A synthesis of γ-trifluoromethyl α,β-unsaturated γ-butyrolactones using CF3SiMe3 as a trifluoromethylating agent

Article abstract of DOI:10.1039/c3ob41247d

A general synthesis of γ-trifluoromethyl α,β-unsaturated γ-butyrolactones is described. The fluoride-catalyzed nucleophilic addition of a trifluoromethyl (CF₃) group generated from (trifluoromethyl)trimethylsilane (CF₃SiMe₃, Ruppert-Prakash reagent) to a masked maleic anhydride 1 (cyclopentadiene-maleic anhydride adduct) provides the corresponding adducts 2 with high stereoselectivity. The γ-trifluoromethyl α,β-unsaturated γ-butyrolactones 4 were obtained after treatment of the adducts 2 with Grignard reagents, followed by flash-vacuum pyrolysis.

Full text of DOI:10.1039/c3ob41247d

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A synthesis of γ-trifluoromethyl α,β-unsaturated
γ-butyrolactones using CF3SiMe3 as a
trifluoromethylating agent†
Cite this: Org. Biomol. Chem., 2013, 11,
6650
Chonticha Masusai,a Darunee Soorukram,a Chutima Kuhakarn,a
Patoomratana Tuchinda,a Chaveng Pakawatchai,b Saowanit Saithong,b
Vichai Reutrakula and Manat Pohmakotr*a
A general synthesis of γ-trifluoromethyl α,β-unsaturated γ-butyrolactones is described. The fluoride-cata-
lyzed nucleophilic addition of a trifluoromethyl (CF3) group generated from (trifluoromethyl)trimethyl-
silane (CF3SiMe3, Ruppert–Prakash reagent) to a masked maleic anhydride 1 (cyclopentadiene–maleic
anhydride adduct) provides the corresponding adducts 2 with high stereoselectivity. The γ-trifluoro-
methyl α,β-unsaturated γ-butyrolactones 4 were obtained after treatment of the adducts 2 with Grignard
reagents, followed by flash-vacuum pyrolysis.
Received 17th June 2013,
Accepted 31st July 2013
DOI: 10.1039/c3ob41247d
www.rsc.org/obc
Fluorine containing compounds possess unique physical and been extensively exploited as a useful method for the prepa-
chemical properties because of the special size of the fluorine ration of trifluoromethyl-containing compounds.19
atom, the high carbon–fluorine bond energy and the special
A few reports were found in the literature related to the
inductive and resonance effects caused by fluorine atom.1 nucleophilic trifluoromethylation of anhydrides. For example,
Therefore, they receive intensive attention in various fields Wakselman and co-workers reported nucleophilic addition of
including agrochemical, pharmaceutical and materials chem- CF3ZnBr to anhydrides in pyridine.8 Later, Viner reported the
istry.2 For example, in medicinal chemistry, incorporation of fluoride-catalyzed trifluoromethylation of succinic anhydride
trifluoromethyl (CF3) groups into the molecular framework of using CF3SiMe3 as a reagent for the synthesis of acetylcholin-
pharmaceuticals is commonly found to improve their biologi- esterase (AChE) inhibitors.20 A recent study on fluoride-cata-
cal activity as a result of the resilience of the trifluoromethyl lyzed nucleophilic addition of PhSCF2SiMe3 to anhydrides
group to metabolism.3 Hence, the development of synthetic yielding the corresponding γ-lactones, which could be further
strategies that achieve incorporation of the trifluoromethyl transformed to γ-difluoromethylated γ-lactams was reported by
functionality in a series of substrates has been the subject of us.21
intense research efforts.4 Methods for the direct trifluoro-
Our research group has longheld an interest in the develop-
methylation of aryl halides, aryl and vinylboronic acids, term- ment of synthetic strategies for the preparation of fluorine-con-
inal alkenes, and primary and secondary alkylboronic acids taining compounds. Herein, we report our efforts in exploring
have been reported.5–18 Among these, fluoride-catalyzed a general approach to the synthesis of γ-trifluoromethyl α,β-un-
nucleophilic addition of the trifluoromethyl (CF3) group saturated γ-butyrolactones using CF3SiMe3 as a trifluoromethyl-
generated from (trifluoromethyl)trimethylsilane (CF3SiMe3, ating agent. It was anticipated that fluoride-catalyzed
Ruppert–Prakash reagent) to various electrophiles, e.g., carbo- trifluoromethylation of a masked maleic anhydride 1 (cyclo-
nyl compounds, esters, imines, enones and cyclic amides has pentadiene–maleic anhydride adduct)22 with CF3SiMe3 would
afford the corresponding adduct 2. Treatment of 2 with
Grignard reagents gives γ-trifluoromethyl γ-butyrolactones 3,
which upon flash-vacuum pyrolysis (FVP) lead to the desired
aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry,
γ-trifluoromethyl α,β-unsaturated γ-butyrolactones
4
as
Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand.
E-mail: manat.poh@mahidol.ac.th; Fax: +66-2-6445126; Tel: +66-2-2015158
bDepartment of Chemistry and Center of Excellence for Innovation in Chemistry,
Faculty of Science, Prince of Songkla University, Hat Yai, Songkla 90112, Thailand
†Electronic supplementary information (ESI) available: Spectroscopic data for all
compounds (copies of 1H, 13C and 19F NMR), and NOESY and NOE of 3a. CCDC
933155 and 933154. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ob41247d
depicted in Scheme 1. It is worth mentioning that a different
approach to the synthesis of trifluoromethylated lactones was
previously reported by Yoshida.23 α,β-Unsaturated γ-butyro-
lactones are important structural motifs, which are widely
found in bioactive natural products.24 This type of compound
has also been employed as a versatile starting material for
6650 | Org. Biomol. Chem., 2013, 11, 6650–6658
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Fig. 1 X-ray crystallographic structure of 2a.
Scheme 1 Proposed synthetic strategy for γ-trifluoromethyl α,β-unsaturated
γ-butyrolactone 4.
standard reaction conditions or at
a
lower temperature
(−78 °C) failed to provide the desired adduct, with only a
complex mixture being obtained.
further synthetic applications. Hence, there is continuing
interest in synthetic approaches for the α,β-unsaturated
γ-butyrolactone synthesis.25
Having established efficient access to compound 2, we
further demonstrated that our method could be used as a
general route for the synthesis of γ-trifluoromethyl α,β-unsatu-
rated γ-butyrolactones. Thus, 2 was subjected to a nucleophilic
addition reaction using hydride or organometallic reagents.
Treatment of 2 with NaCNBH3 in acetic acid with a catalytic
amount of trifluoroacetic acid at 50 °C for 16 h gave an 88%
yield of γ-butyrolactone 3a as a single isomer (Table 1, entry 1).
