A facile synthesis of 6-aryl-5-cyano-1-(β-D-pyranosyl or β-D-furanosyl)-2-thiocytosines

Article abstract of DOI:10.1016/S0040-4020(00)00807-3

The treatment of a piperidinium salt of 6-aryl-5-cyano-2-thiouracil with an O-peracetyl-α-D-pyranosyl bromide produces a mixture of N1-(β-D-pyranosyl)-2-thiouracil and its N1,S²-disubstituted analog. By contrast, the reaction of a silyl derivative of the 2-thiouracil with an O-peracetyl-β-D-pyranose furnishes the mononucleoside selectively. Both the mononucleoside/dinucleoside mixture and pure mononucleoside undergo ammonolysis under mild conditions to give the β-D-nucleoside of 6-aryl-5-cyano-2-thiocytosine. The silyl method also provides an easy access to β-D-ribosyl nucleosides. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00807-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8631±8636
A Facile Synthesis of 6-Aryl-5-cyano-1-(b-d-pyranosyl
or b-d-furanosyl)-2-thiocytosines
²
Ibrahim M. Abdou and Lucjan Strekowski
*
Department of Chemistry, State University, Atlanta, GA 30303, USA
Received 12 July 2000; accepted 6 September 2000
AbstractÐThe treatment of a piperidinium salt of 6-aryl-5-cyano-2-thiouracil with an O-peracetyl-a-d-pyranosyl bromide produces a
mixture of N1-(b-d-pyranosyl)-2-thiouracil and its N1,S2-disubstituted analog. By contrast, the reaction of a silyl derivative of the
2-thiouracil with an O-peracetyl-b-d-pyranose furnishes the mononucleoside selectively. Both the mononucleoside/dinucleoside mixture
and pure mononucleoside undergo ammonolysis under mild conditions to give the b-d-nucleoside of 6-aryl-5-cyano-2-thiocytosine. The silyl
method also provides an easy access to b-d-ribosyl nucleosides. q 2000 Elsevier Science Ltd. All rights reserved.
Ammonolysis of 4-thiouracils is a cornerstone in the
preparation of cytosines.1 Similar selective transformations
of the 4-thioxo function in 2,4-dithiouracils, 2,4-dithio-
barbituric acids, and 2,4-dithiohydantoins are also well
known.2,3 On the other hand, direct conversion of uracils
to cytosines are rare and, as a rule, they are conducted by
using complex reagents and under extremely harsh con-
ditions.4 The exception is ammonolysis of 5-¯uorosulfonyl-
uracil, which takes place at room temperature and furnishes
5-¯uorosulfonylcytosine in a modest yield.5 Recently, we
have also reported the ®rst ammonolysis of 2-thiouracil
nucleosides to 2-thiocytosine nucleosides.6
the ammonolysis reaction, and characterization of all
compounds.
5-Cyano-2-thiouracils are readily available by a number of
methods.7±9 A simple route to 7±9 and other 6-substituted
analogs (Rˆaryl, heteroaryl or tert-alkyl) involves conden-
sation of an aldehyde with ethyl cyanoacetate and thiourea
in the presence of potassium carbonate.7,8 The product is
isolated by acidi®cation followed by crystallization of the
resultant precipitate.
An improved synthesis of 7±9, in which piperidine is substi-
tuted for potassium carbonate, is given in Scheme 1. The
advantages of this method are that (i) a crystalline piper-
idinium salt 1 precipitates directly from the mixture, which
facilitates workup, and (ii) following acidi®cation of the salt
the 2-thiouracil is obtained in a greater yield than that for the
previously described procedure. More importantly, due to
the high purity of the precipitated salt 1, this material can be
used directly in the preparation of 2±6/20 ±60 in the absence
of any additional base. Ammonolysis of the mixtures 2±6/
20 ±60 furnishes the corresponding cytosine b-nucleosides
10±14.
In particular, a mixture of a glycoside 2 and a bis-glycoside
20, obtained by treatment of a 5-cyano-2-thiouracil 7 with
tetra-O-acetyl-1-a-d-glucopyranosyl bromide in the
presence of potassium hydroxide, was subjected to ammo-
nolysis under mild conditions to give a 2-thiocytosine
glucoside 10 in a high yield (structure in Scheme 1).
