An efficient acid- and metal-free one-pot synthesis of benzothiazoles from carboxylic acids

Article abstract of DOI:10.1055/s-2005-872092

Carboxylic acids are converted to benzothiazoles in a one-pot reaction with thionyl chloride followed by treatment with 2-aminothiophenol under acid- and catalyst-free conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872092

PAPER
2521
An Efficient Acid- and Metal-Free One-Pot Synthesis of Benzothiazoles from
Carboxylic Acids
O
S
ne-Pot Synth
a
esis of Be
n
n
zothiazoles
t
C
o
rboxylic Ac
s
ids h Rudrawar, Atul Kondaskar, Asit K. Chakraborti*
National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160062, India
Fax +91(172)2214692; E-mail: akchakraborti@niper.ac.in
Received 7 March 2005; revised 25 April 2005
and toxic substances, requirement of excess of reagents/
Abstract: Carboxylic acids are converted to benzothiazoles in a
one-pot reaction with thionyl chloride followed by treatment with 2-
aminothiophenol under acid- and catalyst-free conditions.
catalysts, and harsh reaction conditions. The products ob-
tained under metal-catalyzed conditions are frequently
contaminated with trace amount of metals, due to strong
coordinating property of thiazole moiety and pose prob-
lem in biological testing. Thus, these disadvantages ne-
cessitate the development of alternate synthetic route.
Key words: benzothiazoles, carboxylic acids, thionyl chloride, 2-
aminothiophenol, acid-free, catalyst-free
Benzothiazoles constitute an important class of com-
pounds with profound interest to medicinal/industrial
chemists, as compounds bearing the benzothiazolyl moi-
ety exhibit diverse biological properties such as antitu-
X
S
B
S
N
A
SH
R
Z
R
Y
N
H
R
NH2
1
1
2
3
mour,
broad spectrum Ca channel antagonist, inhibition of en-
antimicrobial,
+
antiglutamate/antiparkinson ,
4
X = H, Cl, Br, I, SMe; Y = O, Se; Z = H, OH, OR, NH2, Cl
2
5
zymes such as aldose reductase, monoamine oxidase, li- Scheme 1 Strategies for the synthesis of benzothiazoles
6
7
poxygenase, cyclooxygenase, acetylcholine esterase,
8
9
1
thrombine, proteases, H -K ATPase, carbonic anhy-
0
11
+
+
12
We felt that, a direct conversion of carboxylic acids to
benzothiazoles (strategy A, Scheme 1) under acid- and
catalyst-free conditions should be the method of choice.
1
drase, HCV helicase, plant growth regulation, and
3
14
15
1
have industrial applications as antioxidants and vulcani-
6
1
7
zation accelerators.
–
However, the poor leaving group property of the OH an-
The methodologies developed following the strategy A ion does not make the condensation feasible. Thus, we re-
(
with carboxylic acids in the presence of polyphosphoric carboxylic acids with 1 under microwave irradiation.
Scheme 1) involve the reaction of 2-aminothiophenol (1) cently developed a new method by direct condensation of
2
3
1
4,18
19
20
acid
ides, aldehydes under microwave irradiation catalyzed acids due to the loss of the carboxylic acid through subli-
or P O -MeSO H, selenoesters, selenoam- The reaction worked less well with aromatic carboxylic
2 5 3
2
1
2
2
by silica or montmorillonite clay, and esters under heat- mation and decarboxylation. In an alternate strategy, the
2
3
ing at 160 °C or reflux in toluene in the presence of hydroxyl group of the carboxylic acid was converted to
33
2
4
Me Al. The strategy B (Scheme 1) includes oxidative phenolate moiety to serve as a better leaving group.
