Stereoelectronic effect on stereoselective olefination of ketones providing tetrasubstituted olefins via ynolates

Full text of DOI:10.1021/jo000650l

J . Org. Chem. 2000, 65, 5443-5445
5443
Ster eoelectr on ic Effect on Ster eoselective
Sch em e 1
Sch em e 2
Olefin a tion of Keton es P r ovid in g
Tetr a su bstitu ted Olefin s via Yn ola tes
Mitsuru Shindo,* Yusuke Sato, and Kozo Shishido
Institute for Medicinal Resources, University of Tokushima,
Sho-machi 1, Tokushima 770-8505, J apan
shindo@ph2.tokushima-u.ac.jp
Received April 27, 2000
Olefination of a carbonyl group is one of the funda-
mental reactions in synthetic organic chemistry. Con-
ventional methods such as the Horner-Wadsworth-
1
2
Emmons reaction and its variants provide convenient
routes to olefins from aldehydes. However, in the syn-
thesis of tetrasubstituted olefins, which would be impor-
3
In an attempt to elucidate the reaction mechanism,
para-substituted acetophenones were used as substrates.
Surprisingly, the E/ Z selectivity in the olefination reac-
tion with the ynolate was found to be strongly dependent
on the electronic nature of the para-substituents, as
shown in Table 1. The acetophenones with electron
withdrawing groups gave lower E-selectivity (entries
1-3), compared to the unsubstituted case (entry 4). When
nitro was the substituent, the Z-olefin was preferred. On
the other hand, substrates with electron donating groups
gave higher E-selectivity (entries 5-7). Finally we
achieved complete E-selectivity in the synthesis of a
tetrasubstituted olefin by using p-dimethylamino-
acetophenone. As far as we know, this is the first example
of a highly stereoselective olefination of ketones providing
tetrasubstituted olefins. Since the para-substituents are
positioned far from the reaction center (â-lactone enolate),
presumably the stereochemistry is controlled by a ste-
reoelectronic effect as well as by a steric effect.
tant units for organic synthesis, high stereoselectivity
has not been achieved using such reagents with ketones.4
Therefore, development of a reaction with a novel mech-
anism is required for this process.
We previously reported a novel methodology for the
generation of ynolate anions via cleavage of ester di-
5
anions (Scheme 1) as well as new reactions using these
6
unique anions. More recently, we reported the olefina-
tion reaction of aldehydes and ketones with ynolates.7
We now describe the unprecedented stereoelectronic
effect on the stereocontrol in the formation of tetrasub-
stituted olefins using ynolates and the first successful
achievement of high stereoselectivity.
Previously, we reported that ynolates (1) react with
aldehydes (e.g., 2a ) at ambient temperature to give
trisubstituted olefins (5, R ) H) with excellent E-
selectivity via ring opening of the resulting â-lactone
enolates (3) (Scheme 2). The reaction of the ynolate (1)
with acetophenone also provided the tetrasubstituted
olefins (5, R ) Me) with an E/ Z ratio of 6:1. For easier
isolation and purification of the desired olefins, instead
of acidifying the resulting carboxylates, methyl iodide (10
equiv) was added to the solution along with HMPA or
DMF to afford the corresponding methyl esters (4) in good
yields without any loss of stereoselectivity.
To confirm this remarkable stereoelectronic effect, we
then examined the olefination of para-substituted ben-
zophenones, in which the steric effect should be negli-
gible. The reactions proceeded smoothly to afford the
desired tetrasubstituted olefins in excellent yields. As
shown in Table 2, the benzophenones with an electron
donating group (methyl, methoxy, dimethylamino) were
converted into the desired tetrasubstituted olefins with
E-selectivity, up to a ratio of 5:1 (entry 7). On the other
hand, the benzophenones with an electron-withdrawing
group gave the Z-olefin preferentially (entries 1 and 2).
Thus, to investigate the relationship between the
selectivity and the degree of electron donation of the para-
(
1) Wadsworth, W. S., J r. Org. React. 1977, 25, 73-253. Shen, Y.
Acc. Chem. Res. 1998, 31, 584-592.
2) For example: Marshall, J . A.; DeHoff, B. S.; Cleary, D. G. J .
Org. Chem. 1986, 51, 1735-1741.
