3-Substituted 2-oxindoles, addition

Oxindoles are a particular class of cyclic amides which are acidic enough to play the role of pro-nucleophiles in conjugate additions under iminium activation. In particular, the reaction between 3-alkyl substituted oxindoles and ot,p-unsaturated aldehydes leading to the formation of a quaternary stereocenter at the heterocyclic unit has been studied by several authors (Scheme 3.12). The use of 0-trialkylsilyldiarylprolinols like 31a as catalysts led... 

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

Scheme 2.75 Asymmetric organocatalyzed conjugate addition of 3-substituted oxindoles to...

Other activated methylene-containing nucleophiles that have been successfully used in the conjugate addition to nitrooleflns are a-nitroesters [240], a-cyanoesters [240], a-isocyanoesters [259], 2-hydroxy-1,4-naphthoquinones [260], 3-substituted oxindoles [261], and anthrone [262]. For instance, cupreidine-derived catalysts 151 and 152 (see Fig. 2.15) afford very good yields, diastereo- and enantioselectivities... 

The first organocatalyzed stereoselective conjugate addition of 3-substituted oxindoles to nitrooleflns has been recently reported by Barbas et al. using thiourea 168 as catalyst [261a]. The reaction, which is performed in THF as solvent at -20°C, generates adjacent quatemary/tertiary stereocenters and affords the corresponding... 

Calcium VAPOL (2,2 -diphenyl-(4-biphenanthrol)) phosphate (150) has been reported as an efficient catalyst for the enantioselective Michael addition of 3-aryloxindoles to CH2=CHCOMe (<95% ee) and for chlorination of 3-substituted oxindoles with A-chlorosuccinimide (<99% ee). ... 

Michael addition of 3-benzyl-substituted oxindoles to 2-cyclopentenone, catalysed by the chiral guanidine (322), produced 3,3-disubstituted oxindoles (323) at -10 C with 73-98% ee and 9 1 to >20 1 dr ... 

Antilla et al. reported chiral calcium VAPOL phosphate-mediated asymmetric 1,4-addition reactions of 3-substituted oxindoles (Table 13) [59] for reviews of asymmetric reactions of oxindole, see [60-63]. It was showed that VAPOL phosphate could be applied, and the desired products were obtained in excellent yields with high enantioselectivities. Four differently substituted oxindoles worked well in this reaction. 

Based on the enantioselective Michael addition/ISOC (intramolecular silyl nitronate olefin cycloaddition)/lragmentation sequence previously developed by the group of Rodriguez [33a], Shao and coworkers proposed an extrapolation for the construction of spirooxindoles catalyzed by a bifunctional tertiary amine-thiourea catalyst XV between 4-allyl-substituted oxindoles 63 and nitrostyrenes 64 (Scheme 10.21) [33b]. After the addition of TMSCl and EtgN at -30 C, the Michael adduct underwent an ISCX3 to afford the spiro oxime derivatives 65 in very good yields (85-85%), and excellent diastereo (up to >30 1) and enantioselectivities (94-99% ee) after the treatment with TBAF. 

Considering the rapid growth of asymmetric construction of oxindoles, Sun et al. recently reported their assembly of chiral spirooxindoles by combining secondary amine and palladium catalysis in a cascade reaction [55]. The reaction was initiated by the reversible Michael addition of 3-substituted oxindole to enal, which was followed by a metal/organic-cocatalyzed carbocyclization of the aUcyne tether (Scheme 9.60). Similar to the aforementioned dynamic kinetic asymmetric transformations, this chemistry highlighted the cooperative effects of the two catalysts in the same reaction vessel, while either catalyst could not solely promote the overall reaction, and unsatisfactory results were observed when this reaction was conducted in a two-step mode. 

The Michael additions of 3-benzyl-substituted oxindoles to M-substituted maleimides has been reported to proceed with <99% ee in the presence of the C2-symmetric bicyclic guanidine (302) as a basic organocatalyst in toluene at -50 C over 48 h. A plausible transition state has been proposed4 ... 

The highly enantioselective calcium phosphate (392) catalysed chlorination of 3-substituted oxindoles (387) with A -chlorosuccinimide (NCS, 388) in the catalytic enantioselective Michael addition of (387) to methyl vinyl ketone (389) to afford the product (390) and (391) in quantitative yields, with high enantioselectivities, has been described by Antilla et al. (Scheme 102). ... 

