One-pot synthesis of trifluoromethylated phthalans via intramolecular cyclization from 2-alkynylbenzaldehydes

Article abstract of DOI:10.1016/j.tet.2014.04.072

An efficient tandem addition/cyclization procedure for the synthesis of trifluoromethylated phthalans under mild conditions was developed. This procedure involves tetrabutylammonium fluoride (TBAF)-promoted addition of Ruppert-Prakash reagent (TMSCF₃

Full text of DOI:10.1016/j.tet.2014.04.072

Tetrahedron xxx (2014) 1e6
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Tetrahedron
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One-pot synthesis of trifluoromethylated phthalans via
intramolecular cyclization from 2-alkynylbenzaldehydes
,
a
,
b,
Lijun Xu a, Haizhen Jiang a , Jian Hao , Gang Zhao
*
*
*
a Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient tandem addition/cyclization procedure for the synthesis of trifluoromethylated phthalans
under mild conditions was developed. This procedure involves tetrabutylammonium fluoride (TBAF)-
promoted addition of RuppertePrakash reagent (TMSCF3) to 2-alkynylbenzaldehyde to give 2-
alkynylbenzylicalcohols, which would then undergo base-catalyzed selective 5-exo-dig cyclization to
furnish the corresponding products.
Received 9 March 2014
Received in revised form 16 April 2014
Accepted 24 April 2014
Available online xxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethylation
RuppertePrakash reagent
Intramolecular cyclization
Tetrabutylammonium fluoride
2-Alkynylbenzaldehyde
1. Introduction
materials or limited reaction scopes. Our group have reported
a highly efficient regio- and enantioselective synthesis of 1,3-
1,3-Dihydroisobenzofuran compounds (phthalans) have re-
ceived much attention due to their important roles in both chemical
and pharmaceutical industries.1 During the past few decades, many
studies have been reported on the synthesis of this important kind
of heterocyclic compounds.2 On the other hand, trifluoromethylated
compounds have various important applications in material science
and medicinal industry owing to the unique properties of the
fluorine atom. Among the developed reagents for nucleophilic tri-
fluoromethylation, the RuppertePrakash reagent TMSCF3 is one of
the most powerful, general and widely used (usually under catalysis
by the fluoride anion or bases) for the introduction of a tri-
fluoromethyl group (CF3) into a variety of organic substrates, such as
aldehydes,3 hydrocarbon4 and boronic acids.5 To the best of our
knowledge, there have been very few synthetic methods available
for the preparation of CF3-containing phthalans. In 2010, Olah and
co-workers reported an efficient method for the synthesis of tri-
fluoromethylated cyclic ethers via the Mitsunobu reaction.6 More-
over, Gong et al. recently developed a novel synthetic route to
trifluoromethylated phthalans by oxa-Michael reaction.7 However,
these methods suffered from either the availability of starting
dihydroisobenzofuran via a tandem addition/cyclization pro-
cedure from 2-alkynylbenzaldehydes.8 Traditionally, TBAF is used
not only as a reagent for the cleavage of silyl ethers,9 but also as an
effective promoter for the Michael-type reaction,10 nucleophilic
substitution,11 addition reaction,12 fluorination,13 and the homo-
coupling of arylhalides.14 As the nucleophilic addition of the Rup-
pertePrakash reagent TMSCF3 to an aldehyde has been well
documented, we reasoned that a similar cyclization of the in-
termediate alcohol adduct to provide trifluoromethylated phthalans
should also be possible under appropriate conditions (Scheme 1).
We reported herein the details of our research with this strategy, in
which TBAF was found to be an efficient promoter for the cyclization
step.
2. Result and discussion
2-Alkynylbenzaldehydes 1 were synthesized via Sonogashira
coupling reaction according to literature reports.15 The reaction of
1a with TMSCF3 was initially carried out with 10 mol % of Na2CO3 in
DMF at room temperature for 1.0 h, and then 1.5 equiv of TBAF
(1.0 M in THF) was added to the reaction mixture followed by
heating at 55 ꢀC for 5 h. We were pleased to find that the addition of
TMSCF3 to 1a and the subsequent 5-exo-dig cyclization to form the
major product 2a could be done in a one-pot fashion (Table 1, entry
* Corresponding authors. E-mail addresses: hzjiang@shu.edu.cn (H. Jiang), jhao@
shu.edu.cn (J. Hao), zhaog@mail.sioc.ac.cn (G. Zhao).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.072
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2
L. Xu et al. / Tetrahedron xxx (2014) 1e6
Scheme 1. A sampling of methods of trifluoromethylated phthalans.
Table 1
To explore the scope of the reaction, a range of differently
a
Optimization studies of the reaction of 2-alkynylbenzaldehyde with TMSCF3
substituted 2-alkynylbenzaldehyde were examined under the op-
timized conditions (Table 2). In most cases, the major 5-exo-dig
products 2 were formed in good to excellent yields. Substrates
bearing electron-withdrawing groups on the benzene ring like 2b
and 2c (Table 2, entries 2e3) provided higher yields than those
with electron-donating groups (Table 2, entries 4e5). When R2 was
changed to a heterocyclic pyridyl group or thienyl groups, products
(2feh) were also obtained in over 90% yields (Table 2, entries 6e8).
Moreover, 5-fluoro-2-(thiophen-2-ylethynyl)benzaldehyde (1i)
also worked well to afford the corresponding product 2i in a yield of
93% (Table 2, entry 9). When R1 was changed to electron-donating
groups, the products 2j and 2k were obtained in moderate yields
(Table 2, entries 10e11). However, when R2 was an alkyl group, only
Entry
Base 1 (mol %)
Time (h)
Base 2
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
Na2CO3 (10)
K2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (5)
NaH (10)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (10)
1
1
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
NaH
DMF
DMF
DMF
THF
Toluene
THF
THF
THF
THF
THF
51
58
65
80
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Tracec
81
72
the addition product a-trifluoromethylated alcohols were obtained
70
t-BuOK
TBAF
dd
N.D.e
while the cyclization did not take place (Table 2, entries 13e14). The
structure of the product 2h was unambiguously confirmed by
single crystal X-ray crystallographic analysis (Fig. 1). As an illus-
tration of the utility of the reaction, the product 2g was trans-
10
a
Unless otherwise noted, the reaction was carried out with 1a (0.2 mmol), base 1,
and TMSCF3 (0.3 mmol) in the solvent (1.0 mL) and then base 2 (0.3 mmol) was
added.
formed to
g-trifluoromethylated phthalide 4 via oxidation
b
Isolated yield of the major product 2a.
