A new strategy for the synthesis of 1,4-benzodiazepine derivatives based on the tandem N-alkylation-ring opening-cyclization reactions of methyl 1-arylaziridine-2-carboxylates with N-[2-bromomethyl(phenyl)]trifluoroacetamides

Article abstract of DOI:10.1021/jo7024306

(Chemical Equation Presented) A new method for the synthesis of novel 1,4-benzodiazepine derivatives has been established from a one-pot reaction of methyl 1-arylaziridine-2-carboxylates with N-[2-bromomethyl(aryl)] trifluoroacetamides. The reaction proce

Full text of DOI:10.1021/jo7024306

munodeficiency virus (HIV) transactivator Tat antagonists,5 and
reverse transcriptase inhibitors.6 To further discover molecules
with potent and selective biological activity, it is of importance
to explore new methodology for the synthesis of novel 1,4-
benzodiazepine entities. A few synthetic approaches to 1,4-
benzodiazepine skeletons have been reported in literature, and
the most frequently employed methods include (A) the reaction
of 2-aminobenzoic acids and their derivatives or 2-aminoben-
zophone derivatives 1 with R-amino acid derivatives,7 (B) the
cyclocondensation of 2-halobenzoic acids and their derivatives
or 2-halobenzophone derivatives 2 with diamine derivatives,8
and (C) the reaction of diamines 3 with bis-electrophiles9
(Scheme 1). The Pictet-Spengler reaction of 4 with aldehydes
was also used to yield 1,4-benzodiazepine structure10 (D,
Scheme 1). On the basis of oxidative formation of electrophilic
N-acylnitrenium from amide 5, Tellitu, Dominguez, and their
co-workers11 recently introduced an aromatic amidation route
to 1,4-benzodiazepine derivatives (E, Scheme 1).
A New Strategy for the Synthesis of
1,4-Benzodiazepine Derivatives Based on the
Tandem N-Alkylation-Ring
Opening-Cyclization Reactions of Methyl
1-Arylaziridine-2-carboxylates with
N-[2-Bromomethyl(phenyl)]trifluoroacetamides
Jin-Yuan Wang, Xue-Fei Guo, De-Xiang Wang,
Zhi-Tang Huang, and Mei-Xiang Wang*
Beijing National Laboratory for Molecular Sciences, Laboratory
of Chemical Biology, Institute of Chemistry, Chinese Academy
of Sciences, Beijing, 100080, China
mxwang@iccas.ac.cn
ReceiVed NoVember 12, 2007
As a three-membered-ring heterocycle, aziridine compounds
show interesting and diverse reactivity, and they have become
useful synthons in organic synthesis.12 The C-activated aziridine
compounds such as aziridine-2-carboxylic acid derivatives and
aziridine-2-phosphonates, for example, have been reported to
undergo various ring-opening reactions and reactions on both
nitrogen and carbon atoms of the ring, producing a large number
of functionalized organic molecules that are not easily accessible
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A new method for the synthesis of novel 1,4-benzodiazepine
derivatives has been established from a one-pot reaction of
methyl 1-arylaziridine-2-carboxylates with N-[2-bromom-
ethyl(aryl)]trifluoroacetamides. The reaction proceeds through
the N-benzylation and highly regioselective ring-opening
reaction of aziridine by bromide anion followed by Et3N-
mediated intramolecular nucleophilic displacement of the
bromide by the amide nitrogen. The easy availability of
starting materials, simple and convenient synthetic procedure,
and formation of functionalized 1,4-benzodiazepine scaffold
ready for further chemical manipulations render this strategy
useful in synthetic and medicinal chemistry.
(7) (a) Blazevic, N.; Kajfez, F. J. Heterocycl. Chem. 1971, 8, 845. (b)
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1,4-Benzodiazepines are one of the most important and widely
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selective cholecystokinin (CCK) receptor subtype A or B
antagonists,3 platelet-activating factor antagonists,4 human im-
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Scott, M. K.; De Clercq, E.; Pauwels, R.; Andries, K.; Janssen, M. A. C.;
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10.1021/jo7024306 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/30/2008
J. Org. Chem. 2008, 73, 1979-1982
1979

