Synthesis of 3–aryl 3–hydroxyisoindolinones by the Addition of Grignard and Organolithium Reagents to Phthalimides

Abstract

Background: The 3-substituted 3-hydroxyisoindolinone motif is common to a variety of compounds with potent biological activities. In recent years, they have also been increasingly used as substrates in various asymmetric transformations. Current methods for their preparation either do not tolerate wide range of functional groups, or yield 3-hydroxyisoindolinones as N-substituted products, which makes them inapplicable as substrates for the asymmetric transformations.Objective: Aim of this study was a detailed examination of the synthesis of 3-substituted 3hydroxyisoindolinones comprising various functional groups and unsubstituted phthalimide nitrogen.Method: Grignard and organolithium reagents were employed as nucleophiles for the synthesis of 3substituted 3-hydroxyisoindolinones under various reaction conditions. Results: Phenyl substituents with electron donating groups are easily introduced by employing a Grignard reaction, while electron-poor arenes require a lithium exchange or direct lithiation strategy. The protocols are tolerant of various functional groups on the nucleophile, and a wide range of 3-hydroxyisoindolinones were afforded in good to excellent yields. Conclusion:Simple and inexpensive method for the synthesis of 3-substituted 3-hydroxyisoindolinone has been developed. By tweaking the reaction conditions, described protocols are tolerant of a wide range of functional groups, and yield 3-substituted isoindolinone alcohols with unsubstituted phthalimide nitrogen.

Organocatalytic Synthesis of α-Triphenylmethylamines from Diarylketimines and Phenols

“…Melting points were determined using an Electrothermal 9100 apparatus in open capillaries and are uncorrected. Substrates, 3-aryl 3-hydroxyisoindolinones 32 – 41 (see Supporting Information) were synthesized in high yields from readily available starting materials by employing the addition of a Grignard or organolithium reagent to phthalimide …”

“…3-(1-Hydroxynaphthalen-2-yl)-3-phenylisoindolin-1-one (14) 5, 150.8, 150.2, 144.6, 134.1, 131.9, 131.2, 128.4, 128.3, 127.8, 126.8, 126.3, 125.5, 125.4, 125.22, 125.18, 125.16, 123.6, 123.3, 121.9, 118.8, 69.4;Mp 258.4-259.1 °C. νmax (neat): 3446, 2359Mp 258.4-259.1 °C.…”

“…Unless otherwise noted, all compounds were prepared according to General Procedure. 14 General Procedure. To a suspension of 3-aryl 3-hydroxyisoindolinone (0.2 mmol) in cyclohexane (2.0 mL) was added MsOH (19 mg, 14 μL, 0.02 mmol) at 25 °C.…”

“…Information), were synthesized in high yields from readily available starting materials, by employing addition of a Grignard or organolithium reagent to phthalimide 14. …”

Organocatalytic Synthesis of α,α–Diaryl Substituted α–Amino Acid Derivatives by an Interrupted Three-Component Ugi Reaction

“…Substrates, 3-aryl 3-hydroxyisoindolinones, were synthesized in high yields from readily available starting materials, by employing addition of a Grignard or organolithium reagent to phthalimide or 5,6-dichlorophthalimide. [20]…”