Synthesis of 4-Substituted 2-Phenylaminothiazoles from Amidines. a Convenient Route to 4-Trichloromethylthiazoles

Full text of DOI:10.1021/jo0009447

7244
J . Org. Chem. 2000, 65, 7244-7247
isothiocyanate 2 with amidine salts 1a , b, d in a THF-
Syn th esis of 4-Su bstitu ted
50% aqueous sodium hydroxide mixture at 0 °C gave the
thiocarbamoylamidines 3a , b, d (Scheme 1) in good yields
(Table 1). Because of the pronounced hydrolytic sensitiv-
ity, 3c was generated under anhydrous conditions from
formamidine acetate 1c using triethylamine as the base.
Thiocarbamoylamidine 3e was prepared in nearly quan-
titative yield from free trichloroacetamidine 1e.11
2-P h en yla m in oth ia zoles fr om Am id in es. A
Con ven ien t Rou te to
4-Tr ich lor om eth ylth ia zoles
Moise´s Romero-Ortega,*,† Adriana Aviles,†
Raymundo Cruz,‡ Aydee Fuentes,†
Rosa Mar´ıa Go´mez,† and Andre´s Plata†
The reaction of N-thiocarbamoylbenzamidine 3a with
phenacyl bromide 4a occurred readily at room temper-
ature,12 in the presence of 1 equiv of triethylamine,13 to
give 2-phenylamino-4-phenyl-5-benzoylthiazole 6a di-
rectly in 78% yield (Table 2). The thiocarbamoylamidines
3b-d were also converted into the corresponding thia-
zoles 6b-d under identical conditions. In contrast, alky-
lation of the trichloroacetamidine derivative 3e gave the
intermediate S-alkylated 5e in 95% yield. This compound
exist as enol tautomeric form,8,14 as established by 1H
spectroscopy, presumably as a consequence of the high
electrophilicity of the trichloroacetylimino moiety. When
a solution of this compound in toluene was heated at
reflux temperature, ammonia was eliminated and the
expected 4-tricholoromethylthiazole 6e was formed (64%)
(Scheme 2). Under the same conditions but in the
presence of one equivalent of a strong base such as DBU,
the loss of trichloromethide took place (loss of amide
being very unfavorable) and the unexpected 4-aminothia-
zole 6i was obtained instead (66%).
The alkylation of the N-phenylthiocarbamoylamidines
3 with ethyl bromoacetate 4b was also studied. In all the
cases examined (3a ,b,e) the S-alkylated intermediates
5f,g,h were readily isolable although 5g was quite
unstable. The cyclization of 5f,g in toluene containing 1
equiv of DBU gave the expected thiazoles 6f,g, but 5h
gave the 4-aminothiazole 6j under these conditions. As
observed for 5e, however, heating 5h in the absence of
DBU gave the expected 4-trichloromethylthiazole 6h .
Finally, it should be noted that the processes described
herein are not restricted to arylisothiocyanates. For
example, ethyl isothiocyanate with benzamidine hydro-
chloride 1a gives N-ethylthiocarbamoylbenzamidine 3f
in 85%, the reaction with phenacyl bromide 4a gave rise
to 2-(ethylamino)-4-phenyl-5-benzoylthiazole 6k 68%
(Scheme 3). A most attractive feature of this process
therefore is that the substituents can be varied at will
at all of the thiazole carbon atoms. Furthermore, because
the trichloromethyl moiety is readily modified chemi-
cally,15 the diversity of possible substituents in C-4 can
be substantially increased. It is to be expected that this
synthesis of thiazoles will find extensive utility.
