Intermolecular hydrogen abstraction reaction between nitrogen radicals in purine rings and alkyl ethers: A highly selective method for the synthesis of N-9 alkylated purine nucleoside derivatives

Article abstract of DOI:10.1002/adsc.201000682

A highly selective method for the synthesis of N-9 alkylated purine nucleoside derivatives via an intermolecular hydrogen abstraction reaction between nitrogen radicals in purine rings and alkyl ethers was developed. Novel purine nucleoside derivatives we

Full text of DOI:10.1002/adsc.201000682

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DOI: 10.1002/adsc.201000682
Intermolecular Hydrogen Abstraction Reaction between Nitrogen
Radicals in Purine Rings and Alkyl Ethers: A Highly Selective
Method for the Synthesis of N-9 Alkylated Purine Nucleoside
Derivatives
Hai-Ming Guo,a,* Chao Xia,a Hong-Ying Niu,b Xiao-Ting Zhang,a Si-Nan Kong,a
Dong-Chao Wang,a and Gui-Rong Qua,*
a
College of Chemistry and Environmental Science, Key Laboratory of Green Chemical Media and Reactions of Ministry
of Education, Henan Normal University, Xinxiang 453007, Peopleꢀs Republic of China
Fax : (+86)-37-3332-9276; e-mail: guohm518@hotmail.com or quguir@sina.com
School of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang 453003, Peopleꢀs
b
Republic of China
Received: September 2, 2010; Revised: November 11, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000682.
À
Abstract: A highly selective method for the synthe-
sis of N-9 alkylated purine nucleoside derivatives
via an intermolecular hydrogen abstraction reaction
between nitrogen radicals in purine rings and alkyl
ethers was developed. Novel purine nucleoside de-
rivatives were obtained with good to high yields in
the presence of (diacetoxyiodo)benzene (DIB) and
iodine in one-step reaction.
C H of an alkyl ether. Alkyl ethers are cheaper and
more readily available than their corresponding alkyl
halides, which makes this procedure much more at-
tractive. At the same time, alkylation of purines is
rarely regiospecific, and mixtures of N-9 and N-7 iso-
mers are usually obtained.[7] So selective ways for the
alkylation of purine analogues at the N-9 position are
highly desirable.
The intramolecular hydrogen abstraction reaction
promoted by alkoxy radicals has attracted considera-
ble interest among organic synthetic chemists since it
offers the remarkable possibility of carrying out
remote free radical functionalizations of unactivated
carbons.[8] To the best of our knowledge, there are
only few reports on intramolecular hydrogen abstrac-
tion reactions by aminyl radicals.[9] However, there is
Keywords: alkyl ethers; intermolecular hydrogen
abstraction reaction; nitrogen radicals; purine nu-
cleoside derivatives
Purine nucleoside derivatives have provided a pro- no report on an intermolecular hydrogen abstraction
ductive area of chemical and biological research.[1] reaction. According to our previous work on the syn-
For example, some purine nucleoside analogues are thesis of purine nucleoside derivatives,[10] we envi-
used as antiviral (AZT, d4T, 3TC, etc.)[1a] and antitu- sioned that the intermolecular hydrogen abstraction
3
mor agents (AraC, FU, etc.).[1b] Furthermore, N-9 sub- reaction between the sp N H bond of the purine
À
stituted purine nucleoside analogues[2] are a very im- ring and the sp C H bond of an alkyl ether could be
3
À
portant class of heterocyclic compounds in biology, applied to form purine nucleoside derivatives in a
fulfilling functional roles as nucleic acids, coenzymes, more effective way. Herein, we describe the direct N-
À
and constituents in metabolic processes, energy stor- 9 H alkylation of purines with alkyl ether via an in-
age, and cell signaling.[3]
termolecular hydrogen abstraction reaction to give a
Alkylation is one of the commonly used methods series of highly selective N-9 substituted purine nu-
for the synthesis of purine nucleoside derivatives. The cleoside derivatives.
most frequently used alkylating agents of purine
Initially, we investigated the intermolecular hydro-
bases are halogenated compounds,[4] mesylate,[5] and gen abstraction reactions between 2,6-dichloropurine
tosylate.[6] But up to now, there is no report on the and tetrahydrofuran (THF). The solvent effects were
synthesis of purine nucleoside analogues via reaction examined and the results are shown in Table 1 (en-
3
3
À
of the sp N H bond of the purine ring and the sp
tries 1–8). No reaction was observed in DMF, DMSO,
Adv. Synth. Catal. 2011, 353, 53 – 56
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53

