In situ transmetallation

Lewis acids, particularly the boron trifluroride diethyl ether complex, are used to promote the reaction between allyl(trialkyl)- and allyl(triaryl)stannanes and aldehydes and ketones52-54. The mechanism of these Lewis acid promoted reactions may involve coordination of the Lewis acid to the carbonyl compound so increasing its reactivity towards nucleophilic attack, or in situ transmetalation of the allyl(trialkyl)stannane by the Lewis acid to generate a more reactive allylmetal reagent. Which pathway operates in any particular case depends on the order of mixing of the reagents, the Lewis acid, temperature, solvent etc.55- 58. 

The key to the success of the synthesis was the development of a novel method for enantioselective formation of a-arylpyrrolidines. In this method, (-)-sparteine-mediated, enantioselective lithiation of N-Boc-pyrrolidine 19 was followed by an in situ transmetallation to zinc and Pd-catalyzed coupling reaction with aryl bromide 3, which afforded 2-arylpyrrolidine in 63% isolated yield and 92% ee. Notably, the acidic aniline NH2 group was tolerated under the coupling reaction conditions. 

In situ transmetallation of allenylpalladium intermediates with Sml2 provides a route to allenylsamarium reagents [123]. These undergo protonolysis with alcohols to afford mainly allenes (Table 9.59). Additions to ketones yield either allenylcarbi-nols (A) or homopropargylic alcohols (B) depending on the allene substituents (Table 9.60). 

An alternative preparation of enantioenriched anti-homopropargylic alcohols along similar lines uses EtjZn to effect in situ transmetallation of an allenylpalladium intermediate from a propargyl mesylate and 2.5 mol % of Pd OAc)2 PPh3 in the presence of an aldehyde (Table II). The two methods are comparable. 

Transmetalations starting from alkcnylzirconiurn species, which are obtained by hydro-ziiconation using H(Cl)ZrCp2, are readily accomplished . Ichikawa, Minami and coworkers have elegantly shown that difluorovinylzinc iodide 64 is obtained by the addition of ZrCp2 to the alkenyl tosylate 65 . In situ transmetalation reactions have also been reported. 

Alkynyllead triacetates can be prepared by tin-lead or by mercury-lead exchange.88,8811 However, more convenient methods were subsequently devised. In situ transmetallation can be directly realized by lithium-lead or zinc-lead exchange. This avoids the isolation of unstable alkynylmetal derivatives. Ikegami et al. found that, if a THF solution of... 

Scheme 2.118 Mechanism of the synthesis of trifluoromethyl zinc and cadmium reagents (top X, Y = Br, Cl M = Zn, Cd), and the preparation of trifluoromethyl copper(l) by in situ transmetalation (bottom).

On the other hand, quinolinyl nucleophiles as the quinolinylzinc derivatives presented in the following example have been prepared by the in situ transmetallation of quinolinyllithium salts realized by direct halogen-metal exchange of 6-bromo quinoline derivative. The zinc salt was allowed to react with several aryl bromides, affording clean Negishi reactions for the formation of 6-substituted derivatives, which are potent inhibitors of steroid 5a reductases of types 1 and 2 ... 

Enantioselective synthesis of [3.3.1]-bicyclic ketals can be achieved by palladium(ll)-catalyzed 1,4-conjugate addition of 2-hydroxyphenylboronic to enones (Scheme 33). The reaction involves an in situ transmetalation of the boronic acid, that acts as bis(nucleophile) (13CC3360). Similar structures are obtained via a sequential Michael addition—bicyclization reactions... 

Pd-catalyzed cyclization was also applied to the stereocontrolled preparation of chiral substituted tetrahydrofurans. The synthesis of optically active tetrahydrofurans was pioneered by Stork and Poirier,who described effective chirality transfer in the Pd-assisted cyclization of y-hydroxy allylic esters. Williams and Meyer deployed a variant of the 0-capture of 7r-allylpalladium complexes in the reactions of substimted trimethylenemethane palladium complexes developed by Trost, using aUylstannane (Scheme 32). A key intermediate 156 in the synthesis of amphidinolide K, a marine nam-ral product, was therefore synthesized starting from enantiopure diastereomer 160. Compound 160 was prepared by in situ transmetallation using the Corey chiral sulfonamide 159 with optically active aUylstannane 157 and then condensation with functionalized aldehyde 158. Formation of the c -2,5-disubstituted tetrahydrofuran 156 occurred with an excellent diastereoselectivity (cis/trans 13 1) and a good yield (88%) from the syn-1,4-precursor 160. 

Scheme 3.3 Regioselective metalation of abnormal carbene precursors with silver, and in situ transmetalation to form complexes 17-19.

Alkenylzirconium species that are obtained by hydrozirconation of terminal alkynes using H(Cl)ZrCp2 can be readily transmetalated into the corresponding Zn organometallics. It has been shown that difluorovinylzinc iodide (321) can be obtained by the addition of ZrCp2 to the alkenyl tosylate 322. Besides, in situ transmetalation reactions have been reported (Scheme 2-111). 

Hydrozirconation of functionalized alkyne 8 in CH2C32 with the Schwartz reagent followed by in situ transmetallation to Me2Zn and addition of N-diphenyl-phosphinoylimine 15 provides the functionalized trans-aminocydopropane 16 in 60% yield [15]. The cydopropane formation can be rationalized by the formation of a transient zinc-carbenoid species from CH2CI2, which subjected the intermediate allylic amine derivative to an efficient Simmons-Smith-type cydopropanation. 

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