Copper(I)-catalyzed trifluoromethylation of phthalic anhydride derivatives with (trifluoromethyl)trimethylsilane

Article abstract of DOI:10.1002/cjoc.201300357

An efficient copper-catalyzed trifluoromethylation of substituted phthalic anhydrides using (trifluoromethyl) trimethylsilane (Me₃SiCF ₃) as a nucleophilic trifluoromethylating reagent in the presence of 1,10-phenanthroline and KF, followed by quenching the reaction mixture with water has been developed. A possible mechanism was suggested. An efficient copper-mediated trifluoromethylation of substituted phthalic anhydrides using (trifluoromethyl)trimethylsilane (Me₃SiCF₃) as a nucleophilic trifluoromethylating reagent in the presence of 1,10-phenanthroline and KF, followed by quenching the reaction mixture with water has been developed. A possible mechanism was suggested. Copyright

Full text of DOI:10.1002/cjoc.201300357

FULL PAPER
DOI: 10.1002/cjoc. 201300357
Copper(I)-Catalyzed Trifluoromethylation of Phthalic Anhydride
Derivatives with (Trifluoromethyl)trimethylsilane
Mingxi Wu,a Mingjin Wang,a and Song Cao*,a,b
a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science
and Technology, Shanghai 200237, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
An efficient copper-catalyzed trifluoromethylation of substituted phthalic anhydrides using (trifluoromethyl)
trimethylsilane (Me3SiCF3) as a nucleophilic trifluoromethylating reagent in the presence of 1,10-phenanthroline
and KF, followed by quenching the reaction mixture with water has been developed. A possible mechanism was
suggested.
Keywords trifluoromethylation, copper(I)-catalyzed, phthalic anhydrides, (trifluoromethyl)trimethylsilane
Introduction
phthalic anhydride derivatives remain very scarce. It
might be due to the low reactivity of carbonyl group in
phthalic anhydride toward TMSCF3 compared to their
aldehydes and ketones analogues.
The introduction of trifluoromethyl (CF3) group into
biologically active compounds has attracted much atten-
tion due to its specific properties, such as polarity,
thermal and metabolic stability as well as the high lipo-
philicity.[1] Therefore, trifluoromethyl-containing com-
pounds are increasingly being applied in the pharma-
ceutical, agrochemical fields and materials industries.[2]
To date, numerous methods and many useful trifluoro-
methylating reagents have been developed for the
trifluoromethylation of structurally diverse organic mol-
ecules.[3] The incorporation of the trifluoromethyl group
in carbonyl compounds has been reported in the litera-
ture for many years.[4] Among the various trifluoro-
methylating reagents, (trifluoromethyl)trimethylsilane
(TMSCF3) can be considered as the most popular re-
agent for introducing a trifluoromethyl group to car-
bonyl compounds, including aldehydes, ketones, esters,
amides, etc.[5]
Generally, trifluoromethylation of carbonyl com-
pounds especially aldehydes and ketones can proceed
smoothly with TMSCF3 under the initiation by fluoride
sources such as tetrabutylammonium fluoride (TBAF),
tetrabutylammonium triphenyldifluorosilicate (TBAT),
CsF and KF in absence of metal catalyst.[6] However, a
survey of the literature indicated that most of the re-
search to date has been focused on trifluoromethylation
of aldehydes and ketones.[4a] Only a limited number of
methods are available for trifluoromethylation of the
esters and amides.[7] Surprisingly, examples of trifluoro-
methylation of carboxylic acid anhydride especially
The first example of trifluoromethylation of acid
anhydride is reported by Wakselman et al. in 1988.[8]
They used trifluoromethyl bromide as trifluoromethy-
lating reagent to react with acid anhydride such as suc-
cinic anhydride or phthalic anhydride in the presence of
Zn powder under CF3Br atmosphere (3－4 atm). In
2005, Yagupolskii developed a convenient method for
the synthesis of bis-trifluoromethylated 2-organyl-pro-
pan-2-ols by treatment of acid anhydride with TMSCF3
in the presence of TBAF at −50－0 ℃, followed by
acidification of the corresponding trimethylsilyl ethers.[9]
Cai described the trifluoromethylation of phthalic anhy-
dride (only one example) with sodium trifluoroacetate
using CuI as catalyst.[10] More recently, Pohmakotr re-
ported the nucleophilic addition of PhSCF2SiMe3 to
various anhydrides in the presence of 10 mol% TBAT
for the preparation of corresponding γ-difluoro(phenyl-
sulfanyl) methyl-γ-lactols at −10－0 ℃.[11]
In this paper, we reported a novel Cu-catalyzed
trifluoromethylation of substituted phthalic anhydrides
with Me3SiCF3 in the presence of 1,10-phenanthroline
(phen) and KF (Scheme 1).
