Cu-catalyzed in situ generation of thiol using xanthate as a thiol surrogate for the one-pot synthesis of benzothiazoles and benzothiophenes

Article abstract of DOI:10.1039/c3ob26915a

A new copper-catalyzed in situ generation of aryl thiolates strategy was successfully developed for the one-pot synthesis of substituted benzothiazoles from 2-iodoanilides using xanthate as a thiol precursor. A wide range of 2-iodoanilides with both electron-releasing and electron-withdrawing groups produced the corresponding benzothiazoles in good yields. Further, this one-pot protocol was successfully utilized for the synthesis of a potent antitumor agent 2-(3,4-dimethoxyphenyl)-5-fluorobenzo[d]thiazole (PMX 610). Finally, the copper-catalyzed in situ generation of aryl thiolates strategy was successfully applied for the domino synthesis of substituted benzothiophenes from o-haloalkynyl benzenes using xanthate as a thiol precursor.

Full text of DOI:10.1039/c3ob26915a

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PAPER
Cu-catalyzed in situ generation of thiol using xanthate as thiol surrogate
for the one-pot synthesis of benzothiazoles and benzothiophenes†
D. J. C. Prasad and G. Sekar*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A new copperꢀcatalyzed in situ generation of aryl thiolates strategy was successfully developed for the
oneꢀpot synthesis of substituted benzothiazoles from 2ꢀiodoanilides using xanthate as thiol precursor. A
wide range of 2ꢀiodoanilides with both electronꢀreleasing and electronꢀwithdrawing groups produced the
corresponding benzothiazoles in good yields. Further, this oneꢀpot protocol was successfully utilized for
10 the synthesis of a potent antitumor agent 2ꢀ(3,4ꢀdimethoxyphenyl)ꢀ5ꢀfluorobenzo[d]thiazole (PMX 610).
Finally, copperꢀcatalyzed in situ generation of aryl thiolates strategy was successfully applied for the
domino synthesis of substituted benzothiophenes from oꢀhaloalkynyl benzenes using xanthate as thiol
precursor.
The common methods reported in the literature for the
construction of benzothiazole moieties are condensation of 2ꢀ
35 aminothiophenols with different CꢀH
electrophiles,5
Introduction
15 Benzofused sulfurꢀcontaining heterocycles are important class of
compounds in pharmaceuticals, biologically active molecules and
materials.1 Particularly, benzothiazole and benzothiophene motifs
can be found in numerous biologically important molecules such
as antitumor agents,2 fatty acid amide hydrolase inhibitors3 and
20 selective estrogen receptor modulators (SERM's) (Fig. 1).4
functionalized cyclization of thiobenzanilide6 and transition
metalꢀcnatalyzed intramolecular cyclization of 2ꢀhalophenyl
benzothioamide.7 But, these methods are associated with several
limitations like usage of readily oxidizable substituted 2ꢀ
40 aminothiophenols, formation of regioisomers, limited substrate
scope, and high cost of Pd catalysts. In general, thioamides are
prepared from the corresponding amides using P4S10 or
Lawessons reagent, but it is not feasible for substrates consist of
ketone, ester, and amide moieties. The development of Pd or Cuꢀ
45 catalyzed oneꢀpot synthesis of benzothiazoles from 2ꢀhaloanilides
and a thiol surrogate has overcome these difficulties to a great
extent.8 Towards our ongoing research in developing newer
methods for the copperꢀcatalyzed C(aryl)ꢀheteroatom bond
formation and its application in heterocycles synthesis,9 recently
50 we have reported a oneꢀpot protocol for the synthesis of aryl
thioethers using potassium ethyl xanthogenate (xanthate) 1 as
thiol surrogate.10 To extend the application of our copperꢀ
catalyzed in situ generation of aryl thiolate strategy, herein, we
report a oneꢀpot protocol for the synthesis of benzothiazoles and
55 benzothiophenes using xanthate 1 as a sole thiol precursor
(Scheme 1).
Fig.
1 Biologically active molecules containing benzothiazole and
benzothiophene skeleton.
25 Department of Chemistry, Indian Institute of Technology Madras,
Chennai, Tamil Naduꢀ600 036, India. Eꢀmail: gsekar@iitm.ac.in; Fax:
+91 44 2257 4202; Tel: +91 44 2257 4229
† Electronic supplementary information (ESI) available: (Experimental
details, characterization data including 1H NMR spectra, 13C NMR spectra
30 for all compounds)
Scheme
1
Cuꢀcatalyzed oneꢀpot synthesis benzothiazoles and
See DOI: 10.1039/b000000x/
benzothiophenes using xanthate as thiol surrogate.
60
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Results and Discussion
45 2ꢀ(3,4ꢀdimethoxyphenyl)ꢀ5ꢀfluorobenzo[d]thiazole 25 where 2ꢀ
arylbenzo[d]thiazole formation is the key step (Scheme 2).2 Nꢀ(5ꢀ
Fluoroꢀ2ꢀiodophenyl)ꢀ3,4ꢀdimethoxybenzamide 24 was obtained
with 87% yield through acylation of 5ꢀfluoroꢀ2ꢀiodoaniline 22
with 3,4ꢀdimethoxybenzoyl chloride 23. Next, we applied copperꢀ
50 catalyzed oneꢀpot protocol by reacting Nꢀ(5ꢀfluoroꢀ2ꢀ
iodophenyl)ꢀ3,4ꢀdimethoxybenzamide 24 and xanthate 1 as a
thiol precursor. The reaction provided the target molecule
We started our studies by reacting Nꢀ(2ꢀiodophenyl) benzamide 2
with xanthate 1 in the presence of 10 mol% Cu(OAc)2 and 10
mol% of 1,1'ꢀbinaphthylꢀ2,2'ꢀdiamine (BINAM) ligand at 105 oC.
