A Mechanistic Insight into a Simple C−N Bond Formation via S N 2 Displacement: A Synergistic Kinetics and Design of Experiment Approach

A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes was recently identified as new highly potent and selective dopamine (DA) D-3 receptor antagonists. This dais of molecules deserved the Chemical Development special attention to quantify the reliability and robustness of the pivotal S(N)2 displacement step between the 1,2,4-triazol-3-yl-halide derivative (4) and variously substituted azabicyclo[3.1.0]hexanes (5). To reach this goal we applied the classical Design of Experiment (DoE) approach, simultaneously trying to build up a descriptive kinetic model of the chemistry. The synergistic use of these two techniques allowed us to select new, higher-yielding and more robust reaction conditions and, at the same time, to identify their Design Space.