[E0008]
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A Microwave and Conventional Heating Comparative Study |
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Julio A. Seijas*, M. Pilar Vázquez-Tato* and Carlos Álvarez-de-Gabriel
Received: 27 July 2001 / Uploaded 7 August 2001
Imide group is an interesting functionality, due to its wide presence in
the natural products pool and in the pharmacologically active compounds.
This has attracted our attention as a target to be prepared by microwave
irradiation. We had published a general approach to N-substituted cyclic
carboxylic imides [1],
and later we extended our studies towards non substituted cyclic imides,
thus we developed a new synthesis of thalidomide enhanced by microwave
heating [2].
Thalidomide, an old drug with a renewed interest, has two imide groups
in its structure. We carried out two microwave mediated new approaches:
a stepwise synthesis by preparing first N-phthaloyl-L-glutamic acid and
later using urea or thiourea (as the source of nitrogen) to close the glutarimide
ring (scheme 1, right) and a one step reaction (scheme 1, left) from L-glutamic
acid, phthalic anhydride and thiourea in the latter, obtaining with this
procedure thalidomide in a 60% yield with the formation of the two imides
simultaneously.
A feature that attracted very much our interest was the fact that when
urea was used instead, we obtained a lower yield of thalidomide and a considerable
amount of pyroglutamic acid. This, compared with the previous results for
the formation of imides in the only study we know on urea and thiourea [3]
resulted in a reversed reactivity.
SCHEME 1
We decided to study independently the reaction of formation of phthalimide
and glutarimide in the reaction conditions used for thalidomide, to check
if there was any marked difference between formation of phthalimide and
glutarimide rings (scheme 2) which were the responsible for the good behaviour
in the preparation of thalidomide.
SCHEME 2
Thus we studied the formation of glutarimide by heating glutaric acid with
urea and with thiourea. We found that after 15 minutes irradiation in the
(domestic) microwave oven (Electrolux; 1000W, 70%) we obtained, 90% yield
of glutarimide with urea, and 98% yield with thiourea. We also carried
out both experiments in a preheated heating mantle (160ºC) for the
same time as they were irradiated, getting a 50% yield for the reaction
with urea and a 33% when thiourea was used.
The phthalimide formation from phthalic anhydride
was studied in a similar way. The reaction with urea was irradiated for
6 minutes with a quantitative yield of phthalimide. Meanwhile, with the
heating mantle it gave just 43% yield of imide. The use of thiourea with
microwaves gave a lower yield of phthalimide (91%, and required 10 minutes
irradiation), but with the heating mantle it was slightly higher (46%)
than the conventional using urea.
Regarding to the improvement on the synthesis
by microwave of our three component reaction for thalidomide, we think
thiourea is less reactive than urea towards phthalic anhydride than urea,
which could help to lessen the formation of phthalimide as a secondary
product, and at the same time thiourea gives better yield in the formation
of glutarimide ring.
In summary, for the same reaction times, microwave
irradiation is the ideal choice for preparing non substituted cyclic imides.
The use of urea or thiourea led to similar yields.
ACKNOWLEDGEMENTS
DGES (PB96-0932) and
XUNTA DE GALICIA (PGIDT01PXI26203PR) for financial support.
REFERENCES
1.- Seijas, J. A.; Vázquez-Tato, M. P.; Martínez,
M. M.; Nuñez-Corredoira, G. J. Chem . Res. (S), 1999,
420-421.
2.- Seijas, J. A.; Vázquez-Tato, M. P.; González-Bande,
C.; Martínez, M. M.; López-Pacios, B. Synthesis,
2001, 999-1000.
3.- Rahman, A. U. Recl. Trav.
Chim. Pays-Bas, 1956, 75, 164-168. Rahman, A. U.; Medrano,
M. A.; Mittal, O. P., ibid. 1960, 79, 188-192.
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