Tetrahydropyridine-2-carboxylic acid

Tetrahydropyridine-4-carboxylic acid 113 and related 2- and/or 6-methylated analogs were synthesized using the methoxycarbonylation of their corresponding vinyl triflates <96H(43)2131>. 

Condensation of 3-ethoxycarbonyl-, 3-acetyl-, or 3-cyano-l,2,3,4-tetrahydropyridine -carboxylic acid derivatives 275-277 with hydrazine hydrate in boiling ethanol afforded the pyrido[3,4-r/ pyridazine derivatives 278-280, respectively (Equation 20) <2002PS1359>. 

Electrolytic reduction of pyridine-2- and -4-carboxylic acids can be used to give methylpyridines 52 and zinc and acetic acid produce either the methylpyridines or the hydroxymethylpyridines. However, from nicotinic acid the second method produces piperidine, and electrochemical reduction of these acids can be conducted to give piperidine-carboxylic acids, tetrahydropyridine-carboxylic acids and tetrahydro-methylpyridinesi ". ... 

The formation scheme of furfural is speculated as shown in Figure 3. An aldehyde group of furfural reacted with an amino group of lysine to form an imine. The double bond was migrated to form Amadori type compound, which was hydrolyzed to form alpha-keto carboxylic acid. The formed keto carboxylic acid reacted with an intra-molecular amino group to form tetrahydro-pyridine carboxylic acid or reacted with another furfural by aldol condensation, from which furpipate was formed by dehydration of 2 molecules of water. Another possible scheme is that lysine was converted to tetrahydropyridine carboxylic acid, which reacted with furfural to form furpipate. 

Efforts have been made to find stereoselective routes which provide disubstituted azetidines. Palladium catalysed cyclization of an enantiomer of allene-substituted amines and amino acids gives the azetidine ester 2 and a tetrahydropyridine in variable yield and ratio, depending on the substituents and conditions <990L717>. The (TRIS)- and (253I )-isomeis of the substituted azetidine-2-carboxylic acids 3 (R = COjH) are obtained in several steps from the corresponding 3 (R = CHjOSiMejBu ) which, in turn, is produced in high yield by photochemical intramolecular cyclization <98HCA1803>. 

Depending upon the reaction conditions, 2-ethoxy-3,4,5,6-tetrahydropy-ridine and isopropylidene 2-acetylmalonate afforded either perhydropy-rido[2,l-h][l,3]oxazine-2,4-dione (162) or hexahydropyrido[2,l-b][l,3]ox-azine-3-carboxylic acid (163) (86MI1). Reaction of 2-methoxy-3,4,5, 6-tetrahydropyridine with diketene without a solvent gave a mixture of 4H-quinazolin-4-one (164) and hexahydropyrido[2,l-h][l,3]oxazin-4-one (165) [75H(3)927]. 

Alternative reaction pathways exploring different synthetic possibilities have been studied. For instance, electron-rich dihydroazines also react with isocyanides in the presence of an electrophile, generating reactive iminium species that can then be trapped by the isocyanide. In this case, coordination of the electrophile with the isocyanide must be kinetically bypassed or reversible, to enable productive processes. Examples of this chemistry include the hydro-, halo- and seleno-carba-moylation of the DHPs 270, as well as analogous reactions of cyclic enol ethers (Scheme 42a) [223, 224]. p-Toluenesulfonic acid (as proton source), bromine and phenylselenyl chloride have reacted as electrophilic inputs, with DHPs and isocyanides to prepare the corresponding a-carbamoyl-(3-substituted tetrahydro-pyridines 272-274 (Scheme 42b). Wanner has recently, implemented a related and useful process that exploits M-silyl DHPs (275) to promote interesting MCRs. These substrates are reacted with a carboxylic acid and an isocyanide in an Ugi-Reissert-type reaction, that forms the polysubstituted tetrahydropyridines 276 with good diasteroselectivity (Scheme 42c) [225]. The mechanism involves initial protiodesilylation to form the dihydropyridinum salt S, which is then attacked by the isocyanide, en route to the final adducts. 

