First asymmetric synthesis of (un)substituted bridged tetrahydro-2-benzazepines

Article abstract of DOI:10.1016/j.tetasy.2009.12.026

A new and flexible route for the asymmetric synthesis of a variety of alkylated bridged tetrahydro-2-benzazepines has been developed. The key steps are the highly diastereoselective Michael addition of metalated SAMP-hydrazones to α,β-unsaturated esters combined with cyclomethylenation/Mitsunobu coupling reactions to secure the formation of the seven-membered azaheterocycle and of the bridged unit, respectively.

Full text of DOI:10.1016/j.tetasy.2009.12.026

Tetrahedron: Asymmetry 21 (2010) 195–201
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
First asymmetric synthesis of (un)substituted bridged
tetrahydro-2-benzazepines
*
David Dumoulin, Stéphane Lebrun, Axel Couture , Eric Deniau, Pierre Grandclaudon
Univ Lille Nord de France, F-59000 Lille, France
USTL, Laboratoire de Chimie Organique Physique, Bâtiment C3(2), F-59655 Villeneuve d’Ascq, France
CNRS, UMR 8009’COM’, F-59655 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and flexible route for the asymmetric synthesis of a variety of alkylated bridged tetrahydro-2-ben-
zazepines has been developed. The key steps are the highly diastereoselective Michael addition of meta-
Received 30 November 2009
Accepted 21 December 2009
Available online 1 February 2010
lated SAMP-hydrazones to
a,b-unsaturated esters combined with cyclomethylenation/Mitsunobu
coupling reactions to secure the formation of the seven-membered azaheterocycle and of the bridged
unit, respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
the pharmacological profile. To the best of our knowledge, the
assembly of conformationally constrained models has not elicited
Seven-membered nitrogen heterocycles are constituents of a
great variety of poly and diversely substituted models endowed
with chemotherapeutic properties. As a result they have attracted
the particular attention of medicinal chemists.1 The benzo-annu-
lated systems such as 2-benzazepine derivatives fall into this cat-
egory and are known to display potent inhibitory activities
against AchE and SERT,2 broncho-relaxing activity,3 and to promote
skin epithelial cell migration and wound healing.4 Many com-
pounds containing this structure have also been found to interact
with receptors for biogenic amines and to exhibit antipsychotic5
and anticancer actions.6 Several members of this class of azahet-
erocycles are also of significant interest as potent platelet anti-
aggregatory drugs, CNS agents,7 as specific ligands for serotonin
and dopamine-receptor subtypes7 and have also proved to be use-
ful in the treatment of mental disorders and hypoxia.8 A number of
derivatives have been synthesized as non-peptide Arg-Gly-Asp
(RGD) mimetic antagonist of the vitronectin, a receptor of glyco-
protein assumed to play a pivotal role in cell–cell adhesion, signal-
ing, and apoptosis.9 The 2-benzazepine nucleus is also found in a
number of Cephalotaxus and Amaryllidaceae bioactive alkaloids.10
Due to this impressive range of exceptional bioactivities, the last
few decades have witnessed a strong incentive toward the devel-
opment of synthetic approaches to structurally sophisticated mod-
els and the interest in the chemistry of 2-benzazepines continues
unabated.11 In most cases, bioactive benzazepine-centered com-
pounds comprise a benzofused azepine unit tailed with alkyl
chains equipped with appropriate functionalities liable to act on
the interest of synthetic and pharmaceutical groups while benzo-
fused bridged systems remain ignored by the scientific community
in this series. This is notably the case for the azabicyclo[3.2.2]non-
ane derivatives 1 and 2 (Fig. 1) despite the fact that the bicyclic
bridged scaffold is a common structural feature of structurally con-
strained analogues of balanol endowed with promising protein ki-
nase inhibitor properties12 and of heteroaromatic olefinic
compounds that have been recently used as inhibitors of nicotinic
cholinergic receptors.13
R3
R1
R2
N
1 and 2
Figure 1.
Thebenzofusedanalogues also represent themain structuralunit
of the communesins, an emerging class of biologically active Penicil-
lium metabolites.14 The lack of synthetic strategies to build up the
rather constrained framework of 1 and 2 is probably due to the dif-
ficulties associated with the elaboration of parent compounds,
which involve multi-steps,15 a key problematic point hampering
substitution of the azepine nucleus with appropriate functionalities
to secure the required formation of the bridged unit. In this regard,
the construction of models with additional stereocontrol of the car-
bon centers embedded in the bridged bicyclic unit becomes a very
challenging synthetic task and we waited to face the challenge of
preparing such stereopure polycyclic models.
* 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 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.026

196
D. Dumoulin et al. / Tetrahedron: Asymmetry 21 (2010) 195–201
NMR (75 MHz) and indicate the original asymmetric induction be-
2. Results and discussion
cause no diastereomeric enrichment occurred during chromatogra-
phy. The Michael adduct hydrazones 3, 4 were obtained as the
E-isomers exclusively based on the observed characteristic chemical
shifts.17 The (S,S)-absolute configuration of the newly generated ste-
reogenic centers in 3b,c and 4c,d was assigned according to the pre-
viously confirmed mechanism for the asymmetric 1,4-addition of
metalated aldehyde SAMP-hydrazones to enoate Michael accep-
tors.16,18 SAMP-derivatives of this type are usually converted into
We delineate in this paper a concise and conceptually new
asymmetric approach to a variety of diversely substituted bridged
tetrahydro-2-benzazepines 1, 2 that is based upon strategic combi-
nations of the highly diastereo- and enantioselective Michael addi-
tion of SAMP-hydrazones to a
,b-unsaturated esters16 followed by a
reduction/cyclomethylenation sequence with an intramolecular
Mitsunobu reaction. We surmised that the former sequence would
provide the potential for an easy access to an opened precursor of
the NH-free azepine ring system with the concomitant installation
of a mandatory hydroxyalkylated chain.
The first facet of the synthesis which is depicted in Scheme 1 was
the elaboration of the Michael adducts 3a–c, 4c,d. These compounds
were readily assembled by the reaction of the azaenolates of SAMP-
hydrazones 5a–d acting as chiral nucleophiles on diversely substi-
the corresponding a,b-disubstituted ketones as a reliable procedure
for the determination of the absolute configuration of chiral com-
pounds.19 For the synthesis of hydrazines 9a–c, 10c,d, suitable can-
didates for the planned cyclization reactions, hydrazones 3a–c, 4c,d
were subsequently reduced with LiAlH4. This operation delivered al-
most quantitative yields of the desired saturated compounds (R,S)-
9a, (S,S,S)-9b,c and (S,S,S)-10c,d. As anticipated the reduction of
the C@N double bond was accompanied with the conversion of the
ester function into a hydroxyethyl appendage which should serve
a role in synthetic planning. Owing to the limited stability and sen-
sitivity usually exhibited by this type of NH-free hydrazines16–18
thereducedcompounds9, 10were usedin the next step withoutfur-
ther purification. Cyclomethylenation of the unprotected arylalky-
lated hydrazones (R,S)-9a, (S,S,S)-9b,c and (S,S,S)-10c,d proceeded
smoothly by making use of chloromethylmethyl ether (MOMCl) in
acetic acid to provide satisfactory yields of the desired cyclic hydra-
zines (R,S)-11a, (S,S,S)-11b,c and (S,S,S)-12c,d as the sole diastereo-
isomer detectable by NMR upon flash chromatographic treatment.
It is noteworthy that this simple operation did not spare the pendant
hydroxyalkyl chain which was converted into the corresponding
tuted a,b-unsaturated esters 6, 7. Initially, the appropriate aliphatic
carboxaldehydes were converted into the corresponding chiral
hydrazones (S)-5a–d by simply mixing the enantiomerically pure
hydrazine (S)-(–)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)
withthecommerciallyavailablealdehydes8a–d(Scheme1, Table1).
