Eco-friendly synthesis of 1,4-benzodiazepine-2,5-diones in the ionic liquid [bmim]Br

Article abstract of DOI:10.1007/s00706-008-0922-4

The green reaction of isatoic anhydrides with α-amino acids in presence of the ionic liquid 1-butyl-3-methylimidazolium bromide afforded 1,4-benzodiazepine-2,5-diones in excellent yields in absence of a catalyst. The reaction workup is simple and the ionic liquid was easily recovered from the reaction and reused. The methodology was quite general and a range of cyclic and acyclic α-amino acids were examined to produce 1,4-benzodiazepine-2,5- diones.

Full text of DOI:10.1007/s00706-008-0922-4

Monatsh Chem 139, 1229–1232 (2008)
DOI 10.1007/s00706-008-0922-4
Printed in The Netherlands
Eco-friendly synthesis of 1,4-benzodiazepine-2,5-diones in the ionic
liquid [bmim]Br
Khosrow Jadidi1, Ramin Ghahremanzadeh1, Davoud Asgari2, Parisa Eslami1, Hamid Arvin-Nezhad1
1
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
2
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Received 22 February 2008; Accepted 5 March 2008; Published online 26 June 2008
# Springer-Verlag 2008
Abstract The green reaction of isatoic anhydrides
with ꢀ-amino acids in presence of the ionic liquid
1-butyl-3-methylimidazolium bromide afforded 1,4-
benzodiazepine-2,5-diones in excellent yields in ab-
sence of a catalyst. The reaction workup is simple
and the ionic liquid was easily recovered from the
reaction and reused. The methodology was quite gen-
eral and a range of cyclic and acyclic ꢀ-amino acids
were examined to produce 1,4-benzodiazepine-2,5-
diones.
methods have been reported for the synthesis of
BZDs. However, the reported methods suffer from
many limitations, such as requiring harsh reaction
conditions, presence of strong acids as catalyst, vol-
atile and unfriendly organic solvents, long reaction
time, and low yields [7–16]. Due to the above re-
ported synthesis limitations and as a part of our on-
going research program on the study of BZDs [4], and
synthesis of heterocyclic compounds [17], we devel-
oped a simple synthesis route for producing the im-
portant class of 1,4-benzodiazepine-2,5-diones 3 by
condensation of isatoic anhydrides 1 and ꢀ-amino
acids 2 in presence of 1-butyl-3-methylimidazolium
bromide ([bmim]Br) as ionic liquid (Scheme 1).
In this methodology, environmentally unfriendly
organic solvents were replaced with environmentally
friendly, ‘‘greener’’, ionic liquids (ILs). The reac-
tions in environmentally friendly ILs have different
thermodynamic and kinetic behaviors and higher se-
lectivity or conversion have been demonstrated [18–
21]. These useful materials not only dissolve many
organic and inorganic substances, but they can also
Keywords 1,4-Benzodiazepine-2,5-diones; ꢀ-Amino acids;
Ionic liquid; Isatoic anhydride.
Introduction
A literature survey reveals the importance and valu-
able pharmacological properties of 1,4-benzodi-
azepine-2,5-diones (BZDs) in treatment of cancer,
AIDS, hypertension, inflammation, pain, muscle re-
laxation, and depression. There has been a growing
interest in ring systems, such as the pyrrole [2,1-
c][1,4]benzodiazepines (PBDs) in the area of mo-
lecular recognition [1–7]. These molecules (PBDs)
can be recognized and bind to specific sequences
of DNA; therefore, they have been known to be po-
tential antitumor and gene targeted drugs. Several
Correspondence: Khosrow Jadidi, Department of Chemistry,
Shahid Beheshti University, PO Box 1983963113, Tehran,
Iran. E-mail: k-jadidi@cc.sbu.ac.ir
Scheme 1

1230
K. Jadidi et al.
Table 1 Reactions of isatoic anhydrides 1 with ꢀ-amino acids 2 in the presence of [bmin]Br
Entry
Isatoic anh. 1
Amino
acid 2
Product 3
Time=
min
Yield=%a
Mp=ꢀC reported [Ref.]
R
X
1
2
H
Cl
45
90
87
275–278
217–219
>250
[17]
H
Cl
170
–
3
4
5
H
H
H
Cl
H
160
20
89
223–225
218–219
183–188
230–232
[17]
95 (94, 92,
93, 89)b
216–218
[13]
H
95
88
91
–
–
6
7
8
H
H
H
H
80
50
223–226
254–226
144–146
Me
Me
94
89
–
–
140
9
Me
Me
H
125
90
91
248–251
168–169
–
–
10
Cl
45
a
b
Isolated yields; Ionic liquid was used for five times

