Room-temperature ligand-free Pd/C-catalyzed C-S bond formation: Synthesis of 2-substituted benzothiazoles

Article abstract of DOI:10.1021/jo5002752

The synthesis of 2-substituted benzothiazoles has been achieved via cyclization of o-iodothiobenzanilide derivatives using Pd/C as the catalyst at room temperature. The protocol is ligand-free, additive-free, and high-yielding and involves very mild conditions.

Full text of DOI:10.1021/jo5002752

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Note
Room Temperature Ligand-free Pd/C-catalyzed C-S Bond
Formation: Synthesis of 2-Substituted Benzothiazoles
Yannan Cheng, Qian Peng, Weigang Fan, and Pixu Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5002752 • Publication Date (Web): 22 May 2014
Downloaded from http://pubs.acs.org on May 27, 2014
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Room Temperature Ligand-free Pd/C-catalyzed C-S Bond
Formation: Synthesis of 2-Substituted Benzothiazoles
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9
Yannan Cheng, Qian Peng, Weigang Fan, and Pixu Li*
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Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering,
and Materials Science, Soochow University, 199 RenAi Road, Suzhou, Jiangsu, 215123, China
Tel: +86ꢀ512ꢀ65880826; Eꢀmail: lipixu@suda.edu.cn
H
R2
N
N
Pd/C
R1
R2
R1
S
S
DMF, rt
I
24 examples
R2 = Ar, Alkyl, NHAr
No ligand added
No additive added
Simple operation
Ambient temperature
High yielding
Abstract: The synthesis of 2ꢀsubstituted benzothiazoles is achieved via cyclization of
oꢀiodothiobenzanilide derivatives using Pd/C as the catalyst at room temperature. The protocol
features: 1) ligandꢀfree; 2) additiveꢀfree; 3) high yielding; and 4) very mild conditions.
While many efficient and versatile methods have been developed for the formation of CꢀS bond
catalyzed by organometallics, transitionꢀmetal catalyzed CꢀS bond formation reactions remain
underꢀdeveloped compared to methods for the formation of CꢀC, CꢀO, and CꢀN bonds,
presumably because sulfur is known to poison metal catalysts.1 Among all the metal catalysts
used in the CꢀS bond formation reactions, palladium is one of the most widely used
transitionꢀmetals. Palladium on carbon, usually used as hydrogenation and hydrogenolysis
catalyst, was also used as a heterogeneous catalyst in many coupling reaction.2 Pd/C has many
advantages over homogeneous palladium catalysts, such as easy separation/recovery,
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considerably less heavyꢀmetal contamination of the products, wide commercial availablity, and
relatively low cost. However, the applications of Pd/C or other solid supported pallidium catalysts
in the CꢀS bond formation are scarce.3
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2ꢀSubstituted benzothiazole is an important class of heterocyclic compounds due to their broad
biological and pharmaceutical properties.4 It is typically prepared via condensation of
oꢀaminothiophenol or 2ꢀhaloaniline with carbonyl containing compounds or equivalents,5
oxidative intramolecular cyclization of thiobenzanilide,6 transition metalꢀcatalyzed direct CꢀH
functionalization/cyclization of thiobenzanilides7, transitionꢀmetalꢀcatalyzed cyclization of
oꢀhalothiobenzanilides,5m,8 oꢀhaloarylthiourea,8b,9 or oꢀhalobenzanilides with various sulfur
sources8c,10 and other methods.8b,11 Nonetheless, the approaches suffer from limitations such as
limited starting materials, the use of stoichiometric or excess amount of oxidant, more than one
type of metals, or harsh reaction conditions. A highly efficient and mild protocol for the synthesis
of benzothiazoles is always of great interest to synthetic chemists. We present here a heterogenous
Pd/Cꢀcatalyzed CꢀS bond formation method for the preparation of 2ꢀsubstituted benzothiazoles
through cyclization of oꢀiodothiobenzanilides at room temperature without the addition of any
ligands and additives.
During our study of new synthetic methods for the preparation of 2ꢀsubstituted benzothiazoles,7b
it was discovered that oꢀiodothiobenzanilide 1a underwent
cyclization to afford
2ꢀphenylbenzothiazoles 2a in 87% yield with Pd/C catalyst at room temperature in methanol.
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Compared with many other transitionꢀmetalꢀcatalyzed reactions, this reaction system was very
simple because ligand or additives were required (Table 1, entry 1). A quick survey of solvents
showed that DMF gave the best result. Compound 2a was formed in 98% yield after 12 h at room
temperature in DMF (Table 1, entry 4). Meanwhile, the starting material was not fully consumed
when CH2Cl2 and CH3CN were used as the solvents. The product 2a was formed in 32% and 26%
yields, respectively, after 24 h (Table 1, entries 2 and 3). Investigation of catalyst loading showed
that 2 mol % of Pd/C was required. The yields were reduced to 57% and 39%, respectively, when
1 mol % and 0.5 mol % Pd/C were used (Table 1, entries 5 and 6). Attempts to raise the reaction
temperature to reduce catalyst loading were not successful either (Table 1, entries 7ꢀ9).
