Heck-type coupling of intramolecularly-generated thiopalladacycles with alkenes: One pot syntheses of 3-alkenylbenzo[b]thiophenes

Article abstract of DOI:10.1016/j.jorganchem.2012.02.009

A method for stoichiometric functionalization of benzothiophene is developed by Heck-type coupling of alkenes with intramolecularly-generated thiopalladacycles obtained from palladium salts and ortho-thioanisole- substituted propargyl imines. The syntheti

Full text of DOI:10.1016/j.jorganchem.2012.02.009

Journal of Organometallic Chemistry 706-707 (2012) 128e134
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Journal of Organometallic Chemistry
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Heck-type coupling of intramolecularly-generated thiopalladacycles with alkenes:
One pot syntheses of 3-alkenylbenzo[b]thiophenes
,
Manjusha V. Karkhelikar a, Shailesh S. Racharlawar a, Subhas M. Salian a, B. Sridhar b, Pravin R. Likhar a
*
a Organometallic Gp., I & PC Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
b X-ray Crystallography Centre, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for stoichiometric functionalization of benzothiophene is developed by Heck-type coupling of
alkenes with intramolecularly-generated thiopalladacycles obtained from palladium salts and ortho-
thioanisole-substituted propargyl imines. The synthetic strategy for preparing structurally diverse 3-
alkenylbenzo[b]thiophene is also extended to 3-alkenylbenzo[b]selenophenes.
Ó 2012 Elsevier B.V. All rights reserved.
Received 18 September 2011
Received in revised form
30 January 2012
Accepted 8 February 2012
Keywords:
Heck-type coupling
Thiopalladacycle
Alkene
3-alkenylbenzo[b]thiophene
Palladium
1. Introduction
and benzofurans [29e36]. However, the use of transition metals,
including palladium, in the synthesis of functionalized benzothio-
Substituted benzo[b]thiophenes have received great attention
because their structural fragment displays a wide range of biolog-
ical and physiological properties [1e4]. In particular, the 2,3-
disubstituted benzothiophene structural framework constitutes
a core unit of several pharmaceutical candidates and are in devel-
opment of selective oestrogen receptor modulators (SERM) [5e7],
tubulin-binding agents [8e10], modulators of multi-drug resis-
tance [11], angiogenesis inhibitors [12e14], site-directed thrombin
inhibitors [15,16], and anti-inflammatory agents [17,18]. Conven-
tionally, the synthesis and functionalization of heteroaromatics is
achieved by different types of cross-coupling reactions of
a heterocycle bearing a metal-containing functionality (nucleo-
philic component) [19e21] or a halogen atom (electrophilic
component) [1,2,10]. FriedeleCrafts-type alkylation/halogenation
of heteroaromatics is also a well-established [22e24], however it is
limited to electron-rich substrates only. The functionalization of
heterocycles via the activation of unreactive CeH bonds also
constitutes an alternative approach [25e28].
phenes from substituted ortho-thioanisoles is often restricted
because of their incompatibility with sulphur-containing substrates
[37e43]. Recently, the direct synthesis of functionalized benzo[b]
thiophenes has been reported by gold-catalyzed intramolecular
carbothiolation of alkynes [44]. Herein, we report a method for the
functionalization of benzothiophene via Heck-type coupling of
alkenes with intramolecularly-generated thiopalladacycles
obtained from stoichiometric amount of palladium salts and ortho-
thioanisole substituted propargyl imines. An important feature of
the thiopalladacycles is, it provides useful information of inter-
mediate Pd-vinyl species generated via intramolecular thio-
palladation (Fig. 1, Type B) [45]. The palladium-catalyzed (cycliza-
tion) annulation of alkynes to heterocycles, such as indoles and
benzofurans, proceed via an intramolecular pathway and the
formation of a heterocyclic ring system realized through the
generation of organopalladium intermediate species which is
practically not isolated so far to the best of our knowledge (Fig. 1,
Type A) [29e36].
The cyclization of ortho-alkynyl anilines and ortho-alkynyl
phenols in the presence of an organopalladium complex is
a common method for the direct synthesis of functionalized indoles
2. Results and discussion
In view of the importance of substituted benzothiophenes as
useful heterocyclic cores for drug and drug candidates in the
development of new materials [46e49], we have extended our
* Corresponding author. Tel.: þ91 40 27193510; fax: þ91 40 27160921.
E-mail address: plikhar@iict.res.in (P.R. Likhar).
0022-328X/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2012.02.009

M.V. Karkhelikar et al. / Journal of Organometallic Chemistry 706-707 (2012) 128e134
129
Cl
2
Pd
PdX
PdX
R1
NAr
Rf
R3
R2
S
N
O
Y
Ar= Ph, 4-MeOPh, 4-MePh
Rf= CF3, C2F5,C4F9
NOT ISOLATED
Type A: intramolecular palladation
Type B: intramolecular thiopalladation
Fig. 1. Intramolecular palladation of alkynes.
on-going effort to the synthesis of 3-alkenylbenzo[b]thiophenes via
the generation of benzothiophene-based palladacycles.
(benzonitrile) palladium dichloride (1 equiv), n-butyl acrylate
(10 equiv), benzoquinone (2 equiv) and LiCl (2 equiv) in THF at
70 ꢀC. The subsequent reduction with NaBH3CN (4 equiv) in
a mixture of glacial acetic acid and methanol (1:3) at 0 ꢀC afforded
the 3-alkenylbenzo[b]thiophene in 63% yield. In two separate
experiments, the reaction was also carried out using 10 mol%
catalytic amount of PdCl2(PhCN)2 with 5 equiv and 10 equiv of n-
butyl acrylate (Table 1, entries 3 and 4) under the same reaction
conditions, but only low yields of the desired product were
obtained. 2,3-disubstituted benzothiophene, 3a was characterized
by 1H and 13C NMR, mass spectrometry and the structure confirmed
by X-ray diffraction analysis (Fig. 2).
To extend the application of the thiopalladacycles in the
synthesis of 3-alkenylbenzo[b]thiophene, thiopalladacycles were
initially prepared by the reaction of propargyl imine bearing an
ortho-thioanisole with a THF solution of PdCl2(PhCN)2 at 0 ꢀC in
80e85% isolated yield [45]. The dimeric thiopalladacycle was then
used for a Heck-type coupling with an alkene to give a 2,3-
disubstituted benzo[b]thiophene (Scheme 1).