radical cyclization of thioanilides by potassium ferricya- However, the use of 1-methyl-2-pyrrolidone (NMP) as
3
1
8,25
nide,
base-promoted intramolecular nucleophilic aro- solvent and the additional synthetic step required to form
matic substitution of o-halothiobenzanilides in NMP or the aryl esters do not fulfill the projected objectives. The
2
6
DMF, and demethylative cyclization of o-(methyl- use of acid chloride increases the electrophilicity of the
2
7
thio)anilides with phosphonitrile dichloride. Other carbonyl carbon but one feels the necessity to use a base
methods are reaction of copper(I) thiobenzoate with 2-io- either to increase the nucleophilicity of the thiol group or
2
8
34
doaniline in HMPT, treatment of 1 with haloaromatics more importantly to scavenge the liberated HCl. Brem-
35
involving palladium-catalyzed carbonylation under high billa et al. used NMP as solvent that served as scavenger
2
9
pressure, p-TsOH-catalyzed degradative cyclization of 1 of the liberated HCl. However, the method was limited to
with b-chlorocinnamaldehyde derivatives under micro- the commercial availability of the acid chloride and did
3
0
wave irradiation, and palladium-catalyzed Suzuki cou- not include substrates having a hydrogens that are suscep-
pling reaction of 2-bromobenzothiazoles with arylboronic tible to undergo competitive ketene formation. Further-
3
1
acids. These methodologies suffer from one or more of more, the high boiling point and miscibility in water of
the disadvantages such as the lack of ease of availability/ NMP make the solvent recovery difficult and the process
preparation of the starting material, prolonged reaction becomes unattractive both on economic and environmen-
time (four hours to four days), use of costly, air sensitive, tal aspects. The use of diisopropylethylamine as proton
scavenger was associated with the formation of azoxyben-
zene derivative as the byproduct during the reaction of 1
36
with acid chlorides in DMF.
SYNTHESIS 2005, No. 15, pp 2521–2526
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x.
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x
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Advanced online publication: 20.07.2005
DOI: 10.1055/s-2005-872092; Art ID: Z05105SS
Georg Thieme Verlag Stuttgart · New York
©

2
522
S. Rudrawar et al.
PAPER
We thought that in situ generation of the acid chloride ing the expected product in NMP at room temperature
should solve the problem of commercial availability of (entry 7) and at 100 °C (entry 8) after 1 hour. We pre-
–
acid chlorides and the use of a nonpolar reaction medium sumed that in NMP, the naked Cl , generated from the lib-
37,38
circumvent the problem of competitive side reaction of erated HCl, acts as base
for proton abstraction form
acid chlorides bearing a hydrogens and provide a cost ef- acid chloride having a hydrogens and makes the method-
fective synthesis. Additionally, the liberated HCl should ology unsuitable for aliphatic acid chlorides. Thus, vari-
activate the intermediate thioacylated derivative for nu- ous acid chlorides were treated with 1 in toluene and
cleophilic attack by the ortho-amino group and make the excellent results were obtained in most of the cases
cyclization facile and effective under mild condition.
(Table 2).
To test this hypothesis, commercially available phenyl-
acetyl chloride (2, 1 equiv) was treated with 1 (1 equiv) at
room temperature under solvent-free conditions. We were
delighted to observe that 2-benzylbenzothiazole (3) was Entry
obtained in 90% yield in one hour. In trying to establish
Table 2 Synthesis of Benzothiazoles by the Reaction of 1 with Var-
a
ious Acid Chlorides
b
Acid Chloride
Time (h)
0.25
0.5
Yield (%)
1
CH COCl
3
100
80
93
95
97
90
the reproducibility, we noticed a wide variation (50–90%)
in product yields from batch to batch experiments and bis-
2-aminophenyl)disulfide was obtained as byproduct in
2
3
4
5
CH CH COCl
3
2
(
t-BuCOCl
0.25
0.25
0.25
1
those cases where the yields of 3 were less. We thought
that the batchwise variation may be due to the trapping of
the unreacted acid chloride by the precipitated solid prod-
uct (the intermediate thioacylated derivative and the ben-
zothiazole) and the use of a suitable solvent should
circumvent this problem. Therefore, 2 was treated with 1
in various solvents at room temperature (Table 1).
