Abstract
A systematic study of the oxidation of 3-hydroxy-2-substituted isoindolin-1-ones (hydroxylactams) and their conversion to the corresponding phthalimides was undertaken using three oxidants. Of special interest was the introduction of nickel peroxide (NiO2) as an oxidation system for hydroxylactams and comparison of its performance with the commonly used pyridinium chlorochromate (PCC) and iodoxybenzoic acid (IBX) reagents. Using a range of hydroxylactams, optimal conversions of these substrates to the corresponding imides was achieved with 50 equivalents of freshly prepared NiO2 in refluxing toluene over 5–32 h reaction times. By comparison, oxidations of the same substrates using PCC/silica gel (three equivalents) and IBX (three equivalents) required oxidation times of 1–3 h for full conversion but required lengthier purification. While nominal amounts (~25 mg) of substrate hydroxylactams were used to ascertain conversion, scale-up procedures using all three methods gave good to excellent isolated yields of imides.
Highlights
The N-phthaloyl group is a well-established, frequently used protecting group for amine functionality in organic synthesis, and apart from its employment as a protecting group (2-substituted-l-isoindoline-1,3-dione group), it is used as a fundamental means for introducing nitrogen (Gabriel reaction) in a wide range of starting materials and intermediates in organic synthesis [1]
We have introduced nickel peroxide as an oxidant for the conversion of hydroxylactams to imides
While there are isolated examples of nickel peroxide-mediated alcohol oxidation in general, the specific use of NiO2 in this hydroxylactam to imide conversion constitutes a unique application of this reagent preparation, and it compared favorably with two popular oxidation protocols, pyridinium chlorochromate (PCC) and IBX
Summary
The N-phthaloyl (phthalimide) group is a well-established, frequently used protecting group for amine functionality in organic synthesis, and apart from its employment as a protecting group (2-substituted-l-isoindoline-1,3-dione group), it is used as a fundamental means for introducing nitrogen (Gabriel reaction) in a wide range of starting materials and intermediates in organic synthesis [1]. The unique serviceability of the N-phthaloyl group is enhanced by its mild removal from compatible intermediates by a brief treatment with alcoholic hydrazine thereby releasing the desired amine functionality [2]. The N-phthaloyl group I (Figure 1) can serve as a starting point for isoindolinones (lactams) II through its deoxygenation and deoxygenation of its partial reduction product, the corresponding hydroxylactam III [3]. The partial reduction of the imide to the hydroxylactam can be facile and, in some cases, can interfere with the phthaloyl group’s efficacy as a protecting group in a synthetic scheme. Group can act as a latent protecting group by oxidation back to the imide, which can be removed [4]. Inadvertent reduction of a phthalimide protecting group to a hydroxylactam may accompany a desired reduction of a separate functional group within the same molecule.
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