In/InCl3-mediated cross-coupling reactions of methyl vinyl ketone with benzaldehyde in aqueous media

Article abstract of DOI:10.1021/ol006495e

(matrix presented) Various β,γ-unsaturated ketones were successfully prepared by cross-coupling reactions of methyl vinyl ketone (MVK) with benzaldehydes mediated by In/InCl₃ in aqueous media.

Full text of DOI:10.1021/ol006495e

ORGANIC
LETTERS
2
000
Vol. 2, No. 23
615-3617
In/InCl -Mediated Cross-Coupling
3
3
Reactions of Methyl Vinyl Ketone with
Benzaldehyde in Aqueous Media
†
,‡
†
†
†
Soyeon Kang, Taeg-Su Jang, Gyochang Keum, Soon Bang Kang,
‡
,†
So-Yeop Han, and Youseung Kim*
Biochemicals Research Center, Korea Institute of Science and Technology,
Seoul, 130-650, Korea, and Department of Chemistry and DiVision of Molecular Life
Sciences, Ewha Womans UniVersity, Seoul, 120-750, Korea
yosekim@kist.re.kr
Received August 22, 2000
ABSTRACT
Various â,γ-unsaturated ketones were successfully prepared by cross-coupling reactions of methyl vinyl ketone (MVK) with benzaldehydes
mediated by In/InCl in aqueous media.
3
Among versatile metal-mediated organic transformations,
syntheses involving indium are of current interest because
of their distinctive mediatory ability for many organic
3
smoothly in the presence of InCl in aqueous media to form
â,γ-unsaturated ketones. Thus, benzaldehydes were reacted
with methyl vinyl ketone (MVK, 300 mol %) in the presence
1
reactions in aqueous media. The low first ionization potential
3
of indium powder (200 mol %) and InCl (50 mol %) in a
of indium metal compared with that of Mg, Sn, or Zn, as
well as its exceptional stability in water, makes the metal
applicable to many organic reactions.2 We previously
employed its unique reducing property in aqueous media to
solvent mixture of THF and H O (1:2, v/v) at ambient
2
temperature for 6-8 h. Addition of 1 N HCl to the reaction
mixture afforded the desired â,γ-unsaturated ketones in good
to moderate yields (Scheme 1). MVK was used in excess
due to its susceptibility to dimerization.
3
pinacol coupling of benzaldehyde and dehalogenation of
3
-iodomethylcephems.4
In view of the recent interest in the use of indium in some
powerful organic reactions, we have focused our research
on the mediatory effect of indium in the Michael reaction,
which is one of the most efficient methods for carbon-
carbon bond formation and which has broad applications in
Scheme 1. Indium-Mediated Cross-Coupling Reaction of
MVK with Benzaldehyde
5
organic synthesis. Herein we report that indium-mediated
reaction of benzaldehydes and methyl vinyl ketone proceeded
†
Korea Institute of Science and Technology.
Ewha Womans University.
‡
This reaction provides a markedly effective access to â,γ-
(
1) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; John
Wiley & Sons, Inc.: New York, 1997.
2) (a) Cintas, P. Synlett 1995, 1087. (b) Hashmi, A. S. K. J. Prakt. Chem.
998, 340, 84.
3) Lim, H. J.; Keum, G.; Kang, S. B.; Chung, B. Y.; Kim, Y.
Tetrahedron Lett. 1998, 39, 4367.
4) Chae, H.; Cho, S.; Keum, G.; Kang, S. B.; Pae, A. N.; Kim, Y.
Tetrahedron Lett. 2000, 41, 3899.
unsaturated ketones that are known to be useful intermediates
6
(
in the synthesis of fine chemicals. To date, this is the first
1
report that indium can facilitate the coupling reaction of
(
(
(5) (a) Wang, L.; Sun, X.; Zhang, Y. Synth. Comm. 1998, 28, 3263. (b)
Bergman, E. D.; Ginsburg, D.; Rappo, R. Org. React. 1959, 10, 179.
1
0.1021/ol006495e CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/14/2000