PhCH COCl
2
PhCOCl
6
(E)-PhCH=CHCOCl
a
The acid chloride (2.5 mmol) was treated with 1 (2.5 mmol) in tol-
uene (2.5 mL) at r.t.
b
Isolated yield of the corresponding benzothiazole.
Table 1 Effect of Solvent on Benzothiazole Formation from the Re-
a
action of 1 with 2
Since many acid chlorides are not commercially available,
we planned to synthesize benzothiazoles from carboxylic
acids in a one-pot reaction by in situ preparation of the
acid chloride. In a separate experiment, phenylacetic acid
b
Entry
Solvent
toluene
(CH ) O
Yield (%)
1
2
3
4
5
6
7
92
82
73
72
76
65
47
2
4
(
1 equiv) was treated with thionyl chloride (1.2 equiv) un-
(CH CH ) O
2
der neat condition at 80 °C for one hour followed by 2-
aminothiophenol (1, 1 equiv) in toluene at room tempera-
ture for one hour resulting in the formation of 3 in 98%
yield. To establish the generality, various carboxylic acids
were subjected to benzothiazole formation following the
one-pot reaction (Table 3).
2
2 2
(CH ) Cl
2
2
2
MeCN
MeNO2
NMP
Table 3 One-Pot Synthesis of Benzothiazoles from Various Car-
a
boxylic Acids
c
8
NMP
53
a
b,c
Compound 2 (2.5 mmol) was treated with 1 (2.5 mmol) in the sol-
vent (2.5 mL) at r.t. (except entry 8) for 1 h.
HPLC yield of 3.
The reaction was carried out at 100 °C.
Entry
Carboxylic Acid
Yield (%)
b
c
n CO2H
R
1
2
3
4
R = H, n = 1
98
99
92
97
The best results were obtained in nonpolar solvent such as
toluene affording 3 in consistent yields (92–100%) on re-
peated attempts (Table 1). Reasonable yields were ob-
tained in weakly polar solvents such as (CH ) O,
R = 4-OMe; n = 1
R = H, n = 2
2
4
(
ever, inferior results were obtained with aprotic polar sol-
CH CH ) O , (CH ) Cl and MeCN (entries 2–5). How-
R = H, n = 3
2
2 2
2
2 2
2
R4
R3
1
CO2H
vents such as MeNO and NMP (entries 6–8). The better
2
results obtained in weakly polar solvents (entries 2–5) jus-
tified the role of in situ liberated HCl in catalyzing the
condensation in final step. Although NMP has been used
R1
R2
2
3
4
5
6
R = R = R = R = H
98
99
3
5
as a solvent during the reaction of acid chloride with 1,
we observed the formation of a complex mixture contain-
1
R = R = R = H, R = OMe
2
4
3
Synthesis 2005, No. 15, 2521–2526 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Benzothiazoles from Carboxylic Acids
2523
Table 3 One-Pot Synthesis of Benzothiazoles from Various Car-
a
boxylic Acids (continued)
The reactions were carried out in two stages. Initially, the
carboxylic acid was treated with thionyl chloride (1.2
equiv) under neat conditions at 80 °C till complete con-
sumption of the carboxylic acid (1–3 h). The progress of
the acid chloride formation was monitored by quenching
an aliquot portion of the reaction mixture with a few drops
of MeOH followed by TLC. The disappearance of the
starting carboxylic acid and formation of a new spot
b,c
Entry
Carboxylic Acid
Yield (%)
1
R = R = R = H, R = Cl
2
4
3
7
8
9
99
98
0
1
R = R = R = H, R = NO
2
4
3
2
1
2
R = R = R = H, R = NH
4
3
2
3
9
(
methyl ester) revealed completion of acid chloride for-
1
2
4
3
R = R = R = H, R = OH
1
1
1
1
1
1
0
1
2
3
4
5
0
mation. A direct monitoring was not feasible due to the
trailing effect of the acid chloride on the TLC plate. In the
second stage, excess thionyl chloride was distilled off and
the acid chloride treated with 2-aminothiophenol (1, 1
