCH,

phenethyl), 121.2 (ArCH, phenethyl), 129.4 (ArCH, aniline), 129.4

(ArCH, phenethyl), 129.9 (ArCH, aniline), 133.7 (ArCCl), 140.2

(ArCCH₂), 141.8 (ArCN), 159.7 (ArCO) and 170.1 (NCO) ppm. HRMS

(ES⁺) calcd. C₁₇H₁₈³⁵ClNNaO₂[M⁺+Na] 326.0918; found: 326.0924;

calcd. C₁₇H₁₈³⁷ClNNaO₂[M⁺+Na] 328.0889; found: 328.0890.

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N-(4-Chlorophenyl)-N-(3-methoxyphenethyl)propionamide (29b):

Propanoyl chloride (90 μL, 1.01 mmol) was added to a stirring

solution of 14d (150 mg, 0.503 mmol) and pyridine (123 μL,

1.51 mmol) in CH₂Cl₂(2 mL) and the mixture was stirred at RT for

10 h. A white precipitate formed after the first 10 min. The mixture

was then diluted with CH₂Cl₂(10 mL) washed with a sat. aq.

solution of NaHCO₃(2×10 mL) and 1 N HCl (2×10 mL) and the

organic layer was dried with MgSO₄, filtered and evaporated to give

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and 158.1 (C₆À THIQ) ppm. Mp 84–87 C (pet. ether).

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the product as a pale yellow oil (114 mg, 71%) which showed: H

2-(4-Chlorophenyl)-6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydroi-

soquinoline (27e): Synthesised according to the general method

for the Pictet-Spengler cyclisation. The crude compound was

purified by column chromatography (eluent: from 0 to 20% EtOAc

in pet. ether) to give the product as a white solid (94 mg, 23%)

NMR (500 MHz, CDCl₃): δ=1.05 (3H, t, J=7.4 Hz, CH₂CH₃), 2.02 (2H,

q, J=7.4 Hz, CH₂CH₃), 2.78–2.91 (2H, m, CH₂CH₂N), 3.77 (3H, s,

OCH₃), 3.82–3.96 (2H, m, CH₂CH₂N), 6.69–6.72 (1H, m, ArCH, benzyl),

6.72–6.79 (2H, m, 2×ArCH, benzyl), 6.97 (2H, d, J=8.4 Hz, 2×ArCH,

aniline), 7.17 (1H, t, J=7.9 Hz, ArCH, benzyl) and 7.36 (2H, d, J=

8.6 Hz, ArCH, aniline) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=9.5

(CH₂CH₃), 27.9 (CH₂CH₃), 34.1 (CH₂CH₂N), 50.9 (CH₂CH₂N), 55.2

(OCH₃), 112.0 (ArCH, phenethyl), 114.3 (ArCH, phenethyl), 121.2

(ArCH, phenethyl), 129.4 (ArCH, phenethyl), 129.6 (ArCH, aniline),

129.9 (ArCH, aniline), 133.7 (ArCCl), 140.2 (ArCCH₂), 141.5 (ArCN),

159.7 (ArCO) and 173.5 (NCO) ppm. HRMS (ES⁺) calcd. C₁₈H₂₁³⁵ClNO₂

[M⁺+H] 318.1255; found: 318.1255; calcd. C₁₈H₂₁³⁷ClNO₂[M⁺+H]

320.1226; found: 320.1237.

1

which showed: H NMR (500 MHz, CDCl₃): δ=1.28 (6H, s, (CH₃)₂C),

3.14 (2H, s, H₃À THIQ), 3.74 (3H, s, OCH₃), 4.22 (2H, s, H₁À THIQ), 6.68

(1H, dd, J=2.6, 8.4 Hz, H₇À THIQ), 6.79 (2H, d, J=9.0 Hz, 2×ArCH,

phenyl), 6.83 (1H, d, J=2.6 Hz, H₅À THIQ), 6.98 (1H, d, J=8.4 Hz,

H₈À THIQ) and 7.15 (2H, d, J=9.0 Hz, 2×ArCH, phenyl) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=28.1 ((CH₃)₂C), 35.8 (C₄À THIQ), 50.5

(C₁À THIQ), 55.3 (OCH₃), 59.9 (C₃À THIQ), 110.9 (C₅À THIQ), 111.6

(C₇À THIQ), 115.7 (2×ArCH, phenyl), 123.0 (ArCCl), 125.1

(C₁CC₈À THIQ), 127.4 (C₈À THIQ), 129.0 (2×ArCH, phenyl), 145.0

N-(4-Chlorophenyl)-N-(3-methoxyphenethyl)isobutyramide (29c):

Isobutyryl chloride (108 μL, 1.01 mmol) was added to a stirring

solution of 14d (150 mg, 0.503 mmol) and pyridine (123 μL,

1.51 mmol) in CH₂Cl₂(2 mL) and the mixture was stirred at RT for

10 h. A white precipitate formed after the first 10 min. The mixture

was then diluted with CH₂Cl₂(10 mL) washed with a sat. aq.

solution of NaHCO₃(2×10 mL) and 1 N HCl (2×10 mL) and the

organic layer was dried with MgSO₄, filtered and evaporated to give

the product as a pale yellow solid (113 mg, 68%) which showed: ¹H

NMR (500 MHz, CDCl₃): δ=1.01 (6H, d, J=6.7 Hz, (CH₃)₂CH), 2.38

(1H, septet, J=6.7 Hz, (CH₃)₂CH), 2.85 (2H, t, J=7.8 Hz, CH₂CH₂N),

3.77 (3H, s, OCH₃), 3.86 (2H, t, J=7.8 Hz, CH₂CH₂N), 6.71 (1H, s, ArCH,

phenethyl), 6.74 (2H, d, J=8.0 Hz, 2×ArCH, phenethyl), 6.95 (2H, d,

J=8.4 Hz, 2×ArCH, aniline), 7.17 (1H, t, J=7.8 Hz, ArCH, phenethyl)

and 7.35 (2H, d, J=8.6 Hz, 2×ArCH, aniline) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=19.6 ((CH₃)₂CH), 31.3 ((CH₃)₂CH), 34.0

(CH₂CH₂N), 51.0 (CH₂CH₂N), 55.2 (CH₃O), 112.1 (ArCH, phenethyl),

114.3 (ArCH, phenethyl), 121.2 (ArCH, phenethyl), 129.4 (ArCH,

phenethyl), 129.5 (2×ArCH, aniline), 129.8 (2×ArCH, aniline), 133.7

(ArCCl), 140.3 (ArCCH₂), 141.6 (ArCN), 159.7 (ArCO) and 177.0 (NCO)

ppm. HRMS (ES⁺) calcd. C₁₉H₂₃³⁵ClNO₂[M⁺+H] 332.1412; found:

332.1399; calcd. C₁₉H₂₃³⁷ClNO₂[M⁺+H] 334.1382; found: 334.1394.

°

(C₄CC₅À THIQ), 149.5 (ArCN) and 158.4 (C₆À THIQ). Mp 90–93 C (pet.

ether) ppm.

4-Benzyl-2-(4-chlorophenyl)-8-methoxy-1,2,3,4-tetrahydroisoqui-

noline (28d): Synthesised according to the general method for the

Pictet-Spengler cyclisation. The crude compound was purified by

column chromatography (eluent: from 0 to 20% EtOAc in pet.

ether) to give the product as a colourless oil (19 mg, 4%) which

1

showed: H NMR (500 MHz, CDCl₃): δ=2.81–2.88 (1H, m, ArCH₂CH),

2.93–2.99 (2H, m, ArCH₂CH, H₃À THIQ), 3.08–3.16 (1H, m, H₄À THIQ),

3.49 (1H, dd, J=2.6, 12.3 Hz, H₃À THIQ), 3.81 (3H, s, OCH₃), 3.97 (1H,

d, J=16.4 Hz, H₁À THIQ), 4.44 (1H, d, J=16.4 Hz, H₁À THIQ), 6.69 (1H,

d, J=8.1 Hz, H₅or H₇À THIQ), 6.76 (3H, d, J=8.9 Hz, 2×ArCH, N-

phenyl, H₅or H₇À THIQ), 7.10–7.16 (5H, m, 2×ArCH, N-phenyl, 2×

ArCH, C₄-phenyl, H₆À THIQ), 7.18 (1H, t, J=7.2 Hz, ArCH, C₄-phenyl)

and 7.25 (2H, t, J=7.3 Hz, 2×ArCH, C₄-phenyl) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=41.4 (C₃À THIQ), 41.5 (ArCH₂CH), 46.0

(C₁À THIQ), 47.7 (C₄À THIQ), 55.3 (OCH₃), 107.4 (C₇or C₅À THIQ), 115.5

(2×ArCH, N-phenyl), 120.4 (C₇or C₅À THIQ), 122.3 (C₁CC₈À THIQ),

122.8 (ArCCl), 126.3 (ArCH), 126.9 (ArCH, C₄-phenyl), 128.5 (2×

ArCH), 128.9 (2×ArCH), 129.4 (2×ArCH), 139.7 (C₄CC₅À THIQ), 140.3

(ArCCH₂, C₄-phenyl), 149.5 (ArCN) and 156.0 (C₈À THIQ) ppm.

N-(4-Chlorophenyl)-N-(3-methoxyphenethyl)acetamide

(29a):

N-(4-Chlorophenyl)-N-(3-methoxyphenethyl)pivalamide

(29d):

Compound 14d (150 mg, 0.503 mmol) was dissolved in a mixture

of EtOAc (2 mL) and Pyridine (123 μL, 1.51 mmol) and acetylchloride

(13.3 μL, 1.01 mmol) was added dropwise. The mixture was stirred

for 1 h at RT during which time a white precipitate formed. The

mixture was filtered and the filtrate was diluted with EtOAc (5 ml)

washed with 1 N HCl (5 mL) and 1 N NaOH (5 mL). The organic layer

was then dried with MgSO₄, filtered and evaporated to give a white

Pivaloyl chloride (126 μL, 1.01 mmol) was added to a stirring

solution of 14d (150 mg, 0.503 mmol) and pyridine (123 μL,

1.51 mmol) in CH₂Cl₂(2 mL) and the mixture was stirred at RT for

10 h. A white precipitate formed after the first 10 min. The mixture

was then diluted with CH₂Cl₂(10 mL) washed with a sat. aq.

solution of NaHCO₃(2×10 mL) and 1 N HCl (2×10 mL) and the

organic layer was dried with MgSO₄, filtered and evaporated to give

the product as a yellow solid (122 mg, 70%) which showed: ¹H NMR

(500 MHz, CDCl₃): δ=1.03 (9H, s, C(CH₃)₃), 2.79–2.92 (1H, m,

CH₂CH₂N), 3.68–3.83 (2H, m, CH₂CH₂N), 3.77 (3H, s, CH₃O), 6.69–6.72

1

solid (132 mg, 86%) which showed: H NMR (500 MHz, CDCl3): δ=

1.83 (3H, s, COCH₃), 2.83 (2H, t, J=7.8 Hz, ArCH₂CH₂), 3.77 (3H, s,

ArOCH₃), 3.90 (2H, t, J=7.8 Hz, CH₂CH₂N), 6.70 (1H, s, ArCH,

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(1H, m, ArCH, phenethyl), 6.74 (1H, dd, J=2.0, 8.0 Hz, 2×ArCH,

phenethyl), 6.99 (2H, d, J=8.6 Hz, ArCH, aniline), 7.17 (1H, t, J=

7.9 Hz, ArCH, aniline) and 7.33 (2H, d, J=8.6 Hz, ArCH, aniline) ppm.

¹³C NMR (126 MHz, CDCl₃): δ=29.5 (C(CH₃)₃), 33.7 (CH₂CH₂N), 41.0 (C

(CH₃)₃), 55.0 (CH₂CH₂N), 55.2 (OCH₃), 112.0 (ArCH, phenethyl), 114.4

(ArCH, phenethyl), 121.3 (ArCH, phenethyl), 129.3 (2×ArCH, aniline),

129.4 (ArCH, phenethyl), 130.9 (2×ArCH, aniline), 133.7 (ArCCl),

140.5 (ArCCH₂), 142.5 (ArCN), 159.7 (ArCO) and 177.6 (NCO) ppm.

HRMS (ES⁺) calcd. C₂₀H₂₅³⁵ClNO₂[M⁺+H] 346.1568; found:

346.1566; calcd. C₂₀H₂₅³⁷ClNO₂[M⁺+H] 348.1539; found: 348.1537.

to 30% EtOAc in pet. ether) to give the product as a pale yellow

solid (301 mg, 76%) which showed: H NMR (500 MHz, CDCl₃): δ=

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2.31 (1H, t, J=6.5 Hz, CH₂CH₂CO), 2.81 (1H, t, J=7.8 Hz, CH₂CH₂N),

2.91 (1H, t, J=6.5 Hz, CH₂CH₂CO), 3.77 (1H, s, ArOCH₃), 3.87 (1H, t,

J=7.6 Hz, CH₂CH₂N), 6.66–6.79 (2H, m), 7.04–7.10 (1H, m), 7.14–7.21

(1H, m), 7.21–7.25 (1H, m) and 7.26–7.33 (1H, m) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=31.7 (CH₂CH₂CO), 34.0 (CH₂CH₂N), 36.3

(CH₂CH₂CO), 51.0 (CH₂CH₂N), 55.2 (ArOCH₃), 112.0 (2×ArCH), 114.3

(ArCH), 121.2 (ArCH), 126.1 (ArCH), 128.4 (2×ArCH), 128.5 (2×ArCH),

129.4 (ArCH), 129.6 (ArCH), 129.8 (2×ArCH), 133.7 (ArCCl), 140.1

(ArCCH₂CH₂N), 141.0 (ArCCH₂CH₂CO), 141.1 (ArCN), 159.7 (ArCO) and

171.8 (CON) ppm. HRMS (ES⁺) calcd. C₂₄H₂₅³⁵ClNO₂[M⁺+H]

394.1568; found: 394.1571; calcd. C₂₄H₂₅³⁷ClNO₂[M⁺+H] 396.1539;

found: 396.1549.

