Copper-catalyzed synthesis of benzo[ b ]thiophenes and benzothiazoles using thiocarboxylic acids as a coupling partner

Article abstract of DOI:10.1021/jo401353w

An efficient copper-catalyzed approach to benzo[b]thiophene and benzothiazole derivatives using thiocarboxylic acids as a sulfur source has been developed. In the presence of CuI and 1,10-phen, and n-Pr₃N as the base, (2-iodobenzyl)triphenylphosphonium bromide and (2-iodophenylimino) triphenylphosphorane reacted smoothly with thiocarboxylic acids to give benzo[b]thiophene and benzothiazole derivatives in good yields via sequential Ullmann-type C-S bond coupling and Wittig condensation.

Full text of DOI:10.1021/jo401353w

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Note
Copper-Catalyzed Synthesis of Benzo[b]thiophenes and
Benzothiazoles Using Thiocarboxylic acids as a Coupling Partner
Hui Yu, Meishu Zhang, and Yuzhe Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401353w • Publication Date (Web): 19 Aug 2013
Downloaded from http://pubs.acs.org on August 21, 2013
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Page 1 of 15
The Journal of Organic Chemistry
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CopperꢀCatalyzed Synthesis of Benzo[b]thiophenes and Benzothiazoles
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Using Thiocarboxylic Acids as a Coupling Partner
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Hui Yu*, Meishu Zhang, and Yuzhe Li
Department of Chemistry, Tongji University, 1239 Siping Road, Shanghai, 200092 (P. R. China).
yuhui@tongji.edu.cn
PPh3Br
R1
yields up to 87%
20 examples
R1
R1
R2
R2
O
CuI(5%), 1,10-Phen(10%)
I
S
+
HS
R2
n-Pr3N , Dioxane,
N2, 100 , 32h
N
S
N
PPh3
yields up to 97%
21 examples
R1
I
Abstract: An efficient copperꢀcatalyzed approach to benzo[b]thiophene and benzothiazole derivatives
using thiocarboxylic acids as a sulfur source has been developed. In the presence of CuI and 1,10ꢀPhen,
nꢀPr3N as the base, (2ꢀiodobenzyl)triphenylphosphonium bromide and (2ꢀiodophenylimino)
triphenylphosphorane reacted smoothly with thiocarboxylic acids to give benzo[b]thiophene and
benzothiazole derivatives in good yields via sequential Ullmannꢀtype C–S bond coupling and Wittig
condensation.
__________________________________________________________________________________
Benzo[b]thiophene and benzothiazole derivatives are important heterocyclic compounds because of
their broad applications in the biological and pharmaceutical areas.1 These heterocycles exist in
numerous bioactive molecules and natural products, and they are also found in clinically important
drugs such as arzoxifene, zileuton, and zopolrestat. Thus, development of general methods for the
synthesis of these compounds is valuable in drug discovery. Conventional methods for the construction
of benzo[b]thiophene and benzothiazole framework commonly start from thiophenol derivatives.2, 3
However, these methods are limited by the difficulties in the preparation of readily oxidized thiophenol
precursors. Benzo[b]thiophene and benzothiazole can also be synthesized by cyclization reactions of
thioenols or thiocarbonyl compounds. For example, benzo[b]thiophene was synthesized from thioamide
through a nucleophlic displacement procedure, 4 or from thioenol, using a simple palladium catalyst. 5
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Benzothiazoles were synthesized from 2ꢀhalophenylthiobenzamides using Pd or Cu as a catalyst, 6 or
from phenylthiobenzamides via C–H functionalization under oxidative condition.7 Generally, the
preparation of thioamides and thioenols requires P4S10 or Lawesson’s reagent, which is not feasible for
substrates comprised of ketone, ester, and amides. In recent years, the development of transition metalꢀ
catalyzed intermolecular C–S bonds formation has provided a new efficient route to benzo[b]thiophene
and benzothiazole moieties.8 By a Cuꢀ or Pdꢀcatalyzed thiolation annulation strategy,
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benzo[b]thiophenes
and
benzothiazoles
have
been
synthesized
successfully
from
2ꢀbromoalkynylbenzene and 2ꢀhaloaniline derivatives using a dihydrosulfide surrogate as a coupling
partner, 9, 10 such as metal sulfides, thiourea, and HSTIPS. In most cases, these dihydrosulfide surrogates
only contribute one sulfur atom to the structure of the product, and all the functional groups have to be
preassembled on the substrates for the synthesis of a multiꢀsubstituted target molecule. Obviously, using
functionalized dihydrosulfide as coupling partner will make this method more flexible and convienent
for organic syntheses. For example, using benzyl thiols as coupling partners, Liu and coꢀworkers
reported an efficient synthesis of a variety of benzo[b]thiophene and benzothiazole derivatives via a
crossꢀcoupling/intramolecular cyclization process. 11 Here, as another example of this methodology, we
report a new oneꢀpot copperꢀcatalyzed approach to benzo[b]thiophenes and benzothiazoles using
thiocarboxylic acids as the coupling partner. 12
Initially, the coupling of (2ꢀiodobenzyl)triphenylphosphonium bromide 1a with thiobenzoic acid 2a
was examined in DMF with CuI (5 mol%), 1,10ꢀphenthroline (10 mol%) as the catalyst, and DIPEA
(3.0 equiv) as the base at 100°C under N2. The desired product 2ꢀphenylbenzo[b]thiophenes 3a was
isolated in 67% yield (Table 1, entry 1). Then, reaction conditions, including solvents, bases, and ligands,
were screened and the results are listed in Table 1. Various solvents were screened and dioxane was
found to be the best one (Table 1, entries 1–4). Different bases were evaluated and all the tertiary amine
gave good results; in the case of Pr3N, the yield increased to 87%. In contrast, no product could be found
when inorganic bases, such as Cs2CO3 and K3PO4, were introduced in the reaction (Table 1, entries 5–9).