Various reaction conditions were examined to optimize the
Heck-type coupling, including the effect of solvents, ancillary
ligands, temperature and reaction time. The highest yield of the
desired 3-alkenylbenzo[b]thiophene product was obtained from
the reaction of the thiopalladacycle and n-butyl acrylate (10 equiv)
in THF at 70 ꢀC for 3 h in the presence of benzoquinone (2 equiv).
However, the Heck-coupled product obtained from this reaction
was unstable and could not be isolated. It was assumed the highly
unstable nature of the product was due to the presence of imine
moiety in the alkenylated benzothiophene adduct. To overcome
this problem, the imine in the alkenylated benzo[b]thiophene
adduct was reduced in situ to the corresponding secondary amine.
Of the various reducing agents used, a combination of NaBH3CN
(4 equiv) in glacial acetic acid and methanol (1:3) at 0 ꢀC was found
to give greatest yield of the 3-alkenylbenzo[b]thiophene (35%). The
preparation of pure thiopalladacycle for proceeding the coupling
reaction and low yield of the coupling product shows unattractive
protocol for the synthesis of 3-alkenylbenzo[b]thiophene.
To surmount the demerits of the reaction as observed above, an
alternate protocol was investigated for the efficient synthesis of 3-
alkenylbenzo[b]thiophene. Reaction of thioanisole-substituted
propargyl imine with n-butyl acrylate in the presence of
PdCl2(PhCN)2 and benzoquinone at 70 ꢀC and subsequent reduction
of the imine with NaBH3CN/acetic acid, gave the desired coupled
product in good to high yields (Scheme 2).
In order to optimize the reaction conditions, various palladium
salts, ancillary ligands, solvents and temperatures were investi-
gated to obtain the best yield of the desired product (Table 1).
It was found that the best reaction condition for the coupling of
thioanisole perfluoroalkyl propargyl imine 1a, used bis-
To explore the scope of the coupling reaction, several alkenes
were tested with thioanisole-substituted propargyl imines under
optimized conditions and the results are presented in Table 2. It is
clear from the Table 2, that
a,b-unsaturated esters like n-butyl
acrylate (Table 2, entry 1) and methyl acrylate (Table 2, entry 2),
afforded good yields of the coupled product while acrylonitrile and
styrene only gave, 51% and 56% yields, respectively (Table 2, entries
3, 4). The effect of various substituents on aryl imine was also
studied. Aryl imines containing electron-withdrawing groups and
weakly electron-donating group (methyl group) gave the coupled
product in moderate yields (Table 2, entries 5, 6 and 7), while there
was no coupling product observed with aryl imine containing
methoxy group (electron-donating group) (Table 2, entry 10). Good
yields were obtained from coupling thioanisole-substituted prop-
argyl imines with alkene containing long chain perfluoroalkyl
groups (C2F5eC4F9) and with methyl acrylate (Table 2, entries 8e9).
However, in the case of acrylamide (Table 2, entry 11), methyl vinyl
ketone (Table 2, entry 12) and N, N-dimethyl acrylamide (entry 13),
no corresponding coupled product was obtained using the same
optimized reaction conditions.
Taking advantage of our combined strategy for the synthesis of
substituted benzo[b]thiophenes, we focused our attention towards
the synthesis of 3-alkenylbenzo[b]selenophenes (Scheme 3).
Selenoanisole-substituted propargyl imines were prepared in
a similar fashion as compound 1a. The optimized reaction condi-
tions determined for the Heck-type coupling were applied to
various selenoanisole perfluoroalkyl propargyl imines and alkenes
CO2nBu
NHPh
CF3
Cl
CO2nBu
2
Pd
NPh
n
NPh
CO2 Bu
NaBH3CN
Reduction
ligand
S
CF3
S
CF3
S
isolated palladacycle
3a
Scheme 1. Heck-type coupling of dimeric thiopalladacycle with n-butyl acrylate.

130
M.V. Karkhelikar et al. / Journal of Organometallic Chemistry 706-707 (2012) 128e134
NPh
CF3
CO2nBu
NHPh
CO2nBu
NPh
CO2nBu
PdCl2(PhCN)2
NaBH3CN
BQ, THF
LiCl, 70°C
glacial acetic acid,
methanol, 0°C
S
S
CF3
CF3
S
2a
1a
3a
Scheme 2. Heck-type coupling of thioanisole substituted perfluoroalkyl propargyl imines (1a) with n-butyl acrylate.
(see the Experimental section for a typical procedure). Aryl imines
containing electron-withdrawing groups afforded good yields of
the benzo[b]selenophenes while those containing electron-
donating groups failed to give any coupled product (Fig. 3).
Table 2 and Fig. 3 show the high stereoselectivity of the Heck-
type coupling reaction of substituted propargyl imines with
alkenes. In all cases, exclusive formation of the (E)-isomer of 3-
alkenylbenzo[b]thiophenes and 3-alkenylbenzo[b]selenophenes
was observed [29].
The above mentioned results for the synthesis of 3-
alkenylbenzo[b]thiophene indicate the formation and involve-
ment of the thiopalladacycle as the key step of the Heck-type
coupling. Thus the first step involves the coordination of the N
atom in the imine to palladium followed by the interaction of the
triple bond to the electrophilic Pd center. The thiopalladacycle
generated in the reaction undergoes alkene insertion, followed by
PdeH elimination with the release of the 3-alkenylbenzo[b]
thiophene.
3. Conclusion
In conclusion, a new methodology for the synthesis of per-
fluoroalkyl 3-alkenylbenzo[b]thiophenes and 3-alkenylbenzo[b]
selenophenes has been developed using one pot Heck-type
coupling reaction of an alkene and the corresponding heteroatom
substituted propargyl imine. This methodology enables the
synthesis of structurally diverse 3-alkenylbenzo[b]thiophenes and
3-alkenylbenzo[b]selenophenes to give the (E)-isomers exclusively
using various alkynes, perfluoroalkyl groups, substituted anilines
and alkenes. Investigations towards the catalytic use of palladium
salts and the bio-activity of these 3-alkenylbenzo[b]thiophenes and
3-alkenylbenzo[b]selenophenes are in progress.
