Metallation Transmetallation

Carreira and Kruger reported facile transmetallation of silicon enolates to other soft metal enolates including Gu derivatives.499 They reasoned that the use of soft metal fluoride complexes enabled silyl metal transmetallation with catalytic use of a soft metal source. The concept is illustrated in Scheme 103. Normal Lewis acid-catalyzed reactions of silicon enolates with aldehydes proceed via activation of aldehydes by carbonyl oxygen coordination to Lewis acids, as shown in the upper equation of Scheme 103. A key step for catalytic turnover is the desilyation of 233 by the... 

The rearrangement of 5-bromo-3-methoxy-2-phenylimidazolo[l,2-a] pyridine (70) into the 8-isomer 73 also undoubtedly involves a sequential metalation, transmetalation, and metal-halogen exchange pathway involving intermediates 71-75 and the noncatalytic generation of the 5,8-dibromo derivative 75 (Scheme 20) (83S987). 

LDA and related, sterically hindered, lithium dialkylamides, first investigated by Levine [1], have completely replaced the more nucleophilic sodium amide, which had been the base of choice for many years [2], Because the reactivity of an organo-metallic compound depends to a large extent on its state of aggregation (i.e. on the solvent and on additives) and on the metal, transmetalation of the lithiated intermediates and the choice of different solvents and additives emerged as powerful strategies for fine-tuning the reactivity of these valuable nucleophiles. 

Whereas uncatalyzed substitution reactions of organozinc compounds are limited to very reactive electrophiles, metal-transmetallated organozinc compounds are able to perform substitution reactions on various electrophiles. In the case of conjugated electrophiles, these zinc copper reagents can follow a Sn2 or Sn2 mechanism. 

Chapters 9 through 12 focus on the use of microemulsions to modify reaction rate and pathway. Included are studies of porphyrin metalation, transmetalation, the Wacker process, and the hydrolysis of chlorophyll. 

Several years ago, we developed a contrathermodynamic isomerization of a- to 3-pinene via diethylmyrtenylborane obtained from a-pinene by metalation-transmetalation.11 Later, (+)-p-pinene of > 99 % ee was prepared by this method.22 Extending this work to other bicyclic monoterpenes, the isomerization of (+)-2-, (+)-3-carene, and (-)-a-thujene, was studied.13 Among bicyclic monoterpene olefins with an exocyclic double bond, 3(10)-carene is a rare compound reported only a few times in the long history of terpene chemistry, and its rotation is still controversial.23,24 Sabinene is isolated from the oil of savin, and no convenient synthesis of an optically active sabinene is known. 

Initially, the metalation of (+)-2-carene was carried out with n-butyllithium and potassium /erf-butoxide. The metalation product was treated with trimethyl borate and the intermediate ate complex was hydrolyzed with dilute hydrochloric acid. Although the procedure worked well for the transformation of a- into (3-pinene, only a small amount of (+)-3(10)-carene in a mixture with (+)-2- and (+)-3-carene was obtained. Metalation-transmetalation under these conditions leads to organoborane intermediates which are hydrolyzed without isolation. Consequently, a substantial amount of unreacted (+)-2-ca-rene is present, rendering difficult the isolation of (+)-3(10)-carene. 

Recently the first use of the paracyclophane backbone for the placement of two diphenylphosphano groups to give a planar chiral C2-symmetric bisphos-phane was reported [102]. The compound 159 abbreviated as [2.2]PHANEPHOS was used as a ligand in Rh-catalyzed hydrogenations. The catalytic system is exceptionally active and works highly enantioselective [ 103]. The preparation of [2.2]PHANEPHOS starts with rac-4,12-dibromo[2.2]paracyclophane (rac-157), which was metalated, transmetalated and reacted with diphenylphosphoryl chloride to give racemic bisphosphane oxide (rac-158). Resolution with diben-zoyltartaric acid and subsequent reduction of the phosphine oxides led to the enantiomerically pure ligand 159. 

Amide-directed metallation-transmetallation enables allylation to be achieved in the 3-position of the naphthalene derivative 23, cyclisation of which yields the naphtho[2,3-c]pyran-l-one (Scheme 23). Application of similar methodology to benzothiophene afforded the [l]benzothieno[2,3-c]pyran system <01TL5955>. Directed ortho metallation also features in a synthesis of 4-arylisochroman-3-ols <01TL9293>. 

The highly versatile intermediate R-M-X allows further reactions with an organic partner or it can obtain a second organic ligand from another metal (transmetallation). Hence, organic compounds can be formed by a reductive elimination mechanism. 

B.iii.b. (Z)- Substituted Alkenylmetals. The stereodefined (Z)-/3-substituted aUcenyl-metals can generally be prepared by either metallation or metallation-transmetallation of the corresponding (Z)-alkenyl electrophiles. However, several other methods are notable.f i [5 ] P5] a stereoselective synthesis of (Z)-alkenylboranes via hydroboration... 

At present, (Z)-/3-substituted alkenylmetals containing other metals are less readily accessible than those mentioned above, even though the Zr-catalyzed carboalumination of ethyne has been shown to produce (Z)-/S-substituted alkenylalanesJ They are generally prepared via metallation-transmetallation of (Z)-/S-substimted hahdes. Despite this drawback, (Z)-/3-substituted alkenylzincs generated by this procedure have been shown to be superior reagents in the subsequent Pd-catalyzed cross-coupling reactiont (Table 11). 

The DoM C—C cross-coupling was notably employed in the synthesis of telmisartan 75, an angiotensin II receptor antagonist [173]. The reaction pathway is based on a one-pot protocol employing sequential metalation, transmetalation to zincate, and Negishi transition metal-catalyzed cross-coupling. At final step, the oxazoline DMG is removed by hydrolysis to afford the expected carboxylic acid product 75 (Scheme 26.22). 

As shown earlier Fc-NCNH pincer molecules can successfully be used in the synthesis of heterobimetallic complexes. The introduction of a further NCNH unit in Fc-NCNH opens the possibility to prepare the ferrocene-based trimetallic FeM2 complexes 68 and 69 (M = Pd, Pt) by starting from ferrocene 65 (Scheme 6). The reactions shown in Scheme 6 include metallation-transmetallation and oxidative addition processes [49, 63]. 

Various polyfunctionalized a,/3-alkynyl ketones were easily prepared from many simple or functionalized terminal alkynes according to a one-pot procedure metallation-transmetallation-acylation (Scheme 13.26) [29]. 

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