tert‐Butyl Iodide Mediated Reductive Fischer Indolization of Conjugated Hydrazones

Abstract

A novel reductive Fischer indolization of readily available N-aryl conjugated hydrazones with tert-butyl iodide has been developed. In this reaction, tert-butyl iodide is used as anhydrous HI source, and the generated HI acts as a Brønsted acid and a reducing agent. This operationally simple method allows access to various indole derivatives. Furthermore, the procedure can be applied to the synthesis of biologically active compounds.

One-Pot Synthesis of Indole-3-acetic Acid Derivatives through the Cascade Tsuji–Trost Reaction and Heck Coupling

“…1 H NMR spectra were recorded on a Bruker Avance 400 and 600 MHz NMR spectrometer. 13 C NMR spectra were recorded on a Bruker Avance 100 and 150 MHz NMR spectrometer. Chemical shifts were reported in parts per million (ppm, δ) (CDCl 3 δ = 7.26 ppm for 1 H NMR and δ = 77.1 ppm for 13 C NMR; DMSO-d 6 δ = 2.50 ppm for 1 H NMR and δ = 39.5 ppm for 13 C NMR).…”

“…13 C NMR spectra were recorded on a Bruker Avance 100 and 150 MHz NMR spectrometer. Chemical shifts were reported in parts per million (ppm, δ) (CDCl 3 δ = 7.26 ppm for 1 H NMR and δ = 77.1 ppm for 13 C NMR; DMSO-d 6 δ = 2.50 ppm for 1 H NMR and δ = 39.5 ppm for 13 C NMR). Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m).…”

“…Ethyl 2-(1-Tosyl-1H-indol-3-yl)acetate (3aa): 48 Et 3 N as a base, 12 h, EtOAc/PE = 1/15, 293 mg, 82%, pale yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 8.00 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 4.19 (q, J = 6.8 Hz, 2H), 3.70 (s, 2H), 2.34 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H); 13 Ethyl 2-(7-Fluoro-1-tosyl-1H-indol-3-yl)acetate (3ja): 24 h, EtOAc/PE = 1/10 to 1/5, 316 mg, 84%, pale yellow oil; 1 Methyl 3-(2-Ethoxy-2-oxoethyl)-1-tosyl-1H-indole-7-carboxylate (3ka): 12 h, EtOAc/PE = 1/10, 302 mg, 73%, pale yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) 7.61−7.51 (m, 5H), 7.33 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 4.14 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.63 (s, 2H), 2.34 (s, 3H), 1.22 (t, J = 6.8 Hz, 3H); 13 Ethyl 2-(5,7-Difluoro-1-tosyl-1H-indol-3-yl)acetate (3la): 12 h, EtOAc/PE = 1/10 to 1/6, 357 mg, 91%, pale yellow solid; mp 93−94 °C; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 7.96 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (td, J = 9.6, 2.0 Hz, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.85 (s, 2H), 2.36 (s, 3H), 1.20 (t, J = 6.8 Hz, 3H); 13 Ethyl 2-(5-((Pyrrolidin-1-ylsulfonyl)methyl)-1-tosyl-1H-indol-3-yl)acetate (3sa). A three-neck round-bottom flask was charged with a magnetic stir bar, 1l (6.0 g, 11.5 mmol), 2 (2.0 g, 11.5 mmol), Pd(OAc) 2 (78 mg, 0.35 mmol), P(o-tol) 3 (213 mg, 0.70 mmol), and DIPEA (3.6 g, 27.8 mmol) was added anhydrous DMA (50 mL).…”

“…The organic layer was combined, then washed with a saturated NaCl solution (60 mL), and dried over anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (EtOAc/PE = 1:1) to obtain a white solid (2.1 g, 96%): mp 186−188 °C; 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 10.87 (s, 1H), 7.56 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.4, 1.2 Hz, 1H), 4.66 (t, J = 5.4 Hz, 1H), 4.45 (s, 2H), 3.64 (q, J = 6.6 Hz, 2H), 3.12−3.09 (m, 4H), 2.84 (t, J = 7.4 Hz, 2H), 1.77−1.73 (m, 4H); 13 N,N-Dimethyl-2-(5-((pyrrolidin-1-ylsulfonyl)methyl)-1Hindol-3-yl)ethan-1-amine (Almotriptan). To a solution of 3la-2 (1.8 g, 5.8 mmol) in CH 3 CN (30 mL) was added TEA (708 mg, 7.0 mmol) at 0 °C.…”

Recent Advances in the Regioselective Synthesis of Indoles via C–H Activation/Functionalization

“…Recently, Ito et al developed a novel transition-metalfree reductive Fischer indole synthesis by reacting easily available N-aryl hydrazones 40 with tert-butyl iodide as a source of anhydrous HI, which acts as Bronsted acid as well as a reducing agent (Scheme 22). 19 The developed method represents the first ever report on a 1,4-reduction of a conjugated hydrazone with a sequential Fischer indolization reaction of an in situ generated enamine, and can be applied to the synthesis of biologically active C-3 substituted indole derivatives. The role of the solvent was crucial for the transformation as only polar solvents were able to give the desired product.…”