Pyridines with acetylenic esters

Pyridine-Derived Enamines and Related Ylids with Acetylenic Esters... 

Pyridine, and its monomethyl and 3,5-dimethyl derivatives " combine exothermically with dimethyl acetylenedicarboxylate in ether yielding some ether soluble materials, including trimethyl pyrrocoline-1,2,3-tricarboxylate (Section III,F,3) and deep red ether-insoluble gums. A number of crystalline compounds have been isolated from these gums by fractional crystallizations and will now be considered in detail. In the case of pyridine, Diels et al. ° isolated a red labile 1 2 molar adduct, which they formulated as (75), which isomerized rapidly on standing to a yellow stable adduct (76). These formulations are no longer accepted. Diels and Alder also suggested that the acetylenic ester first dimerized to the diradical (74) which then combined with the pyridine. 

Other products commonly isolated from reactions of DMAD with heterocycles include dimethyl fumarate (17), the acetylene presumably acting as a dehydrogenating agent, and dimethyl methoxyfumarate (18).22 The latter could arise from the addition of methanol, present as an impurity, to the acetylene, or by nucleophilic attack on the carbonyl group of the acetylenic ester followed by expulsion of methoxide ion, which then undergoes a normal nucleophilic addition to the activated triple bond. It can be obtained, among other products, from the reaction of pyridine with DMAD in methanol.23... 

To make rosoxacin two heterocyclic systems must be constructed. Workers at the pharmaceutical company Sterling decided to build the pyridine in an ingenious version of the Hantzsch synthesis using acetylenic esters on 3-nitrobenzaldehyde. The ammonia was added as ammonium acetate. Oxidation with nitric acid made the pyridine, hydrolysis of the esters and decarboxylation removed the acid groups, and reduction with Fe(TT) and HC1 converted the nitro group into the amino group required for the quinolone synthesis. 

In tetrahydrofuran the dihydrofurans 8 (X = O, n = 1) react with maleic anhydride at room temperature to yield pyrano[4,3-c]pyridines 205 via a complex addition-rearrangement scheme123 involving betaine 206 (Scheme 51). Furthermore, in the formation of the naphthyridines 207 and 208 from 13 and acetylenic esters or methyl acrylate, the first step consists of a Michael-type attack on the electron-rich C-3116 (Scheme 52). 

Imidazo[2,l-h]thiazolium-3-olate 160 (Section VI,C Scheme 47) underwent rapid cycloaddition with acetylene mono- and dicarboxylic esters to give the imidazo[l,2-a]pyridin-3-yl acyclo C-nucleoside 208 through sulfur extrusion from the intermediate 207 (91MI7) (Scheme 62). 

Adib has shown that pyridines undergo reaction with dialkyl acetylenedicarboxylates in the presence of isocyanates to produce functionalized 2-oxo-l,9a-dihydro-2//-pyrido[l,2-ajpyrimidines 43 in good yield <04TL1803>. The author postulates that the reaction proceeds through initial reaction of the pyridine 44 with the acetylenic ester 45, and the resulting anion then attacks the isocyanate 46 to yield a zwitterionic intermediate. The nitrogen of the zwitterionic intermediate adds to the pyridinium moiety thus generating the pyrido[l,2-a]pyrimidines 43. 

The 1,3-dipolar cycloaddition of pyridine N -unsubstituted N-imines with activated dipolarophiles such as acetylenic esters,58,120,182,184 ketones,185 and nitriles,186 ethyl acetoacetate,154,159 acetylacetone (Section IV.A.6.),154 /J-haloacrylates,54,159 and nitriles138 provides particularly facile entries to many pyrazolo[l,5-a]pyridines and triazolo[l,5-a]pyridines (Eq. 28). 

Nitrogen heterocycles Various cyano-substituted pyridines have been described. They were prepared from 10 and ethyl cyanoacetic ester, and from 10 and acetylenic esters or ketones ". Aromatic aldehydes (e.g. 2-furyl, 4-pyridyl, and 2-thienyl aldehydes) have been condensed with 10 and aromatic ketones to yield 2-amino-3-pyridinecarbonitriles. Benzylidenemalononitrile (43) reacted with 10 in aniline to yield dicyanopyridine 44. ... 

The gas-phase equilibrium between 2-hydroxypyridine and 2-pyridone favours the hydroxy-form, but in the equilibrium between 2-hydroxypyridine iV-oxide and N-hydroxy-2-pyridone, the major tautomer is the hydroxy-pyridone. Bicyclic adducts between 2-pyridones and dimethyl acetylene-dicarboxylate, unobtainable at atmospheric pressure, have been obtained at 10—15 kbar. A novel route to iV-hydroxy-2-pyridone involves the trimethyl-silylation of 2-pyridone followed by oxidation of the resulting 2-(trimethyl-silyloxy)pyridine with the DMF complex of molybdenum pentoxide. p-Nitro-phenols (45) and nitro-acetamides (46) are formed from the reaction of 3,5-dinitro-2-pyridones (43) with the sodium salts of /3-keto-esters (44) (Scheme 20). ... 

Zinc enolate 4, prepared from acetylene ether pyridine i-oxide, mercuric chloride, and zinc, adds to aldehydes to form a-chloro-3-hydroxy esters 5 in good yields ( ). Subsequent treatment with base gives trans-epoxyesters, one of which 6 is converted to 2-amino-2-deoxy-D-ribose stereoselectively in good yields (O. 

Undheim and Riege267 obtained 1 1 adducts from pyridine-2-thiones (60) and acetylenic amides, esters, and ketones. The reaction rate increases with increase in activation of the acetylenic bond by the adjacent carbonyl group and is affected by the pyridine 6-substituent, which may also affect the stereochemical course. Product-isomer ratios corresponding to kinetic control were obtained in chloroform. Amides gave E isomers, ketones gave Z, and esters a slight preponderance of the E isomers (61). Successive addition of n-butyllithium and DMAD to... 

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