Copper-mediated coupling of aminopurines and aminopyrimidines with arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2003.10.088

Selective N-arylation of aminopurines and aminopyrimidines 1-3 with arylboronic acids 4-6 was explored using copper(II) acetate and the corresponding N-arylated purine and pyrimidine derivatives 7-15 were obtained in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2003.10.088

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 195–197
Copper-mediated coupling of aminopurines and
aminopyrimidines with arylboronic acids
*
Ramesh A. Joshi, Pratap S. Patil, M. Muthukrishnan,
C. V. Ramana and Mukund K. Gurjar*
Division of Organic Chemistry Technology, National Chemical Laboratory, Dr. Homibhabha Road, Pune 411 008, India
Received 1August 2003; revised 6 October 2003; accepted 17 October 2003
Dedicated to Professor Goverdhan Mehta on the occasion of his 60th birthday
Abstract—Selective N-arylation of aminopurines and aminopyrimidines 1–3 with arylboronic acids 4–6 was explored using cop-
per(II) acetate and the corresponding N-arylated purine and pyrimidine derivatives 7–15 were obtained in moderate to good yields.
Ó 2003 Elsevier Ltd. All rights reserved.
The purine/pyrimidine substructure and their amino
substituted congeners are frequently occurring motifs in
commercially available drugs. For example, aryl 2-am-
inopyrimidines have been reported for the treatment of
pyrimidines with suitable amines is used as a general
method for the synthesis of amino substituted purines/
pyrimidines. However, the substitution reactions are
sluggish in the case of electron rich or even with neutral
halogenated purines/pyrimidines.
3
1
diseases modulated by the adenosine receptor. The
anti-HIV/HBV drugs abacavir penciclovir and the anti-
atherosclerotic aronixil, are some of the aminopurine
and aminopyrimidine drugs available presently in the
market (Fig. 1). Conventionally, nucleophilic aromatic
substitution of electron deficient halogenated purines/
Recently, in a drug discovery led structure modification
programme, we encountered a need for an efficient
methodology for the synthesis of N-arylamino purine/
pyrimidines. With regard to practicality, we chose to
2
4
explore Chan–Evans–LamÕs copper mediated O/N-
arylations using arylboronic acids. The present
communication describes the amenability of this meth-
odology to the successful N-arylation of aminopurines
as well as of aminopyrimidines for the first time.
HN
O
N
N
N
HN
N
H N
N
2
5
6
7
N
OH
OH
Easily available purine 1, pyrimidines 2 and 3, and
arylboronic acids 4–6 (Fig. 2) were chosen as model
substrates in this regard. Initial explorations started with
H N
N
2
OH
Penciclovir
Abacavir
Cl
N
OH
H C
N
N
N
Cl
Cl
3
H
H
CH3
O
N
N
Me
N
N
N
Aronixil
SMe
H N
N
1
H N
N
2
SMe
H N
N
3
2
2
2
Bn
Figure 1. Aminopurine and aminopyrimidine drugs.
B(OH)2
B(OH)
2
B(OH)2
Keywords: N-arylation; arylboronic acid; aminopurine; aminopyrim-
idine; copper(II) acetate.
MeO
F
4
5
6
*
Corresponding authors. Tel.: +91-20-5893614; fax: +91-20-5882456;
e-mail: rajoshi@dalton.ncl.res.in; gurjar@dalton.ncl.res.in
Figure 2. Selected purines/pyrimidines and arylboronic acids.
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.088

196
R. A. Joshi et al. / Tetrahedron Letters 45 (2004) 195–197
the arylation of the chloro-guanine derivative 1 with
phenylboronic acid 4. After a careful evaluation of a set
of parallel experiments we arrived at conditions
To conclude, a general methodology for coupling
aminopurines and aminopyrimidines with arylboronic
acids has been explored using stoichiometric amounts of
Cu(II) acetate. Studies on orthogonal C- and N-aryl-
ation of 1–3 using arylboronic acids in the presence of
copper and/or palladium are in progress.