4. Experimental section
4.1. General
Though the role of benzoquinone as an oxidant is well estab-
lished in the literature [50,51], in the present Heck-type coupling
reaction it acts as a stabilizing ligand [52]. To confirm the role of
benzoquinone, we conducted a series of reactions in which cyclic
unsaturated enones such as maleic anhydride and cyclohexenone
were used in place of benzoquinone. The results obtained from
these reactions suggest that benzoquinone, maleic anhydride and
cyclohexenone act as stabilizing ligand to palladium during the
coupling reaction. Furthermore, in the absence of these ligands, the
Heck-type coupling reaction does not proceed at all.
All reactions were carried out in oven dried glassware under an
atmosphere of nitrogen. Chemicals were purchased from Aldrich
and used as it is unless mentioned otherwise. All solvents used for
reactions were dried before use. Product purification by column
chromatography was accomplished using silica gel 60e120 mesh.
Technical grade solvents were used for chromatography and
distilled prior to use. NMR spectra were recorded in Fourier
transform mode. The 1H, 13C and 19F NMR spectra were recorded on
a Bruker-Avance (300 MHz), Varian-Inova (400 MHz) and Varian-
Inova (500 MHz) spectrometers in CDCl3 and CFCl3 solvents and
Table 1
Optimization study for the Heck-type coupling of thioanisole-substituted perfluoroalkyl propargyl imine, 1a with n-butyla crylate.a
NPh
n
n
CO2 Bu
CO2 Bu
CO2nBu
'Pd' Salt
CF3
NHPh
CF3
NPh
NaBH3CN
ligand, THF
LiCl,70°C
glacial acetic acid,
methanol, 0°C
S
S
CF3
S
1a
2a
3a
Entry
Palladium salt
Ligand
Solvent
Temp.(ꢀC)
Time(h)
(3a)Yield%b
1
2
3
4
5
6
7
8
9
PdCl2
Pd (OAc)2
BQ
BQ
BQ
BQ
BQ
BQ
BQ
MA
DMF
THF
THF
THF
THF
90
70
70
70
70
70
70
70
70
70
12
12
12
12
6
5
5
5
5
18c
20c
25c
28d
31
PdCl2 (PhCN)2
PdCl2 (PhCN)2
PdCl2
PdCl2 (PhCN)2
PdCl2 (PhCN)2
PdCl2 (PhCN)2
PdCl2 (PhCN)2
PdCl2 (PhCN)2
THF:CH3CN (9:1)
41
63
THF
THF
THF
THF
61
MA
59e
55
10
cyclohexenone
5
BQ ¼ benzoquinone; MA ¼ maleic anhydride.
a
Reaction conditions: 1a (0.25 mmol), n-butyl acrylate (10 equiv), Pd(II) salt (1 equiv), ligand (2 equiv), LiCl (2 equiv), solvent (2 mL).
Isolated yields.
Pd(II) salt (10 mol%), n-butyl acrylate (5 equiv).
Pd(II) salt (10 mol%), n-butyl acrylate (10 equiv).
Under N2 atmosphere.
b
c
d
e

TMS as the internal standard. Multiplicities in the 1H NMR spectra
are described as: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
qt ¼ quintet, m ¼ multiplet, br ¼ broad; coupling constants are
reported in Hz. Infrared spectra were recorded on a Thermo Nicolet
Nicolet Nexus 670 spectrometer and reported in cmꢁ1. Low (MS)
and high resolution mass spectra (HRMS) were recorded on
a Waters 2695 and Thermo Scientific Exactive spectrometer
respectively and mass/charge (m/z) ratios are reported as values in
atomic mass units. Melting points were recorded on a Toshniwal
melting point apparatus. N-aryl perfluoroalkyl propargyl imines
were prepared by the Sonogashira coupling of imidoyl iodide and
alkyne according to the literature procedure [53].
4.2. Typical procedure for the N-aryl perfluoroalkyl propargyl
imines
To a stirred mixture of PdCl2 (PPh3)2 (2 mol%), CuI (4 mol%) in
Et3N (4 mL), alkyne (1 mmol) and N-aryl perfluoroalkyl imidoyl
iodide (1 mmol) were added successively under N2 atmosphere. The
mixture was stirred at room temperature until the starting materials
Fig. 2. Ortep diagram of compound 3a.
Table 2
Heck-type coupling of thioanisole-substituted propargyl imines with alkenesa.
NAr
R2
R2
Rf
R2
NAr
Rf
NHAr
Rf
PdCl2(PhCN)2
NaBH3CN
BQ, THF
glacial acetic acid,
methanol,0°C
Reduction
S
S
S
LiCl,70°C
1a-1j
3a-3i
Entry
1
Ar
Rf
Alkene
Product
Yield (%)b
63
Ph (1a)
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
C4F9
CF3
CF3
CF3
R2 ¼ COn2Bu
R2 ¼ CO2Me
R2 ¼ CN
3a
3b
3c
3d
3e
3f
R2
R2
R2
R2
R2
R2
R2
R2
R2
R2
2
3
Ph (1a)
73
51
56
50
44
40
79
76
e
Ph (1a)
4
Ph (1a)
R2 ¼ Ph
5
4-F-Ph (1e)
4-Cl-Ph (1f)
4-Me-Ph (1g)
Ph (1h)
R2 ¼ CO2Me
R2 ¼ CO2Me
R2 ¼ CO2Me
R2 ¼ CO2Me
R2 ¼ CO2Me
R2 ¼ CO2Me
6
7
3g
3h
3i
8
9
Ph (1i)
10
11
12
4-OMe-Ph (1j)
Ph (1a)
NR
NR
NR
e
CONH2
Ph (1a)
R2 ¼ COMe
e
R2
13
Ph (1a)
CF3
NR
e
CONMe2
For reduction of imine: NaBH3CN (4 equiv), methanol (1.5 mL), glacial acetic acid (0.5 mL) at 0 ꢀC for 1 h.
a
Reaction conditions: Propargyl imine (0.25 mmol), alkene (10 equiv), PdCl2(PhCN)2 (1 equiv), benzoquinone (2 equiv), LiCl (2 equiv), THF (2 mL) at 70 ꢀC for 5 h.
