The Horner-Wadsworth-Emmons reaction of mixed phosphonoacetates and aromatic aldehydes: Geometrical selectivity and computational investigation

Article abstract of DOI:10.1016/S0040-4020(01)00007-2

The substituent effect on the geometrical selectivity in the Horner-Wadsworth-Emmons (HWE) reaction was studied employing several mixed phosphonoacetates. Their reactions with aromatic aldehydes showed a gradual change in Z-selectivity according to the electron-withdrawing ability of the phosphonate substituents, and there was a good correlation between the observed selectivities and ³¹P chemical shifts of the phosphonoacetates. Some variables such as the metal cation and crown ether also affected the selectivity. A computational study using ab initio and semi-empirical calculations suggests that the electron-withdrawing substituents stabilize the intermediates as well as the transition states, which reduces the reversibility to increase Z-products. This is in agreement with the experimentally observed selectivity.

Full text of DOI:10.1016/S0040-4020(01)00007-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1715±1721
The Horner±Wadsworth±Emmons reaction of mixed
phosphonoacetates and aromatic aldehydes: geometrical
selectivity and computational investigation
Jiro Motoyoshiya,p Tatsuya Kusaura, Keisuke Kokin, Sei-ichi Yokoya, Yutaka Takaguchi,
Susumu Narita and Hiromu Aoyama
Department of Chemistry, Faculty of Textile Science and Technology, Shinshu University, Ueda 386-8567, Japan
Received 16 October 2000; accepted 22 December 2000
AbstractÐThe substituent effect on the geometrical selectivity in the Horner±Wadsworth±Emmons (HWE) reaction was studied employ-
ing several mixed phosphonoacetates. Their reactions with aromatic aldehydes showed a gradual change in Z-selectivity according to the
electron-withdrawing ability of the phosphonate substituents, and there was a good correlation between the observed selectivities and 31P
chemical shifts of the phosphonoacetates. Some variables such as the metal cation and crown ether also affected the selectivity. A
computational study using ab initio and semi-empirical calculations suggests that the electron-withdrawing substituents stabilize the inter-
mediates as well as the transition states, which reduces the reversibility to increase Z-products. This is in agreement with the experimentally
observed selectivity. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
enough to serve the practical use under the convenient
reaction conditions. Recently, we have also reported6 that
methyl bis(2,4-di¯uorophenyl)phosphonoacetate (4) is
highly Z-selective even when aliphatic aldehydes were
employed.
The Horner±Wadsworth±Emmons (HWE) reaction1,2 is
one of much versatile tools in organic synthesis. While
the general phosphonoacetates with alkyl phosphonate
substituents, for example, methyl diethylphosphonoacetate
(1) as a representative reagent, give mostly thermodynami-
cally favored E-alkenes in the reactions of aldehydes or
ketones, some Z-selective phosphonoacetates have been
developed so far. For instance, methyl bis(2,2,2-tri¯uoro-
ethyl)phosphonoacetates (2) (Still's reagents)3 are of much
value in the synthesis of Z-unsaturated esters.4 On the other
hand, Ando5 has developed several ethyl diarylphosphono-
acetates (3), which provide a high level of Z-selectivity
Though the central device of above Z-selective HWE
reagents is an introduction of the electron-withdrawing
groups as the phosphonate substituents, the pentacoordinate
spirophosphoranes have also proved to undergo a Wittig
reaction with high Z-selectivity.7 Several works have been
dealing with the HWE reaction from mechanistic view-
points,8 but there remain some problems to be further
elucidated, for instance, the origin of Z-selectivity of the
above phosphonoacetates. Therefore, to explore the effect
of the electron-withdrawing substituents on the selectivity,
we have investigated the HWE reaction of new mixed
phosphonoacetates, which are expected to expose the
electronic effect of the phosphonate substituents on the
selectivity. Additionally, a computational study was made
to explain the experimentally observed substituent effect.
2. Results and discussion
2.1. Preparation of mixed phosphonoacetates (5a±j) and
31P NMR chemical shifts
Keywords: Horner±Wadsworth±Emmons reaction; phosphonoacetate;
selectivity; substituent effect.
Corresponding author. Fax: 181-268-21-5391;
e-mail: jmotoyo@giptc.shinshu-u.ac.jp
The mixed phosphonoacetates used in the present study
were prepared by two reaction procedures as shown in
Scheme 1. The reactions of methyl dichlorophosphinylacetate
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00007-2

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J. Motoyoshiya et al. / Tetrahedron 57 (2001) 1715±1721
Scheme 2.
