Copper-catalyzed cross-coupling reactions of nucleobases with arylboronic acids: An efficient access to N-arylnucleobases

Article abstract of DOI:10.1002/ejoc.200500589

An efficient avenue for the direct N-arylation of nucleobases with arylboronic acids that is catalyzed by simple copper salts was discovered. The N-arylnucleobases were obtained in excellent yields at room temperature within 45 min when methanol and water

Full text of DOI:10.1002/ejoc.200500589

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200500589
Copper-Catalyzed Cross-Coupling Reactions of Nucleobases with Arylboronic
Acids: An Efficient Access to N-Arylnucleobases
Yang Yue,[a] Zhang-Guo Zheng,[a] Bo Wu,[a] Chuan-Qin Xia,[a] and Xiao-Qi Yu*[a]
Keywords: N-arylation / Cytosine / Adenine / Boronic acid / Copper / Cross-coupling
An efficient avenue for the direct N-arylation of nucleobases
with arylboronic acids that is catalyzed by simple copper
salts was discovered. The N-arylnucleobases were obtained
in excellent yields at room temperature within 45 min when
methanol and water were used as a mixed solvent. Under
these conditions, the coupling reaction tolerates both elec-
tron-donating and electron-withdrawing substituents at the
o-, m-, or p-positions of phenylboronic acid and gives the
corresponding coupling products in moderate to excellent
yields. Experimental results show that this route is the most
efficient, facile, and mild method for the synthesis of N-aryl-
nucleobases.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
N-Arylnucleobases are very important compounds be-
The second method is the direct N-arylation of purine
cause of their significant pharmaceutical, biological, and with arylboronic acids through a copper-catalyzed reac-
chemical activities. Several arylnucleobases are agonists or tion.[6] Up to now, only a few examples of the direct N-
antagonists for various receptors[1] and enzymes.[2] Other arylation of N9 of purine were reported. Schultz and co-
bioactivities reported include those against the rubella workers reported the reaction of 2,6-dichloropurine with ar-
virus,[3] and inhibition of rabbit skeletal muscle phosphoryl- ylboronic acids in the presence of cupric acetate and trieth-
ase b.[4]
ylamine, and the desired N9-aryl product was obtained in
The arylation of purine had been reported. To date, there moderate yields.[6a] Recently, an efficient procedure for the
are two ways for the synthesis of arylpurine. One classical regioselective arylation of N9 of purines was reported by
method for the preparation of 9-arylpurines is based on het- Bakkestuen and Gundersen,[6b] and these authors found
erocyclization[5] (Scheme 1). However, it was not an efficient that purines with a variety of substituents can be efficiently
access because of the many tedious steps involved.
arylated at the N9 position with complete regioselectivity
and in most cases high chemoselectivity when treated with
arylboronic acids in the presence of copper() acetate, mo-
lecular sieves, and a base. Unfortunately, N-arylation of ad-
enine was not successful under these anhydrous reaction
conditions.
In addition, there are a few cases for the arylation of
cytosine. Tore reported a case (Scheme 2) for the prepara-
tion of 1-phenylcytosine 2 in which the appropriately substi-
tuted pyrimidinone 1 was reacted with diphenyliodonium
salts in DMF.[7] However, low yields of N-arylpyrimidi-
nones were obtained.
Scheme 1. R = C-substituent; X, Y, Z = other substituents.
[a] Department of Chemistry, Key Laboratory of Green Chemistry
and Technology (Ministry of Education), Sichuan University,
Chengdu, Sichuan 610064, China
Fax: + 86-28-85415886
E-mail: xqyu@tfol.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 2.
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Copper-Catalyzed Cross-Coupling Reactions of Nucleobases with Arylboronic AcidsSHORT COMMUNICATION
Our experience with the copper-catalyzed N-arylation of and with the use of simple copper salts has not been ex-
a number of NH-containing substrates with arylboronic ac- plored previously. Experimental results show that this route
ids[8] inspired us to take a closer look at the N-arylation of is the most efficient, facile, and mild method for the synthe-
nucleobases. In this paper, we report a new method for the sis of N-arylnucleobases.
synthesis of N-arylnucleobases. By using this method, nuc-
Typically, the coupling reaction of N-heterocycles with
leobases can be efficiently arylated at the N9 position of arylboronic acids is usually performed under anhydrous
adenine (4) and the N1 position of cytosine (3) with com- conditions.[9] To our surprise, the coupling reaction of cyto-
plete regioselectivity when treated with arylboronic acids in sine (3) with phenylboronic acid (5a) that is catalyzed by
the presence of copper() acetate as depicted in Scheme 3 Cu(OAc)2 only gave trace amounts of the coupling product
To the best of our knowledge, the direct coupling of nucleo- 6a with CH3OH as the reaction solvent and in the presence
bases with arylboronic acids performed in protic solvents of 4 Å molecular sieves even after 24 h. On the contrary,
Scheme 3.
Table 1. Optimization of the reaction conditions for the coupling reaction.
