Pyridine reaction with dimethyl 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... 

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). 

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. 

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. 

Heath and Rees corrected the earlier conclusions of Potts et al. (66JOC265) and Sai et al. [81IJC(B)10] who had reacted 1,2,4-triazolo[4,3-a]pyridine with dimethyl acetylenedicarboxylate in boiling toluene and benzene. The latter believed that 3-substituted triazolopyridines 209 and 210 were the products. Heath and Rees repeated the experiments in refluxing benzene and in refluxing toluene both in the presence and absence of 5% palladium-on-charcoal, and showed that under all sets of conditions 3-cyano-4-oxo-4f/-pyrido[l,2-a]pyrimidine-2-carboxylate 212, 5-(2-pyridyl)pyrazole-3,4-dicarboxylate 213, and an adduct 211 were isolated from the complex reaction mixtures in 20%, 20%, and 1% yields, respectively (82CC1280). When the reaction was carried out in methanol, only 3-cyano-4-oxo-4//-pyrido[ 1,2-a]pyrimidine-2-carboxylate 212 was obtained... 

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

Neutral borabenzene complexes with pyridine undergo interesting addition processes. For example, the reaction of 74 with dimethyl acetylenedicarboxylate leads to the [4+2] adduct 27, a new borabarrelene derivative, via a Diels-Alder reaction in 90% isolated yield (Scheme 2) <2006OL2875>. Similarly, trapping of the borabenzene ring of 74 with in r(/ -generated benzyne affords the novel benzoborabarrelene 75 in 23% yield. The X-ray crystal stmcture of... 

Such reactions occur readily with alkynic esters, but the products isolated are often complex. Thus, the initial Michael adduct of type 79 from pyridine with dimethyl acetylenedicarboxylate reacts with a second equivalent of alkynic diester to yield 80, and thence 81 and other products. Quinoline and isoquinoline react similarly. 

Furthermore, it has been shown that compounds of type 235 are versatile starting materials for addition and cyclization reactions employing reactive triple and double bonds. With methyl propiolate, syn addition takes place to aiford the adducts 240. In the presence of alcohols, compounds 240 are cyclized to give the imidazo[l,2-a]pyridines and pyrido[l,2-a]pyrimidines 241136 (Scheme 63). By treatment with methyl acrylate, the lactone derivatives 235 give the spiro compounds 242 in an addition and cyclocondensation sequence.137 With dimethyl acetylenedicarboxylate, 235 forms several condensed and unsaturated spiro compounds 243, similar to 242,137 as well as the tricyclic 5-lactone 244 (Scheme 64). 

The independent observations of Neunhoeffer and Lehmann69 and Gompper and Heinemann70 that dimethyl acetylenedicarboxylate is sufficiently reactive to participate in an apparent Diels-Alder reaction with dimethyl 2,6-bis(dimethylamino)pyridine-3,4-dicarboxylate represents the first evidence that pyridine systems appropriately substituted with strong electron-donating groups (pyridyl C-2/C-6) may function as a 2-azadiene system in [4 + 2] cycloadditions with reactive, electron-deficient dienophiles [Eq. (13)]. 

The formation of pyridine IV-imines by an add-catalyzed rearrangement of some diazepinones and related compounds has been extensively investigated by Moore and co-workers (Eq. 9).115 The formation of pyridine N-imines from l/f-l,2-diazepines is also known (Eq. 10).68 69,116,117 Diels-Alder reactions of pyrazoles with dimethyl acetylenedicarboxylate, in the presence of BF3, have been reported to give IV-aminopyridinium salts (Eq. II).118 l,4-Dihydropyrido[l,2-a]-as-triazinium salts and their pyrimido derivatives undergo ring contraction in boiling aqueous acid, yielding 1-aminoimidazo[l,2-a]pyridinium and pyrimidinium salts, respectively (Eq. 