The chiral hydrazones were allowed to react with lithium diisopro-
pylamide (LDA) in THF at ꢀ78 °C followed by warming to 0 °C over
a 3-h period. The (E)-esters 6, 7 were then added at ꢀ100 °C to the
lithium azaenolate generated, furnishing the crude Michael adducts
(R,S)-3a and (S,S,S)-3b,c or (S,S,S)-4c,d which were purified by flash
chromatography. In this way the ester-hydrazones 3, 4 were
obtained in good yields (Table 1) and high diastereoselectivity
(de P 96%). The latter were determined by 1H (300 MHz) and 13C
1) LDA, THF, -78 °C to 0 °C, 3 h
O
2) THF, -110 °C, 1 h
OMe
OEt
R1
R2
CO2Et
R3
then
H2N
N
R3
6, 7
R1
R2
R3
OMe
CH2Cl2, MgSO4
r.t., 12 h
-78 °C, 3 h
N
N
OMe
N
N
(81-89 %)
O
3a-c
4c,d
8a-d
5a-d
AcO
HO
MOMCl, AcOH
1. BH3.THF
reflux, 1 h
THF, reflux, 48 h
LiAlH4, THF
Δ, 12 h
R3
R3
N
then r.t., 1 h
2. NaOH, reflux, 3 h
R1
R2
R1
R2
(67-98 %)
(52-89 %)
OMe
HN
N
OMe
N
(ee > 96 %)
(de > 96 %)
9a-c
11a-c
12c,d
10c,d
HO
DEAD, PPh3
THF, r.t., 12 h
R3
R3
R1
R2
R1
R2
(56-79 %)
ee > 96 %
N
NH
1a-c
2c,d
13a-c
14c,d
Scheme 1.

D. Dumoulin et al. / Tetrahedron: Asymmetry 21 (2010) 195–201
197
Table 1
Compounds produced via Scheme 1
R1
R2
Michael adducts
R3
2-Benzazepine derivatives
Hydroxyethyl 2-benzazepines
Bridged 2
3, 4a (yield %)
11, 12a,b (yield %)
13, 14c (yield %)
2-benzazepines 1, 2c (yield %)
OMe
OMe
OMe
OCH2O
OCH2O
OMe
OMe
OMe
(R,S)-3a (51)
(S,S,S)-3b (48)
(S,S,S)-3c (47)
(S,S,S)-4c (53)
(S,S,S)-4d (47)
H
Me
Et
Et
(R,S)-11a (61)
(S,S,S)-11b (89)
(S,S,S)-11c (55)
(S,S,S)-12c (59)
(S,S,S)-12d (52)
(R)-13a (88)
(S,S)-13b (67)
(S,S)-13c (98)
(S,S)-14c (73)
(S,S)-14d (76)
1a (64)
(S,S)-1b (79)
(S,S)-1c (62)
(S,S)-2c (59)
(S,S)-2d (56)
n-C5H11
a
b
c
Yield of isolated diastereoisomer (de P 96%).
Over two steps.
Yield of isolated virtually enantiopure isomer (ee P 96%).
acetate. However this undesirable reaction was not detrimental to
the outcome of the synthetic process liable to give access to the dia-
stereopure hydroxyalkylated benzazepine derivatives 13a–c, 14c,d,
suitable candidates for the assembly of the title compounds. Indeed
reductive N–N bond cleavage by the BH3ꢁTHF complex triggered off
the release of the chiral appendage with simultaneous regeneration
of the hydroxy functionality and completed the synthesis of the
virtually enantio- and diastereopure 5-hydroxyethyl NH-free tetra-
hydrobenzazepines (R)-13a, (S,S)-13b,c and (S,S)-14c,d, respec-
tively. These amino-hydroxylated compounds were obtained in
good yields with high enantio and diastereoisomeric excesses
(ee P 96%, de P 96%; Table 1). With these compounds in hand, we
were only one cyclization away from the title compounds since they
possess the requisite structure and functional group location to be
easily converted into the bridged seven-membered models under
the agency of the Mitsunobu reaction. Thus treatment of 13a–c,
14c,d with diethyl azidodicarboxylate (DEAD) and triphenylphos-
phine delivered quite satisfactory yields of meso compound 1a and
of the virtually diastereopure benzofused bridged tetrahydroaze-
pines (S,S)-1b,c and (S,S)-2c,d (Scheme 1, Table 1).
SAMP-hydrazones 5a–d were prepared according to a reported
procedure.20 The ,b-unsaturated esters 621 and 722 were synthe-
sized following the literature methods.
a
4.2. Synthesis of the Michael adducts 3a–c and 4c,d. General
procedure
A solution of n-BuLi (4.42 mL, 7.08 mmol, 1.6 M solution in hex-
anes) was added dropwise to a stirred solution of diisopropylamine
(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 and was then cooled
to ꢀ78 °C.
A solution of the appropriate hydrazone 5a–d
(7.08 mmol) in THF (5 mL) was slowly added and the mixture
was stirred at ꢀ78 °C for 45 min. The mixture was allowed to
warm to 0 °C and stirred for an additional 3 h at 0 °C. The mixture
was recooled to ꢀ110 °C and a solution of the appropriate
a,b-
unsaturated ester 6, 7 (7.1 mmol) in dry THF (10 mL) was added
slowly. After stirring for 1 h at ꢀ110 °C, the temperature was al-
lowed to rise slowly to ꢀ78 °C and stirring was maintained for
3 h at this temperature. The reaction was then quenched with a
saturated HCl ethereal solution (5 mL) and allowed to warm to
rt. Water (10 mL) was then added, and the mixture was extracted
with ethyl acetate (3 ꢂ 10 mL). The combined organic layers were
washed with brine (20 mL) and water (20 mL), then dried (MgSO4),
concentrated, and purified by flash column chromatography on sil-
ica gel (ethyl acetate–hexanes, 30:70, as eluent) to yield the hydra-
zones 3a-c and 4c,d as a pale yellow to colorless oil.
3. Conclusion
In conclusion we have devised a new and flexible method for
the diastereoselective synthesis of a variety of diversely substi-
tuted bridged tetrahydro-2-benzazepines. The key steps are the
highly diastereoselective Michael addition of metalated aldehyde
hydrazones to aromatic enoates followed by a double reduction
process to generate hydroxy and hydrazine functionalities com-
bined with a cyclomethylenation reaction to secure the formation
of the benzazepine ring system. Removal of the chiral auxiliary and
an intramolecular Mitsunobu coupling reaction ensured the crea-
tion of the bridged unit to complete the assembly of the title com-
pounds which were obtained with high de values.
4.2.1. (R)-3-(3,4-Dimethoxyphenyl)-5-[(S)-2-(methoxymethyl)
pyrrolidin-1-ylimino]pentanoic ethyl ester 3a
1.42 g (51%); ½a 2D5
ꢃ
¼ ꢀ57:7 (c 0.87, CHCl3); 1H NMR (300 MHz,
CDCl3): d 1.15 (t, J = 7.2 Hz, 3H, CH3), 1.71–2.02 (m, 4H, 2 ꢂ CH2),
2.46–2.68 (m, 4H:2H, CH2CHN + 1H, CH2COO + 1H, CH2N), 2.72
(dd, J = 3.9, 15.3 Hz, 1H CH2CO2Et), 3.29–3.45 (m, 4H:1H, CH2N + 1H,
CH + 1H, ArCH + 1H OCH2), 3.37 (s, 3H, OCH3), 3.47–3.60 (m, 1H,
OCH2), 3.86 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.03 (q, J = 7.2 Hz, 2H,
4. Experimental
4.1. General
COOCH2), 6.46 (t, J = 5.4 Hz, 1H, CH@N), 6.67–6.84 (m, 3H, Harom
)
ppm; 13C NMR (75 MHz, CDCl3): d 14.2 (CH3), 22.1 (CH2), 26.5
(CH2), 39.8 (CH2), 40.4 (ArCH), 40.9 (CH2), 50.2 (CH2), 55.8
(2 ꢂ OCH3), 59.2 (CH), 60.3 (OCH2), 63.3 (OCH3), 74.7 (OCH2),
110.7 (CH), 111.0 (CH), 119.3 (CH), 135.6 (CH@N), 136.1 (C), 147.5
(C), 148.7 (C), 172.3 (CO) ppm. Anal. Calcd for C21H32N2O5: C,
64.26; H, 8.22; N, 7.14. Found: C, 64.32; H, 8.52; N, 7.05.