Eco-friendly synthesis of 1,4-benzodiazepine-2,5-diones
1231
be readily recycled. Using room temperature and
close to room temperature ionic liquids, in particular
those based on the 1-alkyl-3-methylimidazolium cat-
ion, have shown great promise as an attractive alter-
native to conventional solvents [22–24].
Experimental
Typical procedure for the preparation of 1-chloro-7,8,9,10-
tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepine-6,12-
(5H,6aH)-dione (3b, C13H13ClN2O2)
A mixture of 163 mg isatoic anhydride (1b) (1 mmol),
129 mg pipecolinic acid (2b) (1 mmol), and 219 mg
[bmim]Br (1mmol) was placed in a test tube and heated at
70ꢀC. After 170min, product 3b was formed (TLC) (Table 1).
The reaction mixture was cooled to room temperature,
followed by addition of water. The precipitated residue was
filtered off and was recrystallized for further purification
from ethanol to afford the pure product. White powder;
mp 217–219ꢀC; 1H NMR (300 MHz, CDCl3): ꢁ ¼ 1.41–
Results and discussion
The reaction of isatoic anhydrides 1 with ꢀ-amino
acids 2 in the presence of [bmim]X (X ¼ Br, PF6,
BF4), afforded 1,4-benodiazepine-2,5-diones (BZDs)
3 in high yields. The best results were obtained when
[bmim]Br was used at 70ꢀC for 45–170 min. The
results are summarized in Table 1. The products were
obtained in mild condition and no impurities were
observed by TLC. Using simple work-up, the prod-
ucts were isolated and no further chromatographic
purification was performed since no impurities were
observed by NMR. It is worthy to note that no prod-
ucts were obtained when the reaction was run in the
presence of conventional solvents such as methanol
and DMSO instead of ionic IL. Therefore, it can be
suggested that the IL plays a role as promotor be-
sides the role of the media. In other words, the sol-
vophobic properties of the IL are able to generate an
internal pressure and promote the association of the
reactants in a solvent cavity during the activation
process and hence accelerate the reaction. This prop-
erty of the ILs is very efficient for the preparation of
the product 3 in which the entropy of reaction is
decreased in the transition state. New and known
BZDs 3 obtained by this method were completely char-
acterized by IR, mass, 1H, and 13C NMR analyses.
Recovery and reusability of [bmim]Br was another
advantage of using ILs as solvents. To check the
reusability of the IL, a model reaction of isatoic
anhydride and ꢀ-amino acids in [bmim]Br (entry
4, Table 1) was executed. The reaction was run at
70ꢀC for 45 min, and after completing the reaction,
the mixture was washed with water. Water was evap-
