Methyl acetylenedicarboxylate

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. ... 

SnCLu Ti(OPr )2Cl2, and methyl acetylenedicarboxylate (MAD) (bis(2,6-/< r/-butyl-4-methylphenoxy)-methyl-aluminum) are most often used as LA. Meanwhile, nonconventional procedures, for example, the reaction in water (102 and references therein), can be used to perform cycloadditions of nitroalkenes. 

The inverse reaction to that described above and leading to the formation of an ylide by transformation of a phosphorane by thermodynamic evolution has also been observed212-214 (Scheme 40) the phosphorane 151, formed at — 50 °C by addition of P(OMe)3 to methyl acetylenedicarboxylate in the presence of MeOH to trap the 1,3-dipole, is rapidly transformed, at —20 °C, into the ylide 152. 

Arylnaphthalide lignans. A novel synthesis of these lignans involves in situ generation of an isobenzofurane (a) from a substrate such as I, which is trapped by a Diels-Alder reaction with methyl acetylenedicarboxylate. The adduct aromatizes lo u naphthol 2 in the presence of an acid. Selective reduction of the 3-... 

The analogous condensation of methyl acetylenedicarboxylate with substituted thiosemicarbazides leads to 2-imino-3-amino-6-carbomethoxyl-l,3-thiazin-4-ones (67CJC953). 

Another example of the trimethylenemethane type of compound is provided by the tricarbonyliron complex of heptafulvene. This complex undergoes a cycloaddition reaction with methyl acetylenedicarboxylate and the product can be converted into 1,2-dicarbomethyoxyazulene [Eq. (163) (Kerber and Ehntholt, 1973)]. 

The Diels-Alder reaction of the methyl ester of 2H-pyran-2-one-6-carboxyHc acid with methyl acetylenedicarboxylate leads to the 1,2,3-benzenetricarboxyhc ester 51 (hemimellitic triester), because the cycloadduct 50 undergoes thermal cycloreversion with elimination of CO2 [17] ... 

Diels-Alder addition product, from 1-methylpyrrole and maleic anhydride 2 is a further example of this sort of reaction. 2-Methylpyrrole behaves similarly, but the initial product (10) from pyrrole is obtained in small yield because it reacts further (p. 88). Pyrroles such as 2-methyl-, 1,2-dimethyl-and 2,4-dimethyl-pyrrole undergo similar Michael additions with methyl acetylenedicarboxylate s, 254 jn the third instance two molecules of the pyrrole reacting to form (11). 1-Methoxycarbonylpyrrole reacts at the 2-position with acetylene dicarboxylic acid254 as well as giving a Diels-Alder type of product (p. 82). With the same acid, ethyl 3,5-dimethylpyrrole-2-carboxylate undergoes Michael addition at the vacant jS-position giving (12). Other examples of reactions with dienophiles are discussed below... 

The formation from pyrroles and dienophiles of substances which are the results of Michael addition has been mentioned (p. 70). In some cases Diels-Alder addition does occur. Thus, with methyl acetylenedicarboxylate, methyl pyrrole-1-carboxylate gives (50), formed by elimination of acetylene from the initial Diels-Alder product . From 1-methylpyrrole, (51) is obtained , formed from the initial Diels-Alder product by reaction with a second molecule of methyl acetylenedicarboxylate . 1-Benzylpyrrole... 

Danishefsky s diene with methyl acetylenedicarboxylate gives the phenol, dimethyl 4-hydroxy-<9-phthalate on hydrolysis. 

As illustrated in Scheme 8.1, both 2-vinylpyrroles and 3-vinylpyiroles are potential precursors of 4,5,6,7-tetrahydroindolcs via Diels-Alder cyclizations. Vinylpyrroles are relatively reactive dienes. However, they are also rather sensitive compounds and this has tended to restrict their synthetic application. While l-methyl-2-vinylpyrrole gives a good yield of an indole with dimethyl acetylenedicarboxylate, ot-substitiients on the vinyl group result in direct electrophilic attack at C5 of the pyrrole ring. This has been attributed to the stenc restriction on access to the necessary cisoid conformation of the 2-vinyl substituent[l]. 

The reaction of methyl propiolate (82) with acyclic enamines produces acyclic dienamines (100), as was the case with dimethyl acetylenedicarboxylate, and the treatment of the pyrrolidine enamines of cycloheptanone, cyclooctanone, cycloundecanone, and cyclododecanone with methyl propiolate results in ring enlargement products (100,101). When the enamines of cyclohexanone are allowed to react with methyl propiolate, rather anomalous products are formed (100). The pyrrolidine enamine of cyclopentanone forms stable 1,2-cycloaddition adduct 83 with methyl propiolate (82). Adduct 83 rearranges to the simple alkylation product 84 upon standing at room temperature, and heating 83 to about 90° causes ring expansion to 85 (97,100). 

Vinyl ethers undergo many cycloaddition reactions similar to those which take place with enamines. In general, however, these cycloaddition reactions with vinyl ethers take place less readily than those with enamines. These reactions include cycloaddition of vinyl ethers with ketene (200-205), phenyl isocyanate (206), sulfene (207,208), methyl acrylate (209), diethyl acetylenedicarboxylate (210), and diphenylnitrilimine (183). 

Pyrroles react at free a- or -positions with acetylenedicarboxylic acid or the methyl ester yielding mixtures of the corresponding maleic and fumaric acid derivatives. Protons are readily available to satisfy... 

Methyl pyrrole-l-carboxylate (14) and hot dimethyl acetylenedi-carboxylate give trimethyl pyrrole-1,3,4-tricarboxyIate (15) and acetylene, presumably through the addition-elimination sequence shown. Dimethyl acetylenedicarboxylate and 1-methylpyrrole com-... 

Diels et al. showed that acetylenedicarboxylic acid and 1-methyl-pyrrole gave l-methyl-2-pyrrylmaleic anhydride (41) and a second compound. The anhydride on hydrogenation and conversion to the corresponding dimethyl ester gave the same product as obtained from 1-methylpyrrole and maleic anhydride, followed by hydrolysis and... 

Dimethyl acetylenedicarboxylate with 2-methylpyrrole gives two 1 1 molar adducts, both of which on hydrogenation absorbed one mole of hydrogen and gave the same product. The original adducts are, therefore, the dimethyl 2-methyl-5-pyrryI-fumarate (43) and -maleate, but which is which was not established. An exactly similar situation refers to 2,3-dimethylpyrrole, and only one adduct was... 

Methyl pyrrole-l-carboxylate and dimethyl acetylenedicarboxylate combine at 170°-200°C, giving trimethyl pyrrole-1,3,4-tricarboxylate (46) and acetylene. This reaction probably proceeds through the... 

Tricyanovinylindole (57) and its 1-methyl derivative, obtainable from the parent indoles and tetracyanoethylene, combine with dimethyl acetylenedicarboxylate to give the corresponding carbazoles. That derived from indole (58) has been hydrolyzed and esterified yielding (55). 

Dimethyl acetylenedicarboxylate and 4-methylimidazole are re-ported to yield dimethyl 5-methyl-2- (70) or -4-imidazolylmaleate a fumarate might perhaps have been expected and no structure proof was given. 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

A -Alkyl-l,2-dihydropyridines that are not stabilized by electron-withdrawing groups on the ring could behave as dienophiles towards alkynes. For example, N-methyl-l,2-dihydropyridine 41a reacts with dimethyl acetylenedicarboxylate (32) to give [2 + 2] cycloaddition product 42, which rearranges to give the azocine derivative 43 [74JCS(P1)2496],... 

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