Aza-Oxindoles

A versatile route to N-substituted oxindoles has been developed by extending the utility of dilithiated o-alkylanilines. Treatment of N-alkyl-2-methylaniline with one equiv, of n-butyllithium, followed by COj and then a second equiv. of n-butyllithium gave a dilithiated intermediate which reacted with CO to give an oxindole. <94H(37)701> The method was applied to several ring-substituted oxindoles and to 5- and 7-aza-oxindoles. 

A f-BuONa-mediated synthesis of 3,3-disubstituted aza-oxindoles via a Truce-Smiles rearrangement-cyclization pathway has been reported (Scheme 181). ... 

An ingenious new approach to the synthesis of pseudotabersonine (707) has been developed by Carroll and Grieco (391). Here the intermediate oxindole 708 was constructed by a remarkable process in which the anion from the precursor oxindole 709 was alkylated by Grieco s spiroaziridinium triflate 710. A-Benzylation of the product 711, followed by a reverse Diels-Alder fragmentation, then an intramolecular aza-Diels-Alder cyclization, gave the tetracyclic oxindole 708. Introduction of the three-carbon unit into position 2 in 70iB was achieved by condensation with 2-lithio-l,l-diethoxy-2-... 

Further applications of P-ICD as catalyst were extended to asymmetric BH reaction employing isatins as electrophiles. Shi and co-workers [97a], Zhou and co-workers [97c], and Lu and co-workers [97b] independently reported the BH reactions of isatins with HFIP acrylates, acrolein, and MVK, leading to 3-substituted-3-hydroxy-2-oxindoles in good yields and high enantioselectivities regardless of configuration difference (Scheme 9.27). Furthermore, P-ICD-derivatived catalyst 44 was synthesized and turned out to be an efficient catalyst in the asymmetric aza-BH reaction [98]. 

An asymmetric aza-MBH reaction of isatin-derived A-Boc ketimines with methyl vinyl ketone has been developed, giving 3-amino-2-oxindoles bearing quaternary stere-ogenic centres (22), using chiral amine or phosphine catalysts. (S)... 

In a similar way, spirooxindole tetrahydroquinolines (301) were prepared in 94% ee and >25 1 dr via the aza-Michael-Michael domino addition of tosylamide (299) to oxindoles (300), catalysed by the quinine-derived squaramide (283c).2 ... 

A total synthesis of pseudotabersonine (119) by Grieco et al. [39] utilizes both the aminoethylation (cf. Scheme 2.17) and tandem retro Diels-Alder/intramolecular aza Diels-Alder (cf. Scheme 2.18) protocols to construct spirofused indolizidine oxindoles, 122 and 123, which serve as precursors to dehydrosecodine 125 (Scheme 2.19). The pentacyclic backbone of the Aspidosperma alkaloid, pseudotabersonine, is postulated to be biogeni-cally [40] derived from a dehydrosecodine. 

The synthesis commences with alkylation of oxindole 120 with spiroaziri-dinium triflate 109, providing the 3,3-disubstituted 121 in 53% yield (cf. Scheme 2.17). Treatment of 121 with boron trifluoride etherate at 100°C in toluene initiates the tandem retro Diels-Alder/intramolecular aza Diels-Alder process, leading to spiro-tetracyclic oxindoles 122 and 123 (1.5/1) in 61% yield. Addition of 2-lithio-l,l-diethoxy-2-propene to oxindole 122 provides carbinolamine 124 (95%). Exposure of 124 to p-toluenesulfonic acid in acetone-water followed by treatment with excess triethylamine in acetonitrile at 80°C effects the biomimetic transformation to adduct 126, which possesses the pentacyclic carbon framework of pseudotabersonine. This unique two-step one-pot transformation generates the inherently unstable dihydropyridine portion of dehydrosecodine 125, which participates in an intramolecular reverse electron-demand Diels-Alder reaction, providing 126 in 50% yield. The total synthesis is completed by transformation of the formyl group into the requisite carbomethoxy unit followed by N-benzyl deprotection (Scheme 2.19). 

Dou, X., Yao, W., Zhou, B., Lu, Y. (2013). Asymmetric synthesis of 3-spirocyclopropyl-2-oxindoles via intramolecular trapping of chiral aza-ortho-xylylene. Chemical Communications, 49, 9224-9226. 

NHCs have been used to promote reactions of enals with A -substimted isatini-mines ° ° and oxindole-derived a, -unsaturated imines to form spirocyclic y-lactam oxindoles. Asymmetric cross-aza-benzoin reactions of aliphatic aldehydes with A-Boc-protected aryl imines to form RCOCH(Ar)NHBoc have also been NHC catalysed. ... 

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