Efficient Conversion of Substituted Aryl Thioureas to 2-Aminobenzothiazoles Using Benzyltrimethylammonium Tribromide

Article abstract of DOI:10.1021/jo0349431

The reaction of molecular bromine (Br₂) with arylthioureas is known to produce 2-aminobenzothiazoles (Hugerschoff reaction). We show here that benzyltrimethylammonium tribromide (1, PhCH₂NMe ₃Br₃), a stable, crystalline organic ammonium tribromide (OATB), can be readily utilized as an alternative electrophilic bromine source. It is easier to control the stoichiometry of addition with an OATB, which minimizes aromatic bromination caused by excess reagent. We have developed a direct procedure from isothiocyanates and amines using tetrabutylammonium thiocyanate (Bu₄NSCN) and PhCH₂NMe₃Br ₃ to afford functionalized 2-aminobenzothiazoles.

Full text of DOI:10.1021/jo0349431

Efficien t Con ver sion of Su bstitu ted Ar yl
Th iou r ea s to 2-Am in oben zoth ia zoles Usin g
Ben zyltr im eth yla m m on iu m Tr ibr om id e
Alfonzo D. J ordan,* Chi Luo, and Allen B. Reitz
usually proceeds efficiently at room temperature, several
drawbacks are associated with the use of liquid bromine,
which is a highly toxic and corrosive reagent, and can
be difficult to manipulate on small scale. As an alterna-
tive reagent to liquid bromine, organic ammonium tri-
bromides (OATBs) such as benzyltrimethylammonium
tribromide (1, PhCH2NMe3Br3) and tetrabutylammonium
tribromide (2, Bu4NBr3) are high molecular weight,
stable, crystalline solids, which can deliver a stoichio-
metric amount of bromine where small amounts are
necessary for microscale reactions. For example, Bu4NBr3
and PhCH2NMe3Br3 are effective alternatives to bromine
for the bromination of activated aromatic substrates,12-14
alkenes,14 and ketones.15 To date, OATBs have not been
reported as a substitute for bromine in the preparation
of 2-alkylaminobenzothiazoles from arylthioureas. Herein,
we describe an efficient method for the facile conversion
of aryl thioureas to 2-aminobenzothiazoles with an
equimolar amount of PhCH2NMe3Br3 under a variety of
reaction conditions. In addition, this reagent has been
used to prepare 2-aminobenzothiazoles via a one-pot
procedure from isothiocyanates and amines or a substi-
tuted aniline and tetrabutylammonium thiocyanate (Bu4-
NSCN).
Drug Discovery Division, J ohnson & J ohnson
Pharmaceutical Research and Development,
P.O. Box 0776, Welsh and McKean Roads,
Spring House, Pennsylvania 19477-0776
ajordan@prdus.jnj.com
Received J uly 1, 2003
Abstr a ct: The reaction of molecular bromine (Br2) with
arylthioureas is known to produce 2-aminobenzothiazoles
(Hugerschoff reaction). We show here that benzyltrimethy-
lammonium tribromide (1, PhCH2NMe3Br3), a stable, crys-
talline organic ammonium tribromide (OATB), can be readily
utilized as an alternative electrophilic bromine source. It is
easier to control the stoichiometry of addition with an OATB,
which minimizes aromatic bromination caused by excess
reagent. We have developed a direct procedure from isothio-
cyanates and amines using tetrabutylammonium thiocyan-
ate (Bu4NSCN) and PhCH2NMe3Br3 to afford functionalized
2-aminobenzothiazoles.
