Transition-Metal-Free α-Alkylation Of Ketones With Alcohols And Copper-Catalyzed Carbon-Heteroatom Coupling

Carbon-carbon bond forming reactions are of fundamental importance inorganic synthetic chemistry. The α-alkylation of ketones with electrophiles is animportant tool for the construction of C-C bond. The electrophiles can be alkylhalides, carboxylates, phosphonates and sulfonates etc. However, theseelectrophiles will inevitably generate inorganic salt that lead to more side reactionsand also cause pollution to the environment. What’s more, the atom utilization isinefficient. Alcohols are readily available and inexpensive, which have beenobtaining prominence as electrophilic alkylating agents for the green andatom-economic practices since they don’t generate any side products other thanwater in the reaction. Several groups have reported the use of transition metals,such as ruthenium, iridium for the α-alkylation of ketones with alcohols. Theexcellent results from the noble metals catalyzed reactions prompted us to makeα-alkylation of ketones with alcohols by using the low toxicity and readyavailability of copper catalysts. We are very pleased to find that when using lithiumtert-butoxide as the base in toluene solution the reaction generated the product inhigh yield, which did not need a transition metal. The use of LiOtBu purified bysublimation or other different sources of LiOtBu did not dramatically affect thereaction result. We also repeated the experiments with new glassware, and eventook the step of having other laboratories repeat the reactions and confirm thereliability of our observations. The reaction is compatible with various functionalgroups. The activity of aryl methyl ketones were better than alkyl ketones in thereactions. The control experiments proved that the mechanism of the reaction wasnot the “borrowing hydrogen” mechanism which was generally recognized bypredecessors, nor the radical pathway. The detailed reaction mechanism remains tobe further studied in the future.Phenols, anilines and thiophenols are important building blocks forconstructing natural products, pharmaceutical and medicinal compounds, as well asin polymers and materials. The development of a mild and highly efficient methodfor synthesis of them has gained considerable attention in synthetic chemistry.Several efficient palladium/phosphine-catalyzed processes have been developed forselective formation of them. However, the replacement of palladium with less expensive copper (I) salts as catalyst would be allowed for economic benefits andlow toxicity issues. Water is the most economical and environmentally friendlysolvent in the world, which is non-toxicity, low cost, availability and has greaterchemoselectivity. Metal nanoparticles have drawn much attention due to theadvantages offered by these “semi-heterogeneous catalysts”. The characteristics ofheterogeneous catalysis (recovery and recyclability) and those of homogeneouscatalysis (relatively low catalyst loadings and good selectivity) were combined innanoparticles catalyst. We disclosed a very simple, efficient, ligand-freeCuI-nanoparticles-catalyzed selective synthesis of phenols with water as thesolvent under very mild conditions. To our surprise, the coupling reaction gaveselectively anilines when NH3·H2O was added into the system. And thiophenolswould be obtained selectively after reduction appending sulfur powder. Thecompetition experiment proved the order of nucleophilicity is S> N> O.The previous chapter had showed that S had the best reactivity. We judged itcertainly appealing to explore and extend the scope of such advantageous protocol.We report that CuI nanoparticles catalyzed efficiently the C-S cross-coupling ofaryl and alkyl thiols with aryl halides on water at≤80oC conditions. This procedureis particularly noteworthy given its mild conditions, avoiding the undesiredformation of disulfides through oxidative S-S coupling. Many aryl iodides couldtranslate even at room temperature. Synthesis of bisarylated product has also beendemonstrated. The reuse studies of CuI nanoparticles proved that the catalyticactivity of CuI nanoparticles did not decline in the reactions.