Highly Z-selective synthesis of α,β-unsaturated amides with the Peterson reaction between α-silylamides and aldehydes

Article abstract of DOI:10.1039/b004416o

The Peterson reaction of triphenylsilylacetamide Ph₃SiCH₂CONBn₂ with aromatic aldehydes and certain aliphatic aldehydes proceeded to give the corresponding α,β-unsaturated amide with high Z selectivity (up to Z:E = >97:<3).

Full text of DOI:10.1039/b004416o

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Highly Z-selective synthesis of a,b-unsaturated amides with the Peterson
reaction between a-silylamides and aldehydes†
Satoshi Kojima,* Hiroki Inai, Tsugihiko Hidaka and Katsuo Ohkata
Department of Chemistry, Graduate School of Science, Hiroshima University, Kagamiyama, Higashi-Hiroshima
739-8526, Japan. E-mail: skojima@sci.hiroshima-u.ac.jp
Received (in Cambridge, UK) 2nd June 2000, Accepted 3rd August 2000
First published as an Advance Article on the web 4th September 2000
Table 1 Peterson reaction of Ph3SiCH2CONBn2 (1a) with various
The Peterson reaction of triphenylsilylacetamide Ph3Si-
aldehydesa
CH2CONBn2 with aromatic aldehydes and certain aliphatic
aldehydes proceeded to give the corresponding a,b-un-
Entry
R
Z+Eb
Yield (%)c
saturated amide with high Z selectivity (up to Z+E =
> 97+ < 3).
1
2
3
4
5
6
7
8
9
Ph
> 97+ < 3
> 97+ < 3
81+19
88+12
91+9
88
87
72
91
92
47
99
77
82
p-MeOC6H4
o-MeOC6H4
p-ClC6H4
2-Furyl
2-Pyridyl
(E)-PhCH = CH
PhCH2CH2
c-Hexyl
Geometry-defined olefins serve as good building blocks in
organic synthesis. Of particular utility are olefins bearing
electron-withdrawing groups, such as the ester group, since not
only are these groups viable of further functionalization, but
they also activate the olefin moiety for reactions such as
Michael addition and pericyclic reactions. While it is rather
facile to obtain disubstituted E-olefins bearing an electron-
withdrawing group with high selectivity from aldehydes, only a
few methods are available for moderate to highly selective
preparation of the thermodynamically less stable Z-olefins, and
so far they have been limited to the ester,1–5 the cyano,6,7 and
the recently reported methyl ketone group.8 For disubstituted Z-
olefins bearing an amide group, it would be desirable to have a
direct method of preparation from an aldehyde, especially for
multifunctional carbonyl compounds. Peterson olefination with
reagents bearing a trimethylsilyl (TMS) group has been widely
utilized as a useful complementary reaction to that of Wittig
type.9 However, for disubstituted olefins with electron-with-
drawing groups, the selectivity observed for this reaction is
generally low (even for E-olefins) compared with its phospho-
rus counterpart. Previous amide formation with Peterson
reagents bearing the TMS group is no exception.10 Thus, based
upon the notion that a more bulky and more electronegative silyl
group would shift the selectivity towards the Z-olefin, we
examined a reagent bearing the triphenylsilyl group, which had
previously proved to be effective in combination with the cyano
group.6 In accordance with expectations, we have realized the
first highly Z-selective preparation of a,b-unsaturated amides.
Herein we describe our results.
The Peterson reagents 1a,b examined for the reactions were
prepared by treating the lithium enolate of N,N-dibenzylaceta-
