ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 6, pp. 890–893. © Pleiades Publishing, Ltd., 2010. Original Russian Text © O.V. Kushnir, M.V. Vovk, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 6, pp. 894–897.
Heterocyclizations of Functionalized Heterocumulenes with C,N-, C,O-, and C,S-Binucleophiles: XII.* Synthesis of Alkyl 3-Aryl-1,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylates O. V. Kushnira and M. V. Vovkb a b
Fed’kovich Chernovtsy National University, Chernovtsy, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02660 Ukraine e-mail:
[email protected] Received June 9, 2009
Abstract—Alkyl 3-oxo-1,2,3,4-tetrahydroquinoxalin-2-ylideneacetates reacted with α-chlorobenzyl isocyanates to give alkyl 3-aryl-1,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylates.
DOI: 10.1134/S1070428010060187 Alkyl 3-oxo-1,2,3,4-tetrahydroquinoxalin-2-ylideneacetates Ia and Ib are preparatively accessible polyfunctionalized compounds [2, 3] and are important as building blocks in heterocyclic chemistry. The enamino fragment therein was successfully involved in both functionalization of the quinoxaline ring [4–6] and synthesis of fused quinoxaline derivatives. Synthetic approaches to the latter are based on reactions with mono- and difunctional electrophilic reagents, which make it possible to obtain furo[2,3-b]quinoxaline [4, 7], pyrrolo[1,2-a]quinoxaline [8, 9], and pyrido[1,2-a]quinoxaline derivatives [3, 10]; many of these compounds exhibited pronounced pharmacological activity [10–14]. On the other hand, structurally related pyrimido[1,6-a]quinoxaline heterocyclic system remains so far poorly studied. We have found only one publication on the synthesis of 1H-pyrimido[1,6-a]quinoxaline-1,3(2H)-dione 3-oxime via Curtius rearrangement of 2-(hydroxyimino)-3-(quinoxalin-2-yl)propanoyl azide [15]. Taking into account previously revealed general relations holding in the formation of partly hydrogenated pyrimidine ring by condensation of deactivated enamines with α-chlorobenzyl isocyanates [16, 17], in the present work we made an attempt to use the latter for the preparation of polyfunctional pyrimido[1,6-a]quinoxaline derivatives. Quinoxalinones Ia and Ib reacted with α-chlorobenzyl isocyanates ІІa–IIe on heating in boiling meth* For communication XI, see [1].
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ylene chloride to give alkyl 3-aryl-1,5-dioxo-2,3,5,6tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylates ІІІa–IIIi in 51–73% yield. Most probably, the reaction involves benzylidenecarbamic chloride form [18] of α-chlorobenzyl isocyanates ІІ, which adds at the exocyclic carbon atom in quinoxaline I with formation of intermediate A. The latter undergo intramolecular cyclization as a result of attack by the chlorocarbamoyl group on the enamino nitrogen atom (Scheme 1). The reaction in toluene at room temperature in the presence of an organic base was less effective. The yield of the target products was sharply reduced due to considerable tarring. Presumably, the reaction under these conditions was accompanied by side condensation with participation of the NHC(O) fragment in the quinoxaline ring. Compound Іa is known to react with common alkyl isocyanates to give products of C-carbamoylation of the methoxycarbonylmethylene fragment, which are then converted into 3-carbamoylfuro[2,3-b]quinoxalines via intramolecular condensation of the 3-methoxycarbonylmethylene fragment with the carbonyl group in position 2 of the heteroring [19]. The structure of compounds ІІІa–IIIi was confirmed by the IR and 1H and 13C NMR spectra, and their purity was checked by GC–MS. In the IR spectra of ІІІa–IIIi we observed absorption bands typical of stretching vibrations of amide (1635–1650 cm–1 ), ureide (1695–1705 cm–1), and ester carbonyl groups
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Scheme 1. H N
O
Cl
O
+ Ar
OAlk
N H
N
·
Cl
O Ar
Ia, Ib
N
O
IIa–IIe
H N
O
N O H Cl
H OAlk N H
H N
O
O
A
O
N
–HCl
Ar
O
OAlk N H
Ar
IIIa–IIIi
І, Alk = Me (a), Et (b); ІІ, Ar = Ph (a), 2-FC6H4 (b), 3-BrC6H4 (c), 4-O2NC6H4 (d), 3,4-Cl2C6H3 (e); ІІІ, Alk = Me, Ar = Ph (a), 2-FC6H4 (b), 3-BrC6H4 (c), 4-O2NC6H4 (d), 3,4-Cl2C6H3 (e); Alk = Et, Ar = Ph (f), 2-FC6H4 (g), 3-BrC6H4 (h), 3,4-Cl2C6H3 (i).
