Dennstedt Rearrangement

The rearrangement of pyrroles to 3-halo-pyridines upon treatment with haloforms (CHX3 where X = Cl, Br, I) in the presence of a strong base was first described by G.L. Ciamician. Its synthetic utility was later extended by M. Dennstedt to the sodium methoxide catalyzed reaction of pyrrole with methylene iodide to give pyridine. Soon after the initial discovery, the methodology was also extended for the indole series to prepare substituted quinolines. The reaction is known as the Ciamician-Dennstedt rearrangement, but it is also referred to as the abnormal Relmer-Tiemann reaction. 

In an effort to expand the available synthetic tools for the preparation of various metacyclophanes and pyridinophanes, C.B. Reese and co-workers prepared [6](2,4)pyridinophane derivatives by treating 4,5,6,7,8,9-hexahydro-1H-cyclo-octa[it ]pyrrole with dichloro- and dibromocarbene respectively. The dihalocarbenes predominantly inserted into the most substituted (more electron rich) double bond of the pyrrole ring in modest to poor yields. 

The first example for the insertion of an electrogenerated dichlorocarbene into substituted indoles was described by F. De Angelis and co-workers. The dichlorocarbene was generated by reduction of CCU, followed by fragmentation of the resulting trichloromethyl anion. Under these conditions, 2,3-dimethylindole was converted to 3-chloro-2,4-dimethylquinoline and 3-(dichloromethyl)-2,3-dimethyl-3/-/-indole in moderate yield. The study revealed that the reaction mechanism and product formation are determined by the acidity of the solvent. 

In the first step the base (usually an alkoxide, LDA, or NaH) deprotonates the a-proton of the ester to generate an ester enolate that will serve as the nucleophile in the reaction. Next, the enolate attacks the carbonyl group of the other ester (or acyl halide or anhydride) to form a tetrahedral intermediate, which breaks down in the third step by ejecting a leaving group (alkoxide or halide). Since it is adjacent to two carbonyls, the a-proton in the product p-keto ester is more acidic than in the precursor ester. Linder the basic reaction conditions this proton is removed to give rise to a resonance stabilized anion, which is much less reactive than the ester enolate generated in the first step. Therefore, the p-keto ester product does not react further. 

Heathcock and co-workers devised a highly convergent asymmetric total synthesis of (-)-secodaphniphylline, where the key step was a mixed Claisen condensation. In the final stage of the total synthesis, the two major fragments were coupled using the mixed Claisen condensation] the lithium enolate of (-)-methyl homosecodaphniphyllate was reacted with the 2,8-dioxabicyclo[3.2.1]octane acid chloride. The resulting crude mixture of (3-keto esters was subjected to the Krapcho decarboxylation procedure to afford the natural product in 43% yield for two steps. 

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Ciamician-Dennstedt rearrangement Synthesis of 3-halopyridines from pyrroles and 2-haloquinolines from indoles. 84... 

Ciamician-Dennstedt rearrangement. Expansion of the pyrrole ring by heating with chloroform or other halogeno compounds in the alkaline solution. The intermediate dichlorocarbene, by addition to the pyrrole, forms an unstable dihalogeno-cyclopropane that rearranges to a 3-halogenopyri-dine. 

Ciamician-Dennstedt Rearrangement Claisen (see Darzens-Claisen Reaction)... 

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