Preparation of new N6,9-disubstituted 12-phenyl-adenines and corresponding 8-azaadenines. A feasibility study for application to solid-phase synthesis. I [1]

Article abstract of DOI:10.1002/jhet.5570410415

A suitably substituted pyrimidine 1 was converted to a number of title compounds. Nucleophilic substitution involving the chlorine atoms in 1 by treatment with phenylmethanethiol yielded 2 or 3, depending on the reaction temperature. Treatment of 3 with an amine afforded 6-phenylmethanesulfanyl- N⁴-substituted-2-phenyl-pyrimidine-4,5-diamines 4-7. These pyrimidines were converted into 2-phenylpurines 8-11 and 2-phenyl-8-azapurines 12-14, by treatment with triethyl orthoformate in the presence of hydrochloric acid (or acetic anhydride), or with potassium nitrite and acetic acid respectively. The thioether function on C(6) was then converted into a sulfonyl group by oxidation with m-chloroperoxybenzoic acid affording purines 15-18 and their 8-azaanalogs 19-21; these compounds, as crude products, were treated with an amine to yield the corresponding adenines 22-25 or 8-azaadenines 26-31. All reactions were performed under conditions compatible with the possible use of a tniomethyl resin in place of phenylmethanethiol to bind the pyrimidine ring of 1 to a solid phase.

Full text of DOI:10.1002/jhet.5570410415

6
Preparation of New N ,9-Disubstituted 2-phenyl-adenines
and Corresponding 8-Azaadenines.
Jul-Aug 2004
575
A Feasibility Study for Application to Solid-Phase Synthesis. I [1]
Giuliana Biagia, Irene Giorgia*, Oreste Livia, Federica Pacchinia, Valerio Scartonia
and Oreste LeRoy Salernib
a
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno, 6 56126 Pisa. Italy
b
Butler University College of Pharmacy, 4600 Sunset, Indianapolis, IN 46028 USA
Received October 17, 2003
A suitably substituted pyrimidine 1 was converted to a number of title compounds. Nucleophilic substitu-
tion involving the chlorine atoms in 1 by treatment with phenylmethanethiol yielded 2 or 3, depending on the
4
reaction temperature. Treatment of 3 with an amine afforded 6-phenylmethanesulfanyl-N -substituted-2-
phenyl-pyrimidine-4,5-diamines 4-7. These pyrimidines were converted into 2-phenylpurines 8-11 and 2-
phenyl-8-azapurines 12-14, by treatment with triethyl orthoformate in the presence of hydrochloric acid (or
acetic anhydride), or with potassium nitrite and acetic acid respectively. The thioether function on C(6) was
then converted into a sulfonyl group by oxidation with m-chloroperoxybenzoic acid affording purines 15-18
and their 8-azaanalogs 19-21; these compounds, as crude products, were treated with an amine to yield the
corresponding adenines 22-25 or 8-azaadenines 26-31. All reactions were performed under conditions com-
patible with the possible use of a thiomethyl resin in place of phenylmethanethiol to bind the pyrimidine ring
of 1 to a solid phase.
J. Heterocyclic Chem., 41, 575 (2004).
The preparation of purines or their analogs constitutes
methanethiol in the presence of methanolic KOH, at room
temperature, yielded compound 2 in nearly pure form.
When the reaction was carried out at 0 °C the monosubsti-
tuted derivative 3 was obtained in moderately good yield.
In contrast, the analogous 2,4-dichloro-3-nitro-6-
phenylpyrimidine, which is far more reactive than 1
toward nucleophilic aromatic substitution, [13] consis-
tently afforded disubstituted products, even at low temper-
atures. Furthermore, 5-amino-4-chloro-2-phenyl-6-
phenylmethanesulphanylpyrimidine 3 showed a relative
high stability toward nucleophilic agents such as phenyl-
methylamine, p-methoxyphenylmethylamine, cyclopenty-
lamine and cyclohexylamine, which required an elevated
temperature of 130 °C in xylene to convert 3 to tetrasubsti-
tuted pyrimidines, 4-7.
