An alternate route to substituted 6,7-dihydro 5H-dibenz[c,e]azepines from allylbenzamides derived from the Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tet.2014.04.055

An acid-catalyzed modular synthesis of substituted 5H-dibenz[c,e]azepines from a biaryl allylbenzamides prepared from the MBH adducts via a cascade dearoylation and intramolecular cyclization is described. The utility of the product for preparing 7,9-dihydro-4bH-dibenz[c,e]pyrrolo[1,2-a]azepine is also presented.

Full text of DOI:10.1016/j.tet.2014.04.055

Tetrahedron 70 (2014) 4031e4037
Contents lists available at ScienceDirect
Tetrahedron
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An alternate route to substituted 6,7-dihydro 5H-dibenz[c,e]
azepines from allylbenzamides derived from the
MoritaeBayliseHillman adducts
,b,
Subhendu Bhowmik a, Soumya Bhattacharyya a, Sanjay Batra a
*
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road,
PO Box 173, Lucknow 226031, Uttar Pradesh, India
b Academy of Scientific and Innovative Research, New Delhi, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An acid-catalyzed modular synthesis of substituted 5H-dibenz[c,e]azepines from a biaryl allylbenzamides
prepared from the MBH adducts via a cascade dearoylation and intramolecular cyclization is described.
The utility of the product for preparing 7,9-dihydro-4bH-dibenz[c,e]pyrrolo[1,2-a]azepine is also
presented.
Received 18 February 2014
Received in revised form 16 April 2014
Accepted 17 April 2014
Available online 2 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
MoritaeBayliseHillman
Amides
Polycycles
Cascade
Diastereoselectivity
1. Introduction
of this biaryl intermediate, we anticipated it to be the starting
material for preparing substituted 5H-dibenz[c,e]azepine. We rea-
The dibenzazepine is a member of the privileged class of biaryl
frameworks represented in several pharmaceuticals.1 Moreover
such biaryls offers many opportunities to construct a variety of
chiral catalyst systems and atropisomer bioligands (Fig. 1).2 Anal-
ogous tricyclic core is also present in the natural alkaloid allo-
colchicine.3 In our sustained efforts toward exploring the potential
of the MoritaeBayliseHillman (MBH) chemistry4 for the synthesis
of heterocycles,5 natural product mimics,6 and drug intermediates,7
we have recently disclosed diastereoselective synthesis of allo-
colchicine analogs from the allylbenzamides, which were readily
prepared from the MBH adducts of 2-bromobenzaldehyde.8 These
compounds were demonstrated to be useful as the insulin disag-
gregation agents. The success of the one-pot cascade reaction was
attributed to the participation of the alkoxyl anion generated from
the solvent under basic medium. In order to seek unambiguous
support for the mechanism, the reaction was performed in dioxane
instead of alkanol to successfully isolate the biaryl intermediate as
a mixture of atropisomers in 1:1 ratio. Aiming to extend the utility
soned that deprotecting the amide functionality of the biaryl
allylbenzamide under acidic condition would render a free amino
group, which would in situ trigger an intramolecular cyclization via
Schiff base formation to furnish the substituted dibenz[c,e]azepine
ring system. Notably literature describes cleavage of the NH-
benzoyl group under the acidic condition.9
Fig. 1. Biarylazepine core represented by bioactive compounds and chiral catalysts.
It would be pertinent to mention that till date several elegant
strategies for the synthesis of substituted 6,7-dihydro-5H-dibenz
* Corresponding author. Tel.: þ91 522 2772450/2772550X4705/4727; fax: þ91
522 2771941; e-mail addresses: batra_san@yahoo.co.uk, s_batra@cdri.res.in
(S. Batra).
