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Synlett 2015; 26(06): 771-778
DOI: 10.1055/s-0034-1379935
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 2-Acylated Indoles through Palladium-Catalyzed Dehydrogenative Coupling of N-Pyrimidine-Protected Indoles with Aldehydes and Ethyl Glyoxylate

Wenduo Wang
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. of China   Email: ztanze@gmail.com
,
Jidan Liu
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. of China   Email: ztanze@gmail.com
,
Qingwen Gui
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. of China   Email: ztanze@gmail.com
,
Ze Tan*
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. of China   Email: ztanze@gmail.com
› Author Affiliations
Further Information

Publication History

Received: 09 October 2014

Accepted after revision: 24 November 2014

Publication Date:
09 February 2015 (online)

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Abstract

C2-Acylated indoles have been synthesized in good yields through palladium-catalyzed dehydrogenative coupling of N-pyrimidine-protected indoles using aldehydes as the source of acyl reagent and tert-butyl hydroperoxide as the oxidant. 2-Indole carboxylates can be synthesized when aldehydes are substituted by ethyl glyoxylate.

Key words

palladium - dehydrogenative coupling - aldehyde - acylation - indoles

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1379935. Included are experimental procedures, characterization data, and copies of 1H NMR and 13C NMR spectra.
  • Supporting Information
 

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  • 17 General Procedure: To a 25-mL sealed tube were added indole (0.3 mmol), aldehyde (0.45 mmol), Pd(OAc)2 (6.72 mg, 10 mmol%), anhydrous TBHP (ca. 5 M in decane, 4 equiv), and EtOAc (2.0 mL). The tube was capped and stirred under N2 at 125 °C for 24 h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2, filtered through a short pad of Celite, and washed with brine and CH2Cl2. The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography to afford the desired product. [3-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone (3as): Yield: 82%; white solid; mp 153–154 °C. 1H NMR (400 MHz, CDCl3): δ = 8.63 (d, J = 8.0 Hz, 1 H), 8.44 (d, J = 4.0 Hz, 2 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.48–7.40 (m, 2 H), 7.32 (q, J = 8.0 Hz, 3 H), 6.84 (t, J = 4.0 Hz, 1 H), 2.37 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 189.4, 157.5, 157.0, 139.2, 136.4, 133.2, 132.2, 130.2, 128.5, 128.3, 126.1, 122.5, 121.7, 120.1, 116.1, 115.2, 9.3; HRMS: m/z [M]+ calcd for C20H15N3O: 313.1207; found: 313.1210. [7-Methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl](phenyl)methanone (3at): Yield: 80%; yellow solid; mp 36–37 °C. 1H NMR (400 MHz, CDCl3): δ = 8.85 (d, J = 4.0 Hz, 2 H), 7.92 (d, J = 8.0 Hz, 2 H), 7.60–7.55 (m, 2 H), 7.48–7.45 (m, 2 H), 7.39 (t, J = 4.0 Hz, 1 H), 7.20 (s, 1 H), 7.13–7.11 (m, 2 H), 1.96 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 187.0, 159.7, 158.1, 138.3, 138.2, 136.0, 132.4, 129.6, 129.2, 128.2, 127.2, 122.4, 121.9, 121.1, 120.1, 116.4, 19.3. HRMS: m/z [M]+ calcd for C20H15N3O: 313.1207; found: 313.1210. (4-Methoxyphenyl)[1-(pyrimidin-2-yl)-1H-indol-2-yl]methanone (3au): Yield: 76%; white solid; mp 39–40 °C. 1H NMR (400 MHz, CDCl3): δ = 8.61 (d, J = 4.0 Hz, 2 H), 8.39 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 7.02 (t, J = 4.0 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 2 H), 3.83 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 186.4, 163.3, 157.9, 157.2, 138.0, 137.2, 131.8, 130.7, 127.9, 126.1, 122.6, 122.2, 117.3, 114.5, 114.1, 113.5, 55.4; HRMS: m/z [M]+ calcd for C20H15N3O2: 329.1152; found: 329.1159. N-{4-[1-(Pyrimidin-2-yl)-1H-indole-2-carbonyl]phenyl}acetamide (3av): Yield: 67%; yellow solid; mp 138–139 °C. 1H NMR (400 MHz, CDCl3): δ = 9.11 (s, 1 H), 8.56 (d, J = 4.0 Hz, 2 H), 8.37 (d, J = 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 2 H), 7.68–7.61 (m, 3 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 6.99 (t, J = 4.0 Hz, 1 H), 2.09 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 186.8, 169.4, 157.8, 157.0, 142.9, 138.0, 136.9, 132.7, 130.7, 127.8, 126.4, 122.7, 122.3, 118.7, 117.3, 115.1, 114.1, 24.28; HRMS: m/z [M]+ calcd for C21H16N4O2: 356.1273; found: 356.1268.
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