Synthesis of benzothiazoles through copper-catalyzed one-pot three-component reactions with use of sodium hydrosulfide as a sulfur surrogate

Article abstract of DOI:10.1002/ejoc.201101773

Copper-catalyzed one-pot three-component reactions of 2-iodoanilines, aldehydes, and NaSH·n H₂O afford benzothiazoles in good yields. When CuCl was employed as a catalyst in the absence of a ligand, a variety of aromatic aldehydes and substituted 2-iodoanilines reacted with NaSH·n H₂O to produce the corresponding 2-arylbenzothiazoles in 70-98 % yields. The copper catalyst plays a key role in C-S bond formation between NaSH·n H₂O and the aryl iodide that was formed from the condensation of 2-iodoaniline and aldehyde. It was found that NaSH·n H₂O functions as a sulfur surrogate and oxidant in the formation of benzothiazole. 2-Iodoanilines, aldehydes, and NaSH·n H₂O afford benzothiazoles in a one-pot reaction in the presence of a copper catalyst. The desired products can be obtainedin moderate to good yields. The copper catalyst plays a key role in C-S bond formation between aryl iodides and NaSH·n H₂O. Copyright

Full text of DOI:10.1002/ejoc.201101773

FULL PAPER
DOI: 10.1002/ejoc.201101773
Synthesis of Benzothiazoles through Copper-Catalyzed One-Pot Three-
Component Reactions with Use of Sodium Hydrosulfide as a Sulfur Surrogate
Namjin Park,[a] Yumi Heo,[a] Manian Rajesh Kumar,[a] Yong Kim,[a] Kwang Ho Song,*[b]
and Sunwoo Lee*[a]
Keywords: Multicomponent reactions / Homogeneous catalysis / Copper / Nitrogen heterocycles / Sulfur heterocycles
Copper-catalyzed one-pot three-component reactions of 2-
oles in 70–98% yields. The copper catalyst plays a key role
iodoanilines, aldehydes, and NaSH·nH2O afford benzo-
in C–S bond formation between NaSH·nH2O and the aryl
thiazoles in good yields. When CuCl was employed as a cata- iodide that was formed from the condensation of 2-iodoan-
lyst in the absence of a ligand, a variety of aromatic alde-
hydes and substituted 2-iodoanilines reacted with
NaSH·nH2O to produce the corresponding 2-arylbenzothiaz-
iline and aldehyde. It was found that NaSH·nH2O functions
as a sulfur surrogate and oxidant in the formation of benzo-
thiazole.
lead to bad environmental problems and a sealing process
is needed in scale-up operations. Another alternative strat-
egy is the cyclization of thioformanilides, which has been
performed with the aid of transition-metal catalysts,[12]
SNAr conditions,[13] radical conditions,[14] and Jacobson’s
method (cyclization of an arylthioamide through the use of
potassium ferricyanide)[15]; see Scheme 1 (b). These meth-
ods suffer from low functional group tolerance in the prepa-
ration of thioformanilides, because of the use of P4S10 or
Lawesson’s reagent in the conversion of the amide to the
corresponding thioamide; see Scheme 1 (c).[16] Recently,
palladium- or copper-catalyzed coupling reactions of 2-
haloanilides and thiol surrogates such as 2-ethylhexyl 3-
mercaptopropionate and Na2S·9H2O have been used in the
Introduction
The synthesis of 2-substituted azoles such as oxazoles,
imidazoles, indazoles, and thiazoles has attracted much at-
tention because of their important roles in bioactive phar-
maceutical compounds and new materials.[1] In particular,
benzothiazoles have been intensively studied and have
found to be employable in biological applications such as
antitumor,[2] anti-inflammatory,[3] antimicrobial,[4] antitryp-
anosomal,[5] anticonvulsant,[6] and antituberculosis[7] agents
and also as tracers for β-amyloid plaques in Alzheimer’s
disease.[8] Benzothiazole moieties are also found in func-
tional molecules such as nonlinear optical materials[9] and
ligands for phosphorescent complexes.[10] Much effort has
therefore been devoted to the development of new method-
ologies for the construction of this privileged structure.
The most common methods of synthesizing benzo-
thiazoles involve condensations of 2-aminothiophenol with
carboxylic acid derivatives or aldehydes; see Scheme 1
(a).[11] However, they have some drawbacks such as their
drastic reaction conditions, tedious workup procedures, and
the difficulties involved in the preparation of 2-aminothio-
phenols, especially substituted ones, which are readily oxi-
dized. In addition, their strong and disagreeable odors can
[a] Department of Chemistry and Institute of Basic Science,
Chonnam National University,
Gwangju 500-757, Republic of Korea
Fax: +82-62-530-3389
E-mail: sunwoo@chonnam.ac.kr
[b] Department of Chemical & Biological Engineering, Korea
University,
Seoul 136-713, Republic of Korea,
E-mail: khsong@korea.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101773.
Scheme 1. Synthesis of benzothiazoles.
1984
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1984–1993

Synthesis of Benzothiazoles through Three-Component Reaction
synthesis of benzothiazoles – see Scheme 1, (d)[17] – but Table 1. Optimization for the synthesis of benzothiazole.[a]
these reactions also need preparation steps for the starting
materials.
In recent decades, the development of multicomponent
methodologies that combine all fragments in one step to
produce the desired product with the aid of transition-metal
catalysis has received considerable attention.[18] To the best
of our knowledge, however, three-component methodology
for the construction of benzothiazoles has rarely been ex-
ploited, and only the synthesis of 2-N-substituted benzo-
thiazoles falls into this category.[19] Very recently, we have
reported the synthesis of 2H-indazoles[20] and benzimid-
azoles[21] through three-component coupling reactions in
the presence of a copper catalyst. In particular, success in
the synthesis of benzimidazoles from 2-haloanilines, alde-
hydes, and NaN3 prompted us to develop benzothiazoles,
which are analogues of azole compounds. Here we report
one-pot, three-component reactions for the construction of
benzothiazoles.
Entry
3
Catalyst [mol-%] Ligand
Additive
Yield [%][c]
1
2
3
4
5
6
3a Pd(OAc)2(5.0)
3a Pd(dba)2 (5.0)
3a Ni(OAc)2(5.0)
3a CuI (5.0)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
36
13
33
94
99
88
98
32
34
23
32
–
3a CuCl (5.0)
3a CuCl2 (5.0)
3a CuCl (2.0)
3a CuCl (2.0)
3a CuCl (2.0)
3a CuCl (2.0)
3a CuCl (2.0)
3a CuCl (2.0)
3b CuCl (2.0)
3c CuCl (2.0)
3a CuCl (2.0)
3a CuCl (2.0)
3a CuCl (2.0)
3a CuCl (2.0)
7
8[d]
9
[f]
NaHCO3
[f]
10
11
12
13
14
15[e]
16[e]
17[e]
Na2CO3
[g]
RuCl3
[f]
H2O2
–
–
–
–
–
–
70
44
35 (40[h]
)
Results and Discussion
TMEDA
l-proline
diketone[i]
40
16
22
To determine the optimum conditions, 2-iodoaniline
(1a), benzaldehyde (2a), and NaSH·nH2O (3a) were em- 18[e]
ployed as model substrates. The results are summarized in
Table 1.
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), and 3 (0.3 or
0.6 mmol) were treated in the presence of the catalyst and MgSO4
(1.2 mmol) in DMSO at 110 °C for 6 h under air. [b] H2O content
(60 wt.-%) determined by TGA analysis. [c] Determined by GC
with internal standard. [d] Compound 3 (0.3 mmol) was used.
[e] Reactions were conducted at 60 °C for 6 h. [f] 0.6 mmol were
employed. [g] 0.015 mmol were employed. [h] Yield after 48 h.
[i] Pentane-2,4-dione.
