Direct synthesis of 6-arylpurines by reaction of 6-chloropurines with activated aromatics

Article abstract of DOI:10.1021/jo1010334

Highly functionalized C6-aryl-substituted purine analogues were synthesized through direct arylation of 6-chloropurine with aromatics promoted by anhydrous AlCl₃ in a single step. The reactions, which were conducted using a 3-fold excess of AlCl₃ in refluxing 1,2-dichloroethane, gave moderate to excellent product yields in 0.5 h. This work is complementary to the classical coupling reactions for the synthesis of C6-aryl-substituted purine analogues.

Full text of DOI:10.1021/jo1010334

pubs.acs.org/joc
activities.3 The studies on biological activities of 6-arylpurines
Direct Synthesis of 6-Arylpurines by Reaction of
6-Chloropurines with Activated Aromatics
have been limited to easily available purines bearing simple
aryl groups, while those bearing highly substituted and/or
functionalized aryl moieties remain to be explored.4
Hai-Ming Guo,*,† Pu Li,† Hong-Ying Niu,‡
Dong-Chao Wang,† and Gui-Rong Qu*,†
The classical methods for the synthesis of 6-arylpurines
involve the cross-coupling reactions of aryl organometallics
(Ar-M) and 6-halopurines (Scheme 1, eq 1) or aryl halides
(Ar-X) and 6-metalpurines5 (Scheme 1, eq 2). For example,
Suzuki-Miyaura,3a,6 Stille,7 Negishi,7a,8 and Kumada coup-
ling reactions9 have been commonly applied to the prepara-
tion of 6-arylpurines. Though significant attention has been
received over the last several years, these cross-coupling re-
actions usually involve the following aspects: (a) expensive
palladium, nickel, and complex ligands are employed as cata-
lysis systems; (b) the preparation of organometallic re-
agents is usually conducted under rigorous reaction condi-
tions (anhydrous, nitrogen atmosphere); (c) the reaction
with metallic reagents usually requires multistep including
protection of the sensitive functional groups (such as hydro-
xyl, amino, or imino group) in the substrates if necessary.
This generates byproducts and wastes from reagents, sol-
vents, and purification. Therefore, it is still of great impor-
tance to develop alternative methods for the preparation of
6-arylpurines. Herein, we will report direct arylation of
6-chloropurine with arenes promoted by anhydrous AlCl3
for the synthesis of highly functionalized C6-aryl-substituted
purine analogues.
†College of Chemistry and Environmental Science,
Key Laboratory of Green Chemical Media and Reactions of
Ministry of Education, Henan Normal University, Xinxiang
453007, Henan, China, and ‡School of Chemistry and
Chemical Engineering, Henan Institute of Science and
Technology, Xinxiang 453003, China
ghm@htu.cn; quguir@sina.com.cn
Received May 26, 2010
During the ongoing course of our study on the develop-
ment of new methods for the synthesis of nucleoside ana-
logues10 and according to reports on arylation and hetero-
arylation of heterocyclic systems,11 we had predicted that
C6-aryl-substituted purine analogues could be synthesized
Highly functionalized C6-aryl-substituted purine ana-
logues were synthesized through direct arylation of 6-chloro-
purine with aromatics promoted by anhydrous AlCl3 in a
single step. The reactions, which were conducted using a
3-fold excess of AlCl3 in refluxing 1,2-dichloroethane,
gave moderate to excellent product yields in 0.5 h. This
work is complementary to the classical coupling re-
actions for the synthesis of C6-aryl-substituted purine
analogues.
ꢁ
ꢀ
(4) Turek, P.; Kotora, M.; Hocek, M.; Cısarova, I. Tetrahetron. Lett.
2003, 44, 785.
(5) Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam, V.;
Knochel, P. Tetrahetron 1997, 53, 7237.
