Sequential One-Pot Vilsmeier-Haack and Organocatalyzed Mannich Cyclizations to Functionalized Benzoindolizidines and Benzoquinolizidines

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Sequential One-Pot Vilsmeier−Haack and Organocatalyzed Mannich

Cyclizations to Functionalized Benzoindolizidines and

Benzoquinolizidines

́

Johanne Outin, Pauline Quellier, and Guillaume Belanger*

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ABSTRACT: The development of new one-pot sequential

cyclizations involving a Vilsmeier−Haack reaction followed by an

organocatalyzed Mannich reaction is reported. This synthetic

strategy gives access to functionalized indolizidines and quinolizi-

dines in one operation from readily synthesized precursors. Yields

and diastereoselectivities are good to excellent when formamides

are used to trigger the key step, bearing either an electron-rich aryl

or a pyrrole as the nucleophilic partner in the ﬁrst cyclization.

the presence of a latent nucleophile that would be unveiled

after the Vilsmeier−Haack cyclization. One of the best carbon

π-nucleophile we thought would ﬁt this requirement is an

enamine, prepared in situ from the corresponding aldehyde or

ketone 8. This way, we expect to be able to widen the range of

accessible molecular scaﬀolds containing the indolizidines and

quinolizidines 9, with suitable strategic functionalization for

synthetic applications.

INTRODUCTION

■

Substituted indolizidines and quinolizidines are attractive

molecular scaﬀold because of their high occurrence in natural

products exhibiting notable biological activity, as represented

by the Erythrina family (erythraline shown), (+)-oleracein E,

(+)-harmicine, (−)-tangutorine, and vincamine (Figure 1).¹

These scaﬀolds could also be found in several drugs developed

by the pharmaceutical industry.

Although organocatalyzed Mannich reactions have been

extensively studied,⁴⁵using such a reaction in a one-pot

sequential process presents signiﬁcant challenges. First, the

amide activation for the Vilsmeier−Haack cyclization needs to

be performed chemoselectively in the presence of a ketone or

an aldehyde 7.⁶Second, the iminium intermediate 8 has to be

stable enough in solution so that a complete Vilsmeier−Haack

cyclization occurs before the addition of amine to launch the

intramolecular Mannich reaction. Third, water generated

during the amine condensation with the aldehyde or ketone

8 should not hydrolyze the remaining iminium intermediate 8.

Fourth, the amine added for enamine formation must not react

with the iminium intermediate 8 or at least not irreversibly.

Last, enamine regioisomers resulting from amine condensation

with the ketone 8 should reversibly interconvert so that ring

In our previous work, we reported an original approach with

two consecutive nucleophilic cyclizations onto the activated

amide 1 to access the quinolizidines 3 (Scheme 1).²The

originality of such an approach resides in its complementarity

with reported double cyclization strategies usually involving

C−N bond formation.³However, one of the limitations of our

initial approach is the second cyclization (Mannich), suﬀering

from reactivity issues. Indeed, the conjugated iminium

intermediate 2 could be trapped only with an allylsilane,

allylstannane, or indole as the nucleophile. The use of a

stronger nucleophile, such as an enol ether or an enamine 4, is

not possible because that nucleophile reacts in the ﬁrst

cyclization, leading to a conjugated iminium intermediate 5/6

that is essentially not reactive for the last cyclization step.

Another limitation to this initial work is the poor

functionalization of the ﬁnal quinolizidine 3, substituted with

only alkenes that would need to be diﬀerentiated in order to

further transform this scaﬀold into natural products or drugs.

Although strategies to increase the reactivity of the iminium

ion for the Mannich cyclization were envisaged, a simpler

solution is to rather increase the reactivity of the nucleophile.

To do so, we need to run the Vilsmeier−Haack cyclization in

Received: December 30, 2019

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A

The Journal of Organic Chemistry

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Figure 1. Representative indolizidine, quinolizidine, and cyclohexapiperazine alkaloids and drugs.

Scheme 1. Targeted Transformation

size in the organocatalyzed Mannich cyclization could be

controlled.

Scheme 2. Synthesis of the Aldehydes 16a,b

RESULTS AND DISCUSSION

■

We started our investigation by testing the reaction cascade on

substrates bearing an aldehyde. Substrates 16a and 16b were

prepared according to the route detailed in Scheme 2.

Quantitative reduction of 2,2-dimethylglutaric acid (10)

followed by monoprotection and Swern oxidation aﬀorded

aldehyde 12b.⁷Aldehydes 12a⁸and 12b were then

independently subjected to three consecutive steps performed

one-pot, starting with a condensation with amine 13 followed

by reduction of the corresponding imine and formylation with

N-formylbenzotriazole (N-(CHO)Bt). After deprotection of

the silyl ethers 14a,b, a Swern oxidation aﬀorded the desired

aldehydes 16a and 16b.

Upon treatment of the substrate 16a with triﬂic anhydride,

we were pleased to see a complete amide activation and

trapping of the resulting triﬂyliminium ion with the aryle to

generate the iminium ion intermediate 17a with satisfactory

preservation of the aldehyde group (Table 1). To the best of

our knowledge, this is the ﬁrst report of a chemoselective

amide activation and nucleophilic trapping in the presence of

an aldehyde.⁶This Vilsmeier−Haack cyclization was per-

formed at low temperature (−64 to −15 °C) over a period of 1

h. Three equivalents of piperidine were added and the

quinolizidine 18a was obtained in 30% yield as a single

trans-diastereomer (entry 1). To ensure that the Mannich

cyclization was catalyzed by piperidine, the noncatalyzed

B

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a

Table 1. Development of One-pot Vilsmeier−Haack/Organocatalyzed Mannich Cyclizations

d

entry

substrate

additive (equiv)

time

temperature (°C)

product (yield)

18a (30%)

0

d.r.

1

2

3

4

5

6

7

8

9

16a

16b

piperidine (3)

none

CSA (5)

3 d

18 h

rt

−15

70

−15

>19:1

Et₃N (3)

piperidine (3)

piperidine (15)

40

18a (<20%)

18a (52%)

18a (45%)

>19:1

7.5:1

b

pyrrolidine (3)

piperidine (3)

c

18b (37%, 63% brsm )

a

Reaction conditions for the Vilsmeier−Haack cyclization (16 to 17): (i) Tf₂O (1.1 equiv), DTBMP (1.1 equiv), CDCl₃(0.05 M), −64 to −15

b

c

d

°C, 1 h. The reaction mixture was diluted to 0.003 M with CDCl₃. Yield based on the recovered starting material 16b. Diastereomeric ratio

determined by H NMR analysis of crude material.

1

background reaction was tested (no piperidine added) and no

quinolizidine was observed (entry 2). To discard any catalytic

eﬀect of piperidine due to simple enolization of the aldehyde

rather than formation of an enamine, the reaction was tested in

acidic (CSA, entry 3) or basic (Et₃N, entry 4) conditions.

Again, no conversion occurred. Temperature proved to be

critical: increasing temperature from −15 °C to rt or to 70 °C

resulted in a dramatic yield loss (entries 5, 1, and 6,

respectively). To better understand this observation, we

activated the amide 16a without treating with piperidine

Scheme 3. Possible Piperidine Addition to the Iminium

Intermediate

1

afterward and proved by H NMR that the iminium ion 17a

decomposed at 0 °C in less than 30 min.

Besides the poor stability of the iminium intermediate 17a,

we thought two other factors could impede the overall

conversion. One is a competition between intramolecular and

intermolecular addition of the transient piperidine enamine of

the aldehyde 17a. Hence, to favor intramolecular attack of the

enamine, dilution of the reaction medium before addition of

piperidine was operated and, interestingly, the yield improved

signiﬁcantly, now up to 52% (entry 7). The second factor is a

possible competitive addition of piperidine onto the iminium

portion of the intermediate 17a rather than on the aldehyde. If

the addition on the iminium ion occurs and is poorly

reversible, the ﬁnal Mannich cyclization would be hampered

and the intermediate 17a (or its piperidine adduct) would

decompose over time. To verify this last hypothesis, a model

substrate lacking the aldehyde portion was synthesized

(Scheme 3). The substrate 20 was prepared from amine 13

in two almost quantitative steps. Upon activation, amide 20

was trapped with the aryl group. Piperidine was then added to

the resulting iminium ion 21. After 6 days at room

of the molecule. Switching to pyrrolidine (Table 1, entry 8)

accelerated the overall process, and the yield was slightly better

than that with piperidine (entry 5). To increase the yield, it

seemed that the possible options were to accelerate the

organocatalyzed Mannich reaction or to improve the stability

of the iminium intermediate. To accelerate the Mannich

reaction, we opted for a Thorpe−Ingold eﬀect by adding a

gem-dimethyl group on the alkyl chain containing the aldehyde,

combined to a reduction of reaction time to limit a possible

degradation of the iminium intermediate 17b. The anticipated

acceleration did not materialize: roughly the same yield was

obtained with substrates 16b (37%, entry 9) and 16a (40%,

entry 5), with an incomplete conversion for the gem-

dimethylated substrate 16b in the former case.^9,10

To improve the stability of the iminium intermediate, we

decided to switch to ketones instead of aldehydes. Therefore,

the keto-amide 28a was prepared following the synthetic

sequence presented in Scheme 4. The synthesis started with

the quantitative opening of lactone 23 with amine 13 using

AlMe₃, followed by reduction of the resulting amide 24 to the

amino alcohol 25. Attempts to perform a selective formylation

of the amine gave mixtures of monoformylated product 27 and

N,O-diformylated congener 26. Thus, we decided to perform

an extensive formylation of 26 followed by a selective formate

methanolysis to successfully aﬀord the alcohol 27 in 73% yield

1

temperature, analysis of the H NMR spectrum showed that

integrity of the iminium ion 21 was preserved, without any

observable addition of piperidine to form the ammonium 22a

and/or 22b. This proves that addition of the secondary amine

is either not occurring or is reversible with a strong preference

toward the conjugated iminium ion 21 over the ammonium

ions 22a,b. It should be noted that the observed stability of the

iminium 21 over 6 days at rt is a strong indication that the low

stability of the iminium ion 17a is due to the aldehyde portion

C

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(entry 3) and that acid or base-promoted enolization of the

ketone (and subsequent Mannich) is not operating (entries 4

and 5, respectively). Other secondary (morpholine and

diethylamine, entries 6 and 7, respectively) or primary

(cyclohexylamine, entry 8) amines all furnished the bicyclic

product 30a in similar yields. The amount of needed secondary

Scheme 4. Synthesis of the Ketone 28a

1

amine catalyst was determined by H NMR experiment. After

amide activation and Vilsmeier−Haack cyclization, there is 1

equiv of 2,6-di-tert-butyl-4-methylpyridinium triﬂate (DTBMP·

HOTf) generated. Because the secondary amines tested are

more basic than 2,6-di-tert-butyl-4-methylpyridine (DTBMP),

3 equiv of secondary amine were necessary to observe 1 equiv

of basic amine in solution.¹¹Lower amounts of secondary

amine (down to 0.5 equiv of pyrrolidine) still catalyze the

reaction, but a tertiary amine (2 equiv of DIPEA) is usually

needed to ensure enough nonprotonated secondary amine is

present in solution (entry 9). Higher amounts of secondary

amine (up to 35 equiv) accelerate the reaction but ruins any

¹H NMR analysis of the progression of the reaction.

When we get a closer look at the major diastereomers of

quinolizidines 18a and 30a (Figure 2), in the aldehyde and

over the last three steps. A Swern oxidation furnished the

desired keto-amide 28a.

After activation of the amide 28a in the usual conditions, we

were pleased to observe that the iminium intermediate 29 was

much more stable than its aldehyde analogue 17a or 17b; the

Vilsmeier−Haack reaction could now be run at 0 °C for only 5

min, and the integrity of iminium intermediate 29 is preserved

at room temperature over at least 18 h (proven by ¹H NMR).

Preliminary tests with substrate 28a using 3 equiv of

pyrrolidine or piperidine aﬀorded the desired compound 30a

as a single diastereomer in good yields (Table 2, entries 1 and

2, respectively), with pyrrolidine being the best catalyst for the

ketone substrate as well.

Because the condensation of an amine with a ketone may

present diﬀerent kinetics than with an aldehyde, it was

necessary to rule out the uncatalyzed Mannich reaction with

this ketone substrate as well. Hence, we proved that the

secondary amine was necessary for the second cyclisation

Figure 2. X-ray structures of quinolizidines 18a and 30a.¹²

ketone series, respectively, we notice an intriguing opposite

diastereomeric relation. We explain this diﬀerence with a

model presented in Scheme 5. The Mannich cyclization of

aldehyde enamine 31 or ketone enamine 32 should process

through the least hindered transition state TS1 also presenting

the lowest global dipole. Therefore, the direct diastereomeric

product of cyclization should be cis and presents an

equatorially oriented carbonyl substituent. However, the less

congested axially oriented carbonyl in the trans isomer should

be thermodynamically favored, now allowing a trans ring

junction in the quinolizidine portion of the molecule (cf. X-ray

structures of 18a and 30a, Figure 2).^12,13Epimerization to the

axial carbonyl group necessitates enolization, either to the

corresponding enamine (34, X = pyrrole) or ketone (34, X =

O). Such enolization is not likely in the ketone series,

presenting severe steric interactions in 34 (R = Me), and this

may account for the observed trans isomer in the aldehyde

series only. This rationale applies to all quinolizidines and

indolizidines found in Table 3 (vide infra).

a

Table 2. Screening of Amines

entry

additive

yield (%)

1

2

3

4

5

6

7

8

9

pyrrolidine

piperidine

none

CSA

Et₃N

morpholine

Et₂NH

cyclohexylamine

73

44

0

51

48

45

55

The scope of the reaction was studied with a series of

veratrole substrates bearing a formamide or acetamide, linked

to a ketone with diﬀerent tether length. Those substrates

(28b−f, depicted in Table 3) were synthesized following the

strategy described in Scheme 4, starting with lactones of

diﬀerent ring sizes. We also investigated heteroaromatic

nucleophiles for the initial Vilsmeier−Haack cyclization. The

pyrrolidine (0.5 equiv) + DIPEA (2 equiv)

a

Reaction conditions: (i) Tf₂O (1.1 equiv), DTBMP (1.1 equiv),

CDCl₃(0.05 M), 0 °C, 5 min; (ii) additive (3 equiv), rt, 18 h.

D

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a

Scheme 5. Mechanistic Proposition for

Table 3. Substate Scope

Diastereoselectivities Observed in 18a and 30a

pyrrole substrates 41a−c were synthesized according to the

route described in Scheme 6. The iodoethylpyrrole 37 was

obtained from condensation of commercially available 2,5-

dimethoxytetrahydrofuran (35) and 2-aminoethanol followed

by iodination.¹⁴The amines 38a,b were then alkylated with

iodide 37 and the corresponding amino alcohol were bis-

formylated then selectively methanolyzed. The resulting amido

alcohols were oxidized using Dess−Martin periodinane to

aﬀord the desired compound 39a−c.

Finally, indole substrates were also prepared. The 3-

substituted N-methylindoles 44a,b (depicted in Table 3)

were obtained from 1-methyltryptamine following the strategy

described in Scheme 4, whereas the compound 44c

necessitated a diﬀerent approach (Scheme 7). The ketone

chain was prepared from the alcohol 40.¹⁵Iodination and N-

alkylation with the anion of indole 42¹⁶aﬀorded dioxolane 43,

which was hydrolyzed to the desired ketone 44c.

a

Reaction conditions: (i) Tf₂O (1.1 equiv), DTBMP (1.1 equiv),

CDCl₃(0.05 M), 0 °C, 5 min; (ii) pyrrolidine (3 equiv), rt, 18 h.

b

The Vilsmeier−Haack cyclization was run at −15 °C for 45−60 min.

c

d

The Vilsmeier−Haack cyclization was run at rt for 4 h. Reaction run

e

in DCM. Reaction medium was diluted with CDCl₃to 0.003 M prior

to the addition of piperidine (15 equiv). The Mannich cyclization was

run at −15 C for 3 d. With pyrrolidine (3 equiv), 45% yield was

f

obtained. Piperidine (3 equiv) was used for the Mannich cyclization

g

at −15 C for 18 h. With piperidine (3 equiv), 44% yield was

obtained. 6 equiv of pyrrolidine were used. 1.5 equiv of pyrrolidine

was used. Diastereomeric ratio determined by H NMR analysis of

crude material. Major diastereomer not assigned.

h

i

j

1

k

The Vilsmeier−Haack cyclization is endo−exo according to

Ben-Ishai nomenclature for sp²nucleophiles reacting with sp²

electrophiles.¹⁷Hence, the electrophilic triﬂyliminium ion

resulting from amide activation is endocyclic with respect to

the ring in formation, and the nucleophile is exocyclic for all

substrates of Table 3, except for 28f, which presents an endo−

endo cyclization mode.¹⁸The Vilsmeier−Haack cyclization was

run at −15 °C over 1 h for the aldehyde substrates 16a,b,

whereas higher temperature (0 °C) and shorter time (5 min)

were suﬃcient for ketones substrates when formamides (28a,

28b, 28e, 28f, 39c, and 446a−c) were activated. In cases of

activation of acetamides (28c and 28d), the Vilsmeier−Haack

cyclization necessitated prolonged reaction time (4 h) at room

temperature. The Mannich cyclization catalyzed by piperidine

gave higher yields with aldehydes 16a,b, but in general,

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Scheme 6. Preparation of Pyrrole Substrates

Scheme 8. Possible Side Reactions with the Substrate 28f

Scheme 7. Preparation of Indole Substrates

onto iminium ion or retro aza-Michael reaction leading to the

fragmented product 48, which might account for the low yield

observed for quinolizidine 30f (Table 3, entry 8).

For substrates bearing a pyrrole instead of a veratrole unit as

the nucleophilic partner in the Vilsmeier−Haack cyclization,

we observed comparable good-to-excellent yields for the

formation of indolizidines (cf. 30e, entry 7, and 49, entry 9)

and quinolizidines (cf. 30a, entry 3, and 49b, entry 10). For

pyrrole substrate 49c (entry 11) as for the veratrole substrate

28c (entry 5), the formation of a quaternary center at ring

junction from activation of an acetamides proved to be

diﬃcult.

When indole is used as the initial nucleophile in the

Vilsmeier−Haack cyclization, the ensuing organocatalyzed

Mannich reaction is much less eﬃcient (see substrates 44a−

c, entries 12−14). A greater steric hindrance around the

iminium intermediate 53 generated by the N-substituted

indole ring likely accounts for the low overall yield, when

compared to veratrole 51 or pyrrole 52 analogues (Figure 3).

pyrrolidine was the best catalyst. In all cases, the secondary

amine for the organocatalyzed Mannich cyclization was used in

excess (3−6 equiv), and the best conditions are reported in

Table 3. Chloroform and dichloromethane (DCM) were both

good solvents for the sequential one-pot double cyclizations.

As for aldehydes 16a,b (entries 1 and 2), the gem-dimethyl

had essentially no eﬀect on the rate and yield for the Mannich

cyclization of ketone substrates 28a,b (entries 3 and 4,

respectively). For the ketone 28a, we obtained 73% overall

yield for the double cyclizations using pyrrolidine in the

organocatalyzed Mannich reaction, whereas only 44% yield

was obtained when using piperidine. From here, all other

substrates were treated with pyrrolidine only.

The formation of a quaternary center at ring junction from

the activation of acetamides 28c and 28d compared to their

formamide congeners 28a and 28b, respectively, revealed to be

challenging, as expected (entries 3−6). Here too, no Thorpe−

Ingold acceleration was observed with the gem-dimethylated

substrates 28b (cf. entries 3 vs 4) or 28d (cf. entries 5 vs 6).