The reaction of 2 with Grignard reagents as listed in Table 1 in
THF followed by acid-catalyzed lactonization afforded the
corresponding γ-butyrolactones 3b–3i as single isomers in
moderate to high yields (Table 1, entries 2–9). Using isopropyl-
magnesium chloride to react with 2 gave the expected product
3d along with the reduction product 3a in 40 and 35% yields,
respectively (Table 1, entry 4). Improved results were obtained
when the addition of isopropylmagnesium chloride was
carried out at −78 °C. Thus, 3d was obtained in 50% yield
Our initial studies focused on the optimization of the fluor-
ide-catalyzed trifluoromethylation of the masked maleic anhy-
dride 1. After screening for the optimum reaction conditions,
it was found that treatment of 1 with CF3SiMe3 (2 equiv.) cata-
lyzed by 10 mol% TBAT (tetrabutylammoniumtriphenyl
difluorosilicate) in THF at 0 °C, in a reaction mixture which
was then kept below 10 °C for 4 h, followed by quenching with
H2O provided the desired trifluoromethylated adduct 2 in 90%
yield (Scheme 2). It should be mentioned that a longer reac-
tion time was needed and lower yields of the product 2 were
observed when a lesser amount of CF3SiMe3 (1 and 1.5 equiv.)
was used. The reaction proceeded with high stereoselectivity to
give a 97 : 3 mixture of the isomers as determined by 19F and
1H NMR. The relative stereochemistry of the major isomer 2a
was determined by X-ray crystallography (Fig. 1).26 It was
reasoned that formation of 2a as the major diastereomer
occurred because nucleophilic trifluoromethylation selectively
took place at the less sterically hindered convex side of 1. It is
worth mentioning that the reaction of 1 with CF3SiMe3 cata-
lyzed by TBAF (THF, 0 to 10 °C, 4 h) or CsF (THF, 0 °C to rt,
24 h) gave the adduct 2 with similar stereoselectivity but in
lower yields, 78 and 43%, respectively. Notably, the direct
addition of CF3SiMe3 to naked maleic anhydride under the
Table 1 Nucleophilic addition reactions of 2 with NaCNBH3 and Grignard
reagents
Yielda (%)
Entry Reagent
R
3
3a
1
2
3
4
5
6
7
8
9
NaCNBH3
CH3MgCl
CH3CH2MgCl
(CH3)2CHMgCl
CH3(CH2)3MgCl
CH2vCHMgCl
CH2vCH(CH2)2MgBr CH2vCH(CH2)2– 3g, 80
PhMgCl
4-MeO(Ph)MgBr
H–
CH3–
CH3CH2–
(CH3)2CH–
CH3(CH2)3–
CH2vCH–
—
88
—
—
3b, 86
3c, 86
3d, 40 (50)b 35 (19)b
3e, 86
3f, 87
—
—
—
—
—
Ph–
4-MeO(Ph)–
3h, 91
3i, 69
a Yields of isolated products. b The reaction was carried out at −78 °C
for 1 h.
Scheme 2 The fluoride-catalyzed addition of CF3SiMe3 to the masked maleic
anhydride 1 and maleic anhydride.
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Table 2 Preparation of 4 by flash-vacuum pyrolysis of adduct 3
Entry
3, R
4, yielda (%)
1
2
3
4
5
6
7
8
9
3a, H–
3b, CH3–
4a, 82
4b, 54
4c, 87
4d, 91
4e, 98
4f, 87
4g, 99
4h, 96b
4i, 97b
3c, CH3CH2–
3d, (CH3)2CH–
3e, CH3(CH2)3–
3f, CH2vCH–
3g, CH2vCH(CH2)2–
3h, Ph–
Fig. 2 X-ray crystallographic structure of 3i.
together with 3a in 19% yield (Table 1, entry 4). The stereo-
chemistry of compound 3a was confirmed by NOESY and NOE
experiments and in the case of 3i the stereochemistry was con-
firmed by X-ray crystallography (Fig. 2 and see ESI†).
3i, 4-MeO(Ph)–
a Yields of the analytical pure products after FVP. b Isolated yields after
preparative thin-layer chromatography (SiO2).
Based on the NOESY and NOE experimental data of 3a and
the X-ray crystallography of 3i, a transition state for selective
the corresponding γ-trifluoromethyl α,β-unsaturated γ-butyro-
lactones 4a–4i as summarized in Table 2.
nucleophilic addition to
2 was proposed as shown in
Scheme 3. Initially, proton abstraction of 2 with NaCNBH3 or
RMgX followed by ring-opening led to the formation of the
keto-carboxylate 2c, which then underwent stereoselective
nucleophilic addition on the convex side leading to 3 as a
single isomer after lactonization (Scheme 3).
In order to test the possibility of obtaining the required
γ-trifluoromethyl α,β-unsaturated γ-butyrolactones, the adduct
2 (as a 97 : 3 diastereomeric mixture) was directly subjected to
flash-vacuum pyrolysis (375 °C, 0.05 mmHg). It was found that
the reaction of 2 provided γ-hydroxy-γ-trifluoromethyl α,β-un-
saturated γ-butyrolactone (5) in 66% yield (Scheme 4).
Finally, based on the conditions used to synthesize 5, the
preparation of γ-trifluoromethyl α,β-unsaturated γ-butyro-
lactone 4 was accomplished by performing flash-vacuum pyro-
lysis of adduct 3. Thus, 3a–3i were subjected to flash-vacuum
pyrolysis conditions (375 °C, 0.05 mmHg) to give high yields of
Conclusions
We have reported a general fluoride-catalyzed nucleophilic
addition of a CF3 group to an anhydride. The method has
been utilized for the preparation of γ-trifluoromethyl α,β-un-
saturated γ-butyrolactones by performing a fluoride-catalyzed
nucleophilic addition of a CF3 group to a masked maleic anhy-
dride (cyclopentadiene–maleic anhydride adduct) followed by
reaction with a Grignard reagent and flash-vacuum pyrolysis.
This type of compound may be useful as the starting material
for the synthesis of trifluoromethylated organic compounds
including some natural compounds. Investigations in this area
are now in progress.
Experimental
General information
The 1H NMR spectra were recorded using a Bruker 400
(400 MHz) or a Bruker 500 (500 MHz) spectrometer using
CDCl3 as a solvent and tetramethylsilane as an internal stan-
dard. The 13C NMR spectra were recorded using a Bruker 400
(100 MHz) or a Bruker 500 (125 MHz) spectrometer using
CDCl3 as a solvent and the residual non-deuterated solvent
peaks as an internal standard. The 19F NMR spectra were
recorded using a Bruker 400 (376 MHz) or 500 (470 MHz)
spectrometer and the chemical shifts (δ) were measured with
fluorotrichloromethane (δ = 0) as an internal standard. The IR
spectra were recorded using either a Jasco A-302 or a Perkin
Elmer 683 infrared spectrometer with the solvent CHCl3 or
neat. The mass spectra were recorded using a Thermo Finni-
gan Polaris Q mass spectrometer. The high resolution mass
spectra were recorded using either a HR-TOF-MS Micromass
Scheme 3 Proposed stereoselective addition of NaCNBH3 or RMgX to 2.
Scheme 4 Flash-vacuum pyrolysis of 2.
