Copper-catalyzed thiolation cyclization of 1-chloro-1,5-enynes with sodium hydrosulfide: Synthesis of CF3-containing 1H-isothiochromenes

Article abstract of DOI:10.1055/s-0031-1290246

A copper-catalyzed regio- and stereoselective 6-exo-dig cyclization of 1-chloro-1,5-enynes with sodium hydrosulfide has been developed. In the presence of copper(I) iodide and sodium tert-butoxide, a variety of (Z)-1-methylene-3- (trifluoromethyl)-1H-isot

Full text of DOI:10.1055/s-0031-1290246

966▌
PAPER
paper
Copper-Catalyzed Thiolation Cyclization of 1-Chloro-1,5-enynes with Sodium
Hydrosulfide: Synthesis of CF3-Containing 1H-Isothiochromenes
Shuai Shi, Lei-Lei Sun, Zhi-Yong Liao, Xing-Guo Zhang*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Fax +86(577)86689615; E-Mail: zxg@wzu.edu.cn
Received: 12.12.2011; Accepted after revision: 17.01.2012
R1
Abstract: A copper-catalyzed regio- and stereoselective 6-exo-dig
R1
cyclization of 1-chloro-1,5-enynes with sodium hydrosulfide has
I2
(1)
Zeni
been developed. In the presence of copper(I) iodide and sodium
SR2
S
tert-butoxide, a variety of (Z)-1-methylene-3-(trifluoromethyl)-1H-
isothiochromenes were prepared in moderate to good yields via thi-
olation cyclization of 1-alkynyl-2-(2-chloro-3,3,3-trifluoroprop-1-
enyl)benzenes with sodium hydrosulfide.
CF3
CF3
CuI
R2
R2
(2)
NaHS
S
+
Cl
t-BuONa
Key words: copper, thiolation, 6-exo-dig cyclization, 1H-isothio-
this work
chromenes, sodium hydrosulfide
R1
H
R1
Scheme 1 Routes to 1H-isothiochromenes
The isothiochromene derivatives are an important class of
heterocyclic compounds owing to their wide range of bio-
logical activity.1 However, the properties of these com-
pounds have been insufficiently investigated due to the
scarce methods available for their efficient synthesis.2 For
example, the synthesis of trifluoromethyl-containing iso-
thiochromenes remains an unexplored area, although the
introduction of a trifluoromethyl group into organic com-
pounds has a significant effect on their biological activity
and often manifests changes in chemical and physical
properties.3 Most of the reported approaches for the syn-
thesis of 1H-isothiochromenes involve the condensation
reaction of benzoate derivatives with sulfur surrogates,
such as phosphorus pentasulfide4 and carbon disulfide.5
Recently, Zeni and co-workers also described the synthe-
sis of 1H-isothiochromenes by iodocyclization reaction of
2-alkynylbenzyl sulfides (Scheme 1, equation 1).6 During
the past two decades, transition-metal-catalyzed carbon–
sulfur bond-forming reactions have received intensive at-
tention,7 which could provide a more convenient and effi-
cient route for the synthesis of sulfur-containing
heterocyclic compounds.8 Very recently, our group re-
ported the copper-catalyzed annulation of o-bromophenyl
alkynes with sodium sulfide.9 We questioned whether vi-
nyl halides could undergo a similar tandem reaction with
an inexpensive metal sulfide10 to construct sulfur-contain-
ing heterocycles. Herein, we wish to report the stereose-
lective synthesis of (Z)-1-methylene-3-(trifluoromethyl)-
1H-isothiochromenes by copper-catalyzed thiolation and
subsequently 6-exo-dig cyclization of 1-chloro-1,5-
enynes with sodium hydrosulfide hydrate (Scheme 1,
equation 2).
