Substitution transmetallation

Among several propargylic derivatives, the propargylic carbonates 3 were found to be the most reactive and they have been used most extensively because of their high reactivity[2,2a]. The allenylpalladium methoxide 4, formed as an intermediate in catalytic reactions of the methyl propargylic carbonate 3, undergoes two types of transformations. One is substitution of cr-bonded Pd. which proceeds by either insertion or transmetallation. The insertion of an alkene, for example, into the Pd—C cr-bond and elimination of/i-hydrogen affords the allenyl compound 5 (1.2,4-triene). Alkene and CO insertions are typical. The substitution of Pd methoxide with hard carbon nucleophiles or terminal alkynes in the presence of Cul takes place via transmetallation to yield the allenyl compound 6. By these reactions, various allenyl derivatives can be prepared. 

Recently, Aumann et al. reported that rhodium catalysts enhance the reactivity of 3-dialkylamino-substituted Fischer carbene complexes 72 to undergo insertion with enynes 73 and subsequent formation of 4-alkenyl-substituted 5-dialkylamino-2-ethoxycyclopentadienes 75 via the transmetallated carbene intermediate 74 (Scheme 15, Table 2) [73]. It is not obvious whether this transformation is also applicable to complexes of type 72 with substituents other than phenyl in the 3-position. One alkyne 73, with a methoxymethyl group instead of the alkenyl or phenyl, i.e., propargyl methyl ether, was also successfully applied [73]. 

Scheme 15 Formation of 4-alkenyl(phenyl)-substituted 5-dialkylamino-2-ethoxycyclopen-tadienes 75 via transmetallated alkyne-inserted rhodium-carbene complexes 74 [73]. For further details see Table 2...

The coupling of terminal alkynes with aryl or alkenyl halides catalysed by palladium and a copper co-catalyst in a basic medium is known as the Sonogashira reaction. A Cu(I)-acetylide complex is formed in situ and transmetallates to the Pd(II) complex obtained after oxidative addition of the halide. Through a reductive elimination pathway the reaction delivers substituted alkynes as products. 

In terms of scope and chemoselectivity, hydrozirconation takes its place between hydroboration and hydroaiumination. However, the synthetic applications of organozirconocene complexes have been considerably expanded over these last few decades, and it can be expected that they will become more and more attractive in the future. Beside the direct substitution sequences, indirect reaction pathways involving transmetalation or activation by ligand abstraction have been successfully applied in a number of cross-coupling and C-C bond-forming reactions. 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

As part of a study into the activation of metal catalysts in thiol or thiolate-rich environments, X-substituted coenzyme M and thioglycolate derivatives were investigated in a Ni-catalyzed crosscoupling reaction with a zinc co-factor the role of zinc was shown to be in a transmetallation process.571... 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

In general, the syntheses of these complexes are achieved through (i) nucleophilic addition/substitution reactions of silver(i) fluoride or (ii) transmetallation reactions with other metal alkyl, alkenyl, and aryl complexes. 

A tandem enolate-arylation-allylic cyclisation, in which an essential z-butyldimethylsilyl ether protecting group delays the cyclisation step until the Pd-catalysed arylation is complete, enables 1-vinyl-l//-[2]benzopyrans 54 to be prepared from 2-bromobenzaldehyde (Scheme 32) <00CC1675>. 4-Substituted isochromans 55 are formed from aldehydes by a Pd-catalysed termolecular queuing cascade. The sequence involves cyclisation of an aryl iodide onto a proximate alkyne followed by an allene insertion. Transmetallation with indium then allows addition to the aldehyde (Scheme 33) . 

In the case of 1,3-cyclohexadiene with Me2Zn, the dicarboxylation afforded the /rdicarboxylic acid 96 (Scheme 33). In contrast, when Ph2Zn was used instead of Me2Zn as a transmetallation agent, the phenylative carboxylation occurred in high regio- and stereoselectivity to give the l,4-m-substituted-2-cyclohexene 97, as a result of reductive elimination from the phenyl-7r-allylnickel intermediate, prior to the second carboxylation reaction (Scheme 33).47... 

Hetero-substituted r)3-allyltitanocenes have also been studied. Functionalized q3-allyltita-nium complexes (X = SiMe3, OPh, SPh) have been prepared by transmetallation of Cp2TiCl with the corresponding allyllithiums, and were found to react regiospecifically with propionaldehyde to give functionalized homoallylic alcohols 11 (Scheme 13.14) [25]. 

While the transmetalation step is often the rate-determining step for Pd-catalyzed reactions with organometallics, the oxidative addition step is often the rate-determining step in the Heck reactions, although olefin insertion can be rate-limiting in some cases — this is why the Heck reactions of tri- and tetra-substituted olefins sometimes proceed slower than those of di-substituted and terminal olefins. 

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