Synthesis and dopaminergic activity of a series of new 1-aryl tetrahydroisoquinolines and 2-substituted 1-aryl-3-tetrahydrobenzazepines

Article abstract of DOI:10.1016/j.bioorg.2018.06.038

A series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The influence of each substituent on the affinity and selectivity for D₁ and D₂

Full text of DOI:10.1016/j.bioorg.2018.06.038

Accepted Manuscript
Synthesis and dopaminergic activity of a series of new 1-aryl tetrahydroisoqui-
nolines and 2-substituted 1-aryl-3-tetrahydrobenzazepines
Cristina Lucena-Serrano, Ana Lucena-Serrano, Alicia Rivera, Juan Manuel
López-Romero, María Valpuesta, Amelia Díaz
PII:
S0045-2068(18)30548-0
DOI:
https://doi.org/10.1016/j.bioorg.2018.06.038
YBIOO 2418
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 June 2018
28 June 2018
29 June 2018
Please cite this article as: C. Lucena-Serrano, A. Lucena-Serrano, A. Rivera, J. Manuel López-Romero, M.
Valpuesta, A. Díaz, Synthesis and dopaminergic activity of a series of new 1-aryl tetrahydroisoquinolines and 2-
substituted 1-aryl-3-tetrahydrobenzazepines, Bioorganic Chemistry (2018), doi: https://doi.org/10.1016/j.bioorg.
2018.06.038
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Synthesis and dopaminergic activity of a series of new 1-aryl
tetrahydroisoquinolines and 2-substituted 1-aryl-3-
tetrahydrobenzazepines
Cristina Lucena-Serrano a, Ana Lucena-Serrano a, Alicia Rivera b,
Juan Manuel López-Romero a, María Valpuesta a, Amelia Díaz a,*
a
b
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Málaga,
Campus de Teatinos s/n. 29071 Málaga, Spain.
Tel: +34-952-13-19-34
E-mail: amelia@uma.es
Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de
Málaga,
Campus de Teatinos s/n. 29071 Málaga, Spain.
Abstract. A series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several
substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The
influence of each substituent on the affinity and selectivity for D1 and D2 dopaminergic
receptors was studied. Moreover, N-alkyl salts of these tetrahydroisoquinolines were
used as starting material to synthesize a series of new 1-aryl-7,8-dihydroxy 3-
tetrahydrobenzazepines derivatives with electron-withdrawing substituents at C-2
position by the diastereoselective Stevens rearrangement. The structure-activity
relationship of these compounds was explored to evaluate the effect of the functional
group at C-2 in benzazepines and the modification in the aryl group at the isoquinoline
C-1 position towards the affinity and selectivity for the mentioned receptors. The 1-aryl-
6,7-dihydroxy tetrahydroisoquinoline 4c shows significant affinity towards D2 receptor,
with Ki value of 31 nM. This significant affinity can be attributed to the presence of a
thiomethyl group, and it is the most active 1-aryl-6,7-dihydroxy tetrahydroisoquinoline
derivative reported to date.
Keywords:
tetrahydroisoquinolines
/
3-tetrahydrobenzazepines
/
Stevens
rearrangement / dopamine receptors / binding
1

1. Introduction
Dopamine is a significant neurotransmitter present in the central nervous system of
mammals that regulates several biological functions, such as coordination, motivation,
emotion, learning and memory. Based on their pharmacology, dopaminergic receptors
can be considered as two G-protein-coupled receptor families: the D1-like receptors,
including D1 and D5 receptor subtypes, which activate adenylyl cyclase enzyme; and
the D2-like receptors, containing D2, D3 and D4 receptor subtypes, which inhibit the
mentioned enzyme.1 During the last few decades, dopaminergic ligands have remained
a very active area of research for the development of pharmaceutical products.2
The 1-substituted 3-tetrahydrobenzazepines are known to act as dopamine receptor
agonists and antagonists.2,3 These compounds show activity in animal models against
several neurological illnesses, such as Parkinson`s4 and Alzheimer`s5 diseases. In fact,
the discovery of SCH 23390,6 one of the first selective dopamine D1-like receptor
antagonist, and the ethylene bridged restricted tetrahydrobenzazepine (THB)
derivative, SCH 39166,7 represented a great advance in the dopaminergic receptor
studies (Figure 1).
Cl
R1
N CH3
N R2
HO
HO
SCH 39166
SCH 23390 R1=Cl, R2=CH3
SCH 24518 R1=Cl, R2=H
SKF 75670 R1=OH, R2=CH3
SKF 38393 R1=OH, R2=H
Figure 1: Structures of active 3-tetrahydrobenzazepines
2

SCH 39166, also known as ecopipam, improve the overall pharmacological profile of
SCH 23390, maintaining similar affinity and selectivity as D1/D5 antagonist, however
both of them have low oral bioavailability.8 These two compounds are reference for the
design of novel dopaminergic ligands as possible new drugs, and a variety of
analogues, such as SCH 24518,9 SKF 7567010 and SKF 38393,11 have been
developed, the latter being considered as the model for new D1 receptor agonist.
Regarding the structure-activity relationship (SAR), isosteres of catecholic 1-aryl-3-
tetrahydrobenzazepines, a convenient substitution at the nitrogen atom and/or in C-6
position, the substitution pattern on the 1-phenyl group, and the presence of an
azepine ring, are structural modifications that modulate selectivity and improve affinity
of this family of compounds towards dopaminergic receptors (see Figure 2).2,3,12
Figure 2: Reported 1-aryl-3-tetrahydrobenzazepine structure requirements for high activity
For example, the absence of a methyl group at nitrogen atom in the SCH 24518 (nor-
SCH 23390)9 or the presence of a bromophenyl moiety at C-113 increase the D2
receptor affinity, compared with the prototype SCH 23390 (Figure 1). However, the
change of chloride for bromine in C-7 position improved the affinity for D1 receptors.14
In the case of the 7,8-dihydroxy-1-phenyl-3-tetrahydrobenzazepine SKF 38393 (Figure
1), the absence of the methyl group at nitrogen causes a decrease of the activity
against both receptors.15
3

Moreover, other compounds containing the phenylethylamine skeleton as part of their
structure are potent and selective ligands for dopaminergic receptors (Figure 3).16 1-
Substituted
tetrahydroisoquinolines
(THI),
ring-contracted
derivatives
of
tetrahydrobenzazepines, have been evaluated for their ability to inhibit the dopamine
transporter and to display affinity at dopaminergic receptors binding sites in rat brain
tissue.17 The presence of phenolic hydroxyl groups in the ring A is necessary for a
better binding of this type of compounds to dopaminergic receptors.18 However, most of
the reported structural modifications for THI are located at nitrogen (N-alkyl or nor
derivatives) or at C-1 position (1-phenyl, 1-alkyl or 1-benzyl compounds),17,19 and the
majority of the synthesized THI presents a 6-chloro-7-hydroxy tetrahydroisoquinoline
core, being selective for D1 receptors.19a On the other hand, 1-butyl and 1-benzyl
derivatives present high affinity for D2-like receptors due to the flexibility of these
substituents.19c Consequently, the substitution pattern at the C-1 position, is an
essential factor.
Figure 3: Reported structure-activity tetrahydroisoquinoline requirements to modulate
dopaminergic activity.
In addition, regarding the activity of this family of compounds, 7,8-dihydroxy-1-aryl
tetrahydroisoquinoline analogues have also been reported as anti-HIV compounds.20
In this paper, we describe the synthesis of new 1-aryl tetrahydroisoquinolines and 1-
aryl-3-tetrahydrobenzazepines with catecholic hydroxyl groups at ring A, and different
substituents, such as hydroxyl, nitro, amino, dimethylamino and methylthio groups, at
the C-1 aryl group, together with additional electron-withdrawing substituents at the C-2
4

of the 3-tetrahydrobenzazepines. The binding affinity and selectivity of these
compounds at the dopamine receptors are studied to analyze the influence of the
substitution pattern.
2. Results and Discussion
2.1. Synthesis
We have previously described the synthesis of 3-tetrahydrobenzazepines by Stevens
rearrangement by using 1-aryl tetrahydroisoquinolinium salts as starting materials.21
This strategy provides a number of advantages: good yields and mild reaction
conditions; a regio- and diastereoselective control of the reaction; broad applicability
and versatility to incorporate different groups in the molecule.
Based on these results, new 1,2-disubstituted tetrahydrobenzazepines are synthesized
starting from the corresponding benzamide, being intermediate compounds the
corresponding 1-aryl tetrahydroisoquinoline derivatives (see Schemes 1 and 2).
Starting
benzamides
were
prepared
by
condensation
of
2-(3,4-
dimethoxyphenyl)ethylamine and the appropriately substituted arylcarbonyl halide.22
Then, the ring expansion reaction via Stevens rearrangement of
a
tetrahydroisoquinolinium salt allow the azepine ring construction. The posterior
demethylation provides the catecholic structure at ring A, thus complying the
requirements previously established for the dopaminergic activity.18 To avoid side
reactions due to the presence of the catechol group on the phenylethylamine moiety,
we decided to work with dimethoxy derivatives and to carry out the O-demethylation for
both structures (R1= CH3 → R1= H, Scheme 1) in the last step of the synthesis.
The synthesis of tetrahydroisoquinolines has been performed as an outline in Scheme
1.21 The classical Bischler-Napieralski cyclodehydration reaction was used to obtain the
dihydroisoquinolines 1a-e, which by N-methylation and reduction afforded the
tetrahydroisoquinolines 3a-e. Finally, the O-demethylation of the synthesized
5

