Benzotriazole-assisted thioacylation

Article abstract of DOI:10.1021/jo050670t

Benzotriazole reagents for thioacylation (RCSBt), thiocarbamoylation (RR'NCSBt), aryl/alkoxy-thioacylation (ROCSBt), and aryl/alkylthiothioacylation (RSCSBt) are synthesized, and their utility is assessed by syntheses of representative heteroaryl thioureas 3a-g, thioamides 15a-s, thionoesters 16a-h, thiocarbamates 17a-e, dithiocarbamates 18a-d, thiocarbonates 19a-c, and dithiocarbonates 20a-c.

Full text of DOI:10.1021/jo050670t

Benzotriazole-Assisted Thioacylation
Alan R. Katritzky,*,§ Rachel M. Witek,§ Valerie Rodriguez-Garcia,§ Prabhu P. Mohapatra,§
James W. Rogers,§ Janet Cusido,§ Ashraf A. A. Abdel-Fattah,§ and Peter J. Steel|
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville,
Florida 32611-7200, and Department of Chemistry, University of Canterbury, Christchurch, New Zealand
Katritzky@chem.ufl.edu
Received April 5, 2005
Benzotriazole reagents for thioacylation (RCSBt), thiocarbamoylation (RR′NCSBt), aryl/alkoxy-
thioacylation (ROCSBt), and aryl/alkylthiothioacylation (RSCSBt) are synthesized, and their utility
is assessed by syntheses of representative heteroaryl thioureas 3a-g, thioamides 15a-s, thiono-
esters 16a-h, thiocarbamates 17a-e, dithiocarbamates 18a-d, thiocarbonates 19a-c, and
dithiocarbonates 20a-c.
Introduction
such as sulfur dihydride,13 phosphorus pentasulfide,14,15
and Lawesson’s reagent13 convert carbonyls into thiocar-
bonyl compounds.
Classical thioacylating agents, including thiophosgene,1
carbon disulfide,2 and 1,1′-thiocarbonyldiimidazole,3 pro-
vide access to a number of diversely functionalized thio-
amides, thioureas, thionoesters, (di)thiocarbamates, and
(di)thiocarbonates. Thiocarbonyl,4-6 thiocarbamoyl,7-9
and (di)thiocarbonyl10-12 derivatives of these classical
thioacylating agents can also be prepared and reacted
further with nucleophiles. Alternatively, thionating agents
Our group has applied N-acylbenzotriazoles to the
syntheses of amides,16 â-keto sulfones,17 R-substituted
â-ketonitriles,18 oxazolines and thiazolines,19 and C-
acylated pyrroles and indoles.20 We have recently re-
ported the application of the thioacylating reagent bis-
(benzotriazolyl)methanethione (BtCSBt, 1) in the pre-
paration of unsymmetrical di- and trisubstituted thio-
ureas 3 by intermediate 1-(alkyl/arylthiocarbamoyl)-
benzotriazoles (RNHCSBt, 2) (Scheme 1).21
§ University of Florida.
| University of Canterbury.
We have now greatly extended this work by preparing
a range of reagents for thioacylation (RCSBt), thiocar-
bamoylation (RR′NCSBt), aryl/alkoxythioacylation (ROCS-
(1) (a) Satyavan, S. Synthesis, 1978, 803. (b) Mayer, R. In Organo-
sulfur Chemistry; Janssen, M. J., Ed.; Wiley-Interscience: New York,
London, Sydney, 1967; p 219.
(2) Wang, C.; Chen, J.; Song, Q.; Li, Z.; Xi, Z. ARKIVOC 2003, ii,
155.
(3) Staab, H. A.; Walther, G. Ann. Chem. 1962, 98.
(4) Harpp, D. N.; MacDonald, J. G. Tetrahedron Lett. 1983, 24, 4927.
(5) (a) Walter, M.; Radke, M. Liebigs Ann. 1970, 739, 201. (b) Walter,
M.; Radke, M. Liebigs Ann. 1973, 636.
(13) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061.
(14) Trebaul, C.; Teste, J. Bull. Soc. Chim. Fr. 1970, 2272.
(15) Soheeren, J. W.; Ooms, P. H. J.; Nivard, R. J. F. Synthesis 1973,
149.
(6) Voss, J.; Walter, W. Liebigs Ann. 1968, 716, 209.
(7) Eilingsfeld, H.; Moebius, L. Chem. Ber. 1965, 98, 1293.
(8) Bell, F. W.; Cantrell, A. S.; Hogberg, M.; Jaskunas, S. R.;
Johansson, N. G.; Jordan, C. L.; Kinnick, M. D.; Lind, P.; Morin, J.
M., Jr.; 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.
(9) Herrmann, D.; Keune, D. Ann. Chem. 1975, 1025.
(10) Viola, H.; Scheithauer, S.; Mayer, R. Chem. Ber. 1968, 101,
3517.
(16) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65,
8210.
(17) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 1443.
(18) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 4932.
(19) Katritzky, A. R.; Cai, C.; Suzuki, K.; Singh, S. K. J. Org. Chem.
2004, 69, 811.
(20) Katritzky, A. R.; Suzuki, K.; Singh, S. K.; He, H.-Y. J. Org.
Chem. 2003, 68, 5720.
(11) Vedejs, E.; Wu, E. S. C. J. Org. Chem. 1974, 39, 3641.
(12) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351.
(21) Katritzky, A. R.; Ledoux, S.; Witek, R. M.; Nair, S. K. J. Org.
Chem. 2004, 69, 2976.
10.1021/jo050670t CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/26/2005
7866
J. Org. Chem. 2005, 70, 7866-7881

Benzotriazole-Assisted Thioacylation
SCHEME 1
SCHEME 2
Bt), and aryl/alkylthiothioacylation (RSCSBt). In addi-
tion, hitherto unreported reactions of 1, 2, and other
related compounds were explored, allowing access to
thioamides, thionoesters, thio- and dithiocarbonates, and
thio- and dithiocarbamates.
Results and Discussion
TABLE 1. Preparation of Thiocarbonylbenzotriazoles
6a-d
A. Preparation of Benzotriazolethioacylation Re-
agents. A.1. Preparation of Thiocarbonylbenzo-
triazoles (RCSBt). We found that direct reaction of bis-
(benzotriazol-1-yl)methanethione (1) with Grignard re-
agents provides low yields (12-34%) of bis(benzotriazol-
1-yl)diarylsulfidemethanes 4 (Figure 1) instead of the
expected thiocarbonylbenzotriazoles. X-ray crystal struc-
tures of the phenyl and 4-methylphenyl dithioketal
derivatives 4a and 4b, respectively, were determined to
definitively ascertain the structures of these unusual
products of S-arylation and rearrangement (crystal-
lographic data for 4a and 4b are included in the Sup-
porting Information).
6
R
% yield
a
b
c
p-tolyl
63
89
76
42
4-methoxyphenyl
phenyl
4-chlorophenyl
d
SCHEME 3
Reactions of 1 with organolithium reagents resulted
in complex mixtures; neither thiocarbonylbenzotriazoles
nor dithioketals were obtained. In light of these findings,
alternate routes to thiocarbonylbenzotriazoles were in-
vestigated.
are all stable, reddish solids. Structural assignment of
1
6a-d was supported by H and 13C NMR spectra and
elemental analyses.
One limitation of this method is that it is restricted to
Grignard-compatible functionalities. In addition, al-
though benzenoid aryl Grignard reagents react quite
smoothly to give thiocarbonylbenzotriazoles 6, only poor
yields are attained for alkyl, alkynyl, and heteroaryl
Grignard reagents. In our hands, attempts to obtain
n-butyl-substituted thiocarbonylbenzotriazole in higher
yields by conducting the reactions at 0 °C and at -78 °C
failed. Likewise, conversion of n-butyllithium to n-bu-
tylzinc bromide or n-butylcuprous bromide for reactions
with carbon disulfide and 1-chlorobenzotriazole also
failed.
The stability of non-benzenoid thiocarbonylbenzotria-
zoles thus appears to be poor. Rapoport utilized the route
of Scheme 3 to obtain aliphatic thiocarbonyl-1H-6-ni-
trobenzotriazoles in good yields (48-67%).23 Apparently,
the electron-withdrawing nitro group on the benzotriazole
moiety improves the stability and allows the isolation of
aliphatic thiocarbonylbenzotriazoles 10. Following this
method, we have prepared several novel aliphatic and
aromatic thiocarbonyl-1H-6-nitrobenzotriazoles 10a-h
(Scheme 3, Table 2).
In our previously reported syntheses of thioamides in
one-pot reactions from Grignard reagents, carbon disul-
fide and amines mediated by 1-trifluoromethylsulfonyl-
benzotriazole,22 the putative intermediates 6 were evi-
dently formed but were not isolated. The instability of
the thione group and its tendency to form stable C-S
single bonds (i.e., by spontaneous trimerization in the
case of 2-thiopropanone) are well documented.1 Addition-
ally, in situ decomposition of analogous methyl-substi-
tuted thioacylimidazoles prepared from ethanethioyl
chloride and imidazole has been reported.5b We now
report that the use of 1-chlorobenzotriazole (instead of
1-trifluoromethylsulfonylbenzotriazole) as the mediating
reagent allows isolation of 6 in some cases (Scheme 2).
Thiocarbonylbenzotriazoles 6a-d were prepared from
carbon disulfide, 1-chlorobenzotriazole, and the respective
Grignard or organolithium reagents (Table 1). The ben-
zenoid thiocarbonylbenzotriazoles (42-89%, average 68%)
Treatment of 4-nitro-1,2-phenylethylenediamine (7)
with the respective acid chlorides 8 gave regioselectively
amides 9 (83-99%). Resonance and the inductive effect
of the nitro group lowered the nucleophilicity of the amino
group in the para position, leaving the meta-amino group
(22) (a) Katritzky, A. R.; Moutou, J.-L.; Yang, Z. Synlett 1995, 99.
(b) Katritzky, A. R.; Moutou, J.-L.; Yang, Z. Synthesis 1995, 1497.
(23) (a) Shalaby, M. A.; Rapoport, H. J. Org. Chem. 1999, 64,1065.
(b) Shalaby, M. A.; Grote, C. W.; Rapoport, H. J. Org. Chem. 1996, 61,
9045.
FIGURE 1. Structures of bis(benzotriazol-1-yl)diarylsulfi-
demethanes (4).
J. Org. Chem, Vol. 70, No. 20, 2005 7867

Katritzky et al.
SCHEME 4
TABLE 2. Aliphatic and Aromatic
SCHEME 5
Thiocarbonyl-1H-6-nitrobenzotriazoles 10a-h
acid chloride 8
amide 9 thiocarbonyl-6-nitrobenzotriazole 10
R
% yield
% yield from 9
a
b
c
d
e
f
ethyl
4-methylphenyl
2-furanyl
84
98
95
83
86
99
81
91
52
80
80
69
66
45
53
81
4-nitrophenyl
4-methoxyphenyl
4-bromophenyl
pentyl
g
h
2-thienyl
TABLE 4. Synthesis of Aryloxythioacylbenzotriazoles
(ROCSBt)
12
R1
% yield
TABLE 3. Thiocarbamoylbenzotriazoles 2
R1
R2
% yield
mp (°C)
a
b
c
d
e
2-naphthyl
3-pyridinyl
1-naphthyl
phenyl
87
66
81
83
75
2
a
b
c
d
e
f
g
h
i
cyclohexyl
H
H
H
H
H
H
H
85
94
87
89
60
87
76
84
76
92
98
76
128-130
119-120
oil
112-113
61-63
oil
furfuryl
(R)-methylbenzyl
phenethyl
tert-butyl
1,5-dimethylhexyl
-CH2CO2CH3
2,3-dihydroindolyl
pyrrolidinyl
phenyl
4-tert-butylphenyl
Reactions of 1 with primary arylamines (such as
aniline, 4-nitroaniline, and 4-aminobenzoic acid ethyl
ester) did not provide the corresponding thiocarbamoyl-
benzotriazoles; aryl isothiocyanates (11) were isolated
instead (Scheme 4).
129-130
123-124
86-87
137-138
oil
)R1
)R1
j
k
l
methyl
ethyl
methyl
ethyl
n-butyl
oil
A.3. Synthesis of Aryloxythioacylbenzotriazoles
(ROCSBt). Different reactivity is seen in reactions of bis-
(benzotriazol-1-yl)methanethione (1) with alkyl alcohols
vs phenols. Reaction of 1 with 1 equiv of sodium ethoxide
provided O-ethyl benzotriazole-1-carbothioate (12, R1 )
Et) in only 19% yield. Other conditions, such as refluxing
in CH2Cl2 or treatment with Et3N or DBU under reflux,
did not improve the yield. Likewise, reactions of 1 treated
with cyclohexanol or 2-methylcyclohexanol under various
conditions (sodium salt in CH2Cl2 at -78 °C to room
temperature over 4 h, treatment with Na2CO3 in CH3-
CN at room temperature during 14 h, or treatment with
Et3N in CH2Cl2 at room temperature and 0 °C from 4 to
14 h) yielded only complex mixtures.
On the other hand, reactions with phenols occurred
quite readily. For example, treatment of bis(benzotriazol-
1-yl)methanethione (1) with the sodium salt of 2-naphthol
afforded novel thioesterification agent O-naphth-2-yl
benzotriazole-1-carbothioate (12a) in 87% yield (Scheme
5).
to attack the carbonyl of acid chloride 8. Amides 9 were
converted to thioamides in crude yields of 59-96% by
stirring at room temperature with phosphorus pentasul-
fide (Scheme 3, Table 2). Thioamides were cyclized by
treatment with sodium nitrite and acetic acid to afford
thiocarbonyl-1H-6-nitrobenzotriazoles 10a-h in 45-81%
yields from amides 9.
Thiocarbonyl-6-nitro-1H-benzotriazoles 10a-h are
stable crystalline solids. Structural assignment of 10a-h
was supported by 1H and 13C NMR spectra and elemental
analyses. The thiocarbonyl 13C NMR signal of thiocar-
bonyl-6-nitro-1H-benzotriazoles 10 is further downfield
as compared with that of thiocarbonylbenzotriazoles 6
and is found at 211.6 ppm for 10a. Although this method
is general and alkyl derivatives are obtained in moderate
overall yields (44-72%) from 4-nitro-1,2-phenylethylene-
diamine (7) and the respective acid chlorides (8), the
lengthy 3-step procedure is a drawback. Thus, the
Grignard method of Scheme 2 is the preferred means of
obtaining arylthiocarbonylbenzotriazoles.
A.2. Preparation of Thiocarbamoylbenzotriazoles
(RR′NCSBt). Treatment of bis(benzotriazol-1-yl)methane-
thione (1) with primary or secondary (alkyl or heteroaryl)
amines at room temperature in CH2Cl2 affords thiocar-
bamoylbenzotriazoles 2a-l (60-98%) (Scheme 1, Table
3). Thiocarbamoylbenzotriazoles 2a-l are crystalline
solids with the exception of certain alkyl compounds
2c,f,k,l which are viscous oils. A 13C NMR signal at ∼170
ppm is characteristic of thiocarbamoylbenzotriazoles
2a-l.
Aryloxythioacylbenzotriazoles 12a-e were obtained as
stable crystalline solids in good yields (66-83%, average
1
73%) (Table 4) and were characterized by H and 13C
NMR. The 13C NMR peak of the thioester thiocarbonyl
typically appeared at ∼180 ppm for compounds of type
12.
A.4. Preparation of Aryl/Alkylthiothioacylbenzo-
triazoles (RSCSBt). Treatment of bis(benzotriazol-1-
yl)methanethione (1) with thiols in the presence of Et3N
at -78 °C afforded S-alkyl and S-aryl(benzotriazolyl)-
dithiocarbamates 13a-c in 42-63% yields (Scheme 5).
These novel aryl/alkylthiothioacylbenzotriazoles (13) are
7868 J. Org. Chem., Vol. 70, No. 20, 2005

