Asymmetric synthesis of 3- or 4-alkyl or arylbenzo[c]azepines

Article abstract of DOI:10.1016/j.tetasy.2009.07.015

Two flexible routes for the stereoselective synthesis of a variety of 3- or 4-alkylated or arylated tetrahydrobenzazepines have been developed. The key steps are the highly diastereoselective metallation/alkylation reaction and 1,2-addition processes applied to stereopure SAMP hydrazones combined with a cyclomethylenation reaction.

Full text of DOI:10.1016/j.tetasy.2009.07.015

Tetrahedron: Asymmetry 20 (2009) 1903–1911
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of 3- or 4-alkyl or arylbenzo[c]azepines
*
David Dumoulin, Stéphane Lebrun, Axel Couture , Eric Deniau, Pierre Grandclaudon
Université des Sciences et Technologies de Lille 1, LCOP, Bâtiment C3(2), 59655 Villeneuve d’Ascq, France
CNRS, UMR 8009 ‘Chimie Organique et Macromoléculaire’, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Two flexible routes for the stereoselective synthesis of a variety of 3- or 4-alkylated or arylated tetra-
hydrobenzazepines have been developed. The key steps are the highly diastereoselective metallation/
alkylation reaction and 1,2-addition processes applied to stereopure SAMP hydrazones combined with
a cyclomethylenation reaction.
Received 22 June 2009
Accepted 1 July 2009
Available online 2 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
d
a
Benzazepines play an important role in heterocyclic chemistry
because this ring system lies at the heart of a great variety of
poly and diversely functionalized models endowed with profound
chemotherapeutic properties.1 Thus compounds containing the
benzazepine skeleton, mainly at the tetrahydro level, display
important physiological properties and are known to exhibit strong
neuroleptic and neurotropic activities.2 Some representatives have
been found to display anti-HIV activity,3 to promote healing of skin
wounds4 and to treat cardiovascular diseases, especially glaucoma
and hypertension.5 Compounds of this class are also used as anti-
arrythmic6 and CNS agents,7 as inhibitors of PNMT8 and are recom-
mended for the treatment of stomach disorders.9 Finally the
benzazepine nucleus represents the main structural unit of many
naturally occurring molecules, namely those extracted from Cepha-
lotaxus Harringtonia, Papaveraceae and the Amaryllidaceae alkaloids
which could be used in the treatment of Alzheimer’s disease,10 the
most common cause of elderly dementia. Due to the diverse biolog-
ical activities of many of their derivatives the chemistry of 2-ben-
zazepines has been the focus of new synthetic methodologies
during the past decades1 and organic chemists have at their dis-
posal a great number of synthetic methods for the preparation of
these azaheterobicyclic compounds.
N
c
b
Figure 1.
ring expansion methods applied to tetralones (Schmidt rearrange-
ment),11 oxazepinones,12 benzopyranones13 and by a cyclopropa-
nation/ring enlargement of 1,2-dihydroisoquinolones.14 All of
these methods are simple but have been claimed to proceed with
the varying degrees of success. Furthermore their applicability is
unsatisfactory mainly because of restrictions in the choice of sub-
stituents, namely in their nature and position on the azepine ring
system. Finally none of the annulation techniques allows control
of stereogenic centres on the seven-membered azaheterocyclic
unit. Despite the great progress made in asymmetric synthesis in
recent decades few flexible methods are indeed available for the
asymmetric synthesis of alkylated or arylated benzazepines in high
enantiomeric excess. To our knowledge the 1-alkyl derivatives
have been obtained by metallation/alkylation of chiral benzaze-
pine formamidines15 but this method could not be extended to
the asymmetric synthesis of the 3- and 4-substituted analogues.
Therefore the development of synthetic methodologies which
may find generality for constructing a variety of benzo[c]azepines
with alkyl or aryl appendages at C3 or C4 in a stereo and enantio-
selective manner constitutes an area of current interest.
Synthetic routes to the construction of these compounds can be
cursorily classified into two main categories which mainly differ in
the nature of the bond formed in the ultimate step. Thus the forma-
tion of the C–N bond a or b (Fig. 1) can be secured by cyclization of
suitably ortho-disubstituted benzenes whereas the seven-mem-
bered heterocyclic ring has been accessed by creation of the c or
d bond through intramolecular C-aryl coupling reactions.1 Alterna-
tively these compounds have also been obtained by a number of
2. Results and discussion
Herein we report on a straightforward, feasible and highly
stereoselective route to 4- or 3-alkyl(aryl)benzo[c]azepines 1, 2,
respectively. This new synthetic route which is depicted retrosyn-
thetically in Scheme 1 hinges upon combinations of the highly dia-
stereoselective metallation/alkylation reaction (paths a1 and a2)
* Corresponding author. Tel.: +33 (0) 3 20 43 44 32; fax: +33 (0) 3 20 33 63 09.
E-mail address: axel.couture@univ-lille1.fr (A. Couture).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.015

1904
D. Dumoulin et al. / Tetrahedron: Asymmetry 20 (2009) 1903–1911
or nucleophilic 1,2-addition reaction (path b) to chiral aliphatic
hydrazones 3, 4 with a cyclomethylenation reaction. These pro-
cesses should give access to the diastereochemically pure cyclic
hydrazines 5, 6, which are suitable candidates for the asymmetric
synthesis of the title compounds 1, 2, upon cyclization of the preli-
minary formed diastereopure hydrazines 7 and 8, respectively.
Stereopure hydrazines (S,R)-7 or (S,S)-7 would be in turn obtained
by reduction of the corresponding hydrazones 9 which could be
assembled through the reverse sequences depicted in synthetic
pathways a1 and a2 (Scheme 1).
The first facet of the planned asymmetric synthesis of (R)-1 or
(S)-1 was then the elaboration of the diastereochemically pure
alkylated or arylated hydrazones 9. Initially the appropriate alde-
hydes 10i,j and 11d–g were converted into the corresponding chi-
ral hydrazones (S)-3i,j and (S)-4d–g, respectively, by simply mixing
the enantiomerically pure hydrazine (S)-(ꢀ)-1-amino-2-(methoxy-
methyl)pyrrolidine (SAMP) with the easily accessible or commer-
cially available aldehydes 10 and 11 (Scheme 2, Table 1). The
next step was the creation of the stereogenic centre at the b-posi-
tion to the nitrogen atom, that is, at C4 in the final compounds 1,
one of the major synthetic tasks in the synthesis of the targeted
compounds. This operation was secured by taking advantage of
the high level of diastereoselectivity observed upon the deprotona-
almost quantitative yields of the corresponding hydrazines (R,S)-
7a–d,e,g or (S,S)-7d,f (Scheme 2). Owing to the sensitivity of these
NH free hydrazines the reduced compounds were used in the next
step without further purification. Cyclomethylenation of the
unprotected alkyl hydrazines (R,S)-7a–d,e,g or (S,S)-7d,f proceeded
smoothly by making use of chloromethylmethyl ether (MOMCl) in
acetic acid18 to provide moderate to good yields of the desired cyc-
lic hydrazines (R,S)-5a–d,e,g and (S,S)-5d,f as the sole diastereoiso-
mers detectable by NMR upon flash chromatographic treatment.
The subsequent removal of the chiral auxiliary was readily
achieved by basic treatment of the borane. THF complex of (R,S)-
5a-d,e,g and (S,S)-5d,f effected N-N bond cleavage to deliver the
virtually enantiopure (R)-1a–d,e,g or (S)-1d,f albeit in moderate
yields (Scheme 2, Table 1).
The synthetic route leading to the 3-substituted derivatives 2
(retrosynthetic Scheme 1, path b) was significantly shorter. The
key step is based upon the nucleophilic 1,2-addition of organome-
tallic reagents to SAMP hydrazones which are known to proceed in
a highly stereoselective manner (de P 96%)16,19 with the best re-
sults being obtained using organolithium or organocerium re-
agents.16,20,21 The chiral hydrazones 3i,j prepared as previously
described were then allowed to react with methyl or hexyllithium
to afford the diastereochemically enriched free NH hydrazines
(R,S)-8a,d,h which were treated with MOMCl in AcOH to provoke
the cyclomethylenation reaction. This operation gave rise to the
diastereopure cyclic hydrazines (R,S)-6a,d,h (de P 96% after chro-
matographic treatment) making evident the high selectivity of
the diastereofacial 1,2-addition process allowing introduction of
the absolute stereochemistry at this stage of the sequence. Treat-
ment of compounds 6a,d,h with BH3ꢁTHF triggered the release of
the chiral appendage and this operation delivered very satisfactory
yields of the virtually enantiopure NH free 3-alkylbenzazepines
(R)-2a,d,h (Scheme 3, Table 2).
tion/alkylation process
a to the C@N bond of chiral hydrazones, a
property aptly exploited by Enders.16 Deprotonation of (S)-3i,j with
lithium diisopropylamide (LDA) followed by alkylation with a vari-
ety of alkyl halides 13a–c led to the diastereochemically enriched
alkylated hydrazones (R,S)-9a–d. Alternatively the same reaction
sequence involving hydrazones (S)-4d–g and benzyl bromides
12i–l delivered excellent yields of the alkylated hydrazones (S,S)-
9d,f and (R,S)-9e,g (Scheme 2, Table 1). SAMP derivatives of this
type are usually converted into the corresponding
a-substituted
ketone as a reliable standard procedure for the determination of
absolute configuration of chiral compounds.17 The hydrazone pre-
cursors 9 were essentially obtained as a single diastereoisomer
detectable by NMR (de P 96% after chromatographic treatment)
making the high selectivity of the initial metallation/alkylation se-
quence evident.
