Tetrahydropyridine derivative

Dihydro- and 1,4-dihydro derivatives are formed as intermediates in the reduction of quaternary pyridine salts and their homologues with sodium borohydride or formic acid. A proton is added to the present enamine grouping and the formed immonium salts are reduced to the l-methyl-l,2,5,6-tetrahydropyridine derivatives (157) and to completely saturated compounds (158) (254) (Scheme 14). 

Partial hydrogenation of the quaternary pyridinium salts in the presence of triethylamine on palladium in methanol has been used for the synthesis of a large number of alkaloids. The tetrahydropyridine derivatives thus formed undergo various cyclization reactions in acidic media (89). 

With Af-acyl or Af-sulfonyl hydrazines as nucleophiles, Zincke salts serve as sources of iminopyridinium ylides and ylide precursors.Reaction of the nicotinamide-derived Zincke salt 8 with ethyl hydrazino urethane 42 provided salt 43, while the tosyl hydrazine gave ylide 44 (Scheme 8.4.14). ° Benzoyl hydrazines have also been used in reactions with Zincke salts under similar conditions.Af-amino-1,2,3,6-tetrahydropyridine derivatives such as 47 (Scheme 8.4.15), which showed antiinflammatory activity, are also accessible via this route, with borohydride reduction of the initially formed ylide 46. ... 

When the pyridinyl substituted furazan 285 was treated with methyl iodide in acetone, the quaternary salt was formed. Reduction with sodium borohydride affords tetrahydropyridine derivative 286 (Scheme 187 see also Scheme 176) (92W003430). 

Azadienes undergo Diels-Alder reactions to form pyridine, dihydro- and tetrahydropyridine derivatives. N-Vinyl lactim ethers undergo Diels-Alder reactions with a limited set of dienophiles. " Thioketones react with dienes to give Diels-Alder cycloadducts. The carbonyl group of lactams have also been shown to be a dienophile. Certain heterocyclic aromatic rings (among them furans) can also behave as dienes in the Diels-Alder reaction. Some hetero dienes that give the reaction are -C=C-C=0, 0=C-C=0, and N=C-C=N. ... 

IH of aminoalkynes can be performed under mild conditions using CpTiCb or CpTi(Me)2Cl as catalyst precursors to give dihydropyrrole and tetrahydropyridine derivatives (regioselective Exo-Dig processes) in high yield with TOE near 10 h (e.g., Eq. 4.79) [297]. 

Mabic S, Castagnoli N, Jr. Assessment of structural requirements for the monoamine oxidase-B-catalyzed oxidation of l,4-disubstituted-l,2,3,6-tetrahydropyridine derivatives related to the neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. J Med Chem 1996 39( 19) 3694—... 

A regioselective and endo-selective [4+2]-cycloaddition reaction of N-benzenesul-fonylimine 191 was promoted by pressure to yield a tetrahydropyridine derivative [155]. 

Electron-rich alkenes like an enol ether react with N-allenylsulfonamides to assist a 1,3-shift of the sulfonyl group, eventually furnishing formal [4+2]-cycloaddition products, tetrahydropyridine derivatives. The sulfonyl group migrates from the nitrogen to the central allenyl carbon atom [25b, 195]... 

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. 

Scheme 51 CAN-catalyzed four-component synthesis of tetrahydropyridine derivatives...

In sharp contrast to the development of the [4 + 2] cycloaddition reactions of electron-rich 2-azadienes, reports dealing with the chemistry of electron-poor 2-azadienes remained unknown until a few years ago. In fact, the first cycloaddition of an electron-withdrawing substituted 2-azadiene was observed in 1986 by Wulff and Bohnke [86AG(E)90] while they were preparing dehydroaminoacid derivatives (Scheme 48). They isolated AL(arylmethylene)dehydroalanine methyl esters 208 by dehydration of the Schiff base of the serine methyl ester 207 and found that it dimerized through a [4 + 2] cycloaddition to give tetrahydropyridine derivative 209 in 56% yield as a sole diasteroisomer. 

