Regioselective N9 alkylation of purine rings assisted by β-cyclodextrin

Article abstract of DOI:10.1016/j.tet.2012.07.025

Under the assistance of β-cyclodextrin, purine was effectively alkylated at N9 together with up to 99% conversion and good to excellent yield using water as the solvent. High regioselectivity-N9/N7 selectivity>99:1 was attributed to the β-cyclodextrin cav

Full text of DOI:10.1016/j.tet.2012.07.025

Tetrahedron 68 (2012) 7822e7826
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Regioselective N9 alkylation of purine rings assisted by b-cyclodextrin
*
*
Qian Zhang , Gang Cheng, Yong-Zhen Huang, Gui-Rong Qu, Hong-Ying Niu, Hai-Ming Guo
College of Chemical and Environmental Science, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Normal University, 46 Jianshe Road,
Xinxiang, Henan 453007, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Under the assistance of b-cyclodextrin, purine was effectively alkylated at N9 together with up to 99%
Received 29 April 2012
Received in revised form 3 July 2012
Accepted 10 July 2012
conversion and good to excellent yield using water as the solvent. High regioselectivity-N9/N7
selectivity>99:1 was attributed to the -cyclodextrin cavity blocked the N7 of purines ring.
Ó 2012 Elsevier Ltd. All rights reserved.
b
Available online 15 July 2012
Keywords:
b-Cyclodextrin
Purine
Alkylation
Selectivity
1. Introduction
b
-CD is often used to include organic guests selectively11 to increase
their water-solubility or to catalyze chemical reactions in water.12
In continuation of our interest in the synthesis of acyclic nucleo-
sides and the usage of water as a clean media to conduct organic
reactions, herein, we report a new methodology to produce acyclic
Since the groundbreaking discovery of acyclovir1,2 as a potent
antiherpes drug in the mid-1970s, strong interest and intensive
efforts were directed to explore more efficient and potent ana-
logues of acyclic nucleosides.3,4 Subsequently, gencicovir, penci-
clovir and other acyclonucleosides with better activities and fewer
side effects than acyclovir have been extensively exploited.5 What
is more, further experiments have manifested that the anti-HIV
activity and anti-HCMV activity are almost independent of the
acyclic side chain. Among the reported methods to prepare acyclic
nucleosides, the most convergent and straightforward pathways is
the alkylation of the nucleobases with suitable activated alkylating
nucleosides with the aid of b-CD.
agents, Michael addition to
a, b-unsaturated compounds or via
cross-coupling reactions using transition metal catalysts.6e9 How-
ever, the alkylation of purine base usually suffers from poor
regioselectivity; for example, the formation of mixtures of N9
(usually desired), N7, and other regioisomers sometimes is un-
avoidable. As a result, to aid in the further investigation and
development of such nucleobase-containing drugs, more powerful
synthetic protocols with high regioselectivity is of significant
Fig. 1. Schema of b-CD structure.
2. Results and discussions
benefit and in great demand. b-Cyclodextrin (b-CD) are cyclic oli-
The optimization of reaction conditions was begun with
studying the influence of -CD on the model reaction of
6-chloropurine and 1-bromoacetone (5 equiv) in the presence of
K2CO3 in water.
gosaccharides possessing of hydrophobic cavity and two distinct
rims known as primary one (lined with C-6 hydroxyl groups) as
well as secondary one (linked with C-2 and C-3 hydroxyl groups)
(Fig. 1).10 Being soluble in water, nontoxic and readily available,
b
As shown in Table 1, 6-chloropurine and 1-bromoacetone
could react in potassium carbonate solution and 6-chloropurine
was transformed into the product partly, giving low yield of
* Corresponding authors. Tel./fax: þ86 373 3329276; e-mail addresses: zhang-
qian1980@gmail.com (Q. Zhang), guohm518@hotmail.com (H.-M. Guo).