Compounds 4-7, in turn, were transformed into the cor-
responding purines 8-11 in moderately good yield, by
treatment with a mixture of acetic anhydride and triethyl
orthoformate at 120 °C for 1.5 hour. Alternatively, treat-
ment of the cyclohexylamine derivative 5, with triethyl
orthoformate in the presence of 37% hydrochloric acid
afforded the corresponding purine 9 in good yield after 12
hours at room temperature. In comparison, the latter reac-
tion at room temperature, though it required a longer time
for cyclization, allowed a much easier isolation of the final
product.
an important target for medicinal chemists, as compounds
of these classes can interact with many biological
processes or modulate many physiological functions.
Solid-phase synthesis is a relatively recent method to
obtain libraries of biologically active compounds which
belong to the same class but differ about various sub-
stituents. A number of preparative methods for purine
library synthesis have been reported in the literature [2-6].
These methods utilized the intact purine nucleus and were
based on the formation of a covalent bond between a resin
and an appropriately substituted purine, followed by the
introduction of various substituents on the purine ring, and
f i n a l l y, cleavage to the desired products. In another
approach, the manipulation of the pyrimidine core on a
solid phase and subsequent conversion to a purine nucleus
was reported [7]. This technique utilized 4,6-dichloro-5-
nitropyrimidine for linkage to the solid phase.
We wish to report the manipulation of a pyrimidine core,
5-amino-4,6-dichloro-2-phenylpyrimidine 1 [11] to N6-9-
disubstituted-2-phenyladenines or 8-azaadenines. The
conditions shown in the Scheme are compatible with the
possible utilization of a thiomethyl resin [8] for covalent
bonding to pyrimidine 1. In our method, we used a
phenylmethanesulphanyl group, later oxidized to a phenyl-
methanesulfonyl moiety for detachment, as a model for
such a resin. In previous papers, we reported the positive
effect of a phenyl group on C(2) of the adenine nucleus
with regard to activity of such compounds as ADA
enzyme inhibitors and/or A1 receptor ligands [9-11].
Some 9-substituted 8-azaanalogs of 8-11, such as 9-
cyclopentyl- (12 ) or 9-phenylmethyl- (13 ) , or 9-p-
methoxyphenylmethyl-2-phenyl-6-phenylmethanesul-
phanyl-8-azapurine (1 4), were prepared in moderately good
yields by the dropwise addition of aqueous potassium
nitrite to a solution of the corresponding 4,5-diaminopyrim-
idine in tetrahydrofuran and acetic acid at 0 °C.
The reaction of starting material 1 [12] with phenyl-
methanethiol, which would mimic the thiomethyl resin,
deserves some comments. The reaction of 1 with phenyl-

576
G. Biagi, I. Giorgi, O. Livi, F. Pacchini, V. Scartoni and O. L. Salerni
Vol. 41
1
4, 8, 12, 15, 19: R = cyclopentyl
1
5, 9, 16: R = cyclohexyl
1
6, 10, 13, 17, 20: R = phenylmethyl
1
7, 11, 14, 18, 21: R = p-methoxyphenylmethyl
1
2
22, 26: R = cyclopentyl; R = H
1
2
23: R = cyclohexyl; R = 2-hydroxy-1-propyl
1
2
24, 29: R = phenylmethyl; R = cyclohexyl
1
2
25, 31: R = p-methoxyphenylmethyl; R = cyclohexyl
1
2
27: R = cyclopentyl; R = p-chlorophenyl
28: R = phenylmethyl; R = H
30: R = p-methoxyphenylmethyl; R = H
1
2
1
2
Compounds 8-11 and 8-azaanalogs 12-14 were treated
The structures of all the new prepared compounds were
assigned based on known reaction pathways and were con-
firmed by analytical and spectroscopic methods (ms and
1H nmr, Table 2).
with m-chloroperoxybenzoic acid in dichloromethane, at
room temperature, to obtain sulfones 15-18 and 19-21,
r e s p e c t i v e l y, which exhibited a marked instability.