After 10 hours, Nꢀ(2ꢀiodophenyl)benzamide 2 was completely
consumed, then 0.5 mL of concentrated HCl was added to the
reaction mixture and stirred for 8 hours at room temperature to
obtain 24% isolated yield of 2ꢀphenylbenzothiazole 3 along with
20% of 2ꢀphenylbenzoxazole (Table 1, entry 1). When the oneꢀ
5
antitumor
agent
2ꢀ(3,4ꢀdimethoxyphenyl)ꢀ5ꢀfluorobenzo[d]
thiazole 25 in 64% isolated yield.
10 pot reaction was carried out without BINAM ligand, in the
presence of only Cu(OAc)2, the reaction provided 42% yield of 2ꢀ
phenylbenzothiazole 3 (entry 2). Similar result was obtained
55 Table 2 Cuꢀcatalyzed oneꢀpot synthesis of benzothiazoles using thiol
precursor
o
when the reaction was carried out at 80 C with slightly longer
reaction time (entry 3). To increase the efficiency of this oneꢀpot
15 synthesis of benzothiazoles, the amount of xanthate 1 was
increased to three equivalents and as a result, a better yield of
62% was obtained (entry 4). Either by changing the copper salt or
using external base, the yield for benzothiazole formation
decreased (entries 5 and 6). Trace amount of product 3 was
20 observed when the reaction was carried out without Cu(OAc)2
(entry 7).
Table 1 Optimization of reaction conditions for the oneꢀpot synthesis of
benzothiazoles
25
Using the above mentioned optimized reaction conditions,
we initiated our investigation into the scope of the copperꢀ
catalyzed oneꢀpot synthesis of substituted benzothiazoles with a
variety of substituted 2ꢀiodoanilides and xanthate 1 as thiol
30 precursor and the results are summarized in Table 2. A wide
range of 2ꢀiodoanilides with both electronꢀreleasing (entries 2 and
3) and electronꢀwithdrawing groups (entries 5) produced the
corresponding benzothiazoles in good yields. Sterically hindered
orthoꢀsubstituted benzothioamide
35 corresponding benzothiazole
8
also provided the
9
in good yield (entry 4).
Interestingly, 2ꢀalkylꢀsubstituted benzothiazoles were also
synthesized in good yields (entries 7 and 8). We were pleased to
note that under the optimized reaction conditions, 2ꢀiodoanilides
containing functional groups such as ketone and ester also
40 provided the corresponding benzothiazoles in good yields (entries
9 and 10).
The plausible reaction pathway for oneꢀpot synthesis of
60 benzothiazoles is proposed in Scheme 3.8b First, there will be a
copperꢀcatalyzed Ullmann type C(aryl)ꢀS bond formation between
2ꢀiodoanilide 26 with xanthate 1 (xanthate coupling) to give aryl
xanthate 27. Subsequently, this aryl xanthate 27 will be
After completion of
a
wide range of substituted
benzothiazoles synthesis, the oneꢀpot protocol was successfully
applied for the synthesis of a potent antitumor agent (PMX 610)
2
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hydrolyzed by excess xanthate 1 to generate the corresponding
aryl thiolate 28 and this in situ generated thiolate underwent
of 2ꢀiodo alkynylbenzenes including electronꢀreleasing, electronꢀ
withdrawing and sterically hindered orthoꢀsubstituted 2ꢀ
intramolecular condensation to give the corresponding substituted 40 iodoalkynylbenzenes are well tolerated. Heteroatom containing 2ꢀ
benzothiazole 30 (Scheme 3). In this oneꢀpot process the in situ
generation of aryl thiolate 28 was confirmed by trapping with an
electrophile (benzyl bromide).11
((2ꢀiodophenyl)ethynyl) pyridine 43 also provided 93% isolated
yield for the corresponding benzothiophene 44 (entry 7). Less
reactive 2ꢀbromoalkynylbenzenes were also used for this domino
reaction by slightly increasing the reaction temperature to 100 oC
45 (entries 8ꢀ10).
5
O
Cl
OMe
F
NH2
I
H
N
F
THF, rt
+
OMe
Table 3 Optimization of reaction conditions for the Cuꢀcatalyzed domino
synthesis of benzothiophenes
12 h, 87%
OMe
O
I
24
OMe
23
22
S
(i) Cu(OAc)2 (10 mol%)
DMF, 80 oC, 15 h
(ii) HCl, rt, 8 h
KS OEt
1
F
N
S
OMe
25
64%
antitumor agent
OMe
Scheme 2 Synthesis of antitumor agent (PMX 610) using thiol precursor.
Table 4 Cuꢀcatalyzed domino synthesis of benzothiophenes using thiol
50 precursor
R
S
BINAM-Cu(OAc)2 (10 mol%)
+
R
DMF, 80 oC, 35 h
KS
OEt
S
X
1
Yield (%)a
96
Entry
1
Benzothiophene
2-Haloalkyne
Ph
10 Scheme
benzothiazoles.
