Synthesis of Spirooxindoles Bearing Iminothiolactone Moiety from Morita–Baylis–Hillman Carbonates of Isatins and Phenyl Isothiocyanate

Spirooxindoles exist in a huge number of natural substances and pharmaceutically interesting compounds. Thus, tremendous efforts have been devoted to efficient protocols to access these important motifs over the past years. Recently, we also reported diastereoselective synthesis of six-membered carbocyclic spirooxindoles via 6πelectrocyclization of 3-dienylidene-2-oxindoles, palladium-catalyzed synthesis of spirooxindoles by arylative cyclization of 3-(γ,δ-disubstituted)allylidene-2-oxindoles, and one-pot synthesis of spirofluorenyland spiroindeno [1,2-b]indolyloxindoles via sequential interand intramolecular Friedel–Crafts reactions. The Morita–Baylis– Hillman (MBH) adducts of isatins have been extensively used for the synthesis of various spirooxindoles, especially by Chen et al. Very recently, we reported an efficient synthesis of 2aminothiophene derivative from the MBH carbonate of benzaldehyde. The reaction of phosphorous ylide, which was generated from MBH carbonate and PPh3, and phenyl isothiocyanate afforded 2-aminothiophene, as shown in Scheme 1. As a continuing work, we reasoned out that the same approach would afford an interesting spirooxindole 3a bearing 5-iminodihydrothiophenyl moiety by using the MBH carbonate of N-methylisatin 1a. The reaction of 1a and phenyl isothiocyanate (2a) in the presence of PPh3 (1.0 equiv) in benzene (reflux, 8 h) produced 3a (41%) along with unexpected 4a in moderate yield (34%), as shown in Scheme 2. The spirooxindole 3a was formed by the reaction of resonance-stabilized phosphorous ylide I at the α-position via the iminothiolate intermediate II, according to the mechanism shown in Scheme 1. When the γ-carbon atom of I reacts with 2a, compound 4a could be produced via the corresponding intermediates III and IV. In contrast to the formation of a single isomeric 2-aminothiophene in our previous paper, another competitive reaction pathway leading to 4a occurred due to the presence of an electron-delocalizing carbonyl group of oxindole moiety. The structures of 5-imino-2,5-dihydrothiophene-3carboxylate 3a and 5-imino-4,5-dihydrothiophene-3carboxylate 4a were unequivocally confirmed by their crystal structures, as shown in Scheme 2. The stereochemistry of the imine double bonds of both 3a and 4a were Z, and the Z-stereochemistry might be controlled during the formation of iminothiolate intermediate II (see, Scheme 1). The sulfur anion and the nonbonding electron pair of nitrogen atom would be positioned in a trans-relationship by electronic repulsion between them, as also shown in Scheme 1. Encouraged by the successful results, spirooxindoles 3b– 3e and 4b–4e were synthesized by the reactions of MBH carbonates 1a–1d and 2a or benzyl isothiocyanate (2b), as summarized in Table 1. The reaction of 5-methylisatin derivative 1b and 2a afforded 3b (42%) and 4b (35%) in good combined yield. Similarly, the reaction of 5methoxyisatin derivative 1c and 2a produced 3c (36%) and 4c (39%). However, the reaction of 5-chloroisatin derivative 1d and 2a required a long reaction time (20 h) for the completion. It is interesting to note that 4d (a γ-attacked product) was formed in a larger amount. The reaction of 1a and 2b also required a long time (20 h), and 4e was obtained as a major product. The reaction of 1a and tertbutyl isothiocyanate (2c) failed completely presumably due to steric reason. As a next study, an acid-catalyzed hydrolysis of the imine bond of 3a and 4a was examined, as shown in Scheme 3. As expected, thiolactone derivatives 5 (89%) and 6 (80%) were obtained in good yields under the influence of aqueous HCl in THF at room temperature for 2–6 h. In summary, spirooxindoles bearing iminothiolactone and thiolactone moieties have been synthesized by the reaction of MBH carbonates and isothiocyanates in the presence of PPh3 in moderate to good yields.