A novel strategy for the construction of functionalized 1,5-benzodiazepines via a tandem conjugated addition/cyclization process

Article abstract of DOI:10.1002/adsc.200900736

A novel approach for the synthesis of functionalized 1,5-benzodiazepine is described. The protocol is triggered by a tandem conjugated addition/ cyclization process from the readily available starting materials 1,2-phenylenediamine and ethyl propiolate. The products have secondary amino and ester groups, and a β-enamino ester, which can serve in further functionalizations to produce molecular diversity.

Full text of DOI:10.1002/adsc.200900736

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DOI: 10.1002/adsc.200900736
A Novel Strategy for the Construction of Functionalized 1,5-
Benzodiazepines via a Tandem Conjugated Addition/Cyclization
Process
Jian Li,a Shaoyu Li,a Chunju Li,a Yuejin Liu,a and Xueshun Jiaa,b,*
a
Department of Chemistry, Shanghai University, Shanghai 200444, Peopleꢀs Republic of China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6613-4594, phone: (+86)-21-6613-2408; e-mail: xsjia@mail.shu.edu.cn
Received: October 22, 2009; Revised: December 3, 2009; Published online: January 27, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900736.
Abstract: A novel approach for the synthesis of
functionalized 1,5-benzodiazepine is described. The
protocol is triggered by a tandem conjugated addi-
tion/cyclization process from the readily available
starting materials 1,2-phenylenediamine and ethyl
propiolate. The products have secondary amino and
ester groups, and a b-enamino ester, which can
serve in further functionalizations to produce mo-
lecular diversity.
ceeds readily without the addition of any other re-
agents or catalysts.
The rapid and efficient synthesis of nitrogen-con-
taining heterocycles remains a great challenge in or-
ganic and medicinal chemistry.[6] For instance, 1,5-
benzodiazepines have been termed as a privileged
structure because of their regular appearance in di-
verse screening assays and their significant biological
activities.[7] Although they were first introduced into
the pharmaceutical industry almost 40 years ago,
these compounds are still being actively studied.[8]
However, a careful literature search showed that most
synthetic efforts have been focused on the condensa-
tion of o-phenylenediamine with carbonyl compounds
including methyl ketones, b-halo ketones and a,b-un-
saturated ketones.[9] Despite the advances achieved,
Keywords: 1,5-benzodiazepines; conjugated addi-
tion; cyclization; tandem reactions
In recent years, the development of new strategies the application of such methods suffers from poor
that provide synthetic efficiency and atom economy functional diversity, which limits their more extensive
has been an important goal of synthetic chemistry, use in the drug industry. It is well known that structur-
and continues to be a great challenge.[1] Tandem reac- al and functional diversity play an important role in
tions are good candidates for this target as they can the drug discovery process, because they offer means
serve as a powerful tool for the efficient assembly of for structural derivatization. Consequently, the devel-
complex structures from simple starting materials, opment of new synthetic approaches toward 1,5-ben-
with a minimal production of waste.[2]
zodiazepines that provide additional functional diver-
The chemistry of alkynes constitutes a very attrac- sity is highly desirable. Herein we report the first syn-
tive research area since the resulting adducts are thesis of functionalized 1,5-benzodiazepines from 1,2-
prone to further transformations.[3] In particular, ter- phenylenediamine and ethyl propiolate under cata-
minal conjugated alkynes involved in multibond- lyst-free conditions (Scheme 1).
forming processes have been well documented. Gen-
In our initial experiments, o-phenylenediamine 1a
erally, these conversions are initiated by the catalytic was employed as model substrate to react with ethyl
conjugated addition of a tertiary amine or phosphine propiolate 2 (Table 1). At room temperature, this
to a terminal conjugated alkynoate, leading to the for- mixture produced only a large amount of mono-con-
mation of many new carbon-carbon bonds in one jugated addition intermediate without the formation
pot.[4,5] In this context, a practical and catalyst-free of a seven-membered ring.[10] Fortunately, 1,5-benzo-
tandem conjugated addition to synthesize the func- diazepine 3a was obtained when this reaction was car-
tionalized 1,5-benzodiazepine system is reported ried out under reflux. A series of reaction parameters
herein. It is noteworthy that the present protocol pro- were screened and the conversion was found to be
336
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Adv. Synth. Catal. 2010, 352, 336 – 340

