Pd-Catalyzed C-H Carbonylation For Synthesis Of Hetrocycles

Heterocycles are key skeleton structures of many natural products and drug molecules. Using cheaper and easily available starting materials and developing more convenient and atom-ecomonic method for the synthesis of heterocycles is the hot spot of research. The combination of Pd-catalyzed C-H activation and carbonylation with carbon monoxide offers a powerful strategy for the synthesis of heterocycles, and has been applied in organic synthesis widely.The first part introduces Pd-catalyzed carbonylation reactions. It is devided into six aspects:carbon-nitrogen bond formation, carbon-oxygen bond formation, canbon-sulfur bond formation, carbon-carbon bond formation, carbon-halogen bond formation and carbon-hydrogen bond formation. Next, We emphatically intoduces Pd-catalyzed C-H carbonylation reactions, which is devided into two parts:C(sp2)-H carbonylation reactions and C(sp3)-H carbonylation reactions.The second part introduces Pd-catalyzed C-H carbonylation of alkylamines for the synthesis of γ-lactams and γ-amino acids. Using picolinamide as the bidentate directing group, Pd-catalyzed C-H bond activation happened selectivly in the γ-position of alkylamines to afford N-pyridyl protected γ-lactams followed by carbonylation with carbon monoxide and cyclization. TEMPO is crucial in this reaction as the only effecient oxidant. The use of 1 atm of carbon monoxide makes it safe and easy to be handled. Treatment of N-pyridyl protected γ-lactams with base or acid afforded the none-protected γ-lactams or γ-amino acids, respectively. The synthetic potential of this method was demonstrated by total synthesis of rac-Pregabalin.The third part introduces Pd-catalyzed C-H carbonylation of indolines for the synthesis of pyrroloquinazolinediones. Starting from Ethyl carbamoyl protected indolines, Pd-catalyzed C-H bond activation happened selectivly at the C7 position of indolines, affording pyrroloquinazolinediones via following carbonylation with carbon monoxide and cyclization. Pyrroloquinazolinedione could be transformed to indole-based derivative easily after oxidation of DDQ, thus providing an altertive and effective method to C7-selective C-H functionalization of indole derivatives. This two steps transformation avoided the direct C-H carbonylation at C3 position, which was proved by experiment, when indole-based compound was used directly.