Results and Discussion
In 2001, Viner synthesized a trifluoromethylated
lactone by the reaction of succinic anhydride with
Ruppert-Prakash’s reagent choosing TBAF as fluoride
*
E-mail: scao@ecust.edu.cn; Tel.: 0086-21-64253452; Fax: 0086-21-64252603
Received April 26, 2013; accepted June 7, 2013; published online XXXX, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300357 or from the author.
Chin. J. Chem. 2013, XX, 1—5
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Wu, Wang & Cao
FULL PAPER
Scheme 1 Trifluoromethylation of phthalic anhydride deriva-
Table 1 Reaction of phthalic anhydride with TMSCF3 in the
tives with Me3SiCF3
presence of various catalysts, ligands and solvents
KF
Liganda
Solventb Yieldc/%
10 mol% CuI
10 mol% phen
2 equiv. KF
THF, 50 oC, Ar
Entry
Catalyst
CF3
OH
O
(equiv.)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
－
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Cu
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
－
THF
THF
THF
THF
THF
THF
Toluene
Pyridine
CH3CN
DMSO
DMF
NMP
THF
THF
THF
THF
THF
61
22
54
42
55
93
0
20
30
80
82
83
0
TMSCF3
+
O
R
R
O
Cu(AcO)2
CuSO4
CuCl
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
O
O
1a 1h
－
2a 2h
－
ion source at 60 ℃. However, the yield of trifluoro-
methylated product was very low (30%, GC).[12] In this
paper, we firstly carried out the trifluoromethylation
reaction of phthalic anhydride with TMSCF3 in presence
of TBAF according to above-mentioned method. Un-
fortunately, no reaction was observed. Therefore, the
search for an efficient method for trifluoromethylation
of phthalic anhydride derivatives is necessary.
Initially, phthalic anhydride 1a and TMSCF3 were
chosen as model substrates to investigate the reaction
conditions (Scheme 2) and the results are summarized in
Table 1. It was found that the kind of copper catalyst
had an obvious influence on the trifluoromethylation of
carbonyl group in acid anhydride (Table 1, Entries 1－
6). Among the Cu catalysts, CuI exhibited high activity
for the trifluoromethylation reaction (Table 1, Entry 6).
Generally, polar aprotic solvents such as DMF, DMSO
and NMP were used as solvent for these transition-
metal-based protocols for the trifluoromethylation of
aryl halides, terminal alkynes and aryl boronic acids. In
our case, when NMP, DMF, DMSO and toluene etc.
were used as solvent, the yields were unsatisfactory
(Table 1, Entries 7－12). The best results were obtained
when the reaction was conducted in THF. Furthermore,
different ligands were examined (Table 1, Entries 14－
17), and phen was more appropriate for this coversion.
TMEDA
bipy
54
56
75
78
0
PPh3
PCy3
phen
phen
phen
phen
phen
phen
THF
THF
THF
THF
THF
THF
CuI
CuI
CuI
CuI
0.5
1.2
1.5
2.0
2.0
5
56
75
0
—
0
a
Bipy: 2,2-dipyridyl; TMEDA: N,N,N',N'-tetramethyl-ethane-
1,2-diamine; PCy3: tricyclohexylphosphine; PPh3: triphenyl-
phosphine. b All solvents were dried. c Yields were based on GC
analysis.
