Sequential aza-Claisen rearrangement and ring-closing metathesis as a route to 1-benzazepine derivatives

Article abstract of DOI:10.1055/s-0028-1087298

A synthetic strategy based on sequential application of aza-Claisen rearrangement and ring-closing metathesis reaction as key steps has been developed for the synthesis of various 1-benzazepine derivatives of pharmaceutical relevance. Georg Thieme Verlag

Full text of DOI:10.1055/s-0028-1087298

LETTER
3011
Sequential Aza-Claisen Rearrangement and Ring-Closing Metathesis as a
Route to 1-Benzazepine Derivatives
S
ynthesis of 1-Ben
e
zazepine
D
b
e
rivatives alina Ghosh, Latibuddin Thander, Sanjay K. Ghosh, Shital K. Chattopadhyay*
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Fax +91(33)25828282; E-mail: skchatto@yahoo.com
Received 23 June 2008
OH
N
Abstract: A synthetic strategy based on sequential application of
aza-Claisen rearrangement and ring-closing metathesis reaction as
key steps has been developed for the synthesis of various 1-benza-
zepine derivatives of pharmaceutical relevance.
N
N
Cl
Key words: aza-Claisen rearrangement, benzazepine, ring-closing
metathesis
O
O
NH
NH
O
Recent studies have revealed that N-substituted 1-benza-
zepines can act as powerful vasopressin V2 receptor an-
tagonists, and therefore have the potential for use in the
treatment of heart diseases.1 Some of the most promising
derivatives of this class are OPC-312602 (1, Figure 1) and
tolvaptan3 (2), currently undergoing clinical trials. In ad-
dition, several other 1-benzazepine derivatives display
promising biological activities towards a number of im-
portant targets such as enzymes (e.g., compound 3), ion
channels and other G-protein-coupled receptors (e.g.,
compound 4).4 Consequently, several synthetic strategies
for 1-benzazepines have been developed.5 1-Benzazepine
derivatives are most commonly accessed through
Beckmann6 or Schmidt7 ring expansion of derivatives of
1-tetralone or intramolecular Claisen-type condensation.8
Some recent methods involve metal-catalyzed oxidative
cyclization of amino alcohols,9 intramolecular Heck-type
arylation,10 metal-catalyzed intramolecular amination,11
and ring-closing metathesis12,13 of appropriate dienes.
However, a simple and general entry to this pharmaceuti-
cally important scaffold is desirable. We have recently
reported14 the synthesis of various benz- and heteroannu-
lated oxepin and oxocin derivatives involving tandem ap-
plication of Claisen rearrangement and ring-closing
diene/enyne metathesis as key steps. Herein, we report a
synthetic strategy to N-substituted 1-benzazepine deriva-
tives using similar application.
O
1
2
HN
N
H2NOC
OH
N
N
O
N
Ph
NH
4
O
Ph
3
Figure 1 Pharmaceutically important 1-benzazepine derivatives
ence of an additional N-alkyl group in the N-allylaniline
moiety greatly enhances the rate of an aromatic aza-Clais-
en rearrangement.17 This led us to consider selective
monorearrangement of a N,N-diallylaniline derivative as a
possible mean for the direct preparation of a C,N-diallyl
aniline derivative to be used as a diene precursor of a
RCM reaction for the ultimate preparation of the corre-
sponding 1-benzazepine derivative.
Accordingly, we first prepared N,N-diallylaniline 6a
(Scheme 1) by straightforward allylation of aniline with
allyl bromide for studying its selective monorearrange-
ment. After considerable experimentation, it was found
that the desired monorearrangement of 6a proceeds best in
refluxing chlorobenzene in the presence of BF3·OEt2 (1.5
equiv) within a reasonably short period of time (5–6 h) to
provide N,2-diallylaniline (7a, 64%) as the only product,
no double rearrangement being observed. Attempted opti-
mization of the reaction using other high-boiling solvents
or by changing the nature/amount of the Lewis acid or
prolonging the reaction time, either singly or in combina-
tion, had deleterious effects on the outcome of the reaction
since varied amount (up to ca. 40%) of 2,6-diallylaniline
formed along with some unidentified products at the
expense of the desired monorearrangement product 7a.