The intermediate
with PCC, which represents an important structural motif found in
many naturally occurring substances with biological activities16
(Scheme 2).
c
a-trifluoromethylated alcohol was isolated as the major
product.
d
e
The reaction system was complicated.
The cyclization step was run at rt for 8 h. N.D.¼not detected.
We next made
a preliminary exploration on the tri-
fluoromethylation of 2-alkynylbenzimines17 by using TMSCF3. To
our surprise the product isoindolines 7a and 7b were obtained in
yields of 52% and 54%, respectively, at room temperature after
5 h via the tandem addition/cyclization reaction in the absence
of TBAF (Scheme 3). The structure of the product 7a was un-
ambiguously confirmed by single crystal X-ray crystallographic
analysis (Fig. 2). Further studies on the 2-alkynylbenzimine li-
brary and improving the yields are in progress and will be re-
ported in the near future.
1). The yield was improved to 65% when Cs2CO3 was used in the
first addition step with a shortened reaction time (entry 3). The
screen of solvents showed that the yield could be further improved
to 80% when THF was used (entry 4). Pleasingly, the catalytic effi-
ciency was not affected when the loading amount of Cs2CO3 was
reduced to 5 mol % (entry 6). In contrast, when NaH or t-BuOK was
used instead of TBAF in the cyclization step; inferior yields were
obtained (entries 7e8). Moreover, an elevated reaction tempera-
ture for the cyclization step was necessary; when the reaction
mixture after step 1 (the addition step) was stirred at room tem-
perature for 8 h, formation of the product 2a was not observed
(Table 1, entry 10).
3. Conclusion
In summary, we have described an efficient one-pot synthesis
of trifluoromethylated phthalans via
a tandem nucleophilic
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L. Xu et al. / Tetrahedron xxx (2014) 1e6
3
Table 2
The scope of the tandem reaction
Entry
Substrate
R1
R2
Product
Yield (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
H
H
H
H
H
H
H
H
F
Me
OMe
H
H
H
C6H5
4-FC6H4
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
80
85
82
76
65
93
88
90
93
65
60
65
97
98
4-ClC6H4
4-MeC6H4
4-OMeC6H4
3-Pyridyl
2-Thienyl
3-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
(CH2)5CH3
t-Bu
9
10
11
12
13
14
a
Yield of the isolated products after column chromatography.
Fig. 2. X-ray crystal structure of product 7a. (CCDC 925077).
Fig. 1. X-ray crystal structure of product 2h. (CCDC 925076).
addition/intramolecular cyclization of 2-alkynylbenzaldehydes
and TMSCF3. The reaction features a highly selective 5-exo-dig
cyclization process, simple manipulation and mild reaction con-
ditions, which provides an attractive strategy for pharmaceutical
building blocks and medicinal chemistry applications. Current ef-
forts are focused on the nucleophilic trifluoromethylation of 2-
alkynylbenzimines.
Scheme 2. A transformation of 2g to g-trifluoromethylated phthalide 4.
Scheme 3. Trifluoromethylation of 2-alkynylbenzimines 6.
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4
L. Xu et al. / Tetrahedron xxx (2014) 1e6
4. Experimental
IR (KBr): 2926, 1670, 1602, 1467, 1350, 1269, 1234, 1199, 1173, 1135,
1057, 904, 843, 777, 756, 683 cmꢂ1 1H NMR (400 MHz, CDCl3):
5.85 (q, J¼6.0 Hz, 1H), 6.02 (s, 1H), 7.06 (t, J¼8.8 Hz, 2H), 7.40e7.44
(m, 1H), 7.48e7.51 (m, 2H), 7.59 (d, J¼8.0 Hz, 1H), 7.70e7.73 (m,
;
4.1. General information
d
Commercial reagents were used as received without further
purification. All solvents used were dried and purified by distillation.
Melting points were measured on a Temp-Melt apparatus and were
uncorrected. 1H NMR and 13C NMR spectra were recorded on
a Bruker AM-400 or an Agilent AM-400 instrument with Me4Si as
the external standard. 19F NMR spectra were recorded on a Bruker
AM-300 or an Agilent AM-400 instrument with CFCl3 as the internal
2H); 19F NMR (282 MHz, CDCl3):
d
ꢂ77.9 (d, J¼5.9 Hz, 3F), ꢂ115.3
(m, 1F); 13C NMR (100 MHz, (CD3)2CO):
d
81.2 (q, 2JCeCeF¼34 Hz, C),
1
97.5, 115.0, 115.2, 123.4 (q, JCeF¼279 Hz, CF3), 129.5, 129.9, 130.0,
130.4, 131.8, 131.9, 133, 135, 153.6 (d, J¼2.2 Hz), 159.9, 162.3; MS-EI:
m/z (%)¼98, 112, 147, 176, 196, 225, 294 (100); HRMS-EI (m/z) calcd
for C16H10F4O: 294.2436, found: 294.0667.
standard. All chemical shifts (
d
) were given in parts per million. Data
4.2.3. (Z)-1-(4-Chlorobenzylidene)-3-(trifluoromethyl)-1,3-
dihydroisobenzofuran (2c). Yield: 82%; White solid, mp:
109e110 ꢀC; IR (KBr): 2925, 1669, 1491, 1467, 1355, 1289, 1263, 1189,
were reported as follows: chemical shift, integration, multiplicity
(s¼single, d¼doublet, t¼triplet, q¼quartet, br¼broad, m¼multiplet)
and coupling constants (Hertz). FTIR spectra were obtained with
a Nicolet AV-360 spectrometer. Mass spectra were obtained on
a Finnigan GCeMS 4021 or a Finnigan MAT8430 instrument. Single
crystal X-ray structure analysis was performed on a Bruker P4 in-
strument. All reactions were monitored by TLC or 19F NMR.
