Metal-free synthesis of 2-substituted (N, O, C) Benzothiazoles via an intramolecular C-S bond formation

Article abstract of DOI:10.1021/cc9001839

An efficient, economical, and convenient method was developed for the preparation of 2-substituted (N, O, C) benzothiazoles from N′-substituted- N-(2-halophenyl)thioureas, O′-substituted-N-(2-halophenyl) carbamothioates, or N-(2-halophenyl) thioamides via a base-promoted cyclization in dioxane without any transition metal. A one-pot variant combining the synthesis of the thiourea and the cyclization was also demonstrated. High yields were obtained, and a variety of functional groups were tolerated under these conditions. Transition-metal-free, mild reactive conditions, wide application scope, and shorter reaction times make this method superior to the reported methods for the synthesis of 2-substituted benzothiazoles and suitable for combinatorial format.

Full text of DOI:10.1021/cc9001839

422
J. Comb. Chem. 2010, 12, 422–429
Metal-Free Synthesis of 2-Substituted (N, O, C) Benzothiazoles via an
Intramolecular C-S Bond Formation
Enguang Feng, He Huang, Yu Zhou, Deju Ye, Hualiang Jiang, and Hong Liu*
The Center for Drug DiscoVery and Design, State Key Laboratory of Drug Research, Shanghai Institute
of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555
Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P.R. China
ReceiVed December 8, 2009
An efficient, economical, and convenient method was developed for the preparation of 2-substituted (N, O,
C) benzothiazoles from N′-substituted-N-(2-halophenyl)thioureas, O′-substituted-N-(2-halophenyl) carbam-
othioates, or N-(2-halophenyl) thioamides via a base-promoted cyclization in dioxane without any transition
metal. A one-pot variant combining the synthesis of the thiourea and the cyclization was also demonstrated.
High yields were obtained, and a variety of functional groups were tolerated under these conditions. Transition-
metal-free, mild reactive conditions, wide application scope, and shorter reaction times make this method
superior to the reported methods for the synthesis of 2-substituted benzothiazoles and suitable for combinatorial
format.
Introduction
excess amounts of toxic reagents, such as bromine or metals,
is a major drawback of these methods, and low functional
group tolerance also have disadvantages. Synthesized via
palladium- or copper-catalyzed cyclization of ortho-ha-
lobenzo-thioureas,11 or directly functionalized aromatic CsH
bonds to construct CsS bonds,12 provided another access
to benzothiazoles. However, these reactions still require large
amount of catalyst (typically 1 mol % to 20 mol %) to
promote the transformation efficiently. Very recently, the
intramolecular nucleophilic aromatic substitution of o-
halothiobenzanilides (INASOB) promoted by a base was
reported by some groups.13 However, these catalyst-free
methods could produce the 2-(alkyl)arylbenzothiazoles only.
So there is an urgent need to develop less expensive and
easily available catalyst systems for these important
heterocycles.
As a part of our ongoing efforts devoted to the synthesis
of key core blocks in natural products14 and the development
of environmentally benign processes,15 we required an
efficient method to generate a 2-substituted (N, O, C)
benzothiazole based scaffold, with a hope of finding more
active hits or leads for our particular biological assays. In
this paper, we have developed a novel base-promoted
cyclization of ortho-haloaryl precursors 1 through a CsS
bond formation process, leading to a broad range of
2-substituted benzothiazoles 2 (Scheme 1). Yields were
generally good to high for this cyclization, and good
functional group tolerance was observed using our catalyst
In synthetic organic reactions, the scope and application
of organosulfur chemistry have increased tremendously since
sulfur-containing groups serve as an important auxiliary
function in synthetic sequences.1 And the formation of CsS
bonds is one of the most useful and fundamental reactions
since it represents a key step in the synthesis of complex
molecules. Transition metal-mediated cross-coupling of
prefunctionalized substrates is one of the most important
synthetic tools for constructing the CsS bonds.2 Among the
various cross-coupling types, S-arylation has been a subject
of particular interest in recent years. In 1980, Migita et al.3
first reported the cross-coupling of aryl halides with thiols
in the presence of Pd(PPh3)4 as the catalyst and NaOtBu as
a base in ethanol at reflux or dimethyl sulfoxide (DMSO) at
90 °C. Palladium-,3,4 nickel-,5 copper-,6 cobalt-,7 and iron-8
based catalytic systems have been studied later by other
groups. However, transition metal-based protocols, although
successful, usually have some inherent limitations such as
moisture sensitivity, costly metal catalysts, and environmental
toxicity. Moreover, their separation from polar reaction
products, which is of particular importance for the synthesis
of pharmaceutical fine chemicals because of their residual
toxicity in the target compounds, is a central issue to
consider.
Benzothiazoles are a considerably important class of
heterocycles in the medicinal area because of their broad
range of biological activities.9 Two common approaches are
applied for the construction of 2-substituted benzothiazoles.
The first approach used various oxidants, including Jacob-
son’s and Hugershoff’s methods via oxidative cyclization
of thiobenzanilides.10 However, using stoichiometric or
Scheme 1. Synthesis of 2-Substituted Benzothiazoles via a
Base-Promoted Cyclization
* To whom correspondence should be addressed. E-mail: hliu@
mail.shcnc.ac.cn. Phone: +86-21-50807042. Fax: +86-21-50807088.
10.1021/cc9001839  2010 American Chemical Society
Published on Web 04/09/2010

Synthesis of 2-Substituted (N, O, C) Benzothiazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 423
Table 2. Synthesis of 2-Amino-Benzothiazoles via a
Scheme 2. Synthesis of Cyclization Precursors 1 from
ortho-Haloaryl Isothiocyanates 3
Base-Promoted Cyclizationa
Table 1. Optimization of the Reaction Conditionsa
entry
base
solvent time (h) temperature (°C) yield of 2a (%)b
1
2
3
4
5
6
7
8
9
Na2CO3 DME
2
2
2
2
2
2
2
2
2
2
1
0.5
2
2
130
130
130
130
130
130
130
130
130
130
130
130
140
100
130
45
79
10
84
30
89
85
81
85
78
65
35
79
Trace
65
K2CO3
NaOH
DME
DME
Cs2CO3 DME
DBU DME
Cs2CO3 dioxane
Cs2CO3 DMF
Cs2CO3 DMSO
Cs2CO3 toluene
10 Cs2CO3 NMP
11 Cs2CO3 dioxane
12 Cs2CO3 dioxane
13 Cs2CO3 dioxane
14 Cs2CO3 dioxane
a Reaction conditions: 1 (0.2 mmol), base (0.4 mmol), dioxane (2
mL), 130 °C, 2 h, X ) I. b Yield of isolated products. c X ) Br, at 140 °C.
d Reaction time prolonged to 10 h.
c
15 Cs2CO3 dioxane
2
no improvement was observed when the temperature was
further increased or decreased (Table 1, entries 13 and 14).
