Simple Indole Synthesis by One-Pot Sonogashira Coupling-NaOH-Mediated Cyclization

Abstract

Coupling of o-iodoanilines with terminal alkynes under standard Sonogashira conditions, and further treatment with NaOH under conventional heating or microwave irradiation, afford 2-substituted indoles in usually high yields. Functionalities such as halides, nitro, and cyano groups are tolerated under the reaction conditions.

indoles - cyclizations - alkynes - microwave irradiation

References and Notes

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<A NAME="RD22308ST-10">10</A> Aqueous Bu₄NOH has been used for the cyclization of a 2-alkynyl-N-Boc-aniline. See: Sendzik M. Hui HC. Tetrahedron Lett.  2003,  44:  8697 

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<A NAME="RD22308ST-14">14</A> However, when this one-pot procedure was applied to phenylacetylene, as terminal alkyne counterpart, 2-(2-phenylethyl)aniline was generated along with the expected indole derivative 2b. This side reaction due to hydrogenation of intermediate 2-alkynylaniline 1b was easily avoided using DMA instead of DMF. Under the reaction conditions an ammonium formate derivative is probably generated, which is known to act as a source of hydrogen. See, for instance: Nacario R. Kotakonda S. Fouchard DMD. Viranga Tillekeratne LM. Hudson RA. Org. Lett.  2005,  7:  471 

For some examples of Sonogashira reactions using microwave heating, see:

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<A NAME="RD22308ST-15B">15b</A> Schramm OG. Oeser T. Kaiser M. Brun R. Müller TJJ. Synlett  2008,  359 

<A NAME="RD22308ST-16">16</A>

The amount of 2.31 g of indole 2a (67% isolated yield) were easily prepared in one batch from 4.38 g (20 mmol) of
2-iodoaniline 3a.

<A NAME="RD22308ST-17">17</A>

Typical Procedure for the One-Pot Synthesis of 2-Substituted Indoles 2 from o -Iodoanilines 3 under Conventional Heating - Synthesis of 2-Cyclohex-1-enyl-1 H -indole (2c; Table 3, Entry 5)
A mixture of 2-iodoaniline (3a, 219 mg, 1 mmol),
1-ethynylcyclohexene (159 mg, 1.5 mmol), PdCl₂ (PPh₃)₂ (21 mg, 0.03 mmol), CuI (9.5 mg, 0.05 mmol), and Et₂NH (110 mg, 1.5 mmol) in anhyd DMF (3 mL) was stirred under N₂ at r.t. for 1.5 h (the consumption of the starting material was monitored by GC-MS). Then, DMF (2 mL) and freshly powdered NaOH (400 mg, 10 mmol) were added to the reaction mixture, and it was heated at 140 ˚C for 2 h (the end of the cyclization was monitored by GC-MS). The reaction was cooled to r.t. and then, CH₂Cl₂ (15 mL) and HCl aq (20 mL of a 0.5M solution) were added. The separated aqueous phase was extracted with CH₂Cl₂ (2 × 15 mL), and the combined organic layers were washed with H₂O (3 × 50 mL). The organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography on SiO₂ (hexane-EtOAc, 10:1) to afford 2c (162 mg, 82%) as a white solid; mp 137-139 ˚C (lit.^²0 mp 140-141 ˚C). ^¹H NMR (300 MHz, CDCl₃): δ = 8.06 (br s, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.35 (dd, J = 7.8, 1.2 Hz, 1 H), 7.29-7.14 (m, 2 H), 6.53 (d, J = 1.7 Hz, 1 H), 6.15-6.09 (m, 1 H), 2.57-2.48 (m, 2 H), 2.36-2.27 (m, 2 H), 1.92-1.82 (m, 2 H), 1.82-1.72 (m, 2 H). ^¹³C NMR (75.4 MHz, CDCl₃): δ = 139.6 (C), 136.2 (C), 129.1 (C), 129.0 (C), 122.7 (CH), 122.0 (CH), 120.4 (CH), 119.8 (CH), 110.5 (CH), 98.7 (CH), 26.1 (CH₂), 25.6 (CH₂), 22.6 (CH₂), 22.3 (CH₂). LRMS (EI): m/z (%) = 197 (100) [M⁺], 182 (13), 168 (58), 130 (33). HRMS: m/z calcd for C₁₄H₁₅N: 197.1204; found: 197.1199.

<A NAME="RD22308ST-18">18</A> For the reaction of indoles with Ar₂S₂, see: Atkinson JG. Hamel P. Girard Y. Synthesis  1988,  480 

<A NAME="RD22308ST-19">19</A>

Typical Procedure for the One-Pot Synthesis of 3-Arylthio-2-Substituted Indoles 4 from o -Iodoanilines 3 under Microwave Irradiation - Synthesis of 6-Chloro-2-pentyl-3-phenylsulfanyl-1 H -indole (4c)
A mixture of 5-chloro-2-iodoaniline (3d, 127 mg, 0.5 mmol), 1-heptyne (72 mg, 0.75 mmol), PdCl₂ (PPh₃)₂ (10.5 mg, 0.015 mmol), CuI (4.8 mg, 0.025 mmol), and Et₂NH (55 mg, 0.75 mmol) in DMA (2 mL) was charged under air in a 35 mL thick-walled glass sealed tube and irradiated, under stirring, at 70 ˚C in the microwave cavity for 10 min (CEM Focused Microwave System, Discover S-Class). Temperature measurements were conducted using an IR sensor located below the microwave-cavity floor, and reaction times refer to the total hold time at the indicated temperature. The maximum wattage supplied was 70-80 W). After cooling, freshly powdered NaOH (80 mg, 2 mmol) was added to the reaction mixture and it was heated at 180 ˚C in the microwave cavity for 20 min. The reaction mixture was cooled to r.t. and then, Ph₂S₂ (131 mg, 0.6 mmol) was added to the mixture, and it was heated at 140 ˚C in the microwave cavity for 20 min. The reaction was cooled to r.t. and then, CH₂Cl₂ (15 mL) and HCl aq (20 mL of a 0.5 M solution) were added. The separated aqueous phase was extracted with CH₂Cl₂ (2 × 15 mL), and the combined organic layers were washed with H₂O (3 × 50 mL). The organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography on SiO₂ (hexane-EtOAc, 15:1) to afford 4c (133 mg, 81%) as a light brown oil; R _f = 0.27 (hexane-EtOAc, 15:1). ^¹H NMR (300 MHz, CDCl₃): δ = 8.37 (br s, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 1.7 Hz, 1 H), 7.22-7.15 (m, 2 H), 7.15-7.02 (m, 4 H), 2.89 (t, J = 7.5 Hz, 2 H), 1.71-1.60 (m, 2 H), 1.36-1.25 (m, 4 H), 0.86 (t, J = 6.9 Hz, 3 H). ^¹³C NMR (75.4 MHz, CDCl₃): δ = 146.4 (C), 139.2 (C), 135.9 (C), 128.9 (C), 128.8 (2 × CH), 128.0 (C), 125.5 (2 × CH), 124.7 (CH), 121.4 (CH), 120.0 (CH), 111.0 (CH), 99.2 (C), 31.5 (CH₂), 29.2 (CH₂), 26.5 (CH₂), 22.4 (CH₂), 14.0 (CH₃). LRMS (EI): m/z (%) = 331 (37) [M⁺ + 2], 329 (92) [M⁺], 272 (57), 236 (100), 204 (38), 164 (60). IR (neat): 3411, 2931, 1582, 1454, 808, 740, 690 cm^-¹. HRMS: m/z calcd for C₁₉H₂₀ClNS: 329.1005; found: 329.1004.

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