Tetrabutylammonium bromide catalyzed tandem addition/cyclization of o-aralkynylaryl aldehydes with trimethyl(trifluoromethyl)silane: Synthesis of trifluoromethyl group containing phthalans

Article abstract of DOI:10.1055/s-0033-1340076

A tetrabutylammonium bromide catalyzed trifluoromethylation/cyclization reaction of o-aralkynylaryl aldehydes with trimethyl(trifluoromethyl)silane and cesium fluoride has been developed. A variety of 1-alkylidene-3- (trifluoromethyl)phthalans were prepared in moderate to excellent yields by tandem nucleophilic addition and cyclization. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340076

2748▌
LETTER
letter
Tetrabutylammonium Bromide Catalyzed Tandem Addition/Cyclization of
o-Aralkynylaryl Aldehydes with Trimethyl(trifluoromethyl)silane: Synthesis
of Trifluoromethyl Group Containing Phthalans
Trifluoromethyl Group Containing Phthalans
Bo-Lun Hu, Chun-Lin Li, 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: 06.08.2013; Accepted after revision: 01.10.2013
with Ruppert’s reagent, trimethyl(trifluoromethyl)si-
Abstract: A tetrabutylammonium bromide catalyzed trifluoro-
lane (Scheme 1).10
methylation/cyclization reaction of o-aralkynylaryl aldehydes with
trimethyl(trifluoromethyl)silane and cesium fluoride has been de-
CF3
veloped. A variety of 1-alkylidene-3-(trifluoromethyl)phthalans
CsF (2 equiv)
CHO
were prepared in moderate to excellent yields by tandem nucleo-
TBAB (20 mol%)
R
+
TMSCF3
R
O
philic addition and cyclization.
H2O (2 equiv)
toluene, 80 °C
Key words: heterocycles, polycycles, cyclizations, alkylations,
aldehydes, alkynes
Ar
Ar
Scheme 1 Tetrabutylammonium bromide catalyzed tandem trifluo-
romethylation/cyclization reactions of o-aralkynylaryl aldehydes
with trimethyl(trifluoromethyl)silane
The phthalan (1,3-dihydro-2-benzofuran) group is an
important heterocyclic moiety that occurs widely in var-
ious biologically active compounds.1 Moreover, the
phthalan group is a key structural unit in many natural
products, such as pestacin2 and membranolide.3 Conse-
quently, the development of efficient strategies for the
construction of the phthalan scaffold has attracted con-
siderable attention,4 and many reliable and versatile
methods have been developed that involve transition-
metal-catalyzed or base-promoted annulations of o-al-
kynylbenzyl alcohols.5 Most of these protocols suffer
from the need to use metal catalysts or stoichiometric
amounts of base. For example, Wobser and Marks re-
We chose the reaction of 2-(phenylethynyl)benzaldehyde
(1a) with trimethyl(trifluoromethyl)silane and cesium flu-
oride to screen for the optimal conditions for the reaction
(Table 1). Initially, we investigated various metal cata-
lysts including palladium(II) acetate, copper(II) acetate,
copper(II) triflate, and zinc(II) acetate, and we obtained
the desired product 2a in low yields (entries 1–4). Better
results were obtained when phase-transfer catalysts were
used in the tandem reaction (entries 5–8). For example,
treatment of substrate 1a with tetrabutylammonium bro-
mide (10 mol%), trimethyl(trifluoromethyl)silane (3
equiv), and cesium fluoride (2 equiv) in toluene gave the
desired product 2a in 62% yield (entry 6). We were
pleased to find that the yield of 2a increased to 88% when
20 mol% of tetrabutylammonium bromide was used (en-
try 8). In the absence of catalyst, no cyclization product
was obtained, and the nucleophilic addition product was
obtained instead (entry 9). Subsequently, other sources of
fluoride ion were tested for the generation of trifluoro-
methyl anion. A 73% yield was obtained by using potas-
sium fluoride as the base (entry 10), but
tetrabutylammonium fluoride gave no product (entry 11).