2-Aminobenzothiazoles are broadly found in bioorganic
and medicinal chemistry with applications in drug dis-
covery and development for the treatment of diabetes,1
epilepsy,2,3,4 inflammation,5 amyotrophic lateral sclero-
sis,6 analgesia,7 tuberculosis,8 and viral infections.9 In-
vestigations into the preparation of 2-aminobenzothiaz-
oles can be traced to the early 1900s with the work of
Hugerschoff, who found that an arylthiourea can be
cyclized with liquid bromine in chloroform to form an
2-aminobenzothiazole (eq 1).10,11 Although this reaction
Resu lts a n d Discu ssion
During the course of a medicinal chemistry project, we
needed to prepare a series of 2-aminobenzothiazoles and
initially used the method of Ambati and co-workers who
reported a facile synthesis from substituted arylthioureas
and bromine in acetic acid at room temperature.16 They
had reported that N-methyl-N′-phenylthiourea 3 under-
went oxidative cyclization with 1.95 molar equiv of
bromine in acetic acid at room temperature to provide
2-(methylamino)benzothiazole 4 in 75% yield (Table 1,
entry 1). When we repeated this experiment, we obtained
6-bromobenzothiazole 518 in 46% isolated yield with only
* To whom correspondence should be addressed. Phone: 215-628-
5638. Fax: 215-628-4985.
(1) Suter, H.; Zutter, H. Helv. Chim. Acta 1967, 50, 1084.
(2) Hays, S. J .; Rice, M. J .; Ortwine, D. F.; J ohnson, G.; Schwartz,
R. D.; Boyd, D. K.; Copeland, L. F.; Vartanian, M. G.; Boxer, P. A. J .
Pharm. Sci. 1994, 83, 1425.
(3) J imonet, P.; Audiau, F.; Barreau, M.; Blanchard, J .-C.; Boireau,
A.; Bour, Y.; Coleno, M.-A.; Doble, A.; Doerflinger, G., Huu, C. D.;
Donat, M.-H.; Duchesne, J . M.; Ganil, P., Gueremy, C., Honore, E.,
J ust, B.; Kerphirique, R., Gontier, S.; Hubert, P.; Laduron, P. M.; Le
Blevec, J .; Meunier, M.; Miquet, J .-M.; Nemecek, C.; Pasquet, M.; Piot,
O.; Pratt, J .; Rataud, J .; Reibaud, M.; Stutzmann, J .-M.; Mignani, S.
J . Med. Chem. 1999, 42, 2828.
(4) He, Y.; Benz, A.; Fu, T.; Wang, M.; Covey, D. F.; Zorumski, C.
F.; Mennick, S. Neuropharmacology 2002, 42, 199.
(5) Sawhney, S. N.; Arora, S. K.: Singh, J . V.; Bansal, O. P.; Singh,
S. P. Indian J . Chem. 1978, 16B, 605.
(11) Sprague, J . M.; Land, A. H. In Heterocyclic Compounds;
Elderfield, R. C., Ed.; J . Wiley: New York, 1957; Vol. 5, Chapter 8, pp
484-721.
(12) Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Nakamura, H.;
Fujikawa, M. Bull. Chem Soc. J pn. 1987, 60, 4187.
(13) Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Hiromichi, F.;
Fujisaki, S.; Okamoto, T. Bull. Chem Soc. J pn. 1988, 61, 2681.
(14) Chaudhuri, M. K.; Khan, A. T.; Patel, B. K.; Dey, D.; Kharma-
wophlang, W.; Lakshmiprabha, T. R.; Mandal, G. C. Tetrahedron Lett.
1998, 39, 816.
(6) Bensimon, G.; Lacomblez, L.; Meininger, V. New Engl. J . Med.
1994, 330, 585.
(7) Foscolos, G.; Tsatsas, G.; Champagnac, A.; Pommier, M. Ann.
Pharm. Fr. 1977, 35, 295.
(8) Shirke, V. G.; Bobade.; Bhamaria, R. P.; Khadse, B. G.; Sengupta,
S. R. Indian Drugs 1990, 27(6), 350.
(15) Kajigaeshi, S.; Kakinami, T.; Hajime, H.; Okamoto, T.; Naka-
mura, H. Bull. Chem Soc. J pn. 1987, 60, 2667.
(16) Ambati, N. B.; Anad, V.; Hanumanthu, P. Synth. Commun.