No product could be obtained without a ligand, and other ligands including TMEDA, Lꢀproline gave
lower yield than 1,10ꢀPhen (Table 1, entries 10–12). Some other copper salts were also tested and CuI
remained the best one (Table 1, entries 13, 14). (2ꢀBromobenzyl) triphenylphosphonium bromide was
also examined instead of 1a in the present of 0.5 eq KI as an additive to afford 3a in 47% yield, and no
13
product could be isolated without KI (Table 1, entry 15). Finally, a mixture of benzoic acid and
Lawesson’s reagent was used to generate thiobenzoic acid in situ，and 3a was obtain in about 53%
yield but was difficult to separate from the complex reaction mixture (Table 1, entry 16). On the basis of
these results, entry 6 represented the best conditions.
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The Journal of Organic Chemistry
1
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Table 1. Screening conditions
4
5
6
7
O
[Cu], Ligand, N2
PPh3Br
Ph
+
HS
Ph
S
I
Solvent, 100 , 32h
3a
2a
1a
8
9
Entrya
Cat.
Ligand
Base
Solvent
Yield (%)b
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1
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
Cu2O
CuI
1,10ꢀPhen DIPEA
1,10ꢀPhen DIPEA
1,10ꢀPhen DIPEA
1,10ꢀPhen DIPEA
DMF
67
40
Toluene
DMSO
3
53
4
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
75
5
1,10ꢀPhen
Et3N
48
6
1,10-Phen n-Pr3N
1,10ꢀPhen nꢀBu3N
1,10ꢀPhen Cs2CO3
87
7
78
8
Trace
Trace
0
9
1,10ꢀPhen
—
K3PO4
nꢀPr3N
nꢀPr3N
nꢀPr3N
10
11
12
13
14
15
16
TMEDA
LꢀProline
56
35
1,10ꢀPhen nꢀPr3N
1,10ꢀPhen nꢀPr3N
67
79
1,10ꢀPhen
nꢀPr3N
47c
55d
CuI
1,10ꢀPhen
nꢀPr3N
aAt 0.10 mmol, isolated yield, (2ꢀbromobenzyl) triphenylphosphonium bromide was used
instead of 1a with 0.5 eq KI as an additive, mixture of benzoic acid and Lawesson’s reagent
was used instead of thiobenzoic acid.
b
c
d
With the optimized reaction conditions established, the substrate scope was examined, and the results
are summarized in Table 2. Different (2ꢀiodobenzyl)triphenylphosphonium bromides with electronꢀ
donating or electronꢀwithdrawing groups on the benzene ring reacted smoothly with thiobenzoic acid 2a
to give the corresponding 2ꢀphenylbenzo[b]thiophenes in moderateꢀtoꢀgood yields (Table 2, 3b–3h).
However, substrates with a methyl group in the αꢀposition were not active to the reaction, and no desired
product 2ꢀphenylꢀ3ꢀmethyl benzo[b]thiophene was isolated (Table 2, 3i) Next, a variety of substituted
.
thiobenzoic acids was employed to react with 1a. Thiobenzoic acids with electronꢀdonating groups
displayed high reactivity under the present reaction conditions to afford the corresponding products,
regardless of the substituent position on the phenyl ring (Table 2, 3j–3m). In contrast, electronꢀdeficient
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thiobenzoic acids were less reactive under these reaction conditions and only traces of the expected
product were detected (Table 2, 3n). Heteroaryl thiocarboxylic acids were also found to be favored in
the reaction and benzo[b]thiophenes with heteroaryl substituent on Cꢀ2 position were synthesized in
moderate yields, showing the potential of our methodology (Table 2, 3o–3q). This reaction was not
limited to aromatic acids. Aliphatic acids, such as thiophenylacetic acid and thioacetic acid, were also
1
2
3
4
5
6
7
8
9
investigated which provided the desired products in 60% and 40% yields, respectively (Table 2, 3r, 3s).
Finally, thioisophthalic acid was used in the optimized conditions, leading to product 3t in 63% yield.
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Table 2
.
CopperꢀCatalyzed Synthesis of Benzo[b]thiophene Derivativesa,b
CuI(5%), 1,10-Phen(10%)
n-Pr3N (2.5 eq), N2
O
PPh3Br
R1
R2
R1
+
S
HS
R2
I
Dioxane, 100 , 32h
3b-t
1
2
MeO
Ph
S
Ph
Ph
S
t-Bu
F
S
3d, 70%
3c,70%
Cl
3b, 67%
Br
Ph
Ph
Ph
Ph
S
S
S
Cl
3g, 86%
3f, 70%
3e, 86%
Ph
S
O2N
S
S
3j, 78%
3h, 79%
3i, 0%
R
S
O
S
S
3o, 74%
3k, 74%
3l, 81%, R = Me
3m, 70%, R = OMe
3n, trace, R = Cl
Ph
S
S
S
S
3q, 46%
3p, 63%
3r, 60%
S
S
S
3s, 40%
3t, 63%
a On a 0.3 mmol scale; b Isolated yield.
