July 1998
SYNLETT
719
pyrimidines therefore is superior in simplicity and yield compared to
9,10,23
alternative multistep strategies that have been reported.
Further
investigations on the nature of the specific interaction of PPE with the
presumed iminium ion intermediates are currently under way.
Acknowledgements: This work was supported by the Austrian
Academy of Sciences (Austrian Programme for Advanced Research and
Technology, APART 319) and the Austrian Science Fund (FWF, Project
P-11994-CHE).
References and Notes
(1) Synthesis and Reactions of Biginelli Compounds, 12; for part 11,
see: Fabian, W. M. F.; Semones, M. A.; Kappe, C. O. J. Mol.
Struct. (Theochem) 1998, 432, 219.
(2) For a review on dihydropyrimidines of this type, see: Kappe, C. O.
Tetrahedron 1993, 49, 6937.
(3) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; O´Reilly, B. C. J. Med. Chem. 1991,
34, 806. Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S.
D.; Moreland, S.; Gougoutas, J. Z.; O´Reilly, B. C.; Schwartz, J.;
Malley, M. F. J. Med. Chem. 1992, 35, 3254. Cho, H.; Ueda, M.;
Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka, Y.; Takeuchi,
Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda,
M.; Ishihara, T.; Funahashi, K.; Satah, F.; Morita, M.; Noguchi, T.
J. Med. Chem. 1989, 32, 2399. Grover, G. J.; Dzwonczyk, S.;
McMullen, D. M.; Normadinam, C. S.; Sleph, P. G.; Moreland, S.
J. J. Cardiovasc. Pharmacol. 1995, 26, 289. Nagarathanm, D.;
Chiu, G. ; Dhar, T. G. M.; Wong, W. C.; Marzabadi, M. R.;
Gluchowski, C. L.; Lagu, B.; Miao, S. W. PCT Int. Appl. WO 96
14,846; Chem. Abstr. 1996, 125, 142759c.
Figure 1
(4) Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828 and refs
therein. Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J.
Am. Chem. Soc. 1995, 117, 2657 and refs therein.
(5) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A.
J.; DeBrosse, C.; Mai, S.; Truneh, A.; Faulkner, D. J.; Carte, B.;
Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.; Westley, J. W.;
Potts, B. C. M. J. Org. Chem. 1995, 60, 1182. Snider, B.; Chen, J.;
Patil, A. D.; Freyer, A. Tetrahedron Lett. 1996, 37, 6977. Rama
Rao, A. V.; Gurjar, M. K.; Vasudevan, J. J. Chem. Soc., Chem.
Commun. 1995, 1369.
In this context we also wish to report the first isolation of an
intermediate of type 6 in the Biginelli reaction. Treatment of ethyl
trifluoroacetoacetate with benzaldehyde and urea (via both method A
and B) produced hexahydropyrimidine 9 as the only isolable product in
18
diastereomerically pure form (79% yield, mp 162 °C). Based on
comparison of melting points this substance is identical to material (mp
19
165 °C) previously obtained by Rutter and Gustafson in the same way
(method B) who however assigned structure 10 to this product. We find
that only in the presence of strong acids (p-TsOH, refluxing toluene)
and under anhydrous conditions elimination of water from 9 occurs
yielding dihydropyrimidine 10 (mp 156 °C). Undoubtedly the unique
(6) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(7) Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem. Soc.
1932, 54, 3751.
(8) For other reported improvements of the Biginelli reaction, see:
Zavyalov, S. I.; Kulikova, L. B. Khim.-Farm. Zh. 1992, 26, 116.
Gupta, R.; Gupta, A. K.; Paul, S.; Kachroo, P. L. Ind. J. Chem.
1995, 34B, 151. Hu, E. H.; Sidler, D. R.; Dolling, U. H. Patane, M.
A. PCT Int. Appl. WO 97 21,687; Chem. Abstr. 1997, 127,
121750v.
electronic properties of the CF group in this case prevent the
3
elimination step 9 → 10.
(9) O'Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185.
(10) Shutalev, A. D.; Kuksa, V. A. Khim. Geterotsikl. Soedin. 1997,
105. Shutalev, A. D.; Kishko, E. A.; Sivova, N.; Kuznetsov, A. Y.
Molecules 1998, 3, 100.
Scheme 2
(11) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819.
Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997,
62, 2917.
In summary, this report discloses a new and simple modification of the
Biginelli dihydropyrimidine synthesis. Through the use of readily
available polyphosphate ester (PPE) as reaction mediator and THF as
solvent the yields in the one-pot Biginelli protocol can be increased on
average by 30-40% (Table 1). This one-step synthesis of dihydro-
(12) Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
(13) Overman, L. E.; Ricca, D. J. Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I.; Eds.; Pergamon Press: Oxford; Vol. 2,