1997, 27, 1487.
(17) We believe that the earlier work16 had actually produced 5 and
(9) Paget, C. J .; Kisner, K.; Stone, R. L.; Delong, D. C. J . Med. Chem.
1969, 12, 1016.
(10) Hugerschoff, H. Chem. Ber. 1901, 34, 3130. (b) Hugerschoff,
H. Chem. Ber. 1903, 36, 3121.
not 4 and that this product had been improperly characterized.
Consistent with this analysis is our observation that the melting point
we found for 5 (227-228 °C) is closer to what was reported (215 °C)
than the melting point for 4 (140-141 °C).
10.1021/jo0349431 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/03/2003
J . Org. Chem. 2003, 68, 8693-8696
8693

TABLE 1. Hu ger sch off Rea ction Usin g Br 2 a n d OATBs
in Acetic Acid
TABLE 2. Va r ia tion of Solven t in th e Hu ger sch off
Rea ction w ith P h 2CH2NMe3Br 3 (1)
entry
solvent
reaction conditions
% yield
1
2
3
4
5
6
7
AcOH
rt/5 h
rt/1 d
rt/1 d
rt/1 d
rt/1 d
rt/1 d
rt/1 h
81
80
61
68
41
<5
<5
CH2Cl2
CH3CN
1,2-DME
THF
MeOH
DMF
reaction
conditions
% yield % yield
entry
reagent
of 4
of 5
1
2
3
4
Br2 (1.95 molar equiv)16,17 AcOH/rt
75
<5
83
0
46
0
Br2 (1.95 molar equiv)
Br2 (1 molar equiv)
PhCH2NMe3Br3
(1 molar equiv)
PhCH2NMe3Br3
(2.2 molar equiv)
AcOH/rt
AcOH/rt/3 h
AcOH/rt/5 h
81
0
in dichloromethane, 8 was isolated in 77% yield (Table
3, entry 2). The compatibilities of amino and hydroxyl
functionalities were also studied. 2-N-Dimethylamino-
ethyl-N′-phenylthiourea 9 was treated with PhCH2NMe3-
Br3 to give the corresponding aminobenzothiazole 1020
in 29% yield in acetic acid and in 73% in dichloromethane
at room temperature (Table 3, entries 3 and 4). Reaction
of N-2-hydroxyethyl-N′-phenylthiourea 11 with 1 in
acetic acid provided 2-[2-(acetoxy)ethylamino]benzothia-
zole 12 in 73% yield in which the hydroxyl group was
acetylated, whereas the use of dichloromethane as the
solvent provided 2-[2-(hydroxy)ethylamino]benzothiazole
13 in 76% yield (Table 3, entries 5 and 6).
5
AcOH/rt /18 h
0
70
a trace (<5%) of 4 (Table 1, entry 2).17 Compound 5 was
prepared independently in order to unambiguously assign
the structure by reacting N-4-bromophenyl-N′-methyl-
thiourea 6 with one molar equiv of PhCH2NMe3Br3. It is
known for the Hugerschoff reaction that excess bromine
will produce the perbromide of the aminobenzothiazole,
which can then brominate the benzene ring under
prolonged reaction conditions.10,11 We conducted the
reaction with 1 molar equiv of either liquid bromine (3
h) or PhCH2NMe3Br3 (5 h) in acetic acid at room tem-
perature to provide 4 in 83% or 81% yields, respectively
(Table 1, entries 3 and 4). Furthermore, reaction of 3 with
2.2 molar equiv of PhCH2NMe3Br3 provided 2-methyl-
amino-6-bromobenzothiazole 5 in 70% yield (Table 1,
entry 5). We were encouraged by the initial finding that
PhCH2NMe3Br3 could substitute for liquid bromine in the
reaction because it is easier to control the stoichiometry
of addition of PhCH2NMe3Br3 which would minimize the
formation of brominated side products when the reaction
is conducted with an excess of reagent.
