Pyridine derivatives, 1,2,3,6-tetrahydro

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

Reactions of methoxycarbonylformonitrile, furonitrile and substituted benzoni-trile oxides (4-Me, 4-OMe, 3-OMe, 4-C1, 3-C1, 2,4-di-Cl, 4-F as substituents) with dimethyl 7-(diphenylmethylene)bicyclo[2.2. l]hept-2-ene-5,6-dicarboxylate led exclusively to exo cycloadducts 82 (R = C02Me, 2-furyl, substituted phenyl), which, on irradiation with a low-pressure mercury lamp, afforded 3-azabicyclo [4.3.0]nonadiene-7,8-dicarboxylates 83 as the only products. The 1,3-dipolar cycloaddition, followed by a photorearrangement, provides a new method for obtaining tetrahydro-27/ -pyridine derivatives from cyclopentadiene (245). 

Another quite common reaction involving nucleophilic attack at a carbon atom of the ring is the hydrolysis of hexahydro-oxazolo[3,4- ]pyridines and tetrahydro-oxazolo[3,4-tf]pyridin-l-ones. This reaction has been known for years and is best performed under acidic conditions, respectively, producing 2-hydroxymethyl-piperidines or pipe-colic acid derivatives in good yields representative examples are collected in Table 9. Ammoniolysis of tetrahydro-oxazolo[3,4-tf]pyridin-l -ones with amino acid derivatives has also been reported and produces substituted pipecolic acid amides in good yields <2003H(61)259>. 

Isoquinolinium 369 and [2,7]naphthyridin-2-ium 371 salts have also been used for the preparation of 2,3,8,8a-tetrahydro-57/-oxazolo[3,2-tf]pyridine derivatives (Scheme 98) addition of Grignard reagents to 369 is followed by a spontaneous cyclization to 370 <1998JOC1767> while an asymmetric version of the Bradsher cycloaddition between 371 and chiral enol ether 372 gives 373 in good yield and selectivities <1996TL7019>. 

Anabaseine (201) Tetrahydro-pyridinyl pyridine derivative (a nicotinic compound) 3-(2,4-Dimethoxy benzylidene)-anabaseine (DMXBA GTS-21) (202) Neurology (Alzheimer s disease) Enhances cognition it acts as a partial agonist at neural nicotinic acetylcholine receptors. It binds to both the o4p2 and a subtypes, but activates only the a to a significant extent Phase I/II CoMentis 927-933... 

According to Yerma et al. [35] the mechanism of the reaction may be rationalized as involving (3-oxygenation of the bismuth(III) nitrate activated chalcone enolate, which may then undergo a Michael addition to a second a, 3-unsaturated ketone (Scheme 4.52) to form a 1,5-diketone enolate adduct 180. Subsequent heteroannulation with o-PDA via condensation and retro-aldol disproportionation may form 2-hydroxy-1,2,4,6-tetraaryl-1,2,3,4-tetrahydro-pyridine derivatives 181, which may undergo dehydration to yield 1,2,4,6-tetraaryl-1,4-dihydropyridines 177. 

A notably toxic pyridine derivative is l,2,3,6-tetrahydro-l-methyl-4-phenylpyridine (MPTP), which has the structural formula shown below ... 

Pyridine and its derivatives. The most unique pyridine derivative isolated from processed food is l,lt,5,6-tetrahydro-2-ace-topyridine. This compound was prepared by roasting proline and dihydroxyacetone at 92°C in presence of sodium bisulfate, and exhibited a strong odor reminiscent of freshly backed soda crackers (82). 2-Ethylpyridine and 2-pentylpyridine were reported in volatile flavor components of shallow fried (83). Pyridine, 2-methylpyridine, 3-methylpyridine, 2-ethylpyridine, 3-ethylpyri-dine, 5-ethyl-2-methylpyridine, 2-butylpyridine, 2-acetylpyridine, 2-pentylpyridine, 2-hexylpyridine, 3-pentylpyridine, 5-methyl-2-pentylpyridine, and 5-ethyl-2-pentylpyridine were identified in the volatiles of roasted lamb fat (8H). 2,5-Dimethylpyridine and... 

However, studies on the scope of this sequence revealed that the substrate has to be an N-tosyl sulfonamide and that certain boronic acids are not trans-metallated but rather give rise to the formation of the pyrrole 21 or a pyridine derivative 22 (Scheme 7). The peculiar outcome as a carbopalladation-Suzuki sequence is rationalized by co or dinative stabilization of the insertion intermediate 18 by the sulfonyl oxygen atom, as represented in structure 19, now suppressing the usual /3-hydride elimination. If the transmetallation is rapid the Suzuki pathway is entered leading to product 17. However, if the transmetallation is slow, as for furyl or ferrocenyl boronic acid, either /i-hydride elimination or a subsequent cyclic carbopalladation occurs. The former leads to the formation of the diene 20 that is isomerized to the pyrrole 21. The latter furnishes the cyclopropylmethyl Pd species 23, which rearranges with concomitant ring expansion to furnish piperidyl-Pd intermediate 24 that suffers a -hydride elimination to give the methylene tetrahydro pyridine 22. 