Benzotriazole-Assisted Thioacylation
SCHEME 6
TABLE 5. Preparation of Thioamides 15a-j
FIGURE 2. Structure of isopropyl di(benzotriazol-1-yl)methyl
disulfide (14d).
15
R
R1
R2
% yield
a
b
c
d
e
f
4-MeC6H4-
4-MeOC6H4-
4-MeC6H4-
C6H5-
C6H5CH2-
-(CH2)5-
H
99
93
87
97
78
66
91
95
98
80
)R1
C2H5-
H
all crystalline solids characterized as in 13c by benzo-
1
C2H5-
triazole peaks in the aromatic region of the H NMR at
C6H5CH2-
-(CH2)2O(CH2)2-
PhCH2CH2-
-(CH2)2O(CH2)2-
-(CH2)4-
tert-butyl-
C6H5CH2-
7.52 (t, J ) 7.8 Hz, 1H), 7.66 (t, J ) 8.1 Hz, 1H), 8.12 (d,
J ) 8.2 Hz, 1H), and 8.67 ppm (d, J ) 8.4 Hz, 1H) and of
the 13C NMR at 115.5, 120.9, 126.9, 131.4, 132.3, and
147.4 ppm with a thioester thiocarbonyl peak at 196.4
ppm.
With this method, in most cases, only modest yields of
13 were obtained with significant disulfide byproduct
formation even under optimized conditions. Additionally,
the reaction of 1 with the sodium salt of isopropylthiol
under the same reaction conditions afforded the disulfide
14d in 90% yield instead of 13d. The structure of 14d
(Figure 2) was unambiguously determined by single-
crystal X-ray structure analysis (Supporting Informa-
tion).
It is interesting that both Grignard reagents and
alkanethiols preferentially attack the sulfur of the thio-
carbonyl of bis(benzotriazol-1-yl)methanethione (1),
whereas oxygen and nitrogen nucleophiles add to the
carbon of the thiocarbonyl in the normal manner. Sta-
bilization of the resultant carbanion by the two benzo-
triazole moieties and the general polarizabilty of thiols
and the thiocarbonyl bonds may be factors in the prefer-
ence for reaction at the sulfur atom.
C6H5-
)R1
H
4-ClC6H5-
4-BrC6H4-
4-MeC6H4-
4-NO2C6H4-
2-thienyl
g
h
i
)R1
)R1
H
j
H
with ketone alkylidenes afford pyridine-2-thiones.37 Pyr-
roles are synthesized from reactions of N-(benzotriaz-
olylmethyl)thioamides with R,â-unsaturated esters, ke-
tones, or nitriles;38 imidazoles are obtained from reactions
with imines.
Synthetically useful N-monosubstituted and N,N-di-
substituted thioamides 15a-f were readily prepared by
reactions of thiocarbonylbenzotriazoles 6a-d with the
appropriate primary and secondary amines, respectively
(Scheme 6, Table 5). Simple column isolation (5% ethyl
acetate/hexanes) gives thioamides 15a-f in near quan-
titative yields. Formation of the thioamide is indicated
by the loss of benzotriazole signals in H and 13C NMR
1
spectra and the shift of the thiocarbonyl peak to ∼200
ppm.
N-Monosubstituted and N,N-disubstituted thioamides
15g-j were likewise obtained in 80-98% yields from
reactions of thiocarbonyl-6-nitrobenzotriazoles 10b,d,f,h
with the appropriate primary and secondary amines,
respectively, in the presence of Et3N (Table 5).
B. Applications of Thiocarbonylbenzotriazoles
(RCSBt). B.1. Synthesis of Thioamides from Thio-
carbonylbenzotriazoles (RCSBt). Thioamides exhibit
broad biological activity as pesticidal,24,25 fungicidal,26,27
and anthelmintic28 agents. N-Substituted p-alkoxythioben-
zamides possess potent antitubercular activity,29 and
azadecalinthioamides inhibit cholesterol biosynthesis.30
Thioamides are also used in organic synthesis31,32 as
synthons for the preparation of heterocycles,33,34 e.g., to
give thiazoles via Hantzsch reaction with R-haloke-
tones.35,36 Addition-cyclization reactions of thioamides
Classically, thioamides have been synthesized via six
main routes: (i) thionation of an amide by utilization of
phosphorus pentasulfide32 or Lawesson’s reagent, which
have the drawbacks of variable yields and significant
byproduct formation;13 (ii) use of thiocarbonyl transfer
reagents, 1,1′-thiocarbonyldiimidazole (known to be hy-
groscopic and relatively unstable39) or bis(1,2,4-triazole)-
methanethione in reactions with aldolnitrones;4 (iii)
reactions of thiuram monosulfides with organolithium
reagents (65-81% yields);40 (iv) treatment of aryl isothio-
cyanates with Grignard reagents;41,42 (v) reactions of N,N-
dimethylthiocarbamoyl chloride and Grignard reagents
catalyzed by NiCl2 (dppe);43 and (vi) reaction of amines
(24) Hanzlie, R. P.; Cashman, J. R.; Traiger, G. O. J. Toxicol. Appl.
Pharmacol. 1980, 46, 685.
(25) Walter, H.; Zambach, W. PCT Int. Appl. 1996, 74; Chem. Abstr.
1996, 125, 55871.
(26) Wingert, H.; Sauter, H.; Bayer, H.; Oberdorf, K.; Lorenz, G.;
Ammermann, E. Eur. Pat. Appl. 1994, 35; Chem. Abstr. 1994, 121,
533719.
(27) Hara, Y.; Saika, M.; Hamamura, H. Jpn. Kokai Tokkyo Koho
2003, 13; Chem. Abstr. 2003, 138, 132360.
(28) Jeschke, P.; Harder, A.; Etzel, W.; Gau, W.; Thielking, G.;
Bonse, G.; Linuma, K. Pest Manage. Sci. 2001, 57, 1000; Chem. Abstr.
2001, 136, 839295.
(37) Attaby, F. A.; El-Fattah, A. M. Phosphorus, Sulfur Silicon Relat.
Elem. 1999, 155, 253; Chem. Abstr. 2000, 113, 266784.
(38) Katritzky, A. R.; Zhu, L.; Lang, H.; Denisko, O.; Wang, Z.
Tetrahedron 1995, 51, 13271.
(29) Reynard, P.; Moreau, R. C.; Samama, J. P. Bull. Soc. Chim.
Fr. 1965, 12, 3623.
(30) Wannamaker, M. W.; Van Sickle, W. A.; Moore, W. R. U. S.
Pat. Appl. 1991, 16; Chem. Abstr. 1993, 118, 191562.
(31) Singh, H. J. Indian Chem. Soc. 1979, 56, 545.
(32) Chabrier, P.; Renard, S. H. Bull. Soc. Chim. Fr. 1949, D, 172.
(33) Jadodzin˜ski, T. S. Chem. Rev. 2003, 103, 197.
(34) Takahata, H.; Yamazaki, T. Heterocycles 1988, 27, 1953.
(35) Babadjamian, A.; Metzger, J. J. Hetercycl. Chem. 1975, 12, 643.
(36) Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.; Chen, D.-
W. J. Org. Chem. 2003, 68, 7887.
(39) Kim, S.; Yang Yi, K. Y. J. Org. Chem. 1986, 51, 2613.
(40) Gronowitz, S.; Ho¨rnfeldt, A.-B.; Temciuc, M. Synthesis 1993,
483.
(41) Ginwala, K. K.; Trivedi, J. P. J. Indian Chem. Soc. 1971, 48,
791.
(42) Barnikow, G.; Kath, V.; Conrad, H. J. Prakt. Chem. 1966, 32,
259.
(43) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A. Synlett
1994, 719.
J. Org. Chem, Vol. 70, No. 20, 2005 7869

Katritzky et al.
TABLE 6. Synthesis of Thionoesters 16 from
Thioacylating Agents 6 and 10
low-yielding reactions of dithioacids with 2-halo-1-me-
thylpyridinium salts and subsequent treatment with the
respective alcohols;48 and Friedel-Crafts acylations of
unstable 1-chlorothioformates with aromatics.10
thionoesters
alcohol
R1
thioacylating agent
R
16
% yield
The advantages of our thioacylation methodology are
primarily that the use of unstable or hazardous reagents
(e.g., H2S) is avoided, the mild conditions employed are
tolerable to a wide variety of functional groups, and yields
are either higher or comparable to those of known
methods.
B.3. Thiocarbamoylation Using Thiocarbamoyl-
benzotriazoles (RR′NCSBt). As will be discussed be-
low, there are important differences in the reactivity of
N-monosubstituted and N,N-disubstituted thiocarbam-
oyls toward nucleophiles. Our results indicate that N-
monosubstituted thiocarbamoylbenzotriazoles 2a-g are
isothiocyanate synthons, reacting with nucleophiles
(amines, alcohols, and organometallic reagents) by an
elimination-addition mechanism. N,N-Disubstituted thio-
carbamoyls 2h-l appear to react with oxygen, sulfur, and
carbon nucleophiles by an addition-elimination mecha-
nism to effect thiocarbamoylation, but 2h-l are unreac-
tive toward amines.
a
b
c
d
e
4-methoxyphenyl 4-methoxyphenyl (6b)
77
60
88
99
62
ethyl
4-chlorophenyl (6d)
4-methoxyphenyl (10e)
4-nitrophenyl (10d)
2-thienyl (10i)
1-naphthyl
1-naphthyl
1-naphthyl
with aryl thioesters (with arylamines only, 64-99%),29
thiobenzoyl chlorides (5-92%),6 or N-thiobenzoyl triazoles
(0-72% yields).5 In comparison, preparation of N-mono-
substituted and N,N-disubstituted thioamides by reac-
tions of stable and readily accessible thiocarbonylbenzo-
triazoles or thiocarbonyl-1H-6-nitrobenzotriazoles, as
reported previously by Rapoport,23 occurs cleanly and in
near quantitative yields.
B.2. Synthesis of Thionoesters from Thiocarbo-
nylbenzotriazoles (RCSBt). Successful application of
thioacylbenzotriazole reagents to the synthesis of novel
thioamides led to the extension of our methodology to
thionoesters, which are generally less studied than
thioamides or their thiolester counterparts because few
reported syntheses for thionoesters provide sufficiently
general access to these compounds; i.e., most literature
methods are limited to the preparation of O-phenyl
thionoesters.1,15
Despite the lack of efficient methods to provide diverse
thionoesters, these compounds are attractive synthetic
targets because of their utility when incorporated into
macrocycles, such as crown ethers,44 and also for their
application as chemical probes of the enzyme binding
sites of cysteine45 and serine46 proteases.
Thiocarbonylbenzotriazoles 6b and 6d were reacted
with alcohols in the presence of Et3N to give thionoesters
16a and 16b in 77 and 60% yields, respectively (Scheme
6, Table 6). Similarly, thiocarbonyl-6-nitrobenzotriazoles
10d,e,i were reacted with 1-naphthol, providing thion-
oesters 16c-e in 62-99% yields. No observable difference
in reactivity was noted between thioacylation reagents
6 and 10.
In an attempt to extend our methodology to dithioesters,
it was observed that both reactions of 6 and 10 with
phenylthiol or its sodium salt (under reflux conditions
and in the presence of Et3N, pyridine, or DMAP) failed.
However, refluxing 6c with benzyl mercaptan in aceto-
nitrile in the presence of triethylamine provided benzyl
dithiobenzoate in 14% yield.
Although limited to the preparation of thionoesters, our
method compares favorably to classical syntheses (Scheme
7), which have involved treatment of esters with phos-
phorus pentasulfide14,15 or Lawesson’s reagent, both often
requiring a large excess of reagent and long reaction
times;47 reactions of imino esters with hydrogen sulfide,
which often results in significant byproduct formation;13
B.4. Synthesis of Thioamides from Reactions of
C-Nucleophiles with Thiocarbamoylbenzotriazoles
(RR′NCSBt). Reactions of both N-monosubstituted thio-
carbamoylbenzotriazoles 2a-c,e,f and N,N-disubstituted
thiocarbamoylbenzotriazoles 2i,l,j with organolithium or
Grignard reagents provided secondary thioamides 15k-p
in yields of 35-99% (average 68%) and tertiary thioam-
ides 15q-s in 35-99% yields (average 79%), respectively
(Scheme 8, Table 7). As with parallel thioamide formation
by thioacylation agents 6 and 10, confirmation of thio-
amide synthesis is indicated by the loss of the benzo-
1
triazole signals in H and 13C NMR spectra and by the
shift of the thiocarbonyl peak to ∼200 ppm.
Reactions were conducted with excess organometallic
reagent. For example, monosubstituted thiocarbamoyl-
benzotriazoles 2a-c,e,f were reacted with 2.5 equiv of
the organometallic reagent and disubstituted thiocar-
bamoylbenzotriazoles 2i,j,l were reacted with 1.2 equiv.
Commercially available Grignard reagents provided higher
yields of thioamides in comparison with organolithium
reagents prepared by following literature procedures.
Although N-monobenzenoid aryl-substituted thioam-
ides cannot be synthesized because of the incompatibility
of primary benzenoid arylamines for the synthesis of
thiocarbamoylbenzotriazoles 2, our method has the ad-
vantage of milder conditions and higher yields as com-
pared with classical syntheses.
B.5. Syntheses of Heteroaryl-Substituted Thio-
ureas from Reactions of N-Nucleophiles with Thio-
carbamoylbenzotriazoles (RR′NCSBt). Heteroaryl-
substituted thiocarbamoylbenzotriazoles are readily
prepared in moderate yields (57-63%) from reactions of
1 with heteroarylamines, but because conversion to the
isothiocyanates occurs quite easily in solution, yields are
lower in comparison with other thiocarbamoylbenzotria-
zoles 2. To avoid this problem, we now report one-pot
syntheses of symmetrical and asymmetrical heteroaryl-
substituted thioureas 3a-g from heteroaryl-substituted
(44) Jones, B. A.; Bradshaw, J. S.; Brown, P. R.; Christensen, J. J.;
Izatt, R. M. J. Org. Chem. 1983, 48, 2653.
(45) Reid, J. D.; Hussain, S.; Bailey, T. S. F.; Sonkaria, S.; Sreedha-
ran, S. K.; Thomas, E. W.; Resmini, M.; Brocklehurst, K. Biochem. J.
2004, 378, 699.
(46) Campbell, P.; Nashed, N. T.; Lapinskas, B. A.; Gurrieri, J. J.
Biol. Chem. 1983, 258, 59; Chem. Abstr. 1983, 98, 30476.
(47) Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O.
Bull. Soc. Chim. Belg. 1978, 87, 223.
(48) Meeson, J.; McColm, A. A.; Acred, P.; Greenwood, D. J.
Antimicrob. Chemother. 1990, 25, 103; Chem. Abstr. 1990, 131954.
7870 J. Org. Chem., Vol. 70, No. 20, 2005

Benzotriazole-Assisted Thioacylation
SCHEME 7
SCHEME 8
In addition to providing a route to symmetric thioureas,
our method offers access to novel asymmetric thioureas
that are traditionally a more difficult problem.21 The
significance of a mild, high-yielding route to symmetric
and asymmetric thioureas is emphasized in view of the
diverse properties and important applications of thio-
ureas and heteroaryl thioureas. For example, thioureas
display diverse biological activity as phenoloxidase en-
zymatic inhibitors,52 bacteriocides,53 rodenticides,54 and
insecticides.55 Heteroaryl-substituted thioureas are par-
ticularly active, and certain pyridinyl thioureas are HIV
reverse-transcriptase inhibitors.8 Thioureas are also
important synthons for the preparation of five-56 and six-
membered heterocycles.57
B.6. Thiocarbamates from Reactions of O-Nucleo-
philes with Thiocarbamoylbenzotriazoles (RR′NCS-
Bt). Thiocarbamates are potent insecticides,58 herbi-
cides,59 and nematocides.60 3-(1H-Imidazol-4-yl)propyl
N-phenylthiocarbamate is a potent histamine H3-receptor
antagonist,61 and dimethylthiocarbamate is an alcohol-
protecting group.62
To prepare thiocarbamates 17a and 17b (59 and 60%
yields, respectively), N,N-disubstituted thiocarbamoyl-
benzotriazoles 2h and 2j were reacted with benzhydrol
sodium salts (Scheme 8); N-monosubstituted thiocarbam-
oylbenzotriazoles failed to react with oxygen nucleophiles,
either as free alcohols in the presence of Et3N or as salts
at room temperature or under refluxing conditions.
Classical syntheses of thiocarbamates have utilized
either carbon disulfide or thiophosgene in direct reactions
with amines and alcohols, particularly 4-substituted
3-hydroxybutylamines (31-73% yields).1 Also, 1-chlo-
rothioformates, formed by reactions of thiophosgene with
alcohols, have been reacted with amines (49-98%
yields).62,63 Reactions of isothiocyanates64,65 (limited to
thiocarbamoylbenzotriazoles prepared in situ (Scheme 1
(R, R1 ) Het, R2 ) H), Table 8).
Symmetrical heteroaryl-substituted thioureas 3a-d
were prepared in 82-85% yields by refluxing 2 equiv of
the appropriate amines with 1 in CH2Cl2. We have found
that 1H NMR spectra taken in DMSO-d6 provide the
signals expected for symmetric thiourea molecules; how-
ever, an inequivalency of protons was observed in spectra
of thioureas 3c and 3d taken in CDCl3. As Kaminsky et
al.49 have reported, the crystal structure of 3d reveals
that strong intramolecular hydrogen-bonding interactions
occur between the pyridine nitrogen and the thiourea
N-H (Figure 3); the CDCl3 1H NMR signals for 3d show
corresponding differences in the electronic environment
of the methyl groups and the protons of the pyridine
rings.
For asymmetric thiourea 3e, exactly 1 equiv of 2-py-
ridinylamine was refluxed with 1 in CH2Cl2 until TLC
indicated complete conversion of 1 to the expected thio-
carbamoylbenzotriazole intermediate with some isothio-
cyanate formation. 3-Pyridinylamine was added at this
point, and reflux was continued until conversion to
product was complete as indicated by TLC. Asymmetric
thioureas 3f and 3g were similarly prepared in yields of
80 and 83%, respectively.
(52) Makhsumov, A. G.; Safaev, A. S.; Abidova, S. V. Katal. Pererab.
Uglevodordnogo Syr’ya 1968, 101; Chem. Abstr. 1969, 71, 101668v.
(53) Mallams, A. K.; Morton, J. B.; Reichert, P. J. Chem. Soc., Perkin
Trans. 1 1981, 2186.
Our one-pot syntheses of symmetrical and asym-
metrical heteroaryl-substituted thioureas provided 3a-g
in 78-85% yields, offering a definitive advantage over
previously reported syntheses (Table 8). Symmetric thio-
ureas 3b-d were reportedly obtained in poor to moderate
yields by reaction of amines with CS2 at room tempera-
ture in the presence of I2 in pyridine (3b, 23% yield),50
at 100 °C catalyzed by Zn-Al HT(500) (3c, 57% yield),51
and by heating in methanol (3d, 17%).49
(54) Schroeder, D. C. Chem. Rev. 1955, 181.
(55) Sarkis, G. Y.; Faisal, E. D. J. Heterocycl. Chem. 1985, 22, 137.
(56) Klika, K. D.; Bernat, J.; Imrich, J.; Chomca, I.; Sillanpaa, R.;
Pihlaja, K. J. Org. Chem. 2001, 66, 4416.
(57) 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.
(58) Kochansky, J.; Cohen, C. F. J. Agric. Entomol. 1990, 7, 293.
(59) Casida, J. E.; Kimmel, E. C.; Lay, M.; Ohkawa, H.; Rodebush,
J. E.; Gray, R. A.; Tseng, C. K.; Tilles, H. Environ. Qual. Saf., Suppl.
1975, 3, 675.
(60) Koschansky, J.; Feldmesser, J. J. Nematol. 1989, 21, 158.
(61) Stark, H.; Purand, K.; Ligneau, X.; Rouleau, A.; Arrang, J.-M.;
Garbarg, M.; Schwartz, J.-C.; Schunack, W. J. Med. Chem. 1996, 39,
1157.
(62) Barma, D. K.; Bandyopadhyay, A.; Capdevila, J. H.; Falck, J.
R. Org. Lett. 2003, 5, 4755.
(63) Zhang, X.; Lee, Y. K.; Kelley, J. A.; Burke, T. R., Jr. J. Org.
Chem. 2000, 65, 6237.
(49) Kaminsky, W.; Goldberg, K. I.; West, D. X. J. Mol. Struct. 2002,
605, 9.
(50) Deady, L. W.; Ganame, D.; Hughes, A. B.; Quazi, N. H.; Zanatta,
S. D. Aust. J. Chem. 2002, 55, 287.
(51) Ballabeni, M.; Ballini, R.; Bigi, F.; Maggi, R.; Parrini, M.;
Predieri, G.; Sartori, G. J. Org. Chem. 1999, 64, 1029.
J. Org. Chem, Vol. 70, No. 20, 2005 7871