As shown in Table 1, reactions between 1-(2-chloro-
3,3,3-trifluoroprop-1-enyl)-2-(phenylethynyl)benzene
(1a)11 and metal sulfides were carried out to optimize the
reaction conditions. Initially, the reactions of substrate 1a
with various metal sulfides, such as sodium sulfide, potas-
sium sulfide, and sodium hydrosulfide, were examined in
the presence of copper(I) iodide (entries 1–3). The results
demonstrated that all metal sulfides were effective sulfur
sources, and sodium hydrosulfide provided the best re-
sults. Treatment of substrate 1a with sodium hydrosulfide
and copper(I) iodide (10 mol%) in N,N-dimethylform-
amide at 80 °C for two hours afforded the desired (Z)-
1-benzylidene-3-(trifluoromethyl)-1H-isothiochromene
(2a) in 42% yield (entry 3). The configuration of product
2a was unambiguously confirmed by X-ray single-crystal
diffraction analysis (Figure 1). Suggested by our previous
work, in which base could accelerate the thiolation of vi-
nyl and aryl halides with sodium hydrosulfide,12 we inves-
tigated a variety of bases (entries 4–7). The results showed
that the reaction yields were dramatically enhanced in the
presence of a base such as tripotassium phosphate, potas-
sium carbonate, sodium hydroxide, and sodium tert-but-
oxide. The target product 2a could be isolated in 90%
yield when substrate 1a was treated with sodium hydro-
sulfide, sodium tert-butoxide (2 equiv), and copper(I) io-
dide (10 mol%) in N,N-dimethylformamide at 80 °C for
two hours. Subsequently, other copper salts, such as cop-
per(I) bromide, copper(I) chloride, copper(II) triflate, and
copper(II) acetate, were evaluated (entries 8–11). It was
found that they were less effective than copper(I) iodide,
although all of these copper catalysts had catalytic activity
for this reaction. However, 2a was obtained in only 27%
yield in the absence of a copper catalyst, and a lower yield
was observed when the loading of copper(I) iodide was
reduced to 5 mol% (entries 12 and 13). Finally, various
solvents, such as dimethyl sulfoxide, acetonitrile, N-meth-
SYNTHESIS 32190012, 44, 0966–0972
DOI: 10.1055/s-0031-1290246; Art ID: SS-22 011-H1147-OP
© Georg Thieme Verlag Stuttgart · New York
Advanced online publication: 24.02.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
1
0
X

PAPER
Synthesis of CF3-Containing 1H-Isothiochromenes
967
Table 1 Screening Optimal Conditionsa
CF3
CF3
[Cu]
+
metal sulfide
Cl
S
base
solvent
Ph
1a
Ph
2a
Yieldb (%)
Entry
Sulfide
[Cu]
Base
Solvent
1
Na2S
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
MeCN
NMP
toluene
34
26
42
69
61
67
90
88
82
86
81
27
71
64
86
20
trace
2
K2S
–
3
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
NaHS
–
4
K3PO4
5
K2CO3
NaOH
6
7
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
8
9
10
11
12
13c
14
15
16
17
Cu(OTf)2
Cu(OAc)2
–
CuI
CuI
CuI
CuI
CuI
a Reaction conditions: 1a (0.2 mmol), NaHS·xH2O (0.4 mmol), [Cu] (10 mol%), base (2 equiv), solvent (2 mL), N2 atmosphere, 2 h.
b Isolated yield.
c 5 mol% of CuI was used.
yl-2-pyrrolidinone, and toluene, were investigated, but
they were all less effective than N,N-dimethylformamide
(entries 14–17).
With this newly established thiolation cyclization proto-
col in hand, we explored the substrate scope of 1-alkynyl-
2-(2-chloro-3,3,3-trifluoroprop-1-enyl)benzenes for the
thiolation annulations (Table 2). Initially, the substituent
R3 at the terminal alkyne moiety of 1-alkynyl-2-(2-chloro-
3,3,3-trifluoroprop-1-enyl)benzenes 1b–m were evaluat-
ed, and these gave (Z)-1-methylene-3-(trifluoromethyl)-
1H-isothiochromenes 2b–m. The results demonstrated
that both electron-deficient and electron-rich phenyl
groups were well tolerated. For example, substrates 1b–g,
bearing a tolyl or 4-methoxyphenyl group, underwent the
thiolation annulation with sodium hydrosulfide smoothly
to afford the corresponding products 2b–g in moderate to
Figure 1 ORTEP diagram of the single-crystal X-ray structure of
compound 2a
good yields. Isothiochromenes 2h–j, with a phenyl group
bearing an electron-withdrawing group (such as 4-
ClC6H4, 4-O2NC6H4, and 4-NCC6H4 groups), were also
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 966–972

968
S. Shi et al.
PAPER
obtained in moderate yields. We found that the steric ef- the benzene ring moiety, were treated with sodium hydro-
fects of an ortho-substituted phenyl group did not have an sulfide, copper(I) iodide, and sodium tert-butoxide to af-
obvious effect on the reaction; compound 2d, 2f, and 2g ford the corresponding products 2n or 2q in 91 and 61%
could be isolated in 75, 72, and 88% yields, respectively. yields, respectively.
We were also pleased to find that heteroaryl groups (such
Based upon the experimental results and the reported
as 3-pyridyl and 2-thienyl) in the substrates 1k,l were very
well tolerated and provided the corresponding products
2k and 2l in 73 and 90% yields, respectively. However,
1-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2-(3,3-dimethyl-
but-1-ynyl)benzene (1m) bearing an aliphatic alkyl group
gave a low yield (37%) of 2m under the standard condi-
tions even after a prolonged reaction time. Subsequently,
a variety of 1-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2-
(phenylethynyl)benzenes 1 bearing R1 and R2 substituents
on the benzene ring were examined. The results showed
that the thiolation cyclization of substrates 1n–r bearing
various substituents (such as Me, OMe, Cl, and F) on the
benzene ring proceeded successfully to afford products
1n–r in moderate to excellent yields. For example, sub-
strates 1n or 1q, bearing a methyl or fluoro substituent on
mechanism,10a a plausible mechanism for the thiolation
cyclization reaction is outlined in Scheme 2. Initially, ox-
idative addition of substrate 1 to copper(I) iodides affords
intermediate A, followed by ligand exchange with sodium
hydrosulfide in the presence of sodium tert-butoxide to
provide intermediate B. Subsequently, reductive elimina-
tion of intermediate B forms intermediate C and regener-
ates copper(I) iodide. Complexation of copper(I) iodide
with intermediate C provides copper complex D, and then
this undergoes stereoselective 6-exo-dig cyclization to
give intermediate E by intramolecular nucleophilic attack
of S– to the C≡C triple bond of complex D. Finally, the
protonolysis of intermediate E affords (Z)-1-methylene-3-
Table 2 Copper(I) Iodide Catalyzed Thiolation Cyclization of 1-Chloro-1,5-enynes with Sodium Hydrosulfidea
R1
CF3
R1
CF3
CuI (10 mol%)
Cl
+ NaHS
S
R2
R2
t-BuONa (2 equiv)
DMF, 80 °C
R3
R3
1
2
R1
R2
R3
Yieldb (%)
Entry
Product
1
H
H
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
2,4-(MeO)2C6H3
2-MeO-4-ClC6H3
4-ClC6H4
4-O2NC6H4
4-NCC6H4
3-pyridyl
2-thienyl
t-Bu
2b
2c
2d
2e
2f
82
73
75
68
72
88
74
53
70
73
90
37c
91
54
66
61
52
2
H
H
3
H
H
4
H
H
5
H
H
6
H
H
2g
2h
2i
7
H
H
8
H
H
9
H
H
2j
10
11
12
13
14
15
16
17
H
H
2k
2l
H
H
H
H
2m
2n
2o
2p
2q
2r
H
Me
H
Ph
OMe
OMe
H
Ph
OMe
F
Ph
Ph
Cl
H
Ph
a Reaction conditions: 1 (0.2 mmol), NaHS·xH2O (0.4 mmol), CuI (10 mol%), t-BuONa (2 equiv), DMF (2 mL), 80 °C, 2 h.