N-(4-Chlorophenyl)-N-(3-methoxyphenethyl)benzamide

(29e):

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Benzoyl chloride (118 μL, 1.01 mmol) was added to a stirring

solution of 14d (150 mg, 0.503 mmol) and pyridine (123 μL,

1.51 mmol) in CH₂Cl₂(2 mL) and the mixture was stirred at RT for

10 h. A white precipitate was formed after the first 10 min. The

mixture was then diluted with CH₂Cl₂(10 mL) washed with a sat. aq.

solution of NaHCO₃(2×10 mL) and 1 N HCl (2×10 mL) and the

organic layer was dried with MgSO₄, filtered and evaporated to give

a yellow oil (263 mg). The crude compound was purified by column

chromatography (from 0 to 30% EtOAc in pet. ether) to give the

N-(3-Methoxyphenethyl)-N-phenyl-2-phenylacetamide (29h): Phe-

nacetyl chloride (154 μL, 1.14 mmol) was added to a stirring

solution of 14e (300 mg, 1.14 mmol) and Et₃N (398 μL, 2.85 mmol)

in CH₂Cl₂(3 mL), and the mixture was stirred at RT overnight. The

mixture was then diluted with CH₂Cl₂(10 mL) and washed with 1 N

HCl (3×10 mL), 1 N NaOH (3×10 mL) and brine (3×10 mL) then

dried with MgSO₄, filtered and evaporated to give a yellow oil

(336 mg) which partly solidify upon standing. The crude compound

was purified by column chromatography (eluent: from 0 to 30%

EtOAc in pet. ether) to give the product as a pale yellow-brown oil

(289 mg, 73%) which showed:^{[37] 1}H NMR (500 MHz, CDCl₃): δ=2.87

(2H, t, J=6.7 Hz, CH₂CH₂N), 3.42 (2H, s, CH₂CO), 3.75 (3H, s, ArOCH₃),

3.93 (2H, t, J=6.7 Hz, CH₂CH₂N), 6.69–6.79 (3H, m, 3×ArCH), 6.97–

7.09 (3H, m, 3×ArCH), 7.11–7.25 (5H, m, 5×ArCH) and 7.33–7.42

(3H, m, 3×ArCH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=34.0

(CH₂CH₂N), 41.4 (CH₂CO), 51.2 (CH₂CH₂N), 55.2 (ArOCH₃), 112.0

(ArCH), 114.2 (ArCH), 121.2 (ArCH), 126.5 (ArCH), 128.0 (ArCH), 128.3

(2×ArCH), 128.6 (2×ArCH), 129.1 (2×ArCH), 129.4 (ArCH), 129.6 (2×

ArCH), 135.4 (ArCCH₂CO), 140.3 (ArCCH₂CH₂), 142.6 (ArCN), 159.7

(ArCO) and 170.8 (CON) ppm. HRMS (ES⁺) calcd. C₂₃H₂₄NO₂[M⁺+H]

346.1835; found: 346.1832; C₂₃H₂₃NNaO₂[M⁺+Na] 368.1621; found:

368.1639.

1

product as a pale yellow oil (89 mg, 48%) which showed: H NMR

(500 MHz, CDCl₃): δ=2.98 (2H, t, J=6.8 Hz, CH₂CH₂N), 3.77 (3H, s,

OCH₃), 4.10 (2H, t, J=6.8 Hz, CH₂CH₂N), 6.70–6.85 (5H, m), 7.14 (2H,

d, J=8.6 Hz), 7.20 (3H, td, J=7.0, 14.4 Hz) and 7.25–7.31 (3H, m)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=33.8 (CH₂CH₂N), 52.4 (CH₂CH₂N),

55.1 (OCH₃), 112.1, 114.4, 121.3, 127.9, 128.6, 128.7, 129.2, 129.5,

129.8, 132.1 (ArCCl), 135.7 (ArCCO), 140.3 (ArCCH₂), 142.3 (ArCN),

159.7 (ArCO) and 170.3 (NCO) ppm. HRMS (ES⁺) calcd. C₂₂H₂₁³⁵ClNO₂

[M⁺+H] 366.1255; found: 366.1257; calcd. C₂₂H₂₁³⁷ClNO₂[M⁺+H]

368.1226; found: 368.1250.

N-(4-Chlorophenyl)-N-(3-methoxyphenethyl)-2-phenylacetamide

(29f): Phenacetyl chloride (136 μL, 1.01 mmol) was added to a

stirring solution of 14d (150 mg, 0.503 mmol) and pyridine (123 μL,

1.51 mmol) in CH₂Cl₂(2 mL) and the mixture was stirred at RT for

10 h. A white precipitate was formed after the first 10 min. The

mixture was then diluted with CH₂Cl₂(10 mL) washed with a sat. aq.

solution of NaHCO₃(2×10 mL) and 1 N HCl (2×10 mL) and the

organic layer was dried with MgSO₄, filtered and evaporated to give

a yellow oil (140 mg). The crude compound was purified by column

chromatography (from 0 to 30% EtOAc in pet. ether) to give the

N-(3-Methoxyphenethyl)-N-(4-methoxyphenyl)-2-phenylaceta-

mide (29i): Phenacetyl chloride (138 μL, 1.02 mmol) was added to a

stirring solution of 14f (300 mg, 1.02 mmol) and Et₃N (356 μL,

2.55 mmol) in CH₂Cl₂(3 mL) and the mixture was stirred at RT

overnight. The mixture was then diluted with CH₂Cl₂(10 mL) and

washed with 1 N HCl (3×10 mL), 1 N NaOH (3×10 mL) and brine

(3×10 mL) then dried with MgSO₄, filtered and evaporated to give

a yellow oil (379 mg) which partly solidify upon standing. The crude

compound was purified by column chromatography (eluent: from 0

to 30% EtOAc in pet. ether) to give the product as a pale yellow oil

(320 mg, 87%) which showed:^{[23] 1}H NMR (500 MHz, CDCl₃): δ=2.85

(2H, t, J=7.9 Hz, CH₂CH₂N), 3.42 (2H, s, CH₂CO), 3.75 (3H, s, ArOCH₃,

phenethyl), 3.84 (3H, s, ArOCH₃, aniline), 3.89 (2H, t, J=7.9 Hz,

CH₂CH₂N), 6.68–6.79 (3H, m, 3×ArCH, phenethyl), 6.88 (2H, d, J=

17.4 Hz, 2×ArCH, aniline), 6.90 (2H, d, J=17.4 Hz, 2×ArCH, aniline),

7.04 (2H, d, J=7.2 Hz, 2×ArCH, phenacetyl), 7.15 (1H, t, J=7.8 Hz,

ArCH, phenethyl), 7.21 (1H, t, J=6.9 Hz, ArCH, phenacetyl) and 7.23

(2H, t, J=6.9 Hz, 2×ArCH, phenacetyl) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=33.9 (CH₂CH₂N), 41.1 (CH₂CO), 51.1 (CH₂CH₂N), 55.1

(ArOCH₃, phenethyl), 55.5 (ArOCH₃, aniline), 112.0 (ArCH, phenethyl),

114.2 (ArCH, phenethyl), 114.6 (2×ArCH, aniline), 121.2 (ArCH,

phenethyl), 126.5 (ArCH, phenacetyl), 128.3 (2×ArCH, phenacetyl),

129.0 (2×ArCH, phenacetyl), 129.3 (ArCH, phenethyl), 129.5 (2×

ArCH, aniline), 135.3 (ArCN), 135.5 (ArCCH₂CO), 140.3 (ArCCH₂CH₂),

159.0 (ArCO, aniline), 159.6 (ArCO, phenethyl) and 171.2 (CON)

ppm. HRMS (ES⁺) calcd. C₂₄H₂₆NO₃[M⁺+H] 376.1907; found:

376.1918.

1

product as a pale yellow oil (34 mg, 18%) which showed: H NMR

(500 MHz, CDCl₃): δ=2.84 (2H, t, J=7.7 Hz, CH₂CH₂N), 3.41 (2H, s,

ArCH₂CO), 3.75 (3H, s, OCH₃), 3.90 (2H, t, J=7.7 Hz, CH₂CH₂N), 6.65–

6.80 (3H, m, 3×ArCH, phenethyl), 6.88 (2H, d, J=8.5 Hz, 2×ArCH,

aniline), 7.02 (2H, d, J=7.0 Hz, 2×ArCH, phenacetyl), 7.15 (1H, t, J=

7.8 Hz, ArCH, phenethyl), 7.18–7.27 (3H, m, 3×ArCH, phenacetyl)

and 7.32 (2H, d, J=8.5 Hz, 2×ArCH, aniline) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=33.9 (CH₂CH₂N), 41.3 (ArCH₂CO), 51.1

(CH₂CH₂N), 55.1 (OCH₃), 112.0 (ArCH, phenethyl), 114.2 (ArCH,

phenethyl), 121.2 (ArCH, phenethyl), 126.6 (ArCH, phenacetyl), 128.4

(2×ArCH, phenacetyl), 128.9 (2×ArCH, phenacetyl), 129.4 (ArCH,

phenethyl), 129.7 (2×ArCH, aniline), 129.8 (2×ArCH, aniline), 133.8

(ArCCl), 135.0 (ArCCH₂CO), 140.0 (ArCCH₂CH₂), 141.1 (ArCN), 159.7

(ArCO) and 170.6 (NCO) ppm. HRMS (ES⁺) calcd. C₂₃H₂₃³⁵ClNO₂[M⁺

+H] 380.1412; found: 380.1408; calcd. C₂₃H₂₃³⁷ClNO₂[M⁺+H]

382.1382; found: 382.1383.

N-(4-Chlorophenyl)-N-(3-methoxyphenethyl)-3-phenylpropana-

mide (29g): 3-Phenylpropanoyl chloride (153 μL, 1.01 mmol) was

added to a stirring solution of 14d (300 mg, 1.01 mmol) and Et₃N

(353 μL, 2.53 mmol) in CH₂Cl₂(3 mL), and the mixture was stirred at

RT overnight. The mixture was then diluted with CH₂Cl₂(10 mL) and

washed with 1 N HCl (3×10 mL), 1 N NaOH (3×10 mL) and brine

(3×10 mL) then dried with MgSO₄, filtered and evaporated to give

a yellow oil (364 mg) which partly solidify upon standing. The crude

compound was purified by column chromatography (eluent: from 0

General method for the Bischler-Napieralski cyclisation: POCl₃

(836 μL, 8.88 mmol) was added to a stirring solution of 29a

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(450 mg, 1.48 mmol) in anhydrous toluene (15 mL) and the mixture

2-(4-Chlorophenyl)-6-methoxy-1-phenyl-1,2,3,4-tetrahydroisoqui-

noline (30e) : The crude compound was purified by column

chromatography (eluent: 100% pet. ether) to give a colourless oil

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was stirred at 100 C overnight. The mixture was then cooled to RT

and the solvent was evaporated. The residue was dissolved in

MeOH (15 mL) and NaBH₄(343 mg, 8.88 mmol) was added. The

yellow solution started foaming and turned colourless. The mixture

was stirred at RT for 1 h then the solvent was evaporated and the

residue was dissolved in EtOAc (50 mL). The organic layer was

washed with 1 N NaOH (2×50 mL) then dried with MgSO₄, filtered

and evaporated to give a yellow oil (979 mg).

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(342 mg, 68%) which showed: H NMR (400 MHz, CDCl₃): δ=2.80–

2.97 (2H, m, H₄À THIQ), 3.45 (1H, ddd, J=5.7, 8.0, 11.4 Hz, H₃À THIQ),

3.66 (1H, dt, J=5.5, 11.2 Hz, H₃À THIQ), 3.79 (3H, s, OCH₃), 5.71 (1H,

s, H₁À THIQ), 6.71 (1H, d, J=2.6 Hz, H₅À THIQ), 6.74 (2H, d, J=9.1 Hz,

2×ArCH, N-phenyl), 6.77 (2H, dd, J=2.5, 8.3 Hz, H₇À THIQ), 7.14 (2H,

d, J=9.1 Hz, 2×ArCH, N-phenyl) and 7.16–7.25 (6H, m, H₈À THIQ, 5×

ArCH, C₁-phenyl) ppm. ¹³C NMR (101 MHz, CDCl₃): δ=28.2

(C₄À THIQ), 43.8 (C₃À THIQ), 55.2 (OCH₃), 62.3 (C₁À THIQ), 111.9

(C₇À THIQ), 113.2 (C₅À THIQ), 115.1 (2×ArCH, N-phenyl), 122.2

(ArCCl), 126.8 (ArCH), 127.1 (2×ArCH, C₁-phenyl), 128.2 (2×ArCH,

C₁-phenyl), 128.7 (ArCH), 128.9 (2×ArCH, N-phenyl), 129.9

(C₁CC₈À THIQ), 136.7 (C₄CC₅À THIQ), 143.0 (ArCC₁, C₁-phenyl), 148.1

2-(4-Chlorophenyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoqui-

noline (30a) : The crude compound was purified by column

chromatography (eluent: 100% pet. ether) to give white solid

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(292 mg, 69%) which showed: H NMR (500 MHz, CDCl₃): δ=1.39

(3H, d, J=6.6 Hz, CHCH₃), 2.77–2.93 (1H, m, H₄À THIQ), 2.93–3.06

(1H, m, H₄À THIQ), 3.41–3.50 (1H, m, H₃À THIQ), 3.50–3.62 (1H, m,

H₃À THIQ), 3.79 (3H, s, OCH₃), 4.81 (1H, q, J=6.6 Hz, CHCH₃), 6.68

(1H, d, J=2.6 Hz, H₅À THIQ), 6.76 (1H, dd, J=2.6, 8.4 Hz, H₇À THIQ),

6.84 (2H, bs, 2×ArCH, phenyl), 7.04 (1H, d, J=8.4 Hz, H₈À THIQ) and

7.19 (2H, d, J=8.9 Hz, 2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=20.8 (C₁CH₃), 28.6 (C₄À THIQ), 41.2 (C₃À THIQ), 54.0

(C₁À THIQ), 55.3 (OCH₃), 112.4 (C₇À THIQ), 113.2 (C₅À THIQ), 115.8 (2×

ArCH, phenyl), 122.2 (ArCCl), 127.7 (C₈À THIQ), 129.0 (2×ArCH,

phenyl), 131.9 (C₈CC₁), 135.4 (C₅CC₄), 147.9 (ArCN) and 158.0

(C₆À THIQ) ppm. HRMS (ES⁺) calcd. C₁₇H₁₉³⁵ClNO [M⁺+H] 288.1150;

found: 288.1157; calcd. C₁₇H₁₉³⁷ClNO [M⁺+H] 290.1120; found:

°

(ArCN) and 158.6 (C₆À THIQ) ppm. Mp 188–191 C (pet. ether).