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Table 1. Optimization of reaction conditions
Entry Catalyst loading
Solvent
Temp.
Time (h) HPLC yield
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2
3
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6
7
8
2 mol %
2 mol %
2 mol %
2 mol %
1 mol %
0.5 mol %
2 mol %
1 mol %
MeOH
CH3CN
CH2Cl2
DMF
r.t.
r.t.
24
24
24
12
12
12
12
12
87
32
26
98
57
39
96
53
r.t.
r.t.
DMF
r.t.
DMF
r.t.
DMF
50 °C
50 °C
DMF
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9
0.5 mol %
DMF
50 °C
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9
With the optimized reaction conditions identified, we started to investigate the scope and
functional group compatibility of this heterogeneous Pd/C catalyzed cyclization reaction. The
results showed that the reaction was quite general. In some cases higher catalyst loadings were
necessary to accelerate sluggish reactions (Table 2). Substitutions such as methyl, fluoro, and
chloro groups at the para position of the oꢀiodoaniline did not affect the reaction. The
corresponding benzothiazoles were obtained in 83%, 84%, and 94% isolated yields, respectively,
(entries 2ꢀ4). Substitution groups on the other phenyl ring had little impact on the reaction either.
Both strong electronꢀwithdrawing and electronꢀdonating groups were tolerated (71% for
pꢀMethoxy, 80% for oꢀmethoxy, 91% for pꢀchloro, and 75% for pꢀcyano, entries 5ꢀ8). When both
phenyl rings were substituted, the cyclization reactions proceeded well (entries 9ꢀ13).
Heterocyclic compound was suitable substrate too. Compound 2n, in which the phenyl ring was
replaced by pyridyl, was obtained in 78% isolated yield under the standard conditions. Attemps to
extend the reaction to other oꢀhalothiobenzanilide failed. No reaction occurred at the standard
reaction conditions using oꢀbromothiobenzanilide and oꢀchlorothiobenzanilide as the substrates.
Only trace amount of desired cyclization product was observed at elevated temperature.
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Table 2. Synthesis of 2ꢀarylbenzothiazoles. a
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Entry
1
Substrate
Product
Time (h)
Yield b
89
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83c
84c
94
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71c
80
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91
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6
75c
90c
71
9
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13
OMe
H
N
12
6
91c
80c
88
S
1k
F
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6
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H
N
N
14
12
78 d
N
S
N
S
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2n
1n
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a
Reaction conditions: substrate 1 (0.5 mmol) and Pd/C (2 mol %) in DMF (5 mL), room
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temperature. b Isolated yield. c Pd/C (5 mol %). d Pd/C (10 mol %).
Compared with the synthesis of 2ꢀarylbenzothiazoles, the synthetic methods of
2ꢀalkylbenzothiazoles are much less reported. To our delight, the substrates bearing alkyl groups
also proceeded well to give the corresponding 2ꢀalkylbenzothiazoles (Table 3). Substrates with
primary alkyl group, such as methyl, propyl, pentyl, and neopentyl, gave 80%, 82%, 86%, and
80% isolated yields respectively (entries 1ꢀ4). Methyl substitution required higher catalyst
loading and longer reaction time. The reaction was not effected by steric bulkiness of the
substituents. Cyclopropyl and cyclopentyl groups afforded the corresponding products in 79%
and 88% yields, respectively (entries 5ꢀ6). Tertiary alkyl groups, tertꢀbutyl and adamantyl, gave
79% and 91% yields respectively (entries 7ꢀ8). When the alky group was substituted with
functional groups, such as carbamate in compound 1w, the cyclization occurred without problem
(81%, entry 9). Since thioamide 1w was prepared from glycine, it could be envisioned that a
series of benzothiazoles with amino functionality on the Cꢀ2 alkyl substituents could be prepared
starting from other amino acids. The substitution groups were not limited to alkyl groups,
2ꢀ(2ꢀphenylvinyl)benzothiazole was obtained in 86% yield under the standard conditions (entry
10).
Table 3. Synthesis of 2ꢀalkylbenzothiazoles. a
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Entry
1
Substrate
Product
Time (h)
Yield b
80c
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82d
86d
80
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79d
88
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79
7
6
91
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12
6
81
9
N
86
S
10
2x
a Reaction conditions: substrate 1 (0.5 mmol) and Pd/C (2 mol %) in DMF (5 mL), rt. Isolated
b
yield. c Pd/C (10 mol %). d Pd/C (5 mol %).
