Straightforward and highly efficient catalyst-free one-step synthesis of 2-(purin-6-yl)acetoacetic acid ethyl esters, (purin-6-yl)acetates, and 6-methylpurines through SNAr-based reactions of 6-halopurines with ethyl acetoacetate

Article abstract of DOI:10.1021/ol9002256

A novel approach to the synthesis of purines bearing functlonallzed carbon substltuents or methyl In position 6 was developed. Under different reaction conditions, 6-halopurlne derivatives could react with ethyl acetoacetate efficiently to yield 2-(purln-

Full text of DOI:10.1021/ol9002256

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1745-1748
Straightforward and Highly Efficient
Catalyst-Free One-Step Synthesis of
2-(Purin-6-yl)acetoacetic Acid Ethyl
Esters, (Purin-6-yl)acetates, and
6-Methylpurines through SNAr-Based
Reactions of 6-Halopurines with Ethyl
Acetoacetate
Gui-Rong Qu,† Zhi-Jie Mao,† Hong-Ying Niu,‡ Dong-Chao Wang,† Chao Xia,† and
Hai-Ming Guo*,†
College of Chemistry and EnVironmental Science, Henan Normal UniVersity, Xinxiang
453007, Henan, P. R. China, and School of Chemistry and Chemical Engineering,
Henan Institute of Science and Technology, Xinxiang 453003, China.
ghm@henannu.edu.cn
Received February 2, 2009
ABSTRACT
A novel approach to the synthesis of purines bearing functionalized carbon substituents or methyl in position 6 was developed. Under different
reaction conditions, 6-halopurine derivatives could react with ethyl acetoacetate efficiently to yield 2-(purin-6-yl)acetoacetic acid ethyl esters,
(purin-6-yl)acetates and 6-methylpurines respectively. No metal catalyst and ligand were required.
Modifications on purines bearing carbon substituents in
position 6 have been the focus for decades since the highly
cytotoxicity1 and antitumor activity2 of 6-methylpurine and
its ribonucleoside were found. Many of these derivatives
were found to exhibit cytostatic effects. For example,
6-(arylalkynyl)-, 6-(arylalkenyl)-, and 6-(arylalkyl)purines
show cytokinin3 and antioxidant activity.4 9-Benzyl-6-
(2) Clarke, D. A.; Philips, F. S.; Sternberg, S. S.; Stock, C. C. Ann.
N.Y. Acad. Sci. 1954, 60, 235.
† Henan Normal University.
‡ Henan Institute of Science and Technology.
(1) Montgomery, J. A.; Hewson, K. J. Med. Chem. 1968, 11, 48.
(3) Brathe, A.; Gundersen, L.-L.; Rise, F.; Eriksen, A. B.; Vollsnes,
A. V.; Wang, L. Tetrahedron 1999, 55, 211.
10.1021/ol9002256 CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society