2.2. The HWE reaction
The HWE reaction of phosphonoacetates 5a±i and 6 with
aromatic aldehydes was carried out under the kinetically
controlled condition using potassium hexamethyldisilazide
(KHMD) in THF at 2788C in the presence of 18-crown-6
(Scheme 2).3,10 The results are summarized in Table 2. In
some reactions, the yields were low and unreacted alde-
1
hydes were detected by H NMR spectrum, which would
be ascribed to the low reactivity as well as lability of the
phosphonoacetates. As expected, Z-selectivities of the
mixed phosphonoacetates were diminished below half
comparing to the parent Z-selective phosphonoacetates.
For example, while the reactions of 2, 3, and 4 with benzal-
dehyde provided the high Z-selectivities (.98%), those of
mixed phosphonoacetates 5b, 5e and 5f gave E-cinnamate
preferentially under the same reaction condition.3 Only 5a
bearing a highly electron-withdrawing substituent such as a
1,1,1,3,3,3-hexa¯uoroisopropyl group showed the moderate
Z-selectivity. Of particular interest is that the ratios of the
Z-isomer gradually changed according to the electronic
nature of the phosphonate substituents rather than a steric
factor as observed in the reactions of 5a (Rv(CF3)2CH:
Entry 1), 5b (RvCF3CH2: Entry 6), 5c (RvCCl3CH2:
Entry 9) and 5d (RvCBr3CH2: Entry 10). A choice of
the mixed phosphonoacetates clari®ed the substituent effect
on the selectivity, because bis(trichloroethyl)phosphono-
acetate11 is known to be as Z-selective as Still's reagent 2.
In contrast, the effect of aldehyde substituents was much
less than that of the phosphonate substituents (Entries
2±5, 7 and 8), which indicated that the electrophilicity of
the phosphorus atom would control the stereochemistry
rather than the rate of initial addition of the phosphonate
carbanions to aldehydes. The degree of the electrophilicity
of the phosphorus atom can be connected with the phos-
phorus chemical shifts as described in Table 1. Such a
tendency could also be seen in the reactions of 5e±g having
aromatic substituents, namely, the ratio of Z-isomers
increased by the introduction of ¯uorine atoms to benzene
rings (Entries 11±13). Contrary, the alkyl groups attached
on both o-positions in 5h and 5i reduced the Z-isomer
remarkably (Entries 14 and 15). This drastic decrease of
Z-isomers would be attributed to much reduced electro-
philicity of the phosphorus atoms rather than the steric
effect, because more sterically hindered phosphonoacetates
such as methyl bis(2,6-dimethylphenyl)- and bis(2,6-di-
isopropylphenyl)phosphonoacetates provided moderate
Z-selectivity.6b Also in this series of aromatic phosphono-
acetates, the order of Z-selectivity is completely consistent
with the order of the chemical shifts of 5e±i as described in
Table 1. On the other hand, the phosphonothioate (6) gave
only E-cinnamate but in low yield (Entry 16).
Scheme 1. Reagents and conditions: (i) PCl5, heat; (ii) EtOH, Et3N, PhH,
08; (iii) ROH, Et3N, PhH, 08C; (iv) ROH, Et3N, Et2O, 08C; (v)
BrCH2COOMe, heat.
with halogenated alcohols followed by an addition of
ethanol in the presence of triethyl amine gave 5a, 5c and
5d in low to medium yields (Method A). This method was
also applied to the preparation of phosphonothioate 6 using
thiophenol. Alternatively, the Arubzov reaction of mixed
phosphites with methyl bromoacetate afforded 5b, and
5e±i in relatively good yields (Method B). The 31P NMR
spectra of these phosphonoacetates are shown in Table 1.
The phosphorus signals tend to shift to down ®elds as the
electronegativity of the substituent increases among 5a±d.
The difference in the chemical shifts might be related to the
electrophilicity of the phosphorus atoms. The phosphorus
signal of 5e having a phenyl group was observed in a high
®eld, as the phosphorus nuclei bearing phenoxy groups
generally resonate at higher ®elds than those with alkoxy
groups.9 Also in the aromatic series (5e±i), a relationship
between the chemical shifts and the electronic factor of the
substituents on the aromatic rings can be observed.
