InCl3/Me3SiCl-catalyzed direct michael addition of enol acetates to α,β-unsaturated ketones

Article abstract of DOI:10.1021/ol302888k

The direct Michael addition of enol acetates to α,β-unsaturated ketones was achieved using a combination of Lewis acid catalysts, InCl ₃ and Me₃SiCl, which furnished stable enol-form products that could be further transformed into functionalized 1,5-diketones by reactions with various electrophiles.

Full text of DOI:10.1021/ol302888k

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5788–5791
InCl3/Me3SiCl-Catalyzed Direct
Michael Addition of Enol Acetates to
r,β-Unsaturated Ketones
Yoshiharu Onishi, Yuki Yoneda, Yoshihiro Nishimoto, Makoto Yasuda, and
Akio Baba*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received October 19, 2012
ABSTRACT
The direct Michael addition of enol acetates to R,β-unsaturated ketones was achieved using a combination of Lewis acid catalysts, InCl3 and
Me3SiCl, which furnished stable enol-form products that could be further transformed into functionalized 1,5-diketones by reactions with various
electrophiles.
Michael addition of metal enolates to R,β-unsaturated
carbonyl compounds is an efficient route to 1,5-dicarbonyl
compounds.1À3 These compounds are obtained after the
post-treatment hydrolysis of unstable metal enol-forms of
Michael adducts (eq 1, Scheme 1). Despite high potential
as a nucleophile, the isolation and utilization of enol-form
products have not been sufficiently developed because of
instability. Silyl enolate products as Michael adducts have
been isolated only by careful treatment3a,4 and are utilized
in total synthesis.5 Enol acetates are metal-free and stable
nucleophiles, which makes them potential reagents, but
their direct utilization has been limited to some aldol
reactions and oxidative couplings.6,7 Recently, we have
succeeded in the displacement of metal enolates to enol
acetates in coupling reactions with either alcohols or their
derivatives.8 Herein, we report Michael additions using
enol acetates instead of metal enolates (eq 2, Scheme 1).
A catalytic combination of the Lewis acids InCl3 and
Me3SiCl, which specifically activated R,β-unsaturated ketones,
(1) For representative reviews, see: (a) Bergmann, E. D.; Ginsburg,
D.; Pappo, R. In Organic Reactions; Adams, R., Eds.; Wiley: New York,
1959; Vol. 10, pp 179À561. (b) House, H. O. In Modern Synthetic
Reactions, 2nd ed.; W. A. Benjamin: Menlo Park, 1972; pp 595À623.
(2) For pioneering work for the MukaiyamaÀMichael reaction, see:
(a) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223–
1224. (b) Narasaka, K.; Soai, K.; Aikawa, K.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1976, 49, 779–783.
(3) Selected works of the MukaiyamaÀMichael reaction: (a) Wada,
M.; Takeichi, E.; Matsumoto, T. Bull. Chem. Soc. Jpn. 1991, 64, 990–
994. (b) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett 1993,
472–474. (c) Loh, T.-P.; Wei, L.-L. Tetrahedron 1998, 54, 7615–7624. (d)
Marx, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2000, 39, 178–181. (e)
Miura, K.; Nakagawa, T.; Hosomi, A. Synlett 2003, 13, 2068–2070.
(4) (a) Bunce, R. A.; Schlecht, M. F.; Dauben, W. G.; Heathcock,
C. H. Tetrahedron Lett. 1983, 24, 4943–4946. (b) Kobayashi, S.;
Murakami, M.; Mukaiyama, T. Chem. Lett. 1986, 953–956. (c)
Inokuchi, T.; Kurokawa, Y.; Kusumoto, M.; Tanigawa, S.; Takagishi,
S.; Torii, S. Bull. Chem. Soc. Jpn. 1989, 62, 3739–3741. (d) Grieco, P. A.;
Cooke, R. J.; Henry, K. J.; VanderRoest, J. M. Tetrahedron Lett. 1991,
32, 4665–4668. (e) Berl, V.; Helmchen, G.; Preston, S. Tetrahedron Lett.
1994, 35, 233–236.
ꢀ
(5) Selected works: (a) Dratch, S.; Charnikhova, T.; Saraber, F. C.;
Jansen, B. J. M.; de Groot, A. Tetrahedron 2003, 59, 4287–4295. (b)
Saraber, F. C.; Baranovsky, A.; Jansen, B. J. M.; Posthumus, M. A.; de
Groot, A. Tetrahedron 2006, 62, 1726–1742. (c) Jung, M. E.; Chang, J. J.
Org. Lett. 2010, 12, 2962–2965.
ꢀ
(6) (a) Mukaiyama, T.; Izawa, T.; Saigo, K. Chem. Lett. 1974, 323–
326. (b) Masuyama, Y.; Kobayashi, Y.; Yanagi, R.; Kurusu, Y. Chem.
Lett. 1992, 2039–2042. (c) Yanagisawa, M.; Shimamura, T.; Iida, D.;
Matsuo, J.; Mukaiyama, T. Chem. Pharm. Bull. 2000, 48, 1838–1840.
(7) (a) Song, C.-X.; Cai, G.-X.; Farrell, T. R.; Jiang, Z.-P.; Li, H.;
Gan, L.-B.; Shi, Z.-J. Chem. Commun. 2009, 6002–6004. (b) Liu, L.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 3069–3072.
(8) (a) Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A. Angew.
Chem., Int. Ed. 2009, 48, 9131–9134. (b) Onishi, Y.; Nishimoto, Y.;
Yasuda, M.; Baba, A. Org. Lett. 2011, 13, 2762–2765. (c) Onishi, Y.;
Nishimoto, Y.; Yasuda, M.; Baba, A. Chem. Lett. 2011, 40, 1223–1225.
(9) “Indirect” Michael reactions, in which tin enolates derived from
enol esters were employed as enol nucleophiles, have been reported; see:
(a) Hashimoto, Y.; Sugumi, H.; Okauchi, T.; Mukaiyama, T. Chem.
Lett. 1987, 1695–1698. (b) Yanagisawa, A.; Izumi, Y.; Arai, T. Chem.
Lett. 2008, 37, 1092–1093.
r
10.1021/ol302888k
Published on Web 11/06/2012
2012 American Chemical Society

