1 - -1,2,3,4-tetrahydropyridin-4-ones

In a synthesis (Scheme 11) of ( )-18,19-dihydroantirhine (79), Wenkert employs as a key step his method for the formation of immonium salts within a piperidine ring by the decarboxylation of a 3-carboxy-l,4,5,6-tetrahydropyridine. One feature to note is the production of stereoisomer (80) in the hydrogenation of the precursor pyridinium salt this governs the production of the finally required stereoisomer (79). 

A2acyclobutenes have been used to generate l-a2abutadienes, which are intramolecularly as weU as intermolecularly cycli2ed to give tetrahydropyridines, eg, hexahydroquinoli2in-4-one [87842-80-6] (64,65). In the following, FVP = flash vacuum pyrolysis. 

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. 

Treatment of l-(2-acetoxybenzoyl)- and 1-(4-chloro-2-acetoxybenzoyl)-l,2,3,4-tetrahydropyridin-4-ones with aqueous LiOH in THF at room temperature gave 5n,6,7,8,9,l l-hexahydropyridoPd-hlLbSlbenzoxazine-Vdl-diones 47 (X = 0, R = H, Cl) (OOMIPl). 

Two polymorphic forms of 3- 2-[4-(6-fluorobenzisoxazol-3-yl)-l,2,3,6-tetrahydropyridin-l-yl]ethyl -2-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n] pyrimidin-4-one (137 R = H) were prepared (99MIP1). Racemic 9-hydroxy-2-methyl-3- 2-[4-(6-fluorobenzo[r/ isoxazol-3-yl)-l,2,3,6-tetrahydro-l-pyridyl] ethyl -6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidin-4-one was resolved into its (R)- and (5)-isomers (OOMIPIO). 

Reaction of 5-cyano-6-methoxy-l,2,3,4-tetrahydropyridin-2-ones 387 with 1,3-propanediamine in boiling A/, A -dimethylacetamide gave 9-cyano-l,2,3,4,7,8-hexahydro-6//-pyrido-[l,2-n]pyrimidin-6-ones 388 either via route a or via route b (95H(41)2173). 

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). 

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. 

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... 

Using trimethylsilyl triflate, a one-pot reaction of acetoxyallylation and O-silylation of nitrones, gave silylated hydroxylamines (673). Enantiomers of the naturally occurring alkaloid dihydropinidine, potential antifeedants against the pine weevil Hylobius abietis, were prepared by diastereoselective, dimethylzinc mediated addition of pinacolyl 2-propenylboronate to (/ )- and to (S )-2-methyl tetrahydropyridine-A-oxide, obtained from D-alanine and L-alanine, respectively (Scheme 2.190) (674). 

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. 

The regioselectivity is an issue in substrates 141. With two alkyl substituents on the distal position, tetrahydropyridines 142 are the product. With only one alkyl substituent, the cyclic imine 143 was isolated for these rearrangement products it is unknown whether they stem from the enamine generated from a 5-endo-trig or 5-exo-digcydization (Scheme 15.44) [98]. 

Ultrasound irradiation of mixtures of amines RNH2 (R = PI1CH2, Ph or Ar) and methyl pyruvate results in the 3-pyrrolin-2-ones 322377. The silver tetrafluoroborate-catalysed cyclization of the allenic amines 323 leads either to a pyrroline 324 or tetrahydropyridine 325, depending on the structure of the amine. The former is formed from 323 (R = H), the latter from 323 (R = Me)378. 

Unaware of it at the time, the college student s sloppy chemistry had, in addition to synthesizing MPPP, inadvertently created some additional by-products that were very toxic. It turns out that one of the by-products, called l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is very toxic to neurons in... 

As six-membered heterocycles are present in a number of natural products and biologically important molecules, solid-phase synthesis of these has been reported very often (Fig. 3.9). Solid-phase synthesis for nearly every six-membered ring including one nitrogen atom are known piperidines (272) [376], tetrahydropyridines (273) [377, 378], dihydropyridines (274) [219, 379, 380], pyridines (275) [349, 381-386], (Scheme 3.37), piperidinones (276) [387], dihydropyridones (277-279) [313, 378, 388-390], pyridinones (280-281) [328, 329] and piperidindiones (282) [391] derivatives. In contrast, the synthesis of six-membered rings with one single oxygen is rarely described. Nevertheless, solid-phase synthesis of dihydropyrans (283-284) [392-394] and tetrahydropyrans (285) [335, 336] has been reported. 

Noel R, Fargeau-Bellassoued MC, Vanucci-Bacque C, Lhommet G (2008) Convenient one-pot synthesis of chiral tetrahydropyridines via a multicomponent reaction. Synthesis 1948-1954... 

Inhibition mechanisms by A/-cyclopropyl MPTP analogues are also discussed in terms of two catalytic pathways, one of which is based on an initial SET step from the nitrogen lone pair, as proposed by Silverman, and the second is based on an initial a-carbon hydrogen atom transfer (HAT) step, as proposed by Edmondson, leading to a radical and dihydropyridinium product formation. The observation that MAO B catalyzes the efficient oxidation of certain 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridines to the corresponding dihydropyridinium metabolites suggests that the catalytic pathway for these cyclic tertiary allylamines may not proceed via the putative SET-generated aminyl radical cations [122], Further studies will be necessary to clarify all the facets of the mechanism of inhibition of MAO by cyclopropylamines. 

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