1-(Alkyl/Arylthiocarbamoyl)benzotriazoles as Stable Isothiocyanate Equivalents: Synthesis of Di- and Trisubstituted Thioureas

Article abstract of DOI:10.1021/jo035680d

1-(Alkyl/arylthiocarbamoyl)benzotriazoles 4a-i were synthesized in yields of 91-99% from bis(benzotriazolyl)methanethione (3). Reagents 4a-g were then used as isothiocyanate equivalents for the efficient synthesis of 10 secondary and 14 tertiary thioureas

Full text of DOI:10.1021/jo035680d

1-(Alk yl/Ar ylth ioca r ba m oyl)ben zotr ia zoles a s Sta ble
Isoth iocya n a te Equ iva len ts: Syn th esis of Di- a n d Tr isu bstitu ted
Th iou r ea s
Alan R. Katritzky,* Stephane Ledoux, Rachel M. Witek, and Satheesh K. Nair
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received November 14, 2003
1-(Alkyl/arylthiocarbamoyl)benzotriazoles 4a -i were synthesized in yields of 91-99% from bis-
(benzotriazolyl)methanethione (3). Reagents 4a -g were then used as isothiocyanate equivalents
for the efficient synthesis of 10 secondary and 14 tertiary thioureas in high-yielding, convenient
processes.
SCHEME 1
In tr od u ction
Thioureas are of importance in medicinal chemistry1
due to their biological activity,2 e.g., against bacteria and
microbial infection,3 as fungicides, herbicides, and ro-
denticides,4,5 as phenoloxidase enzymatic inhibitors,6 and
in connection with biomimetic models.1,7 Thioureas are
valuable building blocks for the synthesis of five- and six-
membered heterocycles.8 Amines are often derivatized as
stable thioureas.9
Treatment of 2 equiv of a primary or secondary amine
with thiophosgene is the easiest method of making
symmetrical thioureas;10 the unpleasant nature of thio-
phosgene can be avoided by using thiophosgene equiva-
lents such as 1,1′-thiocarbonyldiimidazole.11 Reaction of
isothiocyanates with primary or secondary amines is a
common method of making unsymmetrical thioureas12,13
but suffers from side reactions such as urethane forma-
tion (in alcoholic medium where the reaction is often
carried out) or exchange between the amine and the
isothiocyanate.14 Many isothiocyanates are tedious to
prepare and display poor long-term stability. Hence,
numerous alternative methods have been developed for
the synthesis of both symmetrical and unsymmetrical
thioureas avoiding the use of isothiocyanates. Thus,
symmetrical thioureas are formed as shown in Scheme
1 by (i) either the direct15 or catalyzed16 reaction of carbon
disulfide and amines; (ii) the reaction of carbodiimides
with hydrogen sulfide;17 (iii) the reaction of 2-chloro-
pyridinium salts with sodium trithiocarbonate and
amines;18 or (iv) the reaction of 1,1′-thiocarbonyldiimi-
dazole11 with amines.
(1) Smith, J .; Liras, J . L.; Schneider, S. E.; Anslyn, E. V. J . Org.
Chem. 1996, 61, 8811.
(2) (a) Chalina, E. G.; Chakarova, L. Eur. J . Med. Chem. 1998, 33,
975. (b) Stark, H.; Purand, K.; Ligneau, X.; Rouleau, A.; Arrang, J .-
M.; Garbarg, M.; Schwartz, J .-C.; Schunack, W. J . Med. Chem. 1996,
39, 1157. (c) Walpole, C.; Ko, S. Y.; Brown, M.; Beattie, D.; Campbell,
E.; Dickenson, F.; Ewan, S.; Hughes, G. A.; Lemaire, M.; Lerpiniere,
J .; Patel, S.; Urban, L. J . Med. Chem. 1998, 41, 3159.
(3) Mallams, A. K.; Morton, J . B.; Reichert, P. J . Chem. Soc., Perkin
Trans. 1 1981, 2186.
Methods for the preparation of unsymmetrical thio-
ureas (Scheme 2) include (i) the use of 1-(methyldithio-
carbonyl)imidazole as a thiocarbonyl transfer reagent;19
(ii) the activation of a dithiocarbamate with a 2-halothia-
zolium salt and subsequent reaction with an amine;20 (iii)
(4) Schroeder, D. C. Chem. Rev. 1955, 181.
(5) Sarkis, G. Y.; Faisal, E. D. J . Heterocycl. Chem. 1985, 22, 137.
(6) Makhsumov, A. G.; Safaev, A. S.; Abidova, S. V. Katal Pererab.
Uglevodordn. Syrya 1968, 101; Chem. Abstr. 1969, 71, 101668v.
(7) Tobe, Y.; Sasaki, S.; Hirose, K.; Naemura, K. Tetrahedron Lett.
1997, 38, 4791.
(8) Griffin, T. S.; Woods, T. S.; Klayman, D. L. In Advances in
Heterocyclic Chemistry; Katritzky, A. R, Boulton, A. J ., Eds.; Academic
Press: New York, 1975; Vol. 18, p 99.
(14) Zetzsche, F.; Fredrich, A. Chem. Ber. 1940, 73B, 1420.
(15) Allen, C. F. H.; Edens, C. O.; vanAllan, J . In Organic Synthesis;
Wiley: New York, 1955; Vol. 3, p 394.
(9) Duus, F. In Comprehensive Organic Chemistry; J ones, N. J ., Ed.;
Pergamon Press: Oxford, 1979; Vol. 3, p 465.
(10) Sharma, S. Synthesis 1978, 803.
(16) (a)Yamazaki, N.; Higashi, F.; Iguchi, T. Tetrahedron Lett. 1974,
1191. (b) Ballabeni, M.; Ballini, R.; Bigi, F.; Maggi, R.; Parrini, M.;
Predieri, G.; Sartori, G. J . Org. Chem. 1999, 64, 1029.
(17) Kurzer, F.; Douraghi-Zadeh, K. Chem. Rev. 1967, 67, 107.
(18) Takikawa, Y.; Inoue, N.; Sato, R.; Takizawa, S. Chem. Lett.
1982, 641.
(11) (a) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351. (b)
Staab, H. A.; Walther, G. Leibigs Ann. Chem. 1962, 657, 98.
(12) (a)Neville, R. G.; McGee, J . J . Can. J . Chem. 1963, 41, 2123.
(b) Sridevi, G.; Rao, J .; Reddy, K. K. Synth. Commun. 1989, 19, 965.