Similarly, the rearrangement of each of the diallylanilines
The thermal rearrangement of N-allylanilines require
drastic conditions compared to corresponding aryl allyl
ethers.15 However, such rearrangements usually proceed
with significant rate enhancement under protic or Lewis
acid catalysis.16 It has further been observed that the pres-
SYNLETT 2008, No. 19, pp 3011–3015
x
x
.x
x
.2
0
0
8
Advanced online publication: 23.10.2008
DOI: 10.1055/s-0028-1087298; Art ID: D22608ST
© Georg Thieme Verlag Stuttgart · New York

3012
D. Ghosh et al.
LETTER
Ts
N
Ts
N
NH2
i
N
ii
NH
i
ii
10a–d
R1
R1
R1
R1
R1
O
7a–e
5a–e
6a–e
11a R1 = H
12a R1 = H, 62%
11b R1 = Me
11c R1 = OMe
11d R1 = Cl
12b R1 = Me, 64%
12c R1 = OMe, 72%
12d R1 = Cl, 59%
R2
N
R2
N
iii
iv
Scheme 2 Reagents and conditions: (i) H2, Pd/C (10%), EtOAc, r.t.,
R1
6 h, quant.; (ii) PCC, Celite, benzene, reflux, 24 h, 59–72%.
R1
10a–h
8a–h
responding ketone derivative 12a in moderate yield. Sim-
ilarly, the keto derivatives 12b–d were prepared
(Scheme 2).19
R1, R2
Compound (yield, %)
R1 = H, R2 = Ts
R1 = Me, R2 = Ts
5a, 6a (66), 7a (64), 8a (87), 10a (91)
5b, 6b (71), 7b (69), 8b (85), 10b (83)
5c, 6c (79), 7c (66), 8c (83), 10c (88)
5d, 6d (70), 7d (62), 8d (81), 10d (81)
8e (73), 10e (87)
While several 1-benzazepine derivatives have been pre-
pared and evaluated, little is known about heteroannulated
azepine derivatives. Various common ring-sized azacycle-
annulated coumarin,20 2-quinolone21 and carbazole22 de-
rivatives display interesting biological properties. We
thus considered extending the present study to 6-amino-
coumarin, 6-amino-1-methyl-2-quinolone, and 3-amino-
carbazole with a view to prepare corresponding azepine-
annulated constructs. Thus, N,N-diallyl-6-aminocoumarin
(13, Table 1) was prepared by allylation of 6-aminocou-
marin. Pleasingly, compound 13 underwent smooth
monorearrangement under the developed conditions to
provide the corresponding rearrangement product 14 as
the only regioisomer in good yield. Similarly, the N,N-di-
allylquinolone derivative 17 and the diallylamino-
carbazole derivative 21 also underwent selective
monorearrangement to the corresponding angularly ally-
lated compounds 18 and 22, respectively, in good yields.
The regioselectivity observed in the rearrangement of
each of the compounds 13, 17, and 21 is in line with our
earlier results on the rearrangement of corresponding allyl
ethers.14a–d The bias for an angular rearrangement against
a linear rearrangement of allyl ethers accommodated in an
appropriate coumarin, quinolone, or carbazole scaffold is
well documented. However, it is interesting to note that
such a bias in aza-Claisen rearrangement in these systems
is also operative. The rearranged products 14, 18, and 22
were then converted to the corresponding N-tosyl deriva-
tives 15, 19, and 23, respectively. Ring-closing metathe-
sis of each of these dienes separately under the developed
conditions then led to the corresponding tetrahy-
droazepine derivatives 16, 20, and 24, respectively, in
very good yields.
R
R
R
1 = OMe, R2 = Ts
1 = Cl, R2 = Ts
1 = Me, R2 = COC6H4
R1 = OMe, R2 = COC6H4 8f (78), 10f (80)
R1 = Cl, R2 = COC6H4
R1 = NO2, R2 = COCF3
8g (81), 10g (88)
5e, 6e (64), 7e (59), 8h (67), 10h (78)
Scheme 1 Reagents and conditions: (i) allyl bromide, Et3N, MeCN,
reflux, 18 h; (ii) BF3·OEt2 (1.5 equiv), PhCl, reflux, 5–6 h; (iii) TsCl,
Et3N, CH2Cl2, r.t., 24 h, or (CF3CO)2O, DMAP, Et3N, CH2Cl2, r.t.,
24 h, or benzoyl chloride, Et3N, CH2Cl2, 12 h; (iv) 9 (5 mol%),
CH2Cl2 (0.01 M), r.t., 2–3 h.
