Facile Synthesis of 2-Arylindoles through Plancher-Type Rearrangement of 3-Alkyl-3-Arylindolenines

Abstract

3-Alkylindoles on reaction with a cyclohexa-2,4-dien-1-one catalyzed by BF₃·OEt₂ gave the corresponding 3-alkyl-3-arylindolenines in high yields through a tandem Michael addition/aromatization sequence. In the presence of HCl, these indolenine derivatives underwent a facile Plancher-type C-3 to C-2 aryl rearrangement to deliver the corresponding 2-arylindoles.

Key words

arylindoles - indolenines - Plancher rearrangement - cyclohexadienone - tandem reaction

• References and Notes

• 1a Kaushik NK. Kaushik N. Attri P. Kumar N. Kim CH. Verma AK. Choi EH. Molecules 2013; 18: 6620
• 1b Sharma V. Kumar P. Pathak D. J. Heterocycl. Chem. 2010; 47: 491
• 2a Vicente R. Org. Biomol. Chem. 2011; 9: 6469
• 2b Taber DF. Tirunahari PK. Tetrahedron 2011; 67: 7195
• 2c Patil NT. Yamamoto Y. Chem. Rev. 2008; 108: 3395
• 2d Humphrey GR. Kuethe JT. Chem. Rev. 2006; 106: 2875
• 3a Djakovitch L. Batail N. Genelot M. Molecules 2011; 16: 5241
• 3b Simonetti M. Cannas DM. Panigrahi A. Kujawa S. Kryjewski M. Xie P. Larrosa I. Chem. Eur. J. 2017; 23: 549
• 4a Lebrasseur N. Larrosa I. Adv. Heterocycl. Chem. 2012; 105: 309
• 4b Joucla L. Djakovitch L. Adv. Synth. Catal. 2009; 351: 673
• 5 Rossi R. Lessi M. Manzini C. Marianetti G. Bellina F. Tetrahedron 2016; 72: 1795
• 6a Xu H. Mini-Rev. Org. Chem. 2009; 6: 367
• 6b Monnier F. Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 6954
• 6c Old DW. Harris MC. Buchwald SL. Org. Lett. 2000; 2: 1403
• 6d Hartwig JF. Kawatsura M. Hauck SI. Shaughnessy KH. Alcazar-Roman LM. J. Org. Chem. 1999; 64: 5575

For metal free N-arylations see:
• 6e Xu H. Fan L.-L. Z. Naturforsch., B 2008; 63: 298
• 6f Smith WJ. III. Sawyer JS. Heterocycles 1999; 51: 157
• 6g Maiorana S. Baldoli C. Del Buttero P. Di Ciolo M. Papagni A. Synthesis 1998; 735

For C3-arylation, see:
• 7a Vásquez-Céspedes S. Chepiga KM. Möller N. Schäfer AH. Glorius F. ACS Catal. 2016; 6: 5954
• 7b Pitts AK. O’Hara F. Snell RH. Gaunt MJ. Angew. Chem. Int. Ed. 2015; 54: 5451
• 7c Phipps RJ. Grimster NP. Guant MJ. J. Am. Chem. Soc. 2008; 130: 8172

For C2-arylation, see
• 7d Duan L. Fu R. Zhang B. Shi W. Chen S. Wan Y. ACS Catal. 2016; 6: 1062
• 7e Malmgren J. Nagendiran A. Tai C.-W. Bäckvall J.-E. Olofsson B. Chem. Eur. J. 2014; 20: 13531
• 7f Ibañez S. Oresmaa L. Estevan F. Hirva P. Sanaú M. Úbeda MA. Organometallics 2014; 33: 5378
• 7g Tang D.-TD. Collin KD. Ernst JB. Glorius F. Angew. Chem. Int. Ed. 2014; 53: 1809
• 7h Deprez NR. Kalyani D. Krause A. Sanford MS. J. Am. Chem. Soc. 2006; 128: 4972