(13) McKay, A. F.; Garmaise, D. L.; Gaudry, R.; Baker, H. A.; Paris,
G. Y.; Kay, R. W.; J ust, G. E.; Schwartz, R. J . Am. Chem. Soc. 1955,
81, 4328.
(19) Mohanta, P. K.; Dhar, S.; Samal, S. K.; Ila, H.; J unjappa, H.
Tetrahedron 2000, 56, 629.
10.1021/jo035680d CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/30/2004
2976
J . Org. Chem. 2004, 69, 2976-2982

Synthesis of Di- and Trisubstituted Thioureas
SCHEME 2 a
a
R, R1, R2, R3, R4 ) alkyl or aryl, unless specified.
SCHEME 3 a
a
See Table 2 for designations of R, R1, and R2.
direct displacement, by amines, from 1,3-diphenylthio-
urea (iiia),21 nitrosothiourea (iiib),22 or thiuram disulfide
(iiic);23 or (iv) the reaction of carbon disulfide with
primary amines in the presence of a triaryl phosphite or
a hexaalkyl phosphorustriamide.24 1,1-Disubstituted thio-
ureas are formed by the reaction of secondary amines
with triphenylphosphine-thiocyanogen (v).25 Although
these additional methods are of great utility in the
synthesis of many thioureas, a synthetic equivalent to
isothiocyanate or a protected form of it that is stable,
readily available, and easy to handle would be of con-
siderable benefit. In this paper, we describe the prepara-
tion and utility of 1-(alkyl/arylthiocarbamoyl)benzotria-
zoles, which, in keeping with other classes of acylbenzotri-
azoles,26 are highly effective thioacylating agents behav-
ing as masked isothiocyanates.
Resu lts a n d Discu ssion
P r ep a r a tion of (Alk y/Ar ylth ioca r ba m oyl)ben zo-
tr ia zoles 4. Bis(benzotriazolyl)methanethione (3) is eas-
ily prepared from 1-trimethylsilybenzotriazole and thio-
phosgene in quantitative yield (Scheme 3).27 The literature
shows only one reaction of this compound with an amine,
(20) Sugimoto, H.; Makino, I.; Hirai, K. J . Org. Chem. 1988, 53,
2263.
(21) Ramadas, K.; Srinivasan, N.; J anarthanan, N. Tetrahedron Lett.
1993, 34, 6447.
(22) Xian, M.; Zhu, X.; Li, Q.; Cheng, J .-P. Tetrahedron Lett. 1999,
40, 1957.
(23) Ramadas, K.; Srinivasan, N. Synth. Commun. 1995, 25, 3381.
(24) Yamazaki, N.; Tomioka, T.; Higashi, F. Synthesis 1975, 384.
(25) (a)Tamura, Y.; Adachi, M.; Kawasaki, T.; Kita, Y. Tetrahedron
Lett. 1978, 1753. (b) Tamura, Y.; Kawasaki, T.; Adachi, M.; Kita, Y.
Chem. Pharm. Bull. 1979, 27, 1636.
(26) (a) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J . Org. Chem. 2000,
65, 8210. (b) Katritzky, A. R.; Denisko, O. V.; Fang, Y.; Zhang, L.;
Wang, Z. Arkivoc 2001, xi, 41. (c) Katritzky, A. R.; Yang, H.; Zhang,
S.; Wang, M. Arkivoc 2002, xi, 39. (d) Katritzky, A. R.; Wang, M.;
Zhang, S. Arkivoc 2001, ix, 19. (e) Katritzky, A. R.; Wang, M.; Yang,
H.; Zhang, S.; Akhmedov, N. G. Arkivoc 2002, viii, 134.
(27) Larsen, C.; Steliou, K.; Harpp, D. N. J . Org. Chem. 1978, 43,
337.
J . Org. Chem, Vol. 69, No. 9, 2004 2977

Katritzky et al.
TABLE 1. Th ioca r ba m oyben zotr ia zoles 4 P r ep a r ed
TABLE 2. Di- a n d Tr isu bstitu ted Th iou r ea s 5 P r ep a r ed
with aniline to give diphenylthiourea.27 As part of our
ongoing research on the synthesis and utility of benzo-
triazole-functionalized reagents,28 we considered the pos-
sibility of using 3 as a thiophosgene equivalent in the
synthesis of unsymmetrical thioureas. Thus, the reactiv-
ity of 3 with various primary amines was investigated
first. Treatment of 3 with cyclohexylamine in methylene
chloride at 20 °C followed by a 5% Na2CO3 wash and
recrystallization afforded benzotriazole-1-carbothioic acid
cyclohexylamide (4a ) in 95% yield (Scheme 3, Table 1).
Significantly, 4a was stored at room temperature for
weeks without decomposition. Similarly, compounds
4b-h from other primary amines were also prepared in
nearly quantitative yields (Table 1). As will be shown,
reagents 4a -h are masked isothiocyanates and are
useful alternatives for isothiocyanates in the preparation
of secondary and tertiary thioureas.
5
R
R1
R2
yield (%)
a
cyclohexyl
1,5-dimethylhexyl
4-MeOC6H4CH2
R-(R)-methylbenzyl EtO(CH2)2
furfuryl
2-thiazolyl
allyl
cyclohexyl
allyl
1,5-dimethylhexyl
4-MeOC6H4CH2
R-(R)-methylbenzyl
furfuryl
2-(4-methyl)pyridyl
4-MeOC6H4CH2
1-methylbutyl
H
H
H
H
H
H
H
90
99
93
99
57
95
97
91
92
61
95
92
94
87
b
c
d
e
f
g
h
i
j
k
l
m
n
4-CO2EtC6H4
phenethyl
phenethyl
phenyl
phenethyl
phenyl
methyl
methyl
methyl
-(CH2)5-
-(CH2)2-O-(CH2)2-
-(CH2)5-
2-thiazolyl
3-methylpiperidinyl
carbothioic acid cyclohexylamide (4a ) was treated with
2-amino-(4-methyl)pyridine, thiourea 5a was isolated in
90% yield (Scheme 3, Table 2). The reaction was carried
out in methylene chloride, and the byproduct, benzotria-
zole, was removed by 5% sodium carbonate wash. Similar
reactions of 4a -g with other primary amines afforded
the corresponding secondary thioureas 5b-n in 57-100%
yields (Table 2).
See Table 2 for the designations of R, R1, and R2
P r ep a r a tion of Di- a n d Tr isu bstitu ted Th iou r ea s.