1-Benzyl-2-(4-chlorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoqui-

noline (30f): The crude compound was purified by column

chromatography (eluent: 100% pet. ether) to give a yellow oil

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(437 mg, 78%) which showed: H NMR (500 MHz, CDCl3): δ=2.92–

3.05 (1H, m), 3.05–3.19 (1H, m), 3.29–3.43 (1H, m), 3.67–3.78 (1H, m),

3.80 (3H, s), 3.83–3.92 (1H, m), 3.92–4.03 (1H, m), 4.86–4.96 (1H, m),

6.57 (1H, d, J=7.8 Hz), 6.66 (1H, dd, J=2.6, 8.6 Hz), 6.74 (1H, d, J=

2.5 Hz), 7.03–7.12 (2H, m), 7.19–7.25 (3H, m), 7.32–7.40 (2H, m) and

7.61 (2H, d, J=8.4 Hz) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=25.2,

40.1, 51.4, 55.3, 66.2, 107.0, 113.2, 113.5, 123.5, 123.9, 127.1, 128.4,

128.7, 129.6, 130.1, 134.8, 136.0, 140.4, 142.2 and 159.5 ppm. Mp

°

290.1142. Mp 186–189 C (as a hydrochloride from Et₂O).

2-(4-Chlorophenyl)-1-ethyl-6-methoxy-1,2,3,4-tetrahydroisoqui-

noline (30b): The crude compound was purified by column

chromatography (eluent: 100% pet. ether) to give the product as a

colourless oil (335 mg, 71%) which showed: ¹H NMR (500 MHz,

CDCl₃): δ=0.99 (3H, t, J=7.4 Hz, CH₃CH₂), 1.71 (1H, ddq, J=7.0, 7.4,

14.2 Hz, CH₃CH₂), 1.94 (1H, ddq, J=7.0, 7.4, 14.2 Hz, CH₃CH₂), 2.86

(1H, dd, J=5.7, 15.8 Hz, H₄À THIQ), 2.97 (1H, ddd, J=5.3, 7.8,

15.8 Hz, H₄À THIQ), 3.43–3.55 (1H, m, H₃À THIQ), 3.58 (1H, ddd, J=

5.0, 7.8, 12.6 Hz, H₄À THIQ), 3.80 (3H, s, OCH₃), 4.45 (1H, t, J=7.0 Hz,

H₁À THIQ), 6.71 (1H, d, J=2.6 Hz, H₅À THIQ), 6.75 (1H, dd, J=2.6,

8.4 Hz, H₇À THIQ), 6.78 (2H, d, J=9.1 Hz, 2×ARCH, phenyl), 7.04 (1H,

d, J=8.4 Hz, H₈À THIQ) and 7.18 (2H, d, J=9.1 Hz, 2×ARCH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=11.3 (CH₃CH₂), 27.5 (C₄À THIQ),

29.5 (CH₃CH₂), 42.1 (C₃À THIQ), 55.2 (OCH₃), 60.2 (C₁À THIQ), 111.7

(C₇À THIQ), 113.3 (C₅À THIQ), 114.6 (2×ArCH, phenyl), 121.4 (ArCCl),

128.3 (C₈À THIQ), 128.9 (2×ArCH, phenyl), 130.7 (C₁CC₈À THIQ), 136.0

(C₄CC₅À THIQ), 148.3 (ArCN) and 158.1 (C₆À THIQ) ppm. HRMS (ES⁺)

calcd. C₁₈H₂₁³⁵ClNO [M⁺+H] 302.1306; found: 302.1292; calcd.

°

149–151 C (pet. ether).

2-(4-Chlorophenyl)-6-methoxy-1-phenethyl-1,2,3,4-tetrahydroiso-

quinoline (30g): The crude compound was purified by column

chromatography (eluent: from 0 to 20% EtOAc in pet. ether) to give

a yellow oil (194 mg, 67%) which showed: ¹H NMR (500 MHz,

CDCl₃): δ=1.94–2.05 (1H, m, CHH₂CH₂), 2.17–2.34 (1H, m,

CHCH₂CH₂), 2.66–2.79 (2H, m, CHCH₂CH₂), 2.80–2.90 (1H, m,

H₄À THIQ), 2.90–3.03 (1H, m H₄À THIQ), 3.52–3.68 (2H, m H₃À THIQ),

3.79 (3H, s, OCH₃), 4.55 (1H, t, J=6.9 Hz, H₁À THIQ), 6.68 (1H, d, J=

2.4 Hz, H₅À THIQ), 6.71–6.83 (3H, m, H₇À THIQ, 2×ArCH, N-phenyl),

7.05 (1H, d, J=8.4 Hz, H₈À THIQ), 7.10–7.22 (5H, m, 3×ArCH,

phenethyl, 2×ArCH, N-phenyl) and 7.25–7.31 (2H, m, 2×ArCH,

phenethyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=26.9 (C₄À THIQ), 32.7

(CHCH₂CH₂), 38.0 (CHCH₂CH₂), 43.2 (C₃À THIQ), 55.3 (OCH₃), 59.0

(C₁À THIQ), 112.1, 113.5 (C₅À THIQ), 121.0, 125.9, 128.2 (C₈À THIQ),

128.4 (2×ArCH), 128.5 (2×ArCH), 129.0, 135.9 (C₁CC₈À THIQ), 141.6

(ArCCH₂, phenethyl), 147.7 (ArCN) and 158.3 (C₆À THIQ) ppm. HRMS

(ES⁺) calcd. C₂₄H₂₅³⁷ClNO [M⁺+H] 380.1590; found: 380.1615.

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°

C₁₈H₂₁ClNO [M +H] 304.1277; found: 304.1287. Mp 142–144 C

(pet. ether).

1-Benzyl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline

(30h): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 20% EtOAc in pet. ether) to give a yellow

oil (155 mg, 58%) which showed:^{[37] 1}H NMR (500 MHz, CDCl₃): δ=

2.64–2.83 (1H, m, 1×H₄À THIQ), 2.87–3.06 (2H, m, 1×H₄À THIQ, 1×

CHCH₂), 3.11–3.34 (1H, m, 1×CHCH₂), 3.44–3.58 (1H, m, H₃À THIQ),

3.58–3.70 (1H, m, H₃À THIQ), 3.78 (3H, s, OCH₃), 4.86 (1H, t, J=6.5 Hz,

H₁À THIQ), 6.60 (1H, dd, J=2.4, 8.4 Hz, H₇À THIQ), 6.63 (1H, d, J=

8.4 Hz, H₈À THIQ), 6.67 (1H, d, J=1.8 Hz, H₅À THIQ), 6.70–6.79 (1H,

m), 6.79–6.94 (2H, m), 7.02 (2H, d, J=6.5 Hz) and 7.15–7.25 (5H, m)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=27.8 (C₄À THIQ), 42.1 (C₃À THIQ),

42.4 (CHCH₂), 55.2 (OCH₃), 61.0 (C₁À THIQ), 111.5 (C₇À THIQ), 113.0

(C₅À THIQ), 113.7 (2×ArCH), 117.3 (ArCH), 126.2 (ArCH), 128.1 (2×

ArCH), 128.6 (C₈À THIQ), 129.2 (2×ArCH), 129.6 (C₁CC₈À THIQ), 129.8

(2×ArCH), 136.2 (C₄CC₅À THIQ), 138.7 (ArCCH₂CH), 149.1 (ArCN) and

158.1 (C₆À THIQ) ppm.

2-(4-Chlorophenyl)-1-isopropyl-6-methoxy-1,2,3,4-tetrahydroiso-

quinoline (30c): The crude compound was purified by column

chromatography (eluent: 100% pet. ether) to give a colourless oil

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(267 mg, 56%) which showed: H NMR (500 MHz, CDCl₃): δ=0.92

(3H, d, J=6.6 Hz, (CH₃)₂CH), 1.03 (3H, d, J=6.9 Hz, (CH₃)₂CH)), 2.03–

2.13 (1H, m, (CH₃)₂CH)), 2.92–3.01 (2H, m, H₄À THIQ), 3.36–3.46 (1H,

m, H₃À THIQ), 3.68 (1H, dt, J=6.1, 12.2 Hz, H₃À THIQ), 3.79 (3H, s,

OCH₃), 4.26 (1H, d, J=8.1 Hz, H₁À THIQ), 6.68–6.72 (2H, m,

H₅,H₇À THIQ), 6.76 (2H, d, J=9.1 Hz, 2×ArCH, phenyl), 7.02 (1H, d,

J=7.9 Hz, H₈À THIQ) and 7.14 (2H, d, J=9.1 Hz, 2×ArCH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=20.0 ((CH₃)₂CH), 20.5 ((CH₃)₂CH),

27.5 (C₄À THIQ), 34.4 ((CH₃)₂CH), 42.9 (C₃À THIQ), 55.2 (OCH₃), 64.2

(C₁À THIQ), 111.0 (C₇À THIQ), 113.4 (C₅À THIQ), 114.3 (2×ArCH,

phenyl), 121.1 (ArCCl), 128.8 (2×ArCH, phenyl), 129.2 (C₈À THIQ),

129.6 (C₁CC₈À THIQ), 136.3 (C₅CC₄À THIQ), 148.6 (ArCN) and 158.3

(C₆À THIQ) ppm. HRMS (ES⁺) calcd. C₁₉H₂₃³⁵ClNO [M⁺+H] 316.1463;

found: 316.1460; calcd. C₁₉H₂₃³⁷ClNO [M⁺+H] 318.1433; found:

318.1448.

1-Benzyl-6-methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroiso-

quinoline (30i): The crude compound was purified by column

chromatography (eluent: from 0 to 20% EtOAc in pet. ether) to give

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a yellow oil (182 mg, 61%) which showed:^{[23] 1}H NMR (500 MHz,

CDCl₃): δ=2.62–2.79 (1H, m, 1×H₄À THIQ), 2.86–3.05 (2H, m, 1×

H₄À THIQ, 1×CHCH₂), 3.20 (1H, dd, J=5.4, 13.5 Hz, 1×CHCH₂), 3.43–

3.55 (1H, m, H₃À THIQ), 3.60 (1H, ddd, J=4.5, 9.0, 13.5 Hz, H₃À THIQ),

3.77 (3H, s, OCH₃), 3.79 (3H, s, OCH₃), 4.76 (1H, t, J=6.5 Hz,

H₁À THIQ), 6.59–6.66 (2H, m, H₇À THIQ, H₈À THIQ), 6.67 (1H, d, J=

1.7 Hz, H₅À THIQ), 6.78–6.92 (4H, m), 7.04 (2H, d, J=6.8 Hz) and

7.15–7.29 (3H, m) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=27.5

(C₄À THIQ), 42.0 (CHCH₂), 42.4 (C₃À THIQ), 55.1 (OCH₃), 55.6 (OCH₃),

61.8 (C₁À THIQ), 111.5 (C₇À THIQ), 113.1 (C₅À THIQ), 114.6 (2×ArCH),

116.8 (2×ArCH), 126.0 (ArCH), 128.0 (2×ArCH), 128.6 (C₈À THIQ),

129.7 (2×ArCH), 130.0 (C₁CC₈À THIQ), 136.0 (C₄CC₅À THIQ), 139.3

(ArCCH₂CH), 144.2 (ArCN), 152.4 (ArCO, phenyl) and 158.0 (C₆À THIQ)

ppm.

H₃À THIQ), 5.23 (1H, t, J=6.1 Hz, H₁À THIQ), 6.69 (2H, d, J=8.1 Hz),

6.72 (1H, d, J=7.6 Hz), 6.74–6.85 (2H, m), 7.09–7.17 (6H, m) and

7.17–7.23 (2H, m) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=26.3

(C₄À THIQ), 40.2 (CHCH₂), 41.1 (C₃À THIQ), 55.1 (OCH₃), 56.5 (C₁À THIQ),

107.7 (ArCH), 114.1 (2×ArCH), 120.7 (2×ArCH), 125.9 (ArCH), 126.8

(C_q), 127.9 (2×ArCH), 129.0 (ArCH), 129.5 (2×ArCH), 129.7 (ArCH),

130.9 (ArCH), 136.1 (C₄CC₅À THIQ), 139.8 (C_q), 149.4 (C_q) and 155.6

(C₈À THIQ) ppm. HRMS (ES⁺) calcd. C₂₃H₂₄NO [M⁺+H] 330.1858;

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found: 330.1842. Mp 126–128 C (pet. ether).

