N-Alkylation of 2,6-dichloropurine hydrochloride with a variety of alcohols over alumina catalyst

Article abstract of DOI:10.1080/00397910903162791

2,6-Dichloropurine hydrochloride reacts with various types of alcohols using different alumina catalysts and converts into its N-9-alkyl-2-chloro-6- hydroxy-9H-purine products to an extent of 49-74%. The product selectivity depends on the stability of carbocation generated from the alcohol. More stable carbocation formulates both N-7 and N-9-alkyl-2,6-dichloropurine products, whereas the less stable carbocation results in exclusively N-9-alkyl-2-chloro-6- hydroxy-9H-purine. The catalytic activity of alumina prepared using the sol-gel method has larger Brunauer, Emmett, and Teller (BET) surface area and hence shows significantly greater catalytic activity than the commercially available alumina samples. Copyright

Full text of DOI:10.1080/00397910903162791

This article was downloaded by: [Dalhousie University]
On: 26 December 2012, At: 01:32
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
N-Alkylation of 2,6-Dichloropurine
Hydrochloride with a Variety of Alcohols
over Alumina Catalyst
Harikrishna Tumma a , N. Nagaraju a & K. Vijayakumar Reddy a
a St. Joseph's College Research Center, Bengaluru, India
Version of record first published: 17 May 2010.
To cite this article: Harikrishna Tumma , N. Nagaraju & K. Vijayakumar Reddy (2010): N-Alkylation
of 2,6-Dichloropurine Hydrochloride with a Variety of Alcohols over Alumina Catalyst, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:12, 1856-1866
To link to this article: http://dx.doi.org/10.1080/00397910903162791
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 40: 1856–1866, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903162791
N-ALKYLATION OF 2,6-DICHLOROPURINE
HYDROCHLORIDE WITH A VARIETY OF ALCOHOLS
OVER ALUMINA CATALYST
Harikrishna Tumma, N. Nagaraju, and K. Vijayakumar Reddy
St. Joseph’s College Research Center, Bengaluru, India
2,6-Dichloropurine hydrochloride reacts with various types of alcohols using different
alumina catalysts and converts into its N-9-alkyl-2-chloro-6-hydroxy-9H-purine products
to an extent of 49–74%. The product selectivity depends on the stability of carbocation
generated from the alcohol. More stable carbocation formulates both N-7 and N-9-alkyl-2,6-
dichloropurine products, whereas the less stable carbocation results in exclusively N-9-
alkyl-2-chloro-6-hydroxy-9H-purine. The catalytic activity of alumina prepared using the
sol-gel method has larger Brunauer, Emmett, and Teller (BET) surface area and hence shows
significantly greater catalytic activity than the commercially available alumina samples.
Keywords: Alcohol; alkylation; alumina; 2,6-dichloropurine hydrochloride
INTRODUCTION
Alkylation of 2,6-dichloropurine is an important reaction for the synthesis of
biologically active analogs, such as 2-arylpurines, which are inhibitors of P38a MAP
kinase[1] and cyclin-dependent kinase.[2] For instance, 6-arylpurine nucleosides are
cytostatic[3] and show anti-HCV effect;[4] 9-alkyl-6-arylpurines are antimycobacterial,
antibacterial,[5] and corticotrophin-releasing hormone antagonists;[6] and some 2,6-
diarylpurines are antagonists of A1 and A2 adenosine receptors.[7] Several literature
reports are available for the preparation of N-alkylated purines. These include (a)
solid-phase methodology for building combinatorial libraries of purine derivatives,[8]
(b) Mitsunobu reaction with various types of alcohols,[9] (c) alkylation with alkyl halide
with a strong base such as NaH–dimethylformamide (DMF),[10] and (d) alkylation in
the presence of organometals.[11] These reactions require either long reaction time and
low or very high temperatures. Furthermore, a large amount of effluent waste was
generated under the Mitsunobu conditions, and elevated temperature is required for
the basic conditions. Because of the sensitivity of the reagents, an inert atmosphere
was also required to get good yield and selectivity with respect to the N-7 versus
N-9 alkylated products. Because of intense current interest in purine nucleosides, many
efforts have been made for the development of a general method of preparation of
N-alkylated purine analogs.
Received March 22, 2009.