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica,
Universidad Auto´noma del Estado de Me´xico, Paseo Colo´n/
Paseo Tollocan s/ n Toluca Estado de Me´xico, C.P.50000,
Mexico, and Instituto de Quı´mica, Universidad Nacional
Auto´noma de Me´xico, Ciudad Universitaria, Mexico, D.F.
romero.ortega@usa.net
Received J une 22, 2000
The 2-aminothiazole moiety is frequently found in
biologically active molecules that, for example, may have
utility in the treatment of allergies,1 hypertension,2
inflammation,3 schizophrenia,4 as antibiotics,5 and (HIV)6
infections. They also exhibit some antitumoral proper-
ties.7 In addition, Lin et al.8 have reported that 1-phen-
ylamino-5-aroylthiazoles exhibit good in vivo bacterio-
cidal activity. These compounds were prepared by the
base-induced reaction of phenacyl bromide with N-
phenylthiocarbamoylamidines which in turn were ob-
tained from phenylthioureas and amide acetals.8 This
synthesis is limited to those thiazole derivatives bearing
H, alkyl or aryl groups C-4.9 This paper describes an
alternative route to diverse N-phenylthiocarbamoyla-
midines, which as a consequence, permits the synthesis
of 2-phenylamino-5-acylthiazoles bearing a wide variety
of C-4 substituents.
We reasoned that the required N-phenylthiocarbam-
oylamidines10 ought to be accessible from phenyl isothio-
cyanate 2 and amidines 1, a wide variety of which are
readily available. Indeed, the condensation of phenyl
* To whom correspondence should be addressed. Tel: (7) 2173890.
Fax: (7)2175109.
† Universidad Auto´noma del Estado de Me´xico.
‡ Universidad Nacional Auto´noma de Me´xico.
(1) Hargrave, K. D.; Hess, F. K.; Oliver, J . T. J . Med. Chem. 1983,
26, 1158.
(2) Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J .; Taylor,
D. G.; Connolly, C. J .; Doherty, A. M.; Klutchko, S. R.; Sircar, I.;
Steinbaugh, B. A.; Batley, B. L.; Painchaud, C. A.; Rapundalo, S. T.;
Michniewicz, B. M.; Olson, S. C. J . Med. Chem. 1992, 35, 2562.
(3) (a) Haviv, F.; Ratajczyk, J . D.; DeNet, R. W.; Kerdesky, F. A.;
Waltwers, R. L.; Schmidt, S. P.; Holms, J . H.; Young, P. R.; Carter, G.
W. J . Med. Chem. 1988, 31, 1719. (b) Clemence, F.; Le Martret, O.;
Delevalle, F.; Benzoni, J .; J ouanen, A.; J ouquey, S.; Mouren, M.;
Dereat, R. J . Med. Chem. 1988, 31, 1453.
(4) J aen, J . C.; Wise, L. D.; Caprathe, B. W.; Tecle, H.; Bergmeier,
S.; Humblet, C. C.; Heffner, T. G.; Meltzner, L. T.; Pugsley, T. A. J .
Med. Chem. 1990, 33, 1453.
(5) (a) Dridi, K.; Efrit, E. L.; Baccar, B.; Zantour, H. Synth. Commun.
1998, 29, 167 and references therein. (b) Tsuji, K.; Ishikawa, H. Bioorg.
Med. Chem. Lett. 1994, 4, 1601.
(6) Bell, F. W.; Cantrell, A. S.; Hogberg, M.; J askunas, S. R.;
J ohansson, N. G.; J ordan, C. L.; Kinnick, M. D.; Lind, P.; Morin, J .
M.; Noreen, R.; Oberg, B.; Palkowitz, J . A.; Parrish, C. A.; Pranc, P.;
Sahlberg, C.; Ternansky, R. J .; Vasileff, R. T.; Vrang, L.; West, S. J .;
Zhang, H.; Zhou, X. X. J . Med. Chem. 1995, 38, 4929.
(7) Komar, Y.; Green, R.; Wise, D.; Worting, L. L. J . Med. Chem.
1988, 23, 501.
(11) Albert, A.; Paal, B. Chem. Ind. (London) 1974, 874. Trichloro-
acetamidine is a much weaker base (pKa ) 6.5) than acetamidine (pKa
) 12.4; ref 11).
(12) Dridi, K.; Elefrit, M. L.; Baccar, B.; Zantour, H. Synth. Commun.
1999, 29, 2019.
(13) Brindley, J . C.; Caldwell, J . M.; Meakins, G. D.; Plackett, S. J .;
Price, S. J . Chem. Soc., Perkin Trans. 1 1987, 1153.
(14) (a) Kaye, P. T.; Meakins, G. D.; Smith, A. K.; Tirel, M. D. J .