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model VQ-TOF2 or a Finnigan MAT 95 mass spectrometer. atmosphere. After stirring the reaction mixture for 1 h at
Melting points were measured (uncorrected) using a Büchi −78 °C, or at 0 °C for 40 min, 10% HCl (2 mL) was added at
501 melting point apparatus. The X-ray crystallographic analy- −78 °C or at 0 °C. The aqueous phase was extracted with EtOAc
sis was performed by Kappa CCD. Tetrahydrofuran (THF) was (4 × 20 mL). The combined organic phase was washed with
distilled over sodium benzophenone ketyl. Dichloromethane brine (20 mL) and dried over anhydrous Na2SO4. After the
(CH2Cl2) and toluene were distilled over calcium hydride and removal of the solvents, the crude product was treated with a
were stored over activated molecular sieves (4 Å). All glassware catalytic amount of p-TsOH in dry CH2Cl2 (12 mL) under reflux
and syringes were oven-dried and kept in a desiccator before overnight (16 h). The reaction was quenched with saturated
use. Preparative thin-layer chromatography plates were per- NaHCO3 and extracted with CH2Cl2 (4 × 10 mL). The combined
formed using Merck silica gel 60 PF254 (Art 7747). Column organic phase was washed with brine (10 mL), and dried over
chromatography was performed using Merck silica gel 60 PF254 anhydrous Na2SO4. After removal of the solvent, the crude
(Art 7734). Flash column chromatography was performed product was purified by column chromatography (SiO2) or pre-
using Merck silica gel 60 PF254 (Art 7736). Other common sol- parative thin-layer chromatography (SiO2).
vents (CH2Cl2, hexanes, ethyl acetate (EtOAc), methanol, and
acetone) were distilled before use.
General procedure B. A solution of alkyl or arylbromide
(10.0 mmol) in dry THF (8 mL) was added dropwise to a sus-
pension of Mg (turnings) (0.4 g, 20.0 mmol) in dry THF (7 mL)
under an argon atmosphere at room temperature. After 2 h,
the solution of freshly prepared Grignard reagent was trans-
General procedure for the synthesis of γ-hydroxy
γ-trifluoromethyl γ-butyrolactones 2
A
solution of (trifluoromethyl)trimethylsilane (CF3SiMe3, ferred dropwise to a mixed solution of 2a and 2b (0.5 mmol)
0.6 mL, 4.0 mmol) and 1 (328 mg, 2.0 mmol) in dry THF in THF (20 mL) via a canular at −78 °C or 0 °C under an argon
(10 mL) was treated with a solution of 10 mol% TBAT (108 mg, atmosphere and then stirred for 1 h. The reaction mixture was
0.2 mmol) in dry THF (10 mL) at 0 °C under an argon atmos- quenched with 10% HCl (5 mL) at −78 °C or 0 °C and extracted
phere. The reaction mixture was stirred and kept below 10 °C with EtOAc (4 × 20 mL). The combined organic phase was
for 4 h, then quenched with water and extracted with EtOAc washed with brine (20 mL) and dried over anhydrous Na2SO4.
(4 × 20 mL). The combined organic phase was washed succes- After removal of the solvent, the crude product was treated
sively with water (20 mL), brine (20 mL) and dried over anhy- with a catalytic amount of p-TsOH in dry CH2Cl2 (12 mL)
drous Na2SO4. After removal of the solvents, the crude product under reflux overnight (16 h). The reaction was quenched with
was purified by column chromatography (SiO2, 5% EtOAc in saturated NaHCO3 and extracted with CH2Cl2 (4 × 10 mL). The
hexanes) to give a 97 : 3 diastereomeric mixture of 2a and 2b combined organic phase was washed with brine (10 mL), and
(423 mg, 90%) as a white solid (mp 105–107 °C (CH2Cl2– dried over anhydrous Na2SO4. After removal of the solvent, the
hexanes)). IR (CHCl3): νmax 3189 br, 3030 m, 2998 m, 2875 w, crude product was purified by column chromatography (SiO2)
1785 s, 1312 m, 1241 m, 1183 s, 1049 m, 1004 s cm−1; 1H NMR or preparative thin-layer chromatography (SiO2).
(400 MHz, CDCl3, minor isomer marked *): δ 6.38–6.36 (m,
(3R*,3aS*,4R*,7S*,7aR*)-3-(Trifluoromethyl)-3a,4,7,7a-tetra-
1H, CH), 6.27–6.21 (m, 1H, CH*), 6.20–6.18 (m, 1H, CH), hydro-4,7-methanoisobenzofuran-1(3H)-one (3a). A mixture of
6.14–6.07 (m, 1H, CH*), 4.65 (s, 1H, OH*), 4.49 (s, 1H, OH), 2a and 2b (118 mg, 0.5 mmol) in acetic acid (3 mL) and a cata-
3.61–3.54 (m, 1H, CH*), 3.51–3.48 (m, 1H, CH), 3.36–3.29 (br, lytic amount of TFA was treated with NaCNBH3 (0.3 g,
1H, CH), 3.28–3.25 (m, 2H, 2 × CH), 3.13–3.05 (m, 2H, 2 × 1.5 mmol) at 0 °C. After stirring for 5 min, the reaction
CH*), 1.73 (d, J = 8.8 Hz, 1H, CHH*), 1.67 (d, J = 8.8 Hz, 1H, mixture was heated at 50 °C overnight (16 h). It was quenched
CHH), 1.50 (d, J = 8.8 Hz, 1H, CHH). Due to their low intensity, with 10% NaOH (5 mL), then diluted with water (5 mL) and
some peaks for 2b could not be detected by 1H NMR. 13C NMR extracted with EtOAc (4 × 10 mL). The combined organic phase
(100 MHz, CDCl3, minor isomer marked *): δ 174.0 (C), 136.5 was washed successively with water (10 mL), brine (10 mL) and
(C), 135.9 (C*), 134.1 (C), 122.0 (q, J = 284.0 Hz, CF3), 100.5 (q, dried over anhydrous Na2SO4. After removal of the solvent, the
J = 34.0 Hz, C), 53.7 (CH2*), 52.0 (CH2), 49.8 (CH), 48.8 (CH*), crude product was purified by column chromatography (SiO2,
47.1 (CH*), 45.8 (CH), 45.0 (CH), 44.8 (CH), 44.3 (CH*), 44.2 5% EtOAc–hexanes) to give 3a (96 mg, 88%) as a colorless oil.