(Table 2). Among the different substituted phthalic an-
hydrides tested, most of them could react with TMSCF3
efficiently to give the 3-trifluoromethylated compounds
in good to high yields. Symmetrically substituted
phthalic anhydrides and 1,8-naphthalic anhydride could
afford expected isobenzofuran-1(3H)-one as sole prod-
ucts (2a－2d) and no regioisomers were observed.
In the case of unsymmetrically substituted phthalic
anhydrides, a mixture of two isomers was obtained (2e
and 2e', 2f and 2f', 2g and 2g', 2h and 2h'). Attempts to
isolate the pure isomers of 2f and 2f', 2g and 2g', 2h and
2h' failed due to their very similar chromatographic
properties. Much to our delight, we successfully isolated
the pure isomers of 2e and 2e' in 32% and 48% isolated
yields, respectively. Because the chemical structures of
compound 2e and 2e' are very similar, they can not be
identified by 1H NMR and 13C NMR spectra.
Scheme 2 Model reaction for the Cu-catalyzed trifluoromethy-
lation of 1a with TMSCF3
10 mol% copper catalyst
10 mol% ligand
2 equiv. KF
THF, 50 oC, Ar
CF3
OH
O
O
TMSCF3
+
O
O
2a
O
1a
The amount of KF played a vital role in promoting
the reaction (Table 1, Entries 19－21). A decrease in the
amount of KF to less than 2 equivalents led to lower
transformation. With the use of potassium fluoride di-
hydrate (commercial product), no trifluoromethylated
product was observed (Table 1, Entry 22). In addition,
in the absence of ligand, KF or CuI, the reaction could
not proceed (Table 1, Entries 13, 18 and 23).
With the optimized reaction conditions in hand (Ta-
ble 1, Entry 6), several symmetrically and unsymmetri-
cally substituted phthalic anhydrides were explored to
determine the limitations of this novel copper-catalyzed
trifluoromethylation of substituted phthalic anhydrides
In order to characterize the exact structure of 2e and
1
2e', the H and 13C connectivities in 2e and 2e' were
verified by the HMBC (Heteronuclear Multiple Bond
Correlation) spectrum. On the basis of the HMBC spec-
tral data of compound 2e (Figure 1), the carbonyl car-
bon C-1 (δC 165.4) correlated with two aromatic protons
H-7 (δH 7.55) and H-8 (δH 8.02). The spectrum of the
isomer 2e' (Figure 2) showed a strong correlation be-
tween the carbonyl carbon C-1 (δC 165.4) and H-7 (δH
2
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Chin. J. Chem. 2013, XX, 1—5

Copper(I)-Catalyzed Trifluoromethylation of Phthalic Anhydride Derivatives
Table 2 Trifluoromethylation of phthalic and naphthalic anhy-
Scheme 3 Reduction of 2a to 3a
dride derivativesa
O
CF3
OH
CF3
HO
Cl
Br
CF3
OH
CF3
OH
CF3
OH
NaOH (aq)
X
CF3
ONa
OH
Cl
Cl
Br
Br
O
or
ONa
O
O
O
O
O
O
O
O
O
4a'
4a
2a
Cl
Br
H CF3
OH
2a, 85%
CF3
2b, 82%
2c, 79%
I
I
CF3
OH
LiAlH4
rt
O
OH
CH2OH
O
O
O
O
3a
OH
F3C
2e', 48%
CF3
O
2d, 75%
2e, 32%
O
Cl
Cl
CF3
OH
O
O
Cl
2
CF3
Cl
OH
O
I
O
5
6
O
4
9
OH
OH
3 O
C
OH
F3C
7
1
7
O
F3C
O
H
8
2g and 2g', 90%b,d
8H
2f and 2f', 84%b,c
O
CF3
OH
O
O
O
2e
Br
Br
OH
F3C
O
2h and 2h', 85%b,e
b
a Isolated yield. Combined yields of the mixture of isomers.
c
The ratio of two isomers (2f∶2f') is 1∶3, which was deter-
mined by 19F NMR and the same below. The ratio of two iso-
mers is close to 1∶1. e The ratio of two isomers is close to 1.6∶1.
d
Figure 1 Part of HMBC spectrum of 2e.
