Access to Enantiomerically Pure P-Stereogenic Primary Aminophosphine Sulfides under Reductive Conditions

Abstract

Stereochemically pure phosphines with phosphorus-heteroatom bonds and P-centered chirality are a promising class of functional building blocks for the design of chiral ligands and organocatalysts. A route to enantiomerically pure primary aminophosphine sulfides was opened through stereospecific reductive C-N bond cleavage of phosphorus(V) precursors by lithium in liquid ammonia. The chemoselectivity of the reaction as a function of reaction time, substrate pattern, and chiral auxiliary was investigated. In the presence of exclusively aliphatic groups bound to the phosphorus atom, all competing reductive side reactions are totally prevented. The absolute configurations of all P-stereogenic compounds were determined by single-crystal X-ray diffraction analysis. Their use as synthetic building blocks was demonstrated. The lithium salt of (R)-BINOL-dithiophosphoric acid proved to be a useful stereochemical probe to determine the enantiomeric purity. Insights into the coordination mode of the lithium-based chiral complex formed in solution was provided by NMR spectroscopy and DFT calculations.

Keywords: P-stereogenic compounds; alkali metals; cleavage reactions; phosphorus; structure elucidation.

Figure 1

Previously reported enantiomerically pure P‐stereogenic primary aminophosphines. a) Borane‐protected aminophosphines (A). ^[17d] b) Aminophosphine oxides (B). ^[17j] c) Aminophosphine sulfides (C) reported herein.

Scheme 1

Synthesis of the stereochemically pure phosphorus(V) precursors (S _P,S)‐4 and (S _P,S)‐5.

Figure 2

Molecular structures of compounds (S _P,S)‐4 and (S _P,S)‐5 in the crystal (displacement ellipsoids set at the 50 % probability level).

Figure 3

Molecular structures of compounds (R _P)‐6 and (R _P,S)‐7 (top), and (S _P)‐8 and (rac)‐8 (bottom) in the crystal (displacement ellipsoids set at the 50 % probability level).

Scheme 2

Stereospecific, reductive C−N bond cleavage of (R _P,S)‐12 to enantiomerically pure P‐chiral primary aminophosphine sulfide (R _P)‐13.

Figure 4

Molecular structures of compounds (R _P,S)‐12 and (R _P)‐13 in the crystal (displacement ellipsoids set at the 50 % probability level).

Scheme 3

Determination of the enantiomeric purity of primary aminophosphine sulfides by NMR spectroscopy using lithiated (R)‐BINOL‐PSSH as chiral probe (top). Calculated model (D‐Cy) of the structural proposal D (bottom) [M062X/6‐31+G(d); PCM solvent: dichloromethane].[ ³² , ³³ ]

Scheme 4

Functionalization of the primary amino group of enantiomerically pure (R _P)‐13 through lithiation and reaction with a chlorohydrosilane. The yield refers to crystalline material obtained directly from the mother liquor.

Figure 5

Molecular structure of compound (R _P)‐14 in the crystal (displacement ellipsoids set at the 50 % probability level).