Aryl halides elimination-addition

In Grignard reactions, Mg(0) metal reacts with organic halides of. sp carbons (alkyl halides) more easily than halides of sp carbons (aryl and alkenyl halides). On the other hand. Pd(0) complexes react more easily with halides of carbons. In other words, alkenyl and aryl halides undergo facile oxidative additions to Pd(0) to form complexes 1 which have a Pd—C tr-bond as an initial step. Then mainly two transformations of these intermediate complexes are possible insertion and transmetallation. Unsaturated compounds such as alkenes. conjugated dienes, alkynes, and CO insert into the Pd—C bond. The final step of the reactions is reductive elimination or elimination of /J-hydro-gen. At the same time, the Pd(0) catalytic species is regenerated to start a new catalytic cycle. The transmetallation takes place with organometallic compounds of Li, Mg, Zn, B, Al, Sn, Si, Hg, etc., and the reaction terminates by reductive elimination. 

In the reaction of Q,/3-unsaturated ketones and esters, sometimes simple Michael-type addition (insertion and hydrogenolysis, or hydroarylation, and hydroalkenylation) of alkenes is observed[53,54]. For example, a simple addition product 56 to methyl vinyl ketone was obtained by the reaction of the heteroaromatic iodide 55[S5]. The corresponding bromide affords the usual insertion-elimination product. Saturated ketones are obtained cleanly by hydroarylation of o,/3l-unsaturated ketones with aryl halides in the presence of sodium formate, which hydrogenolyses the R—Pd—I intermediate to R— Pd—H[56]. Intramolecular hydroarylation is a useful reaction. The diiodide 57 reacts smoothly with sodium formate to give a model compound for the afla-toxin 58. (see Section 1.1.6)[57]. Use of triethylammonium formate and BU4NCI gives better results. 

The generally accepted mechanism for nucleophilic aromatic substitution m nitro substituted aryl halides illustrated for the reaction of p fluoromtrobenzene with sodium methoxide is outlined m Figure 23 3 It is a two step addition-elimination mechanism, m which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group Figure 23 4 shows the structure of the key intermediate The mech anism is consistent with the following experimental observations... 

Other aryl halides that give stabilized anions can undergo nucleophilic aromatic substitution by the addition-elimination mechanism Two exam pies are hexafluorobenzene and 2 chloropyridme... 

The reaction between an alkoxide ion and an aryl halide can be used to prepare alkyl aryl ethers only when the ar yl halide is one that reacts rapidly by the addition-elimination mechanism of nucleophilic aromatic substitution (Section 23.6). 

Elimination-addition mechanism (Section 23.8) Two-stage mechanism for nucleophilic aromatic substitution. In the first stage, an aryl halide undergoes elimination to form an aryne intermediate. In the second stage, nucleophilic addition to the aryne yields the product of the reaction. 

In the arylations of enamines with very reactive aryl halides (352,370) such as 2,4-dinitrochlorobenzene, the closely related mechanistic pathway of addition of the enamine to the aromatic system, followed by elimination of halide ion, can be assumed. The use of n-nitroarylhalides furnishes compounds which can be converted to indolic products by reductive cycliza-tion. Less reactive aryl halides, such as p-nitrochlorobenzene, lead only to N-arylation or oxidation products of the enamines under more vigorous conditions. 

Aryl halides undergo substitution, although not through an Sn2 mechanism, but rather via a two-step addition-elimination mechanism. (An elimination-addition mechanism is also possible see Chapter 13, Problem 12.)... 

This reaction is not a bona fide Heck reaction per se for two reasons (a) the starting material underwent a Hg Pd transmetallation first rather than the oxidative addition of an aryl halide or triflate to palladium(O) (b) instead of undergoing a elimination step to give an enone, transformation 134 136... 

The mechanism of action of the cyanation reaction is considered to progress as follows an oxidative addition reaction occurs between the aryl halide and a palladium(O) species to form an arylpalladium halide complex which then undergoes a ligand exchange reaction with CuCN thus transforming to an arylpalladium cyanide. Reductive elimination of the arylpalladium cyanide then gives the aryl cyanide. 

The possible mechanism for the reactions involving stoichiometric amount of preformed Ni(0) complexes is shown in Fig. 9.8. The first step of the mechanism involves the oxidative addition of aryl halides to Ni(0) to form aryl Ni(II) halides. Disproportion of two aryl Ni(II) species leads to a diaryl Ni(II) species and a Ni(II) halide. This diaryl Ni(II) species undergoes rapid reductive elimination to form the biaryl product. The generated Ni(0) species can reenter the catalytic cycle. 

This cycle involves, first, a monoelectronic transfer from the nickel (0) complex to the aryl halide affording a Ni(I) complex and then an oxidative addition affording a 16 electron-nickel (II) which undergoes a nucleophilic substitution of Nu-, then a monoelectronic transfer occurs once again with a second aryl halide, and, last, a reductive elimination of the arylated nucleophile regenerates the active Ni(I) species. 

The palladium(O) complex undergoes first an oxydative addition of the aryl halide. Then a substitution reaction of the halide anion by the amine occurs at the metal. The resulting amino-complex would lose the imine with simultaneous formation of an hydropalladium. A reductive elimination from this 18-electrons complex would give the aromatic hydrocarbon and regenerate at the same time the initial catalyst. 