1-Benzyl-8-methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroiso-

quinoline (31i): The crude compound was purified by column

chromatography (eluent: from 0 to 20% EtOAc in pet. ether) to give

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a yellow oil (25 mg, 8%) which showed: H NMR (500 MHz, CDCl₃):

δ=2.41–2.65 (1H, m, H₄À THIQ), 2.84–2.99 (1H, m, H₄À THIQ), 2.99–

3.23 (2H, m, CHCH₂), 3.44–3.63 (1H, m, H₃À THIQ), 3.70 (3H, s, OCH₃),

3.71–3.75 (1H, m, H₃À THIQ), 3.78 (3H, s, J=30.7 Hz, OCH₃), 5.05 (1H,

bs, H₁À THIQ), 6.61–6.77 (6H, m), 7.09–7.18 (4H, m) and 7.18–7.25

(2H, m) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=25.8 (C₄À THIQ), 40.2

(CHCH₂), 41.6 (C₃À THIQ), 55.1 (OCH₃), 55.7 (OCH₃), 57.1 (H₁À THIQ),

107.5 (ArCH), 114.4 (2×ArCH), 116.5 (ArCH), 120.9 (2×ArCH), 125.8

(ArCH), 127.0 (ArCH), 127.9 (2×ArCH), 129.6 (2×ArCH), 136.2 (C_q),

140.5 (C_q), 144.5 (C_q), 146.9 (ArCN), 151.9 (ArCO) and 155.7 (ArCO)

ppm. HRMS (ES⁺) calcd. C₂₄H₂₆NO₂[M⁺+H] 360.1964; found:

2-(4-Chlorophenyl)-1-ethyl-8-methoxy-1,2,3,4-tetrahydroisoqui-

noline (31b): The crude compound was purified by column

chromatography (eluent: 100% pet. ether) to give a colourless oil

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(24 mg, 5%) which showed: H NMR (400 MHz, CDCl₃): δ=0.97 (3H,

t, J=7.4 Hz, CH₃CH₂), 1.74–1.91 (2H, m, CH₃CH₂), 2.78 (1H, dt, J=5.1,

16.2 Hz, H₄À THIQ), 2.97 (1H, ddd, J=5.9, 8.8, 15.0 Hz, H₄À THIQ),

3.49–3.68 (2H, m, H₃À THIQ), 3.83 (3H, s, OCH₃), 4.87 (1H, dd, J=5.7,

8.0 Hz, H₁À THIQ), 6.71 (1H, d, J=7.9 Hz, H₅or H₇À THIQ), 6.72 (1H, d,

J=7.9 Hz, H₅or H₇À THIQ), 6.80 (2H, d, J=9.1 Hz, 2×ArCH, phenyl),

7.11 (1H, t, J=7.9 Hz, H₆À THIQ) and 7.13 (2H, d, J=9.2 Hz, 2×ArCH,

phenyl) ppm. ¹³C NMR (101 MHz, CDCl₃): δ=11.3 (CH₃CH₂), 26.3

(C₄À THIQ), 27.6 (CH₃CH₂), 41.1 (C₃À THIQ), 54.6 (C₁À THIQ), 55.2

(OCH₃), 107.8 (C₅or C₇À THIQ), 115.0 (2×ArCH, phenyl), 120.8 (C₅or

C₇À THIQ), 121.3 (ArCCl), 126.9 (C₆À THIQ), 127.7 (C₁CC₈À THIQ), 128.8

(2×ArCH, phenyl), 135.9 (C₄CC₅À THIQ), 148.7 (ArCN) and 155.7

(C₈À THIQ) ppm.

2-(4-Chlorophenyl)-1-isopropyl-8-methoxy-1,2,3,4-tetrahydroiso-

quinoline (31c): The crude compound was purified by column

chromatography (eluent: 100% pet. ether) to give a white solid

(57 mg, 12%) which showed: ¹H NMR (400 MHz, CDCl₃): δ=0.86

(3H, d, J=6.7 Hz, (CH₃)₂CH), 1.02 (3H, d, J=6.8 Hz, (CH₃)₂CH), 2.08

(1H, ddt, J=6.8, 9.4, 13.6 Hz, (CH₃)₂CH), 2.92 (1H, ddd, J=4.5, 6.3,

15.8 Hz, H₄À THIQ), 3.02–3.18 (1H, m, H₄À THIQ), 3.31 (1H, ddd, J=

6.3, 9.3, 11.4 Hz, H₃À THIQ), 3.68 (1H, ddd, J=4.5, 6.8, 11.4 Hz,

H₄À THIQ), 3.81 (3H, s, OCH₃), 4.95 (1H, d, J=9.3 Hz, H₁À THIQ), 6.72

(1H, d, J=7.4 Hz, H₅or H₇À THIQ), 6.75 (1H, d, J=7.4 Hz, H₅or

H₇À THIQ), 6.76 (2H, d, J=9.2 Hz, 2×ArCH, phenyl), 7.12 (2H, d, J=

9.2 Hz, 2×ArCH, phenyl) and 7.13 (1H, t, J=7.4 Hz, H₆À THIQ) ppm.

¹³C NMR (101 MHz, CDCl₃): δ=19.8 ((CH₃)₂CH), 20.9 ((CH₃)₂CH), 27.2

(C₄À THIQ), 34.9 ((CH₃)₂CH), 43.3 (C₃À THIQ), 55.1 (OCH₃), 56.5

(C₁À THIQ), 108.0 (C₅or C₇À THIQ), 113.8 (2×ArCH, phenyl), 120.3 (C₅

or C₇À THIQ), 120.5 (ArCCl), 127.2 (C₆À THIQ), 127.6 (C₁CC₈À THIQ),

128.6 (2×ArCH, phenyl), 136.3 (C₄CC₅À THIQ), 148.8 (ArCN) and

155.6 (C₈À THIQ) ppm. HRMS (ES⁺) calcd. C₁₉H₂₃ClNO [M⁺+H]

316.1463; found: 316.1475.

°

360.1973. Mp 114–118 C (pet. ether).

N-(4-Chlorophenyl)-N-(2-(3-methoxyphenyl)propyl)-2-phenylace-

tamide (32a): Phenacetyl chloride (162 μL, 1.20 mmol) was added

to a stirring solution of 26a (300 mg, 1.09 mmol) and Et₃N (229 μL,

1.64 mmol) in CH₂Cl₂(3 mL) and the mixture was stirred overnight

at RT under inert atmosphere. The mixture was then diluted with

CH₂Cl₂(25 mL) washed with 1 N NaOH (3×25 mL), 1 N HCl (3×

25 mL) and brine (25 mL), then dried with MgSO₄, filtered and

evaporated to give a yellow oil (403 mg). The crude compound was

purified by column chromatography (eluent: from 0 to 40% EtOAc

in pet. ether) to give the product as a colourless oil (223 mg, 52%)

1

which showed: H NMR (500 MHz, CDCl₃): δ=1.14 (3H, d, J=7.0 Hz,

CHCH₃), 2.89–3.01 (1H, m, CHCH₃), 3.27 (2H, s, CH₂CO), 3.67 (3H, s,

OCH₃), 3.68–3.73 (1H, m, CH₂N), 3.93 (1H, dd, J=6.9, 13.5 Hz, CH₂N),

6.58 (2H, d, J=7.4 Hz, 2×ArCH, aniline), 6.59–6.61 (1H, m, ArCH,

methoxyphenyl), 6.63 (1H, d, J=7.9 Hz, ArCH, methoxyphenyl), 6.67

(1H, dd, J=2.0, 7.9 Hz, ArCH, methoxyphenyl), 6.85 (2H, d, J=

7.4 Hz, 2×ArCH, aniline), 7.08 (1H, t, J=7.9 Hz, ArCH, meth-

oxyphenyl) and 7.10–7.17 (5H, m, 5×ArCH, phenyl) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=19.9 (CHCH₃), 38.3 (CHCH₃), 41.4 (CH₂CO), 55.2

(OCH₃), 55.9 (CH₂N), 112.1 (ArCH, methoxyphenyl), 113.1 (ArCH,

methoxyphenyl), 120.0 (ArCH, methoxyphenyl), 126.6 (ArCH,

phenyl), 128.4 (2×ArCH, phenyl), 128.8 (2×ArCH, aniline), 129.4

(ArCH, methoxyphenyl), 129.5 (ArCH, phenyl), 129.7 (2×ArCH,

aniline), 133.6 (ArCCl), 135.2 (ArCCH₂), 141.3 (ArCN), 145.7 (ArCCH),

159.7 (ArCO) and 170.9 (CON) ppm.

1-Benzyl-2-(4-chlorophenyl)-8-methoxy-1,2,3,4-tetrahydroisoqui-

noline (31f): The crude compound was purified by column

chromatography (eluent: 100% pet. ether) to give a colourless oil

(62 mg, 11%) which showed: ¹H NMR (400 MHz, CDCl₃): δ=2.55

(1H, dt, J=5.1, 16.2 Hz), 2.87–2.99 (1H, m), 3.04 (1H, dd, J=7.8,

13.5 Hz), 3.15 (1H, dd, J=4.5, 13.5 Hz), 3.51–3.60 (1H, m), 3.66–3.74

(1H, m), 3.78 (3H, s), 5.15 (1H, dd, J=4.5, 7.7 Hz), 6.60 (2H, d, J=

9.1 Hz), 6.66–6.75 (2H, m), 7.04 (2H, d, J=9.1 Hz) and 7.09–7.24 (6H,

m) ppm.

N-(4-Chlorophenyl)-N-(2-(3-methoxyphenyl)butyl)-2-phenylaceta-

mide (32b): Phenacetyl chloride (154 μL, 1.14 mmol) was added to

a stirring solution of 26b (300 mg, 1.04 mmol) and Et₃N (218 μL,

1.56 mmol) in CH₂Cl₂(3 mL) and the mixture was stirred overnight

at RT under inert atmosphere. The mixture was then diluted with

CH₂Cl₂(25 mL) washed with 1 N NaOH (3×25 mL), 1 N HCl (3×

25 mL) and brine (25 mL), then dried with MgSO₄, filtered and

evaporated to give a yellow oil (426 mg). The crude compound was

purified by column chromatography (eluent: from 0 to 40% EtOAc

in pet. ether) to give the product as a colourless oil (361 mg, 85%)

1-Benzyl-8-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline

(31h): The crude compound was purified by column chromatog-

raphy (eluent: from 0 to 20% EtOAc in pet. ether) to give a white

solid (16 mg, 6%) which showed: ¹H NMR (500 MHz, CDCl₃): δ=

2.46–2.73 (1H, m, H₄À THIQ), 2.89–3.03 (1H, m, H₄À THIQ), 3.03–3.24

(2H, m, CHCH₂), 3.53–3.64 (1H, m, H₃À THIQ), 3.67–3.82 (4H, m, OCH₃,

1

which showed: H NMR (500 MHz, CDCl₃): δ=0.68 (3H, t, J=7.4 Hz,

CH₂CH₃), 1.36–1.48 (1H, m, CH₂CH₃), 1.54–1.63 (1H, m, CH₂CH₃),

2.64–2.79 (1H, m, CHCH₂), 3.24 (2H, s, CH₂CO), 3.66 (3H, s, OCH₃),

3.72 (1H, dd, J=9.9, 13.5 Hz, CH₂N), 3.98 (1H, dd, J=6.1, 13.5 Hz,

CH₂N), 6.44–6.53 (2H, m, 2×ArCH, aniline), 6.53–6.57 (1H, m, ArCH,

methoxyphenyl), 6.58 (1H, d, J=7.8 Hz, ArCH, methoxyphenyl), 6.68

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(1H, dd, J=2.1, 7.8 Hz, ArCH, methoxyphenyl), 6.80–6.85 (2H, m, 2×

ArCH, phenyl), 7.07 (2H, t, J=7.8 Hz, ArCH, methoxyphenyl) and

7.09–7.15 (5H, m, 3×ArCH, phenyl, 2×ArCH, aniline) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=11.8 (CH₂CH₃), 27.1 (CH₂CH₃), 41.4 (CH₂CO),

45.8 (CHCH₂), 54.8 (CH₂N), 55.2 (OCH₃), 112.1 (ArCH, meth-

oxyphenyl), 113.8 (ArCH, methoxyphenyl), 120.9 (ArCH, meth-

oxyphenyl), 126.5 (ArCH, phenyl), 128.3 (2×ArCH), 128.8 (2×ArCH),

129.2 (ArCH, methoxyphenyl), 129.4 (2×ArCH), 129.7 (2×ArCH),

133.5 (ArCCl), 135.2 (ArCCH₂), 141.4 (ArCN), 144.0 (ArCCH), 159.6

(ArCO) and 170.8 (CON) ppm.

CH₂CH₃), 2.92–3.05 (2H, m, H₄À THIQ, ArCH₂CH), 3.19 (1H, dd, J=7.2,

13.4 Hz, ArCH₂CH), 3.32 (1H, dd, J=10.5, 13.6 Hz, H₃À THIQ), 3.73

(1H, dd, J=5.8, 13.6 Hz, H₃À THIQ), 3.78 (3H, s, OCH₃), 4.80 (1H, t, J=

6.5 Hz, H₁À THIQ), 6.65 (1H, dd, J=2.6, 8.6 Hz, H₇À THIQ), 6.67 (2H, d,

J=8.8 Hz, 2×ArCH, N-phenyl), 6.77 (1H, d, J=8.5 Hz, H₈À THIQ), 6.81

(1H, d, J=2.2 Hz, H₅À THIQ), 7.02–7.14 (4H, m, 2×ArCH, N-phenyl,

2×ArCH, phenyl), 7.15–7.21 (1H, m, ArCH, phenyl) and 7.21–7.25

(2H, m, 2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=10.9

(CH₂CH₃), 25.8 (CH₂CH₃), 35.9 (C₄À THIQ), 41.7 (ArCH₂CH), 45.8

(C₃À THIQ), 55.2 (OCH₃), 61.8 (C₁À THIQ), 111.3 (C₇À THIQ), 112.3

(C₅À THIQ), 116.9 (2×ArCH, N-phenyl), 120.9 (ArCCl), 126.3 (ArCH,

phenyl), 128.3 (2×ArCH, phenyl), 128.6 (C₈À THIQ), 128.9 (2×ArCH,

N-phenyl), 129.3 (C₁CC₈À THIQ), 129.7 (2×ArCH, phenyl), 138.9

(ArCCH₂CH), 139.4 (C₄CC₅À THIQ), 148.5 (ArCN) and 158.3 (C₆À THIQ)

ppm.

