Nucleophiles functionalized arenes

The symmetric series provides functional cyclohexadienes, whereas the non-symmetric one serves to build deuterated and/or functional arenes and tentacled compounds. In both series, several oxidation states can be used as precursors and provide different types of activation. The complexes bearing a number of valence, electrons over 18 react primarily by electron-transfer (ET). The ability of the sandwich structure to stabilize several oxidation states [21] also allows us to use them as ET reagents in stoichiometric and catalytic ET processes [18, 21, 22]. The last well-developed type of reactions is the nucleophilic substitution of one or two chlorine atoms in the FeCp+ complexes of mono- and o-dichlorobenzene. This chemistry is at least as rich as with the Cr(CO)3 activating group and more facile since FeCp+ activator is stronger than Cr(CO) 3. 

It is well-known that nucleophilic substitution reactions of diaryliodonium salts (74), prepared by the reaction of substituted arenes (73) with iodine(III) reagents such as PIDA, PIFA, Phl=0, and I(OCOCF3)3, smoothly proceed to yield various functionalized arenes (75) [49] [Eq. (15)]. 

Grignard reagents and enolates are especially suitable for such nucleophilic additions. The resulting products are of synthetic interest since oxidation leads to rapid release of the metal group, and the free, functionalized arenes are readily obtained ... 

The use of a strong Lewis acid (AI2CI6) precludes the use of arenes with nucleophilic functional groups (anilines, benzoate esters, etc.) and may also lead to the rearrangement of alkyl substituents bound to the arene. 

Because of their electrophilic and reactive nature, arene oxides also may undergo spontaneous reactions with nucleophilic functionalities present on biomacromolecules. Such reactions lead to modified protein. DNA. and RNA structures and often cau.se dramatic alterations in how these macromoleculcs function. Much of the cytotoxicity and irreversible lesions caused by arcnc oxides are presumed to result from their covalent binding to cellular components. Several wcll-establi.shed examples of reactive arene oxides that cause serious toxicity ate presented below. 

The reactions of HTIB with alkenes (Scheme 3.73) can be rationalized by a polar addition-substitution mechanism similar to the one shown in Scheme 3.70. The first step in this mechanism involves electrophilic flnfi-addition of the reagent to the double bond and the second step is nucleophilic substitution of the iodonium fragment by tosylate anion with inversion of configuration. Such a polar mechanism also explains the skeletal rearrangements in the reactions of HTIB with polycyclic alkenes [227], the participation of external nucleophiles [228] and the intramolecular participation of a nucleophilic functional group with the formation of lactones and other cyclic products [229-231]. An analogous reactivity pattern is also typical of [hydroxy(methanesulfonyloxy)iodo]benzene [232] and other [hydroxy(organosulfonyloxy)iodo]arenes. 

Abstract Electrochemical methodology has been exploited to develop new synthetic routes and to rationalize the mechanism for the C-H functionalization of arenes and heteroarenes. The advantages of the electrochemical approach to perform nucleophilic aromatic substitution reactions, such as a low cost and availability of reagents, atom economy and high yields, provide an environmentally friendly way to functionalize arenes and heteroarenes. 

In this chapter, the applications of douhle-functionalized arenes in the synthesis of five-memhered heterocycles will he discussed. The eontents are divided according to the different types of substrates applied. The subchapters are organized based on the types of nucleophiles o/t/jo-substituted to aryl halides. For the heterocycle synthesis based on C-X bond activation, in general, transition metal catalyst promoted activation of the C-X bond initiated the reaction sequence and was followed by intramolecular or intermolecular cyclization. 

Studies using powerful nucleophiles (so that addition is faster than elimination) at low temperature have shown that the mechanism is not so simple. Kinetic attack is meta to the substituent giving an anionic T) -complex 10.183 (Scheme 10.49). At low temperatures the addition product 10.183 can be intercepted. Mild oxidation gives the free, functionalized arene 10.184. If the addition product 10.183 is allowed to warm up, addition reverses and ultimately addition is at the ipso position, followed by elimination to give the substitution product 10.186 via t -complex 10.185. 

