First asymmetric synthesis of (Un)saturated 1-Alkylbenzo[c]azepin-3-ones: Extension to the corresponding benzazeplnes

Article abstract of DOI:10.1002/ejoc.200900365

A flexible route for the stereoselective synthesis of a variety of structurally diverse (1R)-1-alkyldihydro and tetrahydro-benzazepin(ones) has been developed. The key step is a highly diastereoselective 1,2-addition process applied to a stereopure aromatic hydrazone combined with a ring-closing metathesis reaction to secure the formation of the seven-membered azaheterocycle ring system.

Full text of DOI:10.1002/ejoc.200900365

FULL PAPER
DOI: 10.1002/ejoc.200900365
First Asymmetric Synthesis of (Un)saturated 1-Alkylbenzo[c]azepin-3-ones:
Extension to the Corresponding Benzazepines
David Dumoulin,[a,b] Stéphane Lebrun,[a,b] Eric Deniau,[a,b] Axel Couture,*[a,b] and
Pierre Grandclaudon[a,b]
Keywords: Lactams / Chiral auxiliaries / Cyclization / Hydrazones / Fused-ring systems / Asymmetric synthesis
A flexible route for the stereoselective synthesis of a variety
metathesis reaction to secure the formation of the seven-
of structurally diverse (1R)-1-alkyldihydro and tetrahydro- membered azaheterocycle ring system.
benzazepin(ones) has been developed. The key step is a
highly diastereoselective 1,2-addition process applied to a
stereopure aromatic hydrazone combined with a ring-closing
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
developed and tetrahydro-2-benzazepines have been ac-
cessed through the reduction of products of modified
Schmidt ring-expansion reactions from derivatives of 1-tet-
ralone.[5,12] However, the success of these ring-expansion
methodologies, which require the use of hazardous reagents
(e.g. azides), is highly dependent upon the nature of the
substrate and in all cases a mixture of isomeric compounds
is obtained. Above all, none of these annulation techniques
allows control of the stereogenic centre at C1. Despite the
great progress made in asymmetric synthesis in recent dec-
ades, few flexible methods are available for the asymmetric
synthesis of 1-alkylbenzazepines in high enantiomeric ex-
cess. To the best of our knowledge these chiral compounds
have been only obtained by a multistep sequence involving
metallation/alkylation/hydrazinolysis reactions applied to a
variety of chiral benzazepine formamidines[12] derived from
a free NH model.[5] As a consequence, the development of
synthetic methodologies that may have generality for the
construction of a variety of substituted or unsubstituted
benzazepines equipped with alkyl appendages at C1 in a
stereo- and enantioselective manner is an area of current
interest and alternative methods are currently the object of
synthetic endeavour. In this context, the corresponding sat-
urated or α,β-unsaturated ε-benzolactams can serve a key
role as advanced intermediates prior to the conversion to
the benzazepine derivatives as they possess the requisite
structure and functional group location to be easily con-
verted into the seven-membered azaheterocyclic models
through rather simple chemical manipulation.
Introduction
The synthesis of 1-substituted 2-benzazepines is a topic
of continuing interest because these ring systems lie at the
heart of a great number of poly- and diversely function-
alized compounds that have gained considerable attention
due to their profound chemotherapeutic properties.[1] Thus
compounds of this class have been found to be potent plate-
let anti-aggregatory drugs, anticonvulsants, antidiabetics,
CNS agents[2] and specific ligands for serotonin and dop-
amine receptor sub-types.[2] Compounds containing the 1-
substituted 2-benzazepine skeleton are also known to exhi-
bit PNMT inhibitory activity and α2-adrenoreceptor affin-
ity.[3] They have also been shown to display potent inhibi-
tory activities against AChE and SERT,[4] broncho-relaxing
activity[5] and also to promote the healing of skin wounds.[6]
The 1-alkyl-2-benzazepine nucleus is also found in a
number of Cephalotoxus and Homoerythrina alkaloids.[7]
Synthetic routes to the construction of these heterobicyclic
compounds have mainly been based on Bischler–Napieral-
ski[8] or Pictet–Spengler[9]-type cyclization reactions of acti-
vated 3-phenylpropylamine derivatives under acidic cataly-
sis. However, besides the fact that the formation of a seven-
membered ring by cyclization of an aliphatic chain often
proceeds in low yields,[10] these annulation reactions are
also fraught with difficulties associated with the absence of
electron-donating substituents, for example, OH and OMe,
on the basic aromatic nucleus, which renders the electro-
philic ring-closure less selective and thus it requires more
drastic conditions.[2b,11] Alternative methods have thus been
[a] Université des Sciences et Technologies de Lille 1, LCOP,
Bâtiment C3(2), 59655 Villeneuve d’Ascq, France
Fax: +33-3-20336309
Results and Discussion
Herein we wish to report a conceptually new asymmetric
approach to an array of poly- and diversely substituted 1-
alkyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-ones 1, immediate
E-mail: axel.couture@univ-lille1.fr
[b] CNRS, UMR 8009 “Chimie Organique et Macromoléculaire”,
59655 Villeneuve d’Ascq, France
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D. Dumoulin, S. Lebrun, E. Deniau, A. Couture, P. Grandclaudon
FULL PAPER
precursors of the corresponding chiral 1-alkyl-2,3,4,5-tetra-
hydro-1H-benzo[c]azepines 2 (Table 1). This new synthetic
route, which is depicted retrosynthetically in Scheme 1, is
based upon the use of diastereopure benzo-fused enehydraz-
ides 3 as substrates for catalytic hydrogenation. Ensuing
manipulation of the latent functionalities would provide an
efficient and flexible route to optically active 1-alkylbenz-
azepinones 1 and benzazepines 2. Assembly of these seven-
membered cyclic enehydrazides would be secured by ring-
closure metathesis (RCM) of the diastereochemically pure
styrenic enehydrazides 4. The creation of the stereo-
genic centre would be ensured early in the sequence by tak-
ing advantage of the high degree of diastereoselectivity ob-
served upon nucleophilic 1,2-addition to chiral aromatic hy-
drazones.[13] This operation would be performed on the di-
versely substituted aromatic hydrazones 5 equipped with
appropriate functionalities to secure installation of the
mandatory diolefinic unit.
Scheme 1. Retrosynthetic analysis of chiral benzazepin(on)es.
The first facet of the synthesis was the elaboration of the
monoprotected aromatic hydrazones 5a,b,e,g. These com-
pounds were easily obtained by the three-step sequence de-
picted in Scheme 2 (Table 1). Initially the 2-bromobenzalde-
hydes 6a,b,e,g were protected to give the corresponding ace-
tals 7a,b,e,g and subsequently exposed to nBuLi and then
DMF. This technique allowed the installation of two differ-
entiated carbaldehyde functions onto the symmetrically or
unsymmetrically substituted models 8a,b,e,g. The monopro-
tected aromatic carbaldehydes were converted into the cor-
responding chiral hydrazones (S)-5a,b,e,g by simply mixing
the enantiomerically pure hydrazine (S)-(–)-1-amino-2-
Table 1. Compounds prepared.
1–8, 13–17
R1
R2
R3
R4
a
b
c
d
e
f
OMe
H
H
OMe
H
H
OMe
H
H
H
H
H
H
CH3(CH2)3
Me
CH3(CH2)3
CH3(CH2)5
CH3(CH2)3
Me
H
H
OCH2O
OCH2O
g
OMe
OMe
Me
Scheme 2. Synthesis of the styrenic enehydrazides 4a–g.
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Asymmetric Synthesis of 1-Alkylbenzo[c]azepin-3-ones
(methoxymethyl)pyrrolidine (SAMP; 9) with aromatic car- along with the NH-free (R)-benzazepinones 17c,d released
baldehydes 8a,b,e,g. Owing to the high degree of stereose- from the chiral appendage. We surmised that the formation
lectivity observed upon reaction of the SAMP-hydrazones of these lactams could be attributed to the N–N bond cleav-
with organometallic reagents, a property aptly exploited by age catalysed by the efficient homogeneous ruthenium cata-
Enders and co-workers,[13] the SAMP-hydrazones were al- lyst. The activity of the ruthenium complex in the cleavage
lowed to react with a variety of lithiated reagents 10–12 to of the N–N bonds has indeed been demonstrated for a
afford the alkylated hydrazines 13a–g, which were sub- number of aromatic hydrazines and hydrazides.[16] To corro-
sequently acylated with acryloyl chloride under basic condi- borate this hypothesis, the polysubstituted models 4a,e were
tions to afford the diastereochemically pure enehydrazides in turn exposed to 8 mol-% of the second-generation
14a–g with varying degrees of success, probably due to their Grubbs catalyst in toluene for 12 h, which delivered exclu-
rather congested structure (Scheme 2, Table 2). These pre- sively the chiral unsaturated benzolactams 17a,e in excellent
cursors were obtained essentially as single diastereoisomers yield and enantiopurity. Despite the fact that the RCM re-
detectable by NMR (de Ն 96% after chromatographic action could be a priori performed with the concomitant
treatment), thus revealing the excellent selectivity of the dia- release of the chiral auxiliary we opted to isolate and char-
stereofacial 1,2-addition process.[13] This procedure allowed acterize the easily separable cyclic enehydrazides 3. It was
the introduction, early in the sequence, of the absolute con- indeed anticipated that the olefinic moiety of such com-
figuration at the benzylic α position with respect to the ni- pounds equipped with a stereocontrolling agent could serve
trogen atom, that is, at C1 in the final compounds 1 and 2,
one of the major challenging tasks in the synthesis of the
targeted compounds.
Table 2. Yields of the precursors 8, 5, 14, 15 and 4.
% Yield
8
5
14[a]
15[b]
4
a
b
c
d
e
f
87
85
–
–
74
–
97
88
–
–
91
–
48
78
63
71
47
58
53
66
74
95
84
70
72
59
56
69
47
41
57
66
48
g
91
88
[a] Over two steps. [b] Yield of the crude product.
Regeneration of the retained formyl functionality pro-
ceeded uneventfully to afford satisfactory yields of the
highly functionalized models 15a–g and a final Wittig reac-
tion delivered the opened aromatic dienehydrazides 4a–g,
suitable candidates for the ring-closing metathesis reaction.
The olefin metathesis reaction ranks high in the hierarchy
of synthetic approaches for the elaboration of small, me-
dium and large unsaturated heterocycles,[14] and the propul-
sion of the RCM reaction to the forefront of contemporary
organic chemistry stems mainly from the advent of efficient
homogeneous catalysts.[15] For the ring-closing metathesis
of the styrenic enehydrazides 4a–g we observed that the out-
come of the annulation reaction was strongly conditioned
by the structures of the constitutionally diverse dienic pre-
cursors (Scheme 3, Table 3). Thus, for the methylated com-
pounds 4b,f,g, the best results were obtained by employing
3 mol-% of the second-generation Grubbs catalyst at reflux
for 6 h in toluene, which gave significantly better results
than the usual solvent CH2Cl2. This operation delivered
satisfactory yields of the virtually diastereochemically pure
benzazepinones (R,S)-3b,f,g. Annulation of the bulkier
models 4c,d required an increased amount of ruthenium
catalyst, that is, 5 mol-%, and an extended reaction time,
that is, 12 h. In these cases we observed that the expected
Scheme 3. Asymmetric synthesis of benzazepinones 1a–g and
diastereopure benzazepinones (R,S)-3c,d were obtained benzazepines 2a,b.
Eur. J. Org. Chem. 2009, 3741–3752
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3743

D. Dumoulin, S. Lebrun, E. Deniau, A. Couture, P. Grandclaudon
FULL PAPER
as a chemical handle for alternative functionalization chem- lieve that the formation of unsaturated hydrazide intermedi-
istry. Furthermore, the formation of compounds 3 and 17 ates provides a strong incentive for the elaboration of struc-
was not detrimental to the outcome of the synthetic process turally modified congeners.
liable to give access to the targeted titled compounds. Thus,
catalytic hydrogenation of 3b–d,f,g proceeded uneventfully
Experimental Section
to provide excellent yields of the saturated hydrazides 16b–
d,f,g, a class of compounds endowed with an interesting
synthetic profile. Indeed treatment of 16b–d,f,g with magne-
sium monoperoxyphthalate (MMPP)[17] triggered off the
exclusive release of the chiral appendage and this operation
delivered very satisfactory yields of the virtually enantio-
pure NH-free 1-alkylbenzazepin-2-ones 1b–d,f,g. As far as
we are aware, this synthetic approach can be regarded as
the first asymmetric synthesis of these monoalkylated
benzazepinones as well as their unsaturated congeners 17a–
e. Finally, the reductive N–N bond cleavage by the
BH3·THF complex could be accomplished with the simulta-
neous reduction of the lactam carbonyl functionality of 16b
to complete the synthesis of the chiral 1-alkylbenzazepine
(R)-2b. Alternatively the chiral seven-membered azahetero-
cycles (R)-2a,b could be accessed by LiAlH4 reduction of
the corresponding lactams 1a,b.
General Methods: Tetrahydrofuran (THF) was predried with anhy-
drous Na2SO4 and distilled over sodium benzophenone ketyl under
Ar before use. CH2Cl2, Et3N and toluene were distilled from CaH2.
Dry glassware was obtained by oven-drying and assembly under
dry argon. The glassware was equipped with rubber septa and rea-
gent transfer was performed by syringe techniques. For flash
chromatography, Merck silica gel 60 (40–63 µm; 230–400 mesh
ASTM) was used. The melting points were obtained with a Reich-
ert-Thermopan apparatus and are uncorrected. Optical rotations
were measured with a Perkin–Elmer 343 polarimeter. Elemental
analyses were obtained by using a Carlo–Erba CHNS-11110 instru-
ment. NMR spectra were recorded with a Bruker AM 300 (300
1
and 75 MHz for H, and 13C, respectively) using CDCl3 as the sol-
vent and TMS as the internal standard.
Starting Materials: The o-bromobenzaldehydes 6b,e,g are commer-
cially available and 2-bromo-3,4,5-trimethoxybenzaldehyde (6a)
was prepared according to a reported procedure.[18] o-Bromobenz-
aldehyde acetals 7a,[19] 7b[20] and 7e[21] were synthesized following
literature methods.