Melting points were determined on a Reichert-Thermopan
apparatus and are uncorrected. NMR spectra were recorded on a
Bruker AM 300 spectrometer. These were referenced against inter-
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.
4.2.2. (3S,4S)-3-(3,4-Dimethoxyphenyl)-5-[(S)-2-(methoxymethyl)
pyrrolidin-1-ylimino]-4-methylpentanoic ethyl ester 3b
1.38 g (48%); ½a 2D5
ꢃ
¼ ꢀ68:4 (c 1.18, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.97–1.12 (m, 6H, 2 ꢂ CH3), 1.65–1.95 (m, 4H, 2 ꢂ CH2),
2.41–2.66 (m, 3H:1H, CH + 1H, CH2COO + 1H, CH2N), 2.74 (dd,
J = 5.6, 15.5 Hz, 1H, CH2COO), 3.11–3.41 (m, 4H:1H, CH2N + 1H,
CH + 1H, ArCH + 1H, OCH2), 3.33 (s, 3H, OCH3), 3.49 (dd, J = 3.8,
9.1 Hz, 1H OCH2), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.97 (dq,
J = 2.2, 7.1 Hz, 2H, COOCH2), 6.29 (d, J = 6.7 Hz, 1H, CH@N),

198
D. Dumoulin et al. / Tetrahedron: Asymmetry 21 (2010) 195–201
6.61–6.80 (m, 3H, Harom) ppm;13C NMR (75 MHz, CDCl3): d 14.1 (CH3),
16.7 (CH3), 22.1 (CH2), 26.5 (CH2), 38.1 (CH2), 41.9 (CH), 45.9 (ArCH),
50.2 (CH2N), 55.8 (2 ꢂ OCH3), 59.2 (CH), 60.2 (OCH2), 63.4 (OCH3),
74.6 (OCH2), 110.6 (CH), 111.9 (CH), 120.5 (CH), 134.0 (C), 140.7
(CH@N), 147.4 (C), 148.3 (C), 172.5 (CO) ppm. Anal. Calcd for
C22H34N2O5: C, 65.00; H, 8.43; N, 6.89. Found:C, 64.85; H, 8.45; N, 6.81.
(419 mg, 12 mmol) in dry THF (5 mL) and the resulting mixture
was refluxed overnight. After cooling, water (0.5 mL), 10% aqueous
NaOH (0.5 mL), and water (1 mL) were successively added to the
mixture. The precipitate was removed by filtration and was thor-
oughly washed with CH2Cl2 (2 ꢂ 5 mL) and Et2O (2 ꢂ 5 mL). The fil-
trate was dried (MgSO4) and concentrated under vacuum to afford
the crude hydrazine 9a–c or 10c,d as a colorless oil which was used
in the next step without further purification. MOMCl (161 mg,
0.15 mL, 2.0 mmol) was added to a stirred solution of the crude
hydrazine 9a–c or 10c,d (2.0 mmol) in glacial acetic acid (10 mL)
under Ar and the mixture was refluxed for 1 h and then stirred
at rt for 1 h. The crude reaction mixture was poured onto crushed
ice and neutralized with 50% aqueous NaOH and then was ex-
tracted with ethyl acetate (3 ꢂ 25 mL). The combined organic lay-
ers were washed with water (20 mL) and brine (20 mL), and dried
(MgSO4). Evaporation of the solvent under vacuum afforded an oily
residue, which was purified by flash column chromatography on
silica gel (acetone–hexanes, 20:80, as eluent) to yield the expected
tetrahydrobenzazepines 11a–c, 12c,d as yellow oil.
4.2.3. (3S,4S)-3-(3,4-Dimethoxyphenyl)-4-{[(S)-2-(methoxymethyl)
pyrrolidin-1-yl-imino]methyl}hexanoic ethyl ester 3c
1.40 g (47%); ½a 2D5
ꢃ
¼ ꢀ86:4 (c 0.86, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.87 (t, J = 7.3 Hz, 3H, CH3), 1.08 (t, J = 7.2 Hz, 3H, CH3),
1.20–1.38 (m, 1H, CH2), 1.43–1.60 (m, 1H, CH2), 1.68–1.96 (m, 4H,
2 ꢂ CH2), 2.22–2.40 (m, 1H, CH), 2.49–2.69 (m, 2H:1H,
CH2COO + 1H, CH2N), 2.74 (dd, J = 5.9, 15.3 Hz, 1H, CH2COO), 3.18–
3.39 (m, 4H:1H, CH2N + 1H, CH + 1H, ArCH + 1H, OCH2), 3.32 (s,
3H, OCH3), 3.48 (dd, J = 3.8, 9.2 Hz, 1H, OCH2), 3.82 (s, 3H, OCH3),
3.83 (s, 3H, OCH3), 3.97 (q, 2H, J = 7.0 Hz, COOCH2), 6.18 (d, 1H,
J = 7.6 Hz, CH@N), 6.57–6.81 (m, 3H, Harom) pmm; 13C NMR
(75 MHz, CDCl3): d 11.9 (CH3), 14.1 (CH3), 22.1 (CH2), 24.6 (CH2),
26.5 (CH2), 38.7 (CH2), 44.5 (CH), 48.9 (ArCH), 50.4 (CH2N), 55.8
(2 ꢂ OCH3), 59.1 (CH), 60.1 (OCH2), 63.4 (OCH3), 74.7 (OCH2),
110.5 (CH), 112.0 (CH), 120.8 (CH), 133.7 (C), 139.9 (CH@N), 147.5
(C), 148.3 (C), 172.5 (CO) ppm. Anal. Calcd for C23H36N2O5: C,
65.69; H, 8.63; N, 6.66. Found: C, 65.88; H, 8.39; N, 6.51.
4.3.1. Acetic acid 2-[(R)-7,8-dimethoxy-2-[(S)-2-(methoxymethyl)
pyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]ethyl
ester 11a
495 mg (61%); ½a 2D5
ꢃ
¼ ꢀ82:6 (c 1.58, CHCl3); 1H NMR (300 MHz,
CDCl3): d 1.61–1.87 (m, 4H, 2 ꢂ CH2), 1.88–2.10 (m, 3H:2H,
CH2 + 1H, CH2), 2.06 (s, 3H, CH3), 2.11–2.23 (m, 1H, CH2), 2.68–
2.82 (m, 1H, ArCH), 2.86–3.19 (m, 5H:4H, 2 ꢂ CH2N + 1H, CH),
3.21–3.36 (m, 1H, OCH2), 3.31 (s, 3H, OCH3), 3.46 (dd, 1H, J = 3.2,
9.0 Hz, 1H OCH2), 3.79–3.97 (m, 2H, CH2OAc), 3.84 (s, 3H, OCH3),
3.85 (s, 3H, OCH3), 4.04–4.22 (m, 2H, ArCH2N), 6.64 (s, 1H, Harom),
6.68 (s, 1H, Harom) ppm; 13C NMR (75 MHz, CDCl3): d 21.0 (CH3),
21.4 (CH2), 26.3 (CH2), 32.2 (CH2), 32.7 (CH2), 39.7 (ArCH), 44.0
(CH2N), 44.2 (CH2N), 51.8 (CH2N), 56.0 (2 ꢂ OCH3), 59.0 (OCH3),
59.1 (CH), 63.1 (CH2OAc), 75.3 (OCH2), 113.3 (CH), 113.4 (CH),
130.9 (C), 136.0 (C), 146.6 (C), 147.2 (C), 171.2 (CO) ppm. Anal.
Calcd for C22H34N2O5: C, 65.00; H, 8.43; N, 6.89. Found: C, 64.87;
H, 8.59; N, 6.75.