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The Journal of Organic Chemistry
Subsequently,
a
Cuꢀcatalyzed
annulation
reaction
between
(2ꢀiodophenylimino)
1
2
triphenylphosphorane and thiobenzoic acid 2a was examined under the optimized reaction conditions. In
this case, the amount of nꢀPr3N was decreased to 1.5 equiv. The expected product 2ꢀphenyl
benzothiazole was isolated in high yield, up to 95%. Then, the scope of copperꢀcatalyzed coupling
reaction of substituted (2ꢀiodophenylimino)triphenylphosphorane with thiocarboxylic acids were
examined under the optimized conditions. As shown in Table 3, (2ꢀiodophenylimino)
triphenylphosphoranes with electronꢀdonating group on the phenyl ring gave the products in excellent
yields (Table 3, 5a–5d). The existence of other halides, such as F, Cl, and Br, had no significant effect
on the reaction, and the desired products were obtained in good yields (Table 3, 5e–5g). Notably,
ketones and esters were tolerated in the reaction, and the products were obtained in good yields (Table 3,
5h–5j). Next, a series of substituted thiobenzoic acids was also examined. It is found that substitution at
the 2ꢀposition resulted in lower yields than substitution at the 3ꢀposition or 4ꢀposition, indicating a steric
effect in this reaction (Table 3, 5k–5m). Furthermore, thiobenzoic acids bearing electronꢀdonating
groups on the phenyl ring gave the desired products in higher yields than those with electronꢀ
withdrawing groups (Table 3, 5m–5o). Several heteroaryl thiocarboxylic acids were also tested and the
corresponding products were obtained in good yields (Table 3, 5p–5r). Aliphatic acid, such as
thiophenylacetic acid, gave excellent yields, but thioacetic acid was not suitable for this reaction (Table
3, 5s, 5t). Finally, thiocinnamic acid also underwent this reaction smoothly, generating the
corresponding product in 68% yield (Table 3, 5u). Finally, (2ꢀbromophenylimino)triphenylphosphorane
was also used to react with thiobenzoic acid under optimized conditions, but only trace product could be
isolated for its less reactivity.
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Table 3. CopperꢀCatalyzed Synthesis of Benzothiazole Derivativesa,b
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CuI(5%), 1,10-Phen(10%)
n-Pr3N (1.5 eq), N2
N
I
PPh3
1
2
3
4
O
N
S
+
R1
R2
R1
HS
R2
Dioxane, 100 , 32h
5
2
4
5
6
7
8
9
N
N
N
Ph
Ph
Ph
S
S
EWG
S
X
R
10
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5h, 77%, EWG = NO2
5i, 87%, EWG = Ac
5j, 70%, EWG = COOEt
5a, 95%, R = H
5b, 96%, R = Me
5c, 90%, R = i-Pr
5d, 85%, R = t-Bu
5e, 94%, X = F
5f, 90%, X = Cl
5g, 80%, X = Br
N
R
S
N
N
S
S
5m, 85%, R = Me
5n, 87%, R = OMe
5o, 67%, R = Cl
5k, 72%
5l, 97%
N
N
N
S
S
S
S
O
5q, 75%
5r, 91%
5p, 85%
N
Ph
N
N
Ph
S
S
S
5t, trace
5s, 90%
5u, 68%
a On a 0.3 mmol scale; b Isolated yield.
Based on the present results and a previously reported mechanism, 9a, 10b a proposed mechanism is
outlined below (Scheme 1). Oxidative addition of CuI to substrate 4 or 7 (generated from 1 in the
present of base) afforded intermediate A, which was converted to intermediate B by ligand exchange.
Reductive elimination of B would regenerate CuI and provide C, then C underwent an intramolecular
(azaꢀ)Witttig condensation to give the products spontaneously. Further investigation of the details of the
mechanism is still in progress in our lab.
Scheme 1. Proposed Reaction mechanism
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The Journal of Organic Chemistry
Y
Y
PPh3
PPh3
1
2
3
4
5
6
7
R1
R1
I
Cu I
I
A
4 Y = N
7 Y = CH
Y
S
R1
R2
R2COSH
CuI
HI
8
9
Y
PPh3
Y
PPh3
PO
Ph3
R1
R1
10
11
12
13
14
15
SCOR2
Cu SCOR2
I
C
B
In conclusion, we have developed a practical method for the synthesis of benzo[b]thiophenes and
benzothiazoles by a combination of copperꢀcatalyzed C–S bond formation and a Wittig condensation.
This may be the first example of copperꢀcatalyzed construction of Sꢀheterocycles using thiocarboxylic
acid as a coupling partner. In most cases, the corresponding benzo[b]thiophenes and benzothiazoles
were obtained in goodꢀtoꢀexcellent yields. This method provides a new alternative route for preparing
benzo[b]thiophenes and benzothiazoles derivatives for use in organic and medicinal chemistry.
