Solid-phase synthesis of 1,4-diketones by thiazolium salt promoted addition of aldehydes to chalcones

Article abstract of DOI:10.1016/S0040-4039(02)00972-3

The first report of thiazolium salt promoted Michael addition of aldehydes to chalcones (Stetter reaction) on solid-phase is reported. Reaction conditions have also been devised for cleaving the product 1,4-diketone from the solid-support in good yield an

Full text of DOI:10.1016/S0040-4039(02)00972-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5181–5183
Solid-phase synthesis of 1,4-diketones by thiazolium salt
promoted addition of aldehydes to chalcones†
Sadagopan Raghavan* and Kancharla Anuradha
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 5 February 2002; revised 7 May 2002; accepted 17 May 2002
Abstract—The first report of thiazolium salt promoted Michael addition of aldehydes to chalcones (Stetter reaction) on
solid-phase is reported. Reaction conditions have also been devised for cleaving the product 1,4-diketone from the solid-support
in good yield and high purity. © 2002 Elsevier Science Ltd. All rights reserved.
Parallel synthesis has developed into a powerful tool for
the creation of new chemical entities for drug discovery.1
Solid-phase synthesis has a number of advantages over
conventional solution-phase synthesis and is extensively
employed although considerable effort and time are
required for optimising the reactions. There is an increas-
ing need to expand both the number of available trans-
formations on solid-phase to prepare libraries and the
structural diversity present in those libraries. The cyanide
ion2 or thiazolium salt3 catalysed addition of aldehydes
to Michael acceptors in the presence of a base to afford
1,4-dicarbonyl compounds (Stetter reaction) is a transfor-
mation that permits generation of structural variety
efficiently. A minimum of three elements of diversity, two
from the Michael acceptor and one from the aldehyde,
can be introduced into the product using this reaction.
1,4-Diketones are useful intermediates in the synthesis of
cyclopentenones4 and in the synthesis of heterocycles such
as furans,5 pyrroles,6 thiophenes7 and pyrrolidines.8
The chalcones 1A–D, readily prepared10 by aldol conden-
sation in the solution-phase were anchored to the Wang
resin through the phenolic group using the Mitsunobu
protocol. After much experimentation, initially in the
solution-phase and later on the solid-phase, optimal
conditions were developed for the Stetter reaction. Thus
refluxing the mixture of resin bound chalcone, aldehyde
(9.0 equiv.), Et3N (9.0 equiv.), thiazolium salt (1.5 equiv.),
in dioxane/EtOH (8:2, v/v) for 30 h under a nitrogen
atmosphere afforded the 1,4-diketone in moderate to
good yield after cleavage from the solid-support. A total
of twelve diketones was prepared by reacting four
chalcones (1A–D) with different aldehydes (Table 1). The
reactions of aromatic and heteroaromatic aldehydes were
promoted by thiazolium salt I11 whereas reactions of
aliphatic aldehydes were promoted by thiazolium salt II.11
The following observations are worthy of note: the
chalcones (1B–D) linked by the 3-OH group to the solid
support reacted more readily to afford products in higher
yield than the chalcone 1A bound by the 4-OH group.
Delocalisation of electrons from the resin bound ether
oxygen to the carbonyl group in 1A would make it a
poorer Michael acceptor in comparison to chalcones
1B–D wherein such a delocalisation of electrons is not
possible. Aliphatic and heteroaromatic aldehydes
afforded products in higher yield than aromatic alde-
hydes. This outcome was not surprising since cyanide
catalysiswasfoundtobemostsatisfactoryforthereaction
of aromatic aldehydes with chalcones in the solution-
phase. Attempted cyanide ion catalysis of the reaction
As a continuation of our studies9 aimed at adapting
strategically important processes to solid-phase, we dis-
close herein the first report of the preparation of 1,4-dike-
tones by the thiazolium salt promoted addition of
aliphatic, aromatic and heteroaromatic aldehydes to
chalcones. The chalcones were chosen as the Michael
acceptors because of the ease of their preparation and by
virtueoftheir incorporating twoelements ofdiversity, one
each coming from an aldehyde and an acetophenone (Eq.
(1)).
(1)
Keywords: solid-phase; Stetter reaction; thiazolium salt; DDQ.
* Corresponding author. E-mail: purush101@yahoo.com
† IICT Communication No. 020128.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00972-3

5182
S. Ragha6an, K. Anuradha / Tetrahedron Letters 43 (2002) 5181–5183
Table 1.
with aromatic aldehydes in DMF as the solvent failed
to give any 1,4-diketone after cleavage from the solid
support. While the products elaborated from chal-
cones 1A–C could be cleaved with 25% TFA/DCM in
high yield and purity, identical conditions led to a
complex mixture of products from 1D. DDQ12 in
DCM/water was used to liberate products elaborated
from 1D in high yield and purity.

