Nicotinic synthesis from pyridine

Reaction of -picoline over degassed Raney nickel was found to give 5,5 -dimethyl-2,2 -bipyridine (5), the structure of which was established by its synthesis from 2-bromo-5-methylpyridine. Oxidation of this dimethyl-2,2 -bipyridine, and similar oxidation of the diethyl-2,2 -bipyridine derived from 3-ethylpyridinc, gave the corresponding dicarboxylic acid and the same acid was produced by the action of degassed Raney nickel on sodium nicotinate (in water) or on ethyl nicotinate. These transformations established the 5,5 -substitution pattern for three 2,2 -bipyridines derived from 3-substituted pyridines but such evidence is not available for the biaryls... 

The 3,6-diposition-substituted pyridine compounds are important intermediates for industrial synthesis, especially for production of some agricultural chemicals. This compound can be obtained by chemically synthesized from pyridine, but the process is accompanied by some by-products. Microbial hydroxylation of aromatic compounds is a very efficient method of regioselective reaction. Several methods have been reported for the preparation of 3,6-disubstituted pyridine using microorganisms. In 1985, Lehky et al. reported the microbial production of 6-hydroxynicotinic acid (6-HNA) from nicotinic acid (NA) by Achromobacter xylosoxydans Nagasawa et al. also prepared 6-HNA from NA by using Pseudomonas fluorescens TN5. 

In 1895 Am6 Pictet (1857-1937) published the first nicotine synthesis. [529,530] Key steps are the formation of 3-(lff-pyrrol-l-yl)-pyridine from 3-aminopyridine and mucic acid and its rearrangement to 3-(l//-pyrrol-2-yl)-pyridine at high temperatures. N-Methylation and sequential reduction give eventually racemic nicotine, which can be separated with tartaric acid into its enantiomers. 

Similar reaction mechanisms are the bases for the synthesis of nicotinic acid from 3-methyl pyridine, 3-ethyl pyridine, 3-phenyl pyridine, and 3,3 -... 

III. Synthesis of Pyridine Coensymes from Nicotinamide and Nicotinic Add. 641... 

Of the two pyridine nucleotide coenzymes, NAD is present mainly as the oxidized form in the tissues, whereas NADP is principally present in the reduced form, NADPH2. There are important homeostatic regulation mechanisms which ensure and maintain an appropriate ratio of these coenzymes in then-respective oxidized or reduced forms in healthy tissues. Once converted to coenzymes within the cells, the niacin therein is effectively trapped, and can only diffuse out again after degradation to smaller molecules. This implies, of course, that the synthesis of the essential coenzyme nucleotides must occur within each tissue and cell type, each of which must possess the enzymatic apparatus for their synthesis from the precursor niacin. Loss of nicotinamide and nicotinic acid into the urine is minimized (except when the intake exceeds requirements) by means of an efficient reabsorption from the glomerular filtrate. 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

A synthesis of pyrrolo[2,3-, ]pyridine derivatives from nicotinic acid or 2,6-dichloropyridine affords 1,3- and 1,3,6-substituted pyrrolo[2,3-, ]pyridines <2006JOC5538>. 

The nicotine molecule consists of a pyrrolidine ring attached to a pyridine ring by a bond between carbon atoms in the two-ring systems. Nicotine was isolated in impure form from tobacco in 1809 by Louis Nicholas-Vauquelin (1763—1829). Vauquelin called the substance nicotianine. In 1826, Wilhelm Posselt (1806-1877) and Karl Ludwig Reimann (1804-1872), medical students at Heidelberg University, isolated pure nicotine and published dissertations on its pharmacology in 1828. Louis Henri Melsens (1814—1886) determined nicotines empirical formula. Ame Pictet (1857-1937) and P. Crepieux reported the synthesis of nicotine in 1903. 

An alternative pathway for synthesis of quinoli-nate from aspartate and a triose phosphate exists in bacteria and in plants and provides the major route of nicotinic acid synthesis in nature. In E. coli the reaction is catalyzed by two enzymes, one an FAD-containing L-aspartate oxidase which oxidizes aspartate to a-iminoaspartate.228 The latter condenses with dihydroxyacetone-P to form quinolinate (Eq. 25-13).229 There are at least two other pathways for synthesis of quinolinic acid as well as five or more salvage pathways for resynthesis of degraded pyridine nucleotide coenzymes.224/230/231... 

