Iminophosphoranes in heterocyclic chemistry. A simple one-pot synthesis of dihydropyrimidines and pyrimidines

Article abstract of DOI:10.1055/s-1999-2795

The condensation of N-triphenylphosphoraniliden-benzamidine with acyclic α,β-unsaturated aldehydes produces dihydropyrimidines in good to high yields. The methodology has been extended to alicyclic and heterocyclic aldehydes.

Full text of DOI:10.1055/s-1999-2795

LETTER
1265
Iminophosphoranes in Heterocyclic Chemistry. A Simple One-Pot Synthesis of
Dihydropyrimidines and Pyrimidines
*
Elisabetta Rossi , Giorgio Abbiati, Elena Pini
Istituto di Chimica Organica della Facoltà di Farmacia, Università degli Studi di Milano, Via Venezian, 21, I-20133 Milano, Italy
Fax 0039-02-70638473; E-mail: Elisabetta.Rossi@unimi.it
Received 26 April 1999
Abstract: The condensation of N-triphenylphosphoraniliden-benz-
amidine with acyclic a,b-unsaturated aldehydes produces dihydro-
pyrimidines in good to high yields. The methodology has been
extended to alicyclic and heterocyclic aldehydes.
Key words: amidines, nitrogen-ylids, condensation reactions, dihy-
dropyrimidines, 8pyrimidines
The condensation of amidines with a,b-unsaturated alde-
hydes is an attractive [3+3]-fragment approach to dihy-
dropyrimidines. However, until recently, only few works
Scheme 1
dealing with this reaction have appeared in the literature
and the lack of growing up of this methodology was attrib-
We also report the extension of this methodology to the
uted to the instability of the dihydropyrimidine ring.1
cyclic a,b-unsaturated aldheydes 2h–l. Alicyclic alde-
Some years ago Weis and co-workers successfully devel-
hydes 2h–i are less reactive than acyclic aldehydes and
oped a new synthetic strategy for these condensation reac-
the condensation was successfully attempted using tetra-
tions, starting from the observation that the inaccessibility
line at reflux. Under these conditions 4,5-tetra- and 4,5-
of these compounds was related to the synthetic approach
pentamethylene fused pyrimidines 4a–b were obtained in
used rather than to the intrinsic nature of the dihydropyri-
high yields. Further, 4,6-unsubstituted pyrimidines 4c–d
2
midine ring. The two key steps in the reaction mechanism
were isolated from the reactions between 3-formyl-6-me-
were performed in separate stages: a preparation under
thylchromone 2j and 3-formyl-dihydropyrane 2k with im-
mild conditions of hydroxytetrahydropyrimidine fol-
inophosphorane 1 (Scheme 2). Finally, 1 reacts with (R)-
lowed by thermal or catalysed dehydration to 1,4(1,6)-di-
2
-(benzyloxy)-2,5-dihydrofuran-4-carboxaldehyde
2l,
hydropyrimidine.
with lower overall yields, giving rise to pyrimidines 4e
and 4f, both arising from the initially formed dihydropyri-
midine by loss of molecular hydrogen or benzylformate
Following our studies directed towards the development
of new synthetic methods of nitrogen heterocycles from
amidine systems, we thought that functionalized dihy-
3
(
Scheme 2).
dropyrimidines could be easily prepared in a one-pot reac-
tion between the iminophosphorane derived from
benzamidine and a,b-unsaturated aldehydes. The use of
iminophosphoranes has been emerging as a valuable tool
for the construction of nitrogen-containing heterocycles.4
We have previously published the synthesis of quinazo-
line and dihydroquinazoline ring starting from imino-
5
phosphoranes of N-aryl substituted benzamidines. Based
on these results, we now wish to report the preparation of
dihydropyrimidines 3a–g by the reaction of iminophos-
6
phorane 1 with acyclic a,b-unsaturated aldehydes 2a–g
7
,8
(
Scheme 1).
The reaction mechanism probably involves an aza-Wittig
-
reaction followed by a 6e p-electrocyclic ring closure of
the azatriene intermediate to give dihydropyrimidines.
We describe these latter compounds as a mixture of 1,6-
and 1,4-dihydroisomers because combined X-ray, IR, UV
and NMR data demonstrated that 1,6-dihydropyrimidines
exist in solution and in the solid state in enamine-imine
Scheme 2
1
The obtained results are collected in the Table.
tautomeric equilibrium with the 1,4-isomers.
Synlett 1999, No. 8, 1265–1267 ISSN 0936-5214 © Thieme Stuttgart · New York

