A new route for the synthesis of mono-flourinated allyl alcohols using the stereoselective Wittig olefination via reaction of (α-flurovinyl)triphenylphosphonium triflate

Article abstract of DOI:10.1055/s-2001-16070

The three-component coupling reaction of (α-fluorovinyl)triphenylphosphonium triflate, cesium allylate, and aldehydes in trimethyl orthoformate gave the corresponding mono-fluorinated allyl ethers with good stereoselectivity; the resulting ethers were readily transformed into the corresponding mono-fluorinated allyl alcohols using the Cp₂Zr-mediated reaction.

Full text of DOI:10.1055/s-2001-16070

1320
LETTER
A New Route for the Synthesis of Mono-flourinated Allyl Alcohols Using the
Stereoselective Wittig Olefination via Reaction of ( -flurovinyl)triphenyl-
phosphonium Triflate
Takeshi Hanamoto,* Kazusa Nishiyama, Hiroki Tateishi, Michio Kondo
Department of Chemistry and Applied Chemistry, Saga University, Honjyo-machi 1, Saga 840-8502, Japan
Fax +81-952-28-8704; E-mail: hanamoto@cc.saga-u.ac.jp
Received 4 June 2001
1
isomers were characterized by their H NMR spectra.
Abstract: The three-component coupling reaction of ( -fluorovi-
Counter cations of the allylates in allyl alcohol did not af-
nyl)triphenylphosphonium triflate, cesium allylate, and aldehydes
fect the selectivity of the product 2 (Entries 1-3). Howev-
er, those in ethereal solvents significantly affected the
in trimethyl orthoformate gave the corresponding mono-fluorinated
allyl ethers with good stereoselectivity; the resulting ethers were
readily transformed into the corresponding mono-fluorinated allyl stereoselectivity of 2 (Entries 4-10). Taking into account
alcohols using the Cp2Zr-mediated reaction.
both the stereoselectivity and chemical yield, we adopted
the reaction conditions of Entry 10.9 Attempts to improve
Key words: stereoselective Wittig olefination, mono-fluorinated
allyl alcohol, cesium fluoride (CsF), ( -fluorovinyl)triphenylphos-
phonium triflate
the stereoselectivity at 25 °C resulted in a decreased
chemical yield. We believe that this is the first observation
of the stereoselective Wittig olefination via the fluorine-
containing phosphonium salt.
Fluorinated organic compounds often produce salient
changes in biological and physical properties.1 Therefore,
novel methods for their synthesis have received consider-
able interest. Among them, the stereo-defined mono-flu-
orinated allyl alcohols would constitute a useful class of
compounds.2 The widely used strategy for their prepara-
tion has mainly utilized the reduction of the corresponding
fluoroalkenoates.3 We have been interested in new meth-
odologies for the incorporation of the mono-fluorovinylic
moiety and have recently reported the synthesis of mono-
fluorinated allyl ethers from readily available ( -fluorovi-
nyl)triphenylphosphonium triflate and aldehydes via the
Wittig olefination.4 We considered that the above reaction
proceeding stereoselectively would enable us to develop a
new approach to the stereoselective synthesis of mono-
fluorinated allyl alcohols. Although fluorine-containing
phosphoranium salts have been shown to be efficient
reagents for the stereochemical control of the Wittig ole-
fination,5,6 the reactions of fluorine-containing phospho-
nium salts with high stereoselectivity have been rarely
reported.7,8 We now report the stereoselective synthesis of
mono-fluorinated allyl alcohols using the cesium ion-me-
diated Wittig olefination followed by Cp2Zr mediated
deprotection.
Table 1 Stereoselective Wittig Olefination of Benzaldehyde with
( -flurovinyl)triphenylphosphonium Triflate 1
-
Ph
+
Ph3P
OTf
OM
ii) PhCHO
i)
H
O
F
F
1
2
Yield(%)a
E/Zb
Temp(°C)
Entry
Solvent
M
1
2
Li
allyl alcohol
allyl alcohol
allyl alcohol
THF
25
25
25
25
50
75
50
50
50
50
74
71
80
54
65
46
62
70
81
73
37/63
33/67
36/64
72/28
90/10
90/10
86/14
88/12
85/15
89/11
Na
K
3
4
K
5
Cs
Cs
Cs
Cs
Cs
Cs
THF
6
DME
7
diglyme
8
triglyme
tetraglyme
(MeO)3CH
9
10
aIsolated yield.
bDetermined by capillary GC-MS analysis.