equiv) in toluene at room temperature for one hour. We
observed an exothermic reaction during the addition of 1
to the acid chloride. Therefore, the mixing of the acid
chloride and 1 was carried out at 0–5 °C. Excellent results
were obtained in most of the cases (Table 3). The reaction
worked well for aromatic (entries 5–8, 11–15, 24, and 25),
heteroaromatic (entries 21–23), a,b-unsaturated (entries
1 3
R = R = OMe, R = R = H
2
4
87
98
72
52
1
R = R = H; R = R = OMe
4
2
3
1 4
R = H; R = R = R = OMe
2
3
1
R = H; R = R = OMe, R = OH
2
4
3
1
R = CO H, R = R = R = H
2
3
4
d
94
2
X
CO2H
R
1
9 and 20), arylalkyl (entries 1 – 4, 16 – 18 and 26) and
1
1
1
6
7
8
R = H, X = O
R = Cl, X = O
R = H, X = S
83
88
70
aliphatic carboxylic acids (entry 27). Excellent chemose-
lectivity was observed for substrates susceptible to under-
go nucleophilic substitution reactions, Michael addition,
and reduction as the sulfhydryl moiety is a good nucleo-
phile and thiols are capable to function as single electron-
CO2H
R
40
transfer agents. No aromatic nucleophilic substitution of
41
42
the chloro /nitro (entries 7, 8, and 17) and reduction of
1
2
2
9
0
1
R = H
99
96
80
43
the nitro group (entry 8) took place. No nucleophilic
substitution of the phenoxide moiety was observed during
the reaction with phenoxy, 4-chlorophenoxy, and thiophe-
noxy acetic acids (entries 16–18). Although thiols are
R = OMe
CO H
2
44
commonly used for aryl methyl ether cleavage, no com-
petitive demethylation was observed for substrates con-
taining aryl methyl ether functionality (entries 2, 6, 11–
14, and 20). Cinnamic acid (entry 19) and 4-methoxycin-
namic acid (entry 20) afforded the desired benzothiazole
N
CO2H
X
2
2
2
3
X = S
99
90
45
derivative without any competitive Michael addition or
4
6
X = O
reduction of the double bond. However, the presence of
an amino or hydroxyl group in the carboxylic acid was
found to be detrimental for the formation of the desired
product. No significant benzothiazole formation took
place with 4-hydroxy- and 4-aminobenzoic acids (entries
9 and 10). The TLC of the aliquot portion of the reaction
mixture after quenching with MeOH did not reveal the
formation of the corresponding methyl esters. It is antici-
pated that self condensation involving the acyl chloride
and the hydroxyl/amino groups leads to the side product
formation. The reaction of 3,5-dimethoxy-4-hydroxyben-
zoic acid afforded a 52% yield (entry 14). 2-Hydroxy-
naphthalene and 1-hydroxynaphthalene were identified
R
2
2
2
4
5
6
R = 1-CO H
2
90
93
93
R = 2-CO H
2
CO H
2
d
2
7
HO C
2
94
CO2H
(
GC-MS) as the major products during the reactions with
a
The carboxylic acid (1 equiv) was treated with thionyl chloride (1.2
equiv) at 80 °C for 1 h followed by addition of 1 (1 equiv) at r.t. in
2-hydroxy-1-naphthoic acid and 1-hydroxy-2-naphthoic
acid, respectively, presumably due to decarboxylation.
The reactions with dicarboxylic acids such as phthalic
acid (entry 15) and succinic acid (entry 27) led to the for-
mation of the corresponding monobenzothiazoles. In gen-
eral, the product obtained after the usual work-up was of
sufficient purity (GC-MS) and did not require further pu-
toluene for 1 h.
b
Isolated yield of the corresponding 2-substituted benzothiazole.
1
c
13
All compounds were characterized by IR, H NMR, C NMR and
MS.
d
The corresponding monobenzothiazole was formed.