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The Pd/Cꢀcatalyzed cyclization reaction is not limited to the synthesis of 2ꢀaryl or 2ꢀalkyl
substituted benzothiazoles. We also tested the protocol on oꢀiodoarylthiourea 1y. The reaction
worked with 20 mol % Pd/C catalyst loading. The desired 2ꢀamino substituted product 2y was
obtained in 60% isolated yield at room temperature for 24 h. (Scheme 1)
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Scheme 1. Synthesis of 2ꢀaminobenzothiazole
As aryl iodide is reduced by Pd/C under hydrogen atmosphere, we were curious to see if
compound 1a would be reduced as usual or still undergo cyclization under hydrogen atmosphere.
It turned out that cyclized product 2a was formed in 92% HPLC yield as the only product. On the
contrary, only reduction occurred when oꢀiodobenzanilide 3 was subjected to the otherwise same
conditions (Scheme 2). These results indicated that the sulfur atom played a key role in directing
the reaction pathway.
Scheme 2. Cyclization vs. hydrogenation
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A plausible reaction pathway is proposed in Scheme 3. It was believed that the reaction is likely
initiated by the coordination of sulfur atom to Pd/C,9a leading to the formation of the complex 5.
A subsequent formation of sixꢀmembered palladacycle 6 followed by reductive elimination
affords the 2ꢀsubstituted benzothiazole 2a and regenerates Pd/C.
Scheme 3. Proposed mechanism
In summary, we have developed a synthesis of 2ꢀsubstituted benzothiazoles via cyclization of
oꢀiodothiobenzanilide. CꢀS bond was formed through the transformation. The reaction used
inexpensive, readily available Pd/C as the catalyst without the addition of ligand or additive. It
worked well under very mild conditions. The method could be used for the synthesis of 2ꢀaryl,
2ꢀalkyl, and 2ꢀaminobenzothiazoles. It is complementary to the existing 2ꢀsubstituted
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benzothiazoles synthesis protocols.
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Experimental Section
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General information: All reactions were carried out under a N2 atmosphere using preꢀdried
glassware. Thiobenzanilides were synthesized according to literature methods. Other chemicals
including Pd/C and anhydrous DMF were obtained from commercial sources and were used
without further purification. Column chromatography was performed on silica gel (300ꢀ400 mesh)
using technicalꢀgrade EtOAc and petroleum ether. NMR spectra were recorded in CDCl3 on 300
1
and 400 MHz spectrometers. Chemical shifts for H NMR were reported as δ relative to
tetramethylsilane (0 ppm) or residual CHCl3 (7.26 ppm). Chemical shifts for 13C NMR were
reported as δ relative to the center line signal of the CDCl3 triplet 77.0 ppm. The abbreviations are
used: s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, and m = multiplet. High
resolution mass spectra were measured on TOF high resolution instrument with electrospray
ionization. Melting points are uncorrected. IR data (υmax) are reported in cm−1 and were collected
on a FTꢀIR spectrophotometer. The structures of compounds 2aꢀh were confirmed by comparing
data to those in reference 7e.
General procedure: To a solution of oꢀiodothiobenzanilide 1 (0.5 mmol) in DMF (5 mL) was
added 10% Pd/C (2 mol % unless specified). The reaction mixture was stirred at room
temperature under N2 atmosphere. After reaction completion monitored by TLC, the reaction
mixture was diluted with EtOAc (10 mL). The mixture was filtered through a Celite pad to
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remove Pd/C. The filtrate was added H2O (15 mL). The layers were separated. The aqueous layer
was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10
mL) and dried over MgSO4. Flash silica gel column chromatography rinsed with petroleum
ether/ethylacetate afforded the desired benzothiazole product.
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2-Phenylbenzothiazole
(2a):
The
general
procedure
was
followed
using
Nꢀ(2ꢀiodophenyl)benzothioamide (169.5 mg, 0.5 mmol). Purification by column chromatography
1
yielded 2a (93.8 mg, 89%) as a white solid. Rf = 0.35 (PE/EtOAc = 30:1). H NMR (400 MHz,
CDCl3) δ 8.10ꢀ8.11 (m, 3H), 7.89 (d, J = 7.9 Hz, 1H), 7.49ꢀ7.52 (m, 4H), 7.38 (t, J = 7.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 167.9, 154.0, 135.0, 133.5, 130.9, 128.9, 127.4, 126.2, 125.1,
123.1, 121.5.