3 Plausible reaction pathway for oneꢀpot synthesis of
31
S
32
34
I
Finally, we extended this in situ generation of aryl thiolates
methodology for domino synthesis of substituted
2
96
33
S
I
benzothiophenes from oꢀhaloalkynylbenzenes and xanthate 1 as
15 thiol precursor. The common methods reported in the literature
for the assembly of benzothiophene moieties are electrophilic
cyclization reaction of oꢀalkynylaryl thioether derivatives,12
intramolecular Sꢀarylation of αꢀ(orthoꢀhaloaryl)thioketones13 and
domino Sonogashira coupling between oꢀbromothiophenol and
20 cuprous acetylide followed by cyclization.14 But, these methods
associated with some limitations like usage of readily oxidizable
2ꢀbromothiophenols, limited substrate scope, moderate yields and
high costs of palladium catalysts. The development of transition
metal catalyzed oneꢀpot or domino synthesis of benzothiophenes
25 from oꢀhaloalkynylbenzenes and a thiol precursor has overcome
these difficulties to a great extent.15
3
4
97
97
OCH3
F
S
36
35
I
OCH3
37
S
38
I
5
6
F
99
94
39
S
I
I
40
41
S
S
42
N
7
8
93
43
N
I
Ph
44
Initially, the domino reaction was carried out with 1ꢀiodoꢀ2ꢀ
(phenylethynyl)benzene 31 and xanthate 1 in the presence of 10
68b
45
S
o
32
Br
mol% of Cu(OAc)2 and 10 mol% of BINAM in DMF at 100 C
30 and the reaction provided 94% of 2ꢀphenylbenzothiophene 32
9
64b
70b
46
47
S
(Table 3, entry 1). Similar result was obtained when the reaction
34
Br
Br
o
was carried out at 80 C with slightly increased yield (entry 2).
N
10
The domino reaction provided only 38% of 32 when only
Cu(OAc)2 was used as catalyst without ligand BINAM (entry 4).
S
N
44
a Isolated yield. b Reaction was carried at 100 oC for 48 h.
35
Using the optimized reaction conditions, a variety of
substituted 2ꢀiodoalkynylbenzenes were reacted with xanthate 1
for the domino synthesis of benzothiophenes (Table 4). All types
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The plausible reaction pathway for domino synthesis of 45 are reported in frequency of absorption (cmꢀ1). High resolution
benzothiophenes from oꢀiodoalkynylbenzenes and xanthate 1 is
proposed in Scheme 4.15c Initially, there will be a copper
catalyzed Ullmann type C(aryl)ꢀS bond formation between oꢀ
iodoalkynylbenzene 48 with xanthate 1 (xanthate coupling) to
give intermediate 49. The aryl thiolate 50 is in situ generated
through the hydrolysis of intermediate 49, which then underwent
intramolecular cyclization to yield the analogous benzothiophene
51 (Scheme 4).
mass spectra (HRMS) were recorded on QꢀTof Micro mass
spectrometer.
General procedure for one-pot synthesis of benzothiazoles
5
A mixture of Nꢀ(2ꢀiodophenyl)benzamide 2 (161.5 mg, 0.5
50 mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol) and potassium ethyl
xanthogenate 1 (240.4 mg, 1.50 mmol) were taken in an ovenꢀ
dried reaction tube equipped with a septum. The reaction tube
was evacuated and backꢀfilled with nitrogen. N, Nꢀ
Dimethylformamide (3.0 mL) was added to the reaction mixture
55 at room temperature, the reaction tube was sealed with glass
stopper and the reaction mixture was heated for 15 hours at 80
oC. Then 0.5 mL conc. HCl was added to the cooled reaction
mixture. After 8 hours, 6 mL saturated aq.NaHCO3 was added
and the mixture was extracted with ethyl acetate and water. The
60 organic layer was dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure. The crude residue was
purified by column chromatography on silica gel using ethyl
acetate/hexanes as eluents to give
phenylbenzo[d]thiazole 3 (65.4 mg, 62%) as white solid.
desired product 2ꢀ
10
Scheme
benzothiophenes.
4 Plausible reaction pathway for domino synthesis of
o
65
2-Phenylbenzo[d]thiazole (3).8b White solid; mp 112ꢀ114 C
(lit. 113ꢀ114 oC); Rf 0.46 (1:19 ethyl acetate : hexanes); 1H NMR
(400 MHz, CDCl3): δ 7.36ꢀ7.43 (m, 1H), 7.47ꢀ7.54 (m, 4H), 7.91
(d, J = 7.6 Hz, 1H), 8.07ꢀ8.14 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 121.8, 123.4, 125.3, 126.5, 127.7, 129.2, 131.1, 133.7,
Conclusion
We have developed a new copperꢀcatalyzed copperꢀcatalyzed in
70 135.2, 154.3, 168.2; IR (neat): 3064, 764, 730, 690 cmꢀ1; HRMS
15 situ generation of aryl thiolates strategy for the oneꢀpot synthesis
of substituted benzothiazoles from 2ꢀiodoanilides and xanthate as
thiol precursor. A wide range of 2ꢀiodoanilides with both
electronꢀreleasing and electronꢀwithdrawing groups produced the
corresponding benzothiazoles in good yields. Further, this oneꢀ
20 pot protocol was successfully utilized for the synthesis of a potent
(m/z): [M+H]+ calcd. for C13H10NS: 212.0534; found: 212.0529.
