A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions

Abstract

Detailed mechanistic studies of a Pd-catalyzed asymmetric C–N coupling led to a rational design of a new series of bis-phosphine mono-oxides ligated Pd(ii) pre-catalysts that allow for reliable and complete catalyst activation.

Palladium‐Catalyzed Enantioselective Cacchi Reaction: Asymmetric Synthesis of Axially Chiral 2,3‐Disubstituted Indoles

“…Reaction of 1 c with 2 b using L7 and L8 as ligands instead of L6 under otherwise standard conditions afforded 3 e in yields of 39 % (70 % ee ) and 13 % (7 % ee ), respectively (Scheme a). We have also prepared QuinoxP*(=O)‐PdPhOAc complex ( 10 ) [δ (ppm) 31.3 ( J =3.8 Hz), 62.7 ppm ( J =3.8 Hz)] via the QuinoxP*(=O)‐PdPhI ( 9 ) species as shown in Scheme b . Interestingly, stirring a methanol solution of 1 c with a stoichiometric amount of complex 10 afforded 3 e in 72 % yield with 81 % ee .…”

“…Thes ignificant difference in ee between these two processes implied that the transmetallation might occur before the aminopalladation in our cyclizative arylation process.Indeed, monitoring the reaction by 31 PNMR spectra of the reaction mixture of 1c (R = Ts,R 1 = Bn, R 2 = H) with phenylboronic acid (2b)i ndicated the presence of ap henylpalladium species that was deduced to be the (L6)PdPh(OAc) complex (7a). Since direct ligand exchange between (L6)Pd-(OAc) 2 ( 31 P d = 52.8 ppm, Lit [17] d = 52.3 ppm) and PhB(OH) 2 failed to afford the isolable 7a,a na lternative synthesis of authentic 7a was developed. Reaction of (R,R)-QuinoxP* ligand L6 with phenyl iodide in the presence of as toichio-metric amount of Pd 2 (dba) 3 provided the (L6)PdPhI complex 8a ( 31 PNMR, d (ppm) 38.4 (J = 40.2 Hz), 28.1 (J = 40.2 Hz)] which, upon treatment with silver acetate (AgOAc), was converted cleanly into the (L6)PdPh(OAc) complex 7a.…”

“…Although L6 monooxide (L7)a nd L6 dioxide (L8)w ere not detected by 31 PNMR spectra of the crude mixture,w e prepared L7 and L8 in order to probe their catalytic activities. [17] Reaction of 1c with 2b using L7 and L8 as ligands instead of L6 under otherwise standard conditions afforded 3e in yields of 39 %( 70 % ee)a nd 13 %( 7% ee), respectively (Scheme 4a). We have also prepared QuinoxP*-( = O)-PdPhOAc complex (10) The apparent discrepancy in the reaction outcome between the results shown in Scheme 4a and b( 70 %v s. 81 % ee)w as accounted for by the partial in situ oxidation of the monooxide L7 to dioxide L8 by the Pd II species in the former experiment.…”

Palladium-Catalyzed C–O Cross-Coupling as a Replacement for a Mitsunobu Reaction in the Development of an Androgen Receptor Antagonist

“…On the kilogram scale, some variations in reaction time and reaction onset were observed, suggesting that some activation of the catalyst must occur prior to the coupling. Considering the literature precedent with bisphosphine ligand systems, we hypothesized that the active catalyst in our system might be a bisphosphine monoxide species . This suspicion came from the fact that Pd­(OAc) 2 was the most effective Pd source in our screening and that older bottles of rac -BINAP provided slightly better results.…”

Utilization of BozPhos as an Effective Ligand in Enantioselective C–H Functionalization of Cyclopropanes: Synthesis of Dihydroisoquinolones and Dihydroquinolones

“…Therefore, we synthesized different palladium complexes and were delighted to obtain a crystal structure of complex 5, which had similarities to a precatalyst used for C−N coupling. 33 Although phosphines bind more strongly than phosphine oxides to palladium(II), the P(III)− Pd bond is longer (2.24 Å) than the O−Pd bond (2.18 Å), which is consistent with reported complexes. 15,33,34 The bite angle (P(III)−Pd−O) of complex 5 measures 80.5°.…”