Resin-bound thiourea

The triazene T2 linker14 and the improved T2 linker57 systems offer a unique approach to the formation of guanidines in which all three substituents can be varied to a wide extent. Starting from disubstituted triazene on the T2 linker, deprotonation using NaH/DMF and subsequently acylation by the addition of isothiocyanates (Scheme 12) yielded a library of resin-bound thioureas. For the reaction of the thioureas with amines, the use... 

Zhang and Allen [97] have recently reported an easily prepared, air- and moisture-stable resin-bound palladium catalyst for the Suzuki coupling reaction. Commercially available resin-bound thiourea, Deloxan THP II [98], was used as the starting material. The resin-bound catalyst was prepared simply by treating the wet Deloxan resin with a solution of Pd(OAc)2 in methanol. Suzuki coupling reactions were then carried out using the resin at a... 

Resin-bound benzonitriles 189 were reacted with trimethylsilyl azide in the presence of dibutyltin oxide followed by acidic cleavage to give 5-biphenyl-2-yl-l//-tetrazoles 190 <04OL1143>. Resin-bound thioureas 191 reacted with sodium azide in the presence of mercury(II) chloride followed by acidic cleavage to give 5-aminotetrazoles 192 <04TL7787>. 

The synthesis of a 400 member library of aryl substituted 2-iminohydantoin tripeptide compounds has been accomplished by subjecting resin bound thioureas (36) with 10 equivalents of 1 in the presence of excess triethylamine in DMF for 18 hours.16... 

Supports 3e and 3f derived from a related linker with only one me-thoxy group ortho to the aldehyde have been reported [140] to have a more reactive aldehyde group than 3c or 3d due to lower steric hindrance. Resin 3e was used to synthesize aminothiazoles, which were cleaved under acidic conditions [141]. Thus, amines were anchored reductively to 3e and converted to resin-bound thioureas by reaction with Fmoc-isothiocyanate followed by deprotection. Cyclization by reaction with a-bromomketones gave the desired heterocycles, which were cleaved from the resin by treatment with TFA-H2O (19 1) (Scheme 4). 

Carbamate-bound guanidines have been prepared by the condensation of amines with thioureas linked to insoluble supports as carbamates [519]. The direct reaction of guanidines with resin-bound carbonates or other alkoxycarbonylating agents requires the use of chloroformates or other reactive carbonic acid derivatives [520,521], Carbamate-bound amidines (Entries 7 and 8, Table 3.28) have been prepared by the reaction of amidines with resin-bound 4-nitrophenyl carbonates (0.9 mol/L amidine in DMF/DIPEA, > 4 h [522-524]). 

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. 

The solid-phase synthesis of guanidines, however, focuses mainly on three different approaches the formation of resin bound carbodiimides63 and their reaction with amines, the solid-phase synthesis involving electrophiles in solution,64 and the reaction of supported thioureas with amines.65... 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

Fig. 11. Solid-phase synthesis of bis-cyclic thioureas and bis-cychc guanidines from resin-bound reduced tripeptides.

Another approach to the solid phase synthesis of thiazoles involves an interesting C-sulfanylation step. The starting material for this synthesis is a resin bound piperazine 55 which is converted into a thiourea and then treated with an a-bromoketone to give the thiazole 56. Treatment of 56 with either thiols or disulfides and iodine or sulfonyl chlorides with iodine and triphenylphosphine afforded 5-sulfanylthiazoles 57, which could be obtained in high yields and purity after cleavage from the resin <02EJOC2953>. 

The cycHc urea moiety provides structural rigidity as well as hydrogen-bonding possibihties similar to those of the imidazoles described above. The corresponding 2-imidazolones have been prepared on a soHd phase by tandem aminoacylation of a resin-bound allylic amine with an isocyanate followed by intramolecular Michael addition [73]. However, due to the paucity of data presented on the characterized compounds and the brief experimental procedure, this synthesis is not discussed in detail. Access to cyclic ureas or thioureas has also been obtained by reaction with carbonyl- or thiocarbonyldiimidazole through a cyclo-release mechanism [74—76]. 1,3-Dihydroimidazolones have been obtained by treatment of ureido acetals with TFA and subsequent conversion in an intramolecular cyclization via an N-acyliminium ion [77]. 

The resin-bound polyamine was used as a template for the solid-phase synthesis of a range of heterocyclic compounds, such as cyclic ureas 25 and cyclic thioureas 26. This work exemplifies our ongoing efforts on the solid-phase assembly of individual acyclic and heterocyclic compounds and combinatorial libraries using short peptides as starting materials. 

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. 

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