Hantzsch 1,4-dihydropyridines

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]. 

The synthesis of racemic felodipine (Scheme 11.2) utilizes a stepwise Hantzsch dihydropyridine reaction (Berntsson et al., 1981). 2,3-Dichlorobenzylidineacetyl acetic acid... 

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. 

Recently, we established that several proton acids catalyze the metal-free reduction of ketimines under hydrogen-transfer conditions with Hantzsch dihydropyridine as the hydrogen source.Additionally, we were able to demonstrate a catalytic enantioselective procedure of this new transformation by employing a chiral Br0nsted acid as catalyst.(see Chapter 4.1). 

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. 

Benzo[l,3]dioxol-5-yl-ethyl)-quinoline (20.0mg 0.072 mmol), BINOL-phosphate 1 (0.5 mg, Imol %), Hantzsch dihydropyridine (43.8 mg,... 

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). ... 

As discussed in Section 4.2.3.4.1, pentane-1,5-diones (200) can undergo ring closure to give a pyran (199) or, in the presence of ammonia, a dihydropyridine (201). Oxidative aromatization of these products occurs so easily that it frequently takes place prior to isolation, giving a pyrylium salt (198) or a pyridine (202). The Hantzsch dihydropyridine synthesis is described in Section 4.2.3.4.2. 

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. 

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 ... 

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. 

In the 1,4-dihydropyridine series, there has been much discussion on detailed mechanism. In a study of reduction of-cyanocinnamates with a 4,4-dideutero Hantzsch dihydropyridine, a product that was singly deuterated at only the benzylic position together with the oxidized pyridine product 503 was obtained. This seems to show that the mechanism involves hydride transfer from the 4-position of the 1,4-dihydropyridine followed by proton extraction from the nitrogen of the dihydropyridine <2000J(P2)1857>. 

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