β-(trifluoromethyl)vinyl sulfonium salts: Preparation and reactions with active methylene and methenyl compounds

Article abstract of DOI:10.1021/jo2009033

Two trifluoromethyl-substituted building blocks β-(trifluoromethyl) vinyl sulfonium salts 1 and 2 were developed. Reactions of β- (trifluoromethyl)vinyl sulfonium salt 1 with active methylene compounds containing electron-withdrawing groups using DBU as the base in DMSO occurred to give trifluoromethyl-substituted cyclopropane derivatives 7 as the major products. In contrast, reactions of β-(trifluoromethyl)vinyl sulfonium salt 2 with active methylene compounds occurred with the migration of one of the electron-withdrawing groups to give the products 8 as the major products when NaH was used as the base in DMSO. Moreover, when NaH was used as base in THF/CH₂Cl₂ at -78 °C, reaction of β- (trifluoromethyl)vinyl sulfonium salt 1 gave trifluoromethyl-substituted 2,3-dihydrofuran derivatives 9 as the major products. A working mechanism was proposed to explain the different behaviors of the β-(trifluoromethyl)vinyl sulfonium salts 1 or 2 with active methylene compounds under these different conditions.

Full text of DOI:10.1021/jo2009033

ARTICLE
pubs.acs.org/joc
β-(Trifluoromethyl)vinyl Sulfonium Salts: Preparation and Reactions
with Active Methylene and Methenyl Compounds
Hao Lin, Qilong Shen, and Long Lu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, People's Republic of China
S Supporting Information
b
ABSTRACT: Two trifluoromethyl-substituted building blocks β-
(trifluoromethyl)vinyl sulfonium salts 1 and 2 were developed. Reactions
of β-(trifluoromethyl)vinyl sulfonium salt 1 with active methylene
compounds containing electron-withdrawing groups using DBU as the
base in DMSO occurred to give trifluoromethyl-substituted cyclopro-
pane derivatives 7 as the major products. In contrast, reactions of
β-(trifluoromethyl)vinyl sulfonium salt 2 with active methylene com-
pounds occurred with the migration of one of the electron-withdrawing
groups to give the products 8 as the major products when NaH was used
as the base in DMSO. Moreover, when NaH was used as base in THF/
CH2Cl2 at ꢀ78 °C, reaction of β-(trifluoromethyl)vinyl sulfonium salt 1
gave trifluoromethyl-substituted 2,3-dihydrofuran derivatives 9 as the major products. A working mechanism was proposed to
explain the different behaviors of the β-(trifluoromethyl)vinyl sulfonium salts 1 or 2 with active methylene compounds under these
different conditions.
’ INTRODUCTION
groups migrated, or trifluoromethyl-substituted 2,3-dihydrofur-
an derivatives 9 could be obtained. Herein, we disclose these
findings and propose a working mechanism to explain the
different behaviors of the β-trifluoromethyl-substituted vinylsul-
fonium salts 1 or 2 with active methylene compounds under
different conditions.
Organofluorine compounds have attracted special attention in
the field of drug discovery because of fluorine’s unique physical
and chemical properties.1,2 Consequently, broad research efforts
have been focused on the strategic introduction of fluorine
substitution into drug-like molecules in medicinal and agricultural
chemistry.3 Among all the strategies, using fluorinated building-
blocks that have both fluorine atom and substitutable functional
groups are particularly attractive, since reactions of fluorinated
building-blocks avoid the harsh reaction conditions and special
equipments needed for handling fluorine or other fluorinated
reagents.1,4 On the other hand, because of the intrinsic electro-
philic nature of the sulfonium ions, vinylsulfonium salts are well-
known as good Michael acceptors that undergo addition reac-
tions with various nucleophiles.5 Typically, they are used and act
as ethylene transfer reagents via initial Michael addition and
subsequent elimination of thioether in the synthesis of cyclopro-
panes, oxiranes, aziridines, and other heterocycles.6 Inspired by
the diverse reactivity of vinylsulfonium salts and our long-term
interest in development of trifluoromethylated building-blocks,
we designed two β-trifluoromethyl-substituted vinylsulfoniums
17 and 2. We found that compounds 1 and 2 could be readily
prepared from commercially available 3,3,3-trifluoropropene in
five steps. Subsequent studies disclosed that reactions of various
active methylene or methenyl compounds with β-(trifluoromethyl)-
vinyl sulfonium salts 1 and 2 in the presence of different bases
differed greatly. Three different products trifluoromethyl-sub-
stituted cyclopropane derivatives 7,8 trifluoromethyl-substituted
cyclopropane derivatives 8 with one of the electron-withdrawing
’ RESULTS
1. Preparation of β-(Trifluoromethyl)vinyl Sulfonium Salts
1 and 2. β-(Trifluoromethyl)vinyl sulfonium salts 1 and 2 were
readily prepared from commercially available 3,3,3-trifluoropro-
pene in five steps, as illustrated in Scheme 1. Intermediate 3 was
readily prepared in two steps in 40 g scale according to the
reported literature procedure from 3,3,3-trifluoropropene.9 Es-
terification of the resulting alcohol with 1.2 equiv of triflic
anhydride and 1.2 equiv of pyridine in CH2Cl2 gave intermediate
4 in quantitative yield. Reaction of intermediate 4 with tetra-
hydrothiophene occurred smoothly in toluene at 100 °C to give a
pale gray solid 5b in 84% yield. Reaction of intermediate 4 with
diphenyl sulfide was rather slow under the same conditions,
mainly because of the low nucleophilicity of diphenyl sulfide. The
diphenylsulfonium salt 5a was obtained in 67% yield under
Received: May 6, 2011
Published: July 28, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo2009033 J. Org. Chem. 2011, 76, 7359–7369
|

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ARTICLE
Scheme 1. Preparation of β-(Trifluoromethyl)vinyl Sulfo-
nium Salts 1 and 2
Table 2. Reactions of β-(Trifluoromethyl)vinyl Diphenyl-
sulfonium Salt 1 with Active Methylene Molecules 6 in the
Presence of DBU in DMSOa
Table 1. Optimization of the Conditions for the Reaction of
β-(Trifluoromethyl)vinyl Diphenylsulfonium salt 1 with Ethyl
Malonate 6a
yield (%)a
a Reaction conditions: 1 (0.3 mmol), 6 (0.36 mmol), and DBU (0.36
mmol) in DMSO (9 mL) for 10 min at room temperature. b Determined
by 19F NMR analysis of the crude reaction mixture with R,R,R-
trifluorotoluene as an internal standard. c Isolated yield of 7. d Two
diastereomers of 7 (3:1). e Unseperable mixture of three isomers.
entry
base
DBU
solvent
CH2Cl2
temp, °C
7a
8a
1
2
0
80 (60)b
66
0
0
DBU
Et2O/CH2Cl2
CH3CN
DMF
0
3
DBU
0
92
0
2. Reaction of β-(Trifluoromethyl)vinyl Sulfonium Salt 1
with Active Methylene Compounds in the Presence of DBU
in DMSO. With β-(trifluoromethyl)vinyl sulfonium salts 1 and 2
in hand, we began to study the reactions of β-(trifluoromethyl)-
vinyl sulfonium salt 1 with active methylene molecules in the
presence of different bases in different solvents. Reaction of
β-(trifluoromethyl)vinyl diphenylsulfonium salt 1 with 6a in the
presence of 1.2 equiv of DBU as the base in CH2Cl2 occurred
smoothly at 0 °C for less than 10 min to give the desired
trifluoromethyl-substituted cyclopropane derivative 7a in 60%
yield and a minor side product trifluoromethyl propyne which
was formed through elimination under basic conditions as
determined by 19F NMR spectroscopy (Table 1, entry 1).10,11
The side product trifluoromethyl propyne was not observed
when the reaction was conducted in polar solvents such as
CH3CN, DMF, or DMSO. As a result, reactions in these polar
solvents gave higher yields (Table 1, entries 3ꢀ5). It was further
found that the reaction was not sensitive to bases. Reactions in
the presence of other bases such as NaH, n-BuLi, LiN(TMS)2, or
KN(TMS)2 gave the desired products in good to excellent yields
(Table 1, entries 6ꢀ13). Reactions using NaH as base in polar
solvents such as DMF, HMPA, or DMSO, however, occurred to
generate the desired product 7a in 81ꢀ94% yield and a minor
side product 8a in less than 20% yield (Table 1, entries 8ꢀ10).
Under the optimized conditions (DBU as the base in DMSO
(entry 5 in Table 1)), reactions of β-(trifluoromethyl)vinyl
diphenylsulfonium salt 1 with a variety of active methylene
molecules were studied. The results are summarized in Table 2.
Reactions of active methylene molecules 6 containing electron-
withdrawing groups such as ester, cyano, or sulfone occurred
smoothly to give the desired products in good to excellent yields
(Table 1, entries 1ꢀ9). Reactions of active methylene molecules
4
DBU
RT
RT
RT
RT
RT
60
RT
RT
0
94
0
5
DBU
DMSO
99
0
6
NaH
DMF
89
7
7
NaH
HMPA
90
7
8
NaH
DMSO
85
15
19
4
9
NaH
DMSO
81
10
11
12
13
nBuLi
DMSO
94
LiN(TMS)2
LiN(TMS)2
KN(TMS)2
DMSO
96
0
THF/HMPA
DMSO
92
7
RT
89
0
a Yields were determined by 19F NMR analysis of the crude reaction
mixture with R,R,R-trifluorotoluene as an internal standard. b Isolated
yield.
solvent-free conditions at 100 °C for 48 h. Elimination of
hydrobromide from intermediates 5a and 5b in the presence of
stoichiometric amounts of Ag2O in acetone at room temperature
gave the desired building blocks 1 and 2, respectively, in excellent
yields. Compounds 1 and 2 prepared according to these proce-
dures were E/Z mixtures (6:1), as determined by 19F NMR and
1H NMR spectroscopy.
Interestingly, the Z-isomer of 1 underwent isomerization to
thermodynamically more stable E-isomer easily in the presence
of 5 mol % Ag2O or other weak nucleophiles such as triphenyl-
phosphine, pyridine, or AgOAc (see Supporting Information),
while no isomerization of E- or Z-isomer of 2 was observed under
these conditions.
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Table 3. Reaction of β-(Trifluoromethyl)vinyl Sulfonium
Salt 2 with Active Methylene Compounds 6 in the Presence of
NaH in DMSOa
Figure 1. The ORTEP view of 8l with thermal ellipsoids set at 30%
probability level.
