Synthesis and Functionalization of 3-Azolylquinoxalin-2(1H)-ones

SYNTHESIS Journal of Synthetic Organic Chemistry With compliments of the Author Thieme REPRINT Synthesis and Functionalization of 3-Azolylquinoxalin-2(1H)-ones Oleksandr V. Geraschenko,*a,b Pavel V. Khodakovskiy,a,b Oleg V. Shishkin,c Andrey A. Tolmachev,a,b Pavel K. Mykhailiuk*a,b Synthesis of Heterocycles a Enamine Ltd., Aleksandra Matrosova Street 23, Kyiv 01103, Ukraine Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01033, Ukraine Fax +380(44)2351273; E-mail: Geraschenko.Aleksandr@gmail.com; E-mail: Pavel.Mykhailiuk@gmail.com c STC, Institute for Single Crystals, National Academy of Science of Ukraine, 60 Lenina Ave., Kharkiv 61001, Ukraine Accepted after revision: 21.02.2014; Received: 23.12.2013 b Abstract: Ethyl 2-azolylglyoxylates react smoothly with o-phenylenediamines and 1,2-diaminocyclohexane in acetonitrile at room temperature to give the corresponding 3-azolylquinoxalin-2(1H)ones and their saturated analogues in good to excellent yields. Key words: quinoxalin-2(1H)-ones, 2-azolylglyoxylates, condensation, o-phenylenediamine, 1,2-diaminocyclohexane In recent decades derivatives of quinoxaline have gained widespread application in organic chemistry, medicinal chemistry, and drug discovery.1 Substituted quinoxalines exhibit a broad spectrum of biological activity, e.g. antagonists of NMDA glutamate receptor,2 agents to treat insulin-independent diabetes,3 and matrix metalloproteinase inhibitors4 There are also compounds possessing antibacterial5 and antiviral6 properties. Scientists have synthesized derivatives of quinoxalin2(1H)-ones that are potent thrombin inhibitors,7 anticancer,8 anxiolytic,9 antiallergic,10 and analgesic and antispastic11 agents. FDA-approved antiasthmatic drug bamaquimast and spasmolytic drug caroverine are worth special mention (Figure 1). Among many synthetic approaches to quinoxalin-2(1H)ones,12–16 direct condensation of 1,2-diaminobenzenes with 2-ketocarboxylic acid is probably the most popular. As a part of our research project aimed at the preparation17 and subsequent functionalization18 of ethyl azolylglyoxylates, herein we report on their use to obtain the correspondingly substituted quinoxalin-2(1H)-ones. First we examined the condensation of various ethyl 2azolylglyoxylates 1a–k with o-phenylenediamine (2a) (Scheme 1, Table 1). O N OEt + H2N Y X N O N HN O Me Table 1 Reaction Compounds 1a–k with o-Phenylenediamine (2a) Product Yield (%) 1a 3a OEt Cl 1b 98 N Me 3b N O N O NH OEt N N 1c N O O SYNTHESIS 2014, 46, 1487–1492 Advanced online publication: 03.04.20140039-78 1 437-210X DOI: 10.1055/s-0033-1340983; Art ID: SS-2012-Z0370-OP © Georg Thieme Verlag Stuttgart · New York NH Cl N Me O N O N Ph 95 N Me O Figure 1 Two marketed drugs bearing the quinoxalin-2(1H)-one fragment: bamaquimast (antiasthmatic agent), caroverine (spasmolytic agent) Indeed, the