CuBr catalyzed C-N cross coupling reaction of purines and diaryliodonium salts to 9-arylpurines

Article abstract of DOI:10.1039/c1ob05333g

CuBr was found to be an efficient catalyst for the C-N cross coupling reaction of purine and diaryliodonium salts. 9-Arylpurines were synthesized in excellent yields with short reaction times (2.5 h). The method represents an alternative to the synthesis of 9-arylpurines via Cu(ii) catalyzed C-N coupling reaction with arylboronic acids as arylating agents. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05333g

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CuBr Catalyzed C–N cross coupling reaction of purines and diaryliodonium
salts to 9-arylpurines†
Hong-Ying Niu,a,b Chao Xia,a Gui-Rong Qu,*a Qian Zhang,a Yi Jiang,a Run-Ze Mao,a De-Yang Lia and
Hai-Ming Guo*a
Received 3rd March 2011, Accepted 20th May 2011
DOI: 10.1039/c1ob05333g
CuBr was found to be an efficient catalyst for the C–N
cross coupling reaction of purine and diaryliodonium salts.
9-Arylpurines were synthesized in excellent yields with short
reaction times (2.5 h). The method represents an alternative
to the synthesis of 9-arylpurines via Cu(II) catalyzed C–N
coupling reaction with arylboronic acids as arylating agents.
Diaryliodonium salts,12 which represent one of the most popular
classes of hypervalent iodine compounds,13 have been widely used
as important arylating agents in organic synthesis.14 During the
ongoing course of our study on the synthesis of purine analogues15
and according to the reports on N9-arylation of purines, we
thought that diaryliodonium salts could be utilized as arylating
agents for the synthesis of N9-arylpurines, which has never been
reported as far as we know.
Initially, we investigated the direct arylation between 2,6-
dichloropurine (1a) and Ph2I+Cl- (2a). Several Cu-catalysts were
investigated for this reaction without the protection of nitrogen
(Table 1, entries 1–3). The catalytic activity of Cu(I) was better
than that of Cu(II) under the same reaction conditions and thus
CuBr was chosen as the catalyst for the reaction. We were delighted
to find that the yield was improved dramatically when the process
was conducted under nitrogen atmosphere (entry 4). The screening
of different bases showed that K2CO3 was the best choice for
the reaction (entries 4–6). Under the same reaction conditions,
reducing the amount of 2a also led to lower yields, so the amount
of 2a was chosen as 1.5 eq (entries 6–7). The solvent effect was
also examined and the results showed that CH2Cl2 was the best
choice (entries 7–10).
Under the optimized reaction conditions, various purines were
employed as substrates, and the representative results are listed
in Table 2. Various purine derivatives could react with Ph2I+Cl-
in excellent yields (entries 1–4). Purine derivatives with nitrogen
or oxygen-containing substituents could also afford the desired
products in good to excellent yields (entries 5–9). When 2-chloro-6-
amino-9H-purine (1j) was used as the substrate, no desired product
was formed, which might be due to the fact that 1j is difficult to
dissolve in CH2Cl2 (entry 10).
Some other diaryliodonium salts, including electron-donating
and electron-withdrawing substituents, were also investigated
under the optimized reaction conditions (Table 3). Good yields
were observed when the methyl group was at the para position
(entry 2), and halogen-substituted diaryliodonium salts could also
react smoothly with 2,6-dichloropurine to give the corresponding
products in good to excellent yields (entries 3–4). Because of steric
hindrance, (2,4-Me2C6H3)2I+Br- needed more catalyst to improve
the reaction and gave a moderate yield (entry 5). When there
was no methyl group at the C2 position, the diaryliodonium salts
gave excellent yields (entries 6–7). Due to the poor solubility,
Purine compounds show a wide range of biological and pharma-
ceutical activities such as antiviral or anticancer activities.1 N9-
Substituted purines have applications in the treatment of HSV
infections,2 HIV,3 and hepatitis B.4 Furthermore, N9-arylpurines
are reported to act as enterovirus inhibitors,5 potential antituber-
culosis drugs with high antimycobacterial activities,6 antitumor
agents against NCI-H460 (lung), MCF-7 (breast) and SF-268
(CNS) cancer cell lines.7 Hence, there is considerable interest in
the development of more efficient methods for the synthesis of
N9-arylpurines due to their unique biological activities.
There are two routes for the synthesis of N9-arylpurines. One
route is through heterocyclization from substituted pyrimidine
analogues which usually requires multiple steps.8 Another route is
direct N9-arylation of purine via a C–N cross-coupling reaction.
Aryl iodides and arylboronic acids were widely used as arylating
agents in the presence of copper(II) or palladium(II) for the direct