Table 3. Yields of the benzazepinones 3, 17, 16 and 1 and the
benzazepines 2.
2-(2-Bromo-4,5-dimethoxyphenyl)-1,3-dioxane (7g): A stirred solu-
tion of 2-bromo-4,5-dimethoxybenzaldehyde (6g; 4.90 g, 20 mmol),
1,3-propanediol (4.75 g, 60 mmol) and p-toluenesulfonic acid
(PTSA, 20 mg, catalytic amount) in dry toluene (60 mL) was
heated at reflux in a Dean–Stark apparatus for 5 h. After evapora-
tion of the solvent under reduced pressure, the crude residue was
purified by flash column chromatography (ethyl acetate/hexanes,
40:60, as eluent) to afford the title compound 7g as a white solid
% Yield
3 and/or 17[a]
1(from 17) 16[b](from 3) 1(from 16)
2
a
b
b
c
d
e
f
–
50
–
90
–
–
–
81
–
66
59
–
78
57
68[c]
81[c]
73[d]
–
–
–
72
38
43
11
–
91
–
85
88
–
41
48
42
48
–
90
92
95
90
–
1
(5.46 g, 90%); m.p. 121–122 °C. H NMR (300 MHz, CDCl3): δ =
41
54
82
87
–
–
1.45 (d, J = 13.5 Hz, 1 H, CH2), 2.18–2.34 (m, 1 H, CH2), 3.87 (s,
3 H, OCH3), 3.92 (s, 3 H, OCH3), 4.04 (t, J = 10.1 Hz, 2 H, OCH2),
4.20–4.41 (m, 2 H, OCH2), 5.71 (s, 1 H, OCHO), 6.99 (s, 1 H,
Harom), 7.21 (s, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ
= 25.7 (CH2), 55.9 (2 OCH3), 67.4 (OCH2), 67.5 (OCH2), 100.7
(OCHO), 109.4 (CH), 111.8 (CH), 113.2 (C), 130.6 (C), 147.1 (C),
148.4 (C) ppm. C12H15BrO4 (303.1): calcd. C 47.54, H 4.99; found
C 47.35, H 4.89.
g
–
–
[a] After an extended reaction time (12 h). [b] Yield of the crude product.
[c] LiAlH4 reduction of 1a,b. [d] Treatment of 16b with BH3·THF.
The absolute configurations of the stereogenic centres as
well as the enantiopurities of compounds 1 and 2 were con-
firmed to be R by comparison of the sign, the optical rota-
tion value and the spectroscopic data with that of an au-
thentic sample assembled by a conceptually different syn-
thetic approach, for example, [α]2D5 = –13.2 (c = 1.05,
CHCl3) for (R)-2b and [α]D = +13.3 (c = 9.0, EtOH) for
(S)-2b.[12]
General Procedure for the Synthesis of 2-(1,3-Dioxan-2-yl)benzalde-
hyde Derivatives 8a,b,e,g: nBuLi (6.6 mL, 16.5 mmol, 2.5  solution
in hexanes) was slowly added to a stirred solution of the appropri-
ate protected 2-bromobenzaldehyde 7a,b,e,g (15 mmol) in dry THF
(50 mL) at –78 °C under argon. The mixture was warmed to –50 °C
for 40 min and then cooled to –78 °C. DMF (1.28 mL, 1.20 g,
16.5 mmol) was added and the solution was warmed to room temp.
and then stirred for 3 h. Water (50 mL) was added and the mixture
was extracted with CH2Cl2 (3ϫ5 mL). The combined organic lay-
ers were dried (MgSO4) and the solvent was evaporated under vac-
uum. The crude product was purified by flash column chromatog-
raphy (ethyl acetate/hexanes, 40:60, as eluent) to give compounds
8a,b,e,g as colourless oils.
Conclusions
We have developed a flexible and efficient route for the
stereoselective synthesis of a variety of structurally diverse
1-alkyldihydro and tetrahydro-2-benzazepin(on)es. The key
steps are the highly diastereoselective nucleophilic 1,2-ad-
dition process applied to a diastereopure aromatic hydraz-
one combined with RCM to form the seven-member
azaheterocycle ring system. The synthetic utility of this ap-
proach has been further enhanced by its extension to the
6-(1,3-Dioxan-2-yl)-2,3,4-trimethoxybenzaldehyde
(8a):
Yield
3.68 g, 87%. 1H NMR (300 MHz, CDCl3): δ = 1.47 (d, J = 13.6 Hz,
1 H, CH2), 2.15–2.35 (m, 1 H, CH2), 3.88 (s, 3 H, OCH3), 3.99 (s,
6 H, 2 OCH3), 4.10 (t, J = 12.2 Hz, 2 H, OCH2), 4.25 (dd, J =
10.7, 5.1 Hz, 2 H, OCH2), 6.35 (s, 1 H, OCHO), 7.26 (s, 1 H,
synthesis of the corresponding benzazepines. We also be- Harom), 10.40 (s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3741–3752

Asymmetric Synthesis of 1-Alkylbenzo[c]azepin-3-ones
= 25.8 (CH2), 56.2 (OCH3), 61.0 (OCH3), 62.5 (OCH3), 67.6 (2 130.7 (CH), 134.4 (C), 134.7 (C) ppm. C17H24N2O3 (304.4): calcd.
OCH2), 97.3 (OCHO), 105.7 (CH), 119.1 (C), 133.7 (C), 151.5 (C), C 67.08, H 7.95, N 9.20; found C 67.19, H 7.86, N 9.39.
155.5 (2 C), 190.6 (CHO) ppm. C14H18O6 (282.3): calcd. C 59.57,
{(E)-1-[6-(1,3-Dioxan-2-yl)benzo[1,3]dioxol-5-yl]methylidene}[(S)-2-
H 6.43; found C 59.41, H 6.18.
(methoxymethyl)pyrrolidin-1-yl]amine (5e): Yield 3.17 g, 91%. [α]2D5
1
2-(1,3-Dioxan-2-yl)benzaldehyde (8b):[22] Yield 2.45 g, 85%.
= –63.6 (c = 0.73, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.42
(d, J = 13.5 Hz, 1 H, CH2), 1.81–2.09 (m, 4 H, 2 CH2), 2.12–2.28
(m, 1 H, CH2), 3.08 (q, J = 8.4 Hz, 1 H, CH), 3.38 (s, 3 H, OCH3),
3.54 (t, J = 7.9 Hz, 2 H, CH2N), 3.66 (d, J = 9.8 Hz, 2 H, OCH2),
3.95 (t, J = 10.2 Hz, 2 H, OCH2), 4.19–4.29 (m, 2 H, OCH2), 5.64
(s, 1 H, OCHO), 5.91 (s, 2 H, OCH2O), 7.04 (s, 1 H, Harom), 7.37
(s, 1 H, Harom), 7.53 (s, 1 H, CH=N) ppm. 13C NMR (75 MHz,
CDCl3): δ = 22.2 (CH2), 25.7 (CH2), 26.9 (CH2), 49.3 (NCH2), 59.3
(OCH3), 63.1 (CH), 67.5 (OCH2), 67.5 (OCH2), 74.6 (OCH2), 100.0
(OCHO), 101.0 (OCH2O), 104.7 (CH), 106.5 (CH), 129.0 (C),
129.5 (C), 130.4 (C), 130.5 (CH=N), 146.7 (C), 148.0 (C) ppm.
C18H24N2O5 (348.4): calcd. C 62.05, H 6.94, N 8.04; found C 61.92,
H 6.69, N 8.28.
6-(1,3-Dioxan-2-yl)benzo[1,3]dioxole-5-carbaldehyde (8e): Yield
2.62 g, 74%. 1H NMR (300 MHz, CDCl3): δ = 1.46 (d, J = 13.6 Hz,
1 H, CH2), 2.16–2.34 (m, 1 H, CH2), 4.02 (t, J = 9.9 Hz, 2 H,
OCH2), 4.17–4.31 (m, 2 H, OCH2), 5.91 (s, 1 H, OCHO), 6.01 (s,
2 H, OCH2O), 7.13 (s, 1 H, Harom), 7.34 (s, 1 H, Harom), 10.30 (s,
1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.7 (CH2),
67.5 (OCH2), 67.5 (OCH2), 100.0 (OCHO), 101.1 (OCH2O), 110.5
(CH), 114.7 (CH), 129.6 (C), 140.2 (C), 147.4 (C), 152.3 (C), 190.0
(CHO) ppm. C12H12O5 (236.3): calcd. C 61.02, H 5.12; found C
61.27, H 4.99.
2-(1,3-Dioxan-2-yl)-4,5-dimethoxybenzaldehyde (8g): Yield 3.44 g,
1
91%. H NMR (300 MHz, CDCl3): δ = 1.51 (d, J = 13.4 Hz, 1 H,
{(E)-1-[2-(1,3-Dioxan-2-yl)-4,5-dimethoxyphenyl]methylidene}[(S)-
2-(methoxymethyl)pyrrolidin-1-yl]amine (5g): Yield 3.21 g, 88 %.
CH2), 2.20–2.37 (m, 1 H, CH2), 3.96 (s, 3 H, OCH3), 4.01 (s, 3 H,
OCH3), 4.07 (t, J = 9.9 Hz, 2 H, OCH2), 4.26–4.34 (m, 2 H,
OCH2), 6.04 (s, 1 H, OCHO), 7.28 (s, 1 H, Harom), 7.47 (s, 1 H,
Harom), 10.39 (s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ
= 25.8 (CH2), 55.9 (2 OCH3), 67.5 (OCH2), 67.6 (OCH2), 100.1
(OCHO), 114.4 (CH), 119.1 (CH), 130.5 (C), 139.1 (C), 148.8 (C),
153.4 (C), 189.9 (CHO) ppm. C13H16O5 (252.3): calcd. C 61.90, H
6.39; found C 61.68, H 6.44.
1
[α]2D5 = –65.3 (c = 0.93, CHCl3). H NMR (300 MHz, CDCl3): δ =
1.37 (d, J = 13.5 Hz, 1 H, CH2), 1.74–2.02 (m, 4 H, 2 CH2), 2.11–
2.24 (m, 1 H, CH2), 3.04 (q, J = 8.5 Hz, 1 H, CH), 3.33 (s, 3 H,
OCH3), 3.43 (t, J = 8.0 Hz, 2 H, CH2N), 3.60 (d, J = 10.0 Hz, 2
H, OCH2), 3.83 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.89 (t, J =
10.3 Hz, 2 H, OCH2), 4.09–4.27 (m, 2 H, OCH2), 5.64 (s, 1 H,
OCHO), 7.02 (s, 1 H, Harom), 7.36 (s, 1 H, Harom), 7.50 (s, 1 H,
CH=N) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.3 (CH2), 25.7
(CH2), 26.9 (CH2), 49.5 (NCH2), 55.8 (2 OCH3), 59.3 (OCH3), 63.1
(CH), 67.5 (OCH2), 67.5 (OCH2), 74.8 (OCH2), 100.1 (OCHO),
107.4 (CH), 108.8 (CH), 127.6 (CH=N), 130.8 (C), 130.9 (C), 149.4
(C), 157.1 (C) ppm. C19H28N2O5 (364.4): calcd. C 62.62, H 7.74,
N 7.69; found C 62.45, H 7.87, N 7.41.
General Procedure for the Synthesis of the SAMP-Hydrazones
5a,b,e,g: A solution of the appropriate 2-(1,3-dioxan-2-yl)benzalde-
hyde derivative 8a,b,e,g (0.10 mmol), SAMP (1.56 g, 0.12 mmol)
and MgSO4 (500 mg) in CH2Cl2 (50 mL) was stirred at room temp.
for 12 h. MgSO4 was filtered off and the solvent was evaporated
under vacuum. The crude residue was purified by flash column
chromatography (ethyl acetate/hexanes, 50:50, as eluent) to yield
hydrazones 5a,b,e,g as a yellow viscous oil.
General Procedure for the Synthesis of the Protected (1R)-Alkyl-
enehydrazides 14a–g: Methyllithium (10, 3.75 mL, 6 mmol, 1.6  in
diethyl ether), n-butyllithium (11, 3.75 mL, 6 mmol, 1.6  solution
in hexanes) or hexyllithium (12, 2.6 mL, 6 mmol, 2.3  solution in
hexane) was added dropwise to a stirred solution of the appropriate
hydrazone 5a,b,e,g (2 mmol) in dry THF (10 mL) at –78 °C under
argon. The mixture was then warmed to room temp. and stirred
for a further 3 h. Water (10 mL) was added and the mixture was
extracted with ethyl acetate (3ϫ25 mL). The combined organic
layers were dried (MgSO4) and the solvent was evaporated to give
the corresponding crude hydrazine 13a–g as a brown oil, which was
used without further purification in the next step. Acryloyl chloride
(545 mg, 0.48 mL, 6 mmol) was added dropwise to a stirred solu-
tion of hydrazine 13a–g (1.2 mmol) and Et3N (5 mL) in dry toluene
(12 mL) under argon and the mixture was heated at reflux for 12 h.
The cooled solution was washed with water (3ϫ15 mL) and brine
(15 mL). The organic layer was dried (MgSO4), the solvent was
evaporated under vacuum and the crude product was purified by
flash column chromatography (ethyl acetate/hexanes, 40:60, as elu-
ent) to yield the corresponding enehydrazide 14a–g as a pale
brown-orange oil.
{(E)-1-[6-(1,3-Dioxan-2-yl)-2,3,4-trimethoxyphenyl]methylidene}-
[(S)-2-(methoxymethyl)pyrrolidin-1-yl]amine (5a): Yield 3.83 g,
97%. [α]2D5 = –97.3 (c = 1.28, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.44 (d, J = 13.4 Hz, 1 H, CH2), 1.81–2.13 (m, 4 H, 2 CH2),
2.16–2.39 (m, 1 H, CH2), 3.05 (q, J = 8.5 Hz, 1 H, CH), 3.44 (s, 3
H, OCH3), 3.51–3.63 (m, 2 H, CH2N), 3.65–3.79 (m, 2 H, CH2O),
3.85 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 3.93 (s, 3 H, OCH3),
4.02 (t, J = 10.2 Hz, 2 H, OCH2), 4.21–4.37 (m, 2 H, OCH2), 6.30
(s, 1 H, OCHO), 7.19 (s, 1 H, Harom), 7.52 (s, 1 H, CH=N) ppm.