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N-(4-Chlorophenyl)-N-(2-(3-methoxyphenyl)-3-phenylpropyl)-2-

phenylacetamide (32d): Phenacetyl chloride (127 μL, 0.938 mmol)

was added to a stirring solution of 26d (300 mg, 0.853 mmol) and

Et₃N (179 μL, 1.28 mmol) in CH₂Cl₂(3 mL) and the mixture was

stirred overnight at RT under inert atmosphere. The mixture was

then diluted with CH₂Cl₂(25 mL) washed with 1 N NaOH (3×

25 mL), 1 N HCl (3×25 mL) and brine (25 mL), then dried with

MgSO₄, filtered and evaporated to give a yellow oil (387 mg). The

crude compound was purified by column chromatography (eluent:

from 0 to 40% EtOAc in pet. ether) to give the product as a

colourless oil (153 mg, 38%) which showed: ¹H NMR (500 MHz,

CDCl₃): δ=2.77 (2H, dd, J=8.4, 13.8 Hz, ArCH₂CH), 2.83 (2H, dd, J=

6.5, 13.8 Hz, ArCH₂CH), 3.07–3.17 (1H, m, ArCH₂CH), 3.23 (2H, s,

ArCH₂CO), 3.62 (3H, s, OCH₃), 3.86 (1H, dd, J=9.9, 13.6 Hz, CH₂N),

4.00 (1H, dd, J=6.1, 13.6 Hz, CH₂N), 6.48 (2H, d, J=7.4 Hz, 2×ArCH,

aniline), 6.49–6.52 (1H, m, ArCH, methoxyphenyl), 6.54 (1H, d, J=

7.8 Hz, ArCH, methoxyphenyl), 6.66 (1H, dd, J=2.1, 7.8 Hz, ArCH,

methoxyphenyl), 6.78–6.84 (2H, m, 2×ArCH), 6.88 (2H, d, J=7.0 Hz,

2×ArCH), 7.03 (1H, t, J=7.8 Hz, ArCH, methoxyphenyl) and 7.05–

7.15 (8H, m, 8×ArCH) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=41.0

(ArCH₂CH), 41.4 (ArCH₂CO), 45.6 (ArCH₂CH), 54.0 (CH₂N), 55.2 (OCH₃),

112.4 (ArCH, methoxyphenyl), 113.7 (ArCH, methoxyphenyl), 120.8

(ArCH, methoxyphenyl), 126.0 (ArCH), 126.6 (ArCH), 128.1 (2×ArCH),

128.3 (2×ArCH), 128.8 (2×ArCH), 129.0 (2×ArCH), 129.3 (ArCH,

methoxyphenyl), 129.4 (2×ArCH), 129.7 (2×ArCH), 133.6 (ArCCl),

135.1 (ArCCH₂CO), 139.4 (ArCCH₂CH), 141.1 (ArCN), 143.3 (ArCCH),

159.6 (ArCO) and 170.9 (CON) ppm.

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trans-1,4-Dibenzyl-2-(4-chlorophenyl)-6-methoxy-1,2,3,4-tetrahy-

droisoquinoline (33d): Synthesised according to the general

method for the Bischler-Napieralski cyclisation. The crude com-

pound was purified by column chromatography (eluent: from 0 to

10% EtOAc in pet. ether) to give the product as a colourless oil

(11 mg, 46%) which showed: ¹H NMR (400 MHz, CDCl₃): δ=2.68

(1H, dd, J=8.5, 13.5 Hz), 2.94 (1H, dd, J=6.6, 13.6 Hz), 3.29 (4H, t,

J=10.7 Hz), 3.47 (1H, d, J=7.6 Hz), 3.76 (3H, s), 4.80 (1H, t, J=

6.3 Hz), 6.63–6.73 (3H, m), 6.78 (1H, d, J=8.6 Hz), 6.85 (1H, d, J=

2.5 Hz), 7.01 (2H, d, J=6.4 Hz), 7.07 (2H, d, J=8.9 Hz), 7.14–7.24 (6H,

m) and 7.29–7.37 (2H, m) ppm.

trans-1-Benzyl-4-ethyl-8-methoxy-2-(4-methoxyphenyl)-1,2,3,4-

tetrahydroisoquinoline (34b)

: Synthesised according to the

general method for the Bischler-Napieralski cyclisation. The crude

compound was purified by column chromatography (eluent: from 0

to 10% EtOAc in pet. ether) to give the product as a white solid

(22 mg, 12%) which showed: ¹H NMR (500 MHz, CDCl₃): δ=1.04

(3H, t, J=7.4 Hz, CH₂CH₃), 1.60–1.74 (1H, m, CH₂CH₃), 1.97–2.13 (1H,

m, CH₂CH₃), 2.99–3.12 (2H, m, ArCH₂CH, H₄À THIQ), 3.19 (1H, dd, J=

3.0, 13.8 Hz, ArCH₂CH), 3.51 (1H, dd, J=11.5, 14.3 Hz, H₃À THIQ), 3.82

(1H, dd, J=6.6, 14.3 Hz, H₃À THIQ), 3.89 (3H, s, OCH₃), 5.05 (1H, d, J=

8.1 Hz, H₁À THIQ), 6.50 (2H, d, J=9.0 Hz, 2×ArCH, N-phenyl), 6.72

(1H, d, J=8.1 Hz, H₇À THIQ), 6.92 (1H, d, J=7.8 Hz, H₅À THIQ), 6.95

(2H, d, J=9.0 Hz, 2×ArCH, N-phenyl), 7.15–7.22 (2H, m, 1×ArCH,

phenyl, H₆À THIQ) and 7.22–7.29 (4H, m, 4×ArCH, phenyl) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=10.8 (CH₂CH₃), 25.9 (CH₂CH₃), 34.1

(C₄À THIQ), 39.4 (ArCH₂CH), 44.5 (C₃À THIQ), 55.3 (OCH₃), 58.0

(C₁À THIQ), 107.3 (C₇À THIQ), 116.2 (2×ArCH, N-phenyl), 119.5

(C₅À THIQ), 122.0 (ArCCl), 126.0 (ArCH, phenyl), 127.3 (C₆À THIQ),

127.5 (C₁CC₈À THIQ), 128.2 (2×ArCH, phenyl), 128.6 (2×ArCH, N-

phenyl), 129.4 (2×ArCH, phenyl), 139.5 (C₄CC₅À THIQ), 140.5

(ArCCH₂CH), 148.9 (ArCN) and 155.6 (C₈À THIQ) ppm.

trans-1-Benzyl-2-(4-chlorophenyl)-6-methoxy-4-methyl-1,2,3,4-

tetrahydroisoquinoline (33a): Synthesised according to the gen-

eral method for the Bischler-Napieralski cyclisation. The crude

compound was purified by column chromatography (eluent: from 0

to 10% EtOAc in pet. ether) to give the product as a yellow oil

(22 mg, 36%) which showed: ¹H NMR (500 MHz, CDCl₃): δ=1.32

(3H, d, J=6.8 Hz, CHCH₃), 3.02 (1H, dd, J=5.5, 13.7 Hz, ArCH₂CH),

3.04–3.14 (1H, m, H₄À THIQ), 3.14–3.26 (2H, m, 1×ArCH₂CH, 1×

H₃À THIQ), 3.66–3.74 (1H, m, 1×H₃À THIQ), 3.79 (3H, s, OCH₃), 4.78–

4.87 (1H, m, H₁À THIQ), 6.61 (2H, d, J=9.1 Hz, 2×ArCH, N-phenyl),

6.68 (1H, dd, J=2.6, 8.5 Hz, H₇À THIQ), 6.82 (H, d, J=2.6 Hz,

H₅À THIQ), 6.86 (H, d, J=8.5 Hz, H₈À THIQ), 7.05 (2H, d, J=9.1 Hz, 2×

ArCH, N-phenyl), 7.10–7.15 (2H, m, 2×ArCH, benzyl), 7.18–7.22 (2H,

m, 2×ArCH, benzyl) and 7.22–7.25 (1H, m, ArCH, benzyl) ppm. ¹³C

NMR (126 MHz, CDCl₃): δ=18.0 (CHCH₃), 29.5 (C₄À THIQ), 41.9

(ArCH₂CH), 48.0 (C₃À THIQ), 55.2 (OCH₃), 61.9 (C₁À THIQ), 111.4

(C₇À THIQ), 112.1 (C₅À THIQ), 116.5 (2×ArCH, N-phenyl), 122.5

(ArCCl), 126.3(2×ArCH, benzyl), 128.3(ArCH, benzyl), 128.4(2×ArCH,

N-phenyl), 128.8(C₈À THIQ), 129.0 (C₁CC₈À THIQ), 129.6 (2×ArCH,

benzyl), 139.2 (ArCCH₂), 140.9 (C₄CC₅À THIQ), 148.6 (ArCN) and 158.3

(C₆À THIQ) ppm.

trans-1,4-Dibenzyl-8-methoxy-2-(4-methoxyphenyl)-1,2,3,4-tetra-

hydroisoquinoline (34d): Synthesised according to the general

method for the Bischler-Napieralski cyclisation. The crude com-

pound was purified by column chromatography (eluent: from 0 to

10% EtOAc in pet. ether) to give the product as a colourless oil

1

(2 mg, 8%) which showed: H NMR (500 MHz, CDCl₃): δ=2.64 (1H,

dd, J=9.5, 13.8 Hz), 2.96 (1H, dd, J=9.5, 13.7 Hz), 3.15 (1H, dd, J=

3.1, 13.8 Hz), 3.34–3.54 (3H, m), 3.90 (3H, s), 5.03 (1H, d, J=7.5 Hz),

6.25–6.34 (2H, m), 6.76 (1H, d, J=8.1 Hz), 6.86–6.91 (2H, m), 7.05

(1H, d, J=7.4 Hz), 7.24 (6H, s), 7.24–7.29 (3H, m) and 7.35 (2H, dd,

J=6.4, 13.9 Hz) ppm.

trans-1-Benzyl-2-(4-chlorophenyl)-4-ethyl-6-methoxy-1,2,3,4-tet-

rahydroisoquinoline (33b): Synthesised according to the general

method for the Bischler-Napieralski cyclisation. The crude com-

pound was purified by column chromatography (eluent: from 0 to

10% EtOAc in pet. ether) to give the product as a yellow oil (87 mg,

General method for methoxy deprotection with HBr: 5c (200 mg,

836 μmol) was suspended in 46% HBr (3 mL) and stirred for 3 h at

°

120 C. The mixture became a solution upon heating. The mixture

was then cooled to RT and filtered to give the product as a white

precipitate (230 mg, 90%).

1

46%) which showed: H NMR (500 MHz, CDCl₃): δ=1.03 (3H, t, J=

7.4 Hz, CH₂CH₃), 1.59–1.78 (1H, m, CH₂CH₃), 1.90–2.04 (1H, m,

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General method for methoxy deprotection with BBr₃: 1.0 M

solution of BBr₃(6.7 mL, 6.68 mmol) in CH₂Cl₂was added to a

stirring solution of 7a (200 mg, 0.668 mmol) in anhydrous CH₂Cl₂

yellow precipitate (217 mg, 91%) which showed:^{[23] 1}H NMR

(500 MHz, [D₆]DMSO): δ=2.78 (2H, t, J=5.7 Hz, H₄À THIQ), 3.27 (2H,

t, J=5.9 Hz, H₃À THIQ), 4.05 (2H, s, H₁À THIQ), 6.52 (1H, d, J=2.5 Hz,

H₅À THIQ), 6.56 (1H, dd, J=2.5, 8.2 Hz, H₇À THIQ), 6.66 (2H, d, J=

8.9 Hz, ArH, phenyl), 6.84 (2H, d, J=8.9 Hz, ArH, phenyl), 6.94 (1H, d,

J=8.2 Hz, H₈À THIQ), 8.80 (1H, bs, OH, phenyl) and 9.15 (1H, bs,

OHÀ THIQ) ppm. ¹³C NMR (126 MHz, [D₆]DMSO): δ=28.6 (C₄À THIQ),

47.8 (C₃À THIQ), 51.7 (C₁À THIQ), 113.3 (C₇À THIQ), 114.6 (C₅À THIQ),

115.6 (ArCH, phenyl), 117.7 (ArCH, phenyl), 125.0 (C₁CC₈À THIQ),

127.4 (C₈À THIQ), 135.3 (C₅CC₆À THIQ), 143.9 (ArCN), 150.6 (ArCO,

phenyl) and 155.5 (C₆À THIQ) ppm. LC/MS (ES⁺) t_R=1.96 min (95%),

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°

(1 mL) at 0 C under inert atmosphere. The mixture was stirred for

2 h letting it reach RT then quenched with a minimum amount of

ice and stirred for 10 min. The mixture was filtered and the

precipitate was washed with CH₂Cl₂then dried to give the product

as a yellow solid (168 mg, 74%).

