Preparation and synthetic applications of α-fluorovinylphosphonium salts

Article abstract of DOI:10.1039/a807933a

α-Fluorovinylphosphonium salts 3 and 4 were synthesized and underwent Michael addition followed by Wittig olefination to give the corresponding monofluoroethylene compounds in good yields.

Full text of DOI:10.1039/a807933a

Preparation and synthetic applications of a-fluorovinylphosphonium salts
Takeshi Hanamoto,* Yasuhide Kiguchi, Keiko Shindo, Miki Matsuoka and Michio Kondo
Department of Chemistry, Saga University, Honjyo-machi, Saga 840-8502, Japan.
E-mail: hanamoto@cc.saga-u.ac.jp
Received (in Cambridge, UK) 13th October 1998, Accepted 7th December 1998
Table 1 Reaction of a-fluorovinylphosphonium salts with variuos alde-
a-Fluorovinylphosphonium salts 3 and 4 were synthesized
and underwent Michael addition followed by Wittig olefina-
tion to give the corresponding monofluoroethylene com-
pounds in good yields.
hydes
Entry
R
RA
Yield (%)a
E:Zb
1c
2
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
b
Ph
Ph
Ph
Ph
43
63
52
75
80
70
69
77
82
trace
52:48
40:60
53:47
43:57
35:65
47:53
52:48
41:59
37:63
—
The replacement of a hydrogen atom by a fluorine atom often
causes large changes in the biological activity of organic
compounds, and the preparation of such fluorinated compounds
has recently received much attention in the fields of medical and
agricultural chemicals.1 Although some methods for the direct
exchange of the hydrogen by the fluorine are well-accepted,
special techniques and equipment are required.2 Thus, the
development of versatile fluorinated building blocks has
become a significant task in this field.3 We have considered the
title compounds as promising candidates for a monofluorinated
building block which would be stable and easy to handle. As
vinyltriphenylphosphonium bromide (Schweizer reagent) ex-
hibits excellent performance,4 we would expect similar re-
activity for the title compound. This report describes the first
preparation and reaction of the a-fluorovinylphosphonium salts
as useful reagents for introducing a monofluoroethylene moiety
into carbonyl compounds.5
3c
4
5
6
7
8
9
10
4-MeOC6H4
4-PhC6H4
4-NCC6H4
2-naphthyl
(E)-PhCHNCH
PhCH2CH2
a
c
Isolated yield. Determined by capillary GC–MS analysis. Salt 3 was
used in place of 4.
86%. However, if the reaction temperature exceeded 240 °C,
undesirable 1,1-bis(diphenylphosphinyl)ethylene was produced
as a by-product.
Quaternization of the phosphine 2 with MeI proceeded
smoothly to give the a-fluorovinyldiphenylmethylphosphon-
ium iodide 3 in 91% yield; however, reaction of 2 with aryl
halides or aryl triflates did not take place under various
conditions. Kitamura and co-workers have described the direct
S-arylation of benzo[b]thiophenes to produce the 1-arylben-
zo[b]thiophenium salt.8 This prompted us to use the diarylio-
donium salts for P-arylation of the phosphine 2 instead of S-
arylation of the sulfides. After many unsuccessful experiments,
the a-fluorovinyltriphenylphosphonium triflate 4 was finally
obtained by the reaction of diphenyliodonium triflate in the
presence of CuCl in 1,1,2,2-tetrachloroethane at 140 °C in 82%
yield.† We believe that this P-arylation method provides a new
route for the synthesis of the aryl phosphonium salts.
The b-ethoxy-a-fluoroethyltriphenylphosphonium ylide,
generated via the addition of an ethoxide anion to 4 in ethanol
at room temperature, reacted with benzaldehyde to provide
1-benzylidene-1-fluoro-2-ethoxyethane as a 43:57 mixture of
the E and Z isomers in 75% yield (Table 1, entry 4).‡ The E:Z
ratio was determined by capillary GC–MS analysis. The
geometrical isomers were characterized from their NMR
spectra. The coupling constants with fluorine showed a value of
20 Hz for the E isomer and 39 Hz for the Z isomer. The effects
of the reaction conditions on these relative E:Z ratios have not
been studied. Some selected data are shown in Table 1. The
reactivity of salt 4 was much higher than that of salt 3 (compare
the yields in entries 1 vs. 2 and 3 vs. 4). Although aromatic
aldehydes and an a,b-unsaturated aldehyde gave good results,
the aliphatic aldehyde gave poor results. Studies on the
synthesis of a variety of monofluorinated heterocyclic ring
systems are now in progress in our laboratory.
PPh3•OTf
RO
R′
R′CHO
RONa
+
F
F
H
4
Our synthetic route for the preparation of the a-fluor-
ovinylphosphonium salts 3 or 4 is depicted in Scheme 1.
Initially, we examined the convenient preparation of a-
fluorovinyldiphenylphosphine 2 as a precursor for the salts.
Since it is well-documented that nucleophilic addition followed
by elimination of the fluoride for producing 1,1-difluoro-
ethylene derivatives is facile,6 it was therefore anticipated that
the reaction of lithium diphenylphosphide7 and 1,1-difluoro-
ethylene 1 should afford the facile preparation of the phosphine
2. The modest yield we encountered when conducting the
reaction in THF–toluene at 278 °C led us to controlling the
reaction temperature. When the reaction was conducted over the
temperature range of 260 to 240 °C, the yield improved to
F
F
F
LiPPh2
THF–toluene
–60 to –40 °C
PPh2
1
2
PPh2Me•I
F
MeI
This work was supported by the Mitsubishiyuka Foundation,
the Yamanouchi Foundation, and a Grant-in-Aid for Scientific
Research (10650836) from the Ministry of Education, Science,
and Culture, Japan.
3
2
PPh3•OTf
F
Ph2IOTf
cat. CuCl
140 °C
Notes and references
† Preparation of 2: To a solution of lithium wire (0.54 g, 83.8 mmol) in 40
4
Scheme 1
ml of THF was added diphenylchlorophosphine (6.0 ml, 33.4 mmol) at
Chem. Commun., 1999, 151–152
151