Formation of a 5-membered ring in the Mannich cyclization

was much more eﬃcient (cf. entries 3 vs 7), with a nearly

quantitative overall yield for indolizidine 30e. It should be

noted that in cases depicted in entries 3−7, condensation of

the secondary amine with the ketone results in the most

substituted, thermodynamically favored enamine for the

Mannich cyclization. However, in entry 8, the enamine needs

to be formed in the terminal position (see 46, Scheme 8). If

enamines 46 and 47 equilibrate rapidly, low concentration of

the terminal enamine 46 is expected, thus slowing the Mannich

reaction. Hence, side reaction may take place, such as

intermolecular addition of the thermodynamic enamine 47

Figure 3. Congestion around the iminium ion intermediates 51, 52,

and 53.

CONCLUSIONS

■

In conclusion, we successfully developed a new one-pot

reaction sequence involving a Vilsmeier−Haack cyclization

followed by an organocatalyzed Mannich cyclization as a rapid

access to benzo- and pyrrolo-indolizidines and quinolizidines.

The Vilsmeier−Haack ﬁrst cyclization is compatible with

electron-rich aryl and pyrrole nucleophiles, as well as with free

ketones and even free aldehydes, to a certain extent. Higher

yields were obtained when formamides were reacted compared

to their acetamide congeners. The iminium intermediate

F

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2,2-Dimethyl-5-((triisopropylsilyl)oxy)pentanal (12b). A sol-

ution of crude 11 (9.54 g, 72.2 mmol) in THF (38 mL) was added

dropwise over 20 min to a suspension of NaH (60% dispersion in

mineral oil, 5.77 g, 144 mmol) in THF (150 mL) at 0 °C. The

mixture was stirred for 30 min at rt and then cooled to 0 °C. A

solution of TIPSCl (15.6 mL g, 72.8 mmol) in THF (12 mL) was

added dropwise, and the solution was stirred at 0 °C for 40 min.

Water was added, and the usual work-up (Et₂O) and puriﬁcation (2−

6% EtOAc in hexanes) aﬀorded 2,2-dimethyl-5-((triisopropylsilyl)-

oxy)pentan-1-ol (17.5 g, 84%) as a colorless oil. ¹H NMR (300 MHz,

CDCl₃): δ (ppm) 3.69 (t, J = 6.5 Hz, 2H), 3.35 (d, J = 6.0 Hz, 2H),

1.59−1.48 (m, 3H), 1.34−1.29 (m, 2H), 1.09 (s, 21H), 0.90 (s, 6H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 71.8 (t), 64.3 (t), 35.0

(s), 34.5 (t), 27.5 (t), 24.1 (q), 18.1 (q), 12.1 (d). IR (neat) ν

(cm⁻¹): 3345 (br), 2942, 2891, 2865. HRMS (positive ESI): calcd for

C₁₆H₃₆O₂SiNa [MNa⁺], 311.2377; found, 311.2385. Dimethyl

sulfoxide (DMSO, 5.0 mL, 70.3 mmol) was added to a solution of

oxalyl chloride (3.43 mL, 40.6 mmol) in DCM (200 mL) at −78 °C.

The reaction mixture was stirred for 30 min at −78 °C, and then, a

solution of 2,2-dimethyl-5-((triisopropylsilyl)oxy)pentan-1-ol (7.80 g,

27.0 mmol) in DCM (135 mL) was added. Stirring was continued for

1 h at −78 °C and then triethylamine (18.7 mL, 135 mmol) was

added. The solution was stirred for 1 h at −78 °C then allowed to

warm up to rt over 3 h. Water was added, and the usual work-up

(DCM) and puriﬁcation (2% EtOAc in hexanes) aﬀorded 12b (6.84

g, 88%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ (ppm) 9.43

(s, 1H), 3.64 (t, J = 6.0 Hz, 2H), 1.56−1.38 (m, 4H), 1.03 (s, 27H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 206.3 (d), 63.5 (t), 45.6

resulting from Vilsmeier−Haack cyclization does not interfere

with the enamine formation necessary for the organocatalyzed

Mannich cyclization. The latter gave generally higher yields

when pyrrolidine was used as the secondary amine and proved

to be much more eﬃcient in this organocatalyzed variant than

in our initially reported allylsilane version. Precursors to the

key double cyclizations are easily accessible, and the key

transformation gives high diastereoselectivities. This new

synthetic strategy is suitable for the preparation of libraries

of functionalized indolizidines and quinolizidines as privileged

structures to explore new chemical spaces in medicinal

chemistry programs.

EXPERIMENTAL SECTION

■

General Information. All reactions requiring anhydrous con-

ditions were conducted in ﬂame-dried glassware under a dry nitrogen

or argon atmosphere. Compounds lacking experimental details were

prepared according to the literature as cited and are in agreement with

published spectra. Tetrahydrofuran (THF) was distilled from Na and

benzophenone at atmospheric pressure. DCM, toluene, diisopropy-

lethylamine, triethylamine, and pyrrolidine were distilled from CaH₂

at atmospheric pressure. Triﬂic anhydride (Tf₂O), triﬂuoroacetic

anhydride, and chlorobenzene were distilled over a small amount of

P₂O₅at atmospheric pressure prior to use. Methanol was distilled over

4 Å molecular sieves at atmospheric pressure. DTBMP was

synthesized following the reported procedure in the literature.¹⁹All

other required ﬁne chemicals were used directly without puriﬁcation.

Thin-layer chromatography was conducted with precoated 60 Å 250

μm silica gel plates with a F-254 indicator and visualized using a

combination of UV and anisaldehyde, ceric ammonium molybdate,

iodine on silica, or potassium permanganate staining. Flash column

chromatography was performed using silica gel (230−400 mesh).

Infrared (IR) spectra were recorded with a Fourier-transform IR

instrument by applying substrates as thin ﬁlms. ¹H and proton-

decoupled ¹³C NMR spectra were recorded on 300 and/or 400 MHz

spectrometers. All chemical shifts are referenced to the residual

(s), 33.5 (t), 27.9 (t), 21.4 (q), 18.1 (q), 12.1 (d). IR (neat) ν

(cm⁻¹): 2959, 2944, 2886, 1724. HRMS (positive ESI): calcd for

C₁₆H₃₄O₂SiNa [MNa⁺], 309.2220; found, 309.2222.

N-(5-((tert-Butyldimethylsilyl)oxy)pentyl)-N-(3,4-

dimethoxyphenethyl)formamide (14a). 2-(3, 4-

Dimethoxyphenyl)ethylamine (0.91 mL, 5.41 mmol) was added to

a solution of 5-((tert-butyldimethylsilyl)oxy)pentanal²⁰(1.17 g, 5.41

mmol) in DCM (11 mL) at rt. The solution was stirred for 1 h at rt,

and then, anhydrous MgSO₄(1.30 g, 10.8 mmol) was added. The

mixture was stirred for 1 h at rt then ﬁltered and washed with DCM

(25 mL). MeOH (15 mL) and sodium borohydride (303 mg, 10.8

mmol) were added. The solution was stirred for 18 h at rt. Water (15

mL) was added and the usual work-up (DCM, brine) aﬀorded a

residue that was used directly in the next step. N-Formylbenzotriazole

(1.06 g, 6.49 mmol) was added to the residue dissolved in THF (27

mL). The solution was stirred for 18 h at rt, and then, the solvent was

removed under reduced pressure. The residue was dissolved in DCM

and washed with aqueous NaOH (2 M, 2 × 25 mL). The usual work-

up (DCM) and puriﬁcation (20−55% EtOAc in hexanes) aﬀorded

1

nondeuterated solvent. H NMR coupling constants are reported in

hertz and refer to apparent multiplicities and not true coupling

constants. Data for proton spectra are reported as follows: chemical

shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q),

quintet (quint), and multiplet (m)], integration, coupling constants

[Hz]). Carbon spectra were recorded with complete proton

decoupling and the chemical shifts are reported in ppm. Mass spectra

were recorded with an ESI-Q-TOF instrument.

Usual Reaction Workup and Puriﬁcation. After addition of the

indicated aqueous solution, layers were separated. The aqueous phase

was extracted with the indicated solvent, and the combined organic

phases were washed with the indicated aqueous solution (if needed),

dried over anhydrous MgSO₄, ﬁltered, and concentrated under

reduced pressure using a rotary evaporator. The crude material was

puriﬁed by ﬂash chromatography using silica gel with the indicated

eluent.

2,2-Dimethylpentane-1,5-diol (11). A solution of 2,2-dimethyl-

glutaric acid (10, 5.0 g, 31.2 mmol) in Et₂O (12.0 mL) was added

dropwise to a solution of LiAlH₄(4.0 g, 106 mmol) in Et₂O (170 mL)

at 0 °C, and the mixture was reﬂuxed for 18 h. The resulting mixture

was cooled at 0 °C and quenched with water (4.0 mL). An aqueous

solution of NaOH (15%, 4.0 mL) and water (12.0 mL) were added,

and the mixture was stirred vigorously at rt for 3 h. Anhydrous

Na₂SO₄was added, and the mixture was stirred for 15 min and

ﬁltered over Celite and concentrated under reduced pressure to aﬀord

11 as a colorless oil (4.21 g, 99%). The residue was used directly in

the next step. ¹H NMR (300 MHz, CDCl₃): δ (ppm) 3.64 (t, J = 6.3

Hz, 2H), 3.33 (s, 2H), 1.75 (br s, 2H), 1.59−1.49 (m, 2H), 1.34−

1.28 (m, 2H), 0.88 (s, 6H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ

(ppm) 71.0 (t), 63.3 (t), 34.9 (s), 34.3 (t), 26.9 (t), 24.3 (q). IR

(neat) ν (cm⁻¹): 3318 (br), 2943, 2869. HRMS (positive ESI): calcd

for C₇H₁₆O₂Na [MNa⁺], 155.1043; found, 155.1044.

1

14a (247 mg, 84%) as a colorless oil. H NMR (300 MHz, CDCl₃)

1:0.8 mixture of rotamers: δ (ppm) 8.05 (s) and 7.82 (s) (1H,

rotamers), 6.81−6.74 (m, 2H), 6.69−6.62 (m, 1H), 3.87 (s) and 3.86

(s) (3H, rotamers), 3.62−3.57 (m, 2H), 3.52−3.47 (m, 2H), 3.41 (t, J

= 7.0 Hz, 1H, rotamers), 3.35−3.30 (m, 1H), 3.11 (t, J = 7.0 Hz, 1H,

rotamers), 2.82−2.73 (m, 2H), 1.63−1.46 (m, 4H), 1.39−1.25 (m,

2H), 0.89 (s) and 0.88 (s) (9H, rotamers), 0.04 (s) and 0.03 (s) (6H,

rotamers). ¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ

(ppm) 162.7, 162.6, 149.0, 148.9, 147.8, 147.6, 131.3, 130.3, 120.8,

120.6, 111.9, 111.4, 111.2, 62.9, 62.7, 55.85, 55.82, 49.1, 47.9, 44.2,

42.3, 35.0, 33.2, 32.4, 32.2, 28.5, 27.2, 25.92, 25.89, 23.2, 22.8, 18.28,

18.26, −5.33, −5.35. IR (neat) ν (cm⁻¹): 2930, 2855, 1669, 1515,

1463, 1258, 1236. HRMS (positive ESI): calcd for C₂₂H₃₉NO₄Si

[MNa⁺], 432.2541; found, 432.2540.

N-(3,4-Dimethoxyphenethyl)-N-(2,2-dimethyl-5-

((triisopropylsilyl)oxy)pentyl)formamide (14b). Following the

procedure used to prepare 14a, 12b (2.22 g, 7.76 mmol) was treated

with 2-(3,4-dimethoxyphenyl)ethylamine (1.30 mL, 7.76 mmol) in

DCM (15 mL) and then with sodium borohydride (0.56 g, 15.5

mmol) in MeOH (20 mL). After the usual work-up (DCM, brine),

the residue was treated with N-formylbenzotriazole (1.37 g, 9.31

mmol) in THF (40 mL) and then with NaOH (2 M). The usual

work-up (DCM) and puriﬁcation (20−40% EtOAc in hexanes)

G

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J. Org. Chem. XXXX, XXX, XXX−XXX

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1

aﬀorded 14b (3.7 g, 98%) as a colorless oil. H NMR (300 MHz,

CDCl₃) 1: 0.5 mixture of rotamers: δ (ppm) 8.02 (s) and 7.88 (s)

(1H, rotamers), 6.78 (d, J = 8.5 Hz, 1H), 6.73−6.59 (m, 2H), 3.86

(s) and 3.84 (s) (6H, rotamers), 3.66−3.47 (m, 4H), 3.14 (s) and

2.88 (s) (2H, rotamers), 2.81−2.71 (m, 2H), 1.59−1.43 (m, 2H),

1.31−1.19 (m, 2H), 1.04 (s, 21H), 0.90 (s) and 0.85 (s) (6H,

rotamers). ¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ

(ppm) 163.8 (d), 163.6 (d), 149.0 (s), 148.8 (s), 147.8 (s), 147.5 (s),

131.3 (s), 130.1 (s), 120.8 (d), 120.6 (d), 111.9 (d), 111.3 (d), 111.2

(d), 63.8 (t), 63.5 (t), 58.1 (t), 55.7 (q), 51.6 (t), 51.0 (t), 47.6 (t),

36.8 (t), 36.1 (s), 36.0 (t), 35.3 (s), 34.9 (t), 33.0 (t), 27.5 (t) 27.3

(t), 25.8 (q) 25.1 (q), 17.9 (q), 11.8 (d). IR (neat) ν (cm⁻¹): 2942,

2892, 2864, 2046, 1673. HRMS (positive ESI): calcd for

C₂₇H₄₉NO₄SiNa [MNa⁺], 502.3323; found, 502.3325.

3.12 (t, J = 6.5 Hz, 1H), 2.83−2.74 (m, 2H), 2.52−2.44 (m, 2H),

1.63−1.54 (m, 4H). ¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of

rotamers: δ (ppm) 201.9 (d), 201.4 (d), 162.7 (d), 162.6 (d), 149.0

(s), 148.9 (s), 147.8 (s), 147.6 (s), 131.2 (s), 130.2 (s), 120.8 (d),

120.6 (d), 111.9 (d), 111.4 (d), 111.2 (d), 55.8 (q), 49.0 (t), 47.6 (t),

44.2 (t), 43.2 (t), 43.1 (t), 41.7 (t), 34.9 (t), 33.1 (t), 28.0 (t), 26.7

(t), 19.1 (t), 18.8 (t). IR (neat) ν (cm⁻¹): 2936, 2835, 1718, 1661,

1514, 1260, 1234, 1025. HRMS (positive ESI): calcd for

C₁₆H₂₃NO₄Na [MNa⁺], 316.1519; found, 316.1529.

N-(3,4-Dimethoxyphenethyl)-N-(2,2-dimethyl-5-oxopentyl)-

formamide (16b). Following the procedure used to prepare 16a,

15b (3.74 g, 11.6 mmol) was treated with DMSO (2.14 mL, 30.1

mmol), oxalyl chloride (1.47 mL, 17.4 mmol), and triethylamine

(8.02 mL, 57.9 mmol) in DCM (87 mL). The usual work-up (DCM)

and puriﬁcation (80% EtOAc in hexanes) aﬀorded 16b (2.96 g, 79%)

as a yellow solid. ¹H NMR (300 MHz, CDCl₃) 1:0.8 mixture of

rotamers: δ (ppm) 9.68 (s) and 9.67 (s) (1H, rotamers), 7.95 (s) and

7.79 (s) (1H, rotamers), 6.73−6.71 (m, 1H), 6.66−6.54 (m, 2H),

3.78 (s) and 3.77 (s) (3H, rotamers), 3.76 (s) and 3.75 (s) (3H,

rotamers), 3.50−3.41 (m, 2H), 3.05 (s) and 2.82 (s) (2H, rotamers),

2.75−2.65 (m, 2H), 2.44−2.39 (m, 1H), 2.35−2.29 (m, 1H), 1.45

(dd, J = 16.0, 7.5 Hz, 2H), 0.84 (s) and 0.78 (s) (6H, rotamers).

¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ (ppm)

N-(3,4-Dimethoxyphenethyl)-N-(5-hydroxypentyl)-

formamide (15a). A solution of tetrabutylammonium ﬂuoride

(TBAF, 1.0 M in THF, 2.84 mL, 2.84 mmol) was added dropwise

to a solution of 14a (972 mg, 2.37 mmol) and glacial acetic acid (0.27

mL, 4.74 mmol) in THF (12 mL). The solution was stirred for 18 h at

rt, and then, the solvent was removed under reduced pressure. Usual

puriﬁcation (70−100% EtOAc in hexanes then 5% MeOH in DCM)

1

aﬀorded 15a (631 mg, 90%) as a light brown oil. H NMR (300

MHz, CDCl₃) 1:0.9 mixture of rotamers: δ (ppm) 8.01 (s) and 7.78

(s) (1H, rotamers), 6.78−6.71 (m, 2H), 6.65−6.60 (m, 1H), 3.84 (s)

and 3.83 (s) (3H, rotamers), 3.82 (s, 3H), 3.61−3.56 (m, 2H), 3.49−

3.44 (m, 1H), 3.39 (t, J = 7.0 Hz, 1H, rotamers), 3.32−3.27 (m, 1H),

3.09 (t, J = 7.0 Hz, 1H, rotamers), 2.79−2.70 (m, 2H), 2.30 (br s,

1H), 1.61−1.45 (m, 4H), 1.39−1.22 (m, 2H). ¹³C{¹H} NMR (75

MHz, CDCl₃) mixture of rotamers: δ (ppm) 162.8 (d), 162.7 (d),

148.9 (s), 148.7 (s), 147.7 (s), 147.4 (s), 131.1 (s), 130.1 (s), 120.7

(d), 120.5 (d), 111.81 (d), 111.78 (d), 111.3 (d), 111.1 (d), 62.1 (t),

62.0 (t), 55.8 (q), 49.1 (t), 47.8 (t), 44.1 (t), 42.1 (t), 34.8 (t), 33.1

(t), 32.1 (t), 32.0 (t), 28.3 (t), 27.0 (t), 22.9 (t), 22.6 (t). IR (neat) ν

(cm⁻¹): 3416 (br), 2932, 2858, 2834, 1655, 1510, 1450, 1260, 1234.

HRMS (positive ESI): calcd for C₁₆H₂₅NO₄Na [MNa⁺], 318.1676;

found, 318.1684.

