Improved method for microwave-assisted synthesis of benzodiazepine-2,5-diones from isatoic anhydrides mediated by glacial acetic acid

Article abstract of DOI:10.21577/0103-5053.20180031

An improved and simpler method for the synthesis of benzodiazepin-2,5-diones and 7-iodobenzodiazepin-2,5-diones catalyzed by glacial acetic acid using isatoic anhydride and 6-iodoisatoic anhydride, respectively, as starting materials is reported. The target products were achieved in good yields (up to 71percent) using microwave irradiation as the activating mode of reaction in the presence of acetic acid instead of the traditional polar aprotic solvents as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or dimethylacetamide (DMAC). Moreover, relatively simple purification workup is required. The optimal temperature to obtain the benzodiazepin-2,5-dione derivatives was 130 °C, while the best irradiation time was 3 min. In addition, the methodology for the selective preparation of 6-iodoisatoic anhydride with an overall yield of 62percent is presented. Printed in Brazil-

Full text of DOI:10.21577/0103-5053.20180031

http://dx.doi.org/10.21577/0103-5053.20180031
J. Braz. Chem. Soc., Vol. 29, No. 8, 1607-1611, 2018
Printed in Brazil - ©2018 Sociedade Brasileira de Química
Article
Improved Method for Microwave-Assisted Synthesis of Benzodiazepine-2,5-diones
from Isatoic Anhydrides Mediated by Glacial Acetic Acid
Armando De La Cruz,a Carlos Alejandro Vega-Acevedo,a Ignacio A. Rivero*,a and
Daniel Chávez*,a
aCentro de Graduados e Investigación, Instituto Tecnológico de Tijuana, Apartado Postal 1166,
22000 Tijuana, BC, México
An improved and simpler method for the synthesis of benzodiazepin-2,5-diones and
7-iodobenzodiazepin-2,5-diones catalyzed by glacial acetic acid using isatoic anhydride and
6-iodoisatoic anhydride, respectively, as starting materials is reported. The target products were
achieved in good yields (up to 71%) using microwave irradiation as the activating mode of reaction
in the presence of acetic acid instead of the traditional polar aprotic solvents as dimethylformamide
(DMF), dimethyl sulfoxide (DMSO) or dimethylacetamide (DMAC). Moreover, relatively simple
purification workup is required. The optimal temperature to obtain the benzodiazepin-2,5-dione
derivatives was 130 °C, while the best irradiation time was 3 min. In addition, the methodology
for the selective preparation of 6-iodoisatoic anhydride with an overall yield of 62% is presented.
Keywords: benzodiazepin-2,5-diones, 7-iodobenzodiazepin-2,5-diones, microwave irradiation,
isatoic anhydride, 6-iodoisatoic anhydride
Introduction
organic compounds, using microwaves with excellent
results, such as alkylation of carboxylic acids and phenols19
and 2,4-(1H,3H)-quinazolinediones,20,21 and synthesis of
hydropyridines.22
The goal of this study is to improve yields on the
synthesis of benzodiazepin-2,5-dione derivatives with
either isatoic (1) anhydride or 6-iodoisatoic anhydride (2)
as starting materials, and their condensation with α-amino
acids using microwave irradiation as activating mode and
acetic acid as a polar protic solvent, as shown in Scheme 1.
Benzodiazepines constitute an important class of
biologically active compounds that have been studied
in recent years.1 Some members of this class have been
identified as platelet aggregation inhibitors,2 anticonvulsant
agents,3 antitumor compounds4 and anxiolytic compounds.5
Benzodiazepines are synthesized from a benzodiazepin-
2,5-dione precursor. Most of the synthetic methods of
benzodiazepin-2,5-dione are based almost exclusively on
the condensation of anthranilic acid and an amino acid or
its derivatives, and several alkylating agents.6,7 A variation
of this method is the use of isatoic anhydride (1) instead
of anthranilic acid with very similar results.8-11
Experimental
General procedures
Benzodiazepin-2,5-dione have been synthesized using
solid phase approach, however, this method has some
limitations; for example, the alkylation on the nitrogen of an
amide reduces the number of alkylating agents available.12-17
The use of microwave irradiation as activating mode for the
synthesis of organic compounds18 has increased considerably
in recent times. It reduces reaction times considerably, the
reactions are cleaner and the purification workup is simpler.
