Thiourea reductive amination

Reductive amination of ketones using p-anisidine and the Hantzsch ester for transfer hydrogenation is a low-yielding reaction in toluene at room temperature, but thiourea is an efficient catalyst, and yields of up to 94% are reported at 50 °C.334 A mechanism involving thiourea hydrogen bonding to the intermediate imine is supported by ab initio calculations. 

A mild, acid- and metal-free direct reductive amination of ketones has been achieved that relies on selective imine activation by hydrogen bond formation and utilizes the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea as hydrogen bond donor. The mechanism in Scheme 18, supported by ab initio calculations, has been suggested.358... 

The reaction of an a-haloketone with thiourea gives rise to the 2-aminothiazole. This reaction has been used in a combinatorial approach for the synthesis of libraries of 2-aminothiazoles in excellent yields and purities first in the solution phase <1996BML1409> and then on a solid support using Rink amide MBHA, glycyl-Rink amide MBHA, and reductively aminated ArgoGel MB-CHO resins (Scheme 55) <1998JOG196>. 

Scheme 12 Divergent construction of glycodendrimers built on polyamine scaffolds using reductive amination (67), amide formation (68), thiourea bridging with isothiocyanates (64), thioethers (70), and novel double A -alkylation strategy (71).

It appears also that, for the synthesis of large libraries, there are few reactions that fulfil these prerequisites. Among the reactions that proved to have wide applicability, amide bond formations and peptide-like protecting group strategies can be found. In a general way all amine functionalization reactions are usually effective and lead to stable structures (i.e. sulfonamide, carbamate, urea, thiourea formation, reductive amination and nucleophilic substitution). Moreover, for any of these reactions the suitable linker can be easily selected from various literature sources. 

It agonist activity. Unfortunately, 63d produced no antinociception in both the acetic acid writhing and the hot-plate tests. These outcomes may stem from low efficacy for the t opioid receptor, poor permeability of the blood-brain barrier, or both. Synthesis of twin drugs 63 commenced with reductive amination of N-phenethylpiperidone (66) with mono-Boc-protected alkyldiamines 65 (Scheme 6). Introduction of the guanidine moiety was completed by the reaction of the amine derived from Boc-protected amine 68 with Boc-protected thiourea in the presence of HgCU [76, 77]. 

The Hantzsch strategy has been applied in the synthesis of the dopamine Da-agonist pramipexole, a molecule comprising a fused bicyclic tetrahydrobenzothiazole substructure. The synthesis starts with a-bromination of protected 4-aminocyclohexanone followed by the Hantzsch condensation with thiourea. Deprotection and then chiral resolution yield the -enantiomer. Reductive amination leads to pramipexole, which is isolated as the dihydrochloride. ... 

Solid-phase scavenger methods are employed with increasing frequency as a prehminary reaction cleanup step in combinatorial chemistry, and have recently become commercially available (Argonaut, Calbiochem-Novabiochem, Varian, Alltech). lilly researchers first reported on this approach, employing sohd supported electrophiles and nucleophiles for reaction purification in acylation and alkylation reactions. Yield and purity values reported were 90-95% and 50-99%, respectively, for a library generated by reductive amination. Parke-Davis researchers achieved the removal of known reaction product impurities by the application of custom synthesized polymer supported reagents, specifically polystyrene-divinylbenzene supported derivatives of methylisocyanate and tm(2-aminomethyl)amine for cleanup of by-products resulting from urea, thiourea,sulfonamide,amide, and pyrazole libraries. 

Hantzsch ester (2, R = Et) and an organocatalyst -benzyl isothiouronium chloride, prepared from thiourea, catalysed the reductive amination of aromatic, aliphatic, heterocyclic, and cyclic aldehydes to amines in high yields. Aliphatic aldehydes reacted with difficulty and required a higher temperature. Nitro, nitrile, and carbonyl moieties were not reduced. ... 

Many other examples are known of non-selective reactions of halo groups in pyridopyridazines with amines, alkoxides, sulfur nucleophiles such as hydrosulfide and thiolate ions, or thiourea, hydrazine(s), cyanide ion and dimethyl sulfoxide, or on catalytic reduction. 

Tropolone has been made from 1,2-cycloheptanedione by bromination and reduction, and by reaction with A -bromosuccinimide from cyolo-heptanone by bromination, hydrolysis, and reduction from diethyl pimelate by acyloin condensation and bromination from cyclo-heptatriene by permanganate oxidation from 3,5-dihydroxybenzoic acid by a multistep synthesis from 2,3-dimethoxybenzoic acid by a multistep synthesis from tropone by chlorination and hydrolysis, by amination with hydrazine and hydrolysis, or by photooxidation followed by reduction with thiourea from cyclopentadiene and tetra-fluoroethylene and from cyclopentadiene and dichloroketene. - ... 

Direct measurements on metals such as iron, nickel and stainless steel have shown that adsorption occurs from acid solutions of inhibitors such as iodide ions, carbon monoxide and organic compounds such as amines , thioureas , sulphoxides , sulphidesand mer-captans. These studies have shown that the efficiency of inhibition (expressed as the relative reduction in corrosion rate) can be qualitatively related to the amount of adsorbed inhibitor on the metal surface. However, no detailed quantitative correlation has yet been achieved between these parameters. There is some evidence that adsorption of inhibitor species at low surface coverage d (for complete surface coverage 0=1) may be more effective in producing inhibition than adsorption at high surface coverage. In particular, the adsorption of polyvinyl pyridine on iron in hydrochloric acid at 0 < 0 -1 monolayer has been found to produce an 80% reduction in corrosion rate . 

Fe-HS )jds has been postulated to lead to easier anodic dissolution than that through (Fe-014)3 5. This effect of hydrogen sulphide is thought to be responsible for the acceleration of corrosion of iron observed with some inhibitive sulphur compounds, e.g. thioureas , at low concentrations, since hydrogen sulphide has been identified as a reduction product. However, the effects of hydrogen sulphide are complex, since in the presence of inhibitors such as amines , quaternary ammonium cations , thioureas ", ... 

Acetate, (C6H5)4AsC1, citrate, 2,3-dimercaptopropanol, EDTA, I-, Na5P3O10, SO)-, S20)-, tartrate, tiron, tetraphenylarsonium chloride, triethanolamine, thioglycolic acid Acetylacetone, citrate, CN-, EDTA, I-, NH3, N02, SCN-, S20)-, tartrate, triethanol amine Citrate, CN-, EDTA, I-, NH3, N02, SCN-, S20 -, tartrate, urea Reduction to Pu(IV) with sulfamic acid C20)-, citrate, EDTA, F-, tartrate Oxidation to perrhenate Citrate, tartrate, thiourea CN-, thiourea... 

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