Synlett 2014; 25(10): 1473-1477
DOI: 10.1055/s-0033-1341241
letter
© Georg Thieme Verlag Stuttgart · New York

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: [email protected]
,
Chihiro Tsukano
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan   Fax: +81(75)7534569   Email: [email protected]
,
Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan   Fax: +81(75)7534569   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 19 February 2014

Accepted after revision: 24 March 2014

Publication Date:
30 April 2014 (online)


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.

Supporting Information

 
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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).