arylpurines exhibit antimycobacterial, antibacterial, and cy-
totoxic effects.5 6-Hetaryl-purine ribonucleosides exhibit
potent antiviral activity against HCV.6 6-Hydroxymethyl-9-
(ꢀ-D-ribofuranosyl)purine isolated from collybia maculata
was reported to possess antifungal, cytotoxic, antiviral
properties7 and could be also used as an adenosine deaminase
inhibitor.8 Very recently, Michal Hocek et al. reported a
series of purines bearing functionalized carbon substituents
in position 69 and many of them display significant cytostatic
activity.
The classical method for the synthesis of purines bearing
carbon substituents in position 6 was heterocyclization.10
Another method was radical addition.11 Currently, the most
frequently used methods were transition metal-catalyzed
cross-coupling reactions of 6-halopurines. In this respect, the
Suzuki-,12a Stille-,12b Negish-,12c and Sonogashira-,12d,e
coupling reaction have all been exploited successfully, and
various organometallic reagents12f,g,9f were involved. No
matter what the carbon substituents in position 6 are, these
methods seem to be versatile. For example, purin-6-yl
acetates were prepared previously in moderate yields by
heterocyclization of pyrimidines,10a arylation of malonates13
or ethyl acetoacetate14 with 6-halo or 6-tosyloxypurines
followed by decarboxylation or cleavage of acetoacetate.
However, these methods were laborious or hard to
reduplicate.9f Michal Hocek et al. synthesize these com-
pounds via Pd-catalyzed cross-couplings of 6-chloropurines
with the Reformatsky reagent in the presence of ligands;
6-methylpurine bases were prepared by the conventional and
tedious method of heterocyclization10b-d from 6-methyluracil
with low yield.
Another straightforward method for the synthesis of
6-methylpurine involves the displacement of a suitable
leaving group on the heterocycle by Wittig reagent15 which
usually requires rigorous reaction conditions (anhydrous,
nitrogen atm at -30 to -35 °C). Similarly, cross-coupling
reaction has been also widely applied16 to the synthesis of
6-methylpurine derivatives. Regioselective methylation reac-
tions17 of 2,6-dihalopurines with methylzinc bromide or
trimethylaluminum in the presence of Pd- or Fe- catalysts
were also investigated by Michal Hocek et al. Despite the
cross-coupling reaction provides a general and efficient
methodology for the synthesis of purines bearing carbon
substituents in position 6, the expensive catalyst and rigorous
reaction conditions often make this method less desirable.
In addition to the above-mentioned methods, a most promis-
ing route is the nucleophilic SNAr reaction of 6-alkanesulfo-
nyl- or 6-halopurines with some salts of C-acids14a,b,18 (such
as malonates or acetoacetates), which have been less
developed and usually were not reliably reproducible in
accordance with previous literature.
Based on our preliminary study on various nucleoside
analogues,19 herein, we reported a novel and efficient method
for the synthesis of purines bearing different carbon substit-
uents in position 6 through nucleophilic aromatic substitution
of 6-halopurines and ethyl acetoacetate without catalyst.
Initially, we investigated the SNAr-based reactions between
ethyl acetoacetate and 9-Bn-6-iodopurine.20 As indicated in
Table 1 (entries 1 and 2), our experiments were first
conducted by coupling 9-Bn-6-iodopurine (1 eq) with ethyl
acetoacetate (5 eq) in the absence of catalyst. This reaction
proceeded at 80 °C in DMSO in the presence of 7.5 equiv
of K2CO3 for 6 h to produce the desired (purin-6-yl)acetate
4a in 81% yield along with other unidentified products (entry
1). Later, the unidentified products were confirmed to be
arylation product 3a and 9-Bn-6-methylpurine 5a by HRMS,
1H NMR, and 13C NMR. The initial arylation product 3a
increased when the reaction time was shorten, indicating that
different products could be formed with different reaction
time (entry 2). The same results were obtained when 9-Bn-
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1746
Org. Lett., Vol. 11, No. 8, 2009