tetrahydroisoquinolines was performed by treatment with 47% HBr aqueous solution
followed by basification to pH=8 with sodium bicarbonate, to obtain the resulting
phenolic compounds 4a-e. The compound 4f was obtained by catalytic hydrogenation
of 4b in good yield.
H3CO
H3CO
H3CO
H3CO
N
HN
O
i
70-90%
Benzamides
R
R
1a R=H
1b R=NO2
1c R=SMe
1d R=NMe2
1e R=OMe
H3CO
H3CO
I-
HO
H3CO
H3CO
N
N
ii
78-99%
iii
N
HO
60-92%
R
R
R
4a R=H
2a R=H
3a R=H
4b R=NO2
4c R=SMe
4d R=NMe2
4e R=OH
4f R=NH2
2b R=NO2
2c R=SMe
2d R=NMe2
2e R=OMe
3b R=NO2
3c R=SMe
3d R=NMe2
3e R=OMe
iv
89%
Scheme 1: Synthesis of 4a-f: (i) CH3I/acetone, reflux; for compound 2b was carried out in
CH3CN; (ii) NaBH4/MeOH, room temperature; (iii) HBr 47%, heat 2 hours to 100ºC; (iv) H2/
Pd/C/MeOH
The synthesis of 1-aryl-3-tetrahydrobenzazepine analogues is described in Scheme 2
as the result of the Stevens rearrangement of the 1-aryl tetrahydroisoquinolinium salts
5a-g. The regioselectivity of the ylide formation may be problematic if there is more
than one acidic site in the precursor salt. Two prevent this point we observed that
electron-withdrawing groups as Z substituent in tetrahydroisoquinolinium salt
6

exclusively yields 3-tetrahydrobenzazepines, avoiding secondary reactions.21a As a
consequence, here we used methoxycarbonyl, carbamoyl, p-nitrophenyl or p-
aminophenyl electron-withdrawing groups as N-alkylating agents to prepare the
tetrahydroisoquinolinium salts 5a-g.
3a-3e
i
Br-
H3CO
H3CO
HO
HO
H3CO
H3CO
Z
N
N
iv
N
ii
40-95%
43-90%
Z
Z
R
R
R
R=H, Z=CO2Me
5a
5b
5c
5d
5e
5f
6a
7a
R=NO2, Z=CO2Me
R=SMe, Z=CO2Me
R=NMe2, Z=CO2Me
R=OMe, Z=CO2Me
R=H, Z=CONH2
6b
6c
6d
6e
6f
7b
7c
7d
7e R=OH
7f
iii
87%
R=H, Z=p-NO2C6H4
5g
6g
7g
7h R=NH2, Z=CO2Me
7i R=H, Z=p-NH2C6H4
77%
iii
Scheme 2: Synthesis of 5a-g, 6a-g and 7a-i: (i) BrCH2Z/acetone, room temperature; for 5b,
reflux 168 hours in acetonitrile; for 5f, ClCH2CONH2/NaI/acetone; (ii) DBU/CH3CN, room
temperature; (iii) H2/ Pd/C/MeOH; (iv) BBr3/CH2Cl2, room temperature. The entire compounds 5,
6 and 7 named in this scheme present trans configuration
N-alkylation of compounds 3a-c and 3f,g only yielded trans diastereoisomer salts,
while 5d and 5e were obtained as a mixture of diastereoisomers in a cis:trans ratio of
1:20 and 1:5, respectively. The relative configuration between H-1 and N-methyl group
was established by comparison with the previously described NMR data for similar
tetrahydroisoquinolinium salts.21 It should be noted that in the case of 5b a much longer
period of time and reflux in acetonitrile was necessary to complete the N-alkylation
reaction. The salts 5a, 5f and 5g precipitated from the reaction medium and were
obtained in excellent yields. However, all the attempts to isolate the remaining salts
invariably failed, so we used the reaction crude directly in the next step.
7

The application of optimized conditions for the Stevens rearrangement to the salts 5a-
g, i.e. 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile at room temperature,
afforded the 6a-g with high regio- and diastereoselectivity. As expected, 3-
tetrahydrobenzazepines 6d and 6e were obtained in a ratio similar to the cis/tran ratio
of the starting salts 5d and 5f, which is in concordance with the stereochemical control
of the Stevens rearrangement. The mixture of diasteroisomers 6d and 6e was
separated by silica-gel chromatography to obtain the pure trans diastereoisomers (6d-
trans and 6e-trans). The relative configuration between H-1 and H-2 in 6a-h was
1
determined by H NMR coupling constants values (J1,2trans 6-8 Hz, J1,2cis 1 Hz), in
concordance to data previously reported for other 1,2-disubstituted 3-
tetrahydrobenzazepines.21
Finally, the demethylation step was carried out using the isomers 6-trans in all the
cases. Removal of the O-methyl group by refluxing in 47% HBr aqueous solution,
under the same reaction conditions used for THI structures, failed and only complexes
reaction crudes were obtained. However, the final O-demethylation step was achieved
by treating 6-trans compounds with BBr3 in CH2Cl2, to obtain 3-tetrahydrobenzazepines
7a-f-trans in good yields. Compounds 7h-trans and 7i-trans were obtained by catalytic
hydrogenation of 7b-trans and 7g-trans, respectively (Scheme 2).
2.2. Binding affinities for dopamine receptors
It
is
known
that
the
1-aryltetrahydroisoquinolines17b,17e,19c
and
3-
tetrahydrobenzazepines2,3,11,12 with protected phenolic groups show a lower affinity for
D1 and D2 dopaminergic receptors than their corresponding catechol derivatives:
catechol fragment is an essential feature for effective binding. For this reason, the
catechol tetrahydroisoquinolines 4a-f and 3-tetrahydrobenzazepines 7a-i-trans, were
exclusively tested for their ability to displace the selective radioligands of D1 and D2
dopaminergic receptors (Figure 4). In vitro activity was analyzed on rat striatal
8

membranes by using [3H]-SCH 23390 and [3H]-Raclopride as radioligands for D1 and
D2 receptors. The affinities of these compounds towards D1 and D2 dopaminergic
receptors were determined in competition receptor binding studies.
Previously to study the competition receptor binding experiments, a screening was
carried out (at 10-6 M concentration) in order to determine the ability to displace the
selective radioligand of D1 and D2 dopaminergic receptor of each compound 4a-f and
7a-i-trans.
Figure 4: Screening assay to identify tetrahydroisoquinoline and 3-tetrahydrobenzazepine
derivative compounds with potential affinity for D1-like and D2-like receptors using [3H] SCH
23390 (1 nM) and [3H] raclopride (1 nM), respectively. Data shown are mean values of three
independent experiments each performed in duplicates ± SEM, and they are expressed as
percentages of total binding (grey bars). Non-specific binding (black bars) was determined in
the presence SCH 23390 (50 nM) or butaclamol (50 nM). Differences were set by one-way
ANOVA followed by post hoc Bonferroni t test. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. total
binding.
As can be seen in Figure 4, the tetrahydroisoquinolines 4b-e, which are analogues of
4a with different substituents at para position of the 1-aryl group, show similar activity
9

for D1 receptor, and some of them 4c, 4d and 4e seems to improve their activity
against D2 receptor.
Taking into account this screening, we carried out competition experiments for those
compounds that displaced more than 50% to radioligand in the range of 0.1 mM to 0.1
nM (compounds 4a, 4c-e, Figure 5), to determine their affinity and selectivity towards
D1 and D2 dopaminergic receptor. Binding affinities for D1 and D2 dopaminergic
receptors are summarized in Table 1, illustrating some general trends of the structure-
activity relationship.
Figure 5: Tetrahydroisoquinoline binding assays. Competition inhibition curves of the
tetrahydroisoquinolines 4a (A), 4c (B), 4d (C) and 4e (D) vs. the D1-like receptor antagonist [3H]
SCH 23390 (●) and the D2-like receptor antagonist [3H] raclopride (○) in rat striatal membrane
preparation.
Table 1. Values of affinity constant (Ki, pKi) and selectivity (ratio Ki D1/ Ki D2) determined by
binding experiments to D1 and D2 dopaminergic receptora
Compound
D1
D2
Ki ratio
10

Ki, (nM)
pKi,
Ki (nM)
pKi
D1/D2
-
4a19b
370 ± 82
476 ± 136
181 ± 52
-
290 ± 36b
-
4a
6.48 ± 0.15 148 ± 32
6.78 ± 0.14 31 ± 2.9
6.83 ± 0.09
7.50 ± 0.02
6.79 ± 0.13
3.2
5.8
11.7
4c
4d
1953 ± 618 5.73 ± 0.14 173 ± 53
4e
416 ± 62
1.9
6.38 ± 0.07 178 ± 24
1130c
6.74 ± 0.096 2.3
SKF 7567015a
7f-trans
-
-
-
1438 ± 304 5.84 ± 0.09 394 ± 93
168 ± 45
6.41 ± 0.10
3.6
0.5
7g-trans
6.80 ± 0.13 34 8± 210 6.55 ± 0.30
a
Specific radioligands are [3H] SCH 23390 and [3H] raclopide for D1 and D2 dopamine
receptors respectively. b Specific radioligand is [3H] spiperone for D2. c Specific radioligand is
[3H] spiroperidol for D2.
In general, all the tested tetrahydroisoquinolines showed a major affinity for D2
receptor. In our assay, the racemic 4a showed Ki values of 476 ± 136 nM for D1 and
148 ± 32 nM for D2, which are consistent with the results reported in the literature,
where the affinity for D2 is better than for D1 receptor (Ki 370 ± 82 nM for D1 and 290 ±
36 nM for D2 respectively.19b
Compared to compound 4a, the presence of dimethylamino or hydroxyl substituents in
the 1-aryl group did not affect the D2 binding, and the corresponding compounds 4d
and 4e showed a Ki value of 173 and 178 nM respectively, statistically the same as that
of compound 4a (148 nM). Although the affinity for D2 receptor did not substantially
change, the increase of selectivity towards D2 receptor is observed in the case of 4d
(Table 1, 4d versus 4a, 4c and 4e), being the most selective of the prepared
compounds.
Regarding compound 4c, the affinity was substantially increased towards D2 receptor,
with Ki values of 31 ± 2.9 nM. This interesting affinity can be attributed to the presence
of a methylthio group, being the most active 6,7-dihydroxi-1-aryl tetrahydroisoquinoline
reported to date, with 4.8-fold improvement if compared with 4a.
11