Address correspondence to K. Vijayakumar Reddy, St. Joseph’s College Research Center, 36,
Shanthi Nagar, Lalbagh Road, Bengaluru, India. E-mail: profvkreddy.vkreddy@yahoo.com
1856

REGIOSELECTIVE N-ALKYLATION OF PURINE
1857
Here we report for the first time the N-alkylation of 2,6-dichloropurine
hydrochloride with various types of alcohols in the presence of different aluminas
as catalysts at moderate temperature. The reported method has been found to be
very simple, effective, and ecofriendly and has a good general applicability for the
synthesis of alkylated purines.
RESULTS AND DISCUSSION
The conversion of 2,6-dichloropurine hydrochloride into N-methyl purines
with and without alumina as a catalyst was conducted. It was noticed that the reac-
tion proceeded toward the formation of the desired product with 70% conversion in
the presence of alumina, whereas it was only 12% conversion in the absence of alu-
mina. Further reactions were conducted using different types of alumina samples,
and it was observed that alumina prepared by using sol-gel method (ALM-600)
exhibited greater catalytic activity than the commercial samples (Fig. 1). This result
shows the importance of alumina as well as its high surface area in this reaction.
Powder XRD of ALM-600 exhibited broad diffraction patterns, indicating the
microcrystalline nature of the material. Its thermal gravimetric analysis=differential
scanning calorimetry (TGA=DSC) profiles showed a continuous loss in weight
without any significant exo=endotherms, thus indicating absence of any definite
phase transition during calcination to 600ꢀC. Furthermore, the material also exhib-
ited the greatest Brunauer, Emmett, and Teller (BET) surface area (142 m2=g), show-
ing small particle size.
It was noticed that 2-chloro-6-hydroxy-N-9-methyl-9H-purine was the product
formed in the reaction between 2,6-dichloropurine hydrochloride and methanol
in the presence of alumina. Thus, both nucleophilic substitution (hydroxylation)
and alkylation (methylation) were involved. Hydroxylation at the sixth position is
due to the labile nature of chlorine atom. The hydroxy nucleophile for the reaction
is generated in situ from the liberated water molecule. It is known from both
Figure 1. Comparison of alumina catalysts for the conversion of 2,6-dichloropurine hydrochloride to
2-chloro-6-hydroxy-N-9-methyl-9H-purine.

1858
H. TUMMA, N. NAGARAJU, AND K. V. REDDY
theoretical and experimental studies that the halogen atom at the sixth position is
more reactive toward nucleophilic substitution than at the second position in N-7
and N-9 alkylated halopurines.[12]
It is reported that alumina catalyzes the reaction between an alcohol and
hydrogen chloride in the presence of carbon tetrachloride to form alkyl halides.[13]
Based on this, it may be inferred from the present study that alumina provide more
active sites and facilitates the formation of the methyl chloride and water with
hydrogen chloride from 2,6-dichloropurine and methanol. The methyl chloride thus
generated further reacts with purine to give N-methyl purine (Scheme 1). The higher
nucleophilicity at the N-9 position of 2,6-dichloropurine further accounts for methy-
lation at the N-9 position.
Further studies were conducted using different alcohols for N-alkylation of
2,6-dichloropurine hydrochloride, and it was observed (Fig. 2) that the reaction
proceeded well toward the formation of the desired products (65–74%) in the pres-
ence of alumina, whereas it was only 10 to 15% conversion in the absence of alumina.
Table 1 indicates the observed results in the presence of alumina catalyst with a
variety of alcohols. It is interesting to note that nature of the product formed
depends on the type of alcohol used in the reaction. tert-Butyl alcohol and benzyl
alcohol produced a mixture of alkylated products, that is, N-7 and N-9-alkyl-2,
6-dichloropurine (Table 1, entries 11 and 12), whereas methanol, ethanol,
n-propanol, iso-propanol, n-butanol, iso-butanol, 1,2-dihydroxyethane, cyclopenta-
nol, cyclohexanol, and phenethyl alcohol (Table 1, entries 1 to 10) produced
exclusively N-9-alkyl-2-chloro-6-hydroxy-9H-purine derivatives. This clearly
indicates that stable carbocations, such as tert-butyl and benzyl carbocations,
generated in the reaction result in a mixture of N-7- and N-9-alkylated-2,
6-dichloropurines, and less stable carbocations generated from other alcohols result
in N-9 electrophilic substitution followed by the nucleophilic hydroxy substitution at
the sixth position (Scheme 2) by the water molecule liberated in situ.
