A practical route for the highly stereoselective synthesis of tetrasubstituted fluoroalkenes

Article abstract of DOI:10.1039/c3ob42093k

A series of tetrasubstituted fluoroalkene derivatives were synthesized by the reaction of α-fluoro-β-carbonyl benzothiazol-2-yl sulfones with various nucleophiles in good yields with high stereoselectivities. The predominant cis configuration of fluorine and alkynyl groups was observed. A single isomer was obtained when a ketone, acetate or amide was used as the substrate in the presence of a base.

Full text of DOI:10.1039/c3ob42093k

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A practical route for the highly stereoselective
synthesis of tetrasubstituted fluoroalkenes†
Cite this: Org. Biomol. Chem., 2014,
12, 467
Chun-Ru Cao, Song Ou, Min Jiang and Jin-Tao Liu*
Received 21st October 2013,
Accepted 5th November 2013
A series of tetrasubstituted fluoroalkene derivatives were synthesized by the reaction of α-fluoro-β-carbo-
nyl benzothiazol-2-yl sulfones with various nucleophiles in good yields with high stereoselectivities. The
predominant cis configuration of fluorine and alkynyl groups was observed. A single isomer was obtained
when a ketone, acetate or amide was used as the substrate in the presence of a base.
DOI: 10.1039/c3ob42093k
www.rsc.org/obc
Introduction
The introduction of a fluorine atom into molecules may have a
profound effect on the biological activity, metabolism and
solubility of organic compounds.1,2 Molecules containing
carbon–fluorine bonds are extremely important as pharma-
ceuticals, imaging agents and fine chemicals.3 Among the
various fluoroorganics, functionalized fluoroalkenes are of par-
ticular interest and have been the subject of many investi-
gations due to their potential applications in many fields
including organic synthesis where they can be utilized as syn-
thons for further transformation.4 The HWE5 and Peterson reac-
tion6 are the most common methods for the preparation of
fluoroolefins. In 2002, Lequeux and coworkers reported the first
one step synthesis of fluorinated alkylidenes via a modified
Julia reaction.7 Various functionalized fluoroolefins are now
conveniently accessible by the Julia–Kocienski olefination.8
However, an efficient stereoselective synthesis of tetrasubsti-
tuted fluoroalkenes bearing four different carbon-linked groups
still presents a particular challenge in organic synthesis.
Scheme 1 A series of tetrasubstituted olefins synthesized by the reac-
tion of β-carbonyl benzothiazol-2-yl sulfones with nucleophiles.
tetrasubstituted fluoroalkenes using α-fluoro-β-carbonyl benzo-
thiazol-2-yl sulfones.
Results and discussion
Our first work was the preparation of α-fluoro-β-carbonyl
benzothiazol-2-yl sulfones (SFBT). Based on our earlier work,
the reactions of 2-mercaptobenzothiazole with commercially
available α-bromoacetophenone derivatives S-1 afforded the
thioethers S-2, and then the oxidation of S-2 produced benzo-
thiazolyl sulfones S-3 (Scheme 2, eqn (1)). Zajc and coworkers
Recently, our group developed a novel olefination method
based on the mechanism of modified Julia olefination. In the
new method the reaction of β-carbonyl benzothiazol-2-yl
sulfones with nucleophiles gave the corresponding β-alkoxy-
sulfone intermediates, which underwent
a facile Smiles
rearrangement and spontaneous elimination to yield tetrasub-
stituted alkenes (Scheme 1).9 As an extension of the novel olefi-
nation method, we envisioned that if the fluorine atom is
introduced into the β-carbonyl benzothiazol-2-yl sulfones,
tetrasubstituted fluoroolefins would be obtained. Herein, we
report a novel stereocontrolled method for the synthesis of
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, 345 Lingling Road, Shanghai 200032,
China. E-mail: jtliu@sioc.ac.cn; Fax: +86-21-64166128; Tel: +86-21-54925188
†Electronic supplementary information (ESI) available: NMR spectra of new
compounds. See DOI: 10.1039/c3ob42093k
Scheme 2 Eqn (1) synthesis of benzothiazolyl sulfones from α-bromo-
acetophenone derivatives; eqn (2) fluorination of benzothiazolyl sulfone.
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Table 1 Preparation of substrates 1
Scheme 3 The reaction of SFBT 1a with ethyl propiolate.
Entrya
R1
R2
1
Yieldb (%)
1
2
3
4
5
6
7c
Me
Me
Et
C6H5
2-Thienyl
C6H5
4-MeC6H4
C6H5
4-MeOC6H4
4-MeOC6H4
1a
1b
1c
1d
1e
1f
89
65
91
88
78
73
83
Et
C6H5
C6H5
Me
1g
a Reaction conditions: S-3 (6.0 mmol), Selectfluor™ (9.0 mmol) and
K2CO3 (7.2 mmol) in CH3CN (15.0 mL) at room temperature overnight.
b Isolated yields. c PT group instead of BT.
Fig. 1 Determination of stereochemistry in 3a.
intermediate A, which undergoes decomposition easily to
form byproducts. When 2,2′-bipyridine is added, the ligand
destroys the six-membered cycle of intermediate A to give
intermediate B which undergoes the Smiles rearrangement fol-
lowed by elimination to yield the fluorinated enyne, and the
rearrangement pathway is suppressed (Scheme 4).
have developed a general method for the synthesis of Julia ole-
fination reagents via heterogeneous metalation–fluorination of
appropriate precursors.10 Our initial fluorination of benzothia-
zolyl sulfone S-3a was performed with N-fluorobenzenesulfoni-
mide (NFSI, 1.5 equiv.) in the presence of potassium carbonate
(K2CO3, 1.2 equiv.) at room temperature. The expected product
1a was isolated in 75% yield. Using Selectfluor™ instead of
NFSI, the yield of 1a could be improved to 89%. However,
increasing the temperature to 60 °C reduced the yield of 1a
(Scheme 2, eqn (2)).