We carried out the same procedure for the 1,2-disubstituted 3-tetrahydrobenzazepines
(7a-i) to study the dopaminergic activity. As reported in the initial screening (Figure 4),
the 3-tetrahydrobenzazepines with an additional substituent at C-2 were not
significantly active for D1 receptor, but some of them appeared to displace the
radioligand more than 50% for D2 dopaminergic receptor. The introduction of a
substituent such as a CO2Me (compound 7a-7e, 7h) implied a lack of activity for D1 and
D2 dopaminergic receptors, whereas the substituents CONH2 (7f) and p-C6H4-NO2 (7g)
appeared to improve the activity at D2 dopaminergic receptor, so we carried out the
competition binding experiments for these compounds (Figure 6, Table 1).
As shown in Table 1, both 7f and 7g benzazepine compounds showed an affinity
improvement for D2 (394 and 348 nM, respectively) comparing with SKF 75670 (D1 Ki
1.9 nM, D2 Ki 1130 nM).15a Surprisingly, regarding the selectivity for both receptors, 7f
shows better activity for D2 than for D1, a different behavior to that previously described
for the 3-tetrahydrobenzazepines.
Figure 6: 3-Tetrahydrobenzazepine binding assays. Competition inhibition curves of the 3-
tetrahydrobenzazepines 7f-trans (A) and 7g-trans (B) vs. the D1-like receptor antagonist [3H]
SCH 23390 (●) and the D2-like receptor antagonist [3H] raclopride (○) in rat striatal membrane
preparation.
3. Conclusions
12

In summary, a series of new tetrahydroisoquinolines with different substituents at 1-aryl
group were synthesized in good yields starting from benzamide derivatives. Salts of the
tetrahydroisoquinolines were used as starting material to synthesize a series of new 3-
tetrahydrobenzazepines, by using the diastereoselective Stevens rearrangement as the
key step of the synthesis. Affinity towards D1 and D2 was also analyzed showing the
compound 4c, with a phenyl methylthio ether substituent, a good affinity to D2 (Ki 31
nM). The other prepared catechol derivatives showed moderate affinities to this
receptor.
4. Experimental Section
4.1 General Remarks: Melting points were determined with a Gallenkamp
instrument and are uncorrected. EI-MS data were recorded with an HP-MS 5988A
spectrometer operating at 70 eV and HMRS data with a VG Autospec spectrometer.
NMR spectra were recorded with a Bruker ARX 400 instrument operating at 400 MHz
1
13
for H and 100.6 MHz for C NMR spectroscopy. Chemical shifts are given relative to
residual CHCl3 (δ = 7.24 ppm) and CDCl3 (δ = 77.0 ppm). All solvents were dried and
distilled prior to use. Reaction mixtures were magnetically stirred and monitored by
TLC with silica gel 60 F254 (Merck) plates. Products were purified by column
chromatography with 0.040-0.063 mm silica gel 60.
The compounds 1a,21a 1b,23,24 1d,24 1e,23b,24,25 2a,21a 3a,21a 3e,26 4a,19b 5a,21a 5f,21a 5g,21a
6a,21a 6f,21a 6g,21a have been prepared by following the reported procedures, and
corrected, new or detailed spectroscopic data is included in the supporting information.
4.2. General Procedure for synthesis of 3,4-dihydroisoquinolines (1a-e): A
solution of POCl3 (3.7 mL, 40 mmol) in CH3CN (10 mL) was added dropwise to a
solution of the corresponding amide (20 mmol) in CH3CN (55 mL) under argon. The
13

reaction mixture was heated to reflux for 1 h and concentrated to dryness. The crude
material was dissolved in CH2Cl2 (50 mL) and washed with a saturated solution of
NaHCO3 (3 x 40 mL), NaOH (5%, 2 x 40 mL) and water. The organic layers were dried
with anhydrous MgSO4 and concentrated under vacuum to obtain the corresponding
isoquinoline.
6,7-Dimethoxy-1-(4-methylthiophenyl)-3,4-dihydroisoquinoline (1c)
Isoquinoline 1c (2.3 g, 74%) was obtained from the corresponding amide (3.3 g, 10
1
mmol) as a yellow amorphous solid. M.p. 122-125 ºC. H NMR (400 MHz, CDCl3, 25
ºC): δ = 7.52 (d, 2H, J = 8.5 Hz, H-2´, H-6´), 7.26 (d, 2H, J = 8.5 Hz, H-3´, H-5´), 6.77,
6.75 (2 x s, 1H each, H-5, H-8), 3.91, 3.71 (2 x s, 3H each, 2 x OMe), 3.76 (t, 2H, J =
7.4 Hz, H-3), 2.70 (t, 2H, J = 7.4 Hz, H-4), 2.50 (s, 3H, S-Me) ppm. 13C NMR (100 MHz,
CDCl3, 25 ºC): δ = 166.1 (C-1), 151.0, 147.1 (C-6, C-7), 140.3 (C-4´), 135.5 (C-1´),
132.7 (C-4a), 129.2 (C-2´, C-6´), 125.7 (C-3´, C-5´), 121.3 (C-8a), 111.5, 110.3 (C-5, C-
8), 56.1, 55.9 (2 x OMe), 47.4 (C-3), 25.9 (C-4), 15.4 (S-Me) ppm. EI-MS: m/z (%) =
314 (20), 313 (M+, 82), 312 (100), 282 (18), 266 (26). HR-MS: calcd. for C18H20NO2S
[M + H]+ 314.1209; found 314.1210.
4.3.
General
Procedure
for
synthesis
of
N-methyl-3,4-
dihydroisoquinolinium Salts (2a-e): To a solution of the corresponding
dihydroisoquinoline (8 mmol) in dry acetone (45 mL) was added CH3I (3.5 mL, 56
mmol), and the reaction mixture was refluxed for 3 h. After this time, the yellow solid
formed was filtered to give the corresponding isoquinolinium salt.
6,7-Dimethoxy-N-methyl-1-(4-nitrophenyl)-3,4-dihydroisoquinolinium Iodide (2b)
To a solution of the dihydroisoquinoline 1b (4.4 g, 14 mmol) in CH3CN (75 mL) was
added dropwise CH3I (8.2 mL, 131 mmol) and the mixture was heated to reflux for 42 h
under argon. After this time, the yellow solid formed was filtered to obtain the
1
isoquinolinium salt 2b (5.3 g, 83%) as a yellow amorphous solid. M.p. 202-204 ºC. H
14

NMR (400 MHz, CDCl3+TFA, 25 ºC): δ = 8.51 (d, 2H, J = 8.5 Hz, H-3´, H-5´), 7.82 (d,
2H, J = 8.5 Hz, H-2´, H-6´), 6.95 (s, 1H, H-5), 6.28 (s, 1H, H-8), 4.33 (t, 2H, J = 8.3 Hz,
H-3), 4.03, 3.60 (2 x s, 3H each, 2 x OMe), 3.56 (s, 3H, N-Me), 3.41 (t, 2H, J = 8.3 Hz,
H-4) ppm. 13C NMR (100 MHz, CDCl3+TFA, 25 ºC): δ = 171.8 (C-1), 158.2, 149.9,
148.7 (C-4´, C-6, C-7), 135.4, 134.5 (C-8a, C-1´), 130.2 (C-2´, C6´), 124.7 (C3´, C-5´),
118.8, 111.3 (C-5, C-8), 114.9 (C-4a), 56.9, 56.3 (2 x OMe), 53.0 (C-3), 46.6 (N-Me),
25.7 (C-4) ppm. EI-MS: m/z (%) = 327 (M+, 2), 326 (4), 312 (5), 311 (6), 204 (10), 142
(100), 127 (22). HR-MS: calcd. for C18H19N2O4 [M - I]+ 327.1339; found 327.1339.
6,7-Dimethoxy-N-methyl-1-(4-methylthiophenyl)-3,4-dihydroisoquinolinium Iodide
(2c)
Isoquinolinium salt 2c (3.3 g, 90%) was obtained from the dihydroisoquinoline 1c (2.5
1
g, 8 mmol) as a yellow amorphous solid. M.p. 176-179 ºC. H NMR (400 MHz, CDCl3,
25 ºC): δ = 7.59 (d, 2H, J = 8.4 Hz, H-2´, H-6´), 7.42 (d, 2H, J = 8.4 Hz, H-3´, H-5´),
6.87 (s, 1H, H-5), 6.45 (s, 1H, H-8), 4.45 (t, 2H, J = 8.0 Hz, H-3), 4.00, 3.77 (2 x s, 3H
each, 2 x OMe), 3.62 (s, 3H, N-Me), 3.42 (t, 2H, J = 8.0 Hz, H-4), 2.55 (s, 3H, S-Me)
ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 172.9 (C-1), 156.8, 148.2, 145.4 (C-4´, C-
6, C-7), 134.2 (C8a), 129.8 (C-2´, C-6´), 125.5 (C-3´, C-5´), 125.2, 119.8 (C-4a, C-1´),
115.6, 111.1 (C-5, C-8), 56.9, 56.2 (2 x OMe), 53.1 (C-3), 47.1 (N-Me), 25.9 (C-4), 14.7
(S-Me) ppm. EI-MS: m/z (%) = 328 (M+, 4), 327 (8), 314 (18), 313 (48), 312 (68), 206
(12), 204 (38), 142 (100), 127 (21). HR-MS: calcd. for C19H22NO2S [M - I]+ 328.1366;
found 328.1368.
6,7-Dimethoxy-N-methyl-1-(4-N,N-dimethylamino)-3,4-dihydroisoquinolinium
Iodide (2d)
Isoquinolinium salt 2d (2.66 g, 70%) was obtained from the dihydroisoquinoline 1d (2.6
g, 8.4 mmol) as a yellow amorphous solid. M.p. 194-197 ºC. 1H NMR (400 MHz, CDCl3,
25 ºC): δ = 7.46 (d, 2H, J = 8.8 Hz, H-2´, H-6´), 6.89 (s, 1H, H-5), 6.77 (d, 2H, J = 8.8
Hz, H-3´, H-5´), 6.60 (s, 1H, H-8), 4.34 (t, 2H, J = 7.8 Hz, H-3), 4.00, 3.86 (2 x s, 3H
each, 2 x OMe), 3.66 (s, 3H, N-Me), 3.34 (t, 2H, J = 7.8 Hz, H-4), 3.10 (s, 6H, N-Me2)
15

ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 172.3 (C-1), 156.1 (C-4´), 152.9, 148.0
(C-6, C-7), 134.5 (C-8a), 132.8 (C-2´, C-6´), 120.4 (C-4a), 116.6 (C-1´), 115.1, 110.8
(C-5, C-8), 110.9 (C-3´, C-5´), 56.8, 56.3 (2 x OMe), 53.1 (C-3), 47.1 (N-Me), 40.1 (N-
Me2), 26.4 (C-4) ppm. EI-MS: m/z (%) = 325 (M+, 6), 324 (11), 311 (11), 310 (50), 309
(70), 251 (11), 206 (13), 204 (36), 142 (100), 127 (22). HR-MS: calcd. for C20H25N2O2
[M - I]+ 325.1911; found 325.1911.
6,7-Dimethoxy-1-(4-methoxyphenyl)-N-methyl-3,4-dihydroisoquinolinium iodide
(2e)
Isoquinolinium salt 2e (3.0 g, 85%) was obtained from the dihydroisoquinoline 1e (2.4
1
g, 8 mmol) as a yellow amorphous solid. M.p. 180-183 ºC. H NMR (400 MHz, CDCl3,
25 ºC): δ = 7.64 (d, 2H, J = 8.2 Hz, H-2´, H-6´), 7.09 (d, 2H, J = 8.2 Hz, H-3´, H-5´),
6.95 (s, 1H, H-5), 6.43 (s, 1H, H-8), 4.43 (t, 2H, J = 7.5 Hz, H-3), 3.99, 3.90, 3.77 (3 x s,
3H each, 3 x OMe), 3.60 (s, 3H, N-Me), 3.44 (t, 2H, J = 7.5 Hz, H-4) ppm. 13C NMR
(100 MHz, CDCl3, 25 ºC): δ = 173.2 (C-1), 162.6 (C-4´), 156.7, 148.2 (C-6, C-7), 134.2
(C-8a), 131.7 (C-2´, C-6´), 121.3, 120.1 (C-1´, C-4a), 115.1, 110.9 (C-5, C-8), 114.6 (C-
3´, C-5´), 56.9, 56.2, 55.7 (3 x OMe), 53.1 (C-3), 47.1 (N-Me), 26.0 (C-4) ppm. EI-MS:
m/z (%) = 312 (M+, 5), 311 (18), 298 (17), 297 (75), 296 (100), 268 (15), 251 (19), 238
(29), 206 (13), 204 (30), 142 (78), 127 (17). HR-MS: calcd. for C19H22NO3 [M - I]+
312.1594; found 312.1595.
4.4.
General
Procedure
for
synthesis
of
N-methyl-1,2,3,4-
tetrahydroisoquinolines (3a-e)
To a solution of the corresponding salt (2.6 mmol) in MeOH (80 mL) was added NaBH4
(113 mg, 3 mmol) dropwise over a period of 10 min and the mixture was stirred for 30
min. The solvent was evaporated under vacuum, and the residue obtained was
dissolved in CH2Cl2 (80 mL) and washed with water. The organic layer was dried with
16

anhydrous MgSO4 and the solvent evaporated under vacuum to obtain the
corresponding 1,2,3,4-tetrahydroisoquinoline.
(±)-6,7-Dimethoxy-N-methyl-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (3b)
Isoquinoline 3b (520 mg, 80%) was obtained from the salt 2b (900 mg, 2 mmol) as a
1
yellow amorphous solid. M.p. descomposes. H NMR (400 MHz, CDCl3, 25 ºC): δ =
8.16 (d, 2H, J = 8.9 Hz, H-3´, H-5´), 7.41 (d, 2H, J = 8.9 Hz, H-2´, H-6´), 6.61 (s, 1H, H-
5), 5.99 (s, 1H, H-8), 4.30 (s, 1H, H-1), 3.83, 3.56 (2 x s, 3H each, 2 x OMe), 3.16 (ddd,
1H, J = 15.9, 11.0, 5.4 Hz, H-4ax), 3.06 (ddd, 1H, J = 11.0, 5.4, 3.2 Hz, H-3eq), 2.73
(dt, 1H, J = 15.9, 3.4 Hz, H-4eq), 2.62 (td, 1H, J = 11.0, 3.4 Hz, H-3ax), 2.21 (s, 3H, N-
Me) ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 151.9 (C-4´), 147.9, 147.3 (C-6, C-7),
130.2 (C-2´, C-6´), 129.9, 128.6, 126.7 (C-1´, C-4a, C-8a), 123.5 (C-3´, C-5´), 111.0 (C-
5, C-8), 70.1 (C-1), 55.9, 55.8 (2 x OMe), 51.8 (C-3), 44.2 (N-Me), 28.8 (C-4) ppm. EI-
MS: m/z (%) = 328 (M+, 10), 327 (8), 207 (15), 206 (100.) HR-MS: calcd for C18H21N2O4
[M + H]+ 329.1496, found 329.1494.
(±)-6,7-Dimethoxy-N-methyl-1-(4-methylthiophenyl)-1,2,3,4-tetrahydroisoquinoline
(3c)
Isoquinoline 3c (1.8 g, 78%) was obtained from the salt 2c (3.2 g, 7 mmol) as a yellow
amorphous solid. M.p. 81-84 ºC. 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 7.17 (d, 2H, J =
8.8 Hz, H-2´, H-6´), 7.14 (d, 2H, J = 8.8 Hz, H-3´, H-5´), 6.57 (s, 1H, H-5), 6.08 (s, 1H,
H-8), 4.12 (s, 1H, H-1), 3.81, 3.55 (2 x s, 3H each, 2 x OMe), 3.12 (ddd, 1H, J = 15.7,
11.0, 5.4 Hz, H-4ax), 3.04 (ddd, 1H, J = 11.0, 5.4, 3.5 Hz, H-3eq), 2.70 (dt, 1H, J =
15.7, 3.5 Hz, H-4eq), 2.56 (td, 1H, J = 11.0, 3.5 Hz, H-3ax), 2.44 (s, 3H, S-Me), 2.20 (s,
3H, N-Me) ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 147.4, 147.0 (C-6, C-7), 140.7
(C-4´), 137.1, 130.1, 126.5 (C-1´, C-4a, C-8a), 129.9 (C-2´, C-6´), 126.4 (C-3´, C-5´),
111.5, 110.8 (C-5, C-8), 70.4 (C-1), 55.8, 55.7 (2 x OMe), 51.9 (C-3), 44.1 (N-Me), 28.8
(C-4), 15.7 (S-Me) ppm. EI-MS: m/z (%) = 330 (3), 329 (M+, 15), 328 (9), 207 (12), 206
(100). HR-MS: calcd. for C19H24NO2S [M + H]+ 330.1522; found 330.1522.
17

(±)-6,7-Dimethoxy-N-methyl-1-(4-N,N-dimethylaminophenyl)-1,2,3,4-
tetrahydroisoquinoline (3d)
Isoquinoline 3d (1.3 g, 78%) was obtained from the salt 2d (2.3 g, 5 mmol) as a white
amorphous solid. M.p. 97-99 ºC. 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 7.07 (d, J = 8.7
Hz, 2H, H-2´, H-6´), 6.65 (d, 2H, J = 8.7 Hz, H-3´, H-5´), 6.57 (s, 1H, H-5), 6.16 (s, 1H,
H-8), 4.15 (s, 1H, H-1), 3.82, 3.57 (2 x s, 3H each, 2 x OMe), 3.18-3.06 (m, 2H, H-3eq,
H-4ax), 2.91 (s, 6H, N-Me2), 2.74 (dt, 1H, J = 15.8, 3.2 Hz, H-4eq), 2.60 (td, 1H, J =
13
10.2, 3.2 Hz, H-3ax), 2.22 (s, 3H, N-Me) ppm. C NMR (100 MHz, CDCl3, 25 ºC): δ =
149.8 (C-4´), 147.3, 147.0 (C-6, C-7), 131.4, 131.1, 126.5 (C-1´, C-4a, C-8a), 130.2 (C-
2´, C-6´), 112.3 (C-3´, C-5´), 111.7, 110.7 (C-5, C-8), 70.3 (C-1), 55.9, 55.8 (2 x OMe),
52.0 (C-3), 44.2 (N-Me), 40.6 (N-Me2), 28.9 (C-4) ppm. EI-MS: m/z (%) = 327 (6), 326
(M+, 31), 325 (22), 207 (12), 206 (100). HR-MS: calcd. for C20H27N2O2 [M + H]+
327.2067; found 327.2066.
4.5. General Procedure for the synthesis of 6,7-dihydroxy-N-methyl-
1,2,3,4-tetrahydroisoquinolines (4a-d): A solution of the corresponding
tetrahydroisoquinoline (0.2 mmol) in 47% HBr (2 mL, 43 mmol) was heated at 100 ºC
for 2 h. After this time, the reaction crude mixture was basified with a saturated solution
of NaHCO3 (5 mL) to pH 8 and then was extracted with CHCl3 (2 x 10 mL). The
organic layer was dried with anhydrous MgSO4 and the solvent was concentrated
under vacuum to give the corresponding demethylated tetrahydroisoquinoline in good
yield.
(±)-6,7-Dihydroxy-N-methyl-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (4b)
Tetrahydroisoquinoline 4b (540 mg, 88%) was obtained from the isoquinoline 3b (670
1
mg, 2 mmol) as a pale brown amorphous solid. M.p. 120-123 ºC. H NMR (400 MHz,
CDCl3+ CD3OD, 25 ºC): δ = 8.10 (d, 2H, J = 8.6 Hz, H-3´, H-5´), 7.39 (d, 2H, J = 8.6
Hz, H-2´, H-6´), 6.54 (s, 1H, H-5), 5.93 (s, 1H, H-8), 4.26 (s, 1H, H-1), 3.09-2.98 (m,
18

