Acetylenedicarboxylic acid cycloaddition reactions

Esters of acetylenedicarboxylic acid 1023 are commercially readily available, are very reactive as dipolarophiles, and the carboxylic groups in products of their reactions can be easily converted to many other functionalities. Therefore, they are often the first choice as substrates for 1,3-dipolar cycloaddition to azides 1024 (Huisgen reaction). The reactions are carried out at room or elevated temperature, and the yields of 1,2,3-triazoles 1025 are usually high to quantitative (Equation 22). Several products obtained in this way are presented as structures 1026-1034. Some details about the reactions leading to these products are given in Table 10. 

Tominaga and coworkers322 prepared dimethyl dibcnzo (t,/j]cycl[3.2.2]azinc-l,2-dicar-boxylate (553) by an [8 + 2] cycloaddition reaction of 1 -cyanoisoindolo[2,1-a isoquinoline (552) with dimethyl acetylenedicarboxylate (57), followed by elimination of HCN. A small amount of acetic acid was added to improve the yield of the reaction from 1% to 26%. The double adduct 554 was isolated in minor amounts (equation 159). 

We were not able to obtain any cycloadduct from unactivated 2-azadienes 139 and esters of acetylenedicarboxylic acid. However, we found that 139 did cycloadd to typical electron-poor dienophiles such as esters of azodicarboxylic acid and tetracyanoethylene (Scheme 62). Thus, diethyl and diisopropyl azodicarboxylates underwent a concerted [4 + 2] cycloaddition with 139 to afford in a stereoselective manner triazines 278 in 85-90% yield (86CC1179). The minor reaction-rate variations observed with the solvent polarity excluded zwitterionic intermediates on the other hand, AS was calculated to be 48.1 cal K 1 mol-1 in CC14, a value which is in the range of a concerted [4 + 2] cycloaddition. Azadienes 139 again reacted at room temperature with the cyclic azo derivative 4-phenyl-1,2,4-triazoline-3,5-dione, leading stereoselectively to bicyclic derivatives 279... 

The last factor often is the one that determines the reaction rates of [4+2]-cycloadditions. This factor allows one to understand, for example, why the cycloadditions of ethene or acetylene with butadiene (cf. Figure 15.1) occur only under rather drastic conditions, while the analogous cycloadditions of tetracyanoethene or acetylenedicarboxylic acid esters are relatively rapid. As will be seen, a simple orbital interaction between the reagents at the sites where the new a bonds are formed is responsible for this advantageous reduction of the activation energies of the latter two reactions. 

Triethyl l,3,5-triazine-2,4,6-tricarboxylate and 2,4,6-tris(methylsulfanyl)-1,3,5-triazine react in an inverse electron demand Diels-Alder reaction with several electron-rich dienophiles.6 The tricarboxylate 9 (R1 = C02Et) undergoes a well-defined [4 + 2] cycloaddition reaction with ynamines and enamines. In the case of ynamines, the [4 -1- 2] cycloaddition is followed by a retro Diels - Alder reaction at 40 100 °C with direct formation of the substituted pyrimidines 11. In the case of enamines, the cycloaddition provides stable, isolable [4 + 2] adducts 12. The subsequent retro Diels-Alder reaction and the final aromatization step is catalyzed by a mixture of hydrochloric acid and dioxane, anhydrous p-toluencsulfonic acid or acetic acid. This two-step process can be reduced to a single operation by conducting the reaction in a solution of dichloromethane and acetic acid at 40-100 °C.6 Electron-deficient dienophiles like dimethyl acetylenedicarboxylate or 1,4-naphthoquinone do not react with this triazine. 

Like the esters of acetylenedicarboxylic acid (6), dicyanoacetylene (2) has often been employed in cycloaddition reactions it participates in Diels-Alder and 1,3-dipolar cycloadditions, and ene reactions as well as homo additions are also known [9,11], Although kinetic measurements with 2 seem not to have been performed so far, from working knowledge it appears that 2 is a more reactive dienophile than any other activated acetylene including hexa-... 

Acetic add, frons-cyclohexanediaminetetra-metal complexes, 554 Acetic add, ethylenediaminetetra-in analysis, 522 masking, 558 metal complexes, 554 Acetic acid, iminodi-metal complexes, 554 Acetic acid, nitrilotri-metal complexes titrimetry, 554 Acetoacetic add ethyl ester bromination, 419 Acetone, acetyl-deprotonation metal complexes, 419 metal complexes reactions, 422 Acetone, selenoyl-liquid-liquid extraction, 544 Acetone, thenoyltrifluoro-liquid-liquid extraction, 544 Acetone, trifluorothenoyl-in analysis, 523 Acetonitrile electrochemistry in, 493 exchange reactions, 286 metal complexes hydrolysis, 428 Acetylacetone complexes, 22 liquid-liquid extraction, 543 Acetylacetone, hexafiuorothio-metal complexes gas chromatography, 560 Acetylactone, trifluorothio-metal complexes gas chromatography, 560 Acetylation metal complexes, 421 Acetylenedicarboxylic add dimethyl ester cycloaddition reactions, 458 Acid alizarin black SN metallochromic indicator, 556 Actinoids... 