Table 4. Reaction of β-(Trifluoromethyl)vinyl Sulfonium
Salts 1 or 2 with Active Methenyl Compounds in the Presence
of NaH in DMSOa
a Reaction conditions: 2 (0.3 mmol), 6 (0.36 mmol), and NaH (0.36
mmol) in DMSO (9 mL) for 10 min at room temperature. b Determined
by 19F NMR analysis of the crude reaction mixture with R,R,R-
c
trifluorotoluene as an internal standard. Isolated yield of 8. d 12% of
side product 9 was observed by 19F NMR spectroscopy. e β-(Trifluoro-
f
methyl)vinyl sulfonium salt 1 was used. 14% of side product 9 was
observed by 19F NMR spectroscopy.
containing two different electron-withdrawing groups theoreti-
cally could give two diastereomers. Two diastereomers (dr = 3:1)
were isolated for the reactions of methyl phenylsulfonylacetate
6h or ethyl phenylsulfonylacetate 6i with β-(trifluoromethyl)-
vinyl diphenylsulfonium salt 1 (Table 2, entries 8 and 9). The
major isomer was determined to have a cis relationship of the
trifluoromethyl and carboxyl groups. However, reactions of
active methylene molecules containing a cyano group and an
ester group or a sulfonyl group gave only one product in high
yields (Table 2, entries 5ꢀ7). The configuration of the product
was determined to have a cis relationship of the trifluoromethyl
and cyano group. The stereochemistry of these cyclopropanation
a Reaction conditions: 1 or 2 (0.3 mmol), active methenyl compound
(0.36 mmol), and NaH (0.36 mmol) in DMSO (9 mL) for 10 min at
room temperature. b Determined by 19F NMR analysis of the crude
reaction mixture with R,R,R-trifluorotoluene as an internal standard.
c Isolated yield of 8.
1
constant of cyclopropane proton (3JHH = 6.0 Hz) in H NMR
spectroscopy. Reactions of other active methylene compounds
with β-(trifluoromethyl)vinyl sulfonium salt 2 using NaH as the
base occurred similarly to give 8 in good to excellent yields
(Table 3). For example, reactions of diketones occurred
smoothly to give compounds 8 in good yields (Table 3, entries
5ꢀ6, 11). Reactions of active methylene compounds with one
sulfone group and one ketone group or ester group gave the
corresponding compounds 8 exclusively in 66%, 94%, and 91%
yields, respectively (Table 3, entries, 8ꢀ10).
products was established by comparing their 1H NMR and 19
F
NMR spectra with those reported in the literature.8g
Interestingly, when active methylene molecules containing a
ketone group were reacted under these conditions, three isomers
were isolated in different amounts. For example, reaction of ethyl
acetoacetate with β-(trifluoromethyl)vinyl diphenylsulfonium
salt 1 gave cyclopropane 7k, its isomer 8k, and a dihydrofuran
derivative 9k in 50%, 6%, and 44% yields, respectively, as
determined by 19F NMR spectroscopy.
3. Reaction of β-(Trifluoromethyl)vinyl Sulfonium Salt 2
with Active Methylene Compounds in the Presence of NaH
in DMSO. During the optimization of the conditions for the
reaction of β-(trifluoromethyl)vinyl sulfonium salt 1 with diethy-
lmalonate, it was found that a minor side product 8a in which one
of the electron-withdrawing groups migrated12 was isolated when
NaH was used as the base. Surprisingly, when β-(trifluoromethyl)-
vinyl sulfonium salt 2 was used under the same conditions (NaH
as the base in DMSO), compound 8a was isolated as the major
product in 68% yield (Table 3, entry 1). The structure of
compound 8a was determined by measuring the coupling
The structures of compound 8 were further confirmed by
X-ray crystallographic analysis. The X-ray structure of compound
8l showed that the sulfone is cis to the ketone group and the
trifluoromethyl group is trans to the sulfone or ketone group.
The bond lengths of the carbonꢀcarbon bonds in the trifluoro-
methyl-substituted cyclopropane are 1.489 and 1.497 Å, which
are slightly shorter than those in cyclopropane (Figure 1).8j
4. Reaction of β-(Trifluoromethyl)vinyl Sulfonium Salts 1
and 2 with Active Methenyl Compounds in the Presence of
NaH in DMSO. When active methenyl compounds were reacted
with β-(trifluoromethyl)vinyl sulfonium salt 1 or 2 in the
presence of NaH in DMSO, only the products with the migration
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Table 5. Reaction of β-(Trifluoromethyl)vinyl Sulfonium
Salt 1 with Active Methylene Compounds 6 in the Presence of
NaH in THF/CH2Cl2 at ꢀ78 °Ca
Figure 2. The ORTEP view of 11p with thermal ellipsoids set at 30%
probability level.
a Reaction conditions: 1 (0.3 mmol), active methenyl compound 6 (0.36
mmol), and NaH (0.36 mmol) in THF/CH2Cl2 (4.5 mL/1.5 mL) for 30
min at room temperature. b Determined by 19F NMR analysis of the
crude reaction mixture with R,R,R-trifluorotoluene as an internal
of one of the electron-withdrawing groups were observed
(Table 4). It was found that reactions of β-(trifluoromethyl)vinyl
sulfonium salt 1 or 2 with the same active methenyl compounds
gave similar selectivities and yields (Table 4, entries 1ꢀ4). For
example, reaction of β-(trifluoromethyl)vinyl sulfonium salt 1
with ethyl 2-benzylmalonate afforded the product in 90% in
89:11 diastereoselectivity (Table 4, entry 1), while the same
reaction with β-(trifluoromethyl)vinyl sulfonium salt 2 gave the
corresponding product in 89% yield in 88:12 diastereoselectivity
(Table 4, entry 2). Interestingly, migration of carbonyl group was
preferred for the active methenyl compounds containing both
carbonyl group and ester group (Table 4, entry 6).
The relative configuration of compound 8p was determined by
X-ray crystallographic analysis of single crystals of its derivative
11p. 11p was obtained by first the reduction of 8p with LiAlH4,
followed by esterification of the resulting diol with p-nitroben-
zoyl chloride and recrystallization from chloroform/diethyl ether
(eq 2). From the X-ray structure of 11p, it was unambigously
determined that the trifluoromethyl group is cis to the benzyl
group (Figure 2).
c
standard. Isolated yield of 9. d Three isomers could not be separated.
e DBU was used as base in DMSO.
a model reaction to optimize the conditions. It was found that
reactions using NaH as the base in THF/CH2Cl2 (3:1, v/v) at
ꢀ78 °C occurred to full conversion after 30 min to give com-
pound 9j as the major product and a small amount of compound
7j (Table 5, entry 1). Other active methylene compounds with a
ketone functional group also reacted to give compounds 9m,
9uꢀ9y as the major products under these reaction conditions
(Table 5, entries 2ꢀ8). Interestingly, reaction of ethyl 2-nitroa-
cetate gave exclusively nitrone 9y in quantitative yield (Table 5,
entry 9).
’ DISCUSSION
We proposed a working mechanism to explain the different
behaviors of the reaction between β-(trifluoromethyl)vinyl sul-
fonium salt 1 or 2 and active methylene molecules under different
conditions. The β-(trifluoromethyl)vinyl sulfonium salt 1 or 2
was first nucleophilically attacked by deprotonated active methy-
lene compounds to form intermediate A. When DBU was used as
base in DMSO, the reaction proceeded through path a to form
intermediate B via intramolecular deprotonation or reversible
protonation/deprotonation through DBU H+. B0 as shown by
3
its Newman projection is the most stable conformation of
intermediate B, where the less sterically hindered EWG (EWG =
electron-withdrawing group) is cis to the trifluoromethyl group.
Intermediate B0 then underwent an intramolecular nucleophilic
substitution to form trifluoromethyl-substituted cyclopropane
derivatives 7.
5. Reaction of β-(Trifluoromethyl)vinyl Sulfonium Salt 1
with Active Methylene Compounds in the Presence of NaH
in THF/CH2Cl2 at ꢀ78 °C. In some cases for the reaction of
β-(trifluoromethyl)vinyl sulfonium salt 1 with active methylene
compounds, trifluoromethyl-substitited 2,3-dihydrofuran deri-
vatives13 9 were obtained as the major products (Table 2, entries
10 and 13). The reaction conditions were further investigated to
determine if the formation of trifluoromethyl-substituted 2,3-
dihydrofuran derivatives 9 is general toward other active methy-
lene compounds. We studied the reaction of β-(trifluoromethyl)-
vinyl sulfonium salt 1 with ethyl 3-oxo-3-phenylpropanoate 6j as
When the reaction was conducted using NaH as the base in
DMSO at room temperature, ylide A was formed where sodium
is the counterion, as shown in path b. It is likely that this ylide is
more nucleophilic than the ylide with DBU•H+ as the counter-
ion. As a result, ylide A nucleophilically attacked the carbonyl
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Scheme 2. Proposed Mechanism for the Reaction of β-(Trifluoromethyl)vinyl Sulfonium Salts 1 or 2 with Active Methenyl
Compounds
group to form four-member ring intermediate C in which CF3
was trans to Ph2S+ due to the steric hindrance. Subsequent retro-
Aldol reaction generated the intermediate D, followed by in-
tramolecular nucleophilic substitution to form trifluoromethyl-
substituted cyclopropane derivatives 8. Direct intramolecular
substitution to form epoxide was unfavored because of the high
ring strain in the resulting [2.1.0] bicyclic compound.
When the reaction was conducted using NaH as the base in
THF/CH2Cl2 at ꢀ78 °C, a kinetically favored enol anion
intermediate E was formed. Subsequent intramolecular nucleo-
philic substitution afforded trifluoromethyl-substituted dihydro-
furan derivatives 9, as shown in path c.
β-(trifluoromethyl)vinyl sulfonium salt 1 is more sterically
hindered than the ylide from β-(trifluoromethyl)vinyl sulfonium
salt 2. In addition, the ylide from β-(trifluoromethyl)vinyl sul-
fonium salt 2 is more nucleophilic than ylide from β-(trifluoro-
methyl)vinyl sulfonium salt 1. As a result, the nucleophilic
addition of the ylide from β-(trifluoromethyl)vinyl sulfonium
salt 2 to the carbonyl group was easier than the ylide from
β-(trifluoromethyl)vinyl sulfonium salt 1, as shown in mechan-
ism path b.