Since 4-pyrimidinones lacking the 5-cyano group are inert
toward ammonia, this facile transformation is assisted by
the cyano functionality6 (vide infra).
In this paper we describe a more ef®cient synthetic route to
compounds 2±6/20 ±60 which are precursors to 2-thiocyto-
sine nucleosides 10±14. Presented also are an independent
and ef®cient synthesis of 2±6, full experimental details of
The synthesis of single nucleosides 2±6 is given in Scheme
2. In this method, 2-thiouracils 7±9 are treated with
1,1,1,3,3,3-hexamethyldisilazane (HMDS) and the resultant
bis(trimethylsilyl) derivatives 15, without isolation, are
allowed to react with b-d-glucose pentaacetate, b-d-
galactose pentaacetate or b-d-xylose tetraacetate. After
puri®cation by a single crystallization, the corresponding
products 2±6 are then subjected to ammonolysis to give
10±14.
Keywords: 6-aryl-5-cyano-2-thiouracils; ammonolysis; 1-(b-d-pyranosyl)-
2-thiocytosines; 1-(b-d-furanosyl)-2-thiocytosines.
* Corresponding author. Tel.: 1404-651-0999; fax: 1404-651-1416;
e-mail: lucjan@gsu.edu
Present address: School of Chemistry and Biochemistry, Georgia Insti-
²
The structure determination for 2-thiouracil glucosides 2
tute of Technology, Atlanta, GA 30332, USA.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00807-3

8632
I. M. Abdou, L. Strekowski / Tetrahedron 56 (2000) 8631±8636
Scheme 1.
and 20 and the 2-thiocytosine glucoside 10 has been
discussed previously in detail.6 The remaining compounds
were analyzed in a similar fashion. Brie¯y, the b-con®gura-
tion of the pyranosyl moieties was established by 1H NMR
from a large coupling constant for a diaxial interaction
between H10 and H20.10±12 The N1-substitution at the
pyrimidine of 2±6 and 10±14 was shown by a strong
NOE between H10 and the adjacent protons of the 6-aryl
substituent.
a similar way a doublet at d 5.86 (Jˆ3.6 Hz) is observed for
H10 of 17. These values are typical for 1-(b-d-ribofurano-
syl) derivatives of 6-substituted pyrimidines.12,13 The struc-
tures of 16 and 17 were con®rmed by proton NOE
experiments which gave a strong interaction between H10
of the ribose and ortho protons of the 6-phenyl substituent at
the pyrimidine.
Removal of a sugar moiety from S-nucleosides, such as
20 ±60, under nucleophilic conditions is well known. On
the other hand, the observed transformation of 2±6, 20 ±60
and 16 to the corresponding cytosine nucleosides 10±14, 17
upon treatment with ammonia is an unusual result. Ammo-
nolysis of acyl protected nucleosides is a general, widely
used method for deprotection of such derivatives to free
nucleosides. The treatment of 2±6, 2±6/20 ±60, 16 with
ammonia in methanol to give 10±14, 17 must be conducted
under anhydrous conditions; otherwise a complicated
mixture of products is obtained. In particular, the ammo-
nolysis conducted in wet methanol produces 2-thiouracils
As a brief extension of the silyl method, the silyl derivative
15 (RˆPh) was allowed to react with 1,2,3,5-tetra-O-acetyl-
b-d-ribofuranose in the presence of trimethylsilyl tri¯ate.
Following a standard workup and crystallization from
95% EtOH (again without chromatography) this reaction
furnished a 1-(b-d-ribofuranosyl)-2-thiouracil 16 in an
85% yield. Ammonolysis of 16 gave a 1-(b-d-ribofurano-
syl-2-thiocytosine 17 in an 86% yield after crystallization.
The 1H NMR spectrum of 16 is characterized by a doublet at
d 6.22 for H10 with a coupling constant to H20 of 2.7 Hz. In

I. M. Abdou, L. Strekowski / Tetrahedron 56 (2000) 8631±8636
8633
Scheme 2.