2-Phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide (35c):

Synthesised according to the general method for methoxy

deprotection with HBr. The product was obtained as a white

precipitate (230 mg, 90%) which showed (¹H and ¹³C NMR data

m/z 241.8 [M⁺+H]; (RP, Isocratic, 70% MeOH). HRMS (ES⁺) calcd.

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°

C₁₅H₁₅NO₂[M +H] 242.1176; found: 242.1178. Mp 245–246 C

1

refer to the free base): H NMR (500 MHz, CDCl₃): δ=2.93 (2H, t, J=

(aqueous HBr). Anal. calcd. for C₁₅H₁₆BrNO₂: C 55.9, H 5.01, N 4.35;

found: C 55.7, H 4.99, N 4.17%.

5.8 Hz, H₄À THIQ), 3.54 (2H, t, J=5.8 Hz, H₃À THIQ), 4.34 (2H, s,

H₁À THIQ), 4.75 (1H, bs, OH), 6.63 (1H, d, J=2.6 Hz, H₅À THIQ), 6.68

(1H, dd, J=2.6, 8.2 Hz, H₇À THIQ), 6.83 (1H, t, J=7.3 Hz, ArH, phenyl),

6.97 (2H, d, J=8.8 Hz, ArH, phenyl), 7.03 (1H, d, J=8.2 Hz, H₈À THIQ)

and 7.29 (2H, dd, J=7.3, 8.8 Hz, ArH, phenyl) ppm. ¹³C NMR

(126 MHz, CDCl₃): δ=29.3 (C₄À THIQ), 46.6 (C₃À THIQ), 50.4

(C₁À THIQ), 113.6 (C₇À THIQ), 115.0 (C₅À THIQ), 115.4 (ArCH, phenyl),

118.9 (ArCH, phenyl), 126.9 (C₁CC₈À THIQ), 127.9 (C₈À THIQ), 129.3

(ArCH, phenyl), 136.5 (C₅CC₆À THIQ), 150.7 (ArCN) and 154.1

(C₆À THIQ) ppm. LC/MS (ES⁺) t_R=2.14 min (98%), m/z 225.9 [M⁺+

H]; (RP, Isocratic, 80% MeOH). HRMS (ES⁺) calcd. for C₁₅H₁₆NO [M⁺

2-(3-Hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-ol hydrobro-

mide (35l): Synthesised according to the general method for

methoxy deprotection with HBr. The product was obtained as a

1

black solid (20 mg, 67%) which showed: H NMR (400 MHz, CDCl₃):

δ=2.90 (2H, t, J=5.8 Hz), 3.51 (2H, t, J=5.9 Hz), 4.32 (2H, s), 4.66

(2H, bs), 6.27 (1H, ddd, J=0.7, 2.3, 8.0 Hz), 6.42 (1H, t, J=2.3 Hz),

6.54 (1H, dd, J=2.1, 8.0 Hz), 6.63 (1H, d, J=2.6 Hz), 6.67 (1H, dd, J=

2.7, 8.2 Hz), 7.01 (1H, d, J=8.3 Hz) and 7.12 (1H, t, J=8.1 Hz) ppm.

HRMS (ES⁺) calcd. C₁₅H₁₆NO₂[M⁺+H] 242.1176; found: 242.1187.

°

+H] 226.1226; found: 226.1258. Mp 220–221 C (aqueous HBr).

Anal. calcd. for C₁₅H₁₆BrNO: C 58.54, H 5.27, N 4.57; found: C 58.6, H

5.25, N 4.44%.

2-(3-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-ol hydrobro-

mide (36a): Synthesised according to the general method for

methoxy deprotection with HBr. The product was obtained as a

1

2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-ol hydrobro-

mide (35d): Synthesised according to the general method for

methoxy deprotection with HBr. The product was obtained as a

yellow precipitate (196 mg, 79%) which showed: ¹H NMR (500 MHz,

CDCl₃): δ=2.92 (2H, t, J=5.9 Hz, H₄À THIQ), 3.50 (2H, t, J=5.9 Hz,

H₃À THIQ), 4.30 (2H, s, H₁À THIQ), 4.79 (1H, bs, OH), 6.64 (1H, d, J=

2.6 Hz, H₅À THIQ), 6.68 (1H, dd, J=2.6, 8.2 Hz, H₇À THIQ), 6.87 (2H, d,

J=9.1 Hz, ArH, phenyl), 7.02 (1H, d, J=8.2 Hz, H₈À THIQ) and 7.21

(2H, d, J=9.1 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=

29.2 (C₄À THIQ), 46.6 (C₃À THIQ), 50.3 (C₁À THIQ), 113.7 (C₇À THIQ),

115.0 (C₅À THIQ), 116.3 (ArCH, phenyl), 123.5 (ArCCl), 126.5

(C₁CC₈À THIQ), 127.8 (C₈À THIQ), 129.1 (ArCH, phenyl), 136.3

(C₅CC₆À THIQ), 149.2 (ArCN) and 154.2 (C₆À THIQ) ppm. LC/MS (ES⁺)

t_R=4.39 min (97%), m/z 259.8 [M⁺+H]; (RP, Isocratic, 80% MeOH).

HRMS (ES⁺) calcd. C₁₅H₁₅³⁵ClNO [M⁺+H] 260.0837; found: 260.0845,

calcd. C₁₅H₁₅³⁷ClNO [M⁺+H] 262.0807; found: 262.0845. Mp 196–

yellow solid (35 mg, 64%) which showed: H NMR (500 MHz, [D₆]

DMSO): δ=2.79 (2H, t, J=5.7 Hz, H₄À THIQ), 3.48 (9H, t, J=5.7 Hz,

H₃À THIQ), 4.27 (2H, s, H₁À THIQ), 6.57 (1H, s, H₅À THIQ), 6.60 (1H, dd,

J=2.3, 8.2 Hz, H₇À THIQ), 6.70 (1H, d, J=7.8 Hz, ArCH, phenyl), 6.89

(1H, dd, J=2.2, 8.4 Hz, ArCH, phenyl), 6.92 (1H, s, ArCH, phenyl),

7.01 (1H, d, J=8.2 Hz, H₈À THIQ), 7.20 (1H, t, J=8.1 Hz, ArCH, phenyl)

and 9.29 (1H, bs, OH) ppm. ¹³C NMR (126 MHz, [D₆]DMSO): δ=28.2

(C₄À THIQ), 45.1 (C₃À THIQ), 48.7 (C₁À THIQ), 112.6 (ArCH, phenyl),

113.4 (ArCH, phenyl), 113.5 (C₇À THIQ), 114.5 (C₅À THIQ), 116.8 (ArCH,

phenyl), 124.4 (C₁CC₈À THIQ), 127.5 (C₈À THIQ), 130.5 (ArCH, phenyl),

134.0 (ArCCl), 135.7 (C₄CC₅À THIQ), 151.3 (ArCN) and 155.8 (C₆À THIQ)

ppm. HRMS (ES⁺) calcd. C₁₅H₁₅³⁵ClNO [M⁺+H] 260.0837; found:

260.0825; calcd. C₁₅H₁₅³⁷ClNO [M⁺+H] 262.0807; found: 262.0805.

°

Mp 211–215 C.

2-(4-Hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol hy-

drobromide (37a): Synthesised according to the general method

for methoxy deprotection with BBr₃. The product was obtained as a

°

197 C (aqueous HBr).

1

2-(p-Tolyl)-1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide (35i):

Synthesised according to the general method for methoxy

deprotection with HBr. The product was obtained as a yellow

precipitate (240 mg, 95%) which showed: ¹H NMR (500 MHz, CDCl₃):

δ=2.28 (3H, s, CH₃), 2.92 (2H, t, J=5.8 Hz, H₄À THIQ), 3.48 (2H, t, J=

5.9 Hz, H₃À THIQ), 4.28 (2H, s, H₁À THIQ), 4.77 (1H, bs), 6.62 (1H, d, J=

2.5 Hz, H₅À THIQ), 6.67 (1H, dd, J=2.5, 8.2 Hz, H₇À THIQ), 6.91 (2H, d,

J=8.6 Hz, ArH, phenyl), 7.01 (1H, d, J=8.2 Hz, H₈À THIQ) and 7.09

(2H, d, J=8.6 Hz, ArH, phenyl) ppm. ¹³C NMR (126 MHz, CDCl₃): δ=

20.5 (CH₃), 29.3 (C₄À THIQ), 47.4 (C₃À THIQ), 51.2 (C₁À THIQ), 113.5

(C₇À THIQ), 115.0 (C₅À THIQ), 116.1 (ArCH, phenyl), 127.0

(C₁CC₈À THIQ), 127.8 (C₈À THIQ), 128.6 (ArCCH₃), 129.8 (ArCH, phenyl),

136.4 (C₅CC₆À THIQ), 148.8 (ArCN) and 154.0 (C₆À THIQ) ppm. LC/MS

(ES⁺) t_R=1.73 min (97%), m/z 239.9 [M⁺+H]; (RP, Isocratic, 80%

MeOH). HRMS (ES⁺) calcd. C₁₆H₁₇NO [M⁺+H] 240.1383; found:

yellow solid (168 mg, 74%) which showed: H NMR (500 MHz, D₂O):

δ=3.18 (2H, t, J=6.0 Hz, H₄À THIQ), 3.93 (2H, t, J=6.0 Hz, H₃À THIQ),

4.63 (2H, s, H₁À THIQ), 6.74 (1H, s, H₈À THIQ), 6.84 (1H, s, H₅À THIQ),

7.06 (2H, d, J=8.3 Hz, 2×ArCH, phenyl) and 7.50 (2H, d, J=8.3 Hz,

2×ArCH, phenyl) ppm. ¹³C NMR (126 MHz, D₂O): δ=24.9 (C₄À THIQ),

53.4 (C₃À THIQ), 56.5 (C₁À THIQ), 113.4 (C₈À THIQ), 115.7 (C₅À THIQ),

116.8 (2×ArCH, phenyl), 120.0 (C₁CC₈À THIQ), 122.5 (2×ArCH,

phenyl), 122.9 (C₄CC₅À THIQ), 133.5 (ArCN), 143.2 (C₆À THIQ), 144.2

(C₇À THIQ) and 156.9 (ArCO, phenyl) ppm. HRMS (ES⁺) calcd.

C₁₅H₁₆NO₃[M⁺+H] 258.1125; found: 258.1127. Compound de-

graded before melting.

2-(4-Hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline-5,6,7-triol hy-

drobromide (37b): Synthesised according to the general method

for methoxy deprotection with BBr₃. The product was obtained as a

yellow solid (245 mg, 99%) which showed: ¹H NMR (500 MHz, D2O):

δ=3.10 (2H, t, J=6.3 Hz, H₄À THIQ), 3.94 (2H, t, J=6.4 Hz, H₃À THIQ),

4.61 (2H, s, H₁À THIQ), 6.40 (1H, s, H₈À THIQ), 7.07 (2H, d, J=9.1 Hz,

2×ArCH, phenyl) and 7.49 (2H, d, J=9.1 Hz, 2×ArCH, phenyl) ppm.

¹³C NMR (126 MHz, D₂O): δ=20.6 (C₄À THIQ), 53.1 (C₃À THIQ), 56.4

(C₁À THIQ), 105.5 (C₈À THIQ), 111.4 (C₄CC₅À THIQ), 116.8 (2×ArCH,

°

240.1380. Mp 224–225 C (aqueous HBr). Anal. calcd. for

C₁₆H₁₈BrClNO: C 60.0, H 5.67, N 4.37; found: C 59.5, H 5.69, N 4.32%.

2-(4-Hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolin-6-ol hydrobro-

mide (35k): Synthesised according to the general method for

methoxy deprotection with HBr. The product was obtained as a

ChemMedChem 2020, 15, 1–34

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phenyl), 120.4 (C₁CC₈À THIQ), 122.4 (2×ArCH, phenyl), 132.3

(C₆À THIQ), 133.6 (ArCN), 143.0 (C₅À THIQ), 144.5 (C₇À THIQ) and 156.8

(2×Arch, phenyl), 140.7 (C₄CC₅À THIQ), 149.1 (ArCN) and 155.8

(C₆À THIQ) ppm. HRMS (ES⁺) calcd. C₁₆H₁₇³⁵ClNO [M⁺+H] 274.0993;

found: 274.0956; calcd. C₁₆H₁₇³⁷ClNO [M⁺+H] 276.0965; found:

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(ArCO, phenyl) ppm. Mp 178–181 C.