202.4 (d), 201.4 (d), 163.8 (d), 149.0 (s), 148.8 (s), 147.8 (s), 147.5

(s), 131.2 (s), 130.0 (s), 120.8 (d), 120.6 (d), 111.9 (d), 111.8 (d),

111.4 (d), 111.3 (d), 58.3 (t), 55.9 (q), 55.8 (q), 55.7 (q), 51.3 (t),

51.2 (t), 47.9 (t), 39.0 (t), 38.7 (t), 35.9 (s), 35.2 (s), 34.9 (t), 33.0

(t), 31.7 (t), 31.4 (t), 25.8 (q), 24.6 (q). IR (neat) ν (cm⁻¹): 2958

and 2936 (br), 2871, 2835, 2160, 1719, 1663. HRMS (positive ESI):

calcd for C₁₈H₂₈NO₄[MH⁺], 322.2013; found, 322.2011. mp 62−67

°C.

trans-9,10-Dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido-

[2,1-a]isoquinoline-1-carbaldehyde (18a). Triﬂic anhydride (91

μL, 0.54 mmol) was added dropwise to a solution of 16a (137 mg,

0.47 mmol) and DTBMP (161 mg, 0.78 mmol) in CDCl₃(9.40 mL)

at −60 °C. The reaction mixture was stirred for 45 min at this

temperature and then at −15 °C for 1 h. ¹H NMR analysis of a small

sample of the reaction mixture revealed the presence of iminium ion

N-(3,4-Dimethoxyphenethyl)-N-(5-hydroxy-2,2-

dimethylpentyl)formamide (15b). Following the procedure used

to prepare 15a, 14b (6.54 g, 13.5 mmol) was treated with TBAF (1.0

M in THF, 4.70 mL, 16.4 mmol) in THF (12 mL). The usual

puriﬁcation (80−100% EtOAc in hexanes then 1% MeOH in DCM)

1

17a. H NMR (400 MHz, CDCl₃): δ (ppm) 9.77 (s, 1H), 9.23 (s,

1H), 7.50 (s, 1H), 6.84 (s, 1H), 4.04 (t, J = 7.3 Hz, 2H), 4.01 (s, 3H),

3.96 (t, J = 8.2 Hz, 2H), 3.92 (s, 3H), 3.23 (t, J = 8.2 Hz, 2H), 2.63 (t,

J = 6.7 Hz, 2H), 1.95−1.88 (m, 2H), 1.73−1.64 (m, 2H). Piperidine

(140 μL, 1.41 mmol) was added at −15 °C, and the reaction mixture

was stirred for 3 d at this temperature. Aqueous HCl (1 M, 1 mL) was

added, and the usual work-up (DCM) and puriﬁcation (10−20%

EtOAc in hexanes with 1.5% Et₃N) aﬀorded 18a (51 mg, 40%) as a

1

aﬀorded 15b (3.74 g, 85%) as a white solid. H NMR (300 MHz,

CDCl₃) 1:0.6 mixture of rotamers: δ (ppm) 8.03 (s) and 7.88 (s)

(1H, rotamers), 6.79 (d, J = 8.5 Hz, 1H), 6.74−6.60 (m, 2H), 3.86

(s) and 3.85 (s) (3H, rotamers), 3.84 (s, 3H), 3.60 (t, J = 6.5 Hz,

2H), 3.55−3.48 (m, 2H), 3.13 (s) and 2.89 (s) (2H, rotamers), 2.82−

2.72 (m, 2H), 1.83 (br s, 1H), 1.64−1.46 (m, 2H), 1.31−1.20 (m,

2H), 0.92 (s) and 0.87 (s) (6H, rotamers). ¹³C{¹H} NMR (75 MHz,

CDCl₃) mixture of rotamers: δ (ppm) 164.2 (d), 149.3 (s), 149.1 (s),

148.1 (s), 147.8 (s), 131.5 (s), 130.3 (s), 121.0 (d), 120.8 (d), 112.2

(d), 112.1 (d), 111.6 (d), 111.4 (d), 63.3 (t), 58.5 (t), 56.07 (q),

56.04 (q), 56.03 (q), 56.01 (q), 51.6 (t), 51.5 (t), 48.0 (t), 36.4 (s),

36.3 (t), 36.2 (t), 35.6 (s), 35.3 (t), 33.3 (t), 27.3 (t), 27.2 (t), 26.4

(q), 25.3 (q). IR (neat) ν (cm⁻¹): 3404 (br), 2941, 2872, 2162, 1659.

HRMS (positive ESI): calcd for C₁₈H₃₀NO₄[MH⁺], 324.2169; found,

324.2168. mp 58−63 °C.

N-(3,4-Dimethoxyphenethyl)-N-(5-oxopentyl)formamide

(16a). DMSO (0.38 mL, 5.33 mmol) was added to a solution of

oxalyl chloride (0.26 mL, 3.08 mmol) in DCM (12 mL) at −78 °C.

The solution was stirred for 30 min at −78 °C, and then, a solution of

15a (605 mg, 2.05 mmol) in DCM (8.0 mL) was added. The solution

was stirred for 1 h at −78 °C, and then, triethylamine (1.44 mL, 10.3

mmol) was added. The solution was stirred for 1 h at −78 °C and

then was allowed to warm up to rt over 45 min. Water was added and

the usual work-up (DCM) and puriﬁcation (60−100% EtOAc in

hexanes) aﬀorded 16a (622 mg, 87%) as a yellow oil. ¹H NMR (300

MHz, CDCl₃) 1:0.9 mixture of rotamers: δ (ppm) 9.76 (s, 1H), 8.06

(s) and 7.84 (s) (1H, rotamers), 6.82−6.74 (m, 2H), 6.69−6.63 (m,

1H), 3.88 (s) and 3.87 (s) (3H, rotamers), 3.86 (s, 3H), 3.50 (dd, J =

8.5, 7.0 Hz, 1H), 3.43 (t, J = 7.0 Hz, 1H), 3.34 (t, J = 7.0 Hz, 1H),

1

yellow solid. H NMR (300 MHz, CDCl₃): δ (ppm) 9.42 (s, 1H),

6.61 (s, 1H), 6.60 (s, 1H), 3.85 (s 3H), 3.81 (s, 3H), 3.51 (br s, 1H),

3.13−2.87 (m, 4H), 2.61−2.47 (m, 2H), 2.40−2.30 (m, 2H), 1.72−

1.50 (m, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 206.1,

147.8, 147.7, 128.4, 127.3, 111.8, 108.3, 64.0, 57.2, 56.1, 56.0, 52.7,

49.8, 29.5, 26.1, 22.2. IR (neat) ν (cm⁻¹): 2936, 2751, 1717, 1517,

1248, 1144, 1002. HRMS (positive ESI): calcd for C₁₆H₂₂NO₃

[MH⁺], 276.1594; found, 276.1601. mp 100−104 °C.

trans-9,10-Dimethoxy-3,3-dimethyl-1,3,4,6,7,11b-hexahy-

dro-2H-pyrido[2,1-a]isoquinoline-1-carbaldehyde (18b). Fol-

lowing the procedure used to prepare 18a, 16b (103 mg, 0.32 mmol)

was treated with triﬂic anhydride (59 μL, 0.35 mmol) and DTBMP

1

(72.7 mg, 0.35 mmol) in CDCl₃(6.20 mL). H NMR analysis of a

small sample of the reaction mixture revealed the presence of iminium

ion 17b. ¹H NMR (400 MHz, CDCl₃): δ (ppm) 9.82 (s, 1H), 9.13 (s,

1H), 7.57 (s, 1H), 6.87 (s, 1H), 4.02 (s, 3H), 3.98 (t, J = 8.0 Hz, 2H),

3.94 (s, 3H), 3.87−3.86 (m, 4H), 3.20 (t, J = 8.0 Hz, 2H), 2.64−2.60

(m, 2H), 1.07 (s, 6H). Subsequent treatment with piperidine (95 μL,

0.96 mmol) for 18 h at −15 °C followed by the usual work-up

(DCM) and puriﬁcation (10−100% EtOAc in hexanes with 1.5%

1

Et₃N) aﬀorded 18b (36 mg, 37, 63% brsm) as a yellow oil. H NMR

(300 MHz, CDCl₃): δ (ppm) 9.57 (s, 1H), 6.61 (s, 1H), 6.47 (s, 1H),

3.85 (s, 3H), 3.78 (s, 3H), 3.37 (s, 1H), 3.19−3.07 (m, 1H), 2.93−

2.79 (m, 2H), 2.64−2.52 (m, 3H), 2.24−2.07 (m, 2H), 1.61−1.55

H

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(m, 1H), 0.92 (s, 3H), 0.90 (s, 3H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ (ppm) 207.2 (d), 147.9 (s), 147.7 (s), 128.6 (s), 127.4 (s),

111.8 (d), 108.6 (d), 68.8 (t), 63.4 (d), 56.1 (q), 56.0 (q), 52.7 (t),

49.2 (d), 41.3 (t), 30.9 (s), 29.7 (t), 29.6 (q), 28.3 (q). IR (neat) ν

(cm⁻¹): 2950, 2830, 2750, 2164, 2052, 1715, 1518. HRMS (positive

ESI): calcd for C₁₈H₂₆NO₃[MH⁺], 304.1907; found, 304.1929.

N-(3,4-Dimethoxyphenethyl)formamide (19). N-Formylben-

zotriazole (7.05 g, 43.2 mmol) was added to a solution of 3,4-

dimethoxyphenethylamine (13, 6.28 mL, 36.1 mmol) dissolved in

THF (180 mL) and stirred for 18 h at rt. Then, the solvent was

removed under reduced pressure, and the residue was dissolved in

DCM and washed with aqueous NaOH (2 N, 2 × 45 mL). The usual

work-up (DCM) and puriﬁcation (50−90% EtOAc in hexanes)

aﬀorded 19 (7.40 g, 98%) as a yellow oil. ¹H NMR (300 MHz,

CDCl₃) 1:0.2 mixture of rotamers: δ (ppm) 8.15 (s) and 7.96 (d, J =

12 Hz, 1H, rotamers), 6.82 (d, J = 8.0 Hz, 1H), 6.76−6.67 (m, 2H),

5.49 (br s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.57 (q) and 3.46 (q)

(2H, J = 6.6 Hz, rotamers), 2.80 (t) and 2.76 (t) (2H, J = 7.0 Hz,

rotamers). ¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ

(ppm) 164.5 (d), 161.2 (d), 149.1 (s), 147.8 (s), 131.1 (s), 120.7 (d),

112.0 (d), 111.5 (d), 56.0 (q), 55.9 (q), 43.3 (t), 39.4 (t), 37.4 (t),

35.2 (t). IR (neat) ν (cm⁻¹): 3316, 3054, 2999, 2936, 2835, 1659,

1513, 1258, 1232, 1024, 766. HRMS (positive ESI): calcd for

C₁₁H₁₅NO₃Na [MNa⁺], 232.0944; found, 232.0946.

N-(3,4-Dimethoxyphenethyl)-N-methylformamide (20).

KHMDS (0.5 M in toluene, 2.40 mL, 1.20 mmol) was added

dropwise to a solution of 19 (201 mg, 0.96 mmol) in THF (5.0 mL).

The mixture was stirred for 1 h 30 min at rt, and then, DMF (4.80

mL) and MeI (0.24 mL, 3.84 mmol) were added. The solution was

reﬂuxed for 18 h then allowed to cool to rt and concentrated under

reduced pressure. Water was added and the usual work-up (EtOAc)

and puriﬁcation (50−80% EtOAc in hexanes) aﬀorded 20 (206 mg,

96%) as an orange oil. Analytical data were in accordance with those

reported in the literature.²¹¹H NMR (300 MHz, CDCl₃) 1:0.6

mixture of rotamers: δ (ppm) 7.90 (s) and 7.70 (s) (1H, rotamers),

6.71−6.55 (m, 3H), 3.76 (s) and 3.75 (s) (3H, rotamers), 3.74 (s,

3H), 3.44 (t) and 3.34 (t) (J = 7.0 Hz, 2H, rotamers), 2.78 (s) and

2.75 (s) (3H, rotamers), 2.72−2.65 (m, 2H). ¹³C{¹H} NMR (75

MHz, CDCl₃) mixture of rotamers: δ (ppm) 162.4 (d), 162.2 (d),

148.9 (s), 148.7 (s), 147.7 (s), 147.4 (s), 130.9 (s), 130.1 (s), 120.6

(d), 120.5 (d), 111.8 (d), 111.7 (d), 111.3 (d), 111.2 (d), 55.7 (q),

55.6 (q), 51.1 (t), 45.7 (t), 34.8 (q), 34.2 (t), 32.5 (t), 29.5 (q). IR

(neat) ν (cm⁻¹): 2932, 2835, 1661, 1514, 1259, 1233, 1025.

N-(3,4-Dimethoxyphenethyl)-N-(5-hydroxyhexyl)-

formamide (27). LiAlH₄(4.63 g, 122 mmol) was added in small

portions to a solution of 24 (18.0 g, 61.0 mmol) in THF (203 mL) at

0 °C, and the mixture was reﬂuxed for 18 h. The resulting mixture was

cooled at 0 °C and quenched with water (4.6 mL). An aqueous

solution of NaOH (15%, 4.6 mL) and water (12.0 mL) were added,

and the mixture was stirred vigorously at rt for 5 h. Anhydrous

Na₂SO₄was added, and the mixture was ﬁltered over Celite and

concentrated under reduced pressure. The residue was used directly

in the next step. Following the procedure used to prepare 19, crude

25 was treated with N-formylbenzotriazole (18.8 g, 128 mmol) in

THF (244 mL). The residue was used directly in the next step.

K₂CO₃was added to crude 26 dissolved in MeOH (203 mL). The

reaction mixture was reﬂuxed for 18 h and then cooled to rt. Water

(80 mL) was added, ant the usual work-up (EtOAc) and puriﬁcation

(30−100% EtOAc in hexanes) aﬀorded 27 (13.8 g, 73% over 3 steps)

as a yellow oil. ¹H NMR (300 MHz, CDCl₃) 1:0.9 mixture of

rotamers: δ (ppm) 8.04 (s) and 7.83 (s) (1H, rotamers), 6.81−6.73

(m, 2H), 6.68−6.63 (m, 1H), 3.87 (s) and 3.86 (s) (3H, rotamers),

3.85 (s, 3H), 3.81−3.73 (m, 1H), 3.52−3.47 (m, 1H), 3.41 (t, J = 7.0

Hz, 1H), 3.33 (t, J = 7.5 Hz, 1H), 3.11 (t, J = 7.0 Hz, 1H), 2.82−2.73

(m, 2H), 1.59−1.24 (m, 7H), 1.17 (d, J = 6.0 Hz, 3H). ¹³C{¹H}

NMR (75 MHz, CDCl₃) mixture of rotamers: δ (ppm) 163.0 (d),

162.8 (d), 149.3 (s), 149.1 (s), 148.1 (s), 147.8 (s), 131.5 (s), 130.4

(s), 120.9 (d), 120.8 (d), 112.2 (d), 112.1 (d), 111.6 (d), 111.5 (d),

67.9 (d), 67.8 (d), 56.1 (q), 56.0 (q), 49.3 (t), 48.1 (t), 44.4 (t), 42.3

(t), 38.9 (t), 38.8 (t), 35.2 (t), 33.4 (t), 31.0 (t), 28.9 (t), 27.5 (t),

23.8 (q), 23.7 (q), 23.0 (t), 22.8 (t). IR (neat) ν (cm⁻¹): 3413 (br),

2932, 2859, 1653, 1515, 1026. HRMS (positive ESI): calcd for

C₁₇H₂₇NO₄Na [MNa⁺], 332.1832; found, 332.1836.

N-(3,4-Dimethoxyphenethyl)-N-(5-oxohexyl)formamide

(28a). Following the procedure used to prepare 16a, 27 (1.02 g, 3.30

mmol) was treated with DMSO (0.61 mL, 8.58 mmol), oxalyl

chloride (0.42 mL, 4.95 mmol), and triethylamine (2.30 mL, 16.5

mmol) in DCM (13 mL). The usual work-up (DCM) and

puriﬁcation (40−90% EtOAc in hexanes) aﬀorded 28a (852 mg,

1

84%) as a yellow oil. H NMR (300 MHz, CDCl₃) 1:0.9 mixture of

rotamers: δ (ppm) 8.05 (s) and 7.82 (s) (1H, rotamers), 6.81−6.73

(m, 2H), 6.68−6.62 (m, 1H), 3.87 (s) and 3.86 (s) (3H, rotamers),

3.85 (s, 3H), 3.52−3.46 (m, 1H), 3.41 (t, J = 7.0 Hz, 1H), 3.32 (t, J =

7.0 Hz, 1H), 3.10 (t, J = 6.0 Hz, 1H), 2.82−2.73 (m, 2H), 2.49−2.40

(m, 2H), 2.12 (s, 3H), 1.58−1.48 (m, 4H). ¹³C{¹H} NMR (75 MHz,

CDCl₃) mixture of rotamers: δ (ppm) 208.6 (s), 208.0 (s), 162.9 (d),

162.8 (d), 149.3 (s), 149.1 (s), 148.1 (s), 147.8 (s), 131.4 (s), 130.4

(s), 120.9 (d), 120.8 (d), 112.2 (d), 112.1 (d), 111.6 (d), 111.4 (d),

56.0 (q), 49.2 (t), 48.0 (t), 44.4 (t), 43.0 (t), 42.9 (t), 42.0 (t), 35.2

(t), 33.4 (t), 30.2 (q), 30.1 (q), 28.3 (t), 26.8 (t), 20.9 (t), 20.6 (t).

IR (neat) ν (cm⁻¹): 2936, 1711, 1665, 1515, 1027. HRMS (positive

ESI): calcd for C₁₇H₂₅NO₄[MNa⁺], 330.1675; found, 330.1681.

N-(3,4-Dimethoxyphenethyl)-N-(2,2-dimethyl-5-oxohexyl)-

formamide (28b). Methylmagnesium bromide (221 μL, 1.91 mmol)

was added dropwise to a solution of 16b (410 mg, 1.27 mmol) in

THF (6.0 mL) at −78 °C. The mixture was stirred for 3 h at −78 °C

and then, AcOH was added. The reaction was allowed to warm up at

rt and concentrated under reduced pressure. Saturated aqueous

NH₄Cl was added. The usual work-up (DCM) and puriﬁcation (40−

90% EtOAc in hexanes) aﬀorded N-(3,4-dimethoxyphenethyl)-N-(5-

hydroxy-2,2-dimethylhexyl)formamide (113 mg, 26%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃) 1:0.6 mixture of rotamers: δ (ppm)

8.03 (s) and 7.88 (s) (1H, rotamers), 6.80 (d, J = 8.5 Hz, 1H), 6.74−

6.61 (m, 2H), 3.87 (s) and 3.86 (s) (3H, rotamers), 3.85 (s, 3H),

3.77−3.67 (m, 1H), 3.63−3.48 (m, 2H), 3.14 (s) and 2.89 (s) (2H,

rotamers), 2.79−2.75 (m, 2H), 1.73 (br s, 1H), 1.63−1.09 (m, 7H),

0.90 (d, J = 16.0 Hz) and 0.89 (d, J = 16.0 Hz) (6H, rotamers).

¹³C{¹H} NMR mixture of rotamers (75 MHz, CDCl₃): δ (ppm)

164.2 (d), 149.3 (s), 149.1 (s), 148.1 (s), 147.8 (s), 131.6 (s), 130.3

(s), 121.1 (d), 120.8 (d), 112.2 (d), 112.2 (d), 111.6 (d), 111.5 (d),

68.6 (d), 68.4 (d), 63.3 (t), 58.5 (t), 56.1 (q), 51.5 (t), 48.0 (t), 36.4

(s), 36.2 (s), 35.9 (t), 35.6 (t), 35.3 (t), 33.6 (t), 33.5 (t), 33.3 (t),

26.6 (q), 26.2 (q), 25.4 (q), 25.3 (q), 23.9 (q). IR (neat) ν (cm⁻¹):

Iminium Ion (21). Following the procedure used to prepare 18a,

13 was treated with triﬂic anhydride and DTBMP in CDCl₃. ¹H NMR

analysis of a small sample of the reaction mixture revealed the

1

presence of iminium ion 21. H NMR (400 MHz, CDCl₃): δ (ppm)

9.05 (s, 1H), 7.40 (s, 1H), 6.84 (s, 1H), 4.00 (s, 3H), 3.96 (t, J = 8.5

Hz, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 3.24 (t, J = 8.5 Hz, 2H).

