N N O Me CN PhCH CHCOMe N H X Me H H Ph O MeOC H N H OH Me CONH2 H R O NC H RCH C(CN)CONH2 N H2NOC R CN O Me N H2NOC R CN O Me H 1 3 H 2, EtOH, C5H11N CH3COCH2CONH2 4 X = OH 5 X = OMe O CONH2 NH H 2, EtOH, C5H11N 6 7 N O H2NOC HO Me O NH2 H 2, EtOH, MeCO2NH4 H 2, C5H11N a, R = Ph; b, R = C6H4OMe- o; N H2NOC Me O Me d, e, c, R = C6H4OMe- p; R = C6H4Me- p; f, R = 4-pyridyl N O H2NOC Me O O 8 12 H R = C6H4Me-m; H 2, EtOH, C5H11N 9 H 10 11 13 2, C5H11N 2 J. Chem. Research (S), 1997, 50–51 J.Chem. Research (M), 1997, 0476–0497 Formation of Polysubstituted Pyridin-2-one Derivatives by Michael Addition of 3-Oxobutanamide to a,b-Ethylenic Ketones and Amides Conor N. O’Callaghan,* T. Brian H. McMurry, John E. O’Brien, Sylvia M. Draper and Fiona K. Gormley University Chemical Laboratory, Trinity College, Dublin 2, Ireland Reaction of 3-oxobutanamide with 4-phenylbut-3-en-2-one and with 3-aryl-2-cyanoprop-2-enamides and related compounds affords new di-, tetra- and hexa-hydropyridin-2-one derivatives, the degree of unsaturation of the product depending on the experimental conditions. Pyridin-2-one derivatives are of considerable biological importance, both as cardiotonic agents such as Milrinone 11 and as potential HIV-1 specific reverse transcriptase inhibitors. 2,3 The Michael addition of 3-oxobutanamide 2 to ethylenic ketones C�C·C�O and ethylenic amides C�C·C(�O)NH2, followed by cyclisation, provides a useful synthetic route to these compounds.When 3-oxobutanamide undergoes addition to 4-phenylbut- 3-en-2-one 3, cyclisation takes place through the amide group of the addend, affording the acetyl-substituted piperidin- 2-one derivative 4 (Scheme 1). Recrystallisation from methanol converts this into the methoxy derivative 5, the conformation of which, as determined by X-ray diffraction, is presented in Fig. 1 (where the heterocyclic ring has been numbered in accord with chemical numbering). It is evident that the 3- and 4-protons are axial, as is also the 6-methoxy group. 50 J. CHEM. RESEARCH (S), 1997 *To receive any correspondence. Scheme 1 Fig. 1 Molecular structure of 3-acetyl-6-methoxy-6-methyl- 4-phenylpiperidin-2-one 5, showing the crystallographic numbering system Table Crystallographic data for compound 5 Molecular formula C15H19NO3 Mr 261.31 Crystal system monoclinic Space group p21/a Unit cell dimensions: a/Å b/Å c/Å b/° 11.893(3) 7.4378(8) 17.279(4) 108.877(11) V/A3 Z Dc/g cmµ3 Absorption coefficient/mmµ1 F(000) Crystal size y range Total data measured Total data unique Refinement method Number of parameters Goodness-of-fit on F2 Final R indices [Ia2s(I)] R indices (all data) Largest diff.peak and hole 1446.2(5) 4 1.200 0.083 560 0.45 mmÅ0.45 mmÅ0.35 mm 1.25–21.99° 1879 1769 [R(int)=0.0084] Full-matrix least-squares on F2 248 1.029 R1=0.0524, Rw=0.1266 R1=0.0850, Rw=0.1484 0.198 and µ0.174 e ŵ3In contrast to the reaction which affords the acetyl derivative 4, addition of 3-oxobutanamide to 2-cyanoprop-2-enamides 6 in ethanol containing piperidine results in cyclisation through the acetyl group of the addend, with formation of carbamoyl-substituted piperidin-2-ones 7, the stereochemistry of which is determined by NMR (J values and NOE experiments).(Some carbamoyl derivatives of pyridinones have previously been obtained from the reaction of a,b-unsaturated ketones with malonamide5,6,7 and cyanoacetamide. 8) The degree of saturation of the products obtained from the aryl-substituted amides 6a–e depends on the experimental conditions used.In the presence of ammonium acetate, loss of water occurs during the reaction, which affords tetrahydropyridin-2-ones 8, while in the absence of solvent loss of hydrogen also occurs and 1,2-dihydropyridin- 2-ones 9 are formed. The dipyridyl derivative 9f is readily obtained from 6f under very mild conditions. In a related synthesis, the reaction of 3-oxobutanamide with the bicyclic amide 10 affords the related saturated (11) and unsaturated (13) tricyclic products, together with the dimeric side-product 12.Crystal Structure Determination of the Piperidin-2-one 5.·Data were collected on an Enraf-Nonius CAD-4 diffractometer (Mo radiation, graphite monochromator, w-2y scans) at 20 °C. The crystal data and experimental parameters are summarised in the Table. The final cell parameters were determined using the Celdim routine.It was not found necessary to apply decay or absorption corrections to the data. The data were reduced to give the number of unique reflections and those with |F|a4s|F| were used in the structure solution and refinement. The structure was solved by automatic direct methods using SHELXS-8615 and refined by full-matrix least-squares analysis on F2 with SHELXL.16 The non-hydrogen atoms were refined anisotropically and all the hydrogen atoms were located from subsequent difference Fourier maps and refined with individual temperature factors to a final R value of 5.2%.Techniques used: IR, 1H NMR, 13C NMR, CH COSY and NOE, X-ray crystallography, elemental analysis References: 16 Table 1: Atomic coordinates and equivalent isotropic displacement parameters for 5 Table 2: Bond lengths and angles for 5 Table 3: Anisotropic displacement parameters for 5 Table 4: Mp, yield and IR data for 7c–e Table 5: Microanalytical data for 7c–e Table 6: NMR data for 7c–e Received, 19th August 1996; Accepted, 5th November 1996 PaperE/6/05767E References cited in this synopsis 1 (a) D.W. Robertson, E. E. Beedle, J. K. Swartzendruber, N. D. Jones, T. K. Elzey, R. F. Kauffman, H. Wilson and J. S. Hayes, J. Med. 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