Thus, regioselectivity of the N-alkylation was more predominant with the
alcohols generating less stable carbocations. It is also noticed that the regioselectivity
for N-9-alkylation was more predominant than the N-7-alkylation in the case of
stable carbocations (Table 1, entries 11 and 12).
Scheme 1. Formation of alkyl halide from hydrogen chloride of 2,6-dichloropurine and methanol in the
presence of alumina catalyst and N-alkylation of 2,6-dichloropurine.

REGIOSELECTIVE N-ALKYLATION OF PURINE
1859
Figure 2. Effect with and without alumina catalyst for the conversion of 2,6-dichloropurine hydrochloride
to N-9-alkyl-2-chloro-6-hydroxy-9H-purine.
Table 1. Alkylation of 2,6-dichloropurine: conversion and isolated yield
Substituent at
Reactiona
Temp
(ꢀC)
Time
(h)
Conversion by
HPLC (area %)
Yield
(%)
Entry
R
2
6
1
2
9-Methyl
9-Ethyl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Cl
63–65
77–79
96–98
82–83
98–99
97–98
90–92
80–82
78–80
86–90
82–84
5.0
6.0
6.0
6.0
5.0
6.0
5.0
6.0
6.0
5.0
6.0
70
74
69
66
72
65
62
49
51
62
43
24
32
28
58b
62c
55c
52c
56c
49b
53
25c
26c
47b
24c
15c
17b
15b
3
9-nPropyl
4
9-iPropyl
5
9-nButyl
6
9-iButyl
7
9-(2-Hydroxy) ethyl
9-Cyclopentyl
9-Cyclohexyl
9-Phenethyl
a) 9-tButyl
b) 7-tButyl
a) 9-Benzyl
b) 7-Benzyl
8
9
10
11
12
Cl
Cl
82–85
6.0
aReaction conditions: 2,6-dichloropurine hydrochloride, 1.0 g; alcohol, 25.0 ml; and alumina catalyst,
450 mg.
bIsolated yield, flash column chromatography using silica gel.
cIsolated yield, flash column chromatography using alumina neutral.

1860
H. TUMMA, N. NAGARAJU, AND K. V. REDDY
Scheme 2. Alkylation of 2,6-dichloropurine hydrochloride with a variety of alcohols in the presence of
alumina.
Here, alumina seems to play two important roles for the formation of
N-alkylated purine. First, it assists the formation of alkyl halide by adsorbing the lib-
erated water molecule, and second, it provides a large BET surface area for the reac-
tion to take place more effectively. The second observation is supported by the fact
that percentage conversion of purine was greater using sol-gel-prepared alumina,
which exhibited larger BET surface area than the commercial samples. It is also note-
worthy that for a good reaction conversion, it is not only the nature (acidic=basic=
neutral) of the surface of alumina but also the available surface area that is important.
When the stability of the carbocation formed is greater, the alkylation reaction
is preferred over the nucleophilic substitution. However, the alkylation reaction in
the case where less stable carbocation is generated takes place exclusively at the
N-9 position, where electron density is greater as a result of the participation of a
lone pair electrons of a chlorine atom at the sixth position. This accounts for the
regioselectivity of N-9-alkylation. Amphoteric nature of alumina seems to play an
important role in the controlled release of alkyl carbocation or the hydroxy nucleo-
phile, which in turn depends on the stability of the carbocation.
The labile nature of the chlorine atom in 2,6-dichloropurine at the sixth
position was confirmed by synthesizing two of its arylamine derivatives with 100%
conversion and selectivity (Table 2, entries i and ii). Furthermore, the intact nature
of the chlorine atom at the sixth position in N-9-tert-butyl-2,6-dichloropurine,

REGIOSELECTIVE N-ALKYLATION OF PURINE
1861
Table 2. Nucleophilic substitution of 2,6-dichloropurine and its derivatives with aryl amines
Reactiona
Entry
R
ArNH2
Temp (ꢀC)
Time (h)
Conversion by (area %)
Yieldb (%)
i
ii
9-H
9-H
9-tButyl
C6H5NH2
C6H5CH2NH2
C6H5CH2NH2
66–68
63–65
25–27
8.0
2.0
5.0
100
100
100
96
95
91
iii
aReaction conditions: 2,6-dichloropurine moiety, 1.0 m equiv; aryl amine, 2.0 m equiv; and THF
solvent, 100 rel. vol.
bIsolated yield.
isolated from the reaction performed between tert-butyl alcohol and 2,6-dichloro-
purine hydrochloride, was confirmed by preparing arylamine derivative with 100%
conversion and selectivity (Table 2, entry iii).