(CH*). Due to their low intensity, some peaks for 2b could not IR (neat): νmax 2987 m, 2952 w, 2878 w, 1788 s, 1407 m,
be detected by 13C NMR. 19F NMR (376 MHz, CDCl3, minor 1305 m, 1214 m, 1167 s, 1111 m, 1052 m, 1029 s cm−1 1H
;
isomer marked *): δ −86.8 (s, 3F), −79.4 (s, 3F*); MS: m/z NMR (400 MHz, CDCl3): δ 6.25–6.18 (m, 2H, 2 × CH), 4.71 (dq,
(% relative intensity) 235 (M+ + H, 31), 217 (17), 190 (19), J = 7.6, 7.6 Hz, 1H, CH), 3.46 (dd, J = 8.7, 5.1 Hz, 1H, CH),
119 (13), 91 (48), 66 (100); HRMS (ESI–TOF) calcd for 3.32–3.26 (br.s, 1H, CH), 3.23–3.12 (m, 2H, 2 × CH), 1.71 (d, J =
C10H9F3O3Na [M + Na]+: 257.0401, found 257.0402.
8.7 Hz, 1H, CHH), 1.48 (d, J = 8.7 Hz, 1H, CHH); 13C NMR
(100 MHz, CDCl3): δ 174.8 (C), 136.1 (CH), 134.6 (t, J = 4.0, Hz,
CH), 122.8 (q, J = 278.0 Hz, CF3), 75.6 (q, J = 36.0 Hz, CH),
53.6 (d, J = 16.0 Hz, CH2), 47.4 (CH), 44.6 (2 × CH), 41.4 (CH);
General procedure for the synthesis of γ-trifluoromethyl
γ-butyrolactones 3
General procedure A. A solution of 2a and 2b (0.5 mmol) in 19F NMR (367 MHz, CDCl3): δ −71.5 (s, 3F); MS: m/z (%
dry THF (30 mL) was treated with alkyl or arylmagnesium relative intensity) 218 (M+, 11), 200 (76), 179 (84), 150 (43),
chloride solution (2.5 mmol) at −78 °C or 0 °C under an argon 149 (19), 134 (38), 122 (60), 96 (62), 81 (100), 67 (50); HRMS
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(ESI–TOF) calcd for C10H9F3O2Na [M + Na]+: 241.0452, found J = 8.5 Hz, 1H, CHH), 1.44 (d, J = 8.5 Hz, 1H, CHH), 1.02 (dd,
241.0443.
J = 7.0, 1.3 Hz, 3H, CH3), 0.95 (d, J = 7.0 Hz, 3H, CH3); 13C NMR
(3R*,3aS*,4R*,7S*,7aR*)-3-Methyl-3-(trifluoromethyl)- (125 MHz, CDCl3): δ 175.1 (C), 135.4 (q, J = 4.1 Hz, CH), 135.2
3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3b). (CH), 124.4 (q, J = 284.0 Hz, CF3), 87.1 (q, J = 28.8 Hz, C), 54.4
According to the general procedure A, the reaction of 2a and (CH2), 49.2 (CH), 46.0 (CH), 44.7 (CH), 44.3 (CH), 35.5 (CH),
2b (118 mg, 0.5 mmol) and methylmagnesium chloride (3.0 M 16.9 (CH3), 16.3 (CH3); 19F NMR (470 MHz, CDCl3): δ −76.1 (s,
in THF, 0.83 mL, 2.5 mmol) at 0 °C followed by lactonization 3F); MS: m/z (% relative intensity) 261 (M+ + H, 22), 217 (10),
gave 3b (100 mg, 86%) as a white semi-solid after column 195 (9), 151 (10), 91 (19), 66 (100); HRMS (ESI-TOF) calcd for
chromatography (SiO2, 10% EtOAc in hexanes). IR (CHCl3): C13H15F3O2Na [M + Na]+: 283.0922, found 283.0925.
νmax 2992 m, 1781 s, 1460 m, 1341 m, 1168 m, 1098 m, 963 m
(3R*,3aS*,4R*,7S*,7aR*)-3-Butyl-3-(trifluoromethyl)-3a,4,7,7a-
cm−1 1H NMR (500 MHz, CDCl3): δ 6.25–6.22 (m, 1H, CH), tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3e). Accord-
;
6.19–6.08 (m, 1H, CH), 3.50 (dd, J = 8.5, 5.2 Hz, 1H, CH), 3.25 ing to the general procedure A, the reaction of 2a and 2b
(br.s, 1H, CH), 3.18 (br.s, 1H, CH), 2.87 (dd, J = 8.5, 3.2 Hz, 1H, (118 mg, 0.5 mmol) and butylmagnesium chloride (2.0 M in
CH), 1.71 (d, J = 8.6 Hz, 1H, CHH), 1.53 (s, 3H, CH3), 1.46 (d, THF, 1.25 mL, 2.5 mmol) at 0 °C followed by lactonization
J = 8.6 Hz, 1H, CHH); 13C NMR (125 MHz, CDCl3): δ 174.7 (C), gave 3e (118 mg, 86%) as a colorless oil after column
135.9 (CH), 134.7 (q, J = 5.0 Hz, CH), 123.8 (q, J = 280.0 Hz, chromatography (SiO2, 10% EtOAc in hexanes). IR (neat): νmax
CF3), 81.9 (q, J = 32.5 Hz, C), 53.8 (CH2), 49.2 (CH), 47.6 (CH), 2962 s, 2876 m, 1788 s, 1470 m, 1328 m, 1262 m, 1187 m,
1
45.2 (CH), 44.1 (CH), 25.2 (CH3); 19F NMR (470 MHz, CDCl3): 1164 m, 1018 m cm−1; H NMR (500 MHz, CDCl3): δ 6.18–6.16
δ −75.1 (s, 3F); MS: m/z (% relative intensity) 233 (M+ + H, 40), (m, 1H, CH), 6.13–6.11 (m, 1H, CH), 3.39 (dd, J = 8.8, 5.2 Hz,
211 (9), 178 (25), 169 (13), 128 (15), 115 (16), 91 (28), 66 (100); 1H, CH), 3.21–3.15 (m, 1H, CH), 3.14 (br.s, 1H, CH), 2.87 (dd,
HRMS (ESI–TOF) calcd for C11H11F3O2Na [M + Na]+: 255.0609, J = 8.8, 3.4 Hz, 1H, CH), 1.84–1.68 (m, 2H, CH2), 1.65 (dt, J =
found 255.0603.
8.6, 1.6 Hz, 1H, CHH), 1.42 (d, J = 8.6 Hz, 1H, CHH), 1.40–1.33
(3R*,3aS*,4R*,7S*,7aR*)-3-Ethyl-3-(trifluoromethyl)-3a,4,7,7a- (m, 1H, CHH), 1.32–1.21 (m, 3H, CHH and CH2), 0.86 (t, J =
tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3c). Accord- 7.1 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3): δ 174.9 (C),
ing to the general procedure A, the reaction of 2a and 2b 135.5 (CH), 135.1 (q, J = 4.8 Hz, CH), 124.1 (q, J = 282.0 Hz,
(118 mg, 0.5 mmol) and ethylmagnesium chloride (2.0 M in CF3), 84.2 (q, J = 30.9 Hz, C), 54.1 (CH2), 48.3 (CH), 47.6 (CH),
THF, 1.25 mL, 2.5 mmol) at 0 °C followed by lactonization 45.6 (CH), 44.1 (CH), 38.0 (CH2), 24.7 (CH2), 22.8 (CH2), 13.7
gave 3c (106 mg, 86%) as a colorless oil after column (CH3); 19F NMR (470 MHz, CDCl3): δ −72.1 (s, 3F); MS: m/z
chromatography (SiO2, 10% EtOAc in hexanes). IR (CHCl3): (% relative intensity) 274 (M+, 17), 207 (10), 182 (24), 158 (28),
νmax 3028 m, 2992 m, 2950 m, 2877 w, 1781 s, 1465 m, 1328 m, 147 (79), 116 (34), 96 (100), 65 (58); HRMS (ESI–TOF) calcd for
1263 m, 1168 m, 1100 m, 992 m cm−1
CDCl3): δ 6.18–6.17 (m, 1H, CH), 6.13–6.12 (m, 1H, CH), 3.38
;
1H NMR (500 MHz, C14H17F3O2Na [M + Na]+: 297.1078, found 297.1078.