Essentially, no satisfactory results were obtained when a
smaller amount of Cs2CO3 was used in this cyclization (Table
1, entry 15). In these cases, only N-benzylbenzothiazol-2-
amine 2a resulting from cyclization through CsS bond
formation was observed, with no evidence for the formation
of 1-benzyl-1H-benzoimidazole-2(3H)-thione that would
form from cyclization through the nitrogen atom.18
a Reaction conditions: 1a (0.2 mmol), base (0.4 mmol), solvent (2
mL). b Yield of isolated products. c 0.2 mmol Cs2CO3 was used as the
base.
system. Indeed, the method developed here represents a rare
example of CsS bond formation under transition metal-free
reaction conditions with competitive yields when compared
with its catalyzed versions.3-8
Results and Discussion
After determining the optimized conditions (1.0 equiv of
ortho-haloaryl precursors 1, 2.0 equiv of Cs2CO3, in dioxane
at 130 °C for 2 h), we next examined the generality of the
process. First, we demonstrated that a variety of N′-
substituted-N-(2-halophenyl)thioureas, including primary and
secondary N′-substituted ureas could provide the desired
products 2a-2p in moderate to good yields (56-92%)
(Table 2, entries 1-16). We were pleased to find that the
electronic nature of the benzylamine seems to have little
influence on the reaction, which is evident from the fact that
both the electron-rich (Table 2, entries 2-4) and the electron-
deficient (Table 2, entries 5 and 6) benzylamines gave
satisfactory results. Comparatively, desired product could be
obtained in low yield (25%) by reacting 1-(2-iodophenyl)-
3-phenyl-thiourea 1h under essentially the same conditions
as above, prolonging the reation time to 10 h to give a
moderate yield (60%). Moreover, under the optimized
conditions, 1g and 1i selected for this study gave strong
evidence to suggest that this base-promoted coupling reaction
tolerates N′-heterocyclic groups 2g and 2i (Table 2, entries
7 and 9). In the case of N,N′,N′-trisubstituted thioureas,
excellent yields (>89%) were obtained under these base-
promoted coupling reaction conditions (Table 2, entries
11-16), which was consistent with the order reported
previously.11d It is noteworthy that the coupling of 1n
furnished the expected product 2n in 90% isolated yield, in
The requisite cyclization precursors N′-substituted-N-(2-
halophenyl)ureas or O′-substituted-N-(2-halophenyl) car-
bamothioate 1 are readily synthesized from ortho-haloaryl
isothiocyanates 39b,16 through reactions with base and
different kinds of amines and alcohols in dichloromethane
(Scheme 2). The desired products were obtained in less than
20 min, in quantitative yields. The N-(2-halophenyl) thioa-
mides are readily synthesized according to the relevant
literature.17
1-Benzyl-3-(2-iodophenyl)thiourea 1a was first used as a
model substrate to optimize the reaction conditions, including
different bases, various solvents, reaction temperatures, and
reaction times. The results are shown in Table 1. Intramo-
lecular cyclization of 1a was investigated using 1,2-
dimethoxyethane (DME) as the solvent, at 130 °C for 2 h
with various bases, including inorganic bases Na2CO3,
K2CO3, NaOH, Cs2CO3, and organic base 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU). Good conversion of 1a
to N-benzylbenzothiazol-2-amine 2a was observed with
K2CO3 and Cs2CO3, with Cs2CO3 being superior in 84% yield
(Table 1, entries 1-5). Encouraged by this result, we further
examined this reaction using Cs2CO3 as the base. Dioxane
proved to be best among an array of solvents tested (Table
1, entries 5-10). Reduced reaction time led to a significant
decrease in reaction yields (Table 1, entries 11 and 12) and

424 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Table 3. Synthesis of Various 2-Amino-Benzothiazolesa
Feng et al.
Scheme 3. Tandem Reaction in One Pot
a Reagent and conditions: 3 (0.1 mmol), benylamine (0.1 mmol), and
Et3N (0.2 mmol) in dioxane (2 mL), rt, 5 min; then Cs2CO3 (0.2 mmol)
was added, the vial was sealed and heated at 130 °C for 2 h. b Reaction
time prolonged to 10 h.
Scheme 4. Synthesis of Various 2-Substituted Benzothiazoles
a Reaction conditions: 1 (0.2 mmol), Cs2CO3 (0.4 mmol), dioxane (2
mL), 130 °C, 2 h. b Yield of isolated products.
which the ester group was well tolerated during the reaction
(Table 2, entry 14). The reaction also works with ortho-
bromoaryl precursors, giving somewhat lower yields than
the reactions from the ortho-iodoaryl precursors (Table 2,
entries 1, 2, 3, 6, and 12).
Prompted by the successful synthesis of 2-amino-ben-
zothiazoles 2a-2p, we then investigated the scope of the
process with respect to the aryl substitutents of N′-substituted-
N-(2-halophenyl)thioureas. We found that both the electron-
donating methoxy substituent and the electron-withdrawing
fluoro or trifluoromethyl groups could be readily incorpo-
rated, and good yields of the desired products 2q-2aa were
obtained (Table 3, entries 1-11).
a Reaction conditions: 1 (0.2 mmol), Cs2CO3 (0.4 mmol), dioxane (2
mL), 80 °C, 2 h. b Reaction conditions: 1 (0.2 mmol), Cs2CO3 (0.4 mmol),
dioxane (2 mL), 115 °C, 2 h.
During the preparation of this manuscript, Li et al. reported
a direct strategy to 2-aminobenzothiazoles via an iron-
catalyzed tandem reaction from 2-halobenzenamines with
isothiocyanates.19 To our delight, results for the application
of our metal free conditions in one pot for various substrates
(N′-aryl, alkyl and benzyl) were also obtained in moderate
to good yields (Scheme 3).
amines or alcohols to assemble various products in moderate
to good yields. In this regard, this approach would be
particularly suitable for library synthesis in drug discovery
efforts.
Experimental Section
Finally, we focused our attention on employing O′-
substituted-N-(2-halophenyl) carbamothioate and N-(2-
halophenyl) thioamides as the substrates. In these cases, the
base-promoted coupling reaction proceeded smoothly at 80
and 115 °C, respectively. Under these reaction conditions, a
number of 2-substituted (aryl, alkyl, and ether) precursors 1
were applied, and they all gave the corresponding 2-substi-
tuted-benzothiazoles 2 in good yields (2ab-2ah), thereby
providing an alternative route for the synthesis of these
heterocyclic compounds (Schemes 4).
General Procedure for Synthesis of N′-substituted-N-
(2-halo-phenyl)thioureas (Method 1) and O′-substituted-
N-(2-halophenyl) Carbamothioate (Method 2). Method
1. To a solution of amine (0.5 mmol) and triethylamine
(TEA) (0.5 mmol) in CH2Cl2 (5 mL) at room temperature
(rt), ortho-haloaryl isothiocyanates 3 (0.5 mmol) was added.
The reaction was monitored with thin-layer chromatography
(TLC), and then the reaction mixture was concentrated in
vacuo. The desired products were obtained in high yields
and purity without further purification.