benzaldehydes and methyl vinyl ketone to give â,γ-unsatur-
ated ketones. The results of In/InCl -mediated cross-coupling
reactions of various benzaldehydes with MVK are sum-
marized in Table 1.7
2 3
CuCl , instead of InCl were used, low yields (21-38%)
3
resulted. It should be noted that the reaction using InCl
alone without In also proceeded well to give the â,γ-
unsaturated ketone in 78% yield (entry 16). When an
aldehyde reacted with ethyl vinyl ketone instead of MVK
as a Michael acceptor, a coupling product was produced in
6
2% yield (entry 17). These reaction conditions were
Table 1. Reaction of Various Aldehydes with MVKa
extended to other Michael acceptors such as acrolein,
acrylonitrile, ethyl acrylate, and acrylic acid, but the reaction
did not proceed.
The reaction mechanism is not clear, but we now report
that the reaction is likely to proceed by a radical mechanism
involving the radical-anion intermediate of MVK formed
conditions:b
solvent
isolated
9
entry
R1
4-FPh
4-FPh
4-FPh
4-FPh
4-FPh
4-FPh
Ph
R2
yield (%)
from indium (Figure 1). Then the reaction intermediate
1
2
3
4
5d
6e
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
THF
H2O
67c
59c
79c
79
THF:H2O (1:1)
THF:H2O (1:2)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:2)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:1)
THF:H2O (1:1)
69
74
68
59
71
72
40
44
58
78
62
2-FPh
4-t-BuPh
4-MeO2CPh
4-MeOPh
4-NCPh
4-HOPh
2-furyl
PhCHdCH
4-FPh
1
1
1
1
1
1
0
1
2
3
4
5
Figure 1. Plausible mechanism.
1 f
6
undergos radical cyclopropanation and addition to benz-
aldehyde. Upon addition of BHT (butylated hydroxy-
toluene) to the reaction, a rate retardation effect was
1
7
4-FPh
a
b
All reactions were carried out on a 0.5 mmol scale. Aldehyde:MVK:
c
d
In:InCl3 ) 1:3:2:0.5. GC yield. Without In, 2.5 equiv of InCl3 was used.
e
f
10
1
Without InCl3, 2.5 equiv of In was used. Instead of In and InCl3, 2.5
detected. When the reaction was followed by H NMR in
a 1:1 mixture of THF-d and D O, the cyclopropanyl proton
signals were observed at δ 1.2-0.5 as multiplet. Quench-
equiv of InCl was used.
8
2
11
12
1
3
ing the reaction mixture with DCl in D
2
O after an
Generally, the yields of the products are not affected by
the nature of substituents on the phenyl ring (entries 1-4,
appropriate reaction time and examination of the CDCl
3
-
1
extracted products by H NMR showed the signal of the
7
-13, 16, and 17). The reaction also proceeded with
heteroaromatic aldehyde (entry 14). With the absence of In
or InCl , the reaction did not occur (entries 5 and 6). The
yield decreased when THF or H O was used as the only
solvent (entries 1 and 2). Employing other solvents besides
THF or H O also led to disappointing results. With cinnam-
14
5
-phenyl-4-penten-2-one together with peaks of some MVK
decomposed compounds.
In conclusion, we have extended the scope of indium metal
to a cross-coupling reaction of an R,â-unsaturated ketone
3
2
2
(9) Two types of radical-anion (1,2- and 1,4-) of methyl vinyl ketone
were possible. See: Pons, J.-M.; Zahra, J.-P.; Santelli, M. Tetrahedron Lett.
aldehyde, not only the cross-coupled product but also a small