Synthesis 2005, No. 15, 2521–2526 © Thieme Stuttgart · New York

2
524
S. Rudrawar et al.
PAPER
1
rification. Wherever required, the purification was carried
out either by crystallization (10:1 hexane–EtOAc) or
passing through a column of silica gel (60–120 mesh) and
eluting with 10:1 hexane–EtOAc. Recently a liquid-phase
synthesis of 2-substituted benzothiazole by the reaction of
acid fluoride with 1 in the presence of triethylamine in
H NMR (300 MHz, CDCl ): d = 7.96 (d, J = 8.06 Hz, 1 H), 7.77 (d,
J = 7.92 Hz, 1 H), 7.43–7.38 (m, 1 H), 7.31–7.16 (m, 6 H), 3.09 (t,
J = 7.54 Hz, 2 H), 2.72 (t, J = 7.37 Hz, 2 H), 2.17 (quint, J = 7.4 Hz,
3
2
H).
1
3
C NMR (300 MHz, CDCl ): d = 171.66, 141.10, 132.02, 131.27,
3
1
3
28.34, 128.28, 125.88, 125.77, 124.55, 122.35, 121.34, 34.99,
3.46, 30.96.
4
7
CH Cl has been reported. However, the use of DCC,
2
2
+
MS (CI): m/z = 254 [M + H] .
HF and pyridine for the conversion of the carboxylic acids
to acid fluorides do not make this method attractive as all Anal. Calcd for C16
H15NS: C, 75.85; H, 5.97; N, 5.53. Found: C,
7
5.66; H, 5.87; N, 5.48.
of these reagents are toxic. The mercapto group of 1 reacts
with CH Cl and led to the formation of the corresponding
chloromethyl ether as the major side reaction. No desired
product was obtained during the reaction with phthalic ac-
id.
2
2
2-(3,4-Dimethoxyphenyl)benzothiazole
Mp 132–134 °C.
IR (KBr): 2956, 2939, 2840, 1599, 1521, 1482, 1431, 1337, 1312,
1
–
261, 1167, 1146, 1074, 1018 cm .
1
In conclusion, the present work describes an efficient and
new methodology for synthesis of 2-substituted benzothi-
azoles form carboxylic acids through in situ formation of J = 7.31 Hz, 1 H), 7.37 (t, J = 7.50 Hz, 1 H), 6.96 (d, J = 8.36 Hz, 1
1
H NMR (300 MHz, CDCl ): d = 8.00 (d, J = 8.06 Hz, 1 H), 7.87 (d,
3
J = 7.76 Hz, 1 H), 7.75 (s, 1 H), 7.62 (d, J = 8.32 Hz, 1 H), 7.48 (t,
acid chloride in a one pot reaction under acid-free and cat- H), 4.03 (s, 3 H), 3.96 (s, 3 H).
13
alyst-free conditions.
C NMR (300 MHz, CDCl ): d = 167.92, 154.03, 151.53, 149.29,
3
1
1
34.82, 126.57, 126.21, 124.85, 122.77, 121.47, 121.12, 110.96,
09.72, 56.00.
+
MS (CI): m/z = 272 [M + H] .
One-Pot Synthesis of Benzothiazoles from Carboxylic Acids;
General Procedure
Phenylacetic acid (340 mg, 2.5 mmol) was treated with SOCl (357
Anal. Calcd for C H NO S: C, 66.40; H, 4.83; N, 5.16. Found : C,
1
5
13
2
2
66.21; H, 4.89; N, 5.14.
mg, 0.22 mL, 3.0 mmol, 1.2 equiv) at 80 °C till an aliquot portion
on quenching with a few drops of MeOH revealed the complete
consumption of phenylacetic acid and appearance of a new spot
(methyl ester) in the TLC (1 h). Excess SOCl was distilled off and
2
the cooled (0–5 °C, ice-water) reaction mixture treated with 1 (313
2-(4-Hydroxy-3,5-dimethoxyphenyl)benzothiazole
Mp 142–144 °C.
