A Robust Protocol for the Synthesis of Quinoxalines and 5H-Benzo[e][1,4]di­azepines via the Acidless Ugi Reaction

Abstract

Concise two-step, one-pot protocols for the syntheses of quinoxalines and 5H-benzo[e][1,4]diazepines are reported. An ‘acidless’ Ugi reaction followed by a Boc-deprotection–cyclization sequence is shown to produce arrays of both functionalized scaffolds in good yield. Mono-N-Boc-protected diamines are employed to access quinoxalines and an analogous benzylic amine affords access to 5H-benzo[e][1,4]diazepines in conjunction with supporting reagents in the ‘acidless’ Ugi reaction. Both methodologies are robust, straightforward, and allow installation of at least three points of diversity in the resulting scaffolds.

Key words

multicomponent reaction - combinatorial chemistry - Ugi - quinoxalines - benzodiazepines

• References and Notes

• 1a Ugi I. Angew. Chem., Int. Ed. Engl. 1962; 1: 8
• 1b Marcaccini S, Torroba T. Nat Protoc. 2007; 2: 632
• 2a Hulme C, Gore V. Curr. Med. Chem. 2003; 10: 51
• 2b Tempest P. Curr. Opin. Drug Discovery Devel. 2005; 8: 776
• 2c Ruijter E, Orru RV. A. Drug Discovery Today Technol. 2013; 10: e15
• 2d Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
• 2e Slobbe P, Ruijter E, Orru RV. A. Med. Chem. Commun. 2012; 3: 1189
• 2f Akritopoulou-Zanze I. Curr. Opin. Chem. Biol. 2008; 12: 324
• 3 Trost B. Science 1991; 254: 1471
• 4a Banfi L, Basso A. Synthesis of Heterocycles via Multicomponent Reactions I. In Topics in Heterocyclic Chemistry. Orru RV. A, Ruijter E. Springer; Berlin Heidelberg: 2010: 1-39
• 4b Kalinski C, Lemoine H, Schmidt J, Burdack C, Kolb J, Umkehrer M, Ross G. Synthesis 2008; 4007
• 4c Zhu J. Eur. J. Org. Chem. 2003; 1133
• 5a Hulme C, Dietrich J. Mol. Diversity 2009; 13: 195
• 5b Ayaz M, De Moliner F, Dietrich J, Hulme C In Isocyanide Chemistry: Applications of Isocyanides in IMCRs for the Rapid Generation of Molecular Diversity. Wiley-VCH; Weinheim: 2012: 335-384
• 5c Dömling A. Chem. Rev. 2006; 106: 17
• 5d Hulme C, Peng J, Louridas B, Menard P, Krolikowski P, Kumar NV. Tetrahedron Lett. 1998; 39: 8047
• 5e Hulme C, Peng J, Tang S, Burns CJ, Morize I, Labaudiniere R. J. Org. Chem. 1998; 63: 8021
• 5f Rhoden CR. B, Rivera DG, Kreye O, Bauer AK, Westermann B, Wessjohann LA. J. Comb. Chem. 2009; 11: 1078
• 6 Pan SC, List B. Angew. Chem. Int. Ed. 2008; 47: 3622
• 7 El Kaïm L, Grimaud L In Isocyanide Chemistry: Ugi and Passerini Reactions with Carboxylic Acid Surrogates. Wiley-VCH; Weinheim: 2012: 159-194
• 8a Xu Z, De Moliner F, Cappelli AP, Ayaz M, Hulme C. Synlett 2014; 25: 225
• 8b Shaw AY, McLaren JA, Nichol GS, Hulme C. Tetrahedron Lett. 2012; 53: 2592
• 9 Xu Z, De Moliner F, Cappelli AP, Hulme C. Angew. Chem. Int. Ed. 2012; 51: 8037
• 10a Oble J, El Kaïm L, Gizzi M, Grimaud L. Heterocycles 2007; 73: 503
• 10b Krasavin M, Parchinsky V. Synlett 2008; 645
• 10c Heravi MM, Baghernejad B, Oskooie HA. Tetrahedron Lett. 2009; 50: 767
• 10d Ayaz M, Dietrich J, Hulme C. Tetrahedron Lett. 2011; 52: 4821
• 10e Martinez-Ariza G, Ayaz M, Hulme C. Tetrahedron Lett. 2013; 54: 6719
• 11a Attanasi OA, De Crescentini L, Favi G, Mantellini F, Nicolini S. J. Org. Chem. 2011; 76: 8320
• 11b Wasserman HH, Long YO, Parr J. Tetrahedron Lett. 2003; 44: 361
• 11c Randles KR, Storr RC. J. Chem. Soc., Chem. Commun. 1984; 22: 1485
• 12a Fonseca T, Gigante B, Marques MM, Gilchrist TL, De Clercq E. Bioorg. Med. Chem. 2004; 12: 103
• 12b Zarranz B, Jaso A, Aldana I, Monge A, Maurel S, Deharo E, Jullian V, Sauvain M. Arzneimittelforsch. Drug Res. 2011; 55: 754
