Switchable Chemoselectivity for Organocatalytic, Asymmetric Malononitrile Addition to ortho-Formyl Chalcones

Abstract

Chemoselective 1,2- and 1,4-addition of malononitriles to ortho-formyl chalcones using cinchona alkaloid based bifunctional chiral organocatalysts has been shown by tuning the electronic nature of the malononitriles. Alkyl (hard) malononitriles undergo an asymmetric 1,2-addition followed by oxa-Michael reaction cascade to afford 1,3-disubstituted isobenzofurans with high enantio- and diastereoselectivity. Aryl (soft) malononitriles proceed through 1,4-addition followed by an aldol reaction cascade to provide indanols, having three consecutive stereocenters, in good yields and with good to excellent enantio- and diastereoselectivites.

Organocatalytic Strategies for the Synthesis of Cyclopenta‐Fused Arenes and Heteroarenes

“…Ghorai and co‐workers reported a tandem Michael addition/intramolecular aldol reaction sequence of ortho ‐formyl chalcones 11 for the synthesis of indanols 15 with up to three consecutive chiral centers in excellent diastereo‐ and enantioselectivity (Scheme ) . Bifunctional chiral squaramide 13 catalyzes the Michael addition of malononitriles 12 to chalcones 11 in a chemo‐ and enantioselective manner to form anionic intermediate 14 .…”

“…Ghorai and co-workers reported at andem Michael addition/ intramolecular aldol reaction sequence of ortho-formyl chalcones 11 for the synthesis of indanols 15 with up to three consecutive chiralc enters in excellent diastereo-ande nantioselectivity (Scheme 4). [15] Bifunctionalc hiral squaramide 13 catalyzes the Michael addition of malononitriles 12 to chalcones 11 in a chemo-a nd enantioselective manner to form anionic intermediate 14.Asubsequent diastereoselectivei ntramolecular aldol reactionr esults the formation of indanols 15 in good yields and in excellent enantioselectivity.I nterestingly,a ryl-substituted malononitriles 12 (softer nucleophiles) generatei ndanols of type 15 through an initial Michael addition, whereas alkyl-substituted malononitriles (relativelyh arder nucleophiles) generate isobenzofurans througha ni nitial 1,2-addition.…”

Hexyltriphenylphosphonium Bromide as an Absolutely Chemoselective Ionic Liquid Catalyst in the Three‐Component Reaction of Aryl Aldehydes, Acetophenones and Malononitrile

“…Among various nucleophiles, malononitrile is a classic equivalent of 1,3‐dicarbonyl compounds. It is worth mentioning that the nitrile group of malononitrile is a useful functional group which could be conveniently transformed to other groups . However, in many cases the reaction starts with Michael addition of malononitrile to chalcones yielding open‐chain or cyclic products.…”

Organocatalytic, Chemoselective Hydrophosphenylation/oxa-Michael Addition Cascade toward Diastereo- and Enantioenriched 1,3-Dihydroisobenzofuryl Phosphonates

“…Isobenzofuran is a well-known heterocycle moiety that is found in natural products and drug molecules, for example, RPR 225, 370, an oxygen-bridged analogue of farnesyl transferase inhibitors, and citalopram, an antidepression drug . Moreover, there are rare methods for the synthesis of chiral 1,3-disubstituted isobenzofurans . A hybrid molecule where both 1,3-dihydroisobenzofuran and α-oxophosphonate units are stitched together in enantio- and diastereoenriched form would have prospective utility in pharmaceutical science.…”