Table 1. Investigation on the Nucleophilic SNAr Reaction
between Ethyl Acetoacetate and 9-Bn-6-Chloropurine in the
Absence of Catalysta
Table 2. Reaction of Ethyl Acetoacetate with Various
6-Halopurine Derivatives to Yield 2-(6-Purinyl)acetoacetic Acid
Ethyl Esters 3a
base
(equiv)
temp. time yield of yield of yield of
entry
(°C)
(h) 3a (%)b 4a (%)b 5a (%)b
1c
2c
3
K2CO3 (7.5)
K2CO3 (7.5)
K2CO3 (7.5)
K2CO3 (7.5)
K2CO3 (7.5)
K2CO3 (2)
K2CO3 (7.5)
K3PO43H2O (7.5)
NaH (7.5)
Cs2CO3 (7.5)
Cs2CO3 (2)
Cs2CO3 (7.5)
Cs2CO3 (7.5)
Cs2CO3 (7.5)
K2CO3 (7.5)
K2CO3 (7.5)
80
80
80
80
80
80
80
80
80
80
80
60
80
rt
6
8
45
81
47
75
31
76
57
33
16
37
trace
0
trace
2
0
6
19
0
0
4
1
63
5
7
11
trace
6
7
32
0
0
0
7
1
56
8
1
74
9
0.5
0.5
2
32
trace
0
10
11
12
13d
14
15
16
83
66
0
0.5
0.5
5
24
5
91
0
0
81
0
0
0
83
0
80
120
trace
trace
41
trace
45
76
a Reagents and conditions: 0.5 mmol 1a, 2.5 mmol ethyl acetoacetate
2 in 2 mL solvent for the indicated time. b Isolated yield based on 1a.
c 9-Bn-6-iodopurine was used. d DMF was used.
6-chloropurine21 was used (entries 3-4), demonstrating that
6-chloropurine derivatives could also act as efficient sub-
strates in this reaction. Next, we investigated the effect of
temperature, solvent, reaction time and the type and amount
of base on the relative yields of 3a, 4a and 5a. The
deacylation product 4a need much longer time (entry 5),
while generation of 3a could be performed in a relatively
short time (entries 7 and 10-14). Compared with other
investigated bases (Na2CO3, KOAc, K3PO4·3H2O, KOH,
K2HPO4·3H2O, NaH), Cs2CO3 was inclined to favor the
arylated acetoacetate 3a and was much less effective in the
deacylation reaction, whereas K2CO3 was considered as the
preferred base for the deacylation product 4a (entries 5-7,
10, and 12). K3PO4·3H2O could also serve as an effective
base to yield the arylated acetoacetate 3a (entry 8). When
NaH was used, the reaction proceeded acutely in a very short
time but gave some complex unidentified products (entry
9), which was in agreement with previous literature.9f
The number of stoichiometric equivalents of base used in
the reaction could also make a difference. When 2 equiv of
K2CO3 or 2 equiv of Cs2CO3 was used, the desired products
3a or 4a declined, even in the prolonged reaction time
(entries 6 and 11). Temperature also played an important
role in this reaction. The arylation of ethyl acetoacetate to
yield 3a could proceed smoothly at room temperature, but
required longer reaction time (entry 14). And 60 °C turned
a Reagents and conditions: 0.5 mmol 6-halopurine derivatives 1, 3.75
mmol (7.5 eq) Cs2CO3, 2.5 mmol (5 eq) ethyl acetoacetate 2 in 2 mL DMSO
at 60 °C for the indicated time. b Isolated yield based on 6-chloropurine
derivatives 1. c Reaction was carried out at rt. d Reaction was carried out at
rt and K2CO3 was used as the base.
out to be the best choice to yield 3a (entry 12). Higher
temperature was favorable to the deacylation and decar-
boxylation of 3a (entries 15-16). When the temperature was
elevated to 120 °C, 9-Bn-6-methylpurine 5a was obtained
in 76% within 5 h (entry 16). In all of the investigated
solvents (DMSO, DMAc, DMF, Dioxane), DMSO was
proved to be the most effective solvent, and DMF also gave
a satisfactory result (entry 13). Different from the previous
literature,22 single decarboxylation product of 3a was not
observed in all the cases.
Next, 2-(purin-6-yl)acetoacetic acid ethyl esters 3 were
prepared under the optimized reaction condition (shown in
Table 1, entry 12). The effects of substituents of 6-halopurine
derivatives were investigated. Various 6-halopurine deriva-
tives could react with ethyl acetoacetate smoothly in high
yields within short time (Table 2). 6-Iodopurine and 6-chlo-
ropurine derivatives gave similar results (entries 1-3 and
13-15), indicating that the leaving group at 6 position had
little effects in this reaction. Compared with other 6-chol-
opurine derivatives substituted at N9, 1b and 1d gave the
´
(21) (a) Gundersen, L. L; Bakkestuen, A. K.; Aaaen, A. J.; Øvera´s, H.;
(22) (a) Zeevaart, J. G.; Parkinson, C. J.; de Koning, C. B. Tetrahedron
Lett. 2004, 45, 4261. (b) Zeevaart, J. G; Parkinsona, C. J.; de Koning, C. B.
Tetrahedron Lett. 2007, 48, 3289.
Rise, H. Tetrahedron. 1994, 50, 9743. (b) Kasibhatla, S. R; Hong, K;
Biamonte, M. A. J. Med. Chem. 2007, 50, 2767.
Org. Lett., Vol. 11, No. 8, 2009
1747