(3R*,3aS*,4R*,7S*,7aR*)-3-(Trifluoromethyl)-3-vinyl-3a,4,7,7a-
(dd, J = 8.8, 5.2 Hz, 1H, CH), 3.20–3.16 (m, 1H, CH), 3.15–3.11 tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3f). Accord-
(br.s, 1H, CH), 2.86 (dd, J = 8.8, 3.4 Hz, 1H, CH), 1.89–1.76 (m, ing to the general procedure A, the reaction of 2a and 2b
2H, CH2), 1.66 (d, J = 8.6 Hz, 1H, CHH), 1.42 (d, J = 8.6 Hz, 1H, (118 mg, 0.5 mmol) and vinylmagnesium chloride (1.6 M solu-
CHH), 0.97 (dt, J = 7.5, 0.9 Hz, 3H, CH3); 13C NMR (125 MHz, tion THF, 1.56 mL, 2.5 mmol) at 0 °C followed by lactonization
CDCl3): δ 175.0 (C), 135.6 (CH), 135.1 (q, J = 4.6 Hz, CH), 142.1 gave 3f (107 mg, 87%) as a white semi-solid after column
(q, J = 281.9 Hz, CF3), 84.4 (q, J = 30.6 Hz, C), 54.1 (CH2), 48.3 chromatography (SiO2, 10% EtOAc in hexanes). IR (CHCl3):
(CH), 47.2 (CH), 45.5 (CH), 44.1 (CH), 31.2 (CH2), 7.3 (CH3); 19
F
νmax 3020 m, 2994 m, 2949 w, 2877 w, 1788 s, 1413 w, 1329 s,
1H NMR (500 MHz,
NMR (470 MHz, CDCl3): δ −71.9 (s, 3F); MS: m/z (% relative 1314 m, 1170 m, 1135 m, 1009 s cm−1
;
intensity) 247 (M+ + H, 9), 217 (3), 189 (2), 181 (4), 151 (5), 133 CDCl3): δ 6.31–6.25 (m, 1H, CH), 6.24–6.16 (m, 1H, CH), 5.96
(7), 109 (5), 91 (27), 66 (100); HRMS (ESI–TOF) calcd for (dd, J = 17.0, 10.8 Hz, 1H, CH), 5.48 (d, J = 17.0 Hz, 1H, CHH),
C12H13F3O2Na [M + Na]+: 269.0765, found 269.0762.
5.41 (d, J = 10.8 Hz, 1H, CHH), 3.35 (dd, J = 8.4, 5.3 Hz, 1H,
(3R*,3aS*,4R*,7S*,7aR*)-3-Isopropyl-3-(trifluoromethyl)- CH), 3.29–3.19 (m, 2H, 2 × CH), 2.97 (dd, J = 8.4, 3.3 Hz, 1H,
3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3d). CH), 1.75 (d, J = 8.7 Hz, 1H, CHH), 1.48 (d, J = 8.7 Hz, 1H,
According to the general procedure A, the reaction of 2a and CHH); 13C NMR (125 MHz, CDCl3): δ 174.9 (C), 136.1 (CH),
2b (118 mg, 0.5 mmol) and isopropylmagnesium chloride (2.0 134.7 (q, J = 4.5 Hz, CH), 134.4 (CH), 122.9 (q, J = 282.8 Hz,
M in THF, 1.25 mL, 2.5 mmol) at −78 °C followed by lactoniza- CF3), 118.1 (CH2), 83.1 (q, J = 32.5 Hz, C), 53.8 (CH2), 48.2
tion gave 3d (65 mg, 50%) as a white solid (mp 79–80 °C (CH), 46.4 (CH), 45.2 (CH), 43.9 (CH); 19F NMR (470 MHz,
(CH2Cl2–hexanes)) together with
a
reduction product 3a CDCl3): δ −73.3 (s, 3F); MS: m/z (% relative intensity) 245 (M+ +
(20 mg, 19%) as a colorless oil after column chromatography H, 6), 206 (24), 191 (63), 185 (10), 178 (4), 175 (7), 148 (12), 147
(SiO2, 10% EtOAc in hexanes). IR (CHCl3): νmax 2977 m, 2949 (33), 111 (20), 91 (100), 66 (75); HRMS (ESI–TOF) calcd for
w, 1780 s, 1475 w, 1298 m, 1171 m, 1028 s cm−1 1H NMR C12H11F3O2Na [M + Na]+: 267.0609, found 267.0635.
;
(500 MHz, CDCl3): δ 6.20–6.09 (m, 2H, 2 × CH), 3.30 (dd, J =
(3R*,3aS*,4R*,7S*,7aR*)-3-(But-3-en-1-yl)-3-(trifluoro methyl)-
9.1, 5.1 Hz, 1H, CH), 3.20–3.12 (m, 2H, 2 × CH), 2.86 (dd, 3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3g).
J = 9.1, 3.4 Hz, 1H, CH), 2.18 (sept, J = 7.0 Hz, 1H, CH), 1.66 (d, According to the general procedure B, the reaction of 2a and
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2b (118 mg, 0.5 mmol) and but-3-en-1-ylmagnesium bromide 136.1 (CH), 135.1 (q, J = 4.0 Hz, CH), 130.0 (C), 127.1 (2 × CH),
at −78 °C followed by lactonization gave 3g (108 mg, 80%) as a 123.4 (q, J = 281.0 Hz, CF3), 114.1 (2 × CH), 84.5 (q, J = 32.0 Hz,
colorless oil after column chromatography (SiO2, 5% EtOAc in C), 55.3 (OCH3), 53.9 (CH2), 51.3 (CH), 46.9 (CH), 45.9 (CH),
hexanes). IR (neat): νmax 3083 w, 2986 m, 2877 w, 1789 s, 44.0 (CH); 19F NMR (376 MHz, CDCl3): δ −71.8 (s, 3F); MS: m/z
1645 m, 1456 m, 1330 w, 1186 m, 1164 m, 1044 w, 920 m, (% relative intensity) 325 (M+ + H, 20), 324 (78), 296 (39), 258
1
813 m cm−1; H NMR (400 MHz, CDCl3): δ 6.20–6.11 (m, 2H, (9), 211 (5), 189 (100), 161 (47), 66 (9); HRMS (ESI–TOF) calcd
2 × CH), 5.74–5.64 (m, 1H, CH), 5.01 (d, J = 17.2 Hz, 1H, CHH), for C17H15F3O3Na [M + Na]+: 347.0871, found 347.0872.
