Synthesis of β-monosubstituted α,β-unsaturated amides with z-selectivity using diphenylphosphonoacetamides

Article abstract of DOI:10.1002/hc.20054

The utility of diphenylphosphonoacetamides [(PhO)₂P(O)CH ₂CONRR′] as Horner-Wadsworth-Emmons reagents was examined with five different patterns of substitution upon the amide nitrogen atom (2a: R, R′ = CH₂Ph; 2b: R = CH₂Ph, R′ = H; 2c: R = Me, R′ = OMe; 2d: R, R′ = Ph; 2e: R, R′ = (CH₂) ₄). The reaction of 2a was found to be Z-selective for aromatic aldehydes with selectivities up to 95:5. Reagent 2b led to reasonable selectivity for both benzaldehyde (85:15) and 3-phenylpropionaldehyde (87:13), while 2c was somewhat effective for only the latter alkyl aldehyde (83:17). Compounds 2d and 2e exhibited slightly lower selectivities compared with 2a.

Full text of DOI:10.1002/hc.20054

Heteroatom Chemistry
Volume 15, Number 7, 2004
Synthesis of β-Monosubstituted
α,β-Unsaturated Amides with Z-Selectivity
Using Diphenylphosphonoacetamides
Satoshi Kojima,1,2 Tsugihiko Hidaka,1 and Yuko Ohba1
1Department of Chemistry, Graduate School of Science, Hiroshima University, Higashi-Hiroshima
739-8526, Japan
2Center of Quantum Life Sciences, Hiroshima University, Higashi-Hiroshima 739-8526, Japan
Received 6 August 2004
unsaturated carbonyl compounds has made this
ABSTRACT: The utility of diphenylphosphonoac-
class of compounds attractive building blocks, i.e.,
etamides [(PhO)2P(O)CH2CONRRꢀ] as Horner–
both the carbonyl and the alkene moieties can
Wadsworth–Emmons reagents was examined with
undergo further modification. The stereochemical
five different patterns of substitution upon the amide
outcome of reactions utilizing this class of com-
nitrogen atom (2a: R, Rꢀ = CH2Ph; 2b: R = CH2Ph,
pounds is frequently dependent upon the geometry
Rꢀ = H; 2c: R = Me, Rꢀ = OMe; 2d: R, Rꢀ = Ph; 2e: R,
of the olefin moiety, and thus it is worthwhile to pre-
Rꢀ = (CH2)4). The reaction of 2a was found to be Z-
pare these compounds with high E or Z-selectivity.
selective for aromatic aldehydes with selectivities up to
The preparation of disubstituted E-alkenes of this
95:5. Reagent 2b led to reasonable selectivity for both
type with high selectivity is rather facile. However,
benzaldehyde (85:15) and 3-phenylpropionaldehyde
for the thermodynamically less stable Z-form, only
(87:13), while 2c was somewhat effective for only the
a limited number of methods involving C C bond
latter alkyl aldehyde (83:17). Compounds 2d and 2e
formation with high selectivities have been reported,
exhibited slightly lower selectivities compared with
for ꢀ,ꢁ-unsaturated esters [2–4], carbonitriles [5–8],
ꢁ
C
2a.
2004 Wiley Periodicals, Inc. Heteroatom Chem
methyl ketones [9], and amides [7,10]. As for the
last subgroup of ꢀ,ꢁ-unsaturated compounds,
i.e., amides, preparation with high Z-selectivity
was achieved by the use of 10-P-5 phosphoranes
[7] and Peterson type reagents 1 [10]. However,
there are a few drawbacks with these reagents.
For the former, the preparation of the reagent
requires the use of rather expensive and unpleasant
hexafluoroacetone. For the latter series, applicable
bases in the olefination reaction were rather lim-
ited, and enolizable 2-phenylpropionaldehyde and
hindered 2,2-dimethylpropionaldehyde did not give
olefinic products. Furthermore, for the mono-N-
substituted amide 1c (see Scheme 1), the mere gene-
ration of the amide enolate of 1c led to decomposi-
tion of the reagent. In an attempt to overcome these
deficiencies, we have carried out an examination
15:515–523, 2004; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20054
INTRODUCTION
The Wittig reaction and its variants are extremely
versatile reagents for the regioselective introduction
of unsaturation with concomitant carbon–carbon
bond formation [1]. The applicability of ꢀ,ꢁ-
Correspondence to: Satoshi Kojima; e-mail: skojima@sci.
hiroshima-u.ac.jp.
Contract grant sponsor: The Ministry of Education, Science,
Sports, and Culture, Japan.
Contract grant numbers: 14540497 and 16550098.
2004 Wiley Periodicals, Inc.
c
ꢁ
515

516 Kojima, Hidaka, and Ohba
SCHEME 1
of diphenylphosphonoacetamides, prospectively
Z-selective Horner–Wadsworth–Emmons (HWE)
analogs of the highly successful phosphonoacetates
by Ando [3]. As a result, we have found that with
these easily prepared reagents, more common bases
are applicable and that the reaction proceeds even
with an N-monoalkyl reagent. Herein we present
a full account of results from the reaction of five
different amide reagents [11,12].
SCHEME 3
cation was found to affect the selectivity, with higher
selectivity achieved in the order of Li+ < Na+ < K+.
Especially for KHMDS, the selectivity was as high as
94:6. This is the same cation propensity observed for
the Peterson reagent 1 [10]. It was also found that
NaH and t-BuOK, which could not be used for 1,
could be used here.
The scope of the reagent was next examined
with several aromatic aldehydes (Table 1, entries
1–9). As a result, 4-substituted aromatic aldehydes
gave high selectivity with K+ as the countercation,
with selectivity in the order of 4-MeO (95:5) > H
(94:6) > 4-Cl (89:11) (Table 1, entries 4, 6, and 8).
