1.4- DIHYDROPYRIDINE EQUIVALENT

A STABLE CHIRAL 1,4-DIHYDROPYRIDINE EQUIVALENT FOR THE ASYMMETRIC SYNTHESIS OF SUBSTITUTED PIPERIDINES ... 

DIHYDROPYRIDINE EQUIVALENT, 70, 54 Dihydroquinidine, benzoate ester, 70, 49 DIhydroquinIdIne 4-chlorobenzoate, 70, 47 Dihydroquinidine, 2-naphthoate ester, 70, 49 Dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate, 70, 80 Dilsobutylaluminum hydride, 70, 20... 

A STABLE CHIRAL 1,4-DIHYDROPYRIDINE EQUIVALENT FOR THE ASYMMETRIC SYNTHESIS OF SUBSTITUTED PIPERIDINES 2-CYANO-6-PHENYLOXAZOLOPIPERIDINE (5H-Oxazolo[3,2-aJpyridine-5-carbonltrlle, hexahydro-3-phenyl-,... 

Bard, A. J., Parsons, R. and Jordan, J., 1985. Standard Potentials in Aqueous Solutions, lUPAC Marcel Dekker, New York, USA Bonin, M., Grierson, D. S., Royer, J. and Husson, H. -P., 1992. A stable chiral 1,4-Dihydropyridine equivalent for the asymmetric synthesis of substituted piperidines 2-Cyano-6-Phenyloxazolopiperidine. Org. Synth. 70, 54-57. 

Guerrier, L., Royer, J., Grierson, D. S. and Husson, H. P., 1983. Chiral l,4-dihydropyridine equivalents a new approach to the asymmetric synthesis of alkaloids, the enantiospedfic synthesis of (+)- and (-)-coniine and dihydropinidine. J. Am. Chem. Soc. 105, 7754-7755. Harless, M. L., Yuan, M. and Cowan, J. K., 2000. 9,10-Anthraquinone Applications to Control Biogenic Production of Hydrogen Sulfide in the Near Wellbore Formation in Gas Storage Fields. Corrosion/2000, Paper No. 00121, (Orlando, FL NACE 2000). 

Two equivalents of ethyl tnfluoroacetylacetate reacts with one equivalent of an aldehyde and ammonia to give 2,6 bis(trifluoromethyl)-l, 4-dihydropyridines m good to fair yields [4] (equation 4)... 

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. 

It has been shown that TMSI is capable of mediating the reaction at room temperature. The classical three component coupling was carried out using aldehyde 82 and ketoester 83 with ammonium acetate in acetonitrile at room temperature with in situ generated TMSI. This gave a 73-80% yield of 1,4-dihydropyridines 84 in 6-8 h. The best results were obtained with 1 equivalent of TMSCl and 1 equivalent of Nal. 

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 ... 

A pair of reactions of 1,4-dihydropyridines with electron-accepting alkenes (Scheme 31) shows experimental evidence for the mechanistic spectrum between the pseudoexcitation and transfer bands. Acrylonitrile undergoes an ene reaction [143] (Scheme 31a). This is a reaction in the pseudoexcitation band. A stronger acceptor, alkylidene- and arylmethylydenemalonitriles are reduced [144] (Scheme 31b). This is a reaction in the transfer band, where a hydride equivalent shifts without bond formation between the ti bonds of the donors and acceptors. 

C. A variety of anilines and unsymmetrical ketones (5 equivalents) can be used to broaden the scope of the substituents, particularly five-membered ring heterocycles, to yield a variety of fused dihydropyridines. 

The Hantzsch reaction that allows the synthesis of pyridine derivatives, is a condensation involving two equivalents of a yS-ketoester or a yS-ketoamide, one equivalent of an aldehyde and ammonia. The Hantzsch reaction was used by Patel et al. for the synthesis of a 300 member dihydropyridine library (Scheme 3.27) [287]. 