4.96 (d, J = 10.2 Hz, 1H, CHH), 3.40 (dd, J = 8.8, 5.2 Hz, 1H,
Synthesis of γ-trifluoromethyl α,β-unsaturated
γ-butyrolactones 4
CH), 3.18 (br.s, 1H, CH), 3.15 (br.s, 1H, CH), 2.89 (dd, J = 8.8,
3.3 Hz, 1H, CH), 2.20–2.00 (m, 2H, CH2), 1.86 (t, J = 8.8 Hz, 2H,
CH2), 1.67 (d, J = 8.7 Hz, 1H, CHH), 1.42 (d, J = 8.7 Hz, 1H, Flash-vacuum pyrolysis of 3 (conditions: oven temperature
CHH); 13C NMR (100 MHz, CDCl3): δ 174.9 (C), 136.2 (CH), 240 °C, column temperature 375 °C, pressure 0.05 mmHg)
135.7 (CH), 135.2 (q, J = 5.0 Hz, CH), 124.0 (q, J = 282.0 Hz, gave the expected products 4.
CF3), 116.0 (CH2), 83.8 (q, J = 30.0 Hz, C), 54.3 (CH2), 48.3
5-(Trifluoromethyl)furan-2(5H)-one
(4a). Flash-vacuum
(CH), 47.8 (CH), 45.6 (CH), 44.0 (CH), 37.5 (CH2), 26.9 (CH2); pyrolysis of 3a (78 mg, 0.36 mmol) gave 4a (45 mg, 82%) as a
19F NMR (376 MHz, CDCl3): δ −72.0 (s, 3F); MS: m/z (% relative colorless liquid. IR (neat): νmax 3110 w, 2957 w, 2926 w, 2853
intensity) 273 (M+ + H, 17), 228 (4), 218 (4), 208 (15), 205 (3), w, 1801 s, 1764 s, 1608 w, 1366 m, 1278 m, 1184 m, 1154 m,
200 (10), 185 (7), 152 (7), 148 (4), 142 (8), 116 (7), 91 (23), 66 1106 m, 1061 m, 870 s cm−1 1H NMR (400 MHz, CDCl3):
;
(100); HRMS (ESI–TOF) calcd for C14H15F3O2Na [M + Na]+: δ 7.48 (dd, J = 5.8, 1.5 Hz, 1H, CH), 6.44 (d, J = 5.8 Hz, 1H, CH),
295.0922, found 295.0922.
5.36–5.32 (m, 1H, CH); 13C NMR (100 MHz, CDCl3): δ 170.2
(3S*,3aS*,4R*,7S*,7aR*)-3-Phenyl-3-(trifluoromethyl)-3a,4,7,7a- (C), 146.8 (CH), 125.7 (CH), 121.5 (q, J = 281.0 Hz, CF3), 78.5
tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3h). Accord- (q, J = 36.0 Hz, CH); 19F NMR (367 MHz, CDCl3): δ −76.0 (s,
ing to the general procedure A, the reaction of 2a and 2b 3F); MS: m/z (% relative intensity) 153 (M+ + H, 13), 152 (M+,
(118 mg, 0.5 mmol) and phenylmagnesium chloride (2.0 M in 14), 151 (M+ − H, 15), 127 (26), 113 (13), 97 (36), 91 (50),
THF, 1.25 mL, 2.5 mmol) at 0 °C followed by lactonization 83 (33), 81 (100); HRMS (APCI–TOF) calcd for C12H10F3O3
gave 3h (134 mg, 91%) as a white solid (mp 128–129 °C [M + H]+: 153.0163, found 153.0185.
(CH2Cl2–hexanes)) after column chromatography (SiO2, 10%
5-Methyl-5-(trifluoromethyl)furan-2(5H)-one
(4b). Flash-
EtOAc in hexanes). IR (CHCl3): νmax 3020 w, 2994 w, 2876 w, vacuum pyrolysis of 3b (49 mg, 0.23 mmol) gave 4b (20 mg,
1788 s, 1450 m, 1328 m, 1305 m, 1216 m, 1183 s, 1117 m, 54%) as a colorless liquid. IR (CHCl3): νmax 3030 w, 2928 w,
1
1042 s cm−1; H NMR (500 MHz, CDCl3): δ 7.53–7.51 (m, 2H, 2856 w, 1856 w, 1788 s, 1610 w, 1455 w, 1315 m, 1182 m,
2 × ArH), 7.44–7.38 (m, 3H, 3 × ArH), 6.33–6.28 (m, 2H, 2 × 1106 m, 1060 w, 974 m cm−1 1H NMR (400 MHz, CDCl3):
;
CH), 3.42 (br.s, 1H, CH), 3.39 (dd, J = 8.3, 3.3 Hz, 1H, CH), δ 7.34 (d, J = 5.7 Hz, 1H, CH), 6.25 (d, J = 5.7 Hz, 1H, CH), 1.61
3.26–3.21 (m, 1H, CH), 3.18 (dd, J = 8.3, 5.2 Hz, 1H, CH), 1.77 (d, J = 0.5 Hz, 1H, CH); 13C NMR (100 MHz, CDCl3): δ 170.1
(dt, J = 8.8, 1.6 Hz, 1H, CHH), 1.47 (d, J = 8.8 Hz, 1H, CHH); (C), 151.9 (CH), 124.6 (CH), 122.8 (q, J = 281.0 Hz, CF3), 85.1
13C NMR (125 MHz, CDCl3): δ 174.9 (C), 138.3 (C), 136.1 (CH), (q, J = 34.0 Hz, C), 18.0 (CH3); 19F NMR (367 MHz, CDCl3):
134.9 (q, J = 4.3 Hz, CH), 129.2 (CH), 128.8 (2 × CH), 125.6 (2 × δ −79.2 (s, 3F); MS: m/z (% relative intensity) 167 (M+ + H, 58),
CH), 123.4 (q, J = 281.4 Hz, CF3), 84.6 (q, J = 32.1 Hz, C), 53.9 151 (10), 149 (100), 141 (14), 129 (12), 125 (13), 109 (22),
(CH2), 51.5 (CH), 46.7 (CH), 45.9 (CH), 44.0 (CH); 19F NMR 97 (27); HRMS (APCI–TOF) calcd for C6H6F3O2 [M + H]+:
(470 MHz, CDCl3): δ −71.2 (s, 3F); MS: m/z (% relative inten- 167.0320, found 167.0336.
sity) 295 (M+ + H, 69), 275 (15), 249 (45), 217 (7), 209 (22),
181 (82), 77 (11), 66 (100); HRMS (ESI–TOF) calcd for vacuum pyrolysis of 3c (64 mg, 0.26 mmol) gave 4c (41 mg,
C16H13F3O2Na [M + Na]+: 317.0765, found 317.0765.