mode of biological activity of various quinoxalin-2(1H)-ones depends strongly on the nature and position of the substituents. Therefore, the elaboration of novel strategies aimed at the synthesis of diversely substituted quinoxalin-2(1H)-ones is of true practical importance for drug discovery. N N Me bamaquimast NH OEt N O N O N Me caroverine 3 Scheme 1 Reaction of compounds 1a–k with o-phenylenediamine (2a) N O N 2a O N NH X r.t. 92–99% 1 X = N-Alk, S Y = C, N O Y MeCN O Starting material O N NH2 N Ph 3c 95 l This paper is a copy of the author's personal reprint l ▌1487 PAPER PAPER O. V. Geraschenko et al. Table 1 Reaction Compounds 1a–k with o-Phenylenediamine (2a) (continued) Starting material Product O N Yield (%) O N NH OEt N N 94 N O 1d 3d O N O N OEt NH N N O N 3e O N O N Table 2 Reaction of Ketone 1a with o-Phenylenediamines 2b–e NH OEt N N N O O N 92 N Me 1f 3f N R O 99 N Me N NH N OEt Me N 97 Ph Ph 1i 4b N Me NH N O S S O NH H2N O OEt N O N 97 N O O 2d 4c 1j 3j N O N N O 98 O O NH H2N S OEt S N NH2 O NH 91 O O N 95 F 2c NH2 3i N F F N O N F NH N O N O N N 93 NH H2N 3h N N 4a NH2 O O NH 92 N Me O N Yield (%) N 2b N 1h R O N N Me R Me O OEt N 4a–d N NH2 H2N N Me Product 3g N r.t. 84–95% R 2b–e Starting material NH O 1g NH MeCN N N Me O O N OEt N H2N OEt + 1a O N NH2 l This 1e 94 The reaction proceeded smoothly in acetonitrile at room temperature (Table 1). It was slightly exothermic, but no external cooling was required when working on micromolar quantities. Cooling, however, became necessary when working on a molar scale. After mixing both reagents together in acetonitrile, the rapid formation of a precipitate was observed. To complete the transformation, the reaction mixture was stirred at room temperature for an additional 12 h. After recrystallization, all products 3a–k were obtained as solids in excellent yields of 92–98%. To expand the scope of the performed transformation, we next challenged the reaction of the simplest glyoxylate 1a with substituted o-phenylenediamines 2b–e. We used symmetric diamines in order to avoid the formation of stereoisomers. The target products 4a–d were obtained in 84–95% isolated yields (Table 2). Me N O 84 O O 1k 3k Synthesis 2014, 46, 1487–1492 2e is a copy of the author's personal reprint l 1488 4d © Georg Thieme Verlag Stuttgart · New York We also studied the condensation of some glyoxylates 1a,c,e,g with 1,2-diaminocyclohexane (5) (Table 3); products 6a–d were isolated in moderate yields of 40– 85%. It is interesting to note that though 1,2-diaminocyclohexane was used as a 1:1 mixture of cis and trans isomers, the formed products precipitated from the reaction mixture as a single stereoisomer. Presumably, epimerization occurred during the formation of the intermediate Schiff base.19,20 The trans stereoconfiguration of the obtained compounds was determined by X-ray crystallographic analysis of product 6c (Figure 2). Table 3 Reaction of Compounds 1a,c,e,g with 1,2-Diaminocyclohexane (5) O N OEt H N 2 + N O Alk 1a,c,e,g MeCN 40–48% Alk N O 40 N Me 6a O N O N NH OEt N N N O 48 Ph Ph 1c column chromatography silica gel, air NH N N 62% 6c 7 Scheme 2 Synthesis of compound 7 O NH 1a Finally, to demonstrate the practical importance of the developed procedure, we performed the synthesis of compound 8, an analogue of the launched drug caroverine (Figure 1). In fact, alkylation of quinoxalinone 3a with 2chloro-N,N-diethylethylamine in dimethyl sulfoxide using sodium hydride as the base led to a mixture of N- and O-alkylated products, from which the major N-alkylated isomer 8 was isolated by column chromatography in 53% yield (Scheme 3). 6b O N O N OEt N 1e 85 N N N ClCH2CH2NEt2 53% O N N N Me N 8 (analogue of caroverine) Scheme 3 Synthesis of compound 8, an analogue of the launched drug caroverine (Figure 1) O N OEt N N Me N Me 3a 6c O N NH N O O N NH N 1g NH Yield (%) O N N N N O N N 6a–d N OEt Me N Product O O NH r.t. 5 cis/trans = 1:1 Starting material N N NH2 Figure 2 X-ray diffraction structure of compound 6c21 Me O N 45 6d Unexpectedly, attempts to purify product 6c by column chromatography led to aromatization to form compound 7 (Scheme 2). © Georg Thieme Verlag Stuttgart · New York In summary, we have developed a practical approach to novel 3-azolylquinoxalin-2(1H)-ones and their saturated derivatives from 2-azolylglyoxylates 1 and 1,2-diaminobenzenes and -cyclohexanes. The reaction is practical, it proceeds smoothly in acetonitrile at room temperature, it gives products in excellent yields that requires no purification by column chromatography. The conceptual importance of the developed reaction was demonstrated by the preparation of compound 8, an analogue of the launched drug caroverine. Synthesis 2014, 46, 1487–1492 is a copy of the author's personal reprint l 1489 Synthesis of Heterocycles l This PAPER 1 H and 13C NMR spectra were recorded on a Bruker Avance 500 spectrometer at 499.9 MHz and 124.9 MHz, respectively. 19F NMR spectra were recorded on a Varian 400 instrument at 376 MHz. Internal standard from TMS (1H, 13C) and C6F6 (19F). Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument by chemical ionization (CI). 3-Hetarylquinoxalin-2(1H)-ones 3, 4, 6; General Procedure Glyoxylate 1 (10 mmol) was dissolved in MeCN (1 mL). The solution of 1,2-diamine 2 or 5 (10 mmol) in MeCN (20 mL) was added. The mixture was stirred at r.t. overnight. The formed precipitate was filtered off and was washed with MeCN (2 × 10 mL) on the filter. The pure product was obtained by recrystallization (DMF). 3-(1-Methyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3a) White solid; yield: 4.3 g (95%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 3.78 (s, 3 H), 7.07 (s, 1 H), 7.36 (m, 3 H), 7.59 (t, J = 7.2 Hz, 1 H), 7.82 (d, J = 7.3 Hz, 1 H), 12.76 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 34.87, 116.49, 124.13, 124.58, 128.43, 129.36, 131.47, 132.43, 133.29, 142.64, 148.55, 154.43. 