6-Methyl-2-phenylbenzothiazole (2b): The general procedure was followed using
Nꢀ(2ꢀiodoꢀ4ꢀmethylphenyl)benzothioamide (176.6 mg, 0.5 mmol), 10% Pd/C (0.025 mmol, 5
mol %). Purification by column chromatography yielded 2b (93.3 mg, 83%) as a white solid. Rf =
0.30 (PE/EtOAc = 30:1). 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 3.9, Hz, 2H), 7.96 (d, J = 8.3
13
Hz, 1H), 7.68 (s, 1H), 7.48 – 7.49 (m, 3H), 7.30 (d, J = 8.2 Hz, 1H), 2.40 (s, 3H); C NMR (75
MHz, CDCl3) δ 167.0, 152.2, 135.3, 135.2, 133.7, 130.7, 128.9, 127.9, 127.4, 122.7, 121.3, 21.5.
6-Fluoro-2-phenylbenzothiazole (2c): The general procedure was followed using
Nꢀ(4ꢀfluoroꢀ2ꢀiodophenyl)benzothioamide (178 mg, 0.5 mmol), 10% Pd/C (0.025 mmol, 5
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mol %). Purification by column chromatography yielded 2c (96.3 mg, 84%) as a yellow solid. Rf
6
7
1
= 0.40 (PE/EtOAc = 30:1). H NMR (400 MHz, CDCl3) δ 7.98ꢀ8.04 (m, 3H), 7.56 (dd, J = 7.9,
8
9
1.8 Hz, 1H), 7.47 ꢀ 7.54 (m, 3H), 7.19ꢀ 7.24 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 167.68, 160.4
(d, J = 244.5 Hz), 150.67, 135.94 (d, J = 10.5 Hz), 133.24, 130.92, 128.96, 127.33, 124.03 (d, J =
9.8 Hz), 114.83 (d, J = 24.0 Hz), 107.72 (d, J = 27 Hz).
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6-Chloro-2-phenylbenzothiazole (2d): The general procedure was followed using
Nꢀ(4ꢀchloroꢀ2ꢀiodophenyl)benzothioamide (186.8 mg, 0.5 mmol). Purification by column
chromatography yielded 2d (115 mg, 94%) as a pale yellow solid. Rf = 0.35 (PE/EtOAc = 30:1) .
1H NMR (400 MHz, CDCl3) δ 8.04ꢀ8.06 (m, 2H), 7.96 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 1.6 Hz,
13
1H), 7.48ꢀ7.50 (m, 3H), 7.43 (dd, J = 8.7, 1.6 Hz, 1H); C NMR (75 MHz, CDCl3) δ 168.4 ,
152.6, 136.1, 133.1, 131.1, 131.0, 129.0, 127.4, 127.0, 123.8, 121.1.
2-(4-Methoxyphenyl)benzothiazole (2e): The general procedure was followed using
Nꢀ(2ꢀiodophenyl)ꢀ4ꢀmethoxybenzothioamide (184.6 mg, 0.5 mmol), 10% Pd/C (0.025 mmol, 5
mol %). Purification by column chromatography yielded 2e (85.5 mg, 71%) as a white solid. Rf =
1
0.15 (PE/EtOAc = 30:1). H NMR (300 MHz, CDCl3) δ 8.00ꢀ8.03 (m, 3H), 7.84 (d, J = 7.3 Hz,
1H), 7.45 (t, J = 7.0 Hz, 1H), 7.33 (t, J = 7.0 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 167.8, 161.8, 154.1, 134.8, 129.0, 126.3, 126.1，124.7, 122.7, 121.4,
114.3, 55.3.
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2-(3-Methoxyphenyl)benzothiazole (2f): The general procedure was followed using
Nꢀ(2ꢀiodophenyl)ꢀ3ꢀmethoxybenzothioamide (122 mg, 0.5 mmol). Purification by column
8
9
1
chromatography yielded 2f (96.4 mg, 80%) as a white solid. Rf = 0.25 (PE/EtOAc = 30:1). H
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NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.63 – 7.68 (m, 2H),
13
7.97 (t, J = 7.6 Hz, 1H), 7.37ꢀ7.40 (m, 2H), 7.04 (d, J = 8.1Hz, 1H), 3.92 (s, 3H); C NMR (75
MHz, CDCl3) δ 167.8, 159.9, 153.9, 134.9, 134.7, 129.9, 126.2. 125.1, 123.1, 121.5, 120.1, 117.2,
111.9, 55.3.
2-(4-Chlorophenyl)benzothiazole (2g): The general procedure was followed using
4ꢀchloroꢀNꢀ(2ꢀiodophenyl)benzothioamide (186.8 mg, 0.5 mmol). Purification by column
chromatography yielded 2g (111.5 mg, 91%) as a pale yellow solid. Rf = 0.40 (PE/EtOAc = 30:1).
