Nucleophilic trifluoromethylation of anhydrides employing (trifluoromethyl)trimethylsilane: Synthesis of γ-trifluoromethylated γ-butyrolactones

Article abstract of DOI:10.1016/j.jfluchem.2013.06.006

Fluoride-catalyzed nucleophilic trifluoromethylation of acid anhydrides using CF3SiMe3 provided the corresponding γ-hydroxy-γ- trifluoromethyl-γ-butyrolactones. The utility of these adducts was further demonstrated by treatment with Grignard reagents, lea

Full text of DOI:10.1016/j.jfluchem.2013.06.006

Journal of Fluorine Chemistry 154 (2013) 37–42
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Nucleophilic trifluoromethylation of anhydrides employing
(
g
trifluoromethyl)trimethylsilane: Synthesis of
-butyrolactones
g-trifluoromethylated
Chonticha Masusai, Darunee Soorukram, Chutima Kuhakarn, Patoomratana Tuchinda,
Vichai Reutrakul, Manat Pohmakotr *
Department of Chemistry and Center for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400,
Thailand
A R T I C L E I N F O
A B S T R A C T
Article history:
Fluoride-catalyzed nucleophilic trifluoromethylation of acid anhydrides using CF SiMe provided the
3
3
Received 2 May 2013
corresponding
g
-hydroxy-
g
-trifluoromethyl-
g
-butyrolactones. The utility of these adducts was further
-trifluoromethylated -butyrolactones.
ß 2013 Elsevier B.V. All rights reserved.
Received in revised form 13 June 2013
Accepted 17 June 2013
Available online 27 June 2013
demonstrated by treatment with Grignard reagents, leading to
g
g
Keywords:
Trifluoromethylation
Ruppert–Prakash reagent
Anhydrides
g-Butyrolactones
1
. Introduction
nucleophilic addition with anhydrides to provide the
g-hydroxy-
g
-trifluoromethyl- -butyrolactones, which could be employed as
g
Compounds bearing fluorine atoms have been extensively
intermediates for the preparation of
g-trifluoromethylated g-
applied in a variety of fields including agrochemistry, pharmaceu-
tical chemistry and materials sciences. In particular, trifluoro-
butyrolactones as shown in Scheme 1.
3
methyl group (CF ) is considered as an important fluorinated motif
2. Results and discussion
which is commonly found in useful organic molecules. Therefore,
the development of efficient methodology for the introduction of
trifluoromethyl group into organic molecules has attracted
considerable attention in synthetic community. A number of
strategies developed for trifluoromethylation processes have been
reported [1]. Among those, fluoride-catalyzed nucleophilic tri-
fluoromethylation by using (trifluoromethyl)trimethylsilane
Our optimization began with the fluoride-catalyzed trifluor-
omethylation of CF SiMe with phthalic anhydride. It was found
that the reaction of phthalic anhydride with CF SiMe (2 equiv.)
and 10 mol% of TBAT (tetrabutylammonium triphenyldifluorosi-
licate) in THF at 0 to 10 8C for 4 h followed by quenching with H
provided the expected -hydroxy- -trifluoromethyl- -butyrolac-
tone 1 in 91–95% yields. Similarly, the nucleophilic addition of
CF SiMe with succinic anhydride also readily proceeded, yielding
the corresponding adduct 2 albeit in moderate yield (67% yield)
Scheme 1). Having succeeded in preparing compounds 1 and 2, we
next investigated their reactions with the Grignard reagents,
expecting to obtain the corresponding -trifluoromethylated
butyrolactones 3. Thus, treatment of 1 with 5 equiv. of CH MgCl in
3
3
3
3
2
O
g
g
g
3 3
(CF SiMe , Ruppert–Prakash reagent) [2] has emerged as a general
protocol. While various electrophiles [3], e.g., carbonyl compounds,
esters, imines, enones, and cyclic amides were reported to react
3
3
3 3
with CF SiMe , the reaction with anhydrides has only been
(
scarcely reported in the literature. Recently, we reported fluoride-
catalyzed nucleophilic addition of difluoro(phenylsulfanyl)tri-
g
g-
methylsilane (PhSCF
general entry to -difluoromethylated
envisioned that CF SiMe would also undergo fluoride-catalyzed
2
SiMe
3
) to various anhydrides providing a
3
g
g
-lactams [4]. We therefore
THF at 0 8C for 40 min followed by acidic work-up and treatment of
the resulting crude product with a catalytic amount of p-
3
3
toluenesulfonic acid (p-TsOH) in CH
16 h) afforded the required product 3a in 76% yield. The formation
of 3a could be rationalized that ring-opening of compound 1
mediated by CH MgCl took place to give the corresponding
2 2
Cl under reflux overnight
(
*
Corresponding author. Tel.: +66 2201 5158; fax: +66 2644 5126.
E-mail address: manat.poh@mahidol.ac.th (M. Pohmakotr).
3
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.06.006

3
8
C. Masusai et al. / Journal of Fluorine Chemistry 154 (2013) 37–42
Table 1
Nucleophilic addition reactions of
g-hydroxy-
g-trifluoromethyl-
g-butyrolactones 1 or 2 with Grignard reagents.