We embarked on the stereochemical control of the Wittig
olefination of benzaldehyde using metal allylates and ( -
fluorovinyl)triphenylphosphonium triflate 1 under vari-
ous conditions, as the difficulty in deprotecting an ethoxy
or methoxy group in the products may be a problem as
previously reported.4,5 The ( -allyloxy- -fluoroeth-
yl)triphenylphosphonium ylide, generated via the addi-
tion of the metal allylate to 1, reacted with benzaldehyde
to provide (E)- and (Z)-3-allyloxy-2-fluoro- -phenylpro-
pene 2 (Table 1). The E:Z ratio in the product was deter-
mined by capillary GC-MS analysis, and the geometrical
Representative results of the stereoselective Wittig olefi-
nation with a variety of aldehydes are shown in Table 2.
Although aromatic aldehydes and an
-unsaturated al-
dehyde gave good results, an aliphatic aldehyde gave
complex mixtures, in which we previously observed sim-
ilar results using ( fluorovinyl)triphenylphosphonium
triflate 1 and ethoxide in ethanol.4 As we have not exam-
ined the mechanism of the observed stereoselectivity in
Synlett 2001, No. 8, 1320–1322 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Route for the Synthesis of Mono-flourinated Allyl Alcohols
1321
detail, we believe that the interaction of the cation coordi- In conclusion, we have demonstrated the first stereoselec-
nated aldehyde and the generated ethereal oxygen in the tive Wittig olefination involving the reaction of the fluo-
ylide plays an important role in orienting their approach.
rine-containing phosphonium salt 1. Furthermore, the
utility of the reaction could be expanded for the stereose-
lective synthesis of mono-fluorinated allyl alcohols. Fur-
ther studies on its synthetic utility are now in progress in
our laboratory.
Table 2 Stereoselective Wittig Olefination of Various Aldehydes
with ( -flurovinyl)triphenylphosphonium Triflate 1
Yield(%)a
E/Zb
Entry
Aldehyde
Acknowledgement
1
2
3
4
5
6
7c
8
4-Methoxybenzaldehyde
4-Phenylbenzaldehyde
4-Cyanobenzaldehyde
2-Methylbenzaldehyde
Veratraldehyde
70
64
69
72
55
78
89
0
89/11
88/12
85/15
93/7
This work was partially supported by the Mitsubishiyuka Foundati-
on, the Yamanouchi Foundation, and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, and Culture, Ja-
pan. We thank Chemetall Japan Co., Ltd. for a gift of CsF.
89/11
88/12
77/23
-
References and Notes
2-Naphthaldehyde
(1) Hudlicky, M.; Pavlath, A. E. Chemistry of Organic Fluorine
Compounds II; ACS Monogragh 187; Washington, DC, 1995.
(2) Allmendinger, T.; Angst, C.; Karfunkel, H. J. Fluorine Chem.
1995, 72, 247.
(E)-Cinnamaldehyde
Hydrocinnamaldehyde
aIsolated yield.
(3) Shinada, T.; Sekiya, N.; Bojkova, N.; Yoshihara, K.
Tetrahedron. 1999, 55, 3675; Chevrie, D.; Lequeux, T.;
Pommelet, J. C. Org. Lett. 1999, 1, 1539; Lin, J.; Welch, J. T.
Tetrahedron Lett. 1998, 39, 9613; Pirrung, M. C.; Rowley. E.
G.; Holmes, C. P. J. Org. Chem. 1993, 58, 5683; Mokikawa,
T.; Sasaki, H.; Mori, K.; Shiro, M.; Taguchi, T. Chem. Pharm.
Bull. 1992, 40, 3189, and references cited therein.
(4) Hanamoto, T.; Kiguchi, Y.; Shindo, K.; Matsuoka, M.;
Kondo, M. Chem. Commum. 1999, 151; Hanamoto, T.;
Shindo, K.; Matsuoka, M.; Kiguchi, Y.; Kondo, M. J. Chem.
Soc., Perkin Trans. 1 2000, 103.