8.29). Furthermore, the aromatic proton H-6 had a weak
cross-peak with the carbonyl carbon C-1. However, due
to the steric effect of trifluoromethyl and hydroxyl
group, none cross peak was observed between the car-
bonyl carbon C-1 and the aromatic proton H-5. The
structure of 2e and 2e' further confirmed by single-
crystal X-ray diffraction analysis is under progress in
our laboratory.
2
CF3
5H
5
6H
OH
6
4
9
3 O
1
7
7
H
C
8
O
I
2e'
In addition, attempt to hydrolyze 2a with NaOH so-
lution was unsuccessful and no 4a or 4a' was observed.
Fortunately, trifluoromethylated lactone 2a could be
easily reduced to useful functionalized trifluoro-
methyl-containing building block 3a with LiAlH4
(Scheme 3).
Traditionally, trifluoromethylation of aldehyde or
ketone with TMSCF3 in the presence of fluoride sources
led to the formation of the corresponding trifluoro-
methylated silyl ethers. Hydrolysis of the silyl ethers
with aqueous HCl for several hours furnished the cor-
responding alcohol.[5a] In our case, the reaction of
phthalic anhydrides with Me3SiCF3 was performed in
CuI-phen-KF catalytic system, the trifluoromethylated
alcohols were obtained by hydrolysis of the reaction
mixture just with water. Furthermore, no trifluoro-
methylated siloxy adduct was observed. Therefore, the
mechanism is different from that depicted for aldehyde
or ketone.
Figure 2 Part of HMBC spectrum of 2e'.
A possible mechanism for the trifluoromethylation
of phthalic anhydrides with Me3SiCF3 was outlined in
Scheme 4. Initially, phen-ligated copper iodide I and
active intermediate [(Phen)CuCF3] II were produced
sequentially which is analogous to those proposed in the
literature.[13] Next, the intermediate II underwent nu-
cleophilic addition to the carbonyl group to afford
alkoxide intermediate III. The cleavage of Cu－O bond
resulted in the formation of product IV and simultane-
ous regeneration of the catalytic species I.[14]
Chin. J. Chem. 2013, XX, 1—5
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3

Wu, Wang & Cao
FULL PAPER
Scheme 4 A plausible mechanism for trifluoromethylation of
phthalic anhydride derivatives
troleum ether/ethyl acetate＝3∶1) to afford target
compounds 2a－2h. However, three pairs of isomer
mixtures (2f and 2f', 2g and 2g', 2h and 2h') could not
be separated.
3-Hydroxy-3-trifluoromethyl-2-benzofuran-1(3H)-
one (2a) White solid, m.p. 112.7 ℃; 1H NMR δ: 9.81
(s, 1H, OH), 8.03－7.94 (m, 2H, ArH), 7.87－7.83 (m,
2H, ArH); 19F NMR δ: −82.09 (s, 3F, CF3); 13C NMR δ:
166.9, 142.8, 136.3, 133.0, 126.7, 126.0, 124.6, 122.2 (q,
1JCF＝284.8 Hz), 101.0 (q, 2JCF＝34.9 Hz); HRMS (ESI)
calcd for C9H4F3O3 ([M−H] −) 217.0113, found
217.0108.
F3C
-
F3C
O
OH
+
Phen
CuI
Cu
H2O
O
O
R
R
IV
O
O
KF
CF3TMS
+
V
N
I
N
I
N
Cu CF3
II
4,5,6,7-Tetrachloro-3-hydroxy-3-trifluoromethyl-
N
-
I
2-benzofuran-1(3H)-one (2b)
White solid, m.p.
