New approach to the practical synthesis of tri- or tetrasubstituted pyrimidine derivatives: A four-component coupling reaction from a functionalized silane, two types of aromatic nitriles, and acetals

Article abstract of DOI:10.1021/ol051901l

(Chemical Equation Presented) A new approach to the synthesis of tri- or tetrasubstituted pyrimidines by a four-component coupling reaction using a functionalized silane, two types of aromatic nitriles, and an acetal is described. The efficient transforma

Full text of DOI:10.1021/ol051901l

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4705-4708
New Approach to the Practical
Synthesis of Tri- or Tetrasubstituted
Pyrimidine Derivatives: A
Four-Component Coupling Reaction
from a Functionalized Silane, Two Types
of Aromatic Nitriles, and Acetals
Norio Sakai, Youichi Aoki, Toshiaki Sasada, and Takeo Konakahara*
Department of Pure and Applied Chemistry, Faculty of Science and Technology,
Tokyo UniVersity of Science (RIKADAI), Noda, Chiba 278-8510, Japan
konaka@ci.noda.sut.ac.jp
Received August 8, 2005
ABSTRACT
A new approach to the synthesis of tri- or tetrasubstituted pyrimidines by a four-component coupling reaction using a functionalized silane,
two types of aromatic nitriles, and an acetal is described. The efficient transformation of the pyrimidine framework consisting of an isoxazolyl
ring and an ethoxy group to the 1,3,8-triazanaphthalene skeleton also proceeded in nearly quantitative yield.
The synthesis of pyrimidines has attracted considerable
interest in the scientific community, as this skeleton is
present in many natural products and a variety of biologically
active substances. Although various procedures for the
synthesis of pyrimidine derivatives have been reported,1 most
have been restricted to methodologies involving a Pinner
synthesis (3,4- and 1,6-bond forming reactions, path a);2
1,2- and 2,3-bond forming reactions (path b),3 1,2- and
3,4-bond forming reactions (path c),4 4,5- and 1,6-bond
forming reactions (path d);5 and 2,3- and 4,5-bond forming
reactions (path e).6 The development of a completely new
approach to pyrimidine synthesis has not been extensively
pursued (3,4- and 4,5-bond forming reactions; path f in
Scheme 1).7
Previously, we reported that an N-silyl-1-azaallyl anion8
reacts smoothly with Michael acceptors, such as 1,2-
diketones and R,â-unsaturated ketones, to produce poly-
substituted pyrroles and pyridine derivatives.9 During our
ongoing research on the synthesis of other nitrogen-contain-
(2) For selected papers for the pyrimidine synthesis via path a, see: (a)
Taylor, E. C.; Knoff, R. J.; Meyer, R. F.; Holmes, A.; Hoefle, M. L. J. Am.
Chem. Soc. 1960, 82, 5711. (b) Inoue, S.; Saggiomo, A. J.; Nodiff, E. A.
J. Org. Chem. 1961, 26, 4504. (c) Bredereck, H.; Effenberger, F.; Botsch,
H.; Rehn, H. Chem. Ber. 1965, 98, 1081. (d) Chauhan, S. M. S.; Junjappa,
H. Synthesis 1974, 880. (e) Kreutzberger, A.; Tesch, U.-H. Chem. Ber. 1976,
109, 3255. (f) Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J.
Org. Chem. 1983, 48, 4841. (g) Kvita, V. Synthesis 1986, 786. (h) Schenone,
P.; Sansebastiano, L.; Mosti, L. J. Heterocycl. Chem. 1990, 27, 295. (i)
Papet, A.-L.; Marsura, A. Synthesis 1993, 478. (j) Yamanaka, H.; Takekawa,
T.; Morita, K.; Ishihara, T.; Gupton, J. T. Tetrahedron Lett. 1996, 37, 1829.
(k) Wang, T.; Cloudsdale, I. S. Synth. Commun. 1997, 27, 2521. (l) Ghosh,
U.; Katzenellenbogen, J. A. J. Heterocycl. Chem. 2002, 39, 1101.
* Corresponding author: Tel: +81-4-7122-9502. Fax: +81-4-
7123-9326.
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Science Ltd.: Cambridge, MA, 2000; pp 194-232. (b) Erian, A. W. Chem.
ReV. 1993, 93, 1991.
(3) For selected papers on pyrimidine synthesis via path b, see:
Eilingfeld, H.; Patsch, M.; Scheuermann, H. Chem. Ber. 1968, 101, 2426.
(4) For selected papers on pyrimidine synthesis via path c, see: (a) Sing,
Y. L.; Lee, L. F. J. Heterocycl. Chem. 1989, 26, 7. (b) Alberola, A.; Andreˆs,
C.; Ortega, A. G.; Pedrosa, R.; Vicente, M. Synth. Commun. 1987, 17, 1309.
10.1021/ol051901l CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/21/2005