Hai-Ming Guo et al.
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Table 1. The alkylation of 2,6-dichloropurine with THF.[a]
(entries 1, 3, 4 and 6). 2-Chloro-6-dimethylaminopur-
ine (1h), which was difficult to dissolve in THF, was
conducted in DCE to increase the solubility (entry 8).
As shown in Table 3, several other alkyl ethers
were subjected to the alkylation reactions of 2,6-di-
chloropurine 1a under the optimized reaction condi-
Table 2. Direct alkylation of various purines with THF.[a]
Entry
Solvent
DIB/I2
Yield [%][b]
1
2
3
4
5
6
7
8
DMF[c]
DMSO[c]
DCM
EtOAc
C6H12
CH3CN
DCE
2/0
2/0
2/0
2/0
2/0
2/0
2/0
2/0
2/trace
2/trace
2/trace
2/trace
0/trace
1/trace
1.5/trace
0
0
0
0
10
20
41
45
94
90
50
0
THF
THF
Entry
1
Product
Yield [%][b]
9
10
11
12
13
14
15
DCE
THF[d]
THF[e]
THF
94
0
35
68
THF
THF
[a]
Reaction conditions: 2,6-dichloropurine 1a (1 mmol),
THF 2 (2 mmol), solvent (2 mL), reaction time, 3 h.
Isolated yield based on 2,6-dichloropurine.
The reaction temperature was 708C.
The reaction temperature was 508C.
Room temperature.
[b]
[c]
[d]
[e]
2
3
84
91
DCM, and EtOAc (entries 1–4). The reaction gave a
low yield in cyclohexane presumably due to the poor
solubility of the starting material (entry 5). A higher
yield was obtained in CH3CN, but the result was still
unsatisfactory (entry 6). THF, which is relatively inex-
pensive and easy to handle, was thus chosen as the
solvent for further optimization, although 1,2-di-
chloroethane (DCE) could give the same result (en-
tries 7 and 8). When a trace of iodine was present in
the reaction mixture, a 94% yield was obtained
(entry 9), and DCE also gave a similarly surprising
result (entry 10). The yield decreased with the reduc-
tion temperature, and when the reaction was conduct-
ed at room temperature, product 3a was not observed
(entries 9, 11 and 12). And it was obvious that a suffi-
cient amount of DIB was necessary for this reaction
(entries 13–15).
Under the optimized reaction conditions, various
purines were employed as substrates, and representa-
tive results are listed in Table 2. Various 6-halopurine
derivatives could react with THF smoothly in good to
high yields (entries 1–5). Purine derivatives with ni-
trogen-containing substituent at the C-6 position
could also afford the desired products in good yields
(entries 6–8). When the H at C-2 was replaced by a
halogen atom (Cl or F), the yield increased slightly
4
5
89
85
6
7
84
80
54
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Adv. Synth. Catal. 2011, 353, 53 – 56