37% with N9/N7 ratio of 72:28 (Entry 1). When 10 mol % of b-CD
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.025

Q. Zhang et al. / Tetrahedron 68 (2012) 7822e7826
7823
Table 1
Reaction conditions for the 6-chloropurine with 1-bromoacetone
a
Entry
b
-CD
Base
Conversion (%)
Yield (%)b
N9/N7c
1
2
3
4
5
6
7
8
0 equiv
K2CO3(3 equiv)
K2CO3(3 equiv)
K2CO3(3 equiv)
K2CO3(3 equiv)
K2CO3(3 equiv)
K2CO3(3 equiv)
Cs2CO3(3 equiv)
Et3N (3 equiv)
DMAP(3 equiv)
Py(3 equiv)
K2CO3(0 equiv)
K2CO3(0.5 equiv)
K2CO3(1 equiv)
K2CO3(2 equiv)
K2CO3(3 equiv)
K2CO3(4 equiv)
K2CO3(5 equiv)
58
88
95
＞99
＞99
＞99
＞99
84
66
33
0
85
88
93
＞99
＞99
＞99
37
68
79
91
91
91
90
62
55
20
0
76
80
88
91
90
90
72:28
80:20
86:14
96:4
95:5
95:5
94:6
92:8
91:9
90:10
0.1 equiv
0.3 equiv
0.5 equiv
1.0 equiv
2.0 equiv
0.5 equiv
0.5 equiv
0.5 equiv
0.5 equiv
0.5 equiv
0.5 equiv
0.5 equiv
0.5 equiv
0.5 equiv
0.5 equiv
0.5 equiv
9
10
11
12
13
14
15
16
17
94:6
94:6
95:5
96:4
95:5
94:6
a
Determined by 1H NMR.
b
c
Isolated yield of N9 product.
Determined by 1H NMR spectroscopy of the crude product after extraction by ethyl acetate.
was added into the reaction system, the reaction finished in 83%
yield with N9/N7 ratio as 80:20. By increasing the amount
directional in the space, which made the reaction more efficien-
tly12d,12e (Fig. 2b). Meanwhile, hydroxyl group in the secondary
of
b
-CD to 50 mol %, the yield and N9/N7 selectivity were im-
rim of b-CD could form hydrogen bond with the polar groups on
proved to 91% and 96:4, respectively. Under this condition,
6-chloropurine was converted into the product almost com-
pletely. Increasing the amount of b-CD to 200 mol %, no signifi-
alkyl halides, which facilitated the reaction progress. Inclusion also
increased the solubility of the substrates in water, which made the
reaction complete smoothly.
cant change in yield and selectivity was observed. Different bases
were also attempted to activate the reaction. Experimental results
showed that inorganic bases K2CO3 and Cs2CO3 help to gain
higher yield and N9/N7 selectivity than organic ones (Et3N, Py
and DMAP) (Entries 8e10). So K2CO3 was selected as a suitable
base to promote the reaction. Further research showed that the
yield was improved from 0 to 91% with the amount of K2CO3
changed from 0 mol % to 300 mol %. Continuously increasing of
the amount K2CO3 led to a little decreased yield. Therefore,
Most purines can react smoothly and the kinds of substituent
on purines had some impact on the yields and selectivities. When
R1/R2 was electron-withdrawing group (F, Cl, I, NHAc), the yield
of N9 product exceeded 90% and selectivity exceeded 90:10
(entries 1e7). When R1/R2 was electron-donating group, the re-
action gave medium yield and almost single N9 product, which
might be due to the electron density on the base. In this case, part
of the purine raw material could not convert into the product
completely. Different alkyl halides were also subjected to the
optimized reaction conditions. As can be seen in Table 3, bromide
containing electron-withdrawing group could react ideally
(entries 1e3) and alkyl bromides (entries 4e5) only gave medium
yields, while the reaction of chloride gave low yields (Table 3,
entries 6e7).
50 mol % of
b-CD and 300 mol % of K2CO3 were chose as the
optimized reaction conditions. Further screening of reaction
temperature and time confirmed that reaction can be finished at
room temperature within 1 h.