7±9, the yields of which increase with an increasing content
of water in the solvent. A similar degradation of the
N1-glycosylic bond to give 7±9 as the major products is
also observed for potassium hydroxide mediated hydrolysis
of 2±6, or 2±6/20 ±60, 16 in aqueous methanol. The products
7±9 were easily isolated as precipitates after acidi®cation of
the mixtures.
Experimental
General
All reactions were conducted under an atmosphere of dry
nitrogen. Melting points (pyrex capillary) are not corrected.
Unless stated otherwise, the 1H NMR and selected 13C NMR
spectra were obtained at 400 MHz and 100 MHz, respec-
tively, by using a solution in CDCl3 and TMS as an internal
reference. As shown by elemental analysis, compounds
2±6, 20 ±60, 10±14, 16, and 17 crystallize with water. This
In conclusion, we have described two facile synthetic routes
to mixtures of nucleosides 2±6/20 ±60 and pure nucleosides
2±6, 16. These compounds undergo ef®cient ammonolysis
to the corresponding 1-(b-d-pyranosyl)-2-thiocytosines. For
the ammonolysis reaction, the mixtures 2±6/20 ±60 are puri-
®ed by ¯ash chromatography that does not result in separa-
tion of individual components, and the products 2±6, 16
obtained by the silyl method are puri®ed by a single crystal-
lization.
1
was con®rmed by comparing their H NMR spectra with
that of the solvent. In the spectra of 2±6 and 16 taken in
CDCl3 the H2O singlet at d 1.5±1.6 includes also a signal
for NH. The complete assignments for sugar moieties of
10±14 and 16 were obtained by using COSY. Speci®c
optical rotations (cˆ0.2 g/100 mL in all cases, sodium D
line, 258C) were obtained for solutions in CDCl3 (2±6,
20 ±60, and 16) and MeOH (10±14 and 17).
Currently we are studying the interesting possibility that
the described ammonolysis of 2-thiouracil nucleosides to
2-thiocytosine nucleosides is a particular case of a general
nucleophile-mediated reaction under non-hydrolytic condi-
tions. It also appears that, at least, the ammonolysis reaction
is not limited to the 5-cyanouracil nucleosides and can be
extended on uracil derivatives that contain other electron
withdrawing groups at C5. According to our PM3-AQ
calculations of HOMO electron densities the atom C4 in
the anions derived from such pyrimidin-4(3H)-ones is an
electrophilic site. Thus, the uracil-to-cytosine transforma-
tion may involve a direct nucleophilic addition of ammonia
to C4 followed by elimination of hydroxide ion from the
resultant aminal derivative of the anionic pyrimidine. A
rather complex mechanistic pathway that is consistent
with the computational work albeit limited to 5-cyanoura-
cils has been suggested by us previously.6
2-Thiouracils 7±9. A solution of an aldehyde (RCHO,
10 mmol), ethyl cyanoacetate (1.0 mL, 10 mmol), thiourea
(0.76 g, 10 mmol) and piperidine (2.0 mL, 20 mmol) in
absolute ethanol (50 mL) was heated under re¯ux for 6 h
1
and then cooled. The resultant precipitate (1, RˆPh): H
NMR (DMSO-d6) d 1.57 (m, 6H), 2.97 (m, 4H), 7.48 (m,
3H), 7.72 (m, 2H); 13C NMR (DMSO-d6) d 21.5, 22.1, 43.6,
85.4, 118.6, 127.9, 128.0, 130.0, 137.5, 162.3, 167.4, 182.8.
Anal. Calcd for C16H18N4OS: C, 61.12; H, 5.77; N, 17.82.
Found: C, 61.02; H, 5.67; N, 17.76. The salt 1 was dissolved
in water (6 mL) and the solution was neutralized by slow
addition of 2N HCl that caused crystallization of 7±9.
