Synthesis of novel 9-aryl and heteroarylpurine derivatives via copper mediated coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2014.01.091

A series of 9-(hetero)arylpurine derivatives has been prepared through N-arylation of 6-chloropurine with boronic acids in the presence of copper(II) acetate. Screening reaction conditions in terms of bases and solvents led to the successful coupling of a series of sterically demanding (hetero)arylboronic acids, never described so far. The coupling products were next readily converted into the target adenine derivatives. The described procedure provides easy access to original fragments for screening applications. Moreover these 9-aryl-6-chloropurine derivatives might be useful as intermediates for the preparation of purine derivatives with potential biological properties.

Full text of DOI:10.1016/j.tetlet.2014.01.091

Accepted Manuscript
Synthesis of Novel 9-Aryl and Heteroarylpurine Derivatives via Copper Medi-
ated Coupling Reaction
Laurence Morellato, Valérie Huteau, Sylvie Pochet
PII:
S0040-4039(14)00137-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.091
TETL 44124
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
16 December 2013
19 January 2014
21 January 2014
Please cite this article as: Morellato, L., Huteau, V., Pochet, S., Synthesis of Novel 9-Aryl and Heteroarylpurine
Derivatives via Copper Mediated Coupling Reaction, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.01.091
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Synthesis of Novel 9-Aryl and Heteroaryl-
purine Derivatives via Copper Mediated
Coupling Reaction
Laurence Morellato, Valérie Huteau and Sylvie Pochet*

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Synthesis of Novel 9-Aryl and Heteroarylpurine Derivatives via Copper Mediated
Coupling Reaction
Laurence Morellato, Valérie Huteau and Sylvie Pochet*
Unité de Chimie et Biocatalyse, Institut Pasteur, CNRS, UMR3523, 28 rue du Dr Roux, 75724 Paris cedex, France
* Corresponding author. Tel: +33 140613805; fax: +33 145688404.
E-mail address: spochet@pasteur.fr (S. Pochet)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of 9-(hetero)arylpurine derivatives has been prepared through N-arylation of 6-
chloropurine with boronic acids in the presence of copper(II) acetate. Screening reaction
conditions in terms of bases and solvents led to the successful coupling of a series of sterically
demanding (hetero)arylboronic acids, never described so far. The coupling products were next
readily converted into the target adenine derivatives. The described procedure provides easy
access to original fragments for screening applications. Moreover these 9-aryl-6-chloropurines
derivatives might be useful as intermediates for the preparation of purine derivatives with
potential biological properties.
Available online
Keywords:
N-Arylation
Purine
Cross-coupling
Boronic acids
Adenine derivative
2009 Elsevier Ltd. All rights reserved.
Purine derivatives are an important class of natural and
synthetic compounds with a broad range of biological and
pharmacological properties, including antibacterial, antiviral and
antitumor activities.1 As a result, significant efforts have been
directed to the generation of tri- and tetrasubstituted purine
derivatives through heterocyclizations, nucleophilic substitutions
and alkylation reactions.2 The recent developments in metal-
mediated cross-coupling reactions have greatly expanded the
chemical diversity readily attainable from the purine scaffold.3
regioselective (N9 position), but the conversion requires long
reaction times (up to 3 days) and the yields in isolated products
are sometimes low. Suitably protected or masked purines are
preferred as precursors due to the low solubility of adenine or 2-
amino-6-chloropurine under the general anhydrous conditions.9d
N-arylation of adenine was also conducted in aqueous media with
moderate to good yields.2b,10 Nui et al.11 have reported an
alternative route to the preparation of 9-arylpurines using
diaryliodonium salts and CuBr as catalyst with good to excellent
yields. However, the scope of the reaction is limited almost
entirely to some phenyl derivatives.
As part of our fragment-based strategy for NAD kinase
inhibitors,4 we focus on simple access of a variety of 9-
substituted purine derivatives. While 9-alkylpurines are readily
obtained by direct alkylation of purines with an alkyl halide in
the presence of a base or under Mitsunobu reaction, methods for
the preparation of 9-arylpurines are generally less efficient. The
classical two-step synthesis involves reaction of aryl amines with
appropriate chloro-pyrimidines, followed by the ring closing
reaction of resulting diamino-pyrimidines.5 Microwave-assisted
synthesis led to improved reaction times and yields.6 The other
synthetic route to 9-arylpurines takes advantage of the copper(II)
mediated C-N coupling reaction with arylboronic acids, referred
as the Chan-Lam coupling reaction.7 This methodology has been
successfully applied to various azoles8 such as imidazole,
pyrazole and pyrrole, with variable product yields. Up to now,
only few examples of N-arylation of purines have been reported.9
Herein we report our attempts to extend the substrate scope of
the copper-mediated N-arylation of 6-chloropurine (1) with
boronic acids (2) to different arenes and heteroarenes (Figure 1).
These substrates were chosen among commercially available
boronic acids of various sizes and relative reactivity. The
resulting N9-arylated 6-chloropurines 3 were then readily
converted to the target adenine derivatives 4 (Scheme 1).
Scheme 1. Preparation of target adenine derivatives (4)
Initially described by Schultz and co-workers,9a the coupling
conditions between purines and substituted phenyl boronic acids
have been optimized by Bakkestuen and Grundersen.9b By using
First we applied the anhydrous conditions reported by
Gundersen.9b Thus, 6-chloropurine 1 was reacted with 3 equiv. of
meta- or para-substituted phenyl boronic acid 2a-2d (Figure 1), 1
the Cu(II)/1,10-phenanthroline system,
N-arylation is