Table 3. Reaction of Ethyl Acetoacetate with Various
6-Chloropurine Derivatives to Yield (Purin-6-yl)acetates 4a
Table 4. Reaction of Ethyl Acetoacetate with Various
6-Chloropurine Derivatives to Yield 6-Methylpurines 5a
a Reagents and conditions: 0.5 mmol 6-chloropurine derivatives 1, 3.75
mmol (7.5 eq) K2CO3, 2.5 mmol (5 eq) ethyl acetoacetate 2 in 2 mL DMSO
at 80 °C for the indicated time. b Isolated yield based on 6-chloropurine
derivatives 1.
a Reagents and conditions: 0.5 mmol 6-chloropurine derivatives 1, 3.75
mmol (7.5 eq) K2CO3, 2.5 mmol (5 eq) ethyl acetoacetate 2 in 2 mL DMSO
at 120 °C for the indicated time. b Isolated yield based on 6-chloropurine
derivatives 1.
desired products 3b and 3d in higher yields respectively
(entries 1-5 and 8). While 9-H-6-halopurines did not give
the desired products regardless of the leaving group at 6
position (entries 11-12), which was in agreement with the
previous literature.9f,23 The effect of substituents at C2 were
also studied. Replacement of H by Cl led to a so intense
reaction that it could be performed at rt in 0.5 h (entries 6
and 9-10). When H at C2 was replaced by the nitrogen-
containing substituent, the desired arylation product 3g could
not be obtained even after 6 h (entry 7).
As shown in Table 3, (purin-6-yl)acetates 4 were also
prepared under the optimized reaction condition shown in
Table 1 (entry 5). When there was no substituent at 2
position, all the 6-chloropurine derivatives gave the desired
products 4a-4e in moderate to good yields (entries 1-5).
However, When H at C2 was replaced by Cl, except for
compounds 3f and 5f, no desired product 4f was observed
(entry 6), presumably owing to the electron-donating effect.
By contrast, replacement of H by the nitrogen-containing
substituent which is unfavorable to the nucleophilic SNAr
reaction led to the desired product 4g with only 23% yield
(entry 7).
In conclusion, we have developed a novel and efficient
method24 for the preparation of 2-(6-purinyl)acetoacetic acid
ethyl esters, (purin-6-yl)acetates and 6-methylpurines from
6-chloropurine derivatives and ethyl acetoacetate. Compared
with previously known approaches, the simplicity of this
procedure, the absence of expensive catalyst and ligand, and
generally satisfactory yields make this method particularly
attractive. The presence of a diverse range of substituents
and functional groups in the purines also suggests an
opportunity to acquire many other derivatives from these
initial purines. Extension of this methodology to other active
methylene compounds is undergoing.
Acknowledgment. We are grateful for financial support
from the National Nature Science Foundation of China
(grants 20772024 and 20802016).
Supporting Information Available: NMR data of all
synthesized compounds and full characterization of novel
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Finally, several 6-methylpurines 5 were prepared under
relatively strenuous conditions shown in Table 1 (entry 16),
the results are summarized in Table 4. All the 6-chloropurine
derivatives gave the desired products 5a-5f in moderate to
good yields (entries 1-5). The 2,6-dichloropurine 1f gave
the regioselective monomethylation product 5f under the
same condition (entry 6). However, when H at C2 was
replaced by the nitrogen-containing substituent, the desired
5g could not be obtained even after 10 h (entry 7).
OL9002256
(24) Typical procedure for the SNAr-based reaction between the 9-Bn-
6-chloropurine (1a) and ethyl acetoacetate (2). 9-Bn-6-chloropurine 1a (0.5
mmol), anhydrous cesium carbonate or anhydrous potassium carbonate (3.75
mmol), and ethyl acetoacetate 2 (2.5 mmol) were sequentially added to 2
mL of DMSO. The mixture was then stirred at the indicated temperature
for the indicated time as shown in Tables 2, 3, and 4 (TLC monitoring).
After cooling to room temperature, the resulting mixture was mixed with
an ample amount of water (ca. 10 mL). The mixture was then extracted
with methylene chloride (3 × 10 mL). The collected organic layers were
dried with Na2SO4 and the solvent was evaporated in vacuo. The residue
was purified by silica gel chromatography (petroleum ether/ethyl acetate)
to give the desired products 3a, 4a, and 5a, respectively.
(23) Huang, L. K.; Cherng, Y. C.; Cheng, Y. R.; Jang, J. P.; Chao, Y. L.;
Cherng, Y. J. Tetrahedron 2007, 63, 5323
.
1748
Org. Lett., Vol. 11, No. 8, 2009