Preparation of Stereodefined 2-(3-Oxoindolin-2-yl)-2-Arylacetonitriles via One-Pot Reaction of Indoles with Nitroalkenes

Abstract

Recently discovered reactivity of nitrostyrenes in phosphorous acid to facilitate the diastereoselective [4 + 1]-cycloaddition of indoles in combination with unusual oxazoline ring cleavage and subsequent 1,2-alkyl shift afforded stereochemically defined 2-(3-oxoindolin-2-yl)-2-arylacetonitriles as sole products.

Direct Conversion of 3-(2-Nitroethyl)-1H-Indoles into 2-(1H-Indol-2-yl)Acetonitriles

“…We have previously reported that generation of the key 4 H-spiro[indole-3,5 -isoxazole] 5 [18,19] takes place under acidic conditions, while isomerization of the latter into nitrile 6 occurs in the presence of weak bases [20]. Arguably, activation of nitroalkane 4 toward the desired transformation requires generation of nitronic acid 3 (also known as aci-form), which occurs in a basic medium [18].…”

“…This reaction was repeated in a preparative scale and, after isolation and purification, afforded the target nitrile in 72% yield. Further optimization attempts were unproductive and led to a decreased product yield (entries [15][16][17][18][19][20].…”

“…Most substituents and functional groups tested (Alk, OAlk, Hal, NMe 2 ) were well tolerated. Expectedly, lower yields were obtained for N-substituted indoles (4ja,4ka), because these reactions proceed via a less stable, charged N-methyliminium species 10 (Scheme 3 vide infra) [20]. Product 6bj bearing a bulky and acid-sensitive 3,5-dimethyl-1H-pyrazolyl moiety was also formed in a notably lower yield (Scheme 2).…”

“…This species, however, was susceptible to a facile isomerization into more thermodynamically stable nitroalkane 4, which proved to be inert under the reaction conditions. It was also shown that spiroheterocycles 5 underwent a diastereoselective rearrangement to afford nitriles 6 (Scheme 1) [20]. A shortcut approach involving the formation of nitriles directly from 1 and 2 was also demonstrated.…”

Preparation of spiro[indole-3,5′-isoxazoles] via Grignard conjugate addition/spirocyclization sequence

“…We have recently reported a highly efficient and diastereoselective formal [4 + 1]-spirocyclization of indoles with nitroolens serving as unusual 1,4-CCNO dipoles (Scheme 1). [15][16][17] This reaction proceeded in the presence of phosphorous acid, affording very good yields of spiroindoles 3, hardly accessible by other means. For a series of these compounds promising antitumor activity against neuroblastoma cells was discovered.…”