S. Ragha6an, K. Anuradha / Tetrahedron Letters 43 (2002) 5181–5183
5183
In conclusion, we have adapted the important C–C bond
forming Stetter reaction, to solid-phase. The product
1,4-diketones are important intermediates in the synthesis
of heterocycles and cyclopentenone.
128.6, 122.3, 121.3, 119.7, 118.1, 117.6, 113.7, 111.4, 50.2,
46.0. m/z (EI) 321 (50), 201 (100).
Cleavage using DDQ: To the resin-bound product 1Db
on the solid support (0.2 g, 1.03 meq./g) suspended in
DCM/water (4.0 mL, 9.5:0.5, v/v), DDQ (0.14 g, 0.6
mmol, 3.0 equiv.) was added and the mixture stirred at
rt for 4 h. The resin was filtered and washed thoroughly
with DCM. The combined filtrates were washed succes-
sively with aq. satd NaHCO3, water and brine. Drying
over sodium sulfate and evaporation afforded the crude
product which was purified by column chromatography
to afford 1Db (50 mg, 60%). 1H NMR (200 MHz, CDCl3)
l 8.13 (s, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.2
Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.40–7.20 (m, 4H), 7.0
(d, J=8.2 Hz, 1H), 6.25 (m, 1H), 6.10 (m, 1H), 5.30 (dd,
J=9.6, 2.8 Hz, 1H), 4.05 (dd, J=17.8, 9.6 Hz, 1H), 3.34
(dd, J=17.8, 2.8 Hz, 1H). 13C NMR (50 MHz, CDCl3)
l 197.5, 195.5, 156.1, 150.6, 142.5, 137.9, 137.5, 131.8,
131.1, 130.2, 129.9, 127.4, 122.9, 120.9, 120.7, 111.2,
110.2, 107.2, 42.3, 40.7. m/z (EI) 398 (5), 121 (25).
Typical experimental procedure and data for representative
examples
Mitsunobu reaction: To the suspension of Wang resin (1
g, 1.7 meq./g, 150–300 mM, 2% DVB) in THF (10 mL),
the chalcone 1B (1.14 g, 5.1 mmol) and triphenylphos-
phine (1.34 g, 5.1 mmol) were added and gently stirred
at 0°C for 15 min. DEAD (0.89 g, 5.1 mmol) was added
dropwise and the mixture was stirred for 16 h gradually
allowing it to attain rt. The resin was collected by filtration
and washed successively with THF (3×20 mL), dioxane
(3×20 mL), DCM (3×20 mL), 1:1 DCM/MeOH (3×20
mL), MeOH (3×20 mL), DCM (3×20 mL) and finally with
ether (3×20 mL). The resin was dried in vacuo and used
in the next step.
Aromatic/heteroaromatic aldehyde addition: The catalyst
I (80 mg, 0.32 mmol), Et3N (0.42 g, 5.67 mmol) and
benzaldehyde (0.6 g, 5.67 mmol) were added successively
to the resin (0.5 g, 1.26 meq./g) suspended in dioxane/
EtOH (5 mL, 8:2, v/v) and heated at reflux. Another
portion (80 mg) of the thiazolium salt was added at the
end of 10 and 20 h and the mixture refluxed for a total
of 30 h from the commencement of the reaction. The resin
wasthenfilteredandwashedasmentionedabovetoafford
the diketone 1Bb on the solid support.
Acknowledgements
S.R. is thankful to Dr. J. S. Yadav, Head, Org. Div. I
and Dr. K. V. Raghavan, Director, I.I.C.T. for their
constant support and encouragement. K.A. is thankful
to CSIR (New Delhi) for research associate fellowship.
Cleavage using TFA: The resin bound product 1Bb (0.2
