Metal triflate‐catalysed intermolecular Friedel–Crafts reactions involving electron‐rich benzenoid arenes and spiroepoxyoxindoles at the spiro‐centre have been developed for the exclusive regioselective synthesis of 3‐aryl‐(3‐hydroxymethyl)oxindoles with an all‐carbon quaternary centre. Selective ring opening of spiroepoxyoxindoles with phenols provided a direct access to 3‐(hydroxymethyl)‐3‐(2‐hydroxyaryl)oxindoles. We have utilized this methodology successfully as the key step for the synthesis of benzofuroindolines and 2H‐spiro[benzofuran]‐3,3′‐oxindoles.
A spiro‐pyrrolidine‐catalyzed tandem aza‐1,4‐addition/hemi‐acetalization reaction was developed with excellent enantioselectivity (12 examples of ≥99% ee), and several substrates proceeded with higher ee (up to 10% increase) compared with the literature data. Particularly, an interesting and unusual aza‐1,6‐/oxa‐1,4‐addition for some substrates was also observed.
The enantioselective organocatalytic nucleophilic addition of thiols to isatin‐derived ketimines has been developed utilizing only 1 mol% of an enantiopure BINOL‐derived phosphoric acid. The new protocol provides a series of isatin‐derived N,S‐acetals in high yields (up to 98%) and high enantioselectivities (up to 93% ee).
A quinine‐derived thiourea catalysed the enantioselective addition of 4‐substituted pyrazolones to isatin‐derived ketimines, providing a variety of aminooxindole‐pyrazolone adducts containing congested vicinal tetrasubstituted stereocentres with excellent outcomes (up to 98% yield, >20:1 dr and 98% ee).
The Wittig reaction of isatin derivatives with Morita–Baylis–Hillman bromides of cinnamaldehydes afforded 3‐dienylidene‐2‐oxindoles. These trienes were converted into the corresponding spirooxindoles in a stereoselective manner in refluxing toluene in good yields. The diastereomeric spirooxindoles could be obtained stereoselectively by adding a catalytic amount of palladium(II) acetate via the palladium‐catalyzed isomerization of EEE‐trienes to ZEE‐trienes followed by a more facile 6π‐electrocyclization process. The obtained spirooxindoles could be further functionalized by palladium‐catalyzed oxidative arylation, thionation with Lawesson’s reagent, catalytic hydrogenation and Friedel–Crafts‐type reaction.
A simple and efficient strategy for the construction of 6‐aza/oxa‐spiro[4.5]decane skeletons under the cocatalysis of gold(I)/copper(II) was developed, and its potential utility was demonstrated by a formal synthesis of the biologically active marine alkaloid (±)‐halichlorine.
A facile one‐pot, catalyst‐free reaction has been developed for the synthesis of 2,3,6,7‐tetrahydro‐1H‐pyrrolo[3,2‐c]pyridin‐4(5H)‐ones from readily available 1‐acryloyl‐1‐N‐arylcarbamylcyclopropanes and amines using a domino ring‐opening/cyclization/aza‐addition sequence.
A new type of phosphonium phase‐transfer catalyst prepared from easily available chiral amino acids was evaluated in a model reaction between oxindole and methyl vinyl ketone, and the catalyst derived from isoleucine was found to be the best. Michael additions of 3‐monosubstituted oxindoles to methyl vinyl ketone, acrolein or propargyl aldehyde proceeded smoothly to afford 3,3‐disubstituted oxindoles in good to excellent yields with moderate to excellent ees.
A highly efficient chiral N,N′‐dioxide‐zinc(II) complex catalytic system has been developed for the enantioselective aza‐Friedel–Crafts reaction of isatin‐derived ketimines with indoles. A series of enantiomerically enriched 3‐indolyl‐3‐aminooxindoles containing a tetrasubstituted stereocenter were obtained in up to 99% yield with up to 96% ee. Furthermore, control experiments provide a fundamental sight into the mechanism of the reaction.
A novel asymmetric [4+2] annulation of vinyl ketones with oxindole‐derived α,β‐unsaturated imines has been developed in the presence of a multifunctional thiourea‐phosphine catalyst derived from a natural amino acid, providing the first phosphine‐catalyzed enantioselective synthesis of 2′,3′‐dihydro‐1′H‐spiro[indoline‐3,4′‐pyridin]‐2‐ones in good yields with excellent stereoselectivities under mild conditions.
Asymmetric allylation of (hetero)aromatic aldehydes by a zinc(II)‐allylbutyrolactone species catalyzed by a chiral BINOL‐type phosphoric acid gave β‐substituted α‐methylenebutyrolactones in 68 to >99% ee and 52–91% isolated yield. DFT studies on the intermediate Zn2+‐complex – crucial for chiral induction – suggest a six‐membered ring intermediate, which allows the phosphoric acid moiety to activate the aldehyde. The methodology was applied to the synthesis of the antitumour natural product (S)‐(−)‐hydroxymatairesinol.
