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. 2019 Aug 19;10(40):9292-9301.
doi: 10.1039/c9sc03081f. eCollection 2019 Oct 28.

Tertiary amine-directed and involved carbonylative cyclizations through Pd/Cu-cocatalyzed multiple C-X (X = H or N) bond cleavage

Qiu-Chao Mu  1   2 , Yi-Xue Nie  2 , Xing-Feng Bai  1   2 , Jing Chen  1 , Lei Yang  1   2 , Zheng Xu  2 , Li Li  2 , Chun-Gu Xia  1 , Li-Wen Xu  1   2
Affiliations

Tertiary amine-directed and involved carbonylative cyclizations through Pd/Cu-cocatalyzed multiple C-X (X = H or N) bond cleavage

Qiu-Chao Mu et al. Chem Sci. .

Abstract

A novel Pd/Cu-cocatalyzed carbonylative cyclization by C-H activation and N-dealkylative C-N bond activation has been developed for the chemoselective construction of synthetically useful heterocycles. The N,N-dimethylamine group on o-indolyl-N,N-dimethylarylamines was found to act as both the directing group and reactive component in this C-H carbonylative cyclization reaction. Furthermore, a unique C-H oxidation/carbonylative lactonization of diarylmethylamines is firstly demonstrated under modified reaction conditions, which could be easily applicable to the one-step synthesis of multi-substituted phthalides bearing an N,O-ketal skeleton that is difficult to access by previously reported methods. Mechanistic studies implicate that Pd/Cu-cocatalyzed C-H oxidation/carbonylative lactonization is a sequential reaction system via Cu-catalyzed C(sp3)-H oxidation and Pd-catalyzed oxidative carbonylation of the C(sp2)-H bond. It was found that trace amounts of water are essential to promote the Cu-catalyzed C(sp3)-H oxidation of diarylmethylamine for the formation of the hydroxyl group, which could act as an in situ-formed directing group in the intramolecular carbonylative lactonization step.

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Figures

Scheme 1
Scheme 1. Tertiary amine-directed C–H functionalization: single role as the directing group (previous work) and dual role as the directing group and reactive component (this work).
Scheme 2
Scheme 2. Reaction scope. The reactions were run on a 0.5 mmol scale.
Fig. 1
Fig. 1. Representative examples of biologically active molecules based on the N,O-ketal-containing phthalide core.
Scheme 3
Scheme 3. Reaction scope. The reactions were run on a 0.5 mmol scale.
Scheme 4
Scheme 4. Gram-scale reaction.
Scheme 5
Scheme 5. Control experiments and KIE experiments. aDetermined by GC-MS.
Scheme 6
Scheme 6. Two proposed mechanisms of the double C–H functionalization for Pd/Cu-cocatalyzed oxidative carbonylation/lactonization of diarylmethylamines.
Scheme 7
Scheme 7. Mechanistic studies with control experiments.
Fig. 2
Fig. 2. Calculated catalytic cycle for the double C–H functionalization of diarylmethylamines (4a) catalyzed by the Pd(ii) catalyst.
Fig. 3
Fig. 3. The free energy profiles for the Pd/Cu-cocatalyzed double C–H functionalization/carbonylation. The free energies (in kcal mol–1) are calculated at the B3lyp and BS (BS = 6–31 g (d,p) for main group elements and LanL2DZ for Pd) level of theory.
Scheme 8
Scheme 8. KIE experiments.
See this image and copyright information in PMC

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