(1735–1750 cm–1), as well as of N–H groups (3220– 3245 cm–1). The 1H NMR spectra of ІІІa–IIIi contained doublets from the 3-H and 2-H protons in the regions δ 5.13–5.37 and 8.51–8.81 ppm, respectively, the coupling constant 3J2, 3 being equal to 2.0–4.5 Hz. The C3 signal appeared in the 13C NMR spectra in the region δC 52–61 ppm, which is typical of 3,4-dihydropyrimidinones [17]. EXPERIMENTAL The IR specta were recorded in KBr on a UR-20 spectrometer. The 1 H and 13 C NMR spectra were measured from solutions in DMSO-d 6 on a Bruker Av a n c e D R X - 5 0 0 s p e c t r o me t e r ( 5 0 0 . 1 3 a n d 125.75 MHz, respectively) using tetramethylsilane as internal reference. The mass spectra were obtained on an Agilent 1100/DAD/HSD/VLG 119562 instrument. Initial α-chlorobenzyl isocyanates ІIa–IIe were synthesized according to the procedure described in [17] . Alkyl 3-aryl-1,5-dioxo-2,3,5,6-tetrahydro-1Hpyrimido[1,6-a]quinoxaline-4-carboxylates ІІІa–IIIi (general procedure). α-Chlorobenzyl isocyanate ІІa– IIe, 2.5 mmol, was added to a solution of 2.5 mmol of quinoxaline Іa or Ib in 20 ml of methylene chloride, and the mixture was heated for 3 h under reflux. The mixture was cooled, and the precipitate was filtered off, dried, and recrystallized from ethanol. Methyl 1,5-dioxo-3-phenyl-2,3,5,6-tetrahydro1H-pyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІa). Yield 58%, mp 276–278°C. IR spectrum, ν, cm–1: 3220 (NH); 1745, 1700, 1645 (C=O). 1H NMR spectrum, δ, ppm: 3.68 s (3H, CH3), 5.14 d (1H, 3-H,
J = 2.0 Hz), 7.03–7.10 m (3H, Harom), 7.31–7.43 m (5H, Harom), 7.81 d (1H, Harom, J = 6.5 Hz), 8.59 d (1H, 2-H, J = 2.0 Hz), 11.22 s (1H, 6-H). 13C NMR spectrum, δC, ppm: 52.29 (CH3), 54.29 (C3), 115.86 (C4), 116.91, 120.88, 122.56, 123.25, 124.08, 125.93, 126.77, 128.19, 128.31, 128.86 (Carom), 139.86 (C4a), 151.24 (C1), 155.97 (C5), 168.98 (4-C=O). Mass spectrum: m/z 350 [M + 1]+. Found, %: C 65.81; H 4.18; N 11.89. C19H15N3O4. Calculated, %: C 65.32; H 4.33; N 12.03. M 349.3. Methyl 3-(2-fluorophenyl)-1,5-dioxo-2,3,5,6tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylate (IIІb). Yield 51%, mp 268–270°C. IR spectrum, ν, cm–1: 3230 (NH); 1745, 1705, 1640 (C=O). 1 H NMR spectrum, δ, ppm: 3.63 s (3H, CH3), 5.37 d (1H, 3-H, J = 3.6 Hz), 7.02–7.36 m (7H, Harom), 7.86 d (1H, Harom, J = 6.9 Hz), 8.51 d (1H, 2-H, J = 3.6 Hz), 11.23 s (1H, 6-H). 