Microwave-accelerated conjugate addition of aldehydes to α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2003.10.015

Aldehydes undergo smooth conjugate addition to α,β-unsaturated ketones in the presence of 5-(2-hydroxyethyl)-1,3-thiazolium halides and DBU adsorbed onto the surface of basic alumina under microwave irradiation and solvent-free conditions to afford 1,4-di

Full text of DOI:10.1016/j.tetlet.2003.10.015

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8959–8962
Microwave-accelerated conjugate addition of aldehydes to
a,b-unsaturated ketones
J. S. Yadav,* K. Anuradha, B. V. Subba Reddy and B. Eeshwaraiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 8 May 2003; revised 23 September 2003; accepted 3 October 2003
Abstract—Aldehydes undergo smooth conjugate addition to a,b-unsaturated ketones in the presence of 5-(2-hydroxyethyl)-1,3-thi-
azolium halides and DBU adsorbed onto the surface of basic alumina under microwave irradiation and solvent-free conditions to
afford 1,4-diketones in enhanced yields and reduced reaction times compared to conventional methods.
© 2003 Elsevier Ltd. All rights reserved.
The use of inorganic solid supports as reaction media in
organic synthesis is increasingly widespread due to
improved efficiency of many surface-bound reagents.1
Microwave irradiation has become a powerful synthetic
tool for the rapid synthesis of a variety of organic
compounds.2 Microwave-assisted reactions have
attracted much interest because of the simplicity in
operation and milder reaction conditions. The salient
features of the microwave approach are improved
yields, enhanced reaction rates, formation of pure prod-
ucts in high yields and ease of isolation. Solvent-free
microwave assisted reactions have gained more popu-
larity as they provide an opportunity to work with open
vessels. This avoids the risk of development of high
pressure and provides the possibility of scaling-up the
reaction and helps the induction of the reaction under
dry conditions.3
forward synthetic methods for the synthesis of 1,4-dike-
tones is the conjugate addition of aldehydes to
a,b-unsaturated ketones employing quaternary thia-
zolium salts in the presence of a tertiary amine.6,7 This
conventional approach only provides satisfactory
results with aliphatic aldehydes. The reactions of aro-
matic aldehydes with a,b-unsaturated ketones require
high temperatures and longer reaction times and also
the products are obtained in low to moderate yields.
Thus there is scope to develop a rapid and high yielding
protocol for the preparation of 1,4-diketones of syn-
thetic importance.
In this report, we describe our results on the microwave-
accelerated synthesis of 1,4-diketones using a solid sup-
ported reagent system, thiazolium salt–DBU–Al2O3.
Thus treatment of aliphatic, aromatic and heteroaro-
matic aldehydes with a,b-unsaturated ketones in the
presence of an equimolar ratio of 5-(2-hydroxyethyl)-
1,3-thiazolium chloride or bromide and DBU dispersed
onto the surface of alumina using microwave irradiation
under solvent-free conditions afforded the correspond-
ing g-diketones in high yields (Scheme 1 and Table 1).
1,4-Diketones are very useful precursors for the synthe-
sis of a variety of heterocycles such as pyrroles, furans,
thiophenes and pyridazines.4 In addition, they are valu-
able intermediates in the synthesis of cyclopentenone
derivatives and many others.5 One of the most straight-
Scheme 1.
Keywords: conjugate addition; a,b-unsaturated ketones; microwave; 1,4-diketones.
* Corresponding author. Fax: +91-40-27160512; e-mail: yadav@iict.ap.nic.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.015

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Table 1. Microwave-assisted synthesis of 1,4-dicarbonyl compounds