2H, H-3, H-4), 2.67-2.53 (m, H-3, H-4), 2.17 (s, 3H, N-Me) ppm. 13C NMR (100 MHz,
CDCl3+CD3OD, 25 ºC): δ = 150.9 (C-4´), 147.2 (C-1´), 143.4, 142.7 (C-6, C-7), 130.4
(C-2´, C-6´), 127.9, 125.8 (C-4a, C-8a), 123.4 (C-3´, C-5´), 114.6 (C-5, C-8), 69.9 (C-1),
51.7 (C-3), 43.9 (N-Me), 29.6 (C-4) ppm. EI-MS: m/z (%) = 300 (M+, 10), 299 (7), 179
(16), 178 (100). HR-MS: calcd. for C16H17N2O4 [M + H]+ 301.1183; found 301.1183.
(±)-6,7-Dihydroxy-N-methyl-1-(4-methylthiophenyl)-1,2,3,4-tetrahydroisoquinoline
(4c)
Tetrahydroisoquinoline 4c (55 mg, 60%) was obtained from the isoquinoline 3c (100
1
mg, 0.3 mmol) as a yellow amorphous solid. M.p. 174-177 ºC. H NMR (400 MHz,
CD3OD, 25 ºC): δ =7.26 (d, 2H, J = 7.7 Hz, H-2´, H-6´), 7.18 (d, 2H, J = 7.7 Hz, H-3´,
H-5´), 6.56 (s, 1H, H-5), 6.01 (s, 1H, H-8), 4.34 (s, 1H, H-1), 3.17-3.05 (m, 2H, H-3, H-
4), 2.76-2.61 (m, 2H, H-3, H-4), 2.47 (s, 3H, S-Me), 2.30 (s, 3H, N-Me) ppm. 13C NMR
(100 MHz, CD3OD, 25 ºC): δ = 145.4, 144.7 (C-6, C-7), 140.5, 139.8 (C-1´, C-4´), 131.7
(C-2´, C-6´), 129.8, 126.2 (C-4a, C-8a), 127.5 (C-3´, C-5´), 116.1, 115.6 (C-5, C-8),
71.7 (C-1), 53.3 (C-3), 44.2 (N-Me), 28.8 (C-4), 15.8 (S-Me) ppm. EI-MS: m/z (%) =
302 (10), 301 (M+, 27), 300 (15), 179 (33), 178 (100), 177 (9). HR-MS: calcd for
C17H20NO2S [M + H]+ 302.1209; found 302.1209.
(±)-6,7-Dihydroxy-N-methyl-1-(4-N,N-dimethylaminophenyl)-1,2,3,4-
tetrahydroisoquinoline (4d)
Tetrahydroisoquinoline 4d (40 mg, 88%) was obtained from the isoquinoline 3d (50 mg,
1
0.15 mmol) as a pale brown amorphous solid. M.p. 200-203 ºC. H NMR (400 MHz,
CDCl3, 25ºC): δ = 6.99 (d, 2H, J = 8.6 Hz, H-2´, H-6´), 6.59 (d, 2H, J = 8.6 Hz, H-3´, H-
5´), 6.46 (s, 1H, H-5), 6.06 (s, 1H, H-8), 4.72 (s, 1H, H-1), 3.07-2.99 (m, 2H, H-3, H-4),
2.89 (s, 6H, N-Me2), 2.72-2.60 (m, 2H, H-3, H-4), 2.21 (s, 3H, N-Me) ppm. 13C NMR
(100 MHz, CDCl3, 25ºC): δ = 150.5, (C-4´), 145.2, 144.3 (C-6, C-7), 133.8, 125.3 (C-4a,
C-8a), 131.3 (C-2´, C-6´), 123.0 (C-1´), 114.8, 114.7 (C-5, C-8), 112.1 (C3´, C-5´), 68.5
(C-1), 49.6 (C-3), 41.8 (N-Me), 40.3 (N-Me2), 25.9 (C-4) ppm. EI-MS: m/z (%) = 299
19

(10), 298 (M+, 46), 297 (26), 254 (18), 179 (14), 178 (100), 177 (27). HR-MS: calcd. for
C18H23N2O2 [M + H]+ 299.1754; found 299.1751.
(±)-6,7-Dihydroxy-1-(4-hydroxyphenyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline
(4e)
A solution of the tetrahydroisoquinoline 3e (250 mg, 0.8 mmol) in 47% HBr (8 mL) was
heated at 100 ºC for 4 h. After this time, the crude reaction mixture was concentrated
under vacuum, dissolved in MeOH, stirred with NaHCO3, filtered and concentrated to
give the isoquinoline 4e (200 mg, 92%) as a pale brown amorphous solid. M.p. 232-
1
235 ºC. H NMR (400 MHz, CD3OD, 25 ºC): δ = 7.18 (d, 2H, J = 8.5 Hz, H-2´, H-6´),
6.87 (d, 2H, J = 8.5 Hz, H-3´, H-5´), 6.66 (s, 1H, H-5), 6.10 (s, 1H, H-8), 5.34 (s, 1H, H-
1), 3.70 (ddd, 1H, J = 12.2, 5.6, 4.5 Hz, H-3eq), 3.48 (ddd, 1H, J = 12.2, 10.2, 4.5 Hz,
H-3ax), 3.28-3.20 (m, 1H, H-4ax), 3.00 (dt, 1H, J = 17.3, 4.5 Hz, H-4eq), 2.82 (s, 3H, N-
13
Me) ppm. C NMR (100 MHz, CD3OD, 25 ºC): δ = 160.0 (C-4´), 146.8, 145.6 (C-6, C-
7), 128.6 (C-2´, C-6´), 124.3 (C-1´), 123.8, 123.5 (C-4a, C-8a), 116.9 (C-3´, C-5´),
115.8, 115.6 (C-5, C-8), 70.5 (C-1), 52.3 (C-3), 41.6 (N-Me), 25.5 (C-4) ppm. EI-MS:
m/z (%) = 272 (31), 271 (M+, 45), 270 (23), 179 (68), 178 (100), 177 (13). HR-MS:
calcd. for C16H18NO3 [M + H]+ 272.1281; found 272.1281.
4.6.
General
Procedure
for
synthesis
of
N-mehyl-1,2,3,4-
tetrahydroisoquinolinium salts (5a-g): The appropriate haloderivative (2.4 mmol)
was added to a solution of the corresponding tetrahydroisoquinoline (2 mmol) in dry
acetone (25 mL) under argon. The mixture was stirred at room temperature for 24 h
and the solvent was concentrated under vacuum to give the corresponding salts.
(±)-trans-6,7-Dimethoxy-N-[(methoxycarbonyl)methyl]-N-methyl-1-(4-nitrophenyl)-
1,2,3,4-tetrahydroisoquinolinium bromide (5b-trans)
A mixture of the isoquinoline 3b (680 mg, 2.1 mmol) and methyl bromoacetate (0.23
mL, 2.5 mmol) in CH3CN was refluxed for 168 h. The solvent was evaporated under
20

vacuum and the 1H NMR spectrum of the crude reaction indicated only the presence of
the salt 5b-trans (990 mg). The dry crude salt was used to next step without
purification. 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 8.11 (d, 2H, J = 8.8 Hz, H-3´, H-5´),
7.47 (d, 2H, J = 8.8 Hz, H-2´, H-6´), 7.28 (s, 1H, H-1), 6.73 (s, 1H, H-5), 6.31 (s, 1H, H-
8), 5.78 (d, 1H, J = 17.0 Hz, H-α), 4.49 (d, 1H, J = 17.0 Hz, H-α´), 4.40-4.34 (m, 1H, H-
3), 3.86, 3.78 (2 x s, 3H each, 2 x OMe), 3.64 (s, 3H, COOMe), 3.60-3.53 (m, 1H, H-
13
3´), 3.30 (s, 3H, N-Me), 3.17-2.96 (m, 2H, H-4, H-4´) ppm. C NMR (100 MHz, CDCl3
+TFA, 25 ºC): δ = 165.2 (CO), 149.3 (C-4´), 138.6, 138.3 (C-6, C-7), 124.7, 124.4 (C-
4a, C-8a), 118.7 (C-1´), 115.9 (C-2´, C-6´), 113.0 (C-3´, C-5´), 110.9, 110.2 (C-5, C-8),
73.1 (C-1), 58.3 (C-α), 56.0 (2 x OMe), 53.7, 53.6 (COOMe, C-3), 47.6 (N-Me), 23.5 (C-
4) ppm.
(±)-6,7-Dimethoxy-N-[(methoxycarbonyl)-methyl]-N-methyl-1-(4-
methylthiophenyl)- 1,2,3,4-tetrahydroisoquinolinium bromide (5c-trans)
According to general procedure, the isoquinoline 3c (800 mg, 2.4 mmol) and methyl
1
bromoacetate (0.26 mL, 2.9 mmol) gave a reaction crude, which H NMR spectrum
indicated only the presence of the salt 5c-trans (1.10 g). The dry crude salt was used to
next step without purification. 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 7.20-7.14 (m, 4H,
H-2´, H-3´, H-5´, H-6´), 6.88 (s, 1H, H-1), 6.66, (s, 1H, H-5), 6.32 (s, 1H, H-8), 5.60 (d,
1H, J = 17.5 Hz, H-α), 4.56 (d, 1H, J = 17.5 Hz, H-α´), 4.31 (ddd, 1H, J = 12.7, 5.8, 2.0
Hz, H-3eq), 3.84, 3.75 (2 x s, 3H each, 2 x OMe), 3.65 (s, 3H, COOMe), 3.63-3.56 (m,
1H, H-3ax), 3.35 (s, 3H, N-Me), 3.17 (ddd, 1H, J = 18.5, 5.6, 2.0 Hz, H-4eq), 3.10 (ddd,
1H, J = 18.5, 11.5, 5.8 Hz, H-4ax), 2.43 (s, 3H, S-Me) ppm. 13C NMR (100 MHz, CDCl3,
25ºC): δ = 165.6 (CO), 149.6, 149.0 (C-6, C-7), 142.9 (C-4´), 127.8 (C-1´), 125.6, 125.5
(C-2´, C-3´, C-5´, C-6´), 121.1, 120.2 (C-4a, C-8a), 111.1, 110.3 (C-5, C-8), 73.7 (C-1),
57.2 (C-α), 55.9, 55.8 (2 x OMe), 53.1 (COOMe), 51.9 (C-3), 48.0 (N-Me), 23.6 (C-4),
14.6 (S-Me) ppm.
(±)-6,7-Dimethoxy-N-[(methoxycarbonyl)-methyl]-N-methyl-1-(4-N,N-
dimethylaminophenyl)-1,2,3,4-tetrahydroisoquinolinium bromide (5d)
21