All reactions were carried out in the presence of MgSO4
to accelerate the condensation of 2-iodoaniline with benz-
aldehyde and to capture the water in the form of sodium
hydrosulfide hydrate (NaSH·nH2O). In addition, the reac-
tions were conducted under air. We first investigated a
variety of transition metals for the formation of 4aa. Palla-
dium[22] and nickel[23] catalysts afforded the benzothiazole
in low yields, even though they have been reported to func- tries 16–18). In view of costs and the yields of the product,
tion as good catalysts in the formation of C–S bonds (En- we employed the following optimized conditions for the
tries 1–3). When copper catalysts were employed,[24] CuI one-pot synthesis of benzothiazoles; 2-haloaniline
and CuCl afforded the desired product in 94% and 99% (1.0 equiv.),
aldehydes
(1.0 equiv.),
NaSH·nH2O
yields, respectively (Entries 4 and 5). The yield of the prod- (2.0 equiv.), CuCl (2.0 mol-%), and MgSO4 (2.0 equiv.) at
uct from copper(II) was somewhat lower than that from 110 °C for 6 h.
copper(I) (Entry 6). Decreasing the amount of the catalyst
To evaluate this catalytic system, a variety of aldehydes
to 2 mol-% also produced the benzothiazole with good were employed in the synthesis of benzothiazoles from 2-
yield (Entry 7). When the amount of NaSH·nH2O was re- iodoaniline (1a). The results are summarized in Table 2.
duced to 1 equiv., however, the yield of the product de-
As expected, 2-phenylbenzothiazole (4aa) was isolated in
creased to 32%. Use of oxidants,[11f,11g,11j,25] which have 99% yield (Entry 1). 3-Fluorobenzaldehyde (2b) afforded
been employed in the synthesis of benzothiazoles, or of an the desired product in good yield (Entry 2), as did ortho-
additional base did not give satisfactory results (Entries 9– substituted benzaldehydes (Entries 3 and 4). Benzaldehydes
12). When Na2S·9H2O[17b] was used as a sulfur source in- bearing electron-donating groups such as methyl, methoxy,
stead of NaSH·nH2O, the desired product was obtained in methylthio, and dimethylamine at the para position gave the
70% yield (Entry 13). Potassium thioacetate, however, pro- corresponding benzothiazoles in 98%, 95%, 80%, and 91%
vided only a 44% yield of the product, even though it was yields, respectively (Entries 5–8). Heteroaromatic aldehydes
a good sulfur surrogate in the synthesis of thioethers from such as thiophene-2-carbaldehyde (2i) and pyridine-2-carb-
aryl halides (Entry 14).[26] A reduction in the reaction tem- aldehyde (2j) showed good yields in the formation of
perature to 60 °C resulted in a 35% yield of the product, benzothiazoles (Entries 9 and 10). 1,4-Benzodioxan-6-carb-
but the yield was not significantly improved even when the aldehyde (2k) and piperonal (2l) afforded the corresponding
reaction time was extended to 48 h (Entry 15). The addition benzaldehydes in 77% and 97% yields, respectively (En-
of a variety of ligands such as amines, amino acids, and tries 11 and 12), and 6-methoxy-2-naphthaldehyde (2m)
diketones did not improve the yields of the product (En- also showed a good yield (Entry 13). 4-Chlorobenzaldehyde
Eur. J. Org. Chem. 2012, 1984–1993
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1985

N. Park, Y. Heo, M. R. Kumar, Y. Kim, K. H. Song, S. Lee
FULL PAPER
Table 2. Synthesis of benzothiazoles from 2-iodoaniline.[a]
[a] Reaction conditions: 1a (3.0 mmol), 2 (3.0 mmol), 3a (6.0 mmol) in the presence of MgSO4 (6.0 mmol) in DMSO at 110 °C for 6 h
(% is isolated yield). [b] No product was obtained.
(2n), however, did not produce the desired product (En-
We propose a reaction pathway (Scheme 2) in which the
try 14). Attempts to employ alkyl aldehydes such as isobut- condensation of 2-iodoaniline and benzaldehyde takes place
yraldehyde (2o) and heteroaromatic aldehydes such as first, the copper-catalyzed coupling reaction between N-
furan-2-carbaldehyde (2p) did not result in the synthesis of benzylidene-2-iodoaniline (A) and NaSH·nH2O then pro-
the benzothiazole, even though the corresponding imines duces the 2-(benzylidenamino)benzenethiol (B) as an inter-
were formed (Entries 15 and 16). Formamides such as pyr- mediate, and the desired product 3 is finally formed through
rolidine-1-carbaldehyde (2q) did not produce the desired cyclization and oxidation.
product, because their condensation reactions with 2-
iodoaniline (1a) did not take place under these reaction
conditions (Entry 17).
We next expanded this method to substituted 2-iodo-
aniline derivatives for the formation of benzothiazoles as
shown in Table 3.
2-Iodoaniline derivatives substituted with a single ad-
ditional halogen atom, such as 5-chloro-2-iodoaniline (1b)
and 4-fluoro-2-iodoaniline (1c), produced the correspond-
ing benzothiazoles in good yields (Entries 1–14). The yields
of the product were similar to those of the products ob-
tained from 2-iodoaniline. 2-Iodoaniline derivatives substi-
Scheme 2. Proposed reaction pathway.
tuted with two additional halogen atoms, such as 2,4-
To investigate the proposed reaction pathway in detail,
dichloro-6-iodoaniline (1d) and 4-chloro-2-fluoro-6-iodoan- we performed several experiments. When 2-iodoaniline was
iline (1e), showed somehow lower yields than those substi- treated with NaSH·nH2O in the presence of CuCl, no prod-
tuted with a single additional halogen atom (Entry 4 vs. En- uct containing a C–S bond was found in the reaction mix-
try 15, and Entries 5 and 12 vs. Entry 16). 2-Iodo-4-(tri- ture (Scheme 3). This result supports the hypothesis that
fluoromethyl)aniline (1f) and 2-iodo-4,6-dimethylaniline the condensation of 2-iodoaniline and benzaldehyde occurs
(1g) afforded the desired benzothiazoles in good yields (En- first, rather than NaSH·nH2O-induced C–S bond forma-
tries 17–26).
tion.
1986
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Synthesis of Benzothiazoles through Three-Component Reaction
Table 3. Synthesis of benzothiazoles from substituted 2-iodoanil-
ines.[a]
Table 3. (Continued)
[a] Reaction conditions: 1a (3.0 mmol), 2 (3.0 mmol), and 3a
(6.0 mmol) in the presence of MgSO4 (6.0 mmol) in DMSO at
110 °C for 6 h. [b] Isolated yields.
Scheme 3. Attempted coupling reaction between 2-iodoaniline and
NaSH·nH2O.
To determine the role of CuCl in this reaction, N-benzyl-
idene-2-iodoaniline (A) was treated with NaSH·nH2O un-
der a variety of reaction conditions, as shown in Scheme 4.
In the absence of CuCl, neither 2-(benzylidenamino)benz-
enethiol (B) nor benzothiazole 4 were found in the reaction
mixture. When the reaction was conducted at 110 °C in the
presence of copper, benzothiazole was formed in 98% yield
with a trace amount of B. When the reaction temperature
was decreased to 60 °C, both 2-(benzylidenamino)benz-
enethiol (B) and benzothiazole 4 were found, in 8% and
35% yields, respectively, in the reaction mixture. This result
supports the hypothesis that 2-(benzylidenamino)benz-
enethiol (B) is an intermediate in the reaction pathway.
Scheme 4. The effect of copper on the synthesis of benzothiazole
from N-benzylidene-2-iodoaniline.
To study reaction steps (iii) and (iv) in detail, 2-(benzylid-
enamino)benzenethiol (B) was treated under a variety of
conditions at 60 °C, as shown in Figure 1.
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1987

N. Park, Y. Heo, M. R. Kumar, Y. Kim, K. H. Song, S. Lee
FULL PAPER
Figure 2. Reaction yields of 4aa at 110 °C and 60 °C. Reaction con-
ditions: 1a (0.3 mmol), 2a (0.3 mmol), 3 (0.6 mmol), and CuCl
(0.006 mmol) in the presence of MgSO4 (0.6 mmol) in DMSO.
copper. However, no related structures such as the amino-
thiol and thioamide were found in the reaction mixture.
