Dimethyl pyrrole-2,5-dicarboxylates

Pyrrole-2-carboxylic acid esters have been prepared from ethyl chloroformate and pyrrolylmagnesium bromide1 2 or pyrrolyllithium,3 by hydrolysis and decarboxylation of dimethyl pyrrole-1,2-dicarboxylate followed by re-esterification of the 2-acid4 and by oxidation of pyrrole-2-carboxaldehyde followed by esterification with diazomethane.4... 

H. R = COPh) has been prepared from the nitrile (99, R = Me) and benzoyl chloride followed by treatment with sodium hydrogen carbonate. This compound (98, R = R = Ph, R - Me, R = H, R = COPh) undergoes a 1,3- polar cycloaddition with dimethyl acetylene-dicarboxylate in boiling benzene during 10 minutes, yielding the pyrrole... 

Addition of dienophiles preferentially occurs onto the heterocyclic rings of tropones [c]-fused onto furan and pyrrole [cf. 84CHEC(4)67], Furotro-pone 307a and dimethyl acetylene dicarboxylate (DMAD) give a dimerized adduct that undergoes cycloreversion at higher temperature to form monomeric adduct 527 (Scheme 138 91CB2465). The 5,7-bis(carbomethoxy)... 

Diels-Alder reactions pyrrolesThis azadiene undergoes [4 + 2] cycloaddi-non with unactivated dienophiles to form dimethyl l,2-diazine-3,6-dicarboxylates, hich are reduced by zinc in acetic acid with ring contraction to dimethyl pyrrole-1.5-dicarboxylates. 

SAFETY PROFILE Poison by inhalation and ingestion. A corrosive eye, skin, and mucous membrane irritant. Potentially explosive reaction with water evolves hydrogen chloride and phosphine, which then ignites. Explosive reaction with 2,6-dimethylpyridine N-oxide, dimethyl sulfoxide, ferrocene-1,1 -dicarboxylic acid, pyridine N-oxide (above 60°C), sodium -L heat. Violent reaction or ignition with BI3, carbon disulfide, 2,5-dimethyl pyrrole + dimethyl formamide, organic matter, zinc powder. Reacts with water or steam to produce heat and toxic and corrosive fumes. Incompatible with carbon disulfide, N,N-dimethyl-formamide, 2,5-dimethylpyrrole, 2,6-dimethylpyridine N-oxide, dimethylsulfoxide, ferrocene-1,1-dicarboxylic acid, water, zinc. When heated to decomposition it emits highly toxic fumes of Cl" and POx. 

The results of the photochemical reactions of dimethyl acetylene-dicarboxylate with furan,222 thiophene,18 and 1 //-pyrrole11 were found to differ widely. Furan yielded either a 1 1 or a 2 1 adduct, and thiophene yielded a sulfur-free reaction product, viz., dimethyl phthalate. These products were formed by (4 + 2)-cycloadditions, which—in the case of thiophene—was followed by extrusion of sulfur from the initial Diels-Alder adduct. 1//-pyrrole, however, reacted in a different way because a l//-azepine (195) was isolated. This product was most probably generated by (2 + 2)-cycloaddition of the acetylene to the... 

Several 2-(2-thienyl) and 2-(3-thienyl)pyrrole-3-carboxylates were made by reaction of acetylthiophene oximes with methyl propiolate or dimethyl acetylene-dicarboxylate. <93JCR(S)210> This reaction is related to other sigmatropic rearrangements which have been used in pyrrole and indole synthesis. 

To a suspension of 1.31 g A-acetyl-D,L-alanine (10 mmol) in 10 mL acetic anhydride was added 3.2 mL diethyl acetylenedicarboxylate (20 mmol). The reaction mixture was maintained at 110°C for 2 h, cooled, and then evaporated under reduced pressure. The oily residue was dissolved in hot cyclohexane and left in the refrigerator overnight with crystal seeds. Diethyl 2,5-dimethyl pyrrole-3,4-dicarboxylate was isolated as white needles by filtration, in amount of 274 mg, in a yield of 11.4%. The filtrate was evaporated and chromatographed (dry column vacuum chromatography) using CH2CI2 and then CH2Cl2/EtOH (99 1 to 98 2) to afford 1.58 g 2-(2,5-dimethyl-3,4-diethoxycarbonyl)-pyrrolyl maleic acid diethyl ester as a yellowish oil, in a yield of 39%. 

