ROMPgel-supported thiazolium iodide: An efficient supported organic catalyst for parallel stetter reactions

Article abstract of DOI:10.1021/ol048694u

(Chemical Equation Presented) A high-loading ROMPgel-supported thiazolium iodide was prepared via ROMPolymerization of the corresponding norbornene-derived monomer. The resulting ionic ROMPgel proved to be an efficient organic catalyst for Stetter reactions. The 1,4-dicarbonyl products, important intermediates in the synthesis of cyclopentenones and heterocycles, were obtained in high yields and excellent purities after minimal purification. The ROMPgel could be reused in up to four consecutive reaction cycles without significant loss of catalytic activity.

Full text of DOI:10.1021/ol048694u

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3377-3380
ROMPgel-Supported Thiazolium Iodide:
An Efficient Supported Organic Catalyst
for Parallel Stetter Reactions
Anthony G. M. Barrett,* Andrew C. Love, and Livio Tedeschi
Department of Chemistry, Imperial College London, Exhibition Road,
London SW7 2AZ, England
agmb@imperial.ac.uk
Received July 8, 2004
ABSTRACT
A high-loading ROMPgel-supported thiazolium iodide was prepared via ROMPolymerization of the corresponding norbornene-derived monomer.
The resulting ionic ROMPgel proved to be an efficient organic catalyst for Stetter reactions. The 1,4-dicarbonyl products, important intermediates
in the synthesis of cyclopentenones and heterocycles, were obtained in high yields and excellent purities after minimal purification. The
ROMPgel could be reused in up to four consecutive reaction cycles without significant loss of catalytic activity.
The continued development of clean, rapid, and efficient
methods to generate compound libraries containing a wide
range of chemical diversity remains a strategically important
challenge in the pharmaceutical and agrochemical industry.
To address this need, considerable research interest has
recently focused on the development of new and improved
polymer-supported reagents, catalysts, and scavengers for use
in solution-phase parallel synthesis.1 Polymer-assisted solu-
tion-phase synthesis provides advantages over traditional
solution-phase organic synthesis and classical solid-phase
organic synthesis (SPOS), allowing rapid reaction optimiza-
tion and scale-up in both sequential and multistep syntheses.
Purification is simplified since only filtration and washing
procedures are required, while reaction progress is easily
monitored through classical solution-phase methods.
tion) of substituted norbornene and 7-oxanorbornene mono-
mers.2 The monomers are readily prepared in solution
through a small number of steps and then purified and fully
characterized prior to ROMPolymerization. In the presence
of a cross-linker, numerous well-defined polymers with
respect to molecular weight and polydispersity have been
prepared and used in “purification free” parallel synthesis.2
Continuing our interest in the rapid introduction of
chemical diversity and preparation of functionalized building
blocks through simplified parallel synthesis, we investigated
the synthetically underutilized Stetter reaction.3 The Stetter
reaction and related benzoin and acyloin condensations
represent important classes of umpolung reactivity. Reversal
of the reactivity at a carbonyl carbon atom of an aldehyde,
(2) (a) Barrett, A. G. M.; Hopkins, B. T.; Ko¨bberling, J. Chem. ReV.
2002, 102, 3301-3324. (b) Flynn, D. L.; Hanson, P. R.; Berk, S. C.; Makara,
G. M. Curr. Opin. Drug Discuss. DeV. 2002, 5, 571-579. (c) Barrett, A.
G. M.; Hopkins, B. T.; Love, A. C.; Tedeschi, L. Org. Lett. 2004, 6, 835-
837.
ROMPgel is a general class of high-loading polymer-
supported reagents, catalysts, or scavengers, derived from
ring-opening metathesis polymerization (ROMPolymeriza-
(1) (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S.
J. J. Chem. Soc., Perkin Trans. 1 2000, 23, 3815-4195. (b) Kirschning,
A.; Monenschein, H.; Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650-
679.
(3) (a) Stetter, H.; Schreckenberg, M.Angew. Chem., Int. Ed. Engl. 1973,
12, 81-81. (b) Stetter, H.; Kuhlmann, H. Angew. Chem., Int. Ed. Engl.
1974, 13, 539-539. (c) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15,
639-647. (d) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407-496.
(e) Stetter, H.; Haese, W. Chem. Ber. 1984, 117, 682-693.
10.1021/ol048694u CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/26/2004

