Solvent-free synthesis of novel benzodiazepine derivatives by a three-component base-catalysed reaction of isatoic anhydride, a primary amine and chloroacetyl chloride

Article abstract of DOI:10.3184/174751915X14304939994023

Heating isatoic anhydride with a series of primary amines at 150 °C under solvent-free conditions yielded 2-amino-N-alkylbenzamides which, in the same pot, reacted readily with chloroacetyl chloride in the presence of poly(dimethylaminoethyl acrylamide)-modified magnetic nanoparticles (MNP@PDMA), a base catalyst, to give 4-alkyl-1,4-benzodiazepine-2,5-diones in good yields without formation of by-products.

Full text of DOI:10.3184/174751915X14304939994023

286 RESEARCH PAPER
VOL. 39 MAY, 286–288
JOURNAL OF CHEMICAL RESEARCH 2015
Solvent-free synthesis of novel benzodiazepine derivatives by a three-
component base-catalysed reaction of isatoic anhydride, a primary amine
and chloroacetyl chloride
Mohsen Khalilpour Seydeya*, Zahra Rezaeib and Seyed Saied Homamia
aDepartment of Applied Chemistry, Faculty of Science, Islamic Azad University, South Tehran Branch, Tehran, Iran
bDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences,
Tehran 14176, Iran
Heating isatoic anhydride with a series of primary amines at 150 °C under solvent-free conditions yielded 2-amino-N-alkylbenzamides
which, in the same pot, reacted readily with chloroacetyl chloride in the presence of poly(dimethylaminoethyl acrylamide)-modified
magnetic nanoparticles (MNP@PDMA), a base catalyst, to give 4-alkyl-1,4-benzodiazepine-2,5-diones in good yields without formation
of by-products.
Keywords: 4-alkyl-1,4-benzodiazepine-2,5-diones, 2-amino-N-alkylbenzamides, isatoic anhydride, chloroacetyl chloride, MNP@PDMA
Heterocyclic compounds containing one or more nitrogen atoms
in their ring have much importance in pharmaceutical research.1
alkylbenzamides derivatives 3 are produced in situ by the
reaction of 1 and 2, followed by reaction of intermediate 3 with
compounds 4 to give the title compounds 5 (Scheme 1). Poly
(dimethylaminoethyl acrylamide) (PDMA) modified magnetic
nanoparticles were used as a convenient base catalyst for an
efficient one-pot synthesis.
The benzodiazepines, especially
1,4-benzodiazepine-2,5-
diones, represent significant scaffolds in medicinal chemistry.2
In spite of their popular properties as psychoactive drugs,
which function as anti-anxiety and anti-convulsants,3 they
display other biological properties acting as anti-cancer
agents,4,5 antagonists of cholecystokinin receptors (CCK)6 and
of the platelet glycoprotein IIb–IIIa7 that mimics the arginine–
glycine–aspartic acid (RGD) peptide sequence8 and agonist of
melanocortin receptors.9
Results and discussion
The reaction of isatoic anhydride and reaction with amines has
been explained in detail elsewhere.20,21 Clearly, the nucleophilic
attack of amine on the isatoic anhydride yields an amide with
concurrent elimination of CO2.21 As is known, isatoic anhydride
undergoes ring opening upon heating with various amines to
produce 2-amino-N-alkylbenzamides. Moreover, benzamides
can easily react with chloroacetyl chloride as potential
precursors for nucleophilic attack. Initially, to obtain the best
reaction conditions, the reaction of isatoic anhydride (1 mmol)
and benzylamine (1 mmol) was selected as a model reaction and
starting materials were allowed to react at 150 °C under solvent-
free conditions for 30 minutes. After the completion of reaction
(checked by TLC), chloroacetyl chloride (1 mmol) was added to
the reaction mixture, which continued at the same temperature
in the presence of MNP@PDMA as base catalyst, and after 0.5–
2 h, the reaction was completed. The great advantage of MNP@
PDMA catalyst is the large number of nitrogen atoms in the
polymer structure which induces strong basic properties to the
catalyst. Other than MNP@PDMA as catalyst, all compounds
in the reaction mixture were completely dissolved in ethanol,
There are several synthetic methods for this scaffold, many of
them multicomponent reactions (MCRs)10.11-13 Synthetic organic
chemists are attracted to the use of MCRs for the synthesis of
complex scaffolds because they offer efficient use of energy,
hazard reduction, waste minimisation, and the use of renewable
resources.14 Recently, magnetic nanoparticles (MNPs) acting as
support for catalysts have attracted considerable attention in organic
synthesis.15,16 Great stability, easy synthesis and functionalisation
methods and high surface area are a number of advantages of
magnetic nanoparticles.17,18 A number of researches focused on
modification of silica based surfaces. For example, Zohreh et al.
