The condensation of N-methyl-N-(1-naphthylmethyl)propargylamine (I) with 1-bromo-2-tert-butylacetylene (II) by means of Cu2Cl2 gives N-methyl-N-(1-naphthylmethyl)-6,6-dimethylhept-2,4-diynylamine (III), which is then reduced selectively with diisobutylaluminurn hydride in toluene.
By reductocondensation of amino (IV) with 6,6-dimethylhept-2-en-4-ynal (VI) by means of NaBH4 in methanol.
The condensation of propenal (VII) with tert-butylacetylene (VIII) by means of butyllithium gives 6,6-dimethylhept-1-en-4-yn-3-ol (IX), which is rearranged with HBr to the allyl isomer 6,6-dimethylhept-2-en-4-yn-1-yl bromide (X). Finally, this compound is condensed with amine (IV) by means of Na2CO3 in DMF.
Addition of formaldehyde to benzothiophene-2-sulfonamide (I), followed by condensation with trimethyl phosphite, furnished the dimethyl (sulfonamidomethyl)phosphonate (II). The phosphonate ester function of (II) was then hydrolyzed by means of bromotrimethylsilane, producing phosphonic acid (III). This was finally coupled to 2-fluoro-4-nitrophenol (IV) using trichloroacetonitrile in hot pyridine to afford the title mono-phosphonate ester.
The condensation of N-(1-naphthylmethyl)methylamine (IV) with formaldehyde and 5,5-dimethylhexadiine (V) by means of Cu2Cl2 also gives (III), which is then reduced selectively with diisobutylaluminum hydride in toluene.
1) The Grignard reaction of 1-bromonaphthalene (I) with Mg in THF and then with [14C]-labeled CO2 gives the corresponding 1-naphthoic acid (II), which by reaction with SO2Cl2 and then with methylamine yields [14C]-N-methyl-1-naphthalenecarboxamide (III). The reduction of (III) with LiAlH4 in refluxing THF affords the corresponding amine (IV). Finally, this compound is condensed with 1-bromo-6,6-dimethylhept-2-en-4-yne (V) by means of Na2CO3 in DMF, and treated with ethanolic HCl.
2) By condensation of (E)-N-methyl-N-(1-naphthylmethyl)-N-(pent-2-en-4-ynyl)amine (I) with [14C]-tert-butyl-chloride (II) by means of butyllithium and diethylaluminum chloride in hexane-dichloromethane.
The rearrangement of 6,6-dimethylhept-1-en-4-yn-3-ol (I) (scheme 09027805a, intermediate (IX)) to 1-bromo-6,6-dimethylhept-2(E)-en-4-yne (scheme 09027805a, intermediate (X)) with HBr reports a stereoselectivity E/Z of only 3/1. An exhaustive study of this halogenation/rearrangement reaction has been performed. This reaction ((I) to chloride (II)) has been improved up to and E/Z ratio of 9/1 with reaction yields of 95%, the reaction conditions being BCl3 (1.25 molar ratio) in hexane, with a reaction temperature of 25 C.
A new method for the short preparation of terbinafine has been described: Condensation of (E)-N-(3-bromoallyl)-N-methyl-N-(1-naphthyl)amine (I) with lithium tert-butylethynyl(triisopropoxy)borate (II) by means of Pd(PPh3)4, and CuI in hot DMF.