Pyridine acetylenedicarboxylate

Like pyridines (334), thiazoles undergo addition reactions with dimethyl acetylenedicarboxylate leading to 2 1 molar adducts, the structure of which has been a matter of controversy (335-339). 

Paal-Knorr synthesis, 4, 118, 329 Pariser-Parr-Pople approach, 4, 157 PE spectroscopy, 4, 24, 188-189 photoaddition reactions with aliphatic aldehydes and ketones, 4, 232 photochemical reactions, 4, 67, 201-205 with aliphatic carbonyl compounds, 4, 268 with dimethyl acetylenedicarboxylate, 4, 268 Piloty synthesis, 4, 345 Piloty-Robinson synthesis, 4, 110-111 polymers, 273-274, 295, 301, 302 applications, 4, 376 polymethylation, 4, 224 N-protected, 4, 238 palladation, 4, 83 protonation, 4, 46, 47, 206 pyridazine synthesis from, 3, 52 pyridine complexes NMR, 4, 165... 

A number of other syntheses of coniine have been effected, of which that of Diels and Alder is of special interest. The initial adduct of pyridine and methyl acetylenedicarboxylate, viz., tetraraethylquinolizine-1 2 3 4-tetracarboxylate (IX) on oxidation with dilute nitric acid is converted into methyl indolizinetricarboxylate (X). This, on hydrolysis and decarboxylation, furnishes indolizine, the octahydro-derivative (XI) of which, also known as octahydropyrrocoline, is converted by the cyanogen bromide method (as applied by Winterfeld and Holschneider to lupinane, p. 123) successively into the broraocyanoamide (XII), cyanoaraide (XIII) and dZ-coniine (XIV). A synthesis of the alkaloid, starting from indolizine (pyrrocoline) is described by Ochiai and Tsuda. ... 

Dimethyl acetylenedicarboxylate gave first a similar adduct (2) which then added further molecules of furan yielding (3) and subsequently (4). Between 1931 and 1940 the reactions of acetylenedi-carboxylic acid and its dimethyl ester with a number of nitrogen containing heterocyclic compounds were examined, and structures were proposed for the products. Apart from an unpublished investigation of the products from pyridine and dimethyl acetylenedicar-... 

Pyridine and dimethyl acetylenedicarboxylate in methanol yield - a mixture of (33) and (34). It is tempting to assume that a zwitterion (30) is first formed and that this then adds a proton followed by a methoxide ion (Michael addition) under the influence of both the positive charge on the ring and the assisting ester group. The resulting structure (31) could then add another molecule of the ester and cyclize, as indicated, to (32). Subsequent aromatization accompanied by loss of one, or the other, substituent at position 3 would lead to the two products, (33) and (34), actually isolated. 

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. 

Diels and Meyer found that the exothermic reaction obtained on dropping pyridine into dimethyl acetylenedicarboxylate in methanol gave a mixture of the indolizine (108) and a methoxymethylindolizine formulated as (109), and some dimethyl fumarate and dimethyl methoxyfumarate. Later workers - obtained only the methoxymethylindolizine in rather poor yield. The indolizine (108) has also been isolated from the products obtained when the addition reaction was carried out in ether, but in this case the course of the reaction was very susceptible to the presence of impurities in the ether, and the results indicated that ethanol was necessary as a reactant. ... 

L. ZwiTTERioNs Derived from Pyridine, Pyrazine, Isoquinoline, and Dimethyl Acetylenedicarboxylate... 

The Diels-Alder adduct 4 of dimethyl acetylenedicarboxylate and the triazepine 3 undergoes rearrangement and elimination of methancthiol to give the pyrazolo[3,4-/ ]pyridine 5.342... 

Treatment of 1,2,4-triazines 91a-91e with the electron-deficient die-nophile dimethyl acetylenedicarboxylate gave products, depending on the substituents [77LA( 10) 1718]. Pyrrolo-[2, -/][ ,2,4]triazines 92 were obtained via [4 + 2]-cycloaddition [77LA(9)1413, 77LA( 10)1718] with 91, but interaction with 91b in the absence of solvent gave, in addition to 92, the pyrido[2,l-/][l,2,4]triazine 93 and [l,3]oxazino[2,3-/][l,2,4]-triazine 94. In case of 91a pyridine and benzene derivatives were also formed in addition to 92 (Scheme 23). 

As the Diels-Alder reactions of 2( lff)-pyrazinones with richly substituted acetylenes can be used to generate diversely substituted pyridines and pyridi-nones, these cyclo additions were investigated under microwave irradiation conditions on the 1,2,3-triazole decorated pyrazinone scaffold. As a proof of concept, the pyrazinones bearing a 1,4-disubstituted-1,2,3-triazole unit, linked via a C-0 bond, were reacted with the symmetrical dienophile dimethyl acetylenedicarboxylate (DMAD), in view of minimizing regioselect-ivity problems (Scheme 28). 

N-silylated imines 509 react with the Li salts of tosylmethylisonitriles to give 4,5-disubstituted imidazoles in moderate yields [93]. Acetylation of N-trimethylsilyl imines 509 with acetyl chloride and triethylamine affords 72-80% of the aza-dienes 510 these undergo readily Diels-Alder reactions, e.g. with maleic anhydride at 24 °C to give 511 [94] or with dimethyl acetylenedicarboxylate to give dimethyl pyridine-3,4-dicarboxylates [94] (Scheme 5.29). 

Imidazo[l,2-a]pyridines are formed by condensation of iV-arylacetylimidazoles with dimethyl acetylenedicarboxylate, [ 154H156]... 