Table 2. Michael Additions of Various Enol Acetates 2 to
Chalcone 1ba
Scheme 1
led to this achievement. To the best of our knowledge, this
is the first report of the direct use of enol acetates in
Michael additions.9 In addition, it is noteworthy that
Michael adducts were readily isolated as a pure enol-form
because they are considerably more stable than the corre-
sponding metal enolates.
First, the screening of Lewis acid catalysts was carried
out in the model reaction of (E)-1-phenyl-2-buten-1-one (1a)
with isopropenyl acetate 2a (Table 1). While neither InCl3 nor
Me3SiCl had catalytic ability, their combination provided the
Table 1. Screening of Catalystsa
entry
catalyst
InCl3
additive
yieldb (%)
1c
2c
6
0
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
3
InCl3
InBr3
InI3
69
53
72
0
4
5
6c
TiCl4
AlCl3
a Reaction conditions: 1b (1 mmol), 2 (1.5 mmol), InCl3 (0.05 mmol),
Me3SiCl (0.1 mmol), CH2Cl2 (1 mL), rt, 5 h. b Yield by 1H NMR
analysis. Values in parentheses are isolated yields. c InCl3 (0.15 mmol),
Me3SiCl (0.3 mmol). d dr = 51:49. e dr = 65:35. f InCl3 (0.1 mmol),
Me3SiCl (0.2 mmol), 2e (5 mmol). g dr = 62:38. h dr = 51:49.
7c
0
8c
BF3 OEt2
8
3
9c
BF3 OEt2
Me3SiCl
0
3
10c
11c
12d
13e
14c,f
15g
Sc(OTf)3
BiCl3
InCl3
InCl3
InCl3
InCl3
9
0
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
62
48
0
yields similar to that of InCl3 (entries 4 and 5). Representative
Lewis acids such as TiCl4, AlCl3, and BF3 OEt2 did not
3
promote the desired reaction (entries 6À8), and the result was
not improved by a combination with Me3SiCl (entry 9).
Sc(OTf)3 and BiCl3, which are reported to be effective
catalysts for Michael additions using silyl enolates,3a,b pro-
duced only low yields of 3aa (entries 10 and 11). In toluene, the
desired reaction proceeded sufficiently (entry 12), while co-
ordinative solvents considerably deactivated the catalyst, and,
in particular, THF completely disturbed the reaction (entries
13 and 14). Five equivalents of 2a increased the yield of 3aa to
90
a Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), catalyst (0.05
mmol), additive (0.1 mmol), CH2Cl2 (1 mL), rt, 5 h. b Yield by 1H NMR
analysis. c 1a was considerably recovered. d Toluene (1 mL) was used
instead of CH2Cl2.e MeCN(1mL) wasusedinsteadofCH2Cl2.f THF (1 mL)
was used instead of CH2Cl2. g 2a (5 mmol).
enol-form product 3aa in a 69% yield (entries 1À3).8aÀc,10
Other combinations using InBr3 or InI3 also gave a level of
(10) (a) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Eur. J. Org. Chem.
2002, 1578–1581. (b) Saito, T.; Yasuda, M.; Baba, A. Synlett 2005, 1737–
1739. (c) Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2006, 71,
8516–8522. (d) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org.
Chem. 2007, 72, 8588–8590.
(11) Other combinations of indium halides and silyl halides were
investigated, and the results are shown in the Supporting Information.
(12) The employment of InCl3 was the combination of choice due to
the moisture sensitivity of InBr3 and InI3.
Org. Lett., Vol. 14, No. 22, 2012
5789