€
[c,e]azepine have been reported. Kundig et al. were first to report
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.055

4032
S. Bhowmik et al. / Tetrahedron 70 (2014) 4031e4037
the synthesis of non racemic 5,7-dimethyl-6,7-dihydro-5H-dibenz
[c,e]azepines as a chiral lithium amide base precursor.10 Sub-
sequently Baudoin et al. disclosed the first enantioselective syn-
thesis of 5-methyl-6,7-dihydro-5H-dibenz[c,e]azepines.11 Page
et al. described the synthesis of 5-substituted dibenzazepines
through a chiral auxillary-based approach.12 In recent times Eyck-
en’s group has successfully achieved the synthesis of dibenzazepine
framework either via A3 coupling or Ugi 3-component reaction.13
More recently, Levacher et al. described Meyer’s lactamization ap-
proach to biaryl structures with defined axial chirality.14 Indeed the
Meyer’s lactamization process to access axially chiral 7,5-fused
lactams was earlier employed by Wallace et al. too.15 Besides, Heo
et al. reported a concise synthesis of 6,7-dihydro-5H-dibenz[c,e]
azepin-5-one via initial Suzuki coupling of 2-bromobenzylamides
with 2-methoxycarbonyl phenyl boronic acid followed by intra-
molecular reductive cyclization.16 During the compilation of this
work a novel multicomponent approach to one-step synthesis of
5H-dibenz[c,e]azepin-5-one employing joint palladium/norborene
organometallic catalyst was reported.17 Inspite of such enormous
development, we considered to investigate the envisaged strategy
as it would not only offer an alternate and modular route to the
dibenz[c,e]azepines bearing an allyl chain for further manipulation
but would enhance the synthetic versatility of derivatives prepared
from MBH adducts toward construction of heterocycles. Working
toward this objective we have observed that treating the atropi-
someric mixture of allylbenzamides with HCl in ethanol afforded
substituted 5H-dibenz[c,e]azepines. Moreover these products are
viable precursor to 7,9-dihydro-4bH-dibenz[c,e]pyrrolo[1,2-a]aze-
pine. The results of our study are presented herein.
The success of the protocol prompted us to investigate the scope
of the strategy by preparing a small library of biarylazepines. In this
context, initially different allylbenzamides 1(beg) were reacted
with 2-formylphenylboronic acid (2A) in the presence of Pd(PPh3)4
to furnish different biaryls 3bAe3gA as a mixture of atropisomers
in 1:1 ratio. Treating these biarylbenzamides with HCl in ethanol
gave the required products 4bAe4gA in excellent yields (Table 1,
entries 1e6). The electronic nature of the substituent on the phenyl
ring did not influence the outcome. To enhance the scope sub-
sequently, N-(1-(2-bromophenyl)-2-cyanoallyl)benzamide 1a was
treated with different substituted 2-formylphenylboronic acids
2BeD to prepare diverse biaryls 3aBe3aD. These biaryls upon acid-
mediated cyclization afforded the respective products 4aBe4aD in
88e94% yields (Table 1, entries 7e9). Next to make the protocol
modular 1a,b were treated with 2-formylthiophene boronic acid 2E
to afford the biaryls 3aE and 3bE, respectively. The intramolecular
cyclization here too was successful to furnish the corresponding
biarylazepines 4aE and 4bE in 90e93% yields (Table 1, entries 10
and 11). Further we also employed 4-iodo-susbtituted pyrazole-
based allylamide (1h) for the Suzuki coupling with 2A to obtain
the biaryl 3hA in 65% yield. Treating 3hA with HCl/EtOH afforded 2-
(1-(4-chlorophenyl)-2-phenyl-2,4-dihydrobenzo[c]pyrazolo[4,3-e]
azepin-4-yl)acrylonitrile (4hA) in 58% yield (Table 1, entry 12). Fi-
nally to investigate the influence of aroyl group, if any, on the
dearoylation reaction the benzoyl group in 1a was replaced by 2-
chlorobenzoyl and 2-furoyl groups to generate 1i and 1J, which
were subjected to identical sequence of reactions. It was observed
that these substrates resulted into the formation of dibenzazepine
4aA in excellent yields (Table 1, entries 13 and 14). The result
inferred that invariably the aroyl group is cleaved during the re-
action. Thus it was evident that the protocol for the formation of
biarylazepine was modular and is not affected by the substitutions
present on the aryl rings. Although straightforward, the mechanism
of the reaction is delineated in Fig. 2. A few of the compounds were
investigated for their cytotoxicity, but none of the analogs was
found to be toxic as compared to podophyllotoxin (see SD).