RESULTS AND DISCUSSION
Examined were [(PhO)2P(O)CH2CONRRꢀ] with sev-
eral different patterns of substitution upon the
amide nitrogen (2a: R, Rꢀ = CH2Ph; 2b: R = CH2Ph,
Rꢀ = H; 2c: R = Me, Rꢀ = OMe; 2d: R = Rꢀ = Ph; 2e:
NRRꢀ = pyrrolidinyl). Compound 2a was selected
as a representative of N,N-disubstituted reagents
and for comparison with 1, 2b as that of N-
monosubstituted reagents, and 2c as that having
somewhat electronegative character and bearing
the potential for further transformation to ketones
[13,14]. Two other N,N-disubstituted compounds 2d
and 2e were also briefly examined. The reagents were
prepared by the reaction of diphenyl phosphite with
the corresponding chloroacetamides 3 in the pres-
ence of NaH in fair to good yield (58–90%), as shown
in Scheme 2.
TABLE 1 Reaction of 2a with RꢀꢀCHO in THF
Entry
R ꢀꢀ
Base
Product Z:E Yield (%)
The reaction of 2a with benzaldehyde (see
Scheme 3), an aromatic aldehyde, was first examined
with representative bases (Table 1, entries 1–4). All
the reactions were carried out in THF at −78◦C be-
sides those of n-BuLi, of which reaction temperature
was allowed to gradually warm to 0◦C. The counter-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
Ph
Ph
P h
4-ClC6H4
4-ClC6H4
n-BuLia
NaH
t-BuOK
KHMDS
n-BuLia
KHMDS
4a
4a
4a
4a
4b
4b
4c
4c
4d
4e
4e
4e
4f
73:27
88:12
92:8
95
71
65
96
96
100
100
93
100
77
39
80
96
66
50
92
83
44
94:6
75:25
89:11
56:44
95:5
79:21
67:33
60:40
50:50
29:71
17:83
50:50
35:65
47:53
41:59
4-MeOC6H4 n-BuLia
4-MeOC6H4 KHMDS
2-MeOC6H4 KHMDS
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH3)CH NaH
Ph(CH3)CH KHMDS
c-C6H11
c-C6H11
t-Bu
NaH
t-BuOK
KHMDS
4f
NaH
4g
4g
4h
4h
KHMDS
NaHa
t-Bu
KHMDSa
aReaction temperature was gradually raised to 0◦C.
SCHEME 2

Synthesis of ꢁ-Monosubstituted ꢀ,ꢁ-Unsaturated Amides with Z-Selectivity Using Diphenylphosphonoacetamides 517
TABLE 2 Reaction of 2b with RꢀꢀCHO in THF
The tendency for the electron rich aldehyde to give
higher Z-selectivity has also been observed with 1
[4-MeO (>97:3) = H (>97:3) > 4-Cl (88:12)]. A de-
crease in selectivity was observed for the sterically
more hindered 2-substituted aromatic aldehyde, 2-
anisaldehyde (Table 1, entry 9). Reactions using n-
BuLi showed an opposite trend as compared with
reactions with 1 [4-MeO (69:31) > H (54:46) > 4-Cl
(43:57)]. Here, the more electrophilic aromatic alde-
hyde gave rise to higher selectivity [4-Cl (75:25) > H
(73:27) > 4-MeO (56:44)] (Table 1, entries 1, 5, and 7).
This may be due to the higher reversibility of the ini-
tial adduct for the electron-rich aldehydes compared
with electron-poor aldehydes, although the differ-
ence in reversibility is probably very small. Thus, as
a whole, the Peterson reagent 1 gives higher selec-
tivity than 2a. However, considering the availabil-
ity of the reagent and range of usable bases in the
olefin-forming reaction, it can be considered that 2a
scores fairly with 1 for reactions involving aromatic
aldehydes.
Entry
R ꢀꢀ
Base
Product Z:E Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Ph
Ph
NaHb
5a
5a
5a
5a
5a
5c
5e
5e
5e
5e
5e
5f
85:15
68:32
78:22
81:19
76:24
69:31
84:16
87:13
86:14
80:20
74:26
88:12
74:26
75:25
73:27
84:16
60:40
55
84
91
77
93
75
82
44
77
52
52
78
62
73
50
63
37
NaHc
t-BuOKc
KHMDSb
KHMDSc
4-MeOC6H4 t-BuOKc
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
n-BuLia,b
NaHb
NaHc
KHMDSb
KHMDSc
Ph(CH3)CH NaHc
Ph(CH3)CH t-BuOKc
5f
c-C6H11
c-C6H11
t-Bu
NaHd
5g
5g
5h
5h
KHMDSb
NaHc
t-Bu
t-BuOKc
aReaction temperature was gradually raised to 0◦C.
b1 equiv of base was used.
c2 equiv of base was used.
d1.5 equiv of base was used.
For 3-phenylpropionaldehyde, a typical unbran-
ched aliphatic aldehyde, the selectivity was found to
be only modest, with a maximum of ca. 2:1 (Table 1,
entries 10–12). In this case, though the difference
was rather small, the use of Na+ as the counterca-
tion provide to be best. This unique phenomenon
concerning the countercation has previously been
pointed out for corresponding ester-based reagents
by Ando, although the reason for this behavior
is not yet clear [3].As for ꢀ-branched aldehydes
(Table 1, entries 13–18), however, the Z-selectivity
was even lower, resulting in the preference for
the opposite E-olefin in some cases. This is in
contrast with corresponding phosphonoacetates in
general, where branched and thus hindered alde-
hydes usually give higher Z-selectivity than un-
branched substrates [1–3]. A similar decrease in
Z-selectivity with size was also observed with the
Peterson reagent 1. This could be associated with the
fact that the reaction becomes somewhat sluggish
compared with corresponding ester-based reagents.
Although not marked, reactions using NaH were
again more Z-selective. Nonetheless, the fact that 2-
phenylpropionaldehyde reacted (although with low
selectivity) at all as opposed to the reaction of 1 im-
plies that Peterson-type reagents such as 1 are quite
sensitive to the acidity of the substrate aldehyde.
