include a Pinner-type synthesis8 and a skeletal or func-
tional group transformation from nitrogen-containing
heterocycles such as polysubstituted pyrimidines and
s-triazine.9,10 These procedures have disadvantages inas-
much as they involve stoichiometric additives, such as strong
bases and acids, relatively inaccessible reagents, multiple-
step syntheses, and harsh reaction conditions. Thus, the need
remains for a novel synthetic process for the highly efficient
preparation of 4,5-disubstituted pyrimidines via a single-step
procedure.
our knowledge, this type of [3 + 1 + 1 + 1] annulation process,
shown in Scheme 1, has not previously been reported. In this
Scheme 1. New Approach to 4,5-Disubstituted Pyrimidines
We previously found that intermolecular annulation and
intramolecular cyclization with an N-silyl-1-azaallylic anion11
and its synthetic equivalent, an N-silylenamine, can efficiently
produce a variety of nitrogen-containing heterocycles.12 During
our ongoing studies of Lewis acid mediated synthesis of
nitrogen-containing heterocycles with functionalized enam-
ines,13 we found that zinc chloride (ZnCl2) effectively catalyzes
the three-component coupling reaction of an enamine, triethyl
orthoformate, and ammonium acetate to produce a 4,5-disub-
stituted pyrimidine derivative in a single step. To the best of
communication, we report the preliminary results of this
unprecedented approach to the preparation of heterocycles. We
also disclose the use of methyl ketone derivatives, instead of
enamines, for the production of monosubstituted pyrimidine
derivatives in good yield.
Initially, we prepared commercially unavailable function-
alized enamines 1a-l (Scheme 2).12a For example, when the
Scheme 2. Synthesis of Enamines 1a-l
(7) For selected papers on the Bredereck-type synthesis of 4,5-
disubstituted pyrimidines, see: (a) Bredereck, H.; Gompper, R.; Morlock,
G. Chem. Ber. 1957, 90, 942. (b) Nag, S.; Madapa, S.; Batra, S. Synthesis
2008, 101. (c) Tyagarajan, S.; Chakravarty, P. K. Tetrahedron Lett. 2005,
46, 7889. (d) Ingebrigtsen, T.; Helland, I.; Lejon, T. Heterocycles 2005,
65, 2593. (e) Dominguez, E.; Martinez de Marigorta, E.; Olivera, R.;
SanMartin, R. Synlett 1995, 955. (f) Villa, M. J.; Dominguez, E.; Lete, E.
Heterocycles 1986, 24, 1943. (g) Hirota, T.; Koyama, T.; Nanba, T.; Yamato,
M.; Matsumura, T. Chem. Pharm. Bull. 1978, 26, 245. (h) Koyama, T.;
Hirota, T.; Bashou, C.; Satoh, Y.; Watanabe, Y.; Matsumoto, S.; Shinohara,
Y.; Ohmori, S.; Yamato, M. Chem. Pharm. Bull. 1975, 23, 2158. (i) Hill,
D. T.; Loev, B. J. Org. Chem. 1973, 38, 2102. (j) Tsatsaronis, G. C.;
reaction of 3,5-dimethylisoxazole with benzonitrile, in the
presence of LDA, was carried out in THF at -70 °C for
1 h, quenching with H2O led to the corresponding enamine
1a in 90% yield.
Kehayoglou, A. H. J. Org. Chem. 1970, 35, 438
.
(8) For selected papers on the Pinner-type synthesis of 4,5-disubstituted
pyrimidines, see: (a) Pinner, A. Ber. 1893, 26, 2122. (b) Baran, P. S.; Shenvi,
R. A.; Nguyen, S. A. Heterocycles 2006, 70, 581. (c) Cheng, G.; Li, S.; Li,
J.; Hu, Y. Bioorg. Med. Chem. Lett. 2008, 18, 1177. (d) Winterwerber, M.;
Geiger, R.; Otto, H.-H. Monatsh. Chem. 2006, 137, 1321. (e) Frasinyuk,
M. S.; Bondarenko, S. P.; Khilya, V. P. Chem. Nat. Compd. 2006, 42, 673.
(f) Funabiki, K.; Ohtsuki, T.; Ishihara, T.; Yamanaka, H. Chem. Lett. 1995,
239. (g) Dinsmore, A.; Doyle, P. M.; Young, D. W. Tetrahedron Lett. 1995,
36, 7503. (h) Breaux, E. J.; Zwikelmaier, K. E. J. Heterocycl. Chem. 1981,
On the basis of our previous studies, the three-component
coupling reaction of enamine 1a, orthoester 2, and am-
monium acetate (NH4OAc) was then examined, and the
results are summarized in Table 1. First, when the reaction
of enamine 1a with 3 equiv of orthoester 2 and 2 equiv of
NH4OAc (3) was conducted in toluene at 100 °C for 20 h,
the desired disubstituted pyrimidine 4a was obtained in a
61% yield (run 1). The structure of pyrimidine 4a was
unambiguously confirmed by spectral data, elemental analy-
sis, and X-ray crystallographic analysis.