In our research group, we have synthesized a variety of
Thin-layer chromatography (TLC) was performed
on silica gel F254 plates (Merck). All compounds were
detected using UV light. Melting points were obtained on an
Electrothermal 88629 apparatus and are uncorrected. Infrared
spectra (IR) were recorded on a PerkinElmer FT-IR 1600
spectrophotometer. 1H and 13C nuclear magnetic resonance
(NMR) spectra were obtained on either a Varian Mercury
200 MHz Spectrometer at 200 and 50 MHz, respectively,
or a Bruker Avance III spectrometer at 400 and 100 MHz,
1
*e-mail: irivero@tectijuana.mx; dchavez@tectijuana.mx
respectively. H and 13C NMR spectra were recorded in

1608
Improved Method for Microwave-Assisted Synthesis of Benzodiazepine-2,5-diones
J. Braz. Chem. Soc.
Scheme 1. Synthesis of benzodiazepin-2,5-dione derivatives.
CDCl3, DMSO-d6 or CD3OD with tetramethylsilane (TMS)
as internal standard. Mass spectra were obtained on an
Agilent Technologies 5975C MS Spectrometer at 70 eV by
direct insertion. Optical rotations were determined using
a Rudolph Research Analytical automatic polarimeter.
Microwave equipment was a self-tuning single mode CEM
DiscoverTM Focused Synthesizer.
Results and Discussion
The synthesis of benzodiazepin-2,5-dione derivatives
was carried out using microwave irradiation as the activating
mode of reaction, employing isatoic anhydride (1) and six
α-amino acids with a hydrophobic side chain as glycine,
alanine, proline, phenylalanine, leucine and valine, as
starting materials, to afford compounds 3-8, respectively
(Figure 1). In order to improve the yield of the reaction,
we evaluate different microwave irradiating times and
different heating temperatures, as well as the use of glacial
acetic acid, as a protic solvent, instead of the traditional
dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or
dimethylacetamide (DMAC), or 2-methoxyethanol. The use
of these non-protic solvents have been reported previously
in the condensation of acyclic α-amino acids with isatoic
anhydride, resulting in low yields (up to 25%).10
The condensation of isatoic anhydride (1) and α-amino
acids was evaluated considering four different times (1,
3, 5, and 7 min) and five temperatures (90, 110, 130, 150
and 170 °C) (Table 1). After irradiation, treatment of each
reaction mixture consisted in allowing the reaction to cool
to room temperature with formation of a precipitate. The
precipitate was filtered, washed three times with hot water,
dried under vacuum and then analyzed by TLC and gas
chromatography-mass spectrometry (GC-MS).
When irradiation time was only 1 min, unreacted
isatoic anhydride (1) was detected on all runs. Similar
results were obtained at 90 and 110 °C. Condensation of
isatoic anhydride (1) with the α-amino acids at 150 and
170 °C and longer times than 3 min, resulted mainly in
formation of the open dimer and trimer from the isatoic
anhydride (1). Therefore, the optimal temperature to obtain
the products 3-8 was 130 °C, while the best irradiation time
was 3 min (Table 1). We also try, under the same conditions,
condensation of isatoic anhydride (1) and two charged
α-amino acids, lysine and aspartic acid, but benzodiazepin-
General method for preparing benzodiazepine-2,5-diones
(3-14)
In a microwave vial with a capacity of 10 mL, it was
mixed isatoic anhydride (1) or 6-iodoisatoic anhydride (2)
(10 mmol), the corresponding α-amino acid (10 mmol) and
3 mL of glacial. The reaction was carried out at 130 °C for
3 min. After irradiation, the reaction mixture was cooled
to room temperature forming a precipitate, which was
filtered, washed three times with hot water and filtered
under vacuum to give the products 3-14 as solids. The
percentage recoveries were between 61-71%.
Procedure for the synthesis of 6-iodoisatoic anhydride (1)
Methyl anthranilate (15) (2.0 g, 13.2 mmol), granulated
iodine (3.36 g, 13.2 mmol) and hydrogen peroxide-urea
(1.24 g, 13.2 mmol), were dissolved in 20 mL of ethyl
acetate. The reaction mixture was stirred for 1.5 h at room
temperature and then washed with sodium thiosulfate
(3 × 10 mL) and water (3 × 10 mL); then solvent was
evaporated under reduced pressure to afford methyl
2-amino-5-iodobenzoate (16) as a brown solid (3.33 g,
yield 91%). The solid was hydrolyzed using NaOH/MeOH
(5%) to give 2-amino-5-iodobenzoic acid (17) (2.81 g, yield
89%). Finally, the acid was cyclized with triphosgene and
triethylamine as base affording 6-iodoisatoic anhydride
(6-iodo-1H-benzo[d][1,3]oxazine-2,4-dione, 2) with a
76% yield (2.34 g).