13C NMR spectrum, δC, ppm: 49.82 (CH3), 52.28 (C3), 115.23 (C4), 115.88, 120.82, 122.64, 123.30, 124.08, 125.09, 126.69, 126.84, 127.80, 128.54, 130.48 (Carom), 130.54 (C4a), 151.17 (C1), 155.85 (C5), 159.35 d (C–F, J = 246.5 Hz), 166.65 (4-C=O). Mass spectrum: m/z 368 [M + 1] + . Found, %: C 61.81; H 3.68; N 11.57. C 19 H 14 FN 3 O 4 . Calculated, %: C 62.12; H 3.84; N 11.44. M 367.3. Methyl 3-(3-bromophenyl)-1,5-dioxo-2,3,5,6tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІc). Yield 63%, mp 285–288°C. IR spectrum, ν, cm–1: 3230 (NH); 1750, 1695, 1645 (C=O). 1 H NMR spectrum, δ, ppm: 3.70 s (3H, CH3), 5.19 d (1H, 3-H, J = 2.0 Hz), 6.99–7.05 m (3H, Harom), 7.16– 7.51 m (4H, H arom), 7.79 d (1H, H arom, J = 6.6 Hz), 8.62 d (1H, 2-H, J = 2.0 Hz), 11.21 s (1H, 6-H).
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C NMR spectrum, δ, ppm: 52.34 (CH3), 53.40 (C3), 115.92 (C4), 116.01, 120.92, 121.95, 122.55, 123.10, 124.18, 125.01, 126.84, 128.38, 128.71, 129.09, 131.06 (Carom), 142.55 (C4a), 151.18 (C1), 155.91 (C5), 166.79 (4-C=O). Mass spectrum: m/z 429 [M + 1]+. Found, %: C 53.03; H 3.38; N 9.89. C19H14Br N3O4. Calculated, %: C 53.29; H 3.30; N 9.81. M 428.2. Methyl 3-(4-nitrophenyl)-1,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІd). Yield 60%, mp 295–296°C. IR spectrum, ν, cm–1: 3225 (NH); 1750, 1705, 1650 (C=O). 1H NMR spectrum, δ, ppm: 3.70 s (3H, CH3), 5.36 d (1H, 3-H, J = 4.5 Hz), 6.97–7.02 m (3H, Harom), 7.63–7.81 m (3H, Harom), 8.16 d (1H, Harom, J = 8.7 Hz), 8.30 s (1H, Harom), 8.81 d (1H, 2-H, J = 4.5 Hz), 11.29 s (1H, 6-H). 13 C NMR spectrum, δC, ppm: 52.10 (CH3), 52.51 (C3), 115.45 (C4), 115.87, 121.05, 123.04, 123.76, 124.08, 128.81, 130.16, 131.22, 135.18, 135.98 (Carom), 140.33 (C4a), 149.87 (C1), 154.05 (C5), 165.62 (4-C=O). Mass spectrum: m/z 394 [M + 1] + . Found, %: C 58.08; H 3.41; N 14.00. C19H14N4O4. Calculated, %: C 57.87; H 3.58; N 14.21. M 394.3. Methyl 3-(3,4-dichlorophenyl)-1,5-dioxo-2,3,5,6tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІe). Yield 73%, mp 287–288°C. IR spectrum, ν, cm–1: 3240 (NH); 1735, 1700, 1640 (C=O). 1 H NMR spectrum, δ, ppm: 3.68 s (3H, CH3), 5.19 d (1H, 3-H, J = 4.2 Hz), 6.97–7.03 m (3H, Harom), 7.32 d (1H, H arom, J = 7.2 Hz), 7.55–7.61 m (2H, H arom), 7.76 d (1H, Harom, J = 7.5 Hz), 8.68 d (1H, 2-H, J = 4.2 Hz), 11.26 s (1H, 6-H). 