6b–e under the developed conditions led to the corre-
sponding rearranged products 7b–e in acceptable yields.
In each of the rearrangement reactions, minor amount (ca.
10%) of the unreacted starting material was also recov-
ered. The electronic nature of the substituents in the start-
ing anilines 6b–e was found to have little effect on the
outcome of the reaction as would be consistent with the
concerted nature of the reaction.
Having access to the required aniline derivatives 7a–e, we
then focused on their RCM reaction. To this end, the cor-
responding N-tosyl derivatives 8a–d and the N-benzoyl
derivatives 8e–g were prepared under conventional condi-
tions. The nitroaniline derivative 7e, however, did not un-
dergo clean N-tosylation or N-benzoylation under some
of the attempted conditions. Consequently, it was convert-
ed to the corresponding trifluoroacetamide derivative 8h.
Ring-closing metathesis of the diene 8a proved to be ex-
tremely facile with Grubbs first-generation catalyst ben-
zylidene bistricyclohexylphosphinoruthenium(IV) di-
chloride (9) at room temperature, and a high-yield conver-
sion to the azepine derivative 10a was realized. Similarly,
the dienes 8b–h all underwent smooth RCM to provide
the corresponding tetrahydrobenzazepine derivatives
10b–h in very good to excellent yields.
In summary, we have developed a suitable protocol for the
selective monorearrangement of a N,N-diallylaniline de-
rivative for the preparation of a N-tethered diene as pre-
cursor of the corresponding 1-benzazepine derivative
having three points of diversity relevant to drug design.
The methodology is simple, general in nature, and it in-
volves the use of easily available starting materials and re-
agents. The predetermined mode of ring closure and its
tolerance to electron-withdrawing groups may make the
process complementary to those existing in the literature,
We next considered incorporation of functionalities in the
5-position of the prepared benzazepine derivatives as rel-
evant to compounds 1 and 2. Attempted benzylic oxida-
tion of compound 10a under a range of conditions proved
to be unsuccessful. However, the corresponding saturated
derivative 11a underwent oxidation with pyridinium
chlorochromate18 in refluxing benzene leading to the cor-
Synlett 2008, No. 19, 3011–3015 © Thieme Stuttgart · New York

LETTER
Synthesis of 1-Benzazepine Derivatives
3013
Table 1 Formation of Hetero-Annulated Azepine Derivatives
Entry
1
Diallylaniline (yield)a
Rearranged amine (time, yield)b Precursor diene (yield)c
RCM Product (yield)d
H
N
N
N
N
Ts
Ts
O
O
O
O
O
O
13 (78%)
14 (4 h, 72%)
O
O
16 (79%)
15 (77%)
2
N
N
H
N
Ts
N
Ts
N
O
N
O
N
O
Me
N
O
Me
Me
17 (82%)
Me
20 (82%)
18 (2 h, 85%)
19 (69%)
3
N
Ts
N
H
N
N
Ts
N
N
Et
N
N
Et
Et
21 (73%)
Et
24 (82%)
22 (6 h, 61%)
23 (71%)
a Appropriate amine, allyl bromide, Et3N, MeCN, reflux, 18 h.
b BF3·OEt2 (1.5 equiv), ClPh, reflux, 2–6 h.
c TsCl (1.5 equiv), Et3N (2 equiv), CH2Cl2, r.t., 24 h.
d Grubbs catalyst 9 (5 mol%), CH2Cl2 (0.01 M), r.t., 2–3 h.
(5) (a) Proctor, G. R. Azepines, In Heterocyclic Compounds,
Vol. 43; Wiley: New York, 1984, 637. (b) Smalley, R. K.
Azepines, In Comprehensive Heterocyclic Chemistry, Vol.
N7; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984, 491. (c) Yet, L. Chem. Rev. 2000, 100, 2963.
