Ligand-Controlled Palladium-Catalyzed Regioselective Synthesis Of α-And β-Arylazetidines

α-and β-arylazetidines are found to display a series of pharmacological activities. The first efficient regioselective arylation of N-Boc-3-iodoazetidine to produce α-and β-arylazetidines under Pd-catalyzed system has been developed. The α-vs β-arylation selectivity is controlled by the ligand. When PPh3 was used as ligand, the classical β-arylated products were obtained as main products, whereas the rare a-arylated products are formed with high regioselectivity in the presence of Cy-JohnPhos (Scheme 1).1. Ligand-controlled regioselective synthesis of a-arylazetidines derivativesThe combination of 2 equiv. N-Boc-3-iodoazetidine,1 equiv. pyridine boronic acid ester,5 mol% Pd2(dba)3,10 mol% Cy-JohnPhos and 3 equiv. CS2CO3 in 3 mL DMF/water (15:1) at 80℃ under Ar atmosphere for 24 hours was determined as the optimum condition for regioselective synthesis of a-arylazetidines derivatives. The established reaction affords α-vs β-arylazetidines in moderate yields (up to 62%) and with good regioselectivity (up to 98:2). The study showed that alkoxyl, nitrile and ester groups were well tolerated in the reaction condition (Scheme 2).2. Ligand-controlled regioselective synthesis of β-arylazetidines derivativesThe combination of 1 equiv. N-Boc-3-iodoazetidine,1.5 equiv. pyridine boronic acid ester,5 mol% Pd(PPh3)4,2 equiv. K3PO4, in 3mL DMF/water (15:1) at 60℃ under Ar atmosphere for 24 hours was determined as the optimum condition for regioselective synthesis of β-arylazetidines derivatives. The established reaction affords α-vs β-arylazetidines in moderate to good yields (up to 92%) and with good regioselectivity (up to 2:98). A variety of functional groups (nitrile, ester, cycloalkyl, amino groups) are well tolerated with high regioselectivity (Scheme 3).