amount of the pinacol coupling product was detected (entry
5). When other Lewis acids, such as SnCl
1
981, 22, 3965.
(10) The retardation was analyzed by GC yield of the product formed.
8
In the absence of BHT, the â,γ-unsaturated ketone was formed in 35% and
1
4
, FeCl
3
, and
81% yield after 1 h and 4 h, respectively. In the presence of 0.1 equiv of
BHT, however, the corresponding yields were 28% and 53% and under
0.5 equiv of BHT, the results were 5% and 15% yields, respectively.
(11) H NMR of the cyclopropanol intermediate (entry 7, THF-d8/D2O)
(
6) (a) Valle, L. D.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990,
1
5
1
5, 3019. (b) Chang, S.; Yoon, J.; Brookhart, M. J. Am. Chem. Soc. 1994,
16, 1869. (c) Yoshida, H.; Oomori, K.; Miyata, H.; Onzuka, K.; Fuse, K.
δ 7.4 (m, 5H), 4.9-4.2 (m, 1H), 2.5-2.0 (4s, 3H), 1.2-0.5 (m, 3H).
(12) Some examples of the synthesis of cyclopropanol by cyclopro-
panation of â,γ-unsaturated ketone were reported. (a) With CrCl2: Toratsu,
C.; Fujii, T.; Suzuki, T.; Takai, K. Angew. Chem., Int. Ed. 2000, 39, 2725.
(b) With CrCl2 and a catalytic amount of NiCl2: Montgomery, D.; Reynolds,
K.; Stevenson, P. J. Chem. Soc., Chem. Commun. 1993, 363.; (c) with
Me3SnLi and TiCl4 (cat.): Sato, T.; Watanabe, M.; Watanabe, T.; Onoda,
Y.;, Murayama, E. J. Org. Chem. 1988, 53, 1894. (d) With Zn/HCl:
Elphimoff-Felkin, I.; Sadra, P. Tetrahedron 1975, 31, 2781.
JP 08081406, 1996; Chem. Abstr. 1996, 125, 57554.
7) Typical experimental procedure (Table 1, entry 4): A mixture of
-fluorobenzaldehyde (53.6 µL, 0.5 mmol), In (-100 mesh, 114.8 mg, 1
(
4
mmol), InCl3 (55.3 mg, 0.25 mmol), and MVK (124.9 µL, 1.5 mmol) in a
mixture of THF and H2O (1:2, 3 mL) was stirred at ambient temperature
for 6 h. After the addition of 1 N HCl (1.5 mL), the reaction mixture was
stirred for 30 min and extracted with ethyl acetate (15 mL × 3). The
combined organic phase was washed with brine and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced pressure, and
the residue was purified by flash column chromatography on silica gel with
a mixture of hexane and ethyl acetate (10:1) to give 5-(4-fluorophenyl)-4-
penten-2-one (70.6 mg, 79% yield).
(13) Examples of the ring-opening reactions of cyclopropanols: (a)
Corey, E. J.; Ulrich, P. Tetrahedron Lett. 1975, 3685. (b) Gibson, D. H.;
DePuy, C. H. Chem. ReV. 1974, 74, 605. and see ref 12a.
1
(14) H NMR (300 MHz, CDCl3) δ 7.38-7.19 (m, 5H), 6.46 (d, J )
(
8) In the absence of MVK, the pinacol product of cinnamaldehyde was
16.0 Hz, 1H), 6.30 (dt, J ) 15.9, 6.9 Hz, 2H), 3.32 (d, J ) 6.9 Hz, 2H),
isolated in 79% yield as a mixture of dl and meso isomers (84:16).
2.19 (s, 3H).
3616
Org. Lett., Vol. 2, No. 23, 2000

with benzaldehydes and provided a very effective access to
the â,γ-unsaturated ketones in satisfactory yields. Further
study on the exact reaction mechanism and application of
this protocol to organic synthesis are currently underway in
our laboratory.
Acknowledgment. This work was fully supported by the
Ministry of Science and Technology and the Korea Institute
of Science and Technology.
OL006495E
Org. Lett., Vol. 2, No. 23, 2000
3617