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Experimental Section
General Methods
Commercially available reagents were used as received without further purification unless otherwise
indicated. Reactions were magnetically stirred and monitored by thin layer chromatography (TLC) using
Silica Gel 60 F254 plates and were visualized by fluorescence quenching at 254 nm. For
chromatographic purifications, analytically pure solvents were used and the silica gel 300ꢀ400 mesh was
1
13
used as the solid support. H NMR and C NMR chemical shifts were reported in δ units, parts per
1
million (ppm) relative to the chemical shift of residual solvent. Reference peaks for chloroform in H
NMR and 13C NMR spectra were set at 7.26 ppm and 77.0 ppm, respectively.
Typical experimental procedure for the synthesis of Benzo[b]thiophene
In a 15 mL twoꢀnecked flask, a mixture of (2ꢀIodobenzyl)triphenylphosphonium Bromide (168mg, 0.3
mmol), thiobenzoic acid (53 mg, 0.33 mmol), CuI (2.8 mg, 5% mol), and 1,10ꢀphenthroline (5.2 mg, 10
mol%) in Dioxane (3 mL) were stirred at room temperature under N2 atmosphere for 5 min. Then the
solution was stirred at 100℃ for 32 h until complete consumption of starting material as monitored by
TLC. After the reaction was finished, the mixture was washed with brine, extracted with EtOAc, dried
over anhydrous Na2SO4, and evaporated under vacuum. The residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate, 8/1) to give the product 3a.
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2ꢀphenylbenzo[b]thiophene9a (3a): White solid; 54.9 mg (87% yield); mp 172ꢀ173 ℃; H NMR (400
MHz, CDCl3) δ 7.87 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.59 (s, 1H),
7.47 (t, J = 7.5 Hz, 2H), 7.42 – 7.32 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 144.2, 140.7, 139.5, 134.3,
128.9, 128.3, 126.5, 124.5, 124.3, 123.6, 122.3, 119.4.
1
1
2
3
4
5
6
7
8
9
1
5ꢀMethoxyꢀ2ꢀphenylbenzo[b]thiophene14 (3b): White solid; 48.6 mg (67% yield); mp 143ꢀ144℃; H
10
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NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 7.8, 6.2 Hz, 3H), 7.50 (s, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (t,
13
J = 7.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.8, 2.4 Hz, 1H), 3.91 (s, 3H); C NMR (101
MHz, CDCl3) δ 157.6, 145.4, 141.6, 134.5, 132.1,128.9, 128.2, 126.4, 122.9, 119.3, 114.5, 105.7, 55.5.
1
6ꢀtertꢀButylꢀ2ꢀphenylbenzo[b]thiophene (3c): White solid; 55.9 mg (70% yield); mp 165ꢀ168 ℃; H
NMR (400 MHz, CDCl3) δ 7.75 (d, J = 0.6 Hz, 1H), 7.63 (d, J = 7.0 Hz, 3H), 7.42 (s, 1H), 7.38 ꢀ7.30
13
(m, 3H), 7.26 (d, J = 7.3 Hz, 1H), 1.32 (s, 9H); C NMR (101 MHz, CDCl3) δ 147.7, 143.5, 139.7,
138.4, 134.5, 128.9, 128.0, 126.4, 123.0, 122.8, 119.1, 118.3, 34.9, 31.5. HRMS (ESI) m / z [M + H]+
calcd for C18H19S 267.1207, found 267.1241.
6ꢀFluoroꢀ2ꢀphenylbenzo[b]thiophene9a (3d): White solid; 47.9 mg (70% yield); mp 164ꢀ165 ℃; 1H
NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 13.3, 6.2 Hz, 3H), 7.58 – 7.50 (m, 2H), 7.45 (t, J = 7.5 Hz,
2H), 7.37 (t, J = 7.4 Hz, 1H), 7.13 (td, J = 8.9, 2.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 160.7 (d, JC
－
F = 245.0 Hz), 144.1 (d, JC F = 4.0 Hz), 140.5 , 137.2 , 134.5 , 129.1, 128.6, 126.4 , 124.8 (d, JC F = 9.0 Hz),
－
－
118.8, 113.5 (d, JC F = 24.2 Hz), 108.4 (d, JC F = 25.5 Hz).
－
－
1
6ꢀChloroꢀ2ꢀphenylbenzo[b]thiophene9a (3e):White solid; 63.1 mg (86% yield); mp 193ꢀ195 ℃; H
NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.71 (dd, J = 7.6, 6.2 Hz, 3H), 7.53 (s, 1H), 7.46 (t, J = 7.5 Hz,
13
2H), 7.41 – 7.31 (m, 2H); C NMR (101 MHz, CDCl3) δ 144.9, 140.4, 139.1, 133.8, 130.3, 129.0,
128.5, 126.4, 125.3, 124.3, 121.8, 118.9.