2
Tetrahedron Letters
equiv. of Cu(II)acetate and 2 equiv. of 1,10-phenanthroline in
3p in 69% yield. Compounds 3p-q are valuable starting points
dry CH2Cl2 in the presence of activated molecular sieves at room
temperature and open air. As previously observed by others, the
reaction was slow (2-3 days). The target N9-arylpurines were
isolated in good (68% and 60% of 3a and 3b) to moderate (28%
and 35% of 3c and 3d) yields (Table 1, entries 1-4). Using these
conditions the coupling with more bulky arylboronic acids, such
as biphenyls 2e-2g, terphenyl 2h and fused rings 2i-2k, provided
the corresponding N9-arylpurines 3e-3k in moderate to good
yields (Table 1, entries 7-13). In some cases the isolated yields
are reduced due to tedious separation of products from the
reaction mixture.
for further chemical diversification.
The 9-arylated 6-chloropurines 3 were typically converted into
the target adenine derivatives 4. Thus reaction of 3 with ammonia
in methanol at 60°C afforded a mixture of 6-aminopurine
derivative (4) and 6-methoxypurine derivatives (5) (ratio 7/3)
which were easily separated by flash chromatography. In the case
of 3a, ester was first converted into acid 3r and then into the
purine derivative 4r. Structural assignments of all synthesized
1
compounds were based on H, 13C, NOESY and HMBC NMR
data. The purity of compounds was checked by analytical HPLC
and found > 95%.
Table 1. N-Arylation of 6-chloropurine (1) with boronic acids (2)
B(OH)2
R
Entry
Boronic
Conditions
Product
Isolated
acid (2)
yield (%)
(HO)2B
1
A, rt, 72 h
68
2a
3a
R1
2e R = H
2f R = F
2
3
4
5
6
7
A, rt, 72 h
A, rt, 72 h
A, rt, 72 h
B, rt, 72 h
C, rt, 72 h
A, rt, 48 h
A, rt, 48 h
A, rt, 72 h
A, rt, 72 h
A, rt, 72 h
A, rt, 72 h
A, rt, 72 h
B, 50°C, 36 h
A, rt, 72 h
C, rt, 72 h
B, rt, 72 h
B, 50°C, 24 h
B, rt, 72 h
60
28
35
37
16
67
25
37
36
65
20
78
25
nd
nd
13
22
37
6
2b
2c
2d
2d
2d
2e
3b
3c
3d
3d
3d
3e
R2
(HO)2B
2a R1 = COOMe, R2 = H
2b R1 = CN, R2 = H
2c R1 = F, R2 = OCH2Ph
2d R1 = H, R2 = CN
R
8
9
2g R = H
2h R = Ph
2f
3f
2g
2h
2i
3g
3h
3i
B(OH)2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
(HO)2B
2j
3j
X
2k
2k
2l
3k
3k
3l
R
2i R = H
2j R = OMe
2k X = C
2l X = N
2l
3l
2l
3l
B(OH)2
2la
2m
2n
2na
2oa
2pa
2qa
B(OH)2
B(OH)2
3l
3m
3n
3n
3o
3p
3q
A, rt, 72 h
X
S
X
B, 50°C, 48 h
B, 50°C, 48 h
B, 50°C, 14 h
B, 50°C, 5 h
35
32
69
90
Br
2p X = N
2q X = C
2n X = S
2o X = O
2m
Figure 1. Set of arylboronic acids (2a-2k, 2q) and heteroarylboronic
acids (2l-2p) used in this study.
Reagents and conditions: Boronic acids (3 equiv.), Cu(OAc)2 (1 equiv.),
4Å M.S. (0.75 g/mmol of 1) in the presence of phenanthroline (2 equiv)
in CH2Cl2 (conditions A), Et3N (2 equiv) in DMF (conditions B) or