Method 2. To a solution of alcohol (0.5 mmol) and NaH
(0.5 mmol) in CH2Cl2 (5 mL) at 0 °C, ortho-haloaryl
isothiocyanate 3 (0.5 mmol) was added dropwise. After the
starting materials were completely reacted, the reaction
mixture was diluted with CH2Cl2, washed with water, and
saturated brine, and dried with anhydrous Na2SO4. The
solvent was evaporated under reduced pressure, and the
Conclusion
In conclusion, we have developed a novel protocol for
the elaboration of 2-substituted (N, O, C) benzothiazoles via
a base-promoted intramolecular C-S bond coupling cycliza-
tion without any transition metal. This method enables the
use of a wide range of ortho-haloaryl isothiocyanates and

Synthesis of 2-Substituted (N, O, C) Benzothiazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 425
residue was purified by flash column chromatography
(petroleum ether/ethyl acetate ) 20/1) to yield the expected
product.
by flash chromatography (petroleum ether/ethyl acetate )
8/1). 1H NMR (400 MHz, CDCl3, ppm) δ 3.87 (s, 3H), 4.59
(s, 2H), 6.90 (d, J ) 8.8 Hz, 1H), 6.94 (d, J ) 7.2 Hz, 1H),
7.09 (t, J ) 7.6 Hz, 1H), 7.29 (t, J ) 7.6 Hz, 1H), 7.35 (d,
J ) 7.6 Hz. 1H), 7.51 (d, J ) 8 Hz, 1H), 7.56 (d, J ) 7.6
Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 45.8, 55.3,
110.4, 118.1, 120.5, 120.9, 121.9, 124.9, 126.2, 129.0, 129.4,
129.5, 150.0, 157.5, 168.0; EI-MS m/z (M+) 270; EI-HRMS
calcd. For C15H14N2OS (M+) 270.0827, found 270.0832.
N-(3-(trifluoromethyl)benzyl)benzothiazol-2-amine (2e).
Compound 2e was obtained as a white solid after the
purification by flash chromatography (petroleum ether/ethyl
acetate ) 8/1). 1H NMR (300 MHz, CDCl3, ppm) δ 4.73 (s,
2H), 7.12 (t, J ) 7.5 Hz, 1H), 7.31 (t, J ) 7.5 Hz, 1H),
7.46-7.66 (m, 6H); 13C NMR (100 MHz, CDCl3, ppm) δ
48.7, 119.0, 120.9, 122.0, 124.35, and 124.39 (JC-F, 3.7 Hz),
124.70 and 124.73 (JC-F, 3.5 Hz), 126.2, 129.3, 130.2, 130.9,
138.5, 151.7, 167.1; EI-MS m/z (M+) 308; EI-HRMS calcd.
For C15H11F3N2S (M+) 308.0595, found 308.0586.
N-(4-fluorobenzyl)benzothiazol-2-amine (2f). Compound
2f was obtained as a white solid after the purification by
flash chromatography (petroleum ether/ethyl acetate ) 8/1).
1H NMR (400 MHz, CDCl3, ppm) δ 4.61 (s, 2H), 7.04 (td,
J ) 6.8,Hz, 2 Hz, 2H), 7.10 (td, J ) 8 Hz, 1.6 Hz, 1H),
7.29 (td, J ) 8 Hz, 0.9 Hz, 1H), 7.35-7.39 (m, 2H), 7.49
(dd, J ) 8 Hz, 0.4 Hz, 1H), 7.58 (dd, J ) 8 Hz, 0.8 Hz,
1H); 13C NMR (100 MHz, CDCl3, ppm) δ48.6, 115.59, and
115.80 (2ArCH, JC-F, 21.4 Hz), 118.9, 120.9, 121.8, 126.1,
129.33, and 129.41 (2ArCH, JC-F, 8.1 Hz), 130.2, 133.1,
151.8, 161.16, and 163.61 (JC-F, 245 Hz), 167.3; EI-MS m/z
(M+) 258; EI-HRMS calcd. For C14H11FN2S (M+) 258.0627,
found 258.0624.
General Procedure for Synthesis of 2-Substituted Ben-
zothiazoles 2. To a solution of N′-substituted-N-(2-halophe-
nyl) thiourea (0.5 mmol) in dioxane (2 mL), Cs2CO3 (1.0
mmol) was added. The vial was sealed, and this mixture was
then heated in an oil bath and stirred at 130 °C for 2 h (for
C′ and O′-substituted at 115 and 80 °C, respectively). The
cold mixture was diluted with CH2Cl2, washed with water,
and brine, and dried with anhydrous Na2SO4. The solvent
was then concentrated in vacuum. The residue was purified
by flash column chromatography to yield the expected
products 2a-2ah.
General Procedure for the Tandem Reaction in One
Pot. To a solution of 1-iodo-2-isothiocyanatobenzene 3 (0.1
mmol) and amine (0.1 mmol) in dioxane (2 mL), TEA (0.2
mmol) was added. After being stirred at rt for 5 min, Cs2CO3
(0.2 mmol) was added, then the vial was sealed and the
mixture was heated in an oil bath and stirred at 130 °C for
2 h. The cold mixture was diluted with CH2Cl2, washed with
water, and brine, and dried with anhydrous Na2SO4 and
concentrated in vacuum. The residue was purified by flash
column chromatography to yield the expected products.
N-benzylbenzothiazol-2-amine (2a). Compound 2a was
obtained as a white solid after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 8/1). H
NMR (300 MHz, CDCl3, ppm) δ 4.64 (s, 2H), 7.08 (t, J )
7.2 Hz, 1H), 7.25-7.28 (m, 1H), 7.30-7.40 (m, 5H), 7.43
(d, J ) 3.9 Hz, 1H), 7.58 (d, J ) 4.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3, ppm) δ 49.4, 118.8, 120.8, 121.5, 125.9,
127.6, 127.8, 128.8(2ArCH), 130.3(2ArCH), 137.4, 152.2,
167.7; EI-MS m/z (M+) 240; EI-HRMS calcd. For C14H12N2S
(M+) calcd. 240.0721, found 240.0719.
N-(4-methoxybenzyl)benzothiazol-2-amine (2b). Com-
pound 2b was obtained as a white solid after the purification
by flash chromatography (petroleum ether/ethyl acetate )
8/1). 1H NMR (400 MHz, CDCl3, ppm) δ 3.80 (s, 3H), 4.56
(s, 2H), 6.88 (d, J ) 8.4 Hz, 2H), 7.09 (t, J ) 6.4 Hz, 1H),
7.27 (t, J ) 6.8 Hz, 1H), 7.31 (d, J ) 8.4 Hz, 2H), 7.50 (d,
J ) 8 Hz, 1H), 7.57 (dd, J ) 7.6 Hz, 0.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3, ppm) δ 48.9, 55.3, 114.2(2ArCH), 118.7,
120.9, 121.7, 126.1, 129.1, 129.2, 130.0(2ArCH), 151.6,
159.3, 167.4; EI-MS m/z (M+) 270; EI-HRMS calcd. For
C15H14N2OS (M+) 270.0827, found 270.0832.
N-(pyridin-4-ylmethyl)benzothiazol-2-amine (2g). Com-
pound 2g was obtained as a white solid after the purification
by flash chromatography (petroleum ether/ethyl acetate )
8/1). 1H NMR (300 MHz, CDCl3, ppm) δ 4.71 (s, 2H), 7.12
(t, J ) 7.5 Hz, 1H), 7.28-7.34 (m, 3H), 7.51 (d, J ) 8.4
Hz, 1H), 7.59 (d, 7.5 Hz), 8.58 (br, 2H); 13C NMR (100
MHz,CDCl3,ppm)δ47.8,119.1,120.9,122.1,122.2(2ArCH),
126.2, 130.3, 147.0, 150.0, 151.8(2ArCH), 167.1; EI-MS m/z
(M+) 241; EI-HRMS calcd. For C13H11N3S (M+) 241.0674,
found 241.0683.