1170, 1131, 1087, 1013, 902, 840, 757, 680, 521 cmꢂ1 1H NMR
;
(400 MHz, CDCl3).
d
5.85 (q, J¼6.0 Hz, 1H), 5.98 (s, 1H), 7.31 (d,
J¼8.4 Hz, 2H), 7.41e7.52 (m, 3H), 7.60 (d, J¼8.0 Hz, 1H), 7.66 (d,
J¼8.4 Hz, 2H); 19F NMR (376 MHz, CDCl3):
ꢂ77.9 (d, J¼5.3 Hz, 3F);
d
13C NMR (100 MHz, CDCl3):
d
81.5 (q, 2JCeCeF¼34 Hz, C), 97.9, 120.1,
122.8, 122.9 (q, 1JCeF¼280 Hz, CF3), 128.6, 129.4, 129.5, 130.2, 131.7,
132.9, 133.6, 135.4, 154.2; MS (EI): m/z (%)¼55, 81, 91, 99, 178, 241,
255, 310 (100); HRMS-EI (m/z) calcd for C16H10ClF3O: 310.0372,
found: 310.0370.
4.2. Typical procedure for the tandem addition/intra-
molecular cyclization reaction of 2-alkynylbenzaldehyde and
TMSCF3
To a stirred solution of 2-alkynylbenzaldehyde (1a, 206.3 mg,
1.0 mmol) and anhydrous cesium carbonate (16.3 mg, 0.05 mmol)
in anhydrous tetrahydrofuran (5.0 mL) under nitrogen was added
TMSCF3 (0.179 mL, 1.2 mmol). The resulting mixture was stirred at
room temperature for 12 min. Then TBAF (1.0 M in THF, 1.5 mL,
1.5 mmol) was added slowly to the solution, and then the mixture
was heated at 55 ꢀC for 5 h. At the end of the reaction monitored by
TLC or 19F NMR, the mixture was diluted with water (10 mL) and
extracted with EtOAc (3ꢁ15 mL). The organic layers were washed
with brine (2ꢁ20 mL), dried over sodium sulfate, and then evap-
orated under vacuum. The residue was purified by flash chroma-
tography on silica gel eluting with ethyl acetate/petroleum ether (1/
20) to afford the target product 2a. To a solution of 2g (56.4 mg,
0.2 mmol) in 4 mL of CH2Cl2 was added PCC (1.2 equiv), and after
being stirred for 2 h at room temperature, the mixture was filtered
through Celite and concentrated. The crude product was purified by
column chromatography (silica gel, 5% ethyl acetate in petroleum
4.2.4. (Z)-1-(4-Methylbenzylidene)-3-(trifluoromethyl)-1,3-
dihydroisobenzofuran (2d). Yield: 76%; yellow solid, mp
105e106 ꢀC; IR (KBr): 2926, 1662, 1510, 1465, 1355, 1348, 1263, 1177,
1132, 1059, 878, 844, 762, 684 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
d
2.34 (s, 3H), 5.82 (q, J¼6.0 Hz, 1H), 6.01 (s, 1H), 7.16 (d, J¼8.0 Hz,
2H), 7.38 (d, J¼7.6 Hz, 1H), 7.44e7.47 (m, 2H), 7.56 (d, J¼8.0 Hz, 1H),
7.62 (d, J¼8.0 Hz, 2H); 19F NMR (376 MHz, CDCl3):
d
ꢂ78.0 (d,
J¼5.3 Hz, 3F); 13C NMR (100 MHz, CDCl3):
d 21.3, 81.4 (q,
2JCeCeF¼34 Hz, C), 99.0, 120.0, 122.8, 123.1 (q, JCeF¼280 Hz, CF3),
128.3, 129.0, 129.2, 130.1, 132.2, 132.8, 135.8, 136.1, 153.3; MS-EI: m/
z(%)¼77, 92, 110, 178, 221, 290 (100); HRMS-EI: m/z calcd for
1
C
17H13F3O: 290.0918, found: 290.0922.
4.2.5. (Z)-1-(4-Methoxybenzylidene)-3-(trifluoromethyl)-1,3-
dihydroisobenzofuran (2e). Yield: 65%; Pale yellow solid, mp
69e70 ꢀC; IR (KBr): 2934, 1664, 1604, 1512, 1465, 1252, 1176, 1135,
1056, 1035, 874, 840, 759, 683 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
ether) yielding
g
-trifluoromethylated phthalide 4 as colorless oil in
d
3.83 (s, 3H),
d
3.84 (s, 3H), 5.84 (q, J¼5.9 Hz, 1H), 6.01 (s, 1H), 6.92
81% yield. The spectroscopic values were in good agreement with
(d, J¼8.8 Hz, 2H), 7.39 (d, J¼7.8 Hz, 1H), 7.46e7.49 (m, 2H), 7.57 (d,
those reported in the literature:16c,18 IR (KBr): 1793, 1602, 1468,
J¼8.0 Hz, 1H), 7.69 (d, J¼8.8 Hz, 2H); 19F NMR (376 MHz, CDCl3):
1362, 1294, 1267, 1140, 854, 750, 696 cmꢂ1
;
1H NMR (400 MHz,
d
ꢂ78.0 (d, J¼5.3 Hz, 3F); 13C NMR (100 MHz, CDCl3):
d 54.6, 81.0 (q,
CDCl3):
d
5.70 (q, J¼5.6 Hz, 1H), 7.66e7.71 (m, 2H), 7.78e7.81
2JCeCeF¼34 Hz, C), 98.6, 113.9, 120.0, 123.0, 123.1 (q, 1JCeF¼279 Hz,
CF3), 128.0, 129.0, 129.6, 130.3, 132.7, 135.8, 152.4, 158.1; MS-EI: m/
z(%)¼77, 108, 118, 153, 165, 178, 193, 237, 306 (100); HRMS-EI (m/z)
calcd for C17H13F3O2: 306.0868, found: 306.0865.