The reaction of 2b with benzaldehyde in the pres-
ence of either 1 or 2 equiv of base was found to pro-
ceed with selectivities up to 85:15 (Table 2, entries
1–5). The use of 2 equiv in some cases was to assure
full conversion in the presence of product bearing
a somewhat acidic amide group. The reaction of 3-
phenylpropionaldehyde also proceeded with a rela-
tively high selectivity of 87:13 using NaH (Table 2,
entries 8 and 9). The use of Li+ as counter cation
is usually unfavorable from the point of selectivities
in HWE reactions. However, as it turns out, in this
case with the aliphatic substrate, the extent of decline
was minimal and selectivity was actually a bit better
than K+ (Table 2, entries 7, 8, and 10). In contrast
to 2a, which bears two alkyl substituents upon the
nitrogen atom, reactions with branched alkyl alde-
hydes were Z-selective, with selectivities as high as
88:12 for 2-phenylpropionaldehyde (Table 2, entries
12–17). A general trend was that the use of 2 equiv
of base compared to 1 equiv gave higher yield but
somewhat lower selectivity, and NaH turned out to
be more suitable than potassium bases for both aro-
matic and aliphatic aldehydes. The decrease in se-
lectivity upon using larger amounts of base could be
due to a higher degree of base (nucleophile) induced
isomerization of the product olefins.
The selectivity of the reaction of Weinreb type
HWE reagent 2c with benzaldehyde was found to
be rather disappointing (ca. 2:1) with similar ratios
regardless of which base was used (Table 3, entries
1–4). However, the reaction of 3-phenylpropionalde-
hyde proceeded with a reasonable selectivity of 83:17
using NaH (Table 3, entry 6). Here again for the
aliphatic aldehyde, Na+ was the optimum counter
cation. For the branched cyclohexanecarboxalde-
hyde there was again a drop in selectivity (Table 3,
entry 9). The bulky pivalaldehyde required higher
temperature for reaction to proceed at all, although

518 Kojima, Hidaka, and Ohba
TABLE 3 Reaction of 2c with RꢀꢀCHO in THF
TABLE 5 Reaction of 2e with RꢀꢀCHO in THF
Entry
R ꢀꢀ
Base
Product
Z:E
Yield (%)
Entry
R ꢀꢀ
Base
Product
Z:E
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
n-BuLia
NaH
t-BuOK
KHMDS
6a
6a
6a
6a
6e
6e
6e
6e
6g
6h
67:33
71:29
69:31
72:28
75:25
83:17
65:35
67:33
64:36
82:18
49
79
85
67
90
83
85
92
78
45
1
2
3
4
Ph
Ph
Ph
NaH
t-BuOK
KHMDS
8a
8a
8a
8e
89:11
85:15
85:15
56:44
45
44
46
9
Ph
Ph
Ph
Ph(CH2)2 t-BuOK
Ph(CH2)2 n-BuLia
Ph(CH2)2 NaH
Ph(CH2)2 t-BuOK
Ph(CH2)2 KHMDS
c-C6H11
t-Bu
in Scheme 4, with the one on the left being favored
in the case of phosphonoacetates (Scheme 4). Since
the amide group is generally bulkier than the es-
ter group, contribution of the right-hand side model
should become relatively larger as compared with
ester reagents. Thus, the lower selectivity observed
as a whole for reactions involving amide reagents
compared with phosphonoacetate counterparts is to
some extent inevitable. As for the higher selectivity
achieved with Na+ in comparison with K+, this may
be because Na+ is smaller in size and thus gives rise
to a more compact transition state.
In summary, we have found that the HWE
reaction of N,N-dibenzyl(diphenylphosphono)-
acetamides with aromatic aldehydes gives rise to
ꢀ,ꢁ-unsaturated amides with high Z-selectivities.
The NH amide compound was also found to be Z-
selective, while the Weinreb amide-type compound
was selective only for alkyl aldehydes. Transforma-
tional applications of the products are currently
under investigation.
NaH
10
NaHb
aReaction temperature was gradually raised to 0◦C.
bReaction temperature was 0◦C.
selectivity was maintained over 4:1 (Table 3,
entry 10).
The reaction of 2d with benzaldehyde gave the
corresponding ꢀ,ꢁ-unsaturated amide in fairly good
yields (Table 4, entry 1–3). In contrast with simi-
larly N,N-disubstituted 2a, NaH was found to give
the highest selectivity even with this aromatic alde-
hyde. Or, another way to put it is that a significant
drop in selectivity was observed for reactions involv-
ing K+. The same trend in selectivity (decrease with
K+ and practically no change with Na+), although not
as distinct, was also observed with 2e (Table 5, en-
tries 1–3). In the case of 2e, the reactions were some-
what messy, thus leading to lower reaction yields.
With both compounds (2d and 2e), the reaction with
3-phenylpropionaldehyde gave disappointing results
as anticipated from the results of 2a.
EXPERIMENTAL
Recent sophisticated theoretical calculations on
phosphonoacetates support the widely accepted as-
sumption that at the point of the initial C C for-
mation, the relative conformations of the reacting
aldehydes and the phosphonoester enolates have the
aldehyde carbonyl oxygen, the P O oxygen, and
the enolate oxide oxygen aligned in the same di-
rection owing to electrostatic and/or chelation ef-
fects involving the countercation metal [15]. Thus,
the primary factor governing selectivity becomes the
steric preference between the two models depicted
Melting points were measured on a Yanaco mi-
cromelting point apparatus and are uncorrected. 1H
and 13C NMR spectra were measured on either a
JEOL JNM-LA500 or JEOL GSX-270 spectrometer
1
with CDCl3 as solvent. H NMR chemical shifts are
given in relative ppm from either internal TMS (δ =
0.0) or residual CHCl3 (δ = 7.26). 13C NMR chem-
ical shifts are given in relative ppm from internal
CDCl3 (δ = 77.0). High-resolution mass spectra were
measured on a JEOL JMS-SX102A spectrometer un-
der electron ionization (70 eV) or FAB(+) condi-
tions. Elemental analyses (CHN) were carried out
on a Perkin–Elmer 2400CHN elemental analyzer. All
reactions were carried under N2. THF was freshly
distilled from Na-benzophenone prior to use. Liq-
uid aldehydes and other reagents were distilled prior
to use. Silica gel column chromatography was car-
ried out using Merck 7734 (63–200 mesh) or 9385
(230–400 mesh). Preparative thin layer chromatog-
raphy was carried out with plates prepared with
Merck 7730. All chloroacetamides were prepared
TABLE 4 Reaction of 2d with RꢀꢀCHO in THF
Entry
R ꢀꢀ
Base
Product
Z:E
Yield (%)
1
2
3
4
5
Ph
Ph
Ph
NaH
t-BuOK
KHMDS
7a
7a
7a
7e
7e
87:13
74:26
77:23
61:39
56:44
98
73
76
81
95
Ph(CH2)2 NaH
Ph(CH2)2 t-BuOK

Synthesis of ꢁ-Monosubstituted ꢀ,ꢁ-Unsaturated Amides with Z-Selectivity Using Diphenylphosphonoacetamides 519
SCHEME 4
from the corresponding amine and chloroacetyl
chloride. Compounds 4a–e, g have been reported
[10].
