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C. F. Regan et al.
LETTER
the literature, especially for analogues unsubstituted at the
2-position. The homolytic approach has proven a good al-
ternative strategy to the more conventional methods such
as described in Scheme 2, by reducing the number of steps
and increasing the yield. Useful quantities (>10 g) of ethyl
5-bromopyrimidine-4-carboxylate were successfully syn-
thesized in 48% yield in one step from inexpensive 5-bro-
mopyrimidine.27 The reaction was surprisingly
regioselective, polysubstitution was minimized using a
toluene–water biphasic solvent system, and the addition
of acetic acid was found to increase the conversion. Our
work represents a notable example of radical chemistry
applied to the preparation of pharmacologically active
molecules.
Table 4 Homolytic Ethoxycarbonylation of Diversely Substituted
Pyrimidines
R1
N
R1
N
CO2Et
R2
Me
CO2Et
+
N
N
R2
O
R3
R3
Entry R1
R2
R3
Conversion Yield
(%)a,b (%)c
1
2
H
Br
Cl
I
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
100 (92) 74, 48d
100 (83) 74
99 (90) 50
H
3
H
4
Cl
F
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
Br
Br
Br
15 (6)
8 (5)
–
–
–
–
–
–
References and Notes
5
(1) Capdeville, R. B. E.; Zimmerman, J.; Matter, A. Nat. Rev.
Drug Discovery 2002, 493.
6
SMe
4 (4)
(2) Das, K. C. A. D.; Lewi, P. J.; Heeres, J.; de Jonge, M. R.;
Koymans, L. M. H.; Vinkers, H. M.; Daeyaert, F.; Ludovici,
D. W.; Kukla, M. J.; De Corte, B.; Kavash, R. W.; Ho, C. Y.;
Ye, H.; Lichtenstein, M. A.; Andries, K.; Pauwels, R.;
de Bethune, M.-P.; Boyer, P. L.; Clark, P.; Hughes, S. H.;
Janssen, P. A. J.; Arnold, E. J. Med. Chem. 2004, 2550.
(3) Stenbuck, P.; Hood, H. M. US 3049544, 1962.
(4) Lednicer, D. The Organic Chemistry of Drug Synthesis, Vol.
7; Wiley-Interscience: Hoboken, 2008, 7.
(5) Pierre, F.; O’Brien, S. E.; Haddach, M.; Bourbon, P.;
Schwaebe, M. K.; Stefan, E.; Darjania, L.; Stansfield, R.;
Ho, C.; Siddiqui-Jain, A.; Streiner, N.; Rice, W. G.; Anderes,
K.; Ryckman, D. M. Bioorg. Med. Chem. Lett. 2011, 21,
1687.
(6) Battistutta, R.; Cozza, G.; Pierre, F.; Papinutto, E.; Lolli, G.;
Sarno, S.; O’Brien, S. E.; Siddiqui-Jain, A.; Haddach, M.;
Anderes, K.; Ryckman, D. M.; Meggio, F.; Pinna, L. A.
Biochemistry 2011, 50, 8478.
(7) Pierre, F.; Chua, P. C.; O’Brien, S. E.; Siddiqui-Jain, A.;
Bourbon, P.; Haddach, M.; Michaux, J.; Nagasawa, J.;
Schwaebe, M. K.; Stefan, E.; Vialettes, A.; Whitten, J. P.;
Chen, T. K.; Darjania, L.; Stansfield, R.; Anderes, K.;
Bliesath, J.; Drygin, D.; Ho, C.; Omori, M.; Proffitt, C.;
Streiner, N.; Trent, K.; Rice, W. G.; Ryckman, D. M. J. Med.
Chem. 2011, 54, 635.
7
SO2Me
CO2Me
CN
8 (0)
8
23 (19)
7 (0)
9
10
11
12
13
14
15
16
17
18
19
Me
96 (82) 52
79 (65) 25
86 (62) 36
62 (55) 15
68 (58) 46
NH2
NHi-Pr
N-pyrrolidine
OMe
H
17 (13)
9 (8)
–
–
–
H
CO2Me
Ph
H
4 (4)
H
Me
86 (77) 65
97 (80) 40
H
NH2
a Conversion, expressed by the disappearance (GC–MS) of starting
material.
b Number in parentheses is product (%), a GC–MS peak surface area
ratio of product/byproducts.
(8) Barreau, M.; Cotrel, C.; Jeanmart, C. US 4110450, 1978.
(9) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew.
Chem. Int. Ed. 2006, 45, 2958.
(10) Kress, T. J. J. Org. Chem. 1979, 44, 2081.
(11) Jones, C. D.; Winter, M. A.; Hirsch, K. S.; Stamm, N.;
Taylor, H. M.; Holden, H. E.; Davenport, J. D.; Krumkalns,
E. V.; Suhr, R. G. J. Med. Chem. 1990, 33, 416.
(12) Bernardi, R. C. T.; Galli, R.; Minisci, F.; Perchinunno, M.
Tetrahedron Lett. 1973, 9, 645.
c Isolated yield after chromatography. All reactions were performed
on a 2-mmol scale.
d Performed on a 100-mmol scale.27
philic alkoxycarbonyl radical.12 An EWG at the 2-position
may prohibit protonation of the weakly basic 5-bromo-
pyrimidine core whereas an EDG increases the basicity of
the pyrimidine allowing protonation to occur and substi-
tution to take place. Finally, it is noteworthy that the regio-
selectivity was high in all the examples of Table 4. The 2-
isomer was either undetected or present in quantities
smaller than 3%, as measured by GC–MS.
(13) Minisci, F.; Fontana, F.; Vismara, E. J. Heterocycl. Chem.
1990, 27, 79.
(14) Minisci, F. Synthesis 1973, 1.
(15) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28,
489.
(16) Heinisch, G.; Lotsch, G. Angew. Chem., Int. Ed. Engl. 1985,
24, 692.
(17) Yurovskaya, M. A.; Mitkin, O. D. Chem. Heterocycl.
Compd. 1997, 33, 1299.
(18) Haider, N.; Kaferbock, J. Heterocycles 2000, 53, 2527.
(19) Coppa, F.; Fontana, F.; Lazzarini, E.; Minisci, F.; Pianese,
G.; Zhao, L. Tetrahedron Lett. 1992, 33, 3057.
In summary, we have developed a novel and practical syn-
thesis of 5-halopyrimidine-4-carboxylic acid esters via
the Minisci alkoxycarbonylation of 5-halopyrimidines.
Methods for the preparation of these molecules are rare in
Synlett 2012, 23, 443–447
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