Mendeleev Communications Electronic Version, Issue 4, 1998 (pp. 129–168) Cascade and stepwise oxidation of 4-phenyl- and 4-( -pyridyl)tetrahydropyridines Anatoly T. Soldatenkov,* Ayalew W. Temesgen, Ives A. Bekro, Svetlana A. Soldatova and Boris N. Anissimov Peoples’ Friendship University of Russia, 117198 Moscow, Russian Federation. Fax: + 7 095 433 1511 A general cascade and stepwise oxidation scheme for 4-aryl-substituted 1,2,3,6-tetrahydropyridines with KMnO4 is described, which includes the consecutive oxidative transformation of the carbon triad in the substrate allylamine fragment, yielding tetrahydropyridin-2-ones, 3,4-dihydroxypiperidin-2-ones and, finally, 1-formylamino-3-arylpropan-3-ones. The ability of 1,2,3,6-tetrahydropyridines (THP) to react with aqueous KMnO4 was reported1 to depend considerably on the nature of the substituent present at the 4-position of the pyridine ring.For example, the 4-methyl-substituted THPs are easily hydroxylated under the classical conditions of the Vagner reaction (cooling, water–alcohol solution), whereas their 4-phenyl analogues appeared to be completely inert.1 This latter fact appears to be connected with the coplanarity of the phenyl and tetrahydropyridine moities which increases steric hindrance to permanganate anion attack on the double bond.Nevertheless, we have recently found2,3 that 4-phenylTHP 1a and 4-(g-pyridyl)THP 1b can be readily polyfunctionalised by a one-pot oxidation protocol, making available a high-yield synthetic method for the preparation of 3,4-dihydroxypiperidin- 2-ones 3a,b under slightly modified conditions (20–35 °C, water–acetonitrile solution).Our subsequent investigation4 of the one-pot oxidations has demonstrated the possibility of 2-oxo-4-phenylTHP 2a and 1-formylamino-3-phenylpropan- 3-one 4a formation starting in each case from 1a. The data thus obtained have prompted us to pose two important questions: are the compounds 2a–4a recovered in the different experiments formed as a result of a gradual elevation of the degree of oxidation in one reaction sequence; and, if so, can this cascade reaction be considered as a general one, at least for the 4-arylsubstituted THP series? In order to answer these questions it was decided to use the same one-pot procedures4 to afford new 2-oxo-THP 2b and aminopropanone 4b from 1b. Their successful repetition together with the separate oxidation of the lactam 2a into the lactamdiol 3a, the separate oxidative conversion of the latter through ring cleavage into the aminoketone 4a, and repeating the same experimental sequence with 2b and 3b, would provide supporting evidence for generalising both the cascade and the stepwise routes for the THP oxidative transformations. All the reactions were carried out in the presence of KMnO4 in water– acetonitrile solutions and afforded unambiguously the expected results.It was therefore established that oxidation of 4-pyridyl- THP 1b into 2b and 4b proceeded well, though with lower yields (27% and 58%, respectively) in comparison with the analogous reactions of 4-phenylTHP.2,4 The lactams 2a,b were readily hydroxylated at < 0 °C (in contrast to the inert 4-aryl THP 11) into the cis-diol lactams 3a,b with yields 54% and 45%, respectively.However, at room temperature the yield of 3a was increased to 76%. Apart from the importance of the 1 ® 2 ® 3 conversions, it is worth pointing out the decisive role of the amide group in the 2 ® 3 reaction.The presence of the electron-accepting amide group seems likely to significantly polarize the C=C bond in lactams 2 thus leading (even < 0 °C) to successful dihydroxylation of the 4-aryl THP system. The final stage in the oxidative transformation study consisted of proving the fact that the lactam diols 3 were intermediate products in the formation of amidoketones 4. On treatment of 3 with KMnO4 under elevated temperatures (up to 50 °C), TLC showed complete conversion to compounds 4.On work-up a colourless, thick oil of 4 was obtained in 34% to 58% yield. In the case of one-pot oxidation of 1b hydrochloride at room temperature the amide 4b was chromatographically separated in 43% yield. The structures of new compounds 2b and 4b were confirmed spectroscopically.