Asymmetric Synthesis of Homoallylic Alcohols Featuring Vicinal Tetrasubstituted Carbon Centers via Dual Pd/Photoredox Catalysis

Abstract

a 1a (0.10 mmol), 2a (0.15 mmol), Ir(ppy)2(dtbbpy)PF6 (1.0 mol%), Pd2(dba)3 (2.5 mol%), L* (6.0 mol%), Cs2CO3 (0.10 mmol) were combined in CH3CN (2.0 mL) at 25 °C under blue LED radiation (445 nm, 0.7 A, corresponding to a photon flux of 1.2 µeinstein/s) for 2 h. Yields and b/l ratios were determined by 1 H NMR analysis using CH2Br2 as an internal standard. Enantiomeric ratios (er) were determined by UPC2. b In the absence of Cs2CO3. c In the absence of Ir(ppy)2(dtbbpy)PF6. d In the dark. e In the absence of Cs2CO3, under blue LED radiation (445 nm, 1.0 A, corresponding to a photon flux of 1.6 µeinstein/s).The use of other diphosphine ligands (L9-L15) did not improve the process outcome (entries 9-15). Further variations of the protocol (entries 16-19) were first carried out with (R)-DTBM-SegPhos being cheaper than (R)-3,5-tBu-MeOBIPHEP, but providing nearly the same regio-and enantiocontrol (cf., entries 4 versus 5). In the absence of Cs2CO3, 3aa was obtained in a slightly higher yield and er (entry 16 versus 4), and therefore was omitted for the optimized conditions (vide infra). Omitting the iridium PC (entry 17) gave 3aa in 25% yield suggesting that Hantzsch ester 2a could itself also serve as a photoreductant to form a radical cation that subsequently generates, through homolytic cleavage, the requisite alkyl radical for the CC coupling. 12 As expected, no product was detected without blue LED irradiation, but by further increasing the light intensity, the yield of 3aa increased to 71% (entry 19). With these alternative conditions in hand, we then re-used (R)-3,5-tBu-MeOBIPHEP L5 as ligand, which afforded the product in 75% yield and with an er of 89:11 (entry 20).Scheme 2. Product scope using various VCCs to generate quaternary carbon stereocenters. Reaction conditions: 1 (0.10 mmol), 2a (0.15 mmol), Ir(ppy)2(dtbbpy)PF6 (1.0 mol%), Pd2(dba)3 (2.5 mol%), (R)-3,5-tBu-MeOBIPHEP L5 (6.0 mol%), CH3CN (2 mL), 2 h, blue LED (445 nm, 1 A, corresponding to a photon flux of 1.6 µeinstein/s). Yields of the isolated, column-purified products are reported. The enantiomeric ratios (er values) were determined by UPC2. The b/l ratios were determined by 1 H NMR analysis.With these optimized conditions we then examined the generality of similar substrate combinations providing homoallylic alcohols with quaternary carbon stereocenters (Scheme 2, 3aa-3ja). Variation of the aryl substituents on the VCC in the presence of Hantzsch ester 2a generally provided the homoallylic alcohols with remarkable branch-selectivity (b:l >95:5) and in appreciable isolated yields of up to 78% (3ga). Good enantio-induction levels of up to 89:11 er for the majority of the products were achieved except for 3fa, 3ha and 3ja. Whereas for 3ha the presence of the thiophen-2-yl group could interfere through coordination to Pd(allyl) intermediates, the use of a VCC with an additional substituent (R 1 = Ph, 1j) on the vinyl group hence increasing the steric demand substrate activation was detrimental to both the product yield (33%) and optical purity ...

Regio- and Enantioselective Decarboxylative Allylic Benzylation Enabled by Dual Palladium/Photoredox Catalysis

“…This phenomenon suggests that a benzyl radical is perhaps the key intermediate of this reaction. On the basis of this result and previously published work concerning palladium metallaphotoredox catalysis, we propose a plausible pathway for this enantioselective radical decarboxylative allylic benzylation (Figure b). A carboxylic anion reductively quenches an excited photocatalyst Ir­(III)* to give the corresponding benzyl radical 10 and an Ir­(II) complex .…”

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis

“…Kleij and co-workers leveraged dual palladium photoredox catalysis in the decarboxylative asymmetric allylic alkylation of vinyl cyclic carbonates using Hantzsch-type esters as radical precursors affording vicinal α,β-tri/tetra- or α,β-tetrasubstituted homoallylic alcohols …”

“…Kleij and co-workers leveraged dual palladium photoredox catalysis in the decarboxylative asymmetric allylic alkylation of vinyl cyclic carbonates using Hantzsch-type esters as radical precursors affording vicinal α,β-tri/tetraor α,β-tetrasubstituted homoallylic alcohols. 311 Yu and co-workers developed dual-catalytic conditions for the enantioselective allylation of stabilized radicals, coupling racemic allylic acetates and 1,4-DHP radical precursors to afford the corresponding enantioenriched C−C coupled products in good yields and high levels of enantioselectivity. 312 The authors proposed that precedented radical generation from 1,4-DHP derivatives 84,85,88 could smoothly interface with a palladium oxidative addition, radical capture, and reductive elimination mechanism, with enantioselectivity induced by a chiral diphosphine ligand in the first highly enantioselective dual palladium-and photoredox-catalyzed coupling.…”

Boron, silicon, nitrogen and sulfur-based contemporary precursors for the generation of alkyl radicals by single electron transfer and their synthetic utilization

“…Very recently, a close protocol of dual Pd/Ir catalysis was also developed with vinyl cyclic carbonates allowing the asymmetric synthesis of homoallylic alcohols. 109…”