Therefore, fluorination of β-carbonyl benzothiazol-2-yl sul-
fones S-3 with Selectfluor™ (1.5 equiv.) was carried out in
CH3CN in the presence of K2CO3 (1.2 equiv.) at room tempera-
ture and a series of substrates 1a–1f were synthesized in good
yields (Table 1, entries 1–6). By this method, α-fluoro-β-carbo-
nyl-1-phenyl-1H-tetrazol-5-yl sulfone (SFPT) 1g was prepared
successfully in 83% yield similarly (entry 7).
With the desired reagents 1 in hand, we next studied their
olefination reaction and the associated stereoselectivity in the
presence of nucleophiles. In our previous report,9 alkynyl
lithium was a kind of suitable nucleophile to afford a series of
conjugated enynes in good to excellent yields. Therefore, we
carried out the reaction of ethyl propiolate 2a with SFBT 1a in
the presence of LDA under the Barbier procedure11 at −78 °C.
Only a trace of the expected product 3a was observed followed
by byproducts which were identified as decomposed com-
pounds by 19F NMR. This problem could not be solved by
changing the solvent, the lithium reagent, or the reaction
temperature or using tetramethylethylenediamine (TMEDA) as
an additive. However, when 1.5 equiv. of 2,2′-bipyridine was
added into the reaction mixture, enyne 3a was obtained in
82% yield with high stereoselectivity (93 : 7) (Scheme 3). The
NOESY data of the major isomer in 3a showed a correlation
between the protons in the phenyl ring and the methyl
protons, supporting the assignment of Z-configuration (Fig. 1).
The transformation might be explained as follows: the
Using 2,2′-bipyridine as the additive, the scope of the olefi-
nation reaction was examined. As shown in Table 2, the olefi-
nation procedure tolerated a broad range of functional groups.
It can be seen that the reaction of alkynyl lithiums bearing
ester-, aryl-, or alkyl-substitution proceeded well to give the
corresponding fluorinated conjugated enynes in moderate to
good yields under the optimal reaction conditions. For
different R2 substituents including electron-rich aryl and
thienyl, the reaction of SFBTs 1b–1d afforded the products 3b–
3g in excellent stereoselectivities (up to 97/3) and the predomi-
nant cis configuration of fluorine and alkynyl groups was
observed (entries 2–7). In the case of sulfones 1e and 1f in
which R1 was the phenyl group, the desired products 3h and 3i
were not obtained (entries 8 and 9). Furthermore, the reaction
of SFPT 1g gave enyne 3j with lower stereoselectivity (85 : 15,
entry 10).
Scheme 4 Proposed mechanism for the reaction of SFBT with alkynyl
lithium in the presence of 2,2’-bipyridine.
addition of alkynyl lithium to substrate
1
generates
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Table 2 The reaction of SFBTs with alkynyl lithiums
Table 3 The olefinations of 1a with 4
Entrya
1
R1
R2
2, R3
3
Yieldb (%) Z/Ec
Entrya
1
4
Product (5)
Yieldb (%)
74
1
2
3
4
5
6
7
8
9
10
1a Me
1b Me
1c Et
1c Et
1c Et
1d Et
1d Et
C6H5
2-Thienyl
C6H5
C6H5
C6H5
4-MeC6H4
4-MeC6H4
2a, CO2Et 3a 78(82)
93/7
5/95
96/4
96/4
93/7
96/4
97/3
—
2c, C4H9
2b, C6H5
2c, C4H9
3b 89(95)
3c 92(99)
3d 79(84)
2
3
71
61
2a, CO2Et 3e 76(81)
2b, C6H5
2c, C4H9
2c, C4H9
3f 93(97)
3g 48(51)
3h
3i
d
1e C6H5 C6H5
1f C6H5 4-MeOC6H4 2b, C6H5
1g Me 4-MeOC6H4 2b, C6H5
—
—
d
—
3j 82(87)
85/15
4
57
a Reaction conditions: 1 (0.5 mmol), 2,2′-bipyridine (0.75 mmol),
alkyne (1.0 mmol) and LDA (0.75 mmol) in THF (5.0 mL) at −78 °C for
3
h. b Isolated yields and the yields in the parentheses were
determined by 19F NMR using PhCF3 as an internal standard. c Ratio
of Z/E structure was determined by 19F NMR. d The product was not
obtained.
5
6
69
62
We further investigated the addition of other nucleophiles
and found that α-fluoro-substituted sulfone was more reactive
than unfluorinated sulfone. The reaction of SFBT 1a with
acetone 4a (4.0 equiv.) in the presence of LDA (2.0 equiv.)
afforded fluoroalkene 5a in 10% yield along with a large
amount of byproducts. Surprisingly, only one isomer of fluori-
nated alkene 5a was observed. 2,2′-Bipyridine, which promoted
good results in the reaction of alkynyl lithium, improved
slightly the yield of 5a to 15% (Scheme 5).
Berthelette’s group reported that hexamethylphosphor-
amide (HMPA) as an additive could improve the yield in Julia
olefination to afford substituted vinyl ethers,12 and Hu’s group
also found that HMPA gave monofluoroalkenes with excellent
E/Z stereocontrol in the reaction of α-fluorosulfoximine with
nitrone.13 In those reactions HMPA played an important role
in the stabilization of the tetrahedral intermediate. Therefore,
we added 0.5 mL of HMPA (VHMPA : VTHF = 1 : 10) to the reac-
tion mixture. Gratifyingly, the yield of 5a was improved to 74%
without any erosion in stereoselectivity (Scheme 5).
