The reaction of thioesters with nitriles. A new synthetic approach to the preparation of substituted 4-alkylthio- and 4-arylthiopyrimidine derivatives

Article abstract of DOI:10.1016/S0040-4020(03)01133-5

S-Alkyl and S-aryl thioesters react with nitriles in the presence of triflic anhydride to form substituted 4-alkylthio- and 4-arylthiopyrimidines. However, when methyl thiocyanate is used as nitrile, dithioimidocarbonates are formed. A mechanism to explain these differences is postulated.

Full text of DOI:10.1016/S0040-4020(03)01133-5

Tetrahedron 59 (2003) 7331–7336
The reaction of thioesters with nitriles. A new synthetic approach
to the preparation of substituted 4-alkylthio- and
4-arylthiopyrimidine derivatives
*
Antonio Herrera, Roberto Martınez-Alvarez and Pedro Ramiro
´
´ ´ ´
Departamento de Quımica Organica, Facultad de Ciencias Quımicas, Universidad Complutense, E-28040 Madrid, Spain
Received 24 April 2003; revised 22 July 2003; accepted 23 July 2003
Abstract—S-Alkyl and S-aryl thioesters react with nitriles in the presence of triflic anhydride to form substituted 4-alkylthio- and
4-arylthiopyrimidines. However, when methyl thiocyanate is used as nitrile, dithioimidocarbonates are formed. A mechanism to explain
these differences is postulated.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
than their parent compounds in inhibiting the multiplication
of HIV-1 in vitro.11
The pyrimidine ring system is present in many natural
products, pharmaceuticals, agrochemicals, etc. Thus, there
is a continuous quest for efficient methods of synthesis of
pyrimidine derivatives.1,2 Among these substances,
alkylthio and arylthiopyrimidines are compounds of great
interest. Alkylthiopyrimidines are widely used as agro-
chemicals. Particularly, 4-alkylthiopyrimidine derivatives
have shown excellent broad spectrum herbicidal activity in
transplanted paddy rice.3 Alkylthiopyrimidones are pre-
cursors for the preparation of anilinopyrimidones, which are
useful as insecticidal and acaricidal agents capable of
controlling pest of agrohorticultural plants.4 2-Alkylthio-
pyrimidine derivatives have also found application as
agrochemical fungicides.5,6 Herbicidal compositions based
on 5-alkylthiopyrimidines are used as postemergence
herbicides for cereals.7,8 Recent investigations have demon-
strated that substituted 6-methylthiopyrimidines present
antimicrobial activity against pathogenic bacterial agents
including Mycobacterium tuberculosis.9 The worldwide
resurgence of tuberculosis caused by multiresistant strains
of this bacteria has made this application significant.
Cephalosporin compounds which have 3-[(aminopyri-
diniumyl)thio]methyl substituents show high antimicrobial
activity against various bacterial species including Pseudo-
monas aeruginosa.10 Alkylthio analogs of dihydroalkoxy-
benzyloxopyrimidines (DABOs) are 10-fold more potent
In the field of synthetic organic chemistry, alkylthio and
arylthiopyrimidines are useful intermediates in the prep-
aration of highly substituted pyrimidines by nucleophilic
substitution reactions.12 2-Methylthiopyrimidines are par-
ticularly reactive substrates toward the palladium-catalyzed
cross-coupling reaction with benzylic reagents.13
Many methods for preparing alkylthio- and arylthiopyrimi-
dines are described in the literature.1 In spite of their
importance, only a few procedures for the preparation of
these compounds do not involve multiple step sequences.
The cocyclization of ketones and aliphatic and aromatic
nitriles promoted by Tf2O is a versatile route to substituted
alkyl and arylpyrimidines.14 The pyrimidine ring is formed
by a cyclization reaction of two nitrile units and one unit of
the corresponding carbonyl compound. The two cyano
carbons become C2, C6 (or C4 depending on the IUPAC
nomenclature rules) of the pyrimidine ring while the alpha
and carbonyl carbons become C5, C4 (or C6), respectively
(Scheme 1).
Keywords: thioesters; triflic anhydride; alkylthiopyrimidines;
arylthiopyrimidines.