introduced in 201419 magnetic iron oxide nanoparticles surface-
modified by polyamides (MNP@PDMA) as a catalyst.
We now present a green synthesis of various derivatives of
4-alkyl-1,4-benzodiazepine-2,5-diones 5 using a sequential
one-pot three-component reaction of isatoic anhydride 1, an
amine 2 and chloroacetyl chloride 4, in which 2-amino-N-
O
O
R1
Free Solvent
H2N
2
O
+
+
N
H
R1
150 °C, 0.5 h
N
O
NH2
-CO2
H
1
3
O
MN
R1
O
P@
PD
MA
O
ca
tali
st
R1
O
N
N
Cl
H
Cl
Free Solvent
110 °C, 0.5-2 h
N
NH2
H
5
4
3
Scheme 1
* Correspondent. E-mail: kpsmohsen@gmail.com

JOURNAL OF CHEMICAL RESEARCH 2015 287
Table 1 Yields/reaction times for the preparation of 4-alkyl-3,4-dihydro-
1H-benzo[e][1,4]diazepine- 2,5-diones 5a–h from a variety of amines
R1NH2 (Scheme 1)
and thus the catalyst was easily removed from the mixture by
simple filtration for 10 min. In the next step, the crude product
was purified by column chromatography on silica gel using
petroleum ether and ethyl acetate (4:1) as eluent. The product
was obtained in 85% yield. Seven other amines reacted readily
under these optimal conditions to give similar products, as
revealed by their spectral data. The results are shown in Table 1.
As can be seen, arylamines 5d and 5f reacted more slowly and
gave lower yields than alkylamines.
Wetheninvestigatedthemechanismofthereaction.According
to the literature,22 the first step in the modified Neimentowski
synthesis of a quinazolinone involves condensation of an
amine group with the keto function of the original amide. To
confirm our mechanism of reaction, the structure of the product
Entry
R1NH2
Product Time/ h Yield/%a
1
2
3
4
5
6
Benzylamine
Furfurylamine
2-Cholorobenzylamine
Aniline
4-Methoxibenzylamine
4-Methoxianiline
5a
5b
5c
5d
5e
5f
1
86
85
78
72
81
68
1.5
1.5
2
1
2
2-(2,4-Dimethoxyphenyl)
ethanamine
Propylamine
7
5g
5h
1.5
1.5
80
84
8
a Isolated yield.
1
1
was characterised by its H and 13C NMR spectra. In the H
NMR spectrum, a signal due to the NH group was observed
at δ 7.9–8.1 ppm. In the 13C NMR spectrum, the presence of
two signals at δ 167.6 and 176.4 ppm attributed to two amide
carbonyl groups provided further evidence for the formation of
a 1,4 benzodiazepine-2,5-dione instead of a quinazolinone.
column chromatography. The elemental analyses were performed for
C, H, N using an Elementar Vario EL III element analyser. TLC was
performed using silica gel 60/Kieselguhr F254 precoated on aluminum
sheets (thickness 0.2 mm) (Merck). Visualisation of spots on TLC plates
was accomplished with UV light.
