The Suzuki-Miyaura cross-coupling reactions of 6-halopurines with boronic acids leading to 6-aryl- and 6-alkenylpurines

Article abstract of DOI:10.1055/s-1999-2753

The Suzuki-Miyaura cross-coupling reactions of 9-benzyl-6-chloropurine with boronic acids gave 6-alkylated purines in moderate to excellent yields. The best results with electron rich arylboronic acids were obtained in toluene in the presence of anhydrous

Full text of DOI:10.1055/s-1999-2753

LETTER
1145
The Suzuki-Miyaura Cross-Coupling Reactions of 6-Halopurines with
Boronic Acids Leading to 6-Aryl- and 6-Alkenylpurines
Martina Havelkováa, Michal Hocekb*, Michal »esnekb, Dalimil Dvo¯áka*
a Department of Organic Chemistry, Prague Institute of Chemical Technology, 166 28 Prague 6, Czech Republic
E-mail: dvorakd@vscht.cz
b Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, CZ-16610 Prague 6, Czech Republic
E-mail: hocek@uochb.cas.cz
Received 16 March 1999
In this communication we wish to report our results in this
Abstract: The Suzuki-Myiaura cross-coupling reactions of 9-ben-
field.
zyl-6-chloropurine with boronic acids gave 6-alkylated purines in
moderate to excellent yields. The best results with electron rich
arylboronic acids were obtained in toluene in the presence of anhy-
drous K2CO3 as a base, while electron poor boronic acids and alke-
nyl boronic acids gave better results using aqueous K2CO3 in DME.
The reaction was successfully applied for the synthesis of 6-phe-
nylpurine bases and nucleosides.
To test the Suzuki-Myiaura coupling reaction of purine
derivatives we chose 6-halo-9-benzylpurines as model
compounds. Thus Pd(PPh3)4 catalysed reaction of 9-ben-
zyl-6-chloropurine (1) with phenylboronic acid in the
presence of K2CO3 in toluene at 100 °C afforded after 24
h 9-benzyl-6-phenylpurine (2a) in excellent yield (95%)
(Scheme 1).
Key words: purines, nucleosides, cross-couplings, boronic acids
Purine bases modified in the 6-position and their nucleo-
side and nucleotide derivatives and analogues possess a
broad spectrum of biological activity. The cytotoxicity of
6-methylpurine and its nucleosides is well known,1 while
a promising cytostatic activity of 6-(aminoalkyl)purine
derivatives (as cytokinines analogues) has been recently
discovered.2 Many 6-alkylaminopurine nucleosides are
important adenosine receptors antagonists3 and acyclic
nucleotide analogues derived from 6-(di)alkylaminopu-
rines are strong antivirals, antineoplastic agents and im-
munomodulators.4 Recently, several 6-(arylalkynyl)-, 6-
(arylalkenyl)- and 6-(arylalkyl)purines were reported5 to
exhibit cytokinine activity.
Scheme 1
In the last decade, with the development of the cross-cou-
pling methodology, many 6-C-substituted purines have
been prepared.6 Thus 6-halopurine derivatives react with
alkyl(aryl)zinc or tin reagents,6a-e trialkylaluminum6f or
alkylcuprates6g-i to give the 6-alkylpurine derivatives.
Also another approach based on the reaction of purine-6-
zinc iodide with aryl or vinyl halides has recently been de-
scribed.7 For the synthesis of 6-arylpurines, an alternative
based on radical photochemical reactions of adenine de-
rivatives with aromatic compounds was used,8 but this
method is very unselective and for substituted benzenes,
mixtures of all ortho-, meta- and para-substituted deriva-
tives were obtained. To the best of our knowledge, no suc-
cessful Suzuki-Myiaura type of cross-coupling9 of 6-
halopurines with alkyl- or arylboronic acid has been de-
scribed. The advantage of this reaction compared to the
above mentioned methods would be the high stability of
boronic acids, the low toxicity of boron compounds, easy
work-up and isolation of the product along with availabil-
ity of starting boronic acids (a number of boronic acids,
especially the aromatic ones, is commercially available).
9-Benzyl-6-iodopurine reacted faster giving similarly
high yield (92%) of 2a, however, the reaction mixture was
not as clean as in the case of 1. Also 9-benzyl-7-chloropu-
rine (3) reacted smoothly with phenylboronic acid giving
70% isolated yield of 7-benzyl-6-phenylpurine (4) in 7.5
h under the above mentioned conditions showing the
higher reactivity of 3 compared to 1. Interestingly, bases
other than potassium carbonate - Na2CO3, Cs2CO3, ethyl-
diisopropylamine and sodium methoxide did not give de-
tectable amounts of 2a. When xylene was used instead of
toluene at 130 °C under otherwise identical conditions,
the reaction was completed in nearly quantitative yield in
9 h, but the product was contaminated with small amount
of by-products which were difficult to separate. Reaction
in the presence of aqueous K2CO3 in DME was very fast
affording 95% yield in 6 h. In contrary the reaction in
DMF at 100 °C was very slow giving 2a in 35% after 24
h and 68% after 45 h, probably as a result of catalyst de-
composition.
Synlett 1999, No. 07, 1145–1147 ISSN 0936-5214 © Thieme Stuttgart · New York