Katritzky et al.
% yield
TABLE 7. Preparation of Secondary Thioamides 15k-s from Thiocarbamoylbenzotriazoles 2
thiocarbamoylbenzotriazole
R-M
2
thioamide
R
M
R1
R2
15
phenyl
pentyl
2-furanyl
phenyl
4-methoxyphenyl
2-pyridinyl
allyl
2-thienyl
allyl
MgBr
MgBr
Li
MgBr
MgBr
Li
MgBr
Li
MgBr
2a
2b
2e
2f
2c
2a
2l
cyclohexyl
furfuryl
H
H
H
H
H
H
15k
15l
87
99
47
56
85
35
98
53
78
tert-butyl
15m
15n
15o
15p
15q
15r
15s
1,5-dimethylhexyl
(R)-methylbenzyl
cyclohexyl
n-Butyl
piperidinyl
phenyl
methyl
2i
2j
)R1
methyl
TABLE 8. Symmetrical and Asymmetrical Heteroaryl-Substituted Thioureas 3a-g
thiourea
3
het1
het2
% yield
% lit. yield
a
b
c
d
e
f
4-pyridinyl
4-pyridinyl
85
83
82
83
78
80
83
3-pyridinyl
3-pyridinyl
2350
5751
1749
2-pyridinyl
2-(4,6-dimethyl)pyridinyl
2-pyridinyl
4-pyridinyl
2-pyridinyl
2-pyridinyl
2-(4,6-dimethyl)pyridinyl
3-pyridinyl
2-pyridinyl
2-(4,6-dimethyl)pyridinyl
g
Dithiocarbamates have been prepared (Scheme 9) in
the following ways: (i) by activation of a dithiocarbamate
with a 2-halothiazolium salt and subsequent reaction
with a thiol (two examples, 37% and 87% yields),66 (ii)
by reaction of a dithiocarbamate with an alkyl or aryl-
halide,67 (iii) by reaction of an organolithium reagent with
a thiuram disulfide at -70 °C under N2,40 and (iv) by
zeolite-catalyzed (Zn-Al HT) reaction of carbon disulfide
with 2-aminothiophenol.51
The main advantage of our benzotriazole-assisted
thiocarbamoylation methodology is the use of stable
reagents, which provide high yields (60-99%) and clean
conversion to dithiocarbamates in short reaction times
under mild conditions.
FIGURE 3. Intramolecular hydrogen-bonding interactions
influencing the conformation of 1,3-bis(4,6-dimethylpyridin-
2-yl)thiourea (3d).
TABLE 9. Dithiocarbamates Prepared (18: RSCSNR1R2)
C. Alkoxythiocarbonylations with Aryloxythio-
acylbenzotriazoles (ROCSBt). C.1. Synthesis of Thio-
noesters 16. Reactions of Grignard reagents with
O-naphth-2-yl benzotriazole-1-carbothioate (12a) pro-
vided thionoesters 16f-h in good yields (64-76%) (Scheme
10, Table 10). This general method complements the
preparation of thionoesters from thiocarbonylbenzotria-
zoles 6 or thiocarbonyl-1H-6-nitrobenzotriazoles 10, shar-
ing the advantages of these methods over classical routes.
C.2. Synthesis of Thiocarbamates 17 from Ary-
loxythioacylbenzotriazole 12a. Thiocarbamates 17c-e
were prepared by refluxing aryloxythioacylbenzotriazole
12a with amines in CH2Cl2 for 2 h (Scheme 10, Table
11). Column chromatography (silica gel, 1:10 ethyl acetate/
hexanes) afforded thiocarbamates 17c-e in 70-85%
yields.
reagent
2
dithiocarbamate
thiol
R
%
18
R1
R2 yield
a
b
c
3-methoxyphenyl 2,3-dihydroindolyl )R1 99
3-methoxyphenyl furfuryl
benzyl
phenyl
H
H
H
83
92
60
cyclohexyl
phenethyl
d
allyl and aryl isothiocyanates) or chlorothiocarbamoyls7
with alcohols are traditional alternatives. Our method,
although limited to reactions of N,N-disubstituted thio-
carbamoylbenzotriazoles with sodium salts of alcohols,
offers a viable alternative to classical syntheses that
avoids the use of hazardous or unstable reagents.
B.7. Dithiocarbamates from Reactions of S-
Nucleophiles with Thiocarbamoylbenzotriazoles
(RR′NCSBt). In reactions with sulfur nucleophiles,
dithiocarbamates 18 were prepared from both N-mono-
substituted and N,N-disubstituted thiocarbamoylbenzo-
triazoles (Scheme 8, Table 9). N-Monosubstituted thio-
carbamoylbenzotriazoles (2a,b,d) did not require the use
of salts because the reactions occurred readily at room
temperature in the presence of 1 equiv of Et3N.
Reaction of aryloxythioacylbenzotriazoles 12 with
amines does not require use of a base and is a mild and
efficient means of preparing thiocarbamates 17c-e.
Therefore, this synthetic route is preferred in comparison
with the alternative preparation of thiocarbamates 17
from N,N-disubstituted thiocarbamoylbenzotriazoles 2
(64) Walter, W.; Bode, K. D. Ann. Chem. 1965, 681, 64.
(65) (a) Elderfield, R. C.; Short, F. W. J. Org. Chem. 1953, 18, 1092.
(b) Bost, R. W.; Andrews, E. R. J. Am. Chem. Soc. 1943, 65, 900.
(66) Sugimoto, H.; Makino, I.; Hirai, K. J. Org. Chem. 1988, 53,
2263.
(67) Rasheed, K.; Warkentin, J. D. J. Org. Chem. 1977, 42, 1265.
7872 J. Org. Chem., Vol. 70, No. 20, 2005

Benzotriazole-Assisted Thioacylation
SCHEME 9
TABLE 12. Synthesis of Thiocarbonates 19 from
Aryloxythioacylbenzotriazole 12a
SCHEME 10
thiocarbonate
reagent 12
alcohol
R
19
R1
% yield
a
b
c
2-naphthyl
2-naphthyl
2-naphthyl
ethyl
70
72
70
3-pyridinyl
4-methylphenyl
TABLE 13. Synthesis of Dithiocarbonates 20 from
Aryloxythioacylbenzotriazole 12a
dithiocarbonate
reagent 12
thiol
R
20
R1
% yield
TABLE 10. Synthesis of Thionoesters 16 from
Aryloxythioacylbenzotriazole 12a
a
b
c
2-naphthyl
2-naphthyl
2-naphthyl
4-methylphenyl
dodecyl
i-propyl
70
70
60
organometallic reagent
thionoester reagent 12a
16
R1
R
M(X)
% yield
f
g
h
2-naphthyl
2-naphthyl
2-naphthyl
4-methylphenyl MgBr
70
76
64
phenyl
methyl
MgBr
MgBr
In comparison, thiocarbonates have been previously
prepared by reactions of alcohols with 1-chlorothiofor-
mates derived from thiophosgene,74 1,2-dihydroxy com-
pounds with thiophosgene75 or 1,1′-thiocarbonyl-2,2′-
pyridone (requiring synthesis from di-2-pyridylthiono-
carbonate),76 alcohols with 1,1′-thiocarbonyldiimidazole
(known to be hygroscopic and relatively unstable),3,12,39
and alkenes with osmium tetraoxide and subsequent
treatment with 1,1′-thiocarbonyldiimidazole.77 Most sig-
nificantly, the primary advantage of our methodology is
the use of a stable, non-hazardous reagent.
C.4. Preparation of Dithiocarbonates 20 from
Aryloxythioacylbenzotriazole 12a. Similar to the
preparation of thiocarbonates 19, dithiocarbonates 20a-c
were readily provided in 60-70% yields from aryloxy-
thioacylbenzotriazole 12a (Scheme 10, Table 13). Reac-
tions occur with both alkyl- and aryl-thiols, providing
dithiocarbonates in good yields.
TABLE 11. Synthesis of Thiocarbamates 17 from
Aryloxythioacylbenzotriazole 12a
amine
thiocarbamate
reagent 12
17
R1
R
R2
% yield
c
d
e
2-naphthyl
2-naphthyl
2-naphthyl
morpholinyl
benzyl
pyrrolidinyl
)R
H
)R
70
85
85
because reactions of 2 with sodium salts of alcohols
require use of excess sodium hydride to obtain good yields
(∼60%).
C.3. Preparation of Thiocarbonates 19 from Aryl-
oxythioacylbenzotriazole 12a. Thiocarbonates have
utility as intermediates in olefin synthesis.11,68-71 Nota-
bly, stereospecific Corey-Winter alkene synthesis in-
volves reactions of cyclic thiocarbonates with alkyl phos-
phites.72,73
Dithiocarbonates have been classically prepared for
Barton-McCombie reactions by reacting alkylhalides
(usually MeI; lower yields are obtained with other
alkylhalides), carbon disulfide, and alcohols.78-80 Syn-
thesis from 1-chlorodithioformate and sodium thiolates
has also been reported.81 Benzotriazole-assisted aryloxy-
Reactions of aryloxythioacylbenzotriazole 12a with
alcohols provide a general and efficient route to thiocar-
bonates 19. Good yields of thiocarbonates 19a-c (70-
72%) were obtained under mild conditions (stirring the
sodium salt of the alcohol in CH2Cl2 at room temperature)
(Scheme 10, Table 12).
(74) Emerson, C. D.; Aideness, P. C. Chem. Abstr. 1973, 78, 3753.
(75) Bender, A. D.; Berkoff, C. E.; Groves, W. G.; Sofranko, L. M.;
Wellman, G. R.; Liu, J. H.; Begosh, P. P.; Horodniak, J. W. J. Med.
Chem. 1975, 18, 1094.
(68) Corey, E. J.; Schulman, J. I. Tetrahedron Lett. 1968, 3655.
(69) Paquette, L. A.; Philips, J. C.; Wingard, R. E., Jr. J. Am. Chem.
Soc. 1971, 93, 4516.
(70) Harimann, W.; Fischer, H. M.; Heine, H. G. Tetrahedron Lett.
1972, 853.
(71) Harton, D.; Tindall, C. G., Jr. J. Org. Chem. 1970, 35, 3558.
(72) Corey, E. J.; Winters, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677.
(73) Corey, E. J.; Carey, F. A.; Winters, R. A. E. J. Am. Chem. Soc.
1965, 87, 934.
(76) Danishefsky, S. J.; DeNinno, M. P. J. Org. Chem. 1986, 51, 5.
(77) Labar, D.; Dumont, W.; Hevesi, L.; Krief, A. Tetrahedron Lett.
1978, 19, 1145.
(78) Weinstock, J.; Lewis, S. N. J. Am. Chem. Soc. 1957, 79, 6243.
(79) Cole, S. J.; Kirwan, J. N.; Roberts, B. P.; Willis, C. R. J. Chem.
Soc., Perkin Trans. 1 1991, 103.
(80) Skinner, S. G.; Bicking, J. B. J. Am. Chem. Soc. 1950, 72, 1140.
J. Org. Chem, Vol. 70, No. 20, 2005 7873

Katritzky et al.
Anal. Calcd for C13H16N4S: C, 59.97; H, 6.19; N, 21.52.
Found: C, 60.07; H, 6.32; N, 21.60.
thioacylation of thiols is a mild and general method,
which offers a competitive alternative to traditional
syntheses.
Benzotriazole-1-carbothioic Acid (Furan-2-ylmethyl)-
amide (2b): brown and colorless needles (94%); mp 119-120
°C (lit.21 mp 117-119 °C); 1H NMR δ 5.04 (d, J ) 5.1 Hz, 2H),
6.38-6.46 (m, 2H), 7.44-7.52 (m, 2H), 7.62-7.70 (m, 1H), 8.10
(d, J ) 8.1 Hz, 1H), 8.91 (d, J ) 8.4 Hz, 1H), 9.30 (br s, 1H);
13C NMR δ 41.8, 103.4, 109.4, 110.7, 116.0, 120.4, 125.8, 130.5,
143.0, 147.1, 148.5, 174.3. Anal. Calcd for C12H10N4OS: C,
55.80; H, 3.90; N, 21.69. Found: C, 56.10; H, 3.86; N, 21.70.
Benzotriazole-1-carbothioic Acid ((R)-1-Phenylethyl)-
amide (2c): purified by column chromatography with hex-
anes/EtOAc (90:10) as eluent to afford yellow oil (87%); 1H
NMR (CDCl3) δ 1.77 (d, J ) 7.2 Hz, 3H), 5.74-5.84 (m, 1H),
7.30-7.50 (m, 6H), 7.61-7.66 (m, 1H), 8.09 (d, J ) 8.2 Hz,
1H), 8.90 (d, J ) 8.5 Hz, 1H), 9.32 (d, J ) 6.3 Hz, 1H); 13C
NMR δ 21.0, 54.0, 116.0, 120.1, 125.6, 126.4, 127.9, 128.8,
130.2, 132.3, 141.0, 147.0, 173.3. Anal. Calcd for C15H14N4S:
C, 63.80; H, 5.00; N, 19.84. Found: C, 63.63; H, 4.95; N, 19.82.
Benzotriazole-1-carbothioic Acid Phenethylamide
Conclusion
We have developed and applied benzotriazole reagents
for thioacylation (RCSBt), thiocarbamoylation (RR′NCS-
Bt), aryl/alkoxythioacylation (ROCSBt), and aryl/alkyl-
thiothioacylation (RSCSBt) to the syntheses of numerous
novel thioamides, thionoesters, dithioesters, heteroaryl
thioureas, thiocarbamates, dithiocarbamates, thiocar-
bonates, and dithiocarbonates. Thioamide formation by
thiocarbamoylbenzotriazoles and thioacylbenzotriazoles
is complementary, with one method being the reverse
order of steps in respect to the other. Complementary
methods for thionoester synthesis (from thioacylbenzo-
triazoles or aryloxythioacylbenzotriazoles) and thiocar-
bamate preparation (from thiocarbamoylbenzotriazoles
or aryloxythioacylbenzotriazoles) have also been de-
scribed. Advantages of benzotriazole methods are pri-
marily that the use of unstable or hazardous reagents is
avoided, the mild conditions employed are tolerable of a
large variety of functional groups, and yields are com-
parable and in many cases higher than those in previ-
ously reported methods.
1
(2d): white needles (89%); mp 112-113 °C; H NMR δ 3.12
(t, J ) 6.9 Hz, 2H), 4.07-4.14 (m, 2H), 7.22-7.39 (m, 5H),
7.43-7.51 (m, 1H), 7.60-7.68 (m, 1H), 8.09 (d, J ) 8.7 Hz,
1H), 8.92 (d, J ) 8.7 Hz, 1H), 9.14 (br s, 1H); 13C NMR δ 34.1,
46.1, 116.0, 120.2, 125.7, 127.0, 128.7, 128.9, 130.3, 132.4,
137.8, 147.0, 174.4. Anal. Calcd for C15H14N4S: C, 63.80; H,
5.00; N, 19.84. Found: C, 63.81; H, 4.90; N, 19.70.
Benzotriazole-1-carbothioic Acid tert-Butylamide
1
(2e): yellow needles (60%); mp 61-63 °C; H NMR δ 1.71 (s,
9H), 7.45 (t, J ) 7.8 Hz, 1H), 7.59-7.64 (m, 1H), 8.07 (d, J )
8.4 Hz, 1H), 8.91 (d, J ) 8.7 Hz, 1H), 9.05 (br s, 1H); 13C NMR
δ 27.9, 55.5, 103.3, 116.4, 120.1, 125.4, 130.0, 132.2, 147.1,
172.6. Anal. Calcd for C11H14N4S: C, 56.38; H, 6.02; N, 23.91.
Found: C, 56.31; H, 5.93; N, 24.10.
Experimental Section
Melting points were uncorrected. 1H (300 MHz) and 13C (75
MHz) NMR spectra were recorded on a 300 MHz NMR
spectrometer in chloroform-d solution unless otherwise stated.
Column chromatography was performed on silica gel (230-
425 mesh). THF was distilled from sodium-benzophenone
ketyl prior to use. Commercially available Grignard reagents
were used for the preparation of thioamides. Bis(benzotriazol-
1-yl)methanethione (now available from a commercial supplier)
was prepared according to a literature procedure.82 The
organometallic reactions were performed under a nitrogen
atmosphere and in oven-dried glassware.
General Procedure for the Preparation of 1-Alkyl/
Arylthiocarbamoylbenzotriazoles 2a-l. Bis(benzotriazol-
1-yl)methanethione82 (1) (0.56 g, 2 mmol) was dissolved in
CH2Cl2 at room temperature. The appropriate amine (2 mmol)
was added dropwise, and the reaction mixture was stirred for
18 h. Solvent was removed under vacuum, and the residue
was redissolved in EtOAc and washed with 5% aqueous
sodium carbonate, water, and brine before drying over anhy-
drous Na2SO4. Solvent was removed under vacuum, and the
1-alkyl/arylthiocarbamoylbenzotriazole (2) was recrystallized
from EtOAc/hexanes or by column chromatography as indi-
cated.
Benzotriazole-1-carbothioic Acid (1,5-Dimethylhexyl)-
amide (2f): purified by column chromatography with hexanes/
1
EtOAc (94:6) as eluent to afford yellow oil (87%); H NMR δ
0.87 (d, J ) 6.3 Hz, 6H), 1.22-1.85 (m, 10H), 4.60-4.75 (m,
1H), 7.42-7.51 (m, 1H) 7.58-7.68 (m, 1H), 8.08 (d, J ) 8.1
Hz, 1H), 8.92-8.95 (m, 2H); 13C NMR δ 19.5, 22.5, 23.7, 27.8,
36.1, 38.6, 51.0, 116.1, 120.1, 125.5, 130.1, 132.4, 147.0, 173.3.
Anal. Calcd for C15H22N4S: C, 62.03; H, 7.64; N, 19.29.
Found: C, 62.16; H, 7.96; N, 19.68.
[(Benzotriazole-1-carbothioyl)amino] Acetic Acid Meth-
1
yl Ester (2g): cream flakes (76%); mp 129-130 °C; H NMR
δ 3.87 (s, 3H), 4.62 (d, J ) 3.6 Hz, 2H), 7.50 (t, J ) 7.5 Hz,
1H), 7.68 (t, J ) 7.5 Hz, 1H), 8.12 (d, J ) 8.1 Hz, 1H), 8.86 (d,
J ) 8.7 Hz, 1H), 9.53 (br s, 1H); 13C NMR δ 46.2, 52.8, 115.8,
120.4, 125.8, 130.5, 132.3, 147.0, 168.5, 174.7. Anal. Calcd for
C10H10N4O2S: C, 47.99; H, 4.03; N, 22.39. Found: C, 48.42;
H, 4.18; N, 21.92.
1H-1,2,3-Benzotriazol-1-yl(2,3-dihydro-1H-indol-1-yl)-
methanethione (2h): purified by column chromatography
with hexanes/EtOAc (91:9) as eluent to afford yellow flakes
(84%); mp 123-124 °C; 1H NMR (DMSO-d6) δ 3.26 (t, J ) 7.5
Hz, 2H), 4.53 (t, J ) 7.5 Hz, 2H), 7.02 (s, 1H), 7.14 (t, J ) 7.5
Hz, 1H), 7.41 (d, J ) 7.5 Hz, 1H), 7.53-7.58 (m, 1H), 7.68-
7.73 (m, 1H), 7.99 (d, J ) 8.4 Hz, 1H), 8.20 (d, J ) 8.7 Hz,
2H); 13C NMR (DMSO-d6) δ 26.6, 56.7, 112.7, 115.9, 119.5,
125.2, 125.7, 126.0, 126.6, 129.2, 131.4, 135.5, 140.9, 145.1,
168.8. Anal. Calcd for C15H12N4S: C, 64.26; H, 4.31; N, 19.98.
Found: C, 64.26; H, 4.21; N, 20.15.
Benzotriazol-1-yl-piperidin-1-yl-methanethione (2i):
yellow prisms (76%); mp 86-87 °C; 1H NMR δ 1.71-2.03 (m,
6H), 3.60 (s, 2H), 4.33 (s, 2H), 7.41-7.47 (m, 1H), 7.57-7.62
(m, 2H), 8.07 (d, J ) 9.0 Hz, 2H); 13C NMR δ 24.0, 25.4, 26.8,
52.7, 53.4, 113.7, 119.8, 125.0, 128.8, 133.3, 146.0, 174.1. Anal.
Calcd for C12H14N4S: C, 58.51; H, 5.73; N, 22.74. Found: C,
58.88; H, 5.73; N, 22.95.
Ethyl 4-isothiocyanatobenzoate (11a) is provided as a
representative example of isocyanates obtained from reactions
of primary arylamines with bis(benzotriazolyl)methanethione
under the above conditions.
Benzotriazole-1-carbothioic Acid Cyclohexylamide
(2a): white cubes (from EtOAc/hexanes) (95%); mp 72-73 °C
1
(lit.21 mp 72-73 °C); H NMR (CDCl3) δ 1.25-1.58 (m, 5H),
1.69-1.85 (m, 3H), 2.04-2.23 (m, 2H), 4.45-4.48 (m, 1H), 7.47
(t, J ) 7.7 Hz, 1H), 7.63 (t, J ) 7.7 Hz, 1H), 8.09 (d, J ) 8.4
Hz, 1H), 8.99 (br d, J ) 6.0 Hz, 1H); 13C NMR (CDCl3) δ 24.6,
25.4, 31.6, 53.6, 116.1, 120.1, 125.5, 130.1, 132.4, 147.0, 173.0.
(81) Barany, G.; Schroll, A. L.; Mott, A. W.; Halsrud, D. A. J. Org.
Benzotriazole-1-carbothioic Acid N-Methyl-N-pheny-
lamide (2j): colorless plates (92%); mp 138 °C; 1H NMR δ
3.96 (s, 3H), 7.01-7.10 (m, 2H), 7.15-7.26 (m, 3H), 7.36-7.42
Chem. 1983, 48, 4750.
(82) Larsen, C.; Steliou, K.; Harpp, D. N. J. Org. Chem. 1978, 43,
337.
7874 J. Org. Chem., Vol. 70, No. 20, 2005