to provide a nucleophilic (d1) entity (umpolung),4 and
subsequent transformations showing the nucleophilic addition
of acyl-anions to acceptors bearing an activated double bond
have recently attracted considerable research interest.5 Reac-
tions may be traditionally catalyzed by cyanide ions or
thiazolium salts (and more recently 1H-imidazolium and
triazolium salts),5 under basic conditions. While the mech-
anism for cyanide catalysis is well established,6 contention
as to the nature of the active catalytic azolium species
remains.5b The Stetter reaction is an efficient method for the
generation of 1,4-dicarbonyl compounds, important inter-
mediates in the synthesis of cyclopentenone derivatives7 and
heterocycles, including furans,8 pyrroles,9 pyrrolidines,10 and
thiophenes.11 The thiazolium-catalyzed Stetter reaction has
recently been successfully employed in SPOS,12 but attempts
to attach the catalyst to a polymer have not always provided
satisfactory results.13 Usually lower yields were obtained than
when using soluble thiazolium salts, and often the catalysts
could only be partially regenerated, so they rapidly lost their
effectiveness. 1,4-Diketones were recently synthesized using
a solid-supported reagent, i.e., thiazolium salt-DBU-
Al2O3,14 under microwave irradiation.15 This system allowed
for reduced reaction times and the preparation of synthetically
challenging γ-diketones from aromatic aldehydes in good
yields. The development of a task-specific ionic liquid
(TSIL), effectively replacing the polymeric support with an
imidazolium salt, was recently shown to promote a Stetter
reaction with minimal purification.16 However, this approach
introduces additional steps in attaching and detaching the
ionic liquid component and reduces possible structure
diversity. Applying ROMPgel methods, we investigated the
preparation of a supported thiazolium iodide catalyst 6 for
application in parallel Stetter reactions (Scheme 1).
Scheme 1. Preparation of ROMPgel-Supported Thiazolium
Iodide
yield). Quarternization of 2 with iodomethane gave the
thiazolium salt monomer, which was polymerized in the
presence of cross-linker 42c (11 mol %), using the second-
generation Grubbs catalyst 5 to give the ROMPgel 6 with a
loading of 2.52 mmol g-1.
After considerable experimentation, we found the ROMP-
gel 6 catalyzed the Stetter reaction in DMF in the presence
of either DBU, 1,1,3,3-tetramethylguanidine, or triethyl-
amine, in similar yield and purity. However, in terms of
practicality, successful recovery of the active catalyst on
completion of the reaction was only achieved when triethyl-
amine was used as the base. The catalyst was recovered by
filtration, rinsed, and reused in a further four consecutive
reactions without significant loss in catalytic activity. Despite
the associated high reactivity of the aldehyde, often resulting
in high yields of self-condensation or benzoin products,13
we were pleased to observe preferential reaction of equimolar
quantities of aliphatic aldehydes with R,â-unsaturated ketones
via the Stetter reaction pathway. Addition of alcohol cosol-
vents (n-BuOH, i-PrOH) promoted small increases in relative
reaction rates, but only partial recovery of active catalyst
was possible. In an attempt to increase the rate of reaction,
the effect of polymer architecture on the swelling properties
was also investigated. Previous work using ROMPgel-
supported ethyl 1-diazo-2-oxopropyl-phosphonate revealed
that significant increases in the relative reaction rates could
be achieved through addition of a more polar comonomer.2c
Unfortunately, the addition of more polar comonomers failed
to provide any significant rate increase. ROMPgel 6 catalyzed
the equimolar addition of aliphatic aldehydes to a number
of electron-deficient double bonds in near quantitative yield
(Table 1). The reaction proceeded in very high purity with
electron-withdrawing aryl substituents on either, or both,
sides of the R,â-unsaturated system. Reactions proceeded
well in the presence of ortho and para substituents. High
purities were also obtained with electron-donating aryl
substituents on either, or both, sides of the R,â-unsaturated
system, but slightly longer reaction times were required to
ensure complete conversion. The Stetter reaction between
an aryl aldehyde and enone (8m) was found to proceed with
The Diels-Alder reaction between commercially available
4-methyl-5-vinyl-1,3-thiazole (1) and cyclopentadiene gave
a (1:9.5) mixture of exo and endo cycloadducts (2) (53%
(4) Seebach, D. Angew. Chem. 1979, 91, 259-278. (b) Seebach, D.
Angew. Chem., Int. Ed. Engl. 1979, 18, 239-258.
(5) (a) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326-1328. (b)
Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534-541.
(6) Lapworth, A. J. Chem. Soc. 1903, 83, 995-1005.
(7) (a) Stetter, H.; Kuhlmann, H. Synthesis 1975, 379-382. (b) Stetter,
H.; Mohrmann, K.-H.; Schlenker, W. Chem. Ber. 1981, 114, 581-596. (c)
Galopin, C. C. Tetrahedron Lett. 2001, 42, 5589-5591. (d) Nova´k, L.;
Baa´n, G.; Marosfalvi, J.; Sza´ntay, C. Chem. Ber. 1980, 113, 2939-2949.
(8) El-Haji, T.; Martin, J. C.; Descotes, G. J. J. Heterocycl. Chem. 1983,
20, 233-235.
(9) Perrine, D. M.; Kagan, J.; Huang, D.-B.; Zeng, K.; Theo, B.-K. J.
Org. Chem. 1987, 52, 2213-2216.
(10) Jones, T. H.; Franko, J. B.; Blum, M. S.; Fales, H. M. Tetrahedron
Lett. 1980, 21, 789-792.
(11) Wynberg, H.; Metselaar, J. Synth. Commun. 1984, 14, 1-9.
(12) (a) Kobayashi, N.; Kaku, Y.; Higurashi, K.; Yamauchi, T.; Ishibashi,
A.; Okamoto, Y. Bioorg. Med. Chem. Lett. 2002, 12, 1747-1750. (b)
Raghavan, S.; Anuradha, K. Tetrahedron Lett. 2002, 43, 5181-5183. (c)
Kobayashi, N.; Okamoto, Y.; Higurashi, K.; Kaku, Y.; Ishibashi, A.;
Yamauchi, T. PCT Int. Appl. WO 03/062230 A1 2003.
(13) (a) Castells, J.; Dunach, E.; Geijo, F.; Pujol, F.; Segura, P. M. Isr.
J. Chem. 1978, 17, 278-283. (b) Sell, C. S.; Dorman, L. A. J. Chem. Soc.,
Chem. Commun. 1982, 629-630. (c) Chang, B.-H.; Chang, Y. L. J. Chin.
Chem. Soc. 1983, 30, 55-58. (d) Ho, T.-L.; Liu, S.-H. Synth. Commun.
1983, 13, 1125-1127.
(14) DBU ) 1,8-diazabicyclo[5.4.0]undec-7-ene.
(15) Yadav, J. S.; Anuradha, K.; Subba Reddy, B. V.; Eeshwaraiah, B.
Tetrahedron Lett. 2003, 44, 8959-8962.
(16) Anjaiah, S.; Chandrasekhar, S.; Gre´e, R. Tetrahedron Lett. 2004,
45, 569-571.
3378
Org. Lett., Vol. 6, No. 19, 2004