Finally, several solvents (tetrahydrofuran, acetonitrile,
and N,N-dimethylformamide) were examined, but all
were less effective than toluene. It is noteworthy that two
equivalents of water played a key role in the tandem reac-
tions and that the required product could not be obtained
in the absence of water.11 Presumably water enhances the
nucleophilicity of the alkoxide ion and provides the pro-
tons required to form the cyclization product.7
ported
a
thorium-catalyzed
hydroalkoxy-
lation/cyclization of alkynyl alcohols to give
methylene-1,3-dihydro-2-benzofurans.6 Abbiati and co-
workers developed a base-promoted synthesis of
dihydro-2-benzo-furans by domino addition/annulation
reactions of o-alkynylbenzaldehydes with alcohols.7
However, to the best of our knowledge, the synthesis of
trifluoromethylated phthalans has not been explored,
although the incorporation of a trifluoromethyl groups
into aromatic compounds often enhances their biologi-
cal activity, and this has become a powerful and widely
employed tactic in the process of drug design.8 As a part
of our ongoing studies on syntheses of trifluoromethyl-
ated aromatic compounds,9 we wished to prepare triflu-
oromethyl group containing phthalans from cheap and
commercially available trifluoromethylated reagents.
Here, we report a simple and efficient protocol for the
synthesis of 3-trifluoromethylated phthalans by tetrabu-
tylammonium bromide catalyzed tandem nucleophilic
addition and cyclization of o-aralkynylaryl aldehydes
Having identified the optimal reaction conditions,12
we explored the substrate scope with respect to the
o-alkynylaryl aldehyde (Scheme 2).
SYNLETT 2013, 24, 2748–2750
Advanced online publication: 08.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340076; Art ID: ST-2013-W0758-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Trifluoromethyl Group Containing Phthalans
2749
CF3
Table 1 Optimization of the Reaction Conditions
CsF (2 equiv)
CHO
TBAB (20 mol%)
CF3
O
R1
R1
+
TMSCF3
O
CHO
catalyst
H2O (2 equiv)
toluene, 80 °C
TMSCF3
+
R2
R2
base
2b–p
CF3
O
1b–p
Ph
Ph
1a
2a
CF3
CF3
O
Entrya
Base
Catalyst (mol%)
Solvent
Yieldb (%)
O
Me
Me
1
2
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
KF
Pd(OAc)2 (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
Zn(OAc)2 (10)
TBAF (10)
TBAB (10)
Bu4NOAc (10)
TBAB (20)
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
18
31
38
26
54
62
46
88
0
Me
2b, 71%
2c, 82%
2d, 77%
CF3
3
CF3
CF3
4
O
O
O
5
6
Br
Cl
OMe
2e, 72%
2f, 68%
2g, 78%
7
CF3
CF3
CF3
8
MeO
O
O
O
9
S
10
11
12
13
14
15c
TBAB (20)
TBAB (20)
TBAB (20)
TBAB (20)
TBAB (20)
TBAB (20)
73
0
CN
TBAF
CsF
CsF
CsF
CsF
2h, 53%
2i, 83%
2j, 61%
CF3
CF3
MeO
CF3
5
MeO
O
O
MeCN
DMF
20
10
0
O
O
O
Me
2l, 60%
CF3
Cl
S
toluene
2k, 55%
2m, 65%
a Reaction conditions: 1a (0.3 mmol), TMSCF3 (3 equiv), base (2
equiv), catalyst, 0 °C, 1 h, then H2O (2 equiv), stirring, 80 °C, 6 h.
b Isolated yield.
CF3
CF3
F3C
Cl
O
c In the absence of H2O.
O
O
Cl
Initially, we examined the effects of substituents on the
aryl group of the aralkyne moiety. Both electron-rich and
electron-deficient aryl groups were tolerated and the cor-
responding products were obtained in moderate to good
yields (2b–h). Aldehydes containing p-, m-, and o-tolyl
groups gave the corresponding products 2b–d in yields of
71, 82, and 77%, respectively. The 4-methoxylphenyl
2n, 62%
2o, 71%
2p, 93%
Scheme 2 Trifluoromethylation/cyclization of o-aralkynylaryl alde-
hydes with trimethyl(trifluoromethyl)silane. Reagents and condi-
tions: 1b–p (0.3 mmol), TMSCF3 (0.9 mmol), CsF (0.6 mmol),
TBAB (0.06 mmol), toluene, 0 °C, 1 h, then H2O (2 equiv), stirring,
80 °C, 6 h.
product 2e was obtained in 72% yield. Similar results
were obtained for the 4-chlorophenyl and 4-bromophenyl
products 2f and 2g, respectively. The configuration of
product 2f was unambiguously confirmed by single-crys-
tal X-ray diffraction analysis (Figure 1).13
The electron-deficient 4-cyanophenyl-substituted alde-
hyde gave the corresponding product 2h in 53% yield. In-
terestingly, the 2-thienyl group was also compatible with
the reaction, and the corresponding product 2i was ob-
tained in 83% yield. However, with alkanols, the cycliza-
tion reaction failed although the nucleophilic addition
proceeded smoothly.
