1 -Methyl-1,4,5,6-tetrahydropyridine formation

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). 

Enol ethers 268a-c reacted with N-tosy]-4-vinylidene-l,3-oxazolidin-2-ones to give bicyclic tetrahydropyridine derivatives 269a-c (Table 12.12). Methyl /Tmcthoxyacry-late afforded 269c without formation of the [2 + 2] adduct. 

More recently, Menendez et al. reported a closely related four-component access to tetrahydropyridines, the amino alcohol being replaced by a primary amine and an alcohol. Thus, the cerium(IV) ammonium nitrate (CAN)-catalyzed reaction between primary aliphatic amines, 1,3-dicarbonyls, cx,p-unsaturated aldehydes, and alcohols resulted in the formation of 6-aUcoxy-2-methyl-l,4,5,6-tetrahydropyridines with... 

There has been extensive research into electrophilic additions to 3-substituted-l,4-dihydropyridines, such as N-methyl-3-cyano-l,4-dihydropyridine 138, which readily undergoes addition across the more reactive enamine-like 5,6-alkene to give 2,3,5-trisubstituted-l,2,3,4-tetrahydropyridines (Scheme 38) <1998JOC2728, 2000CEJ1763, 2003TL8449>. In an unusual example, the reaction with sulfinyl chlorides and triethylamine results in the formation of the 1,4-dihydropyridine sulfoxide 139, where in the absence of an additional nucleophile, the iminium intermediate is deprotonated to yield the monosubstituted 1,4-dihydropyridine product 139. 

Triflic acid catalyzes the arylation of Af-methyl-l,2,3,6-tetrahydropyridine 227 to give 4-phenylpiperidine 229 (Scheme 59) <2001TL5821>. The reaction is believed to proceed by initial formation of a 1,4-dication 228, which forms in preference to the 1,3-dication 231. When yV-methyl-5-phenyl-l,2,3,6-tetrahydropyridine 230 is arylated under the same conditions, 3,3-diphenylpiperidine 232 is formed as the sole product showing the stabilization of the 1,3-dication intermediate 231 by the tertiary 5-position. Intramolecular arylation of 2- and 6-benzyl-substituted 1,2,3,6-tetrahydropyridines can also be catalyzed by triflic acid <20050L4309>. 

A formal total synthesis of ( )-morphine has been achieved by adopting the above synthetic route (Scheme 18). The tetrahydropyridine 91, prepared from the reaction of A/ -methyl-4-piperidone with 2,3-dimethoxy-phenyllithium, followed by dehydration, was converted to the bicyclic en-amine 92 by treatment with the ylic dibromide. Kinetic protonation of 92 with perchloric acid gave the trans-fused immonium salt, which upon dissolution in methanol equilibrated to the thermodynamically prefered cis isomer 93. Treatment of 93 with diazomethane brought about the formation of the aziridinium salt 94, which was readily transformed into the a-amino aldehyde 95 by its oxidation with dimethyl sulfoxide. It is also worth noting that the Komblum oxidation of aziridinium salts leads to the construction of a-amino aldehydes efficiently. Lewis-acid-catalyzed cyclization of 95 afforded the morphinan carbinol 96 in 80% yield. Successive mesylation and reduction of the mesylate derived from 96 with LiBEtjH afforded morphinan (97) in excellent yield. In this instance, direct conversion of 93 to 97 by treatment with diazomethane gave approximately 1 % of the desired product. Lemieux-Johnson oxidation of 97 under acidic conditions furnished the ketone 98, which was previously transformed into ( )-morphine by Gates. In order to confirm the structure of 98, its conversion to the known... 

A-Alkylpyridinium ions are smoothly reduced by NaBH4. Product formation can be controlled by the pH of the reaction medium and the nature of the substituents. Thus, 1-methylpyridinium chloride 122 is converted into 1-methyl-1,2-dihydropyridine 123 by NaBH4 in H2O at pH > 7, but at pH 2-5 it is transformed into 1-methyl-1,2,3,6-tetrahydropyridine 124 ... 

Treatment of 1-methyl-1,2,3,6-tetrahydropyridine (105) with base gives l-methyl-l,2,3,4-tetrahydropyridine (106). The enamine (106) is estimated to be at least 4.0 kcal mol more stable than the allylamine (105) (Scheme 41). Irradiation of (105) with light of wavelength 185 nm results in the formation of buta-1,3-diene and the cyclic trimer (107). At 10% conversion, the yields of butadiene and H2C=NMe monomer are 74 and 22% respectively. 

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