Efficient catalyst-free Domino approach for the synthesis of novel 2-benzazepine derivatives in water

Article abstract of DOI:10.1016/j.tetlet.2010.04.020

A novel one-pot eco-friendly protocol for the synthesis of 2-benzazepine derivatives in water has been developed. 4-Chloro-3-formyl coumarin reacts with benzyl amines under catalyst-free conditions in aqueous medium to afford substituted 5-(2′-hydroxyaryl)-4-amido-2-benzazepines in excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.04.020

Tetrahedron Letters 51 (2010) 3109–3111
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient catalyst-free Domino approach for the synthesis of novel
2-benzazepine derivatives in water
J. Venkata Prasad, Maddela Prabhakar, K. Manjulatha, D. Rambabu, K. Anand Solomon, G. Gopi Krishna,
*
K. Anil Kumar
Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 February 2010
Revised 7 April 2010
Accepted 8 April 2010
Available online 11 April 2010
A novel one-pot eco-friendly protocol for the synthesis of 2-benzazepine derivatives in water has been
developed. 4-Chloro-3-formyl coumarin reacts with benzyl amines under catalyst-free conditions in
aqueous medium to afford substituted 5-(20-hydroxyaryl)-4-amido-2-benzazepines in excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Benzazepines
Coumarin
Benzyl amines
Catalyst-free
One-pot synthesis
Scaffold hopping
Green chemistry
Azepines are prevalent motifs in several natural products pos-
sessing diverse biological properties.1 Benzazepine is a fused N-het-
erocyclic moiety present as a key structural fragment in various
biologically active molecules2 and naturally occurring alkaloids,
such as aphanorphine, lennoxamine, and cephalotaxine, which are
known to have anxiolytic action.3 The structural complexity and bio-
logical importance of benzazepines prompted intense research by
organic chemists to develop novel methodologies for their synthe-
sis. Although considerable amount of work has been carried out on
1- and 3-benzazepines,4–13 there are very few reports for the synthe-
sis of 2-benzazepines.14 The classical synthesis of 2-benzazepines
apply Bischler–Napieralski15 cyclization or the Friedel–Crafts acyla-
tion reaction. Gschwend reported the synthesis of 1-phenyl-2-ben-
zazepin-5-ones using acid-catalyzed cyclization of substituted
benzophenones,16 while Eugene J. Trybulski et al. reported the syn-
thesis using substituted aminobenzophenones.17 However, most of
the above-mentioned methods utilize expensive organic solvents
and catalysts which employ multi-step synthetic methodologies.
Recently, there has been enormous emphasis on the green and
sustainable chemistry, where high importance has been given for
the development of novel and eco-friendly methodologies which
can reduce or eliminate the use and generation of hazardous indus-
trial wastes.18 Water being the most inexpensive and non-hazard-
ous natural source has contributed generously in addressing most
of the above-described problems and in the course of time has
turned out as an inevitable alternative to many volatile organic sol-
vents in several synthetic methodologies.19 A major breakthrough
in this direction was first demonstrated by Breslow and Rideout
who reported Diels–Alder reactions in water.20 Recently, Yao and
co-workers have described an elegant method for the synthesis
of indolyl(nitro)chromans with very high diastereoselectivities un-
der catalyst-free aqueous conditions.21 Also, several reports have
been documented in recent years where water has been employed
as a preferred solvent for the synthesis of numerous elusive nitro-
gen-containing heterocyclic molecules.22 Hence, it would be of
considerable interest to demonstrate the synthesis of these imper-
ative heterocyclic frameworks using green technology platforms.
In quest to identify a general approach to highly functionalized
benzazepines under mild conditions from readily available starting
materials, we have envisaged a versatile scaffold hopping method-
ology starting from 4-chloro-3-formyl coumarin to achieve re-
quired disubstituted benzazepines 3a–k.23
4-Chloro-3-formyl coumarin when reacted with 2 equiv of
p-methyl benzyl amine in water yields a white precipitate of ben-
zazepine 3a in 3 h with 83% yield. The process did not require any
work-up procedures and the product was obtained as white precip-
itate in pure form from the reaction mixture which was isolated by
simple filtration. This is a straightforward and high yielding one-
step protocol for the generation of substituted 5-(20-hydroxyaryl)-
* Corresponding author. Tel.: +91 40 66571627; fax: +91 40 66571581.
E-mail address: anilkumark@ilsresearch.org (K. Anil Kumar).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.020