(6) (a) Lakshman, M. K.; Hilmer, J. H.; Martin, J. Q.; Keeler, J. C.; Dinh,
Y. Q. V.; Ngassa, F. N.; Russon, L. M. J. Am. Chem. Soc. 2001, 123, 7779.
ꢁ
ꢁ
ꢀꢁ ꢀ
(b) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. J. Org. Chem. 2008, 73,
9048. (c) Lakshman, M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.;
Sevova, N.; Boggess, B. Org. Lett. 2002, 4, 1479. (d) Gunda, P.; Russon,
L. M.; Lakshman, M. K. Angew. Chem., Int. Ed. 2004, 43, 6372. (e) Lakshman,
M. K.; Gunda, P.; Pardhan, P. J. Org. Chem. 2005, 73, 10329. (f) Liu, J. Q.;
Robins, M. J. Org. Lett. 2005, 7, 1149. (g) Liu, J. Q.; Robins, M. J. Org. Lett.
2004, 6, 3421. (h) Kang, F. A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc.
2008, 130, 11300.
Purine bases and purine nucleoside derivatives play pro-
minent roles in biology, biochemistry, and pharmaceutical
areas.1 Purine analogues with various substituents at C6
have received great attention due to their high cytotoxicity,
antitumor activity, and broad spectrum of biological activities.2
6-Arylpurine bases and their nucleosides are of particular
importance due to anti-HCV, cytostatic, and antimycobacterial
(7) (a) Gundersen, L. L.; Langli, G.; Rise, F. Tetrahedron Lett. 1995, 36,
1945. (b) Gundersen, L. L.; Langli, G.; Rise, F. Tetrahedron 1996, 52, 5625.
ꢀ
ꢁꢀ
(c) Havelkova, M.; Dvorak, D.; Hocek, M. Tetrahedron 2002, 58, 7431.
(8) Brændvang, M.; Gundersen, L. L. Bioorg. Med. Chem. 2005, 13, 6360.
ꢀ
(9) Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc.
2002, 124, 13856.
(10) (a) Qu, G. R.; Xia, R.; Yang, X. N.; Li, J. G.; Wang, D. C.; Guo,
H. M. J. Org. Chem. 2008, 73, 2416. (b) Qu, G. R.; Zhao, L.; Wang, D. C.;
Wu, J.; Guo, H. M. Green Chem. 2008, 10, 287. (c) Qu, G. R.; Mao, Z. J.; Niu,
H. Y.; Wang, D. C.; Xia, C.; Guo, H. M. Org. Lett. 2009, 11, 1745. (d) Qu.,
G. R.; Wu., J.; Wu., Y. Y.; Zhang., F.; Guo, H. M. Green Chem. 2009, 11,
760. (e) Guo, H. M.; Wu, Y. Y.; Niu, H. Y.; Wang, D. C.; Qu, G. R. J. Org.
Chem. 2010, 75, 3863. (f) Guo, H. M.; Wu, J.; Niu, H. Y.; Wang, D. C.;
Zhang, F.; Qu, G. R. Bioorg. Med. Chem. Lett. 2010, 20, 3098.
(11) (a) Pal, M.; Batchu, V. R.; Parasuraman, K.; Yeleswarapu, K. R.
J. Org. Chem. 2003, 68, 6806. (b) Pal, M.; Batchu, V. R.; Dager, I.; Swamy,
N. K.; Padakanti, S. J. Org. Chem. 2005, 70, 2376. (c) Pal, M.; Batchu, V. R.;
Khanna, S.; Yeleswarapu, K. R. Tetrahedron 2002, 58, 9933. (d) Kodimuthali,
A.; Nishad, T. C.; Prasunamba, P. L.; Pal, M. Tetrahedron Lett. 2009, 50,
354.
(1) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987.
