A Short Preparation of Pyrroloquinoxalinones via a Cascade Reaction of N-Aryl-5-alkylamino-2-nitrosoanilines with Methyl 2-Cyanoalkanoates: Unexpected Direction of Nucleophilic Substitution of Hydrogen

Abstract

N-Aryl-2-nitrosoanilines possessing 5-alkylamino groups undergo a bisheteroannulation reaction with anions of 2-cyanoalkanecarboxylates resulting in pyrroloquinoxalinone derivatives. The cascade reaction involves condensation of the cyanoester anions with the nitroso group, unusual nucleophilic substitution of hydrogen in the nitrosoaniline-derived intermediate with the second carbanion molecule, and double intramolecular acylation of the amino functions.

Key words

carbanions - condensation - heterocycles - annulation - nucleophilic aromatic substitution

• References and Notes

• 1 Nicolaou KC, Edmonds DJ, Bulger PG. Angew. Chem. Int. Ed. 2006; 45: 7134
• 2a Wróbel Z, Kwast A. Synlett 2007; 1525
• 2b Wróbel Z, Kwast A. Synthesis 2010; 3865
• 3a Mąkosza M. Chem. Soc. Rev. 2010; 39: 2855
• 3b Mąkosza M, Wojciechowski K. Chem. Rev. 2004; 104: 2631
• 3c Mąkosza M. Synthesis 2011; 2341
• 4 Kwast A, Stachowska K, Trawczyński A, Wróbel Z. Tetrahedron Lett. 2011; 6484
• 5 Wróbel Z, Stachowska K, Grudzień K, Kwast A. Synlett 2011; 1439
• 6 Wróbel Z, Stachowska K, Kwast A, Gościk A, Królikiewicz M, Pawłowski R, Turska I. Helv. Chim. Acta 2013;
• 7 Królikiewicz M, Wróbel Z. J. Heterocycl. Chem. 2013; in press
• 8 Analytical Data for Representative New Products Compound 3e: yellow crystals; mp 246 °C (dec.; hexane–EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 1.24 (s, 9 H), 2.54 (s, 3 H), 4.15 (s, 1 H), 5.77 (d, J = 2.1 Hz, 1 H), 6.59 (dd, J = 9.2, 2.1 Hz, 1 H), 7.26-7.29 (m, 2 H), 7.58–7.61 (m, 2 H), 8.17 (d, J = 9.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 11.7, 29.4, 51.4, 97.7, 112.3, 121.5, 122.6, 130.1, 130.5, 134.6, 134.8, 135.4, 135.9, 149.5, 157.2. ESI-MS: m/z = 380 [M + Na]⁺, 358 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₉H₂₁N₃O₂ ³⁵Cl [M + H]⁺: 358.1322; found: 358.1234. Compound 4a: white crystals; mp 179–180 °C (hexane–EtOAc). IR (KBr): 2236 (CN), 1755, 1672, 1621 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.17 (t, J = 7.4 Hz, 3 H), 1.35 (t, J = 7.4 Hz, 3 H), 2.38–2.45 (m, 2 H), 2.46 (s, 3 H), 2.96 (q, J = 7.4 Hz, 2 H), 3.64 (s, 3 H), 3.78 (s, 3 H), 6.11 (s, 1 H), 7.14–7.18 (m, 1 H), 7.38–7.43 (m, 1 H), 7.92 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 9.7, 10.8, 21.3, 27.1, 28.5, 50.0, 54.5, 56.0, 97.7, 118.1, 120.6, 126.9, 127.7, 127.8, 128.6, 130.9, 131.0, 132.9, 135.8, 139.7, 154.8, 156.9, 160.4, 168.7. MS (EI): m/z 420 (16), 419 (57), 390 (10), 361 (27), 360 (100), 333 (12). HRMS (EI): m/z calcd for C₂₄H₂₅N₃O₄: 419.1845; found: 419.1841. Compound 6b: yellow crystals; mp 148–151 °C (hexane–EtOAc). IR (KBr): 2241 (CN), 1731, 1670, 1627 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (t, J = 7.4 Hz, 3 H), 1.36 (t, J = 7.4 Hz, 3 H), 1.51 (s, 9 H), 2.18–2.30 (m, 2 H), 2.93–3.02 (m, 2 H), 6.51 (s, 1 H), 7.25–7.29 (m, 2 H), 7.61–7.65 (m, 2 H), 7.85 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 8.0, 10.5, 27.0, 28.7, 31.6, 47.2, 59.3, 99.9, 117.0, 121.6, 124.9, 128.3, 129.5, 129.6, 130.6, 130.7, 134.2, 135.0, 135.8, 144.1, 154.4, 160.9, 170.9. MS (EI): m/z (%) = 450 (16), 449 (17), 448 (34), 395 (15), 394 (47), 393 (40), 392 (100), 365 (17), 364 (19), 363 (27), 337 (21), 336 (20), 335 (43). HRMS (EI): m/z calcd for C₂₅H₂₅N₄O₂Cl: 448.1666; found: 448.1687.