Hz), 120.62 (d, JCP = 5 Hz), 44.0, 34.9 (d, JCP = 131
Hz). HRMS (EI): Calcd for C21H20NO4P 381.1130,
found 381.1132. Anal. Calcd for C21H20NO4P: C,
66.14%; H, 5.11%; N, 3.50%. Found: C, 66.25%; H,
5.11%; N, 3.50%.
N,N-Bis(phenylmethyl)-2-
(diphenylphosphono)acetamide (2a)
N-Methoxy-N-methyl-2-
To a suspension of prewashed sodium hydride (60%
in mineral oil, 579 mg, 14.5 mmol) in THF (5 mL)
was added diphenyl phosphite (2.75 mL, 14.3 mmol)
at 0◦C under N2. After stirring at 0◦C for 30 min,
2-chloro-N,N-bis(phenylmethyl)acetamide (1.93 g,
7.05 mmol) in THF (3 mL) was added to this clear
solution. The reaction mixture was allowed to warm
at room temperature and stirring was continued
overnight. The solution was quenched with satu-
rated NH4Cl, and the organic solvent was removed
under reduced pressure. The aqueous layer was ex-
tracted with CH2Cl2, and the combined organic layer
was washed with water followed by brine, dried
over MgSO4, and evaporated. The crude product
was chromatographed (hexane/EtOAc = 4/1) to af-
ford 2a in 87% yield (2.90 g) as a colorless solid.
Mp: 68–69◦C. 1H NMR (CDCl3): δ 7.43–7.06 (m, 20H),
4.69 (s, 2H), 4.65 (s, 2H), 3.42 (d, J = 22.5 Hz,
2H). 13C NMR (CDCl3): δ 164.52 (JCP = 6 Hz), 149.98
(JCP = 10 Hz), 136.50, 135.84, 129.69, 129.00, 128.59,
(diphenylphosphono)acetamide (2c)
According to the procedure for 2a, diphenyl phos-
phite (2.80 mL, 14.6 mmol), NaH (63% in mineral
oil, 565 mg, 14.8 mmol), and 2-chloro-N-methoxy-
N-methylacetamide (1.85 g, 13.4 mmol) were re-
acted. The crude product was chromatographed
(hexane/EtOAc = 4/1) to afford 2c in 61% (2.72 g)
1
as a pale yellow oil. H NMR (CDCl3): δ 7.36–7.14
(m, 10H), 3.74 (s, 3H), 3.48 (d, J = 21.9 Hz, 2H),
3.24 (s, 3H). 13C NMR (CDCl3): δ 164.85 (JCP = 6 Hz),
150.08 (JCP = 8 Hz), 129.68, 125.31, 120.70 (JCP = 4
Hz), 61.46, 32.19, 31.15 (JCP = 141 Hz). HRMS (EI):
Calcd for C16H18NO5P 335.0922, found 335.0909.
Anal. Calcd for C16H18NO5P: C, 57.31%; H, 5.41%;
N, 4.18%. Found: C, 57.40%; H, 5.44%; N, 3.88%.
N,N-Diphenyl-2-(diphenylphosphono)acetamide
(2d)
127.91, 127.73, 127.37, 126.22, 125.39, 120.75 (JCP
=
According to the procedure for 2a, diphenyl phos-
phite (2.70 mL, 14.2 mmol), NaH (60% in mineral
oil, 570 mg, 14.2 mmol), and N,N-diphenylchloro-
acetamide (1.70 mL, 6.94 mmol) were reacted. After
aqueous workup, the crude product was directly re-
crystallized from hexane-AcOEt to give 2d in 73%
4 Hz), 50.91, 48.90, 33.38 (JCP = 137 Hz). HRMS (EI):
Calcd for C28H26NO4P 471.1599, found 471.1621.
Anal. Calcd for C28H26NO4P: C, 71.33%; H, 5.56%;
N, 2.97%. Found: C, 71.28%; H, 5.73%; N, 3.00%.
(2.24 g) yield as a white solid. Mp: 134–135◦C. H
1
N-Phenylmethyl-2-
(diphenylphosphono)acetamide (2b)
NMR (CDCl3): δ 7.50–7.00 (m, 20H), 3.31 (d, J =
22 Hz, 2H). 13C NMR (CDCl3): δ 163.91, 150.09 (d,
JCP = 8 Hz), 129.97, 129.72, 129.02, 128.70, 126.45,
125.32, 120.79 (d, JCP = 4 Hz), 33.58 (d, JCP = 138
Hz). 31P NMR (CDCl3): δ 14.7. HRMS (EI): Calcd for
C26H22O4NP 443.1286, found, 443.1248. Anal. Calcd
for C26H22O4NP: C, 70.42%; H, 5.00%; N, 3.16%.
Found: C, 70.61%; H, 4.76%; N, 3.00%.