Table 1. Yields and Purities of γ-Diones
Org. Lett., Vol. 6, No. 19, 2004
3379

Table 1. (Continued)
a Yields refer to isolated products. Purities as judged by 1H and 13C NMR spectra, GC-MS, and microanalysis. b 7a (1.4 equiv) was used used;
7-hydroxydodecan-6-one (5%) was observed as a side product. Daynard, T. S.; Eby, P. S.; Hutchinson, J. H. Can. J. Chem. 1993, 71, 1022-1028. Fleming,
I.; Roberts, R. S.; Smith, S. C. J. Chem. Soc., Perkin Trans. 1 1998, 1215-1228. c 7i (1.4 equiv) was used; 7-hydroxydodecan-6-one (5%) was observed as
a side product. d 8k (30%). e 2-Hydroxy-1,2-diphenylethanone (10k) (14%) was observed as a side product.
moderate selectivity; competing benzoin17 product formation
(14% yield) was also observed. Reaction of a heteroaromatic
aldehyde with an aliphatic enone was found to give the
desired Stetter product 9j in 86% yield, along with 6%
recovered aldehyde.
lyst was found to catalyze the equimolar addition of aliphatic
aldehydes to a range of enones to provide the corresponding
γ-diones in both high yields and purities. The 1,4-dicarbonyl
products are important intermediates in the synthesis of
cyclopentenones7 and heterocycles, including furans,8 pyr-
roles,9 pyrrolidines,10 and thiophenes,11 allowing rapid in-
troduction of skeletal and chemical diversity. The ROMPgel
catalyst could be readily recovered and reused in a further
four consecutive reactions with no significant loss in activity.
Scheme 2. Parallel Synthesis of 1,4-Dicarbonyls Using a
ROMPgel-Supported Thiazolium Iodide
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B); Pfizer, Merck KGaA,
and the EPSRC for generous grant support; The Royal
Society and the Wolfson Foundation for a Royal Society-
Wolfson Research Merit Award (to A.G.M.B); and the
Wolfson Foundation for establishing the Wolfson Centre for
Organic Chemistry in Medicinal Science at Imperial College
London.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, a high-loading ROMPgel-supported thia-
zolium iodide 6 has been prepared in three steps from
commercially available compounds. The immobilized cata-
(17) Wang, X.; Zhang, Y Synth. Commun. 2003, 33, 2627-2634.
OL048694U
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Org. Lett., Vol. 6, No. 19, 2004