The first bismuth(III)-catalyzed guanylation of thioureas

This work describes the first catalytic bismuth-promoted synthesis of polysubstituted guanidines in good yields through the guanylation reaction of N-benzoyl or N-phenylthioureas with primary and secondary amines, but now employing equimolar amounts of each organic reagent. Both bismuth iodine and bismuth nitrate were efficient as inorganic thiophiles at only 5 mol % in relation to substrates, being the first example of inorganic thiophiles acting in guanylation at catalytic levels.     

Heterobimetallic dianionic guanidinate complexes of lanthanide and lithium: highly efficient precatalysts for catalytic addition of amines to carbodiimides to synthesize guanidines

A series of heterobimetallic dianionic guanidinate complexes of lanthanide and lithium, [Li(THF)(DME)]₃Ln[μ-η²η¹(ⁱPrN)₂C(NC₆H₄p-R)]₃ [R=Cl, Ln=Nd (I), Y (II), La (III); R=H, Ln=Nd (IV)] were synthesized and fully characterized. These complexes were found to be highly efficient precatalysts for the addition of various primary and secondary amines, and aromatic and aliphatic diamines to carbodiimides to give the corresponding monoguanidine and biguanidine derivatives under mild condition (at 25-60 °C), which provides an efficient way for the synthesis of biguanidines compounds. The activity depends on the central metals and ligands: La>Nd>Y for the metals and [(ⁱPrN)₂C(NC₆H₄p-Cl)]²⁻>[(ⁱPrN)₂C(NC₆H₅)]²⁻ for the ligands were observed.     

Cyclisation reactions of bis-protected guanidines

The cyclisation of N-allyl- and N-homoallylguanidines using DMDO or I₂/K₂CO₂ leading to novel heterocycles is reported.     

Über N1- und N2-substituierte 2-Amino-5,6-dihydro-4(1H)-pyrimidinone

The reactions of the monosubstituted guanidines2 b-h with methyl acrylate in dimethylformamide or ethanol as solvent preferentially afford 1-substituted 2-amino-5,6-dihydro-4(1H)-pyrimidinones6 b-h. The structures of 1-hexyl- and 1-benzyl-4-pyrimidinones6 c, e and of the picrate of 1-phenylpyrimidinone6 g were proved by comparison with authentic samples, which were prepared from N-substituted ethyl 3-amino-propionates14 c, e andg and cyanamide. Accordingly,6 g is not identical with authentic 2-phenylaminopyrimidinone7 g (prepared from 2-methylthio-4-pyrimidinone10 and 2-thioxo-4-pyrimidinone12 respectively, compare¹⁰).N,N-Disubstituted guanidines2 i-m react with methyl acrylate in dimethylformamide as solvent to afford N²,N²-disubstituted 2-amino-5,6-dihydro-4-(1H)-pyrimidinones7 i-m. Action of morpholine-4-carboxamidine (21) on methyl acrylate in ethanol yields 2-morpholinopyrimidinone71 as byproduct and 3-ethoxy-N-[morpholino(amino)methylene]propionamide (91) as mainproduct.

Herrn Prof. Dr.Robert Ott mit den besten Wünschen zum 60. Geburtstag gewidmet.     

胍类催化剂

胍类化合物是一种有机强碱，在生理条件下处于完全质子化状态，在催化有机酸碱反应时，催化性能明显优于无机碱和其它有机碱催化剂。此外，经修饰后的胍类化合物可以用于不对称催化；如果对其进行生理模拟，又可以用于酶催化反应。本文主要对胍类化合物所催化的反应进行介绍。     

‘One-flask’ transformation of isocyanates and isothiocyanates to guanidines hydrochloride by using sodium bis(trimethylsilyl)amide

A ‘one-flask’ synthesis of guanidines was developed by reacting isocyanates and isothiocyanates with sodium bis(trimethylsilyl)amide followed by addition of primary or secondary amines with a catalytic amount of AlCl₃. The desired guanidines were obtained in good yields and the reaction was applicable to aliphatic and aromatic substrates. A plausible mechanism was proposed through the generation of cyanamide anion from isocyanates or isothiocyanates with sodium bis(trimethylsilyl)amide. Addition of amines and catalytic amount of AlCl₃ smoothly converted the cyanamides to the desired guanidines.     

Synthesis of substituted 2-amino-4-quinazolinones via ortho-fluorobenzoyl guanidines

A novel route to 12 substituted 2-amino-4-quinazolinones is described. Starting from 2,6-difluoro-4-methoxybenzonitrile, substitution of one of the fluorine atoms either directly or indirectly with heterocycles (e.g., pyridyl, thiazolyl, pyrazolyl) followed by hydrolysis of the nitrile gave a series of o-fluorobenzoic acid derivatives. Condensation with a set of six N,N-disubstituted guanidines followed by base-promoted ring closure afforded 2-amino-4-quinazolinone derivatives.     

Transamidation reactions of 2-(2-sulfonylguanidino)acetamides

The reactivity of a series of sulfonylguanidinoacetamides 2A-E towards amines is reported. Guanidinoacetamides 2A-C, containing the arylsulfonylimino moiety, undergo a facile transamidation to give substituted carboxamides 4A-C, through the imidazolidinone intermediate 3. Acetamide 2D, having a methanesulfonylimino substituent, affords the imidazolidinone 3D and no transamidated carboxamides 4 are detected. In the case of guanidinoacetamide 2E, with a p-nitrobenzenesulfonylimino substituent, a Smiles rearrangement was observed.     

Preparation and evaluation of a polymer-supported Mukaiyama reagent

The synthesis of a polymer-supported Mukaiyama reagent is described. This preparation was thoroughly optimized using a DoE approach to achieve optimum loading, and the procedure was successfully applied to prepare the supported reagent on a 10 g scale. This reagent proved to be effective for the formation of carbodiimides through the dehydration of thioureas and for a one-pot guanylation of primary amines.     

Synthesis and biological activity of fluorinated 7-aryl-2-pyridyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amines

In our lead finding program, 12 new fluorinated 7-aryl-2-pyridyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amines were prepared via a practical three-step procedure starting from (iso)nicotinic hydrazides. The fluorine substituted aryl fragment was introduced in the last step through cyclocondensation of N-(3-pyridyl-1,2,4-triazol-5-yl)guanidines and fluoro/trifluoromethyl substituted benzaldehydes. The structures of the compounds were confirmed by ¹H and ¹³C NMR spectral data. The tautomeric preferences for the compounds were established using 2D NOESY experiments. The antiproliferative activity of the synthesized 1,2,4-triazolo[1,5-a][1,3,5]triazines was evaluated against breast, colon and lung cancer cell lines. The highest antiproliferative activity in the series was found for 2-(pyridine-3-yl)-7-(4-trifluoromethylphenyl)-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amine. The lack of inhibitory activity against bovine dihydrofolate reductase (DHFR) indicated that the antiproliferative activity was realized via other mechanisms.