2. Results and discussion
In the first stage of the study we embarked on the synthesis of the
biaryl intermediate following the reported procedure.8 Accordingly,
the Suzuki cross coupling reaction between the N-(1-(2-
bromophenyl)-2-cyanoallyl)benzamide 1a and 2-formylphen
ylboronic acid 2A in the presence of Pd(PPh3)4 (5 mol %) and
aq Na2CO3 in dioxane as the medium at 80 ꢀC was performed to
obtain the expected N-(2-cyano-1-(20-formyl-[1,10-biphenyl]-2-yl)
allyl)benzamide 3aA as a mixture of atropisomers (as evident from
NMR spectra). With the biaryl allylbenzamide 3aA in hand, next we
set out to explore a suitable condition for the cascade NH-
debenzoylation and intramolecular cyclization via an imine forma-
tion leading to 5H-dibenz[c,e]azepine. After a short screening of
several acidic conditions, we discovered that performing the re-
action in a 1:3 mixture of HCl/EtOH at 80 ꢀC led to its completion
within 2 h to afford a solid product in more than 95% yield (Scheme
1). The spectroscopic characterization led us to establish the struc-
ture of the product as 2-(5H-dibenz[c,e]azepin-5-yl)acrylonitrile
4aA. It is worthwhile to mention that the reaction failed to yield
a product when performed at room temperature.
Having established the scope of the protocol to prepare a variety
of biarylazepine frameworks, we turned our attention to investigate
the utility of these products for the synthesis of benzpyrroloazepine.
It may be noted that benzpyrroloazepine is an important core
present in a variety of natural products and pharmaceuticals.18 Ac-
cordingly in a representative set of experiment the imine func-
tionality of 4aA was reduced with NaBH3CN in a mixture of glacial
AcOH/EtOH (1:9) at room temperature for 1.5 h to prepare the amine
5 in 86% yield. Treating this amine 5 with allyl bromide in the
presence of K2CO3 in DMFas the medium gave the bisallyl derivative
6 in 81% yield. Finally the ring closing metathesis reaction in the
presence of 10 mol % Grubbs second generation catalyst furnished
the desired dibenzpyrroloazepine 7 in 62% yield (Scheme 2).
3. Conclusions
In summary we have disclosed herein an alternate, modular, and
efficient route to 6,7-dihydro-5H-dibenz[c,e]azepines from allyl-
benzamides prepared from the MBH adducts. The protocol is
compatible to a variety of substrates, which can be readily prepared
from easily available starting materials. Further work is underway
to study the utility of the reduced product 5 for generating more
complex systems.
4. Experimental section
4.1. General
Scheme 1. Reagents and conditions: (i) Pd(PPh3)4 (5 mol %), aq Na2CO3, dioxane, 80 ꢀC,
Melting points are uncorrected and were determined in capil-
lary tubes on a Precision melting point apparatus containing silicon
2 h; (ii) HCl/EtOH (1:3), 80 ꢀC, 2 h.

S. Bhowmik et al. / Tetrahedron 70 (2014) 4031e4037
4033
Table 1
Scope of the acid-catalyzed cascade reaction of biaryl allylbenzamides (3)a for the synthesis of biarylazepines (4)
Entry
1
Allylamide (1)
Boronic acid (2)
Biaryl (3)
Product (4)
Yield [%] of 4b
92
96
89
92
90
83
86
94
2
3
4
5
6
7
8
9
88
(continued on next page)

4034
S. Bhowmik et al. / Tetrahedron 70 (2014) 4031e4037
Table 1 (continued )
Entry
Allylamide (1)
Boronic acid (2)
Biaryl (3)
Product (4)
Yield [%] of 4b
10
11
93
90
58
12
13
89
61
14
a
Compound 3 (0.3 mmol), HCl/EtOH (4 mL, 1:3 v/v).
Isolated yields.
b
4.2. General procedure for the synthesis of 3aAe3jA, 3aBeaE,
3bE as exemplified for 3aA
A suspension of 1a (0.20 g, 0.59 mmol), 2-formylphenylboronic
acid 2A (0.09 g, 0.65 mmol), 2(M) aq Na2CO3 (0.13 g, 1.18 mmol) in
dioxane (3 mL) was degassed under N2 for 15 min. Then a weighed
amount of Pd(PPh3)4 (0.03 g, 0.03 mmol) was added to it and the
reaction mixture was transferred to an oil bath and heated at 80 ꢀC
until all the starting materials were consumed. The excess 2-
propanol was evaporated under reduced pressure and the crude
mixture was worked up with EtOAc (3ꢁ10 mL). Thereafter the
combined organic layer was washed with brine solution, dried over
anhydrous Na2SO4, and evaporated under reduced pressure to yield
the crude product as brown oil, which after chromatographic pu-
rification [silica gel, hexane/EtOAc (80:20)] yielded the pure 3aA
(0.18 g, 79%) as a white solid.
