Photochemistry of ortho-Azidocinnamoyl Derivatives: Facile and Modular Synthesis of 2-Acylated Indoles and 2-Substituted Quinolines under Solvent Control

Abstract

The light-promoted potential of ortho-azidocinnamoyl compounds is evaluated for heterocycle synthesis. Depending on the nature of the solvent, 2-acylated indoles were obtained under aprotic conditions, whereas the use of a protic medium led to 2-substituted quinolines. The synthetic significance of this metal-free method is that, by simply changing the solvent, the reaction outcome can be directed towards different key heterocyclic scaffolds.

Key words

photochemistry - azides - indoles - quinolines - nitrenes - solvent effect - rearrangement

• References and Notes

• 1 S.C. and N.M.P. contributed equally to this work.
• 2 Bräse S. Banert K. Organic Azides: Syntheses and Applications . Wiley; Chichester: 2010

For recent reviews dealing with the CuAAC reaction, see:
• 3a Li L. Zhang Z. Molecules 2016; 21: 1393/1
• 3b Chassaing S. Bénéteau V. Pale P. Catal. Sci. Technol. 2016; 6: 923
• 3c Haldon E. Nicasio MC. Perez PJ. Org. Biomol. Chem. 2015; 13: 9528
• 3d Sokolova NV. Nenadjenko VG. RSC Adv. 2013; 3: 16212
• 3e Ganesh V. Sudhi VS. Kundu T. Chandrasekaran S. Chem. Asian J. 2011; 6: 2670
• 3f Hein JE. Fokin VV. Chem. Soc. Rev. 2010; 39: 1302
• 4a Wentrup C. Chem. Rev. 2017; 117: 4562
• 4b Gras E. Chassaing S. In Organic Reaction Mechanisms, 2013 . Knipe AC. Wiley; Chichester: 2016: 177
• 4c Shin K. Kim H. Chang S. Acc. Chem. Res. 2015; 48: 1040
• 4d Gras E. Chassaing S. In Organic Reaction Mechanisms, 2012 . Knipe AC. Wiley; Chichester: 2015: 171
• 4e Intrieri D. Zardi P. Caselli A. Gallo E. Chem. Commun. 2014; 50: 11440
• 4f Gras E. Chassaing S. In Organic Reaction Mechanisms, 2011 . Knipe AC. Wiley; Chichester: 2014: 199
• 4g Jewett JC. Bertozzi CR. Chem. Soc. Rev. 2010; 39: 1272
• 4h Lang S. Murphy JA. Chem. Soc. Rev. 2006; 35: 146
• 4i Lang S. Murphy JA. ACS Chem. Biol. 2006; 1: 644
• 4j Abraham H.-W. In Synthetic Organic Photochemistry . Griesbeck AG. Mattay J. Marcel Dekker; New York: 2004: 391
• 4k Bräse S. Gil C. Knepper K. Zimmermann V. Angew. Chem. Int. Ed. 2005; 44: 5188
• 4l Scriven EF. V. Turnbull K. Chem. Rev. 1988; 88: 297
• 4m L’abbe G. Chem. Rev. 1969; 69: 345

For examples of bioactive indole-based compounds, see:
• 5a Ishikura M. Abe T. Choshi T. Hibino S. Nat. Prod. Rep. 2015; 32: 1389
• 5b Ishikura M. Abe T. Choshi T. Hibino S. Nat. Prod. Rep. 2013; 30: 694
• 5c Ishikura M. Yamada K. Abe T. Nat. Prod. Rep. 2010; 27: 1630
• 5d Kochanowska-Karamyan AJ. Hamann MT. Chem. Rev. 2010; 110: 4489

For examples of bioactive quinoline-based compounds, see:
• 6a Froehlich T. Tsogoeva SB. J. Med. Chem. 2016; 59: 9668
• 6b Hussaini SM. A. Exp. Opin. Ther. Pat. 2016; 26: 1201
• 6c Afzal O. Kumar S. Haider MR. Kumar R. Jaggi M. Bawa S. Eur. J. Med. Chem. 2015; 97: 871
• 6d Vandekerckhove S. D’hooghe M. Bioorg. Med. Chem. 2015; 23: 5098
• 6e Prajapati SM. Patel KD. Vekariya RH. Panchal SN. Patel HD. RSC Adv. 2014; 4: 24463
• 6f Kumar S. Bawa S. Gupta H. Mini-Rev. Med. Chem. 2009; 9: 1648
• 7a Kong C. Jana N. Jones C. Driver TG. J. Am. Chem. Soc. 2016; 138: 13271
• 7b Alt IT. Plietker B. Angew. Chem. Int. Ed. 2016; 55: 1519
• 7c Goriya Y. Ramana CV. Chem. Commun. 2014; 50: 7790
• 7d Stokes BJ. Liu S. Driver TG. J. Am. Chem. Soc. 2011; 133: 4702
• 7e Liu Y. Wei J. Che C.-M. Chem. Commun. 2010; 46: 6926
• 8a Li Z. Wang W. Zhang X. Hu C. Zhang W. Synlett 2013; 24: 73
• 8b Gairns RS. Moody CJ. Rees CW. J. Chem. Soc., Perkin Trans. 1 1986; 501