87%) as a colorless liquid. IR (CHCl3): νmax 3098 w, 2987 w,
5-Ethyl-5-(trifluoromethyl)furan-2(5H)-one (4c). Flash-
(3S*,3aS*,4R*,7S*,7aR*)-3-(4-Methoxyphenyl)-3-(trifluoro- 2949 w, 2892 w, 1809 s, 1782 s, 1610 w, 1464 w, 1298 m,
methyl)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)- 1179 m, 1127 m, 1015 m, 979 m, 904 m, 824 m cm−1; 1H NMR
one (3i). According to the general procedure B, the reaction of (400 MHz, CDCl3): δ 7.29 (d, J = 5.8 Hz, 1H, CH), 6.35 (d, J =
2a and 2b (118 mg, 0.5 mmol) and 4-methoxyphenyl mag- 5.8 Hz, 1H, CH), 2.20 (dq, J = 14.8, 7.4 Hz, 1H, CHH), 2.01 (dq,
nesium bromide at 0 °C followed by lactonization gave 3i J = 14.8, 7.4 Hz, 1H, CHH), 0.87 (dt, J = 7.2, 0.4 Hz, 3H, CH3);
(225 mg, 69%) as a white solid (mp 104–106 °C (CH2Cl2– 13C NMR (100 MHz, CDCl3): δ 170.4 (C), 150.6 (CH), 125.6
hexanes)) after column chromatography (SiO2, 5% EtOAc in (CH), 122.9 (q, J = 282.0 Hz, CF3), 88.1 (q, J = 31.0 Hz, C), 23.5
hexanes). IR (CHCl3): νmax 3020 m, 2996 w, 2841 w, 1785 s, (CH2), 6.3 (CH3); 19F NMR (367 MHz, CDCl3): δ −77.8 (s, 3F);
1611 s, 1514 s, 1464 m, 1306 m, 1258 m, 1179 s, 1041 s cm−1
;
MS: m/z (% relative intensity) 181 (M+ + H, 20), 151 (26),
1H NMR (400 MHz, CDCl3): δ 7.35 (d, J = 8.6 Hz, 2H, 2 × ArH), 126 (17), 123 (30), 111 (79), 82 (17), 71 (100); HRMS (ESI–TOF)
6.84 (d, J = 8.6 Hz, 2H, 2 × ArH), 6.24–6.20 (m, 2H, 2 × CH), calcd for C7H7F3O2Na [M + Na]+: 203.0296, found 203.0295.
3.73 (s, 3H, OCH3), 3.33–3.27 (m, 2H, 2 × CH), 3.15–3.09 (m,
5-Isopropyl-5-(trifluoromethyl)furan-2(5H)-one (4d). Flash-
2H, 2 × CH), 1.68 (d, J = 8.8 Hz, 1H, CHH), 1.39 (d, J = 8.8 Hz, vacuum pyrolysis of 3d (92 mg, 0.35 mmol) gave 4d (63 mg,
1H, CHH); 13C NMR (100 MHz, CDCl3): δ 175.1 (C), 160.2 (C), 91%) as a colorless liquid. IR (neat): νmax 3097 w, 2982 m,
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2949 w, 1810 s, 1794 s, 1778 s, 1608 w, 1472 w, 1291 s, 1175 s,
5-Phenyl-5-(trifluoromethyl)furan-2(5H)-one
(4h). Flash-
1
1122 m, 1043 m, 1026 m, 991 m, 908 m, 820 s cm−1; H NMR vacuum pyrolysis of 3h (114 mg, 0.39 mmol) gave 4h (84 mg,
(400 MHz, CDCl3): δ 7.38 (d, J = 5.8 Hz, 1H, CH), 6.37 (d, J = 96%) as a colorless liquid. IR (neat): νmax 3031 m, 1813 s, 1785
1
5.8 Hz, 1H, CH), 2.49 (sept, J = 6.9 Hz, 1H, CH), 1.08 (dd, J = s, 1452 m, 1281 s, 1114 s, 1025 s, 958 s, 907 s, 815 s cm−1; H
6.9, 0.9 Hz, 3H, CH3), 0.99 (d, J = 6.9 Hz, 3H, CH3); 13C NMR NMR (400 MHz, CDCl3): δ 7.75 (d, J = 5.2 Hz, 1H, CH), 7.47 (br.
(100 MHz, CDCl3): δ 170.4 (C), 150.0 (CH), 125.6 (CH), 123.2 s, 2H, 2 × ArH), 7.37 (br.s, 3H, 3 × ArH), 6.29 (d, J = 5.2 Hz, 1H,
(q, J = 283.0 Hz, CF3), 90.2 (q, J = 32.1 Hz, C), 30.5 (CH), 17.3 CH); 13C NMR (100 MHz, CDCl3): δ 169.8 (C), 150.9 (CH), 130.9
(d, J = 1.0 Hz, CH3), 16.6 (CH3); 19F NMR (367 MHz, CDCl3): (C), 130.1 (CH), 129.0 (2 × CH), 126.6 (2 × CH), 124.2 (CH),
δ −73.6 (s, 3F); MS: m/z (% relative intensity) 195 (M+ + H, 3), 122.4 (q, J = 282.0 Hz, CF3), 87.5 (q, J = 24.6 Hz, C); 19F NMR
175 (15), 152 (18), 138 (16), 125 (22), 111 (42), 82 (25), 71 (46), (367 MHz, CDCl3): δ −76.9 (s, 3F); MS: m/z (% relative inten-
69 (60), 57 (100); HRMS (ESI–TOF) calcd for C8H9F3O2Na sity) 229 (M+ + H, 21), 228 (M+, 2), 184 (10), 160 (100), 152 (2),
[M + Na]+: 217.0452, found 217.0453.
104 (27); HRMS (ESI–TOF) calcd for C11H7F3O2Na [M + Na]+:
5-Butyl-5-(trifluoromethyl)furan-2(5H)-one (4e). Flash- 251.0296, found 251.0290.
vacuum pyrolysis of 3e (118 mg, 0.43 mmol) gave 4e (87 mg,
5-(4-Methoxyphenyl)-5-(trifluoromethyl)furan-2(5H)-one (4i).