3) For examples, Sharpless asymmetric epoxidation to trisubsti-
(
(
tuted allylic alcohols (tetrasubstituted olefins) provide the correspond-
ing epoxides with high enantioselectivity. Since the products possess
contiguous asymmetric carbons, they would be useful for synthesis of
natural products. See: Erickson, T. J . J . Org. Chem. 1986, 51, 934-
q
q
q
substituents, plots of ∆∆G (∆G
E
Z
- ∆G (kcal/mol))
9
1
35; Marshall, J . A.; J enson, T. M.; J . Org. Chem. 1984, 49, 1707-
versus σ values of the Hammett equation were con-
structed. As shown in Figure 1, the plot gave straight
lines. This good linear relationship indicates that in-
creasing electron density on the phenyl substituents
tends to increase E-selectivity. Electron-rich aryl groups
tend to wind up trans to the ester.
712.
(4) Gallagher. J r., G.; Webb, R. L. Synthesis 1974, 122-124; S. E.
Kelly, In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Perga-
mon Press: New York, 1991; Vol. 1, pp 729-817.
(5) (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433-4436. (b)
Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54, 2411-2422.
For review: (c) Shindo, M, Chem. Soc. Rev. 1998, 27, 367-374.
(6) (a) Shindo, M.; Sato, Y.; Shishido, K., J . Am. Chem. Soc. 1999,
The reaction with 4-methoxy-4′-nitrobenzophenone
gave the expected tetrasubstituted olefin with an E/Z
ratio of 4:1, where the electron-donating group and the
withdrawing group work concertedly (Scheme 3). Clearly,
in these reactions, the stereochemistry was controlled
only by a stereoelectronic effect.
1
21, 6507-6508. (b) Shindo, M.; Oya, S.; Sato, Y.; Shishido, K.
Heterocycles 1998, 49, 113-116. (c) Shindo, M.; Oya, S.; Sato, Y.;
Shishido, K. Heterocycles 2000, 52, 545-548.
(7) (a) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 1998,
3
9, 4857-4860. Pioneering works of this type of the reaction: (b)
Kowalski C. J .; Fields, K. W. J . Am. Chem. Soc. 1982, 104, 321-323.
c) Mulzer, J .; Kerkmann, T. J . Am. Chem. Soc. 1980, 102, 3620-3622.
(
1
0.1021/jo000650l CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/03/2000

5
444 J . Org. Chem., Vol. 65, No. 17, 2000
Notes
Ta ble 1. Olefin a tion of P a r a -Su bstitu ted Acetop h en on es
Sch em e 3
a
via Yn ola tes
b
E/Zc
0.67
2.45
4.0
6.0
10
∆∆Gq d
σe
entry
X
yield (%)
1
2
3
4
5
6
7
NO2
Cl
61
68
88
82f
89
80
64
0.24
-0.53
-0.82
-1.07
-1.36
-1.77
<-2.7
0.778
0.227
0.062
0
-0.17
-0.268
-0.83
F
H
Me
MeO
Me2N
20
>99
not activated by Lewis acid.13 Rondan and Houk reported
substituent electronic effects on the ring-opening of
cyclobutenes and their theoretical caliculations. Our
results may also be explained by their effects, since
π-orbitals on the phenyl group can be considered as donor
orbitals. The differences of selectivity found for the
acetophenones and the benzophenones may be attributed
to steric interaction between the butyl and methyl
groups. For further detail mechanistic consideration,
theoretical calculations are in progress.
a
14
The dibromoester (1.0 mmol) and acetophenones (1.5 mmol)
b
c
were used. The yields were based on the dibromoesters. The
d
q
stereochemistry was determined by NOE experiments. ∆∆G )
q
q
e
∆
G E - ∆G Z (kcal/mol). T ) 298 K. Substituent constant of
f
Hammett equation. The yield of the carboxylic acids.
Ta ble 2. Olefin a tion of P a r a -Su bstitu ted
b
Ben zop h en on es via Yn ola tes
In conclusion, we have found a novel stereoelectronic
effect on the stereoselectivity in the ring-opening reaction
of â-lactone enolates derived from ynolates. We have also
achieved, for the first time, the highly stereoselective
olefination of ketones providing tetrasubstituted alkenes.
This work represents a new methodology for stereo-
selective construction of olefins and also shows the
synthetic utility of ynolates.