3. Conclusion
In conclusion we have devised a new, convenient and flexible
method for the highly diastereo- and enantioselective synthesis
of (R) and (S)-4-alkyl and aryl-2-benzazepines and of the (R)-3-
For the synthesis of title compounds 1, hydrazones (R,S)-9a–
d,e,g or (S,S)-9d,f were subsequently reduced with LiAlH4 to afford
R1
R1
R2
R2
R6
N
R6
path b
R6M
R3
HN
R3
6 R7 = SMP
2 R7 = H
R1
R4
R7
R4
R1
SMP
R4
R2
R3
8
N
SMP
R1
R1
R4
R5
(R or S)
R5
R5
3
R2
R3
R2
R3
R2
R3
(R or S)
(R or S)
path a1
R5X
N
N
HN
R7
R4
R4
SMP
SMP
7
9
5 R7 = SMP
1 R7 = H
path a2
R5
R1
R4
R2
R3
OMe
Br
+
SMP =
N
N
SMP
4
Scheme 1.

D. Dumoulin et al. / Tetrahedron: Asymmetry 20 (2009) 1903–1911
1905
OMe
H2N
N
1. LDA , THF
R1
R1
0 ºC to -90 ºC
CH2Cl2 , MgSO4
r.t. , 12 h
R2
R3
2. R5X (13a-c)
R2
R3
O
N
SMP
R4
R4
R1
R4
10i,j
3i,j
R5
R2
R3
(R or S)
1. LDA , THF
N
LiAlH4
0 ºC to -90 ºC
SMP
(2 equiv) ,
THF ,
OMe
2.
R1
9a-g
H2N
r.t. , 12 h
R2
R3
N
Br
R5
R5
CH2Cl2 , MgSO4
r.t. , 12 h
R1
R4
R4
R5
12i-l
R2
R3
(R or S)
O
N
SMP
4d-g
HN
SMP
11d-g
7a-g
MOMCl
(1equiv)
1. BH3.THF (10 equiv)
THF , 0 ºC , then , 48 h
R1
R4
R1
AcOH ,
Δ
R5
R5
reflux ,1h ,
then r.t. , 1 h
R2
R3
R2
R3
Δ
2. 10% aq NaOH , , 1 h
(R or S)
(R or S)
N
N
SMP
H
R4
1a-g
5a-g
Scheme 2.
Table 1
Hydrazones 3, 4, 9 and benzazepines 5 and 1 prepared from 10 and 11 via paths a1 and a2
Path
R1
R2
R3
R4
R5
Hydrazones
3, 4 (yield %)
Halides
13, 12
Hydrazones
Benzazepines
Benzazepinesc
1 (yield %)
9 (yield %)a
5 (yield %)a,b
a1
a1
a1
a1
a2
a2
a2
a2
H
H
H
H
H
H
MeO
H
MeO
MeO
MeO
MeO
MeO
MeO
MeO
OCH2O
MeO
MeO
MeO
MeO
MeO
MeO
H
MeO
MeO
MeO
H
H
MeO
H
Me
Bn
CH2OMe
Me
Me
(S)-3i (68)
(S)-3i
(S)-3i
(S)-3j (74)
(S)-4d (89)
(S)-4e (87)
(S)-4f (85)
(S)-4g (78)
13a
13b
13c
13a
12j
12i
12k
12l
(R,S)-9a (57)
(R,S)-9b (42)
(R,S)-9c (51)
(R,S)-9d (59)
(S,S)-9d (62)
(R,S)-9e (47)
(S,S)-9f (57)
(R,S)-9g (55)
(R,S)-5a (50)
(R,S)-5b (44)
(R,S)-5c (53)
(R,S)-5d (52)
(S,S)-5d (54)
(R,S)-5e (46)
(S,S)-5f (58)
(R,S)-5g (42)
(R)-1a (58)
(R)-1b (48)
(R)-1c (49)
(R)-1d (53)
(S)-1d (55)
(R)-1e (48)
(S)-1f (52)
(R)-1g (51)
Ph
C5H11
(CH2)2OBn
H
a
Yield of isolated (S,S) or (S,R) diastereomer (de P 96%).
Over two steps.
Ee P 96% determined by chiral HPLC (Chiracel OD).
b
c
alkyl analogues. The key steps are the highly diastereoselective
metallation/alkylation and nucleophilic 1,2-addition to SAMP
hydrazones combined with a cyclomethylenation reaction to se-
cure the formation of the azepine ring system. Owing to the avail-
ability of the RAMP chiral auxiliary we believe that this synthetic
strategy should also allow for the assembly of both antipodes of
these alkyl(aryl)ated benzazepines.
nal tetramethylsilane; Coupling constants (J) are rounded to the
nearest 0.1 Hz. Optical rotations were measured on a Perkin–Elmer
343 polarimeter. Elemental analyses were obtained using a Carlo-
Erba CHNS-11110 equipment. The silica gel used for flash column
chromatography was Merck Kieselgel of 0.040–0.063 mm particle
size. Dry glassware was obtained by oven-drying and assembly un-
der argon (Ar). Ar was used as the inert atmosphere and was
passed through a drying tube to remove moisture. The glassware
was equipped with rubber septa and reagent transfer was per-
formed by syringe techniques. Tetrahydrofuran (THF) was distilled
from sodium benzophenone ketyl immediately before use.
Carboxaldehydes 10i,22 10j23 and 11g24 were prepared accord-
ing to reported procedures. The benzyl bromides 12i,25 12j,26
12k27 and 12l28 were synthesized following the literature
methods.
4. Experimental
4.1. General
Melting points were determined on a Reichert-Thermopan
apparatus and are uncorrected. NMR spectra were recorded on
Bruker AM 300 spectrometer. They were referenced against inter-

1906
D. Dumoulin et al. / Tetrahedron: Asymmetry 20 (2009) 1903–1911
1. R6Li (3 equiv) ,
THF ,
4.2.3. N-[3-(3,4-Dimethoxyphenyl)propylidene]-[(S)-2-meth-
oxymethylpyrrolidin-1-yl]amine 3j
2.27 g (74%); ½a 2D5
ꢂ
¼ ꢀ69:8 (c 1.01, CHCl3); 1H NMR (300 MHz,
R1
R4
R1
R4
-78 ºC to r.t.
R2
R3
R2
R3
2. H3O+
CDCl3) d: 1.63–2.04 (m, 4H, 2 ꢃ CH2), 2.46–2.59 (m, 2H, CH2),
2.65–2.84 (m, 3H:2H, ArCH2 + 1H, CH2N), 3.39 (s, 3H, OCH3),
3.27–3.49 (m, 3H:2H, CH2O + 1H, CH2N), 3.51–3.76 (m, 1H, CH),
3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.66 (t, J = 5.1, 1H, CH@N),
6.71–6.88 (m, 3H, Harom); 13C NMR (75 MHz, CDCl3) d: 22.2 (CH2),
26.6 (CH2), 33.7 (CH2), 35.1 (ArCH2), 50.4 (CH2N), 55.8 (OCH3),
55.9 (OCH3), 59.2 (OCH3), 63.5 (CH), 74.8 (CH2O), 111.1 (CH),
111.7 (CH), 120.2 (CH), 134.3 (C), 137.7 (CH@N), 147.1 (C), 148.7
(C). Anal. Calcd for C17H26N2O3: C, 66.64; H, 8.55; N, 9.14. Found:
C, 66.47; H, 8.44; N, 8.88.
R6
N
HN
SMP
SMP
3i,j
8a,d,h
R1
MOMCl (1equiv) , ACOH ,
reflux ,1 h ,then r.t. , 1 h
R2
R3
R6
N
R4
SMP
4.2.4. [(S)-2-Methoxymethylpyrrolidin-1-yl]-N-propylidene-
amine 4d
6a,d,h
1.51 g (89%); ½a 2D5
ꢂ
¼ ꢀ142:8 (c 1.28, CHCl3) {lit.:29
½
a 2D3
ꢂ
¼ ꢀ143:3
(c 1.11, CHCl3)}.
1. BH3.THF (10 equiv) , THF , 0 ºC ,
then Δ , 48 h
2. 10% aq NaOH , Δ , 1 h
R1
R4
R2
R3
4.2.5. [(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[2-phenylethyl-
R6
idene]amine (4e)30
2.02 g (87%); ½a 2D5
ꢂ
¼ ꢀ115:7 (c 0.99, CHCl3).
N
H
4.2.6. N-Heptylidene-[(S)-2-methoxymethylpyrrolidin-1-yl]-
2a,d,h
amine 4f
1.92 g (85%); ½a 2D5
ꢂ
¼ ꢀ105:3 (c 1.42, CHCl3) {lit.:31
½
a 2D2
ꢂ
¼ ꢀ106:6
Scheme 3.
(neat)}.
