Nicotin aldehyde

The formation of a carbon-carbon bond at the p-position of amines is made possible by the reaction of these enecarbamates with electrophiles. The acylation, Vilsmeyer reaction and hydroboration at the P-position of carbamates have been achieved by using this technique31. The syntheses of a derivative of hydrolulolidine 49 and nicotin-aldehyde 50 are shown below as typical examples. 

A simple one-step synthesis of this oxazole type base has been devised. p-Hydroxymandelonitrile was first reacted with thionyl chloride in the presence of hydrogen chloride in ether. The addition of nicotine aldehyde was followed by saturation with hydrogen chloride. The reaction mixture was set aside for 2 days at room temperature after which it was possible to isolate halfordinol (104) in 16% yield (123). 

Likewise, nicotine aldehyde can be obtained from 1-dimethylamino-butadiene and chlorodimethylformiminium chloride ( ). 

In the last example, a more direct approach to make the vinyl group may be via a Wittig strategy from a nicotinic aldehyde or via a direct aromatic substitution strategy. It should be noted that the Wittig and Heck reactions were known at the time the Merck, Gates, and Martin plans of quinine were disclosed. 

Section 15 11 Oxidation of alcohols to aldehydes and ketones is a common biological reaction Most require a coenzyme such as the oxidized form of nicotin amide adenine dmucleotide (NAD" )... 

In addition to natural muscarine and the so-called choline-muscarine referred to above, two other products have been given names suggesting relationship to muscarine, viz. (1) isomuscarine, Me3N(OH). CHOH. CH2OH prepared by Bode and shown to be toxic, but distinct from muscarine in type of action, and (2) anhydromuscarine (betaine aldehyde) made first by Berlinerblau and later by Fischer and which, according to Voet possesses nicotine and curare-like properties. 

Colour Reactions. Rochelmeyer (1939) has provided a list of colour reactions given by solasodine and solasodiene (solanosodine), with reagents usually applied to the sterols, and Briggs et al. have found that when concentrated sulphuric acid (1 mil) is carefully added to a solution of solasonine or solasodine in hot alcohol (1 mil) a characteristic, intense, greenish-yellow fluorescence is produced, a reaction which is not given by solanine or solanidine. They have also found that intense colours are formed when solasonine or solasodine is mixed with resorcinol, or one of a variety of aldehydes, and boiled with concentrated hydrochloric acid. Colours are also produced with this test by cholesterol, digitonin, jacobine carbazole, pyrrole, or nicotine, the most intense colours being formed with p-hydroxybenzaldehyde or anisaldehyde. 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

Nicotine is extensively metabolized to a nnmber of metabolites (Fig. 3) by the liver. Six primary metabolites of nicotine have been identified. Qnantitatively, the most important metabolite of nicotine in most mammalian species is the lactam derivative, cotinine. In humans, about 70-80% of nicotine is converted to cotinine. This transformation involves two steps. The first is mediated primarily by CYP2A6 to produce nicotine-A -iminium ion, which is in equilibrium with 5 -hydroxynicotine. The second step is catalyzed by a cytoplasmic aldehyde oxidase. Nicotine iminiiim ion has received considerable interest since it is an alkylating agent and, as such, could play a role in the pharmacology of nicotine (Shigenaga etal. 1988). 

Brandange S, Lindblom L (1979) The enzyme aldehyde oxidase is animinium oxidase. Reaction with nicotine delta 1(5 ) iminium ion. Biochem Biophys Res Commun 91 991-996 Byrd GD, Chang KM, Greene JM, deBethizy JD (1992) Evidence for urinary excretion of glu-curonide conjugates of nicotine, cotinine, and trans-3 -hydroxycotinine in smokers. Drug Metab Dispos 20 192-197... 

Tobacco smoke contains more than 3800 different compounds. About 10% of these constimte the particulate phase, which contains nicotine and tar. The remaining 90% contains volatile substances such as carbon monoxide, carbon dioxide, cyanides, various hydrocarbons, aldehydes, and organic acids. Although all of these substances affect the smoker to some degree, nicotine is generally considered to be the primary substance responsible for the pharmacological responses to smoking (Nielsen et al. 2001). 

Aldehydes are obtained in 86% and 75% yields, respectively, from benzoic acid on refluxing for 6 hours and from nicotinic acid on standing at room temperature for 24 hours with bis(N-methylpiperazino)alane in tetrahydro-furan [963]. Reduction of 3-fluorosalicylic acid with 2% sodium amalgam in aqueous solution containing sodium chloride, boric acid and p-toluidine gave, at 13-15°, a Schiff base which on hydrolysis with hydrochloric acid and steam distillation afforded 3-fluorosalicylaldehyde in 57% yield [136. The purpose of p-toluidine is to react with the aldehyde as it is formed and protect it from further reduction. 

Oxidative reactions at carbon predominate in the biotransformation of cyclic amiiies, and an important consequence of this is often the cleavage of the carbon-nitrogen bond. For example, A-dealkylation of N- alkyl substituted pyrrolidine (or piperidine, morpholine, etc.) involves an initial oxidative attack at the a- alkyl carbon atom to yield an N hydroxyalkyl derivative (carbinolamine), which is then metabolized to a secondary amine and the corresponding aldehyde. The metabolic conversion of nicotine to nornicotine (30 see Scheme 3) probably involves this mechanism, although the iminium ion (31) has also been suggested as an intermediate in the biotransformation (76JMC1168). Carbinolamines are unstable intermediates and have been identified only in a few cases, e.g. A-hydroxymethylcarbazole... 

These enzymes catalyze the two-electron oxidation of purines, aldehydes and pyrimidines, sulfite, formate and nicotinic acid in the general reaction shown in equation (49). These enzymes show some differences in properties. Xanthine oxidase, xanthine dehydrogenase and aldehyde oxidase all have relatively low redox potentials and a unique cyanolyzable sulfur atom, and so will be discussed together. 

The slight solubility of yellow phosphorus in several other liquids has been notioed— e.g. ethyl chloride, ethylene chloride, chloroform, bromoform, ohloral, acetic ether, acetone aldehyde, cacodyl sulphide, allyl thiooyanate, mercury methide, valerianic acid, amyl valerate, fusel oil, benzoyl chloride, stannic chloride, ethyl nitrite, nicotine, coniine, cavutchin, styrene, aniline, quinoline, creosote, etc. J. Hartmann found that 100 grms. of bile at 38-5° dissolved 0 02424 grm. of phosphorus, and more at a higher temp. 

Toxicologically it is of interest that the FMO enzyme is responsible for the oxidation of nicotine to nicotine F-N-oxide, whereas the oxidation of nicotine to cotinine is catalyzed by two enzymes acting in sequence CYP followed by a soluble aldehyde dehydrogenase. Thus nicotine is metabolized by two different routes, the relative contributions of which may vary with both the extrinsic and intrinsic factors outlined in Chapter 9. 

Nicotine can be alkylated at C-5 via the disilyl-l,4-dihydronicotine 107 using a modification of the Tsuge reaction. Addition of an aldehyde and a catalytic amount of TBAF to 107 affords the C-5 alkylnicotines 112 in moderate to good yield (Equation 36) <20060L179>. 

---