Solvent-Free Mechanochemical Diaza-Cope Rearrangement

Abstract

Chiral vicinal diamines represent an important class of organic building blocks that play essential roles in various fields in chemical and material sciences. Their syntheses have continued to attract attention to enhance their yield, selectivity, and scope, but all of the procedures reported so far in the literature are solvent-based reactions. We herein report the first example of mechanochemical diaza-Cope rearrangement to convert a wide variety of aldehyde substrates into chiral diimines, which upon hydrolysis lead to the formation of chiral vicinal diamines. This solvent-free protocol is highlighted with high yield, fast reaction, and simple synthetic operation with commercially available precursors and is easily scalable to gram quantity. Mechanistic investigations revealed a distinct reaction profile for mechanochemical-induced reactions compared to solution-based reactions. Reaction time course studies showed that the diaza-Cope rearrangement step, which requires a highly ordered six-membered chair-like TS, is rapid in mechanochemical-induced reactions. This enhanced rate stems from the formation of effective solid-state packing in mechanochemical reaction settings. The powder X-ray diffraction analysis of the milled sample confirmed the formation of a new crystalline phase during the mechanochemical reaction, which leads to continuation of the reaction even after ball milling is stopped. Furthermore, we developed a one-pot two-step procedure to synthesize chiral salen metal complexes, a “privileged” chiral catalyst, directly from arylaldehydes without the need for isolating the rearrangement products. From a practicality perspective, this work demonstrates a mechanochemical synthesis of chiral vicinal diamines that can be readily adapted in academic laboratories and, potentially, in industrial settings.

Enantioselective 1,3-Dipolar Cycloaddition Using (Z)-α-Amidonitroalkenes as a Key Step to the Access to Chiral cis-3,4-Diaminopyrrolidines

“…According to the refinement program employed (see the experimental section), the degree of similarity was 67.0% for endo-9bd (E1) and only 0.6% for ent-endo-9bd (E2). Cu(OTf) 0 --14 4 Cu(OTf) 2 0 --1 Conversion was determined by analysis of the 1 H NMR spectra of the crude compound. 2 The ratio was determined by analysis of the 1 H NMR spectra of the crude compound.…”

“…3 Determined by HPLC analysis using chiral stationary phase columns for the major endo-9ba diastereoisomer. 4 The reaction was performed at 0 • C. 5 The reaction was performed with AgClO 4 (10 mol%) and Et 3 N (10 mol%). 6 The reaction was performed with AgClO 4 (2.5 mol%).…”

“…Currently, there is no unified approach to synthesize these chiral vicinal diamines, and they are often challenging to obtain, especially if unsymmetrically substituted. Recent studies dealt with the protonation of enamines [ 2 ], borylcopper-mediated homocouplins [ 3 ], diaza-Cope rearrangements [ 4 ], transformations of diols [ 5 ] and mefloquine [ 6 ], metal catalysis [ 7 , 8 , 9 ], Mannich reactions [ 10 ], nucleophilic trifluoromethylation [ 11 , 12 ], enantioselective reductive coupling of imines [ 13 , 14 ], syn -diamination of alkenes [ 15 ], etc.…”

“…Chemical yields isolated after flash chromatography 3. Determined by HPLC analysis using chiral stationary phase columns, for the major endo-9aa diastereoisomer 4. Complex with toluene 5.…”

Mechanochemical C−X/C−H Functionalization: An Alternative Strategic Access to Pharmaceuticals

“…Looking into the future, reports on mechanochemical reactions with practical applications are expected to increase, including but not limited to mechanochemical post‐functionalization, solid‐/liquid‐/gas‐gas reactions, [6j] rearrangements, [6,112] enantioselective synthesis [113] as well as high throughput mechanochemistry [114] . Despite mechanochemistry has reached the stage of maturity in the laboratory, they are still far from being for large‐ or plant‐scale synthesis of pharmaceuticals.…”