1
. RMgX (excess), THF
HO
o
_
o
R
H
CF3
0 C, 40 min or 78 C, 1 h
CF3
and / or
CF3
o
or NaBH , MeOH, 0 C, 2 h
4
O
O
O
2
. p-TsOH (cat.), CH Cl2
2
reflux, overnight
O
O
O
3
4
1
or 2
a
a
Entry
1
1 or 2
Reagent
MeMgCl
3; yield (%)
4; yield (%)
–
HO
Me
CF3
CF3
O
O
3a; 76
O
O
b
2
1
EtMgCl
40 (10)
Et
iPr
Bu
CF3
O
3b; 23 (63)b
3c; 11 (34)b
3d; 21 (66)b
O
b
3
4
1
1
iPrMgCl
50 (25)
CF3
O
O
b
BuMgCl
45 (11)
CF3
O
O
5
1
VinylMgCl
À
CF3
3e; 80
O
O
6
7
1
1
PhMgCl
À
À
Ph
CF3
O
3f; 99
O
4-MeO(Ph)MgBr
MeO
CF3 3g; 98
O
O
8
9
1
NaBH
4
À
63
–
PhMgCl
HO
Ph
CF3
CF
3
O
O
3h; 67
O
O
1
0
2
BuMgCl
Bu
CF3
O
3i; 18b,c
O

C. Masusai et al. / Journal of Fluorine Chemistry 154 (2013) 37–42
39
Table 1 (Continued )
a
a
Entry
1 or 2
Reagent
3; yield (%)
4; yield (%)
1
1
2
4-MeO(Ph)MgBr
–
MeO
CF3 3j; 37
O
O
a
b
c
Yields of isolated products. The reaction was carried out at À78 8C for 1 h. Lactonization was performed by using TFAA under reflux conditions.
Scheme 1. Trifluoromethylation of anhydrides with CF
3
SiMe
3
followed by nucleophilic addition reaction with Grignard reagents.
trifluoromethyl ketocarboxylate 1A, which subsequently reacted
3. Conclusion
with a second equivalent of CH
after lactonization (Scheme 1).
3
MgCl to provide 1B and then 3a
In conclusion, we have reported a fluoride-catalyzed nucleo-
philic addition of CF SiMe to anhydrides to provide -hydroxy-
trifluoromethyl- -butyrolactones, which could be further trans-
formed to -trifluoromethylated -butyrolactones after treatment
with Grignard reagents followed by lactonization. Our developed
method may be useful for synthesis of highly substituted
The optimal reaction conditions were also effective for addition
of other Grignard reagents to the firstly formed -hydroxy-
trifluoromethyl- -butyrolactone 1. Thus, the reactions of com-
pound 1 with vinyl-, phenyl-, and 4-methoxyphenylmagnesium
reagents provided the corresponding -trifluoromethylated
3
3
g
g-
g
g
-
g
g
g
g
g
g
-
g-
butyrolactones 3e, 3f, and 3g in 80%, 99%, and 98% yields,
respectively, after lactonization (Table 1, entries 5–7). However,
ethylmagnesium chloride, isopropylmagnesium chloride and
butylmagnesium chloride reacted with compound 1, yielding
trifluoromethylated g-butyrolactones.
4. Experimental
the corresponding
g-trifluoromethylated
g
-butyrolactones 3b, 3c,
4.1. General information
and 3d in significantly lower yields; 23%, 11%, and 21% yields,
respectively. The major product obtained from each of those was
1
The H NMR spectra were recorded on a Bruker-400 (400 MHz)
found to be
and 45% yields, respectively (Table 1, entries 2–4). The formation of
can be attributed to the reduction of the intermediate 1A by a
g
-trifluoromethylated
g
-butyrolactone 4 in 40%, 50%
spectrometer in CDCl using tetramethylsilane as an internal
3
1
3
standard. The C NMR spectra were recorded on a Bruker 400
(100 MHz) spectrometer in CDCl3 using residual non-deuterated
4
b-
1
9
hydride transfer from the Grignard reagents. Improved results
were obtained when the reactions were carried out at low
temperature (À78 8C) for 1 h. Under the optimized reaction
solvent peaks as an internal standard. The F NMR spectra were
recorded on a Bruker-400 (376 MHz) spectrometer and chemical
shifts (d) were measured with fluorotrichloromethane (d = 0) as an
internal standard. The IR spectra were recorded on either a Jasco A-
conditions, the corresponding
g
-trifluoromethylated
g-butyrolac-
tones 3b, 3c, and 3d were obtained in 63%, 34%, and 66% yields,
together with the side product 4 in 10%, 25%, and 11% yields,
respectively (Table 1, entries 2–4). It should be mentioned that the
302 or a Perkin Elmer 683 infrared spectrometer in CHCl or neat.
The electron impact mass spectra were recorded by using Thermo
3
Finnigan Polaris Q mass spectrometer. The high resolution mass
spectra were recorded on HR-TOF-MS Micromass model VQ-TOF2
mass spectrometer. Melting points were recorded on a B u¨ chi 501
melting point apparatus and uncorrected. Tetrahydrofuran (THF)
was distilled from sodium-benzophenone ketyl. Dichloromethane
(CH Cl ) was distilled over calcium hydride and stored over
g
6
-trifluoromethylated
3% yield from the reduction of compound 1 by using NaBH
MeOH at 0 8C for 2 h followed by lactonization (Table 1, entry 8).
Under the standard reaction conditions, -hydroxy- -trifluoro-
methyl- -butyrolactone 2 reacted with phenylmagnesium chlo-
ride, butylmagnesium chloride, and 4-methoxyphenylmagnesium
bromide, to provide the desired -trifluoromethylated -butyr-
g
-butyrolactone 4 was directly obtained in
4
in
g
g
g
2
2
activated molecular sieves (4 A˚ ). All glass wares and syringes were
g
g
oven-dried and kept in a desiccator before use. Preparative thin-
layer chromatography plates were performed by using Merck silica
gel 60 PF254 (Art 7747). Column chromatography was performed
olactones 3h, 3i, and 3j, after lactonization, in 67%, 18%, and 37%
yields, respectively (Table 1, entries 9–11).

4
0
C. Masusai et al. / Journal of Fluorine Chemistry 154 (2013) 37–42
by using Merck silica gel 60 PF254 (Art 7734). Other common
solvents (CH Cl , hexanes, ethyl acetate (EtOAc), methanol, and
acetone) were distilled before use.
