Alkenes hydride-mediated

A useful aspect of the mercury(II) hydride method is that it can be directly coupled with the many standard techniques for heteromercuration of alkenes and cyclopropanes. The resulting overall transformation adds a heteroatom and a carbon atom across the carbon-carbon double bond of an alkene or the carbon-carbon single bond of a cyclopropane. This is a difficult transformation to conduct by standard ionic techniques. An alkene thus becomes an equivalent of synthon (12) and a cyclopropane of synthon (13 Scheme 34). Many equivalent transformations (like haloetherification and phenylselenolactoniza-tion) are available to make precursors for tin hydride mediated additions. 

Neutral aminyl radicals generated from tin hydride-mediated reactions of sulfenamides (Section II,F) have been shown to undergo cyclizations when energetically favored by addition to a strained alkene or by formation of a stabilized intermediate benzylic radical. In both cases, the reverse reaction, cleavage of the /3-amino radical, apparently did not occur (92TL4993). 

Tributyltin hydride-mediated radical cyclization of alkenes 403 (R = OPh or OAc) led to three types of product (Equation 58). The yields of the 4/6/6 ring system were low and the ratio of the isomers varied with the nature of R but the major product was 404 in each case <1996TL1363>. 

Radical coupling of organic halides with alkenes or alkynes takes place intermolecularly (Equation (12)).54 Tin hydride-mediated radical additions to a series of a-methyleneglutarates furnish 2,4-dialkyl-substituted glutarates.55 Using MgBr2-OEt2 as an additive, exclusive yy/t-selectivities are achieved upon tert-butyl radical addition at —78 °C. 

Sml2-mediated radical cyclisations involving alkyl, alkenyl and aryl radical intermediates can be used to construct efficiently five-membered and, in certain cases, six-membered ring systems. This approach provides a useful alternative to trialkyltin hydride-mediated methods as toxic reagents and problematic tin byproducts are avoided. In addition, the use of Sml2 to induce radical cyclisations has led to the development of a number of powerful, radical/anionic sequential processes for the construction of complex systems. Sequential reactions involving radical-alkene/alkyne cyclisations are discussed in Chapter 6. 

The addition of nucleophiles to alkenes is mediated by Hg(II) salts and catalyzed by Pd(II) salts. The difference between the two reactions is the fate of the alkylmetal(II) intermediate obtained after addition of the nucleophile to the tt complex. The alkylmer-cury(II) intermediate is stable and isolable, whereas the alkylpalladium(II) intermediate undergoes rapid /3-hydride elimination. 

The live-ring closure of prostereogenic radicals constructs two new stereogenic centers with good diastereoselectivity, as demonstrated by the trimethyltin hydride mediated cyclization of an ester-substituted diene4. The reaction proceeds via regioselective addition of the stannyl radical to the terminal end of the less substituted alkene and subsequent cyclization. 

If the substrate lacks a hydrogen suitable for p elimination and there is another alkene present in the molecule, the a-alkyl palladium intermediate can follow a Heck pathway to form a bicyclic structure in a tandem reaction sequence. Once again, the final step is a palladium-hydride-mediated isomerization to give the endocyclic alkene. 

The tributyltin hydride-mediated carbon-carbon bond formation via radical addition and cyclization of alkyl halides with alkenes has often been a choice for construction of various organic molecules [1], However, the requirement for high-temperature initiators or photo initiation and the difficulties associated with purification of the products from tributyltin halides tend to limit the widespread use of these methods, despite the efforts to make the methods easier [Ic, 2], Recently, nickel-mediated radical additions and cyclizations have been introduced as promising alternatives to the tributyltin hydride methods. These are the nickel powder-acetic acid method for cyclization of haloamides to y-lactams, y -lactams and in-dolones, the borohydride exchange resin-nickel boride method for radical addition, nickel-catalyzed electroreductive cyclization and nickel-catalyzed Kharasch addition of polyhalo compounds. 