The 1,3-dipolar cycloaddition of acetylenes and alkenes with oxazolones is widely used for the construction of the pyrrole ring. The presence of a CFs-group in the 1,3-dipolar component opens a pathway to 2-CF3-pyrroles, while the application of trifluoromethylated dipolarophiles provides 3-CF3-pyiroles. For example, the dimethyl pyrroledicarboxylate 120 was synthesized in 78 % yield by the reaction of the CFs-containing oxazolone 118, prepared from proline 117 and trifluoroacetic anhydride (TFAA), with dimethyl acetylene dicarboxylate (DMAD) [53]. 

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... 

SCHEME 16 Formation of pyrroles by a three-component reaction of primary alkyl amines, dimethyl acetylene dicarboxylate, and propiolate using N-methyHmidazole as the catalyst. 

Sarkar and Mukhopadhyay have developed a three-component green methodology to synthesize ethyl/methyl 4-hydroxy-5-oxo-l,2-diaryl-2,5-dihydro-lH-pyrrole-3-carboxylates under admicellar catalysis by Ti02 nanoparticles at room temperature [59]. The catalyst in aqueous CTAB solution promotes the formation of admicelles, and the reaction occurs in admicellar environment. A number of aromatic aldehydes 51, amines 9, and diethyl/dimethyl acetylene dicarboxylate (DEAD/DMAD, 70) react to give the products 71 in good yields (Scheme 23). In this reaction, aldehydes have also been replaced with isatin 55 to give spiro-fused products. 

These Michael-type products are similar to structures obtained by Kotsuki [36] by cycloaddition reactions of N-sub-stituted pyrroles 94 with dimethyl acetylene dicarboxylate. If the substituent on the nitrogen is electron donating (R=Me), a primary 1 1 Diels-Alder cycloadduct 95 reacts further to give Michael-type reaction product 96 (Scheme 23). Described substituent influence on the susceptibility of 7-azabicyclo[2.2.1]hept-2-enes to Michael reaction is in good accord with results obtained by Scheeren [37] who has shown that the hi -pressure Diels-Alder reaction of 3-thiosubstituted N-carbomethoxypyrrole derivatives with electron-poor alkenes (12kbar, MeCN, 50°C, 16h) affords 2-thiosubstituted 7-azabicyclo[2.2.1]hept-2-enes in high yields. 

Pyrrole-2,5-dicarboxylic acid, 3,4-dimethyl-diethyl ester bromination, 4, 271... 

The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene A, O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S1513>. 

Dipolar cycloaddition is another route to benzopyrrolo[l,2-a]azepines by pyrrole ring formation. The azomethine ylide derived from imine 88 and difluorocarbene adds to DMAD to produce dimethyl 3-fluoro-9H-dibenzo[c,/]-pyrrolo[l,2-fl]azepine-l,2-dicarboxylate 89 in 20% yield (Equation (12)... 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

The reaction of dimethyl 3,6-di-/i< r/-butyl-l,4-dihydropyrrolo[3,2-3]pyrrole-l,4-dicarboxylate 58a with CSI gave anhydride 328 with a trace of the expected 329. The structute of 328 was confirmed by solvolysis giving 330 or 331. On heating 328 in toluene for 1 h, evolution of CO2 occurred to give a bimolecular condensation product 332 (Scheme 32) <1996H(43)2361>. 

Pyrroles, indoles and benzo[ft]thiophene act as good dienophiles in inverse electron demand Diels-Alder reactions with 1,2-diazines, 1,2,4-triazines and sy/n/n-tetrazines. This is examplified by the formation of compounds (189) in excellent yields on interaction of indoles and benzo[c]thiophene with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (87JOC4610 90JOC3257). There are also many examples of such intramolecular reactions, e.g. (190 — 191). 

The intermediates which are assumed to be involved in the Knorr cyclization can also be prepared by addition of a-amino ketones to electrophilic alkynes (equation 77). This methodology has found use primarily with dimethyl acetylenedicarboxylate to form pyrrole-2,3-dicarboxylate esters (equation 77), but methyl propiolate is also reactive (68T1567,69T527, 64JA107, 62JOC3346). 

Preparation and Diels-Alder Reaction of a Reactive, Electron-Deficient Heterocyclic Azadiene Dimethyl 1,2,4,5-Tetrazine-3,S-Dicarboxylate. 1,2-Diazine and Pyrrole Introduction. 

Fig. 10 4-Acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-9]pyrrole 58, dimethyl 6-acetylamino-2-[3-(trifluoromethyl)phenyl]-l-benzofuran-3,4-dicarboxylate 70 [18]...

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