13C NMR (75 MHz, CDCl3): δ = 22.2 (CH2), 25.7 (CH2), 26.8
(CH2), 49.1 (NCH2), 55.9 (OCH3), 56.0 (OCH3), 59.4 (OCH3), 60.8
(OCH3), 63.6 (CH), 67.3 (OCH2), 67.4 (OCH2), 74.9 (OCH2), 99.0
(OCHO), 102.9 (CH), 121.3 (C), 129.6 (CH=N), 131.5 (C), 134.3
(C), 151.2 (C), 153.2 (C) ppm. C20H30N2O6 (394.46): calcd. C
60.90, H 7.67, N 7.10; found C 61.09, H 7.77, N 7.46.
{(E)-1-[2-(1,3-Dioxan-2-yl)phenyl]methylidene}[(S)-2-(methoxy-
methyl)pyrrolidin-1-yl]amine (5b): Yield 2.68 g, 88%. [α]2D5 = –68.9
1
(c = 0.89, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.44 (d, J =
13.4 Hz, 1 H, CH2), 1.86–2.07 (m, 4 H, 2 CH2), 2.16–2.37 (m, 1 H,
CH2), 3.10 (q, J = 8.5 Hz, 1 H, CH), 3.40 (s, 3 H, OCH3), 3.52 (t,
J = 7.9 Hz, 2 H, CH2N), 3.68 (dd, J = 3.5, 10.2 Hz, 2 H, OCH2),
N-{(R)-1-[6-(1,3-Dioxan-2-yl)-2,3,4-trimethoxyphenyl]pentyl}-N-
[(S)-2-(methoxymethyl)pyrrolidin-1-yl]acrylamide (14a): Yield
3.97 (t, J = 10.1 Hz, 2 H, OCH2), 4.26 (dd, J = 5.0, 6.0 Hz, 2 H, 292 mg, 48%. [α]2D5 = –66.6 (c = 0.95, CHCl3). 1H NMR (300 MHz,
OCH2), 5.75 (s, 1 H, CH), 7.22 (sext., J = 6.1 Hz, 2 H, Harom), 7.52 CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3 H, CH3), 1.09–1.52 (m, 5 H, 4
(dd, J = 1.1, 7.7 Hz, 1 H, Harom), 7.63 (s, 1 H, CH=N), 7.85 (dd,
H, 2 CH2 + 1 H, CH2), 1.53–1.79 (m, 4 H, 2 CH2), 1.81–1.99 (m,
J = 1.6, 7.8 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ 2 H, CH2), 2.03–2.27 (m, 1 H, CH2), 2.47–2.74 (m, 1 H, CH2N),
= 21.0 (CH2), 25.8 (CH2), 27.0 (CH2), 49.1 (NCH2), 59.2 (OCH3), 2.77–2.98 (m, 1 H, CH2N), 3.01–3.17 (m, 2 H, OCH2), 3.11 (s, 3
63.0 (CH), 67.4 (OCH2), 67.5 (OCH2), 74.7 (OCH2), 101.0 H, OCH3), 3.35–3.51 (m, 1 H, CH), 3.74–4.02 (m, 2 H, OCH2),
(OCHO), 125.1 (CH), 126.1 (CH=N), 126.5 (CH), 128.7 (CH),
3.77 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3),
Eur. J. Org. Chem. 2009, 3741–3752
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3745

D. Dumoulin, S. Lebrun, E. Deniau, A. Couture, P. Grandclaudon
FULL PAPER
4.09–4.31 (m, 2 H, OCH2), 5.39–5.48 (m, 1 H, ArCHN), 5.55 (s, 1
H, OCHO), 5.61 (dd, J = 2.2, 10.3 Hz, 1 H, CH2=), 6.35 (dd, J =
31.7 (CH2), 34.1 (CH2), 50.7 (NCH2), 56.3 (ArCHN), 57.8 (OCH3),
58.3 (CH), 67.5 (OCH2), 67.6 (OCH2), 72.9 (OCH2), 101.5
2.2, 15.1 Hz, 1 H, CH2=), 7.06 (dd, J = 6.9, 10.3 Hz, 1 H, CH=), (OCHO), 126.1 (CH2=), 127.0 (CH), 127.1 (CH), 128.9 (CH=),
7.09 (s, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1
129.3 (CH), 130.2 (CH), 134.9 (C), 142.3 (C), 170.6 (CO) ppm.
(CH3), 21.6 (CH2), 22.5 (CH2), 25.9 (CH2), 26.9 (CH2), 29.8 (CH2), C26H40N2O4 (444.6): calcd. C 70.24, H 9.07, N 6.30; found C 70.27,
33.9 (CH2), 50.8 (NCH2), 55.8 (OCH3), 55.9 (OCH3), 56.6
(ArCHN), 57.8 (OCH3), 58.4 (CH), 60.8 (OCH3), 67.5 (OCH2),
67.6 (OCH2), 72.9 (OCH2), 100.2 (OCHO), 103.2 (CH), 121.3 (C),
126.2 (CH2=), 129.4 (CH=), 131.7 (C), 134.6 (C), 150.8 (C), 152.1
(C), 170.8 (CO) ppm. C27H42N2O7 (506.6): calcd. C 64.01, H 8.36,
N 5.53; found C 63.78, H 8.13, N 5.38.
H 8.88, N 6.18.
N-{(R)-1-[6-(1,3-Dioxan-2-yl)benzo[1,3]dioxol-5-yl]pentyl}-N-[(S)-2-
(methoxymethyl)pyrrolidin-1-yl]acrylamide (14e): Yield 260 mg,
47%. [α]2D5 = –18.6 (c = 0.83, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 0.90 (t, J = 6.6 Hz, 3 H, CH3), 1.11–1.51 (m, 5 H, 4 H, 2 CH2
+ 1 H, CH2), 1.53–1.81 (m, 4 H, 2 CH2), 1.83–2.01 (m, 2 H, CH2),
2.07–2.31 (m, 1 H, CH2), 2.48–2.76 (m, 1 H, CH2N), 2.78–2.96 (m,
1 H, CH2N), 3.09 (dd, J = 4.1, 8.9 Hz, 2 H, OCH2), 3.11 (s, 3 H,
OCH3), 3.37–3.50 (m, 1 H, CH), 3.77–4.09 (m, 2 H, OCH2), 4.11–
4.35 (m, 2 H, OCH2), 5.39–5.48 (m, 1 H, ArCHN), 5.55 (s, 1 H,
OCHO), 5.61 (dd, J = 2.2, 10.4 Hz, 1 H, CH2=), 5.88 (s, 2 H,
OCH2O), 6.35 (dd, J = 2.2, 15.1 Hz, 1 H, CH2=), 7.05 (s, 1 H,
Harom), 7.06 (dd, J = 6.9, 10.4 Hz, 1 H, CH=), 7.45 (s, 1 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 22.3
(CH2), 22.6 (CH2), 25.8 (CH2), 27.0 (CH2), 29.6 (CH2), 34.1 (CH2),
50.8 (NCH2), 56.0 (ArCHN), 58.1 (OCH3), 58.5 (CH), 67.5
(OCH2), 67.5 (OCH2), 73.0 (OCH2), 100.3 (OCHO), 101.1
(OCH2O), 107.1 (CH), 109.0 (CH), 126.4 (CH2=), 128.7 (C), 130.1
(CH=), 132.3 (C), 146.5 (C), 148.1 (C), 170.4 (CO) ppm.
C25H36N2O6 (460.6): calcd. C 65.20, H 7.88, N 6.08; found C 64.99,
H 7.74, N 6.19.
N-{(R)-1-[2-(1,3-Dioxan-2-yl)phenyl]ethyl}-N-[(S)-2-(methoxymeth-
yl)pyrrolidin-1-yl]acrylamide (14b): Yield 350 mg, 78%. [α]2D5
=
–55.8 (c = 0.90, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.47 (d,
J = 13.6 Hz, 1 H, CH2), 1.51–1.69 (m, 4 H, 2 CH2), 1.82 (d, J =
7.3 Hz, 3 H, CH3), 2.12–2.43 (m, 1 H, CH2), 2.63 (q, J = 7.75 Hz,
1 H, CH2N), 2.78–2.92 (m, 1 H, CH2N), 3.05 (d, J = 11.6 Hz, 2
H, OCH2), 3.06 (s, 3 H, OCH3), 3.38–3.51 (m, 1 H, CH), 3.82–4.11
(m, 2 H, OCH2), 4.17–4.31 (m, 2 H, OCH2), 5.61 (dd, J = 2.2,
9.9 Hz, 1 H, CH2=), 5.62 (s, 1 H, OCHO), 5.72 (q, J = 7.2 Hz, 1
H, ArCH), 6.37 (dd, J = 2.3, 14.9 Hz, 1 H, CH2=), 7.07 (dd, J =
6.9, 10.4 Hz, 1 H, CH=), 7.23–7.40 (m, 2 H, Harom), 7.51 (d, J =
7.7 Hz, 1 H, Harom), 7.87 (d, J = 7.8 Hz, 1 H, Harom) ppm. 13C
NMR (75 MHz, CDCl3): δ = 21.2 (CH3), 21.8 (CH2), 25.9 (CH2),
27.1 (CH2), 50.9 (NCH2), 51.5 (CH), 58.1 (OCH3), 58.6 (CH), 67.6
(OCH2), 67.7 (OCH2), 73 (OCH2), 101.1 (OCHO), 126.4 (CH2=),
126.8 (CH), 127.4 (CH), 128.6 (CH=), 129.4 (CH), 130.0 (CH),
135.2 (C), 141.2 (C), 170.3 (CO) ppm. C21H30N2O4 (374.5): calcd.
C 67.36, H 8.07, N 7.48; found C 67.63, H 8.14, N 7.69.
N-{(R)-1-[6-(1,3-Dioxan-2-yl)benzo[1,3]dioxol-5-yl]ethyl}-N-[(S)-2-
(methoxymethyl)pyrrolidin-1-yl]acrylamide (14f): Yield 291 mg,
58%. [α]2D5 = –15.4 (c = 0.96, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.37 (d, J = 13.7 Hz, 1 H, CH2), 1.40–1.68 (m, 4 H, 2 CH2),
1.73 (d, J = 7.2 Hz, 3 H, CH3), 2.0–2.28 (m, 1 H, CH2), 2.63 (q, J
= 7.6 Hz, 1 H, CH2N), 2.68–2.93 (m, 1 H, CH2N), 3.02 (dd, J =
3.0, 9.7 Hz, 2 H, OCH2), 3.03 (s, 3 H, OCH3), 3.38–3.51 (m, 1 H,
CH), 3.62–3.97 (m, 2 H, OCH2), 4.07–4.24 (m, 2 H, OCH2), 5.49
(s, 1 H, OCHO), 5.54 (dd, J = 2.8, 9.6 Hz, 1 H, CH2=), 5.59–5.77
(m, 1 H, CH), 5.86 (s, 2 H, OCH2O), 6.29 (dd, J = 2.5, 15.2 Hz, 1
H, CH2=), 6.98 (s, 1 H, Harom), 7.01 (dd, J = 6.9, 10.4 Hz, 1 H,
CH=), 7.33 (s, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.3 (CH3), 21.8 (CH2), 25.7 (CH2), 27.1 (CH2), 50.9 (NCH2), 51.3
(CH), 58.2 (CH), 58.5 (OCH3), 67.4 (OCH2), 67.5 (OCH2), 73.0
(OCH2), 100.0 (OCHO), 101.1 (OCH2O), 107.0 (CH), 108.6 (CH),
126.4 (CH2=), 129.4 (C), 129.8 (CH=), 135.3 (C), 146.6 (C), 148.0
(C), 170.1 (CO) ppm. C22H30N2O6 (418.5): calcd. C 63.14, H 7.23,
N 6.69; found C 63.29, H 7.05, N 6.51.
N-{(R)-1-[2-(1,3-Dioxan-2-yl)phenyl]pentyl}-N-[(S)-2-(methoxy-
methyl)pyrrolidin-1-yl]acrylamide (14c): Yield 315 mg, 63%. [α]2D5
=
–59.4 (c = 0.95, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.88 (t,
J = 7.3 Hz, 3 H, CH3), 1.12–1.42 (m, 4 H, 2 CH2), 1.45 (d, J =
13.5 Hz, 1 H, CH2), 1.51–1.82 (m, 4 H, 2 CH2), 1.83–2.04 (m, 2 H,
CH2), 2.13–2.34 (m, 1 H, CH2), 2.60–2.79 (m, 1 H, CH2N), 2.81–
2.94 (m, 1 H, CH2N), 2.93–3.06 (m, 5 H, OCH2, OCH3), 3.25–3.38
(m, 1 H, CH), 3.84–4.11 (m, 2 H, OCH2), 4.14–4.32 (m, 2 H,
OCH2), 5.43 (q, J = 5.6 Hz, 1 H, ArCHN), 5.58 (dd, J = 2.3,
10.2 Hz, 1 H, CH2=), 5.59 (s, 1 H, OCHO), 6.34 (dd, J = 2.3,
14.9 Hz, 1 H, CH2=), 7.08 (dd, J = 6.9, 10.4 Hz, 1 H, CH=), 7.23–
7.28 (m, 2 H, Harom), 7.47 (d, J = 7.6 Hz, 1 H, Harom), 7.92 (d, J
= 7.4 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.7
(CH3), 21.6 (CH2), 22.5 (CH2), 25.9 (CH2), 26.8 (CH2), 29.8 (CH2),
33.8 (CH2), 50.6 (NCH2), 56.4 (ArCHN), 57.7 (OCH3), 58.3 (CH),
67.5 (OCH2), 67.6 (OCH2), 72.8 (OCH2), 101.6 (OCHO), 126.1
(CH2=), 127.0 (CH), 127.1 (CH), 128.8 (CH=), 129.3 (CH), 130.2
(CH), 134.8 (C), 140.1 (C), 170.6 (CO) ppm. C24H36N2O4 (416.5):
calcd. C 69.20, H 8.71, N 6.72; found C 69.38, H 8.84, N 6.99.