2-(4-Methoxyphenyl)benzo[d]thiazole (5).7a White solid; mp
o
o
121 C (lit. 120ꢀ121 C); Rf 0.25 (1:19 ethyl acetate : hexanes);
1H NMR (400 MHz, CDCl3): δ 3.88 (s, 3H), 7.00 (d, J = 7.6 Hz,
75 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.88 (d, J =
7.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 55.6, 114.5, 121.6, 123.0, 124.9, 126.4, 126.6, 129.3,
135.0, 154.4, 162.1, 168.0; IR (neat): 3063, 2995, 2923, 2837,
832, 758, 623 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for C14H12NOS:
80 242.0640; found: 242.0636.
antitumor
agent
2ꢀ(3,4ꢀdimethoxyphenyl)ꢀ5ꢀfluorobenzo[d]
thiazole (PMX 610). Finally, copperꢀcatalyzed in situ generation
of aryl thiolates strategy was successfully applied for the domino
synthesis of substituted benzothiophenes from oꢀhaloalkynyl
25 benzenes and xanthate as a sole thiol precursor.
2-(3-Methoxyphenyl)benzo[d]thiazole (7).7b White solid; mp
Experimental Section
o
o
1
82ꢀ83 C (lit. 81ꢀ82 C); Rf 0.65 (1:9 ethyl acetate : hexanes); H
NMR (400 MHz, CDCl3): δ 3.92 (s, 3H), 7.04 (dd, J = 8.0 & 2.4
Hz, 1H), 7.35ꢀ7.43 (m, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.65 (d, J =
85 7.6 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H),
8.09 (d, J = 8.0 Hz, 1H) ; 13C NMR (100 MHz, CDCl3): δ 55.6,
112.1, 117.5, 120.4, 121.7, 123.3, 125.4, 126.5, 130.2, 134.9,
135.1, 154.1, 160.2, 168.1; IR (neat): 3061, 3002, 2932, 2837,
792, 761, 731, 689 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for
90 C14H12NOS: 242.0640; found: 242.0643.
General information
1,1'ꢀBinaphthylꢀ2,2'ꢀdiamine (BINAM) ligand was purchased
from GERCHEM chemicals, Hyderabad, India. Cu(OAc)2ꢁH2O
30 was purchased from Merck, India and oven dried to obtain
anhydrous Cu(OAc)2. Aryl halides, acid chlorides, alkynes and
potassium ethyl xanthogenate were purchased from sigma
Aldrich Chemical Company. All the solvents used for the
reactions were obtained from Rankem, India and dried by
35 Vogel’s procedure. Reaction temperatures were controlled by
Varivolt temperature modulator, Thinꢀlayer chromatography
(TLC) was performed using Merck silica gel 60 F254 precoated
plates (0.25 mm) and visualized by UV fluorescence quenching.
Silica gel (particle size 100ꢀ200 mesh) purchased from SRL India
40 was used for chromatography. 1H and 13C NMR spectra were
recorded on a Bruker 400 MHz instrument. 1H NMR spectra were
reported relative to Me4Si (δ 0.0 ppm) or residual CHCl3 (δ 7.26
ppm). 13C NMR were reported relative to CDCl3 (δ 77.16 ppm).
FTIR spectra were recorded on a Nicolet 6700 spectrometer and
2-o-Tolylbenzo[d]thiazole (9).7b White solid; mp 52ꢀ53 oC (lit.
o
1
51ꢀ53 C); Rf 0.58 (1:19 ethyl acetate : hexanes); H NMR (400
MHz, CDCl3): δ 2.57 (s, 3H), 7.18ꢀ7.35 (m, 4H), 7.38ꢀ7.45 (m,
1H), 7.67 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 8.02 (d, J
95 = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 21.5, 121.5,
123.5, 125.2, 126.2, 130.1, 130.7, 131.7, 133.2, 135.7, 137.4,
142.6, 153.9, 168.1; IR (neat): 3060, 2964, 2924, 723, 687 cmꢀ1;
HRMS (m/z): [M+H]+ calcd. for C14H12NS: 226.0690; found:
226.0685.
4
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2-(4-Fluorophenyl)benzo[d]thiazole (11).7b White solid; mp
101ꢀ102 oC (lit. 100ꢀ102 oC); Rf 0.44 (1:19 ethyl acetate :
hexanes); 1H NMR (400 MHz, CDCl3): δ 7.19 (t, J = 8.8 Hz, 2H),
7.39 (t, J = 8.0 Hz, 1H), 7.47ꢀ7.53 (m, 1H), 7.90 (d, J = 8.0 Hz,
4.02 (s, 3H), 6.94 (d, J = 8.4 Hz, 1H), 7.12 (td, J = 8.4 & 2.4 Hz,
1H), 7.58 (dd, J = 8.4 & 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H),
7.70 (dd, J = 9.2 & 2.4 Hz, 1H), 7.78 (dd, J = 8.8 & 5.2 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ 56.2, 56.3, 109.2 (d, J = 23.5
5
1H), 8.04ꢀ8.12 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 116.3 (d, 60 Hz), 109.9, 111.2, 113.6 (d, J = 24.8 Hz), 121.3, 122.2 (d, J = 9.8
J = 22.0 Hz), 121.8, 123.3, 125.4, 126.6, 129.7 (d, J = 8.7 Hz),
130.1, 135.2, 154.3, 164.6 (d, J = 250.4 Hz), 166.9; IR (neat):
3063, 837, 756, 728 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for
C13H9NSF: 230.0440; found: 230.0438.
