Facile Synthesis of Enantiomerically Pure P‐Chiral 1‐Alkoxy‐2,3‐dihydrophospholes via Nucleophilic P‐N Bond Cleavage of a 1‐Phospha‐2‐azanorbornene

Abstract

The reactive P−N bond in a racemic mixture of endo‐1‐phospha‐2‐azanorbornene (PAN) (RP/SP)‐endo‐1 is readily cleaved with enantiomerically pure lithium alkoxides followed by protonation to afford diastereomeric mixtures of P‐chiral 1‐alkoxy‐2,3‐dihydrophosphole derivatives. The isolation of these compounds is rather challenging due to the reversibility of the reaction (elimination of alcohols). However, methylation of the sulfonamide moiety of the intermediate lithium salts and sulfur protection of the phosphorus atom prevent the elimination reaction. The resulting air‐stable P‐chiral diastereomeric 1‐alkoxy‐2,3‐dihydrophosphole sulfide mixtures can be readily isolated and fully characterized. The diastereomers can be separated by crystallization. The 1‐alkoxy‐2,3‐dihydrophosphole sulfides are readily reduced with Raney nickel to afford phosphorus(III) P‐stereogenic 1‐alkoxy‐2,3‐dihydrophospholes with potential use in asymmetric homogeneous transition metal catalysis.

Ring-Opening Reaction of 1-Phospha-2-Azanorbornenes via P-N Bond Cleavage and Reversibility Studies

“…When the solvent was evaporated in vacuum, the ring-closing reaction took place, yielding predominantly endo-1b. A similar behavior was already observed for the ring-opening reaction of endo-1b with H2O and alkoxides [9,33].…”

“…Herein, we report the P-N bond cleavage of PANs endo-1a-d (Scheme 1) with ethanol, resulting in the reversible formation of 1-ethoxy-2,3-dihydrophospholes 6a-d, thus hampering the isolation of the final products. This behavior was already observed during the ring-opening reaction of endo-1b with H 2 O and alkoxides [9,33]. Consequently, the nature of this reversibility and its possible mechanism were studied.…”

“…Interestingly the second isomer was only produced when small nucleophiles were used, corroborating the logical dependence of the nucleophile size and number of products. Thus, in P-N bond cleavage reactions with bulky lithium alkoxides, only one isomer was formed [33]. The P-N cleavage reaction of endo-1b with MeOH is also reversible and undergoes a ring-closing reaction to form endo-1b when the reaction mixture is concentrated in vacuo.…”

“…Thus, the P-N bond of PAN endo-1b can be cleaved by achiral nucleophiles, namely H 2 O, H 2 S, and EtMgBr, to give 2,3-dihydrophosphole derivatives (5a,b or 3, Scheme 1). Enantiopure lithium alkoxides have also been used as powerful nucleophiles to afford diastereomeric mixtures of 1-alkoxy-2,3-dihydrophospholes (4a-c, Scheme 1), as well as enantiopure compounds obtained via the crystallization of the diastereomers (4b,c, Scheme 1) [33]. Furthermore, the reduction of PAN endo-1b with lithium aluminum hydride yielded a seven-membered phosphorus heterocycle (2, Scheme 1) [34].…”

Access to Enantiomerically Pure P-Chiral 1-Phosphanorbornane Silyl Ethers

“…Phospholes are known to undergo hetero-Diels-Alder (HDA) reactions with various dienophiles to afford P-heterocyclic compounds [39], and recently, we reported the unprecedented phospha-aza-Diels-Alder reaction using an N-sulfonyl α-imino ester to produce 1-phospha-2-azanorbornenes (PANs) [40]. We also showed that the reactive P-N bond of PANs can be cleaved by both achiral and enantiopure nucleophiles to yield racemic 2,3-dihydrophosphole and optically pure 1-alkoxy-2,3-dihydrophosphole derivatives, respectively [40,41]. Moreover, the reduction of PAN with lithium aluminum hydride (LAH) resulted in a seven-membered P-heterocycle [42].…”