According to the procedure for 2a, diphenyl phos-
phite (3.00 mL, 15.7 mmol), NaH (60% in mineral oil,
628 mg, 15.7 mmol), and N-benzylchloroacetamide
(2.37 g, 13.0 mmol) were reacted. After aqueous
workup, the crude product was directly recrystal-
lized from hexane-AcOEt to give 2b in 90% (4.43 g)
yield as a white solid. Mp: 150–151◦C. 1H NMR
(CDCl3): δ 7.34–7.13 (m, 15H), 7.10–7.00 (bs, 1H),
4.43 (d, J = 5.8 Hz, 2H), 3.20 (d, J = 20.7 Hz,
2H). 13C NMR (CDCl3): δ 162.56, 149.80, 137.56,
129.91, 128.69, 127.67, 127.48, 125.73 (d, JCP = 2
1-[(Diphenylphosphono)acetyl]pyrrolidine (2e)
According to the procedure for 2a, diphenyl phos-
phite (5.70 mL, 29.9 mmol), NaH (60% in mineral oil,

520 Kojima, Hidaka, and Ohba
128.56, 128.54, 128.37, 127.59, 127.41, 127.25,
126.58, 126.50, 119.18, 115.44, 50.12, 48.84, 42.30,
20.62. HRMS (EI) (Z-isomer): Calcd for C25H25NO
355.1936, found 355.1950. (E-isomer): Calcd for
C25H25NO 355.1936, found 355.1953.
1.20 g, 30.0 mmol), and N-(chloroacetyl)pyrrolidine
(4.39 g, 29.7 mmol) were reacted. After aqueous
workup, the crude product was directly recrystal-
lized from hexane-AcOEt to give 2e in 58% (5.90
g) yield as a white solid. Mp: 89–90◦C. 1H NMR
(CDCl3): δ 7.50–7.10 (m, 10H), 3.73–3.39 (m, 4H),
3.30 (d, J = 20.4 Hz, 2H), and 2.20–1.80 (m, 4H).
13C NMR (CDCl3): δ 161.8, 150.1 (d, JCP = 8 Hz),
129.7, 125.3, 120.7 (d, JCP = 4 Hz), 47.6, 46.2, 34.5 (d,
JCP = 136 Hz), 26.0, 24.4. 31P NMR (CDCl3): δ 15.0.
HRMS (EI): Calcd for C18H20O4NP 345.1130, found
345.1144. Anal. Calcd for C18H20O4NP: C, 62.61%; H,
5.84%; N, 4.06%. Found: C, 62.54%; H, 6.04%; N,
4.06%.
4,4-Dimethyl-N,N-bis(phenylmethyl)-2-
pentenamide (4h)
1H NMR (CDCl3) (Z-isomer): δ 7.39–7.14 (m, 10H),
5.83 (d, J = 13.1 Hz, 1H), 5.68 (d, J = 13.1 Hz, 1H),
4.57 (s, 2H), 4.49 (s, 2H), 1.12 (s, 9H). (E-isomer): δ
7.39–7.14 (m, 10H), 7.05 (d, J = 15.2 Hz, 1H), 6.16
(d, J = 15.2 Hz, 1H), 4.65 (s, 2H), 4.51 (s, 2H), 1.03 (s,
9H). 13C NMR (CDCl3) (Z-isomer): δ 169.61, 147.15,
136.77, 136.28, 129.02, 128.85, 128.45, 127.62,
127.44, 127.00, 119.98, 50.64, 46.59, 34.51, 29.54.
(E-isomer): δ 167.86, 157.62, 137.42, 136.87, 128.83,
128.55, 128.40, 127.59, 127.35, 126.67, 115.35, 50.12,
48.71, 33.76, 28.83. HRMS (EI) (mixture of Z- and
E-isomers): Calcd for C21H25NO 307.1936, found
307.1921.
General Procedure for the Reaction of the
Phosphonoamides (Example Using 2d,
Benzaldehyde, and t-BuOK)
A solution of 2d (229 mg, 0.517 mmol) in THF
(5.0 mL) was added dropwise to a suspension of
t-BuOK (58.0 mg, 0.517 mmol) in THF (3.0 mL)
at −78◦C under N2, and the resulting mixture was
stirred at 0◦C for 0.5 h. Benzaldehyde (50.0 mg,
0.470 mmol) in THF (1.5 mL) was then added at
−78◦C, and the mixture was stirred at the same tem-
perature for 3 h. The solution was quenched with
saturated NH4Cl and extracted with ether. The com-
bined organic layer was washed with water followed
by brine, dried over Na2SO4, and evaporated. The
residue was purified by preparative TLC (silica gel,
hexane-AcOEt = 5:1) to give 7a in 73% (98.8 mg, mix-
ture of geometric isomers, Z/E = 74/26) combined
yield. In reactions using NaH, the phosphonate so-
lution was added to the suspension containing the
base as in the case of t-BuOK. In the case of KHMDS
and n-BuLi, the base was directly added to the solu-
tion of the phosphonate. Furthermore, in reactions
using n-BuLi, the reaction mixture was allowed to
gradually warm to 0◦C.
3-Phenyl-N-phenylmethyl-2-propenamide (5a)
1H NMR (CDCl3) (Z-isomer): δ 7.6–7.0 (m, 10H),
6.77 (d, J = 12.5 Hz, 1H), 6.01 (d, J = 12.5 Hz,1H),
5.8 (bs, 1H), 4.40 (d, J = 6.1 Hz, 2H). (E-isomer):
δ 7.68 (d, J = 15.5 Hz, 1H), 7.6–7.2 (m, 10H), 6.41
(d, J = 15.5 Hz, 1H) and 5.9 (bs, 1H) and 4.58
(d, J = 5.8 Hz, 2H). 13C NMR (CDCl3) (Z-isomer):
δ 166.84, 137.57, 136.44, 134.88, 128.86, 128.56,
128.49, 128.37, 127.91, 127.42, 124.65, 43.52. (E-
isomer): δ 165.99, 140.98, 138.17, 134.71, 129.50,
128.65, 128.53, 127.68, 127.66, 127.30, 120.66,
43.61. HRMS (EI) (Z-isomer): Calcd for C16H15NO
237.1154, found, 237.1141. (E-isomer): Calcd for
C16H15NO 237.1154, found, 237.1188.
