J . Org. Chem. 1997, 62, 2999-3001
2999
Rea ctivity of Th ioa ld eh yd e: Cycliza tion
Sch em e 1
Rea ction of 6-Am in o-1,3-d im eth yl-5-
th iofor m ylu r a cil w ith En a m in es in to
P yr id o[2,3-d ]p yr im id in e-2,4-(1H,3H)-d ion es
Kosaku Hirota,* Keiko Kubo, Hironao Sajiki,
Yukio Kitade, Magoichi Sako, and Yoshifumi Maki
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical
University, Mitahora-higashi, Gifu 502, J apan
Received November 25, 1996
Until quite recently investigation of the chemical
properties of monomeric thioaldehydes was considered
1
difficult because of their extreme instability. Although
two types of stable monomeric thioaldehydes are known
2
,3
in literature to be kinetically stabilized or thermody-
namically stabilized compounds,4 only a few reports
have appeared concerning the reactivities of stable thio-
,5
aldehydes.3
,5,6
We recently reported the synthesis and
5c
various morpholino enamines 2b-g in anhydrous aceto-
nitrile. The results are summarized in Table 1. The
cyclization proceeded in good yields in the case of enam-
reactivities of 6-amino-5-thioformyluracils (e.g., 1) which
are kinetically stabilized by the mesomeric effect of the
6
-amino group. In order to gain further understanding
1
2
ines 2a -d with aliphatic substituents (R and R ) (entry
of the reactivity of the thioformyluracils, we have evalu-
ated the reactions of 6-amino-1,3-dimethyl-5-thioformyl-
uracil (1) with enamines.
1
-4). Most importantly, the cyclization regiospecificity
proceeded by use of unsymmetric enamines (entry 3-6).
In contrast to the case of the alkyl-substituted enamines
In our initial study, the thioaldehyde 1 reacted with
morpholino enamine 2a in anhydrous acetonitrile at rt
to afford the pyrido[2,3-d]pyrimidine derivative 3a in 75%
yield (Table 1). The structure of 3a was confirmed in
the conversion of 3a into the literature known 5-deaza-
2
a -d , the reaction with phenyl-substituted enamines 2e
and 2f gave a considerable amount of byproduct 5
together with the expected products 3e and 3f, respec-
tively (entry 5 and 6). The structure of 5 was presumed
to be 1,3-dimethyl-7-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tet-
rahydropyrimidin-5-yl)pyrimido[4,5-d]pyrimidine-2,4-
7
alloxazine 4 by sulfur oxidation.
(1H,3H)-dione on the basis of its microanalytical and
spectral data. The ultimate proof of the structure was
provided by an alternative synthesis of 5 from 6-imino-
1
,3-dimethyl-5-[(dimethylamino)methylene]-5,6-dihy-
drouracil hydrochloride (6) and 5-carbamoyl-1,3-di-
methyluracil (7) according to our method.8 In particular,
the cyclization with diphenylenamine 2g gave only the
byproduct 5 in 61% yield (entry 7). In addition, the
reaction with less reactive olefins such as methyl acrylate
and acrylonitrile resulted in the recovery of the starting
material under a variety of thermal or photoreaction
conditions. These results indicate that the substitution
of the electron-donating groups on enamine is crucial in
these cyclization reactions.
To establish the generality of this cyclization, the
thioaldehyde 1 was subjected to analogous reactions with
(
1) For reviews see: (a) Duus, F. In Comprehensive Organic
Chemistry; Barton, D H. R., Ollis, W. D., Eds.; Pergamon: Oxford,
979; Vol. 3, pp 374-403. (b) Okazaki, R. J . Synth. Org. Chem. J pn.
988, 46, 1149. (c) McGregor, W. M.; Sherington, D. C. Chem. Soc.
1
1
Rev. 1993, 199.
2) (a) Okazaki, R.; Ishii, A.; Fukuda, N.; Oyama, H.; Inamoto, N.