4ꢀChloroꢀ2ꢀphenylbenzo[b]thiophene15 (3f):White solid; 51.3 mg (70% yield); mp 110ꢀ111 ℃; 1H NMR
(400 MHz, CDCl3) δ 7.90 – 7.63 (m, 4H), 7.56 – 7.34 (m, 4H), 7.26 (t, J = 7.9 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 145.3, 140.5, 138.9, 133.8, 129.0, 128.7, 128.5, 126.6, 124.9, 124.5, 120.8, 117.6. 4ꢀ
chloroꢀ2ꢀphenylbenzo[b]thiophene
1
5ꢀBromoꢀ2ꢀphenylbenzo[b]thiophene16 (3g): White solid; 74.6 mg (86% yield); mp 186ꢀ187℃; H
13
NMR (400 MHz, CDCl3) δ 7.93 (d, J = 1.7 Hz, 1H), 7.71 (t, J = 7.6 Hz, 3H), 7.53 – 7.38 (m, 5H); C
NMR (101 MHz, CDCl3) δ 146.2, 142.2, 138.0, 133.8, 129.0, 128.7, 127.3, 126.5, 126.1, 123.6, 118.5,
118.5.
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6ꢀNitroꢀ2ꢀphenylbenzo[b]thiophene (3h): Brown solid; 60.4 mg (79% yield); mp 196ꢀ197 ℃; H NMR
4
(400 MHz, CDCl3) δ 8.79 (s, 1H), 8.25 (dd, J = 8.8, 1.9 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.77 (d, J =
5
6
7
13
7.1 Hz, 2H), 7.66 (s, 1H), 7.49 (dt, J = 14.2, 6.9 Hz, 3H); C NMR (101 MHz, CDCl3) δ 151.4, 145.1,
8
9
139.0, 133.2, 129.5, 129.2, 126.8, 123.6, 119.9, 119.0, 118.7. HRMS (EI) m / z [M+] calcd for
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C14H9NO2S 255.0354, found 255.0362.
2ꢀoꢀTolylbenzo[b]thiophene9d (3j): White solid; 52.2 mg (78% yield); mp 68ꢀ70 ℃; H NMR (400
1
MHz, CDCl3) δ 7.92 (d, J = 7.9 Hz, 1H), 7.89 – 7.84 (m, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.48 – 7.30 (m,
6H), 2.55 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 143.5, 140.2, 140.1, 136.5, 134.3, 130.8, 130.7, 128.3,
126.4, 126.1, 124.4, 124.1, 123.5, 123.0, 122.0, 21.1.
2ꢀmꢀTolylbenzo[b]thiophene9a (3k): White solid; 49.5 mg (74% yield); mp 117ꢀ118℃; H NMR (400
1
MHz, CDCl3) δ 7.86 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 8.5 Hz, 3H), 7.41 – 7.30
13
(m, 3H), 7.19 (d, J = 7.7 Hz, 1H), 2.45 (s, 3H); C NMR (101 MHz, CDCl3) δ 144.4, 140.7, 139.4,
138.6, 134.2, 129.0, 128.8, 127.2, 124.4, 124.2, 123.6, 123.5, 122.2, 119.3, 21.4.
2ꢀpꢀTolylbenzo[b]thiophene9a (3l): White solid; 54.2 mg (81% yield); mp 166ꢀ168 ℃; H NMR (400
1
MHz, CDCl3) δ 7.86 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.54 (s, 1H),
13
7.34ꢀ7.38 (m, 2H), 7.27 (d, J = 8.2 Hz, 2H), 2.43 (s, 3H); C NMR (101 MHz, CDCl3) δ 144.4, 140.8,
139.3, 138.3, 131.5, 129.6, 126.4, 124.4, 124.1, 123.4, 122.2, 118.8, 21.2.
2ꢀ(4ꢀMethoxyphenyl)benzo[b]thiophene9a (3m): White solid; 50.8 mg (70% yield); mp 188ꢀ190℃; H
1
NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H),
7.45 (s, 1H), 7.40 ꢀ 7.30 (m, 2H), 6.99 (d, J = 8.6 Hz, 2H), 3.88 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
159.8, 144.1, 140.9, 139.2, 127.7, 127.0, 124.4, 123.9, 123.2, 122.1, 118.2, 114.3, 55.4.
2ꢀ(Fruanꢀ2ꢀyl)benzo[b]thiophene11 (3o): White solid; 44.4 mg (74% yield); mp 113ꢀ114 ℃; H NMR
1
(400 MHz, CDCl3) δ 7.80 (dd, J = 20.2, 7.8 Hz, 2H), 7.51 (s, 2H), 7.35 (dt, J = 15.1, 7.2 Hz, 2H), 6.60
13
(dd, J = 60.0, 2.3 Hz, 2H); C NMR (101 MHz, CDCl3) δ 149.3, 142.5, 140.2, 138.9, 133.3, 124.6,
124.4, 123.5, 122.2, 118.5, 111.9, 107.0.
2ꢀ(Thiophenꢀ2ꢀyl)benzo[b]thiophene9a (3p): White solid;40.8 mg (63% yield); mp 119ꢀ120 ℃; H
1
NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.43 (s, 1H), 7.40 ꢀ 7.30
13
(m, 4H), 7.13 – 7.04 (m, 1H); C NMR (101 MHz, CDCl3) δ 140.3, 139.1, 137.4, 137.2, 127.9, 125.4,
125.0, 124.6, 124.4, 123.4, 122.1, 119.7.