Benzotriazole-Assisted Thioacylation
(m, 1H), 7.56-7.61 (m, 1H), 7.94 (d, J ) 8.4 Hz, 1H), 8.13 (d,
J ) 8.4 Hz, 1H); 13C NMR δ 46.0, 113.0, 119.8, 124.6, 124.8,
127.7, 128.8, 129.4, 133.0, 145.4, 145.5, 175.7. Anal. Calcd for
C14H12N4S: C, 62.66; H, 4.51; N, 20.88. Found: C, 63.00; H,
4.49; N, 20.97.
1-(Pyridin-2-yl)-3-(pyrid-3-yl)thiourea (3e): white mi-
1
crocrystals (78%); mp 180-181 °C; H NMR δ 7.01 (dd, J )
6.6, 5.2 Hz, 1H), 7.16 (d, J ) 8.4 Hz, 1H), 7.35 (dd, J ) 8.2,
4.8 Hz, 1H), 7.69 (t, J ) 8.9 Hz, 1H), 8.23 (dd, J ) 5.0, 1.1 Hz,
1H), 8.32 (dd, J ) 8.2, 3.6 Hz, 1H), 8.46 (dd, J ) 4.8, 1.3 Hz,
1H), 8.76 (d, J ) 2.3 Hz, 1H), 10.41 (br s, 2H); 13C NMR δ
113.0, 118.2, 123.0, 132.0, 135.7, 138.9, 145.2, 145.8, 146.5,
153.4, 179.6. Anal. Calcd for C11H10N4S: C, 57.37; H, 4.38; N,
24.33. Found: C, 57.70; H, 4.43; N, 24.05.
1-(Pyridin-2-yl)-3-(pyrid-4-yl)thiourea (3f): white mi-
crocrystals (80%); mp 183-184 °C; 1H NMR δ 7.17 (t, J ) 6.0
Hz, 1H), 7.29 (d, J ) 8.2 Hz, 1H), 7.88 (t, J ) 8.2 Hz, 1H),
7.97 (d, J ) 5.7 Hz, 2H), 8.39 (d, J ) 4.5 Hz, 1H), 8.53 (d, J )
5.6 Hz, 2H), 11.17 (br, 1H); 13C NMR δ 113.1, 116.5, 118.6,
139.6, 145.6, 145.8, 150.0, 153.2, 178.1. Anal. Calcd for
C11H10N4S: C, 57.37; H, 4.38; N, 24.33. Found: C, 57.49; H,
4.30; N, 24.22.
Benzotriazol-1-yl-(N,N-diethyl)methanethione (2k): yel-
1
low needles (98%); mp 37-38 °C; H NMR δ 1.33 (t, J ) 6.9
Hz, 3H), 1.49 (t, J ) 6.9 Hz, 3H), 3.51 (q, J ) 6.6 Hz, 2H),
4.12 (q, J ) 6.6 Hz, 2H), 7.43 (t, J ) 6.9 Hz, 1H), 7.60-7.55
(m, 1H), 8.08-8.02 (m, 2H); 13C NMR δ 10.1, 14.0, 48.1, 48.2,
113.5, 119.7, 124.9, 128.7, 133.2, 145.8, 174.7. Anal. Calcd for
C11H14N4S: C, 56.38; H, 6.02; N, 23.91. Found: C, 55.94; H,
5.81; N, 23.99.
Benzotriazole-1-carbothioic Acid N-Butyl-N-methyl-
amide (2l): purified by column chromatography with hexanes/
EtOAc (90:10) as eluent to afford yellow oil (76%); rotamers
(50:50 ratio) observed in1H NMR at 25 °C; signals double the
1
expected proton signals; H NMR δ 0.76 (t, J ) 7.4 Hz, 3H),
1-(4,6-Dimethylpyridin-2-yl)-3-(pyrid-3-yl)thiourea
1
1.02 (t, J ) 7.5 Hz, 3H), 1.10-1.18 (m, 2H), 1.43-1.55 (m, 2H),
1.64-1.76 (m, 2H), 1.82-1.93 (m, 2H), 3.23 (s, 3H), 3.49-3.59
(m, 5H), 4.09 (t, J ) 7.7 Hz, 2H), 7.42 (t, J ) 7.7 Hz, 2H), 7.58
(t, J ) 7.7 Hz, 2H), 7.99-8.10 (m, 4H); 13C NMR δ 13.2, 13.6,
19.4, 19.8, 27.4, 30.0, 41.4, 42.0, 55.6, 55.7, 113.2, 113.6, 119.5,
124.8, 128.6, 128.7, 132.9, 133.1, 145.6, 174.8, 175.3. Anal.
Calcd for C12H16N4S: C, 58.04; H, 6.49; N, 22.56. Found: C,
57.81; H, 6.41; N, 22.85.
(3g): white microcrystals (83%); mp 180-181 °C; H NMR δ
2.32 (s, 3H), 2.48 (s, 3H), 6.41 (s, 1H), 6.73 (s, 1H), 7.33-7.38
(m, 1H), 8.39 (s, 1H), 8.45 (d, J ) 4.8 Hz, 1H), 8.56 (d, J ) 8.4
Hz, 1H), 8.69 (d, J ) 2.4 Hz, 1H); 13C NMR δ 21.4, 23.9, 109.5,
119.6, 123.4, 131.1, 136.1, 145.1, 146.8, 151.4, 152.6, 155.1,
179.3. Anal. Calcd for C13H14N4S: C, 60.44; H, 5.46; N, 21.69.
Found: C, 60.62; H, 5.54; N, 21.65.
General Procedure for the Preparation of Bis(benzo-
triazol-1-yl)diarylsulfidemethanes 4. To bis(benzotriazol-
1-yl)methanethione (1) (0.56 g, 2 mmol) in THF at room
temperature was added the appropriate Grignard reagent (2
mmol). After stirring overnight at room temperature, solvent
was removed in vacuo. The residue was redissolved in EtOAc
(100 mL) and washed with 5% Na2CO3 solution (3 × 100 mL),
1 M HCl (2 × 100 mL), water, and brine. The collected organic
layers were dried with Na2SO4, and then solvent was removed
under vacuum. Recrystallization from EtOAc/hexanes afforded
the desired bis(benzotriazol-1-yl)diarylsulfidemethanes (4).
Compounds 4a and 4b are given as representative examples.
Bis(benzotriazolyl)-bis(phenylthio)methane (4a): yel-
Ethyl 4-Isothiocyanatobenzoate (11a): yellow needles
(99%); mp 47-50 °C (lit.83 mp 50-53 °C); 1H NMR δ 1.44 (t, J
) 8.4 Hz, 3H), 4.42 (q, J ) 8.0 Hz, 2H), 7.31 (d, J ) 8.4 Hz,
1H), 7.55 (d, J ) 8.7 Hz, 1H), 8.09 (t, J ) 8.1 Hz, 2H); 13C
NMR δ 14.2, 61.3, 123.3, 125.6, 128.2, 129.0, 130.9, 131.0,
141.2, 165.4.
General Procedure for the One-Pot Preparation of
Symmetrical Thioureas 3a-d. To 0.28 g of bis(benzotriazol-
1-yl)methanethione (1) (1 mmol) in 30 mL of THF was added
the appropriate primary amine (2 mmol), and the mixture was
refluxed for 5 h. Solvent was evaporated, and the crude product
was purified by column chromatography on alumina (30%
EtOAc/hexanes). Recrystallization from CH2Cl2 afforded crys-
talline thioureas in 82-85% yields.
1
low orthorhombic crystals (23%); mp 162-163 °C; H NMR δ
6.86 (d, J ) 8.4 Hz, 2H), 7.12-7.19 (m, 8H), 7.27 (t, J ) 7.2
Hz, 2H), 7.31-7.40 (m, 4H), 8.06 (d, J ) 8.4 Hz, 2H); 13C NMR
δ 111.6, 120.4, 123.8, 124.9, 128.5, 129.6, 131.4, 136.9, 141.5,
146.7. Anal. Calcd for C25H18N6S2: C, 64.36; H, 3.89; N, 18.01.
Found: C, 63.71; H, 3.41; N, 18.01.
1,3-Dipyridin-4-ylthiourea (3a). Yellow granules (85%),
1
mp 179-180 °C, H NMR (DMSO-d6) δ 7.65 (d, J ) 5.9 Hz,
4H), 8.46 (d, J ) 5.9 Hz, 4H); 13C NMR (DMSO-d6) δ 179.0,
149.3, 147.8, 115.8. Anal. Calcd for C11H10N4S: C, 57.37; H,
4.38; N, 24.33. Found: C, 57.33; H, 4.27; N, 24.04.
Bis(benzotriazolyl)-bis(4-methylphenylthio)-
1,3-Dipyridin-3-ylthiourea (3b): yellow granules (83%);
mp 179-180 °C (lit.40 mp 178-180 °C); 1H NMR (DMSO-d6) δ
7.45 (dd, J ) 8.2, 4.8 Hz, 2H), 8.03 (d, J ) 8.2 Hz, 2H), 8.38
(d, J ) 4.5 Hz, 2H), 8.70 (d, J ) 2.2 Hz, 2H), 10.36 (br s, 2H);
13C NMR (DMSO-d6) δ 123.6, 132.1, 136.3, 144.7, 144.9, 180.9.
1,3-Dipyridin-2-ylthiourea (3c): white powder (82%); mp
methane (4b): yellow monoclinic crystals (34%); mp 189-190
1
°C; H NMR δ 2.27 (s, 6H), 6.81 (d, J ) 8.4 Hz, 2H), 6.92 (s,
8H), 7.21 (t, J ) 8.1 Hz, 2H), 7.31 (t, J ) 8.1 Hz, 2H), 8.02 (d,
J ) 8.4 Hz, 2H); 13C NMR δ 21.3, 111.7, 120.4, 123.8, 124.9,
128.4, 129.6, 131.4, 136.9, 141.5, 146.7. Anal. Calcd for
C27H22N6S2: H, 4.48; N, 16.99. Found: H, 4.29; N, 16.68.
General Procedure for the Preparation of Thiocar-
bonylbenzotriazoles 6a-d. To 4-methylphenylmagnesium
bromide (10 mL, 1 M) in THF at room temperature was added
carbon disulfide (0.9 mL, 10 mmol). The reaction mixture was
heated under reflux for 3 h and then cooled to room temper-
ature, and 1-chlorobenzotriazole (3.06 g, 20 mmol) was added.
After stirring overnight at room temperature, solvent was
removed in vacuo and the mixture was separated on a silica
gel column (2% EtOAc/hexanes). Recrystallization from EtOAc/
hexanes provided the desired thiocarbonylbenzotriazoles 6a-
d.
1
163-164 °C (lit.51 mp 163 °C); H NMR δ 7.04 (bs, 3H), 7.70
(bs, 2H), 8.37 (bs, 2H), 8.85 (bs, 1H), 9.99 (bs, 1H), 14.41 (bs,
1H); 13C NMR δ 114.5, 119.3, 137.9, 146.9, 152.5, 177.4.
1,3-Bis-(4,6-dimethylpyridin-2-yl)thiourea (3d): yellow
granules (83%); mp 214-216 °C (lit.49 mp 218-219 °C); 1H
NMR δ 2.11 (s, 3H), 2.25 (s, 3H), 2.27 (s, 3H), 2.54 (s, 3H),
6.21 (s, 2H), 6.36 (s, 1H), 7.00 (s, 1H); 13C NMR δ 19.4, 21.1,
21.3, 21.8, 107.3, 114.1, 115.0, 115.7, 145.6, 148.9, 151.4, 152.5,
155.6, 157.0, 167.2.
General Procedure for the One-Pot Preparation of
Asymmetrical Thioureas 3e-g. To bis(benzotriazol-1-yl)-
methanethione (1) (0.28 g, 1 mmol) in THF (30 mL) was added
the appropriate primary amine (1 mmol), and the mixture was
heated under reflux for 5 h. Then, the second primary amine
or a secondary amine (1 mmol) was added, and the mixture
was stirred for 48 h. Solvent was evaporated, and the crude
product was purified by column chromatography on alumina
(30% EtOAc/hexanes).
Benzotriazol-1-yl-4-methylphenyl Methanethione (6a):
1
red needles (63%); mp 140-142 °C; H NMR δ 2.49 (s, 3H),
7.39 (d, J ) 8.4 Hz, 2H), 7.55 (t, J ) 7.5 Hz, 1H), 7.71 (t, J )
7.5 Hz, 1H), 8.14-8.19 (m, 3H), 8.39 (d, J ) 8.4 Hz, 1H); 13C
NMR δ 21.8, 114.8, 120.1, 126.2, 128.6, 129.2, 130.3, 131.9,
144.9, 171.8. Anal. Calcd for C14H11N3S: C, 66.38; H, 4.38; N,
16.59. Found: C, 66.83; H, 4.34; N, 16.66.
Benzotriazol-1-yl-4-methoxyphenyl Methanethione
1
(6b): red-orange needles (89%); mp 131-134 °C; H NMR δ
(83) Sayigh, A. A. R.; Ulrich, H.; Potts, J. S. J. Org. Chem. 1965,
30, 2465.
3.92 (s, 3H), 6.95 (d, J ) 6.9 Hz, 2H), 7.55 (t, J ) 8.1 Hz, 1H),
J. Org. Chem, Vol. 70, No. 20, 2005 7875

