New N6-substituted 8-alkyl-2-phenylmethylsulfanyl-adenines. II [1]

Article abstract of DOI:10.1002/jhet.5570410416

Title compounds bearing substituents on C(2), C(6) and C(8) were prepared from a newly synthesized pyrimidine derivative 11. The new pyrimidine 11 was generated from compound 2 through two different synthetic schemes. In one pathway, compound 2 was nitrosated, reduced and alkylated to produce compounds 9, 10 and 11 respectively (Scheme). In an alternate route using compound 2 as the starting material, a coupling reaction using the diazonium salt derived from p-methylaniline afforded the azo derivative 7, which was subsequently alkylated and reductively cleaved to form compounds 8 and 11 respectively (See Scheme). Compound 11 was annulated to the corresponding hypoxanthine derivatives 12-14; compounds 12 and 13 were chlorinated with phosphorus oxychloride, then reacted with amines to yield compound 17 and 20 respectively. Compounds 21, 22 and 23 were obtained by oxidation of the corresponding sulfide as depicted in Scheme. Alkylation of the thiol function of 1 gave a mixture of 3 and 4. Compound 3 was chlorinated to 5. Nitration of 5 resulted in electrophilic aromatic substitution of the aryl ring and concomitant oxidation of the sulfide to the sulfoxide, producing 6.

Full text of DOI:10.1002/jhet.5570410416

6
Jul-Aug 2004
581
New N -Substituted 8-Alkyl-2-Phenylmethylsulfanyl-Adenines. II [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 December 11, 2003
Title compounds bearing substituents on C(2), C(6) and C(8) were prepared from a newly synthesized
pyrimidine derivative 11. The new pyrimidine 11 was generated from compound 2 through two different
synthetic schemes. In one pathway, compound 2 was nitrosated, reduced and alkylated to produce com-
pounds 9, 10 and 11 respectively (Scheme). In an alternate route using compound 2 as the starting material,
a coupling reaction using the diazonium salt derived from p-methylaniline afforded the azo derivative 7,
which was subsequently alkylated and reductively cleaved to form compounds 8 and 11 respectively (See
Scheme). Compound 11 was annulated to the corresponding hypoxanthine derivatives 12-14; compounds 12
and 13 were chlorinated with phosphorus oxychloride, then reacted with amines to yield compound 17 and
20 respectively. Compounds 2 1, 22 and 23 were obtained by oxidation of the corresponding sulfide as
depicted in Scheme. Alkylation of the thiol function of 1 gave a mixture of 3 and 4. Compound 3 was chlo-
rinated to 5. Nitration of 5 resulted in electrophilic aromatic substitution of the aryl ring and concomitant
oxidation of the sulfide to the sulfoxide, producing 6.
J. Heterocyclic Chem., 41, 581 (2004).
In an earlier paper in this series [1] we reported the
which no product could be isolated. When 3 was treated
with phosphorus oxychloride, the corresponding dichloro
derivative 5 [13] was isolated. However, nitration of this
compound resulted in a poor yield of 6. The desired intro-
duction of a nitro group at the 5-position did not occur.
The benzylation of 1 and the nitration of 5 deserve
some comments. When we attempted to reproduce the
benzylation of pyrimidine 1 to prepare 3, as recently
described in the literature [13], we obtained the expected
S-alkylated product but we also observed a benzylation
at C(5) to form compound 4. The two compounds 3 and
4 were isolated by column chromatography and charac-
terized by a 1H nmr spectrum. The 1H nmr spectrum of 4
reveals signals at 3.52 and 4.38 δ, indicative of two sets
of methylene protons. Aromatic protons signals have a
total intensity corresponding to ten protons. In the spec-
trum of 3 a signal at 5.17 δ, attributable to a proton
bound to C(5) is present, which is lacking in that of com-
pound 4. The correct structure of 6 was assigned on the
basis of analytical data (elemental analysis, mass spec-
trum, 1H nmr spectrum). In fact, in the 1H nmr spectrum
the pattern of aromatic protons signals revealed the pres-
ence of a p-nitro substituent. The magnetic non equiva-
lence of the benzylic protons suggested they were adja-
cent to a chiral center; this chiral center could only be
the sulfur atom in an oxidation state corresponding to a
sulfoxide group. In addition, the signal attributable to H-
C(5) at 8.22 δ, clearly indicated the absence of a nitro
group in this position. Our inability to isolate a C(5)-
nitro derivative by nitration of 5 may indicate this prod-
uct is formed only in very low yield or not at all, owing
to inactivation of the pyrimidine ring bearing two elec-
tron withdrawing chlorine atoms, which is detrimental to
electrophilic substitution reactions.