4.2.4. (3S,4S)-3-Benzo[1,3]dioxol-5-yl-4-{[(S)-2-(methoxymethyl)
pyrrolidin-1-ylimino]methyl}hexanoic ethyl ester 4c
1.43 g (53%); ½a 2D5
ꢃ
¼ ꢀ90:4 (c 4.58, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.81 (t, J = 7.3 Hz, 3H, CH3), 1.05 (t, J = 7.1 Hz, 3H, CH3),
1.18–1.32 (m, 1H, CH2), 1.38–1.52 (m, 1H, CH2), 1.64–1.94 (m,
4H, 2 ꢂ CH2), 2.18–2.30 (m, 1H, CH), 2.47–2.61 (m, 2H:1H,
CH2COO + 1H, CH2N), 2.67 (dd, J = 5.8, 15.6 Hz, 1H, CH2COO),
3.13–3.36 (m, 4H:1H, CH2N + 1H, CH + 1H, ArCH + 1H, OCH2),
3.29 (s, 3H, OCH3), 3.44 (dd, J = 3.1, 8.5 Hz, 1H, OCH2), 3.94 (q,
J = 7.0 Hz, 2H, COOCH2), 5.84 (s, 2H, OCH2O), 6.14 (d, J = 7.7 Hz,
1H, CH@N), 6.48–6.67 (m, 3H, Harom) ppm; 13C NMR (75 MHz,
CDCl3): d 11.9 (CH3), 14.1 (CH3), 22.1 (CH2), 24.6 (CH2), 26.6
(CH2), 38.8 (CH2), 44.6 (CH), 48.9 (ArCH), 50.6 (CH2N), 59.2 (CH),
60.2 (OCH2), 63.4 (OCH3), 74.7 (OCH2), 100.8 (OCH2O), 107.7
(CH), 109.1 (CH), 121.2 (CH), 134.9 (C), 139.7 (CH@N), 146.0 (C),
147.2 (C), 172.4 (CO) ppm. Anal. Calcd for C22H32N2O5: C, 65.32;
H, 7.97; N, 6.93. Found: C, 65.12; H, 7.78; N, 6.87.
4.3.2. Acetic acid 2-{(4S,5S)-7,8-dimethoxy-2-[(S)-2-(methoxy
methyl)pyrrolidin-1-yl]-4-methyl-2,3,4,5-tetrahydro-1H-2-
benzazepin-5-yl}ethyl ester 11b
748 mg (89%); ½a 2D5
ꢃ
¼ ꢀ86:0 (c 1.40, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.93 (d, J = 6.9 Hz, 3H, CH3), 1.59–1.85 (m, 4H, 2 ꢂ CH2),
1.86–2.08 (m, 2H, CH2), 2.03 (s, 3H, CH3), 2.09–2.27 (m, 1H, CH),
2.54–2.69 (m, 1H, ArCH), 2.70–2.90 (m, 3H:2H, CH2N + CH), 2.95–
3.12 (m, 2H, CH2N), 3.25–3.35 (m, 1H, OCH2), 3.31 (s, 3H, OCH3),
3.45 (dd, J = 3.1, 9.2 Hz, 1H, OCH2), 3.78–3.92 (m, 1H, ArCH2N),
3.84 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.98 (t, J = 6.1 Hz, 2H,
CH2OAc), 4.15 (d, J = 13.9 Hz, 1H, ArCH2N), 6.54 (s, 1H, Harom),
6.68 (s, 1H, Harom) ppm; 13C NMR (75 MHz, CDCl3): d 18.9 (CH3),
21.0 (CH3), 21.2 (CH2), 25.6 (CH2), 32.3 (CH2), 35.5 (ArCH), 43.6
(ArCH2N), 48.6 (CH), 51.8 (CH2N), 51.9 (CH2N), 55.8 (OCH3), 55.9
(OCH3), 58.9 (OCH3), 59.2 (CH), 63.1 (CH2OAc), 74.9 (OCH2),
114.1 (CH), 115.1 (CH), 130.0 (C), 132.8 (C), 146.7 (C), 146.8 (C),
171.1 (CO) ppm. Anal. Calcd for C23H36N2O5: C, 65.69; H, 8.63; N,
6.66. Found: C, 65.41; H, 8.56; N, 6.56.
4.2.5. (3S,4S)-3-Benzo[1,3]dioxol-5-yl-4-{[(S)-2-(methoxymethyl)
pyrrolidin-1-ylimino]methyl}nonanoic ethyl ester 4d
1.49 g (47%); ½a 2D5
ꢃ
¼ ꢀ82:6 (c 1.58, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.83 (t, J = 6.7 Hz, 3H, CH3), 1.09 (t, J = 7.0 Hz, 3H, CH3),
1.13–1.51 (m, 8H, 4 ꢂ CH2), 1.65–1.98 (m, 4H, 2 ꢂ CH2), 2.29–
2.43 (m, 1H, CH), 2.49–2.65 (m, 2H:1H, CH2COO + 1H, CH2N),
2.72 (dd, J = 5.9, 15.6 Hz, 1H, CH2COO), 3.12–3.40 (m, 4H:1H,
CH2N + 1H, CH + 1H, ArCH + 1H, OCH2), 3.33 (s, 3H, OCH3), 3.48
(dd, J = 3.5, 8.8 Hz, 1H, OCH2), 3.98 (dq, J = 2.1, 7.2 Hz, 2H, COOCH2),
5.87 (s, 2H, OCH2O), 6.18 (d, J = 7.6 Hz, 1H, CH@N), 6.52–6.71 (m,
3H, Harom) ppm; 13C NMR (75 MHz, CDCl3): d 14.1 (2 ꢂ CH3), 22.1
(CH2), 22.5 (CH2), 26.5 (CH2), 26.9 (CH2), 31.7 (CH2), 31.8 (CH2),
38.8 (CH2), 44.9 (CH), 47.1 (ArCH), 50.6 (CH2N), 59.1 (CH), 60.1
(OCH2), 63.4 (OCH3), 74.7 (OCH2), 100.8 (OCH2O), 107.6 (CH),
109.0 (CH), 121.8 (CH), 134.9 (C), 139.9 (CH@N), 145.9 (C), 147.2
(C), 172.3 (CO) ppm. Anal. Calcd for C25H38N2O5: C, 67.24; H,
8.58; N, 6.27. Found: C, 67.12; H, 8.37; N, 6.51.
4.3.3. Acetic acid 2-{(4S,5S)-4-ethyl-7,8-dimethoxy-2-[(S)-2-
(methoxymethyl)pyrrolidin-1-yl]-2,3,4,5-tetrahydro-1H-2-
benzazepin-5-yl}ethyl ester 11c
478 mg (55%); ½a 2D5
ꢃ
¼ ꢀ55:8 (c 1.46, CHCl3); 1H NMR (300 MHz,
4.3. Synthesis of tetrahydrobenzazepine derivatives 11a–c, 12c,d.
General procedure
CDCl3): d 0.85 (t, J = 7.3 Hz, 3H, CH3), 1.12–1.46 (m, 2H, CH2), 1.57–
1.83 (m, 4H, 2 ꢂ CH2), 1.87–1.98 (m, 1H, CH), 1.99–2.25 (m, 2H,
CH2), 2.02 (s, 3H, CH3), 2.68–2.90 (m, 3H:2H, CH2N + 1H, CH),
2.92–3.09 (m, 3H:2H, CH2N + 1H, ArCH), 3.23–3.40 (m, 1H,
OCH2), 3.30 (s, 3H, OCH3), 3.46 (dd, J = 2.9, 9.2 Hz, 1H, OCH2),
A solution of Michael adduct 3a–c or 4c,d (4.0 mmol) in THF
(10 mL) was slowly added to a stirred suspension of LiAlH4

D. Dumoulin et al. / Tetrahedron: Asymmetry 21 (2010) 195–201
199
3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.88 (d, J = 13.7 Hz, 1H,
ArCH2N), 4.00 (t, 2H, J = 7.0 Hz, CH2OAc), 4.16 (d, J = 13.7 Hz, 1H,
ArCH2N), 6.51 (s, 1H, Harom), 6.66 (s, 1H, Harom) ppm; 13C NMR
(75 MHz, CDCl3): d 12.3 (CH3), 21.0 (CH3), 21.1 (CH2), 25.2 (CH2),
25.6 (CH2), 32.1 (CH2), 42.8 (ArCH), 43.4 (ArCH2N), 46.6 (CH),
49.4 (2 ꢂ CH2N), 55.8 (OCH3), 55.9 (OCH3), 59.0 (OCH3), 59.2
(CH), 63.2 (CH2OAc), 74.8 (OCH2), 114.2 (CH), 115.0 (CH), 129.5
(C), 132.9 (C), 146.7 (Ca), 146.8 (C), 171.2 (CO) ppm. Anal. Calcd
for C24H38N2O5: C, 66.33; H, 8.81; N, 6.45. Found: C, 66.51; H,
8.97; N, 6.53.