g, 1.1 meq./g) was suspended in 25% TFA/DCM and
stirred at rt for 4 h. The resin was filtered and washed
with DCM (3×10 mL). The combined filtrates were
evaporated and the residue dissolved in DCM and washed
successively with satd aq. NaHCO3, water and brine.
Drying over Na2SO4 and evaporation of the solvent gave
acrudeproductwhichwaspurifiedbycolumnchromatog-
raphy on silica gel using EtOAc/pet. ether as the eluent
to afford 1Bb (41 mg, 57%). 1H NMR (400 MHz, CDCl3)
l 7.97 (d, J=6.7 Hz, 2H), 7.47–6.96 (m, 12H), 5.26 (dd,
J=10.4, 3.7 Hz, 1H), 4.12 (dd, J=18.6, 10.4 Hz, 1H),
3.19 (dd, J=18.6, 3.7 Hz, 1H). 13C NMR (50 MHz,
CDCl3) l 199.9, 198.6, 156.4, 138.2, 137.5, 136.2, 133.0,
129.6, 129.1, 128.8, 128.4, 128.1, 127.3, 120.7, 120.2,
114.7, 48.7, 43.8. m/z (EI) 330 (5), 225 (100), 121 (50).
References
1. Balkenhohl, F.; von dem Bussche-Hunnefeld, C.; Lansky,
A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2289.
2. (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed.
Engl. 1973, 12, 81; (b) Stetter, H. Angew. Chem., Int. Ed.
Engl. 1976, 15, 639; (c) For cyanide ion promoted Riessert
complex formation on solid-phase see: Lorsbach, B. A.;
Bagdanoff, J. J.; Miller, R. B.; Kurth, M. J. J. Org. Chem.
1998, 63, 2244.
3. Stetter, H.; Kuhlmann, H. Angew. Chem., Int. Ed. Engl.
1974, 13, 539.
4. (a) Stetter, H.; Kuhlmann, H. Synthesis 1975, 379; (b)
Stetter, H.; Mohrmann, K.-H.; Schlenker, W. Chem. Ber.
1981, 114, 581.
5. El-Haji, T.; Martin, J. C.; Descotes, G. J. J. Heterocycl.
1Aa: 1H NMR (200 MHz, CDCl3) l 8.50 (d, J=4.1 Hz,
1H), 7.67–7.0 (m, 8H), 4.60 (dd, J=9.6, 5.5 Hz, 1H), 3.95
(dd, J=19.2, 9.6 Hz, 1H), 3.25 (dd, J=19.2, 5.5 Hz, 1H),
2.68–2.35 (m, 2H), 1.68–1.47 (m, 2H), 1.21–1.12 (m, 2H),
0.80 (t, J=8.2 Hz, 3H). 13C NMR (50 MHz, CDCl3) l
211.2, 197.2, 161.3, 137.9, 130.6, 129.1, 128.8, 128.3,
127.5, 115.4, 53.4, 42.0, 41.7, 25.6, 22.0, 13.7. m/z (FAB)
311 (65), 281 (28), 121 (100).
Chem. 1983, 20, 233.
6. Perrine, D. M.; Kagan, J.; Huang, D. B.; Zeng, K.; Theo,
B. K. J. Org. Chem. 1987, 52, 2213.
7. Wynberg, H.; Metselaar, J. Synth. Commun. 1984, 14, 1.
8. Jones, T. H.; Franko, J. B.; Blum, M. S.; Fales, H. M.
Tetrahedron Lett. 1980, 21, 789.
9. Raghavan, S.; Tony, K. A.; Ramakrishna Reddy, S.
Tetrahedron Lett. 2001, 42, 8383.
10. Org. Synth. Collective Volume 1, pp. 78, Benzalacetophe-
none.
1
1Cc: H NMR (200 MHz, DMSO-d6) l 9.20 (brs, 1H),
11. Stetter, H.; Kuhlmann, H. Chem. Ber. 1976, 109, 2890.
12. (a) Deegan, T. L.; Gooding, O. W.; Baudart, S.; Porco, J.
A., Jr. Tetrahedron Lett. 1997, 38, 4973; (b) Ito, Y.; Ogawa,
T. J. Am. Chem. Soc. 1996, 118, 12246.
8.50 (m, 1H), 7.64–6.92 (m, 9H), 6.50 (m, 1H), 5.25 (dd,
J=9.5, 4.4 Hz, 1H), 4.10 (dd, J=18.3, 9.5 Hz, 1H), 3.42
(dd, J=18.3, 4.4 Hz, 1H). 13C (50 MHz, CDCl3+DMSO-
d6) l 196.5, 185.2, 156.7, 151.0, 148.6, 145.8, 136.7, 136.1,