Acetylene pyridine synthesis

STEVENS REARRANGEMENT-ELIMINATION Dialkylcarbonium fluoroborates. SUCCINOYLATION Succinic anhydride. SULFONATION Sulfur trioxide-Pyridine. SYNTHESIS OF ACETYLENE Trimethyl-ailyldiazomethane. 

The reaction proceeds through initial Diels-Alder reaction of 2-pyrazinones 4 with an acetylene forming bicyclic intermediate 5. This is followed by spontaneous elimination of cyanogen chloride or an isocyanate to obtain 2-pyridone 6 and pyridine 7, respectively. Additionally, continuous flow reactors have been designed for microwave reactions, which improve the energy efficiency. The eontinuous flow microwave reaction was illustrated using a mierowave assisted Bohlmann-Rahtz pyridine synthesis <05JOC7003>. 

Pyridine synthesis. This organometaUic reagent catalyzes the reaction of acetylene and monosubstituted acetylenes with nitriles to form pyridines (equations I and II). Disubstituted acetylenes do not undergo this reaction. 

Pyridines.—Synthesis. A full report on the synthesis of pyridones from acetylenic alcohols and N-cyanopyrrolidine, noted in Volume 7 of Aromatic and Heteroaromatic Chemistry , has appeared.2-Imino-l,2-dihydropyridines (1)... 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

The final steps in a total synthesis of (+ )-gloeosporone (3, a natural germination inhibitor of a fungus) required oxidation of the acetylene group of 1 to a diketone group. The oxidation was carried out in 74% yield by the catalytic Ru02 procedure of Sharpless. On liberation (pyridine-HF) of the C7-hydroxyl group, the hydroxy... 

The cobalt-catalyzed synthesis enables 2,2 -dipyridyl to be prepared directly from 2-cyanopyridine and acetylene in a 72% yield with a cyanopy-ridine conversion of 21%. The pyridine benzene ratio in the product is 2.7 1 [Eq.(18)]. 

A number of routes are available for the synthesis of 2,2 -bipyridines where one of the pyridine rings is built up from simpler entities. For example, condensation of 2-(aminomethyl)pyridine (31) with acetaldehyde or acetylene over a silicon-alumina catalyst at 450°C gives 2,2 -bipyridine, ° whereas 2-cyanopyridine reacts with acetylene at 120°C in the presence of a cobalt catalyst to afford 2,2 -bipyridine in 95% yield.2-Acetylpyridine with acrolein and ammonia gives 2,2 -bipyridine in the presence of dehydrating and dehydrogenating catalysts, and related condensations afford substituted 2,2 -bipyridines. ° In a similar vein, condensation of benzaldehyde with 2 mol of 2-acetylpyridine in the presence of ammonia at 250°C affords 2,6-di(2-pyridyl)-4-phenylpyridine, ° and related syntheses of substituted 2,2 6, 2"-terpyridines have been described. Likewise, formaldehyde with two moles of ethyl picolinoylacetate and ammonia, followed by oxidation of the product and hydrolysis and decarboxylation, affords a good... 

Zinc chloride-doped natural phosphate was shown to have catalytic behavior in the 1,3-dipolar cycloadditions of nucleoside acetylenes with azides to form triazolonucleosides <99SC1057>. A soluble polymer-supported 1,3-dipolar cycloaddition of carbohydrate-derived 1,2,3-triazoles has been reported <99H(51)1807>. 2-Styrylchromones and sodium azide were employed in the synthesis of 4(5)-aryl-5(4)-(2-chromonyl)-1,2,3-triazoles <99H(51)481>. Lead(IV) acetate oxidation of mixed bis-aroyl hydrazones of biacetyl led to l-(a-aroyloxyarylideneamino)-3,5-dimethyl-l,2,3-triazoles <99H(51)599>. Reaction of 1-amino-3-methylbenzimidazolium chloride with lead(fV) acetate afforded l-methyl-l/f-benzotriazole <99BML961>. Hydrogenation reactions of some [l,2,3]triazolo[l,5-a]pyridines, [l,2,3]triazolo[l,5-a]quinolines, and [l,2,3]triazolo[l,5-a]isoquinolines were studied <99T12881>. 