General procedure C: a solution of arylbromide (10.0 mmol) in
dry THF (8 mL) was added dropwise into a suspension of Mg
(turning) (0.4 g, 20.0 mmol) in dry THF (7 mL) under an argon
atmosphere at room temperature. After 2 h, a solution of freshly
prepared Grignard reagent was transferred dropwise via a canular
to a solution of 1 or 2 (0.5 mmol) in THF (10 mL) at 0 8C under an
argon atmosphere and then stirred for 1 h. The reaction mixture
was quenched with 10% HCl (5 mL) at 0 8C and extracted with
EtOAc (4Â 20 mL). The combined organic phase was washed with
2
2
4.2. Synthesis of g-hydroxy-g-trifluoromethyl-g-butyrolactones
General procedure A: a solution of (trifluoromethyl)trimethylsi-
lane (CF SiMe , 0.6 mL, 4.0 mmol) and anhydride (2.0 mmol) in dry
THF (10 mL) was treated with a solution of 10 mol% of TBAT
108 mg, 0.2 mmol) in dry THF (10 mL) at 0 8C under an argon
atmosphere. The reaction mixture was stirred and kept below
0 8C for 4 h, then quenched with water and extracted with EtOAc
4Â 20 mL). The combined organic phase was washed successively
with water (20 mL), brine (20 mL) and dried over anhydrous
Na SO . After the removal of the solvent, the crude product was
purified by column chromatography (SiO ).
3
3
(
brine (20 mL) and dried over anhydrous Na
of the solvent, the crude product was treated with a catalytic
amount of p-TsOH in dry CH Cl (12 mL) under reflux overnight
(16 h). The reaction was quenched with saturated NaHCO and
extracted with CH Cl
(4Â 10 mL). The combined organic phase
was washed with brine (10 mL), and dried over anhydrous Na SO
After the removal of the solvent, the crude product was purified by
column chromatography (SiO ) or preparative thin-layer chroma-
tography (SiO ).
2 4
SO . After the removal
1
(
2
2
3
2
2
2
4
2
4
.
2
2
4
.2.1. 3-Hydroxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (1)
According to the general procedure A, the reaction of phthalic
anhydride (297 mg, 2.0 mmol) and CF SiMe (0.6 mL, 4.0 mmol) at
8C gave 1 (393 mg, 91% yield) as a white solid after column
2
3
3
4.3.1. 3-Methyl-3-(trifluoromethyl)isobenzofuran-1(3H)-one (3a)
According to the general procedure B, the reaction of 1 (110 mg,
0.5 mmol) and methylmagnesium chloride (3.0 M in THF, 0.83 mL,
2.5 mmol) at 0 8C followed by lactonization gave 3a (83 mg, 76%
yield) as a colorless oil after preparative thin-layer chromatogra-
0
chromatography (SiO
2
, 10–30% EtOAc in hexanes). Mp 95–96 8C
); 3152 (OH), 3032 (m), 2986 (w),
852 (w), 1792 (s), 1607 (w), 1469 (m), 1274 (m), 1162 (m), 1145
(CH
2
Cl
2
/hexanes). IR (CHCl
3
n
2
À1
1
(m), 1081 (m), 988 (s), 941 (m) cm . H NMR (400 MHz, CDCl
3
):
d
phy (SiO
2
, 15% EtOAc in hexanes). IR (neat); n 3029 (m), 3004 (w),
5
.27–5.44 (br s, 1H, OH), 7.70–7.84 (m, 3H, 3 arom. H), 7.90 (d,
2947 (w), 1788 (s), 1603 (w), 1469 (m), 1319 (m), 1271 (s), 1181
3
13
À1
1
J
H,H = 7.6 Hz, 1H, arom. H), C NMR (100 MHz, CDCl
3
):
d
100.0 (q,
(s), 1102 (m), 1076 (s), 1030 (s), 952 (m) cm . H NMR (400 MHz,
2
1
3
J = 36.0 Hz, C), 121.4 (q, J = 284.0 Hz, CF
3
), 124.0 (CH), 126.0 (CH),
3 3
CDCl d 1.85 (s, 3H, CH ), 7.60 (d, JH,H = 7.6 Hz, 1H, arom. H), 7.66
):
19
3
3
1
(
[
26.7 (C), 132.4 (CH), 135.5 (CH), 141.8 (C), 167.3 (C). F NMR
367 MHz, CDCl ): ). EIMS, m/z (rel. int.): 219 (14)
À82.8 (s, 3F, CF
M+H] , 201 (4), 149 (100), 121 (22), 74 (13), 65 (2); HRMS (ESI-
(t, JH,H = 7.6 Hz, 1H, arom. H), 7.77 (t, JH,H = 7.6 Hz, 1H, arom. H),
3
13
3
d
3
7.94 (d, JH,H = 7.6 Hz, 1H, arom. H). C NMR (100 MHz, CDCl
3
):
), 82.8 (q, J = 34.0 Hz, C), 122.6 (CH), 123.5 (q,
J = 281.0 Hz, CF ), 125.9 (C), 126.3 (CH), 130.9 (CH), 134.9 (CH),
145.8 (C), 168.1 (C). F NMR (367 MHz, CDCl
d
+
2
19.7 (CH
3
+
+
1
TOF), m/z: calcd. for C
9
H
5
F
3
O
3
Na 241.0088 [M+Na] ; found
3
1
9
2
41.0088.
3
):
d
À76.3 (s, 3F, CF
3
).
+
+
EIMS, m/z (rel. int.): 217 (6) [M+H] , 216 (11) [M] , 201 (8), 199
4
.2.2. 5-Hydroxy-5-(trifluoromethyl)dihydrofuran-2(3H)-one (2)
According to the general procedure A, the reaction of succinic
(100), 198 (41), 178 (26), 134 (5), 133 (7), 121 (17), 105 (7), 77 (46).
+
+
7 3 2
HRMS (ESI-TOF), m/z: calcd. for C10H F O Na 239.0296 [M+Na] ;
anhydride (200 mg, 2.0 mmol) and CF
3
SiMe
3
(0.6 mL, 4.0 mmol) at
found 239.0296.