IR (KBr): 3480, 2938, 1614, 1529, 1481, 1451, 1427, 1366, 1334,
1
–
1
282, 1211, 1199 cm .
mg, 0.268 mL, 2.5 mmol) in toluene (5 mL) followed by stirring
1
(
(
magnetically) at r.t. for 1 h. The mixture was diluted with EtOAc
10 mL) and sat. aq NaHCO (5 mL). The organic layer was sepa-
H NMR (300 MHz, CDCl ): d = 8.03 (d, J = 8.04 Hz, 1 H), 7.87 (d,
3
3
J = 7.79 Hz, 1 H), 7.47 (t, J = 7.60 Hz, 1 H), 7.38–7.34 (m, 3 H),
6.01 (s, 1 H, OH, exchangeable with D O), 3.99 (s, 6 H).
rated and the aqueous layer extracted with EtOAc (3 × 5 mL). The
combined EtOAc extracts were washed with H O (3 × 5 mL), dried
2
2
13
C NMR (300 MHz, CDCl ): d = 168.13, 154.07, 147.35, 137.71,
3
(Na SO ) and concentrated under reduced pressure to afford 3 (550
mg, 98%), identical (mp, IR, NMR and MS) with an authentic sam-
2 4
1
5
34.82, 126.25, 125.11, 124.87, 122.85, 121.54, 121.48, 106.64,
6.59.
3
2
ple. The remaining reactions were carried out following this gen-
eral procedure. The physical data (mp, IR, NMR and MS) of all
reported compounds were identical with those of the literature re-
ports (Table 3).
+
MS (CI): m/z = 288 [M + H] .
Anal. Calcd for C H NO S: C, 62.70; H, 4.56; N, 4.87. Found : C,
3
1
5
13
6
2.91; H, 4.47; N,4.90.
Scale up of 2-(4-Chlorophenoxymethyl)benzothiazole
4-Chlorophenoxyacetic acid (3.72 g, 20 mmol) was treated with
SOCl (2.97 g, 1.88 mL, 3.0 mmol, 1.25 equiv) at 80 °C till an ali-
quot portion on quenching with a few drops of MeOH revealed the
complete consumption of 4-chlorophenoxyacetic acid and appear-
ance of a new spot (methyl ester) in the TLC (2 h). Excess SOCl2
was distilled off and the cooled (0–5 °C, ice-water) reaction mixture
treated with 1 (2.5 g, 2.13 mL, 20 mmol) in toluene (50 mL) fol-
lowed by stirring (magnetically) at r.t. for 2 h. The mixture was di-
2-(4-Chlorophenoxymethyl)benzothiazole
Mp 105–107 °C.
2
IR (KBr): 3057, 2919, 1598, 1525, 1492, 1454, 1365, 1315, 1286,
1
–
249, 1188, 1172, 1096, 1048, 1009, 819 cm .
1
1
H NMR (300 MHz, CD OD): d = 8.03 (d, J = 8.07 Hz, 1 H), 7.90
3
(d, J = 7.94 Hz, 1 H), 7.53–7.48 (m, 1 H), 7.41 (t, J = 7.56 Hz, 1 H),
7.25 (d, J = 8.93 Hz, 2 H), 6.96 (d, J = 8.93 Hz, 2 H), 5.46 (s, 2 H).
13
C NMR (300 MHz, CDCl ): d = 167.75, 156.26, 152.79, 134.90,
3
luted with EtOAc (25 mL) and sat. aq NaHCO (20 mL). The
3
organic layer was separated and the aqueous layer extracted with
EtOAc (3 × 25 mL). The combined EtOAc extracts were washed
1
29.45, 126.76, 126.15, 125.27, 123.07, 121.72, 116.15, 67.95.
+
MS (CI): m/z = 276 [M + H] .
with H O (3 × 25 mL), dried (Na SO ) and concentrated under re-
4
2
2
Anal. Calcd for C H ClNOS: C, 60.98; H, 3.66; N, 5.08. Found:
1
4
10
duced pressure to afford 2-(4-chlorophenoxymethyl)benzothiazole
C, 61.21; H, 3.58; N, 5.12.
(
(
4.91 g, 89%) after crystallization from EtOAc and hexane mixture
1:10).
