(E)-Selective Horner-Wadsworth-Emmons reaction of aryl alkyl ketones with bis(2,2,2-trifluoroethyl)phosphonoacetic acid

Article abstract of DOI:10.1016/j.tetlet.2003.09.185

The stereoselective Horner-Wadsworth-Emmons reaction of aryl alkyl ketones with bis(2,2,2-trifluoroethyl)phosphonoacetic acid utilizing lithium hexamethyldisilazide in DMF afforded (E)-α,β-unsaturated carboxylic acids as the major products.

Full text of DOI:10.1016/j.tetlet.2003.09.185

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8853–8855
(E)-Selective Horner–Wadsworth–Emmons reaction of aryl alkyl
ketones with bis(2,2,2-trifluoroethyl)phosphonoacetic acid
Shigeki Sano,* Yuka Takemoto and Yoshimitsu Nagao*
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Received 20 August 2003; revised 18 September 2003; accepted 22 September 2003
Abstract—The stereoselective Horner–Wadsworth–Emmons reaction of aryl alkyl ketones with bis(2,2,2-trifluoro-
ethyl)phosphonoacetic acid utilizing lithium hexamethyldisilazide in DMF afforded (E)-a,b-unsaturated carboxylic acids as the
major products.
© 2003 Elsevier Ltd. All rights reserved.
Recently, a number of studies have attempted to
develop a highly stereoselective method for synthesizing
trisubstituted alkenes.1–4 Although one such method,
(E:Z=<1:>99) was observed in the HWE reaction of
methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1)12
with phenyl ethyl ketone (2a) using Sn(OSO2CF3)2 and
N-ethylpiperidine, as shown in Scheme 1. In this com-
munication, we report a convenient HWE reaction of
bis(2,2,2-trifluoroethyl)phosphonoacetic acid (4) with
various aryl alkyl ketones using lithium hexamethyldisi-
lazide (LHMDS). To the best of our knowledge, this is
the first example of an appreciably stereoselective HWE
reaction of aryl alkyl ketones for the synthesis of
(E)-a,b-unsaturated esters (E)-3.
the
stereoselective
Horner–Wadsworth–Emmons
(HWE) reaction of aldehydes, has been well estab-
lished,5–7 moderate reactivity and selectivity are gener-
ally observed in the HWE reactions with ketones.8,9 We
have previously reported a versatile method for the
stereoselective HWE reaction with aryl alkyl ketones
that can be utilized to prepare (Z)-a,b-unsaturated
esters.10,11 For example, an excellent Z-selectivity
Scheme 1. Reagents and conditions: (i) Sn(OSO2CF3)2/N-ethylpiperidine/CH2Cl2/0°C/1 h; (ii) PhCOEt (2a)/0°C/18 h; (iii) PLE
(Sigma, E-2884)/0.1 M phosphate buffer (pH 7.4)–acetone (9:1); (iv) i-PrMgBr or LHMDS/THF or DMF/0 °C /1 h; (v) R1COR2
(2); (vi) TMSCHN2/MeOH–benzene (2:7)/rt/30 min.
Keywords: Horner–Wadsworth–Emmons reactions; olefination; stereoselection; a,b-unsaturated carboxylic acids; a,b-unsaturated esters; Wittig
reactions.
* Corresponding authors. Tel.: +81-88-633-7273; fax: +81-88-633-9503; e-mail: ssano@ph.tokushima-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.185

