Asymmetric synthesis of 1-aryl 2,3,4,5-tetrahydro-2-benz[c]azepines

Article abstract of DOI:10.1016/S0040-4039(00)01881-5

The first stereoselective synthesis of 1-aryl-2-benz[c]azepines is described using oxazolidines as chiral inducers.

Full text of DOI:10.1016/S0040-4039(00)01881-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9–12
Asymmetric synthesis of 1-aryl
2,3,4,5-tetrahydro-2-benz[c]azepines
Roc´ıo Ga´mez-Montan˜o, Mar´ıa Isabel Cha´vez, Georges Roussi and Raymundo Cruz-Almanza*
Instituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Circuito Exterior, Ciudad Universitaria Coyoacan,
Me´xico D.F. 04510, Mexico
Received 20 September 2000; revised 19 October 2000; accepted 23 October 2000
Abstract—The first stereoselective synthesis of 1-aryl-2-benz[c]azepines is described using oxazolidines as chiral inducers. © 2000
Elsevier Science Ltd. All rights reserved.
addition, oxazolidines can be easily prepared from
The synthesis of 1-phenyl tetrahydrobenzazepines is a
aminoalcohols.12
topic of continuing interest since these types of com-
pounds have been found to exhibit antihypertensive1 1,
The most practical route to the synthesis of aminoalco-
hols is the opening of epoxide rings with amines.
anticonvulsant2 2 and antiarrhythmic3 3 activities. Fur-
thermore, these compounds are useful for treatment of
mental disorders and hypoxia4 4 (Fig. 1). Several syn-
Usually, unsymmetrical epoxides undergo regioselective
thetic strategies have been employed for the construction
addition of the nucleophile to the less substituted carbon
of racemic 1-aryl-2-benzazepine system based mainly on
atom. In the case of styrene oxide, however, it is possible
classical processes such as the Bischler Napieralski5 and
to obtain a reversal of the regiochemistry of the opening
Pictet–Spengler6 reactions or miscellaneous methods
process.13
such as the intramolecular phenolic cyclization,7 Meisen-
heimer rearrangement8 and palladium catalyzed aryla-
On the basis of the above information, we envisaged the
tion.9 The asymmetric synthesis of this system remains
preparation of two different chiral oxazolidines 10 and
unexplored, however.
11 (Scheme 1) from the two aminoalcohols 6 and 7. We
carried out the reaction of benzazepine 5 with (R)-(+)-
In the present work we describe the asymmetric synthesis
of 1-aryl-2-benzazepines using an oxazolidine moiety as
a chiral inducer. Oxazolidines have been widely exploited
as chiral auxiliaries directed to the formation of a new
stereogenic center.10 Indeed, the particular addition of
organometallic reagents to chiral oxazolidines has en-
joyed widespread success in asymmetric synthesis.11 In
styrene oxide under different conditions to afford iso-
meric mixtures of aminoalcohols 6 and 7. The use of 1
equiv. of NaH in dry THF gave the aminoalcohol 6 as
the major product (9:1) in 83% yield. Otherwise using 1
equiv. of LiClO4 gave reversal ratio; in this case aminoal-
cohol 7 was the major product (9:1) in 81% yield. These
compounds were separated by fractional crystallization.
Figure 1.
Keywords: chirals 1-arylbenzazepines; 1,3-oxazolidines; aminoalcohols.
* Corresponding author. Tel.: 5256224428; fax: 52 56 16 22 17; e-mail: raymundo@servidor.unam.mx
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01881-5