N-(3,4-Dimethoxyphenethyl)-5-hydroxyhexanamide (24). A

solution of AlMe₃(2.0 M in toluene, 20.0 mL, 40 mmol) was added

to a solution of 13 (6.80 mL, 40 mmol) in DCM (200 mL) at rt. The

reaction mixture was stirred for 30 min at rt then a solution of δ-

caprolactone (23, 2.20 mL, 20 mmol) was added at 0 °C. The

solution was stirred for 30 min at 0 °C and then for 18 h at rt and

ﬁnally cooled to 0 °C. Water was slowly added at 0 °C followed by a

saturated solution of potassium sodium tartrate, and the mixture was

stirred vigorously for 4 h at rt. The usual workup (DCM) and

puriﬁcation (70−100% EtOAc in hexanes then 5% MeOH in EtOAc)

aﬀorded 24 (5.90 g, 99%) as a yellow oil. ¹H NMR (300 MHz,

CDCl₃): δ (ppm) 6.79 (d, J = 8.5 Hz, 1H), 6.72−6.70 (m, 2H), 5.68

(br s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79−3.69 (m, 1H), 3.51−3.45

(m, 2H), 2.74 (t, J = 7.0 Hz, 2H), 2.20 (br s, 1H), 2.15 (t, J = 7.5 Hz,

2H), 1.69 (dt, J = 15.0, 7.0 Hz, 2H), 1.45−1.37 (m, 2H), 1.15 (d, J =

6.0 Hz, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 173.2 (s),

149.1 (s), 147.7 (s), 131.5 (s), 120.7 (d), 112.0 (d), 111.4 (d), 67.3

(d), 56.0 (q), 55.9 (q), 40.7 (t), 38.5 (t), 36.3 (t), 35.3 (t), 23.6 (q),

21.7 (t). IR (neat) ν (cm⁻¹): 3304 (br), 2933, 2837, 1645, 1515,

1260, 1235, 1027. HRMS (positive ESI): calcd for C₁₆H₂₅NO₄Na

[MNa⁺], 318.1676; found, 318.1678.

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2958 (br), 2936, 2870, 2162, 2010, 1728, 1660. HRMS (positive

ESI): calcd for C₁₉H₃₁NO₄Na [M + Na⁺], 360.2145; found,

360.2147. Following the procedure used to prepare 16a, N-(3,4-

dimethoxyphenethyl)-N-(5-hydroxy-2,2-dimethylhexyl)formamide

(371 mg, 1.10 mmol) was treated with DMSO (0.20 mL, 2.86 mmol),

oxalyl chloride (0.14 mL, 1.65 mmol), and triethylamine (0.76 mL,

5.50 mmol) in DCM (8 + 5.5 mL). The usual work-up (DCM) and

puriﬁcation (40−90% EtOAc in hexanes) aﬀorded 28b (253 mg,

and saturated Na₂S₂O₃(30 mL) were added, and the mixture was

stirred for 30 min. The usual workup (DCM) and puriﬁcation (40−

100% EtOAc in hexanes) aﬀorded 28c (548 mg, 83%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃) 1:0.9 mixture of rotamers: δ (ppm)

6.82−6.65 (m, 3H), 3.87 (s, 3H), 3.86 (s) and 3.85 (s) (3H,

rotamers), 3.51−3.42 (m, 2H), 3.32 (t, J = 7.0 Hz, 1H), 3.11 (t, J =

7.0 Hz, 1H), 2.81−2.76 (m, 2H), 2.49−2.42 (m, 2H), 2.13 (s, 3H),

2.08 (s) and 1.90 (s) (3H, rotamers), 1.57−1.50 (m, 4H). ¹³C{¹H}

NMR mixture of rotamers (75 MHz, CDCl₃): δ (ppm) 208.8 (s),

208.0 (s), 170.3 (s), 170.1 (s), 149.0 (s), 148.8 (s), 147.8 (s), 147.4

(s), 131.9 (s), 130.7 (s), 120.7 (d), 120.6 (d), 112.0 (d), 111.9 (d),

111.4 (d), 111.2 (d), 55.9 (q), 55.8 (q), 50.4 (t), 49.3 (t), 48.1 (t),

45.1 (t), 43.1 (t), 42.9 (t), 34.7 (t), 33.6 (t), 29.9 (q), 28.4 (t), 27.0

(t), 21.6 (q), 21.3 (q), 20.9 (t), 20.7 (t). IR (neat) ν (cm⁻¹): 2834,

1635, 1542. HRMS (positive ESI): calcd for C₁₈H₂₇NO₄Na [M +

Na⁺], 344.1832; found, 344.1839.

1

69%) as a yellow oil. H NMR (300 MHz, CDCl₃) 1:0.7 mixture of

rotamers: δ (ppm) 8.03 (s) and 7.88 (s) (1H, rotamers), 6.80 (d, J =

8.5 Hz, 1H), 6.75−6.60 (m, 2H), 6.87 (s, 3H), 6.86 (s, 3H), 3.53 (dt,

J = 14.5, 7.0 Hz, 2H), 3.12 (s) and 2.88 (s) (2H, rotamers), 2.83−

2.73 (m, 2H), 2.53−2.34 (m, 2H), 2.15 (s, 3H), 1.55−1.45 (m, 2H),

0.91 (s, 3H), 0.85 (s, 3H). ¹³C{¹H} NMR mixture of rotamers (75

MHz, CDCl₃): δ (ppm) 209.1 (s), 208.1 (s), 164.0 (d), 163.9 (d),

149.2 (s), 149.0 (s), 148.0 (d), 147.7 (s), 131.4 (s), 130.2 (s), 120.9

(d), 120.7 (d), 112.1 (d), 112.0 (d), 111.5 (d), 111.4 (d), 58.6 (t),

55.9 (q), 51.4 (t), 51.3 (t), 48.0 (t), 38.7 (t), 38.3 (t), 36.0 (s), 35.3

(s), 35.1 (t), 33.7 (t), 33.7 (t), 33.3 (t), 33.1 (t), 30.0 (q), 26.0 (q),

24.8 (q). IR (neat) ν (cm⁻¹): 2960 and 2941 (br), 2871, 2833, 2168,

2032, 1712, 1663. HRMS (positive ESI): calcd for C₁₉H₂₉NO₄Na [M

+ Na⁺], 358.1989; found, 358.1993.

N-(3,4-Dimethoxyphenethyl)-N-(2,2-dimethyl-5-oxohexyl)-

acetamide (28d). 2-(3,4-Dimethoxyphenyl)ethylamine (4.00 mL,

23.9 mmol) was added to a solution of the aldehyde 12b (6.84 g, 23.9

mmol) in DCM (50 mL) and stirred for 1 h at rt. Then, anhydrous

Na₂SO₄(6.78 g, 47.7 mmol) was added to the reaction and stirred for

1 h 30 min at rt. The resulting mixture was ﬁltered and washed with

DCM (30 mL). MeOH (66 mL) and sodium borohydride (1.80 g,

47.7 mmol) were added to the reaction, stirred for 18 h at rt, and

quenched with water. The usual work-up (DCM, brine) aﬀorded a

residue that was used directly in the next step. Pyridine (1.10 mL,

13.2 mmol) was added to the residue dissolved in DCM (133 mL)

and cooled to 0 °C. Freshly distilled acetyl chloride (0.47 mL, 6.60

mL) was added to the reaction and stirred for 1 h at 0 °C and then

allowed to warm up to rt and stirred for 18 h. Then water was added.

The usual work-up (DCM) and puriﬁcation (20−40% EtOAc in

hexanes) aﬀorded N-(3,4-dimethoxyphenethyl)-N-(2,2-dimethyl-5-

((triisopropylsilyl)oxy)pentyl)acetamide (2.69 g, 83%) as a yellow

oil. ¹H NMR (300 MHz, CDCl₃) 1:0.7 mixture of rotamers: δ (ppm)

6.82−6.74 (m, 1H), 6.74−6.62 (m, 2H), 3.87 (s, 3H), 3.86 (s) and

3.85 (s) (3H, rotamers), 3.64 (t, J = 6.5 Hz, 2H), 3.58−3.50 (m, 2H),

3.21 (s) and 2.98 (s) (2H, rotamers), 2.83−2.73 (m, 2H), 2.10 (s)

and 1.99 (s) (3H, rotamers), 1.58−1.44 (m, 2H), 1.29−1.24 (m, 2H),

1.05 (s, 21H), 0.91 (s) and 0.89 (s) (6H, rotamers). ¹³C{¹H} NMR

(75 MHz, CDCl₃) mixture of rotamers: δ (ppm) 171.7 (s), 171.5 (s),

149.2 (s), 149.0 (s), 148.0 (s), 147.6 (s), 132.3 (s), 130.9 (s), 120.9

(d), 120.8 (d), 112.3 (d), 112.1 (d), 111.6 (d), 111.4 (d), 64.2 (t),

63.9 (t), 59.6 (t), 56.1 (q), 56.0 (q), 54.6 (t), 52.5 (t), 50.9 (t), 37.3

(t), 37.1 (t), 36.7 (s), 36.6 (s), 34.7 (t), 33.0 (t), 27.8 (t), 27.6 (t),

26.1 (q), 25.9 (q), 22.5 (q), 21.7 (q), 18.2 (q), 12.2 (d), 12.1 (d). IR

(neat) ν (cm⁻¹): 2937, 2869, 2147, 1648. HRMS (positive ESI):

calcd for C₂₈H₅₁NO₄SiNa [M + Na⁺], 516.3480; found, 516.3478. A

solution of TBAF (1.0 M in THF, 1.90 mL, 6.54 mmol) was added

dropwise to a solution of N-(3,4-dimethoxyphenethyl)-N-(2,2-

dimethyl-5-((triisopropylsilyl)oxy)pentyl)acetamide (2.69 g, 5.45

mmol) in THF (7.0 mL) and stirred for 1 h at rt. The solvent was

removed under reduced pressure, and puriﬁcation (100% EtOAc then

2% MeOH in EtOAc) aﬀorded N-(3,4-dimethoxyphenethyl)-N-(5-

hydroxy-2,2-dimethylpentyl)acetamide (1.62 g, 88%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃) 1:0.4 mixture of rotamers: δ (ppm)

N-(3,4-Dimethoxyphenethyl)-N-(5-oxohexyl)acetamide

(28c). Following the procedure to prepare 27, 24 (5.32 g, 18.0 mmol)

was treated with LiAlH₄(1.37 g, 36.0 mmol) in THF (60 mL), then

with water (1.37 mL), NaOH (15%, 1.37 mL), and water (4.10 mL)

to aﬀord a residue that was used directly in the next step. Et₃N (1.98

mL, 14.2 mmol) and AcCl (0.53 mL, 7.43 mmol) were added to the

residue dissolved in DCM (18 mL) at 0 °C and stirred for 18 h at rt.

The residue was washed with a saturated solution of NaHCO₃(2 ×

25 mL). The usual work-up (DCM) and puriﬁcation (40−100%

EtOAc in hexanes) aﬀorded 6-(N-(3,4-dimethoxyphenethyl)-

acetamido)hexan-2-yl acetate (772 mg, 60% over 2 steps) as a yellow

oil. ¹H NMR (300 MHz, CDCl₃) 1:0.9 mixture of rotamers: δ (ppm)

6.82−6.75 (m, 2H), 6.73−6.65 (m, 1H), 4.93−4.83 (m, 1H), 3.87 (s,

3H), 3.86 (s) and 3.85 (s) (3H, rotamers), 3.51−3.41 (m, 2H), 3.35−

3.28 (m, 1H), 3.10 (t, J = 7.5 Hz, 1H), 2.82−2.75 (m, 2H), 2.09 (s)

and 1.90 (s) (3H, rotamers), 2.02 (s, 3H), 1.63−1.41 (m, 4H), 1.36−

1.25 (m, 2H), 1.20 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR mixture of

rotamers (75 MHz, CDCl₃): δ (ppm) 170.8 (s), 170.7 (s), 170.2 (s),

170.1 (s), 149.1 (s), 148.9 (s), 147.9 (s), 147.5 (s), 132.0 (s), 130.7

(s), 120.8 (d), 120.7 (d), 112.1 (d), 112.0 (d), 111.5 (d), 111.3 (d),

70.7 (d), 70.4 (d), 55.9 (q), 55.8 (q), 50.4 (t), 49.4 (t), 48.2 (t), 45.4

(t), 35.7 (t), 35.6 (t), 34.8 (t), 33.6 (t), 28.7 (t), 27.5 (t), 22.8 (t),

22.7 (t), 21.6 (q), 21.4 (q), 21.3 (q), 19.9 (q), 19.8 (q). IR (neat) ν

(cm⁻¹): 2832, 1864, 1546. HRMS (positive ESI): calcd for

C₂₀H₃₁NO₅Na [M + Na⁺], 388.2094; found, 388.2102. K₂CO₃

(730 mg, 5.28 mmol) was added to a solution of 6-(N-(3,4-

dimethoxyphenethyl)acetamido)hexan-2-yl acetate (772 mg, 2.11

mmol) dissolved in MeOH (7.0 mL) and reﬂuxed for 18 h. Water

was added and the usual work-up (EtOAc) and puriﬁcation (60−

100% EtOAc in hexanes) aﬀorded N-(3,4-dimethoxyphenethyl)-N-(5-

1

hydroxyhexyl)acetamide (662 mg, 97%) as a colorless oil. H NMR

(300 MHz, CDCl₃) 1:0.9 mixture of rotamers: δ (ppm) 6.82−6.64

(m, 3H), 3.87 (s, 3H), 3.86 (s) and 3.85 (s) (3H, rotamers), 3.82−

3.74 (m, 1H), 3.51−3.42 (m, 2H), 3.33 (t, J = 7.5 Hz, 1H), 3.12 (t, J

= 7.5 Hz, 1H), 2.82−2.75 (m, 2H), 2.08 (s) and 1.91 (s) (3H,

rotamers), 1.57−1.31 (m, 7H), 1.19 (d, J = 3.0 Hz) and 1.17 (d, J =

3.0 Hz) (3H, rotamers). ¹³C{¹H} NMR mixture of rotamers (75

MHz, CDCl₃): δ (ppm) 170.5 (s), 170.2 (s), 149.1 (s), 148.9 (s),

147.9 (s), 147.5 (s), 132.0 (s), 130.7 (s), 120.8 (d), 120.7 (d), 112.1

(d), 112.0 (d), 111.5 (d), 111.3 (d), 67.6 (d), 67.4 (d), 55.9 (q), 50.5

(t), 49.5 (t), 48.2 (t), 45.5 (t), 38.9 (t), 38.8 (t), 34.8 (t), 33.6 (t),

29.0 (t), 27.6 (t), 23.7 (q), 23.5 (q), 23.0 (t), 21.6 (q), 21.4 (q). IR

(neat) ν (cm⁻¹): 3301 (br), 2943, 1648. HRMS (positive ESI): calcd

for C₁₈H₂₉NO₄Na [M + Na⁺], 346.1989; found, 346.1985. Dess−

Martin periodinane (2.78 g, 6.56 mmol) was added to a solution of N-

(3,4-dimethoxyphenethyl)-N-(5-hydroxyhexyl)acetamide (662 mg,

2.05 mmol) in DCM (41 mL). The reaction mixture was stirred for

2 h 30 min, then a saturated aqueous solution of NaHCO₃(20 mL)

6.83−6.78 (m, 1H), 6.74−6.63 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H),

3.65−3.51 (m, 4H), 3.20 (s) and 3.00 (s) (2H, rotamers), 2.83−2.74

(m, 2H), 2.11 (s) and 2.00 (s) (3H, rotamers), 1.90 (t, J = 5.0 Hz,

1H), 1.65−1.48 (m, 2H), 1.30−1.24 (m, 2H), 0.93 (s) and 0.90 (s)

(6H, rotamers). ¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of

rotamers: δ (ppm) 172.0 (s), 171.8 (s), 149.2 (s), 149.0 (s), 148.0

(s), 147.6 (s), 132.2 (s), 130.7 (s), 120.8 (d), 120.7 (d), 112.3 (d),

112.1 (d), 111.6 (d), 111.4 (d), 63.3 (t), 63.2 (t), 59.5 (t), 56.1 (q),

56.0 (q), 54.1 (t), 52.7 (t), 51.0 (t), 37.2 (t), 36.7 (s), 36.6 (s), 36.2

(t), 34.6 (t), 33.0 (t), 27.4 (t), 27.2 (t), 26.4 (q), 25.8 (q), 22.5 (q),

21.8 (q). IR (neat) ν (cm⁻¹): 3402 (br), 2944, 2150, 2017, 1623.

HRMS (positive ESI): calcd for C₁₉H₃₁NO₄Na [M + Na⁺], 360.2145;

found, 360.2155. Following the procedure used to prepare 16a, N-

(3,4-dimethoxyphenethyl)-N-(5-hydroxy-2,2-dimethylpentyl)-

acetamide (1.62 g, 4.80 mmol) was treated with DMSO (0.89 mL,

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12.5 mmol), oxalyl chloride (0.61 mL, 47.2 mmol), and triethylamine

(3.33 mL, 24.0 mmol) in DCM (36 + 24 mL). The usual work-up

(DCM) and puriﬁcation (80% EtOAc in hexanes) aﬀorded N-(3,4-

dimethoxyphenethyl)-N-(2,2-dimethyl-5-oxopentyl)acetamide (1.41

35.3 (t), 34.4 (t), 33.4 (t), 23.7 (q). IR (neat) ν (cm⁻¹): 3305 (br),

2976, 1632. HRMS (positive ESI): calcd for C₁₅H₂₃NO₄Na [MNa⁺],

304.1519; found, 304.1511. mp 70−73 °C. Following the procedure

to prepare 27, N-(3,4-dimethoxyphenethyl)-N-(4-hydroxy)-

pentanamide (2.0 g, 7.11 mmol) was treated with LiAlH₄(539 mg,

14.2 mmol) in THF (24 mL), then with water (0.54 mL), NaOH

(15%, 0.54 mL), and water (1.62 mL) to aﬀord a residue that was

used directly in the next step. Following the procedure used to

prepare 19, crude the residue was treated with N-formylbenzotriazole

(562 mg, 3.82 mmol) in THF (6.0 mL) then with NaOH (2 M, 2 × 5

mL). The residue was used directly in the next step. K₂CO₃(528 mg,

3.82 mmol) was added to the residue dissolved in MeOH (6.0 mL)

and reﬂuxed for 18 h. Water was added (10 mL). The usual work-up

(EtOAc) and puriﬁcation (40−100% EtOAc in hexanes then 3%

MeOH in EtOAc) aﬀorded N-(3,4-dimethoxyphenethyl)-N-(4-

hydroxypentyl)formamide (365 mg, 66% over 3 steps) as a colorless

1

g, 88%) as a yellow oil. H NMR (300 MHz, CDCl₃) 1:0.3 mixture

of rotamers: δ (ppm) 9.76 (t, J = 1.5 Hz, 1H), 6.82−6.78 (m, 1H),

6.74−6.62 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.53 (t, J = 7.5 Hz,

2H), 3.20 (s) and 2.99 (s) (2H, rotamers), 2.84−2.74 (m, 2H), 2.52−

2.39 (m, 2H), 2.11 (s) and 2.00 (s) (3H, rotamers), 1.56−1.51 (m,

2H), 0.91 (s) and 0.90 (s) (6H, rotamers). ¹³C{¹H} NMR (75 MHz,

CDCl₃) mixture of rotamers: δ (ppm) 171.7 (s), 171.6 (s), 149.2 (s),

148.9 (s), 148.0 (s), 147.5 (s), 132.0 (s), 130.6 (s), 120.8 (d), 120.7

(d), 112.2 (d), 112.0 (d), 111.6 (d), 111.3 (d), 59.6 (t), 56.1 (q),

56.0 (q), 54.0 (t), 52.6 (t), 51.1 (t), 39.4 (t), 38.9 (t), 36.3 (s), 34.5

(t), 32.9 (t), 32.4 (t), 32.0 (t), 26.0 (q), 25.4 (q), 22.4 (q), 21.6 (q).

IR (neat) ν (cm⁻¹): 2955, 2872, 2833, 2057, 1720. HRMS (positive

ESI): calcd for C₁₉H₂₉NO₄Na [MNa⁺], 358.1989; found, 358.1990.