1
182.5 ℃; H NMR δ: 10.34 (s, 1H, OH); 19F NMR δ:
F3C
N
−79.12 (s, 3F, CF3); 13C NMR δ: 161.2, 140.6, 140.0,
O
O
1
Cu
O
137.8, 130.9, 129.3, 124.9, 121.5 (q, JCF＝286.8 Hz),
N
O
O
100.3 (q, 2JCF ＝ 36.2 Hz); HRMS (ESI) calcd for
C9Cl4F3O3 ([M−H] −) 352.8554, found 352.8533.
4,5,6,7-Tetrabromo-3-hydroxy-3-trifluoromethyl-
2-benzofuran-1(3H)-one (2c) White solid, m.p. 202.0
R
O
R
III
Conclusions
1
℃; H NMR δ: 6.82 (q, JHF＝5.2 Hz, 1H, OH); 19F
NMR δ: −72.56 (d, JHF＝5.2 Hz, 3F, CF3); 13C NMR δ:
In summary, we reported a novel copper-catalyzed
trifluoromethylation of substituted phthalic anhydrides
with (trifluoromethyl)trimethylsilane (Me3SiCF3) in the
presence of 1,10-phenanthroline and KF. Symmetrically
substituted phthalic anhydrides and 1,8-naphthalic an-
hydride could afford the expected 3-trifluoromethylated
compounds as sole products in good to high yields.
163.6, 139.9, 139.8, 136.7, 131.4, 128.4, 124.9, 122.6 (q,
2
1JCF＝282.8 Hz), 74.7 (q, JCF＝34.5 Hz); HRMS (ESI)
calcd for C9Br4F3O3 ([M−H] −) 528.6533, found
528.6563.
3-Hydroxy-3-trifluoromethyl-1H,3H-benzo[de]iso-
1
chromen-1-one (2d) White solid, m.p. 160.1 ℃; H
NMR δ: 8.48－8.46 (m, 1H, ArH), 8.37－8.35 (m, 1H,
ArH), 8.24－8.22 (m, 1H, ArH), 8.05－8.03 (m, 1H,
ArH), 7.83－7.78 (m, 2H, ArH), 6.87 (s, 1H, OH); 19F
NMR δ: −85.93 (s, 3F, CF3); 13C NMR δ: 161.0, 134.7,
131.8, 130.8, 130.5, 127.7, 126.9, 126.8, 123.7, 122.3 (q,
1JCF＝287.9 Hz), 118.3, 98.9 (q, 2JCF＝33.8 Hz); HRMS
(ESI) calcd for C13H6F3O3 ([M−H] −) 267.0269, found
267.0251.
Experimental
1H NMR, 13C NMR and HMBC spectra were re-
corded on a Bruker AM-400 spectrometer (400 MHz for
1H NMR and 100 MHz for 13C NMR, respectively) us-
ing TMS as the internal standard. DMSO-d6 was used as
the NMR solvent in all cases except compound 2d
(acetonitrile-d3). The 19F NMR spectra were recorded on
a Bruker AM-400 spectrometer (376 MHz) using
CF3CO2H as external standard. Melting points were
measured in an open capillary with a Büchi melting
point B-540 apparatus. GC-MS were recorded on HP
5973 MSD with 6890 GC. High resolution mass spectra
(ESI or EI) were recorded with a MicroMass LCTTM
spectrometer.
