Reductive Coupling of Phthalimides with Ketones and Aldehydes by Low-Valent Titanium: One-Pot Synthesis of Alkylideneisoindolin-1-ones

Abstract

The reductive coupling of phthalimides with ketones and aldehydes by Zn-TiCl4 in THF gave two- and four-electron reduced products, 3-hydroxy-3-(1-hydroxyalkyl)isoindolin-1-ones and alkylideneisoindolin-1-ones, selectively by controlling the reaction conditions. Therefore, the one-pot synthesis of alkylideneisoindolin-1-ones from phthalimides was effected by this reaction. Although the alkylideneisoindolin-1-ones prepared from phthalimides and aldehydes were formed as mixtures of geometric isomers in most cases, the geometric ratios could be increased by reflux in cat. PPTS/toluene. After the isomerization, the E-isomers of N-methyl substituted alkylideneisoindolin-1-ones (X = Me, R(1) = R, R(2) = H) and the Z-isomers of N-unsubstituted alkylideneisoindolin-1-ones (X = H, R(1) = H, R(2) = R) were obtained preferentially.

The photodecarboxylative addition of carboxylates to phthalimides as a key-step in the synthesis of biologically active 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones

“…The change in stability may be caused by a stabilizing ionic–π interaction for the Z -isomer during isomerization [ 61 ]. A similar thermal isomerization towards the more stable isomer induced by catalytic amounts of pyridinium p -toluenesulfonate has been recently reported by Kise and co-workers [ 12 ].…”

“…The simple reaction protocol enabled parallel operations in a Radleys Carousel 6 Plus Reaction Station™. In line with DFT calculations by Kise et al [ 12 ] and independently by Li and Janesko [ 21 ], the thermodynamically favored E -isomer was obtained as the main or sole product. The high E -selectivity was furthermore confirmed by 1 H NMR analyses.…”

“…The high stereoselectivity during the formation of compounds 7a–q is supported by the higher stability of the E -isomer, as shown for other simple N -substituted benzylideneisoindolin-1-ones [ 12 , 21 ]. Remarkably, acidic reaction conditions induced thermal isomerization of compounds 8a–y , possibly via an acylaminium cation intermediate ( Scheme 9 ) [ 60 ].…”

Continuous Flow Photochemical and Thermal Multi-Step Synthesis of Bioactive 3-Arylmethylene-2,3-Dihydro-1H-Isoindolin-1-Ones

“…Dehydrations of the photoproducts 3a-e readily furnished the corresponding olefins 4a-e with near complete E-selectivity. Using DFT calculations, Kise et al [26] and independently Li and Janesko [27] showed that the E-isomers of N-substituted 3-arylmethyleneisoindolin-1-ones are thermodynamically more stable than their Z-counterparts. The current results are in line with these findings.…”

Synthesis of 3–aryl 3–hydroxyisoindolinones by the Addition of Grignard and Organolithium Reagents to Phthalimides

“…Recently, Li et al used the same palladium catalyst for the cyclization with phenylglyoxylic acids [23]. Other methods for obtaining isoindolinone alcohols include fluoride-catalyzed nucleophilic additions [24,25], reductive couplings with aldehydes, ketones and olefins [26][27][28][29], and photodecarboxylative additions of carboxylates to phthalimides [30,31].…”