Therefore they were converted as soon as prepared into
the final compounds 22-25 and 26-31. This conversion
was accomplished by use of 33% aqueous ammonia in
ethanol or an appropriate amine in a vial with a stopper
at 110° C for 5-16 hours (Table 1). A similar reaction was
described starting from a 6-phenylsulfanylpurine [3].
Methoxyethanol was used as solvent, in place of ethanol,
when the 8-azaanalogs 19 and 21 reacted. Isolation of
reaction products was realized by dilution of the reaction
mixture with chloroform, washing of the organic layer
with dilute hydrochloric acid and water followed by evap-
oration. Alternatively, simple acidification of the reaction
mixture with dilute hydrochloric acid yielded the products.
EXPERIMENTAL
Melting points were determined on a Kofler hot-stage appara-
tus and are uncorrected. IR spectra in Nujol mulls were recorded
1
on a Mattson Genisis series FTIR spectrometer. H nmr spectra
were recorded on a Varian Gemini 200 spectrometer; chemical
shifts are expressed in ppm (δ) from TMS as an internal standard;
the compounds were dissolved in deuteriochloroform. Mass
spectra were measured on a Hewlett-Packard GC/MS System
5988A. TLC was performed on precoated silica gel F
plates
254
(Merck). Flash-column chromatography was performed using
Merck Kieselgel 60 (230-400 mesh). Microanalyses (C H N)
were carried out on a Carlo Erba elemental analyser (Model

Preparation of New N6,9-Disubstituted 2-phenyl-adenines
Jul-Aug 2004
577
Table 1
Chemical and Physical Properties of Compounds 2-14 and 22, 23, 25, 27, 30, 31
Compound
Yield
%
Cryst. solvent
M.p.(°C)
R [ b]
Formula
Analyses C, H, N
Calcd.% / Found%
f
2
40
62
66
61
77
50
64
70
72
37
70
71
56
63
60
45
80
73
60
95% Ethanol
95% Ethanol
2-Propanol
2-Propanol
2-Propanol
148-149
118-119
130
0.39[+]
0.36[+]
0.40 [#]
0.40 [#]
0.37[§]
0.28[§]
0.20[§]
0.20[§]
0.39[§]
0.20[§]
0.37[+]
0.40[+]
0.38[§]
0.30[°]
0.39[°]
0.36[⊥]
0.32[†]
0.30[⊥]
0.30[§]
C
H
24 21
N S
3 2
69.36
5.09
5.21
4.30
4.33
6.42
6.43
6.71
6.69
5.56
5.77
5.64
5.92
5.74
5.61
6.04
6.34
4.93
4.68
5.06
5.02
5.46
5.11
4.68
4.44
4.82
4.58
6.13
6.18
7.17
7.12
6.58
6.44
4.90
5.17
4.85
4.73
6.32
6.40
10.11
69.47
62.28
62.36
70.18
70.25
70.74
70.41
72.33
72.40
70.07
69.83
71.47
71.30
71.97
71.81
73.50
73.86
71.21
71.20
68.19
67.92
70.39
70.25
68.32
68.07
68.79
68.88
68.35
68.24
72.61
72.32
64.53
64.85
65.05
64.98
69.54
69.80
10.31
12.82
12.93
14.88
15.01
14.35
14.44
14.06
14.36
13.07
12.88
14.50
14.21
13.99
13.61
13.71
13.91
12.78
12.59
18.07
17.79
17.10
17.06
15.93
15.85
25.07
25.32
19.93
19.60
16.94
17.06
21.50
21.74
25.29
25.05
20.27
20.33
3
C H ClN S
17 14 3
4
C H N S
22 24 4
5
128
C
H N S
23 26 4
6
132
C
H N S
24 22 4
7
Dichloromethane-
2-propanol
96
C H N OS
25 24 4
8
Absolute ethanol
122
C
H
23 22
N S
4
9
95% Ethanol
Absolute ethanol
Absolute ethanol
2-Propanol
132-135
125
C
C
H
N S
24 24
4
10
11
12
13
14
22
23
25
27
30
31
H
N S
25 20
4
148
C
H
N OS
26 22
4
138
C
H
N S
22 21
5
2-Propanol
123
C H N S
24 19 5
Dichloromethane-
2-propanol
100
C H N OS
25 21 5
95% Ethanol
162-165
190
C H N
16 17 5
95% Ethanol
95% Ethanol
95% Ethanol
95% Ethanol
2-Propanol
C H N O
20 25 5
132-135
225
C H N O
20 25 5
C
H ClN
21 19 6
145
C
H N O
18 16 6
170
C
H N O
24 26 6
Eluents: [+] petroleum ether-chloroform 3:2; [#] petroleum ether-chloroform 4:1; [§] dichloromethane; [†]petroleum ether-
dichloromethane 1:2; [°] dichloromethane-methanol 9.5:0.5; [⊥] chloroform-methanol 9.8:0.2.