To evaluate the general applicability and versatility of the
method, a group of different purine derivatives were subjected to
the optimized reaction conditions and the results were summa-
rized in Table 2. As shown in Table 2, purines could react with
1-bromoacetone in water and gave low yields, which might be due
to the poor solubility of substrates in water. The isolated yields and
3. Conclusion
b
-CD was introduced to promote N9 alkylation reaction on
purine rings smoothly. The substrates were included into the
cavity of -CD. The inclusion increases the solubility of the sub-
selectivities all increased with the addition of
the presence of -CD had important influence on the reaction.
According to the reports by Xu et al.,13 adenine can be included in
-CD cavity to form hosteguest complexes. Here N9 was located at
b-CD, which meant
b
b
strates in water, results in the approach and orientation in space,
and protects N7 of purines. The hydrogen bond between hydroxyl
groups on the b-CD rim with substrates also might make sub-
b
secondary rim while N7 was included into CD cavity deeply and
blocked by CD cavity14(Fig. 2a). As a result, purines reacted with
alkyl halides at secondary rim through N9 and then the reaction
gave higher N9 selectivity. On the other hand, after forming
strate activated. As a result, the reaction can be finished smoothly,
giving high yields and high chemselectivity. A number of func-
tional groups can be well tolerated. Electron-withdrawing groups
on purines and polar group in alkyl halides contribute to the
reaction.
complexes with
b-CD, substituent becomes more adjacent and

7824
Q. Zhang et al. / Tetrahedron 68 (2012) 7822e7826
Table 2
Purine scope of the reaction
Entry
R1
R2
Product
Conversion (%)a
Yield (%)b
N9/N7c
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
I
I
H
F
NHAc
Cl
H
Cl
H
H
a
b
c
d
e
f
>99
>99
>99
>99
>99
>99
>99
55
91(37e)
90(33e)
90(35e)
90(33e)
94(35e)
90(34e)
90(20e)
40d(13e)
96:4(72:28f)
92:8(70:30f)
94:6(72:28f)
93:7(71:29f)
96:4(76:24f)
92:8(75:25f)
93:7(72:28f)
99:1(71:29f)
NHAc
Et2N
g
h
9
H
i
53
35d(17e)
99:1(86:14f)
10
11
NH2
Cl
H
NH2
j
k
68
44
62d(31e)
30d(8e)
99:1(83:17f)
99:1(85:15f)
a
Determined by 1H NMR spectroscopy.
b
c
d
e
f
Isolated yield of N9 product when b-CD participate in the reaction.
Determined by 1H NMR spectroscopy of the crude product after extraction by ethyl acetate.
Prolonged reaction time and elevated temperature had no significant effect.
Isolated yield of N9 product when b-CD was not added into the reaction system.
The ratio of N9/N7 when
b-CD was not added into the reaction system.
4. Experimental
4.1. General
All reagents were purchased and used without further purifi-
cation except that -CD was recrystallized three times from water.
b
Thin layer chromatography (TLC) was used to detect all reaction
and 200e300 mesh silica gel was used as the stationary phase for
column chromatography. Melting points were detected with a mi-
cro melting point apparatus and uncorrected. NMR spectra were
recorded with a 400 MHz NMR spectrometer for 1H NMR and
100 MHz for 13C NMR. DMSO-d6 or CDCl3 were used as the solvent
(a)
(b)
Fig. 2. (a) The binding mode of adenine and b-CD reported by Xu et al.; (b) possible
binding mode of substrates and b-CD.
for the 1H NMR and 13C NMR. Chemical shifts (
d) were given in parts
per million after calibration to residual isotopic solvent (CHCl3:
Table 3
Alkyl halides scope of the reaction
a
Entry
ReX
Product
Conversion (%)
Yield （%）b
N9/N7c
1
2
3
4
5
6
7
BrCH2COCH3
BrCH2CN
BrCH2COOC2H5
BrCH2CH2OH
BrCH2CH3
a
l
>99
96
>99
64
54
46
91（40d）
88（46d）
90（38d）
52（28d）
45（19d）
35（11d）
28（14d）
96:4（72:28e）
94:6（76:24e）
91:9（76:24e）
90:10（71:29e）
91:9（72:28e）
91:9（74:26e）
90:10（74:26e）
m
n
o
m
n
ClCH2COOC2H5
ClCH2CH2OH
35
a
Determined by 1H NMR spectroscopy.
b
c
The yield of N9 product when
b-CD participate in the reaction.