4.4.1. 2-[(R)-7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-
5-yl]ethanol 13a
221 mg (88%); ½a 2D5
ꢃ
¼ ꢀ15:5 (c 1.51, CHCl3); 1H NMR (300 MHz,
CDCl3): d 1.42–1.91 (m, 5H:4H, 2 ꢂ CH2 + 1H, NH + 1H, OH), 1.92–
2.11 (m, 1H, CH2), 2.69–3.21 (m, 3H:2H, CH2N + 1H, ArCH), 3.42–
3.67 (m, 2H, CH2O), 3.69–3.99 (m, 2H, ArCH2N), 3.77 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 6.56 (s, 1H, Harom), 6.64 (s, 1H, Harom
)
ppm; 13C NMR (75 MHz, CDCl3): d 28.1 (CH2N), 34.6 (CH2), 37.3
(ArCH), 52.7 (ArCH2N), 54.2 (CH2N), 54.9 (OCH3), 55.1 (OCH3),
59.7 (CH2OH), 109.5 (CH), 110.1 (CH), 132.8 (C), 135.9 (C), 145.4
(C), 146.3 (C) ppm. Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42;
N, 5.57. Found: C, 67.09; H, 8.45; N, 5.82.
4.3.4. Acetic acid 2-{(8S,9S)-8-ethyl-6-[(S)-2-(methoxymethyl)
pyrrolidin-1-yl]-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclo-
hepta[f]inden-9-yl}ethyl ester 12c
4.4.2. 2-[(4S,5S)-7,8-Dimethoxy-4-methyl-2,3,4,5-tetrahydro-1H-
494 mg (59%); ½a 2D5
ꢃ
¼ ꢀ54:0 (c 0.69, CHCl3); 1H NMR (300 MHz,
2-benzazepin-5-yl]ethanol 13b
177 mg (67%); ½a 2D5
ꢃ
¼ ꢀ14:7 (c 1.26, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.86 (t, J = 7.2 Hz, 3H, CH3), 1.11–1.44 (m, 2H, CH2), 1.59–
1.86 (m, 4H, 2 ꢂ CH2), 1.84–1.97 (m, 1H, CH), 2.02–2.21 (m, 2H,
CH2), 2.01 (s, 3H, CH3), 2.69–2.93 (m, 3H:2H, CH2N + CH), 2.91–
3.06 (m, 3H:2H, CH2N + 1H, ArCH), 3.21–3.39 (m, 1H, OCH2), 3.31
(s, 3H, OCH3), 3.44 (dd, J = 2.8–9.1 Hz, 1H, OCH2), 3.86 (d,
J = 13.5 Hz, 1H, ArCH2N), 4.03 (t, J = 7.1 Hz, 2H, CH2OAc), 4.17 (d,
J = 13.5 Hz, 1H, ArCH2N), 5.91 (d, J = 11.5 Hz, 2H, OCH2O), 6.51 (s,
1H, Harom), 6.64 (s, 1H, Harom) ppm; 13C NMR (75 MHz, CDCl3): d
12.1 (CH3), 21.0 (CH3), 21.2 (CH2), 25.1 (CH2), 25.6 (CH2), 32.2
(CH2), 42.4 (ArCH), 43.3 (ArCH2N), 46.7 (CH), 49.2 (2 ꢂ CH2N),
59.0 (OCH3), 59.1 (CH), 63.2 (CH2OAc), 75.1 (OCH2), 99.9 (OCH2O),
107.6 (CH), 108.1 (CH), 134.2 (C), 138.5 (C), 145.7 (C), 146.6 (C),
171.1 (CO) ppm. Anal. Calcd for C23H34N2O5: C, 66.00; H, 8.19; N,
6.69. Found: C, 65.87; H, 8.36; N, 6.77.
CDCl3): d 0.88 (d, J = 7.1 Hz, 3H, CH3), 1.80–2.02 (m, 2H, CH2), 2.05–
2.23 (m, 1H, CH), 2.53–2.87 (m, 3H:1H, NH + 1H, ArCH + 1H, OH),
2.95 (dd, J = 2.9, 14.2 Hz, 1H, CH2N), 3.34 (dd, J = 2.2, 14.3 Hz, 1H,
CH2N), 3.44–3.65 (m, 2H, CH2O), 3.74 (d, J = 15.2 Hz, 1H, ArCH2N),
3.84 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.05 (d, J = 15.2 Hz, 1H,
ArCH2N), 6.59 (s, 1H, Harom), 6.66 (s, 1H, Harom) ppm; 13C NMR
(75 MHz, CDCl3): d 17.9 (CH3), 35.7 (ArCH), 36.1 (CH2), 49.1 (CH),
52.0 (ArCH2N), 54.1 (CH2N), 55.9 (OCH3), 56.1 (OCH3), 60.9
(CH2OH), 113.3 (CH), 115.6 (CH), 132.6 (C), 134.0 (C), 146.6 (C),
147.0 (C) ppm. Anal. Calcd for C15H23NO3: C, 67.90; H, 8.74; N,
5.28. Found: C, 68.12; H, 8.89; N, 5.52.
4.4.3. 2-[(4S,5S)-7,8-Dimethoxy-4-ethyl-2,3,4,5-tetrahydro-1H-
2-benzazepin-5-yl]ethanol 13c
273 mg (98%); ½a 2D5
ꢃ
¼ ꢀ13:5 (c 1.33, CHCl3); 1H NMR (300 MHz,
4.3.5. Acetic acid 2-{(8S,9S)-6-[(S)-2-(methoxymethyl)pyrrolidin-
1-yl]-8-pentyl-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-azacyclohepta
[f]inden-9-yl}ethyl ester 12d
CDCl3): d 0.89 (t, J = 7.2 Hz, 3H, CH3), 1.15–1.31 (m, 2H, CH2), 1.81–
2.02 (m, 2H, CH), 2.08–2.23 (m, 1H, CH), 2.25–2.49 (br s, 2H,
OH + NH), 2.81–2.96 (m, 1H, ArCH), 3.08 (d, J = 12.0 Hz, 1H,
CH2N), 3.27 (d, J = 14.3 Hz, 1H, CH2N), 3.49–3.67 (m, 2H, CH2O),
3.73 (d, J = 15.2 Hz, 1H, ArCH2N), 3.83 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 4.07 (d, J = 15.2 Hz, 1H, ArCH2N), 6.58 (s, 1H, Harom), 6.66
(s, 1H, Harom) ppm; 13C NMR (75 MHz, CDCl3): d 12.0 (CH3), 24.2
(CH2), 36.0 (CH2), 43.0 (ArCH), 47.2 (CH), 49.7 (ArCH2N), 54.5
(CH2N), 55.9 (OCH3), 56.1 (OCH3), 61.1 (CH2OH), 113.3 (CH),
115.5 (CH), 133.9 (C), 134.0 (C), 146.6 (C), 147.0 (C) ppm. Anal.
Calcd for C16H25NO3: C, 68.79; H, 9.02; N, 5.01. Found: C, 68.97;
H, 8.78; N, 5.23.