To confirm the selective alkylation at the N-9 position in the presence of less
stable carbocation, 2-chloro-6-hydroxy-7=9-(2-hydroxy ethyl)-7=9-H-purine moiety
(Table 1, entry 7) has been randomly selected, and the positions were confirmed
Table 3. Selected correlations from the HMBC spectrum of the 2-chloro-6-hydroxy-N-9-(2-hydroxy
ethyl)-9H-purine (7)
C-4
C-5
X
C-6
C-8
X
C-10
C-20
H-8
CH2-10
CH2-20
X
X
X
X
X
X

1862
H. TUMMA, N. NAGARAJU, AND K. V. REDDY
1
by heteronuclear multiple bond correlation (HMBC) (Table 3). The H NMR shift
of the methylene (CH2-10) protons at 4.55 ppm serves as an obvious starting point for
the elucidation of the structure of compound 7 (Table 1, entry 7). The methylene
proton (CH2-10) correlates to C-4 (157.17 ppm) as well as to C-10 (69.17 ppm) and
C-20 (59.57 ppm). The H-8 proton (8.41 ppm) correlates with C-4 (157.17 ppm),
C-5 (117.32 ppm), and C-8 (144.20 ppm). These spectral data confirm the hydroxy
ethyl group positioned at N-9 in compound 7.
CONCLUSION
Based on our experimental results, here we report that the 2,6-dichloropurine
hydrochloride can be effectively converted into its N-alkylated purines with various
alcohols over alumina to an extent of 74%. The percentage conversion depends on
the surface area of alumina catalyst. Electrophilic substitution takes place at N-7
and=or N-9 position of 2,6-dichloropurine. The regioselectivity of electrophilic
substitution of purine depends on the stability of alkyl carbocation. The less stable
carbocations of different alcohols gave exclusively N-9-alkylated-2-chloro-6-
hydroxy-9H-purine, whereas more stable tert-butyl and benzyl carbocations yielded
both N-7 and N-9-alkylated-2,6-dichloropurine derivatives.
EXPERIMENTAL
Alumina catalyst was prepared by the sol-gel method using aluminium
isopropoxide[14] and dried in hot air oven (110–120 ꢀC) for about 12.0 h, followed
by calcination in a muffle furnace at 600 ꢀC for 2.0 h (abbreviated as ALM-600).
Three other commercial samples of alumina (acidic, ALM-A; basic, ALM-B; and
neutral, ALM-N) were also procured. These samples were dried at 110 ꢀC for 4.0 h
under reduced pressure to remove any adsorbed water and used for the catalytic
activity comparison.
2,6-Dichloropurine hydrochloride precursor was synthesized as per Scheme 3.
2,6-Dimercaptopurine (VII) was prepared[15] in five consecutive steps, and 2,6-
dichloropurine (VIII) was prepared[16] by passing chlorine gas through the slurry
mass of 2,6-dimercaptopurine (VII) in saturated methanolic hydrogen chloride
mixture at 0 ꢀC. Hydrochloride salt of 2,6-dichloropurine (IX) was prepared
Scheme 3. Synthetic scheme for the preparation of 2,6-dichloropurine hydrochloride precursor.

REGIOSELECTIVE N-ALKYLATION OF PURINE
1863
by passing the dry hydrogen chloride gas through the clear solution of
2,6-dichloropurine in acetone.
A powder X-ray diffraction (XRD) pattern of the alumina catalyst obtained
through the sol-gel method using aluminum isopropoxide and calcined at 600 ꢀC
as well on the other commercial aluminas was found to be c-alumina (JCPDS
10-0425). The BET surface area of the catalytic materials was determined by the
N2-adsorption technique. The synthesized alumina catalyst (ALM-600) had greater
surface area than the other commercial samples. All the commercial samples exhib-
ited surface areas that are more or less similar to one another within the experimental
error limits.
Synthesis of N-Alkyl Purine Derivatives (1–12)
A typical procedure for the preparation of 2-chloro-6-hydroxy-N-9-methyl-
9H-purine (1) is as follows: 2,6-dichloropurine hydrochloride (1.0 g), methanol
(25.0 mL), and alumina (450.0 mg) were mixed together at ambient temperature.
The temperature of the mixture was raised to 63 to 65ꢀC and stirred for 5.0 h.