b Isolated yield.
c For 12 h.
Synthesis 2012, 44, 966–972
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of CF3-Containing 1H-Isothiochromenes
969
13C NMR (125 MHz, CDCl3): δ = 135.3, 131.8, 131.0, 130.2, 129.8,
129.4, 129.0, 128.7, 128.2, 127.8, 126.2, 125.2, 124.5 (q, JC-F = 33.6
Hz), 124.4 (q, JC-F = 5.5 Hz), 121.9 (q, JC-F = 271.0 Hz).
(trifluoromethyl)-1H-isothiochromenes 2 and regenerates
the active copper(I) iodide.
LRMS (EI, 70 eV): m/z (%) = 304 (M+, 100), 234 (42), 202 (22),
I
CF3
I
117 (16).
F3C
Cu
F3C
Cu
Cl
NaHS
HRMS (EI): m/z [M]+ calcd for C17H11F3S: 304.0528; found:
Cl
SNa
304.0534.
R
1
CuI
(Z)-1-(4-Methylbenzylidene)-3-(trifluoromethyl)-1H-isothio-
chromene (2b)
HCl
A
B
R
White solid; yield: 52.8 mg (82%); mp 175–176 °C.
R
2
IR (neat): 1625, 1508, 1448, 1296, 1269, 964, 856 cm–1.
CuI
H+
1H NMR (500 MHz, CDCl3): δ = 7.61 (d, J = 7.5 Hz, 1 H), 7.45–
7.42 (m, 1 H), 7.37–7.35 (m, 3 H), 7.23–7.20 (m, 3 H), 7.09 (s, 1 H),
7.00 (s, 1 H), 2.38 (s, 3 H).
CF3
CF3
CF3
13C NMR (125 MHz, CDCl3): δ = 137.8, 132.6, 132.0, 131.0, 130.2,
129.8, 129.3, 128.9, 128.9, 128.8, 125.2, 124.8, 124.6 (q, JC-F = 33.0
Hz), 124.4 (q, JC-F = 5.3 Hz), 121.9 (q, JC-F = 271.0 Hz), 21.3.
S
S–
SNa
6-exo-dig
CuI
R
R
ICu
R
CuI
C
LRMS (EI, 70 eV): m/z (%) = 318 (M+, 100), 303 (39), 270 (11).
E
D
HRMS (EI): m/z [M]+ calcd for C18H13F3S: 318.0685; found:
Scheme 2 Possible mechanism
318.0688.
(Z)-1-(3-Methylbenzylidene)-3-(trifluoromethyl)-1H-isothio-
chromene (2c)
In summary, we have developed a copper(I) iodide cata-
lyzed highly regio- and stereoselective synthetic method
for 1-methylene-3-(trifluoromethyl)-1H-isothiochromenes.
In the presence of copper(I) iodide and sodium tert-butox-
ide, a variety of 1-alkynyl-2-(2-chloro-3,3,3-trifluoro-
prop-1-enyl)benzenes underwent tandem thiolation and 6-
exo-dig heterocyclization reaction with sodium hydrosul-
fide hydrate to afford trifluoromethyl-containing isothio-
chromenes in moderate to excellent yields. The present
procedure could be served as synthetic applications of tri-
fluoromethyl-containing building blocks and also a new
optional route for constructing the isothiochromene ring.
White solid; yield: 46.8 mg (73%); mp 122–123 °C.
IR (neat): 1674, 1444, 1291, 1264, 1161, 1123, 967, 754 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 8.0 Hz, 1 H), 7.46–
7.42 (m, 1 H), 7.38–7.34 (m, 1 H), 7.33–7.27 (m, 2 H), 7.25–7.20
(m, 2 H), 7.13 (d, J = 7.0 Hz, 1 H), 7.09 (s, 1 H), 7.00 (s, 1 H), 2.40
(s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 137.9, 135.3, 131.8, 131.0, 130.2,
130.1, 129.8, 129.0, 128.9, 128.6, 128.1, 126.4, 126.0, 125.2, 124.7
(q, JC-F = 33.0 Hz), 124.4 (q, JC-F = 5.5 Hz), 122.0 (q, JC-F = 271.0
Hz), 21.5.