*
Corresponding author. Tel.: þ34-91-3944325; fax: þ34-91-3944103;
e-mail: rma@quim.ucm.es
Scheme 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01133-5

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A. Herrera et al. / Tetrahedron 59 (2003) 7331–7336
Table 1. Substituted 4-alkylthio- 3 and 4-arylthiopyrimidines 4 prepared
Substitution at the a position of the carbonyl compound
leads to 5-F2 substituted pyrimidines. Direct functionaliza-
tion F1 at the carbonyl group leads to 4-substituted
pyrimidines. In this regard, application of this reaction to
a-haloketones15 or aliphatic esters16 provided a convenient
route to 5-halopyrimidines and 4-alkoxypyrimidines
respectively. On the other hand, the use of functionalized
nitriles permits the introduction of both functions F3 at
positions 2 and 6 of the pyrimidine ring. As a consequence,
the use of methylthiocyanate as nitrile produces 2,4-
bis(methylthio)pyrimidines.17
Entry
R
Product
Yielda
1
2
3
4
5
6
7
8
CH3–
CH3(CH2)7–
C6H5–
4-CH3C6H4–
4-ClC6H4–
3,4-(CH3O)2C6H3–
C6H5CH2–
4-CH3C6H4CH2–
4-ClC6H4CH2–
CH3–
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
92
60
53
86
87
64
80
50
41
43
53
48
56
9
10
11
12
13
C6H5–
4-CH3C6H4–
3,4-(CH3O)2C6H3–
The preparation of monothioalkyl or monothioaryl sub-
stituted pyrimidines requires the use of a carbonyl
compound bearing the thioalkyl or thioaryl moiety. The
introduction of this functionality should afford a direct
approach to the synthetically interesting intermediates
4-thiosubstituted pyrimidines. The easy nucleophilic
replacement of the 4-alkylthio or 4-arylthiogroup permits
the introduction of a range of functionalities.
a
% Yield of isolated product.
thioesters leads to the preparation of pyrimidines with the
C5 position unsubstituted.
When the reaction was carried out with S-phenyl ethane-
thioate 2, the corresponding substituted 4-arylthiopyrimi-
dines 4 were isolated together with the corresponding ortho
ester 5. The formation of 5 could be explained by an ortho
esterification process induced by the triflic anhydride. To
test this side reaction, the treatment of 2 with Tf2O in the
same reaction conditions employed for the preparation of 4
produces the ortho ester 5. Thus, the yields obtained in the
synthesis of 4 were reduced by the formation of 5
(Scheme 3). The ortho esterification process did not takes
place when alkylthioesters were used as starting materials.
We report here the reaction of S-alkyl and S-arylthioesters
with nitriles in the presence of triflic anhydride. The
reaction easily produces 4-alkylthio and 4-arylthiopyri-
midines in good yields. The results can be explained by the
general mechanism proposed for the reaction of ketones,
nitriles and triflic anhydride.14,18
The use of nitriles of lower nucleophilic character such as
thiocyanates leads to rearranged dithioiminocarbonates.
Experiments were carried out to clarify these reactivity
differences and to determine the origin of the
rearrangement.
2. Results and discussion
Scheme 3.
4-Alkylthio substituted pyrimidines 3 and 4-arylthio sub-
stituted pyrimidines 4 are easily obtained from the simpler
starting materials S-methyl butanethioate 1 and S-phenyl
ethanethioate 2. Thus, the reaction of these thioesters with
various aliphatic and aromatic nitriles in the presence of
triflic anhydride leads to the formation of the target
pyrimidines in moderate to good yield and high purity.
The process and results are presented in Scheme 2 and
Table 1. The relatively high reactivities of the thioesters
require low temperatures for their reactions with nitriles and
triflic anhydride. It is noteworthy that the use of S-aryl
Substituted 4-alkylthiopyrimidines 3 and substituted
4-arylthiopyrimidines 4 were easily obtained using alkyl,
aryl and benzyl nitriles.
To extend this synthetic procedure to the preparation of
tris(alkylthio)pyrimidines, intermediates desired for their
synthetic potential, we investigated the reaction between
thioesters and methylthiocyanate. When the latter reacts
with S-methyl butanothioate 1 in the presence of triflic
anhydride, a new product 7 was isolated instead the
anticipated 2,4,6-trimethylthiopyrimidine 6 (Scheme 4).
Scheme 2.
Scheme 4.