Addition of a typical Lewis acid, such as InCl3, Cu(OTf)2,
or Yb(OTf)3, was ineffective for improvement of the product
yield (runs 2-4). Interestingly, the use of a zinc catalyst, such
as ZnCl2, ZnBr2, or Zn(OTf)2, remarkably enhanced the yield
of product 4a (runs 5-7). In addition, employment of aceto-
nitrile or 1,2-dichloroethane as a solvent and ammonium
chloride (NH4Cl) instead of NH4OAc as the nitrogen source
resulted in decreased yields (runs 8-10). Thus, we found that
heating in PhMe at 100 °C in the presence of 0.1 equiv of ZnCl2
were the best conditions for a coupling reaction.
18, 183
.
(9) For selected papers on the skeletal transformation to 4,5-disubstituted
pyrimidines, see: (a) Nishiwaki, N.; Ariga, M. Top. Heterocycl. Chem. 2007,
8, 43. (b) Nishiwaki, N.; Tamura, M.; Hori, K.; Tohda, Y.; Ariga, M.
Molecules 2003, 8, 500. (c) Bilbao, E. R.; Alvarado, M.; Masaguer, C. F.;
Ravina, E. Tetrahedron Lett. 2002, 43, 3551. (d) Nishiwaki, N.; Adachi,
T.; Matsuo, K.; Wang, H.-P.; Matsunaga, T.; Tohda, Y.; Ariga, M. J. Chem.
Soc., Perkin Trans. 1 2000, 27. (e) Boger, D. L.; Schumacher, J.; Mullican,
M. D.; Patel, M.; Panek, J. S. J. Org. Chem. 1982, 47, 2673. (f) Huffman,
K. R.; Schaefer, F. C.; Peters, G. A. J. Org. Chem. 1962, 27, 551
.
(10) For selected papers on the functional group transformation to 4,5-
disubstituted pyrimidines, see: (a) Sard, H.; Gonzalez, M. D.; Mahadevan,
A.; McKew, J. J. Org. Chem. 2000, 65, 9261. (b) Boudet, N.; Dubbaka,
S. R.; Knochel, P. Org. Lett. 2008, 10, 1715. (c) Schlosser, M.; Lefebvre,
O.; Ondi, L. Eur. J. Org. Chem. 2006, 1593. (d) Togo, H.; Ishigami, S.;
Fujii, M.; Ikuma, T.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1 1994,
2931. (e) Mattson, R. J.; Sloan, C. P. J. Org. Chem. 1990, 55, 3410. (f)
Yamanaka, H.; Sakamoto, T.; Nishimura, S.; Sagi, M. Chem. Pharm. Bull.
1987, 35, 3119. (g) Kress, T. J. J. Org. Chem. 1985, 50, 3073. (h) Kress,
T. J. J. Org. Chem. 1979, 44, 2081
(11) Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. ReV. 2004,
104, 2353.
.
(12) (a) Sasada, T.; Sakai, N.; Konakahara, T. J. Org. Chem. 2008, 73,
6905. (b) Sakai, N.; Aoki, Y.; Sasada, T.; Konakahara, T. Org. Lett. 2005,
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Kakehi, A.; Konakahara, T. J. Org. Chem. 2007, 72, 5878. (d) Sakai, N.;
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(e) Sakai, N.; Hattori, N.; Tomizawa, N.; Abe, N.; Konakahara, T.
Heterocycles 2005, 65, 2799.
To extend the generality of this coupling process, annu-
lation using various multifunctionalized enamines was
examined under our optimized conditions. The results are
summarized in Table 2.
Enamines 1b-d with an electron-donating group and an
electron-withdrawing group on the benzene ring produced the
(13) (a) Stanovnik, B.; Svete, J. Chem. ReV. 2004, 104, 2433. (b) Erian,
A. W. Chem. ReV. 1993, 93, 1991.
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