7
46
a Reaction conditions: 1 (0.5 mmol), 4 (2.0 mmol), HMPA (0.5 mL) and
LDA (1.0 mmol) in THF (5.0 mL) at −78 °C for 3 h. b Isolated yields.
worth mentioning that cyclohexanone also produced the
corresponding product 5d in 57% yield under optimal reaction
conditions (entry 4). Using ethyl acetate or N,N-dimethylacet-
amide (DMA) as the substrate, the corresponding fluoroolefins
5e and 5f were obtained in 69% and 62% yield, respectively
(entries 5 and 6). The reaction of nitromethane 4g with 1a
could also occur to give fluoroolefin 5g, but a lower yield was
obtained (46%, entry 7). Each product in Table 3 was obtained
as a single isomer and the stereochemistry of the newly
formed double bond was determined as E by the NOE experi-
ments of 5f.
On the basis of the above experimental and reported
results,9 comparison of the reactivity of unfluorinated sulfone
and α-fluorinated sulfone indicates that the latter is much
more active and easier to decompose during the reaction.
In the presence of HMPA, we examined the reaction of
SFBT with various carbon nucleophiles 4 in THF and the
results are summarized in Table 3. Using phenyl methyl
ketone 4b or 3,3-dimethyl-2-butanone 4c instead of acetone,
the reactions worked well and afforded fluoroalkenes 5b and
5c in 71% and 61% yield, respectively (entries 2 and 3). It is
Conclusions
In summary, making use of the novel olefination reaction of
α-fluoro-β-carbonyl benzothiazol-2-yl sulfones with various
nucleophiles, a series of tetrasubstituted fluoroalkenes were
prepared with excellent stereoselectivities. These tetrasubsti-
tuted fluoroalkenes are useful structural motifs in the syn-
thesis of many natural products and bioactive compounds.
Scheme 5 The reaction of SFBT 1a with acetone.
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anhydrous Na2SO4. After removal of the solvent, the residue
was purified by column chromatography on silica gel (PE) to
give 3.
Experimental section
General information
Unless otherwise mentioned, solvents and reagents were pur-
chased from commercial sources and used as received. 1H
Procedure for the olefination reaction with 4
NMR and 19F NMR spectra were recorded on 1H at 300 MHz SFBT 1a (0.5 mmol), 4 (2.0 mmol) and HMPA (0.5 mL) were
and 19F at 282 MHz, respectively. 13C NMR spectra were dissolved in THF (5 mL) and cooled to −78 °C. To the solution
recorded on a Bruker AM-400 spectrometer with CFCl3 as the was added LDA (1.0 mL, 1.0 M in THF/hexane = 1/1). The
external standard. IR spectra were obtained using a Nicolet resulting mixture was stirred at −78 °C for 3 hours, then
AV-360 spectrophotometer. Mass spectra were taken on an warmed to room temperature and quenched with saturated
HP5989A spectrometer. High-resolution mass data were aqueous NH4Cl solution. The aqueous layer was extracted with
obtained on a high-resolution mass spectrometer in the EI ethyl ether (10 mL × 3). The combined organic layer was
mode.
washed with H2O (10 mL × 3) and dried over anhydrous
Na2SO4. After removal of the solvent, the residue was purified
by column chromatography on silica gel (PE) to give 5.
Typical procedure for the preparation of SFBT
2-(Benzothiazole-2-sulfonyl)-2-fluoro-1-phenyl-propan-1-one
(1a). 1.87 g, 89%; a white solid, m.p. 98–100 °C; IR (KBr,
cm−1): υ 1686, 1597, 1465, 1449, 1350, 1264, 1172, 1155, 979,
763, 704, 626; ESI-MS (m/z, %): 350.0 (M + H)+; HRMS (ESI),
calcd for C16H13FNO3S3 (M + H)+: 350.0315. Found: 350.0324;
Anal. calcd for C16H12FNO3S2: C, 55.00; H, 3.46; F, 5.44; N,
4.01; S, 18.35. Found: C, 55.37; H, 3.88; F, 5.38; N, 4.00; S,
18.69%; 1H NMR (300 MHz, CDCl3): δ 8.23–8.18 (m, 1H),
8.02–7.98 (m, 3H), 7.67–7.51 (m, 3H), 7.42–7.24 (m, 2H), 2.25
(dd, J = 22.0, 16.3 Hz, 3H) ppm; 19F NMR (282 MHz, CDCl3): δ
−144.99 (q, J = 22.0 Hz, 1F) ppm.
2-(Benzothiazole-2-sulfonyl)-2-fluoro-1-thiophen-3-yl-propan-
1-one (1b). 1.38 g, 65%; a white solid, m.p. 112–114 °C; IR
(KBr, cm−1): υ 1653, 1559, 1409, 1351, 1271, 1168, 852, 763,
729; ESI-MS (m/z, %): 355.9 (M + H)+; HRMS (ESI), calcd for
C14H11FNO3S3 (M + H)+: 355.9880. Found: 355.9890; Anal.
calcd for C14H10FNO3S3: C, 47.31; H, 2.84; N, 3.94; S, 27.06.
Found: C, 47.36; H, 3.03; N, 3.77; S, 27.39%; 1H NMR
(300 MHz, CDCl3): δ 8.21–8.20 (m, 1H), 8.02–7.94 (m, 2H),
7.70–7.61 (m, 3H), 7.01 (t, J = 4.5 Hz, 1H), 2.24 (d, J = 22.8 Hz,
3H) ppm; 19F NMR (282 MHz, CDCl3): δ −146.74 (q, J =
22.8 Hz, 1F) ppm.
To a 50 mL vessel containing 2-mercaptobenzothiazole (BTSH,
1.67 g, 10 mmol) were added CH2Cl2 (20 mL) and Et3N (2 mL).
