Mechanochemical Asymmetric Cross‐Dehydrogenative Coupling Reaction: Liquid‐Assisted Grinding Enables Reaction Acceleration and Enantioselectivity Control

Abstract

We report here a mechanochemical protocol for asymmetric cross‐dehydrogenative coupling (CDC) reaction of unreactive 3‐arylmethyl indoles with 1,3‐dicarbonyl by liquid‐assisted grinding. Small drops of liquid additive n‐butyl acetate (n‐BuOAc) are key to achieve high yield and enantioselectivity in this transformation. The catalyst can be lowered to 5 mol% and reused for three times. Pharmaceutical useful chiral dihydrocoumarins are further achieved through one‐pot tandem asymmetric CDC and cyclization with excellent enantioselectivities. Experimental and computational studies on the reaction mechanism suggest that n‐BuOAc is participated to the catalytic cycle, forming a chiral metal species during the reaction process and thereby revealed the origin of stereoselectivity.

Liquid‐Assisted Grinding Mechanochemistry in the Synthesis of Pharmaceuticals

“…However, most above mentioned approaches have reliance on toxic solvent, low temperature and/or inert atmosphere which are critical to the success of enantiocontrol. As the continuous study of LAG accelerated indole functionalization, Su's group recently reported a mechanochemical asymmetric cross‐dehydrogenative coupling reaction for the synthesis of chiral indoles (Scheme 15b) [99] . Essential to the success was the addition of catalytic amount of n ‐BuOAc enabling the dual‐control of reactivity and enantioselectivity.…”

“…Su's group recently reported a mechanochemical asymmetric cross-dehydrogenative coupling reaction for the synthesis of chiral indoles (Scheme 15b). [99] Essential to the success was the addition of catalytic amount of n-BuOAc enabling the dual-control of reactivity and enantioselectivity.…”

Mechanochemistry in Portugal—A Step towards Sustainable Chemical Synthesis

“…Strong covalent bonds, such as carbon-carbon and carbon-heteroatom (C-N, C-O, C-halogen, C-S, C-Se, and C-Te), can be activated by solid-state grinding under mild conditions of temperature and reagents. Examples of organic covalent reactions performed by mechanochemistry include dehydrogenative coupling, oxidation, reduction, and organocatalytic reactions [ 9 , 10 , 11 , 12 , 13 , 14 ]. Mechanochemistry has also been showing promising advances in organometallic synthesis [ 15 ].…”

Rate Dependence on Inductive and Resonance Effects for the Organocatalyzed Enantioselective Conjugate Addition of Alkenyl and Alkynyl Boronic Acids to β-Indolyl Enones and β-Pyrrolyl Enones

“…Concordantly, many recent reports have described efforts to develop new strategies and catalysts to synthesize heteroaryl-bearing stereocenters with absolute stereocontrol. To cite limited examples, transition metal-mediated couplings [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ], Petasis-like reactions [ 27 , 28 , 29 ], C—H functionalizations [ 30 , 31 , 32 , 33 , 34 , 35 ], Friedel–Crafts reactions [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ,…”

“…When heteroaryl trifluoroborate salts are used as nucleophiles, bis-heteroaryl stereocenters Concordantly, many recent reports have described efforts to develop new strategies and catalysts to synthesize heteroaryl-bearing stereocenters with absolute stereocontrol. To cite limited examples, transition metal-mediated couplings [17][18][19][20][21][22][23][24][25][26], Petasis-like reactions [27][28][29], C-H functionalizations [30][31][32][33][34][35], Friedel-Crafts reactions , and conjugate additions have provided significant advances . We have contributed to this area by demonstrating that α-chiral heterocycles can be synthesized through 3,3′-(bisperfluoroaryl)-BINOL (6)-catalyzed conjugate addition of aryl, alkenyl, and alkynyl boronic acids and trifluoroborate salts to β-heteroaryl-appended enones and enals [87][88][89][90].…”