’ CONCLUSION
For reaction of β-(trifluoromethyl)vinyl sulfonium salts 1 or 2
with active methenyl compounds in the presence of NaH in
DMSO, the reaction proceeded via path b to form intermediate
C. Retro-Aldol reaction generated the intermediate D, where the
less sterically hindered R group is cis to the trifluoromethyl
group. Subsequent intramolecular nucleophilic substitution
formed trifluoromethyl-substituted cyclopropane derivatives 8
(Scheme 2).
The reaction between β-(trifluoromethyl)vinyl sulfonium salt
1 or 2 and active methylene molecules differed greatly mainly due
to the different properties of the ylides generated from these
salts in the presence of base. The ylide generated from
In summary, we have developed two trifluoromethyl-substi-
tuted building block β-(trifluoromethyl)vinyl sulfonium salts 1
and 2. Subsequent studies disclosed that reactions of various
active methylene or methenyl compounds with β-(trifluoromethyl)-
vinyl sulfonium salt 1 or 2 differ greatly under different condi-
tions. Reactions of β-(trifluoromethyl)vinyl sulfonium salt 1
with active methylene compounds containing electron-with-
drawing groups such as ester, cyano, or sulfone using DBU as
the base in DMSO afforded trifluoromethyl-substituted cyclo-
propane derivatives 7 as the major products. In contrast, reac-
tions of β-(trifluoromethyl)vinyl sulfonium salt 2 with active
methylene compounds occurred with the migration of one of the
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electron-withdrawing groups to give 8 as the major products
when NaH was used as the base in polar solvent such as DMSO.
Moreover, when NaH was used as base in THF/CH2Cl2 at
ꢀ78 °C, reactions of β-(trifluoromethyl)vinyl sulfonium salt 1
gave trifluoromethyl-substituted 2,3-dihydrofuran derivatives 9
as the major products. A working mechanism was proposed to
explain the different behaviors of the β-trifluoromethyl-substi-
tuted vinylsulfonium salts 1 or 2 with active methylene com-
pounds under these different conditions.
1 H), 4.14 (dd, J = 14.4, 10.4 Hz, 1 H), 3.98ꢀ3.88 (m, 4 H), 2.58ꢀ2.54
(m, 2 H), 2.46ꢀ2.42 (m, 2 H); 19F NMR (282 MHz, acetone-d6)
δ ꢀ71.68 (d, J = 7.0 Hz, 3 F), ꢀ78.77 (s, 3 F); 13C NMR (100.5 MHz,
acetone-d6) δ 123.3 (q, J = 278 Hz), 121.2 (q, J = 321 Hz), 46.4, 45.3,
44.1, 40.7 (q, J = 34 Hz), 28.9, 28.8. Anal. Calcd For C8H11F6O3S2Br: C
23.25, H 2.68; Found: C 23.46, H 2.47. MS (ESI+): m/z 263.0 [M+ ꢀ
OTf], 265.0 [M ꢀ OTf+2+]; MS (ESIꢀ): m/z 149.0 [TfOꢀ]; HRMS
(ESI+) Calcd for C7H11F3BrS+ (M+ ꢀ OTf): 262.9711, Found: 262.9715.
IR (cmꢀ1): 2991, 2941, 1374, 1259, 1164, 1120, 1033, 641.
Preparation of E-β-(Trifluoromethyl)vinyl Diphenylsulfonium Tri-
fluoromethanesulfonate 1. To a stirred solution of (2-bromo-3,3,3-
trifluoropropyl)diphenylsulfonium trifluoromethanesulfonate 5a (4.8 g,
9.3 mmol) in acetone (15 mL) was added silver(I) oxide (1.3 g, 5.6
mmol) at room temperature. The reaction was stirred for 5ꢀ9 h as
determined by 19F NMR spectroscopy. Longer reaction time would lead
to increased byproduct (δ = ꢀ62 ppm). The mixture was filtered and
washed with acetone (10 mL). The combined organic layer was dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was then diluted with acetone (10 mL), and a catalytic amount of
Ag2O (90 mg, 0.4 mmol) was added. The mixture of E/Z isomers (E:Z =
6:1, δE = ꢀ65 ppm, δZ = ꢀ60 ppm) was stirred at room temperature for
1ꢀ2 days until the disappearance of Z isomer as determined by 19F
NMR spectroscopy. The mixture was filtered, concentrated under
vacuum. The residue was purified by flash column chromatography
(CH2Cl2/acetone =2:1) to give 1 as a white solid (3.71 g, 93%): mp
71ꢀ72 °C [lit.7 mp 68ꢀ70 °C]. 1H NMR (300 MHz, CDCl3) δ 8.16 (d,
J = 14.7 Hz, 1 H), 8.14ꢀ8.02 (m, 4 H), 7.80ꢀ7.67 (m, 6 H), 7.19 (m, 1
H); 19F NMR (282 MHz, CDCl3) δ ꢀ64.7 (d, J = 6.2 Hz, 3 F), ꢀ78.4
(s, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 137.2 (q, J = 37 Hz), 135.1,
131.7, 130.8, 126.6 (q, J = 6.6 Hz), 123.5, 120.5 (q, J = 320 Hz), 119.9
(q, J = 273 Hz).
Preparation of E/Z-β-(Trifluoromethyl)vinyl Tetramethylenesulfo-
nium Trifluoromethanesulfonate 2. To a stirred solution of (2-bromo-
3,3,3-trifluoropropyl) tetramethylenesulfonium trifluoromethanesulfo-
nate 5b (4.1 g, 9.8 mmol) in acetone (15 mL) was added silver(I) oxide
(1.4 g, 5.9 mmol) at room temperature (27 °C). The mixture was stirred
overnight. The reaction was stirred for 5 h as determined by 19F NMR
spectroscopy. The mixture of E/Z isomers (E/Z = 6:1) was filtered and
washed with acetone (15 mL). The combined organic layer was dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (CH2Cl2/acetone
= 2:1) to give 2 as a white solid (3.1 g, 93%, E/Z isomers): mp 61ꢀ63 °C
for E/Z isomers. 1H NMR (300 MHz, acetone-d6) δ 7.54 (dd, J = 15.0,
1.5 Hz, 1 H), 7.25 (m, 1 H), 3.93 (m, 4 H), 2.43 (m, 4 H); 19F NMR (282
MHz, acetone-d6) δ ꢀ65.82 (dd, J = 6.2, 2.0 Hz, 3 F), ꢀ79.09 (s, 3 F);
13C NMR (100.5 MHz, acetone-d6) δ 132.6 (q, J = 36 Hz), 129.5 (q, J =
7.5 Hz), 121.1 (q, J = 288 Hz), 120.8 (q, J = 304 Hz), 47.5, 28.8. MS
(ESI+): m/z 183.0 [M+ ꢀ OTf]; MS (ESIꢀ): m/z 148.9 [TfOꢀ];
HRMS (ESI+) Calcd for C7H10F3S1+ (M+ ꢀ OTꢀf): 183.0450, Found:
183.0443; HRMS (ESIꢀ) Calcd for C1F3O3S1 (OTf): 148.9526,
Found: 148.9519. IR (cmꢀ1): 3058, 1652, 1322, 1263, 1158, 1035,
966, 640.
Typical Procedure for Reaction of β-(Trifluoromethyl)vinyl Sulfo-
nium Salt 1 with Active Methylene Compounds in the Presence of DBU
in DMSO. To a stirred solution of active methylene compound 6 (0.36
mmol) in DMSO (6 mL) was added DBU (0.36 mmol) under argon at
room temperature. After 10 min, the reaction mixture was treated with a
solution of 1 (130 mg, 0.3 mmol) in DMSO (3 mL) dropwise over 2ꢀ3
min. The reaction mixture was stirred for extra 5 min and then quenched
with sat. NH4Cl (aq, 15 mL). The mixture was then extracted with
EtOAc (3 ꢁ 15 mL) and washed with water (2 ꢁ 20 mL) and brine
(20 mL). The combined organic layer was dried over Na2SO4, filtered,
and concentrated under vacuum. The residue was then purified by flash
column chromatography.
’ EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reactions were
performed in oven-dried glassware under an Ar atmosphere. Commer-
cially obtained reagents were used without further purification. All
solvents were purified by standard methods. 1H, 13C, 19F NMR spectra
were recorded on a 300 MHz (or 400 MHz), 100.5 MHz, or 282 MHz
spectrometer. 1H and 13C NMR chemical shifts were determined
relative to internal standard TMS at δ 0.0, and 19F NMR chemical
shifts were determined relative to CFCl3 as internal standard. All
reactions were monitored by TLC or 19F NMR spectroscopy. Flash
column chromatography was performed on silica gel (300ꢀ400 mesh)
unless otherwise stated.
Preparation of 2-Bromo-3,3,3-trifluoropropyl Trifluoromethanesul-
fonate 4.14 Trifluoromethanesulfonic anhydride (18.5 g, 65.6 mmol)
was added dropwise to a stirred solution of pyridine (5.45 g, 68.9 mmol)
in anhydrous CH2Cl2 (90 mL) at ꢀ20 °C under argon, and the mixture
was stirred for 10 min. 2-Bromo-3,3,3-trifluoropropanol (10.5 g, 54.4
mmol) was added dropwise. The cooling bath was removed, and the
reaction was stirred overnight at room temperature. The resulting
suspension was filtered and concentrated (using a rotary evaporator,
keeping the water bath temperature below 20 °C), and petroleum ether
(80 mL) was added. The mixture was filtered and concentrated again
under reduced pressure to give the title product as a clear pale-brown oil
(16.6 g, 94%). It was used directly in the next step without further
1
purification. H NMR (300 MHz, CDCl3) δ 4.87ꢀ4.74 (m, 2 H),
4.50ꢀ4.41 (m, 1 H); 19F NMR (282 MHz, CDCl3) δ ꢀ70.62 (d, J = 5.9
Hz, 3 F), ꢀ74.78 (s, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 122.4 (q, J =
278 Hz), 118.5 (q, J = 319 Hz), 71.4, 41.1 (q, J = 34 Hz). IR (cmꢀ1):
2987, 1425, 1328, 1249, 1216, 1143, 1051, 990, 951, 814, 613.