(
On the other hand, the corresponding aldehyde 8 did
not react with enamines 2a and 2b under the same
conditions, and the starting material was recovered even
under reflux conditions. As the cycloadditions of uracil-
dienols were achieved only with electron-deficient dieno-
J . Chem. Soc., Chem. Commun. 1982, 1187. (b) Okazaki, R.; Ishii, A.;
Fukuda, N.; Oyama, H.; Inamoto, N. Tetrahedron Lett. 1984, 25, 849.
c) Ando, W.; Ohtaki, T.; Suzuki, T.; Kabe, Y. J . Am. Chem. Soc. 1991,
13, 7782. (d) Tokitoh, N.; Takeda, N.; Okazaki, R. J . Am. Chem. Soc.
994, 116, 7907.
(
1
1
(3) (a) Vedejs, E.; Perry, D. A. J . Am. Chem. Soc. 1983, 105, 2985.
(
1
1
b) Okazaki, R.; Fukuda, N.; Oyama, H.; Inamoto, N. Chem. Lett. 1984,
01. (c) Vedejs, E.; Perry, D. A.; Wilde, R. G. J . Am. Chem. Soc. 1986,
08, 2985. (d) Vedejs, E.; Wild, R. G. J . Org. Chem. 1986, 51, 117. (e)
9
philes in the literature, the reaction should proceed in
Okazaki, R.; Ishii, A.; Inamoto, N. J . Am. Chem. Soc. 1987, 109, 279.
f) Ishii, A.; Ishida, T.; Kumon, N.; Fukuda, N.; Oyama, H.; Inamoto,
N.; Iwasaki, F.; Okazaki, R. Bull. Chem. Soc. J pn. 1996, 69, 709.
4) (a) Woodward, R. B.; Ayer, W. A.; Beaton, J . M.; Bickelhaupt,
F.; Bonnet, R.; Buchshacher, P.; Closs, G. L.; Dutler, H.; Hannah, J .;
Hauck, F. P.; Ito, S.; Langemann, A.; Le Goff, E.; Leimgruber, W.;
Lwowski, W.; Sauer, J .; Valenta, Z.; Volz, H. J . Am. Chem. Soc. 1960,
(5) (a) Mackie, R. K.; McKenzie, S.; Reid, D. H.; Webster, R. G. J .
Chem. Soc., Perkin Trans. 1 1973, 657. (b) Muraoka, M.; Yamamoto,
T.; Enomoto, K.; Takeshima, T. J . Chem. Soc., Perkin Trans. 1 1989,
1241. (c) Hirota, K.; Sajiki, H.; Kubo, K.; Kido, M.; Nakagawa, K.
Tetrahedron 1996, 52, 9971.
(6) Hofstra, G.; Kamphuis, J .; Bos, H. J . T. Tetrahedron Lett. 1984,
25, 873.
(
(
8
1
1
2, 3800. (b) McKenzie, S.; Reid, D. H. J . Chem. Soc., Chem. Commun.
966, 401. (c) Dingwall, J . G.; Reid, D. H.; Wade, K. J . Chem. Soc. (C)
969, 913. (d) McKenzie, S.; Reid, D. H. Ibid. 1970, 145. (e) McKinnon,
(7) Yoneda, F.; Takayama, F.; Koshiro, A. Chem. Pharm. Bull. 1979,
27, 2507.
(8) Hirota, K.; Kitade, Y.; Sajiki, H.; Maki, Y. Synthesis 1984, 589.
(9) Senda, S.; Asao, T.; Sugiyama, I.; Hirota, K. Tetrahedron Lett.
1980, 21, 531.
(10) For reviews on the hetero Diels-Alder reactions of 1-azadiene,
see: (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger, D. L.;
Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis;
Academic Press: San Diego, 1987; pp 240-255.
D. M.; Buchshriber, J . M. Can. J . Chem. 1971, 49, 3299. (f) Dabrowski,
J .; Kamienska-Trela, K. Org. Magn. Reson. 1972, 4, 421. (g) Tang, S.
C.; Weinstein, G. N.; Holm, R. H. J . Am. Chem. Soc. 1973, 95, 613. (h)
Davy, H.; Vialle, J . Bull. Soc. Chim. Fr. 1975, 1435. (i) Muraoka, M.;
Yamamoto, T.; Takeshima, T. Chem. Lett. 1982, 101. (j) Muraoka, M.;
Yamamoto, T. J . Chem. Soc., Chem. Commun. 1985, 1299.
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