Electrophilic heteroatom cyclizations

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

This chapter on electrophilic heteroatom cyclizations covers reactions of carbon-carbon ir-bonds in which activation by an external electrophilic reagent results in addition of an internal heteroatom nucleophile. The general reaction is illustrated in Scheme 1. These cyclization reactions generate heterocyclic products, but many synthetic applications involve subsequent cleavage of the newly formed heterocyclic ring. 

The identity of the heteroatom present in a target molecule dictates the identity of the nucleophilic atom (Z) to be used in an electrophilic heteroatom cyclization reaction of the type shown in Scheme 1. However, successful application of this strategy to the synthesis of specific target molecules also requires selection of appropriate combinations of nucleophilic functionality (Z-R) and activating electrophile. Therefore, major subdivisions within this chapter are based on the identity of the heteroatom, although comparisons between results observed for the different heteroatoms will be made. 

In a few cases, detailed mechanistic studies have shown that the cyclization step is rate limiting. 6-7 One method has been to demonstrate that the overall rate of reaction is a function of the nucleophilicity of the ZR group or of the formed ring size.5-6 However, the cyclization step need not be the rate-limiting step in all electrophilic heteroatom cyclizations.8 The uncertainty about which step is rate limiting complicates attempts to derive general rationales for predicting the stereochemical results of these reactions. 

The most successful examples of stereochemical control in electrophilic heteroatom cyclizations are those in which the substitution pattern constrains the substrate so that the two diastereofaces of the tt-system are significantly different. The most straightforward prediction of stereochemistry involves incorporating both the ir-system and the directing chiral center into a ring such that rotation about the vinylic bond that attaches the nucleophile to the double bond is highly restricted. Comparison of equations (1) and (2) illustrates this difference. For this reason, in the sections on cyclizations to form five- and six-membered rings, examples with constrained C=C—C bonds will be discussed separately. 

While the regiochemistry of simple electrophilic additions to double bonds is controlled by a combination of electronic (Maikovnikov rule), stereoelectronic (trans diaxial addition to cyclohexenes) and steric factors,9 the intramolecular nature of electrophilic heteroatom cyclizations introduces additional conformational, stereoelectronic and entropic factors. The combination of these factors in cyclofunctionalization reactions results in a general preference for exo cyclization over endo cyclization (Scheme 4).310 However, endo closure may predominate in cases where electronic or ring strain factors strongly favor that mode of cyclization. The observed regiochemistry may differ under conditions of kinetic control from that observed under conditions of thermodynamic control. 

Electrophilic heteroatom cyclizations of systems involving alkyne and allene ir-systems have attracted significant attention. A major difference from alkene cyclizations is that the electrophilic group in the initial product may be a vinyl substituent, and, in the case of metal electrophiles, possess different reactivity patterns than when attached to a saturated carbon. 

Allenes can also act as the -participant in electrophilic heteroatom cyclizations. Reviews of electrophilic additions to allenes discuss early examples of this type of cyclization.ld le-202 Numerous examples of cyclizations of a-functionalized allenes, including carboxylic acids, phosphonates, sulfinates and alcohols, to form five-membered heterocycles (equation 84) are cited in these reviews. The silver nitrate-mediated conversion of ot-allenic alcohols to 2,5-dihydrofurans203 has recently been applied to trimethylsilyl-substituted systems.204... 

Chemistry of azetidin-3-ones, oxetan-3-ones, and thietan-3-ones 02CRV29. Formation of four-membered heterocycles through electrophilic heteroatom cyclization 02EJ03099. 

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