2
involving the use of 2 equiv of Cu(OAc) , DMAP in
catalytic amounts and 3 equiv of boronic acid, added in
three portions to the reaction mixture at room temper-
ature. The arylated guanine derivative 7 was obtained in
4
9% yield. Similarly, coupling of guanine 1 with boronic
8
acids 5 and 6 gave the corresponding N-aryl guanines 8
and 9 in 67% and 65% yields, respectively. As anti-
cipated, no cross-coupling of the chloro substituent with
phenylboronic acid was observed. In general, coupling
of halo-purines/pyrimidines with phenylboronic acid is
Acknowledgements
9
We thank Mr. V. G. Shah for providing the microana-
lytical data and Mr. V. T. Sathe for recording the NMR
spectra.
9
carried out with palladium catalysts (Scheme 1).
After initial success in the arylation of guanine deriva-
tive 1, we extended the same protocol to the N-arylation
6
of 5-methyl-2-methylthiopyrimidin-4-amine 2 and of
7
References and Notes
4
-chloro-2-methylthiopyrimidin-6-amine 3 with aryl-
boronic acids 4–6. N-arylated pyrimidines 10–12 and
3–15, respectively, were obtained in moderate to good
1
. Borroni, E. M.; Huber-Trottmann, G.; Kilpatrick, G. J.;
Norcross, R. D. Patent WO 0162233, 2001.
1
8
yields. It has already been reported by Liebeskind and
Srogl, that Pd (cat.) in the presence of stoichiometric
amounts of Cu(I) salts can be used for thioether cross-
2. (a) Ferrero, M.; Gotor, V. Chem. Rev. 2000, 100, 4319–
4348; (b) Balzarini, J.; Naesens, L.; Clercq, E. D. Curr.
Opin. Microbiol. 1998, 1, 535–546.
3. Fiorini, M. T.; Abell, C. Tetrahedron Lett. 1998, 39, 1827–
1
10
coupling with arylboronic acids. However, in our
present experiments [using Cu(II) salts] with either 2 or
830.
4
. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.;
Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–2936; (b)
Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett.
3
, we have not noticed the presence of any products
resulting from the thioether cross-coupling. The stability
of both chloro and thiomethyl groups under these con-
ditions provides an opportunity for orthogonal N/C-
arylations using all three substituents of pyrimidine 3
1
998, 39, 2937–2940; (c) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944. For a
comprehensive compilation of citations dealing with
copper mediated N-arylations using arylboronic acids
see: (d) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C.
G. Tetrahedron Lett. 2003, 44, 4927–4931.
(
Scheme 2).
5
. Langli, G.; Gundersen, L. L.; Rise, F. Tetrahedron 1996,
5
Cl
N
B(OH)
2
Cl
N
2, 5625–5638.
R
N
N
Cu(OAc)
2
N
N
6. Brooks, J. D.; Charlton, P. T.; Macey, P. E.; Peak, D. A.;
Short, W. F. J. Chem. Soc. 1950, 452–459.
7. Baker, B. R.; Joseph, J. P.; Schaub, R. E. J. Org. Chem.
1954, 19, 631–637.
N
+
Et N, DMAP
H N
N
3
N
H
2
CHCl
Bn
3
Bn
R
4 - 6
2
4 h
1
7 (49%) R = H
(67%) R = OMe
(65%) R = F
8
. At room temperature, a suspension of purine 1 (260 mg, 1
mmol), p-methoxyphenylboronic acid 5 (150 mg, 1 mmol)
and cupric acetate (36 mg, 2 mmol) in chloroform (15 mL)
was treated with triethylamine (200 mg, 2 mmol) and
DMAP (20 mg) and the stirring was continued at room
temperature. The reaction mixture was treated with
additional 5 (150 mg, 1 mmol) after 6 h and again after
8
9
Scheme 1.