Hz), 126.6, 130.4, 149.5, 151.9, 155.2 (d, J = 12.4 Hz), 162.1 (d,
J = 241.6 Hz), 170.6; IR (neat): 3011, 2961, 2933, 2843, 843, 795
cmꢀ1; HRMS (m/z): [M+H]+ calcd. for C15H13NO2FS: 290.0651;
found: 290.0654.
10
6-Methyl-2-phenylbenzo[d]thiazole (13).7b White solid; mp
65 Experimental procedure for trapping of aryl thiolate 28
149ꢀ150 oC (lit. 150ꢀ151 oC); Rf 0.28 (1:19 ethyl acetate :
1
hexanes); H NMR (400 MHz, CDCl3): δ 2.50 (s, 3H), 7.31 (d, J
A mixture of Nꢀ(2ꢀIodophenyl)pivalamide 14 (151.5 mg, 0.5
mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol) and potassium ethyl
xanthogenate 1 (80.1 mg, 0.50 mmol) were taken in an ovenꢀ
dried reaction tube equipped with a septum. N, NꢀDimethyl
70 formamide (3.0 mL) was added to the reaction mixture at room
temperature, the reaction tube was sealed with glass stopper and
the reaction mixture was heated for 10 hours at 80 oC. Then
potassium ethyl xanthogenate 1 (160.3 mg, 1.0 mmol) and benzyl
bromide (85.5 mg, 0.50 mmol) were added to the reaction
= 8.4 Hz, 1H), 7.45ꢀ7.54 (m, 3H), 7.69 (s, 1H), 7.96 (d, J = 8.0
Hz, 1H), 8.04ꢀ8.12 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
15 21.7, 121.5, 122.9, 127.6, 128.1, 129.1, 130.9, 133.9, 135.4,
135.5, 152.4, 167.1; IR (neat): 3021, 2919, 2852, 815, 766, 690
cmꢀ1; HRMS (m/z): [M+H]+ calcd. for C14H12NS: 226.0690;
found: 226.0698.
2-tert-Butylbenzo[d]thiazole (15).16 Pale yellow solid; mp 64ꢀ
o
o
1
20 66 C (lit. 65ꢀ67 C); Rf 0.60 (1:9 ethyl acetate : hexanes); H
NMR (400 MHz, CDCl3): δ 1.53 (s, 9H), 7.30ꢀ7.37 (m, 1H),
7.41ꢀ7.48 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 30.9, 38.4, 121.6, 122.8,
124.6, 125.8, 135.1, 153.4, 182.0; IR (neat): 2964, 2867, 1511,
25 1336, 1045, 756, 687 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for
C11H14NS: 192.0847; found: 192.0847.
o
75 mixture and the resulting mixture was further heated to 80 C for
2.5 hours. The reaction mixture was extracted with ethyl acetate
and water. The organic layer was dried over anhydrous Na2SO4
and then the solvent was removed under reduced pressure. The
crude residue was purified by column chromatography on silica
80 gel using dichloromethane/ hexanes as eluents to give Nꢀ(2ꢀ
(benzylthio)phenyl)pivalamide 28a (34.2 mg, 23%).
2-Ethylbenzo[d]thiazole (17).7b Pale yellow liquid; Rf 0.67
(1:9 ethyl acetate : hexanes); 1H NMR (400 MHz, CDCl3): δ 1.47
(t, J = 7.6 Hz, 3H), 3.16 (q, J = 7.6 Hz, 2H), 7.31ꢀ7.37 (m, 1H),
30 7.45 (td, J = 8.4 & 1.2 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.97 (d,
J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 13.9, 27.9,
121.6, 122.6, 124.8, 126.0, 135.1, 153.2, 173.8; IR (neat): 3061,
2974, 2934, 759, 729 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for
C9H10NS: 164.0534; found: 164.0538.
N-(2-(benzylthio)phenyl)pivalamide (28a). Pale yellow oil;
Rf 0.23 (1:4 dichloromethane : hexanes); H NMR (400 MHz,
1
CDCl3): δ 1.16 (s, 9H), 3.81 (s, 2H), 6.90ꢀ6.97 (m, 3H), 7.12ꢀ7.20
85 (m, 3H), 7.26 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 8.35
(d, J = 8.4 Hz, 1H), 8.68 (bs, 1H); 13C NMR (100 MHz, CDCl3):
δ 27.7, 40.3, 41.8, 119.9, 122.2, 123.9, 127.6, 128.8, 129.1,
130.4, 136.3, 137.8, 140.6, 176.8; FTIR (neat): 3362, 3062, 3029,
2960, 2926, 2869, 1684, 756, 698, 669 cmꢀ1; HRMS: m/z [M+H]+
35
Phenyl(2-phenylbenzo[d]thiazol-6-yl)methanone (19). White 90 calcd for C18H22NOS: 300.1422; found: 300.1421.