Isolated yields. NR ¼ no reaction.
b

132
M.V. Karkhelikar et al. / Journal of Organometallic Chemistry 706-707 (2012) 128e134
Scheme 3. Heck-type coupling of selenoanisole substituted propargyl imines with alkenes.
are consumed. The reaction mixture was filtered and solvent was
removed from filtrate. The crude product obtained was purified by
column chromatography using hexane-ethyl acetate mixture.
4.3.4. (4-Methyl-phenyl)-[3-(2-methylthio-phenyl)-1-
trifluoromethyl-prop-2-ynylidene]-amine (1g)
Yield: 73%; Yellow solid. Mp: 58e60 ꢀC 1H NMR (300 MHz,
CDCl3):
d
7.44e7.34 (m, 4H), 7.25e7.16 (m, 3H), 7.10 (t, J ¼ 7.5 Hz,
1H), 2.47 (s, 3H), 2.39 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
d
144.6,
4.3. Characterization of the compounds 1a, 1ee1h, 4a and 4c
144.0, 138.0, 137.1 (q, J ¼ 39.6 Hz), 133.9, 131.0, 129.4, 124.6, 124.4,
122.2, 118.3, 115.2 (q, J ¼ 277.2 Hz), 97.3, 85.2, 21.2, 15.1. 19F NMR
(376.3 MHz, CDCl3): ꢁ70.79 (s, 3H). FTIR (KBr): 2963, 2923, 2184,
1606, 1575, 1266 cmꢁ1. MS (ESI): m/z ¼ 334 [M þ H]þ. HRMS: m/z
calcd for C18H15F3NS [M þ H]þ 334.0871; Found 334.0870.
4.3.1. (Phenyl)-[3-(2-methylthio-phenyl)-1-trifluoromethyl-prop-
2-ynylidene]-amine (1a)
Yield: 79%; Yellow solid. Mp: 89e91 ꢀC 1H NMR (300 MHz,
CDCl3):
d
7.40 (t, J ¼ 7.8 Hz, 2H), 7.37e7.31 (m, 4H), 7.27e7.23 (m,
1H), 7.14 (d, J ¼ 7.8 Hz, 1H), 7.06 (t, J ¼ 7.8 Hz, 1H), 2.43 (s, 3H). 13C
4.3.5. [3-(2-methylsulfanyl-phenyl)-1-pentafluoroethyl-prop-2-
ynylidene]-phenyl-amine (1h)
NMR (75.5 MHz, CDCl3):
d
147.4, 144.2, 135.8 (q, J ¼ 37 Hz), 134.0,
131.1, 128.8, 127.3, 124.6, 124.3, 121.5, 118.0, 115.0 (q, J ¼ 278.8), 97.4,
Yield: 78%; Yellow liquid. 1H NMR (300 MHz, CDCl3):
d
7.48e7.28
(m, 7H), 7.16 ( d, J ¼ 8.1 Hz, 1H), 7.08 (t, J ¼ 7.5 Hz, 1H), 2.44 (s, 3H).
13C NMR (75.5 MHz, CDCl3):
84.1, 15.0. 19F NMR (376.3 MHz, CDCl3):
d
ꢁ70.99 (s, 3F). FTIR (KBr):
2923, 2185, 1608, 1220, 1135 cmꢁ1. MS (ESI): m/z ¼ 320 [M þ H]þ.
HRMS: m/z calcd for C17H13F3NS [M þ H]þ 320.0715; Found
320.0713.
d
147.6144.1, 139.5 (t, J ¼ 28.6 Hz),
134.0,131.2,128.8, 127.5,124.5,124.3,121.5,120.5, 118.0,116.74, 98.1,
85.1, 15.0. 19F NMR (376.3 MHz, CDCl3): ꢁ81.54 (t, J ¼ 1.9 Hz, 2F),
ꢁ116.20e116.24 (m, 3F). FTIR (KBr): 2925, 2191, 1609, 1206 cmꢁ1
.
4.3.2. (4-Fluoro-phenyl)-[3-(2-methylthio-phenyl)-1-
trifluoromethyl-prop-2-ynylidene]-amine (1e)
MS (ESI): m/z ¼ 370 [M þ H]þ. HRMS: m/z calcd for C18H13F5NS
[M þ H]þ 370.0683; Found 370.0687.
Yield: 82%; Yellow solid. Mp: 86e88 ꢀC 1H NMR (300 MHz,
CDCl3):
d
7.51e7.43 (m, 2H), 7.40e7.32 (m, 2H), 7.17e7.05 (m, 4H),
161.9 (d, J ¼ 248.8 Hz),
2.45 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
d
4.3.6. [3-(2-methylseleno-phenyl)-1-trifluoromethyl-prop-2-
ynylidene]-phenyl-amine (4a)
144.2, 143.3, 138.6 (q, J ¼ 39 Hz), 134.1, 131.3, 124.5 (d, J ¼ 18.1 Hz),
124.1, 124.0, 118.7 (q, J ¼ 277.9 Hz), 117.9, 115.7 (d, J ¼ 22.7 Hz), 97.9,
84.8, 15.1. 19F NMR (376.3 MHz, CDCl3): ꢁ70.91 (s, 3F),
ꢁ113.76e113.85 (m, 1F). FTIR (KBr): 2924, 2189, 1614, 1575,
1269 cmꢁ1. MS (ESI): m/z ¼ 338 [M þ H]þ. HRMS: m/z calcd for
C17H12F4NS [M þ H]þ 338.0621; Found 338.0620.
Yield: 76%; Yellow solid. Mp: 80e82 ꢀC 1H NMR (300 MHz,
CDCl3):
NMR (75.5 MHz, CDCl3):
d
7.41 (t, J ¼ 7.6 Hz, 2H), 7.35e7.23 (m, 6H), 2.28 (s, 3H). 13
C
d
147.5, 138.1 (q, J ¼ 28.5 Hz), 134.2, 131.1,
128.9, 128.5, 127.4, 125.4, 121.3, 120.5, 119.5, 115.0 (q, J ¼ 282 Hz),
98.1, 83.9, 6.4. 19F NMR (376.3 MHz, CDCl3): ꢁ71.38 (s, 3H). FTIR
(KBr): 2923, 2853, 2183, 1608, 1265 cmꢁ1. MS (ESI): m/z ¼ 368
[M þ H]þ. HRMS: m/z calcd for C17H13F3NSe [M þ H]þ 368.0160;
Found 368.0161.