Samples were periodically taken, and the reaction progress was monitored by
high-performance liquid chromatography (HPLC). The reaction was cooled to
ambient temperature. The catalyst was filtered through Whatman filter paper, and
the filter cake was washed with methanol (2 ꢁ 5.0 mL). The filtrate was passed
through sodium bicarbonate (5.0 g). The methanol layer was concentrated under
reduced pressure at 50 ꢀC. The material was purified by flash column chromato-
graphy with silica gel (25.0 g) by eluting with dichloromethane followed by the
mixture of 2-propanol in dichloromethane (3% v=v).
Preparation of Arylamine Derivatives of 2,6-Dichloropurine and
Its N-Alkylated Product (i–iii)
A typical procedure for the preparation of 6-benzylamino-2-chloro-9-N-
tert-butyl-9H-purine (iii) is as follows: 9-tert-Butyl-2,6-dichloro-9H-purine (11a,
100.0 mg, 0.4 mmol) was taken in a 50.0-ml round-bottomed flask charged with
tetrahydrofuran (10.0 mL) followed by benzyl amine (87.0 mg, 0.8 mmol). The reac-
tion mixture was stirred at 25–27 ꢀC for 5.0 h. The reaction progress was monitored
by HPLC. The hydrochloride salts of benzyl amine were filtered through Whatman
filter paper, and the filter cake with was washed tetrahydrofuran (5.0 mL). The tetra-
hydrofuran layer was concentrated under reduced pressure at 50 ꢀC. Water was
charged to the resulting white material and stirred for 30 min at ambient tempera-
ture. The solid was filtered and dried under reduced pressure at 50 ꢀC for 3.0 h.
1H and 13C NMR (delta values in ppm), gas chromatography=mass
spectrometry (GC-MS; M=z values), and elemental analysis data of synthesized
N-alkylated purine products support the structural confirmation.
Spectral Data
2-Chloro-6-hydroxy-N-9-methyl-9H-purine (1). 1H NMR (DMSO-d6,
200 MHz): d 4.08 (s, 3H), 8.38 (s, 1H), 13.59 (bs, 1H). 13C NMR (DMSO-d6,

1864
H. TUMMA, N. NAGARAJU, AND K. V. REDDY
50.3 MHz): ppm 55.11 (N-CH3), 143.89 (N¼CH-). GC- MS: M=z 184 þ 2; melting
point: 218–219.5 ꢀC. Anal. calcd. for C6H5N4ClO (184.58): C, 39.04; H, 2.73; N,
30.35. Found: C, 39.12; H, 2.69; N, 30.95.
2-Chloro-6-hydroxy-N-9-ethyl-9H-purine (2). 1H NMR (DMSO-d6,
200 MHz): d 1.35 (t, 3H, J7.2 Hz), 4.55 (q, 2H, J ¼ 7.2 Hz), 8.35 (s, 1H). 13C NMR
(DMSO-d6, 50.3 MHz): ppm 14.09 (-CH3), 63.42 (N-CH2-), 143.51 (N¼CH-).
GC- MS: M=z 198 þ 2; melting point: 252–256 ꢀC. Anal. calcd. for C7H7N4ClO
(198.61): C, 42.33; H, 3.55; N, 28.21. Found: C, 42.29; H, 3.56; N, 28.32.
2-Chloro-6-hydroxy-N-9-npropyl-9H-purine (3). 1H NMR (DMSO-d6,
200 MHz): d 0.99 (t, 3H, J ¼ 7.2 Hz), 1.81 (sextet, 2H, J ¼ 7.2 Hz), 4.47 (t, 2H,
J ¼ 7.2 Hz), 8.36 (s, 1H). 13C NMR (DMSO-d6, 50.3 MHz): ppm 9.98 (ꢂCH3),
21.49 (ꢂCH2ꢂ), 68.86 (NꢂCH2ꢂ), 143.53 (N¼CHꢂ). GC-MS: M=z 212 þ 2; melt-
ing point: 203–208ꢀC. Anal. calcd. for C8H9N4ClO (212.64): C, 45.19; H, 4.27; N,
26.35. Found: C, 45.26; H, 4.32; N, 26.29.
2-Chloro-6-hydroxy-N-9-ipropyl-9H-purine (4). 1H NMR (DMSO-d6,
200 MHz): d 1.39 (d, 6H, J ¼ 7.1 Hz), 5.50 (septet, 1H, J ¼ 7.1 Hz), 8.34 (s, 1H).
13C NMR (DMSO-d6, 50.3 MHz): ppm 21.52 (2, ꢂCH3), 70.87 (N-CH-), 143.38
(N¼CHꢂ). GC-MS: M=z 212 þ 2; melting point: 226–230 ꢀC. Anal. calcd. for
C8H9N4ClO (212.64): C, 45.19; H, 4.27; N, 26.35. Found: C, 45.12; H, 4.21; N,
26.39.