Preparation of (2-Bromo-3,3,3-trifluoropropyl) Diphenylsulfonium
Trifluoromethanesulfonate 5a. 2-Bromo-3,3,3-trifluoropropyl trifluor-
omethanesulfonate 4 (9.5 g, 29.2 mmol) was added to diphenyl sulfide
(20 mL). The stirred mixture was then heated to 100 °C for 48 h. The
mixture was cooled to room temperature, and the solid was crystallized
from CH2Cl2/Et2O (ca. 5 mL/30 mL) to give compound 5 as white
crystals (9.9 g, 67%): mp 90ꢀ91 °C. 1H NMR (300 MHz, CDCl3) δ
8.19 (d, J = 7.2 Hz, 4 H), 7.77ꢀ7.66 (m, 6 H), 5.08 (dd, J = 12.9, 3.3 Hz,
1 H), 4.89ꢀ4.77 (m, 2 H); 19F NMR (282 MHz, CDCl3) δ ꢀ70.64 (d,
J = 5.3 Hz, 3 F), ꢀ78.30 (s, 3 F); 13C NMR (100.5 MHz, CDCl3) δ
135.3, 135.2, 131.9, 131.8, 131.0, 131.0, 124.6, 124.0, 122.5 (q, J = 279 Hz),
120.7 (q, J = 320 Hz), 47.4, 39.4 (q, J = 36 Hz). Anal. Calcd. For
C16H13F6O3S2Br: C 37.59, H 2.56; Found: C 37.54, H 2.60. MS (ESI+):
m/z 360.9 [M+], 362.9 [M + 2+]; MS (ESIꢀ): m/z 148.9 [TfOꢀ]. IR
(cmꢀ1): 3446, 3069, 3003, 2978, 1282, 1255, 1233, 1151, 1118, 1031, 757, 639.
Preparation of (2-Bromo-3,3,3-trifluoropropyl) Tetramethylenesul-
fonium Trifluoromethanesulfonate 5b. To a solution of 2-bromo-3,3,3-
trifluoropropyl trifluoromethanesulfonate 4 (14.1 g, 43.4 mmol) in
toluene (35 mL) was added tetrahydrothiophene (4.43 g, 50.1 mmol).
The mixture was heated to 100 °C for 5 h. After cooling to room
temperature, Et2O (20 mL) was added to facilitate the precipitation of
the product. The mixture was then filtered and washed with Et2O
(30 mL) to give 5b as a gray solid (15.2 g, 84%): mp 151ꢀ152 °C. 1H
NMR (400 MHz, acetone-d6) δ 5.39 (m, 1 H), 4.30 (dd, J = 14.0, 4.4 Hz,
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7a (Table 2, entry 1).15 Condition: 6a (58 mg, 0.36 mmol), DBU (55
mg, 0.36 mmol), 1 (130 mg, 0.3 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 40:1. 7a: 67 mg, 87%, colorless oil. 1H
NMR (300 MHz, CDCl3) δ 4.23 (m, 4 H), 2.55 (m, 1 H), 1.80 (dd, J =
7.2, 5.5 Hz, 1 H), 1.56 (dd, J = 9.7, 5.5 Hz, 1 H), 1.28 (m, 6 H); 19F NMR
(282 MHz, CDCl3) δ ꢀ64.86 (d, J = 7.9 Hz, 3 F). MS (ESI+): m/z 255.0
[M + H+].
7b (Table 2, entry 2). Condition: 6b (63 mg, 0.48 mmol), DBU
(73 mg, 0.48 mmol), 1 (172 mg, 0.4 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 30:1. 7b: 72 mg, 79%, colorless oil. 1H
NMR (300 MHz, CDCl3) δ 3.80 (s, 3 H), 3.79 (s, 3 H), 2.58 (m, 1 H),
1.83 (dd, J = 6.6, 6.3 Hz, 1 H), 1.59 (dd, J = 9.6, 6.0 Hz, 1 H); 19F NMR
(282 MHz, CDCl3) δ ꢀ64.61 (d, J = 7.3 Hz, 3 F); 13C NMR (100.5
MHz, CDCl3) δ 168.6, 165.6, 123.9 (q, J = 273 Hz), 53.4, 53.2, 32.8, 27.1
(q, J = 37 Hz), 15.5. MS (ESI+): m/z 227 [M + H]+; HRMS (ESI+)
Calcd for C8H9F3Na1O4 (M + Na+): 249.0345, Found: 249.0350. IR
(cmꢀ1): 3011, 2961, 1743, 1270, 1151.
7c (Table 2, entry 3). Condition: 6c (102 mg, 0.36 mmol), DBU (55
mg, 0.36 mmol), 1 (130 mg, 0.3 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 40:1. 7c: 107 mg, 93%, colorless oil. 1H
NMR (300 MHz, CDCl3) δ 7.28 (m, 10 H), 5.14 (m, 4 H), 2.60 (m, 1
H), 1.85 (dd, = 7.0, 6.0 Hz, 1 H), 1.59 (dd, J = 9.0, 5.6 Hz, 1 H); 19F
NMR (282 MHz, CDCl3) δ ꢀ64.68 (d, J = 7.9, 3 F); 13C NMR (100.5
MHz, CDCl3) δ 168.0, 164.9, 134.9, 134.8, 128.7, 128.6, 128.5, 128.5,
128.0, 124.1 (q, J = 273 Hz), 68.3, 68.1, 33.3, 27.5 (q, J = 38 Hz), 15.6.
MS (EI+): m/z 378 (M+, 1.17), 91 (100), 107 (79.52), 181 (29.77);
HRMS (EI+) Calcd for C20H17F3O4 (M +): 378.1079, Found: 378.1073.
IR (cmꢀ1): 3036, 2958, 1738, 1269, 1148, 749, 697.
1 H), 7.60 (dd, J = 7.7, 7.5 Hz, 2 H), 3.69 (s, 3 H), 2.70 (m, 1 H), 2.21
(dd, J = 10.1, 6.6 Hz, 1 H), 2.07 (dd, J = 7.7, 6.7 Hz, 1 H); 19F NMR (282
MHz, CDCl3) δ ꢀ63.29 (d, J = 7.2 Hz, 3 F); 13C NMR (100.5 MHz,
CDCl3) δ 162.7, 137.8, 134.6, 129.2, 129.1, 123.3 (q, J = 273 Hz), 53.6,
49.2, 27.4 (q, J = 30 Hz), 13.6. MS (ESI+): m/z 309.1 [M + H+]. 7 h0: 19
mg, 19%, oil. 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2 H),
7.68 (t, J = 7.5 Hz, 1 H), 7.57 (dd, J = 10.6, 3.0 Hz, 1 H), 3.66 (s, 3H),
2.60 (m, 2 H), 1.20 (dd, J = 9.6, 5.4 Hz, 1 H); 19F NMR (282 MHz,
CDCl3) δ ꢀ56.71 (d, J = 7.2 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ
165.5, 139.8, 134.2, 129.5, 128.8, 123.2 (q, J = 274 Hz), 53.5, 49.7, 32.4
(q, J = 42 Hz), 17.9. MS (ESI+): m/z 309 [M + H]+; HRMS (ESI+)
Calcd for C12H11F3Na1O4S1 (M + H+): 331.0222, Found: 331.0226. IR
(cmꢀ1): 3111, 3064, 2959, 1743, 1335, 1275, 1144.
7i/7i0 (Table 2, entry 9). Condition: 6i (83 mg, 0.36 mmol), DBU
(55 mg, 0.36 mmol), 1 (130 mg, 0.3 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 15:1. 7i: 64 mg, 66%, white solid: mp
71ꢀ73 °C. 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.8 Hz, 2 H), 7.72
(t, J = 7.5 Hz, 1 H), 7.60 (dd, J = 7.8, 7.5 Hz, 2 H), 4.13 (m, 2H), 2.71 (m,
1 H), 2.21 (dd, J = 10, 6.6 Hz, 1 H), 2.07 (dd, J = 7.2, 7.1 Hz, 1 H), 1.14
(t, J = 7.1 Hz, 3 H); 19F NMR (282 MHz, CDCl3) δ ꢀ63.65 (d, J = 7.8
Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 162.0, 137.9, 134.5, 129.2,
129.1, 123.0 (q, J = 275 Hz), 63.1, 49.3, 27.4 (q, J = 39 Hz), 13.5, 13.5.
MS (ESI+): m/z 323 [M + H+]; HRMS (ESI+) Calcd for C13H13F3
Na1O4S1 (M + Na+): 345.03789, Found: 345.03841. IR (cmꢀ1): 3105,
3075, 3046, 2988, 1739, 1311, 1267, 1146. 7i0: 22 mg, 22%, oil. 1H NMR
(300 MHz, CDCl3) δ 8.04 (d, J = 8.3 Hz, 2 H), 7.68 (t, J = 6.9 Hz, 1 H),
7.56 (dd, J = 8.1, 6.3 Hz, 2 H), 4.11 (q, J = 7.1 Hz, 2 H), 2.64 (m, 1 H),
2.55 (m, 1 H), 2.12 (dd, J = 9.8, 5.2 Hz, 1 H), 1.16 (t, J = 7.2 Hz, 3 H); 19F
NMR (282 MHz, CDCl3) δ ꢀ56.51 (d, J = 7.3 Hz, 3 F); 13C NMR
(100.5 MHz, CDCl3) δ 165.1, 140.0, 134.1, 129.5, 128.7, 123.3 (q,
J = 274 Hz), 63.3, 49.6, 32.3 (q, J = 42 Hz), 18.1, 13.7. MS (ESI+): m/z
7d (Table 2, entry 4).15 Condition: 6d (24 mg, 0.36 mmol), DBU (55
mg, 0.36 mmol), 1 (180 mg, 0.42 mmol), DMSO (4 + 2 mL). Eluent:
petroleum ether/ethyl acetate = 6:1. 7d: 50 mg, 86%, colorless oil. 1H
NMR (300 MHz, CDCl3) δ 2.81ꢀ2.73 (m, 1 H), 2.21ꢀ2.18 (m, 2 H);
19F NMR (282 MHz, CDCl3) δ ꢀ64.87 (d, J = 6.2 Hz, 3 F). MS (EI+):
m/z 160 (M+, 4.74), 64 (100), 69 (88.28), 82 (18.85).
+
323 [M + H+], 340 [M + NH4 ]; HRMS (ESI+) Calcd for C13H13F3Na1
O4S1 (M + Na+): 345.03789, Found: 345.03811. IR (cmꢀ1): 3110,
3064, 2986, 2941, 1732, 1331, 1262, 1135.
7e (Table 2, entry 5).15 Condition: 6e (54 mg, 0.48 mmol), DBU (73
mg, 0.48 mmol), 1 (172 mg, 0.4 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 15:1. 7e: 67 mg, 81%, colorless oil. 1H
NMR (300 MHz, CDCl3) δ 4.33 (q, J = 7.2 Hz, 2 H), 2.66 (m, 1 H), 1.98
(m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ65.02 (d, J = 7.9 Hz, 3 F). m/z (ESI+): 208 [M + H]+.