98%) as a colorless liquid. IR (neat): νmax 3098 w, 2965 m, Flash-vacuum pyrolysis of 3i (114 mg, 0.35 mmol) gave 4i
2938 m, 2877 w, 1608 w, 1471 w, 1303 m, 1261 w, 1176 m, (88 mg, 97%) as a colorless liquid. IR (neat): νmax 3028 m, 2963
1151 m, 1131 m, 1008 w cm−1 1H NMR (400 MHz, CDCl3): w, 2842 w, 1814 s, 1785 s, 1612 s, 1515 s, 1464 m, 1307 m,
;
δ 7.25 (d, J = 5.7 Hz, 1H, CH), 6.27 (d, J = 5.7 Hz, 1H, CH), 1259 m, 1098 s, 1025 s, 958 m, 909 m cm−1 1H NMR
;
2.14–2.00 (m, 1H, CHH), 1.98–1.82 (m, 1H, CHH), 1.36–0.98 (400 MHz, CDCl3): δ 7.73 (d, J = 4.8 Hz, 1H, CH), 7.38 (d, J =
(m, 4H, 2 × CH2), 0.83 (t, J = 7.2 Hz, 3H, CH3); 13C NMR 7.8 Hz, 2H, 2 × ArH), 6.87 (d, J = 7.8 Hz, 2H, 2 × ArH), 6.28 (d,
(100 MHz, CDCl3): δ 170.4 (C), 150.9 (CH), 125.3 (CH), 122.9 J = 4.8 Hz, 1H, CH), 3.73 (s, 3H, OCH3); 13C NMR (100 MHz,
(q, J = 282.0 Hz, CF3), 87.8 (q, J = 33.5 Hz, C), 29.7 (d, J = CDCl3): δ 169.9 (C), 160.8 (C), 150.9 (CH), 128.0 (2 × CH), 124.0
8.0 Hz, CH2), 24.0 (CH2), 22.4 (CH2), 13.7 (CH3); 19F NMR (CH), 122.7 (C), 122.4 (q, J = 282.0 Hz, CF3), 114.3 (2 × CH),
(367 MHz, CDCl3): δ −77.9 (s, 3F); MS: m/z (% relative inten- 87.3 (q, J = 31.5 Hz, C), 55.3 (OCH3); 19F NMR (367 MHz,
sity) 209 (M+ + H, 6), 151 (7), 139 (11), 97 (55), 85 (50), 71 (79), CDCl3): δ −77.2 (s, 3F); MS: m/z (% relative intensity) 259
57 (100); HRMS (ESI–TOF) calcd for C9H11F3O2Na [M + Na]+: (M+ + H, 21), 190 (100), 161 (33), 133 (18), 118 (5), 77 (5),
231.0609, found 231.0606.
63 (4); HRMS (ESI–TOF) calcd for C12H9F3O3Na [M + Na]+:
5-(Trifluoromethyl)-5-vinylfuran-2(5H)-one (4f). Flash- 281.0401, found 281.0403.
vacuum pyrolysis of 3f (90 mg, 0.37 mmol) gave 4f (57 mg,
87%) as a colorless liquid. IR (neat): νmax 3031 w, 2928 w,
1813 m, 1786 s, 1291 m, 1183 s, 1161 s, 1004 m, 817 m cm−1
;
Synthesis of γ-hydroxy γ-trifluoromethyl α,β-unsaturated
γ-butyrolactone 5
1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 5.7 Hz, 1H, CH), 6.32
(d, J = 5.7 Hz, 1H, CH), 6.06 (dd, J = 17.2, 10.8 Hz, 1H, CH),
5.69 (d, J = 17.2 Hz, 1H, CHH), 5.57 (d, J = 10.8 Hz, 1H, CHH);
13C NMR (100 MHz, CDCl3): δ 169.9 (C), 150.0 (CH), 126.8
(CH), 123.9 (CH), 122.1 (q, J = 283.0 Hz, CF3), 122.0 (CH2), 86.8
(q, J = 33.7 Hz, C); 19F NMR (367 MHz, CDCl3): δ −77.6 (s, 3F);
MS: m/z (% relative intensity) 178 (M+, 31), 149 (60), 121 (28),
109 (16), 81 (43), 77 (62), 67 (35); HRMS (APCI-TOF) calcd for
C7H6F3O2 [M + H]+: 179.0320, found 179.0338.
Flash-vacuum pyrolysis of 2 (118 mg, 0.5 mmol) (conditions:
oven temperature 240 °C, column temperature 375 °C,
pressure 0.05 mmHg) gave 5 (55 mg, 66%) as a white semi-
solid after column chromatography (SiO2, 30% EtOAc in
hexanes). IR (neat): νmax 3400 br (OH), 2876 w, 1815 s, 1786 s,
1632 m, 1444 w, 1333 m, 1291 m, 1185 s, 1085 m, 1051 m,
1
996 m, 916 m, 835 m cm−1; H NMR (500 MHz, CDCl3): δ 7.27
(d, J = 5.6 Hz, 1H, CH), 6.34 (d, J = 5.5 Hz, 1H, CH); 13C NMR
(125 MHz, CDCl3): δ 169.4 (C), 148.1 (CH), 126.8 (CH), 120.8
(q, J = 283.1 Hz, CF3), 101.6 (q, J = 36.0 Hz, CH); 19F NMR
(470 MHz, CDCl3): δ −82.2 (s, 3F); MS: m/z (% relative inten-
sity) 169 (M+ + H, 12), 167 (M+ − H, 7), 151 (100), 123 (37),
99 (68), 81 (54), 67 (36), 55 (47); HRMS (ESI–TOF) calcd for
C5H3F3O3Na [M + Na]+: 190.9932, Found 190.9942.
5-(But-3-en-1-yl)-5-(trifluoromethyl)furan-2(5H)-one
(4g).
Flash-vacuum pyrolysis of 3g (56 mg, 0.21 mmol) gave 4g
(42 mg, 99%) as a colorless liquid. IR (neat): νmax 3091 w,
2939 w, 2862 w, 1804 s, 1781 s, 1644 w, 1453 w, 1311 w,
1264 w, 1176 m, 1150 m, 1071 m, 985 m cm−1 1H NMR
;
(400 MHz, CDCl3): δ 7.34 (d, J = 5.7 Hz, 1H, CH), 6.35 (d, J =
5.7 Hz, 1H, CH), 5.79–5.69 (m, 1H, CH), 5.06 (d, J = 5.3 Hz, 1H,
CHH), 5.02 (s, 1H, CHH), 2.32–2.20 (m, 1H, CHH), 2.13–1.89
(m, 3H, CHH and CH2); 13C NMR (100 MHz, CDCl3): δ 170.2
(C), 150.6 (CH), 135.8 (CH), 127.0 (CH), 122.8 (q, J = 282.0 Hz,
CF3), 116.4 (CH2), 87.5 (q, J = 31.0 Hz, C), 29.3 (CH2), 26.2
Acknowledgements
(CH2); 19F NMR (367 MHz, CDCl3): δ −77.9 (s, 3F); MS: m/z We acknowledge financial support from the Thailand Research
(% relative intensity) 207 (M+ + H, 17), 151 (22), 149 (100), 137 Fund (BRG5380019), the office of the Higher Education Com-
(21), 125 (41), 111 (52), 95 (65), 82 (48), 71 (76), 67 (84); mission and Mahidol University under the National Research
HRMS (ESI–TOF) calcd for C9H9F3O2Na [M + Na]+: 229.0452, Universities Initiative, and the Center of Excellence for Inno-
found 229.0442.
vation in Chemistry (PERCH-CIC).
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