Chem. Soc., Perkin Trans. 1 1983, 1677. (b) Meslin, J . C.; Quiniou, H.
Tetrahedron 1975, 31, 3055. (c) Meslin, J . C.; Quiniou, H. Synthesis
1974, 298.
(8) Yang-i Lin, C. M.; Seifert, S. M.; Kang, J . P.; Lang, S. A. J .
Heterocycl. Chem. 1979, 16, 1377.
(9) Hanessian, S.; Moralioglu, E. Can. J . Chem. 1972, 50, 233.
(10) Kurzer, F.; Tertink, W. J . Chem. Soc. 1959, 2851.
(15) (a) Romero, M.; Fuentes, A.; Gonzalez, C.; Morales, D.; Cruz,
R. Synthesis 1999, 225. (b) Guzman, A.; Romero, M.; Talamas, F. X.;
Villena, R.; Grennhouse, R.; Muchowski, J . M. J . Org. Chem. 1996,
61, 2470.
10.1021/jo0009447 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/27/2000

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7245
Sch em e 1
Ta ble 1. F or m a tion of Th ioca r ba m oyla m id in es 3 fr om
Am id in es
Sch em e 2
thiocarbamoylamidine 3
compd
yield (%)
a
b
c
d
e
76
63
a
71
98
a
Unstable, not purified identified by IR and 1H NMR spectros-
copy.
Ta ble 2. P r ep a r a tion of 2,4,5-Tr isu bstitu ted Th ia zoles 6
fr om Th ioca r ba m oyla m id in es 3
S-alkylated product 5
2-phenylaminothiazole 6
yield (%) from 3
compd
yield (%)
a
b
c
d
e
f
g
h
i
a
a
a
78
71
83
53
64
76
68
35
66
41
a
95
75
b
90
j
triethylamine, and DBU were commercially available from
Aldrich Chemical Co. and were used without further purification.
All solvents were purified and dried prior to use.16 Trichloro-
acetamidine,11 and diethoxyacetamidine hydrobromide17 were
a
b
Not observed. Unstable, not purified.
Exp er im en ta l Section
Benzamidine hydrochloride, acetamidine hydrochloride, for-
mamidine acetate, phenyl isothiocyanate, ethyl isothiocyanate,
phenacyl bromide, ethyl bromoacetate, trichloroacetonitrile,
(16) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.
(17) Schaefer, F. C.; Peters, G. A. J . Org. Chem. 1961, 26, 412.

7246 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
N-P h en ylth iocar bam oyltr ich lor oacetam idin e (3e). Phen-
yl isothiocyanate 2 (4.0 mL, 0.03 mol) was added to solution of
trichloroacetamidine11 1e (5 g, 0.03 mol) in dichloromethane (5
mL) at room temperature. It was stirred for 1 h. Crystallization
of this solid from hexane-dichloromethane gave 3e (98%): mp
Sch em e 3
86-87 °C; IR 3451, 3377, 1640, 1095 cm-1 1H NMR δ 7.15-
;
7.32 (m, 3H), 7.35-7.51 (m, 2H), 8.56 (broad, 1H, NH), 8.80
(broad, 2H, NH2); mass spectrum m/ z 295 (42, M+), 90 (100).
Anal. Calcd for C9H8Cl3N3S: C, 36.44; H, 2.71; Cl, 35.85; N,
14.16. Found: C, 36.14; H, 2.67; Cl, 35.69; N, 14.32.
N-Eth ylth ioca r ba m oylben za m id in e (3f). Prepared in the
same manner as described for 3a except that ethyl isothiocy-
anate was used instead phenyl isothiocyanate 2. The residue
was purified by column chromatography on silica gel using
hexanes-ethyl acetate (9:1), 3f was obtained in 85% as an oil:
IR 3297, 2974, 2931, 1615, 1507, 1446 cm-1; 1H NMR δ 1.25 (t,
3H), 3.63 (q, 2H), 7.40-7.55 (m, 3H), 7.78-8.17 (m, 2H); mass
spectrum m/z 207 (100, M+), 163 (34), 104 (82). Anal. Calcd for
C10H13N3S: C, 57.94; H, 6.31; N, 20.27; S, 15.47. Found: C,
57.85; H, 6.66; N, 20.12; S, 15.20.