According to general procedure, the isoquinoline 3d (310 mg, 0.9 mmol) and methyl
1
bromoacetate (0.1 mL, 1.2 mmol) gave a reaction crude, which H NMR spectrum
indicated the presence of a mixture of stereoisomers 5d in a cis/trans ratio of 1:20 (440
mg). The dry crude salt was used to next step without purification.
5d-trans. 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 6.66-6.53 (m, 4H, H-2´, H-3´, H-5´, H-
6´), 6.65 (s, 1H, H-1), 6.60 (s, 1H, H-5), 6.26 (s, 1H, H-8), 5.35 (d, 1H, J = 17.5 Hz, H-
α), 4.56 (d, 1H, J = 17.5 Hz, H-α´), 4.24-4.21 (m, 1H, H-3), 3.81, 3.79 (2 x s, 3H each, 2
x OMe), 3.70-3.60 (m, 1H, H-3´), 3.60 (s, 3H, COOMe), 3.31 (s, 3H, N-Me), 3.16-3.04
13
(m, 2H, H-4, H-4´), 2.90 (s, 6H, N-Me2) ppm. C NMR (100 MHz, CDCl3, 25 ºC): δ =
165.2 (CO), 151.0, 148.9 (C-6, C-7), 148.3 (C-4´), 133.8 (C-2´, C-6´), 121.7 (C-1´),
120.2, 117.3 (C-4a, C-8a), 111.1 (C-3´, C-5´), 110.8, 110.0 (C-5, C-8), 74.6 (C-1), 56.8
(Cα), 55.6, 55.5 (2 x OMe), 52.7 (COOMe), 51.3 (C-3), 47.5 (N-Me), 40.0 (N-Me2), 23.5
(C-4) ppm.
(±)-6,7-Dimethoxy-N-[(methoxycarbonyl)-mehyl]-1-(4-methoxyphenyl)-N-methyl-
1,2,3,4-tetrahydroisoquinolinium bromide (5e)
According to general procedure, the isoquinoline 3e (950 mg, 3.0 mmol) and methyl
1
bromoacetate (0.3 mL, 3.5 mmol) gave a reaction crude, which H NMR spectrum
indicated the presence of a mixture of stereoisomers 5e in a cis/trans ratio of 1:5 (1.35
g). The dry crude salt was used to next step without purification.
5e-trans. 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 6.90-6.68 (m, 4H, H-2´, H-3´, H-5´, H-
6´), 6.81 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.31 (s, 1H, H-8), 5.52 (d, 1H, J = 17.7 Hz, H-
α), 4.55 (d, 1H, J = 17.7 Hz, H-α´), 4.28 (ddd, 1H, J = 13.0, 5.7, 1.4 Hz, H-3eq), 3.83,
3.76, 3.74 (3 x s, 3H each, 3 x OMe), 3.63 (s, 3H, COOMe), 3.61-3.51 (m, 1H, H-3ax),
3.31 (s, 3H, N-Me), 3.16 (ddd, 1H, J = 18.3, 5.1, 1.4 Hz, H-4eq), 3.07 (ddd, 1H, J =
18.3, 11.5, 5.7 Hz, H-4ax) ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 165.7 (CO),
161.4 (C-4´), 149.7, 149.2 (C-6, C-7), 133.5 (C-2´, C-6´), 123.6, 121.7 (C-4a, C-8a),
123.4 (C-1´), 114.5 (C-3´, C-5´), 111.2, 110.4 (C-5, C-8), 73.8 (C-1), 57.2 (Cα), 56.1 (2
x OMe), 55.4 (OMe), 52.5 (COOMe), 52.1 (C-3), 47.9 (N-Me), 23.7 (C-4) ppm.
22

4.7. General procedure for the Stevens Rearrangement: DBU (0.4 mL, 2.7
mmol) was added to a solution of the corresponding salt (2 mmol) in CH3CN (90 mL),
and the resulting mixture was stirred at room temperature for 1 h. After this time, the
solvent was evaporated under vacuum, and the crude reaction mixture was purified by
column chromatography to yield the corresponding benzazepine.
(±)-trans-7,8-Dimethoxy-2-methoxycarbonyl-N-methyl-1-(4-nitrophenyl)-2,3,4,5-
tetrahydro-1H-3-benzazepine (6b-trans)
Benzazepine 6b-trans (328 mg, 40%) was obtained from the crude salt 5b-trans (990
mg, 2 mmol) after purification by column chromatography (SiO2, cyclohexane/EtOAc
1
2:8) as an amorphous solid. M.p. 130-133 ºC. H NMR (400 MHz, CDCl3, 25 ºC): δ =
8.12 (d, 2H, J = 8.9 Hz, H-3´, H-5´), 7.32 (d, 2H, J = 8.9 Hz, H-2´, H-6´), 6.62 (s, 1H, H-
6), 6.58 (s, 1H, H-9), 4.62 (d, 1H, J = 5.6 Hz, H-1), 4.27 (d, 1H, J = 5.6 Hz, H-2), 3.86,
3.81 (2 x s, 3H each, 2 x OMe), 3.55 (s, 3H, COOMe), 3.31 (td, 1H, J = 10.9, 2.2 Hz, H-
4), 2.69-2.62 (m, 2H, H-4´, H-5), 2.56 (s, 3H, N-Me), 2.46 (ddd, 1H, J = 14.7, 6.0, 2.2
Hz, H-5´) ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 172.6 (CO), 148.7 (C-4´), 148.2,
146.3 (C-7, C-8), 147.1 (C-1´), 133.8, 129.5 (C-5a, C-9a), 128.7 (C-2´, C-6´), 123.3 (C-
3´, C-5´), 114.7, 113.6 (C-6, C-9), 66.4 (C-2), 56.2, 55.8 (2 x OMe), 51.9 (COOMe),
51.0, 50.3 (C-1, C-4), 46.0 (N-Me), 34.8 (C-5) ppm. EI-MS: m/z (%) = 400 (M+, 8), 342
(20), 341 (100), 284 (8). HR-MS: calcd for C21H25N2O6 [M + H]+ 401.1707, found
401.1704.
(±)-7,8-Dimethoxy-2-methoxycarbonyl-N-methyl-1-(4-methylthiophenyl)-2,3,4,5-
tetrahydro-1H-3-benzazepine (6c-trans)
Benzazepine 6c-trans (460 mg, 57%) was obtained from the crude salt 5c-trans (960
mg, 2 mmol) after purification by column chromatography (SiO2, cyclohexane/EtOAc
1:1) as a white amorphous solid. M.p. 144-147 ºC. 1H NMR (400 MHz, CDCl3, 25 ºC): δ
= 7.17 (d, 2H, J = 8.2 Hz, H-2´, H-6´), 7.09 (d, 2H, J = 8.2 Hz, H-3´, H-5´), 6.62 (s, 1H,
H-6), 6.50 (s, 1H, H-9), 4.55 (d, 1H, J = 6.5 Hz, H-1), 4.13 (d, 1H, J = 6.5 Hz, H-2),
23

3.85, 3.75 (2 x s, 3H each, 2 x OMe), 3.53 (s, 3H, COOMe), 3.28-3.23 (m, 1H, H-4),
2.78-2.62 (m, 3H, H-4´, H-5, H-5´), 2.50 (s, 3H, S-Me), 2.44 (s, 3H, N-Me) ppm. 13C
NMR (100 MHz, CDCl3, 25 ºC): δ = 172.2 (CO), 147.5, 146.8 (C-7, C-8), 137.3, 135.9,
133.3, 130.7 (C-1´, C-4´, C-5a, C-9a), 128.5 (C-2´, C-6´), 126.4 (C-3´, C-5´), 114.1,
113.1 (C-6, C-9), 67.2 (C-2), 55.9, 55.7 (2 x OMe), 51.1, 50.8 (C-4, COOMe), 50.2 (C-
1), 45.6 (N-Me), 34.3 (C-5), 15.7 (S-Me) ppm. EI-MS: m/z (%) = 402 (5), 401 (M+, 11),
343 (25), 342 (100), 285 (18). HR-MS: calcd. for C22H28NO4S [M + H]+ 402.1734; found
402.1735.
(±)-7,8-Dimethoxy-2-methoxycarbonyl-N-methyl-1-(4-N,N-dimethylaminophenyl)-
2,3,4,5-tetrahydro-1H-3-benzazepine (6d)
A mixture of stereoisomers of 6d were obtained in a cis/trans ratio 1:20 from the crude
salts 5d (cis/trans 1:20, 200 mg, 0.4 mmol). Both stereoisomers of 6d were isolated by
column chromatography (SiO2, cyclohexane/EtOAc, 3:7) to yield 6d-trans (80 mg, 48%)
and 6d-cis (4 mg, 2%).
6d-trans: orange oil. 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 7.04 (d, 2H, J = 8.9 Hz, H-
2´, H-6´), 6.67 (d, 2H, J = 8.9 Hz, H-3´, H-5´), 6.63 (s, 1H, H-6), 6.52 (s, 1H, H-9), 4.52
(d, 1H, J = 7.0 Hz, H-1), 4.05 (d, 1H, J = 7.0 Hz, H-2), 3.84, 3.72 (2 x s, 3H each, 2 x
OMe), 3.52 (s, 3H, COOMe), 3.22 (ddd, 1H, J = 11.5, 7.5, 3.8 Hz, H-4), 2.91 (s, 6H, N-
Me2), 2.86-2.71 (m, 2H, H-5, H-5´), 2.68 (ddd, 1H, J = 11.5, 6.8, 5.0 Hz, H-4´), 2.46 (s,
3H, N-Me) ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 172.7 (CO), 149.2 (C-4´),
147.4, 146.9 (C-7, C-8), 133.1, 131.9, 128.0 (C-1´, C-5a, C-9a), 128.9 (C-2´, C-6´),
113.9, 112.9 (C-6, C-9), 112.6 (C-3´, C-5´), 68.2 (C-2), 56.0, 55.8 (2 x OMe), 50.8
(COOMe), 50.6 (C-4), 50.4 (C-1), 45.6 (N-Me), 40.6 (N-Me2), 34.2 (C-5) ppm. EI-MS:
m/z (%) = 399 (8), 398 (M+, 26), 340 (26), 339 (100), 282 (48). HR-MS: calcd. for
C23H31N2O4 [M + H]+ 399.2278; found 399.2275.
6d-cis: yellow oil. 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 7.21 (d, 2H, J = 8.8 Hz, H-2´,
H-6´), 6.72 (d, 2H, J = 8.8 Hz, H-3´, H-5´), 6.63 (s, 1H, H-6), 6.29 (s, 1H, H-9), 4.68 (br.
s, 1H, H-1), 3.97 (br. s, 1H, H-2), 3.83, 3.57 (2 x s, 3H each, 2 x OMe), 3.52 (s, 3H,
24

