An Efficient and Convenient Protocol for the Synthesis of 1,1-Difluoro-6-nitro-2,3-dihydro-1H-indene Derivatives

Abstract

A convenient and efficient synthesis of gem-difluorinated compounds is reported. The synthetic route toward various 2-substituted and 3-substituted 1,1-difluoro-6-nitro-2,3-dihydro-1H-indene derivatives is described starting from commercially available indanone. The key gem-difluorination step is accomplished in good yield by treatment of in situ generated bromine fluoride (BrF) with a dithioketal. A plausible mechanism discussing the competition between substitution and elimination is provided to rationalize the outcome of the reactions of the 3-brominated compounds with different amines.

Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia

“…Briefly, the key intermediate 23 was synthesized according to our reported method using commercially available 2,3-dihydro-1H-inden-1-one as the starting material. 17 The following reduction of the NO 2 group afforded the amine intermediate 24, which was reacted with the substituted benzoic acids (15a and 15b) to give the amide intermediates 25a and 25b, respectively. Compounds 25a and 25b were converted to the target Compound 3e was prepared from compound 26, which was prepared according to our published method, 17 by a similar procedure.…”

“…The designed difluoro-indene compounds 3a – e were prepared using a palladium-catalyzed Sonogashira coupling reaction as the key step (Scheme ). Briefly, the key intermediate 23 was synthesized according to our reported method using commercially available 2,3-dihydro-1 H -inden-1-one as the starting material . The following reduction of the NO 2 group afforded the amine intermediate 24 , which was reacted with the substituted benzoic acids ( 15a and 15b ) to give the amide intermediates 25a and 25b , respectively.…”

Recent Advances in the Synthesis of Indanes and Indenes

“…Haloindanes, aminoindanes and indanols have also been used as starting materials for the preparation of differently functionalized indanes . In a recent example, 1,1‐difluoro‐6‐nitroaminoindanes 177 were easily synthesized from bromo‐1,1‐difluoro‐6‐nitroindanes 176 by treatment with an amine in the presence of K 2 CO 3 as a base in DMF at RT (Scheme ) . In another process, nonracemic ( S , R )‐ and ( R , S )‐2‐azidoindan‐1‐ol ( 180 and 181 , respectively) were synthesized with excellent ee values by conversion of racemic trans ‐2‐bromoindan‐1‐ol 178 to racemic cis ‐2‐azidoindan‐1‐ol 179 followed by kinetic resolution with lipase, as shown in Scheme .…”

Mono‐ and Difluorination of Benz­ylic Carbon Atoms

“…Compound 36 is then debrominated to give 1,1-difluoro-6-nitro-1H-indene (37). [46] Direct fluorination of indanone 34 with DAST or Deoxofluor failed to give compound 37. In 2012 Hagooly and Rozen disclosed a fluorodesulfurization procedure for benzylic 1,3-dithianes 38 by use of PyBrF 3 .…”