The mixture was stirred at room temperature for a few
minutes. α-Bromoketone (10 mmol) was then added, and the
resulting mixture was stirred for about 3 hours at room temp-
erature till the completion of the reaction (monitored by TLC).
The mixture was diluted with ether (50 mL), washed with water
and saturated aqueous NaCl solution, and dried over Na2SO4.
Evaporation of the solvent gave the crude thioether which was
pure enough for the following oxidation reaction.
The crude thioether was dissolved in CH2Cl2 (20 mL). To
the solution were added H2O (20 mL) and CH3CN (20 mL) as
co-solvents. Then NaIO4 (5.32 g, 25 mmol) and RuCl3·nH2O
(0.03 g) were added. The resulting mixture was stirred over-
night at room temperature. The organic layer was separated.
The aqueous layer was extracted three times with CH2Cl2
(30 mL). The combined organic layer was washed three times
with H2O, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(PE–EtOAc, 4 : 1) to give sulfone S-3.
To a solution of sulfone S-3 (6.0 mmol) in CH3CN (15 mL)
were added Selectfluor™ (3.18 g, 9.0 mmol) and K2CO3 (1.0 g,
7.2 mmol) at room temperature. The mixture was stirred over-
night. And then the system was quenched with water (20 mL).
The aqueous layer was extracted with ethyl acetate (10 mL × 3).
The combined organic layer was washed with H2O and satu-
rated aqueous NaCl solution and dried over anhydrous
Na2SO4. After removal of the solvent, the residue was purified
by column chromatography on silica gel (PE–EtOAc, 2 : 1) to
give SFBT 1.
2-(Benzothiazole-2-sulfonyl)-2-fluoro-1-phenyl-butan-1-one
(1c). 1.99 g, 91%; a white solid, m.p. 105–107 °C; IR (KBr,
cm−1): υ 1682, 1596, 1559, 1460, 1350, 1253, 1161, 1016, 853,
762; ESI-MS (m/z, %): 364.0 (M + H)+; HRMS (ESI), calcd for
C17H15FNO3S2 (M + H)+: 364.0485. Found: 364.0480; Anal.
calcd for C17H14FNO3S2: C, 56.18; H, 3.88; N, 3.85; F, 5.23; S,
1
17.65. Found: C, 56.27; H, 4.02; N, 3.81; F, 5.29; S, 17.96%; H
NMR (300 MHz, CDCl3): δ 8.22–8.18 (m, 1H), 7.99–7.92 (m,
3H), 7.63–7.60 (m, 3H), 7.40–7.35 (m, 2H), 3.03–2.81 (m, 1H),
2.58–2.52 (m, 1H), 1.03 (m, 3H) ppm; 19F NMR (282 MHz,
CDCl3): δ −156.35 (dd, J = 37.4, 10.4 Hz, 1F) ppm.
Procedure for the olefination reaction with alkynyl lithium
SFBT 1 (0.5 mmol), alkyne (1.0 mmol) and 2,2′-bipyridine
2-(Benzothiazole-2-sulfonyl)-2-fluoro-1-p-tolyl-butan-1-one
(117 mg, 0.75 mmol) were dissolved in THF (12 mL). To the (1d). 1.99 g, 88%; a white solid, m.p. 104–106 °C; IR (KBr,
solution was added LDA (0.75 mL, 1.0 M in THF/hexane = 1/1) cm−1): υ 1677, 1606, 1464, 1351, 1259, 1116, 1015, 850, 763,
at −78 °C. The resulting mixture was stirred at −78 °C for 729, 615; ESI-MS (m/z, %): 377.9 (M + H)+; HRMS (ESI), calcd
3 hours, then warmed to room temperature and quenched for C18H17FNO3S3 (M + H)+: 378.0628. Found: 378.0634; Anal.
with saturated aqueous NH4Cl solution. The aqueous layer was calcd for C18H16FNO3S2: C, 57.28; H, 4.27; N, 3.71; F, 5.03.
extracted with ethyl ether (10 mL × 3). The combined organic Found: C, 57.11; H, 4.46; N, 3.57; F, 4.94%; 1H NMR (300 MHz,
layer was washed with H2O (10 mL × 3) and dried over CDCl3): δ 8.19–8.16 (m, 1H), 7.98–7.95 (m, 1H), 7.83 (d, J =
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8.1 Hz, 2H), 7.62–7.57 (m, 2H), 7.15 (d, J = 8.1 Hz, 2H), 13C NMR (100 MHz, CDCl3): δ 161.6 (d, JC–F = 269.0 Hz), 126.5,
3.00–2.79 (m, 1H), 2.56–2.44 (m, 1H), 2.33 (s, 3H), 1.00 (t, J = 126.3, 126.2, 125.3, 125.2, 94.8, 75.4, 30.8, 22.0, 19.1, 17.5 (d,
7.5 Hz, 3H) ppm; 19F NMR (282 MHz, CDCl3): δ −156.26 (dd, JC–F = 22.0 Hz), 13.6 ppm; 19F NMR (282 MHz, CDCl3):
J = 50.6, 11.0 Hz, 1F) ppm.
δ −85.95 (q, J = 16.9 Hz, 1F) ppm.