0
8C gave 2 (228 mg, 67% yield) as a colorless oil after column
chromatography (SiO
2
, 10–80% EtOAc in hexanes). IR (neat);
n
4.3.2. 3-Ethyl-3-(trifluoromethyl)isobenzofuran-1(3H)-one (3b)
According to the general procedure B, the reaction of 1 (110 mg,
0.5 mmol) and ethylmagnesium chloride (2.0 M in THF, 1.25 mL,
2.5 mmol) at À78 8C followed by lactonization gave 3b (73 mg, 63%
yield) as a white solid together with a reduction product 4 (12 mg,
10% yield) as a colorless oil after preparative thin-layer chroma-
3
150 (OH), 2985 (w), 2850 (w), 1794 (s), 1605 (w), 1466 (m), 1271
À1
1
(
m), 1160 (m), 1147 (m), 1085 (m) cm
CDCl ): 2.25–3.00 (m, 4H, 2CH
NMR (100 MHz, CDCl ): 27.5 (CH
J = 36.0 Hz, C), 121.7 (q, J = 284.0 Hz, CF
367 MHz, CDCl ): ). EIMS, m/z (rel. int.): 171 (6)
À85.4 (s, 3F, CF
.
H NMR (400 MHz,
1
3
3
d
2
), 4.70–6.00 (br s, 1H, OH).
), 28.2 (CH ), 101.5 (q,
), 175.1 (C). F NMR
C
3
d
2
2
2
1
19
3
(
3
d
3
tography (SiO
hexanes). IR (CH
1785 (s), 1603 (m), 1469 (s), 1306 (m), 1283 (s), 1182 (s), 1083 (s),
2
, 10% EtOAc in hexanes). Mp 55–56 8C (CH
2 2
Cl /
+
+
+
[
M+H] , 169 (10) [MÀH] , 153 (12) [MÀOH] . HRMS (ESI-TOF), m/z:
3
Cl ); 3030 (m), 2984 (m), 2944 (w), 2887 (w),
3
n
+
+
calcd. for C
5
H
4
F
3
O
3
169.0113 [MÀH] ; found 169.0107.
À1
1
1
051 (s), 988 (s) cm
.
H NMR (400 MHz, CDCl
3
):
H,H = 7.3 Hz, 1H,
JH,H = 7.3 Hz, 1H, CHH), 7.48 (d,
d 0.63 (t,
3
2
3
4.3. Synthesis of
g
-trifluoromethylated
g
-butyrolactones 3 and 4
3
JH,H = 7.6 Hz, 3H, CH ), 2.19 (dq, JH,H = 14.5, J
2
3
CHH), 2.39 (dq,
3
J
H,H = 14.5,
3
General procedure B: a solution of 1 or 2 (0.5 mmol) in dry THF
15 mL) was treated with alkyl- or arylmagnesium chloride
JH,H = 7.6 Hz, 1H, arom. H), 7.56 (t, JH,H = 7.6 Hz, 1H, arom. H), 7.70
(t, JH,H = 7.6 Hz, 1H, arom. H), 7.87 (d, JH,H = 7.6 Hz, 1H, arom. H).
C NMR (100 MHz, CDCl
J = 31.0 Hz, C), 122.8 (CH), 123.7 (q, J = 282.0 Hz, CF
126.9 (C), 130.9 (CH), 134.9 (CH), 143.9 (C), 168.5 (C). F NMR
(367 MHz, CDCl ): –78.7 (s, 3F, CF ). EIMS, m/z (rel. int.): 231 (3)
[M+H] , 204 (7), 199 (100), 161 (21), 133 (10), 121 (10), 105 (7), 77
(31). HRMS (ESI-TOF), m/z: calcd. for C11
[M+Na] ; found 253.0452.
3
3
(
1
3
solution (2.5 mmol) at À78 8C or 0 8C under an argon atmosphere.
After stirring the reaction mixture 1 h at À78 8C, or 40 min at 0 8C,
3
):
d
19.7 (CH
3
), 24.6 (CH
2
), 86.2 (q,
2
1
3
), 126.1 (CH),
19
1
0% HCl (2 mL) was added at À78 8C or at 0 8C. The aqueous phase
was extracted with EtOAc (4Â 20 mL). The combined organic phase
was washed with brine (20 mL) and dried over anhydrous Na SO
After the removal of the solvent, the crude product was treated
with a catalytic amount of p-TsOH in dry CH Cl (12 mL) under
reflux overnight (16 h) or treated with trifluoroacetic anhydride
0.5 mL) under reflux (8 h). The reaction was quenched with
saturated NaHCO and extracted with CH Cl
(4Â 10 mL). The
combined organic phase was washed with brine (10 mL), and dried
over anhydrous Na SO . After the removal of the solvent, the crude
product was purified by column chromatography (SiO ) or
preparative thin-layer chromatography (SiO ).
3
d
3
+
2
4
.
+
H
9
F
3
O
2
Na 253.0452
+
2
2
(
4.3.3. 3-Isopropyl-3-(trifluoromethyl)isobenzofuran-1(3H)-one (3c)
According to the general procedure B, the reaction of 1 (110 mg,
0.5 mmol) and isopropylmagnesium chloride (2.0 M in THF,
1.25 mL, 2.5 mmol) at À78 8C followed by lactonization gave 3c
(24 mg, 34% yield) as a colorless oil together with a reduction
product 4 (25 mg, 25% yield) as a colorless oil after preparative
3
2
2
2
4
2
2

C. Masusai et al. / Journal of Fluorine Chemistry 154 (2013) 37–42
41
3
thin-layer chromatography (SiO
2
, 15% EtOAc in hexanes). IR
(m, 2H, 2 arom. H), 7.84 (t,
J
J
H,H = 7.5 Hz, 1H, arom. H), 7.94 (d,
3
3
13
(CH
3
Cl
3
);
n
3029 (w), 2980 (w), 2928 (w), 1784 (s), 1600 (w),
H,H = 7.7 Hz, 1H, arom. H), 8.00 (d, JH,H = 7.7 Hz, 1H, arom. H).