N-{(R)-1-[2-(1,3-Dioxan-2-yl)-4,5-dimethoxyphenyl]ethyl}-N-[(S)-2-
(methoxymethyl)pyrrolidin-1-yl]acrylamide (14g): Yield 276 mg,
53%. [α]2D5 = –29.1 (c = 0.83, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.44 (d, J = 13.4 Hz, 1 H, CH), 1.49–1.76 (m, 4 H, 2 CH2),
1.81 (d, J = 7.2 Hz, 3 H, CH3), 2.1–2.33 (m, 1 H, CH2), 2.65 (q, J
N-{(R)-1-[2-(1,3-Dioxan-2-yl)phenyl]heptyl}-N-[(S)-2-(methoxy- = 7.6 Hz, 1 H, CH2N), 2.83–2.96 (m, 1 H, CH2N), 2.97–3.06 (m,
methyl)pyrrolidin-1-yl]acrylamide (14d): Yield 379 mg, 71%. [α]2D5
–57.5 (c = 1.10, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.72– 4.06 (m, 2 H, OCH2), 3.85 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3),
0.93 (m, 3 H, CH3), 1.12–1.41 (m, 8 H, 4 CH2), 1.46 (d, J = 4.13–4.31 (m, 2 H, OCH2), 5.57 (dd, J = 1.9, 8.2 Hz, 1 H, CH2=),
=
2 H, OCH2), 3.07 (s, 3 H, OCH3), 3.31–3.5 (m, 1 H, CH), 3.76–
1
13.6 Hz, 1 H, CH2), 1.51–1.79 (m, 4 H, 2 CH2), 1.82–2.03 (m, 2 H,
CH2), 2.05–2.32 (m, 1 H, CH2), 2.58–2.79 (m, 1 H, CH2N), 2.81–
5.58 (s, 1 H, OCHO), 5.69 (q, J = 7.2 Hz, 1 H, CH), 6.32 (dd, J =
2.3, 14.9 Hz, 1 H, CH2=), 7.04 (dd, J = 6.9, 10.4 Hz, 1 H, CH=),
2.93 (m, 1 H, CH2N), 2.94–3.04 (m, 5 H, OCH2, OCH3), 3.34 (m, 7.05 (s, 1 H, Harom), 7.49 (s, 1 H, Harom) ppm. 13C NMR (75 MHz,
1 H, CH), 3.82–4.08 (m, 2 H, OCH2), 4.13–4.34 (m, 2 H, OCH2),
5.44 (q, J = 5.6 Hz, 1 H, ArCHN), 5.58 (dd, J = 2.3, 9.9 Hz, 1 H,
CH2=), 5.60 (s, 1 H, OCHO), 6.34 (dd, J = 2.3, 14.9 Hz, 1 H,
CDCl3): δ = 21.3 (CH3), 21.8 (CH2), 25.7 (CH2), 27.0 (CH2), 50.8
(NCH2), 51.2 (CH), 55.8 (OCH3), 55.9 (OCH3), 58.2 (CH), 58.7
(OCH3), 67.5 (OCH2), 67.6 (OCH2), 73.2 (OCH2), 100.4 (OCHO),
CH2=), 7.08 (dd, J = 6.9, 10.4 Hz, 1 H, CH=), 7.18–7.39 (m, 2 H, 109.1 (CH), 111.6 (CH), 126.2 (CH2=), 127.8 (C), 130.1 (CH=),
Harom), 7.47 (d, J = 7.5 Hz, 1 H, Harom), 7.91 (d, J = 7.5 Hz, 1 H, 134.0 (CH), 147.7 (C), 149.1 (C), 170.3 (CO) ppm. C23H34N2O6
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 21.7 (434.5): calcd. C 63.57, H 7.89, N 6.45; found C 63.79, H 7.89, N
(CH2), 22.6 (CH2), 25.9 (CH2), 26.9 (CH2), 27.5 (CH2), 29.1 (CH2), 6.65.
3746
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3741–3752

Asymmetric Synthesis of 1-Alkylbenzo[c]azepin-3-ones
General Procedure for the Deprotection of the Benzaldehyde Moiety (CH=), 131.2 (CH), 134.3 (CH), 136.1 (C), 147.2 (C), 170.8 (CO),
of the (1R)-Alkyl-enehydrazides 14a–g: A mixture of the protected
194.3 (CHO) ppm. C21H30N2O3 (358.5): calcd. C 70.36, H 8.44, N
enehydrazide 14a–g (1 mmol) and FeCl3·6H2O (946 mg, 3.5 mmol) 7.81; found C 70.69, H 8.68, N 7.58.
in CH2Cl2 (15 mL) was stirred at room temp. for 3 h and then
N-[(R)-1-(2-Formylphenyl)heptyl]-N-[(S)-2-(methoxymethyl)pyrrol-
quenched by the addition of saturated aqueous NaHCO3 (10 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ15 mL) and the
combined organic phases were washed with brine (20 mL), dried
(MgSO4) and concentrated under vacuum. The resulting oily solu-
tion was filtered through a short pad of silica gel to remove any
remaining iron species. The deprotected aldehydes were eluted by
using an EtOAc/hexanes (60:40) mixture. Evaporation of the sol-
vent delivered benzaldehyde derivative 15a–g as a yellow-orange
oil, which was used in the next step without further purification.
idin-1-yl]acrylamide (15d): Yield 325 mg, 84%. [α]2D5 = –104.1 (c =
0.64, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.84 (t, J = 6.6 Hz,
3 H, CH3), 1.11–1.42 (m, 8 H, 4 CH2), 1.51–1.64 (m, 2 H, CH2),
1.67–1.83 (m, 2 H, CH2), 1.87–2.04 (m, 2 H, CH2), 2.58–2.79 (m,
1 H, CH2N), 2.85–2.96 (m, 2 H, CH2O), 2.92 (s, 3 H, OCH3), 3.12
(q, J = 7.8 Hz, 1 H, CH2N), 3.28–3.41 (m, 1 H, CH), 5.61 (dd, J
= 2.2, 10.2 Hz, 1 H, CH2=), 5.87 (q, J = 5.4 Hz, 1 H, ArCHN),
6.36 (dd, J = 2.2, 15.0 Hz, 1 H, CH2=), 7.13 (dd, J = 6.8, 10.5 Hz,
1 H, CH=), 7.32 (t, J = 6.5 Hz, 1 H, Harom), 7.57 (td, J = 1.2,
6.3 Hz, 1 H, Harom), 7.72 (dd, J = 1.4, 6.1 Hz, 1 H, Harom), 8.18
(d, J = 7.7 Hz, 1 H, Harom), 10.08 (s, 1 H, CHO) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1 (CH3), 21.7 (CH2), 22.6 (CH2), 26.9
(CH2), 27.6 (CH2), 29.1 (CH2), 31.7 (CH2), 34.1 (CH2), 50.8
(NCH2), 55.9 (ArCHN), 58.1 (OCH3), 58.3 (CH), 73.3 (OCH2),
126.1 (CH2=), 127.0 (CH), 129.8 (CH), 130.1 (CH=), 131.3 (CH),
134.4 (CH), 136.9 (C), 147.3 (C), 170.6 (CO), 194.2 (CHO) ppm.
C23H34N2O3 (386.5): calcd. C 71.47, H 8.87, N 7.25; found C 71.20,
H 8.94, N 6.97.
N-[(R)-1-(6-Formyl-2,3,4-trimethoxyphenyl)pentyl]-N-[(S)-2-(meth-
oxymethyl)pyrrolidin-1-yl]acrylamide (15a): Yield 296 mg, 66 %.
[α]2D5 = –73.5 (c = 0.88, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
0.85 (t, J = 7.7 Hz, 3 H, CH3), 1.04–1.41 (m, 4 H, 2 CH2), 1.56–
1.91 (m, 2 H, CH2), 1.93–2.35 (m, 4 H, 2 CH2), 2.82 (s, 3 H,
OCH3), 2.87–3.39 (m, 2 H, CH2N), 3.49–3.73 (m, 2 H, OCH2),
3.79–4.01 (m, 1 H, CH), 3.88 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3),
3.95 (s, 3 H, OCH3), 5.77 (dd, J = 1.9, 8.5 Hz, 1 H, CH2=), 5.92–
6.12 (m, 1 H, ArCHN), 6.44 (dd, J = 2.2, 14.2 Hz, 1 H, CH2=),
6.96 (dd, J = 6.7, 10.4 Hz, 1 H, CH=), 7.35 (s, 1 H, Harom), 10.60
(s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3),
21.9 (CH2), 22.6 (CH2), 28.1 (CH2), 29.5 (CH2), 36.8 (CH2), 50.6
(NCH2), 55.9 (OCH3), 56.0 (OCH3), 56.8 (ArCHN), 58.2 (OCH3),
58.6 (CH), 60.8 (OCH3), 73.8 (OCH2), 106.4 (CH), 126.6 (C), 127.8
(CH2=), 128.3 (C), 129.6 (CH=), 133.7 (C), 151.6 (C), 152.9 (C),
170.8 (CO), 193.2 (CHO) ppm. C24H36N2O6 (448.5): calcd. C
64.26, H 8.09, N 6.25; found C 64.14, H 8.31, N 6.49.
N-[(R)-1-(2-Formylbenzo[1,3]dioxol-5-yl)pentyl]-N-[(S)-2-(methoxy-
methyl)pyrrolidin-1-yl]acrylamide (15e): Yield 282 mg, 70%. [α]2D5
=
1
–172.8 (c = 1.39, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.87
(t, J = 7.7 Hz, 3 H, CH3), 1.02–1.44 (m, 4 H, 2 CH2), 1.53–1.68
(m, 2 H, CH2), 1.70–1.91 (m, 4 H, 2 CH2), 2.53–2.72 (m, 1 H,
CH2N), 2.79–2.93 (m, 1 H, CH2N), 2.97 (d, J = 9.8 Hz, 2 H,
OCH2), 3.05 (s, 3 H, OCH3), 2.94–3.15 (m, 1 H, CH), 5.63 (dd, J
= 2.2, 8.3 Hz, 1 H, CH2=), 5.88 (q, J = 5.8 Hz, 1 H, ArCHN), 6.06
(s, 2 H, OCH2O), 6.36 (dd, J = 14.9–2.3 Hz, 1 H, CH2=), 7.13 (dd,
J = 6.7, 10.4 Hz, 1 H, CH=), 7.16 (s, 1 H, Harom), 7.80 (s, 1 H,
Harom), 9.94 (s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.1 (CH3), 21.4 (CH2), 22.6 (CH2), 26.8 (CH2), 29.6 (CH2), 34.7
(CH2), 50.7 (NCH2), 55.2 (ArCHN), 58.7 (OCH3), 58.7 (CH), 73.3
(OCH2), 102.1 (OCH2O), 110.8 (CH), 113.4 (CH), 126.0 (C), 126.6
(CH2=), 130.1 (CH=), 144.9 (C), 152.5 (C), 170.9 (CO), 191.4
(CHO) ppm. C22H30N2O5 (402.5): calcd. C 65.65, H 7.51, N 6.96;
found C 65.49, H 7.68, N 6.98.
N-[(R)-1-(2-Formylphenyl)ethyl]-N-[(S)-2-(methoxymethyl)pyrrol-
idin-1-yl]acrylamide (15b): Yield 234 mg, 74%. [α]2D5 = –228.6 (c =
0.81, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.49–1.67 (m, 2
H, CH2), 1.70–1.89 (m, 2 H, CH2), 1.83 (d, J = 7.0 Hz, 3 H, CH3),
2.72–2.87 (m, 1 H, CH2N), 3.08 (s, 3 H, OCH3), 2.95–3.03 (m, 2
H, CH2N in part + CH), 3.04–3.18 (m, 2 H, CH2O), 5.64 (dd, J =
2.2, 8.2 Hz, 1 H, CH2=), 6.00 (q, J = 7.0 Hz, 1 H, CH), 6.39 (dd,
J = 2.3, 14.9 Hz, 1 H, CH2=), 7.18 (dd, J = 6.9, 10.4 Hz, 1 H,
CH=), 7.44 (t, J = 6.4 Hz, 1 H, Harom), 7.58 (td, J = 1.3, 6.3 Hz,
1 H, Harom), 7.76 (dd, J = 1.3, 6.3 Hz, 1 H, Harom), 8.03 (d, J =
7.75 Hz, 1 H, Harom), 10.10 (s, 1 H, CHO) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.3 (CH3), 21.6 (CH2), 27.0 (CH2), 50.9
(NCH2), 51.3 (CH), 58.6 (CH), 58.7 (OCH3), 73.3 (OCH2), 126.8
(CH2=), 127.4 (CH), 129.7 (CH), 129.9 (CH=), 131.1 (CH), 134.3
(CH), 136.1 (C), 146.8 (C), 171.6 (CO), 194.2 (CHO) ppm.
C18H24N2O3 (316.4): calcd. C 68.33, H 7.65, N 8.85; found C 68.57,
H 7.83, N 8.69.
N-[(R)-1-(2-Formylbenzo[1,3]dioxol-5-yl)ethyl]-N-[(S)-2-(methoxy-
methyl)pyrrolidin-1-yl]acrylamide (15f): Yield 259 mg, 72%. [α]2D5
=
1
–183.6 (c = 0.44, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.29–
1.68 (m, 2 H, CH2), 1.79 (d, J = 7.0 Hz, 3 H, CH3), 1.71–1.92 (m,
2 H, CH2), 2.79–2.94 (m, 1 H, CH2N), 3.09 (s, 3 H, OCH3), 2.97–
3.16 (m, 4 H, 2 H, CH2O + 1 H, CH2N + 1 H, CH), 5.63 (dd, J
= 2.2, 8.2 Hz, 1 H, CH2=), 6.02 (q, J = 7.0 Hz, 1 H, CH), 6.06 (s,
2 H, OCH2O), 6.36 (dd, J = 2.2, 15.1 Hz, 1 H, CH2=), 7.13 (dd, J
= 6.9, 10.4 Hz, 1 H, CH=), 7.16 (s, 1 H, Harom), 7.60 (s, 1 H,
Harom), 9.92 (s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.6 (CH3), 21.7 (CH2), 26.9 (CH2), 50.9 (NCH2), 51.2 (CH), 58.7
(OCH3), 58.8 (CH), 73.4 (OCH2), 102.1 (OCH2O), 110.3 (CH),
113.5 (CH), 125.7 (C), 126.8 (CH2=), 129.9 (CH=), 144.5 (C), 146.8
(C), 152.4 (C), 170.6 (CO), 191.2 (CHO) ppm. C19H24N2O5 (360.4):
calcd. C 63.32, H 6.71, N 7.77; found C 63.52, H 7.02, N 7.54.
