The 3-cyanopyridin-2(1H)-ones are of both theoretical and practical interest. In particular, they are synthons for annelated heterocyclic systems [1–4] while 3-cyanopyridin-2(1H)-ones show cardiotonic and inotropic activity as phosphodiesterase inhibitors [5–7].

We have previously prepared 5-cyanopyrano[3,4-c]pyridin-6(7H)-ones which contain alkyl and aryl substituents in position 8 [8]. With the aim of introducing cyclic amine fragments into the pyridine ring, we have developed a method for preparing condensed 3-cyanopyridin-2(1H)-ones through Smiles rearrangement.

We have used the condensed 3-cyanopyridin-2(1H)-thiones 1a-i [9–12] as starting materials. Initially, we unsuccessfully attempted to carry out preparation of the condensed 3-cyanopyridin-2(1H)-ones via nucleophilic substitution of the S-methyl and S-benzyl derivatives of the 3-cyanopyridine-2(1H)-thiones 2j-m [10–14] using an aqueous alcoholic solution of sodium hydroxide. Subsequently this task was achieved using the 2-hydroxyethylsulfanyl derivatives 2a-i which underwent a Smiles rearrangement using sodium hydroxide under analogous conditions to give the 3-cyanopyridin-2(1H)-ones 3a-i.

Rearrangement of the 2-hydroxyethylsulfanyl derivatives 2a-i occurred in the presence of a tenfold excess of sodium hydroxide in quite good yields (65-90%) which reached 85-90% in the case of the 8-morpholino- or 8-piperidino-substituted derivatives 3a,b,e,h (Table 1). Decreasing the amount of base caused a decrease in the product yield. The cleavage product - thiirane (4) is also formed in the reaction mixture and may

figure a

polymerize under basic conditions [15, 16]. A similar O–S Smiles rearrangement is observed in furazan and furoxazan derivatives [17]. The patent [18] reports the preparation of the pyridin-2(1H)-one 3a using 2-bromoethanol without isolation of the 2-hydroxyethyl derivative 2a under more forcing conditions (heating at 135°C) without a study of the reaction chemistry. However, in the patent, the melting point, IR and mass spectra, and elemental analysis are absent with only a questionable 1H NMR spectrum. The proposed intramolecular nucleophilic substitution reaction mechanism is presented in the following scheme.

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Table 1 Physicochemical Characteristics of Compounds 2, 3a-i
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It is known from the literature that 2-hydroxypyridines are in tautomeric equilibrium with 2-pyridones [19]. The IR spectra of compounds 3a-i show amide carbonyl stretching vibration bands at 1640-1650 cm-1, a nitrile group at 2210-2215 cm-1, and weak NH group vibrations at 3110-3150 cm-1. The 1H NMR spectra recorded in DMSO-d6 show the NH group protons as broad signals in the region 10.31-11.45 ppm (Table 2).

Table 2 1H NMR spectra of Compounds 2, 3a-i
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According to X-ray structural analysis, the crystalline form of compound 3a exists in the pyridone form (Fig. 1).

Fig. 1
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Structure of the compound 3a molecule with representation of atoms with thermal vibration ellipsoids of 50% probability.

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The pyran ring has a "half chair" conformation with the C(1), C(4), C(5), and C(10) atoms in a single plane (the maximum deviation being 1.0144(29) Å) with deviations from this plane for the O(2) and C(3) atoms of 0.3160(30) and 0.4788(30) Å, respectively (Fig. 1). It was found that the morpholine ring also has a "half chair" conformation with deviations from the mean plane formed by C(16), C(17), C(19), and C(20) of 0.6560(33) and 0.6795(22) Å, respectively, for the O(18) and N(15) atoms. From the study it was found clearly that an intermolecular hydrogen bond exists between the N(8)–H(8) and O(21) atoms such that the molecule occurs as a dimeric pair. The length of the donor-acceptor bond is 2.756 Å (Fig. 2).

Fig. 2
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Structure of the dimeric pair of the compound 3a molecule formed with the aid of the intermolecular hydrogen bonds (symmetry notation [i: -x, 1-y, 1-z]).

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Thus, we have developed a method for the preparation of condensed 3-cyanopyridin-2(1H)-ones. X-ray structural analysis and other physicochemical methods have confirmed the structure of the compounds synthesized.