°

276.0967. Mp 205–209 C.

2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-ol hydrobro-

mide (38b): Synthesised according to the general method for

methoxy deprotection with HBr. The product was obtained as a

2-(4-Chlorophenyl)-4-ethyl-1,2,3,4-tetrahydroisoquinolin-6-ol hy-

drobromide (41b): Synthesised according to the general method

for methoxy deprotection with BBr₃. Filtration afforded the product

as a yellow precipitate (161 mg, 47%) which showed: ¹H NMR

(500 MHz, [D₆]DMSO): δ=0.97 (3H, t, J=7.4 Hz, CH₂CH₃), 1.50–1.70

(2H, m, CH₂CH₃), 2.66–2.78 (1H, m, H₄À THIQ), 3.27 (1H, dd, J=3.9,

12.3 Hz, H₃À THIQ), 3.56 (1H, dd, J=4.4, 12.3 Hz, H₃À THIQ), 4.11 (1H,

d, J=15.0 Hz, H₁À THIQ), 4.35 (1H, d, J=15.0 Hz, H₁À THIQ), 6.58–6.67

(2H, m, H₅, H₇À THIQ), 6.94 (2H, d, J=9.0 Hz, 2×ArCH, phenyl), 7.01

(1H, d, J=8.9 Hz, H₈À THIQ), 7.24 (2H, d, J=9.0 Hz, 2×ArCH, phenyl)

and 9.25 (1H, bs, OH) ppm. ¹³C NMR (126 MHz, [D₆]DMSO): δ=11.8

(CH₂CH₃), 26.6 (CH₂CH₃), 39.6 (C₄À THIQ), 48.7 (C₃À THIQ), 48.8

(C₁À THIQ), 113.4 (C₅or C₇À THIQ), 114.0 (C₅or C₇À THIQ), 115.1 (2×

ArCH, phenyl), 120.6 (ArCCl), 123.7 (C₁CC₈À THIQ), 127.4 (C₈À THIQ),

128.6 (2×ArCH, phenyl), 139.6 (C₄CC₅À THIQ), 149.1 (ArCN) and

155.6 (C₆À THIQ) ppm. HRMS (ES⁺) calcd. C₁₇H₁₉³⁵ClNO [M⁺+H]

288.1150; found: 288.1148; calcd. C₁₇H₁₉³⁷ClNO [M⁺+H] 290.1120;

1

yellow precipitate (92 mg, 74%) which showed: H NMR (500 MHz,

[D₆]DMSO): δ=2.75 (2H, t, J=5.9 Hz, H₄À THIQ), 3.48 (2H, t, J=

5.9 Hz, H₃À THIQ), 4.27 (2H, s, H₁À THIQ), 6.58 (1H, dd, J=2.4, 8.2 Hz,

H₆À THIQ), 6.60 (1H, d, J=2.4 Hz, H₈À THIQ), 6.94 (1H, d, J=8.2 Hz,

H₅À THIQ), 6.97 (2H, d, J=9.1 Hz, ArH, phenyl), 7.22 (2H, d, J=9.1 Hz,

ArH, phenyl) and 9.20 (1H, bs, OH) ppm. ¹³C NMR (126 MHz, [D₆]

DMSO): δ=27.0 (C₄À THIQ), 45.9 (C₃À THIQ), 49.7 (C₁À THIQ), 112.8

(C₈À THIQ), 113.8 (C₆À THIQ), 116.0 (ArCH, phenyl), 121.2 (ArCCl),

124.6 (C₄CC₅À THIQ), 128.7 (ArCH, phenyl), 129.2 (C₅À THIQ), 135.0

(C₁CC₈À THIQ), 148.9 (ArCN) and 155.4 (C₇À THIQ) ppm. HRMS (ES⁺)

calcd. C₁₅H₁₅³⁵ClNO [M⁺+H] 260.0837; found: 260.0827; calcd.

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°

C₁₅H₁₅ClNO [M +H] 262.0807; found: 262.0831. Mp 225–228 C.

2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-5-ol hydrobro-

mide (39b): Synthesised according to the general method for

methoxy deprotection with HBr. The product was obtained as a

°

found: 290.1150. Mp 119–123 C.

1

brown precipitate (47 mg, 75%) which showed: H NMR (500 MHz,

[D₆]DMSO): δ=2.69 (2H, t, J=5.9 Hz, H₄À THIQ), 3.51 (2H, t, J=

5.9 Hz, H₃À THIQ), 4.31 (2H, s, H₁À THIQ), 6.64 (1H, d, J=7.9 Hz,

H₆À THIQ), 6.65 (1H, d, J=7.9 Hz, H₈À THIQ), 6.97 (1H, t, J=7.9 Hz,

H₇À THIQ), 7.00 (2H, d, J=9.1 Hz, ArH, phenyl), 7.22 (2H, d, J=9.1 Hz,

ArH, phenyl) and 9.37 (1H, bs, OH) ppm. ¹³C NMR (126 MHz, [D₆]

DMSO): δ=22.2 (C₄À THIQ), 45.6 (C₃À THIQ), 49.9 (C₁À THIQ), 112.2

(C₆À THIQ), 116.4 (ArCH, phenyl), 117.1 (C₈À THIQ), 121.3

(C₄CC₅À THIQ), 121.4 (ArCCl), 126.3 (C₇À THIQ), 128.7 (ArCH, phenyl),

135.4 (C₁CC₈À THIQ), 149.0 (ArCN) and 154.7 (C₅À THIQ) ppm. HRMS

(ES⁺) calcd. C₁₅H₁₅³⁵ClNO [M⁺+H] 260.0837; found: 260.0826; calcd.

2-(4-Chlorophenyl)-4-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-ol

hydrobromide (41c): Synthesised according to the general method

for methoxy deprotection with BBr₃. Filtration afforded the product

1

as a pale yellow precipitate (12 mg, 31%) which showed: H NMR

(500 MHz, [D₆]DMSO): δ=0.86 (3H, d, J=6.7 Hz, (CH₃)₂CH), 0.92 (3H,

d, J=6.8 Hz, (CH₃)₂CH), 1.80–1.97 (1H, m, (CH₃)₂CH), 2.57 (1H, dt, J=

3.6, 7.1 Hz, H₄À THIQ), 3.15 (1H, dd, J=3.7, 12.4 Hz, H₃À THIQ), 3.75

(1H, dd, J=3.9, 12.4 Hz, H₃À THIQ), 4.11 (1H, d, J=15.1 Hz, H₁À THIQ),

4.37 (1H, d, J=15.0 Hz, H₁À THIQ), 6.62 (1H, d, J=2.1 Hz, H₅À THIQ),

6.64 (1H, dd, J=2.4, 8.2 Hz, H₇À THIQ), 6.91 (2H, d, J=9.0 Hz, 2×

ArCH, phenyl), 7.03 (1H, d, J=8.2 Hz, H₈À THIQ), 7.23 (2H, d, J=

9.0 Hz, 2×ArCH, phenyl) and 9.27 (1H, bs, OH) ppm. ¹³C NMR

(126 MHz, [D₆]DMSO): δ=19.7 ((CH₃)₂CH), 21.1 ((CH₃)₂CH), 30.1

((CH₃)₂CH), 44.8 (C₄À THIQ), 45.7 (C₃À THIQ), 48.6 (C₁₄À THIQ), 113.5

(C₇À THIQ), 114.3 (2×ArCH, phenyl), 114.8 (C₅À THIQ), 120.1 (ArCCl),

123.9 (C₁CC₈À THIQ), 127.5 (C₈À THIQ), 128.6 (2×ArCH, phenyl), 138.9

(C₁CC₄À THIQ), 148.5 (ArCN) and 155.3 (C₆À THIQ) ppm. Mp 190–

37

+

°

C₁₅H₁₅ClNO [M +H] 262.0807; found: 262.0830. Mp 271–274 C

(as hydrobromide).

2-(4-Chlorophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol

hydrobromide (40a): Synthesised according to the general method

for methoxy deprotection with BBr₃. Filtration afforded the product

as a white precipitate (429 mg, 87%) which showed: ¹H NMR

(500 MHz, [D₆]DMSO): δ=0.91 (3H, d, J=6.5 Hz, CHCH₃), 2.59 (1H,

dd, J=1.6, 15.7 Hz, H₄À THIQ), 3.06 (1H, dd, J=5.3, 15.7 Hz,

H₄À THIQ), 4.03 (1H, d, J=15.3 Hz, H₁À THIQ), 4.29–4.31 (1H, m,

H₃À THIQ), 4.32 (1H, d, J=15.3 Hz, H₁À THIQ), 6.60 (1H, d, J=2.2 Hz,

H₅À THIQ), 6.63 (1H, dd, J=2.2, 8.2 Hz, H₇À THIQ), 6.93 (2H, d, J=

9.1 Hz, 2×ArCH, phenyl), 7.04 (1H, d, J=8.2 Hz, H₈À THIQ), 7.23 (2H,

d, J=9.0 Hz, 2×ArCH, phenyl) and 9.26 (1H, bs, OH) ppm. ¹³C NMR

(126 MHz, [D₆]DMSO): δ=15.3 (CHCH₃), 34.9 (C₄À THIQ), 44.9

(C₁À THIQ), 47.5 (C₃À THIQ), 113.3 (C₇À THIQ), 115.0 (C₅À THIQ), 115.1

(2×ArCH, phenyl), 120.4 (ArCCl), 123.3 (C₁CC₈À THIQ), 127.2

(C₈À THIQ), 128.7 (2×ArCH, phenyl), 133.8 (C₁CC₄-THI), 147.8 (ArCN)

°

193 C.

4-Benzyl-2-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

hydrobromide (41d): Synthesised according to the general method

for methoxy deprotection with BBr₃. The crude compound was

purified by reversed phase column chromatography (eluent: from

10 to 100% MeOH in water) to give the desired product as a yellow

1

solid (201 mg, 66%) which showed: H NMR (500 MHz, [D₆]DMSO):

δ=2.78 (1H, dd, J=10.2, 13.3 Hz, ArCH₂, benzyl), 2.96 (1H, dd, J=

4.9, 13.5 Hz, ArCH₂, benzyl), 3.05 (1H, dd, J=3.2, 12.1 Hz, H₃À THIQ),

3.11–3.20 (1H, m, H₄À THIQ), 3.38 (3H, dd, J=4.3, 12.1 Hz, H₃À THIQ),

4.08 (1H, d, J=15.0 Hz, H₁À THIQ), 4.45 (1H, d, J=15.0 Hz, H₄À THIQ),

6.60–6.69 (2H, m, H₅, H₇À THIQ), 6.80 (2H, d, J=8.9 Hz, 2×ArCH,

phenyl), 7.04 (1H, d, J=8.9 Hz, H₈À THIQ), 7.18–7.28 (5H, m, 3×ArCH,

benzyl, 2×ArCH, phenyl), 7.32 (2H, t, J=7.4 Hz, 2×ArCH, benzyl)

°

and 155.8 (C₆À THIQ) ppm. Mp 240–242 C.

2-(4-Chlorophenyl)-4-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol

hydrobromide (41a): Synthesised according to the general method

for methoxy deprotection with BBr₃. Filtration afforded the product

as a yellow precipitate (178 mg, 58%) which showed: ¹H NMR

(500 MHz, [D₆]DMSO): δ=1.25 (3H, d, J=6.9 Hz, CHCH₃), 2.92–3.04

(1H, m, H₄À THIQ), 3.21 (1H, dd, J=6.6, 12.2 Hz, H₃À THIQ), 3.47 (1H,

dd, J=4.4, 12.2 Hz, H₃À THIQ), 4.20 (1H, d, J=15.0 Hz, H₁À THIQ), 4.28

(1H, d, J=15.0 Hz, H₁À THIQ), 6.61 (1H, dd, J=2.3, 8.3 Hz, H₇À THIQ),

6.66 (1H, d, J=2.3 Hz, H₅À THIQ), 6.95 (2H, d, J=9.0 Hz, 2×ArCH,

phenyl), 7.00 (1H, d, J=8.3 Hz, H₈À THIQ), 7.23 (2H, d, J=9.0 Hz, 2×

ArCH, phenyl) and 9.25 (1H, bs, OH) ppm. ¹³C NMR (126 MHz, [D₆]

DMSO): δ=19.3 (CHCH₃), 32.3 (C₄À THIQ), 49.0 (C₁À THIQ), 52.2

(C₃À THIQ), 113.2 (C₅À THIQ), 113.3 (C₇À THIQ), 115.5 (2×ArCH,

phenyl), 120.8 (ArCCl), 123.7 (C₁CC₈À THIQ), 127.3 (C₈À THIQ), 128.6

°

and 9.30 (1H, bs, OH) ppm. Mp 172–175 C.

2-(4-Chlorophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-

ol hydrobromide (41f): Synthesised according to the general

method for methoxy deprotection with BBr₃. Filtration afforded the

product as a white precipitate (81 mg, 85%) which showed: ¹H NMR

(500 MHz, [D₆]DMSO): δ=1.26 (6H, s, (CH₃)₂C), 3.22 (2H, s, H₃À THIQ),

4.23 (2H, s, H₁À THIQ), 6.61 (1H, dd, J=2.3, 8.3 Hz, H₇À THIQ), 6.77

(1H, d, J=2.3 Hz, H₅À THIQ), 6.98 (1H, d, J=8.3 Hz), 6.98 (2H, d, J=

9.1 Hz, 2×ArCH, phenyl), 7.25 (2H, d, J=9.1 Hz, 2×ArCH, phenyl)

and 9.20 (1H, bs, OH) ppm. ¹³C NMR (126 MHz, [D₆]DMSO): δ=27.7

((CH₃)₂C), 35.2 (C₄À THIQ), 49.6 (C₁À THIQ), 58.5 (C₃À THIQ), 111.4

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(C₅À THIQ), 113.4 (C₇À THIQ), 115.6 (2×ArCH, phenyl), 121.0 (ArCCl),

122.8 (C₁CC₈À THIQ), 127.3 (C₈À THIQ), 128.6 (2×ArCH, phenyl), 144.5

(C₄CC₅À THIQ), 149.3 (ArCN) and 155.9 (C₆À THIQ) ppm. HRMS (ES⁺)

calcd. C₁₇H₁₉³⁵ClNO [M⁺+H] 288.1150; found: 288.1137; calcd.

(1H, dd, J=2.5, 8.2 Hz, H₇À THIQ), 6.74 (2H, d, J=9.0 Hz, 2×ArCH, N-

phenyl), 7.14 (1H, d, J=8.2 Hz, H₈À THIQ), 7.15 (2H, d, J=9.0 Hz, 2×

ArCH, N-phenyl), 7.19 (2H, d, J=6.9 Hz, 2×ArCH, C₁-phenyl) and

7.22–7.27 (3H, m, 3×ArCH, C₁-phenyl) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ=28.0 (C₄À THIQ), 43.8 (C₃À THIQ), 62.3 (C₁À THIQ), 113.3

(C₇À THIQ), 114.7 (C₅À THIQ), 115.1 (2×ArCH, N-phenyl), 122.3

(ArCCl), 126.9 (ArCH, C₁-phenyl), 127.2 (2×ArCH, C₁-phenyl), 128.3

(2×ArCH, C₁-phenyl), 128.9 (2×ArCH, N-phenyl), 129.0 (C₈À THIQ),

130.1 (C₁CC₈À THIQ), 137.1 (C₄CC₅À THIQ), 142.9 (ArCCH₂, C₁-phenyl),

148.1 (ArCN) and 154.5 (C₆À THIQ) ppm. HRMS (ES⁺) calcd.

