Negishi alkynations

Cis-olefins or cis./rjns-dienes can be obtained from alkynes in similar reaction sequences. The alkyne is first hydroborated and then treated with alkaline iodine. If the other substituents on boron are alkyl groups, a cis-olefin is formed (G. Zweifel, 1967). If they are cir-alkenyls, a cis, trans-diene results. The reactions are thought to be iodine-assisted migrations of the cis-alkenyl group followed by (rans-deiodoboronation (G. Zweifel, 1968). Trans, trans-dienes are made from haloalkynes and alkynes. These compounds are added one after the other to thexylborane. The alkenyl(l-haloalkenyl)thexylboranes are converted with sodium methoxide into trans, trans-dienes (E. Negishi, 1973). The thexyl group does not migrate. 

Scheme 1.13. Synthesis of alkene- and alkyne-ZrCp2 complexes by P-H abstraction of dialkylzirconocenes in the presence of 7t-compounds (Negishi-Takahashi protocol).

In 1978, Negishi et al. reported highly regio- and stereoselective methylalumination of alkynes with Me3Al using a zirconocene catalyst [59]. The involvement of cationic zirconocene species in the activation of carbon—carbon triple bonds was suggested in a reaction mechanism featuring electrophilic activation by aluminum (Scheme 8.30). 

The result of the retrosynthetic analysis of rac-lO is 2-hydroxyphenazine (9) and the terpenoid unit rac-23, which may be linked by ether formation [29]. The rac-23 component can be dissected into the alkyl halide rac-24 and the (E)-vinyl halide 25. A Pd(0)-catalyzed sp -sp coupling reaction is meant to ensure both the reaction of rac-24 and 25 and the ( )-geometry of the C-6, C-7 double bond. Following Negishi, 25 is accessible via carboalumination from alkyne 27, which might be traced back to (E,E)-farnesyl acetone (28). The idea was to produce 9 in accordance with one of the methods reported in the literature, and to obtain rac-24 in a few steps from symmetrical 3-methyl-pentane-1,5-diol (26) by selective functionalization of either of the two hydroxyl groups. 

The preparation of vinyl iodide 39 first required the transformation of (E,E)-farnesyl acetone (28), performed according to Negishi, to the terminal alkyne 27 with 75% yield [35]. The latter then gave (E)-vinyl iodide 39 in dia-stereomerically pure form and 74% yield by Zr-catalyzed carboalumination with trimethylaluminum and trapping of the intermediate vinylaluminum species with iodine [36]. The alkyl iodide rac-29 necessary to ensure the coupling with 39 was obtained by selective monofunctionalization of 3-methyl-pentane-1,5-diol (26) in a few steps [37]. 

The stereospecific construction of the trisubstituted double bond of the side chain at C-1 of carbazomadurins A (253) and B (254) was achieved using Negishi s zirconium-catalyzed carboalumination of alkynes 758 and 763, respectively. Reaction of 5-methyl-l-hexyne (758) with trimethylalane in the presence of zirconocene dichloride, followed by the addition of iodine, afforded the vinyl iodide 759 with the desired E-configuration of the double bond. Halogen-metal exchange with ferf-butyllithium, and reaction of the intermediate vinyllithium compound with tributyltin chloride, provided the vinylstannane 751a (603) (Scheme 5.79). 

Regarding efficiency in terms of achieving a maximum increase of molecular complexity in a minimum number of operational steps, the zipper-mode tetracyclization of the open-chain trienediyne 102 leading to the tetracyclic steroidal skeleton 103, as accomplished by Negishi et al. is particularly impressive (Scheme 28). This transformation involves four intramolecular carbopalladations with two alkyne relays forming four new G,G-bonds with the creation of four rings. 

A short synthesis of retinal was described by Taylor et al. [42] based on the addition of a C]3 vinylalane to a methylpyrylium salt. The 13Z-retinal (48%) was isomerised to all E retinal by a previous procedure [43]. P-Ionone was first converted into the alkyne and then into the vinylalane, using the Negishi methodology [44], Addition of an excess of this alane to 4-methylpyrilium tetrafluoroborate [45] gave 13Z-retinal, being isomerized to the all E isomer (L in benzene/ether), Fig. (18). 

Carbometallation of alkenes and alkynes is attracting considerable interest as a potential new method for C—C bond formation. A general treatment is available by Negishi a leading expert of the field.632... 

Alternately, CpjZr can also be prepared by the reaction of Cp2ZrCl2with two equivalents of n-BuLi at —78°C E.-I Negishi, F. K. Cederbaum and T. Takahashi, Reaction of zirconocene dichloride with alkyl lithiums or alkyl Grignard reagents as a convenient method for generating a zirconocene equivalent and its use in zirconium promoted cyclization of alkenes, alkynes dienes, eneynes and diynes, Tetrahedron Lett. 27 2829 (1986). 

Cadiot-Chodkiewicz reaction, 11, 19 Hiyama reaction, 11, 23 Kumada-Tamao-Corriu reaction, 11, 20 Migita-Kosugi-Stille reaction, 11, 12 Negishi coupling, 11, 27 overview, 11, 1-37 Suzuki-Miyaura reaction, 11, 2 terminal alkyne reactions, 11, 15 Cu-mediated reactions acetylenes, 10, 551 dienes, 10, 552... 

Cross-coupling reactions 5-alkenylboron boron compounds, 9, 208 with alkenylpalladium(II) complexes, 8, 280 5-alkylboron boron, 9, 206 in alkyne C-H activations, 10, 157 5-alkynylboron compounds, 9, 212 5-allylboron compounds, 9, 212 allystannanes, 3, 840 for aryl and alkenyl ethers via copper catalysts, 10, 650 via palladium catalysts, 10, 654 5-arylboron boron compounds, 9, 208 with bis(alkoxide)titanium alkyne complexes, 4, 276 carbonyls and imines, 11, 66 in catalytic C-F activation, 1, 737, 1, 748 for C-C bond formation Cadiot-Chodkiewicz reaction, 11, 19 Hiyama reaction, 11, 23 Kumada-Tamao-Corriu reaction, 11, 20 via Migita-Kosugi-Stille reaction, 11, 12 Negishi coupling, 11, 27 overview, 11, 1-37 via Suzuki-Miyaura reaction, 11, 2 terminal alkyne reactions, 11, 15 for C-H activation, 10, 116-117 for C-N bonds via amination, 10, 706 diborons, 9, 167... 

Negishi and co-workers developed this carbometalation reaction of alkynes with organoalane-zirconocene derivatives, and it has since turned into an often used route to stereo- and regiodefined... 

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