C
À1 1
2
1
469 (m), 1250 (m), 1182 (s), 1072 (m), 1033 (m), 993 (m) cm . H
NMR (100 MHz, CDCl
3
):
), 124.2 (CH), 125.9 (C), 126.5 (CH), 126.6 (CH),
128.9 (2CH), 130.0 (2CH), 131.1 (CH), 132.3 (C), 134.9 (CH), 144.9
d 85.6 (q, J = 32.0 Hz, C), 123.2 (q,
3
1
NMR (400 MHz, CDCl
3
):
d
0.85, (d, JH,H = 6.8 Hz, 3H, CH
3
), 0.95 (d,
H,H = 6.8 Hz, 1H, CH),
J = 283.0 Hz, CF
3
3
3
J
H,H = 6.8 Hz, 3H, CH
3
), 2.57–2.65 (sept,
J
3
3
19
7
.51 (d, JH,H = 7.7 Hz, 1H, arom. H), 7.56 (t, JH,H = 7.5 Hz, 1H, arom.
(C), 168.0 (C). F NMR (367 MHz, CDCl
m/z (rel. int.): 279 (4) [M+H] , 278 (2) [M] , 209 (100), 201 (2), 183
(3), 163 (2), 153 (15), 152 (22), 151 (5), 105 (2), 77 (4). HRMS (ESI-
3
):
d
À76.3 (s, 3F, CF
3
). EIMS,
3
3
+
+
H), 7.69 (t,
arom. H). C NMR (100 MHz, CDCl
CH
CF
JH,H = 7.5 Hz, 1H, arom. H), 7.88 (d, JH,H = 7.7 Hz, 1H,
13
3
):
), 88.5 (q, J = 31.0 Hz, C), 123.1 (CH), 123.8 (q, J = 282.0 Hz,
), 126.2 (CH), 126.8 (C), 130.7 (CH), 134.6 (CH), 144.4 (C), 168.6
d
16.7 (CH
3
), 16.9 (CH
3
), 31.6
2
1
+
+
(
2
9 3 2
TOF), m/z: calcd. for C15H F O Na 301.0452 [M+Na] ; found
3
301.0452.
1
9
(
C). F NMR (367 MHz, CDCl
3
):
d
–73.9 (s, 3F, CF
3
). EIMS, m/z (rel.
+
+
int.): 245 (5) [M+H] , 244 (2) [M] , 202 (100), 182 (15), 175 (3), 151
4.3.7. 3-(4-Methoxyphenyl)-3-(trifluoromethyl)isobenzofuran-
1(3H)-one (3g)
(
C
24), 133 (7), 104 (14), 77 (13). HRMS (ESI-TOF), m/z: calcd. for
+
+
12
H
11
F
3
O
2
Na 267.0609 [M+Na] ; found 267.0606.
According to the general procedure C, the reaction of 1 (219 mg,
1
.0 mmol) and 4-methoxyphenyl magnesium bromide at 0 8C
followed by lactonization gave 3 g (302 mg, 98% yield) as a
colorless oil in after column chromatography (SiO , 5% EtOAc in
4
.3.4. 3-Butyl-3-(trifluoromethyl)isobenzofuran-1(3H)-one (3d)
According to the general procedure B, the reaction of 1 (110 mg,
.5 mmol) and butylmagnesium chloride (2.0 M in THF, 1.25 mL,
2
0
hexanes). IR (neat):
(s), 1516 (s), 1467 (s), 1261 (m), 1173 (s), 1078 (s), 1028 (s) cm
n
3008 (w), 2939 (w), 2842 (w), 1790 (s), 1611
À1
2
.5 mmol) at À78 8C followed by lactonization gave 3d (85 mg, 66%
yield) as a colorless oil together with a reduction product 4 (11 mg,
1% yield) as a colorless oil in after preparative thin-layer
chromatography (SiO , 15% EtOAc in hexanes). IR (CHCl ):
962 (s), 2935 (s), 2875 (m), 1789 (s), 1603 (m), 1469 (s), 1305 (m),
.
1
H NMR (400 MHz, CDCl
3
):
3
d 3.82 (s, 3H, OCH ), 6.96 (d,
3
1
J
H,H = 7.9 Hz, 2H, 2 arom. H), 7.60 À 7.70 (m, 3H, 3 arom. H),
3
3
2
3
n
7.83 (t, JH,H = 7.4 Hz, 1H, arom. H), 7.91 (d, JH,H = 7.4 Hz, 1H, arom.
3
13
2
1
H), 7.99 (d, JH,H = 7.4 Hz, 1H, arom. H). C NMR (100 MHz, CDCl
3
):
), 85.5 (q, J = 32.0 Hz, C), 114.1 (2CH), 123.2 (q,
J = 282.0 Hz, CF ), 123.9 (C), 124.1 (CH), 125.9 (C), 126.4 (CH),
128.2 (2CH), 130.9 (CH), 134.8 (CH), 144.9 (C), 160.6 (C), 168.0 (C).
À1
1
2
261 (m), 1214 (m), 1179 (m), 1084 (m), 1059 (m) cm . H NMR
d 55.3 (OCH
3
3
1
(400 MHz, CDCl
3
):
d
0.64–0.78 (m, 1H, CHH), 0.81 (t, JH,H = 7.2 Hz,
and CHH), 2.16–2.20 (m, 1H, CHH),
3
3
H, CH
3
), 1.11–1.36 (m, 3H, CH
2
3
19
2
.31–2.38 (m, 1H, CHH), 7.56 (d, JH,H = 7.8 Hz, 1H, arom. H), 7.66 (t,
H,H = 7.8 Hz, 1H, arom. H), 7.78 (t, JH,H = 7.8 Hz, 1H, arom. H), 7.95
F NMR (367 MHz, CDCl
3
):
d
À76.5 (s, 3F, CF
3
). EIMS, m/z (rel. int.):
3
3
+
+
J
309 (5) [M+H] , 308 (15) [M] , 239 (100), 201 (4), 168 (7), 152 (8),
3
13
+
(
(
d, JH,H = 7.8 Hz, 1H, arom. H). C NMR (100 MHz, CDCl
CH
3
):
), 85.9 (q, J = 31.0 Hz, C),
3
), 126.2 (CH), 126.8 (C), 130.8
d
13.6
133 (4), 77 (3). HRMS (ESI-TOF), m/z: calcd. for C16
H
11
F
3
O
3
Na
2
+
3
), 22.3 (CH
2
), 23.8 (CH
22.7 (CH), 123.6 (q, J = 282.0 Hz, CF
2
), 31.0 (CH
2
331.0558 [M+Na] ; found 331.0556.