For C3-arylation, see:
• 8a Joucla L. Batail N. Djakovitch L. Adv. Synth. Catal. 2010; 352: 2929
• 8b Bellina F. Benelli F. Rossi R. J. Org. Chem. 2008; 73: 5529
• 8c Zhang Z. Hu Z. Yu Z. Lei P. Chi H. Wang Y. He R. Tetrahedron Lett. 2007; 48: 2415

For C2-arylation, see Ref. 8 (a) and:
• 8d Lane BS. Brown MA. Sames D. J. Am. Chem. Soc. 2005; 127: 8050
• 8e Wang X. Lane BS. Sames D. J. Am. Chem. Soc. 2005; 127: 4996
• 8f Xu Z. Xu Y. Lu H. Yang T. Lin X. Shao L. Ren F. Tetrahedron 2015; 71: 2616
• 8g Islam S. Larrosa I. Chem. Eur. J. 2013; 19: 15093

For C3-arylation, see:
• 9a Yamaguchi K. Kondo H. Yamaguchi J. Itami K. Chem. Sci. 2013; 4: 3753

For C2-arylation, see:
• 9b Yang S.-D. Sun C.-L. Fang Z. Li B.-J. Li Y.-Z. Shi Z.-J. Angew. Chem. Int. Ed. 2008; 47: 1473
• 9c Zhang L. Li P. Liu C. Yang J. Wang M. Wang L. Catal. Sci. Technol. 2014; 4: 1979
• 10 For C2-arylation, see: Zhao J. Zhang Y. Cheng K. J. Org. Chem. 2008; 73: 7428
• 11 For C2-arylation, see: Li Z. Zhou H. Xu J. Wu X. Yao H. Tetrahedron 2013; 69: 3281
• 12 For C2-arylation, see: Liang Z. Yao B. Zhang Y. Org. Lett. 2010; 12: 3185
• 13 For C2-arylation, see: Liu C. Ding L. Guo G. Liu W. Yang F.-L. Org. Biomol. Chem. 2016; 14: 2824
• 14 For C2-arylation, see: Miao T. Li P. Wang G.-W. Wang L. Chem. Asian J. 2013; 8: 3185
• 15a Ye Y. Wang H. Fan R. Synlett 2011; 923
• 15b Yadav JS. Reddy BV. S. Shankar KS. Swamy T. Premalatha K. Bull. Korean Chem. Soc. 2008; 29: 1418
• 15c Hsieh MF. Rao PD. Liao C.-C. Chem. Commun. 1999; 1441

For the synthesis of 3-arylindoles by ClO₄/SiO₂ catalyzed reaction of cyclohexa-2,4-dien-1-ones and 3-unsubstituted indoles, see:
• 15d Chittimalla SK. Bandi C. Putturu S. Kuppusamy R. Boellaard KC. Tan DC. A. Lum DM. J. Eur. J. Org. Chem. 2014; 2565
• 16 Parumala SK. R. Peddinti RK. Org. Lett. 2013; 15: 3546
• 17 See Supporting Information.

For indole C-3 to C-2 alkyl migration furnishing 2-alkylated indoles see:
• 18a Wu Q.-F. Zhen C. Zhuo C.-X. You S.-L. Chem. Sci. 2016; 7: 4453
• 18b Mari M. Lucarini S. Bartoccini F. Piersanti G. Spadoni G. Beilstein J. Org. Chem. 2014; 10: 1991
• 18c Bajtos B. Yu M. Zhao H. Pagenkopf BL. J. Am. Chem. Soc. 2007; 129: 9631

For indole C-3 to C-2 aryl migration furnishing 2-arylindole derivatives see:
• 18d Chai Z. Chen J.-N. Liu Z. Li X.-F. Yang P.-J. Hu J.-P. Yang G. Org. Biomol. Chem. 2016; 14: 1024
• 18e Zhu S. MacMillan DW. C. J. Am. Chem. Soc. 2012; 134: 10815