pyridine (2 equiv) in CH2Cl2 (conditions C). a 2 equiv. of boronic acid
were used. nd, not detectable.
The coupling of 1 with the heteroarylboronic acids (2l-2p)
was found to be less effective under the conditions used above,
no reaction or only traces of products were detected. Taking
isoquinoline-4-boronic acid (2l) as a model, initial conditions
were modified including the use of other bases (Et3N, pyridine,
TMEDA) and solvents (DMF, MeOH) as well as the reaction
temperature.12 In our hands, the best product yield was obtained
using Et3N/DMF and increasing the reaction temperature to 50°C
(Table 1, entries 15-18). Thus 3l was isolated in 22% yield, while
no product or only trace was detected using pyridine/CH2Cl2 or
aqueous MeOH/TMEAD. Additionally, a variety of hindered
heteroarenes were found to be substrates under these optimized
conditions affording the corresponding 9-arylpurines 3m-3o in
acceptable yields, even using 2 equiv. of boronic acid. No N7-
products were detected. The use of pyridine/CH2Cl2 or
Et3N/DMF system with arylboronic acid 2d or 2k did not
improve the yields (entries 5 & 6). It is noteworthy that these
conditions are compatible with the presence of functional
reactive groups. Thus, coupling between 3-bromo-phenylboronic
acid (2q) and 1 in the presence of Et3N in DMF was complete
after 5h at 50°C, and 3q was isolated in 90% yield. Similarly,
coupling of 3-bromo-pyridine boronic acid (2p) with 1 afforded
In summary, a wide assortment of commercially available
(hetero)arylboronic acids was coupled to 6-chloropurine
providing novel 9-arylated derivatives in modest to excellent
yield. While the arylation using the Cu(OAc)2/phenanthroline
system tolerated various substitution patterns on the phenyl rings,
these conditions were found ineffective with our selected
heteroarylboronic acids. In our hands, the Cu(OAc)2/Et3N/DMF
system allowed N-arylation with sterically demanding boronic
acids in acceptable yield. The described two-step procedure
provides a simple and rapid access to original adenine fragments.
These original chemotypes constitute valuable starting points for
fragment-based screening applications, as well as for further
chemical diversification into potential therapeutic agents.13
Acknowledgments
This work was supported by grants from the ANR, Institut
Pasteur and CNRS. LM is grateful to the ANR for a post-doctoral
fellowship. The authors would like to thank Cedric Simon and
Tiphanie Courtiol for technical assistance.

3
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Supplementary Material
Supplementary data associated with this article can be found
in the online version, at http:
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