C₂₁H₁₉³⁵ClNO [M⁺+H] 336.1150; found: 336.1133; calcd.

1

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37

+

°

C₁₇H₁₉ClNO [M +H] 290.1120; found: 290.1141. Mp 207–211 C.

2-(4-Chlorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol

hydrobromide (42a): Synthesised according to the general method

for methoxy deprotection with BBr₃. The product was obtained as a

white solid (130 mg, 41%) which showed: ¹H NMR (500 MHz,

CDCl₃): δ=1.37 (3H, d, J=6.7 Hz, CH₃), 2.81 (1H, dt, J=4.6, 16.0 Hz,

H₄À THIQ), 2.88–3.05 (1H, m, H₄À THIQ), 3.35–3.49 (1H, m, H₃À THIQ),

3.54 (1H, dt, J=5.2, 12.2 Hz, H₃À THIQ), 4.79 (1H, q, J=6.7 Hz,

H₁THIQ), 6.63 (1H, d, J=2.5 Hz, H₅À THIQ), 6.68 (1H, dd, J=2.6,

8.3 Hz, H₇À THIQ), 6.81 (2H, d, J=9.1 Hz, 2×ArCH, phenyl), 6.99 (1H,

d, J=8.3 Hz, H₈À THIQ) and 7.19 (2H, d, J=9.1 Hz, 2×ArCH, phenyl)

ppm. ¹³C NMR (126 MHz, CDCl₃): δ=20.8 (CH₃), 28.4 (C₄À THIQ), 41.0

(C₃À THIQ), 54.0 (C₁À THIQ), 113.5 (C₇À THIQ), 114.8 (C₅À THIQ), 115.8

(2×ArCH, phenyl), 122.3 (ArCCl), 128.0 (C₈À THIQ), 129.0 (2×ArCH,

phenyl), 132.0 (C₁CC₈À THIQ), 135.8 (C₄CC₅À THIQ), 148.1 (ArCN) and

153.9 (C₆À THIQ) ppm. HRMS (ES⁺) calcd. C₁₆H₁₇³⁵ClNO [M⁺+H]

274.0993; found: 274.0979; calcd. C₁₆H₁₇³⁷ClNO [M⁺+H] 276.0964;

37

+

°

C₁₆H₁₇ClNO [M +H] 338.1120; found: 338.1140. Mp 227–228 C.

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1-Benzyl-2-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

hydrobromide (42f): Synthesised according to the general method

for methoxy deprotection with BBr₃. The product was obtained as a

yellow precipitate (62 mg, 44%) which showed:^{[38] 1}H NMR

(400 MHz, CDCl3): δ=2.64 (1H, dt, J=5.7, 15.9 Hz), 2.80–2.91 (1H,

m), 2.94 (1H, dd, J=7.1, 13.3 Hz), 3.15 (1H, dd, J=6.0, 13.3 Hz),

3.38–3.49 (1H, m), 3.50–3.61 (1H, m), 4.75 (1H, t, J=6.5 Hz), 6.53–

6.62 (2H, m), 6.64 (1H, d, J=2.1 Hz), 6.69 (2H, d, J=9.1 Hz), 6.99 (2H,

dd, J=1.8, 7.5 Hz), 7.13 (2H, d, J=9.1 Hz) and 7.16–7.23 (3H, m)

ppm. HRMS (ES⁺) calcd. C₂₂H₂₁³⁵ClNO [M⁺+H] 350.1306; found:

350.1296; calcd. C₂₁H₁₉³⁷ClNO [M⁺+H] 352.1277; found: 352.1331.

°

found: 276.0981. Mp 210–213 C.

2-(4-Chlorophenyl)-1-ethyl-1,2,3,4-tetrahydroisoquinolin-6-ol hy-

drobromide (42b): Synthesised according to the general method

for methoxy deprotection with BBr₃. The product was obtained as a

white solid (57 mg, 61%) which showed: ¹H NMR (500 MHz, [D₆]

DMSO): δ=0.88 (3H, t, J=7.3 Hz, CH₃), 1.52–1.68 (1H, m, CH₃CH₂),

1.72–1.87 (1H, m, CH₃CH₂), 2.73 (1H, dt, J=5.5, 16.0 Hz, H₄À THIQ),

2.83 (1H, dt, J=6.5, 13.3 Hz, H₄À THIQ), 3.43–3.50 (2H, m, H₃À THIQ),

4.49 (1H, t, J=7.0 Hz, H₁À THIQ), 6.48–6.63 (2H, m, H₅, H₇À THIQ), 6.84

(2H, d, J=8.8 Hz, 2×ArCH, phenyl), 6.96 (1H, d, J=8.0 Hz, H₈À THIQ),

7.17 (2H, d, J=8.8 Hz, 2×ArCH, phenyl) and 9.33 (1H, bs, OH) ppm.

¹³C NMR (126 MHz, [D₆]DMSO): δ=11.1 (CH₃), 26.4 (C₄À THIQ), 28.9

(CH₃CH₂), 41.0 (C₃À THIQ), 58.9 (C₁À THIQ), 112.9 (C₅or C₇À THIQ),

114.4 (2×ArCH, phenyl), 114.6 (C₅or C₇À THIQ), 119.5 (ArCCl), 128.3

(C₈À THIQ), 128.6 (C₁CC₈À THIQ), 128.7 (2×ArCH, phenyl), 135.6

(C₄CC₅À THIQ), 148.1 (ArCN) and 155.8 (C₆À THIQ) ppm. HRMS (ES⁺)

calcd. C₁₇H₁₉³⁵ClNO [M⁺+H] 290.1120; found: 290.1107. Mp 184–

°

Mp 143–147 C.

2-(4-Chlorophenyl)-1-phenethyl-1,2,3,4-tetrahydroisoquinolin-6-

ol hydrobromide (42g): Synthesised according to the general

method for methoxy deprotection with BBr₃. The product was

obtained as a white precipitate (98 mg, 61%) which showed: ¹H

NMR (500 MHz, [D₆]DMSO): δ=1.85–2.01 (1H, m, ArCH₂CH₂CH),

2.01–2.13 (1H, m, ArCH₂CH₂CH), 2.58–2.70 (2H, m, ArCH₂CH₂CH),

2.74 (1H, dt, J=6.1, 14.0 Hz, H₄À THIQ), 2.85 (1H, dt, J=6.1, 14.0 Hz,

H₄À THIQ), 3.53 (2H, t, J=6.1 Hz, H₃À THIQ), 4.62 (1H, t, J=7.0 Hz,

H₁À THIQ), 6.56 (1H, d, J=2.3 Hz, H₅À THIQ), 6.59 (1H, dd, J=2.3,

8.3 Hz, H₅À THIQ), 6.82 (2H, d, J=9.1 Hz, 2×ArCH, N-phenyl), 7.02

(1H, d, J=8.3 Hz, H₈À THIQ), 7.12–7.18 (3H, m, 2×ArCH, N-phenyl,

ArCH, phenyl), 7.19 (2H, d, J=7.4 Hz, 2×ArCH, phenyl), 7.27 (2H, t,

J=7.5 Hz, 2×ArCH, phenyl) and 9.27 (1H, bs, OH) ppm. ¹³C NMR

(126 MHz, [D₆]DMSO): δ=26.1 (C₄À THIQ), 32.2 (ArCH₂CH₂CH), 37.9

(ArCH₂CH₂CH), 40.8 (C₃À THIQ), 57.1 (C₁À THIQ), 113.0 (C₇À THIQ),

114.6 (C₅À THIQ), 114.7 (2×ArCH, N-phenyl), 119.8 (ArCCl), 125.7

(ArCH, phenyl), 128.1 (C₈À THIQ), 128.2 (2×ArCH, phenyl), 128.3 (2×

ArCH, phenyl), 128.6 (C₁CC₈À THIQ), 128.7 (2×ArCH, N-phenyl), 135.7

(C₄CC₅À THIQ), 141.7 (ArCCH₂, phenyl), 148.0 (ArCN) and 155.8

(C₆À THIQ) ppm. HRMS (ES⁺) calcd. C₂₃H₂₃³⁵ClNO [M⁺+H] 364.1463;

found: 364.1456; calcd. C₂₃H₂₃³⁷ClNO [M⁺+H] 366.1433; found:

°

187 C.

2-(4-Chlorophenyl)-1-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-ol

hydrobromide (42c): Synthesised according to the general method

for methoxy deprotection with BBr₃. The product was obtained as a

pale grey solid (37 mg, 58%) which showed: ¹H NMR (500 MHz, [D₆]

DMSO): δ=0.86 (3H, d, J=6.3 Hz, (CH₃)₂CH), 0.93 (3H, d, J=6.9 Hz,

(CH₃)₂CH), 1.98 (1H, td, J=6.8, 13.8 Hz, (CH₃)₂CH), 2.76–2.94 (2H, m,

H₄À THIQ), 3.37–3.40 (1H, m, H₃À THIQ), 3.58 (1H, dt, J=6.1, 12.4 Hz,

H₃À THIQ), 4.31 (1H, d, J=8.6 Hz, H₁À THIQ), 6.54 (1H, d, J=8.2 Hz,

H₇À THIQ), 6.56 (1H, s, H₅À THIQ), 6.86 (2H, d, J=8.6 Hz, 2×ArCH,

phenyl), 6.95 (1H, d, J=8.2 Hz, H₈À THIQ), 7.14 (2H, d, J=8.0 Hz, 2×

ArCH, phenyl) and 9.30 (1H, bs, OH) ppm. ¹³C NMR (126 MHz, [D₆]

DMSO): δ=19.9 ((CH₃)₂CH), 20.3 ((CH₃)₂CH), 26.4 (C₄À THIQ), 33.6

((CH₃)₂CH), 41.9 (C₃À THIQ), 62.9 (C₁À THIQ), 112.2 (C₇À THIQ), 114.2

(2×ArCH, phenyl), 114.7 (C₅À THIQ), 119.2 (ArCCl), 127.7

(C₁CC₈À THIQ), 128.5 (2×ArCH, phenyl), 129.1 (C₈À THIQ), 135.8

(C₄CC₅À THIQ), 148.5 (ArCN) and 156.0 (C₆À THIQ) ppm. HRMS (ES^À)

calcd. C₁₈H₁₉³⁵ClNO [M^ÀÀ H] 300.1155; found: 300.1151; calcd.

°

366.1465. Mp 190–192 C.

1-Benzyl-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol hydrobro-

mide (42h): Synthesised according to the general method for

methoxy deprotection with BBr₃. The product was obtained as a

dark green precipitate (118 mg, 87%) which showed:^{[31] 1}H NMR

(500 MHz, [D₆]DMSO): δ=2.62 (1H, dt, J=4.7, 16.2 Hz, H₄À THIQ),

2.78–2.90 (1H, m, H₄À THIQ), 2.95 (1H, dd, J=6.8, 13.4 Hz, CH₂CH),

3.11 (1H, dd, J=6.8, 13.4 Hz, CH₂CH), 3.49–3.64 (2H, m, H₃À THIQ),

4.87 (1H, t, J=6.8 Hz, H₁À THIQ), 6.48 (1H, dd, J=2.2, 8.2 Hz,

H₇À THIQ), 6.53 (1H, d, J=2.2 Hz, H₅À THIQ), 6.59 (1H, t, J=7.2 Hz,

ArCH), 6.72–6.81 (3H, m, 2×ArCH, H₈À THIQ), 7.11 (2H, t, J=7.9 Hz,

2×ArCH), 7.13–7.19 (3H, m, 3×ArCH), 7.23 (2H, t, J=7.3 Hz, 2×

ArCH) and 9.21 (1H, bs, OH) ppm. ¹³C NMR (126 MHz, [D₆]DMSO):

δ=26.1 (C₄À THIQ), 40.3 (C₃À THIQ), 41.7 (CH₂CH), 59.8 (C₁À THIQ),

112.7 (C₇À THIQ), 113.3 (2×ArCH), 114.5 (C₅À THIQ), 116.5 (ArCH),

125.9 (ArCH), 127.9 (2×ArCH), 128.1 (C₁CC₈À THIQ), 128.3 (C₈À THIQ),

129.0 (2×ArCH), 129.5 (2×ArCH), 135.8 (C₄CC₅À THIQ), 139.1

37

À

°

C₁₈H₁₉ClNO [M À H] 302.1131; found: 302.1135. Mp 111–115 C.

2-(4-Chlorophenyl)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol

hydrobromide (42e): Synthesised according to the general method

for methoxy deprotection with BBr₃. The product was obtained as a

white solid (247 mg, 79%) which showed: ¹H NMR (500 MHz,

CDCl₃): δ=2.80–2.94 (2H, m, H₄À THIQ), 3.44 (1H, ddd, J=5.7, 8.1,

11.4 Hz, H₃À THIQ), 3.65 (1H, dt, J=5.5, 11.2 Hz, H₃À THIQ), 4.69 (1H,

bs, OH), 5.70 (1H, s, H₁À THIQ), 6.65 (1H, d, J=2.5 H, H₅À THIQ), 6.70

°

(ArCCH₂CH), 149.1 (ArCN) and 155.6 (C₆À THIQ) ppm. Mp 137–141 C.

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Article Doi

N-Phenyl-1,2,3,4-tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β-Hydroxysteroid Dehydrogenase 1 Inhibitors

DOI: 10.1002/cmdc.202000762

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