Solid-phase combinatorial synthesis of 5-arylalkylidene rhodanine

Article abstract of DOI:10.1016/S0040-4039(00)00866-2

Rhodanine-3-acetic acid was loaded on Wang resin or Rink amide resin. Alternatively, the thiocarbonyl-diimidazole-activated Wang amino acid resin or 2-chlorotrityl resin was reacted with methyl thioglycolate to yield the rhodanine moieties. It was then co

Full text of DOI:10.1016/S0040-4039(00)00866-2

Tetrahedron Letters 41 (2000) 5729±5732
Solid-phase combinatorial synthesis of 5-arylalkylidene
rhodanine
Cheng Leng Lee and Mui Mui Sim*
Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Singapore
Received 22 March 2000; accepted 23 May 2000
Abstract
Rhodanine-3-acetic acid was loaded on Wang resin or Rink amide resin. Alternatively, the thiocarbonyl-
diimidazole-activated Wang amino acid resin or 2-chlorotrityl resin was reacted with methyl thioglycolate
to yield the rhodanine moieties. It was then condensed at the C-5 active methylene with either aromatic
aldehydes or aromatic ketones. 5-Arylalkylidene rhodanine was obtained upon resin cleavage. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: solid-phase synthesis; rhodanine; aldehydes; ketones; condensation.
Solid-phase and solution-phase organic synthesis as applied to the assembly of chemical
libraries is widely practiced in many academic and industrial laboratories throughout the world.
Combinatorial chemistry is now regarded as an important component of the drug discovery
process.1
Thiazolidinone derivatives are reported to have anticonvulsant,2 antibacterial,3 antiviral4 and
anti-diabetic properties.5 For example, pioglitazone and rosiglitazone were launched recently
for type II diabetes mellitus. The rhodanine (2-thioxo-4-thiazolidinone) moiety was synthesized
by various methods such as the addition of isothiocyanate to mercaptoacetic acid followed by
acid cyclization, or the reaction of ammonia or primary amines with carbon disul®de and chloro-
acetic acid in the presence of bases.6 Knoevenagel condensation with aromatic aldehydes at the
nucleophilic C-5 active methylene was accomplished using piperidinium benzoate in re¯uxing
toluene7 or sodium acetate in re¯uxing glacial acetic acid.6 However, the acidic conditions are
unsuitable for acid labile Rink amide, 2-chlorotrityl and Wang resin.
In this paper, we reported a simple and straightforward procedure using milder conditions for
solid-phase combinatorial synthesis of 5-arylalkylidene rhodanine. Two synthetic routes were
employed for the formation of rhodanine moieties on solid supports (Scheme 1). Rhodanine-3-
acetic acid was independently coupled to Wang resin and Rink amide resin by standard conditions
* Corresponding author. Tel: (65) 874 7823; fax: (65) 779 1117; e-mail: mcbsimmm@imcb.nus.edu.sg
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00866-2

5730
Scheme 1. Formation of rhodanine moieties on solid supports
to give 1a and 1b, respectively (Route A). For additional diversity, Fmoc-Ala-Wang resin, Fmoc-
Phe-Wang resin and 4-aminomethylbenzyl alcohol 2-chlorotrityl resin were also employed to give 1c,
1d and 1e, respectively (Route B).8 Synthesis of these linkers involved the generation of thiourea
by reacting thiocarbonyldiimidazole9 with their respective amines. Displacement of imidazole by
methyl thioglycolate followed by spontaneous cyclization gave the rhodanine moiety.
Knoevenagel condensation of the C-5 active methylene of rhodanine (1a±e) with aromatic
aldehydes proceeded very smoothly to completion by heating only, whereas that with aromatic
ketones proceeded only in the presence of ammonium acetate with heating (Scheme 2). Heating at
a high temperature (110ꢀC) was essential to ensure complete condensation. Toluene was therefore
chosen as the solvent for its high boiling point and its good swelling property.
Scheme 2. Condensation of 1 with aldehydes and ketones
1
The cleaved 5-arylalkylidene rhodanines (2) were characterized by H NMR and MS. Twelve
representative examples were randomly selected and their crude yields and purities were sum-
marized in Table 1. Condensation of the C-5 active methylene of rhodanine (1a±e) with aldehydes
and ketones gave comparable yields. The yields of the ®nal products were not a€ected by the
bulkiness of aldehydes and ketones. Only the thermodynamically stable Z-isomer was obtained
except in entry 4 which gave a 1:1 (E:Z) mixture.10 The rhodanine formation and condensation

5731
Table 1
The yield and HPLC purity of compound 2
with carbonyl compounds worked equally well with Rink amide, Wang and 2-chlorotrityl resins
as indicated by the isolated yields of compound 2, which were above 60%. Their HPLC purities
ranged from 54 to 90%. There was no signi®cant increase in yield when the condensation reaction
was repeated twice (entry 7).
This paper demonstrated the ®rst solid-phase synthesis of 5-arylalkylidene rhodanine by
Knoevenagel condensation of carbonyl compounds with the C-5 active methylene of rhodanine.
The conditions employed were mild and the synthesis is applicable to both acid and base sensitive
linkers. We are currently exploring the reaction using di€erent resin linkers.

5732
Acknowledgements
This work was supported by the National Science and Technology Board of Singapore. We
thank Miss Wan Theng Sing for her assistance in this project.
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8. Preparation of 1d: To 370 mg of Fmoc-Phe-Wang resin (0.55 mmol/g, Novabiochem) were added 20% piperidine
in DMF and the mixture shaken for 30 min. The resin was washed (DMF, MeOH and CH2Cl2) and dried under
vacuum. A mixture of resin, thiocarbonyldiimidazole (5 mol equiv.) and triethylamine (3 mol equiv.) in CH2Cl2
was shaken for 1 h. The ®ltrate was drained away. The resin was swollen in CH2Cl2 and methyl thioglycolate
(5 mol equiv.) was added. The reaction mixture was further shaken for 12 h. The resin was washed (DMF, MeOH
and CH2Cl2) and dried. Preparation of 2: The loaded resin (1a±1b) (200 mg), a ketone and ammonium acetate
(5 mol equiv. each) were suspended in toluene (4 mL) and heated at 110ꢀC for 3 days. In the case of aldehydes,
the loaded resin (1a±1e) (200 mg) and an aldehyde (5 mol equiv.) was heated in toluene (4 mL) at 110ꢀC for 12 h.
The resin was washed (DMF, MeOH and CH2Cl2), resuspended in TFA:CH2Cl2 (20:80), and shaken for 1 h. The
®ltrate was pooled and concentrated to yield product 2.
9. Munson, M. C.; Cook, A. W.; Josey, J. A.; Rao, C. Tetrahedron Lett. 1998, 39, 7223±7226. Thiocarbonyldiimidazole
was used instead of carbonyldiimidazole.
10. The stereochemistry was determined according to Ref. 5a and b. It was reported that only the thermodynamically
stable Z-isomer was observed for all arylidene rhodanines and the methylene proton of Z-isomer was more
down®eld (7.9 ppm) than that of the E-isomer (7.4 ppm) due to the interaction with the carbonyl group at the 4-
position.
1
11. Racemization was determined by H NMR using the chiral lanthanide shift reagent tris[3-(tri¯uoromethylhydroxy-
methylene)-(+)-camphorato]europium(III) as an additive in CDCl3. We observed 75 and 100% of the S-
con®guration in the Ala- and Phe-derived products, respectively.