Esterification of Polystyrene Wang resin with 5-hexynoic acid; solid-supported ester alkyneSyntheticPage 88 (2001)
Submitted 17th Aug 2001, published 17th Aug 2001
A contribution from the Caddick Group, Sussex
Polystyrene Wang resin, Novabiochem, 0.77mmol/g
5-Hexynoic acid (Lancaster)
(HATU, Rapp Polymere)
Diisopropylethylamine (DIPEA, Hünig's base, any supplier)
N,N-dimethylformamide (anhydrous, Aldrich)
Add DIPEA (1.34 mL, 10 eq, 7.7 mmol) to 5-Hexynoic acid (0.435 mL, 3.85 mmol, 5eq) solution in 5 mL dry DMF then add HATU (1.46 g, 3.85 mmol, 5 eq) and allow to stand for about 10 mins to activate acid. Add to Wang resin (1.0 g, 0.77 mmol, 0.77 mmol/g, 1 eq) preswollen in minimum volume dry DMF (about 5-10 mL). Shake overnight at room temperature. Wash 4 x 20 mL each with DMF, DCM and Methanol Use 25 mL Alltech tube as reaction vessel. Yield typically quantitative.
This provides a means of attaching an isolated alkyne to a solid support and has been repeated about 6 times on scales of 200mg resin - 2g resin with no change in yield (as assessed in later steps - see below). We went on to use this acceptor in radical addition reactions as in lead reference below.
The use of HATU is probably not critical although it does give good yields. This is a general procedure for the coupling of a carboxylic acid to a p-hydroxybenzyl resin and works also for PEG-based resins such as Tentagel. HATU is not compatible with alpha,beta-unsaturated acids such as acrylic acid. Use DIC/catalytic DMAP instead and no organic base.
Yield can be assessed by cleaving off hexynoic acid with 95%(aq) TFA for about 2h, but in the lead reference below, loading was assumed to be quantitative and yields were assessed after reaction on the triple bond followed by cleavage.
Caddick, S.; Hamza, D.; Wadman, S.N. Tetrahedron Lett. 1999, 40, 7285-7288.
1. S.-S. Wang (1973) J. Am. Chem. Soc. 95 1328.
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