Pyridine derivatives, synthesis

Rayama, A., Rinoshita-Nagaoka, J., Rawano, H., Rameda, S. and Mukuriya, M. (1998) Cycloauration of 2-substituted pyridine derivatives. Synthesis, structure and reactivity of srx-membered cycloaurated complexes of 2-anilino-, 2-phenoxy- and 2-(phenylsulfanyl)-pyridine. Journal of the Chemical Society Dalton Transactions, (24), 4095. 

Pyridine derivatives, synthesis from 2-methyleneglutaronitrile 81YGK813. Pyridines, synthesis from aldehydes and ammonia 75KGS1587. 

An efficient Cu(OTf)2-catalyzed 2,4,6-trisubstituted pyridine derivatives synthesis via C-N bond cleavage of aromatic methylamines and C(sp )-H bond activated of ketones was developed by Jiang s group (Scheme 8.80). A wide range of 2,4,6-trisubstituted pyridines could be obtained up to 95% yield at 100 °C under CU/O2 under this catalytic system with neat conditions. This process should be initiated by copper-catalyzed aerobic oxidative cleavage of C-N bond of aromatic methylamines [150]. 

Hantzsch synthesis The formation of pyridine derivatives by the condensation of ethyl acetoacetate with ammonia and an aldehyde. Also applied to similar syntheses of pyrroles. 

Pyridine ring syntheses (48) can be classified into essentially two categories ring synthesis from nonheterocyclic compounds, and synthesis from other ring systems. The synthesis of pyridine derivatives by transformations on the pyridine ring atoms and side-chain atoms have been considered in the previous section. 

The formation of pyridine derivatives from a, P-unsaturated aldehydes and ammonia involves formation of three bonds during the ring synthesis. For example, with an a, P-unsaturated aldehyde, both 2,5-substituted as well as 3,4-substituted pyridines can be obtained, depending on whether a 1,2- (eq. 17) or 1,4-addition (eq. 18) occurs with ammonia. Reactions are performed in the vapor phase with catalysts. 

Raw Material and Energy Aspects to Pyridine Manufacture. The majority of pyridine and pyridine derivatives are based on raw materials like aldehydes or ketones. These are petroleum-derived starting materials and their manufacture entails cracking and distillation of alkanes and alkenes, and oxidation of alkanes, alkenes, or alcohols. Ammonia is usually the source of the nitrogen atom in pyridine compounds. Gas-phase synthesis of pyridines requires high temperatures (350—550°C) and is therefore somewhat energy intensive. 

This reaction procedure has also been used for the synthesis of oxazolo[3,2-fl]pyridine and imidazo[l,2-fl]pyridine derivatives, and the numerous variations studied, allowing changes of the substituent pattern and the number and position of the nitrogen atoms in the six-membered ring, are described in Chapters 4.10 and 4.29. 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

Kelly applied this chemistry to the synthesis of cyclosexipyridine 66. This is an example of an intramolecular variation to this method. Masked enal 65 was prepared and treated with the standard reagents. The acidic medium liberated the aldehyde from its acetal protection. This in situ formation of the reactive species, similar to the above example, then undergoes cyclization to the expected pyridine derivative 66. 

The Boger pyridine synthesis involves the reaction of triazine 1 with activated alkene 2 in a hetero-Diels-Alder fashion. The intermediate bicyclic species 3 is unstable and a facile cycloreversion takes place due to the loss of nitrogen gas to afford the appropriately substituted pyridine derivative 4. 

This is the most convenient preparation of 4 pyridinesulfonic add, a useful intermediate for the synthesis of various pyridine derivatives... 

Jones G (1996) Pyridines and their benzo derivatives synthesis. In McKillop A (ed) Comprehensive heterocyclic chemistry 11. Pergamon Press, Oxford, p 167/Chap. 5.05... 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

An intramolecular variant of this cycloaddition process is combined with a Knoevenagel reaction in a total synthesis of the insectan leporin A, a pyrano[3,2-c]pyridine derivative <96JOC2839>. 

Chand P, Kotian PL, Morris PE, Bantia S, Walsh DA, Babu YS (2005b) Synthesis and inhibitory activity of benzoic add and pyridine derivatives on influenza neuraminidase. Bioorg Med Chem 13 2665-2678... 

Transition metal complexes have been used in a number of reactions leading to the direct synthesis of pyridine derivatives from acyclic compounds and from other heterocycles. It is pertinent also to describe two methods that have been employed to prepare difficultly accessible 3-alkyl-, 3-formyl-, and 3-acylpyridines. By elaborating on reported194,195 procedures used in aromatic reactions, it is possible to convert 3-bromopyridines to products containing a 3-oxoalkyl function196 (Scheme 129). A minor problem in this simple catalytic process is caused by the formation in some cases of 2-substituted pyridines but this is minimized by using dimethyl-formamide as the solvent.196... 

The cobalt-catalyzed cooligomerization of diynes with nitriles allows a simple one-step synthesis222 of condensed pyridine derivatives including difficultly accessible 5,6,7,8-tetrahydroisoquinolines223 The synthesis is a versatile one in that pyridines condensed with five- and seven-membered carbocyclic rings can also be achieved in moderate yield in similar fashion. Additional attractive features of this simple synthesis are the formation of condensed isoquinolines by the use of functionalized nitriles and the pronounced regioselectivity observed when dissymmetrical diacetylenes are employed (Scheme 148).222... 

Reductive cleavage of 5-silyl-, 3-, 4-, and 5-silylmethylisoxazoles 1 gave silyl (3-enaminones 2, useful synthons in the regioselective synthesis of silyl- and silylmethylpyrazoles 3, as well as pyrrole-, pyrimidine-, and pyridine derivatives <06T611>. 

A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP only procedures involving solvent-free conditions under the action of irradiation led to the aromatized pyridine derivatives. 

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