The Mizoroki-Heck reaction is a metal catalysed transformation that involves the reaction of a non-functionalised olefin with an aryl or alkenyl group to yield a more substituted aUcene [11,12]. The reaction mechanism is described as a sequence of oxidative addition of the catalytic active species to an aryl halide, coordination of the alkene and migratory insertion, P-hydride elimination, and final reductive elimination of the hydride, facilitated by a base, to regenerate the active species and complete the catalytic cycle (Scheme 6.5). 

The mechanism involves a Pd(0) monocoordinate complex as the active species that undergoes oxidative addition to the aryl halide [141]. Thereafter, coordination of the amine to the palladium centre and deprotonation by the external base results in halide abstraction. After reductive elimination, the coupling product is obtained and the catalytic active species regenerated (Scheme 6.45). 

Several studies were performed in order to establish the mechaiusm (5-7). The currently accepted mechartism, presented in Scheme 26.1 for the Pd(BINAP) catalyzed amination, involves the formation of a complex, Pd(BINAP)2 from a catalyst precursor (usually Pd(OAc)2 or Pd2(dba)3) and ligand this complex lies outside the catalytic cycle and undertakes dissociation of one BINAP to form Pd(BINAP) the following steps are the oxidative addition of the aryl halide to the Pd(BINAP), reaction with amine and base, and the reductive elimination of the product to reform Pd(BlNAP). 

There are a number of procedures for coupling of terminal alkynes with halides and sulfonates, a reaction that is known as the Sonogashira reaction.161 A combination of Pd(PPh3)4 and Cu(I) effects coupling of terminal alkynes with vinyl or aryl halides.162 The reaction can be carried out directly with the alkyne, using amines for deprotonation. The alkyne is presumably converted to the copper acetylide, and the halide reacts with Pd(0) by oxidative addition. Transfer of the acetylide group to Pd results in reductive elimination and formation of the observed product. 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

A general mechanistic description of the copper-promoted nucleophilic substitution involves an oxidative addition of the aryl halide to Cu(I) followed by collapse of the arylcopper intermediate with a ligand transfer (reductive elimination).140... 

The present reaction may be reasonably explained by the smooth oxidative addition of aryl halides to metallic nickel to give aryl nickel halides, followed by disproportionation to bisarylnickels, which upon reductive elimination afford the dehalogenative coupled products. Providing strong support for this mechanism, the intermediates, arylnickel halide and bisarylnickel (Ar=C F ), were isolated as the phosphine complexes. 

In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

In addition to /3-H elimination, olefin insertion, and protonolysis, the cr-metal intermediate has also proved to be capable of undergoing a reductive elimination to bring about an alkylative alkoxylation. Under Pd catalysis, the reaction of 4-alkenols with aryl halides affords aryl-substituted THF rings instead of the aryl ethers that would be produced by a simple cross-coupling mechanism (Equation (126)).452 It has been suggested that G-O bond formation occurs in this case by yy/z-insertion of a coordinated alcohol rather than anti-attack onto a 7r-alkene complex.453... 

Larock and co-workers described the one-step Pd-catalyzed reaction of o-haloanilines with internal alkynes to give indoles [385, 386]. This excellent reaction, which is shown for the synthesis of indoles 303, involves oxidative addition of the aryl halide (usually iodide) to Pd(0),. vyw-insertion of the alkyne into the ArPd bond, nitrogen displacement of the Pd in the resulting vinyl-Pd intermediate, and final reductive elimination of Pd(0). 

Arylation of cycloalkenes.1 Aryl halides undergo Heck coupling with cy-cloalkenes in the presence of a palladium catalyst. The reaction involves addition of an arylpalladium intermediate to the double bond followed by elimination of a palladium hydride. 

The proposed mechanism involves the usual oxidative addition of the aryl halide to the Pd(0) complex affording a Pd(II) intermediate (Ar-Pd-Hal), subsequent coordination of allene 8 and migratory insertion of the allene into the Pd-C bond to form the jt-allylpalladium(II) species 123. A remarkable C-C bond cleavage of 123 leads by decarbopalladation to 1,3-diene 120 and a-hydroxyalkylpalladium species 124. /8-H elimination of 124 affords aldehyde 121 and the H-Pd-Hal species, which delivers Pd(0) again by reaction with base (Scheme 14.29). The originally expected cyclization of intermediate 123 by employment of the internal nucleophilic hydroxyl group to form a pyran derivative 122 was observed in a single case only (Scheme 14.29). 

Alkanesulfonyl halides are not the only alkanesulfonyl derivatives that can undergo substitution by an elimination-addition mechanism. A number of aryl esters of phenylmethanesulfonic acid, PhCH2SOzOAr, undergo alkaline hydrolysis and aminolysis by such a pathway, and study of these reactions has been particularly valuable in providing insight into the detailed mechanism for sulfene formation (Williams et al., 1974 King and Beatson, 1975 Davy et al., 1977). 

The first step, as usual with aryl halides, is oxidative addition of Pd(0) to the C-I bond. This step makes C2 reactive. Coordination of the alkyne to Pd(IE) and insertion makes the C2-C7 bond and gives an alkenylpalladium(II) complex. Finally, coordination of N to Pd(IE), removal of HI by the base, and reductive elimination provides the product and regenerates Pd(0). 

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