3-Hydroxy-4-iodo-3-trifluoromethyl-2-benzofuran-
1(3H)-one (2e) and 3-hydroxy-7-iodo-3-trifluorometh-
yl-2-benzofuran-1(3H)-one (2e') 2e: White solid,
1
m.p. 163.3 ℃; H NMR δ: 10.05 (s, 1H, OH), 8.39－
8.38 (m, 1H, ArH), 8.02－8.00 (m, 1H, ArH), 7.56－
7.52 (m, 1H, ArH); 19F NMR δ: −77.93 (s, 3F, CF3); 13
C
NMR δ: 165.4, 147.5, 144.4, 134.2, 129.3, 125.8, 122.2
(q, 1JCF＝287.1 Hz), 102.6 (q, 2JCF＝34.9 Hz), 91.0. 2e':
1
Synthesis of 3-hydroxy-3-trifluoromethyl-2-benzo-
furan-1(3H)-one analogues (2a－2h)
White solid, m.p. 163.4 ℃; H NMR δ: 9.82 (s, 1H,
OH), 8.30－8.28 (m, 1H, ArH), 7.86－7.84 (m, 1H,
ArH), 7.66－7.62 (m, 1H, ArH); 19F NMR δ: −81.99 (s,
3F, CF3); 13C NMR δ: 165.4, 144.9, 143.8, 137.0, 127.8,
To a solution of 1a－1h (1 mmol) in anhydrous THF
(5 mL) were added cuprous iodide (0.019 g, 0.1 mmol),
1,10-phenanthroline (0.018 g, 0.1 mmol) and anhydrous
KF (0.116 g, 2 mmol) under argon atmosphere. And
then, TMSCF3 (0.18 mL, 1.2 mmol) was added to the
solution and the reaction was allowed to continue stir-
ring for a further 6 h at 50 ℃. After the reaction was
completed, the solution was dissolved in dichloro-
methane (10 mL). The organic layer was washed by
water and dried over anhydrous Na2SO4. The CH2Cl2
was removed under reduced pressure, and the residue
was purified by silica gel column chromatograph (pe-
1
2
124.4, 121.9 (q, JCF＝284.9 Hz), 98.8 (q, JCF＝34.7
Hz), 93.6; HRMS (ESI) calcd for C9H3F3IO3 ([M−H] −)
342.9079, found 342.8835.
4-Chloro-3-hydroxy-3-trifluoromethyl-2-benzo-
furan-1-(3H)-one and 7-chloro-3-hydroxy-3-tri-
fluoromethyl-2-benzofuran-1(3H)-one (2f and 2f')
Yellow oil, a mixture of isomers (1∶3) (minor isomer
marked with *, the same as below); 1H NMR δ: 9.97* (s,
1H, OH), 9.73 (s, 1H, OH), 7.97－7.95* (m, 2H, ArH),
7.91－7.88 (m, 1H, ArH), 7.83－7.78 (m, 2H, ArH),
4
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, XX, 1—5

Copper(I)-Catalyzed Trifluoromethylation of Phthalic Anhydride Derivatives
7.76* (m, 1H, ArH); 19F NMR δ: −82.42 (s, 3F, CF3),
−79.77* (s, 3F, CF3); 13C NMR δ: 165.5*, 163.9, 145.4,
139.1*, 136.9, 134.2*, 133.6, 132.5, 130.8*, 130.1*,
124.5*, 123.4, 123.1, 122.0* (q, 1JCF＝285.9 Hz), 121.9
(q, 1JCF＝284.6 Hz), 101.8* (q, 2JCF＝35.9 Hz), 99.7 (q,
2JCF＝35.1 Hz); HRMS (ESI) calcd for C9H3ClF3O3
([M−H]−) 250.9723, found 250.9607.
125.9 (q, 1JCF＝283.1 Hz), 66.9 (q, 2JCF＝30.7 Hz), 61.3;
HRMS (EI) calcd for C9H9F3O2 ([M]＋) 206.0555, found
206.0548.
Acknowledgement
We are grateful for financial supports from the Na-
tional Natural Science Foundation of China (Nos.
21072057, 21272070), the 973 Program (No.
2010CB126101), the Key Project in the National Sci-
ence & Technology Pillar Program of China in the
twelfth five-year plan period (No. 2011BAE06B05).
