Endo closure

Substituent effects on cyclizations of simple nucleophilic hexenyl radicals have been well studied, and much quantitative rate data is available.12 The trends that emerge from this data can often be translated to qualitative predictions in more complex settings. Once the large preference for S-exo cyclization is understood, other substituent effects can often be interpreted in the same terms as for addition reactions. For example, electronegative substituents activate the alkene towards attack, and alkyl substituents retard attack at the carbon that bears them. The simple hexenyl radical provides a useful dividing point = 2 x 10s s-1. More rapid cyclizations are easily conducted by many methods, but slower cyclizations may cause difficulties. Like the hexenyl radical, most substituted analogs undergo irreversible S-exo closure as the predominate path. However, important examples of kinetic 6-endo closure and reversible cyclization will be presented. 

In the cyclization of 3-unsaturated acids, /1-lactones are preferentially formed over y-lac-tones20. Also, y-lactones are preferentially obtained over <5-lactones under kinetic conditions and in the absence of overwhelming electronic factors21. Under thermodynamic control the preferred ring sizes for lactones are 5 > 4, 5 > 6 and 6 > 7, and many examples of the preference for 5-exo over 6-endo closure are known10. 

The regiochemistry of this reaction depends on electronic factors. Moreover, the kinetic or thermodynamic conditions utilized appear to direct the regioselectivity towards 5-exo or 6-endo closures, respectively1. 

On the other hand, when A-bromosuccinimide was employed as the electrophile a 6-endo closure occurred to give the 5-bromo-l,4,5,6-tetrahydropyrimidine 3, most probably as a different reaction mechanism involving a radical as the intermediate is operating in this case166. 

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. 

The cyclofunctionalization of 4-alkynoic and 5-alkynoic acids generates y-alkylidene-y-lactones and 5-alkylidene-S-lactones, respectively (equation 76 and Table 22). The initial products from the reactions catalyzed by mercury or silver salts undergo protiodemetallation under the reaction conditions. The vi-nylpalladium intermediates undergo either protiodemetallation or coupling with an added allyl halide. The palladium(II)-catalyzed cyclization of 3-alkynoic acids proceeds by 5-endo closure to give 3-buten-4-olides (Table 22, entry 2).50 190... 

The rate constant measured for 1-endo closure in the simple heptenyl radical is near the lower limit for synthetic utility (ki ndo l x 102 s 1) [73]. Nonetheless, 1-endo and %-endo cyclizations do occur when the (conformationally restrained) intermediate radicals possess... 

Satisfactorily, the 1-endo closure became the predominat route when a temporary substituent was introduced at the 6-exo position of the alkene acceptor, a tactic previously used in similar 1-endo cyclizations involving aryl <4TL2335>, vinyl <05JOC519> or alkyl <06OL831> radicals. Hence, cyclization of selenoester 30b, which incorporates a 2-bromo-2-propenyl instead of an allyl moiety, led to the tricyclic substructure of mersicarpine 32 in a synthetically acceptable 62% yield, pyridoindole 31 being now the minor product (19%). The excess hydride ensured the final reductive removal of the bromine atom after the cyclization step <07JOC4562>. 

Let us focus attention on the unfavorable ring closures. Why, for example, should formation of a five-membered ring by an endo-trig process be difficult The answer is provided by a consideration of the trajectory of approach of the nucleophile." If Z is an electron-attracting conjugating group of the type necessary to activate the double bond to nucleophilic attack, the reaction would involve the LUMO of the conjugated system, a 7t ... 

Normant and coworkers ° have recently studied the intramolecular addition of nucleophiles to vinyl sulfones. The presence of the sulfonyl group in equations 58 and 59 is essential for the disfavored 5-endo-trigonal closure . In contrast, the corresponding sulfoxide gives no cyclic product when treated with potassium hydride and only decomposition occurs. 

Electrophilic cyclizations are useful for closure of a variety of oxygen-, nitrogen-, and sulfur-containing rings. The product structure depends on the ring size and the exo-endo selectivity. The most common cases are formation of five- and six-membered... 

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