A novel one-pot three-(in situ five-)component condensation reaction: an unexpected approach for the synthesis of tetrahydro-2,4-dioxo-1H-benzo[b][1,5] diazepine3-yl-2-methylpropanamide derivatives

Article abstract of DOI:10.1021/ol901196z

A novel and efficient method has been developed for the synthesis of tetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-3-yl-2-methylpropanamide derivatives using an aromatic diamine, Meldrum's acid, and an isocyanide in CH₂Cl₂ at ambien

Full text of DOI:10.1021/ol901196z

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3342-3345
A Novel One-Pot Three-(in Situ
Five-)Component Condensation Reaction:
An Unexpected Approach for the Synthesis
of Tetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-
3-yl-2-methylpropanamide Derivatives
Ahmad Shaabani,*,† Ali Hossein Rezayan,† Sajjad Keshipour,† Afshin Sarvary,†
and Seik Weng Ng‡
Department of Chemistry, Shahid Beheshti UniVersity, P.O. Box 19396-4716, Tehran, Iran,
and Department of Chemistry, UniVersity of Malaya, 50603, Kuala Lumpur, Malaysia
a-shaabani@cc.sbu.ac.ir
Received May 28, 2009
ABSTRACT
A novel and efficient method has been developed for the synthesis of tetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-3-yl-2-methylpropanamide
derivatives using an aromatic diamine, Meldrum’s acid, and an isocyanide in CH2Cl2 at ambient temperature in high yields without using any
catalyst or activation. The procedure provides an alternative method for the synthesis of benzo[b][1,5]diazepine derivatives. These compounds
have closely related ring systems such as triflubazam, clobazam, and 1,5-benzodiazepines, which have a broad spectrum of biological activities.
Benzodiazepines have been an important pharmacophore in
the pharmaceutical industry.1 The therapeutic applications
of benzodiazepines include anxiolytics,2 antiarrhythmics,3
vasopressin antagonists,4 HIV reverse transcriptase inhibi-
tors,5 and cholecystokinin antagonists.6 Molecules with the
1,5-benzodiazepin-2-one scaffold are privileged substructures
exhibiting a range of biological activities. Some of them have
been clinically used as anxiolytic agents, such as triflubazam
A7 and clobazam B.8 Furthermore, they exhibit activities
including interleukin-1ꢀ converting enzyme inhibition, such
as C,9 and 3-(aryloxycarbonyl)amino-2,4-dioxo-5-phenyl-
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine D10 as a chole-
cystokinin-B receptor antagonists (Figure 1). On the other
† Shahid Beheshti University.
‡ University of Malaya.
(1) (a) Archer, G. A.; Sternbach, L. H. Chem. ReV. 1968, 68, 747–784.
(b) Sternbach, L. H. Prog. Drug Res. 1978, 22, 229–266. (c) Lee, J.;
Gauthier, D.; Rivero, R. A. J. Org. Chem. 1999, 64, 3060–3065. (d)
Cepanec, I.; Litvic, M.; Pogorelic, I. Org. Proc. Res. DeV. 2006, 10, 1192–
1198.
Figure 1. Examples of some biologically active benzodiazepine
(2) Wright, W. B.; Brabander, H. J.; Greenblatt, E. N.; Day, I. P.; Hardy,
R. A. J. Med. Chem. 1978, 21, 1087–1089.
derivatives.
(3) Selnick, H. G.; Liverton, N. J.; Baldwin, J. J.; Butcher, J. W.;
Claremon, D. A.; Elliotte, J. M.; Freidinger, R. M.; King, S. A.; Libby,
B. E.; Mcintyre, C. J.; Pribush, D. A.; Remy, D. C.; Smith, G. R.; Tebben,
A. J.; Jurkiewicz, N. K.; Lynch, J. J.; Salata, J. J.; Sanguinetti, M. C.; Siegal,
P. K. S.; Slaughter, D. E.; Vyas, K. J. Med. Chem. 1997, 40, 3865–3868.
hand, two recently published patents indicate that tetrahydro-
1H-1,5-benzodiazepine derivatives carrying carboxamide
10.1021/ol901196z CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