N-9-nButyl-2-chloro-6-hydroxy-9H-purine
(5). 1H
NMR
(CDCl3,
200 MHz): d 0.99 (t, 3H, J ¼ 10.3 Hz), 1.53 (sextet, 2H, J ¼ 10.3 Hz), 1.87 (quintet,
2H, J ¼ 10.3 Hz), 4.64 (t, 2H, J ¼ 10.3), 8.10 (s, 1H). GC- MS: M=z 226 þ 2; melting
point: 189–192 ꢀC. Anal. calcd. for C9H11N4ClO (226.67): C, 47.69; H, 4.89; N,
24.72. Found: C, 47.75; H, 4.79; N, 24.69.
N-9-iButyl-2-chloro-6-hydroxy-9H-purine
(6). 1H
NMR
(CDCl3,
200 MHz): d 1.00 (d, 6H, J ¼ 9.3 Hz), 1.98–2.20 (m, 1H), 4.28 (d, 2H, J ¼ 9.3 Hz),
8.37 (s, 1H), 13.54 (bs, H). GC- MS: M=z 226 þ 2; melting point: 202–204 ꢀC. Anal.
calcd. for C9H11N4ClO (226.67): C, 47.69; H, 4.89; N, 24.72. Found: C, 47.71; H,
4.55; N, 24.81.
2-Chloro-6-hydroxy-N-9-(2-hydroxy-ethyl)-9H-purine
(7). 1H
NMR
(DMSO-d6, 200 MHz): d 3.82 (t, 2H, J ¼ 5.4), 4.55 (t, 2H, J ¼ 5.4), 8.41 (s, 1H).
13C NMR (DMSO-d6, 50.3 MHz): ppm 59.01 (NꢂCH2ꢂ), 69.23 (ꢂCH2ꢂOH),
143.73 (N¼CHꢂ). DIP- MS: M=z 214 þ 2; melting point: 252–254 ꢀC. Anal. calcd.
for C7H7N4ClO2 (214.61): C, 39.18; H, 3.29; N, 26.11. Found: C, 39.26; H, 3.40;
N, 26.03.
2-Chloro-N-9-cyclopentyl-6-hydroxy-9H-purine (8). 1H NMR (CDCl3 þ
DMSO-d6, 200 MHz): d 1.58–2.20 (m, 8H), 5.66–5.79 (m, 1H), 7.98 (s, 1H), 12.84
(bs, 1H). 13C NMR (CDCl3 þ DMSO-d6, 50.3 MHz): ppm 23.12 (2, ꢂCH2ꢂ), 32.07
(2, ꢂCH2ꢂ), 79.94 (NꢂCHꢂ), 140.38 (N¼CHꢂ). GC- MS: M=z 238 þ 2; melting
point: >380ꢀC. Anal. calcd. for C10H11N4ClO (238.68): C, 50.32; H, 4.65; N, 23.47.
2-Chloro-N-9-cyclohexyl-6-hydroxy-9H-purine (9). 1H NMR (DMSO-d6,
200 MHz): d 1.19–2.08 (m, 10H), 5.17–5.33 (m, 1H), 8.39 (s, 1H). 13C NMR

REGIOSELECTIVE N-ALKYLATION OF PURINE
1865
(DMSO-d6, 50.3 MHz): ppm 23.23 (2, ꢂCH2ꢂ), 24.88 (ꢂCH2ꢂ), 31.11 (2, ꢂCH2ꢂ),
75.49 (NꢂCHꢂ), 143.67 (N¼CHꢂ). GC-MS: M=z 252 þ 2; melting point: >380ꢀC.
Anal. calcd. for C11H13N4ClO (252.70): C, 52.28; H, 5.19; N, 22.17.
