New Application of 1,4-Dihydropyridine System: Michael Reactions Mediated by 1,4-Dihydropyridine-Enolate Adduct in Micellar Medium

Article abstract of DOI:10.1246/cl.2003.1064

1,4-dihydropyridine-acetophenone enolate adduct, in catalytic amount effects Michael reactions in aqueous cationic micelles of cetyltrimethylammonium bromide. The enolate, generated by dissociation of the adduct abstracts a proton from readily enolizable substrates to bring about the Michael reaction under mild conditions in fair to good yields without side products.

Full text of DOI:10.1246/cl.2003.1064

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064
Chemistry Letters Vol.32, No.11 (2003)
New Application of 1,4-Dihydropyridine System: Michael Reactions Mediated
by 1,4-Dihydropyridine–Enolate Adduct in Micellar Medium
Ã
Sabir H. Mashraqui and Madhavi A. Karnik
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz-E, Mumbai-400 098, India
(Received August 6, 2003; CL-030731)
1
,4-dihydropyridine-acetophenone enolate adduct, in cata-
lytic amount effects Michael reactions in aqueous cationic mi-
celles of cetyltrimethylammonium bromide. The enolate, gener-
ated by dissociation of the adduct abstracts a proton from readily
enolizable substrates to bring about the Michael reaction under
mild conditions in fair to good yields without side products.
1
Although, the Michael reaction is one of the oldest C–C
bonds forming reactions known, yet it continues to enjoy wide
applications in synthetic organic chemistry. A plethora of con-
2
ditions, and reagents, which include various inorganic and or-
ganic bases, acidic and Lewis acid catalysts, metal ion com-
plexes, and solid supported reagents have been employed to
3
effect the Michael additions with varying degree of successes.
Several side reactions such as secondary condensation, cycliza-
tion, isomerization, rearrangements, and polymerization are
known to accompany these conditions, thus necessitating con-
tinuing investigation of this versatile reaction.
Scheme 1.
changes would ensue, as illustrated in the Scheme 1.
In context to the NAD(P)H mediated enzymatic processes,
the redox chemistry of model 1,4-dihydropyridines has been ex-
tensively studied. In analogy to the hydride transfer reactions,
To translate the idea of Scheme 1 into practice, we chose an
aqueous cationic micelles as the reaction medium on the consid-
erations that, i) a number of dihydropyridinium–anion covalent
adducts (cyano, keto, and thiolate adducts) tend to dissociate
in aqueous or polar media to form pyridinium ion–anion ion
4
5
6
1
,4-dihydropyridine-enolate adduct 1 and thiolate adduct 2
(
Chart 1) have also been shown to transfer enolate and thiolate
anions, respectively to electrophilic acceptor substrates under
metal ion or Lewis acid catalysis. In the present paper, we wish
to report a novel application of adduct 1 in the mediation of
Michael reaction under practically neutral conditions.
9
–11
pairs, and ii) the aqueous micellar domain would be expected
to facilitate dissociation of the adduct 1 by providing the counter
anion and, iii) cationic micelles are known to promote nucleo-
philic processes.
To test the validity these assumptions, as a test case we set
up a reaction between a Michael donor, acetyl acetone, and the
Michael acceptor, benzylidine acetophenone in the presence of a
1
2
The mechanistic rationale is based on the premise that the
highly basic acetophenone enolate (pKa = 24.7) formed upon
7
ionization of 1 under suitable conditions would be expected to
spontaneously remove a proton from relatively more acidic sub-
5
8
catalytic amount of 1 (10 mol %), in aqueous solution of a well-
known cationic surfactant, cetyltrimethylammonium bromide
strates i.e. active methylene compounds (pKa ꢀ 9–11) to form
the corresponding stabilized carbanions. The latter would be
captured by the added elctrophilic olefins to form the Michael
addition products and a catalytic cycle involving proton ex-
À3
(
1:37 Â 10 M). The reaction after 8 h of vigorously stirring
at room temperature, followed by a simple workup procedure
provided to our delight the desired Michael product (Table, En-
try 1) in 80% yield. No Michael reaction occurred in the absence
1
3
of 1 or only in the presence of pyridine as the base. Anionic
surfactants, sodium dodecyl sulphate, or neutral surfactants such
as Triton X-100 were ineffective in promoting the Michael reac-