synthesis of N6 substituted adenines and 8-azaadenines
by displacement of a benzylsulphonyl group at the C(6)
position. Because of our continuing interest in adenine
derivatives, we report the synthesis of 2-benzylthiolsub-
stituted adenines. The ability of the benzylthiolgroup to
act as a precursor to the benzylsulphonyl moiety as a
leaving group at C(2) position was investigated, as pre-
viously reported for this functionality on C(6) [1], but
replacement of the benzylsulphonyl function with a vari-
ety of nucleophilic amines at C(2) position was not pos-
sible. However C(2) benzylsulphanyladenines could be a
new class of ligands at P2Y purinoreceptors. Recent
reports [2-9] have identified potent P2Y purinoreceptor
agonists as derivatives of adenosine-5-monophosphate
in which an alkylthiol group is bound to C(2) as a key
structural feature.
A number of synthetic routes are available for the prepa-
ration of 2-thioalkylpurines. One scheme employs the
intact purine ring. In this methodology, a halogen of a
2-halopurine can be substituted by a thioalkyl group [10],
or the thiol function of a 2-thioxopurine can be alkylated
[11]. Alternatively, the introduction of a thioalkyl function
(by alkylation of the thiol) on a pyrimidine nucleus can be
accomplished prior to cyclization to the purine [12].
However, we elected to use the commercially available
thiobarbituric acid derivative 1 or 4-amino-thiobarbituric
acid 2 as starting products (Scheme). Initially, compound 1
was benzylated resulting in a mixture of products 3 [13]
and 4. Then we attempted an electrophilic substitution to
introduce a functional group at C(5) position which would
lead ultimately to the formation of a purine ring. For exam-
ple, compound 3, obtained by benzylation of 1, was
nitrated to produce a very complex reaction mixture from

582
G. Biagi, I. Giorgi, O. Livi, F. Pacchini, V. Scartoni and O. L. Salerni
Vol. 41
In another approach to functionalization of C(5), com-
pyrimidine [14], was transformed in a 5-nitroso derivative 9
[15], followed by nitroso group reduction to l0 [16] which,
in turn, was treated by benzylchloride to obtain 11[12].
Compound 11 was annulated to form the hypoxanthines
12-14. Hypoxanthine 12 had previously been reported by
alkylation of 6-hydroxy-2-mercaptopurine [11]. These
hypoxanthines, in turn were converted to amino deriva-
tives 17-20, by successive use of phosphorus oxychloride
and alkylamine, a procedure employed by Nugent & co-
workers [13].
pound 2 was transformed in 11 following two parallel
routes. The first concerns the treatment of 2 with the diazo-
nium salt obtained from p-methylaniline affording 7; this
reaction was followed by the alkylation of the thiol function
with benzyl chloride giving 8. Compound 8 was converted
to compound 11 by reductive cleavage of a diazo group
employing a aqueous sodium hydrosulfite solution.
Alternatively, compound 2, following a known path for the
synthesis of 5-15 N-4-amino-6-hydroxy-5-nitroso-2-thio-

New N6-Substituted 8-Alkyl-2-Phenylmethylsulfanyl-Adenines. II
Jul-Aug 2004
583
The reaction product from 12 and phosphorus oxychlo-
ride was used directly, without characterization, to pre-
pare compounds 17 and 18 by reaction with n-butylamine
and 1-amino-2-propanol respectively. Compound 18 was
previously synthesized by another route [17]. The chlo-
ride formed from the reaction of 13 and phosphorus oxy-
chloride [18] was also converted to the amino derivatives
19 and 2 0, by reaction with appropriate amines.