Commercial development of a range of cycloalkene-cobalt homogeneous catalysts has prompted their application in the synthesis of pyridine and 2-substituted pyridines. Thus, bis(cyclopentadienyl)cobalt catalyzes the reaction of acetylene with hydrogen cyanide, acetonitrile or acrylonitrile to yield pyridine, 2-methylpyridine and 2-vinylpyridine respectively (Scheme 4 R = H, Me or CH=CH2) (76S26, 78AG(E)505, 75BEP846350). The high cost of the catalyst has so far limited full commercial realization of this route. Acrylonitrile... 

The synthesis of 2-arylbenzofurans 226 by heterocyclic ring closure of acetylenic compounds 225 with pyridine hydrochloride is a variation487 of the general method of heterocyclic ring closure of acetylenic compounds 221. 

Much recent work has been done on the synthesis of pyridines from alkynes and nitriles over cobalt catalysts. For example, 2-vtnylpyndine has heen obtained in good yield from acetylene and acrylonitrile using a cyclopentadienyl-cobalt catalyst. Pyridine has also been obtained from cyclopentadiene and ammonia over a sihca/alumina catalyst. 

Bora and co-workers44 have developed a microwave-assisted three-component synthesis of indolizines. The reaction involves a 1,3-dipolar cycloaddition reaction between the in situ generated dipole (from the bromoacetophenone and pyridine) and acetylene, Scheme 5.26. The developed method provides fast access to cycloadducts, which otherwise are accessible only through multi-step synthesis. 

Among the important reagents for which preparative procedures are given are 2,2 -bipyridine (by nickel directed and catalyzed dehydrogenation of pyridine p. 5), formamidine acetate (p. 39), phenyltrichloromethylmercury (p. 98), and trimethyl- and triethyloxonium fluoroborate (pp. 120, 113). The preparation of palladium catalyst ( Lindlar ) for the selective reduction of acetylenes is described (p. 89), as is the use of di-phenyliodonium-2-carboxylate, as a precursor of benzyne in the synthesis of 1,2,3,4-tetraphenylnaphthalene (p. 107). 

The reaction of pyridines and picolines with acetylenic compounds provides a useful synthesis of indolizines.48 The reaction of such compounds with dimethyl acetylenedicarboxylate (DMAD), originally investigated by Diels and co-workers (see Ref. 4) has been reexamined more recently by several groups.48-52 The two major adducts are now thought to be the quinolizines 26 and 27, although Wiley and Knabeschuh63 obtained the indolizine triester 28 when the reaction was carried out in ether as solvent. The adduct of type 27 is oxidized by nitric acid to 28. 

An attempt to reproduce the synthesis of O-vinyloximes (70ZOR2146) from oximes and acetylene in an aqueous solution by generating acetylene in situ from calcium carbide, gave pyridines instead of the expected products (75KGS1427). 2,4,6-Trimethylpyridine (105), for example, was obtained from acetoxime in 10% yield. 

The reaction was carried out at 200-220°C in a rotating autoclave for 8 hr. Maximum pressure developed in the course of synthesis is 27 atm. Under these conditions, when acetylene instead of CaC2 is used, the yield of pyridines grows to 20-30% (80KGS1299 84MI1). Thus, from cyclohexanone oxime 6-methyl-l,2,3,4,6,8,9,10-octahydrophenanthridine (106) can be prepared. 

A modified procedure illustrated by the synthesis of a diynediol (Expt 5.27) from the acetylenic alcohol, 2-methylbut-3-yn-2-ol, uses methanol and pyridine as the solvent, the latter acting also as a complexing agent for the copper(i) ions. An alternative effective coupling system involves the use of copper(n) acetate in pyridine which does not require the use of air or oxygen. 

The triple bond of the nitrile group can be cotrimerized with two alkynes to produce pyridines. The cobalt-catalysed cocyclization of alkyne and nitrile in a ratio of 2 1 is a good synthetic route to pyridine derivatives [70], Two regioisomers, 174 and 175, are obtained by the reaction of propyne with MeCN. The reaction is carried out in a large excess of MeCN, and potentially useful for commerical production of pyridine derivatives [71]. The reaction of acetylene itself with various nitriles produces the a-substituted pyridine 176 in the presence of water under irradiation [72], HCN cannot be used for this cocyclization. The reaction has been applied to alkaloid synthesis. 

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