New C(2)-substituted 8-alkylsulfanyl-9-phenylmethyl-hypoxanthines III

Article abstract of DOI:10.1002/jhet.5570420501

Title compounds were obtained starting from the key imidazole intermediate, 5-amino-1-phenylmethyl-2-mercapto-1H-imidazole-4-carboxylic acid amide 5, readily derived from the base catalyzed rearrangement of a thiazole, 5-amino-2-phenylmethylaminothiazole-4-carboxylic acid amide 4. Alkylation of the thiol function on 5 with phenylmethyl and allylic chlorides gave compounds 6 and 7 respectively. Cyclization of 6 with a variety of esters afforded 8-phenylmethylthiohypoxanthines, 8-11. Similarly, 7 was cyclized to 8-allylthiohypoxanthines, 20-21. Compound 5 was also cyclized, but formed 8-mercaptohypoxanthines, 22-24. Alkylation of 8-mercaptohypoxanthines afforded 8-alkylthiohypoxanthines, 8, 9, 25 and 26 (see Scheme 2). Chlorination of 9-11 afforded 16-18; adenine 19 was derived from 16. Oxidation of hypoxanthines 8-11 with m-chloroperbenzoic acid gave the corresponding 8-phenylmethylsulfonyl derivatives 12-15. These derivatives proved resistant to nucleophilic displacement reactions with primary amines.

Full text of DOI:10.1002/jhet.5570420501

Jul-Aug 2005
743
New C(2)-Substituted 8-Alkylsulfanyl-
9-phenylmethyl-hypoxanthines III
a
a
a
a
Giuliana Biagi , Irene Giorgi *, Oreste Livi , Federica Pacchini , Oreste LeRoy
b
a
Salerni , and Valerio Scartoni
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 March 4, 2004
Title compounds were obtained starting from the key imidazole intermediate, 5-amino-1-phenyl-
methyl-2-mercapto-1H-imidazole-4-carboxylic acid amide 5, readily derived from the base catalyzed
rearrangement of a thiazole, 5-amino-2-phenylmethylaminothiazole-4-carboxylic acid amide 4. Alkylation
of the thiol function on 5 with phenylmethyl and allylic chlorides gave compounds 6 and 7 respectively.
Cyclization of 6 with a variety of esters afforded 8-phenylmethylthiohypoxanthines, 8-11. Similarly, 7 was
cyclized to 8-allylthiohypoxanthines, 20-21. Compound 5 was also cyclized, but formed 8-mercaptohypox-
anthines, 22-24. Alkylation of 8-mercaptohypoxanthines afforded 8-alkylthiohypoxanthines, 8, 9, 25 and 26
(see Scheme 2). Chlorination of 9-11 afforded 16-18; adenine 19 was derived from 16. Oxidation of hypox-
anthines 8-11 with m-chloroperbenzoic acid gave the corresponding 8-phenylmethylsulfonyl derivatives 12–
15. These derivatives proved resistant to nucleophilic displacement reactions with primary amines.
J. Heterocyclic Chem., 42, 743 (2005).
In previous papers in this series [1,2], we reported the
methylsulfanyl-1,9-dihydropurine-6-one, B [3], 6-
(dimethylamino)-9-(4-methylphenylmethyl)-8-
methylthio-2-(trifluoromethyl)-9H-purine C [4] and 8-
(phenylmethylthio)-6-dimethylamino-9-(4-methylphenyl-
methyl)-2-(trifluoromethyl)-9H-purine D [4] are known.
Other tetrasubstituted purines are known but they have the
2-alkylthio group at the 2 position, not the 8 position [2
and references cited therein].
We have devised a synthetic pathway to produce new 8-
alkylthiopurines with additional substituents in the 2, 6,
and 9-positions. The various substituents at these sites are
intended to explore possible interactions with a diverse
array of purinoreceptors.
preparation of polysubstituted purine derivatives with a
phenylmethylsulfanyl group attached to the 2 or the 6 posi-
tion. The sulfides were synthesised as potential precursors
to the corresponding 2-amino and 6-aminopolysubstituted
purines after their oxidation to sulfones. In this paper, a
logical extension to our earlier studies, we wish to report a
synthetic route to 8-alkylsulfanylpolysubstituted purines A
as depicted in Figure 1.