A
possible explanation for the formation of
a
Synthesis of 4-alkyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
1,4-benzodaizepine-2,5-dione is based on SN2 nucleophilic
substitution. The first step is the formation of a 2-amino-N-
alkylbenzamide 3 from the reaction of isatoic anhydride 1
and an amine 2. Then chloroacetyl chloride 4 is added to 3
in the presence of base catalyst. This chloroacatylates 3 by
nucleophilic attack of the Cole group by the aromatic amine. A
cyclisation reaction is followed by an elimination of the other
chloro group to afford compound 5. In the absence of catalyst,
condensation is the main reaction which leads to quinazolinone
as the product.22 This proves the necessity of using MNP@
PDMA for obtaining 1,4-benzodiazepine-2,5-diones. The
most important feature of the catalyst is its selectivity in the
formation of 1,4-benzodiazepine-2,5-diones which might be
due to the strong basic nature of the catalyst. It is known that
the thermodynamically more stable quinazolinone with a six
memberedringisthemainproductwhennocatalystisused.Using
the base catalyst MNP@PDMA strongly activates the nitrogen
of amide for a nucleophilic attack. Therefore the attack occurs
on the C-Cl bond, while the activated nucleophile prefers the
more electrophilic carbon in the mentioned bond. As mentioned
above, it was observed that arylamines reacted more slowly and
gave a lower yield than alkylamines. This is due to the ability
of the nitrogen atom of arylamines to participate in resonance
with the aromatic ring, which decreases the nucleophilic
reactivity of their amino groups.
diones 5a-h; general procedure
A mixture of isatoic anhydride (1 mmol) and an amine (1 mmol)
was heated at 150 °C under solvent-free conditions for 30 min. Then
chloroacetyl chloride (1 mmol) and a catalytic amount of MNP@
PDMA19 (15 mol%) was added to the reaction mixture, and heating
was continued at 110 °C. After 0.5–2 h the reaction was complete
(checked by TLC). The crude products were purified by column
chromatography on silica gel using petroleum ether and ethyl acetate
(4:1) as eluent. The pure products 5a-h were obtained in 68–86%
yield. (The reaction time required for the formation of each product
and the yield obtained are listed in Table 1.) All the products, which
were novel, were recrystallised in EtOH, their IR and 1H and 13C NMR
recorded and their elemental analyses determined.
4-Benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (5a):
White powder; m.p. 118–122 °C (EtOH); IR (KBr): 3335 (NH), 1698
(C=O), 1650 (C=O) cm–1; 1H NMR: δ 4.43 (s, 2H, C3H), 5.03 (s, 2 H,
NCH2), 6.80 (m, 1 H, C9H), 6.99–7.05 (m, 2 H, C2′H, C6′H), 7.17–7.19
(m, 3 H, C3′H, C4′H ,C5′H), 7.26–7.27 (m, 1 H, C7H), 7.36 (m, 1 H,
C8H), 7.98 (s, 1H, NH, Amid), 8.21 (m, 1 H, C6H); 13C NMR: δ 48.5,
56.5, 116.4, 117.9, 119.1, 126.7, 126.9, 128.2, 132.2, 133.9, 138.2, 145.8,
167.6, 176.4. Anal. calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52;
found: C, 72.30; H, 5.40; N, 10.68%.
4-(Furan-2-ylmethyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione (5b): White needles; m.p. 115–118 oC (EtOH); IR (KBR): 3366
(NH), 1695 (C=O), 1625 (C=O) cm-1; H NMR: δ 4.37(s, 2H, C3H),
1
5.17 (s, 2 H, NCH2), 6.28–6.29 (m, 2 H, furan), 6.71 (dd, J = 7.6, 0.9
Hz, 1 H, C9H), 6.92 (dt, J = 7.6, 0.9 Hz, 1 H, C7H), 7.30 (dd, J = 3.0,
1.0 Hz, 1 H, furan), 7.34 (dt, J = 7.6, 1.4 Hz, 1 H, C8H), 8.01(s, 1H, NH,
Amid), 8.21 (dd, J = 7.6, 1.4 Hz, 1 H, C6H); 13C NMR: δ 42.1, 57.8,
108.1, 110.2, 118.2, 118.9, 119.6, 133.5, 134.1, 141.6, 144.6, 151.4, 167.2,
173.2. Anal. calcd for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93; found:
C, 65.72; H, 4.78; N, 11.00%.