2-Chloro-6-hydroxy-N-9-(2-phenethyl)-9H-purine
(10). 1H
NMR
(DMSO-d6, 200 MHz): d 3.12 (t, 2H, J ¼ 8.8 Hz), 4.63 (t, 2H, J ¼ 8.8 Hz),
7.09–7.35 (m, 5H), 8.38 (s, 1H), 13.53 (bs, 1H). 13C NMR (DMSO-d6, 50.3 MHz):
ppm 34.37 (-CH2-Ph), 68.00 (N–CH2-), 126.44 (Ar-CH-), 128.39 (2, Ar-CH-), 128.96
(2, Ar-CHꢂ), 137.77 (N¼CHꢂ). DIP- MS: M=z 275þ 2; melting point: 200–204ꢀC.
Anal. calcd. for C13H11N4ClO (274.71): C, 56.84; H, 4.04; N, 20.39. Found: C,
57.02; H, 4.12; N, 20.35.
N-9-tButyl-2,6-dichloro-9H-purine (11a). 1H NMR (CDCl3, 200 MHz): d
1.83 (s, 9H), 8.18 (s, 1H). 13C NMR (CDCl3, 50.3 MHz): ppm 29.00 (3, -CH3),
143.57 (N¼CHꢂ). GC-MS: M=z 244 þ 4; melting point: 175–180 ꢀC. Anal. calcd.
for C9H10N4Cl2 (245.11): C, 44.10; H, 4.11; N, 22.86. Found: C, 44.38; H, 4.20;
N, 22.69.
N-7-tButyl-2,6-dichloro-7H-purine (11b). 1H NMR (CDCl3, 200 MHz): d
1.91 (s, 9H), 8.47 (s, 1H). 13C NMR (CDCl3, 50.3 MHz): ppm 31.11 (3, ꢂCH3),
148.26 (N¼CHꢂ). GC-MS: M=z 244 þ 4; melting point: 200–205 ꢀC. Anal. calcd.
for C9H10N4Cl2 (245.11): C, 44.10; H, 4.11; N, 22.86. Found: C, 43.98; H, 4.26;
N, 22.67.
N-9-Benzyl-2,6-dichloro-9H-purine (12a). 1H NMR (CDCl3, 200 MHz): d
5.46 (s, 2H), 7.27–7.42 (m, 5H), 8.06 (s, 1H). 13C NMR (CDCl3, 50.3 MHz): ppm
47.99 (Ph-CH2-), 128.03 (2, Ar-CH-), 129.02 (Ar-CH-), 129.32 (2, Ar-CH-), 145.55
(N¼CHꢂ). GC- MS: M=z 277 þ 4; melting point: 135–142 ꢀC. Anal. calcd. for
C12H8N4Cl2 (279.13): C, 51.64; H, 2.89; N, 20.07. Found: C, 52.02; H, 2.66; N,
20.67.
N-7-Benzyl-2,6-dichloro-7H-purine (12b). 1H NMR (CDCl3, 200 MHz): d
5.68 (s, 2H), 7.11–7.44 (m, 5H), 8.22 (s, 1H). 13C NMR (CDCl3, 50.3 MHz): ppm
50.91 (Ph-CH2-), 127.08 (2, Ar-CH-), 129.11 (Ar-CH-), 129.48 (2, Ar-CH-), 150.35
(N¼CHꢂ). GC-MS: M=z 278 þ 4; melting point: 152–154ꢀC. Anal. calcd. for
C12H8N4Cl2 (279.13): C, 51.64; H, 2.89; N, 20.07. Found: C, 51.72; H, 2.89; N,
20.24.
REFERENCES
1. Wan, Z.; Boehm, J. C.; Bower, M. J.; Kassis, S.; Lee, J. C.; Zhao, B.; Adams, J. L.
N-Phenyl-N-purin-6-yl ureas: The design and synthesis of p38aMAP kinase inhibitors.
Bioorg. Med. Chem. Lett. 2003, 13, 1191–1194.
2. Vandromme, L.; Piguel, S.; Lozach, O.; Meijer, L.; Legraverend, M.; Grierson, D. S.
Suzuki-type Pd(0) coupling reactions in the synthesis of 2-arylpurines as Cdk inhibitors.
Bioorg. Med. Chem. Lett. 2006, 16, 3144–3146.
3. Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. Synthesis and cytostatic activity of
substituted 6-phenylpurine bases and nucleosides: Application of Suzuki–Miyaura
cross-coupling reactions of 6-chloropurine derivatives with phenylboronic acids. J.
Med. Chem. 2000, 43, 1817–1825.

