Synthesis of P-stereogenic compounds based on the diastereoselective ortho-lithiation of phosphinimidic amides

The extension of the diastereoselective functionalization of the Ph2P group of C-chiral P,P-diphenyl phosphinimidic amides via directed ortho-lithiation (DoLi)-electrophilic quench reactions as a method for the preparation of structurally diverse P-stereogenic compounds is described. Transformations at both the phosphorus-containing and the ortho-functional groups provide access to a large variety of P-stereogenic derivatives with excellent stereocontrol. These transformations include aza-Wittig reactions, N-alkylations, methanolysis, nucleophilic displacements with Grignard reagents, phosphine oxide reductions, azide to amine conversions, halogen/metal exchange, and Suzuki cross-coupling and condensation reactions. These transformations increase the diversity of functional groups at the ortho-disubstituted phenyl ring and enable the synthesis of enantiopure ortho-formyl- and ortho-stannyl-phosphinic amides that are difficult to prepare by other methods. The new products synthesized might be used as building blocks for the construction of high value added P-stereogenic compounds. This is illustrated by the synthesis of [1,5,2]diazaphosphinin-6(5H)-one 21, a phosphazenylphosphinate (SPN,RPO)-22 and the analogues of relevant bidentate and tridentate privileged structures such as PHOX-like 23 and the heteroatomic N,O,P-tridentate ligand 25.

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Methyl ((SP)-(2-methylphenyl){methyl[(1R)-1-phenylethyl]amino}phenylphosphoranylidene)carbamateC24H27N2O2P[α]D25 = +16.2 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SP,RC)

Methyl ((SP)-(2-iodophenyl){methyl[(1R)-1-phenylethyl]amino}phenylphosphoranylidene)carbamateC23H24IN2O2P[α]D25 = +51.9 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SP,RC)

Methyl {(SP)-{methyl[(1R)-1-phenylethyl]amino}(phenyl)[2-(trimethylsilyl)phenyl]phosphoranylidene}carbamateC26H33N2O2PSi[α]D25 = −2.6 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SP,RC)

Methyl ((SP)-(2-(trimethylstannyl)phenyl){methyl[(1R)-1-phenylethyl]amino}phenylphosphanylidene)carbamateC26H33N2O2PSn[α]D25 = −2.6 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SP,RC)

(RP)-P-(2-Methylphenyl)-P-phenyl-N-[(R)-1-phenylethyl]phosphinic amideC21H22NOP[α]D25 = −8.6 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-P-(2I)-P-phenyl-N-[(R)-1-phenylethyl]phosphinic amideC20H19INOP[α]D25 = −22.3 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-P-Phenyl-N-[(R)-1-phenylethyl]-P-[2-(trimethylsilyl)phenyl]phosphonic amideC23H28NOPSi[α]D25 = −6.4 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-P-(2-(Diphenylphosphoryl)phenyl)-P-phenyl-N-((R)-1-phenylethyl)phosphinic amideC32H29NO2P2[α]D25 = +14.6 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-N-Methyl-P-phenyl-N-((R)-1-phenylethyl)-P-(o-tolyl)phosphinic amideC22H24NOP[α]D25 = +4.5 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-P-(2-Iodophenyl)-N-methyl-P-phenyl-N-((R)-1-phenylethyl)phosphinic amideC21H21INOP[α]D25 = −0.8 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-N-Methyl-P-phenyl-N-((R)-1-phenylethyl)-P-(2-(trimethylsilyl)phenyl)phosphinic amideC24H30NOPSi[α]D25 = +20.8 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-N-Methyl-P-phenyl-N-((R)-1-phenylethyl)-P-(o-tolyl)phosphinothioic amideC22H24NPS[α]D25 = −10.0 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-N-Methyl-P-phenyl-P-(phenyl-2-d)-N-((R)-1-phenylethyl)phosphinic amideC21H21DNOP[α]D25 = +17.0 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-P-(2′-Methoxy-[1,1′-biphenyl]-2-yl)-N-methyl-P-phenyl-N-((R)-1-phenylethyl)phosphinic amideC28H28NO2P[α]D25 = −1.1 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

Methyl (R)-phenyl(o-tolyl)phosphinateC14H15O2P[α]D25 = −9.5 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP)

Methyl (R)-(2-iodophenyl)(phenyl)phosphinateC13H12IO2P[α]D25 = −3.8 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP)

(RP)-Methyl(phenyl)(o-tolyl)phosphine oxideC14H15OP[α]D25 = +29.6 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP)

Methyl ((SP)-(2-aminophenyl)(phenyl){[(1R)-1-phenylethyl]amino}phosphoranylidene)carbamateC23H26N3O2P[α]D25 = −58.5 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SP, RC)

(RP)-P-(2-Aminophenyl)-P-phenyl-N-((R)-1-phenylethyl)phosphinic amideC20H21N2OP[α]D25 = −80.8 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

Methyl (RP)-(2-aminophenyl)(phenyl)phosphinateC13H14NO2P[α]D25 = +115.5 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP)

(SP)-1-Phenyl-1-(((R)-1-phenylethyl)amino)-1λ5-benzo[c][1,5,2] diazaphosphinin-3(4H)-oneC21H20N3OP[α]D25 = +2.0 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SP,RC)

Methyl (RP)-(2-(((SP)-methyl(phenyl)(o-tolyl)-λ5-phosphanylidene) amino)phenyl)(phenyl)phosphinateC27H27NO2P2[α]D25 = −14.3 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,SP)

(RP)-P-(2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl)-N-methyl-P-phenyl-N-((R)-1-phenylethyl)phosphinic amideC26H29N2O2P[α]D25 = −60.0 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-P-(2-((R)-4-Isopropyl-4,5-dihydrooxazol-2-yl)phenyl)-N-methyl-P-phenyl-N-((R)-1-phenylethyl)phosphinic amideC27H31N2O2P[α]D25 = −25.4 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)

(RP)-P-(2-(((E)-3,5-Di-tert-butyl-2-hydroxybenzylidene)amino)phenyl)-P-phenyl-N-((R)-1-phenylethyl)phosphinic amideC35H41N2O2P[α]D25 = +2.0 (c 1, CH2Cl2)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RP,RC)