Palladium-Catalyzed Synthesis of Free-NH Indole 2-Acetamides and Derivatives from Ethyl 3-(o-Trifluoroacetamidoaryl)-1-propargylic Carbonates

Abstract

The reaction of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates with primary or secondary amines in the presence of Pd₂(dba)₃, dppf, and carbon monoxide in THF at 80 ˚C provides ready access to free-NH indole 2-acetamides. The reaction can be applied to the synthesis of free-NH indole 2-acetic acid methyl esters.

Key words

palladium - carbonylation - indoles - alkynes - propargylic esters

References and Notes

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7

Compounds 1b, 1c and 1f were prepared via Sonogashira cross-coupling of o-iodoanilines with the THP derivative of propargyl alcohol. The cross-coupling products were treated with (CF₃CO)₂O. The resultant trifluoroacetamido derivatives were deprotected and subjected to ethyl chlorocarbonate to give the title propargylic esters.

8

Typical Procedure for the Preparation of Free-NH Indole 2-Acetamides (3): A stainless steel reaction vessel was charged with 1a (94.5 mg, 0.3 mmol), Pd₂ (dba)₃ (6.9 mg, 0.0075 mmol), dppf (8.3 mg, 0.015 mmol), 2d (185.7 mg, 0.9 mmol), and anhydrous THF (10 mL). The reactor was pressured to 40 atm with CO, warmed to 80 ˚C, and stirred for 24 h. After cooling and eliminating CO, the volatile materials were evaporated at reduced pressure and the residue was purified by chromatography on neutral aluminum oxide (Brockmann 1; n-hexane-EtOAc, 90:10→70:30) to afford 3d (87 mg, 80% yield); viscous oil; IR (KBr): 3296, 3064, 2989, 2929, 2852, 1630 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 9.36 (br s, 1 H), 7.59-7.58 (m, 1 H), 7.36-7.34 (m, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.18-7.12 (m, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 6.31 (s, 1 H), 3.90 (s, 2 H), 3.84 (s, 3 H), 3.69-3.68 (m, 2 H), 3.58-3.56 (m, 2 H), 3.44 (s, 2 H), 2.43-2.40 (m, 2 H), 2.37-2.35 (m, 2 H); ^¹³C NMR (100.6 MHz, CDCl₃): δ = 168.4, 159.0, 136.5, 132.0, 130.4, 129.6, 128.4, 121.6, 120.0, 119.7, 113.8, 111.1, 101.0, 62.1, 55.3, 52.9, 52.5, 46.4, 42.1, 33.3; MS: m/z (%) = 121 (100) [M - C₁₄H₁₆N₃O]⁺, 85 (50), 78 (44), 56 (52); Anal. Calcd. for C₂₂H₂₅N₃O₂: C, 72.70; H, 6.93; Found: C, 72.63; H, 6.91.

10

Typical Procedure for the Preparation of Free-NH Indole 2-Acetic Acid Methyl Esters (7): A stainless steel reaction vessel was charged with 1e (99 mg, 0.3 mmol),
Pd₂ (dba)₃ (6.9 mg, 0.0075 mmol), dppf (8.3 mg, 0.015 mmol), anhydrous THF (10 mL), and MeOH (1 mL). The reactor was pressured to 40 atm with CO, warmed to 80 ˚C, and stirred for 24 h. After cooling and eliminating CO, the volatile materials were evaporated at reduced pressure and the residue was purified by chromatography on silica gel (n-hexane-EtOAc, 80:20) to afford of 7b (40.2 mg, 66% yield); mp 90-93 ˚C; IR (KBr): 3356, 2952, 1714, 1458, 1427
cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 8.55 (br s, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 7.12 (t, J = 7.9 Hz, 1 H), 6.41 (s, 1 H), 4.00 (q, J = 7.1 Hz, 1 H), 3.77 (s, 3 H), 1.66 (d, J = 7.2 Hz, 3 H); ^¹³C NMR (100.6 MHz, CDCl₃): δ = 174.1, 136.7, 136.2, 128.2, 121.9, 120.3, 119.9, 110.9, 100.3, 52.5, 39.2, 17.5; Anal. Calcd. for C₁₂H₁₃NO₂: C, 70.92; H, 6.45; Found: C, 70.83; H, 6.47.