Table 1. Select 31P chemical shifts
R
d (ppm)a
CH3CH2
(CF3)2CH
CF3CH2
CCl3CH2
CBr3CH2
Ph
2,4-Di¯uorophenyl
2,6-Di¯uorophenyl
2,6-Xylyl
(1)
20.1
23.1
21.9
21.2
20.2
17.1
18.2
19.0
16.5
16.1
(5a)
(5b)
(5c)
(5d)
(5e)
(5f)
(5g)
(5h)
(5i)
2,6-Diisopropylphenyl
Measured in CDCl3.
85% H3PO4 as a standard.
a

J. Motoyoshiya et al. / Tetrahedron 57 (2001) 1715±1721
Table 2. Reaction of phosphonoacetates (5a±i, 6) with ArCHO
1717
Entrya
R
Ar
Yield (%)b
Z/Ec
1
2
3
4
5
6
7
8
(CF3)2CH
(5a)
(5b)
Ph
55
53
88:12
72:28d
71:29
67:33
±
49:51
43:57
35:65
35:65
29:71
31:69
p-NO2±C6H4±
p-ClÐC6H4±
p-MeO±C6H4-
p-Me2N±C6H4±
Ph
p-NO2±C6H4±
p-MeO±C6H4±
Ph
41
37e
f
±
CF3CH2
56
77
52
37
62
80
9
10
11
CCl3CH2
CBr3CH2
Ph
(5c)
(5d)
(5e)
Ph
Ph
12
13
(5f)
Ph
Ph
68
41:59
(5g)
80
65:35
14
15
(5h)
Ph
62
15:85
(5i)
(6)
Ph
Ph
74
25
6:94
16
PhS
Only E
a
Reaction condition: KHMDS/18-crown-6/THF/2788C.
Isolated yield by column chromatography.
Determined by 1H NMR otherwise noted.
Determined by gas chromatography.
This yield was estimated by 1H NMR.
No reaction.
b
c
d
e
f
2.3. Effect of some variables on the selectivity
undecene) as a base14 instead of KHMDS led to much
decrease of the ratio of Z-cinnamate (Entry 3), drastic
increase of Z-isomer and the yield was observed when KI
and crown ether were present (Entry 4). Whereas increase of
Z-isomer in the presence of KI was also observed in DMF
(Entry 5±7), the de®nite effect of crown ether could not be
seen in this solvent because of its high polarity (Entry 7±9).
Probably, chelation of the metal cation by the negatively
charged oxyanion as well as ester and phosphoryl oxygens
As it is known that the variables such as the base, metal
cation, crown ether and solvent affect the selectivity,12
several controlled experiments were made using 5a and
benzaldehyde. The results are summarized in Table 3.
Removal of crown ether13 markedly lowered the
Z-selectivity as well as the yield of cinnamate (Entries 1
and 2). While the use of DBU (1,8-diazabicyclo[5.4.0]-7-
Table 3. The HWE reaction of 5a and PhCHO. Effect of reaction conditions on the ratio of Z- and E-cinnamates
Entry
Base/additive
Solvent/temperature (8C)
Yield (%)a
Z/Eb
1
2
3
4
5
6
7
8
9
KHMDS/18-crown-6
KHMDS
THF/278
THF/278
THF/278
THF/278
DMF/0
DMF/0
DMF/0
DMF/0
DMF/0
55
12
25
74
43
55
37
62
49
88:12
44:56
15:85d
53:47
8:92
15:85
20:80
15:85
25:75
DBUc
DBU/KI/18-crown-6 (1/5/5)e
DBU
DBU/KI (1/1)
DBU/KI (1/5)
DBU/KI/18-crown-6 (1/1/5)
DBU/KI/18-crown-6 (1/5/5)
a
Isolated yield.
Determined by 1H NMR spectrum.
1,8-Diazabicyclo[5,4.0]-7-undecene.
The ¯uctuating Z/E ratios from 3:97 upto 33:67 were observed under the same system at 08C.
Molar ratio of base and additives.
b
c
d
e

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J. Motoyoshiya et al. / Tetrahedron 57 (2001) 1715±1721
Table 4. Relative energies of oxaphosphetanes formed from the metal free phosphonoacetates and formaldehyde (RHF/6-311Gp)
Phosphonoacetate
R
R0
DG (kcal/mol)
1
2
5a
5b
5c
Et
CF3CH2
Et
Et
Et
Et
13.39
23.45
22.57
21.11
21.56
CF3CH2
(CF3)2CH
CF3CH2
Cl3CH2
Relative energy is a difference from the sum of the energies of the reactants. All oxaphosphetanes are slightly puckered with the OR0 group at an apical
Ê
position. Bond lengths for P±C: 1.86±1.89 A, C±C: 153 A, C±O: 1.39 A, P±O: 1.76±1.82 A.