1
266
E. Rossi et al.
LETTER
In conclusion, this synthesis, starting from the easily ob-
tainable iminophosphorane 1 and acyclic a,b-unsaturated
aldehydes 2a–g, enables a general and easy access to
1
,6(1,4)-dihydropyrimidines. Particularly noteworthy is
the success of this one-pot protocol with a,b-unsaturated
aldehydes ranging from unsubstituted to alkyl, aryl and
substituted aryl aldehydes. Extension of this methodology
to cyclic aldehydes 2h–l allows the preparation of the
9
fused pyrimidine 4a , and of the new fused derivatives 4b
and 4e. Finally, the presence of an oxygen atom in the g
position of the aldehyde moiety (2j–k) prevents the isola-
tion of the expected tricyclic and bicyclic dihydropyrim-
idines which evolve to the corresponding pyrimidines by
1
0
fission of the oxygenated ring. Further work is in
progress in order to evaluate the scope and limitations of
these reactions and, in particular, with the aim to extend
the synthetic procedure to the preparation of fused dihy-
dropyrimidines and/or pyrimidines.
Acknowledgement
Financial support from CNR (Roma) is gratefully acknowledged.
References and Notes
(
1) a) Weis, A. L. In Advances in Heterocyclic Chemistry,
Katritzky, A. L., Ed., Academic, Orlando (FL), 1985; 38, p 45.
b) Weis, A. L., van der Plas, H. C. Heterocycles 1986, 1433.
c) Brown, D. J. In The Chemistry of Heterocyclic Compounds,
Taylor, E. C., Weissberger, A., Eds., John Wiley, N. Y., 1994,
52, p 817.
(
(
2) a) Weis, A. L.; Frolow, F.; Zamir, D.; Bernstein, M.
Heterocycles 1984, 22, 657. b) Weis, A. L. Synthesis 1985,
528. c) Weis, A. L.; Zamir, D. J. Org. Chem. 1987, 52, 3421.
3) a) Rossi, E.; Pini, E. Tetrahedron 1996, 52, 7939, and
references cited therein. b) Rossi, E.; Abbiati, G.; Pini, E.
Tetrahedron 1997, 53, 14107. c) Rossi, E.; Abbiati, G.; Pini,
E. Tetrahedron 1999, 55, 6961.
(
4) For recent reviews on iminophosphoranes see: a) Gussar, N. I.
Russ. Chem. Rev. 1991, 60, 146. b) Eguchi, S.; Matsushita, Y.;
Yamashita, K. Org. Prep. Proced. Int. 1992, 24, 209.
c) Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197.
d) Wamhoff, H.; Richardt, G.; Stölben, S. In Advances in
Heterocyclic Chemistry, Katritzky, A. L., Ed., Academic,
Orlando (FL), 1995; 64, p 159. For some of recent leading
references see: a) Okawa, T.; Eguchi, S. Tetrahedron 1998,
54, 5853. b) Quintela, J. M.; Alvarez-Sarandés, R.; Peinador,
C. Tetrahedron 1998, 54, 8107. c) Saito, T.; Ohkubo, T.;
Kuboki, H.; Maeda, M.; Tsuda, K.; Karakasa, T.;
Satsumabayashi, S. J. Chem. Soc., Perkin Trans. 1 1998,
3065. d) Takahashi, M.; Suga, D. Synthesis 1998, 986. e)
Okawa, T.; Toda, M.; Eguchi, S.; Kakehi, A. Synthesis 1998,
1467. f) Okawa, T.; Kawase, M.; Eguchi, S. Synthesis 1998,
1185.
(
(
5) a) Rossi, E.; Celentano, G.; Stradi, R.; Strada, A. Tetrahedron
Lett. 1990, 31, 903. b) Rossi, E.; Calabrese, D.; Farma, F.
Tetrahedron 1991, 47, 5819.
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T.; Inokawa, S. Bull. Chem. Soc. Jpn. 1979, 52, 1541.
(
7) a,b-Unsaturated aldehydes 2a–e and 2j are commercially
available, 2f–i and 2k–l were prepared according to the
following references: 2f–g : Babler, J. H. Synth. Commun.
1982, 12, 839; 2h: Heilbron, I.; Jones, E. R. H.; Richardson,
Synlett 1999, No. 8, 1265–1267 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Iminophosphorane Mediated Synthesis of Pyrimidine Ring
1267
R. W.; Sondheimer, F. J. Chem. Soc. 1949, 737; 2i: Braude, E.
6.3); 4.30 (m, 1H); 4.82 (dd, 1H, J = 3.3, 7.4); 5.90 (bs, 1H);
1
3
A.; Evans, E. A. J. Chem. Soc. 1955, 3334; 2k: Piancatelli, G.;
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8) A typical procedure for dihydropyrimidines 3 is as follow: a
6.30 (d, 1H, J = 7.4); 7.37 (m, 3H); 7.66 (m, 2H). C-NMR d
25.9, 47.7, 108.4, 127.1, 129.0, 130.1, 131.3, 134.7, 155.0.
(9) a) Baumgarten, H. E.; Creger, P. L.; Villars, C. E. J. Am.
Chem. Soc. 1958, 80, 6609; b) Zumbrunn, A.; Lamberth, C.;
Schaub, F. Synth. Commun. 1998, 28, 474.
(
6
solution of iminophosphorane 1 (0.5 g, 1.31 mmol) and
crotonaldehyde 2b (0.12 g, 1.71 mmol) in dry xylene (15 mL)
was heated under reflux for 2 h. The solvent was then removed
under reduced pressure. The residue, purified by flash
chromatography (silica gel, 8:2:2 v/v petroleum ether/ethyl
(10) a) Löwe, W. Synthesis 1976, 274; b) Löwe, W. Liebigs Ann.
Chem. 1977, 1050; c) Pene, C.; Hubert-Habart, M. J.
Heterocyc. Chem. 1980, 17, 329.
1
acetate/triethylamine) afforded 3b (0.194 g, 86 % yield). H
NMR and 13C-NMR were recorded in commercial CDCl3,
under these conditions average spectra, between 1,4- and 1,6
Article Identifier:
1437-2096,E;1999,0,08,1265,1267,ftx,en;G12799ST.pdf
1
a 1
dihydro forms, were obtained . H-NMR d 1.28 (d, 3H, J =
Synlett 1999, No. 8, 1265–1267 ISSN 0936-5214 © Thieme Stuttgart · New York