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Synlett 2008(17): 2716-2720  
DOI: 10.1055/s-0028-1083505
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 3-Arylideneindolin-2-ones from 2-Aminophenols by Ugi Four-Component Reaction and Heck Carbocyclization [¹]

Wei-Min Dai*a,b, Jianyu Shia, Jinlong Wua
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax: +86(571)87953128; e-Mail: chdai@zju.edu.cn;
b Department of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
F: ; E: ;
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Publication History

Received 1 July 2008
Publication Date:
01 October 2008 (online)

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Abstract

2-Aminophenols underwent the Ugi four-component reaction (U-4CR) with trans-cinnamic acids, aromatic aldehydes and isocyanides in MeOH (50 ˚C, 48 h) to give the linear α-[N-(2-hydroxyphenyl)-substituted amido] carboxamides in 54-80% yields. Treatment of the 2-hydroxyphenyl moiety in the U-4CR products with NaH and PhNTf2 afforded the corresponding aryl triflates (77-100%), which were subjected to the intramolecular Heck reaction (IMHR) catalyzed by 3-5 mol% Pd(OAc)2-BINAP (MeCN, 180 ˚C, 30-60 min) under microwave heating to furnish α-(3-arylidene-2-oxindol-1-yl) carboxamides in 52-77% yields.

Key words

2-aminophenol - aryl triflate - Heck reaction - 2-oxindole - Ugi four-component reaction

1

Part 11: Chemistry of Aminophenols. For part 10, see ref. 17d.

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1

Part 11: Chemistry of Aminophenols. For part 10, see ref. 17d.

18

General Procedure for Synthesis of U-4CR Products 13
A solution of a 2-aminophenol 9 (3.0 mmol) and an aldehyde 10 (3.0 mmol) in MeOH (5 mL) was stirred at r.t. for 15 min. To the resultant mixture was added a carboxylic acid 11 (3.0 mmol) followed by stirring for 5 min. An isocyanide 12 (3.0 mmol) was then added to the above mixture followed by stirring at 50 ˚C for 48 h. The white precipitate of the U-4CR product 13 was collected by filtration and the solid was washed with MeOH (3 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel [eluting with 20% EtOAc in PE (bp 60-90 ˚C)] to give additional portion of the U-4CR product 13. The yields of
U-4CR 13a-g are given in Table  [¹] .
Characterization Data for 13d
White solid; mp 233-236 ˚C (CHCl3-hexane); R f  = 0.26 (20% EtOAc-hexane). IR (KBr): 3326, 3030, 1654, 1649, 1363 cm-¹. ¹H NMR (400 MHz, CDCl3): δ [major atropisomer (76% in CDCl3 at r.t.)] = 10.71 (s, 1 H), 7.61 (d, J = 15.6 Hz, 1 H), 7.32-7.13 (m, 15 H), 6.86 (d, J = 2.0 Hz, 1 H), 6.82 (s, 1 H), 6.71 (t, J = 5.6 Hz, 1 H), 6.29 (s, 1 H), 6.23 (d, J = 15.6 Hz, 1 H), 6.12 (d, J = 1.2 Hz, 1 H), 4.60 and 4.49 (ABqd, J = 15.2, 6.0 Hz, 2 H), 1.95 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ [major atropisomer (76% in CDCl3 at r.t.)] = 173.1, 167.6, 153.6, 143.4, 137.2, 134.9, 133.1, 132.0, 130.8, 130.1 (2×), 129.6, 129.4, 129.3, 128.6 (2×), 128.5 (2×), 128.4 (2×), 128.0 (2×), 127.6 (2×), 127.5, 124.4, 117.7, 117.3, 65.5, 44.1, 19.9. MS (ESI-): m/z (%) = 475 (100) [M - H]. Anal. Calcd for C31H28N2O3: C, 78.13; H, 5.92; N, 5.88. Found: C, 78.13; H, 5.91; N, 5.84.