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 Perkin-Elmer Model 1310 spectrometer. H nmr spectra
were recorded on a Varian Gemini 200 spectrometer; chemical
shifts are expressed in δ units from TMS as an internal standard;
solvents employed are specified in the Table. Mass spectra were
performed on a Hewlett-Packard GC/MS System 5988A. TLC
Sulfonyl derivatives 21, 22 and 23, were derived from
12, 17 and 19 respectively, by treatment with a monoper-
sulfate compound (Oxone®, Aldrich). All the sulfones
showed a good stability toward nucleophilic displacement
as they were recovered unchanged after prolonged heating
with n-butylamine at 130 °C in a closed steel vial. The lack
of reactivity of 21, 22 and 23 in which the sulfonyl sub-
stituent should be a good leaving group may be explained
in the folIowing way. In basic conditions, ionization of the
weak acids lead to an anion formation. Electron delocal-
ization of the anionic structure suggests that C(2) of purine
ring in these compounds may be an electron-rich site,
therefore not conducive to nucleophilic displacement.
The structures of all the newly prepared compounds
were easily assigned upon the basis of known reaction
mechanisms and were confirmed by analytical and spec-
troscopic methods (ir, ms and lH nmr).
was performed on precoated silica gel F plates (Merck). Flash-
254
column chromatographies were performed using Merck
Kieselgel 60 (230-400 mesh). Microanalyses (C H N) were car-
ried out on a Carlo Erba elemental analyser (Model 1106) and
were within ±0.4% of the theoretical values.
4,6-Dihydroxy-2-phenylmethylsulphanyl-pyrimidine (3) [11]
and 4,6-Dihydroxy-5-phenylmethyl-2-phenylmethylsulphanyl-
pyrimidine (4).
To a solution of 4,6-dihydroxy-2-thiopyrimidine (1) (5.22 g,
36 mmoles) in 52 mL of 95% ethanol, 11.2 mL of a 3.25 N solu-
tion (36 mmoles) of sodium hydroxide was added and the result-
ing mixture was refluxed for 30 minutes. Then, 4.3 mL (36
mmoles) of benzyl bromide was added and the reaction mixture
was stirred under reflux for 2 hours. The white precipitate was
collected by filtration, washed with ice-water, ethanol and flash-
chromatographed on silica gel using chloroform-methanol 97:3
as the eluent. Both compounds 3 (4.55 g, 54%, mp >320 °C dec.
Table
1
Mass Spectra, H nmr Spectra and Elemental Analyses
1
Comp. Mass m/z
H nmr (δ,ppm)
Analyses C, H, N
Calcd./Found %
+
M (%) Base
4
324(1.1) 91
331(1) 136
DMSO-d : 7.46-7.19 (m, 12H, 10H arom + 2H exch); 4.38 (s, 2H, aliph); 3.52 (s, 2H, benzyl)
66.64 4.97
66.72 5.03
8.64
8.77
6
6
DMSO-d : 8.22 (s, 1H, arom); 8.17 (d, J=8.8 Hz, 2H, arom); 7.42 (d, J=8.8 Hz, 2H, arom)
39.93 2.22 12.43
39.78 2.12 12.65
50.56 4.24 26.80
50.31 4.35 26.65
61.52 4.88 19.93
61.53 4.71 20.05
57.34 4.44 20.57
57.19 4.29 20.73
58.72 4.93 19.57