SCHEME 1. Reported Synthetic Approaches to
1,4-Benzodiazepine Derivatives
SCHEME 3. Reaction of
N-[2-Bromomethyl(phenyl)]trifluoroacetamide 11a with
Methyl 1-Phenylaziridine-2-carboxylate 12a
TABLE 1. Intramolecular Cyclization Reaction of 13a and 14a
SCHEME 2. Highly Regioselective Ring Opening Reaction
of C-Activated Aziridines with Benzyl Bromide and a
Nucleophile
entry
1
2
3
4
5
base
NaOH
K2CO3
31
47
Cs2CO3
65
21
Et3N
80
7
DABCOb
15a (%)a
16a (%)a
82
73
by other means. Very recently, we13 and other research groups14
have revealed that aziridine-2-carboxylic acid derivatives 6 are
able to react with benzyl bromide to give a mixture of ring-
opening products 8 and 9. Treatment of the mixture with
nucleophilic agents such as an amine led to the formation of
vicinal diamine products 10. The exclusive formation of 10
indicated an equilibrium of 8 and 9 with aziridinium species 7
(Scheme 2).
We envisioned that, instead of using consecutively benzyl
bromide and amine, the employment of a bifunctional reactant
containing both electrophilic and nucleophilic sites in such a
reaction as depicted in Scheme 2 would result in the formation
of N-heterocyclic products. Herein we report a novel and very
convenient synthesis of new 1,4-benzodiazepine derivatives from
the reaction of 1-arylaziridine-2-carboxylates with N-[2-bro-
momethyl(aryl)]trifluoroacetamides.
a Isolated yield. b 1,4-Diazabicyclo[2.2.2]octane.
in 11 h, as monitored by TLC, the reaction was quenched and
a mixture of ring- opening products 13a and 14a was isolated
in 86% combined yield. The ratio of 13a over 14a, which was
1
determined by H NMR spectroscopy, was 10:1, indicating a
highly regioselective attack of bromide to the C-2 position of
the aziridine ring. It should be noted that, under the reaction
conditions, viz. refluxing in acetonitrile, no intramolecular
cyclization was observed. This was most probably due to the
low nucleophilicity of the nitrogen atom of the trifluoroaceta-
mide moiety. Elongating the reaction period to 24 h did not
effect intramolecular cyclization either. Instead, the ratio of 13a
over 14a was decreased from 10:1 to 6:1. The variation of the
ratio 13a:14a upon heating for a long period reflected that 13a
was able to transform into its thermodynamically more stable
isomer 14a via aziridinium intermediate 7.
To facilitate the intramolecular nucleophilic displacement of
bromide by amide, several bases were used to enhance the
nucleophilicity of the nitrogen of trifluoroacetamide. As sum-
marized in Table 1, the use of NaOH (2 equiv) did not lead to
the desired cyclization reaction. On the contrary, the ring-
opening products 13a/14a underwent decomposition to give
N-[2-anilinomethyl(phenyl)]trifluoroacetamide 16a as the major
product (entry 1, Table 1). Fortunately, K2CO3 assisted the
cyclization reaction to afford 2-methoxycarbonyl-4-phenyl-1-
trifluoroacetyl-1,4-benzodiazepine product 15a in a moderate
yield (entry 2, Table 1). The yield of 15a was improved to 65%
when Cs2CO3 was used as an inorganic base (entry 3, Table 1).
While a strong organic base such as DABCO caused decom-
position of 13a/14a (entry 5, Table 1), triethylamine acted as
an effective organic base to facilitate the formation of 15a in
high yield (entry 4, Table 1). It was noteworthy that, in all cases,
no 3-methoxycarbonyl-4-phenyl-1-trifluoroacetyl-1,4-benzodi-
azepine isomer was found, suggesting that the intramolecular
We first tested the reaction of N-[2-bromomethyl(phenyl)]-
trifluoroacetamide 11a with methyl 1-phenylaziridine-2-car-
boxylate 12a (Scheme 3). The reaction proceeded smoothly in
refluxing acetonitrile. After consumption of starting materials
(12) (a) For aziridinecarboxylate, see: Zhou, P.; Chen, B.-C.; Davis, F.
A. Asymmetric syntheses with aziridinecarboxylate and aziridinephospho-
nate building blocks. In Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH: New York, 2006; Chapter 3. (b) For a
recent monograph, see: Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH: New York, 2006. For recent reviews, see:
(c) Osborn, H. M.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693.
(d) Xu, X. E. Tetrahedron 2004, 60, 2701.
(13) (a) Wang, J.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Huang, Z.-T.; Wang,
M.-X. J. Org. Chem. 2007, 72, 2040. (b) Wang, J.-Y.; Wang, D.-X.; Pan,
J.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2007, 72, 9391.
(14) (a) D’hooghe, M.; De Kimpe, N. Synlett 2006, 2089. (b) D’hooghe,
M.; De Kimpe, N.; Van Speybroeck, V.; Waroquier, M.; De Kimper, N.
Chem. Commun. 2006, 1554. (c) Couturier, C.; Blanchet, J.; Schlama, T.;
Zhu, J. Org. Lett. 2006, 8, 2183. (d) Kim, Y.; Ha, H.-J.; Han, K.; Ko, S.
W.; Yun, H.; Yoon, H. J.; Kim, M. S.; Lee, W. K. Tetrahedron Lett. 2005,
46, 4407. (e) Lee, B. K.; Kim, M. S.; Hahm, H. S.; Kim, D. S.; Lee, W.
K.; Ha, H.-J. Tetrahedron 2006, 62, 8393. (f) Denolf, B.; Mangelinkx, S.;
To¨rnroos, K. W.; De Kimpe, N. Org. Lett. 2006, 8, 3129.
1980 J. Org. Chem., Vol. 73, No. 5, 2008