N-phenylbenzothiazol-2-amine (2h). Compound 2h was
obtained as a white solid after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 8/1). H
NMR (300 MHz, CDCl3, ppm) δ 7.14-7.20 (m, 2H), 7.34
(t, J ) 7.2 Hz, 1H), 7.39-7.44 (m, 2H), 7.52 (d, J ) 8.1
Hz, 2H), 7.60 (d, J ) 7.8 Hz, 1H), 7.64 (d, J ) 7.8 Hz,
1H);13CNMR(100MHz,CDCl3,ppm)δ119.4,120.2(2ArCH),
120.8, 122.4, 124.4, 126.1, 129.6, 129.9(2ArCH), 139.8,
151.3, 164.6; EI-MS m/z (M+) 226; EI-HRMS calcd. For
C13H10N2S (M+) 226.0565, found 226.0568.
N-(3-methoxybenzyl)benzothiazol-2-amine (2c). Com-
pound 2c was obtained as a white solid after the purification
by flash chromatography (petroleum ether/ethyl acetate )
8/1). 1H NMR (400 MHz, CDCl3, ppm) δ 3.78 (s, 3H), 4.59
(s, 2H), 6.85 (dd, J ) 8 Hz, 2 Hz, 1H), 6.94 (s, 1H), 6.97
(d, J ) 7.6 Hz, 1H), 7.13 (t, J ) 8 Hz, 1H), 7.27 (t, J ) 8
Hz, 1H), 7.32 (d, J ) 8 Hz, 1H), 7.49 (d, J ) 8 Hz, 1H),
7.55 (dd, J ) 8 Hz, 0.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3, ppm) δ 49.7, 55.2, 113.1, 113.5, 117.7, 119.8, 121.1,
122.3, 126.6, 128.2, 129.9, 138.0, 148.6, 160.0, 168.3; EI-
MS m/z (M+) 270; EI-HRMS calcd. For C15H14N2OS (M+)
270.0827, found 270.0832.
N-(thiazol-2-yl)benzothiazol-2-amine (2i). Compound 2i
was obtained as a yellow solid after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 8/1). H
NMR (300 MHz, DMSO-d6, ppm) δ 7.12 (d, J ) 3.6 Hz,1H),
7.20 (td, J ) 7.5 Hz, 1.2 Hz, 1H), 7.43 (d, J ) 3.6 Hz, 1H),
7.58 (d, J ) 8.1 Hz, 1H), 7.84 (d, J ) 7.5 Hz, 1H), 12.46
(br, 1H); 13C NMR (100 MHz, DMSO-d6, ppm) δ 111.7,
N-(2-methoxybenzyl)benzothiazol-2-amine (2d). Com-
pound 2d was obtained as a white solid after the purification

426 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Feng et al.
121.8, 122.6(2ArCH), 126.2, 130.3, 161.6; ESI-MS m/z
[M+H]+ 234; HRMS (ESI) calcd for C10H8N3S2 [M+H]+
234.0160 found 234.0165.
by flash chromatography (petroleum ether/ethyl acetate )
8/1). H NMR (400 MHz, CDCl3, ppm) δ 3.33 (t, J ) 5.2
1
Hz, 4H), 3.81 (t, J ) 5.2 Hz, 4H), 6.93 (t, J ) 7.2 Hz, 1H),
6.98 (d, J ) 8 Hz, 2H), 7.10 (td, J ) 8 Hz, 1.2 Hz, 1H),
7.30-7.34 (m, 3H), 7.58 (d, J ) 8 Hz, 1H), 7.62 (dd, J )
8 Hz, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ
48.3(2CH2), 49.1(2CH2), 116.9(2ArCH), 119.2, 120.7, 120.8,
121.6, 126.1, 129.3(2ArCH), 130.7, 151.0, 152.6, 168.7; EI-
MS m/z (M+) 295; EI-HRMS calcd. For C17H17N3S (M+)
295.1143, found 295.1135.
N-butylbenzothiazol-2-amine (2j). Compound 2j was
obtained as a white solid after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 8/1). H
NMR (300 MHz, CDCl3, ppm) δ 0.96 (t, J ) 7.2 Hz, 3H),
1.37-1.48 (m, 2H), 1.61-1.73 (m, 2H), 3.41 (t, J ) 7.2
Hz, 2H), 7.07 (t, J ) 7.8 Hz, 1H), 7.29 (t, J ) 7.5 Hz, 1H),
7.52 (d, J ) 8.1 Hz, 1H), 7.59 (d, J ) 7.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3, ppm) δ 13.7, 20.0, 31.6, 45.4,
118.5, 120.8, 121.3, 125.9, 130.2, 152.4, 168.0; EI-MS m/z
(M+) 206; EI-HRMS calcd. For C11H14N2S (M+) 206.0878,
found 206.0883.
2-(Pyrrolidin-1-yl)benzothiazole (2p). Compound 2p was
obtained as a white solid after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 8/1). H
NMR (400 MHz, CDCl3, ppm) δ 2.07-2.09 (m, 4H),
3.57-3.61 (m, 4H), 7.04 (dd, J ) 8 Hz, 1.2 Hz, 1H), 7.28
(dd, J ) 8 Hz, 1.2 Hz, 1H), 7.58 (d, J ) 8 Hz, 2H); 13C
NMR (100 MHz, CDCl3, ppm) δ 25.6(2CH2), 49.5(2CH2),
118.6, 120.6(2ArCH), 125.9, 130.6, 153.1, 165.4; EI-MS m/z
(M+) 204; EI-HRMS calcd. For C11H12N2S (M+) 204.0721,
found 204.0724.
N-benzyl-6-fluorobenzo[d]thiazol-2-amine (2q). Com-
pound 2q was obtained as a white solid after the purification
by flash chromatography (petroleum ether/ethyl acetate )
8/1). 1H NMR (400 MHz, CDCl3, ppm) δ 4.63 (s, 2H), 5.67
(br, 1H), 7.02 (td, J ) 9.2 Hz, 2.8 Hz, 1H), 7.28 (dd, J ) 8
Hz, 2.4 Hz, 1H), 7.30-7.41 (m, 5H), 7.44 (dd, J ) 8.8 Hz,
4.8 Hz, 1H; 13C NMR (100 MHz, CDCl3, ppm) δ 49.3,
N,N-diethylbenzothiazol-2-amine (2k). Compound 2k
was obtained as a white solid after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 8/1). H
NMR (300 MHz, CDCl3, ppm) δ 1.29 (t, J ) 7.2 Hz, 6H),
3.57 (q, J ) 7.2 Hz, 4H), 7.02 (td, J ) 7.8 Hz, 1.2 Hz, 1H),
7.26 (td, J ) 7.5 Hz, 1.2 Hz, 1H), 7.53 (d, J ) 7.8 Hz, 1H),
7.57 (dd, J ) 7.5 Hz, 0.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3, ppm) δ 12.8(2CH3), 45.3(2CH2), 118.5, 120.5, 120.7,
125.8, 130.6, 153.3, 167.3; EI-MS m/z (M+) 206; EI-HRMS
calcd. For C11H14N2S (M+) 206.0878, found 206.0881.