(2) (a) Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.; Gilligan,
P. Bioorg. Med. Chem. Lett. 1999, 9, 1063. (b) Verdugo, D. E.; Cancilla,
M. T.; Ge, X.; Gray, N. S.; Chang, Y.-T.; Schultz, P. G.; Negishi, M.; Leary,
J. A.; Bertozzi, C. R. J. Med. Chem. 2001, 44, 2683.
ꢀ
ꢁꢀ
ꢀ
(3) (a) Hocek, M.; Holy, A; Votruba, I; Dvorakova, H. J. Med. Chem.
2000, 43, 1817. (b) Gundersen, L. L; Nissen-Meyer, J.; Rise, F.; Spilsberg, B.
J. Med. Chem. 2002, 45, 1383. (c) Bakkestuen, A. K.; Gundersen, L. L.;
ꢁ
Utenova, B. T. J. Med. Chem. 2005, 48, 2710. (d) Hocek, M.; Naus, P.; Pohl,
R; Votruba, I.; Furman, P. A.; Tharnish, P. M.; Otto, M. J. J. Med. Chem.
2005, 48, 5869.
6016 J. Org. Chem. 2010, 75, 6016–6018
Published on Web 08/10/2010
DOI: 10.1021/jo1010334
r
2010 American Chemical Society

Guo et al.
JOCNote
SCHEME 1. Different Routes for the Synthesis of
6-Arylpurines
TABLE 2. Reaction of Ar-H with 9-Bn-6-chloropurinea,b
TABLE 1. Reaction of 1-Naphthol with Various 6-Chloropurines
Derivativesa
aReaction conditions: 9-Bn-6-chloropurine (0.5 mmol), 2 (1 mmol),
AlCl3 (1.5 mmol), 1,2-dichloroethane (5 mL). bIsolated yields based on
nucleobases. cReaction time: 10 h.
at room temperature, the direct arylation proceeded success-
fully to produce the desired product 3a.
During optimization of reactions conditions, we found
that when the reaction of 9-Bn-6-chloropurine with 1-naph-
thol was carried out in 1,2-dichloroethane at reflux tempera-
ture in the presence of 300 mol % of AlCl3, the product was
isolated in 75% yield in 0.5 h (see the Supporting Informa-
tion for details).
To evaluate the generality of the reaction, a number of
6-chloropurine derivatives with various substituents at N9
were subjected to the optimized conditions (Table 1, entries
1-4), affording the desired products in moderate to good
isolated yields (53-76%). It was found that the kind of sub-
stituents at N9 had little impact on the yields of the products.
To study the influence of substituent groups at C2, a series
of 2,6-dichloropurines and 2-amino-6-chloropurines were
employed as the substrates under the optimized reaction
conditions (Table 1, entries 5-10). In most cases, the re-
placement of hydrogen with Cl or NH2 led to better yields
when the same functional group presents at N9.
The substrate scope of aryl compounds under the opti-
mized conditions was also examined (Table 2). First, the
naphthol derivatives were explored. Whether 1-naphthol,
2-naphthol, or 1-naphthol methyl ether (3a, 4a, and 4b) was
used as starting material, good to high yields were obtained.
While 1-naphthylamine (4c) gave a low yield of 25% even in a
aReaction condition: 6-chloropurine derivatives (0.5 mmol), 1-naphthol
(1 mmol), AlCl3 (1.5 mmol), 1,2-dichloroethane (5 mL). Isolated yields
based on nucleobases.
b
through direct arylation of 6-chloropurine with electron-rich
aromatics or heteroaromatics promoted by anhydrous AlCl3
(Scheme 1, eq 3). Thus, when the reaction of 9-Bn-6-chloro-
purine with 1-naphthol was conducted in 1,2-dichloroethane
J. Org. Chem. Vol. 75, No. 17, 2010 6017

Guo et al.
JOCNote
prolonged time (10 h). Subsequently, various phenol deriva-
tives were also investigated (4d-g). It is noteworthy that no
product was observed when phenol was used as starting
material under the optimized conditions (4d). But other subs-
trates gave moderate to high yields (4e-g). It was also found
that the reaction could proceed using p-toluidine as a sub-
strate with prolonged reaction time (4h). The use of hetero-
arenes such as indole and N-methylindole also afforded the
corresponding products in good yields (4i and 4j).