Syn th esis of th e 2-P h en yla m in o-5-ben zoylth ia zoles (6)
w ith ou t Isola tion of (5). Phenacyl bromide 4a in acetone (1
equiv, 5 mL/ mmol) was added to a solution of the N-phenyl-
thiocarbamoylamidine 3 (1 equiv) in acetone (2.5-5 mL/mmol
amidine derivative) containing triethylamine (1 equiv) at room
temperature. After the mixture was stirred for 5-8 h, ethyl
acetate was added and the organic phase was washed with
saturated NaCl solution, dried (Na2SO4), and evaporated in
vacuo. Crystallization of the solid residue from hexane-dichlo-
romethane gave the thiazoles 6.
prepared according to the published procedures. Melting points
are uncorrected and were measured on a Mel-Temp II apparatus.
1H NMR spectra were recorded on a 200 MHz spectrometer using
CDCl3 as solvent and are reported in (δ) ppm from internal
tetramethylsilane. 13C NMR spectra were also recorded in CDCl3
solution. The IR spectra were measured in CHCl3 solution.
Syn th esis of th e N-P h en ylth ioca r ba m oyla m id in es (3).
A suspension of amidine salt (1 equiv) in THF (2-5 mL/mmol
amidine) was added at 0 °C to aqueous sodium hydroxide (1
equiv) and phenyl isothiocyanate 2 (1 equiv), and the reaction
mixture was stirred for 1-2 h at this temperature. It was then
diluted with ethyl acetate (20 mL), and the organic phase was
washed with saturated sodium chloride solution and dried
(Na2SO4). Evaporation of the solvent in vacuo gave the crude
products as solids. The pure material was obtained after
crystallization from hexane-dichloromethane.
2-P h en yla m in o-4-p h en yl-5-ben zoylth ia zole (6a ). N-Phen-
ylcarbamoylbenzamidine 3a was converted into the correspond-
ing 2-phenylamino-5-benzoylthiazole 6a as described in general
method. After crystallization 6a was obtained in 78% yield: mp
1
201-3 °C; IR 3392, 1601, 1532 cm-1; H NMR δ 7.04-7.34 (m,
13H), 7.46-7.51 (m, 2H), 8.92 (broad, 1H); mass spectrum m/ z
356 (100, M+). Anal. Calcd for C22H16N2OS: C, 74.13; H, 4.52;
N,7.85; S, 8.99. Found: C, 74.07; H, 4.47, N, 7.86; S, 8.82.
2-P h en yla m in o-4-m eth yl-5-ben zoylth ia zole (6b). N-Phen-
ylcarbamoylacetamidine 3b was converted into the correspond-
ing 2-phenylamino-4-methyl-5-benzoylthiazole 6b as described
in the general method. 6b was obtained in 71% after crystal-
N-P h en ylth ioca r ba m oylben za m id in e (3a ). Benzamidine
hydrochloride 1a was converted into the corresponding N-
phenylthiocarbamoylbenzamidine 3a as described in the general
method. After crystallization, 3a was obtained in 76% as yellow
1
crystals: mp 116-118 °C; IR 3473, 3394, 1615, 1085 cm-1; H
NMR δ 7.15-7.65 (m, 8 H), 7.78-7.98 (m, 2 H), 8.78 (br, 1 H,
NH), 11.2 (broad, 2 H, NH2); mass spectrum m/ z 255 (20, M+),
135 (100). Anal. Calcd for C14H13N3S: C, 65.85; H, 5.13; N, 16.45.
Found: C, 65.74; H, 5.14; N, 16.30.
lization: mp 170-72 °C; IR 3393, 2847, 1598, 1534 cm-1 1H
;
NMR δ 2.41 (s, 3H), 7.16-7.54 (m, 8H) 7.70-7.75 (m, 2H); mass
spectrum m/ z 294 (70, M+), 293 (100). Anal. Calcd for C17H14N2-
OS: C, 69.36; H, 4.79; N,9.51; S, 10.89. Found: C, 69.30; H, 4.86,
N, 9.81; S, 11.09.