A literature survey reveals few examples of known
structures as depicted in Figure 1. Only 2,9-dimethyl-8-
Inspection of the retrosynthetic pathway displayed in
Figure 2, clearly indicates that an imidazole derivative
with a thiol function in the 2-position H, would be an ideal
starting point for the synthesis of polysubstituted purines E
having a thioether at the 8-position.
Further, imidazoles G or H could be annulated to F
(R =H or alkyl) trying the Yamazaki reaction conditions
3

744
G. Biagi, I. Giorgi, O. Livi, F. Pacchini, O. L. Salerni, and V. Scartoni
Vol. 42
[5] which, to date, have never been applied to the synthesis
of compounds F.
The base catalyzed rearrangement of suitably substi-
tuted thiazoles to imidazoles was described by Cook et
al. [6] and Sen et al. [7]. Cook at al. reported that 5-
amino-2-methylamino or 2-allylamino-thiazole-4-car-
unstable and was used immediately on preparation. So,
to an ethereal solution of 2, cooled to -18 °C in a steel
vial, ammonia dissolved in ethanol was added. Under
these conditions, the amide 3 [8] was obtained in good
yield. In contrast, we attempted to obtain 3 in a more
direct approach involving only two steps. 2-
Cyanoacetamide was nitrosated using identical condi-
tions employed for the nitrosation of ethyl cyanoacetate
[9]. But subsequent reductions with sodium hydrosul-
fite, or freshly prepared aluminum amalgam, or hydro-
genation at 3 atm with Raney nickel [9] did not give a
satisfactory yield of 3. The reaction of 3 with phenyl-
methylisothiocyanate gave the N-phenylmethylthiazole
derivative 4 [7]. This product was initially insoluble in
5% sodium carbonate solution, but after heating for a
brief time, was converted to a soluble product 5 via
rearrangement, which was isolated upon neutralization
with hydrochloric acid. We also discovered that the thi-
azole 4 can be converted directly to compounds 6 and 7,
without isolation of the intermediate thiol 5, by addition
of sodium hydroxide and the appropriate alkylating
agent to the reaction mixture (Scheme 1).
Cyclization of compounds 6 and 7 (Scheme 2) to form
the purine nucleus was performed according to the
Yamazaki procedure [5] by use of sodium ethoxide and
a variety of esters. The base catalysis activated the
amino group in the 5-amino-1-benzyl-2-thioxo-2,3-
dihydro-1H-imidazole-4-carboxamide that reacted with
the carbonyl group of the ester which looses ethoxide
ion. Subsequently intramolecular cyclization occured
between the 4-carboxamide group and the acylamino
group formed with elimination of water. All these reac-
tions produced 8-alkylthiopolysubstituted hypoxan-
thines, 8-11 and 20, 21. Chlorination of 9-11 afforded
16-18; these compounds are instable and soon decom-
posed; from 16, the adenine 19 was derived by immedi-
ate treatment with p-methoxyphenylmethylamine.
Oxidation of hypoxanthines 8-11 with m-chloroperben-
zoic acid gave the corresponding 8-phenylmethylsul-
fonyl derivatives 12-15. These derivatives proved resis-
tant to nucleophilic displacement reactions with
primary amines.
boxamide I (R =CH or CH =CHCH ), prepared from
4
3,
2
2
2-amino-2-cyanoacetamide and methyl or allyl isothio-
cyanato, can be transposed to 1-methyl or 1-allyl-5-
amino-2-thioxo-2,3-dihydro-1H-imidazole-4-carbox-
amide H (R = CH or CH =CHCH ) [6]. Sen et al.,
4
3
2
2
instead, described the condensation of 2-amino-2-
cyanoacetamide with 3-diethylamino-propyl-1-isothio-
cyanate to the corresponding 2-thioxoimidazol H
(R=(CH ) N(CH ) CH ) [7]. To expand the scope of
3 2
2 2
3
the base-catalyzed rearrangement, we placed the thia-
zole 4, a phenylmethyl analog of I in an alkaline envi-
ronment, which permitted the realization of the phenyl-
methyl derivative of the imidazole 5 [7] (Scheme 1).