3-(4-Methoxyphenyl)-N-phenylmethyl-2-
propenamide (5c)
4-Phenyl-N,N-bis(phenylmethyl)-2-pentenamide
1H NMR (CDCl3) (Z-isomer): δ 7.42 (dt, J = 8.5,
2.0 Hz, 2H), 7.3–7.2 (m, 5H), 6.78 (dt, J = 8.5,
2.0 Hz, 2H), 6.69 (d, J = 12.9 Hz, 1H), 5.88 (d,
J = 12.9 Hz, 1H), 5.8 (bs, 1H), 4.44 (d, J = 5.8
Hz, 1H), 3.79 (s, 3H). (E-isomer): δ 7.63 (d, J =
15.5 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.4–7.25
(m, 5H), 6.78 (d, J = 8.8 Hz, 2H), 6.28 (d, J =
15.5 Hz, 1H), 5.8 (bs, 1H), 4.58 (d, J = 5.2 Hz,
2H), 3.83 (s, 3H). 13C NMR (CDCl3) (Z-isomer):
δ 167.02, 159.86, 137.78, 136.57, 130.80, 128.59,
128.00, 127.42, 127.38, 122.38, 113.69, 55.21, 43.50.
(E-isomer): δ 160.90, 140.99, 138.33, 130.79, 129.33,
128.70, 127.89, 127.50, 118.02, 114.23, 113.73, 55.32,
(4f)
1H NMR (CDCl3) (Z-isomer): δ 7.36–7.17 (m, 13H),
7.11 (d, J = 7.0 Hz, 2H), 6.11–6.01 (m, 2H), 4.75
(d, J = 14.6 Hz, 1H), 4.52–4.33 (m, 4H), 1.43 (d,
J = 7.0 Hz, 3H). (E-isomer): δ 7.39–7.09 (m, 16H),
6.21 (dd, J = 14.9, 1.2 Hz, 1H), 4.72–4.55 (m, 2H),
4.46 (s, 2H), 3.58 (quint, J = 7.0 Hz, 1H), 1.38
(d, J = 7.0 Hz, 3H). 13C NMR (CDCl3) (Z-isomer):
δ 167.99, 152.03, 146.99, 144.95, 136.43, 128.86,
128.63, 128.55, 128.37, 127.62, 127.44, 127.07,
126.73, 126.27, 119.99, 50.37, 47.32, 38.72, 21.25.
(E-isomer): δ 167.54, 151.35, 143.65, 129.44, 128.85,

Synthesis of ꢁ-Monosubstituted ꢀ,ꢁ-Unsaturated Amides with Z-Selectivity Using Diphenylphosphonoacetamides 521
43.80. HRMS (EI) (Z-isomer): Calcd for C17H17NO2,
267.1259, found 267.1229. (E-isomer): Calcd for
C17H17NO2, 267.1259, found 267.1258.
120.10, 43.45, 37.16, 32.81, 26.09, 25.61. (E-isomer):
δ 166.30, 150.40, 138.42, 128.76, 127.98, 127.57,
120.93, 43.73, 40.33, 31.99, 26.04, 25.84. HRMS
(EI) (Z-isomer): Calcd for C16H21NO 243.1623, found
243.1632. (E-isomer): Calcd for C16H21NO 243.1623,
found 243.1629.
5-Phenyl-N-phenylmethyl-2-pentenamide (5e)
1H NMR (CDCl3) (Z-isomer): δ 7.4–7.1 (m, 10H), 6.01
(dt, J = 11.6, 7.6 Hz, 1H), 5.71 (d, J = 11.6 Hz, 1H),
5.5 (bs, 1H), 4.42 (d, J = 5.8 Hz, 2H), 2.98 (tdd,
J = 7.5, 7.5, 1.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H).
(E-isomer): δ 7.4–7.1 (m, 11H), 6.93 (dt, J = 15.5,
7.0 Hz, 1H), 5.79 (d, J = 15.5 Hz, 1H), 5.6 (bs, 1H),
4.51 (d, J = 5.8 Hz, 1H), 2.77 (t, J = 7.8 Hz, 2H),
2.51 (tdd, J = 7.8, 7., 1.0 Hz, 2H). 13C NMR (CDCl3)
(Z-isomer): δ 166.19, 143.87, 141.18, 138.24, 128.56,
128.50, 128.26, 127.76, 127.35, 125.88, 122.84, 43.18,
35.14, 30.23. (E-isomer): δ 165.67, 143.97, 140.93,
138.25, 128.66, 128.41, 128.32, 127.82, 127.48,
126.67, 123.90, 43.53, 34.53, 33.77. HRMS (EI)
(Z-isomer): Calcd for C18H19NO 265.1467, found
265.1456. (E-isomer): Calcd for C18H19NO 265.1467,
found 265.1454.
4,4-Dimethyl-N-phenylmethyl-2-pentenamide
(5h)
1H NMR (CDCl3) (Z-isomer): δ 7.4–7.2 (m, 5H), 5.75
(d, J = 12.9 Hz, 1H), 5.68 (d, J = 12.9 Hz, 1H), 5.8–
5.6 (bs, 1H) 4.52 (d, J = 5.7 Hz, 2H), 1.17 (s, 9H). (E-
isomer): δ 7.5–7.2 (m, 5H), 6.87 (d, J = 15.6 Hz, 1H),
5.8–5.6 (bs, 1H), 5.65 (d, 15.6, 1H), 4.49 (d, J = 5.7
Hz, 2H), 1.02 (s, 9H). 13C NMR (CDCl3) (Z-isomer):
δ 167.60, 149.52, 138.20, 128.68, 127.98, 127.53,
121.13, 43.60, 34.18, 29.83. (E-isomer): δ 166.29,
155.08, 138.32, 128.67, 127.92, 127.48, 118.58, 43.67,
33.44, 28.82. HRMS (EI) (Z-isomer): Calcd for
C14H19NO 217.1467, found 217.1467. (E-isomer):
Calcd for C14H19NO 217.1467, found 217.1482.
4-Phenyl-N-phenylmethyl-2-pentenamide (5f)
1H NMR (CDCl3): (Z-isomer) δ 7.3–7.0 (m, 10H), 6.09
(dd, J = 11.3, 10.4 Hz, 1H), 5.77 (bs, 1H), 5.65 (d,
J = 11.3 Hz, 1H), 4.97 (qd, J = 10.4, 6.7 Hz, 1H),
4.49 (d, J = 5.7 Hz, 2H), 1.40 (d, J = 6.7 Hz, 3H).