N-P h en ylth ioca r ba m oyla ceta m id in e (3b). Acetamidine
hydrochloride 1b was converted into the corresponding N-
phenylthiocarbamoylacetamidine 3b as described in the general
method. 3b was obtained in 63% as yellow crystals: mp 93-95
2-P h en yla m in o-5-ben zoylth ia zole (6c). Prepared in the
general manner except that the thiocarbamoylformamidine 3c
was used as crude material. The pure material was obtained in
83% yield after crystallization: mp 125-6 °C; IR 3403, 1599,
°C; IR 3437, 3389, 1618, 1102 cm-1 1H NMR δ 2.17 (s, 3H),
;
7.11-7.48 (m, 3H), 7.61-7.64 (m, 2H); mass spectrum m/ z 193
(10, M+), 135 (100). Anal. Calcd for C9H11N3S: C, 55.92; H, 5.73;
N, 21.75. Found: C,55.63; H, 5.60; N, 21.78.
1530 cm-1 1H NMR δ 6.85 (s, 1H), 7.04-7.45 (m, 8H), 7.83-
;
7.88 (m, 2H); mass spectrum m/ z 280 (5, M+), 252 (100). Anal.
Calcd for C16H12N2OS: C, 68.55; H, 4.31; N,9.99; S, 11.43.
Found: C, 68.70; H, 4.37, N, 9.86; S, 11.26.
N-P h en ylth ioca r ba m oylfor m a m id in e (3c). It was not
possible to obtain an analytically pure sample of this compound
because of the pronounced tendency of N-phenylthiocarbamoyl-
formamidine 3c to be converted into the hydrolysis product
under aqueous conditions, therefore this substance was gener-
ated and used directly without purification. Thus, to a suspen-
sion of formamidine acetate 1c (1.2 g, 0.011 mol) in anhydrous
THF (25 mL) containing anhydrous triethylamine (1.5 mL, 1.11
g, 0.011 mol) was added phenyl isothiocyanate 2 (1.3 mL, 1.48
g, 0.011 mol) at 0 °C. The reaction mixture was stirred at 0 °C
for 3 h. It was then diluted with ethyl acetate (50 mL) and the
organic phase was washed with saturated sodium chloride
solution, and dried (Na2SO4). Evaporation of the solvent in vacuo
gave a residue that without purification was used for the
synthesis of 2-phenylamino-5-benzoylthiazole 6c.
2-P h en ylam in o-4(dieth oxy)m eth yl-5-ben zoylth iazole (6d).
N-Phenylthiocarbamoyldiethoxyacetamidine 3a was converted
into the corresponding 2-phenylamino-4-(diethoxy)methyl-5-
benzoylthiazole 6d as described in the general method. 6d was
obtained in 53% yield after crystallization: mp 158-9 °C; IR
3288, 2976, 2928, 2895, 1599, 1557 cm-1; 1H NMR δ 1.23 (t, 6H),
3.65-3.81 (m, 4H), 5.69 (s, 1H), 7.24-7.58 (m, 8H), 7.77-7.82
(m, 2H); 13C NMR δ 15.31, 63.62, 97.24, 120.57, 122.11, 125.07,
128.69, 129.79, 132.41, 139.34, 140.30, 157.29, 169.25, 187.56;
mass spectrum m/ z 382 (10, M+), 307 (100). Anal. Calcd for
C
21H22N2O3S: C, 65.94; H, 5.79; N, 7.32; S, 8.38. Found: C,
65.46; H, 5.97; N, 7.42; S, 8.70.
