Mechanochemical Ruthenium-Catalyzed Ortho-Alkenylation of N-Heteroaryl Arenes with Alkynes under Ball-Milling Conditions

Abstract

The mechanochemical, solvent-free Ru­(II)-catalyzed alkenylation of N-heteroaryl arenes with alkynes has been successfully described. A wide spectrum of arenes bearing N-heteroaryl moieties such as imidazo­[1,2-a]­pyridine, imidazo­[1,2-a]­pyrimidine, benzo­[d]­imidazo­[2,1-b]­thiazole, imidazo­[2,1-b]­thiazole, 2H-indazole, 1H-indazole, 1H-pyrazole, and 1,2,4-oxadiazol-5­(4H)-one as a directing group reacted with various substituted alkynes under ball milling in the presence of [Ru­(p-cymene)­Cl2]2, affording dialkenylated products in moderate to good yields. The reaction of 2,3-dihydro­phthalazine-1,4-dione with 1-phenyl-1-propyne afforded a monoalkenylated product. Similarly, reaction of 2-phenyl­imidazo­[1,2-a]­pyridine with aliphatic terminal alkynes produced a monoalkenylated derivative as the major product along with minor amount of dialkenylated product. The developed method exhibited excellent functional group compatibility, broad substrate scope, shorter reaction times, and no external heating. Moreover, the method can be readily scaled-up as demonstrated by gram-scale synthesis of 2-(2,6-bis­((E)­1-phenyl­prop-1-en-2-yl)­phenyl)­imidazo­[1,2-a]­pyridine.

Grind-and-Heat: Solvent-free Catalytic C–H and C–X Functionalization Without a Ball Mill

“…The remarkable versatility of the C-B bond has propelled catalytic C-H borylation reactions, particularly Ir(I)-catalyzed variants, to the forefront of transformative methodologies for functionalizing (hetero)aromatic systems. Ball milling [31] Grind-and-heat Ar atm., 30 Hz, 99 min [31] Ar atm., 30 Hz, 99 min [31] 79% Under air., 10 Hz, 4.5 h [32] (1.2 equiv.) with LAG: 93% a without LAG: 50% a , 45% b with LAG: 60% a determined by 1 H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.…”

Synthesis and site selective C–H functionalization of imidazo-[1,2-a]pyridines

“…This method featured good functional group acceptance, shorter reaction times, a wide substrate scope, and no external heating, and can be used for the gram scale preparation of products (Scheme 10). 53…”

“…This method featured good functional group acceptance, shorter reaction times, a wide substrate scope, and no external heating, and can be used for the gram scale preparation of products (Scheme 10). 53 In the same period Sakhuja and co-workers reported Ru(II) and potassium hexafluorophosphate (KPF 6 ) catalyzed amidation at the ortho-C2 on the phenyl ring of 2-phenylimidazo[1,2a]pyridine 34 with aryl-isocyanates 35 through a chelationassisted pathway, which delivers a regioselective method for the preparation of a library of ortho-amidations at the C2′ of phenylimidazo[1,2-a]pyridines 36 (Scheme 11). 54 As a continuation of C2′ functionalization, a double carbon-cyanide bond 38 was afforded by the Hao group, which disclosed a rhodium-mediated site-selective double cyanation of 2-phenyllimidazo[1,2-a]pyridines 28 with N-cyano-N-phenylp-methylbenzenesulfonamide (NCTS) 37 through internal chelation-assisted ortho dual C-H functionalization.…”

Ball-Milling-Enabled Zn(OTf)2-Catalyzed Friedel–Crafts Hydroxyalkylation of Imidazo[1,2-a]pyridines and Indoles

“…Brindisi et al developed a solvent-free mechanochemical method for the synthesis of indoles and indolines by Fischer indolization of arylhydrazines and carbonyl compounds . As part of our continued interest in C–H functionalization of heterocycles under ball-milling, herein we report a mechanochemical Zn­(OTf) 2 -catalyzed hydroxyalkylation of imidazo­[1,2- a ]­pyridines and indoles with ethyl glyoxylate and formaldehyde (Scheme b).…”