The latter, on reaction with phenylmethyl and allyl
halides formed 6 and 7 respectively. Thiazole 4 was pre-
pared starting from ethyl cyanoacetate which was
nitrosated in a solution whose pH was controlled, to
obtain the hydroxyimino derivative 1 (Aldrich Chem.
Co.). Reduction of the oxime to the primary amine 2
was carried out with sodium hydrosulfite in a saturated
solution of sodium bicarbonate [8]. Compound 2 proved
Compound 5 was annulated with sodium ethoxide and
various esters to form 8-mercaptopolysubstituted hypox-
anthines, 22-24. The alkylation of 22 and 23 on the HS-
C(8) function formed 8-alkylthiopolysubstituted hypoxan-
thines 8 and 9 or 25 and 26; benzyl bromide to 8 and 9 or
hexyl bromide to 25 and 26 in the presence of 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) were used.
Chemical structures of the intermediates and final com-
pounds were assigned on the basis of the well known
mechanism of the reactions carried out and were con-
1
13
firmed by their ms, ir, H and C nmr spectra which were

Jul-Aug 2005
New C(2)-Substituted 8-Alkylsulfanyl-9-phenylmethyl-hypoxanthines III
745
Scheme 2
13
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 2 and 3.
Mass spectra were performed with a Hewlett Packard GC/MS
consistent with the proposed structures. C nmr spectra of
the compounds 8-15 and 19-26 evidenced in the 165-118 δ
region the five signals attributable to purine nucleus car-
bon atoms and the signals attributable to phenyl carbons;
the signals between 99 and 11 δ are due to other carbon
atoms as specified in Table 3. Infrared spectra (Table) of
same compounds showed a carbonyl absorption in the
System 5988A. TLC was performed on precoated silica gel F
254
plates (Merck). Microanalyses (C H N) were carried out on a
Carlo Erba elemental analyser (Model 1106) and were within
±0.4% of the theoretical values.
-1
1676-1699 cm region, typical of hypoxanthine deriva-
tives. Molecular mass of compounds 5-7 were confirmed
by their ms spectra. Finally, H nmr spectra of all synthe-
5-Amino-2-mercapto-1-phenylmethyl-1H-imidazole-4-car-
boxylic Acid Amide (5).
1
The product was prepared as described in the literature [5] for
the alkaline catalyzed rearrangement of the thiazole ring to an
imidazole nucleus. A 10% solution of sodium carbonate (300
mL) was added to 5-amino-2-phenylmethylamino-thiazole-4-
carboxylic acid amide (4) (10.4 g, 0.042 mole) and the mixture
was stirred under reflux until complete dissolution of the starting
product (about 30 minutes). After cooling, the solution was neu-
tralized with hydrochloric acid. The solid precipitated was col-
lected by filtration: yield 70%, m.p. 240 °C (lett.242-243°C). See
Table 2 for nmr and ms data.
sized compounds (5-26) were consistent with the structure
assigned.
EXPERIMENTAL
Melting points were determined on a Kofler hot-stage appara-
tus and are uncorrected; ir spectra in Nujol mulls were recorded
1
13
on a ATI Mattson Genesis Series FTIR spectrometer. H and
C

746
G. Biagi, I. Giorgi, O. Livi, F. Pacchini, O. L. Salerni, and V. Scartoni
Vol. 42
Table 1
Chemical and physical properties of the compounds 6-26.