A. Herrera et al. / Tetrahedron 59 (2003) 7331–7336
7333
The formation of 7 can be explained by the relatively low
nucleophilic character of the methylthiocyanate compared
to aliphatic and aromatic nitriles. The trifliloxycarbenium
ion formed initially (Scheme 5) is not attacked by a second
molecule of methylthiocyanate. Instead, this intermediate
rearranges with migration of one of the methylthio groups.
After hydrolysis the imidocarbonate 7 is formed.
Scheme 7.
1
(Scheme 7). The complete assignment of the H and 13C
NMR signals of 8 was carried out from a 2D HMQC
spectrum.
This result shows clearly that carbonyl and thioethyl groups
are cis to each other. Because only one of the possible
isomers was detected, the reaction involves a stereoselective
rearrangement process.
We conclude that thioesters react with aliphatic and
aromatic nitriles in the presence of triflic anhydride yielding
substituted 4-alkylthio and 4-arylthiopyrimidines. When
the reaction is carried out using thiocyanates as nitriles, a
new process takes place yielding substituted
dithioimidocarbonates.
Scheme 5.
To identify the migrating thioalkyl group (from methylthio-
cyanate or from methylthioester) and to test the postulated
mechanism, we investigated this reaction using ethylthio-
cyanate. The obtained product corresponds to the ethyl
methyl butyryldithioimidocarbonate 8, indicating that the
thioalkyl group which rearranges comes from the starting
thioester (Scheme 6).
3. Experimental
3.1. General
All reagents were commercial grade and were used as
received unless otherwise indicated. Triflic anhydride was
prepared from triflic acid19 and redistilled twice prior to use.
TLC analyses were performed on silica gel 60F250 plates
and flash chromatography was carried out on silica gel 60
(70–230 mesh). Melting points were measured on a
Gallenkamp apparatus and are uncorrected. Infrared spectra
were taken on a Shimadzu FTIR 8300. Sample pellets were
1
produced with spectroscopic grade potassium bromide. H
NMR and 13C NMR spectra were recorded on a Bruker DPX
300 at 300 MHz for 1H and 75.47 MHz for 13C. The
chemical shifts (dH and dC) are assigned to residual CHCl3
(7.26 and 77.0 ppm, respectively). Coupling constants (J)
are given in Hz. Mass spectra were carried out on a HP
5989A quadrupole instrument at 70 eV (EI) with a source
temperature of 2508C. Electrospray mass spectra (ESI) were
obtained on a Bruker Esquire-LCe using 3500 V as the
ionization voltage, nitrogen as nebulizer gas and methanol
as solvent. Elemental analyses: Perkin–Elmer 2400 CHN.
Scheme 6.
3.2. Preparation of substituted 4-alkylthiopyrimidines
(3a–i) and substituted 4-arylthiopyrimidines (4a–d):
general procedure
In order to determine the stereochemical relationship of
the substituents attached at the CvN bond in 8, we
carried out NOE experiments. Thus, the selective
irradiation of the methyl protons of the butyl group
appearing at d 0.96 produced a clear NOE effect on the
signal corresponding to the methylene protons of the
thioethyl moiety. Moreover, smaller enhancements of
the signals for the CH3 protons of the thioethyl group and
the CH2CO protons were observed. The total absence of the
NOE effect on the SCH3 signal confirms the structure
A mixture of S-methyl butanethioate 1 (1 g, 8.4 mmol) or
S-phenyl ethanethioate 2 (1 g, 6.5 mmol) and the corre-
sponding nitrile (33.6 mmol) dissolved in 30 mL of CH2Cl2
was cooled at 2788C. Triflic anhydride (3.55 g, 12.6 mmol)
in 20 mL of CH2Cl2 is added dropwise. The reaction
mixture is allowed to stand at 08C and stirred at this
temperature during 4 days. The reaction can be monitored

7334
A. Herrera et al. / Tetrahedron 59 (2003) 7331–7336
by TLC. The reaction mixture was hydrolyzed by careful
addition of saturated aqueous solution of sodium hydrogen
carbonate until was basic (pH.8). The organic layer was
separated, washed with brine and dried over MgSO4. The
solvent was evaporated and the residue purified by flash
chromatography using hexane/ethyl acetate 7:3 as eluent.
The crude product was distilled (3a–b, 3g) or recrystallized.