LRMS (EI, 70 eV): m/z (%) = 318 (M+, 100), 303 (18), 249 (12),
234 (32).
HRMS (EI): m/z [M]+ calcd for C18H13F3S: 318.0685; found:
Chemicals were either purchased or purified by standard tech-
1
niques. H and 13C NMR were determined in a CDCl3 soln with a
318.0689.
Bruker Avance (300 or 500 MHz) spectrometer using TMS as the
internal standard. All reactions under a N2 atmosphere were con-
ducted using standard Schlenk techniques. Column chromatogra-
phy was performed using EM Silica gel 60 (300–400 mesh).
(Z)-1-(2-Methylbenzylidene)-3-(trifluoromethyl)-1H-isothio-
chromene (2d)
White solid; yield: 47.3 mg (75%); mp 111–112 °C.
IR (neat): 1737, 1624, 1559, 1457, 1375, 1260, 1118 cm–1.
(Z)-1-Benzylidene-3-(trifluoromethyl)-1H-isothiochromenes 2;
General Procedure
1H NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 7.0 Hz, 1 H), 7.39–
7.37 (m, 1 H), 7.33–7.30 (m, 1 H), 7.26 (s, 1 H), 7.20–7.18 (m, 4 H),
7.01 (s, 1 H), 6.96 (s, 1 H), 2.24 (s, 3 H).
A mixture of 1-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2-(phenyle-
thynyl)benzene 1 (0.2 mmol), CuI (3.8 mg, 10 mol%), NaHS·xH2O
(22.4 mg, 2 equiv), and t-BuONa (38.4 mg, 2 equiv) in DMF (2 mL)
was evacuated and backfilled with N2 (3 ×) and then stirred at 80 °C
for 2 h or until complete consumption of the starting material (TLC
or GC-MS analysis). When the reaction was complete, the mixture
was filtered through a glass filter and washed with EtOAc. The mix-
ture was washed with brine and extracted with EtOAc. The organic
layers were dried (anhyd Na2SO4) and evaporated under vacuum,
and the residue was purified by flash column chromatography
(hexane–EtOAc) to give product 2.
13C NMR (125 MHz, CDCl3): δ = 136.7, 134.5, 131.4, 131.0, 130.5,
130.2, 129.9, 129.1, 129.0, 128.2, 127.5, 127.2, 125.6, 125.2, 125.1
(q, JC-F = 33.2 Hz), 124.2 (q, JC-F = 5.5 Hz), 121.9 (q, JC-F = 271.0
Hz), 20.0.
LRMS (EI, 70 eV): m/z (%) = 318 (M+, 100), 285 (18), 265 (25),
215 (37).
HRMS (EI): m/z [M]+ calcd for C18H13F3S: 318.0685; found:
318.0692.
(Z)-1-Benzylidene-3-(trifluoromethyl)-1H-isothiochromene
(2a)
(Z)-1-(4-Methoxybenzylidene)-3-(trifluoromethyl)-1H-isothio-
chromene (2e)
Yellow solid; yield: 55.2 mg (90%); mp 83–84 °C.
Yellow oil; yield: 45.6 mg (68%).
IR (neat): 1589, 1511, 1473, 1448, 963, 952, 890 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.64 (d, J = 8.0 Hz, 1 H), 7.48–
7.41 (m, 5 H), 7.38–7.35 (m, 1 H), 7.33–7.30 (m, 1 H), 7.24–7.22
(m, 1 H), 7.11 (s, 1 H), 7.03 (s, 1 H).
IR (neat): 1663, 1597, 1506, 1293, 1117, 756 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.52 (d, J = 8.0 Hz, 1 H), 7.39–
7.34 (m, 3 H), 7.28–7.26 (m, 1 H), 7.13 (d, J = 7.5 Hz, 1 H), 7.01 (s,
1 H), 6.88–6.87 (m, 3 H), 3.77 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 966–972

970
S. Shi et al.
PAPER
13C NMR (125 MHz, CDCl3): δ = 159.1, 133.0, 132.2, 131.0, 130.9,
130.1, 129.7, 128.7, 128.6, 128.2, 125.2, 124.6 (q, JC-F = 7.5 Hz),
124.5 (q, JC-F = 33.5 Hz), 122.0 (q, JC-F = 271.0 Hz), 113.6, 55.3.
1H NMR (500 MHz, CDCl3): δ = 8.18 (d, J = 8.0 Hz, 2 H), 7.63 (d,
J = 8.0 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 2 H), 7.45–7.36 (m, 2 H), 7.22
(d, J = 7.5 Hz, 1 H), 7.10 (s, 1 H), 6.99 (s, 1 H).
LRMS (EI, 70 eV): m/z (%) = 334 (M+, 100), 319 (46), 221 (29),
13C NMR (125 MHz, CDCl3): δ = 146.4, 141.6, 131.4, 131.2, 130.7,
130.3, 130.2, 130.0, 129.8, 125.3, 125.1, 124.7 (q, JC-F = 5.3 Hz),
123.6, 123.5 (q, JC-F = 34.0 Hz), 121.8 (q, JC-F = 271.0 Hz).
