Thiazole formation via traceless cleavage of Rink resin

Article abstract of DOI:10.1016/S0040-4039(00)00748-6

The traceless cleavage of Rink amide resin to form thiazoles has been achieved using commercially available reagents. Conversion of Rink amide species to thioamides by use of Lawesson's reagent prepares the resin bound substrates for traceless cleavage. C

Full text of DOI:10.1016/S0040-4039(00)00748-6

Tetrahedron Letters 41 (2000) 4965±4968
Thiazole formation via traceless cleavage of Rink resin
Jean-Francois Pons, Qayum Mishir, Andre Nouvet and Frederick Brook®eld*
Oxford Asymmetry International, 151 Milton Park, Abingdon, Oxford OX11 4RD, UK
Received 3 March 2000; accepted 8 May 2000
Abstract
The traceless cleavage of Rink amide resin to form thiazoles has been achieved using commercially
available reagents. Conversion of Rink amide species to thioamides by use of Lawesson's reagent prepares
the resin bound substrates for traceless cleavage. Cleavage using limiting amounts of a-haloketones provides
thiazole bearing compounds of high purity. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: a-haloketones; Lawesson's reagent; Rink amide resin; thiazole; traceless.
The use of combinatorial chemistry has recently been at the forefront of chemical science due
to its impact on the drug discovery process.1 The majority of compounds obtained when cleaved
from resin are primary carboxamides, carboxylic acids or amines; however, quite often these
functional groups are not desired within drug like molecules. The formation of compounds
derived from solid phase which do not contain these groups is relatively limited.2 The challenge
for medicinal chemists has been to develop solid phase methodologies that a€ord `privileged'
drug-like molecules, preferably without the undesired functional groups normally associated with
solid phase organic chemistry. Heterocycle bearing substrates are particularly desirable structures
for screening and are prevalent in drugs that have reached the market place.3
We would like to report a protocol for the synthesis of thiazoles via traceless cleavage of
modi®ed Rink resin bound substrates (Scheme 1).
Scheme 1. General reaction scheme
* Corresponding author. E-mail: fbrook®eld@oai.co.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00748-6

4966
The synthesis begins with the attachment of a carboxylic acid to Rink amide resin by any of the
plethora of published methods to give resin bound amide (2).4 Treatment of this resin bound
amide with a threefold excess of Lawesson's reagent in THF at re¯ux for 4 h cleanly converts the
amide into a thioamide (3).5 The reaction can be conveniently monitored by infra-red analysis of
the resin beads which show a disappearance of the amide carbonyl stretch at ꢀ1670 cm^1.
Treatment of the resin bound thioamide (3) with a limiting amount (0.6 equiv.) of an a-bromo-
ketone (4) in re¯uxing THF over a period of 16 h causes cleavage of the resin with concomitant
formation of the thiazole (5) (Scheme 2) in excellent purity and high yield based on the a-halo-
ketone.6
Scheme 2. Synthetic route
The initial part of the reaction is likely to follow the accepted Hantsch mechanism and it is
assumed that formation of an iminium cation during cyclisation provides an ideal activated sub-
strate required for cleavage from resin (Scheme 3).
Scheme 3. Proposed mechanism of cleavage
Interestingly, when 2-bromoindanone was used as a cleavage reagent, we observed only the
desired thiazole. This indicated that the dehydration of the thiazoline to form the thiazole is ecient
and gives us the ability to form 2,4,5-trisubstituted thiazoles and relatively complex fused poly-
cyclic frameworks.
An array providing 25 discrete compounds was prepared in order to determine the robustness
of the methodology. The array contained electron rich and electron poor substrates as well as

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aliphatic and aromatic substituents. Yields and purities were generally excellent; however, it was
noted that a-chloroketones required more elevated temperatures, and while the purity of the ®nal
compound was generally not as high as the a-bromoketones the only other major impurity in the
cleavage mixture was unreacted a-chloroketone (Fig. 1). Treatment of the cleavage mixture with
aminomethyl polystyrene allows the sequestration of excess a-chloroketone. The results are shown
in Table 1.
1
Figure 1. Typical H NMR spectrum of crude cleavage mixture (84% pure by HPLC, Table 1)
Table 1
Purity/observed mass ion of crude thiazole cleavages{

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In conclusion, we have reported a method for the formation of thiazoles with excellent purity
and yield in a traceless manner from Rink resin.
Acknowledgements
Thanks to Dr. E. A. Boyd, Dr. A. D. Baxter and Professor S. G. Davies for useful discussions.
References
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6. Typical experimental procedures: thioamide formation: 1.5 g (0.71 mmol g^1) of resin bound amide was suspended
in 30 ml of THF. Lawesson's reagent (1.5 g, 3.7 mmol, 3 equiv.) was then added and the reaction mixture heated at
re¯ux for 4 h (monitoring by IR). The resin was washed with (DMFÂ3, DCMÂ3 and tert-butylmethyl etherÂ3)Â3.
Thiazole forming cleavage: 300 mg of resin bound thioamide was suspended in 5 ml of THF. 3-Nitrophenacyl
bromide (44 mg, 0.18 mmol, 0.6 equiv.) was added and the reaction mixture heated at re¯ux for 16 h.