Preparations of Z-α,β-unsaturated amides by using Horner-Wadsworth-Emmons reagents (diphenylphosphono)acetamides

Article abstract of DOI:10.1055/s-2001-16072

New Horner-Wadsworth-Emmons reagents (diphenylphosphono)acetamides 2 react with a variety of aldehydes to give the corresponding Z-α,β-unsaturated amides stereoselectively (up to Z:E = 98: 2).

Full text of DOI:10.1055/s-2001-16072

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LETTER
Preparations of Z- , -Unsaturated Amides by Using Horner-Wadsworth-
Emmons Reagents, (Diphenylphosphono)acetamides
Kaori Ando*
College of Education, University of the Ryukyus, Nishihara-cho, Okinawa 903-0213, Japan
Fax +81-98-895-8356; E-mail: ando@edu.u-ryukyu.ac.jp
Received 22 May 2001
Abstract: New Horner-Wadsworth-Emmons reagents, (diphe-
nylphosphono)acetamides 2 react with a variety of aldehydes to
give the corresponding Z- , -unsaturated amides stereoselectively
(up to Z:E = 98: 2).
Key words: amides, alkenes, aldehydes, Horner-Wadsworth-Em-
mons reaction, Z-selective
, -Unsaturated amides are useful synthetic intermediates
in organic synthesis. They can not only be transformed to
a variety of compounds, but also have been used as
Michael acceptors or Diels-Alder dienophiles. Stereo-de-
fined synthesis of carbon-carbon double bonds with high
selectivity is critically important for the stereoselective re-
actions. The Wittig reaction,1 the Horner-Wadsworth-
Emmons (HWE) reaction,2-4 and the Peterson olefination5
have been used for the synthesis of , -unsaturated
Scheme
amides. While it is rather easy to obtain thermodynami-
cally favored E isomers, only one direct preparation of
Z-isomers has been reported by Peterson olefination.5b
Since more general and practical methods are desirable,
Table 1 The HWE reaction of 2a with aldehydes in THF
we studied Z-selective synthesis of , -unsaturated
amides as an extension of our HWE reaction using (dia-
rylphosphono)acetate reagents 1.6 We prepared (diphe-
nylphosphono)acetamide reagents 2 and performed the
HWE reaction with representative aldehydes under vari-
ous conditions.7 Herein we report our results.
The N,N-dimethyl(diphenylphosphono)acetamide 2a was
prepared by acylation of diphenyl methylphosphonate as
shown in Scheme in 55% yields (not optimized). The re-
sults of the HWE reaction of 2a with aldehydes were sum-
marized in Table 1. When Triton B (40% benzyltri-
methylammonium hydroxide in MeOH) was used as base
for the reaction with benzaldehyde, only a low yield of the
olefin products was obtained along with a large quantity
of phenol (entry 1). Treating 2a with tBuOK at 0 °C also
caused partial decomposition of 2a (entry 2). These re-
sults show that the anion from 2a is labile and easily de-
composes. The reaction successfully gave 3a in 95%
Z-selectivity and in 90% yield by treating 2a with tBuOK
at 78 °C before the addition of PhCHO (entry 3). Fur-
thermore, 98% Z-selectivity was obtained in the presence
of 18-crown-6 (1 equiv) (entry 5). In the same condition,
2E-hexenal gave Z-olefin in 88% selectivity (entry 8).
Disappointingly, the reaction of 2a with aliphatic alde-
hydes showed only moderate Z-selectivities (entries 9-
14). The best Z-selectivities were obtained when
The reaction was carried out at 78 °C (entries 1-5) and from 78
to 0 °C (entries 6-14). a: The number in parentheses is the recovered
yield of 2a, b: 2a was treated with base at 0 °C, c: HMPA(2 eq), d:
18-crown-6 (1 eq), e: 18-crown-6 (2 eq).
Synlett 2001, No. 8, 1272–1274 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Preparations of Z- , -Unsaturated Amides
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NaHMDS8 was used as base (77% and 75% Z, entries 10 NaH gave a highest selectivity (79%). In the presence of
and 13).
MgBr2 (0.1 equiv.), the Z-selectivity slightly increased to
81%. Increasing the quantity of MgBr2 (1 equiv.) only
caused a diminished yield (63%, 81% Z). The reaction
with n-octanal using NaH gave the olefin products with
75% Z-selectivity. Although these selectivities are just
moderate, the Z-olefins can be easily obtained in pure
form by column chromatography or recrystallization.
In order to see the substituent effect of 2, N-phenyl(diphe-
nylphosphono)acetamide 2b and N-methoxy-N-meth-
yl(diphenylphosphono)acetamide 2c were prepared by the
reaction of diphenyl phosphite, bromoacetyl bromide, and
the corresponding amines in one pot. The results of the re-
action of 2b are given in Table 2. When 2b was treated
with tBuOK at 78 °C and the reaction with benzalde-
hyde was performed at 78 °C, 90% Z-selectivity was ob-
tained in 98% yield (entry 1). At 95 °C, slightly better
selectivity of 92% was attained (entry 2). In the presence
