New reaction mode of the Horner-Wadsworth-Emmons reaction for the preparation of α-fluoro-α,β-unsaturated esters

Article abstract of DOI:10.1055/s-1998-1780

Excellent E-selectivity was observed in the Horner-Wadsworth-Emmons (HWE) reactions of ethyl 2-fluoro-2-diethylphosphonoacetate 1 with alkyl aryl ketones 2a-f using Sn(OSO₂CF₃)₂ and N-ethylpiperidine. Mg(II)-promoted HWE r

Full text of DOI:10.1055/s-1998-1780

July 1998
SYNLETT
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New Reaction Mode of the Horner-Wadsworth-Emmons Reaction for the Preparation of α-
Fluoro-α,β-unsaturated Esters
Shigeki Sano, Tsuyoshi Ando, Kenji Yokoyama, and Yoshimitsu Nagao*
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Fax +81-886-33-9503; E-mail ynagao@ph.tokushima-u.ac.jp
Received 14 April 1998
Abstract: Excellent E-selectivity was observed in the Horner-
Wadsworth-Emmons (HWE) reactions of ethyl 2-fluoro-2-
diethylphosphonoacetate
1
with alkyl aryl ketones 2a-f using
Sn(OSO CF ) and N-ethylpiperidine. Mg(II)-promoted HWE reactions
2
3 2
of 1 with aldehydes 2h,i afforded α-fluoro-α,β-unsaturated esters 3h,i in
a Z-selective manner depending on the reaction temperatures.
α-Fluoro-α,β-unsaturated esters play an important role in the
preparation of biologically active fluorine compounds, and various
1
synthetic methods have been developed. Most of the construction
methods for the α-fluoro-α,β-unsaturated esters have shown Z-
2
selectivity. However, Horner-Wadsworth-Emmons (HWE) reactions of
aldehydes with ethyl 2-fluoro-2-diethylphosphonoacetate
preferentially furnish E-α-fluoro-α,β-unsaturated esters. There have
1
can
3-5
been a few reports on the HWE reactions with ketones in the presence of
6
some base but the stereoselectivity is not clear or poor. Recently, we
have developed a new reaction mode of the HWE reaction using
Sn(OSO CF ) and N-ethylpiperidine to obtain excellent Z-selectivity
2
3 2
in the reactions of methyl bis(trifluoroethyl)phosphonoacetate with l
7
alkyl aryl ketones. We now wish to report highly E-selective HWE
reactions of ethyl 2-fluoro-2-diethylphosphonoacetate 1 with alkyl aryl
ketones 2a-f using Sn(OSO CF ) and N-ethylpiperidine as shown in
2
3 2
Scheme 1. A tendency to afford Z-alkenes in the Mg(II)-mediated HWE
reactions of fluorophosphonate 1 with aldehydes is also described. All
reaction conditions and results are summarized in Tables 1-3.
Scheme 1
The HWE reactions of alkyl aryl ketones 2a-f with 1 in the presence of
sodium hydride in THF 0 °C gave the corresponding α-fluoro-α,β-
unsaturated esters 3a-f with modest E-selectivity (Table 1, entries 1-6).
On the other hand, treatment of 2a-f with 1 in the presence of
Sn(OSO CF ) and N-ethylpiperidine in CH Cl at 0 °C afforded
2
3 2
2
2
alkenes 3a-f in a highly E-selective manner, respectively (Table 2,