Fig. 2. Plausible mechanism for the formation of the observed product.
Scheme 2. Reagents and conditions: (i) NaBH3CN, glacial AcOH/EtOH (1:9), rt, 1.5 h;
(ii) Allyl bromide, K2CO3, DMF, rt, 1.5 h; (iii) Grubbs II, CH2Cl2, 40 ꢀC, 6 h.
4.3. General procedure for the synthesis of 4aAe4hA,
4aBe4aE, 4bE as exemplified for 4aA
oil. IR spectra were recorded using a Perkin Elmer’s RX I FTIR
spectrophotometer. 1H NMR and 13C NMR spectra were recorded
either on Bruker Avance DRX-300 or Bruker 400 MHz spectrome-
ters, using TMS as an internal standard. The ESMS were recorded on
Thermo Finnigan LCQ Advantage, Ion Trap Mass spectrometer. The
HRMS spectra were recorded as EI-HRMS on Agilent 6520 Q-TOF,
LC-MS/MS mass spectrometer. The synthesis of the starting amides
was published earlier.8 The spectroscopic details of unreported
amides and the biaryl allylbenzamides are included in the
Supplementary data.
To a solution of concd HCl (12 N, 1 mL) and EtOH (3 mL), 3aA
(0.1 g, 0.27 mmol) was added at room temperature and the mixture
was heated to reflux for 2 h. After complete consumption of the
starting material the solvent was evaporated under vacuum. The
resulting oily mixture was then basified to pH 9 with aq NaHCO3
and extracted with EtOAc (3ꢁ10 mL). The organic layers were
combined, washed with brine (25 mL), and dried over anhydrous
Na2SO4. Evaporation of solvent in vacuo gave a residue, which upon

S. Bhowmik et al. / Tetrahedron 70 (2014) 4031e4037
4035
purification via silica-gel column chromatography (hexane/EtOAc,
85:15) afforded the desired dibenzazepine 4aA (0.06 g, 95%) as
a white solid.
109.9, 113.1, 126.8, 128.4, 128.6, 129.1, 129.6, 129.9, 130.3, 132.5,
139.7, 140.1, 142.2, 160.2, 160.9, 166.5; mass (ESþ) m/z¼322.0
(MþþH); ES-HRMS calcd for C20H20NO3 322.1443 (MþþH), Found
322.1439.
4.3.1. 2-(5H-Dibenz[c,e]azepin-5-yl)acrylonitrile
(4aA). 95%
as
a white solid (0.06 g from 0.10 g); mp¼159e161 ꢀC; Rf¼0.52 (hex-
4.3.7. 2-(2,3-Dimethoxy-5H-dibenz[c,e]azepin-5-yl)acrylonitrile
(4gA). 83% as a white solid (0.06 g from 0.10 g); mp¼135e137 ꢀC;
Rf¼0.36 (hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1619 (C]N), 2216
anes/EtOAc, 80:20, v/v); nmax (KBr) 1626 (C]N), 2220 (CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3)
(s, 1H, CH2), 7.43e7.64 (m, 7H, ArH), 7.83 (d, 1H, J¼7.8 Hz, ArH), 8.46
(s, 1H, CH); 13C NMR (75 MHz, CDCl3)
d¼4.46 (s, 1H, CH), 6.50 (s, 1H, CH2), 6.82
(CN) cmꢂ1; 1H NMR (400 MHz, CDCl3)
3H, OCH3), 4.31 (s, 1H, CH), 6.43 (s, 1H, CH2), 6.78 (s, 1H, CH2), 6.85
d
¼3.87 (s, 3H, OCH3), 3.89 (s,
d
¼63.1, 118.5, 123.1, 124.6,
127.8, 128.4, 128.9, 129.0, 129.2, 129.5, 130.7, 132.5, 133.8, 137.1,
138.6, 139.5, 160.9; mass (ESþ) m/z¼245.1 (MþþH); ES-HRMS calcd
for C17H13N2 245.1079 (MþþH), Found 245.1074.
(s, 1H, ArH), 7.04 (s, 1H, ArH), 7.42e7.58 (m, 3H, ArH), 7.73 (d, 1H,
J¼7.8 Hz, ArH), 8.37 (s, 1H, CH); 13C NMR (100 MHz, CDCl3)
¼56.2,
d
56.3, 62.7, 107.8, 112.3, 114.2, 118.4, 123.2, 127.3, 128.6, 129.4, 129.8,
130.7, 131.3, 132.5, 133.9, 149.1, 149.9, 160.9; mass (ESþ) m/z¼305.1
(MþþH); ES-HRMS calcd for C19H17N2O2 305.1290 (MþþH), Found
305.1288.