triazanaphthalene starting from a tetrasubstituted pyrimidine
via an intramolecular cyclization.
Scheme 1
We initially examined a one-pot synthesis of an amidine
derivative. When the functionalized silane 1 was reacted with
benzonitrile in THF at -70 °C for 1 h in the presence of
n-BuLi, 1-azaallyl anion 2 was generated in situ, and after
addition of 2-cyanopyrazine, the desired amidine 3a was
produced in 90% yield (Scheme 3).
Scheme 3. One-Pot Synthesis of Amidine Derivative 3a
ing heterocycles, we found that the reaction of a vinyl
amidine, formed from the 1-azaallyl anion and an aromatic
nitrile, with an acetal could lead to the production of a
pyrimidine derivative (Scheme 2). We report herein on a
Scheme 2
The reaction of this amidine with an acetal was then
investigated under several conditions, and the results are
shown in Table 1. When amidine 3a was reacted with
Table 1. Reaction of Amidine 3a with Acetals 4 and 5
Leading to the Trisubstituted Pyrimidine 6aa
highly effective and novel method for the synthesis of tri-
or tetrasubstituted pyrimidine derivatives by the four-
component coupling reaction of a functionalized silane, two
types of an aromatic nitrile, and an acetal. We also present
details of a new approach to the synthesis of 1,3,8-
run
acetal
solvent
temp (°C)
time (h)
yield (%)b
1
2
3
4
5
6
7
4
4
4
5
5
5
5
THF
THF
rt
24
24
24
24
24
2
trace
trace
6
13
62
reflux
100
rt
reflux
100
130
(5) For selected papers on pyrimidine synthesis via path d, see: (a)
Guzmaˆn, A.; Romero, M.; Talamaˆs, F. X.; Villena, R.; Greenhouse, R.;
Muchowski, J. M. J. Org. Chem. 1996, 61, 2470. (b) Guzmaˆn, A.; Romero,
M.; Talamaˆs, F. X.; Muchowski, J. M. Tetrahedron Lett. 1992, 24, 3449.
(6) For selected papers on pyrimidine synthesis via path e, see: (a)
Pourzal, A.-A. Synthesis 1983, 717. (b) Mart´ınez, A. G.; Fernandez, A. H.;
Alvarez, R. M.; Losada, M. C. S.; Vilchez, D. M.; Subramanian, L. R.;
Hanack, M. Synthesis 1990, 881. (c) Martˆınez, A. G.; Fernaˆndez, A. H.;
Fraile, A. G.; Subramanian, L. R.; Hanack, M. J. Org. Chem. 1992, 57,
1627. (d) Martˆınez, A. G.; Fernaˆndez, A. H.; Aˆ lvarez, R. M.; Vilchez, M.
D. M.; Gutieˆrrez, M. L. L.; Subramanian, L. R. Tetrahedron 1999, 55, 4825.
(e) Ghosez, L.; Jnoff, E.; Bayard, P.; Sainte, F.; Beaudegnies, R. Tetrahedron
1999, 55, 3387.
(7) For example, sets of numbers in 3,4- and 1,6-bond forming reactions
shown in Scheme 1 denote the position of bonds formed between N(3)-
C(4) and N(1)-C(6).
(8) (a) Konakahara, T.; Sato, K. Bull. Chem. Soc. Jpn. 1983, 56, 1241.
(b) Mangelinckx, S.; Giubellina, N.; Kimpe, N. D. Chem. ReV. 2004, 104,
2353.
(9) (a) Konakahara, T.; Kurosaki, Y. J. Chem. Res. 1989, 130. (b)
Konakahara, T.; Watanabe, A.; Maehara, K.; Nagata, M.; Hojahmat, M.
Heterocycles 1993, 35, 1171. (c) Konakahara, T.; Mojahmat, M.; Sujimoto,
K. Heterocycles 1997, 45, 271. (d) Konakahara, T.; Hojahmat, M.; Tamura,
S. J. Chem. Soc., Perkin Trans. 1 1999, 2803. (e) Hojahmat, M.;
Konakahara, T.; Tamura, S. Heterocycles 2000, 53, 629. (f) Konakahara,
T.; Ogawa, R.; Tamura, S.; Kakehi, A.; Sakai, N. Heterocycles 2001, 55,
1737. (g) Konakahara, T.; Sugama, N.; Yamada, A.; Kakehi, A.; Sakai, N.
Heterocycles 2001, 55, 313.
THF
THF
90
99
2
a X ) 3-methyl-5-isoxazolyl. b Isolated yields.
trimethyl orthoformate (4) in THF, the expected cyclization
reaction did not proceed (runs 1 and 2). However, when
acetal 4 was used in the absence of solvent, a small amount
of the desired 2,4,5-trisubstituted pyrimidine 6a was pro-
duced (run 3). The structure of 6a was confirmed by 1H and
13C NMR spectroscopy and by mass spectrometry. We next
chose N,N-dimethylformamide diethylacetal (5) as an ap-
propriate substrate, as the amide anion was expected to be a
better leaving group than a methoxy anion. As expected,
when cyclization of the amidine with the N,O-acetal was
conducted in THF at 70 °C for 24 h, the yield of product 6a
was increased to 62% (run 5). Moreover, it was noteworthy
4706
Org. Lett., Vol. 7, No. 21, 2005

