Microwave promoted C6-alkylation of purines through SNAr-based reaction of 6-chloropurines with 3-alkyl-acetylacetone

Article abstract of DOI:10.1039/c0ob01213k

C6-Alkylated purine analogues were obtained in good to excellent isolated yields by S_NAr reaction of 6-chloropurine derivatives with 3-alkyl-acetylacetone. 3-Alkyl-acetylacetones were employed as alkylating agents and C6-alkylated purines were obtained highly selectively within short reaction time under microwave irradiation conditions. This work is complementary to the classical coupling reactions for the synthesis of C6-alkylated purine analogues.

Full text of DOI:10.1039/c0ob01213k

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Microwave promoted C6-alkylation of purines through SNAr-based reaction
of 6-chloropurines with 3-alkyl-acetylacetone†
Hai-Ming Guo,*a Yu Zhang,a Hong-Ying Niu,b Dong-Chao Wang,a Zhi-Liang Chua and Gui-Rong Qu*a
Received 20th December 2010, Accepted 25th January 2011
DOI: 10.1039/c0ob01213k
C6-Alkylated purine analogues were obtained in good
to excellent isolated yields by SNAr reaction of 6-
chloropurine derivatives with 3-alkyl-acetylacetone. 3-Alkyl-
acetylacetones were employed as alkylating agents and C6-
alkylated purines were obtained highly selectively within short
reaction time under microwave irradiation conditions. This
work is complementary to the classical coupling reactions for
the synthesis of C6-alkylated purine analogues.
The biological activities of C6 modified purine derivatives span
a wide range from antiviral and antineoplastic to hypertensive.1
In particular, C6-alkylated purine analogues or other (hetero)aryl
derivatives possess a broad spectrum of biological effects such
Scheme 1 Different routes for the synthesis of C6-alkylated purines.
as cytostatic,2 antiviral3 and antimicrobial activities4 or receptor
modulation.5 For example, 6-methylpurine and its ribonucleoside
catalysts or alkyl organometallic reagents under rigorous reaction
have highly cytotoxic6 and antitumor activities.7 So it is not
conditions such as anhydrous and nitrogen atmosphere.
surprising that the preparation of these purine derivatives has
We have recently reported the reactions of 6-halopurines with
received considerable attention lately.
ethyl acetoacetate to yield 2-(purin-6-yl)acetoacetic acid ethyl
The most common method for the synthesis of C6-
esters, (purin-6-yl)acetates and 6-methylpurines under different
alkylated purines is transition metal catalyzed cross coupling
reaction conditions.18 So we predicted that 3-alkyl-acetylacetone
reaction of C6-substituted purines and alkyl organometallics
could also be a kind of alkylating agent. Up until now, there has
(eq 1, Scheme 1). In this respect, Suzuki-,8 Stille-,9 Negishi-,10 and
been no report on the synthesis of alkylated purines, heterocycles,
Kumada-11 coupling reactions have all been exploited success-
or arenes using alkyl-acetylacetones as alkylating agents. On
fully, and various organometallic reagents12 are involved. Hana
the basis of our research interest toward the modification of
purines,19 herein, we describe new results concerning the synthesis
of C6-alkylpurine analogues through a microwave-promoted SNAr
Dvorˇa´kova´ et al. synthesized these compounds via a secondary
or tertiary Grignard reagent with 6-chloropurines.13 Michal Ho-
cek et al. reported the synthesis of these compounds via Pd-
reaction of 6-chloropurine derivatives with 3-alkyl-acetylacetone
catalyzed cross-couplings of 6-chloropurines with Reformatsky
(eq 2, Scheme 1). For the first time, 3-alkyl-acetylacetones were
reagent in the presence of ligands.14 6-Methylpurine derivatives
used as alkylating agents, thus avoiding the use of organometallics
were prepared by Pd-catalyzed cross-couplings of 6-chloropurines
and noble metal catalysts.
with methylzinc bromide15 or trimethylaluminium.16 Other 6-
We began our investigation by examining the microwave
alkylpurines were also prepared by Ni-, Fe-, or Cu- catalyzed
promoted nucleophilic substitution reaction between 9-benzyl-6-
couplings of 6-halo or 6-methylsulfanylpurines with Grignard
chloropurine 1, and acetylacetone 2 in the presence of various
solvents (Table 1, entries 1–4). The results showed that DMSO
was the best solvent for the reaction. In DMSO, the desired
reagents.17 However, these methods employed either noble metal
aCollege of Chemistry and Environmental Science, Key Laboratory of
Green Chemical Media and Reactions of Ministry of Education, Henan
Normal University, Xinxiang 453007, Henan, China. E-mail: guohm518@
product 9-benzyl-6-methyl purine 3 was obtained in 89% yield
at 80 ◦C in the presence of 7.5 equiv of K2CO3 for 10 min
(entry 4). Next, we examined the effect of base on the yields
of 9-benzyl-6-methyl purine 3. No product was obtained when
the reaction was conducted without any base (entry 5). It was
evident that anhydrous K2CO3 was the most effective base for
this transformation compared with the other investigated bases