13C NMR spectrum, δC, ppm: 52.85 (CH3), 53.08 (C3), 115.63 (C4), 115.93, 121.12, 121.87, 122.58, 123.90, 124.64, 125.31, 127.29, 128.43, 128.80, 129.66, 131.92 (Carom), 141.85 (C4a), 151.44 (C1), 155.77 (C5), 166.35 (4-C=O). Mass spectrum: m/z 418 [M + 1]+. Found, %: C 54.79; H 3.18; N 9.91. C 19 H 13 Cl 2 N 3 O 4 . Calculated, %: C 54.56; H 3.13; N 10.05. M 418.2. Ethyl 1,5-dioxo-3-phenyl-2,3,5,6-tetrahydro-1Hpyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІf). Yield 55%, mp 298–300°C. IR spectrum, ν, cm–1: 3220 (NH); 1750, 1700, 1645 (C=O). 1H NMR spectrum, δ, ppm: 1.19 t (3H, CH3, J = 6.5 Hz), 4.14 d (1H, CH2, J = 6.5 Hz), 5.13 d (1H, 3-H, J = 2.5 Hz), 6.99–7.03 m (3H, Harom), 7.31–7.39 m (5H, Harom), 7.80 d (1H, Harom, J = 7.0 Hz), 8.57 d (1H, 2-H, J = 2.5 Hz), 11.21 s (1H, 6-H). 13C NMR spectrum, δC, ppm: 13.61 (CH3), 54.44 (CH2), 60.91 (C3), 115.82 (C4), 117.34, 120.86, 122.55, 123.29, 124.05, 125.93, 126.79, 127.97, 128.18, 128.82 (Carom), 139.85 (C4a), 151.27 (C1), 155.98 (C5), 166.38
(4-C=O). Mass spectrum: m/z 364 [M + 1]+. Found, %: C 65.89; H 4.58; N 11.69. C20H17N3O4. Calculated, %: C 66.11; H 4.72; N 11.56. M 363.4. Ethyl 3-(2-fluorophenyl)-1,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІg). Yield 58%, mp 280–282°C. IR spectrum, ν, cm–1: 3230 (NH); 1745, 1705, 1645 (C=O). 1H NMR spectrum, δ, ppm: 1.16 t (3H, CH3, J = 6.5 Hz), 4.12 d (1H, CH2, J = 6.5 Hz), 5.37 d (1H, 3-H, J = 3.5 Hz), 7.03–7.39 m (7H, H arom ), 7.91 d (1H, H arom , J = 7.2 Hz), 8.47 d (1H, 2-H, J = 3.5 Hz), 11.21 s (1H, 6-H). 13C NMR spectrum, δC, ppm: 13.54 (CH3), 49.91 (CH2), 60.87 (C3), 115.38 (C4), 115.84, 120.79, 123.34, 124.04, 125.04, 126.71, 126.89, 127.81, 128.15, 130.45 (Carom), 130.58 (C4a), 151.19 (C1), 155.88 (C5), 159.32 d (C–F, J = 244.8 Hz), 166.98 (4-C=O). Mass spectrum: m/z 382 [M + 1]+. Found, %: C 63.21; H 4.28; N 10.87. C 20 H 16 FN 3 O 4 . Calculated, %: C 62.99; H 4.23; N 11.02. M 381.4. Ethyl 3-(3-bromophenyl)-1,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІh). Yield 65%, mp 294–296°C. IR spectrum, ν, cm–1: 3240 (NH); 1750, 1700, 1645 (C=O). 1H NMR spectrum, δ, ppm: 1.22 t (3H, CH3, J = 6.5 Hz), 4.17 d (1H, CH2, J = 6.5 Hz), 5.21 d (1H, 3-H, J = 3.0 Hz), 7.00–7.06 m (3H, Harom), 7.34 m (1H, Harom), 7.55– 7.60 m (2H, H arom), 7.80 d (1H, H arom, J = 7.6 Hz), 8.66 d (1H, 2-H, J = 3.0 Hz), 11.25 s (1H, 6-H). 