Amidolithium and Amidoaluminum Catalyzed Synthesis of Substituted Guanidines: An Interplay of DFT Modeling and Experiment

Abstract

The synthesis of substituted guanidines is of significant interest for their use as versatile ligands and for the synthesis of bioactive molecules. Lithium amides supported by tetramethylethylenediamine have recently been shown to catalyze the guanylation of amines with carbodiimide. In this report, density functional theory (DFT) calculations are used to provide insight into the mechanism of this transformation. The mechanism identified through our calculations is a carbodiimide insertion into the lithium-amide bond to form a lithium guanidinate, followed by a proton transfer from the amine. The proton transfer transition state requires the dissociation of one of the chelating nitrogen centers of the lithium guanidinate, proton abstraction from the amine, and bond formation between the lithium center and the amine nitrogen. On the basis of this mechanism, further calculations predicted that aluminum amides would also function as active catalysts for the guanylation of amines. We confirm this experimentally and report the development of aluminum amides as a new main group catalyst for the guanylation of a range of electron-poor amines with carbodiimide.

The Flexible Coordination Modes of Guanidine Ligands in Zn Alkyl and Halide Complexes: Chances for Catalysis

“…In addition to the guanidino function, this ligand offers the pyridine N atom for metal coordination. It was prepared according to a literature procedure [16] (for analytical data, see ref. [17] ) and subsequently brought to reaction with ZnMe 2 .…”

Synthesis of Oligomeric Zinc Complexes with Bicyclic and Acyclic Guanidinate Ligands

“…L1H 2 was synthesized as described previously. [40,41] IR spectra were recorded with a BIORAD Excalibur FTS 3000 instrument. NMR spectra were recorded with BRUKER Avance II 400 or BRUKER Avance DPX AC200 spectrometers.…”

“…The ligands were prepared by the reaction between N,NЈ-diisopropylcarbodiimide and 2-aminopyridine (for L1H 2 ) [40,41] or 2-aminoquinoline (for L2H 2 ) with catalytic AlClMe 2 . In addition to the guanidino N atoms, these ligands bind to the Zn centre through the additional N atom in the aromatic ring.…”

Guanidines from ‘toxic substances’ to compounds with multiple biological applications – Detailed outlook on synthetic procedures employed for the synthesis of guanidines

“…), further calculations predicted that aluminum amides could also function as active catalysts for the guanylation of amine. [53] The commercially readily available alkyl aluminums, such as AlMe 3 (Scheme 33. ), AlEt 3 , and AlEt 2 Cl, could serve as excellent catalyst precursors for the catalytic addition of amines to carbodiimides, yielding quantitatively their corresponding trisubstituted guanidines.…”

“…), lacking the aryl group which according to them was not responsible for receptor recognition by π-stacking. These rather contained a hydrophobic substituent and a carboxymethyl substitution and were found to be tasteless or to have significantly lower 53 sweetness potency than the corresponding trisubstituted compounds. However, they did not study the effect of nitro and cyano substituted aryl substituents and identified guanidinoacetic acid as the pharmacophore responsible for non sweet taste of the synthesized guanidines.…”