Determined by 1H NMR spectroscopy of the crude product after extraction by ethyl acetate.
d
e
The yield of N9 product when
b-CD was not added into the reaction system.
The rate of N9/N7 when -CD was not added into the reaction system.
b

Q. Zhang et al. / Tetrahedron 68 (2012) 7822e7826
7825
dH¼7.26 ppm, dC¼77.0 ppm; DMSO: dH¼2.50 ppm, dC¼39.4 ppm).
Coupling constants (J) were given in hertz. electrospray ionization
time-of-flight mass spectrometry (ESI-TOFMS) produced on
a Bruker micrOTOF mss spectrometer. Infrared spectra were
recorded in KBr with an Avatar360E. S. P. FTIR spectrophotometer.
(100 MHz, CDCl3) 13.5, 27.1, 43.1, 51.9, 119.0,138.4, 150.4, 152.6, 153.8,
200.3. HRMS (ESIþ) m/z calcd for C12H18N5O [MþH]þ248.1513, obsd
248.1516. IR (KBr disc) cmꢁ1: 3709, 2963, 2930, 2873, 1729, 1592,
1484, 1439, 1341, 1284, 1173.
4.2.9. 1-(6-(Pyrrolidin-1-yl)-9H-purin-9-yl) propan-2-one (i). Light
yellow solid; mp: 180e182 ꢀC; dH (400 MHz, CDCl3) 8.33 (s, 1H), 7.71
(s, 1H), 5.01 (s, 2H), 4.22e4.16 (m, 2H), 3.78e3.76 (m, 2H), 2.29 (s,
3H) 2.07e2.02 (m, 4H). dc (100 MHz, CDCl3) 26.1, 27.1, 51.9, 107.0,
119.6, 139.0, 150.1, 152.9, 153.1, 200.2. HRMS (ESIþ) m/z calcd for
C12H15ClN5ONa [MþNa]þ 268.1164, obsd 268.1169. IR (KBr disc)
cmꢁ1: 3112, 2978, 2957, 2879,1726,1595,1472,1391,1367,1317,1182.
4.2. Typical experimental procedure for the reaction of pu-
rine with alkyl halides assisted by
b-CD in water
b-CD (0.5 mmol) was dissolved in 10 mL deionized water. Then
purine (1 mmol) was added and the mixture was stirred at room
temperature for 20 min. K2CO3 (3 mmol) and alkyl halides (5 mmol)
were added and stirred for another 1 h. The resulting mixture was
quenched with 1 M HCl and extracted with ethyl acetate. The or-
ganic layer was dried with anhydrous Na2SO4 and evaporated to
dryness. The crude mixture was purified by silica gel chromatog-
raphy to give target product.
4.2.10. 1-(6-Amino-9H-purin-9-yl) propan-2-one (j). Light yellow
solid; mp: 247e248 ꢀC (Lit:16 247e248 ꢀC); dH (400 MHz, CDCl3)
8.35 (s, 1H), 7.80 (s, 1H), 5.05 (s, 2H), 2.33 (s, 3H). HRMS (ESIþ) m/z
calcd for C8H10N5O [MþH]þ192.0887, obsd 192.0885.
4.2.1. 1-(6-Chloro-9H-purin-9-yl)propan-2-one (a). Yellow solid;
mp: 168e171 ꢀC (Lit:15 164e166 ꢀC); dH (400 MHz, CDCl3) 8.72
(s, 1H), 8.11 (s, 1H), 5.15 (s, 2H), 2.37 (s, 3H). dc (100 MHz, CDCl3)
27.2, 52.4, 130.7, 145.9, 150.9, 151.8, 152.1, 198.8. HRMS (ESIþ) m/z
calcd for C8H8ClN4O [MþH]þ 211.0388, obsd 211.0385.
