Highly efficient synthesis of 4-trifluoromethylfuran derivatives via a sequential deprotection-annulation reaction

Article abstract of DOI:10.1016/j.tetlet.2006.04.110

(E)-O-protected-2-trifluoromethyl-1-bromo-1-substituted allylic alcohol reacted with terminal alkynes under Sonogashira reaction condition to give the corresponding (E)-2-en-4-ynoic alcohol derivatives, which was further converted to the corresponding 4-t

Full text of DOI:10.1016/j.tetlet.2006.04.110

Tetrahedron Letters 47 (2006) 4737–4739
Highly efficient synthesis of 4-trifluoromethylfuran derivatives
via a sequential deprotection-annulation reaction
Jiming Zhang, Xiaoming Zhao, Youhua Li and Long Lu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, PR China
Received 15 March 2006; revised 20 April 2006; accepted 21 April 2006
Available online 19 May 2006
Abstract—(E)-O-protected-2-trifluoromethyl-1-bromo-1-substituted allylic alcohol reacted with terminal alkynes under Sonogashira
reaction condition to give the corresponding (E)-2-en-4-ynoic alcohol derivatives, which was further converted to the corresponding
4-trifluoromethylfuran derivatives via a sequential deprotection-annulation reaction in moderate to excellent yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Table 1. Preparation of (E)-O-protected-2-trifluoromethyl-1-bromo-1-
substituted allylic alcohol 2a–c
Polysubstituted furans play an important role in organic
chemistry because of their presence as a structural unit
in many biologically active and naturally occurring com-
F3C
TBSO
R
n-BuLi, -78oC
F3C
TBSO
Br
Br
F3C
Li
pounds.1 There has been considerable interest in
organofluorine compounds as pharmaceutical and agro-
chemical agents as well.2 The introduction of fluorine
atoms may alter the physiochemical and biological
properties of organic compounds.3,4 Although many
fluorinated furans have been reported,5,6 it is still desir-
able to develop an efficient method for the synthesis of
trifluoromethylated furans. Recently, a stereoselective
lithium–bromine exchange reaction of O-protected-
2-trifluoromethyl-1,1-dibromoallylic alcohols has been
developed in our laboratory.7 Based on this work, we
would like to report a synthetic approach towards the
RX
Br
2a-c
THF
TBSO
Br
1
RX
2 (Yield, %)a
a
b
c
MeOH
MeI
BnBr
70
79
58
a Isolated yield after chromatography.
Compounds 2a–c reacted with a series of terminal alky-
nes under Sonogashira reaction condition to give the
corresponding coupling products 3 in 47–97% yields
(Table 2). The TBS group was removed with TBAF at
0 ꢁC, followed by cyclization and aromatization, to give
the corresponding 2,3-disubstituted-4-trifluoromethyl-
furans 6 in 42–94% yields (Table 2). However, in the
case of R being n-pentyl, no furan derivative was
obtained (entries 6 and 12) (Scheme 1).
polysubstituted 4-trifluoromethylfurans through
sequential deprotection-annulation reaction.
a
O-Protected-2-trifluoromethyl-1,1-dibromoallylic alcohol
1 stereoselectively underwent a lithium–bromine ex-
change reaction in THF, followed by quenching with
methanol, methyl iodide or benzyl bromide, to give the
corresponding
(E)-O-protected-2-trifluoromethyl-1-
bromo-1-substituted allylic alcohol (2a, 2b and 2c) in
58–79% yields (Table 1). The structures of 2a–c were
The structure of 2,3-disubstituted-4-trifluoromethyl-
1
13
established by their H, 19F and C NMR spectra.7
furans was characterized with H, 13C and 19F NMR
1
spectra.8,9 For example, the 1H NMR and 1H 13C COSY
spectra of compound 6aa showed two singlets at 6.17
(1H) and 7.65 (1H) ppm which were assigned to 3-H
and 5-H of the furan ring. Two signals at 103.8 and
141.0 (q, J = 6.0 Hz) ppm in 13C NMR were assigned
to 3-C and 5-C of the furan ring, which was also in
Keywords: Trifluoromethyl; Lithium-bromide exchange reaction;
Furan.
*
Corresponding author. E-mail: lulong@mail.sioc.ac.cn
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.110