b
E/Zc
∆∆Gq d
σe
entry
X
yield (%)
1
2
3
4
5
6
7
NO2
Cl
92
92
0.34
0.67
1.0
1.0
1.5
0.64
0.24
0.0
0.778
0.227
0.062
0
-0.17
-0.268
-0.83
F
H
>99f
82
0.0
Me
MeO
Me2N
90
99
90
-0.24
-0.41
-0.95
2.0
5.0
Exp er im en ta l Section
a
1
The dibromoester (1.0 mmol) and benzophenones (0.8 mmol)
Gen er a l Meth od s. H NMR were measured in CDCl
3
solu-
b
c
13
were used. The yields were based on the benzophenones. The
tion and referenced to TMS (0.00 ppm). C NMR were measured
in CDCl solution and referenced to CDCl (77.0 ppm). All
d
q
stereochemistry was determined by NOE experiments. ∆∆G )
3
3
q
q
e
∆
G E - ∆G Z (kcal/mol). T ) 298 K. Substituent constant of
reactions were performed in oven-dried glassware under positive
pressure of argon, unless otherwise noted. Reaction mixtures
were stirred magnetically. Solutions of alkyllithium reagents
were transferred by syringe or cannula and were introduced into
reaction vessels through rubber septa.
f
Hammett equation. The yield of the carboxylic acids.
(8) Vieregge, H.; Bos, H. J . T.; Arens, J . F. Recl. Trav. Chim Pays-
Bas 1959, 78, 664-666. Vieregge, H.; Schmidt, H. M.; Renema, J .; Bos,
H. J . T.; Arens, J . F. Recl. Trav. Chim Pays-Bas 1966, 85, 929-951.
Bos, H. J . T.; Boleij, J . Recl. Trav. Chim Pays-Bas 1969, 88, 465-473.
Pornet, J .; Khouz, B.; Miginiac, L. Tetrahedron Lett. 1985, 26, 1861-
1
5
862. Pornet, J .; Rayadh, A.; Miginiac, L. Tetrahedron Lett. 1986, 27,
479-5482. Zakarya, D.; Rayadh, A.; Samih, M: Lakhlifi, T. Tetra-
hedron Lett. 1994, 35, 405-408. Zakarya, D.; Rayadh, A.; Samih, M.;
Lakhlifi, T. Tetrahedron Lett. 1994, 35, 2345-2348. Crich, D.; Crich,
J . Z., Tetrahedron Lett. 1994, 35, 2469-2472.
(9) The addition of ynamines (alkynylamines) to aldehydes and
ketones giving olefins: Fuks, R.; Viehe, H. G. Chem. Ber. 1970, 103,
64-572.
10) The Lewis acid-catalyzed addition of alkynylsulfides to imines
giving olefins: Ishitani, H.; Nagayama, S.; Kobayashi, S. J . Org. Chem.
996, 61, 1902-1903.
11) Isolation of the intermediate alkoxyoxetenes: (a) Middleton, W.
5
(
1
(
J . J . Org. Chem. 1965, 30, 1307. (b) Oblin, M.; Parrain, J .-L.; Rajzmann,
M.; Pons, J .-M. Chem. Commun. 1998, 1619-1620.
q
F igu r e 1. Plots of σ value vs ∆∆G for the olefination of para-
(
12) Theoretical calculations for the ring opening of oxetene: Yu,
substituted acetophenones and benzophenones.
H.; Chan, W.-T.; Goddard, J . D. J . Am. Chem. Soc. 1990, 122, 7529-
7
537.
(
13) The conversion of the â-lactone enolate into an olefin via
It is known that Lewis acid activates reactions of
“forbidden” â-elimination has been reported by Mulzer. This mecha-
nism cannot be ruled out: see ref 7c.
(
aldehydes or ketones with alkynyl ethers to provide
14) Kirmse, W.; Rondan, N. G.; Houk, K. N. J . Am. Chem. Soc.
olefins.8
-10
The mechanism proposed is that an interme-
1
984, 106, 7989-7991. Rondan, N. G.; Houk, K. N. J . Am. Chem. Soc.
diate alkoxyoxetene is formed and its conrotatory ring-
1985, 107, 2099-2111. Spellmeyer, D. C.; Houk, K. N. J . Am. Chem.
Soc. 1988, 110, 3412-3416. Kallel, E. A.; Wang, Y.; Spellmeyer, D.
C.; Houk, K. N. J . Am. Chem. Soc. 1990, 112, 6759-6763. Li, Y.; Rubin,
Y.; Diederich, F.; Houk, K. N. J . Am. Chem. Soc. 1990, 112, 1618-
1623.
