Synthesis of 3,3-Disubstituted 2-Aminoindolenines by Palladium-Catalyzed Allylic Amidination with Isocyanide

Abstract

Synthesis of 3,3-disubstituted 2-aminoindolenines was achieved by palladium-catalyzed allylic amidination with an isocyanide. It was found that isocyanides are effective building blocks in palladium-catalyzed allylic functionalizations, analogous to carbon monoxide. This approach enables the direct construction of the indolenine ring along with the formation of a quaternary carbon and the introduction of an amino substituent in one step under mild conditions.

Key words

palladium - isocyanide - allylic amidination - cyclization - indoles

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• 12 Substrates 1a and 1b were synthesized by Suzuki coupling of N-formyl-2-iodoaniline with vinyl boronic esters followed by formation of the carbonate or ester and then the isocyanide. See the Supporting Information for more detail.
• 13 General Procedure for the Synthesis of 3,3-Disubstituted 2-Aminoindolenines To a stirred solution of 1 (0.1 mmol), amine (0.2 mmol), and Et₃N (0.028 mL, 0.201 mmol) in THF (2 mL) were added Pd(dba)₂ (5.8 mg, 0.0101 mmol) and (2-furyl)₃P (4.6 mg, 0.0198 mmol). After stirring for 12 h at r.t., the reaction mixture was diluted with toluene and extracted with 2 M aq HCl. The combined extracts were basified with 2 M aq NaOH and extracted with EtOAc. The resultant organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane–EtOAc) to give 2.
• 14 Analytical Data for 2a A colorless block, which was recrystallized from Et₂O: mp 83.0–86.0 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.16–7.12 (m, 2 H), 6.92 (d, 1 H, J = 7.2 Hz), 6.86 (ddd, 1 H, J ₁ = J ₂ = 6.6 Hz, J ₃ = 1.7 Hz), 5.90 (dd, 1 H, J ₁ = 17.5 Hz, J ₂ = 10.6 Hz), 5.35 (d, 1 H, J = 17.5 Hz), 5.22 (d, 1 H, J = 10.6 Hz), 3.71–3.63 (m, 4 H), 1.67–1.58 (m, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 176.2, 154.7, 140.6, 138.9, 128.1, 121.2, 120.8, 115.7, 113.6, 55.6, 47.4, 26.0, 24.3, 20.7. IR (ATR): 2934, 1632, 1542, 1458, 1448 cm^–1. MS–FAB: m/z = 241 [M + H]⁺. HRMS–FAB⁺: m/z calcd for C₁₆H₂₁N₂ [M + H]⁺: 241.1705; found: 241.1708.
• 15 As previously reported on the synthesis of amidines using palladium catalysis and isocyanides,^9g,h path A is also possible. In this case, the diastereoselectivity of 2m would be derived from a selective reaction of one enantiomer of racemic B and l-proline methyl ester (i.e., matched pair).