4.3.2. Ethyl 2-(5H-dibenz[c,e]azepin-5-yl)acrylate (4bA). 92% as
brown oil (0.06 g from 0.10 g); Rf¼0.50 (hexanes/EtOAc, 70:30, v/v);
nmax (neat) 1627 (C]N), 1711 (CO2Et) cmꢂ1 1H NMR (300 MHz,
;
CDCl3)
d
¼1.15 (t, 3H, J¼7.1 Hz, CH3), 4.09e4.13 (m, 2H, CH2), 4.81 (s,
4.3.8. 2-(10-Methyl-5H-dibenz[c,e]azepin-5-yl)acrylonitrile
(4aB). 86% as a white solid (0.06 g from 0.10 g); mp¼128e130 ꢀC;
Rf¼0.44 (hexanes/EtOAc, 70:30, v/v); nmax (KBr) 1621 (C]N), 2221
1H, CH), 6.85 (s, 2H, CH2), 7.35e7.38 (m, 2H, ArH), 7.48e7.61 (m, 5H,
ArH), 7.84 (d, 1H, J¼7.6 Hz, ArH), 8.47 (d, 1H, J¼1.8 Hz, CH); 13C NMR
(50 MHz, CDCl3)
d¼14.1, 60.7, 61.4, 124.2, 127.5, 127.6, 128.4, 128.6,
(CN) cmꢂ1; 1H NMR (300 MHz, CDCl3)
d¼2.53 (s, 3H, CH3), 4.44 (s,
128.8, 129.0, 129.2, 130.2, 132.8, 137.0, 140.0, 140.2, 141.0, 160.5,
1H, CH), 6.48 (s, 1H, CH2), 6.80 (s, 1H, CH2), 7.35 (d, 1H, J¼7.9 Hz,
ArH), 7.40e7.50 (m, 4H, ArH), 7.62 (d, 2H, J¼5.8 Hz, ArH), 8.41 (d,
166.6; mass (ESþ) m/z¼292.0 (MþþH); ES-HRMS calcd for
C
19H18NO2 292.1338 (MþþH), Found 292.1343.
1H, J¼1.9 Hz, CH); 13C NMR (75 MHz, CDCl3)
¼21.8, 63.2, 118.5,
d
123.3, 124.5, 128.3, 128.8, 129.2, 129.4, 130.2, 133.7, 137.2, 138.4,
139.5, 141.0, 160.9; mass (ESþ) m/z¼259.0 (MþþH); ES-HRMS calcd
for C18H15N2 259.1235 (MþþH), Found 259.1233.
4.3.3. 2-(3-Fluoro-5H-dibenz[c,e]azepin-5-yl)acrylonitrile
(4cA). 96% as a white solid (0.07 g from 0.10 g); mp¼138e140 ꢀC;
Rf¼0.46 (hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1621 (C]N), 2217
(CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼4.44 (s, 1H, CH), 6.52 (s,
4.3.9. 2-(10-Fluoro-5H-dibenz[c,e]azepin-5-yl)acrylonitrile
(4aC). 94% as a white solid (0.06 g from 0.10 g); mp¼210e212 ꢀC;
Rf¼0.46 (hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1621 (C]N), 2216
1H, CH2), 6.85 (s, 1H, CH2), 7.15 (t, 2H, J¼6.7 Hz, ArH), 7.52e7.65 (m,
4H, ArH), 7.77 (d, 1H, J¼7.6 Hz, ArH), 8.45 (s, 1H, CH); 13C NMR
(75 MHz, CDCl3)
d¼62.8, 111.9 (d, J¼23.1 Hz), 115.5 (d, J¼21.6 Hz),
(CN) cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
¼4.46 (d,1H, J¼10.2 Hz, CH),
118.2, 122.5, 127.9, 128.9, 129.3, 130.8, 131.0, 132.3, 133.3, 134.4,
138.5, 140.4, 161.4, 163.5 (d, J¼247.9 Hz); mass (ESþ) m/z¼263.1
(MþþH); ES-HRMS calcd for C17H12FN2 263.0985 (MþþH), Found
263.0988.