4.3.3. (4-Chloro-phenyl)-[3-(2-methylthio-phenyl)-1-
trifluoromethyl-prop-2-ynylidene]-amine (1f)
Yield: 80%; Yellow liquid. 1H NMR (500 MHz, CDCl3):
d
7.52e7.46
(m, 1H), 7.39e7.27 (m, 3H), 7.23e7.16 (m, 2H), 7.16e7.04 (m, 2H),
2.39 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
144.4, 134.1, 133.5 (q,
J ¼ 39.5 Hz), 131.4, 130.1, 129.5, 127.2, 127.1, 124.5, 124.4, 124.3, 120.3
4.3.7. (4-Chloro-phenyl)-[3- (2-methylseleno-phenyl)-1-
trifluoromethyl-prop-2-ynylidene]-amine (4c)
d
Yield: 74%; Yellow liquid. 1H NMR (300 MHz, CDCl3):
d
7.52e7.45
(m, 1H), 7.35e7.27 (m, 4H), 7.24e7.09 (m, 3H), 2.27 (s, 3H). 13C NMR
(75.5 MHz, CDCl3):
(q,
J
¼
289.8 Hz), 98.7, 84.4, 15.0. 19F NMR (376.3 MHz,
CDCl3): ꢁ71.02 (s, 3H). FTIR (KBr): 2923, 2187, 1619, 1273 cmꢁ1. MS
(ESI): m/z ¼ 354 [M þ H]þ. HRMS: m/z calcd for C17H12F3NClS
[M þ H]þ 354.0325; Found 354.0326.
d
145.5, 142.4 (q, J ¼ 39 Hz), 138.6, 134.3, 131.4,
130.1, 128.3, 127.3, 127.2, 125.7, 125.4, 120.3 (q, J ¼ 278 Hz), 99.4,
83.5, 6.5. 19F NMR (376.3 MHz, CDCl3): ꢁ70.99 (s, 3F). FTIR (KBr):
n
CO2Me
NHPh
CO2Me
HN
CO2 Bu
NHPh
CF3
Cl
Se
6a
CF3
(60%)
Se
Se
CF3
6c
(51%)
6b
(54%)
Fig. 3. Synthesis of 3-alkenylbenzo[b]selenophenes.

M.V. Karkhelikar et al. / Journal of Organometallic Chemistry 706-707 (2012) 128e134
133
2927, 2853, 1620, 1271 cmꢁ1. MS (ESI): m/z ¼ 401 [M þ H]þ. HRMS:
m/z calcd for C17H12F3NClSe [M þ H]þ 401.9770; Found 401.9767.
2214 (s) cmꢁ1. MS (ESI): m/z ¼ 381 [M þ Na]þ. HRMS: m/z Calcd for
C19H13F3N2S [M þ Na]þ 381.0649; Found 381.0648.
4.5.4. (E)-N-(2,2,2-trifluoro-1-(3-styrylbenzo[b]thiophen-2-yl)
ethyl)benzenamine (3d)
4.4. Typical procedure for the Heck-type coupling of N-aryl
perfluoroalkyl propargyl imines and alkenes
Yield: 56%; Yellow solid. Mp: 146e148 ꢀC 1H NMR (300 MHz,
CDCl3):
d
7.93 (d, J ¼ 7.7 Hz, 1H), 7.81 (d, J ¼ 7.9 Hz, 1H), 7.55 (d,
To
a solution of N-aryl perfluoroalkyl propargyl imine
J ¼ 6.9 Hz, 2H), 7.48e7.33 (m, 2H), 7.29e7.02 (m, 8H), 6.92 (t,
(0.25 mmol) in dry THF (2 mL) was added PdCl2(PhCN)2
(0.25 mmol), benzoquinone (2 equiv), LiCl (2 equiv) and alkene
(10 equiv) successively and the mixture was stirred at 70 ꢀC for 5 h.
The mixture was allowed to cool to room temperature and partially
concentrated under reduced pressure.
The imine solution was diluted with methanol (1.5 mL) and
NaBH3CN (4 equiv) was added at 0 ꢀC over 15 min followed by
glacial acetic acid (0.5 mL) under a nitrogen atmosphere. The
resulting mixture was stirred at room temperature for 1 h, then
filter through celite bed with EtOAc (25 mL). The organic filtrate
was washed with saturated aqueous NaHCO3 followed by brine
solution. The separated organic layer was dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated under reduced
pressure and the product was purified by column chromatography,
eluting with EtOAc/hexane (1:99).
J ¼ 7.2 Hz, 1H), 6.82 (s, 1H), 5.54 (q, J ¼ 6.9 Hz, 1H). 13C NMR
(75.5 MHz, CDCl3)
d 147.5, 140.7, 140.5, 137.1, 135.2, 131.5, 129.1,
128.6, 128.3, 127.5, 126.8, 125.2, 124.9 (q, J ¼ 286.5 Hz), 124.7, 123.9,
123.2, 122.9, 121.6, 118.6, 105.7, 63.8 (q, J ¼ 32.9 Hz). 19F NMR
(376.3 MHz, CDCl3):
d
ꢁ77.08 (d, J ¼ 7.4 Hz, 3F). FTIR (KBr): 1727 (s)
cmꢁ1. MS (ESI): m/z ¼ 410 [M þ H]þ. Anal. Calcd. for C24H18F3NS: C
70.04, H 4.34, N 3.12; Found C 70.01, H 4.33, N 3.17.
