A new method of forming resin bound thioesters and their use as 'traceless' linkers in solid phase synthesis

Article abstract of DOI:10.1016/S0040-4039(99)02345-X

Resin bound thioesters can be prepared by heating thioamides in aqueous DMF with Merrifield resin in the presence of sodium iodide. These thioamides can be cleaved to give alcohols, ketones and lactones by a variety of methods. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02345-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1627–1630
A new method of forming resin bound thioesters and their use as
‘traceless’ linkers in solid phase synthesis
Peter J. May,a Mark Bradley,a,∗ David C. Harrowven a,∗ and David Pallin b
aDepartment of Chemistry, The University, Southampton, S017 1BJ, UK
bRhône-Poulenc Rorer Ltd., Dagenham Research Centre, Dagenham Road South, Dagenham, Essex, RM10 7XS, UK
Received 19 November 1999; accepted 16 December 1999
Abstract
Resin bound thioesters can be prepared by heating thioamides in aqueous DMF with Merrifield resin in the
presence of sodium iodide. These thioamides can be cleaved to give alcohols, ketones and lactones by a variety of
methods. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: combinatorial chemistry; lactones; solid phase synthesis; thioamide; thioester.
Thioesters are activated carboxylic acid derivatives which exhibit acylating properties similar to those
of acid anhydrides.1 Usually prepared by condensation of a thiol and an acid chloride, they have found
widespread application in synthetic chemistry as precursors to aldehydes, ketones, acids, esters, lactones,
amides, lactams and heterocycles.2 Surprisingly, in view of the diverse chemistry this functional group
offers, it has attracted scant interest from combinatorial chemists.3 This may be attributed to a number
of factors including the limited availability of methods to prepare resin bound thioesters and practical
difficulties associated with resin bound acid chlorides.3–5 In this communication we present a new method
for synthesising thioesters on a solid support and show how these materials may serve as precursors of
1°-alcohols, 3°-alcohols, ketones and lactones (Scheme 1).
Scheme 1.
The method used to generate resin bound thioesters involved heating aqueous DMF solutions of a
thioamide with sodium iodide and Merrifield resin.6 These conditions differ from those used in solution
phase chemistry.7,8 In particular, the inclusion of NaI and use of a higher boiling solvent were necessary
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02345-X
tetl 16273

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to achieve reasonable loadings (estimated to be 40% of the theoretical maximum)9 in an acceptable time
frame. Importantly, the reaction had broad scope and was used to access resin-bound aromatic, aliphatic
and α-ketothioesters. Characterisation by ATR reflectance infra-red spectroscopy was also possible:10 in
each case a strong carbonyl stretching frequency was observed within 5 cm−1 of those data reported for
the corresponding S-benzylthioester (Table 1).7,11
Table 1
Formation of resin supported thioesters from thioamides
Several methods for cleaving resin bound thioesters were investigated. The known reduction of these
materials with lithium borohydride produced the expected alcohols in good yield (e.g. Scheme 2).3,13
Interestingly, the resin bound α-ketothioester 6 underwent over-reduction with lithium borohydride to
give alcohol 12 rather than the expected diol 13 (Scheme 3).
Reactions with organometallic reagents likewise gave rise to some unexpected observations. For
example, it has been reported that resin bound thioesters react with Grignard reagents to give ketones.12

1629
Scheme 2.
Scheme 3.
In our study, 3°-alcohols were produced when resin linked thioesters such as 2 were treated with phenyl-
magnesium bromide while ketones were produced when these substrates were exposed to organocopper
reagents (Scheme 4).13
Scheme 4.
Cleavage of thioester 4 to benzofuranone 16 was also accomplished in excellent yield using boron
trichloride. Though the scope of this reaction is limited, it provides an interesting method for substrate
cleavage that has little precedent in the literature (Scheme 5).8,14
Scheme 5.
In conclusion, we have developed a new method of preparing resin bound thioesters that is simple to
effect and broad in scope. It proceeds through sequential activation of Merrifield resin, S-alkylation of
a thioamide and hydrolysis of the resulting salt (Scheme 6).6,7 Additionally, we have shown that these
materials cleave readily to give alcohols with lithium borohydride and Grignard reagents and ketones with
organocuprates. The release of benzofuranone 16 when 4 was exposed to boron trichloride is similarly
noteworthy.

1630
Scheme 6.
Acknowledgements
The authors thank Rhône-Poulenc Rorer and the EPSRC for their financial support through the CASE
studentship scheme. We also thank Matthew Lucas and Helen Russell for their help and interest in this
work.
References
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5, 231; (b) Voss, J. Comp. Org. Synth. 1991, 6, 435; (c) Bauer, W.; Kühlein, K. Methoden Org. Chim. (Houben-Weyl), 1985,
E5, 832; (d) Barrett, G. C. In Organic Compounds of Sulphur, Selenium and Telluriums; Hogg, D. R., Ed.; RSC: London,
1981; Vol. 6, p. 13; (e) Voss, J. In The Chemistry of Acid Derivatives; Patai, S., Ed.; Wiley: Chichester, 1979; suppl. B., pt.
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6. Merrifield resin with a copoly [styrene-1% DVB] polymer matrix, a bead size range of 200–400 mesh and a theoretical
loading of between 1.24 and 1.49 mmol/g was used as purchased from Novabiochem.
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9. Subsequent yield calculations are based on resin loadings of 40%. This figure was estimated using IR spectroscopy (intensity
of the C_O stretching frequency compared to resin supported thioesters of known loading) and chemical cleavage.
10. IR spectra were recorded using a Bio-Rad FTS 135 Fourier transform infrared spectrometer equipped with a Golden Gate
Single Reflection Diamond ATR.
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