10.1021/om011049w.s001 Simon Doherty Simon Doherty Edward G. Robins Edward G. Robins Mark Nieuwenhuyzen Mark Nieuwenhuyzen Julian G. Knight Julian G. Knight Paul A. Champkin Paul A. Champkin William Clegg William Clegg 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 American Chemical Society 2002 copper diene reagent catalyst mixtures NUPHOS derivatives 2 bi intramolecular reductive cyclization phenyl boronic acid regioselective reductive cyclization TOF Ph BINAP 2002-03-07 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/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/3769473 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>).