mide with Ph3SiCl or Me3SiCl, regioselectively giving the C-
silylated products in moderate yield.10,11 The results of using
the triphenylsilyl reagent 1a are given in Table 1. Since a
countercation effect is usually observed for the analogous
Horner–Wadsworth–Emmons (HWE) reaction, the examina-
tion of various metal-containing bases was first carried out in
the reaction with benzaldehyde. The effect of the countercation
proved to be quite significant as the ratio of Z-amide increased
from 54+46 with n-BuLi to 80+20 with NaHMDS, and an
exclusive > 97+ < 3 with KHMDS‡ (entry 1). In the case of n-
BuLi, the reaction temperature was gradually raised from 278
to 0 °C in order to effect reaction. More common bases such as
NaH and t-BuOK were found to be unsuitable. The reaction of
1a and 3-phenylpropionaldehyde with KHMDS as base (entry
8) was also found to be Z-selective, although not quite as high
as with benzaldehyde. In seeking a possible improvement in
59+41
81+19
91+9
83+17
a All reactions were carried out in THF at 278 °C with KHMDS as base.
b Determined by 500 MHz 1H NMR measurement of crude mixture.
c Combined isolated yield of E and Z olefins.
selectivity, an examination of solvents was carried out.
However, neither a decrease (ether, 74+26, 15%) or increase
(THF–HMPA mixture, 71+29, 64%) in polarity proved fruitful.
Lowering of the reaction temperature to 295 °C led to a slight
increase in selectivity to 94:6 but with a lower yield of 58%.
Under the standard conditions of using THF and KHMDS at
278 °C, other aldehydes were examined.§ For 4-substituted
benzaldehyde derivatives, a drop-off in selectivity was observed
with the electronegative Cl substituent (entry 4), but remained
high with the electron-donating MeO group (entry 2). Although
sterically hindered 2-substituted aromatic aldehydes are usually
more Z-selective than their 4-substituted counterparts in HWE
reactions, with the MeO group the Peterson reaction here gave
lower selectivity (entry 3). With heterocyclic aldehydes, the
highly electronegative pyridylaldehyde showed very low se-
lectivity (entry 6), whereas that of furfural was highly Z-
selective (entry 5). The conjugated E-cinnamaldehyde also
furnished the Z-product as the predominant isomer (entry 7).
As for other aliphatic aldehydes, whereas a-branched
2-phenylpropionaldehyde did not react, the same a-branched
cyclohexanecarboxyaldehyde did, giving the Z-olefin as the
major product (entry 9). This indicates that with readily
enolizable aldehydes, enolization is favoured over the olefina-
tion reaction. Apparently due to steric factors, pivalaldehyde
was unreactive.
The 4-substituent effect observed with KHMDS as base was
more profound upon using n-BuLi as base, with the Z-
selectivity decreasing with increasing electron-withdrawing
ability; from 69+31 with p-MeOC6H4CHO to 54+46 with
benzaldehyde and 43+57 with p-ClC6H4CHO.
The efficacy of the triphenylsilyl group was confirmed by
making comparisons with reactions of trimethylsilyl reagent 1b
† Electronic supplementary information (ESI) available: synthesis and
characterisation data for 1a,b and 3a–i. See http://www.rsc.org/suppdata/
cc/b0/b004416o/
Scheme 1
DOI: 10.1039/b004416o
Chem. Commun., 2000, 1795–1796
This journal is © The Royal Society of Chemistry 2000
1795