8854
S. Sano et al. / Tetrahedron Letters 44 (2003) 8853–8855
Table 1. Stereoselective HWE reactions of phenyl ethyl ketone (2a) with bis(2,2,2-trifluoroethyl)phosphonoacetic acid (4)
Entry
Conditionsa
Solventb
Temperature
Yield (%) of 3ac
(E)-5a:(Z)-5ad
1
2
3
4
5
6
7
8
9
i-PrMgBr
i-PrMgBr
i-PrMgBr
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
THF
THF
THF
THF
MeCN
DMA
DMF
DMF
DMF
Reflux
rt
0°C
0°C
0°C
0°C
60°C
0°C
70
42
22
56
82
84
87
91
50
76:24
85:15
95:5
89:11
88:12
94:6
88:12
93:7
96:4
−40°C
a i-PrMgBr=4/i-PrMgBr/2a (1.2:2.5:1 molar ratio)/25 h; LHMDS=4/LHMDS/2a (1.2:2.5:1 molar ratio)/25 h.
b DMA: N,N-dimethylacetamide, DMF: N,N-dimethylformamide.
c Isolated yields.
d Determined by 1H NMR (400 MHz, CDCl3) analysis.
(300 MHz, CDCl3) in 3a. The E:Z ratios of 5a were
Recently, we reported the Z-selective HWE reaction of
aldehydes with 2-fluoro-2-diethylphosphonoacetic acid,
and the E-selective HWE reaction of aldehydes with
phosphonoacetic acid 4 under i-PrMgBr conditions.13,14
In these and other studies, we have focused our atten-
tion on stereoselection of the HWE reaction with aryl
alkyl ketones.10,15,16 Taking into account an electro-
static repulsion between the aromatic moiety of aryl
alkyl ketones and the carboxylate anion derived from
phosphonoacetic acid 4, a magnesium salt of the dian-
ion of 4 was treated with phenyl ethyl ketone (2a) in
THF to yield the a,b-unsaturated carboxylic acid 5a.
Esterification of crude 5a with an excess amount of
trimethylsilyldiazomethane (TMSCHN2)17 provided the
desired a,b-unsaturated esters 3a, as shown in Scheme
1. Under i-PrMgBr conditions in THF, temperature-
dependent improvement of E-selectivity up to 95:5
(E:Z) was achieved in the reactions of 4 with 2a (Table
1, entries 1–3). After optimization of the reaction con-
ditions, we found that LHMDS in DMF was a suitable
base for use in this HWE reaction (Table 1, entry 8).18
A lower reaction temperature was found to lead to an
increase in the stereoselectivity of 5a in the HWE
reactions of 4 with 2a under LHMDS conditions (Table
1, entries 7–9). In the HWE reactions of phosphonoac-
etate 1 with 2a employing LHMDS (1.25 mol equiv.,
DMF, 0°C, 25 h), a,b-unsaturated ester 3a was scarcely
obtained (86% recovery of 2a). Moderate Z-selectivity
and yield of 3a (25%, E:Z=35:65, 55% recovery of 2a)
were observed in the HWE reaction of 1 with 2a by
employing LHMDS (1.25 mol equiv., 0°C, 25 h) in
THF. The HWE reaction of phosphonoacetate 1 with
2a by employing NaH (1.5 mol equiv., 0°C, 23 h) in
THF also afforded 3a with moderate Z-selectivity
(93%, E:Z=39:61).10 On the other hand, the HWE
reactions of ethyl diethylphosphonoacetate 6 (1.25 mol
equiv. of LHMDS, DMF, 0°C, 25 h) or diethylphos-
phonoacetic acid 7 (2.5 mol equiv. of LHMDS, DMF,
0°C, 25 h) with 2a afforded 8 (trace amount) or 5a
(28%, E:Z=87:13) with moderate yields and selectivity.
Phosphonoacetic acid 4 was prepared in 92% yield by
enzymatic hydrolysis of 1 with porcine liver esterase
(PLE) in 0.1 M phosphate buffer (pH 7.4)–acetone
(9:1).14 The geometry of 5a was confirmed by measure-
determined by the integration of appropriate proton
1
absorptions obtained by H NMR (400 MHz) analysis.
A fairly good E-selectivity was observed in the HWE
reaction of 4 with aryl alkyl ketones 2b,c,e,f, as shown
in Table 2. It was hard to obtain a satisfactory yield by
the HWE reaction with ketone 2c bearing the bulky
isopropyl group (Table 2, entry 3). No reaction
occurred when phenyl tert-butyl ketone (2d) was used
(Table 2, entry 4). We also carried out HWE reactions
of 4 with aryl alkyl ketones 2g–j bearing various sub-
stituents on the aromatic moiety. In the cases of aro-
matic compounds 2g,h having an electron-donating
methoxy or methyl group, the E:Z stereoselectivity was
good, with ratios of 93:7 and 95:5, respectively (Table
2, entries 7 and 8). In contrast, the similar reactions of
ketones 2i,j having an electron-withdrawing chloro or
nitro group, resulted in a lower stereoselectivity (Table
2, entries 9–11). The HWE reactions of phenetyl ethyl
ketone (2k) with 4 gave a 54:46 mixture of E- and
Z-isomers of 5k (Table 2, entry 12).
Table 2. Stereoselective HWE reactions of ketone 2 with
bis(2,2,2-trifluoroethyl)phosphonoacetic acid (4)a
Entry
Ketone
Temperature
Yield (%)b
E:Zc
1
2
3
4
5
6
7
8
2b
2b
2c
2d
2e
2f
2g
2h
2i
0°C
−40°C
0°C
0°C
0°C
0°C
0°C
0°C
0°C
89 (3b)
45 (3b)
18 (3c)
0 (3d)
85 (3e)
81 (3f)
77 (3g)
94 (3h)
70 (3i)
91 (3j)
86 (3j)
76 (3k)
88:12 (5b)
91:9 (5b)
95:5 (5c)
– (5d)
92:8 (5e)
90:10 (5f)
93:7 (5g)
95:5 (5h)
90:10 (5i)
78:22 (5j)
85:15 (5j)
54:46 (5k)d
9
10
11
12
2j
2j
2k
0°C
−40°C
0°C
a DMF, 4/LHMDS/2 (1.2:2.5:1 molar ratio)/25 h.
b Isolated yields.
c Determined by 1H NMR (400 MHz, CDCl3) analysis.
d Determined by 1H NMR (400 MHz, CD3OD) analysis.
1
ment of the H–1H nuclear Overhauser effect (NOE)