2-(Benzothiazole-2-sulfonyl)-2-fluoro-1,2-diphenyl-ethanone
(4-Fluoro-3-phenyl-hex-3-en-1-ynyl)-benzene (3c). 115 mg,
(1e). 1.93 g, 78%; a white solid, m.p. 124–126 °C; IR (KBr, 92%; colorless liquid; IR (film, cm−1): υ 2966, 1256, 1084,
cm−1): υ 1687, 1596, 1464, 1449, 1351, 1256, 1158, 1022, 763, 1029, 807; EIMS (m/z, %): 250 (M+, 100.00), 235 (33.30), 220
694, 612; ESI-MS (m/z, %): 411.9 (M + H)+; HRMS (ESI), calcd (22.26), 215 (40.39); HRMS (EI) calcd for C18H15F (M+):
for C21H15FNO3S2 (M + H)+: 412.0472. Found: 412.0486; Anal. 250.1158. Found: 250.1159; Z-isomer: 1H NMR (300 MHz,
calcd for C21H14FNO3S2: C, 61.30; H, 3.43; N, 3.40; F, 4.62; S, CDCl3): δ 7.67–7.64 (m, 2H), 7.46–7.24 (m, 8H), 2.84–2.69 (dq,
15.59. Found: C, 61.00; H, 3.70; N, 3.32; F, 4.40; S, 15.25%; J = 23.1, 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H) ppm; 13C NMR
1H NMR (300 MHz, CDCl3): δ 8.20–8.18 (m, 1H), 8.00–7.96 (100 MHz, CDCl3): δ 168.0 (d, JC–F = 273.0 Hz), 133.8, 131.3,
(m, 1H), 7.77–7.72 (m, 4H), 7.67–7.45 (m, 6H), 7.40–7.23 (m, 2H) 128.6, 128.5, 128.4, 128.2, 127.4, 123.4, 103.5 (d, JC–F
=
ppm; 19F NMR (282 MHz, CDCl3): δ −147.47 (s, 1F) ppm.
24.5 Hz), 93.17 (d, JC–F = 8.0 Hz), 86.0 (d, JC–F = 13.3 Hz), 25.5
2-(Benzothiazole-2-sulfonyl)-2-fluoro-1-(4-methoxyphenyl)- (d, JC–F = 25.8 Hz), 10.7 ppm; 19F NMR (282 MHz, CDCl3):
2-phenylethanone (1f). 1.94 g, 73%; a white solid, m.p. δ −97.70 (t, J = 21.7 Hz, 1F) ppm.
128–130 °C; IR (KBr, cm−1): υ 1734, 1654, 1596, 1351, 1263,
[1-(1-Fluoro-propylidene)-hept-2-ynyl]-benzene (3d). 91 mg,
1158, 1025, 695, 617; ESI-MS (m/z, %): 441.8 (M + H)+; HRMS 79%; colorless liquid; IR (film, cm−1): υ 2958, 2926, 2853,
(ESI), calcd for C22H17FNO4S2 (M + H)+: 442.0603. Found: 1736, 1638, 1561, 1494, 1378, 878, 763, 694; EIMS (m/z, %): 230
442.0596; Anal. calcd for C22H16FNO4S2: C, 59.85; H, 3.65; F, (M+, 81.06), 191 (22.99), 173 (22.88), 159 (34.29), 149 (100.00);
4.30; N, 3.17; S, 14.53. Found: C, 59.60; H, 3.94; F, 4.27; N, HRMS (EI) calcd for C16H19F (M+): 230.1471. Found: 230.1468;
3.13; S, 14.82%; 1H NMR (300 MHz, CDCl3): δ 8.20–8.18 (m, Z-isomer: 1H NMR (300 MHz, CDCl3): δ 7.60–7.55 (m, 2H),
1H), 8.00–7.96 (m, 1H), 7.78–7.45 (m, 7H), 7.24 (d, J = 8.7 Hz, 7.32–7.20 (m, 3H), 2.66 (dq, J = 22.2, 7.8 Hz, 2H), 2.36–2.32 (m,
2H), 6.82–6.79 (m, 2H), 3.79 (d, J = 8.1 Hz, 3H) ppm; 19F NMR 2H), 1.56–1.40 (m, 4H), 1.21–1.13 (m, 3H), 0.96–0.86 (m, 3H)
(282 MHz, CDCl3): δ −146.00 (s, 1F) ppm.
ppm; 13C NMR (100 MHz, CDCl3): δ 167.2 (d, JC–F = 270.0 Hz),
2-Fluoro-1-(4-methoxy-phenyl)-2-(1-phenyl-1H-tetrazole-5- 134.4, 128.5, 128.4, 128.0, 127.1, 103.4 (d, JC–F = 24.1 Hz), 94.0,
sulfonyl)-propan-1-one (1g). 2.06 g, 83%; a white solid, m.p. 30.9, 25.2 (d, JC–F = 26.4 Hz), 22.0, 19.2, 13.6, 10.7 ppm; 19F
106–108 °C; IR (KBr, cm−1): υ 1599, 1497, 1367, 1268, 1173, NMR (282 MHz, CDCl3): δ −101.2 (t, J = 20.4 Hz, 1F) ppm.
844, 763, 690; ESI-MS (m/z, %): 413.0 (M + Na)+; HRMS (ESI),
5-Fluoro-4-phenyl-hept-4-en-2-ynoic
acid
ethyl
ester
calcd for C17H16FN4NaO4S (M + Na)+: 413.0690. Found: (3e). 93 mg, 76%; colorless liquid; IR (film, cm−1): υ 2963,
413.0695; Anal. calcd for C17H15FN4O4S: C, 52.30; H, 3.87; N, 2928, 2213, 1708, 1638, 1494, 1367, 1236, 1201, 1118, 927, 763;
1
14.35; F, 4.87. Found: C, 52.37; H, 3.91; N, 14.67; F, 4.68%; H EIMS (m/z, %): 246 (M+, 100.00), 218 (21.92), 201 (65.00), 174
NMR (300 MHz, CDCl3): δ 7.95–7.89 (m, 2H), 7.62–7.56 (m, (40.63), 159 (44.39); HRMS (EI) calcd for C15H15FO2 (M+):
4H), 7.30–7.26 (m, 1H), 6.96–6.88 (d, J = 7.6 Hz, 2H), 3.90 (dd, 246.1232. Found: 246.1237; Z-isomer: 1H NMR (300 MHz,
J = 8.7, 3.0 Hz, 3H), 2.25 (dd, J = 19.2, 7.2 Hz, 3H) ppm; 19F CDCl3): δ 7.30–7.22 (m, 5H), 4.17 (q, J = 7.2 Hz, 2H), 2.39–2.22
NMR (282 MHz, CDCl3): δ −157.00 (q, J = 21.0 Hz, 1F) ppm.