cal data are reported in Tables 1 and 2.
1106) and were within ±0.4% of the theoretical values.
Petroleum-ether corresponds to fraction boiling at 40-60 °C.
5-Amino-4-chloro-2-phenyl-6-phenylmethanesulphanylpyrimi -
dine (3).
4 , 6 - B i s ( p h e n y l m e t h a n e s u l p h a n y l ) - 2 - p h e n y l p y r i m i d i n e - 5 -
ylamine (2).
To a solution of 5-amino-4,6-dichloro-2-phenylpyrimidine 1
(1.25 g, 5.2 mmoles) in methanol (4 mL) and phenylmethanethiol
(0.6 mL), cooled in an ice-bath, a solution of potassium hydrox-
ide (0.3 g, 5.8 mmoles) in methanol (10 mL) was added drop-
wise. The resulting mixture was stirred for 1 hour at 0 °C and for
another 1 hour at room temperature. Then water (2-3 mL) was
added to give a pink precipitate that was collected by filtration
and dissolved in dichloromethane. This solution was washed with
w a t e r, filtered and evaporated to dryness to give pure 3.
Experimental and analytical data are reported in Tables 1 and 2.
To a solution of 5-amino-4,6-dichloro-2-phenylpyrimidine 1
(1.25 g, 5.2 mmoles) and phenylmethanethiol (0.6 mL) in
methanol (4 mL), a solution of potassium hydroxide (0.3 g, 5.8
mmoles) in methanol (10 mL) was added dropwise. The resulting
mixture was stirred for 1 hour at room temperature. Then water
(2-3 mL) was added to give a pink precipitate that was collected
by filtration and dissolved in dichloromethane. This solution was
washed with water, filtered and evaporated to dryness to give
compound 2, which was crystallized. Experimental and analyti-

578
G. Biagi, I. Giorgi, O. Livi, F. Pacchini, V. Scartoni and O. L. Salerni
Vol. 41
Table
2
1
Mass and H nmr Spectra of Compounds 2-14 and 22, 23, 25, 27, 30, 31
1
Compound
Mass m/z
H nmr (δ, ppm)
+
M (%)
Base
2
3
4
415(1.5)
327(5)
376(4)
91
91
91
8.45 (m, 2H, arom); 7.48-7.27 (m, 13H, arom); 4.69 (s, 4H, benz CH ); 3.67 (s, 2H, exch)
2
8.37 (m, 2H, arom); 7.45 (m, 5H, arom); 7.39 (m, 3H, arom); 4.70 (s, 2H, benz CH ); 4.11 (s, 2H, exch)
8.45 (m, 2H, arom); 7.43-7.25 (m, 8H, arom); 4.80 (d, 1H, exch); 4.63 (s, 2H, benz CH ); 4.51 (m, 1H, aliph);
2
2
2.95 (br s, 2H, exch); 2.24 (m, 2H, aliph); 1.92-1.24 (m, 6H, aliph)
8.43 (m, 2H, arom); 7.44 (m, 5H, arom); 7.27 (m, 3H, arom); 4.71 (d, 1H, exch); 4.63 (s, 2H, benz CH );
5
390(22)
398(8)
91
91
2
4.15 (m, 1H, aliph); 2.93 (br s, 2H, exch); 2.14 (m, 2H, aliph); 1.92-1.20 (m, 8H, aliph)
8.46 (m, 2H, arom); 7.44-7.25 (m, 13H, arom); 5.17 (br t, 1H, exch); 4.83 (d, 2H, benz CH ); 4.65 (s, 2H,
6
2
benz CH ); 2.95 (br s, 2H, exch)