These results support the proposed reaction pathway shown
in Scheme 2. It was found that the rate-determining step is
step (ii), because it required a higher temperature than the
other steps.
Figure 1. Synthesis of benzothiazole from 2-(benzylidenamino)-
benzenethiol. Reaction conditions: B (1.0 mmol) was treated in the
presence of MgSO4 (2.0 mmol) in DMSO at 60 °C under the fol-
lowing conditions: a) in the absence of CuCl and NaSH·nH2O un-
der N2, b) CuCl (0.02 mmol) was added in the absence of
NaSH·nH2O under N2, c) NaSH·nH2O (1.0 mmol) was added in
the absence of CuCl under N2, and d) CuCl (0.02 mmol) and
NaSH·nH2O (1.0 mmol) were added under air.
Conclusions
In summary, a copper-based catalytic system has been
developed and successfully applied to one-pot syntheses of
benzothiazoles from 2-iodoanilines, aldehydes, and
NaSH·nH2O. This one-pot reaction system represents a sig-
nificant advantage in not requiring the isolation of the in-
termediate prior to execution of C–S bond formation and
in most instances does not require the preparation of the
starting materials. To the best of our knowledge, this is the
first example of the employment of NaSH·nH2O as a sulfur
source, not only in the synthesis of the benzothiazole, but
also in transition-metal-catalyzed C–S bond formation. In
addition, the employment of NaSH·nH2O offered econ-
omic and environmental advantages, due to its low cost and
odor-free nature. From mechanistic studies, we found the
following: 1) copper is the crucial factor in the formation
of the iminothiol from the reaction between the aryl iodide
and NaSH·nH2O, 2) reaction step (ii) requires higher tem-
peratures than reaction steps (iii) and (iv), and
3) NaSH·nH2O accelerated the rates of reaction steps (iii)
and (iv).
No benzothiazole was formed in the absence of the cop-
per catalyst and NaSH·nH2O under nitrogen; see Figure 1
(a). Benzothiazole was formed in good yield when 2-(benz-
ylidenamino)benzenethiol
(B)
was
treated
with
NaSH·nH2O in the absence of the copper catalyst under
nitrogen; see Figure 1 (c). However, the yield was very low
when the reaction was conducted with only the copper cata-
lyst in the absence of NaSH·nH2O under nitrogen; see Fig-
ure 1 (b). When the optimized conditions, with use of the
copper catalyst, NaSH·nH2O, and air, were employed in
this reaction, the yield of the product was the highest; see
Figure 1 (d). However, we failed to detect the intermediate
C in any of the reaction mixtures. From these results we
inferred that NaSH·nH2O acts not only as a sulfur source,
but also as an oxidant, and that the role of the copper cata-
lyst in the cyclization and oxidation reactions is marginal.
Although 2-(benzylidenamino)benzenethiol (B) produced
the desired benzothiazole in 92% yield at 60 °C, this three-
component reaction of 2-iodoaniline, benzaldehyde, and
NaSH·nH2O required a temperature of 110 °C to produce
a high yield of the product, as shown in Figure 2. Unsatis-
factory yields were obtained when the reaction was con-
ducted at 60 °C.
Experimental Section
General Procedure for the Synthesis of Benzothiazoles from 2-
Iodoaniline: CuCl (14.9 mg, 0.15 mmol), NaSH·nH2O (60 wt.-%,
560.6 mg, 6.00 mmol), 2-iodoaniline (3.00 mmol), benzaldehyde
(3.00 mmol), and MgSO4 (1083.3 mg, 9.00 mmol) were placed in a
small round-bottomed flask. DMSO (10.0 mL) was added and the
reaction mixture was stirred for 6 h at 110 °C under air and then
allowed to cool to room temperature. The reaction mixture was
To study the possible existence of another reaction path-
way in which NaSH·nH2O attacks at the carbon of the im-
ine in N-benzylidene-2-iodoaniline (A) and then produces
the benzothiazole, we carried out trapping experiments to
investigate reaction mixtures in which N-benzylidenaniline
and NaSH·nH2O were allowed to react in the presence of poured into distilled water (10 mL) and extracted with Et2O
1988
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Synthesis of Benzothiazoles through Three-Component Reaction
(3ϫ15 mL). The combined ether extracts were washed with brine
(40 mL), dried with MgSO4, and passed through celite. The solvent
was removed under vacuum and the resulting crude product was
purified by flash chromatography on silica gel (eluent hexane).
2-(4-Methoxyphenyl)benzothiazole (4af):[27] Table 2, Entry 6. 2-
Iodoaniline (1a, 657 mg, 3.00 mmol) was coupled with 4-methoxy-
benzaldehyde (2f, 408 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%,
560.6 mg, 6.00 mmol) to give 4af (687 mg, 2.85 mmol, 95%) as an
apricot solid after chromatography; m.p. 114–116 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.09–7.98 (m, 3 H), 7.87 (dd, J = 7.9,
0.6 Hz, 1 H), 7.47 (ddd, J = 8.3, 7.3, 1.3 Hz, 1 H), 7.30 (m, 1 H),
7.04–6.95 (m, 2 H), 3.87 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 167.9, 162.0, 154.3, 134.9, 129.2, 126.5, 126.3, 124.9, 122.9,
121.6, 114.4, 55.5 ppm. EI-MS: m/z = 241 (100) [M]+, 226 (33), 198
(31), 108 (10), 69 (20).
2-Phenylbenzothiazole (4aa):[27] Table 2, Entry 1. 2-Iodoaniline (1a,
657 mg, 3.00 mmol) was coupled with benzaldehyde (2a, 318 mg,
3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to
give 4aa (627 mg, 2.97 mmol, 99%) as
a white solid after
chromatography; m.p. 97–99 °C. 1H NMR (300 MHz, CDCl3): δ =
8.18–8.03 (m, 3 H), 7.90 (dd, J = 4.6, 4.0 Hz, 1 H), 7.58–7.43 (m,
4 H), 7.40 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.2,
154.2, 135.1, 133.7, 131.1, 129.1, 127.6, 126.4, 125.3, 123.3,
121.7 ppm. HRMS (FAB) calcd. for C13H10NS [M + H]+ 212.0528;
found 212.0533.
2-[4-(Methylthio)phenyl]benzothiazole (4ag): Table 2, Entry 7. 2-
Iodoaniline (1a, 657 mg, 3.00 mmol) was coupled with 4-(meth-
ylthio)benzaldehyde (2g, 457 mg, 3.00 mmol) and NaSH·nH2O
(60 wt.-%, 560.6 mg, 6.00 mmol) to give 4ag (617 mg, 2.40 mmol,
80%) as a light apricot solid after chromatography; m.p. 142–
2-(3-Fluorophenyl)benzothiazole (4ab):[28] Table 2, Entry 2. 2-
Iodoaniline (1a, 657 mg, 3.00 mmol) was coupled with 3-fluoro-
benzaldehyde (2b, 372 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%,
560.6 mg, 6.00 mmol) to give 4ab (673 mg, 2.94 mmol, 98%) as a
yellow solid after chromatography; m.p. 85–87 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.09 (ddd, J = 8.2, 1.2, 0.6 Hz, 1 H), 7.90
(ddd, J = 7.9, 1.3, 0.6 Hz, 1 H), 7.86–7.82 (m, 2 H), 7.55–7.36 (m,
3 H), 7.18 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.5
(d, J = 3.1 Hz), 163.1 (d, J = 245.6 Hz), 154.0, 135.7 (d, J =
7.9 Hz), 135.1, 130.7 (d, J = 8.2 Hz), 126.6, 125.6, 123.5, 123.4 (d,
J = 2.7 Hz), 121.7, 117.9 (d, J = 21.2 Hz), 114.4 (d, J =
23.4 Hz) ppm. EI-MS: m/z = 229 (100) [M]+, 108 (50), 82 (30), 69
(40).
