Heteroatoms electrophilic

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... 

Carbenes, generated by several methods, are reactive intermediates and used for further reactions without isolation. Carbenes can also be stabilized by coordination to some transition metals and can be isolated as carbene complexes which have formal metal-to-carbon double bonds. They are classified, based on the reactivity of the carbene, as electrophilic heteroatom-stabilized carbenes (Fischer type), and nucleophilic methylene or alkylidene carbenes (Schrock type). 

It is possible to use the reverse polarity with a nucleophilic carbon synthon 6 and an electrophilic heteroatom synthon 7 but only with second or third row elements such as S, Si, P and Se. These synthons are represented by organometallic compounds 8 or 9 and compounds 10 such as RSC1, MesSiCl and PI12PCI and we shall consider these later. 

The direct activation and transformation of a C-H bond adjacent to a carbonyl group into a C-Het bond can take place via a variety of mechanisms, depending on the organocatalyst applied. When secondary amines are used as the catalyst, the first step is the formation of an enamine intermediate, as presented in the mechanism as outlined in Scheme 2.25. The enamine is formed by reaction of the carbonyl compound with the amine, leading to an iminium intermediate, which is then converted to the enamine intermediate by cleavage of the C-H bond. This enamine has a nucleophilic carbon atom which reacts with the electrophilic heteroatom, leading to formation of the new C-Het bond. The optically active product and the chiral amine are released after hydrolysis. 

Fig. 2.5 Electronic and steric interactions in the approach of the electrophilic heteroatom (Het) to the nucleophilic carbon atom in the chiral enamine intermediate.

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