that increasing the reaction temperature to 130 °C without
any reaction solvent dramatically improved the product yield
to 99% (runs 6 and 7).
Table 3. Reaction of Amidine 3a with Acetal 9a
To examine the general applicability of this cycliza-
tion, the reactions of five types of amidines with several
acetals were carried out under the above-optimized condi-
tions, and the results are summarized in Table 2. With
run additive
solvent
temp (°C) time (h) yield (%)b
Table 2. Cyclization of Amidine 3 with Acetal 5 or 7a
1
2
3
4
5
6
7
8
9c
160
130
reflux
130
130
36
24
48
24
24
24
72
65
60
34
trace
12
52
6
73
64
80
78
1,2-C6H4Cl2
PhMe
1,2-C6H4Cl2
ZnCl2
Zn(OTf)2 1,2-C6H4Cl2
ZnBr2
ZnCl2
ZnBr2
ZnBr2
1,2-C6H4Cl2
PhMe
PhMe
130
reflux
reflux
reflux
amidine 3
R1
PhMe
yield (%)b
a X ) 3-methyl-5-isoxazolyl. b Isolated yields. c ZnBr2 (0.4 equiv) was
used.
run
Ar
acetal
1
2
3
4
5
6
7
4-MeO-C6H4 2-pyrazyl
4-Me2N-C6H4 2-pyrazyl
3b
3c
3d
5
5
5
5
5
7
7
6b
6c
6d
6e
6f
88
90
92
90
97
80
82
4-Cl-C6H4
2-pyrazyl
the reaction described above to a 1,3,8-triazanaphthalene
derivative (pyrido[2,3-d]pyrimidin-5(1H)-one), the analo-
gous skeletons of which are widely distributed in natural
products and biologically active substances (Scheme 4).12
Ph
Ph
4-CF3-C6H4 3e
2-pyrimidyl
3f
3b
3c
4-MeO-C6H4 2-pyrazyl
4-Me2N-C6H4 2-pyrazyl
8b
8c
a X ) 3-methyl-5-isoxazolyl. b Isolated yields.
Scheme 4. Synthesis of 1,3,8-Triazanaphthalene Derivative 12
amidines containing an electron-donating group, an electron-
withdrawing group, and a heterocycle, when these systems
were treated with acetal 5, the desired trisubstituted pyrim-
idines 6 were obtained in all cases, in good to excellent yields
(runs 1-5). Similarly, by employing acetal 7, the present
reaction could be adapted to the preparation of a tetra-
substituted pyrimidine containing an alkyl group on C-4 atom
(runs 6 and 7).
We next attempted the synthesis of a tetrasubstituted
pyrimidine having an ethoxy group acting as the leaving
group. Unfortunately, when the reaction of amidine 3a with
tetraethyl orthocarbonate (9) was carried out under the above
conditions, the yield of the expected product 10 was moderate
(run 1 in Table 3). To increase the product yield, the reaction
was carried out using several different solvents and a Lewis
acid as an additive, and the results are listed in Table 3. We
found that when the reaction was conducted in PhMe at 110
°C in the presence of a catalytic amount of ZnBr2, the desired
product 10 was obtained in 80% yield (run 8).10
The reductive opening of the isoxazole ring with a catalytic
amount of Mo(CO)6 initially produced pyrimidine 11;13