COOMe), 3.29 (dd, 1H, J = 12.8, 11.6 Hz, H-4), 3.09 (ddd, 1H, J = 14.3, 11.6, 1.9 Hz,
H-5), 2.93 (s, 6H, N-Me2), 2.82 (ddd, 1H, J = 12.8, 6.0, 1.9 Hz, H-4´), 2.72 (dd, 1H, J =
14.3, 6.0 Hz, H-5´), 2.47 (s, 3H, N-Me) ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ =
171.0 (CO), 149.2 (C-4´), 146.9, 146.8 (C-7, C-8), 133.8, 132.7, 129.0 (C-1´, C-5a, C-
9a), 129.7 (C-2´, C-6´), 112.9, 112.4 (C-6, C-9), 112.5 (C-3´, C-5´), 68.4 (C-2), 56.0,
55.8 (2 x OMe), 51.2, 50.8 (C-1, C-4, COOMe), 44.9 (N-Me), 40.6 (N-Me2), 34.9 (C-5)
ppm.
(±)-7,8-Dimethoxy-2-methoxycarbonyl-1-(4-methoxyphenyl)-N-methyl-2,3,4,5-
tetrahydro-1H-3-benzazepine (6e)
A mixture of stereoisomers of 6e were obtained in a cis/trans ratio 1:5 from the crude
salts 5e (cis/trans 1:5, 900 mg, 1.9 mmol). Both stereoisomers of 6e were isolated by
column chromatography (SiO2, cyclohexane/EtOAc, 4:6) to yield of pure 6e-trans (323
mg, 44%), pure 6e-cis (64 mg, 8%).
6e-trans: white amorphous solid: M.p. 114-117 ºC. 1H NMR (400 MHz, CDCl3, 25 ºC): δ
= 7.10 (d, 2H, J = 8.9 Hz, H-2´, H-6´), 6.83 (d, 2H, J = 8.9 Hz, H-3´, H-5´), 6.63 (s, 1H,
H-6), 6.50 (s, 1H, H-9), 4.54 (d, 1H, J = 7.0 Hz, H-1), 4.08 (d, 1H, J = 7.0 Hz, H-2),
3.84, 3.77, 3.73 (3 x s, 3H each, 3 x OMe), 3.54 (s, 3H, COOMe), 3.27-3.21 (m, 1H, H-
4), 2.81-2.64 (m, 3H, H-4´, H-5, H-5´), 2.48 (s, 3H, N-Me) ppm. 13C NMR (100 MHz,
CDCl3, 25 ºC): δ = 172.6 (CO), 158.1 (C-4´), 147.6, 146.9 (C-7, C-8), 133.3, 132.4,
131.5 (C-1´, C-5a, C-9a), 129.3 (C-2´, C-6´), 114.0, 113.1 (C-6, C-9), 113.7 (C-3´, C-
5´), 68.0 (C-2), 56.1, 55.9, 55.2 (3 x OMe), 50.9 (COOMe), 50.8, 50.4 (C-1, C-4), 45.7
(N-Me), 34.3 (C-5) ppm. EI-MS: m/z (%) = 385 (M+, 6), 327 (22), 326 (100), 269 (18).
HR-MS: calcd. for C22H28NO5 [M + H]+ 386.1962; found 386.1958.
6e-cis: colourless oil: 1H NMR (400 MHz, CDCl3, 25 ºC): δ = 7.29 (d, 2H, J = 8.9 Hz, H-
2´, H-6´), 6.86 (d, 2H, J = 8.9 Hz, H-3´, H-5´), 6.64 (s, 1H, H-6), 6.20 (s, 1H, H-9), 4.73
(br. s, 1H, H-1), 3.99 (br. s, 1H, H-2), 3.83, 3.80, 3.56 (3 x s, 3H cada, 3 x OMe), 3.52
(s, 3H, COOMe), 3.29 (ddd, 1H, J = 13.9, 11.6, 1.6 Hz, H-5), 3.11 (t, 1H, J = 11.6 Hz,
H-4), 2.82 (ddd, 1H, J = 11.6, 5.9, 1.6 Hz, H-4´), 2.73 (dd, 1H, J = 13.9, 5.9 Hz, H-5´),
25

2.48 (s, 3H, N-Me) ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 171.3 (CO), 158.1 (C-
4´), 147.0, 146.8 (C-7, C-8), 133.8, 133.6, 132.9 (C-1´, C-5a, C-9a), 130.1 (C-2´, C-6´),
113.7 (C-3´, C-5´), 112.8, 112.5 (C-6, C-9), 68.3 (C-2), 56.0, 55.9, 55.2 (3 x OMe),
51.3, 51.1, 50.9 (C-1, C-4, COOMe), 45.1 (N-Me), 35.2 (C-5) ppm.
4.8. General Procedure for synthesis of 7,8-dihydroxy-N-methyl-2,3,4,5-
tetrahydro-1H-3-benzazepines (7a-g):
A
solution of the corresponding
benzazepine (6a-g, 0.3 mmol) in CH2Cl2 (4 mL) was cooled to -78ºC. Subsequently, a
solution of Br3B in CH2Cl2 (0.8 mL, 4.6 mmol) was added dropwise. After 15 min, the
reaction mixture was warmed up to room temperature and stirred for 3 h. After this
period, the reaction was quenched with MeOH and stirred for another 30 min. The
solvent was evaporated under vacuum, and the residue obtained was dissolved in
EtOAc (2 mL), made alkaline with 25% aqueous NH4OH to pH 11, and neutralized with
37% HCl to pH 7-8. The aqueous layer was extracted with EtOAc (2 x 10 mL). The
organic layer was dried with anhydrous MgSO4, the solvent evaporated under vacuum
and the crude reaction was purified by column chromatography (SiO2, CH2Cl2/MeOH,
9:1 to 8:2) to obtain the corresponding demethylated benzazepine in moderated and
good yield.
(±)-trans-7,8-Dihydroxy-2-(methoxycarbonyl)-N-methyl-1-phenyl-
tetrahydro-1H-3-benzazepine (7a-trans)
2,3,4,5-
Benzazepine 7a-trans (50 mg, 57%) was obtained from the benzazepine 6a-trans (95
1
mg, 0.27 mmol) as a pale brown amorphous solid. M.p.: 119-122 ºC. H NMR (400
MHz, CDCl3, 25 ºC): δ = 7.32-7.20 (m, 5H, Ph), 6.53 (s, 1H, H-6), 6.28 (s, 1H, H-9),
4.55 (d, 1H, J = 8.0 Hz, H-1), 4.04 (d, 1H, J = 8.0 Hz, H-2), 3.54 (s, 3H, COOMe), 3.22-
3.17 (m, 1H, H-4), 2.88-2.84 (m, 1H, H-5), 2.72-2.65 (m, 2H, H-4´, H-5´), 2.42 (s, 3H,
N-Me) ppm. 13C NMR (100 MHz, CDCl3, 25 ºC): δ = 172.0 (CO), 143.0, 142.4 (C-7, C-
8), 139.5 (C-1´), 131.3, 130.0 (C-5a, C-9a), 128.4, 128.3, 126.6 (CH Ph), 117.1, 116.7
26