Tetrahydro-lH-pyrazolo[3,4-c]pyridine derivatives, (II), and other 5-6 to 5-7 heterobicycles prepared by Pinto (3) were effective as trypsin-like serine protease inhibitors, especially for factor Xa. 

Treatment of piperidine derivatives 387 with DBU at 70-80°C for 21 hr afforded a mixture of nitrogen bridge-head compounds 388 and tetrahydro-pyridine derivatives 389 in 21-22 and 50-59% yields, respectively (85H831). 

Heterocyclic Compounds. Such materials undergo catalytic hydrogenation to yield the corresponding saturated derivatives. Thus, pyrrole is slowly converted to pyrrolidine at 200 C over either a nickel or copper-chromium oxide catalyst pyridine and pyridine derivatives behave similarly. Compounds such as furan and dihydropyran reduce rapidly and behave more like olefins in reactivity. Similarly, thiophene is converted to the tetrahydro derivative. 

Liping et al. [68] reported the iodine-catalyzed one-pot multicomponent reaction of ethyl trifluoroacetoacetate, indan-l,3-dione, ammonium acetate, and aromatic aldehyde which gave ethyl-6 -hydroxy-l,3-dioxo-2, 4 -diaryl-6 -(trifluoromethyl)-l,3-dihydrospiro[indene-2,3 -piperidine]-5 -carboxylate derivatives 50 as the major product and 2-trifluoromethyl-2,3,4,5-tetrahydro-l/f-indeno[l,2-b]pyridine derivative 51 as the minor product (Scheme 10.33). 

Finally, the sulfone group on resin 22 was displaced by a desulfonative substitution reaction with the corresponding amines (R" R N diversity elements) in THF (tetrahydro-furan). This process, which is accompanied by concurrent cleavage from the resin, furnished the final thiazolo[4,5-6]pyridine derivatives 3 (50 examples 50-13% five-step overall yields from Merrifield resin 1, Table 10.2), which were purified by column chromatography (>95% purities as judged from LC-MS traces (integration of diode array 200—400 nm traces)). 

The 1,2-dihydro derivative is formed by reduction of pyridine with LiAlH4 (85). Analogous reduction with sodium in 95 % alcohol affords the 1,4-dihydro derivative. Monomeric N-trimethylsilyl-l,2,3,4-tetrahydro (28)... 

Hydrogenation of i-butyl nicotinate methobromide, followed by hydrolysis of the 1-methyl-3-tert-butoxycarbonyl-1,4,5,6-tetrahydro-pyridine product (205) in the presence of indole affords, on decarboxylation, the -substituted derivative (206) (325). The formation of... 

A variety of l,2,3,4-tetrahydro-j8-carbolines have been prepared from 3-piperidone phenylhydrazone derivatives. Used initially to obtain pentacyclic derivatives (35) related to the yohimbe alkaloids, this route was later extended to the synthesis of tetracyclic compounds (36). l-Methyl-5,6,7,8-tetrahydro-j8-carboline (37) was prepared in low yield by heating cyclohexanone 2-methyl-3-pyridylhydrazone with zinc chloride, a synthesis probably based on the similar preparation of the tetracyclic compound 38 starting from the corresponding quinolylhydrazine. Abramovitch and Adams extended this approach to the cyclization of cyclohexanone 3-pyri-dylhydrazone (39) itself. The main product was 6,7,8,9-tetrahydro-8-carboline (40), a smaller amount of the j8-isomer (41) also being obtained. This provides a convenient and readily reproducible route to the otherwise difficultly accessible 8-carboline ring system. The favored attack at carbon-2 over carbon-4 of the pyridine nucleus... 

The results are consistent with the rate-determining step being addition of the aryl radical to the aromatic ring, Eq. (9). Support for this mechanism is derived from the results of three other studies (a) When A -nitrosoacetanilide is decomposed in pyridine, the benzene formed by abstraction of hydrogen from pyridine by phenyl radical accounts for only 1 part in 120 of the reaction leading to phenyl-pyridines. (b) 9,9, 10,lCK-Tetrahydro-10,10 -diphenyl-9,9 -bianthryl is formed in the reaction between phenyl radicals and anthracene, probably by the addition mechanism in Eq. (11). Adducts are also formed in the reactions of benzyl radicals with anthracene- and acridine. ... 

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