4-(Benzothiazol-2-yl)morpholine (2l). Compound 2l was
obtained as a white solid after the purification by flash
1
chromatography (petroleum ether/ethyl acetate )1/1). H
107.44, and 107.71 (JC-F, 25.4 Hz), 113.51 and 113.75 (JC-F
,
NMR (400 MHz, CDCl3, ppm) δ 3.62 (t, J ) 4.8 Hz, 4H),
3.84 (t, J ) 4.8 Hz, 4H), 7.10 (dd, J ) 8.4 Hz, 0.8 Hz, 1H),
7.31 (dd, J ) 8.4 Hz, 0.8 Hz, 1H), 7.57 (d, J ) 8 Hz, 1H),
7.61 (d, J ) 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm)
δ48.5(2CH2), 66.2(2CH2), 119.3, 120.8, 121.7, 126.1, 130.6,
152.5; EI-MS m/z (M+) 220; EI-HRMS calcd. For
C11H12N2OS (M+) 220.0670, found 220.0668.
23.6 Hz), 119.39 and 119.48 (JC-F, 8.6 Hz), 127.7(2ArCH),
128.0, 128.9(2ArCH), 131.15 and 131.25 (JC-F, 10.9 Hz),
137.3, 148.7, 157.1 and 159.5(JC-F, 238.7 Hz), 166.6; EI-
MS m/z (M+) 258; EI-HRMS calcd. For C14H11FN2S (M+)
258.0627, found 258.0628.
Ethyl 4-(2-Methyl-3-oxo-2H-1,4-benzoxazin-4(3H)-yl)-
benzoate (2r). Compound 2r was obtained as a white solid
after the purification by flash chromatography (petroleum
ether/ethyl acetate ) 8/1). 1H NMR (300 MHz, CDCl3, ppm)
δ 4.63 (s, 2H), 7.06 (dd, J ) 8.4 Hz, 1.8 Hz, 1H), 7.31-7.42
(m, 5H), 7.46 (d, J ) 4.2 Hz, 1H), 7.48 (d, J ) 1.8 Hz, 1H);
13C NMR (100 MHz, CDCl3, ppm) δ 49.4, 119.0, 121.4,
121.8, 127.5, 127.7, 128.0, 128.7, 128.9, 131.9(2ArCH),
137.0, 153.3, 168.5; EI-MS m/z (M+) 274; EI-HRMS calcd.
For C14H11ClN2S (M+) 274.0331, found 274.0333.
N-benzyl-5-methoxybenzothiazol-2-amine (2s). Com-
pound 2s was obtained as a white solid after the purification
by flash chromatography (petroleum ether/ethyl acetate )
8/1). 1H NMR (300 MHz, CDCl3, ppm) δ 3.76 (s, 3H), 4.61
(s, 2H), 6.71 (dd, J ) 8.4 Hz, 2.1 Hz, 1H), 7.04 (d, J ) 2.4
Hz, 1H), 7.30-7.42 (m, 6H); 13C NMR (100 MHz, CDCl3,
ppm) δ 49.4, 55.4, 103.0, 110.1, 121.0, 121.4, 127.5(2ArCH),
127.8, 128.7(2ArCH), 137.3, 153.0, 159.0, 169.5; EI-MS m/z
(M+) 270; EI-HRMS calcd. For C15H14N2OS (M+) 270.0827,
found 270.0830.
6-Fluoro-N-(4-methoxybenzyl)benzothiazol-2-amine (2t).
Compound 2t was obtained as a white solid after the
purification by flash chromatography (petroleum ether/ethyl
acetate ) 8/1). 1H NMR (300 MHz, CDCl3, ppm) δ 3.81 (s,
3H), 4.55 (s, 2H), 5.66 (br, 1H), 6.90 (d, J ) 8.7 Hz, 2H),
7.01 (td, J ) 9 Hz, 2.4 Hz, 1H), 7.26 (d, J ) 2.4 Hz, 1H),
2-(Piperidin-1-yl)benzothiazole (2m). Compound 2m was
obtained as a white solid after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 8/1). H
NMR (300 MHz, CDCl3, ppm) δ 1.69 (br, 6H), 3.59 (br,
4H), 7.04 (dd, J ) 7.8 Hz, 1.2 Hz, 1H), 7.27 (dd, J ) 7.8
Hz, 0.9 Hz, 1H), 7.53 (dd, J ) 8.1 Hz, 0.6 Hz, 1H), 7.57
(dd, J ) 7.8 Hz, 0.6 Hz, 1H); 13C NMR (100 MHz, CDCl3,
ppm) δ 24.2, 25.3(2CH2), 49.6(2CH2), 118.7, 120.5, 121.0,
125.8, 130.6, 152.9, 168.9; EI-MS m/z (M+) 218; EI-HRMS
calcd. For C12H14N2S (M+) 218.0878, found 218.0871.
Ethyl 1-(Benzothiazol-2-yl)piperidine-4-carboxylate (2n).
Compound 2n was obtained as a white solid after the
purification by flash chromatography (petroleum ether/ethyl
acetate ) 8/1). 1H NMR (300 MHz, CDCl3, ppm) δ 1.27 (t,
J ) 7.2 Hz, 3H), 1.82-1.92 (m, 2H), 2.02-2.07 (m, 2H),
2.53-2.58 (m, 1H), 3.19-3.28 (m, 2H), 4.05-4.13 (m, 2H),
4.16 (q, J ) 7.2 Hz, 2H), 7.07 (td, J ) 7.8 Hz, 0.9 Hz, 1H),
7.29 (td, J ) 7.5 Hz, 1.5 Hz, 1H), 7.55 (d, J ) 8.1 Hz, 1H),
7.59 (d, J ) 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm)
δ 14.1, 27.4(2CH2), 40.8, 47.9(2CH2), 60.6, 118.9, 120.6,
121.3, 125.9, 130.7, 152.7, 168.6, 174.0; EI-MS m/z (M+)
290; EI-HRMS calcd. For C15H18N2O2S (M+) 290.1089,
found 290.1082.
2-(4-Phenylpiperazin-1-yl)benzothiazole (2o). Com-
pound 2o was obtained as a white solid after the purification

Synthesis of 2-Substituted (N, O, C) Benzothiazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 427
7.32 (d, J ) 8.7 Hz, 2H), 7.43 (dd, J ) 8.4 Hz, 4.8 Hz, 1H);
13C NMR (100 MHz, CDCl3, ppm) δ 48.8, 55.3, 107.42,
and 107.69 (JC-F, 26.9 Hz), 113.47 and 113.71 (JC-F, 23.6
Hz), 114.2(2ArCH), 119.31 and 119.40 (JC-F, 8.7 Hz),
129.1(2ArCH), 129.2, 131.1, 148.7, 157.07, and 159.35
(JC-F, 227.1 Hz), 159.5, 166.6; EI-MS m/z (M+) 288; EI-
HRMS calcd. For C15H13FN2OS (M+) 288.0733, found
288.0731.