For indole C-3 arylation with masked; p-benzoquinones see:
• 18f Shu C. Liao L.-H. Liao Y.-J. Hu X.-Y. Zhang Y.-H. Yuan W.-C. Zhang X.-M. Eur. J. Org. Chem. 2014; 4467
• 19 BF₃·OEt₂-Catalyzed Reaction of a Cyclohexadienone and an Alkylindole; Typical Procedure BF₃·OEt₂ (0.067 mL, 0.54 mmol) was added to a stirred solution of cyclohexadienone 1a (100 mg, 0.54 mmol) and skatole (2a; 71 mg, 0.54 mmol) in CH₂Cl₂ (2.0 mL) at –78 °C, and the mixture was stirred at –78 °C for 3 h. MeOH (2 mL) was added and the mixture was stirred for 30 min. The solvent was removed by rotary evaporation, and the crude residue was purified by flash column chromatography (silica gel, 0–30% EtOAc–hexanes) to give 3aa (62 mg, 27%), 3aa′′ (55 mg, 24%) and 3aa′ (30 mg, 13%), along with inseparable mixture of other uncharacterized products. 2,3-Dimethoxy-5-(3-methyl-1H-indol-2-yl)phenol (3aa) ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (br s, 1 H), 7.60–7.57 (m, 1 H), 7.37–7.34 (m, 1 H), 7.24–7.18 (m, 1 H), 7.17–7.12 (m, 1 H), 6.82 (d, J = 2.0 Hz, 1 H), 6.68 (d, J = 2.0 Hz, 1 H), 5.89 (br, s 1 H), 3.97 (s, 3 H), 3.93 (s, 3 H), 2.46 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 152.5 (C), 149.5 (C), 135.7 (C), 135.0 (C), 133.8 (C), 130.0 (C), 129.4 (C), 122.3 (CH), 119.5 (CH), 118.9 (CH), 110.6 (CH), 108.5 (C), 107.6 (CH), 104.0 (CH), 61.1 (CH₃), 56.0 (CH₃), 9.7 (CH₃). ESI-MS: m/z = 284 [C₁₇H₁₇NO₃ + H]⁺. 2,3-Dimethoxy-5-(3-methyl-3H-indol-3-yl)phenol (3aa′) ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (s, 1 H), 7.66 (app d, J = 8.0 Hz, 1 H), 7.40–7.34 (m, 1 H), 7.28–7.27 (m, 2 H), 6.56 (d, J = 2.0 Hz, 1 H), 5.79, (s, 1 H), 6.12 (d, J = 2.0 Hz, 1 H), 3.86 (s, 3 H), 3.73 (s, 3 H), 1.68 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 178.1 (CH), 154.3 (C), 152.5 (C), 149.6 (C), 144.5 (C), 135.0 (C), 134.0 (C), 128.1 (CH), 126.7 (CH), 122.5 (CH), 121.4 (CH), 106.4 (CH), 102.1 (CH), 61.1 (CH₃), 60.8 (C), 55.8 (CH₃), 20.2 (CH₃). ESI-MS: m/z = 284 [C₁₇H₁₇NO₃ + H]⁺. 2,3-Dimethoxy-5-(3-methyl-1H-indol-1-yl)phenol (3aa′′) ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.56 (m, 2 H), 7.25–7.14 (m, 2 H), 7.09 (app q, J = 1.2 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 6.60 (d, J = 2.4 Hz, 1 H), 5.93 (s, 1 H), 3.96 (s, 3 H), 3.89 (s, 3 H), 2.38 (d, J =1.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 152.8 (C), 149.8 (C), 136.2 (C), 136.0 (C), 133.7 (C), 129.7 (C), 125.5 (CH), 122.3 (CH), 119.7 (CH), 119.2 (CH), 112.6 (C), 110.5 (CH), 104.1 (CH), 100.7 (CH), 61.1 (CH₃), 56.1 (CH₃), 9.5 (CH₃). ESI-MS m/z 284 [C₁₇H₁₇NO₃ + H]⁺. Methyl 4-[3-(3-Hydroxy-4,5-dimethoxyphenyl)-3H-indol-3-yl]butanoate (3ac′); Typical Procedure A freshly prepared stock solution of BF₃·Et₂O (0.3 mL, 0.54 mmol, 1 mL) in CH₂Cl₂ (4 mL) was added to stirred solution of cyclohexadienone 