Pd(II)-catalyzed ortho arylation of 6-arylpurines with aryl iodides via purine-directed C-H activation: A new strategy for modification of 6-arylpurine derivatives

Article abstract of DOI:10.1021/ol200405w

Purine is utilized as a new directing group for the Pd-catalyzed monoarylation of 6-arylpurines with simple aryl iodides via C-H bond activation in good yields, providing a complementary tool for the modification of 6-arylpurines (nucleosides). Most impor

Full text of DOI:10.1021/ol200405w

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2008–2011
Pd(II)-Catalyzed Ortho Arylation of
6-Arylpurines with Aryl Iodides via
Purine-Directed CÀH Activation:
A New Strategy for Modification of
6-Arylpurine Derivatives
Hai-Ming Guo,*,† Li-Li Jiang,† Hong-Ying Niu,‡ Wei-Hao Rao,† Lei Liang,†
Run-Ze Mao,† De-Yang Li,† and Gui-Rong Qu*,†
College of Chemistry and Environmental Science, Key Laboratory of Green Chemical
Media and Reactions of Ministry of Education, Henan Normal University, Xinxiang,
453007, China, and School of Chemistry and Chemical Engineering,
Henan Institute of Science and Technology, Xinxiang 453003, China
guohm518@hotmail.com; quguir@sina.com
Received February 14, 2011
ABSTRACT
Purine is utilized as a new directing group for the Pd-catalyzed monoarylation of 6-arylpurines with simple aryl iodides via CÀH bond activation in
good yields, providing a complementary tool for the modification of 6-arylpurines (nucleosides). Most importantly, purine can be used as a
building block for nucleoside derivatives, and the use of purine as a directing group helps avoid additional synthetic steps.
In recent years, significant advances in the transition-
metal-catalyzed construction of CÀC bonds have been
made,1 which provides a useful tool for synthesizing
complex organic compounds and constructing some
pharmaceutical scaffolds.2 Traditionally, the formation
of biaryl linkages involves standard cross-coupling reac-
tions3 (i.e., SuzukiÀMiyaura, Stille, Hiyama, Kumada, and
Negishi reactions). Despite their widespread application,
these coupling reactions are usually conducted under fairly
harsh reaction conditions utilizing catalysts comprised of
expensive organometallic reagents and complex auxiliary
ligands, which in some instances may limit their practical
applications in synthesis. To overcome these drawbacks,
organic chemists have developed a transition-metal-catalyzed
† Henan Normal University.
‡ Henan Institute of Science and Technology.
(1) For reviews on this topic, see: (a) Lewis, J. C.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (b) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Ritleng, V.; Sirlin, C.;
Pfeffer, M. Chem. Rev. 2002, 102, 1731. (d) Campeau, L.-C.; Fagnou, K.
Chem. Commun. 2006, 6, 1253. (e) Davies, H. M. L. Angew. Chem., Int.
Ed. 2006, 45, 6422. (f) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008,
41, 1461. (g) Seregin, I. V.; Gevorgyan, V. J. Chem. Soc., Chem. Rev.
2007, 36, 1173. (h) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 7, 949.
(i) Ackermann, L. Synlett 2007, 4, 507. (j) Godula, K.; Sames, D. Science
2006, 312, 67. (k) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu
J.-Q. Chem. Soc. Rev. 2009, 38, 3242.
(2) (a) Shao, B.; Victory, S.; Ilyin, V. I.; Goehring, R. R.; Sun, Q.;
Hogenkamp, D.; Hodges, D. D.; Islam, K.; Sha, D.; Zhang, C.; Nguyen,
P.; Robledo, S.; Sakellaropoulos, G.; Carter, R. B. J. Med. Chem. 2004,
47, 4277. (b) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849. (c) Giri,
R.; Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686. (d) Wang
D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315.
(3) (a) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835.
(b) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508. (c) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457. (d) Hatanaka, Y.; Hiyama, T.
J. Org. Chem. 1988, 53, 918. (e) Negishi, E.; Anastasia, L. Chem. Rev.
2003, 103, 1979. (f) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem.
Commun. 1972, 144. (g) Tamao, K.; Sumitani, K.; Kumada, M. J. Am.
Chem. Soc. 1972, 94, 4374.
(4) For selected reviews on this topic, see: (a) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Fagnou, K. In Topics
in Current Chemistry; Yu, J.-Q., Shi, Z.-J., Eds.; Springer Press: Berlin,
2010; Vol. 292, pp 35À56.
r
10.1021/ol200405w
Published on Web 03/24/2011
2011 American Chemical Society