13 MS (APCI): m/z = 244 [M + 1]. Anal. Calcd for C12H10N4O: C, 63.71; H, 4.4; N, 24.76. Found: C, 63.94; H, 4.75; N, 24.83. 3-(5-Chloro-1-methyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3b) Yellow solid; yield: 5.2 g (98%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 3.67 (s, 3 H), 7.20 (s, 1 H), 7.36 (s, 2 H), 7.61 (t, J = 7.3 Hz, 1 H), 7.83 (d, J = 7.3 Hz, 1 H), 12.73 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 32.52, 115.95, 119.76, 124.08, 125.76, 129.52, 131.86, 132.11, 133.0, 142.73, 148.78, 154.20. 13 MS (APCI): m/z = 261 [M + 1]. Anal. Calcd for C12H9ClN4O: C, 55.29; H, 3.48; Cl, 13.60; N, 21.49. Found: C, 55.47; H, 3.61; Cl, 13.52; N, 21.68. 3-(1-Benzyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3c) Yellow solid; yield: 3.8 g (95%); mp >200 °C (DMF). 1 H NMR (500 MHz, DMSO-d6): δ = 5.46 (s, 2 H), 7.10–7.17 (m, 3 H), 7.21 (m, 1 H), 7.23–7.29 (m, 2 H), 7.34 (s, 2 H), 7.43 (s, 1 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.75 (d, J = 7.2 Hz, 1 H), 12.67 (s, 1 H). C NMR (125 MHz, DMSO-d6): δ = 50.77, 116.34, 123.47, 123.88, 124.18, 127.79, 127.97, 128.86, 128.93, 129.25, 131.55, 132.27, 133.13, 138.15, 142.19, 154.36. 13 H NMR (500 MHz, DMSO-d6): δ = 4.84 (s, 2 H), 5.01 (d, J = 16.9 Hz, 1 H), 5.09(d, J = 10.1 Hz, 1 H), 5.97 (m, 1 H), 7.11 (s, 1 H), 7.36 (s, 3 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.81 (d, J = 7.5 Hz, 1 H), 12.70 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 49.85, 116.29, 117.91, 123.30, 124.17, 128.68, 129.35, 131.56, 132.32, 133.21, 134.86, 142.12, 149.04, 154.40. 13 MS (APCI): m/z = 253 [M + 1]. Anal. Calcd for C14H12N4O: C, 66.66; H, 4.79; N, 22.21. Found: C, 66.92; H, 4.85; N, 22.15. 3-(1-Butyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3f) Brown solid; yield: 3.5 g (92%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 0.82 (t, J = 7.4 Hz, 3 H), 1.23 (m, J = 7.1 Hz, 2 H), 1.70 (m, J = 6.7 Hz, 2 H), 4.15 (m, 2 H), 7.09 (s, 1 H), 7.38 (s, 2 H), 7.42 (s, 1 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.80 (d, J = 7.5 Hz, 1 H), 12.63 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 13.88, 19.66, 33.20, 47.07, 115.62, 123.43, 124.25, 126.09, 128.47, 129.23, 131.46, 132.51, 133.51, 141.95, 154.50. 13 MS (APCI): m/z = 269 [M + 1]. Anal. Calcd for C15H16N4O: C, 67.15; H, 6.01; N, 20.88. Found: C, 67.31; H, 6.25; N, 21.05. 3-(1-Methyl-1H-benzimidazol-2-yl)quinoxalin-2(1H)-one (3g) Brown solid; yield: 4.7 g (99%); mp >200 °C (DMF). 1 H NMR (500 MHz, DMSO-d6): δ = 3.87 (s, 3 H), 7.30 (t, J = 7.0 Hz, 1 H), 7.36–7.43 (m, 3 H), 7.66 (d, J = 7.6 Hz, 2 H), 7.73 (d, J = 7.3 Hz, 1 H), 7.90 (d, J = 7.3 Hz, 1 H), 12.84 (s, 1 H). C NMR (125 MHz, DMSO-d6): δ =31.68, 111.10, 116.31, 120.17, 122.72, 123.80, 124.27, 129.80, 132.35, 133.30, 136.22, 142.71, 148.54, 149.82, 154.45, 154.46. 