Figure 1 Structure of product 2f
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2748–2750

2750
B.-L. Hu et al.
LETTER
W.; Tooru, F.; Takeshi, T. J. Am. Chem. Soc. 1997, 119,
We also investigated the effects of ring substituents on the
aryl aldehyde moiety. Methoxy-substituted o-aralkynyl-
benzaldehydes gave the corresponding product 2j–m in
55–65% yield. 5-Chloro-2-(phenylethynyl)benzaldehyde
gave the corresponding product 2n in 62% yield. Electron-
1127.
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deficient
5-(trifluoromethyl)-2-(phenylethynyl)benz-
aldehyde gave product 2o in 71% yield. To our surprise, the
reaction of 2-(phenylethynyl)thiophene-3-carbaldehyde
also proceeded successfully to give the thienofuran product
2p in 93% yield.
In summary, we have developed a tetrabutylammonium
bromide catalyzed tandem trifluoromethylation/cycliza-
tion reaction. In the presence of tetrabutylammonium bro-
mide and cesium fluoride, a variety of o-aralkynylaryl
aldehydes underwent tandem nucleophilic addition and 5-
exo-dig heterocyclization with trimethyl(trifluorometh-
yl)silane to give the corresponding (Z)-1-alkylidene-3-
(trifluoromethyl)phthalans in moderate to excellent
yields. This regio- and stereospecific reaction shows good
functional-group tolerance. The one-pot procedure and
the use of an inexpensive catalyst and trifluoromethyl
source are significant advantages of this reaction. The
process might facilitate the synthetic applications of tri-
fluoromethyl-containing building blocks and provides a
new option for constructing the 1,3-dihydro-2-benzofuran
ring system.
(6) Wobser, S.; Marks, T. Organometallics 2013, 32, 2517.
(7) Dell’Acqua, M.; Facoetti, D.; Abbiati, G.; Rossi, E.
Synthesis 2010, 2367.
(8) (a) Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005,
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(d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(9) (a) Chen, M.-W.; Zhang, X.-G.; Zhong, P.; Hu, M.-L.
Synthesis 2009, 1431. (b) Dong, S.-X.; Zhang, X.-G.; Liu,
Q.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Synthesis 2010, 1521.
(c) Li, C.-L.; Zhang, X.-G.; Tang, R.-Y.; Zhong, P.; Li, J.-H.
J. Org. Chem. 2010, 75, 7037. (d) Sun, L.-L.; Liao, Z.-Y.;
Tang, R.-Y.; Deng, C.-L.; Zhang, X.-G. J. Org. Chem. 2012,
77, 2850. (e) Shi, S.; Sun, L.-L.; Liao, Z.-Y.; Zhang, X.-G.
Synthesis 2012, 966. (f) Wang, W.-Y.; Feng, X.; Hu, B.-L.;
Deng, C.-L.; Zhang, X.-G. J. Org. Chem. 2013, 78, 6025.
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Acknowledgments
We thank the National Natural Science Foundation of China (No.
21002070, 21272177 and 21276200) for financial support.
(11) Yao, X.-Q.; Li, C.-J. Org. Lett. 2006, 8, 1953.
(12) 1-Alkylidine-3-(trifluoromethyl)-1,3-dihydro-2-
benzofurans 2; General Procedure
A flame-dried Schlenk tube equipped with a magnetic
stirring bar was charged with o-aralkynylaryl aldehyde 1
(0.3 mmol), TMSCF3 (0.9 mmol), CsF (0.6 mmol), TBAB
(0.06 mmol), and anhyd toluene (2 mL), and the mixture was
stirred at 0 °C for 1 h. H2O (2 equiv) was added and the
mixture was stirred at 80 °C for 6 h. The mixture was then
poured into EtOAc and extracted with EtOAc (3 × 10 mL).
The organic layers were combined, dried (Na2SO4), and
concentrated under vacuum. The residue was purified by
flash column chromatography (hexane–EtOAc).
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Synlett 2013, 24, 2748–2750
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