5-Fluoro-4-phenyl-hex-4-en-2-ynoic acid ethyl
(dq, J = 22.2, 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H), 1.08 (t, J =
ester 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 172.1 (d, JC–F
=
(3a). 90 mg, 78%; colorless liquid; IR (film, cm−1): υ 2985, 274.0 Hz), 154.0, 133.3, 129.0, 128.2, 127.9, 102.0 (d, JC–F = 18.5
2213, 1710, 1648, 1368, 1246, 1126, 933, 764; EIMS (m/z, %): Hz), 85.4 (d, JC–F = 8.8 Hz), 81.5, 62.0, 23.5 (d, JC–F = 25.0 Hz),
232 (M+, 100.00), 204 (29.69), 187 (93.44), 160 (94.16), 133 14.1, 10.7 ppm; 19F NMR (282 MHz, CDCl3): δ −83.99 (t, J =
(48.34); HRMS (EI) calcd for C14H13FO2 (M+): 232.0900. Found: 30.4 Hz, 1F) ppm.
232.0903; Z-isomer: 1H NMR (300 MHz, CDCl3): δ 7.36–7.29
1-(2-Fluoro-1-phenylethynyl-but-1-enyl)-4-methyl-benzene (3f).
(m, 5H), 4.22 (q, J = 7.2 Hz, 2H), 2.12 (d, J = 17.1 Hz, 3H), 1.29 122 mg, 93%; colorless liquid; IR (film, cm−1): υ 2925, 1639,
(t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 168.1 (d, 1138, 893; EIMS (m/z, %): 264 (M+, 100.00), 249 (42.00), 233
J = 271.0 Hz), 154.0, 133.3, 129.0, 128.4, 128.2, 102.6 (d, JC–F
17.6 Hz), 85.5 (d, JC–F = 8.8 Hz), 81.3, 62.0, 16.8 (d, JC–F
=
=
(48.37), 221 (50.77), 119 (71.13); HRMS (EI) calcd for C19H17F
(M+): 264.1314. Found: 264.1307; Z-isomer: 1H NMR (300 MHz,
26.4 Hz), 13.6 ppm; 19F NMR (282 MHz, CDCl3): δ −73.36 (q, CDCl3): δ 7.59–7.55 (m, 2H), 7.45–7.48 (m, 2H), 7.35–7.30 (m,
J = 19.0 Hz, 1F) ppm.
3H), 7.19–7.15 (m, 2H), 2.85–2.71 (dq, J = 22.2, 7.5 Hz, 2H),
2-[1-(1-Fluoro-ethylidene)-hept-2-ynyl]-thiophene (3b). 98 mg, 2.34 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (100 MHz,
89%; colorless liquid; IR (film, cm−1): υ 2920, 1465, 1265, CDCl3): δ 167.6 (d, JC–F = 273.0 Hz), 137.2, 131.3, 130.9, 128.9,
1020, 807; EIMS (m/z, %): 222 (M+, 100.00), 179 (22.02), 165 128.4, 128.3, 128.1, 123.5, 103.3 (d, JC–F = 25.1 Hz), 93.0 (d,
(14.75), 146 (16.84), 115 (17.48); HRMS (EI) calcd for C13H15FS JC–F = 7.3 Hz), 86.2 (d, JC–F = 13.3 Hz), 25.4 (d, JC–F = 25.8 Hz),
(M+): 222.0878. Found: 222.0886; E-isomer: 1H NMR (300 MHz, 21.2, 10.7 ppm; 19F NMR (282 MHz, CDCl3): δ −99.32 (t, J =
CDCl3): δ 7.32 (d, J = 3.6 Hz, 1H), 7.26 (d, J = 4.2 Hz, 1H), 21.7 Hz, 1F) ppm.
7.08–7.05 (m, 1H), 2.44 (t, J = 6.6 Hz, 2H), 2.32 (dd, J = 16.8,
1-[1-(1-Fluoro-propylidene)-hept-2-ynyl]-4-methyl-benzene (3g).
3.6 Hz, 3H), 1.64–1.26 (m, 4H), 0.97 (t, J = 7.4 Hz, 3H) ppm; 58 mg, 48%; colorless liquid; IR (film, cm−1): υ 3029, 2960,
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2932, 2875, 1639, 1513, 1463, 1201, 1188, 1057, 818; EIMS 1.93 (d, J = 18.0 Hz, 3H), 1.12 (s, 9H); 13C NMR (100 MHz,
(m/z, %): 244 (M+, 100.00), 187 (24.51), 173 (30.70); HRMS (EI) CDCl3):
212.3, 156.1 (d, JC–F 251.6 Hz), 139.0 (d,
calcd for C17H21F (M+): 244.1627. Found: 244.1633; Z-isomer: JC–F = 8.7 Hz), 128.9 (d, JC–F = 2.8 Hz), 128.3, 126.9, 113.3 (d,
δ
=
1H NMR (300 MHz, CDCl3): δ 7.50 (d, J = 7.8 Hz, 2H), 7.14 (d, JC–F = 19.2 Hz), 44.3, 38.6 (d, JC–F = 6.4 Hz), 26.4, 15.7 (d, JC–F
=
J = 7.8 Hz, 2H), 2.75–2.60 (dq, J = 22.2, 7.5 Hz, 2H), 2.40–2.33 30.2 Hz); 19F NMR (282 MHz, CDCl3): δ −96.68 (q, J =
(m, 5H), 1.58–1.42 (m, 4H), 1.20 (t, J = 7.5 Hz, 3H), 0.97 (t, J = 18.0 Hz, 1F).
