4-aminopyridine-based catalysts

A range of metal-free organocatalysts have been used to good effect in the kinetic resolution of alcohols. A number of enantiomerically pure 4-aminopyridine-based catalysts effect kinetic resolution with high S values. These include the conforma-tionallyrestricted2,3-dihydroimidazo[l,2-a]pyridine (12.98) and the atropiso-meric catalyst (12.99). N-heterocyclic carbenes also function as nucleophilic... 

The desymmetrisation of meso-l,2-diols has been achieved by Oriyama using enantiopure diamines including (12.103),and also atropisomeric 4-aminopyridines. Metal-based catalysts have also been used to good effect in... 

The structure-based pharmacophore was built using the crystallographic coordinates of argatroban complexed with thrombin [101] and the functional group definitions contained within the CATALYST software to predict the effects on the K[ values of structural modification of a set of homologous 4-aminopyridine (4-AP) thrombin inhibitors. 

Cyclization of a 2-aminoheterocycle by reaction with a 1,3-dicarbony compound is a widely used method for the synthesis of a fused pyrimidin-4-one (see also pp. 284-286). The conversion of 2-aminopyridine into a pyridopyrim-idinone by heating with an acetoacetate in the presence of a Friedel-Crafts reaction-type catalyst is typical PPA and PPE vary in their effectiveness from one reaction to another [2250, 2289, 2296]. This reaction is also catalysed by bases such as piperidine [2501]. 

While Wheland (91) suggests that 4-aminopyridine is an aromatic amine little success has been achieved in hydrogenation. Orthner (92) cites failure with platinum catalysts under a variety of conditions. Very low yield (16.5%) resulted from reduction of the hydrochloride salt with platinum catalyst under 80 atm pressure (93). In the reduction of A7-(4-pyridyl)morpholine where the 4-amino nitrogen atom is tertiary, hydrogenation in alcohol was successful with ruthenium (5), but unsuccessful with rhodium on alumina or platinum oxide in acetic acid. It is possible that the pressure conditions used for reduction with ruthenium catalysts may be conducive to conversion of 4-aminopyridine, since these catalysts are less inhibited by strong nitrogen bases. 

A systematic study on the use of [CpCo(CO)(dmfu)] (dmfu = dimethyl fumarate) [12] as a precatalyst for the cocyclization of alkynes and nitriles was published in 2011 [13]. By this catalyst, the incorporation of electron-deficient nitriles into the pyridine core was realized. 3- or 4-Aminopyridines can be produced regioselectively by modifying the substitution pattern at the yne-ynamide. Based on DFT computations, the author suggested that 3-aminopyridines are formed by formal [4 + 2] cycloaddition between the nitrile and the intermediate cobaltacyclopenta-diene, whereas 4-aminopyridines arise from an insertion pathway. This catalytic system was applied in the synthesis of bicyclic 3- or 4-aminopyridines from yne-ynamides and nitriles (Scheme 3.1) [14]. 

The reaction with some of the less-reactive aryl bromides bearing electron-donor substituents, such as o-bromoaniline or 5-bromo-2-aminopyridine, is better carried out in aqueous DMF with high content of water, in the presence of an inorganic base such as K2CO3 and palladium catalyst with (0-MeC6H4)3P ligands ... 

Oxidation of aliphatic C-H groups with HP is efficiently catalysed by cis-a-aminopyridine manganese complexes in the presence of acetic acid. The reaction demonstrated excellent efficiency (up to TON = 970), site selectivity, and stereospecificity (up to >99%). Manganese(II) and iron(II) complexes based on ligands with a rigid, chiral diamine derived from proline and two benzimidazoles (2) were synthesized and applied in epoxidation reaction with aqueous HP. Mn-complex catalyses the epoxidation of olefins. Isolated yields of 60-99% and up to 95% ee were obtained with 0.01-0.2mol% catalyst loading. The turnover frequencies and turnover numbers reached 59,000 h and 9600, respectively. Iron(II) complex exhibited a... 

EPR spectroscopy has been successfully applied to clarify the mechanism of catalytic action of Mn-salen complexes, which remains under debate. Whilst Mn-salen complexes have proven successful as oxidation catalysts, they suffer from low catalyst turnover numbers, in part due to fast catalyst oxidation. To overcome this drawback, several groups have reported an alternative system based on aminopyridine ligands which demonstrated high yields (90-99%) using only 0.1 mol% catalyst. Although analogies have been made with the Mn(salen) complexes, until recently no direct experimental evidence was available to support the nature of the active intermediates for the Mn-aminopyridine systems. 

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