13 MS (APCI): m/z = 277 [M + 1]. Anal. Calcd for C16H12N4O: C, 69.55; H, 4.38; N, 20.28. Found: C, 69.72; H, 4.53; N, 20.22. 3-(2-Methyl-2H-1,2,4-triazol-3-yl)quinoxalin-2(1H)-one (3h) Yellow solid; yield: 3.8 g (92%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 3.94 (s, 3 H), 7.37–7.41 (m, 2 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 8.01 (s, 1 H), 12.87 (s, 1 H). 1 13 C NMR (125 MHz, DMSO-d6): δ = 37.36, 116.16, 124.24, 129.80, 132.10, 132.55, 133.25, 148.05, 149.99, 150.96, 153.95. MS (APCI): m/z = 303 [M + 1]. MS (APCI): m/z = 228 [M + 1]. Anal. Calcd for C18H14N4O: C, 71.51; H, 4.67; N, 18.53. Found: C, 71.75; H, 4.95; N, 18.71. Anal. Calcd for C11H9N5O: C, 58.15; H, 3.99; N, 30.82. Found: C, 58.32; H, 4.11; N, 30.76. 3-(1-Vinyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3d) Brown solid; yield: 4.2 g (94%); mp >200 °C (DMF). 3-(2-Benzyl-2H-1,2,4-triazol-3-yl)quinoxalin-2(1H)-one (3i) Yellow solid; yield: 4.4 g (97%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 4.87 (d, J = 8.3 Hz, 1 H), 5.50 (d, J = 15.4 Hz, 1 H), 7.18 (s, 1 H), 7.24 (m, 1 H), 7.34–7.38 (m, 2 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.89 (s, 1 H), 12.71 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 102.56, 116.09, 118.26, 124.05, 129.57, 129.99, 130.95, 131.91, 132.24, 133.19, 142.07, 149.16, 154.50. 13 MS (APCI): m/z = 239 [M + 1]. Anal. Calcd for C13H10N4O: C, 65.54; H, 4.23; N, 23.52. Found: C, 65.81; H, 4.38; N, 23.68. 3-(1-Allyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3e) Brown solid; yield: 3.1 g (94%); mp >200 °C (DMF). Synthesis 2014, 46, 1487–1492 H NMR (500 MHz, DMSO-d6): δ = 5.52 (s, 2 H), 7.25 (m, 3 H), 7.30 (m, 2 H), 7.38 (m, 2 H), 7.66 (t, J = 7.3 Hz, 1 H), 7.82 (d, J = 7.3 Hz, 1 H), 8.15 (s, 1 H), 12.86 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 53.16, 116.18, 124.26, 128.20, 128.45, 128.85, 129.74, 132.03, 132.63, 133.31, 136.70, 148.02, 150.02, 151.43, 154.0. 13 MS (APCI): m/z = 304 [M + 1]. Anal. Calcd for C17H13N5O: C, 67.32; H, 4.32; N, 23.09. Found: C, 67.40; H, 4.38; N, 23.17. 3-(4-Methylthiazol-2-yl)quinoxalin-2(1H)-one (3j) Black solid; yield: 5.7 g (97%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 2.51 (s, 3 H), 7.40 (m, 2 H), 7.60 (m, 2 H), 7.94 (d, J = 7.8 Hz, 1 H), 12.96 (s, 1 H). 1 © Georg Thieme Verlag Stuttgart · New York is a copy of the author's personal reprint l PAPER O. V. Geraschenko et al. l This 1490 MS (APCI): m/z = 244 [M + 1]. Anal. Calcd for C12H9N3OS: C, 59.24; H, 3.73; N, 17.27; S, 13.18. Found: C, 59.43; H, 3.85; N, 17.23; S, 13.22. 3-Benzothiazol-2-ylquinoxalin-2(1H)-one (3k) Black solid; yield: 4.9 g (98%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 7.44 (m, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 8.01 (d, J = 8.1 Hz, 1 H), 8.22 (m, 2 H), 13.08 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 116.14, 122.68, 124.36, 124.65, 126.80, 127.18, 130.16, 132.56, 132.68, 132.82, 137.16, 147.81, 152.89, 154.34, 160.48. 