Halogen-lithium exchange, Parham cyclization

Several chromans have been synthesized using the Parham cycloalkylation technique (76JOC1184). l-Bromo-3-(2-bromophenoxy)propane, prepared from phenol and 1,3-dibromopropane, is treated with n-butyllithium at — 100 °C. Halogen-lithium exchange yields the aryllithium (278) which cyclizes either at — 100°C or in some instances only at an acceptable rate at higher temperatures. This method offers the advantage of regio-specificity since cyclization is controlled by the location of the o-bromine atom (Scheme 72). 

The Parham cyclization is the generation by halogen-lithium exchange of aryllith-iums and heteroaryllithiums, and their subsequent intramolecular cyclization onto an electrophilic site. 

The main variation of the Parham cyclization might be considered the generation of the requisite aryllithium or hetaryllithium species by "directed-lithiation", rather than via halogen-lithium exchange. However, this protocol does not fall under the rubric of the classic Parham cyclization and is not covered herein. 

One alternative to the halogen-lithium exchange that has been employed in a Parham cyclization is halogen-magnesium exchange, as exemplified by the synthesis of 5-substituted 2,3-dihydrobenzofurans 05)- The use of n-butyllithium is less successful and leads to butylated by products. Lithium tributylmagnesate has also been employed, e.g., 16- 17. ... 

In view of three excellent recent reviews on the Parham cyclization, " this section focuses mainly on the more recent literature. While -butyllithium and tert-butyllithium are commonly used to effect halogen-lithium exchange, these reagents do present problems as delineated earlier. Mesityllithium does not pose such problems since the resulting mesityl halides are not susceptible to the side reactions inherent with -butyl and tert-butyl halides. Mesityllithium has been used to prepare the camptothecin precursor 28. This base can also be used with added electrophiles, as for the conversion of 29 to phthalides 30. A more conventional Parham synthesis of phthalides, i.e., 31—>32, has been applied to the synthesis of the aristocularine alkaloids. ... 

A Parham cyclization can be followed in the same pot by a second, remote halogen-lithium exchange and intermolecular reaction. Such a case is 33—>34. ° A related one-pot sequential lithiation process has... 

A Parham cyclization strategy has been used to synthesize a wide variety of isoquinolines. For example, iodide 66 is smoothly converted to 67, which can be reduced (sodium borohydride/trifluoroacetic acid, 99%) or treated with nucleophiles and a Lewis acid to effect a-amidoalkylation. Likewise, imidazo[4,3-a]isoquinolinones (68), ° thiazolo[4,3-a]isoquinolinones (69), ° pyrrolo[2,l-a]isoquinolines (70), pyrrolo[ 1,2-6] isoquinolines (71), pyrrolo[l,2-6]acridinones (72), ° pyirolo[l,2-g]quinolones (73), ° thieno[3,2-y]indolizinones (74), ° and furo[3,2-/lindolizinones (75). ° It should be noted that the latter ring system 63 was prepared by deprotonation (LDA) rather than halogen-lithium exchange. °... 

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-... 

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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