Only one synthetic approach has been reported in which a pyridine ring was elaborated onto a triazine. The reaction of (121) with dimethyl acetylenedicarboxylate gave several products, and the... 

The reaction of 3-imino-N,l,3-triphenylprop-l-enamine (14) with dimethyl acetylenedicarboxylate (DMAD) gives the pyridone (15). If the enamine is /8-disubstituted, as in compound (16), then initial attack occurs on the imine nitrogen rather than the enamine carbon. Electrocyclization followed by loss of aniline then yields the pyridine (17) (Scheme 8). ... 

Meso-lonlc Thiazolo[2,3-6]thiazoles.—Thiazoline-2-thione (179) reacts readily with 2-bromo-2-phenyIacetyl chloride in the presence of base (Scheme 16) to produce 2-phenylthiazolo[2,3-6]thiazolium-3-olate (180), which undergoes cycloaddition reactions with acetylenic and olefinic dipolarophiles in much the same way as (175). With dimethyl acetylenedicarboxylate, for example, the thiazolo(3,2-a]pyridin-5-one (181) is formed. ... 

A special kind of acylpyridinium compoimd may be the initial product in the reaction of ketenes with pyridine. From dimethylketene the isolated product is (79, R = Me). In the case of ketene itself, (79, R = H) is probably formed, but it undergoes further reaction . A possible sequence for the formation of compounds (79) involves initial attack at nitrogen, followed by nucleophilic substitution, as in the reaction of pyridine with dimethyl acetylenedicarboxylate ... 

The reactions of pyridines with dimethyl acetylenedicarboxylate continue to receive attentioni247, The structure of the product formed with ketene... 

In 2008, Jones et cd. disclosed a stoichiometric Rh(III)-mediated reaction of JV-benzylidenemethylamine with dimethyl acetylenedicarboxylate to give the corresponding isoquinolinium salt [52a]. Inspired by this work, in 2012 we developed a Rh(III)-catalyzed one-pot synthesis of isoquinolinium salts 104 from benzaldehydes, primary amines, and internal alkynes by C-H activation and annulation [52b]. This was the first report for the synthesis of isoquinohnium salts by catalytic C-H activation. It is noteworthy that the current procedure was successfully apphed to the total synthesis of isoquinolinone alkaloid oxy-chelerythrine 105 (Eq. (5.99)). In 2013, our group and Huang independently found that various isoquinohnium salts could be synthesized from aryl ketimines, 2-phenyl pyridines, and alkynes under similar reaction conditions, as shown in Eqs. (5.100)-(5.102) [52c-e]. 

Selenophens.— The preparation of selenophen by the action of sodium hydrogen selenide on bis(trimethylsilyl)butadiyne, Me3SiC=C—C=CSiMe3, has been described. The reaction of dimethyl acetylenedicarboxylate with the potassium salt PhC=CSe yields the ester (270), together with a little of the diselenole (271). Treatment of dibenzylideneacetone with selenium tetrabromide gives compound (272), which is converted into the benzoselenophen (273 R = COCH=CHPh) in the presence of pyridine.The ester (273 R = C02Et) has been obtained by cyclization of ethyl o-methylselenocinnamate (274) by means of bromine and pyridine. 

Several new examples of the reactivity of thioamides towards compounds containing activated carbon-carbon double or triple bonds have appeared. Thus little-known thiazine derivatives have been synthesized by treatment of primary thioamides with a -unsaturated ketones pyridine-2-thiones afforded, on treatment wi a-bromo-a 3-unsaturated acids or acetylenedicarboxylic acid, dihydrothiazolo[3,2-a]pyridinium salts, whereas die vinyl sulphides (263) were the products obtained in their reactions with propiolic or phenylpropiolic acid a Diels-Alder adduct was produced by the reaction of the thioamide (264) with dimethyl acetylenedicarboxylate. NN -Disubstituted phenylpropiolamidines (265),... 

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-... 

---