direct arylation of a CÀH bond to construct a variety of CÀC
bonds.4 However, selective direct arylation of substrates with
similar CÀH bonds tends to require various auxiliary ligands.
Over the past decade, more effort has been devoted to
substrate-directed metal-catalyzed CÀH bond arylation5
as a complementary tool for standard cross-coupling
reactions. Consequently, most nitrogen-containing groups
and carboxyl groups have been explored for directing
metal-catalyzed CÀH bond arylation. The majority of
the directing groups, which are necessary for the selective
transformation, often are difficult to attach or remove,
thus limiting these methodologies to particular types of
substrates.5d,e Extending these methodologies to include
other substrates seems to be urgent. Meanwhile, aryl
boronic acids6 and diaryliodonium salts7 were extensively
applied to the arylation of heteroaromatic substrates.
However, aryl boronic acids are expensive or require
multistep preparation, and diaryliodonium salts are not
atom economic and generate waste and purification pro-
blems. Furthermore, direct arylation of ArÀH via CÀH
bond activation has been known to suffer from over-
functionalization or regioselectivity issues.8,5g
Table 1. Monophenylation of 6-Phenyl Purine via Pd-Catalyzed
CÀH Bond Activationa
entry
X (equiv)
Ag source
yield (%)b
1
I (5)
AgOAc
Ag2O
15
2
I (10)
I (10)
I (30)
I (40)
Cl (30)
Br (30)
I (30)
I (30)
I (30)
12
3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOTf
20
4
82
5
82
6
N.R.c
N.R.
N.R.
N.R.
40
7
8d
9e
10
a Unless otherwise mentioned, all of the reactions were carried out
with 0.2 mmol of 1a, 5 mol % Pd(OAc)2, 0.4 mmol of Ag source, and 0.5
mL of AcOH in a Schlenk tube at 120 °C for 60 h under a N2 atmosphere.
b Isolated yields. c N.R. = No Reaction. d Without N2 protection. e In
the absence of AcOH.
C6-Arylpurine nucleosides are of particular importance
since they have displayed anti-HCV, cytostatic, and anti-
mycobacterial activities,9 and continued methodological
efforts have been made in recent years. Purine contains
four nitrogen atoms and belongs to a special class of
aromatic heterocycles. To our knowledge, there have been
no reports of purine-directed palladium-catalyzed CÀH
bond activation thus far. During the ongoing course of our
study on the modification of purine analogues10 and
according to the reports on transition-metal-catalyzed
arylation of substrate-directed CÀH bond, we choose
purine as a directing group for CÀH bond arylation with
aryl iodides, since purine may offer a nitrogen atom for
effectively participating in cyclopalladation. Purine is
more challenging than simple pyridine since it possesses
three additional nitrogen atoms that could potentially bind
and poison the catalyst.11 Most importantly, this directing
group is a useful building block for the desired nucleoside
derivatives. This functionalization is highly regiospecific,
thus making the process simple and more synthetically
desirable. This CÀH functionalization approach offers an
alternative strategy for modification of 6-arylpurine deri-
vatives, providing access to molecules that may have great
importance in medicinal chemistry.12
(5) For recent reviews about substrate-directed CÀH arylation, see:
(a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b)
Daugulis, O.; Do, H.-Q; Shabashov, D. Acc. Chem. Res. 2009, 42,
1074. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094. For other recent examples about substrate-
directed CÀH arylation, see:(d) Wasa, M.; Worrell, B. T.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2010, 49, 1275. (e) Chernyak, N.; Dudnik, A. S.;
Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 8270. (f) Yeung,
C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci. 2010, 1, 331. (g)
Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837.
(h) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 5858. (i) Yoshikai, N.; Matsumoto, A.; Norinder,
J.; Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, 2925.
(6) (a) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc.
2008, 130, 7190. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.;
Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007,
129, 3510.
(7) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330. (b) Deprez, N. R.; Kalyani, D.; Krause, A.;
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. (c) Deprez, N. R.;
Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234. (d) Xiao, B.; Fu, Y.;
Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132,
468. (e) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44,
4046. (f) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc.
2008, 130, 8172. (g) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(8) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790. (b) Vickers, C. J.; Mei, T.-S.; Yu, J.-Q. Org. Lett.
2010, 12, 2511.
Withthisinmind, weinitially carriedout our experiment
by choosing 6-phenyl-9-benzylpurine (1a) as the substrate
and Pd(OAc)2 as the catalyst (Table 1). To our delight, we
found the phenylation of 1a took place in the presence of a
catalytic amount of Pd(OAc)2, 5 equiv of PhI, and 2 equiv
(9) Bakkestuen, A. K.; Gundersen, L. L.; Utenova, B. T. J. Med.
Chem. 2005, 48, 2710.
(10) (a) Qu, G. R.; Mao, Z. J.; Niu, H. Y.; Wang, D. C.; Xia, C.; Guo,
H. M. Org. Lett. 2009, 11, 1745. (b) Guo, H. M.; Wu, Y. Y.; Niu, H. Y.;
Wang, D. C.; Qu, G. R. J. Org. Chem. 2010, 75, 3863. (c) Guo, H. M.; Li,
P.; Niu, H. Y.; Wang, D. C.; Qu, G. R. J. Org. Chem. 2010, 75, 6016. (d)
Qu, G. R.; Xia, R.; Yang, X. N.; Li, J. G.; Wang, D. C.; Guo, H. M. J.
Org. Chem. 2008, 73, 2416. (e) Qu, G. R.; Ren, B.; Niu, H. Y.; Mao, Z. J.;
Guo, H. M. J. Org. Chem. 2008, 73, 2450. (f) Guo, H. M.; Xin, P. Y.;
Niu, H. Y.; Wang, D. C.; Jiang, Y.; Qu, G. R. Green Chem. 2010, 12,
2131. (g) Qu, G. R.; Wu, J.; Wu, Y. Y.; Zhang, F.; Guo, H. M. Green
Chem. 2009, 11, 760. (h) Qu, G. R.; Zhao, L.; Wang, D. C.; Wu, J.; Guo,
H. M. Green Chem. 2008, 10, 287. (i) Guo, H. M.; Wu, J.; Niu, H. Y.;
Wang, D. C.; Zhang, F.; Qu, G. R. Bioorg. Med. Chem. Lett. 2010, 20,
3098.
(11) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781.
ꢀ
ꢁꢀ
ꢀ
(12) (a) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med.
ꢁ
Chem. 2000, 43, 1817. (b) Hocek, M.; Naus, P.; Pohl, R.; Votruba, I.;
Furman, P. A.; Tharnish, P. M.; Otto, M. J. J. Med. Chem. 2005, 48,
5869. (c) Gundersen, L.-L.; Nissen-Meyer, J.; Spilsberg, B. J. Med.
Chem. 2002, 45, 1383. (d) Andresen, G.; Gundersen, L.-L.; Nissen-
Meyer, J.; Rise, F.; Spilsberg, B. Bioorg. Med. Chem. Lett. 2002, 12, 567.
(e) Hauser, D. R. J.; Scior, T.; Domeyer, D. M.; Kammerer, B.; Laufer,
S. A. J. Med. Chem. 2007, 50, 2060.
Org. Lett., Vol. 13, No. 8, 2011
2009

