Pyrrole 2.5- dimethyl-, ring synthesis

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. 

There are numerous studies on the synthesis of pyrrolizines from enam-ines. In these reactions, one of the step is the closure to a new hydrogenated pyrrole ring. In polar solvents, the reaction of enamines with dimethyl acetylenedicarboxylate follows two different pathways, the formation of cycloadducts (18) and Michael adducts (19) (81T3525). Subsequent studies of this reaction have demonstrated (by low-temperature NMR) that compounds of the type 20 are intermediates in this cyclization (83JA4775). On the basis of this information (83JA4775), the authors then studied this type of cyclization using dienamines (21). The reaction follows the scheme shown, with a [1,6] antarafacial hydrogen shift and the formation of a dipo-... 

More recently [31] the same authors reported the synthesis of Co(OMTPC)PPh3 via self-condensation of 3,4-dimethyl-2-(a-hydroxybenzyl)-pyrrole-5-carboxylic acid. The procedure represents the first example of direct formation of the corrole ring from a monopyrrolic precursor. 

The 3-chloro-l,7-dimethylpyridazino[3,4-(7][l,3]oxazine-4,5-dione (149) was prepared in a four-step synthesis starting with (Z)-methyl-3-(3,6-dichloro-l-methyl-4-oxo-l,4-dihydropyridazin-5-yl)-2-methylacrylate (146) which is converted with sodium azide into the 6-azido compound (147). Heating in o-dichlorobenzene at 150°C results in cyclization to methyl 3-chloro-l,6-dimethyl-4-oxo-1,4-dihydro(7//)pyrrolo[2,3-c]pyridazine-5-carboxylate (148) via a nitrene intermediate. Ozonolysis effects ring-enlargement of the pyrrole ring into the 3-chloro-l,7-dimethylpyridazino[3,4-d][l,3]oxazine-4,5-dione (149) (Scheme 26) <79JHC1213>. 

Of lesser relevance to this discussion are halogenation methods involving the modification of the carbon skeleton (synthesis and degradation). The Hunsdiecker reaction, as applied to certain heterocyclic acids, has had limited application for the synthesis of halogen derivatives. The preparation of 3-bromo-4,6-dimethyl-2-pyridone from the silver salt of the respective 3-carboxylic acid by treatment with bromine in carbon tetrachloride is a rare example of success.13 The interaction of carbenes with heterocycles also has been employed infrequently, but recent advances in carbene generation may reactivate this approach.14 The Ciamician-Dennstedt ring expansion of pyrrole to / -halopyridines is a case in point18 [Eq. (4)] ... 

Although the Birch reduction (alkali metals in liquid NH3) of the pyrrole ring is apparently unknown (c/. equation 8), the partial reduction of pyrroles to 2,5-dihydropyrroles using Zn/HCl has been of considerable utility. For example, pyrrole gives 2,5-dihydropynole as the major product upon treatment with Zn dust/20% aq. HCl (equation 9), and Lemal and McGregor observed that 2,5-dimethylpyrrole gives a mixture of trans- (78%) and c/5-2,5-dimethyl-2,5-dihydropyrrole (22%) under similar conditions (47% yield). In one of these studies, Hudson and Robertson demonstrated that 2,5-dihydropyrrole is not reduced to pyrrolidine under these reaction conditions. Using these same conditions, Schumacher and Hall reported the reduction of 2-benzylpyrrole to the 2,5-dihydro derivative (67%) in a synthesis of the antibiotic anisomycin. ... 

The azomethine ylide represents one of the most reactive and versatile classes of 1,3-dipoles and is trapped readily by a range of dipolarophiles, forming substituted pyrroles or pyrrolidines (Coldham and Hufton 2005). Synthesis of aziridines by reaction of a fluorocarbene with imines under ultrasonic irradiation was described previously (Konev et al. 2005). This reaction proceeds by the formation of an azomethine ylide (9), which can be trapped with dimethyl maleate (13) to produce pyrrolidines (14) or pyrrole rings (15) in moderate yields (Scheme 8.5). 

Cycloaddition Reactions.— Acetylenes undergo many types of cycloaddition reaction and provide valuable starting materials for the synthesis of carbo-and hetero-cyclic systems. Many acetylenes are dipolarophiles, and dimethyl acetylenedicarboxylate (DMAD), because of its ready availability, often plays this role in the formation of a variety of heterocycles. Mesoionic systems often function as the 1,3-dipoles, as in the formation of pyrrole (99) from the A -oxazolium-5-olates (munchnones) (100) and DMAD. The procedure can be extended to fuse pyrrole rings on to the piperidine rings of (101) and (102) in moderate yields. Further examples of... 

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