7j (Table 2, entry 10). Condition: 6j (38 mg, 0.2 mmol), DBU (22
mg, 0.22 mmol), 1 (103 mg, 0.24 mmol), DMSO (4 + 2 mL). Eluent:
petroleum ether/ethyl acetate = 80:1. 7j: 9 mg, 15%, oil. 1H NMR (300
MHz, CDCl3) δ 7.91 (d, J = 6.9 Hz, 2 H), 7.59 (d, J = 7.2 Hz, 1 H), 7.47
(d, J = 7.5 Hz, 2 H), 4.06 (m, 2 H), 2.94 (m, 1 H), 2.28 (dd, J = 6.9, 5.4
Hz, 1 H), 1.54 (dd, J = 8.1, 5.7 Hz, 1 H), 0.97 (t, J = 7.5 Hz, 3 H); 19F
NMR (282 MHz, CDCl3) δ ꢀ61.44 (d, J = 8.2 Hz, 3 F); 13C NMR
(100.5 MHz, CDCl3) δ 191.9, 166.8, 135.9, 133.5, 128.8, 128.3, 124.5
(q, J = 273 Hz), 62.3, 38.6, 26.0 (q, J = 39 Hz), 16.5, 13.44. MS (ESI+):
m/z 287 [M + H]+, 309 [M + Na]+; HRMS (ESI+) Calcd for
C14H13F3Na1O3 (M + Na+): 309.07090, Found: 309.07103. IR
(cmꢀ1): 3051, 2985, 2940, 1745, 1690, 1600, 1450, 1413, 1316, 1274,
1209, 1151.
7m (Table 2, entry 13). Condition: 6m (70 mg, 0.62 mmol), DBU
(95 mg, 0.62 mmol), 1 (215 mg, 0.5 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 2:1. 7m: 20 mg, 19%, oil. 1H NMR (400
MHz, CDCl3) δ 2.82ꢀ2.58 (m, 4 H), 2.42 (m, 1 H), 2.33 (m, 1 H),
2.26ꢀ2.07 (m, 2 H), 2.0ꢀ1.97 (m, 1 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ59.76 (d, J = 7.9 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 204.3,
200.8, 123.5 (q, J = 274 Hz), 43.0, 39.8, 39.3, 38.5 (q, J = 40 Hz), 17.5.
MS (EI+): m/z 206 (M+, 46.99), 178 (100), 42 (67.19), 108 (66.97),
136 (50.75); HRMS (EI+) Calcd for C9H9F3O2 (M+): 206.0555,
Found: 206.0560. IR (cmꢀ1): 3112, 2962, 1727, 1701, 1401, 1325,
1269, 1151, 1099.
7f (Table 2, entry 6).15 Condition: 6f (65 mg, 0.36 mmol), DBU (55
mg, 0.36 mmol), 1 (130 mg, 0.3 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 15:1. 7f: 72 mg, 86%, white solid: mp
104ꢀ105 °C. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 7.2 Hz, 2 H),
7.82 (t, J = 7.5 Hz, 1 H), 7.69 (dd, J = 7.8, 7.8 Hz, 2 H), 2.88 (m, 1 H),
2.26 (dd, J = 9.6, 7.0 Hz, 1 H), 2.06 (dd, J = 7.2, 7.1 Hz, 1 H); 19F NMR
(282 MHz, CDCl3) δ ꢀ65.32 (d, J = 7.0 Hz, 3 F). MS (EI+): m/z 275
(M+, 12.4), 77 (100), 141 (76.64), 51 (26.50).
7g (Table 2, entry 7). Condition: 6g (70 mg, 0.36 mmol), DBU
(55 mg, 0.36 mmol), 1 (130 mg, 0.3 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 10:1. 7g: 83 mg, 95%, white solid: mp
105ꢀ106 °C. 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.1 Hz, 2 H),
7.47 (d, J = 8.4 Hz, 2 H), 2.92ꢀ2.84 (m, 1 H), 2.50 (s, 3 H), 2.24 (m, 1
H), 2.03 (dd, J = 7.5, 6.9 Hz, 1 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ65.31 (d, J = 5.9 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 147.3,
132.6, 130.6, 129.2, 122.3 (q, J = 274 Hz), 112.0, 35.49, 27.8 (q, J = 40
Hz), 21.8, 16.6 (q, J = 2.9 Hz). MS (ESI+): m/z 290 [M + H]+; HRMS
(ESI+) Calcd for C12H10F3NaNO2S1 (M + Na+): 312.0277, Found:
312.0269. IR (cmꢀ1): 3111, 3066, 3028, 2247, 1599, 1414, 1337, 1269,
1154, 627, 521.
Typical Procedure for Reaction of β-(Trifluoromethyl)vinyl Sulfo-
nium Salt 2 with Active Methylene Compounds in the Presence of NaH
in DMSO. To a stirred solution of active methylene compound 6 (0.36
mmol) in DMSO (6 mL) was added NaH (60% in oil, 14.4 mg, 0.36
mmol) under argon at room temperature. After 10 min, a solution of 2
(100 mg, 0.3 mmol) in DMSO (3 mL) was added dropwise over 2ꢀ3 min.
7h/7h0 (Table 2, entry 8).15 Condition: 6h (77 mg, 0.36 mmol),
DBU (55 mg, 0.36 mmol), 1 (130 mg, 0.3 mmol), DMSO (6 + 3 mL).
1
Eluent: petroleum ether/ethyl acetate = 8:1. 7h: 63 mg, 68%, oil. H
NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.8 Hz, 2 H), 7.73 (t, J = 7.4 Hz,
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The reaction mixture was stirred for extra 5 min and then quenched with
sat. NH4Cl (aq, 15 mL). The mixture was then extracted with EtOAc
(3 ꢁ 15 mL) and washed with water (2 ꢁ 20 mL) and brine (20 mL).
The combined organic layer was dried over Na2SO4, filtered, and
concentrated under vacuum. The residue was then purified by flash
column chromatography.
87ꢀ89 °C. 1H NMR (300 MHz, CDCl3) δ 2.80 (m, 1 H), 2.61 (d, J =
6.0 Hz, 2 H), 2.30 (s, 6 H); 19F NMR (282 MHz, CDCl3) δ ꢀ66.81 (d,
J = 6.2 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 200.1, 124.1 (q, J =
271 Hz), 32.2, 30.5, 25.8 (q, J = 38 Hz); MS (ESI+): m/z 195 [M + H]+;
HRMS (ESI+) Calcd for C8H9F3Na1O2 (M + Na+): 217.0447, Found:
217.0449. IR (cmꢀ1): 3063, 3020, 2926, 1712, 1369, 1323, 1256, 1142.
8l (Table 3, entry 7). Condition: 6l (52 mg, 0.2 mmol), NaH (8.8 mg,
0.22 mmol), 2 (80 mg, 0.24 mmol), DMSO (3 + 1.5 mL). Recrystalliza-
tion from petroleum ether/ethyl acetate. 8l: 47 mg, 66%, needle crystals:
mp 165ꢀ166 °C. 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2
H), 7.73 (d, J = 7.5 Hz, 2 H), 7.59 (m, 2 H), 7.40 (m, 4 H), 3.42ꢀ3.37
(m, 2 H), 2.26 (dd, J = 9.0, 7.8 Hz, 1 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ67.15 (d, J = 4.0 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 187.5,
138.9, 136.0, 134.3, 134.1, 129.4, 128.9, 128.8, 127.9, 123.6 (q, J = 273
Hz), 43.3, 30.0, 24.3 (q, J = 40 Hz). Anal. Calcd. for C17H13F3O3S: C:
57.62 H: 3.70; Found C: 57.59 H: 3.85. MS (ESI+): m/z 355 [M + H]+;
HRMS (ESI+) Calcd for C17H13F3NaO3S1 (M + Na+): 377.0430,
Found: 377.0437. IR (cmꢀ1): 3043, 3029, 1686, 1449, 1343, 1317,
1279, 1153, 1141, 736.
8h (Table 3, entry 9). Condition: 8h (76 mg, 0.36 mmol), NaH (14.4
mg, 0.36 mmol), 2 (99 mg, 0.3 mmol), DMSO (4 + 2 mL). Eluent:
petroleum ether/ethyl acetate = 7:1. 8h: 87 mg, 94%, white solid: mp
84ꢀ85 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 2 H), 7.71
(dd, J = 7.6, 7.2 Hz, 1 H), 7.61 (dd, J = 8.0, 7.6 Hz, 2 H), 3.80 (s, 3 H),
3.14ꢀ3.11 (m, 2 H), 2.63 (dd, J = 9.6, 7.2 Hz, 1 H); 19F NMR (282
MHz, CDCl3) δ ꢀ66.73 (d, J = 4.2 Hz, 3 F); 13C NMR (100.5 MHz,
CDCl3) δ 164.7, 139.2, 134.5, 129.5, 127.95, 123.2 (q, J = 273 Hz), 53.2,
41.3 (q, J = 1.5 Hz), 25.8 (q, J = 3.0 Hz), 25.0 (q, J = 40 Hz). MS (EI+):
m/z 308 (M+, 0.81), 77 (100), 141 (30.05), 277 (21.64), 185 (21.25);
HRMS (EI+) Calcd for C12H11F3O4S (M+): 308.0330, Found:
308.0332. IR (cmꢀ1): 3054, 3036, 2960, 1755, 1736, 1449, 1348,
1330, 1280, 1258, 1159, 1133, 733.
8a (Table 3, entry 1). Condition: 6a (71 mg, 0.44 mmol), NaH (19.7
mg, 0.49 mmol), 2 (171 mg, 0.52 mmol), DMSO (6 + 3 mL). Eluent:
1
petroleum ether/ethyl acetate = 120:1. 8a: 77 mg, 68%, oil. H NMR
(300 MHz, CDCl3) δ 4.19 (q, J = 7.2 Hz, 4 H), 2.79 (m, 1 H), 2.42 (d, J =
6.0 Hz, 2 H), 1.28 (t, J = 7.2 Hz, 6 H); 19F NMR (282 MHz, CDCl3) δ
ꢀ67.08 (d, J = 6.2 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 166.7,
123.9 (q, J = 272 Hz), 61.81, 25.4 (q, J = 39 Hz), 24.1 (q, J = 2.2 Hz),
14.0. MS (ESI+): m/z 255.1 [M + H]+; HRMS (ESI+) Calcd for
C10H13F3Na1O4 (M + Na+): 277.0658, Found: 277.0668. IR (cmꢀ1):
3059, 2987, 2938, 1744, 1400, 1378, 1351, 1319, 1259, 1146, 1041.