Experimental

IR spectra were recorded on a UR-20 spectrometer using vaseline oil. 1H NMR spectra were recorded on a Mercury 300 instrument (300 MHz) using DMSO-d6 with TMS as standard. Mass spectra were recorded on an MKh-1320 instrument through direct introduction of the sample into the ion source (EI, 50 eV). Elemental analysis was performed on a Euro EA 3000 Elemental Analyzer. Melting points were recorded on a Boetius micro hot stage apparatus.

8-R 1 -6-(2-Hydroxyethylsulfanyl)-3,3-dimethyl-3,4-dihydro-1 H -pyrano[3,4-c]pyridine-5-carbonitriles 2a-c, 3-(2-hydroxyethylsulfanyl)-7-methyl-1-morpholino-5,6,7,8-tetrahydro[2,7]-naphthyridine-4-carbo-nitrile (2d), 1-R 1 -3-(2-hydroxyethylsulfanyl)-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles 2e-g, and 1-R 1 -3-(2-hydroxyethylsulfanyl)-6,7-dihydro-5 H -cyclopenta[ c] pyridine-4-carbonitriles 2h,i (General Method). A solution of compound 1a-i (0.01 mol) in MeOH (20 ml) was added to a solution of NaOH (0.4 g, 0.01 mol) in water (10 ml). The mixture was stirred at 20-22°C for 10 min to the formation of a clear solution followed by the dropwise addition of 2-chloroethanol (0.8 g, 0.01 mol). The solution was stirred at 20-22°C for 10 h, and the crystals formed were filtered off, washed with water, and recrystallized from EtOH.

Compounds 2a-i. IR spectrum, ν, cm-1: 1560-1570 (C=C Ar), 2200-2205 (CN), 3450-3500 (OH).

8-R 1 -3,3-Dimethyl-6-oxo-3,4,6,7-tetrahydro-1 H -pyrano[3,4- c ]pyridine-5-carbonitriles 3a-c, 7-methyl- 1-morpholino-3-oxo-2,3,5,6,7,8-hexahydro[2,7]naphthyridine-4-carbonitrile (3d), 1-R 1 -3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitriles 3e-g, and 1-R 1 -3-oxo-3,5,6,7-tetrahydro-2 H -cyclopenta[ c ]pyridine- 4-carbonitriles 3h,i (General Method). 50% Aqueous NaOH solution (8 g, 0.1 mol) was added to a solution of compound 2a-i (0.01 mol) in EtOH (50 ml). The mixture was refluxed for 10 h. After cooling, the white precipitate of the thiirane (4) polymer was filtered off. The filtrate was diluted with water and washed with chloroform to remove unreacted starting compound 2a-i. The aqueous layer was acidified with HCl and the precipitated crystals of compound 3a-i were filtered off, washed with water, and recrystallized from a mixture of chloroform and ethanol (1:2).

Compounds 3a-i. IR spectrum, ν, cm-1: 1640-1650 (C=O), 2210-2215 (CN), 3110-3150 (NH). Compound 3a. Mass spectrum, m/z (I rel, %): 289 [M]+ (100), 288 (17), 274 (20), 258 (33), 244 (14), 231 (24).

Thiirane (4) polymer. Yield 0.5 g (83%, alone preparation of compound 3a), white powder, mp 160-162°C. Mass spectrum, m/z (I rel, %): 60 [M]+ (100), 59 (21), 58 (52), 45 (75), 28 (23).

X-ray Structural Study of Compound 3a. Crystals of compound 3a (C15H19N3O, M 289.34) are monoclinic and were prepared by crystallization from chloroform. At 20°C: a 6.7098(13), b 12.620(3), c 17.826(4) Å; β 99.05(3)°; V 1490.6(5) Å3, Z 4, space group P21/c. Parameters were measured on an Enraf-Nonius CAD-4 automatic diffractometer for 22 reflections with 12.77<θ<14.77. The intensities of 4675 reflections were measured in the range 0 ≤ h ≤ 9, -17 ≤ k ≤ 0, -25 ≤ l ≤ 24; θmax 30° (MoKα radiation, graphite monochromator). All of the calculations were carried out using the SHELXTL program package [20]. After averaging of symmetrically equivalent reflections, the array contained 4338 independent reflections (R int 0.016) of which 2919 had I > 2σ(I). The structure was solved by the direct method and the hydrogen atom coordinates were determined from the difference Fourier syntheses. The structure was refined in full-matrix least-squares analysis in the anisotropic approximation for non-hydrogen atoms and the isotropic approximation for hydrogen atoms. The final probability factors were R 0.052, S 1.018. The crystallographic data for compound 3a has been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 917444).