4.2.7. N-(4-Benzyloxybutylidene)-[(S)-2-methoxymethylpyrr-
4.2. Synthesis of the SAMP-hydrazones 3i,j and 4d–g
4.2.1. General procedure
A solution of the appropriate carboxaldehydes 10i,j or 11d–g
(0.10 mmol), SAMP (1.56 g, 0.12 mmol) and MgSO4 (500 mg) in
CH2Cl2 (50 mL) was stirred at rt for 12 h. MgSO4 was filtered off
and the solvent was evaporated under vacuum. The crude residue
was purified by flash column chromatography on silica gel (ethyl
acetate/hexanes, 40:60, as eluent) to yield hydrazones 3i,j as yel-
low viscous oil or 4d–g as colourless viscous oil.
olidin-1-yl]amine 4g
2.27 g (78%); ½a 2D5
ꢂ
¼ ꢀ83:0 (c 0.79, CHCl3) {lit.:32
½
a 2D5
ꢂ
¼ ꢀ84:0
(c 3.80, CHCl3)}.
4.3. Alkylation of the SAMP-hydrazones 3i,j and 4d–g (path a)
4.3.1. General procedure
A solution of n-BuLi (4.42 mL, 7.08 mmol, 1.6 M solution in
hexanes) was added dropwise to a stirred solution of diisopro-
pylamine (715 mg, 1.0 mL, 7.08 mmol) in dry THF (5 mL) at
0 °C under Ar. The mixture was stirred for 15 min at 0 °C then
cooled to ꢀ78 °C. A solution of the appropriate hydrazones 3i,j
or 4d–g (7.08 mmol) in THF (5 mL) was slowly added and the
mixture was stirred at ꢀ78 °C for 45 min. The mixture was al-
lowed to warm to 0 °C and stirred for an additional 1 h at
0 °C. The mixture was recooled to –90 °C and a solution of the
appropriate alkyl halides 13a–c or 12i–l (7.1 mmol) in dry THF
(5 mL) was added dropwise. After stirring for 1 h at –90 °C, the
temperature was allowed to rise to rt and stirring was main-
tained overnight. The mixture was then quenched with aqueous
sat NaHCO3 solution (20 mL) and extracted with ethyl acetate
(3 ꢃ 10 mL). The combined organic layers were washed with
brine (20 mL) and water (20 mL), then dried over MgSO4, con-
4.2.2. [(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[3-(3,4,5-trime-
thoxyphenyl)propylidene]amine 3i
2.29 g (68%); ½a 2D5
ꢂ
¼ ꢀ73:5 (c 1.07, CHCl3); 1H NMR (300 MHz,
CDCl3) d: 1.72–2.04 (m, 4H, 2 ꢃ CH2), 2.47–2.63 (m, 2H, CH2),
2.67–2.85 (m, 3H:2H, ArCH2 + 1H, CH2N), 3.39 (s, 3H, OCH3),
3.29–3.50 (m, 3H, 2H; CH2O + 1H, CH2N), 3.51–3.65 (m, 1H, CH),
3.84 (s, 3H, OCH3), 3.86 (s, 6H, 2 ꢃ OCH3), 6.45 (s, 2H, Harom),
6.68 (t, J = 5.2 Hz, 1H, CH@N); 13C NMR (75 MHz, CDCl3) d: 22.2
(CH2), 26.6 (CH2), 34.5 (CH2), 34.9 (ArCH2), 50.4 (CH2N), 56.0
(2 ꢃ OCH3), 59.2 (OCH3), 60.9 (OCH3), 63.5 (CH), 74.9 (CH2O),
105.2 (2 ꢃ CH), 137.4 (2 ꢃ C), 137.5 (CH@N), 153.1 (2 ꢃ C)). Anal.
Calcd for C18H28N2O4: C, 64.26; H, 8.39; N, 8.33. Found: C, 64.13;
H, 8.44; N, 8.13.
Table 2
Benzazepines 6, 2 prepared via path b
R1
R2
R3
R4
R6
Hydrazones
3
R6Li
Benzazepines
Benzazepinesc
2 (yield %)
6 (yield %)a,b
H
H
H
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H
H
Me
Me
C6H13
(S)-3i
(S)-3j
(S)-3j
CH3Li
CH3Li
C6H13Li
(R,S)-6a (47)
(R,S)-6d (48)
(R,S)-6h (50)
(R)-2a (58)
(R)-2d (53)
(R)-2h (56)
a
Yield of isolated (R,S) diastereomer (de P 96%).
Over two steps.
Ee P 96% determined by chiral HPLC (Chiracel OD).
b
c

D. Dumoulin et al. / Tetrahedron: Asymmetry 20 (2009) 1903–1911
1907
centrated and purified by flash column chromatography on silica
gel (ethyl acetate/hexanes, 30:70, as eluent).
2.48 (dd, J = 8.0, 13.0 Hz, 1H, ArCH2), 2.54–2.68 (m, 2H:1H,
CH + 1H, NCH2), 2.78 (dd, J = 6.0, 13.0 Hz, 1H, ArCH2), 3.23–3.44
(m, 3H, OCH2 + CH), 3.34 (s, 3H, OCH3), 3.52 (dd, J = 3.7, 8.9 Hz,
1H, NCH2), 3.81 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.52 (d,
J = 6.0 Hz, 1H, CH@N), 6.62 6–6.79 (m, 3H, Harom); 13C NMR
(75 MHz, CDCl3): 18.3 (CH3), 22.1 (CH2), 26.5 (CH2), 38.8 (CH),
41.3 (ArCH2), 50.3 (NCH2), 55.7 (OCH3), 55.8 (OCH3), 59.2 (OCH3),
63.4 (CH), 74.7 (CH2O), 110.9 (CH), 112.3 (CH), 121.2 (CH), 132.9
(C), 142.9 (CH@N), 147.1 (C), 148.5 (C). Anal. Calcd for
C18H28N2O3: C, 67.47; H, 8.81; N, 8.74. Found: C, 67.28; H, 8.66;
N, 9.00.
4.3.2. [(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[(R)-2-methyl-
3-(3,4,5-trimethoxyphenyl)propylidene]amine 9a
1.41 g (57%); ½a 2D5
ꢂ
¼ ꢀ122:3 (c 1.09, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.00 (d, J = 6.5 Hz, 3H, CH3), 1.59–1.96 (m, 4H, 2 ꢃ CH2),
2.42–2.50 (m, 1H, ArCH2), 2.51–2.84 (m, 3H:1H, CH3 + 1H,
CH2 + 1H, NCH2), 3.28–3.41 (m, 3H, CH2O + CH), 3.31 (s, 3H,
OCH3), 3.43–3.56 (m, 1H, NCH2), 3.79 (br s, 9H, 3 ꢃ OCH3), 6.36
(s, 2H, Harom), 6.50 (m, 1H, CH@N); 13C NMR (75 MHz, CDCl3):
18.5 (CH3), 22.1 (CH2), 26.6 (CH2), 38.6 (CH), 42.1 (ArCH2), 50.2
(NCH2), 55.9 (2 ꢃ OCH3), 59.1 (OCH3), 60.8 (OCH3), 63.4 (CH),
74.7 (CH2O), 106.0 (2 ꢃ CH), 136.2 (2 ꢃ C), 142.4 (CH@N), 152.8
(2 ꢃ C). Anal. Calcd for C19H30N2O4: C, 65.12; H, 8.63; N, 7.99.
Found: C, 65.01; H, 8.41; N, 8.15.
4.3.7. [(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[(S)-2-phenyl-3-
(3,4,5-trimethoxyphenyl)propylidene]amine 9e
1.37 g (47%); ½a 2D5
ꢂ
¼ ꢀ86:6 (c 1.10, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.70–2.01 (m, 4H, 2 ꢃ CH2), 2.74 (q, J = 8.0 Hz, 1H, NCH2),