For synthetic methods towards quinolines involving iminophosphoranes as alternative intermediates, see:
• 9a Kim HJ. Jeong EM. Lee K.-J. J. Heterocycl. Chem. 2011; 48: 965
• 9b Han E.-G. Kim HJ. Lee K.-J. Tetrahedron 2009; 65: 9616
• 9c Luheshi A.-BN. Salem SM. Smalley RK. Kennewell PD. Westwood R. Tetrahedron Lett. 1990; 31: 6561
• 10a Chaabouni S. Simonet F. François A. Abid S. Galaup C. Chassaing S. Eur. J. Org. Chem. 2017; 271
• 10b Veau D. Krykun S. Mori G. Orena BS. Pasca MR. Frongia C. Lobjois V. Chassaing S. Lherbet C. Baltas M. ChemMedChem 2016; 11: 1078
• 11 For details on methods for preparing cinnamoylated azides 1a–k from commercially available ortho-nitrobenzaldehydes, see the Supporting Information.
• 12 The bench-top light source we used was the LUMOS 43^® marketed by Atlas Photonics.
• 13 In spite of the crude products giving clean ¹H NMR spectra, the fact that the yields are not higher could be explained by the formation of polymeric by-products due to rearrangement processes involving the highly reactive nitrene.

For representative examples dealing with photoaffinity labeling using azides, see:
• 14a Lord SJ. Lee H.-L. Samuel R. Weber R. Liu N. Conley NR. Thompson MA. Twoeg RJ. Moerner WE. J. Phys. Chem. B 2010; 114: 14157
• 14b Voskresenska V. Wilson RM. Panov M. Tarnovsky AN. Krause JA. Vyas S. Winter AH. Hadad CM. J. Am. Chem. Soc. 2009; 131: 11535
• 14c Cline MR. Mandel SM. Platz MS. Biochemistry 2007; 46: 1981
• 14d Chehade KA. H. Spielmann HP. J. Org. Chem. 2000; 65: 4949
• 15 Typical Procedure: In a quartz tube under argon were successively added ortho-azidocinnamoyl derivative 1a–k and the appropriate solvent to give a concentration of 3.2 mM. The resulting mixture was then irradiated using either the LUMOS 43^® (1.5 h stirring time with CH₂Cl₂ as solvent) or a conventional tungsten lamp [6 h stirring time with EtOH–H₂O (1:1) as solvent], as light sources. After evaporation of the solvent, purification of the crude product by column chromatography, eluting with an appropriate cyclohexane–EtOAc mixture, furnished the desired photocyclized products 2a–k or 3/4 in pure form.
• 16 Analytical Data for 2,3-Diacetyl-6-N,N-dimethylamino-1H-indole (2k, Scheme [2]): Orange solid; mp 176–179 °C; R_f 0.40 (cyclohexane–EtOAc, 70:30). FTIR (ATR, neat): 3322, 2921, 1670 (C=O), 1311 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 9.30 (br s, 1 H, NH), 7.65 (d, J = 9.2 Hz, 1 H), 6.87 (dd, J = 2.3, 9.2 Hz, 1 H), 6.53 (d, J = 2.3 Hz, 1 H), 3.02 (s, 6 H), 2.76 (s, 3 H), 2.62 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 197.8, 191.4, 150.0, 137.3, 132.4, 122.6, 122.1, 117.9, 112.2, 92.4, 40.8, 32.1, 28.7. MS (DCI, +): m/z (%) = 245 (100) [M + H]⁺. HRMS (DCI, +): m/z [M + H]⁺ calcd for C₁₄H₁₇N₂O₂: 245.1290; found: 245.1289.
• 17 Analytical Data for 2-Methyl-3-acetyl-7-N,N-dimethylaminoquinoline (3k, Scheme [3]): Orange-red solid; mp 118–121 °C; R_f 0.23 (cyclohexane–EtOAc, 70:30). FTIR (ATR, neat): 2925, 1666 (C=O), 1616, 1511, 1422 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 8.34 (s, 1 H), 7.66 (d, J = 9.0 Hz, 1 H), 7.12 (dd, J = 2.5, 9.0 Hz, 1 H), 7.05 (d, J = 2.5 Hz, 1 H), 3.13 (s, 6 H), 2.88 (s, 3 H), 2.65 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 198.9, 158.9, 152.9, 150.3, 138.7, 129.4, 126.4, 117.7, 115.6, 105.6, 40.3, 28.7, 26.2. MS (DCI, +): m/z (%) = 229 (100) [M + H]⁺. HRMS (DCI, +): m/z [M + H]⁺ calcd for C₁₄H₁₇N₂O: 229.1341; found: 229.1347.