Compound
Yield %
Cryst. solvent
M.p.(°C)
Rf
Formula
Analyses C, H, N
Calc. % / Found %
6
60/70[a]
90% Ethanol
Ethanol
150
115
0.30[§]
0.11[§]
0.30[§]
0.15[§]
0.46[§]
0.40[§]
0.14[§]
0.20[§]
0.30[§]
0.40[§]
0.43[§]
0.50[†]
0.77[†]
0.69[§]
0.13[§]
0.10[§]
0.17[§]
C18H18N4OS
C14H16N4OS
C19H16N4OS
C21H20N4OS
C24H26N4O3S
C25H20N4OS
C19H16N4O3S
C21H20N4O3S
C24H26N4O5S
C25H20N4O3S
C21H19ClN4S
C24H25ClN4O2S
C25H19ClN4S
C29H29N5OS
C15H14N4OS
C17H18N4OS
C12H10N4OS
C14H14N4OS
C17H20N4O3S
C18H22N4OS
C20H26N4OS
63.88 5.36 16.56
63.86 5.13 16.28
58.31 5.59 19.43
58.18 5.55 19.20
65.50 4.63 16.08
65.21 4.58 15.86
67.00 5.35 14.88
66.83 5.14 14.68
63.98 5.82 12.44
63.70 5.76 12.17
70.73 4.75 13.20
70.59 4.65 13.04
59.99 4.24 14.73
60.14 4.48 14.89
61.75 4.94 13.72
61.51 4.67 13.44
59.74 5.43 11.61
59.91 5.66 11.72
65.77 4.42 12.27
65.48 4.33 12.14
63.87 4.85 14.19
63.98 4.95 14.23
61.46 5.37 11.95
61.63 5.54 11.80
67.79 4.32 12.65
67.84 4.41 12.52
70.27 5.90 14.13
70.40 5.99 14.21
60.38 4.73 18.78
60.13 4.59 18.72
62.55 5.56 17.16
62.28 5.50 17.08
55.80 3.90 21.69
55.62 3.86 21.45
58.72 4.93 19.57
58.54 4.66 19.40
56.65 5.59 15.54
56.37 5.50 15.28
63.13 6.48 16.36
62.88 6.33 16.25
64.83 7.07 15.12
64.55 6.85 15.01
7
65/75[b]
65/50[c]
89/70[d]
60
8
Ethanol
214-216
207-209
167
9
Ethanol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Ethanol
52
Ethanol
243
65
Isopropanol
Isopropanol
Isopropanol
Isopropanol
Ethanol
198-200
132-135
150
70
65
60
260
50
106-108
150
54
Ethanol
52
Ethanol
175
95
Ethanol
103-105
237
58
Ethanol
62
Ethanol
200-201
313-315
70
Ethanol
68
Ethanol
335 (dec.) 0.11[§]
65
Ethanol
215
120
0.13[§]
0.15[§]
0.16[§]
45
Isopropanol
Isopropanol
70
165-167
[a] Yield 60% starting from 5, yield 70% starting from 4; [b] Yield 65% starting from 5, yield 75% starting
from 4; [d] Yield 89% starting from 7, yield 70% starting from 23; [§] eluent: chloroform-methanol 10:0.5;
[†] eluent: chloroform.
5-Amino-1-phenylmethyl-2-substitutedsulfanyl-1H-imidazole-4-
carboxylic Acid Amides 6 and 7.
a clear solution was obtained. After cooling, phenylmethyl or
allyl chloride (0.084 mole) was added and the mixture stirred for
1 h at room temperature. The solid obtained was (compound 6 or
7) was collected by filtration and washed with water and ethyl
ether, then crystallized. See Table 1 for yields, crystallization sol-
vent, physicochemical properties and elemental analysis; see
Table 2 for nmr and ms data.
Method A.
The appropriate chloride, phenylmethyl or allyl, (0.034 mole)
was added to a solution of 5-amino-1-phenylmethyl-2-mercapto-
1H-imidazole-4-carboxylic acid amide 5 (2.9 g, 0.017 mole) in 1
N sodium hydroxide (12 mL). The reaction mixture was stirred at
room temperature for 1 hour. The solid obtained (compound 6 or
7) was filtered and washed with water and ethyl ether, then crys-
tallized. See Table 1 for yields, crystallization solvent, physico-
chemical properties and elemental analysis; see Table 2 for nmr
and ms data.
9-Phenylmethyl-8-substitutedsulfanyl-1,9-dihydropurin-6-one
(8, 20) and 9-Phenylmethyl-2-substituted-8-substitutedsulfanyl-
1,9-dihydropurin-6-one (9-11, 21).
5-Amino-1-phenylmethyl-2-substitutedsulfanyl-1H-imida-
zole-4-carboxylic acid amide (6) or (7) (1.47 mmoles) was added
to a solution prepared from sodium (0.23 g, 0.01 mole) dissolved
in 8.5 mL of absolute ethanol. The mixture was refluxed with
stirring for 1 hour. Then a solution of the appropriate ester (7.5
mmoles) in 5 mL of ethanol was added dropwise and the solution
was stirred under reflux for 48 hours. After cooling, ice was
Method B.