5-Cyano-6-phenyl-2-thiouracil (7). Yield 67%; mp 297±
2998C (reported9,14 mp 298±3008C); 1H NMR (DMSO-d6) d

8634
I. M. Abdou, L. Strekowski / Tetrahedron 56 (2000) 8631±8636
7.63 (m, 5H), 13.14 (bs, exchangeable with D2O, 2H); 13C
NMR (DMSO-d6) d 90.8, 114.7, 128.3, 128.8, 129.3, 132.2,
158.5, 161.0, 176.2.
1H), 5.23 (t, Jˆ9.2 Hz), 5.34 (t, Jˆ9.2 Hz), 5.76 (d,
Jˆ10.0 Hz, 1H, H10), 7.35 (d, Jˆ6.0 Hz, 2H), 7.95 (d,
Jˆ6.0 Hz, 2H). Anal. Calcd for C26H27N3O10S´2H2O: C,
51.23; H, 5.13; N, 6.89; Found: C, 51.36; H, 4.89; N,
7.03.
5-Cyano-6-(4-tolyl)-2-thiouracil (8). Yield 65%; mp 245±
478C (reported14 mp 2458C); 1H NMR (DMSO-d6) d 2.40 (s,
3H), 7.37 (d, Jˆ8.1 Hz, 2H), 7.57 (d, Jˆ8.1 Hz, 2H), 13.11
(bs, exchangeable with D2O, 2H).
1-(20,30,40,60-Tetra-O-acetyl-b-d-glucopyranosyl)-2-(200,
300,400,600-tetra-O-acetyl-b-d-glucopyranosylthio)-5-
cyano-6-(p-tolyl)-pyrimidin-4(1H)-one (30). Yield 36%;
mp 118±208C; [a]ˆ38.0; 1H NMR d 1.98±2.01 (m,
24H), 2.44 (s, 3H), 4.25 (m, 6H), 5.16 (m, 3H), 5.34 (m,
3H), 5.73 (d, Jˆ10.3 Hz, 1H, H10), 6.15 (d, Jˆ7.5 Hz, 1H,
H100), 7.42 (d, Jˆ11.0 Hz, 2H), 7.97 (d, Jˆ11.0 Hz, 2H).
Anal. Calcd for C40H45N3O19S´0.5 H2O: C, 52.63; H, 5.04;
N, 4.60; Found: C, 52.54; H, 5.00; N, 4.39.
5-Cyano-6-(2-naphthyl)-2-thiouracil (9). Yield 63%; mp
276±788C; H NMR (DMSO-d6) d 7.72 (m, 3H), 8.03 (s,
1
1H), 8.09 (m, 3H), 13.20 (bs, exchangeable with D2O, 1H),
13.22 (bs, exchangeable with D2O, 1H); 13C NMR (DMSO-
d6) d 90.8, 114.4, 124.7, 126.5, 127.0, 127.6, 127.9, 128.2,
128.6, 129.3, 131.6, 134.0, 158.2, 160.7,176.1. Anal. Calcd
for C15H9N3OS: C, 64.50; H, 3.25; N, 15.04. Found: C,
64.61; H, 3.19; N, 14.95.
1-(20,30,40,60-Tetra-O-acetyl-b-d-glucopyranosyl)-5-
cyano-6-(2-naphthyl)-2-thiouracil (4). Yield 23%; mp
1
Nucleosides 2±6 and dinucleosides 20 ±60. The salt 1
obtained from aldehyde RCHO (10 mmol, Rˆphenyl,
4-tolyl, 2-naphthyl) as described above was dissolved in
water (6 mL). After addition of tetra-O-acetyl-1-a-d-gluco-
pyranosyl bromide, tetra-O-acetyl-1-a-d-galactopyranosyl
bromide or tri-O-acetyl-1-a-d-xylopyranosyl bromide
(15 mmol) in acetone (20 mL) the mixture was stirred at
238C for 6 h. Concentration under reduced pressure
followed by addition of CHCl3 (100 mL) to the residue,
then washing of the organic solution with water
(3£25 mL), drying (Na2SO4), and concentration gave a
crude mixture 2±6/20 ±60. For the subsequent ammonolysis
reaction this mixture was pre-puri®ed by ¯ash chromato-
graphy (20 g of silica gel; hexanes/ether/CHCl3, 1:2:2)
that did not result in separation of 2±6 and 20 ±60. For char-
acterization of individual compounds a sample of the
mixture (1 g) was separated by chromatography under the
same conditions. The separated compounds were crystal-
lized from 95% EtOH. The yields given below are based
on the starting aldehyde RCHO.