(6) Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.;
Sakane, S.; Hattori, K.; Yamamoto, H. J. Am. Chem. Soc.
1983, 105, 283.
in particular, for the preparation of substituted 1-benza-
zepines, which are otherwise difficult to access. It may
also find application in the synthesis of other medium-
sized azacycle-annulated aromatic compounds of interest.
Work will be continued along these directions.
Acknowledgment
(7) Grunwald, G. L.; Dahanukar, V. H.; Ching, P.; Kriscione,
K. R. J. Med. Chem. 1996, 39, 3539.
Financial assistance from DST, New Delhi (Grant No. SR/S1/OC-
51/2005) is gratefully acknowledged. Two of us (DG and LT) are
thankful to CSIR, New Delhi, for fellowships.
(8) (a) Learmonth, D. A.; Proctor, G. R.; Scopes, D. I. C.
J. Chem. Soc., Perkin Trans. 1 1997, 2569. (b) Ikemoto, T.;
Ito, T.; Nishiguchi, A.; Miura, S.; Tomimatsu, K. Org.
Process Res. Dev. 2005, 9, 168.
References and Notes
(9) Fujita, K.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2002,
4, 2691.
(1) Blakeney, J. S.; Reid, R. C.; Le, G. T.; Fairlie, D. P. Chem.
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Miyamoto, H.; Kan, K.; Kitano, K.; Tanaka, M.; Nagaya, K.;
Nakamura, S.; Mori, T.; Tominaga, M.; Yabuuchi, Y.
J. Med. Chem. 1996, 39, 3547. (b) Mayanoff, B. E. Acc.
Chem. Res. 2006, 39, 831.
(3) (a) Miyazaki, T.; Fujiki, H.; Yamamura, Y.; Nakamura, S.;
Mori, T. Cardiovasc. Drug Rev. 2007, 25, 1. (b) Torisawa,
Y.; Furuta, T.; Nishi, T.; Aki, S.; Minamikawa, J. Bioorg.
Med. Chem. Lett. 2007, 17, 6455. (c) Cordero-Vargas, A.;
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(4) (a) Caggiano, T. J. Drugs Future 2002, 27, 248.
(b) Mayanoff, B. E. Drug Discovery and Development, Vol.
1; Chorghade, M. S., Ed.; Wiley: New Jersey, 2006, 313.
(10) (a) Gibson, S. E.; Middleton, R. J. J. Chem. Soc., Chem.
Commun. 1995, 1743. (b) Cropper, E. L.; White, A. J. P.;
Ford, A.; Hii, K. K. J. Org. Chem. 2006, 71, 1732.
(11) (a) Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider,
R.; Fort, Y. Org. Lett. 2003, 5, 2311. (b) Margolis, B. J.;
Swidorski, J. J.; Rogers, B. N. J. Org. Chem. 2003, 68, 644.
(c) Qadir, M.; Priestley, R. E.; Rising, T. W. D. F.; Gelbrich,
T.; Coles, S. J.; Hursthouse, M. B.; Sheldrake, P. W.;
Whittall, N.; Hii, K. K. Tetrahedron Lett. 2003, 44, 3675.
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72, 5835. (b) Qadir, M.; Cobb, J.; Sheldrake, P. W.;
Whittall, N.; White, A. J. P.; Hii (Mimi), K. K.; Horton,
P. N.; Hursthouse, M. B. J. Org. Chem. 2005, 70, 1545.
(c) Dolman, S. J.; Schrock, R. R.; Hoveyada, A. H. Org. Lett.
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Synlett 2008, No. 19, 3011–3015 © Thieme Stuttgart · New York

3014
D. Ghosh et al.
LETTER
(13) For a recent review on medium-ring heterocycle formation
by RCM, see: Chattopadhyay, S. K.; Karmakar, S.; Biswas,
T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron
2007, 63, 3919.