5-Amino-2-phenylmethylamino-thiazole-4-carboxylic acid
amide (4) (10.4 g, 0.042 mole) was added to a solution of 1 N
sodium hydroxide (300 ml) and the mixture heated at 80 °C until

Jul-Aug 2005
New C(2)-Substituted 8-Alkylsulfanyl-9-phenylmethyl-hypoxanthines III
747
Table 2
Spectroscopic data of the compounds 5-26.
Compound
(solvent)
ms (m/z, %)
ir cm-1 (C=O)
1H nmr ( , ppm)
aromatic H
benzylic H
aliphatic H
exch. H
5
248 (M+, 10)
338 (M+, 5.7)
288 (M+, 7)
7.30 (m, 5H + 2H exch) 5.23 (s, 2H)
6.12 (br s, 1H)
6.90 (br s, 2H)
7.30 (br s, 2H)
5.10 (br s, 1H)
6.70 (br s, 1H)
(DMSO-d6)
6
6.94 (m, 2H)
7.12 (m, 2H)
7.28 (m, 6H)
7.14 (m, 2H)
7.36 (m, 3H)
4.09 (s, 2H, S-CH2)
4.72 (s, 2H, N-CH2 +
2H exch)
5.14 (s, 2H, N-CH2 +
2H exch)
(CDCl3)
7
5.05 (d, 2H, SCH2 J= 9.4 Hz)
5.85 (m, 1H, CH=CH2)
3.51 (d, 2H, CH=CH2, J= 7.4Hz)
4.79 (br s, 2H)
(CDCl3)
8
1683
1676
7.28 (m, 10H)
8.04 (s, 1H)
7.28 (m, 10H)
4.62 (s, 2H, S-CH2)
5.24 (s, 2H, N-CH2)
4.56 (s, 2H, S-CH2)
5.21 (s, 2H, N-CH2)
12.96 (br s, 1H)
12.01 (br s, 1H)
(CDCl3)
9
1.34 (t, 3H, CH2CH3, J=7.6 Hz)
2.32 (q, 2H, CH2CH3, J=7.6 Hz)
(CDCl3)
10
1683
1678
7.29 (m, 10H)
4.60 (s, 2H, S-CH2)
5.22 (s, 2H, N-CH2)
1.27 (t, 6H, CH2CH3, J=7.0 Hz)
3.68 (m, 4H, O-CH2CH3)
5.37 (s, 1H, CHO(Et)2)
9.72 (br s, 1H)
10.85 (br s, 1H)
(CDCl3)
11
7.31 (m, 10H)
7.58 (m, 3H)
8.12 (m, 2H)
4.60 (s, 2H, S-CH2)
5.29 (s, 2H, N-CH2)
(CDCl3)
12
(CDCl3)
13
1684
1685
1689
7.28 (m, 10H+ H exch.) 4.76 (s, 2H, SO2-CH2)
8.24 (s,1H)
7.32 (m, 10H)
5.49 (s, 2H, N-CH2)
4.70 (s,2H, SO2-CH2)
5.43 (s, 2H, N-CH2)
4.87 (s,2H,SO2-CH2)
5.30 (s, 2H, N-CH2)
1.41 (t, 3H, CH2-CH3, J=7.4 Hz)
2.92 (q, 2H, CH2-CH3, J=7.4 Hz)
1.14 (t, 6H, CH2-CH3, J=6.8 Hz)
3.62 (m, 4H, CH2-CH3)
12.24 (br s, 1H)
12.62 (br s, 1H)
(CDCl3)
14
7.26 (m, 10H)
(DMSO-d6)
5.33 (s, 1H, CH(OEt)2)
15
1698
8.12 (m, 2H)
7.54 (m, 3H)
7.25 (m, 10H)
7.30 (m, 10H)
4.87 (s,2H,SO2-CH2)
5.30 (s, 2H, N-CH2)
12.75 (br s, 1H)
(DMSO-d6)
16
(CDCl3)
17
4.66 (s, 2H, SO2-CH2) 1.40 (t, 3H, CH2-CH3, J=7.6 Hz)
5.30 (s, 2H, N-CH2)
4.59 (s, 2H, S-CH2)
5.22 (s, 2H, N-CH2)
3.04 (q, 2H, CH2-CH3, J=7.6 Hz)
1.29 (t, 6H, CH2CH3 , J=7.2 Hz)
3.68 (m, 4H, O-CH2CH3)
7.28 (m, 10H)
(DMSO-d6)
5.35 (s, 1H, CHO(Et)2)
18
8.53 (m, 2H)
4.70 (s, 2H, S-CH2)
5.38 (s, 2H, N-CH2)
5.17 (s, 2H, N-CH2)
4.47 (s, 2H, S-CH2)
(CDCl3)
19