S. Sano et al. / Tetrahedron Letters 44 (2003) 8853–8855
8855
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Pharm. Bull. 2002, 50, 706–709.
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4405–4408.
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43, 9183–9186.
14. Sano, S.; Takemoto, Y.; Nagao, Y. Arkivoc part (viii),
Figure 1. Plausible transition state for the E-selective HWE
reaction of 4 with 2a in terms of the electrostatic repulsion
between the carboxylate anion and the phenyl group.
93–101
(http://www.arkat-usa.org/ark/journal/2003/
Fukumoto/KF-777H/KF-777H.htm)
15. Sano, S.; Ando, T.; Yokoyama, K.; Nagao, Y. Synlett 1998,
777–779.
A plausible transition state of the E-selective HWE
reactions of phosphonoacetic acid 4 with phenyl ethyl
ketone (2a) is shown in Figure 1. The transition state
for the formation of (Z)-5a from pro-(Z)-oxyanion
may be less favorable than that from pro-(E)-oxyanion
to (E)-5a because of an electrostatic repulsion between
the carboxylate anion and the phenyl group of the
oxyanion intermediate.13,14,19–21 Consequently, (E)-a,b-
unsaturated carboxylic acid (E)-5a was obtained as the
major product. In general, decreasing reaction tempera-
ture tends to enhance E-selection of the HWE reaction
of phosphonoacetic acid 4 with aryl alkyl ketone 2. In
the case of p-nitrophenyl ethyl ketone (2j), such an
electrostatic repulsion may not be effective for the
E-selective HWE reaction at 0°C.22–26
16. Sano, S. Yakugaku Zasshi 2000, 120, 432–444.
17. Shioiri, T.; Aoyama, T. J. Synth. Org. Chem., Jpn. 1986,
44, 149–159.
18. TypicalprocedureofE-selectiveHWEreaction:Toastirred
solution of phosphonoacetic acid 4 (98 mg, 0.32 mmol) in
anhydrous DMF (5 mL) was added a 1.06 mol/L solution
of LHMDS (0.63 mL, 0.67 mmol) in n-hexane at 0°C under
argon. The mixture was stirred at 0°C for 1 h, and phenyl
ethyl ketone (2a) (35.7 mL, 0.27 mmol) was added to the
solution. After being stirred at 0°C for 25 h, the reaction
mixture was treated with H2O (10 mL) and then washed
with CHCl3 (20 mL). The water layer was acidified with
10% HCl and extracted with AcOEt (60 mL×3). 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 5a (E:Z=93:7). To the solution of
5a in MeOH (2 mL) and benzene (7 mL) was added an excess
amount of TMSCHN2 (2.0 mol/L solution in n-hexane, ca.
0.5 mL, ca. 1 mmol). After being stirred at room temper-
ature for 30 min, the reaction mixture was evaporated in
vacuo to afford a crude product, which was purified by
chromatography on a silica gel column eluted with n-hex-
ane–AcOEt (10:1), giving a mimxture of a,b-unsaturated
esters (E)- and (Z)-3a (46 mg, 91%, E:Z=94:6) as a
colorless oil.
In summary, we have developed an improved E-selec-
tive HWE reaction of phosphonoacetic acid 4 with
various aryl alkyl ketones utilizing LHMDS as a base
in DMF. In addition to the Z-selective HWE reaction
of aryl alkyl ketones under Sn(OSO2CF3)2 condi-
tions,10,11 this novel procedure may find application in
the organic synthesis of various trisubstituted alkenes.
Acknowledgements
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This work was partially supported by a Grant-in-Aid
for Scientific Research (C) from the Japan Society for
the Promotion of Science.
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21. McCarthy, A. A.; Walsh, M. A.; Verma, C. S.; O’Connell,
D. P.; Reinhold, M.; Yalloway, G. N.; d’Arcy, D.; Higgins,
T. M.; Voordouw, G.; Mayhew, S. G. Biochemistry 2002,
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