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2ꢀ(Naphthalenꢀ2ꢀyl)benzo[b]thiophene17 (3q): White solid; 35.9 mg (46% yield); mp 221ꢀ222 ℃; H
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3
4
5
NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.85－7.91 (m, 6H), 7.71 (s, 1H), 7.58 – 7.48 (m, 2H), 7.44 –ꢀ
13
7.33 (m, 2H).; C NMR (101 MHz, CDCl3) δ 144.2, 140.7, 139.5, 133.5, 133.1, 132.6, 131.6, 128.6,
6
7
128.2, 127.7, 126.7, 126.3, 125.3, 124.6, 124.3, 123.6, 122.3, 119.9.
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2ꢀBenzylbenzo[b]thiophene18 (3r): White solid; 40.3 mg (60% yield); mp 76ꢀ78 ℃; H NMR (400
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MHz, CDCl3) δ 7.76 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.41 – 7.22 (m, 8H), 4.25 (s, 2H); 13C
NMR (101 MHz, CDCl3) δ 145.1, 140.0, 139.8, 139.5, 128.7, 128.6, 126.7, 124.1, 123.6, 122.9, 122.1,
121.6, 37.0.
2ꢀMethylbenzo[b]thiophene19 (3s):White solid; 17.8 mg (40% yield); mp 47ꢀ52 ℃; 1H NMR (400 MHz,
CDCl3) δ 7.80 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.38 – 7.25 (m, 2H), 7.02 (s, 1H), 2.63 (d, J
13
= 1.0 Hz, 3H); C NMR (101 MHz, CDCl3) δ 140.8, 140.5, 139.7, 124.0, 123.3, 122.5, 122.0, 121.6,
16.1.
1
1,3ꢀDi(benzo[b]thiophenꢀ2ꢀyl)benzene (3t): White solid; 64.6 mg (63% yield); mp 169ꢀ171 ℃; H
NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.84 (d, J = 7.2 Hz, 2H), 7.72 (dd, J =
7.8, 1.6 Hz, 2H), 7.66 (s, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.45ꢀ7.33 (m, 4H); 13C NMR (101 MHz, CDCl3)
δ 143.5, 140.6, 139.5, 135.1, 129.5, 126.3, 124.6, 124.5, 123.7, 122.3, 120.0. HRMS (ESI) m / z
[M+H]+ calcd for C22H15S2 343.0615, found 343.0627.
Typical experimental procedure for the synthesis of Benzothiazole
In a 15 mL twoꢀnecked flask, a mixture of (2ꢀIodophenylimino)triphenylphosphorane (168mg, 0.3
mmol), thiobenzoic acid (53 mg, 0.33 mmol), CuI (2.8 mg, 5% mol), and 1,10ꢀphenthroline (5.2 mg, 10
mol%) in Dioxane (3 mL) were stirred at room temperature under N2 atmosphere for 5 min. Then the
solution was stirred at 100℃ for 32 h until complete consumption of starting material as monitored by
TLC. After the reaction was finished, the mixture was washed with brine, extracted with EtOAc, dried
over anhydrous Na2SO4, and evaporated under vacuum. The residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate, 4/1) to give the product 5a.
1
2ꢀphenylbenzo[d]thiazole10a (5a): White solid; 60.1mg (95% yield) M.p. 107ꢀ110 ℃; H NMR (400
MHz, CDCl3) δ 8.15 – 8.09 (m, 3H), 7.94 (d, J = 7.6 Hz, 1H), 7.55 – 7.50 (m, 4H), 7.42 (t, J = 7.6 Hz,
13
1H); C NMR (101 MHz, CDCl3) δ 208.8, 168.0, 154.1, 135.1, 133.6, 130.9, 129.0, 127.5, 125.2,
123.2, 121.6.
1
6ꢀMethylꢀ2ꢀphenylbenzothiazole10a (5b): white solid; 67.4 mg (96% yield); mp 149ꢀ150 ℃; H NMR
(400 MHz, CDCl3) δ 8.13 – 8.07 (m, 2H), 7.98 (d, J = 8.3 Hz, 1H), 7.72 (s, 1H), 7.54 – 7.48 (m, 3H),
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7.33 (dd, J = 8.3, 1.0 Hz, 1H), 2.53 (s, 3H); C NMR (101 MHz, CDCl3) δ 167.0, 152.3, 135.3, 135.2,
1
2
3
133.7, 130.7, 128.9, 127.9, 127.4, 122.7, 121.3, 21.5.
4
5
1
6ꢀisoꢀPropylꢀ2ꢀphenylbenzothiazole (5c): White solid; 68.3 mg (90% yield); mp 137ꢀ139℃; H NMR
6
7
(400 MHz, CDCl3) δ 8.14 – 8.08 (m, 2H), 8.03 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.54ꢀ7.49
8
9
13
(m, 3H), 7.40 (dd, J = 8.4, 1.6 Hz, 1H), 3.09 (dt, J = 13.8, 6.9 Hz, 1H), 1.36 (d, J = 6.9 Hz, 6H); C
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NMR (101 MHz, CDCl3) δ 167.2, 152.5, 146.4, 135.3, 133.8, 130.7, 129.0, 127.4, 125.5, 122.9, 118.7,
34.3, 24.2. HRMS (ESI) m / z [M+H]+ calcd for C16H16NS 254.1003, found 254.1005.