intramolecular cyclization of the pyrimidine with the teth-
ered amino group was then effected with base, leading
to the production of the triazanaphthalene 12 in excellent
yield.
In conclusion, we have reported a new synthesis of tri- or
tetrasubstituted pyrimidines through the cyclization of a vinyl
amidine and an acetal, and the four-component coupling
reaction of a functionalized silane, two types of aromatic
nitriles, and an acetal. We have also succeeded in transform-
Finally, to illustrate the utility of an isoxazole ring,11 we
examined the transformation of pyrimidine 10 prepared by
(10) Typical Lewis acids, such as AlCl3, BF3•OEt2, Cu(OTf)2, and
MgBr2, were not effective for the reaction.
(11) We previously found that the isoxazole ring acts as a good
substituent to promote in situ generation of this type of 1-azaallyl anion
derivative,9a namely, the existence of the ring affects an easy preparation
of this type of a vinyl amidine derivative. Actually, the reaction of the
1-azaallyl anion having a pyridine ring instead of the isoxazole ring with
2-cyanopyrazine did not produce the corresponding vinyl amidine in a
practical yield (<10%). Although the reaction of a vinyl amidine involving
other aromatic rings with an acetal was not examined, the reaction would
proceed. The detailed results will be published elsewhere.
(12) (a) Gangjee, A.; Adair, O. O.; Queener, S. F. J. Med. Chem. 2003,
46, 5074. (b) Perner, R. J.; Gu, Y.-G.; Lee, C.-H.; Bayburt, E. K.; McKie,
J.; Alexander, K. M.; Kohlhaas, K. L.; Wismer, C. T.; Mikusa, J.; Jarvis,
M. F.; Kowaluk, E. A.; Bhagwat, S. S. J. Med. Chem. 2003, 46, 5249. (c)
Sanmartˆın, C.; Echeverrˆıa, M.; Mendˆıvil, B.; Cordeu, L.; Cubedo, E.; Garcˆıa-
Foncillas, J.; Font, M.; Palop, J. A. Bioorg. Med. Chem. 2005, 13, 2031.
(13) Li, C.-S.; Lacasse, E. Tetrahedron Lett. 2002, 43, 3565.
Org. Lett., Vol. 7, No. 21, 2005
4707

ing a pyrimidine framework containing an isoxazolyl group
and an ethoxy group to the 1,3,8-triazanaphthalene skeleton.
Further investigations directed toward the preparation of other
types of pyrimidine derivatives are currently in progress.
Project for Private Universities: a matching fund subsidy
from MEXT, 2000-2004.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of novel compounds prepared.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was partially supported by
Grants-in-Aid for Scientific Research from MEXT (16550148),
2004-2005, a grant from the Japan Private School Promotion
Foundation, and a fund for “High-Tech Research Center”
OL051901L
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Org. Lett., Vol. 7, No. 21, 2005