Diastereoselective synthesis of 1,2-disubstituted 2,3,4,5-tetrahydro1H-3- benzazepines by means of the Stevens rearrangement

Article abstract of DOI:10.1002/ejoc.201000512

1,2-Disubstituted 2,3,4,5-tetrahydro-1H-3-benzazepines were conveniently obtained by making use of the regio- and diastereoselective Stevens rearrangement of the corresponding isoquinolinium salts with 1,8-diazabicyclo[5.4.0]undec-7-ene in acetonitrile, T

Full text of DOI:10.1002/ejoc.201000512

FULL PAPER
DOI: 10.1002/ejoc.201000512
Diastereoselective Synthesis of 1,2-Disubstituted 2,3,4,5-Tetrahydro-
1H-3-benzazepines by Means of the Stevens Rearrangement
María Valpuesta,*[a] Manuela Ariza,[a] Amelia Díaz,*[a] and Rafael Suau[a]
Dedicated to Professor Janine Cossy on the occasion of her 60th birthday
Keywords: Benzazepines / Rearrangement / Diastereoselectivity / Ylides / Isoquinolines
1,2-Disubstituted 2,3,4,5-tetrahydro-1H-3-benzazepines were isoquinolinium salts with 1,8-diazabicyclo[5.4.0]undec-7-ene
conveniently obtained by making use of the regio- and dia-
stereoselective Stevens rearrangement of the corresponding
in acetonitrile. This procedure has provided a good number
of novel analogue compounds of SCH 23390.
Introduction
substituted derivatives have been prepared and studied as
Dopamine-mediated neurotransmission plays a role in dopamine receptor agonists and antagonists.[4] Moreover,
several psychiatric and neurological disorders, and for this 1H-3-benzazepines are active in animal models of various
reason there has been great interest in the search for novel neurological disorders, for example, Parkinson’s and Alzhei-
dopamine receptor agonists and antagonists.[1] The action mer’s diseases. A significant example of a potent D1 recep-
of dopamine is mediated by five different receptor subtypes tor agonist is fenoldopam, which acts peripherally to pro-
classified into two families: D1-like (D1 and D5) and D2- duce selectively systemic vasodilation (Figure 1).[5] On the
like (D2, D3, and D4).[2] During the last several decades, other hand, 1H-3-benzazepine SCH 23390 and its confor-
dopaminergic ligands have remained a very active area in mationally restricted analogue SCH 39166 are two classical
the development of central-nervous-system pharmaceutical highly potent and selective D1/D5 antagonists. In fact,
products.[3] In general, seven-membered nitrogen heterocy- compound SCH 39166 was developed for the treatment of
cles are constituents of a number of compounds with re- a variety of diseases, including schizophrenia, cocaine ad-
markable pharmacological properties. The 2,3,4,5-tetra- diction, and obesity, and it was studied in human clinical
hydro-1H-3-benzazepine ring attracts a great deal of inter- trials.[1,5a,6] However, both compounds displayed low
est from a medicinal chemistry viewpoint, because it con- plasma levels and poor oral bioavailability due to the rapid
tains the phenethylamine substructure. Specifically, 1-aryl- first-pass metabolism of the phenol moieties.
Figure 1. Relevant structures of 1H-3-benzazepines.
The preparation of 1H-3-benzazepine compounds is
nowadays an object of considerable interest due to their po-
[a] Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Málaga
tential dopaminergic activity. Synthetic approaches to 1H-
Campus de Teatinos s/n, 29071 Málaga, Spain
3-benzazepines include different strategies, most of them
based on two disconnections (Figure 2). Disconnection (a),
which is the most common route, makes use of Friedel–
Fax: +34-952-131941
E-mail: mvalpuesta@uma.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000512.
Eur. J. Org. Chem. 2010, 4393–4401
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M. Valpuesta, M. Ariza, A. Díaz, R. Suau
FULL PAPER
Crafts-type reactions implying halogen,[7] alcohol,[8] or car- to take place under the applied conditions. Specifically, a
bamate compounds.[4a] The cyclization process involved in collection of novel analogues of SCH 23390 and
these reactions requires an excess of acid and is poorly flexi- SCH 39166 were thus prepared. The aim was to generate
ble in the selection of substituents. This disconnection may new variants of 1H-3-benzazepines that could be used to
also exploit the intramolecular Heck reductive reaction[9] help understand the structure/activity relationships in this
and the radical cyclization of highly reactive aryl radicals family of compounds.
onto double and triple bonds.[10] Disconnection (b) consists
of ring enlargement of a six-membered cyclic precursor via
an aziridinium intermediate.[11] A parallel approach based
on the Stevens rearrangement of tetrahydroisoquinolinium
Results and Discussion
We hereby report the results obtained in the Stevens re-
arrangement of the 1-phenyltetrahydroisoquinolinium salts
5 (Figure 3). The regioselectivity of the ylide formation may
be problematic if there is more than one acidic site in the
precursor salt. In such a case, the Stevens rearrangement
may afford two compounds: 1,2-disubstituted 1H-3-benz-
azepines 1, if the exocyclic nitrogen ylide is formed at C-α,
and the 1,1-disubstituted isoquinolines 6 with the endo-
cyclic nitrogen ylide being the key intermediate. The reac-
tion preference is largely dependent on the nature of the Z
substituent so that electron-withdrawing groups exclusively
yield 1H-3-benzazepines 1.
salts could be developed. This reaction has been employed
by Padwa et al.[12] for the synthesis of isoindolo-benzazep-
ines via carbenoid precursors. Nevertheless, the regioselec-
tive ylide formation was difficult to attain by this method.
Figure 2. Strategies for the synthesis of 1H-3-benzazepines.
In previous work we have made use of the Stevens re-
We have chosen (Ϯ)-trans-6,7-dimethoxy-N-[(methoxy-
arrangement for the synthesis of 8-(arylmethyl)berbine.[13] carbonyl)methyl]-N-methyl-1-phenyl-1,2,3,4-tetrahydroiso-
As a continuation of our exploratory study of the Stevens quinolinium bromide (5a-trans) as a model compound to
rearrangement as a highly efficient reaction to synthesize study the rearrangement reaction under different conditions
nitrogen-containing compounds, we have now extended this (Scheme 1).
methodology to the synthesis of 1H-3-benzazepines.
The synthesis of this isoquinolium salt 5a is based on
In this paper we describe an effective and short synthesis classical methods. We employed the Bischler–Napieralski
of 1,2-disubstituted 1H-3-benzazepines by using the Stevens cyclization of the corresponding amide followed by N-
rearrangement in a regio- and diastereoselective approach. methylation and reduction to afford the isoquinoline inter-
No alternative reaction, such as the Hofmann elimination mediate 4. The standard N-alkylation of this compound[14]
and the Sommelet–Hauser rearrangement[12] were observed yielded the cis/trans mixture of diastereoisomers 5a in a
Figure 3. Stevens rearrangement of isoquinolinium salts.
Scheme 1. Synthesis of salts 5a–i: (i) CH3I/acetone, reflux; (ii) NaBH4/MeOH, r.t.; (iii) XCH2Z/acetone, r.t.
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1,2-Disubstituted 2,3,4,5-tetrahydro-1H-3-benzazepines
5:95 ratio. The trans diastereoisomer was isolated from this ported for other 1,2-disubstituted 1H-3-benzazepines;[15]
mixture by fractional precipitation. The configuration of 1- the stereoisomer 1a-trans exhibits a large 1-H/2-H coupling
H relative to the (methoxycarbonyl)methyl substituent was constant (J1,2 = 7.0 Hz), whereas in stereoisomer 1a-cis 1-
assessed by the occurrence of an intense NOE effect be- H and 2-H appear as a pair of broad unresolved doublets
tween 1-H and α-H in the H,H-NOESY spectra. However, (with J1,2 Ͻ 1.8 Hz). In the H,H-NOESY experiment, both
several attempts to isolate the cis diastereoisomer failed due diastereoisomers show NOE correlation between 1-H and
to the low proportion in this mixture.
