First one-pot stereoselective synthesis of cis-2,3-dihydro-4- perfluoroalkyl-1H-1,5-benzodiazepines via a catalyst-free three-component reaction

Article abstract of DOI:10.1039/c0cc05039c

cis-2,3-Dihydro-4-perfluoroalkyl-1H-1,5-benzodiazepines were stereoselectively synthesized using a one-pot, catalyst-free, three-component reaction. This novel, efficient and convenient approach was used to synthesize 22 related products in moderate to ex

Full text of DOI:10.1039/c0cc05039c

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First one-pot stereoselective synthesis of cis-2,3-dihydro-4-perfluoroalkyl-
1H-1,5-benzodiazepines via a catalyst-free three-component reactionw
Jiechao Xu,a Jiamei Wei,a Linglin Bian,a Jiaping Zhang,a Jie Chen,a Hongmei Deng,a
Xiaoyu Wu,*a Hui Zhang*a and Weiguo Cao*abc
Received 19th November 2010, Accepted 21st January 2011
DOI: 10.1039/c0cc05039c
cis-2,3-Dihydro-4-perfluoroalkyl-1H-1,5-benzodiazepines were
stereoselectively synthesized using a one-pot, catalyst-free,
three-component reaction. This novel, efficient and convenient
approach was used to synthesize 22 related products in moderate
to excellent yields, demonstrating the scope and potential
economic impact of the reaction.
some remarkable changes in the physical properties, chemical
reactivity and biological activity of the derived fluorinated
compounds,11 there are few reports about the synthesis of
perfluoroalkylated 1,5-benzodiazepines which can serve as
synthons for developing new drugs.12 Moreover, to the best
of our knowledge, there have been no reports of stereoselective
synthesis of cis-2,3-dihydro-4-perfluoroalkyl-1H-1,5-benzo-
diazepines. Thus, in continuing our endeavor to find novel
synthetic methodologies to develop new drugs,13 in this
communication, we describe a novel and efficient method for
one-pot catalyst-free three-component synthesis of perfluoro-
alkylated 1,5-benzodiazepines with high stereoselectivity.
Initially, due to the powerful electron-withdrawing ability of
RF groups and thus the enhancement of electrophilicity
of the carbonyl group of acetylenic ester, we tried to obtain
4-perfluoroalkylated 1,5-benzodiazepine-2-ones 414 by reacting
o-phenylenediamine 1 (1.0 equiv.) with methyl 4,4,4-trifluorobut-
2-ynoate 2a15 (1.0 equiv.) in ethanol without any catalyst at
room temperature (Scheme 1). However, no desired product,
4-(trifluoromethyl)-1H-benzo[b][1,4] diazepin-2(5H)-one 4a,
was obtained. Only (Z)-methyl 3-(2-aminophenylamino)-
4,4,4-trifluorobut-2-enoate 3a was isolated as the major
product. When the reaction was performed under reflux, both
compounds 4a and 3a could be obtained, but the yield of 4a
was very low (23%). One broadened one-proton singlet at
9.25 ppm (N–H atom involved in the formation of the
1,5-Benzodiazepines occupy an important place in the area of
heterocyclic chemistry because they are important precursors
of a variety of fused ring compounds1,2 and also possess
significant pharmaceutical properties.3,4 They are also
commercially important dyes for acrylic fibers.5 These
pharmacological and industrial applications have made their
synthesis considerably important in the field of synthetic
organic chemistry.
Typically, 1,5-benzodiazepines are prepared by cyclo-
condensation of o-phenylenediamine with a,b-unsaturated
carbonyl compounds,6 b-haloketones,7 or ketones in the
presence of Lewis acids and transition-metal salts as
catalysts.8–10 Unfortunately, many of the synthetic methods
also catalyze the formation of side products, involve long
reaction times, give low yields, or use expensive reagents.
Furthermore, the use of such catalysts gives rise to tedious
work-up procedures for their separation for recycling or
disposal. Therefore, the search continues for better methods
for the synthesis of 1,5-benzodiazepines in terms of mild
reaction conditions, operational simplicity, economic viability
and selectivity.
Though it is well known that the introduction of poly-
fluoroalkyl groups into organic molecules can bring about
a Department of Chemistry, Shanghai University, 99 Shangda Rd,
Shanghai 200444, People’s Republic of China.
E-mail: wgcao@staff.shu.edu.cn, yehao7171@shu.edu.cn,
wuxy@shu.edu.cn; Fax: +86 21-66134856
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, People’s Republic of China
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
People’s Republic of China
w Electronic supplementary information (ESI) available: Synthesis
and characterization of compounds. CCDC 762456 (6f). For crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c0cc05039c.
Scheme 1
c
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and the time of reaction slightly depended on the chain length
of the polyfluoroalkyl group (the smaller the substituent, the
higher the yield), but were very sensitive to the temperature.
The reactions were completed upon refluxing within 24 h.
While at room temperature, it took about two to three days, in
the latter case yields being lower than 10%. We also found that
4,5-disubstituded o-benzodiamines could also be applicable to
the reaction (entries 13 and 14). However, when 3-methyl-
benzene-1,2-diamine was used as a substrate, two main
products, which were proved to be a pair of isomers in the ratio
of 3 : 1—methyl 2-(4-methoxyphenyl)-6-methyl-4-(trifluoro-