1
1
19
(CH), 134.9 (CH), 144.3 (C), 168.4 (C). F NMR (367 MHz, CDCl
3
):
d
4.3.8. 5-Phenyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (3h)
+
À78.8 (s, 3F, CF
3
). EIMS, m/z (rel. int.): 258 (5) [M] , 201 (15), 189
According to the general procedure B, the reaction of 2 (88 mg,
0.5 mmol) and phenylmagnesium chloride (2.0 M in THF,
1.25 mL, 2.5 mmol) at 0 8C followed by lactonization gave 3 h
(79 mg, 67% yield) as a colorless oil after preparative-thin layer
(10), 178 (37), 175 (7), 163 (10), 155 (11), 133 (16), 107 (20), 95
(81), 81 (100), 77 (37), 67 (87), 55 (69). HRMS (ESI-TOF), m/z: calcd.
+
+
13 3 2
for C13H F O Na 281.0765 [M+Na] ; found 281.0765.
chromatography (SiO
3067 (w), 2952 (w), 1807 (s), 1451 (m), 1281 (m), 1171 (s), 1094
2
, 40% CH
2
Cl
2
in hexanes (Â2)). IR (neat):
n
4.3.5. 3-(Trifluoromethyl)-3-vinylisobenzofuran-1(3H)-one (3e)
À1
1
According to the general procedure B, the reaction of 1 (110 mg,
.5 mmol) and vinylmagnesium chloride (1.6 M in THF, 1.56 mL,
.5 mmol) at 0 8C followed by lactonization gave 3e (91 mg, 80%
(m), 1067 (m), 896 (s), 706 (s) cm . H NMR (400 MHz, CDCl
2.55–2.77 (m, 2H, 2CHH), 2.75–2.90 (m, 1H, CHH), 2.96–3.07
(m, 1H, CHH), 7.42–7.49 (m, 3H, 3 arom. H), 7.51–7.57 (m, 2H, 2
3
):
0
2
d
1
3
yield) as a colorless oil after preparative thin-layer chromatogra-
phy (SiO , 15% EtOAc in hexanes). IR (CHCl ): 3075 (w), 2929 (w),
792 (s), 1603 (m), 1469 (s), 1412 (m), 1303 (m), 1250 (m), 1183
arom. H). C NMR (100 MHz, CDCl
3
):
d
27.5 (CH
), 126.2 (2CH),
128.7 (2CH), 129.6 (CH), 134.9 (C), 174.2 (C). F NMR (367 MHz,
2 2
), 29.6 (CH ),
2
1
2
3
n
84.9 (q, J = 31.0 Hz, C), 124.2 (q, J = 282.0 Hz, CF
3
1
9
1
À1
1
+
(m), 1079 (m), 955 (m), 764 (s) cm . H NMR (400 MHz, CDCl
3
):
d
CDCl
3
):
d
À80.0 (s, 3F, CF ). EIMS, m/z (rel. int.): 229 (5) [MÀH] ,
3
3
3
5
6
.56 (d, JH,H = 10.8 Hz, 1H, CHH), 5.74 (d, JH,H = 17.1 Hz, 1H, CHH),
209 (14), 182 (46), 166 (16), 153 (5), 77 (20), 66 (100). HRMS
3
3
3
+
+
.28 (dd, JH,H = 17.1, JH,H = 10.8 Hz, 1H, CH), 7.65 (d, JH,H = 7.5 Hz,
9 3 2
(ESI-TOF), m/z: calcd. for C11H F O Na 253.0452 [M+Na] ;
3
1
H, arom. H), 7.69 (t,
J
H,H = 7.5 Hz, 1H, arom. H), 7.80 (t,
found 253.0453.
3
3
J
H,H = 7.5 Hz, 1H, arom. H), 7.97 (d, JH,H = 7.5 Hz, 1H, arom. H).
1
3
2
C NMR (100 MHz, CDCl
3
):
d
84.6 (q, J = 33.0 Hz, C), 121.4 (CH
), 123.4 (CH), 125.5 (C), 126.5 (CH), 128.3
2
),
4.3.9. 5-Butyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (3i)
According to the general procedure B, the reaction of 2 (174 mg,
1.0 mmol) and butylmagnesium chloride (2.0 M in THF, 2.50 mL,
5.0 mmol) at À78 8C followed by lactonization with TFAA (0.5 mL)
under reflux overnight (16 h) gave 3i (37 mg, 18% yield) as a
1
1
(
(
22.8 (q, J = 282.0 Hz, CF
CH), 131.1 (CH), 134.9 (CH), 143.9 (C), 167.9 (C). F NMR
367 MHz, CDCl ): ). EIMS, m/z (rel. int.): 228 (18)
3
1
9
3
d
À78.1 (s, 3F, CF
3
+
[
M] , 215 (15), 209 (87), 178 (97), 171 (23), 161 (35), 133 (23), 107
(
14), 87 (56), 81 (76), 77 (63), 67 (87), 55 (100). HRMS (ESI-TOF), m/
colorless oil after column chromatography (SiO
hexanes). IR (neat): 2962 (s), 2935 (s), 2876 (m), 1799 (s), 1470
m), 1171 (s), 1128 (m), 1035 (m) cm . H NMR (400 MHz, CDCl
0.84–1.00 (m, 3H, CH ), 1.30–1.48 (m, 4H, 2CH ), 1.71–1.84 (m,
1H, CHH), 1.91–2.04 (m, 1H, CHH), 2.15–2.28 (m, 1H, CHH), 2.43
2
, 5% EtOAc in
+
+
z: calcd. for C11
H
7
F
3
O
2
Na 251.0296 [M+Na] ; found 251.0295.