189 (11).
HRMS (EI): m/z [M]+ calcd for C18H13F3OS: 334.0634; found:
334.0639.
LRMS (EI, 70 eV): m/z (%) = 349 (M+, 100), 281 (32), 234 (41),
207 (68).
(Z)-1-(2,4-Dimethoxybenzylidene)-3-(trifluoromethyl)-1H-iso-
thiochromene (2f)
HRMS (EI): m/z [M]+ calcd for C17H10F3NO2S: 349.0379; found:
349.0372.
White solid; yield: 52.8 mg (72%); mp 86–87 °C.
IR (neat): 1608, 1577, 1500, 1457, 1299, 796 cm–1.
(Z)-4-{[3-(Trifluoromethyl)-1H-isothiochromen-1-yli-
dene]methyl}benzonitrile (2j)
1H NMR (500 MHz, CDCl3): δ = 7.52 (d, J = 7.5 Hz, 1 H), 7.35–
7.32 (m, 1 H), 7.27–7.23 (m, 2 H), 7.10 (d, J = 7.5 Hz, 1 H), 7.01 (s,
1 H), 7.00 (s, 1 H), 6.48–6.46 (m, 1 H), 6.40 (s, 1 H), 3.76 (s, 3 H),
3.73 (s, 3 H).
Yellow solid; yield: 45.9 mg (70%); mp 96–97 °C.
IR (neat): 2228, 1601, 1296, 1276, 1214, 1159, 1118, 966, 855, 814,
770 cm–1.
13C NMR (125 MHz, CDCl3): δ = 160.9, 158.3, 132.5, 130.8, 130.7,
130.2, 129.6, 128.6, 125.6, 125.0 (q, JC-F = 33.0 Hz), 124.6 (q,
1H NMR (500 MHz, CDCl3): δ = 7.70–7.68 (m, 3 H), 7.57 (d,
J = 8.0 Hz, 2 H), 7.52–7.43 (m, 2 H), 7.29 (d, J = 7.5 Hz, 1 H), 7.17
(s, 1 H), 7.02 (s, 1 H).
J
C-F = 5.5 Hz), 124.6, 124.3, 122.0 (q, JC-F = 271.0 Hz), 117.6,
103.4, 98.4, 55.40, 55.38.
13C NMR (125 MHz, CDCl3): δ = 139.6, 130.7, 131.9, 131.3, 130.7,
LRMS (EI, 70 eV): m/z (%) = 364 (M+, 10), 228 (100), 208 (8).
130.2, 130.16, 130.11, 129.7, 129.6, 125.8, 125.0, 124.6 (q, JC-F =
5.3 Hz), 123.6 (q, JC-F = 34.0 Hz), 121.7 (q, JC-F = 271.0 Hz), 118.7.
LRMS (EI, 70 eV): m/z (%) = 329 (M+, 100), 259 (38), 227 (18).
HRMS (EI): m/z [M]+ calcd for C19H15F3O2S: 364.0739; found:
364.0743.
HRMS (EI): m/z [M]+ calcd for C18H10F3NS: 329.0481; found:
(Z)-1-(4-Chloro-2-methoxybenzylidene)-3-(trifluoromethyl)-
1H-isothiochromene (2g)
329.0491.
Yellow solid; yield: 65.1 mg (88%); mp 109–110 °C.
(Z)-3-{[3-(Trifluoromethyl)-1H-isothiochromen-1-yli-
dene]methyl}pyridine (2k)
IR (neat): 1737, 1478, 1475, 1461, 1293, 1214, 1111, 1020, 968,
895, 880, 813, 803, 760 cm–1.
Yellow solid; yield: 44.2 mg (73%); mp 75–76 °C.
1H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 8.0 Hz, 1 H), 7.38–
7.35 (m, 1 H), 7.30–7.27 (m, 2 H), 7.18–7.14 (m, 2 H), 7.02 (s, 1 H),
7.00 (s, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 3.73 (s, 3 H).
IR (neat): 1587, 1559, 1447, 1419, 757 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.63 (s, 1 H), 8.46 (s, 1 H), 7.81
(d, J = 8.0 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.43–7.40 (m, 1 H),
7.36–7.29 (m, 2 H), 7.21–7.18 (m, 1 H), 7.07 (s, 1 H), 6.90 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 155.6, 131.6, 131.0, 130.2, 129.8,
129.5, 129.1, 128.9, 128.0, 125.8, 125.4, 124.9, 124.6 (q, JC-F = 33.0
Hz), 124.5 (q, JC-F = 5.5 Hz), 123.0, 122.0 (q, JC-F = 271.0 Hz),
111.5, 55.7.
13C NMR (125 MHz, CDCl3): δ = 150.3, 147.9, 135.9, 131.4, 131.2,
131.0, 130.1, 130.0, 129.5, 129.4, 125.0, 124.7 (q, JC-F = 5.3 Hz),
124.1, 123.8 (q, JC-F = 34.0 Hz), 123.1, 121.8 (q, JC-F = 271.0 Hz).
LRMS (EI, 70 eV): m/z (%) = 368 (M+, 5), 319 (14), 227 (100), 151
LRMS (EI, 70 eV): m/z (%) = 305 (M+, 100), 236 (15), 118 (13).