methyl)-2,3-dihydro-1H-benzo[b][1,4]diazepine-3-carboxylate 6u
and methyl 2-(4-methoxyphenyl)-9-methyl-4-(trifluoromethyl)-
2,3-dihydro-1H-benzo[b][1,4]diazepine-3-carboxylate 6u0, were
obtained in 64% yield. They couldn’t be separated from each
other by column chromatography, so the ratio and the structures
Scheme 2
1
intramolecular hydrogen bond) in H NMR (CDCl3) spectra
confirmed the double-bond configuration of 3a.
By heating the reaction mixture of 3a (1.0 equiv.)
and benzaldehyde (1.0 equiv.) in ethanol under reflux, the
a-addition product methyl 2-phenyl-4-(trifluoromethyl)-2,3-
dihydro-1H-benzo[b][1,4]diazepine-3-carboxylate 6g was produced
in moderate yield (72%). In view of the utility of multi-
component reactions (MCRs) in the process of drug discovery
and the total synthesis of complex natural products,16 we
examined the reaction in detail using o-phenylenediamine 1,
methyl 2-perfluoroalkynoates 2 and aldehydes 5 as starting
materials, including aromatic and aliphatic aldehydes
(Scheme 2). When all substrates were simultaneously mixed
in one pot and heated to reflux in ethanol for 20–24 h, the
desired products 6 were obtained in moderate to excellent yield
(Table 1).
1
of compounds 6u and 6u0 were determined by H NMR and
NOSEY techniques.
The 1H NMR spectra of compounds 6 manifested them-
selves in a similar manner. The coupling constant of the two
vicinal protons was in the range of 5.0–5.5 Hz, which is a
distinctive clue for deducing a cis relationship between two
vicinal protons at 2 and 3 positions of the seven-membered
ring. A 3D perspective view of the crystal structure of 6f
proved unequivocally to be the cis-isomer by X-ray crystallo-
graphic analysis, that is, the ester group and R are on the same
side of the bicyclic system (Fig. 1).z Thus, the ring closure
occurred stereoselectively to afford the single product cis-2,3-
dihydrogen-4-perfluoroalkyl-1,5-benzodiazepines.
The results indicate the scope and the generality of the
reaction with respect to the examples described. As shown in
Table 1, both aromatic and aliphatic aldehydes reacted readily
with o-phenylenediamine and methyl 2-perfluoroalkynoates
to afford the corresponding 4-perfluoroalkylated 1,5-benzo-
diazepines. Benzaldehydes with electron-donating groups at
the para position gave much better results than those with
electron-withdrawing groups, which is probably due to the
push-pull type electron-effect (entries 2–7). The result of using
o-bromobenzaldehyde indicated that this reaction was influenced
by steric effects (entry 1). Furthermore, 1-naphthaldehyde,
2-furancarboxaldehyde and 1H-indole-3-carbaldehyde were
all applicable for this reaction (entries 8, 10, 11). The yields
On the basis of previous reports,10,17 the proposed mechanism
is shown in Scheme 3. Michael addition first occurred between
o-phenylenediamine 1 and methyl 2-perfluoroalkynoate 2 to
give intermediate enamine 3, which was stabilized by an
intramolecular hydrogen bond. Then, 3 was condensed with
aldehyde 5 to form A. To convert A to dihydrobenzodiazepines,
the transformation from the most stable conformer A to the
Table 1 One-pot synthesis of 4-perfluoroalkylated-1,5-benzodiazepinesa
(cis)Yieldb
Entry R1
R1
RF
R
Product (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
o-Bromophenyl
p-Bromophenyl
p-Methylphenyl
p-Fluorophenyl
p-Methoxyphenyl 6e
p-Nitrophenyl
Phenyl
3-1H-Indolyl
n-Heptyl
Cyclohexyl
1-Naphthalenyl
2-Furanyl
p-Methoxyphenyl 6m
p-Methoxyphenyl 6n
p-Nitrophenyl
p-Methylphenyl
6a
6b
6c
6d
57
73
90
54
80
50
72
56
56
68
85
81
62
60
31
61
51
71
74
70
6f
6g
6h
6i
6j
6k
6l
9
10
11
12
13
14
15
16
17
18
19
20
Fig. 1 X-Ray structure of compound 6f.
CH3 CH3 CF3
Cl
H
H
H
H
H
H
Cl
H
H
H
H
H
H
CF3
C2F5
C2F5
C2F5
C2F5
6o
6p
p-Methoxyphenyl 6q
p-Bromophenyl
6r
6s
6t
n-C3F7 1-Naphthalenyl
n-C3F7 p-Bromophenyl
a
Conditions: o-phenylenediamine 1 (0.5 mmol), methyl 2-perfluoro-
alkynoates 2 (0.5 mmol), aldehyde 5 (0.5 mmol) in ethanol (5 mL),
b
reflux for 20–24 h. Isolated yield.
Scheme 3
c
3608 Chem. Commun., 2011, 47, 3607–3609
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twisted B suitable for subsequent cyclization would be
necessary.17a The anionic carbon a to the ester group in B
attacked the carbon of the imine intramolecularly from the
back side of the plane b to afford the sole a-addition product
cis-2,3-dihydrogen-4-perfluoroalkyl-1,5-benzodiazepines.
In conclusion, we have developed a novel one-pot three-
component reaction of aldehydes, o-phenylenediamines, and
methyl 2-perfluoroalkynoates in the absence of a catalyst. The
main feature of this reaction is the formation of cis-a-addition
perfluoroalkylated products. The easy work-up, mild reaction
conditions, good yields and high stereoselectivity of the
reaction make the present methodology attractive for the
preparation of a wide variety of biologically relevant 1,5-
benzodiazepines.
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The authors are grateful to the National Natural Science
Foundation of China (Grant Nos 20872088, 21072126) and
The Leading Academic Discipline Projects of Shanghai
Municipal Education Commission (Grant No. J50102) for
their financial support. We also thank Dr Jonathan F. Lovell
for his editing.
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Chem. Commun., 2011, 47, 3607–3609 3609