Synthesis of Ortho-alkoxy-aryl Carboxamides via Palladium-Catalyzed Aminocarbonylation

Abstract

Various aryl carboxamides with alkoxy substituents at the ortho-position, applicable as direct intermediates toward novel ligands, were synthesised via aminocarbonylation of aryl-iodides (2-iodoanisole, 5-chloro-7-iodo-8-methoxy-quinoline, and 5-chloro-7-iodo-8-benzyloxy-quinoline) in the presence of in situ generated palladium(0) catalysts. Simple primary and secondary amines as well as aminoacid esters were used as N-nucleophiles. The optimization of the reaction conditions allowed the preferential formation of carboxamides or ketocarboxamides by simple or double carbon monoxide insertion, respectively. A strong dependence of the chemoselectivity on carbon monoxide pressure was observed.

Keywords:

• Aminocarbonylation
• carbon monoxide
• carbonylation
• iodo-aromatics
• palladium
• quinoline

ACKNOWLEDGMENT

The authors thank the Hungarian Research Fund (OTKA NI61591), the Portuguese FCT project (PTDC/QUI/66015/2006), and the Joint Project of the European Union–Hungarian National Development Program (GVOP-3.2.1-2004-04-0168/3) for the financial support and Johnson Matthey for the generous gift of palladium(II) acetate. A. F. Peixoto (SFRH/BD/29681/2006) and A. R. Abreu (SFRH/BD/21314/2005) are thankful for their PhD grants.

Notes

^a Reaction conditions: 0.025 mmol Pd(OAc)₂; 0.05 mmol PPh₃, 1 mmol 1; 3 mmol unfunctionalized amine (or 1.1 mmol amino acid methylester hydrochloride), 0.5 ml triethylamine; 10 ml DMF, 50°C.

^b Determined by GC-MS.

^c Isolated yields are based on the amount of the starting material 1.

^d The ketocarboxamide derivative (3e) was isolated and characterized only.

^a Reaction conditions: 0.025 mmol Pd(OAc₂); 0.05 mmol PPh₃; 0.5 mmol substrate; 15 ml DMF; 0.5 ml Et₃N; and 1.5 mmol tBuNH₂ (or piperidine).

^b Determined by GC-MS.

^c Isolated yields (in brackets) are based on the amount of the starting material (5 or 8).

^d The substrate (4) has been converted to 5-chloro-8-hydroxyquinoline (4′).