189±928C; [a]ˆ32.0; H NMR d 1.96±2.12 (4 s, 12H),
4.04 (m, 1H), 4.10 (m, 1H), 4.16 (m 1H), 4.97 (m, 1H),
5.04 (m, 1H), 5.45 (m, 1H), 5.91 (d, Jˆ10.8 Hz, 1H, H10),
7.61 (m, 2H), 7.98 (m, 4H), 8.45 (s, 1H). Anal. Calcd for
C29H27N3O10S´0.5H2O: C, 56.25; H, 4.52; N, 6.78; Found:
C, 56.28; H, 4.30; N, 7.02.
1-(20,30,40,60-Tetra-O-acetyl-b-d-glucopyranosyl)-2-(200,
300,400,600-tetra-O-acetyl-b-d-glucopyranosylthio)-5-
cyano-6-(2-naphthyl)-pyrimidin-4(1H)-one (40). Yield
1
32%; mp 131±338C; [a]ˆ29.0; H NMR d 1.88±2.12 (m,
24H), 4.45 (m, 6H), 5.22 (m, 3H), 5.48 (m, 3H), 6.21 (d,
Jˆ10.3 Hz, 1H, H10), 6.60 (d, Jˆ7.5 Hz, 1H, H100), 7.58 (m,
2H), 7.93 (m, 4H), 8.41 (s, 1H). Anal. Calcd for
C43H45N3O19S´1.5 H2O: C, 53.36; H, 4.96; N, 4.34;
Found: C, 53.27; H, 5.12; N, 4.28.
1-(20,30,40,60-Tetra-O-acetyl-b-d-galactopyranosyl)-5-
cyano-6-phenyl-2-thiouracil (5). Yield 30%; mp 232±
1
348C; [a]ˆ36.4; H NMR d 1.99,2.02 (2 s, 12H), 4.03
(m, 2H), 4.33 (m, 1H), 5.15 (m, 1H), 5.36 (t, Jˆ10.8 Hz,
1H), 5.54 (m, 1H), 5.99 (d, Jˆ10.8 Hz, 1H, H10), 7.60 (m,
3H), 8.07 (m, 2H). Anal. Calcd for C25H25N3O10S´2.5H2O:
C, 49.62; H, 4.96; N, 6.95; Found: C, 49.38; H, 4.69; N,
6.78.
1-(20,30,40,60-Tetra-O-acetyl-b-d-glucopyranosyl)-5-cyano-
6-phenyl-2-thiouracil (2). Yield 25%; mp 214±2168C;
1
[a]ˆ38.3; H NMR d 1.90±2.14 (4s, 12H), 4.03 (m, 2H),
4.43 (m, 1H), 5.15 (m, 1H), 5.35 (m, 1H), 5.54 (m, 1H), 5.99
(d, Jˆ10.9 Hz, 1H, H10), 7.64 (m, 3H), 8.08 (m, 2H); 13C
NMR d 20.4, 20.5, 20.6, 20.8, 61.5, 66.5, 67.4, 71.7, 74.6,
82.2, 90.1, 118.7, 128.3, 128.4, 131.1, 136.0, 167.8, 169.8,
169.9, 170.0, 170.5, 170.7, 173.5. Anal. Calcd for
C25H25N3O10S´2H2O: C, 50.42; H, 4.91; N, 7.05. Found:
C, 50.37; H, 4.92; N, 6.99.