(5) Cox, D. G.; Gurusamy, N.; Burton, D. J. J. Am. Chem. Soc.
1985, 107, 2811; Burton, D. J. and Cox, D. G. J. Am. Chem.
Soc. 1983, 105, 650.
(6) The highly stereoselective Horner-Emmmons olefination
using alkyl diethylphosphono-2-fluoroacetates are well-
accepted in the literature. Etemad-Moghadam, G.; Seyden-
Penne, J. Bull. Soc. Chim. Fr. 1985, 448.
bDetermined by capillary GC-MS analysis.
cThe reaction was carried out for 96 hr.
Finally we performed experiments involving the depro-
tection of the allyl group using the Zr-mediated reaction.
When the mono-fluorinated allyl ether 2 was subjected to
the standard conditions described in the literature,10 the
corresponding mono-fluorinated allyl alcohol 3 was ob-
tained in 93% with the E/Z ratio of 95:5 (Table 3, entry 1).
This observation suggested that the Zr-reagent exclusive-
ly reacted not with the mono-fluorinated allyl moiety but
with the allyl moiety in the mono-fluorinated allyl ether.
These results are listed in Table 3.11,12 No regeneration of
the deallylated alcohol was noted in the presence of the
cyano group (Table 3, entry 4).
(7) Patrick, T. B.; Lanahan, M. V.; Yang, C.; Walker, J. K.;
Hutchinson, C. L.; Neal, B. E. J. Org. Chem. 1994, 59, 1210;
Burton, D. J.; Green, P. E. J. Org Chem. 1975, 40, 2796.
(8) For a general review of fluorinated ylide and related
compound: Burton, D. J.; Yang, Z. Y.; Qiu, W. Chem. Rev.
1996, 96, 1641.
(9) A typical experimental procedures (Table 1, entry 10) is as
follows: CsF (233.0 mg, 1.53 mmol) was added to a solution
of allyloxytrimethylsilane (126 L, 0.76 mmol) in
trimethylorthoformate (2 mL) at 50 °C. After stirring for 2 h,
Table 3 Preparation of Mono-fluorinated Allyl Alcohols
R
R
i) "Cp2Zr"
ii) H3O+
H
O
H
OH
F
F
2
3
Yield(%)a E/Zb
Entry
R
Product
(
fluorovinyl)triphenylphosphonium triflate (119.2 mg,
0.26 mmol) was added to the reaction mixture. After stirring
for 2 h, benzaldehyde (18 L, 0.18 mmol) was added to the
reaction mixture. The resulting mixture was stirred for 48 h at
this temperature. After usual workup, column
1
2
3
4
5
6
7
Phenyl
93
96
88
0
95/5
94/6
94/6
-
3a
3b
3c
-
4-Methoxyphenyl
4-Biphenyl
chromatography (silica gel, hexane-ethyl acetate = 30:1) of
the residue afforded 25.2 mg of (E)- and (Z)-3-allyloxy-2-
fluoro-1-phenylpropene (73% yield): IR (neat): = 3062,
3028, 2860, 1735, 1702, 1496, 1450, 1352, 1083, 923, 754 and
4-Cyanophenyl
2-Methylphenyl
Veratry
84
91
66
95/5
3d
3e
3f
696 cm-1; (E)-isomer: 1H NMR
MHz, CDCl3,TMS): 4.06
90/10
89/11
(2H, d, J = 5.9 Hz), 4.19 (2H, d, J = 23.0 Hz), 5.18-5.29 (2H,
m), 5.85-6.00 (1H, m), 6.47 (1H, d, J = 19.5 Hz), 7.21-7.38
2-Naphthyl
(5H, m); (Z)-isomer: 1H NMR
MHz, CDCl3,TMS) 4.09-
aIsolated yield.
bDetermined by capillary GC-MS analysis.