2.93 (dd, J = 5.3, 13.6 Hz, 1H, ArCH2), 3.23 (dd, J = 6.6, 13.6 Hz,
1H, ArCH2), 3.28–3.49 (m, 4H:2H, 2 ꢃ CH + 1H, NCH2 + 1H, CH2O),
3.35 (s, 3H, OCH3), 3.56 (d, J = 5.1 Hz, 1H, CH2O), 3.70 (s, 6H,
2 ꢃ OCH3), 3.78 (s, 3H, OCH3), 6.20 (s, 2H, Harom), 6.76 (d,
J = 5.7 Hz, 1H, CH@N), 7.07–7.34 (m, 5H, Harom); 13C NMR
(75 MHz, CDCl3): 22.1 (CH2), 26.6 (CH2), 41.4 (ArCH2), 50.1
(NCH2), 50.8 (CH), 55.9 (2 ꢃ OCH3), 59.2 (CH), 60.8 (OCH3), 63.4
(OCH3), 74.8 (CH2O), 106.2 (2 ꢃ CH), 126.4 (CH), 128.2 (2 ꢃ CH),
128.4 (2 ꢃ CH), 135.8 (C), 135.9 (C), 139.1 (CH@N), 142.6 (C),
152.6 (2 ꢃ C). Anal. Calcd for C24H32N2O4: C, 69.88; H, 7.82; N,
6.79. Found: C, 69.95; H, 7.74; N, 6.96.
4.3.3. N-[(R)-2-Benzyl-3-(3,4,5-trimethoxyphenyl)propylidene]-
[(S)-2-methoxymethylpyrrolidin-1-yl]amine 9b
1.27 g (42%); ½a 2D5
ꢂ
¼ ꢀ52:9 (c 0.83, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.69–1.98 (m, 4H, 2 ꢃ CH2), 2.58–2.96 (m, 6H:1H,
CH + 4H, 2 ꢃ ArCH2 + 1H, NCH2), 3.19–3.41 (m, 3H, OCH2 + CH),
3.32 (s, 3H, OCH3), 3.41–3.51 (m, 1H, NCH2), 3.82 (s, 9H, 3 ꢃ OCH3),
6.38 (s, 2H, Harom), 6.48 (d, J = 5.8, 1H, CH@N), 7.12–7.20 (m, 3H, H),
7.21–7.30 (m, 2H, H); 13C NMR (75 MHz, CDCl3): 22.1 (CH2), 26.6
(CH2), 39.5 (PhCH2), 40.0 (ArCH2), 45.2 (CH), 50.3 (NCH2), 56.0
(2 ꢃ OCH3), 59.2 (OCH3), 60.8 (OCH3), 63.3 (CH), 74.7 (CH2O),
106.1 (2 ꢃ CH), 125.9 (CH), 128.1 (2 ꢃ CH), 129.4 (2 ꢃ CH), 136.0
(2 ꢃ C), 140.1 (2 ꢃ C), 140.3 (CH@N), 152.9 (C). Anal. Calcd for
C25H34N2O4: C, 70.40; H, 8.03; N, 6.57. Found: C, 70.72; H, 7.89;
N, 6.55.
4.3.8. N-[(S)-2-(2,3-Dimethoxybenzyl)heptylidene]-[(S)-2-
methoxymethylpyrrolidin-1-yl]amine 9f
1.52 g (57%); ½a 2D5
ꢂ
¼ ꢀ29:8 (c 1.09, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.85 (t, J = 6.3 Hz, 3H, CH3), 1.14–1.51 (m, 8H, 4 ꢃ CH2),
1.67–2.02 (m, 4H, 2 ꢃ CH2), 2.49–2.68 (m, 2H:1H, ArCH2 + 1H,
CH), 2.70–2.83 (m, 2H:1H, ArCH2 + 1H, NCH2), 3.29–3.42 (m, 3H,
OCH2 + CH), 3.34 (s, 3H, OCH3), 3.52 (dd, J = 3.5, 9.1 Hz, 1H,
NCH2), 3.80 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.51 (d, J = 6.6 Hz,
1H, CH@N), 6.59–6.80 (m, 2H, Harom), 6.88–6.99 (m, 1H, Harom);
13C NMR (75 MHz, CDCl3): 14.1 (CH3), 22.0 (CH2), 22.6 (CH2),
26.4 (CH2), 26.8 (CH2), 31.9 (CH2), 33.4 (CH2), 33.7 (CH2), 43.3
(CH), 50.3 (NCH2), 55.6 (OCH3), 55.7 (OCH3), 59.1 (OCH3), 63.4
(CH), 74.7 (CH2O), 110.0 (CH), 122.8 (CH), 123.4 (CH), 134.3 (C),
143.1 (CH@N), 147.4 (C), 152.6 (C). Anal. Calcd for C22H36N2O3: C,
70.18; H, 9.64; N, 7.44. Found: C, 69.91; H, 9.54; N, 7.67.
4.3.4. [(S)-2-Methoxymethylpyrrolidin-1-yl]-N-[(R)-2-methoxy-
methyl-3-(3,4,5-trimethoxyphenyl)propylidene]amine 9c
1.37 g (51%); ½a 2D5
ꢂ
¼ ꢀ95:9 (c 0.99, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.69–2.04 (m, 4H, 2 ꢃ CH2), 2.68–2.88 (m, 4H:2H,
ArCH2 + 1H, CH + 1H, NCH2), 3.21–3.46 (m, 5H, 2 ꢃ OCH2 + CH),
3.32 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 3.51 (dd, J = 3.7, 8.3 Hz,
1H, NCH2), 3.75–3.91 (m, 9H, 3 ꢃ OCH3), 6.41 (s, 2H, Harom), 6.53
(br s, 1H, CH@N); 13C NMR (75 MHz, CDCl3): 22.1 (CH2), 26.6
(CH2), 36.9 (ArCH2), 44.2 (CH), 50.0 (NCH2), 56.0 (2 ꢃ OCH3), 58.9
(OCH3), 59.2 (OCH3), 60.8 (OCH3), 63.2 (CH), 74.0 (CH2O), 74.7
(CH2O), 105.2 (2 ꢃ CH), 135.7 (2 ꢃ C), 138.0 (CH@N), 152.9
(2 ꢃ C). Anal. Calcd for C20H32N2O5: C, 63.13; H, 8.48; N, 7.36.
Found: C, 62.79; H, 8.21; N, 7.54.
4.3.9. N-[(R)-2-Benzo[1,3]dioxol-5-ylmethyl-4-benzyloxy-
butylidene]-[(S)-2-methoxymethylpyrrolidin-1-yl]amine 9g
1.65 g (55%); ½a 2D5
ꢂ
¼ ꢀ43:2 (c 0.87, CHCl3); 1H NMR (300 MHz,
4.3.5. N-[(R)-3-(3,4-Dimethoxyphenyl)-2-methylpropylidene]-
[(S)-2-methoxymethylpyrrolidin-1-yl]amine (R,S)-9d
CDCl3): 1.65–2.04 (m, 6H, 3 ꢃ CH2), 2.59–2.85 (m, 4H:1H,
CH + 2H, ArCH2 + 1H, NCH2), 3.23–3.64 (m, 6H:2H, OCH2 + 1H,
CH + 2H, CH2OBn + 1H, NCH2), 3.38 (s, 3H, OCH3), 4.49 (s, 2H,
OCH2Ph), 5.91 (s, 2H, OCH2O), 6.50 (d, J = 5.4, 1H, CH@N), 6.58–
6.67 (m, 1H, Harom), 6.68–6.76 (m, 2H, Harom), 7.26–7.41 (m, 5H,
Harom); 13C NMR (75 MHz, CDCl3): 22.1 (CH2), 26.5 (CH2), 32.9
(CH2), 40.1 (ArCH2), 41.3 (CH), 50.3 (NCH2), 59.2 (OCH3), 63.4
(CH), 68.6 (CH2O), 73.0 (PhCH2O), 74.7 (CH2O), 100.7 (OCH2O),
107.9 (CH), 109.8 (CH), 122.2 (CH), 127.5 (2 ꢃ CH), 127.7
(2 ꢃ CH), 128.3 (CH), 133.8 (C), 138.6 (C), 140.8 (CH@N), 145.7
(C), 147.4 (C). Anal. Calcd for C25H32N2O4: C, 70.73; H, 7.60; N,
6.60. Found: C, 70.54; H, 7.47; N, 6.45.
1.34 g (59%); ½a 2D5
ꢂ
¼ ꢀ124:0 (c 0.72, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.97 (d, J = 6.8 Hz, 3H, CH3), 1.61–1.94 (m, 4H, 2 ꢃ CH2),
2.46 (dd, J = 7.9, 12.9 Hz, 1H, ArCH2), 2.51–2.65 (m, 2H, CH + NCH2),
2.77 (dd, J = 6.0, 12.8 Hz, 1H, ArCH2), 3.22–3.45 (m, 3H, OCH2 + CH),
3.36 (s, 3H, OCH3), 3.53 (dd, J = 3.8, 8.9 Hz, 1H, NCH2), 3.80 (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 6.51 (d, J = 6.1 Hz, 1H, CH@N), 6.61–6.78
(m, 3H, Harom); 13C NMR (75 MHz, CDCl3): 18.4 (CH3), 22.1 (CH2),
26.6 (CH2), 38.7 (CH), 41.8 (ArCH2), 50.2 (NCH2), 55.8 (OCH3),
55.9 (OCH3), 59.1 (OCH3), 63.4 (CH), 74.6 (CH2O), 110.8 (CH),
112.1 (CH), 121.3 (CH), 133.0 (C), 142.6 (CH@N), 147.4 (C), 148.1
(C). Anal. Calcd for C18H28N2O3: C, 67.47; H, 8.81; N, 8.74. Found:
C, 67.51; H, 8.56; N, 8.64.
