Phase-transfer catalysis excels in N-alkylations for many different nitrogen heterocycles. Most of the PTC N-alkylations of nitrogen heterocycles have aromatic rings, carbonyls or other electron withdrawing groups that increase the acidity of the N-H group. Azetidine does not contain such activating functional groups and it is also a strained ring. As a result, we speculate that the mechanism does not involve the formation of the N-anion. The choice of TBAB as the phase-transfer catalyst is interesting because there is very likely PTC bromide co-catalysis that forms the more reactive acid bromide in-situ from the acid chloride. An additional role of PTC is sometimes to solubilize polar amines in non-polar reaction solvents by hydrogen bonding to the N-H group.
The use of 20 mole% TBAB is probably overkill and may have been chosen for convenience on the sub-gram scale for which this reaction was reported. The use of potassium carbonate provides a base to absorb the HCl byproduct while avoiding hydrolysis of the acid chloride (bicarbonate is the byproduct). The choice of chloroform as solvent is unclear.
The same reaction was performed using 3-fluoroazetidine and gave a higher isolated yield after 39 hours at room temperature.
If you desire higher performance from your N-alkylations in production or in development, now contact Marc Halpern of PTC Organics Inc. to integrate highly specialized expertise in industrial phase-transfer catalysis with your commercial goals.
About Marc Halpern
Dr. Halpern is founder and president of PTC Organics, Inc., the only company dedicated exclusively to developing low-cost high-performance green chemistry processes for the manufacture of organic chemicals using Phase Transfer Catalysis. Dr. Halpern has innovated PTC breakthroughs for pharmaceuticals, agrochemicals, petrochemicals, monomers, polymers, flavors & fragrances, dyes & pigments and solvents. Dr. Halpern has provided PTC services on-site at more than 260 industrial process R&D departments in 37 countries and has helped chemical companies save > $200 million. Dr. Halpern co-authored five books including the best-selling “Phase-Transfer Catalysis: Fundamentals, Applications and Industrial Perspectives” and has presented the 2-day course “Practical Phase-Transfer Catalysis” at 50 locations in the US, Europe and Asia.
Dr. Halpern founded the journal “Industrial Phase-Transfer Catalysis” and “The PTC Tip of the Month” enjoyed by 2,100 qualified subscribers, now beyond 130 issues. In 2014, Dr. Halpern is celebrating his 30th year in the chemical industry, including serving as a process chemist at Dow Chemical, a supervisor of process chemistry at ICI, Director of R&D at Sybron Chemicals and founder and president of PTC Organics Inc. (15 years) and PTC Communications Inc. (20 years). Dr. Halpern also co-founded PTC Interface Inc. in 1989 and PTC Value Recovery Inc. in 1999. His academic breakthroughs include the PTC pKa Guidelines, the q-value for quat accessibility and he has achieved industrial PTC breakthroughs for a dozen strong base reactions as well as esterifications, transesterifications, epoxidations and chloromethylations plus contributed to more than 100 other industrial PTC process development projects.
Dr. Halpern has dedicated his adult life to his family and to phase-transfer catalysis (in that order!).