4-(2-Chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione (5c): White needles; m.p. 128–131 oC (EtOH); IR (KBR): 3338
(NH), 1697 (C=O), 1622 (C=O) cm-1; 1H NMR: δ 4.37 (s, 2 H, C3H),
5.26 (s, 2 H, NCH2), 6.76 (dd, J = 8.2, 1.0 Hz, 1 H, C9H), 6.95 (ddd, J
= 8.2, 6.5, 1.1 Hz, 1 H, C5′H), 7.05 (t, J = 7.0 Hz, 1 H, C7H), 7.14–7.17
(m, 2 H, C4′H, C6′H), 7.34 (dd, J = 6.5, 3.0 Hz, 1 H, C3′H), 7.38 (ddd, J
= 8.2, 7.0, 1.5 Hz, 1 H, C8H), 7.95 (s, 1H, NH, Amid), 8.20 (dd, J = 7.0,
1.5 Hz, 1 H, C6H); 13C NMR: δ 47.3, 58.0, 118.4, 119.1, 119.9, 126.6,
127.0, 127.9, 129.4, 132.9, 133.5, 134.3, 135.1, 144.8, 167.6, 173.5. Anal.
calcd for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31; found: C, 63.82; H,
4.28; N, 9.18%.
Conclusion
In conclusion, we have developed a facile heterogeneous
base catalyst for a simple and highly efficient green protocol
for the synthesis of potential pharmaceutically active
1,4-benzodiazepine-2,5-diones derivatives. The advantages
of this work are its green procedure, simple workup and good
yields, which make it one of the most convenient methods for
the synthesis of this class of heterocycles.
Experimental
Melting points were taken on a Kofler hot stage apparatus and are
uncorrected. NMR spectra were obtained on a Bruker FT-500
spectrometer (1H NMR at 500 Hz, 13C NMR at 125 Hz) in CDCl3 using
TMS as internal standard. Chemical shifts (δ) are given in ppm and
coupling constants (J) in Hz. The IR spectra were obtained in the range
of 400–4000 cm–1 on a Shimadzu FTIR-8400S spectrophotometer. All
reagents and solvents were obtained from Merck or Aldrich and used
without any purification. Silica gel 60 (0.040-0.063 mm) was used for
4-Phenyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (5d):
White needles; m.p. 133–136 oC (EtOH); IR (KBR): 3470 (NH), 1691

288 JOURNAL OF CHEMICAL RESEARCH 2015
(C=O), 1645 (C=O) cm-1; 1H NMR: δ 4.53 (s, 2 H, C3H), 5.13 (d, J =
15.7 Hz, 1 H, NCH2), 6.77 (d, J = 8.1 Hz, 1 H, C9H), 6.89 (t, J = 7.5 Hz,
1 H, C7H), 6.98–7.00 (m, 1 H, C4′H), 7.06–7.11 (m, 2 H, C2′H, C6′H),
7.29–7.39 (m, 3 H, C8H, C3′H, C5′H), 8.11 (d, J = 7.5 Hz, 1 H, C6H);
13C NMR: δ 61.2, 118.1, 119.0, 119.6, 126.5, 126.8, 127.7, 129.2, 132.6,
133.2, 134.2, 134.9, 144.7, 167.5, 173.7. Anal. calcd for C15H12N2O2: C,
71.42; H, 4.79; N, 11.10; found: C, 71.60; H, 4.93; N, 10.96%.
Support of this investigation by a grant from the Islamic Azad
University Tehran South Branch is gratefully acknowledged.
