KF-alumina-mediated selective double Michael additions of aryl methyl ketones: A facile entry to the synthesis of functionalized pimelate esters and derivatives

Article abstract of DOI:10.1055/s-2004-831339

Here we describe simple and efficient double Michael additions of aromatic and aliphatic methyl ketones to electron deficient alkenes promoted on a surface of KF-alumina. This one-pot procedure provides an easy access to a host of functionalized pimelate

Full text of DOI:10.1055/s-2004-831339

2
224
LETTER
KF–Alumina-Mediated Selective Double Michael Additions of Aryl Methyl
Ketones: A Facile Entry to the Synthesis of Functionalized Pimelate Esters and
Derivatives
K
B
F–Alumina-M
e
a
diated Sele
s
ctive Dou
u
ble Michael
d
Department of Chemistry, North Bengal University, Darjeeling 734 430, India
E-mail: basu_nbu@indiatimes.com
Received 17 May 2004
pot procedure for the double Michael reactions promoted
on a surface of KF–alumina leading to the synthesis of a
host of functionalized pimelate esters. To the best of our
Abstract: Here we describe simple and efficient double Michael
additions of aromatic and aliphatic methyl ketones to electron defi-
cient alkenes promoted on a surface of KF–alumina. This one-pot
procedure provides an easy access to a host of functionalized pime- knowledge, this is the first example of selective double
late esters, which can be subsequently converted in to 3-acylcyclo- Michael additions of aromatic and aliphatic methyl ke-
hexanones.
tones to electron deficient alkenes mediated by KF–alu-
Key words: double Michael additions, acetophenone, KF–alu- mina (Scheme 1).
mina, pimelate esters, cyclohexanones
9
The reaction protocol is very simple. An adsorbed mix-
ture of acetophenone (1.0 mmol) and ethyl acrylate (3.0
mmol) on preformed8 KF–alumina (1 g) was stirred
initially at room temperature for one hour and then heated
at 50 °C with stirring for ten hours to produce the double
Michael adduct (67% yield) along with a small amount of
the mono-adduct (8% yield, entry 1). The reaction occurs
smoothly to double addition and does not require high
temperature; usual work up afforded the product. It ap-
peared from the product distribution that the rate of the
second Michael addition is faster than that of the first ad-
dition. This was further supported by the fact that the re-
action of acetophenone (1.0 mmol) and ethyl acrylate (1.2
mmol) on KF–alumina (1 g) had produced the double
Michael adduct as the major product. After the initial suc-
cess with acetophenone, we tested this synthetic proce-
dure with substituted acetophenones and either ethyl
acrylate or acrylonitrile (Table 1, entries 2–7). The reac-
tion was extended to meta- and para-substituted ace-
tophenones and no significant electronic effects were
observed. The yields of the reactions were comparable
and in general, the reaction yielded the pimelate ester or
pimelonitrile as the major product.
a
The Michael addition reaction, an important C-C bond-
1
forming reaction, is known to produce mono-adducts,
2
which have found wide synthetic applications. Several
acid and base catalysts are used to effect this reaction.
Side reactions, frequently encountered in the presence of
a base catalyst, are secondary condensations, polymeriza-
