Suzuki-miyaura and sonogashira coupling of 6-chloropurines and-nucleosides in water

Article abstract of DOI:10.1021/ol9007475

A general protocol is reported for the efficient Suzuki-Miyaura and the copper-free Sonogashira coupling of unprotected 6-chloropurines and unprotected β-D-ribofuranosyl-6-chloropurine in water or in water/n-butanol utilizing Na₂PdCI₄

Full text of DOI:10.1021/ol9007475

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2551-2554
Suzuki-Miyaura and Sonogashira
Coupling of 6-Chloropurines and
-Nucleosides in Water
Jan Pschierer and Herbert Plenio*
Anorganische Chemie im Zintl-Institut, TU Darmstadt, Petersenstrasse 18,
64287 Darmstadt, Germany
plenio@tu-darmstadt.de
Received April 15, 2009
This paper was withdrawn on November 12, 2010 (Org. Lett. 2010, 12, 5358).
ABSTRACT
A general protocol is reported for the efficient Suzuki-Miyaura and the copper-free Sonogashira coupling of unprotected 6-chloropurines and
unprotected ꢀ-D-ribofuranosyl-6-chloropurine in water or in water/n-butanol utilizing Na2PdCl4 and a disulfonated and highly water-soluble
fluorenylphosphine (cataCXium F sulf).
The enormous progress in catalyst development has enabled
the routine use of aryl chlorides in Pd-mediated cross-
coupling chemistry.1 Nonetheless, a number of difficult and
potentially coordinating heteroatom-containing functional
groups such as N- or S-heterocycles, amino, and hydroxy
groups remain challenging, and the respective aryl chloride
reactions require relatively high catalyst loading.2 Chloro-
purines and the related chloropurine nucelosides contain
several of these problematic functional groups. Thus, despite
the interest in purine chemistry3 (especially with 6-aryl and
6-ethynyl-substituted purines due to their cytostatic activ-
ity),4,5 in the Suzuki and the Sonogashira couplings of
chloropurines protective groups are normally employed,
while coupling reactions of unprotected chloropurines are
rare.6-8 With chloropurine nucleoside coupling, normally
protective groups are employed:9,10 only Hocek briefly
reported on the Suzuki coupling of unprotected nucleosides.7
More often, the respective aryl bromides or iodides with11-14
or without protective groups15,16 were employed. As a
consequence of these deficits, Kang et al. developed a method
for the Suzuki coupling of tautomerizable purines via enolate
(6) Capek, P.; Vra´bel, M.; Hasn´ık, Z.; Pohl, R.; Hocek, M. Synthesis
2006, 3515
(7) Capek, P.; Pohl, R.; Hocek, M. Org. Biomol. Chem. 2006, 4, 2278
(8) Fleckenstein, C. A.; Plenio, H. Chem.sEur. J. 2008, 14, 4267
(9) Alonso, N.; Caamano, O.; Fernandez, F.; Garcia-Mera, X.; Morales,
M.; Rodriguez-Borges, J. E.; De Clercq, E. Synthesis 2008, 1845
.
.
.
.
(10) Lakshman, M. K.; Gunda, P.; Pradhan, P. J. Org. Chem. 2005, 70,
10329
.
(11) Cerna, I.; Pohl, R.; Klepeta´rova´, B.; Hocek, M. J. Org. Chem. 2007,
73, 9048
(12) Garc´ıa, M. D.; Caaman˜o, O.; Ferna´ndez, F.; Garc´ıa-Mera, X.; Pe´rez-
.
(1) Zapf, A.; Beller, M. Chem. Commun. 2005, 431.
(2) Hartwig, J. F. Synthesis 2006, 1283.
Castro, I. Synthesis 2006, 3967
.
(3) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. Lett. 2006,
14, 3987.
(13) Liu, J.; Robins, M. J. Org. Lett. 2005, 7, 1149
.
(14) Brændvang, M.; Gundersen, L.-L. Bioorg. Med. Chem. 2005, 13,
(4) Hocek, M.; Nau, P.; Pohl, R.; Votruba, I.; Furman, P. A.; Tharnish,
6360
.
P. M.; Otto, M. J. J. Med. Chem. 2005, 48, 5869
(5) Hocek, M.; Stepnicka, P.; Ludvik, J.; Cisarova, I.; Votruba, I.; Reha,
D.; Hobza, P. Chem.sEur. J. 2004, 10, 2058
.
(15) Western, E. C.; Shaughnessy, K. H. J. Org. Chem. 2005, 70, 6378
(16) Western, E. C.; Daft, J. R.; Edward, M.; Johnson, I.; Gannett, P. M.;
.
.
Shaughnessy, K. H. J. Org. Chem. 2003, 68, 6767.
10.1021/ol9007475 CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