2-H, but only the stereoisomer 1a-cis exhibits an NOE ef-
As shown in Table 1, we first examined the reactivity of fect between 1-H and 4-H. The spectral differences ob-
5a-trans with dimsylsodium in DMSO, since we have pre- served between the two diastereoisomers are well supported
viously reported that no competitive reactions take place by molecular modeling.[16] Owing to the presence of a
under such conditions.[13] This treatment gave a mixture of seven-membered ring, the benzazepine molecule may adopt
1a and 4 in a ratio 1:1, due to the initial salt dealkylation a number of different conformations. The relative spatial
(Table 1, Entry 1). To improve this result a variety of bases positions of 1-H/2-H/4-H in the preferred conformations
were tried. Although the use of sodium hexamethyldisilaz- for 1a-trans and 1a-cis benzazepines (Figure 4) are consis-
ane or potassium tert-butoxide preferentially yields the tent with H,H-NOESY results. Furthermore, the calculated
benzazepine skeleton, the reaction did not cleanly proceed 1-H–2-H dihedral angles are in agreement with the coupling
1
(Table 1, Entries 2 and 3). Despite the fact that the treat- constant differences observed in the H NMR spectra of
ment of the 5a-trans salt with potassium carbonate in THF trans and cis diastereoisomers.
led to a significant increase in yield, much longer periods
of time were needed for a complete conversion (Table 1, En-
try 4). The most advantageous procedure for the generation
of the 1H-3-benzazepine 1a-trans makes use of 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) in acetonitrile; under these
conditions the reaction proceeded with high stereoselec-
tively so that the desired compound 1a-trans was obtained
in excellent yield (Table 1, Entry 5). A possible explanation
for such a good result is that the use of a medium organic
base in a highly polar solvent favored both the salt solubil-
ity and the intermediate ylide formation.
Table 1. Stevens rearrangement of the 5a-trans salt with different
bases.
Figure 4. 3D model structures of the most stable conformations of
1a-trans and 1a-cis diastereoisomers with an indication of the NOE
effects observed in each case.
The conditions optimized for the rearrangement of 5a
were then applied to the reaction of a set of tetrahydroiso-
quinolinium salts 5b–g containing different electron-with-
drawing substituents on the nitrogen atom. The synthesis
of these salts was carried out according to the reaction
route shown in Scheme 1, which afforded exclusively the
trans diastereoisomer in all cases. The Stevens rearrange-
ment of 5b–g occurred regio- and diastereoselectively to
yield exclusively the corresponding trans-benzazepine deriv-
atives 1b–g (Table 2). In fact, the H,H-NOESY data of
Entry
Base
Solvent
t
Yield[a]
1
2
3
4
5
NaCH2SOCH3
NaHMDS
tBuOK
DMSO
THF
THF
THF
CH3CN
1 h
1 h
2 h
48 h
30 min
50%
70%
72%
80%
95%
K2CO3
DBU
[a] The reaction was carried out at room temperature.
these compounds were fully consistent with their trans con-
1
To corroborate the stereoselectivity of the reaction, we figuration, and the H NMR spectroscopic coupling con-
evaluated it with a mixture of diastereoisomers 5a, enriched stants were in accordance with the dihedral angles calcu-
in 5a-cis. The treatment of this mixture with DBU in aceto- lated by molecular modeling.[16]
nitrile yielded diastereoisomers 1a in a ratio similar to the
Conversely, the application of the optimized conditions
cis/trans ratio of the starting isoquinolinium salts confirm- to the isoquinolium salts 5h–i (Scheme 2) failed to give the
ing the stereochemical control of the Stevens rearrange- ring enlargement toward the 1H-3-benzazepines, apparently
ment.[13] The relative configuration between 1-H and 2-H due to the absence of the electron-withdrawing group in
in the 1H-3-benzazepines 1a was evidenced by both 1H these compounds. Moreover, the use of a stronger base,
NMR and H,H-NOESY spectroscopic analysis. Clear dif- such as potassium tert-butoxide in THF afforded regioselec-
ferences in the coupling constant values were observed for tively the 1,1-tetrahydroisoquinolines 6a,b in good yield, de-
the two diastereomers according to data previously re- rived from a nitrogen ylide at C-1.
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M. Valpuesta, M. Ariza, A. Díaz, R. Suau
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Table 2. Synthesis of 1H-3-benzazepines 1a–g by the Stevens re- figuration between 1-H and 2-H in 1H-3-benzazepine 11
1
arrangement.
was also confirmed by H NMR (coupling constant J1,2
=
7.0 Hz) and H,H-NOESY spectroscopic analysis.
Conclusions
We have developed a short and efficient approach to the
synthesis of 1,2-disubstituted 1H-3-benzazepines by using a
diastereoselective Stevens rearrangement. The application
of this methodology has provided a fair number of novel
analogue compounds of SCH 23390. Furthermore, the ade-
quate choice of the isoquinolinium salt allowed us to con-
trol the Stevens rearrangement to obtain exclusively either
the 1H-3-benzazepines or the 1,1-disubstituted isoquinol-
ines.
Further application of this methodology to the synthesis
of 1H-3-benzazepines SCH 23390 and SCH 39166 ana-
logues along with the evaluation of the bioactivity of the
newly synthesized compounds are currently underway.
Entry trans-Benzazepine Z substituent
t
Yield[a] J1,2
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
CO2Me
CONH2
CONMe2
COMe
COPh
C6H4NO2-4
30 min 95%
1 h
1 h
30 min 85%
30 min 89%
2 h
7.0 Hz
85%[b] 5.0 Hz
90%[b] 9.1 Hz
7.8 Hz
7.5 Hz
7.5 Hz
5.5 Hz
84%
1g
CH=CHCO2Me 30 min 85%
[a] Isolated yields after silica-gel chromatography. [b] The reaction
was carried out under reflux for 1 h.
Experimental Section
General Remarks: Melting points were determined with a Gallen-
kamp instrument and are uncorrected. MS (EI) data were recorded
with an HP-MS 5988A spectrometer operating at 70 eV and
HRMS data with a VG Autospec spectrometer. IR spectra were
obtained with an ATR accessory (MIRacle ATR, PIKE Technol-
ogies, USA) coupled to an FTIR spectrometer (FT/IR-4100, JA-
SCO). All spectra were recorded in the range from 4000 to 600 cm–1
with a resolution of 4 cm–1. NMR spectra were recorded with a
Bruker AC 200 instrument operating at 200 MHz for 1H and
50.3 MHz for 13C NMR spectroscopy, or with a Bruker ARX 400
instrument operating at 400 MHz for 1H and 100.6 MHz for 13C
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 magneti-
cally stirred and monitored by TLC with silica gel 60 F254 (Merck)
plates. Products were purified by column chromatography with
0.063–0.200 mm silica gel (Merck 7734).
Scheme 2. Synthesis of 1,1-disubstituted isoquinolines 6a,b: (i)
tBuOK/THF, r.t.
Given the importance of a chlorine atom in the A ring
of 1H-3-benzazepines SCH 23390 and SCH 39166 for their
biological activity,[3,5a] our next aim was to synthesize the
novel chloro-substituted 1H-3-benzazepine 11 by means of
the Stevens rearrangement. As shown in Scheme 3, the iso-
quinolinium salt 10 was prepared from the dihydroisoquin-
oline 7 according to the standard procedure previously de-
scribed for salts 5a–i. The Stevens rearrangement of the dia-
stereomerically pure trans salt 10 afforded stereoselectively
the desired 1H-3-benzazepine 11 in excellent yield, with full
Preparation of 1-Phenyl-3,4-dihydroisoquinolines 2 and 7: A solution
of POCl3 (6.7 mL, 70.3 mmol) in CH3CN (5 mL) was added drop-
retention of the initial salt configuration. The relative con- wise to a solution of the corresponding amide (35.1 mmol) in
Scheme 3. Synthesis of the 1H-3-benzazepine 11: (i) CH3I/acetone, reflux; (ii) NaBH4/MeOH, r.t.; (iii) BrCH2CO2Me/acetone, r.t.; (iv)
DBU/CH3CN, r.t.
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1,2-Disubstituted 2,3,4,5-tetrahydro-1H-3-benzazepines
CH3CN (60 mL) under argon. The reaction mixture was refluxed
for 2 h and then concentrated to dryness. The crude material was
dissolved in CH2Cl2 (60 mL) and washed with a saturated solution
1Ј), 132.2 (C-5), 130.5, 130.4 (C-4a, C-8a), 129.8, 129.2, 129.0 (CH
Ph), 126.6 (C-6), 116.0 (C-8), 56.1 (OMe), 53.5 (C-3), 48.0 (N-Me),
24.8 (C-4) ppm. IR (neat): ν = 3010, 2937, 1638, 1598, 1502, 1460,
˜
of NaHCO3 (50 mL), NaOH (5%, 2ϫ50 mL), and water. The 1369 cm–1. EI-MS: m/z (%) = 288 (3), 287 (7), 286 (10) [M]+, 285
organic layers were dried with MgSO4 and concentrated under vac-
uum to give the corresponding isoquinoline.
(16), 273 (9), 271 (24), 210 (33), 209 (12), 208 (92), 196 (36), 194
(100), 127 (17). HR-MS: calcd. for C17H17ClNO 286.0993; found
286.0986.