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.3 Hz, 1H), 8.03 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 7.9
13
Hz, 1H), 7.46ꢀ7.53 (m, 3H), 7.40 (t, J =7.6 Hz); C NMR (100 MHz, CDCl3) δ 166.6, 154.0,
137.0, 135.0, 132.0, 129.2, 128.6, 126.4, 125.4, 123.2, 121.6.
2-(4-Cyanophenyl)benzothiazole (2h): The general procedure was followed using
4ꢀcyanoꢀNꢀ(2ꢀiodophenyl)benzothioamide (182.1 mg, 0.5 mmol), 10% Pd/C (0.025 mmol, 5
mol %). Purification by column chromatography yielded 2h (88.5 mg, 75%) as a white solid. Rf =
0.15 (PE/EtOAc = 30:1). 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.1
Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.1Hz, 1H), 7.41 (t, J =
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7.3Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 165.2, 153.9, 137.3, 135.2, 132.6, 127.7, 126.7, 126.0,
123.7, 121.7, 118.2, 113.9.
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2-(4-Methoxyphenyl)-6-methylbenzothiazole (2i)12: The general procedure was followed using
Nꢀ(2ꢀiodoꢀ4ꢀmethylphenyl)ꢀ4ꢀmethoxybenzothioamide (191.6 mg, 0.5 mmol), 10% Pd/C (0.025
mmol, 5 mol %). Purification by column chromatography yielded 2i (114.7 mg, 90%) as a white
solid. Rf = 0.15 (PE/EtOAc = 30:1). m.p.= 177.7ꢀ179.0 °C (lit. 174ꢀ177 °C). 1H NMR (400 MHz,
CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H),
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6.89 (d, J = 8.3 Hz, 2H), 3.77 (s, 3H), 2.39 (s, 3H); C NMR (100 MHz, CDCl3) δ 166.8, 161.7,
152.3, 135.0, 134.8, 128.9, 127.7, 126.5, 122.3, 121.3, 114.3, 55.4, 21.5; IR: 2994, 2920, 2833,
2042, 1596, 1435, 1247, 962, 825, 563 cmꢀ1
256.0796, found 256.0786.
;
HRMS (ESI) calcd for [M+H]+ C15H14NOS
2-(4-Chlorophenyl)-6-methylbenzothiazole (2j)11b: The general procedure was followed using
4ꢀchloroꢀNꢀ(2ꢀiodoꢀ4ꢀmethylphenyl)benzothioamide (193.9 mg, 0.5 mmol). Purification by
column chromatography yielded 2j (92.2 mg, 71%) as a pale yellow solid. Rf = 0.35 (PE/EtOAc =
30:1). m.p.= 193.2ꢀ193.9 °C (lit. 136ꢀ138 °C). 1HꢀNMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.2 Hz,
2H), 7.92 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.2 Hz, 1H), 2.48
(s, 3H); 13CꢀNMR (75 MHz, CDCl3) δ 165.5, 152.1, 136.7, 135.6, 135.2, 132.2, 129.2, 128.5,
128.1, 122.7, 121.3; IR: 2911, 2848, 1902, 1474, 1399, 1087, 965, 810, 688, 617, 563 cmꢀ1;
HRMS (ESI) calcd for [M+H]+ C14H11ClNS 260.0301, found 260.0297.
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6-Fluoro-2-(4-methoxyphenyl)benzothiazole (2k)12: The general procedure was followed using
Nꢀ(4ꢀfluoroꢀ2ꢀiodophenyl)ꢀ4ꢀmethoxybenzothioamide (193.6 mg, 0.5 mmol), 10% Pd/C (0.025
mmol, 5 mol %). Purification by column chromatography yielded 2k (117.8 mg, 91%) as a white
solid. Rf = 0.20 (PE/EtOAc = 30:1). m.p.= 132.9ꢀ133.7 °C (lit. 110ꢀ112 °C). 1H NMR (400 MHz,
CDCl3) δ 7.92ꢀ7.97 (m, 3H), 7.51 (dd, J = 8.0, 1.9 Hz, 1H), 7.18 (td, J = 8.0, 2.0 Hz, 1H), 6.96 (d,
J = 8.6 Hz, 2H); 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.50, 161.87, 160.2 (d, J =
244.0Hz), 150.77, 135.74 (d, J = 11 Hz), 128.92, 126.08, 123.55 (d, J = 9 Hz), 114.64 (d, J = 24.0
Hz) , 114.34, 107.70 (d, J = 27.0 Hz) 55.39; IR: 3080, 2836, 2357, 1601, 1453, 1250, 968, 813,
697, 575 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C14H11FNOS 260.0545, found 260.0534.