5-Chloro-N-(4-methoxybenzyl)benzothiazol-2-amine (2u).
Compound 2u was obtained as a white solid after the
purification by flash chromatography (petroleum ether/ethyl
acetate ) 8/1). 1H NMR (300 MHz, CDCl3, ppm) δ 3.81 (s,
3H), 4.54 (s, 2H), 6.90 (d, J ) 8.7 Hz, 2H), 7.04 (dd, J )
8.4 Hz, 1.8 Hz, 1H), 7.32 (d, J ) 8.4 Hz, 2H), 7.39 (d, J )
2.1 Hz, 1H), 7.45 (d, J ) 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3, ppm) δ 49.2, 55.3, 114.3(2ArCH), 118.6, 121.4,
121.8, 128.0, 128.6, 129.1(2ArCH), 131.9, 152.7, 159.4,
169.4; EI-MS m/z (M+) 304; EI-HRMS calcd. For
C15H13ClN2OS (M+) 304.0437, found 304.0425.
5-Methoxy-N-(4-methoxybenzyl)benzothiazol-2-amine (2v).
Compound 2v was obtained as a white solid after the
purification by flash chromatography (petroleum ether/ethyl
acetate ) 8/1). 1H NMR (400 MHz, CDCl3, ppm) δ 3.81 (s,
3H), 3.83 (s, 3H), 4.55 (s, 2H), 5.73 (br, 1H), 6.72 (dd, J )
8.7 Hz, 2.4 Hz, 1H), 6.89 (dt, J ) 8.7 Hz, 2.7 Hz, 2H), 7.10
(d, J ) 2.1 Hz, 1H), 7.31 (dt, J ) 8.7 Hz, 3 Hz, 2H), 7.42
(d, J ) 9 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ
48.8, 55.3, 55.5, 103.4, 110.1, 114.2(2ArCH), 121.0, 121.9,
129.1(2ArCH), 129.4, 153.5, 159.0, 159.3, 168.5; EI-MS m/z
(M+) 300; EI-HRMS calcd. For C16H16N2O2S (M+) 300.0932,
found 300.0927.
Hz, 1H), 7.48 (d, J ) 8.4 Hz, 1H), 7.53 (d, J ) 2 Hz, 1H);
13C NMR (100 MHz, CDCl3, ppm) δ 48.4(2CH2),
66.1(2CH2), 119.2, 121.3, 121.7, 128.7, 131.9, 153.5, 170.0;
EI-MS m/z (M+) 254; EI-HRMS calcd. For C11H11ClN2OS
(M+) 254.0281, found 254.0289.
4-(5-Methoxybenzothiazol-2-yl)morpholine (2z). Com-
pound 2z was obtained as a white solid after the purification
by flash chromatography (petroleum ether/ethyl acetate )
1
8/1). H NMR (300 MHz, CDCl3, ppm) δ 3.60 (t, J ) 5.1
Hz, 4H), 3.81-3.84 (m, 7H), 6.73 (dd, J ) 8.7 Hz, 2.7 Hz,
1H), 7.14 (d, J ) 2.1 Hz, 1H), 7.45 (d, J ) 8.7 Hz, 1H); 13
C
NMR (100 MHz, CDCl3, ppm) δ 48.3(2CH2), 55.4(2CH2),
66.1, 103.3, 110.3, 120.9, 121.9, 153.5, 159.0, 170.2; EI-
MS m/z (M+) 250; EI-HRMS calcd. For C12H14N2O2S (M+)
250.0776, found 250.0776.
4-(6-(Trifluoromethyl)benzothiazol-2-yl)morpholine (2aa).
Compound 2aa was obtained as a white solid after the
purification by flash chromatography (petroleum ether/ethyl
acetate ) 8/1). 1H NMR (300 MHz, CDCl3, ppm) δ 3.65 (t,
J ) 4.5 Hz, 4H), 3.84 (t, J ) 4.8 Hz, 4H), 7.54 (d, J ) 9.3
Hz, 1H), 7.59 (d, J ) 8.4 Hz, 1H), 7.87 (s, 1H); 13C NMR
(100 MHz, CDCl3, ppm) δ 48.4(2CH2), 66.1(2CH2), 118.19
and 118.23 (JC-F, 4.1 Hz), 119.0, 123.33, and 123.36 (JC-F
,
3.2 Hz), 123.13 and 128.53 (JC-F, 539.8 Hz), 123.68 and
125.83 (JC-F, 214.9 Hz), 130.6, 155.1, 170.5; EI-MS m/z
(M+) 288; EI-HRMS calcd. For C12H11F3N2OS (M+)
288.0544, found 288.0549.
2-Methoxybenzothiazole (2ab). Compound 2ab was
obtained as a colorless oil after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 20/1). H
NMR (300 MHz, CDCl3, ppm) δ 4.20 (s, 3H), 7.23 (dd, J
) 8.1 Hz, 0.9 Hz, 1H), 7.37 (dd, J ) 8.1 Hz, 0.9 Hz, 1H),
7.63 (dd, J ) 7.8 Hz, 0.6 Hz, 1H), 7.71(d, J ) 8.1 Hz, 1H);
13C NMR (100 MHz, CDCl3, ppm) δ 58.4, 120.7, 121.2,
123.4, 125.9, 149.2, 173.4; EI-MS m/z (M+) 165; EI-HRMS
calcd. For C8H7NOS (M+) 165.0248, found 165.0232.
2-Ethoxybenzothiazole (2ac). Compound 2ac was ob-
tained as a colorless oil after the purification by flash
N-(4-methoxybenzyl)-6-(trifluoromethyl)benzothiazol-
2-amine (2w). Compound 2w was obtained as a white solid
after the purification by flash chromatography (petroleum
ether/ethyl acetate ) 8/1). 1H NMR (300 MHz, CDCl3, ppm)
δ 3.50 (s, 1H), 3.81 (s, 3H), 4.58 (s, 2H), 6.90 (d, J ) 8.4
Hz, 2H), 7.32 (d, J ) 9 Hz, 2H), 7.51-7.52 (m, 2H), 7.84
(s, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 49.0, 55.3,
114.3(2ArCH), 118.28 and 118.57 (JC-F, 29.6 Hz), 123.12
and 123.29 (2ArCH, JC-F, 16 Hz), 128.7, 129.1(2ArCH),
130.5, 154.7, 159.5, 169.2; EI-MS m/z (M+) 338; EI-HRMS
calcd. For C16H13F3N2OS (M+) 338.0701, found 338.0703.
4-(6-Fluorobenzothiazol-2-yl)morpholine (2x). Com-
pound 2x was obtained as a white solid after the purification
by flash chromatography (petroleum ether/ethyl acetate )
1
chromatography (petroleum ether/ethyl acetate ) 20/1). H
NMR (300 MHz, CDCl3, ppm) δ 1.49 (t, J ) 7.2 Hz, 3H),
4.63 (q, J ) 7.2 Hz, 2H), 7.22 (t, J ) 7.5 Hz, 1H), 7.36 (t,
J ) 7.8 Hz, 1H), 7.63 (d, J ) 7.5 Hz, 1H), 7.69 (d, J ) 7.8
Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ14.4, 67.9,
120.7, 121.2, 123.3, 125.9, 131.8, 149.4, 172.9; EI-MS m/z
(M+) 179; EI-HRMS calcd. For C9H9NOS (M+) 179.0405,
found 179.0410.