6,7-Dimethoxy-1-phenyl-3,4-dihydroisoquinoline (2):[17a] The iso-
quinoline 2 (9.3 g, 99%) was obtained from the corresponding
amide[17] (10.0 g, 35.1 mmol) as a pale-yellow solid. M.p. 192–
Preparation of N-Methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolines 4
and 9: NaBH4 (220 mg, 5.8 mmol) was added dropwise over a
195 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.68 (d, J = period of 10 min to a solution of the corresponding salt (5.0 mmol)
7.0 Hz, 2 H, Ph), 7.55–7.46 (m, 3 H, Ph), 6.82, 6.81 (2ϫ s, 1 H
each, 5-H, 8-H), 3.95, 3.71 (2ϫ s, 3 H each, 2ϫ OMe), 3.89 (t, J
= 7.5 Hz, 2 H, 3-H), 2.86 (t, J = 7.5 Hz, 2 H, 4-H) ppm. 13C NMR
in MeOH (40 mL), and the mixture was stirred for 2 h. The solvent
was evaporated under vacuum, and the residue obtained was dis-
solved in CH2Cl2 (30 mL) and washed with water. The organic
(100 MHz, CDCl3, 25 °C): δ = 166.8 (C-1), 151.0, 146.9 (C-6, C- layer was dried with anhydrous MgSO4 and the solvent evaporated
7), 138.3, 132.5, 121.1 (C-1Ј, C-4a, C-8a), 129.4, 128.7, 128.0 (CH
Ph), 111.5, 110.1 (C-5, C-8), 55.9, 55.8 (2ϫ OMe), 47.0 (C-3), 25.7
under vacuum to give the corresponding 1,2,3,4-tetrahydroisoquin-
oline.
(C-4) ppm. IR (neat): ν = 3056, 3003, 2944, 1639, 1600, 1560, 1496,
˜
6,7-Dimethoxy-N-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline
(4):[21] The isoquinoline 4 (1.4 g, 99%) was obtained from the salt
3 (2.0 g, 5.0 mmol) as a pale-yellow solid. M.p. 77–79 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.30–7.21 (m, 5 H, Ph), 6.58, 6.08
(2ϫ s, 1 H each, 5-H, 8-H), 4.16 (s, 1 H, 1-H), 3.82, 3.54 (2ϫ s, 3
H each, 2ϫ OMe), 3.20–3.05 (m, 2 H, 3-H, 4-H), 2.72 (dt, J =
15.6, 3.2 Hz, 1 H, 3Ј-H), 2.59 (dt, J = 10.7, 3.8 Hz, 1 H, 4Ј-H),
2.22 (s, 3 H, N-Me) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
1457, 1408, 1374 cm–1. EI-MS: m/z (%) = 268 (14), 267 (64) [M]+,
266 (100), 236 (17). HR-MS: calcd. for C17H17NO2 267.1259; found
267.1266.
6-Chloro-7-methoxy-1-phenyl-3,4-dihidroisoquinoline (7):[18] The
isoquinoline 7 (0.4 g, 42%) was obtained from the corresponding
amide[19] (1.0 mmol, 3.5 mmol) as a yellow oil, after purification
1
by column chromatography (SiO2; CH2Cl2). H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.60–7.55 (m, 2 H, Ph), 7.43–7.40 (m, 3 H, Ph), = 147.2, 146.9 (C-6, C-7), 143.7 (C-1Ј), 130.2, 126.4 (C-4a, C-8a),
7.26 (s, 1 H, 5-H), 6.80 (s, 1 H, 8-H), 3.79 (t, J = 7.3 Hz, 2 H, 3- 129.4, 128.1, 127.2 (CH Ph), 111.3, 110.5 (C-5, C-8), 70.9 (C-1),
H), 3.70 (s, 3 H, OMe), 2.67 (t, J = 7.3 Hz, 2 H, 4-H) ppm. 13C
55.6, 55.5 (2ϫ OMe), 52.1 (C-3), 44.2 (N-Me), 28.9 (C-4) ppm. IR
NMR (100 MHz, CDCl3, 25 °C): δ = 166.3 (C-1), 153.4 (C-7), (neat): ν = 3058, 3009, 2976, 2834, 1609, 1513, 1489, 1453,
˜
138.4, 131.8 (C-1Ј, C-8a), 129.5, 128.6, 128.2 (CH Ph), 128.9 (C-
5), 127.7, 124.6 (C-4a, C-6), 111.8 (C-8), 56.2 (OMe), 47.6 (C-3),
1365 cm–1. EI-MS: m/z (%) = 288 (4), 283 (20) [M]+, 282 (18), 207
(24), 206 (100). HR-MS: calcd. for C18H21NO2 283.1572; found
283.1574.
25.0 (C-4) ppm. IR (neat): ν = 3055, 2938, 1593, 1556, 1489, 1443,
˜
1390 cm–1. EI-MS: m/z (%) = 273 (22), 272 (43), 271 (62) [M]+, 270
(100), 240 (12), 192 (11). HR-MS: calcd. for C16H15ClNO [M +
H]+ 272.0837; found 272.0827.
6-Chloro-7-methoxy-N-methyl-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline (9):[19] The isoquinoline 9 (340 mg, 98%) was obtained
from the salt 8 (500 mg, 1.2 mmol) as a pale-yellow solid. M.p.
230–232 °C. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 7.47–7.34 (m,
5 H, Ph), 7.11 (s, 1 H, 5-H), 6.14 (s, 1 H, 8-H), 4.17 (s, 1 H, 1-H),
3.55 (s, 3 H, OMe), 3.20–3.01 (m, 2 H, 3-H, 4-H), 2.75–2.50 (m, 2
H, 3Ј-H, 4Ј-H), 2.21 (s, 3 H, N-Me) ppm. 13C NMR (50 MHz,
CDCl3, 25 °C): δ = 152.7 (C-7), 143.2 (C-1Ј), 138.0, 127.6 (C-4a,
C-8a), 129.5 (C-5), 129.4, 128.3, 127.5 (CH Ph), 120.2 (C-6), 112.1
(C-8), 71.0 (C-1), 55.9 (OMe), 51.8 (C-3), 44.1 (N-Me), 28.2 (C-4)
Preparation of N-Methyl-1-phenyl-3,4-dihydroisoquinolinium Salts 3
and 8: To a solution of the corresponding isoquinoline (18.7 mmol)
in dry acetone (60 mL) was added CH3I (6 mL, 96 mmol), and the
reaction mixture was refluxed for 1 h. After this time, the yellow
solid formed was filtered and the solution concentrated under vac-
uum to give the corresponding isoquinolinium salt.
6,7-Dimethoxy-N-methyl-1-phenyl-3,4-dihydroisoquinolinium Iodide
(3):[20] The isoquinolium salt 3 (7.3 g, 95%) was obtained from the
isoquinoline 2 (5.0 g, 18.7 mmol) as a yellow solid. M.p. 183–
ppm. IR (neat): ν = 3023, 2976, 1624, 1601, 1492, 1452, 1396 cm–1.
˜
EI-MS: m/z (%) = 289 (7), 288 (8), 287 (20) [M]+, 286 (15), 212
(35), 210 (100). HR-MS: calcd. for C17H19ClNO [M + H]+
288.1150; found 288.1149.
1
185 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.69–7.58 (m, 5
H, Ph), 6.97, 6.33 (2ϫ s, 1 H each, 5-H, 8-H), 4.47 (t, J = 8.1 Hz,
2 H, 3-H), 3.99, 3.70 (2ϫ s, 3 H each, 2ϫ OMe), 3.54 (s, 3 H, N-
Me), 3.51 (t, J = 8.1 Hz, 2 H, 4-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 172.7 (C-1), 156.3, 147.6 (C-6, C-7), 133.6 (C-
Preparation of N-Methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolinium
Salts 5a–i and 10: The corresponding halo derivative (2.1 mmol)
was added to a solution of the corresponding isoquinoline
1Ј), 131.6, 119.2 (C-4a, C-8a), 129.2, 128.8, 128.4 (CH Ph), 114.9, (1.8 mmol) in dried acetone (20 mL) under argon. After the mix-
110.8 (C-5, C-8), 56.7 (C-3), 55.6, 52.5 (2ϫ OMe), 46.6 (N-Me), ture had been stirred at room temperature for 24 h, a precipitate
25.4 (C-4) ppm. IR (neat): ν = 3020, 2995, 2933, 1630, 1598, 1559,
had formed that was filtered and washed with several portions of
˜
1491, 1455, 1381 cm–1. EI-MS: m/z (%) = 282 (4) [M]+, 281 (8), 267 diethyl ether. The acetone solution was reduced to 10 mL, and di-
(78), 266 (100), 208 (22), 206 (20), 204 (20), 127 (24). HR-MS:
calcd. for C18H20NO2 282.1494; found 282.1501.
ethyl ether was added to precipitate the remaining isoquinolinium
salt.