TABLE 3. Com p a tibility of Differ en t F u n ction a l Gr ou p s
in th e Hu ger sch off Rea ction Usin g 1
starting X in 7, 9,
X in 8, 10,
%
entry material and 11 solvent product 12, and 13 yield
1
2
3
4
5
6
7
7
9
9
11
11
CO2Me
CO2Me
NMe2
NMe2
OH
AcOH
CH2Cl2
AcOH
8
8
10
CO2Me
CO2Me
NMe2
NMe2
OAc
84
77
29
73
73
76
The arylthioureas used in this study were prepared by
reacting the appropriate aryl isothiocyanate and alkyl-
amine in refluxing methanol, and subsequent conversion
of the resulting arylthioureas with PhCH2NMe3Br3 in
acetic acid provided the 2-alkylamino benzothiazoles as
hydrobromide salts.
CH2Cl2 10
AcOH 12
CH2Cl2 13
OH
OH
We then examined the effects of aromatic substitution
involving electron-donating (methoxy and methyl) and
electron-withdrawing (bromo and nitro) groups. The
reaction of 3-methoxyphenylthiourea analogue 14 and 1
in acetic acid proceeded readily (<30 min) to give product
1521 in 87% yield (Table 4, entry 1). However, the reaction
of 3-methylphenylthiourea 16 and 1 in acetic acid pro-
duced a 3:2 inseparable mixture of products 17 and 18
in 88% yield as evidenced by doubling of key aromatic
resonances in the 1H and 13C NMR (Table 4, entry 2).
The reaction of 3-bromophenylthiourea 19 and 1 pro-
duced a 1:1 mixture of isomeric products 20 and 21 in
70% yield (Table 4, entry 3). The reaction of 3-nitrophe-
nylthiourea compound 22 was slower (2 days) and
We investigated the effects of varying solvent in this
reaction. Compound 3 was reacted with 1 molar equiv of
PhCH2NMe3Br3 (Table 2, entry 2) in CH2Cl2 at room
temperature for 1 day to give desired product 4 in 80%
yield. Acetonitrile, 1,2-dimethoxyethane, and tetrahydro-
furan were also found to be effective (Table 2, entries
3-5), whereas polar solvents, such as methanol and
dimethylformamide, gave little (<5%) or no product
(Table 2, entries 6 and 7). To investigate the compatibility
of the ester functional group, thiourea 7 was prepared
from aniline and methyl 3-(isothiocyanato)propionate in
refluxing methanol and reacted with PhCH2NMe3Br3 in
acetic acid to give an 84% yield of aminobenzothiazole
819 (Table 3, entry 1). When the cyclization was conducted
(20) Walczy_ski, K.; Guryn, R.; Zuiderveld, O. P.; Timmerman, H.
Arch. Pharm. Pharm. Med. Chem. 1999, 332, 389.
(21) Masuda, K.; Kizawa, H.; Suzuki, T. J P Patent 75-74155, J une
18, 1975. Chem. Abstr. 1976, 86, 122716.
(18) Hunter, R. F.; Parken, E. R.; Short, E. M. J . Chem. Soc., Abstr.
1959, 784.
(19) Ambartsumova, R. F. Chem. Heterocycl. Compd. 1997, 33, 859.
8694 J . Org. Chem., Vol. 68, No. 22, 2003

TABLE 4. In flu en ce of 3-P h en yl Su bstitu tion in th e
Hu ger sch off Rea ction Usin g 1
SCHEME 3
We initially reacted substituted anilines, methyl isothio-
cyanate, and 1, but the only products detected were
brominated aniline hydrobromide salts 28 because aniline
is highly activated for electrophilic bromination and
protonated bromoanilines are inert to further reaction
with alkyl isothiocyanate. Therefore, we adopted an
alternative strategy in which 4 was prepared by the
reaction of phenyl isothiocyanate and methylamine hy-
drochloride in the presence of DBU and 1 in either CH2-
Cl2 or THF (Table 5, entries 1 and 2). We anticipated
that the arylthioureas would form in situ from aryl
isothiocyanates and amines and then spontaneously
convert to the desired 2-aminobenzothiazoles in the
presence of 1. The treatment of phenyl isothiocyanate
with propylamine and 1 in methylene chloride was
complete in 18 h to give 29 in 73% yield (Table 5, entry
3). Similarly, reaction of phenyl isothiocyanate and
piperidine afforded aminobenzothiazole 3020,27 in 69%
yield (Table 5, entry 4). Phenyl isothiocyanate was stirred
with methyl 4-aminobutyrate hydrochloride, triethy-
lamine, and 1 furnishing amino ester 31 in 38% yield
(Table 5, entry 5).