Intermolecular Hydrogen Abstraction Reaction between Nitrogen Radicals in Purine Rings and Alkyl Ethers
Table 2. (Continued)
Entry
Product
Yield [%][b]
8
75[c]
[a]
Reaction conditions:
1
(1 mmol), DIB (2 mmol), I2
(trace), THF (2 mL), 708C, 3 h.
Isolated yield based on 1.
DCE as solvent.
[b]
[c]
Scheme 1. Mechanism of the alkylation reaction between
2,6-dichloropurine and THF.
Table 3. Direct alkylation of 2,6-dichloropurine with various
alkyl ethers.[a]
high yields (entry 3), and the yield decreased obvious-
ly with the increase of the carbon number of the
chain ethers. Methyl ethers gave low yields (entries 4
and 5). It should be noted that the reaction only oc-
curred at the carbon atom of the methylene unit in-
stead of the methyl group on dimethoxyethane and
benzyl methyl ether to afford the products 5e and 5f.
Methyl tert-butyl ether (MTBE) could not give the
desired product 5g until 1 equiv. I2 was added, but the
yield was low (entry 6). Because of steric hindrance,
we did not obtain the desired products from diiso-
propyl ether (entry 7).
Entry
Product
Yield [%][b]
1
2
3a
5a
94
85
n=1 5b
n=2 5c
n=3 5d
96
82
60
3
4
A possible mechanism[11] of the direct alkylation re-
action is depicted in Scheme 1. The N-radical I was
generated by homolytic fragmentation of a hypotheti-
cal iodoamide formed in situ by the reaction of amide
with DIB and iodine under irradiation with a 200-W
tungsten filament lamp at 708C. The C-radical II,
which was initially formed by hydrogen atom transfer
(HAT) to the electrophilic N-radical I, could be sub-
sequently oxidized by the excess reagent present in
the reaction medium to an oxocarbenium ion III,
which was then trapped by the nucleophilic purine N-
9 position.
5e
80
5
6
5f
72
5g
5h
43[c]
0
7
[a]
In summary, we have developed a novel and effi-
cient method for the preparation of purine nucleoside
analogues from purine bases and a series of ethers via
intermolecular hydrogen abstraction reaction between
Reaction conditions: 2,6-dichloropurine (1 mmol), alkyl
ether (1 mL), DCE (1 mL), DIB (2 mmol), I2 (trace),
under nitrogen and irradiation with a 200-W tungsten fil-
ament lamp at 708C for 4.5 h.
Isolated yield based on 2,6-dichloropurine.
I2 (1 equiv.) was used.
[b]
[c]
3
3
À
À
sp C H and sp N H bonds. And the alkylation ex-
clusively occurred on the N-9 position of purine ana-
logues. Compared to previously known approaches,
the simplicity of this procedure and the generally sat-
tions shown in Table 1 (entry 10), and to get better re- isfactory regioselectivities and yields make this
sults, the reaction was irradiated with a 200-W tung- method particularly attractive. The presence of a di-
sten filament lamp. Cyclic ether compounds, either verse range of substituents and functional groups in
five- or six-membered ring, could react well (entries 1 the purines also opens an opportunity to acquire
and 2). The straight chain ethers (4b–4d) afforded the many other derivatives from these initial purines. Fur-
corresponding products 5b, 5c and 5d in moderate to ther developments might find other applications of
Adv. Synth. Catal. 2011, 353, 53 – 56
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55

Hai-Ming Guo et al.
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Experimental Section
Typical Experimental Procedure for Intermolecular
Hydrogen Abstraction Reaction between N-Radicals
in Purine Rings and Alkyl Ether
Purine 1a (1 mmol) was put in a 10-mL glass vial equipped
with a small magnetic stirring bar. To this were added 2 mL
THF, trace iodine and 2 equiv. DIB. The mixture was stirred
in an oil heating bath at 708C for 3 h. Then the vial was
cooled to room temperature. After evaporation of the sol-
vent, the crude product was purified by column chromatog-
raphy over silica gel using EtOAc/petroleum ether (v/v=
1:4) as the eluent, to give 3a.
´
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d=8.20 (s, 1H), 6.30–6.27 (m, 1H), 4.31–4.26 (m, 1H), 4.10–
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Acknowledgements
We are grateful for financial support from the National
Nature Science Foundation of China (grants 20772024,
20802016, and 21072047), the Program for New Century Ex-
cellent Talents in University of Ministry of Education
(NCET-09-0122), the National Students Innovation Experi-
ment Program (091047614), and the Program for Innovative
Research Team in University of Henan Province
(2008IRTSTHN002).
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Adv. Synth. Catal. 2011, 353, 53 – 56