Efficient Multigram-Scale Synthesis of 7-Substituted 3-Methyltetral-1-ones and 6-Fluoromenadione

Abstract

Herein is reported a safe and economical multigram synthesis of 6-fluoromenadione, an intermediate in the synthesis of novel antiparasitic agents. The keys to this 6-steps sequence process involves the condensation of the readily available starting 4'-fluoropropiophenone and glyoxylic acid, a bromination-elimination sequence from the 7-fluoro-3-methyltetral-1-one allowing the aromatization of the naphthol intermediate, which is then oxidized into the corresponding 6-fluoromenadione. The multigram process has been demonstrated from 25 g starting material scale with an improved overall yield of 50%, and then applied to five other 7-substituted-3-methyltetralones and their corresponding 6substituted-menadiones.

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging

“…Based on our previous works, , we first synthesized a series of 3-benzylmenadiones involving various substituted aromatic groups via two different routes (linear or bottom-up) and starting from precursors presenting a H ( 1a ) or F ( 1b ) atom in position 6 of the protected menadione moiety (Scheme ). − The fluorine atom was introduced on the molecular scaffold to improve its metabolic stability, as observed in antimalarial studies, and to increase its bioavailability compared to its non-fluorinated derivative. , …”

Expeditious Synthesis of Gwanakoside A and the Chloronaphthol Glycoside Congeners

“…Thus, 7-methoxy-3methyltetral-1-one (5) was effectively prepared from commercially available 4′-methoxypropiophenone in a three-step process according to the reported methods in comparable yields (see the Supporting Information). 10 Subsequent αbromination of 5 with N-bromosuccinimide (NBS) and tosylic acid (PTSA) in CH 2 Cl 2 under reflux, followed by elimination under the action of Li 2 CO 3 in N,N-dimethylformamide (DMF) at 100 °C, gave naphthol 6 in a 59% yield. 10,11 The para-and ortho-selective chlorination of phenols has been extensively studied.…”

“…10 Subsequent αbromination of 5 with N-bromosuccinimide (NBS) and tosylic acid (PTSA) in CH 2 Cl 2 under reflux, followed by elimination under the action of Li 2 CO 3 in N,N-dimethylformamide (DMF) at 100 °C, gave naphthol 6 in a 59% yield. 10,11 The para-and ortho-selective chlorination of phenols has been extensively studied. 12−16 Attempts to directly electrophilically dichlorinate a naphthalene-1,7-diol such as 6, however, have not been reported, resulting in complex outcomes.…”

“…Thus, 7-methoxy-3-methyltetral-1-one ( 5 ) was effectively prepared from commercially available 4′-methoxypropiophenone in a three-step process according to the reported methods in comparable yields (see the Supporting Information). Subsequent α-bromination of 5 with N -bromosuccinimide (NBS) and tosylic acid (PTSA) in CH 2 Cl 2 under reflux, followed by elimination under the action of Li 2 CO 3 in N , N -dimethylformamide (DMF) at 100 °C, gave naphthol 6 in a 59% yield. , The para - and ortho -selective chlorination of phenols has been extensively studied. − Attempts to directly electrophilically dichlorinate a naphthalene-1,7-diol such as 6 , however, have not been reported, resulting in complex outcomes. Nevertheless, the synthesis of ortho -chlorinated phenols could be achieved through alternative routes, such as the elimination of gem -dichloro compounds. , Thus, tetralone 5 was α,α-dichlorinated to provide 2,2-dichlorotetralone 8 in the presence of bleach; subsequent elimination under basic conditions furnished 2-chloronaphthol 9 in excellent yield (90% for two steps).…”

“…Our synthesis commenced with the preparation of chlorinated naphthol 12 (Scheme 1). Initially, we conceived the synthesis of naphthol 6, which has been reported, 10 followed by subsequent chlorination. Thus, 7-methoxy-3methyltetral-1-one (5) was effectively prepared from commercially available 4′-methoxypropiophenone in a three-step process according to the reported methods in comparable yields (see the Supporting Information).…”