starting
entry material
R
reaction conditions product
% yield
1
2
3
4
14
16
19
22
MeO AcOH/rt/30 min
Me
Br
15
87
AcOH/rt/30 min
AcOH/rt/18 h
17, 18
20, 21
23
88 (mixture)
70 (mixture)
<5
NO2 AcOH/rt/2d
SCHEME 1
provided a minor amount (<5%) of 2-(methylamino)-
nitrobenzothiazole 23 (uncharacterized regioisomeric
ratio, Table 4, entry 4). 4-Methylphenylthiourea 24 was
reacted with 1 in acetic acid for 18 h to provide ami-
nobenzothiazole 2522 in 69% yield, and 2-methylamino-
6-bromobenzothiazole 5 was also prepared in 75% yield
(Scheme 1). The substituent effects we observed support
a bromine-mediated cyclization process involving elec-
trophilic addition to the thiocarbonyl of the thiourea to
afford 26 as a transient intermediate, which is then
attacked by the π system of the aromatic ring to give 27
followed by rapid formation of 4 (Scheme 2).23,24
TABLE 5. Dir ect Syn th esis of
2-Alk yla m in oben zoth ia zoles fr om Ar ylisoth iocya n a tes
SCHEME 2
We investigated the direct reaction of substituted
anilines with tetrabutylammonium thiocyanate and pre-
pared riluzole (32), a marketed therapeutic for the
treatment of amylotrophic lateral sclerosis (ALS).25 Com-
pound 32 was synthesized in 61% isolated yield by
condensing equimolar amounts of 4-(trifluoromethoxy)-
aniline, tetrabutylammonium thiocyanate, and 1 in
dichloromethane at room temperature (Table 6, entry 1).
We also prepared 32 by reaction of the aniline with 1
molar equiv of ammonium thiocyanate and 1 in aceto-
nitrile in 71% yield (Table 6, entry 2). In addition,
p-toluidine and 4-bromoaniline were reacted with nBu4-
SCN and 1 in methylene chloride to provide 2-aminoben-
We extended this synthetic methodology to the direct
(one-pot) synthesis of aminobenzothiazoles (Scheme 3).
(22) Pande, A. V.; Lokhande, S. R.; Patel, M. R.; Khadse, B. G.
Indian Drugs 1982, 19, 342.
(23) Bohrisch, J .; Patzel, M.; Grubert, L.; Liebscher, J . Phos. Sulfur
Silicon 1993, 84, 253.
(24) Huang, Z.-T.; Yang, J .-K. Heteroatom Chem. 1992, 3, 487.
(25) Mizoule, J . U.S. Patent 4,370,338, J an 25, 1983.
(26) Iwakura, Y.; Kurita, K. Bull. Chem. Soc. J pn. 1970, 43, 2535.
(27) Grube, H.; Suhr, H. Chem. Ber. 1969, 102, 1570.
