Resin-bound carbodiimides

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

Resin bound carbodiimides are used in the formation of diphenol monomers used in the synthesis of tyrosine derived pseudo polypeptides. ... 

The present procedure2 describes the conversion of resin-bound, primary aliphatic amines into isothiocyanates and the conversion of the latter into 3-aminothiophenes. The generation of isothiocyanates is related to known procedures,3 in which amines are first treated with carbon disulfide and the resulting dithiocarba-mates are desulfurized by treatment with a condensing agent (alkyl chloroformates, carbodiimides, lead or mercury salts, etc.). The presence of resin-bound isothiocyanates on the polystyrene support could be qualitatively ascertained by infrared spectroscopy (KBr-pellet strong absorption at 2091 cm-1). 

A carbodiimide-grafted polystyrene resin was reacted with tetramethyl-guanidine to give an interesting biguanide structure (Scheme 13). This was assayed as a catalyst for a transesterification reaction.33 Incidentally, resin-bound guanidines are useful bases for processes involving resin capture.34... 

Both aliphatic alcohols and phenols have been immobilized as esters of support-bound carboxylic acids. The esterification can be achieved by treatment of resin-bound acids with alcohols and a carbodiimide, under Mitsunobu conditions, or by acylation of alcohols with support-bound acyl halides (see Section 13.4). 

For the solid-phase synthesis of amides, it makes a significant difference whether the amine or the acid is linked to the support. Resin-bound amines are readily acy-lated by adding first a carboxylic acid and then a carbodiimide (Table 13.3). The acid/ carbodiimide ratio is not critical, because both the O-acylisourea (ratio 1 1) and the symmetric anhydride (ratio 2 1) will lead to N-acylation. It should, however, be borne in mind that the half-lives of O-acylisoureas are shorter than those of anhydrides, and for difficult couplings it might be advantageous to acylate with a symmetric anhydride (two equivalents of acid and one of carbodiimide). 

The esterification of support-bound carboxylic acids has not been investigated as thoroughly as the esterification of support-bound alcohols. Resin-bound activated acid derivatives that are well suited to the preparation of esters include O-acylisoureas (formed from acids and carbodiimides), acyl halides [23,226-228], and mixed anhydrides (Table 13.15). A-Acylurea formation does not compete with esterifications as efficiently as it does with the formation of amides from support-bound acids. Esters can also be prepared from carboxylic acids on insoluble supports by acid-catalyzed esterification [152,229]. Alternatively, support-bound carboxylic acids can be esteri-fied by O-alkylation, either with primary or secondary aliphatic alcohols under Mitsu-nobu conditions or with reactive alkyl halides or sulfonates (Table 13.15). 

Resin-bound iminophosphoranes 103 derived from the reaction of resin-bound 2-aminobenzimidazole 102 with triphenylphosphine oxide were reacted with aryl isocyanates in an abnormal aza-Wittig reaction with a chemoselectivity that depends on the reaction temperature and the nature of the aryl isocyanate (Scheme 22). The mechanism considered for the solid phase synthesis reaction involves the loss of triphenylphosphin-imide instead of triphenylphosphine oxide, resulting in the formation of isocyanates instead of carbodiimides as intermediates. Optimization studies revealed that employing electron-poor aryl isocyanates at high temperature leads to 95% of the abnormal aza-Wittig products 3-aryl 2,4-dioxo-l,3,5,-triazino[l,2-fl]benzimidazoles 104 [76]. 

A hydantoin library of 800 compounds has been reported by Dress-mann et al. [61]. In this approach, 20 different amino acids and over 80 primary amines were incorporated. Selected amino acids were attached via their iV-terminus to hydroxymethyl polystyrene resin by using a carbamate linker. This enabled generation of the free acid resin-bound intermediates, which could then be converted to their corresponding amides by standard carbodiimide coupling reactions and excess primary amine. Concomitant... 

Aminomethylated, crosslinked polystyrenes constitute very valuable and versatile resins for a variety of applications. The amino group can be easily acylated for the introduction of spacer and linker molecules and it was also used for the synthesis of polymer-bound carbodiimides. - In Scheme 1 S.4.4, some of the most common synthetic accesses to aminomethylated polystyrenes are summarised. 

Lam et al. is outlined partly in Scheme 10 (177]. The nitro group of resin-bound intermediate 53 was reduced to 1,3-deiamine 54 which gave 55 by carbodiimide-mediated cychzation. Final products 56 (19 examples) were obtained after TEA cleavage followed by HPLC in 46-83% yields with 72-94% purity. 

Synthesis of Imidazolones. In general, the synthesis of imadazolones is achieved by the treatment of resin-bound amino acids with isocyanates or isothiocyanates to form the corresponding ureas and thioureas that then undergo an oxidation reaction resulting in a carbodiimide intermediate. Mukaiy ama s reagent or other oxidative reagents are employed. The carbodiimide intermediate is treated with primary or secondary amines to form the imidazolone scaffolds. 

The first parallel solid-phase 1,3,5-triazino-annulation S5mthesis has been achieved by Hoesl et al. [28]. Aza-Wittig reaction of an iminophosphorane generated in situ from a resin-bound 2-aminobenzimidazole (under Mitsunobu conditions) resulted in the formation of a highly reactive carbodiimide intermediate, which subsequently underwent intramolecular heterocyclization to afford the corresponding triazinobenzimidazoles (Scheme 7). 

Schiltz and Reinbolt, 1975) combined the diisothiocyanate and carbodiimide procedures to permit sequencing of peptides that lack lysine. The peptide is first coupled by its NH2-terminus to aminopolystyrene using p-phenylene diisothiocyanate. With the peptide bound to the resin, the COOH-terminal is then coupled using a carbodiimide. This procedure is reported to be useful for larger peptides that do not couple efficiently with the carbodiimide alone (Schiltz, 1975). 

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