among various silver salts in this protocol (entries 1À2 and
10). Importantly, the use of both AcOH and N2 protection
was critical for such success (entries 8 and 9). It was
considered that AcOH played three roles in the reaction:
(i) it might serve as a good solvent, (ii) it might facilitate the
reductive elimination step,13 and (iii) it might help to
overcome the catalyst poison ascribable to multiple nitro-
gens in purine. It was noteworthy that the monophenyla-
tion reaction was selective at the ortho site of the C6-phenyl
ring, which differed from previous reports14 that the
C8ÀH bond of purine was prior to be arylated. This
indicated such success was predominantly controlled by
the N1 atom of purine.
Table 2. Highly Regioselective Monophenylation of Various
6-Arylpurines with PhIa
Table 3. Monoarylation of 9-Butyl-6-phenylpurine with Various
Aryl Iodidesa
a Unless otherwise mentioned, all of the reactions were carried out
with 0.2 mmol of 1, 30 equiv of 2a, 5 mol % Pd(OAc)2, 0.4 mmol of
AgOAc, and 0.5 mL of HOAc in a Schlenk tube at 120 °C for 60 h under
a N2 atmosphere. b Isolated yields were reported. c The reaction pro-
ceeded for 48 h.
a The reactions were carried out with 0.2 mmol of 1c, 30 equiv of aryl
iodide (2), and 0.5 mL of HOAc in a Schlenk tube at 120 °C for 60 h
under a N2 atmosphere. b Isolated yields were reported.
With the optimized conditions in hand, this new
phenylation protocol was extended to a scope of aryl-
purines, and the results are shown in Table 2. A series of
6-aryl-9-substituted purines including i-Pr (1b), n-Bu
(1c), and triacetyl-β-ribofuranosyl (1d) were subjected
to our catalytic system and the corresponding products
were obtained in high yields (3bÀ3d). Notably, a
of AgOAc as an oxidant but in poor yield (15%, entry 1).
Further studies showed that elevated amounts of PhI led to
higher yields, but the yield did not increase when the
amount of PhI was higher than 30 equiv (entries 4À5).
Unfortunately, the phenylation reaction was almost sup-
pressed when PhI was replaced by PhCl or PhBr even
under the same reaction conditions (entries 6 and 7).
Presumably, the PhÀCl/Br bond is more difficult to cleave
in the course of palladium-mediated oxidative addition.
Further investigations showed AgOAc was the best choice
(13) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
ꢁ
(14) (a) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. Org. Lett.
ꢁ
ꢀꢁ
ꢀ
ꢁ
ꢁ
2006, 8, 5389. (b) Cerna, I.; Pohl, R.; Hocek, M. Chem. Commun. 2007,
45, 4729.
2010
Org. Lett., Vol. 13, No. 8, 2011

