Synthesis of 6-ethynylpurine derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.04.011

A series of 6-(arylethynyl)purine derivatives are synthesized from the corresponding 6-halopurines via sequential and 'one-pot' Sonogashira-coupling reactions. The nature of the acetylene source was found to have a profound influence on the efficiency of

Full text of DOI:10.1016/j.tetlet.2008.04.011

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3782–3784
Synthesis of 6-ethynylpurine derivatives
*
´
´
Andras Nagy, Andras Kotschy
Institute of Chemistry, Eo¨tvo¨s Lora´nd University, Pa´zma´ny Pe´ter se´ta´ny 1/A., Budapest H-1117, Hungary
Received 5 February 2008; revised 18 March 2008; accepted 2 April 2008
Available online 4 April 2008
Dedicated to Professor Heinrich Wamhoff on the occasion of his 70th birthday
Abstract
A series of 6-(arylethynyl)purine derivatives are synthesized from the corresponding 6-halopurines via sequential and ‘one-pot’ Sono-
gashira-coupling reactions. The nature of the acetylene source was found to have a profound influence on the efficiency of the process. In
sequential couplings, 2-methyl-but-3-yn-2-ol was found to be an efficient acetylene surrogate, while in the ‘one-pot’ reaction, 1-ethynyl-
cyclohexanol gave superior results.
Ó 2008 Elsevier Ltd. All rights reserved.
The structural modification of purine bases, nucleosides
and nucleotides has been a prime target in medicinal chem-
istry since the introduction of a substituent onto the hetero-
cyclic ring may dramatically influence their base-pairing
ability and the selectivity of their binding to targets. Pur-
ines, bearing a C-substituent at position 6 display a broad
spectrum of activity ranging from cytotoxicity1 to antiviral
effects, 2 so it is not surprising that the preparation of these
purine derivatives has received considerable attention
lately. Cross-coupling reactions in particular, have facili-
tated the introduction of C-based substituents starting
from 6-halopurines. The Suzuki,3 Stille4 and Negishi5 cou-
plings have all been exploited successfully in this respect.
The 6-vinyl- and 6-ethynylpurine derivatives were also
utilized as a platform for further elaboration.6,7 The Sono-
gashira-coupling was extended to some unprotected
purines too.8
approach would involve the coupling of 6-ethynylpurines
with different aryl halides, but to date the reagent of choice
for this transformation is trimethylsilylacetylene,11 which is
not economic for large scale applications.
Our studies were aimed towards establishing a general
synthetic route to 6-ethynylpurine derivatives by devising
a scalable synthesis of 6-ethynylpurine and coupling of this
compound with a series of aryl halides. We also wanted to
study the feasibility of two recently published one-pot pro-
cedures,12,13 which utilize halopurines, aryl halides and a
simple acetylene surrogate as coupling partners.
Our choice of purine derivatives was based on the 2-
amino-6-halopurine skeleton. Thus, 2-amino-9-benzyl-6-
iodo-purine (1) was reacted with 2-methyl-3-butyn-2-ol
(2a) or 1-ethynyl-cyclohexanol (2b) in the presence of 2
mol % PdCl2(PPh3)2, 2 mol % CuI and triethylamine at
room temperature14 to furnish the appropriate ethynylpu-
rine derivatives 3b or 3c in good yield (Scheme 1). These
reactions took place smoothly on a multigram scale and
the products could be obtained in a pure form by filtration
and subsequent washing. Using the chloride-analog of 1 led
to similar results, although more forcing conditions and
prolonged reaction times were required to achieve complete
conversion, however, the overall yield decreased. The
advantage of the acetylene derivatives 2a and 2b, besides
their low cost, is the fact that their substituents(R) can
Although the Sonogashira-coupling of 6-halopurines
and acetylene derivatives has been reported,9,10 there are
a number of limitations to this process: (i) the number of
commercially available monosubstituted acetylenes is lim-
ited, and (ii) the economy of such processes is poor due
to the price of the aforementioned acetylenes. An alternate
*
Corresponding author. Tel.: +36 1 372 2910; fax: +36 1 372 2909.
E-mail address: kotschy@elte.hu (A. Kotschy).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.011

