"Syn-Effect" in the Conversion of (E)-α,β-Unsaturated Esters to the Corresponding β,γ-Unsaturated Esters

Article abstract of DOI:10.1246/cl.2003.778

The stereochemistry in the conversion of (E)-α,β-unsaturated esters to the corresponding β,γ-unsaturated esters by treatment with lithium hexamethyldisilazide in the presence of HMPA was investigated. The Z/E ratios of the resulting β,γ-unsaturated esters varied according to the γ-substituents of the (E)-α,β-unsaturated esters. This phenomenon was rationalized by "syn-effect" which may be attributed primarily to σ → π* interaction and/or 6π-electron homoaromaticity.

Full text of DOI:10.1246/cl.2003.778

778
Chemistry Letters Vol.32, No.8 (2003)
‘‘Syn-Effect’’ in the Conversion of (E)-ꢀ,ꢁ-Unsaturated Esters
to the Corresponding ꢁ,ꢂ-Unsaturated Esters
Samar Kumar Guha, Atsushi Shibayama, Daisuke Abe, Yutaka Ukaji,ꢀ and Katsuhiko Inomataꢀ
Department of Chemical Science, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma, Kanazawa 920-1192
(Received May 23, 2003; CL-030455)
The stereochemistry in the conversion of (E)-ꢀ,ꢁ-unsaturat-
(Z)-Selectivity among the ꢂ-alkyl substituents decreased
ed esters to the corresponding ꢁ,ꢂ-unsaturated esters by treat-
ment with lithium hexamethyldisilazide in the presence of
HMPA was investigated. The Z=E ratios of the resulting ꢁ,ꢂ-
unsaturated esters varied according to the ꢂ-substituents of the
(E)-ꢀ,ꢁ-unsaturated esters. This phenomenon was rationalized
by ‘‘syn-effect’’ which may be attributed primarily to ꢃ ! ꢄꢀ
interaction and/or 6ꢄ-electron homoaromaticity.
along with their bulkiness; CH3- > CH3CH2- > (CH3)2CH- >
(CH3)3C- (Entries 1, 3–5). For example, methyl group realized
high (Z)-selectivity, whereas (E)-product was exclusively ob-
t
tained in the case of Bu substituent. In the case of ꢂ-phenyl
substituent, high (E)-selectivity was observed (Entry 6). ꢂ-Fluo-
ro and ꢂ-benzyloxy groups have been found to show the com-
plete (Z)-selectivity (Entries 7, 8), while ꢂ-benzylthio substitut-
ed 2-alkenoate 1i afforded almost 1/1 mixture of (Z)- and (E)-3-
alkenoates 2i (Entry 9). In the cases of ꢂ-methyl and ꢂ-fluoro
substituted esters 1a,g, the isolated yields of the products 2a,g
were a little lower compared with other ꢂ-substituents (Entries
1, 7). This is due to the high volatility of those products. In fact,
the use of ester 1b derived from a higher alcohol realized better
chemical yield (Entry 2). The relative degree of ‘‘syn-effect’’ de-
pending on the ꢂ-substitutents R of (E)-ꢀ,ꢁ-unsaturated esters 1
was found for their conversion to the corresponding ꢁ,ꢂ-unsatu-
rated esters 2 as follows;
It is well known that treatment of dienolates derived from
ꢀ,ꢁ-unsaturated carbonyl compounds with electrophiles, such
as proton or alkyl halides, afforded deconjugated ꢁ,ꢂ-unsaturat-
ed carbonyl compounds.1,2 The reaction of ethyl (E)-2-alke-
noates with lithium amides in the presence of HMPA was re-
ported to give sterically unfavored (Z)-3-alkenoates as main
products. The stereoselectivity was explained by the stability
of the produced anion or cyclic transition model at the deproto-
nation.1a-c Furthermore, the deconjugative ꢀ-alkylation of (E)-4-
methoxy-2-butenoate gave (Z)-4-methoxy-3-butenoate selecti-
vely2b and (E)-4-methylthio-2-butenoate produced a mixture of
(E)- and (Z)-4-methylthio-3-butenoate.2a However, there was
no explanation about the stereochemical outcomes. The rational
elucidation for the origin of these puzzling phenomena has been
strongly desired.