orated and the recycled IL was washed with diethyl
ether for further purification and reused for the next
reaction. Its activity did not show any significant
decrease even after four runs.
3
1.78 (m, 6H), 1.98 (d, JHH ¼ 13.2 Hz, 1H), 2.64 (t,
3JHH ¼ 13.1 Hz, 1H), 4.28 (m, 1H), 7.05 (d, JHH
¼
¼
3
3
3
7.9 Hz, 1H), 7.29 (d, JHH ¼ 7.5 Hz, 1H), 7.41 (t, JHH
7.9 Hz, 1H), 10.44 (s, 1H) ppm; 13C NMR (75 MHz,
CDCl3): ꢁ ¼ 19.8, 23.3, 23.5, 40.6, 50.6 (N–CH), 119.9,
126.3, 126.5, 131.8, 133.1, 139.1, 165.9, 171.7 ppm; IR
(KBr): ꢂꢀ¼ 3477, 1706, 1639cmꢁ1; MS (70 eV): m=z (%) ¼
265 (Mþ, 36), 235 (75), 207 (26), 180 (55), 153 (41), 126 (55),
84 (100), 55 (55).
7,8,9,10-Tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepine-
6,12(5H,6aH)-dione (3e, C13H14N2O2)
White powder; mp 183–188ꢀC; 1H NMR (300MHz, CDCl3):
3
ꢁ ¼ 1.59–1.76 (m, 5H), 2.25 (d, JHH ¼ 13.5 Hz, 1H), 3.01
3
(m, 1H), 4.18 (m, 1H), 4.55 (d, JHH ¼ 13.7Hz, 1H), 6.99
3
3
(d, JHH ¼ 7.99 Hz, 1H), 7.28 (t, JHH ¼ 8.6 Hz, 1H), 7.47 (t,
3JHH ¼ 7.46Hz, 1H), 7.95 (d, JHH ¼ 7.6 Hz, 1H), 8.49 (s,
3
1H) ppm; 13C NMR (75 MHz, CDCl3): ꢁ ¼ 19.2, 22.8, 23.2,
40.4, 51.1, 120.4, 125.1, 127.6, 131.2, 132.1, 135.9, 168.6,
170.2ppm; IR (KBr): ꢂꢀ¼ 3415, 1678, 1647 cmꢁ1; MS
(70 eV): m=z (%) ¼ 230 (Mþ, 76), 201 (95), 173 (43), 146
(85), 119 (66), 84 (100), 55 (52).
4-Methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione
(3f, C10H10N2O2)
White powder; mp 223–226ꢀC; 1H NMR (300MHz, CDCl3):
3
ꢁ ¼ 3.31 (s, 3H), 3.92 (s, 2H), 7.023 (d, JHH ¼ 8.02 Hz, 1H),
3
3
7.29 (t, JHH ¼ 7.61 Hz, 1H), 7.49 (t, JHH ¼ 7.65 Hz, 1H),
3
7.98 (d, JHH ¼ 7.8 Hz, 1H), 8.61 (s, 1H) ppm; 13C NMR
(75 MHz, CDCl3): ꢁ ¼ 36.5 (N–CH3), 52.5 (CH2), 120.5,
125.3, 126.6, 131.7, 132.5, 135.6, 167.2, 170.2 ppm; IR
(KBr): ꢂꢀ¼ 3211, 1697, 1636 cmꢁ1; MS (70 eV): m=z (%) ¼
190 (Mþ, 70), 161 (75), 119 (83), 90 (70), 63 (39), 44 (100).
10-Methyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]-
diazepine-5,11-(10H,11aH)-dione (3g, C13H14N2O2)
White powder; mp 254–258ꢀC; 1H NMR (300MHz, CDCl3):
ꢁ ¼ 2.02–2.13 (m, 3H), 2.75 (m, 1H), 3.41 (s, 3H), 3.57 (m,
In conclusion, we developed a simple, efficient,
and green methodology for the synthesis of 1,4-ben-
zodiazepine-2,5-diones using [bmim]Br. The simple
experimental procedure and utilization of an inex-
pensive and reusable catalyst with excellent yields
are the advantages of the present method.
3
1H), 3.83 (m, 1H), 4.06 (d, JHH ¼ 5.46Hz, 1H), 7.22 (d,
3JHH ¼ 8.14Hz, 1H), 7.31 (t, JHH ¼ 7.37Hz, 1H), 7.53 (t,
3
3JHH ¼ 7.5 Hz, 1H), 7.93 (d, JHH ¼ 6 Hz, 1H) ppm; 13C
3
NMR (75 MHz, CDCl3): ꢁ ¼ 21.7, 22.2, 34.0, 44.7, 55.1,
119.6, 123.5, 127.7, 128.1, 130.0, 138.6, 163.2, 167.9 ppm;