75.41, H 6.63, N 8.38, S 9.59, found C 76.09, H 6.03, N
7.97, S 9.22.
3.2.5. 2,4-Bis(4-chlorophenyl)-5-ethyl-6-(methylthio)-
pyrimidine 3e. Purification of crude product by chroma-
tography affords 2.73 g (87%) of a white solid, mp 151–
1528C (MeOH); n (KBr): 1524, 1487, 1389 cm21; 1H NMR
(CDCl3) d: 1.19 (t, 3H, J¼7.5 Hz, CH3), 2.70 (c, 2H,
J¼7.5 Hz, CH2), 2.72 (s, 3H, CH3S), 7.40–7.49 (m, 6H, Ar-
H), 8.41–8.45 (m, 2H, Ar-H) ppm; 13C NMR (CDCl3) d:
12.99 (CH3CH2), 13.16 (CH3S), 21.70 (CH2), 128.56,
129.17, 129.41, 130.08, 134.99, 136.23, 136.54, 137.26,
159.47, 161.63, 170.16 (arom.) ppm; m/z (EI, 70 eV): 374
(Mþz,62), 373 (100), 359 (16), 341 (30). Anal. calcd for
C19H16Cl2N2S: C 60.80, H 4.30, N 7.46, S 8.54, found C
61.01, H 4.11, N 7.39, S 8.95.
3.2.1. 5-Ethyl-2,4-dimethyl-6-(methylthio)pyrimidine 3a.
Purification of crude product by flash chromatography
affords 1.4 g (92%) of a yellow liquid, bp 1508C/0.3 Torr,
(kugelrohr); n (film): 2968, 2930, 1701, 1541, 1433,
1
858 cm21; H NMR (CDCl3) d: 1.14 (t, 3H, J¼7.6 Hz,
CH3), 2.41 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.58 (s, 3H,
CH3), 2.63 (c, 2H, J¼7.6 Hz, CH2) ppm; 13C NMR (CDCl3)
d: 11.70 (CH3CH2), 12.46 (CH3S), 20.47 (CH3), 20.96
(CH2), 25.09 (CH3), 127.99, 160.41, 163.29, 168.0
(arom.) ppm; m/z (EI, 70 eV): 182 (Mþz,8), 167 (20), 149
(13), 71 (45), 57 (40), 43 (100). Anal. calcd for C9H14N2S:
C 59.30, H 7.74, N 15.37, S 17.59, found C 58.97, H 7.23, N
15.55, S 16.85.
3.2.6. 2,4-Bis(3,4-dimethoxyphenyl)-5-ethyl-6-
(methylthio)pyrimidine 3f. Purification of crude product
by column chromatography affords 2.29 g (64%) of a white
solid, mp 141–1428C (MeOH); n (KBr): 1508, 1387,
1
1269 cm21; H NMR (CDCl3) d: 1.23 (t, 3H, J¼7.5 Hz,
3.2.2. 5-Ethyl-4-(methylthio)-2,6-dioctylpyrimidine 3b.
Purification of crude product by flash chromatography
affords 1.89 g (60%) of a yellow liquid, bp 1508C/0.5 Torr
CH3), 2.73 (s, 3H, CH3S), 2.75 (c, 2H, J¼7.5 Hz, CH2),
3.94–3.98 (broad s, 12H, OCH3), 6.94–7.16 (m, 4H, Ar-H),
8.10–8.18 (m, 2H, Ar-H) ppm; 13C NMR (CDCl3) d: 13.03
(CH3CH2), 13.18 (CH3S), 21.78 (CH2), 55.87, 55.89, 55.94
(OCH3), 110.67, 110.76, 110.95, 112.29, 121.38, 121.43,
128.15, 130.90, 131.74, 148.68, 148.73, 149.54, 151.05,
159.93, 162.29, 169.36 (arom.) ppm; m/z (EI, 70 eV): 426
(Mþz,99), 425 (100), 411 (46), 393 (30). Anal. calcd for
C23H26N2O4S: C 64.77, H 6.14, N 6.57, S 7.52, found: C
64.11, H, 6.39, N 6.11, S, 7.98.