Previously we investigated the stereochemistry in the iso-
merization of ꢀ-unsubstituted (E)-vinylic sulfones to the corre-
sponding allylic sulfones and the desulfonylation reaction of
ꢀ; ꢀ-dialkylated allylic sulfones with a base.3a,b In both cases,
the sterically unfavorable (Z)-allylic sulfones and (Z)-alkadienes
were predominantly formed, respectively. These results were ra-
tionalized by ‘‘conformational acidity’’ which essentially im-
plies ‘‘syn-effect.’’4 We proposed that the ‘‘syn-effect’’ was pri-
marily caused by 6ꢄ-electron homoaromaticity and/or ꢃ ! ꢄꢀ
interaction.3b Very recently we have investigated the ‘‘syn-ef-
fect’’ in the conversion of ꢀ-fluorinated (E)-vinylic sulfones to
the corresponding allylic sulfones and have shown that
ꢃ ! ꢄꢀ interaction is the most important factor for the ‘‘syn-ef-
fect.’’3c In the present study, we precisely investigated the ster-
eochemistry in the conversion of (E)-ꢀ,ꢁ-unsaturated esters to
the corresponding ꢁ,ꢂ-unsaturated esters by treatment with a
base. The Z=E ratios of the resulting ꢁ,ꢂ-unsaturated esters
were rationalized by ‘‘syn-effect,’’ which mainly arose from
the ꢃ ! ꢄꢀ interaction in the transition state of deprotonation.
In order to investigate the ‘‘syn-effect’’ for (E)-ꢀ,ꢁ-unsatu-
rated esters (E)-1 bearing various substituents at the ꢂ-position,5
they were converted to the corresponding ꢁ,ꢂ-unsaturated esters
2 by treating with lithium hexamethyldisilazide (LiHMDS) in
the presence of HMPA, followed by quenching with diluted
aq. HCl in EtOH. The results were summarized in Table 1.
ꢁ
F- ¼ BnO- > CH3- > CH3CH2- > (CH3)2CH- >
BnS- > Ph- > (CH3)3C-
The relative degree of Z=E ratios seems to be possible to ra-
tionalize by ‘‘syn-effect’’ in the transition state of deprotonation.
It was reported that C–CH3 eclipsed conformation of ethyl (E)-
2-pentenoate (1a) was preferred due to the hyperconjugation of
C–H bond at ꢂ-position to ꢄꢀ
orbital of electron deficient
C=C
olefin moiety.6 In the transition state of deprotonation, hyper-
Table 1. Conversion of the (E)-ꢀ,ꢁ-unsaturated esters (E)-1 to the corre-
sponding ꢁ,ꢂ-unsaturated esters 2
i) LiHMDS (1.1 equiv.)
HMPA (4.4 equiv.)
THF, −70 °C, 30 min
O
O
β
R
←
OR'
OR'
ii) HCl in EtOH, −70 °C
rt
γ
α
R
(E)-1
Entry
2
Yield b
of 2 / %
R
1/2a Z/E of 2a
R'
1
CH3
CH3
CH2CH3
CH(CH )
C(CH3)3
Ph
F
0/100
0/100
0/100
0/100
28/72
0/100
0/100
0/100
7/93
91/9
94/6
42
69
70
68
47
99
55
78
84
CH2CH3
(CH2)7CH3
CH2CH3
a
b
c
d
e
f
g
h
i
2
3
4
5
6
7
85/15
70/30
0/100
16/84
100/0
100/0
44/56
3 2 CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
8c OBn
9
SBn
aThe ratios were determined by 400 MHz 1H NMR spectra.
bIsolated yield.
cQuenched with Et3NÁHCl in EtOH instead of aq. HCl in EtOH to avoid the
hydrolysis of a vinyl ether moiety of the product 2h.