2-Eth yla m in o-4-p h en yl-5-ben zoylth ia zole (6k ). This com-
pound was prepared in the same manner as described in the
general method except that N-ethylthiocarbamoylbenzamidine
3f was used. After crystallization, 6k was obtained in 68%
yield: mp 165-6 °C (hexane-dichloromethane); IR 3411, 3201,
2980, 1601, 1545, 1475 cm-1; 1H NMR δ 1.11 (t, 3H), 1.88 (broad,
1H), 3.15 (q, 2H), 7.02-7.28 (m, 8H), 7.40-7.48 (m, 2H); 13C
NMR δ 13.89, 41.34, 127.67, 127.81, 128.75, 129.13, 129.81,
131.24, 135.13, 138.46, 159.44, 172.75, 188.68; mass spectrum
m/ z 308 (100, M+), 279 (11). Anal. Calcd for C18H16N2OS: C,
N-P h en ylth ioca r ba m oyld ieth oxya ceta m id in e (3d ). Di-
ethoxyacetamidine hydrobromide17 1d was converted into the
corresponding N-phenylthiocarbamoyldiethoxyacetamidine 3d
as described in general method. 3d was obtained in 71% as
yellow crystals: mp 90-92 °C; IR 3437, 3395, 2981, 2891 cm-1
;
1H NMR δ 1.25 (t, 6H), 3.55-3.79 (m, 4H), 4.95 (s, 1H), 7.21-
7.56 (m, 3H), 7.60-7.78 (m, 2H); mass spectrum m/ z 281 (48,
M+), 135 (100). Anal. Calcd for C13H19N3O2S: C, 55.49; H, 6.80;
S, 11.39. Found: C, 55.02; H, 6.77; S, 11.19.

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7247
70.10; H, 5.23; N, 9.08; S, 10.39. Found: C, 69.87, H, 5.32; N,
9.08; S, 10.50.
2-P h en yla m in o-4-m eth yl-5-eth oxyca r bon ylth ia zole (6g).
Ethyl bromoacetate 4b (0.55 mL, 0.835 g, 5 mmol) was added
to a stirred solution of the N-phenylthiocarbamoylacetamidine
3b (0.965 g, 5 mmol), containing triethylamine (0.7 mL, 0.5 g, 5
mmol), at room temperature. The reaction mixture was stirred
for 2 h, ethyl acetate (50 mL) was added to the reaction mixture,
and the organic phase was separated, washed with saturated
NaCl solution, and dried (Na2SO4). Evaporation of the solvent
in vacuo, gave a residue that was dissolved in toluene (20 mL),
DBU (0.75 mL, 0.761 g, 5 mmol) was added, and the solution
was then heated at 100 °C in a nitrogen atmosphere for 2 h.
The solution was cooled to room temperature, diluted with ethyl
acetate (50 mL), washed successively with water and saturated
NaCl solution, dried (Na2SO4), and evaporated in vacuo. The
product was then obtained from the residue by column chroma-
tography from hexanes-ethyl acetate (8:2) 6g was obtained after
crystallization from hexane-dichloromethane in 68% yield: mp
138-9 °C; IR 3396, 2983, 2934, 1694, 1597 cm-1; 1H NMR δ 1.33
(t, 3H), 2.58 (s, 3H), 4.28 (q, 2H), 7.11-7.44 (m, 5H), 8.16 (broad,
1H); mass spectrum m/ z 262 (100, M+). Anal. Calcd for
P h en a cyl Br om id e (4a )/Eth yl Br om oa ceta te (4b) S-
Alk yla tion of N-P h en ylth ioca r ba m oyla m id in es (3). Gen -
er a l P r oced u r e. The R-bromo carbonyl compound (1 equiv) was
added slowly at room temperature to a stirred solution of the
N-phenylthiocarbamoylamidine (3, 1 equiv) in anhydrous THF
(2 mL) containing anhydrous triethylamine (1 equiv) maintained
in a nitrogen atmosphere. The reaction mixture was stirred for
an additional 2-3 h, it was then diluted with ethyl acetate (20
mL), the mixture was washed with saturated NH4Cl solution
(30 mL), and the organic phase was separated, dried (Na2SO4),
and evaporated in vacuo.
S-Alk yla tion of N-P h en ylth ioca r ba m oyltr ich lor oa cet-
a m id in e (3e) w ith P h en a cyl Br om id e (4a ). 5e was obtained
in 95% yield after crystallization of the solid residue from
hexane-dichloromethane: mp 115-6 °C; IR 3394, 3062, 1684,
1662, 1652, 1557 cm-1; 1H NMR δ 2.65 (broad, 2H), 5.92 (s, 1H),
7.06-7.64 (m, 6H), 7.99-8.05 (m, 4H); mass spectrum m/ z 413
(5, M+), 105 (100). Anal. Calcd for C17H14Cl3N3OS: C, 49.23; H,
3.40; N, 10.13; S, 7.73. Found: C, 49.30; H, 3.52; N, 9.81, S, 7.73.
