Enantioselective α-Fluorination and α-Chlorination of N-Acyl Pyrazoles Catalyzed by a Non-C₂-Symmetric Chiral-at-Rhodium Catalyst

Abstract

A non-C 2 -symmetric and sterically demanding chiral-at-rhodium catalyst is demonstrated to efficiently catalyze the highly enantioselective α-fluorination [12 examples, up to >99% enantiomeric excess (ee)] and α-chlorination (12 examples, up to 98% ee) of N-acyl pyrazoles in high yields. Based on two sterically distinct cyclometalating ligands, the nonracemic rhodium(III) catalyst can conveniently be accessed in an enantiomerically pure fashion (>99% ee) via an established auxiliary-mediated approach. Comparison of the catalytic performance with the related C 2 -symmetric rhodium catalysts revealed the explicit superiority of the non-C 2 -symmetric design for the presented α-halogenation reactions, which are generally featured by a very simple synthetic protocol.

Cyclometalated Chiral-at-Ruthenium Catalyst for Enantioselective Ring-Closing C(sp3)–H Carbene Insertion to Access Chiral Flavanones

“…We next tested two new chiral ruthenium catalysts both containing one cyclometalating ligand and a stereogenic metal center (with exclusively achiral ligands). The catalyst Λ- Ru4 , which bears a cyclometalating phenylbenzothiazole ligand and a coordinated 1,10-phenanthroline, provided the flavanone ( R )- 3 in 99% yield and with 87% ee (entry 5), while Λ- Ru5 bearing a cyclometalating phenylpyrazole ligand instead afforded the flavanone ( R )- 3 with the same almost quantitative yield but an improved 94% ee (entry 6). These cyclometalated ruthenium complexes appeared to be highly suitable for the ring-closing C­(sp 3 )–H insertion reaction to yield flavanones.…”

A π–Cu(II)−π Complex as an Extremely Active Catalyst for Enantioselective α-Halogenation of N-Acyl-3,5-dimethylpyrazoles

“…Enantioselective carbon–halogen (Cl, Br) bond formations are particularly important due to their potential as synthetic intermediates as well as marine natural products and pharmaceuticals. , Among the various methods available to build carbon–halogen bonds, the enantioselective electrophilic α-halogenation of carbonyl compounds is one of the most common. Over the past few decades, α-halogenation reactions using 1,3-dicarbonyl compounds, aldehydes, and ketones have been well established. − However, few reports are available on catalytic enantioselective α-chlorination for carboxylic acid derivatives with p K a values that are relatively high, and hence it has been considered to be challenging to generate enolate species catalytically . In 2001, Lectka et al reported the cinchona alkaloid catalyzed enantioselective chlorination , and bromination , /esterification of acyl chlorides (tandem method, Scheme a).…”

Oxidation: C–X Bond Formation (X = Halogen, S, Se)

“…Selectfluor in the presence of a non-C 2 -symmetrical chiral-atrhodium catalyst provided the fluorinated product in high ee values (Scheme 18). 33 The catalytic performance of the non-C 2 -symmetrical rhodium catalysts revealed to be superior to the related C 2 -symmetrical rhodium catalysts.…”

“…These less acidic carboxylic acid derivatives, compared to the above mentioned substrates, were engaged in the enantioselective chlorination using trifluoromethanesulfonyl chloride as chlorine source and a non-C 2 -symmetrical chiral-atrhodium catalyst (Scheme 26a). 33 This piece of work followed the -fluorination reported in section 7.9.2.4. N-acyl pyrazoles featuring a -(het)aryl residue provided the chlorinated products in high ee values while the -propyl substrates could not be converted.…”