Mild reaction conditions for the Cadiot–Chodkiewicz cross coupling process have been developed for the highly selective and efficient synthesis of unsymmetrical diynes. The most abundant, economic, environmentally friendly, green solvent, water was employed as the sole reaction medium in combination with a minimal amount (5 equiv.) of piperidine base. The reported new reaction conditions provide operational simplicity, high selectivity for hetero coupling (>97%), use of water, and low basicity of the reaction medium compared to commonly used highly basic conditions, i.e., 30–70% amine in water or 100% piperidine. Various sensitive functional groups were found to be highly compatible with the developed low basic reaction conditions. This study supports the fact that the Cadiot–Chodkiewicz cross coupling can be a greener reaction, has a very broad substrate scope, but has always been employed in non-green highly basic conditions and with limited substrate scope.