To better understand the product structure, we attempted
to grow crystals of 6-arylpurines suitable for X-ray diffrac-
tion analysis. The crystal of 3b proved that the substitution
reaction occurred on the para position of the hydroxyl group
of 1-naphthol to give 4-[9-(2-chlorobenzyl)-9H-purin-6-yl]-
naphthalen-1-ol (3b) (see the Supporting Information)
In conclusion, we have developed an unprecedented met-
hod for the synthesis of highly functionalized C6-aryl sub-
stituted purine analogues by direct arylation of purine with
electron-rich aromatics or heteroaromatics promoted by
anhydrous AlCl3. Application of AlCl3-promoted coupling
reactions between purine bases and aryls allows the synthesis
of biologically important 6-aryl-substituted purine ana-
logues to be carried out under mild condition in one step with-
out protection of sensitive functional groups. This method
avoids the use of transition-metal catalysts, organometallic
reagents, complex ligands, rigorous reaction conditions, multi-
ple steps, or the formation of byproducts and represents an
important complement to the classical coupling reactions for
synthesis of C6-aryl-substituted purine analogues when sub-
strates and products are stable toward AlCl3.
dichloroethane (5 mL) were put into a 25 mL glass vial equip-
ped with a small magnetic stirring bar. To this were added
1-naphthol 2a (144 mg, 1 mmol) and anhydrous AlCl3 (200 mg,
1.5 mmol). The reaction mixture was stirred in a boiling heating
bath at reflux temperature for 0.5 h. The vial was cooled to room
temperature, and the mixture was poured into water (20 mL), stir-
red for 15 min, and then extracted with ethyl acetate (3 ꢀ 10 mL).
The organic layers were collected, combined, washed with water
(3 ꢀ 10 mL), dried over anhydrous Na2SO4, and concentrated
under vacuum. The resulting residue was purified by column chro-
matography over silica gel (dichloroethane/ethyl acetate) to give
the desired product 3a.
Compound 3a: light yellow powder; mp 282-284 °C; 1H
NMR (DMSO-d6, 400 MHz) δ 10.76 (s, 1H), 9.03 (s, 1H), 8.71
(s, 1H), 8.45 (t, J = 5.6 Hz, 1H), 8.26 (t, J = 2.8 Hz, 1H), 8.04 (d,
J = 8.0 Hz, 1H), 7.49 (t, J = 4.0 Hz, 2H), 7.41 (d, J = 8.0 Hz,
2H), 7.36 (t, J = 4.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.05 (d,
J = 8.0 Hz, 1H), 5.55 (s, 2H); 13C NMR (DMSO-d6, 100 MHz)
δ 156.3, 154.9, 151.3, 151.2, 145.5, 136.1, 131.6, 131.5, 131.2,
128.3, 127.5, 127.3, 126.3, 125.3, 124.3, 124.2, 122.4, 121.8,
106.9, 46.0; HRMS calcd for C22H17N4O [MþHþ] 353.1402,
found 353.1403.
Acknowledgment. We are grateful for financial support
from the National Nature Science Foundation of China
(Grant Nos. 20772024 and 20802016), the Program for New
Century Excellent Talents in University of Ministry of Educa-
tion (NCET-09-0122), the Program for Innovative Research
Team in University of Henan Province (2008IRTSTHN002),
and the Henan National Nature Science Foundation
(092300410225).
Supporting Information Available: Optimization of reaction
conditions, X-ray structure of 3b, and experimental procedures,
including spectroscopic information. This material is available
free of charge via the Internet at http://pubs.acs.org.
Experimental Section
Typical Experimental Procedure for the Reaction of Purines
with 1-Naphthol. Purine base 1a (122 mg, 0.5 mmol) and 1,2-
6018 J. Org. Chem. Vol. 75, No. 17, 2010