Pyridine ring formation

Ring Synthesis From Nonheterocyclic Compounds. These methods may be further classified based on the number of bonds formed during the pyridine ring formation. Synthesis of a-picoline (2) from 5-oxohexanenitrile is a one-bond formation reaction (eq. 16) (49). The nitrile is obtained by reaction between acetone and acrylonitrile (50). If both reaction steps are considered together, the synthesis must be considered a two-bond forming one, ie, formation of (2) from acetone and acrylonitrile in a single step comes under the category of two-bond formation reaction. 

Houghton C, RB Cain (1972) Microbial metabolism of the pyridine ring. Formation of pyridinediols (dihydroxypyridines) as intermediates in the degradation of pyridine compounds by microorganisms. Biochem J 130 879-893. 

Thermolysis of 2/7-aziridines having cyclopropyl ring substitution yielded pyridines <95H(40)511>. Steric inhibition of pyridine ring formation was noted for some aziridines. Aza-Wittig reaction on aziridines yields tetrahydropyridines <95TL(36)3557>. 

These enones reacted with substituted phenacyl pyridinium bromides and ammonium acetate under pyridine ring formation. Cleavage was performed with 25 % TFA/CH2CI2. Twelve compounds were synthesized, with yields of the crude products ranging from 50 % to 85% (HPLC-purities 76-97%). 

Pyridine ring formation. " Thermolysis of oxime 0-allyI ethers in the presence of BF5 OEt2 leads to pyridine derivatives. 

Pyrolysis of oxime 0-allyl ether (16) resulted in pyridine ring formation, (17), in reasonable yield, along with minor isomer (18) (Scheme 7) <93CPB(41)1297). 

Polymers containing pyridine moieties in the mainchain (13) are likewise obtainable by the reaction of the polymers (3) with nitriles (scheme 9). In this case, polymers containing pyridine moieties (about 80%) are produced with an increase of the molecular weight of the polymers. The increase of the molecular weight is most probably due to the pyridine formation of the nitriles with the acetylene moieties at the polymer end catalyzed by the eliminated ( n -cyclopentadienyl)cobalt(I). In fact, it is also possible to prepare pyridine-containing polymers directly from diynes and nitriles in the presence of catalytic amount of 4 (scheme 10). Within the examined combinations, this catalytic polymerization by the pyridine-ring-formation process is... 

A one-pot Hantzsch reaction in aqueous medium without any solvent or catalyst is known for the synthesis of 1,4-dihydropyridines. Tamaddon and coworkers have reported the synthesis of 1,4-dihydropyridines 107 by the reaction of aldehydes 51 and methyl/ethyl acetoacetates 106 in aqueous ammonium carbonate at 55-60 °C (Scheme 35) [88]. Recently, a similar study has also been carried out by Yang and coworkers to obtain dihydro-pyridines [89]. Another example of dihydro pyridine ring formation in water employs methyl/ethyl acetoacetates and aromatic aldehydes with 6-amino-l,3-dimethyluracil in the presence of thiourea dioxide as the catalyst [90]. The utilization of water as a solvent and indium(III) chloride as a promoter for the formation of dihydropyridine ring is reported by Khurana and coworkers in the reaction of with 6-amino-l,3-dimethyluracil, aldehydes, and 1,3-diketones [91]. 

The basic discovery of the transition-metal-mediated pyridine ring formation between C=N and alkynes was reported by Wu et al. in 1986 (Scheme 19.2) [1]. 

Based on these precedents for C—X bond formation between C=N and alkene intermediates (derived from alkynes), the Larock group developed the first transition-metal-mediated pyridine ring formation by direct reaction between C=N and alkynes. Using terminal alkynes 11, rcrt-butylimines 10 were subjected to Sonogashira coupling followed by Cu(I)-catalyzed annulation to afford isoquinolines or pyridines 12 in moderate to good yields (46 to 95%, Scheme 19.5) [5]. A variety of terminal alkynes and aryl/alkenyl halides can be used in the reaction. The stepwise reaction also worked well to form the same products. Similarly, p- and y -carbolines were synthesized effectively, as shown in Scheme 19.6 [6]. 

