Sixth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-6), 1-30 September
SYNTHESIS OF NAFTIFINE VIA CINNAMAMIDE DERIVATIVE
Vladimir N. Bulavka
“Slavich Company”, Mendeleev sq. 2, Pereslavl-Zalesskiy, Yaroslavl reg.,
152025, Russian Federation. E-mail: firstname.lastname@example.org
Abstract. Four-step and three-step syntheses of naftifine starting from 1-naphthaldehyde and including reduction of N-methyl-N-(1-naphthylmethyl)-cinnamamide with lithium aluminium hydride in 16-18% total yield described.
Keywords: naftifine, antifungal agents, cinnamamides, allylamines.
Naftifine, (E)-N-methyl-N-(3-phenyl-2-propenyl)-1-naphthalenemethanamine (I) is a firstly discovered allylamine functionalized antifungal agent inhibiting fungal squalene epoxidase . The synthetic procedures for I production usually involves alkylation methods [2, 3, 4]. A number of synthetic approaches, such as cinnamic Schiff base reduction - reductive methylation, acetophenone Mannich reaction - reduction - dehydration, phenylacetylene Mannich reacion - hydrogenation, and above mentioned alkylation with cinnamyl halides were described in paper . Although the synthesis of N-methyl-N-(1-naphthalene-methyl)cinnamamide (II) from N-methyl-1-naphthalenemethanamine (III) and cinnamoylchloride was described , the reduction of II to I was not described.
The cinnamamides exists almost exclusively in (E)-forms and this reduces the problem of stereoisomers formation. However, the reduction of cinnamamides with lithium aluminium hydride leads to different products depending of the process conditions and substitution at N-atom. Thus, after reduction with lithium aluminium hydride of cinnamoylpiperidine crude cinnamylpiperidine in 21% yield , and of diethylcinnamamide cinnamyl alcohol 30% (from initially formed cinnamaldehyde)  were isolated from the reaction mixtures. Newertheless, the way utilising cinnamoyl synthons can to be an alternative route for I obtaining.
We have obtained amine synthon III starting from 1-naphthaldehyde (IV):
Reaction of IV with 25% aqueous methylamine gives 77% of Schiff base V [8, 9] which on reduction with excess of sodium borohydride in ethanol gives amine III in 90% yield. Alternative way is the one-pot synthesis without isolation of V by its reduction with zinc dust and 5% aqueous sodium hydroxide according to  (75% yield of III).
We have synthesised II from III and ethyl cinnamate (VI) and have modified the procedure of II reduction.
Reaction of III and VI on heating in boiling o-xylene produced II in 80% yield. The latter was reduced with lithium aluminium hydride by method similar to described  in 1,2-dimethoxyethane at reflux in nitrogen atmosphere to produce after work up desired I in 30% yield. Total yield in four stage synthesis of I from starting IV was 16%, in three step synthesis including one-pot procedure total yield of I was 18%.
References and notes
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3. D. Berney. (Sandoz-Patent G.m.b.H.). (2-Propenyl)-(1-naphthyl)amine derivatives. DE 2809211 (C07C 87/29), 06.09.1979; appl. 03.03.1978. (Chem. Abstr. 1980, 92: 58500d).
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6. H. R. Snyder, R. E. Putham. Reductive coupling and polymerization of unsaturated amides. II. Effect of substituents. J. Am. Chem. Soc. 1954, 76(7), 1893-1898.
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8. S. Takeuchi, M. Kochi, A. Kawarada, S. Esumi, K. Sasaki, S. Kawabata, T. Saida, Y. Inoue, T. Yamamoto et al. (Kaken Pharmaceuticals Co., Ltd.) Preparation of N-benzylidene- and N-naphthylideneamines and formulation of anticancer agents containing them. JP 63-10721 (A61K 31/15), 18.01.1988; appl. 62-65350, 19.03.1987. (Chem. Abstr. 1989, 110: 101780z).
9. Appearance: yellow oil. GC-MS: RT = 14 min. 53.25 sec., m/z (%): 170 (9), 169 (58), 168 (100), 167 (23) - isotopic peaks of M+, 165 (7), 154 (6), 153 (12), 139 (4), 129 (5), 127 (13), 126 (8), 77 (3), 76 (2.5), 75 (3), 74 (3), 63 (4), 62 (2), 51 (2.5), 50 (2), 42 (7), 41 (2.5). 1H NMR (p. p. m.): 3.67 (s., 3H, =NCH3), 7.48-7.68 (m., 3H, ar.-4,5,8-H), 7.85-7.95 (m., 3H, ar.-3,6,7-H), 8.86 (d., 1H, ar.-2-H), 8.96 (s., 1H, 1-CH=N). 13C NMR (p. p. m.): 49.59, 124.65, 125.73, 126.47, 127.52, 128.77, 129.09, 131.30, 134.34, 135.75, 137.04, 162. 44.
10. T. Tsukinoki, Y. Mitoma, S. Nagashima, T. Kawaji, I. Hashimoto, M. Tashiro. Organic reactions in water. 1. A convenient method for reduction of imines using zinc powder. Tetrahedron Lett. 1998, 39(48), 8873-8876.