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6-Chloro-2-(4-methoxyphenyl)benzothiazole (2l)12: The general procedure was followed using
Nꢀ(4ꢀchloroꢀ2ꢀiodophenyl)ꢀ4ꢀmethoxybenzothioamide (201.9 mg, 0.5 mmol), 10% Pd/C (0.025
mmol, 5 mol%). Purification by column chromatography yielded 2l (110 mg, 80%) as a pale
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yellow solid. Rf = 0.20 (PE/EtOAc = 30:1). m.p.= 160.7ꢀ161.1 °C (lit. 134ꢀ137 °C). H NMR
(300 MHz, CDCl3) δ 7.97 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H),
7.40 (dd, J = 8.7, 2.1 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
168.3, 162.0, 152.7, 135.9, 130.5, 129.0, 126.9, 125.9, 123.4, 121.0, 114.4, 55.4. IR: 3063, 2839, 2360,
1604, 1480, 1239, 1096, 965, 822, 694, 567 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C14H11ClNOS
276.0250, found 276.0234.
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6-Chloro-2-(4-chlorophenyl)benzothiazole (2m): The general procedure was followed using
4ꢀchloroꢀNꢀ(4ꢀchloroꢀ2ꢀiodophenyl)benzothioamide (203.4 mg, 0.5 mmol). Purification by
column chromatography yielded 2m (123 mg, 88%) as a white solid. Rf = 0.40 (PE/EtOAc =
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40:1). m.p.= 200.9ꢀ203.1 °C. H NMR (400 MHz, CDCl3) δ 7.92ꢀ7.97 (m, 3H), 7.84 (s, 1H),
7.45ꢀ7.43 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 167.1, 152.6, 1 37.3, 136.2, 131.7, 131.3,
129.3, 128.7, 127.3, 124.0, 121.2; IR: 3083, 2357, 1893, 1593, 1471, 1396, 1298, 1087, 956, 816,
652, 563 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C13H8Cl2NS 279.9755, found 279.9749.
2-Phenylthiazolo[5,4-c]pyridine (2n)13: The general procedure was followed using
Nꢀ(3ꢀiodopyridinꢀ4ꢀyl)benzothioamide (51 mg, 0.15 mmol), 10% Pd/C (0.015 mmol, 10 mol%),
DMF(1.5 mL). Purification by column chromatographyyielded 2n (24 mg, 78%) as white solid.
Rf = 0.28 (PE/EtOAc = 3:1). m.p.= 137.8ꢀ138.4 °C (lit. 135ꢀ136 °C). 1H NMR (400 MHz, CDCl3)
δ 9.20 (d, J = 0.7 Hz, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.13 (dd, J = 8.0, 1.5 Hz, 2H), 7.93 (dd, J =
5.6, 0.7 Hz, 1H), 7.59 – 7.49 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 173.3, 158.8, 145.9, 144.2,
132.7, 132.1, 132.0, 129.2, 128.00, 117.4; IR: 3036, 2363, 1578, 1474, 1405, 1230, 965, 843, 772,
688, 569 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C12H9N2S 213.0490, found 213.0481.
2-Methylbenzothiazole
(2o):
The
general
procedure
was
followed
using
Nꢀ(2ꢀiodophenyl)ethanethioamide (138.5 mg, 0.5 mmol), 10% Pd/C (0.05 mmol, 10 mol %).
Purification by column chromatography yielded 2o (60 mg, 80%) as colorless oil. Rf = 0.15
(PE/EtOAc = 30:1). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.9 Hz,
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1H), 7.44 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 10.6 Hz, 1H), 2.84(s, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.9, 153.3, 135.6, 125.9, 124.7, 122.2, 121.3, 20.1; IR: 2922, 2848, 1715, 1462, 1256, 1012,
807, 739 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C8H8NS 150.0377, found 150.0379.
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2-Propylbenzothiazole
(2p):
The
general
procedure
was
followed
using
Nꢀ(2ꢀiodophenyl)butanethioamide (152.5 mg, 0.5 mmol), 10% Pd/C (0.025 mmol, 5 mol %).
Purification by column chromatography yielded 2p (72.5 mg, 82%) as colorless oil. Rf = 0.25
(PE/EtOAc = 30:1). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.9 Hz,
1H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 3.08 (t, J = 7.6 Hz, 2H), 1.86ꢀ1.95 (m, 2H),
1.05 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.0, 153.1, 135.0, 125.7, 124.5, 122.3,
121.3, 36.1, 22.9, 13.6; IR: 3066, 2967, 2872, 1524, 1435, 1307, 1152, 1063, 763, 724, 430 cmꢀ1;
HRMS (ESI) calcd for [M+H]+ C10H12NS 178.0690, found 178.0687.