N-[(R)-1-(2-Formylphenyl)pentyl]-N-[(S)-2-(methoxymethyl)pyrrol-
idin-1-yl]acrylamide (15c): Yield 340 mg, 95%. [α]2D5 = –111.2 (c =
0.74, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 7.0 Hz,
3 H, CH3), 1.14–1.41 (m, 4 H, 2 CH2), 1.51–1.66 (m, 2 H, CH2),
1.68–1.83 (m, 2 H, CH2), 1.85–2.06 (m, 2 H, CH2), 2.61–2.81 (m,
1 H, CH2N), 2.96–3.07 (m, 2 H, CH2O), 2.99 (s, 3 H, OCH3), 3.13
(q, J = 8.0 Hz, 1 H, CH2N), 3.3–3.42 (m, 1 H, CH), 5.61 (dd, J =
2.2, 10.4 Hz, 1 H, CH2=), 5.89 (q, J = 5.3 Hz, 1 H, ArCHN), 6.38
(dd, J = 2.2, 14.9 Hz, 1 H, CH2=), 7.16 (dd, J = 6.9, 10.4 Hz, 1 H,
CH=), 7.33 (t, J = 6.4 Hz, 1 H, Harom), 7.57 (td, J = 1.2, 6.3 Hz,
1 H, Harom), 7.74 (dd, J = 1.4, 6.2 Hz, 1 H, Harom), 8.22 (d, J =
N-[(R)-1-(2-Formyl-4,5-dimethoxyphenyl)ethyl]-N-[(S)-2-(methoxy-
methyl)pyrrolidin-1-yl]acrylamide (15g): Yield 222 mg, 59%. [α]2D5
–170.0 (c = 1.69, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.43–
1.66 (m, 2 H, CH2), 1.68–1.88 (m, 2 H, CH2), 1.82 (d, J = 7.0 Hz,
=
1
7.75 Hz, 1 H, Harom), 10.09 (s, 1 H, CHO) ppm. 13C NMR 3 H, CH3), 2.78–2.94 (m, 1 H, CH2N), 3.03 (s, 3 H, OCH3), 2.95–
(CDCl3): δ = 14.0 (CH3), 21.6 (CH2), 22.5 (CH2), 26.8 (CH2), 29.8
(CH2), 33.8 (CH2), 50.9 (NCH2), 55.3 (ArCHN), 58.4 (OCH3), 58.5 2 OCH3), 5.60 (dd, J = 2.1, 8.3 Hz, 1 H, CH2=), 6.00 (q, J =
(CH), 73.9 (OCH2), 126.4 (CH2=), 127.1 (CH), 130.1 (CH), 130.2 7.0 Hz, 1 H, CH), 6.33 (dd, J = 2.1, 15.2 Hz, 1 H, CH2=), 7.14
3.15 (m, 4 H, 2 H, CH2O + 1 H, CH2N + 1 H, CH), 3.94 (s, 6 H,
Eur. J. Org. Chem. 2009, 3741–3752
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3747

D. Dumoulin, S. Lebrun, E. Deniau, A. Couture, P. Grandclaudon
FULL PAPER
(dd, J = 6.9, 10.4 Hz, 1 H, CH=), 7.19 (s, 1 H, Harom), 7.78 (s, 1
3.23 (m, 1 H, CH), 5.0 (t, J = 7.6 Hz, 1 H, ArCHN), 5.39 (dd, J
= 1.2, 9.7 Hz, 1 H, CH2=), 5.57–5.69 (m, 2 H, 2ϫ1 H, 2 CH2=),
H, Harom), 10.0 (s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.6 (CH3), 21.6 (CH2), 26.9 (CH2), 50.8 (CH), 50.9 (NCH2), 6.38 (dd, J = 2.3, 14.9 Hz, 1 H, CH2=), 6.91–7.17 (m, 2 H, Harom),
56.0 (OCH3), 56.2 (OCH3), 58.7 (OCH3), 58.8 (CH), 73.6 (OCH2), 7.19–7.37 (m, 2 H, 2 CH=), 7.41 (dd, J = 2.1, 6.6 Hz, 1 H, Harom),
112.8 (CH), 116.4 (CH), 124.2 (C), 126.3 (CH2=), 130.2 (CH=), 7.88 (d, J = 7.7 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3):
142.3 (C), 147.6 (C), 153.7 (C), 170.8 (CO), 191.7 (CHO) ppm.
C20H28N2O5 (376.4): calcd. C 63.81, H 7.50, N 7.44; found C 63.52,
H 7.61, N 7.66.
δ = 14.1 (CH3), 21.6 (CH2), 22.6 (CH2), 27.1 (CH2), 29.7 (CH2),
33.9 (CH2), 50.9 (NCH2), 57.0 (ArCHN), 58.2 (CH), 58.5 (OCH3),
72.9 (OCH2), 117.5 (CH2=), 126.4 (CH), 126.6 (CH2=), 127.5 (2
CH), 128.1 (C), 128.3 (CH + CH=), 129.8 (C), 134.4 (CH=), 170.3
(CO) ppm. C22H32N2O2 (356.5): calcd. C 74.12, H 9.05, N 7.86;
found C 74.32, H 8.87, N 8.10.
General Procedure for the Synthesis of the (1R)-Alkyl-dienehydraz-
ides 4a–g: nBuLi (0.5 mL, 0.8 mmol, 1.6  solution in hexanes) was
added slowly to a stirred suspension of methyl(triphenyl)phospho-
nium bromide (286 mg, 0.8 mmol) in dry degassed THF (8 mL) at
room temp. under argon. The yellowish solution was stirred for an
additional 30 min. Enehydrazide 15a–g (0.8 mmol) in dry degassed
THF (4 mL) was then added and the resulting solution was heated
at reflux for 12 h. Saturated aqueous NH4Cl solution (10 mL) was
added and the mixture was extracted with CH2Cl2 (3ϫ10 mL). The
combined organic layers were washed with brine (3ϫ10 mL) and
water (2ϫ10 mL) and dried (MgSO4). After evaporation of the
solvent under vacuum the crude residue was purified by flash col-
umn chromatography (ethyl acetate/hexanes, 20:80, as eluent) to
afford dienehydrazide 4a–g as a pale-yellow oil.
N-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-N-[(R)-1-(2-vinylphenyl)-
heptyl]acrylamide (4d): Yield 132 mg, 41%. [α]2D5 = –88.3 (c = 1.64,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 6.7 Hz, 3
H, CH3), 1.14–1.51 (m, 8 H, 4 CH2), 1.51–1.85 (m, 4 H, CH2),
1.87–2.16 (m, 2 H, CH2), 2.51–2.66 (m, 1 H, CH2N), 2.73 (q, J =
7.6 Hz, 1 H, CH2N), 2.84–2.97 (m, 2 H, OCH2), 3.01 (s, 3 H,
OCH3), 3.08–3.21 (m, 1 H, CH), 5.0 (t, J = 7.9 Hz, 1 H, ArCHN),
5.40 (dd, J = 1.3, 9.6 Hz, 1 H, CH2=), 5.57–5.68 (m, 2 H, 2ϫ1 H,
2 CH2=), 6.39 (dd, J = 2.2, 15.0 Hz, 1 H, CH2=), 6.92–7.16 (m, 2
H, Harom), 7.18–7.37 (m, 2 H, 2 CH=), 7.42 (dd, J = 2.2, 6.5 Hz,
1 H, Harom), 7.88 (d, J = 7.6 Hz, 1 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1 (CH3), 21.7 (CH2), 22.6 (CH2), 27.1
(CH2), 27.5 (CH2), 29.2 (CH2), 31.8 (CH2), 34.2 (CH2), 50.9
(NCH2), 57.0 (ArCHN), 58.2 (CH), 58.5 (OCH3), 72.9 (OCH2),
117.5 (CH2=), 126.4 (CH), 126.6 (CH2=), 127.5 (CH), 128.3 (CH
+ CH=), 129.8 (C), 134.3 (CH=), 136.1 (CH), 139.9 (C), 170.3
(CO) ppm. C24H36N2O2 (384.6): calcd. C 74.96, H 9.44, N 7.28;
found C 74.88, H 9.29, N 7.11.
N-[(S)-2-(Methoxymethyl)pyrrolidin-1-yl]-N-[(R)-1-(2,3,4-trimeth-
oxy-6-vinylphenyl)pentyl]acrylamide (4a): Yield 200 mg, 56%. [α]2D5
1
= –63.2 (c = 2.16, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.83
(t, J = 7.0 Hz, 3 H, CH3), 1.08–1.41 (m, 4 H, 2 CH2), 1.56–1.83
(m, 2 H, CH2), 1.85–2.08 (m, 4 H, 2 CH2), 2.25–2.42 (m, 1 H,
CH2N), 2.64–2.83 (m, 1 H, CH2N), 2.90 (s, 3 H, OCH3), 3.01–3.31
(m, 3 H, OCH2 + CH), 3.84 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3),
3.89 (s, 3 H, OCH3), 5.31 (dd, J = 1.2, 10.2 Hz, 1 H, CH2=), 5.42
(t, J = 5.7 Hz, 1 H, ArCHN), 5.53 (dd, J = 1.2, 15.8 Hz, 1 H,
CH2=), 5.69 (dd, J = 2.2, 8.2 Hz, 1 H, CH2=), 6.22–6.44 (m, 1 H,
CH2=), 6.74 (s, 1 H, Harom), 6.79–7.04 (m, 2 H, 2 CH=) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 22.0 (CH2), 22.6 (CH2),
27.6 (CH2), 29.8 (CH2), 34.2 (CH2), 49.9 (NCH2), 55.7 (OCH3),
56.2 (OCH3), 56.8 (ArCHN), 58.2 (OCH3), 58.4 (CH), 60.7
(OCH3), 73.6 (OCH2), 105.6 (CH), 114.0 (CH2=), 126.2 (CH2=),
127.0 (C), 127.8 (C), 129.9 (CH=), 130.0 (C), 134.1 (CH=), 150.9
(C), 152.9 (C), 167.5 (CO) ppm. C25H38N2O5 (446.6): calcd. C
67.24, H 8.58, N 6.27; found C 67.32, H 8.29, N 6.47.
N-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-N-[(R)-1-(6-vinylbenzo-
[1,3]dioxol-5-yl)pentyl]acrylamide (4e): Yield 183 mg, 57%. [α]2D5
=
–48.0 (c = 1.03, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.89 (t,
J = 7.0 Hz, 3 H, CH3), 1.12–1.48 (m, 4 H, 2 CH2), 1.53–1.83 (m,
4 H, 2 CH2), 1.85–2.08 (m, 2 H, CH2), 2.46–2.63 (m, 1 H, CH2N),
2.72–2.86 (m, 1 H, CH2N), 2.89–3.01 (m, 2 H, OCH2), 3.09 (s, 3
H, OCH3), 3.11–3.23 (m, 1 H, CH), 4.92 (t, J = 5.6 Hz, 1 H,
ArCHN), 5.30 (dd, J = 1.2, 10.2 Hz, 1 H, CH2=), 5.51 (dd, J =
1.2, 15.9 Hz, 1 H, CH2=), 5.62 (dd, J = 2.2, 8.2 Hz, 1 H, CH2=),
5.95 (s, 2 H, OCH2O), 6.36 (dd, J = 2.3, 14.9 Hz, 1 H, CH2=),
6.79–6.97 (m, 1 H, CH=), 6.90 (s, 1 H, Harom), 7.05 (dd, J = 6.9,
10.4 Hz, 1 H, CH=), 7.28 (s, 1 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.1 (CH3), 21.6 (CH2), 22.6 (CH2), 27.1 (CH2), 29.6
(CH2), 33.8 (CH2), 51.1 (NCH2), 56.9 (ArCHN), 58.3 (CH), 58.6
(OCH3), 73.0 (OCH2), 101.2 (OCH2O), 106.0 (CH), 108.7 (CH),
116.1 (CH2=), 126.7 (CH2=), 129.8 (CH=), 130.1 (C), 133.9 (CH=),
134.0 (C), 147.8 (C), 154.3 (C), 170.1 (CO) ppm. C23H32N2O4
(400.5): calcd. C 68.97, H 8.05, N 6.99; found C 68.74, H 7.92, N
6.71.
N-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-N-[(R)-1-(2-vinylphenyl)-
ethyl]acrylamide (4b): Yield 174 mg, 69%. [α]2D5 = –81.7 (c = 1.59,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.18–1.36 (m, 2 H,
CH2), 1.53–1.68 (m, 2 H, CH2), 1.82 (d, J = 7.2 Hz, 3 H, CH3),
2.64 (q, J = 8.0 Hz, 2 H, CH2N), 2.83–2.98 (m, 2 H, OCH2), 3.10
(s, 3 H, OCH3), 3.19–3.32 (m, 1 H, CH), 5.23–5.42 (m, 2 H, 1 H,
CH2= +1 H, CH), 5.63 (dd, J = 2.3, 8.2 Hz, 1 H, CH2=), 6.39 (dd,
J = 2.2, 15.1 Hz, 1 H, CH2=), 6.84–7.13 (m, 2 H, CH2= + CH=),
7.20–7.36 (m, 3 H, CH= + 2 Harom), 7.42 (dd, J = 2.3, 6.7 Hz, 1 H,
Harom), 7.72 (d, J = 7.7 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.4 (CH3), 21.7 (CH2), 27.3 (CH2), 51.2 (NCH2), 52.3
(CH), 58.5 (CH), 58.7 (OCH3), 73.2 (OCH2), 117.3 (CH2=), 126.2
(CH), 126.9 (CH2=), 127.6 (CH), 127.9 (2 CH), 128.1 (C), 128.6
(CH=), 129.4 (C), 129.4 (CH=), 170.8 (CO) ppm. C19H26N2O2
(314.4): calcd. C 72.58, H 8.33, N 8.91; found C 72.46, H 8.63, N
8.97.