1
144 °C. H NMR (300 MHz, CDCl3): δ = 8.05 (ddd, J = 8.2, 1.2,
0.6 Hz, 1 H), 8.02–7.94 (m, 2 H), 7.86 (ddd, J = 7.9, 1.3, 0.6 Hz, 1
H), 7.47 (m, 1 H), 7.36 (ddd, J = 8.0, 7.2, 1.2 Hz, 1 H), 7.33–7.27
(m, 2 H), 2.52 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.6, 154.2, 142.8, 134.9, 130.1, 127.8, 126.3, 125.9, 125.1, 123.0,
121.6, 15.2 ppm. HRMS (FAB) calcd. for C14H12NS2 [M + H]+
258.0411; found 258.0411.
4-(Benzothiazol-2-yl)-N,N-dimethylaniline (4ah):[30] Table 2, En-
try 8. 2-Iodoaniline (1a, 657 mg, 3.00 mmol) was coupled with 4-
(dimethylamino)benzaldehyde (2h, 537 mg, 3.00 mmol) and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4ah (694 mg,
2.73 mmol, 91%) as a yellow solid after chromatography; m.p. 161–
163 °C. 1H NMR (300 MHz, CDCl3): δ = 8.01–7.93 (m, 3 H), 7.84
(ddd, J = 7.9, 1.3, 0.6 Hz, 1 H), 7.44 (m, 1 H), 7.30 (ddd, J = 7.9,
7.3, 1.2 Hz, 1 H), 6.79–6.71 (m, 2 H), 3.08–3.04 (m, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.9, 154.5, 152.3, 134.6, 128.9,
126.1, 124.3, 122.3, 121.4, 111.8, 40.3 ppm. EI-MS: m/z = 254 (100)
[M]+, 238 (20), 145 (20), 127 (21), 108 (20), 69 (20).
2-(Benzothiazol-2-yl)aniline (4ac):[29] Table 2, Entry 3. 2-Iodoan-
iline (1a, 657 mg, 3.00 mmol) was coupled with 2-nitrobenzalde-
hyde (2c, 453 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%,
560.6 mg, 6.00 mmol) to give 4ac (556 mg, 2.46 mmol, 82%) as a
yellow solid after chromatography; m.p. 120–122 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.99 (ddd, J = 8.1, 1.2, 0.6 Hz, 1 H), 7.88
(ddd, J = 7.9, 1.3, 0.6 Hz, 1 H), 7.72 (ddd, J = 7.8, 1.5, 0.3 Hz, 1
H), 7.46 (m, 1 H), 7.36 (ddd, J = 7.9, 7.3, 1.2 Hz, 1 H), 7.24 (m, 1
H), 6.83–6.71 (m, 2 H), 6.42 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.3, 153.8, 146.8, 133.3, 131.6, 130.4, 126.1, 124.9,
122.5, 121.2, 116.9, 116.8, 115.3 ppm. HRMS (FAB) calcd. for
C13H11N2S [M + H]+ 227.0643; found 227.0642.
2-(Thiophen-2-yl)benzothiazole (4ai):[31] Table 2, Entry 9. 2-Iodoan-
iline (1a, 657 mg, 3.00 mmol) was coupled with thiophene-2-carb-
aldehyde (2i, 336 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%,
560.6 mg, 6.00 mmol) to give 4ai (586 mg, 2.70 mmol, 90%) as a
1
dark brown solid after chromatography; m.p. 92–94 °C. H NMR
(300 MHz, CDCl3): δ = 8.04 (ddd, J = 8.2, 1.2, 0.6 Hz, 1 H), 7.85
(ddd, J = 7.9, 1.3, 0.6 Hz, 1 H), 7.65 (dd, J = 3.7, 1.1 Hz, 1 H),
7.52–7.45 (m, 2 H), 7.37 (ddd, J = 8.0, 7.3, 1.2 Hz, 1 H), 7.13 (dd,
J = 5.1, 3.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.4,
153.7, 137.4, 134.7, 129.4, 128.7, 128.1, 126.5, 125.3, 123.0,
121.5 ppm. EI-MS: m/z = 217 (100) [M]+, 108 (40), 82 (25), 69 (49).
2-(Pyridin-2-yl)benzothiazole (4aj):[27] Table 2, Entry 10. 2-Iodoan-
iline (1a, 657 mg, 3.00 mmol) was coupled with pyridine-2-carb-
aldehyde (2j, 321 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%,
560.6 mg, 6.00 mmol) to give 4aj (534 mg, 2.52 mmol, 84%) as a
yellow solid after chromatography; m.p. 126–128 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.67 (ddd, J = 4.8, 1.7, 0.9 Hz, 1 H), 8.36
(dt, J = 7.9, 1.1 Hz, 1 H), 8.09 (ddd, J = 8.2, 1.2, 0.6 Hz, 1 H),
7.95 (ddd, J = 7.9, 1.3, 0.6 Hz, 1 H), 7.82 (td, J = 7.7, 1.7 Hz, 1
H), 7.50 (m, 1 H), 7.43–7.32 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.4, 154.3, 151.4, 149.7, 137.0, 136.1, 126.3, 125.7,
125.3, 123.6, 122.1, 120.8 ppm. EI-MS: m/z = 212 (100) [M]+, 108
(21), 78 (22), 69 (30), 51 (25).
2-o-Tolylbenzothiazole (4ad):[27] Table 2, Entry 4. 2-Iodoaniline (1a,
657 mg, 3.00 mmol) was coupled with o-tolualdehyde (2d, 360 mg,
3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to
give 4ad (635 mg, 2.82 mmol, 94%) as a brown oil after chromatog-
raphy. 1H NMR (300 MHz, CDCl3): δ = 8.11 (ddd, J = 8.2, 1.2,
0.6 Hz, 1 H), 7.94 (ddd, J = 7.9, 1.3, 0.6 Hz, 1 H), 7.76 (d, J =
7.7 Hz, 1 H), 7.41 (m, 1 H), 7.45–7.32 (m, 4 H), 2.67 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.1, 153.9, 137.3, 135.7, 133.2,
131.6, 130.6, 130.1, 126.2 (2 C), 125.2, 123.5, 121.5, 21.48 ppm. EI-
MS: m/z = 225 [M]+ (90), 224 (100), 223 (20), 116 (13), 108 (10),
89 (20), 82 (15), 69 (30), 51 (10).
2-p-Tolylbenzothiazole (4ae):[27] Table 2, Entry 5. 2-Iodoaniline (1a,
657 mg, 3.00 mmol) was coupled with p-tolualdehyde (2e, 360 mg,
3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to
give 4ae (662 mg, 2.94 mmol, 98%) as a brown solid after
chromatography; m.p. 86–88 °C. 1H NMR (300 MHz, CDCl3): δ =
8.08 (ddd, J = 8.2, 1.2, 0.6 Hz, 1 H), 8.01–7.97 (m, 2 H), 7.88 (ddd,
J = 7.9, 1.3, 0.6 Hz, 1 H), 7.49 (m, 1 H), 7.37 (ddd, J = 8.0, 7.2,
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)benzothiazole (4ak): Table 2,
1.2 Hz, 1 H), 7.31–7.27 (m, 2 H), 2.42 (s, 3 H) ppm. 13C NMR Entry 11. 2-Iodoaniline (1a, 657 mg, 3.00 mmol) was coupled with
(75 MHz, CDCl3): δ = 168.2, 154.2, 141.4, 135.0, 131.0, 129.7, 1,4-benzodioxan-6-carbaldehyde (2k, 492 mg, 3.00 mmol) and
127.5, 126.3, 125.0, 123.1, 121.6, 21.5 ppm. EI-MS: m/z = 225 (100)
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4ak (622 mg,
2.31 mmol, 77%) as a light brown solid after chromatography; m.p.
[M]+, 116 (13), 108 (20), 89 (14), 82 (17), 69 (25).