A series of aryl radical cyclizations were reported by a group at Novartis [10], and some of these processes were also compared with bond formation by Pd-mediated Heck cyclization of the same substrates. The tributyltin hydride-mediated reaction of iodo alkenes 7 (Scheme 3), immobilized on polystyrene resin through a linker, gave dihydrobenzofurans 8 [11]. It was also possible to perform a tandem cyclization using allyltributyltin to give the allylated product 9, although the yields were less satisfactory. The radical cyclization onto enol ethers was demonstrated [12] by the conversion of 10 to 11. For best results, the tributyltin hydride and AIBN were added portionwise every 5-8 h. The impressive 95% yield was in fact higher than that for the solid-phase Heck cyclization of 10. Similarly, cyclization of anilide 12 afforded the phenanthridine 13. 

Oxidation of ethylene in alcohol with PdCl2 in the presence of a base gives an acetal and vinyl ether[106,107], The reaction of alkenes with alcohols mediated by PdCl2 affords acetals 64 as major products and vinyl ethers 65 as minor products. No deuterium incorporation was observed in the acetal formed from ethylene and MeOD, indicating that hydride shift takes place and the acetal is not formed by the addition of methanol to methyl vinyl etherjlOS], The reaction can be carried out catalytically using CuClj under oxygen[28]. 

C-C bond formation can be favored over /3-hydride elimination by changing the nature of the catalyst. Hence, cyclizations can be mediated by iridium carbene complexes resulting from a formal intramolecular cross-coupling of the alkene with an. s -C-H bond (Equation (40)). 

A mechanism was proposed in which entry into the catalytic cycle is achieved via Et2AlCl-mediated cobalt hydride generation. Diene hydrometallation affords the cobalt-complexed -jr-allyl A-5, which inserts the tethered alkene to furnish intermediate B-4. Elimination of LnCoOBn provides the cyclization product. Reduction of LnCoOBn by Et2AlCl regenerates cobalt hydride to complete the catalytic cycle (Scheme 17). 

The free-radical construction of C—C bonds either inter- or intramolecularly using a hydride as mediator is of great importance in chemical synthesis. The propagation steps for the intermolecular version are shown in Scheme 2. For a successful outcome, it is important (i) that the R sSi radical reacts faster with RZ (the precursor of radical R ) than with the alkene and (ii) that the alkyl radical reacts faster with alkene (to form the adduct radical) than with the silane. In other words, for a synthetically useful radical chain reaction, the intermediates must be disciplined. Therefore, in a synthetic plan one is faced with the task of considering kinetic data or substituent influence on the selectivity of radicals. The reader should note that the hydrogen donation step controls the radical sequence and, often, the concentration of silane provides the variable by which the products distribution can be influenced. 

Next, we considered the activation of 13 towards hydrolysis by K-complexation of a cationic metal unit to the electron-rich diene system. On the basis of the well-known palladium-mediated addition of nucleophiles to alkenamines, it was anticipated that the enol ether function in 13 would add H2O in the presence of Pd(II).21 Interestingly, exposure of 13 to a slight excess of Pd(OAc)2 led to the isolation of 14 (Scheme 8). This material suggested the exploitation of the existing Pd-C linkage for carbon-carbon bond formation with an appropriate A-side chain. In particular, the intramolecular syn insertion of the allylic double bond in the rrans-butenyl substituent in 15b and subsequent syn (3-hydride elimination would give the desired E-alkene 17. This proposal was examined using alkene 15a as a model system, synthesized in a manner similar to 13. Upon exposure to Pd(OAc)2 under the conditions... 

Unsymmetrical ketones can be synthesized by the formal double alkylation of carbon monoxide [21] in which the three-component coupling of alkyl halides, carbon monoxide, and electron-deficient alkenes is carried out using tributyltin hydride as a radical chain mediator (Scheme 6.13) [22], The use of a slower radical mediator such as (TMS)3SiH [23] has subsequently proven to be superior to tribu-... 

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