13 MS (APCI): m/z = 280 [M + 1]. Anal. Calcd for C15H9N3OS: C, 64.50; H, 3.25; N, 15.04; S, 11.48. Found: C, 64.72; H, 3.48; N, 15.12; S, 11.64. 6,7-Dimethyl-3-(1-methyl-1H-imidazol-2-yl)quinoxalin-2(1H)one (4a) Yellow solid; yield: 3.4 g (93%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 2.32 (s, 3 H), 2.35 (s, 3 H), 3.79 (s, 3 H), 7.07 (s, 1 H), 7.16 (s, 1 H), 7.35 (s, 1 H), 7.60 (s, 1 H), 12.66 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 19.43, 20.38, 34.86, 116.80, 124.39, 128.15, 129.03, 131.21, 131.71, 133.14, 141.40, 142.81, 146.93, 154.57. 13 MS (APCI): m/z = 255 [M + 1]. 1491 H NMR (500 MHz, DMSO-d6): δ = 2.18 (m, J = 5.1 Hz, 2 H), 3.80 (s, 3 H), 4.20 (t, J = 5.1 Hz, 2 H), 4.28 (t, J = 5.1 Hz, 2 H), 6.94 (s, 1 H), 7.08 (s, 1 H), 7.36 (s, 1 H), 7.41 (s, 1 H), 12.63 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 31.58, 34.98, 71.29, 71.38, 107.84, 120.44, 124.55, 127.97, 128.94, 130.57, 142.61, 145.87, 148.62, 154.41, 154.97. 13 MS (APCI): m/z = 299 [M + 1]. Anal. Calcd for C15H14N4O3: C, 60.40; H, 4.73; N, 18.78. Found: C, 60.53; H, 4.85; N, 18.67. 3-(1-Methyl-1H-imidazol-2-yl)-4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one (6a) White solid; yield: 2.4 g (40%); mp >200 °C (DMF). 1 H NMR (500 MHz, DMSO-d6): δ = 1.25–1.46 (m, 4 H), 1.71 (m, 1 H), 1.78 (m, 1 H), 1.95 (m, 1 H), 2.23 (m, 1 H), 3.14 (m, 1 H), 3.25 (m, 1 H), 3.68 (s, 3 H), 6.94 (s, 1 H), 7.23 (s, 1 H), 8.60 (s, 1 H). C NMR (125 MHz, DMSO-d6): δ = 23.75, 25.23, 30.65, 31.87, 34.48, 53.83, 63.06, 123.96, 127.93, 142.36, 156.05, 156.61. 13 MS (APCI): m/z = 233 [M + 1]. Anal. Calcd for C12H16N4O: C, 62.05; H, 6.94; N, 24.12. Found: C, 62.27; H, 7.11; N, 24.18. 3-(1-Benzyl-1H-imidazol-2-yl)-4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one (6b) White solid; yield: 2.9 g (48%); mp >200 °C (DMF). 1 H NMR (500 MHz, DMSO-d6): δ = 1.20–1.42 (m, 4 H), 1.68 (m, 1 H), 1.75 (m, 1 H), 1.91 (m, 1 H), 2.19 (m, 1 H), 2.97 (m, 1 H), 3.18 (m, 1 H), 5.30 (d, J = 15.2 Hz, 1 H), 5.30 (d, J = 15.2 Hz, 1 H), 7.00 (s, 1 H), 7.18 (m, 2 H), 7.25–7.36 (m, 4 H), 8.56 (s, 1 H). Anal. Calcd for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found: C, 66.30; H, 5.68; N, 22.18. 13 6,7-Difluoro-3-(1-methyl-1H-imidazol-2-yl)quinoxalin-2(1H)one (4b) Grey solid; yield: 3.6 g (95%); mp >200 °C (DMF). MS (APCI): m/z = 309 [M + 1]. C NMR (125 MHz, DMSO-d6): δ = 23.71, 25.17, 30.58, 31.81, 50.22, 53.71, 62.93, 123.26, 127.98, 128.01, 128.32, 128.92, 138.08, 142.0, 156.02, 156.51. 1 H NMR (500 MHz, DMSO-d6): δ = 3.91 (s, 3 H), 7.14 (s, 1 H), 7.43 (m, 2 H), 7.95 (s, 1 H), 13.24 (s, 1 H). Anal. Calcd for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C, 70.29; H, 6.72; N, 18.09. C NMR (125 MHz, DMSO-d6): δ = 35.51, 105.84, 116.47, 116.61, 125.51, 128.09, 129.73, 132.17, 142.03, 147.12 (d, JCF = 260.3 Hz), 151.57 (dd, JCF = 252.1 Hz, 3JCF = 14.5 Hz), 154.62. 