7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.82 (d, J =
2-(2-Fluoro-1-phenylprop-1-en-1-yl)cyclohexanone (5d). 70 mg,
269.0 Hz), 136.9, 131.6, 128.7, 128.3, 128.3, 103.3 (d, JC–F = 23.6 61%, colorless liquid; IR (film, cm−1): υ 2938, 2861, 1713,
Hz), 93.9 (d, JC–F = 7.9 Hz), 30.9, 25.2 (d, JC–F = 26.4 Hz), 22.0, 1492, 1449, 1383, 1191, 1125, 895, 703; EIMS (m/z, %): 232
21.2, 19.2, 13.6, 10.7 ppm; 19F NMR (282 MHz, CDCl3): (M+, 100.00), 203 (87.35), 147 (38.37), 146 (40.53), 142 (43.56),
δ −102.02 (t, J = 22.1 Hz, 1F) ppm.
141 (41.63), 129 (46.79), 115 (40.70); HRMS (EI) calcd for
1-(2-Fluoro-1-phenylethynyl-propenyl)-4-methoxy-benzene (3j). C15H17FO (M+): 232.1263. Found: 232.1266; 1H NMR
109 mg, 82%; colorless liquid; IR (film, cm−1): υ 2931, 2204, (300 MHz, CDCl3): δ 7.22–7.10 (m, 5H), 3.58 (dd, J = 12.7,
1725, 1509, 1512, 1490, 1444, 1252, 1177, 1035, 923, 835, 757, 5.6 Hz, 1H), 2.43–2.23 (m, 2H), 1.98–1.85 (m, 2H), 1.74 (d, J =
691; EIMS (m/z, %): 266 (M+, 100.00), 237 (11.37), 202 (15.68), 17.9 Hz, 3H), 1.74–1.34 (m, 4H); 13C NMR (100 MHz, CDCl3):
135 (26.93), 129 (34.53); HRMS (EI) calcd for C18H15FO (M+): δ 209.0, 155.7 (d, JC–F = 252.8 Hz), 137.6 (d, JC–F = 8.9 Hz),
266.1107. Found: 266.1101; Z-isomer: 1H NMR (300 MHz, 130.1 (d, JC–F = 2.9 Hz), 128.1, 127.0, 116.5 (d, JC–F = 17.1 Hz),
CDCl3): δ 7.62–7.53 (m, 2H), 7.47–7.27 (m, 6H), 6.89 (d, J = 52.0 (d, JC–F = 4.0 Hz), 42.0, 31.9 (d, JC–F = 1.6 Hz), 26.8, 25.2,
7.5 Hz, 2H), 3.81 (s, 3H), 2.12 (d, J = 17.1 Hz, 3H) ppm; 15.9 (d, JC–F = 30.5 Hz); 19F NMR (282 MHz, CDCl3): δ −97.13
13C NMR (100 MHz, CDCl3): δ 162.8 (d, JC–F = 265.0 Hz), 131.9, (q, J = 17.9 Hz, 1F).
131.5, 130.1, 129.1, 128.4, 128.2, 128.0, 123.5, 113.9 (d, JC–F
29.2 Hz), 94.1 (d, JC–F = 8.8 Hz), 84.6, 55.3, 16.6 (d, JC–F
=
=
Ethyl 4-fluoro-3-phenylpent-3-enoate (5e). 76 mg, 69%;
colorless liquid; IR (film, cm−1): υ 3481, 3059, 3022, 2924,
27.8 Hz) ppm; 19F NMR (282 MHz, CDCl3): δ −81.53 (q, J = 1698, 1650, 1494, 1444, 1365, 1191, 1139, 702; EIMS (m/z, %):
17.1 Hz, 1F) ppm.
223 (M + H+, 7.00), 202 (27.36), 174 (25.49), 145 (21.09), 130
5-Fluoro-4-phenylhex-4-en-2-one (5a). 71 mg, 74%; colorless (27.76), 118 (16.16), 103 (23.18), 77 (24.97); HRMS (EI) calcd
liquid; IR (film, cm−1): υ 3057, 3924, 2923, 1716, 1384, 1357, for C13H15FO2 (M+): 222.1056. Found: 222.1059; 1H NMR
1193, 1160, 701; EIMS (m/z, %): 192 (M+, 66.41), 150 (29.48), (300 MHz, CDCl3): δ 7.33–7.21 (m, 5H), 4.08 (q, J = 7.1 Hz, 2H),
149 (40.02), 130 (26.26), 129 (71.90), 128 (56.27), 127 (25.26), 3.44 (d, J = 1.9 Hz, 2H), 1.93 (d, J = 18.0 Hz, 3H), 1.17 (t, J =
43 (100.00); HRMS (EI) calcd for C12H13FO (M+): 192.0950. 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.0 (d, JC–F
=
Found: 192.0953; 1H NMR (300 MHz, CDCl3): δ 7.36–7.18 2.6 Hz), 156.4 (d, JC–F = 253.7 Hz), 138.3 (d, JC–F = 8.2 Hz),
(m, 5H), 3.52 (s, 2H), 2.14 (s, 3H), 2.10 (d, J = 18.0 Hz, 3H); 129.0 (d, JC–F = 2.9 Hz), 128.4, 127.2, 112.5 (d, JC–F = 18.4 Hz),
13C NMR (100 MHz, CDCl3): δ 205.7 (d, JC–F = 2.2 Hz), 156.4 (d, 60.7, 35.8 (d, JC–F = 7.2 Hz), 15.7 (d, JC–F = 29.9 Hz), 14.1;
JC–F = 252.9 Hz), 138.2 (d, JC–F = 8.4 Hz), 128.7 (d, JC–F
2.8 Hz), 128.4, 127.2, 112.8 (d, JC–F = 19.0 Hz), 45.4 (d, JC–F
=
=
19F NMR (282 MHz, CDCl3): δ −96.29 (q, J = 18.0 Hz, 1F).
