Synthesis of a New Class of 1,4-Bis(diphenylphosphino)-1,3-butadiene Bridged Diphosphine, NUPHOS, via Zirconium-Mediated Reductive Coupling of Alkynes and Diynes:  Applications in Palladium-Catalyzed Cross-Coupling Reactions DohertySimon RobinsEdward G. NieuwenhuyzenMark KnightJulian G. ChampkinPaul A. CleggWilliam 2002 Zirconium-mediated inter- and intramolecular reductive cyclization of alkynes and diynes has been used to prepare a new class of bidentate phosphine, based on a four-carbon sp<sup>2</sup>-hybridized tether. Intermolecular coupling of diphenylacetylene and but-2-yne with Negishi's reagent followed by transmetalation with copper chloride prior to quenching with chlorodiphenylphosphine affords the corresponding acyclic diphosphines 1,4-bis(diphenylphosphino)-1,2,3,4-tetraphenyl-1,3-butadiene (<b>2a</b>; 1,2,3,4-Ph<sub>4</sub>-NUPHOS) and 1,4-bis(diphenylphosphino)-1,2,3,4-tetramethyl-1,3-butadiene (<b>2b</b>; 1,2,3,4-Me<sub>4</sub>-NUPHOS), respectively. A single-crystal X-ray analysis of the former has been obtained. Surprisingly, 1-phenylpropyne undergoes a highly regioselective reductive cyclization to afford 1,4-bis(diphenylphosphino)-1,3-diphenyl-2,4-dimethyl-1,3-butadiene (<b>2c</b>; 1,3-Ph<sub>2</sub>-2,4-Me<sub>2</sub>-NUPHOS). Similarly, transmetalation of the zirconacyclopentadiene generated from 3,9-dodecadiyne and 1,8-diphenyloctadiyne followed by electrophilic liberation of the resulting copper diene reagent with chlorodiphenylphosphine gave 1,2-bis(1-(diphenylphosphino)prop-1-ylidene)cyclohexane (<b>2d</b>; 1,4-Et<sub>2</sub>-2,3-cyclo-C<sub>6</sub>H<sub>8</sub>-NUPHOS) and 1,2-bis(1-(diphenylphosphino)benzylidene)cyclohexane (<b>2e</b>; 1,4-Ph<sub>2</sub>-2,3-cyclo-C<sub>6</sub>H<sub>8</sub>-NUPHOS), respectively. This methodology provides a convenient and versatile one-pot synthesis of a wide range of 1,3-diene bridged diphosphines. Single-crystal X-ray analyses of [(1,2,3,4-Ph<sub>4</sub>-NUPHOS)PdCl<sub>2</sub>], [(1,3-Ph<sub>2</sub>-2,4-Me<sub>2</sub>-NUPHOS)PdCl<sub>2</sub>], and [(1,4-Ph<sub>2</sub>-2,3-cyclo-C<sub>6</sub>H<sub>8</sub>-NUPHOS)PtCl<sub>2</sub>] reveal that these new phosphines coordinate to palladium and platinum in much the same manner as BINAP and dpbp, with a significant torsional twist about the C(2)−C(3) bond of the backbone. The copper diphosphine intermediate [Cu(1,4-Et<sub>2</sub>-2,3-cyclo-C<sub>6</sub>H<sub>8</sub>-NUPHOS)Cl]<sub>2</sub> (<b>1d</b>) has also been isolated and characterized by single-crystal X-ray analysis and exists as the chloro-bridged dimer in which the 1,2-bis(1-(diphenylphosphino)prop-1-ylidene)cyclohexane coordinates in a bidentate manner. Palladium complexes of these new diphosphines are highly active for the cross-coupling of bromobenzene and <i>sec</i>-butylmagnesium bromide. Catalyst mixtures based on 1,2,3,4-Ph<sub>4</sub>-NUPHOS are far superior to those based on BINAP, with activities of 6900 and 260 (mol of product) (mol of palladium)<sup>-1</sup> h<sup>-1</sup>, respectively. In fact, catalysts based on 1,2,3,4-Ph<sub>4</sub>-NUPHOS are ∼30 times more active than the most active catalyst reported to date for this coupling. In comparison, the selectivity of the corresponding cross-coupling with 2-bromopropene depends markedly on the nature of the NUPHOS derivative. In general, those based on NUPHOS derivatives with acyclic tethers, namely <b>2a</b>−<b>c,</b> are highly selective for the formation of 2,3-dimethylpentene, while those formed from <b>2d</b>,<b>e</b> gave a mixture of 2,3-dimethylpentene, 2-methylhexene, and 2,3-dimethylbutadiene. The initial TOF, measured after 20 min, also shows a marked variation on the nature of the phosphine and while all NUPHOS-based catalysts outperform those based on BINAP, catalyst mixtures based on dppf showed both high selectivity (>99%) and impressive activity. Mixtures of Pd<sub>2</sub>(dba)<sub>3</sub> and the NUPHOS derivatives <b>2a</b>−<b>e</b> also catalyze the Suzuki cross-coupling of bromobenzene and 4-bromoacetophenone with phenyl boronic acid, with conversions up to 100% at catalyst loadings as low as 0.0001 mol % Pd (TON = 1 × 10<sup>6</sup>).