Ê
Ê
Ê
would stabilize the kinetically favored erythro-transition
states, the precursors of erythro-oxaphosphetanes and
Z-products, as can be seen in erythro-selective aldol
condensation of Z-enolates and aldehydes15 or erythro-
selective addition of the phosphorus stabilized carbanions
to aldehydes.16 The effect of the crown ether seems to
con¯ict with the chelate effect at the transition state, but
assuming that this chelation is stronger than that by the
crown ether and it diminishes along with the structural
transformation to the oxaphosphetane, a possible explana-
tion of the role of the crown ether is increase of the electro-
philicity of the oxyanion leading to rapid ring closure to the
oxaphosphetane.
ing step is ring closure to the oxaphosphetane.18,19 Although
the predominance of E-ole®ns in the general HWE reactions
has been explained,19 a theoretical inquiry of the factors
enhancing Z-selectivity should be made toward further
understanding of this subject. According to the previously
proposed mechanism for Z-selectivity,2b stabilization of the
transition state for ring closure suppresses the reverse
process and increases a proportion of the kinetic inter-
mediate, erythro-oxaphosphetane whose rapid decomposi-
tion forms a Z-ole®n. When the Hammond postulate is
applied, the factor that stabilizes the transition states
would also affect the stabilization of the oxaphosphetanes,
because of a structural similarity among the transition
state for ring closure and the oxaphosphetane.17 Therefore,
we compared the energies of the oxaphosphetanes
formed from the selected phosphonate carbanions and
formaldehyde using ab initio RHF calculations with the
6-311Gp basis set.20 Comparison of the relative energies
of oxaphosphetanes in Table 4 revealed the effect of
2.4. Calculations
Recent theoretical investigations of the HWE reaction
suggest that the reaction proceeds via a scarcely detected
oxaphosphetane17 as an intermediate and the rate determin-
Figure 1. Structures, relative energies and atomic distances of the forming C±C bonds (parenthesis) of the transition states in the reaction of 1 and 2 with
benzaldehyde in the presence of potassium ions (PM3).

J. Motoyoshiya et al. / Tetrahedron 57 (2001) 1715±1721
1719
electron-withdrawing substituents on the stabilization of the
corresponding oxaphosphetanes, namely, the larger stabili-
zation in 2 and 5a than in 1, 5b and 5c is in agreement with a
known matter that electron-withdrawing groups at the apical
positions stabilize the pentacoordinated phosphorus
compounds. Next, we settled for an investigation to
compare the stability of threo- and erythro-transition states,
the precursors for E- and Z-ole®ns, respectively. The calcu-
lations were done by semi-empirical PM3 method21 to
submit the realistic model systems.22 The reactions of potas-
sium salts of the phosphonoacetates 1 and 2, the former is a
typical E-selective HWE reagent and the latter is the
Z-selective one, with benzaldehyde were chosen as the
representatives. Our calculation23 provided two transition
states, erythro-TS1 and TS2 for each initial addition and
ring closure to erythro-oxaphosphetane, respectively, but a
sole transition state, threo-TS, was located for the formation
of threo-oxaphosphetanes as previously noted.19 The struc-
tures and relative energies of these transition states are
described in Fig. 1. The lower energies of both erythro-
TS1s than threo-TSs agree with the previously reported
result,19 but we can point out that erythro-TS2 having
2,2,2-tri¯uoroethyl groups is more stabilized than that
having ethyl groups. This supports the preference of
Z-product in the reaction of 2.
was added to a solution of methyl (dichlorophosphoryl)-
acetate (13.11 g, 69 mmol) in benzene (60 ml) at 08C.