TABLE 2. One-Pot Synthesis of 1,4-Benzodiazepine Derivatives
15a-j
SCHEME 4. Hydrolysis of Compound 15h
molecules that are not readily available by other synthetic
methods. In addition, the products obtained from the current
study are very useful for further chemical modification. When
treated with K2CO3, for example, 15h underwent efficient
hydrolysis to afford 17 in 89% yield (Scheme 4). Synthesis of
a 1,4-benzodiazepine library based on further functionalizations
on the secondary amino group and carboxylic group of 17 is
feasible.
In conclusion, we have established a new strategy for the
synthesis of 1,4-benzodiazepine derivatives based on the
interaction of methyl 1-arylaziridine-2-carboxylates with N-[2-
bromomethyl(phenyl)]trifluoroacetamides. This one-pot syn-
thesis proceeded via the N-benzylation and highly regioselective
ring-opening reaction of aziridine by bromide anion followed
by the Et3N-mediated intramolecular cyclocondensation between
amide nitrogen and alkyl bromide moieties. The easy availability
of starting materials, simple and convenient synthetic procedure,
and formation of functionalized 1,4-benzodiazepine scaffold
ready for further chemical modifications render this method very
useful in synthetic and medicinal chemistry.
entry
11
R
12
Ar
15
yield (%)a
1
2
3
4
5
6
7
8
9
11a
11a
11a
11a
11a
11a
11b
11c
11d
11e
H
H
H
H
H
H
12a
12b
12c
12d
12e
12f
12a
12a
12a
12a
C6H5
15a
15b
15c
15d
15e
15f
15g
15h
15i
65
71
54
54
49
53
53
48
51
25
4-F-C6H5
4-Cl-C6H5
4-Me-C6H5
3-Me-C6H5
4-MeO-C6H5
C6H5
5-Cl
4-Cl
4-Me
3-Cl
C6H5
C6H5
C6H5
10
15j
a Isolated yield.
cyclization reaction did not occur with intermediate 14a. This
outcome might be rationalized most probably by the lower
reactivity of nonactivated alkyl bromide within 14a along with
the low content of 14a presented in an equilibrium with 15a
via aziridinium species.
Experimental Section
Encouraged by the aforementioned results, we then attempted
the one-pot synthesis of 15a from the tandem ring-opening
reaction of 12a with 11a followed, without isolation of
intermediates 13a and 14a, by the Et3N-mediated intramolecular
cyclization reaction. Gratifyingly, the reaction proceeded ef-
fectively to furnish 15a in good yield (entry 1, Table 2). To
examine its scope and limitation, this one-pot synthesis of 1,4-
benzodiazepine derivatives was further studied with a number
of substituted N-[2-bromomethyl(phenyl)]trifluoroacetamides
11b-e and methyl 1-arylaziridine-2-carboxylates 12b-f. As
demonstrated in Table 2, with the exception of 11e, with a Cl
atom at the meta position of the benzene ring, all substrates
irrespective of the electronic nature of the substituents on both
benzene rings underwent efficient tandem reaction to produce
the corresponding 1,4-benzodiazepine products 15b-i in mod-
erate to good yields (entries 2 to 9, Table 2). The low chemical
yield obtained for product 15j was probably attributable to the
steric hindrance of reactant 11e. In other words, the 3-chloro
substituent might pose an unfavorable steric effect on the
reactivity of benzyl bromide.
All spectroscopic data and microanalysis results were in
agreement with the structure of 1,4-benzodiazepine products.
However, 2- and 3-methoxycarbonyl-1,4-benzodiazepines are
not easily differentiated on the basis of spectra. To allow a
definitive assignment of structure, X-ray crystallographic analy-
sis was performed on 15e (Figure S1, Supporting Information).
It is interesting to note that the 1,4-benzodiazepine molecule
adopts a boat conformation with the substituents on both
