Abnormal Reimer-Tiemann products

The total synthesis of the tricyclic sesquiterpene (+)-P-copaene was accomplished by E. Wenkert and co-workers. The required bicyclic starting material was prepared in three steps from carvacrol. In the first step, carvacrol was subjected to typical Reimer-Tiemann conditions. The abnormal Reimer-Tiemann product, 6-dichloromethyl-3-isopropyl-6-methyl-cyclohexa-2,4-dienone, was obtained, and upon treatment with sodium carbonate in DMSO, cyclization occurred to afford a bicyclic halo ketone. The double bonds were then hydrogenated in the presence of Pd(C) catalyst. 

Ab initio and density functional calculations indicate that the first step of the abnormal Reimer-Tiemann reaction involves barrierless formation of an intermediate by nucleophilic attack on CCl2 of the /3-carbon of pyrrole anion. " This is followed by a single, concerted step to give the product, 3-chloropyridine. 

The abnormal Reimer-Tiemann reaction involves a ring expansion, in the classical case from a pyrrole to a 3-chloropyridine, resulting from an attack of dichlorocarbene on a double bond. An electrochemical equivalent can be made by electrolysis in a chloroform solution, where the electrogenerated base produces dichlorocarbene. By using this method, 2,3-dimethylindole could be transformed to 3-chloro-2,4-dimethylquinoline in fair yield some of the normal Reimer-Tiemann product, 3-dichloromethyl-2,3-dimethyl-3//-indole, was also formed [164]. 

Although at first these ketonic by-products were mere curiosities, their potential value was noted by Woodward, who used the abnormal Reimer-Tiemann reaction for a synthesis of /ranr-10-methyldeca-lone from P-(ar)-tetralol (equation 11). This author applied this principle for the preparation of a 9-methyldecalone from an a-(ar)-tertralol (equation 12). ... 

It is interesting to compare early experimental work with the facilities available in a modem laboratory. Von Auwers was the first to separate the chloro ketones from the normal phenolic aldehydes of the Reimer-Tiemann reaction. Identirication and strocture proof by chemical means followed. It is a tribute to von Auwers skill and insight that his identification procedures have withstood the onslaught of modem spectroscopic means. Although the chloro ketones (equations 8-10) have been called the abnormal products of the reaction, in cases where the ortho and para positions are occupied (see equation 10) only ketonic material is obtained.In fact, the presence of the dichloro ketones provides one of the better arguments for the intermediacy of dichlorocarbene in the reaction mechanism. ... 

As is the case with the normal reaction, the abnormal reaction can also be influenced by the use of 3-cyclodextrin to give higher selectivity for the para position. Australian chemists have carried out a careful product analysis of the normal, abnormal and ring-expansion products resulting from the Reimer-Tiemann reaction with a series of 4-alkylguaiacols. ... 

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