After being stirred for 3 h at room temperature, a solution
of ethanol (3.18 g, 69 mmol) and triethylamine (6.98 g,
69 mmol) in benzene (80 ml) was then added at 08C, and
the mixture was stirred at room temperature for 3 h. After
removal of precipitated ammonium chloride and the
solvent, the oily residue was distilled in vacuo to give 5a
as a colorless oil (14.17 g, yield 60%); bp 78±808C, 3 mm
Hg (Found M1: 332.0230. C8H11O5F6P requires 332.0246);
1H NMR (400 MHz) dˆ1.07 (t, 3H, CH3CH2O, Jˆ7.2 Hz),
2.87 (d, 2H, P(O)CH2, JPHˆ22.4 Hz), 3.45 (s, 3H,
COOCH3), 3.91±4.02 (m, 2H, CH3CH2O), 5.23±5.29 (m,
1H, (CF3)2CHO); 13C NMR (100 MHz) dˆ16.1
(CH3CH2O), 34.4 (d, P(O)CH2, JPCˆ40.9 Hz), 53.0
(COOCH3), 64.2 (CH3CH2O), 69.9±71.3 (m, (CF3)2CH2O),
123.6 (m, (CF3)2CHO, JFCˆ280.5 Hz), 165.1 (CvO); m/z
332 (M1).
4.1.2. Methyl ethyl(2,2,2-tri¯uoroethyl)phosphonoacet-
ate (5b). Typical procedure B. A mixture of diethyl 2,2,2-
tri¯uoroethyl phosphite (2.61 g, 12.19 mmol) and methyl
bromoacetate (1.05 ml, 11.09 mmol) was heated at 1208C
for 24 h. The oily product was puri®ed by bulb-to-bulb
distillation under reduced pressure to give 5b (1.92 g,
84%). Bp 1308C at 12 mm Hg (oven temp.) (Found M1:
264.0355. C7H12O5FP requires 264.0373); 1H NMR
(400 MHz) dˆ1.37 (t, 3H, CH3CH2O, Jˆ7.2 Hz), 3.07 (d,
2H, P(O)CH2, JPHˆ21.2 Hz), 3.76 (s, 3H, COOCH3), 4.19±
3. Conclusions
4.25 (m, 2H, CH3CH2O) 4.41±4.50 (m, 2H, CF3CH2O); 13
C
The present study showed a close relationship between the
electronic nature of the phosphonate substituents and
geometrical selectivity in the HWE reaction. A gradual
enhancement of Z-selectivity due to electron-withdrawing
groups was observed in a series of the reactions of the mixed
phosphonoacetates. This effect is ascribed to the changeable
electrophilicity of the phosphorus atoms and the stability of
the oxaphosphetane intermediates as well as the transition
states, which was supported by the computational study.
NMR (100 MHz) dˆ16.3 (CH3CH2O), 34.2 (d, P(O)CH2,
JPCˆ140.0 Hz), 53.0 (COOCH3), 63.2 (CH3CH2O), 63.5
(CF3CH2O), 123.1 (m, CF3CH2O, JFCˆ260.0 Hz), 166.1
(CvO); m/z 264 (M1).
4.1.3. Methyl ethyl(2,2,2-trichloroethyl)phosphonoacet-
ate (5c). Prepared in 21% yield by procedure A (Found
1
M1: 311.9527. C7H12O5Cl3P requires 311.9487); H NMR
(400 MHz) dˆ1.39 (t, 3H, CH3CH2O, Jˆ6.8 Hz), 3.12 (d,
2H, P(O)CH2, JPHˆ21.6 Hz), 3.77 (s, 3H, COOCH3), 4.25±
4.30 (m, 2H, CH3CH2O), 4.65±4.68 (d, 2H, CCl3CH2O);
13C NMR (100 MHz) dˆ16.2 (s, CH3CH2O), 34.0 (d,
P(O)CH2, JPCˆ136.1 Hz), 52.7 (COOCH3), 63.2
(CH3CH2O), 76.2 (CCl3CH2O), 95.5 (CCl3CH2O), 165.7
(s, CvO); m/z 312(M1) (as Clˆ35).
4. Experimental
1H NMR (400 or 60 MHz), 13C NMR (100 MHz) and 31P
NMR (162 MHz) spectra were taken in CDCl3 as a solvent,
using tetramethylsilane (TMS) as the internal standard for
1H and 13C NMR, and 85% phosphoric acid as the external
standard for 31P NMR. The mass spectra were determined at
an ionizing voltage of 70 eV. Analytical gas chromato-
graphy was performed using PEG-20M or DC-550 packed
column. All solvents were dried by standard methods. The
column chromatography was done with Wacogel C-200.