1-(20,30,40,60-Tetra-O-acetyl-b-d-galactopyranosyl)-2-
(200,300,400,600-tetra-O-acetyl-b-d-galactopyranosylthio)-5-
cyano-6-phenyl pyrimidin-4(1H)-one (50). Yield 35%, mp
128±308C; [a]ˆ23.0; 1H NMR d 1.89±2.12 (m, 24H), 4.23
(m, 6H), 5.23 (t, Jˆ5.7 Hz, 1H), 5.32 (t, Jˆ5.7 Hz, 1H),
5.45 (t, Jˆ5.4 Hz, 1H), 5.55 (t, Jˆ5.4 Hz, 1H), 6.15 (d,
Jˆ8.0 Hz, 1H, H10), 6.81 (d, Jˆ10.8 Hz, 1H, H100), 7.52
(m, 3H), 7.82 (m, 2H). Anal. Calcd for C39H43N3O19S´H2O:
C, 51.60; H, 5.00; N, 4.63; Found: C, 52.00; H, 4.85; N,
4.47.
1-(20,30,40,60-Tetra-O-acetyl-b-d-glucopyranosyl)-2-(200,300,
400,600-tetra-O-acetyl-b-d-glucopyranosylthio)-5-cyano-
6-phenyl pyrimidin-4(1H)-one (20). Yield 35%; mp 114±
168C; [a]ˆ45.0; 1H NMR d 1.83±2.01 (m, 24H), 4.25 (m,
6H), 5.11 (m, 4H), 5.55 (m, 2H), 5.98 (d, Jˆ10.4 Hz, 1H,
H10), 6.50 (d, Jˆ8.0 Hz, 1H, H100), 7.62 (m, 3H), 8.08 (m,
2H). Anal. Calcd for C39H43N3O19S´0.5H2O: C, 52.07; H,
4.89; N, 4.78. Found: C, 52.15; H, 4.78; N, 4.68.
1-(20,30,50-Tri-O-acetyl-b-d-xylopyranosyl)-5-cyano-6-
(2-naphthyl)-2-thiouracil (6). Yield 20%; mp 165±688C;
1
[a]ˆ26.7; H NMR d 2.00±2.03 (3s, 9H), 3.65 (m, 1H),
4.10 (m, 1H), 4.09 (m, 1H), 5.06 (m, 1H), 5.33 (t, Jˆ8.4 Hz,
1H), 6.03 (d, Jˆ8.4 Hz, 1H, H10), 7.63 (m, 2H), 8.07
(m, 4H), 8.51 (s, 1H). Anal. Calcd for C26H23N3O8S´H2O:
C, 56.21; H, 4.54; N, 7.56; Found: C, 56.28; H, 4.38; N,
7.26.
1-(20,30,40,60-Tetra-O-acetyl-b-d-glucopyranosyl)-5-
cyano-6-(p-tolyl)-2-thiouracil (3). Yield 30%; mp 189±
1
928C; [a]ˆ23.0; H NMR d 1.98±2.18 (4 s, 12H), 2.46
(s, 3H), 3.91 (m, 1H), 4.11 (m, 2H), 5.13 (d, Jˆ10.0 Hz,

I. M. Abdou, L. Strekowski / Tetrahedron 56 (2000) 8631±8636
8635
1-(20,30,50-Tri-O-acetyl-b-d-xylopyranosyl)-)-2-(200,300,
500-tri-O-acetyl-b-d-xylopyranosylthio)-6-(2-naphthyl)-
pyrimidin-4(3H)-one (60). Yield 35%; mp 123±258C;
[a]ˆ21.6; 1H NMR d 1.99±2.06 (6s, 18H), 3.78 (t,
Jˆ9.3 Hz, 1H), 3.92 (t, Jˆ5.4 Hz, 1H), 4.07 (t, Jˆ9.3 Hz,
1H), 4.22 (t, Jˆ5.4 Hz, 1H), 4.95 (m, 2H), 5.10 (m, 2H),
5.27 (t, Jˆ9.0 Hz, 1H), 5.50 (t, Jˆ4.5 Hz, 1H), 6.06 (d,
Jˆ9.0 Hz, 1H, H10), 6.61 (d, Jˆ4.5 Hz, 1H, H100), 7.66
(m, 2H), 8.10 (m, 4H), 8.64 (s, 1H). Anal. Calcd for
C37H37N3O15S´H2O: C, 54.61; H, 4.79; N, 5.16; Found: C,
54.82; H, 4.65; N, 5.01.