Sodium cyanoborohydride (10) produces mainly 1,4-dihydropyridines (11) in the reduction of 3,5-di-cyano- and 3,5-diethoxycarbonyl-pyridines, diborane produces more of the 1,2-isomer. With NBH, mixtures of 1,2- and 1,4-dihydro adducts are produced, the latter predominating when carried out in pyridine solution. Nicotinamide (13) in ethanol can be reduced to (8) in moderate yield at 140 C in diglyme the tetrahydropyridine (8) was isolated in admixture with the piperidine (14), presumably via dehydration of the amide. 3-Nitropyridine affords 3-nitropiperidine in moderate yield when reduced in ethanol. The carboxylic acid and halo derivatives of pyridine are generally not reactive toward NBH. 

Tetrahydropyridine-2-carboxylic acid ( 96 ) occurs in the sea-weed Corallina officinalis (J.C. Madgwick et al., Arch.Biochem.Biophys., 1970, 141, 766), and pegaline from... 

A biomimetic synthesis of the tobacco alkaloid anatabine (1,2,3,6-tetrahydro-2,3 -bipyridine) (69) has been reported starting from 1,2,3,6-tetrahydropyridine-2-carboxylic acid (68) labelled with carbon-13 and deuterium at C-2 (Scheme 15).9" ... 

Imines with acceptor substitutents, for instance the A/ -tosylimine of the glyoxylic ester 187, add to 1,3-dienes (e.g. 2,3-dimethylbuta-1,3-diene) to produce tetrahydropyridines (e.g. 188). Elimination of sulfinic acid, saponification and dehydrogenation lead to pyridine-2-carboxylic acids (e.g. 189) ... 

Biosynthesis From lysine via 2-aminoadipic acid hemialdehyde and 2,3,4,5-tetrahydropyridine-2-carboxylic acid or via 3,4,5,6-tetrahydropyridine-2-carboxylic acid. ... 

L-Baikiain (1 3,6-tetrahydropyridine-a-carboxylic acid), a rare nonproteogenic amino acid first isolated... 

Guvacine (h -Tetrahydropyridine-3-carboxylic acid, h. -tetrahydr[Pg.145]

Intramolecular Reactions of Alkynes with Carboxylic Acids, Alcohols, and Amines. Addition of carboxylic acids, alcohols, and amines to alkynes via oxypaUadation and aminopallada-tion proceeds with catalysis by Pd salts. Intramolecular additions are particularly facile. Unsaturated y-lactones are obtained by the treatment of 3-alkynoic acid and 4-alkynoic acid with Pd(PhCN)2Cl2 in THF in the presence of Et3N (eq 54), and -lactones are obtained from5-alkynoic acids. 5-Hydroxyalkynes are converted to the cyclic enol ethers (eq 55). The oxypalla-dation is a irons addition. Thus stereoselective enol ether formation by reaction of the alkynoic alcohol with Pd(PhCN)2Cl2, followed by reduction with ammonium formate, has been applied to the synthesis of prostacyclin (eq 56). Intramolecular addition of amines affords cyclic imines. 3-Alkynylamines are cyclized to 1-pyrrolines while 5-alkynylamines are converted to 2,3,4,5-tetrahydropyridines (eq 57). ... 

Alkyl-1,4-dihydropyridines on reaction with peracids undergo either extensive decomposition or biomimetic oxidation to A-alkylpyridinum salts (98JOC10001). However, A-methoxycarbonyl derivatives of 1,4- and 1,2-dihydro-pyridines (74) and (8a) react with m-CPBA to give the methyl tmns-2- 2>-chlorobenzoyloxy)-3-hydroxy-1,2,3,4-tetrahydropyridine-l-carboxylate (75) and methyl rran.s-2-(3-chlorobenzoyloxy)-3-hydroxy-l,2,3,6-tetrahydropyridine-l-carboxylate (76) in 65% and 66% yield, respectively (nonbiomimetic oxidation). The reaction is related to the interaction of peracids with enol ethers and involves the initial formation of an aminoepoxide, which is opened in situ by m-chlorobenzoic acid regio- and stereoselectively (57JA3234, 93JA7593). 

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