4.4. Synthesis of the 4-substituted benzo[c]azepines 5a–g
4.3.6. N-[(S)-3-(3,4-Dimethoxyphenyl)-2-methylpropylidene]-
[(S)-2-methoxymethylpyrrolidin-1-yl]amine (S,S)-9d
4.4.1. General procedure
A solution of hydrazones 9a–g (4.0 mmol) in THF (10 mL) was
1.41 g (62%); ½a 2D5
ꢂ
¼ ꢀ37:0 (c 1.22, CHCl3); 1H NMR (300 MHz,
slowly added to
a stirred suspension of lithium aluminium
CDCl3): 0.99 (d, J = 6.6 Hz, 3H, CH3), 1.66–1.97 (m, 4H, 2 ꢃ CH2),
hydride (349 mg, 10 mmol) in dry THF (5 mL). The resulting

1908
D. Dumoulin et al. / Tetrahedron: Asymmetry 20 (2009) 1903–1911
mixture was refluxed for 6 h then stirring at rt was maintained
overnight. Water (0.5 mL), 10% aqueous sodium hydroxide
(0.5 mL) and water (1 mL) were successively added to the mix-
ture. The precipitate was removed by filtration and thoroughly
washed with Et2O and CH2Cl2 and the combined organic layers
were dried (MgSO4). After evaporation of the solvent, the crude
hydrazines 7a–g, obtained as a pale yellow oil, were used in
the next step without further purification. MOMCl (161 mg,
0.15 mL, 2.0 mmol) was added to a stirred solution of crude
hydrazines 7a–g (2.0 mmol) in glacial acetic acid (10 mL) under
Ar. The mixture was then refluxed for 1 h and stirring at rt
was maintained for 1 h. The mixture was poured onto crushed
ice, neutralized with 50% aqueous NaOH and then extracted with
ethyl acetate (3 ꢃ 25 mL). The combined organic layers were
washed with water (20 mL) and brine (20 mL) and then dried
(MgSO4). Evaporation of the solvent under vacuum afforded an
oily residue, which was purified by flash column chromatogra-
phy on silica gel (acetone/hexanes, 20:80, as eluent).
(C), 150.8 (C), 151.3 (C). Anal. Calcd for C21H34N2O5: C, 63.93; H,
8.69; N, 7.10. Found: C, 63.82; H, 8.72; N, 6.89.
4.4.5. (R)-7,8-Dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-
yl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (S,R)-5d
348 mg (52%);
½
a 2D5
ꢂ
¼ ꢀ38:8 (c 0.51, CHCl3); 1H NMR
(300 MHz, CDCl3): 0.95 (d, J = 6.9 Hz, 3H, CH3), 1.49–1.97 (m,
5H, 2 ꢃ CH2 + CH), 2.52–2.83 (m, 4H, ArCH2 + CH2N), 2.97–3.11
(m, 2H:1H, CH + 1H, OCH2), 3.17 (d, J = 11.4 Hz, 1H, NCH2),
3.22–3.30 (m, 1H, OCH2), 3.32 (s, 3H, OCH3), 3.51 (dd, J = 3.4,
9.1 Hz, 1H, NCH2), 3.73–3.81 (br s, 2H, ArCH2N), 3.85 (s, 6H,
2 ꢃ OCH3), 6.62 (s, 1H, Harom), 6.70 (s, 1H, Harom); 13C NMR
(75 MHz, CDCl3): 20.6 (CH3), 21.4 (CH2), 26.4 (CH2), 33.7 (CH),
42.3 (ArCH2), 44.2 (NCH2), 55.9 (OCH3), 56.0 (OCH3), 57.9
(ArCH2N), 59.1 (CH), 59.2 (OCH3), 65.4 (CH2N), 75.3 (CH2O),
112.8 (CH), 113.1 (CH), 131.2 (C), 133.3 (C), 146.6 (C), 147.2
(C). Anal. Calcd for C19H30N2O3: C, 68.23; H, 9.04; N, 8.38. Found:
C, 68.53; H, 8.98; N, 8.23.
4.4.2. (R)-7,8,9-Trimethoxy-2-[(S)-2-methoxymethylpyrrolidin-
1-yl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine 5a
4.4.6. (S)-7,8-Dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-
yl]-4-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (S,S)-5d
364 mg (50%); ½a 2D5
ꢂ
¼ ꢀ46:8 (c 0.71, CHCl3); 1H NMR (300 MHz,
361 mg (54%); ½a 2D5
ꢂ
¼ ꢀ32:6 (c 0.58, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.93 (d, J = 6.7 Hz, 3H, CH3), 1.59–1.99 (m, 5H,
2 ꢃ CH2 + CH), 2.56–2.88 (m, 4H, ArCH2 + CH2N), 2.98–3.11 (m,
2H:1H, CH + 1H, OCH2), 3.13–3.27 (m, 2H:1H, NCH2 + 1H, OCH2),
3.29 (s, 3H, OCH3), 3.48 (dd, J = 3.1, 8.9 Hz, 1H, NCH2), 3.76–3.97
(m, 11H, 3 ꢃ OCH3 + ArCH2N), 6.42 (s, 1H, Harom); 13C NMR
(75 MHz, CDCl3): 19.8 (CH3), 21.4 (CH2), 26.6 (CH2), 33.1 (CH),
42.6 (ArCH2), 44.8 (NCH2), 48.9 (ArCH2N), 55.9 (OCH3), 58.3 (CH),
59.1 (OCH3), 60.8 (OCH3), 61.3 (OCH3), 65.7 (CH2N), 75.7 (CH2O),
109.1 (CH), 125.1 (C), 136.9 (C), 140.1 (C), 150.9 (C), 151.3 (C). Anal.
Calcd for C20H32N2O4: C, 65.91; H, 8.85; N, 7.69. Found: C, 66.14; H,
8.56; N, 7.38.
CDCl3): 0.93 (d, J = 6.8 Hz, 3H, CH3), 1.47–1.99 (m, 5H, 2 ꢃ CH2 + CH),
2.51–2.77 (m, 4H, ArCH2 + CH2N), 2.93–3.04 (m, 2H:1H, CH + 1H,
OCH2), 3.16 (d, J = 11.4 Hz, 1H, NCH2), 3.19–3.27 (m, 1H, OCH2),
3.33 (s, 3H, OCH3), 3.41–3.58 (m, 1H, NCH2), 3.71–3.83 (br s, 2H,
ArCH2N), 3.84 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 6.63 (s, 1H, Harom),
6.69 (s, 1H, Harom); 13C NMR (75 MHz, CDCl3): 20.5 (CH3), 21.4
(CH2), 26.4 (CH2), 33.8 (CH), 42.2 (ArCH2), 44.2 (NCH2), 55.9
(OCH3), 56.0 (OCH3), 57.8 (ArCH2N), 59.1 (CH), 59.3 (OCH3), 65.6
(CH2N), 75.5 (CH2O), 112.9 (CH), 113.3 (CH.), 131.1 (C), 133.2 (C),
146.6 (C), 147.1 (C). Anal. Calcd for C19H30N2O3: C, 68.23; H, 9.04;
N, 8.38. Found: C, 68.44; H, 9.22; N, 8.65.
4.4.7. (R)-7,8,9-Trimethoxy-2-[(S)-2-methoxymethylpyrrolidin-
1-yl]-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine 5e
4.4.3. (R)-4-Benzyl-7,8,9-trimethoxy-2-[(S)-2-methoxymeth-
ylpyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-benzo[c]azepine 5b
392 mg (46%); ½a 2D5
ꢂ
¼ ꢀ58:3 (c 1.75, CHCl3); 1H NMR (300 MHz,
388 mg (44%); ½a 2D5
ꢂ
¼ ꢀ37:8 (c 0.72, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.53–1.95 (m, 4H, 2 ꢃ CH2), 2.72–2.88 (m, 2H:1H,
NCH2 + 1H, ArCH2), 2.92–3.18 (m, 4H:1H, ArCH2 + 2H, CH2N + 1H,
CH), 3.20–3.47 (m, 3H:1H, NCH2 + 1H, CH + 1H, CH2O), 3.33 (s,
3H, OCH3), 3.57 (dd, J = 3.1, 8.8 Hz, 1H, CH2O), 3.74–3.98 (m, 1H,
ArCH2N), 3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.94 (s, 3H,
OCH3), 4.49 (d, J = 14.6 Hz, 1H, ArCH2N), 6.47 (s, 1H, Harom), 7.05–
7.43 (m, 5H, Harom); 13C NMR (75 MHz, CDCl3): 21.5 (CH2), 26.5
(CH2), 41.7 (ArCH2), 43.5 (NCH2), 45.8 (CH), 46.9 (ArCH2N), 55.9
(OCH3), 59.1 (OCH3), 59.2 (OCH3), 60.8 (OCH3), 61.3 (CH), 63.9
(CH2N), 75.6 (CH2O), 108.6 (CH), 125.0 (C), 126.9 (CH), 127.0
(2 ꢃ CH), 128.5 (2 ꢃ CH), 137.4 (C), 140.4 (C), 145.7 (C), 151.1 (C),
151.7 (C). Anal. Calcd for C25H34N2O4: C, 70.39; H, 8.03; N, 6.57.
Found: C, 70.44; H, 7.92; N, 6.80.
CDCl3): 1.59–1.95 (m, 4H, 2 ꢃ CH2), 2.13–2.37 (m, 1H, CH), 2.46–
2.70 (m, 3H: 1H, ArCH2 + 1H, CH2N + 1H, NCH2), 2.77–2.93 (m,
2H:1H, ArCH2 + 1H, CH2N), 2.95–3.23 (m, 4H:1H, NCH2 + 1H,
CH + 2H, ArCH2), 3.33 (s, 3H, OCH3), 3.49–3.71 (m, 2H, OCH2),
3.80 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.04–
4.29 (m, 2H, ArCH2N), 6.29 (s, 1H, Harom), 7.08–7.36 (m, 5H, Harom);
13C NMR (75 MHz, CDCl3): 21.3 (CH2), 26.5 (CH2), 39.5 (CH), 39.6
(PhCH2), 42.9 (ArCH2), 43.7 (NCH2), 47.8 (ArCH2N), 55.9 (OCH3),
58.8 (CH), 59.1 (OCH3), 60.8 (OCH3), 61.3 (OCH3), 64.4 (CH2N),
75.5 (CH2O), 109.6 (CH), 124.7 (C), 125.8 (CH), 128.2 (2 ꢃ CH),
129.3 (2 ꢃ CH), 136.2 (C), 140.2 (C), 140.9 (C), 150.9 (C), 151.3
(C). Anal. Calcd for C26H36N2O4: C, 70.88; H, 8.24; N, 6.36. Found:
C, 70.89; H, 8.44; N, 6.27.
