An Efficient Synthesis of Dihydroxyfluorenones via in Situ Pd(0)-Catalyzed Cross-Coupling

Abstract

All six dimethoxyfluorenones 6a-f and dihydroxyfluorenones 7a-f , wherein substitution occurs at only one aromatic ring, were conveniently prepared by palladium(0)-catalyzed cross-coupling reactions of aryl bromides/triflates 2a-e with in situ generated arylboranes, derived from o -bromobenzamide 1a and o -bromophenyloxazoline 1b .Fluorenone derivatives are known to display a variety of biological activities. 1-3 Also, several methoxy and hydroxyfluorenone derivatives are natural products whose syntheses have recently been described. [4][5][6][7][8][9] As part of our investigation into the protein kinase inhibitory activity of substituted fluorenones, 10 we desired a convenient method for preparing all possible dihydroxy regioisomers in which substitution occurs on only one aromatic ring of the fluorenone nucleus.Some syntheses of fluorenones employ fluorene, 11 benzophenone, 12 or hexahydrofluorenone 13a precursors. Unfortunately, these procedures either give isomeric mixtures, are low yielding or offer limited access to certain isomers. Increased accessibility of substituted biphenyls through numerous cross-coupling techniques makes the intramolecular acylation reactions of biphenyl carboxylic acids 11 and biphenyl amides 14 an attractive approach to fluorenones. Of note are the recently reported in situ Suzuki cross-coupling methods which obviate the need for isolation of boronic acid intermediates. 15 Furthermore, the respective cyclization chemistries of biaryl-2-carboxylic acids and biaryl-2-carboxamides, the classical and anionic equivalent of the Friedel-Crafts reaction, are complementary and enable the preparation of a complete isomeric set. In an effort to obtain all possible dihydroxyfluorenone regioisomers 7a-f , we have employed and here report a convenient synthetic approach utilizing, 1) an efficient in situ generation and Pd(0)-catalyzed crosscoupling of aryl boranes to prepare substituted biaryls; 2) regiospecific remote aromatic metalation cyclization; and 3) a complementary Friedel-Crafts acylation cyclization.Thus, 2-bromo-N , N -diethylbenzamide (1a) (Scheme 1) undergoes lithium-halogen exchange and boronation at the 2-position. Treatment of the boronate with dimethoxyaryl bromides and aryl triflates 2a-e under modified in situ Suzuki conditions gave the biarylamides 3a-e . Intramolecular cyclization occurs when 3a-e react with LDA in a remote metalation process as described by Snieckus. 14 The five dimethoxyfluorenone regioisomers 6a-e thus formed are easily demethylated with refluxing HBr/AcOH to give dihydroxyfluorenones 7a-e in good yield.In order to obtain the sixth regioisomer 7f , we employed the same in situ coupling procedure using 2a and oxazoline 1b as a masked carboxylic acid (Scheme 2). Acid hydrolysis of the ring-opened 16 intermediate 4 gave biaryl-2-benzoic acid 5 which underwent normal Friedel-Crafts cyclization to regioselectively provide 2,3-dimethoxyfluoren-9-one (6f) in high yield. 17 Fluorenone 6f cannot be prepared by the anionic equivalent route since the more acidic o...

Diazo Group Electrophilicity in Kinamycins and Lomaiviticin A: Potential Insights into the Molecular Mechanism of Antibacterial and Antitumor Activity

“…Our synthetic strategy to the diazobenzo[ a ]fluorene 4 was based on a Suzuki coupling. , Pd-catalyzed coupling of boronic acid 8 and aryl bromide 10 afforded the biaryl 11 . Anionic cyclization of 11 and demethylation gave 14 .…”

The Expedient and Regioselective Metalation of Unprotected Biphenyl‐2‐, ‐3‐, and ‐4‐carboxylic Acids

“…HCl (4 m) until the pH reached 1. The aqueous layer was washed with diethyl ether (6 × 50 mL), the combined ether layer was dried with MgSO 4 and concentrated in vacuo, and the residue was recrystallized (heptane/ethyl acetate) to give the product.…”

“…[2] Their importance as precursors of biologically active molecules notwithstanding, very little attention has been paid to the synthesis of biphenyl-2-carboxylic acid derivatives through lithiation reactions. Treatment of tertiary biphenyl-2-carboxamides and biphenyl-2-yloxazolines with LDA or tBuLi affords the fluorenone skeleton directly by remote metalation, [3,4] with alkyllithium metalation occurring exclusively ortho to the amide group. The carbonyl group is invariably protected prior to metalation Regioselective lithiation of biphenylcarboxylic acids is a new challenge because of the previously demonstrated ortho directing effect of the carboxylic acid group in benzenoid Table 1.…”

Site-Selective Suzuki-Miyaura Reactions of the Bis(triflate) of 5,10-dihydroxy-11H-benzo[b]fluoren-11-one

“…7 Fluorenones are also important compounds in photochemistry. 8 Fluorenones have been prepared by intramolecular Friedel-Crafts acylations of biaryls, 9 by [4+2]-cycloadditions of conjugated enynes, 10 by oxidation of fluorenes, 11 based on remote aromatic metalations, 12 by reaction of malonic acid dinitrile with aromatic aldehydes and methylketones, 13 by Suzuki reaction of boronic acids of benzoic acid amides with aryl triflates and subsequent cyclization, 14 by acid-mediated intramolecular Friedel-Crafts cyclization of 2-methoxycarbonylbiaryls, and by Suzuki reactions of salicylate-derived enol triflates. 15 We have recently reported a synthetic approach to functionalized fluorenones based on formal [3+3]-cyclizations of 1,3-bis(silyloxy)-1,3-butadienes.…”