1146
M. Havelková et al.
LETTER
The influence of the catalytic system on the course of the
reaction was examined in the reaction of 7-benzyl-6-chlo-
ropurine (3) and 9-benzyl-6-chloropurine (1) with phenyl-
boronic acid in toluene at 100 °C (Table 1). As expected,
a lower phosphine to Pd ratio and using AsPh3 instead of
PPh3 resulted in acceleration of the reaction (Table 1).
However the reaction was not as clean as the reaction in
the presence of Pd(PPh3)4.
The optimum conditions for the reaction of 1 with phenyl-
boronic acid (2.5 mol% Pd(PPh3)4, K2CO3, toluene,
100 °C) were used for the reaction of 1 with other boronic
acids10 (Table 2). The reaction gives good to excellent re-
sults with aromatic boronic acids bearing electron donor,
neutral or weak acceptor substituents at the aromatic ring
(entries 1,3,6,7) including 4-fluorophenyl derivative and
sterically hindered 2-methylphenyl derivative. Introduc-
tion of stronger electron acceptors on the aromatic ring re-
sulted in dramatic lowering of the reaction rate. Thus 3-
nitrophenylboronic acid gave only 19% yield after 48 h
(Table 2, entry 4) and an extreme case of pentafluorophe-
nylboronic acid (entry 16) did not react at all. While 2-
thienyl boronic acid gave fair yield of the corresponding
coupled product 2f, somewhat surprisingly alkenylboron-
ic acids (entries 10,12) gave only low yields of the cou-
pled products 2g and 2h under the above conditions.
Similar low yields were obtained also with butylboronic
acid (entry 14). Better results of the coupling of alkenyl as
well as 2-thienyl and 3-nitrophenyl boronic acids were ob-
tained in DME in the presence of aqueous K2CO3 (entries
5, 9, 11, 13). The (E)-geometry on the double bond of the
alkenyl boronic acids used, remained unchanged under
the both reaction conditions and any isomerised product
was observed. None coupled product was obtained using
aqueous K2CO3 in the case of butylboronic and perfluo-
rophenylboronic acids.
ed under the above mentioned conditions with phenylbo-
ronic acid to give the THP-protected 6-phenylpurines 7
and 8 in nearly quantitative yields. They were deprotected
by a standard procedure11 with the use of wet Dowex
50X8 (H+) in methanol to give the known 6-phenylpurine
bases 9 and 10 in high yields. For comparison, unprotect-
ed 6-chloropurine and 2-amino-6-chloropurine bases
were submitted for direct cross-coupling reactions to phe-
nylboronic acid under the same conditions but the conver-
sions were very low even after prolonged reaction times
probably due to both lower reactivity and lower solubility
of the free purines. Analogously, the tri-O-acetyl protect-
ed nucleosides derived from 6-chloropurine and 2-amino-
6-chloropurine 11 and 12 reacted with phenylboronic acid
to give the corresponding 6-phenylpurine derivatives 13
and 14 in high yields (the conversion was quantitative, the
yields were somewhat lowered by partial deacetylation
during work-up). Base-catalyzed deacetylation12 of the
protected nucleosides 13 and 14 using sodium methoxide
in methanol afforded quantitatively the free nucleosides
15 and 16 that were purified by crystallisation.
In conclusion, the Suzuki-Miyaura cross-coupling reac-