Thiocarbamoylbenzotriazoles 4a -g were reacted with a
second primary amine to generate the corresponding
disubstituted thioureas. Thus, when benzotriazole-1-
(28) (a) Katritzky, A. R. J . Heterocyl. Chem. 1999, 36, 1501. (b)
Katritzky, A. R.; Denisko, O. V. Pure Appl. Chem. 2000, 72, 1597. (c)
Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J . Org. Chem. 1997, 62,
4155.
(N,N)-Disu b st it u t ed Th ioca r b a m oylb en zot r ia -
zoles. Reaction of secondary amines with bis(benzotria-
zolyl)methanethione (3) also proceeded smoothly. Thus,
2978 J . Org. Chem., Vol. 69, No. 9, 2004

Synthesis of Di- and Trisubstituted Thioureas
SCHEME 4
the thiocarbamoylbenzotriazole 4i was prepared in 99%
yield from pyrrolidine and 3. The reaction of 4i with a
second secondary amine was attempted with the expected
formation of the corresponding tetrasubstituted thiourea.
However, in this case, substitution of the second benzo-
triazole group did not proceed even with a primary amine
under forcing conditions (refluxing DMF) and unreacted
reagent 4i was recovered.
We believe that reactions of 4a -g with primary amines
proceed with the intermediate formation of isothiocyan-
ates, which add the amine to form the thiourea. This is
supported by the observation that 4i failed to give
thiourea by the reaction with a second amine. (Evidently,
electronic assistance from a nitrogen lone pair is insuf-
ficient to energetically favor benzotriazole group dis-
placement.) Moreover, on reaction with 3, aromatic
amines (p-anisidine, p-ethoxycarbonylaniline) gave the
corresponding isothiocyanates instead of the expected
thiocarbamoyl reagents. This result could be advanta-
geous since such isothiocyanate formation was observed
only in those cases where the isothiocyanate is stabilized
as in aromatic isothiocyanates. In cases where the
isothiocyanate has a low stability (e.g., alkyl isothio-
cyanates), the reaction stops at the thiocarbamoylben-
zotriazole-formation stage, which is in fact a protected
isothiocyanate. Thus, reagents 4a -h can potentially
replace unstable isothiocyanates.
Reagent 3 also has advantages over its close counter-
part, 1,1-thiocarbonyldiimidazole (7), which is hygro-
scopic and relatively unstable29 even though 7 has been
extensively used as a thiocarbonyl transfer reagent.11,30
Bis(benzotriazolyl)methanethione 3 is stable at room
temperature for months without any loss in reactivity.
On reaction with primary amines (e.g., benzylamine),
1,1′-thiocarbamoyldiimidazole (7) reportedly produced a
mixture of the corresponding thiocarbamoylimidazole 8,
isothiocyanate 9, and the bisthiourea 10 in yields of 48,
38, and 6%, respectively (Scheme 4).31 In contrast, 3
afforded the thiocarbamoylbenzotriazole 4h (Table 1) as
the sole product in 97% yield from benzylamine. The bis-
substitution product was never detected in the reactions
of 3 with 1 equiv of a primary amine unlike the case of
thiophosgene, where the reaction mixture is often con-
taminated by the bis-substitution product.4
On e-P ot Syn th esis of Un sym m etr ica l Th iou r ea s.
In a further demonstration of the utility of intermediate
thiocarbamoylbenzotriazoles in the preparation of un-
symmetrical thioureas, we have utilized 3 in a one-pot
reaction with a primary and a secondary amine in a
sequential fashion. Thus, when 3 was treated with
aniline in methylene chloride followed by the addition of
pyrrolidine, the corresponding trisubstituted thiourea 17
was isolated in 93% yield. A distinct advantage is that
the purification requires only a mild base (5% Na2CO3)
wash to remove the eliminated benzotriazole. Other
trisubstituted thioureas 12-16 and 20 were also pre-
pared in good to excellent yields by reacting, sequentially,
the appropriate primary and secondary amine, respec-
tively, with 3 (Table 3). Sequential use of two different
primary amines in the one-pot reaction also afforded
disubstituted thioureas 11, 18, and 19 in 89-97% yields
(Table 3).
Con clu sion
In conclusion, we have demonstrated the utility of
1-(alkyl/arylthiocarbamoyl)benzotriazoles (4) as masked
isothiocyanates and bis(benzotriazolyl)methanethione (3)
as a thiophosgene equivalent. Reactions of 4 with amines
are faster, high-yielding, and less laborious in isolation
and purification procedures than those with isothiocy-
anates. Di- and trisubstituted thioureas can be prepared
from 4 in either one-pot or two-step procedures. Com-
pared to thiocarbamoyl chloride and isothiocyanates,
thiocarbamoylbenzotriazoles (in most cases) and bis-
(benzotriazolyl)methanethione are stable crystalline sol-
ids that can be stored for extended periods.
Exp er im en ta l Section
Melting points were determined on a hot-stage apparatus
and are uncorrected. 1H (300 MHz) and 13C (75 MHz) NMR
spectra were recorded on a 300 MHz NMR spectrometer in
chloroform-d or DMSO-d6 solution with tetramethylsilane as
an internal reference for 1H and solvent as an internal
reference for 13C. Column chromatography was performed on
silica gel (230-425 mesh).
Gen er a l P r oced u r e for th e P r ep a r a tion of Rea gen ts
4a -i. Bisbenzotriazol-1-yl methanethione27 (0.56 g, 2 mmol)
was dissolved in methylene chloride at room temperature. The
appropriate primary amine (2 mmol) was added dropwise, and
the reaction mixture was stirred for 18 h. Solvent was removed
(29) Ref 31 reports that 1,1′-thiocarbonyldiimidazole had decom-
posed 80% upon exposure to the atmosphere at room temperature for
1 day, and complete decomposition occurred after 2 days.
(30) (a)Harpp, D. N.; MacDonald, J . G. Tetrahedron Lett. 1983, 24,
4927. (b) Harpp, D. N.; MacDonald, J . G.; Larsen, C. Can. J . Chem.
1985, 63, 951.
(31) Kim, S.; Yang Yi, K. Y. J . Org. Chem. 1986, 51, 2613.
J . Org. Chem, Vol. 69, No. 9, 2004 2979

Katritzky et al.