2
7
428(2)
121
91
9.85 (br t, 1H, exch); 8.03 (m, 2H, arom); 7.42-7.18 (m, 10H, arom); 6.74 (d, 2H, arom); 5.80 (br s, 2H, exch);
4.75 (d, 2H, benz CH ); 4.65 (s, 2H, benz CH ); 3.69 (s, 3H, aliph)
8.57 (m, 2H, arom); 7.98 (s, 1H, arom); 7.51 (m, 5H, arom); 7.32 (m, 4H, 3 arom + 1 exch); 5.04 (m, 1H, aliph);
2
2
8
386(30)
400(48)
408(11)
438(2)
4.80 (s, 2H, benz CH ); 2.34 (m, 2H, aliph); 2.16-1.81 (m, 6H, aliph)
8.58 (m, 2H, arom); 8.03 (s, 1H, arom); 7.49 (m, 6H, 5 arom + 1 exch); 7.31 (m, 3H, arom); 4.81 (s, 2H, benz
2
9
91
CH ); 4.58 (m, 1H, aliph); 2.23 (m, 2H, aliph); 2.01-1.54 (m, 8H, aliph)
2
10
11
12
91
8.58 (m, 2H, arom); 7.92 (s, 1H, arom); 7.50 (m, 8H, arom); 7.35 (m, 5H, arom); 5.48 (m, 2H, benz CH );
2
4.81 (s, 2H, benz CH )
2
8.57 (m, 2H, arom); 7.89 (s, 1H, arom); 7.50 (m, 8H, arom); 7.35 (d, 2H, arom); 6.89 (d, 2H, arom); 5.41 (s, 2H,
121
91
benz CH ); 4.81 (s, 2H, benz CH ); 3.80 (s, 3H, aliph)
2
8.58 (m, 2H, arom); 7.53 (m, 5H, arom); 7.29 (m, 3H, arom); 5.43 (m, 1H, aliph); 4.84 (s, 2H, benz CH );
2
387(29)
2
2.34 (m, 4H, aliph); 2.10 (m, 2H, aliph); 1.84 (m, 2H, aliph)
8.60 (m, 2H, arom); 7.53 (m, 8H, arom); 7.33 (m, 5H, arom); 5.88 (s, 2H, benz CH ); 4.84 (s, 2H, benz CH )
13
14
409(9)
439(1)
91
121
2
8.60 (m, 2H, arom); 7.53 (m, 8H, arom); 7.31 (d, 2H, arom); 6.87 (d, 2H, arom); 5.88 (s, 2H, benz CH );
2
2
4.81 (s, 2H, benz CH ); 3.77 (s, 3H, aliph)
2
23
25
27
30
31
351(7)
413(14)
390(21)
332(6)
414(3)
225
91
8.43 (m, 2H, arom); 8.02 (s, 1H, arom); 7.48 (m, 3H, arom); 4.55 (m, 1H, aliph); 4.17 (m, 1H, aliph), 3.91 (m,
1H, aliph); 3.70 (m, 1H, aliph); 2.23-1.32 (m, 13H aliph, + 2H, exch)
8.50 (m, 2H, arom); 7.68 (s, 1H, arom); 7.45 (m, 3H, arom); 7.33 (d, 2H, arom); 6.88 (d, 2H, arom); 5.68 (br s,
1H, exch); 5.36 (s, 2H, benz CH ); 4.34 (m, 1H, aliph); 3.80 (s, 3H, aliph); 2.18-1.25 (m, 10H, aliph)
2
41
8.51 (m, 2H, arom); 8.28 (br s, 1H, exch); 7.93 (d, 2H, arom); 7.51 (m, 3H, arom); 7.45 (d, 2H, arom); 5.42 (m,
1H, aliph); 2.28-1.80 (m, 8H, aliph)
8.51 (m, 2H, arom); 7.52 (m, 5H, arom); 6.88 (d, 2H, arom); 5.77 (s, 2H, benz CH ); 3.79 (s, 3H, aliph); 2.13 (br
121
121
2
s, 2H, exch)
8.51 (br s, 1H, exch); 8.10 (m, 2H, arom); 7.63 (m, 2H, arom) 7.49 (m, 3H, arom); 6.88 (m, 2H, arom); 5.73 (s,
2H, benz CH ); 4.42 (q, 1H, aliph); 2.28-1.80 (m, 8H, aliph)
2
4
A mixture of acetic anhydride (0.86 g, 8.4 mmoles), triethyl
orthoformate (1.25 g, 8.4 mmoles) and 4 (or 6 or 7) (0.84 mmole)
N -Cycloalkyl-2-phenylpyrimidine-6-phenylmethanesulfanyl-
4,5-diamines (4,5).