479 mg (52%); ½a 2D5
ꢃ
¼ ꢀ53:4 (c 0.52, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.72–0.91 (m, 3H, CH3), 0.93–1.45 (m, 8H, 4 ꢂ CH2), 1.49–
1.83 (m, 4H, 2 ꢂ CH2), 1.85–2.28 (m, 3H:1H, CH + 2H, CH2), 2.04 (s,
3H, CH3), 2.64–2.87 (m, 3H:2H, CH2N + 1H, CH), 2.88–3.04 (m,
3H:2H, CH2N + 1H, ArCH), 3.21–3.41 (m, 1H, OCH2), 3.31 (s, 3H,
OCH3), 3.46 (dd, J = 2.9, 9.2 Hz, 1H, OCH2), 3.63–3.72 (m, 1H,
ArCH2N), 3.81–4.04 (m, 2H, CH2OAc), 4.06–4.20 (m, 1H, ArCH2N),
5.92 (d, J = 11.6 Hz, 2H, OCH2O), 6.51 (s, 1H, Harom), 6.63 (s, 1H, Har-
om); 13C NMR (75 MHz, CDCl3): d 14.1 (CH3), 21.0 (CH3), 21.1 (CH2),
22.4 (CH2), 22.6 (CH2), 25.7 (CH2), 26.2 (CH2), 28.3 (CH2), 32.0
(CH2), 41.2 (ArCH), 43.3 (ArCH2N), 47.6 (CH), 49.4 (CH2N), 49.6
(CH2N), 58.9 (OCH3), 59.2 (CH), 63.2 (CH2OAc), 75.3 (OCH2), 99.7
(OCH2O), 107.5 (CH), 108.2 (CH), 134.2 (C), 138.6 (C), 145.6 (C),
146.5 (C), 171.2 (CO) ppm. Anal. Calcd for C26H40N2O5: C, 67.80;
H, 8.75; N, 6.08. Found: C, 68.07; H, 8.92; N, 6.76.
4.4.4. 2-[(8S,9S)-8-Ethyl-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-
azacyclohepta[f]inden-9-yl]ethanol 14c
192 mg (73%); ½a 2D5
ꢃ
¼ ꢀ10:6 (c 0.80, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.86 (t, J = 7.1 Hz, 3H, CH3), 1.16–1.34 (m, 2H, CH2), 1.83–
2.01 (m, 2H, CH2), 2.07–2.23 (m, 1H, CH), 2.24–2.51 (br s, 2H,
OH + NH), 2.83–2.99 (m, 1H, ArCH), 3.07 (d, J = 12.1 Hz, 1H,
CH2N), 3.28 (d, J = 12.1 Hz, 1H, CH2N), 3.49–3.69 (m, 2H, CH2O),
3.74 (d, J = 15.1 Hz, 1H, ArCH2N), 4.06 (d, J = 15.1 Hz, 1H , ArCH2N),
4.4. Synthesis of hydroxyethyltetrahydro-2-benzazepines 13a–c
and 14c,d. General procedure
5.92 (s, 2H, OCH2O), 6.61 (s, 1H, Harom), 6.66 (s, 1H, Harom) ppm; 13
C
Boran–tetrahydrofuran complex (BH3ꢁTHF, 10 mL, 10 mmol,
1 M solution in THF) was slowly added to an ice-cooled stirred
solution of benzazepine derivative 11a–c, 12c,d (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 re-
fluxed for 3 h. After cooling to rt, water (10 mL) was added and
the mixture was extracted with ethyl ether (3 ꢂ 25 mL). The com-
bined organic layers were washed with water (2 ꢂ 5 mL), brine
(5 mL), and then dried (MgSO4). Concentration under vacuum
afforded a pale yellow oil which was purified by flash column chro-
matography on silica gel (acetone–MeOH–Et3N, 80:10:10, as elu-
ent) to yield the expected benzazepines 13a–c, 14c,d.
NMR (75 MHz, CDCl3): d 12.2 (CH3), 24.1 (CH2), 36.0 (CH2), 42.8
(ArCH), 47.1 (CH), 49.8 (ArCH2N), 54.2 (CH2N), 61.0 (CH2OH),
100.9 (OCH2O), 108.2 (CH), 108.6 (CH), 135.9 (C), 137.2 (C), 145.8
(C), 146.2 (C) ppm. Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04;
N, 5.32. Found: C, 68.53; H, 7.94; N, 5.21.
4.4.5. 2-[(8S,9S)-8-Pentyl-6,7,8,9-tetrahydro-5H-1,3-dioxa-6-
azacyclohepta[f]inden-9-yl]ethanol 14d
232 mg (76%); ½a 2D5
ꢃ
¼ ꢀ6:9 (c 1.63, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.83 (t, J = 7.0 Hz, 3H, CH3), 0.98–1.49 (m, 6H, 3 ꢂ CH2),
1.51–1.68 (m, 2H, CH2), 1.69–1.83 (m, 1H, CH), 1.86–2.12 (m,
4H:2H, CH2 + 1H, OH + 1H, NH), 2.71–2.97 (m, 1H, ArCH), 3.31–
3.67 (m, 4H:2H, CH2N + 2H, CH2O), 3.69–3.86 (m, 1H, ArCH2N),

200
D. Dumoulin et al. / Tetrahedron: Asymmetry 21 (2010) 195–201
4.02–4.21 (m, 1H, ArCH2N), 5.93 (s, 2H, OCH2O), 6.64 (s, 1H, Harom),
6.67 (s, 1H, Harom) ppm; 13C NMR (75 MHz, CDCl3): d 14.1 (CH3),
22.6 (CH2), 26.7 (CH2), 27.2 (CH2), 31.7 (CH2), 35.8 (CH2), 38.9
(CH), 42.1 (ArCH), 45.6 (ArCH2N), 51.7 (CH2N), 61.9 (CH2OH),
100.8 (OCH2O), 107.9 (CH), 108.5 (CH), 135.8 (C), 137.1 (C), 145.7
(C), 146.2 (C) ppm. Anal. Calcd for C18H27NO3: C, 70.79; H, 8.91;
N, 4.59. Found: C, 70.86; H, 9.12; N, 4.34.
4.5.4. (1S,11S)-4,5-Methylenedioxy-11-ethyl-9-azatricyclo
[7.2.2.02,7]trideca-2,4,6-triene 2c
72 mg (59%); ½a 2D5
ꢃ
¼ ꢀ1:1 (c 0.83, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.88 (t, J = 7.1 Hz, 3H, CH3), 1.01–1.17 (m, 2H, CH2),
1.83–1.99 (m, 1H, CH), 2.01–2.24 (m, 2H, CH2), 2.49 (dd, J = 8.2,
13.4 Hz, 1H, CH2N), 2.73–2.83 (m, 1H, CH2N), 3.00–3.19 (m,
2H:1H, ArCH + 1H, CH2N), 3.33 (dd, J = 8.6, 13.7 Hz, 1H, CH2N),
4.11 (d, JAB = 17.2 Hz, 1H, ArCH2N), 4.18 (d, JAB = 17.2 Hz, 1H,
ArCH2N), 5.92 (d, J = 6.0 Hz, 2H, OCH2O), 6.52 (s, 1H, Harom), 6.56
(s, 1H, Harom) ppm; 13C NMR (75 MHz, CDCl3): d 10.0 (CH3), 26.8
(CH2), 31.2 (CH2), 39.9 (CH), 40.8 (CH), 46.2 (CH2N), 52.8 (CH2N),
61.9 (ArCH2N), 100.6 (OCH2O), 107.2 (CH), 110.2 (CH), 132.1 (C),
135.2 (C), 145.8 (C), 146.1 (C) ppm. Anal. Calcd for C15H19NO2: C,
73.44; H, 7.81; N, 5.71. Found: C, 73.59; H, 7.69; N, 5.62.
4.5. Synthesis of the bridged tetrahydro-2-benzazepines 1a–c,
2c,d. General procedure
A solution of the appropriate hydroxyethyl-tetrahydro-2-ben-
zazepine 13a–c, 14c,d (0.5 mmol) in dry THF (5 mL) was slowly
added to a stirred solution of triphenylphosphine (PPh3, 184 mg,
0.7 mmol) and DEAD (0.27 mL, 40% in toluene, 0.6 mmol) in dry
THF (5 mL) at rt under Ar. The solution was stirred overnight at
rt, water (2 mL) was then added and the resulting mixture was
concentrated under reduced pressure. The oily residue was puri-
fied by flash column chromatography on silica gel (acetone–
MeOH–Et3N, 85:5:10, as eluent) to yield the bridged tetra-
hydrobenzazepine 1a–c, 2c,d as foam.