2-Butylbenzothiazole
(2q):
The
general
procedure
was
followed
using
Nꢀ(2ꢀiodophenyl)pentanethioamide (159.6 mg, 0.5 mmol), 10% Pd/C (0.025 mmol, 5 mol %).
Purification by column chromatography yielded 2q (73 mg, 86%) as colorless oil. Rf = 0.25
(PE/EtOAc = 30:1). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.7 Hz,
1H), 7.43 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 3.11(t, J = 7.6 Hz, 2H), 1.82ꢀ1.88 (m, 2H),
1.44ꢀ1.49 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.3, 153.2, 135.0,
125.7, 124.5, 122.4, 121.4, 34.0, 31.7, 22.2 13.7; IR: 3066, 2961, 2857, 1521, 1432, 1075, 760,
727 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C11H14NS 192.0847, found 192.0841.
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2-Neopentylbenzothiazole (2r)14: The general procedure was followed using
Nꢀ(2ꢀiodophenyl)ꢀ3,3ꢀdimethylbutanethioamide (166.5 mg, 0.5 mmol). Purification by column
chromatography yielded 2r (82 mg, 80%) as pale yellow solid. Rf = 0.30 (PE/EtOAc = 30:1).
m.p.= 53.6ꢀ54.4 °C (lit. 54 °C). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 1H), 7.84 (d, J
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= 7.9 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 3.01 (s, 2H), 1.09 (s, 9H); C
NMR (75 MHz, CDCl3) δ 169.0, 153.2, 135.5, 125.7, 124.6, 122.6, 121.2, 47.9, 32.0, 29.6;
IR:3051, 2952, 2360, 1509, 1438, 1239, 1102, 766, 650, 602 cmꢀ1; HRMS (ESI) calcd for [M+H]+
C12H16NS 206.1003, found 206.0991.
2-Cyclopropylbenzothiazole (2s): The general procedure was followed using
Nꢀ(2ꢀiodophenyl)cyclopropanecarbothioamide (151.5 mg, 0.5 mmol), 10% Pd/C (0.025 mmol, 5
mol %). Purification by column chromatography yielded 2s (69 mg, 79%) as colorless oil. Rf =
0.25 (PE/EtOAc = 30:1). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 7.9
Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 2.36ꢀ2.42 (m, 1H), 1.22 (d, J = 6.2 Hz,
4H); 13C NMR (75 MHz, CDCl3) δ 174.5, 153.2, 134.0, 125.9, 124.2, 122.0, 121.3, 15.2, 11.6; IR:
3066, 2926, 1724, 1515, 1435, 1242, 1111, 1048, 757, 724, 700 cmꢀ1; HRMS (ESI) calcd for
[M+H]+ C10H10NS 176.0534, found 176.0553.
2-Cyclohexylbenzothiazole (2t): The general procedure was followed using
Nꢀ(2ꢀiodophenyl)cyclohexanecarbothioamide (172.6 mg, 0.5 mmol). Purification by column
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chromatography yielded 2t (95.5 mg, 88%) as colorless oil. Rf = 0.25 (PE/EtOAc = 30:1). H
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 7.6 Hz,
1H), 7.32 (t, J = 7.5 Hz, 1H), 3.06ꢀ3.12(m, 1H), 2.19 (d, J = 12.4 Hz, 2H), 1.87 (d, J = 12.8 Hz,
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2H), 1.75 (d, J = 12.1 Hz, 1H), 1.59ꢀ1.68 (m, 2H), 1.39ꢀ1.48 (m, 2H), 1.25ꢀ1.35 (m, 1H); C
NMR (75 MHz, CDCl3) δ 177.5, 153.0, 134.4, 125.7, 124.4, 122.5, 121.4, 43.3, 33.2, 26.0, 25.7;
IR: 3063, 2926, 2851, 1515, 1435, 1248, 989, 751, 727, 430 cmꢀ1; HRMS (ESI) calcd for [M+H]+
C13H16NS 218.1003, found 218.0993.
2-Tert-butylbenzothiazole
(2u):
The
general
procedure
was
followed
using
Nꢀ(2ꢀiodophenyl)ꢀ2,2ꢀdimethylpropanethioamide (159.6 mg, 0.5 mmol). Purification by column
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chromatography yielded 2u (75.4 mg, 79%) as colorless oil. Rf = 0.35 (PE/EtOAc = 30:1). H
NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 7.6 Hz,
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1H), 7.33 (t, J = 7.5 Hz, 1H), 1.53 (s, 9H); C NMR (75 MHz, CDCl3) δ 181.7, 153.2, 134.9,
125.6, 124.4, 122.6, 121.4, 38.2, 30.7; IR: 3063, 2961, 2926, 1679, 1509, 1435, 1361, 1256, 1048,
1007, 751, 727, 441 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C11H14NS 192.0847, found 192.0847.