(kugelrohr); n (film): 2957, 2926, 1537, 1466, 1402 cm21
;
1H NMR (CDCl3) d: 0.83–0.98 (m, 6H, CH3), 0.99 (t, 2H,
J¼7.4 Hz, CH2), 1.16 (t, 3H, CH2, J¼7.4 Hz), 1.25–1.40
(m, 18H, CH2), 1.57–1.82 (m, 4H, CH2), 2.53 (s, 3H,
CH3S), 2.63 (c and t overlapped, 4H, J¼7.4 Hz, CH2), 2.82
(t, 2H, J¼7.4 Hz, CH2) ppm; 13C NMR (CDCl3) d: 12.56,
12.79, 13.99 (CH3), 20.81, 22.57, 22.58, 28.37, 29.15,
29.19, 29.35, 29.42, 29.71, 31.77, 31.82, 34.11, 38.97
(CH2), 127.55, 164.73, 167.07, 167.65 (arom.) ppm; m/z
(EI, 70 eV): 378 (Mþz,7), 363 (24), 293 (27), 280 (42), 265
(100). Anal. calcd for C23H42N2S: C 72.96, H 11.18, N 7.40,
S 8.47, found C 73.18, H 10.89, N 6.93, S 8.75.
3.2.7. 2,4-Dibenzyl-5-ethyl-6-(methylthio)pyrimidine 3g.
Purification of crude product by column chromatography
affords 2.24 g (80%) of a yellow liquid, bp 2008C/0.4 Torr
(kugelrohr); n (film): 2968, 2928, 1537, 1393, 698 cm21; 1H
NMR (CDCl3) d: 1.00 (t, 3H, J¼7.5 Hz, CH3), 2.47 (s, 3H,
CH3S), 2.60 (c, 2H, J¼7.5 Hz, CH2), 4.07 (s, 2H, Ar-CH2-
Ar), 4.19 (s, 2H, Ar-CH2-Ar), 7.17–7.40 (m, 10H, Ar-
H) ppm; 13C NMR (CDCl3) d: 12.19 (CH3CH2), 12.75
(CH3S), 21.02 (CH2), 40.65, 45.57 (Ar-CH2-Ar), 126.18,
126.33, 128.12, 128.37, 128.65, 128.81, 129.36, 138.34,
138.83, 162.85, 165.54, 168.92 (arom.) ppm; m/z (EI,
70 eV): 334 (Mþz,66), 319 (100), 301 (30), 91 (34). Anal.
calcd for C21H22N2S: C 75.41, H 6.63, N 8.38, S 9.59, found
C 75.03, H 6.12, N 8.45, S 9.89.
3.2.3. 5-Ethyl-4-(methylthio)-2,6-diphenylpyrimidine 3c.
Purification of crude product by column chromatography
affords 1.35 g (53%) of a white solid, mp 96–978C
1
(MeOH); n (KBr): 2959, 2922, 1527, 1391, 694 cm21; H
NMR (CDCl3) d: 1.19 (t, 3H, J¼7.5 Hz, CH3), 2.72 (c, 2H,
J¼7.5 Hz, CH2), 2.74 (s, 3H, CH3S), 7.44–7.55 (m, 8H, Ar-
H), 8.49 (m, 2H, Ar-H) ppm; 13C NMR (CDCl3) d: 13.04,
13.09 (CH3), 21.71 (CH2), 128.07, 128.21, 128.29, 128.64,
128.98, 130.22, 137.87, 138.98, 160.30, 162.82, 169.6
(arom.) ppm; m/z (EI, 70 eV): 306 (Mþz,63), 305 (100), 291
(22), 273 (32). Anal. calcd for C19H18N2S: C 74.47, H 5.92,
N 9.14, S 10.46, found C 73.85, H 5.01, N 9.25, S 10.39.