TABLE 3. Th iou r ea s P r ep a r ed Usin g 1 in On e-P ot Rea ction s w ith P r im a r y a n d Secon d a r y Am in es
under vacuum, and the residue was redissolved in EtOAc and
washed with 5% aqueous sodium carbonate, water, and brine
before drying over anhydrous sodium sulfate. Solvent was
removed under vacuum and 1-thiocarbamoylbenzotriazole was
recrystallized from ethyl acetate.
Ben zotr ia zole-1-ca r both ioic Acid (F u r a n -2-ylm eth yl)-
a m id e (4e): brown needles (from EtOAc/hexanes), 99%, mp
117-119 °C; 1H NMR (CDCl3) δ 5.03 (d, 2H, J ) 5.4 Hz), 6.37-
6.45 (m, 2H), 7.43-7.50 (m, 2H), 7.61-7.67 (m, 1H), 8.09 (d,
1H, J ) 8.1 Hz), 8.90 (d, 1H, J ) 8.4 Hz), 9.32 (br s, 1H); 13C
NMR (CDCl3) δ 41.8, 109.3, 110.6, 115.9, 120.3, 125.7, 130.4,
132.4, 143.0, 147.0, 148.5, 174.2. Anal. Calcd for C12H10N4OS:
C, 55.80; H, 3.90; N, 21.69. Found: C, 56.04; H, 3.85; N, 21.81.
Ben zotr ia zole-1-ca r both ioic Acid [(R)-1-P h en yleth yl]-
a m id e (4f): yellow oil, 99%; 1H NMR (CDCl3) δ 1.77 (d, 3H, J
) 7.2 Hz), 5.74-5.84 (m, 1H), 7.30-7.50 (m, 6H), 7.61-7.66
(m, 1H), 8.09 (d, 1H, J ) 8.2 Hz), 8.90 (d, 1H, J ) 8.5 Hz),
9.32 (d, 1H, J ) 6.3 Hz); 13C NMR (CDCl3) δ 21.0, 54.1, 116.1,
120.2, 125.7, 126.5, 128.0, 128.9, 130.3, 132.5, 141.1, 147.1,
173.4. Anal. Calcd for C15H14N4S: C, 63.80; H, 5.00; N, 19.84.
Found: C, 64.06; H, 4.93; N, 20.29.
Ben zot r ia zole-1-ca r b ot h ioic Acid 4-Met h oxyb en zyl-
a m id e (4g): white needles, 97%, mp 82-83 °C; 1H NMR
(CDCl3) δ 3.81 (s, 3H), 4.95 (d, 2H, J ) 5.4 Hz), 6.91 (dd, 2H,
J ) 6.6, 2.1 Hz), 7.35 (d, 2H, J ) 8.4 Hz), 7.44-7.50 (m, 1H),
7.62-7.69 (m, 1H), 8.07 (d, 1H, J ) 8.1 Hz), 8.92 (d, 1H, J )
8.4 Hz), 9.25 (br s, 1H); 13C NMR (CDCl3) δ 48.6, 55.3, 114.3,
116.0, 120.2, 125.6, 127.5, 129.7, 130.3, 132.4, 147.0, 159.6,
174.1. Anal. Calcd for C15H14N4OS: C, 60.38; H, 4.73; N, 18.78.
Found: C, 60.48; H, 4.49; N, 19.56.
Ben zot r ia zole-1-ca r b ot h ioic Acid Ben zyla m id e (4h ):
white needles (from EtOAc/hexanes), 97%, mp 108-109 °C;
1H NMR (CDCl3) δ 5.04 (d, 2H, J ) 4.2 Hz), 7.33-7.52 (m,
6H), 7.66 (t, 1H, J ) 7.2 Hz), 8.10 (d, 1H, J ) 8.4 Hz), 8.94 (d,
1H, J ) 8.7 Hz), 9.32 (br s, 1H); 13C NMR (CDCl3) δ 49.0, 116.0,
120.3, 125.7, 128.2, 128.3, 129.0, 130.4, 132.4, 135.5, 147.1,
174.4. Anal. Calcd for C14H12N4S: C, 62.66; H, 4.51; N, 20.88.
Found: C, 62.79; H, 4.44; N, 20.82.
Ben zot r ia zol-1-ylp yr r olid in -1-ylm et h a n et h ion e (4i):
white needles (from EtOAc/hexanes), 99%, mp 144-145 °C;
1H NMR (CDCl3) δ 2.02-2.09 (m, 2H), 2.11-2.18 (m, 2H), 3.98
(t, 1H, J ) 6.9 Hz), 4.11 (t, 2H, J ) 6.9 Hz), 7.46-7.52 (m,
Ben zot r ia zole-1-ca r b ot h ioic Acid Cycloh exyla m id e
(4a ): white cubes (from EtOAc/hexanes), 95%, mp 72-73 °C;
1H NMR (CDCl3) δ 1.25-1.55 (m, 5H), 1.69-1.85 (m, 3H),
2.04-2.23 (m, 2H), 4.45-4.48 (m, 1H), 7.47-7.50 (m, 1H),
7.63-7.66 (m, 1H), 8.08 (dd, 1H, J ) 8.1, 0.6 Hz), 8.92-9.00
(m, 2H); 13C NMR (CDCl3) δ 24.6, 25.4, 31.7, 53.7, 116.2, 120.2,
125.6, 130.2, 132.5, 147.1, 173.1. Anal. Calcd for C13H16N4S:
C, 59.97; H, 6.19; N, 21.52. Found: C, 59.83; H, 6.17; N, 21.50.
Ben zotr ia zole-1-ca r both ioic Acid (1,5-Dim eth ylh exyl)-
1
a m id e (4b): yellow oil, 99%; H NMR (CDCl3) δ 0.86 (d, 6H,
J ) 6.6 Hz), 1.20-1.28 (m, 2H), 1.39-1.81 (m, 8H), 4.66-4.71
(m, 1H), 7.45-7.50 (m, 1H), 7.62-7.67 (m, 1H), 8.09 (d, 1H, J
) 8.2 Hz), 8.90-8.95 (m, 2H); 13C NMR (CDCl3) δ 19.5, 22.5,
23.7, 27.8, 36.2, 38.6, 51.0, 116.2, 120.2, 125.6, 130.2, 132.5,
147.1, 173.4. Anal. Calcd for C15H22N4S: C, 62.03; H, 7.64; N,
19.29. Found: C, 62.48; H, 7.70; N, 19.52.
Ben zotr ia zole-1-ca r both ioic Acid Allyla m id e (4c): yel-
low needles (from EtOAc/hexanes), 93%, mp 56-57 °C; 1H
NMR (CDCl3) δ 4.50 (t, 2H, J ) 5.7 Hz), 5.32-5.45 (m, 2H),
5.97-6.10 (m, 1H), 7.49 (t, 1H, J ) 8.1 Hz), 7.66 (t, 1H, J )
7.5 Hz), 8.11 (d, 1H, J ) 8.1 Hz), 8.91 (d, 1H, J ) 8.7 Hz),
9.16 (br s, 1H); 13C NMR (CDCl3) δ 47.2, 116.0, 118.8, 120.2,
125.7, 130.4, 131.3, 147.1, 155.4, 174.5. Anal. Calcd for
C
10H10N4S: C, 55.03; H, 4.62; N, 25.67. Found: C, 55.21; H,
4.51; N, 25.86.