3-(1-Allyl-1H-imidazol-2-yl)-4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one (6c) White solid; yield: 8.2 g (85%); 90% purity. The analytical sample was obtained by crystallization (DMF); mp >200 °C (DMF). 13 F NMR (376 MHz, DMSO-d6): δ = –142.24 (br s, 1 F), –132.20 (m, 1 F). 19 MS (APCI): m/z = 263 [M + 1]. Anal. Calcd for C12H8F2N4O: C, 54.97; H, 3.08; N, 21.37. Found: C, 55.13; H, 3.27; N, 21.45. 8-(1-Methyl-1H-imidazol-2-yl)-2,3-dihydro[1,4]dioxino[2,3g]quinoxalin-7(6H)-one (4c) Black solid; yield: 3.8 g (91%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 3.83 (s, 3 H), 4.32 (s, 2 H), 4.38 (s, 2 H), 6.85 (s, 1 H), 7.09 (s, 1 H), 7.30 (s, 1 H), 7.36 (s, 1 H), 12.53 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 35.08, 64.30, 65.22, 103.37, 115.29, 124.52, 127.69, 128.23, 129.71, 141.60, 142.69, 144.26, 147.63, 154.42. 13 MS (APCI): m/z = 285 [M + 1]. Anal. Calcd for C14H12N4O3: C, 59.15; H, 4.25; N, 19.71. Found: C, 59.34; H, 4.36; N, 19.62. 3-(1-Methyl-1H-imidazol-2-yl)-8,9-dihydro-7H-[1,4]dioxepino[2,3-g]quinoxalin-2(1H)-one (4d) Black solid; yield: 2.9 g (84%); mp >200 °C (DMF). © Georg Thieme Verlag Stuttgart · New York H NMR (500 MHz, DMSO-d6): δ = 1.22–1.45 (m, 4 H), 1.72 (m, 1 H), 1.77 (m, 1 H), 1.96 (m, 1 H), 2.25 (m, 1 H), 3.12 (m, 1 H), 3.23 (m, 1 H), 4.68 (dd, 2J = 15.6 Hz, 3J = 5.2 Hz, 1 H), 4.78 (dd, 2J = 15.6 Hz, 3J = 5.2 Hz, 1 H), 5.05 (d, J = 17.2 Hz, 1 H), 5.14 (d, J = 10.1 Hz, 1 H), 5.91 (m, 1 H), 6.98 (s, 1 H), 7.24 (s, 1 H), 8.58 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 23.54, 25.20, 30.64, 31.85, 53.77, 55.49, 63.02, 117.94, 122.75, 128.11, 134.68, 141.93, 156.54, 159.09. 13 MS (APCI): m/z = 259 [M + 1]. Anal. Calcd for C14H18N4O: C, 65.09; H, 7.02; N, 21.69. Found: C, 65.27; H, 7.24; N, 21.50. 3-(1-Allyl-1H-imidazol-2-yl)-5,6,7,8-tetrahydroquinoxalin2(1H)-one (7) Compound 6c (100 mg) was dissolved in MeOH (5mL) and silica gel (5 g) was added. The solvent was evaporated in vacuo. The solid was transferred into to the column charged with silica gel (tBuOMe). Evaporation of the solvent afforded the pure compound 7 as a brown solid; yield: 52 mg (62%); mp 85 °C. H NMR (500 MHz, CDCl3): δ = 1.88 (m, 4 H), 2.83 (m, 2 H), 2.86 (m, 2 H), 5.11 (d, J = 16.7 Hz, 1 H), 5.20 (d, J = 10 Hz, 1 H), 5.35 (d, J = 5.5 Hz, 2 H), 6.02 (m, 1 H), 7.0 (s, 1 H), 7.10 (s, 1 H), 13.90 (s, 1 H). 1 Synthesis 2014, 46, 1487–1492 is a copy of the author's personal reprint l C NMR (125 MHz, DMSO-d6): δ = 17.42, 116.03, 120.87, 124.44, 129.75, 131.52, 132.16, 132.66, 147.28, 153.89, 154.14, 158.08. 13 Synthesis of Heterocycles l This PAPER C NMR (125 MHz, CDCl3): δ = 22.21, 22.59, 30.52, 31.43, 50.54, 117.35, 122.26, 125.17, 126.99, 133.13, 141.40, 142.35, 149.38, 156.97. 13 MS (APCI): m/z = 257 [M + 1]. Anal. Calcd for C14H16N4O: C, 65.61; H, 6.29; N, 21.86. Found: C, 65.74; H, 6.38; N, 21.79. 