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. 2021 Jul 9;1(8):1257-1265.
doi: 10.1021/jacsau.1c00221. eCollection 2021 Aug 23.

Palladium-Catalyzed Domino Aminocarbonylation of Alkynols: Direct and Selective Synthesis of Itaconimides

Yao Ge  1 , Fei Ye  1   2 , Ji Yang  1 , Anke Spannenberg  1 , Ralf Jackstell  1 , Matthias Beller  1
Affiliations

Palladium-Catalyzed Domino Aminocarbonylation of Alkynols: Direct and Selective Synthesis of Itaconimides

Yao Ge et al. JACS Au. .

Abstract

The first direct and selective synthesis of substituted itaconimdes by palladium-catalyzed aminocarbonylation of alkynols is reported. Key to the success of this transformation is the use of a novel catalyst system involving ligand L11 and appropriate reaction conditions. In the protocol here presented, easily available propargylic alcohols react with N-nucleophiles including aryl- and alkylamines as well as aryl hydrazines to provide a broad variety of interesting heterocycles with high catalyst activity and excellent selectivity. The synthetic utility of the protocol is demonstrated in the synthesis of natural product 11 with aminocarbonylation as the key step. Mechanistic studies and control experiments reveal the crucial role of the hydroxyl group in the substrate for the control of selectivity.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Importance of Itaconimides: Selected Examples of Natural Compounds, Biologically Active Molecules, and Interesting Postfunctionalizations
Scheme 2
Scheme 2. Summary of the Main Synthesis Methods of Itaconimides
Figure 1
Figure 1
Pd-catalyzed aminocarbonylation of 1-ethynyl-1-cyclohexanol 1a: influence of phosphine ligands. Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Pd(MeCN)2Cl2 (1.0 mol %), bisphosphine ligand (2.0 mol %) or monophosphine ligand (4.0 mol %), CO (40 atm), CH2Cl2 (2.0 mL), 20 h at 120 °C. The yields of products were determined by GC analysis with mesitylene as an internal standard. [a] indicates the following conditions: Pd(cod)Cl2 (1.0 mol %), 2a (0.75 mmol), pentane (2.0 mL). [b] indicates the following conditions: Pd(cod)Cl2 (1.0 mol %), 2a (0.75 mmol), PTSA·H2O (10 mol %), pentane (2.0 mL), 100 °C.
Scheme 3
Scheme 3. (a) Control Experiments, (b) Kinetic Monitoring of Intermediates over Time, and (c) Proposed Catalytic Cycle
Standard conditions: Pd(cod)Cl2 (1.0 mol %), L11 (4.0 mol %), PTSA·H2O (10 mol %), pentane (2.0 mL), CO (40 atm), 100 °C, 20 h, 1a or 4–10 (0.5 mmol), 4-fluoroaniline (0.75 mmol). The yields of products were determined by crude 1H NMR analysis using dibromomethane as the internal standard.
Scheme 4
Scheme 4. Synthesis of Natural Product 11 with Aminocarbonylation as Key Step
See this image and copyright information in PMC

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