Ben zot r ia zole-1-ca r b ot h ioic Acid Th ia zol-2-yla m id e
(4d ): yellow powder, 91%, mp 160-161 °C; 1H NMR (DMSO-
d6) δ 7.45-7.58 (m, 3H), 7.73 (t, 1H, J ) 7.3 Hz), 7.96 (d, 1H,
J ) 4.4 Hz), 8.18 (d, 1H, J ) 8.2 Hz), 8.88 (d, 1H, J ) 8.4 Hz);
13C NMR (DMSO-d6) δ 112.2, 116.3, 119.4, 125.1, 125.9, 129.0,
130.6, 130.9, 146.0, 170.3. Anal. Calcd for C10H7N5S2: C, 45.96;
H, 2.70; N, 26.80. Found: C, 45.48; H, 2.66; N, 26.26.
2980 J . Org. Chem., Vol. 69, No. 9, 2004

Synthesis of Di- and Trisubstituted Thioureas
1H), 7.62-7.67 (m, 1H), 8.13 (dd, 1H, J ) 8.1, 0.9 Hz), 8.30
(dd, 1H, J ) 8.4, 0.6 Hz); 13C NMR (CDCl3) δ 24.3, 26.4, 54.3,
54.6, 114.5, 119.8, 125.1, 128.8, 133.0, 145.8, 172.0. Anal. Calcd
for C11H12N4S: C, 56.87; H, 5.21; N, 24.12. Found: C, 56.64;
H, 5.02; N, 23.89.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th iou r ea s
5a -n . The appropriate thiocarbamoylbenzotriazole (1 mmol)
was dissolved in methylene chloride at room temperature. The
corresponding amine (1 mmol) was added followed by triethyl-
amine (0.3 mL, 2 mmol), and the reaction mixture was stirred
for 24 h. Solvent was removed under vacuum, and the residue
was redissolved in EtOAc, washed with 5% aqueous sodium
carbonate, 1 M HCl, water, and brine before drying over
anhydrous sodium sulfate. Solvent was removed under vacuum,
and the thioureas 5a -n were purified by recrystallization (in
the case of solids) or column chromatography (in the case of
oils) on silica gel (200-400 mesh, EtOAc/hexanes).
Anal. Calcd for C12H13N3S2: C, 54.72; H, 4.97; N, 15.95.
Found: C, 54.99; H, 4.80; N, 15.93.
1-Allyl-3-p h en eth ylth iou r ea (5g): yellow oil, 97%; 1H
NMR (CDCl3) δ 2.91 (t, 2H, J ) 6.9 Hz); 3.76-3.78 (d, 2H, J
) 5.1 Hz); 3.92 (s, 2H); 5.09-5.17 (m, 2H); 5.71-5.80 (m, 1H);
5.99 (br s, 1H); 6.24 (br s, 1H); 7.19-7.33 (m, 5H); 13C NMR
(CDCl3) δ 35.0, 45.7, 46.5, 117.6, 126.7, 128.7, 132.9, 138.3,
182.0. Anal. Calcd for C12H16N2S: C, 65.41; H, 7.32; N, 12.71.
Found: C, 65.62; H, 7.41; N, 13.10.
3-Cycloh exyl-1-m eth yl-1-p h en ylth iou r ea (5h ): yellow
oil, 91%; 1H NMR (CDCl3) δ 0.93-1.12 (m, 3H), 1.29-1.41 (m,
2H), 1.54 (d, 3H, J ) 10.2 Hz), 1.94 (d, 2H, J ) 9.9 Hz), 3.66
(s, 3H), 4.21-4.31 (m, 1H), 5.19 (d, 1H, J ) 7.2 Hz), 7.21-
7.23 (m, 2H), 7.37-7.42 (m, 1H) 7.47-7.52 (m, 2H); 13C NMR
(CDCl3) δ 24.5, 25.4, 32.5, 43.0, 53.8, 127.0, 128.3, 130.5, 142.9,
180.6. Anal. Calcd for C14H20N2S: C, 67.70; H, 8.12; N, 11.28.
Found: C, 67.59; H, 8.22; N, 11.32.
1-Cycloh exyl-3-(4-m et h ylp yr id in -2-yl)t h iou r ea (5a ):
plates (from EtOAc/hexanes), 90%, mp 167-168 °C; 1H NMR
(CDCl3) δ 1.33-1.54 (m, 4H), 1.59-1.82 (m, 4H), 1.83-2.07-
2.10 (m, 2H) 2.32 (s, 3H), 4.33-4.37 (m, 1H), 6.61 (s, 1H), 6.76
(d, 1H, J ) 5.4 Hz), 8.01 (d, 1H, J ) 5.1 Hz) 8.71 (br s, 1H),
11.82 (br s, 1H); 13C NMR (CDCl3) δ 21.1, 24.3, 25.6, 32.0, 53.8,
112.1, 119.1, 145.2, 150.0, 153.6, 177.8. Anal. Calcd for
3-Allyl-1-m eth yl-1-p h en eth ylth iou r ea (5i): yellow oil,
92%; 1H NMR (CDCl3) δ 2.98 (t, 2H, J ) 7.5 Hz), 3.05 (s, 3H),
4.00 (t, 2H, J ) 7.2 Hz), 4.27 (t, 2H, J ) 5.4 Hz), 5.14-5.22
(m, 2H), 5.23 (br s, 1H), 5.83-5.94 (m, 1H), 7.21-7.38 (m, 5H);
13C NMR (CDCl3) δ 33.8, 38.0, 48.5, 55.8, 116.8, 126.5, 128.6,
128.8, 134.2, 138.7, 181.6. Anal. Calcd for C13H18N2S: C, 66.62;
H, 7.74; N, 11.95. Found: C, 66.31; H, 7.79; N, 12.37.