Katritzky et al.
7.69 (t, J ) 7.5 Hz, 1H), 7.84 (d, J ) 6.9 Hz, 2H), 8.18 (d, J )
8.1 Hz, 1H), 8.52 (d, J ) 8.4 Hz, 1H); 13C NMR δ 55.7, 113.6,
113.9, 114.8, 115.2, 120.1, 120.4, 126.1, 126.4, 133.7, 134.4,
147.0, 164.1. Anal. Calcd for C14H11N3OS: C, 62.43; H, 4.12;
N, 15.60. Found: C, 62.02; H, 4.17; N, 15.43.
Benzotriazol-1-yl-phenyl Methanethione (6c): red-pink
needles (76%); mp 134-136 °C (lit.5b mp 139-141 °C); 1H NMR
δ 7.46 (t, J ) 7.5 Hz, 2H), 7.64-7.56 (m, 2H), 7.70-7.79 (m,
3H), 8.19 (d, J ) 8.4 Hz, 1H), 8.63 (d, J ) 8.4 Hz, 1H); 13C
NMR δ 115.4, 120.5, 126.8, 128.0, 130.6, 130.7, 132.5, 133.2,
142.7, 147.0, 202.1.
Benzotriazol-1-yl-4-chlorophenyl Methanethione (6d):
red-pink needles (42%); mp 123-124 °C; 1H NMR δ 7.43 (t, J
) 8.7 Hz, 2H), 7.59 (t, J ) 7.8 Hz, 1H), 7.73 (t, J ) 6.9 Hz,
1H), 7.73 (d, J ) 8.7 Hz, 1H), 8.19 (d, J ) 8.1 Hz, 1H), 8.63 (d,
J ) 8.1 Hz, 1H); 13C NMR δ 115.4, 120.6, 127.0, 128.3, 130.9,
131.9, 133.1, 139.1, 140.9, 147.0, 200.2. Anal. Calcd for C13H8-
ClN3S: H, 2.95; N, 15.35. Found: H, 2.80; N, 15.06.
General Procedure for the Preparation of 2-Amino-
5-nitrophenylamides 9a-h. Et3N (3.0 g, 30 mmol) was
added to a solution of 4-nitro-1,2-phenylenediamine (3.06 g,
20 mmol) in THF (100 mL) at -40 °C, followed by dropwise
addition of the respective acid chloride (20 mmol). The mixture
was stirred at -40 °C for 3 h and at room temperature
overnight. The precipitate was filtered off, and the filtrate
evaporated to dryness in vacuo. The residue was recrystallized
from EtOH to afford the desired 2-amino-5-nitrophenylamides
9a-h in 81-99% yields.
N-(2-Amino-5-nitrophenyl)propionamide (9a): yellow
microcrystals (84%); mp 189-191 °C (lit.23 mp 191 °C); 1H
NMR δ 1.10 (t, J ) 7.6 Hz, 3H), 2.38 (q, J ) 7.6 Hz, 2H), 6.49
(br s, 2H), 6.76 (d, J ) 9.0 Hz, 1H), 7.84 (dd, J ) 9.0, 2.5 Hz,
1H), 8.27 (d, J ) 2.5 Hz, 1H), 9.13 (s, 1H); 13C NMR δ 9.6,
28.9, 113.6, 121.2, 121.7, 122.6, 135.5, 148.9, 172.6.
N-(2-Amino-5-nitrophenyl)-4-methylbenzamide (9b):
yellow needles (98%); mp 197-198 °C; 1H NMR δ 2.39 (s, 3H),
6.59 (s, 2H), 6.82 (d, J ) 9.1 Hz, 1H), 7.34 (d, J ) 8.1 Hz, 2H),
7.91 (d, J ) 9.2 Hz, 1H), 7.93 (d, J ) 8.1 Hz, 2H), 8.15 (d, J )
2.6 Hz, 1H), 9.68 (s, 1H); 13C NMR δ 21.0, 113.9, 121.4, 123.5,
128.0, 128.8, 131.4, 135.4, 141.6, 150.6, 165.9. Anal. Calcd. For
C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 62.35; H,
4.76; N, 15.13.
Furan-2-yl Carboxylic Acid (2-Amino-5-nitrophenyl)-
amide (9c): yellow needles (95%); mp 176-178 °C. 1H NMR
δ 6.61 (s, 2H), 6.71 (dd, J ) 3.3, 1.5 Hz, 1H), 6.81 (d, J ) 9.0
Hz, 1H), 7.33 (d, J ) 3.6 Hz, 1H), 7.91-7.94 (m, 2H), 8.06 (d,
J ) 2.4 Hz, 1H), 9.69 (s, 1H). 13C NMR δ 112.1, 113.9, 114.9,
120.4, 123.8, 135.4, 145.6, 147.4, 150.9, 157.0, 168.0. Anal.
Calcd for C11H9N3O4: C, 53.44; H, 3.67; N, 17.00. Found: C,
54.65; H, 3.28; N, 13.25.
N-(2-Amino-5-nitrophenyl)hexylamide (9g): brown
needles (81%); mp 130-131 °C; 1H NMR δ 0.90 (t, J ) 6.6 Hz,
3H), 1.32-1.34 (m, 4H), 1.62 (quintet, J ) 6.6 Hz, 2H), 2.37
(t, J ) 6.6 Hz, 2H), 6.49 (s, 2H), 6.78 (d, J ) 9 Hz, 1H), 7.85
(dd, J ) 9.0, 2.4 Hz, 1H), 8.31 (d, J ) 2.4 Hz, 1H), 9.16 (s,
1H); 13C NMR δ 14.0, 22.1, 24.9, 31.1, 36.0, 113.8, 121.2, 121.9,
122.7, 135.7, 148.8, 172.1. Anal. Calcd for C12H17N3O3: C,
57.36; H, 6.82; N, 16.72. Found: C, 57.88; H, 7.04; N, 15.97.
Thien-2-yl Carboxylic Acid (2-Amino-5-nitrophenyl)-
amide (9h): brown needles (91%); mp 192-196 °C; 1H NMR
δ 6.65 (s, 2H), 6.81 (d, J ) 9 Hz, 1H), 7.22-7.25 (m, 1H), 7.86-
7.95 (m, 2H), 8.03-8.09 (m, 2H), 9.81 (s, 1H); 13C NMR δ 114.0,
120.8, 124.0, 128.2, 129.9, 131.9, 135.5, 139.5, 151.1, 160.8,
167.6. Anal. Calcd for C11H9N3O3S: C, 50.18; H, 3.45; N, 15.96.
Found: C, 49.98; H, 3.29; N, 15.43.
General Procedure for the Preparation of Thiocar-
bonyl-1H-6-nitrobenzotriazoles 10a-h. Phosphorus pen-
tasulfide (2.22 g, 10 mmol) was mixed with Na2CO3 (0.54 g, 5
mmol) in dry THF (150 mL). The mixture was stirred at room
temperature for 1 h and then cooled to 0 °C. The amide (9)
(10 mmol) was added in one portion, and the resulting mixture
was stirred at 0 °C for 3 h and at room temperature for 10 h.
The mixture was filtered, and the filtrate evaporated to
dryness. The residue was dissolved in EtOAc (100 mL) and
washed with 5% NaHCO3 (2 × 30 mL), and the aqueous layers
were back-extracted with EtOAc (100 mL). The combined
organic layers were washed with brine, dried with MgSO4, and
evaporated to obtain a residue. The residue was placed on a
silica gel column and eluted with hexanes/EtOAc (5:1) to give
thioamides in crude yields of 59-96%.
Sodium nitrite (0.21 g, 3 mmol) was added to a stirred
solution of the obtained thioamide (2 mmol), dissolved by
gentle warming in aqueous acetic acid (95%, 25 mL), and then
cooled to 0 °C. The resulting mixture was stirred at 0 °C for
45 min, ice-cold water (100 mL) was added, and the precipi-
tated product was filtered and washed with water. Compound
10g was an exception requiring sonication and extraction with
EtOAc, which entailed washing the aqueous solution three
times with 50 mL of EtOAc, collecting the organic layers and
washing them with water (2 × 30 mL) and brine (40 mL),
drying with sodium sulfate, and filtration. The obtained solid
was dried in vacuo overnight to afford the desired thiocarbonyl-
1H-6-nitrobenzotriazoles 10a-h in 45-81% yields from the
amide (9).
(6-Nitrobenzotriazol-1-yl)propane-1-thione (10a): or-
ange microcrystals (52%); mp 107-109 °C (lit.23 mp 108 °C);
1H NMR δ 1.54 (t, J ) 7.1 Hz, 3H), 3.79 (q, J ) 7.1 Hz, 2H),
8.31 (d, J ) 9.0 Hz, 1H), 8.44 (dd, J ) 9.0, 1.8 Hz, 1H), 9.74
(s, 1H); 13C NMR δ 13.4, 40.6, 113.1, 121.2, 121.7, 131.7, 149.0,
149.4, 211.6.
(4-Methylphenyl)(6-nitrobenzotriazol-1-yl)methaneth-
ione (10b): red microcrystals (80%); mp 140-141 °C; 1H NMR
δ 2.45 (s, 3H), 7.29 (d, J ) 8.0 Hz, 2H), 7.72 (d, J ) 8.0 Hz,
2H), 8.32 (d, J ) 9.0 Hz, 1H), 8.44 (dd, J ) 9.0, 1.1 Hz, 1H),
9.42 (s, 1H); 13C NMR δ 21.8, 112.1, 121.2, 121.5, 129.1, 131.2,
133.1, 139.4, 145.1, 148.8, 148.9, 200.5. Anal. Calcd for
C14H10N4O2S: C, 56.37; H, 3.38; N, 18.78. Found: C, 56.65;
H, 3.29; N, 18.69.
Furan-2-yl-(6-nitrobenzotriazol-1-yl)-methanethione
(10c): orange microcrystals (80%); mp 162 °C; 1H NMR δ 6.79
(dd, J ) 3, 1.5 Hz, 1H), 7.66 (d, J ) 3.6 Hz, 1H), 8.00 (d, J )
0.9 Hz, 1H), 8.32 (d, J ) 9 Hz, 1H), 8.43 (dd, J ) 9, 2.1 Hz, 1
H), 9.47 (d, J ) 1.8 Hz, 1H); 13C NMR δ 112.1, 114.4, 121.2,
121.4, 122.4, 132.9, 148.6, 148.8, 151.8, 154.3, 180.1. Anal.
Calcd for C11H6N4O3S: C, 48.17; H, 2.21. Found C, 47.83; H,
2.12.
N-(2-Amino-5-nitrophenyl)-4-nitrobenzylamide (9d):
brown needles (83%); mp 303-305 °C; 1H NMR δ 6.58 (s, 2H),
6.84 (d, J ) 9 Hz, 1H), 7.93 (dd, J ) 9, 2.4 Hz, 1H), 8.25-8.30
(m, 4H), 8.38 (s, 1H); 13C NMR δ 113.6, 122.8, 123.1, 123.8,
129.3, 129.6, 129.7, 148.0, 148.4, 150.8, 193.5. Anal. Calcd for
C13H10N4O5: C, 51.66; H, 3.33. Found: C, 52.03; H, 3.39.
N-(2-Amino-5-nitrophenyl)-4-methoxybenzylamide (9e):
brown needles (86%); mp 221-224 °C; 1H NMR δ 3.84 (s, 3H),
6.59 (s, 2H), 6.80 (d, J ) 9.3 Hz, 1H), 7.08 (d, J ) 9.3 Hz, 2H),
7.91 (dd, J ) 9.3, 2.7 Hz, 1H), 8.00 (d, J ) 2.7 Hz, 1H), 8.11
(d, J ) 2.4 Hz, 1H), 9.62 (s, 1H); 13C NMR δ 55.6, 113.6, 114.0,
121.7, 123.7, 130.1, 130.8, 135.5, 150.9, 162.1, 165.6, 204.5.
Anal. Calcd for C14H13N3O3: C, 58.53; H, 4.56; N, 14.63.
Found: C, 58.55; H, 4.57; N, 14.09.
N-(2-Amino-5-nitrophenyl)-4-bromobenzylamide
1
(9f): brown needles (99%); mp 222-223 °C; H NMR δ 6.65
(4-Nitrophenyl)(6-nitrobenzotriazol-1-yl)methaneth-
ione (10d): orange needles (69%); mp 174 °C; 1H NMR δ 7.46
(d, J ) 8.7 Hz, 2H), 7.82 (d, J ) 8.7 Hz, 2H), 7.93 (d, J ) 8.7
(s, 2H), 6.80 (d, J ) 9 Hz, 1H), 7.75 (d, J ) 8.4 Hz, 2H), 7.91-
7.98 (m, 3H), 8.11 (s, 1H), 9.83 (s, 1H); 13C NMR δ 114.0, 121.1,
124.0, 125.6, 130.3, 131.4, 133.5, 135.4, 151.0, 161.8, 165.4.
Anal. Calcd for C13H10NBrO2: C, 46.45; H, 3.00; N, 12.50.
Found: C, 46.34; H, 2.93; N, 11.89.
Hz, 1H), 8.02 (d, J ) 8.7 Hz, 2H), 9.00 (d, J ) 1.8 Hz, 1H); 13
C
NMR δ 114.3, 114.7, 121.1, 123.4, 123.9, 130.9, 131.4, 136.4,
7876 J. Org. Chem., Vol. 70, No. 20, 2005