2-Naphthalen-2-ylbenzothiazole
Mp 124–126 °C.
The physical data of new compounds are provided below.
IR (KBr): 3048, 2922, 2856, 1594, 1497, 1450, 1428, 1362, 1306,
1
2-(3-Phenylpropyl)benzothiazole
Yellow oil.
–1
270, 1174, 1123, 983, 934, 879, 860 cm .
1
H NMR (300 MHz, CDCl ): d = 8.51 (s, 1 H), 8.16 (d, J = 8.53 Hz,
3
IR (neat): 3368, 2921, 1602, 1578, 1514, 1434, 1286, 1241, 1158,
1
1
3
H), 8.09 (d, J = 8.10 Hz, 1 H), 7.92–7.81 (m, 4 H), 7.51–7.45 (m,
H), 7.37–7.32 (m, 1 H).
–
114 cm .
1
Synthesis 2005, No. 15, 2521–2526 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Benzothiazoles from Carboxylic Acids
2525
1
3
C NMR (300 MHz, CDCl ): d = 168.07, 154.22, 135.11, 134.56,
3
(10) Matthews, J. H.; Krishnan, R.; Costanzo, M. J.; Maryanoff,
B. E.; Tulinsky, A. Biophys. J. 1996, 2830.
(11) Caccese, R. G.; DiJoseph, J. F.; Scotnicki, J. S.; Borella, L.
E.; Adams, L. M. Agents Actions 1991, 34, 223.
1
1
33.14, 130.94, 128.78, 127.83, 127.53, 127.41, 126.83, 126.34,
25.20, 124.39, 123.20, 121.61.
+
MS (CI): m/z = 262 [M + H] .
(
12) Sohn, S. K.; Chang, M. S.; Choi, W. S.; Kim, K. B.; Woo, T.
W.; Lee, S. B.; Chung, Y. K. Can. J. Physiol. Pharmacol.
Anal. Calcd for C H NS: C, 78.13; H, 4.24; N, 5.36. Found: C,
11
17
7
8.01; H, 4.36; N, 5.31.
1999, 77, 330.
(
13) Surgue, M. F.; Gautheron, P.; Schmitt, C.; Viader, M. P.;
Conquet, P.; Smith, R. L.; Share, N. N.; Stone, C. A. J.
Pharmacol. Exp. Ther. 1985, 232, 534.
3-Benzothiazol-2-yl-propionic Acid
Mp 88–90 °C.
(
(
(
14) Phoon, C. W.; Ng, P. Y.; Ting, A. E.; Yeo, S. L.; Sim, M. M.
Bioorg. Med. Chem. Lett. 2001, 11, 1647.
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the references cited therein.
16) Ivanov, S. K.; Yuritsyn, V. S. Neftekhimiya 1971, 11, 99;
Chem. Abstr. 1971, 74, 124487m.
IR (KBr): 2922, 2649, 2500 1713, 1505, 1437, 1368, 1314, 1270,
1
–1
249, 1196, 1160 cm .
1
H NMR (300 MHz, CDCl ): d = 9.61 (br s, 1 H), 8.25–6.58 (m, 4
3
H), 3.45 (s, 2 H), 3.01 (s, 2 H).
1
3
C NMR (300 MHz, CDCl ): d = 176.59, 170.27, 152.47, 134.79,
3
1
26.17, 125.07, 122.45, 121.51, 33.00, 28.71.
(17) Monsanto Co., British Patent 1106577, 1968; Chem. Abstr.
1968, 68, 96660.
+
MS (CI): m/z = 208 [M + H] .
(
18) Kashiyama, E.; Hutchinson, I.; Chua, M. S.; Stinson, S. F.;
Phillips, L. R.; Kaur, G.; Sausville, E. A.; Bradshaw, T. D.;
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Anal. Calcd for C H NO S: C, 57.95; H, 4.38; N, 6.76. Found: C,
1
5
0
9
2
7.78; H, 4.49; N, 6.74.
4172.
(
(
19) Boger, D. E. J. Org. Chem. 1978, 43, 2296.
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