n
À1
1
(
d
3
):
4
.3.6. 3-Phenyl-3-(trifluoromethyl)isobenzofuran-1(3H)-one (3f)
3
2
According to the general procedure B, the reaction of 1 (110 mg,
.5 mmol) and phenylmagnesium chloride (2.0 M in THF, 1.25 mL,
.5 mmol) at 0 8C followed by lactonization gave 3f (142 mg, 80%
13
0
2
(m, 1H, CHH), 2.61 (m, 1H, CHH), 2.73 (m, 1H, CHH). C NMR
(100 MHz, CDCl ): 13.8 (CH ), 22.7 (CH ), 24.1 (CH ), 25.5 (CH ),
27.9 (CH ), 32.8 (CH ), 84.6 (q, J = 29.0 Hz, C), 125.1 (q,
J = 282.3 Hz, CF ), 175.0 (C).
À81.2 (s, 3F, CF ). EIMS, m/z (rel. int.): 211 (55) [M+H] , 153 (43),
141 (44), 97 (84), 55 (100). HRMS (ESI-TOF), m/z: calcd. for
3
d
3
2
2
2
2
yield) as a colorless oil after preparative thin-layer chromatogra-
phy (SiO , 15% EtOAc in hexanes). IR (neat): 3069 (w), 1792 (s),
600 (m), 1468 (m), 1451 (m), 1296 (m), 1281 (m), 1229 (m), 1179
2
2
1
19
2
n
3
3
F NMR (367 MHz, CDCl ): d
+
1
(
(
3
À1
1
s), 1072 (s), 1025 (s) cm . H NMR (400 MHz, CDCl d 7.41–7.50
3
):
m, 3H, 3 arom. H), 7.69 (t, JH,H = 7.5 Hz, 1H, arom. H), 7.75–7.81
3
+
+
9 13 3 2
C H F O Na 233.0765 [M+Na] ; found 233.0764.

4
2
C. Masusai et al. / Journal of Fluorine Chemistry 154 (2013) 37–42
+
4
2
.3.10. 5-(4-Methoxyphenyl)-5-(trifluoromethyl)dihydrofuran-
67 (61), 55 (97). HRMS (ESI-TOF), m/z: calcd. for C
225.0139 [M+Na] ; found 225.0132.
9
H
5
F
3
O
2
Na
+
(3H)-one (3j)
According to the general procedure C, the reaction of 2 (85 mg,
.5 mmol) and 4-methoxyphenyl magnesium bromide at 0 8C
0
Acknowledgements
followed by lactonization gave 3j (49 mg, 37% yield) as a
colorless oil after preparative-thin layer chromatography (SiO
2
,
We acknowledge financial supports from the Thailand Research
Fund (BRG5380019), the office of the Higher Education Commis-
sion and Mahidol University under the National Research
Universities Initiative, and the Center of Excellence for Innovation
in Chemistry (PERCH-CIC).
4
2
0% CH
2
Cl
2
in hexanes (Â2)). IR (neat):
n 3006 (w), 2962 (w),
843 (w), 1806 (s), 1614 (m), 1516 (s), 1464 (w), 1256 (m), 1175
À1
1
(
(
s), 1078 (m), 996 (m), 899 (m), 832 (m) cm
400 MHz, CDCl ): 2.46–2.60 (m, 1H, CHH), 2.65–2.80 (m, 1H,
), 6.88 (d,
H,H = 8.8 Hz, 2H, 2 arom.
.
H NMR
3
d
CHH), 2.82–2.95 (m, 1H, CHH), 3.76 (s, 3H, OCH
3
3
3
J
H,H = 8.8 Hz, 2H, 2 arom. H), 7.36 (d, J
1
3
2
References
H). C NMR (100 MHz, CDCl
3
):
d
84.8 (q, J = 31.0 Hz, C), 114.0
), 126.7 (C), 127.6 (2CH), 160.5
C), 174.3 (C). F NMR (367 MHz, CDCl ): ).
À80.3 (s, 3F, CF
1
(
(
2CH), 124.2 (q, J = 281.7 Hz, CF
3
1
9
[1] (a) J.-A. Ma, D. Cahard, Chem. Rev. 104 (2004) 6119–6146;
3
d
3
(b) T. Hiyama, M. Shimizu, Angew. Chem. Int. Ed. 44 (2005) 214–231;
+
EIMS, m/z (rel. int.): 260 (27) [M] , 191 (100), 163 (18), 135 (44).
(c) J. Xu, Y. Fu, D.-F. Luo, Y.-Y. Jiang, B. Xiao, Z.-J. Liu, T.-J. Gong, L. Liu, J. Am. Chem.
Soc. 133 (2011) 15300–15303;
(d) O.A. Tomashenko, V.V. Grushin, Chem. Rev. 111 (2011) 4475–4521;
+
HRMS (ESI-TOF), m/z: calcd. for
12 11 3 2
C H F O Na 283.0558
+
[
M+Na] ; found 283.0558.