Benzotriazole-Assisted Thioacylation
150.2, 166.0, 208.0. Anal. Calcd for C13H7N5O4S: C, 47.42; H,
2.14; N, 21.27. Found C, 47.50; H, 2.02; N, 20.93.
7.42-7.52 (m, 1H), 7.56-7.64 (m, 3H), 7.76 (t, J ) 8.0 Hz, 1H),
8.24 (d, J ) 8.0 Hz, 1H), 8.55 (d, J ) 8.4 Hz, 1H); 13C NMR δ
115.2, 120.9, 122.1, 126.4, 122.3, 129.9, 130.8, 131.7, 146.7,
152.7, 182.2. Anal. Calcd for C13H9N3OS: C, 61.16; H, 3.55.
Found: C, 60.79; H, 3.48.
(4-Methoxyphenyl)(6-nitrobenzotriazol-1-yl)methane-
1
thione (10e): orange needles (66%); mp 162 °C; H NMR δ
3.93 (s, 3H), 6.98 (d, J ) 9.0 Hz, 2H), 7.86 (d, J ) 9.0 Hz, 2H),
8.31 (d, J ) 9.0 Hz, 1H), 8.42 (dd, J ) 9.0, 2.1 Hz, 1H), 9.37
(d, J ) 2.1 Hz, 1H); 13C NMR δ 55.8, 112.0, 113.9, 112.1, 133.3,
134.0, 134.7, 148.6, 148.9, 164.8, 198.4. Anal. Calcd for
C14H10N4O3S: C, 53.50; H, 3.21; N, 17.82. Found C, 53.61; H,
3.14; N, 17.62.
O-4-tert-Butylphenyl Benzotriazole-1-carbothioate
1
(12e): yellow microcrystals (75%); mp 122-123 °C; H NMR
δ 1.38 (s, 9H), 7.21 (d, J ) 9.0 Hz, 2H), 7.53 (d, J ) 9.0 Hz,
2H), 7.55 (t, J ) 8.1 Hz, 1H), 7.69 (t, J ) 7.5 Hz, 1H), 8.19 (d,
J ) 8.4 Hz, 1H), 8.48 (d, J ) 8.4 Hz, 1H); 13C NMR δ 115.2,
120.9, 122.1, 126.4, 122.3, 129.9, 130.8, 131.7, 146.7, 152.7,
182.2. Anal. Calcd for C17H17N3OS: C, 65.57; H, 5.50; N, 13.49.
Found: C, 65.77; H, 5.54; N, 13.50.
(4-Bromophenyl)(6-nitrobenzotriazol-1-yl)methane-
thione (10f): orange microcrystals (45%); mp 170 °C; 1H NMR
δ 7.67-7.74 (m, 4H), 8.39 (d, J ) 9 Hz, 1H), 8.52 (dd, J ) 9,
1.8 Hz, 1H), 9.54 (d, J ) 2.1 Hz, 1H); 13C NMR δ 112.1, 121.4,
121.9, 128.8, 131.6, 132.1, 132.8, 140.6, 149.0, 149.1, 199.6.
Anal. Calcd for C13H7BrN4O2S: C, 42.99; H, 1.94. Found: C,
42.81; H, 1.79.
(6-Nitrobenzotriazol-1-yl)-1-hexylthioamide (10g): yel-
low microcrystals (53%); mp 94-97 °C; 1H NMR δ 0.94 (t, J )
6.9 Hz, 3H), 1.37-1.52 (m, 4H), 1.95-2.05 (m, 2H), 3.78 (t, J
) 7.5 Hz, 2H), 8.30 (d, J ) 9.0 Hz, 1H), 8.44 (dd, J ) 9.0, 1.8
Hz, 1H), 9.79 (d, J ) 2.1 Hz, 1H); 13C NMR δ 13.9, 22.3, 29.4,
31.1, 47.6, 113.1, 121.2, 121.8, 131.7, 149.1, 149.4, 210.7. Anal.
Calcd for C12H14N4O2S: C, 51.78; H, 5.07; N, 20.13. Found:
C, 52.14; H, 5.12; N, 19.79.
(6-Nitrobenzotriazol-1-yl)thiophen-2-yl Methaneth-
ione (10h): orange microcrystals (81%); mp 134 °C; 1H NMR
δ 7.25 (dd, J ) 4.0, 1.2 Hz, 1H), 7.97 (d, J ) 4.8 Hz, 1H), 8.10
(d, J ) 4.0 Hz, 1H), 8.31 (d, J ) 8.7 Hz, 1H), 8.42 (d, J ) 8.7
Hz, 1H), 9.45 (s, 1H); 13C NMR δ 112.3, 121.2, 121.4, 129.2,
133.0, 136.5, 140.5, 146.6, 148.7, 187.3. Anal. Calcd for
C11H6N4O2S2: C, 45.51; H, 2.08; N, 19.30. Found: C, 44.66;
H, 1.90; N, 18.45.
General Procedure for the Preparation of O-Aryloxy-
thioacylbenzotriazoles 12a-e. Bis(benzotriazol-1-yl)methane-
thione (0.28 g, 1 mmol) was dissolved in 10 mL of CH2Cl2. In
another flask, the aryl alcohol (1 mmol) and NaH (0.18 g, 4.5
mmol) were stirred for 5 min in CH2Cl2 (10 mL). The solution
of the sodium salt was added to the bis(benzotriazol-1-yl)-
methanethione solution, and the mixture was stirred for 24
h. The solvent was evaporated and water was added and
extracted with EtOAc (2 × 25 mL). The organic layer was
washed with water and 10% Na2CO3 solution (2 × 30 mL),
dried over Mg2SO4, filtered, and concentrated. Recrystalliza-
tion from hexanes gave 12a-e in 66-87% yields.
General Procedure for the Preparation of Aryl/Alkyl-
thiothioacylbenzotriazoles 13a-c and Disulfides 14a,b,d.
To bis(benzotriazol-1-yl)methanethione (10 mmol) in CH2Cl2
at room temperature was added thiol (10 mmol) and a catalytic
amount of Et3N. Stirring was continued for 3 h, and then
solvent was removed under vacuum, water was added, and
the organic layer was extracted with EtOAc (2 × 25 mL). The
organic layer was washed with water and 10% Na2CO3 solution
(2 × 30 mL), dried over Na2SO4, and filtered. Concentration
under reduced pressure gave a mixture, which was further
purified by column chromatography (1:10 EtOAc/hexanes).
Phenyl-1H-benzotriazole-1-carbodithioate (13a): yel-
1
low microcrystals (46%); mp 85-87 °C; H NMR δ 7.46-7.64
(m, 7H), 8.12 (d, J ) 8.1 Hz, 1H), 8.63 (d, J ) 8.4 Hz, 1H); 13
C
NMR δ 115.7, 120.8, 126.7, 129.4, 129.9, 131.0, 131.3, 132.4,
136.6, 147.4, 198.1. Anal. Calcd for C13H9N3S2: C, 57.54; H,
3.34; N, 15.49. Found: C, 57.93; H, 3.33; N, 15.39.
Benzyl-1H-benzotriazole-1-carbodithioate (13b): yellow
microcrystals (42%); mp 108-109 °C; 1H NMR δ 4.57 (s, 2H),
7.25-7.37 (m, 3H), 7.41-7.51 (m, 3H), 7.62 (t, J ) 8.4 Hz, 1H),
8.09 (d, J ) 8.2 Hz, 1H), 8.71 (d, J ) 8.4 Hz, 1H); 13C NMR δ
41.0, 115.7, 120.8, 126.7, 128.1, 128.9, 129.7, 131.2, 132.4,
134.1, 147.3, 197.6. Anal. Calcd for C14H11N3S2: C, 58.92; H,
3.88; N, 14.72. Found: C, 58.86; H, 3.81; N, 14.66.
Ethyl-2-[(1H-benzotriazol-1-ylcarbothioyl)sulfanyl]-
1
acetate (13c): yellow microcrystals (63%); mp 67-68 °C; H
NMR δ 1.33 (t, J ) 7.1 Hz, 3H), 4.20 (s, 2H), 4.27 (q, J ) 7.1
Hz, 2H), 7.52 (t, J ) 7.8 Hz, 1H), 7.66 (t, J ) 8.1 Hz, 1H), 8.12
(d, J ) 8.2 Hz, 1H), 8.67 (d, J ) 8.4 Hz, 1H); 13C NMR δ 14.3,
37.9, 62.3, 115.5, 120.9, 126.9, 131.4, 132.3, 147.4, 167.2, 196.4.
Anal. Calcd for C11H11N3O2S2: C, 46.96; H, 3.94; N, 14.93.
Found: C, 47.25; H, 3.92; N, 14.78.
O-Naphth-2-yl Benzotriazole-1-carbothioate (12a): col-
Phenyl Di(benzotriazol-1-yl)methyl Disulfide (14a):
1
1
orless microcrystals (87%); mp 159-160 °C; H NMR δ 7.41
yellow microcrystals (21%); mp 95-96 °C; H NMR δ 6.93-
(dd, J ) 8.8, 2.4 Hz, 1H), 7.53-7.58 (m, 3H), 7.68-7.73 (m,
2H), 7.87-7.94 (m, 2H), 7.98 (d, J ) 8.9 Hz, 1H), 8.20 (d, J )
8.2 Hz, 1H), 8.52 (d, J ) 8.4 Hz, 1H); 13C NMR δ 115.4, 119.7,
121.1, 121.2, 126.6, 126.7, 127.2, 128.1, 128.2, 130.1, 131.0,
132.0, 132.3, 133.9, 146.9, 150.5, 182.4. Anal. Calcd for
C17H11N3OS: C, 66.87; H, 3.63; N, 13.76. Found: C, 66.77; H,
3.57; N, 13.46.
7.02 (m, 3H), 7.18 (d, J ) 7.0 Hz, 2H), 7.30 (t, J ) 7.7 Hz,
2H), 7.80 (d, J ) 8.2 Hz, 2H), 7.94 (d, J ) 8.4 Hz, 2H), 8.45 (s,
1H); 13C NMR δ 76.2, 110.9, 120.3, 125.0, 128.5, 128.8, 128.9,
130.4, 131.4, 133.3, 146.4. Anal. Calcd for C19H14N6S2: C,
58.44; H, 3.61; N, 21.52. Found: C, 58.25; H, 3.51; N, 21.46.
Benzyl Di(benzotriazol-1-yl)methyl Disulfide (14b):
1
white microcrystals (44%); mp 115-116 °C; H NMR δ 3.63
O-Pyridin-3-yl benzotriazole-1-carbothioate (12b): gran-
ules (66%); mp 139-140 °C; 1H NMR δ 7.52-7.48 (m, 1H),
7.61 (t, J ) 7.3 Hz, 1H), 7.68-7.64 (m, 1H), 7.74 (t, J ) 8.2
Hz, 1H), 8.21 (d, J ) 8.2 Hz, 1H), 8.52 (d, J ) 8.4 Hz, 1H),
8.63 (d, J ) 2.7 Hz, 1H), 8.66 (dd, J ) 4.7, 1.1 Hz, 1H); 13C
NMR δ 115.1, 121.1, 124.4, 126.7, 130.2, 131.1, 131.9, 144.2,
146.7, 148.5, 149.5, 181.4. Anal. Calcd for C12H8N4OS: C,
56.24; H, 3.15; N, 21.86. Found: C, 56.27; H, 3.04; N, 21.64.
O-Naphth-1-yl Benzotriazole-1-carbothioate (12c): col-
(s, 2H), 7.19-7.25 (m, 2H), 7.30-7.41 (m, 5H), 7.49 (t, J ) 7.1
Hz, 2H), 7.64 (s, 1H), 7.78 (d, J ) 8.4 Hz, 2H), 8.03 (d, J ) 8.4
Hz, 2H); 13C NMR δ 43.0, 75.3, 111.2, 120.4, 125.2, 128.3,
128.8, 129.1, 129.8, 131.5, 135.9, 146.5. Anal. Calcd for
C20H16N6S2: C, 59.38; H, 3.99; N, 20.78. Found: C, 59.25; H,
3.97; N, 20.45.
Isopropyl Di(benzotriazol-1-yl)methyl Disulfide (14d):
1
white microcrystals (90%); mp 107-108 °C; H NMR δ 1.11
(d, J ) 6.7 Hz, 6H), 2.43 (m, 1H), 7.39 (t, J ) 7.3 Hz, 2H),
7.52 (t, J ) 7.3 Hz, 2H), 7.97 (d, J ) 8.4 Hz, 2H), 8.06 (d, J )
8.4 Hz, 2H), 8.47 (s, 1H); 13C NMR δ 22.2, 41.0, 76.9, 111.0,
120.4, 125.2, 128.9, 131.5, 146.4. Anal. Calcd for C16H16N6S2:
C, 53.91; H, 4.52; N, 23.58. Found: C, 53.73; H, 4.56; N, 23.25.
General Procedure for the Preparation of Thioamides
15a-f. The appropriate amine (0.5 mmol) and Et3N (0.05 g,
0.5 mmol) were added to the respective thiocarbonylbenzo-
triazole (6) (0.5 mmol) dissolved in CH2Cl2 (30 mL) at room
temperature. Stirring was continued overnight, and then
1
orless microcrystals (81%); mp 148-149 °C; H NMR δ 7.44
(d, J ) 7.4 Hz, 1H), 7.49-7.62 (m, 4H), 7.69-7.74 (m, 1H),
7.89-7.97 (m, 3H), 8.24 (d, J ) 8.2 Hz, 1H), 8.55 (d, J ) 8.4
Hz, 1H); 13C NMR δ 115.4, 119.3, 121.2, 121.3, 125.5, 126.5,
126.6, 127.1, 127.3, 127.7, 128.5, 131.1, 132.1, 135.1, 147.0,
148.9, 182.0. Anal. Calcd for C17H11N3OS: C, 66.87; H, 3.63;
N, 13.76. Found: C, 66.76; H, 3.49; N, 13.71.
O-Phenyl Benzotriazole-1-carbothioate (12d): yellow
microcrystals (83%); mp 68 °C; 1H NMR δ 7.30-7.36 (m, 2H),
J. Org. Chem, Vol. 70, No. 20, 2005 7877

Katritzky et al.
solvent was removed by rotary evaporation. The residue was
redissolved in EtOAc (100 mL) and washed with 5% Na2CO3
solution (3 × 100 mL), 1 M HCl (2 × 100 mL), water, and brine.
The collected organic layers were dried with Na2SO4, and the
solvent was removed under vacuum. Recrystallization from
EtOAc/hexanes afforded thioamides 15a-f in 91-99% yields.
4-Methylthiobenzoic Acid Benzylamide (15a): colorless
needles (99%); mp 78-79 °C (lit.32 mp 87.5-88.5 °C); 1H NMR
δ 2.37 (s, 3H), 5.00 (d, J ) 5.1 Hz, 2H), 7.17 (d, J ) 8.1 Hz,
2H), 7.39-7.41 (m, 5H), 7.67 (d, J ) 8.1 Hz, 3H); 13C NMR δ
21.3, 51.0, 126.7, 128.2, 128.4, 129.0, 129.1, 136.3, 138.8, 141.8,
198.9. Anal. Calcd for C15H15NS: C, 74.65; H, 6.26; N, 5.80.
Found: C, 74.43; H, 6.31; N, 6.38.
138.8, 141.1, 197.4. Anal. Calcd for C12H15NS: C, 70.20; N,
6.82. Found: C, 70.38; N, 6.74.
N-tert-Butyl-4-nitrothiobenzamide (15i): orange powder
(98%); mp 143-147 °C (lit.88 mp 140-141 °C). 1H NMR δ 1.67
(s, 9H), 7.42 (br s, 1H), 7.74 (d, J ) 8.7 Hz, 2H), 8.18 (d, J )
8.7 Hz, 2H); 13C NMR δ 27.5, 56.8, 123.6, 127.3, 148.3, 149.6,
196.1.
Thiophene-2-carbothioic Acid Benzylamide (15j): yel-
low needles (80%); mp 87-88 °C (lit.89 mp 85-87 °C); 1H NMR
δ 4.98 (d, J ) 5.4 Hz, 2H), 7.02-7.05 (m, 1H), 7.32-7.42 (m,
5H), 7.41-7.42 (m, 1H), 7.48-7.50 (m, 1H), 7.68 (br s, 1H);
13C NMR δ 50.4, 124.4, 127.7, 128.1, 128.2, 128.9, 132.2, 136.0,
146.2, 188.3.
1-(4-Methoxythiobenzoyl)piperidine (15b): yellow
needles (93%); mp 94-97 °C (lit.84 mp 107-108 °C); 1H NMR
δ 1.58-1.59 (m, 2H), 1.75-1.82 (m, 4H), 3.56-3.60 (m, 2H),
3.82 (s, 3H), 4.32-4.36 (m, 2H), 6.86 (d, J ) 6.6 Hz, 2H), 7.27
(d, J ) 6.6 Hz, 2H); 13C NMR δ 24.2, 25.5, 26.9, 51.0, 53.3,
55.3, 113.6, 127.5, 128.8, 135.9, 159.8, 199.8.
General Procedure for the Preparation of N-Mono-
substituted Thioamides 15k-p. The thiocarbamoylbenzo-
triazole 2 (0.495 mmol) was dissolved in 10 mL of dry THF
under a nitrogen atmosphere. The desired Grignard or orga-
nolithium reagent (1.24 mmol) was added dropwise at room
temperature, and the reaction mixture was stirred for 16 h.
Water was added, and the organic layer was extracted with
EtOAc (20 mL × 3). The organic layers were combined, washed
with water, washed with 10% Na2CO3 solution (35 mL × 5),
washed with brine, dried over Na2SO4, and filtered. Concen-
tration under reduced pressure gave the pure product or a
mixture, which was further purified either by recrystallization
from EtOAc/hexanes or column chromatography.
N,N-Diethyl-4-methylthiobenzamide (15c): yellow
1
powder (87%); mp 89-90 °C (lit.85 mp 93-94 °C); H NMR δ
1.05 (t, J ) 7.2 Hz, 3H), 1.29 (t, J ) 7.2 Hz, 3H), 2.26 (s, 3H),
3.36 (q, J ) 7.2 Hz, 2H), 4.03 (q, J ) 7.2 Hz, 2H), 7.05 (s, 4H);
13C NMR δ 11.1, 13.7, 21.0, 45.9, 47.6, 124.8, 127.7, 128.7,
137.7, 140.9, 200.4. Anal. Calcd for C13H19NS: C, 69.51; H,
8.26; N, 6.76. Found: C, 69.87; H, 8.47; N, 6.67.
N-Benzyl Thiobenzamide (15d): white needles (97%); mp
86 °C (lit.86 mp 87-88 °C); 1H NMR δ 4.99 (d, J ) 4.8 Hz,
1H), 7.35-7.46 (m, 8H), 7.75 (d, J ) 7.5 Hz, 3H); 13C NMR δ
51.0, 126.7, 128.2, 128.4, 128.5, 129.0, 131.1, 136.1, 141.6,
199.1.
N-Cyclohexylthiobenzamide (15k): purified by column
chromatography with hexanes/EtOAc (91:9) as eluent and
obtained as yellow microcrystals (87%); mp 84-86 °C (lit.90
1
mp 91-92 °C); H NMR δ 1.19-1.60 (m, 5H), 1.62-1.85 (m,
3H), 2.17-2.25 (m, 2H), 4.48-4.61 (m, 1H), 7.33-7.49 (m, 4H),
7.68-7.74 (m, 2H); 13C NMR δ 24.6, 25.5, 31.6, 54.8, 126.5,
128.5, 130.9, 142.4, 197.7. Anal. Calcd for C13H17NS: C, 71.18;
H, 7.81; N, 6.39. Found: C, 70.96; H, 7.94; N, 6.48.
1-Thiobenzoyl Morpholine (15e): clear needles (78%);
1
mp 135-136 °C (lit.5a mp 137-138 °C); H NMR δ 3.62 (d, J
) 5.4 Hz, 4H), 3.89 (t, J ) 4.8 Hz, 2H), 4.45 (t, J ) 4.8 Hz,
2H), 7.26-7.32 (m, 2H), 7.34-7.38 (m, 3H); 13C NMR δ 49.5,
52.5, 66.5, 66.7, 125.9, 128.5, 128.9, 142.5, 201.0.
Hexanethioic Acid (Furan-2-ylmethyl)amide (15l):
brown oil (99%); 1H NMR δ 0.89 (t, J ) 7.2 Hz, 3H), 1.25-
1.40 (m, 4H), 1.72-1.83 (m, 2H), 2.66 (t, J ) 7.8 Hz, 2H), 4.82
(d, J ) 4.8 Hz, 2H), 6.33-6.37 (m, 2H), 7.39-7.45 (m, 2H);
13C NMR δ 13.9, 22.3, 29.0, 31.0, 42.9, 47.0, 108.9, 110.6, 142.6,
149.1, 205.8. Anal. Calcd for C11H17NOS: C, 62.52; H, 8.11;
N, 6.63. Found: C, 62.86; H, 8.43; N, 6.63.
Furan-2-carbothioic Acid tert-Butylamide (15m): puri-
fied by column chromatography with hexanes/EtOAc (90:10)
as eluent and obtained as brown oil (47%) (lit.91 mp 45-46
°C); 1H NMR δ 1.65 (s, 9H), 6.45 (dd, J ) 3.3, 1.8 Hz, 1H),
7.33 (d, J ) 3.6 Hz, 1H), 7.39 (m, 1H), 7.82 (br s, 1H); 13C NMR
δ 28.0, 55.5, 113.1, 116.8, 143.0, 153.2, 181.3. Anal. Calcd for
C9H13NOS: C, 59.82; H, 7.15; N, 7.64. Found: C, 59.22; H,
7.29; N, 7.93.
4-Chlorothiobenzoic Acid Phenethylamide (15f): yel-
1
low needles (66%); mp 103-105 °C; H NMR δ 3.07 (s, 2H),
4.08 (d, J ) 5.1 Hz, 2H), 7.27-7.32 (m, 7H), 7.55 (d, J ) 7.2
Hz, 3H). 13C NMR δ 33.7, 47.5, 126.9, 127.8, 128.6, 128.7,
128.9, 137.2, 138.1, 140.1, 197.7. Anal. Calcd for C15H14ClNS:
C, 65.32; H, 5.12; N, 5.08. Found: C, 64.99; H, 5.13; N, 4.99.
General Procedure for the Preparation of Thioamides
15g-j. The appropriate amine (0.5 mmol) and triethylamine
(0.05 g, 0.5 mmol) were added to the respective thiocarbonyl-
1H-6-nitrobenzotriazole 10 dissolved in CH2Cl2 (30 mL) at
room temperature. Stirring was continued overnight, and then
solvent was removed by rotary evaporation. The residue was
redissolved in EtOAc (100 mL) and washed with 5% Na2CO3
solution (3 × 100 mL), 1 M HCl (2 × 100 mL), water, and brine.
The collected organic layers were dried with Na2SO4, and then
the solvent was removed under vacuum. Recrystallization from
EtOAc/hexanes afforded thioamides 15g-j in 80-98% yields.
1-(4-Bromothiobenzoyl)morpholine (15g): yellow gran-
ules (91%); mp 135-136 °C (lit.87 mp 134-135 °C). Broadening
N-(1,5-Dimethylhexyl)thiobenzamide (15n): purified by
column chromatography with hexanes/EtOAc (92:8) as eluent
1
and obtained as yellow oil (56%); H NMR δ 0.88 (d, J ) 6.6
Hz, 6H), 1.20-1.26 (m, 2H), 1.32 (d, J ) 6.6 Hz, 3H), 1.35-
1.70 (m, 5H), 4.72-4.77 (m, 1H), 7.34-7.47 (m, 4H), 7.67-
7.70 (m, 2H); 13C NMR δ 19.4, 22.5, 23.7, 27.8, 36.2, 38.7, 52.0,
126.5, 128.4, 130.8, 142.4, 198.0. Anal. Calcd for C15H23NS:
C, 72.23; H, 9.29; N, 5.62. Found: C, 72.00; H, 9.50; N, 5.90.
1
of the morpholine-ring signals are observed in H NMR and
13C NMR spectra due to restricted rotation and ring flipping.
1H NMR δ 3.62-3.65 (m, 4Η), 3.88-3.89 (m, 2H), 4.41-4.42
(m, 2H), 7.18 (d, J ) 8.1 Hz, 2H), 7.51 (d, J ) 7.5 Hz, 2H); 13
C
4-Methoxy-N-((R)-1-phenylethyl)thiobenzamide (15o):
purified by column chromatography with hexanes/EtOAc (90:
10) as eluent and obtained as yellow needles (85%); mp 89-
NMR δ 49.1, 52.1, 65.9, 66.2, 122.5, 127.2, 131.2, 140.8, 198.8.
1-(4-Methylthiobenzoyl)pyrrolidine (15h): yellow pow-
der (95%); mp 150-152 °C; 1H NMR δ 1.85-1.93 (m, 2H),
1.96-2.03 (m, 2H), 2.26 (s, 3H), 3.42 (t, J ) 6.6 Hz, 2H), 3.99
(t, J ) 6.9 Hz, 2H), 7.06 (d, J ) 7.8 Hz, 2H), 7.19 (d, J ) 7.8
Hz, 2H); 13C NMR δ 21.2, 24.6, 26.4, 53.5, 53.8, 125.7, 128.8,
1
91 °C; H NMR δ 1.68 (d, J ) 6.6 Hz, 3H), 3.81 (s, 3H), 5.90
(quintet, J ) 7.2 Hz, 1H), 6.84 (d, J ) 8.7 Hz, 2H), 7.25-7.42
(m, 5H), 7.62-7.74 (m, 3H); 13C NMR δ 20.2, 55.0, 55.4, 113.5,
126.5, 127.7, 128.4, 128.8, 134.2, 141.5, 162.1, 196.8. Anal.
(84) Trepanier, D. L.; Reifschneider, W.; Shumaker, W.; Tharpe, D.
S. J. Org. Chem. 1965, 30, 2228.
(88) Voss, J.; Walter, W. Ann. Chem. 1971, 743, 177.
(89) Oh, H. K.; Woo, S. Y.; Shin, C. H.; Lee, I. Int. J. Chem. Kinet.
1998, 30, 849.
(85) Kato, S.; Shibahashi, H.; Katada, T.; Takagi, T.; Noda, I. Ann.
Chem. 1982, 1229.
(90) Alliger, G.; Smith, G. E. P.; Carr, E. L.; Stevens, H. P. J. Org.
Chem. 1949, 14, 962.
(86) Barrett, A. G. M.; Barton, D. H. R.; Colle, R. J. Chem. Soc.,
Perkin Trans. 1 1980, 665.
(87) Santus, M. Pol. J. Chem. 1980, 54, 661.
(91) Jagodzinski, T. S.; Dziembowska, T. M.; Szczodrowska, B. Bull.
Soc. Chim. Belg. 1989, 98, 327.
7878 J. Org. Chem., Vol. 70, No. 20, 2005

