Ketones, synthesis using cross-coupling reaction

Alkylzinc reagents undergo transmetallation in the presence of Co(II) salts to provide the corresponding organocobalt derivatives. These intermediates are stable below —10 °C in mixtures ofTHF and NMP and have proved useful for the synthesis of symmetrical ketones [310, 311]. Cross-coupling reactions with alkylzincs can also be performed using catalytic amounts of Co(II) salts. In contrast to arylzinc reagents, however, disclosed examples [312, 313] are still rather scarce. 

The hydrosi(ly)lations of alkenes and alkynes are very important catalytic processes for the synthesis of alkyl- and alkenyl-silanes, respectively, which can be further transformed into aldehydes, ketones or alcohols by estabhshed stoichiometric organic transformations, or used as nucleophiles in cross-coupling reactions. Hydrosilylation is also used for the derivatisation of Si containing polymers. The drawbacks of the most widespread hydrosilylation catalysts [the Speier s system, H PtCl/PrOH, and Karstedt s complex [Pt2(divinyl-disiloxane)3] include the formation of side-products, in addition to the desired anh-Markovnikov Si-H addition product. In the hydrosilylation of alkynes, formation of di-silanes (by competing further reaction of the product alkenyl-silane) and of geometrical isomers (a-isomer from the Markovnikov addition and Z-p and -P from the anh-Markovnikov addition. Scheme 2.6) are also possible. 

Thioesters have been used for carbon-carbon bond formation in transition metal-catalysed Grignard reactions. In the accompanying scheme two sequential cross-coupling reactions with 5-phenvl carbonochloridothioate and Grignard reagents led to a general and efficient ketone synthesis [377,378]. 

An example prepared by tin-lithium transmetallation is compound 637, which reacts with enolizable ketones, after transmetallation with cerium(III) chloride895. This intermediate was transformed into the corresponding vinylzinc reagent and, after palladium(O)-catalyzed cross-coupling reactions with aryl iodides, was used in the synthesis of the antitumor antibiotic rineomycinone B2 methyl ester940,941. The vinyllithium 627 has also been transformed into the corresponding vinyl iodide by stannylation followed by reaction with iodine. The arylation has been performed in this case by a palladium(0)-catalyzed... 

For the ketone synthesis via the present protocol, acid chlorides are useful precursors, in deed. Nevertheless, carbonylative cross coupling with organic halides is strategically the most simple and direct way to this purpose. The palladium-catalyzed carbonylative cross-coupling reaction with various organic halides has been extensively investigated, because of its merits from synthetic as well as phenomenal point of view. Acid chlorides are not always readily available, and their preparation is not always compatible with many sensitive functionalities. Therefore the development of this type of reaction widens the scope of the ketone synthesis in the present protocol because of the ready availability and storability of organic halides and pseudohalides. 

We have found that alkynylsilanes are smoothly converted into alkynylcopper compounds by treatment with CuCl in l,3-dimethyl-2-imidazohdinone (DMI) the copper reagents can be isolated in good yields [563]. This study was the first example of preparation and isolation of organocopper compounds by use of organosilicon reagents. The Si-Cu transmetalation is applicable to the synthesis of alkynyl ketones by Cu-catalyzed alkynylation of acid chlorides (Scheme 10.217). We have also shown that a Cu-mediated system is effective in the cross-coupling reaction between arylsilanes or heteroarylsilanes and aryl hahdes [564]. 

Fluorophenyl 3-pyridazinyl ketone has been used as starting material for the synthesis of 3-pyridazinyl substituted 1,4-benzodiazepines, quinolines, 2,1-benzisoxazolines and for the preparation of diazaacridones of type 23 and 24 [94H(38)125]. Pd(0) cross-coupling reactions of pyridazine triflates permits to prepare 3-alkynylpyridazines of type 25 [94H(38)1273]. 

In the total synthesis of (+)-lycopladine A by Toste et al. [30], a gold-catalyzed 5-endo cyclization of an iodoalkyne with a silyl enol ether has been used (Scheme 16.25). This transformation efficiently produces a -unsaturated bicyclic ketone that possesses the required quaternary asymmetric center at the position a to the carbonyl group. The vinyl iodide functionaiity generated during the cyclization was subsequently used in a palladium-catalyzed cross-coupling reaction in order to construct the pyridine ring of (-F)-lycopladine A. 

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