N-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-N-[(R)-1-(6-vinylbenzo-
[1,3]dioxol-5-yl)ethyl]acrylamide (4f): Yield 189 mg, 66%. [α]2D5
=
1
–56.5 (c = 2.23, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.44–
1.73 (m, 4 H, 2 CH2), 1.77 (d, J = 7.2 Hz, 3 H, CH3), 2.71 (q, J =
7.75 Hz, 1 H, NCH2), 2.87–3.02 (m, 2 H, OCH2), 3.04–3.11 (m, 1
H, CH2N), 3.18 (s, 3 H, OCH3), 3.20–3.31 (m, 1 H, CH), 5.17–
5.33 (m, 1 H, CH), 5.28 (d, J = 9.6 Hz, 1 H, CH2=), 5.51 (d, J =
17.1 Hz, 1 H, CH2=), 5.62 (dd, J = 2.2, 8.2 Hz, 1 H, CH2=), 5.95
N-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-N-[(R)-1-(2-vinylphenyl)- (s, 2 H, OCH2O), 6.39 (dd, J = 2.2, 15.1 Hz, 1 H, CH2=), 6.78–
pentyl]acrylamide (4c): Yield 134 mg, 47%. [α]2D5 = –149.7 (c = 1.51,
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3
H, CH3), 1.15–1.48 (m, 4 H, 2 CH2), 1.51–1.86 (m, 4 H, 2 CH2),
1.89–2.21 (m, 2 H, CH2), 2.52–2.68 (m, 1 H, CH2N), 2.70–2.82 (m,
6.93 (m, 1 H, CH=), 6.91 (s, 1 H, Harom), 7.05 (dd, J = 6.9, 10.4 Hz,
1 H, CH=), 7.34 (s, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3):
δ = 20.8 (CH3), 21.8 (CH2), 27.3 (CH2), 51.1 (NCH2), 52.2 (CH),
58.5 (OCH3), 58.8 (CH), 73.2 (OCH2), 101.1 (OCH2O), 105.9
1
1 H, CH2N), 2.84–2.99 (m, 2 H, OCH2), 3.02 (s, 3 H, OCH3), 3.08– (CH), 108.3 (CH), 115.9 (CH2=), 126.9 (CH2=), 129.5 (CH=),
3748
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3741–3752

Asymmetric Synthesis of 1-Alkylbenzo[c]azepin-3-ones
130.0 (C), 133.7 (CH=), 134.0 (C), 147.6 (C), 154.4 (C), 170.0 165.0 (CO) ppm. C17H22N2O2 (286.4): calcd. C 71.30, H 7.74, N
(CO) ppm. C20H26N2O4 (358.4): calcd. C 67.02, H 7.31, N 7.82;
found C 66.84, H 7.23, N 7.75.
9.78; found C 71.53, H 7.91, N 9.66.
(1R)-1-Methyl-1,2-dihydrobenzo[c]azepin-3-one (17b): From the
mixture of 3b and 17b (42 mg, 41%). [α]2D5 = –92.4 (c = 0.74,
N-[(R)-1-(4,5-Dimethoxy-2-vinylphenyl)ethyl]-N-[(S)-2-(methoxy-
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.72 (d, J = 7.0 Hz, 3
methyl)pyrrolidin-1-yl]acrylamide (4g): Yield 144 mg, 48%. [α]2D5
=
H, CH3), 4.40 (q, J = 6.3 Hz, 1 H, CH), 6.35 (d, J = 12.0 Hz, 1 H,
=CHCO), 6.83 (br. s, 1 H, NH), 7.17 (d, J = 12.1 Hz, 1 H,
ArCH=), 7.23–7.48 (m, 4 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 17.1 (CH3), 48.3 (CH), 123.8 (=CH), 126.2 (CH),
127.7 (CH), 129.7 (CH), 130.0 (CH), 134.8 (C), 138.7 (ArCH=),
141.3 (C), 168.6 (CO) ppm. C11H11NO (173.2): calcd. C 76.28, H
6.40, N 8.09; found C 76.04, H 6.22, N 8.27.
1
–73.4 (c = 1.90, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.42–
1.71 (m, 4 H, 2 CH2), 1.83 (d, J = 7.2 Hz, 3 H, CH3), 2.65 (q, J =
8.0 Hz, 1 H, NCH2), 2.89–2.98 (m, 2 H, OCH2), 3.02–3.20 (m, 4
H, 1 H, CH2N + 3 H, OCH3), 3.21–3.32 (m, 1 H, CH), 3.88 (s, 3
H, OCH3), 3.89 (s, 3 H, OCH3), 5.24–5.42 (m, 2 H, 1 H, CH + 1
H, CH2=), 5.41–5.61 (m, 1 H, CH2=), 5.64 (dd, J = 1.8, 10.8 Hz,
1 H, CH2=), 6.35 (dd, J = 2.3, 14.9 Hz, 1 H, CH2=), 6.89–7.04 (m,
2 H, Harom + CH=), 7.07 (dd, J = 6.8, 10.5 Hz, 1 H, CH=), 7.44
(s, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.2 (CH3),
21.7 (CH2), 27.2 (CH2), 51.0 (NCH2), 51.7 (CH), 55.9 (OCH3),
56.0 (OCH3), 58.5 (OCH3), 58.7 (CH), 73.3 (OCH2), 108.6 (CH),
111.2 (CH), 115.5 (CH2=), 126.5 (CH2=), 128.3 (C), 129.7 (CH=),
132.9 (C), 133.6 (CH=), 148.1 (C), 148.9 (C), 170.2 (CO) ppm.
C21H30N2O4 (374.5): calcd. C 67.36, H 8.07, N 7.48; found C 67.61,
H 7.98, N 7.14.
(1R)-1-Butyl-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-1,2-dihydro-
benzo[c]azepin-3-one (3c): After an extended reaction time a mix-
ture of 3c (85 mg, 43%) and 17c was obtained. [α]2D5 = –94.5 (c =
0.83, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.81 (t, J = 7.2 Hz,
3 H, CH3), 1.07–1.51 (m, 4 H, 2 CH2), 1.53–1.92 (m, 4 H, 2 CH2),
1.93–2.31 (m, 2 H, CH2), 2.52 (dd, J = 3.7, 6.0 Hz, 1 H, CH2N),
2.63 (dd, J = 2.5, 7.0 Hz, 1 H, CH2N), 2.93 (s, 3 H, OCH3), 3.12–
3.51 (m, 3 H, CH2O + CH), 4.23 (t, J = 7.0 Hz, 1 H, ArCHN),
6.42 (d, J = 11.9 Hz, 1 H, =CHCO), 6.99 (d, J = 12.2 Hz, 1 H,
ArCH=), 7.21–7.30 (m, 1 H, Harom), 7.31–7.49 (m, 3 H,
General Procedure for the Synthesis of the (1R)-Alkyl-(S)-N-SMP-
benzo[c]azepinones 3b–d,f,g and (1R)-Alkylbenzo[c]azepinones 17a–
e: A stirred mixture of the dienehydrazide 4a,f,g (0.6 mmol) and the
second-generation Grubbs catalyst (15 mg, 3 mol-%) in dry toluene
(8 mL) was heated at reflux for 6 h under argon. Further of the
second-generation Grubbs catalyst (10 mg, 2 mol-% for the diene-
hydrazides 4b–d or 25 mg, 5 mol-% for 4a,e) was added after cool-
ing, and the reaction mixture was heated at reflux for an additional
6 h. The solution was then filtered through a pad of Celite that was
washed with dichloromethane (20 mL). Evaporation of the solvent
left a dark oil, which was separated by flash column chromatog-
raphy. Compounds 3b–d,f,g eluted first (ethyl acetate/hexanes,
30:70, as eluent) followed by compounds 17a–e (ethyl acetate/hex-
anes, 70:30, as eluent).
H
arom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 22.4
(CH2), 23.0 (CH2), 27.4 (CH2), 27.8 (CH2), 29.3 (CH2), 53.6
(NCH2), 59.4 (ArCHN), 60.1 (CH), 60.4 (OCH3), 74.7 (OCH2),
124.5 (=CH), 127.3 (CH), 127.8 (CH), 128.3 (CH), 128.7 (CH),
129.4 (ArCH=), 130.5 (C), 136.1 (C), 164.7 (CO) ppm.
C20H28N2O2 (328.5): calcd. C 73.14, H 8.59, N 8.53; found C 73.39,
H 8.65, N 8.55.
(1R)-1-Butyl-1,2-dihydrobenzo[c]azepin-3-one (17c): From the mix-
ture of 3b and 17b (62 mg, 48%). [α]2D5 = –89.7 (c = 0.67, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3 H, CH3),
1.13–1.62 (m, 4 H, 2 CH2), 1.96–2.11 (m, 2 H, CH2), 4.14 (t, J =
7.0 Hz, 1 H, ArCHN), 6.32 (dd, J = 10.4, 1.75 Hz, 1 H, =CHCO),
6.90 (br. s, 1 H, NH), 7.14 (d, J = 12.1 Hz, 1 H, ArCH=), 7.23–
7.31 (m, 1 H, Harom), 7.32–7.49 (m, 3 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.0 (CH3), 22.4 (CH2), 28.9 (CH2), 30.8
(CH2), 53.9 (ArCHN), 125.0 (=CH), 126.4 (CH), 127.6 (CH), 129.6
(CH), 130.2 (CH), 134.8 (C), 138.5 (ArCH=), 140.7 (C), 168.4
(CO) ppm. C14H17NO (215.3): calcd. C 78.10, H 7.96, N 6.51;
found C 77.97, H 8.17, N 6.66.
(1R)-1-Butyl-7,8,9-trimethoxy-1,2-dihydrobenzo[c]azepin-3-one
(17a): After an extended reaction time. Yield 92 mg, 50%. [α]2D5
=
1
–168.3 (c = 0.65, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.81
(t, J = 7.2 Hz, 3 H, CH3), 1.09–1.39 (m, 4 H, 2 CH2), 1.53–1.95
(m, 2 H, CH2), 3.88 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 3.96 (s,
3 H, OCH3), 5.07–5.22 (m, 1 H, ArCHN), 6.18 (d, J = 12.0 Hz,
1 H, =CHCO), 6.62 (s, 1 H, Harom), 6.88 (d, J = 12.2 Hz, 1 H,
ArCH=) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 22.6
(CH2), 29.8 (CH2), 33.4 (CH2), 55.8 (ArCHN), 55.9 (2 OCH3), 60.8
(OCH3), 109.0 (CH), 126.9 (=CH), 127.1 (C), 127.9 (C), 131.2 (C),
135.9 (ArCH=), 148.9 (C), 152.3 (C), 168.2 (CO) ppm. C17H23NO4
(305.4): calcd. C 66.86, H 7.59, N 4.59; found C 67.02, H 7.67, N
4.86.
(1R)-1-Hexyl-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-1,2-dihydro-
benzo[c]azepin-3-one (3d): After an extended reaction time a mix-
ture of 3d (23 mg, 11%) and 17d was obtained. [α]2D5 = –112.2 (c =
0.42, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.86 (t, J = 7.1 Hz,
3 H, CH3), 1.04–1.45 (m, 6 H, 3 CH2), 1.46–1.92 (m, 6 H, 3 CH2),
1.93–2.04 (m, 2 H, CH2), 2.49–2.61 (m, 1 H, CH2N), 2.63–2.74 (m,
1 H, CH2N), 3.01 (s, 3 H, OCH3), 3.07–3.57 (m, 3 H, OCH2O +
CH), 4.15 (t, J = 6.9 Hz, 1 H, ArCHN), 6.32 (d, J = 11.9 Hz, 1 H,
=CHCO), 7.13 (d, J = 12.0 Hz, 1 H, ArCH=), 7.23–7.44 (m, 4 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 22.5
(CH2), 23.0 (CH2), 26.7 (CH2), 27.3 (CH2), 29.1 (CH2), 30.9 (CH2),
31.7 (CH2), 53.1 (NCH2), 58.9 (OCH3), 59.0 (ArCHN), 59.3 (CH),
74.8 (OCH2), 124.8 (=CH), 126.9 (CH), 127.7 (CH), 128.4 (CH),
128.9 (CH), 129.4 (ArCH=), 130.2 (C), 136.0 (C), 168.4 (CO) ppm.
C22H32N2O2 (356.5): calcd. C 74.12, H 9.05, N 7.86; found C 74.01,
H 9.32, N 7.69.
(1R)-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-1-methyl-1,2-dihydro-
benzo[c]azepin-3-one (3b): Yield 124 mg, 72%. After an extended
reaction time a mixture of 3b (66 mg, 38%) and 17b was obtained.
1
[α]2D5 = –105.5 (c = 0.97, CHCl3). H NMR (300 MHz, CDCl3): δ
= 1.50 (d, J = 7.3 Hz, 2 H, CH2), 1.71 (d, J = 7.0 Hz, 3 H, CH3),
1.82–1.98 (m, 2 H, CH2), 2.43–2.52 (m, 1 H, CH2N), 2.53–2.64 (m,
1 H, CH2N), 3.05 (s, 3 H, OCH3), 3.02–3.14 (m, 1 H, OCH2), 3.28–
3.41 (m, 1 H, OCH2), 3.51 (q, J = 7.8 Hz, 1 H, CH), 4.40 (q, J =
7.0 Hz, 1 H, CH), 6.32 (d, J = 12.0 Hz, 1 H, =CHCO), 7.01 (d, J
= 12.0 Hz, 1 H, ArCH=), 7.21–7.32 (m, 2 H, Harom), 7.33–7.42 (m,
2 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3),
(1R)-1-Hexyl-1,2-dihydrobenzo[c]azepin-3-one (17d): From the mix-
ture of 3d and 17d (61 mg, 42%). [α]2D5 = –99.5 (c = 1.22, CHCl3).