Gabriele et al. reported a transition-metal-catalyzed pyridine ring formation in 2007 [95]. Substituted quinolines 196 were synthesized efficiently by copper-catalyzed 6-endo-dig cyclization and dehydration of alkynylanilines 195 (Scheme 19.50). The reaction of silylated alkynes (R" = TMS) can also be catalyzed by Pdl2/KI to give quinolines 196a by a cyclodehydration-desilylation sequence. When the palladium-catalyzed reaction was carried out in the presence of CO and MeOH under oxidative conditions, the alkynes 195 were converted selectively into quinoline-3-carboxylic esters 197 in good yields. Quite interestingly, under nonoxidative... 

Oda, K., Nakagami, R., Nishizono, N., and Machida, M., Pyridine ring formation through the photoreaction of arenecarbothioamides with diene-conjugated carbonyl compounds,/. Chem. Soc., Chem. Commun., 2371,1999. 

Finally, a novel synthetic route involves formation of the pyridine ring from a fused pyran intermediate, e.g. (139) - (140) (70CB1250, 80JOC1918, 73JCS(P1)823). If a pyrylium salt is used, a quaternary pyridopyrimidinium salt such as (141) is formed 77KGS14S4). 

Reactions involving quinoline hydrazide derivatives have been noted in the pyridazino-[4,3-c]- (64MI21500), -[4,5-f ]- (31M(58)238) and -[4,5-c]-quinoline (71CB3341) series, whilst the double cyclization of (358) to the pyridazino[4,5-f ]quinoline (359) (80CPB3457) and related cyclizations in the same series (80H(14)267) are of a basically similar type. A lone cyclization of this type from cinnoline intermediates involves the o-acetonylcarboxamide type formation of the pyridine ring to give the pyrido[3,4-c]cinnoline (360) (76JCS(Pl)592). 

Reduction of isoindoles with dissolving metals or catalytically occurs in the pyrrole ring. Reduction of indolizine with hydrogen and a platinum catalyst gives an octahydro derivative. With a palladium catalyst in neutral solution, reduction occurs in the pyridine ring but in the presence of acid, reduction occurs in the five-membered ring (Scheme 38). Reductive metallation of 1,3-diphenylisobenzofuran results in stereoselective formation of the cw-1,3-dihydro derivative (Scheme 39) (80JOC3982). 

As foretold in the introduction, ring formation via attack on a double bond in the endo-trig mode is not well exemplified. The palladium(II) catalyzed oxidative cyclization of o-aminostyrenes to indoles has been described (78JA5800). The treatment of o-methyl-selenocinnamates with bromine in pyridine gives excellent yields of benzoselenophene-2-carboxylates (Scheme 10a) (77BSF157). The base promoted conversion of dienoic thioamides to 2-aminothiophenes is another synthetically useful example of this type (Scheme 10b) (73RTC1331). 

The formation of cotar none from cotar nine methine methiodide by the action of potash (IX—X) led Roser to represent cotarnine and its salts by the following formulae, the loss of a molecule of water in the formation of cotarnine salts being explained by the production of a partially reduced pyridine ring, which is fully hydrogenated in the reduction of cotarnine to hydrocotarnine. In the reverse process, oxidation of liydrocotarnine to cotarnine, Roser assumed the scission of the ring at the point indicated, with the formation of a hydration product, and oxidation of the latter to cotarnine thus —... 

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

It has been shown that acetamidothiophenes 22 can be converted to either chlorothieno[2,3-h]pyridines 23 or chlorothieno[2,3-h]pyridinecarboxaldehydes 24 using POCI3 and DMF by appropriate choice of reaction conditions. However, unlike the acetanilides, initial ring formylation rather than side-chain formylation is believed to lead to the formation of the pyridine ring. These reactions have been extended to the synthesis of the isomeric thieno[3,2-I>]- and thieno[3,4-I>]pyridines, 25 and 26, from 3-acetamidothiophene and 3-acetamido-2,5-dimethylthiophene, respectively. 