Methylmagnesium bromide (2.90 mL, 2.51 mmol) was added

dropwise to a solution of N-(3,4-dimethoxyphenethyl)-N-(2,2-

dimethyl-5-oxopentyl)acetamide (560 mg, 1.67 mmol) in THF (8.0

mL) at −78 °C. The mixture was stirred for 3 h at −78 °C then

AcOH was added. The reaction was allowed to warm up at rt and

concentrated under reduced pressure. Saturated aqueous NH₄Cl was

added. The usual work-up (DCM) and puriﬁcation (20−80% EtOAc

in hexanes) aﬀorded N-(3,4-dimethoxyphenethyl)-N-(5-hydroxy-2,2-

1

oil. H NMR (300 MHz, CDCl₃) 1:1 mixture of rotamers: δ (ppm)

8.05 (s) and 7.82 (s) (1H, rotamer), 6.81−6.73 (m, 2H), 6.68−6.62

(m, 1H), 3.87 (s) and 3.86 (s) (3H, rotamers), 3.85 (s, 3H), 3.81−

3.72 (m, 1H), 3.53−3.47 (m, 1H), 3.38−3.26 (m, 1H), 3.43 (t, J =

7.0 Hz, 1H), 3.38−3.26 (m, 1H), 3.14 (t, J = 7.0 Hz, 1H), 2.83−2.74

(m, 2H), 1.90 (br s, 1H), 1.75−1.32 (m, 5H), 1.18 (d, J = 6.2 Hz,

1H). ¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ (ppm)

162.7 (d), 162.6 (d), 148.8 (s), 148.6 (s), 147.6 (s), 147.3 (s), 131.0

(s), 130.0 (s), 120.6 (d), 120.4 (d), 111.8 (d), 111.3 (d), 111.1 (d),

66.8 (d), 66.7 (d), 55.6 (q), 55.5 (q), 48.9 (t), 47.8 (t), 43.9 (t), 42.0

(t), 35.7 (t), 35.4 (t), 34.6 (t), 32.9 (t), 24.7 (t), 23.5 (t), 23.4 (q),

23.3 (q). IR (neat) ν (cm⁻¹): 3402 (br), 2942, 1644, 1502. HRMS

(positive ESI): calcd for C₁₆H₂₅NO₄[M + Na⁺], 318.1676; found,

318.1664. Following the procedure to prepare 28c, N-(3,4-

dimethoxyphenethyl)-N-(4-hydroxypentyl)formamide (365 mg, 1.24

mmol) was treated with Dess−Martin periodinane (1.68 g, 3.97

mmol) in DCM (24 mL) for 18 h. The usual workup (DCM) and

puriﬁcation (40−100% EtOAc in hexanes) aﬀorded 28e (295 mg,

1

dimethylhexyl)acetamide (237 mg, 40%) as a yellow oil. H NMR

(300 MHz, CDCl₃) mixture of rotamers: δ (ppm) 6.82−6.63 (m,

3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.76−3.66 (m, 1H), 3.61−3.45 (m,

2H), 3.30−2.99 (m, 2H), 2.83−2.73 (m, 2H), 2.11 (s) and 1.99 (s)

(3H, rotamers), 1.72 (br s, 1H), 1.65−1.10 (m, 7H), 0.91−0.89 (m,

6H). ¹³C{¹H} NMR mixture of rotamers (75 MHz, CDCl₃): δ (ppm)

172.0 (s), 171.8 (s), 149.3 (s), 149.1 (s), 148.1 (s), 132.3 (s), 130.8

(s), 120.9 (d), 120.8 (d), 112.3 (d), 112.2 (d), 111.7 (s), 111.4 (s),

68.6 (d), 68.2 (d), 56.1 (q), 53.9 (q), 52.8 (t), 37.3 (t), 36.6 (s), 35.7

(t), 34.7 (t), 33.6 (t), 33.5 (t), 33.1 (t), 26.9 (q), 26.5 (q), 26.3 (q),

26.3 (q), 25.6 (q), 23.9 (q), 22.5 (q), 21.8 (q). IR (neat) ν (cm⁻¹):

2962 (br), 2929, 2868, 2166, 1726, 1628. HRMS (positive ESI): calcd

for C₂₀H₃₃NO₄Na [MNa⁺], 374.2302; found, 374.2306. Following

the procedure used to prepare 16a, N-(3,4-dimethoxyphenethyl)-N-

(5-hydroxy-2,2-dimethylhexyl)acetamide (353 mg, 1.00 mmol) was

treated with DMSO (0.19 mL, 2.60 mmol), oxalyl chloride (0.13 mL,

1.50 mmol), and triethylamine (0.70 mL, 5.00 mmol) in DCM (8.0 +

5.5 mL). The usual work-up (DCM) and puriﬁcation (20−80%

1

81%) as a yellow oil. H NMR (300 MHz, CDCl₃) 1:0.9 mixture of

rotamers: δ (ppm) 8.01 (s) and 7.82 (s) (1H, rotamers), 6.80−6.72

(m, 2H), 6.68−6.63 (m, 1H), 3.87 (s) and 3.86 (s) (3H, rotamers),

3.84 (s, 3H), 3.52−3.47 (m, 1H), 3.42 (t, J = 7.0 Hz, 1H), 3.34−3.29

(m, 1H), 3.11 (t, J = 7.0 Hz, 1H), 2.82−2.74 (m, 2H), 2.46 (t, J = 7.0

Hz, 1H), 2.38 (t, J = 6.9 Hz, 1H), 2.13 (s) and 2.12 (s) (3H,

rotamers), 1.86−1.72 (m, 2H). ¹³C{¹H} NMR (75 MHz, CDCl₃)

mixture of rotamers: δ (ppm) 208.0 (s), 207.2 (s), 162.9 (d), 162.7

(d), 149.0 (s), 148.9 (s), 147.8 (s), 147.6 (s), 131.1 (s), 130.2 (s),

120.8 (d), 120.7 (d), 111.9 (d), 111.4 (d), 111.3 (d), 55.9 (q), 49.0

(t), 46.9 (t), 44.0 (t), 41.3 (t), 40.4 (t), 39.5 (t), 34.9 (t), 33.1 (t),

30.0 (q), 22.3 (t), 21.3 (t). IR (neat) ν (cm⁻¹): 2902, 1701, 1685,

1512. HRMS (positive ESI): calcd for C₁₆H₂₃NO₄Na [M + Na⁺],

316.1519; found, 316.1524.

N-(3,4-Dimethoxyphenethyl)-N-(3-oxobutyl)formamide

(28f). Following the procedure used to prepare 24, 13 (2.50 mL, 15.0

mmol) was treated with AlMe₃(2.0 M in toluene, 7.50 mL, 15.0

mmol) and then β-butyrolactone (1.02 mL, 12.5 mmol) in DCM (75

mL). The usual workup (DCM) and puriﬁcation (50−100% EtOAc

in hexanes then 1−3% MeOH in EtOAc) aﬀorded N-(3,4-

dimethoxyphenethyl)-3-hydroxybutanamide (3.32 g, 99%) as a yellow

oil. ¹H NMR (300 MHz, CDCl₃) 6.81 (d, J = 8.5 Hz, 1H), 6.74−6.71

(m, 2H), 5.71 (br s, 1H), 4.21−4.11 (m, 1H), 3.87 (s, 3H), 3.86 (s,

3H), 3.58 (d, J = 3.0 Hz, 1H), 3.56−3.48 (m, 2H), 2.77 (t, J = 7.0 Hz,

2H), 2.32−2.17 (m, 2H), 1.20 (d, J = 6.5 Hz, 3H). ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ (ppm) 172.4 (s), 148.9 (s), 147.6 (s), 131.3 (s),

120.6 (d), 111.9 (d), 111.4 (d), 64.8 (d), 55.9 (q), 55.8 (q), 43.9 (t),

40.6 (t), 35.1 (t), 22.8 (q). IR (neat) ν (cm⁻¹): 3333 (br), 2932,

2833, 1642, 1514, 1259, 1024. HRMS (positive ESI): calcd for

C₁₄H₂₁NO₄Na [M + Na⁺], 290.1363; found, 290.1368. Following the

procedure to prepare 27, N-(3,4-dimethoxyphenethyl)-3-hydroxybu-

tanamide (3.37 g, 12.6 mmol) was treated with LiAlH₄(956 mg, 25.2

mmol) in THF (42 mL), then with water (0.96 mL), NaOH (15%,

0.96 mL), and water (2.88 mL). The usual puriﬁcation (60−100%

EtOAc in hexanes then 3−6% MeOH in EtOAc with 1.5% Et₃N)

aﬀorded N-(3,4-dimethoxyphenethyl)-N-methyl-5-oxohexanamide

1

EtOAc in hexanes) aﬀorded 28d (232 mg, 66%) as a yellow oil. H

NMR (300 MHz, CDCl₃) mixture of rotamers: δ (ppm) 6.80−6.61

(m, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.56−3.49 (m, 2H), 3.16 (s) and

2.06 (s) (2H, rotamers), 2.81−2.71 (m, 2H), 2.49−2.33 (m, 2H),

2.13 (s, 3H), 2.09 (s) and 1.97 (s) (3H, rotamers), 1.54−1.44 (m,

2H), 0.88 (s, 3H), 0.86 (s, 3H). ¹³C{¹H} NMR mixture of rotamers

(75 MHz, CDCl₃): δ (ppm) 209.4 (s), 202.9 (s), 171.6 (s), 149.2 (s),

149.0 (s), 148.0 (s), 147.6 (s), 130.7 (s), 130.7 (s), 120.8 (d), 112.2

(d), 112.1 (d), 111.6 (d), 111.4 (d), 56.1 (q), 56.0 (q), 54.1 (t), 54.0

(t), 52.7 (t), 52.6 (t), 38.9 (t), 36.3 (s), 34.6 (t), 34.0 (t), 30.1 (q),

30.1 (q), 26.1 (q), 25.4 (q), 21.7 (q). IR (neat) ν (cm⁻¹): 2963 and

2939 (br), 2871, 2838, 2166, 1975, 1715, 1634. HRMS (positive

ESI): calcd for C₂₀H₃₁NO₄[MNa⁺], 372.2145; found, 372.2149.

N-(3,4-Dimethoxyphenethyl)-N-(4-oxopentyl)formamide

(28e). Following the procedure used to prepare 24, 13 (4.05 mL, 24.0

mmol) was treated with AlMe₃(2.0 M in toluene, 12.0 mL, 24.0

mmol) and then γ-valerolactone (38, 1.91 mL, 20.0 mmol) in DCM

(96 mL). The usual workup (DCM) and puriﬁcation (70−100%

EtOAc in hexanes then 2−9% MeOH in EtOAc) aﬀorded N-(3,4-

dimethoxyphenethyl)-N-(4-hydroxy)pentanamide (4.05 g, 72%) as a

1

white solid. H NMR (300 MHz, CDCl₃): δ (ppm) 6.80−6.77 (m,

1H), 6.72−6.69 (m, 2H), 5.89 (br s, 1H), 3.85 (s, 3H), 3.84 (s, 3H),

3.80−3.72 (m, 1H), 3.46 (q, J = 13.0, 7.0 Hz, 1H), 3.14 (br s, 1H),

2.74 (t, J = 7.0 Hz, 1H), 2.28 (t, J = 7.0 Hz, 1H), 1.82−1.72 (m, 1H),

1.69−1.57 (m, 1H), 1.16 (d, J = 6.0 Hz, 3H). ¹³C{¹H} NMR (75

MHz, CDCl₃): δ (ppm) 173.7 (s), 149.1 (s), 147.8 (s), 131.4 (s),

120.7 (d), 112.0 (d), 111.5 (d), 67.5 (d), 56.1 (q), 56.0 (q), 40.9 (t),

K

https://dx.doi.org/10.1021/acs.joc.9b03449

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

(3.0 g, 94%) as a yellow oil. H NMR (300 MHz, CDCl₃): δ (ppm)

lowing the procedure used to prepare 18a, 28b (117. mg, 0.35 mmol)

was treated with triﬂic anhydride (66 μL, 0.39 mmol) and DTBMP

(80 mg, 0.39 mmol) in CHCl₃(7.0 mL). ¹H NMR analysis of a small

sample of the reaction mixture revealed the presence of an iminium

6.80 (d, J = 8.0 Hz, 1H), 6.74−6.71 (m, 2H), 4.02−3.92 (m, 1H),

3.87 (s, 3H), 3.85 (s, 3H), 3.67 (br s, 2H), 3.02−2.72 (m, 6H), 1.63−

1.41 (m, 2H), 1.16 (d, J = 6.0 Hz, 3H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ (ppm) 149.1 (s), 147.7 (s), 132.1 (s), 120.7 (d), 112.0

(d), 111.5 (d), 69.6 (d), 56.1 (q), 56.0 (q), 50.9 (t), 48.8 (t), 36.6 (t),

35.7 (t), 23.7 (q). IR (neat) ν (cm⁻¹): 3348 (br), 2960, 2932, 2836,

1514, 1260. HRMS (positive ESI): calcd for C₁₄H₂₄NO₃[M + H⁺],

254.1751; found, 254.1755. Following the procedure used to prepare

19, N-(3,4-dimethoxyphenethyl)-N-methyl-5-oxohexanamide (1.48 g,

5.84 mmol) was treated with N-formylbenzotriazole (1.81 g, 12.3

mmol) in THF (19 mL) then with NaOH (2 M, 2 × 25 mL). The

usual work-up (DCM) and puriﬁcation (50−100% EtOAc in hexanes

then 1−4% MeOH in EtOAc) aﬀorded N-(3,4-dimethoxyphenethyl)-

1

ion resulting from the Vilsmeier−Haack cyclization. H NMR (300

MHz, CDCl₃): δ (ppm) 8.94 (s, 1H), 7.47 (s, 1H), 6.90 (s, 1H), 4.01

(s, 3H), 4.00−3.94 (m, 2H), 3.91 (s, 3H), 3.86−3.80 (m, 2H), 3.19

(t, J = 8.0 Hz, 2H), 2.59−2.54 (m, 2H), 2.18 (s, 3H), 1.65−1.60 (m,

2H), 1.04 (s, 6H). Subsequent treatment with pyrrolidine (175 μL,

2.10 mmol) added at 0 °C then stirred at rt for 18 h followed by the

usual work-up (DCM) and puriﬁcation (5−20% EtOAc in hexanes

1

with 1.5% Et₃N) aﬀorded 30b (81 mg, 73%) as a yellow solid. H

NMR (300 MHz, CDCl₃): δ (ppm) 6.56 (s, 1H), 6.48 (s, 1H), 3.83

(s, 3H), 3.74 (s, 3H), 3.62 (d, J = 10.0 Hz, 1H), 3.07−2.87 (m, 3H),

2.65−2.50 (m, 3H), 2.36−2.32 (m, 1H), 2.25 (s, 3H), 1.62−1.56 (m,

1H), 1.47−1.39 (m, 1H), 1.08 (s, 3H), 0.92 (s, 3H). ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ (ppm) 214.0 (s), 147.4 (s), 146.7 (s), 129.3 (s),

128.4 (s), 111.8 (d), 109.6 (d), 67.6 (t), 63.9 (d), 55.9 (q), 55.8 (q),

53.1 (d), 52.5 (t), 43.2 (t), 31.7 (q), 30.4 (s), 30.0 (t), 29.4 (q), 25.3

(q). IR (neat) ν (cm⁻¹): 2943, 1704, 1516, 1256. HRMS (positive

ESI): calcd for C₁₉H₂₈NO₃[M + H⁺], 318.2064; found, 318.2068. mp

98−100 °C.

1

N-(3-hydroxybutyl)formamide (1.63 g, 99%) as a colorless oil. H

NMR (300 MHz, CDCl₃) 1:0.3 mixture of rotamers: δ (ppm) 8.10

(s) and 7.84 (s) (1H, rotamers), 6.82−6.62 (m, 3H), 3.96−3.90 (m,

1H), 3.88 (s) and 8.87 (s) (3H, rotamers), 3.86 (s, 3H), 3.77 (br s,

1H), 3.65−3.55 (m, 2H), 3.44 (t, J = 7.0 Hz, 2H), 3.39−3.02 (m,

1H), 2.84−2.77 (m, 2H), 1.59−1.43 (m, 1H), 1.22−1.18 (m, 3H).

¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ (ppm)

163.6 (d), 163.0 (d), 149.0 (s), 148.8 (s), 147.8 (s), 147.5 (s), 131.2

(s), 129.9 (s), 120.7 (d), 120.6 (d), 111.9 (d), 111.8 (d), 111.4 (d),

111.2 (d), 64.1 (d), 63.8 (d), 55.8 (q), 55.7 (q), 49.4 (t), 44.6 (t),

44.1 (t), 39.4 (t), 37.5 (t), 36.7 (t), 34.8 (t), 33.1 (t), 23.8 (q), 22.7

(q). IR (neat) ν (cm⁻¹): 3402 (br), 2946, 2841, 1651, 1515, 1025.

HRMS (positive ESI): calcd for C₁₅H₂₃NO₄Na [M + Na⁺], 304.1519;

found, 304.1518. Following the procedure used to prepare 16a, N-

(3,4-dimethoxyphenethyl)-N-(3-hydroxybutyl)formamide (1.63 g,

5.79 mmol) was treated with DMSO (1.07 mL, 15.0 mmol), oxalyl

chloride (0.75 mL, 8.69 mmol), and triethylamine (4.04 mL, 29.0

mmol) in DCM (43 + 23 mL). The usual work-up (DCM) and

puriﬁcation (40−100% EtOAc in hexanes then 1−4% MeOH in

cis-1-(9,10-Dimethoxy-11b-methyl-1,3,4,6,7,11b-hexahy-

dro-2H-pyrido[2,1-a]isoquinolin-1-yl)ethan-1-one (30c). Fol-

lowing the procedure used to prepare 18a, 28c (97 mg, 0.30

mmol) was treated with triﬂic anhydride (56 μL, 0.33 mmol) and

DTBMP (68 mg, 0.33 mmol) in CHCl₃(6.0 mL). ¹H NMR analysis

of a small sample of the reaction mixture revealed the presence of an

iminium ion resulting from the Vilsmeier−Haack cyclization. ¹H

NMR (300 MHz, CDCl₃): δ (ppm) 7.23 (s, 1H), 6.82 (s, 1H), 4.00−

3.87 (m, 10H), 3.12 (t, J = 7.5 Hz, 2H), 2.82 (s, 3H), 2.60 (t, J = 7.0

Hz, 2H), 2.16 (s, 3H), 1.92−1.81 (m, 2H), 1.72−1.65 (m, 2H).

Subsequent treatment with pyrrolidine (0.15 mL, 1.80 mmol) added

at 0 °C then stirred at rt for 18 h followed by the usual work-up

(DCM) and puriﬁcation (5−35% EtOAc in hexanes with 1.5% Et₃N)

1

EtOAc) aﬀorded 28f (1.51 g, 93%) as a white solid. H NMR (300

MHz, CDCl₃) 1:0.6 mixture of rotamers: δ (ppm) 8.06 (s) and 7.71

(s) (1H, rotamers), 6.75 (d, J = 8.0 Hz, 1H), 6.60−6.60 (m, 2H),

3.82 (s) and 3.81 (s) (3H, rotamers), 3.79 (s, 3H), 3.50−3.34 (m,

4H), 2.77−2.69 (m, 3H), 2.53 (t, J = 6.5 Hz, 1H), 2.10 (s) and 2.06

(s) (3H, rotamers). ¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of

rotamers: δ (ppm) 206.9 (s), 205.6 (s), 163.1 (d), 162.8 (d), 149.0

(s), 148.8 (s), 147.7 (s), 147.5 (s), 131.1 (s), 130.1 (s), 120.8 (d),

120.6 (d), 111.9 (d), 111.8 (d), 111.4 (d), 111.2 (d), 55.8 (q), 49.9

(t), 44.5 (t), 42.1 (t), 42.0 (t), 41.4 (t), 37.8 (t), 35.0 (t), 33.0 (t),

30.2 (q), 29.9 (q). IR (neat) ν (cm⁻¹): 3507, 2934, 2836, 1710, 1655,

1514, 1025. HRMS (positive ESI): calcd for C₁₅H₂₁NO₄Na [M +

Na⁺], 302.1363; found, 302.1364. mp 75−77 °C.

cis-1-(9,10-Dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido-

[2,1-a]isoquinolin-1-yl)ethan-1-one (30a). Following the proce-

dure used to prepare 18a, 28a (107.6 mg, 0.35 mmol) was treated

with triﬂic anhydride (66 μL, 0.39 mmol) and DTBMP (80 mg, 0.39

mmol) in CHCl₃(7.0 mL). ¹H NMR analysis of a small sample of the

1

aﬀorded 30c (22 mg, 24%) as a yellow oil. H NMR (300 MHz,

CDCl₃): δ (ppm) 6.54 (s, 1H), 6.53 (s, 1H), 3.84 (s, 3H), 3.75 (s,

3H), 3.45−3.29 (m, 2H), 3.26−2.16 (m, 2H), 2.91−2.72 (m, 4H),

2.17 (s, 3H), 3.09 (s, 3H), 1.64 (s, 3H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ (ppm) 214.1 (s), 147.4 (s), 146.8 (s), 134.8 (s), 126.6 (s),

111.6 (d), 109.7 (d), 59.6 (s), 55.9 (q), 55.8 (q), 54.0 (d), 49.4 (t),

45.9 (t), 34.1 (q), 30.0 (t), 25.6 (t), 21.0 (t), 19.1 (q). IR (neat) ν

(cm⁻¹): 2929, 2845, 1701, 1514, 1254. HRMS (positive ESI): calcd

for C₁₈H₂₆NO₃[M + H⁺], 304.1907; found, 304.1910.

cis-1-(9,10-Dimethoxy-3,3,11b-trimethyl-1,3,4,6,7,11b-hex-

ahydro-2H-pyrido[2,1-a]isoquinolin-1-yl)ethan-1-one (30d).