3-(1,5-Dim eth ylh exyl)-1-m eth yl-1-p h en ylth iou r ea (5j):
C
13H19N3S: C, 62.61; H, 7.68; N, 16.85. Found: C, 62.62; H,
1
7.83; N, 16.79.
orange oil, 61%; H NMR (CDCl3) δ 0.82-0.85 (dd, 6H, J )
1-(1,5-Dim et h ylh exyl)-3-(4-m et h oxyb en zyl)t h iou r ea
(5b): orange needles (from EtOAc/hexanes), 100%, mp 57-62
6.6, 1.5 Hz), 1.07-1.52 (m, 10H), 3.66 (s, 3H), 4.40-4.51 (m,
1H), 5.06 (d, 1H, J ) 8.1 Hz), 7.21 (d, 2H, J ) 7.2 Hz), 7.39 (t,
1H, J ) 7.5 Hz), 7.47-7.51 (m, 2H); 13C NMR (CDCl3) δ 20.3,
22.4, 23.5, 27.7, 36.6, 38.6, 43.1, 51.4, 127.1, 128.4, 130.5, 142.9,
181.0. Anal. Calcd for C16H26N2S: C, 69.01; H, 9.41; N, 10.06.
Found: C, 69.33; H, 9.61; N, 10.29.
1
°C; H NMR (CDCl3) δ 0.84 (m, 6H, J ) 6.6 Hz), 1.07-1.55
(m, 10H), 3.80 (s, 3H), 4.04 (br s, 1H), 4.55 (br s, 2H), 5.56 (br
s, 1H), 5.94 (br s, 1H), 6.87-6.90 (m, 2H), 7.25 (d, 2H, J ) 8.4
Hz); 13C NMR (CDCl3) δ 20.5, 22.5, 23.5, 27.8, 36.9, 38.7, 47.8,
50.4, 55.2, 114.3, 128.9, 159.3, 180.7. Anal. Calcd for C17H28N2-
OS: C, 66.19; H, 9.15; N, 9.08. Found: C, 66.41; H, 9.19; N,
9.33.
P ip er id in e-1-ca r both ioic Acid 4-Meth oxyben zyla m id e
1
(5k ): yellow oil, 95%; H NMR (CDCl3) δ 1.65-1.68 (m, 6H),
3.81-3.81 (m, 7H), 4.82 (d, 2H, J ) 4.5 Hz), 5.64 (br s, 1H),
6.91 (d, 2H, J ) 8.4 Hz), 7.31 (d, 2H, J ) 8.4 Hz); 13C NMR
(CDCl3) δ 24.1, 25.3, 48.8, 49.8, 55.2, 114.0, 129.4, 130.1, 159.0,
180.9. Anal. Calcd for C14H20N2OS: C, 63.60; H, 7.62; N, 10.60.
Found: C, 63.09; H, 7.50; N, 11.31.
1-(4-Meth oxyben zyl)-3-(1-m eth ylbu tyl)th iou r ea (5c):
1
yellow oil, 93%; H NMR (CDCl3) δ 0.88 (t, 3H, J ) 7.2 Hz),
1.15 (d, 3H, J ) 6.6 Hz), 1.20-1.50 (m, 5H), 3.81 (s, 3H), 4.05
(br s, 1H), 4.55 (br s, 2H), 5.56 (s, 1H), 5.94 (s, 1H), 6.89 (d,
2H, J ) 8.7 Hz), 7.25 (d, 2H, J ) 7.5 Hz); 13C NMR (CDCl3) δ
13.9,19.0, 20.6, 38.9, 47.9, 50.2, 55.3, 114.3, 125.9, 128.9, 159.3,
180.7. Anal. Calcd for C14H22N2OS: C, 63.12; H, 8.32; N, 10.52.
Found: C, 63.50; H, 8.70; N, 11.41.
Mor p h olin e-4-ca r b ot h ioic Acid [(R)-1-P h en ylet h yl]-
a m id e (5l): white needles (from EtOAc/hexanes), 92%, mp
25
117-119 °C; [R]D -3.5° (c 0.04, CH2Cl2); 1H NMR (CDCl3) δ
1.61 (d, 3H, J ) 6.6 Hz), 3.72-3.84 (m, 8H), 5.66 (br s, 1H),
5.77-5.87 (m, 1H), 7.26-7.44 (m, 5H); 13C NMR (CDCl3) δ
21.4, 47.4, 54.6, 66.1, 126.4, 127.5, 128.7, 142.9, 181.9. Anal.
Calcd for C13H18N2OS: C, 62.36; H, 7.25; N, 11.19. Found: C,
62.05; H, 7.25; N, 11.62.
1-(2-Eth oxyeth yl)-3-[(R)-1-p h en yleth yl]th iou r ea (5d ):
yellow oil, 99%; [R]D25 +0.1° (c 0.04, CH2Cl2); 1H NMR (CDCl3)
δ 1.05 (t, 3H, J ) 6.9 Hz), 1.53 (d, 3H, J ) 6.6 Hz), 3.32-3.60
(m, 7H), 5.02 (br s, 1H), 6.11 (br s, 1H), 7.21-7.38 (m, 5H);
13C NMR (CDCl3) δ 14.8, 22.9, 44.7, 53.8, 66.3, 69.0, 125.8,
127.4, 128.6, 142.4, 181.3. Anal. Calcd for C13H20N2OS: C,
61.87; H, 7.99; N, 11.10. Found: C, 61.65; H, 8.22; N, 11.10.
4-(3-F u r a n -2-ylm eth ylth iou r eid o)ben zoic Acid Eth yl
Ester (5e): green needles (from EtOAc/hexanes), 57%, mp
115-116 °C; 1H NMR (CDCl3) δ 1.39 (t, 3H, J ) 7.2 Hz), 4.36
(q, 2H, J ) 7.2 Hz), 4.86 (d, 2H, J ) 5.1 Hz), 6.31-6.34 (m,
2H), 6.55 (br s, 1H), 7.28 (d, 2H, J ) 8.4 Hz), 7.35-7.36 (m,
1H), 8.06 (d, 2H, J ) 8.4 Hz), 8.38 (s, 1H); 13C NMR (CDCl3)
δ 14.2, 42.4, 61.2, 108.5, 110.5, 123.0, 128.1, 131.5, 140.4, 142.6,
149.7, 165.6, 180.1. Anal. Calcd for C15H16N2O3S: C, 59.19;
H, 5.30; N, 9.20. Found: C, 59.06; H, 5.25; N, 9.34.