J . Org. Chem, Vol. 68, No. 22, 2003 8695

TABLE 6. Dir ect Syn th esis of
2-Alk yla m in oben zoth ia zoles Usin g R4NSCN
night. The reaction was diluted with CH2Cl2 (25 mL) and
neutralized with aqueous NaHCO3. The organic layer was
washed with H2O, dried over Na2SO4, filtered, and concentrated
to provide a residue. The crude product was purified by tapered
preparative TLC (2% MeOH in CHCl3) and furnished 140.2 mg
1
(73%) of 29 as an off-white crystalline solid: mp 79-80 °C; H
NMR (DMSO-d6 300 MHz) δ 8.00-7.98 (m. 1H, NH), 7.64 (d, J
) 7.8 Hz, 1H), 7.37 (d, J ) 7.9 Hz, 1H), 7.23-7.18 (m, 1H), 7.02-
6.97 (m, 1H), 3.3 (q, J ) 6.8 Hz, 2H), 1.66-1.54 (m, 2H), 0.93 (t,
J ) 7.4 Hz, 3H); 13C NMR (DMSO-d6 75.5 MHz) δ 166.05, 152.63,
130.10, 125.37, 120.73, 120.61, 117.78, 45.65, 21.93, 11.31; MS
MH+ (rel int) 193.1 (100). Anal. Calcd for C10H12N2S: C, 62.47;
H, 6.29; N, 14.57; S, 16.68. Found: C, 62.29; H, 6.25; N, 14.47;
S, 16.50.
entry
R
R′
solvent
product
% yield
1
2
3
4
CF3O
CF3O
Me
Bu
H
Bu
Bu
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
32
32
33
34
61
71
40
41
Br
Meth yl 2-[(3-Ca r boxyp r op yl)a m in o]ben zoth ia zole (31).
A mixture of methyl 4-aminobutyrate (154.1 mg, 1.003 mmol)
and triethylamine 155 µL, 1.11 mmol) in CH2Cl2 (5 mL) was
stirred for 15 min and then treated with phenyl isocyanate (120
µL, 1.00 mmol). The resultant mixture was stirred for 1 h at
room temperature, treated with 1 (390.5 mg, 1.00 mmol), and
stirred overnight. The reaction was diluted with CH2Cl2 (25 mL)
and neutralized with aqueous NaHCO3. The organic layer was
washed with H2O, dried over Na2SO4, filtered, and concentrated
to provide a residue. The crude product was purified by tapered
preparative TLC (2% MeOH in CHCl3) and furnished 95.0 mg
(38%) of 31 as an off-white solid: mp 110-111 °C; 1H NMR
(DMSO-d6 300 MHz) δ 8.02 (t, J ) 5.2 Hz, 1H, NH), 7.65 (d, J
) 7.7 Hz, 1H), 7.37 (d, J ) 8.0 Hz, 1H), 7.21 (t, J ) 7.5 Hz, 1H),
7.00 (t, J ) 8.0 Hz, 1H), 3.59 (s, 3H), 3.40-3.32 (m, 2H), 2.41 (t,
J ) 7.4 Hz, 2H), 1.90-1.80 (m, 2H); 13C NMR (DMSO-d6 75.5
MHz) δ 172.94, 165.97, 152.52, 130.14, 125.40, 120.78, 120.74,
117.88, 51.19, 43.01, 30.59, 24.08; MS MH+ (rel int) 251.1 (100).
Anal. Calcd for C12H14N2O2S: C, 57.58; H, 5.64; N, 11.19; S,
12.81. Found: C, 57.54; H, 5.73; N, 11.13; S, 12.62.
zothiazoles 33 and 343 in 40 and 41% yields, respectively
(Table 6, entries 3 and 4).
Con clu sion
PhCH2NMe3Br3 (1) is a stable, electrophilic bromine
source for the conversion of substituted arylthioureas to
2-aminobenzothiazoles (Hugerschoff reaction) under mild
conditions in a variety of solvents with good yields. One
of the key benefits for this reagent when compared with
molecular bromine is ease of addition and handling,
which minimizes the risk of forming brominated side
products.16,17 We have extended the use of this reagent
to a direct, one-pot synthesis of 2-aminobenzothiazoles
from either aryl isothiocyanates and amines or tetrabu-
tylammonium thiocyanate and anilines in the presence
of a stoichiometric amount of PhCH2NMe3Br3.