4.4.8. (S)-6,7-Dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-
yl]-4-pentyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine 5f
4.4.4. (R)-7,8,9-Trimethoxy-4-methoxymethyl-2-[(S)-2-meth-
oxymethylpyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-benzo[c]-
azepine 5c
453 mg (58%); ½a 2D5
ꢂ
¼ ꢀ48:2 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.89 (t, J = 6.7 Hz, 3H, CH3), 1.12–1.53 (m, 8H, 4 ꢃ CH2),
1.59–1.95 (m, 5H, 2 ꢃ CH2 + CH), 2.41–2.64 (m, 1H, ArCH2), 2.70–
2.93 (m, 2H:1H, NCH2 + 1H, ArCH2), 2.94–3.22 (m, 4H:1H, CH,+ 2H,
CH2N + 1H, NCH2), 3.22–3.43 (m, 1H, CH2O), 3.33 (s, 3H, OCH3),
3.52 (d, J = 6.5 Hz, 1H, CH2O), 3.66–4.00 (m, 2H, ArCH2N), 3.86 (s,
6H, 2 ꢃ OCH3), 6.53–6.77 (m, 2H, Harom); 13C NMR (75 MHz, CDCl3):
14.2 (CH3), 21.4 (CH2), 22.7 (CH2), 26.3 (CH2), 26.9 (CH2), 30.2 (CH2),
32.1 (CH2), 38.0 (CH), 43.8 (ArCH2), 43.9 (NCH2), 47.8 (ArCH2N), 55.6
(OCH3), 59.1 (OCH3), 59.4 (OCH3), 60.9 (CH), 63.2 (CH2N), 75.2
(CH2O), 107.4 (CH), 119.4 (CH), 126.6 (C), 133.2 (C), 142.8 (C),
145.4 (C). Anal. Calcd for C23H38N2O3: C, 70.73; H, 9.81; N, 7.17.
Found: C, 70.84; H, 9.80; N, 7.35.
418 mg (53%); ½a 2D5
ꢂ
¼ ꢀ44:0 (c 0.61, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.54–1.92 (m, 4H, 2 ꢃ CH2), 2.05–2.16 (m, 1H, CH), 2.63–
2.90 (m, 3H:1H, ArCH2 + 1H, CH2N + 1H, NCH2), 2.96–3.11 (m,
3H:1H, ArCH2 + 1H, CH2N + 1H, CH), 3.13–3.39 (m, 4H, OCH2 + -
CH2OMe), 3.28 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 3.46 (d,
J = 6.6 Hz, 1H, NCH2), 3.65 (d, J = 12.5 Hz, 1H, ArCH2N), 3.78–3.98
(m, 9H, 3 ꢃ OCH3), 4.09 (d, J = 13.1 Hz, 1H, ArCH2N), 6.46 (s, 1H,
Harom); 13C NMR (75 MHz, CDCl3): 21.4 (CH2), 26.3 (CH2), 37.4
(ArCH2), 38.1 (CH), 43.9 (NCH2), 48.4 (ArCH2N), 55.9 (OCH3), 58.7
(OCH3), 59.1 (OCH3 + CH), 60.8 (OCH3), 61.2 (OCH3), 61.5 (CH2N),
74.8 (OCH2), 75.4 (CH2O), 109.2 (CH), 125.0 (C), 136.1 (C), 140.2

D. Dumoulin et al. / Tetrahedron: Asymmetry 20 (2009) 1903–1911
1909
4.4.9. (R)-8-(2-Benzyloxyethyl)-6-[(S)-2-methoxymethylpyrr-
4.5.3. (R)-3-Hexyl-7,8-dimethoxy-2-[(S)-2-methoxymeth-
olidin-1-yl]-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclohepta-
[f]indene 5g
ylpyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-benzo[c]azepine 6h
404 mg (50%); ½a 2D5
ꢂ
¼ ꢀ46:3 (c 0.49, CHCl3); 1H NMR (300 MHz,
368 mg (42%); ½a 2D5
ꢂ
¼ ꢀ46:6 (c 0.67, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.91 (t, J = 6.7 Hz, 3H, CH3), 1.05–1.41 (m, 8H, 4 ꢃ CH2),
1.43–1.80 (m, 4H, 2 ꢃ CH2), 1.81–2.13 (m, 4H, 2 ꢃ CH2), 2.68–
2.83 (m, 2H, CH2N), 2.84–2.95 (m, 1H, CH), 2.98–3.18 (m, 3H,
CH + ArCH2), 3.21–3.39 (m, 1H, CH2O), 3.30 (s, 3H, OCH3), 3.55
(dd, J = 2.2, 5.7 Hz, 1H, CH2O), 3.75 (q, J = 15.2 Hz, 2H, ArCH2N),
3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.63 (s, 1H, Harom), 6.69 (s,
1H, Harom); 13C NMR (75 MHz, CDCl3): 14.2 (CH3), 22.0 (CH2),
22.7 (CH2), 26.4 (CH2), 27.3 (CH2), 29.8 (CH2), 31.9 (CH2), 32.0
(CH2), 32.9 (ArCH2), 33.3 (CH2), 41.5 (NCH2), 53.4 (ArCH2N), 55.9
(OCH3), 56.1 (OCH3), 58.9 (CH), 59.7 (OCH3), 66.6 (CH), 76.0
(CH2O), 112.2 (CH), 112.5 (CH), 131.6 (C), 135.1 (C), 146.5 (C),
147.1 (C). Anal. Calcd for C24H40N2O3: C, 71.25; H, 9.97; N, 6.92.
Found: C, 70.99; H, 9.87; N, 7.10.
CDCl3): 1.42–1.87 (m, 7H, 3 ꢃ CH2 + CH), 2.51–3.11 (m, 7H,
ArCH2 + 2 ꢃ CH2N + CH), 3.24 (t, J = 8.8 Hz, 1H, CH2O), 3.31 (s, 3H,
OCH3), 3.40–3.58 (m, 3H:2H, CH2OBn + 1H, CH2O), 3.75 (dd,
J = 9.1, 13.6 Hz, 2H, ArCH2N), 4.49 (s, 2H, OCH2Ph) 5.89 (s, 2H,
OCH2O), 6.51 (s, 1H, Harom), 6.64 (s, 1H, Harom), 7.22–7.41 (m, 5H,
Harom); 13C NMR (75 MHz, CDCl3): 21.3 (CH2), 26.1 (CH2), 34.8
(CH), 39.9 (CH2), 43.9 (ArCH2), 44.0 (NCH2), 55.8 (ArCH2N), 59.2
(OCH3), 59.2 (CH), 62.6 (CH2N), 68.1 (CH2OBn), 73.0 (OCH2Ar),
75.3 (CH2O), 100.7 (OCH2O), 109.6 (CH), 110.3 (CH), 127.6
(2 ꢃ CH), 127.8 (2 ꢃ CH), 128.4 (CH), 132.6 (C), 133.8 (C), 138.5
(C), 145.4 (C), 145.9 (C). Anal. Calcd for C26H34N2O4: C, 71.21; H,
7.81; N, 6.39. Found: C, 71.02; H, 7.58; N, 6.45.
4.5. Synthesis of the 3-substituted 2-benzo[c]azepines 6a,d,h
(path b)
4.6. Removal of the chiral appendage. Synthesis of the targeted
benzazepines 1a–g and 2a,d,h
Methyllithium (6.0 mmol, 3.75 mL, 1.6 M solution in diethyl-
ether) or hexyllithium (6.0 mmol, 2.6 mL, 2.3 M solution in hex-
ane) was added dropwise to a stirred solution of the appropriate
hydrazones 3i,j (2.0 mmol) in THF (10 mL) at ꢀ78 °C under Ar.
The mixture was then allowed to warm to rt and stirred for 3 h.
Water (10 mL) was added and the mixture was extracted with
ethyl acetate (3 ꢃ 25 mL). The combined organic layers were dried
(MgSO4). Evaporation of the solvent afforded the corresponding
crude hydrazines 8a,d,h as brown oil, which was used without fur-
ther purification in the reaction with MOMCl as previously de-
scribed for the synthesis of 5a–g. Purification by flash column
chromatography on silica gel (acetone/hexanes, 20:80, as eluent)
delivered the benzazepines 6a,d,h as a foam.
4.6.1. General procedure
Boran–tetrahydrofuran complex (BH3ꢁTHF, 10 mL, 10 mmol,
1 M solution in THF) was slowly added to an ice-cooled stirred
solution of benzazepines 5a–g or 6a,d,h (1.0 mmol) in dry THF
(5 mL) under Ar and the resulting mixture was refluxed for 48 h.