o
1
solid; mp 120ꢀ122 C; Rf 0.49 (1:9 ethyl acetate : hexanes); H
NMR (400 MHz, CDCl3): δ 7.47ꢀ7.66 (m, 6H), 7.84 (d, J = 7.2
Hz, 2H), 7.96 (d, J = 8.0 Hz, 1H), 8.08ꢀ8.19 (m, 3H), 8.39 (s,
1H); 13C NMR (100 MHz, CDCl3): δ 122.9, 124.5, 127.9, 128.4,
Typical experimental procedure for domino synthesis of
benzothiophenes
A mixture of Cu(OAc)2 (9.1 mg, 0.05 mmol), BINAM (14.2 mg,
0.05 mmol) and potassium ethyl xanthogenate 1 (240.4 mg, 1.50
95 mmol) were taken in an oven dried reaction tube equipped with a
septum. The reaction tube was evacuated and backꢀfilled with
nitrogen. 1ꢀIodoꢀ2ꢀ(phenylethynyl)benzene 31 (159.1 mg, 0.50
mmol) and N,Nꢀdimethylformamide (3.0 mL) were added to the
reaction mixture at room temperature. The reaction tube was
100 closed with glass stopper and the reaction mixture was heated for
35 hours at 80 oC. Then, the reaction mixture was allowed to cool
to room temperature and extracted with ethyl acetate and
saturated NaCl solution. The organic layer was dried over
anhydrous Na2SO4 and the solvent was removed under reduced
105 pressure. The crude residue was purified by column
chromatography on silica gel using ethyl acetate/hexanes as
eluents to give 2ꢀphenylbenzo[b]thiophene 32 (101.0 mg, 96%)
as white solid.
40 128.5, 129.3, 130.1, 131.8, 132.6, 133.3, 134.4, 135.1, 137.9,
156.8, 171.8, 195.9; IR (neat): 3055, 3023, 2922, 2852, 1647,
755, 689 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for C20H14NOS:
316.0796; found: 316.0801.
Methyl 2-phenylbenzo[d]thiazole-6-carboxylate (21).17
o
o
45 White solid; mp 164ꢀ166 C (lit. 164.5ꢀ165.5 C); Rf 0.53 (1:9
1
ethyl acetate : hexanes); H NMR (400 MHz, CDCl3): δ 3.97 (s,
3H), 7.50ꢀ7.55 (m, 3H), 8.07ꢀ8.14 (m, 3H), 8.17 (dd, J = 8.4 &
1.6 Hz, 1H), 8.64 (d, J = 1.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 52.5, 123.0, 124.0, 127.1, 127.7, 127.9, 129.3, 131.8,
50 133.4, 135.1, 157.2, 166.8, 171.7; IR (neat): 3062, 3022, 2986,
2945, 2842, 1712, 770, 687 cmꢀ1; HRMS (m/z): [M+H]+ calcd.
for C15H12NO2S: 270.0589; found: 270.0597.
2-(3,4-Dimethoxyphenyl)-5-fluorobenzo[d]thiazole
(25).2
White solid; mp 109ꢀ110 oC (lit. 110 oC); Rf 0.32 (1:9 ethyl
1
55 acetate : hexanes); H NMR (400 MHz, CDCl3): δ 3.96 (s, 3H),
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2-Phenylbenzo[b]thiophene (32).15a White solid; mp 164ꢀ165
2-(Benzo[b]thiophen-2-yl)pyridine (44).19 White solid; mp
125ꢀ126 oC (lit. 126 oC); Rf 0.55 (1:9 ethyl acetate : hexanes); 1H
NMR (400 MHz, CDCl3): δ 7.18ꢀ7.23 (m, 1H), 7.32ꢀ7.39 (m,
2H), 7.73 (td, J = 8.0 & 2.0 Hz, 1H), 7.78ꢀ7.82 (m, 2H), 7.83 (s,
o
1
oC (lit. 164ꢀ166 C); Rf 0.63 (in hexanes); H NMR (400 MHz,
CDCl3): δ 7.30ꢀ7.40 (m, 3H), 7.44 (t, J = 8.0 Hz, 2H), 7.56 (s,
1H), 7.74 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.85 (d, J
5
= 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 119.6, 122.4, 60 1H), 7.85ꢀ7.90 (m, 1H), 8.62ꢀ8.66 (m, 1H); 13C NMR (100 MHz,
123.7, 124.5, 124.6, 126.6, 128.4, 129.1, 134.5, 139.7, 140.8,
144.4; IR (neat): 3052, 3027, 2924, 2855, 752, 731, 690 cmꢀ1;
HRMS (m/z): [M+H]+ calcd. for C14H11S: 211.0581; found:
211.0580.
CDCl3): δ 119.7, 121.2, 122.7, 124.2, 124.6, 125.2, 136.7, 140.6,
140.8, 144.9, 149.9, 152.7; IR (neat): 3045, 2991, 782, 752, 738
cmꢀ1.
Acknowledgments
10
2-p-Tolylbenzo[b]thiophene (34).15a White solid; mp 167ꢀ168
oC (lit. 166.1ꢀ168.2 oC); Rf 0.64 (in hexanes); 1H NMR (400
MHz, CDCl3): δ 2.28 (s, 3H), 7.11 (d, J = 8.0 Hz, 2H), 7.16ꢀ7.26
(m, 2H), 7.38 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.6
Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
65 We thank CSIR (01(2378)/10/EMRꢀII) and DST New Delhi,
India for the financial support. D. J. C. P. thanks UGC, New
Delhi, India for senior research fellowship. We thank DST, New
Delhi for the funding towards the 400 MHz NMR instrument to
the Department of Chemistry, IIT Madras under the IRPHA
70 scheme and ESIꢀMS facility under the FIST programme.