6-Chloro-7-methoxy-N-methyl-1-phenyl-3,4-dihydroisoquinolin- (؎)-trans-6,7-Dimethoxy-N-[(methoxycarbonyl)methyl]-N-methyl-1-
ium Iodide (8): The isoquinolium salt 8 (1.1 g, 92%) was obtained
phenyl-1,2,3,4-tetrahydroisoquinolinium Bromide (5a): The isoquin-
olinium salt 5a was obtained from the isoquinoline 4 (500 mg,
from the isoquinoline 7 (780 mg, 2.9 mmol) as a yellow solid. M.p.
1
167–169 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.79 (d, J = 1.8 mmol). The 1H NMR spectrum of the crude product indicated
8.1 Hz, 2 H, Ph), 7.64–7.56 (m, 3 H, Ph), 7.38 (s, 1 H, 5-H), 6.40 a mixture of stereoisomers 5a in a cis/trans ratio of 5:95. The major
(s, 1 H, 8-H), 4.53 (t, J = 8.1 Hz, 2 H, 3-H), 3.76 (s, 3 H, OMe), diastereoisomer 5a-trans (741 mg, 94%) was isolated by fractional
3.55 (s, 3 H, N-Me), 3.46 (t, J = 8.1 Hz, 2 H, 4-H) ppm. 13C NMR
(50 MHz, CDCl3, 25 °C): δ = 174.1 (C-1), 154.3 (C-7), 132.5 (C-
precipitation with diethyl ether as a pale-yellow solid. M.p. 131–
1
133 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.42–7.36 (m, 5
Eur. J. Org. Chem. 2010, 4393–4401
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4397

M. Valpuesta, M. Ariza, A. Díaz, R. Suau
H, Ph), 6.93 (s, 1 H, 1-H), 6.68 (s, 1 H, 5-H), 6.32 (s, 1 H, 8-H), (19), 296 (100), 283 (42), 282 (93), 206 (71). HR-MS: calcd. for
FULL PAPER
5.64 (d, J = 17.5 Hz, 1 H, α-H), 4.62 (d, J = 17.5 Hz, 1 H, αЈ-H),
4.36 (dd, J = 13.2, 5.1 Hz, 1 H, 3-H), 3.85, 3.64 (2ϫ s, 3 H each,
2ϫ OMe), 3.76 (s, 3 H, COOMe), 3.70–3.64 (m, 1 H, 3Ј-H), 3.36
(s, 3 H, N-Me), 3.22–3.05 (m, 2 H, 4-H, 4Ј-H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 165.2 (CO), 149.2, 148.6 (C-6, C-
7), 131.6 (C-1Ј), 130.5, 128.7 (CH Ph), 120.8, 120.1 (C-4a C-8a),
110.7, 110.1 (C-5, C-8), 73.7 (C-1), 57.1 (C-α), 55.7, 55.6 (2 ϫ
OMe), 52.8 (COOMe), 51.8 (C-3), 47.8 (N-Me), 23.3 (C-4) ppm.
C21H26NO3 340.1907; found 340.1900.
(؎)-trans-N-(Benzoylmethyl)-6,7-dimethoxy-N-methyl-1-phenyl-
1,2,3,4-tetrahydroisoquinolinium Bromide (5e): The isoquinolinium
salt 5e (826 mg, 95 %) was obtained from the isoquinoline 4
(500 mg, 1.8 mmol) as a pale-yellow solid. M.p. 139–140 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 8.12 (d, J = 8.1 Hz, 2 H, 2ЈЈ-
H, 6ЈЈ-H COPh), 7.62 (t, J = 8.1 Hz, 1 H, 4ЈЈ-H COPh), 7.49 (t, J
= 8.1 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H COPh), 7.47–7.41 (m, 5 H, Ph), 7.21
(s, 1 H, 1-H), 6.65 (s, 1 H, 5-H), 6.40 (s, 1 H, 8-H), 5.33–5.20 (m,
1 H, α-H), 4.69–4.66 (m, 2 H, 3-H, αЈ-H), 3.85, 3.69 (2ϫ s, 3 H
each, 2ϫ OMe), 3.74–3.64 (m, 1 H, 3Ј-H), 3.39 (s, 3 H, N-Me),
3.20–3.13 (m, 2 H, 4-H, 4Ј-H) ppm. 13C NMR (50 MHz, CDCl3,
25 °C): δ = 191.6 (CO), 149.3, 148.7 (C-6, C-7), 134.7, 132.0, 130.5,
128.8, 128.2 (CH Ph, COPh), 133.8, 132.6 (C-1Ј, C-1ЈЈ), 121.3,
120.3 (C-4a C-8a), 110.9, 110.1 (C-5, C-8), 74.0 (C-1), 61.7 (C-α),
55.7, 55.6 (2ϫ OMe), 51.7 (C-3), 48.0 (N-Me), 23.6 (C-4) ppm. IR
IR (neat): ν = 3040, 2934, 1745, 1612, 1517, 1456, 1369 cm–1. EI-
˜
MS: m/z (%) = 297 (15), 296 (72), 283 (28), 282 (67), 268 (66), 206
(100). HR-MS: calcd. for C21H26NO4 356.1862; found 356.1855.
(؎)-trans-N-(Carbamoylmethyl)-6,7-dimethoxy-N-methyl-1-
phenyl-1,2,3,4-tetrahydroisoquinolinium Iodide (5b): The isoquinol-
inium salt 5b (791 mg, 94%) was obtained from the isoquinoline 4
(500 mg, 1.8 mmol) as a white solid. M.p. 195–196 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 8.12 (s, 1 H, NH), 7.48–7.40 (m, 5
H, Ph), 6.73 (s, 1 H, 5-H), 6.51 (s, 1 H, 1-H), 6.27 (s, 1 H, 8-H),
6.18 (s, 1 H, NH), 4.85 (d, J = 14.2 Hz, 1 H, α-H), 4.73 (d, J =
14.2 Hz, 1 H, αЈ-H), 4.20–4.15 (m, 1 H, 3-H), 3.87, 3.65 (2ϫ s, 3
H each, 2ϫ OMe), 3.72–3.67 (m, 1 H, 3Ј-H), 3.46–3.38 (m, 1 H,
4-H), 3.26–3.20 (m, 1 H, 4Ј-H), 3.14 (s, 3 H, N-Me) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 165.4 (CO), 149.7, 149.0 (C-6, C-
7), 132.0 (C-1Ј), 131.0, 129.3 (CH Ph), 120.9, 120.6 (C-4a C-8a),
110.9, 110.5 (C-5, C-8), 74.3 (C-1), 59.1 (C-α), 56.0, 55.9 (2 ϫ
(neat): ν = 3032, 2975, 1683, 1597, 1583, 1495, 1451, 1370 cm–1.
˜
EI-MS: m/z (%) = 297 (19), 296 (100), 283 (12), 282 (24), 206 (83),
105 (15). HR-MS: calcd. for C26H28NO3 402.2069; found 402.2072.
(؎)-trans-6,7-Dimethoxy-N-methyl-N-(p-nitrobenzyl)-1-phenyl-
1,2,3,4-tetrahydroisoquinolinium Bromide (5f): The isoquinolinium
salt 5f (846 mg, 94 %) was obtained from the isoquinoline 4
(500 mg, 1.8 mmol) as a pale-yellow solid. M.p. 198–200 °C. 1H
NMR (400 MHz, CDCl3 + CD3OD, 25 °C): δ = 8.26 (d, J =
8.6 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 7.87 (d, J = 8.6 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H),
7.44–7.36 (m, 5 H, Ph), 6.79 (s, 1 H, 5-H), 6.34 (s, 1 H, 8-H), 6.10
(s, 1 H, 1-H), 5.39 (d, J = 12.9 Hz, 1 H, α-H), 5.00 (d, J = 12.9 Hz,
1 H, αЈ-H), 4.07–4.00 (m, 1 H, 3-H), 3.87, 3.67 (2ϫ s, 3 H each,
2ϫ OMe), 3.55–3.46 (m, 2 H, 3Ј-H, 4-H), 3.32–3.24 (m, 1 H, 4Ј-
OMe), 54.3 (C-3), 48.4 (N-Me), 23.6 (C-4) ppm. IR (neat): ν =
˜
3427, 3351, 3008, 2965, 2929, 1698, 1610, 1515, 1461, 1369,
1316 cm–1. EI-MS: m/z (%) = 341 (1) [M]+, 340 (2), 283 (27), 282
(43), 268 (100), 206 (98), 127 (15). HR-MS: calcd. for C20H25N2O3
341.1865; found 341.1869.