The mixture was concentrated under reduced pressure, then made
basic by adding 10% aqueous NaOH (10 mL) and refluxed for 3 h.
The combined organic layers were dried (MgSO4) and concentrated
under vacuum for afford a colourless oil, which was purified by
flash column chromatography on silica gel (acetone/MeOH,
90:10, as eluent).
4.6.2. (R)-7,8,9-Trimethoxy-4-methyl-2,3,4,5-tetrahydro-1H-
benzo[c]azepine 1a
4.5.1. (R)-7,8,9-Trimethoxy-2-[(S)-2-methoxymethylpyrrolidin-
1-yl]-3-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine 6a
146 mg (58%); ½a 2D5
ꢂ
¼ ꢀ39:4 (c 0.72, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.92 (d, J = 6.8 Hz, 3H, CH3), 1.65–1.79 (m, 1H, CH), 2.58–
2.73 (m, 3H:2H, ArCH2 + 1H, CH2N), 3.08–3.21 (m, 1H, CH2N),
3.74–4.01 (m, 2H, ArCH2N), 3.84 (s, 6H, 2 ꢃ OCH3), 3.88 (s, 3H,
OCH3), 6.44 (s, 1H, Harom); 13C NMR (75 MHz, CDCl3): 19.8 (CH3),
33.8 (CH), 42.9 (ArCH2), 48.7 (ArCH2N), 55.9 (OCH3), 56.0 (OCH3),
58.7 (OCH3), 60.3 (CH2N), 108.6 (CH), 126.1 (C), 136.6 (C), 139.8
(C), 150.6 (C), 151.2 (C). Anal. Calcd for C14H21NO3: C, 66.91; H,
8.42; N, 5.57. Found: C, 67.02; H, 8.54; N, 5.58.
343 mg (47%); ½a 2D5
ꢂ
¼ ꢀ43:8 (c 1.25, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.13 (d, J = 6.0 Hz, 3H, CH3), 1.39–1.54 (m, 1H, CH2), 1.55–
1.82 (m, 3H:1H, CH2 + 2H, CH2), 1.83–2.00 (m, 2H:2 ꢃ 1H, 2 ꢃ CH2),
2.66 (dd, J = 7.4, 6.9 Hz, 1H, CH2N), 2.73–2.99 (m, 4H:1H,
CH2N + 2H, ArCH2 + 1H, CH), 3.06–3.22 (m, 2H:1H, CH + 1H,
CH2O), 3.28 (s, 3H, OCH3), 3.35 (d, J = 13.6 Hz, 1H, ArCH2N), 3.53
(d, J = 6.7 Hz, 1H, CH2O), 3.83 (s, 3H, OCH3), 3.84 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 4.34 (d, J = 13.6 Hz, 1H, ArCH2N), 6.44 (s, 1H, Har-
om); 13C NMR (75 MHz, CDCl3): 21.9 (CH3), 22.0 (CH2), 27.1 (CH2),
33.3 (ArCH2), 36.6 (CH2), 40.5 (NCH), 45.4 (ArCH2N), 55.9 (OCH3),
58.9 (CH), 59.1 (OCH3), 60.7 (OCH3), 61.0 (OCH3), 62.5 (CH), 76.1
(CH2O), 107.7 (CH), 125.1 (C), 139.3 (C), 139.9 (C), 151.1 (C),
151.5 (C). Anal. Calcd for C20H32N2O4: C, 65.91; H, 8.85; N, 7.69.
Found: C, 66.09; H, 8.58; N, 7.89.
4.6.3. (R)-4-Benzyl-7,8,9-trimethoxy-2,3,4,5-tetrahydro-1H-
benzo[c]azepine 1b
157 mg (48%); ½a 2D5
ꢂ
¼ ꢀ72:8 (c 0.39, CHCl3); 1H NMR (300 MHz,
CDCl3): 2.06–2.23 (m, 1H, CH), 2.52–2.91 (m, 4H, PhCH2 + CH2N),
2.96–3.09 (m, 2H, ArCH2), 3.78–3.96 (m, 2H, ArCH2N), 3.86 (s,
6H, 2 ꢃ OCH3), 3.88 (s, 3H, OCH3), 6.39 (s, 1H, Harom), 7.02–7.27
(m, 5H, Harom); 13C NMR (75 MHz, CDCl3): 38.9 (CH), 39.4 (CH2),
42.6 (CH2), 48.1 (ArCH2N), 55.9 (OCH3), 56.1 (OCH3), 58.6 (OCH3),
61.9 (CH2N), 109.3 (CH), 124.6 (C), 125.4 (CH), 128.3 (2 ꢃ CH),
129.4 (2 ꢃ CH), 136.1 (C), 140.7 (C), 140.9 (C), 151.0 (C), 151.2
(C). Anal. Calcd for C20H25NO3: C, 73.37; H, 7.70; N, 4.28. Found:
C, 73.25; H, 7.58; N, 4.50.
4.5.2. (R)-7,8-Dimethoxy-2-[(S)-2-methoxymethylpyrrolidin-1-
yl]-3-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine 6d
321 mg (48%); ½a 2D5
ꢂ
¼ ꢀ50:3 (c 0.31, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.15 (d, J = 6.2, 3H, CH3), 1.40–1.56 (m, 1H, CH2), 1.57–1.82
(m, 3H:1H, CH2 + 2H, CH2), 1.83–2.01 (m, 2H:2 ꢃ 1H, 2 ꢃ CH2),
2.67 (dd, J = 7.5, 6.9 Hz, 1H, CH2N), 2.71–2.96 (m, 4H:1H, CH2N + 2H,
ArCH2 + 1H, CH), 2.97–3.13 (m, 2H:1H, CH + 1H CH2O), 3.30 (s, 3H,
OCH3), 3.55 (dd, J = 2.2, 5.4 Hz, 1H, CH2O), 3.73 (q, J = 13.6 Hz, 2H,
ArCH2N), 3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.64 (s, 1H, Harom),
6.70 (s, 1H, Harom); 13C NMR (75 MHz, CDCl3): 21.8 (CH3), 22.1
(CH2), 27.3 (CH2), 32.5 (ArCH2), 36.8 (CH2), 40.8 (NCH2), 54.0
(ArCH2N), 55.9 (OCH3), 56.1 (OCH3), 58.9 (CH), 59.7 (OCH3), 62.4
(CH), 76.1 (CH2O), 112.2 (CH), 112.6 (CH), 131.5 (C), 135.2 (C),
146.6 (C), 147.2 (C). Anal. Calcd for C19H30N2O3: C, 68.23; H, 9.04;
N, 8.38. Found: C, 68.53; H, 8.98; N, 8.23.
4.6.4. (R)-7,8,9-Trimethoxy-4-methoxymethyl-2,3,4,5-tetra-
hydro-1H-benzo[c]azepine 1c
138 mg (49%); ½a 2D5
ꢂ
¼ ꢀ44:2 (c 0.41, CHCl3); 1H NMR (300 MHz,
CDCl3): 2.05–2.18 (m, 1H, CH), 2.63–2.98 (m, 4H, ArCH2 + CH2N),
3.26–3.39 (m, 2H, CH2OMe), 3.29 (s, 3H, OCH3), 3.76–4.02 (m,
2H, ArCH2N), 3.86 (s, 6H, 2 ꢃ OCH3), 3.88 (s, 3H, OCH3), 6.42 (s,
1H, Harom); 13C NMR (75 MHz, CDCl3): 38.2 (CH2), 38.9 (CH), 48.1
(ArCH2N), 55.9 (OCH3), 56.4 (OCH3), 60.8 (OCH3), 61.2 (OCH3),
61.9 (CH2N), 74.6 (OCH2), 108.4 (CH), 125.1 (C), 136.3 (C), 140.2

1910
D. Dumoulin et al. / Tetrahedron: Asymmetry 20 (2009) 1903–1911
(C), 150.9 (C), 151.2 (C). Anal. Calcd for C15H23NO4: C, 64.03; H,
8.24; N, 4.98. Found: C, 63.94; H, 8.23; N, 5.12.
2.02 (m, 1H, CH2), 2.49–2.88 (m, 2H, CH2), 2.89–3.15 (m, 2H,
CH + NH), 3.57 (d, J = 14.6 Hz, 1H, ArCH2N), 3.84 (s, 9H, 3 ꢃ OCH3),
4.46 (d, J = 14.5 Hz, 1H, ArCH2N), 6.50 (s, 1H, Harom); 13C NMR
(75 MHz, CDCl3): 23.4 (CH3), 34.9 (CH2), 36.7 (CH2), 44.0 (ArCH2N),
56.0 (OCH3), 58.9 (OCH3), 60.8 (OCH3), 61.6 (CH), 108.8 (CH), 127.0
(C), 138.7 (C), 140.7 (C), 151.0 (C), 151.7 (C). Anal. Calcd for
C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C, 67.07; H, 8.67;
N, 5.78.