Vol. 29, No. 8, 2018
De La Cruz et al.
1609
Figure 1. Structures of benzodiazepin-2,5-diones (3-14).
Table 1. Conditions used for obtaining benzodiazepin-2,5-diones 3-8, and yields
Condition, yield / %
Reaction time / min
90 °C
ND
110 °C
ND
130 °C
ND
150 °C
< 10%
170 °C
< 10%
1
3
< 10%
< 10%
61-71%
< 20%
ND
dimer + trimer
dimer + trimer
5
7
< 10%
< 10%
< 10%
< 10%
< 20%
dimer + trimer
ND
ND
dimer + trimer
dimer + trimer
ND
ND
ND
dimer + trimer
dimer + trimer
dimer + trimer
ND: benzodiazepin-2,5-diones not detected; dimer: 2-(2-aminobenzamido)benzoic acid; trimer: 2-(2-(2-aminobenzamido)benzamido)benzoic acid.
2,5-diones were not obtained, instead only open dimer and
trimer from the isatoic anhydride were detected.
In order to use the previous methodology, it was
necessary to synthesize 6-iodoisatoic anhydride (2).
Using 2-aminobenzoic acid and hydrogen peroxide-urea
led to no product formation. However, when methyl
anthranilate (15) was used, methyl 2-amino-5-iodobenzoate
(16) was obtained, with a 91% yield. Basic hydrolysis gave
2-amino-5-iodobenzoic acid (17) and finally cyclization
with triphosgene bis(trichloromethyl) carbonate (BTC)
afforded 6-iodoisatoic anhydride (2) with an overall yield
of 62% (Scheme 2).
Following the same procedure as for 3-8 (130 °C,
3 min), condensation of 6-iodoisatoic anhydride (2) and
the six α-amino acids, using glacial acetic acid, lead to the
7-iodobenzodiazepin-2,5-diones 9-14, with similar yields
(65 to 70%), and simple purification workup.
Optical rotation obtained from products 4-8 and 10-14
indicated that no isomerization on the chiral center coming
from α-amino acids via enol-form occurred. Thus, the
proposed method to obtain benzodiazepin-2,5-diones 3-8
and 7-iodobenzodiazepin-2,5-diones 9-14, mediated by
glacial acetic acid and using microwave irradiation, shows
a good improvement to the traditional use of DMSO as
The synthesis of benzodiazepin-2,5-diones 3-8 was
achieved with good yields (61 to 71%), with very simple
purification procedures. Benzodiazepin-2,5-diones 3-8 were
identified by comparison of IR, NMR, and electron impact
mass spectrometry (EIMS) data with those published in
the literature.9-11,15,23 As mentioned above, benzodiazepines
participate in important biological activities, and analogues
with groups, such as iodine in the aromatic system would
modify the structure and, consequently, their properties will
be affected. Preparation of new molecules with improved
properties is of current importance. Therefore, including
halides in the aromatic system, in particular iodine, results
in very important intermediates for the synthesis of more
complicated molecules, since it allows a wide range of
reactions such as Sonogashira,24 Suzuki,25 Stille,26 Heck,27
Hiyama,28 Negishi,29 etc. Preparation of compounds with
groups such as iodine are of a high synthetic value and a
wide variety of reactions can be performed. Therefore, the
synthesis of 7-iodobenzodiazepin-2,5-diones derivatives
was proposed.

1610
Improved Method for Microwave-Assisted Synthesis of Benzodiazepine-2,5-diones
J. Braz. Chem. Soc.
Scheme 2. Synthesis of 6-iodoisatoic anhydride (2).
solvent. Comparison of yields published by Jadidi et al.10 on
obtaining benzodiazepin-2,5-diones 3, 4, 6 and 7, showed
that irradiation at 130 °C for 3 min results in better yields
than irradiation at full power (600 W) for 7 min (Table 2).
