Polymer-supported reagents alkylation

Weik and Rademann have described the use of phosphoranes as polymer-bound acylation equivalents [65]. The authors chose a norstatine isostere as a synthetic target and employed classical polymer-bound triphenylphosphine in their studies (Scheme 7.54). Initial alkylation of the polymer-supported reagent was achieved with bromoacetonitrile under microwave irradiation. Simple treatment with triethyl-amine transformed the polymer-bound phosphonium salt into the corresponding stable phosphorane, which could be efficiently coupled with various protected amino acids. In this acylation step, the exclusion of water was crucial. 

Polymer-supported reagent. HMPT supported on a polystyrene-type resin is a catalyst for SN2 reactions5-7 and for reduction of ketones by NaBIi4.7 It also has a marked effect on the alkylation of ethyl acetoacetate with diethyl sulfate. In the presence of solid HMPT the enolales undergo 60 70% O-alkylation. In the absence of HMPT, the lithium enolate does not react and the sodium and potassium enolates undergo C-alkylation (90-100%). There is some difference in the effect of solid and liquid I1MPT The solid HMPT increases the reactivity of the K. enolate more than the liquid form, whereas the reverse is true with the Li enolate.8... 

Allyltributyltin can be used in combinatorial radical allylation. Moreover, a polymer-supported reagent bearing an allyltin group was also developed and it can be used for the radical allylation of alkyl halides. 

Microwave chemistry is beginning to play a greater role also in solid-phase chemistry and in cases where polymer-supported reagents are utilized. The main drawback with these methodologies concerns the slow kinetics, which makes reaction scouting and optimization tedious. An impressive example of a microwave accelerated and polymer assisted process was recently described by Linclau. In this report, a set of carboxylic acids were fully 0-alkylated after only 3-5 min of microwave heating (Reaction Scheme 4). 

An efficient and selective solid-phase synthesis of trans 3-alkyl-4-aryl-P-lactams from nonactivated acid chlorides has been accomplished <04TL4085>. The [2+2] cycloaddition between an aldehyde-derived resin-bound imine and a solution-generated ketene has been used to generate a variety of stereochemically pure cw-P-lactams <04JOC5439>. A new polymer-supported reagent has been used for the preparation of P-... 

Among the other published works, Parlow et al. [60] and Xu et al. [61] reported the use of anion-exchange resins for the synthesis of solution-phase libraries of aryl and heteroaryl ethers via formation of a resin-bound phenol salt and its subsequent alkylation [60] (two pools of 10 compounds each) or with a one-pot procedure [61] (13 discretes). Polyme supported reagents being established tools in classical organic chemistry, their use for the synthesis of high-quality solution-phase libraries, possibly in combination with other solid-support-... 

Solid-phase scavenger methods are employed with increasing frequency as a prehminary reaction cleanup step in combinatorial chemistry, and have recently become commercially available (Argonaut, Calbiochem-Novabiochem, Varian, Alltech). lilly researchers first reported on this approach, employing sohd supported electrophiles and nucleophiles for reaction purification in acylation and alkylation reactions. Yield and purity values reported were 90-95% and 50-99%, respectively, for a library generated by reductive amination. Parke-Davis researchers achieved the removal of known reaction product impurities by the application of custom synthesized polymer supported reagents, specifically polystyrene-divinylbenzene supported derivatives of methylisocyanate and tm(2-aminomethyl)amine for cleanup of by-products resulting from urea, thiourea,sulfonamide,amide, and pyrazole libraries. 

Other isocyanate syntheses that have recently been reported include several well-known reactions. One area which has attracted considerable attention is that of the direct production of isocyanates by the carbonylation of nitro-arenes. Both mono- and di-isocyanates are claimed to have been produced using various catalysts palladium, rhodium, and iron compounds often being cited. Other preparative reactions for isocyanates which have appeared in the literature include the acid catalysed hydrolysis of isocyanide dihalides and the reaction between alkyl halides and alkali-metal cyanates, although the latter has been given a modern flavour by the use of a polymer-supported reagent. ... 

Alkyl and acyl thiocyanates and isothiocyanates are prepared in good yields from the corresponding halides by use of polymer-supported reagents, and a convenient approach to the synthesis of dialkylaminoalkyl isothiocyanates ... 

Two papers this year have described the use of chromate ions for the conversion of alkyl halides or alcohols into aldehydes or ketones (Equation 4). The reaction can be conducted in HMPA in the presence of a crown ether, and although yields are good for allylic and benzylic halides (ca. 80%) they are not so high for saturated halides. " The chromate ion, however, can be supported on an insoluble polymer matrix as the tetra-alkylammonium salt and this both enhances the nucleophilicity of the ion and simplifies the work up procedure. Using the polymer-supported reagent a variety of primary and secondary alcohols were oxidized to the corresponding aldehyde or ketone in excellent yield (ca. 90%). ... 

A similar purification method for the alkene product employs a polymer-supported reagent. Westman has developed a one-pot Wittig reaction of alkyl halides with aldehydes mediated by a polymer-supported phosphine and potassium carbonate under microwave irradiation (Scheme 32) [147]. Recently,... 

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

Polymer-supported amino alcohols and quaternary ammonium salts catalyze the enan-tioselective addition of dialkylzinc reagents to aldehydes (Table 31). When the quaternary ammonium salt F is used in hexane, it is in the solid state, and it catalyzes the alkylation of benzaldehyde with diethylzinc in good chemical yield and moderate enantioselectivity. On the other hand, when a mixture of dimethylformamide and hexane is used as solvent, the ammonium salt is soluble and no enantioselectivity is observed21. 

The group of Lindau has demonstrated the effective O-alkylation of carboxylic acids using a polymer-supported O-methylisourea reagent [123], Under conventional conditions, complete esterifications were observed only after refluxing for several hours in tetrahydrofuran, and the acidic work-up required limited the scope of applicable substituents. In contrast, employing microwave heating led to complete esterifications within 15-20 min, with only 2 equivalents of the polymer-bound... 

In the main, the original extractive alkylation procedures of the late 1960s, which used stoichiometric amounts of the quaternary ammonium salt, have now been superseded by solid-liquid phase-transfer catalytic processes [e.g. 9-13]. Combined soliddiquid phase-transfer catalysis and microwave irradiation [e.g. 14-17], or ultrasound [13], reduces reaction times while retaining the high yields. Polymer-supported catalysts have also been used [e.g. 18] and it has been noted that not only are such reactions slower but the order in which the reagents are added is important in order to promote diffusion into the polymer. 

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