2-Am in o-6-m eth ylben zoth ia zole (33). To a mixture of
p-toluidine (215.6 mg, 2.01 mmol) and tetrabutylammonium
thiocyanate (604.8 mg, 2.01 mmol) in CH2Cl2 (12 mL) was added
1 (784.3 mg, 2.01 mmol) at ambient temperature. The reaction
mixture was stirred for 1 d. The reaction mixture was diluted
with CH2Cl2 (40 mL) and neutralized with aqueous NaHCO3,
and the organic layer was washed with H2O (50 mL), dried over
Na2SO4, filtered, and concentrated to provide a residue. The
crude product was purified by tapered preparative TLC (50%
EtOAc in heptane) and yielded 131.0 mg (40%) of 33 as a white
Exp er im en ta l Section
Syn th esis of 2-(Meth yla m in o)ben zoth ia zole (4). Gen er a l
P r oced u r e for th e Hu ger sch off Rea ction Usin g P h CH2-
NMe3Br 3. N-Methyl-N′-phenylthiourea 3 (164.6 mg, 1.000 mmol)
was dissolved in acetic acid (5 mL) and treated with 1 (390.6
mg, 1.002 mmol) at ambient temperature. The reaction mixture
was stirred for 5 h and was slowly poured into ice-cold saturated
NaHCO3 and extracted into EtOAc (3 × 40 mL) The organic
extracts were dried over Na2SO4, filtered, and concentrated. The
isolated residue was purified by preparative TLC eluting with
2% MeOH in CHCl3 and gave 131.4 mg (81%) of 4 as a white
solid: mp 140-141 °C (lit.16 215 °C); 1H NMR (DMSO-d6 300
MHz) δ 7.93-7.91 (m. 1H), 7.67-7.64 (m, 1H), 7.38 (d, J ) 7.7
Hz, 1H), 7.24-7.19 (m, 1H), 7.03-6.98 (m, 1H), 2.94-2.93 (m,
3H); 13C NMR (DMSO-d6 75.5 MHz) δ 166.72, 152.60, 130.23,
125.41, 120.80, 120.68, 117.87, 30.39; MS MH+ (rel int) 165.2
(100). Anal. Calcd for C8H8N2S: C, 58.51; H, 4.91; N, 17.06; S,
19.52. Found: C, 58.27; H, 4.95; N, 17.07; S, 19.41.
1
crystalline solid: mp 132.5-133.5 °C; H NMR (DMSO-d6 300
MHz) δ 7.43 (s, 1H), 7.31 (s, 2H, 2NH), 7.21 (d, J ) 8.2 Hz, 1H),
2.30 (s, 3H); 13C NMR (DMSO-d6 75.5 MHz) δ 166.02, 151.03,
131.39, 130.22, 126.76, 121.15, 117.77, 21.08; MS MH+ (rel int)
165.2 (100). Anal. Calcd for C8H8N2S: C, 58.51; H, 4.91; N, 17.06;
S, 19.52. Found: C, 58.47; H, 4.94; N, 16.99; S, 19.57.
Ack n ow led gm en t. We thank Profs. Daniel Comins
and Barry Snider for their suggestions and advice.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods and experimental procedures to prepare 5, 8, 10,
12, 13, 15, 17/18, 20/21, 25, 32, and 34. This material is
available free of charge via the Internet at http://pubs.acs.org.
Dir ect P r ep a r a tion of 2-(P r op yla m in o)ben zoth ia zole
(29). A mixture of phenyl isocyanate (120 µL, 1.00 mmol) and
propylamine (85 µL, 1.03 mmol) was dissolved in CH2Cl2 (5 mL),
stirred for 30 min, and then treated with 1 (390.2 mg, 1.00 mmol)
at room temperature. The reaction mixture was stirred over-
J O0349431
8696 J . Org. Chem., Vol. 68, No. 22, 2003