(6).
HRMS (EI): m/z [M]+ calcd for C16H10F3NS: 305.0481; found:
HRMS (EI): m/z [M]+ calcd for C18H12ClF3S: 368.0244; found:
305.0489.
368.0248.
(Z)-1-(Thiophen-2-ylmethylene)-3-(trifluoromethyl)-1H-iso-
thiochromene (2l)
(Z)-1-(4-Chlorobenzylidene)-3-(trifluoromethyl)-1H-isothio-
chromene (2h)
Yellow solid; yield: 55.5 mg (90%); mp 60–61 °C.
Yellow solid; yield: 49.5 mg (74%); mp 103–104 °C.
IR (neat): 1624, 1447, 1422, 1290, 1266, 1211, 966, 883, 758 cm–1.
IR (neat): 2978, 1749, 1733, 1684, 1587, 1375, 1294, 1255, 1240,
1H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 8.0 Hz, 1 H), 7.45–
7.42 (m, 1 H), 7.39 (d, J = 5.0 Hz, 1 H), 7.36–7.33 (m, 1 H), 7.26
(d, J = 3.5 Hz, 1 H), 7.22 (d, J = 7.0 Hz, 1 H), 7.19 (s, 1 H), 7.12–
7.10 (m, 2 H).
1166, 1047 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.61 (d, J = 7.5 Hz, 1 H), 7.47–
7.43 (m, 1 H), 7.40–7.36 (m, 5 H), 7.23 (d, J = 7.0 Hz, 1 H), 7.11 (s,
1 H), 6.95 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 139.0, 131.5, 131.1, 130.2, 130.0,
129.4, 128.8, 127.1, 127.0, 124.6 (q, JC-F = 5.3 Hz), 124.4, 124.2 (q,
13C NMR (125 MHz, CDCl3): δ = 133.8, 133.4, 131.4, 131.1, 130.5,
130.1, 129.9, 129.2, 128.5, 127.1, 127.1, 125.1, 124.5 (q, JC-F = 5.3
Hz), 124.2 (q, JC-F = 33.8 Hz), 121.9 (q, JC-F = 271.1 Hz).
J
C-F = 34.0 Hz), 123.0, 121.5 (q, JC-F = 271.0 Hz), 120.7.
LRMS (EI, 70 eV): m/z (%) = 310 (M+, 100), 265 (16), 257 (12),
LRMS (EI, 70 eV): m/z (%) = 338 (M+, 100), 340 (M+, 37), 303
120 (14).
(29), 270 (22).
HRMS (EI): m/z [M]+ calcd for C15H9F3S2: 310.0092; found:
HRMS (EI): m/z [M]+ calcd for C17H10ClF3S: 338.0138; found:
310.0097.
338.0144.
(Z)-1-(2,2-Dimethylpropylidene)-3-(trifluoromethyl)-1H-iso-
thiochromene (2m)
(Z)-1-(4-Nitrobenzylidene)-3-(trifluoromethyl)-1H-isothio-
chromene (2i)
Yellow oil; yield: 21.8 mg (37%).
White solid; yield: 37.3 mg (53%); mp 151–152 °C.
IR (neat): 2357, 2341, 1749, 1739, 1457, 1357, 1257, 1241, 1235
IR (neat): 1731, 1590, 1554, 1506, 1336, 1107, 970, 852, 754, 690
cm–1.
cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.54 (s, 1 H), 7.37–7.28 (m, 4 H),
6.83 (s, 1 H), 1.30 (s, 9 H).
Synthesis 2012, 44, 966–972
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of CF3-Containing 1H-Isothiochromenes
971
13C NMR (125 MHz, CDCl3): δ = 153.6, 139.8, 138.7, 134.2, 131.1,
130.2, 129.4, 128.5, 128.4 (q, JC-F = 32.4 Hz), 126.7, 121.5 (q,
Hz), 123.5 (d, JC-F = 5.5 Hz), 121.8 (q, JC-F = 271.0 Hz), 116.2 (d,
J
C-F = 22.0 Hz), 112.0 (d, JC-F = 23.5 Hz).
J
C-F = 271.3 Hz), 39.8, 29.4.
LRMS (EI, 70 eV): m/z (%) = 322 (M+, 100), 253 (28), 252 (40),
LRMS (EI, 70 eV): m/z (%) = 256 (28), 165 (100), 91 (11).
220 (27).
HRMS (EI): m/z [M]+ calcd for C15H15F3S: 284.0841; found:
HRMS (EI): m/z [M]+ calcd for C17H10F4S: 322.0434; found:
284.0844.
322.0444.
(Z)-1-Benzylidene-7-methyl-3-(trifluoromethyl)-1H-isothio-
chromene (2n)
(Z)-1-Benzylidene-6-chloro-3-(trifluoromethyl)-1H-isothio-
chromene (2r)
Yellow solid; yield: 57.6 mg (91%); mp 64–65 °C.
Yellow solid; yield: 35.7 mg (52%); mp 99–101 °C.
IR (neat): 1749, 173, 1684, 1599, 1375, 1126 cm–1.