3.2.8. 5-Ethyl-2,4-bis(4-methylbenzyl)-6-(methylthio)-
pyrimidine 3h. Purification of the crude product affords
1.52 g of an undistillable oil; n (film): 2970, 2928,
1
3.2.4. 5-Ethyl-2,4-bis(4-methylphenyl)-6 (methylthio)-
pyrimidine 3d. Purification of crude product affords
2.41 g of a white solid, mp 104–1058C (MeOH); n (KBr):
1539, 1514, 908 cm21; H NMR (CDCl3) d: 1.01 (t, 3H,
J¼7.5 Hz, CH3), 2.30 (s, 3H, Ar-CH3), 2.33 (s, 3H, Ar-CH3),
2.49 (s, 3H, CH3S), 2.59 (c, 2H, J¼7.5 Hz, CH2), 4.03
(s, 2H, Ar-CH2Ar), 4.15 (s, 2H, Ar-CH2-Ar), 7.07–7.34
(m, 8H, Ar-H) ppm; 13C NMR (CDCl3) d: 12.19
(CH3CH2), 12.70 (CH3S), 20.93, 20.95 (Ar-CH3), 20.98
(CH2), 40.24, 45.16 (Ar-CH2-Ar), 128.48, 128.65,
128.79, 129.02, 129.17, 135.26, 135.75, 135.80,
163.04, 165.61, 168.77 (arom) ppm; m/z (EI, 70 eV):
362 (Mþz,53), 347 (100), 329 (18). Anal. calcd for
C23H26N2S: C 76.20, H 7.23, N 7.73, S 8.84, found C
75.75, H 6.91, N 7.00, S 8.21.
1
1528, 1506, 1391 cm21; H NMR (CDCl3) n: 1.19 (t, 3H,
J¼7.7 Hz, CH3), 2.42 (s, 3H, CH3S), 2.44 (s, 3H, CH3), 2.72
(c, 2H, J¼7.7 Hz, CH2), 2.73 (s, 3H, CH3), 7.24–7.31 (m,
4H, Ar-H), 7.46–7.50 (m, 2H, Ar-H), 8.39–8.43 (m, 2H,
Ar-H) ppm; 13C NMR (CDCl3) n: 13.13 (CH3CH2), 21.33
(CH2), 21.47 (CH3-Ar), 21.74 (CH3S), 128.10, 128.66,
128.91, 129.03, 135.22, 136.18, 138.58, 140.35, 160.33,
162.75, 169.40 (arom.) ppm; m/z (EI, 70 eV): 334 (Mþz,59),
333 (100), 319 (47), 301 (37). Anal. calcd for C21H22N2S: C

A. Herrera et al. / Tetrahedron 59 (2003) 7331–7336
7335
3.2.9. 2,4-Bis(4-chlorobenzyl)-5-ethyl-6-(methylthio)-
pyrimidine 3i. Purification of crude product affords 1.38 g
(41%) of an undistillable oil; n (film): 2970, 2932, 2253,
1541, 1491, 1391, 908, 733 cm21; 1H NMR (CDCl3) d: 1.03
(t, 3H, J¼7.6 Hz, CH3), 2.47 (s, 3H, CH3S), 2.60 (c, 2H,
J¼7.6 Hz, CH2), 4.01 (s, 2H, Ar-CH2-Ar), 4.13 (s, 2H, Ar-
CH2-Ar), 7.08–7.34 (m, 8H, Ar-H) ppm; 13C NMR
(CDCl3) d: 12.35 (CH3CH2), 12.87 (CH3S), 21.09 (CH2),
39.80, 44.76 (Ar-CH2-Ar), 128.17, 128.43, 128.77, 129.98,
130.66, 132.05, 132.20, 136.70, 137.11, 162.34, 165.14,
169.21 (arom) ppm; m/z (EI, 70 eV): 402 (Mþz,56), 387
(100), 369 (23). Anal. calcd for C21H20Cl2N2S: C 62.53,
H 5.00, N 6.94, S 7.95, found C 62.11, H 4.37, N 6.01, S
7.28.
NMR (CDCl3) d: 55.77, 55.84, 55.89, 55.96 (OCH3),
109.15, 109.99, 110.60, 110.96, 111.00, 120.15, 121.66,
128.75, 129.44, 129.56, 129.71, 130.34, 135.96, 148.66,
149.17, 151.34, 151.41, 162.30, 163.11, 171.72
(arom.) ppm; m/z (EI, 70 eV): 460 (Mþz,100), 459 (78),
445 (15), 429 (7), 414 (16). Anal. calcd for C26H24N2O4S: C
67.81, H 5.25, N 6.08, S 6.96, found C 67.75, H 5.39, N
5.91, S, 7.07.
