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

Abstract

One-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and subsequent acid-assisted spirocyclization allowed for diastereoselective preparation of 4′H-spiro[indole-3,5′-isoxazoles].

Synthetic Studies toward 1,2,3,3a,4,8b-Hexahydropyrrolo[3,2-b]indole Core. Unusual Fragmentation with 1,2-Aryl Shift

“…Recently, we have reported on diastereoselective [4 + 1]-spirocyclization between nitroalkenes 1 and indoles 2 in the presence of phosphorous acid at or below room temperature. , This unusual transformation allows for highly efficient assembly of spirocyclic isoxazoles 3 in diastereomerically pure forms (Scheme ). It was also demonstrated that, at slightly elevated temperatures in the presence of weak acids or bases, 3 underwent stereoselective rearrangements into 2-(3-oxoindolin-2-yl)­acetonitriles 4 , which can also be routinely accessed in a one-pot fashion directly from precursors 1 and 2 (Scheme ).…”

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].…”

“…Thus, synthetic methods for selective preparation of these 1H-indole derivatives remain the focus of many research groups. Recently, we reported an unusual, acid-assisted [4+1]-cycloaddition of indoles 1 with nitroalkenes 2 that provides 4 H-spiro[indole-3,5isoxazoles] 5 in a diastereomerically pure form (Scheme 1) [18,19]. It was confirmed that this spirocyclization occurs via nitronate intermediate 3.…”

Reconstructive Methodology in the Synthesis of 2-Aminopurine

“…In addition, the structure of 5-nitropyrimidine-2,4-diamine 5 was finally determined by X-ray diffraction analysis (Figure 2). Nitro compounds are important building blocks for further important transformations [19].…”