5-Cyano-1-(b-d-glucopyranosyl)-6-phenyl-2-thiocyto-
1
sine (10). Yield 86%; mp 190±938C; [a]ˆ21.0; H NMR
(DMSO-d6) d 3.21 (m, 3H, H20, H30, H40), 3.48 (m, 2H,
H260), 3.68 (m, 1H, H50), 4.80 (m, exchangeable with D2O,
4H), 5.37 (d, Jˆ10.0 Hz, 1H, H10), 7.18 (bs, exchangeable
with D2O, 2H), 7.47 (m, 3H), 7.80 (m, 2H). Anal. Calcd for
C17H18N4O5S´1.5H2O: C, 48.92; H, 5.03; N, 13.42; S, 7.67;
Found: C, 48.84; H, 5.10; N, 13.33; S, 7.73.
5-Cyano-1-(b-d-glucopyranosyl)-6-(4-tolyl)-2-thiocyto-
1
sine (11). Yield 86%; mp 190±938C; [a]ˆ25.5; H NMR
(DMSO-d6) d 2.36 (s, 3H), 3.15 (m, 2H, H20, H30), 3.46 (m,
4H, H40, H50, H260), 4.80 (m, exchangeable with D2O, 4H),
5.35 (d, Jˆ10.2 Hz, 1H, H10), 7.15 (bs, exchangeable with
D2O, 2H), 7.26 (d, Jˆ8.0 Hz, 2H), 7.72 (d, Jˆ8.0 Hz, 2H).
Anal. Calcd for C18H20N4O5S´2H2O: C, 49.08; H, 5.49; N,
12.72. Found: C, 48.95; H, 5.60; N, 12.65.
The Silyl Method for 2±6 and 16. A mixture of a 2-thio-
uracil 7±9 (10 mmol), HMDS (60 mL), and (NH4)2SO4
(125 mg) was heated under re¯ux for 6 h. Excess HMDS
was removed by distillation and then residual HMDS was
removed under a reduced pressure. A solution of the
resultant silyl intermediate 15 in anhydrous MeCN
(20 mL) was stirred and treated with a solution of b-d-
glucose pentaacetate, b-d-galactose pentaacetate or b-d-
xylose tetraacetate (9 mmol) in anhydrous MeCN
(20 mL). Following cooling to 58C and then addition of
anhydrous SnCl4 (1.6 mL), the mixture was stirred at
238C for 16 h. The mixture was diluted with CHCl3
(150 mL), washed with a saturated solution of NaHCO3
(50 mL) and water (2£25 mL), and then dried (Na2SO4).
Removal of solvent under a reduced pressure followed
by crystallization (2£) of the residue by diluting an ether
solution with hexanes and then from 95% EtOH gave
an analytically pure compound 2±6. Compound, yield: 2,
65%; 3, 65%; 4, 62%; 5, 61%; 6, 60%. Only one crystal-
lization was conducted before the subsequent ammonolysis
of 2±6.
5-Cyano-1-(b-d-glucopyranosyl)-6-(2-naphthyl)-2-thio-
1
cytosine (12). Yield 83%; mp 198±2018C; [a]ˆ19.3; H
NMR (DMSO-d6) d 3.15 (m, 5H, H20, H30, H40, H260),
4.00 (m, 1H, H50), 4.91 (m, exchangeable with D2O, 4H),
5.39 (d, Jˆ10.4 Hz, 1H, H10), 7.18 (bs, exchangeable with
D2O, 2H), 7.60 (m, 2H), 7.98 (m, 4H), 8.22 (s, 1H). Anal.
Calcd for C21H20N4O5S´2H2O: C, 52.93; H, 5.08; N, 11.76.
Found: C, 52.86; H, 5.22; N, 11.64.
5-Cyano-1-(b-d-galactopyranosyl)-6-phenyl-2-thiocyto-
1
sine (13). Yield 87%; mp 192±958C; [a]ˆ22.6; H NMR
(DMSO-d6) d 3.54 (m, 6H, H20, H30, H40, H50, H260), 4.80
(m, exchangeable with D2O, 4H,), 5.13 (d, Jˆ10.0 Hz, 1H,
H10), 7.02 (bs, exchangeable with D2O, 2H), 7.46 (m, 3H),
7.78 (m, 2H). Anal. Calcd for C17H18N4O5S´1.5H2O: C,
48.92; H, 5.03; N, 13.42. Found: C, 49.18; H, 4.75; N, 13.17.