4.5.5. (E)-methyl 3-(2-(2,2,2-trifluoro-1-(4-fluorophenylamino)
ethyl)-benzo[b] thiophen-3-yl)acrylate (3e)
Yield: 50%; Yellow liquid. 1H NMR (500 MHz, CDCl3):
d 7.95e7.88
(m, 2H), 7.78 (d, J ¼ 7.7 Hz,1H), 7.44e7.36 (m, 2H), 6.84 (t, J ¼ 8.6 Hz,
2H), 6.58e6.53 (m, 2H), 6.43 (d, J ¼ 16.4 Hz, 1H), 5.41 (qt, J ¼ 6.7 Hz,
1H), 4.15 (d, J ¼ 6.7 Hz,1H), 3.85 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
d
166.9, 157.2 (d, J ¼ 139.3 Hz), 140.7, 139.3, 138.9, 137.5, 135.3, 131.5,
125.8, 125.3, 122.9, 122.8, 122.7, 122.4 (q, J ¼ 283.2), 116.1 (d,
4.5. Characterization of the compounds 3ae3i and 6ae6c
J ¼ 21.9 Hz), 115.6 (d, J ¼ 6.6 Hz), 56.5 (q, J ¼ 30.7 Hz), 52.0. 19F NMR
(400 MHz, CDCl3):
d
ꢁ73.76 (d, J ¼ 6.1 Hz, 3F), ꢁ124.53e124.62 (m,
4.5.1. (E)-butyl 3-(2-(2,2,2-trifluoro-1-(phenylamino)ethyl)benzo
[b]thiophen-3-yl)acrylate (3a)
1F). FTIR (KBr): 3379, 1711 (s) cmꢁ1. MS (ESI): m/z ¼ 432 [M þ Na]þ.
HRMS: m/z Calcd for C20H15F4NO2S [M þ Na]þ 432.0657; Found
432.0658.
Yield: 63%; Yellow solid. Mp: 80e82 ꢀC 1H NMR (300 MHz,
CDCl3):
d
7.99e7.93 (m, 2H), 7.79 (d, J ¼ 7.4 Hz, 1H), 7.46e7.36 (dqt,
J ¼ 7.2 Hz, 1.3 Hz, 2H), 7.14 (t, J ¼ 7.6 Hz, 2H), 6.78 (t, J ¼ 7.4 Hz, 1H),
6.60 (d, J ¼ 7.9 Hz, 2H), 6.45 (d, J ¼ 16.2 Hz, 1H), 5.52 (qt, J ¼ 6.8 Hz,
1H), 4.33e4.21 (m, 3H), 1.74 (qt, J ¼ 6.8 Hz, 2H), 1.55e1.41 (m, 2H),
4.5.6. (E)-methyl 3-(2-(1-(4-chlorophenylamino)-2,2,2-
trifluoroethyl)-benzo [b]thiophen-3-yl)acrylate (3f)
Yield: 44%; Yellow liquid. 1H NMR (300 MHz, CDCl3):
d 7.97e7.89
1.02 (t, J ¼ 7.4 Hz, 3H). 13C NMR (75.5 MHz, CDCl3):
d
166.6, 144.5,
(m, 2H), 7.81e7.76 (m, 1H), 7.46e7.35 (m, 2H), 7.09 (d, J ¼ 8.8 Hz,
2H), 6.53 (d, J ¼ 8.8 Hz, 2H), 6.44 (d, J ¼ 16.2 Hz, 1H), 5.44 (qt,
J ¼ 6.8 Hz, 1H), 4.29 (d, J ¼ 7.4 Hz, 1H), 3.86 (s, 3H). 13C NMR
139.5, 138.9, 137.6, 135.1, 131.4, 129.5, 125.7, 125.2, 124.4 (q,
J ¼ 283.2 Hz), 123.2, 123.0, 122.7, 120.1, 114.1, 64.9, 55.7 (q,
J ¼ 30.7 Hz), 30.7, 19.2, 13.7.19F NMR (376.3 MHz, CDCl3)
d
ꢁ73.77 (d,
(75.5 MHz, CDCl3): d 166.8, 143.1, 138.9, 137.5, 135.3, 131.6, 129.4,
J ¼ 6.2 Hz, 3F). FTIR (KBr): 3365 (s), 1704 (s) cmꢁ1. MS (ESI): m/
z ¼ 456 [M þ Na]þ. HRMS: m/z Calcd for C23H22O2SF3 [M þ Na]þ
456.1221; Found 456.1233.
125.8, 125.4, 125.1, 124.3 (q, J ¼ 282.6 Hz), 123.1, 122.7, 122.5, 122.4,
115.3, 55.9 (q, J ¼ 31.8 Hz), 52.0. 19F NMR (376.3 MHz, CDCl3)
d
ꢁ73.72 (d, J ¼ 7.4 Hz, 3F). FTIR (KBr): 3362 (s), 1712 (s) cmꢁ1. MS
(ESI): m/z ¼ 448 [M þ Na]þ. HRMS: m/z Calcd for C20H15ClF3NO2S
[M þ Na]þ448.0361; Found 448.0351.
4.5.2. (E)-methyl 3-(2-(2,2,2-trifluoro-1-(phenylamino)ethyl)benzo
[b]thiophen-3-yl) acrylate (3b)
Yield: 73%; Yellow solid. Mp: 82e84 ꢀC 1H NMR (500 MHz,
4.5.7. (E)-methyl 3-(2-(2,2,2-trifluoro-1-p-tolylethylamino)benzo
[b]thiophen-3-yl)acrylate (3g)
CDCl3):
d
7.99e7.92 (m, 2H), 7.78 (d, J ¼ 7.7 Hz,1H), 7.44e7.35 (m,
2H), 7.13 (t, J ¼ 7.7 Hz, 2H), 6.77 (t, J ¼ 7.7 Hz, 1H), 6.59 (d, J ¼ 7.7 Hz,
2H), 6.46 (d, J ¼ 16.4 Hz, 1H), 5.50 (qt, J ¼ 6.7 Hz, 1H), 4.28 (d,
Yield: 40%; Yellow liquid. 1H NMR (300 MHz, CDCl3):
d 8.04e7.91
(m, 2H), 7.79 (d, J ¼ 7.4 Hz, 1H), 7.48e7.35 (m, 2H), 6.96 (d,
J ¼ 8.1 Hz, 2H), 6.58e6.46 (m, 3H), 5.49 (qt, J ¼ 6.8 Hz, 1H), 4.26 (d,
J ¼ 6.9 Hz,1H), 3.87 (s, 3H), 2.20 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
J ¼ 6.7 Hz, 1H), 3.86 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
d 166.9,
144.4, 139.8, 138.9, 137.6, 135.4, 131.3, 129.5, 125.7, 125.2, 124.3 (q,
J ¼ 283.2 Hz), 122.9, 122.7, 122.5, 120.2, 114.1, 55.7 (q, J ¼ 31.8 Hz),
d
166.9, 142.1, 140.0, 138.9, 137.6, 135.4, 131.2, 129.9, 129.6, 126.2,
52.0. 19F NMR (400 MHz, CDCl3):
d
ꢁ73.77 (d, J ¼ 6.2 Hz, 3F). FTIR
125.6, 125.1, 123.9 (q, J ¼ 288.0 Hz), 122.9, 122.7, 114.4, 56.2 (q,
(KBr): 3385 (s), 1703 (s) cmꢁ1. MS (ESI): m/z ¼ 414 [M þ Na]þ.
