Intramolecular electrophilic addition

A concerted addition of this kind, involving simultaneous intramolecular electrophilic assistance by the magnesium bound to oxygen, and intermolecular nucleophilic attack by 

The formation of cyclic terpenoids involves intramolecular electrophilic addition, and this can be exemplified by the following monoterpene structures, again with all reactions being enzyme controlled. 

In this chapter, both intermolecular and intramolecular electrophilic [1] and nucleophilic additions [2, 3] to allenes will be discussed. For electrophilic addition, the regio- and stereoselectivity depend on the steric and electronic effects of the substituents on the allenes and the nature of the electrophiles. However, nucleophilic addition usually occurs at the central carbon atom with very limited exceptions. 

Cationic polymerization is, of course, an inter-molecular electrophilic addition process. Intramolecular electrophilic addition involving two double bonds in the same molecule may be used to generate a cyclic system. Thus, the trienone shown is converted into a mixture of cyclic products when treated with sulfuric acid. 

Protonation on oxygen opens the epoxide ring and gives a tertiary carbocation at C4. Intramolecular electrophilic addition of C4 to the 5,10 double bond then yields a tertiary monocyclic carbocation at C10. 

When the nucleophilic and the electrophilic positions of the reagent confronted to the aryne are not c-bonded, a cascade intermolecular nucleophilic addition-intramolecular electrophilic cycUzation of arynes can take place. The fragmentation step, which is cmcial for the insertion reaction of arynes into a-bonds, is not involved in annulation processes because the intermediate obtained from the cyclization is usually a stable five- or six-membered ring system. 

When imines are the nucleophiles used, the initially formed iminium intermediates can undergo intramolecular electrophilic alkylation of the other ligands (e.g. Entry 2, Table 2.10 see also [143]). In addition to this, carbyne complexes can also react with azides to give metallatriazoles [185,186] (Entry 6, Table 2.10). 

With Mn(OAc)3, generated by oxidation of Mn(OAc)2 as mediator, a tandem reaction consisting of an intermolecular radical addition followed by an intramolecular electrophilic aromatic substitution can be accomplished [Eq. (21b)] [225b]. Further Mn(III)-mediated additions of 1,3-dicarbonyl compound to olefins are shown in Table 11 (numbers 8b,c, and 9a). Mediated by in situ generated Mn(III), methyl dibromoacetate, trichloro-bromomethane, perfluoroctyl iodide, dimethyl bromomalonate, and active methylene compounds have been added via radicals to olefins [225d]. 

Those syntheses of pyrido[3,2-d]pyrimidines in which pyrimidines are the starting materials are completed either by an intramolecular electrophilic cyclization of a pyrimidine with a vacant 4-position (route i) or by the addition of the C-5 and C-6 atoms to a 4-substituted-5-aminopyrimidinc (route ii). 

Attempted preparation of acetonides from a 4a-methyl-4/(,6a-diol, or the analogous 6a-methyl-4oc,6j -diol, also gave cyclic ethers resulting from intramolecular electrophilic addition to an olefinic bond (see p. 247). Comparable cyclizations occurred on solvolysis of the 5,10-secosteroid (101)— (102) (see also Part II, Chap. 2, p. 404), and in the synthetically useful formation of 

A process that has proved valnable in synthesis is the addition of singlet oxygen to A-alkyl- and especially A-acyl-pyrroles ° prodncing 2,3-dioxa-7-aza-bicyclo[2.2.1]heptanes, which react with nncleophiles, such as silyl enol ethers, mediated by tin(II) chloride, generating 2-substitnted-pyrroles that can be nsed, as the example shows, for the synthesis of indoles via intramolecular electrophilic attack by the carbonyl group at the pyrrole P-position. 

The second part of lanosterol biosynthesis is catalyzed by oxidosqualene lanosterol cyclase and occurs as shown in Figure 27.14. Squalene is folded by the enzyme into a conformation that aligns the various double bonds for undergoing a cascade of successive intramolecular electrophilic additions, followed by a series of hydride and methyl migrations. Except for the initial epoxide protonation/cyclization, the process is probably stepwise and appears to involve discrete carbocation intermediates that are stabilized by electrostatic interactions with electron-rich aromatic amino acids in the enzyme. 

Thiiranes can be formed directly and stereospecifically from 1,2-disubstituted alkenes by addition of trimethylsilylsulfenyl bromide, formed at -78 C from reaction of bromine with bis(trimethylsilyl) sulfide (Scheme 7).12 A two-step synthesis of thiiranes can be achieved by addition of succinimide-A/-sulfe-nyl chloride or phthalimide-A -sulfenyl chloride to alkenes followed by lithium aluminum hydride cleavage of the adducts (Scheme 8).13 Thiaheterocycles can also be formed by intramolecular electrophilic addition of sulfenyl chlorides to alkenes, e.g. as seen in Schemes 914 and 10.13 Related examples involving sulfur dichloride are shown in Schemes 1116 and 12.17 In the former case addition of sulfur dichloride to 1,5-cyclooctadiene affords a bicyclic dichloro sulfide via regio- and stereo-specific intramolecular addition of an intermediate sulfenyl chloride. Removal of chlorine by lithium aluminum hydride reduction affords 9-thiabicyclo[3.3.1]nonane, which can be further transformed into bicyclo[3.3.0]oct-1,5-ene.16 

As noted in the introduction, in contrast to attack by nucleophiles, attack of electrophiles on saturated alkene-, polyene- or polyenyl-metal complexes creates special problems in that normally unstable 16-electron, unsaturated species are formed. To be isolated, these species must be stabilized by intramolecular coordination or via intermolecular addition of a ligand. Nevertheless, as illustrated in this chapter, reactions of significant synthetic utility can be developed with attention to these points. It is likely that this area will see considerable development in the future. In addition to refinement of electrophilic reactions of metal-diene complexes, synthetic applications may evolve from the coupling of carbon electrophiles with electron-rich transition metal complexes of alkenes, alkynes and polyenes, as well as allyl- and dienyl-metal complexes. Sequential addition of electrophiles followed by nucleophiles is also viable to rapidly assemble complex structures. 

In qualitative terms, the rearrangement reaction is considerably more efficient for the oxime acetate 107b than for the oxime ether 107a. As a result, the photochemical reactivity of the oxime acetates 109 and 110 was probed. Irradiation of 109 for 3 hr, under the same conditions used for 107, affords the cyclopropane 111 (25%) as a 1 2 mixture of Z.E isomers. Likewise, DCA-sensitized irradiation of 110 for 1 hr yields the cyclopropane derivative 112 (16%) and the dihydroisoxazole 113 (18%). It is unclear at this point how 113 arises in the SET-sensitized reaction of 110. However, this cyclization process is similar to that observed in our studies of the DCA-sensitized reaction of the 7,8-unsaturated oximes 114, which affords the 5,6-dihydro-4//-l,2-oxazines 115 [68]. A possible mechanism to justify the formation of 113 could involve intramolecular electrophilic addition to the alkene unit in 116 of the oxygen from the oxime localized radical-cation, followed by transfer of an acyl cation to any of the radical-anions present in the reaction medium. 

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