58.52 5.09 19.77
6
4.70 (d, J=13.2 Hz, 1H, benzyl); 4.50 (d, J=13.2 Hz, 1H, benzyl)
7
DMSO-d : 12.93 (br s, 1H, exch); 10.17 (s, 1H, exch); 9.00 (br s, 1H, exch); 7.83 (d, J=8.2 Hz,
6
2H, arom); 7.30 (d, J=8.2 Hz, 2H, arom); 2.34 (s, 3H, aliph)
8
351(18) 91
270(25) 91
286(21) 91
313(38) 91
DMSO-d : 9.88 (br s, 1H, exch); 7.52 (d, 2H, arom); 7.43 (d, 2H, arom); 7.26 (m, 5H, arom);
6
4.32 (s, 2H, benzyl); 3.31 (s, 2H, exch); 2.32 (s, 3H, aliph)
DMSO-d : 7.30 (m, 5H, arom); 4.41 (s, 2H, benzyl); 3.34 (s, 1H, exch); 2.38 (s, 3H, C(8)-Me)
6
13
14
17
DMSO-d : 12.13 (br s, 1H, exch); 7.30 (m, 5H, arom); 4.42 (s, 2H, benzyl); 2.71 (q, J=7.4 Hz,
6
2H, aliph); 1.25 (t, J=7.4 Hz, 3H, aliph)
DMSO-d : 12.85 (s br, 1H, exch); 7.96 (s 1H, C(8)-H); 7.79 (br, 1H, exch); 7.42 (m, 2H, arom); 61.31
6
6.11 22.34
4.37 (s, 2H, benzyl); 3.42 (m, 2H, aliph); 1.53 (m, 2H, aliph); 1.32 (m, 2H, aliph);
0.88, (t, J=7.2 Hz, 3H, aliph)
61.55 5.99 22.49
18
19
20
315 (22) 91
327(36) 91
304(10) 91
DMSO-d : 12.80 (s, 1H, exch); 8.05 (m, 1H, exch); 7.97 (s br, 1H, C(8)-H); 7.42 (m, 2H, arom); 57.12 5.43 22.21
6
7.29 (m, 3H, arom); 4.36 (s, 2H, benzyl); 3.83 (m,1H, aliph)¸ 3.39 (m, 2H, aliph);
1.05 (d, J=6.4 Hz, 3H, aliph)
56.92 5.55 19.98
DMSO-d : 12.48 (s, 1H, exch); 7.61 (s, 1H, exch); 7.46 (m, 2H, arom); 7.30 (m, 3H, arom);
4.35 (s, 2H, benzyl); 3.42 (m, 2H, aliph); 2.38 (s, 3H, C(8)-Me); 1.53 (m, 2H, aliph); 1.29 (m,
2H, aliph); 0.86 (t, J=5.2 Hz, 3H, aliph)
62.36 6.46 21.39
62.11 6.59 21.48
6
DMSO-d :12.52 (s, 1H, exch), 7.41 (m, 2H, arom); 7.28(m, 3H, arom); 4.76 (m, 1H, exch),
4.34 (s, 2H, benzyl); 3.83 (m, 1H, aliph); 3.39 (m, 2H, aliph) 2.38 (s, 3H, C(8)-Me); 1.04 (d,
J=6.4 Hz, 3H, aliph)
58.34 5.58 21.26
58.01 5.62 21.49
6
21
22
23
DMSO-d : 13.75 (s br, 1H, exch); 8.46 (s, 1H, C(8)-H); 7.34 (m, 5H, arom); 4.95 (s, 2H,
benzyl); 3.45 (s, br 1H, exch)
49.65 3.47 19.30
49.78 3.68 19.52
55.63 5.54 20.27
55.30 5.24 19.99
56.81 5.89 19.48
57.09 6.21 19.24
6
345(1) 91
DMSO-d : 8.33 (m, 1H, exch); 8.32 (s 1H, C(8)-H); 7.29 (m, 5H, arom); 4.85 (s, 2H, benzyl);
6
3.48 (m, 2H, aliph); 1.59 (m, 2H, aliph); 1.37 (m, 2H, aliph); 0.89 (t, J=7.2 Hz, 3H, aliph)
DMSO-d : 8.17 (m, 1H, exch); 7.30 (m, 5H, arom); 4.82 (s, 2H, benzyl); 3.42 (m, 2H, aliph);
6
2.45 (s, 3H, C(8)-Me); 1.56 (m, 2H, aliph); 1.32 (m, 2H aliph); 0.85 (t, J=7.2 Hz, 3H, aliph)

584
G. Biagi, I. Giorgi, O. Livi, F. Pacchini, V. Scartoni and O. L. Salerni
Vol. 41
[ 11]), and 4, an oil, (4.19 g, 36% yield) were obtained.
Analytical and spectral data are reported in the Table.
utes, then 1.96 g (15.6 mmoles) of benzyl chloride was added and
the resulting mixture was heated under reflux. When the pH of
mixture was 7 the heating was discontinued. The white precipitate
afforded 11 (2.9 g, 70%, mp 180 °C. Lit. [12] 185-187 °C).