nitrogen atoms being cis-oriented.
Ring-Opening Reaction of Methyl 1-Phenylaziridine-2-car-
boxylate 12a with N-(2-(Bromomethyl)phenyl)-2,2,2-trifluoro-
acetamide 11a. A mixture of methyl 1-phenylaziridine-2-car-
boxylate 12a (1 mmol) and N-(2-(bromomethyl)phenyl)-2,2,2-
trifluoroacetamide 11a (1 mmol) in acetonitrile (10 mL) was
refluxed for 11 h. After completion of the reaction, as monitored
by TLC (ethyl acetate:petroleum ether ) 1:8), the reaction
mixture was cooled to room temperature and the solvent was
removed under vacuum. The residue was chromatographed on a
silica gel column eluting with a mixture of petroleum ether and
ethyl acetate (10:1) to give a mixture of 13a and 14a. Products
13a and 14a were not separable by column chromatography, but
their ratio could be estimated satisfactorily from the 1H NMR
spectrum of the mixture.
Intramolecular Cyclization Reaction of 13a + 14a. A mixture
of 13a and 14a (0.5 mmol) and base (0.6 mmol) (see Table 1) in
acetonitrile (10 mL) was refluxed for 12 h until the starting 13a
and 14a was consumed, which was monitored by TLC (ethyl
acetate:petroleum ether ) 1:8). After the reaction mixture was
cooled to room temperature, the solvent was removed under
vacuum. The product was extracted into ether, the organic phase
was dried with anhydrous MgSO4, and the solvent was evaporated
in vacuo. The residue was chromatographed on a silica gel column
eluting with a mixture of petroleum ether and ethyl acetate (10:1)
to give pure product 15a.
General Procedure for Synthesis of 1,4-Benzodiazepine
Derivatives 15 from the One-Pot Reaction of N-[2-Bromom-
ethyl(phenyl)]trifluoroacetamides 11 and Methyl 1-Arylaziri-
dine-2-carboxylates 12. A mixture of 11 (1mmol) and 12 (1 mmol)
in acetonitrile (10 mL) was refluxed. After the starting materials
were consumed (11 h), which was monitored by TLC (ethyl acetate:
petroleum ether ) 1:8), the mixture was cooled and triethyla-
mine (1.2 mmol) was added. The resulting mixture was then
refluxed for another 12 h. The solvent was removed under
vacuum, and water (30 mL) was added. After extraction with diethyl
ether (20 × 3 mL), the organic phase was dried with anhydrous
The reaction between N-[2-bromomethyl(phenyl)]trifluoro-
acetamides and methyl 1-arylaziridine-2-carboxylates not only
provided a straightforward synthetic route to the 1,4-benzodi-
azepine core structure, but also generated a set of functionalized
J. Org. Chem, Vol. 73, No. 5, 2008 1981

MgSO4, and the solvent was removed under vacuum. The residue
was chromatographed on a silica gel column eluting with a mixture
of petroleum ether and ethyl acetate (10:1) to give pure product
15.
Acknowledgment. We thank the Ministry of Science and
Technology (2003CB716005, 2006CB806106), the National
Natural Science Foundation of China, and the Chinese Academy
of Sciences for financial support.
Hydrolysis of Compound 15h. A solution of 15h (1 mmol) and
K2CO3 (5 mmol) in a mixture of methanol and water (v:v ) 5:2,
10 mL) was stirred for 2 days until the starting 15h was consumed,
which was monitored by TLC. After removal of the solvent under
vacuum, the residue was chromatographed on a reverse-phase ODS
column (35-70 µm) eluting with a mixture of water and methanol
to give pure product 17 in 89% yield.
Supporting Information Available: Full characterization of all
products, 1H and 13C NMR spectra of products 15, and X-ray single-
crystal structure of 15e (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JO7024306
1982 J. Org. Chem., Vol. 73, No. 5, 2008