2ꢀAdamantanebenzothiazole (2v)15: The general procedure was followed using
Nꢀ(2ꢀiodophenyl)adamantanethioamide (198.7 mg, 0.5 mmol). Purification by column
chromatography yielded 2v (122.4 mg, 91%) as white solid. Rf = 0.33 (PE/EtOAc = 30:1). m.p.=
84.9ꢀ85.9 °C (lit. 103.5ꢀ104.5 °C). 1H NMR (400 MHz, CDCl3) δ 7.99(d, J = 8.1 Hz, 1H), 7.84 (d,
13
J = 7.9 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 2.14 (s, 9H), 1.81 (s, 6H); C
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NMR (75 MHz, CDCl3) δ 182.0, 153.1, 134.3, 125.6, 124.2, 122.5, 121.4, 42.9, 40.0, 36.4, 28.5;
IR: 2899, 2842, 2366, 1510, 1438, 1001, 804, 754, 724, 676 cmꢀ1; HRMS (ESI) calcd for
[M+H]+ C17H20NS 270.1316, found 270.1299.
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Benzyl benzothiazol-2-ylmethylcarbamate (2w): The general procedure was followed using
benzyl 2ꢀ(2ꢀiodophenylamino)ꢀ2ꢀthioxoethylcarbamate (106.5 mg, 0.25 mmol), DMF(2.5 mL).
Purification by column chromatography yielded 2w (60 mg, 81%) as white solid. Rf = 0.30
(PE/EtOAc = 3:1). m.p.= 118.4ꢀ119.7 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H),
7.82 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.36 (m, 6H), 5.88 (s, 1H), 5.16 (s, 2H), 4.78 (d,
J = 5.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 168.9 , 156.3 , 152.9 , 136.1, 135.0, 128.5, 128.2,
128.1, 126.1, 125.1, 122.8, 121.7, 67.2, 43.4. IR: 3289, 3030, 2354, 1682, 1536, 1259, 962, 754,
697, 572 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C16H15N2O2S 299.0860, found 299.0849.
2-Styrylbenzothiazole
(2x)16:
The
general
procedure
was
followed
using
(E)ꢀNꢀ(2ꢀiodophenyl)ꢀ3ꢀphenylpropꢀ2ꢀenethioamide (182.6 mg, 0.5 mmol). Purification by
column chromatography yielded 2x (101.9 mg, 86%) as white solid. Rf = 0.20 (PE/EtOAc = 30:1).
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m.p.= 108.5ꢀ109.5 °C (lit. 106ꢀ108 °C). H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 8.1 Hz, 1H),
7.84 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 6.6 Hz, 2H), 7.33ꢀ7.49 (m, 7H); 13C NMR (75 MHz, CDCl3)
δ 166.9, 153.7, 137.5, 135.3, 134.2, 129.3, 128.8, 127.3, 126.2, 125.2, 122.8, 122.0, 121.4; IR:
3054, 2363, 1628, 1477, 1447, 1319, 1188, 953, 745, 688, 664, 611, 548 cmꢀ1; HRMS (ESI) calcd
for [M+H]+ C15H12NS 238.0690, found 238.0679.
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N-Phenylbenzothiazol-2-amine (2y)17: The general procedure was followed using
1ꢀ(2ꢀiodophenyl)ꢀ3ꢀphenylthiourea (177 mg, 0.5 mmol), 10% Pd/C (0.1 mmol, 20 mol%).
Purification by column chromatography yielded 2w (68 mg, 60%) as white solid. Rf = 0.20
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(PE/EtOAc = 10:1). m.p.= 163.8ꢀ164.2 °C (lit. 158ꢀ159 °C). H NMR (400 MHz, CDCl3) δ 7.63
(d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.49ꢀ7.51 (m, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.32 (t, J
= 7.1 Hz, 1H), 7.13ꢀ7.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.0, 151.2, 139.9, 129.7, 129.5,
126.1, 124.4, 122.3, 120.8, 120.4, 119.2; IR: 3185, 2940, 2360, 1623, 1557, 1444, 1218, 920, 742,
668, 587 cmꢀ1; HRMS (ESI) calcd for [M+H]+ C13H11N2S 227.0643, found 227.0628.
Acknowledgements: Financial support is provided by NSFC (21102097), Beijing National
Laboratory for Molecular Sciences (BNLMS), and the Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry.
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Supporting information: H and C NMR spectra of all products, IR spectra for compounds 2iꢀ2y,
and Xꢀray crystallography data for compound 2k. This material is available free of charge via the
Internet at http://pubs.acs.org/.
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