1
8/1). H NMR (400 MHz, CDCl3, ppm) δ 3.58-3.61 (m,
4H), 3.82-3.86 (m, 4H), 7.03 (td, J ) 9.3 Hz, 2.4 Hz, 1H),
7.32 (dd, J ) 7.8 Hz, 2.7 Hz, 1H), 7.49 (dd, J ) 9 Hz, 2.1
Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 48.4(2CH2),
66.2(2CH2), 107.36 and 107.63 (JC-F, 26.8 Hz), 113.66 and
113.90 (JC-F, 23.8 Hz), 119.69 and 119.78 (JC-F, 8.8 Hz),
128.8, 148.9, 157.02, and 159.41 (JC-F, 238.2 Hz), 159.4,
168.6; EI-MS m/z (M+) 238; EI-HRMS calcd. For
C11H11FN2OS (M+) 238.0576, found 238.0568.
2-(But-3-yn-1-yloxy)benzothiazole (2ad). Compound 2ad
was obtained as a white solid after the purification by flash
chromatography (petroleum ether/ethyl acetate ) 20/1). H
1
NMR (300 MHz, CDCl3, ppm) δ 2.06 (t, J ) 2.8 Hz, 1H),
2.78 (td, J ) 6.8 Hz, 2.8 Hz, 2H), 4.67 (t, J ) 6.8 Hz, 2H),
7.23 (td, J ) 8.4 Hz, 0.8 Hz, 1H), 7.37 (td, J ) 8.4 Hz, 0.8
Hz, 1H), 7.64(d, J ) 8 Hz, 1H), 7.68(d, J ) 8 Hz, 1H); 13
C
NMR (100 MHz, CDCl3, ppm) δ 19.1, 69.1, 70.3, 79.6,
120.9, 121.3, 123.6, 126.0, 131.9, 149.2, 172.3; EI-MS m/z
(M+) 203; EI-HRMS calcd. For C11H9NOS (M+) 203.0405,
found 203.0397.
2-(Benzyloxy)benzothiazole (2ae). Compound 2ae was
obtained as a colorless oil after the purification by flash
4-(5-Chlorobenzo[d]thiazol-2-yl)morpholine (2y). Com-
pound 2y was obtained as a white solid after the purification
by flash chromatography (petroleum ether/ethyl acetate )
1
8/1). H NMR (400 MHz, CDCl3, ppm) δ 3.61 (t, J ) 4.8
Hz, 4H), 3.82 (t, J ) 4.8 Hz, 4H), 7.05 (dd, J ) 8.8 Hz, 2

428 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Feng et al.
1
8677. (c) Ferna´ndez-Rodr´ıguez, M. A.; Shen, Q.; Hartwig,
J. F. Chem.sEur. J. 2006, 12, 7782. (d) Fernandez-Rodriguez,
M. A.; Shen, Q. L.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 2180. (e) Alvaro, E.; Hartwig, J. F. J. Am. Chem. Soc.
2009, 131, 7858.
chromatography (petroleum ether/ethyl acetate ) 20/1). H
NMR (300 MHz, CDCl3, ppm) δ 5.61 (s, 2H), 7.22-7.46
(m, 5H), 7.50-7.53 (m, 2H), 7.66 (dd, J ) 7.8 Hz, 0.9 Hz,
1H), 7.74 (dd, J ) 8.1 Hz, 0.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3,ppm)δ73.3,120.8,121.3,123.6,126.0,128.5(2ArCH),
128.6(2ArCH), 129.4, 132.0, 135.2, 149.2, 172.7; EI-MS m/z
(M+) 241; EI-HRMS calcd. For C14H11NOS (M+) 241.0561,
found 241.0559.
(5) (a) Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007, 9,
3495. (b) Jammi, S.; Barua, P.; Rout, L.; Saha, P.; Punnlya-
murthy, T. Tetrahedron Lett. 2008, 49, 1484.
(6) (a) She, J.; Jiang, Z.; Wang, Y. G. Tetrahedron Lett. 2009,
50, 593. (b) Herrero, M. T.; SanMartin, R.; Dominguez, E.
Tetrahedron 2009, 65, 1500. (c) Fukuzawa, S.; Shimizu, E.;
Atsuumi, Y.; Haga, M.; Ogata, K. Tetrahedron Lett. 2009,
50, 2374. (d) Xu, H. J.; Zhao, X. Y.; Fu, Y.; Feng, Y. S.
Synlett 2008, 19, 3063. (e) Sperotto, E.; van Klink, G. P. M.;
de Vries, J. G.; van Koten, G. J. Org. Chem. 2008, 73, 5625.
(f) Buranaprasertsuk, P.; Chang, J. W. W.; Chavasiri, W.;
Chan, P. W. H. Tetrahedron Lett. 2008, 49, 2023.
(7) Wong, Y. C.; Jayanth, T. T.; Cheng, C. H. Org. Lett. 2006,
8, 5613.
2-Phenylbenzothiazole (2af). Compound 2af was ob-
tained as a colorless oil after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 20/1). H
NMR (300 MHz, CDCl3, ppm) δ 7.40 (t, J ) 7.8 Hz, 1H),
7.48-7.54 (m, 4H), 7.92 (d, J ) 8.1 Hz, 1H), 8.08-8.13
(m, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 121.6, 123.2,
125.2, 126.3, 127.5(2ArCH), 129.0(2ArCH), 131.0, 133.6,
135.0, 154.1, 168.1; ESI-MS m/z [M+H]+ 212; HRMS (ESI)
calcd for C13H10NS [M+H]+ 212.0534 found 212.0549.
2-Benzylbenzothiazole (2ag). Compound 2ag was ob-
tained as a colorless oil after the purification by flash
(8) (a) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed.
2008, 47, 2880. (b) Jegelka, M.; Plietker, B. Org. Lett. 2009,
11, 3462.
(9) (a) Serdons, K.; Terwinghe, C.; Vermaelen, P.; Van Laere,
K.; Kung, H.; Mortelmans, L.; Bormans, G.; Verbruggen, A.
J. Med. Chem. 2009, 52, 1428. (b) Kai, H.; Morioka, Y.;
Koriyama, Y.; Okamoto, K.; Hasegawa, Y.; Hattori, M.;
Koike, K.; Chiba, H.; Shinohara, S.; Iwamoto, Y.; Takahashi,
K.; Tanimoto, N. Bioorg. Med. Chem. Lett. 2008, 18, 6444.
(c) Sparks, R. B.; Polam, P.; Zhu, W.; Crawley, M. L.;
Takvorian, A.; McLaughlin, E.; Wei, M.; Ala, P. J.; Gonnev-
ille, L.; Taylor, N.; Li, Y.; Wynn, R.; Burn, T. C.; Liu, P. C.;
Combs, A. P. Bioorg. Med. Chem. Lett. 2007, 17, 736. (d)
Kai, H.; Morioka, Y.; Tomida, M.; Takahashi, T.; Hattori,
M.; Hanasaki, K.; Koike, K.; Chiba, H.; Shinohara, S.;
Kanemasa, T.; Iwamoto, Y.; Takahashi, K.; Yamaguchi, Y.;
Baba, T.; Yoshikawa, T.; Takenaka, H. Bioorg. Med. Chem.