As already described for the all-carbon-Diels-Alder reaction, a hetero-Diels-Alder reaction can also be followed by a retro-hetero-Diels-Alder reaction. This type of process, which has long been known, is especially useful for the synthesis of heterocyclic compounds. Sanchez and coworkers described the synthesis of 2-aminopyridines [48] and 2-glycosylaminopyridines 4-144 [49] by a hetero-Diels-Alder reaction of pyrimidines as 4-143 with dimethyl acetylenedicarboxylate followed by extrusion of methyl isocyanate to give the desired compounds (Scheme 4.30). This approach represents a new method for the synthesis of 2-aminopyridine nucleoside analogues. In addition to the pyridines 4-144, small amounts of pyrimidine derivatives are formed by a Michael-type addition. 

Reaction of pyridines with dialkyl acetylenedicarboxylates in the presence of isocyanates in dry CH2C12 at room temperature produced 1-substituted 2-oxo-l,9a-dihydro-2/7-pyrido[l,2-tf]pyrimidine-3,4-dicarboxylates <2004TL1803>. One-pot, three-component synthesis of 1-substituted 2-oxo-l,llb-dihydro-2//-pyrimido[2,l- ]iso-quinoline-3,4-dicarboxylates and 4-(3-chloro-4-methylphenyl)-3-oxo-4,4a-dihydro-3/7-pyrimido[l,2-tf]quinoline-l,2-dicarboxylate was realized by the reaction of isoquinoline and quinoline with isocyanates and dialkyl acetylenedicarboxylates <2004S861>. Diastereomeric mixtures of l-tosyl-2-aryl-l,llb-dihydro-2/7-pyrimido[2,Ttf]isoquinoline-3,4-dicarboxylates were obtained from isoquinoline, iV-tosyl-benzaldehyde imines, and DMAD <2002OL3575>. 

Treatment of 3-(2-pyrrolidino)pyridine with 2 molar equiv of diethyl acetylenedicarboxylate under microwave conditions gives the tetrahydropyrrolonaphthyridine 283 and (presumably) diethyl maleate or fumarate. Under conventional heating conditions, decarboxylated products are also observed (Scheme 71) <2005TL3953>. 

Reactivity of azides towards acetylenedicarboxylates is very dependent on their electron density (energy HOMO). Thus, strongly electron-deficient 3,5-dicyano-2,4,6-triazidopyridine 1039 reacts slowly with dimethyl acetylenedicarboxylate to give triazole derivative 1038 in 34% yield with most of the starting material recovered unchanged. Under comparable conditions, less electron-deficient 3,5-dichloro-2,4,6-triazidopyridine 1040 reacts with dimethyl acetylenedicarboxylate to provide 2,6-bis(l,2,3-triazol-lyl)pyridine derivative 1041 in 75% yield (Scheme 171) <2001CHE861>. 

A recent method for the synthesis of the indolizine skeleton is represented by a three-component reaction between a-bromo ketones 16, pyridine 17, and ethyl propiolate or diethyl acetylenedicarboxylate. These three reagents, under microwave irradiation and catalysis by basic alumina, afforded a good variety of 3-aroyl indolizines 18 <20030L435> (Scheme 4). 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dUiydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl yhdes generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desUylation (31,53,129) protocol as well as the reaction with 1,3-dithiohum-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (5)-methylides formed by the N2-extmsion or desilylation method leads to stable 2,5-dUiydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

In a reinvestigation of earlier work (33LA(505)103) by Diels and Alder, Acheson et al. (60JCS1691) established that the stable isomer obtained by addition of two moles of dimethyl acetylenedicarboxylate to one of pyridine was the 4/7-quinolizine (96) and that this with bromine was oxidized to a quinolizinium salt (97 Scheme 65). 4iT-Quinolizines obtained from isoquinoline (62JCS748) and phenanthridine (63JCS3888) were similarly aromatized to afford benzo[a]quinolizinium (98) and dibenzo[a,c]quinolizinium ions (99) respectively. 

Compound 1 fails to react with dimethyl acetylenedicarboxylate (DMADE) even after two years.25 At room temperature, 2-aminotriazolo-pyridine 295 gives a diadduct (296) with methyl propiolate and a tricyclic compound (297), which becomes the only isolated product on heating.269 Compound 3 reacts with DMADE to give the 3-substituted derivative 298.65... 

The ultraviolet absorption spectra have been used to distinguish between the tautomers obtained by addition of dimethyl acetylene-dicarboxylate to pyridines. The 4/f-quinolizines show a band around 265 mfi. which is missing from the spectra of the 9a/f-quinolizines. Acheson and Taylor26 have successfully used this information to settle the constitution of the stable and labile adducts obtained by the action of acetylenedicarboxylic esters on pyridines. The ultraviolet spectra of the stable adducts formed by the above methods show... 

Such reactions occur readily with alkynic esters, but the products isolated are often complex. Thus, the initial Michael adduct of type (68) from pyridine with acetylenedicarboxylic ester reacts with more alkynic ester to yield (66), (67) and other products. Quinoline and isoquinoline react similarly. 

Indolizines can also be produced from pyridine and acetylenedicarboxylic ester (Section 3.2.1.3.7). 

A convenient synthesis of thieno[3,2-6]pyridines using the enamine (299), prepared in high yield by the Michael addition of (293) to dimethyl acetylenedicarboxylate, has been described (equation 26) (78JCR(S)393). The cyclization to (300) is effected by sodium hydride in DMF. 

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. 

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