Copyright Ó 2003The Chemical Society of Japan

Chemistry Letters Vol.32, No.8 (2003)
779
conjugation of developing anion generated by the interaction of
H
H
CO2Et
H
with a base becomes more effective in the eclipsed confor-
H
H
ꢂ
mations A and B, in both of which the developing anion is
orbital and other conformations could
H
aligned with the ꢄꢀ
C=C
be neglected (Figure 1). Our recent proposal that ꢃ ! ꢄꢀ inter-
action is the most probable explanation for the ‘‘syn-effect’’ is
well consistent with this consideration. At the deprotonation
of ꢂ-alkyl-2-butenoates 1a-e, the C–C eclipsed syn-conforma-
tion A might be preferred rather than C–H eclipsed form B be-
Figure 3.
B:
π
H
CO2Et
H
cause hyperconjugative electron donation by C–H bond is
ꢂ2
σ
H
more effective than that by C–C bond,6,7 since H can also in-
ꢂ2
H
σ
σC-S
BnS
teract with a base to afford the developing anion. In the cases of
ꢂ-fluoro- and ꢂ-benzyloxy substituted ꢀ,ꢁ-unsaturated esters
1g,h, C–H eclipsed form B is unfavorable due to low donor abil-
ity of C–F and C–O bonds7c,8 resulting in the exclusive (Z)-se-
lectivities.
←
π
* interaction
Figure 4.
sible for the predominance of the C–H eclipsed form B (R =
BnS) in Figure 1 to increase (E)-selectivity.10 The order in the
relative degree of ‘‘syn-effect’’ of benzylthio substituent was dif-
ferent from the previous result observed in the conversion of vi-
nylic sulfones to the corresponding allylic sulfones, probably
due to the difference between the present electron deficient con-
jugated olefinic system and the non-conjugated olefinic system
in vinylic sulfones.
In conclusion, the stereochemistry in the conversion of (E)-
ꢀ,ꢁ-unsaturated esters to the corresponding ꢁ,ꢂ-unsaturated es-
ters is well rationalized by ‘‘syn-effect’’ in the transition state of
deprotonation, which arose from the ꢃ ! ꢄꢀ interaction and/or
6ꢄ-electron homoaromaticity. In the reaction using ꢂ-fluoro and
ꢂ-benzyloxy substituted esters, the complete (Z)-selectivity was
observed.
B:
Hγ1 H
B:
π
π
H
H
CO2Et
H
CO2Et
H
σ
σ
H
σ
R
σ
H
Hγ2
R
H
(A)
(B)
Figure 1. ꢃ ! ꢄꢀ interaction in two eclipsed conformations
A and B.
In the cases of 1a–c,g,h, it is also possible to stabilize the
syn-conformation at the transition state by 6ꢄ-electron homoar-
omaticity (as another origin of ‘‘syn-effect’’) involving the de-
veloping charge at the ꢂ-position and a pseudo p-orbital of
the ꢅ–CH2 (Figure 2a, R = R0CH2), or a lone pair of electrons
in a p-orbital of the hetero atom (Figure 2b), respectively.4,9
References and Notes
1
a) E.-P. Krebs, Helv. Chim. Acta, 64, 1023(1981). b) A. S. Kende and B. H.
Toder, J. Org. Chem., 47, 163(1982). c) P. Galatsis, J. J. Manwell, and S. D.
Millan, Tetrahedron Lett., 37, 5261 (1996). d) K. Tomooka, A. Nagasawa,
S.-Y. Wei, and T. Nakai, Tetrahedron Lett., 37, 8895 (1996). e) K. Tomooka,
A. Nagasawa, and T. Nakai, Chem. Lett., 1998, 1049 and references cited
therein.
B:
CO2Et
H
β
-
H+
H
α
γ
H
H
δ
R'
H
2
a) A. S. Kende, D. Constantinides, S. J. Lee, and L. Liebeskind, Tetrahedron
Lett., 16, 405 (1975). b) M. P. Zimmerman, Synth. Commun., 7, 189 (1977).
a) 6π-electron homoaromaticity
γ
in −alkyl-substituted system.
3a) T. Hirata, Y. Sasada, T. Ohtani, T. Asada, H. Kinoshita, H. Senda, and K.