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Table 2 Comparison between differently substituted reagents 1a, b, and
2a
Peterson reaction. Further examination of substituent effects are
underway.
Entry
Reagent
R
Z+Eb
Yield (%)c
Notes and references
‡ Olefin geometries were determined by the coupling constants and
chemical shifts of the olefinic protons, and were verified by NOE
experiments for representative products.
§ The general procedure for the Peterson reaction is given as follows as the
example of the reaction of benzaldehyde. To a solution of 1a (206 mg, 0.415
mmol) in THF (4 mL) cooled to 278 °C was added KHMDS (0.5 M in
toluene, 0.98 mL, 0.49 mmol). After stirring for 30 min at 0 °C, the solution
was recooled to 278 °C. To this solution was added benzaldehyde (39.0 mg,
0.368 mmol) in THF (2.5 mL), and stirring was continued for 3 h. Water was
then added to quench the solution, and extraction was carried out with ether.
After the usual workup and chromatographic purification by preparative
TLC (SiO2; hexane+ethyl acetate = 5+1), (Z)-N,N-dibenzylcinnamamide
(106 mg) was obtained as a viscous oil in 88% yield.
1
2
3
4
5
6
Ph3SiCH2CONBn2
Me3SiCH2CONBn2
Ph3SiCH2CO2Et
Ph3SiCH2CONBn2
Me3SiCH2CONBn2
Ph3SiCH2CO2Et
Ph
Ph
Ph
> 97+ < 3
27+73
71+29
91+9
—
77+23
88
63
82
77
0
PhCH2CH2
PhCH2CH2
PhCH2CH2
78
a All reactions were carried out in THF at 278 °C with KHMDS as base.
b Determined by 500 MHz 1H NMR measurement of crude mixture.
c Combined isolated yield of E and Z olefins.
1 M. Larcheveque and A. Debal, J. Chem. Soc., Chem. Commun., 1981,
877–878.
using KHMDS as base, as shown in Table 2.10 The reaction of
1b with benzaldehyde resulted in a complete turnaround in
selectivity, favouring E-olefin formation (entry 2) while that
with 3-phenylpropionaldehyde gave no olefin product (entry 5).
The effectiveness of the amide group for high Z-selectivity was
exhibited by comparing corresponding reactions of an ester
analogue 2. The reaction of ethyl triphenylsilylacetate with
benzaldehyde (entry 3) and 3-phenylpropionaldehyde (entry 6)
with KHMDS as base gave the corresponding electron-deficient
olefin as Z+E = 71+29 and 77+23 mixtures, respectively, which
are clearly inferior ratios compared with those of corresponding
amide reactions (entries 1, 4). Thus, we have the general trend
in which the larger the electron-donating ability of the group
directly attached to the carbonyl group in both the aldehyde and
the silyl reagent, the higher the Z-selectivity tends to be.
Considering these electronic effects, the results we have
obtained here fit in well with the generally accepted mechanism
which involves an intermediate formed by rearrangement of the
silyl group from a carbon to an oxygen atom, preceding olefin
formation.12
2 W. C. Still and C. Gennari, Tetrahedron Lett., 1983, 24, 4405–4408.
3 K. Ando, Tetrahedron Lett., 1995, 36, 4105–4108; K. Ando, J. Org.
Chem., 1997, 62, 1934–1939; K. Ando, J. Org. Chem., 1998, 63,
8411–8416; K. Ando, J. Org. Chem., 1999, 64, 8406–8408.
4 S. Kojima, R. Takagi and K.-y. Akiba, J. Am. Chem. Soc., 1997, 119,
5970–5971.
5 K. Kokin, J. Motoyoshiya, S. Hayashi and H. Aoyama, Synth. Commun.,
1997, 27, 2387–2392.
6 Y. Yamakado, M. Ishiguro, N. Ikeda and H. Yamamoto, J. Am. Chem.
Soc., 1981, 103, 5568–5570.
7 T. Y. Zhang, J. C. O’Toole and J. M. Dunigan, Tetrahedron Lett., 1998,
39, 1461–1464.
8 W. Yu, M. Su and Z. Jin, Tetrahedron Lett., 1998, 40, 6725–6728.
9 For reviews on the Peterson reaction: D. J. Ager, Synthesis, 1984,
384–398; D. J. Ager, Org. React., 1990, 38, 1–223.
10 For the use of Me3SiCH2CONMe2 with LDA see: R. P. Woodbury and
M. W. Rathke, J. Org. Chem., 1978, 43, 1947–1949.
11 For the regioselectivity of silylation see: M. W. Rathke and D. F.
Sullivan, Synth. Commun., 1973, 3, 67–72; P. F. Hudrlik, D. Peterson
and D. Chou, Synth. Commun., 1975, 5, 359–365; G. L. Larson and
L. M. Fuentes, J. Am. Chem. Soc., 1981, 103, 2418–2419.
12 K. Yamamoto, Y. Tomo and S. Suzuki, Tetrahedron Lett., 1980, 21,
2861–2864.
In summary, we have developed a highly geometry-selective
method of preparing Z-unsaturated amides based upon the
1796
Chem. Commun., 2000, 1795–1796