1866
H. TUMMA, N. NAGARAJU, AND K. V. REDDY
4. Hocek, M.; Nau, P.; Pohl, R.; Votruba, I.; Furman, P. A.; Tharnish, P. M.; Otto, M. J.
Cytostatic 6-arylpurine nucleosides, 6: SAR in anti-HIV and cytostatic activity of
extended series of 6-hetarylpurine ribonucleosides. J. Med. Chem. 2005, 48, 5869–5873.
5. Bakkestuen, A. K.; Gundersen, L. L.; Utenova, B. T. Synthesis, biological activity, and
SAR of antimycobacterial 9-aryl-, 9-arylsulfonyl-, and 9-benzyl-6-(2-furyl) purines.
J. Med. Chem. 2005, 48, 2710–2723.
6. Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.; Gilligan, P. Use of the Suzuki
reaction for the synthesis of aryl-substituted heterocycles as corticotrophin-releasing
hormone (CRH) antagonists. Bioorg. Med. Chem. Lett. 1999, 9, 1063–1066.
7. (a) Baraldi, P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.; Fruttarolo, F.; Romagnoli, R.;
Moorman, A. R.; Gessi, S.; Merighi, S.; Varani, K.; Borea, P. A. [3H]-MRE 2029-F20,
a selective antagonist radioligand for the human A2B adenosine receptors. Bioorg. Med.
Chem. Lett. 2004, 14, 3607–3610; (b) Chang, L. C. W.; Spanjersberg, R. F.; von Frijtag
Drabbe Kunzel, J. K.; Mulder-Krieger, T.; Brussee, J.; Izerman, A. P. 2,6-Disubstituted
and 2,6,8-trisubstituted purines as adenosine receptor antagonists. J. Med. Chem. 2006,
49, 2861–2867.
8. Norman, T. C.; Gray, N. S.; Koh, J. T.; Schultz, P. G. A structure-based library approach
to kinase inhibitors. J. Am. Chem. Soc. 1996, 118, 7430–7431.
9. Toyota, A.; Katagiri, N.; Kaneko, C. Mitsunobu reaction for the synthesis of carbocyclic
analogues of nucleosides: Examination of the regioselectivity. Synth. Commun. 1993, 23,
1295–1305.
10. (a) Kelley, J. L.; Linn, J. A.; Krochmal, M. P.; Selway, J. W. T. 9-Benzyl-6-
(dimethylamino)-9H-purines with antirhinovirus activity. J. Med. Chem. 1988, 31,
2001–2004; (b) Schow, S. R.; Mackman, R. L.; Blum, C. L.; Brooks, E.; Horsma,
A. G.; Joly, A.; Kerwar, S. S.; Lee, G.; Shiffman, D.; Nelson, M. G.; Wang, X.; Wick,
M. M.; Zhang, X.; Lum, R. T. Synthesis and activity of 2,6,9-trisubstituted purines.
Bioorg. Med. Chem. Lett. 1997, 7, 2697–2702.
11. Gundersen, L. L.; Langli, G.; Rise, F. Regioselective Pd-mediated coupling between
2,6-dichloropurines and organometallic reagents. Tetrahedron Lett. 1995, 36, 1945–1948.
12. (a) Barlin, G. B. Kinetics of reactions in heterocycles, part IV: The reaction of chloropur-
ines and their 9-methyl derivatives with sodium ethoxide or piperidine. J. Chem. Soc. B.
1967, 954–958; (b) Pullman, B. Electronic structure, chemical reactivity, and basicity of
purines and pyrazolopyrimidines. J. Chem. Soc. 1959, 1621–1623; (c) Miller, R. L.; Lykos,
P. G.; Schmeising, H. N. A quantum theoretical study of some N-heteroaromatic
compounds. J. Am. Chem. Soc. 1962, 84, 4623–4627.
13. Xiuyuan, Y.; Wucheng, Z.; Yongan, M.; Lei, Z. Methosd for production of chloro-
methane with tetrachloromethane. CN Patent 1,982,267 A, 2007.
14. Macedo, M. I. F. Sol-gel synthesis of transparent alumina gel and pure gamma alumina
by urea hydrolysis of aluminium nitrate. J. Sol-Gel Sci. Technol. 2004, 30, 135–140.
15. Beaman, A. G. New synthesis of purine. J. Am. Chem. Soc. 1954, 76, 5633–5636.
16. Beaman, A. G.; Robins, R. K. Potential purine antagonists, XXXIII: Synthesis of
chloropurines. J. Appl. Chem. 1962, 12, 432–437.