4,6-Dichloro-2-phenylmethylsulphanyl-pyrimidine (5) [11].
A mixture of 2.6 g (11 mmoles) of 3, N,N-diethylaniline (4
mL) and phosphorus oxychloride (11.4 mL) was stirred under
reflux at 90 °C for 2 hours. After evaporation, the mixture was
treated with ice and the aqueous phase was extracted with ethyl
acetate. The organic phase was flash-chromatographed on silica
gel using n-hexane-toluene 1:1 as the eluent to give pure com-
pound 5 as an oil (2.2 g, 72%).
2-Phenylmethylsulphanylhypoxanthine (12).
To a mixture of triethyl orthoacetate (28.2 g, 0.17 mole) and 12
N HCl (0.14 mL), compound 11 (4.6 g, 18 mmoles) was added.
The reaction mixture was stirred at room temperature for 12
hours. The precipitate was crystallized from ethanol-n-hexane to
give pure compound 12 (3.2 g, 70%, mp >300 °C. Lit. [11] mp
>300 °C).
4,6-Dichloro-2-(p-nitrophenyl)-methylsulphinyl-pyrimidine (6).
2-Phenylmethylsulphanyl-8-methylhypoxanthine (13).
96% Nitric acid (2.15 mL) was added slowly to 0.54 g (2.0
mmoles) of 5 cooled in an ice-bath at 0-5 °C. After the addition
was complete, the reaction mixture was stirred to a room temper-
ature for 1 hour. Addition of ice afforded 6 (0.59 g, 90%).
Analytical and spectral data are reported in the Table.
To a mixture of triethyl orthoacetate (28.2 g, 0.17 mole) and
acetic anhydride (17.7 g, 0.17 mole), compound 11 (4.6 g, 18
mmoles) was added. The reaction mixture was stirred at 120 °C
for ninety minutes and the precipitate gave pure compound 13
(2.2 g, 44%, mp 240 °C). Analytical and spectral data are
reported in the Table.
4-Amino-6-hydroxy-2-thio-5-p-toluenazopurine (7).
Solution A was prepared by addition of a solution of sodium
nitrite (2.8 g, 40 mmoles) in 40.2 mL of water to a solution of
p-toluidine (4.3 g, 39 mmoles) in 11.8 mL of 37% hydrochloric
acid. Separately, solution B, consisting of 3.8 g (26 mmoles) of 2 in
12 mL of 2.4 N sodium hydroxide was prepared and cooled to 0-5
°C. Solution A, cooled to 0 °C in an ice-bath, was added dropwise
to iced solution B and the reaction mixture was stirred at 0 °C for 1
hour. The orange mixture obtained was treated with hydrochloric
acid until the pH reaches 3 or 4; and the red solid obtained was col-
lected by filtration and dried to give 7 (6.5 g, 98%, mp 280 °C).
Analytical and spectral data are reported in the Table.
2-Phenylmethylsulphanyl-8-ethyl-hypoxanthine (14).
To a mixture of triethyl orthopropionate (6.2 g, 35 mmoles)
and acetic anhydride (3.8 g, 37 mmoles), compound 11 (1.0 g, 18
mmoles) was added. The reaction mixture was stirred at 120 °C
for ninety minutes and the precipitate gave pure compound 14
(2.3 g, 45%, mp 130 °C). Analytical and spectral data are
reported in the Table.
6-Chloro-2-phenylmethylsulphanylpurine (1 5) and 6-Chloro-2-
phenylmethyl-sulphanyl-8-methylpurine (16).
To a mixture of 12 or 13 (4.0 mmoles) and N,N-diethylaniline
(0.60 g, 40 mmoles), phosphorus oxychloride (6.1 g, 40 mmoles)
was added and the resulting mixture was stirred at 110 °C for 5
hours. After evaporation the residue was used for the next reac-
tion without purification.
4-Amino-2-phenylmethylsulphanyl-6-hydroxy-5-p-toluenazo-
pyrimidine (8).