3.2.14. {[1,1-bis(phenylthio)ethyl]thio}benzene 5. Triflic
anhydride (3.7 g, 13.14 mmol) in 20 mL of CH2Cl2 was
added to a solution containing 1 g (6.57 mmol) of S-phenyl
ethanethioate 2 in 30 mL of CH2Cl2. The reaction mixture is
allowed to stand at 08C during one week. The reaction
mixture was hydrolyzed by addition of saturated aqueous
solution of sodium hydrogen carbonate. The organic layer
was separated, dried and the solvent removed under reduced
pressure. The crude solid was purified by column chroma-
tography affording 0.81 g (35%) of a yellow solid, mp 140–
3.2.10. 2,4-Dimethyl-6-(phenylthio)pyrimidine 4a. Puri-
fication of crude product affords 0.70 g (43%) of a white
solid, mp 52–548C (MeOH); n (KBr): 2218, 1560, 1541,
908, 733 cm21; 1H NMR (CDCl3) d: 2.31 (s, 3H, CH3), 2.64
(s, 3H, CH3S), 6.37 (s, 1H,), 7.48–7.64 (m, 5H, Ar-H) ppm;
13C NMR (CDCl3) d: 23.86, 25.55 (CH3), 112.67, 128.05,
129.72, 129.84, 135.51, 165.81, 166.77, 172.51
(arom.) ppm; m/z (EI, 70 eV): 216 (Mþz,58), 215 (100),
201 (17), 176 (31). Anal. calcd for C12H12N2S: C 66.64, H
5.55, N 12.95, S 14.82, found C 66.39, H 5.03, N 12.83, S
15.01.
1
1418C (EtOH); n (KBr): 1464, 754, 704 cm21; H NMR
(CDCl3) d: 1.41 (s, 3H, CH3), 7.34–7.41 (m, 9H), 7.65–
7.69 (m, 6H) ppm; 13C NMR (CDCl3) d: 29.23 (CH3), 70.55
(C), 128.52, 129.40, 132.31, 136.84 (arom.) ppm; m/z (ESI):
377 [MþNa]þ. Anal. calcd for C20H18S3: C 67.75, H 5.12, S
27.13, found C 67.59, H 5.05, S 26.89.
3.2.15. Dimethyl butyryldithioimidocarbonate 7. Follow-
ing the general procedure for the preparation of substituted
4-alkylthiopyrimidines, when S-methyl butanethioate was
reacted with methyl thiocyanate, purification of the crude
product by chromatography affords 0.96 g of a colorless
liquid, bp 1008C/0.5 Torr (kugelrohr); n (film): 2962, 2928,
1691, 1578, 1460, 1153 cm21; 1H NMR (CDCl3) d: 0.96 (t,
3H, J¼7.5 Hz, CH3), 1.68 (hex, 2H, J¼7.5 Hz, CH2), 2.48
(t, 2H, J¼7.5 Hz, CH2), 2.48 (s, 6H, 2 SCH3) ppm; 13C
NMR (CDCl3) d: 13.63 (CH3), 15.29 (CH3S), 18.08, 40.48
(CH2), 170.12 (CvN), 184.78 (CvO) ppm; m/z (ESI): 230
[MþK]þ, 214 [MþNa]þ, 192 [MþH]þ. Anal. calcd for
C7H13NOS2: C 43.95, H 6.85, N 7.32, S 33.52, found C
43.75, H 6.33, N 7.01, S 33.01.
3.2.11. 2,4-Diphenyl-6-(phenylthio)pyrimidine 4b. Puri-
fication of crude product by column chromatography affords
1.18 g (53%) of a white solid, mp 104–1068C (MeOH); n
(KBr): 1553, 1520, 1369, 745, 689 cm21; 1H NMR (CDCl3)
d: 7.13 (s, 1H), 7.47–7.56 (m, 9H), 7.71–7.76 (m, 2H),
8.01–8.06 (m, 2H), 8.49–8.54 (m, 2H) ppm; 13C NMR
(CDCl3) d: 110.34, 127.14, 128.34, 128.45, 128.50, 128.77,
129.71, 129.89, 130.73, 135.78, 136.81, 136.97, 137.38,
163.06, 163.67, 172.82 (arom) ppm; m/z (EI, 70 eV): 340
(Mþz,71), 339 (100), 263 (9), 236 (21). Anal. calcd for
C22H16N2S: C 77.62, H 4.74, N 8.23, S 9.42, found C 77.01,
H 4.49, N 7.85, S 9.07.