HRMS: m/z Calcd for C20H16F3NO2S [M þ Na]þ 414.0751; Found
414.0749.
J ¼ 31.9 Hz), 51.9, 20.3. 19F NMR (400 MHz, CDCl3):
d
ꢁ73.8 (d,
J ¼ 7.3 Hz, 3F). FTIR (KBr): 3406, 1714 (s) cmꢁ1. MS (ESI): m/z ¼ 406
[M þ H]þ. Anal. Calcd. for C21H18F3NO2S: C 62.22, H 4.44, N 3.45;
Found C 62.20, H 4.43, N 3.43.
4.5.3. (E)-3-(2-(2,2,2-trifluoro-1-(phenylamino)ethyl)benzo[b]
thiophen-3-yl)acrylo-nitrile (3c)
4.5.8. (E)-methyl 3-(2-(2,2,3,3,3-pentafluoro-1-(phenylamino)
propyl)benzo[b]-thiophen-3-yl)acrylate (3h)
Yield: 51%; Yellow solid. Mp: 104e106 ꢀC 1H NMR (300 MHz,
CDCl3):
d
7.89e7.78 (m, 2H), 7.67 (d, J ¼ 16.6 Hz, 1H), 7.48e7.38 (m,
Yield: 79%; Yellow solid. mp: 90e92 ꢀC 1H NMR (500 MHz,
2H), 7.16 (t, J ¼ 7.7 Hz, 2H), 6.82 (t, J ¼ 7.4 Hz, 1H), 6.59 (d, J ¼ 7.7 Hz,
CDCl3):
d
7.94e7.88 (m, 2H), 7.77 (d, J ¼ 7.8 Hz, 1H), 7.43e7.34 (m,
2H), 5.92 (d, J ¼ 16.6 Hz, 1H), 5.38 (qt, J ¼ 6.6 Hz, 1H), 4.27 (d,
2H), 7.12 (t, J ¼ 7.8 Hz, 2H), 6.76 (t, J ¼ 6.8 Hz, 1H), 6.58 (d, J ¼ 8.8 Hz,
2H), 6.42 (d, J ¼ 15.7 Hz, 1H), 5.67e5.58 (m, 1H), 4.16 (d, J ¼ 8.8 Hz,
J ¼ 6.6 Hz, 1H). 13C NMR (75.5 MHz, CDCl3):
d 144.2, 141.5, 140.8,
139.7, 138.9, 136.9, 129.6, 126.1, 125.7, 124.1 (q, J ¼ 283.2 Hz), 122.9,
1H), 3.87 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
d 166.8, 143.9, 139.0,
122.4, 120.5, 117.5, 114.1, 101.6, 55.9 (q, J ¼ 31.8 Hz). 19F NMR
137.5, 135.3, 129.5, 126.4 (q, J ¼ 287.6 Hz), 125.7, 125.2, 122.9, 122.6,
(376.3 MHz, CDCl3):
d
ꢁ73.69 (d, J ¼ 7.4 Hz, 3F). FTIR (KBr): 3335 (s),
122.4, 122.1, 120.3, 119.9, 116.6, 114.2, 53.4 (m), 52.0. 19F NMR

134
M.V. Karkhelikar et al. / Journal of Organometallic Chemistry 706-707 (2012) 128e134
[2] D. Yue, R.C. Larock, J. Org. Chem. 67 (2002) 1905e1909.
(376.3 MHz, CDCl3)
d
ꢁ81.62 (s, 3F), ꢁ115.79 (dd, J ¼ 6.2, 275.6 Hz,
[3] D.A. Bradley, A.G. Godfrey, C.R. Schmid, Tetrahedron Lett. 40 (1999)
5155e5159.
[4] T.A. Grese, L.D. Pennington, J.P. Sluka, M.D. Adrian, H.W. Cole, T.R. Fuson,
D.E. Magee, D.L. Phillips, E.R. Rowley, P.L. Shetler, L.L. Short, M. Venugopalan,
N.N. Yanf, M. Sato, A.L. Glasebtook, H.U. Bryant, J. Med. Chem. 41 (1998)
1272e1283.
1F), ꢁ126.59 (dd, J ¼ 19.7, 275.6 Hz,1F). FTIR (KBr): 3387 (s),1707 (s)
cmꢁ1. MS (ESI): m/z ¼ 464 [M þ Na]þ. HRMS: m/z Calcd for
C21H16F5NO2S [M þ Na]þ 464.0719; Found 464.0717.
4.5.9. (E)-methyl 3-(2-(2,2,3,3,4,4,5,5,5-nonafluoro-1-
(phenylamino)pentyl)benzo[b] thiophen-3-yl)acrylate (3i)
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H.U. Bryant, J. Med. Chem. 40 (1997) 1407e1416.
Yield: 76%; Yellow liquid. 1H NMR (300 MHz, CDCl3):
d 7.96e7.88
(m, 2H), 7.75 (dd, J ¼ 6.8, 2.3 Hz, 1H), 7.42e7.32 (m, 2H), 7.12 (t,
J ¼ 7.6 Hz, 2H), 6.75 (t, J ¼ 7.6 Hz,1H), 6.58 (d, J ¼ 7.6 Hz, 2H), 6.42 (d,
J ¼ 15.9 Hz, 1H), 5.81e5.68 (m, 1H), 4.20 (d, J ¼ 9.8 Hz, 1H), 3.87 (s,
[7] U. Schopfer, P. Schoeffter, S.F. Bischoff, J. Nozulak, D. Feuerbach, P. Floersheim,
J. Med. Chem. 45 (2002) 1399e1401.
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V.L. Narayanan, K.-H. Lee, J. Med. Chem. 42 (1999) 4081e4087.
