Heterocycles halogen-lithium exchange using

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

Halogen-metal exchange is useful particularly for the synthesis of heterocycles bearing lithium at less acidic sites - for example, the 3-position of both pyridine and of the 5-membered heterocycles. The schemes below show the synthesis of some P-lithiated 5-membered heterocycles (a-lithiation can be achieved using direct deprotonation methods - see section 2.2.3). 3-Lithiothiophene 93 in an important intermediate in the industrial synthesis of the vasodilator cetiedil 94.84... 

Bi- and Poly-heterocycles.—Extensive work on the synthesis, optical resolution, and conformation of 3,3 -bithienyls, as well as detailed studies of their c.d. curves, has appeared. " Most 3,3 -bithienyls were prepared by the coupling of 3-thienyl-lithium derivatives followed by the introduction of the appropriate substituents by electrophilic substitution or by the modification of substituents by reduction, - ° oxidation, - - or side-chain bromination. In particular, halogen-metal exchange in bromo-substituted 3,3 -bithienyls was very useful for the modification of substituents. - - Ullman coupling of 3-bromo-2,4-dimethoxycarbonylthiophen was used for the synth is of 2,2, 4,4 -tetra-... 

Thienyl-lithium derivatives prepared through halogen-metal exchange and containing acetal-protected carbonyl groups have been used in the synthesis of di- and tri-formyl derivatives of thiophen, t-butoxy-sub-stituted thiophen aldehydes, and formylacetylthiophens. Symmetrical thienyl-substituted ketones have been obtained from thienyl-lithium derivatives and carbamates. " Mixed heterocyclic carbinols have been obtained through the reaction of thienyl-lithium derivatives with heterocyclic aldehydes. Thienyl-lithium derivatives react with cyclohexanone, and various phenylthiophens have been made by aromatization of the intermediate cyclohexenyl derivative. The reaction of thienyl-lithium derivatives with NN-dimethylacetamide, which has been used for the synthesis of... 

This reaction was initially developed by Parham in 1975 and extended primarily by Bradsher after Parham s death in 1976. It is the synthesis of aryl or heteroaryl ring fused carbocylces or heterocycles through the intramolecular reaction between a side chain electrophile and an aryl or heteroaryllithium generated from lithium-halogen exchange. Therefore, this reaction is generally known as the Parham cyclization. Occasionally, it is also referred to as the Parham reaction. J This reaction is very useful for the synthesis of alkaloids. ... 

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