of 18-crown-6 (1 equiv), the selectivity increased to 94%
(entry 3). The reaction with 2E-hexenal was also found to
be Z-selective, although the selectivity was not quite high
(85%, entry 4). The HWE reactions with n-octanal, 2-eth-
ylhexanal, and pivalaldehyde were carried out using
NaHMDS8 (entries 5-7). The resulting olefin products
contain 91-94% Z-isomers in almost quantitative yields.
Thus, the reagent 2b gives a wide range of Z- , -unsatur-
ated amides in high selectivities.9
Table 3 The HWE reaction of 2c with aldehydes in THF
Table 2 The HWE reaction of 2b with aldehydes in THF
The reaction was carried out at 78 °C(entries 1-3) and from 78 to
0 °C (entries 4-8). a: The number in parentheses is the recovered yield
of 2c, b: MgBr2 (0.1 eq)
All new compounds described here were characterized by
1H NMR, mass, and high-resolution mass spectrum. The
Z:E ratios of 3 were determined by integrating the vinyl
proton signals in the 500 MHz 1H NMR spectra. These as-
signments were confirmed by NOE experiments.
In summary, the HWE reaction described above provides
a direct route to a wide range of Z- , -unsaturated amides.
Further efforts to expand the scope and utility of the re-
agents 2 are in progress in this laboratory.
The reaction was carried out at 78 °C (entries 1-3) and from 78 to
10 °C (entries 4-7). a: The number in parentheses is the recovered
yield of 2b, b: at -95 °C, c: 18-crown-6 (1 eq)
Acknowledgement
Further, we studied the HWE reaction of the reagent 2c.
Since the initial report from Weinreb group,10 the N-meth-
oxy-N-methylamides (Winreb amides) have served as
valuable intermediates in organic synthesis. The Wittig or
HWE reagents containing this amide moiety were report-
ed.1,3 These reagents are useful for converting aldehydes
into , -unsaturated N-methoxy-N-methylamides with
high E-selectivity. Hoping 2c gives Z-isomers selectively,
the HWE reaction of 2c with benzaldehyde, 2-ethylhexa-
nal, and n-octanal was performed (Table 3). Since the an-
ion derived from 2c is stable at 0 °C, 2c was treated with
tBuOK at 0 °C and the reaction with benzaldehyde was
carried out at 78 °C. Disappointingly, 66% Z-selectivity
was obtained in 94% yield (entry 1). The use of LDA in-
stead of tBuOK slightly improved the Z-selectivity (77%).
The HWE reaction of 2c with 2-ethylhexanal was also
performed using NaH, tBuOK, and LDA (entries 4-6).
K. A. is grateful to Grant-in-Aid for Scientific Research on Priority
Areas (A) (403) for financial support of this work.
References and Notes
(1) Evans., D. A.; Kaldor S. W.; Jones, T. K.; Clardy, J.; Stout, T.
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(2) (a) Shahak, I.; Almog, J.; Bergmann, E. D. Israel J. Chem.
1969, 7, 585-588; (b) Tay, M. K.; About-Jaudet, E.;
Collignon, N.; Savignac, P. Tetrahedron 1989, 45, 4415-
4430.
(3) (a) Nuzillard, J.-M.; Boumendjel, A.; Massiot, G.
Tetrahedron Lett. 1989, 30, 3779-3780; (b) Netz, D. F.;
Seidel, J. L. Tetrahedron Lett. 1992, 33, 1957-1958.
(4) For chiral amide reagents: Abiko, A.; Masamune, S.
Tetrahedron Lett. 1996, 37, 1077-1080.
(5) (a) Woodbury, R. P.; Rathke, M. W. J. Org. Chem. 1978, 43,
1947-1949; (b) Kojima, S.; Inai, H.; Hidaka, T.; Ohkata, K.
Chem. Commun. 2000, 1795-1796.
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K. Ando
LETTER
(6) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105-4108;
(b) Ando, K. J. Org. Chem. 1997, 62, 1934-1939; (c) Ando, K.
J. Org. Chem. 1998, 63, 8411-8416; (d) Ando, K. J. Org.
Chem. 1999, 64, 8406-8408; (e) Ando, K.; Oishi, T.; Hirama,
M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745-4749.
(7) A private communication: A similar study is in progress in Dr.
Satoshi Kojima’s group.
(8) When 2a and 2b were treated with NaH at 0 °C and the
reaction was performed from 78 °C to 0 °C, only low yields
of the olefin products were obtained along with phenol.
Therefore, base was added at 78 °C. Since NaHMDS can
deprotonate 2 at a lower temperature, NaHMDS gave slightly
better results than NaH in some cases.
TMS2NH (0.45 mmol) in THF (1 mL) was treated with NaH
(0.45 mmol) for 30 min, the resulting suspension was added to
a solution of 2b (0.3 mmol) in THF (5 mL) at 78 °C. 20 min
later, pivalaldehyde (0.33 mmol) was added and the resulting
mixture was gradually warmed to 10 °C over 2.5 h. After the
usual workup and chromatographic purification, N-phenyl-
4,4-dimethyl-2-pentenoamide was obtained in 95% yield
(Z:E = 94:6).
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
Article Identifier:
(9) The typical procedure of the HWE reaction of 2b with
pivalaldehyde (entry 7 in Table 2): After a solution of
1437-2096,E;2001,0,08,1272,1274,ftx,en;Y11001ST.pdf
Synlett 2001, No. 8, 1272–1274 ISSN 0936-5214 © Thieme Stuttgart · New York