8b (Table 3, entry 2). Condition: 6b (49 mg, 0.36 mmol), NaH (14.4
mg, 0.36 mmol), 2 (99 mg, 0.3 mmol), DMSO (4 + 2 mL). Eluent:
1
petroleum ether/ethyl acetate = 20:1. 8b: 49 mg, 77%, oil. H NMR
(300 MHz, CDCl3) δ 3.74 (m, 6 H), 2.80 (m, 1 H), 2.44 (d, J = 6.0 Hz, 2
H); 19F NMR (282 MHz, CDCl3) δ ꢀ67.10 (d, J = 6.2 Hz, 3 F); 13
C
NMR (100.5 MHz, CDCl3) δ 167.3, 123.8 (q, J = 271 Hz), 52.7, 25.6 (q,
J = 39 Hz), 23.8 (q, J = 2.2 Hz). MS (ESI+): m/z 227 [M + H]+; HRMS
(ESI+) Calcd for C8H9F3Na1O4 (M + Na+): 249.0345, Found:
249.0343. IR (cmꢀ1): 3059, 2960, 1747, 1438, 1368, 1323, 1259,
1214, 1145.
8c (Table 3, entry 3). Condition: 6c (144 mg, 0.51 mmol), NaH
(20.3 mg, 0.51 mmol), 2 (141 mg, 0.42 mmol), DMSO (6 + 3 mL).
Eluent: petroleum ether/ethyl acetate = 70:1. 8c: 138 mg, 86%, oil. 1H
NMR (300 MHz, CDCl3) δ 7.34ꢀ7.29 (m, 10 H), 5.06 (s, 4 H), 2.85 (m
1 H), 2.48 (d, J = 6.0 Hz, 2 H); 19F NMR (282 MHz, CDCl3) δ ꢀ66.97
(d, J = 6.2 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 166.5, 135.1,
128.7, 128.6, 128.6, 123.9 (q, J = 271 Hz), 67.6, 25.6 (q, J = 39 Hz), 24.2
(q, J = 2.2 Hz). MS (EI+): m/z 378 (M+, 0.14), 107 (100), 91 (79.37),
181 (19.39), 92 (15.96). HRMS (EI+) Calcd for C20H17F3O4 (M+):
378.1079, Found: 378.1076. IR (cmꢀ1): 3066, 3036, 2959, 1747, 1456,
1392, 1352, 1316, 1262, 1147, 739, 698.
8j (Table 3, entry 4). Condition: 6j (54 mg, 0.28 mmol), NaH (9.6
mg, 0.24 mmol), 2 (66 mg, 0.2 mmol), DMSO (4 + 2 mL). Eluent:
petroleum ether/ethyl acetate = 100:1. 8j: 42 mg, 73%, white solid: mp
71ꢀ73 °C. 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 7.7 Hz, 2 H), 7.62
(t, J = 7.5 Hz, 1 H), 7.50 (dd, J = 7.8, 7.2 Hz, 2 H), 4.04 (q, J = 7.0 Hz, 2
H), 3.14 (dd, J = 10.0, 6.1 Hz, 1 H), 3.02 (m, 1 H), 2.65 (dd, J = 10.0, 5.7
Hz, 1 H), 1.08 (t, J = 7.1 Hz, 3 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ67.19 (d, J = 5.9 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 190.8,
166.8, 136.1, 133.9, 128.8, 128.5, 124.3 (q, J = 272 Hz), 61.7, 28.2, 25.4,
25.2 (q, J = 38 Hz), 13.9. MS (ESI+): m/z 287 [M + H]+; HRMS (ESI+)
Calcd for C14H13F3Na1O3 (M + Na+): 309.0709, Found: 309.0713. IR
(cmꢀ1): 3068, 3038, 2981, 2933, 1727. 1686, 1356, 1266, 1131.
8n (Table 3, entry 5). Condition: 6n (39 mg, 0.24 mmol), NaH (9.6
mg, 0.24 mmol), 2 (66 mg, 0.2 mmol), DMSO (3 + 1.5 mL). Eluent:
petroleum ether/ethyl acetate = 12:1. 8n: 35 mg, 61%, white solid: mp
107ꢀ109 °C. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 2 H),
7.62 (t, J = 7.8 Hz, 1 H), 7.50 (dd, J = 7.2, 7.2 Hz, 2 H), 3.22 (dd, J = 9.6,
6.0 Hz, 1 H), 3.03 (m, 1 H), 2.79 (dd, J = 9.9, 6.0 Hz, 1 H), 2.27 (s, 3 H);
19F NMR (282 MHz, CDCl3) δ ꢀ66.58 (d, J = 6.2 Hz, 3 F); 13C NMR
(100.5 MHz, CDCl3) δ 199.8, 191.3, 136.1, 134.0, 128.9, 128.5, 124.4
(q, J = 271 Hz), 32.2, 30.7, 29.8, 25.8 (q, J = 38 Hz); MS (ESI+): m/z 257
[M + H]+; HRMS (ESI+) Calcd for C13H11F3Na1O2 (M + Na+):
279.0603, Found: 279.0606. IR (cmꢀ1): 3062, 3037, 2922, 1710, 1682,
1324, 1265, 1139.
8i (Table 3, entry 10). Condition: 6i (89 mg, 0.39 mmol), NaH (14.4
mg, 0.36 mmol), 2 (99 mg, 0.3 mmol), DMSO (4 + 2 mL). Eluent:
petroleum ether/ethyl acetate = 6:1. 8i: 89 mg, 91%, solid: mp
92ꢀ93 °C. 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 7.5 Hz, 2 H),
7.71 (dd, J = 7.5, 7.2 Hz, 1 H), 7.59 (dd, J = 7.8, 7.2 Hz, 2 H), 4.29ꢀ4.23
(m, 2 H), 3.13 (m, 2 H), 2.63 (dd, J = 9.6, 7.2 Hz, 1 H), 1.32 (t, J = 7.2 Hz,
3 H); 19F NMR (282 MHz, CDCl3) δ ꢀ66.99 (d, J = 5.1 Hz, 3 F); 13
C
NMR (100.5 MHz, CDCl3) δ 164.2, 139.3, 134.4, 129.5, 128.0, 123.3 (q,
J = 272 Hz), 62.6, 41.4 (q, J = 2.2 Hz), 26.0 (q, J = 2.2 Hz), 25.0 (q, J = 40
Hz), 13.9. MS (EI+): m/z 322 (M+), 77 (100), 277 (33.68), 141 (26.32),
125 (24.22); HRMS (EI+) Calcd for C13H13F3O4S (M+): 322.0487,
Found: 322.0488. IR (cmꢀ1): 3044, 2988, 1743, 1448, 1372, 1331, 1280,
1211, 1155, 737, 688.
8m (Table 3, entry 11). Condition: 8m (55 mg, 0.49 mmol), NaH
(19.2 mg, 0.48 mmol), 2 (133 mg, 0.4 mmol), DMSO (6 + 3 mL).
Eluent: petroleum ether/ethyl acetate = 3:1. 8m: 48 mg, 58%, solid: mp
105ꢀ106 °C. 1H NMR (400 MHz, CDCl3) δ 2.97 (m, 1 H), 2.69ꢀ2.62
(m, 4 H), 2.54 (d, J = 6.4 Hz, 2 H), 2.01ꢀ1.95 (m, 1 H), 1.73ꢀ1.66 (m, 1
H); 19F NMR (282 MHz, CDCl3) δ ꢀ67.09 (d, J = 5.1 Hz, 3 F); 13
C
NMR (100.5 MHz, CDCl3) δ 203.0, 123.4 (q, J = 273 Hz), 41.3, 31.2 (q,
J = 1.7 Hz), 28.6 (q, J = 39 Hz), 22.1. MS (EI+): m/z 206 (M+, 9.12), 178
(100), 136 (72.84), 108 (27.17), 55 (19.64); HRMS (EI+) Calcd for
C9H9F3O2 (M+): 206.0555, Found: 206.0559. IR (cmꢀ1): 3070, 2972,
1690, 1456, 1334, 1298, 1267, 1222, 1147, 1130.
8p (Table 4, entries 1 and 2). Condition: 6p (125 mg, 0.5 mmol),
NaH (22.5 mg, 0.56 mmol), 1 (270 mg, 0.62 mmol), DMSO (6 + 3 mL).
Eluent: petroleum ether/ethyl acetate = 80:1. 8p: 140 mg, 80%, oil,
mixed with trace amount of 6p (8p: 6p = 13:1). 1H NMR (300 MHz,
CDCl3) δ 7.27 (m, 5 H), 4.18 (q, J = 7.2 Hz, 2 H), 4.03 (m, 2 H), 3.43 (d,
J = 15.3 Hz, 1 H), 3.12 (d, J = 15.3 Hz, 1 H), 2.94 (m, 1 H), 2.41 (d, J =
6.6 Hz, 1 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.08 (t, J = 7.2 Hz, 3 H); 19F NMR
(282 MHz, CDCl3) δ ꢀ60.72 (d, J = 7.6 Hz, 3 F).
8o (Table 3, entry 6). Condition: 6o (37 mg, 0.37 mmol), NaH (9.6
mg, 0.24 mmol), 2 (66 mg, 0.2 mmol), DMSO (3 + 1.5 mL). Eluent:
petroleum ether/ethyl acetate = 5:1. 8o: 16 mg, 41%, white solid: mp
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Preparation of 10p. To a suspension of LiAlH4 (330 mg, 8.6 mmol)
in Et2O (5 mL) was added a solution of 7p (381 mg, 1.1 mmol) in Et2O
(5 mL) dropwise at room temperature under argon. The mixture was
stirred at room temperature for 2 h and was then heated to reflux for 1 h.