S-Alk yla t ion of N-P h en ylt h ioca r b a m oylb en za m id in e
(3a ) w ith Eth yl Br om oa ceta te (4b). 5f was obtained in 75%
yield after column chromatography purification on silica gel
using hexane-dichloromethane (8:2): mp 141-2 °C; IR 3435,
C
13H14N2O2S: C, 59.52; H, 5.37; N, 10.67; S, 12.22. Found: C,
59.46; H, 5.36; N, 10.90.
2-P h en yla m in o-4-tr ich lor om eth yl-5-eth oxyca r bon ylth i-
a zole (6h ). This compound was prepared from the S-alkylated
compound 5h in the same manner as described for the synthesis
of 6e, after crystallization from hexane-dichloromethane pure
6h was obtained in 35% yield: mp 122-3 °C; IR 3393, 1723,
2983, 2903, 1743, 1574 cm-1 1H NMR δ 1.17 (t, 3H), 3.90 (s,
;
2H), 4.10 (q, 2H), 6.47-7.51 (m, 8H), 7.86-7.90 (m, 2H); mass
spectrum m/ z 341 (50, M+), 222 (100). Anal. Calcd for
1557, 1538, 1505 cm-1 1H NMR δ 1.35 (t, 3H), 4.33 (q, 2H),
;
C
18H19N3O2S: C, 63.32, H, 5.60; N, 12.30; S, 9.39. Found: C,
7.14-7.45 (m, 5H), 7.63 (broad, 1H); 13C NMR δ 14.29, 62.08,
112.75, 119.81, 125.30, 130.06, 138.74, 154.80, 159.56, 163.73;
mass spectrum m/ z 364 (70, M+), 265 (100). Anal. Calcd for
C13H11Cl3N2O2S: C, 42.69; H, 3.03; Cl, 29.08; N, 7.65. Found:
C, 42.82; H, 3.20; Cl, 30.50; N, 7.68.
63.38; H, 5.79, N, 12.11; S, 9.63.
S-Alk yla tion of N-P h en ylth ioca r ba m oyltr ich lor oa cet-
a m id in e (3e) w ith Eth yl Br om oa ceta te (4b). 5h was ob-
tained in 90% yield after crystallization of the solid residue from
hexane-dichloromethane: mp 132-3 °C; IR 3463, 1735, 1629,
2-P h en yla m in o-4-a m in o-5-ben zoylth ia zole (6i). This com-
pound was prepared from the S-alkylated compound 5e in the
same manner as described for the synthesis of 6e, except that
DBU (1 equiv) was necessary. After crystallization from hexane-
dichloromethane pure 6i was obtained in 66% yield: mp 186-8
°C (hexane-dichloromethane (lit.18 186-87 °C)); IR 3019, 1594,
1590 cm-1 1H NMR δ 1.24 (t, 3H), 3.91 (s, 2H), 4.15 (q, 2H),
;
7.01-7.40 (m, 5H); 13C NMR δ 14.30, 34.56, 61.71, 95.02, 121.97,
125.19, 129.28, 146.48, 158.77, 163.83, 169.45; mass spectrum
m/ z 381 (10, M+), 262 (100). Anal. Calcd for C13H14Cl3N3O2S:
C, 40.79; H, 3.68; N, 10.97; S, 8.37. Found: C,40.75; H, 3.75; N,
10.97; S, 8.19.
1543, 1448 cm-1 1H NMR δ 7.01 (broad, 2H), 7.14-7.75 (m,
;
2-P h en ylam in o-4-tr ich lor om eth yl-5-ben zoylth iazole (6e).