tions of 6-chloropurines with various alkyl-, alkenyl- and
arylboronic acids were investigated. Under anhydrous
conditions the best results were achieved with the use of
electron rich arylboronic acids (Ar = phenyl, electron-do-
nating group substituted phenyl), while electron poor aryl-
(nitro-, pentafluorophenyl), alkenyl- and alkylboronic ac-
ids gave low or negligible conversions. Reaction in the
presence of aqueous K2CO3 is faster and can be used to
prepare coupling products of alkenyl- and some electron
poor arylboronic acids in reasonable yield in cases of sub-
strates stable to aqueous K2CO3. The relatively mild con-
Finally, to test the synthetic utility of this method, we have
applied the Suzuki reaction of phenylboronic acid with 6-
chloropurines for the synthesis of 6-phenylpurine bases
and nucleosides. To prevent hydrolysis of acetate protect-
ing groups the non-aqueous conditions were used. Thus
the tetrahydropyran-2-yl (THP) protected 6-chloropurine
5 or bis(THP)-protected 2-amino-6-chloropurine 6 react-
Synlett 1999, No. 07, 1145–1147 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The Suzuki-Miyaura Cross-Coupling Reactions of 6-Halopurines with Boronic Acids Leading
1147
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Scheme 2
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(10) Typical procedure: Coupling of 9-benzyl-6-chloropurine
(1) with 3-methoxyphenylboronic acid. A mixture of 9-
benzyl-6-chloropurine (1) (0.122 g; 0.5 mmol), 3-
methoxyphenylboronic acid (0.114g; 0.75 mmol), anhydrous
K2CO3 (0.086 g; 0.625 mmol), Pd(PPh3)4 (0.014 g; 0.012
mmol) and toluene (10 ml) was stirred under argon at 100 °C
for 4 h, filtered, evaporated and chromatographed on silicagel
(Chromatotron, 2 mm plate, CHCl3 : MeOH 98:2) to give 9-
benzyl-6-(3-methoxyphenyl)purine (2b) (0.097 g; 62%) as a
white solid, m.p. 111-114 °C, ref.8b 114-116 °C), 1H NMR
(300 MHz, CDCl3) d = 3.93 (s, 3H, CH3), 5.49 (s, 2H, CH2),
7.08 (m, 1H, ArH), 7.35 (m, 5H, CH2Ph), 7.47 (t, J = 8 Hz,
ArH), 8.09 (s, 1H, H-8 Pu), 8.36 (m, 1H, ArH), 8.45 (m, 1H,
ArH), 9.06 (s, 1H, H-2 Pu).
ditions used, good yields of cross-coupling reactions, the
use of relatively cheap, stable and non-toxic boronic acids
and tolerance to various functionalities (including amino
groups) makes this methodology a good alternative for the
synthesis of 6-arylpurines. An application of this method-
ology for the synthesis of a series of 6-arylpurine bases
and nucleosides of potential biological interest is in
progress and will be published in due course.
Acknowledgement
This work was supported by the Grant Agency of the Czech Repu-
blic (grants No. 203/96/005 and 203/98/P027) and by Prague Insti-
tute of Chemical Technology (grant No. 110010015).
The reaction under aqueous conditions was analogous, except
of the higher amount of K2CO3 (0.187 g; 1.35 mmol) together
with water (0.7 ml) in DME (5ml) was used. The reaction
mixture was than stirred under argon at 80 °C for the time
reported in Table 2. The following work up was the same as
above.
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Article Identifier:
1437-2096,E;1999,0,07,1145,1147,ftx,en;G10199ST.pdf
Synlett 1999, No. 07, 1145–1147 ISSN 0936-5214 © Thieme Stuttgart · New York