(E-isomer): δ 7.2–7.1 (m, 10H), 7.05 (dd, J = 15.2
Hz, 6.4, 1H), 5.69 (d, J = 15.2 Hz, 1H). 5.69 (bs,
1H), 4.49 (d, J = 5.8 Hz, 2H), 3.60 (qd, J = 7.0, 6.4
Hz, 2H), 1.42 (d, J = 7.0 Hz, 3H). 13C NMR (CDCl3)
(Z-isomer): δ 165.97, 149.66, 145.09, 138.15, 128.65,
128.51, 127.81, 127.45, 127.02, 126.22, 120.15, 43.33,
37.39, 21.23. (E-isomer): δ 165.75, 148.75, 143.61,
138.18, 128.64, 128.56, 127.87, 127.46, 127.35,
126.58, 122.29, 43.62, 41.81, 20.47. HRMS (EI)
(Z-isomer): Calcd for C18H19NO 265.1467, found
265.1439. (E-isomer): Calcd for C18H19NO 265.1467,
found 265.1458.
N-Methoxy-N-methyl-3-phenyl-2-propenamide
(6a)
1H NMR (CDCl3) (Z-isomer): δ 7.6–7.2 (m, 5H), 6.76
(d, J = 12.5 Hz, 1H), 6.28 (bs, 1H), 3.66 (s, 3H), 3.25
(s, 3H). (E-isomer): δ 7.74 (d, J = 15.8 Hz, 1H), 7.6–
7.2 (m, 5H), 7.04 (d, J = 15.8 Hz, 1H), 3.77 (s, 3H),
3.32 (s, 3H). 13C NMR (CDCl3) (Z-isomer): δ 168.02,
137.63, 135.12, 128.98, 128.49, 128.17, 120.51, 61.59,
32.13. (E-isomer): δ 166.86, 143.33, 135.07, 129.73,
128.69, 127.92, 115.72, 61.76, 32.42. HRMS (EI):
Calcd for C11H13NO2 191.0946, found 191.0938.
N-Methoxy-N-methyl-5-phenyl-2-pentenamide
(6e)
1H NMR (CDCl3) (Z-isomer): δ 7.4–7.1 (m, 5H), 6.24
(br d, J = 10.7 Hz, 1H), 6.12 (dt, J = 11.6, 7.3 Hz,
1H), 3.59 (s, 3H), 3.18 (s, 3H), 2.96 (q, J = 7.3 Hz,
2H), 2.77 (t, J = 7.3 Hz, 2H). (E-isomer): δ 7.3–7.1
(m, 5H), 7.01 (dt, J = 15.2, 7.0 Hz, 1H), 6.38 (d,
J = 15.2 Hz, 1H), 3.62 (s, 3H), 3.22 (s, 3H), 2.79
(t, J = 7.9 Hz, 2H), 2.60–2.52 (m, 2H). 13C NMR
(CDCl3) (Z-isomer): δ 167.23, 145.96, 141.32, 128.43,
128.18, 125.75, 118.69, 61.32, 35.16, 31.91, 30.36.
(E-isomer): δ 166.78, 146.46, 140.91, 128.32 (two
peaks overlap), 125.96, 119.26, 61.54, 34.48, 34.06,
32.26. HRMS (EI) (Z-isomer): Calcd for C13H17NO2
219.1259, found 219.1261. (E-isomer): Calcd for
C13H17NO2 219.1259, found 219.1249.
3-Cyclohexyl-N-phenylmethyl-2-propenamide
(5g)
1H NMR (CDCl3) (Z-isomer): δ 7.4–7.2 (m, 5H), 5.8
(bs, 1H), 5.82 (dd, J = 11.3, 10.1 Hz, 1H), 5.59 (d,
J = 11.3 Hz, 1H), 4.46 (d, J = 5.5 Hz, 2H), 3.5–3.3
(m, 1H), 1.8–1.6 (m, 5H), 1.4–1.3 (m, 2H), 1.3–1.0
(m, 3H). (E-isomer): δ 7.4–7.2 (m, 5H), 6.83 (dd,
J = 15.5, 6.7 Hz, 1H), 5.72 (dd, J = 15.5, 1.2 Hz, 1H),
5.7–5.6 (bs, 1H), 4.51 (d, J = 5.5 Hz, 2H), 2.2–2.0 (m,
1H), 1.8–1.7 (m, 4H), 1.7–1.6 (m, 1H), 1.4–1.2 (m,
2H), 1.2–1.1 (m, 3H). 13C NMR (CDCl3) (Z-isomer):
δ 166.39, 151.63, 138.50, 128.81, 127.95, 127.59,

522 Kojima, Hidaka, and Ohba
125.80, 122.84, 35.06, 30.27. (E-isomer): δ 165.92,
145.77, 142.71, 140.90, 129.08, 128.34, 128.33, 128–
126 (br), 125.94, 123.13, 34.40, 33.98. HRMS (EI)
(Z-isomer): Calcd for C23H21NO 327.1623, found,
327.1609. (E-isomer): Calcd for C23H21NO 327.1623,
found, 327.1640.
3-Cyclohexyl-N-methoxy-N-methyl-2-
propenamide (6g)
1H NMR (CDCl3) (Z-isomer): δ 6.13 (d, J = 11.6 Hz,
1H), 5.92 (dd, J = 11.6, 9.8 Hz, 1H), 3.68 (s, 3H),
3.22 (s, 3H), 3.3–3.1 (m, 1H), 1.8–1.5 (m, 5H), 1.4–
1.2 (m, 2H), 1.2–1.0 (m, 3H). (E-isomer): δ 6.93 (dd,
J = 15.5, 7.0 Hz, 1H), 6.34 (d, J = 15.5 Hz, 1H), 3.70
(s, 3H), 3.24 (s, 3H), 2.2–2.0 (m, 1H), 1.9–1.6 (m, 5H),
1.3–1.2 (m, 2H), 1.2–1.1 (m, 3H). 13C NMR (CDCl3)
(Z-isomer): δ 167.42, 152.72. 116.02, 61.40, 37.31,
32.56, 32.02, 25.97, 25.46. (E-isomer): δ 167.58,
153.08, 116.34, 61.73, 40.87, 32.57, 32.13, 26.12,
25.91. HRMS (EI) (Z-isomer): Calcd for C11H19NO2
197.1416, found 197.1411. (FAB+) (E-isomer): Calcd
for C11H19NO2 198.1494, found 198.1495.