(m, 1H), 7.98 (d, J¼7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 76.1 (q,
2JCeCeF¼35.7 Hz, C), 122.3 (q, JCeF¼278.7 Hz, CF3), 123.5, 126.4,
1
131.2, 134.9; 140.6, 168.3; 19F NMR (376 MHz, CDCl3):
d
ꢂ76.7 (d,
J¼6.8 Hz, 3F); MS (ESI): m/z¼225.0 (MþNa)þ. HRMS (ESI): m/z calcd
for (C9H5F3O2þH)þ: 203.0320; found: 203.0310.
4.2.6. (Z)-3-((3-(Trifluoromethyl)isobenzofuran-1(3H)-ylidene)
methyl)pyridine (2f). Yield: 93%; White solid, mp 110e111 ꢀC; IR
(KBr): 2922, 1669, 1482, 1467, 1416, 1352, 1272, 1172, 1138, 1058,
4 . 2 .1. ( Z ) - 1 - B e n z y l i d e n e - 3 - ( t r i fl u o r o m e t h y l ) - 1, 3 -
dihydroisobenzofuran (2a). Yield: 80%; White solid, mp 75e76 ꢀC;
IR (KBr): 2924, 1668, 1493, 1467, 1350, 1273, 1171, 1139, 1058, 904,
759, 707, 684 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
5.87 (q, J¼5.6 Hz,
1H), 6.00 (s, 1H), 7.28 (t, J¼4.8 Hz, 1H), 7.43e7.62 (m, 4H), 7.63 (d,
875, 819, 761, 692 cmꢂ1 1H NMR (400 MHz, CDCl3):
; d 5.85 (q,
J¼7.6 Hz, 1H), 8.16 (d, J¼8.0 Hz, 1H), 8.41 (d, J¼4.4 Hz, 1H), 8.80 (s,
J¼6.0 Hz, 1H), 6.01 (s, 1H), 7.01 (d, J¼8.8 Hz, 1H), 7.35e7.61 (m, 5H),
1H); 19F NMR (376 MHz, CDCl3):
d
ꢂ77.9 (d, J¼5.3 Hz, 3F); 13C NMR
7.78 (d, J¼8.0 Hz, 1H), 7.82 (d, J¼8.0 Hz, 2H); 19F NMR (376 MHz,
(100 MHz, CDCl3):
d
81.6 (q, JCeCeF¼34 Hz, C), 95.7, 120.1 (q,
2
CDCl3):
d
ꢂ77.9 (d, J¼5.2 Hz, 3F); 13C NMR (100 MHz, CDCl3):
d
81.5
1JCeF¼280 Hz, CF3), 120.3, 122.9, 123.4, 129.8, 130.3, 131.2, 133.1,
134.7, 135.0, 146.9, 149.5, 155.7; MS-EI: m/z (%)¼76, 103, 127, 152,
181, 208, 277 (100); HRMS-EI (m/z) calcd for C15H10F3NO: 277.0714,
found: 277.0718.
2
1
(q, JCeCeF¼34 Hz, C), 99.04, 120.0, 122.9, 123.0 (q, JCeF¼280 Hz,
CF3), 126.3, 128.3, 128.4, 129.2, 130.1, 132.8, 135.0, 135.7, 153.8; MS-
EI: m/z (%)¼77, 89, 105, 132, 178, 207, 276 (100); HRMS-EI (m/z)
calcd for C16H11F3O: 276.0762, found: 276.0766.
4.2.7. (Z)-1-(Thiophen-2-ylmethylene)-3-(trifluoromethyl)-1,3-
dihydroisobenzofuran (2g). Yield: 88%; Pale yellow solid, mp
51e52 ꢀC; IR (KBr): 2924, 1663, 1468, 1362, 1346, 1270, 1171, 1139,
4.2.2. (Z)-1-(4-Fluorobenzylidene)-3-(trifluoromethyl)-1,3-
dihydroisobenzofuran (2b). Yield: 85%; White solid, mp 72e73 ꢀC;
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L. Xu et al. / Tetrahedron xxx (2014) 1e6
5
1059, 903, 875, 851, 830, 756, 685, 649 cmꢂ1
CDCl3):
;
1H NMR (400 MHz,
CDCl3):
d
5.91 (q, J¼5.8 Hz, 1H), 6.83 (s, 1H), 7.05 (dd, J¼3.7, 5.0 Hz,
d
5.75 (q, J¼5.9 Hz, 1H), 6.25 (s, 1H), 6.94 (t, J¼4.0 Hz, 1H),
1H), 7.27e7.32 (m, 3H), 7.78 (d, J¼7.8 Hz, 1H), 8.69 (d, J¼4.76, 1H);
7.12 (d, J¼4.0, 1H), 7.16 (d, J¼4.0 Hz, 1H), 7.28 (d, J¼7.6 Hz, 1H), 7.35
19F NMR (376 MHz, CDCl3):
(100 MHz, CDCl3):
d
ꢂ82.4 (d, J¼5.2 Hz, 3F); 13C NMR
(t, J¼7.4 Hz, 2H), 7.43 (d, J¼7.6 Hz, 1H); 19F NMR (376 MHz, CDCl3):
d
80.0 (q, JCeCeF¼34 Hz, C), 95.5, 122.6 (q,
2
d
ꢂ78.8 (d, J¼5.6 Hz, 3F); 13C NMR (100 MHz, CDCl3):
d
81.5 (q,
1JCeF¼280 Hz, CF3), 122.9, 126.1, 127.2, 127.3, 131.2, 137.3, 149.8,
152.4, 153.6; MS-EI: m/z (%)¼69, 115, 142, 154, 186, 214, 254, 283
(100); HRMS-EI (m/z) for C13H8F3NOS: 283.0279, found: 283.0282.