tion, whereas the common phase transfer catalyst, tributylammo-
nium bromide (2–5% aq solution) gave a maximum of 20% con-
version. These results clearly suggest a unique role of the
cationic micelles in promoting both the dissociation of 1 and
subsequent proton exchange processes (Scheme 1).
The generality of the process is evident from the examples
cited in the Table 1. The reactions are free from side products;
only a small amount of acetophenone, generated on proton ex-
change accompanies the Michael adducts. In general, yields
are high and in most cases, the product isolation (except for En-
Chart 1.
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.11 (2003)
1065
tries 6, 10, and 11, which require extractive workup) consists of
simple filtration and crystallisation. Although, only slightly
more acidic than acetophenone, phenylacetonitrile (pKa =
7
2
1.9) also successfully participated, giving a high yield of the
Michael product (Entry 14, Table 1). Since, in none of the cases,
could we detect the Michael reaction of acetophenone enolate, it
is evident that proton exchange with the active methylene sub-
strates must be relatively rapid processes.
In addition to the C–C bond formation, we could also suc-
cessfully excute C–S and C–N bond formations. Thus, as repre-
sentative case, the Michael reaction of benzylidene acetophe-
adduct 1 and cationic CTAB micelles has emerged as a practical-
ly non-basic methodology for C–C, C–S, and C–N bond forma-
17
tions. Our work extends the scope of NADH analogues such as
8
none with thiophenol (pKa = 6.52) and benzotriazole (pKa =
the adduct 1 in so far unchartered area of C–C, C–S, and C–N
bond formations. Work is currently in progress to use recyclable,
immobilized cationic surfactants to enhance the utility of the
present procedure.
1
4
8
.2) was readily accomplished to provide the Michael adducts
16
(Eqs 1 and 2) in high yields in the cationic micellar medium
using a catalytic amount of the adduct 1.
Notable features of the present procedure are the use of
cheap, environmentally friendly aqueous medium, milder condi-
tion and simple product isolation. Thus, a unique combination of
References and Notes
1
2
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a
1
5
Table 1. Michael reaction in aq CTAB micelles
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4
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6
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7
8
9
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1
1
0
1
(
1981).
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Attempts to effect the Michael reaction between acetyl acetone and benzylidene
acetophenone using a catalytic amount of the adduct 1 in methanol solvent con-
taining Mg(ClO4)2 gave only yield 13% of the corresponding Michael adduct
after 36 h at room temperature, whereas no reaction occurred in acetonitrile sol-
vent.
1
2
3
(
1
1
1
4
5
J. E. Fagel, Jr. and G. W. Ewing, J. Am. Chem. Soc., 73, 4360 (1951).
Typical procedure: To an aqueous solution of cetyl trimethylammonium bro-
À3
mide (1:37 Â 10 M, 100 mL) was added adduct 1 (180 mg, 0.5 mmol), ben-
zylidene acetophenone (1.04 g, 5 mmol) and acetyl acetone (550 mg, 5.5 mmol).
The reaction mixture was stirred vigorously at room temperture for 8 h whereby
the initial yellow color due to the starting chalcone diminished and a white, co-
pious precipitate was formed. The reaction was filtered, and the solid product
washed with 60% aqueous ethanol and air dried. Crystallisation from ethanol
afforded the desired Michael product, 4-acetyl-1,3-diphenylhexane-1,5-dione
ꢁ
ꢁ
in 80% yield, mp 145–46 C (lit. mp 146 C; A. Garcia-Raso, B. Garcia-Raso,
B. Campaner, R. Mestres, and J. V. Sinisterra, Synthesis, 1982, 1037). The prep-
aration of adduct 1 is given as a supplementary information.
Structures of Michael adducts have been characterised by elemental analysis, IR
and H-NMR spectral data.
1
1
6
7
A few examples of the Michael reactions in aq CTAB/NaOH condition have
been reported. However, the reaction medium is basic in nature with a pH of
ca 10.5. See: C. D. Mudaliar, K. R. Nivalkar, and S. H. Mashraqui, OPPI Briefs,
29, 584 (1997).
aMichael acceptor 3-9 are PhCH=CH-COPh, p-MeOC6H4CH=CHCOPh,
PhCH=CHCOCH3, PhCOCH=CH2, CH3COCH=CH2, PhCH=CH-CO-
CO2C2H5 and PhCH=CH-NO2, respectively.
Published on the web (Advance View) October 20, 2003; DOI 10.1246/cl.2003.1064