(
(
(
(
(
e) A.D. Dilman, V.V. Levin, Eur. J. Org. Chem. (2011) 831–841;
f) T.S.N. Zhao, K.T. Szab o´ , Org. Lett. 14 (2012) 3966–3969;
g) N.D. Litvinas, P.S. Fier, J.F. Hartwig, Angew. Chem. Int. Ed. 51 (2012) 536–539;
h) T. Liu, X. Shao, Y. Wu, Q. Shen, Angew. Chem. Int. Ed. 51 (2012) 540–543;
i) S.P. Frist, T.H. West, E.M. McGarrigle, V.K. Aggarwal, Org. Lett. 14 (2012) 6370–
4.3.11. 3-(Trifluoromethyl)isobenzofuran-1(3H)-one (4)
To the reaction mixture of 1 (61 mg, 0.28 mmol) in dry MeOH
(
1 mL) was added NaBH
4
(53 mg, 1.4 mmol) as a portionwise at
6373;
0
8C. After 2 h, the reaction mixture was quenched with 10% HCl
(j) Y. Ye, M.S. Sanford, Synlett 23 (2012) 2005–2013;
(
k) S. Mizuta, S. Verhoog, K.M. Engle, T. Khotavivattana, M. O’Duill, K. Wheelhouse,
G. Rassias, M. M e´ debielle, V. Gouverneur, J. Am. Chem. Soc. 135 (2013) 2505–2508;
l) Y.-S. Feng, C.-Q. Xie, W.-L. Qiao, H.-J. Xu, Org. Lett. 15 (2013) 936–939;
(m) J. Liu, L. Chu, F.-L. Qing, Org. Lett. 15 (2013) 894–897;
n) M. Liu, J. Li, X. Xiao, Y. Xie, Y. Shi, Chem. Commun. 49 (2013) 1404–1406.
2] (a) D.W. Nelson, J. Owens, D. Hiraldo, J. Org. Chem. 66 (2001) 2572–2582;
b) G.K.S. Prakash, A.K. Yudin, Chem. Rev. 97 (1997) 757–786;
(c) S. Mizuta, N. Shibata, T. Sato, H. Fujimoto, S. Nakamura, T. Toru, Synlett (2006)
267–0270;
at 0 8C then the solvents were removed by vacuo. The resulting
mixture was extracted with EtOAc (4 Â 5 mL). The combined
organic phase was washed successively with water (10 mL),
(
(
brine (10 mL) and dried over anhydrous Na
removal of the solvent, the crude product was lactonized by
using a catalytic amount of p-TsOH in dry CH Cl (10 mL) under
reflux overnight. The reaction mixture was quenched with
saturated NaHCO and extracted with CH Cl
(4 Â 10 mL), brine
10 mL), and dried over anhydrous Na SO . After the removal of
2 4
SO . After the
[
(
2
2
0
(d) T. Billard, B.R. Langlois, Eur. J. Org. Chem. (2007) 891–897;
3
2
2
(e) E.J. Cho, T.D. Senecal, T. Kinzel, Y. Zhang, D.A. Watson, S.L. Buchwald, Science
(
2
4
328 (2010) 1679–2168;
(
(
(
f) L. Chu, F.-L. Qing, Org. Lett 12 (2010) 5060–5063;
g) T.D. Senecal, A.T. Parsons, S.L. Buchwald, J. Org. Chem. 76 (2011) 1174–1176;
h) F. Wang, T. Luo, J. Hu, Y. Wang, H.S. Krishnan, P.V. Jog, S.K. Ganesh, G.K.S.
the solvent, the crude product was purified by preparative thin-
layer chromatography (20% EtOAc in hexanes) to give 4 (35 mg,
6
3% yield) as a colorless oil. IR (neat):
n
3030 (w), 2928 (w), 2855
Prakash, G.A. Olah, Angew. Chem. Int. Ed. 50 (2011) 7153–7157;
(i) X. Jiang, L. Chu, F.-L. Qing, J. Org. Chem. 77 (2012) 1251–1257;
(j) X. Wu, L. Chu, F.-L. Qing, Tetrahedron Lett. 54 (2013) 249–251;
(
w), 1791 (s), 1603 (w), 1361 (m), 1296 (m), 1270 (s), 1181 (s),
À1
1
1
145 (s), 1039 (s) cm
.
H NMR (400 MHz, CDCl
3
):
d 5.64 (q,
(
k) E. Obijalska, G. Mlosto n´ , G. Utecht, H. Heimgartner, J. Fluorine Chem. 151
3
3
J
H,F = 5.7 Hz, 1H, CH), 7.60 (d, JH,H = 7.5 Hz, 1H, arom. H), 7.63
(2013) 7–11.
3
3
(
t,
H), 7.92 (d,
CDCl ): 76.0 (q, J = 35.4 Hz, C), 122.2 (q, J = 278.7 Hz, CF
23.5 (CH), 125.8 (C), 126.1 (CH), 131.1 (CH), 134.9 (CH), 140.5
J
H,H = 7.5 Hz, 1H, arom. H), 7.73 (t,
J
H,H = 7.5 Hz, 1H, arom.
13
[3] (a) A. Hoffman–R o¨ der, P. Seiler, F. Diederich, Org. Biomol. Chem. 2 (2004) 2267–
2269;
3
J
H,H = 7.5 Hz, 1H, arom. H). C NMR (100 MHz,
(b) S. Mizuta, N. Shibata, S. Ogawa, H. Fujimoto, S. Nakamura, T. Toru, Chem.
2
1
3
d
3
),
Commun. (2006) 2575–2577;
(c) J. Gawronski, N. Wascinska, J. Gagewy, Chem. Rev. 108 (2008) 5227–5252;
(d) H. Kawai, K. Tachi, E. Tokunaga, M. Shiro, N. Shibata, Org. Lett. 12 (2010) 5104–
1
1
9
(
C), 168.3 (C). F NMR (367 MHz, CDCl
3
):
EIMS, m/z (rel. int.): 203 (9) [M+H] , 199 (82), 183 (19), 178 (47),
43 (45), 133 (17), 126 (20), 105 (17), 97 (46), 87 (100), 77 (54),
d
À76.7 (s, 3F, CF
3
).
5107.
+
[
4] V. Pharikronburee, T. Punirun, D. Soorukram, C. Kuhakarn, P. Tuchinda, V. Reu-
trakul, M. Pohmakotr, Org. Biomol. Chem. 11 (2013) 2022–2033.
1