Table 1. Suzuki-Miyaura Coupling of 6-Chloropurines with Pd/cataCXium F sulfc
a Solvent water. b 3.0 equiv of boronic acid were used. c Reaction conditions: 1.0 equiv of chloropurine, 1.5 equiv of boronic acid, 2.5 equiv of K2CO3,
degassed water (1.5 mL), n-butanol (4.5 mL), 100 °C, reaction time 16 h, catalyst stock solution in water (c Pd ) 1.0 mol %/mL, Na2PdCl4/cataCXium F
sulf L/Pd 2:1. Yields correspond to isolated material after column chromatography (silica), CH2Cl2/MeOH/NEt3 ) 5/1/1.
activation, which was also applied to an unprotected purine
nucleoside.17 The Sonogashira coupling of chloropurines is
also challenging and requires protective groups5,18-20 or the
use of more reactive bromo- or iodopurines.21-23
ropurine nucleosides using Na2PdCl4 and the water-soluble
and commercially available fluorenylphosphine (cataCXium
F sulf) recently reported by us.24,25 This ligand already
(17) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008, 130,
11300
.
(18) Liu, J.; Janeba, Z.; Robins, M. J. Org. Lett. 2004, 6, 2917
(19) Tanji, K. I.; Higashino, T. Chem. Pharm. Bull. 1988, 36, 1935
(20) Volpini, R.; Costanzi, S.; Lambertucci, C.; Taffi, S.; Vittori, S.;
Klotz, K.-N.; Cristalli, G. J. Med. Chem. 2002, 45, 3271
(21) Firth, A. G.; Fairlamb, I. J. S.; Darley, K.; Baumann, C. G.
Tetrahedron Lett. 2006, 47, 3529
(22) Liu, J.; Janeba, Z.; Robins, M. J. Org. Lett. 2004, 6, 2917
(23) Hocek, M. Eur. J. Org. Chem. 2003, 245
(24) Fleckenstein, C. A.; Plenio, H. Chem.sEur. J. 2007, 13, 2701
.
.
.
.
.
We report here a simple Pd-based protocol for both the
Suzuki and the Sonogashira coupling of unprotected chlo-
.
.
2552
Org. Lett., Vol. 11, No. 12, 2009

Table 2. Suzuki-Miyaura Coupling of 6-Chloropurine
Table 3. Sonogashira Coupling of 6-Chloropurine with Pd/
Nucleosides with Pd/cataCXium F sulfb
cataCXium F sulfa
a Solvent water. b Reaction conditions: see legend of Table 1.
a Reaction conditions: 1.0 equiv of chloropurine, 1.13 equiv of acetylene,
1.33 equiv of K2CO3, water, 95 °C, reaction time 16 h, catalyst stock solution
in water (c Pd ) 1.0 mol %/mL, Na2PdCl4/CataCXium F sulf L/Pd 2:1.
Yields correspond to isolated material after column chromatography (silica),
cyclohexane/EtOAc/NEt3 ) 9/1/1.
demonstrated its high efficiency in aqueous cross-coupling
chemistry.26-28
We first expanded on the known Suzuki coupling of
unprotected 6-chloropurine (Table 1).8 The reaction of
6-chloropurine and tolylboronic acid (Table 1, entry 1) gives
respectable yields (78%) with as little as 0.25 mol % [Pd].
This compares favorably with the use of 5 mol % of
Pd(OAc)2, 12.5 mol % of phosphine, and microwave
irradiation needed to afford good yields of closely related
coupling products.7
It is important to note that the formation of butyl ethers was
never observed in such reactions.
Suzuki reactions of 2-amino-6-chloropurine also require
1-2 mol % [Pd] (Table 1, entries 3- 5 and 7). The reaction
of 2-amino-6-chloropurine with 3-bromophenylboronic acid
(Table 1, entry 5) is highly instructive since it is the purine
C-Cl bond which undergoes the Suzuki reaction and not
the C-Br bond in the boronic acid. This points toward the
strongly activating nature of the purine ring15 and shows that
the difficulties in the cross-coupling of chloropurines result
from the overall inhibition of the catalyst and not from lack
of reactivity of the C-Cl bond. In 2,6-dichloropurine, it is
possible to introduce aryl groups selectively, first at the
With sterically demanding boronic acids (Table 1, entries
2, 4, and 6), 1-2 mol % is needed. The use of water/n-
butanol 1:3 in the presence of K2CO3 gives only slightly
better yields than with water alone (Table 1, entries 1 and
3). Employment of a biphasic system facilitates the isolation
of product. The simple separation of the aqueous layer leads
to the removal of the salts as well as of excess boronic acid,
while the products are isolated from the n-butanol solution.
(26) Fleckenstein, C. A.; Plenio, H. Green Chem. 2008, 10, 563.
(27) Fleckenstein, C. A.; Plenio, H. J. Org. Chem. 2008, 73, 3236.
(28) Fleckenstein, C. A.; Plenio, H. Green Chem. 2007, 9, 1287.
(25) Fleckenstein, C. A.; Kadyrov, R.; Plenio, H. Org. Process Res.
DeV. 2008, 12, 475.
Org. Lett., Vol. 11, No. 12, 2009
2553

