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 1). The fluorine atom was introduced on the molecular scaffold to improve its metabolization resistance, as observed on antimalarial studies, and to increase its bioavailability compared to its non-fluorinated derivative. In the linear approach, the insertion of the cyclic diamine was performed by Buchwald-Hartwig coupling in the presence of palladium complex catalyst as well as imidazolium salt as ligand (whose optimized conditions were presented in Table ). This reaction involved the prior functionalization of the amino moiety by nucleophilic substitution with the corresponding benzyl halide giving various monobenzyl diamines, which subsequently were used for the amination Although this first route seemed promising thanks to its rapid realization (only two steps from 1a-b), the diamine's functionalization before coupling remained a notable limitation. Indeed, the experimental conditions (6 equivalents of amino compound for one equivalent of benzyl halide) and the potential instability of this type of diazacycles as a function of the compounds present, led us to devise and develop a more convergent strategy for the synthesis of the proposed 3-benzylmenadiones (Scheme 1). In this top-down approach, a cyclic mono N-Boc diamine was introduced onto precursor 1a via the same Buchwald-Hartwig coupling, leading to compound 2a in 86% yield. Acidic deprotection of N-Boc and reductive amination of the trifluoroacetate salt 2b in the presence of NaBH(OAc)3 afforded corresponding 1,4-dimethoxynaphthalene derivatives 3c-h in excellent yields. Finally, the latter were treated with a BCl3 solution giving their oxidized analogues 4c-e and 4g-h with moderate to good yields (30 to 95%), except for compound 4f which was only obtained in 17% yield. Such result was explained by the competitive demethylation reaction of the terminal methoxy in addition to the two methoxy functions present on the 1,4-dimethoxynaphthalene derivative despite milder reaction conditions (8h reaction time and 4.0 equivalents of BCl3, not shown here). Carbo-aromatics, such as benzyl or phenyl rings, generally exhibit increased lipophilicity, affecting the use of compounds with these motifs in biological applications In order to improve the water solubility of the molecules of interest, N-heteroaromatic analogues 6a-d and 9a-e, whether containing pyridine or pyrimidine functions in place of alkylating agents or of 3benzyl moiety, were synthesized following synthesis methodologies previously described in the laboratory. The synthesis of compounds 6a-d, based on a convergent methodology, is shown in scheme To complement compounds 6a-d, 3-pyrimidyl and 3-pyridylmenadione derivatives (9a-e, scheme 3) were prepared via the linear synthetic approach starting from precursors 7a-b, previously described. These intermediates were involved in a Buchwald-Hartwig coupling with monobenzyl diamines S5a-b giving compounds 8a-e. Then, the final compounds 9a-e were obtained by oxidative demethylation in excellent yields, except for compounds 9b and 9e (50 and 31%, respectively), due to the competitive demethylation of the terminal methoxy moiety in addition to the two presents on 1,4-dimethoxynaphthalene derivatives. In order to study the influence of the nature and properties (electronic, steric hindrance, etc.)