Inomata, Bull. Chem. Soc. Jpn., 65, 75 (1992). b) A. Shibayama, T. Nakamura,
T. Asada, T. Shintani, Y. Ukaji, H. Kinoshita, and K. Inomata, Bull. Chem. Soc.
Jpn., 70, 381 (1997). c) T. Nakamura, S. K. Guha, Y. Ohta, D. Abe, Y. Ukaji,
and K. Inomata, Bull. Chem. Soc. Jpn., 75, 2031 (2002).
B:
CO2Et
H
H
β
-
H+
H
α
γ
4
‘‘Syn-effect’’ is herein defined as an effect which stabilizes the syn-conformation
against the steric hindrance: a) D. Cremer, J. Am. Chem. Soc., 101, 7199 (1979).
b) K. N. Houk, R. W. Strozier, N. G. Rondan, R. R. Fraser, and N. Chuaqui-Of-
fermanns, J. Am. Chem. Soc., 102, 1426 (1980). c) E. Block, R. E. Penn, A. A.
Bazzi, and D. Cremer, Tetrahedron Lett., 22, 29 (1981) and
references cited therein.
(E)-ꢀ,ꢁ-Unsaturated esters 1a–e,h were prepared by Horner-Emmons-Wads-
worth reaction. Compounds 1g,i were prepared from ethyl 4-bromocrotonate
by treating with AgF or BnSH in the presence of triethylamine, respectively.
ꢂ-Phenyl substituted (E)-ꢀ,ꢁ-unsaturated ester 1f was prepared as follows: Eth-
yl (phenylthio)acetate was treated with sodium hydride, followed by the addi-
tion of (2-bromoethyl)benzene, oxidizing with m-CPBA, and finally refluxing
in toluene to afford 1f.
B. W. Gung and M. M. Yanik, J. Org. Chem., 61, 947 (1996).
Although there were debates on the relative donor ability of C–H and C–C,
recently the former is reported to be better than the latter: a) T. Laube and H.
U. Stilz, J. Am. Chem. Soc., 109, 5876 (1987). b) T. Laube and T.-K. Ha, J.
Am. Chem. Soc., 110, 5511 (1988). c) P. R. Rablen, R. W. Hoffmann, D. A.
Hrovat, and W. T. Borden, J. Chem. Soc., Perkin Trans. 2, 1999, 1719.
Y. Apeloig, P. v. R. Schleyer, and J. A. Pople, J. Am. Chem. Soc., 99, 5901
(1977).
X
R'
-electron homoaromaticity in
−heteroatom-substituted system.
b) 6
π
γ
Figure 2.
5
i
In the case of Pr substituted ester 1d, 6ꢄ-electron homoar-
omaticity is difficult to be considered, however, the sterically
unfavorable (Z)-isomer was still obtained as the major products.
So, it is clear that the ‘‘syn-effect’’ is arisen from the ꢃ ! ꢄꢀ
t
interaction. In the case of Bu and Ph substituted esters 1e,f,
6
7
(E)-ꢁ,ꢂ-unsaturated esters 2e,f were obtained as the major prod-
ucts. This result is probably due to the bulkiness of the Bu
group, which excludes syn-conformation at the transition state
from consideration. Steric interaction between ꢀ-proton of ester
and o-proton of benzene ring also avoids C–C eclipsed form in
the case of Ph group (Figure 3).
In the case of ꢂ-benzylthio substituted ester 1i, the contribu-
tion of the empty d-orbital of S-atom, such as ꢃC-H ! d, is still
unclear, but ꢃC-S ! ꢄꢀ interaction (Figure 4) might be respon-
t
8
9
P. v. R. Schleyer, J. D. Dill, J. A. Pople, and W. J. Hehre, Tetrahedron, 33, 2497
(1977).
10 The significance of the ꢃC-S ! ꢄꢀ interaction in ꢀ-alkylthio carbonyl com-
pounds was pointed out: P. R. Olivato, S. A. Guerrero, Y. Hase, and R. Rittner,
J. Chem. Soc., Perkin Trans. 2, 1990, 465 and references cited therein.
Published on the web (Advance View) July 30, 2003; DOI 10.1246/cl.2003.778