5-Chloro-3-hydroxy-3-trifluoromethyl-2-benzo-
furan-1(3H)-one and 6-chloro-3-hydroxy-3-trifluoro-
methyl-2-benzofuran-1(3H)-one (2g and 2g') Yel-
1
low oil, a mixture of isomers (1.25∶1); H NMR δ:
9.92* (s, 1H, OH), 9.92 (s, 1H, OH), 8.00－7.82* (m,
3H, ArH), 8.00－7.82 (m, 3H, ArH); 19F NMR δ:
−82.33* (s, 3F, CF3), −82.29 (s, 3F, CF3); 13C NMR δ:
165.7, 165.5*, 144.6, 141.3, 138.0*, 135.9*, 133.2,
128.9*, 127.5, 126.2*, 125.6*, 125.6, 124.6, 121.9* (q,
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2633; (c) Mikami, K.; Fustero, S.; Sánchez-Roselló, M.; Aceña, J. L.;
Soloshonok, V.; Sorochinsky, A. Synthesis 2011, 19, 3045.
[3] (a) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Asian J. 2012, 7,
1744; (b) Sato, K.; Tarui, A.; Omote, M.; Ando, A.; Kumadaki, I.
Synthesis 2010, 11, 1865; (c) Pan, F.; Shi, Z.-J. Acta Chim. Sinica
2012, 70, 1679; (d) Qing, F.-L. Chin. J. Org. Chem. 2012, 32, 815;
(e) Lü, C.-P.; Shen, Q.-L.; Liu, D. Chin. J. Org. Chem. 2012, 32,
1380.
1
1JCF＝286.9 Hz), 121.9 (q, JCF＝286.9 Hz), 100.9* (q,
2JCF＝35.1 Hz), 100.4 (q, 2JCF＝35.0 Hz); HRMS (ESI)
calcd for C9H3ClF3O3 ([M−H] −) 250.9723, found
250.9663.
5-Bromo-3-hydroxy-3-trifluoromethyl-2-benzo-
furan-1-(3H)-one and 6-bromo-3-hydroxy-3-trifluoro-
methyl-2-benzofuran-1(3H)-one (2h and 2h') Yel-
1
low oil, a mixture of isomers (1.6∶1); H NMR δ:
9.94* (s, 1H, OH), 9.04 (s, 1H, OH), 8.24* (s, 1H, ArH),
8.15* (d, J＝8.0 Hz, 1H, ArH), 8.09 (s, 1H, ArH), 8.07
(d, J＝8.0 Hz, 1H, ArH), 7.95 (d, J＝8.0 Hz, 1H, ArH),
7.79* (d, J＝8.0 Hz, 1H, ArH); 19F NMR δ: −81.89* (s,
3F, CF3), −81.82 (s, 3F, CF3); 13C NMR δ: 165.4*, 165.4,
144.5*, 141.6*, 139.2, 136.5, 130.4, 129.8, 128.0, 127.9,
[4] (a) Boechat, N.; Bastos, M. M. Curr. Org. Synth. 2010, 7, 403; (b)
Prakash, G. K. S.; Zhang, Z.; Wang, F.; Munoz, S.; Olah, G. A. J.
Org. Chem. 2013, 7, 3300.
[5] (a) Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah,
G. A. Angew. Chem. Int. Ed. 1998, 37, 820; (b) Prakash, G. K. S.;
Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393; (c)
Wu, S.-X.; Zeng, W.; Wang, Q.; Chen, F.-X. Org. Biomol. Chem.
2012, 10, 9334; (d) Prakash, G. K. S.; Panja, C.; Vaghoo, H.;
Surampudi, V.; Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.;
Olah, G. A. J. Org. Chem. 2006, 71, 6806; (e) Matsukawa, S.; Saijo,
M. Tetrahedron Lett. 2008, 49, 4655.
[6] (a) Kusuda, A.; Kawai, H.; Nakamura, S.; Shibata, N. Green Chem.
2009, 11, 1733; (b) Mizuta, S.; Shibata, N.; Akiti, S.; Fujimoto, H.;
Nakamura, S.; Toru, T. Org. Lett. 2007, 9, 3707; (c) Singh, R. P.;
Chakraborty, D.; Shreeve, J. M. J. Fluorine Chem. 2001, 111, 153.