† The data thus obtained allow us to conclude that a general cascade and stepwise scheme for the transformation of 4-arylsubstituted THP can be elaborated, based on the gradual elevation of the degree of oxidation of the triad of carbon atoms present in the allylamine moiety of the initial THP.These schemes can be useful in understanding certain azine oxidation mechanisms and can also serve as new, effective laboratory methods for the synthesis of three important groups of compounds.We thank the Russian Foundation for Basic Research (grant no. 96-03-33432a) for supporting the investigation. † 1H NMR spectra were recorded at 300 MHz in CDCl3, standard TMS. Compound 2b was prepared by oxidation of 1b with KMnO4 (1a:KMnO4 = 1:1.5) in MeCN at 20 °C, 1.5 h; yield 27%, mp 84–85 °C. 1H NMR, d: 2.78 and 3.58 (t, 2×2H, 5-CH2 and 6-CH2, 2J 7.0 Hz, 3J 7.0 Hz), 3.03 (s, 3H, Me), 6.43 (s, 1H, 3-H), 7.37 and 8.64 (dd, 2×2H, AA'BB', 2J 5.0 Hz, 3J 1.5 Hz); MS (EI, 70 eV, 80 °C), m/z (%): 188 (100) [M+]; IR (KBr, n/cm–1): 1650 (NC=O), 1600 (C=C). Found (%): C, 69.86; H, 6.83; N, 14.82. Calc. for C11H12N2O (%): C,70.21; H, 6.38; N, 14.89. Compound 2a was obtained similarly from 1a (1a:KMnO4 = 1:1.5, 0.75 h); yield 65%, mp 78–80 °C.4 Compound 3a was obtained by hydroxylation of 2a in aqueous MeCN (2a:KMnO4 = 1:1.5) at 0 °C, 1.5 h; yield 54%, mp 117 °C.2 The yield of 3a was increased to 76% at 20 °C, 2 h.One-pot oxodihydroxylation of 1a in aqueous MeCN (1a:KMnO4 = 1:1.5) at 20 °C, 2 h gave 3a in 76% yield.2 Compound 3b was prepared by hydroxylation of 2b in aqueous MeCN (2b:KMnO4 = 1:1.5) at 0 °C, 2 h; yield 45%, mp 220–222 °C.3 One-pot oxodihydroxylation of 1b in aqueous MeCN (1b:KMnO4 = 1:1.5) at 20 °C yielded 65% of 3b in 2 h.3 Compound 4a was obtained from one-pot oxidation of 1a·HCl in acetone (1a·HCl:KMnO4 = 1:1.5) at 20 °C, 2 h; yield 85%, colourless oil, Rf 0.73 in acetone.4 4a was also obtained from oxidation of 3a in MeCN (3a:KMnO4 = 1:1.5) at 50 °C, 0.5 h; yield 34%.Compound 4b was prepared by oxidation of 3b in MeCN (3b:KMnO4 = 1:1.5) at 50 °C, 0.5 h; yield 58%, colourless thick oil (purified by chromatography on silica gel column, eluent diethyl ether, Rf 0.41 in acetone). Compound 4b was also prepared by one-pot 1b·HCl oxidation (1b·HCl:KMnO4 = 1:1.5) in acetone at 20 °C, 2 h; yield 43%.In the 1H NMR spectrum of the amide 4b a double set of N(Me)CHO group signals are observed. 1H NMR, d: 2.92 and 3.12 (s, 2×1.5H, Me), 3.3 (t, 2H, 1-CH2, 2J 6.0 Hz, 3J 6.0 Hz), 3.8 (t, 2H, 2J 6.0 Hz, 3J 6.0 Hz), 7.75 and 8.85 (dd, 2×2H, AA'BB', 2J 4.5 Hz, 3J 1.5 Hz), 8.01 and 8.2 (s, 2×0.5H, NCHO); MS (100 °C), m/z (%): 192 (80) [M+], 107 (36), 106 (81), 86 (100), 78 (74), 72 (59), 58 (44); IR (paraffin oil, n/cm–1): 1676 and 1646 (C=O).Found (%): C, 61.96; H, 6.47; N, 14.21. Calc. for C10H12N2O2 (%): C, 62.50; H, 6.25; N, 14.58. g N Ar Me N Ar Me O N Me O OH Ar OH N CHO O Ar Me a Ar = Ph b Ar = 4-Py 1a,b 2a,b 3a,b 4a,b Scheme 1Mendeleev Communications Electronic Version, Issue 4, 1998 (pp. 129-168) References 1 T. N. Maksimova, V. B. Mochalin and B. V. Unkovskii, Khim. Geterotsikl. Soedin., 1980, 783 [Chem. Heterocycl. Compd. (Engl. Transl.), 1980, 604]. 2 A. T. Soldatenkov, I. A. Bekro, J. A. Mamyrbekova, S. A. Soldatova, A. W. Temesgen, N. D. Sergeeva, L. N. Kuleshova and V. N. Khrustalev, Khim. Geterotsikl. Soedin., 1996, 222 [Chem. Heterocycl. Compd. (Engl. Transl.), 1996, 197]. 3 A. T. Soldatenkov, I. A. Bekro, S. A. Soldatova, E. Glover, A. Temesgen, L. N. Kuleshova, V. N. Khrustalev and N. D. Sergeeva, Izv. Akad. Nauk, Ser. Khim., 1997, 2020 (Russ. Chem. Bull., 1997, 46, 1916). 4 A. T. Soldatenkov, A. W. Temesgen, I. A. Bekro, T. P. Khristoforova, S. A. Soldatova and B. N. Anissimov, Mendeleev Commun., 1997, 243. Received: Moscow, 14th May 1998 Cambridge, 23rd June 1998; Com. 8/03650K