3-(1-Methyl-1H-benzimidazol-2-yl)-4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one (6d) White solid; yield: 2.6 g (45%); mp >200 °C (DMF). H NMR (500 MHz, DMSO-d6): δ = 1.21–1.49 (m, 4 H), 1.72 (m, 1 H), 1.79 (m, 1 H), 1.99 (m, 1 H), 2.29 (m, 1 H), 3.27 (m, 1 H), 3.41 (m, 1 H), 3.82 (s, 3 H), 7.28 (t, J = 7.7 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.60 (d, J = 7.7 Hz, 1 H), 7.69 (d, J = 7.7 Hz, 1 H), 8.80 (s, 1 H). 1 C NMR (125 MHz, DMSO-d6): δ = 23.17, 25.27, 30.67, 31.43, 31.71, 53.92, 63.50, 111.01, 120.06, 122.63, 123.65, 135.96, 142.36, 148.25, 156.52, 156.78. 13 MS (APCI): m/z = 283 [M + 1]. Anal. Calcd for C16H18N4O: C, 68.06; H, 6.43; N, 19.84. Found: C, 68.21; H, 6.57; N, 19.72. 1-[2-(Diethylamino)ethyl]-3-(1-methyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (8) NaH (80 mg, 60% in mineral oil, 2 mmol) was added to a solution of 3a (226.2 mg, 1 mmol) in DMSO (5 mL). After stirring the mixture for 1 h at r.t., 2-chloro-N,N-diethylethylamine hydrochloride (172.1 mg, 1 mmol) was added. The mixture was stirred overnight at r.t. for 12 h. It was then poured into H2O (100 mL) and extracted with EtOAc (2 × 20 mL). The organic layer was washed with brine, dried (Na2SO4), and evaporated under vacuum. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane–EtOAc, 1:1) to give 8 (172 mg, 0.53 mol, 53%) as an yellow oil. H NMR (500 MHz, CDCl3): δ = 1.07 (t, J = 6.7 Hz, 6 H), 2.67 (q, J = 6.7 Hz, 4 H), 2.80 (t, J = 7.5 Hz, 2 H), 3.91 (s, 3 H), 4.40 (t, J = 7.5 Hz, 2 H), 7.02 (s, 1 H), 7.23 (s, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.42 (d, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.88 (d, J = 7.8 Hz, 1 H). 1 13 C NMR (125 MHz, CDCl3): δ = 11.95, 35.52, 41.16, 47.61, 49.29, 113.73, 123.72, 124.16, 129.51, 130.68, 131.18, 132.66, 132.86, 142.29, 146.55, 153.43. MS (APCI): m/z = 326 [M + 1]. Anal. Calcd for C18H23N5O: C, 66.44; H, 7.12; N, 21.52. Found: C, 66.58; H, 7.30; N, 21.63. Acknowledgement All authors are grateful to Dr. Oleg Lozinski for help with the manuscript preparation. Synthesis 2014, 46, 1487–1492 Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis.SnoumIfrpigtSa References (1) Carta, A.; Piras, S.; Loriga, G.; Paglietti, G. Mini-Rev. Med. Chem. 2006, 6, 1179; and references therein. (2) Nikam, S. S.; Bigge, C. F. Drugs Future 1999, 24, 1107. (3) Hyae-Gyeong, C.; Chul-Min, L.; Beom-Tae, K.; Ki-jun, H. Bioorg. Med. Chem. Lett. 2004, 14, 2661. (4) Xun, L.; Yonggang, L.; Wenfang, X.; Jian, Z.; Huawei, Z. Bioorg. Med. Chem. 2010, 18, 1516. (5) El-Sabbagh, O. I.; El-Sadek, M. E.; Lashine, S. M.; Yassin, S. H.; El-Nabtity, S. M. Med. Chem. Res. 2009, 18, 782. (6) Patel, M.; Mchugh, R. J.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Trainor, G. L.; Rodgers, J. D. Bioorg. Med. Chem. 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