23.0 (CH2), 27.5 (CH2), 52.9 (CH2N), 58.5 (OCH3), 58.5 (CH), 1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.9 Hz, 3 H, CH3),
58.7 (CH), 74.8 (OCH2O), 124.0 (=CH), 127.4 (CH), 128.0 (CH), 1.04–1.46 (m, 7 H, 6 H, 3 CH2 + 1 H, CH2), 1.48–1.64 (m, 1 H,
128.9 (CH), 129.3 (ArCH=), 130.1 (CH), 130.7 (C), 136.1 (C), CH2), 1.91–2.04 (m, 2 H, CH2), 4.13 (t, J = 7.0 Hz, 1 H, ArCHN),
Eur. J. Org. Chem. 2009, 3741–3752
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3749

D. Dumoulin, S. Lebrun, E. Deniau, A. Couture, P. Grandclaudon
FULL PAPER
6.32 (dd, J = 1.5, 10.7 Hz, 1 H, =CHCO), 7.13 (d, J = 12.0 Hz, 1
(1R)-1-Butyl-7,8,9-trimethoxy-1,2,4,5-tetrahydrobenzo[c]azepin-3-
H, ArCH=), 7.23–7.44 (m, 4 H, Harom) ppm. 13C NMR (75 MHz, one (1a): Yield 70 mg, 90%. [α]2D5 = –36.2 (c = 0.50, CHCl3). 1H
CDCl3): δ = 14.1 (CH3), 22.6 (CH2), 26.7 (CH2), 29.0 (CH2), 31.0 NMR (300 MHz, CDCl3): δ = 0.66–0.99 (m, 3 H, CH3), 1.04–1.51
(CH2), 31.7 (CH2), 54.0 (ArCHN), 125.0 (=CH), 126.4 (CH), 127.6 (m, 4 H, 2 CH2), 1.53–1.94 (m, 2 H, CH2), 2.46–2.64 (m, 1 H,
(CH), 129.6 (CH), 130.2 (CH), 134.8 (C), 138.4 (ArCH=), 140.7
(C), 168.4 (CO) ppm. C16H21NO (243.4): calcd. C 78.97, H 8.70,
N 5.76; found C 79.13, H 8.47, N 6.01.
CH2CO), 2.75–3.19 (m, 3 H, 1 H, CH2CO + 2 H, ArCH2), 3.84 (s,
3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 5.09–5.23
(m, 1 H, ArCHN), 6.06–6.27 (br. s, 1 H, NH), 6.61 (s, 1 H,
H
arom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 22.5
(5R)-5-Butyl-5,6-dihydro-1,3-dioxa-6-azacyclohepta[f]inden-7-one
(CH2), 29.3 (CH2), 29.7 (CH2), 32.6 (ArCH2), 37.0 (CH2CO), 55.8
(ArCHN), 55.9 (OCH3), 56.0 (OCH3), 59.0 (OCH3), 108.5 (CH),
127.4 (C), 127.6 (C), 129.9 (C), 149.1 (C), 151.2 (C), 171.3
(CO) ppm. C17H25NO4 (307.4): calcd. C 66.43, H 8.20, N 4.56;
found C 66.56, H 8.24, N 4.35.
(17e): After an extended reaction time. Yield 75 mg, 48%. [α]2D5
=
1
–114.4 (c = 0.75, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.75–
1.03 (m, 3 H, CH3), 1.14–1.48 (m, 4 H, 2 CH2), 1.89–2.08 (m, 2 H,
CH2), 4.02–4.18 (m, 1 H, ArCHN), 6.03 (s, 2 H, OCH2O), 6.05–
6.17 (br. s, 1 H, NH), 6.25 (dd, J = 1.4, 10.6 Hz, 1 H, =CHCO),
6.82 (s, 1 H, Harom), 7.02 (d, J = 12.0 Hz, 1 H, ArCH=), 7.28 (s, 1
H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3 (CH3), 22.5
(CH2), 29.8 (CH2), 33.6 (CH2), 54.1 (ArCHN), 101.6 (OCH2O),
104.9 (CH), 108.7 (CH), 126.4 (=CH), 129.1 (C), 129.3 (C), 135.7
(ArCH=), 135.8 (C), 141.2 (C), 166.4 (CO) ppm. C15H17NO3
(259.3): calcd. C 69.48, H 6.61, N 5.40; found C 69.58, H 6.54, N
5.22.
(1R)-1-Methyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (1b): Yield
47 mg, 90%. [α]2D5 = –15.1 (c = 0.60, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.66 (d, J = 7.0 Hz, 3 H, CH3), 2.49–2.68 (m, 1 H,
CH2CO), 2.79–3.04 (m, 2 H, ArCH2), 3.19–3.41 (m, 1 H, CH2CO),
4.85–5.01 (m, 1 H, CH), 6.16–6.44 (br. s, 1 H, NH), 7.05–7.31 (m,
4 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.9 (CH3),
29.4 (ArCH2), 35.3 (CH2CO), 47.7 (ArCHN), 124.0 (C), 126.8 (C),
128.2 (C), 128.9 (C), 139.9 (C), 140.4 (C), 173.9 (CO) ppm.
C11H13NO (175.2): calcd. C 75.40, H 7.48, N 7.99; found C 75.62,
H 7.77, N 8.11.
(5R)-6-[(S)-2-(Methoxymethyl)pyrrolidin-1-yl]-5-methyl-5,6-dihy-
dro-1,3-dioxa-6-azacyclohepta[f]inden-7-one (3f): Yield 81 mg, 41%.
[α]2D5 = –129.6 (c = 0.63, CHCl3). H NMR (300 MHz, CDCl3): δ
1
(1R)-1-Butyl-1,2,4,5-tetrahydro-2-benzazepin-3-one (1c): Yield
59 mg, 92%. [α]2D5 = –18.1 (c = 0.64, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.61–1.02 (m, 3 H, CH3), 1.04–1.65 (m, 4 H, 2 CH2),
1.81–2.14 (m, 2 H, CH2), 2.49–2.73 (m, 1 H, CH2CO), 2.75–3.01
(m, 2 H, ArCH2), 3.04–3.41 (m, 1 H, CH2CO), 4.49–4.69 (m, 1 H,
ArCHN), 6.26–6.51 (br. s, 1 H, NH), 7.06–7.51 (m, 4 H,
= 1.56–1.69 (m, 2 H, CH2), 1.73 (d, J = 7.0 Hz, 3 H, CH3), 1.88–
2.05 (m, 2 H, CH2), 2.70 (dd, J = 1.0, 4.4 Hz, 1 H, CH2N), 3.05
(s, 3 H, OCH3), 3.11–3.22 (m, 1 H, CH2N), 3.23–3.51 (m, 2 H,
OCH2), 5.58 (q, J = 7.75 Hz, 1 H, CH), 4.39 (q, J = 7.2 Hz, 1 H,
ArCHN), 6.02 (s, 2 H, OCH2O), 6.31 (d, J = 12.0 Hz, 1 H,
=CHCO), 6.83 (s, 1 H, Harom), 6.93 (s, 1 H, Harom), 6.96 (d, J =
12.0 Hz, 1 H, ArCH=) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.4
(CH3), 23.0 (CH2), 27.3 (CH2), 52.9 (NCH2), 54.9 (CH), 58.7 (CH),
58.8 (OCH3), 74.6 (OCH2), 101.5 (OCH2O), 104.9 (CH), 108.7
(CH), 126.5 (=CH), 129.3 (2 C), 135.8 (ArCH=), 136.5 (C), 141.3
(C), 164.8 (CO) ppm. C18H22N2O4 (330.4): calcd. C 65.44, H 6.71,
N 8.48; found C 65.21, H 6.58, N 8.15.
H
arom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 22.5
(CH2), 28.4 (CH2), 28.9 (CH2), 33.3 (ArCH2), 35.6 (CH2CO), 53.4
(ArCHN), 125.1 (CH), 126.7 (CH), 128.0 (CH), 129.2 (CH), 139.8
(C), 140.0 (C), 174.1 (CO) ppm. C14H19NO (217.3): calcd. C 77.38,
H 8.81, N 6.45; found C 77.21, H 8.54, N 6.54.
(1R)-1-Hexyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (1d): Yield
58 mg, 95%. [α]2D5 = –16.9 (c = 0.71, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.92 (t, J = 6.8 Hz, 3 H, CH3), 1.03–1.66 (m, 8 H, 4
CH2), 1.80–2.15 (m, 2 H, CH2), 2.55–2.73 (m, 1 H, CH2CO), 2.78–
3.01 (m, 2 H, ArCH2), 3.09–3.32 (m, 1 H, CH2CO), 4.50–4.68 (m,
1 H, ArCHN), 6.26–6.57 (br. s, 1 H, NH), 7.09–7.32 (m, 1 H,
Harom), 7.35–7.51 (m, 2 H, Harom), 7.58–7.67 (m, 1 H, Harom) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 22.6 (CH2), 26.7
(CH2), 28.4 (CH2), 29.1 (CH2), 31.6 (CH2), 33.5 (ArCH2), 35.5
(CH2CO), 53.4 (ArCHN), 126.8 (CH), 128.6 (2 CH), 129.1 (CH),
137.1 (C), 139.8 (C), 174.0 (CO) ppm. C16H23NO (245.4): calcd. C
78.32, H 9.45, N 5.71; found C 78.53, H 9.51, N 5.56.
(1R)-7,8-Dimethoxy-2-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-1-
methyl-1,2-dihydrobenzo[c]azepin-3-one (3g): Yield 112 mg, 54 %.
[α]2D5 = –107.3 (c = 0.88, CHCl3). H NMR (300 MHz, CDCl3): δ
1
= 1.51–1.69 (m, 2 H, CH2), 1.78 (d, J = 7.1 Hz, 3 H, CH3), 1.89–
2.04 (m, 2 H, CH2), 2.58–2.73 (m, 2 H, CH2N), 2.99 (s, 3 H,
OCH3), 3.10–3.21 (m, 1 H, CH), 3.26–3.52 (m, 2 H, CH2O), 3.92
(s, 3 H, OCH3), 3.97 (s, 3 H, OCH3), 4.42 (q, J = 7.0 Hz, 1 H,
ArCHN), 6.33 (d, J = 11.9 Hz, 1 H, =CHCO), 6.87 (s, 1 H, Harom),
6.93 (s, 1 H, Harom), 7.01 (d, J = 12.0 Hz, 1 H, ArCH=) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.2 (CH3), 23.0 (CH2), 27.3 (CH2),
53.0 (NCH2), 54.9 (CH), 56.0 (OCH3), 56.1 (OCH3), 58.8 (CH),
59.1 (OCH3), 74.8 (OCH2), 107.1 (C), 111.7 (C), 126.3 (=CH),
128.1 (C), 132.6 (C), 134.8 (C), 135.9 (ArCH=), 148.0 (C), 165.3
(CO) ppm. C19H26N2O4 (346.4): calcd. C 65.88, H 7.56, N 8.09;
found C 66.07, H 7.47, N 7.83.
(5R)-5-Butyl-5,6,8,9-tetrahydro-1,3-dioxa-6-azacyclohepta[f]inden-
1
7-one (1e): Yield 70 mg, 90%. [α]2D5 = –36.2 (c = 0.50, CHCl3). H
NMR (300 MHz, CDCl3): δ = 0.76–1.02 (m, 3 H, CH3), 1.09–1.49
(m, 4 H, 2 CH2), 1.87–2.09 (m, 2 H, CH2), 2.52–2.77 (m, 1 H,
CH2CO), 2.78–3.28 (m, 3 H, 1 H, CH2CO + 2 H, ArCH2), 4.42–
4.69 (m, 1 H, ArCHN), 6.03 (s, 2 H, OCH2O), 6.09–6.32 (br. s, 1
H, NH), 6.83 (s, 1 H, Harom), 6.96 (s, 1 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 18.3 (CH3), 22.5 (CH2), 28.8 (CH2), 29.6
(CH2), 32.8 (ArCH2), 35.4 (CH2CO), 53.9 (ArCHN), 101.2
(OCH2O), 104.9 (CH), 108.6 (CH), 129.1 (C), 129.3 (C), 136.1 (C),
141.2 (C), 172.8 (CO) ppm. C15H19NO3 (261.3): calcd. C 68.94, H
7.33, N 5.36; found C 68.98, H 7.07, N 5.14.
General Procedure for the Synthesis of (1R)-Alkyl-1,2,4,5-tetra-
hydrobenzo[c]azepin-3-ones 1a–e Starting from (1R)-Alkyl-2-benzo-
[c]azepinones 17a–e: A solution of the appropriate benzazepinone
17a–e (0.3 mmol) in anhydrous EtOH (8 mL) was stirred with acti-
vated Pd/C (10%, 5 mg) at room temp. under hydrogen for 12 h
after which time TLC indicated complete consumption of the start-
ing material. The mixture was filtered through a pad of Celite,
which was further eluted with EtOH (10 mL) and then CH2Cl2
(20 mL). Evaporation of the solvent furnished an oily product,
which was purified by flash column chromatography using ethyl
acetate as eluent to afford the corresponding 1a–e as a viscous yel-
low oil.
General Procedure for the Synthesis of the (1R)-Alkyltetrahydro-3H-
benzo[c]azepinones 1b–d,f,g Starting from (1R)-Alkyl-(S)-N-SMP-
2-benzazepinones 3b–d,f,g: Catalytic hydrogenation as described
previously delivered the appropriate alkyltetrahydro-2-benzazep-
3750
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3741–3752

Asymmetric Synthesis of 1-Alkylbenzo[c]azepin-3-ones
inone 16b–d,f,g as pale-grey oils, which was used in the next step
without further purification. Magnesium monoperoxyphthalate
hexahydrate (MMPP) (247 mg, 0.5 mmol) was added to a solution
of the alkyltetrahydro-2-benzazepinone 16b–d,f,g (0.2 mmol) in
MeOH (5 mL) and the resulting mixture was then stirred at room
temp. under argon for 48 h. The mixture was then poured into
CH2Cl2 (20 mL) and treated with a saturated NaHCO3 solution
(20 mL). The aqueous layer was extracted with CH2Cl2 (3ϫ15 mL)
and the combined extracts washed successively with water (10 mL)
and brine (10 mL) and finally dried (MgSO4). Evaporation of the
solvent furnished an oily product, which was purified by flash col-
umn chromatography using ethyl acetate as eluent to yield the cor-
responding 1b–d,f,g as a viscous yellow oil.
