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

Takeshi Nanjo; Chihiro Tsukano; Yoshiji Takemoto

doi:10.1055/s-0033-1341241

Synlett, Table of Contents

Synlett 2014; 25(10): 1473-1477
DOI: 10.1055/s-0033-1341241

letter

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

Takeshi Nanjo

Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan Fax: +81(75)7534569 Email: takemoto@pharm.kyoto-u.ac.jp

,

Chihiro Tsukano

Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan Fax: +81(75)7534569 Email: takemoto@pharm.kyoto-u.ac.jp

,

Yoshiji Takemoto*

Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan Fax: +81(75)7534569 Email: takemoto@pharm.kyoto-u.ac.jp

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Abstract

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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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References

References and Notes

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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).

Supplementary Material

Supporting Information