substituents are potentially important as a therapeutic and
prophylactic agents for diabetes, diabetic nephropathy, or
glomerulosclerosis.11 Some research has been undertaken on
the benzodiazepine-3-carboxamide derivatives. These com-
pounds have been synthesized via multistep approach in the
presence of expensive catalysts under sensitive condi-
tions.1d,7-10 Therefore, development of a synthetic method
that could be used to prepare a variety of these templates
remains an important task.
and an isocyanide 3 in CH2Cl2 at ambient temperature in
high yields (Scheme 1). This route permits us to introduce
Scheme 1. Synthesis of Tetrahydro-2,4-dioxo-
1H-benzo[b][1,5]diazepine-3-yl-2-methylpropanamide
Derivatives 4a-o
Multicomponent reactions (MCRs) are special types of
synthetically useful organic reactions in which three or more
different starting materials react to give a final product in a
one-pot procedure. Such reactions are atom-efficient pro-
cesses by incorporating the essential parts of the starting
materials into the final product. MCRs are powerful tools in
the modern drug discovery process and allow the fast,
automated, and high-throughput generation of organic com-
pounds.12 Recently, the pharmaceutical industries have
focused more and more on diversity oriented and biased
combinatorial libraries.13 Furthermore, the discovery of novel
MCRs can be considered as an interesting topic for academic
research, which also satisfies a practical interest of applied
science.14
Recently, our reserch group reported the synthesis of
2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-carboxamides,
4,5,6,7-tetrahydro-1H-1,4-diazepine-5-carboxamides, fully
substituted 3,4-dihydrocoumarins, highly substituted quino-
lizines, 4H-furo[3,4-b]pyrans, pyrano[2,3-c]pyrazoles, amides,
fully substituted imino and spiroiminocyclopentenes, 2,5-
dihydro-2-methylfuran-3,4-dicarboxylates, and bis(4H-
chromene-) and 4H-benzo[g]chromene-3,4-dicarboxylate li-
braries using isocyanide-based multicomponent reactions.15
Herein, we wish to report a novel and efficient method to
prepare tetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-3-
yl-2-methyl propanamide derivatives 4a-o via the one-pot
condensation of an aromatic diamine 1, Meldrum’s acid 2,
great molecular diversity under mild reaction conditions,
including substitution and scaffold diversity. A large number
of derivatives can be rapidly synthesized in excellent purity
and high yield by using this method.
The reaction is straightforward, and treatment of various
alkyl, aryl, and alicyclic isocyanides and various o-phe-
nylenediamines with Meldrum’s acid in CH2Cl2 at room
temperature led to the formation of the tetrahydro-2,4-dioxo-
1H-benzo[b][1,5]diazepine-3-yl-2-methylpropanamide de-
rivatives in high yields.
The structure of compounds 4a-o was deduced from their
IR, mass,1H NMR, 13C NMR, and HMQC spectra data for
1
4f. For example, the H NMR spectrum of 4f exhibited a
multiplet for the cyclohexyl ring and two methyl groups at
δ ) 1.19-2.07, a singlet identified as methyl group at δ )
2.27, a broad singlet at δ ) 3.46 for CH-NH of cyclohexyl,
a multiplet at δ ) 6.92-7.00 for H-aromatic and -NH of
amide, and a broad singlet at δ ) 10.26 for two NH groups.
1
The H-decoupled 13C NMR spectrum of 4f showed 17
distinct resonances in agreement with the proposed structure.
The mass spectra of these compounds displayed molecular
ion peaks at the appropriate m/z values.
Finally, the structure of the product 4a was confirmed
unambiguously by single-crystal X-ray analysis (Figure 2).
(4) Albright, J. D.; Feich, M. F.; Santos, E. G. D.; Dusza, J. P.; Sum,
F. W.; Venkatesan, A. M.; Coupet, J.; Chan, P. S.; Ru, X.; Mazandarani,
H.; Bailey, T. J. Med. Chem. 1998, 41, 2442–2444.
(5) Breslin, H. J.; Kukla, M. J.; Ludovici, D. W.; Mohrbacher, R.; Ho,
W.; Miranda, M.; Rodgers, J. D.; Hitchens, T. K.; Leo, G.; Gauthier, D. A.;
Ho, C. Y.; Scott, M. K.; De Clercq, E.; Pauwels, R.; Andries, K.; Janssen,
M. A. C.; Janssen, P. A. J. Med. Chem. 1995, 38, 771–793.
(6) Castro, J. L.; Broughton, H. B.; Russell, M. G. N.; Rathbone, D.;
Watt, A. P.; Ball, R. G.; Chapman, K. L.; Patel, S.; Smith, A. J.; Marshall,
G. R.; Matassa, V. G. J. Med. Chem. 1987, 40, 2491–2501.
(7) Nicholson, A. N.; Stone, B. M.; Clarke, C. H. Br. J. Clin. Pharmacol.
1977, 4, 567–572.
(8) Kruse, H. Drug DeV. Res. 1982, 2, 145–151.
(9) (a) Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.;
Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513–521. (b) Zhao, H. Y.;
Liu, G. J. Comb. Chem. 2007, 9, 1164–1176.
(10) Ursini, A.; Capelli, A. M.; Carr, R. A. E.; Cassara, P.; Corsi, M.;
Curcuruto, O.; Curotto, G.; Cin, M. D.; Davalli, S.; Donati, D.; Feriani,
A.; Finch, H.; Finizia, G.; Gaviraghi, G.; Marien, M.; Pentassuglia, G.;
Polinelli, S.; Ratti, E.; Reggiani, A.; Tarzia, G.; Tedesco, G.; Tranquillini,
M. E.; Trist, D. G.; Van Amsterdam, F. T. M. J. Med. Chem. 2000, 43,
3596–3613.
(11) (a) Ohtake, Y.; Fukaya, Y. E. Patent 1 820 799 A1, 2007. (b) Finch,
H.; Shah, P.; Carr, R. A. E. U.S. Patent 5 585 376, 1996.
(12) Weber, L. Curr. Med. Chem. 2002, 9, 1241–1253.
Figure 2. ORTEP diagram for 4a.
(13) Schreiber, S. L. Science 2000, 287, 1964–1969.
(14) (a) Do¨mling, A. Chem. ReV. 2006, 106, 17–89. (b) Orru, R. V. A.;
Greef, M. Synthesis 2003, 1471–1499. (c) Bienayme, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem.sEur. J. 2000, 6, 3321–3329. (d) Zhu, J.; Bienayme,
H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005.
In view of the success of the above-mentioned reaction,
we explored the scope of this promising reaction by varying
Org. Lett., Vol. 11, No. 15, 2009
3343

