Cyclization Parham

The Parham Cyclization describes the generation by halogen-lithium exchange of aryllithiums and hetaryllithiums, and their subsequent intramolecular cyclization onto an electrophilic site, 1— 2— 3.  

Parham also discovered that added electrophiles can be incorporated in the cyclization sequence. Thus, 2-bromophenethyl bromide (7) is selectively lithiated to afford 8, which upon reaction with cyclohexanone affords spiro[cyclohexane-l,r-isochroman] (9) in good yield. It is also possible to execute twin Parham cyclizations, as in the synthesis of benzo[l,2 4,5]dicyclobutene (11).  

Despite its apparent simplicity, the halogen-lithium exchange reaction remains mechanistically intriguing. - Depending on the substrate and conditions, halogen-lithium exchange may involve a four-center transition State, radical intermediates via a single-electron transfer (SET) mechanism, or a nucleophilic mechanism perhaps via an ate  

The equilibria implied in the nucleophilic mechanism are firmly grounded in experiment. The ate complex 12 formed in the reaction of phenyllithium with iodobenzene has been characterized at low temperature, and that from (pentafluorophenyl)lithium and iodopentafluorobenzene, 13, has been isolated and characterized by X-ray crystallography.  

Although halogen-lithium exchange can occur at very low temperatures ( -100 °C), it is often necessary to employ two equivalents of alkyllithium for each equivalent of aryl halide so as to neutralize the alkyl halide, lest it destroy the aryllithium. This is illustrated below for the reaction between 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOT 10.I007/978-3-319-03979-4 203, Springer International Publishing Switzerland 2014 

Gribble, G. W. Parham cyclization. In Name Reactions for Homologadons-Part II Li, J. J., Ed. Wiley Hoboken, NJ, 2009, pp 749-764. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 190, Springer-Verlag Berlin Heidelberg 2009 

Annulation of aryl halides with ortho side chains bearing a pendant electi ophilic moiety via treatment with an organolithium reagent, involving halogen-metal exchange and subsequent nucleophilic cyclization to form 4- to 7-membered rings. 

Couture, A. Deniau, E. Grandclaudon, P. J. Chem. Soc., Chem. Commun. 1994, 1329. 

Collado, M. 1. Osante, L Ruiz, J. Sotomayor, N. Lete, E. In Targets in Heterocyclic Systems Vol. 5 Atanassi, O., Spinelli, D., Eds. Italian Society of Chemistry Rome, 2001 p 393. (Review). 

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The Parham cyclization of the iodinated imide 270 by BuLi in dry THF at —78°C afforded 1 lZ -hydroxy-l,3,4,6,7,l lZ -hexahydro[l,4]oxazine[3,4-a]iso-quinolin-4-one 258 (97JOC2080). Iodide-lithium exchange was faster then addition to the carbonyl group of imide 270 and intramolecular cyclization of the initially formed anion gave compound 258. 

The very fast metal-halogen exchange allows intramolecular cyclization reactions, which are known as Parham cyclizations171. The potential of Parham cyclizations as a useful stereoselective cyclization procedure has proven to be extremely interesting172. Thus, it has been recently demonstrated that iodinated IV-phenethylimides tolerate iodine-lithium exchange, giving rise to the isoquinoline nucleus 304, via a Parham-... 

The well-known Parham cyclization of bromoaromatic carboxylic acid derivatives can be exemplified by the examples in equations (27)-(29). The reaction is usually run at very low temperature in ether or llIF and provides surprisingly good yields of aromatic ketones. The method has been reviewed recently. ... 

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. ... 

Other references related to the Parham cyclization are cited in the literature. ... 

Paal-Knorr Pyrrole Synthesis Parham Cyclization Passerini Reaction Patemo-Biichi Reaction Pauson-Khand Reaction Payne Rearrangement Pechmann Condensation Pechmann Pyrazole Synthesis Pellizzari Reaction Pelouze Synthesis Periodic Acid Oxidation Perkin Alicyclic Synthesis Perkin Reaction Perkin Rearrangement Perkow Reaction Peterson Reaction... 

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