Methyl (dichlorophosphoryl)acetate was prepared by Still's
method.3 Diethyl phenyl phosphite, diethyl (2,2,2-tri¯uoro-
ethyl) phosphite, diethyl (2,6-xylyl) phosphite and diethyl
(2,6-diisopropylphenyl) phosphite were prepared according
to the procedure previously reported.6b
4.1.4. Methyl ethyl(2,2,2-tribromoethyl)phosphonoacet-
ate (5d). Prepared in 25% yield by procedure A (Found
M1 11: 446.8047. C7H13O5PBr3 (M111) requires
446.8032); 1H NMR (400 MHz) dˆ1.40 (dt, 3H,
CH3CH2O, Jˆ7.1 Hz), 3.15 (d, 2H, P(O)CH2,
JPHˆ20.0 Hz), 3.78 (s, 3H, COOCH3), 4.29±4.34 (m, 2H,
CH3CH2O), 4.82±4.84 (d, 2H, CBr3CH2O); 13C NMR
(100 MHz) dˆ16.5 (s, CH3CH2O), 34.2 (d, P(O)CH2,
JPCˆ137.2 Hz), 37.6 (CH3CH2O), 52.9 (COOCH3), 63.5
(CH3CH2O), 76.8 (CBr3CH2O), 165.9 (CvO); m/z 447
(M111).
4.1. Preparation of mixed phosphonoacetates
4.1.5. Methyl ethylphenylphosphonoacetate (5e).
Prepared in 60% yield by procedure B (Found M1:
258.0642. C11H15O5P requires 258.0656); 1H NMR
(400 MHz) dˆ1.33 (t, 3H, CH3CH2O, Jˆ7.2 Hz), 3.12
(d, 2H, P(O)CH2, JPHˆ21.6 Hz), 3.74 (s, 3H, COOCH3),
4.1.1. Methyl ethyl(1,1,1,3,3,3-hexa¯uoroisopropyl)phos-
phonoacetate (5a). Typical procedure A. A solution of
1,1,1,3,3,3-hexa¯uoroisopropylalcohol (7.2 ml, 69 mmol)
and triethyl amine (6.98 g, 69 mmol) in benzene (80 ml)

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J. Motoyoshiya et al. / Tetrahedron 57 (2001) 1715±1721
4.23±4.30 (m, 2H, CH3CH2O), 7.16±7.36 (m, 5H, ArH);
13C NMR (100 MHz) dˆ16.6 (s, CH3CH2O), 34.3 (d,
P(O)CH2, JPCˆ140.0 Hz), 53.0 (COOCH3), 64.20
(CH3CH2O), 120.9, 121.0, 125.7, 130.1, 150.5 (Aromatic
C), 166.1 (CvO); m/z 258 (M1).
274.0439. C11H15O4SP requires 274.0427); 1H NMR
(60 MHz) dˆ1.32 (t, 3H, CH3CH2O), 2.97 (d, 2H,
P(O)CH2, JPHˆ18.0 Hz), 3.56 (s, 3H, COOCH3), 3.83±
4.36 (m, 2H, CH3CH2O, JPHˆ7.0 Hz), 7.13±7.43 (m, 5H,
ArH); m/z 274 (M1).
4.1.6. Methyl ethyl(2,4-di¯uorophenyl)phosphonoacet-
ate (5f). Prepared in 67% yield by procedure B (Found
M1: 265.0057. C9H18O5F2P (M121C2H5) requires
265.0076); 1H NMR (400 MHz) dˆ1.35 (t, 3H,
CH3CH2O, Jˆ7 Hz), 3.18 (d, 2H, P(O)CH2, JPHˆ22 Hz),
3.76 (s, 3H, COOCH3), 4.28±4.35 (m, 2H, CH3CH2O),
6.82±6.95, 7.12±7.41 (m, 3H, ArH); 13C NMR (100 MHz)
dˆ16.5 (d, CH3CH2O, JPCˆ6 Hz), 34.4 (d, P(O)CH2,
JPCˆ137 Hz), 53.1 (COOCH3), 64.3 (d, CH3CH2O,
JPCˆ7 Hz), 105.3±105.8 (m, ArC3), 111.5±111.8 (m,
ArC5), 123.8±123.9 (m, ArC6), 134.5±134.7 (m, ArC1),
152.7±161.0 (m, ArC2, C4), 165.5 (d, CvO, JPCˆ5 Hz);
m/z 294 (M1).