H), 2.91 (s, 3 H, N-Me) ppm. 13C NMR (100 MHz, CDCl3
+
(؎)-trans-6,7-Dimethoxy-N-[(NЈ,NЈ-dimethylcarbamoyl)methyl]-N-
methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolinium Iodide (5c): The
isoquinolinium salt 5c (803 mg, 90%) was obtained from the iso-
quinoline 4 (500 mg, 1.8 mmol) as a pale-yellow solid. M.p. 187–
CD3OD, 25 °C): δ = 149.8, 149.1, 149.0 (C-6, C-7, C-4ЈЈ), 134.4
(C-2ЈЈ, C-6ЈЈ), 134.0 (C-1ЈЈ), 132.0 (C-1Ј), 130.9, 129.2 (CH Ph),
124.1 (C-3ЈЈ, C-5ЈЈ), 121.2, 120.4 (C-4a C-8a), 110.7, 110.6 (C-5, C-
8), 73.5 (C-1), 61.9 (C-α), 55.9, 55.8 (2ϫ OMe), 52.7 (C-3), 46.9
1
189 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.34–7.26 (m, 5
(N-Me), 23.5 (C-4) ppm. IR (neat): ν = 3082, 2997, 1607, 1524,
˜
H, Ph), 6.83 (s, 1 H, 1-H), 6.67 (s, 1 H, 5-H), 6.21 (s, 1 H, 8-H),
5.22 (d, J = 16.1 Hz, 1 H, α-H), 4.63–4.56 (m, 1 H, 3-H), 4.60 (d,
J = 16.1 Hz, 1 H, αЈ-H), 3.76, 3.53 (2ϫ s, 3 H each, 2ϫ OMe),
3.56–3.49 (m, 1 H, 3Ј-H), 3.17–3.11 (m, 2 H, 4-H, 4Ј-H), 3.14 (s, 3
H, N-Me), 3.02, 2.83 (2ϫ s, 3 H each, CONMe2) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 163.1 (CO), 149.2, 148.5 (C-6, C-
7), 132.1 (C-1Ј), 130.4, 128.7 (CH Ph), 121.1, 120.5 (C-4a C-8a),
110.7, 110.2 (C-5, C-8), 73.3 (C-1), 57.0 (C-α), 55.8, 55.6 (2 ϫ
OMe), 52.5 (C-3), 48.0 (N-Me), 37.4, 35.6 (CONMe2), 23.5 (C-4)
1453, 1346 cm–1. EI-MS: m/z (%) = 283 (9), 206 (100), 136 (25).
HR-MS: calcd. for C25H27N2O4 419.1971; found 419.1968.
(؎)-trans-6,7-Dimethoxy-N-[(methoxycarbonyl)allyl]-N-methyl-1-
phenyl-1,2,3,4-tetrahydroisoquinolinium Bromide (5g): The iso-
quinolinium salt 5g (790 mg, 95%) was obtained from the isoquin-
1
oline 4 (500 mg, 1.8 mmol) as a white solid. M.p. 187–189 °C. H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.48–7.38 (m, 5 H, Ph), 6.95
(dt, J = 15.0, 7.5 Hz, 1 H, β-H), 6.70 (s, 1 H, 5-H), 6.65 (s, 1 H, 1-
H), 6.58 (d, J = 15.0 Hz, 1 H, γ-H), 6.35 (s, 1 H, 8-H), 5.40 (dd, J
= 14.0, 7.5 Hz, 1 H, α-H), 4.58 (dd, J = 14.0, 7.5 Hz, 1 H, αЈ-H),
3.88, 3.76, 3.67 (3ϫ s, 3 H each, 3ϫ OMe), 3.64 (m, 2 H, 3-H, 3Ј-
H), 3.24 (m, 2 H, 4-H, 4Ј-H), 3.14 (s, 3 H, N-Me) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 164.5 (CO), 149.4, 148.7 (C-6, C-
7), 132.4, 131.9 (C-β, C-γ), 132.3 (C-1Ј), 130.6, 128.9 (CH Ph),
121.3, 120.1 (C-4a C-8a), 110.8, 110.3 (C-5, C-8), 73.4 (C-1), 60.0
(C-α), 55.8, 55.7 (2ϫ OMe), 52.1 (C-3), 51.9 (COOMe), 47.5 (N-
ppm. IR (neat): ν = 3006, 2971, 1649, 1612, 1518, 1459, 1318 cm–1.
˜
EI-MS: m/z (%) = 283 (16), 282 (22), 268 (58), 206 (100), 127 (6).
HR-MS: calcd. for C22H29N2O3 369.2178; found 369.2186.
(؎)-trans-N-(Acetylmethyl)-6,7-dimethoxy-N-methyl-1-phenyl-
1,2,3,4-tetrahydroisoquinolinium Iodide (5d): The isoquinolinium
salt 5d (789 mg, 94 %) was obtained from the isoquinoline 4
(500 mg, 1.8 mmol) as a white solid. M.p. 185–187 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.48–7.40 (m, 5 H, Ph), 6.70, 6.69
(2ϫ s, 1 H each, 1-H, 5-H), 6.31 (s, 1 H, 8-H), 5.78 (d, J = 18.8 Hz,
1 H, α-H), 4.99 (d, J = 18.8 Hz, 1 H, αЈ-H), 4.42 (dd, J = 10.7,
3.8 Hz, 1 H, 3-H), 3.89, 3.68 (2ϫ s, 3 H each, 2ϫ OMe), 3.67–
3.59 (m, 1 H, 3Ј-H), 3.27 (s, 3 H, N-Me), 3.23–3.08 (m, 2 H, 4-H,
4Ј-H), 3.31 (s, 3 H, COMe) ppm. 13C NMR (50 MHz, CDCl3,
Me), 23.4 (C-4) ppm. IR (neat): ν = 3020, 3002, 2960, 1723, 1644,
˜
1610, 1518, 1458, 1379 cm–1. EI-MS: m/z (%) = 381 (1), 290 (15),
283 (11), 206 (100). HR-MS: calcd. for C23H28NO4 382.2013; found
382.2007.
(؎)-trans-N-Benzyl-6,7-dimethoxy-N-methyl-1-phenyl-1,2,3,4-tetra-
25 °C): δ = 200.1 (CO), 149.6, 149.0 (C-6, C-7), 131.6 (C-1Ј), 130.9, hydroisoquinolinium Bromide (5h): The isoquinolinium salt 5h
129.1 (CH Ph), 120.9, 120.3 (C-4a C-8a), 110.8, 110.5 (C-5, C-8), (727 mg, 89 %) was obtained from the isoquinoline 4 (500 mg,
73.7 (C-1), 64.0 (C-α), 56.0, 55.9 (2ϫ OMe), 52.4 (C-3), 47.9 (N- 1.8 mmol) as a white solid. M.p. 186–188 °C. 1H NMR (400 MHz,
Me), 29.5 (COMe), 23.6 (C-4) ppm. IR (neat): ν = 3007, 2911,
CDCl3, 25 °C): δ = 7.66 (d, J = 6.7 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 7.49–
7.34 (m, 8 H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H, Ph), 6.78 (s, 1 H, 5-H), 6.45 (s,
˜
1723, 1612, 1520, 1494, 1463, 1373 cm–1. EI-MS: m/z (%) = 297
4398
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4393–4401

1,2-Disubstituted 2,3,4,5-tetrahydro-1H-3-benzazepines
1 H, 1-H), 6.36 (s, 1 H, 8-H), 5.31 (d, J = 12.9 Hz, 1 H, α-H), 5.09 1 H, 2-H), 3.85, 3.73 (2ϫ s, 3 H each, 2ϫ OMe), 3.53 (s, 3 H,
(d, J = 12.9 Hz, 1 H, αЈ-H), 4.13–4.08 (m, 1 H, 3-H), 3.90, 3.69
(2ϫ s, 3H each, 2ϫ OMe), 3.56–3.41 (m, 2 H, 3Ј-H, 4-H), 3.26
COOMe), 3.25 (dd, J = 13.4, 8.3 Hz, 1 H, 4-H), 2.80–2.63 (m, 3
H, 5-H, 4Ј-H, 5Ј-H), 2.50 (s, 3 H, N-Me) ppm. 13C NMR
(dd, J = 15.0, 5.9 Hz, 1 H, 4Ј-H), 2.96 (s, 3 H, N-Me) ppm. 13C (100 MHz, CDCl3, 25 °C): δ = 172.5 (CO), 147.5, 146.8 (C-7, C-
NMR (100 MHz, CDCl3, 25 °C): δ = 149.3, 148.6 (C-6, C-7), 132.9 8), 140.4 (C-1Ј), 133.4, 131.0 (C-5a, C-9a), 128.2, 128.1, 126.3 (CH
(C-2ЈЈ, C-6ЈЈ), 132.5 (C-1Ј), 130.4, 130.3, 129.0, 128.8 (CH Ph, C-
3ЈЈ, C-4ЈЈ, C-5ЈЈ), 126.9 (C-1ЈЈ), 121.6, 120.4 (C-4a C-8a), 110.6, (COOMe), 50.9 (C-1), 50.3 (C-4), 45.7 (N-Me), 34.4 (C-5) ppm. IR
110.4 (C-5, C-8), 72.7 (C-1), 63.2 (C-α), 55.8, 55.7 (2ϫ OMe), 51.5 (neat): ν = 3085, 3058, 2990, 2957, 1720, 1608, 1579, 1509, 1459,
Ph), 114.1, 113.0 (C-6, C-9), 67.4 (C-2), 55.9, 55.8 (2ϫ OMe), 51.6
˜
(C-3), 46.4 (N-Me), 23.5 (C-4) ppm. IR (neat): ν = 3055, 3001, 1447, 1383 cm–1. EI-MS: m/z (%) = 355 (13) [M]+, 297 (31), 296
˜
2983, 1608, 1519, 1500, 1458, 1374 cm–1. EI-MS: m/z (%) = 283
(9), 206 (100), 91 (67). HR-MS: calcd. for C25H28NO2 374.2115;
found 374.2109.