room temperature under argon. The solution was stirred for 3 h and followed
by the addition of 40 ml of toluene. After stirring for an additional 1 h, the
solution was cooled to 260 °C. At this temperature, argon was replaced
with 1,1-difluoroethylene. The mixture was gradually warmed to 240 °C
and quenched with sat. NH4Cl solution. After the usual workup, the residue
was chromatographed on silica gel (hexane–EtOAc 100:1) to give the
desired product (6.3 g, 86%): n(neat)/cm21 3056, 1622, 1482, 1435, 1153,
1095, 1027, 997, 916, 885, 742 and 694; dH(CDCl3) 4.97 (1H, ddd, J 2.9,
6.3, 50.8), 5.39 (1H, ddd, J 2.9, 21.0, 23.4), 7.25–7.80 (m, 10 H); HRMS:
230.0661(M+); Calc. for C14H12FP: C, 73.04; H, 5.25. Found: C, 72.96; H,
5.28%.
4.18 (2H, d, J 22.95), 6.45 (1H, d, J 20.02), 7.24–7.38 (5H, m); m/z 180 (30,
M+), 151 (46), 135 (60), 133 (56), 115 (80), 109 (100), 104 (30); Calc. for
C11H13FO: C, 73.31; H, 7.27. Found: C, 73.54; H, 7.44%. (Z)-isomer:
n(neat)/cm21 3025, 2978, 2865, 1695, 1598, 1496, 1450, 1351, 1099, 880,
755 and 694; dH(CDCl3) 1.27 (3H, t, J 6.83), 3.60 (2H, q, J 6.83), 4.12 (2H,
d, J 15.14), 5.76 (1H, d, J 38.57), 7.21–7.53 (5H, m); m/z 180 (52, M+), 151
(52), 135 (76), 133 (62), 115 (90), 109 (100); Calc. for C11H13FO: C, 73.31;
H, 7.27. Found: C, 73.44; H, 7.35%.
1 J. T. Welch, Tetrahedron, 1987, 43, 3123; M. Schlosser, Tetrahedron,
1978, 34, 3; Biomedical Aspects of Fluorine Chemistry, ed. R. Filler and
Y. Kobayashi, Kodansha, Tokyo, 1982.
Preparation of 4: A mixture of a-fluorovinyldiphenylphosphine 2 (1.47 g,
6.4 mmol), diphenyliodonium triflate (3.30 g, 7.7 mmol), copper(I) chloride
(63.3 mg, 0.64 mmol), a catalytic amount of Cu wire (30 mg) and 4 Å
molecular sieves (0.5 g) in 1,1,2,2-tetrachloroethane (1.5 ml) was heated at
140 °C for 30 min under argon. After cooling the reaction mixture to room
temperature, it was chromatographed on silica gel (CH2Cl2 then CH2Cl2–
acetone 2:1) to give the desired product (2.41g, 82%). Further purification
for the combustion analysis was conducted by recrystallization from
ButOH–Et2O: mp 101.2–101.7 °C; n(KBr)/cm21 3137, 3062, 3007, 1632,
1588, 1581, 1486, 1482, 1441, 1370, 1257, 1227, 1172, 1152, 1114, 1029,
995, 935, 913, 760, 736, 709, 689 and 641; dH(CDCl3) 5.79 (1H, ddd, J 6.4,
7.3, 49.3), 6.49 (1H, ddd, J 6.4, 21.5, 29.8), 7.7–8.0 (m, 15 H); m/z (FAB)
307 (M+ 2 OTf); Calc. for C21H17F4O3PS: C, 55.27; H, 3.75. Found: C,
55.08; H, 3.67%.
‡ General procedure: To a solution of NaH (1.2 equiv.) in EtOH (5 ml)
under Ar was added a-fluorovinyltriphenylphosphonium triflate (0.5 mmol)
at room temperature. The resulting solution was stirred for 10 min,
benzaldehyde (1.2 equiv.) was added to the solution, and the reaction
mixture was stirred for 16 h. After the usual workup, column chromatog-
raphy (silica gel, hexane–EtOAc 30:1) of the residue afforded 27.7 mg of
(E)-1-benzylidene-2-ethoxy-1-fluoroethane and 39.1 mg of (Z)-1-benzyli-
dene-2-ethoxy-1-fluoroethane (total 75% yield). (E)-isomer: n(neat)/cm21
2978, 2924, 2873, 1685, 1598, 1489, 1447, 1380, 1261, 1143, 1098, 997,
883, 750, 699 and 630; dH(CDCl3) 1.25 (3H, t, J 6.84), 3.58 (2H, q, J 6.83),
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3 J. R. McCarthy, E. W. Huber, T-B. Le, F. M. Laskovics and D. P.
Matthews, Tetrahedron, 1996, 52, 45; T. Ernet and G. Haufe,
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and D. J. Burton, Tetrahedron, 1996, 52, 37; P. J. Crowley, J. M. Percy
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therein.
4 E. E. Schweizer, L. D. Smucker and R. J. Votral, J. Org. Chem., 1966, 31,
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5 The synthesis of a-fluorovinylphosphonates has been reported. G. M.
Blackburn and M. J. Parratt, J. Chem. Soc., Perkin Trans. 1, 1986, 1417;
G. M. Blackburn and M. J. Parratt, J. Chem. Soc., Chem. Commun., 1982,
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Communication 8/07933A
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Chem. Commun., 1999, 151–152