4.2. The HWE reaction
4.2.1. Typical procedure (KHMDS, 18-crown-6, 2788C,
THF). A solution of KHMDS (0.5 mol/l toluene solution,
2.0 ml, 1.00 mmol) was added dropwise to a solution of 5a
(0.33 g, 1.00 mmol) and 18-crown-6 (1.32 g, 5.00 mmol) in
THF (20 ml) at 2788C, and the mixture was stirred at this
temperature for 1 h under N2. A solution of benzaldehyde
(0.11 g, 1.00 mmol) in THF (2 ml) was then added and the
mixture was stirred for 18 h at that temperature. After the
reaction was quenched with saturated NH4Cl at room
temperature, the THF layer was separated, and the products
were further extracted with Et2O (20 ml£2) from an
aqueous layer. The combined extract was washed with
brine and dried over Na2SO4. After removal of the solvent
under reduced pressure, the residue was chromatographed
on silica gel using benzene as an eluant to give methyl
cinnamate (0.09 g, 55%). The ratio of Z/E cinnamate was
4.1.7. Methyl ethyl(2,6-di¯uorophenyl)phosphonoacet-
ate (5g). Prepared in 72% yield by procedure B (Found
1
M1: 294.0446. C11H13O5F2P requires 294.0467); H NMR
(400 MHz) dˆ1.39 (t, 3H, CH3CH2O, Jˆ7 Hz), 3.27 (d,
2H, P(O)CH2, JPHˆ22 Hz), 3.77 (s, 3H, COOCH3), 4.32±
4.41 (m, 2H, CH3CH2O), 6.94±6.99, 7.08±7.10 (m, 3H,
ArH); 13C NMR (100 MHz) dˆ16.5 (d, CH3CH2O,
JPCˆ6 Hz), 34.7 (d, P(O)CH2, JPCˆ137 Hz), 53.1
(COOCH3), 64.2 (d, CH3CH2O, JPCˆ7 Hz), 112.5±112.7
(m, ArC3, C5), 125.6±125.9 (m, ArC4), 128.7 (ArC1),
154.2±156.7 (m, ArC2, C6), 165.7 (d, CvO, JPCˆ6 Hz);
m/z294 (M1).
1
determined by H NMR comparing integrations of vinyl
protons which appeared at d 5.74 (PhCHvCHCOOMe,
Jˆ12 Hz) as a doublet for Z-cinnamate and d 6.24
(PhCHvCHCOOMe, Jˆ16 Hz) as a doublet for E-cin-
namate. On the other hand, the Z/E ratios of the substituted
methyl cinnamates were estimated by gas chromatography
1
when the signals of vinyl protons in H NMR were over-
lapped.
4.1.8. Methyl ethyl(2,6-xylyl)phosphonoacetate (5h).
Prepared in 79% yield by procedure B (Found M1:
286.0988. Cl3H19O5P requires 286.0968); 1H NMR
(400 MHz) dˆ1.22 (t, 3H, CH3CH2O, Jˆ7 Hz), 2.53 (s,
6H, ArCH3), 3.20 (d, 2H, P(O)CH2, JPHˆ21 Hz), 3.77 (s,
3H, COOCH3), 4.28±4.35 (m, 2H, CH3CH2O), 6.94±7.12
(m, 3H, ArH); 13C NMR (100 MHz) dˆ16.2 (d, CH3CH2O,
JPCˆ5 Hz), 17.4 (ArCH3), 34.7 (d, P(O)CH2, JPCˆ139 Hz),
52.6 (COOCH3), 64.1 (d, CH3CH2O, JPCˆ7 Hz), 125.2,
129.0 (ArC3, C4, C5), 130.5 (d, ArC2, C6, JPCˆ3 Hz),
147.5 (d, ArC1, JPCˆ11 Hz), 166.0 (d, CvO, JPCˆ6 Hz);
m/z 286 (M1).
4.2.2. Entry 1 (KHMDS, 2788C, THF). The same pro-
cedure described above was done without addition of
18-crown-6.
4.2.3. Entry 2 (DBU, 2788C, THF). A solution of DBU
(0.15 g, 1.00 mmol) in THF (20 ml) was added dropwise to
5a (0.33 g, 1.00 mmol) in THF (20 ml) at 2788C, and the
mixture was stirred at this temperature for 1 h under N2. A
solution of benzaldehyde (0.11 g, 1.00 mmol) in THF (2 ml)
was then added, and the mixture was stirred for 18 h. The
similar work-up described in the typical procedure was
done.
