Hetero arenes alkylation

While electrophilic substitution reactions enabled the direct functionalizations of (hetero)arenes, Fittig observed, during the nineteenth century, that halogenated arenes could be employed for the preparation of alkylated arenes in the presence of sodium under Wurtz s reaction conditions [24—26]. 

The radical alkylation of protonated heteroaromatic compounds-the so-called Minisci reaction-has been intensively investigated [2e, g, 111]. Protonated hetero-arenes are electron-deficient substrates, which react with nucleophilic radicals with high regioselectivity to yield the corresponding homolytic aromahc substitution products. For para-substituted pyridine derivatives the reaction occurs with complete regioselectivity at the 2-position, whereas for nonprotonated pyridines, arylations occur with low regioselectivity and in low yields. 

Ackermann L (2010) Metal-catalyzed direct alkylations of (hetero)arenes via C-H bond cleavages with unactivated alkyl halides. Chem Commun 46(27) 4866 877... 

In this chapter, the recent progress in transition-metal-catalyzed C-H alkylation (until the end of 2011) will be presented. These reactions have been divided into three categories differing in the nature of the alkylating agent an electrophilic alkyl source (Scheme 19.2a, part 2), an alkyl metal (Scheme 19.2b, part 3), or an alkene (hydroarylation of alkenes. Scheme 19.2c, part 4). Reactions that do not involve the formation of a (hetero)arene-transition metal intermediate during the catalytic cycle have been excluded. Extensions to nonaromatic C(sp )-H bonds, that is, C(sp )-H of alkenes, and C(sp )-H bonds wiU also be reviewed. As for... 

Intramolecular palladium-catalyzed alkylations of (hetero)arenes have been pioneered by Wong and Song [25], who described in 1994 a direct benzylation of furans within a domino sequence starting with the intermolecular Suzuki- Miyaura coupling of furylboroxines with o-bis(bromomethyl)arenes (Scheme 19.14). Mixtures of the cross-coupled product and the corresponding homocoupled furan were almost always obtained. 

In addition to directed and intramolecular C-H alkylations, palladium-catalyzed intermolecular C-H alkylations have been reported. In this case, the regioselec-tivity of the C-H bond cleavage is controlled by the natural reactivity of the (hetero)arenes, which corresponds to the longest C-H bond, often correlating with the most acidic C-H bond, in the CMD mechanism [31]. 

The iron-catalyzed alkylation of hetero(arenes) has also been described by employing a similar metallation strategy (Scheme 19.34) [54]. Furan, thiophene, and pyridine proved to be successftd heteroaromatic partners with both primary and secondary alkyl halide electrophiles. Electron-deficient arenes were also efficiently alkylated, but less acidic substrates such as tetrafluoroanisole failed to provide the desired alkylated product... 

Scheme 19.34 Iron-catalyzed alkylation of (hetero)arenes.

Scheme 19.56 (a, b) Alkylation of (hetero)arenes directed by a formyl group. 

Horie and coworkers used phosphine-free conditions in NMP to couple 4,4-bis(2-alkyl)-4//-eyelopenta[2,l-ft 3,4-fc ]dithiophene (CPDT), A -(l-alkyl)dithieno[3,2-b 2, 3 -fi(]pyrrole and 4,4 -bis(2-alkyl)dithieno[3,2- ) 2, 3 -t/]-silole with dibrominated (hetero)arenes to give polymers 19-23 (Chart 19.5). Polymers with high molecular weights were only achieved for 19 (M = 72 kDa, PDI = 4.5) due to side reactions and insolubiUty of the other polymers. ... 

These early examples provided the impetus for the development of C-H bond activation in alkanes and arenes. An important advance in this respect was the example reported by Chatt for the [Ru(0)(dmpe)2] 12 catalyzed C-H bond activation of naphthalene 13 (also some amount of C H activated product of the alkyl phosphines could be observed). It is the first reported example of the C-H bond activation of (hetero)arenes by a transition metal complex and Chatt has therefore been credited to have laid the foundation for the rapid development of synthetically viable and environmentally attractive C C bond forming technologies via C-H bond activation (Fig. 5). Later Chatt suggested that the above transformation could be occurring through an oxidative addition mechanism which has been since then commonly accepted. 

Alkyne replacements have also been reported. In 2008, Sakai et al. described the use of alkynylsilanes instead of terminal alkynes in the Cu-catalyzed synthesis of propargyl-amines, which was applicable to both secondary and primary aliphatic amines, although the latter afforded the corresponding products in low yield [145]. Very recently. Van der Eycken et al. applied the A -coupling to the C—H alkylation of azoles through a copper-catalyzed hetero-arene-amine-aldehyde/ketone coupling [146]. This reaction is proposed to proceed through the initial condensation of... 

Abstract The selective catalytic activation/functionalization of sp C-H bonds is expected to improve synthesis methods by better step number and atom economy. This chapter describes the recent achievements of ruthenium(II) catalysed transformations of sp C-H bonds for cross-coupled C-C bond formation. First arylation and heteroarylation with aromatic halides of a variety of (hetero)arenes, that are directed at ortho position by heterocycle or imine groups, are presented. The role of carboxylate partners is shown for Ru(II) catalysts that are able to operate profitably in water and to selectively produce diarylated or monoarylated products. The alkylation of (hetero)arenes with primary and secondary alkylhalides, and by hydroarylation of alkene C=C bonds is presented. The recent access to functional alkenes via oxidative dehydrogenative functionalization of C-H bonds with alkenes first, and then with alkynes, is shown to be catalysed by a Ru(ll) species associated with a silver salt in the presence of an oxidant such as Cu(OAc)2. Finally the catalytic oxidative annulations with alkynes to rapidly form a variety of heterocycles are described by initial activation of C-H followed by that of N-H or O-H bonds and by formation of a second C-C bond on reaction with C=0, C=N, and sp C-H bonds. Most catalytic cycles leading from C-H to C-C bond are discussed. 

Ruthenium(II)-Catalysed Alkylation of Alkenes and (Hetero)arenes. 142... 

Alkylation of (Hetero)arenes and Alkenes with Alcohols. 149... 

Simple ruthenium(II) catalysts can now perform heterocycle directed alkylation and Friedel-Crafts type reactions at orf/io-positions of arenes and heteroarenes. The former reaction takes places without p elimination and the latter reaction takes place without addition of Lewis acid to form arenes containing a ketone, amide, or ester functionality. Hydroarylation of strained alkenes can be performed to obtain ortho alkyl (hetero)arenes and alkylation of sp C-H bond can be observed using alcohol as a precursor. 

Ruthenium(II)-catalysed activation of C-H bond offers many challenges to overcome. One of the first deals with regioselectivity, especially for the activation of para and meta C-H bonds of (hetero)arenes instead of the ortho C-H bonds. A few examples have already appeared in the selective sulfonation and alkylation with secondary alkylhalides of arenes. New efforts will probably lead to fill this gap. 

The unrestricted and free electron transfer (FET) from donor molecules to solvent radical cations of alkanes and alkyl chlorides has been studied by electron pulse radiolysis in the nanosecond time range. In the presence of arenes with hetero-atom-centered substituents, such as phenols, aromatic amines, benzylsilanes, and aromatic sulfides as electron donors, this electron transfer leads to the practically simultaneous formation of two distinguishable products, namely donor radical cations and fragment radicals, in comparable amounts. 

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