Hantzsch dihydropyridines, oxidation

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. 

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>. 

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. ... 

A new strategy for the synthesis of heterocyclic a-amino acids utilizing the Hantzsch dihydropyridine synthesis was developed in the laboratory of A. Dondoni." ° The enantiopure oxazolidinyl keto ester was condensed with benzaldehyde and fert-butyl amino crotonate in the presence of molecular sieves in 2-methyl-2-propanol to give a 85% yield of diastereomeric 1,4-dihydropyridines. The acetonide protecting group was removed and the resulting amino alcohol was oxidized to the target 2-pyridyl a-alanine derivative. 

Syntheses of Pyridines via Domino/One-Pot Hantzsch Synthesis-Oxidation Combination of the Hantzsch 1,4-dihydropyridine synthesis with subsequent oxidation in a domino process enables the direct access to substituted pyridines. 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

The immediate outcome of the Hantzsch synthesis is the dihydropyridine which requires a subsequent oxidation step to generate the pyridine core. Classically, this has been accomplished with nitric acid. Alternative reagents include oxygen, sodium nitrite, ferric nitrate/cupric nitrate, bromine/sodium acetate, chromium trioxide, sulfur, potassium permanganate, chloranil, DDQ, Pd/C and DBU. More recently, ceric ammonium nitrate (CAN) has been found to be an efficient reagent to carry out this transformation. When 100 was treated with 2 equivalents of CAN in aqueous acetone, the reaction to 101 was complete in 10 minutes at room temperature and in excellent yield. 

A general method for the construction of a pyridine ring is the Hantzsch synthesis. A condensation reaction of two equivalents of a /3-ketoester 1 with an aldehyde 2 and ammonia leads to a 1,4-dihydropyridine 3, which can be oxidized to the corresponding pyridine 4—for example by nitric acid ... 

Pyridines are traditionally prepared using the Hantzsch reaction, a condensation between 2 mol of a 6-ketoester, 1 mol of an aldehyde and 1 mol of ammonia. The product of this reaction is a 1,4-dihydropyridine which can be further oxidized to the corresponding pyridine compound (as 155 in Scheme 54). A first report described the Hantzsch reaction carried out under microwave irradiation on Bentonite clay and ammonium nitrate as ammonia... 

The oxidation of Hantzsch 1,4-dihydropyridines has been a long standing method for preparation of pyridines. The development of mild oxidants that do not affect other functional groups about the ring has been a specific point of interest. Yadav and co-workers... 

Hantzsch 1,4-dihydropyridines were oxidized quantitatively to give the corresponding pyridine derivatives by irradiation in CCI4. A photo-induced electron-transfer mechanism is involved. The critical step in this mechanism is the fast dechlorination of CCI4 (Scheme A)P... 

The most used route to pyridines is called the Hantzsch synthesis. This uses a 1,3-dicarbonyl compound, frequently a 1,3-keto ester [ethyl ace-toacetate (ethyl 3-oxobutanoate)], and an aldehyde, which are heated together with ammonia (Scheme 2.18). At the end of the reaction the dihydropyridine is oxidized to the corresponding pyridine with nitric acid (or another oxidant such as Mn02). The normal Hantzsch procedure leads to symmetrical dihydropyridines. Two different 1,3-dicarbonyl compounds may not be used as two enoiate anions might form, giving mixed products when reacted with the aldehyde. The aldehyde itself should preferably be non-enolizable, otherwise the chance of aldoliza-tion exists, but with care this can be avoided. 

There are some methods that are specific to HCHO. For example, the Hantzsch reaction of HCHO, collected with a diffusion scrubber, with ammonium acetate, acetic acid, and acetylacetone to form diacetyldihydrolutidine, which is measured using its fluorescence at 470 nm, has been applied to air measurements (Dasgupta et al., 1988, 1990 Kleindienst et al., 1988a,b Lawson et al., 1990 Khare et al., 1997). Reaction with 1,3-cyclohexanedione and ammonium acetate to form a dihydropyridine derivative that is measured by fluorescence has been used in conjunction with a diffusion scrubber (Fan and Dasgupta, 1994). Enzymatic methods have been used in which formaldehyde dehydrogenase catalyzes the oxidation of HCHO to HCOOH in the presence of -nicotinamide adenine dinucleotide, NAD+, which is reduced to NADH. The latter is measured by fluorescence at 450 nm (Lazrus et al., 1988 Ho and Richards, 1990). 

Hantzsch synthesis The reaction of 1,3-dicarbonyl compounds with aldehydes and NH3 provides a 1,4-dihydropyridine, which can be aromatized by oxidation with nitric acid or nitric oxide. Instead of NH3, primary amine can be used to give 1-substituted 1,4-dihydropyridines. 

MISCELLANEOUS REACTIONS OF DIHYDROPYRIDINES Additional tests for net hydride transfers initiated by single-electron transfer include the use of substrates in which such pathways would necessarily involve readily ring-opened cyclopropylmethyl or readily cyclized 5-hexenyl radicals. Products from these radical reactions are not formed in NAD+/ NADH dependent enzymic reductions or oxidations (Maclnnes et al., 1982, 1983 Laurie et al., 1986 Chung and Park, 1982). Such tests have also been applied in non-enzymic reductions. Thus cyclopropane rings in cyclopropyl 2-pyridyl ketones, or imines of formylcyclopropane (van Niel and Pandit, 1983, 1985 Meijer et al., 1984) survive Mg+2 catalysed reduction by BNAH or Hantzsch esters but are opened by treatment with tributylin hydride. 

The Hantzsch synthesis produces a reduced pyridine but there are many syntheses that go directly to pyridines. One of the simplest is to use hydroxylamine (NH2OH) instead of ammonia as the nucleophile. Reaction with a 1,5-diketone gives a dihydropyridine but then water is lost and no oxidation is needed. 

The Hantzsch pyridine synthesis affords 1,4-dihydropyridines 214, although spontaneous oxidation to pyridines often occurs. In its simplest form it involves the condensation of two molecules of a -keto ester with an aldehyde and ammonia (Scheme 119) . Compounds resulting from the condensation of ammonia with one of the carbonyl components can be used in the Hantzsch synthesis. Thus, -aminocrotonic ester 215 can replace the ammonia and one mole of acetoacetic ester in Scheme 119. The mechanism of the Hantzsch synthesis has been clarified by 13C and 1SN NMR spectroscopy <1987T5171>. 

Zhu XQ, Zhao BJ, Cheng JP (2000) Mechanisms of the oxidations of NAD(P)H model Hantzsch 1, 4-dihydropyridines by nitric oxide and its donor N-methyl-N-nitrosotoluene-P-sulfonamide. J Org Chem 65 8158-8163... 

Pfister, J. R. Rapid, high-yield oxidation of Hantzsch-type 1,4-dihydropyridines with ceric ammonium nitrate. Synthesis 1990, 689-690. 

Mashraqui, S. H., Karnik, M. A. Catalytic oxidation of Hantzsch 1,4-dihydropyridines by RUCI3 under oxygen atmosphere. Tetrahedron Lett. 

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