Benzotriazole-Assisted Thioacylation
Calcd for C16H17NOS: C, 70.81; H, 6.31; N, 5.16. Found: C,
70.78; H, 6.27; N, 5.11.
210.5. Anal. Calcd for C15H14O3S: C, 65.67; H, 5.14. Found:
C, 65.47; H, 5.14.
Pyridine-2-carbothioic Acid Cyclohexylamide (15p):
purified by column chromatography with hexanes/EtOAc (95:
5) as eluent and obtained as yellow oil (35%); 1H NMR δ 1.25-
1.90 (m, 9H), 2.13-2.29 (m, 2H), 4.52-4.68 (m, 1H), 7.46 (dd,
J ) 7.2, 5.4 Hz, 1H), 7.87 (t, J ) 7.8 Hz, 1H), 8.53 (d, J ) 4.5
Hz, 1H), 8.76 (d, J ) 8.1 Hz, 1H), 10.13 (br s, 1H); 13C NMR
δ 24.6, 25.6, 31.4, 53.8, 124.9, 125.8, 137.1, 146.8, 151.2, 188.8.
Anal. Calcd for C12H16N2S: C, 65.41; H, 7.32; N, 12.71.
Found: C, 65.79; H, 7.58; N, 12.57.
General Procedure for the Preparation of Tertiary
Thioamides 15q-s. The appropriate thiocarbamoylbenzo-
triazole 2 (0.495 mmol) was dissolved in 10 mL of dry THF
under a nitrogen atmosphere. The desired Grignard or orga-
nolithium reagent (0.743 mmol) was added dropwise at room
temperature, and the reaction mixture was stirred for 16 h.
Water was added, and the organic layer was extracted with
EtOAc (20 mL × 3). The organic layers were combined, washed
with water, washed with 10% Na2CO3 solution (35 mL × 5),
washed with brine, dried over Na2SO4, and filtered. Concen-
tration under reduced pressure gave crude product, which was
further purified by column chromatography.
O-Ethyl 4-Chlorothiobenzoate (16b): yellow powder
(60%); mp 34-35 °C (lit.93 mp 36 °C);
1H NMR δ 1.53 (t, J )
7.2 Hz, 3H), 4.72 (q, J ) 7.2 Hz, 2H), 7.35 (d, J ) 8.7 Hz, 2H),
8.12 (d, J ) 8.7 Hz, 2H);
13C NMR δ 13.7, 68.7, 128.2, 130.0,
136.6, 139.2, 209.8.
O-Naphth-1-yl 4-Methoxythiobenzoate (16c): yellow
1
needles (88%); mp 93-95 °C; H NMR δ 3.91 (s, 3H), 6.98 (d,
J ) 9.0 Hz, 2H), 7.24-7.27 (m, 1H), 7.44-7.56 (m, 3H), 7.80
(t, J ) 6.3 Hz, 2H), 7.90 (d, J ) 7.8 Hz, 1H), 8.49 (d, J ) 9.0
Hz, 2H); 13C NMR δ 55.7, 113.7, 119.0, 121.6, 125.4, 126.4,
126.6, 126.8, 128.2, 131.0, 131.8, 134.8, 151.0, 164.3, 209.6.
Anal. Calcd for C18H14O2S: C, 73.44; H, 4.79. Found: C, 72.65;
H, 4.89.
O-Naphth-1-yl 4-Nitrothiobenzoate (16d): red needles
1
(99%); mp 139-140 °C; H NMR δ 7.28 (d, J ) 7.5 Hz, 1H),
7.46-7.59 (m, 3H), 7.73 (d, J ) 8.4 Hz, 1H), 7.86 (d, J ) 8.4
Hz, 1H), 7.94 (d, J ) 7.8 Hz, 1H), 8.35 (d, J ) 9.0 Hz, 2H),
8.61 (d, J ) 9.0 Hz, 2H); 13C NMR δ 118.6, 121.0, 123.6, 125.4,
126.1, 126.75, 126.84, 127.0, 128.4, 130.2, 134.8, 141.7, 150.4,
150.5, 207.2; Anal. Calcd for C17H11NO3S: C, 66.01; H, 3.58;
N, 4.53. Found: C, 66.07; H, 3.47; N, 4.45.
But-3-enethioic Acid N-Butyl-N-methylamide (15q):
purified by column chromatography with hexanes/EtOAc (95:
5) as eluent and obtained as brown oil (98%); rotamers (50:50
ratio) observed in1H NMR at 25 °C; signals are double the
expected proton signals; 1H NMR δ 0.96 (t, 6H), 1.30-1.43 (m,
4H), 1.60-1.75 (m, 4H), 3.25 (s, 3H), 3.43 (s, 3H), 3.53-3.67
(m, 6H), 3.99 (t, J ) 7.8 Hz, 2H), 5.11-5.22 (m, 4H), 5.90-
6.03 (m, 2H); 13C NMR δ 13.6, 13.7, 19.8, 19.9, 27.6, 30.1, 39.5,
42.4, 47.8, 48.8, 54.2, 55.7, 116.8, 117.0, 132.7, 133.5, 199.9.
Anal. Calcd for C9H17NS: C, 63.10; H, 10.00; N, 8.18. Found:
C, 62.89; H, 10.30; N, 8.40.
O-Naphth-1-yl 2-Thienylcarbothioate (16e): yellow
needles (62%); mp 97-98 °C; 1H NMR δ 7.08 (dd, J ) 4.8, 3.9
Hz, 1H), 7.24 (d, J ) 7.5 Hz, 1H), 7.39-7.49 (m, 3H), 7.57 (dd,
J ) 4.8, 1.2 Hz, 1H), 7.75 (d, J ) 8.4 Hz, 1H), 7.81-7.85 (m,
2H), 8.07 (dd, J ) 3.9, 1.2 Hz, 1H); 13C NMR δ 119.3, 121.6,
125.5, 126.8, 126.9, 128.4, 128.8, 132.9, 134.8, 135.3, 144.8,
150.3, 201.7. Anal. Calcd for C15H10OS2: C, 66.64; H, 3.73.
Found: C, 66.23; H, 3.71.
General Procedure for the Preparation of Thion-
oesters 16f-h. O-Naphth-2-yl benzotriazole-1-carbothioate
(13a) (0.3 g, 1 mmol) was dissolved in 10 mL of dry THF under
nitrogen atmosphere. The appropriate Grignard reagent (1
mmol) was added dropwise at room temperature, and the
reaction mixture was stirred for 12 h. A solution of saturated
NH4Cl (25 mL) was added, and the organic layer was extracted
with EtOAc (30 mL × 2). The organic layers were combined,
washed with water (10 mL × 2), washed with brine, dried over
Na2SO4, and filtered. Concentration under reduced pressure
gave the crude product, which was further purified by column
chromatography (hexanes) and recrystallized from Et2O.
O-Naphth-2-yl 4-Methylthiobenzoate (16f): yellow mi-
crocrystals (70%); mp 108-109 °C; 1H NMR δ 2.44 (s, 3H),
7.24-7.30 (m, 3H), 7.47-7.57 (m, 3H), 7.82-7.93 (m, 3H), 8.30
(d, J ) 8.1 Hz, 2H); 13C NMR δ 21.9, 119.3, 121.9, 126.1, 126.8,
128.0, 128.1, 129.2, 129.6, 131.9, 134.0, 135.8, 144.7, 152.6,
211.2. Anal. Calcd for C18H14OS: C, 77.66; H, 5.07. Found: C,
77.35; H, 5.42.
Piperidin-1-ylthiophen-2-ylmethanethione (15r): puri-
fied by column chromatography with hexanes/EtOAc (90:10)
as eluent and obtained as yellow cubes (53%); mp 85-86 °C
(lit.92 mp 89 °C); broadening of the piperidine-ring signals are
1
observed in H NMR and 13C NMR spectra due to restricted
1
rotation and ring flipping; H NMR (DMSO-d6) δ 1.67 (br s,
6H), 3.83 (br s, 2H), 4.21 (br s, 2H), 7.02-7.06 (m, 1H), 7.14-
7.15 (m, 1H), 7.67-7.69 (m, 1H); 13C NMR (DMSO-d6) δ 23.8,
25.8, 26.8, 51.9, 52.9, 125.6, 126.8, 129.7, 145.0, 188.7. Anal.
Calcd for C10H13NS2: C, 56.83; H, 6.20; N, 6.63. Found: C,
56.96; H, 6.27; N, 6.55.
But-3-enethioic Acid N-Methyl-N-phenylamide (15s):
purified by column chromatography with hexanes/EtOAc (85:
15) as eluent and obtained as brown oil (78%); 1H NMR δ 3.30
(d, J ) 6.6 Hz, 2H), 3.74 (s, 3H), 4.86 (dd, J ) 17.1, 1.2 Hz,
1H), 5.03 (d, J ) 9.9 Hz, 1H), 5.89-6.02 (m, 1H), 7.17-7.20
(m, 2H), 7.38-7.50 (m, 3H); 13C NMR δ 45.8, 48.5, 116.9, 125.7,
128.6, 129.8, 134.3, 145.3, 202.7. Anal. Calcd for C11H13NS:
C, 69.06; H, 6.85; N, 7.32. Found: C, 69.18; H, 7.14; N, 7.53.
General Procedure for the Preparation of Thiono-
esters 16a-e. The appropriate alcohol (0.5 mmol) and Et3N
(0.05 g, 0.5 mmol) were added to the respective thiocarbonyl-
benzotriazole 6 or thiocarbonyl-6-nitrobenzotriazole 10 dis-
solved in CH2Cl2 (30 mL) at room temperature. Stirring was
continued overnight, and then solvent was removed by rotary
evaporation. The residue was redissolved in EtOAc (100 mL),
washed with 5% Na2CO3 solution (3 × 100 mL), 1 M HCl (2 ×
100 mL), water, and brine. The collected organic layers were
dried with Na2SO4, and the solvent was removed under
vacuum. Recrystallization from EtOAc/hexanes afforded thio-
noesters 16a-e.
O-Naphth-2-yl Thiobenzoate (16g): yellow microcrystals
(76%); mp 52-53 °C; 1H NMR δ 7.23 (d, J ) 8.8 Hz, 1H), 7.38-
7.46 (m, 4H), 7.52-7.58 (m, 2H), 7.76-7.87 (m, 3H), 8.38 (d,
J ) 8.1 Hz, 2H); 13C NMR δ 119.2, 121.7, 126.1, 126.8, 127.9,
128.1, 128.4, 129.4, 129.6, 131.8, 133.5, 134.0, 138.0, 152.6,
211.2. Anal. Calcd for C17H12OS: C, 77.24; H, 4.58. Found: C,
77.17; H, 4.56.
O-Naphth-2-yl Ethanecarbothioate (16h): yellow micro-
1
crystals (64%); mp 94-95 °C (lit.94 mp 95-96 °C); H NMR δ
2.87 (s, 3H), 7.19 (dd, J ) 9.0, 1.8 Hz, 2H), 7.48-7.51 (m, 3H),
7.80-7.86 (m, 3H), 7.89 (d, J ) 9.0 Hz, 1H); 13C NMR δ 34.7,
119.0, 121.5, 126.2, 126.9, 128.0, 128.1, 129.7, 131.9, 133.9,-
152.4, 220.0.
General Procedure for the Preparation of Tertiary
Thiocarbamates 17a,b from Thiocarbamoylbenzotriaz-
oles. The desired thiocarbamoylbenzotriazole (2) (0.36 mmol)
was dissolved in CH2Cl2 (7 mL). In another flask, the desired
alcohol (0.36 mmol) and NaH (0.17 g, 4.32 mmol) were stirred
O-(4-Methoxyphenyl)-4-methoxythiobenzoate (16a): yel-
1
low powder (77%); mp 105-106 °C; H NMR δ 3.83 (s, 3H),
3.89 (s, 3H), 6.92 (d, J ) 9.0 Hz, 2H), 6.96 (d, J ) 9.0 Hz, 2H),
7.03 (d, J ) 9.0 Hz, 2H), 8.34 (d, J ) 9.0 Hz, 2H); 13C NMR δ
55.6, 113.4, 114.4, 122.9, 131.1, 131.7, 148.3, 157.5, 164.1,
(93) Mizukami, S.; Nagata, K. Chem. Pharm. Bull. 1966, 14, 1249;
Chem. Abstr. 1967, 66, 65255.
(94) Curphey, T. J. J. Org. Chem. 2002, 67, 6461.
(92) Mayer, R.; Scheithauer, S. Chem. Ber. 1965, 829.
J. Org. Chem, Vol. 70, No. 20, 2005 7879