1
2 h and stirring continued for another 24 h. The reaction
mixture was filtered through Celite and the Celite pad was
washed with chloroform and the combined filtrates were
concentrated and purified over a silica gel column. The N-
aryl purine 8 (245 mg, 67%) was obtained as a colourless
solid. (a) Spectral data of 8: mp 1 9°8C; H NMR
3
(500 MHz, CDCl ) d 3.65 (s, 3H), 5.16 (br s, 2H), 6.72 (d,
B(OH)2
R
Cu(OAc)2
R
Me
N
Me
N
+
Et N, DMAP
3
N
H
N
SMe
1
H N
2
N
SMe
CHCl
3
2
4 h
1
1
1
0 (65%) R = H
2
4 - 6
1 (69%) R = OMe
2 (72%) R = F
Cl
2H, J ¼ 8:9 Hz), 7.17–7.23 (m, 5H), 7.45 (d, 2H,
1
3
J ¼ 8:9 Hz), 7.69 (s, 1H); C NMR (125 MHz, CDCl
3
)
Cl
B(OH)
2
d 47.1, 55.1, 113.5, 120.4, 127.5, 128.1, 128.6, 132.6, 134.9,
141.7; MS-ESI: 389.05 (85%), 366.05 ([M+1] , 100%),
R
þ
Cu(OAc)2
N
N
+
2
96.05 (20%), 279.05 (20%), 252.05 (50%), 250.05 (50%);
Anal. Calcd for C19 O: C, 62.38; H, 4.41; N,
9.14; Found: C, 62.06; H, 4.69; N, 18.91. (b) Spectral
Et N, DMAP
H N
2
N
SMe
3
N
H
N
SMe
H16ClN
5
CHCl
3
R
1
2
4 h
1
1
1
3 (70%) R = H
4 (72%) R = OMe
5 (69%) R = F
3
1
4
- 6
data of 11: mp: 112 °C; H NMR (500 MHz, CDCl
2.10 (s, 3H), 2.48 (s, 3H), 3.82 (s, 3H), 6.36 (br s, 1H), 6.92
3
) d
(
d, 2H, J ¼ 8:9 Hz), 7.45 (d, 2H, J ¼ 8:9 Hz), 7.69 (s, 1H);
1
3
Scheme 2.
3
C NMR (125 MHz, CDCl ) d 13.3, 14.1, 55.5, 108.9,

R. A. Joshi et al. / Tetrahedron Letters 45 (2004) 195–197
197
1
3
13.9, 123.4, 131.4, 154.4, 156.4, 158.7, 169.3; MS-ESI:
þ
129.5, 157.7, 159.9, 162.1, 172.3; MS-ESI: 284.05 (80%),
þ
þ
00.05 ([M+K] , 5%), 278.05 ([M+NH
þ
3
] , 15%), 264.05
282.05 ([M+1] , 100%), 209.05 (45%); Anal. Calcd for
(
30%), 262.05 ([M+1] , 100%); Anal. Calcd for
12 3
C H12ClN OS: C, 51.15; H, 4.29; N, 14.91; S, 11.38;
C
13
H
15
N
3
OS: C, 59.74; H, 5.79; N, 16.08; S, 12.27;
Found: C, 59.89; H, 6.07; N, 15.76, S, 11.83. (c) Spectral
Found: C, 50.89; H, 4.51; N, 14.56; S, 10.97.
9. Wade, J. V.; Krueger, C. A. J. Comb. Chem. 2003, 5, 267–
272.
10. (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979–981;
(b) Kusturin, C. L.; Liebeskind, L. S.; Neumann, W. L.
Org. Lett. 2002, 4, 983–985.
1
data of 14: mp: 124 °C; H NMR (300 MHz, CDCl
3
) d
.52 (s, 3H), 3.84 (s, 3H), 6.18 (s, 1H), 6.92 (d, 2H,
2
1
3
J ¼ 8:9 Hz), 7.20 (d, 2H, J ¼ 8:9 Hz);
C NMR
(
3
125 MHz, CDCl ) d 14.1, 55.5, 97.6, 114.8, 125.9,