Some illustrative examples:
• 9a Shuman RT, Ornstein PL, Paschal JW, Gesellchen PD. J. Org. Chem. 1990; 55: 738
• 9b Yousif MM, Saeki S, Hamana M. Chem. Pharm. Bull. 1982; 30: 2326
• 9c Tagawa Y, Nomura M, Yamashita H, Goto Y, Hamana M. Heterocycles 1999; 51: 2385
• 9d Yousif MM, Saeki S, Hamana M. J. Heterocycl. Chem. 1980; 17: 305
• 9e Douglass JE, Gebhart MA. J. Heterocycl. Chem. 1990; 27: 1433
• 10 Witanowski M, Stefaniak L, Webb GA. Nitrogen NMR Spectroscopy, In Annual Reports on NMR Spectroscopy . Webb GA. Academic Press; London: 1982: 1-486 Part B, Vol. 11
• 11a Fife TH, Duddy NW. J. Am. Chem. Soc. 1983; 105: 74
• 11b RajanBabu TV, Chenard BL, Petti MA. J. Org. Chem. 1986; 51: 1704
• 11c Karp GM, Condon ME. J. Heterocycl. Chem. 1994; 31: 1513
• 11d Tichenor MS, Kastrinsky DB, Boger DL. J. Am. Chem. Soc. 2004; 26: 8396
• 12 General Procedure for the Synthesis of Pyrrolo-quinoxalinones 6a–j 5-Amino-N-aryl-2-nitrosoaniline (0.5 mmol) and methyl 2-cyanoalkanoate (1.1 mmol) were dissolved in dry MeCN (5 mL). DBU (0.4 mL, 2.68 mmol) was added in one portion, and the mixture was stirred at r.t. for the time specified in Table 2. The mixture was poured into sat. NH₄Cl (10 mL) and H₂O (10 mL), extracted with EtOAc (3 × 20 mL), dried with Na₂SO₄, and the crude product was chromatographed.
• 13a Aurich G. Chem. Ber. 1965; 98: 3917
• 13b Mąkosza M, Jagusztyn-Grochowska M, Ludwikow M, Jawdosiuk M. Tetrahedron 1974; 30: 3723
• 13c Jawdosiuk M, Ostrowska B, Mąkosza M. J. Chem. Soc. D 1971; 548
• 14a Conant JB, Fieser LF. J. Am. Chem. Soc. 1924; 46: 1858
• 14b Pethig BR, Gascoyne PR. C, Mclaughlin JA, Szent-Gyorgyi A. Proc. Natl. Acad. Sci. U.S.A. 1983; 80: 129
• 15 Ritzmann G, Ienaga K, Kiriasis L. Chem. Ber. 1980; 113: 1535