Also, the corresponding 7-iodobenzodiazepin-2,5-diones
9, 10, 11 and 13, were obtained with good yields.
Scheme 3. Feasible formation of mixed anhydride.
Table 2. Comparison of yields using DMSO orACOH in the condensation
of acyclic α-amino acids with isatoic anhydride
Conclusions
We are presenting an easy, efficient and improved
method to obtain benzodiazepin-2,5-diones and
7-iodobenzodiazepin-2,5-diones, catalyzed by glacial
acetic acid, using microwave irradiation as the activating
mode of reaction. The synthesis is carried out with
inexpensive reagents and short reaction times compared
to traditional methods. Purification required washing the
reaction mixture with hot water and dried in vacuo. This
method provides good yields, up to 71%, on the preparation
of benzodiazepin-2,5-dione derivatives which may be
attributed to the use of acetic acid as solvent, possibly
forming a mixed anhydride which is a more reactive
intermediate.
Compound
Yielda / %
Yieldb / % Compound Yielda / %
3
4
5
6
7
8
62
65
np
71
69
np
20
25
68
15
20
61
9
68
70
69
65
70
69
10
11
12
13
14
aAcOH, 130 °C, 3 min; bDMSO, 600 W, 7 min, obtained from the
publication.10 np: data not published in reference 10.
Thegoodyieldsobtained(upto71%)onthecondensation
of isatoic anhydride (1) or 6-iodoisatoic anhydride (2) with
α-amino acids, via microwave irradiation, were achieved
when glacial acetic acid was used as a solvent. It is clear
that the role of acetic acid is not only as a solvent, but
facilitates the reaction, perhaps forming a more reactive
intermediate, like a mixed anhydride.
The methodology for the selective synthesis of
6-iodoisatoic anhydride (2) with a global yield of 62% is
also presented.
Supplementary Information
In order to support this proposal with experimental
evidence, in a microwave vial it was added isatoic
anhydride (1) and glacial acetic acid and irradiated at
130 °C for 3 min. After the mixture was cooled, the NMR
spectra were obtained. In addition to the signals for the
isatoic anhydride and acetic acid, a new set of NMR signals
were detected, at dH 8.53 (d, J 7.6 Hz, H-3), 8.00 (dd, J 7.9,
1.6 Hz, H-6), 7.55 (ddd, J 7.9, 7.6, 1.6 Hz, H-5), 8.53 (ddd,
J 7.6, 7.6, 1.3 Hz, H-4), 2.16 (s, CH3) and dC 170.9 (C=O),
169.9 (C=O), 142.4 (C-2), 135.2 (C-4), 132.4 (C-6), 123.6
(C-5), 121.0 (C-3), 117.3 (C-1), 26.0 (CH3), which can be
attributed to the acetic 2-aminobenzoic anhydride (18).
Therefore, when glacial acetic acid is used, the mixed
anhydride 18 is formed (Scheme 3), which is a more
reactive intermediate, increasing yields in the condensation
of acyclic α-amino acids with isatoic anhydride.
Supplementary information (spectroscopic data,
1H NMR and 13C NMR spectra and mass spectra (EI)) is
available free of charge at http://jbcs.sbq.org.br as PDF file.
Acknowledgments
We gratefully acknowledge support for this project by
Consejo Nacional de Ciencia y Tecnología (CONACyT,
grant No. SEP-2004-CO1-47835 and CB 2010-155029-B)
and Dirección General de Educación Superior Tecnológica
(DGEST). We are grateful to Dr Gabriela Huelgas-
Saavedra, Departamento de Ciencias Químico-Biológicas
de la Universidad de las Américas Puebla, for obtaining
optical rotations. A. D. L. C. also acknowledges Consejo
Nacional de Ciencia y Tecnología (CONACyT) for graduate

Vol. 29, No. 8, 2018
De La Cruz et al.
1611
scholarship. We thank CONACyT for ITT NMR facilities
(grants INFR-2011-3-173395).
14. Moroder, L.; Lutz, J.; Grams, F.; Rudolph-Bohner, S.; Osapay,
G.; Goodman, M.; Kolbeck, W.; Biopolymers 1996, 38, 295.
15. Boojamra, C.; Burow, K.; Thompson, L.; Ellman, J.; J. Org.
Chem. 1997, 62, 1240.