After cooling to room temperature, the mixture was quenched with
EtOH, diluted with H2O and extracted with CH2Cl2 (3 ꢁ 15 mL). The
combined organic layer was dried over Na2SO4, filtered, concentrated
under vacuum. The residue was purified by flash column chromatogra-
phy (petroleum ether/ethyl acetate = 1:1) to give 10p as a pale yellow oil
(275 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 7.35ꢀ7.26 (m, 5 H),
4.10 (dd, J = 12.0, 5.1 Hz, 1 H), 3.95 (d, J = 12.0 Hz, 1 H), 3,39 (dd, J =
11.7, 10.8 Hz, 1 H), 3.23 (d, J = 12.3 Hz, 1 H), 3.10 (d, J = 14.7 Hz, 1 H),
2.89 (d, J = 14.7 Hz, 1 H), 2.70 (br, 2 H), 1.86 (m, 1 H), 1.45 (m, 1 H);
19F NMR (282 MHz, CDCl3) δ ꢀ59.34 (d, J = 7.9 Hz, 3 F); 13C NMR
(100.5 MHz, CDCl3) δ 138.4, 129.3, 128.8, 126.9, 126.0 (q, J = 272 Hz),
64.9, 61.7, 36.7, 32.5, 29.3 (q, J = 37 Hz), 28.5. MS (ESI+): m/z 283 [M +
Na]+; HRMS (ESI+) Calcd for C13H15F3Na1O2 (M + Na+): 283.0916,
Found: 283.0913. IR (cmꢀ1): 3347, 3030, 2832, 2891, 1456, 1278, 1132,
1099, 1030, 729, 702.
2 H), 4.09 (m, 2 H), 3.10 (m, 1 H), 2.82 (d, J = 6.3 Hz, 1 H), 1.33 (t, J =
7.2 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ61.67 (d, J = 7.1 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 168.1,
167.64, 132.3, 129.5, 128.7, 123.9 (q, J = 273 Hz), 62.1, 61.9, 42.5, 30.6
(q, J = 37 Hz), 29.0, 14.1, 13.8. MS (EI+): m/z 330 (M+, 10.94), 183
(100), 229 (87.86), 284 (87.03), 115 (75.12); HRMS (EI+) Calcd for
C16H17F3O4 (M+): 330.1079, Found: 330.1078. IR (cmꢀ1): 3062, 2985,
2940, 1745, 1467, 1449, 1372, 1345, 1265, 1182, 1136, 703.
8q0 (Table 4, entries 3 and 4). Twelve milligrams, 12%, oil. 1H NMR
(300 MHz, CDCl3) δ 7.32 (m, 5 H), 4.25ꢀ4.03 (m, 2 H), 3.98 (q, J =
7.2 Hz, 2 H), 3.18 (d, J = 6.0 Hz, 1 H), 2.96 (m, 1 H), 1.18 (t, J = 7.2 Hz,
3 H), 1.06 (d, J = 7.2 Hz, 3 H); 19F NMR (282 MHz, CDCl3) δ ꢀ63.28
(d, J = 5.9 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 167.2, 166.9,
133.5, 129.1, 128.7, 128.6, 124.2 (q, J = 273 Hz), 62.4, 61.5, 42.2, 30.9 (q,
J = 38 Hz), 28.3, 13.9, 13.7. MS (EI+): m/z 330 (M+, 54.96), 115 (100),
183 (91.2), 228 (79.49), 133 (61.52); HRMS (EI+) Calcd for
C16H17F3O4 (M+): 330.1079, Found: 330.1081. IR (cmꢀ1): 3062,
2985, 2940, 1736, 1467, 1449, 1371, 1345, 1282, 1257, 1165, 1134, 1036,
737, 698.
Preparation of 11p. To a solution of 10p (50 mg, 0.19 mmol) in
CH2Cl2 (1.5 mL) were added NEt3 (158 mg, 1.56 mmol) and
4-nitrobenzoyl chloride (286 mg, 1.54 mmol) at room temperature.
The mixture was then heated to reflux for 2 days. After cooling to room
temperature, the solvent was then removed under reduced pressure. The
residue was purified by flash column chromatography (petroleum ether/
ethyl acetate = 5:1) to give compound 11p as a solid (21 mg, 20%). 1H
NMR: (300 MHz, CDCl3) δ 8.28 (d, J = 8.4 Hz, 2 H), 8.23 (d, J = 9.0 Hz,
2 H), 8.11 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2 H), 7.26ꢀ7.20 (m, 5
H), 4.83 (dd, J = 12.3, 6.6 Hz, 1 H), 4.40 (d, J = 11.7 Hz, 1 H), 4.26 (d, J =
12.3 Hz, 1 H), 4.18 (d, J = 11.7 Hz, 1 H), 3.25 (d, J = 14.7 Hz, 1 H), 2.78
(d, J = 14.4 Hz, 1 H), 2.33 (m, 1 H), 2.02 (m, 1 H); 19F NMR (282 MHz,
CDCl3) δ ꢀ59.59 (d, J = 7.9 Hz, 3F); 13C NMR (100.5 MHz, CDCl3) δ
164.3, 164.1, 150.8, 150.8, 137.6, 134.8, 134.7, 130.8, 129.2, 128.8, 127.0,
125.4 (q, J = 272 Hz), 123.7, 123.5, 66.2, 63.7, 35.6, 30.5, 30.2 (q, J = 36
Hz), 26.1 (q, J = 2.4 Hz). MS (ESI+): m/z 581 [M + Na]+; HRMS
(ESI+) Calcd for C27H21F3N2Na1O8 (M + Na+): 581.1142, Found:
581.1163. IR (cmꢀ1): 3112, 2922, 1725, 1525, 1349, 1274, 1103, 718.
8r (Table 4, entry 5). Condition: 6r (52 mg, 0.3 mmol), NaH (14.4
mg, 0.36 mmol), 1 (172 mg, 0.4 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 30:1. 8r: 26 mg, 32%, oil (excess 6r was
1
removed under reduced pressure by oil pump). H NMR (300 MHz,
CDCl3) δ 4.20ꢀ4.12 (m, 4 H) 2.08 (m, 1 H), 2.40 (d, J = 6.3 Hz, 1 H),
1.55 (s, 3 H), 1.30ꢀ1.24 (m, 6 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ61.15 (d, J = 8.2 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 169.4,
167.7, 124.5 (q, J = 273 Hz), 61.9, 61.6, 32.3, 31.1, 29.9 (q, J = 37 Hz),
15.1, 14.1, 14.0. MS (ESI+): m/z 269 [M + H]+; HRMS (ESI+) Calcd for
C11H15F3Na1O4 (M + Na+): 291.0815, Found: 291.0816. IR (cmꢀ1):
2987, 2943, 1744, 1452, 1373, 1346, 1269, 1153, 1185, 1125, 1099, 1024.
8s (Table 4, entry 6). Condition: 6s (73 mg, 0.43 mmol), NaH (9.6
mg, 0.24 mmol), 1 (86 mg, 0.2 mmol), DMSO (4 + 2 mL). Eluent:
petroleum ether/ethyl acetate = 15:1. 8s: 25 mg, 47%, oil. 1H NMR (400
MHz, CDCl3) δ 4.16ꢀ4.11 (m, 2 H), 3.02 (m, 1 H), 2.56 (m, 1 H), 2.29
(d, J = 6.4 Hz, 1 H), 2.28ꢀ1.82 (m, 7 H), 1.25 (t, J = 7.2 Hz, 3 H); 19
F
NMR (282 MHz, CDCl3) δ ꢀ60.78 (d, J = 8.2 Hz, 3 F); 13C NMR
(100.5 MHz, CDCl3) δ 202.5, 167.3, 124.7 (q, J = 273 Hz), 61.6, 41.4 (q,
J = 1.6 Hz), 41.3, 32.0 (q, J = 5 Hz), 30.5, 27.9 (q, J = 38 Hz), 26.3, 24.1,
14.1. MS (ESI+): m/z 265 [M + H]+; HRMS (ESI+) Calcd for
C12H15F3Na1O3 (M + Na+): 287.08655, Found: 287.08671. IR
(cmꢀ1): 3041, 2943, 2869, 1740, 1450, 1372, 1344, 1295, 1261, 1190,
1135, 1102.
1
8p0 (Table 4, entries 1 and 2). Seventeen milligrams, 10%, oil. H
NMR (400 MHz, CDCl3) δ 7.24 (t, J = 6.8 Hz, 2 H), 7.19 (d, J = 7.2 Hz,
1 H), 7.09 (d, J = 7.2 Hz, 2 H), 4.20ꢀ4.06 (m, 4 H), 3.62 (d, J = 15.6 Hz,
1 H), 3.08 (d, J = 6.4 Hz, 1 H), 3.03 (d, J = 15.6 Hz, 1 H), 2.50 (m, 1 H),
1.23 (t, J = 7.2 Hz, 3 H), 1.14 (t, J = 7.2 Hz, 3 H); 19F NMR (282 MHz,
CDCl3) δ ꢀ62.63 (d, J = 5.9 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ
168.7, 167.5, 136.9, 128.4, 128.4, 126.8, 124.0 (q, J = 272 Hz), 62.1, 61.8,
38.1, 34.6, 32.3 (q, J = 39 Hz), 27.2, 14.0, 13.7. MS (ESI+): m/z 345 [M +
H]+; HRMS (ESI+) Calcd for C17H19F3NaO4 (M + Na+): 367.1128,
Found: 167.1132. IR (cmꢀ1): 3034, 2984, 2937, 1732, 1456, 1374, 1281,
1239, 1191, 1153, 1125, 1044.
Typical Procedure To Remove Small Amount of Compound 6 via
Decarboxylation. To a solution of 8 or 9 (mixed with 1,3-dicarbonyl
compound 6 or 7, isolated from cyclopropantion reaction) in DMSO
(1 mL) were added NaCl (10ꢀ20 equiv) and H2O (20ꢀ30 equiv) at
room temperature in a sealed tube. The mixture was then heated to
150 °C for 2ꢀ3 days. After cooling to room temperature, the mixture
was diluted with H2O and extracted with ethyl acetate (3 ꢁ 10 mL). The
combined organic layer was wash with H2O (2 ꢁ 15 mL) and brine
(15 mL), dried over Na2SO4, filtered, and concentrated under vacuum.
The residue was purified by flash column chromatography.
Typical Procedure for Reaction of β-(Trifluoromethyl)vinyl Sulfo-
nium Salts 1 and 2 with Active Methenyl Compounds in the Presence
of NaH in DMSO. To a stirred solution of active methylene compound 6
(0.36 mmol) in THF (4.5 mL) was added NaH (60% in oil, 14.4 mg,
0.36 mmol) under argon at room temperature. After 10 min, a solution
of 1 (129 mg, 0.3 mmol) in CH2Cl2 (3 mL) was added dropwise over
2ꢀ3 min. The reaction mixture was stirred for extra 5 min and then
quenched with sat. NH4Cl (aq, 15 mL), extracted with CH2Cl2 (3 ꢁ
15 mL), and washed with water (2 ꢁ 20 mL) and brine (20 mL). The
combined organic layer was dried over Na2SO4, filtered, and concen-
trated under vacuum. The residue was then purified by flash column
chromatography.