(100). HR-MS: calcd. for C21H26NO4 [M + H]+ 356.1862; found
356.1872.
(1R*,2S*)-7,8-Dimethoxy-2-(methoxycarbonyl)-N-methyl-1-phen-
yl-2,3,4,5-tetrahydro-1H-3-benzazepine (1a-cis): The benzazepine
1a-cis (14 mg, 85%) was obtained from a mixture of diastereoiso-
mers 5a (cis/trans ratio 2:1; 30 mg, 0.07 mmol) as a white solid.
M.p. 132–134 °C. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 7.38–
7.20 (m, 5 H, Ph), 6.68 (s, 1 H, 6-H), 6.19 (s, 1 H, 9-H), 4.83 (br.
s, 1 H, 1-H), 4.07 (br. s, 1 H, 2-H), 3.87, 3.77 (2ϫ s, 3 H each, 2ϫ
OMe), 3.57 (s, 3 H, COOMe), 3.36–3.10 (m, 2 H, 4-H, 5-H), 2.91–
2.66 (m, 2 H, 4Ј-H, 5Ј-H), 2.53 (s, 3 H, N-Me) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 172.5 (CO), 147.5, 146.8 (C-7, C-
8), 140.4 (C-1Ј), 133.4, 130.9 (C-5a, C-9a), 129.0, 128.3, 126.6 (CH
Ph), 112.5, 112.3 (C-6, C-9), 67.7 (C-2), 55.9, 55.8 (2ϫ OMe), 51.6
(COOMe), 51.2 (C-1), 50.3 (C-4), 45.0 (N-Me), 34.4 (C-5) ppm. IR
(؎)-trans-N-Allyl-6,7-dimethoxy-N-methyl-1-phenyl-1,2,3,4-tetra-
hydroisoquinolinium Bromide (5i): The isoquinolinium salt 5i
(700 mg, 96 %) was obtained from the isoquinoline 4 (500 mg,
1.8 mmol) as a pale-yellow solid. M.p. 75–77 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.40–7.30 (m, 5 H, Ph), 6.70 (s, 1
H, 5-H), 6.39 (s, 1 H, 1-H), 6.29 (s, 1 H, 8-H), 6.09 (ddt, J = 16.7,
10.7, 7.2 Hz, 1 H, β-H), 5.74 (d, J = 16.7 Hz, 1 H, γ-H), 5.66 (d, J
= 10.7 Hz, 1 H, γЈ-H), 4.78 (dd, J = 13.4, 7.2 Hz, 1 H, α-H), 4.31
(dd, J = 13.4, 7.2 Hz, 1 H, αЈ-H), 3.82, 3.59 (2ϫ s, 3 H each, 2ϫ
OMe), 3.73–3.67 (m, 1 H, 3-H), 3.58–3.50 (m, 1 H, 3Ј-H), 3.24–
3.21 (m, 2 H, 4-H, 4Ј-H), 3.02 (s, 3 H, N-Me) ppm. 13C NMR
(50 MHz, CDCl3, 25 °C): δ = 149.4, 148.7 (C-6, C-7), 132.7 (C-1Ј),
130.4, 128.9 (CH Ph), 129.7, 124.6 (C-β, C-γ), 121.7, 120.4 (C-4a
C-8a), 110.9, 110.3 (C-5, C-8), 72.8 (C-1), 62.7 (C-α), 55.9, 55.8
(neat): ν = 3080, 3050, 2990, 2960, 1719, 1608, 1579, 1509, 1459,
˜
1445, 1373 cm–1. EI-MS: m/z (%) = 355 (5) [M]+, 297 (22), 296
(100). HR-MS: calcd. for C21H26NO4 [M + H]+ 356.1862; found
356.1872.
(2ϫ OMe), 51.5 (C-3), 47.4 (N-Me), 23.4 (C-4) ppm. IR (neat): ν
˜
= 3080, 3007, 2935, 1645, 1611, 1560, 1516, 1456, 1364 cm–1. EI-
MS: m/z (%) = 283 (12), 206 (100). HR-MS: calcd. for C21H26NO2
324.1958; found 324.1951.
(1R*,2R*)-2-Carbamoyl-7,8-dimethoxy-N-methyl-1-phenyl-2,3,4,5-
tetrahydro-1H-3-benzazepine (1b): The benzazepine 1b (38 mg,
85%) was obtained from the salt 5b (60 mg, 0.13 mmol) after re-
(؎)-trans-6-Chloro-7-methoxy-N-[(methoxycarbonyl)methyl]-N-
methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolinium Bromide (10): The
isoquinolinium salt 10 (409 mg, 93%) was obtained from the iso-
quinoline 9 (300 mg, 1.0 mmol) as a pale-yellow solid. M.p. 115–
1
fluxing for 1 h as a pale-yellow solid. M.p. 195–197 °C. H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.28–7.16 (m, 5 H, Ph), 6.90 (br. s,
1 H, NH), 6.62 (s, 1 H, 6-H), 6.57 (s, 1 H, 9-H), 5.43 (br. s, 1 H,
NH), 4.92 (d, J = 5.0 Hz, 1 H, 1-H), 4.01 (d, J = 5.0 Hz, 1 H, 2-
H), 3.85, 3.73 (2ϫ s, 3 H each, 2ϫ OMe), 3.05–2.95 (m, 3 H, 4-
H, 4Ј-H, 5-H), 2.81 (ddd, J = 15.0, 11.3, 5.4 Hz, 1 H, 5Ј-H), 2.27
(s, 3 H, N-Me) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
175.2 (CO), 147.4, 147.1 (C-7, C-8), 142.6 (C-1Ј), 132.4, 129.9 (C-
5a, C-9a), 128.3, 128.2, 126.1 (CH Ph), 115.2, 112.9 (C-6, C-9),
71.0 (C-2), 55.8, 55.7 (2ϫ OMe), 51.0 (C-4), 50.8 (C-1), 45.4 (N-
1
116 °C. H NMR (200 MHz, CDCl3, 25 °C): δ = 7.48–7.36 (m, 5
H, Ph), 7.29 (s, 1 H, 5-H), 7.16 (s, 1 H, 1-H), 6.44 (s, 1 H, 8-H),
5.76 (d, J = 17.4 Hz, 1 H, α-H), 4.47 (d, J = 17.4 Hz, 1 H, αЈ-H),
4.34 (dd, J = 13.1, 4.6 Hz, 1 H, 3-H), 3.70–3.60 (m, 1 H, 3Ј-H),
3.77 (s, 3 H, OMe), 3.67 (s, 3 H, COOMe), 3.38 (s, 3 H, N-Me),
3.19–3.06 (m, 2 H, 4-H, 4Ј-H) ppm. 13C NMR (50 MHz, CDCl3,
25 °C): δ = 164.9 (CO), 154.2 (C-7), 131.1, 130.7 (C-1Ј, C-5), 129.7,
128.8 (CH Ph), 123.4 (C-6), 120.6, 120.5 (C-4a, C-8a), 111.7 (C-8),
73.5 (C-1), 57.2 (C-α), 55.9 (OMe), 52.9 (COOMe), 51.6 (C-3), 47.8
Me), 33.2 (C-5) ppm. IR (neat): ν = 3408, 3312, 3016, 2952, 1660,
˜
1603, 1515, 1443, 1377, 1310 cm–1. EI-MS: m/z (%) = 340 (1)
[M]+, 297 (22), 296 (100). HR-MS: calcd. for C20H25N2O3 [M +
H]+ 341.1865; found 341.1862.
(N-Me), 22.6 (C-4) ppm. IR (neat): ν = 3025, 2924, 1747, 1605,
˜
1536, 1498, 1457, 1403 cm–1. EI-MS: m/z (%) = 303 (3), 302 (9),
301 (10), 300 (21), 289 (9), 288 (16), 287 (24), 286 (36), 274 (7), 272
(19), 212 (34), 210 (100), 209 (18), 208 (14). HR-MS: calcd. for
C20H23ClNO3 360.1366; found 360.1364.