A. Nagy, A. Kotschy / Tetrahedron Letters 49 (2008) 3782–3784
3783
Table 1
R
The Sonogashira-coupling of 3a and aryl halides 4a–k
I
R
Ar
N
N
Ba(OH)2
2a,b
N
N
N
N
N
N
N
[Pd/Cu]
TEA
65%
from 3b
[Pd/Cu/base]
H2N
N
N
N
H2N
H2N
N
N
N
N
N
Ar-X
+
N
Bn
Bn
Bn
3a
method A, B
1
3b,c
H2N
4a-i
N
H2N
N
OH
Bn
3a
Bn
3b: R=
3c: R=
82%
82%
OH
5a-i
Ar–X
Method
Yield (%)
Scheme 1. The synthesis of 6-ethynylpurines 3a–c.
A
B
72
55
MeO
I
4a
4b
be removed under alkaline conditions. To obtain the 6-
ethynylpurine derivative 3a, a solution of 3b in toluene or
DMA was treated with an inorganic base (KOH or
Ba(OH)2, respectively) at elevated temperatures to give 3a
in 65% yield on a 10 g scale. The analogous transformation
of 3c to 3a was also realized, but with inferior efficiency.15
In the first set of coupling reactions, 3a was reacted with
various aryl halides using either the conventional Sono-
gashira-coupling conditions (Table 1, method A) or the
modified conditions of Mori16 (method B). When aryl
iodides were used as coupling partners, the former condi-
tions usually gave superior yields. Electron rich and elec-
tron deficient aromatic compounds could both be
introduced into the desired products. In the case of the less
reactive aryl bromides, however, method A usually gave
very poor yields. In these reactions the conditions described
in method B gave better results, although these were still
mediocre in most cases.
O2N
I
A
A
92
61
I
4c
I
A
A
68
80
Cl
F
4d
4e
I
O
H
N
A
B
22
45
O
I
N
H
4f
It was also possible to carry out Sonogashira-coupling
on 3b or 3c, but in these cases the reaction had to be carried
out in the presence of a base, which facilitates the removal
of the end-groups prior to the coupling.17 A convenient
solution to this problem could be the use of biphasic con-
ditions with a strongly alkaline aqueous phase and phase
transfer catalysis,18 as reported for analogous 4-aryl-2-
methyl-3-butyn-2-ols. We conducted a series of experi-
ments with 3b and different aryl halides (Table 2, method
A) but isolated the desired products in very poor yields.
The reason behind this poor efficiency is that to achieve
complete conversion the reactions had to be run for a pro-
longed period of time. During this period, we observed the
formation of ethynylpurine 3a and decomposition prod-
ucts of 3a and 3b.
The alternative approach to this problem is the use of
the cyclohexanone protected 6-ethynylpurine 3c. In this
case, the previously applied biphasic conditions led to no
discernible product formation. On screening possible sol-
vent-base combinations, we found that on running the
deprotection–coupling sequence in the presence of barium
hydroxide in DMF (Table 2, method B), we obtained
acceptable yields in most cases.19 In light of the fact that
removal of the cyclohexanone from 3c was accomplished
in mediocre yield, and in this procedure we carried out
the two steps sequentially, the yields are even more
valuable.
Br
A
B
B
65
44
33
N
4g
Cl
Br
4h
F
Br
4i
Method A: 5% PdCl2(PPh3)2, 5% CuI, 2 equiv TEA, DMF, 80 °C.
Method B: 3% PdCl2(PPh3)2, 3% CuI, 2 equiv TBAF, THF, rt.
There is also a third possible, even more elegant way to
accomplish the synthesis of arylethynyl-purines, where
starting from the halopurine, aryl halide and the masked
acetylene, the three steps are performed in the same flask,
without isolation of the intermediates. We investigated a
series of different conditions to obtain the desired products
in this domino process, but even if successful, we obtained
only traces of the arylethynyl-purines after tedious chro-
matographic separation.
In summary, a series of 6-(arylethynyl)purine derivatives
were prepared starting from the appropriate 6-iodopurine,
aryl halides and an acetylene surrogate (2-methyl-3-butyn-
2-ol or 1-ethynyl-cyclohexanol). Attempts were made at
carrying out the coupling and deprotection steps both