Eur. J. Org. Chem. 2012, 1984–1993
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1989

N. Park, Y. Heo, M. R. Kumar, Y. Kim, K. H. Song, S. Lee
FULL PAPER
121–123 °C. H NMR (300 MHz, CDCl3): δ = 8.03 (ddd, J = 8.2, 150–152 °C. 1H NMR (300 MHz, CDCl3): δ = 8.04–7.95 (m, 3 H),
1
1.1, 0.6 Hz, 1 H), 7.86 (ddd, J = 7.9, 1.2, 0.6 Hz, 1 H), 7.65–7.56
(m, 2 H), 7.46 (ddd, J = 8.2, 7.3, 1.3 Hz, 1 H), 7.34 (ddd, J = 8.1,
7.75 (d, J = 8.5 Hz, 1 H), 7.31 (dd, J = 8.5, 2.0 Hz, 1 H), 7.03–6.93
(m, 2 H), 3.88 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
7.3, 1.2 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 4.30 (s, 4 H) ppm. 13C 169.8, 162.3, 155.2, 133.2, 132.2, 129.3, 126.1, 125.2, 122.7, 122.2,
NMR (75 MHz, CDCl3): δ = 167.6, 154.2, 146.2, 143.9, 135.0,
114.5, 55.5 ppm. EI-MS: m/z = 277 (35) [M + 2]+, 275 (100) [M]+,
127.3, 126.2, 124.9, 122.9, 121.5, 121.1, 117.8, 116.6, 64.6, 260 (30), 232 (30), 196 (16), 107 (20), 63 (35).
64.3 ppm. HRMS (FAB) calcd. for C15H12NO2S [M + H]+
270.0589; found 270.0590.
5-Chloro-2-[4-(methylthio)phenyl]benzothiazole (4bg): Table 3, En-
try 4. 5-Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was coupled
with 4-(methylthio)benzaldehyde (2g, 457 mg, 3.00 mmol) and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4bg (786 mg,
2.70 mmol, 90%) as a yellow solid after chromatography; m.p. 159–
161 °C. 1H NMR (300 MHz, CDCl3): δ = 8.02 (dd, J = 2.0, 0.4 Hz,
1 H), 8.00–7.93 (m, 2 H), 7.78 (dd, J = 8.5, 0.5 Hz, 1 H), 7.36–7.31
(m, 2 H), 7.30 (m, 1 H), 2.54 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.5, 155.1, 143.5, 133.2, 132.4, 129.8, 127.9, 126.0,
125.6, 122.9, 122.3, 15.2 ppm. HRMS (FAB) calcd. for
C14H11ClNS2 [M + H]+ 292.0021; found 292.0020.
2-(Benzo[d][1,3]dioxol-5-yl)benzothiazole (4al):[32] Table 2, Entry 12.
2-Iodoaniline (1a, 657 mg, 3.00 mmol) was coupled with piperonal
(2l, 450 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg,
6.00 mmol) to give 4al (742 mg, 2.91 mmol, 97%) as a light yellow
solid after chromatography; m.p. 179–181 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.02 (ddd, J = 8.2, 1.2, 0.6 Hz, 1 H), 7.87 (ddd, J =
7.9, 1.3, 0.6 Hz, 1 H), 7.62–7.58 (m, 2 H), 7.48 (m, 1 H), 7.36 (m,
1 H), 6.91 (dd, J = 7.8, 0.7 Hz, 1 H), 6.06 (s, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.6, 154.1, 150.2, 148.5, 134.9, 128.1,
126.4, 125.1, 123.0, 122.6, 121.6, 108.8, 107.6, 101.8 ppm. EI-MS:
m/z = 255 (100) [M]+, 196 (20), 108 (30), 82 (20), 69 (20).
4-(5-Chlorobenzothiazol-2-yl)-N,N-dimethylaniline (4bh): Table 3,
Entry 5. 5-Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was cou-
pled with 4-(dimethylamino)benzaldehyde (2h, 537 mg, 3.00 mmol)
and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4bh
(735 mg, 2.55 mmol, 85%) as a dark yellow solid after chromatog-
raphy; m.p. 150–152 °C. 1H NMR (300 MHz, CDCl3): δ = 7.96–
7.94 (m, 2 H), 7.91 (m, 1 H), 7.73 (d, J = 8.5 Hz, 1 H), 7.27 (dd, J
= 8.5, 2.0 Hz, 2 H), 6.74 (d, J = 9.0 Hz, 2 H), 3.06 (s, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 170.7, 155.4, 152.5, 132.9, 132.0,
129.1, 124.6, 122.19, 122.1, 121.0, 111.7, 40.3 ppm. HRMS (FAB)
calcd. for C15H14ClN2S [M + H]+ 289.0566; found 289.0569.
2-(6-Methoxynaphthalen-2-yl)benzothiazole (4am): Table 2, En-
try 13. 2-Iodoaniline (1a, 657 mg, 3.00 mmol) was coupled with 6-
methoxy-2-naphthaldehyde (2m, 559 mg, 3.00 mmol) and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4am
(795 mg, 2.73 mmol, 91%) as a yellow solid after chromatography;
m.p. 141–143 °C. 1H NMR (300 MHz, CDCl3): δ = 8.49 (d, J =
1.3 Hz, 1 H), 8.17 (dd, J = 8.6, 1.9 Hz, 1 H), 8.09 (ddd, J = 8.2,
1.2, 0.6 Hz, 1 H), 7.92 (ddd, J = 7.9, 1.3, 0.6 Hz, 1 H), 7.85 (t, J =
9.3 Hz, 2 H), 7.50 (ddd, J = 7.9, 7.2, 1.2 Hz, 1 H), 7.39 (ddd, J =
7.9, 7.2, 1.2 Hz, 1 H), 7.24–7.16 (m, 2 H), 3.95 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 168.4, 159.1, 154.4, 136.2, 135.1,
130.5, 129.0, 128.7, 127.6, 127.5, 126.4, 125.1, 123.1, 121.7 (2 C),
119.9, 106.0, 55.5 ppm. HRMS (FAB) calcd. for C18H14NOS [M +
H]+ 292.0796; found 292.0793.
5-Chloro-2-phenylbenzothiazole (4ba):[33] Table 3, Entry 1. 5-
Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was coupled with
benzaldehyde (2a, 318 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-
%, 560.6 mg, 6.00 mmol) to give 4ba (698 mg, 2.85 mmol, 95%) as
a yellow solid after chromatography; m.p. 135–137 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.11–8.03 (m, 3 H), 7.81 (dd, J = 8.4,
0.3 Hz, 1 H), 7.54–7.46 (m, 3 H), 7.36 (dd, J = 8.5, 2.0 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.0, 155.1, 133.4,
133.3, 132.4, 131.4, 129.2, 127.7, 125.7, 123.1, 122.4 ppm. EI-MS:
m/z = 247 (35) [M + 2]+, 245 (100) [M]+, 142 (30), 107 (30), 63
(30).
5-Chloro-2-(thiophen-2-yl)benzothiazole (4bi):[35] Table 3, Entry 6.
5-Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was coupled with
thiophene-2-carbaldehyde
(2i,
336 mg,
3.00 mmol)
and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4bi (489 mg,
1.95 mmol, 65%) as a brown solid after chromatography; m.p. 99–
101 °C. 1H NMR (300 MHz, CDCl3): δ = 7.99 (dd, J = 2.0, 0.5 Hz,
1 H), 7.72 (dd, J = 8.5, 0.5 Hz, 1 H), 7.64 (dd, J = 3.7, 1.2 Hz, 1
H), 7.52 (dd, J = 5.1, 1.2 Hz, 1 H), 7.32 (dd, J = 8.5, 2.0 Hz, 1 H),
7.13 (dd, J = 5.1, 3.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 163.2, 154.6, 137.0, 133.0, 132.5, 129.9, 129.1, 128.2, 125.7,
122.8, 122.2 ppm. EI-MS: m/z = 253 (35) [M + 2]+, 251 (100)
[M]+, 142 (29), 107 (31), 63 (32).
