Synthesis of nicotine

Craig s synthesis of nicotine (V to VII, p. 42) proceeds via nomicotine. Nicotinic acid nitrile reacts with the Grignard reagent derived from ethyl y-bromopropyl ether to give 3-pyridyl-y-ethoxypropyl ketone (V). This yields an oily oxime (VI) reducible to a-(3-pyridyl)-a-amino-8-ethoxy-w-butane (VII), which with 48 per cent, hydrobromic acid at 130-3° gives womicotine, and this on methylation yields dZ-nicotine. 

The Hofmann-Loeffler-Freytag reaction has been described with A-chloro-as well as A-bromoamines—the former however usually give better yields. A-chlorinated primary amines react well in the presence of Fe-(II) ions. Just like the Barton reaction, the Hofmann-Loeffler-Freytag reaction has been applied mainly in steroid chemistry. An interesting example from alkaloid chemistry is the synthesis of nicotine 12 by Loeffler ... 

Tndecanedione, 47, 95 Tnethylamine, 46, 18 dehydrobromination of o-bromo-y-butyrolactone with, 46, 23 dehydrobromination of or.a -dibromo-dibenzyl ketone, 47, 62 dehydrochlormation of cyclohexane-carbonyl chloride, 47, 34 in synthesis of nicotinic anhydride with phosgene, 47, 90 Tnethyl orthoformate, condensation with N,N diphenylethylene-diaminc, 47,14... 

Figure 4.18 Synthesis map showing starting materials used for the synthesis of nicotine.

Scheme 4.10 Craig synthesis of nicotine showing key atoms for hypsicity (oxidation level) analysis.

Synthetic organics dominate the field of new insecticides. Much time and money have been spent in attempting to determine the chemical structures of rotenone, pyre-thrum, and other natural insecticides, and to reconstruct them through synthesis. A great deal has been learned about the chemical structures of these compounds, but little success has been attained toward synthesis. Nicotine and, recently, a pyrethrumlike compound are exceptions, but the synthesis of nicotine is too expensive to be practical. The basic information obtained has possibly been helpful in directing the thoughts of the chemist to the synthesis of entirely new compounds. 

The synthetic viability of this protocol was demonstrated by the efficient synthesis of an isoindole alkaloid from the Mexican sponge Reniera. a-Cyanosi-lylamine (9) was treated with AgF, in the presence of dipolarophile 10 to furnish the requisite cycloadduct in 68%. An advanced intermediate in the synthesis of nicotine was also prepared by cycloaddition of 11 with phenylvinylsulfone giving the requisite adduct 12 in a 3 1 diastereomic mixture (Schem 3.3). 

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. 

Breining, S.R. 2004. Recent developments in the synthesis of nicotinic acetylcholine receptor ligands. Curr Top Med Chem 4, 609-629. 

One aspect of the reactivity of unsymmetrical formamidines such as those shown in Scheme 6 is the selective deprotonation at a benzylic position. This selectivity was used in the illustrated synthesis of nicotine, which also demonstrates the mild conditions for removal of the formamidine activating group by hydrazinolysis. ... 

Pellagra is currently thought to be due to imbalance of dietary amino acids and deficiency of niacin. The common variety of maize is rich in leucine, which inhibits synthesis of nicotinic acid mononucleotide and causes deficiency of NAD+ and NADP+. A strain of maize known as opaque 2 contains less leucine and does not cause pellagra unless excess leucine is added to the diet. 

Chini EN, Chini CC, Kato I, Takasawa S, Okamoto H. CD38 is the major enzyme responsible for synthesis of nicotinic acid-adenine dinncleotide phosphate in mam-mahan tissues. Biochem J 2002 362(Part 1) 125-130. 

A double, regiospecific intramolecular cyclization was employed in the selective generation of 143, an intermediate in a new synthesis of nicotine <04HCA2712>. 

Martin, and A. Rodgman Effect of treatment of tobacco with ammonia or various ammonium salts on the levels of pyridines and pyrazines in smoke RDR, 1976, No. 3, January 29, see www.ijrtdocs.com 501003985 -4047. Mizusaki, S., Y. Tanabe, M. Noguchi, and E. Tamaki Phytochemical studies on tobacco alkaloids. XIV. The occurrence and properties of putrescine V-methyltransferase in tobacco roots Plant Cell Physiol. 12 (1971) 633-640. Mozayani, A. Phencychdine Effects on human performance and behavior, Eorensic Sd. Rev. 15 (2002) 61-73. Pailer, M. Chemistry of nicotine and related compounds (including biosynthetic aspects) in Tobacco alkaloids and related compounds, edited by U.S. Von Euler, MacMillan, New York, NY (1965) pp. 15-36. Pictet, A. and A. Rotschy Synthese des Nikotins [Synthesis of nicotine] Chem. Ber. 37 (1904) 1225-1235. 

In a third synthesis of nicotine (373), nicotinonitrile (CLVI) was reacted with 7-ethoxypropyhnagnesium bromide (CLVII). The product of the reaction, 3-pyridyI-7-ethox3rpropylketone (CLVIII) formed an oxime (CLIX) which was reduced to a-(3-pyridyl)-o -amino-3-ethoxy-7i-butane (CLX) and this amino derivative, on heating to 150-155° with 48% hydrobromic acid was converted to dl-nomicotine (CLXI) which in turn has been methylated to dZ-nicotine ... 

A synthesis of 2, 2-nornicotine and 2, 2-nicotine was accomplished by Craig (383) from picolinonitrile in a series of reactions exactly paralleling those used in his synthesis of nicotine (373). 

The synthesis of nicotine has shown that the group substituted in the j3-position is pyrrolidine ring (559) in which the hydrogen atom joined to the nitrogen atom has been replaced by a methyl radical —... 

Ethyl-2-methylpyridine 164 (the educt in the industrial synthesis of nicotinic acid, see p 291) is formed from acetaldehyde or but-2-enal (crotonaldehyde) and aqueous NH3 in a similar process. 

Recent advances in the synthesis of nicotine and its derivatives 07T8065. 

Peixoto S, Ngueyen TM, Crich D, Delpech B, Marazano C. One-pot formation of piperidine- and pyrrolidine-substituted pyridinum salts via addition of 5-alkylamino-penta-2,4-dienals to N-acyliminium ions Applications to the synthesis of (+/-)-nicotine and analogs. Org Lett 2010 12(21) 4760-3. 

The alkylation can be intramolecular, as in the following final step in a laboratory synthesis of nicotine ... 

The Schmidt reaction of the tertiary alcohol 111 is used as a key step in the synthesis of nicotine. The reaction proceeds through 112, which undergoes a regioselective ring expansion to give imine 113. 

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