(14) (a) Chattopadhyay, S. K.; Maity, S.; Panja, S. Tetrahedron
Lett. 2002, 43, 7781. (b) Chattopadhyay, S. K.; Biswas, T.;
Neogi, K. Chem. Lett. 2006, 35, 376. (c) Chattopadhyay,
S. K.; Dey, R.; Biswas, S. Synthesis 2005, 403.
viscous liquid (1.7 g, 85%). IR (CHCl3): 1638, 1598, 1497,
1349, 1219, 1164, 1062 cm–1. 1H NMR (300 MHz, CDCl3):
d = 7.58 (d, 2 H, J = 8.2 Hz), 7.26 (d, 2 H, J = 8.1 Hz), 7.09
(s, 1 H), 6.85 (d, 1 H, J = 7.9 Hz), 6.46 (d, 1 H, J = 8.0 Hz),
5.97–5.84 (m, 1 H), 5.80–5.68 (m, 1 H), 5.14–5.08 (m, 2 H),
5.01–4.93 (m, 2 H), 4.30 (dd, 1 H, J = 14.0, 5.6 Hz), 3.85
(dd, 1 H, J = 14.0, 7.6 Hz), 3.55 (dd, 1 H, J = 15.5, 6.5 Hz),
3.45 (dd, 1 H, J = 15.4, 6.5 Hz), 2.44 (s, 3 H), 2.30 (s, 3 H).
Anal. Calcd for C20H23NO2S: C, 70.35; H, 6.79; N, 4.10.
Found: C, 70.48; H, 6.88; N, 4.29.
7-Methyl-1-tosyl-2,5-dihydro-1H-benzo[b]azepine (10b)
Catalyst 9 (14 mg, 5 mol%) was added to a solution of 8b
(0.11g, 0.32 mmol) in dry, degassed CH2Cl2 (30 mL) under
nitrogen, and the reaction mixture was stirred at r.t. for 2 h.
It was then concentrated under reduced pressure and the
residue was chromatographed over SiO2 using EtOAc–PE
(1:13) as eluent to give the product 10b (83 mg, 83%) as a
colorless solid; mp 114 °C. IR (CHCl3): 1598, 1496, 1343,
1157 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.64 (d, 2 H,
J = 8.2 Hz), 7.24 (d, 2 H, J = 8.5 Hz), 7.16 (d, 1 H, J = 8.0
Hz), 7.00 (d, 1 H, J = 7.9 Hz), 6.87 (s, 1 H), 5.66–5.60 (m,
1 H), 5.45–5.41 (m, 1 H), 4.35 (br s, 2 H), 2.92 (br s, 2 H),
2.42 (s, 3 H), 2.29 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 143.1, 140.8, 138.7, 138.3, 136.0, 129.9, 129.7, 129.4,
128.0, 127.0, 125.8, 125.3, 49.1, 32.2, 21.5, 21.0. Anal.
Calcd for C18H19NO2S: C, 68.98; H, 6.11; N, 4.47. Found: C,
69.13; H, 6.18; N, 4.58. MS (TOFMS ES+): m/z = 336 [M+ +
Na].
(d) Chattopadhyay, S. K.; Roy, S. P.; Ghosh, D.; Biswas, G.
Tetrahedron Lett. 2006, 47, 6895. (e) Chattopadhyay, S. K.;
Biswas, T.; Maity, S. Synlett 2006, 2211.
(15) For some recent reviews on Claisen rearrangement, see:
(a) Nubbemeyer, U. Synthesis 2003, 961. (b) Castro,
A. M. M. Chem. Rev. 2004, 104, 2939.
(16) Nubbemeyer, U. Top. Curr. Chem. 2005, 244, 149.
(17) Krowichi, K.; Paillous, N.; Riviere, M.; Lattes, A.
J. Heterocycl. Chem. 1976, 13, 555.
(18) Rathore, R.; Saxena, N.; Chandrasekaran, S. Synth.
Commun. 1986, 16, 1493.