Following the procedure used to prepare 18a, 28d (76.5 mg, 0.22

mmol) was treated with triﬂic anhydride (40 μL, 0.24 mmol) and

DTBMP (49 mg, 0.24 mmol) in DCM (4.4 mL). ¹H NMR analysis of

a small sample of the reaction mixture revealed the presence of an

iminium ion resulting from the Vilsmeier−Haack cyclization. ¹H

NMR (300 MHz, CDCl₃): δ (ppm) 7.51 (s, 1H), 6.84 (s, 1H), 4.02−

4.00 (m, 5H), 3.94 (s, 3H), 3.89−3.81 (m, 2H), 3.14−3.09 (m, 2H),

2.86 (s, 3H), 2.60−2.54 (m, 2H), 2.20 (s, 3H), 1.72−1.67 (m, 2H),

1.15 (s, 3H), 1.09 (s, 3H). Subsequent treatment with pyrrolidine (55

μL, 0.66 mmol) added at 0 °C then stirred at rt for 18 h followed by

the usual work-up (DCM) and puriﬁcation (2−10% EtOAc in

hexanes with 1.5% Et₃N) aﬀorded 30d (13 mg, 18%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ (ppm) 6.59 (s, 1H), 6.54 (s, 1H),

1

reaction mixture revealed the presence of iminium ion 29. H NMR

(300 MHz, CD₂Cl₂): δ (ppm) 8.97 (s, 1H), 7.39 (s, 1H), 6.85 (s,

1H), 3.97−3.77 (m, 10H), 3.21 (t, J = 8.0 Hz, 2H), 2.56 (t, J = 6.5

Hz, 2H), 2.11 (s, 3H), 1.91−1.81 (m, 2H), 1.65−1.58 (m, 2H).

Subsequent treatment with pyrrolidine (88 μL, 1.05 mmol) added at

0 °C then stirred at rt for 18 h followed by the usual work-up (DCM)

and puriﬁcation (8−70% EtOAc in hexanes with 1.5% Et₃N) aﬀorded

30a (74 mg, 73%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ

(ppm) 6.57 (s, 1H), 6.43 (s, 1H), 3.96 (d, J = 10.0 Hz, 1H), 3.83 (s,

3H), 3.74 (s, 3H), 3.26−3.18 (m, 1H), 3.06−2.89 (m, 3H), 2.84 (t, J

= 6.0 Hz, 2H), 2.77−2.70 (m, 1H), 2.04 (s, 3H), 1.90−1.45 (m, 4H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 213.6 (s), 147.8 (s),

3.84 (s, 3H), 3.74 (s, 3H), 3.10 (dd, J = 13.0, 3.0 Hz, 1H), 3.05−2.83

(m, 3H), 2.61−2.46 (m, 2H), 2.18 (dd, J = 12.0, 2.0 Hz, 1H), 2.12 (s,

3H), 1.70 (t, J = 13.5 Hz, 1H), 1.46 (s, 3H), 1.34−1.25 (m, 1H), 1.09

(s, 3H), 0.91 (s, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm)

214.7 (s), 147.2 (s), 146.8 (s), 136.0 (s), 127.8 (s), 111.7 (d), 109.8

(d), 61.5 (t), 60.8 (s), 55.9 (q), 55.8 (q), 55.4 (d), 47.4 (t), 39.9 (t),

33.9 (q), 31.2 (t), 30.3 (s), 29.4 (q), 26.2 (q), 13.4 (q). IR (neat) ν

(cm⁻¹): 2948, 2823, 1703, 1514, 1254. HRMS (positive ESI): calcd

for C₂₀H₃₀NO₃[M + H⁺], 332.2220; found, 332.2221.

146.8 (s), 129.1 (s), 126.7 (s), 111.7 (d), 110.2 (d), 61.7 (d), 55.9

(q), 55.8 (q), 54.7 (t), 51.5 (d), 46.9 (t), 32.5 (q), 29.1 (t), 29.0 (t),

20.2 (t). IR (neat) ν (cm⁻¹): 2930, 2856, 1701, 1516, 1265, 1227,

1019. HRMS (positive ESI): calcd for C₁₇H₂₄NO₃[MH⁺], 290.1750;

found, 290.1756. mp 98−101 °C.

cis-1-(9,10-Dimethoxy-3,3-dimethyl-1,3,4,6,7,11b-hexahy-

dro-2H-pyrido[2,1-a]isoquinolin-1-yl)ethan-1-one (30b). Fol-

cis-1-(8,9-Dimethoxy-1,2,3,5,6,10b-hexahydropyrrolo[2,1-

a]isoquinolin-1-yl)ethan-1-one (30e). Following the procedure

L

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used to prepare 18a, 28e (88 mg, 0.30 mmol) was treated with triﬂic

anhydride (56 μL, 0.33 mmol) and DTBMP (68 mg, 0.33 mmol) in

DCM (6.0 mL). H NMR analysis of a small sample of the reaction

1495, 1276, 721. HRMS (positive ESI): calcd for C₆H₉NI [MH⁺],

221.9774; found, 221.9764.

1

N-(2-(1H-Pyrrol-1-yl)ethyl)-N-(4-oxopentyl)formamide

(39a). K₂CO₃(4.50 g, 32.4 mmol) was added to a solution of 37

(2.38 g, 10.8 mmol) and 38a (1.11 g, 10.8 mmol) in THF (36 mL) in

a sealed tube. The reaction mixture was stirred for 18 h at 90 °C, then

K₂CO₃was ﬁltered, and solvent was removed under reduced pressure

to aﬀord crude alkylated amine that was used directly in the next step.

Following the procedure used to prepare 19, the residue was treated

with N-formylbenzotriazole (3.18 g, 21.6 mmol) in THF (27 mL)

then with NaOH (2 M). The usual work-up (DCM) aﬀorded a crude

N,O-bisformylated product that was used directly in the next step.

K₂CO₃(4.48 g, 32.4 mmol) was added to a solution of the residue in

MeOH (35 mL). The reaction mixture was reﬂuxed for 2 h and then

allowed to cool to rt. Water was added, and the usual work-up

(EtOAc) aﬀorded crude hydroxy-formamide that was used directly in

the next step. Following the procedure to prepare 28c, the residue was

treated with Dess−Martin periodinane in DCM (20 mL) for 18 h.

The usual workup (DCM) and puriﬁcation (20−80% EtOAc in

hexanes) aﬀorded 39a (354 mg, 56% over 4 steps) as an orange oil.

¹H NMR (300 MHz, CDCl₃) 1:0.6 mixture of rotamers: δ (ppm)

mixture revealed the presence of an iminium ion resulting from the

Vilsmeier−Haack cyclization. ¹H NMR (300 MHz, CDCl₃): δ (ppm)

9.04 (s, 1H), 7.41 (s, 1H), 6.86 (s, 1H), 4.00−3.94 (m, 7H), 3.90 (s,

3H), 3.23 (t, J = 8.5 Hz, 2H), 2.69 (t, J = 6.5 Hz, 2H), 2.14 (s, 3H),

2.13−2.06 (m, 2H). Subsequent treatment with pyrrolidine (75 μL,

0.90 mmol) added at 0 °C then stirred at rt for 18 h followed by the

usual work-up (DCM) and puriﬁcation (10−70% EtOAc in hexanes

with 1.5% Et₃N) aﬀorded 30e (79 mg, 95%) as a yellow oil. ¹H NMR

(300 MHz, CDCl₃): δ (ppm) 6.58 (s, 1H), 6.45 (s, 1H), 4.15 (d, J =

8.0 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.13−3.01 (m, 3H), 2.96−

2.69 (m, 4H), 2.42−2.32 (m, 1H), 2.29 (s, 3H), 1.97−1.85 (m, 1H).

¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ (ppm)

210.5 (s), 147.7 (s), 147.5 (s), 129.5 (s), 126.2 (s), 111.5 (d), 109.1

(d), 63.6 (d), 57.9 (d), 56.1 (q), 56.0 (q), 52.7 (t), 47.5 (t), 30.1 (q),

28.8 (t), 27.4 (t). IR (neat) ν (cm⁻¹): 2928, 2831, 1703, 1511, 1255,

1013. HRMS (positive ESI): calcd for C₁₆H₂₂NO₃[M + H⁺],

276.1594; found, 276.1598.

9,10-Dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]-

isoquinolin-2-one (30f). Following the procedure used to prepare

18a, 28f (100 mg, 0.36 mmol) was treated with triﬂic anhydride (67

μL, 0.40 mmol) and DTBMP (82 mg, 0.40 mmol) in DCM (7.2 mL).

Subsequent treatment with pyrrolidine (45 μL, 0.54 mmol) added at

0 °C then stirred at rt for 18 h followed by the usual work-up (DCM)

and puriﬁcation (5−90% EtOAc in hexanes with 1.5% Et₃N) aﬀorded

30f (28 mg, 30%) as an orange solid. ¹H NMR (300 MHz, CDCl₃): δ

(ppm) 6.61 (s, 1H), 6.53 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.60−

3.53 (m, 1H), 3.34−3.24 (m, 1H), 3.15−3.13 (m, 2H), 2.91 (d, J =

14.0 Hz, 1H), 2.81−2.42 (m, 6H). ¹³C{¹H} NMR (75 MHz, CDCl₃):

δ (ppm) 208.5 (s), 148.0 (s), 147.7 (s), 128.3 (s), 126.1 (s), 111.6

(d), 107.9 (d), 61.6 (d), 56.1 (q), 56.0 (q), 54.8 (t), 50.9 (t), 47.5 (t),

41.1 (t), 29.2 (t). IR (neat) ν (cm⁻¹): 2924, 1712, 1514. HRMS

(positive ESI): calcd for C₁₅H₂₀NO₃[M + H⁺], 262.1438; found,

262.1439. mp 148−151 °C.

2-(1H-Pyrrol-1-yl)ethan-1-ol (36). Ethanolamine (66 mL, 1.09

mmol) was added to glacial acetic acid (120 mL) at 0 °C a rate such

that the temperature was maintained at 15−25 °C. Then, 2,5-

dimethoxytetrahydrofuran (32 mL, 0.25 mmol) was added in one

portion and the reaction was stirred at 110−120 °C, at which point

distillation of a liquid commenced. After 1 h 30 min at that

temperature, 25 mL of a distillate was collected. The residual liquid in

the reaction vessel was cooled to rt and water was added. The usual

work-up (DCM, brine, saturated aqueous Na₂CO₃) aﬀorded a residue

that was dissolved in MeOH (67 mL). NaOH (20 wt %, 33 mL) was

added, and the solution was stirred at rt for 1 h, then poured into

brine, and extracted with DCM. The solvent was removed under

reduced pressure to aﬀord 36 (17 g, 61%) as a yellow oil. Analytical

data were in accordance with those reported in the literature.²²¹H

NMR (300 MHz, CDCl₃): δ (ppm) 6.71−6.70 (m, 2H), 6.19−6.18

(m, 2H), 4.02 (t, J = 5.0 Hz, 2H), 3.84 (t, J = 5.0 Hz, 2H), 1.73 (s,

1H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 120.8 (d), 108.2

(d), 62.5 (t), 51.7 (t). IR (neat) ν (cm⁻¹): 3401 (br), 2927, 2881.

HRMS (positive ESI): calcd for C₆H₉NONa [MNa⁺], 134.0576;

found, 134.0571.

8.04 (s) and 7.53 (s) (1H, rotamers), 6.64−6.57 (m, 2H), 6.16−6.12

(m, 2H), 4.09 (t, J = 6.0 Hz, 1H), 4.02−3.99 (m, 1H), 3.57−3.49 (m,

2H), 3.26−3.21 (m, 1H), 2.81−2.76 (m, 1H), 2.45 (t, J = 7.0 Hz,

1H), 2.30 (t, J = 7.0 Hz, 1H), 2.14 (s) and 2.11 (s) (3H, rotamers),

1.83−1.74 (m, 1H), 1.67−1.57 (m, 1H). ¹³C{¹H} NMR (75 MHz,

CDCl₃) mixture of rotamers: δ (ppm) 207.9 (s), 207.1 (s), 162.9 (d),

162.7 (d), 120.6 (d), 120.4 (d), 109.2 (d), 108.7 (d), 48.6 (t), 48.0

(t), 47.2 (t), 46.9 (t), 44.5 (t), 41.3 (t), 40.2 (t), 39.5 (t), 30.1 (q),

30.0 (q), 22.2 (t), 21.2 (t). IR (neat) ν (cm⁻¹): 3458 (br), 1707,

1652, 730. HRMS (positive ESI): calcd for C₁₂H₁₈N₂O₂Na [MNa⁺],

245.1260; found, 245.1267.

N-(2-(1H-Pyrrol-1-yl)ethyl)-N-(5-oxohexyl)formamide (39b).

Following the procedure used to prepare 39a, 38b (1.22 g, 10.4

mmol) was treated with K₂CO₃(4.30 g, 31.2 mmol) and 37 (2.29 g,

10.4 mmol) in THF (35 mL) to aﬀord a crude alkylated amine that

was used directly in the next step. The residue was then treated with

N-formylbenzotriazole (3.06 g, 20.8 mmol) in THF (26 mL) to aﬀord

crude N,O-bisformylated product that was used directly in the next

step. The residue then treated with K₂CO₃(4.31 g, 31.2 mmol) in

MeOH (35 mL) and the usual work-up (EtOAc) and puriﬁcation

(20−100% EtOAc in hexanes with 1.5% Et₃N, then 5% MeOH in

EtOAc with 1.5% Et₃N) aﬀorded N-(2-(1H-pyrrol-1-yl)ethyl)-N-(5-

hydroxyhexyl)formamide (1.52 g, 61% over 3 steps) as an orange oil.

¹H NMR (300 MHz, CDCl₃) 1:0.5 mixture of rotamers: δ (ppm)

8.07 (s) and 7.57 (s) (1H, rotamers), 6.64−6.58 (m, 2H), 6.18−6.14

(m, 2H), 4.11−3.97 (m, 2H), 3.82−3.69 (m, 1H), 3.57−3.48 (m,

2H), 3.28−3.23 (m, 1H), 2.81 (t, J = 7.0 Hz, 1H), 1.55−1.25 (m,

7H), 1.18 (d, J = 6.0 Hz) and 1.17 (d, J = 6.0 Hz) (3H, rotamers).

¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ (ppm)

163.0 (d), 162.7 (d), 120.6 (d), 120.5 (d), 109.3 (d), 108.8 (d), 67.6

(d), 67.5 (d), 48.8 (t), 48.3 (t), 48.2 (t), 47.0 (t), 44.7 (t), 42.3 (t),

38.7 (t), 38.5 (t), 28.6 (t), 27.4 (t), 23.6 (q), 23.5 (q), 22.9 (t), 22.6

(t). IR (neat) ν (cm⁻¹): 3410 (br), 2934, 2860, 1657, 724. HRMS

(positive ESI): calcd for C₁₃H₂₂N₂O₂Na [MNa⁺], 261.1573; found,

261.1576. Following the procedure to prepare 28c, N-(2-(1H-pyrrol-

1-yl)ethyl)-N-(5-hydroxyhexyl)formamide (83 mg, 0.35 mmol) was

treated with Dess−Martin periodinane (297 mg, 0.70 mmol) in DCM

(7.0 mL) for 18 h. The usual workup (DCM) and puriﬁcation (20−

80% EtOAc in hexanes) aﬀorded 39b (41 mg, 49%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃) 1:0.6 mixture of rotamers: δ (ppm)

8.06 (s) and 7.55 (s) (1H, rotamers), 6.63−6.57 (m, 2H), 6.17−6.13

(m, 2H), 4.09 (t, J = 6.0 Hz, 1H), 3.99 (t, J = 6.0 Hz, 1H), 3.56−3.48

(m, 2H), 3.23 (t, J = 6.5 Hz, 1H), 2.78 (t, J = 7.0 Hz, 1H), 2.46 (t, J =

6.5 Hz, 1H), 2.38 (t, J = 7.0 Hz, 1H), 2.13 (s) and 2.11 (s) (3H,

rotamers), 1.54−1.19 (m, 4H). ¹³C{¹H} NMR (75 MHz, CDCl₃)

mixture of rotamers: δ (ppm) 208.6 (s), 208.0 (s), 163.1 (d), 162.8

(d), 120.8 (d), 120.6 (d), 109.5 (d), 108.9 (d), 48.9 (t), 48.4 (t), 48.3

(t), 47.2 (t), 45.0 (t), 42.9 (t), 42.8 (t), 42.1 (t), 30.2 (q), 30.1 (q),

28.1 (t), 26.9 (t), 20.8 (t), 20.5 (t). IR (neat) ν (cm⁻¹): 2938, 2866,

1-(2-Iodoethyl)-1H-pyrrole (37). Iodide (1.40 g, 5.50 mmol)

was added in three portions to a solution of triphenylphosphine (1.43

g, 5.45 mmol) and imidazole (450 mg, 6.60 mmol) in DCM (55 mL)

at 0 °C, protected from the light. The mixture was stirred for 30 min

at 0 °C, and then, a solution of 36 (611 mg, 5.50 mmol) in DCM (6.0

mL) was added. The reaction mixture was stirred for 18 h at rt, and

then, saturated aqueous Na₂S₂O₃was added. The usual work-up

(DCM) and puriﬁcation (10−20% DCM in hexanes) aﬀorded 37

(968 mg, 79%) as a yellow oil. Analytical data were in accordance

with those reported in the literature.²³¹H NMR (300 MHz, CDCl₃):

δ (ppm) 6.71−6.70 (m, 2H), 6.22−6.21 (m, 2H), 4.27 (t, J = 7.5 Hz,

2H), 3.41 (t, J = 7.5 Hz, 2H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ

(ppm) 120.4 (d), 108.8 (d), 51.9 (t), 3.4 (t). IR (neat) ν (cm⁻¹):

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1711, 1664, 727. HRMS (positive ESI): calcd for C₁₃H₂₀N₂O₂Na

[MNa⁺], 259.1417; found, 259.1418.