15 δ 21.4, 118.9, 122.3, 123.5, 124.2, 124.6, 126.5, 129.7, 131.6,
138.4, 139.4, 140.9, 144.5; IR (neat): 3051, 3021, 2913, 2856,
808, 733, 721 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for C15H13S:
225.0738; found: 225.0742.
Notes and references
2-m-Tolylbenzo[b]thiophene (36).15c White solid; mp 116ꢀ
1
(a) I. P. Beletskaya and V. P. Ananikov, Chem. Rev., 2011, 111,
1596; (b) T. Kondo and T. Mitsudo, Chem. Rev., 2000, 100, 3205;
(c) Y. Liu and J. ꢀP. Wan, Org. Biomol. Chem., 2011, 9, 6873; (d) L.
L. Bozec and C. J. Moody, Aust. J. Chem., 2009, 62, 639; (e) T.
Kashiki, S. Shinamura, M. Kohara, E. Miyazaki, K. Takimiya, M.
Ikeda and H. Kuwabara, Org. Lett., 2009, 11, 2473.
20 118 C (lit. 117ꢀ118 oC); Rf 0.73 (in hexanes); H NMR (400
MHz, CDCl3): δ 2.44 (s, 3H), 7.17 (d, J = 7.2 Hz, 1H), 7.29ꢀ7.39
(m, 3H), 7.52ꢀ7.56 (m, 3H), 7.78 (d, J = 7.6 Hz, 1H), 7.84 (d, J =
7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 21.6, 119.4, 122.4,
123.6, 123.7, 124.3, 124.6, 127.3, 128.9, 129.2, 134.3, 138.7,
25 139.6, 140.8, 144.5; IR (neat): 3056, 3027, 2921, 2854, 832, 786,
747 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for C15H13S: 225.0738;
found: 225.0745.
o
1
75
80
2
3
4
S. Aiello, G. Wells, E. L. Stone, H. Kadri, R. Bazzi, D. R. Bell, M.
F. G. Stevens, C. S. Matthews, T. D. Bradshaw and A. D. Westwell,
J. Med. Chem., 2008, 51, 5135.
X. Wang, K. Sarris, K. Kage, D. Zhang, S.P. Brown, T. Kolasa, C.
Surowy, O. F. El Kouhen, S. W. Muchmore, J. D. Brioni and A. O.
Stewart, J. Med. Chem., 2009, 52, 170.
(a) Z. Qin, I. Kastrati, R. E. P. Chandrasena, H. Liu, P. Yao, P. A.
Petukhov, J. L. Bolton and G. R. J. Thatcher, J. Med. Chem., 2007,
50, 2682; (b) C. S. Bryan, J. A. Braunger and M. Lautens, Angew.
Chem. Int. Ed., 2009, 48, 7064.
2-(4-Methoxy-2-methylphenyl)benzo[b]thiophene
(38).
o
1
White solid; mp 68ꢀ69 C; Rf 0.37 (in hexanes); H NMR (400
30 MHz, CDCl3): δ 2.47 (s, 3H), 3.85 (s, 3H), 6.79ꢀ6.84 (m, 1H),
6.86 (d, J = 2.4 Hz, 1H), 7.21 (s, 1H), 7.30ꢀ7.40 (m, 2H), 7.42 (d,
J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 21.5, 55.4, 111.4, 116.3,
122.1, 122.7, 123.4, 124.0, 124.4, 126.8, 131.9, 138.1, 140.1,
35 140.4, 143.6, 159.7; IR (neat): 3052, 3001, 2962, 2932, 2835,
811, 744, 727 cmꢀ1; HRMS (m/z): [M+H]+ calcd. for C16H15OS:
255.0844; found: 255.0836.
85
5
6
J. A. Seijas, M. P. VázquezꢀTato, M. R. CarballidoꢀReboredo, J.
CrecenteꢀCampo and L. RomarꢀLópez, Synlett., 2007, 313.
(a) X. J. Mu, J. P. Zou, R. S. Zeng and J. C. Wu, Tetrahedron Lett.,
2005, 46, 4345; (b) D.S. Bose and M. Idrees, Tetrahedron Lett.,
2007, 48, 669.
90
7
8
(a) G. Evindar and R. A. Batey, J. Org. Chem., 2006, 71, 1802; (b)
E. A. Jaseer, D. J. C. Prasad, A. Dandapat and G. Sekar,
Tetrahedron Lett., 2010, 51, 5009.
95
2-(4-Fluorophenyl)benzo[b]thiophene (40).18 White solid;
(a) T. Itoh and T. Mase, Org. Lett., 2007, 9, 3687; (b) D. Ma et al.
reported a CuIꢀcatalyzed method for the synthesis of benzothiazoles
from 2ꢀhaloanilides using sodium sulfide as thiol precursor. Sodium
sulfide is a strongly alkaline like sodium hydroxide. Hence, under
these reaction conditions base sensitive functional groups like ester
was hydrolyzed and the corresponding acid is isolated. See, D. Ma,
S. Xie, P. Xue, X. Zhang, J. Dong and Y. Jiang, Angew. Chem. Int.
Ed., 2009, 48, 4222.
