Acylation reactions, polymer-supporte

A strategy involving sequential 1,3-dipolar cycloadditions has been reported for the synthesis of novel bis-isoxazolo substituted piperidines 192a and 192b (Eqs. 18 and 19) [53]. It consists of the Michael addition of an unsaturated alkox-ide 185 to )3-nitrostyrene 184 followed by an INOC or ISOC reaction to provide isoxazolines 187-189 (Eq. 18 and Table 18). A polymer supported acyl chloride... 

As mentioned before for other azolide reactions, acylations can be carried out with polymer-supported azolides as acylating reagents. For example, acetic acid hydrazide can be prepared with a polymer of l-acetyl-4-vinyl-imidazole/divinylbenzene (96 4) and hydrazine (no diacylation occurs when this method is used) [122]... 

Alkyl and glycosyl isocyanates and isothiocyanates are produced in good yield under phase-transfer catalytic conditions using either conventional soluble catalysts or polymer-supported catalysts [32, 33]. Acyl isothiocyanates are obtained under similar conditions [34]. A-Aryl phosphoramidates are converted via their reaction with carbon disulphide under basic conditions into the corresponding aryl isothiocyanates, when the reaction is catalysed by tetra-n-butylammonium bromide [35]. 

In 1982 Cardillo used a three-step sequence involving two supported reagent systems to convert /i-iodoamines into amino alcohols (Scheme 2.23) [45]. Polymer-supported acetate ions were used for the substitution of the iodide which immediately underwent acyl transfer to the amine. The resulting compound (10) was directly treated with hydrochloric acid to cleave the amide and the free base was subsequently obtained from the reaction by treatment with a resin-bound carbonate. This was of particularly synthetic value because of the high water solubiHty of these amino alcohol compounds that would have made aqueous work-up challenging. 

Undesirable intermolecular reactions can be avoided during certain synthetic conversions. Thus it is often useful to carry out C-alkylation and C-acylation of compounds that form enolate anions, for example, esters with a-hydrogens. Such reactions are often complicated by self-condensation since the enolate anion can attack the carbonyl group of a second ester molecule. Attachment of the enolizable ester to a polymer support at low loading levels allows the alkylation and acylation reactions (Eq. 9-79) to be performed under... 

A related series of 5-substituted-2-amino-oxadiazole compounds have also been prepared in a one-pot procedure using a microwave-assisted cyclisation procedure (Scheme 6.26)164. Rapid preparation of the pre-requisite ureas from the mono acyl hydrazines and various isocyanates (or the isothiocyanate) was easily achieved by simple mixing. The resulting products were then cyclo dehydrated by one of the two procedures either by the addition of polymer-supported DMAP and tosyl chloride or alternatively with an immobilised carbodiimide and catalytic sulphonic acid. Purity in most cases was excellent after only filtration through a small plug of silica but an SCX-2 cartridge (sulphonic acid functionalised - catch and release) could be used in the cases where reactions required additional purification. 

The solid-state synthesis of thienopyridines by the Gewald reaction was documented. For example, 214 was prepared in 92% yield by cyanoacetylation of a polymer support and the reaction of the resulting ester on the polymer support with sulfur and piperidin-4-one 212 followed by acylation and elimination of the polymer matrix (2001TL7181). 

In the synthesis of a compound library of allosteric Akt kinase inhibitors 39, Lindsley and coworkers employed different HTS techniques (Scheme 24) [54]. A polymer-supported base and a fluorous thiol scavenger were used in the alkylation reaction of 40. F-SPE purified intermediate was then used for microwave-assisted cycloaddition of 41. Similar intermediates have been used for generation of an unnatural canthine alkaloid library 42 by performing cycloaddition reactions with an indo-tethered acyl hy-drazide [55]. 

Three approaches leading to 8 were considered (Figure 3.6.9) Following the biosynthetic pathway directly, polymer-supported thiamine 9 was constructed (path A) and could lead via crossed acyloin couplings to the target structure. Polymer-supported hydrazones 10 were reported to add directly to aldehydes in a non-catalyzed Umpolung reaction (path B) with results reported in due course. Finally, phosphine ylides 11 were investigated as polymer-supported acyl anion equivalents (path C). 

A robust catch, cyclize, and release preparation of 3-thioalkyl-1,2,4-triazoles mediated by the polymer-bound base P-BEMP has been described <02TL5305>. Reaction of solid-supported hydrazides 103 with isocyanates or isothiocyanates followed by base-induced cyclization/cleavage afforded 1,2,4-trisubstituted urazoles and thiourazoles 104 <02JCO491, 02TL3899>. Polymer-supported V-acyl-1 //-benzotriazole- 1-carboximidamides 105 reacted with hydrazines followed by acidic cyclizative release to give 3-alkylamino-l,2,4-triazoles 106 <02OL1751>. 

Nafion is another choice of polymer support for Sc-based Lewis acids. Nafion-Sc catalyst is readily prepared by treatment of Nafion with ScCb 6H2O in acetonitrile under reflux [116]. Nafion-Sc catalyst has been found to be effective in several synthetic reactions including allylation of carbonyl compounds with tetraallyltin, Diels-Alder reaction, Friedel-Crafts acylation, and imino Diels-Alder reactions. The use of Nafion-Sc in flow systems has also been tested. 

T. Nukada, A. Berces, and D. M. Whitfield, Acyl transfer as a problematic side reaction in polymer-supported oligosaccharide synthesis,./. Org. Chem., 64 (1999) 9030-9045. 

Alternative catalysts for this reaction are polymer-supported alkyl sulfonic acids [231], even if they show lower performances than the zeolite. Two of the problems in the reactions are the need to vaporize the reactant and the periodic regeneration of the rapidly deactivating zeolite catalysts. It was thus proposed recently that continuous catalytic Friedel-Crafts acylation can be performed in the biphasic medium of an ionic liquid and supercritical carbon dioxide [232]. 

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