Transformations of 1-phenethyl-1,2,3,6-tetrahydropyridines in the presence of trifluoromethanesulfonic acid
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Transformations of 1-phenethyl-1,2,3,6-tetrahydropyridines in the presence of trifluoromethanesulfonic acid Vera A. Shadrikova1*, Alexander S. Popov1, Maria V. Termelyova1, Marat R. Baimuratov1, Yuri N. Klimochkin1 1
Samara State Technical University, 244 Molodogvardeiskaya St., Samara 443100, Russia; е-mail: [email protected]
Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(7), 909–914
Submitted May 6, 2020 Accepted May 28, 2020
1-Phenethyl-1,2,3,6-tetrahydropyridines undergo intramolecular Friedel–Crafts reaction in trifluoromethanesulfonic acid medium, resulting in the formation of azatricyclic structures. It was shown that the direction of this reaction depended on the position of the substituent relative to the multiple bond in tetrahydropyridine. The structures of the obtained compounds were confirmed by a set of spectral analysis methods. Keywords: hexahydroazonine, 1-phenethyl-1,2,3,6-tetrahydropyridine, tetrahydroazocine, Friedel–Crafts reaction, hydroarylation.
Despite the two hundred years of accumulated knowledge in the field of morphan derivatives and related compounds, there is a continuing interest among organic chemists in developing more potent analogs of opiate alkaloids, which would lack the side effects typical for this family of drugs: rise of tolerance and dependence after prolonged use, respiratory system suppression, immunodeficiency, hyperalgesia, and others.1 The common structural motif of such compounds is the benzomorphan nucleus (Fig. 1). One of the synthetic routes that provides access to these compounds involves transformations of 1,2,3,6-tetrahydropyridine derivatives.2
In a continuation of our research in the area of electrophilic reactions involving 1-substituted tetrahydropyridines,3 we achieved the transformation of 1-phenethyl1,2,3,6-tetrahydropyridines 2a–h into the benzomorphan analogs 3a–h through a Friedel–Crafts reaction that was catalyzed by trifluoromethanesulfonic acid (TfOH). The application of superacids in the role of catalysts for organic synthesis reactions often provides access to new, complex molecular structures or enables the introduction of new functional groups into the molecules of previously known compounds.4 The starting 1,2,3,6-tetrahydropyridines 2a–h were obtained via the reduction of 1-phenethylpyridinium bromides 1a–h,5a–d which, in turn, were obtained by standard quaternization reactions of pyridine and its analogs with phenethyl bromide5e,f (Scheme 1, Table 1). Subsequently, the reactions of 1,2,3,6-tetrahydropyridines 2a–h with TfOH provided the cyclic products of intramolecular Friedel–Crafts reaction (1,4,5,6-tetrahydro2H-3,6-ethano[3]benzazocines 3а–е and 7-methyl1,2,4,5,6,7-hexahydro-3,7-methano[3]benzazonines 3f–h) in moderate yields (Scheme 2, Table 2). The reaction was performed in an excess of TfOH by heating for 48 h
Figure 1. Some structural analogs of benzomorphan, which have found medicinal uses as analgesic drugs: pentazocine (A), phenazocine (B), and nalbuphine (C). 0009-3122/20/56(7)-0909©2020 Springer Scie
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