Entry[a]
PhB(OH)2
[mmol]
Copper salt
[0.5 mmol]
Base
CH3OH/H2O
[v:v]
Reaction
temperature
[°C]
Yield
of 6a
[%][b]
[1 mmol]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0.5
1.5
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuSO4·5H2O
CuCl
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
Pyridine
CH3OH
8:1
5:1
4:1
3:1
2:1
1:1
H2O
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
trace
44
84
90
86
69
22
0
90
trace
trace
trace
trace
58
40
16
11
82
75
54
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
DMAP
1,10-Phenanthroline
TEA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
40
60
80
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
CuCl2
CuBr
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
88
86
67
90
91
[a] Conditions: 3 (0.5 mmol), 45 min. [b] Isolated yield.
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Y. Yue, Z.-G. Zheng, B. Wu, C.-Q. Xia, X.-Q. Yu
SHORT COMMUNICATION
when Cu(OAc)2 was replaced by Cu(OAc)2·H2O, the yield phenylboronic acids by both electron-donating and elec-
of the coupling product was increased significantly in the tron-withdrawing substituents at the o-, m-, or p-position
absence of 4 Å molecular sieves. On the basis of this result of the phenyl group (Table 2, entries 3, 4, 5, 8, 10 13 and
we tried to study the coupling reaction in a mixed protic 14).
solvent and found that when a small quantity of water
(CH3OH/H2O 8:1) was added, the coupling yield was in-
creased to 44%, and when a 4:1 ratio for CH3OH/H2O was
Table 2. Coupling reaction of 3 and 4 with various substituted
phenylboronic acids.[10]
used, the coupling yield was 90% (Table 1, entries 2 and 4).
However, below a ratio of 3:1, the yield of the coupling
product continuously decreased (Table 1, entries 5, 6, 7 and
8). So the mixed solvent with a 4:1 ratio for CH3OH/H2O
is the optimum solvent for the coupling of cytosine with
arylboronic acid, and the results are shown in Table 1. It
can therefore be deduced that the solvent effect is one of
the most important factors that influence the coupling of
nucleobases with arylboronic acids – the mixed solvent is
essential to the coupling reaction.
Subsequently, our exploration focused on the cross-coup-
ling of cytosine and phenylboronic acid under different re-
action conditions. Detailed results are summarized in
Table 1. The effect of various bases and/or Cu ligands on
the reaction of cytosine and phenylboronic acid was studied
(Table 1, entries 9–13). Only with TMEDA can the coupling
product be obtained in good yield (90%, entry 9); however,
the cross-coupling reaction is not efficient with TEA, pyri-
dine, DMAP, and 1,10-phenanthroline as base (Table 1, en-
tries 10–13). The effect of reaction temperature on the
chemical yield was also examined. The results show that at
room temperature, a yield of 90% was obtained (Table 1,
entry 9); however, lower yields, 58, 40, 16, and 11%, were
obtained when the reaction was carried out at 0, 40, 60 and
80 °C, respectively (Table 1, entries 14–17). Therefore, the
optimum temperature is room temperature. In addition, se-
veral simple copper salts such as CuSO4·5H2O, CuCl,
CuCl2, CuBr, and Cu(OTf)2 were tested as catalysts to pro-
mote the coupling reaction. As shown in Table 1, all the
copper salts that we used gave the desired products in high
yields (Table 1, entries 18, 19, 21 and 22), except for CuCl2,
which gave the coupling product in moderate yield (Table 1,
entry 20). The ratio of phenylboronic acid to cytosine is
also an important factor for this coupling reaction. We
found that when the ratio is more than 1:1, N1-phenylcyto-
sine was obtained in over 90% yield (Table 1, entries 9, 24
and 25). Decreasing the ratio to 0.5:1, N1-phenylcytosine
was obtained in only 67% yield (Table 1, entry 23). So the
effect of the amount of phenylboronic acid on the coupling
reaction was slight with an increase in phenylboronic acid
loading from 1 equiv. to 2 equiv.
[a] Conditions:
3 or 4 (0.5 mmol), substituted boronic acid
Several substituted arylboronic acids were evaluated un-
der the above-mentioned reaction conditions, and adenine
was also used as a coupling substrate. As shown in Table 2,
the catalytic system has proven to be highly efficient for the
(1 mmol), TMEDA (1 mmol), Cu(OAc)2 (0.5 mmol), methanol
(36 mL), water (9 mL), r.t., 45 min. [b] Isolated yield.
In summary, a mild and efficient avenue for the direct
coupling of other arylboronic acids with cytosine or ade- N-arylation of nucleobases with arylboronic acids that is
nine. The results show that when the o-, m-, and p-tolylbo- catalyzed by simple copper salts, which is cost-effective,
ronic acids, phenylboronic acids, and naphthylboronic acid easy to handle, and does not need an insert atmosphere, was
were used, the corresponding N-arylation products were developed for the first time. The N-arylnucleobases were
obtained in over 80% yield (Table 2, entries 1, 2, 6, 7, 9, 11 obtained in excellent yields at room temperature within
and 12). Moderate yields were obtained with substituted 45 min when methanol and water was used as a mixed sol-
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Eur. J. Org. Chem. 2005, 5154–5157

