Amines, acylation polymer-bound

Then N-Boc-O-benzylserine is coupled to the free amino group with DCC. This concludes one cycle (N° -deprotection, neutralization, coupling) in solid-phase synthesis. All three steps can be driven to very high total yields (< 99.5%) since excesses of Boc-amino acids and DCC (about fourfold) in CHjClj can be used and since side-reactions which lead to soluble products do not lower the yield of condensation product. One side-reaction in DCC-promoted condensations leads to N-acylated ureas. These products will remain in solution and not reaa with the polymer-bound amine. At the end of the reaction time, the polymer is filtered off and washed. The times consumed for 99% completion of condensation vary from 5 min for small amino acids to several hours for a bulky amino acid, e.g. Boc-Ile, with other bulky amino acids on a resin. A new cycle can begin without any workup problems (R.B. Merrifield, 1969 B.W. Erickson, 1976 M. Bodanszky, 1976). 

Acid derivatives that can be converted to amides include thiol acids (RCOSH), thiol esters (RCOSR), ° acyloxyboranes [RCOB(OR )2]. silicic esters [(RCOO)4Si], 1,1,1-trihalo ketones (RCOCXa), a-keto nitriles, acyl azides, and non-enolizable ketones (see the Haller-Bauer reaction 12-31). A polymer-bound acyl derivative was converted to an amide using tributylvinyl tin, trifluoroacetic acid, AsPh3, and a palladium catalyst. The source of amine in this reaction was the polymer itself, which was an amide resin. 

It is interesting that one observes exclusive TV-acylation of ethanolamine even when the molar ratio of polymer-bound acylimidazole to amine is 1 2. 

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. 

A variation of this method led to the generation of bis-benzimidazoles [81, 82], The versatile immobilized ortho-phenylenediamine template was prepared as described above in several microwave-mediated steps. Additional N-acylation exclusively at the primary aromatic amine moiety was achieved utilizing the initially used 4-fluoro-3-nitrobenzoic acid at room temperature (Scheme 7.72). Various amines were used to introduce diversity through nucleophilic aromatic substitution. Cyclization to the polymer-bound benzimidazole was achieved by refluxing for several hours in a mixture of trifluoroacetic acid and chloroform. Individual steps at ambient temperature for selective reduction, cyclization with several aldehydes, and final detachment from the polymer support were necessary in order to obtain the desired bis-benzimidazoles. A set of 13 examples was prepared in high yields and good purities [81]. 

One type of synthesis was described by Ding et al.15 (Fig. 1). A drawback to this approach is the low reactivity of a polymer-bound amine. This problem may be alleviated to some extent by activating the heterocycle with ammonium salts16 and by the choice of linker. Mainly acid-labile indole24 (28) and PAL linkers25 (26) have been employed. The possibility of activating C2 by acylation of N626 of the purine scaffold was not... 

Another example of a polymer-bound phenolic leaving group has been reported by Huang et al. [22]. Supported 8-acyloxyquinolines were shown to readily acylate primary and secondary amines and anilines at room temperature. Neighboring group participation was proposed for the quinoline nitrogen atom. 

Combinatorial sequences that comprise amine acylation can frequently be expanded to sulfonamide formation using sulfonyl chlorides (unspecified sulfochlorides [9, 52] aliphatic and aromatic sulfochlorides [19] aromatic sulfochlorides [80,102]). Sulfonation of aliphatic diamines with protected (3-aminoalkane sulfonyl chlorides was carried out in the presence of polymer-bound 4-dialkylaminopyridine [130] (see also Table 3.11). 

The polymer-bound allylic amines can be employed in several reactions. Figure 6.10 shows acylation, alkylation and sulfonation as possible modifications. 

Polymer-bound triphenylphenylphosphine [354] has been converted to a phosphonium salt 8i by reaction with 2-nitrobenzyl bromide. The nitro group was then reduced to an amine and acylated. The resulting product formed a resin-bound ylide in the presence of base, which underwent a Wittig reaction with aldehydes that released alkenes into solution with the phosphine oxide by-product remaining bound to the solid support [355]. 

A solid-phase submonomer approach to A-substituted j8-aminopro-pionic acid oligomers or )8-peptoids has been developed by Hamper et al. [63]. It is based on a simple two-step acylation and Michael addition reaction sequence. Treatment of Wang resin with 2 equiv. of acryloyl chloride in the presence of triethylamine in excess afforded the corresponding acrylate resin 86 (Scheme 23) [63]. Michael addition of a 6- to 10-fold excess of a given primary amine in DMSO afforded polymer-bound A-substituted -alanines (87). Trimeric A-benzyl-j8-aminopropionic acid (88) was prepared in 67% overall yield by repetition of this two-step sequence. 

In a related and more recent study a variety of solid-supported acylating agents were synthesized and used for microwave-mediated transformation of amines, alcohols, phenols, and thiophenols [123]. In a microwave-mediated procedure, Mer-rifield resin was first modified by attaching 1,4-butanediol to introduce a spacer unit. Bromination and subsequent reaction with commercially available 6-methyl-2-thiouracil then treatment with corresponding acyl chloride afforded the desired polymer-bound pyrimidines (Scheme 16.81). The acylating ability of this supported reagent has been proven by reaction with benzylamine. 

Deprotection of Fmoc-amino acid Wang resins under standard conditions yielded the polymer-bound amino acids 1. Condensation with 3,4-dichlorobenzaldehyde gave aldimines 2. Subsequent alkylation with electrophiles such as benzyl-, naphthyl- or allylbromide in the presence of 2-[(l,l-dimethylethyl)imino]- W,N-diethyl - 2,2,3,4,5,6- hexahydro-1,3-dimethyl-1,2,3-diazaphosphorin-2(lH)-amine (BEMP) gave the disubstituted aldimines 3. Transketalisation with hydroxylamine hydrochloride yielded the free amine 4 which was acylated and cleaved to give the final product 5 in good yields and purities. 

On reviewing the couphng methods proposed for application in solid phase peptide synthesis one finds that most known methods of peptide bond formation have been tried but no new approach was designed specially for the acylation of the polymer bound amine component. Therefore we will limit the discussion in this section to two well established procedures, coupling with the help of carbodiimides and acylation via active esters. 

Finally, while it is not obvious how both the amine-component and the carboxyl component could be applied in polymeric form, this dilemma was solved (Cohen et al. 1981) by the introduction of a mediator. A solution of imidazole is circulated through separate beds of the insoluble reactive carboxyl-component and the polymer-bound amine-component. The acyl-imidazoles generated in the active ester bed are excellent acylating agents which transfer... 

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