J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 8959–8962
8961
References
The reaction proceeded efficiently under microwave
irradiation and solvent-free conditions. The reactions
were carried out both under microwave as well as
thermal conditions. Microwave irradiations were car-
ried out using a BPL, BMO-800T domestic microwave
oven operated at 2450 MHz (450 W). The reaction
temperature was controlled using a pulsed irradiation
technique (1 min with 20 s intervals). The temperature
was measured after each pulse. The lowest observed
temperature was 80°C after irradiation for one-minute
at 450 W and the highest temperature was 110°C after
3 min irradiation at the same power. The reaction rates
and yields were dramatically enhanced by microwave
irradiation. The rate enhancement under microwave
irradiation may be attributed to the absorption of more
microwave energy by the polar media, which generates
sufficient heat energy to promote the reaction. The
same reaction, under thermal conditions, at 110°C took
6–10 h to afford yields comparable with those obtained
by microwave irradiation. All the products were char-
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1
acterized by H, 13C NMR, IR, and mass spectroscopic
data. Aliphatic aldehydes afforded excellent yields of
products comparable to aromatic analogues. However,
in the case of aromatic aldehydes, 5-(2-hydroxyethyl)-
1,3-thiazolium bromide was used to promote the reac-
tion as it was found to be more effective than the
corresponding chloride. The scope and generality of
this process is illustrated with respect to various alde-
hydes including aliphatic, aromatic, and heterocyclic
ones as well as a,b-unsaturated ketones; the results are
presented in Table 1.8 In the absence of the base, the
reactions of aromatic aldehydes proceeded only to a
minor extent (15–25%) when the reactants were sub-
jected to microwave irradiation under the influence of
the thiozolium salt and basic alumina. In contrast,
aliphatic aldehydes reacted smoothly with enones even
in the absence of base under similar reaction condi-
tions. Among various bases such as Et3N, DBU,
DABCO, and DBN studied for this reaction, DBU was
found to be more efficient in promoting these reactions.
7. (a) Stetter, H.; Kuhlmann, H. Synthesis 1975, 379–380; (b)
Novak, L.; Majoros, B.; Szantay, C. Heterocycles 1979,
12, 396–398; (c) Novak, L.; Baan, G.; Marosfalvi, J.;
Szantay, C. Tetrahedron Lett. 1978, 19, 487–490; (d)
Raghavan, S.; Anuradha, K. Tetrahedron Lett. 2002, 43,
5181–5183.
8. Typical procedure: n-Heptanal (3 equiv.), 1,3-diphenyl-(E)-
2-propen-1-one (1 equiv.), thiazolium salt (40 mol%) and
DBU (1.5 equiv.) were admixed with basic Al2O3 (1.0 g)
and the resulting solid was subjected to microwave irradia-
tion using a BPL, BMO-800T domestic oven operated at
450 W for an appropriate time (Table 1). After completion
of the reaction as indicated by TLC, the reaction mixture
was filtered and washed with dichloromethane (2×15 mL).
The combined organic layers were washed with water,
brine and dried over anhydrous Na2SO4. Removal of the
solvent under reduced pressure followed by purification on
silica gel (Merck, 100–200 mesh, ethyl acetate–hexane 1:9)
afforded the corresponding 1,4-diketone pure. Spectral
data for selected compounds: 3a: 1H NMR (CDCl3, 200
MHz): l 1.84 (s, 3H), 2.12 (s, 3H), 3.02 (dd, 1H, J=18.0,
3.9 Hz), 4.01 (dd, 1H, J=18.0, 9.9 Hz), 4.37 (dd, 1H,
J=9.9, 3.9 Hz), 6.07 (s, 1H), 7.21–7.53 (m, 8H), 7.96 (d,
2H, J=7.8 Hz). 13C NMR (CDCl3): l 20.8, 27.6, 42.0,
54.0, 123.5, 127.1, 128.0, 128.3, 128.8, 129.6, 132.8, 136.6,
138.8, 156.3, 197.9, 198.0. EIMS: m/z (%): 292 (M+ 10),
210 (15), 141 (20), 105 (85), 83 (100), 77 (70). HRMS calcd
for C20H20O2: 292.1463. Found: 292.1498.
In summary, we have developed a simple, convenient
and rapid method for the synthesis of 1,4-diketones
from aldehydes and a,b-unsaturated ketones using a
solid supported reagent system, i.e. thiazolium salt–
DBU–Al2O3 under microwave irradiation. The present
method avoids the use of solvent and extended reaction
times and is a very useful preparation of g-diketones
especially from aromatic aldehydes, which typically give
low yields of adducts under conventional conditions.
The reduced reaction times together with the minimiza-
tion of thermal decomposition of the products are the
main advantages of microwave heating and further
improvement would be facilitated by the availability of
a continuous microwave reactor.
1
3e: H NMR (CDCl3, 200 MHz): l 3.37 (dd, 1H, J=18.5,
3.7 Hz), 4.21 (dd, 1H, J=18.5, 10.3 Hz), 5.50 (dd, 1H,
J=10.4, 3.7 Hz), 6.88–7.62 (m, 8H), 7.94 (d, 2H, J=8.9
Hz), 8.10 (d, 2H, J=9.0 Hz). 13C NMR (CDCl3): l 43.0,
44.2, 115.8, 125.2, 126.0, 127.3, 128.1, 128.6, 131.5, 132.5,
133.3, 136.1, 140.3, 167.3, 196.1, 197.5. EIMS: m/z: 338
(M+ 35), 123 (100), 95 (40), 77 (25). HRMS calcd for
C20H15O2SF: 338.0776. Found: 338.0729.
Acknowledgements
3g: 1H NMR (CDCl3, 200 MHz) l: 0.90 (t, 3H, J=6.8
Hz), Hz), 1.13–1.28 (m, 2H), 1.40–1.58 (m, 2H), 2.32–2.65
B.V.S. and K.A. thank CSIR New Delhi for financial
assistance.

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J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 8959–8962
55.2, 114.7, 119.5, 120.7, 122.4, 123.3, 129.3, 137.3, 137.4,
(m, 2H), 3.22(dd, 1H, J=18.2, 5.3Hz), 3.94(dd, 1H, J=18.2,
149.1, 156.9, 157.5, 198.0, 208.4. EIMS: m/z: 311 (M+ 90),
226 (5), 190 (8), 121 (15), 106 (40), 81 (60), 55 (100). HRMS
calcd for C19H21O3N: 311.1521. Found: 311.1561.
9.0 Hz), 4.58 (dd, 1H, J=9.0, 5.3 Hz) 6.90 (d, 1H, J=9.0
Hz), 7.08–7.41 (m, 5H), 7.63 (t, 1H, J=7.8 Hz), 8.55 (d, 1H,
J=5.3 Hz). 13C NMR (CDCl3) l: 13.4, 21.8, 25.4, 40.6, 41.5,