Received 26 December 2015; accepted 30 April 2015
Paper 1403107 doi: 10.3184/174751915X14304939994023
Published online: 08 May 2015
4-(4-Methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione (5e): White powder; m.p. 120–122 C (EtOH); IR (KBr): 3329
References
o
(NH), 1694 (C=O), 1649 (C=O) cm-1; 1H NMR: δ 3.76 (s, 3 H, OCH3),
4.43 (s, 2 H, C3H), 5.14 (s, 2H, NCH2), 6.71 (d, J = 7.3 Hz, 1 H, C9H),
6.81 (d, J = 8.6 Hz, 2 H, C3′H, C5′H), 6.90 (t, J = 7.3 Hz, 1H, C7H),
7.32 (dt, J = 7.3, 1.5 Hz, 1 H, C8H), 7.36 (d, J = 8.6 Hz, 2 H, C2′H,
C6′H), 7.90 (s, 1H, NH, Amid), 8.19 (dd, J = 7.3, 1.5 Hz, 1 H, C6H);
13C NMR: δ 48.7, 55.1, 60.9, 113.5, 118.3, 118.8, 119.3, 129.8, 130.2,
133.2, 134.0, 144.3, 158.5, 167.7, 173.1. Anal. calcd for C17H16N2O3: C,
68.91; H, 5.44; N, 9.45; found: C, 68.75; H, 5.36; N, 9.35%.
1
O. Sharma, R. K. Singla and B. Shrivastava, Indo Glob. J. Pharm. Sci.,
2012, 2, 142.
2
3
4
L. Costantino and D. Barlocco, Curr. Med. Chem., 2006, 13, 65.
U. Rudolph and H. Möhler, Curr. Opin. Pharmacol., 2006, 6, 18.
H. K. Koblish, S. Zhao, C. F. Franks, R. R. Donatelli, R. M. Tominovich,
L. V. LaFrance, K. A. Leonard, J. M. Gushue, D. J. Parks and R. R. Calvo,
Mol. Cancer. Ther., 2006, 5, 160.
5
6
D. J. Parks, L. V. LaFrance, R. R. Calvo, K. L. Milkiewicz, J. Jose Marugan,
P. Raboisson, C. Schubert, H. K. Koblish, S. Zhao and C. F. Franks, Bioorg.
Med. Chem. Lett., 2006, 16, 3310.
A. Ursini, A. M. Capelli, R. A. Carr, P. Cassara, M. Corsi, O. Curcuruto,
G. Curotto, M. Dal Cin, S. Davalli and D. Donati, J. Med. Chem., 2000,
43, 3596.
4-(4-Methoxyphenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione (5f): White needles; m.p. 128–133 oC (EtOH); IR (KBR); 3320
(NH), 1698 (C=O), 1647 (C=O) cm-1; 1H NMR: δ 3.77 (s, 3 H, OCH3),
4.42 (s, 2 H, C3H), 5.12 (s, 2 H, NCH2), 6.70 (d, J = 8.1 Hz, 1 H, C9H),
6.82 (d, J = 8.5 Hz, 2 H, C3′H, C5′H), 6.91 (t, J = 7.6 Hz, 1 H, C7H),
7.31–7.34 (m, 3 H, C8H, C2′H, C6′H), 7.94 (s, 1H, NH, Amid), 8.20
(dd, J = 7.6, 1.4 Hz, 1 H, C6H); 13C NMR: δ 24.4, 48.7, 55.1, 57.7, 113.6,
114.1, 118.4, 118.8, 119.4, 129.4, 130.2, 133.4, 134.0, 144.5, 158.5, 167.8,
173.0. Anal. calcd for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92; found: C,
68.18; H, 5.18; N, 10.04%.
4-(3,5-Dimethoxyphenethyl)-3,4-dihydro-1H-benzo[e][1,4]
diazepine-2,5-dione (5g): White powder; m.p. 133–135 oC (EtOH); IR
(KBr): 3377 (NH), 1688(C=O), 1640 (C=O) cm-1; 1H NMR: δ 2.87 (t, J
= 7.8 Hz, 2 H, NCH2CH2), 3.85 (s, 6 H, OCH3), 4.13 (t, J = 7.8 Hz, 2 H,
NCH2CH2), 4.47 (s, 2 H, C3H), 6.72–6.80 (m, 4 H, C9H, C2′H, C4′H,
C6′H), 6.90 (t, J = 7.5 Hz, 1 H, C7H), 7.32 (t, J = 7.5 Hz, 1 H, C8H),
7.96 (s, 1H, NH, Amid), 8.12 (d, J = 7.5 Hz, 1 H, C6H); 13C NMR: δ
34.1, 48.2, 55.7, 55.8, 57.8, 112.1, 118.8, 119.5, 120.7, 132.4, 133.1,
134.0, 144.4, 147.4, 148.6, 168.1, 173.2. Anal. calcd for C19H20N2O4: C,
67.05; H, 5.92; N, 8.23; found: C, 66.90; H, 5.78; N, 8.38%.
