Polymer-bound, amide bases

The catalytic system has been successfully extended to polymer-bound lithium amide co-bases of type 65 (see Table 4) which, like C—Li bases of type 63 and 64, are efficient regenerating agents of HCLA and poorly reactive toward oxiranes. For instance, the isomerization of cyclohexene oxide by 0.05 equiv of HCLA 55 in the presence of 1.45 equiv of 65 affords ( l-cyclohexenol in 92% ee (entry 15). It is of interest to note that, similarly to co-bases 63 and 64, the use of 65 leads to an increase of selectivity compared to the stoichiometric reaction at room temperature (Table 2, entry. ... 

In some cases, when Schwesinger base is used in reaction sequences, removal of polymer-associated base may be difficult In such cases, a fivefold wash with CH2CI2/ACOH (4 1, v/v) may be employed. The loss of polymer-bound substrate attached to a Rink linker via amide or amine functions is very minimal during this treatment. 

Polymer-supported triphenylphosphine ditriflate (37) has been prepared by treatment of polymer bound (polystyrene-2% divinylbenzene copolymer resin) triphenylphosphine oxide (36) with triflic anhydride in dichloromethane, the structure being confirmed by gel-phase 31P NMR [54, 55] (Scheme 7.12). This reagent is effective in various dehydration reactions such as ester (from primary and secondary alcohols) and amide formation in the presence of diisopropylethylamine as base, the polymer-supported triphenylphosphine oxide being recovered after the coupling reaction and reused. Interestingly, with amide formation, the reactive acyloxyphosphonium salt was preformed by addition of the carboxylic acid to 37 prior to addition of the corresponding amine. This order of addition ensured that the amine did not react competitively with 37 to form the unreactive polymer-sup-ported aminophosphonium triflate. 

For this purpose, our model reaction can be modified as shown in Figure 3.1.5 using a polymer-bound chloroformate linking the mixed anhydride intermediate to a solid support and, thus, allowing easy removal of excess base by simple washing. After coupling with amines R -NHj, only amide 3 and excess amine remain in solution which can be easily separated as previously described. 

The method of esterification, based on the double activation route to macro-lides, mentioned earlier (Scheme 26, p. 135) has been found to be equally effective in the formation of amides from carboxylic acids and primary or secondary amines. The well known method for amide bond formation in peptide synthesis using mixtures of triphenylphosphine and 2,2 -dipyridyl disulphide has been modified by employing polymer-bound triphenylphosphine. In a similar vein, mixtures of triphenylphosphine and carbon tetrachloride have been reported to be useful in the formation of amide linkages in peptide synthesis.A similar method using polymer-bound phosphine with carbon tetrachloride and tiiethylamine has also been reported. ... 

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. 

A convergent synthesis of the potent selective inhibitor of the enzyme phosphodiesterase sildenafil (Viagra) has been based on polymer supported reagents [134], In this synthesis, the HOBt-supported resin 126 has been used for the isolation and preparation of the resin-bound active ester 128, performed by coupling polymer 126 with the benzoic acid sulfonamide derivative 127 by means of PyBrop (Scheme 7.40). Subsequent reaction of active ester 128 with aminopyrazole 129 gave rise to the clean synthesis of amide 130, which has been transformed into sildenafil (131) after a base-promoted pyrimidinone formation. 

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