and effectively gave Michael adducts 3 as an enol acetate
form (entries 1 and 2). Enol acetates 2c and 2d, which bear
a substituent at the vinyl terminus, also provided the
corresponding products in 72 and 95% yields, respectively
(entries 3 and 4). Reactions using cyclohexanone-derived
cyclic enol acetate 2e and R-tetralone-derived 2f proceeded
smoothly to give the desired product in moderate to high
yield (entries 5 and 6). Unfortunately, sterically hindered
enol acetate 2g furnished no Michael adduct (entry 7). We
confirmed that all of the obtained enol acetates 3 had the
Z-configuration in their olefin moieties.13
Table 3. Michael Additions Using Diverse R,β-Unsaturated
Ketonesa
Table 3 shows that diverseR,β-unsaturated ketones were
applicable to this reaction. (E)-1-(4-Methoxyphenyl)-2-bu-
ten-1-one (1c) gave a lower yield than 4-chlorophenyl-sub-
stituted derivative 1d (entries 1 and 2). These results indicate
that the electronic factor on the phenyl ring apparently affects
the reactivity of R,β-unsaturated ketones. Acyclic aliphatic
unsaturated ketone 1e gave no adduct, but cyclic 1f produced
the E-form of 3fb in excellent yield (entries 3 and 4). Enol
acetate 2b reacted with tert-butyl ketone derivative 1g to
provide Michael adduct 3gb in an 85% yield (entry 5). In the
reaction of dibenzylideneacetone 1h, the desired product 3hb
was obtained in 89% yield (entry 6). In contrast to entries 1
and 2, benzalacetone 1i and its analogues 1jÀl furnished
Michael adducts in high yields, regardless of the electronic
factor on the phenyl ring. In addition, mixtures of E and Z
isomers were produced unexpectedly (entries 7À10). The
introduction of a methyl group at the vinylic R-position of the
Scheme 2. Further Application of Enol-Form Michael
Adducts 3
a Reaction conditions: 1 (1 mmol), 2 (5 mmol), InCl3 (0.05 mmol),
Me3SiCl (0.1 mmol), CH2Cl2 (1 mL), rt, 5 h. b Yield by 1H NMR
analysis. Values in parentheses are isolated yields. c 0 °C. d InCl3
(0.1 mmol), Me3SiCl (0.2 mmol). e 2b (1.5 mmol). f E/Z = 17:83. g 2b
(1.5 mmol), InCl3 (0.1 mmol), Me3SiCl (0.2 mmol). h E/Z = 11:89. i E/Z
= 19:81. j E/Z = 15:85. k In toluene solvent, careful treatment was
required (see the Supporting Information).
carbonyl group dramatically lowered the yield of adduct 3mb
to only 15% (entry 11). The reaction using phenyl vinyl
ketone 1n, which was easily polymerized, was also successful
by the following treatment in a toluene solution to give
Michael adduct 3nb in a 56% yield.
90% (entry 15), but we found that the conditions employed in
entry 3 were the ones that were practical and optimal.11,12
The scope of enol acetates was investigated by reactions
using chalcone 1b (Table 2). Enol acetates 2a and 2b were
derived from aliphatic and aromatic ketones, respectively,
Synthetic applications of the easily isolated enol form of
Michael adducts 3 are shown in Scheme 2. Pd/C-catalyzed
5790
Org. Lett., Vol. 14, No. 22, 2012