(entries 7–8). Changing the amount of K2CO3 showed that 7.5
hotmail.com, quguir@sina.com; Fax: +86 373 3329276; Tel: +86 373
3329255
bSchool of Chemistry and Chemical Engineering, Henan Institute of Science
and Technology, Xinxiang 453003, China
† Electronic supplementary information (ESI) available: General informa-
tion, experimental procedures, and characterization data for the products
including spectroscopic information. See DOI: 10.1039/c0ob01213k
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Table 1 Microwave promoted nucleophilic substitution reaction of 9-
benzyl-6-chloropurine 1 with acetylacetone 2a
Table 2 Microwave promoted nucleophilic substitution reaction of 9-
benzyl-6-chloropurine 1 with 3-alkyl-acetylacetones 2a
Entry Solvent Temp. (◦C) Base (7.5 eq) Time (min) Yield (%)b
Entry
1
R
H
Product
Yield (%)b
89
1
2
3
4
5
6
7
8
9
10
11
12
THF
CH2Cl2
DMF
65
40
80
80
80
80
80
80
80
80
60
K2CO3
K2CO3
K2CO3
K2CO3
No base
10
10
10
10
10
10
10
10
5
NRc
NRc
10
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
89
NRc
88
d
K2CO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
68
72
52
90
66
88
2
3
CH3
82
15
10
10
DMSO 100
a Reagents and conditions: 0.5 mmol 1, 2.5 mmol acetylacetone 2 in 2 mL
solvent for the indicated time, 7.5 equiv base and MWI (200 W). b Isolated
yields based on purines. c NR = no reaction. d 8.5 eq K2CO3.
n-Pr
68(80)c
equiv of K2CO3 was the best choice (entries 4 and 6). Irradiation
time had some influence on the yields (entries 9–10); it seemed that
the reaction reached chemical equilibrium after being irradiated
for 10 min. When the reaction time was longer than 10 min, the
yield remained almost unchanged (entries 4 and 10), therefore
10 min was the optimized reaction time. Further screening of the
reaction temperature (entries 11–12) confirmed that 80 ◦C was the
best choice.
4
n-Bu
52(76)c
Under the optimized reaction conditions, the scope and gener-
ality of the reaction with a series of 3-alkyl-acetylacetones were
explored. As shown in Table 2, the yield of the product became
lower from 89% to 52% when the R group became gradually
longer (entries 1–4). Also, 3-allyl- and 3-benzyl-acetylacetone gave
moderate yield (entries 5 and 6). In general, the reaction proceeded
smoothly for various substituted acetylacetone to produce the
desired 9-benzyl-6-alkylated purines.
Naturally, after the development of various 3-alkyl-
acetylacetones, we further explored the alkylation of various N9-
substituted purine analogues, including purine nucleosides. As
shown in Table 3, when the H atom on N9 was substituted by an
alkyl group, good yields were obtained (entries 1–2, 4–5). And to
our delight, the reactions starting from acyclic nucleoside (entry
3) and protected nucleoside (entry 6) gave 92% and 62% yields,
respectively. Unfortunately, when active hydrogen occurred on the
N9 position of purine, no desired product was obtained (entries
7–8).
Finally, direct alkylation using various active methylene com-
pounds such as b-diketone, b-keto ester and b-diester with 9-
benzyl-6-chloropurine was examined. The results are summarized
in Table 4. The reaction proceeded smoothly for b-diketone and
b-keto ester to give C6-methylated products within a short time
(entries 1–3). However, b-diester gave a low yield because the
decarboxylation reaction was difficult when two ester groups
occurred on the substrate 2 (entry 4).
5
6
72
76
Bn
a Reagents and conditions: 0.5 mmol 1, 2.5 mmol 2, 3.75 mmol K2CO3 in
2 mL DMSO and MWI 200 W (80 ◦C) for 10 min. b Isolated yields based
on purines. c The yields in parentheses were obtained after 20 min.
In conclusion, this work describes a new SNAr based reac-
tion between 6-chloropurines and 3-alkyl-acetylacetones under
microwave irradiation. The application of 3-alkyl-acetylacetones
as alkylating agents allows the reaction to be carried out under
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Table 3 Microwave promoted nucleophilic substitution reaction of 6-
chloropurine derivatives 1 with acetylacetone 2a
generally satisfactory yields. This work opens an effective new
route for modification at C6 of purines and is complementary
to the classical coupling reactions for synthesis of C6-alkylated
purine analogues.
Acknowledgements
R1
H
R2
Product
Yield (%)b
89
We are grateful for financial support from the National Nature
Science Foundation of China (Grant Nos. 20772024, 20802016,
and 21072047), the Program for New Century Excellent Talents
in University of Ministry of Education (NCET-09-0122), the
Program for Innovative Research Team in University of Henan
Province (2008IRTSTHN002), and the Henan Nature Science
Foundation (102300410253).
Entry
1
3a
2
3
H
H
3g
3h
76
92
Notes and references
4
5
H
3i
3j
88
87
ˇ
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R2
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2
3
4
CH3
CH3
CH3CH2
CH3CH2O
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89
85
82
32
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