the structure of the o-phenylenediamine and isocyanide
component. As indicated in Figure 3, the reaction proceeds
Scheme 3
.
Possible Mechanism for the Formation of Products
4a-o
established chemistry of reaction of isocyanides with electron-
deficient R,ꢀ-unsaturated carbonyl compounds,18 interme-
diate 11 was produced by nucleophilic attack of an isocya-
nide 3 to 3-(propan-2-ylidene)-1H-benzo[b][1,5]diazepine-
2,4(3H,5H)-dione 10 via a Michael-type addition reaction,
followed by nucleophilic attack of a H2O molecule on the
nitrilium moiety to produce compound 12. Finally, tautomer-
ization of compound 12 produces the 2,3,4,5-tetrahydro-1H-
1,5-benzodiazepine-2-carboxamide derivatives 4a-o.
To the best of our knowledge, this is the first report in
which Meldrum’s acid is decomposed to three parts (1,3-
dicarbonyl moiety, acetone, and water) under mild reaction
conditions, while all of them participate in the reaction,
respectively.
Figure3.Synthesisoftetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-
3-yl-2-methylpropanamide derivatives 4a-o.
very cleanly under mild reaction conditions at room tem-
perature, and no undesirable byproduct was observed. Owing
to the great diversity of substitution patterns, this reaction
may be used in the production of combinatorial libraries. In
this reaction, when 4-nitrobenzene-1,2-diamine and (3,4-
diaminophenyl)(phenyl)methanone were used, the desired
reaction did not proceed after 24 h.
The versatility of this multicomponent reaction with
respect to the o-phenylenediamine 1 was also studied
(Scheme 2). As indicated in Scheme 2, 2-aminophenol 5 and
To clarify the mechanism, the reaction of 4,5-dimethyl-
benzene-1,2-diamine 1, Meldrum’s acid 2, and cyclohexyl
isocyanide 3 in the presence of 1,1,1,3,3,3-hexafluoropropan-
2-one 13 under the same reaction conditions was checked.
As can be seen from Scheme 4, the desired product 14 was
Scheme 4. Clarification of the Mechanism
Scheme 2
.
Use of 2-Aminophenol Instead of
o-Phenylenediamine
Meldrum’s acid 2 with cyclohexyl isocyanides 3 in CH2Cl2
led to the formation of N-cyclohexyl-2-(2,3,4,5-tetrahydro-
7-methyl-2,4-dioxobenzo[b][1,5]oxazepin-3-yl)-2-methylpro-
panamide 6 after 24 h. It should be mentioned that only
cyclohexyl isocyanide could participate in this reaction.
A possible mechanism for the formation of products 4a-o
is shown in Scheme 3. It is conceivable that the initial event
is the formation of 1H-benzo[b][1,5]diazepine-2,4(3H,5H)-
dione 916a,b from condensation reaction between o-phe-
nylenediamine and Meldrum’s acid.16c Then, intermediate
1H-benzo[b][1,5]diazepine-2,4(3H,5H)-dione 9 under a Kno-
evenagel condensation reaction with in situ liberated acetone
7 produces the intermediate 10.17 On the basis of the well-
obtained. On the other hand, this result shows the 1,1,1,3,3,3-
hexafluoropropan-2-one 13 was replaced with liberated
acetone 7 from Meldrum’s acid.
In conclusion, we have developed a novel one-pot three-
(in situ five-)component condensation reaction leading to
tetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-3-yl-2-me-
thylpropanamide derivatives starting from simple and readily
available inputs under neutral conditions without any activa-
tion or modifications. Our literature survey shows that this
is the first example in which Meldrum’s acid is converted
to three components such as 1,3-dicarbonyl moiety, acetone,
3344
Org. Lett., Vol. 11, No. 15, 2009