opening gives the corresponding R,â-unsaturated es-
ter.1
1,12
Our reaction may also be regarded as an
electrocyclic ring-opening reaction of an oxetene, although

Notes
J . Org. Chem., Vol. 65, No. 17, 2000 5445
Gen er a l P r oced u r e for th e Syn th esis of Meth yl 2-Bu tyl-
-(4-n itr op h en yl)-2-bu ten oa te (5b) fr om Bu tyl-Su bstitu ted
Lith iu m Yn ola te (Ta ble 1, En tr y 1). To a solution of ethyl
,2-dibromohexanoate (302 mg, 1.0 mmol) in 6 mL of dry THF,
cooled to -78 °C under argon, was added dropwise a solution of
tert-butyllithium (2.70 mL, 4.0 mmol, 1.48 M in pentane). The
yellow solution was stirred for 3 h at -78 °C and allowed to
warm to 0 °C. After 30 min, the resulting colorless reaction
mixture was warmed to room temperature and then a solution
of p-nitroacetophenone (248 mg, 1.5 mmol) in THF (2 mL) was
added dropwise. After 0.5 h, methyl iodide (0.62 mL, 10 mmol)
added dropwise. After 0.5 h, methyl iodide (0.62 mL, 10 mmol)
and HMPA (1.7 mL, 10 mmol) were added. After 15 h, NH Cl
4
solution (8 mL) was added and then the resulting mixture was
3
2
extracted with ethyl acetate (10 mL × 3). The organic phase
was washed with water (10 mL × 3), saturated NaHCO
3
solution, and saturated NaCl solution, dried over MgSO
4
,
filtered, and concentrated to afford a yellow oil, which was
chromatographed over silica gel (2% ethyl acetate in hexane) to
yield 170 mg (69%) of ester as a pale yellow oil. It was separated
into the E- and Z-olefins with preparative HPLC (eluent: 5%
AcOEt in hexane).
4
and HMPA (1.7 mL, 10 mmol) were added. After 15 h, NH Cl
solution (8 mL) was added, and then the resulting mixture was
(
E)-Meth yl 2-Bu tyl-3-(4-n itr op h en yl)-3-p h en yla cr yla te.
1
Pale yellow oil. H NMR (300 MHz, CDCl
.2 Hz, 3H), 1.30 (tq, J ) 7.2, 7.2 Hz, 2H), 1.47 (m, 2H), 2.32
dd, J ) 8.0, 8.0 Hz, 2H), 3.50 (s, 3H), 7.09 (m, 2H), 7.27 (m,
H), 7.35 (d, J ) 8.6 Hz, 2H), 8.21 (d, J ) 8.6 Hz, 2H). C NMR
75 MHz, CDCl ) δ: 13.8 (q), 22.5 (t), 30.9 (t), 32.0 (t), 51.7 (q),
23.6 (d), 128.0 (d), 128.3 (d), 128.4 (d), 130.1 (d), 135.7 (s), 140.8
3
, TMS) δ: 0.86 (t, J )
extracted with ethyl acetate (10 mL × 3). The organic phase
7
(
3
(
1
(
was washed with water (10 mL × 3), saturated NaHCO
3
solution, saturated NaCl solution, dried over MgSO
4
, filtered,
13
and concentrated to afford a yellow oil, which was chromato-
graphed over silica gel (2% ethyl acetate in hexane) to yield 170
mg (69%) of ester as a pale yellow oil. It was separated into the
E- and Z-olefins with preparative HPLC (eluent: 2% AcOEt in
hexane).
3
s), 142.8 (s), 147.5 (s), 170.7 (s). IR (Neat): 1717, 1598, 1520
-1
+
cm . MS m/z: 339 (M ), 340 (M + 1), 43 (100). HRMS (EI):
+
4
calcd for C20H21NO (M ) 339.1471, found 339.1495. Preparative
(
E)-Meth yl 2-Bu tyl-3-(4-n itr op h en yl)-2-bu ten oa te. Pale
HPLC (5% EtOAc/hexane, 10 mL/min, LiChrosorb Si 60 (7 mm))
retention time: 33.8 min.
(
Pale yellow oil. H NMR (300 MHz, CDCl
.2 Hz, 3H), 1.30 (tq, J ) 7.2, 7.2 Hz, 2 H,), 1.46 (m, 2 H,), 2.38
dd, J ) 8.0, 8.0 Hz, 2H), 3.51 (s, 3H), 7.13 (dd, J ) 8.0, 1.6 Hz,
1
yellow oil. H NMR (300 MHz, CDCl , TMS) δ: 0.76 (t, J ) 7.2
3
Hz, 3 H,), 1.15 (tq, J ) 7.2, 7.2 Hz, 2H), 1.28 (m, 2H), 2.09 (dd,
Z)-Meth yl 2-Bu tyl-3-(4-n itr op h en yl)-3-p h en yla cr yla te.