Lett. 2007, 17, 3925. (e) Kai, H.; Morioka, Y.; Murashi, T.;
Morita, K.; Shinonome, S.; Nakazato, H.; Kawamoto, K.;
Hanasaki, K.; Takahashi, F.; Mihara, S. I.; Arai, T.; Abe, K.;
Okabe, H.; Baba, T.; Yoshikawa, T.; Takenaka, H. Bioorg.
Med. Chem. Lett. 2007, 17, 4030. (f) Hutchinson, I.; Chua,
M. S.; Browne, H. L.; Trapani, V.; Bradshaw, T. D.; Westwell,
A. D.; Stevens, M. F. G. J. Med. Chem. 2001, 44, 1446. (g)
Nikulin, V. I.; Rakov, I. M.; De los Angeles, J. E.; Mehta,
R. C.; Boyd, L. Y.; Feller, D. R.; Miller, D. D. Bioorg. Med.
Chem. 2006, 14, 1684. (h) Yoshino, K.; Kohno, T.; Uno, T.;
Morita, T.; Tsukamoto, G. J. Med. Chem. 1986, 29, 820. (i)
Henriksen, G.; Hauser, A. I.; Westwell, A. D.; Yousefi, B. H.;
Schwaiger, M.; Drzezga, A.; Wester, H. J. J. Med. Chem.
2007, 50, 1087.
(10) (a) Bose, D. S.; Idrees, M. Tetrahedron Lett. 2007, 48, 669.
(b) Bose, D. S.; Idrees, M. J. Org. Chem. 2006, 71, 8261. (c)
Downer-Riley, N. K.; Jackson, Y. A. Tetrahedron 2008, 64,
7741. (d) Xian, H.; Jing, T. Tetrahedron 2003, 59, 4851. (e)
Garin, J.; Melendez, E.; Merchan, F. L.; Merino, P.; Orduna,
J.; Tejero, T. Syn. Commun. 1990, 20, 2327.
(11) (a) Vera, M. D.; Pelletier, J. C. J. Comb. Chem. 2007, 9, 569.
(b) Spatz, J. H.; Bach, T.; Umkehrer, M.; Bardin, J.; Ross,
G.; Burdack, C.; Kolb, J. Tetrahedron Lett. 2007, 48, 9030.
(c) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802.
(d) Joyce, L. L.; Evindar, G.; Batey, R. A. Chem. Commun.
2004, 4, 446. (e) Benedi, C.; Bravo, F.; Uriz, P.; Fernandez,
E.; Claver, C.; Castillon, S. Tetrahedron Lett. 2003, 44, 6073.
(12) (a) Joyce, L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792. (b)
Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett.
2008, 10, 5147.
1
chromatography (petroleum ether/ethyl acetate ) 20/1). H
NMR (300 MHz, CDCl3, ppm) δ 4.46 (s, 2H), 7.30-7.39
(m, 6), 7.46 (t, J ) 7.8 Hz, 1H), 7.79 (d, J ) 8.1 Hz, 1H),
8.02 (d, J ) 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm)
δ 40.6, 121.5, 122.7, 124.8, 125.9, 127.3, 128.8(2ArCH),
129.1(2ArCH), 135.6, 137.1, 153.2, 171.1; ESI-MS m/z
[M+H]+ 226; HRMS (ESI) calcd for C14H12NS [M+H]+
226.0690 found 226.0674.
2-Cyclohexylbenzothiazole (2ah). Compound 2ah was
obtained as a colorless oil after the purification by flash
1
chromatography (petroleum ether/ethyl acetate ) 20/1). H
NMR (300 MHz, CDCl3, ppm) δ 1.24-1.52 (m, 3H),
1.58-1.71 (m, 2H), 1.73-1.79 (m, 1H), 1.86-1.92 (m, 2H),
2.18-2.23 (m, 2H), 3.06-3.15 (m, 1H), 7.32 (td, J ) 7.5
Hz, 1.2 Hz,1H, 7.43 (td, J ) 7.5 Hz, 1.2 Hz, 1H), 7.83 (dd,
J ) 7.8 Hz, 1.5 Hz, 1H), 7.97 (m, 1H); 13C NMR (100 MHz,
CDCl3, ppm) δ 25.7, 26.0(2CH2), 33.4(2CH2), 43.4, 121.5,
122.5, 124.4, 125.7, 134.5, 153.0, 177.6 ESI-MS m/z
[M+H]+ 218; HRMS (ESI) calcd for C13H16NS [M+H]+
218.1003 found 218.1010.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation of
China (Grants 20721003 and 20872153), State Key Program
of Basic Research of China (2009CB918502) and the 863
Hi-Tech Program of China (Grants 2006AA020602 and
2006AA01A124).
Supporting Information Available. Part of the experi-
1
mental details, general information, and H and 13C NMR
spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
References and Notes
(1) (a) Voss, J. J. Sulfur. Chem. 2009, 30, 167. (b) Schaumann,
E. Top. Curr. Chem. 2007, 274, 1. (c) Toru, T.; Bolm, C.
Angew. Chem., Int. Ed. 2009, 48, 2078.
(2) Kondo, T.; Mitsudo, T.-a. Chem. ReV. 2000, 100, 3205.
(3) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.;
Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385.
(13) (a) Bernardi, D.; Ba, L. A.; Kirsch, G. Synlett 2007, 13, 2121.
(b) Ding, Q.; Huang, X.-G.; Wu, J. J. Comb. Chem. 2009,
11, 1047.
(4) (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (b) Li,
G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66,
(14) (a) Feng, E. G.; Huang, H.; Zhou, Y.; Ye, D. J.; Jiang, H. L.;
Liu, H. J. Org. Chem. 2009, 74, 2846. (b) Li, Z. G.; Huang,

Synthesis of 2-Substituted (N, O, C) Benzothiazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 429
H.; Sun, H. B.; Hang, H. L.; Liu, H. J. Comb. Chem. 2008,
10, 484. (c) Li, Z. G.; Sun, H. B.; Jiang, H. L.; Liu, H. Org.
Lett. 2008, 10, 3263.
(18) Confirmation that cyclization occurred through S′, rather than
N′, was established by comparison of the isolated product 2a
with a sample independently synthesized by the nucleophilic
displacement reaction of benzylamine with 2-Chloroben-
zothiazole.
(15) Ye, D. J.; Wang, J. F.; Zhang, X.; Zhou, Y.; Ding, X.; Feng,
E. G.; Sun, H. F.; Liu, G. N.; Jiang, H. L.; Liu, H. Green
Chem. 2009, 11, 1201.
(16) Leclerc, G.; Amlaiky, N.; Decker, N.; Schwartz, J. Eur. J. Med.
Chem. 1983, 18, 379.
(19) Qiu, J.; Zhang, X.; Tang, R.; Zhong, P.; Li, J. AdV. Synth.
Catal. 2009, 351, 2319.
(17) Moreira, D. R. M. Synlett 2008, 3, 463.
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