Solid-phase synthesis of trisubsituted guanidines

The solid-phase library synthesis of trisubstituted guanidines was accomplished. Amines were loaded onto the 4-formyl-3,5-dimethoxyphenoxymethyl linker via reductive amination. Subsequent acylation with Fmoc-4-aminomethylbenzoic acid followed by Fmoc deprotection gave solid-supported primary amines. Alternatively, sulfonylation of resin-bound secondary amines with 4-cyanobenzenesulfonyl chloride followed by borane reduction also gave solid-supported primary amines. Both resins were acylated with isocyanates to furnish solid-supported ureas. Dehydration of ureas with p-toluenesulfonyl chloride in pyridine gave solid-supported carbodiimides. Nucleophilic addition of amines to the carbodiimide bond followed by cleavage off the solid support gave trisubstituted guanidines.     

Synthesis of 2-amino-4-pyrimidinones from resin-bound guanidines prepared using bis(allyloxycarbonyl)-protected triflylguanidine

We have synthesized novel heterocyclic compounds from resin-bound guanidines. For this purpose, an amine immobilized on a solid support was acylated with protected amino acids. Following the deprotection, the liberated amines were guanidinylated utilizing a new member of the family of diurethane-protected triflyl guanidine reagents, N,N'-bis(allyloxycarbonyl)-N' '-triflylguanidine. The deprotected guanidines were subsequently regioselectively cyclized with beta-keto esters yielding novel compounds containing heterocyclic structures in high purities.     

A novel solid-phase synthesis of highly diverse guanidines: reactions of primary amines attached to the T2 linker

The reaction of primary amines with the T2 diazonium resin generates polymer-bound triazenes, which can in turn be acylated by the addition of isothiocyanate. The formed thioureas are readily transformed into the corresponding guanidines by the reaction with amines in the presence of mercury(II) oxide, tosyl chloride, or silver nitrate. This reaction sequence furnishes trisubstituted guanidines that are potentially useful pharmacophores.     

A novel traceless resin-bound guanidinylating reagent for secondary amines to prepare N,N-disubstituted guanidines

[reaction: see text]. We report the development of a solid support-linked guanidinylating reagent. This reagent consists of a urethane-protected triflyl guanidine attached to the resin via a carbamate linker. It allows for rapid synthesis of guanidines from a variety of amines. It provides access to N-alkyl/aryl- or N,N-dialkylguanidines under mild conditions. Cleavage with 50% TFA produces target molecules in high yields and purity. The ability to guanidinylate secondary amines is a significant feature of this guanidinylating reagent.     

Solid-phase synthesis of substituted guanidines using a novel acid labile linker

A novel acid labile linker for solid-phase synthesis of substituted guanidines has been developed. Its synthetic utility is exemplified by high-yielding pyrazole displacement with structurally and electronically diverse sets of aliphatic and aromatic amines. The final cleavage is achieved by treatment with 95:5 trifluoroacetic acid/water for 1 h. The corresponding guanidines were obtained in high purity (80-95%) and good isolated yields (50-95%). The scope and limitations of this linker were further demonstrated by the solid-phase synthesis of an 880-member library of individual trisubstituted arylguanidines employing pyrazole displacement with a set of 11 anilines and two subsequent Mitsunobu N-alkylations with sets of 10 and 8 alcohols, respectively.     

Phase-transfer-catalyzed alkylation of guanidines by alkyl halides under biphasic conditions: a convenient protocol for the synthesis of highly functionalized guanidines

An operationally straightforward and efficient method for the alkylation of carbamate-protected guanidines with various alkyl halides and mesylates is described. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine under biphasic conditions using a catalytic amount of a tetrabutylammonium salt as a phase-transfer catalyst. In this manner, highly functionalized guanidines can be obtained. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine component. In addition, the reaction is sufficiently mild such that simple aqueous workup and filtration through a short silica gel column yields the substituted guanidines in high purity. In conjunction with the EDCI-mediated guanylation of disubstituted thioureas with amines, phase-transfer catalyzed alkylation of guanidines via a one-pot, three-component synthesis of substituted guanidines was achieved.     

Substituted guanidines: introducing diversity in combinatorial chemistry

The guanidine moiety is an important motif present in many biologically active compounds. Fully substituted guanidines are of key importance for the development of bioactive molecules. The present paper reports on an efficient procedure for the direct solid-phase conversion of amines to fully substituted guanidines under very mild conditions.     

Chiral bicyclic guanidines: a concise and efficient aziridine-based synthesis

A series of chiral bicyclic guanidines, either symmetrical or non-symmetrical, was synthesized using a concise and efficient aziridine-based synthetic methodology. Starting from commercial amino alcohols, five synthetic steps were performed, with only three requiring chromatographic purification, giving the desired guanidines in 43-71% overall yield. Preliminary studies using these guanidines showed moderate enantioselectivity for several Michael reactions.     

Microwave-assisted synthesis of highly functionalized guanidines on soluble polymer support

An efficient method for the N,N′-di(Boc)-protected guanidines containing piperazine and homopiperazine scaffolds has been developed under multi-step microwave irradiation. Followed by alkylation of carbamate-protected guanidines with various alkyl halides is also explored. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine by sodium hydride on soluble polymer support. In this manner, highly functionalized guanidines were obtained after cleavage from the support. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine components. In addition, the reaction is sufficiently simple workup by precipitation in each step to yield the substituted guanidines in high purity. In conjunction with microwave irradiation and soluble polymer support, this method provides an efficient route to access highly functionalized guanidines.     