A Novel Strategy for the Construction of Functionalized 1,5-Benzodiazepines
strongly dependent on the reaction conditions. The
choice of solvent was especially critical: dichloro-
ethane (DCE) and CH3CN gave poor yields, while
very complex mixtures were obtained when THF and
acetone were used (Table 1). It seemed that MeOH
and dichloromethane (DCM) gave better results, and
MeOH was proven to be the best choice because use
of DCM as solvent did not afford the seven-mem-
bered ring when an electron-withdrawing group was
present in substrate 1. Interestingly, the amount of
1,2-phenylenediamine added relative to the amount
of substrate 2 also influenced the yield of product 3a.
The yield of 3a increased to 89% when 0.6 equivalent
of o-phenylenediamine was used, while using 1 equiv-
alent of substrate 1a gave only a 73% yield (Table 1).
With optimized reaction conditions in hand, we
next explored the scope of the reaction. Various sub-
stituted 1,2-phenylenediamines 1 were reacted with
ethyl propiolate 2 to afford the functionalized 1,5-
benzodiazepines and the results are summarized in
Table 2. The transformations proceeded smoothly
under the optimized conditions to give seven-mem-
bered ring products. All new compounds were charac-
Scheme 1. The tandem conjugated addition/cyclization reac-
tion of 1,2-phenylenediamine and ethyl propiolate.
Table 1. Optimization of reaction conditions.[a]
Entry Substrate 1a (equiv.) Solvent Time [h] Yield [%][b]
1
2
3
4
5
6
7
8
9
10
1
MeOH 10
MeOH 10
MeOH 10
MeOH 24
EtOH 12
73
85
89
49
69
0.8
0.6
0.5
0.6
0.6
0.6
0.6
0.6
0.6
[c]
THF
CH3CN 24
DCE 24
acetone 24
DCM 24
24
–
11
17
1
terized by IR, H NMR, 13C NMR, MS and EA, and
[c]
–
the structure of compound 4e was confirmed by a
single crystal X-ray analysis (Figure 1).[11] The analysis
showed that two isomers 3 and 4 were isolated when
the substituents R1 and R2 were different (Table 2, en-
tries 2, 3, 5–9, 11, 12). Normally, these two isomers
86
[a]
All reactions were carried out with 1 mmol of ethyl pro-
piolate 2 in 5 mL solvent under reflux in air.
Yields of product after silica gel chromatography.
A very complex mixture was obtained.
[b]
[c]
Table 2. Syntheses of functionalized 1,5-benzodiazepines.[a]
Entry
Substrate 1
Time [h]
Product
Yield [%][b]
89
1
1a
R1 =R2 =H
10
3a
2
3
1b
1c
R1 =Cl, R2 =H
R1 =Br, R2 =H
7
10
3b+4b
3c+4c
36+54
35+59
4
1d
7
3d
90
5
6
7
8
9
1e
1f
1g
1h
1i
R1 =NO2, R2 =H
R1 =CN, R2 =H
36
16
18
18
22
3e+4e
3f+4f
3g+4g
3h+4h
3i+4i
28+66
32+57
42+50
38+49
50+39
R1 =COOMe, R2 =H
R1 =COOEt, R2 =H
R1 =PhCO, R2 =H
10
1j
6
3j
91
11
1k
1l
R1 =CH3O, R2 =H
R1 =CH3, R2 =H
7
5
3k+4k
3l+4l
36+60
47+47
12c
[a]
Reactions conditions: 0.6 mmol diamine 1, 1 mmol ethyl propiolate 2 in 5 mL MeOH under reflux.
Yields of products isolated after silica gel chromatography.
[b]
[c]
The ratio of 3l and 4l was confirmed from the 1H NMR spectrum.
Adv. Synth. Catal. 2010, 352, 336 – 340
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asc.wiley-vch.de
337

