Toward (Z)-selective Horner-Wadsworth-Emmons reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid

Article abstract of DOI:10.1016/S0040-4039(02)02269-4

The stereoselective Horner-Wadsworth-Emmons reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid utilizing i-PrMgBr afforded (Z)-α-fluoro-α,β-unsaturated carboxylic acids as the major products.

Full text of DOI:10.1016/S0040-4039(02)02269-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9183–9186
Toward (Z)-selective Horner–Wadsworth–Emmons reaction of
aldehydes with 2-fluoro-2-diethylphosphonoacetic acid
Shigeki Sano,* Rie Teranishi and Yoshimitsu Nagao*
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Received 12 August 2002; revised 19 September 2002; accepted 4 October 2002
Abstract—The stereoselective Horner–Wadsworth–Emmons reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid
utilizing i-PrMgBr afforded (Z)-a-fluoro-a,b-unsaturated carboxylic acids as the major products. © 2002 Elsevier Science Ltd. All
rights reserved.
Ethyl 2-fluoro-2-diethylphosphonoacetate (1) is an
efficient fluorinated building-block used in organic syn-
thesis.1,2 A number of methods employing the Horner–
Wadsworth–Emmons (HWE) reaction involving
phosphonate 1 have been developed for the stereoselec-
tive synthesis of (E)-a-fluoro-a,b-unsaturated esters
(E)-3.3–15 However, using the HWE reaction for the
preparation of (Z)-3 is much less common.16,17 In addi-
tion, (Z)-fluoroolefins A play an important role as
(s-Z)-amide B isosteres, from the standpoint of a mimic
of the steric demand, bond lengths, and bond angles of
B.18–24 Recently, we reported the Sn(II)-promoted
stereoselective HWE reaction of various phosphonates
with aryl alkyl ketones.25–29 We have also demonstrated
the Mg(II)-promoted HWE reaction of aldehydes 2b,f
with phosphonate 1 for the preparation of a-fluoro-a,b-
unsaturated esters 3b,f with a moderate (Z)-selectivity
depending on the reaction temperature.26 Herein, we
wish to describe the HWE reaction of aldehydes 2a–f
with a dianion, prepared by magnesiation of 2-fluoro-2-
diethylphosphonoacetic acid (4) utilizing i-PrMgBr in
THF. The HWE reaction afforded (Z)-a-fluoro-a,b-
unsaturated carboxylic acids (Z)-5a–f as the major
products.
The HWE reaction (reflux or 0°C) of phosphonate 1
with cyclohexylcarboxaldehyde (2a) in the presence of
n-BuLi in THF gave (E)-a-fluoro-a,b-unsaturated ester
(E)-3a with E:Z ratios of 94:6 and 92:8, independent of
the reaction temperature (Table 1, entries 3 and 4).13
On the other hand, increasing the reaction temperature
tended to decrease E-selectivity in the Mg(II)-promoted
HWE reactions of phosphonate 1 with aldehyde 2a
(Table 1, entries 1 and 2). Taking into account the
oxophilicity of Mg(II),30–35 a magnesium salt of dianion
of 4 was treated with 2a in THF to yield the a-fluoro-
a,b-unsaturated carboxylic acid 5a. Phosphonoacetic
acid 4 was readily prepared by the hydrolysis of phos-
phonate 1 in 99% yield. Esterification of 5a with an
excess
amount
of
trimethylsilyldiazomethane
Table 1. Stereoselective HWE reactions of aldehydes 2a with ethyl 2-fluoro-2-diethylphosphonoacetate 1
Entry
Conditionsa
Temperature
Time (h)
Yield (%) of 3ab
(E)-3a:(Z)-3ac
1
2
3
4
i-PrMgBr
i-PrMgBr
n-BuLi
Reflux
0°C
Reflux
0°C
1
12
1
95
91
83
80
55:45
83:17
94:6
n-BuLi
12
92:8
a i-PrMgBr=THF, 1/i-PrMgBr/2a (1.2:1.25:1); n-BuLi=THF, 1/n-BuLi/2a (1.2:1.25:1).
b Isolated yields.
c Determined by 1H NMR (300 MHz, CDCl3) analysis.
Keywords: Horner–Wadsworth–Emmons reactions; fluorine and compounds; magnesium and compounds; a-fluoro-a,b-unsaturated carboxylic
acids; a-fluoro-a,b-unsaturated esters; Wittig reactions.
* Corresponding authors. Tel.: +81-88-633-7273; fax: +81-88-633-9503; e-mail: ssano@ph2.tokushima-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02269-4

