Reaction prospecting by 31P NMR: enantioselective rhodium-DuPhos catalysed addition of ZnMe2 to diphenylphosphinoylimines

Chiral shift 31P NMR spectroscopy allows the identification of ligand leads in asymmetric catalyst systems for ZnMe2 addition to ArCHNP(O)Ph2. Subsequent GC-based optimisation shows [RhCl(CH2CH2)2]2 and (R,R)-MeDuPhos to be the optimal pre-catalyst combination (product in 78–93% ee). Transmetallation of [(MeDuPhos)Rh{N(P(O)Ph2–CHMeAr}] with ZnMe2 appears to be the rate limiting step of the catalytic cycle as competing coordination by the imine starting material leads to Ph2P(O)NHCH2Ar via MVP hydrogen-transfer. This limitation can largely be overcome by the slow addition of the imine.

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(R)-P,P-Diphenyl-N-(1-phenylethyl)phosphinic amideC20H20NOPEe = 93%[α]D = +31.0 (c 1.07, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-P,P-Diphenyl-N-(1-p-tolylethyl)phosphinic amideC21H22NOPEe = 92%[α]D = +26.1 (c 1.03, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-N-(1-(4-Fluorophenyl)ethyl)-P,P-diphenylphosphinic amideC20H19FNOPEe = 84%[α]D = +14.5 (c 1.01, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-N-(1-(4-Chlorophenyl)ethyl)-P,P-diphenylphosphinic amideC20H19ClNOPEe = 86%[α]D = +24.6 (c 1.00, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-N-(1-(4-Bromophenyl)ethyl)-P,P-diphenylphosphinic amideC20H19BrNOPEe = 75%[α]D = +27.9 (c 1.04, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-P,P-Diphenyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)phosphinic amideC21H19F3NOPEe = 78%[α]D = +17.1 (c 1.17, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-P,P-Diphenyl-N-(1-m-tolylethyl)phosphinic amideC21H22NOPEe = 89%[α]D = +11.4 (c 0.54, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-N-(1-(3-Chlorophenyl)ethyl)-P,P-diphenylphosphinic amideC20H19ClNOPEe = 78%[α]D = +15.5 (c 1.06, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-P,P-Diphenyl-N-(1-o-tolylethyl)phosphinic amideC21H22NOPEe = 79%[α]D = +7.1 (c 1.02, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-N-(1-(Naphthalen-2-yl)ethyl)-P,P-diphenylphosphinic amideC24H22NOPEe = 84%[α]D = +24.9 (c 1.06, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-2,2,2-Trifluoro-N-(1-phenylethyl)acetamideC10H10F3NOEe = 93%[α]D = +60.6 (c 1.03, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-N-(1-(4-Chlorophenyl)ethyl)-2,2,2-trifluoroacetamideC10H9ClF3NOEe = 86%[α]D = +44.8 (c 1.10, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-2,2,2-Trifluoro-N-(1-(4-fluorophenyl)ethyl)acetamideC10H9F4NOEe = 84%[α]D = +75.1 (c 1.23, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-N-(1-(4-Bromophenyl)ethyl)-2,2,2-trifluoroacetamideC10H9BrF3NOEe = 75%[α]D = +45.5 (c 1.20, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-2,2,2-Trifluoro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamideC11H9F6NOEe = 78%[α]D = +106.7 (c 1.16, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)

(R)-2,2,2-Trifluoro-N-(1-o-tolylethyl)acetamideC11H12F3NOEe = 79%[α]D = +39.0 (c 1.15, MeOH)Source of chirality: asymmetric catalysisAbsolute configuration: (R)