One-pot three-component highly diastereoselective synthesis of isoindolin-1-one-3-phosphonates under solvent and catalyst free-conditions

The one-pot three-component reaction of 2-formylbenzoic acid with (S)- and (R)-methylbenzylamine and dimethyl phosphite (Kabachnik–Fields reaction) proceeded in short reaction times under solvent and catalyst free-conditions to afford the corresponding (3R,1′S)- and (3S,1′R)-isoindolin-1-one-3-phosphonates 3, respectively, in good yield and with high diastereoselectivity (95:5 dr). The use of a solvent decreases the diastereoselectivity and slows the reaction rate. The reaction rate was also influenced by CO2H functionality through protonation of the imine intermediate. The absolute configuration at the new stereogenic center was determined by X-ray crystal analysis, and a mechanism was proposed to explain the high diastereoselectivity.

Figure optionsDownload as PowerPoint slide

Dimethyl (3R,1′S)-2-(1′-methylbenzyl)isoindolin-1-one-3-yl)phosphonateC18H20NO4Pds > 98%[α]D = −19.2 (c 1.0, CHCl3)Source of chirality: (S)-α-methylbenzylamineAbsolute configuration: (3R,1′S)

Dimethyl (3S,2′R)-2-(2′-phenylethanol)isoindolin-1-one-3-yl)phosphonateC18H20NO5Pds > 97%[α]D = +64 (c 1.0, CHCl3)Source of chirality: (R)-α-phenylglycinolAbsolute configuration: (3S,2′R)

Dimethyl (3R,2′R)-2-(2′-phenylethanol)isoindolin-1-one-3-yl)phosphonateC18H20NO5Pds > 97%[α]D = +32 (c 1.0, CHCl3)Source of chirality: (R)-α-phenylglycinolAbsolute configuration: (3R,2′R)

Dimethyl (3R,2′S)-2-(2′-(3,3-dimethylbuthyl)isoindolin-1-one-3-yl)phosphonateC16H24NO4Pds > 98%[α]D = +9.2 (c 1.0, CHCl3)Source of chirality: (S)-3,3-dimethyl-2-butylamineAbsolute configuration: (3R,2′S)