References
16. Kamal,A.; Kumar, G.; Raghavan, S.; Bioorg. Med. Chem. Lett.
2001, 11, 387.
1. Keating, T.A.;Armstrong, R. W.; J. Org. Chem. 1996, 61, 8935.
2. McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L.
R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T.
C.; Thorsett, E. D.; Tischler, M.; Webb II, R. R.; Venuti, M. C.;
J. Am. Chem. Soc. 1994, 116, 5077.
17. Kamal, A.; Kumar, G.; Laxma, K.; Tetrahedron Lett. 2001, 42,
6969.
18. Santagada,V.; Perissutti, E.; Fiorino, F.;Vivenzio, B.; Caliendo,
G.; Tetrahedron Lett. 2001, 42, 2397.
3. Osman, A. N.; El-Gendy, A. A.; Osmar, R. H.; Wagdy, L.;
Osmar, A. H.; Indian J. Chem. 2002, 41B, 871.
4. Jones, G. B.; Davey, C. L.; Jenkins, T. C.; Kamal, A.; Kneale,
G. G.; Neidle, S.; Webster, G. D.; Thurston, D. E.; Anti-Cancer
Drug Des. 1990, 5, 248.
19. Guerrero, L.; Rivero, I. A.; Arkivoc 2008, xi, 295.
20. Rivero, I. A.; Guerrero, L.; Espinoza, K. A.; Meza, M. C.;
Rodríguez, J. R.; Molecules 2009, 14, 1860.
21. Guerrero, L.; Rivero, I. A.; J. Mex. Chem. Soc. 2012, 56, 201.
22. Montes-Ávila, J.; Delgado-Vargas, F.; Díaz-Camacho, S. P.;
Rivero, I. A.; RSC Adv. 2012, 2, 1827.
5. Wright Jr., W. B.; Brabander, H. J.; Greenblatt, E. N.; Day, I.
P.; Hardy Jr., R. A.; Med. Chem. 1978, 21, 1087.
6. Uskokovíc, M.; Iacobelli, J.; Wenner, W.; J. Org. Chem. 1962,
27, 3606.
23. Mohiuddin, G.; Reddy, P. S. N.; Ahmed, K.; Ratnam, C. V.;
Indian J. Chem. 1985, 24B, 905.
24. Sonogashira, K.; Tohda, Y.; Hagihara, N.; Tetrahedron Lett.
1975, 16, 4467.
7. Liu, A.; Zhou, H.; Su, G.; Zhang, W.;Yan, B.; J. Comb. Chem.
2009, 11, 1083.
25. Han, J.; Liu, Y.; Guo, R.; J. Am. Chem. Soc. 2009, 131, 2060.
26. Huang, C.-W.; Shanmugasundaram, M.; Chang, H.-M.; Cheng,
C.-H.; Tetrahedron 2003, 59, 3635.
8. Takahashi, M.; Onizawa, S.; Shioda, R.; Nippon Kagaku Kaishi
1972, 7, 1259.
9. Jadidi, K.; Ghahremanzadeh, R.;Asgari, D.; Eslami, P.;Arvin-
Nezhad, H.; Monatsh. Chem. 2008, 139, 1229.
10. Jadidi, K.;Aryan, R.; Mehrdad, M.; Lugger, T.; Hahn, E.;Weng,
S.; J. Mol. Struct. 2004, 692, 37.
27. Karimi, B.; Enders, D.; Org. Lett. 2006, 8, 1237.
28. Monguchi, Y.;Yanase, T.; Mori, S.; Sajiki, H.; Synthesis 2013,
45, 40.
29. Liu, J.; Deng,Y.; Wang, H.; Zhang, H.;Yu, G.; Wu, B.; Zhang,
H.; Li, Q.; Marder, T. B.;Yang, Z.; Lei, A.; Org. Lett. 2008, 10,
2661.
11. Nain, S.; Arya, M.; Gupta, V.; Sirohi, R.; Kishore, D.; Int. J.
Chem. Sci. 2009, 7, 1255.
12. Boojamra, C. G.; Burow, K. M.; Ellman, J. A.; J. Org. Chem.
1995, 60, 5742.
Submitted: November 9, 2017
13. Goff, D. A.; Zuckermann, R. N.; J. Org. Chem. 1995, 60, 5744.
Published online: February 26, 2018
This is an open-access article distributed under the terms of the Creative Commons Attribution License.