Tethered libraries: solid-phase synthesis of substituted urea-linked bicyclic guanidines

The general concept of tethered combinatorial libraries of compounds in which two pharmacophores are found is described. In particular, an improved method for the solid-phase synthesis of bicyclic guanidines from reduced N-acylated dipeptides, and its use in the synthesis of urea-linked bicyclic guanidines, is described. The exhaustive reduction of glutamine-containing resin-bound N-acylated dipeptides, using borane-THF, generated compounds containing three secondary amines and one primary amine. Following selective trityl protection of the primary amine, treatment of the three secondary amines with thiocarbonyldiimidazole (CSIm2) and mercuric acetate (Hg(OAc)2) generated the resin-bound bicyclic guanidines. Following trityl deprotection, an Fmoc-amino acid was coupled. Upon removal of the Fmoc protecting group, the resulting primary amine was treated with hexyl isocyanate to generate the urea-linked bicyclic guanidines. The desired products were cleaved from the resin using hydrogen fluoride. The selection of building blocks and characterization of controls for the synthesis of a combinatorial library is discussed.     

胍类化合物的制备及在有机合成中的应用

综述了胍类化合物的制备及其在有机合成中的应用，特别着重合成方法研究的 近期进展及在不对称合成中的应用。     

胍基化合物研究进展

胍基官能团受到重视的原因在于它的生理活性,易于形成氢键,稳定性。在较大的pH范围内保持正电性,以及对碳酸酯、磷酸酯、金属的高度亲合性。这篇综述总结了胍类化合物在分子识别和药理作用、催化作用、金属络合及合成四方面的研究进展。     

Modified guanidines as chiral auxiliaries

Investigations on modified guanidines, prepared by newly developed methods, as potential chiral auxiliaries led to reasonable asymmetric induction not only in catalytic but also in stoichiometric asymmetric syntheses. These guanidine-mediated reactions may contribute to the development of green chemistry because of their possible application as re-cyclable (economically favored) and easily functionalizable (widely applicable) auxiliaries.     

Modified guanidines as potential chiral superbases. 1. Preparation Of 1,3-disubstituted 2-iminoimidazolidines and the related guanidines through chloroamidine derivatives

Modified guanidines were explored as potential chiral superbases. Thus, chiral 1,3-dimethyl-2-iminoimidazolidines with or without 4, 5-diphenyl groups, their guanidinium salts, and the 2-iminoimidazolidines with (S)-1-phenylethyl groups on the ring nitrogens were prepared by treatment of 2-chloroimidazolinium chlorides with appropriate amines. Bicyclic guanidines were also prepared from a prolinamide using a similar procedure.     

A 1,3-Diaza-Claisen rearrangement that affords guanidines

[reaction: see text] N-Alkyl-N'-tosylthioureas activated by EDCI react with azanorbonenes at room temperature through a 1,3-diaza-Claisen rearrangement, affording highly substituted, bicyclic guanidines in moderate to good yields.     

Modified guanidines as potential chiral superbases. 3. Preparation Of 1,4,6-triazabicyclooctene systems and 1,4-disubstituted 2-iminoimidazolidines by the 2-chloro-1,3-dimethylimidazolinium chloride-induced cyclization of guanidines with a hydroxyethyl substituent

Simple preparation methods of modified guanidines have been explored as potential chiral superbases. Thus, 3,7,8-trisubstituted and 3,6,7, 8-tetrasubstituted 1,4,6-triazabicyclooctene systems were prepared from (1S,2S)-1,2-diphenylethylenediamine through stepwise 2-chloro-1, 3-dimethylimidazolinium chloride (DMC)-induced cyclizations of protected thioureas to the corresponding 2-iminoimidazolidines and then of 2-(2-hydroxyethylimino)imidazolidines to the bicyclic systems. Linear guanidines with a 2-hydroxyethyl functional group were prepared by the reaction of carbodiimides with 2-amino alcohols. Reaction of linear-type guanidines with DMC followed by base treatment afforded 1,4-disubstitued 2-iminoimidazolidines. Furthermore, another type of 1,4,6-triazabicyclooctene was also prepared through double DMC-induced cyclization of guanidines with two 2-hydroxyethyl substituents.     

Ab initioSCF study of guanidine and substituted guanidines

Proton affinities, geometries with optimized parameters, and net atomic charges are reported for guanidine-, methyl-, amino-, and fluoro-substituted guanidines. The results are obtained using the ab initio SCF method as implemented by the GAUSSIAN-70 computer program with a 6–31G basis set. Basicity is discussed in terms of electron distribution and intramolecular attraction forces.     

Combinatorial synthesis of heterocycles: solid-phase synthesis of 6-amino-2,4-dioxo-3,4-dihydro-1,3,5-triazine derivatives

A new solid-phase synthesis of trisubstituted 6-amino-2,4-dioxo-3,4-dihydro-1,3,5-triazines from a resin-bound amine component is described. The amine was readily converted to the corresponding polymer-bound S-methylthiopseudourea, which upon reaction with secondary amines gave the disubstituted guanidines. Cyclization of the polymer-bound guanidines with chlorocarbonylisocyanate afforded the triazinediones. The third point of diversity was introduced by the Mitsunobu reaction. The method is amenable for iterative combinatorial library generation.     

A novel solid-phase synthesis of cyclic guanidines

We have developed a robust solid-phase approach to cyclic guanidines based on the Staudinger protocol. The synthetic sequence involves the reaction of the immobilized aza-Wittig reagents derived from the respective azidobenzoic acids with bifunctional amines. Convenient isolation and good yields of the desired products (34-84%) along with the diversity of the targeted molecules are distinctive features of the resultant library.