1232
K. Jadidi et al.
IR (KBr): ꢂꢀ¼ 1664, 1631 cmꢁ1; MS (70eV): m=z (%) ¼ 230
References
(Mþ, 55), 201 (20), 161 (61), 133 (71), 105 (83), 70 (100), 41 (61).
1. Cho NS, Song Y, Parkanyi C (1989) J Heterocycl Chem
26:1807
2. Thurston DE, Bose DS (1994) Chem Rev 94:433
3. Tucker HD, Lecount J (1996) In: Katritzky AR, Scriven
EF (eds) Comprehensive Heterocyclic Chemistry, vol 9.
Pergmon Press, New York, p 151
5-Methyl-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]-
diazepine-6,12-(5H,6aH)dione (3h, C14H16N2O2)
White powder; mp 144–146ꢀC. 1H NMR (300MHz, CDCl3):
ꢁ ¼ 1.53–1.73 (m, 3H), 1.83–1.87 (m, 1H), 1.98–2.02 (m,
1H), 2.19–2.23 (m, 1H), 2.94–2.98 (m, 1H), 3.38 (s, 3H),
4. Jadidi K, Aryan R, Mehrdad M, Lugger T, Hahn FE, Ng
SW (2004) J Mol Struc 692:37
3
4.17–4.20 (m, 1H), 4.52 (d, JHH ¼ 13.61 Hz, 1H), 7.18 (d,
3
3JHH ¼ 8.20 Hz, 1H), 7.28 (t, JHH ¼ 7.08 Hz, 1H), 7.50 (t,
5. Baraldi PG, Balboni G, Cacciari B, Guiotto A,
Manfredini S, Romagnoli R, Spalluto G, Thurston DE,
Howard PW, Bianchi N, Rutigliano C, Mischiati C,
Gambari R (1999) J Med Chem 42:5131
6. Jones GB, Davey CL, Jenkins TC, Kamal A, Kneale GG,
Neidle S, Webster GD, Thurston DE (1990) Anti-cancer
Drug Des 5:249
3JHH ¼ 7.97 Hz, 1H), 7.84 (d, 3JHH ¼ 7.47 Hz, 1H) ppm; 13
C
NMR (75 MHz, CDCl3): ꢁ ¼ 19.2, 23.2, 23.4, 34.5, 34.7,
51.1, 120.6, 125.5, 129.5, 130.2, 131.8, 140.9, 168.54,
170.32 ppm; IR (KBr): ꢂꢀ¼ 1673, 1634 cmꢁ1; MS (70 eV):
m=z (%) ¼ 245 (Mþ, 30), 161 (29), 133 (29), 104 (38), 84
(100), 55 (24).
7. Mohiuddin G, Keddy PS, Ahmed K, Ratnam CV (1986)
Heterocycles 24:3489
8. Wright WB (1976) US Pat 3947408; (1976) Chem Abstr
85:46771
9. Mori M, Kiura M, Uozumi Y, Ban Y (1985) Tetrahedron
Lett 26:5947
10. Keating TA, Armstrong RW (1996) J Org Chem 61:8935
11. Mohiuddin G, Neddy PSN, Ahmed K, Ratanam CV
(1985) Indian J Chem 24B:905
12. Akssira M, Boumzebra M, Kasmi H, Dahdouh A (1993)
Synth Commun 23:2265
13. Akssira M, Boumzebra M, Kasmi H, Dahdouh A (1994)
Tetrahedron 50:9051
1,4-Dimethyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione (3i, C11H12N2O2)
White powder; mp 248–251ꢀC; 1H NMR (300 MHz, CDCl3):
3
ꢁ ¼ 3.09 (s, 3H), 2.28 (s, 3H), 3.69 (d, JHH ¼ 14.77 Hz, 1H),
3
3
4.03 (d, JHH ¼ 14.9 Hz, 1H), 7.30 (t, JHH ¼ 7.16 Hz, 1H),
3
3
7.40 (d, JHH ¼ 7.97 Hz, 1H), 7.39 (t, JHH ¼ 7.39 Hz, 1H),
7.68 (d, JHH ¼ 7.54Hz, 1H) ppm; 13C NMR (75 MHz,
3
CDCl3): ꢁ ¼ 35.2, 52.3, 57.6, 121.3, 125.0, 128.3, 129.9, 131.8,
140.8, 166.3, 168.4 ppm; IR (KBr): ꢂꢀ¼ 1676, 1642 cmꢁ1
;
MS (70 eV): m=z (%) ¼ 205 (Mþ, 98), 175 (76), 161 (40), 133
(52), 105 (100), 77 (43), 42 (90).
6-Chloro-10-methyl-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a]-
[1,4]diazepine-5,11 (10H,11aH)-dione (3j, C13H13ClN2O2)
White powder; mp 168–169ꢀC; 1H NMR (300 MHz, CDCl3):
14. Kamal A, Reddy BSN, Reddy GSK (1999) Synlett:1251
15. Kamal A, Laxman E, Arifuddin M (2000) Tetrahedron
Lett 41:7743
16. Fabienne HE, WO 2000 069835
ꢁ ¼ 2.05–2.08 (m, 3H), 2.71 (m, 1H), 3.38 (s, 3H), 3.54–3.58
3
17. Jadidi K, Gharemanzadeh R, Mehrdad M, Darabi HR,
Khavasi HR, Asgari D (2008) Ultrason Sonochem 15:124
18. Holbrey JD, Seddon KR (1999) Clean Products Processes
1:223
19. Elare MJ, Seddon KR (2000) Pure Appl Chem 72:1391
20. Welton T (1999) Chem Rev 99:2071
21. Wasserschied P, Kiem M (2000) Angew Chem Int Ed
39:3772
(m, 1H), 3.88 (m, 1H), 4.09–4.12 (m, 1H), 7.14 (d, JHH
¼
7.0 Hz, 1H), 7.37–7.42 (m, 2H) ppm; 13C NMR (75 MHz,
CDCl3): ꢁ ¼ 23.4, 26.5, 36.0, 45.8, 57.4 (NCH3), 120.2,
128.1, 128.8, 131.0, 133.7, 141.9, 162.0, 170.4 ppm; IR
(KBr): ꢂꢀ¼ 1682, 1649 cmꢁ1; MS (70 eV): m=z (%) ¼ 265
(Mþ, 75), 195 (33), 180 (29), 167 (55), 139 (41), 112 (14),
70 (100), 41 (30).
22. Olivier-Bourbigou H, Magna L (2002) J Mol Catal A
182:419
23. Wilks JS (2004) J Mol Catal A 214:11
24. Jain N, Kumar A, Chauhan S, Chauhan SMS (2005)
Tetrahedron 61:1015
Acknowledgements
We gratefully acknowledge the financial support from the
Research Council of Shahid Beheshti University.