and water and all of them recombined in the reaction
sequence, respectively. The reaction shows good functional
group tolerance and is high-yielding, and product isolation
is very straightforward. We hope that this approach may be
of value to others seeking novel synthetic fragments with
unique properties for medicinal chemistry programs.
Acknowledgment. We gratefully acknowledge financial
support from the Research Council of Shahid Beheshti
University.
Supporting Information Available: Experimental pro-
cedures, characterization data and spectra of products, IR,
mass, 1H and 13C NMR for 4a-o, 6, 14, HMQC spectra for
4f, 19F NMR for 14, and crystallographic data for 4a in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) (a) Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem. 2007,
72, 6309–6311. (b) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-
Rad, J. J. Org. Chem. 2008, 73, 3925–3927. (c) Shaabani, A.; Maleki, A.;
Mofakham, H.; Khavasi, H. R. J. Comb. Chem. 2008, 10, 323–326. (d)
Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R.
Org. Lett. 2008, 10, 2581–2584. (e) Shaabani, A.; Soleimani, E.; Sarvary,
A.; Rezayan, A. H. Bioorg. Med. Chem. Lett. 2008, 18, 3968–3970. (f)
Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Tetrahedron
Lett. 2008, 49, 1469–1472. (g) Shaabani, A.; Sarvary, A.; Rezayan, A. H.;
Keshipour, S. Tetrahedron 2009, 65, 3492–3495. (h) Shaabani, A.; Rezayan,
A. H.; Sarvary, A.; Rahmati, A.; Khavasi, H. R. Catal. Commun. 2008, 9,
1082–1086. (i) Shaabani, A.; Rezayan, A. H.; Ghasemi, S.; Sarvary, A.
Tetrahedron Lett. 2009, 50, 1456–1458. (j) Shaabani, A.; Soleimani, E.;
Rezayan, A. H. Tetrahedron Lett. 2007, 48, 6137–6141. (k) Shaabani, A.;
Rezayan, A. H.; Rahmati, A.; Sarvary, A. Synlett 2007, 1458–1460. (l)
Shaabani, A.; Ghadari, R.; Sarvary, A.; Rezayan, A. H. J. Org. Chem. 2009,
74, 4372–4374.
OL901196Z
(17) (a) McNab, H. Chem. Soc. ReV. 1978, 7, 345–358. (b) Chen, C. H.;
Reynolds, G. A.; Luss, H. R.; Perlstein, J. H. J. Org. Chem. 1986, 51, 3282–
3289.
(18) (a) Huang, X.; Chen, C. C.; Wu, Q. L. Tetrahedron Lett. 1982, 23,
75–76. (b) Yavari, I.; Habibi, A. Synthesis 2004, 989–991. (c) Adib, M.;
Mahdavi, M.; Alizadeh Noghani, M.; Bijanzadeh, H. R. Tetrahedron Lett.
2007, 48, 8056–8059. (d) Shaabani, A.; Yavari, I.; Teimouri, M. B.; Bazgir,
A.; Bijanzadeh, H. R. Tetrahedron 2001, 57, 1375–1378. (e) Shaabani, A.;
Bazgir, A.; Soleimani, K.; Bijanzahdeh, H. R. J. Fluorine Chem. 2002,
116, 93–95. (f) Shaabani, A.; Farrokhzad, F. J. Chem. Res., Synop. 1997,
344–344.
(16) (a) Archer, G. A.; Sternbach, L. H. Chem. ReV. 1968, 68, 747–
784. (b) Shriner, R. L.; Boermans, P. G. J. Am. Chem. Soc. 1944, 66, 1810–
1812. (c) Huang, X. Youji Huaxue 1986, 5, 329–334.
Org. Lett., Vol. 11, No. 15, 2009
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