3
tions and double additions. However, the reactions in
which two C-C bonds are selectively formed by intermo-
lecular double Michael reactions in one-pot are very rare.4
Both, alumina and KF–alumina, have been earlier used for
Michael additions of 1,3-diketones, b-ketoesters and ni-
troalkanes to a variety of a,b-unsaturated carbonyl com-
5
pounds. Nitroalkanes and b-ketoesters are also reported
to produce Michael adducts via inter- and intramolecular
double Michael additions, catalyzed by fluoride anion.6
But none of these reports described selective formation of
a double Michael adduct in one-pot intermolecular reac-
tions of methyl ketones with Michael acceptors. Forrester
et al. reported partial bis-adduct formation while prepar-
ing the mono-adduct from acetophenone and methacry-
lonitrile in the presence of potassium methoxide in
To broaden the scope of the reaction, we examined
Michael reaction of acetone (entry 8) and iso-butylmethyl
ketone (entry 9). Both aliphatic ketones underwent bis-
7
benzene. Over the past few years, we are actively en-
gaged in developing organic reactions mediated on a sur-
8
face of KF–alumina. We report herein an efficient one-
Scheme 1
SYNLETT 2004, No. 12, pp 2224–2226
0
1
.1
0
.2
0
0
4
Advanced online publication: 03.09.2004
DOI: 10.1055/s-2004-831339; Art ID: D12104ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
KF–Alumina-Mediated Selective Double Michael Additions
2225
addition with similar efficiencies and afforded the desired methyl methacrylate yielded the desired double Michael
products. Acetone gave the bis-adduct, diethyl 3-acetyl- adduct in 72% yield (entry 12).
heptanedioate in 63% yield, with no reaction of the other
methyl group.
Attempt to conduct the experiment with cinnamaldehyde
led to an intractable mixture, probably due to polymeriza-
Similar reactions were tested employing methyl crotonate tion of the unsaturated aldehyde on the solid surface
(
entry 10) and methyl cinnamate (entry 11) as the Michael (entry 13).
acceptors, but the reaction ended up with the mono-ad-
ducts only even after prolonged reaction time and elevated
temperatures. The possible reason for this may be attrib-
uted to the steric inhibition at the b-carbon of the conju-
gated olefins. On the other hand, similar reactions with
Adsorption of potassium fluoride on alumina is believed
to increase its basicity by which poorly acidic carbon
10
compounds (pK ca. 18–30) may be ionized. Therefore,
a
the acetophenone is likely to act as the Michael donor on
a surface of KF–alumina, but the faster second addition is
Table 1 Double Michael Addition of Acetophenones with Alkenes on KF–Alumina
Entry
Ketone
Acceptor
Condition
Product
Yield (%)a
1
2
3
4
5
R = H
50 °C/10 h
60 °C/10 h
60 °C/10 h
55 °C/12 h
56 °C/10 h
R = H
67
59
79
70
61
R = p-Me
R = p-OMe
R = p-Br
R = m-NO2
R = p-Me
R = p-OMe
R = p-Br
R = m-NO2
6
7
8
R = H
40 °C/10 h
40 °C/10 h
40 °C/12 h
R = H
62
68
63
R = p-Cl
R = p-Cl
9
50 °C/10 h
60 °C/12 h
60 °C/12 h
50 °C/12 h
66
70
75
72b
1
1
1
0
1
2
1
3
40 °C/6 h
No adduct was isolated
a
The products were characterized by IR, H NMR and 13C NMR spectral data.
1
b
The compound was a mixture of stereoisomers.
Synlett 2004, No. 12, 2224–2226 © Thieme Stuttgart · New York