(19) Representative Procedure for the Sequence of Reactions
in Scheme 1: N,N-Diallyl-4-methylaniline (6b)
Allyl bromide (2.7 mL, 31.4 mmol) was added dropwise to
a solution of 5b (1.7 g, 15.7 mmol) and Et3N (4.4 mL, 31.4
mmol) in dry MeCN (25 mL), and the mixture was heated to
reflux for 18 h. It was then allowed to come to r.t.,
concentrated under reduced pressure, and the residual mass
was extracted with EtOAc (50 mL). The extract was washed
successively with H2O (25 mL), brine (25 mL), and then
dried (Na2SO4). It was filtered, concentrated under reduced
pressure, and the residue was purified by chromatography
over SiO2 using PE as eluent to afford 6b as a pale yellow
viscous liquid (2.09 g, 71%). IR(neat): 1642, 1619, 1521,
1235, 1182 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.01 (d,
2 H, J = 8.2 Hz), 6.62 (d, 2 H, J = 7.8 Hz), 5.89–5.80 (m,
2 H), 5.20–5.12 (m, 4 H), 3.88 (d, 4 H, J = 4.8 Hz), 2.23 (s,
3 H). Anal. Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48.
Found: C, 83.34; H, 9.28; N, 7.39.
Selected Data
Compound 10c: Mp 128 °C. IR (KBr): 1602, 1500, 1341,
1159 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.63 (d, 2 H,
J = 8.2 Hz), 7.24 (d, 2 H, J = 8.1 Hz), 7.19 (d, 1 H, J = 8.8
Hz), 6.71 (dd, 1 H, J = 8.6, 2.9 Hz), 6.58 (d, 1 H, J = 2.7 Hz),
5.65–5.59 (m, 1 H), 5.45–5.41 (m, 1 H), 4.35 (br s, 2 H), 3.78
(s, 3 H), 2.88 (br s, 2 H), 2.42 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 159.2, 143.1, 142.5, 138.6, 131.2, 131.1, 129.4,
127.0, 125.9, 124.9, 114.6, 112.1, 55.3, 49.2, 32.4, 21.5.
Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25.
Found: C, 65.80; H, 5.98; N, 4.43. MS (TOFMS ES+):
m/z = 352 [M+ + Na].
Compound 12b: Mp 135 °C. IR (KBr): 1715, 1596, 1491,
1352, 1168 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.91 (d,
2 H, J = 8.3 Hz), 7.41 (d, 1 H, J = 8.0 Hz), 7.32 (d, 2 H,
J = 8.1 Hz), 7.18 (d, 1 H, J = 8.1 Hz), 7.03 (s, 1 H), 2.48–
2.44 (m, 2 H), 2.38 (s, 3 H), 2.23 (s, 3 H), 2.10–2.04 (m,
3 H), 1.79–1.77 (m, 1 H). 13C NMR (75 MHz, CDCl3):
d = 172.7, 144.8, 139.4, 136.6, 135.8, 133.4, 129.7, 129.3,
129.1, 128.8, 127.9, 34.4, 29.1, 27.3, 21.7, 21.1. Anal. Calcd
for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C,
65.78; H, 6.04; N, 4.48. MS (TOFMS ES+): m/z = 352 [M+ +
Na].
Compound 16: IR (CHCl3): 1735, 1597, 1342, 1160, 1109
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.91 (d, 1 H, J = 10.0
Hz), 7.68 (d, 2 H, J = 8.2 Hz), 7.35 (d, 1 H, J = 8.8 Hz), 7.30
(d, 2 H, J = 8.1 Hz), 7.17 (d, 1 H, J = 8.7 Hz), 6.43 (d, 1 H,
J = 9.9 Hz), 5.79–5.71 (m, 1 H), 5.54–5.50 (m, 1 H), 4.37 (br
s, 2 H), 3.34 (d, 2 H, J = 4.0 Hz), 2.45 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 159.7, 153.7, 143.6, 140.3, 139.6, 138.0,
135.2, 132.6, 129.7, 126.9, 126.7, 123.5, 116.5, 116.3,
115.5, 48.7, 24.6, 21.4. Anal. Calcd for C20H17NO4S: C,
65.38; H, 4.66; N, 3.81. Found: C, 65.66; H, 4.83; N, 3.96.
MS (TOFMS ES+): m/z (%) = 390(100) [M + Na], 368(41)
[M + H].
N,2-Diallyl-4-methylaniline (7b)
Boron trifluoride etherate (1.8 mL, 15 mmol) was slowly
added to a solution of 6b (1.9 g, 10 mmol) in PhCl (15 mL)
under nitrogen, and the mixture was heated to reflux for 5 h.