4.5.5. (1S,11S)-4,5-Methylenedioxy-11-pentyl-9-azatricyclo
[7.2.2.02,7]trideca-2,4,6-triene 2d
80 mg (56%); ½a 2D5
ꢃ
¼ þ2:2 (c 0.63, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.87 (t, J = 7.0 Hz, 3H, CH3), 0.97–1.41 (m, 8H, 4 ꢂ CH2),
1.87–2.15 (m, 3H:1H, CH + 2H, CH2), 2.44 (dd, J = 8.5, 13.6 Hz, 1H,
CH2N), 2.63–2.77 (m, 1H, CH2N), 2.91–3.14 (m, 2H:1H, ArCH + 1H,
CH2N), 3.27 (dd, J = 8.8, 13.6 Hz, 1H, CH2N), 4.15 (d, JAB = 17.4 Hz,
1H, ArCH2N), 4.23 (d, JAB = 17.4 Hz, 1H, ArCH2N), 5.92 (d,
4.5.1. 4,5-Dimethoxy-9-aza-tricyclo[7.2.2.02,7]trideca-2,4,6-
triene 1a
J = 6.0 Hz, 2H, OCH2O), 6.51 (s, 1H, Harom), 6.54 (s, 1H, Harom
)
ppm; 13C NMR (75 MHz, CDCl3): d 14.1 (CH3), 22.6 (CH2), 26.8
(CH2), 31.4 (CH2), 32.0 (CH2), 33.9 (CH2), 39.0 (CH), 40.6 (CH),
46.9 (CH2N), 53.0 (CH2N), 62.1 (ArCH2N), 100.8 (OCH2O), 107.1
(CH), 110.0 (CH), 131.9 (C), 135.3 (C), 145.6 (C), 146.0 (C) ppm.
Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C,
75.07; H, 8.56; N, 5.02.
74 mg (64%); 1H NMR (300 MHz, CDCl3): d 1.97–2.14 (m, 4H,
2 ꢂ CH2), 2.83–2.92 (m, 1H, CH), 3.00–3.17 (m, 2H, CH2N), 3.18–
3.32 (m, 2H, CH2N), 3.85 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.33
(s, 2H, ArCH2N), 6.59 (s, 1H, Harom), 6.60 (s, 1H, Harom) ppm; 13C
NMR (75 MHz, CDCl3): d 29.0 (2 ꢂ CH2), 35.4 (CH), 46.0 (CH2N),
46.3 (CH2N), 55.9 (2 ꢂ OCH3), 61.2 (ArCH2N), 110.4 (CH), 111.7
(CH), 128.9 (C), 136.9 (C), 147.3 (C), 147.4 (C) ppm. Anal. Calcd
for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 71.89; H,
8.12; N, 5.88.
Acknowledgments
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).
4.5.2. (1S,11S)-4,5-Dimethoxy-11-methyl-9-azatricyclo[7.2.2.02,7
]
trideca-2,4,6-triene 1b
97 mg (79%); ½a 2D5
ꢃ
¼ ꢀ2:3 (c 0.92, CHCl3); 1H NMR (300 MHz,
References
CDCl3): d 0.75 (d, J = 6.7 Hz, 3H, CH3), 2.03–2.22 (m, 3H:2H,
CH2 + 1H, CH), 2.41 (dd, J = 8.8, 13.4 Hz, 1H, CH2N), 2.53–2.69 (m,
1H, CH2N), 2.98–3.14 (m, 2H:1H, ArCH + 1H, CH2N), 3.32 (dd,
J = 8.5, 13.6 Hz, 1H, CH2N), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3),
4.21 (d, JAB = 17.1 Hz, 1H, ArCH2N), 4.31 (d, JAB = 17.1 Hz, 1H,
ArCH2N), 6.50 (s, 1H, Harom), 6.55 (s, 1H, Harom) ppm; 13C NMR
(75 MHz, CDCl3): d 18.5 (CH3), 30.8 (CH2), 33.2 (CH), 42.1 (ArCH),
46.6 (CH2N), 53.6 (CH2N), 55.8 (OCH3), 56.0 (OCH3), 61.6 (ArCH2N),
110.2 (CH), 113.4 (CH), 129.0 (C), 133.7 (C), 146.9 (C), 147.3 (C)
ppm. Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found:
C, 72.69; H, 8.42; N, 5.83.
1. (a) Smalley, R. K. Methods Org. Chem. (Houben-Weyl) 1997, E9d, 207–298; (b)
O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637–651.
2. (a) Toda, N.; Tago, K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.; Koyama,
K.; Naruto, S.; Abe, K.; Yamazaki, R.; Hara, T.; Aoyagi, A.; Abe, Y.; Kaneko, T.;
Kogen, H. Bioorg. Med. Chem. 2003, 11, 4389–4415; (b) Kogen, H.; Toda, N.;
Tago, K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.; Koyama, K.; Naruto, S.;
Abe, K.; Yamazaki, R.; Hara, T.; Aoyagi, A.; Abe, Y.; Kaneko, T. Org. Lett. 2002, 4,
3359–3362.
3. (a) Dalence-Guzmán, M. F.; Berglund, M.; Skogvall, S.; Sterner, O. Bioorg. Med.
Chem. 2008, 16, 2499–2512; (b) Berglund, M.; Dalence-Guzmán, M. F.; Skogvall,
S.; Sterner, O. Bioorg. Med. Chem. 2008, 16, 2513–2528.
4. (a) Matsuura, K.; Kuratani, T.; Gondo, T.; Kamimura, A.; Inui, M. Eur. J.
Pharmacol. 2007, 563, 83–87; Ishibashi, H.; Kobayashi, T.; Nakashima, S.;
Tamura, O. J. Org. Chem. 2000, 65, 9022–9027.
5. Iorio, L. C.; Barnett, A.; Leitz, F. H.; Houser, V. P.; Korduba, C. A. J. Pharmacol. Exp.
Ther. 1983, 226, 462–468.
4.5.3. (1S,11S)-4,5-Dimethoxy-11-ethyl-9-azatricyclo[7.2.2.02,7
]
trideca-2,4,6-triene 1c
6. Xia, W.; Spector, S.; Hardy, L.; Zhao, S.; Saluk, A.; Alemane, L.; Spector, N. L. Proc.
Natl. Acad. Sci. U.S.A. 2000, 97, 7494–7499.
81 mg (62%); ½a 2D5
ꢃ
¼ ꢀ1:6 (c 1.36, CHCl3); 1H NMR (300 MHz,
7. (a) Schafer, S.; Steioff, K.; Linz, W.; Bleich, M.; Busch, A. E.; Lohn, M. Eur. J.
Pharmacol. 2004, 484, 361–362; (b) Busacca, C. A.; Johnson, R. E. Tetrahedron
Lett. 1992, 33, 165–168; (c) Gentles, R. G.; Middlemiss, D.; Proctor, G. R.;
Sneddon, A. H. J. Chem. Soc., Perkin Trans. 1 1991, 1423–1431; (d) Fujizawa,
Pharmaceutical Co. Ltd, JP 03,095,160, 1991; Chem. Abstr., 1991, 115, 158987.;
(e) Flynn, G. A.; Beight, D. W.; Huber, E. W.; Bey, P. Tetrahedron Lett. 1990, 31,
815–818; Clark, M. T.; Chang, J.; Navran, S. S.; Akbar, H.; Mukhopadhyay, A.;
Amin, H.; Feller, D. R.; Miller, D. D. J. Med. Chem. 1986, 29, 181–185.
8. (a) Banwell, M. G.; Kokas, O. J.; Willis, A. C. Org. Lett. 2007, 9, 3503–3506; (b)
Mach, U. R.; Hackling, A. E.; Perachon, S.; Ferry, S.; Wermuth, C. G.; Schwartz, J.-
C.; Sokoloff, P.; Stark, H. ChemBioChem 2004, 5, 508–518; (c) Sha, C.-K.; Hong,
A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177–2179; (d) Guillou, C.; Beunard, J.-L.;
Gras, E.; Thal, C. Angew. Chem., Int. Ed. 2001, 40, 4745–4746; Jin, J.; Weinreb, S.