5-Chloro-2-(pyridin-2-yl)benzothiazole (4bj): Table 3, Entry 7. 5-
Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was coupled with
pyridine-2-carbaldehyde (2j, 321 mg, 3.00 mmol) and NaSH·nH2O
(60 wt.-%, 560.6 mg, 6.00 mmol) to give 4bj (576 mg, 2.34 mmol,
78%) as a yellow solid after chromatography; m.p. 154–157 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.69 (ddd, J = 4.8, 1.7, 0.9 Hz, 1
H), 8.36 (dt, J = 7.9, 1.1 Hz, 1 H), 8.07 (d, J = 2.0 Hz, 1 H),
7.90–7.84 (m, 2 H), 7.45–7.37 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.4, 155.2, 151.1, 149.8, 137.2, 134.5, 132.4, 126.2,
125.7, 123.4, 122.8, 121.0 ppm. HRMS (FAB) calcd. for
C12H8ClN2S [M + H]+ 247.0097; found 247.0097.
5-Chloro-2-(3-fluorophenyl)benzothiazole (4bb): Table 3, Entry 2. 5-
Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was coupled with 3-
fluorobenzaldehyde (2b, 372 mg, 3.00 mmol) and NaSH·nH2O
(60 wt.-%, 560.6 mg, 6.00 mmol) to give 4bb (686 mg, 2.61 mmol,
1
87%) as a white solid after chromatography; m.p. 143–145 °C. H
NMR (300 MHz, CDCl3): δ = 8.03 (d, J = 2.0 Hz, 1 H), 7.82–7.75
(m, 3 H), 7.45 (m, 1 H), 7.36 (dd, J = 8.5, 2.0 Hz, 1 H), 7.19 (tdd,
J = 8.3, 2.5, 1.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
168.3 (d, J = 2.9 Hz), 163.1 (d, J = 246.1 Hz), 154.8, 135.3 (d, J =
7.9 Hz), 133.3, 132.6, 130.8 (d, J = 8.2 Hz), 126.0, 123.4 (d, J =
2.8 Hz), 123.3, 122.4, 118.2 (d, J = 21.2 Hz), 114.4 (d, J =
23.4 Hz) ppm. HRMS (FAB) calcd. for C13H8ClFNS [M + H]+
264.0050; found 264.0047.
5-Chloro-2-(4-methoxyphenyl)benzothiazole (4bf):[34] Table 3, En-
try 3. 5-Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was coupled
with 4-methoxybenzaldehyde (2f, 408 mg, 3.00 mmol) and
5-Chloro-2-(pyridin-2-yl)benzothiazole (4bk): Table 3, Entry 8. 5-
Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was coupled with
1,4-benzodioxan-6-carbaldehyde (2k, 492 mg, 3.00 mmol) and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4bk (645 mg,
2.13 mmol, 71%) as a yellow solid after chromatography; m.p. 139–
141 °C. 1H NMR (300 MHz, CDCl3): δ = 7.99 (dd, J = 1.8, 0.4 Hz,
1 H), 7.75 (dd, J = 8.5, 0.4 Hz, 1 H), 7.61–7.53 (m, 2 H), 7.31 (dd,
J = 8.5, 2.0 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 4.33–4.28 (m, 4
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4bf (701 mg, H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.5, 155.1, 146.6,
2.55 mmol, 85%) as a yellowish solid after chromatography; m.p.
143.9, 133.3, 132.2, 126.9, 125.3, 122.8, 122.2, 121.2, 117.9, 116.7,
1990
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1984–1993

Synthesis of Benzothiazoles through Three-Component Reaction
64.7, 64.3 ppm. HRMS (FAB) calcd. for C15H11ClNO2S [M +
H]+ 304.0199; found 304.0197.
= 26.9 Hz) ppm. HRMS (FAB) calcd. for C11H7FNS2 [M + H]+
236.0004; found 236.0004.
2-(Benzo[d][1,3]dioxol-5-yl)-5-chlorobenzothiazole (4bl):[36] Table 3,
Entry 9. 5-Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol) was cou-
pled with piperonal (2l, 450 mg, 3.00 mmol) and NaSH·nH2O
(60 wt.-%, 560.6 mg, 6.00 mmol) to give 4bl (650 mg, 2.25 mmol,
75%) as a yellow solid after chromatography; m.p. 172–174 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.99 (dd, J = 2.0, 0.4 Hz, 1 H), 7.76
(dd, J = 8.5, 0.4 Hz, 1 H), 7.58–7.55 (m, 2 H), 7.32 (dd, J = 8.5,
2.0 Hz, 1 H), 6.89 (m, 1 H), 6.06 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.5, 155.0, 150.5, 148.5, 133.2, 132.3, 127.7, 125.4,
122.8, 122.8, 122.2, 108.8, 107.6, 101.9 ppm. EI-MS: m/z = 291 (35)
[M + 2]+, 289 (100) [M]+, 196 (25), 144 (12), 107 (19), 63 (31).
6-Fluoro-2-(pyridin-2-yl)benzothiazole (4cj): Table 3, Entry 14. 4-
Fluoro-2-iodoaniline (1c, 710 mg, 3.00 mmol) was coupled with
pyridine-2-carbaldehyde (2j, 321 mg, 3.00 mmol) and NaSH·nH2O
(60 wt.-%, 560.6 mg, 6.00 mmol) to give 4cj (649 mg, 2.82 mmol,
94%) as a light yellow solid after chromatography; m.p. 150–
1
152 °C. H NMR (300 MHz, CDCl3): δ = 8.65 (ddd, J = 4.8, 1.7,
1.0 Hz, 1 H), 8.29 (dt, J = 7.9, 1.1 Hz, 1 H), 7.99 (m, 1 H), 7.81
(m, 1 H), 7.59 (m, 1 H), 7.35 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H), 7.21
(td, J = 8.9, 2.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.2 (d, J = 3.7 Hz), 160.8 (d, J = 246.6 Hz), 151.1, 151.0, 149.7,
137.3 (d, J = 11.3 Hz), 137.1, 125.3, 124.6 (d, J = 9.5 Hz), 120.6,
115.1 (d, J = 24.9 Hz), 108.2 (d, J = 26.7 Hz) ppm. HRMS (FAB)
calcd. for C12H8FN2S [M + H]+ 231.0392; found 231.0394.
5-Chloro-2-(6-methoxynaphthalen-2-yl)benzothiazole
(4bm):
Table 3, Entry 10. 5-Chloro-2-iodoaniline (1b, 759 mg, 3.00 mmol)
was coupled with 6-methoxy-2-naphthaldehyde (2m, 559 mg,
3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to
give 4bm (878 mg, 2.70 mmol, 90%) as a yellow solid after
chromatography; m.p. 205–207 °C. 1H NMR (300 MHz, CDCl3): δ
= 8.46 (d, J = 1.3 Hz, 1 H), 8.13 (dd, J = 8.6, 1.9 Hz, 1 H), 8.06
(dd, J = 2.1, 0.3 Hz, 1 H), 7.89–7.79 (m, 3 H), 7.36 (dd, J = 8.5,
2.0 Hz, 1 H), 7.25–7.15 (m, 2 H), 3.96 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.3, 159.2, 155.2, 136.4, 133.3 (2 C), 132.4
(2 C), 130.5, 128.6, 127.7, 125.6, 125.0, 122.9, 122.4, 120.0, 106.0,
55.5 ppm. HRMS (FAB) calcd. for C18H13NOSCl [M + H]+
326.0406; found 326.0406.
4,6-Dichloro-2-[4-(methylthio)phenyl]benzothiazole (4dg): Table 3,
Entry 15. 2,4-Dichloro-6-iodoaniline (1d, 860 mg, 3.00 mmol) was
coupled with 4-(methylthio)benzaldehyde (2g, 457 mg, 3.00 mmol)
and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4dg
(634 mg, 1.95 mmol, 65%) as a white solid after chromatography;
m.p. 170–172 °C. 1H NMR (300 MHz, CDCl3): δ = 8.00 (d, J =
8.8 Hz, 2 H), 7.75 (d, J = 1.9 Hz, 1 H), 7.50 (d, J = 1.9 Hz, 1 H),
7.31 (d, J = 8.8 Hz, 2 H), 2.55 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 168.8, 150.0, 143.9, 137.0, 130.8, 129.3, 128.3, 128.1,
127.2, 125.9, 119.9, 15.2 ppm. HRMS (FAB) calcd. for
C14H10Cl2NS2 [M + H]+ 325.9632; found 325.9635.