6.50 (d, 1H, J¼10.8 Hz, CH2), 6.82 (d, 1H, J¼10.2 Hz, CH2), 7.20e7.25
(m,1H, ArH), 7.43e7.60 (m, 6H, ArH), 8.42 (d,1H, J¼11.2 Hz, CH); 13
C
NMR (50 MHz, CDCl3)
d
¼63.1, 115.5 (d, J¼22.1 Hz), 118.4, 122.9,
124.8,128.6,129.4,129.5,131.7,131.9,134.0,136.1,138.3,142.1,142.3,
160.3 (d, J¼44.7 Hz), 165.8; mass (ESþ) m/z¼263.1 (MþþH); ES-
HRMS calcd for C17H12FN2 263.0985 (MþþH), Found 263.0989.
4.3.4. Ethyl 2-(3-fluoro-5H-dibenz[c,e]azepin-5-yl)acrylate (4dA). 89%
as brown oil (0.06 g from 0.10 g); Rf¼0.42 (hexanes/EtOAc, 80:20, v/
v); nmax (KBr) 1627 (C]N), 1712 (CO2Et) cmꢂ1
;
1H NMR (300 MHz,
4.3.10. 2-(9-Methoxy-5H-dibenz[c,e]azepin-5-yl)acrylonitrile
(4aD). 88% as a white solid (0.07 g from 0.10 g); mp¼124e126 ꢀC;
Rf¼0.38 (hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1623 (NHCO), 2221
CDCl3)
d¼1.18e1.21 (m, 3H, CH3), 4.11e4.15 (m, 2H, CH2), 4.80 (s, 1H,
CH), 6.86 (s, 2H, CH2), 6.94e7.06 (m, 2H, ArH), 7.55e7.58 (m, 4H,
ArH), 7.77 (d, 1H, J¼3.4 Hz, ArH), 8.47 (s, 1H, CH); 13C NMR (50 MHz,
(CN) cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
¼3.92 (s, 3H, OCH3), 4.44 (s,
CDCl3)
d
¼14.2, 60.9, 61.1, 111.5 (d, J¼22.1 Hz), 114.6 (d, J¼21.4 Hz),
1H, CH), 6.48 (s,1H, CH2), 6.79 (s,1H, CH2), 7.03 (s,1H, ArH), 7.19 (d,1H,
J¼8.4 Hz, ArH), 7.43 (d, 3H, J¼2.5 Hz, ArH), 7.51 (d,1H, J¼4.8 Hz, ArH),
7.75 (d, 1H, J¼8.7 Hz, ArH), 8.39 (s,1H, CH); 13C NMR (50 MHz, CDCl3)
127.6, 128.4, 128.5, 128.7, 129.2, 129.7, 130.3, 132.9, 133.6, 139.0, 139.5,
163.8 (d, J¼261.5 Hz), 166.8, 170.9; mass (ESþ) m/z¼310.1 (MþþH);
ES-HRMS calcd for C19H17FNO2 310.1243 (MþþH), Found 310.1244.
d
¼55.7, 63.3, 112.6, 117.8, 118.5, 123.3, 124.6,128.2, 128.4, 129.0, 130.5,
132.3, 133.7, 137.0, 137.8, 159.0, 160.5; mass (ESþ) m/z¼275.1 (MþþH);
4.3.5. 2-(3-Methoxy-5H-dibenz[c,e]azepin-5-yl)acrylonitrile
(4eA). 92% as a white solid (0.06 g from 0.10 g); mp¼85e87 ꢀC;
Rf¼0.39 (hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1618 (C]N), 2217
ES-HRMS calcd for C18H15N2O 275.1184 (MþþH), Found 275.1187.