Water is of course the most prevalent nucleophile in the body, but by no means the only one. Deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, and enzymes also have nucleophilic functional groups and occasionally such groups can compete with water in the opening of arene... 

The concept of a diastereoselective Friedel-Crafts alkylation of a-chiral benzyl alcohols was first examined by Bach and coworkers [62, 63]. The initial protocol required stoichiometric amounts of strong Brpnsted acids like HBF4 and was followed by a more valuable methodology in which catalytic amounts of AuC L were employed for the diastereoselective functionalization of chiral benzyl alcohols [64], Beside arenes, allyl silanes, 2,4-pentanediones and silyl enol ethers have been used as nucleophiles. Depending on the diastereodiscriminating group and on the catalyst (Brpnsted or Lewis acid), the authors observed either the syn or the anti diastereoisomer as the major product. 

Related studies have recently been reported by the same author on propargyl steres reactions with dicarbonyl compounds or electron-rich arenes [135], to provide an atom-economical functionalization of carbon nucleophiles under catalytic conditions, using a very different method of addition catalyzed by Lewis acids [136]. 

Considerable advances were made in the organic chemistry of the methinyltricobalt enneacarbonyls. It was shown that the C03C core can function as an electron donor as well as an electron acceptor 143), allowing electrophilic and nucleophilic attack at the apical carbon atom. Arenes and Co3(CO)9CHal form Co3(CO)9CAr... 

The synthetic application of vicarious nucleophilic substitution, whereby hydrogen of an electrophilic arene is replaced by an a-functionalized alkyl substituent, has been reviewed 177 the sequence usually involves attack on a nitroalkene by a carbanion containing a leaving group X at the carbanionic centre, /i-elimination of HX from the er-adduct, and rearomatization on subsequent protonation. 

The Knoevenagel reaction is a base-catalyzed condensation between a dialdehyde and an arene possessing two sites with relatively acidic protons. In this polymerization, shown schematically in Scheme 34, deprotonation affords a difunctional nucleophile that subsequently attacks the carbonyl functionalities present in the other monomers. Elimination is the final step in the Knoevenagel sequence, and the use of monomers with highly acidic protons drives the reaction to completion. A number of research groups have employed this method to obtain PPV and its substituted analogs 29 [126,140-146]. 

Iodine, NIS, PhSeCl, and AUCI3 have been shown to trigger the electrophilic 6(O) "-endo-dig cyclization of 2-(alk-l-ynyl)alk-2-en-l-ones (22) to produce highly substituted furans (23) (Scheme 3). Various nucleophiles, including functionally substituted alcohols, H2O, carboxylic acids, 1,3-diketones, and electron-rich arenes, and a range of cyclic and acyclic 2-(alk-l-ynyl)alk-2-en-l-ones readily participate in these cyclizations.40... 

Of particular interest is the observation that in certain cases products such as 24 resulting from domino processes are obtained After the formation of the furan, evidently a double Michael-type addition of these intermediates to the remaining starting material 23 can take place at the unsubstituted 5-position. Preliminary experiments to investigate scope and limitations of such addition reactions in the presence of gold salts also confirm the applicability to the functionalization of other electron-rich arenes (Scheme 6) Besides furans, azulene 28 and di- and trialkoxybenzene are suitable as nucleophiles for the reaction with unsaturated carbonyl compounds [14]. For instance, 2-methylfuran (25) reacts at the reactive 5-position with methyl vinyl ketone 26 to give the addition product 27, and with azulene 28 a twofold... 

The scope and value of the benzannulation reaction is further increased by the substitution pattern of the arene ring, which can be modified by the incorporation of allcynes bearing additional functional groups such as silyl, stannyl, or boryl substituents. These functional groups have been used in various palladium-catalyzed (cross)-coupling reactions [63, 64]. Further structural elaboration may be based on benzannulation followed by nucleophilic aromatic addition [63b]. 

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