Another route from five-membered 0-heterocycles to oxepines uses 2,3-dihydrofurans as starting materials and involves their [2 -I- 2] cycloaddition reaction with ethyne or ethylene compounds, followed by cleavage of bicyclic compounds formed by thermolysis or Lewis acid catalysis <83CB1691, 87TL1501,92JOC5102). These transformations are presented in Scheme 29 by starting from dimethyl acetylenedicarboxylate and 2,3-dihydrofuran or its 5-substituted derivatives <87TL1501>. 

Removal of the allylic alkoxy group in the 2,3-diene, 2, was effected by treatment with sodium cyanoborohydride and dry hydrochloric acid in ethanol (55) [a similar process has recently been reported by Chapleur (36)] to afford compound 44 (Figure 13). Compound 44 underwent cycloaddition reaction with dimethyl acetylenedicarboxylate (DMAD) in refluxing toluene to give a mixture of two epimeric cycloadducts 45 and 46 in a 4 1 ratio. 

Atroposelective cycloaddition reactions of A-2-(r-butylphenyl)- and A-2,5-(di-r-butylphenyl)-maleimide show good to excellent stereoselectivities and the high rotation barriers prevent cycloadducts from interconverting. The stereospeciflc hetero-Diels-Alder reaction of o-quinone methides (80) with o-quinones (79) in MeOH at room temperature produce the 4a,8-di(hydroxymethyl)chromane derivatives (81) and (82) in high yields (Scheme 29). The intramolecular inverse-electron-demand Diels-Alder reaction of o-quinone methides (84) derived from 2-(l-hydroxy-5-alkenyl)phenol derivatives (83) produces l,2,3,3a,4,9b-hexahydrocyclopenta[c][l]benzopyrans (85) under mild acidic conditions (Scheme 30). The Diels-Alder reactions between dimethyl-cyclohexadiene derivatives and di-(-)-menthyl acetylenedicarboxylate exhibit modest diastereoselectivity. ... 

With electron-deficient acetylenes, the dithioate anions can be involved in the reactions of both 1,3-anionic cyclo- and nucleophilic additions [550], The reactions of 1,3-anionic cycloaddition are typical provided that the central atom of [S-C-S] has aromatic substituents ensuring the anion stabilization [551,552], For instance, potassium pyrrole-l-carbodithioate selectively reacts (acetonitrile, -30°C, CH3COOH) with dimethyl ester of acetylenedicarboxylic acid to form rapidly polymerizing 2-(pyrrol-l-yl)-4,5-dimethoxycarbonyl-l,3-dithiol (Scheme 2.80) [552,553]. 

Equimolar quantities of acetylenedicarboxylic acid esters (166) and 2-N-substituted l,3-dithiolan-2-imines (169) undergo a 1,3-dipolar cycloaddition, with elimination of ethylene, to yield A -thiazoline-2-thiones (168). The same products result from 2-alkylthio-l,3,4-thiadiazoline-5-thiones (167), with loss of alkyl thiocyanate as shown. They are desulphurized to the corresponding thiazolinones (172) by the action of mercuric acetate in acetone-acetic acid. They react with two further moles of the acetylenic reagent (166) to produce the spiranes (170 e.g. = R = COzMe), which are in turn desulphurized and cleaved by Raney nickel to the AMhiazoline derivatives (171). An analogous series of reactions was carried out using propiolic acid esters. ... 

A simple preparation of electron-poor 2-azadienes and the preliminary study of their ability to participate in [4 + 2] cycloadditions was done almost simultaneously by out group (87CC1195) (Scheme 49). The preparation of 2-azadienes 212 with two appended methoxycarbonyl groups was achieved, in a multigram scale and in nearly quantitative yield, by the insertion reaction of N- trimethylsilyl imines 210 into the carbon—carbon triple bond of dimethyl acetylenedicarboxylate to give 211 followed by protodesilylation with CsF/MeOH. Azadienes 212 underwent at room temperature inverse-electron demand [4 + 2] cycloaddition with cyclic enamines to give exclusively exo-cycloadducts 213 in 82-95% yield. Acid hydrolysis of them resulted in their aromatization to yield 2-pyrindine (n = 1] and isoquinoline (n = 2) derivatives 214. 

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