Ring closure of 2-chloro-l-phenethylpyridinium ion (247) (prepared in situ) to l,2-dihydro-3,4-benzoquinolizium ion involves intramolecular nucleophilic displacement of the chloro group by the phenyl 77-electrons. A related intermolecular reaction involving a more activated pyridine ring and more nucleophilic 7r-electrons is the formation of 4-( -dimethylaminophenyl)pyridine (and benzaldehyde) from dimethylaniline and 1-benzoylpyridinium chloride (cf. Section III,B,4,c). 

Cyclization of the 5-(A -arylcarboxamido)-4-hydrazino-6methylpyrim-idin-2-ones 104 with two molar equivalents of formaldehyde in the presence of pyridine caused the concomittant triazole and pyrimidine ring formation to yield the 4-aryl-l,3,4,10-tetrahydro-6-methyl-l,2,4-tria-zolo-[2,3,4-c,d]pyrimido[4,5-d]pyrimidine-5,8-diones 105 (89AP599)... 

Extension of this work by studying the reaction of 3-methyl-5-nitro-pyrimidin-4(3//)-one with -X-arylketones in the presence of ammonium acetate surprisingly revealed the formation of a mixture of 4-arylpyrimidines and 6-arylpyridin-2(l//)-ones (00JCS(P1)27). The ratio between pyridine and pyrimidine formation is dependent on the substituent X. With electron-donating substituents the formation of the pyridin-2(l//)-ones is favored, with electron-attracting substituents the formation of the pyrimidine derivatives (Scheme 21) In the formation of the 6-arylpyridin-2(l//)-ones the C-4- C-5-C-6 part of the pyrimidone-4 is the building block in the construction of the pyridine ring. Therefore, the pyrimidone can be considered as an activated o -nitroformylacetic acid (Scheme 21). 

The key intermediate 21 is in principle accessible in any of several ways. Thus reaction of thiophenecarbox-aldehyde with amninoacetal would lead to the Schiff base 20 treatment with acid would result in formation of the fused thiophene-pyridine ring (21). Alkylation of that intermediate with benzyl chloride gives the corresponding ternary imini urn salt 23. Treatment with sodium borohydride leads to reduction of the quinolinium ring and thus formation of ticlopidine (24). ... 

O-isopropylidene derivative (57) must exist in pyridine solution in a conformation which favors anhydro-ring formation rather than elimination. Considerable degradation occurred when the 5-iodo derivative (63) was treated with silver fluoride in pyridine (36). The products, which were isolated in small yield, were identified as thymine and l-[2-(5-methylfuryl)]-thymine (65). This same compound (65) was formed in high yield when the 5 -mesylate 64 was treated with potassium tert-hx Xy -ate in dimethyl sulfoxide (16). The formation of 65 from 63 or 64 clearly involves the rearrangement of an intermediate 2, 4 -diene. In a different approach to the problem of introducing terminal unsaturation into pento-furanoid nucleosides, Robins and co-workers (32,37) have employed mild base catalyzed E2 elimination reactions. Thus, treatment of the 5 -tosylate (59) with potassium tert-butylate in tert-butyl alcohol afforded a high yield of the 4 -ene (60) (37). This reaction may proceed via the 2,5 ... 

After reduction of the nitro function of the porphyrin, the porphyrinamine intermediate can be reacted with z./l-unsaturated carbonyl compounds to yield porphyrins with a fused pyridine ring, which is formed by Michael addition, imine formation and dehydrogenation. 

The transformation of isoquinoline has been studied both under photochemical conditions with hydrogen peroxide, and in the dark with hydroxyl radicals (Beitz et al. 1998). The former resulted in fission of the pyridine ring with the formation of phthalic dialdehyde and phthalimide, whereas the major product from the latter reaction involved oxidation of the benzene ring with formation of the isoquinoline-5,8-quinone and a hydroxylated quinone. 

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