IR (neat): 1736, 1601, 1573, 1492, 1472, 1374, 1240, 958, 828 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.48–7.46 (m, 3 H), 7.43–7.40 (m,
2 H), 7.32–7.30 (m, 1 H), 7.18 (d, J = 7.5 Hz, 1 H), 7.12 (d, J = 7.5
Hz, 1 H), 7.08 (s, 1 H), 7.04 (s, 1 H), 2.42 (s, 3 H).
1H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 8.5 Hz, 1 H), 7.46–
7.39 (m, 5 H), 7.35–7.32 (m, 1 H), 7.21 (s, 1 H), 7.02 (s, 1 H), 6.99
(s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 141.3, 135.4, 131.6, 129.9, 129.8,
129.3, 128.2, 128.1, 127.6, 127.6, 126.5, 125.7, 124.3 (q, JC-F = 5.5
Hz), 123.3 (q, JC-F = 33.6 Hz), 122.0 (q, JC-F = 270.7 Hz), 21.7.
13C NMR (125 MHz, CDCl3): δ = 135.0, 134.9, 131.8, 130.9, 130.2,
129.4, 129.3, 129.2, 128.3, 128.0, 126.7, 126.5 (q, JC-F = 33.8 Hz),
125.1, 123.3 (q, JC-F = 5.5 Hz), 121.7 (q, JC-F = 271.4 Hz).
LRMS (EI, 70 eV): m/z (%) = 318 (M+, 100), 302 (16), 234 (24),
LRMS (EI, 70 eV): m/z (%) = 338 (M+, 100), 340 (M+, 36), 301
215 (10).
(41), 234 (23), 151 (13).
HRMS (EI): m/z [M]+ calcd for C18H13F3S: 318.0685; found:
HRMS (EI): m/z [M]+ calcd for C17H10ClF3S: 338.0138; found:
318.0689.
338.0138.
(Z)-1-Benzylidene-6-methoxy-3-(trifluoromethyl)-1H-isothio-
chromene (2o)
Acknowledgment
Yellow solid; yield: 35.8 mg (54%); mp 111–113 °C.
We thank the National Natural Science Foundation of China (No.
21002070), Zhejiang Provincial Natural Science Foundation of
China (No. Y4100307) and for financial support.
IR (neat): 1750, 1738, 1674, 1661, 1596, 1559, 1375, 1295, 1125
cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 8.5 Hz, 1 H), 7.47–
7.40 (m, 4 H), 7.31–7.29 (m, 1 H), 7.05 (s, 1 H), 7.02–6.99 (m, 1 H),
6.93 (s, 1 H), 6.74 (s, 1 H), 3.85 (s, 3 H).
Supporting Information for this article is available online at
13C NMR (125 MHz, CDCl3): δ = 160.1, 135.6, 131.5, 129.2, 128.2,
127.5, 126.7, 126.5, 126.2, 125.2 (q, JC-F = 33.6 Hz), 124.6, 124.2
(q, JC-F = 5.1 Hz), 121.9 (q, JC-F = 271.1 Hz), 117.4, 113.8, 55.5.
http://www.thieme-connect.com/ejournals/toc/synthesis.omnorinIftangonmSorniuifIatoprtngiSutpor
References
LRMS (EI, 70 eV): m/z (%) = 334 (M+, 100), 179 (36), 176 (31), 57
(1) (a) Crenshaw, R. R.; Jeffries, A. T.; Luke, G. M.; Cheney,
C.; Bialy, G. J. Med. Chem. 1971, 14, 1185. (b) Natsugari,
H.; Tawadа, H.; Ikeda, H. EP 481,383, 1992; Chem. Abstr.
1992, 117, 48326. (c) Attardo, G.; Kraus, J. L.; Courchesne,
M.; Lamonthe, S.; Lavallee, J. F.; Lebeau, E.; Nguyen, D.;
Rej, R.; St-Denis, Y.; Wang, W.; Xu, Y.-C.; Barbeau, F.;
Belleau, B. US 5,593,970 1997; Chem. Abstr. 1997, 126,
199791. (d) Bertenshaw, S. R.; Talley, J. J.; Rogier, D. J.;
Graneto, M. J.; Koboldt, C. M.; Zhang, Y. Bioorg. Med.
Chem. Lett. 1996, 6, 2827. (e) Toshima, K.; Ohta, K.;
Ohtsuka, A.; Matsumura, S.; Nakata, M. J. Chem. Soc.,
Chem. Commun. 1993, 1406.
(29).
HRMS (EI): m/z [M]+ calcd for C18H13F3OS: 334.0634; found:
334.0632.
(Z)-1-Benzylidene-6,7-dimethoxy-3-(trifluoromethyl)-1H-iso-
thiochromene (2p)
Yellow oil; yield: 48.1 mg (66%).
IR (neat): 2978, 1734, 1597, 1558 1516, 1464, 1374, 1360, 1273,
1125 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.46 (d, J = 7.5 Hz, 2 H), 7.44–
7.40 (m, 2 H), 7.32–7.29 (m, 1 H), 7.14 (s, 1 H), 7.04 (s, 1 H), 6.96
(s, 1 H), 6.71 (s, 1 H), 3.99 (s, 3 H), 3.93 (s, 3 H).
(2) (a) Pokhodylol, N. T.; Matiychukl, V. S.; Obushak, M. D.
Chem. Heterocycl. Compd. (Engl. Transl.) 2010, 46, 140.
