Abstract
Cascade reactions of ortho-carbonyl-substituted benzonitriles with ((chloromethyl)sulfonyl)benzenes as pronucleophiles led to new isoindolin-1-ones with a tetrasubstituted C-3 position or to (Z)-3-(sulfonyl-methylene)isoindolin-1-ones. The reactions start from readily available materials, are carried out under mild conditions, and do not require metal catalysis. Promoted only by the cheap and environmentally benign K2CO3 as the base, up to six elemental steps can be combined in a single pot. Hence, a sequential one-pot cascade/β-elimination/alkylation furnished useful intermediates for the synthesis of aristolactam natural products. The observed selectivity and the mechanism were investigated by DFT studies.
Highlights
Heterocyclic compounds bearing isoindolin-1-one and 3-methyleneisoindolin-1-one motifs have received increased interest owing to both their biological activities and their properties as functional materials.1−6 For example, taliscanine, a natural product isolated from Aristolochia taliscana, shows a range of promising activities on CNS, such as in the treatment of Parkinson’s disease and Alzheimer’s disease.1a,c A difluorosubstituted isoindolinonecarboxamide with a tetrasubstituted C3 was developed as a drug for the treatment of cardiac arrhythmias because of its potassium channel-inhibiting activity.1d sulfonyl-substituted 3-methyleneisoindolin1-ones are synthetic precursors of aristolactams.2a exo-methylene-substituted isoindolinones show unique mechanochromic properties as luminogens (Figure 1).2b
The possibility of using ((chloromethyl)sulfonyl)benzenederived carbanions carrying a leaving group (LG) in the αposition in reactions with 2-acylbenzonitriles 1 attracted our interest because the alkoxide intermediates, such as 4a, generated upon nucleophilic attack at the carbonyl group have two options to form stable products: they may undergo either cyclization with the formation of epoxides (Darzens reaction, path a) or cyclization via nucleophilic attack at the cyano group
The use of weaker bases like K2CO3 did not guarantee good conversion (Table 1, entries 3 and 4), while Et3N was not effective (Table 1, entry 6). This is the first important outcome of the present study because to our knowledge only either weak bases like K2CO3 or tertiary amines or transition metals as catalysts have been used in the past to promote cascade reactions of 2-carbonyl benzonitriles
Summary
Heterocyclic compounds bearing isoindolin-1-one and 3-methyleneisoindolin-1-one motifs have received increased interest owing to both their biological activities and their properties as functional materials.− For example, taliscanine, a natural product isolated from Aristolochia taliscana, shows a range of promising activities on CNS, such as in the treatment of Parkinson’s disease and Alzheimer’s disease.1a,c A difluorosubstituted isoindolinonecarboxamide with a tetrasubstituted C3 was developed as a drug for the treatment of cardiac arrhythmias because of its potassium channel-inhibiting activity.1d sulfonyl-substituted 3-methyleneisoindolin1-ones are synthetic precursors of aristolactams.2a exo-methylene-substituted isoindolinones show unique mechanochromic properties as luminogens (Figure 1).2baccess to these materials is often rather challenging because of the necessity to use transition metals as catalysts, expensive additives, or harsh reaction conditions.− In this context, one-pot cross-aldol-initiated cascade reactions of 2-formylbenzonitriles (2-cyanobenzaldehydes) with C−H-active compounds under mild basic conditions have been proven to provide reliable access to several classes of heterocycles, including a wide range of 3-substituted isoindolinones.1b,4 In addition, despite the well-known lower electrophilicities of ketones and the possibility of competitive enolization, we have recently found that 2-acylbenzonitriles react with a range of pronucleophiles under mild conditions to yield 3,3disubstituted isoindolin-1-ones. These products could be related to bioactive analogues bearing a tetrasubstituted carbon, whose syntheses have been reported to be challenging.1b,d,6 Quantification of the electrophilicity of such ortho-carbonyl-substituted benzonitriles would avail the prediction of the scope and selectivities of these cascade reactions. Heterocyclic compounds bearing isoindolin-1-one and 3-methyleneisoindolin-1-one motifs have received increased interest owing to both their biological activities and their properties as functional materials.− For example, taliscanine, a natural product isolated from Aristolochia taliscana, shows a range of promising activities on CNS, such as in the treatment of Parkinson’s disease and Alzheimer’s disease.1a,c A difluorosubstituted isoindolinonecarboxamide with a tetrasubstituted C3 was developed as a drug for the treatment of cardiac arrhythmias because of its potassium channel-inhibiting activity.1d sulfonyl-substituted 3-methyleneisoindolin1-ones are synthetic precursors of aristolactams.2a exo-methylene-substituted isoindolinones show unique mechanochromic properties as luminogens (Figure 1).2b Access to these materials is often rather challenging because of the necessity to use transition metals as catalysts, expensive additives, or harsh reaction conditions.− In this context, one-pot cross-aldol-initiated cascade reactions of 2-.
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