13 C NMR spectrum, δ C , ppm: 13.49 (CH 3 ), 51.74 (CH2), 53.55 (C3), 115.73 (C4), 115.77, 120.90, 121.84, 122.65, 123.18, 124.03, 125.12, 126.69, 128.48, 128.72, 129.03, 131.15 (C arom), 142.54 (C 4a), 151.06 (C 1 ), 155.94 (C5), 166.63 (4-C=O). Mass spectrum: m/z 442 [M + 1] + . Found, %: C 54.07; H 3.58; N 9.39. C 20 H 16 BrN 3 O 4 . Calculated, %: C 54.32; H 3.65; N 9.50. M 442.3. Ethyl 3-(3,4-dichlorophenyl)-1,5-dioxo-2,3,5,6tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІi). Yield 68%, mp 284–286°C. IR spectrum, ν, cm–1: 3245 (NH); 1740, 1700, 1635 (C=O). 1 H NMR spectrum, δ, ppm: 1.22 t (3H, CH 3 , J = 6.5 Hz), 4.17 d (1H, CH2, J = 6.5 Hz), 5.21 d (1H, 3-H, J = 3.0 Hz), 7.00–7.06 m (3H, H arom), 7.34 m (1H, Harom), 7.55–7.60 m (2H, Harom), 7.80 d (2H, Harom, J = 7.6 Hz), 8.66 d (1H, 2-H, J = 3.0 Hz), 11.25 s (1H, 6-H). 13C NMR spectrum, δC, ppm: 13.40 (CH3), 51.67 (CH2), 53.18 (C3), 115.65 (C4), 115.98, 121.10, 121.67, 122.58, 123.96, 124.69, 125.21, 127.30, 128.48, 128.81, 129.70, 131.96 (C arom), 141.88 (C 4a), 151.45 (C 1 ), 155.72 (C5), 166.44 (4-C=O). Mass spectrum: m/z 433
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[M + 1] + . Found, %: C 55.69; H 3.63; N 9.51. C 19 H 13 Cl 2 N 3 O 4 . Calculated, %: C 55.57; H 3.50; N 9.72. M 432.3. REFERENCES 1. Vovk, M.V., Kushnir, O.V., Sukach, V.A., and Tsymbal, I.F., Russ. J. Org. Chem., 2010, vol. 46, p. 709. 2. Kawahara, N., Nakajima, T., Itoh, T., and Ogura, H., Heterocycles, 1983, vol. 20, p. 1721. 3. Kawahara, N., Shimamori, T., Itoh, T., Takayanagi, H., and Ogura, H., Chem. Pharm. Bull., 1987, vol. 35, p. 457. 4. Kurasawa, Y., Moritaki, Y., Ebukuro, T., and Takada, A., Chem. Pharm. Bull., 1983, vol. 31, p. 3897. 5. Kurasawa, Y., Muramatsu, M., Hotehama, K., Okamoto, K., and Takada, A., J. Heterocycl. Chem., 1985, vol. 22, p. 1711. 6. Arai, K., Okamoto, Y., and Takada, A., J. Heterocycl. Chem., 1987, vol. 24, p. 1229. 7. Kurasawa, Y. and Takada, A., Chem. Pharm. Bull., 1981, vol. 29, p. 2871. 8. Maslivets, A.N., Golovnina, O.V., Krasnykh, O.P., and Aliev, Z.G., Khim. Geterotsikl. Soedin., 2000, p. 113. 9. Maslivets, A.N., Aliev, Z.G., Krasnykh, O.P., Golovnina, O.V., and Atovmyan, L.O., Khim. Geterotsikl. Soedin., 2004, p. 1501.
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