An iron-catalyzed reaction of an a,P-unsaturated oxime such as 68 with a P-oxo ester also gave pyridine derivatives such as nicotinic acid 69 [99]. Under the reaction conditions (150-160 °C, without solvent) first Michael adducts such as intermediate 70 are presumably formed, which further condense via intermediate 71. This method is not restricted to a centric symmetry in the substitution pattern, which is an advantage compared with the Hantzsch synthesis. Moreover, the method starts with hydroxylamine being two oxidation stages above ammonia therefore, no oxidation in the final stage from dihydro- to pyridine is necessary (Scheme 8.31). 

Problem 31.12 Because of the difficulty of nitrating pyridine, 3-aminopyridine is most conveniently made via nicotinic acid. Outline the synthesis of 3-aminopyridine from /3-picoline. 

Good use is made of this chemistry in the synthesis of nifluminic acid 69, an analgesic with a pyridine ring. Disconnection of the C—N bond suggests a 2-chloropyridine 70 starting material easily derived from nicotinic acid 60 and a simple aromatic amine 72 available by functionalisation of trifluorobenzene 74. 69 Is actually available as niflumic acid from Aldrich. 

Figure 2. Synthesis of the functionalized bromo-pyridine building block, starting from the commercially available 6-chloro-nicotinic acid. The reactions can be performed on a multigram scale with one workup in the final step (TBDMS = butyl-dimethylsilyl).

Interest in alkaloids of the nicotine group appears to be on the increase. A review has appeared covering tobacco-specific nitrosamines, which may be causative factors in tobacco-related cancers. The solution conformation, and proton, deuterium, carbon-13, and nitrogen-15 n.m.r. spectra of nicotine and its 2- and 4-isomers, have been studied. A new synthesis of nornicotine and nicotine has been described, and a quantitative carbon-13 n.m.r. spectral analysis of nicotine that is labelled at positions 1, 2, and 3 with carbon-13 been presented. The synthesis and mass spectrometry of several structurally related nicotinoids have been reported. Nicotine is dehydrogenated on irradiation in benzene solution in the presence of benzophenone to l -methyl-2 -(3-pyri-dyl)pyrrole. ° Nornicotine has been synthesized in four steps from 3-bromo-pyridine and N-3-butenyl-phthalimide, using a palladium-catalysed vinylic... 

Pyridine-substituted nicotines, nornicotines, and anabasines are available from a-cyano-amines by a new synthesis. The syntheses of ( )-[l - N]nornicotine and ( )-[l - N]nicotine have been described, from cyclopropyl 3-pyridyl ketone and [ N]formamide. 4-Methylnicotine has been prepared it shows no nicotine-like pharmacological activity. " An investigation into the stereochemical factors involved in the behaviour of nicotine and related compounds in the Menschutkin reaction has been conducted.A bridged nicotine , 1,2,3,5,6,10b-hexahydropyrido[2,3-g]indolizine (44), has been synthesized by carboxylation of the dilithium derivative of 2-methylnornicotine followed by cyclisation and reduction with borane in tetrahydrofuran. Several 5-halogeno-nicotines have been prepared and their pK values and biological activities measured. ... 

Pyridine alkaloids a group of alkaloids containing the pyridine ring system, which occur in various unrelated plants, and as metabolic products of microorganisms. Important examples are Nicotiana alkaloids (see), Areca alkaloids (see), Gentiana alkaloids (see), and Valeriana alkaloids (see). They are biosynthesized either from nicotinic acid, or as products of terpene synthesis. 

Hydroformylation can be highly tolerant of functional groups. An azide, normally highly reactive towards transition metals, can survive. This property has been exploited in a synthesis of the pyridine alkaloids anaba-sine 4.158 and nicotine 4.159 from the same hydroformylation reaction (Scheme 4.58). Another approach to both of these alkaloids can be found in Chapter 8, Schemes 8.76 and 8.77. Double hydroformylation of the azido diene 4.160 gave the bis-aldehyde 4.161 (Scheme 4.59). Tandem azide reduction and double reductive amination then gave the indolizidine alkaloid, lupinine 4.162. ... 

---