4738
J. Zhang et al. / Tetrahedron Letters 47 (2006) 4737–4739
Table 2. Palladium-catalyzed reaction of 2 with terminal alkynes, followed by the treatment with TBAF
Entry
2
R
R0
3 (Yield, %)a
6 (Yield, %)a
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2c
2c
2c
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Ph
3aa, 90
3ab, 93
3ac, 80
3ad, 87
3ae, 91
3af, 97
3ba, 96
3bb, 95
3bc, 87
3bd, 96
3be, 85
3bf, 89
3ca, 59
3cb, 47
3cc, 55
6aa, 87
6ab, 94
6ac, 83
6ad, 82
6ae, 46
—
6ba, 86
6bb, 86
6bc, 50
6bd, 85
6be, 42
—
4-MeO–Ph
4-MeOOC–Ph
4-Me–Ph
CH2OBn
n-Pentyl
Ph
4-MeO–Ph
4-MeOOC–Ph
4-Me–Ph
CH2OBn
n-Pentyl
9
10
11
12
13
14
15
Ph
6ca, 73
6cb, 76
6cc, 67
4-MeO–Ph
4-MeOOC–Ph
a Isolated yield.
F3C
R
F3C
R
F3C
TBSO
R
TBAF
THF
R'
R'
TBSO
Pd(PPh3)2Cl2
CuI, Et2NH
Br
O
3
6
2a-c
R'
Scheme 1.
Figure 1. The ORTEP view of 6bc and 6cb with all H atoms omitted for clarity.
agreement with the literature.10 The single crystal X-ray
diffraction study of 6bc and 6cb further proved the ste-
reochemistry of the furans (Fig. 1).11
mode. Consequently, intermediate 5 was aromatized to
the final products 6 in situ. The formation of dihydro-
furan 5 (R = H, R0 = CH2OBn, Scheme 2) was moni-
tored by 1H NMR, in which there was a singlet at
6.57 ppm characteristic for the double bond on the five
member ring, a singlet at 5.08 ppm for the CH2 group
of the ring, and a triplet at 4.88 ppm (J = 6.9 Hz) for
another proton on the exocyclic double bond. Unfortu-
nately, it was difficult to isolate the pure dihydrofurans
A possible mechanism for the formation of 2,3-disubsti-
tuted-4-trifluoromethylfurans was proposed in Scheme
2,12 which involved the deprotection of TBS group of
3 with TBAF, followed by a ring-forming through intra-
molecular nucleophilic attack to alkyne in 5-Exo-Dig
F3C
R
F3C
TBSO
R
F3C
H
R
F3C
R
TBAF
THF
R'
R'
OH
4
O
O
3
6
5
R'
R'
Scheme 2.

J. Zhang et al. / Tetrahedron Letters 47 (2006) 4737–4739
4739
6. (a) Kawada, K.; Kitagawa, O.; Mandal, B. K.; Filler, R.;
Beery, J. W. J. Fluorine Chem. 1997, 81, 123–128; (b)
Burger, K.; Helmreich, B. J. Chem. Soc., Chem. Commun.
1992, 348–349; (c) Bambury, R. E.; Yaktin, H. K.;
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5, which were labile to cyclization during the course of
the workup.13
In summary, we have developed an efficient method for
the preparation of CF3-containing polysubstituted fur-
ans, which is potentially useful for further conversion
to the trifluoromethylated analogues of natural and bio-
logically active compounds.
7. Li, Y.; Lu, L.; Zhao, X. Org. Lett. 2004, 6, 4467–4470.
8. Typical experimental procedure for 6aa–cc: To a stirred
solution of 3ba (284 mg, 0.8 mmol) in THF (4 mL),
1.6 mL of TBAF (1 M solution in THF, containing ca.
5% water) was added dropwise at 0 ꢁC under an argon
atmosphere. The reaction was completed (TLC) in 20 min
and then 5 mL of water was added. The reaction mixture
was extracted with Et2O (3 · 10 mL), washed with water
(2 · 10 mL) and then brine (20 mL), successively. The
organic phases were dried over Na2SO4 and concentrated
under vacuum. The crude product was purified by
chromatography on silica gel (PE) to afford 6ba (165 mg)
Acknowledgements
We thank the National Natural Science Foundation of
China (Grant Number 29825104 and 29632003) for the
financial support.
1
References and notes
in 86% yield: H NMR (300 MHz, CDCl3) d 7.53 (s, 1H),
7.30–7.14 (m, 5H), 3.89 (s, 2H), 2.05 (s, 3H); 19F NMR
(282 MHz, CDCl3) d ꢀ59.7; 13C NMR (75 MHz, CDCl3)
d 152.1, 140.7 (q, J = 7.2 Hz), 137.7, 128.7, 128.4, 126.7,
123.1 (q, J = 265.6 Hz), 118.9 (q, J = 34.3 Hz), 112.9,
32.1, 7.9; IR (film) 3033, 1576, 1345, 1169, 1130, 1030,
725 cmꢀ1; MS (EI) m/z 240 (M+, 100), 239 (31), 225 (69),
177 (20), 163 (22), 143 (17); HRMS calcd for C13H11F3O:
240.0759, found: 240.0751.
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