(C-6, C-9), 67.8 (C-2), 51.2 (COOMe), 50.7, 50.1 (C-1, C-4), 45.1 (N-Me), 32.8 (C-5)
ppm. EI-MS: m/z (%) = 327 (M+, 3), 269 (20), 268 (100), 178 (12). HR-MS: calcd for
C19H22NO4 [M + H]+ 328.1543; found 328.1543.
(±)-trans-7,8-Dihydroxy-2-methoxycarbonyl-N-methyl-1-(4-nitrophenyl)-2,3,4,5-
tetrahydro-1H-3-benzazepine (7b-trans)
Benzazepine 7b-trans (80 mg, 72 %) was obtained from the benzazepine 6b-trans
1
(120 mg, 0.3 mmol) as an orange amorphous solid. M.p. 103-105 ºC. H NMR (400
MHz, CDCl3+CD3OD, 25 ºC): δ = 8.10 (d, 2H, J = 8.8 Hz, H-3´, H-5´), 7.32 (d, 2H, J =
8.8 Hz, H-2´, H-6´), 6.58, 6.52 (2 x s, 1H each, H-6, H-9), 4.55 (d, 1H, J = 5.9 Hz, H-1),
4.20 (d, 1H, J = 5.9 Hz, H-2), 3.55 (s, 3H, COOMe), 3.26 (ddd, 1H, J = 12.5, 9.8, 3.1
13
Hz, H-4), 2.66-2.42 (m, 3H, H-4´, H-5, H-5´), 2.52 (s, 3H, N-Me) ppm. C NMR (100
MHz, CDCl3+CD3OD, 25 ºC): δ = 172.2 (CO), 148.9, 146.2, 143.2, 142.3 (C-1´, C-4´,
C-7, C-8), 133.2, 129.4 (C-5a, C-9a), 128.9 (C-2´, C-6´), 123.2 (C-3´, C-5´), 117.9,
117.1 (C-6, C-9), 66.7 (C-2), 51.5, 51.1, 50.5 (C-1, C-4, COOMe), 45.8 (N-Me), 34.2
(C-5) ppm. EI-MS: m/z (%) = 372 (M+, 5), 314 (29), 313 (100), 267 (12), 178 (9), 176
(14). HR-MS: calcd. for C19H21N2O6 [M + H]+ 373.1394; found 373.1393.
(±)-trans-7,8-Dihydroxy-2-methoxycarbonyl-N-methyl-1-(4-methylthiophenyl)-
2,3,4,5-tetrahydro-1H-3-benzazepine (7c-trans)
Benzazepine 7c-trans (40 mg, 43 %) was obtained from the benzazepine 6c-trans (100
1
mg, 0.25 mmol) as a pale brown amorphous solid. M.p. 114-117 ºC. H NMR (400
MHz, CDCl3, 25 ºC): δ = 7.17 (d, 2H, J = 8.5 Hz, H-2´, H-6´), 7.13 (d, 2H, J = 8.5 Hz, H-
3´, H-5´), 6.57 (s, 1H, H-6), 6.34 (s, 1H, H-9), 4.49 (d, 1H, J = 7.8 Hz, H-1), 4.05 (d, 1H,
J = 7.8 Hz, H-2), 3.53 (s, 3H, COOMe), 3.25-3.19 (m, 1H, H-4), 2.84-2.79 (m, 1H, H-5),
2.74-2.66 (m, 2H, H-4´, H-5´), 2.45 (s, 3H, S-Me), 2.44 (s, 3H, N-Me) ppm. 13C NMR
(100 MHz, CDCl3, 25 ºC): δ = 172.3 (CO), 142.7,142.3 (C-7, C-8), 136.6, 136.5 (C-1´,
C-4´), 131.4, 130.5 (C-5a, C-9a), 129.1 (C-2´, C-6´), 126.5 (C-3´, C-5´), 116.9, 116.8
(C-6, C-9), 67.8 (C-2), 51.3 (COOMe), 50.3, 49.9 (C-1, C-4), 45.0 (N-Me), 32.7 (C-5),
27

15.7 (S-Me) ppm. EI-MS: m/z (%) = 373 (M+, 7), 315 (27), 314 (100), 257 (9), 178 (14),
176 (14). HR-MS: calcd. for C20H24NO4S [M + H]+ 374.1421; found 374.1421.
(±)-trans-7,8-Dihydroxy-2-methoxycarbonyl-1-(4-N,N-dimethylaminophenyl)-N-
methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (7d-trans)
Benzazepine 7d-trans (15 mg, 81 %) was obtained from the benzazepine 6d-trans (20
1
mg, 0.05 mmol) as a yellow amorphous solid. M.p. 125-128 ºC. H NMR (400 MHz,
CDCl3, 25 ºC): δ = 7.07 (d, 2H, J = 8.3 Hz, H-2´, H-6´), 6.67 (d, 2H, J = 8.3 Hz, H-3´, H-
5´), 6.61 (s, 1H, H-6), 6.39 (s, 1H, H-9), 4.44 (d, 1H, J = 7.8 Hz, H-1), 4.03 (d, 1H, J =
7.8 Hz, H-2), 3.51 (s, 3H, COOMe), 3.28-3.23 (m, 1H, H-4), 2.88 (s, 6H, N-Me2), 2.83-
13
2.70 (m, 3H, H-4´, H-5, H-5´), 2.46 (s, 3H, N-Me) ppm. C NMR (100 MHz, CDCl3, 25
ºC): δ = 172.2 (CO), 149.4 (C-4´), 142.7, 142.3 (C-7, C-8), 131.2, 131.1, 127.4 (C-1´,
C-5a, C-9a), 129.3 (C-2´, C-6´), 116.7, 116.5 (C-6, C-9), 112.8 (C-3´, C-5´), 68.4 (C-2),
51.3 (COOMe), 50.6, 49.6 (C-1, C-4), 45.1 (N-Me), 40.7 (N-Me2), 29.6 (C-5) ppm. EI-
MS: m/z (%) = 371 (7), 370 (M+, 30), 312 (26), 311 (100), 254 (34), 178 (13), 176 (16).
HR-MS: calcd. for C21H27N2O4 [M + H]+ 317.1965; found 317.1966.
(±)-trans-7,8-Dihydroxy-1-(4-hydroxyphenyl)-2-methoxycarbonyl-N-methyl-
2,3,4,5-tetrahydro-1H-3-benzazepine (7e-trans)
A solution of the benzazepine 6e-trans (100 mg, 0.3 mmol) and Br3B (1.2 mL, 7 mmol)
in CH2Cl2 (4 mL) was stirred to room temperature for 3 h. After this time, the reaction
was terminated by addition of MeOH and the crude reaction mixture was concentrated
under vacuum to obtain the benzazepine 7e-trans (80 mg, 90%) as a pale brown
amorphous solid. M.p. 209-212 ºC. 1H NMR (400 MHz, CD3OD, 25 ºC): δ = 7.05 (d, 2H,
J = 8.1 Hz, H-2´, H-6´), 6.81 (d, 2H, J = 8.1 Hz, H-3´, H-5´), 6.70 (s, 1H, H-6), 6.49 (s,
1H, H-9), 4.82 (d, 1H, J = 5.9 Hz, H-1), 4.65 (d, 1H, J = 5.9 Hz, H-2), 3.59 (s, 3H,
13
COOMe), 2.98-2.84 (m, 4H, H-4, H-4´, H-5, H-5´), 2.68 (s, 3H, N-Me) ppm. C NMR
(100 MHz, CD3OD, 25 ºC): δ = 171.0 (CO), 157.7 (C-4´), 145.7, 145.1 (C-7, C-8),
131.5, 130.6, 129.7 (C-1´, C-5a, C-9a), 130.6 (C-2´, C-6´), 119.3, 118.4 (C-6, C-9),
116.8 (C-3´, C-5´), 69.5 (C-2), 53.6 (C-1), 52.9, 51.3 (C-4, COOMe), 45.8 (N-Me), 32.9
28

(C-5) ppm. EI-MS: m/z (%) = 343 (M+, 2), 285 (43), 284 (68), 283 (43), 228 (25), 227
(32), 179 (22), 178 (100), 177 (26). HR-MS: calcd. for C19H22NO5 [M + H]+ 344.1493;
found 344.1493.
(±)-trans-2-Carbamoyl-7,8-dihydroxy-N-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-
benzazepine (7f-trans)
Benzazepine 7f-trans (40 mg, 44%) was obtained from the benzazepine 6f-trans (100
1
mg, 0.3 mmol) as a yellow amorphous solid. M.p. 200-202 ºC. H NMR (400 MHz,
CD3OD, 25 ºC): δ = 7.31-7.18 (m, 5H, Ph), 6.58 (s, 1H, H-6), 6.30 (s, 1H, H-9), 4.63 (d,
1H, J = 8.0 Hz, H-1), 3.83 (d, 1H, J = 8.0 Hz, H-2), 3.16-3.10 (m, 1H, H-4), 3.04-2.96
(m, 1H, H-5), 2.78-2.68 (m, 2H, H-4´, H-5´), 2.33 (s, 3H, N-Me) ppm. 13C NMR (100
MHz, CD3OD, 25 ºC): δ = 176.8 (CO), 144.8, 144.4 (C-7, C-8), 142.7 (CPh), 132.4,
131.9 (C-5a, C-9a), 130.4, 129.5, 127.7 (CH Ph), 118.4, 117.6 (C-6, C-9), 70.5 (C-2),
52.2 (C-4), 51.7 (C-1), 45.2 (N-Me), 33.6 (C-5) ppm. EI-MS: m/z (%) = 312 (M+, 2), 270
(25), 269 (79), 268 (100), 178 (15). HR-MS: calcd for C18H21N2O3 [M + H]+ 313.1547;
found 313.1547.
(±)-trans-7,8-Dihydroxy-N-methyl-N-2-(4-nitrophenyl)-1-phenyl-2,3,4,5-tetrahydro-
1H-3-benzazepine (7g-trans)
Benzazepine 7g-trans (130 mg, 70 %) was obtained from the benzazepine 6g-trans
(200 mg, 0.5 mmol) as a yellow amorphous solid. M.p. 140-143 ºC. 1H NMR (400 MHz,
CDCl3+CD3OD, 25 ºC): δ = 8.04 (d, 2H, J = 8.5 Hz, H3´, H-5´), 7.35 (d, 2H, J = 8.5 Hz,
H-2´, H-6´), 7.19-7.08 (m, 5H, Ph), 6.75 (s, 1H, H-6), 6.32 (s, 1H, H-9), 4.55-4.48 (m,
2H, H-1, H-2), 3.13-2.82 (m, 4H, H-4, H-5), 2.13 (s, 3H, N-Me) ppm. 13C NMR (100
MHz, CDCl3 + CD3OD, 25 ºC): δ = 147.4, 146.9, 142.4, 140.4 (C-1´, C-4´, C-7, C-8),
140.3 (CPh), 131.4, 130.8 (C-5a, C-9a), 130.0 (C-2´, C-6´), 129.1, 128.3, 126.6 (CH
Ph), 123.1 (C-3´, C-5´), 116.8, 116.5 (C-6, C-9), 70.4 (C-2), 53.6 (C-1), 50.8 (C-4), 44.8
(N-Me), 32.8 (C-5) ppm. EI-MS: m/z (%) = 391 (20), 390 (M+, 80), 300 (21), 299 (100),
268 (7), 211 (37), 178 (64), 177 (33), 165 (45). HR-MS: calcd for C23H23N2O4 [M + H]+
391.1652; found 391.1652.
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