was stirred at reflux for 1.5 hour. The resulting solution was
evaporated to dryness and the residue crystallized. Experimental
and analytical data are reported in Tables 1 and 2.
A mixture of 3 (0.40 g, 1.22 mmole), xylene (1 mL) and the
appropriate amine (2.23 mmoles) was stirred at reflux temperature
for 16 hours. The resulting solution was evaporated and the residue
was dissolved in chloroform and washed successively with 10%
hydrochloric acid and water. After evaporation of the organic layer,
the residue was crystallized to yield the title compound.
Experimental and analytical data are reported in Tables 1 and 2.
9-Cyclohexyl-2-phenyl-6-phenylmethanesulphanylpurines (9).
A mixture of 5 (0.20 g, 0.47 mmole), triethyl orthoformate
(0.70 g, 4.7 mmoles) and 12 N hydrochloric acid (0.14 mL) was
stirred at room temperature overnight. The precipitate obtained
was collected by filtration and crystallized. Experimental and
analytical data are reported in Tables 1 and 2.
4
N -Alkyl-2-phenylpyrimidine 6-phenylmethanesulfanyl-4,5-
diamines (6,7).
A mixture of 3 (0.20 g, 0.61 mmole), xylene (1 mL) and the
appropriate amines (2.11 mmoles) was stirred at reflux tempera-
ture for 4 hours. The resulting solution was evaporated and the
residue was dissolved in chloroform and washed successively
with 10% hydrochloric acid and water. After evaporation of the
organic layer, the residue was crystallized. Experimental and ana-
lytical data are reported in Tables 1 and 2.
9-Alkyl(cycloalkyl)-2-phenyl-6-phenylmethanesulphanyl-8-aza-
purines (12-14).
To an iced mixture of 4 (or 6 or 7) (0.28 mmole), acetic acid
(0.4 mL), water (0.9 mL) and tetrahydrofuran (3.2 mL) an iced
solution of potassium nitrite (0.3 mmole) in water was added
dropwise. The mixture was stirred for 3 hours and the precipitate
formed was collected by filtration, washed with water, and dried
to give compounds 12, 13 and 14 respectively. Experimental and
analytical data are reported in Tables 1 and 2.
9-Alkyl(cycloalkyl)-2-phenyl-6-phenylmethanesulphanylpurines
(8,10,11).

Preparation of New N6,9-Disubstituted 2-phenyl-adenines
Jul-Aug 2004
579
General Procedure for 9-Alkyl(cycloalkyl)-2-phenyl-6-phenyl-
methanesulphonylpurines (15-18) or 8-Azapurines (19-21).
ture was worked up as described for the previous reaction.
Experimental and analytical data are reported in Tables 1 and 2.