1-(1-Oxo-3-phenyl-2-propenyl)pyrrolidine (8a)
[16]
1H NMR (CDCl3) (Z-isomer): δ 7.5–7.1 (m, 5H), 6.63
(d, J = 12.8 Hz, 1H), 6.06 (d, J = 12.8 Hz, 1H), 3.51
(t, J = 6.7 Hz, 2H), 3.18 (t, J = 6.7 Hz, 2H), 1.9–1.6
(m, 4H). (E-isomer): δ 7.77 (d, J = 15.5, 1H), 7.5–
7.1 (m, 5H), 6.74 (d, J = 15.5, 1H), 3.7–3.5 (m, 4H),
2.1–1.8 (m, 4H). HRMS (EI): Calcd for C13H15NO
201.1154, found 201.1162.
N-Methoxy-N,4,4-trimethyl-2-pentenamide (6h)
1H NMR (CDCl3) (Z-isomer): δ 5.87 (bs, 1H), 5.78
(d, J = 12.5 Hz, 1H), 3.67 (s, 3H), 3.22 (s, 3H),
1.15 (s, 9H). (E-isomer): δ 7.00 (d, J = 15.5 Hz,
1H), 6.30 (d, J = 15.5 Hz, 1H), 3.71 (s, 3H), 3.25
(s, 3H), 1.10 (s, 9H). 13C NMR (CDCl3) (Z-isomer):
δ 169.29, 149.35, 118.50, 61.09, 34.14, 32.16, 29.57.
(E-isomer): δ 167.50, 157.73, 113.75, 61.53, 33.72,
32.42, 28.82. HRMS (EI) (Z-isomer): Calcd for
C7H11O [(M-NMeOMe)+] 111.0810, found 111.0814.
(E-isomer): Calcd for C9H17NO2 171.1259, found
171.1264.
1-(1-Oxo-5-phenyl-2-pentenyl)pyrrolidine (8e)
1H NMR (CDCl3) (Z-isomer): δ 7.4–7.0 (m, 5H),
6.1–5.9 (m, 2H), 3.48 (t, J = 6.4 Hz, 2H), 3.30 (t,
J = 6.4 Hz, 2H), 3.0–2.8 (m, 2H), 2.76 (t, J = 6.8
Hz, 2H), 2.0–1.8 (m, 4H). (E-isomer) [17]: δ 7.4–
6.8 (m, 5H), 6.96 (dt, J = 15.1, 6.8 Hz, 1H), 6.09
(d, J = 15.1 Hz,1H), 3.52 (t, J = 6.8 Hz, 2H), 3.45
(t, J = 6.6 Hz, 2H), 2.78 (t, J = 7.3 Hz, 2H), 2.51
(td, J = 7.3, 6.8 Hz, 2H), 2.0–1.8 (m, 4H). 13C NMR
(CDCl3) (Z-isomer): δ 165.70, 142.31, 141.44, 128.53,
128.14, 125.73, 122.40, 46.72, 45.21, 35.19, 30.38,
26.04, 24.27. (E-isomer): δ 164.71, 144.22, 141.09,
128.34, 128.32, 125.95, 122.33, 46.40, 45.70, 34.68,
34.04, 26.04, 24.25. HRMS (EI) (Z-isomer): Calcd
for C15H19NO 229.1467, found 229.1490. (E-isomer):
Calcd for C15H19NO 229.1467, found 229.1493.
N,N,3-Triphenyl-2-propenamide (7a)
1H NMR (CDCl3) (Z-isomer): δ 7.6–7.5 (m, 2H), 7.4–
7.1 (m, 11H), 7.1–6.9 (m, 2H), 7.51 (d, J = 12.5 Hz,
1H), 5.95 (d, J = 12.5, 1H). (E-isomer): δ 7.70 (d,
J = 15.5 Hz, 1H), 7.4–7.1 (m, 15H), and 6.48 (d, J =
15.5 Hz, 1H). 13C NMR (CDCl3) (Z-isomer): δ 167.44,
142.59, 142.40, 136.50, 135.38, 129.68, 129.23,
128.96, 128.70, 128.56, 128.19, 127.94, 127–126 (br),
126.29, 124.21, 119.77. (E-isomer): δ 166.18, 142.78,
142.62, 135.09, 129.70. 129.24, 128.72, 127.96, 127–
126 (br), 119.78. HRMS (EI) (Z-isomer): Calcd for
C21H17NO 229.1310, found 229.1358. (E-isomer):
Calcd for C21H17NO 229.1310, found 229.1328.
ACKNOWLEDGMENT
NMR and HRMS were measured at the Instrument
Center for Chemical Analysis of Hiroshima
University.
REFERENCES
[1] For leading preferences see: (a) Wadsworth, W. S.,
Jr. Org React 1977, 25, 73–253; (b) Cadogan, J. I.
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1H NMR (CDCl3) (Z-isomer): δ 7.4–7.0 (m, 15H), 5.97
(dt, J = 11.6, 7.5 Hz, 1H), 5.71 (d, J = 11.6 Hz, 1H),
3.02 (tdd, J = 7.3, 7.3, 1.5 Hz, 2H), 2.78 (t, J = 7.5,
2H). (E-isomer): δ 7.4–7.1 (m, 15H), 7.04 (td, J = 6.8,
14.9 Hz, 2H), 5.82 (d, J = 14.9 Hz, 1H), 2.70 (t,
J = 7.3 Hz, 2H), 2.44 (td, J = 6.7, 7.0 Hz, 2H). 13C
NMR (CDCl3) (Z-isomer): δ 166.41, 145.23, 142.57,
141.35, 129.21, 129.01, 128.51, 128.19, 128–126 (br)

Synthesis of ꢁ-Monosubstituted ꢀ,ꢁ-Unsaturated Amides with Z-Selectivity Using Diphenylphosphonoacetamides 523
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