Copper/guanidine-catalyzed asymmetric alkynylation of isatin-derived ketimines

Abstract

Isatin-derived ketimines undergo enantioselective alkynylation reactions in the presence of copper iodide and easily accessible guanidine-amides. The corresponding 3-alkynyl-3-aminooxyindoles are obtained in up to 95% yield and 96% ee. The guanidine plays a role in the formation of copper acetylide and the enantiodetermining step and the basic additive is excluded.

Synthesis of Spirooxindoles Bearing 1,3‐Oxathiolane‐2‐thione Moiety From Isatin‐Derived Propargylic Alcohols

“…The propargylic amine N-Boc derivative 3a was prepared by the reaction of isatinderived N-Boc ketimine and phenylethynylmagnesium bromide. 11 The reaction of 3a under the typical reaction condition (−15 C) did not produce spirooxindole 4a, and no reaction was also observed even at elevated temperature (50 C). The failure might be due to steric hindrance around the nitrogen atom and delocalization of the anion at nitrogen atom to oxygen atom of the Boc moiety.…”

“…As a last entry, we examined the synthesis of nitrogen analog 4 , as shown in Scheme 3. The propargylic amine N ‐Boc derivative 3a was prepared by the reaction of isatin‐derived N ‐Boc ketimine and phenylethynylmagnesium bromide 11 . The reaction of 3a under the typical reaction condition (−15 °C) did not produce spirooxindole 4a , and no reaction was also observed even at elevated temperature (50 °C).…”

“…To a stirred solution of isatin‐derived N ‐Boc ketimine (260 mg, 1.0 mmol) in anhydrous THF (2 mL) was added dropwise phenylethynylmagnesium bromide (1.0 M solution in THF, 4.0 mL, 2.0 mmol) for 10 min at 0 °C, and the reaction mixture was stirred for 2 h under N 2 balloon atmosphere 11 . After the usual aqueous extractive workup and column chromatographic purification process (CH 2 Cl 2 /EtOAc, 15:1) propargylic amine N ‐Boc derivative 3a (181 mg, 50%) was obtained as a pale yellow solid 11 . The spectroscopic data of 3a are as follows.…”

“…Pale yellow 11 solid, mp 168–170 °C; IR (KBr) 3313, 2233, 1735, 1710, 1614, 1495, 1371 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz) δ 1.27 (s, 9H), 3.29 (s, 3H), 5.64 (br s, 1H), 6.86 (d, J = 7.8 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.23–7.36 (m, 4H), 7.37–7.40 (m, 2H), 7.47 (d, J = 7.3 Hz, 1H); 13 C NMR (CDCl 3 , 125 MHz) δ 27.1, 28.2, 56.7, 81.0, 83.8, 85.1, 108.7, 121.5, 123.4, 123.5, 128.4, 129.2, 129.7, 132.2, 143.2, 153.2, 172.7 (one carbon was overlapped); ESIMS m/z 363 [M + H] + .…”

Chiral Guanidine/Copper Catalyzed Asymmetric Azide‐Alkyne Cycloaddition/[2+2] Cascade Reaction

“…Although the role of copper salt and ligands in the 1,3‐dipolar cycloaddition of azides is not easily explained, we envisioned that if an appropriate chiral ligand is introduced into this copper catalyzed three‐component azide‐alkyne cycloaddition/[2+2] cascade reactions, it might allow an alternative enantioselective version by trapping a chiral ligand coordinated copper ketenimine species (Scheme b, right). Recently, our group and others have successfully explored chiral guanidine/CuI complexes in the asymmetric reactions, including C−H insertion of α‐diazoesters to terminal alkynes, and asymmetric alkynylation ,. Our study demonstrated that enantioselective trapping of allenoate‐ or acetylide copper(I) species are effective under chiral guanidine ligands.…”