• 12c Gazit A, Yee K, Uecker A, Böhmer F, Sjöblom T, Östman A, Waltenberger J, Golomb G, Banai S, Heinrich MC, Levitzki A. Bioorg. Med. Chem. 2003; 11: 2007
• 13a Bauer A, Danneberg P, Weber KH, Minck K. J. Med. Chem. 1973; 16: 1011
• 13b Sternbach LH. J. Med. Chem. 1979; 22: 1
• 13c Aastha P, Navneet K, Anshu A, Pratima S, Dharma K. Res. J. Chem. Sci. 2013; 3: 90
• 14 Preparation of Quinoxaline 10c; Typical Procedure 4-Fluorophenylglyoxaldehyde (1.0 equiv, 1.0 mmol, 152 mg) and tert-butyl (2-aminophenyl)carbamate (1.0 equiv, 1.0 mmol, 208 mg) were combined in CH₂Cl₂ (2 mL). n-Butyl isocyanide (1.0 equiv, 1.0 mmol, 83 mg, 0.104 mL) and phenylphosphinic acid (0.1 equiv, 0.1 mmol, 14 mg) were added, and the reaction was stirred for 16 h at r.t. The progress of the reaction was monitored by LC–MS and TLC. Upon completion, the solvent was evaporated in vacuo, the residue was dissolved in 20% TFA–DCE (3.0 mL), and the reaction mixture was heated in a microwave (Biotage Initiator^TM) at 140 °C for 20 min. The reaction was allowed to cool to r.t. at which time the mixture was diluted with EtOAc (15 mL), and the organic layer was washed with sat. aq NaHCO₃ (2 × 20 mL) and brine (2 × 20 mL). The organic phase was dried over MgSO₄ and concentrated under reduced pressure, and the crude was purified by flash chromatography (hexane–EtOAc, 0–100%) using an ISCO™ purification system to afford N-butyl-3-(4-fluorophenyl)quinoxaline-2-carboxamide as a beige solid (155 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃): δ = 8.18–8.06 (m, 2 H), 7.96–7.66 (m, 4 H), 7.55 (s, 1 H), 7.16 (m, 2 H), 3.48–3.43 (m, 2 H), 1.68–1.53 (m, 2 H), 1.50–1.34 (m, 2 H), 0.96 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.5, 162.2, 152.6. 144.9, 142.3, 139.2, 134.5, 131.6, 130.9, 130.7, 130.5, 129.2, 129.1, 115.2, 115.0, 39.5. 31.5, 20.1, 13.7. ESI-MS: m/z = 324 [M + H]⁺.
• 15 Preparation of 5H-Benzo[e][1,4]diazepine 13b; Typical Procedure 3-Bromophenylglyoxaldehyde (1.0 equiv, 1.0 mmol, 213 mg) and tert-butyl 2-aminobenzylcarbamate (1.0 equiv, 1.0 mmol, 223 mg) were combined in CH₂Cl₂ (2 mL). 2-Isocyano-1,3-dimethylbenzene (1.0 equiv, 1.0 mmol, 131 mg) and phenylphosphinic acid (0.1 equiv, 0.1 mmol, 14 mg) were added, and the reaction was stirred for 16 h at r.t. while regularly monitoring the reaction progress by LC–MS and TLC. Upon completion, the solvent was evaporated in vacuo, the residue was dissolved in 20% TFA–DCE (3.0 mL), and the reaction mixture was heated in microwave at 140 °C for 20 min. After cooling the reaction to r.t., the reaction mixture was diluted with EtOAc (15 mL), and the organic layer was washed with sat. aq NaHCO₃ (2 × 20 mL) and brine (2 × 20 mL). The organic phase was dried over MgSO₄ and concentrated under reduced pressure, and the crude was purified by flash chromatography (hexane–EtOAc, 0–100%) using an ISCO™ purification system to afford 3-(3-bromophenyl)-N-(2,6-dimethylphenyl)-5H-benzo[e][1,4]diazepine-2-carboxamide as a yellow solid (250 mg, 56% yield). ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (br s, 1 H), 7.99–7.96 (m, 1 H), 7.83–7.81(m, 1 H), 7.61–7.53 (m, 2 H), 7.50–7.44 (m, 1 H), 7.41 (dd, J = 7.7, 1.5 Hz, 1 H), 7.37–7.28 (m, 2 H), 7.10–6.98 (m, 3 H), 4.88 (d, J = 10.5 Hz, 1 H), 4.01 (d, J = 10.5 Hz, 1 H), 2.15 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.4, 160.5, 155.6, 147.2, 139.9, 135.2, 133.7, 132.7, 130.2, 130.1, 129.2, 128.6, 128.2, 128.1, 127.6, 127.4, 126.8, 125.7, 122.8, 54.4, 18.6. ESI-MS: m/z = 446 [M + H]⁺.