2JCeCeF¼34 Hz, C), 93.5, 119.8, 123.0, 123.0 (q, JCeF¼280 Hz, CF3),
124.9, 125.8, 127.1, 129.2, 130.2, 133.3, 134.8, 138.1, 152.4; MS-EI: m/z
(%)¼92, 141, 152, 184, 213, 253, 282 (100); HRMS-EI (m/z) calcd for
1
C
14H9F3OS: 282.0326, found: 282.0325.
4.2.13. 2,2,2-Trifluoro-1-(2-(oct-1-yn-1-yl)phenyl)ethanol
(2m). Yield: 97%; Yellow liquid; IR (KBr): 3440, 1487, 1450, 1263,
1174, 1131, 1060, 882, 867, 828, 760, 688 cmꢂ1; 1H NMR (400 MHz,
4.2.8. (Z)-1-(Thiophen-3-ylmethylene)-3-(trifluoromethyl)-1,3-
dihydroisobenzofuran (2h). Yield: 90%; pale yellow solid, mp
55e56 ꢀC; IR (KBr): 2925, 1787, 1671, 1467, 1363, 1267, 1138, 1060,
903, 875, 818, 772, 681, 638, 609 cmꢂ1; 1H NMR (400 MHz, CDCl3):
CDCl3):
d
0.93 (t, J¼6.8 Hz, 3H), 1.35 (m, 2H), 1.47 (m, 2H), 1.62 (m,
2H), 3.28 (d, J¼3.9 Hz, 1H), 5.61 (m, 1H), 7.32e7.36 (m, 2H),
7.45e7.46 (m, 1H), 7.56 (d, J¼6.4 Hz, 1H); 19F NMR (376 MHz,
d
5.65 (q, J¼5.6 Hz,1H), 6.00 (s,1H), 7.15 (m,1H), 7.22 (d, J¼7.7 Hz,1H),
CDCl3):
d
ꢂ77.7 (d, J¼6.7 Hz, 3F); 13C NMR (100 MHz, CDCl3):
d 13.9,
7.27e7.30 (m, 3H), 7.37 (d, J¼7.6 Hz, 1H), 7.41 (d, J¼2.3 Hz, 1H); 19
F
19.4, 22.5, 28.5, 28.6, 31.3, 70.7 (q, JCeCeF¼34 Hz, C), 77.6, 96.3,
123.7, 124.5 (q, 1JCeF¼280 Hz, CF3), 127.3, 127.9, 129.0, 132.4, 135.3;
MS-EI: m/z (%)¼95, 115, 117, 129, 145, 197, 213, 237, 284 (100);
HRMS-EI (m/z) for C16H19F3O: 284.1388, found: 284.1387.
2
NMR (282 MHz, CDCl3):
CDCl3):
d
ꢂ77.9 (d, J¼5.9 Hz, 3F); 13C NMR (100 MHz,
d
81.5 (q, 2JCeCeF¼34 Hz, C), 93.9,119.9,122.3,123.0,123.2 (q,
1JCeF¼280 Hz, CF3),125.1,128.5,129.1,130.2,133.1,135.4,135.8,153.2;
MS-EI: m/z (%)¼92, 106, 141, 152, 169, 184, 213, 282 (100); HRMS-EI
(m/z) calcd for C14H9F3OS: 282.0326, found: 282.0323.
4.2.14. 1-(2-(3,3-Dimethylbut-1-yn-1-yl)phenyl)-2,2,2-
trifluoroethanol (2n). Yield: 98%; White solid, mp 58e59 ꢀC; IR
(KBr): 3419, 1487, 1475, 1450, 1363, 1265, 1173, 1131, 1109, 1060, 832,
4.2.9. (Z)-5-Fluoro-1-(thiophen-2-ylmethylene)-3-(trifluoromethyl)-
1,3-dihydroisobenz-ofuran (2i). Yield: 93%; White solid, mp
79e80 ꢀC; IR (KBr): 2924, 1664, 1602, 1483, 1441, 1362, 1282, 1264,
760, 701, 628 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
1.34 (s, 9H), 3.54
(d, J¼5.2 Hz,1H), 5.58 (m,1H), 7.30e7.33 (m, 2H), 7.42e7.45 (m, 2H),
1249, 1188, 1151, 1062, 854, 839, 689 cmꢂ1
;
1H NMR (400 MHz,
7.56 (m, 1H); 19F NMR (376 MHz, CDCl3):
d
ꢂ77.7 (d, J¼7.1 Hz, 3F);
CDCl3):
7.17e7.22 (m, 3H), 7.45 (d, J¼2.6 Hz, 1H), 7.51 (dd, J¼4.64, 8.4 Hz,
1H); 19F NMR (376 MHz, CDCl3):
ꢂ82.3 (d, J¼5.2 Hz, 3F), ꢂ114.9;
13C NMR (100 MHz, CDCl3):
d
5.85 (q, J¼5.8 Hz, 1H), 6.28 (s, 1H), 7.02e7.04 (m, 1H),
13C NMR (100 MHz, CDCl3):
d
1
28.2, 30.7, 70.9 (q, 2JCeCeF¼32 Hz, C),
76.2, 104.5, 123.5, 124.5 (q, JCeF¼281 Hz, CF3), 127.4, 127.9, 128.9,
132.2, 135.3; MS-EI: m/z (%)¼41, 77, 115, 128, 172, 183, 213, 223, 241,
256 (100); HRMS-EI (m/z) for C14H15F3O: 256.1075, found: 256.1072.
d
2
d
81.0 (qd, JCeCeF¼34, 3.1 Hz, C), 93.3
(d, J¼2.2 Hz), 110.4, 118.1, 118.3, 121.3, 121.4, 122.67 (q, 1JCeF¼280 Hz,
CF3), 124.9, 125.8, 127.0, 151.3, 161.9, 164.4; MS-EI: m/z (%)¼75, 84,
101, 115, 159, 170, 202, 231, 271, 300 (100); HRMS-EI (m/z) calcd for
4.3. General procedure for the synthesis of imines 6aeb
To a solution of 1a (1.0 mmol) in CH2Cl2 (1.0 mL) were added the
C
14H8F4OS: 300.0232, found: 300.0230.