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R. Ga´mez-Montan˜o et al. / Tetrahedron Letters 42 (2001) 9–12
Scheme 1. Reagents and conditions: (a) NaH, THF, 80°C; (b) H2O2 30%, MeOH, 10°C; (c) BuLi, THF, −78°C; (d) RMgBr,
THF, −78°C; (e) MeI, CH3CN. 60°C, t-BuOK/t-BuOH, 80°C; (f) CH3CN, LiClO4, 30°C; (g) H2O2 30%, MeOH, rt; (h) H2 Pd/C.
Compound 6 and 7 were transformed into the corre-
sponding N-oxides 8 and 9 by treatment with hydrogen
peroxide (5 equiv.) in 90% yield. These compounds
were air and light sensitive and were used for the next
reaction without further purification.14
diastereoisomers 12a/12b, 13a/13b and 13c/13d in a 8:2,
9:1 and 9:1 ratio in 58, 65 and 60% yield, respectively.
The diastereomeric ratios of 12a/12b, 13a/13b and 13c/
13d were determined from the mixture by analyzing
1
relevant signals in the H NMR spectra.
N-Oxides 8 and 9 were treated with BuLi to afford
pairs of the diastereomeric oxazolidines 10a/10b (8:2)
and 11a/11b (95:05) in 51 and 58% yield, respectively.15
The diastereomeric ratio and the absolute configuration
of the major products 10a and 11a were determined by
1H NMR and NOESY experimental analyses.16 The
b-orientation of H-11b for compound 10a was ascer-
tained by the observed dipolar interactions between this
hydrogen with H-7b (l 2.93), H-5b (l 2.70) and H-3b
(l 2.67) (Fig. 2). The observed cross-peaks between
H-3a (l 3.63), H-2a (l 5.30) and H-5a (l 3.41) con-
firmed the assigned configuration at C-11b and estab-
lished the extended conformation of the seven-mem-
bered ring. Furthermore, the configuration for 10a was
confirmed by X-ray analysis (Fig. 2). A similar analysis
by NMR was made for compound 11a.
NOESY experiments performed on 12a indicated that
the stereochemistry at C-1 remained unchanged due to
the interactions between H-1 (l 5.02), with H-9 (l
6.96), and with the pro-S hydrogen at C-1%. The minor
compound 12b possesses the phenyl group attached at
C-1 with a b-orientation, since H-9 is shielded (l 6.81)
in comparison with the major stereoisomer 12a, where
H-9 resonates at l 6.96 and therefore the phenyl group
is a-oriented (Fig. 3). A NOESY correlation between
H-1a and H-2% for 12b confirmed the stereochemical
assignments. Similar analyses by NMR were performed
for compounds 13.
The diastereoselectivity of this reaction can be rational-
ized by assuming that the Grignard reagent approaches
the oxygen atom of the 1,3-oxazolidine ring to give a
favorable intermediate immonium salt and nucleophilic
attack occurs from the same face, in agreement with
previous observations.17
The diastereoselective addition of Grignard reagents to
chiral oxazolidines 10a and 11a gave the mixture of
Figure 2.

