Hantzsch dihydropyridines, and

Dissymmetric ferrocenyldiphosphines have been synthesized from (R)-(+)-N, N -dimethylaminoethylferrocene. The diphosphines have been used as ligands in asymmetric transfer hydrogenation of acetophenone in the presence of ruthenium catalysts.297 Asymmetric transfer hydrogenation of a,/S-unsaturated aldehydes with Hantzsch dihydropyridines and a catalytic amount of MacMillan imidazolidinone salt (12) leads to the saturated carbonyl compounds in high yields and excellent chemo-and enantio-selectivities.298 ... 

Another well-known method for the preparation of heterocycles is the Hantzsch dihydropyridine synthesis. In 2001, Ohberg and Westman presented a microwave-... 

The Hantzsch dihydropyridine synthesis has been performed [75] in a singlemode microwave cavity. In comparison with both conventional methods and microwave-assisted reactions performed in a domestic oven, reaction times were shorter and yields were higher (Scheme 8.51). 

For example, it was reported in several independent articles that multicomponent treatment of 5-amino-3-methylpyrazles with 1,3-cyclohexandiones and aldehydes under refluxing in EtOH [82, 83], in DMF with methanol [84], or with application of continuous-flow microwave-assisted procedure in DMSO [85] yielded exclusively pyrazoloquinolinones 50 (Scheme 23). On the other hand, the treatment of 3-unsub-stituted 5-aminopyrazoles with cyclic p-diketones or ketosulfones gave mixtures of Hantzsch dihydropyridines 51 and Biginelly dihydropyrimidines 52 in different ratios [86]. 

Scheme 1 Hantzsch s dihydropyridines and Biginelli s dihydropyrimidinones synthesis...

Imine, catalyst (20 mol %), Hantzsch dihydropyridine (1.4 equiv) and benzene were added to a screw-capped vial and the mixture was exposed to an argon atmosphere. The resulting yellow solution was allowed to stir at 60 °C for 3 days or until the solution became colourless. The solvent was evaporated in vacuo, and the residue was purified by column chromatography to afford the corresponding amine. 

In a typical experiment quinoline (20 mg), catalyst (1-2 mol %) and Hantzsch dihydropyridine (2.4 equiv) were suspended in benzene (2mL) in a screw-capped vial and flushed with argon. The resulting mixture was allowed to stir at 60 °C for 12 h. The solvent was removed under reduced pressure and purification of the crude product by column chromatography on silica gel afforded the pure 1,2,3,4-tetrahydroquinoline. 

The Brpnsted acid catalyzed hydrogenation of quinolines with Hantzsch dihydropyridine as reducing agent provides a direct access to a variety of substituted tetrahydroquinolines (Table 4.2). The mild reaction conditions of this metal-free reduction of heteroaromatic compounds, high yields, operational simplicity and practicability, broad scope, functional group tolerance and remarkably low catalyst loading render this environment-friendly process an attractive approach to optically active tetrahydroquinolines and their derivatives (Table 4.3) (see page 176). ... 

Khadilkar, B.M., Gaikar, V.G. and Chitnavis, A.A., Aqueous hydrotrope solution as a safer medium for microwave enhanced Hantzsch dihydropyridine ester synthesis, Tetrahedron Lett., 1995, 36, 8083-8083 Khadilkar, B.M. and Chitnavis, A.A., Rate enhancement in the synthesis of some 4-aryl- 1,4-dihydropyridines using methyl 3-aminocrotonate, under microwave irradiation, Indian J. Chem., Sect. B, 1995, 34, 652-653. 

Ohberg,L. and Westman, J., An efficient and fast procedure for the Hantzsch dihydropyridine synthesis under microwave conditions, Synlett, 2001, 1293—1296. 

A number of MCRs having enolate-derived nucleophilic components were subsequently discovered (Scheme 7.3), including the Hantzsch dihydropyridine synthesis [13], the Biginelli reaction [14, 15] and the Mannich reaction [16-20], An added complication in many of these MCRs is the potential irreversible addition of the nucleophile to the carbonyl component, leading to carbonyl addition products. Such MCRs, however, become feasible by the appropriate selection of components that do not favor such alternative transformations. For example, the use of formaldehyde is more effective in the Mannich reaction, because its greater reactivity towards the amine prevents its undesired reaction with the enolate component. 

A major synthetic use of l,4-dihydropyridine-3,5-dicarboxylates is as reducing agents. In particular, the so-called Hantzsch dihydropyridine 123 is frequently used, and an interesting example is formation of cyclopropane 124 from bromomethylcinnamates 122 (Scheme 33) <2001JOC344>. It was found that the reaction of either (/. )-122 or (Z)-122 gave identical yields of only the (-E)-isomer of cyclopropane 124. The same conditions can also be used to form indanes 126 from benzylic bromides 125. 

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

An alternative method for the organocatalytic reduction of imines employs Bronsted acids as catalysts and Hantzsch dihydropyridine as a reducing reagent. This topic is described in Chapter 11 (on Bronsted acids) [86]. 

Hantzsch dihydropyridine synthesis. The original Hantzsch synthesis2 involves condensation of two equivalents of a keto ester with an aldehyde in the presence of ammonia. In an enantioselective version.5 the chirality is introduced by use of a chiral hydrazone (2) of an alkyl acetoacetate prepared from 1. The anion of 2 is then treated with Michael acceptors to form adducts (3), which cyclize to 4-aryl-l,4-dihydropyridines (4), in 64-72% overall yield and in 84-98% ee. 

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. 

With the chiral BINOL-phosphates in hand we started to examine the enantioselective transferhydrogenation of ketimines 1. After reaction optimization, including a survey of different solvents, temperatures, BINOL-phosphates, and Hantzsch dihydropyridines, we found that indeed enantioselectivities are observed and the best selectivities are obtained with Brpnsted acid 5a and Hantzsch ester 2a (Table 2). In general, for the first time, high enantioselectivities and good yields are observed in this newly developed metal-free reduction procedure (Rueping et al. 2005b Hofmann et al. 2005 Storer et al. 2006). 

There are numerous variations in the Hantzsch protocol deriving from variations in the aldehydes, ammonia derivatives and active methylene compounds employed. The final products are 1,4-dihydropyridine and pyridine derivatives as well as pyrroles. 

This review deals with the formation of reduced pyridines and their benzo analogs from the parent heteroaromatic bases. Included are acridines, isoquinolines, pyridines and quinolines and their quaternary ammonium salts and N-oxides. The formation of the reduced species by other methods, e.g. Hantzsch dihydropyridine synthesis, is not addressed. 

A Hantzsch dihydropyridine in conjunction with a scandium catalyst has been used. " An interesting variation uses a benzylic alcohol in a reaction with a primary amine, and a mixture of Mn02 and NaBH4, giving in situ oxidation to the aldehyde and reductive amination to give the amine as the final product. ... 

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