4.2.11. 1-(2-Amino-6-chloro-9H-purin-9-yl)propan-2-one
(k). White solid; mp: 272e275 ꢀC; dH (400 MHz, DMSO-d6) 7.95 (s,
1H), 6.88e6.87 (m, 2H), 5.06 (s, 2H), 2.21 (s,3H). dC (100 MHz, DMSO-
d6) 27.3, 52.5, 123.4, 144. 1, 154.7, 160.2, 201.8. HRMS (ESIþ) m/z calcd
for C8H9ClN5O [MþH]þ226.0497, obsd 226.0496. IR (KBr disc) cmꢁ1
:
3324, 2918, 1720, 1612, 1403, 1360, 1218, 1173, 1048, 1024.
4.2.2. 1-(6-Chloro-2-fluoro-9H-purin-9-yl)propan-2-one (b). White
solid; mp: 185e187 ꢀC; dH (400 MHz, CDCl3)
d
¼8.07 (s, 1H), 5.09
4.2.12. 3-(6-Chloro-9H-purin-9-yl)propanenitrile (l). Green oil
(mp:145e146 ꢀC17); dH (400 MHz, CDCl3) 8.84 (s, 1H), 8.35 (s, 1H),
5.31e5.27 (t, 2H, J¼8.2 Hz), 4.45e4.39 (t, 2H, J¼8.6 Hz). HRMS
(ESIþ) m/z calcd for C8H7ClN5 [MþH]þ208.0392, obsd 208.0395.
(s, 2H), 2.38 (s, 3H). dc (100 MHz, CDCl3) 27.2, 52.3, 129.8, 146.2,
153.8, 156.2, 158.4, 198.1. HRMS (ESIþ) m/z calcd for C8H6ClFN4O
[MþH]þ 229.0284, obsd 229.0287. IR (KBr disc) cmꢁ1: 3115, 2930,
2855, 1720, 1600, 1505, 1439, 1364, 1233, 1188.
4.2.13. Ethyl 2-(6-chloro-9H-purin-9-yl)acetate (m). Colourless
sheet crystals; mp: 96e98 ꢀC (Lit:1896e98 ꢀC) dH (400 MHz, CDCl3)
8.78 (s, 1H), 8.20 (s, 1H), 5.06 (s, 2H), 4.30e4.25 (q, 2H, J¼7.0 Hz)
1.32e1.28 (t, 3H, J¼7.0 Hz). HRMS (ESIþ) m/z calcd for C9H10ClN4O2
[MþH]þ241.0494, obsd 241.0495.
4.2.3. N-(6-Chloro-9-(2-oxopropyl)-9H-purin-2-yl)acetamide
(c). White solid; mp: 153e156 ꢀC; dH (400 MHz, CDCl3) 7.98 (s, 1H),
5.07 (s, 2H), 2.47 (s, 3H), 2.36 (s, 3H). dc (100 MHz, CDCl3) 25.1, 27.3,
52.2, 127.6, 145.0, 151.4, 152.0, 152.8, 171.0, 198.7. HRMS (ESIþ) m/z
calcd for C10H11ClN5O2 [MþH]þ268.0593, obsd 268.0596. IR (KBr
disc) cmꢁ1: 3109, 2925, 2850,1722,1678,1605,1500,1304,1235,1170.
4.2.14. 2-(6-Chloro-9H-purin-9-yl) ethanol (n). White power; mp:
158e161 ꢀC (Lit:18 154e157 ꢀC); dH(400 MHz, CDCl3) 8.79 (s, 1H),
8.33 (s, 1H), 4.6e4.63 (t, 2H, J¼4.8 Hz), 4.14e4.11 (m, 2H). HRMS
(ESIþ) m/z calcd for C7H8ClN4O [MþH]þ199.0388, obsd 199.0386.
