ChemInform Abstract: A Platform of Regioselective Methodologies to Access Polysubstituted 2‐Methyl‐1,4‐naphthoquinone Derivatives: Scope and Limitations.

Abstract

A library of title compounds is envisaged where the derivatives are functionalized at the aromatic part of the naphthoquinone scaffold.

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

“…The previously reported synthesis to afford 6-fluoromenadione used in our laboratory was based on a 5-steps synthesis (Scheme 2). 12 Starting from commercial 4'-fluoropropiophenone 14a, the 2-bromo-4'-fluoropropiophenone 16 was prepared in the presence of bromine in acetic acid, 13 and the corresponding xanthate 17 was formed by using potassium ethylxanthate. Then, the synthesis of the 7-fluoro-3-methyl-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl pivalate 18 was achieved, but in moderate yields, by using a xanthate-mediated free-radical addition/cyclization sequence based on the methodology pioneered by Zard and coworkers, 14 following radical addition of xanthate 17 to vinyl pivalate and using dilauroyl peroxide as initiator.…”

“…21,22 Finally, the 6-fluoromenadione 15a was obtained after oxidation with PIDA (see supporting information, Table S3 for optimization conditions). 12 Noteworthy is to mention that each step was followed by a chromatographic purification during the optimization of the methodology, despite the little amount of side products giving an overall yield of 32% over six steps, versus 9% using the first generation route.…”

“…Application to other 7-substituted-3-methyltetralones 1b-f and 6-substitutedmenadiones 15b-f. Gram scale synthesis of 6-methoxymenadione 15b and 6methylmenadione 15c was performed according to this strategy from commercially available 4'-methoxypropiophenone 14b and 4'-methylpropiophenone 14c, with 12% and 35% over 6 steps, respectively (Scheme 5), versus 33% and 70% through the first generation route. 12 Nevertheless, the scope of the second generation route lies mainly to the generation of 7substituted-3-methyl-naphthols 20b and 20c (e.g. 7-methoxy and 7-methyl groups, produced with 35% and 43% yield, respectively), which are regioisomers of the reported 7-substituted-2methyl-naphthols produced in the first generation route.…”

“…. 12 According to general procedure F, 328 mg (35% yield, yellow solid) of 15b were obtained by flash chromatography on silica gel (Toluene/ethyl acetate, gradient from 10/0 to 9/1, v/v, UV). M.p.…”