3.2.12. 2,4-Bis(4-methylphenyl)-6-(phenylthio)pyri-
midine 4c. Purification of crude product by column
chromatography affords 1.16 g (48%) of a white solid, mp
150–1528C (MeOH); n (KBr): 1545, 1516, 1504, 1367,
1321 cm21; 1H NMR (CDCl3) d: 2.41 (s, 3H, CH3), 2.42 (s,
3H, CH3), 7.06 (s, 1H), 7.25–7.28 (m, 4H), 7.51–7.54 (m,
3H), 7.69–7.74 (m, 2H), 7.89–7.93 (m, 2H), 8.36–8.40 (m,
2H) ppm; 13C NMR (CDCl3) d: 21.39, 21.48 (CH3), 109.73,
127.04, 128.41, 128.71, 129.07, 129.46, 129.64, 129.77,
134.28, 134.79, 135.76, 140.88, 141.01, 162.99, 163.69,
172.44 (arom.) ppm; m/z (EI, 70 eV): 368 (Mþz,67), 367
(100), 277 (5), 250 (10). Anal. calcd for C24H20N2S: C
78.23, H 5.47, N 7.60, S 8.70, found C 77.77, H 5.11, N
7.85, S 8.99.
3.2.16. Ethyl methyl butyryldithioimidocarbonate 8.
Following the general procedure for the preparation of
substituted 4-alkylthiopyrimidines, when S-methyl butane-
thioate was reacted with ethyl thiocyanate, purification of
the crude product by chromatography affords 0.44 g of a
colorless liquid, bp 758C/0.4 Torr (kugelrohr); n (film):
1
1670, 1578, 1215 cm21; H NMR (CDCl3) d: 0.96 (t, 3H,
J¼7.5 Hz, CH3CH2), 1.32 (t, J¼7.5 Hz, 3H, CH3CH2S),
1.68 (hex., 2H, J¼7.5 Hz, CH3CH2CH2), 2.46 (t, 2H,
J¼7.5 Hz, CH2CO), 2.46 (s, 3H, SCH3), 3.05 (c, 2H,
J¼7.5 Hz, CH2S) ppm; 13C NMR (CDCl3) d: 13.78 (CH3),
14.00 (CH3CH2S), 15.39 (CH3S), 18.21 (CH3CH2CH2),
26.88 (CH2S), 40.41 (CH2CO), 168.78 (CvN),
184.77 (CvO) ppm; m/z (ESI): 228 [MþNa]þ, 206
[MþH]þ. Anal. calcd for C8H15NOS2: C 46.80, H 7.36,
N 6.82, S 31.23, found C 46.39, H 7.11, N 6.51, S
30.29.
3.2.13. 2,4-Bis(3,4-dimethoxyphenyl)-6-(phenylthio)-
pyrimidine 4d. Purification of crude product by column
chromatography affords 1.69 g (56%) of a white solid, mp
165–1668C (MeOH);
;
n (KBr): 1556, 1512, 1258,
1232 cm21 1H NMR (CDCl3) d: 3.92 (s, 3H, OCH3),
3.95 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 3.99 (s, 3H, OCH3),
6.92–6.97 (m, 2H), 7.08 (s, 1H), 7.49–7.56 (m, 4H), 7.69–
7.73 (m, 3H), 7.92 (m, 1H), 8.10–8.14 (m, 1H) ppm; 13C
Acknowledgements
We gratefully acknowledge the DGSEIC (Spain, grant

7336
A. Herrera et al. / Tetrahedron 59 (2003) 7331–7336
S. S.; Shukla, P. K.; Ram, V. J. Bioorg. Med. Chem. Lett. 2000,
10, 703.
PB98-0803) for financial support. We thank the CAIs of the
UCM for determining NMR, mass spectra and elemental
analyses. We thank Dr J. Almy (California State University,
Stanislaus) for his fruitful discussions.
10. Kim, Y.-Z.; Lim, J.-C.; Yeo, J.-H.; Bang, C.-S.; Kim, W.-S.;
Kim, S.-S.; Woo, Y.-M.; Yang, D.-H.; Oh, H.; Nahm, K.
J. Med. Chem. 1994, 37, 3828.
11. Mai, A.; Artico, M.; Sbardella, G.; Massa, S.; Loi, A. G.;
Tramontano, E.; Scano, P.; La Colla, P. J. Med. Chem. 1995,
38, 3258.
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