32.1 (ArCH2), 35.4 (CH2CO), 52.9 (NCH2), 54.7 (CH), 58.7 (CH),
58.8 (OCH3), 74.6 (OCH2), 101.4 (OCH2O), 105.2 (CH), 108.4
(CH), 129.2 (C), 129.3 (C), 136.2 (C), 141.8 (C), 169.8 (CO) ppm.
(1R)-7,8-Dimethoxy-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-1-
methyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (16g): Yield 91 mg,
87%. [α]2D5 = –19.6 (c = 0.83, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.39–1.58 (m, 2 H, CH2), 1.72 (d, J = 7.0 Hz, 3 H, CH3), 1.84–
1.99 (m, 1 H, CH2), 2.02–2.17 (m, 1 H, CH2), 2.54–2.67 (m, 1 H,
CH2N), 2.69–3.03 (m, 5 H, 4 H, 2 CH2 + 1, CH2N), 3.07 (s, 3 H,
OCH3), 3.11–3.22 (m, 1 H, CH), 3.23–3.51 (m, 2 H, CH2O), 3.88
(s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 4.87–5.02 (m, 1 H, ArCHN),
6.88 (s, 1 H, Harom), 6.94 (s, 1 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 18.4 (CH3), 22.9 (CH2), 27.4 (CH2), 31.4 (ArCH2),
35.4 (CH2CO), 52.9 (NCH2), 54.2 (CHCH3), 56.0 (OCH3), 56.1
(OCH3), 58.9 (CH), 59.0 (OCH3), 74.9 (OCH2O), 107.2 (CH),
111.5 (CH), 128.0 (C), 132.6 (C), 134.7 (C), 148.1 (C), 171.9
(CO) ppm.
(1R)-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-1-methyl-1,2,4,5-
tetrahydrobenzo[c]azepin-3-one (16b): Yield 66 mg, 91%. [α]2D5
=
1
–17.3 (c = 1.05, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.15–
1.30 (m, 1 H, CH2), 1.51–1.65 (m, 1 H, CH2), 1.70 (d, J = 7.0 Hz,
3 H, CH3), 1.80–1.94 (m, 1 H, CH2), 1.96–2.13 (m, 1 H, CH2),
2.67–3.02 (m, 5 H, 1 H,CH2N + 4 H, 2 CH2), 3.07 (s, 3 H, OCH3),
3.09–3.18 (m, 2 H, OCH2), 3.23–3.44 (m, 1 H, CH2N), 3.51–3.76
(m, 1 H, CH), 4.98–5.11 (m, 1 H, CH), 7.06–7.22 (m, 4 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.9 (CH3), 22.9
(CH2), 27.3 (CH2), 29.4 (ArCH2), 35.3 (CH2CO), 47.7 (ArCHN),
52.9 (NCH2), 58.6 (CH), 58.8 (OCH3), 74.7 (OCH2O), 124.0 (CH),
126.7 (CH), 128.2 (CH), 128.8 (CH), 139.8 (C), 140.1 (C), 173.6
(CO) ppm.
(1R)-1-Methyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (1b): Yield
28 mg, 81%.
(1R)-1-Butyl-1,2,4,5-tetrahydro-2-benzazepin-3-one (1c): Yield
28 mg, 66%.
(1R)-1-Hexyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (1d): Yield
24 mg, 59%.
(5R)-5-Methyl-5,6,8,9-tetrahydro-1,3-dioxa-6-azacyclohepta[f]inden-
1
7-one (1f): Yield 34 mg, 78%. [α]2D5 = –25.5 (c = 0.47, CHCl3). H
(1R)-1-Butyl-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-1,2,4,5-tetra-
hydrobenzo[c]azepin-3-one (16c): Yield 84 mg, 85%. [α]2D5 = –19.7 (c
= 0.74, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J =
7.0 Hz, 3 H, CH3), 1.02–1.64 (m, 6 H, 3 CH2), 1.80–1.91 (m, 1 H,
CH2), 1.94–2.33 (m, 3 H, 1 H, CH2 + 2 H, CH2), 2.67–3.02 (m, 5
H, 1 H, CH2N + 4 H, 2 CH2), 3.08 (s, 3 H, OCH3), 3.12–3.31 (m,
3 H, 1 H, CH2N + 2 H, OCH2), 3.51–3.76 (m, 1 H, CH), 4.89–
5.06 (m, 1 H, ArCHN), 7.02–7.26 (m, 4 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1 (CH3), 22.5 (CH2), 22.8 (CH2), 27.4
(CH2), 28.4 (CH2), 28.9 (CH2), 33.3 (ArCH2), 35.6 (CH2CO), 53.0
(NCH2), 53.4 (ArCHN), 58.8 (CH), 58.9 (OCH3), 74.5 (OCH2),
125.1 (CH), 126.7 (CH), 128.0 (CH), 129.2 (CH), 139.8 (C), 140.0
(C), 174.1 (CO) ppm.
NMR (300 MHz, CDCl3): δ = 1.64 (d, J = 7.1 Hz, 3 H, CH3),
2.52–2.72 (m, 1 H, CH2CO), 2.75–3.01 (m, 2 H, ArCH2), 3.04–3.28
(m, 1 H, CH2CO), 4.62–4.81 (m, 1 H, CH), 6.01 (s, 2 H, OCH2O),
6.04–6.27 (br. s, 1 H, NH), 6.88 (s, 1 H, Harom), 6.92 (s, 1 H,
H
arom) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.3 (CH3), 32.1
(ArCH2), 35.9 (CH2CO), 50.9 (ArCHN), 101.1 (OCH2O), 104.8
(CH), 108.8 (CH), 129.4 (C), 129.5 (C), 136.2 (C), 141.5 (C), 172.9
(CO) ppm. C12H13NO3 (219.22): calcd. C 65.74, H 5.98, N 6.39;
found C 65.48, H 6.12, N 6.65.
(1R)-7,8-Dimethoxy-1-methyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-
one (1g): Yield 27 mg, 57%. [α]2D5 = –17.4 (c = 0.51, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.68 (d, J = 6.9 Hz, 3 H, CH3),
2.51–2.69 (m, 1 H, CH2CO), 2.76–2.99 (m, 2 H, ArCH2), 3.12–3.31
(m, 1 H, CH2CO), 3.88 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 4.82–
5.03 (m, 1 H, CH), 6.72 (s, 1 H, Harom), 6.74 (s, 1 H, Harom) ppm.
13C NMR (75 MHz, CDCl3): δ = 19.6 (CH3), 29.3 (ArCH2), 36.1
(CH2CO), 48.3 (ArCHN), 55.9 (OCH3), 56.1 (OCH3), 110.6 (CH),
111.2 (CH), 128.0 (C), 132.8 (C), 146.8 (C), 147.3 (C), 174.9
(CO) ppm. C13H17NO3 (235.3): calcd. C 66.36, H 7.28, N 5.95;
found C 66.56, H 7.58, N 6.11.
(1R)-1-Hexyl-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]-1,2,4,5-
tetrahydrobenzo[c]azepin-3-one (16d): Yield 95 mg, 88%. [α]2D5
=
–21.4 (c = 0.64, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.85 (t,
J = 7.1 Hz, 3 H, CH3), 1.03–1.72 (m, 8 H, 4 CH2), 1.74–1.93 (m,
3 H, 1 H, CH2 + 2 H, CH2), 1.96–2.29 (m, 3 H, 1 H, CH2 + 2 H,
CH2), 2.62–3.01 (m, 5 H, 1 H, CH2N + 4 H, 2 CH2), 3.05 (s, 3 H,
OCH3), 3.09–3.26 (m, 3 H, 1 H, CH2N + 2 H, OCH2), 3.44–3.62
(m, 1 H, CH), 4.77–4.96 (m, 1 H, ArCHN), 6.98–7.23 (m, 4 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 22.5
(CH2), 22.7 (CH2), 26.7 (CH2), 27.5 (CH2), 28.4 (CH2), 29.1 (CH2),
31.7 (CH2), 33.5 (ArCH2), 35.4 (CH2CO), 52.9 (NCH2), 53.6
(ArCHN), 58.7 (CH), 58.8 (OCH3), 74.6 (OCH2), 126.8 (CH),
128.5 (CH), 128.6 (CH), 129.1 (CH), 137.1 (C), 139.8 (C), 174.0
(CO) ppm.
Synthesis of (1R)-1-Methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine
(2b) from 10b by Concomitant Cleavage of the N–N Bond and Re-
duction of the Lactam: BH3·THF (3.3 mL, 3.3 mmol, 1  solution
in THF) was added to an ice-cooled stirred solution of tetrahydro-
benzazepinone 16b (65 mg, 0.22 mmol) in dry THF (4 mL) under
argon. The mixture was stirred at 0 °C for 1 h and then heated at
reflux for 24 h. Aqueous 6  HCl (2 mL) was added to the cooled
reaction mixture and the resulting mixture was stirred at room tem-
perature for 1 h and then heated at reflux for 1 h. The mixture
was concentrated under vacuum, the residue was made basic with
(5R)-6-[(S)-(2-(methoxymethyl)pyrrolidin-1-yl]-5-methyl-5,6,8,9-
tetrahydro-1,3-dioxa-6-azacyclohepta[f]inden-7-one (16f): Yield
82 mg, 82%. [α]2D5 = –36.9 (c = 0.48, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.46–1.63 (m, 2 H, CH2), 1.74 (d, J = 7.0 Hz, 3 H, aqueous 2  NaOH and extracted with CH2Cl2 (3ϫ10 mL). The
CH3), 1.86–2.05 (m, 2 H, CH2), 2.51–2.64 (m, 1 H, CH2N), 2.68–
3.09 (m, 5 H, 4 H, 2 CH2 + 1 H, CH2N), 3.06 (s, 3 H, OCH3),
combined organic layers were dried (MgSO4) and the solvent evap-
orated under vacuum. Purification by flash column chromatog-
3.10–3.48 (m, 3 H, CH + OCH2), 4.77–4.95 (m, 1 H, ArCHN), 6.01 raphy (acetone/MeOH, 95:5, as eluent) delivered (1R)-1-methyl-
(s, 2 H, OCH2O), 6.86 (s, 1 H, Harom), 6.93 (s, 1 H, Harom) ppm. 13
2,3,4,5-tetrahydro-1H-benzo[c]azepine (2b). Yield 26 mg, 73% as a
NMR (75 MHz, CDCl3): δ = 16.7 (CH3), 23.0 (CH2), 27.3 (CH2), light-yellow oil. The structure of (R)-2b was clearly established
C
Eur. J. Org. Chem. 2009, 3741–3752
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3751

D. Dumoulin, S. Lebrun, E. Deniau, A. Couture, P. Grandclaudon
FULL PAPER
from the optical rotation value {[α]2D5 = –13.2 (c = 1.05, CHCl3)}
and from the spectroscopic data which matched those reported for
(S)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine {[α]D = +13.3
(c = 9.0, EtOH)}, but with the opposite sign.[12]
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Synthesis of (1R)-1-Alkyl-2,3,4,5-tetrahydro-1H-benzo[c]azepines
2a,b by Reduction of Lactams 1a,b: A solution of lactam 1a,b
(0.2 mmol) in THF (2 mL) was added slowly at 0 °C under Ar to
a suspension of LiAlH4 (15 mg, 0.4 mmol, 1.5 equiv.) in anhydrous
THF (5 mL). The resulting mixture was stirred under reflux for
3 h. After careful hydrolysis with ice-water (0.5 mL) the resulting
suspension was filtered. The residue was washed thoroughly with
Et2O (5 mL) and CH2Cl2 (5 mL). The filtrate was extracted with
CH2Cl2 (3 ϫ 5 mL). The combined organic layers were dried
(Na2SO4) and the solvent evaporated under vacuum. Purification
by flash column chromatography (acetone/MeOH, 95:5, as eluent)
afforded benzazepine 2a,b as a pale-yellow oil.
(1R)-1-Butyl-7,8,9-trimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]az-
1
epine (2a): Yield 44 mg, 68%. [α]2D5 = –21.4 (c = 0.43, CHCl3). H
NMR (300 MHz, CDCl3): δ = 0.79–1.01 (m, 3 H, CH3), 1.12–1.63
(m, 7 H, 3 CH2 + NH), 1.56–1.97 (m, 3 H, 2 H, CH2 + 1 H, CH2),
2.69–3.12 (m, 3 H, CH2 + 1H from CH2), 3.77 (s, 3 H, OCH3),
3.79 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.87–4.03 (m, 1 H,
ArCHN), 6.17 (s, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.0 (CH3), 22.5 (CH2), 29.2 (CH2), 29.9 (CH2), 30.0 (CH2),
35.2 (ArCH2), 51.1 (NCH2), 55.8 (OCH3), 55.8 (ArCHN), 55.9
(OCH3), 57.9 (OCH3), 105.7 (CH), 123.1 (C), 127.7 (C), 132.6 (C),
148.2 (C), 150.1 (C) ppm. C17H27NO3 (293.4): calcd. C 69.59, H
9.28, N 4.77; found C 69.55, H 9.54, N 4.58.
(1R)-1-Methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (2b): Yield
26 mg, 81%.
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Acknowledgments
We are grateful to the Centre National de la Recherche Scientifique
(CNRS) and the Région Nord-Pas-de-Calais for financial support
(grant to D. D.). This work was also supported by the Programme
PRIM (Région Nord-Pas-de-Calais).
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Received: April 3, 2009
Published Online: June 16, 2009
3752
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3741–3752