[7] (a) Singh, R. P.; Cao, G.-F.; Kirchmeier, R. L.; Shreeve, J. M. J. Org.
Chem. 1999, 64, 2873; (b) Allendörfer, N.; Es-Sayed, M.; Nieger, M.;
Bräse, S. Tetrahedron Lett. 2012, 53, 388; (c) Hoffmann-Röder, A.;
Seiler, P.; Diederich, F. Org. Biomol. Chem. 2004, 2, 2267; (d) Levin,
V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.;
Tartakovsky, V. A. Eur. J. Org. Chem. 2008, 31, 5226; (e) Prakash, G.
K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123.
[8] Francèse, C.; Tordeux, M.; Wakselman, C. Tetrahedron Lett. 1988,
29, 1029.
[9] Babadzhanova, L. A.; Kirij, N. V.; Yagupolskii, Y. L.; Tyrra, W.;
Naumann, D. Tetrahedron 2005, 61, 1813.
[10] Chang, Y.; Cai, C. J. Fluorine Chem. 2005, 126, 937.
[11] Pharikronburee, V.; Punirun, T.; Soorukram, D.; Kuhakarn, C.; Tu-
chinda, P.; Reutrakul, V.; Pohmakotr, M. Org. Biomol. Chem. 2013,
11, 2022.
[12] Doucet-Personeni, C.; Bentley, P. D.; Fletcher, R. J.; Kinkaid, A.;
Kryger, G.; Pirard, B.; Taylor, A.; Taylor, R.; Taylor, J.; Viner, R.;
Silman, I.; Sussman, J. L.; Greenblatt, H. M.; Lewis, T. J. Med.
Chem. 2001, 44, 3203.
1
126.9*, 126.6*, 126.4*, 125.9*, 121.9* (q, JCF＝285.0
1
2
Hz), 121.9 (q, JCF＝285.0 Hz), 100.5* (q, JCF＝35.5
2
Hz), 100.5 (q, JCF＝35.5 Hz); HRMS (ESI) calcd for
C9H3BrF3O3 ([M−H] −) 294.9218, found 294.9230.
Synthesis of 2,2,2-trifluoro-1-(2-(hydroxylmethyl)-
phenyl)ethanol (3a)
To a stirred solution of 2a (1 mmol) in anhydrous
tetrahydrofuran (5 mL) was added lithium aluminum
hydride (0.152 g, 4 mmol). The mixture was then stirred
for 1 h, and the progress of the reaction was monitored
by TLC. When the reaction was completed, the solution
was dissolved in ethyl acetate (5 mL) and quenched
with a mixture (water/methanol＝1∶1). The resulting
suspension was filtered, and the filtrate was diluted with
ethyl acetate, washed successively with water and brine,
dried with anhydrous Na2SO4, and concentrated under
reduced pressure to leave the crude product. The crude
residue was purified by chromatography on silica gel
(petroleum ether/ethyl acetate＝3∶1) to afford target
compound 3a.
2,2,2-Trifluoro-1-(2-(hydroxymethyl)phenyl)etha-
1
nol (3a) White solid, m.p. 85.7 ℃, yield 85%; H
NMR δ: 7.68 (d, J＝7.0 Hz, 1H, ArH), 7.50 (d, J＝6.1
Hz, 1H, ArH), 7.44－7.33 (m, 2H, ArH), 6.82－6.81 (m,
1H), 5.62－5.55 (m, 1H), 5.40－5.37 (m, 1H), 4.79－
4.57 (m, 2H, CH2); 19F NMR δ: −76.14 (m, 3F, CF3);
13C NMR δ: 140.7, 134.2, 128.9, 128.2, 128.1, 127.5,
[13] Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.
[14] Wu, S.-X.; Guo, J.-Y.; Sohail, M.; Cao, C.-Y.; Chen, F.-X. J. Fluo-
rine Chem. 2013, 148, 19.
(Pan, B.; Qin, X.)
Chin. J. Chem. 2013, XX, 1—5
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