Asyimnetric catalytic method to generate C-C bond with adjacent quatemaiy-tertiary stereocenters ranains a challenging synthetic task. In this regard, the use of 3-substituted oxindoles as carbon-nucleophiles has attracted intensive interests due to their relevance in synthesizing bioactive indole alkaloids. Melchiorre recently reported asymmetric Michael addition of 3-substituted oxindoles to a,P-unsaturated aldehydes catalyzed by a primary amine thiourea catalyst 114 (Scheme 5.29). Good diasteieoselectivity and enantioselectivity have been achieved in most cases. However, the reactions were generally sluggish [56]. 

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

Hartwig has reported an intramolecular/intermolecular process affording the 3-aryloxindoles 105 (Scheme 32).115 The intermolecular arylation of acetanilide derivative 104 is slower than the intramolecular arylation to form the oxindole. Thus, the overall transformation starts with cyclization followed by intermolecular arylation of indole. In order to slow down the intermolecular process and speed up the intramolecular reaction, chloroarene and bromine-substituted acetanilide precursors are used according to their respective reactivity with palladium(O) in the oxidative addition process. 

Intramolecular nucleophilic substitution by the anions of o-haloanilides is another viable oxindole synthesis. This is a special example of the category Ic process described in Section 3.06.2.3. The reaction is photo-stimulated and the mechanism is believed to be of the electron-transfer type SRN1 rather than a classical addition-elimination mechanism. The reaction is effective when R = H if 2 equivalents of the base are used to generate the dianion (equation 202) (80JA3646). 

Interestingly, cyclic / -keto esters, e.g. 69, can be also fhiorinated with enantioselectivity up to 80% ee, although the yield and enantioselectivity depend strongly on the type of substrate. A representative example of asymmetric fluorination of a cyclic ester is shown in Scheme 3.27, Eq. (2). In addition, oxindoles 71 have been successfully fhiorinated, as shown in Scheme 3.27, Eq. (3). Under optimized conditions, the desired 3-substituted 3-fluorooxindole, 72, was obtained in 79% yield and with enantioselectivity of 82% ee. 

The synthesis of 2-vinylindoles continues to be of interest due to the vast potential of these species for further chemical elaboration. In developing a strategy for carbazole synthesis, a Michael-type addition of 4,7-dihydroindole to dimethyl acetylenedicarboxylate was employed to afford, after DDQ oxidation, functionalized 2-vinylindoles <06JOC7793>. In a metal-mediated approach, Nakao, Hiyama, and co-workers prepared propyl-substituted 2-vinylindoles from A-protected 3-cyanoindoles via treatment with 4-octyne in the presence of catalytic nickel <06JACS8146>. Aryl, vinyl, and alkynyl substituents were installed by direct coupling with an A-protected 2-trifluoromethanesulfonyloxyindole, prepared from oxindole <06S299>. 

Reaction of 3-substituted indoles with halogens can be more complex initial 3-halogenation occurs generating a 3-halo-3//-indole, ° but the actual products obtained then depend upon the reaction conditions, solvent etc. Thus, nucleophiles can add at C-2 in the intermediate 3-halo-3//-indoles when, after loss of hydrogen halide, a 2-substituted indole is obtained as final product, for example in aqueous solvents, water addition produces oxindoles (20.13.1) comparable methanol addition gives 2-methoxyindoles. 2-Bromination of 3-substituted indoles can be carried ont nsing A -bromosuccinimide in the absence of radical initiators. 2-Bromo- and 2-iodo-indoles can be prepared very efficiently via a-lithiation (20.5.1). 2-Halo-indoles are also available from the reaction of oxindoles with phosphoryl halides. Some 2,3-diiodo-indoles can be obtained by iodination of the indol-2-ylcarboxyfic acid. ... 

Conversion of isatins into oxindoles can be achieved by catalytic reduction in acid, or by the Wolff-Kischner process.3-Substituted indoles result from Grignard addition at the ketone carbonyl, followed by lithium aluminium hydride reduction of the residual amide, then dehydration. The reaction of isatin with triphenylphosphine provides an easy synthesis of 3-(triphenylphosphorylidene)oxindole, a Wittig reagent. ... 

S02-extrusion affords the electrophilic radical 49 (Scheme 10). Intramolecular homolytic substitution eventually gives tetrahydronaphthalene 50 (92%). Beckwith showed that the A-(o-bromophenyl)amide 51 can be transformed into the corresponding oxindole 54 (70%) at high temperatures using BusSnH via tandem radical translocation of the initially formed aryl radical 52 to form 53 with subsequent intramolecular homolytic substitution [77]. The nucleophilic a-aminomethyl radical 55 reacted in a tandem addition/homolytic aromatic substitution reaction via radical 56 to tetrahydroquinoline 57 [78]. Radical 55 can either be prepared by oxida-... 

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