Base-Promoted Cascade Reactions for the Synthesis of 3,3-Dialkylated Isoindolin-1-ones and 3-Methyleneisoindolin-1-ones

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 K 2 CO 3 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.

Scalable (Enantioselective) Syntheses of Novel 3-Methylated Analogs of Pazinaclone, (S)-PD172938 and Related Biologically Relevant Isoindolinones

“…A combination of both ionic and hydrogen bond interactions with 21 should favor the intramolecular aza-Michael reaction from the re face of prochiral intermediate c leading to 7 ( Scheme 5 ). The mechanism of the reaction is proposed based on previous experimental [ 31 , 33 ] and theoretical studies [ 32 ]. After deprotonation of dimethylmalonate, the resulting carboanion leads to carbonyl addition to ketone, followed by cyclization at cyano group and formation of the cyclic imidate b , which will give then rearrangement to the final product 7 .…”

“…However, the construction of the isoindolinone ring with a tetrasubstituted carbon stereocenter is a major challenge, especially when this has to be asymmetrically performed [ 14 , 23 , 24 ]. To our knowledge there are no examples in literature of 3-methylated analogs of the compounds described in Figure 2 and very few protocols on the synthesis of 3,3-disubstituted isoindolinones introducing a methyl group on the C-3 position have been reported [ 14 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. For instance, as described by Heibel in 2005, an asymmetric synthesis of 3,3-disubstituted isoindolinones involved the use of readily available (+) or (−)-trans-2-(α-cumyl) cyclohexanol (TCC) as the chiral auxiliary after the treatment with NaHMDS at temperatures ranging between −100 °C and −115 °C leading to good diastereoselectivity [ 25 ].…”

“…However, all these methodologies have several drawbacks, such as harsh reaction conditions, low scale set up and, most importantly, they are not suitable for the synthesis of 3-methylated analogs of the bioactive compounds of Figure 2 . In this context, we report a convenient approach to 3,3-disubstituted isoindolinones via cascade reactions of readily available 2-acylbenzonitriles with several nucleophiles promoted by cheap and environmentally friendly K 2 CO 3 [ 30 , 31 , 32 ]. Asymmetric versions of these reactions have also been developed [ 33 ].…”

“…Based on our continuing research interest in the synthesis of isoindolinones [ 31 , 32 , 33 , 34 , 35 ], we report the application of our efficient and practical K 2 CO 3 promoted a cascade reaction to the first synthesis of 3-methylated analogs of Pazinaclone, PD172938 and related structures ( Scheme 1 ). An efficient asymmetric synthesis of 3-methylated analog of ( S )-PD172938 was also developed based on the combination of the asymmetric-phase transfer catalysis process and a recrystallization step.…”

Asymmetric Cascade Aza-Henry/Lactamization Reaction in the Highly Enantioselective Organocatalytic Synthesis of 3-(Nitromethyl)isoindolin-1-ones from α-Amido Sulfones

“… 10 , 11 Cascade reactions of 2-cyanobenzaldehyde with active methylene compounds or heteronucleophiles are important tools in the synthesis of 3-monosubstituted isoindolinones ( Scheme 1 b). 12 We also developed asymmetric versions of this reaction promoted by both organocatalysts and chiral phase-transfer catalysts. 5 However, in the presence of nitromethane, only decomposition products were observed.…”