catalyst loading of between 0.5 and 2 mol % [Pd] is sufficient
to obtain isolated yields after chromatography of between
77 and 91% yield. All of these reactions can also be
conducted in pure water as the reaction solvent. The yields
are only slightly lower than in n-butanol/water (Table 1,
entries 1 and 3, Table 2, entries 3-5).
Table 4. Sonogashira Coupling of a 6-Chloropurine Nucleoside
with Pd/cataCXium F sulfa
The same catalyst recipe was applied in the copper-free
Sonogashira coupling of unprotected chloropurines (Table
3). Amounts of 2 mol % of Na2PdCl4 and 4 mol % of
cataCXium F sulf are sufficient to synthesize the respective
6-ethinylpurines in isolated yields of between 71 and 99%
after chromatography. These coupling reactions work for aryl
acetylene and also for the more difficult ferrocenyl (Fc )
ferrocenyl) and alkyl acetylenes.
The same protocol was applied to the copper-free Sono-
gashira coupling of unprotected ꢀ-D-ribofuranosyl-6-chlo-
ropurine (Table 4). The isolated yields are only slightly lower
than with chloropurine, and the respective ethynylated
products were isolated in 67-90% yield. With respect to
the yield, it does not make any difference whether the
Sonogashira reactions are carried out in water/n-butanol 1:3
or in pure water. Finally, it is interesting to note that the
catalyst loadings in the Sonogashira and Suzuki reactions
of chloropurines are in the same range as for Sonogashira
reactions of aryl chlorides,30 while drastically less [Pd] is
required in the Suzuki reactions of “normal” aryl chlorides.31
In conclusion, we have developed a simple Suzuki and
copper-free Sonogashira coupling protocol for the reactions
of unprotected 6-chloropurines and ꢀ-D-ribofuranosyl-6-
chloropurine with various arylboronic acids and aryl- or
alkylacetylenes. Catalyst loadings between 0.25 and 2 mol
% Na2PdCl4 and twice as much of the disulfonated fluore-
nylphosphine (cataCXium F sulf) in water or n-butanol/water
used a simple base (K2CO3) to produce excellent yields of
cross-coupling products.
a Reaction conditions: see legend of Table 3.
Acknowledgment. This work was supported by the DFG
and the Fonds der Chemischen Industrie.
6-position and then at the 2-position (Table 1, entries 9-12).
Protodeboronation reactions of thiophene- and furanboronic
acids are not of relevance in the present context.27
The protocol developed for the 6-chloropurine coupling
was also applied to ꢀ-D-ribofuranosyl-6-chloropurine (Table
2). We tested a normal (Table 2, entry 1), a sterically
demanding (entry 2), two heterocyclic (entries 3 and 4), and
an electrochemically active boronic acid (Table 2, entry 5)
useful as a marker.29 In the absence of protective groups, a
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9007475
(30) Ko¨llhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed.
2003, 42, 1056.
(29) Plenio, H.; Aberle, C. Chem.sEur. J. 2001, 7, 4438.
(31) an der Heiden, M. R.; Plenio, H. Chem.sEur. J. 2004, 10, 1789.
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