Rapid α-Amination of N-Substituted Indoles by Using DBU-Activated N-Haloimides as Nitrogen Sources

Abstract

By using the N-haloimide/DBU protocol, the electrophilic imidation at C2-position of N-substituted indoles has been achieved in high efficiency. The dual activation of N-haloimide by DBU to simultaneously achieve a more electrophilic bromine and a more nucleophilic nitrogen atom, is demonstrated to be crucial in this transformation. The process involves tandem bromonium ion formation, electrophilic addition, and elimination of HBr. The protocol provides a novel, efficient, green, and complimentary access to α-imidated indoles under mild conditions, without the necessity of external nitrogen sources.

Key words

indoles - amination - N-haloimides - DBU

• References and Notes

• 1a Eicher T, Hauptmann S. The Chemistry of Heterocycles. Wiley-VCH; Weinheim: 2003
• 1b Joule JA, Mills K. Heterocyclic Chemistry. Blackwell Science; Oxford: 2000
• 1c Sundberg RJ. Indoles. Academic Press; New York: 1996
• 1d Taylor EC, Jones RA. Pyrroles. Wiley; New York: 1990

Metal-catalyzed oxidative amination/amidation, see:
• 2a Shuai Q, Deng GZ, Chua DS, Bohle LiC.-J. Adv. Synth. Catal. 2010; 352: 632
• 2b Liu X.-Y, Gao P, Shen Y.-W, Liang Y.-M. Org. Lett. 2011; 13: 4196
• 2c Shi J, Zhou B, Yang Y, Li Y. Org. Biomol. Chem. 2012; 10: 8953

Halogen-mediated amination/amidation, see:
• 3a Li Y.-X, Ji K.-G, Wang H.-X, Ali S, Liang Y.-M. J. Org. Chem. 2011; 76: 744
• 3b Li Y.-X, Wang H.-X, Ali S, Xia X.-F, Liang Y.-M. Chem. Commun. 2012; 48: 2343
• 3c Cai Z.-J, Wang S.-Y, Ji S.-J. Org. Lett. 2013; 15: 5226
• 3d Wu W.-B, Huang J.-M. Org. Lett. 2012; 14: 5832
• 3e Ghosh S, Nagarajan R. RSC Adv. 2014; 4: 20136
• 4a Wei Y, Lin S, Liang F. Org. Lett. 2012; 14: 4202
• 4b Wei Y, Lin S, Liang F, Zhang J. Org. Lett. 2013; 15: 852
• 4c Wei Y, Liang F, Zhang X. Org. Lett. 2013; 15: 5186
• 4d Li M, Yuan H, Zhao B, Liang F, Zhang J. Chem. Commun. 2014; 50: 2360
• 5 For a recent nice example of using N-succinimidylperester as a self-immolating imidation reagent, see: Foo K, Sella E, Thomé I, Eastgate MD, Baran PS. J. Am. Chem. Soc. 2014; 136: 5279
• 6 As one reviewer suggested, the reaction with Na₂CO₃ and Cs₂CO₃ as the base was explored. As a result, Na₂CO₃ gave no reaction, and Cs₂CO₃ afforded product 2a in 61% yield.
• 7 Reaction performed under N₂ protection gave similar yield to that in the open air, indicating that molecular oxygen has no effect on the reaction, contrary to our previous observation in ref. 4b.
• 8 The experimental result is well consistent with the theoretical calculation result shown in the mechanism part.
• 9 Preparation of 2a; Typical ProcedureTo a solution of NBS (2.2 mmol, 0.3916 g) and DBU (2.2 mmol, 0.3344 g) in super dry DMF (2.0 mL, with the addition of 120 μL H₂O), N-methylindole 1a (1.0 mmol, 0.1312 g) was added. The reaction mixture was stirred at r.t. for 3 min. After the starting material 1a was consumed as indicated by TLC, the reaction mixture was poured into H₂O and then extracted with CH₂Cl₂ (3 × 10 mL). The combined organic phase was washed with H₂O (3 × 10 mL), dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel; PE–EtOAc, 8:1) to give 2a (0.1917 g, 84%) as a white solid.1-(1-Methyl-1H-indol-2-yl)pyrrolidine-2,5-dione (2a)Mp 171–173 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.01 (s, 4 H), 3.55 (s, 3 H), 6.50 (s, 1 H), 7.13–7.16 (m, 1 H), 7.28 (d, J = 7.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃) δ = 28.4, 29.3, 99.9, 109.6, 120.1, 121.2, 122.6, 125.9, 126.2, 135.9, 175.8. ESI-HRMS: m/z calcd for C₁₃H₁₂N₂O₂ [M + H]⁺: 229.0977; found: 229.0988.
• 10 In most cases, 3-bromoindole derivatives 3 could be observed. It seems that the electron-donating group on the indole ring is favorable for the formation of α-aminated product, and the electron-withdrawing group on the indole ring affords 3-bromoindoles as the main products.
• 11 3-Haloindole derivatives are important building blocks in the functionalization of indoles at the 3-position.
• 12 In the presence of NBS (2.2 equiv) and DBU (2.2 equiv), a bromoimidation product was obtained in 92% yield.
• 13 To a solution of NBS (2.2 equiv), DBU (2.2 equiv) in DMF (2.0 mL), and H₂O (120 μL), TEMPO (2.2 equiv) was added. Then substrate 1a (1.0 mmol) was added under stirring. No reaction was observed within an hour. This result may help to exclude a possible radical mechanism.
• 14a For evidence for the formation of the ion-pair intermediate, see refs. 9–11. For a recent review of NBS activation by Lewis base, see: Denmark SE, Kuester WE, Burk MT. Angew. Chem. Int. Ed. 2012; 51: 10938
• 14b Selected papers – for NBS/Ph₃P, see: Sakakura A, Ukai A, Ishihara K. Nature (London, U.K.) 2007; 445: 900
• 14c For Et₂SBr·SbCl₅Br, see: Snyder SA, Treitler DS. Angew. Chem. Int. Ed. 2009; 48: 7899
• 14d For bromocollidinium ion, see: Cui X.-L, Brown RS. J. Org. Chem. 2000; 65: 5653
• 15 The theoretical calculation result supports the proposed ion-pair intermediate in which three molecules of water are required. The role of the water is supposed to distribute the negative charge on the succinimde anion, thus stabilizing the ion pair formed.
• 16 The ion-pair intermediate is also supported by measuring the ion conductivities of NBS/DBU vs. NBS in DMF. The ion conductivity for the former is two orders of magnitude higher than the latter.
• 17 As a reviewer suggested, DBU (0.25 mmol) and NBS (0.25 mmol) were dissolved in CDCl₃, and the ¹H NMR spectrum was measured. Compared with the NMR data of free NBS and DBU, the chemical shifts of the NBS/DBU mixture change to some extent (the protons on DBU move downfield and protons on NBS move toward upfield) indicating intermolecular interaction exits between NBS and DBU.

For Lewis base stabilized bromonium intermediates, refer to:
• 18a Denmark SE, Burk MT. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 20655
• 18b Cheng YA, Chen T, Tan CK, Heng JJ, Yeung Y.-Y. J. Am. Chem. Soc. 2012; 134: 16492

For the possible structures of bromonium ion, see:
• 19a Yates K, McDonald RS. J. Org. Chem. 1973; 38: 2465
• 19b Shellhamer DF, Davenport KJ, Forberg HK, Herrick MP, Jones RN, Rodriguez SJ, Sanabria SN, Trager N, Weiss RJ, Heasley VL, Boatz JA. J. Org. Chem. 2008; 73: 4532