A solution of S-alkylated compound 5e (0.413 g, 1 mmol) in
toluene (5 mL) in a nitrogen atmosphere was heated at reflux
temperature for 1.5 h. The solution was cooled to room temper-
ature, diluted with ethyl acetate (20 mL), and washed succes-
sively with water and saturated NH4Cl solution. The organic
phase was dried (Na2SO4) and evaporated in vacuo. The product
was then obtained from the residue by column chromatography
on silica gel using hexanes-ethyl acetate (9:1). 6e was obtained
after crystallization from hexane-dichloromethane in 64%
10H), 8.59 (broad, 1H); 13C NMR δ 120.75, 125.47, 127.38,
128.66, 129.91, 130.83, 138.51, 141.55, 164.60, 167.67, 169.84,
185.27; mass spectrum m/ z 295 (100, M+), 218 (10). Anal. Calcd
for C16H13N3OS: C, 65.06; H, 4.43; N, 14.22; S, 10.85. Found:
C, 64.91, H, 4.55; N, 14.11; S, 11.10.
2-P h en yla m in o-4-a m in o-5-eth oxyca r bon ylth ia zole (6j).
This compound was prepared from S-alkylated compound 5h in
the same manner as described for the synthesis of 6h , except
that DBU (1 equiv) was necessary. After crystallization from
hexane-dichloromethane pure 6j was obtained in 41% yield: mp
144-6 °C (hexane-dichloromethane,); IR 3502, 3384, 1683,
1654, 1602, 1569 cm-1; 1H NMR δ 1.30 (t, 3H), 4.23 (q, 2H), 5.8
(broad, 2H), 7.12-7.43 (m, 5H), 8.30 (broad, 1H); 13C NMR δ
14.78, 59.98, 120.25, 124.96, 129.86, 139.01, 168.17; mass
spectrum m/ z 263 (100, M+), 235 (25). Anal. Calcd for
1
yield: mp 119 °C; IR 3391, 2360, 1659, 1597 cm-1; H NMR δ
7.12-7.66 (m, 7H). 7.84 (broad, 1H), 7.79-7.95 (m, 3H); 13C NMR
δ 92.01, 119.92, 125.14, 128.92, 130.00, 134.31, 137.91, 139.08,
149.47, 163.89, 187.94; mass spectrum m/ z 396 (50, M+). Anal.
Calcd for C17H11Cl3N2OS: C, 51.34; H, 2.78; Cl, 26.74; N, 7.04;
S, 8.32. Found: C, 51.58; H, 2.88; Cl, 26.27; N, 6.92; S, 8.32.
2-P h en yla m in o-4-p h en yl-5-eth oxyca r bon ylth ia zole (6f).
A solution of S-alkylated compound 5f (0.341 g, 1 mmol) in
toluene (10 mL) containing DBU (0.1 mL, 0.102 g, 1 mmol) in a
nitrogen atmosphere was heated at reflux temperature for 2 h.
The solution was cooled to room temperature, diluted with ethyl
acetate (40 mL), and washed successively with water and
saturated NaCl solution. The organic phase was dried (Na2SO4)
and evaporated in vacuo, and the product was then obtained
from the residue by column chromatography on silica gel using
hexanes-ethyl acetate (6:4). 6f was obtained after crystallization
from hexane-dichloromethane in 76% yield: mp 185-6 °C; IR
C
12H13N3O2S: C, 54.73; H, 4.97; N, 15.95; S, 12.11. Found: C,
54.77, H, 4.93; N, 15.99; S, 12.11.
Ack n ow led gm en t. Financial support for this re-
search from “Consejo Nacional de Ciencia y Tecnolog´ıa”,
CONACyT (clave 25338-N) is gratefully acknowledged.
We thank Dr. Horacio F. Olivo (University of Iowa) for
13C NMR spectra and helpful discussions. The authors
wish to thank Professor J oseph M. Muchowski from
Roche Bioscience for helpful discussions and his interest
in our work.
3434, 2978, 1729, 1523 cm-1 1H NMR δ 1.25 (t, 3H), 4.19 (q,
;
J O0009447
2H), 7.09-7.41 (m, 8H). 7.70-7.75 (m, 2H), 8.26 (broad, 1H);
mass spectrum m/ z 324 (100, M+). Anal. Calcd for
C18H16N2O2S: C, 66.64; H, 4.97; N, 8.63; S, 9.88. Found: C,
66.42; H, 5.30; N, 8.67; S, 9.65.
(18) Rajasekharan, K. N.; Nair, K. P.; J enardanan, G. C. Synthesis
1986, 353.