Cross-coupling, sequential

Zr>Catalyzed Asymmetric Carboalumination of Alkenes (ZACA) ZACA-Pd- or Cu-Catalyzed Cross-Coupling Sequential Processes as a General Route to Enantiomerically Enriched Chiral Oiganic Compounds... 

ZACA-Pd-Catalyzed Cross-Coupling Sequential Processes for the Synthesis of Deoxypolypropionates and Related Compounds... 

Scheme 16 Construction of a nine-membered cyclic ether with a (Z,Z)-1,3-diene unit by sequential RCM and silicon-assisted intramolecular cross coupling in Denmark s synthesis of brasilenyne (85) [65]...

Scheme 6.20 Sequential one-pot nucleophilic aromatic substitution and Suzuki cross-coupling reactions.

Sequential arylzinc formation and Negishi cross-coupling. 

Bromoalkynes also couple with vinylstannanes readily to result in enynes. Synthesis of protected enynals via cross-coupling of vinylstannanes with 1-bromoalkynes in the presence of a catalytic amount of Pd(II) has been reported (equation 143)252. Hiyama and coworkers extended the Stille methodology for sequential three-component coupling of trimethylstannyl(trimethylsilyl)acetylene with a vinyl iodide in the first step and cross-coupling of the intermediate trimethylsilylethyne with another alkenyl iodide in the presence of tris(diethylamino)sulphonium trimethyldifluorosilicate in the second step to generate a dienyne (equation 144)253. Both steps occur under palladium catalysis, in one-pot, to result in stereodefined l,5-dien-3-ynes. 

TMS group and the Suzuki cross-coupling reaction is again repeated. This sequential process allows for the introduction of different aromatic groups at positions 3 and 4 of the pyrrole system. The synthesis of the Furstner intermediate (6) is completed by removal of the sulfonamide group. 

Other tin reagents have found use in Pd-catalyzed cross-couplings with halopyridines as well. The Stille coupling of 3-iodopyridine with ethoxy(tributylstannyl)acetylene gave rise to 3-ethoxyethynylpyridine (100), which was then hydrolyzed to the corresponding ethyl 3-pyridylacetate (101) [88], Carbamoylstannane 102 was prepared by sequential treatment of lithiated piperidine with carbon monoxide and trimethyltin chloride. Stille coupling of carbamoylstannane 102 and 3-bromopyridine provided a unique entry to amide 103 [89],... 

Snieckus et al. enlisted a combination of directed orrAo-lithiation and Suzuki coupling to assemble some unsymmetrical heterobiaryls [22], Carboxamidophenylboronic acid 30 was derived from sequential metalation of amide 29 and treatment with B(OMe)3 followed by acidic workup. Hetero cross-coupling of 30 with 2-bromothiazole occurred smoothly to furnish phenylthiazole 31. Similarly, a hetero cross-coupling between 2-bromothiazole and 3-formyl-4-methoxyphenylboronic acid produced a heterobiaryl as an intermediate of an orally bioavailable NKi receptor antagonist [23]. 

Sequential cross-coupling can be used also for synthesis of 1,1-disubstituted alkenes from 2,3-dibromopropene (Aldrich). The allylic halogen couples directly with a Grignard reagent vinylic coupling is slower and requires a catalyst (equation I). 

The sequential approach is also common in proposals written by synthetic chemists (a multistep synthesis is inherently step by step). Vyvyan (excerpt 13N), for example, proposes a strategy to synthesize a select group of heliannuols (alleo-pathic natural products isolated from the sunflower) in an optically pure form. One approach that he will explore involves enantioselective cross-coupling reactions between an alkyl zinc reagent and an aryl bromide. He begins with experiments that will utilize recently developed catalysts and produce products with known optical rotation data. Subsequent reactions are described that will lead potentially to the desired stereospecific heliannuols A and D. 

To make the transformation even more useful, different carbon electrophiles should be connected sequentially in a stepwise manner. For this purpose, a transition-metal-catalyzed cross-coupling reaction opened the way. As shown in Scheme 22, cinnamyl chloride is treated with bis(iodozincio)methane (3) in the presence of palladium catalyst with various phosphine ligands. Phosphine ligands, having an electron-withdrawing group, such as tris[3,5-bis(trifluoromethyl)phenyl]phosphine and tris(2-furanyl)phosphine, show excellent results47. 

Another very important aspect of these transition metal-catalysed cross-coupling reactions stems from the high selectivity observed with stereo-defined vinyl sulfides. Applications to the stereoselective syntheses of pheromones were straightforward (see [321] and references therein), as shown in the two-step synthesis of muscalure from (Z)-l-bromo-2-phenylthioethylene [322] involving its sequential coupling through the bromo and phenylthio substituents with the appropriate derivatives. 

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]. 

A similar but conceptually distinct approach to difunctionalization of terminal alkynes consists of sequential carboboration-palladium-catalyzed cross-coupling 137 equation (33) illustrates that this method also provides alkenes of high stereochemical purity by net syn Markovnikov addition. Benzyne-contain-ing molecules can act as highly activated substrates for vicinal difunctionalizations initiated by nucleophiles 138-140 thus, nucleophilic addition-electrophilic trapping can serve as an alternative to sequential directed metallation for the production of 1,2-disubstituted and 1,2,3-trisubstituted aromatic systems (equation 34).141... 

Sequential Suzuki-Miyaura cross-couplings and Cadogan cyclizations were developed under microwave dielectric heating conditions to access a variety of 2-substituted carbazoles and other fused heterocyclic systems (Scheme 13). The use of microwave irradiation not only minimized the proto-... 

V Fiandanese, Sequential Cross-Coupling Reactions as a Versatile Synthetic Tool, PureAppl. Chem. 1990, 62, 1987-1992. 

Corsico, E.F. and Rossi, R.A. (2002) Sequential photostimulated reactions of trimethylstannyl anions with aromatic compounds followed by palladium-catalyzed cross-coupling processes. Journal of Organic Chemistry, 67, 3311-3316. 

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