4-(6-Chloro-4-fluorobenzothiazol-2-yl)-N,N-dimethylaniline (4eh):
Table 3, Entry 16. 4-Chloro-2-fluoro-6-iodoaniline (1e, 813 mg,
3.00 mmol) was coupled with 4-(dimethylamino)benzaldehyde (2h,
537 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg,
6.00 mmol) to give 4eh (595 mg, 1.83 mmol, 61%) as a yellow solid
after chromatography; m.p. 193–195 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.95 (d, J = 9.1 Hz, 2 H), 7.59 (dd, J = 1.9, 0.9 Hz, 1
H), 7.16 (dd, J = 10.1, 1.9 Hz, 1 H), 6.73 (d, J = 9.1 Hz, 2 H), 3.07
(s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.8, 154.6 (d, J
= 258.7 Hz), 152.6, 143.6 (d, J = 210.9 Hz), 137.9 (d, J = 4.7 Hz),
129.7 (d, J = 8.9 Hz), 129.3, 120.6, 117.0 (d, J = 4.2 Hz), 113.4 (d,
6-Fluoro-2-(4-methoxyphenyl)benzothiazole (4cf):[32] Table 3, En-
try 11. 4-Fluoro-2-iodoaniline (1c, 710 mg, 3.00 mmol) was cou-
pled with 4-methoxybenzaldehyde (2f, 408 mg, 3.00 mmol) and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4cf (707 mg,
2.73 mmol, 91%) as light yellow solid after chromatography; m.p.
126–128 °C. 1H NMR (300 MHz, CDCl3): δ = 7.99–7.91 (m, 3 H),
7.51 (m, 1 H), 7.18 (td, J = 8.9, 2.6 Hz, 1 H), 6.97 (d, J = 9.0 Hz,
2 H), 3.89 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.6
(d, J = 2.9 Hz), 162.0, 160.3 (d, J = 245.4 Hz), 150.9, 135.8 (d, J
= 11.2 Hz), 129.0, 126.2, 123.7 (d, J = 9.3 Hz), 114.7 (d, J =
24.5 Hz), 114.4, 107.8 (d, J = 26.8 Hz), 55.5 ppm. HRMS (FAB)
calcd. for C14H11FNOS [M + H]+ 260.0545; found 260.0543.
J
= 21.8 Hz), 111.7, 40.3 ppm. HRMS (FAB) calcd. for
C15H13ClFN2S [M + H]+ 307.0472; found 307.0472.
2-Phenyl-6-(trifluoromethyl)benzothiazole (4fa):[37] Table 3, En-
try 17. 2-Iodo-4-(trifluoromethyl)aniline (1f, 861 mg, 3.00 mmol)
was coupled with benzaldehyde (2a, 318 mg, 3.00 mmol) and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4fa (812 mg,
2.91 mmol, 97%) as a white solid after chromatography; m.p. 152–
4-(6-Fluorobenzothiazol-2-yl)-N,N-dimethylaniline (4ch): Table 3,
Entry 12. 4-Fluoro-2-iodoaniline (1c, 710 mg, 3.00 mmol) was cou-
pled with 4-(dimethylamino)benzaldehyde (2h, 537 mg, 3.00 mmol)
and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4ch
(596 mg, 2.19 mmol, 73%) as a brown solid after chromatography;
1
1
m.p. 199–201 °C. H NMR (300 MHz, CDCl3): δ = 7.94–7.86 (m,
154 °C. H NMR (300 MHz, CDCl3): δ = 8.17 (m, 1 H), 8.13 (d,
3 H), 7.50 (m, 1 H), 7.16 (td, J = 9.0, 2.6 Hz, 1 H), 6.73 (d, J =
9.1 Hz, 2 H), 3.05 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
168.6 (d, J = 2.9 Hz), 160.0 (d, J = 244.0 Hz), 152.2, 151.1, 135.6
(d, J = 11.2 Hz), 128.8, 123.0 (d, J = 9.2 Hz), 121.2, 114.4 (d, J =
24.5 Hz), 111.8, 107.7 (d, J = 26.5 Hz), 40.2 ppm. HRMS (FAB)
calcd. for C15H14FN2S [M + H]+ 27.30862; found 273.0865.
J = 8.6 Hz, 1 H), 8.11–8.06 (m, 2 H), 7.72 (m, 1 H), 7.56–7.46 (m,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.2, 156.1, 135.2,
133.1, 131.7, 129.2, 127.8, 127.3 (q, J = 53.9 Hz), 124.3 (q, J =
272.3 Hz), 123.6, 123.4 (q, J = 3.3 Hz), 119.4 (q, J = 4.2 Hz) ppm.
EI-MS: m/z = 279 (100) [M]+, 157 (25), 132 (20), 63 (20), 51 (15).
2-(4-Methoxyphenyl)-6-(trifluoromethyl)benzothiazole
(4ff):[37]
6-Fluoro-2-(thiophen-2-yl)benzothiazole (4ci): Table 3, Entry 13. 4- Table 3, Entry 18. 2-Iodo-4-(trifluoromethyl)aniline (1f, 861 mg,
Fluoro-2-iodoaniline (1c, 710 mg, 3.00 mmol) was coupled with
thiophene-2-carbaldehyde (2i, 336 mg, 3.00 mmol) and
3.00 mmol) was coupled with 4-methoxybenzaldehyde (2f, 408 mg,
3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4ci (508 mg,
2.16 mmol, 72%) as a light yellow solid after chromatography; m.p.
156–158 °C. 1H NMR (300 MHz, CDCl3): δ = 7.96 (dd, J = 9.0,
give 4ff (705 mg, 2.28 mmol, 76%) as a white solid after
chromatography; m.p. 157–159 °C. 1H NMR (300 MHz, CDCl3): δ
= 8.15 (m, 1 H), 8.09 (m, 1 H), 8.04 (d, J = 9.0 Hz, 2 H), 7.70
4.7 Hz, 1 H), 7.62 (dd, J = 3.7, 1.1 Hz, 1 H), 7.56–7.48 (m, 2 H), (ddd, J = 8.6, 1.8, 0.6 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 2 H), 3.89 (s,
7.20 (td, J = 8.9, 2.6 Hz, 1 H), 7.14 (dd, J = 5.1, 3.7 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 161.2 (d, J = 0.6 Hz), 160.6 (d,
J = 246.1 Hz), 150.4, 137.1, 135.8 (d, J = 11.2 Hz), 129.5, 128.7,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.0, 162.6, 156.3,
135.0, 129.5, 126.9 (q, J = 32.5 Hz), 125.9, 124.3 (q, J = 272.0 Hz),
123.3 (q, J = 3.5 Hz), 123.1, 119.2 (q, J = 4.1 Hz), 114.6, 55.6 ppm.
128.2, 123.9 (d, J = 9.4 Hz), 115.1 (d, J = 24.6 Hz), 107.9 (d, J EI-MS: m/z = 309 (100) [M]+, 294 (30), 266 (50), 63 (20).
Eur. J. Org. Chem. 2012, 1984–1993
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1991

N. Park, Y. Heo, M. R. Kumar, Y. Kim, K. H. Song, S. Lee
FULL PAPER
2-[4-(Methylthio)phenyl]-6-(trifluoromethyl)benzothiazole
(4fg): 171.5, 159.4, 156.3, 136.6, 135.1, 130.6, 128.6, 128.4, 128.0, 127.8,
Table 3, Entry 19. 2-Iodo-4-(trifluoromethyl)aniline (1f, 861 mg,
3.00 mmol) was coupled with 4-(methylthio)benzaldehyde (2g,
457 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg,
6.00 mmol) to give 4fg (692 mg, 2.13 mmol, 71%) as a light yellow
solid after chromatography; m.p. 172–174 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.17 (m, 1 H), 8.11 (m, 1 H), 8.00 (d, J = 8.8 Hz, 2
H), 7.71 (ddd, J = 8.6, 1.8, 0.6 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 2 H),
2.55 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.7, 156.2,
144.0, 135.0, 129.5, 128.0, 127.2 (q, J = 32.8 Hz), 126.0, 124.3 (q,
J = 272.3 Hz), 123.4 (q, J = 3.4 Hz), 123.3, 119.3 (q, J = 4.2 Hz),
15.1 ppm. HRMS (FAB) calcd. for C15H11F3NS2 [M + H]+
326.0285; found 326.0282.