4.3.11. 2-(6H-Benz[c]thieno[3,2-e]azepin-6-yl)acrylonitrile
(CN) cmꢂ1; 1H NMR (300 MHz, CDCl3)
d¼3.87 (s, 3H, OCH3), 4.45 (s,
(4aE). 93% as brown solid (0.06 g from 0.10 g); mp¼64e66 ꢀC;
Rf¼0.43 (hexanes/EtOAc, 80:20, v/v); nmax (neat) 1632 (C]N), 2232
1H, CH), 6.50 (s, 1H, CH2), 6.82 (s, 1H, CH2), 6.95e6.99 (m, 2H, ArH),
7.48e7.62 (m, 4H, ArH), 7.76 (d, 1H, J¼7.4 Hz, ArH), 8.44 (s, 1H, CH);
(CN) cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼4.46 (s, 1H, CH), 6.49 (s,
13C NMR (50 MHz, CDCl3)
d
¼55.6, 63.2, 110.3, 114.0, 118.4, 123.1,
1H, CH2), 6.79 (s, 1H, CH2), 7.42e7.56 (m, 4H, ArH), 7.62e7.68 (m,
127.2, 128.6, 129.3, 129.9, 130.2, 130.6, 132.2, 134.0, 139.3, 139.7,
2H, ArH), 8.47 (s, 1H, CH); 13C NMR (50 MHz, CDCl3)
d¼64.6, 118.5,
160.5, 161.4; mass (ESþ) m/z¼275.1 (MþþH); ES-HRMS calcd for
123.4, 125.8, 127.4, 127.6, 128.3, 129.5, 129.8, 133.5, 133.7, 134.1,
134.3, 144.3, 153.7; mass (ESþ) m/z¼251.0 (MþþH); ES-HRMS calcd
for C15H11N2S 251.0643 (MþþH), Found 251.0644.
C
18H15N2O 275.1184 (MþþH), Found 275.1191.
4.3.6. Ethyl 2-(3-methoxy-5H-dibenz[c,e]azepin-5-yl)acrylate (4fA).
90% as brown oil (0.07 g from 0.10 g); Rf¼0.38 (hexanes/EtOAc,
4.3.12. Ethyl 2-(6H-benz[c]thieno[3,2-e]azepin-6-yl)acrylate (4bE).
90% as a white solid (0.06 g from 0.10 g); mp¼96e98 ꢀC; Rf¼0.42
(hexanes/EtOAc, 80:20, v/v); nmax (KBr) 1632 (NHCO), 1714
80:20, v/v); nmax (KBr) 1624 (C]N), 1711 (CO2Et) cmꢂ1 1H NMR
;
(300 MHz, CDCl3)
d
¼1.16 (t, 3H, J¼7.1 Hz, CH3), 3.78 (s, 3H, OCH3),
4.06e4.17 (m, 2H, CH2), 4.82 (s, 1H, CH), 6.79e6.91 (m, 4H, ArH),
7.41e7.57 (m, 4H, ArH), 7.76 (d, 1H, J¼7.7 Hz, ArH), 8.46 (d, 1H,
(CO2Et) cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼1.15 (t, 3H, J¼7.1 Hz,
CH3), 4.03e4.22 (m, 2H, CH2), 4.79 (s, 1H, CH), 6.84 (d, 2H, J¼1.9 Hz,
J¼1.9 Hz, CH); 13C NMR (50 MHz, CDCl3)
¼14.1, 55.4, 60.7, 61.4,
d
CH2), 7.28e7.42 (m, 3H, ArH), 7.54e7.58 (m, 2H, ArH), 7.61e7.64 (m,

4036
S. Bhowmik et al. / Tetrahedron 70 (2014) 4031e4037
1H, ArH), 8.47 (d, 1H, J¼2.1 Hz, CH); 13C NMR (50 MHz, CDCl3)
chloride (10 mL) was stirred at 40 ꢀC for 6 h. The solvent was
evaporated and the crude mixture was purified via column chro-
matography over silica gel by eluting with hexane/EtOAc (90:10) to
afford 7 (0.02 g, 62%) as a brown solid. Mp¼173e175 ꢀC; Rf¼0.24
d
¼14.2, 60.7, 62.9, 125.4, 127.3, 127.4, 127.5, 128.6, 129.3, 133.4,
134.5, 136.4, 140.7, 144.5, 153.1, 166.7; mass (ESþ) m/z¼298.0
(MþþH); ES-HRMS calcd for C17H16NO2S 298.0902 (MþþH), Found
298.0903.
