6198
G. Jenner / Tetrahedron Letters 45 (2004) 6195–6198
7. Aron, Z. D.; Overman, L. E. Chem. Commun. 2004, 253–
265.
8. Yadav, J. S.; Subba Reddy, B. V.; Srinivas, R.; Venu-
gopal, C.; Ramalingam, T. Synthesis 2001, 1341–
1345.
9. Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori,
G. Tetrahedron Lett. 1999, 40, 3465–3468.
10. Yadav, J. S.; Subba Reddy, B. V.; Sidhar, P.; Reddy, J. S.;
Nagaiah, K.; Lingaiah, N.; Saiprasad, P. S. Eur. J. Org.
Chem. 2004, 552–557.
ketoester) at either 0.1 or 300 MPa for 15–24 h showed
complete transformation into 4. The fact that pressure
had no effect on the following steps leading to 3 and 4
gives support to Kappe’s suggestion, the rate-deter-
mining step being apparently the formation of 1. Th e
major pressure effect detected in the present hindered
Biginelli reactions is, therefore, a consequence of steric
constraints. The result is of primary importance and
stays in full harmony with those previously reported in
our laboratory.12;13;16
11. Jenner, G. J. Chem. Soc.,Faraday Trans. 1 1985, 81, 2437–
2460.
12. Jenner, G. Tetrahedron Lett. 2002, 43, 1235–1238.
13. Jenner, G.; Ben Salem, R.; Kim, J. C.; Matsumoto, K.
Tetrahedron Lett. 2003, 44, 447–449.
Conclusion
14. Fujita, T.; Iwamura, H. Top. Curr. Chem. 1983, 114, 119–
157.
The three-component Biginelli reaction giving access to
dihydropyrimidinones is little sensitive to pressure as
long as unhindered aldehydes are involved. With
increasing steric congestion, however the sensitivity of
the reaction to pressure is clearly enhanced. The results
also support a multistep mechanism where the first step
consisting of the nucleophilic addition of aldehyde to
urea would be rate determining. The remarkable
capacity of high pressure to relieve steric inhibition is
probably in relation withan early transition state, which
is shifted to product when steric constraints gain more
importance. Pressure is therefore, an essential physical
parameter in difficult Biginelli syntheses like micro-
waves, which may also have an activation effect.20
15. Typical experimental procedure: A mixture of zinc iodide
(25 mg, 0.08 mmol), urea (72 mg, 1.2 mmol), ethyl aceto-
acetate (104 mg, 0.8 mmol), and pivalaldehyde (70 mg,
0.80 mmol) was placed in a flexible 1 mL PTFE tube. The
volume was adjusted with acetonitrile. Then the ampoule
was closed, introduced in the vessel thermostated at 80 °C
and pressurized to 300 MPa. After release of pressure the
content was poured into a flask and the volatile com-
pounds were removed in vacuo. The solid residue was
weighed. Then ice-cold water was added to remove the
catalyst and unreacted urea. After filtration, the white
solid was dried, carefully weighed and, finally analyzed by
NMR (DMSO-d6).
Some spectroscopic data: Dihydropyrimidinone from urea
and pivalaldehyde: 1H NMR: 0.75 (s, 9H), 1.19 (t, 3H),
2.16 (s, 3H), 3.88 (d, 1H), 4.08 (q, 2H), 4.90 (br, 1H), 7.36
(br, 1H); 13C NMR: 167.1, 153.9, 148.1, 97.8, 59.6, 58.7,
25.6, 18.0, 14.6; Dihydropyrimidinone from N-methylurea
and pivalaldehyde: 1H NMR: 0.73 (s, 9H), 1.20 (t, 3H),
2.33 (s, 3H), 3.00 (s, 3H), 3.87 (d, 1H), 4.09 (q, 2H), 7.15
(br, 1H); 13C NMR: 167.5, 154.5, 149.3, 101.6, 59.9, 57.6,
30.0, 25.4, 16.5, 14.6.
References and notes
€
1. Domling, A.; Ugi, I. Angew. Chem.,Int. Ed. Engl. 2000,
39, 3168–3210.
2. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 565–
600.
3. Kappe, C. O. Tetrahedron 1993, 49, 6937–6963.
4. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270–6272.
16. Jenner, G. Tetrahedron Lett. 2001, 42, 243–245.
17. Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55,
3784–3791.
18. Kappe, O. C. J. Org. Chem. 1997, 62, 7201–7204.
19. Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem.
1998, 63, 3454–3457.
5. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000,
65, 3864–3868.
20. Stadler, A.; Kappe, O. C. J. Combinatorial Chem. 2001, 3,
624–630.
6. Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. Synlett
2001, 863–865.