29.8 (q), 24.4 (t), 22.8 (t). IR (neat) ν (cm⁻¹): 3287, 2918, 2855,

1653. HRMS (positive ESI): calcd for C₁₂H₁₄N₂ONa [MNa⁺],

225.0998; found, 225.0998. mp 71−74 °C. A solution of 42 (218 mg,

1.08 mmol) in THF (0.54 mL) was added to a suspension of NaH

(60% in min. oil, 86 mg, 2.16 mmol) in THF (2.2 mL). The reaction

mixture was stirred for 15 min at rt, and then, 41 (276 mg, 1.08

mmol) was added. The resulting mixture was stirred for 3 h at rt, and

then, water was added. The usual work-up (DCM) and puriﬁcation

(70−100% EtOAc in hexanes then 2% MeOH in EtOAc) aﬀorded 43

N-(2-(1H-Pyrrol-1-yl)ethyl)-N-(5-oxohexyl)acetamide (39c).

Following the procedure used to prepare 39a, 38b (870 mg, 7.42

mmol) was treated with K₂CO₃(3.08 g, 22.3 mmol) and 37 (1.64 g,

7.42 mmol) in THF (25 mL) to aﬀord a crude alkylated amine that

was used directly in the next step. The residue was dissolved in DCM

(37 mL) at 0 °C and Et₃N (4.14 mL, 29.7 mmol) was added, followed

by a dropwise addition of acetyl chloride (1.11 mL, 15.6 mmol). The

reaction mixture was stirred for 18 h at rt, then quenched, and washed

with a saturated aqueous solution of NaHCO₃(2 × 25 mL). The

usual workup (DCM) aﬀorded crude N,O-bisacetylated product that

was used directly in the next step. Following the procedure used to

prepare 39a, the residue then treated with K₂CO₃(3.08 g, 22.3

mmol) in MeOH (25 mL) and the usual work-up (EtOAc) and

puriﬁcation (20−100% EtOAc in hexanes with 1.5% Et₃N, then 5%

MeOH in EtOAc with 1.5% Et₃N) aﬀorded crude hydroxy-acetamide

that was used directly in the next step. Following the procedure to

prepare 28c, the residue was treated with Dess−Martin periodinane

(1.0 g, 2.36 mmol) in DCM (16 mL) and the usual workup (DCM)

and puriﬁcation (10−100% EtOAc in hexanes with 1.5% Et₃N)

1

(242 mg, 68%) as a yellow oil. H NMR (300 MHz, CDCl₃) 1:0.5

mixture of rotamers: δ (ppm) 8.06 (s) and 7.83 (s) (1H, rotamers),

7.63 (d, J = 8.0 Hz) and 7.54 (d, J = 8.0 Hz) (1H, rotamers), 7.34 (d,

J = 3.5 Hz) and 7.31 (d, J = 3.5 Hz) (1H, rotamers), 7.24−7.18 (m,

1H), 7.14−7.08 (m, 1H), 6.97 (s) and 6.88 (s) (1H, rotamers), 4.09

(t, J = 7.0 Hz, 2H), 3.97−3.86 (m, 4H), 3.67−3.62 (m) and 3.55−

3.50 (m) (2H, rotamers), 3.03−2.97 (m, 2H), 2.93 (s) and 2.88 (s)

(3H, rotamers), 1.92 (dt, J = 12.0, 7.5 Hz, 2H), 1.66 (dd, J = 10.0, 6.0

Hz, 2H), 1.29 (s) and 1.28 (s) (3H, rotamers). ¹³C{¹H} NMR

mixture of rotamers (75 MHz, CDCl₃): δ (ppm) 162.6 (d), 162.3 (d),

136.3 (s), 136.2 (s), 127.7 (s), 127.3 (s), 125.8 (d), 125.5 (d), 121.6

(d), 121.4 (d), 118.8 (d), 118.7 (d), 118.3 (d), 111.1 (s), 110.1 (s),

109.6 (d), 109.5 (s), 109.3 (d), 64.5 (t), 50.0 (t), 46.1 (t), 46.0 (t),

44.9 (t), 36.2 (t), 36.1 (t), 34.8 (q), 29.5 (q), 24.7 (t), 24.3 (t), 23.8

(q), 22.6 (t). IR (neat) ν (cm⁻¹): 2944, 2877, 1667, 1063. HRMS

(positive ESI): calcd for C₁₉H₂₆N₂O₃Na [MNa⁺], 353.1836; found,

353.1835.

1

aﬀorded 39c (142 mg, 29% over 4 steps) as a yellow oil. H NMR

(300 MHz, CDCl₃) 1:0.4 mixture of rotamers: δ (ppm) 6.62−6.57

(m, 2H), 6.16−6.12 (m, 2H), 4.08 (t, J = 6.0 Hz) and 4.01 (t, J = 6.0

Hz) (2H, rotamers), 3.53 (t, J = 6.0 Hz, 2H), 3.25 (t, J = 7.0 Hz, 1H),

2.80−2.75 (m, 1H), 2.46 (t, J = 6.5 Hz, 1H), 2.38 (t, J = 7.0 Hz, 1H),

2.13 (s) and 2.12 (s) (3H, rotamers), 2.08 (s) and 1.63 (s) (3H,

rotamers), 1.54−1.25 (m, 4H). ¹³C{¹H} NMR (75 MHz, CDCl₃)

mixture of rotamers: δ (ppm) 208.5 (s), 207.9 (s), 170.7 (s), 170.4

(s), 120.6 (d), 109.1 (d), 108.5 (d), 49.9 (t), 49.6 (t), 48.3 (t), 47.8

(t), 47.3 (t), 44.8 (t), 42.9 (t), 42.7 (t), 29.9 (q), 27.9 (t), 26.8 (t),

21.4 (q), 20.8 (t), 20.6 (t), 20.5 (q). IR (neat) ν (cm⁻¹): 2941, 1709,

1636, 1419. HRMS (positive ESI): calcd for C₁₄H₂₂N₂O₂Na [MNa⁺],

273.1573; found, 273.1572.

2-(3-Iodopropyl)-2-methyl-1,3-dioxolane (41). Iodide (327

mg, 1.29 mmol) was added in three diﬀerent portions to a solution of

triphenylphosphine (336 mg, 1.28 mmol) and imidazole (106 mg,

1.55 mmol) in DCM (13 mL) at 0 °C, protected from the light. After

stirring for 30 min at 0 °C, a solution of 40 (188 mg, 1.29 mmol) in

DCM (1.5 mL) was added. The reaction was stirred for 18 h at rt.

Saturated aqueous NaHSO₃was added. The usual work-up (Et₂O)

and puriﬁcation (50−100% EtOAc in hexanes) aﬀorded 41 (276 mg,

84%) as a colorless oil. Analytical data were in accordance with those

reported in the literature.²⁴¹H NMR (300 MHz, CDCl₃): δ (ppm)

3.96−3.91 (m, 4H), 3.21 (t, J = 7.0 Hz, 2H), 2.00−1.90 (m, 2H),

1.77−1.72 (m, 2H), 1.32 (s, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃):

δ (ppm) 109.5 (s), 64.8 (t), 39.9 (t), 28.4 (t), 24.1 (q), 7.1 (t). IR

(neat) ν (cm⁻¹): 2978, 2364.

N-Methyl-N-(2-(1-(3-(2-methyl-1,3-dioxolan-2-yl)propyl)-

1H-indol-3-yl)ethyl)formamide (43). Following the procedure

used to prepare 27, ethyl (2-(1H-indol-3-yl)ethyl)carbamate²⁵(300

mg, 1.29 mmol) was ﬁrst treated with LiAlH₄(147 mg, 3.87 mmol) in

THF (6.5 mL), then with water (0.1 mL), NaOH (15%, 0.1 mL), and

water (0.3 mL) to aﬀord a crude amino-alcohol that was used directly

in the next step. Following the procedure used to prepare 19, crude

amino-alcohol was treated with N-formylbenzotriazole (228 mg, 1.55

mmol) in THF (6.0 mL) and the usual work-up (DCM) and

puriﬁcation (60−100% EtOAc in hexanes then 2% MeOH in EtOAc)

aﬀorded N-(2-(1H-indol-3-yl)ethyl)-N-methylformamide (42, 220

mg, 84% over 2 steps) as a white solid. Analytical data were in

accordance with those reported in the literature.²⁶¹H NMR (300

MHz, CDCl₃) 1:0.5 mixture of rotamers: δ (ppm) 8.19 (br s, 1H),

8.06 (s) and 7.77 (s) (1H, rotamers), 7.65 (d, J = 8.0 Hz) and 7.56

(d, J = 8.0 Hz) (1H, rotamers), 7.37 (d, J = 8.0 Hz, 1H), 7.24−7.11

(m, 2H), 7.06 (s) and 6.96 (s) (1H, rotamers), 3.70−3.65 (m) and

3.57−3.52 (m) (2H, rotamers), 3.06−2.99 (m, 2H), 2.94 (s) and 2.89

(s) (3H, rotamers). ¹³C{¹H} NMR mixture of rotamers (75 MHz,

CDCl₃): δ (ppm) 163.0 (d), 162.7 (d), 136.5 (s), 136.4 (s), 127.4

(s), 126.9 (s), 122.7 (d), 122.1 (d), 122.0 (d), 119.5 (d), 119.3 (d),

118.6 (d), 118.2 (d), 111.6 (d), 111.4 (d), 50.2 (t), 45.0 (t), 35.1 (q),

N-(2-(1-Methyl-1H-indol-3-yl)ethyl)-N-(4-oxopentyl)-

formamide (44a). Triﬂuroroacetic acid (1.5 mL, 19.4 mmol) was

added to a solution of tert-butyl (2-(1-methyl-1H-indol-3-yl)ethyl)-

carbamate (886 mg, 3.23 mmol) in DCM (16 mL) at 0 °C. The

solution was stirred for 18 h at rt, and then, a saturated aqueous

solution of Na₂CO₃(20 mL) was added. The usual workup (DCM)

aﬀorded the crude primary amine (338 mg, 1.94 mmol) that was used

directly in the next step. Following the procedure used to prepare 24,

crude primary amine was treated with AlMe₃(2.0 M in toluene, 0.97

mL, 1.94 mmol) and γ-valerolactone (0.15 mL, 1.62 mmol) in DCM

(13 mL). The usual workup (DCM) and puriﬁcation (50−100%

EtOAc in hexanes then 1% MeOH in EtOAc) aﬀorded 4-hydroxy-N-

(2-(1-methyl-1H-indol-3-yl)ethyl)pentanamide (405 mg, 91%) as an

1

orange oil. H NMR (300 MHz, CDCl₃): δ (ppm) 7.59 (d, J = 8.0

Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.0, 1.0 Hz, 1H), 7.12

(ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.90 (s, 1H), 5.66 (br s, 1H), 3.83−

3.78 (m, 1H), 3.76 (s, 3H), 3.59 (dd, J = 13.0, 6.5 Hz, 2H), 2.96 (t, J

= 7.0 Hz, 2H), 2.80 (br s, 1H), 2.27 (dd, J = 10.5, 4.0 Hz, 2H), 1.83−

1.58 (m, 2H), 1.17 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ (ppm) 173.8 (s), 137.2 (s), 127.9 (s), 126.9 (d), 121.8

(d), 119.0 (d), 118.9 (d), 111.5 (s), 109.4 (d), 67.4 (d), 40.1 (t), 34.4

(t), 33.3 (t), 32.7 (q), 25.2 (t), 23.6 (q). IR (neat) ν (cm⁻¹): 3305

(br), 2922, 1639, 1549, 739. HRMS (positive ESI): calcd for

C₁₆H₂₂N₂O₂Na [MNa⁺], 297.1573; found, 297.1579. Following the

procedure used to prepare 27, 4-hydroxy-N-(2-(1-methyl-1H-indol-3-

yl)ethyl)pentanamide (405 mg, 1.48 mmol) was ﬁrst treated with

LiAlH₄(112 mg, 2.96 mmol) in THF (5.0 mL), then with water (0.11

mL), NaOH (15%, 0.11 mL), and water (0.33 mL) to aﬀord a crude

amino-alcohol that was used directly in the next step. Following the

procedure used to prepare 19, crude amino-alcohol was treated with

N-formylbenzotriazole (458 mg, 3.11 mmol) in THF (5 mL) to aﬀord

crude N,O-bisformylated product that was used directly in the next

step. The residue then treated with K₂CO₃(430 mg, 3.11 mmol) in

MeOH (10 mL) and the usual work-up (EtOAc) and puriﬁcation

(40−100% EtOAc in hexanes then 1−3% MeOH in EtOAc) aﬀorded

N-(4-hydroxypentyl)-N-(2-(1-methyl-1H-indol-3-yl)ethyl)formamide

1

(252 mg, 59% over 3 steps) as a yellow oil. H NMR (300 MHz,

CDCl₃) 1:0.8 mixture of rotamers: δ (ppm) 8.09 (s) and 7.82 (s)

(1H, rotamers), 7.64 (d, J = 8.0 Hz) and 7.53 (d, J = 8.0 Hz) (1H,

rotamers), 7.31 (d, J = 3.5 Hz) and 7.29 (d, J = 3.5 Hz) (1H

rotamers), 7.25−7.20 (m, 1H), 7.15−7.09 (m, 1H), 6.91 (s) and 6.82

(s) (1H, rotamers), 3.89−3.79 (m, 1H), 3.74 (s, 3H), 3.63−3.58 (m,

1H), 3.51 (t, J = 7.0 Hz, 1H), 3.49−3.31 (m, 1H), 3.18 (t, J = 7.1 Hz,

1H), 3.00 (dt, J = 11.0, 8.0 Hz, 2H). 1.84−1.31 (m, 5H), 1.19 (d, J =

N

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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Article

6.0 Hz) and 1.16 (d, J = 6.0 Hz) (3H, rotamers). ¹³C{¹H} NMR (75

MHz, CDCl₃) mixture of rotamers: δ (ppm) 163.1 (d), 162.9 (d),

137.2 (s), 137.0 (s), 127.8 (s), 127.4 (s), 127.2 (d), 126.9 (d), 121.9

(d), 121.7 (d), 119.1 (d), 118.9 (d), 118.8 (d), 118.4 (d), 111.4 (s),

110.2 (s), 109.5 (d), 109.3 (d), 67.5 (d), 67.4 (d), 48.1 (t), 48.0 (t),

43.4 (t), 42.3 (t), 36.1 (t), 35.8 (t), 32.8 (q), 32.7 (q), 25.2 (t), 25.1

(t), 23.9 (t), 23.8 (q), 23.7 (q), 23.2 (t). IR (neat) ν (cm⁻¹): 3390

(br), 2928, 1650, 738. HRMS (positive ESI): calcd for

C₁₇H₂₄N₂O₂Na [MNa⁺], 311.1730; found, 311.1728. N-(4-hydrox-

ypentyl)-N-(2-(1-methyl-1H-indol-3-yl)ethyl)formamide (84 mg,

0.29 mmol) was then treated with Dess−Martin periodinane (246

mg, 0.58 mmol) in DCM (2.0 mL) and the usual workup (DCM) and

puriﬁcation (60−100% EtOAc in hexanes then 1% MeOH in EtOAc)

1H), 3.51 (t, J = 7.0 Hz, 1H), 3.38 (t, J = 7.5 Hz, 1H), 3.16 (t, J = 7.0

Hz, 1H), 2.99 (dt, J = 10.0, 7.5 Hz, 2H), 1.65−1.26 (m, 7H), 1.19 (d,

J = 4.5 Hz) and 1.17 (d, J = 4.5 Hz) (3H, rotamers). ¹³C{¹H} NMR

(75 MHz, CDCl₃) mixture of rotamers: δ (ppm) 163.0 (d), 162.8 (d),

137.1 (s), 137.0 (s), 127.8 (s), 127.3 (s), 127.1 (d), 126.8 (d), 121.8

(d), 121.6 (d), 119.0 (d), 118.9 (d), 118.8 (d), 118.3 (d), 111.3 (s),

110.2 (s), 109.5 (d), 109.2 (d), 67.6 (d), 67.5 (d), 48.0 (t), 47.9 (t),

43.3 (t), 42.1 (t), 38.7 (t), 38.6 (t), 32.7 (q), 32.6 (q), 28.7 (t), 27.4

(t), 25.0 (t), 23.6 (q), 23.5 (q), 23.2 (t), 23.0 (t), 22.7 (t). IR (neat)

ν (cm⁻¹): 3407 (br), 2930, 2861, 1652. HRMS (positive ESI): calcd

for C₁₈H₂₆N₂O₂Na [MNa⁺], 325.1886; found, 325.1890. Following

the procedure to prepare 28c, N-(5-hydroxyhexyl)-N-(2-(1-methyl-

1H-indol-3-yl)ethyl)formamide (86 mg, 0.28 mmol) was treated with

Dess−Martin periodinane (178 mg, 0.42 mmol) in DCM (5.6 mL)

and the usual workup (DCM) and puriﬁcation (40−100% EtOAc in

1

aﬀorded 44a (56 mg, 67%) as a yellow oil. H NMR (300 MHz,

CDCl₃) 1:0.7 mixture of rotamers: δ (ppm) 8.05 (s) and 7.80 (s)

(1H, rotamers), 7.65 (d, J = 8.0 Hz) and 7.54 (d, J = 8.0 Hz) (1H,

rotamers), 7.31−7.20 (m, 2H), 7.12 (t, J = 7.0 Hz, 1H), 6.91 (s) and

6.82 (s) (1H, rotamers), 3.73 (s, 3H), 3.62−3.57 (m, 1H), 3.50 (t, J =

7.0 Hz, 1H), 3.37 (t, J = 7.0 Hz, 1H), 3.16 (t, J = 7.0 Hz, 1H), 3.03−

2.95 (m, 2H), 2.46 (t, J = 7.0 Hz) and 2.36 (t, J = 7.0 Hz) (2H,

rotamers), 2.13 (s) and 2.10 (s) (3H, rotamers), 1.92−1.72 (m, 2H).

¹³C{¹H} NMR (75 MHz, CDCl₃) mixture of rotamers: δ (ppm)

208.0 (s), 207.3 (s), 163.2 (d), 162.8 (d), 137.2 (s), 137.0 (s), 127.8

(s), 127.4 (s), 127.2 (d), 126.8 (d), 121.9 (d), 121.7 (d), 119.1 (d),

119.0 (d), 118.9 (d), 118.4 (d), 111.3 (s), 110.2 (s), 109.5 (d), 109.3

(d), 47.9 (t), 46.9 (t), 43.3 (t), 41.4 (t), 40.6 (t), 39.7 (t), 32.8 (q),

32.7 (q), 30.1 (q), 30.0 (q), 25.0 (t), 23.2 (t), 22.4 (t), 21.4 (t). IR

(neat) ν (cm⁻¹): 2932, 1711, 1662, 740. HRMS (positive ESI): calcd

for C₁₇H₂₂N₂O₂Na [MNa⁺], 309.1573; found, 309.1579.

1

hexanes) aﬀorded 44b (53 mg, 63%) as a yellow oil. H NMR (300

MHz, CDCl₃) 1:0.8 mixture of rotamers: δ (ppm) 8.08 (s) and 7.81

(s) (1H, rotamers), 7.63 (d, J = 8.0 Hz) and 7.53 (d, J = 8.0 Hz) (1H,

rotamers), 7.31 (d, J = 3.5 Hz) and 7.28 (d, J = 3.5 Hz) (1H,

rotamers), 7.25−7.20 (m, 1H), 7.12 (ddd, J = 8.5, 3.0, 1.5 Hz, 1H),

6.91 (s) and 6.83 (s) (1H, rotamers), 3.74 (s, 3H), 3.60 (dd, J = 8.5,

7.0 Hz, 1H), 3.50 (t, J = 7.0 Hz, 1H), 3.37 (t, J = 7.0 Hz, 1H), 3.14 (t,

J = 6.5 Hz, 1H), 2.99 (m, 2H), 2.49−2.35 (m, 2H), 2.13 (s) and 2.11

(s) (3H, rotamers), 1.60−1.46 (m, 4H). ¹³C{¹H} NMR (75 MHz,

CDCl₃) mixture of rotamers: δ (ppm) 208.7 (s), 208.1 (s), 163.0 (d),

162.8 (d), 137.2 (s), 137.1 (s), 127.8 (s), 127.4 (s), 127.2 (d), 126.9

(d), 121.9 (d), 121.7 (d), 119.1 (d), 119.0 (d), 118.8 (d), 118.4 (d),

111.4 (s), 110.2 (s), 109.6 (d), 109.3 (d), 48.0 (t), 47.9 (t), 43.4 (t),

43.0 (t), 42.9 (t), 41.8 (t), 32.8 (q), 32.7 (q), 30.1 (q), 30.0 (q), 28.3

(t), 26.8 (t), 25.1 (t), 23.3 (t), 20.9 (t), 20.6 (t). IR (neat) ν (cm⁻¹):

2936, 2871, 1710, 1659. HRMS (positive ESI): calcd for

C₁₈H₂₄N₂O₂Na [MNa⁺], 323.1730; found, 323.1730.