(b) Klein, T. R.; Bergemann, M.; Yehia, N. A. M.;
Fanghänel, E. J. Org. Chem. 1998, 63, 4626.
13C NMR (125 MHz, CDCl3): δ = 151.2, 149.9, 135.5, 129.2, 128.2,
127.4, 126.9, 125.7, 125.0, 123.9 (q, JC-F = 5.5 Hz), 123.7, 122.1 (q,
J
C-F = 270.6 Hz), 122.0 (q, JC-F = 33.7 Hz), 111.8, 107.6, 56.1, 56.1.
(3) (a) Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 214.
(b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
1881. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V. Chem. Soc. Rev. 2008, 37, 320. (d) Hagmann, W. K. J.
Med. Chem. 2008, 51, 4359. (e) Welch, J. T. Tetrahedron
1987, 43, 3123.
LRMS (EI, 70 eV): m/z (%) = 364 (M+, 100), 289 (23), 208 (16).
HRMS (EI): m/z [M]+ calcd for C19H15F3O2S: 364.0739; found:
364.0745.
(Z)-1-Benzylidene-7-fluoro-3-(trifluoromethyl)-1H-isothio-
chromene (2q)
(4) Legrand, L.; Lozac’h, N. Bull. Soc. Chim. Fr. 1970, 2244.
(5) Kobayashi, G.; Matsuda, Y.; Natsuki, R.; Yamaguchi, H.;
Tominaga, Y. Yakugaku Zasshi 1972, 92, 449.
Yellow oil; yield: 39.5 mg (61%).
IR (neat): 1750, 1668, 1606, 1576, 1496, 1449, 1413, 1128 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.58–7.52 (m, 1 H), 7.47–7.44 (m,
3 H), 7.36–7.34 (m, 2 H), 7.24–7.23 (m, 1 H), 7.15–7.09 (m, 2 H),
7.03 (s, 1 H).
(6) Schneider, C. C.; Bortolatto, C.; Back, D. F.; Menezes, P. H.;
Zeni, G. Synthesis 2011, 413.
(7) (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111,
1596. (b) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed.
2003, 42, 5400. (c) Kondo, T.; Mitsudo, T. Chem. Rev. 2000,
100, 3205. (d) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41,
13C NMR (125 MHz, CDCl3): δ = 162.1 (d, JC-F = 249.5 Hz), 134.9,
133.9 (d, JC-F = 7.8 Hz), 132.3, 131.7 (d, JC-F = 12.5 Hz), 131.0,
129.4, 128.3, 128.1, 126.5 (d, JC-F = 2.8 Hz), 125.3 (d, JC-F = 2.5
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 966–972

972
S. Shi et al.
PAPER
1450. (e) Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.;
Ma, D. Org. Lett. 2009, 11, 5250. (f) Xu, H.-J.; Liang, Y.-F.;
Cai, Z.-Y.; Qi, H.-X.; Yang, C.-Y.; Feng, Y.-S. J. Org.
Chem. 2011, 76, 2296.
(10) (a) Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y.
Angew. Chem. Int. Ed. 2010, 48, 4222. (b) Zhu, J.-T.; Chen,
Z.-X.; Xie, H.-B.; Li, S.; Wu, Y.-M. Org. Lett. 2010, 12,
2434. (c) You, W.; Yan, X.-Y.; Liao, Q.; Xi, C.-J. Org. Lett.
2010, 12, 3930. (d) Kashiki, T.; Shinamura, S.; Kohara, M.;
Miyazaki, E.; Takimiya, K.; Ikeda, M.; Kuwabara, H. Org.
Lett. 2009, 11, 2473. (e) Saito, M.; Yamamoto, T.; Osaka, I.;
Miyazaki, E.; Takimiya, K.; Kuwabara, H.; Ikeda, M.
Tetrahedron Lett. 2010, 51, 5277.
(8) (a) Samanta, R.; Antonchick, A. P. Angew. Chem. Int. Ed.
2011, 50, 5217. (b) Zeng, F.; Alper, H. Org. Lett. 2011, 13,
2868. (c) Qin, X.; Cong, X.; Zhao, D.; You, J.; Lan, J. Chem.
Commun. 2011, 47, 5611. (d) Guilarte, V.; Fernández-
Rodríguez, M. A.; García-García, P.; Hernando, E.; Sanz, R.
Org. Lett. 2011, 13, 5100. (e) Nakamura, I.; Sato, T.;
Terada, M.; Yamamoto, Y. Org. Lett. 2007, 9, 4081. (f) Shi,
L.; Liu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2011,
76, 4200. (g) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428.
(11) This compound was prepared from the Sonogashira reaction
of 2-bromobenzaldehyde and phenylacetylene, and then
reacted with CF3CCl3, see: (a) Gao, K.; Wu, J. Org. Lett.
2008, 10, 2251. (b) Fujita, M.; Hiyama, T. Bull. Chem. Soc.
Jpn. 1987, 60, 4377.
(9) Sun, L.-L.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G. J. Org.
Chem. 2011, 76, 7546.
(12) Li, C.-L.; Zhang, X.-G.; Tang, R.-Y.; Zhong, P.; Li, J.-H.
J. Org. Chem. 2010, 75, 7037.
Synthesis 2012, 44, 966–972
© Georg Thieme Verlag Stuttgart · New York