Cyclization reactions electrophilic heteroatom

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

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. 

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. 

Electrophile-mediated cyclization reactions of alkynes tethered to pendant heteroatom nucleophiles is an emerging strategy for the synthesis of heterocycles. This methodology has now been applied to the synthesis of pyrroles. The iodocyclization of 3-aminoalkynes 1 led to the formation of dihydropyrrole 2 <07TL7906>. Treatment of the latter with mesyl chloride in the presence of triethylamine then gave (i-iodopyrrolcs 3. 

Palladium-catalyzed reactions have been widely investigated and have become an indispensable synthetic tool for constructing carbon-carbon and carbon-heteroatom bonds in organic synthesis. Especially, the Tsuji-Trost reaction and palladium(II)-catalyzed cyclization reaction are representative of palladium-catalyzed reactions. These reactions are based on the electrophilic nature of palladium intermediates, such as n-allylpalladium and (Ti-alkyne)palladium complexes. Recently, it has been revealed that certain palladium intermediates, such as bis-7i-allylpalladium, vinylpalladium, and arylpalladium, act as a nucleophile and react with electron-deficient carbon-heteroatom and carbon-carbon multiple bonds [1]. Palladium-catalyzed nucleophilic reactions are classified into three categories as shown in Scheme 1 (a) nucleophilic and amphiphilic reactions of bis-n-allylpalladium, (b) nucleophilic reactions of allylmetals, which are catalytically generated from n-allylpalladium, with carbon-heteroatom double bonds, and (c) nucleophilic reaction of vinyl- and arylpalladium with carbon-heteroatom multiple bonds. According to this classification, recent developments of palladium-catalyzed nucleophilic reactions are described in this chapter. 

We will usually make the rings by cyclization reactions with the heteroatom (O, N, S) as a nucleophile and a suitably functionalized carbon atom as the electrophile. This electrophile... 

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. 

As with the other procedures for the preparation of six-membered heterocyclic systems which proceed via formation of only one ring bond there are relatively few methods which involve formation of a ring bond y to the heteroatom and which can best be classified as [6 + 0] processes rather than [4 + 2], [3 + 3], etc, processes. Of those which can be so represented, however, a number are important processes which are widely used for the synthesis of saturated, partially saturated and aromatic six-membered heterocyclic systems and their benzo derivatives. Mechanistically, the nucleophile —> electrophile approach is by far the most common, but in contrast to the reactions discussed in the previous three sections, radical cyclizations are of considerable utility here. 

The electrophilic one-carbon species can be an aldehyde, ketone, carboxylic acid, phosgene, thiophosgene, carbonyl diimidazole (CDI), etc., and the reaction essentially involves condensation with a 1,5-dinucleophile. The 1,5-dinucleophile invariably contains at least one heteroatom at a terminus, and more often than not two, so that the cyclization always involves the formation of at least one bond between carbon and a heteroatom. 

These heterocyclization reactions provide initial products with a functionality (3 to the heteroatom, except for cases where a proton is the electrophile. Synthetic applications often depend upon further transformation of this functionality. Useful transformations include replacement by hydrogen, elimination to form a ir-bond, nucleophilic substitution, and substitution via radical intermediates. These reactions will be discussed only when understanding the cyclization step requires inclusion of the functional group transformation. 

Electrophilic substitutions of alkenyl-, aryl-, and alkynylsilanes with heteroatom-stabilized cationic carbon species generated by the action of a Lewis or Brpnsted acid (acyl cation, oxocarbenium ion, etc.) provide powerful methods for carbon-carbon bond formation. Particularly, intramolecular reactions of alkenylsilanes with oxocarbenium and iminium ions are very valuable for stereoselective construction of cyclic ether and amine units.21-23 For example, the BFj OEt -promoted reaction of (E)- and (Z)-alkenylsilanes bearing an acetal moiety in the alkenyl ligand gives 2,6-disubstituted dihydropyrans in a stereospecific manner (Scheme l).23 Arylsilanes also can be utilized for a similar cyclization.24... 

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