ꢀ
aromatic amine (1.0 mmol) and 4 A MS (20 mg), and the
4.2.10. (Z)-5-Methyl-1-(thiophen-2-ylmethylene)-3-(tri-
fluoromethyl)-1,3-dihydroisobe-nzofuran (1j). Yield: 65%; white
solid, mp 79e80 ꢀC; IR (KBr): 2926, 1661, 1488, 1366, 1343, 1282,
1272, 1237, 1196, 1162, 1151, 1140, 1057, 861, 805, 693 cmꢂ1; 1H NMR
mixture was stirred at room temperature for 12 h. The mixture was
filtered and the solvent was removed under reduced pressure to
give crude imine. Imine was used for next reaction though the
recrystallization.
(400 MHz, CDCl3):
d
2.44 (s, 3H), 5.83 (q, J¼6.3 Hz, 1H), 6.30 (s, 1H),
7.04 (dd, J¼3.6, 5.2 Hz,1H), 7.20 (d, J¼3.6 Hz,1H), 7.25e7.29 (m, 3H),
4.3.1. 4-Chloro-N-(2-(phenylethynyl)benzylidene)aniline
(6a). Yield: 86%; Yellow solid, mp 102e103 ꢀC; IR (KBr):1624, 1486,
1441, 1292, 1093, 1008, 909, 822, 756, 687, 671, 546; 1H NMR
7.44 (d, J¼8.4 Hz, 1H); 19F NMR (376 MHz, CDCl3):
d
ꢂ78.0 (d,
J¼6.3 Hz, 3F); 13C NMR (100 MHz, CDCl3):
d 21.5, 81.4 (q,
2JCeCeF¼34 Hz, C), 92.6, 119.6, 123.0 (q, JCeF¼280 Hz, CF3), 123.3,
124.5, 125.4, 127.0, 131.3, 132.2, 133.6, 138.2, 139.7, 152.5; MS-EI: m/z
(%)¼77, 84, 106, 115, 165, 184, 199, 227, 267, 296 (100); HRMS-EI (m/
z) calcd for C15H11F3OS: 296.0483, found: 296.0480.
(400 MHz, CDCl3):
(m, 2H), 7.52e7.55 (m, 2H), 7.61e7.63 (m, 1H), 8.24e8.26 (m, 1H);
9.07 (s, 1H); 13C NMR (100 MHz, CDCl3):
86.2, 95.6, 122.4, 122.7,
d 7.19e7.22 (m, 2H), 7.37e7.39 (m, 5H), 7.44e7.47
1
d
125.2, 126.7, 128.6,128.7, 128.8,129.4, 131.1, 131.6, 131.7, 132.8, 136.4,
150.7, 159.2; MS (ESI): m/z¼316.0 (MþH)þ. HRMS (ESI): m/z calcd
for (C21H14ClNþH)þ: 316.0893; found: 316.0887.
4.2.11. (Z)-5-Methoxy-1-(thiophen-2-ylmethylene)-3-(tri-
fluoromethyl)-1,3-dihydroisob-enzofu-ran (1k). Yield: 60%; white
solid, mp 95e96 ꢀC; IR (KBr): 2904, 1660, 1611, 1593, 1514, 1490,
1465, 1435, 1365, 1255, 1181, 1161, 1068, 1028, 848, 830, 690,
4.3.2. 4-Bromo-N-(2-(phenylethynyl)benzylidene)aniline
(6b). Yield: 85%; Yellow solid, mp 103e104 ꢀC; IR (KBr): 1624, 1592,
582 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
3.86 (s, 3H), 5.82 (q,
1482, 1189, 1161, 1069, 1005, 972, 821, 750, 687, 657, 540 cmꢂ1 1H
;
J¼5.6 Hz, 1H), 6.21 (s, 1H), 6.95 (s, 1H) 7.01e7.04 (m, 2H), 7.16 (d,
NMR (400 MHz, CDCl3):
d
7.15 (d, J¼8.4 Hz, 2H), 7.37e7.39 (m, 3H),
J¼2.8 Hz, 1H), 7.22 (d, J¼5.2 Hz, 1H), 7.45 (d, J¼8.4 Hz, 1H); 19F NMR
7.43e7.49 (m, 2H), 7.52e7.54 (m, 4H), 7.62 (d, J¼6.8 Hz, 1H), 8.26 (d,
(376 MHz, CDCl3):
CDCl3):
d
ꢂ77.9 (d, J¼5.6 Hz, 3F); 13C NMR (100 MHz,
J¼6.4 Hz, 1H); 9.08 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 86.2, 95.7,
2
d
55.7, 81.2 (q, JCeCeF¼34 Hz, C), 91.7, 107.4, 117.4, 121.0,
119.6, 122.7, 122.8,125.3, 126.7, 128.6, 128.7, 128.8, 131.2,131.6,132.3,
132.8,136.5,151.2,159.3; MS (ESI): m/z¼360.0 (MþH)þ. HRMS (ESI):
m/z calcd for (C21H14BrNþH)þ: 360.0388; found: 360.0381.
122.9 (q, 1JCeF¼280 Hz, CF3), 124.2, 125.0, 126.9, 127.3, 135.0, 138.3,
152.3,160.9; MS-EI: m/z (%)¼69, 75, 106, 121, 156, 171, 184, 200, 228,
243, 279, 312 (100); HRMS-EI (m/z) calcd for
C15H11F3O2S:
312.0432, found: 312.0429.