Copper-Catalyzed Cross-Coupling Reactions of Nucleobases with Arylboronic AcidsSHORT COMMUNICATION
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electron-donating and electron-withdrawing substituents at
the o-, m-, or p-positions of phenylboronic acid and gives
corresponding coupling products in moderate to excellent
yields.
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Acknowledgments
[8] a) J.-B. Lan, L. Chen, X.-Q. Yu, J.-S. You, R.-G. Xie, Chem.
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This work was financially supported by the National Natural Sci-
ence Foundation of China (Nos.: 20132020, 20372051, 20471038),
Program for New Century Excellent Talents in University, Special-
ized Research Fund for the Doctoral Program of Higher Educa-
tion, and Scientific Fund of Sichuan Province for Outstanding
Young Scientists.
[9] S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42,
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[10] General Procedure for the Cross-Coupling Reaction: Compound
3 (0.0556 g, 0.5 mmol), 5 (1 mmol), Cu(OAc)2·H2O (0.099 g,
0.5 mmol), TMEDA (150 µL, 1 mmol), CH3OH (36 mL), and
H2O (9 mL) were placed in a 100 mL vial. The reaction mixture
was vigorously stirred under an atmosphere of air at room tem-
perature for 45 min. The solvents were evaporated, and the
product purified by flash column chromatography on silica gel
(CH2Cl2/CH3OH, 5:1) to give 6. Selected Data for N1-Phenyl-
cytosine (6a): White powder solid. M.p. Ͼ300 °C. IR (neat):
3334, 3066, 1638, 1486, 1372, 1294, 1174, 1128, 784, 698 cm–1.
1H NMR (400 M Hz, [D6]DMSO): δ = 5.78–5.80 (d, J =
8.0 Hz, 1 H, CH), 7.24 (s, 1 H, NH), 7.32 (s, 1 H, NH), 7.34–
7.38 (m, 3 H, Ph-H), 7.45 (t, 2 H, J = 7.6 Hz, Ph-H), 7.62–
7.64 (d, J = 8.0 Hz, 1 H, CH) ppm. 13C NMR (200 MHz, [D6]-
DMSO): δ = 94.26, 126.75, 127.50, 128.99, 141.46, 146.03,
154.93, 166.21 ppm. MS (ESI): m/z = 188.3 [M + H]+. HRMS
(ESI): for C10H10N3O [M + H]+: calcd. m/z = 188.0818; found
m/z = 188.0822.
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Received: August 2, 2005
Published Online: November 2, 2005
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