1
mp 162 oC (lit. 162ꢀ164 oC); Rf 0.69 (in hexanes); H NMR (400
40 MHz, CDCl3): δ 7.09ꢀ7.16 (m, 2H), 7.30ꢀ7.40 (m, 2H), 7.47 (s,
1H), 7.65ꢀ7.71 (m, 2H), 7.77 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 7.6
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 116.1 (d, J = 21.8 Hz),
119.6, 122.4, 123.7, 124.5, 124.8, 128.3 (d, J = 8.0 Hz), 130.7,
139.6, 140.8, 143.2, 162.9 (d, J = 246.8 Hz); IR (neat): 3061,
45 3033, 821, 745, 727 cmꢀ1.
100
105
110
9
(a) A. B. Naidu, E. A. Jaseer and G. Sekar, J. Org. Chem., 2009, 74,
3675; (b) R. K. Rao, A. B. Naidu and G. Sekar, Org. Lett., 2009, 11,
1923; (c) D. J. C. Prasad and G. Sekar, Org. Biomol. Chem., 2009,
7, 5091; (d) D. J. C. Prasad, A. B. Naidu and G. Sekar, Tetrahedron
Lett., 2009, 50, 1411; (e) D. J. C. Prasad and G. Sekar, Synthesis,
2010, 79; (f) K. G. Thakur and G. Sekar, Chem. Commun., 2011, 47,
6692; (g) K. G. Thakur, D. Ganapathy and G. Sekar, Chem.
Commun., 2011, 47, 5076.
2-Cyclohexenylbenzo[b]thiophene (42).15b White solid; mp
85ꢀ86 oC (lit. 84ꢀ86 oC); Rf 0.72 (in hexanes); 1H NMR (400
MHz, CDCl3): δ 1.57ꢀ1.64 (m, 2H), 1.69ꢀ1.76 (m, 2H), 2.13ꢀ2.20
(m, 2H), 2.39ꢀ2.45 (m, 2H), 6.23 (t, J = 4.0 Hz, 1H), 7.03 (s, 1H),
50 7.14ꢀ7.23 (m, 2H), 7.56ꢀ7.60 (m, 1H), 7.65 (d, J = 7.2 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ 22.2, 22.8, 25.9, 27.1, 117.9,
122.1, 123.3, 124.2, 124.3, 127.2, 131.7, 138.4, 140.6, 146.9; IR
10 D. J. C. Prasad and G. Sekar, Org. Lett., 2011, 13, 1008.
11 The in situ generated aryl thiolate 28 was trapped with benzyl
bromide and the corresponding aryl thioether 28a was isolated in
32% yield. (See experimental section for details)
12 (a) D. Yue and R. C. Larock, J. Org. Chem., 2002, 67, 1905; (b) B.
L. Flynn, P. VerdierꢀPinard and E. Hamel, Org. Lett., 2001, 3, 651;
(c) I. Nakamura, T. Sato and Y. Yamamoto, Angew. Chem. Int. Ed.,
2006, 45, 4473.
(neat): 3050, 3022, 2927, 2855, 2826, 1632, 817, 740, 722 cmꢀ1; 115
HRMS (m/z): [M+H]+ calcd. for C14H15S: 215.0894; found:
55 215.0903.
6
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13 M. C. Willis, D. Taylor and A. T. Gillmore, Tetrahedron, 2006, 62,
11513.
14 A. M. Malte and C. E. Castro, J. Am. Chem. Soc., 1967, 89, 6770.
15 (a) M. Kuhn, F. C. Falk and J. Paradies, Org. Lett., 2011, 13, 4100;
(b) V. Guilarte, M. A. FernándezꢀRodríguez, P. GarcíaꢀGarcía, E.
Hernando and R. Sanz, Org. Lett., 2011, 13, 5100; (c) L. L. Sun, C.
L. Deng, R. Y. Tang and X. G. Zhang, J. Org. Chem., 2011, 76,
7546.
16 C. Benedí, F. Bravo, P. Uriz, E. Fernández, C. Claverb and S.
Castillón, Tetrahedron Lett., 2003, 44, 6073.
17 Y. Cheng, J. Yang, Y. Qu and P. Li, Org. Lett., 2012, 14, 98.
18 A. B. Bíró and A. Kotschy, Eur. J. Org. Chem., 2007, 1364.
19 M. Baghbanzadeh, C. Pilger and C. O. Kappe, J. Org. Chem., 2011,
76, 8138.
5
10
15
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Graphical Abstract
_____________________________________________________________
Cu-catalyzed in situ Generation of Thiol Using Xanthate as Thiol Surrogate for the
One-pot Synthesis of Benzothiazoles and Benzothiophenes
D. J. C. Prasad and G. Sekar*
R
H
N
R'
S
N
S
O
R
X
I
R
R'
KS
OEt
S
R
Cu catalyst
Benzothiophenes
Benzothiazoles
A new copper-catalyzed in situ generation of aryl thiolates strategy was successfully developed for the one-pot
synthesis of substituted benzothiazoles from 2-iodoanilides using xanthate as thiol precursor. A wide range of 2-
iodoanilides with both electron-releasing and electron-withdrawing groups produced the corresponding benzothiazoles
in good yields. Further, this one-pot protocol was successfully utilized for the synthesis of a potent antitumor agent 2-
(3,4-dimethoxyphenyl)-5-fluorobenzo[d]thiazole (PMX 610). Finally, copper-catalyzed in situ generation of aryl
thiolates strategy was successfully applied for the domino synthesis of substituted benzothiophenes from o-haloalkynyl
benzenes using xanthate as thiol precursor.
_____________________________________________________________________________________________