(hexanes/EtOAc, 80:20, v/v); nmax (KBr) 2223 (CN) cmꢂ1 1H NMR
;
(300 MHz, CDCl3)
CH2), 5.81 (s, 1H, CH), 7.17 (d, 1H, J¼7.2 Hz, CH), 7.31e7.53 (m, 8H,
ArH); 13C NMR (100 MHz, CDCl3)
127.8,127.9,128.9,129.3,129.9,130.2,131.6,132.2,139.4,141.0; mass
(ESþ) m/z¼259.1 (MþþH); ES-HRMS calcd for C18H15N2 259.1235
(MþþH), Found 259.1244.
d
¼3.29e3.41 (m, 2H, CH2), 3.52e3.66 (m, 2H,
4.3.13. 2-(1-(4-Chlorophenyl)-2-phenyl-2,4-dihydrobenz[b]pyrazolo
[4,3-d]azepin-4-yl)acrylonitrile (4hA). 58% as a white solid (0.04 g
from 0.10 g); mp¼190e192 ꢀC; Rf¼0.29 (hexanes/EtOAc, 80:20, v/
d
¼56.1, 56.2, 70.1, 114.2, 125.3,
v); nmax (KBr) 1633 (C]N), 2210 (CN) cmꢂ1 1H NMR (300 MHz,
;
CDCl3)
d
¼4.84 (s, 1H, CH), 6.39 (s, 1H, CH2), 6.70 (s, 1H, CH2),
7.00e7.04 (m, 3H, ArH), 7.12 (d, 2H, J¼7.6 Hz, ArH), 7.22e7.31 (m,
7H, ArH), 7.55 (d, 1H, J¼7.1 Hz, ArH), 8.59 (s, 1H, CH); 13C NMR
Acknowledgements
(75 MHz, CDCl3)
d
¼59.4, 117.1, 118.7, 121.9, 125.5, 126.2, 126.7, 127.5,
128.1, 128.2, 128.8, 129.8, 130.1, 130.2, 130.9, 131.9, 132.7, 132.8,
139.2, 139.6, 141.1, 151.0, 163.1; mass (ESþ) m/z¼421.1 (MþþH); ES-
HRMS calcd for C26H18ClN4 421.1220 (MþþH), Found 421.1229.
Two of the authors (S.B., S.B.) acknowledge the financial support
in the form of fellowship from Council of Scientific and Industrial
Research, New Delhi. The authors acknowledge the SAIF Division of
CSIR-CDRI for furnishing the spectroscopic data. The authors ac-
knowledge Dr. Kumkum Srivastava, Parasitology Division, CSIR-
CDRI for providing the cytotoxicity data of compounds. This work
was carried out under the project funded by Department of Science
and Technology, Ministry of Science and Technology (SR/S1/OC-01/
2010), New Delhi. The CDRI communication no. for this manuscript
is MS. 8664.
4.4. Typical procedure for the synthesis of 2-(6,7-dihydro-5H-
dibenz[c,e]azepin-5-yl)acrylonitrile (5)
To a mixture of 4aA (0.05 g, 0.20 mmol) in AcOH (0.5 mL) and
EtOH (4.5 mL) at 0 ꢀC, NaBH3CN (0.02 g, 0.30 mmol) was added and
the reaction was allowed to continue at room temperature for 1.5 h.
Thereafter the solvent was removed and the residue was basified to
pH 9 with aq NaHCO3. The resulting mixture was extracted with
EtOAc (3ꢁ10 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo to
afford a residue, which upon purification by column chromatog-
raphy on silica gel (hexane/EtOAc¼75:25) gave 5 (0.04 g, 86%) as
a colorless oil. Rf¼0.12 (hexanes/EtOAc, 80:20, v/v); nmax (neat) 2219
Supplementary data
The spectroscopic details of remaining compounds and copies of
1H and 13C NMR spectra of all compounds and HR-EIMS of all final
compounds are provided. Result of the cytotoxicity assay of a few
analogs is also included. Supplementary data related to this article
can be found at http://dx.doi.org/10.1016/j.tet.2014.04.055. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
(CN), 3401 (NH) cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
¼2.27 (br s, 1H,
NH), 3.49 (d, 1H, J¼13.3 Hz, CH2), 3.71 (d, 1H, J¼13.3 Hz, CH2), 4.33
(s, 1H, CH), 6.04 (d, 2H, J¼7.8 Hz, CH2), 7.23e7.44 (m, 8H, ArH); 13
C
NMR (100 MHz, CDCl3)
d
¼48.8, 59.3, 119.5, 121.7, 128.0, 128.1, 128.4,
128.6, 128.7, 129.2, 135.7, 140.4, 136.6, 140.8; mass (ESþ) m/z¼247.1
(MþþH); ES-HRMS calcd for C17H15N2 247.1235 (MþþH), Found
247.1239.
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(s, 1H, CH), 5.17 (d, 1H, J¼10.2 Hz, CH2), 5.25 (d, 1H, J1¼17.2 Hz,
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