Hantzsch ester pyridine

Diethoxycarbonyl-2,6-dimethyl-l,4-dihydro-pyridin (Hantzsch-Ester)... 

Inspired by the recent observation that imines are reduced with Hantzsch esters in the presence of achiral Lewis or Brpnsted acid catalysts (Itoh et al. 2004), we envisioned a catalytic cycle for the reductive amination of ketones which is initiated by protonation of the in situ generated ketimine 10 from a chiral Brdnsted acid catalyst (Scheme 13). The resulting iminium ion pair, which may be stabilized by hydrogen bonding, is chiral and its reaction with the Hantzsch dihydropyridine 11 could give an enantiomerically enriched amine 12 and pyridine 13. 

A brief discussion of some aspects of alcohol dehydrogenase will be used to illustrate the potential for catalysis. This system is chosen for illustration because it has been studied so extensively. Lessons drawn can be applied in a broader context. The 1,4-dihydropyridine (2a) is the reductant and this affords a nico-tinium ion (1) on transfer of hydride, as illustrated in equation (1). This process is mimicked in many abiotic systems by derivatives of (2 R = alkyl or benzyl), by Hantzsch esters (7), which are synthetically readily accessible, and 1,4-dihydro derivatives (8) of pyridine-3,5-dicarboxylic acid. A typical abiotic reaction is the reduction of the activated carbonyl group of an alkyl phenylglyoxylate (9), activated by a stoichiometric amount of the powerful electrophile Mg(CI04)2, by, for example, (2b equation 8). After acrimonious debate the consensus seems to be that such reactions involve a one-step mechanism (i.e. equation 5), unless the reaction partner strongly demands a radical intermediate, as in the reduction of iron(II) to iron(III). 

Hantzsch esters like (7b) react with appropriate acceptors to provide reduced product and pyridine (75), as shown in equation (32). The elements of hydrogen are transferred, but there are no effective ways to transform (75) cleanly back to (7b) so that a catalytic cycle may be established. 

In this transfer hydrogenation, aromatization of the dihydropyridine (Hantzsch ester) to form a pyridine derivative is essential for it to act as the hydride source. 

Oxidation of Hantzsch esters. Nitric acid supported on bentonite oxidizes Hantzsch esters to the pyridines. The reaction is assisted by microwave irradiation. 

According to the proposed mechanism (Scheme 6.20), the first step of this cascade reaction is protonation of the substituted pyridine by CPA to generate the pyridinium salt 51. Then, the reduction of 51 by 1,4-hydride transfer from the Hantzsch ester gives the enamine intermediate 52, which isomeri-zes to iminium 53 in the presence of CPA. The subsequent AFC reaction will afford the desired product and release the chiral phosphoric acid. 

Our own approach to the combination of crown ether and dihydropyridine chemistry has involved constructing the dihydropyridine as an integral portion of the macrocyclic crown ether ring (see 24b, for example). The first synthetic approach involved ring-closure of an alicyclic precursor by means of the Hantzsch 1,4-dihydropyridine synthesis as illustrated for the preparation of (50, eq. 24). Such Hantzsch esters (general type 46) are attractive in that the acid functionalities at the 3,5-positions can be used as handles for attaching the (dihydro)pyridine... 

Substituted 3-aminoindolizines could be obtained via one-pot multistep reactions, from 2-pyridine carboxyaldehide and various nitriles, after 3 h reaction in toluene at 105°C, by adding 1.1 eq of Hantzsch ester as a hydride transfer agent and catalytic amounts of piperidinium acetate [20]. 

Romanelli and coworkers reported the solvent-free mnlti-component synthesis of pyridines nsing the Wells-Dawson (WD) heteropoly acid as the catalyst [59], The reaction of 3-formy Ichromones 80 with acetoacetic esters 81 and ammonium acetate gave the corresponding pyridines 83 in good yields (64-99%). As shown in Scheme 11.12, Hantzsch esters 82 were obtained in variable yields (0-36%) as the by-products. 

Based on previous studies where the imines were reduced with Hantzsch dihydropyridines in the presence of achiral Lewis [43] or Brpnsted acid catalysts, [44] joined to the capacity of phosphoric acids to activate imines (for reviews about chiral phosphoric acid catalysis, see [45-58]), the authors proposed a reasonable catalytic cycle to explain the course of the reaction (Scheme 3) [41]. A first protonation of the ketimine with the chiral Brpnsted acid catalyst would initiate the cycle. The resulting chiral iminium ion pair A would react with the Hantzsch ester lb giving an enantiomerically enriched amine product and the protonated pyridine salt B (Scheme 3). The catalyst is finally recovered and the byproduct 11 is obtained in the last step. Later, other research groups also supported this mechanism (for mechanistic studies of this reaction, see [59-61]). 

After great success in the reduction of imines, quinolines, and pyridines. Rueping et al. designed a chiral phosphoric acid-catalyzed cascade reaction, in which enamines and enones are heated with Hantzsch ester la and (R)-6, then a Michael addition, cyclization, isomerization and hydride transfer reaction take place successively to afford chiral tetrahydropyridine 59 and azadecaUnone 60 products in excellent enantioselectiYities (Scheme 32.11) [33]. Remarkably,... 

Zhou et al. have successfully developed an efficient method for regeneration of the Hantzsch ester (378) from the Hantzsch pyridine (379), with... 

Dihydropyridines find important applications in medicine (mainly as calcium channel blockers) and their chemistry has been thoroughly investigated over the last decades [11-14]. The first synthesis of dihydropyridines 4 was reported by Arthur Rudolf Hantzsch over a century ago and involved the condensation between ammonia, an aldehyde and two molecules of a P-ketoester (Scheme 2.1) [15]. Use of a modified procedure allowed synthesis of unsymmetrical dihydropyridmes starting from two different P-ketoesters [16], Compounds 4 are known as Hantzsch esters and have been extensively used as pyridine precursors in the synthesis of heterocyclic compounds. 

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