A mixture of the appropriate 9-alkyl(cycloalkyl)-2-phenyl-6-
phenylmethanesulphanylpurine (8, 9, 10 or 11) or 8-azapurine
(12, 13, or 14) (0.25 mmole), m-chloroperoxybenzoic acid (0.55
mmole) and dichloromethane (2.2 mL) was stirred at room tem-
perature overnight. The reaction mixture was treated with 5%
aqueous sodium bicarbonate and extracted with dichloro-
methane. The organic phase was evaporated to dryness at room
temperature to yield a solid residue which was used without
purification as soon as possible for the next reaction.
9-Phenylmethyl-2-phenyl-8-azapurine (28) [10].
A mixture of 2-phenyl-9-phenylmethyl-6-phenylmethane-
sulphonyl-8-azapurine (2 0) (0.2 mmole), 35% aqueous ammonia
(0.4 mL) and ethanol (1 mL) was stirred at 110 °C in a Pyrex vial
with stopper in place for 6 hours. The reaction mixture was worked
up as described for the previous reaction. The melting point and
nmr data of 2 8 are consistent with the literature data [10].
6
N -Cyclohexyl-2-phenyl-9-phenylmethyl-8-azapurine (29) [16].
A mixture of 20 (0.2 mmole) and cyclohexylamine (0.4 mL)
was stirred at 110 °C in a Pyrex vial with stopper in place for 6
hours. The reaction mixture was worked up as described for the
previous reaction. The melting point and nmr data of 29 are con-
sistent with the literature data [16].
9-Cyclopentyl-2-phenyladenine (22) [14].
A mixture of 15 (0.15 g, 0.36 mmole), 35% aqueous ammonia
(0.7 mL) and ethanol (2 mL) was stirred at 110 °C in a Pyrex vial
with stopper in place for 6 hours. The resulting mixture was
diluted with chloroform and washed successively with 10%
hydrochloric acid and water. The organic phase was evaporated
to obtain an oil that crystallized from ethanol. The melting point
and nmr data of 22 are consistent with the literature data [14].
9-(4-Methoxyphenylmethyl)-2-phenyl-8-azaadenine (30).
A mixture of 21 (0.2 mmole), 35% aqueous ammonia (0.4 mL)
and 2-methoxyethanol (0.5 mL) was stirred at 110 °C in a Pyrex
vial with stopper in place for 6 hours. The reaction mixture was
worked up as described for the previous reaction. Experimental
and analytical data are reported in Tables 1 and 2.
6
9-Cyclohexyl-N -(2-hydroxy-1-propyl)-2-phenyladenine (23).
A mixture of 9-cyclohexyl-2-phenyl-6-phenylmethanesulpho-
nylpurine (1 6) (0.2 mmole) and 1-amino-2-propanol (0.4 mL)
was stirred at 110 °C in a Pyrex vial with stopper in place for 5
hours. The resulting mixture was worked up as described for the
previous reaction. Experimental and analytical data are reported
in Tables 1 and 2.
6
N -Cyclohexyl-9-(4-methoxyphenylmethyl)-2-phenyl-8-azaade-
nine (31).
A mixture of 21 (0.2 mmole) and cyclohexylamine (0.4 mL)
was stirred at 110 °C in a Pyrex vial with stopper in place for 6
hours. The reaction mixture was worked up as described for the
previous reaction. Experimental and analytical data are reported
in Tables 1 and 2.
6
N -Cyclohexyl-2-phenyl-9-phenylmethyladenine (24) [15].
A mixture of 2-phenyl-9-phenylmethyl-6-phenylmethane-
sulphonylpurine (17) (0.2 mmole) and cyclohexylamine (0.4 mL)
was stirred at 110 °C in a Pyrex vial with stopper in place for 8
hours. The resulting mixture was worked up as described for the
previous reaction. The melting point and nmr data of 24 are con-
sistent with the literature data [15].
REFERENCES AND NOTES
*
To whom correspondence should be addressed: Prof. Irene
Giorgi Department of Pharmaceutical Sciences, Pisa University, via
Bonanno, 6 – 56126 Pisa; e-mail: igiorgi@farm.unipi.it; Tel. +39 050
2219549.