3784
A. Nagy, A. Kotschy / Tetrahedron Letters 49 (2008) 3782–3784
Table 2
References and notes
The tandem deprotection–Sonogashira-coupling of protected 6-ethynyl-
purines 3b,c with different aryl halides
1. Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem.
2000, 43, 1817–1825.
2. Hocek, M.; Naus, P.; Pohl, R.; Votruba, I.; Furman, P. A.; Tharnish,
P. M.; Otto, M. J. J. Med. Chem. 2005, 48, 5869–5873.
R
Ar
´
´
3. Capek, P.; Vrabel, M.; Hasnık , Z.; Pohl, R.; Hocek, M. Synthesis
[Pd/Cu/base]
N
N
2006, 3515–3526.
N
N
Ar-X
+
N
method A, B
4. Langli, G.; Gundersen, L.-L.; Rise, F. Tetrahedron 1996, 52, 5625–
5638.
5. Guthmann, H.; Koenemann, M.; Bach, T. Eur. J. Org. Chem. 2007,
632–638.
N
H2N
4a-k
N
H2N
N
Bn
3b,c
Bn
5a-k
6. Kuchar, M.; Pohl, R.; Votruba, I.; Hocek, M. Eur. J. Org. Chem.
2006, 5083–5098.
7. Overas, A. T.; Bakkestuen, A. K.; Gundersen, L.-L.; Rise, F. Acta
Chem. Scand. 1997, 51, 1116–1124.
8. Firth, A. G.; Fairlamb, I. J. S.; Darley, K.; Baumann, C. G.
Tetrahedron Lett. 2006, 47, 3529–3533.
9. Berg, T. C.; Bakken, V.; Gundersen, L.-L.; Petersen, D. Tetrahedron
2006, 62, 6121–6131.
10. Turek, P.; Novak, P.; Pohl, R.; Hocek, M.; Kotora, M. J. Org. Chem.
2006, 71, 8978–8981.
11. A representative example was published by: Mio, M. J.; Kopel, L. C.;
Braun, J. B.; Gidzikwa, T. L.; Hull, K. L.; Brisbois, R. G.;
Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4, 3199.
Ar–X
Purine
Method
Yield (%)
3b
3c
A
B
9
80
MeO
I
4a
4b
3b
3c
A
B
18
91
O2N
I
3b
3c
A
B
5
44
I
4c
´
12. Novak, Z.; Nemes, P.; Kotschy, A. Org. Lett. 2004, 6, 4917–4920.
3b
3c
A
B
17
75
I
´
´
13. Csekei, M.; Novak, Z.; Kotschy, A. Tetrahedron 2008, 64, 975–982.
14. General procedure: A mixture of 5.00 g (14.2 mmol) of 1, 200 mg
(0.285 mmol, 2 mol %) of PdCl2(PPh3)2 and 54 mg (0.285 mmol,
2 mol %) of CuI was stirred in 20 ml of THF at ambient temperature,
under an argon atmosphere. After 1 min, 16 mmol of 2-methyl-
3-butyn-2-ol or 1-ethynyl-cyclohexanol and 5.0 ml (35.5 mmol) of
triethylamine were added to the mixture. Stirring was continued until
the starting material was consumed (ca. 16 h) and then the resulting
thick suspension was filtered. The precipitate was washed with water
and cold ethyl acetate and dried in vacuum to yield the appropriate
compound (3b or 3c) as a white solid.
F
4e
3b
3c
A
B
28
71
Br
N
4g
3b
3c
A
B
35
75
Cl
Br
4h
15. The coupling reactions of 2-amino-6-iodopurine with 2a and 2b were
also successful but we were unable to remove the organic end-groups
(acetone or cyclohexanone) from the resulting compounds without
significant decomposition.
3b
3c
A
B
16
53
I
4j
16. Mori, A.; Shimada, T.; Kondo, T.; Sekiguchi, A. Synlett 2001, 649–
651.
Br
3c
B
47
N
4k
´
17. Nagy, A.; Novak, Z.; Kotschy, A. J. Organomet. Chem. 2005, 690,
4453–4461.
Method A: 5% PdCl2(PPh3)2, 10% CuI, 5M NaOH, TBAB, toluene.
Method B: 3% PdCl2(PPh3)2, 3% CuI, 2 equiv TEA, 0.7 equiv Ba(OH)2,
DMF.
18. Chow, H.; Wan, C.; Low, K.; Yeung, Y. J. Org. Chem. 2001, 66,
1910.
19. Typical procedure: 100 mg (0.29 mmol) of 3c, 7 mol % (14 mg,
0.02 mmol) of PdCl2(PPh3)2, 7 mol % (4 mg, 0.02 mmol) of CuI,
70 mol % (38 mg, 0.20 mmol) of Ba(OH)2 and 1.1 equiv (75 mg,
0.32 mmol) of 4-iodoanisole (4a) were mixed in 3 ml of DMA.
Triethylamine (1.2 equiv, 124 ll) was added and the mixture was
heated to 85 °C. The reaction reached full conversion in most cases in
approximately 24 h. The solvent was evaporated and the residue was
purified by flash column chromatography on silica gel (hexane–ethyl
acetate gradient from 90:10 to 20:80) to give 82 mg (80%) of 5a as a
white solid. 1H NMR (500 MHz, CDCl3): 7.72 (s, 1H), 7.59 (d, 2H,
J = 8.7 Hz), 7.29–7.15 (m, 5H), 6.81 (d, 2H, J = 8.8 Hz), 5.41 (br s,
2H), 5.18 (s, 2H), 3.75 (s, 3H). 13C NMR (125 MHz, CDCl3): 159.90,
158.83, 152.57, 141.58, 141.34, 134.28, 133.45, 131.03, 128.05, 127.41,
separately and in a one-pot fashion. Of the possible combi-
nations tested the direct coupling of 6-ethynylpurines with
aryl halides and sequential deprotection–coupling of
the appropriate ethynyl-cyclohexanol derivative and aryl
halides were the most effective. Some of the studied reac-
tions were also carried out on multigram scale.
Acknowledgements
126.64, 113.10, 97.41, 82.08, 54.33, 45.78. MS (EI-70 eV): 355 (M+Å
10%), 281 (34%), 277 (19%), 147 (43%), 57 (100%). Anal. Calcd for
21H17N5O: C, 70.97; H, 4.82; N, 19.71%. Found: C, 70.56; H, 4.93;
N, 19.50%.
,
The financial support of Sumitomo Chemicals Co. as
´ ´
well as the technical assistance of Ms. A. Beatrix Bıro
C
´
and Dr. Antal Csampai are gratefully acknowledged.