In the synthesis of 16 the intermediate silyl derivative 15
was allowed to react with 1,2,3,5-tetra-O-acetyl-b-d-
ribofuranose in the presence of CF3SO3SiMe3 instead of
SnCl4 under otherwise identical conditions. Following a
similar workup, product 16 was crystallized from 95%
EtOH.
5-Cyano-6-(2-naphthyl)-(1-b-d-xylopyranosyl)-2-thio-
1
cytosine (14): Yield 84%; mp 196±988C; [a]ˆ16.8; H
NMR (DMSO-d6) d 3.12 (dd, Jˆ8.8, 9.9 Hz, 1H, H20),
3.20 (t, Jˆ9.9 Hz, 1H, H30), 3.39 (m, 2H, H250), 3.79 (m,
1H, H40), 5.07 (bs, exchangeable with D2O, 3H), 5.46 (d,
Jˆ8.8 Hz, 1H, H10), 7.20 (bs, exchangeable with D2O, 2H),
7.60 (m, 2H), 7.90 (m, 1H), 8.00 (m, 3H), 8.38 (s, 1H). Anal.
Calcd for C20H18N4O4S´2H2O: C, 53.81; H, 4.93; N, 12.55.
Found: C, 54.18; H, 4.98; N, 12.20.
1-(20,30,50-Tri-O-acetyl-b-d-ribofuranosyl)-5-cyano-6-
phenyl-2-thiouracil (16). Yield 85%; mp 248±518C;
1
[a]ˆ23.0; H NMR d 1.99±2.01 (3s, 9H), 4.09 (m, 1H,
H40), 4.33 (m, 2H, H250), 5.42 (m, 1H, H30), 5.62 (m, 1H,
H20), 6.22 (d, Jˆ2.7 Hz, 1H, H10), 7.60 (m, 3H), 7.86 (m,
2H); 13C NMR d 20.1, 20.2, 20.5, 62.1, 69.7, 74.9, 79.5,
85.6, 93.6, 115.5, 128.2, 128.5, 131.7, 134.8, 161.5, 163.2,
166.0, 169.0, 169.3, 169.8. Anal. Calcd for
C22H21N3O8S´H2O: C, 52.27; H, 4.59; N, 8.31. Found: C,
52.12; H, 4.55; N, 8.22.
5-Cyano-6-phenyl-1-(b-d-ribofuranosyl)-2-thiocytosine
1
(17). Yield 86%; mp 192±1958C; [a]ˆ21.0; H NMR d
3.47 (m, 1H), 3.76 (m, 1H), 3.87 (m, 1H), 4.00 (m, 1H),
4.76 (br s, 1H), 4.97 (m, 1H), 5.38 (br s, 1H), 5.86 (d,
Jˆ3.6 Hz, H10), 6.65 (br s, 1H), 7.24 (br s, 2H), 7.47 (m,
3H), 7.75 (m, 2H). Anal. Calcd for C16H16N4O4S´2H2O: C,
48.48; H, 5.09; N, 14.13. Found: C, 48.15; H, 5.25; N, 13.95.
Ammonolysis of 2±6, 2±6/20 ±60, and 16. A solution of an
individual nucleoside 2±6 (1 mmol), a mixture 2±6/20 ±60
(total 1 mmol) or 16 (1 mmol) in anhydrous MeOH (10 mL)
was added at 08C to a saturated solution of anhydrous NH3
in anhydrous MeOH (25 mL) and the mixture was stirred at
08C for 4 h and then at 238C for an additional 12 h. Concen-
tration followed by silica gel chromatography (MeOH/
CHCl3, 1:19) and then crystallization from 95% MeOH
gave an analytically pure compound 10±14. The yields for
the ammonolysis of 2±6 or the corresponding mixture 2±6/
20 ±60 were virtually identical.
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