NAD is one of Nature s most important oxidizing agents it can be considered as a biological equivalent of the chromium(VI) ion. NAD is shorthand for nicotinamide adenine dinucleotide it is a co-enzyme, which together with an enzyme is essential for several life-sustaining processes (Box 2.2). On reduction it forms the corresponding 1,4-dihydropyridine, NADH, The oxidation of ethanol to acetaldehyde (ethanal) is effected by the enzyme alcohol dehydrogenase and mediated by NAD (Scheme 2.31). 

Triazines react also with electron-rich dienophiles such as ethyl vinyl ether (401 R = Et) or vinyl acetate (401 R = Ac) in boiling dioxane to yield the pyridine derivatives (376). After the usual [4 + 2] cycloaddition and nitrogen elimination from the bicyclic compound (402), the dihydropyridines (403) eliminate ethanol or acetic acid to give the aromatic pyridines (376). The dienophiles (401) can therefore be used as alkyne equivalents (69TL5171). 

Acyl-2-alkyl-2,3-dihydro-4( 1 //)-pyridones A are readily available heterocycles in both racemic and chiral form. l-Acyl-2-alkyl-l,2-dihydropyridines B are much less readily accessible, especially enantiopure, but are much sought after building blocks for alkaloid synthesis. A very efficient (83-96%) and simple procedure has now been developed for the A — B transformation, illustrated as follows treatment of l-allyloxycarbonyl-2-cyclohexyl-2,3-dihydro-4-pyridone with one equivalent of the Vilsmeier reagent in trichloroethylene at room temperature gave l-allyloxycarbonyl-4-chloro-2-cyclohexyl-l,2-dihydropyridine in 92% yield. 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

This reaction allows the preparation of dihydropyridine derivatives by condensation of an aldehyde with two equivalents of a p-ketoester in the presence of ammonia. Subsequent oxidation (or dehydrogenation) gives pyridine-3,5-dicarboxylates, which may also be decarboxylated to yield the corresponding pyridines. 

The Hantzsch synthesis of dihydropyridines represents a classical example of MCR, generating an array of diversely substituted heterocycles in a one-pot reaction procedure. Given that the reaction requires elevated temperatures and extended reaction times to proceed, acceleration of the process by microwave irradiation could be envisioned. Indeed, dielectric heating of aldehyde (aliphatic or aromatic) and 5 equivalents of /i-keloesler in aqueous 25% NH4OH (used both as reagent and solvent) at 140-150 °C for merely 10-15 min furnished 4-aryl-l,4-dihydropyridines in 51-92% yield after purification on a silica gel column [100]. The Hantzsch synthesis under reflux conditions ( 100 °C) featured a remarkably longer time (12 hours) and lower yields (15- 72%). To demonstrate the suitability of the procedure for the needs of combinatorial chemistry, a 24-membered library of 1,4-dihydropyridines (DHP) was prepared (Scheme 36). 

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. 

Pyridinium salts were reduced to dihydropyridines via radical pathways induced by Zn-Cu and sonication <02CC850>. In a novel approach to 4-arylpyridines, pyridinium salt 42 was converted into dihydropyridine 43 on treatment with sulfite ion. After ring opening (43—>44) a second equivalent of the pyridinium salt (42) was added with base to form aminoheptatriene 45. Cyclization and re-aromatization (46— 47) afforded the product in modest yield (Scheme 7)<02EJO4123>. The chemistry of dihydropyridines was reviewed in 2002 by Lavilla <02 JCS(P 1)1141 >. 

The same reaction was later carried out by Greenhill and coworkers240 using two equivalents of a cyclohexanedione derivative and 2-alkylaminoacroleins with the result of isolating unexpected acridinedione derivatives (equation 170). The reaction is explained by loss of the formyl group of aminoacrolein as a formic acid and is reminiscent of the Hantzsch synthesis of 1,4-dihydropyridines. 

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