rapid optimization of reactions in parallel, and several
ecofriendly advantages in the context of green chemis-
try.7-14 Thus, this protocol should be welcome in these
environmentally conscious days.
Novel Salicylaldehyde-Based
Mineral-Supported Expeditious Synthesis
of Benzoxazin-2-ones
Considering the above reports and in pursuing our
work on new solvent-free cyclization procedures,15-18 we
devised an original montmorillonite K-10 clay catalyzed
MW-activated synthesis of hitherto unknown 4-hydra-
zinobenzoxazinone derivatives 9 which involves cyclo-
isomerization of the intermediate salicylaldehyde/2-hy-
droxyacetophenone semicarbazones 5 (Scheme 1).
Interestingly, this is the first example of the synthesis
of 4-hydrazinobenzoxazinones 9 and their reductive de-
hydrazination to 10. The key element in our approach is
the novel utilization of salicylaldehyde as a bifunctional
building block whose application to the construction of
various benzo-fused oxygen heterocycles of chemical and
biological interest is well documented.19-24
After some preliminary experimentation, it was found
that the synthesis of hydrazines 9 envisaged can be
effected either starting from salicylaldehyde/2-hydroxy-
acetophenone hydrazones 1 and aryl-/alkylureas 2 (route
1) or salicylaldehydes/2-hydroxyacetophenone 3 and 4-
aryl-/alkylsemicarbazides 4 (route 2) (Scheme 1). More-
over, the synthesis of the target compounds 9 is more
convenient through route 1 because route 2 utilizes
4-aryl-/alkylsemicarbazides 4 whose preparation usually
involves highly toxic, corrosive, and hygroscopic aryl
isocyanates demanding special care in handling. There-
fore, although almost the same yield is obtained through
both routes, we have preferred route 1.
The present synthesis in its entirety involves intermit-
tent irradiation of an mixture of the reactants (1 and 2
or 3 and 4) and montmorillonite K-10 clay for 2 min in
an MW oven25 at 560 W followed by thorough mixing for
2 min outside the oven. This intermittent irradiation-
mixing cycle was repeated for the total irradiation time
specified in Table 1 to afford 4-hydrazinobenzoxazin-2-
ones 9 in 78-89% yield (Table 1). However, the use of
other mineral supports, viz., silica gel, neutral or basic
alumina, was far less effective resulting in either no
reaction (in the case of basic alumina) or relatively very
low yields (20-35%) of 9 (in the case of silica gel and
neutral alumina). Moreover, the reactions did not take
Lal Dhar S. Yadav* and Ritu Kapoor
Department of Chemistry, University of Allahabad,
Allahabad-211002, India
Received May 6, 2004
Abstract: One-pot montmorillonite K-10 clay supported
reactions of either salicylaldehyde/2-hydroxyacetophenone
hydrazones and aryl-/alkylureas or salicylaldehydes/2-hy-
droxyacetophenone and 4-aryl-/alkylsemicarbazides expedi-
tiously yield 3,4-dihydro-4-hydrazino-2H-benz[e]-1,3-oxazin-
2-ones (9) via cycloisomerization of the intermediate salicyl-
aldehyde/2-hydroxyacetophenone 4-aryl-/alkylsemicarba-
zones (5) under solvent-free microwave irradiation. Under
the same conditions, hydrazines (9) readily underwent
reductive dehydrazination on alumina-supported copper(II)
sulfate to furnish 2H-benz[e]-1,3-oxazin-2-ones (10).
Efavirenz (Sustiva), a benzoxazinone derivative, is a
nonnucleoside reverse transcriptase inhibitor that was
approved by the FDA in 1998 and is presently in clinical
use for the treatment of AIDS. The fight against HIV by
developing more efficacious drugs than Efavirenz has
been the prime driving force for benzoxazinone deriva-
tization which has attained considerable attention.1-6
Recent years have witnessed a phenomenal growth in
the application of microwave (MW) irradiation7-11 and
recyclable less expensive mineral supports for organic
transformations.12-14 The application of MW irradiation
in conjunction with the use of mineral-supported reagents
under solvent-free conditions provides unique chemical
processes with special attributes such as enhanced reac-
tion rates, higher yields of pure products, easier workup,
(1) Patel, M.; Ko, S. S.; McHugh, R. J., Jr.; Markwalder, J. A.;
Srivastava, A. S.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.;
Trainor; G. L.; Seitz S. P. Bioorg. Med. Chem. Lett. 1999, 9, 2805-
2810.
(2) Patel, M.; McHugh, R. J., Jr.; Cordova, B. C.; Klabe, R. M.;
Erickson-Viitanen, S.; Trainor, G. L.; Koo, S. S. Bioorg. Med. Chem.
Lett. 1999, 9, 3221-3226.
(3) Waxman, L.; Darke, P. L. Antivir. Chem. Chemother. 2000, 11,
1-6.
(15) Yadav, L. D. S.; Singh, A. Tetrahedron Lett. 2003, 44, 5637-
5640.
(4) Klasek, A.; Koristek, K.; Polis, J.; Kosmrlj, J. Tetrahedron 2000,
56, 1551-1560.
(16) Yadav, L. D. S.; Dubey, S.; Yadav. B. S. Tetrahedron 2003, 59,
5411-5415.
(5) Girgis, A. S. Pharmazie 2000, 426-430.
(17) Yadav, L. D. S.; Kapoor, R. Tetrahedron Lett. 2003, 44, 8951-
8954.
(6) Mindl, J.; Hrabik, O.; Sterba, V.; Kavalek, J. Collect. Czech.
Chem. Commun. 2000, 65, 1262-1272.
(18) Yadav, L. D. S.; Singh, S. Synthesis 2003, 63-66.
(19) O’Callaghan, C. N.; McMurry, T. B. M. J. Chem. Res., Synop.
1997, 78-79. (M) 0643-0649.
(7) Caddick, S. Tetrahedron 1995, 51, 10403-10432.
(8) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Bouller, F.; Jacquault,
P.; Mathe, D. Synthesis 1998, 1213-1234.
(20) Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor. R. W. J. Org.
Chem. 1996, 61, 7355-7359.
(9) Varma, R. S. Green Chem. 1999, 1, 43-55.
(10) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283.
(21) Varma, R. S.; Kumar, D.; Liesen, P. J. J. Chem. Soc., Perkin
Trans. 1 1998, 4093-4096.
(11) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199-9223.
(12) Balogh, M.; Laszlo, P. Organic Chemistry Using Clays;
Springer: Berlin, 1993.
(22) Bandgar, B. P.; Uppalla, L. S.; Kurule, D. S. Green Chem. 1999,
1, 243-245.
(23) Varma, R. S.; Dahiya, R. J. Org. Chem. 1998, 63, 8038-8041.
(24) Yadav, L. D. S.; Saigal, S.; Pal, D. R. J. Chem. Res., Synop.
1998, 307.
(13) Chisem, J.; Chisem, I. C.; Rafelt, J. S.; Macquarrie, D. J.; Clark,
J. H. Chem. Commun. 1997, 2203-2204.
(14) Meshram, H. M.; Shekhar, K. C.; Ganesh, Y. S. S.; Yadav, J. S.
Synlett 2000, 1273-1275.
(25) An unmodified domestic microwave oven (operating at 2450
MHz) was used at an output of 560 W for all of the experiments.
10.1021/jo0492315 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/09/2004
8118
J. Org. Chem. 2004, 69, 8118-8120