Katritzky et al.
for 10 min in CH2Cl2 (7 mL). The sodium salt solution was
added to the thiocarbamoylbenzotriazole solution, and the
mixture was stirred for 18 h. The solvent was removed under
vacuum; water was added and extracted with EtOAc (2 × 25
mL). The organic layer was washed with water and 10% Na2-
CO3 solution (2 × 30 mL), dried over Na2SO4, and filtered.
Concentration under reduced pressure gave the crude product,
which was further purified by recrystallization.
NMR (DMSO-d6 at 70 °C) δ 26.7, 54.8, 55.1, 115.8, 117.7, 121.7,
125.0, 125.1, 126.0, 128.5, 129.6, 131.0, 135.0, 143.2, 159.3,
190.5. Anal. Calcd for C16H15NOS2: C, 63.75; H, 5.02; N, 4.65.
Found: C, 63.38; H, 5.03; N, 4.28.
General Procedure for the Preparation of Secondary
Dithiocarbamates 18b-d. The secondary thiocarbamoyl-
benzotriazole 2 (0.36 mmol) was dissolved in CH2Cl2 (7 mL).
The mercapto reagent (0.36 mmol) was added dropwise fol-
lowed by exactly 1 equiv of Et3N (0.36 mmol). The reaction
mixture was stirred for 16 h. The solvent was removed under
vacuum, water was added, and the organic layer was extracted
with EtOAc (2 × 25 mL). The organic layer was washed with
water, dried over Na2SO4, and filtered. Concentration under
reduced pressure gave a crude product that was further
purified by column chromatography.
2,3-Dihydroindole-1-carbothioic Acid O-Benzhydrol
Ester (17a): colorless prisms (from EtOAc hexanes) (59%); mp
1
150-154 °C; H NMR δ 3.12 (t, J ) 8.4 Hz, 2H), 4.40 (t, J )
8.4 Hz, 2H), 6.99-7.42 (m, 12H), 7.76-7.87 (m, 2H); 13C NMR
δ 26.6, 54.2, 83.9, 117.7, 124.3, 125.5, 127.6, 127.7, 128.0, 128.5,
133.6, 139.6, 141.3, 184.0. Anal. Calcd for C22H19NOS: C,
76.49; H, 5.54; N, 4.05. Found: C, 76.62; H, 5.55; N, 4.04.
N-Methyl-N-phenylthiocarbamic Acid Benzhydrol Es-
ter (17b): colorless plates (from EtOAc) (60%); mp 102-103
Furan-2-ylmethyldithiocarbamic Acid 3-Methoxyphe-
nyl Ester (18b): purified by column chromatography with
hexanes/EtOAc (95:5) as eluent and obtained as white prisms
(83%); mp 73-75 °C; 1H NMR (DMSO-d6) δ 1.05-1.35 (m, 5H),
1.55-1.62 (m, 1H), 1.67-1.76 (m, 2H), 1.84-1.95 (m, 2H), 4.25
(s, 1H), 4.49 (s, 2H), 7.20-7.42 (m, 5H), 9.86 (d, J ) 7.2 Hz,
1H); 13C NMR (DMSO-d6) δ 24.7, 25.1, 31.0, 38.0, 56.0, 127.1,
128.5, 129.0, 137.5, 194.1. Anal. Calcd for C13H13NO2S2: C,
55.89; H, 4.69; N, 5.01. Found: C, 55.90; H, 4.71; N, 5.01.
Cyclohexyldithiocarbamic Acid Benzyl Ester (18c):
purified by column chromatography with hexanes/EtOAc (95:
5) as eluent and obtained as colorless crystals (92%); mp 70-
1
°C; H NMR δ 3.62 (s, 3H), 7.09-7.49 (m, 16H); 13C NMR δ
44.0, 83.3, 126.1, 126.8, 127.6, 128.3, 129.2, 130.0, 140.3, 143.5,
187.3. Anal. Calcd for C21H19NOS: C, 75.64; H, 5.74; N, 4.20.
Found: C, 75.65; H, 5.91; N, 4.17.
General Procedure for the Preparation of Thiocar-
bamates 17c-e from Aryloxythioacylbenzotriazole 12a.
To O-naphth-2-yl benzotriazole-1-carbothioate (12a) (1 mmol)-
in 20 mL of CH2Cl2 at room temperature was added 1 mmol
of amine, and the reaction mixture was refluxed for 2 h.
Solvent was evaporated, and the crude product was purified
by recrystallization from EtOH.
1
71 °C (lit.96 mp 66-67 °C); H NMR (DMSO-d6) δ 1.05-1.35
(m, 5H), 1.55-1.62 (m, 1H), 1.67-1.76 (m, 2H), 1.84-1.95 (m,
2H), 4.25 (s, 1H), 4.49 (s, 2H), 7.20-7.42 (m, 5H), 9.86 (d, J )
7.2 Hz, 1H); 13C NMR (DMSO-d6) δ 24.7, 25.1, 31.0, 38.0, 56.0,
127.1, 128.5, 129.0, 137.5, 194.1. Anal. Calcd for C14H19NS2:
C, 63.35; H, 7.21; N, 5.28. Found: C, 63.42; H, 7.38; N, 5.22.
Phenethyldithiocarbamic Acid Phenyl Ester (18d):
purified by column chromatography with hexanes/EtOAc (95:
5) as eluent and obtained as colorless crystals (60%); mp 70-
71 °C (lit.97 mp 73-74 °C); 1H NMR δ 2.82 (t, J ) 6.6 Hz, 2H),
3.87 (q, J ) 6.3 Hz, 2H), 6.55 (s, 1H), 6.94-6.97 (m, 2H), 7.20-
7.22 (m, 3H), 7.37-7.39 (m, 4H), 7.42-7.50 (m, 1H); 13C NMR
δ 33.6, 46.9, 126.6, 128.0, 128.4, 128.8, 130.3, 131.0, 135.4,
137.5, 194.8. Anal. Calcd for C15H15NS2: C, 65.89; H, 5.53.
Found: C, 65.00; H, 5.58.
General Procedure for the Preparation of Thiocar-
bamates 19a-c. To the appropriate alcohol (1 mmol) was
added NaH (0.18 g, 4.5 mmol) dissolved in CH2Cl2 (10 mL) at
room temperature. In another flask, aryloxythioacylbenzo-
triazole 12a (0.30 g, 1 mmol) was dissolved in CH2Cl2 (10 mL).
The prepared salt solution was added to the solution of 12a,
and the mixture was allowed to stir at room temperature for
24 h. The solvent was evaporated to give a crude residue, to
which water (25 mL) was added and the organic phase was
extracted with EtOAc (2 × 30 mL). The combined organic
fractions were washed with water (2 × 10 mL) and 10% Na2-
CO3 solution (2 × 30 mL), dried over MgSO4, and filtered.
Solvent was removed in vacuo and the product was purified
by recrystallization from EtOAc/hexanes to afford thiocarbam-
ates 19a-c in 70-72% yields.
Morpholine-1-carbothioic Acid O-Naphthalen-2-yl Es-
ter (17c): colorless microcrystals (70%); mp 145-146 °C (lit.95
1
mp 145-146 °C); H NMR δ 3.79 (t, J ) 5.1 Hz, 2H), 3.84 (t,
J ) 5.1 Hz, 2H), 4.02 (t, J ) 4.7 Hz, 2H), 4.18 (t, J ) 4.7 Hz,
2H), 7.24 (d, J ) 9.0 Hz, 1H), 7.45-7.49 (m, 3H), 7.79-7.87
(m, 3H); 13C NMR δ 47.0, 50.4, 66.4, 66.6, 119.7, 122.5, 126.0,
126.7, 127.9, 128.1, 129.2, 131.8, 133.9, 151.6, 187.6.
Benzyl-1-carbothioic Acid O-Naphthalen-2-yl Ester
(17d): colorless microcrystals (80%), mp 47-48 °C; 70:30 ratio
of rotamers was observed in 1H NMR at 25 °C; 1H NMR signals
are reported for the major rotamer; 1H NMR δ 4.91 (d, J )
5.3 Hz, 2H), 7.05 (br, 1H), 7.61-7.29 (m, 9H), 7.94-7.87 (m,
3H); 13C NMR δ 50.2, 119.8, 122.4, 126.1, 126.8, 128.0, 128.4,
129.2, 129.3, 131.8, 133.8, 136.5, 150.9, 189.9. Anal. Calcd for
C18H15NOS: H, 5.15; N, 4.77. Found: H, 5.31; N, 4.46.
Pyrrolidine-1-carbothioic Acid O-Naphthalen-2-yl Es-
1
ter (17e): colorless oil (85%); H NMR δ 1.79-2.00 (m, 4H),
3.71-3.79 (m, 4H), 7.27 (d, J ) 8.8 Hz, 1H), 7.42-7.51 (m,
3H), 7.77-7.85 (m, 3H); 13C NMR δ 24.6, 25.8, 48.8, 52.5, 119.5,
122.6, 125.6, 126.4, 127.7, 127.8, 128.9, 131.4, 133.6, 151.3,
184.4. Anal. Calcd for C15H15NOS: C, 70.01; H, 5.87; N, 5.44.
Found: C, 69.89; H, 6.00; N, 5.37.
General Procedure for the Preparation of Tertiary
Dithiocarbamate 18a. The desired thiocarbamoylbenzotria-
zole 2 (0.32 mmol) was dissolved in CH2Cl2 (7 mL). In another
flask, the desired mercapto reagent (0.36 mmol) and NaH (0.02
g, 0.49 mmol) were stirred for 10 min in CH2Cl2 (7 mL). The
sodium salt solution was added to the thiocarbamoylbenzo-
triazole solution, and the mixture was stirred for 18 h. The
solvent was removed under vacuum; water was added and
extracted with EtOAc (2 × 25 mL). The organic layer was
washed with water and 10% Na2CO3 solution (2 × 30 mL),
dried over Na2SO4, and filtered. Concentration under reduced
pressure gave a residue, which was further purified by column
chromatography.
Thiocarbonic Acid Ethyl Ester Naphthalen-2-yl Ester
(19a): white microcrystals (70%); mp 33-34 °C (lit.98 mp 33-
34 °C); 1H NMR δ 1.45 (t, J ) 7.1 Hz, 3H), 4.60 (q, J ) 7.1 Hz,
2H), 7.26 (dd, J ) 8.8, 2.2 Hz, 1H), 7.45-7.54 (m, 3H), 7.78-
7.87 (m, 3H); 13C NMR δ 13.9, 70.6, 119.1, 121.5, 126.2, 126.8,
128.0 (2C), 129.6, 131.9, 133.8, 151.0, 195.4.
Thiocarbonic Acid Pyridin-3-yl Ester Naphthalen-2-
yl Ester (19b): white microcrystals (72%); mp 91-92 °C; 1H
NMR δ 7.34-7.40 (m, 2H), 7.46-7.54 (m, 2H), 7.56-7.60 (m,
1H), 7.66 (d, J ) 2.2 Hz, 1H), 7.82-7.92 (m, 3H), 8.56 (dd, J
2,3-Dihydroindole-1-Carbodithioic Acid 3-Methoxy-
phenyl Ester (18a): purified by column chromatography with
hexanes/EtOAc (92:8) as eluent and obtained as orange powder
1
(99%); mp 104-105 °C; H NMR (DMSO-d6 at 70 °C) δ 3.23
(t, J ) 8.1 Hz, 2H), 3.79 (s, 3H), 4.56 (t, J ) 7.5 Hz, 2H), 7.04-
7.43 (m, 5H), 7.34-7.43 (m, 2H), 8.93 (d, J ) 8.1 Hz, 1H); 13
C
(96) Wakamori, S.; Tsuchidate, T.; Ishii, Y. Agric. Biol. Chem. 1969,
1682; Chem. Abstr. 1970, 72, 54013.
(97) Rieche, A.; Hilgetag, G.; Martin, D.; Kreyzi, I. Arch. Pharm.
1963, 296, 310.
(95) Noguchi, T.; Hashimoto, Y.; Miyazaki, K.; Kaji, A. Yakugaku
Zasshi 1968, 227.
(98) Rivier, H.; Schalch, J. Helv. Chim. Acta 1923, 6, 612.
7880 J. Org. Chem., Vol. 70, No. 20, 2005

Benzotriazole-Assisted Thioacylation
) 4.7, 1.1 Hz, 2H), 8.60 (d, J ) 2.6 Hz, 1H); 13C NMR δ 119.0,
120.8, 124.2, 126.5, 127.1, 128.0, 128.1, 129.8, 130.0, 132.0,
133.7, 144.0, 148.0, 150.3, 151.1, 194.5. Anal. Calcd for C16H11-
NO2S: C, 68.31; H, 3.94; N, 4.98. Found: C, 68.13; H, 3.77;
N, 4.94.
Thiocarbonic Acid 4-Methoxyphenyl Ester Naphtha-
len-2-yl Ester (19c): white microcrystals (70%); mp 163-
164 °C; 1H NMR δ 3.82 (s, 3H), 6.96 (d, J ) 9.0 Hz, 2H), 7.15-
7.18 (m, 2H), 7.36 (dd, J ) 9.0, 2.1 Hz, 2H), 7.47-7.54 (m,
2H), 7.66 (s, 1H), 7.93-7.84 (m, 3H); 13C NMR δ 55.8, 114.8,
119.1, 121.3, 122.8, 126.4, 127.0, 128.1 (2C), 129.9, 132.0,
133.9, 147.4, 151.3, 158.1, 195.7. Anal. Calcd for C18H14O3S:
C, 69.66; H, 4.55. Found: C, 69.26; H, 4.42.
Dithiocarbonic Acid O-Naphthalen-2-yl Ester S-(Dode-
1
cyl)ester (20b): yellow oil (70%); H NMR δ 0.98 (t, J ) 6.3
Hz, 3H), 1.36 (m, 18H), 1.87 (quintet, J ) 7.5 Hz, 2H), 3.33 (t,
J ) 7.4 Hz, 2H), 7.37 (dd, J ) 8.7, 2.1 Hz, 1H), 7.56-7.64 (m,
3H), 7.88-7.97 (m, 3H); 13C NMR δ 14.3, 22.9, 28.2, 29.1, 29.3,
29.5, 29.6, 29.8 (2C), 32.1, 37.4, 119.3, 121.6, 126.2, 126.8, 128.0
(2C), 129.6, 131.9, 133.9, 152.3, 215.3. Anal. Calcd for C23H32-
OS2: C, 71.08; H, 8.30. Found: C, 70.82; H, 8.97.
Dithiocarbonic Acid O-Naphthalen-2-yl Ester S-Iso-
propyl Ester (20c): yellow oil (60%); 1H NMR δ 1.46 (d, J )
6.9 Hz, 6H), 3.89 (septet, J ) 7.0 Hz, 1H), 7.23 (dd, J ) 8.9,
2.2 Hz, 1H), 7.45-7.53 (m, 3H), 7.77-7.86 (m, 3H); 13C NMR
δ 22.3, 42.5, 119.4, 121.6, 126.2, 126.8, 127.9, 128.0, 129.6,
131.9, 133.8, 152.0, 214.5. Anal. Calcd for C14H14O2S2: C,
64.08; H, 5.38. Found: C, 64.20; H, 5.58.
General Procedure for the Preparation of Dithiocar-
bamates 20a-c. The appropriate thiol (1 mmol) was dissolved
in an aqueous solution (10 mL) of NaOH (0.08 g, 2 mmol) at
room temperature. A solution of the aryloxythioacylbenzo-
triazole 12a (0.3 g, 1 mmol) in THF (10 mL) was added
dropwise to the aqueous mixture, which was then allowed to
stir at room temperature for 12 h. The mixture was diluted
with water (25 mL) and extracted with EtOAc (2 × 30 mL).
The combined organic fractions were washed with water (2 ×
10 mL), dried over MgSO4, and filtered. Solvent was removed
in vacuo, and the crude product was purified by column
chromatography (silica gel, hexanes/EtOAc, 3:1 as eluent) to
afford dithiocarbamates 20a-c in 60-70% yields.
Acknowledgment. The authors thank Alexander
Shestopalov for his preparation of aryl/alkylthiothio-
acylbenzotriazoles and scouting of aryl/alkoxythioacy-
lation reagents. The initial investigations of bis(benzo-
triazolyl)methanethione reactivity with amines21 and
phenol conducted by Dr. Stephane Ledoux were also a
substantial contribution.
Supporting Information Available: Crystallographic
data (CIF and PDF formats) for bis(benzotriazol-1-yl)diaryl-
sulfidemethanes (4a and 4b) (Figure 1) and isopropyl di-
(benzotriazol-1-yl)methyl disulfide (14d) (Figure 2). This in-
formation is available free of charge via the Internet at
http://pubs.acs.org.
Dithiocarbonic Acid O-Naphthalen-2-yl Ester S-(4-
Methylphenyl)ester (20a): yellow microcrystals (70%); mp
1
88-89 °C; H NMR δ 2.22 (s, 3H), 7.09-7.13 (m, 3H), 7.28-
7.35 (m, 2H), 7.38-7.40 (m, 3H), 7.61-7.70 (m, 3H); 13C NMR
δ 21.6, 119.2, 121.3, 126.2, 126.8, 127.0, 127.9, 128.0, 129.6,
130.4, 131.8, 133.7, 135.2, 140.9, 152.2, 214.0. Anal. Calcd for
C18H14OS2: C, 69.64; H, 4.55. Found: C, 69.51; H, 4.62.
JO050670T
J. Org. Chem, Vol. 70, No. 20, 2005 7881