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.     

Modified guanidines as potential chiral superbases. 2. Preparation Of 1,3-unsubstituted and 1-substituted 2-iminoimidazolidine derivatives and a related guanidine by the 2-chloro-1, 3-dimethylimidazolinium chloride-induced cyclization of thioureas

Simple preparation methods for modified guanidines were explored for new chiral superbases. Thus, (4S,5S)-4,5-diphenyl- and diastereomeric cyclohexane-fused 2-iminoimidazolidines were prepared from (1S,2S)-1,2-diphenylethylenediamine and (1R,2R)- or (1S,2S)-1, 2-diaminocyclohexanes through cyclization of protected thiourea intermediates with 2-chloro-1,3-dimethylimidazolinium chloride (DMC) as a key reaction. In the (4S,5S)-4,5-diphenyl series 1-methyl-2-iminoimidazolidines and 2-diethylaminoimidazoline were also prepared as related guanidines.     

Simple preparation of chiral 1,3-dimethyl-2-iminoimidazolidines (monocyclic guanidines) and applications to asymmetric alkylative esterification

New chiral 1,3-dimethyl-2-iminoimidazolidines (monocyclic guanidines) were simply prepared by the action of primary amines on 2-chloro-1,3-dimethylimidazolinium chlorides, derived from the corresponding urea, in high yields. Modest asymmetric induction in alkylative esterification of benzoic acid with (1-bromoethyl)benzene was observed when the 1,3-dimethyl-4,5-diphenyl-2-[(1-phenyl- or 1-naphthyl)ethylimino]imidazolidines with all S (or R) configurations were used as bases.     

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.     

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.     

New methods for the preparation of aryl 2-iminoimidazolidines

A divergent strategy for the synthesis of 1-aryl- and 2-aryl-2-iminoimidazolidines is presented. Cyclization of N-Boc-N′-aryl-N′′-(2-hydroxyethyl)guanidines in the presence of methanesulfonyl chloride and triethylamine or sodium hydride at 0 °C affords the corresponding 2-iminoimidazolidines in good yields.     

Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN

An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyanamides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered guanidines, which were isolated in good to excellent yields (70–96%). The chiral guanidines were prepared in an effort to design sophisticated chiral guanidine catalysts for asymmetric synthesis.     

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.     

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.     

A simple one-pot synthesis of triflyl guanidines: access to highly substituted electron-poor guanidines

Unsymmetrical di- and trisubstituted triflyl guanidines are accessed through a simple, one-pot protocol from the corresponding isothiocyanate and amine. Furthermore, in the presence of base, trisubstituted triflyl guanidines are alkylated to obtain tetrasubstituted triflyl guanidines in high yields and complete regioselectivity.     

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.     

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.     

Solid-phase and solution-phase syntheses of oligomeric guanidines bearing peptide side chains

[reaction: see text] Synthetic strategies for preparing N,N'-bridged oligomeric guanidines bearing peptide side chains both on solid support and in solution are presented. Monomers are prepared from common alpha-amino acids and therefore contain conventionally protected peptide side chains. The side chains include alkyl, aromatic, hydroxyl, amino, carboxylic acid, and amide functional groups. Oligomer elongation utilizes acid-sensitive sulfonyl activated thiourea through the formation of carbodiimide intermediate. With proper preparation of monomers, synthesis of oligomer can be performed in two directions (equivalent to N to C terminal or C to N terminal in a peptide sequence) with excellent efficiency.     

Synthesis of purines and other fused imidazoles from acyclic amidines and guanidines

[reaction: see text] Purines, xanthines, and other fused imidazoles can be prepared from amidines or guanidines, with retrosynthetic disconnection at the ring fusion. Ring closure proceeds using Cu(I), with no special ligands required. The method allows for easy modification of the heterocyclic nucleus and is tolerant of functionality pendant to the ring system.     

Guanidine chemistry

Guanidines are categorized as strong organobases; however, their catalytic utility in organic synthesis has not been discussed thoroughly. The author's group has extensively and systematically studied their potential ability focusing on: 1) modified guanidines as chiral auxiliaries; 2) guanidinium ylides for aziridine formation; 3) the affinity of bisguanidine for proton and metal salts; and 4) the potential chirality of bisguanidine. Under the first topic, a variety of chiral guanidines was designed by the introduction of chirality on the three guanidinyl nitrogens, and the modified guanidines prepared using our original methods were found to be effective not only in catalytic but also in stoichiometric asymmetric syntheses. Under the second topic, the reaction of guanidinium salts carrying a glycinate function with aromatic or unsaturated aldehydes under basic conditions unexpectedly afforded aziridine-2-carboxylates, which were available as useful building blocks in organic synthesis due to their convertibility to functionalized amino acid derivatives in the ring-opening reaction, together with urea compounds recyclable to the starting guanidinium salts. The introduction of a chiral template to the guanidinium salt allowed us to expand the cyclic aziridination reaction to an asymmetric version. Under the third topic, effective complexabilty of bisguanidines with either proton or metal ions in water was observed, suggesting their possible application to the removal of toxic substances from polluted water and recovery of rare elements as material sources. Under the final topic, monomethylation or monoethylation of bisguanidine afforded a chiral product via asymmetric crystallization, indicating that bisguanidines have a potential chiral character due to the plane asymmetry.     

An original traceless linker strategy for solid-phase synthesis of N,N',N'-substituted guanidines

An original sequence for solution- and solid-phase synthesis of N,N',N"-trisubstituted guanidines is described. The sequence involves as key intermediate a bis-electrophilic chlorothioformamidine that is stable, easy to prepare and also easy to handle. Supported chlorothioformamidine, prepared in two steps from Merrifield resin, undergoes smooth nucleophilic addition of a primary amine to afford the corresponding supported isothiourea. The guanidine is obtained in satisfactory yield and good purity through a functionalizing-release process by heating the supported isothiourea in the presence of a primary amine in toluene at 100 degrees C. Compatibility of this sequence with several functional groups is demonstrated.     

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.     

A new entry for the synthesis of N-acyl-N′-substituted guanidines

An efficient synthesis of N-acyl-N′-substituted guanidines by condensation reaction of thiourea and (Me₃Si)₂NH in the presence of EDCI is described. Various guanidines were synthesized in a simple manner.     

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.