N9-arylation of purines to give moderate yields.9 Gundersen
et al. reported the synthesis of 9-arylpurines in the presence of
copper(II) acetate used arylboronic acids as arylation agents.9a And
Buchwald and coworkers reported CuI(I) catalyzed N-arylation
of nitrogen-containing heterocycles employing aryl iodides as
arylating agents in the presence of diamine ligands, and only one
purine analogue was obtained in a yield of 66%.10
Starting from the early 1990s, the chemistry of polyvalent iodine
organic compounds has experienced an explosive development.11
aCollege of Chemistry and Environmental Science, Key Laboratory
of Green Chemical Media and Reactions of Ministry of Education,
Henan Normal University, Xinxiang, 453007, China. E-mail: guohm518@
hotmail.com, quguir@sina.com; Fax: 86 373 3329276
bSchool of Chemistry and Chemical Engineering, Henan Institute of Science
and Technology, Xinxiang, 453003, China
† Electronic supplementary information (ESI) available: Experimental
procedures, compound characterizations, and the copies of 1H NMR
and 13C NMR spectra. CCDC reference number 825895. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05333g
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Table 1 Optimization of the direct N9-arylation catalyzed by Cu
Table 2 Direct phenylation of various purines at the N9 position with
compoundsa
Ph2I+Cl-a
Product (yield)b
Entry
6
Product (yield)b
Time Yield
(h)
Entry
1
Entry Ph2I+Cl- (eq)
Cat (mol%)
Solvent Base
(%)b
1c
2c
3c
4
2
2
2
1.5
1.5
1.5
1.2
1.5
1.5
1.5
Cu(OAc)2 (20) CH2Cl2 Et3N
CuI (20)
24
24
24
2.5
28
54
60
80
50
>99
82
28
30
32
CH2Cl2 Et3N
CH2Cl2 Et3N
CH2Cl2 Et3N
CuBr (20)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
5
6
7
CH2Cl2 DIPEA 3
CH2Cl2 K2CO3 2.5
CH2Cl2 K2CO3 2.5
DMSO K2CO3 2.5
toluene K2CO3 2.5
CH3CN K2CO3 2.5
2c
7c
8d
9d
10d
a Reaction conditions: 2,6-dichloropurine 1a (0.5 mmol), solvent (2 mL),
2 equiv base, under nitrogen. b Isolated yield based on 2,6-dichloropurine.
c Without N2 protection. d The reaction temperature was 40 ◦C.
3
8
9
(3-NO2C6H4)2I+Br- underwent no reaction (entry 8), and (3-NO2-
6-MeC6H3)2I+Br- gave a low yield (20%) (entry 9). However (3-
COOEtC6H4)2I+Br- gave a moderate yield (60%) (entry 10).
To better understand the product structure, we attempted
to grow crystals of 9-arylpurines suitable for X-ray diffraction
analysis. The crystal of 3l proved that the arylation reaction
occurred on the N9-position of the purines and gave 2,6-dichloro-
9-(4-chlorophenyl)-9H-purine (3l). (Fig. 1)
4c
5
10
Fig. 1 X-Ray structure of 3l.
In conclusion, we have developed a novel and efficient CuBr-
catalyzed direct N9-arylation of purine bases with diaryliodonium
salts. Diaryliodonium salts were firstly used as effective arylation
agents for the N9-arylation of purines catalyzed by 10 mol%
CuBr to give the products in excellent yields in 2.5 h and thus
the catalyst amount and reaction time were greatly reduced
while the yields were dramatically enhanced compared to the
previously reported methods. The scope of the direct arylation
has been shown to tolerate a variety of purine analogues and
diaryliodonium salts. The simplicity of this procedure, the absence
of expensive catalyst and ligand, the low amount of catalyst, the
short reaction time, and excellent yield and regioselectivity make
this method more synthetically attractive. The method represents
an alternative to the previously available synthesis of 9-arylpurines
via C–N coupling reaction with arylboronic acids as arylating
a Reaction conditions: purines 1 (0.5 mmol), Ph2I+Cl- 2a (0.75 mmol),
CuBr (0.05 mmol), K2CO3 (1.0 mmol), DCM (2 mL), reflux for 2.5 h
under N2 protection. b Isolated yields based on purines. c 50 mol% CuBr
was used.
agents. Investigations into the scope of these Cu-catalyzed direct
arylations are in progress.
Acknowledgements
We are grateful for financial support from the National Nat-
ural Science Foundation of China (Grant Nos 20802016, and
21072047), the Program for New Century Excellent Talents in
University of the Ministry of Education (No. NCET-09-0122), the
5040 | Org. Biomol. Chem., 2011, 9, 5039–5042
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Table 3 Direct arylation of 2,6-dichloropurine at the N9 position with
Table 3 (Contd.)
Ar2I+X-a
Entry
8
Ar2I+X-
Product
Yield (%)b
0
Entry
1
Ar2I+X-
Product
Yield (%)b
> 99
9
20
60
2
86
10
3
99
82
76
96
a Reaction conditions: 2,6-dichloropurine 1a (0.5 mmol), Ar2I+X-
(0.75 mmol), CuBr (0.05 mmol), K2CO3 (1.0 mmol), DCM (2 mL), reflux
for 2.5 h under N2 protection. b Isolated yield based on 2,6-dichloropurine.
c 50 mol% CuBr was used.
2
4
Excellent Youth Foundation of Henan Scientific Committee (No.
114100510012), the National Students Innovation Experiment
Program, the Excellent Youth Program of Henan Normal Uni-
versity, and Henan Nature Science Foundation (102300410253).
5c
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