Synthesis of 1-{4a,6-dimethyl-4a,9a-dihydropyrano-[3,4-b]indol-9(1H)-yl}ethanone

Abstract

Heating of the bromination product of 4-methyl-3,6-dihydro-2H-pyran with 4-toluidine or 2-bromo-4-methylamiline in triethylamine gave 4-methyl-N-(4-methylphenyl)-and N-(2-bromo-4-methylphenyl)-4-methyl-3,6-dihydro-2H-pyran-3-amines which were converted into the corresponding amides by reaction with bromo-or chloroacetyl chloride. indol-9(1H)-yl}-ethanone was synthesized in good yield by heating N- (2-bromo-4-methylphenyl)-N-(4-methyl-3,6-dihydro-2H-pyran-3-yl)acetamide in boiling toluene in the presence of palladium(II) acetate, triphenylphosphine, copper(II) acetate, triethylamine, and potassium carbonate.Representatives of the pyranoindole series are few in number; nevertheless, some pyranoindole derivatives exhibit biological activity [1][2][3]. In the present work we tried to build up fused pyranoindole system by cyclization of a mixture of syn and anti atropisomers of N-(2-bromo-4-methylphenyl)-N-(4-methyl-3,6-dihydro-2H-pyran-3-yl)acetamide (IIa) under conditions of metal complex catalysis, which is widely used in the synthesis of nitrogen-containing heterocycles [4,5]. Compounds syn-IIa and anti-IIa were synthesized by reaction of acetyl bromide with N-pyranyl-substituted 2-bromo-4-methylaniline (I). The latter was prepared by reaction of 2-bromo-4-methylaniline [6] with the product of bromine addition to 4-methyl-3,6-dihydro-2H-pyran in carbon tetrachloride [7] (Scheme 1).The existence of compound IIa as two atropisomers was determined by spectral methods. Signals in the 1 H NMR spectra from the 3-H and 5-H protons in the pyran ring were assigned to particular atropisomers on the basis of published data [8]. According to the 1 H NMR data, the syn/anti ratio was 1 : 3. The minor syn atropisomer was characterized by a broadened singlet from 3-H at δ 4.72 ppm. The corresponding signal of the major anti isomer was observed in a weaker field (δ 5.37 ppm, br.s). The 5-H proton resonated as a broadened singlet at δ 5.47 (syn) or 5.64 ppm (anti). Likewise, by reaction of compound I with chloroacetyl chloride we obtained a mixture of syn and anti atropisomers IIb whose 1 H and 13 C NMR spectra also contained double sets of some signals. For comparison, amine III having no substituent in the ortho position of the aromatic ring was converted into compound IV, and its 1 H NMR spectrum showed the absence of atropisomerism.Heterocyclization of amide IIa using the system copper(II) acetate-palladium(II) acetate with addition of triphenylphosphine, triethylamine, and potassium carbonate gave dihydropyrano [3,4-b]indole (V) in good yield. The reaction is likely to involve initial formation of palladium intermediate A or B. Both structures do not contradict published data [8][9][10]. Elimination of PdHL 2 Br from palladium derivative D formed as a result of successive transformations yields pyranoindole V.The structure of compound V was determined on the basis of its elemental composition and spectral parameters. The mass spectrum of V contained the molecular ion peak with m/z 244 [M + H] + . Signals in the 1 H NMR spectru...