(1R*,2R*)-7,8-Dimethoxy-2-(NЈ,NЈ-dimethylcarbamoyl)-N-methyl-
1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1c): The benzazep-
ine 1c (40 mg, 90 %) was obtained from the salt 5c (60 mg,
0.12 mmol) after refluxing for 1 h as a pale-yellow solid. M.p. 103–
General Method for the Stevens Rearrangement: DBU (49 µL,
0.31 mmol) was added to a solution of the corresponding salt
(0.23 mmol) in CH3CN (10 mL), and the resulting mixture was
stirred at room temperature for 30 min. After this time, the solvent
was evaporated in vacuo, and the crude reaction mixture was puri-
fied by column chromatography (SiO2; cyclohexane/EtOAc) to
yield the benzazepine.
1
105 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.33–7.20 (m, 5
H, Ph), 6.70 (s, 1 H, 6-H), 6.50 (s, 1 H, 9-H), 4.89 (d, J = 9.1 Hz,
1 H, 1-H), 4.14 (d, J = 9.1 Hz, 1 H, 2-H), 3.85, 3.64 (2ϫ s, 3 H
each, 2ϫ OMe), 3.24–3.09 (m, 2 H, 4-H, 5-H), 2.93–2.86 (m, 2 H,
4Ј-H, 5Ј-H), 2.83, 2.78 (2ϫ s, 3 H each, CONMe2), 2.28 (s, 3 H,
N-Me) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 172.0 (CO),
147.3, 147.2 (C-7, C-8), 141.4 (C-1Ј), 131.9, 131.3 (C-5a, C-9a),
129.3, 128.5, 126.8 (CH Ph), 112.6, 112.4 (C-6, C-9), 64.3 (C-2),
55.9, 55.8 (2ϫ OMe), 51.9 (C-4), 50.5 (C-1), 42.9 (N-Me), 37.2,
(1R*,2R*)-7,8-Dimethoxy-2-(methoxycarbonyl)-N-methyl-1-phen-
yl-2,3,4,5-tetrahydro-1H-3-benzazepine (1a-trans): The benzazepine
1a-trans (47 mg, 95 %) was obtained from the salt 5a (60 mg,
0.14 mmol) as a white solid. M.p. 122–124 °C. 1H NMR (400 MHz,
35.6 (CONMe ), 33.1 (C-5) ppm. IR (neat): ν = 3010, 2931, 1635,
˜
2
1512, 1450, 1398 cm–1. EI-MS: m/z (%) = 368 (1), 337 (3), 297 (20),
CDCl3, 25 °C): δ = 7.31–7.17 (m, 5 H, Ph), 6.64 (s, 1 H, 6-H), 6.51 296 (100). HR-MS: calcd. for C22H29N2O3 [M + H]+ 369.2178;
(s, 1 H, 9-H), 4.60 (d, J = 7.0 Hz, 1 H, 1-H), 4.16 (d, J = 7.0 Hz, found 369.2158.
Eur. J. Org. Chem. 2010, 4393–4401
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4399

M. Valpuesta, M. Ariza, A. Díaz, R. Suau
FULL PAPER
(1R*,2R*)-2-Acetyl-7,8-dimethoxy-N-methyl-1-phenyl-2,3,4,5-tetra-
hydro-1H-3-benzazepine (1d): The benzazepine 1d (61 mg, 86%)
was obtained from the salt 5d (100 mg, 0.21 mmol) as a pale-yellow
solid. M.p. 99–101 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
7.30–7.16 (m, 5 H, Ph), 6.64 (s, 1 H, 6-H), 6.47 (s, 1 H, 9-H), 4.65
147.5, 147.0 (C-7, C-8), 145.3 (C-α), 140.9 (C-1Ј), 133.1, 130.8 (C-
5a, C-9a), 128.2, 127.9, 126.2 (CH Ph), 123.7 (C-β), 114.8, 113.4
(C-6, C-9), 65.7 (C-2), 55.9, 55.8 (2ϫ OMe), 54.9 (COOMe), 51.5
(C-1), 49.8 (C-4), 45.5 (N-Me), 35.1 (C-5) ppm. IR (neat): ν = 3038,
˜
3010, 2951, 1720, 1606, 1515, 1495, 1444, 1375 cm–1. EI-MS: m/z
(d, J = 7.8 Hz, 1 H, 1-H), 3.93 (d, J = 7.8 Hz, 1 H, 2-H), 3.84, 3.68 (%) = 382 (24), 381 (100) [M]+, 350 (9), 322 (21), 290 (44), 253 (27),
(2ϫ s, 3 H each, 2ϫ OMe), 3.20–3.13 (m, 1 H, 4-H), 2.95–2.77
252 (61), 140 (48). HR-MS: calcd. for C23H27NO4 381.1940; found
(m, 3 H, 4Ј-H, 5-H, 5Ј-H), 2.33 (s, 3 H, N-Me), 2.04 (s, 3 H, 381.1956.
COCH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 209.6
(CO), 147.3, 147.1 (C-7, C-8), 141.3 (C-1Ј), 132.2, 131.4 0 (C-5a,
C-9a), 128.6, 128.4, 126.5 (CH Ph), 113.6, 112.8 (C-6, C-9), 73.8
(C-2), 55.8, 55.7 (2ϫ OMe), 51.9 (C-1), 49.6 (C-4), 44.1 (N-Me),
(1R*,2R*)-7-Chloro-8-methoxy-2-(methoxycarbonyl)-N-methyl-1-
phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (11): The benzazepine
11 (77 mg, 93 %) was obtained from the salt 10 (100 mg,
0.23 mmol) as a white solid. M.p. 100–102 °C. 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.36–7.17 (m, 5 H, Ph), 7.11 (s, 1 H, 6-H), 6.55
(s, 1 H, 9-H), 4.65 (d, J = 7.0 Hz, 1 H, 1-H), 4.15 (d, J = 7.0 Hz,
1 H, 2-H), 3.74, 3.55 (2ϫ s, 3 H each, 2ϫ OMe), 3.24–3.15 (m, 1
H, 4-H), 2.75–2.61 (m, 3 H, 4Ј-H, 5-H, 5Ј-H), 2.49 (s, 3 H, N-Me)
ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 172.2 (CO), 153.1
(C-8), 139.5, 139.0, 134.0 (C-1Ј, C-5a, C-9a), 130.7 (C-6), 128.3,
128.2, 126.6 (CH Ph), 120.3 (C-7), 114.2 (C-9), 67.4 (C-2), 56.1
(OMe), 51.7 (COOMe), 51.0, 50.0 (C-1, C-4), 45.6 (N-Me), 33.3
33.9 (C-5), 29.5 (COCH ) ppm. IR (neat): ν = 3070, 2938, 1706,
˜
3
1604, 1515, 1497, 1449, 1382 cm–1. EI-MS: m/z (%) = 297 (21), 296
(100). HR-MS: calcd. for C21H26NO3 [M + H]+ 340.1907; found
340.1904.
(1R*,2R*)-2-Benzoyl-7,8-dimethoxy-N-methyl-1-phenyl-2,3,4,5-
tetrahydro-1H-3-benzazepine (1e): The benzazepine 1e (75 mg,
89%) was obtained from the salt 5e (100 mg, 0.21 mmol) as a pale-
yellow oil. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.79 (d, J =
8.1 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H COPh), 7.48 (t, J = 8.1 Hz, 1 H, 4ЈЈ-H
COPh), 7.37 (t, J = 8.1 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H COPh), 7.25–7.12
(m, 5 H, Ph), 6.68 (s, 1 H, 6-H), 6.34 (s, 1 H, 9-H), 4.91 (d, J =
7.5 Hz, 1 H, 1-H), 4.86 (d, J = 7.5 Hz, 1 H, 2-H), 3.86, 3.63 (2ϫ
s, 3 H each, 2ϫ OMe), 3.28–3.22 (m, 1 H, 4-H), 3.03–2.96 (m, 2
H, 4Ј-H, 5-H), 2.92–2.85 (m, 1 H, 5Ј-H), 2.36 (s, 3 H, N-Me) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 200.5 (CO), 147.3, 146.9
(C-7, C-8), 141.3, 137.7 (C-1Ј, C-1ЈЈ), 132.5, 128.4, 128.3, 127.8,
126.3 (CH Ph, COPh), 131.9, 131.4 (C-5a, C-9a), 113.6, 112.8 (C-
6, C-9), 67.3 (C-2), 55.7, 55.6 (2ϫ OMe), 51.5 (C-1), 49.7 (C-4),
(C-5) ppm. IR (neat): ν = 3052, 2954, 1735, 1599, 1499, 1468, 1447,
˜
1385 cm–1. EI-MS: m/z (%) = 359 (2) [M]+, 303 (7), 302 (37), 301
(24), 300 (100). HR-MS: calcd. for C20H23ClNO3 [M + H]+
360.1366; found 360.1359.