4-Fluoro-N,N-dimethyl-3-phenylpent-3-enamide (5f). 69 mg,
6.0 Hz), 29.3, 15.7 (d, JC–F = 30.0 Hz); 19F NMR (282 MHz, 62%, colorless liquid; IR (film, cm−1): υ 3059, 3022, 2924,
CDCl3): δ −94.87 (q, J = 18.0 Hz, 1F).
1697, 1655, 1493, 1396, 1191, 1183, 702; EIMS (m/z, %): 221
4-Fluoro-1,3-diphenylpent-3-en-1-one (5b). 90 mg, 71%; col- (M+, 31.59), 201 (10.11), 200 (9.87), 133 (7.30), 129 (8.72),
orless liquid; IR (film, cm−1): υ 3057, 2956, 2921, 2861, 1693, 128 (10.38), 77 (5.61), 72 (100.00); HRMS (EI) calcd for
1493, 1447, 1383, 1334, 1213, 1191, 1011; EIMS (m/z, %): 254 C13H16FNO (M+): 221.1216. Found: 221.1217; 1H NMR
(M+, 10.44), 133 (3.90), 128 (4.80), 106 (8.30), 105 (100.00), 78 (300 MHz, CDCl3): δ 7.35–7.22 (m, 5H), 3.47 (d, J = 1.2 Hz, 2H),
(3.26), 77 (38.72), 51 (9.25); HRMS (EI) calcd for C17H15FO 2.97 (s, 3H), 2.88 (s, 3H), 1.92 (d, J = 18.0 Hz, 3H); 13C NMR
1
(M+): 254.1107. Found: 254.1103; H NMR (300 MHz, CDCl3): (100 MHz, CDCl3): δ 170.1 (d, JC–F = 2.4 Hz), 155.7 (d, JC–F
=
δ 7.93–7.90 (m, 2H), 7.54–7.16 (m, 8H), 4.07 (d, J = 1.8 Hz, 2H), 252.1 Hz), 138.4 (d, JC–F = 8.4 Hz), 129.1 (d, JC–F = 2.9 Hz),
1.94 (d, J = 18.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 196.8, 128.3, 127.1, 113.5 (d, JC–F = 18.3 Hz), 37.3, 35.6, 35.3 (d, JC–F
=
156.2 (d, JC–F = 252.7 Hz), 138.5 (d, JC–F = 8.5 Hz), 136.8, 6.5 Hz), 15.7 (d, JC–F = 30.2 Hz); 19F NMR (282 MHz, CDCl3): δ
133.0, 129.0 (d, JC–F = 2.9 Hz), 128.5, 128.4, 128.2, 127.1 −97.14 (q, J = 18.0 Hz, 1F).
112.9 (d, JC–F = 18.4 Hz), 40.7 (d, JC–F = 6.1 Hz), 15.8 (d, JC–F
29.9 Hz); 19F NMR (282 MHz, CDCl3): δ −95.15 (q, J = colorless liquid; IR (film, cm−1): υ 2925, 1696, 1558, 1386,
18.0 Hz, 1F).
1371, 1200, 1075, 975, 702; EIMS (m/z, %): 195 (M+, 2.31),
=
(3-Fluoro-1-nitrobut-2-en-2-yl)benzene (5g). 45 mg, 46%;
6-Fluoro-2,2-dimethyl-5-phenylhept-5-en-3-one (5c). 66 mg, 149 (100.00), 133 (17.36), 129 (58.05); HRMS (EI) calcd for
57%; colorless liquid; IR (film, cm−1): υ 2938, 2861, 1713, C10H10FNO2 (M+): 195.0696. Found: 195.0694; 1H NMR
1492, 1449, 1383, 1191, 1125, 895, 703; EIMS (m/z, %): 234 (300 MHz, CDCl3): δ 7.32–7.14 (m, 5H), 5.21 (s, 2H), 1.94 (d, J =
(M+, 5.47), 57 (100.00), 158 (12.95), 150 (7.90), 149 (8.21), 129 18.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 161.3 (d, JC–F
=
(10.85), 128 (11.41), 85 (11.54), 41 (17.06); HRMS (EI) calcd for 197.0 Hz), 135.2, 129.0, 129.0, 128.2, 110.4 (d, JC–F = 12.0 Hz),
C15H19FO (M+): 234.1420. Found: 234.1422; 1H NMR 74.3, 15.9 (d, JC–F = 21.5 Hz); 19F NMR (282 MHz, CDCl3):
(300 MHz, CDCl3): δ 7.33–7.18 (m, 5H), 3.61 (d, J = 2.3 Hz, 2H), δ −89.17 (q, J = 18.1 Hz, 1F).
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Paper
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Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (no. 21172243) is gratefully acknowledged.
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(0.5 mmol) and ethyl propiolate 2a (1.0 mmol) were dis-
solved in THF (5 mL). To the solution was added LDA
(0.75 mL, 1.0 M in THF) at −78 °C. The resulting mixture
was stirred at −78 °C for 3 hours.
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