P ip er id in e-1-ca r b ot h ioic Acid (F u r a n -2-ylm et h yl)-
a m id e (5m ): white needles (from EtOAc/hexanes), 94%, mp
104-107 °C; 1H NMR (CDCl3) δ 1.66 (br s, 6H), 3.78-3.80 (m,
4H), 4.87 (d, 2H, J ) 4.8 Hz), 5.64 (br s, 1H), 6.30-6.34 (m,
2H) 7.38 (s, 1H); 13C NMR (CDCl3) δ 24.2, 25.4, 43.1, 48.8,
108.0, 110.5, 142.2, 151.1, 181.0. Anal. Calcd for C11H16N2OS:
C, 58.90; H, 7.19; N, 12.49. Found: C, 58.35; H, 7.31; N, 12.28.
3-Met h ylp ip er id in e-1-ca r b ot h ioic Acid Th ia zol-2-yl-
a m id e (5n ): orange oil, 87%; 1H NMR (CDCl3) δ 0.89 (d, 3H,
J ) 6.6 Hz), 1.10-1.26 (m, 1H), 1.45-1.85 (m, 4H), 2.66 (t,
1H, J ) 11.1 Hz), 2.89-3.03 (m, 1H), 4.84 (t, 2H, J ) 14.1 Hz)
6.62 (d, 1H, J ) 4.2 Hz), 7.16 (d, 1H, J ) 4.2 Hz); 13C NMR
(CDCl3) δ 18.9, 25.1, 31.3, 33.0, 48.6, 55.2, 109.9, 127.6, 167.8,
180.6. Anal. Calcd for C10H15N3S2: C, 49.76; H, 6.26; N, 17.41.
Found: C, 49.99; H, 6.28; N, 17.11.
Gen er a l P r oced u r e for th e On e-P ot P r ep a r a tion of
Th iou r ea s 11-20. To 0.56 g of bis-benzotriazol-1-yl-meth-
anethione (2 mmol) in 30 mL of THF was added the appropri-
ate primary amine (2 mmol), and the mixture was stirred for
36 h. Then, triethylamine (0.6 mL, 4 mmol) and the second
primary amine or a secondary amine (2 mmol) were added,
and the mixture was stirred for an additional 36 h. Solvent
was evaporated, and the remaining oil was dissolved in ethyl
acetate and washed with 1 M HCl, 10% aqueous solution
sodium carbonate, water, and brine. The organic layer was
1-P h en eth yl-3-th ia zol-2-ylth iou r ea (5f): orange needles
(from EtOAc/hexanes), 95%, mp 162-164 °C (lit.32 mp 169.5-
170.5 °C); 1H NMR (CDCl3) δ 3.03 (t, 2H, J ) 7.2 Hz), 3.99 (q,
2H, J ) 7.2 Hz), 6.80 (d, 1H, J ) 3.6 Hz), 7.20-7.35 (m, 6H),
10.50 (br s, 1H), 10.83 (br s, 1H); 13C NMR (CDCl3) δ 34.8,
47.0, 111.1, 126.6, 128.6, 128.9, 137.6, 138.5, 161.6, 177.6.
(32) 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., J r.; Noreen, R.; Oberg, B.; Palkowitz, J . A.; Parrish, C. A.; Pranc,
P.; Sahlberg, C.; Teransky, R. J .; Vasileff, R. T.; Vrang, L.; West, S. J .;
Zhang, H.; Zhou, X.-X. J . Med. Chem. 1995, 38, 4929.
(33) Viswanathan, N.; Sidhaye, A. R. Indian J . Chem. 1986, 25B,
659.
J . Org. Chem, Vol. 69, No. 9, 2004 2981

Katritzky et al.
dried over anhydrous sodium sulfate, concentrated, and puri-
fied by recrystallization or column chromatography (10%
EtOAc/hexanes).
(3-Ben zyl-1-p h en ylth iou r eid o)a cetic Acid Eth yl Ester
(16): red oil, 52%; 1H NMR (CDCl3) δ 1.30 (t, 3H, J ) 7.2 Hz),
4.24 (q, 2H, J ) 7.2 Hz), 4.82 (d, 2H, J ) 5.4 Hz), 4.89 (s, 2H),
5.76 (br s, 1H), 7.17-7.48 (m, 10H); 13C NMR (CDCl3) δ 14.1,
49.9, 56.4, 61.2, 127.2, 127.4, 127.9, 128.6, 129.1, 130.6, 137.7,
141.4, 169.3, 182.9. Anal. Calcd for C18H20N2O2S: C, 65.83;
H, 6.14; N, 8.53. Found: C, 66.19; H, 6.20; N, 8.62.
1-(4-Meth oxyp h en yl)-3-p h en eth ylth iou r ea (11): gray
needles (from EtOAc/hexanes), 94%, mp 104-105 °C; 1H NMR
(CDCl3) δ 2.89 (t, 2H, J ) 6.9 Hz), 3.81 (s, 3H), 3.86 (q, 2H, J
) 6.9 Hz), 5.75 (br s, 1H), 6.82-6.86 (m, 2H), 6.95 (d, 2H, J )
8.7 Hz), 7.10-7.13 (m, 2H), 7.21-7.29 (m, 3H), 7.51 (br s, 1H);
13C NMR (CDCl3) δ 34.8, 46.1, 55.4, 115.1, 126.5, 127.6, 128.1,
128.6, 128.7, 138.4, 158.8, 180.9. Anal. Calcd for C16H18N2OS:
C, 67.10; H, 6.33; N, 9.78. Found: C, 67.29; H, 6.38; N, 9.96.
Mor p h olin e-1-ca r b ot h ioic Acid 4-Met h oxyp h en yl-
a m id e (12): colorless microcrystals (from ethanol), 99%, mp
155-156 °C (lit.33 158-159 °C); 1H NMR (CDCl3) δ 3.65-3.73
(m, 4H), 3.75-3.85 (m, 7H), 6.85 (d, 2H, J ) 8.7 Hz), 7.09 (d,
2H, J ) 8.7 Hz), 7.28 (br s, 1H); 13C NMR (CDCl3) δ 49.0, 55.4,
66.1, 114.2, 126.0, 132.6, 157.5, 183.8.