19

General Procedure for Formation of Aryl Triflates 14
To a suspension of NaH (1.5 mmol) in dry THF (3 mL) cooled in an ice-water bath was added a solution of the
U-4CR product 13 (1.0 mmol) in dry THF (7 mL) under a nitrogen atmosphere. After stirring for 10 min, a solution of PhNTf2 (1.2 mmol) in dry THF (8 mL) was added via a syringe. The resultant mixture was stirred at r.t. for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatog-raphy over silica gel [eluting with 20% EtOAc in PE (bp 60-90 ˚C)] to give the aryl triflate 14. The yields of aryl triflates 14a-g are given in Table  [¹] .
Characterization Data for 14d
Colorless crystals; mp 146-148 ˚C (EtOAc-hexane); R f  = 0.29 (20% EtOAc-hexane). IR (KBr): 3322, 1681, 1652, 1601, 1366, 1212, 1139 cm-¹. ¹H NMR (400 MHz, CDCl3): δ [major atropisomer (83% in CDCl3 at r.t.)] = 7.96-7.90 (br s, 1 H), 7.67 (d, J = 15.6 Hz, 1 H), 7.35-7.10 (m, 16 H), 6.88 (d, J = 8.4 Hz, 1 H), 6.78-6.64 (br s, 1 H), 6.30-6.23 (br s, 1 H), 6.24 (d, J = 15.6 Hz, 1 H), 4.62-4.41 (m, 2 H), 2.39 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ [ major atropisomer (83% in CDCl3 at r.t.)] = 170.1, 166.8, 144.1, 143.5, 139.2, 138.1, 135.3, 135.0, 132.4, 131.3, 131.0, 130.9 (2×), 129.6, 128.7, 128.5 (2×), 128.4 (2×), 128.0 (2×), 127.9 (2×), 127.3 (2×), 127.1, 120.6, 118.2, 118.1 (q, J C-F = 317.9 Hz), 65.2, 43.6, 20.8. MS (ESI+): m/z (%) = 631 (100) [M + Na+]. Anal. Calcd for C32H27F3N2O5S: C, 63.15; H, 4.47; N, 4.60. Found: C, 63.17; H, 4.43; N, 4.51.

21

General Procedure for Microwave-Accelerated Synthesis of IMHR Products 15
A 10 mL pressurized process vial was charged with the aryl triflate 14 (0.26 mmol), Pd(OAc)2 (1.3˙10-² mmol, 5 mol%), and (±)-BINAP (1.3˙10-² mmol, 5 mol%). The vial was sealed with a cap containing a silicon septum. The vial was evacuated and backfilled with N2 (repeated for three times) through the cap using a needle. To the degassed vial was added degassed anhyd MeCN (5 mL) and Et3N (1.04 mmol) through the cap using a syringe. The loaded vial was then placed into the microwave reactor cavity and was heated at 180 ˚C for 20-60 min. After cooling to r.t. the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography over silica gel [eluting with 17% EtOAc in PE (bp 60-90 ˚C)] to give the 3-arylideneindolin-2-ones (E)-15 and (Z)-15. The yields of 15a-g and E/Z isomer ratios are given in Table  [³] .
Characterization Data for ( E )-15d
Orange crystals; mp 180-182 ˚C (acetone-hexane); R f  = 0.34 (20% EtOAc-hexane). IR (KBr): 3326, 1685, 1619, 1445, 1153 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 8.97 (t, J = 5.6 Hz, 1 H), 7.76 (s, 1 H), 7.72 (d, J = 7.2 Hz, 2 H), 7.55-7.45 (m, 4 H), 7.40-7.22 (m, 10 H), 6.68 (s, 1 H), 6.67 (d, J = 6.8 Hz, 1 H), 6.38 (s, 1 H), 4.45 and 4.38 (ABqd, J = 14.8, 5.6 Hz, 2 H), 2.11 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 167.8, 167.2, 142.7, 139.4, 139.1, 135.6, 135.3, 134.5, 129.7, 129.3 (2×), 128.8 (2×), 128.4 (2×), 128.3 (2×), 128.2 (2×), 127.8, 127.4 (2×), 126.8, 126.2, 122.2, 121.7, 118.1, 112.5, 57.5, 42.7, 21.6. MS (ESI+): m/z (%) = 481 (100) [M + Na+]. Anal. Calcd for C31H26N2O2: C, 81.20; H, 5.72; N, 6.11. Found: C, 81.35; H, 5.52; N, 5.94.
Characterization Data for ( Z )-15d
Orange needles; mp 180-182 ˚C (acetone-hexane); R f  = 0.39 (20% EtOAc-hexane). IR (KBr): 3314, 1669, 1612, 1452, 1170 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 8.91 (t, J = 6.0 Hz, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 8.36 (d, J = 7.2 Hz, 1 H), 7.85 (s, 1 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.50-7.45 (m, 3 H), 7.40-7.20 (m, 10 H), 6.83 (d, J = 7.6 Hz, 1 H), 6.58 (s, 1 H), 6.30 (s, 1 H), 4.43 and 4.32 (ABqd, J = 14.8, 6.0 Hz, 2 H), 2.16 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 167.3, 165.7, 140.6, 139.1, 138.1, 136.3, 135.4, 133.9, 131.8 (2×), 130.3, 128.3 (2×), 128.3 (2×), 128.1 (2×), 128.1 (2×), 127.7, 127.4 (2×), 126.7, 125.2, 122.2, 121.6, 119.3, 111.8, 57.2, 42.6, 21.6. MS (ESI-): m/z (%) = 457 (100) [M - H]. Anal. Calcd for C31H26N2O2: C, 81.20; H, 5.72; N, 6.11. Found: C, 81.31; H, 5.65; N, 6.10. The ¹H NMR and ¹³C NMR spectra of 15a-g can be found in the Supporting Information.