4.4. Typical procedure for the tandem addition/intra-
molecular cyclization reaction of 2-alkynylbenzimine and
TMSCF3
4.2.12. (Z)-7-(Thiophen-2-ylmethylene)-5-(trifluoromethyl)-5,7-
dihydrofuro[3,4-b]pyri-dine (2l). Yield: 65%; White solid, mp
102e103 ꢀC; IR (KBr): 2923, 1667, 1588, 1472, 1416, 1345, 1277, 1171,
To a stirred solution of 2-alkynylbenzimine (6a, 63.2 mg,
0.2 mmol) and anhydrous cesium carbonate (6.5 mg, 0.02 mmol) in
1140, 1052, 906, 859, 843, 789, 702 cmꢂ1
;
1H NMR (400 MHz,
Please cite this article in press as: Xu, L.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.072

6
L. Xu et al. / Tetrahedron xxx (2014) 1e6
anhydrous tetrahydrofuran (2.0 mL) under nitrogen was added
TMSCF3 (0.179 mL, 1.2 mmol). The resulting mixture was stirred at
room temperature for 5 h. At the end of the reaction monitored by
TLC or 19F NMR, the mixture was diluted with water (10 mL) and
extracted with Et2O (3ꢁ10 mL). The organic layers were washed
with brine (2ꢁ20 mL), dried over sodium sulfate, and then evap-
orated under vacuum. The residue was purified by flash chroma-
tography on silica gel eluting with petroleum ether to afford the
product 7a.
References and notes
1. (a) Raman, B.; Sharma, B. A.; Ghugare, P. D.; Karmuse, P. P.; Kumar, A. J. Pharm.
Biomed. Anal. 2009, 50, 377e383; (b) Zhang, P.; Cyriac, G.; Kopajtic, T.; Zhao, Y.;
Javitch, J. A.; Katz, J. L.; Newman, A. H. J. Med. Chem. 2010, 53, 6112e6121.
2. (a) Barluenga, J.; Henar, V.; Ballesteros, A. J. Am. Chem. Soc. 2003, 125,
9028e9029; (b) Patil, N.; Yamamoto, Y. J. Org. Chem. 2004, 69, 5139e5142; (c)
Yue, D.; Larock, R. Org. Lett. 2004, 6, 1581e1584; (d) Yao, X. Q.; Li, C. J. Org. Lett.
2006, 8, 1953e1955; (e) Ye, S. Q.; Yang, X. D.; Wu, J. Chem. Commun. 2010,
5238e5240; (f) Li, S. Y.; Wu, J. Org. Lett. 2011, 13, 712e715; (g) Handa, S.;
Slaughter, L. M. Angew. Chem., Int. Ed. 2012, 51, 2912e2915; (h) Malhotra, D.;
Liu, L.; Mashuta, M. S.; Hammond, G. B. Chem.dEur. J. 2013, 19, 4043e4050; (i)
Joo, J. H.; Youn, S. W. Adv. Synth. Catal. 2013, 355, 559e568.
4.4.1. (Z)-2-(4-Chlorophenyl)-1-(phenyl(trimethylsilyl)methylene)-3-
(trifluoromethyl)is-oindoline (7a). Yield: 52%; yellow solid, mp
116e117 ꢀC; IR (KBr): 1604, 1586, 1491, 1346, 1262, 1164, 1123, 859,
3. (a) Patel, N. R.; Kirchmeier, R. L. Inorg. Chem. 1992, 31, 2537e2540; (b) Kawai, H.;
Kusuda, A.; Mizuta, S.; Nakamura, S.; Funahashi, Y.; Masuda, H.; Shibata, N. J.
Fluorine Chem. 2009, 130, 762e765; (c) Wu, S. X.; Guo, J. Y.; Sohail, M.; Cao, C. Y.;
Chen, F. X. J. Fluorine Chem. 2013, 148, 19e29; (d) Kim, J.; Shreeve, J. W. Org.
Biomol. Chem. 2004, 2, 2728e2734.
4. (a) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909e1911; (b) Fur-
utachi, H.; Furutachi, H.; Vicic, D. J. Am. Chem. Soc. 2008, 130, 8600e8601; (c)
Morimoto, H.; Tsubogo, H.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed.
2011, 50, 3793e3798; (d) Chu, L.; Qing, F. L. J. Am. Chem. Soc. 2012, 134,
1298e1304.
5. (a) Chu, L.; Qing, F. L. Org. Lett. 2010, 12, 5060e5063; (b) Senecal, T. D.; Parsons,
A. T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174e1176.
6. Prakash, S. G.; Do, C.; Wang, F.; Mathew, T.; Olah, G. A. Synthesis 2010, 11,
1891e1898.
7. Yuan, H.; Gong, Y. F. J. Fluorine Chem. 2013, 149, 125e129.
8. Chai, Z.; Zhao, G. J. Org. Chem. 2008, 73, 2947e2950.
837, 700 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
ꢂ0.15 (s, 9H), 4.76
(q, J¼6.8 Hz,1H), 6.07 (d, J¼7.6 Hz,1H), 6.97e7.01 (m, 2H), 7.19e7.23
(m, 2H), 7.26e7.38 (m, 7H), 7.45e7.49 (m, 1H); 19F NMR (376 MHz,
CDCl3):
d
ꢂ74.4 (d, J¼6.8 Hz, 3F); 13C NMR (100 MHz, CDCl3):
ꢂ1.1,
d
71.8 (q, 2JCeCeF¼31 Hz, C), 122.8,124.0,124.8,125.1 (q, 1JCeF¼280 Hz,
CF3), 126.3,127.9,128.2,128.5,128.7,128.8,128.9,129.0,129.4,134.3,
138.4, 141.9, 149.9, 150.4; MS-EI: m/z (%)¼45, 73, 91, 139, 203, 280,
314, 364, 388, 442, 457 (100); HRMS-EI (m/z) for C25H23ClF3NSi:
457.1240, found: 457.1241.