glycosidic bond existing in substrates 1d, 1j, and 1k was
well tolerated under the reaction conditions, and the
reaction time was relatively short among the tested
substrates, which expanded the field of nucleosidic
modification. We further investigated the electronic
and steric effect on the arylation of 6-arylpurines. Sub-
strates bearing electron-donating groups at their meta
site such as Me (1g), MeO (1h) proceeded smoothly to
afford the corresponding products 3g (90%) and 3h
(89%). At the same time, a strong electron-withdrawing
group like ÀNO2 at the meta site of C6-phenyl also
produced the corresponding product 3i in 83% isolated
yield. For substrates containing the Me (1e), MeO (1f)
group at the para site, the corresponding products (3e,
3f) were also obtained in good yield, although somewhat
lower than that of the meta substituted counterparts (3g,
3h), which might be the result of a slight steric effect
arising from the position discrimination.
As showed in Table 3, a variety of aryl iodides were
further explored. The reaction with various substituted aryl
iodides all proceeded efficiently regardless of their electron-
donating (i.e., p-Me, p-MeO, m-dimethyl) and electron-
withdrawing (i.e., m-Br, p-Br, p-COOEt, m-NO2) ability.
Notably, the bromo and ester substituents were well toler-
ated under the reaction conditions, which was favorable for
further transformation. Remarkably, the selective monoar-
ylation overwhelmingly occurred even though excess aryl
iodides were present in the reaction mixture.
In summary, we have developed a new method for a highly
regioselective monoarylation of C6-arylpurines via purine-
directed CÀH bond activation. Multiple-nitrogen-contain-
ing purine was first explored as a directing group for Pd-
catalyzed CÀH bond activation. Notably, this directing
group is a useful building block for the desired nucleoside
derivatives. The monoarylated products were overwhel-
mingly obtained by employing simple aryl iodides as arylat-
ing agents. A variety of functional groups such as MeÀ,
MeOÀ, ÀNO2, ÀCOOEt, and ÀBr could be well toler-
ated. Additionally, the approach provides a new access
to a variety of arylated purines (nucleosides) which are
of great importance in medicinal chemistry. The appli-
cation of purine as a directing group to construct a
CÀheteroatom bond and further investigation on the
detailed mechanism are underway in our laboratory.
Acknowledgment. We are grateful for financial support
from the National Nature Science Foundation of China
(Grant Nos. 20802016 and 21072047), the Program for
New Century Excellent Talents in University of Ministry
of Education (NCET-09-0122), and the National Students
Innovation Experiment Program (101047605).
Supporting Information Available. Typical experimental
procedures, characterization of compounds, and compound
spectroscopic information. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 8, 2011
2011