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LETTERS
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9
which was quite different from that with Sn(II). Thus, tentative HWE
reactions of benzaldehyde 2h with 1 at various temperatures employing
MgBr -triethylamine or i-PrMgBr gave Z-selective 3h (Table 3, entries
2
1-5), which was contrary to the E-selectivity in the cases of Sn(II)- and
NaH-promoted reactions at 0 °C (Table 1, entry 8; Table 2 entry 9). The
Mg(II)-promoted HWE reaction of 2i with 1 gave 3i in the modest Z-
selective manner (Table 3, entry 9). Interestingly, the stereoselectivity of
α-fluoro-α,β-unsaturated esters 3h,i in the Mg(II)-promoted reactions
of aldehydes 2h,i with 1 was variable depending on the reaction
temperatures. The Z-selective manner (Table 3, entries 2-5 and 9) in the
Mg(II)-promoted reactions of 2h,i changed to E-selective one (Table 3,
4
entries 7, 10, and 11) with decreasing the reaction temperature. These
results made it possible to prepare the Z-isomers of α-fluoro-α,β-
unsaturated esters by exploiting the Mg(II)-promoted HWE reaction.
8
entries 1,2, and 4-7). The geometry of α-fluoro-α,β-unsaturated esters
1
1
References and Notes
3a-g was assigned on the basis of H- H NOE experiments (400 MHz,
CDCl ) of the corresponding primary alcohols derived by reduction of
(1) Burton, D. J.; Yang, Z.-Y.; Qui, W. Chem. Rev. 1996, 96, 1641 and
3
3a-g with DIBAL-H in CH Cl at 0 °C. When THF was employed as
references cited therein.
2
2
the solvent instead of CH Cl in the same Sn(II)-promoted reaction of
2
2
(2) Normant, J. F.; Foulon, J. P.; Masure, D.; Sauvetre, R.; Villieras, J.
Synthesis 1975, 122. Ishihara, T.; Kuroboshi, M. Chemistry Lett.
1987, 1145. Matsuo, N.; Kende, A. S. J. Org. Chem. 1988, 53,
2304. Welch, J. T.; Herbert, R. W. J. Org. Chem. 1990, 55, 4782.
Allmendinger, T. Tetrahedron 1991, 47, 4905. Usuki, Y.; Iwaoka,
M.; Tomoda, S. J. Chem. Soc., Chem. Commun. 1992, 1148.
Clemenceau, D.; Cousseau, J. Tetrahedron Lett. 1993, 34, 6903.
alkyl aryl ketone 2b with 1, E-selectivity of the alkenic product 3b
decreased from 99 : 1 to 93 : 7. Interestingly, the NaH-promoted
reactions of the ketones 2c,d bearing bulky i-Pr or t-Bu group in THF
was hard to obtain the highly E-selective products 3c,d (Table 1, entries
3 and 4), while the Sn(II)-promoted reactions of 2c,d in CH Cl gave
2
2
3c,d in an excellent E-selective manner and in good yields (Table 2,
entries 4 and 5) as well as those of the ketones 2a,b. Thus, the
(3) Liu, R. S. H.; Matsumoto, H.; Asato, A. E.; Denny, M.; Shichida,
Y.; Yoshizawa, T.; Dahlquist, F. W. J. Am. Chem. Soc. 1981, 103,
7195. Asato, A. E.; Kini, A.; Denny, M.; Liu, R. S. H. J. Am.
Chem. Soc. 1983, 105, 2923. Tsai, H.-J.; Thenappan, A.; Burton,
D. J. Tetrahedron Lett. 1992, 33, 6579. Patrick, T. B.; Lanahan, M.
V.; Yang, C.; Walker, J. K.; Hutchinson, C. L.; Neal, B. E. J. Org.
Chem. 1994, 59, 1210. Tsai, H.-J.; Thenappan, A.; Burton, D. J. J.
Org. Chem. 1994, 59, 7085. Piva, O. Synlett 1994, 729. Shinada,
T.; Sekiya, N.; Bojkova, N.; Yoshihara, K. Synlett 1995, 1247.
stereochemical outcome with high E-selectivity in the Sn(OSO CF ) -
mediated HWE reactions of ketones 2a-f with fluorophosphonate 1 can
2
3 2
be rationalized in terms of a six-membered transition state as shown in
7
Fig. 1 (e.g. 2b). The stereoselectivity in the NaH-promoted HWE
reactions of 2a-g with 1 seems to depend on the relative bulkiness
between both substituents of the ketones in a plausible non-chelation-
controlled transition state. Under both reaction conditions as described
above, the HWE reactions of ketone 2g with 1 gave a ca. 1 : 1 mixture of
E- and Z-isomers of 3g (Table 1, entry 7; Table 2, entry 8), respectively.
(4) Etemad-Moghadam, G.; Seyden-Penne, J. Bull. Soc. Chim. Fr.
1985, 448.
Subsequently, the similar Sn(II)- and NaH-promoted reactions of
aldehydes 2h,i with fluorophosphonate 1 afforded the corresponding α-
fluoro-α,β-unsaturated esters 3h,i with a good or excellent E-selectivity
(Table 1, entries 8 and 9; Table 2, entries 9 and 10). The geometry of
(5) Thenappan, A.; Burton, D. J. J. Org. Chem. 1990, 55, 4639.
(6) Machleidt, H.; Wessendorf, R. Justus Liebigs Ann. Chem. 1964,
674, 1. Lovey, A. J.; Pawson, B. A. J. Med. Chem. 1982, 25, 71.
Elkik, E.; Francesch, C. Bull. Soc. Chim. Fr. 1985, 783.
3h,i was determined by the coupling constants between fluorine and the
1
(7) Sano, S.; Yokoyama, K.; Fukushima, M.; Yagi, T.; Nagao, Y.
adjacent olefinic proton in their H NMR analysis (400 MHz, CDCl ) as
3
5
Chem. Commun. 1997, 559.
follows; E-3h (J
= 22.3 Hz, lit. 22 Hz), Z-3h (J
= 35.1 Hz), E-3i
H-F
H-F
(J
= 21.4 Hz), and Z-3i (J
= 32.8 Hz). Previously, we reported a
(8)
A
typical procedure is as follows. To
a suspension of
H-F
H-F
characteristic reaction mode with Mg(II) in the aldol type reactions,
Sn(OSO CF )
(820 mg, 1.97 mmol) and 2-fluoro-2-
2
3 2