4.23 (4H, m), 5.23-5.37 (2H, m), 5.77 (1H, d, J = 38.6 Hz),
5.88-6.00 (1H, m), 7.25-7.43 (3H, m), 7.51-7.54 (2H, m); E-
isomer: MS m/z 192 (0.1, M+), 147 (42), 136 (36), 135 (80),
Synlett 2001, No. 8, 1320–1322 ISSN 0936-5214 © Thieme Stuttgart · New York

1322
T. Hanamoto et al.
LETTER
133 (56), 123 (35), 115 (94), 109 (30), 104 (40), 103 (100), 77
(36); elemental analysis: calcd. for C12H13FO: C, 74.98; H,
6.82. Found: C, 74.98; H, 6.97%).
J = 20.0 Hz), 7.23-7.38 (5H, m); MS m/z 152 (56, M+), 133
(37), 131 (65), 103 (62), 91 (93), 78 (100), 77 (69), 51 (59);
elemental analysis: calcd. for C9H9FO: C, 71.04; H, 5.96.
(10) Ito, H.; Taguchi, T.; Hanzawa, Y. J. Org. Chem. 1993, 58,
774.
Found: C, 71.20; H, 6.14%). (Z)-isomer: 1H NMR
MHz,
CDCl3,TMS) 1.84 (1H, t, J = 6.4 Hz), 4.30 (2H, dd, J = 6.4,
14.7 Hz), 5.79 (1H, d, J = 38.6 Hz), 7.23-7.38 (3H, m), 7.50-
7.53 (2H, m).
(11) A typical experimental procedures (Table 3, entry 1) is as
follows: A solution of nBuLi (1.59 M in hexane, 750 L, 1.19
mmol) was added dropwise to a solution of zirconocene
dichloride (172.7 mg, 0.59 mmol) in THF (3 mL) at -78 °C
with stirring. After stirring for 60 min at -78 °C, a solution of
(E)- and (Z)-3-allyloxy-2-fluoro-1-phenylpropene (87.0 mg,
0.45 mmol) in THF (3 mL) was added, and the cooling bath
was removed. After the mixture was stirred for 60 min at room
temperature, 2N HCl was added at 0 °C, and the mixture was
extracted with hexane-ether = 3:1. After the organic layer was
dried over Na2SO4, the solution was concentrated in vacuo.
The residue was purified by silica gel column chromatography
(hexane-ethyl acetate = 4:1) to give 60.4 mg of (E)-2-fluoro-
3-phenyl-2-propen-1-ol and 3.2 mg of (Z)-2-fluoro-3-phenyl-
2-propen-1-ol (3a, 93% yield). (E)-isomer: IR (neat):
= 3351, 2930, 1685, 1497, 1447, 1252, 1139, 1025, 882, 750
(12) 1H NMR spectra (270 MHz, CDCl3, TMS) for all major (E)-
isomers (3b~3f) follow: 3b 1.84 (1H, t, J = 6.3 Hz), 3.81 (3H,
s), 4.37 (2H, dd, J = 6.4, 22.5 Hz), 6.35 (1H, d, J = 20.0 Hz),
6.88 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz); 3c 1.93 (1H,
brs), 4.43 (2H, d, J = 22.0 Hz), 6.44 (1H, d, J = 19.5 Hz), 7.31-
7.61 (9H, m); 3d 1.83 (1H, t, J = 5.9 Hz), 2.27 (3H, s), 4.28
(2H, dd, J = 5.9, 21.0 Hz), 6.38 (1H, d, J = 19.5 Hz), 7.14-7.21
(4H, m); 3e 1.94 (1H, brs), 3.88 (3H, s), 3.89 (3H, s), 4.38 (2H,
d, J = 22.5 Hz), 6.36 (1H, d, J = 19.5 Hz), 6.79-6.87 (3H, m);
3f 1.90 (1H, t, J = 6.4 Hz), 4.45 (2H, dd, J = 6.4, 22.0 Hz),
6.55 (1H, d, J = 20.0 Hz), 7.36 (1H, dd, J = 1.5, 8.3 Hz), 7.45-
7.55 (2H, m), 7.70 (1H, s), 7.80-7.85 (3H, m).
and 699 cm-1; 1H NMR
J = 5.9 Hz), 4.38 (2H, dd, J = 5.9, 22.0 Hz), 6.41 (1H, d,
MHz, CDCl3,TMS) 1.90 (1H, t,
Article Identifier:
1437-2096,E;2001,0,08,1320,1322,ftx,en;Y10801ST.pdf
Synlett 2001, No. 8, 1320–1322 ISSN 0936-5214 © Thieme Stuttgart · New York