General Procedure for the Synthesis of 1,1-Disubstituted Isoquinol-
ines 6a,b: A solution of the corresponding salt 5 (0.23 mmol) and
tBuOK (300 mg, 2.5 mmol) in dry THF (25 mL) was stirred at
room temperature for 1 h. The solvent was evaporated in vacuo,
and the residue obtained was dissolved in CH2Cl2 (20 mL) and
washed with water. The organic layer was dried with anhydrous
MgSO4 and the solvent evaporated under vacuum. The crude reac-
tion product was purified by column chromatography (SiO2;
CH2Cl2/MeOH) to yield the corresponding 1,1-disubstituted iso-
quinoline.
43.5 (N-Me), 33.9 (C-5) ppm. IR (neat): ν = 3056, 2998, 1654, 1595,
˜
1578, 1492, 1447, 1361 cm–1. EI-MS: m/z (%) = 297 (20), 296 (100).
HR-MS: calcd. for C26H27NO3 401.1991; found 401.1915.
(1R*,2R*)-7,8-Dimethoxy-N-methyl-2-(p-nitrobenzyl)-1-phenyl-
2,3,4,5-tetrahydro-1H-3-benzazepine (1f): The benzazepine 1f
(71 mg, 85%) was obtained from the salt 5f (100 mg, 0.20 mmol)
(1R*)-1-Benzyl-6,7-dimethoxy-N-methyl-1-phenyl-1,2,3,4-tetra-
hydroisoquinoline (6a): The isoquinoline 6a (75 mg, 91%) was ob-
tained from the salt 5h (100 mg, 0.22 mmol) as a pale-yellow solid.
1
as a yellow solid. M.p. 194–196 °C. H NMR (400 MHz, CDCl3,
1
25 °C): δ = 8.03 (d, J = 9.1 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 7.26 (d, J =
9.1 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 7.24–7.13 (m, 5 H, Ph), 6.74 (s, 1 H, 6-
H), 6.36 (s, 1 H, 9-H), 4.49 (d, J = 7.5 Hz, 1 H, 1-H), 4.40 (d, J =
7.5 Hz, 1 H, 2-H), 3.89, 3.62 (2ϫ s, 3 H each, 2ϫ OMe), 3.10–
2.99 (m, 2 H, 5-H, 5Ј-H), 2.93 (ddd, J = 17.2, 11.9, 5.1 Hz, 1 H, 4-
H), 2.72 (ddd, J = 11.9, 8.0, 5.1 Hz, 1 H, 4Ј-H), 2.13 (s, 3 H, N-
Me) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 148.3, 147.5,
147.0, 146.7 (C-1ЈЈ, C-7, C-8, C-4ЈЈ), 140.9 (C-1Ј), 132.2, 131.7 (C-
5a, C-9a), 129.8 (C-2ЈЈ, C-6ЈЈ), 128.8, 128.3, 126.5 (CH Ph), 122.9
(C-3ЈЈ, C-5ЈЈ), 113.8, 112.8 (C-6, C-9), 70.3 (C-2), 55.9, 55.8 (2ϫ
OMe), 54.4 (C-1), 50.6 (C-4), 45.2 (N-Me), 34.0 (C-5) ppm. IR
M.p. 95–97 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.29–7.19
(m, 5 H, Ph), 7.05–6.99 (m, 3 H, CH2Ph), 6.83 (d, J = 8.1 Hz, 2
H, CH2Ph), 6.35 (s, 1 H, 5-H), 6.29 (s, 1 H, 8-H), 3.84 (d, J =
13.4 Hz, 1 H, α-H), 3.80, 3.62 (2ϫ s, 3 H each, 2ϫ OMe), 3.23 (d,
J = 13.4 Hz, 1 H, αЈ-H), 2.76 (ddd, J = 11.8, 10.2, 3.8 Hz, 1 H, 3-
H), 2.56 (dt, J = 11.8, 4.8 Hz, 1 H, 3Ј-H), 2.43 (dt, J = 15.0, 4.8 Hz,
1 H, 4-H), 2.27 (ddd, J = 15.0, 10.2, 4.8 Hz, 1 H, 4Ј-H), 2.17 (s, 3
H, N-Me) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 146.8,
146.6 (C-6, C-7), 145.3, 138.5 (C-1Ј, C-1ЈЈ), 132.5, 129.3 (C-4a C-
8a), 130.9, 128.4, 127.3, 126.7, 126.2, 125.4 (CH Ph, CH2Ph), 112.3,
109.7 (C-5, C-8), 66.6 (C-1), 55.8, 55.5 (2ϫ OMe), 47.1 (C-3), 42.2
(neat): ν = 3019, 2934, 1602, 1513, 1460, 1449, 1377 cm–1. EI-MS:
˜
(N-Me), 38.9 (C-α), 29.4 (C-4) ppm. IR (neat): ν = 3055, 3001,
˜
m/z (%) = 419 (15), 418 (57) [M]+, 362 (25), 328 (19), 327 (100).
HR-MS: calcd. for C25H27N2O4 [M + H]+ 419.1971; found
419.1978.
2980, 1607, 1510, 1494, 1462, 1367 cm–1. EI-MS: m/z (%) = 283
(17), 282 (100) 91 (13). HR-MS: calcd. for C25H27NO2 373.2042;
found 373.2056.
(1R*,2R*)-7,8-Dimethoxy-2-[(methoxycarbonyl)allyl]-N-methyl-1-
phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1g): The benzazepine
1g (70 mg, 84 %) was obtained from the salt 5g (100 mg,
0.22 mmol) as a pale-yellow solid. M.p. 89–91 °C. 1H NMR
(1R*)-1-Allyl-6,7-dimethoxy-N-methyl-1-phenyl-1,2,3,4-tetrahydro-
isoquinoline (6b): The isoquinoline 6b (34 mg, 81%) was obtained
from the salt 5i (51 mg, 0.13 mmol) as a yellow oil. 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.29–7.11 (m, 5 H, Ph), 6.57 (s, 1
(200 MHz, CDCl3, 25 °C): δ = 7.31–7.13 (m, 5 H, Ph), 6.85 (dd, J H, 5-H), 6.28 (s, 1 H, 8-H), 5.62 (ddd, J = 17.1, 9.8, 7.3 Hz, 1 H,
= 15.7, 8.5 Hz, 1 H, β-H), 6.65 (s, 1 H, 6-H), 6.50 (s, 1 H, 9-H),
5.91 (d, J = 15.7 Hz, 1 H, α-H), 4.09 (d, J = 5.5 Hz, 1 H, 1-H)
4.07–4.00 (m, 1 H, 2-H), 3.87, 3.77, 3.68 (3ϫ s, 3 H each, 3ϫ
β-H), 5.00 (d, J = 17.1 Hz, 1 H, γ-H), 4.90 (d, J = 9.8 Hz, 1 H, γЈ-
H), 3.85, 3.61 (2ϫ s, 3 H each, 2ϫ OMe), 3.35 (dd, J = 14.6,
7.3 Hz, 1 H, α-H), 3.04–2.64 (m, 5 H, αЈ-H, 3-H, 3Ј-H, 4-H, 4Ј-H),
OMe), 2.92–2.48 (m, 4 H, 4-H, 4Ј-H, 5-H, 5Ј-H), 2.31 (s, 3 H, N- 2.09 (s, 3 H, N-Me) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ =
Me) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 166.2 (CO),
147.1, 147.0 (C-6, C-7), 143.6 (C-1Ј), 135.9 (C-β), 132.5, 128.4 (C-
4400
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4393–4401

1,2-Disubstituted 2,3,4,5-tetrahydro-1H-3-benzazepines
Webb, N. R. A. Beeley, M. Martin, M. Morgan, S. Espitia,
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4a C-8a), 128.7, 127.2, 126.4 (CH Ph), 116.1 (C-γ), 111.5, 110.2
(C-5, C-8), 65.7 (C-1), 55.9, 55.6 (2ϫ OMe), 47.0 (C-3), 40.7 (N-
Me), 38.3 (C-α), 29.1 (C-4) ppm. IR (neat): ν = 3080, 3067, 2978,
˜
1637, 1608, 1509, 1492, 1455, 1365 cm–1. EI-MS: m/z (%) = 283
(30), 282 (100). HR-MS: calcd. for C21H26NO2 [M + H]+ 324.1963;
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Supporting Information (see footnote on the first page of this arti-
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Acknowledgments
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Received: April 14, 2010
Published Online: July 1, 2010
Eur. J. Org. Chem. 2010, 4393–4401
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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