1a (100 mg, 0.54 mmol) and methyl 4-(1H-indol-3-yl)butanoate (2c; 120 mg, 0.54 mmol) in CH₂Cl₂ (2.5 mL) at 0 °C, and the mixture was stirred for 30 min. The mixture was then diluted with sat. aq NH₄Cl (10 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The extracts were concentrated by rotary evaporation and the crude product was purified by column chromatography (silica gel, 0–70% EtOAc–hexane) to give a brown solid; yield: 180 mg (90%). ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (s, 1 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.40–7.27 (m, 3 H), 6.58 (d, J = 2.0 Hz, 1 H), 6.22 (d, J = 2.0 Hz, 1 H), 5.82 (br s, 1 H), 3.85 (s, 3 H), 3.75 (s, 3 H), 3.62 (s, 3 H), 2.26–2.17 (m, 4 H), 1.53–1.47 (m, 1 H), 1.32–1.26 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 177.0 (CH), 173.3 (C), 154.9 (C), 152.6 (C), 149.7 (C), 142.0 (C), 135.0 (C), 133.2 (C), 128.2 (CH), 126.6 (CH), 123.2 (CH), 121.5 (CH), 106.8 (CH), 102.5 (CH), 65.2 (C), 60.8 (CH₃), 55.9 (CH₃), 51.5 (CH₃), 34.3 (CH₂), 33.8 (CH₂), 19.9 (CH₂). ESI-MS: m/z = 370 [C₂₁H₂₃NO₅ + H]⁺. 5-(3,5-Dimethyl-1H-indol-2-yl)-2,3-dimethoxyphenol (3ah); Typical Procedure A freshly prepared stock solution of BF₃·Et₂O (0.3 mL, 0.54 mmol, 1 mL) in CH₂Cl₂ (4 mL) was added to stirred solution of cyclohexadienone 1a (100 mg, 0.54 mmol) and 3,5-dimethyl-1H-indole (2h, 79 mg, 0.54 mmol) in CH₂Cl₂ (2.5 mL) at 0 °C, and the mixture was stirred for 30 min, the solvent was removed to give a residue. The residue was then diluted with 2 N aq HCl (10 mL) and stirred for 2–6 h (16 h for reactions of indole 2e). The mixture was extracted with EtOAc (3 × 20 mL), and the extracts were dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 0–70% EtOAc–hexane) to give a reddish solid; yield: 131 mg (82%). ¹H NMR (400 MHz, CDCl₃): δ = 7.87 (br s, 1 H), 7.37 (br s, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.03 (dd, J = 8.0, 1.2 Hz, 1 H), 6.81 (d, J = 1.6 Hz, 1 H), 6.67 (d, J = 1.6 Hz, 1 H), 5.89 (br s, 1 H), 3.96 (s, 3 H), 3.93 (s, 3 H), 2.48 (s, 3 H), 2.44 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 152.5 (C), 149.5 (C), 134.9 (C), 134.0 (C), 133.9 (C), 130.0 (C), 129.6 (C), 128.8 (C), 123.9 (CH), 118.6 (CH), 110.3 (CH), 108.1 (C), 107.5 (CH), 104.0 (CH), 61.1 (CH₃), 56.0 (CH₃), 21.5 (CH₃), 9.6 (CH₃). ESI-MS: m/z 298 [C₁₈H₁₉NO₃ + H]⁺.
• 20 Even with N-substituted indoles 2i–k as substrates, it appeared that C-3-arylation occurred first, and only after HCl treatment did these reaction mixtures become cleaner for isolation. We found that a prolonging reaction time under BF₃·OEt₂-catalyzed condition for the Plancher-type rearrangement was not suitable for delivering 2-arylindole derivatives. Under these conditions, 2-arylindoles were obtained in low yields together with uncharacterized product mixtures.