R. Ga´mez-Montan˜o et al. / Tetrahedron Letters 42 (2001) 9–12
11
Figure 3.
A mixture of 12a/12b (8:2) was converted into the
N-methylammonium salt by treatment with methyl io-
dide in acetonitrile and reacted in situ with t-BuOK in
t-BuOH to afford 14a (8:2 ee) in 50% yield. Compounds
13a/13b and 13c/13d were treated under catalytic hydro-
genation with Pd/C to afford the desired arylben-
zazepine 14b (9:1 ee) in 55% yield and 14c (9:1ee) in 60%
yield.18
11. Poerwono, H.; Higashiyama, K.; Takahashi, H. J. Org.
Chem. 1998, 63, 2711.
12. Yamauchi, T.; Takahashi, H.; Higashiyama, K. Chem.
Pharm. Bull. 1998, 46, 384.
13. Chini, M.; Crotti, P.; Macchia, F. J. Org. Chem. 1991, 56,
5939.
14. An analytical sample was obtained in order to get their
spectroscopic data.
15. Carbonnelle, A. C.; Gott, V.; Rousi, G. Heterocycles 1993,
36, 1763.
In summary, 1,3-oxazolidines 10a and 11a are useful
chiral inducers in the stereoselective synthesis to 1-aryl-
2-benz[c]azepines. To the best of our knowledge, this
procedure represents the first asymmetric synthesis for
these kind of compounds.
16. Spectral data of selected products: Compound 10a: 1H
NMR (500 MHz, CDCl3): l 2.67 (td, J=12.0, 12.0, 3.0
Hz, 1H, H-3b), 3.63 (dd, J=10.0, 5.0 Hz, 1H, H-3a), 5.30
(dd, J=10.0, 5.0 Hz, 1H, H-2a), 5.4 (s, 1H, H-11b); 13C
NMR (125 MHz, CDCl3): l 28.10 (C-6), 34.59 (C-7), 56.40
(C-5), 64.44 (C-3), 78.37 (C-2), 95.31 (C-12), 123.77 (C-11),
126.13 (C-2%, C-6%), 126.44 (C-10), 127.69 (C-9), 127.89
(C-4%), 128.49 (C-3%, C-5%), 129.0 (C-8), 139.42 (C-7a),
140.39 (C-1%), 140.42 (C-11a); IR (CHCl3): 1149.5, 1105.2,
1060.8 cm−1; MS: E.I m/z (%) M+ 265 (8.6), 264 (M−1),
(50.3) 159 (100). Compound 11a: 1H NMR (500 MHz,
CDCl3): l 3.83 (dd, J=3.0, 3.5 Hz, 2H, H-2b, H-3a), 4.31
(dd, J=3.0, 3.5 Hz, 2a), 5.34 (s, 1H, H-11b); 13C NMR
(75 MHz, CDCl3): l 28.22 (C-6), 34.85 (C-7), 54.37 (C-5),
70.24 (C-3), 73.30 (C-2), 95.45 (C-11b), 123.66 (C-11),
127.45 (C-10), 127.88 (C-4%), 127.96 (C-2%, C-6%), 128.49
(C-3%, C-5%), 129.02 (C-8), 129.23 (C-9), 138.15 (C-1%),
139.78 (C-8a), 140.99 (C-11a); IR (CHCl3): 1199.7, 1175.0,
1122.5 cm−1; MS: Fab m/z (%) M+ 265 (34), 264 M−1
(100), 154 (65), 136 (42).
Acknowledgements
Financial support from CONACYT is gratefully ac-
knowledged. We also want to thank to A. Toscano, A.
Pen˜a, L. Velasco, R. Patin˜o, W. Matus, C. Ma´rquez and
J. Pe´rez for technical support.
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18. Selected spectral data of final products: Compound 14a:
1H NMR (200 MHz, CDCl3): l 1.70 (m, 2H, H-4), 2.41
(s, 3H, Me), 2.76 (ddd, J=14.0, 9.5, 3.5 Hz, 2H, H-5a,
H-5-b), 2.91 (ddd, J=8.4, 4.5, 3.4 Hz, 1H, H-3b), 3.17
(ddd, J=10.7, 7.4, 3.0 Hz, H-3a), 5.03 (s, 1H, H-1b), 7.0
(d, J=6.5 Hz, 1H, H-9), 7.1–7.6 (m, 8H); IR: (CHCl3)
2928.3, 2854.4, 1600.2 cm−1; MS: E.I m/z (%) 237 M+
(28.9), 160 (100). Compound 14b: 1H NMR (500 MHz,
CDCl3): l 1.77 (m, 2H, H-4), 2.92 (ddd, 1H, H-5b), 3.12
(ddd, 1H, H-5a), 3.18 (ddd, 1H, H-3b), 3.37 (ddd, 1H,
H-3a), 5.19 (s, 1H, H-1b), 6.61 (d, 1H, H-9), 7.0 (ddd, 1H,
H-7), 7.18 (d, 1H, H-4%), 7.31 (d, J=7.0, 2H, H-2%, H-6%),
7.36 (dd, J=7.0, 7.0, 2H, H-3%, H-5%); 13C NMR (125
MHz, CDCl3): l 29.85 (C-4), 35.69 (C-5), 50.71 (C-3),
65.70 (C-1), 125.97 (C-8), 126.93 (C-7), 126.97 (C-4%),
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R. Ga´mez-Montan˜o et al. / Tetrahedron Letters 42 (2001) 9–12
127.87 (C-2%, C-6%), 127.97 (C-9), 128.44 (C-3%, C-5%),
J=7.5, 1.0, 1H, H-3%), 7.08–7.21 (m, 4H); 13C NMR (75
MHz, CDCl3): l 29.62 (C-4), 30.39 (C-5), 39.34 (C-1),
40.51 (C-3), 102.14(C-4%), 109.10 (C-3%), 109.96 (C-5%),
122.5 (C-2%), 127.61 (C-8), 127.86 (C-7), 130.31 (C-6),
131.70 (C-9), 136.07 (C-9a), 139.97 (C-6a), 139.97 (C-1%),
147.29 (C-2a%), 149.23 (C-3a%); IR (CHCl3): 2929.0, 2854.5
cm−1; MS: C.I. m/z (%) 268 M+1 (100), 252 (72), 146
(21).
129.72 (C-6), 132.56 (C-6a), 142.42 (C-9a), 142.42 (C-1%);
IR (CHCl3): 3445.8, 2933.6 cm−1; MS: E.I m/z (%) 223 M+
(30), 160 (100). Compound 14c: 1H NMR (500 MHz,
CD3OD): l 1.84 (m, 2H, H-4), 2.67 (ddd, J=15.6, 7.8, 7.8
Hz, 2H, H-5a, H-5b), 2.88 (ddd, J=15.6, 7.8, 7.8 Hz, 2H,
H-3a, H-3b), 3.94 (s, 1H, H-1), 5.86 (s, 2H, OCH2O), 6.56
(s, 1H, H-5%), 6.57 (d, J=7.8 Hz, 1H, H-2%), 6.70 (dd,
.