7.36 (m, 13H)
7.13-7.34 (m, 12H)
6.85 (d, 2H)
1693
1685
1.22 (t, 3H, CH2CH3, J=7.6 Hz)
2.67 (q, 2H, CH2CH3, J=7.6 Hz)
8.05 (br s, 1H)
(DMSO)
3.31 (d, 2H, CH2-NH) 3.70 (s, 3H, OCH3)
5.27(s, 2H, N-CH2) 3.99 (d, 2H, CH=CH2, J=7.2 Hz)
20
7.97 (s, 1H)
7.27 (m, 5H)
(CDCl3)
4.70 (d, 2H, SCH2, J=5.6 Hz)
5.90 (m, 1H, CH=CH2)
added and then the mixture was neutralized with 50% acetic acid.
The precipitate that formed was collected by filtration and crys-
tallized. See Table 1 for yields, crystallization solvent, physico-
chemical properties and elemental analysis; see Table 2 and 3 for
ir and nmr data.
6-Chloro-9-phenylmethyl-8-phenylmethylsulfanyl-2-substituted-
1H-purine (16-18).
A mixture 9 (or 10 or 11) (0.015 mole), chloroform (76 mL),
N,N-dimethylformamide (2.9 mL) and thionyl chloride (13.2
mL) was heated slowly up to 70 °C, and then refluxed with stir-
ring for 2 hours. The reaction mixture was evaporated in vacuo at
a temperature maintained below 35 °C. The residue was triturated
with ethyl ether, fliltered and crystallized from ethanol. See Table
1 for yields, crystallization solvent, physicochemical properties
and elemental analysis; see Table 2 for nmr data.
9-Phenylmethyl-8-phenylmethanesulfonyl-1,9-dihydropurin-6-
one (12) and 9-Phenylmethyl-2-substituted-8-phenylmethanesul-
fonyl-1,9-dihydropurin-6-one (13-15).
A mixture of 8 (or 9 or 10 or 11) (2.6 mmoles) and meta-
chloroperoxybenzoic acid (5.2 mmoles) in dichloromethane (20
ml) was stirred at room temperature overnight. The reaction mix-
ture was treated with 5% sodium bicarbonate and extracted with
dichloromethane. The organic phase was evaporated in vacuo to
obtain a white solid which was purified by crystallization. See
Table 1 for yields, crystallization solvent, physicochemical proper-
ties and elemental analysis; see Table 2 and 3 for ir and nmr data.
(2-Ethyl-9-phenylmethyl-8-phenylmethylsulfanyl-1H-purin-6-
yl)-(4-methoxy-phenylmethyl)-amine (19).
To a mixture consisting of 6-chloro-2-ethyl-9-phenylmethyl-8-
phenylmethylsulfanyl-1H-purine (16) (0.60 g, 1.52 mmoles), p-
methoxyphenylmethylamine (0.42 g, 3.04 mmoles), and absolute

748
G. Biagi, I. Giorgi, O. Livi, F. Pacchini, O. L. Salerni, and V. Scartoni
Vol. 42
Table 3
13C nmr data ( , ppm, DMSO-d6) of the compounds 8-15 and 19-26.