3110
J. Venkata Prasad et al. / Tetrahedron Letters 51 (2010) 3109–3111
4-amido-2-benzazepines and to the best of our knowledge a first re-
port for the synthesis of 2-benzazepines in water. To validate our
choice of water as a solvent and the effect of other organic solvents
on the reaction, we have screened various solvents for optimization
of the method. As shown in Table 1 (entries 1–6), the reaction was
comparatively slower in non polar solvents such as dichlorometh-
ane and chloroform than the polar solvents such as acetonitrile,
methanol, ethanol, and water. Water was found to be the best sol-
vent from our observations which could afford excellent yield of
the product in short reaction times (Table 1, entry 1). As shown in
Scheme 1, the reaction was presumed to go through substitution
of chloro group in coumarin by benzyl amine giving rise to an inter-
mediate I, followed by a cyclization to afford intermediate II. The fi-
nal step of the reaction involves second molecule of benzyl amine
which participates in a ring opening of the coumarin followed by
subsequent amidation resulting in benzazepine 3a in one-pot.
To confirm the proposed mechanism, an attempt was made to
isolate intermediates I and II (Scheme 1), and experiments were
conducted in water with 1 equiv of p-methyl benzyl amine and
4-chloro-3-formyl coumarin. Intermediate I was obtained as a
white precipitate after 20 min of stirring the reaction mixture at
room temperature and on further continuation of the reaction for
90 min, cyclized intermediate II was obtained. Both the intermedi-
ates were isolated in separate experiments and were characterized
completely to support the proposed mechanism (see Supplemen-
tary data). While ring opening of coumarins has been previously
described,24 the typical procedures employed strong bases such
as lithium aluminum hydride and sodium hydroxide leading to
harsh reaction conditions.
O
O
O
NH2
H
O
O
Water
NH
r.t, 3 h.
CHO
Cl
1
2a
Intermediate I
NH2
O
N
O
NH
O
OH
N
Intermediate II
3a
Scheme 1. Proposed reaction mechanism for the synthesis of 2-benzazepine 3a.
reaction and substrate scope with a series of benzyl amines (2a–
k). As illustrated in Table 1, p-methyl benzyl amine reacts with
4-chloro-3-formyl coumarin to afford the benzazepine product
3a in good yield (Table 1, entry 1). Similarly, other electron-rich
benzyl amines having p-OMe, o-Me, and m-Me substitutions react
in 3–5 h and the corresponding products were isolated in good
yields (Table 1, entries 7, 11, and 12). Unsubstituted benzyl amine
and benzyl amines having various chloro and fluoro substitutions
also react smoothly to afford the corresponding benzazepine prod-
ucts in 3 h with 80–92% yields (Table 1, entries 8–10, 13, and 16).
Disubstituted benzyl amines such as 3,4-dimethoxy and 2,3-di-
fluoro benzyl amines also react well under the reaction conditions
to afford the corresponding benazepine derivatives in 4 and 6 h,
respectively (Table 1, entries 14 and 15).
However, we could accomplish the required ring opening in the
present protocol under very mild reaction conditions under cata-
lyst-free conditions along with the in situ formation of an amide
bond. With the above-mentioned optimized conditions in hand,
further experiments were conducted to expand the utility of the
Table 1
In general, the reaction has a wide applicability to a variety of
benzyl amine substrates affording their corresponding products
in good to excellent yields. In hope of further broadening the scope
of the reaction and with the aim to achieve higher diversity, a
mixed substrate combination was also attempted. To explore the
above-mentioned possibility a reaction was performed with equi-
molar amounts of 4-chloro-3-formyl coumarin, p-methyl benzyl
amine, and o-chlorobenzyl amine in one-pot. To 4-chloro-3-formyl
coumarin in water, p-methyl benzyl amine and o-chlorobenzyl
amine were added sequentially to generate benzazepine 4 (Scheme
2) with higher diversity as a single product.
In summary, we have developed a novel and efficient route for
the synthesis of 4,5-disubstituted-2-benzazepine scaffolds from
readily available 4-chloro-3-formyl coumarin and benzyl amines
in water. Moreover, the synthesis does not involve complicated
work-up procedures and avoids the use of expensive organic sol-
vents making the protocol highly attractive for greener
technologies.
Synthesis of 2-benzazepines 3a–k
R3
R2
R1
NH2
HN
O
O
Water
O
R1
R2
+
R3
R2
r. t ,3-6h.
CHO
Cl
N
R3
OH
1
R1
3a-k
2a-k
Entry 2a–k
Producta Solvent
Time (h) Yieldsb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
R1 = R2 = H, R3 = CH3
R1 = R2 = H, R3 = CH3
R1 = R2 = H, R3 = CH3
R1 = R2 = H, R3 = CH3
R1 = R2 = H, R3 = CH3
R1 = R2 = H, R3=CH3
R1 = R2 = H, R3 = OCH3 3b
R1 = R2 = H, R3 = Cl
1 = R2 = H, R3 = F
R1 = R3 = H, R2 = Cl
R1 = CH3, R2 = R3 = H
R1 = R3 = H, R2 = CH3
R1 = R2 = R3 = H
R1 = H, R2 = R3 = OCH3 3i
R1 = R2 = F, R3 = H
1 = Cl, R2 = R3 = H
3a
3a
3a
3a
3a
3a
H2O
3
5
6
83
75
76
77
25
35
81
89
82
90
84
82
80
85
90
92
CH3OH
C2H5OH
CH3CN
CH2Cl2
CHCl3
H2O
H2O
H2O
H2O
H2O
4
10
10
5
3
3
3
5
3
3
3c
3d
3e
3f
3g
3h
Cl
R
NH2
NH2
O
O
Cl
NH
Water
3h, r.t.
O
H2O
H2O
H2O
H2O
CHO
Cl
6
4
3
OH
N
3j
3k
R
H2O
4
a
All the products were characterized by IR, NMR, and mass spectroscopy.
Isolated yields after column chromatography.
b
Scheme 2. Synthesis of 2-benzazepine 4 by sequential method.

J. Venkata Prasad et al. / Tetrahedron Letters 51 (2010) 3109–3111
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3111
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ILS.
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