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S. Sano et al. / Tetrahedron Letters 43 (2002) 9183–9186
(TMSCHN2)36 provided the desired a-fluoro-a,b-unsat-
urated ester 6a without isolation of 5a, as shown in
Scheme 1. Under reflux conditions in THF utilizing
i-PrMgBr, the reaction of phosphonoacetic acid 4 with
aldehyde 2a proceeded in a moderate Z-selective man-
ner (E:Z=32:68), while under 0°C conditions, the E:Z
ratio was 50:50 (Table 2, entries 1 and 2). All of the
remaining reactions of phosphonoacetic acid 4 with
various aldehydes 2b–f by use of i-PrMgBr under reflux
conditions each afforded (Z)-5b–f as the major prod-
ucts. In particular, the reaction with benzaldehyde (2f)
or a,b-unsaturated aldehydes 2c–e gave the correspond-
ing Z-isomers (Z)-5c–f in a highly stereoselective man-
ner in a range of E:Z ratios, i.e. 19:81–<1:>99. The
HWE reactions of phosphonoacetic acid 4 with alde-
hydes 2a–f employing n-BuLi gave a mixture of both
stereoisomers under reflux conditions in a range of E:Z
ratios, i.e. 60:40–37:63, as listed in Table 2. The
stereoselectivity in the Mg(II)-promoted reactions of
phosphonoacetic acid 4 with benzaldehyde (2f) did not
vary with the reaction temperature (Table 2, entries
13–15). However, the reactions of 4 with 2f in the case
of n-BuLi exhibited a slight tendency toward tempera-
ture dependence of the stereoselectivity (Table 2, entries
16–18). The geometry and the diastereomer ratios of
5a–f were confirmed on the basis of coupling constants
between fluorine and the adjacent olefinic proton
(3JH,F) and integration of the appropriate proton
1
absorptions obtained by H NMR (300 or 400 MHz)
analysis.
In a typical procedure, i-PrMgBr (0.63 mol/L solution
in THF, 2.62 mL, 1.65 mmol) was added to a stirred
solution of phosphonoacetic acid 4 (170 mg, 0.79
mmol) in anhydrous THF (10 mL) at 0°C under argon.
The mixture was stirred at 0°C for 1 h and then
refluxed. Benzaldehyde (2f) (66.8 mL, 0.66 mmol) was
added to the refluxing solution. After being refluxed for
1 h, the reaction mixture was treated with H2O (10 mL)
and then washed with CHCl3 (100 mL). The water layer
Scheme 1. Reagents and conditions: (i) 1N NaOH/rt/20 h; (ii) H+; (iii) i-PrMgBr or n-BuLi/THF/1 h; (iv) RCHO 2a–f; (v)
TMSCHN2/MeOH–benzene (2:7)/rt/30 min.
Table 2. Stereoselective HWE reactions of aldehydes 2a–f with 2-fluoro-2-diethylphosphonoacetic acid 4
Entry
Aldehyde
Conditionsa
Temperature
Time (h)
Yield (%)b
E:Zc
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
i-PrMgBr
i-PrMgBr
n-BuLi
n-BuLi
i-PrMgBr
n-BuLi
i-PrMgBr
n-BuLi
i-PrMgBr
n-BuLi
i-PrMgBr
n-BuLi
i-PrMgBr
i-PrMgBr
i-PrMgBr
n-BuLi
Reflux
0°C
Reflux
0°C
1
12
1
12
1
1
1
1
1
1
1
1
1
12
12
1
12
12
81 (6a)
83 (6a)
86 (6a)
98 (6a)
72 (6b)
87 (6b)
81 (6c)
77 (6c)
83 (6d)
76 (6d)
84 (6e)
92 (6e)
84 (6f)
81 (6f)
51 (6f)
84 (6f)
98 (6f)
81 (6f)
32:68 (5a)
50:50 (5a)
60:40 (5a)
58:42 (5a)
19:81 (5b)
56:44 (5b)
12:88 (5c)d
42:58 (5c)d
15:85 (5d)e
42:58 (5d)e
10:90 (5e)e
49:51 (5e)e
B1:\99 (5f)
B1:\99 (5f)
B1:\99 (5f)
37:63 (5f)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
0°C
9
10
11
12
13
14
15
16
17
18
2f
2f
2f
2f
−78°C
Reflux
0°C
n-BuLi
n-BuLi
48:52 (5f)
54:46 (5f)
2f
−78°C
a i-PrMgBr=THF, 4/i-PrMgBr/2 (1.2:2.5:1); n-BuLi=THF, 4/n-BuLi/2 (1.2:2.5:1).
b Isolated yields.
c Determined by 1H NMR (300 MHz, CDCl3) analysis.
d Determined by 1H NMR (400 MHz, CDCl3) analysis.
e Determined by 1H NMR (300 MHz, C6D6) analysis.

S. Sano et al. / Tetrahedron Letters 43 (2002) 9183–9186
9185
Scheme 2.
was acidified with 5% HCl and extracted with AcOEt
(100 mL×5). The extract was washed with brine (20
mL) and dried over anhydrous MgSO4. The organic
layer was evaporated in vacuo to afford a crude
product 5f (E:Z=<1:>99). To the solution of 5f in
MeOH (2 mL) and benzene (7 mL) was added an excess
amount of TMSCHN2 (2.0 mol/L solution in n-hexane,
ca. 1 mL, ca. 2 mmol). After being stirred at room
temperature for 30 min, the reaction mixture was evap-
orated in vacuo to afford a crude product, which was
purified by chromatography on a silica gel column
eluted with n-hexane–AcOEt (25:1), giving a-fluoro-
a,b-unsaturated ester (Z)-6f (100 mg, 84%) as a color-
less oil.
of Science. A research grant from the Faculty of Phar-
maceutical Sciences at the University of Tokushima is
also greatly appreciated.
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