Compound
Purine and phenyl carbons
Others
8
155.3; 149.9; 146.3; 145.3; 136.8; 135.6; 128.7; 128.5; 128.3;
127.6; 127.3; 127.0; 123.9
45.8 (CH2-N); 35.9 (CH2-S)
9
159.2; 156.1; 150.4; 145.6; 137.0; 135.8; 128.9; 127.7; 127.4;
127.3; 118.3
45.7 (CH2-N); 35.9 (CH2-S); 27.4 (CH2); 11.6 (CH3)
10
11
12
13
14
15
19
20
21
156.3; 154.0; 150.2; 147.6; 137.6; 136.4; 129.6; 129.3; 129.1;
128.5; 128.1; 127.9; 124.2
156.9; 153.4; 151.1; 147.6; 137.7; 136.6; 132.8; 132.0; 129.6;
129.4; 129.2; 128.5; 128.4; 128.2; 128.1; 123.4
166.0; 156.3; 148.9; 143.0; 135.7; 131.3; 129.0; 128.8; 128.5;
127.9; 127.8; 127.0; 123.7
162.7; 156.9; 149.9; 142.6; 135.8; 131.3; 128.9; 128.7; 128.5,
127.8; 127.3; 126.6; 120.9
156.6; 156.5; 149.0; 143.3; 135.7; 131.3; 128.9; 128.5; 128.4;
127.8: 127.2; 126.5; 123.1
99.3 (O-CH-O); 63.1 (CH2-O); 46.6 (CH2-N); 36.7 (CH2-
S); 15.7 (CH3)
46.6 (CH2-N); 36.7 (CH2-S)
60.5 (CH2-SO2); 47.1 (CH2-N)
60.5 (CH2-SO2); 46.9 (CH2-N); 27.6 (CH2); 11.2 (CH3)
98.5 (O-CH-O); 62.5 (CH2-O); 60.5 (CH2-SO2); 47.1
(CH2-N); 15.0 (CH3)
60.5 (CH2-SO2); 46.9 (CH2-N)
156.5; 156.6; 149.8; 143.0, 136.9, 135.7; 131.6; 131.2; 128.8;
128.5; 128.4; 127.9; 127.6; 127.4; 127.2; 126.5; 118.1
164.0; 158.0; 146.1; 136.2; 132.0; 128.9; 128.5; 128.4; 127.5;
127.4; 127.1; 113.9; 113.5
55.0 (CH3-O); 45.2 (CH2-N); 35.9 (CH2-S); 32.0 (CH2);
12.9 (CH3)
133.4 (CH=);118.0 (CH2=); 45.3 (CH2-N);
34.7 (CH2-S)
133.5 (CH=);118.6 (CH2=); 46.1 (CH2-N);
35.6 (CH2-S); 27.7 (CH2); 11.8 (CH3)
45.4 (CH2-N)
168.4; 150.9; 150.2; 143.0; 136.6; 128.3; 127.4; 127.0; 118.1
159.5; 156.3; 150.1; 145.6; 136.5; 128.9; 128.0; 127.6; 122.3
22
23
24
25
166.4; 150.5; 147.1; 146.4; 136.1; 128.3; 127.6; 127.4; 112.3
166.1; 160.2; 151.1; 147.5; 136.2; 128.3; 127.9; 127.4; 110.1
166.7; 154.2; 150.8; 146.6; 136.1; 128.3; 127.8; 127.4; 111.8
155.2; 149.3; 147.8; 147.2; 135.8; 128.6; 127.7; 127.1; 119.3
45.3 (CH2-N); 27.3 (CH2); 11.4 (CH3)
98.3 (O-CH-O); 62.4 (CH2-O); 45.5 (CH2-N); 15.0 (CH3)
45.9 (CH2-N); 30.8, 29.1, 27.7, 25.6, 21.9 (5 CH2); 13.9
(CH3)
26
159.2; 156.3; 150.0; 146.1; 136.0; 128.6; 127.7; 127.2; 121.9
45.7 (CH2-N); 31.9, 30.7, 28.9, 27.7, 27.5, 22.0 (6 CH2);
13.9, 11.7 (2 CH3)
ethanol (0.5 mL), some drops of N,N-diethylaniline were added.
The mixture was stirred at 110 °C in a stopped vial for 2 hours;
after cooling, the precipitate was collected by filtration and crys-
tallized. See Table 1 for yields, crystallization solvent, physico-
chemical properties and elemental analysis; see Table 2 and 3 for
ir and nmr data.
was stirred to a room temperature for 1 hour. Then the mixture
reaction was diluted with water and extracted with chloroform.
The organic phase was evaporated and the residue was triturated
with ethyl ether. The solid was collected by filtration and crystal-
lized. See Table 1 for yields, crystallization solvent, physico-
chemical properties and elemental analysis; see Table 2 and 3 for
ir and nmr data.
