From tetrahydropyridine

It has been noted that for the ammonium ylide generation copper catalysts such as copper(ii) acetylacetonate [Cu(acac)2] and Cu(hfacac)2 are superior over Rh(ii) catalysts. Sweeney and co-workers have recently reported copper-catalyzed [2,3]-sigmatropic rearrangement of ammonium ylide generated from tetrahydropyridines 150 and diazo ester 129 (Equation (22)). A detailed study on the reaction conditions has revealed that Cu(acac)2 is the best catalyst for this reaction. 

Ketone 45 was synthesized by Judd et al. [17] as summarized in Scheme 4. The lithiated enamine 23 prepared from tetrahydropyridine 22 was alkylated, followed by refluxing in an acetonitrile solution in the presence of... 

The enamides 323 were prepared from tetrahydropyridine with 3,5-hexa-dienoyl chloride. Heating of a 1% solution of 322 in toluene resulted in the subsequential cheletropic expulsion of sulfur dioxide, followed by an intramolecular Diels-Alder reaction to give the hydroindoles 324 in 45-67% yields. Then 324a was converted to hydrolulolidine (325) and 324c to the ketolactam 326, thereby furnishing a new formal total synthesis of aspidospermine (327) (152) (Scheme 117). 

Only one paper reports this bicyclic ring system. The perhydro derivative (269) was synthesized from tetrahydropyridine, acetaldehyde, and hydrogen sulfide (Equation (58)) <9iMi 824-01 >. 

Dihydropyridinium salt 31 was initially selected to check the viability of the proposal. This salt was prepared from tetrahydropyridine 30, which was accessible in six steps from methyl nicotinate, by treatment of the corresponding N-oxide derivative (mixture of two diastereoisomers) under Polonovski-Potier reaction conditions (Scheme 11). Reaction of the crude salt 31 with the sodium salt of diethyl 1,3-acetonedicarboxylate gave a mixture of two diastereoisomeric adducts 32 (two isolable enol forms) and 33 in 87% overall yield, the undesired stereoisomers 32 (axial amino-methyl chain) predominating (69 31 ratio). 

Scheme 2.6 PdIC-catalyzed synthesis of pyridines from tetrahydropyridines.

Hofmann degradation of l,l-dimethyl-2-methylenepyrrolidinium hydroxide furnishes dimethylamine and dimethyl-3-pentynylamine 198). 1,1,4,4-Tetramethyltetrahydropyridinium hydroxide was obtained from l-dimethylamino-4,5-dibromopentane by means of silver oxide. Hofmann degradation of the product gives I,4,4-trimethyl-/j -tetrahydropyridine 199). 

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

The reaction of 1-methyl-1,2,3,4-tetrahydropyridine 62 and azides 50a-c in dry ether at 25°C afforded the l-methylpiperidylidene-2-sulfon(cyan)amides 65a-c in good yield (82JHC1259). The reaction proceeds via a triazoline intermediate 63, which loses nitrogen to afford 65. The elimination of nitrogen from triazoline intermediate 63 occurs by two possible mechanisms [68JCS(C)277]. In path A, the 63 could eliminate nitrogen to give first an unstable 2,7-diazabicyclo[4.1.0]heptane... 

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

Schopf recommends that this solvent be reused in later runs.2,3 The submitters found that substantial amounts of product can be recovered from this distillate after a few days of standing. Thus it appears that some tetrahydropyridine distils as monomer with the ethanol and trimerizes in the distillate. The checkers found that when the reaction was worked up after 24 hours of standing, the majority of the product was in the ethanol distillate. Therefore, they allowed the distillate to stand for several days, concentrated it by rotary evaporation, and crystallized the residue from acetone. The resulting tetrahydropyridine trimer was combined with that otherwise obtained. 

The intramolecular cycloaddition has proven to be the method of choice for the preparation of steroids. A diastereomeric mixture of 204, prepared from 191 and tosylate 203 has been cleanly converted to dl-estra-1,3,5(10)-trien-17-one (205) in 85% yield (equation 130). A second example of the intramolecular cycloaddition reaction is the formation of the cycloadduct (209), the key intermediate in a synthesis of the As-pidosperma alkaloid aspidospermine, upon heating 208 at 600 °C (equation 131)124. The sulfone 208 can be prepared by reaction of 3-ethyl-3,4,5,6-tetrahydropyridine (206) with the acid chloride 207. 

Oxa-tetrahydropyridines are interesting intermediates for the preparation of pharmaceuticals and natural product based alkaloid systems. A modified Hantzsch reaction was developed under microwave irradiation for the preparation of 2-oxa-tetrahydropyridines 173 by reaction of Meldrum s acid, a /3-ketoester and an aldehyde, using NH4OAC as the source of ammonia (Scheme 62). Yields ranged from 81 to 91% at temperatures of 100-130 °C depending on the substrate (the aldehyde) employed. All the products obtained have the same structure except for the aromatic substituent in position 4 [109]. 

Scheme 26 Synthesis of 2-aikyl-4-halo-1 -tosyl-1,2,5,6-tetrahydropyridines from A-tosyl homopropargyl amine and aldehydes using FeX3 as promotor...

These IHs have been applied to the synthesis of several pyrroHnes and 2,3,4,5-tetrahydropyridines known as venom constituents from ant species [278]. 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

Flash vacuum thermolysis (FVP) at 600°C or microwave excitation of 1-substituted perhydropyrido[l,2-f][l,3]oxa-zines afforded 1-substituted 1,4,5,6-tetrahydropyridines <2005TL5451>. Perhydropyrido[l,2-f][l,3]oxazin-l-ones were hydrolyzed with 2M ethanolic KOH to 2-(2-hydroxyalkyl)piperidines <1996CJC2434, 2005EJ01378>. (+)-9- />z -6-Epipinidinol 102 was similarly obtained from 3,8-dimethylperhydropyrido[l,2-f][l,3]oxazin-l-one 101 (Equation 16) <1998T13505>. 

Phenyl-l,2,3,6-tetrahydropyrido[2,l- ][l,3]thiazino[3,2- ]quinolin-6-ones were prepared by the reaction of 2-mercapto-5-phenyl-l,4-dihydroquinolin-4-ones with 1,3-dihalopropane <1997JAK97/278780>. 7-Acetyl-2-aryl-9-cyano-6-methyl-8-phenyl-3,4-dihydro-277,877-pyrido[2,l- ][l,3]thiazin-4-ones were obtained from 5-acetyl-3-cyano-6-methyl-4-phenyl-l,2,3,4-tetrahydropyridine-2-thione with 3-aryl-2-propenoyl chloride <2002CHE761>. Reaction... 

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