N-(2-(1-Methyl-1H-indol-3-yl)ethyl)-N-(5-oxohexyl)-

formamideformamide (44b). Following the procedure used to

prepare 44a, tert-butyl (2-(1-methyl-1H-indol-3-yl)ethyl)carbamate

(886 mg, 3.23 mmol) was treated with triﬂuroroacetic acid (1.5 mL,

19.4 mmol) in DCM (16 mL) to aﬀord the crude primary amine (218

mg, 1.25 mmol) that was used directly in the next step. Following the

procedure used to prepare 24, crude primary amine was treated with

AlMe₃(2.0 M in toluene, 0.63 mL, 1.25 mmol) and 23 (0.11 mL, 1.04

mmol) in DCM (8.3 mL). The usual workup (DCM) and puriﬁcation

(80−100% EtOAc in hexanes then 2% MeOH in EtOAc) aﬀorded 5-

hydroxy-N-(2-(1-methyl-1H-indol-3-yl)ethyl)hexanamide (298 mg,

N-Methyl-N-(2-(1-(4-oxopentyl)-1H-indol-3-yl)ethyl)-

formamide (44c). p-TsOH (42 mg, 0.22 mmol) was added to a

solution of 43 (242 mg, 0.73 mmol) in acetone/H₂O (1:1, 4.0 mL).

The solution was stirred for 18 h at rt, and then, a saturated solution

of NaHCO₃was added. The usual workup (Et₂O) and puriﬁcation

(50−100% EtOAc in hexanes then 2% MeOH in EtOAc) aﬀorded

1

44c (175 mg, 84%) as a yellow oil. H NMR (300 MHz, CDCl₃)

1:0.5 mixture of rotamers: δ (ppm) 8.06 (s) and 7.74 (s) (1H,

rotamers), 7.63 (d, J = 8.0 Hz) and 7.54 (d, J = 8.0 Hz) (1H,

rotamers), 7.33 (d, J = 4.0 Hz) and 7.30 (d, J = 4.0 Hz) (1H,

rotamers), 7.25−7.18 (m, 1H), 7.15−7.09 (m, 1H), 6.94 (s) and 6.83

(s) (1H, rotamers), 4.11 (t, J = 7.0 Hz, 2H), 3.68−3.63 (m) and

3.55−3.50 (m) (2H, rotamers), 3.03−2.97 (m, 2H), 2.93 (s) and 2.91

(s) (3H, rotamers), 2.39−2.32 (m, 2H), 2.12−2.03 (m, 5H). ¹³C{¹H}

NMR mixture of rotamers (75 MHz, CDCl₃): δ (ppm) 207.8 (s),

207.7 (s), 162.7 (d), 162.4 (d), 136.4 (s), 136.3 (s), 127.8 (s), 127.3

(s), 126.0 (d), 125.5 (d), 121.9 (d), 121.7 (d), 119.1 (d), 118.9 (d),

118.8 (d), 118.5 (d), 111.5 (s), 110.4 (s), 109.6 (d), 109.4 (d), 50.0

(t), 44.9 (t), 39.9 (t), 39.8 (t), 34.9 (q), 30.0 (q), 29.5 (q), 24.2 (t),

24.1 (t), 24.0 (t), 22.6 (t). IR (neat) ν (cm⁻¹): 2932, 1711, 1666.

HRMS (positive ESI): calcd for C₁₇H₂₂N₂O₂Na [MNa⁺], 309.1573;

found, 309.1571.

1

99%) as a yellow oil. H NMR (300 MHz, CDCl₃): δ (ppm) 7.59

(d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.0, 1.0 Hz,

1H), 7.12 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.89 (s, 1H), 5.57 (br s,

1H), 3.76 (s, 3H), 3.73−3.69 (m, 1H), 3.59 (dd, J = 12.5, 6.5 Hz,

2H), 2.96 (t, J = 7.0 Hz, 2H), 2.14 (td, J = 7.0, 2.5 Hz, 2H), 1.84 (br

s, 1H), 1.73−1.63 (m, 2H), 1.45−1.38 (m, 2H), 1.16 (d, J = 6.0 Hz,

3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 173.2 (s), 137.2 (s),

127.9 (s), 126.9 (d), 121.9 (d), 119.0 (d), 118.9 (d), 111.6 (s), 109.4

(d), 67.4 (d), 40.0 (t), 38.7 (t), 36.4 (t), 32.7 (q), 25.3 (t), 23.6 (q),

21.7 (t). IR (neat) ν (cm⁻¹): 3294 (br), 2928, 1641, 1550. HRMS

(positive ESI): calcd for C₁₇H₂₄N₂O₂Na [MNa⁺], 311.1730; found,

311.1735. Following the procedure used to prepare 27, 5-hydroxy-N-

(2-(1-methyl-1H-indol-3-yl)ethyl)hexanamide (332 mg, 1.15 mmol)

was ﬁrst treated with LiAlH₄(87 mg, 2.30 mmol) in THF (8.3 mL),

then with water (0.09 mL), NaOH (15%, 0.09 mL), and water (0.27

mL) to aﬀord a crude amino-alcohol that was used directly in the next

step. Following the procedure used to prepare 19, crude amino-

alcohol was treated with N-formylbenzotriazole (244 mg, 1.66 mmol)

in THF (2.6 mL) to aﬀord crude N,O-bisformylated product that was

used directly in the next step. The residue then treated with K₂CO₃

(229 mg, 1.66 mmol) in MeOH (2.6 mL) and the usual work-up

(EtOAc) and puriﬁcation (60−100% EtOAc in hexanes then 3%

MeOH in EtOAc) aﬀorded N-(5-hydroxyhexyl)-N-(2-(1-methyl-1H-

indol-3-yl)ethyl)formamide (171 mg, 72% over 3 steps) as a yellow

oil. ¹H NMR (300 MHz, CDCl₃) 1:0.9 mixture of rotamers: δ (ppm)

8.09 (s) and 7.82 (s) (1H, rotamers), 7.64 (d, J = 8.0 Hz) and 7.53

(d, J = 8.0 Hz) (1H, rotamers), 7.32 (d, J = 3.5 Hz) and 7.29 (d, J =

3.5 Hz) (1H, rotamers), 7.23 (dd, J = 3.5, 1.0 Hz) and 7.21 (dd, J =

3.5, 1.0 Hz) (1H, rotamers), 7.15−7.09 (m, 1H), 6.91 (s) and 6.83

(s) (1H, rotamers), 3.83−3.78 (m, 1H), 3.75 (s, 3H), 3.63−3.68 (m,

cis-1-(1,2,3,5,6,10b-Hexahydrodipyrrolo[1,2-a:2′,1′-c]-

pyrazin-1-yl)ethan-1-one (49a). Following the procedure used to

prepare 18a, 39a (67 mg, 0.30 mmol) was treated with triﬂic

anhydride (56 μL, 0.33 mmol) and DTBMP (68 mg, 0.33 mmol) in

1

DCM (6.0 mL). H NMR analysis of a small sample of the reaction

mixture revealed the presence of an iminium ion resulting from the

Vilsmeier−Haack cyclization. ¹H NMR (300 MHz, CDCl₃): δ (ppm)

8.70 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 6.48 (dd, J = 4.5, 2.5 Hz,

1H), 4.49−4.45 (m, 2H), 4.10 (t, J = 6.5 Hz, 2H), 3.91 (t, J = 7.0 Hz,

2H), 2.68−2.63 (m, 2H), 2.12 (s, 3H), 2.11−2.01 (m, 2H).

Subsequent treatment with pyrrolidine (75 μL, 0.90 mmol) added

at 0 °C then stirred at rt for 18 h followed by the usual work-up

(DCM) and puriﬁcation (5−80% EtOAc in hexanes with 1.5% Et₃N)

1

aﬀorded 49a (53 mg, 87%) as a yellow solid. H NMR (300 MHz,

CDCl₃): δ (ppm) 6.57−6.55 (m, 1H), 6.14−6.12 (m, 1H), 5.81−5.80

(m, 1H), 4.09−4.01 (m, 2H), 3.92 (dt, J = 12.0, 4.0 Hz, 1H), 3.22−

O

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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3.13 (m, 2H), 3.08−2.93 (m, 2H), 2.87−2.79 (m, 1H), 2.29 (s, 3H),

2.08−1.92 (m, 2H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm)

209.2 (s), 129.8 (s), 119.1 (d), 108.1 (d), 103.3 (d), 61.2 (d), 56.8

(d), 51.9 (t), 47.5 (t), 43.0 (t), 30.0 (q), 28.1 (t). IR (neat) ν (cm⁻¹):

2921, 1706, 720. HRMS (positive ESI): calcd for C₁₂H₁₇N₂O [M +

H⁺], 205.1335; found, 205.1340.

CDCl₃): δ (ppm) 209.7 (s), 138.2 (s), 134.9 (s), 126.6 (s), 121.6 (d),

119.5 (d), 118.3 (d), 110.8 (s), 109.1 (d), 62.2 (d), 57.3 (t), 53.4 (t),

51.1 (d), 31.7 (q), 30.2 (q), 27.5 (t), 22.3 (t), 22.0 (t). IR (neat) ν

(cm⁻¹): 2942, 2918, 1699, 1468, 736. R_f= 0.82, 70% EtOAc/hexanes

with Et₃N. HRMS (positive ESI): calcd for C₁₈H₂₃N₂O [M + H⁺],

283.1805; found, 283.1808.

cis-1-(3-Methyl-2,3,3a,4,5,6-hexahydro-1H-indolo[3,2,1-de]-

[1,5]naphthyridin-4-yl)ethan-1-one (50c). Following the proce-

dure used to prepare 18a, 44c (66 mg, 0.23 mmol) was treated with

triﬂic anhydride (42 μL, 0.25 mmol) and DTBMP (51 mg, 0.25

mmol) in DCM (4.6 mL). Subsequent treatment with DIPEA (80 μL,

0.46 mmol) and ^L-prolinamide (6.0 mg, 0.05 mmol) added at 0 °C

then stirred at rt for 18 h followed by the usual work-up (DCM) and

puriﬁcation (5−70% EtOAc in hexanes with 1.5% Et₃N) aﬀorded 50c

(30 mg, 48%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ (ppm)

7.50 (d, J = 7.5 Hz, 1H), 7.28 (m, 1H), 7.20−7.09 (m, 2H), 4.32−

4.23 (m, 1H), 4.21 (d, J = 11.0 Hz, 1H), 3.76−3.66 (m, 1H), 3.24−

2.67 (m, 6H), 2.39 (s, 3H), 2.29 (s, 3H), 2.26−2.17 (m, 1H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 209.8, 137.1, 132.7,

cis-1-(5,6,9,10,11,11a-Hexahydro-8H-pyrido[1,2-a]pyrrolo-

[2,1-c]pyrazin-11-yl)ethan-1-one (49b). Following the procedure

used to prepare 18a, 39b (14 mg, 0.06 mmol) was treated with triﬂic

anhydride (12 μL, 0.07 mmol) and DTBMP (14 mg, 0.07 mmol) in

1

CDCl₃(1.2 mL). H NMR analysis of a small sample of the reaction

mixture revealed the presence of an iminium ion resulting from the

Vilsmeier−Haack cyclization. ¹H NMR (300 MHz, CDCl₃): δ (ppm)

8.72 (s, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 6.48 (dd, J = 4.0, 2.5 Hz,

1H), 4.47 (t, J = 6.5 Hz, 2H), 4.09 (t, J = 6.5 Hz, 2H), 3.92 (t, J = 7.0

Hz, 2H), 2.55 (t, J = 6.5 Hz, 2H), 2.12 (s, 3H), 1.87−1.77 (m, 2H),

1.67−1.61 (m, 2H). Subsequent treatment with pyrrolidine (30 μL,

0.36 mmol) added at 0 °C then stirred at rt for 3 h followed by the

usual work-up (DCM) and puriﬁcation (2−50% EtOAc in hexanes

1

128.0, 121.2, 119.8, 118.5, 109.4, 106.3, 59.8, 53.7, 50.1, 41.8, 38.6,

29.6, 27.2, 18.8. IR (neat) ν (cm⁻¹): 2956, 1732, 1402. HRMS

(positive ESI): calcd for C₁₇H₂₁N₂O [M + H⁺], 269.1648; found,

269.1660.

with 1.5% Et₃N) aﬀorded 49b (53 mg, 87%) as a yellow solid. H

NMR (300 MHz, CDCl₃): δ (ppm) 6.52−6.47 (m, 1H), 6.07−6.05

(m, 1H), 5.57 (d, J = 3.5 Hz, 1H), 4.09 (td, J = 12.0, 5.0 Hz, 1H),

3.90 (dd, J = 11.0, 3.5 Hz, 1H), 3.62 (d, J = 10.0 Hz, 1H), 3.02−2.75

(m, 4H), 2.42−2.37 (m, 1H), 2.32 (s, 3H), 2.00−1.95 (m, 1H),

1.77−1.63 (m, 2H), 1.50−1.36 (m, 1H). ¹³C{¹H} NMR (75 MHz,

CDCl₃): δ (ppm) 211.6 (s), 129.4 (s), 119.0 (d), 108.2 (d), 103.8

(d), 60.9 (d), 55.0 (t), 54.6 (d), 52.7 (t), 44.8 (t), 30.3 (q), 28.8 (t),

24.7 (t). IR (neat) ν (cm⁻¹): 2923, 2790, 1705. HRMS (positive

ESI): calcd for C₁₃H₁₉N₂O [M + H⁺], 219.1492; found, 219.1503. mp

104−107 °C.

cis-1-(11-Methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino-

[8,7-b]indol-1-yl)ethan-1-one (50a). Following the procedure

used to prepare 18a, 44a (52 mg, 0.18 mmol) was treated with

triﬂic anhydride (34 μL, 0.20 mmol) and DTBMP (41 mg, 0.20

mmol) in DCM (3.6 mL). Subsequent treatment with pyrrolidine (45

μL, 0.54 mmol) added at 0 °C then stirred at rt for 18 h followed by

the usual work-up (DCM) and puriﬁcation (5−70% EtOAc in

hexanes with 1.5% Et₃N) aﬀorded 50a (9.0 mg, 19%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.49 (d, J = 8.0 Hz, 1H),

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.9b03449.

■

sı

Copies ¹H and ¹³C NMR spectra for all new compounds

(PDF)

Crystallographic data (CIF)

7.24−7.07 (m, 3H), 4.94 (d, J = 5.0 Hz, 1H), 3.50 (s, 3H), 3.29−2.89

(m, 6H), 2.71−2.62 (m, 1H), 2.31 (s, 3H), 2.08−1.98 (m, 2H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ (ppm) 208.6 (s), 137.5 (s),

135.9 (s), 126.8 (s), 121.5 (d), 119.3 (d), 118.3 (d), 108.9 (d), 107.5

(s), 57.3 (d), 56.6 (d), 50.2 (t), 46.0 (t), 30.5 (q), 29.9 (t), 28.9 (q),

17.5 (t). IR (neat) ν (cm⁻¹): 2921, 1707, 748. HRMS (positive ESI):

calcd for C₁₇H₂₁N₂O [M + H⁺], 269.1648; found, 269.1652.

AUTHOR INFORMATION

Corresponding Author

■

́

Guillaume Belanger − Departement de Chimie, Universite de

́

Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada;

orcid.org/0000-0002-7454-8760;

Email: Guillaume.Belanger@USherbrooke.ca

1-(12-Methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-

quinolizin-1-yl)ethan-1-one (50b). Following the procedure used

to prepare 18a, 44b (99 mg, 0.33 mmol) was treated with triﬂic

anhydride (61 μL, 0.36 mmol) and DTBMP (74 mg, 0.36 mmol) in

CHCl₃(6.6 mL). Subsequent treatment with pyrrolidine (0.17 mL,

1.98 mmol) added at 0 °C then stirred at 0 °C for 2 h then at rt for 18

h followed by concentration under reduce pressure and the usual

puriﬁcation (2−80% EtOAc in hexanes with 1.5% Et₃N) aﬀorded cis-

50b (22 mg) and trans-50b (20 mg) (49%) as yellow oils. cis-50b: ¹H

NMR (300 MHz, CDCl₃): δ (ppm) 7.50 (d, J = 8.0 Hz, 1H), 7.23−

7.17 (m, 2H), 7.13−7.07 (m, 1H), 4.12 (d, J = 10.0 Hz, 1H), 3.63−

3.52 (m, 1H), 3.39 (s, 3H), 3.31−3.21 (m, 3H), 3.00−2.89 (m, 3H),

2.04−1.86 (m, 3H), 1.83 (s, 3H), 1.46−1.39 (m, 1H). ¹³C{¹H} NMR

(75 MHz, CDCl₃): δ (ppm) 212.6 (s), 138.5 (s), 136.3 (s), 127.5 (s),

121.8 (d), 119.4 (d), 118.4 (d), 109.7 (d), 108.2 (s), 56.5 (d), 54.5

(t), 49.6 (d), 43.9 (t), 32.4 (q), 30.9 (q), 27.8 (t), 21.6 (t), 18.3 (t).

IR (neat) ν (cm⁻¹): 2933, 2857, 1701, 1467, 737. HRMS (positive

ESI): calcd for C₁₈H₂₃N₂O [M + H⁺], 283.1805; found, 283.1802. R_f

Authors

Johanne Outin − Departement de Chimie, Universite de

́

Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada

́

Pauline Quellier − Departement de Chimie, Universite de

́

Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.9b03449

Author Contributions

The manuscript was written through contributions of all

authors. All authors have given approval to the ﬁnal version of

the manuscript.

Notes

The authors declare no competing ﬁnancial interest.

1

= 0.49, 70% EtOAc/hexanes with Et₃N. trans-50b: H NMR (300

ACKNOWLEDGMENTS

■

MHz, CDCl₃): δ (ppm) 7.50 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz,

1H), 7.21 (t, J = 7.0 Hz, 1H), 7.14−7.10 (m, 1H), 3.79 (d, J = 2.0 Hz,

1H), 3.75 (s, 3H), 3.18−3.16 (m, 1H), 3.12−2.89 (m, 3H), 2.76−

2.69 (m, 1H), 2.63−2.51 (m, 2H), 2.41−2.37 (m, 1H), 2.18−2.00

(m, 1H), 1.70 (s, 3H), 1.67−1.55 (m, 2H). ¹³C{¹H} NMR (75 MHz,

The authors want to thank Dr Daniel Fortin (U. Sherbrooke)

for X-ray diﬀraction analyses. This research was supported by

the Natural Science and Engineering Research Council

́

(NSERC) of Canada and the Universite de Sherbrooke.

P

https://dx.doi.org/10.1021/acs.joc.9b03449

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

catalyzed by chiral bifunctional thiourea-phosphonium salts. Tetrahe-

dron 2019, 75, 1697−1705. (f) Mukhopadhyay, S.; Pan, S. C. An

Organocatalytic Asymmetric Mannich Reaction for the Synthesis of

3,3-Disubstituted-3,4-dihydro-2-quinolones. Org. Biomol. Chem. 2018,

16, 5407−5411.

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