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226
B. Basu et al.
LETTER
unexpected. However, the reaction is limited with b-un-
(2) (a) Oare, D. A.; Heathcock, C. H. In Topics in
Stereochemistry, Vol. 19; Eliel, E. L.; Wilen, S. H., Eds.;
John Wiley and Sons: New York, 1989, 277. (b) d’Angelo,
J.; Revial, G.; Costa, P. R. R.; Castro, R. N.; Antunes, O. A.
C. Tetrahedron: Asymmetry 1991, 2, 199. (c) List, B.;
Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
substituted Michael acceptors only.
The double Michael adducts are potentially useful build-
ing blocks for the preparation of functionalized cyclo-
1
1
hexanone derivatives. As an application, diethyl (4-
methoxybenzoyl) heptanedioate was subjected to Dieck-
(d) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611.
1
2
(3) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th ed.; John Wiley and Sons: New York, 2001,
mann cyclization and the desired product 4-(4-methoxy-
benzoyl) cyclohexanone was isolated in 57% yield
1022.
(
Scheme 2).
(
4) (a) Bhardwaj, C. L.; Ireson, J. C.; Lee, J. B.; Tyler, M. J.
Tetrahedron 1977, 33, 3279. (b) Giardini, A.; Lesma, G.;
Passarella, D.; Perez, M.; Silvani, A. Synlett 2001, 132.
(
c) Hughes, F. Jr.; Grossman, R. B. Org. Lett. 2001, 3, 2911.
5) (a) Bergbreiter, D. E.; Lalonde, J. J. J. Org. Chem. 1987, 52,
601. (b) Ranu, B. C.; Bhar, S. Tetrahedron 1992, 48, 1327.
6) (a) Irie, H.; Mizuno, Y.; Taga, T.; Osaki, K. J. Chem. Soc.,
Perkin Trans. 1 1982, 25. (b) Clark, J. H.; Cork, D. G.;
Robertson, M. S. Chem. Lett. 1983, 1145. (c) Yamawaki, J.;
Kawate, T.; Ando, T.; Hanafusa, T. Bull. Chem. Soc. Jpn.
(
(
1
Scheme 2
1983, 56, 1885.
In conclusion, a novel and expedient method for selective
double Michael additions of aromatic and aliphatic meth-
yl ketones to activated olefins mediated by KF–alumina
has been developed. That provides rapid access to a host
of functionalized heptanedioic acids and derivatives of
high synthetic utility. The method is operationally
straightforward and the yields of the double Michael ad-
duct are typically very good. The functionalized diesters
can be induced to cyclize yielding 4-acylcyclohexanones,
which are valuable building blocks for natural product
synthesis. We feel that the procedure will find important
applications in synthetic organic chemistry.
(7) Forrester, A. R.; Irikawa, H.; Thomson, R. H.; Woo, S. O.;
King, T. J. J. Chem. Soc., Perkin Trans. 1 1981, 1712.
(
8) (a) Basu, B.; Jha, S.; Mridha, N. K.; Bhuiyan, M. M. H.
Tetrahedron Lett. 2002, 43, 7967. (b) Basu, B.; Das, P.;
Bhuiyan, M. M. H.; Jha, S. Tetrahedron Lett. 2003, 44,
3817.
(
9) Representative Experimental Procedure: A mixture of 4-
methoxyacetophenone (300 mg, 2 mmol) and ethyl acrylate
(600 mg, 6 mmol) was added in one portion to dry preformed
KF–alumina (2 g) and the solid mixture was stirred at 60 °C
for 10 h. TLC was checked and the mixture was packed on a
column of silica gel and eluted with petroleum ether–EtOAc
(9:1) to afford diethyl (4-methoxybenzoyl) heptanedioate as
colorless viscous oil (553 mg, 79%). IR (neat): 1735, 1680,
–
1 1
1
588 cm . H NMR (300 MHz, CDCl ): d = 1.22 (t, 6 H,
3
J = 7.1 Hz, 2 OCH CH ), 1.80–1.88 (m, 2 H, 2 CHCH CO),
2
3
2
Acknowledgment
2
.05–2.12 (m, 2 H, 2 CHCH CO), 2.19–2.41 (m, 4 H, 2
2
We are thankful to the Council of Scientific and Industrial Re-
search, New Delhi (No.01-1863/03/EMR-II) for financial support.
PD and IH are grateful to CSIR for their fellowships.
CH
OCH
2
CH
2
CO), 3.56–3.63 (m, 1 H, COCHCH
CH
2
), 3.87 (s, 3 H,
), 6.95 (d, 2 H,
), 4.10 (q, 4 H, J = 7.1 Hz, 2 OCH
3
2
3
1
3
J = 8.8 Hz, ArH), 7.99 (d, 2 H, J = 8.8 Hz, ArH). C NMR
75 MHz, CDCl ): d = 14.0, 26.9, 31.5, 43.2, 55.3, 60.2,
(
3
1
13.8, 129.9, 130.6, 163.6, 172.9, 201.2.
(10) (a) Villemin, D.; Ricard, M. Tetrahedron Lett. 1984, 25,
059. (b) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet,
References
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(
(
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Synlett 2004, No. 12, 2224–2226 © Thieme Stuttgart · New York