Another example is the indirect acetonylation of a 1,2,3,4-tetrahydropyridine derivative at the (3-position of the enamide system [99]. The reaction involves a double alkylation to furnish an acetylcyclopropane which undergoes fragmentation on acid treatment. It is noted that polarity alternation and ring strain relief allow the facile and regiospecific C-C bond cleavage to proceed, the intervention of a cyclopropane intermediate also leads to disjoint system. This is a fundamental strategy [100] which has been frequently employed to gain access to compounds with disjoint functionalities. 

Maret G, Testa B, Jenner P, et al. The MPTP story MAO activates tetrahydropyridine derivatives to toxins causing parkinsonism. Drug Metab Rev 1990 22 291. 

The reductive cleavage of the C—O bond in 2- and 4-substituted hydroxy-methylpyridines was mentioned in Part I. The optically active l-(4-pyridyl)-alkanols are reduced in good yield to the optically inactive alkylpyridine, whereas the 2-substituted derivatives were reduced in lower yield to the optically active alkylpyridine (and some tetrahydropyridine derivatives).384,385 The difference in behavior was explained by orientation of the adsorbed pro-tonated pyridine, allowing contact between the electrode and the 2-substituent, but not the 4-substituent. This model was used in later work however, not excluded was the possibility that the higher stability of the p-quinonoid dihydropyridine intermediate, compared to the o-quinonoid dihydropyridine, played a role in the relative ease of reduction of the 4- and 2-substi-tuted pyridines. 

Specially substituted tetrahydropyridine derivatives with a coronary dilatory action were produced by electrochemical reduction of thecorrespondingdihydropyridines4,4). 

Exceptionally tetrahydropyridine derivatives undergo isomerization, but the products cannot be isolated as monomers. Apparently in a subsequent thermal reaction diastereomeric dimers are formed, as depicted with enamine 20 as substrate (Scheme 5). 

Another route to this tetracyclic system involves the decarboxylative cyclization of indolylethyl-tetrahydropyridine derivatives. As an example, heating the diester (120) with aqueous alkali results in hydrolysis, decarboxylation, and cyclization, with the formation (after re-esterification) of one diastereoisomer of the tetracyclic monoester (121).776 However, the stereochemistry of this product has not yet been clarified. 

Cyclization of an indolylethyl-tetrahydropyridine derivative is also a key stage in an extremely brief and elegant synthesis of the yohimbine ring system and a number of ajmalicinoid bases by Wenkert and his collaborators.78 Thus, internal nucleophilic attack by enolate anion at the y-position to the nitrogen atom in (122) gave a tetrahydropyridine derivative which readily cyclized to the pentacyclic enamine (123), reduction of which gave (db)-pseudoyohimbone (124) (Scheme 11). 

Blechert et al. have opened a very elegant alternative to the classical hetero Diels-Alder methodology by generating the cationic radical 3-31 - which might be conceived as 1-aza-1,3-butadiene - from the 2-vinyl indole 3-30 by means of a single electron transfer process. In the presence of the tetrahydropyridine derivative 3-32 the radicalic intermediate was transformed into the tetracyclic compound 3-33 which contains the complete skeleton of the alkaloid gonio-mitine [250, 251]. The authors have postulated a stepwise mechanism for this [4+2] process, therefore it should be understood as a formal hetero Diels-Alder reaction (Fig. 3-11). 

An intramolecular aza Diels-Alder reaction of as well electronically neutral N-aryl imines useful for the synthesis of novel tetrahydropyridine derivatives has been introduced by our group [268]. The reactive intermediate 3-43 exhibiting the 2-aza-l,3-butadiene subunit was generated in situ from the aldehyde 3-41 and the amino isoxazole 3-42 and led directly to the diastereomerically pure cycloadduct 3-44 (Fig. 3-14). In contrast to the reactions studied by Barlu-enga, the 2-aza-1,3-butadiene acts as electron-deficient component in this case. 