127.4 (q, J = 119.3 Hz), 127.2 (q, J = 33.4 Hz), 125.0, 123.4 (q, J
= 3.2 Hz), 123.3, 120.1, 119.3 (q, J = 4.4 Hz), 106.0, 55.5 ppm.
HRMS (FAB) calcd. for C19H13F3NOS [M + H]+ 360.0670; found
360.0668.
2-(4-Methoxyphenyl)-4,6-dimethylbenzothiazole (4gf): Table 3, En-
try 24. 2-Iodo-4,6-dimethylaniline (1g, 741 mg, 3.00 mmol) was
coupled with 4-methoxybenzaldehyde (2f, 408 mg, 3.00 mmol) and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4gf (581 mg,
2.16 mmol, 72%) as a light yellow solid after chromatography; m.p.
141–143 °C. 1H NMR (300 MHz, CDCl3): δ = 8.03 (d, J = 9.0 Hz,
2 H), 7.48 (m, 1 H), 7.08 (m, 1 H), 6.99 (d, J = 9.0 Hz, 2 H), 3.88
(s, 3 H), 2.76 (s, 3 H), 2.44 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.4, 161.6, 151.8, 135.0, 134.8, 132.4, 129.0, 128.4,
127.1, 118.7, 114.3, 55.5, 21.6, 18.4 ppm. HRMS (FAB) calcd. for
C16H16NOS [M + H]+ 270.0953; found 270.0952.
N,N-Dimethyl-4-[6-(trifluoromethyl)benzothiazol-2-yl]aniline (4fh):
Table 3, Entry 20. 2-Iodo-4-(trifluoromethyl)aniline (1f, 861 mg,
3.00 mmol) was coupled with 4-(dimethylamino)benzaldehyde (2h,
537 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg,
6.00 mmol) to give 4fh (870 mg, 2.70 mmol, 90%) as a yellow solid
after chromatography; m.p. 196–198 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.11 (m, 1 H), 8.03 (m, 1 H), 7.96 (d, J = 9.1 Hz, 2
H), 7.66 (ddd, J = 8.6, 1.9, 0.6 Hz, 1 H), 6.74 (d, J = 9.1 Hz, 2 H),
3.07 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.9, 156.6,
152.7, 134.7, 131.0, 129.3, 127.6 (q, J = 199.2 Hz), 126.2 (q, J =
32.0 Hz), 123.1 (q, J = 3.1 Hz), 122.4, 120.7, 119.0 (q, J = 3.5 Hz),
111.7, 40.2 ppm. HRMS (FAB) calcd. for C16H14F3N2S [M + H]+
323.0830; found 323.0833.
4-(4,6-Dimethylbenzothiazol-2-yl)-N,N-dimethylaniline
(4gh):
Table 3, Entry 25. 2-Iodo-4,6-dimethylaniline (1g, 741 mg,
3.00 mmol) was coupled with 4-(dimethylamino)benzaldehyde (2h,
537 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg,
6.00 mmol) to give 4gh (601 mg, 2.13 mmol, 71%) as a brown solid
after chromatography; m.p. 130–132 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.96 (d, J = 9.0 Hz, 2 H), 7.46 (d, J = 0.6 Hz, 1 H),
7.05 (d, J = 0.6 Hz, 1 H), 6.74 (d, J = 8.9 Hz, 2 H), 3.05 (s, 6 H),
2.74 (s, 3 H), 2.43 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.4, 152.0, 151.9, 134.7, 134.1, 131.9, 128.7, 128.2, 122.2, 118.7,
111.8, 40.3, 21.5, 18.4 ppm. HRMS (FAB) calcd. for C17H19NS2
[M + H]+ 283.1269; found 283.1269.
2-(Thiophen-2-yl)-6-(trifluoromethyl)benzothiazole (4fi): Table 3,
Entry 21.
2-Iodo-4-(trifluoromethyl)aniline
(1f,
861 mg,
3.00 mmol) was coupled with thiophene-2-carbaldehyde (2i,
336 mg, 3.00 mmol) and NaSH·nH2O (60 wt.-%, 560.6 mg,
6.00 mmol) to give 4fi (667 mg, 2.34 mmol, 78%) as a white solid
after chromatography; m.p. 153–155 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.14 (m, 1 H), 8.09 (d, J = 8.6 Hz, 1 H), 7.75–7.67 (m,
2 H), 7.57 (dd, J = 5.0, 1.1 Hz, 1 H), 7.17 (dd, J = 5.0, 3.8 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.4, 155.8, 136.8,
134.9, 130.5, 129.7, 128.4, 127.4 (q, J = 32.3 Hz), 124.2 (q, J =
271.4 Hz), 123.6 (q, J = 3.5 Hz), 123.3, 119.2 (q, J = 4.2 Hz) ppm.
HRMS (FAB) calcd. for C12H7F3NS2 [M + H]+ 285.9972; found
285.9970.
4,6-Dimethyl-2-(pyridin-2-yl)benzothiazole (4gj): Table 3, Entry 26.
2-Iodo-4,6-dimethylaniline (1g, 741 mg, 3.00 mmol) was coupled
with pyridine-2-carbaldehyde (2j, 321 mg, 3.00 mmol) and
NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4fj (562 mg,
2.34 mmol, 78%) as light yellow solid after chromatography; m.p.
1
120–122 °C. H NMR (300 MHz, CDCl3): δ = 8.67 (ddd, J = 4.9,
1.7, 0.9 Hz, 1 H), 8.40 (dt, J = 8.1, 1.2 Hz, 1 H), 7.81 (m, 1 H),
7.57 (m, 1 H), 7.35 (ddd, J = 7.5, 4.9, 1.2 Hz, 1 H), 7.11 (m, 1 H),
2.77 (s, 3 H), 2.46 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.9, 152.0 (2 C), 149.6, 136.9, 136.3, 135.8, 133.1, 128.5, 124.9,
120.8, 119.2, 21.7, 18.2 ppm. HRMS (FAB) calcd. for C14H13N2S
[M + H]+ 241.0799; found 241.0798.
2-(Pyridin-2-yl)-6-(trifluoromethyl)benzothiazole (4fj): Table 3, En-
try 22. 2-Iodo-4-(trifluoromethyl)aniline (1f, 861 mg, 3.00 mmol)
was coupled with pyridine-2-carbaldehyde (2j, 321 mg, 3.00 mmol)
and NaSH·nH2O (60 wt.-%, 560.6 mg, 6.00 mmol) to give 4fj
(638 mg, 2.28 mmol, 76%) as a white solid after chromatography;
m.p. 163–165 °C. 1H NMR (300 MHz, CDCl3): δ = 8.71 (ddd, J =
4.8, 1.7, 0.9 Hz, 1 H), 8.38 (dt, J = 7.9, 1.1 Hz, 1 H), 8.26 (m, 1
H), 8.17 (m, 1 H), 7.88 (td, J = 7.8, 1.8 Hz, 1 H), 7.74 (ddd, J =
8.6, 1.8, 0.5 Hz, 1 H), 7.43 (ddd, J = 7.6, 4.8, 1.2 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 172.7, 156.3, 150.9, 149.9, 137.3,
136.3, 127.8 (q, J = 32.5 Hz), 126.0, 124.3 (q, J = 271.8 Hz), 124.0,
123.3 (q, J = 3.2 Hz), 121.1, 119.8 (q, J = 4.2 Hz) ppm. HRMS
(FAB) calcd. for C13H9F3N2S [M + H]+ 281.0360; found 281.0363.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Acknowledgments
This work was supported by the Korean Government (grant
number 2009-0072357, National Research Foundation). Spectro-
scopic data were obtained from the Korea Basic Science Institute,
Gwangju branch.
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Received: December 9, 2011
Published Online: February 16, 2012
Eur. J. Org. Chem. 2012, 1984–1993
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