4.1.9. Methyl ethyl(2,6-diisopropylphenyl)phosphono-
acetate (5i). Prepared in 81% yield by procedure B
4.2.4. Entry 3 (DBU, 2788C, THF, KI, 18-crown-6). This
reaction was done in a similar manner described above
except addition of KI (0.85 g, 5.00 mmol) and 18-crown-6
(1.32 g, 5.00 mmol) to a solution of 5a in THF before
cooling.
z
(Found M12 CH3: 327.1382. C16H24O5P (M12zCH3)
1
requires 327.1359); H NMR (400 MHz) dˆ1.19 (t, 3H,
CH3CH2O, Jˆ7 Hz), 1.21, 1.22 (d, 12H, (CH3)2CH,
Jˆ7 Hz), 3.22 (d, 2H, P(O)CH2, JPHˆ22 Hz), 3.44±3.51
(m, 2H, (CH3)2CH), 3.77 (s, 3H, COOCH3), 4.09±4.21
(m, 2H, CH3CH2O), 7.13 (s, 3H, ArH); 13C NMR
(100 MHz) dˆ16.5 (d, CH3CH2O, JPCˆ6 Hz), 23.8, 23.9
((CH3)2CH), 27.5 ((CH3)2CH), 34.9 (d, P(O)CH2,
JPCˆ138 Hz), 52.9 (COOCH3), 65.1 (d, CH3CH2O,
JPCˆ6 Hz), 124.6, 126.2 (ArC3, C4, C5), 141.0 (d, ArC2,
C6, JPCˆ3 Hz), 145.2 (d, ArC1, JPCˆ11 Hz), 166.4 (d,
CvO, JPCˆ6 Hz); m/z342 (M1).
4.2.5. Entry 4 (DBU, 08C, DMF). A solution of DBU
(0.15 g, 1.00 mmol) in DMF (20 ml) was added dropwise
to 5a (0.33 g, 1.00 mmol) in DMF (20 ml) at 08C, and the
mixture was stirred at this temperature for 1 h under N2. A
solution of benzaldehyde (0.11 g, 1.00 mmol) in DMF
(2 ml) was then added, and the mixture was stirred for
18 h. The reaction was quenched with saturated NH4Cl at
room temperature. The products were extracted with Et2O
(20 ml£2) from the mixture, and the extract was washed
with brine and dried over Na2SO4. The solvent was
removed under reduced pressure, and the residue was
4.1.10. Methyl (ethoxyphenylthiophosphoryl)acetate (6).
Prepared in 17% yield by procedure A (Found M1:

J. Motoyoshiya et al. / Tetrahedron 57 (2001) 1715±1721
1721
9. Emsley, J.; Hall, D. The Chemistry of Phosphorus, Harper &
Row: NY, USA, 1976 (Chapter 2).
chromatographed on silica gel using benzene as an eluant to
give methyl cinnamate (0.07 g, 43%).
10. Kann, N.; Rein, T. J. Org. Chem. 1993, 58, 3802.
11. (a) Reddy, A. M.; Gopal, V. R.; Rao, V. J. Indian J. Chem.
1996, 35B, 312. (b) In our preliminary experiment the reaction
of methyl (2,2,2-tribromoethyl)phosphonoacetate and benzal-
dehyde also gave an almost same extent of Z-cinnamate.
12. Thompson, S. K.; Heathcock, C. H. J. Org Chem. 1990, 55,
3386.
4.2.6. Entry 5, 6, 7 and 8 (DBU, 08C, DMF, KI). These
reactions were done by the similar manner described above
except addition of the corresponding amount of KI and
18-crown-6 to the solution of 5a in DMF before cooling.
13. Baker, R.; Sims, R. J. Synthesis 1981, 117.
Acknowledgements
14. (a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
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Chem. 1985, 50, 2624. (c) Ruebsam, F.; Evers, A. M.; Michel,
C.; Giannis, A. Tetrahedron 1997, 53, 1707.
The authors thank Mrs Teruko Tsuchida (Faculty of
Engineering, Shinshu University) for the measurements of
high resolution mass spectrum (HRMS). This work was
partially supported by Grant-in-Aid for COE Research
(10CE2003) by the Ministry of Education, Science, Sports
and Culture of Japan.
15. (a) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead,
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Dubois, J. E. Tetrahedron 1978, 34, 1349. (c) Kleschick,
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