Mor p h olin e-1-ca r both ioic Acid Cycloh exyla m id e (13):
colorless prisms (from ethanol), 91%, mp 127-130 °C; 1H NMR
(CDCl3) δ 1.10-1.23 (m, 3H), 1.36-1.49 (m, 2H), 1.63-1.75
(m, 3H), 2.09-2.18 (m, 2H), 3.75 (d, 8H, J ) 3.6 Hz), 4.32-
4.42 (m, 1H), 5.35 (d, 1H, J ) 6.3 Hz); 13C NMR (CDCl3) δ
24.8, 25.5, 33.0, 47.2, 54.3, 66.0, 181.4. Anal. Calcd for
P yr r olid in e-1-ca r both ioic Acid P h en yla m id e (17): col-
1
orless prisms (from ethanol), 93%, mp 116-118 °C; H NMR
(CDCl3) δ 1.95-2.01 (m, 4H), 3.67 (t, 4H, J ) 6.6 Hz), 6.90 (br
s, 1H), 7.12-7.16 (m, 1H), 7.24-7.37 (m, 4H); 13C NMR (CDCl3)
δ 25.4, 50.3, 125.1, 125.3, 128.5, 139.7, 179.1. Anal. Calcd for
C
11H14N2S: C, 64.04; H, 6.84; N, 13.58. Found: C, 64.26; H,
7.05; N, 13.63.
1-(3-Dim eth ylam in opr opyl)-3-ph en yl th iou r ea (18): Yel-
low needles (from EtOAc/hexanes), 97%, mp 99-100 °C; 1H
NMR (CDCl3) δ 1.65-1.72 (m, 2H), 1.88 (s, 6H), 2.38 (t, 2H, J
) 5.7 Hz), 3.74 (br s, 2H), 7.23-7.29 (m, 3H), 7.39 (t, 2H, J )
7.8 Hz), 8.00 (br s, 1H), 8.82 (br s, 1H); 13C NMR (CDCl3) δ
24.2, 44.5, 47.0, 59.0, 115.0, 125.6, 126.6, 129.2, 129.5, 136.8,
180.3. Anal. Calcd for C12H19N3S: C, 60.72; H, 8.07; N, 17.70.
Found: C, 60.40; H, 8.01; N, 17.72.
1-Ben zyl-3-(3-im id a zol-1-ylp r op yl)th iou r ea (19): color-
1
C
11H20N2OS: C, 57.86; H, 8.83; N, 12.27. Found: C, 58.15; H,
less oil, 89%; H NMR (CDCl3) δ 1.96-2.06 (m, 2H), 3.48 (q,
8.98; N, 12.35.
2H, J ) 5.7 Hz), 3.89 (t, 2H, J ) 6.6 Hz), 4.65 (d, 2H, J ) 3.6
Hz), 6.86 (s, 2H), 7.19 (s, 1H), 7.26-7.33 (m, 7H); 13C NMR
(CDCl3) δ 30.3, 41.2, 44.3, 48.0, 119.1, 127.4, 127.5, 128.6,
128.7, 136.8, 137.5, 183.0. Anal. Calcd for C14H18N4S: C, 61.28;
H, 6.61; N, 20.42. Found: C, 60.93; H, 6.79; N, 20.02.
1-Ben zoth ia zolyl-3-m eth yl-3-(bu tyl)th iou r ea (20): yel-
4-[(2,3-Dih ydr oin dole-1-car both ioyl)am in o]ben zoic Acid
Eth yl Ester (14): gray needles (from EtOAc/hexanes), 87%,
1
mp 122-123 °C; H NMR (CDCl3) δ 1.38 (t, 3H, J ) 7.2 Hz),
3.12 (t, 2H, J ) 8.1 Hz), 4.35 (q, 2H, J ) 7.2 Hz), 4.45 (t, 2H,
J ) 8.1 Hz), 7.04 (t, 1H, J ) 7.5 Hz), 7.17 (t, 1H, J ) 7.8 Hz),
7.29 (d, 1H, J ) 7.5 Hz), 7.43-7.50 (m, 3H), 7.83 (br s, 1H),
8.00 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 14.4, 27.3, 55.0,
60.9, 114.9, 121.7, 124.4, 126.3, 126.6, 127.5, 130.6, 134.7,
141.5, 143.1, 166.1, 177.7. Anal. Calcd for C18H18N2O2S: C,
66.23; H, 5.56; N, 8.58. Found: C, 66.53; H, 5.61; N, 8.60.
1-Bu tyl-1-m eth yl-3-[2-(4-m eth ylben zoyl)p h en yl] Th io-
u r ea (15): yellow oil, 76%; 1H NMR (CDCl3) δ 0.98 (t, 3H, J )
7.2 Hz), 1.38-1.46 (m, 2H), 1.67-1.77 (m, 2H), 2.44 (s, 3H),
3.38 (s, 3H), 3.87 (br s, 2H), 7.05-7.11 (m, 1H), 7.28 (d, 2H, J
) 8.1 Hz), 7.49-7.56 (m, 2H), 7.67 (d, 2H, J ) 8.1 Hz), 8.72
(d, 1H, J ) 8.4 Hz), 10.69 (s, 1H); 13C NMR (CDCl3) δ 13.9,
20.1, 21.7, 29.2, 53.7, 122.1, 125.0, 125.9, 129.0, 130.5, 132.4,
132.6, 135.5, 142.2, 143.6, 179.6, 199.1. Anal. Calcd for
1
low powder (from EtOAc/hexanes), 68%, mp 114-116 °C; H
NMR (DMSO-d6) δ 0.92 (t, 3H, J ) 7.2 Hz), 1.22 (d, 3H, J )
6.6 Hz), 1.32-1.43 (m, 2H), 1.48-1.67 (m, 2H), 4.30-4.39 (m,
1H), 7.28 (t, 1H, J ) 7.8 Hz), 7.41 (t, 1H, J ) 6.9 Hz), 7.64 (d,
1H, J ) 7.8 Hz), 7.90 (d, 1H, J ) 7.8 Hz), 9.84 (br s, 1H), 11.74
(br s, 1H); 13C NMR (DMSO-d6) δ 13.8, 18.6, 19.7, 37.6, 49.8,
119.1, 121.7, 123.6, 126.2, 129.6, 161.5, 178.1. Anal. Calcd for
C
13H17N3S2: C, 55.88; H, 6.13; N, 15.04. Found: C, 55.20; H,
5.99; N, 15.04.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 4b, 4f, 4g, 5c, 5i, 5k , 5m , and 15. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
20H24N2OS: C, 70.55; H, 7.10; N, 8.23. Found: C, 70.19; H,
7.18; N, 8.64.
J O035680D
2982 J . Org. Chem., Vol. 69, No. 9, 2004