1
6ꢀtertꢀButylꢀ2ꢀphenylbenzothiazole (5d): White solid; 68.1 mg (85% yield); mp 125ꢀ128℃; H NMR
(400 MHz, CDCl3) δ 8.13ꢀ8.08 (m, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.58 (dd, J =
8.7, 1.9 Hz, 1H), 7.54 – 7.49 (m, 3H), 1.44 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 167.4, 152.1, 148.7,
135.1, 133.8, 130.7, 129.0, 127.4, 124.5, 122.5, 117.7, 35.1, 31.5. HRMS (ESI) m / z [M+H]+ calcd for
C17H18NS 268.1160, found 268.1170.
1
6ꢀFluoroꢀ2ꢀphenylbenzothiazole10a (5e): White solid; 64.6 mg (94% yield); mp 152ꢀ153℃; H NMR
(400 MHz, CDCl3) δ 8.11 – 8.06 (m, 2H), 8.04 (dd, J = 9.0, 4.8 Hz, 1H), 7.61 (dd, J = 8.1, 2.6 Hz, 1H),
13
7.52 (dd, J = 6.8, 3.6 Hz, 3H), 7.25 (td, J = 9.0, 2.6 Hz, 1H); C NMR (101 MHz, CDCl3) δ 167.8,
160.5 (d, JC F = 245.8 Hz), 150.8, 136.0 (d, JC F = 11.3 Hz), 133.3, 131.0, 129.1, 127.4, 124.1 (d, JC
－
－
－
F
= 9.4 Hz), 114.9 (d, JC F = 24.7 Hz), 107.8 (d, JC F = 26.8 Hz).
－
－
1
6ꢀChloroꢀ2ꢀphenylbenzothiazole10a (5f):White solid; 66.3 mg (90% yield); mp 156ꢀ157 ℃; H NMR
(400 MHz, CDCl3) δ 8.11 – 8.05 (m, 2H), 7.99 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.55 – 7.50
13
(m, 3H), 7.47 (dd, J = 8.7, 2.1 Hz, 1H); C NMR (101 MHz, CDCl3) δ 168.5, 152.7, 136.2, 133.2,
131.2, 131.1, 129.1, 127.5, 127.1, 123.9, 121.3.
1
6ꢀBromoꢀ2ꢀphenylbenzothiazole7d (5g): White solid; 62.4 mg (80% yield); mp 150ꢀ151 ℃; H NMR
(400 MHz, CDCl3) δ 8.13 – 8.07 (m, 2H), 8.06 (d, J = 1.7 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.61 (dd, J
13
= 8.7, 1.7 Hz, 1H), 7.56 – 7.48 (m, 3H); C NMR (101 MHz, CDCl3) δ 168.5, 153.0, 136.7, 133.2,
131.3, 129.8, 129.1, 127.5, 124.3, 124.1, 118.7.
1
6ꢀNitroꢀ2ꢀphenylbenzothiazole7d (5h): Yellow solid; 59.1 mg (77% yield); mp 189ꢀ190 ℃; H NMR
(400 MHz, CDCl3) δ 8.86 (d, J = 2.1 Hz, 1H), 8.39 (dd, J = 9.0, 2.2 Hz, 1H), 8.15 (m, 3H), 7.64 – 7.52
13
(m, 3H); C NMR (101 MHz, CDCl3) δ 173.8, 157.8, 144.9, 135.3, 132.7, 132.2, 129.3, 127.9, 123.3,
121.9, 118.2.
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1ꢀ(2ꢀPhenylbenzothiazolꢀ6ꢀyl)ethanone10a (5i):Yellow solid; 66.0 mg (87% yield); mp 185ꢀ188℃; H
NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.12 (d, J = 8.9 Hz, 4H), 7.54 (d, J = 6.1 Hz, 3H), 2.71 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 197.0, 171.8, 157.0, 135.3, 133.9, 133.2, 131.6, 129.1, 127.8, 126.5,
123.0, 122.5, 26.8. HRMS (ESI) m / z [M+H]+ calcd for C15H12NOS 254.0640, found 254.0653.
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5
6
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8
9
Ethyl 2ꢀphenylbenzothiazoleꢀ6ꢀcarboxylate10a (5j]: White solid; 59.4 mg (70% yield); mp 196ꢀ197 ℃;
1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 1.1 Hz, 1H), 8.20 (dd, J = 8.6, 1.6 Hz, 1H), 8.17 – 8.09 (m,
3H), 7.55 (d, J = 1.7 Hz, 2H), 7.54 (d, J = 1.7 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 171.4, 166.1, 157.0, 134.9, 133.2, 131.5, 129.1, 127.7, 127.5, 127.3,
123.7, 122.8, 61.2, 14.3.
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2ꢀoꢀTolylbenzothiazole20 (5k): White solid; 48.4 mg (72% yield); mp 53ꢀ54 ℃; H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.55 – 7.47 (m,
13
1H), 7.43 – 7.28 (m, 4H), 2.66 (s, 3H); C NMR (101 MHz, CDCl3) δ 168.1, 153.8, 137.2, 135.6,
133.1, 131.5, 130.5, 130.1, 126.1, 125.1, 123.4, 121.3, 21.4.
