Intramolecular electrophilic addition

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. 

Detailed mechanistic studies by Fodor demonstrated the intermediacy of both imidoyl chlorides (6) and nitrilium salts (7) in Bischler-Napieralski reactions promoted by a variety of reagents such as PCI5, POCI3, and SOCh)/ For example, amide 1 reacts with POCI3 to afford imidoyl chloride 6. Upon heating, intermediate 6 is converted to nitrilium salt 7, which undergoes intramolecular electrophilic aromatic substitution to afford the dihydroisoquinoline 2. Fodor s studies showed that the imidoyl chloride and nitrilium salt intermediates could be generated under mild conditions and characterized spectroscopically. Fodor also found that the cyclization of the imidoyl chlorides is accelerated by the addition of Lewis acids (SnCU, ZnCh), which provides further evidence to support the intermediacy of nitrilium salts. ... 

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). 

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. 

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. 

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. 

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). 

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. 

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. 

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. 

Electrophilic additions to 7t-deficient heterocycles are less common than those to 7t-excessive heterocycles. However, intramolecular electrophilic cyclizations have been used to access the heterocycles of interest in this chapter <1996CHEC-II(7)49>. Recent examples include the preparation of a pyrrolo[2,3-f]pyrazole 165 by acid-catalyzed condensation of 163 and 164 (Equation 37) <1999SC311> and the reaction of 3-(4-pyrazolyl)acrylic acids 166 with excess thionyl chloride in the presence of benzyltriethylammonium chloride (BTEAC) to afford 4-chlorothieno[2,3-f]pyrazole-5-carbonyl chlorides 167 (Equation 38) <2003RJ0893, 2003ZOK942>. In the latter case, the reaction products were readily manipulated to prepare corresponding carboxylic acids, esters, and amides using standard procedures. 

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

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. 

While examples of intermolecular electrophilic additions to 7t-deficient heterocycles are reported less frequently than with -excessive heterocycles, intramolecular electrophilic cyclization strategies can be used to access some heterocycles of interest. In some cases, different reaction conditions can afford isomeric heterocycles as exemplified in the cyclization of 1,2-diaryl ketols with 2-amino-pyrazoles. With hydrogen chloride in the reaction media, pyrrolo[2,3-c]pyrazoles (170) are obtained, whereas imidazo[l,2-6]pyrazoles (171) were obtained in the absence of hydrogen chloride (Scheme 29) <84JHC945>. Cycloacylation of the a-(thiazolylthio)acetic acid (172) was accomplished with phosphorus oxychloride to give thiazole (173) (Equation (50)) <56AC(R)275>. 

A number of useful enantioselective syntheses can be performed by attaching a chiral auxihary group to the selenium atom of an appropriate reagent. Examples of such chiral auxiliaries include (49-53). Most of the asymmetric selenium reactions reported to date have involved inter- or intramolecular electrophilic additions to alkenes (i.e. enantioselective variations of processes such as shown in equations (23) and (15), respectively) but others include the desymmefrization of epoxides by ringopening with chiral selenolates, asymmetric selenoxide eliminations to afford chiral allenes or cyclohexenes, and the enantioselective formation of allylic alcohols by [2,3]sigmafropic rearrangement of allylic selenoxides or related species. 

In the absence of efficient Nps-Q (92) capture, this intermediate reacts with the indole side chain of tryptophan residues to produce the related 2-Nps derivatives 96 (Scheme 48). Although reaction of sulfenyl hahdes with indoles was exploited by Wieland et al.t for the synthesis of phaUoidin, this side reaction leads to irreversible modification of Trp-containing peptides.This side reaction does not occur via an intramolecular electrophilic substitution as postulated previously,but by a direct attack of the Nps-Cl (92) in fact, it is efficiently suppressed by the addition of a large excess of an indole derivative as a scavenger.These scavengers serve also to decrease the proton activity of the acids vide supra). Due to the unpleasant odor of 2-methylindole the less volatile 1-acetyltryptophan butyl ester has been proposed as scavenger.f ... 

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... 

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]. 

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. 

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