Ketones traceless linkers

Cleavage followed by decarboxylation has been used for the preparation of ketones [4-6], nitriles [5, 7], amides [8], quinazolines [9], amines [10], and 3-methylindoles [11]. Because decarboxylation generally requires an additional functional group to promote decarboxylation, which reveals the original point of attachment, this cleavage strategy usually does not enable the preparation of unfunctionalized hydrocarbons, and does therefore not belong to the class of truely traceless linkers. 

FIGURE 14. Cr(CO), a v-p, PS Grignard addition to ketones bound via Cr-based traceless linker. [430, 431]... 

The first traceless linker was developed by Kamogawa and coworkers in 1983 [82]. Starting from a polymer-bound sulfonylhydrazine, sulfonylhydrazone resin 88 was formed by reaction with ketones or aldehydes. The cleavage step was conducted either by reduction with sodium borohydride or lithium aluminium hydride to yield alkanes 89 or by treatment with base to give the corresponding alkenes 90 in a Bamford-Stevens reaction (Scheme 16.20). This work was a pioneering approach in the field of traceless tinkers. 

Aminopyrimidine. Early representative examples of a sulfone traceless linker were demonstrated by Villalgordo et al. and Gayo and Suto in the synthesis of 2-aminopyrimidines. The sulfur linkage was obtained by treating Merrifield resin with thiourea to provide the isothiouronium salts 1 (Scheme 12.5). Condensation of 1 with acetylenic ketones 2 or malononitrile derivatives 3 yielded the pyrimidine skeleton 4. Oxidation of the alkylthio linkage with mCPBA provided the corresponding sulfone derivatives that underwent nucleophilic substitution with various amines to form 2-aminopyrimidines 5. 

Related isoflavones have been prepared, using SPOS, by Harikrishnan and Showalter. Resin-bound salicyl aldehyde derivatives 336, immobilized via a traceless silyl linker unit, were prepared and treated with a Grignard reagent to introduce the first point of diversity. Subsequent re-oxidation with 2-iodoxybenzoic acid (IBX), and deprotection of the methoxymethyl (MOM) group provided ketone 338. Treatment of ketone 338 with amide acetals promoted an unusual cyclization, which concurrently installed R to give 339. Final traceless cleavage with CsF or TBAF releases isoflavones 340 (Scheme 3.59). 

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