8-Mercapto-9-phenylmethyl-1,9-dihydropurin-6-one (22) and 8-
Mercapto-9-phenylmethyl-2-substituted-1,9-dihydropurin-6-one
(23-24).
8-Benzyl-9-phenylmethyl-1,9-dihydro-purin-6-one (8), 2-Ethyl-
8-benzyl-9-phenylmethyl-1,9-dihydropurin-6-one (9) from 22
and 23 Respectively.
5-Amino-2-mercapto-1-phenylmethyl-1H-imidazole-4-car-
boxylic acid amide (5) (0.365 g, 1.47 mmoles) was added to a
solution of sodium ethoxide prepared from sodium (0.23 g, 0.01
mole) in 8.5 mL of absolute ethanol. The mixture was then
refluxed with stirring for 1 hour. A solution of the appropriate
ester (7.5 mmoles) in 5 mL of ethanol was added dropwise and
the solution was stirred under reflux for 48 hours. After cooling,
ice was added and then the mixture was neutralized with 50%
acetic acid. The precipitate formed was collected by filtration and
crystallized. See Table 1 for yields, crystallization solvent,
physicochemical properties and elemental analysis; see Table 2
and 3 for ir and nmr data.
A solution consisting of 22 or 23 (1.19 mmoles), the minimal
amount of N,N-dimethylformamide, benzyl bromide (1.18
mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.18 mmoles)
was stirred to a room temperature for 1 hour. Then the mixture
reaction was diluted with water and extracted with chloroform.
The organic phase was evaporated and the residue was triturated
with ethyl ether. The solid was collected by filtration and crys-
tallized. See Table 1 for yields, crystallization solvent, physico-
chemical properties and elemental analysis; see Table 2 and 3 for
ir and nmr data.
Treatment of Compounds 12-15 with Amines.
8-Hexylsulfanyl-9-phenylmethyl-1,9-dihydro-purin-6-one (25)
and 2-Ethyl-8-hexylsulfanyl-9-phenylmethyl-1,9-dihydro-purin-
6-one (26).
Compounds 12-15 (1 mmol) were treated in turn with an
excess of n-butylamine or benzylamine (3 ml); the mixture was
heated at 120° for 2 h. The following dilution with cold 10%
hydrochloric acid allowed the nearly complete recovering of the
starting products.
A solution consisting of 22 or 23 (1.19 mmoles), the minimal
amount of N,N-dimethylformamide, 1-bromohexane (1.18
mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.18 mmoles)

Jul-Aug 2005
New C(2)-Substituted 8-Alkylsulfanyl-9-phenylmethyl-hypoxanthines III
749
REFERENCES AND NOTES
27B, 1371 (1974).
[4] J. L. Kelley, J. A. Linn and J. W. T. Selway, J. Med. Chem.,
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[5] A. Yamazaki, I. Kamashiro and T. Takenishi, J. Org. Chem.,
3258 (1967).
[6] A. H. Cook, I. Heilbron and E. Smith, J. Chem. Soc., 1440
(1949).
*
To whom correspondence should be addressed: Prof. Irene
Giorgi - Department of Pharmaceutical Sciences, Pisa University, via
Bonanno, 6 – 56126 Pisa, Italy; e-mail: igiorgi@farm.unipi.it; Tel. +39
050 500209; Fax +39 050 40517.
[7] A. K. Sen and S. Ray, Indian J. Chem., 14B, 351 (1976).
[8] H. Heitsch, A. Wagner, N. Yadav-Bhatnagar and C.
Griffoul-Marteau, Synthesis, 1325 (1996).
[9] C. S. Miller, S. Gurin, and D. W. Wilson J. Am. Chem. Soc.,
74, 2892 (1952).
[1] G. Biagi, I. Giorgi, O. Livi, F. Pacchini, V. Scartoni and O.
L. Salerni, J. Heterocyclic Chem. 41, 575 (2004).
[2] G. Biagi, I. Giorgi, O. Livi, V. Scartoni and O. L. Salerni, J.
Heterocyclic Chem. 41, 581 (2004).
[3] D. J. Brown and L. G. Stephanson, Australian J. Chem.,