A solution of 7 (1.00 g, 38 mmoles), 1.2 mL of water, 0.15 g
(38 mmoles) of sodium hydroxide and 6 mL of ethanol was
heated for few minutes. Then benzyl chloride (4.8 g, 38 mmoles)
was added. The resulting mixture was stirred under reflux until
pH was 7. The yellow precipitate was filtered and dried to give 8
(0.9 g, 70%, mp 235 °C). Analytical and spectral data are
reported in the Table.
6
2-Phenylmethylsulphanyl-N -substitutedadenines (17, 18).
A mixture of 15 (17 mmoles), an appropriate amine (34
mmoles) and ethanol (1 mL) was stirred at 120 °C in a steel vial
for 5 hours. The residue obtained was crystallized from ethanol to
give 17 (0.48 g, 90%, mp 240 °C, the literature [17] reports melt-
ing point 250 °C) or 18 (0.48 g, 90% yield, mp 150 °C dec).
Analytical and spectral data are reported in the Table.
4-Amino-6-hydroxy-5-nitroso-2-thiopyrimidine (9).
A solution of 5 (2.28 g, 15 mmoles) in 65 mL of 1 N
hydrochloric acid was cooled to 0 °C. A solution of sodium
nitrite (1.20 g, 17 mmoles) in 6 mL of water was added dropwise.
The resulting red suspension was stirred for 7 hours. The precipi-
tate obtained was washed with ice-water, ethanol and acetone to
give 9 (2.3 g, 87%, mp 270 °C dec. Lit.[12]>240 °C )
6
2-Phenylmethylsulphanyl-N -substituted-8-methyladenine (1 9,
20).
A mixture of 16 (17 mmoles), an appropriate amine (34
mmoles) and ethanol (1 mL) was stirred at 120 °C in a steel vial
for 5 hours. The residue obtained was crystallized from ethanol to
give 19 (0.48 g, 85% yield, mp 175 °C) or 20 (0.5 g, 90% yield,
mp 245 °C) Analytical and spectral data are reported in the Table.
4,5-Diamino-6-hydroxy-2-thiopyrimidine (10).
To a solution of 9 (5.3 g, 31 mmoles) in 120 mL of 1 N sodium
hydroxide (12.2 g, 0.11 mole), sodium hydrosulfite (12.25 g, 0.11
mole) was added and the mixture was stirred at room temperature
for 20 hours. The white solid afforded compound 10 (4.66 g,
96%, mp>350 °C. Lit.[12]mp>240 °C).
2-Phenylmethylsulphonyl-8-methylhypoxantine (21).
A mixture of 12 (2.72 g, 10 mmoles) in methanol (40 mL) was
®
cooled to 0 °C, and a solution of 18.45 g of Oxone in 40 mL of
water was added. The resulting mixture was stirred at room tem-
perature for 4 hours and then diluted with water to obtain a white
precipitate that was collected by filtration and dried to give 21
(1.5 g, 50%, mp 268 °C). Analytical and spectral data are
reported in the Table.
4,5-Diamino-2-phenylmethylsulphanyl-6-hydroxy-pyrimidine
(11).
A mixture of 10 (2.50 g, 16 mmoles), 0.62 g. of sodium hydrox-
ide, 5 mL of water and 6 mL of ethanol was heated for a few min-

New N6-Substituted 8-Alkyl-2-Phenylmethylsulfanyl-Adenines. II
Jul-Aug 2004
585
6
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2-Phenylmethylsulphonyl-N -substituted-8-methyladenines (2 2,
23).
A mixture of 17 or 19 (1.1 mmoles) in 4 mL ethanol) was
®
cooled to 0 °C, and a solution of Oxone (2.0 g in 4 mL of water)
added. The resulting mixture was stirred at room temperature for
12 hours and then diluted with water to obtain a white precipitate
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Tel. +39 050 2219549 Fax +39 050 2219605.
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1
[18] H Nmr spectrum for 2-phenylmethyl-6-chloro-8-methyl-
adenine in DMSO-d : 7.46 (m, 2H, arom); 7.30 (m, 3H, arom); 4.42
(s, 2H, benzyl); 2.55 (s, 3H, aliph).
[6] Q. Ai-Dong, A. C. Zambon, P. A. Insel and R. A. Nichols,
Mol. Pharm., 60, 1375 (2001).
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