Solid-supported reagents acylation

Scheme 7.110 Synthesis of a novel solid-supported reagent and its use in acylation.

Petricci, E., Botta, M., Corelli, F. and Mugnaini, C., An improved synthesis of solid-supported reagents (SSRs) for selective acylation of amines by microwave irradiation, Tetrahedron Lett., 2002, 43,6507. 

Weakly nucleophilic heterocyclic amines have efficiently been acylated utilizing solid-supported reagent 7 [13]. Here, the electron-deficient phenol group allows for intermediate anchoring of an acyl chloride onto the resin which then is released upon treatment with various 2-aminopyridines and 2-aminothiazoles. Traces of unreacted starting material were then conveniently removed by addition of the acidic ion exchange resin Amberlite IRA-120. 

One of the more recent solid-supported reagents utilized by Ley and co-workers is an azide monolith, used to synthesize a series of azides from their respective acyl halide, as illustrated in Scheme 49 (Baumann et al., 2008a). The authors report the fabrication of the azide monolith 177 (2.00 mmol g-1) in a glass Omnifit reactor [15 mm (i.d.)xlOcm (long)] via thermal polymerization and quantified the columns total void volume (6.4 ml) using mercury intrusion analysis. 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

A collection of highly functionalized benzoxazoles (xLiii) have been synthesized by Radi et al. [69] following a one pot, two step microwave assisted, solid-phase synthetic protocol starting from acylating solid supported reagents (xLii). 

A recyclable solid supported reagent has been developed for acylations and was easily applied in a parallel synthesis of the corresponding amides starting from amines (Scheme 16.80) [122]. The solid-supported reagent could be removed by simple filtration after the reaction and the product isolated by evaporation. The supported reagent could be re-used at least twice before any decrease in the reaction yield. 

Kim, K. and Le, K. (1999) Two efficient A-acylation methods mediated by solid-supported reagents for weakly nucleophilic heterocyclic amines. Synlett, 1957-1959. 

Similarly, a solid-supported imide has been reported to serve as an acylating reagent under microwave conditions by Nicewonger and coworkers [130], The starting imide was immobilized on aminomethyl polystyrene and in this case benzoyl chloride was chosen to prepare the acylating reagent (Scheme 7.111). Primary amines and piperazines were smoothly acylated at room temperature, but more hindered secondary amines required more time and higher temperatures, and anilines... 

Kaldor [49 i, 55] demonstrated the advantages of applying solid-supported scavengers to the preparation of parallel arrays in a multi-step fashion. In these studies he examined the clean-up of multiple amine alkylation and acylation reactions using a variety of immobilized electrophilic and nucleophilic scavenger reagents including an amine, isocyanate, aldehyde and acid chloride (Tab. 2.1). 

An extended application of the resin-capture-release technique is depicted in Scheme 13. With the help of reagent 31, a functionalized pyridine was captured as an acyl pyridinium cation 32 on a solid support which was followed by Grignard addition and hydrolysis under acidic conditions to afford polymer-supported N-acylated dehydropyridinones 33 [39]. Advantageously, any unreacted acylium complex collapses to the parent resin upon workup. These heterocycles, which ideally can serve as scaffolds, are then released under basic conditions. 

This reagent, benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (14, PyBOP)P l (Scheme 4), was designed in order to avoid the formation of toxic HMPA during acylation. As with BOP, it is assumed that the first step is the carboxylic acid activation which involves formation of an acyloxyphosphonium salt.P This initial salt is then attacked by the benzotriazolyloxy anion to form the benzotriazolyl active ester which then reacts with the amino component. PyBOP can easily replace the BOP reagent and is especially suitable for solid-phase peptide synthesis. It is soluble in a wide range of solvents such as DMF, di-chloromethane, THF, and NMP. PyBOP is more useful in peptide synthesis on solid support than in solution. The byproduct, tris(pyrrolidino)phosphine oxide is partially water-soluble and is easily removed by washing. PyBOP is used under the same experimental conditions as BOP. Note that PyBOP is a white, crystalline and non-hygroscopic solid. It can be kept as a solid, but solutions of PyBOP cannot be stored for more than 24 hours. 

The concept of selective sequestration of non-product species was first demonstrated using solid-supported scavengers with electrophilic and nucleophilic character in amine acylation, amine alkylation, and reductive amination protocols [46]. Since then, a wide range of scavenger reagents has become commercially available from various suppliers. The structures and functions of these scavenger resins are shown in Table 1. 

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