9. (a) Murai, T.; Nonoyama, T. Tetrahedron 2012, 68, 10489e10495; (b) Pachon, L.
D.; Thathagar, M.; Hartl, F.; Rothenberg, G. Phys. Chem. Chem. Phys. 2006, 8,
151e157; (c) Wang, D. K.; Zhou, Y. G.; Tang, Y.; Hou, X. L.; Dai, L. X. J. Org. Chem.
1999, 64, 4233e4237; (d) Kawai, H.; Tachi, K.; Tokunaga, E.; Shiro, M.; Shibata,
N. Org. Lett. 2010, 12, 5104e5107; (e) Chintareddy, V. R.; Wadhwa, K.; Verkade,
J. G. J. Org. Chem. 2011, 76, 4482e4488.
4.4.2. (Z)-2-(4-Bromophenyl)-1-(phenyl(trimethylsilyl)methylene)-
3-(trifluoromethyl)is-oindoline (7b). Yield: 54%; yellow solid, mp
129e130 ꢀC; IR (KBr): 1609, 1583, 1487, 1464, 1355, 1268, 1160, 1127,
1006, 932, 860, 838, 710, 635 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
10. (a) Matsumoto, K. Angew. Chem., Int. Ed. Engl. 1981, 20, 770e771; (b) Hiroya, K.;
Jouka, R.; Kameda, M.; Sakamoto, T. Tetrahedron 2001, 57, 9697e9710.
11. Murakami, Y.; Watanabe, T.; Suzuki, H.; Kotake, N.; Takahashi, T.; Toyonari, K.;
Ohno, M.; Takase, K.; Suzuki, T.; Kondo, K. Chem. Pharm. Bull. 1997, 45,
1739e1744; (b) Anthony, S. P. J. Am. Chem. Soc. 1995, 117, 5166e5167.
12. Pless, J. J. Org. Chem. 1974, 39, 2644e2646.
d
ꢂ0.15 (s, 9H), 4.76 (q, J¼6.8 Hz, 1H), 6.06 (d, J¼8.0 Hz, 1H),
6.97e7.01 (m, 2H), 7.18e7.27 (m, 4H), 7.32e7.37 (m, 3H), 7.42e7.48
(m, 3H); 19F NMR (376 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d
ꢂ74.4 (d, J¼6.8 Hz, 3F); 13C
2
d
ꢂ1.1, 71.7 (q, JCeCeF¼31 Hz, C), 115.7,
123.0, 123.9, 124.8, 125.1 (q, 1JCeF¼280 Hz, CF3), 126.3, 127.9, 128.5,
128.7, 128.8, 130.3,132.3, 134.2, 138.3, 141.9, 149.7, 150.8; MS-EI: m/z
(%)¼59, 73, 91, 139, 204, 280, 349, 360, 390, 410, 434, 488, 503
13. Cox, D. P.; Terpinski, J.; Lawrynowicz, W. J. Org. Chem. 1984, 49, 3216e3219.
14. (a) Albanese, D.; Landini, D.; Penso, M.; Petricci, S. Synlett 1999, 199e200; (b)
Lee, E.; HookerRitter, J. M.; Ritter, T. J. Am. Chem. Soc. 2012, 134, 17456e17458;
(c) Pitteloud, J. P.; Zhang, Z. T.; Liang, Y.; Cabrera, L.; Wnuk, S. F. J. Org. Chem.
2010, 75, 8199e8212.
(100); HRMS-EI (m/z) for
501.0734.
C25H23BrF3NSi: 501.0735, found:
ꢁ
15. (a) Malkov, A. V.; Westwater, M. M.; Gutnov, A.; Ramírez-Lopeza, P.; Friscourta,
ꢂ
ꢁ
ꢂ
ꢁ
ꢂ
ꢁ
F.; Kadlcíkova, A.; Hodacovac, J.; Rankovic, Z.; Kotora, M.; Kocovsky, P. Tetra-
hedron 2008, 64, 11335e11348; (b) Yu, X.; Wu, J. J. Comb. Chem. 2010, 12,
238e244; (c) Ding, Q. P.; Wu, J. Org. Lett. 2007, 9, 4959e4962; (d) Margrey, K.
A.; Hazzard, A. D.; Scheerer, J. R. Org. Lett. 2014, 16, 904e907.
Acknowledgements
Financial support for this project was provided by National Basic
Research Program of China (973 Program, 2010CB833300), the
National Natural Science Foundation of China (Nos. 21032006,
203900502, 20532040, 21290184).
16. (a) Kuethe, J. T.; Maloney, K. M. Tetrahedron 2013, 69, 5248e5258; (b) Mal, D.;
Pahari, P. Chem. Rev. 2007, 107, 1893e1918; (c) Masusai, C.; Soorukram, D.;
Kuhakarn, C.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M.; Pohmakotr, M. J.
Fluorine Chem. 2013, 154, 37e42.
17. (a) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72,
4462e4468; (b) Levin, V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M.; Tar-
takovsky, V. A. Eur. J. Org. Chem. 2008, 31, 5226e5230; (c) Bernardi, L.; Indrigo,
E.; Pollicino, S.; Ricci, A. Chem. Commun. 2012, 1428e1430; (d) Yin, Y.; Ma, W. Y.;
Supplementary data
ꢁ
Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72, 5731e5736; (e) Santos, F.; Moscardo, J.;
ꢁ
ꢁ
Sanchez-Rosello, M.; Rodríguez, E.; Barrio, P. Org. Lett. 2010, 12, 5494e5497.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.04.072.
18. Pedrosa, R.; Sayalero, S.; Vicente, M. Tetrahedron 2006, 62, 10400e10407.
Please cite this article in press as: Xu, L.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.072