1,4-Dihydropyridine synthesis

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). 

Yadav JS, Reddy BVS, Basak AK, Baishya G, Narsaiah AV (2006) lodoxybenzoic acid (IBX) an efficient and novel oxidizing agent for the aromatization of 1,4-dihydropyridines. Synthesis 451 54... 

Dexivacaine, 95 DBxnorgBstrel acetime, 152 Diabetes, 116 Diamocaine, 336 Diapamide, 93 Diaveridine, 302 Diazepam, 452 Diazoxide, 395 Dibenzepin, 424, 471 DichloroisopTTOterenol, 106 Diclofenac, 70 Dicyanamide, 21 Dieckmann cyclization, 72 Difenoximide, 331 Difenoxin, 331 Diflucortolone, 192 Diflumidone, 98 Diflunisal, 85, 86 Difluoromethylene groups, from ketones, 196 Difluprednate, 191 Dihydrocodeinone, 318 Dihydropyridine synthesis, 283... 

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. 

The classical Hantzch dihydropyridine synthesis has been reported under microwave flash heating conditions45,46. More unusually, Hantzch products have also been obtained from Biginelli reaction under microwave flash heating conditions (Scheme 3.27)47. 

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. 

The methyl ester of nicotinic acid is selectively reduced to the 1,2-dihydropyridine 166 in a vast improvement over previous methods (Equation 87) <20010L201>. Low temperatures and choice of pyridinium-activating agent are crucial to avoid 1,4-dihydropyridine formation. A modification of Fowler s dihydropyridine synthesis was used to prepare the iV-acyldihydropyridine 167 (Equation 88) <20060L2961>. 

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. 

Shah A, Gaveriya H, Motohashi N, Kawase M, Saito S, Sakagami H, Satoh K, Tada Y, Solymosi A, Walfard K, Molnar J (2000) 3,5-diacetyl-1,4-dihydropyridines synthesis and MDR reversal in tumor cells. Anticancer Res 20 373-377... 

Formyl-l//-pyrroles have also been used as synthons for the preparation of polysubstituted 4-(l//-pyrrol-3-yl)-1,4-dihydropyridines 1307-1310 under the conditions of the standard and modified Hantzsch s dihydropyridine synthesis or by regioselective alkylation of the 1,4-dihydropyridine skeleton (Scheme 250) <2005ARK127>. 

Hantzsch A (1882) Ueber die Synthese pyridinartiger Verbindungen aus Acetessigather und Aldehydammoniak (Hantzsch dihydropyridine synthesis). Justus Liehegs Ann Chem 215 1-82... 

Several papers have been published that highlight the use of the Hantzsch reaction for the synthesis of compounds that exhibit ion channel modulating activity. The majority of protocols invoke dihydropyridine synthesis as outlined in Schemes 13 and 14. 

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. 

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