Jian Li et al.
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ing (entries 4 and 10). It should also be noted that
when substrate 1l was used, products 3l and 4l could
not be separated with the usual methods (entry 12).
In such cases, the product ratio was determined from
1
the H NMR spectra. Overall, this one-pot, catalyst-
free tandem conjugated addition/cyclization process
constructs two carbon-nitrogen bonds, one carbon-
carbon bond and a seven-membered ring in an effi-
cient and atom-economical manner. Also, the proto-
col utilizes simple and commercially available materi-
als without the formation of any wastes. The function-
alized products which include secondary amino and
ester groups, and a b-enamino esters can produce mo-
lecular diversity in further functionalizations. Many
functionalizations of the enamino ester moiety have
Figure 1. Single-crystal X-ray structure of compound 4e.
could be separated efficiently by careful silica gel been reported, including the reaction with acryloyl
chromatography, and product 4 was usually isolated chloride and trans-b-nitrostyrene to form privileged
as the major component.[12] As expected, the above bicyclic heterocycles.[13] These transformations are
process was affected dramatically by the substituents being developed in our laboratory, and they will be
on the aromatic ring in substrate 1. Electron-donating reported in due course.
substituents such as methyl and methoxy group essen-
A possible mechanism is proposed to account for
tially build up the nucleophilicity of the amino the formation of the seven-membered ring
groups, thus facilitating the corresponding conjugated (Scheme 2). Conjugated addition of 1,2-phenylenedi-
addition and cyclization process (entries 10, 11 and
ACHTUNGTRENaNGNU mine to one equivalent of ethyl propiolate leads to
12). Shorter reaction times were observed in such the formation of intermediates A and B, which then
cases. By contrast, the presence of electron-withdraw- undergo further addition of another equivalent of
ing groups disfavors the present conversion. In partic- ethyl propiolate to afford C. These in situ-generated
ular, when a substrate with a strong electron-with- reactive intermediates subsequently experience intra-
drawing group such as a nitro group was used, the re- molecular cyclization followed by proton transfer to
action became quite sluggish (entry 5). Substitution of produce the functionalized seven-membered rings 3
a bromo group slightly affected reaction time. To our and 4.
delight, symmetrical aromatic diamines led to the for-
In conclusion, we have described a practical
mation of the seven-membered ring system 3 exclu- tandem conjugated addition/cyclization process to
sively, without the observation of any isomer (en- generate functionalized 1,5-benzodiazepines in an ef-
tries 1, 4 and 10). For instance, the reaction of 2 with ficient and atom-economical manner. The protocol
4,5-dichloro-1,2-phenylenediamine or 4,5-dimethyl- utilizes simple and commercially available starting
1,2-phenylenediamine was quite clean and high yield- materials without formation of any wastes. This pro-
Scheme 2. Proposed mechanism for the formation of 3 and 4.
338
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Adv. Synth. Catal. 2010, 352, 336 – 340

A Novel Strategy for the Construction of Functionalized 1,5-Benzodiazepines
Org. Chem. 2007, 72, 5454; c) P. de Armas, F. Garcꢂa-
cedure represents an operationally very simple yet
powerful method for the construction of two carbon-
nitrogen bonds, one carbon-carbon bond and a seven-
membered ring in a one-pot synthesis. Furthermore,
the seven-membered ring compounds have reactive
secondary amino and ester groups and enamino
esters, which enable further modifications leading to
molecular diversity. Thus the present method has the
potential to be applied in medicinal and synthetic
chemistry. Studies of the reaction mechanism and
broadening the scope of the reaction are currently in
progress in our laboratory.
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Experimental Section
General Procedure for the Synthesis of
Functionalized 1,5-Benzodiazepines
1,2-Phenylenediamine 1a (64.8 mg, 0.6 mmol) was added to
a solution of ethyl propiolate 2 (98 mg, 1.0 mmol) in 5 mL
MeOH. After being stirred for 10 h under reflux, the reac-
tion mixture was concentrated under vacuum. The residue
was purified by column chromatoragraphy on silica gel to
afford the desired product 3a.
Acknowledgements
The authors thank the National Natural Science Foundation
of China (Nos. 20872087 and 20902057), the Key Laboratory
of Synthetic Chemistry of Natural Substances, the Chinese
Academy of Sciences, the Leading Academic Discipline Proj-
ect of Shanghai Municipal Education Commission (No.
J50101) and the Innovation Fund of Shanghai University for
financial support.
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Adv. Synth. Catal. 2010, 352, 336 – 340
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asc.wiley-vch.de
339

Jian Li et al.
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