Summary of the technology
The trifluoromethyl copper derivative useful in trifluoromethylation reactions is prepared at room temperature from readily available and cheap reagents and in high yield, i.e. without the formation of side-products associated to the fast decomposition of the trifluoromethyl anion, that usually forms in processes involving the deprotonation of fluoroform. This is the first method to date for deprotonation-free, direct cupration of fluoroform, a longly sought after reaction.
Description of the technology
Use of fluoroform as CF3 source in trifluoromethylation reactions We have developed a method to produce trifluoromethyl copper reagents useful in trifluoromethylation reactions from fluoroform, a readily available and cheap reagent. The CF3 group is found in many drugs and agrochemicals, hence the importance of finding a sustainable process for its introduction. We are interested in licensing the method and joint development of the technology.
Trifluoromethyl copper (I) compounds that are particularly useful in various trifluoromethylation reactions of organic molecules are conventionally made using costly CF3 sources. Fluoroform, CF3H, is an ideal source of CF3 because it is inexpensive, readily available in large industrial quantities, non-toxic, and not an ozone depleter. However, the few known methods to prepare trifluoromethyl copper (I) compounds from fluoroform are all not only multistep and low-yielding, but also require low temperatures (-10 - -50 ºC) to minimize the extremely facile decomposition of the highly unstable trifluoromethyl anion that is generated in the first, CF3H deprotonation step. Our technology does not involve deprotonation of CF3H. Instead, the CuCF3 reagents are formed via direct cupration that is not mediated by the unstable trifluoromethyl anion and/or difluorocarbene. As a result, our CuCF3 synthesis proceeds cleanly at room temperature while avoiding the formation of side-products. The trifluoromethyl copper reagents are obtained in high yield of up to >90% and can be used directly in various reactions, including aromatic trifluoromethylation. Treatment of a copper(I) source with 2 equivalents of an alkali metal alkoxide results in the formation of highly reactive dialkoxycuprates that directly metalate fluoroform to give CuCF3 compounds in one step. These CuCF3 reagents can then be used in various reactions with electrophiles to give trifluoromethylated products, including trifluoromethylated aromatic and heterocyclic derivatives.
Main advantages of its use
- Clean production of trifluromethylcopper reagent
- Environmentally friendly process (fluoroform, which is consumed in the process is a potent greenhouse gas, obtained as a by-product in the preparation of chlorodifluoroethane)
- Inexpensive and abundant trifluoromethyl source
- Low-cost reagents
- Possible stabilization of the trifluoromethyl copper compound
- Process works at room temperature and atmospheric pressure
- Scalable process
- Chemical compounds bearing a trifluoromethyl group (CF3) are widely used in the production of various pharmaceuticals and agrochemicals as well as specialty materials, polymers, composites, building blocks, and intermediates for various needs
- Preparation of advanced chemical intermediates, polymer chemistry, pharmaceutical companies, agrochemical companies
Intellectual property status