RCM reactions are most frequently employed in the synthesis of 2,5-dihydrofurans as well as dihydropyrrole derivatives . Likewise, RCM provides the most general approach to 3,6-dihydropyrans . In a specific example, dihydropyran 127 bearing a chiral oxacyclic diene can be constructed via enyne metathesis of the chiral ether 126 (Scheme 68) <2002T5627>. The analogous tetrahydropyridine derivatives are prepared by a similar RCM procedure . 

In the second method (30), stress was placed upon obtaining compounds of the type of XXXI. Tryptophyl bromide readily reacts with pyridines to yield the corresponding quaternary compounds, which on reduction with sodium borohydride gave tetrahydropyridine derivatives. These could be fully reduced catalytically and ultimately dehydrogenated. 

The 1,2-dihydro derivative is formed by reduction of pyridine with LiAlH4359. Analogous reduction with sodium in 95% ethanol affords the 1,4-dihydro derivative. Monomeric iV-trimethylsilyl-1,2-dihydro and 1,4-dihydro derivatives of pyridine have been prepared by treatment of pyridine with trimethylsilane in the presence of palladium360. Pyridines with a carbonyl function in the 3-position can be hydrogenated to the corresponding 1,4,5,6-tetrahydropyridine derivatives in good yield361. 

Dihydropyridone and 2,3,5,6-tetrahydropyridine derivatives have previously been prepared and are described (3). 

Triallylborane 80 reacts both as activating agent and nucleophile. Interestingly, due to the lability of the N-B bond, the process leads to N-H derivatives, ready for further derivatization. A noteworthy transformation is the double allylation of pyridines by triallylboron 80 leading to the tetrahydropyridine derivative 81. 

In this chapter, we describe our effort to develop GGTIs with novel scaffolds [13,14]. Our approach commenced with the constrnction of a novel library of dihydropyrroles and tetrahydropyridines derived from the phosphine-catalyzed annulation of resin-bound allenoates and A-sulfonyl imines. Derivatization of one of the initial hits, dihydropyrrole-carboxyhc... 

In the presence of 10 mol % Sc(OTf)3, A-benzylideneaniline reacts with 2-trans-l-methoxy-3-trimethylsiloxy-l, 3-butadiene (Danishefsky s diene) [23] to afford the corresponding aza Diels-Alder adduct, a tetrahydropyridine derivative, quantitatively (Eq. 7) [24]. In the reaction of A -benzylideneaniline with cyclopentadiene under the same conditions, on the other hand, the reaction course ehanged and a tetrahydroqui-noline derivative was obtained (Eq. 8). In this reaction, the imine aeted as an azadiene toward one of the double bonds of cyclopentadiene as a dienophile [25]. In the reaction with 2,3-dimethylbutadiene a mixture of tetrahydropyridine and tetrahydroqui-noline derivatives was obtained. A vinyl sulfide, a vinyl ether, and a silyl enol ether worked well as dienophiles to afford the tetrahydroquinoline derivatives in high yields [26,27]. 

Sc(OTf)3-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have been examined. In the presence of 10 mol % Sc(OTf)3 and magnesium sulfate, benzaldehyde was treated with aniline and Danishefsky s diene. The desired three-component reaction proceeded smoothly to afford the corresponding tetrahydropyridine derivative in 83 % yield (Eq. 9) [24b]. Under the same reaetion conditions, cyclopentadiene was used instead of Danishefsky s diene to afford the corresponding tetrahydroquinoline derivative (Eq. 10). Different combinations of aldehydes, amines, and alkenes are possible in these reactions, and afford diverse tetrahydroquinoline derivatives in high yields. 

When the piperidine 198 was heated in DBU at about 70°C for 4 days, the required 1,2,3,6-tetrahydropyridine derivative 199 was accompanied by only 4% of by-product 200 (85H831). 

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