with InCl3, and the silicon center activates enone 1. Then,
the succesive nucleophilic attack of enol acetate 2 forms
silyl enolate 11. Finally, an intramoleculer acyl migration
produces the desired adduct 3 along with the regeneration
of combined Lewis acid 10. According to this mechanism,
only the Z-isomer of 3 may be obtained. But only the
reactions using benzalacetone 1i and its analogues 1jÀl
(entries 7À10, Table 3) were accompanied by the E-isomer
as a minor product. The involvement of the s-trans form of
R,β-unsaturated ketones 1 may give E-isomers in the
addition step with 2. It is also conceivable that ketoÀenol
tautomerization of 11 takes place, but as yet there is no
proof of that assertion.17 We confirmed that no tautomer-
ization of obtained E-isomer 3ib took place under the
reaction conditions.
In summary, we have achieved the first successful direct
Michael addition using enol acetates as enol nucleophiles.
The combination of the Lewis acids InCl3 and Me3SiCl
was the turning point in this reaction system. It is note-
worthy that Michael adducts can be easily isolated as an
enol-form.
Figure 1. Tentative mechanism.
hydrogenation selectively promoted the CÀC double bond
reduction to produce alkyl acetate 4 in a 72% yield (eq 3).
These results indicate the great advantage of utilizing enol
acetates 3, because the preparation of 4 from the correspond-
ing 1,5-diketone is quite burdensome. The tin enolate gener-
ated from Michael adduct 3nb and Bu3SnOMe in situ
occurred in a successive radical coupling with methyl R-
bromoacetate 5 to furnish tricarbonyl compound 6 in a 62%
yield (eq 4).14 A nitroso aldol reaction was also successful
to produce R-hydroxyamino ketone 8 in a moderate yield
(eq 5).15 Furthermore, when the 1,5-diketone corresponding
to Michel adduct 3 was sought, Bu2SnO-catalyzed transes-
terification was effectively employed (eq 6).16
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (Nos. 24750090,
24350047, and 243500680) and for Scientific Research on
Innovative Areas (No. 24106725, “Organic Synthesis
Based on Reaction Integration. Development of New
Methods and Creation of New Substances”, and No.
23105525, “Molecular Activation Directed toward Straight-
forward Synthesis”) and Challenging Exploratory Research
(No. 23655083 and No. 24655030) from the Ministry
of Education, Culture, Sports, Science and Technology
(Japan). Y.O. thanks JSPS Research Fellowships for
Young Scientists.
Figure 1 shows a plausible reaction mechanism. The
Lewis acidity of Me3SiCl is enhanced by the combination
Supporting Information Available. Experimental pro-
cedures, characterization, and spectral data. This materi-
al is available free of charge via the Internet at http://
pubs.acs.org.
(13) The geometry of the olefin moiety in enol acetates 3bb, 3ca, 3gb,
3ib, 3jb, 3hb, 3lb, and 3nb was assigned as the Z-configuration by
NOESY.
(14) Miura, K.; Fujisawa, N.; Saito, H.; Wang, D.; Hosomi, A. Org.
Lett. 2001, 3, 2591–2594.
(15) Momiyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579–3582.
(16) Poller, R. C.; Retout, S. P. J. Organomet. Chem. 1979, 173,
C7–C8.
(17) To the best of our knowledge, there are no reports for ketoÀenol
tautomerization of silyl enolates.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
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