[1] Part of a communication to the 13th Noordwijkerhout-
Camerino Symposium, The Netherlands, 6 - 11 May 2001.
[2] N. S. Gray, S. Kwon and P. G. Schultz, Tetrahedron Lett., 38,
1161 (1997).
6
N -Cyclohexyl-9-(4-methoxyphenylmethyl)-2-phenyladenine (2 5) .
A mixture of 9-(4-methoxyphenylmethyl)-2-phenyl-6-phenyl-
methanesulphonylpurine (18) (0.2 mmole) and cyclohexylamine
(0.4 mL) was stirred at 110°C in a Pyrex vial with stopper in
place for 5 hours. The resulting mixture was worked up as
described for the previous reaction. Experimental and analytical
data are reported in Tables 1 and 2.
[3] S. Ding, N. S. Gray, Q. Ding and P. G. Schultz, J. Org. Chem.,
66, 8273 (2001).
[4] P. H. Dorff and R. S. Garigipati, Tetrahedron Lett., 42, 2771
(2001).
[5] S. Ding, N. S. Gray, Q. Ding and P. G. Schultz, Tetrahedron
Lett., 42, 8751 (2001).
[6] S. Ding, N. S. Gray, Q. Ding, X. Wu and P. G. Schultz, J.
Comb. Chem., 4, 183 (2002).
[7] R. Di Lucrezia, I. H. Gilbert and C. D. Floyd, J. Comb. Chem.,
2, 249 (2000)
[8] A thiomethyl resin is one of numerous resins commercially
available from Kokusan Chemical Works, Ltd, Japan.
[9] G. Biagi, I. Giorgi, O. Livi, V. Scartoni and A. Lucacchini, Il
Farmaco, 47,1547 (1992).
9-Cyclohexyl-2-phenyl-8-azapurine (26) [14].
A mixture of 9-cyclohexyl-2-phenyl-6-phenylmethanesulpho-
nyl-8-azapurine (19) (0.2 mmole), 35% aqueous ammonia (0.4
mL) and ethanol (1 mL) was stirred at 110°C in a Pyrex vial with
stopper in place for 6 hours. The reaction mixture was treated
with 10% hydrochloric acid and the precipitate formed was col-
lected by filtration, washed with water and dried to give com-
pound 26 which was crystallized. The melting point and nmr data
of 26 are consistent with the literature data [14].
6
N -(4-Chlorophenyl)-9-cyclohexyl-2-phenyl-8-azapurine (27).
[10] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, A. Lucacchini, C.
Martini and P. Tacchi, Il Farmaco, 49, 93 (1994).
[11] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, A. Lucacchini, C.
Martini and P. Tacchi, Il Farmaco, 49, 187 (1994).
[12] H. W. van Meeteren and H. C. van der Plas, Rec. Trav. Chim.
A mixture of 9-cyclohexyl-2-phenyl-6-phenylmethanesulpho-
nyl-8-azapurine (19) (0.2 mmole), 4-chloroaniline (80 mg, 0.63
mmole) and 2-methoxyethanol (0.5 mL) was stirred at 110 °C in
a Pyrex vial with stopper in place for 6 hours. The reaction mix-

580
G. Biagi, I. Giorgi, O. Livi, F. Pacchini, V. Scartoni and O. L. Salerni
Vol. 41
Pays-Bas, 87, 1089 (1968).
[13] G. Biagi, I. Giorgi, O. Livi, V. Scartoni and A. Lucacchini, Il
Farmaco, 52, 61 (1997).
[15] A. M. Bianucci, G. Biagi, A. Coi, I. Giorgi, O. Livi, F.
Pacchini, V. Scartoni, A. Lucacchini and B. Costa, Drug Dev. Res. 54, 52
(2001).
[16] G. Biagi, I. Giorgi, O. Livi, V. Scartoni and A. Lucacchini, Il
Farmaco, 51, 395 (1996).
[14] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, A. Lucacchini, C.
Breschi, C. Martini and R. Scatizzi, Il Farmaco, 50, 659 (1995).