4.2.4. 1-(2,6-Dichloro-9H-purin-9-yl)propan-2-one (d). Light yel-
low solid; mp: 178e180 ꢀC; dH (400 MHz, CDCl3) 8.09 (s, 1H), 5.13
(s, 2H), 2.39 (s, 3H). dc (100 MHz, CDCl3) 27.2, 52.3, 130.3, 146.3,
151.9, 152.1, 153.1, 198.1. HRMS (ESIþ) m/z calcd for C8H8I1N4O
[MþH]þ 302.9745, obsd 302.9747. IR (KBr disc) cmꢁ1: 3115, 2981,
2939, 1729, 1603, 1559, 1508, 1338, 1248.
4.2.15. 6-Chloro-9-ethyl-9H-purine(o). White power; mp: 81e84 ꢀC
(Lit:18 81e84 ꢀC); dH (400 MHz, CDCl3) 8.75 (s, 1H), 8.14 (s, 1H),
4.39e4.33 (q, 2H, J¼7.3 Hz), 1.60e1.57 (t, 3H, J¼7.2 Hz). HRMS (ESIþ)
m/z calcd for C7H7ClN4Na [MþNa]þ205.0259, obsd 205.0257.
4.2.5. 1-(6-Iodo-9H-purin-9-yl)propan-2-one
(e). Light yellow
solid; mp: 167e169 ꢀC (Lit:15 167e169 ꢀC); dH (400 MHz, CDCl3)
8.60 (s, 1H), 8.12 (s, 1H), 5.12 (s, 2H), 2.36 (s, 3H). dc (100 MHz,
CDCl3) 27.2, 52.2, 122.2, 138.2, 145.0, 152.0, 152. 1, 198.0. HRMS
(ESIþ) m/z calcd for C8H7Cl2N4O [MþH]þ244.9999, obsd 244.9997.
Acknowledgements
The authors thank the National Science Foundation of China (No.
21102038) and the Program for Henan Science and Technology
Program (082300450530) and Henan Natural Science Research
(2011B150019).
4.2.6. 1-(2-Chloro-6-iodo-9H-purin-9-yl)propan-2-one
(f). Light
yellow solid; mp: 176e178 ꢀC; dH (400 MHz, CDCl3) 8.10 (s, 1H), 5.09
(s, 2H), 2.38 (s, 3H). dc (100 MHz, CDCl3) 27.2, 52.3, 122.4, 137.5,
145.7, 149.3, 152.1, 198.6. HRMS (ESIþ) m/z calcd for C8H6ClIN4O
[MþH]þ336.9342, obsd 336.9348. IR (KBr disc) cmꢁ1: 3121, 2978,
2939, 1735, 1583, 1550, 1493, 1347, 1224,1197, 1158.
References and notes
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Schaeffer, H. J. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 5716e5720.
2. Schaeffer, H. J.; Beauchamp, L.; Miranda, P.; de; Elion, G. B.; Bauer, D. J.; Collins,
P. Nature 1978, 272, 583e588.
4.2.7. N-(9-(2-Oxopropyl)-9H-purin-6-yl)ace amide (g). White
power; mp: 200e202 ꢀC (Lit:15 200e1202 ꢀC); dH (400 MHz, CDCl3)
8.66 (s, 1H), 7.98 (s, 1H), 5.11 (s, 2H), 2.62 (s, 3H), 2.36 (s, 3H). HRMS
(ESIþ) m/z calcd for C10H12N5O2 [MþH]þ 234.0993, obsd 234.0995.
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4.2.8. 1-(6-(Diethyl amino)-9H-purin-9-yl) propan-2-one (h). White
power; dH (400 MHz, CDCl3) 8.29 (s, 1H), 7.70 (s, 1H), 4.99 (s, 2H),
3.99e3.96 (m, 4H), 2.27 (s, 3H), 1.30e1.27 (t, 6H, J¼6.8 Hz). dc

7826
Q. Zhang et al. / Tetrahedron 68 (2012) 7822e7826
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