Heteroaryl Oxindoles

 

 

Mechanistic Overview
All the above reactions exclusively produced C3-aryl/heteroaryl oxindoles. Mechanistically, both SN2 attack of arenes/heteroarenres at the highly steric congested tertiary centre of spiroepoxides 1 and unlike generation of positive  charge at the α-position of carbonyl group via direct SN1 mechanism are ruled out.

 

Thus it was earlier proposed that these F-C reactions could only proceed through 2H-indol-2-one 14 via SN1 type mecha- nism (Scheme 14).[15] At this point, the arenes/heteroarenes can easily add to the planar C3-position of the reactive indol-2-one intermediate 14 to afford the 3-aryl/heteroaryl oxindoles 3/8/9/ 11 with excellent regioselectivity. Recently, we found that chiral spiroaziridine oxindoles undergo regio- and stereoselective ring opening reaction at the C3 centre with retention of configura- tion.[17] This results led us to reinvestigate the mechanism of ring-opening reactions of spiro-epoxyoxindoles 1.

Thus, to understand the ring-opening mechanism of spiro-epoxide and also with a view towards asymmetric F-C reaction, we synthesized non-racemic spiro-epoxide via 19 Corey-Chaykovsky reaction of chiral isatin 18 (Scheme 15). To synthe- size non-racemic spiroepoxide 19, we started to synthesize the compound 16 by Cu (I) catalyzed amination between iodo- benzene and (S)-(-)-α-methylbenzylamine 15. Isatin 17 was syn- thesized in toluene employing oxalyl chloride. Further bromin- ation afforded the (S)-5-bromo-1-(1-phenylethyl)indoline-2,3- dione 18. Heating of suspended mixture of chiral isatin 18, trimethyl sulfonium iodide (TMSI) and Cs2CO3 in CH3CN gave chi- ral spiroepoxides as a mixture of 1:1 ratio. The chiral epoxides could be separated by silica-gel column chromatogra- phy. It is to be noted that without bromo-substitution the dia- stereomeric spiroepoxides were found to be non-separable.

After successful synthesis of two diastereomeric and non- racemic spiroepoxides 19 and 19, these were independently subjected to the F-C reaction with p-cresol both under Method A as well as Method B (Scheme 16). Interestingly, both gave ring-opening product 20 with 1:1 diastereoselectivity under both the conditions (Methods A and B). This revealed that the stereoselectivity of the chiral spiro-epoxides 19/19 were not carried over to the F-C reaction. It, therefore, must be proceed through a common intermediate, where stereochemistry of the spiro-center was destroyed. Thus the reactive intermediate for this F-C reaction of spiroepoxides was proposed to be 2H-indol- 2-one intermediate 21. These results once again proved our presumption.

Conclusion
In summary, we have developed a highly efficient, versatile protocol for the synthesis of all carbon quaternary centers at the C3-position of oxindole. Apart from previously performed Lewis acid catalysed F-C reactions, we have developed Brønsted acid assisted regioselective ring-opening of a range of spiro-epoxy- oxindoles with indoles and arenes in organic solvent as well as on-water as an alternative. In contrast to the Lewis acid cata- lysed condition, simple phenol preferred to react through its less hindered para-position under Brønsted acid conditions. Thus by altering the conditions, we can simply switch the reac- tivity of phenol. Although on-water reaction provides relatively less yield than the other methods; still it introduces a relatively cheaper approach for the F-C reaction of spiro-epoxides. The ring opening reactions are easily monitored up to gram scale  in these methods. Finally, we have synthesized a conceptually new diastereoselective spiro-epoxide and the corresponding opening of such epoxide with arene initially reveals a probable mechanistic insight of the ring opening reaction. This result strongly supports our presumption that the indol-2-one is the reactive intermediate for the ring opening reaction of the spiro- epoxyoxindoles. We have the intention to continue our research efforts towards the amplification of this concept with other carbon as well as heteroatomic nucleophiles and to find out a precise mechanistic aspect of such ring opening reactions.

 

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