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Chem. 65 (2000) 8811e8815.
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Chem. Lett. 9 (1999) 3381e3386.
3H).13C NMR (75.5 MHz, CDCl3):
d 166.4, 143.9, 139.1, 138.9, 137.6,
135.4,131.9,129.7,125.8,125.7,125.3,123.7,123.2,123.1,122.7,120.5,
114.3, 53.4 (m), 51.9. 19F NMR (400 MHz, CDCl3):
d
ꢁ81.17 (t,
J ¼ 12.3 Hz, 3F), ꢁ111.70eꢁ112.96 (m,1F), ꢁ121.50eꢁ122.29 (m,
1F), ꢁ122.62eꢁ122.96 (m, 2F), ꢁ124.98eꢁ127.72 (m, 2F). FTIR
(KBr): 3366 (s),1716 (s) cmꢁ1. MS (ESI): miz ¼ 564 [M þ Na]þ. HRMS:
m/z Calcd for C23H16F9NO2S [M þ Na]þ 564.0655; Found 564.0640.
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4.5.10. (E)-methyl 3-(2-(2,2,2-trifluoro-1-(phenylamino)ethyl)
benzo[b]selenophen-3-yl)acrylate (6a)
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K. Takeuchi, K.J. Thrasher, J.M. Tinsley, B.G. Utterback, S.B. Yan, M. Zhang,
J. Med. Chem. 40 (1997) 3489e3493.
Yield: 60%; Pale brown oil. 1H NMR (300 MHz, CDCl3):
d
7.89e7.75 (m, 3H), 7.40e7.24 (m, 3H), 7.10 (t, J ¼ 7.6 Hz, 2H), 6.75 (t,
J ¼ 7.4 Hz,1H), 6.56 (d, J ¼ 7.7 Hz, 2H), 6.32 (d, J ¼ 16.1 Hz,1H), 5.39 (q,
J ¼ 6.6 Hz, 1H), 3.80 (s, 3H). 13C NMR (75.5 MHz, CDCl3):
d 166.8,
144.6,140.5,140.2,137.0,134.7,129.5,126.2,125.9,125.7,125.2,124.8,
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A.E. Munson, Toxicology 98 (1995) 111e123.
123.8, 123.6 (q, J ¼ 285.4 Hz), 120.2, 114.2, 57.3 (q, J ¼ 30.7 Hz), 52.0.
19F NMR (400 MHz, CDCl3):
d
ꢁ73.78 (d, J ¼ 6.2, 3F). FTIR (KBr): 3376,
1714 (s) cmꢁ1. MS (ESI): m/z 440 [M þ H]þ. HRMS: m/z Calcd for
C20H17F3NO2Se [M þ H]þ 440.0376; Found 440.0387.
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4.5.11. (E)-butyl 3-(2-(2,2,2-trifluoro-1-(phenylamino)ethyl)benzo
[b]selenophen-3-yl)acrylate (6b)
Yield: 54%; Brown oil. 1H NMR (300 MHz, CDCl3):
d 7.88e7.73
(m, 3H), 7.40e7.24 (m, 2H), 7.09 (t, J ¼ 7.6 Hz, 2H), 6.74 (t,
J ¼ 7.4 Hz, 1H), 6.56 (d, J ¼ 7.7 Hz, 2H), 6.30 (d, J ¼ 16.2 Hz, 1H), 5.39
(q, J ¼ 6.2 Hz, 1H), 4.28e4.14 (m, 2H), 1.65 (qt, J ¼ 6.8 Hz, 2H),
1.45e1.33 (m, 2H), 0.91 (t, J ¼ 7.4 Hz, 3H). 13C NMR (75.5 MHz,
CDCl3):
d
166.4, 144.6, 143.5, 140.5, 136.7, 134.8, 129.5, 125.9, 125.6,
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B. Jagadeesh, Organometallics 28 (2009) 3966e3969.
125.2, 124.9, 124.3, 123. 5 (q, J ¼ 292.0 Hz), 120.2, 119.9, 114.1, 64.9,
57.2 (q, J ¼ 30.7 Hz), 30.6, 19.2, 13.7. 19F NMR (400 MHz, CDCl3):
d
ꢁ73.81 (d, J ¼ 6.2 Hz, 3F). FTIR (KBr): 3365,1711 (s) cmꢁ1. MS (ESI):
m/z 482 [M þ H]þ. HRMS: m/z Calcd for C23H23F3NO2Se [M þ H]þ
482.0846; Found 482.0869.
4.5.12. (E)-methyl 3-(2-(1-(4-chlorophenylamino)-2,2,2-
trifluoroethyl)benzo[b]-selenophen-3-yl)acrylate (6c)
Yield: 51%; Yellow oil. 1H NMR (300 MHz, CDCl3):
d 7.92e7.80
(m, 3H), 7.45e7.30 (m, 2H), 7.11 (d, J ¼ 8.9 Hz, 2H), 6.54 (d,
J ¼ 8.7 Hz, 2H), 6.33 (d, J ¼ 16.1 Hz, 1H), 4.26 (d, J ¼ 4.7 Hz, 1H), 3.86
(s, 3H). 13C NMR (75.5 MHz, CDCl3):
d 166.6, 143.2, 142.7, 140.1,
136.9, 135.1, 129.4, 126.1, 125.8, 125.7, 125.3, 125.2, 124.9, 124.2,
123.8 (q, J ¼ 271.8 Hz), 115.5, 57.4 (q, J ¼ 31.4 Hz), 52.0. 19F NMR
(400 MHz, CDCl3):
d
ꢁ73.80 (d, J ¼ 7.4 Hz, 3F). FTIR (KBr): 3363,
1719 (s) cmꢁ1. MS (ESI): m/z 474[M þ H]þ. HRMS: m/z Calcd for
C20H16F3NO2ClSe [M þ H]þ 473.9986; Found 473.9979.
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3996e4004.
Acknowledgements
M. V. K thanks UGC and S. S. R thanks CSIR, India for their
fellowships.
[51] J.-H. Chu, C.-C. Chen, M.-J. Wu, Organometallics 27 (2008) 5173e5176.
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Org. Biomol. Chem. 7 (2009) 85e93.
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