It was then allowed to come to r.t., quenched with sat. aq
NaHCO3 solution (20 mL), and the aqueous layer was
extracted with EtOAc (2 × 25 mL). The combined organic
mixture was washed successively with H2O (25 mL), brine
(25 mL), and then dried (Na2SO4). It was filtered,
concentrated under reduced pressure, and the residue was
purified by chromatography over SiO2 using PE as eluent to
give starting 6b (0.17g, 9%) followed by the product 7b
(1.31g, 69%) as a pale yellow viscous liquid. IR(neat): 3442,
3387, 1636, 1618, 1515, 1313 cm–1. 1H NMR (300 MHz,
CDCl3): d = 6.94 (d, 1 H, J = 8.1 Hz), 6.87 (s, 1 H), 6.55 (d,
1 H, J = 8.1 Hz), 5.98–5.92 (m, 2 H), 5.28–5.06 (m, 5 H),
3.76 (dt, 2 H, J = 5.4, 1.5 Hz), 3.28 (d, 2 H, J = 6.2 Hz), 2.24
(s, 3 H). Anal. Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48.
Found: C, 83.40; H, 9.26; N, 7.43.
N-Allyl-N-(2-allyl-4-methylphenyl)-4-methylbenzene-
sulfonamide (8b)
p-Toluenesulfonyl chloride (1.71 g, 9 mmol) was added to a
solution of 7b (1.1g, 5.9 mmol) and Et3N (1.7 mL, 12 mmol)
in dry CH2Cl2 (20 mL), and the reaction mixture was stirred
at r.t. for 12 h. It was then diluted with CH2Cl2 (20 mL), and
the solution was washed successively with HCl (1 N, 2 × 25
mL), H2O (25 mL), brine (25 mL), and then dried (Na2SO4).
It was filtered, concentrated under reduced pressure, and the
residue was purified by chromatography over SiO2 using
EtOAc–PE (1:19) as eluent to give the product as a colorless
Compound 20: mp 224 °C IR (KBr): 1654, 1578, 1455,
1333, 1158, 1123 cm–1. 1H NMR (300 MHz, CDCl3):
d = 7.90 (d, 1 H, J = 10.0 Hz), 7.68 (d, 2 H, J = 8.2 Hz), 7.47
(d, 1 H, J = 9.0 Hz), 7.30–7.22 (m, 3 H), 6.72 (d, 1 H,
Synlett 2008, No. 19, 3011–3015 © Thieme Stuttgart · New York

LETTER
J = 10.0 Hz), 5.80–5.73 (m, 1 H), 5.52–5.48 (m, 1 H), 4.13
Synthesis of 1-Benzazepine Derivatives
3015
(21) (a) Thorsett, E. D.; Latimer, L. H. Curr. Opin. Chem. Biol.
2000, 4, 377. (b) Chevalier, J.; Atifi, S.; Eyraud, A.;
Mahamoud, A.; Barbe, J.; Pages, J.-M. J. Med. Chem. 2001,
44, 4023.
(22) (a) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102,
4303. (b) Gallagher, P. T. In Science of Synthesis (Houben-
Weyl), Vol. 10; Thomas, E. J., Ed.; Thieme: Stuttgart, 2001,
693. (c) Knölker, H.-J. Top. Curr. Chem. 2005, 244, 115.
(br s, 2 H), 3.71 (s, 3 H), 3.35 (d, 2 H, J = 4.3 Hz), 2.44 (s,
3 H). 13C NMR (75 MHz, CDCl3): d = 161.6, 143.5, 140.2,
140.1, 138.4, 134.5, 133.4, 131.6, 129.7, 126.9, 124.1,
121.7, 118.1, 113.2, 49.0, 29.8, 24.6, 21.5. Anal. Calcd for
C21H20N2O3S: C, 66.29; H, 5.30; N, 7.36. Found: C, 66.36;
H, 5.41; N, 7.24. MS (TOFMS ES+): m/z = 403 [M + Na].
(20) (a) O’Kennedy, R.; Thornes, R. D. Coumarins: Biology,
Applications and Mode of Action; Wiley and Sons:
Chichester, 1997. (b) Fylaktakidou, K. C.; Hadjipavlou-
Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr. Pharm.
Des. 2004, 10, 3813.
Synlett 2008, No. 19, 3011–3015 © Thieme Stuttgart · New York