1
2ꢀmꢀTolylbenzothiazole10a (5l): White solid; 65.2 mg (97% yield); mp 69ꢀ70 ℃; H NMR (400 MHz,
CDCl3) δ 8.11 (d, J = 8.2 Hz, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.55
13
– 7.48 (m, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 2.48 (s, 3H); C NMR (101 MHz,
CDCl3) δ 168.3, 154.1, 138.8, 135.0, 133.6, 131.8, 128.9, 128.0, 126.2, 125.1, 124.8, 123.2, 121.6, 21.3.
1
2ꢀpꢀTolylbenzothiazole10a (5m): White solid; 57.1 mg (85% yield);mp 85ꢀ86 ℃; H NMR (400 MHz,
CDCl3) δ 8.10 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 7.9 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.40
(t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.2, 154.2,
141.4, 134.9, 130.9, 129.7, 127.5, 126.2, 125.1, 123.0, 121.5, 21.5.
1
2ꢀ(4ꢀMethoxyphenyl)benzothiazole10a (5n): White solid; 62.9 mg (87% yield); mp 121ꢀ122 ℃; H
NMR (400 MHz, CDCl3) δ 8.06 (m, 3H), 7.90 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.38 (t, J =
7.3 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 167.8, 161.9, 154.2,
134.8, 129.1, 126.4, 126.2, 124.8, 122.8, 121.5, 114.4, 55.4.
1
2ꢀ(4ꢀChlorophenyl)benzothiazole10a (5o): Straw yellow solid; 49.3 mg (67% yield); mp 118ꢀ120 ℃; H
NMR (400 MHz, CDCl3) δ 8.11 – 8.04 (m, 3H), 7.94 (d, J = 8.0 Hz, 1H), 7.57 – 7.47 (m, 3H), 7.45 –
7.40 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 166.6, 154.1, 137.0, 135.0, 132.1, 129.2, 128.7, 126.4,
125.4, 123.3, 121.6.
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2ꢀ(Furanꢀ2ꢀyl)benzothiazole10a (5p): White solid; 51.5 mg (85% yield); mp 106ꢀ107 ℃; H NMR (400
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1
2
3
4
5
MHz, CDCl3) δ 8.08 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 1.0 Hz, 1H), 7.57 – 7.47
13
(m, 1H), 7.46 – 7.36 (m, 1H), 7.22 (d, J = 3.1 Hz, 1H), 6.63 (dd, J = 3.5, 1.8 Hz, 1H); C NMR (101
MHz, CDCl3) δ 157.5, 153.7, 148.8, 144.7, 134.3, 126.4, 125.2, 123.1, 121.5, 112.5, 111.4.
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7
8
9
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2ꢀ(Thiophenꢀ2ꢀyl)benzothiazole21 (5q): Yellow solid; 48.8 mg (75% yield); mp 99ꢀ100 ℃; H NMR
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(400 MHz, CDCl3) δ 8.05 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.68 (dd, J = 3.7, 0.9 Hz, 1H),
7.56 – 7.52 (m, 1H), 7.49 (dd, J = 11.3, 4.2 Hz, 1H), 7.40 (dd, J = 11.1, 4.1 Hz, 1H), 7.16 (dd, J = 5.0,
13
3.8 Hz, 1H); C NMR (101 MHz, CDCl3) δ 161.4, 153.7, 137.3, 134.7, 129.2, 128.6, 128.0, 126.4,
125.2, 123.0, 121.4.
1
2ꢀ(Naphthalenꢀ2ꢀyl)benzothiazole22 (5r): White solid; 71.2 mg (91% yield); mp 125ꢀ127 ℃; H NMR
(400 MHz, CDCl3) δ 8.60 (s, 1H), 8.25 (dd, J = 8.6, 1.7 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 8.03 – 7.88
13
(m, 4H), 7.61 – 7.52 (m, 3H), 7.48 – 7.40 (m, 1H); C NMR (101 MHz, CDCl3) δ 168.1, 154.2, 135.1,
134.6, 133.2, 131.0, 128.8, 127.9, 127.6, 127.4, 126.9, 126.4, 125.3, 124.4, 123.2, 121.6.
1
2ꢀBenzylbenzothiazole7a (5s): White solid; 60.8 mg (90% yield); mp 158ꢀ160 ℃; H NMR (400 MHz,
CDCl3) δ 8.04 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.52 – 7.45 (m, 1H), 7.44 – 7.30 (m, 6H),
13
4.47 (s, 2H); C NMR (101 MHz, CDCl3) δ 171.1, 153.3, 137.2, 135.7, 129.2, 128.9, 127.3, 125.9,
124.8, 122.8, 121.5, 40.6.
1
2ꢀStyrylbenzothiazole23 (5u): White solid;48.3 mg (67% yield); mp 106ꢀ108 ℃; H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 9.0 Hz, 2H), 7.55 – 7.36 (m,
13
7H); C NMR (101 MHz, CDCl3) δ 166.9, 153.9, 137.6, 135.4, 134.3, 129.4, 128.9, 127.40, 126.3,
125.4, 122.9, 122.1, 121.5.
Acknowledgement The financial support from NSFC (20802053) is highly appreciated.
1
Supporting Information Available: Copies of H NMR and 13C NMR of all the products. This
material is available free of charge via the Internet at http://pubs.acs.org.
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