4-Propyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (5h):
White needles; m.p. 114–116 oC (EtOH); IR (KBR): 3367 (NH), 1687
(C=O), 1634 (C=O) cm-1; 1H NMR: δ 0.78 (t, J=7.5 Hz, 3H, CH3), 1.60
(m, 2H, CH2), 3.87 (t, J=8.9 Hz, 2H, NCH), 4.52(s, 2H, C3H), 6.70 (dd,
J=8.1, 1.2 Hz, 1H, C9H), 6.89 (t, J=8.2 Hz, 1H,C7H), 7.32 (t, J=8.45
Hz, 1H, C8H), 8.13 (s, 1H, NH, Amid), 8.35 (dd, J=8.4, 1.2 Hz, 1H,
C6H); 13C NMR: δ 11.3, 21.4, 48.0, 57.7, 118.4, 118.8, 119.4, 126.5,
133.2, 133.9, 144.4, 163.2, 169.1. Anal. calcd for C12H14N2O2: C, 66.04;
H, 6.47; N, 12.84; found: C, 66.18; H, 6.56; N, 12.78%.
7
8
B. K. Blackburn, A. Lee, M. Baier, B. Kohl, A. G. Olivero, R. Matamoros,
K. D. Robarge and R. S. McDowell, J. Med. Chem., 1997, 40, 717.
R. S. McDowell, B. K. Blackburn, T. R. Gadek, L. R. McGee, T. Rawson,
M. E. Reynolds, K. D. Robarge, T. C. Somers and E. D. Thorsett, J. Am.
Chem. Soc., 1994, 116, 5077.
9
C. G. Joseph, K. R. Wilson, M. S. Wood, N. B. Sorenson, D. V. Phan, Z.
Xiang, R. M. Witek and C. Haskell-Luevano, J. Med. Chem., 2008, 51,
1423.
10 A. Domling, Chem. Rev., 2006, 106, 17.
11 S. Gunawan, M. Ayaz, F. De Moliner, B. Frett, C. Kaiser, N. Patrick, Z. Xu
and C. Hulme, Tetrahedron, 2012, 68, 5606.
12 J. R. Donald, R. R. Wood and S. F. Martin, ACS Combi. Sci., 2012, 14, 135.
13 M. Mahdavi, M. Asadi, M. Saeedi, Z. Rezaei, H. Moghbel, A. Foroumadi
and A. Shafiee, Synlett., 2012, 23, 2521.
14 P. T. Anastas and J. C. Warner, Green chemistry: theory and practice.
Oxford University Press: 2000.
15 R. N. Baig, and R. S. Varma, Chem., Commun., 2013, 49, 752.
16 J. Y. Kim, J. T. Kim, E. A. Song, Y. K. Min and H. O. Hamaguchi,
Macromolecules, 2008, 41, 2886.
17 D. K. Yi, S. S. Lee and J. Y. Ying, Chem. Mater., 2006, 18, 2459.
18 P. D. Stevens, J. Fan, H. M. Gardimalla, M. Yen and Y. Gao, Org. Lett.,
2005, 7, 2085.
19 N. Zohreh, S. H. Hosseini, A. Pourjavadi and C. Bennett, RSC Adv., 2014,
4, 50047.
20 G. M. Coppola, Synthesis., 1980, 505.
21 R. H. Clark and E. Wagner, J. Org. Chem., 1944, 9, 55.
22 P. Wiklund and J. Bergman, Curr. Org. Synth., 2006, 3, 379.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.