M. J. Am. Chem. Soc. 1997, 119, 2050–2051; (f) Johnson, R. E.; Busacca, C. A.
Sterling drug Inc., U.S. Patent 5098,901, 1992; Chem. Abstr. 1992, 117, 7949.; (g)
Boente, J. M.; Castedo, L.; Cuadros, R.; Saá, J. M.; Suau, R.; Perales, A.; Martínez-
CDCl3): d 0.87 (t, J = 7.3 Hz, 3H, CH3), 1.02–1.19 (m, 2H, CH2),
1.81–1.99 (m, 1H, CH), 2.00–2.23 (m, 2H, CH2), 2.48 (dd, J = 8.3,
13.6 Hz, 1H, CH2N), 2.71–2.81 (m, 1H, CH2N), 3.01–3.16 (m,
2H:1H, ArCH + 1H, CH2N), 3.34 (dd, J = 8.6, 13.7 Hz, 1H, CH2N),
3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.22 (d, JAB = 17.1 Hz, 1H,
ArCH2N), 4.31 (d, JAB = 17.1 Hz, 1H, ArCH2N), 6.52 (s, 1H, Harom),
6.56 (s, 1H, Harom) ppm; 13C NMR (75 MHz, CDCl3): d 9.8 (CH3),
26.6 (CH2), 30.9 (CH2), 39.7 (CH), 40.6 (CH), 46.0 (CH2N), 52.7
(CH2N), 55.8 (OCH3), 56.0 (OCH3), 61.6 (ArCH2N), 110.2 (CH),
113.1 (CH), 129.1 (C), 133.9 (C), 146.9 (C), 147.2 (C) ppm. Anal.
Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C, 73.58;
H, 8.85; N, 5.12.

D. Dumoulin et al. / Tetrahedron: Asymmetry 21 (2010) 195–201
201
Ripoll, M.; Fayos, J. Tetrahedron Lett. 1983, 24, 2029–2030; Trybulski, E. J.; Fryer,
R. I.; Reeder, E.; Walser, A.; Blount, J. J. Med. Chem. 1983, 26, 1596–1601; (i)
Croisier, P.; Rodriguez, L. UCB S. A., Ger. Offen. 2733,868, 1978; Chem. Abstr.
1978, 88, 152455.; (j) Meschino, J. A., McNeil Laboratories Inc., U.S. Patent
3483,186, 1969; Chem. Abstr. 1970, 72, 121383.; (k) Fujimura, H.; Hori, M.,
Takeda Chemical Industries, Ltd, U.S. Patent 3409,607, 1969; Chem. Abstr. 1969,
70, 77827.
Hemscheidt, T. K. J. Org. Chem. 2003, 68, 1640; Jadulco, R.; Edrada, R. A.; Ebel,
R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004,
67, 78–81; (d) Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci., Biotechnol.,
Biochem. 2004, 68, 753–756.
15. Miller, W. H.; Alberts, D. P.; Bhatnagar, P. K.; Bondinell, W. E.; Callahan, J. F.;
Calvo, R. R.; Cousins, R. D.; Erhard, K. F.; Heerding, D. A.; Keenan, R. M.; Kwon,
C.; Manley, P. J.; Newlander, K. A.; Ross, S. T.; Samanen, J. M.; Uzinskas, I. N.;
Venslavsky, J. W.; Yuan, C. C.-K.; Haltiwanger, R. C.; Gowen, M.; Hwang, S.-M.;
James, I. E.; Lark, M. W.; Rieman, D. J.; Stroup, G. B.; Azzarano, L. M.; Salyers, K.
L.; Smith, B. R.; Ward, K. W.; Johanson, K. O.; Huffman, W. F. J. Med. Chem. 2000,
43, 22–26; (b) Callahan, J. F.; Cousins, R. D.; Keenan, R. M.; Kwon, C.; Miller, W.
H.; Uzinkas, I. N. U.S. Patent, WO 14,192, 1998; Chem. Abstr. 1998, 128, 282853.
16. Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253–2329.
17. Enders, D.; Teschner, P.; Gröbner, R.; Raabe, G. Synthesis 1999, 237–242.
18. (a) Enders, D.; Kownatka, D.; Hundertmark, T.; Propopenko, O. F.; Runsink, J.
Synthesis 1997, 649–652; (b) Enders, D.; Papadopoulos, K.; Rendenbach, B. E.
M.; Appel, R.; Knoch, F. Tetrahedron Lett. 1986, 27, 3491–3494; (c) Enders, D.;
Papadopoulos, K. Tetrahedron Lett. 1983, 24, 4967–4970.
9. Feuston, B. P.; Culberson, J. C.; Duggan, M. E.; Hartman, G. D.; Leu, C.-T.; Rodan,
S. B. J. Med. Chem. 2002, 45, 5640–5648.
10. Maelicke, A.; Albuquerque, E. X. Drug Discovery Today 1996, 1, 53–59.
11. (a) Vieira, T. O.; Alper, H. Org. Lett. 2008, 10, 485–487; (b) Ferraccioli, R.;
Carenzi, D.; Catellani, M. Tetrahedron Lett. 2004, 45, 6903–6907; (c) Basavaiah,
D.; Satyanarayana, T. Chem. Commun. 2004, 32–33; (d) Nyerges, M.; Virányi, A.;
Pintér, A.; Töke, L. Tetrahedron Lett. 2003, 44, 793–794; (e) Kamimura, A.;
Taguchi, Y.; Omata, Y.; Hagihara, M. J. Org. Chem. 2003, 68, 4996–4998; (f)
Katritzky, A. R.; Maimait, R.; Xu, Y.-J.; Akhmedova, R. G. Synthesis 2002, 601–
604; (g) Martins, J. C.; Rompaey, K. V.; Wittman, G.; Tömböly, C.; Tóth, G.; De
Kimpe, N.; Tourwe´, D. J. Org. Chem. 2001, 66, 2884–2886; (h) Gámez-Montaão,
R.; Chávez, M. I.; Roussi, G.; Cruz-Almanza, R. Tetrahedron Lett. 2001, 42, 9–12;
(i) Kouznetsov, V.; Palma, A.; Ewert, C. Curr. Org. Chem. 2001, 5, 519–551; (j)
Griesbeck, A. G.; Mauder, H. Angew. Chem., Int. Ed. Engl. 1992, 31, 73–75.
12. (a) Mendoza, J. S.; Jagdmann, G. E., Jr.; Gosnell, P. A. Bioorg. Med. Chem. Lett.
1995, 5, 2211–2216; (b) Lai, Y.-S.; Mendoza, J. S.; Jagdmann, G. E., Jr.;
Menaldino, D. S.; Biggers, K. C.; Heerding, J. M.; Wilson, J. W.; Hall, S. E.; Jiang, J.
B.; Janzen, W. P.; Ballas, L. M. J. Med. Chem. 1997, 40, 226–235.
19. (a) Andersen, M. W.; Hildebrandt, B.; Hoffmann, R. W. Angew. Chem. 1991, 103,
90–92; (b) Andersen, M. W.; Hildebrandt, B.; Dahmann, G.; Hoffmann, R. W.
Chem. Ber. 1991, 124, 2127–2139; (c) Fischer, J.; Kilpert, C.; Klein, U.; Steglich,
W. Tetrahedron 1986, 42, 2063–2074.
20. Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett. 2007, 9, 2473–
2476.
13. Clark, T. J. PCT Int. Appl. WO 009599, 2004; Chem. Abstr. 2004, 140, 80696.
14. Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem.
2001, 66, 8717–8721; (b) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.;
21. Klemm, L. H.; Olson, D. R. J. Org. Chem. 1973, 38, 3390–3394.
22. Pearl, I. A.; Beyer, D. L. J. Org. Chem. 1951, 16, 216–220.