4.6.5. (R)-7,8-Dimethoxy-4-methyl-2,3,4,5-tetrahydro-1H-
benzo[c]azepine (R)-1d
117 mg (53%); ½a 2D5
ꢂ
¼ ꢀ56:5 (c 0.63, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.90 (d, J = 6.9, 3H, CH3), 1.61–1.78 (m, 1H, CH), 2.63–2.84
(m, 3H:2H, ArCH2 + 1H, CH2N), 3.23 (d, J = 13.1 Hz, 1H, CH2N),
3.71–4.04 (m, 2H, ArCH2N), 3.85 (s, 3H, OCH3), 3.86 (s, 3H,
OCH3), 6.68 (s, 2H, Harom); 13C NMR (75 MHz, CDCl3): 19.9 (CH3),
34.5 (CH), 43.3 (CH2), 54.0 (ArCH2N), 56.0 (2 ꢃ OCH3), 60.1
(CH2N), 112.2 (CH), 113.6 (CH), 133.3 (C), 134.2 (C), 146.5 (C),
147.3 (C). Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33.
Found: C, 70.45; H, 8.55; N, 6.21.
4.6.11. (R)-7,8-Dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H-
benzo[c]azepine 2d
117 mg (53%); ½a 2D5
ꢂ
¼ ꢀ69:7 (c 0.41, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.23 (d, J = 6.3 Hz, 3H, CH3), 1.42–1.51 (m, 1H, CH2), 1.88–
2.07 (dd, J = 6.8, 7.0 Hz, 1H, CH), 2.76 (dd, J = 6.6, 14.6 Hz, 1H, CH2),
2.97 (t, J = 13.7 Hz, 1H, CH2), 3.07–3.23 (m, 1H, CH), 3.75–4.04 (m,
2H, ArCH2N), 3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.70 (s, 1H, Har-
om), 6.73 (s, 1H, Harom); 13C NMR (75 MHz, CDCl3): 22.8 (CH3), 33.8
(CH2), 36.3 (CH2), 52.1 (ArCH2N), 56.0 (OCH3), 56.1 (OCH3), 58.5
(CH), 112.9 (2 ꢃ CH), 132.1 (C), 134.7 (C), 146.7 (C), 147.2 (C). Anal.
Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.46; H,
8.51; N, 6.14.
4.6.6. (S)-7,8-Dimethoxy-4-methyl-2,3,4,5-tetrahydro-1H-2-
benzo[c]azepine (S)-1d
115 mg (55%); ½a 2D5
¼ þ53:6 (c 0.52, CHCl3).
ꢂ
4.6.7. (R)-6,7-Dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-
benzo[c]azepine 1e
Yield: 48% (150 mg); ½a D25
ꢂ
¼ þ24:3 (c 0.38, CHCl3); 1H NMR
4.6.12. (3R)-7,8-Dimethoxy-3-hexyl-2,3,4,5-tetrahydro-1H-2-
(300 MHz, CDCl3): 2.42 (br s, 1H, NH), 2.78–2.97 (m, 2H, ArCH2),
3.04–3.21 (m, 1H, CH), 3.38–3.53 (m, 2H, CH2N), 3.67 (d,
J = 14.5 Hz, 1H, ArCH2N), 3.83 (s, 3H, OCH3), 3.88 (s, 6H, 2 ꢃ OCH3),
4.54 (d, J = 14.8 Hz, 1H, ArCH2N), 6.53 (s, 1H, H), 7.16–7.45 (m, 5H,
Harom). 13C NMR (75 MHz, CDCl3): 41.2 (CH2), 45.2 (CH), 46.8
(ArCH2N), 55.9 (OCH3), 59.1 (OCH3), 60.6 (OCH3), 62.9 (CH2N),
108.8 (CH), 124.9 (C), 126.8 (CH), 126.9 (2 ꢃ CH), 128.6 (2 ꢃ CH),
137.3 (C), 140.6 (C), 145.6 (C), 150.9 (C), 151.8 (C). Anal. Calcd
for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C, 73.07; H,
7.54; N, 4.45.
benzazepine 2h
163 mg (56%); ½a 2D5
ꢂ
¼ ꢀ29:6 (c 0.73, CHCl3); 1H NMR (300 MHz,
CDCl3): 0.89 (t, J = 6.6 Hz, 3H, CH3), 1.18–1.49 (m, 11H:10H,
5 ꢃ CH2 + 1H, CH2), 1.77–2.03 (m, 2H:1H, CH2 + NH), 2.74 (dd,
J = 6.6, 14.5 Hz, 1H, ArCH2), 2.79–2.91 (m, 1H, CH), 2.97 (t,
J = 13.6 Hz, 1H, ArCH2), 3.77–4.03 (m, 2H, ArCH2N), 3.86 (s, 6H,
2 ꢃ OCH3), 6.69 (s, 1H, Harom), 6.70 (s, 1H, Harom); 13C NMR
(75 MHz, CDCl3): 14.1 (CH3), 22.6 (CH2), 26.2 (CH2), 29.5 (CH2),
31.8 (CH2), 34.3 (CH2), 35.8 (CH2), 38.0 (CH), 53.4 (ArCH2N), 56.0
(2 ꢃ OCH3), 63.4 (CH), 112.4 (CH), 113.1 (CH), 134.5 (C), 134.9
(C), 146.5 (C), 147.3 (C). Anal. Calcd for C18H29NO2: C, 74.18; H,
10.03; N, 4.81. Found: C, 74.45; H, 9.78; N, 4.62.
4.6.8. (S)-6,7-Dimethoxy-4-pentyl-2,3,4,5-tetrahydro-1H-
benzo[c]azepine 1f
144 mg (52%); ½a 2D5
ꢂ
¼ ꢀ6:8 (c 0.47, CHCl3); 1H NMR (300 MHz,
Acknowledgements
CDCl3): 0.89 (t, J = 6.7 Hz, 3H, CH3), 1.03–1.65 (m, 9H,
4 ꢃ CH2 + CH), 2.51–2.99 (m, 3H:1H, NH + 1H, CH2N + 1H from
ArCH2), 3.05–3.33 (m, 2H:1H, CH2N + 1H, ArCH2), 3.70–3.99 (m,
8H, 2 ꢃ OCH3 + ArCH2N), 6.54–6.72 (m, 2H, Harom); 13C NMR
(75 MHz, CDCl3): 14.1 (CH3), 22.6 (CH2), 26.7 (CH2), 30.9 (CH2),
32.0 (2 ꢃ CH2), 38.8 (CH), 54.3 (ArCH2N), 56.0 (2 ꢃ OCH3), 58.6
(CH2N), 107.2 (CH), 123.3 (CH), 136.5 (2 ꢃ C), 143.4 (Ca), 145.8
(C). Anal. Calcd for C17H27NO2: C, 73.61; H, 9.81; N, 5.05. Found:
C, 73.73; H, 9.98; N, 5.21.
We are grateful to the Centre National de la Recherche Scientif-
ique (CNRS) and the Région Nord-Pas-de-Calais for financial sup-
port (grant to D.D.). This work was also supported by the
Programme PRIM (Région Nord-Pas-de-Calais).
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4. Ishibashi, H.; Kobayashi, T.; Nakashima, T.; Tamura, S. J. Org. Chem. 2000, 65,
9022–9027.
5. (a) Das, J. U.S. Patent 4,774,239, 1988; Chem. Abstr. 1989; 110, 23752.; (b) Floyd,
D. M.; Kimball, S. D.; Krapcho, J.; Das, J.; Turk, C. F.; Moquin, R. V.; Lago, M. W.;
Duff, K. J.; Lee, V. G.; White, R. E.; Ridgewell, R. E.; Moreland, S.; Brittain, R. J.;
166 mg: (51%); ½a D25
ꢂ
¼ ꢀ12:6 (c 0.61, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.52 (q, J = 6.4 Hz, 2H, CH2), 1.78–1.93 (m, 1H, CH), 2.72
(dd, J = 8.6, 14.4, 1H, ArCH2), 2.80–3.01 (m, 2H:1H, ArCH2 + 1H,
CH2N), 3.25 (dd, J = 2.2, 11.4 Hz, 1H, CH2N), 3.53 (t, J = 6.3 Hz, 2H,
CH2O), 3.62 (br s, 1H, NH), 3.86 (s, 2H, ArCH2N), 4.51 (s, 2H,
OCH2), 5.91 (s, 2H, OCH2O), 6.59 (s, 1H, Harom), 6.64 (s, 1H, Harom),
7.25–7.44 (m, 5H, Harom); 13C NMR (75 MHz, CDCl3): 32.8 (CH2),
35.3 (CH), 40.6 (CH2), 53.8 (ArCH2N), 57.5 (CH2N), 67.9 (OCH2),
73.0 (OCH2), 100.9 (OCH2O), 109.3 (CH), 110.7 (CH), 127.6
(2 ꢃ CH), 127.7 (2 ꢃ CH), 128.4 (CH), 134.0 (C), 134.2 (C), 138.4
(C), 145.5 (C), 146.3 (C). Anal. Calcd for C20H23NO3: C, 73.82; H,
7.12; N, 4.30. Found: C, 73.51; H, 7.08; N, 4.25.
4.6.10. (R)-7,8,9-Trimethoxy-3-methyl-2,3,4,5-tetrahydro-1H-
benzo[c]azepine 2a
146 mg (58%); ½a 2D5
ꢂ
¼ ꢀ81:1 (c 0.54, CHCl3); 1H NMR (300 MHz,
CDCl3): 1.17 (d, J = 6.3 Hz, 3H, CH3), 1.22–1.45 (m, 1H, CH2), 1.81–

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