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SYNLETT
779
diethylphosphonoacetate 1 (330 µL, 1.64 mmol) in anhydrous
CH Cl (5 mL) was added N-ethylpiperidine (247 µL, 1.80 mmol)
q, J = 7.3 Hz), 7.10-7.17 (2 H, m), 7.30-7.38 (3 H, m); IR (NaCl)
2980, 2937, 1729, 1656, 1444, 1265, 1151, 763, 700 cm ; HREI-
-1
2
2
MS calcd for C
(M ); Anal. Calcd for C
69.96; H, 6.92. Z-3b: H NMR (400 MHz, CDCl ) δ 1.03 (3 H, t,
J = 7.3 Hz), 1.37 (3 H, t, J = 7.3 Hz), 2.90 (2 H, dq, J
H O F MW 222.1056, found m/e 222.1057
at 0 °C. The mixture was stirred at 0 °C for 1 h under argon, and
alkyl aryl ketone 2b (155 µL, 1.17 mmol) was added. After being
stirred at 0 °C for 21 h under argon, the reaction mixture was
poured into H O (15 mL) and then extracted with CHCl (3 x 50
13 15 2
+
H O F: C, 70.25; H, 6.80. Found: C,
13 15 2
1
3
4
= 1.8
H,F
2
3
Hz, J = 7.3 Hz), 4.34 (2 H, q, J = 7.3 Hz), 7.28-7.43 (5 H, m); IR
(NaCl) 2975, 2932, 1725, 1642, 1445, 1247, 1142, 766, 699 cm ;
mL). To the CHCl extract was added n-hexane (300 mL), and the
3
-1
mixture was submitted to filtration through a silica gel short
column. The filtrate was evaporated in vacuo to afford a crude
product 3b (E : Z = 99 : 1), which was purified by chromatography
on a silica gel column eluting with n-hexane/AcOEt (20 : 1) to
HREI-MS calcd for C
222.1069 (M ).
H O F MW 222.1056, found m/e
13 15 2
+
(9) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama,
S.; Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097. Sano,
S.; Liu, X.-K.; Takebayashi, M.; Kobayashi, Y.; Tabata, K.; Shiro,
M.; Nagao, Y. Tetrahedron Lett. 1995, 36, 4101. Hayashi, K.;
Kogiso, H.; Sano, S.; Nagao, Y. Synlett 1996, 1203.
obtain α-fluoro-α,β-unsaturated esters E-3b (37.6 mg, 91%) and
1
Z-3b (2.4 mg, 1%) as a pale yellow oil, respectively. E-3b:
H
NMR (400 MHz, CDCl ) δ 0.99 (3 H, t, J = 7.3 Hz), 1.00 (3 H, t,
3
4
J = 7.3 Hz), 2.55 (2 H, dq, J = 3.6 Hz, J = 7.3 Hz), 4.02 (2 H,
H,F