Highly regio‐ and diastereoselective 1,2‐addition of organolithium reagents to chiral fluoroalkyl α,β‐unsaturated N‐tert‐butanesulfinyl ketimines was developed, providing a general and efficient method for the asymmetric synthesis of structurally diverse α‐tertiary fluoroalkyl allylic amines in high yields and with excellent diastereoselectivities (dr up to>99:1). The synthetic application of the method was demonstrated by the rapid and convenient preparation of challenging α‐fluoroalkyl α‐amino acids with α‐tetrasubstituted carbon.
A facile and efficient one‐pot synthesis of isoxazol‐3(2H)‐ones has been developed starting from α‐acyl cinnamides and tosyliminophenyliodinane catalyzed by copper(II) acetate [Cu(OAc)2] under very mild conditions involving a tandem aza‐Michael addition and intramolecular cyclization sequence.
A simple combination of dichloro(para‐cymene)ruthenium(II) dimer, a chiral amino alcohol and isopropyl alcohol allowed for in‐situ generation of the bifunctional catalyst responsible for the transfer hydrogenation reaction of trifluoromethyl ketimines in excellent yields with high enantioselectivities (up to 93% ee). Herein, we describe the optimization, scope, limitations, and applications of the method.
The palladium‐catalyzed, one‐pot arylative cyclization of 3‐(γ,δ‐disubstituted)allylidene‐2‐oxindoles afforded spirodihydronaphthalene‐2‐oxindole frameworks via an oxidative Heck arylation (Fujiwara–Moritani reaction), an allylic palladium migration, and an aryl C H bond functionalization/arylation cascade of reactions. This is a first example of the palladium‐catalyzed oxidative arylation and an aryl C H bond functionalization/arylation cascade reaction which involves an electrophilic arylative quenching of a π‐allylpalladium intermediate and a regio‐controlled aryl C H bond activation assisted by a weak palladium‐arene interaction.
An enantioselective protonation by means of chiral scandium complex‐catalyzed aza‐Michael reaction was realized. A series of α‐aryl‐substituted vinyl ketones reacted with pyrazoles smoothly, affording the corresponding enantiomerically enriched pyrazole derivatives with excellent results (up to 99% yield, 94% ee). Water and hydrogen chloride were found to accelerate the protonation process.
A method to prepare highly enantioenriched azaflavanones using an organocatalytic 6‐endo aza‐Michael addition has been described. A variety of 2‐aryl‐, 2‐vinyl‐ and 2‐methylazaflavanones were prepared in good yields (53–84%) and excellent enantioselectivities (97.6:2.4 to 99.3:0.7 er).
In the presence of a Cinchona alkaloid‐based squaramide organocatalyst, the [3+2] cycloaddition of isatin‐derived azomethine ylides with maleimides proceeded readily, thus delivering the desired pyrrolidine‐fused spirooxindoles in 61–89% yields with >20:1 dr and 12 to >99 % ee. The absolute configuration of 5‐chloro‐1,5′‐dimethyl‐3′‐phenyl‐3′,3a′‐dihydro‐2′H‐spiro[indoline‐3,1′‐pyrrolo[3,4‐c]pyrrole]‐2,4′,6′(5′H,6a′H)‐trione was unambiguously determined by means of X‐ray single crystal structure analysis. The reaction mechanism was hypothesized to account for the enantioselective formation of 5‐chloro‐1,5′‐dimethyl‐3′‐phenyl‐3′,3a′‐dihydro‐2′H‐spiro[indoline‐3,1′‐pyrrolo[3,4‐c]pyrrole]‐2,4′,6′(5′H,6a′H)‐trione.
The catalytic asymmetric [4+2] annulations of isatins with but‐3‐yn‐2‐one catalyzed by the Cinchona alkaloids‐derived oragnocatalyst (DHQD)2PHAL have been developed in the presence of 3.0 equivalents of D ‐diethyl tartrate in the mixed solvent (diphenyl ether/diethyl ether=1/1) or a slightly modified one, affording the corresponding substituted spiro[indoline‐3,2′‐pyran]‐2,4′(3′H)‐diones in good to excellent yields with high enantioselectivities under mild conditions.
An (R/S)‐titanium(IV) BINOLate‐catalyzed highly enantioselective intramolecular Heck/aza‐Diels–Alder cycloaddition (IHADA) cascade was developed to prepare tetrahydropyridoindoles (tHPs) and octahydropyrazinopyridoindoles (oHPPs) from in situ generated (R/S)‐BINOL α‐phosphoryloxy carbamate ( αPPC2 ) in one pot. Chiral cooperativity between (R/S)‐αPPC2 and (R/S)‐titanium(IV) BINOLate was observed and successfully utilized for the construction of various tHPs (7 examples) and oHPPs (17 examples).
