Microwave assisted synthesis of pyrrolo[2,1-c][1,4]benzodiazepine-5,11- diones

Article abstract of DOI:10.1055/s-1999-2812

In a simple microwave assisted and environmentally benign approach isatoic anhydride reacts readily with proline to afford pyrrolo[2, 1- c][1,4]benzodiazepines-5,11-diones under solvent-free conditions.

Full text of DOI:10.1055/s-1999-2812

LETTER
1251
Microwave Assisted Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-
diones#
Ahmed Kamal*, B. S. Narayan Reddy, G. Suresh Kumar Reddy
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax 040-7173757; E-mail: ahmedkamal@iict.ap.nic.in
Received 26 May 1999
anhydride with proline in presence of catalase has been
developed in this laboratory for the synthesis of PBD di-
lactams. Though this is performed under mild conditions
while it is not suitable for large scale preparations.5e
Abstract: In a simple microwave assisted and environmentally be-
nign approach isatoic anhydride reacts readily with proline to afford
pyrrolo[2,1-c][1,4]benzodiazepines-5,11-diones under solvent-free
conditions.
Keywords: imines, dilactams, micro wave energy and cyclocon- Recently, the use of microwave energy6 in organic synthe-
densation
sis has received much attention, in view of the mild, clean,
convenient and spontaneity of the reaction process in
comparison to the conventional solution phase reactions.
There is an increasing interest in the use of environmen-
tally benign reagents, conditions and in particular solvent-
free procedures. This trend to avoid organic solvents dur-
ing the organic reactions could lead to cleaner, efficient
and economical processes. Microwave irradiation using
commercial domestic ovens has recently been employed
to accelerate many organic reactions7 like esterification,
etherification, oxidation, hydrolysis, Claisen, Diels-Al-
der, Reformatsky, Knoevenagel and Bischler-Napieralski
reactions. The in situ generation of heat is very efficient
and can be used to significantly reduce reaction times of
numerous synthetically useful organic transformations.8
Thus microwave assisted organic synthesis as mentioned
above has several advantages over conventional process-
es. Moreover, these processes are energy efficient and
generally lead to improved isolated yields of the desired
product.
In recent years there has been considerable interest in ring
systems such as pyrrolo[2,1-c][1,4]benzodiazepines
(PBDs) that can recognize and bind to specific sequence
of DNA.1,2 These compounds have been obtained natural-
ly from streptomyces species and have been synthesised
with various structural modifications. Among the well
known methods for the synthesis of these compounds imi-
no thioether approach has been extensively employed for
the synthesis of some naturally occurring PBD imines or
their methyl ethers such as tomaymycin and chicamycin,
and as well for the structurally modified synthetic PBDs.3
In this method pyrrolo[2,1-c][1,4]benzodiazepine-5,11-
diones have been used as the intermediates. Further, these
dilactams are also precursors for the PBD cyclic second-
ary amines which have been recently employed by us for
the preparation of PBD imines through TPAP oxidation
method4 (Scheme 1).
In the present work a microwave assisted process has been
successfully developed for the synthesis of the non-cova-
lent DNA-binding agents like pyrrolo[2,1-c][1,4]benzodi-
azepine-5,11-diones (PBD dilactams). Herein, we wish to
report an improved solvent free preparation of PBD dilac-
tams employing microwave energy. In this process isatoic
anhydride and L-proline have been mixed thoroughly and
irradiated for 2-3 min with one min intervals (Scheme 2).
Scheme 1
There are mainly two methods known in the literature for
the synthesis of these PBD dilactams. Firstly, one of the
method is cyclocondensation of isatoic anhydrides with
the corresponding proline in presence of DMF at temper-
Scheme 2
0
atures ranging from 100 to 110 C. Secondly, the other
In a typical procedure, a mixture of isatoic anhydride
(0.163 g, 1.0 mmol) and L-proline (0.115 g, 1.0 mmol) is
placed in a test-tube inside the alumina bath (heat sink)
and the contents are irradiated in a microwave oven at full
method is reductive cyclization of nitro and azido proline
esters.5a-c The former method has been extensively uti-
lised in the literature.5d Based on this approach another en-
zymatic process involving condensation of isatoic
Synlett 1999, No. 8, 1251–1252 ISSN 0936-5214 © Thieme Stuttgart · New York

1252
A. Kamal et al.
LETTER
power (600 W) for 3 min (3 x 1 min) with 1 min intervals.
The reaction is monitored by TLC (ethyl acetate-hexane
6:4), and the reaction mixture is cooled to room tempera-
ture and charged on silicagel pad and eluted with ethyl ac-
etate-hexane (7:3) to afford the PBD dilactam in 87%
yield.
Acknowledgement
BSNR is thankful to UGC (New Delhi) for the award of a Senior
Research Fellowship. GSKR is thankful to CSIR (New Delhi) for
the award of a Junior Research Fellowship.
References and Notes
#IICT Communication No. 4294
Table 1. Microwave assisted cyclocondensation of isatoic anhydride
with L-proline
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In conclusion, microwave assisted synthesis of pyrro-
lo[2,1-c][1,4]-sbenzodiazepine-5,11-diones proceeds in
less than 3 min under mild, clean and efficient conditions.
This condensation reaction which affords giving quantita-
tive yields under solvent-free conditions is a practical al-
ternative approach to the earlier reported methods.
Article Identifier:
1437-2096,E;1999,0,08,1251,1252,ftx,en;L07399ST.pdf
Synlett 1999, No. 8, 1251–1252 ISSN 0936-5214 © Thieme Stuttgart · New York