9j (Table 5, entry 1). Condition: 6j (40 mg, 0.21 mmol), NaH (9.6
mg, 0.24 mmol), 1 (112 mg, 0.26 mmol), THF/CH2Cl2 (4 + 0.8 mL).
Eluent: petroleum ether/ethyl acetate = 100:1. 9j: 42 mg, 70%, oil. 1H
NMR (300 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2 H), 7.47ꢀ7.38 (m, 3
H), 4.74 (dd, J = 10.5, 3.0 Hz, 1 H), 4.58 (dd, J = 10.2, 9.9 Hz, 1 H),
4.18ꢀ4.07 (m, 3 H), 1.21 (t, J = 7.2 Hz, 3 H); 19F NMR (282 MHz,
CDCl3) δ ꢀ73.40 (d, J = 7.9 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ
170.1, 163.7, 131.4, 129.9, 128.8, 127.7, 126.3 (q, J = 281 Hz), 98.8, 69.9
(q, J = 3.7 Hz), 60.2, 48.1 (q, J = 29 Hz), 14.1. MS (EI+): m/z 286 (M+,
46.14), 105 (100), 77 (86.03), 217 (83.00), 115 (64.56), 241 (64.56),
8q (Table 4, entries 3 and 4). Condition: (1) 6q (158 mg, 0.67
mmol), NaH (19.7 mg, 0.5 mmol), 2 (176 mg, 0.41 mmol), DMSO (6 +
3 mL). Eluent: petroleum ether/ethyl acetate = 80:1. (2) NaCl (435 mg,
7.4 mmol), H2O (206 mg, 11.4 mmol), DMSO (1 mL). Eluent:
1
petroleum ether/ethyl acetate = 80:1. 8q: 56% for two steps, oil. H
NMR (300 MHz, CDCl3) δ 7.46ꢀ7.34 (m, 5 H), 4.24 (q, J = 7.2 Hz,
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The Journal of Organic Chemistry
ARTICLE
145 (61.70), 171 (59.75); HRMS (EI+) Calcd for C14H13F3O3 (M+):
286.0817, Found: 286.0820. IR (cmꢀ1): 2984, 2909, 1709, 1624, 1598,
1494, 1362, 1335, 1227, 1149, 1124, 1088, 939, 763, 696.
Found: 249.0298. IR (cmꢀ1): 2994, 1729, 1620, 1407, 1390, 1372, 1283,
1244, 1171, 1026, 905, 769, 754.
8u (Table 5, entry 2). Condition: (1) 6u (86 mg, 0.36 mmol), NaH
(14.4 mg, 0.36 mmol), 1 (130 mg, 0.3 mmol), THF/CH2Cl2 (4.5 +
1.5 mL). Eluent: petroleum ether/ethyl acetate = 12:1. 8u and 6u: 53
mg; (2) NaCl (44 mg, 0.75 mmol), H2O (44 mg, 2.44 mmol), DMSO
(1.2 mL); Eluent: petroleum ether/ethyl acetate = 10:1; 8u: 27 mg, 27%
for two steps, solid: mp 129ꢀ130 °C. 1H NMR (300 MHz, CDCl3) δ
8.37 (d, J = 8.4 Hz, 2 H), 8.20 (d, J = 8.7 Hz, 2 H), 4.06 (q, J = 7.2 Hz, 2
H), 3.15 (dd, J = 9.9, 6.0 Hz, 1 H), 3.05 (m, 1 H), 2.73 (dd, J = 9.9, 6.0
Hz, 1 H), 1.13 (t, J = 7.2 Hz, 3 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ67.22 (d, J = 5.9 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 189.7,
166.6, 150.8, 140.4, 129.46, 124.1, 124.0 (q, J = 271 Hz), 62.0, 28.2, 25.7,
25.4 (q, J = 39 Hz), 13.9. MS (EI+): m/z 331 (M+, 5.60), 150 (100), 286
(24.41), 104 (15.59), 76 (11.12); HRMS (EI+) Calcd for C14H12F3O5N
(M+): 331.0668, Found: 331.0664. IR (cmꢀ1): 3110, 3079, 3037, 1724,
1692, 1524, 1355, 1321, 1265, 1226, 1146.
9u (Table 5, entry 2). Condition: 6u (86 mg, 0.36 mmol), NaH
(14.4 mg, 0.36 mmol), 1 (130 mg, 0.3 mmol), THF/CH2Cl2 (4.5 +
1.5 mL). Eluent: petroleum ether/ethyl acetate = 12:1. 9u: 50 mg, 50%,
solid: mp 62ꢀ63 °C. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 9.2 Hz,
2 H), 8.00 (d, J = 8.8 Hz, 2 H), 4.80 (dd, J = 10.8, 3.6 Hz, 1 H), 4.66 (dd,
J = 10.4, 10.0 Hz, 1 H), 4.22ꢀ4.13 (m, 3 H), 1.23 (t, J = 7.2 Hz, 3 H); 19F
NMR (282 MHz, CDCl3) δ ꢀ72.42 (d, J = 8.2 Hz, 3 F); 13C NMR
(100.5 MHz, CDCl3) δ 167.1, 163.1, 149.2, 134.7, 131.1, 125.9 (q, J =
281 Hz), 122.8, 101.5, 70.4 (q, J = 2.9 Hz), 60.7, 48.2 (q, J = 30 Hz), 14.0.
MS (EI+): m/z 331 (M+, 40.87), 115 (100), 262 (96.50), 190 (78.95),
76 (73.24); HRMS (EI+) Calcd for C14H12NF3O5 (M+): 331.0668,
Found: 331.0670. IR (cmꢀ1): 3117, 2983, 2915, 1709, 1631, 1593, 1526,
1350, 1228, 1127, 1090, 1029, 1015, 859, 834.
’ ASSOCIATED CONTENT
S
Supporting Information. NMR spectra. This material is
b
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lulong@mail.sioc.ac.cn.
’ ACKNOWLEDGMENT
The authors gratefully acknowledge the financial support from
Special Fund for Agro-scientific Research in the Public Interest
(201103007), National Natural Science Foundation of China
(Grant Number 29825104 and 29632003), National Basic
Research Program of China (2010CB126103), the Key Program
of National Natural Science Foundation of China (21032006)
(Q.S.), and SIOC startup fund (Q.S.) for financial support.
’ REFERENCES
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9x (Table 5, entry 5). Condition: 6x (122 mg, 0.6 mmol), NaH (24.8
mg, 0.6 mmol), 1 (192 mg, 0.45 mmol), THF/CH2Cl2 (6 + 3 mL).
Eluent: petroleum ether/ethyl acetate = 30:1. 9x: 104 mg, 80%, solid:
mp 50ꢀ51 °C. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 3.9 Hz, 1 H),
7.58 (d, J = 5.1 Hz, 1 H), 7.12 (dd, J = 5.2, 4.8 Hz, 1 H), 4.72 (dd, J = 12.9,
2.4 Hz, 1 H), 4.54 (dd, J = 10.2, 9.9 Hz, 1 H), 4.32ꢀ4.20 (m, 2 H), 4.06
(m, 1 H), 1.31 (t, J = 7.2 Hz, 3 H); 19F NMR (282 MHz, CDCl3)
δ ꢀ72.51 (d, J = 7.3 Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 163.9,
163.0, 134.2, 131.9, 130.1, 127.4, 126.2 (q, J = 281 Hz), 96.7, 69.7 (q, J =
9 Hz), 60.3, 48.2 (q, J = 30 Hz), 14.2. MS (EI+): m/z 292 (M+, 41.86),
111 (100), 223 (89.45), 292 (41.86), 247 (38.74); HRMS (EI+) Calcd
for C12H11F3O3S (M+): 292.0381, Found: 292.0386. IR (cmꢀ1): 3079,
2982, 1689, 1603, 1424, 1358, 1263, 1221, 1143, 1080, 1053, 738.
9m (Table 5, entry 8). Condition: 6m (70 mg, 0.62 mmol), DBU (95
mg, 0.62 mmol), 1 (215 mg, 0.5 mmol), DMSO (6 + 3 mL). Eluent:
petroleum ether/ethyl acetate = 3:1. 9m: 66 mg, 64%, oil. 1H NMR (400
MHz, CDCl3) δ 4.73 (dd, J = 10.8, 4.0 Hz, 1 H), 4.58 (dd, J = 10.8, 10.0
Hz, 1 H), 3.92 (m, 1 H), 2.59ꢀ2.43 (m, 3 H), 2.37ꢀ2.29 (m, 1 H),
2.11ꢀ2.04 (m, 2 H); 19F NMR (282 MHz, CDCl3) δ ꢀ72.50 (d, J = 7.9
Hz, 3 F); 13C NMR (100.5 MHz, CDCl3) δ 193.3, 181.4, 125.8 (q, J =
277 Hz), 109.1, 72.6 (q, J = 3.1 Hz), 43.9 (q, J = 32 Hz), 36.7, 24.1, 21.1.
MS (EI+): m/z 206 (M+, 33.75), 178 (100), 206 (33.75); HRMS (EI+)
Calcd for C9H9F3O2 (M+): 206.0555, Found: 206.0556. IR (cmꢀ1):
2955, 1664, 1629, 1425, 1407, 1270, 1236, 1220, 1185, 1124, 997, 979.
9y (Table 5, entry 9). Condition: 6y (67 mg, 0.5 mmol), DBU (51
mg, 0.33 mmol), 1 (86 mg, 0.2 mmol), DMSO (3 + 1.5 mL). Eluent:
petroleum ether/ethyl acetate = 8:1. 9y: 43 mg, 99%, solid: mp
55ꢀ56 °C. 1H NMR (300 MHz, CDCl3) δ 4.76 (d, J = 9.0 Hz, 1 H),
4.67 (dd, J = 9.0, 9.0 Hz, 1 H), 4.39ꢀ4.27 (m, 3 H), 1.35 (t, J = 7.2 Hz, 3
H); 19F NMR (282 MHz, CDCl3) δ ꢀ71.56 (d, J = 7.1 Hz, 3 F); 13
C
NMR (100.5 MHz, CDCl3) δ 157.7, 124.6 (q, J = 281 Hz), 103.6, 64.2
(q, J = 2.9 Hz), 62.3, 47.8 (q, J = 32 Hz), 14.0. MS (ESI+): m/z 228 [M +
H]+; HRMS (ESI+) Calcd for C7H8F3N1Na1O4 (M + Na+): 250.0298,
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7368
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