J ) 7.2, 7.2 Hz, 2H), 2.17 (s, 3H), 3.83 (s, 3H), 7.31 (d, J ) 8.6
1
3
, TMS) δ: 0.86 (t, J )
1
3
Hz, 2H), 8.23 (d, J ) 8.6 Hz, 2H). C NMR (75 MHz, CDCl
3
) δ:
7
(
2
1
1
(
1
2
3.7 (q), 22.3 (t), 22.9 (q), 30.8 (t), 31.0 (t), 51.7 (q), 123.8 (d),
28.3 (d), 132.2 (s), 140.8 (s), 146.9 (s), 149.8 (s), 169.8 (s). IR
13
H), 7.32 (m, 5H), 8.12 (d, J ) 8.0 Hz, 2H). C NMR (75 MHz,
CDCl ) δ: 13.7 (q), 22.5 (t), 30.9 (t), 31.9 (t), 51.7 (q), 123.3 (d),
28.1 (d), 128.5 (d), 128.9 (d), 129.3 (d), 136.0 (d), 139.5 (s), 143.6
s), 146.9 (s), 149.1 (s), 170.4 (s). IR (neat): 1718, 1595, 1519
-
1
+
neat): 1715, 1600, 1519 cm . MS m/z: 277 (M ), 278 (M + 1),
29 (100). HRMS (EI) calcd for C15
77.1292. Preparative HPLC (2% EtOAc/hexane, 10 mL/min,
3
+
4
H19NO (M ) 277.1314, found
1
(
LiChrosorb Si 60 (7 mm)) retention time: 67.5 min.
Z)-Meth yl 2-Bu tyl-3-(4-n itr op h en yl)-2-bu ten oa te. Pale
-1
+
cm . MS m/z: 339 (M , 100), 340 (M + 1). HRMS (EI) calcd for
(
+
C
(
20
H
21NO
4
(M ) 339.1471, found 339.1458. Preparative HPLC
5% EtOAc/hexane, 10 mL/min, LiChrosorb Si 60 (7 mm))
retention time: 29.1 min. NOE experiments: irradiation of CH
1
yellow oil. H NMR (300 MHz, CDCl , TMS) δ: 0.95 (t, J ) 7.0
3
Hz, 3 H,), 1.33-1.52 (m, 4H), 2.11 (s, 3H), 2.47 (dd, J ) 7.4, 7.4
Hz, 2H), 3.42 (s, 3H), 7.29 (d, J ) 8.6 Hz, 2H), 8.17 (d, J ) 8.6
2
of allylic position produced an enhancement of the ortho protons
of the phenyl group without the nitro substituent.
1
3
3
Hz, 2H). C NMR (75 MHz, CDCl ) δ: 13.9 (q), 21.0 (q), 22.5
(
(
t), 30.2 (t), 30.7 (t), 51.4 (q), 123.4 (d), 127.8 (d), 133.2 (s), 140.6
s), 146.7 (s), 151.2 (s), 169.8 (s). IR (neat): 1717, 1600, 1520
-
1
+
Ack n ow led gm en t. We thank Professor Hiroshi
Chuman (University of Tokushima) for theoretical
calculations. We also thank Dr. Seiji Mori (University
of Kyoto) for helpful discussions. This work was sup-
ported by Grants-in-Aid for Scientific Research on
Priority Areas (No. 283, “Innovative Synthetic Reac-
tions”) from the Ministry of Education, Science, Sports
and Culture, Government of J apan, and the Eisai
Award in Synthetic Organic Chemistry, J apan.
cm . MS m/z: 277 (M ), 278 (M + 1), 128 (100%). HRMS (EI):
calcd for C15
+
4
H19NO (M ) 277.1314, found 277.1306. Preparative
HPLC (2% EtOAc/hexane, 10 mL/min, LiChrosorb Si 60 (7 mm))
retention time: 55.1 min. NOE experiments: irradiation of CH
of allylic position produced an enhancement of the allylic CH
resonance.
2
3
Gen er a l P r oced u r e. Syn th esis of (E)-Meth yl 2-Bu tyl-3-
(
4-n itr op h en yl)-3-p h en yla cr yla te fr om Bu tyl-Su bstitu ted
Lith iu m Yn ola te (Ta ble 2, En tr y 1). To a solution of ethyl
,2-dibromohexanoate (302 mg, 1.0 mmol) in 6 mL of dry THF,
2
cooled to -78 °C under argon, was added dropwise a solution of
tert-butyllithium (2.70 mL, 4.0 mmol, 1.48 M in pentane). The
yellow solution was stirred for 3 h at -78 °C and allowed to
warm to 0 °C. After 30 min, the resulting colorless reaction
mixture was warmed to room temperature and then a solution
of p-nitrobenzophenone (182 mg, 0.8 mmol) in THF (2 mL) was
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O000650L