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

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.

References and Notes

• 2a Mohammadi M. McMahon G. Sun L. Tang C. Hirth P. Yeh BK. Hubbard SR. Schlessinger J. Science  1997,  276:  955 
• 2b Woodard CL. Li Z. Kathcart AK. Terrell J. Gerena L. Lopez-Sanchez M. Kyle DE. Bhattacharjee AK. Nichols DA. Ellis W. Prigge ST. Geyer JA. Waters NC. J. Med. Chem.  2003,  46:  3877 
• 2c Huwe A. Mazitschek R. Giannis A. Angew. Chem. Int. Ed.  2003,  42:  2122 
• For 3-substituted methyleneindolin-2-ones prepared by condensation of 2-oxindoles with carbonyl compounds, see:
• 3a Sun L. Tran N. Tang F. App H. Hirth P. McMahon G. Tang C. J. Med. Chem.  1998,  41:  2588 
• 3b Sun L. Tran N. Liang C. Tang F. Rice A. Schreck R. Waltz K. Shawver LK. McMahon G. Tang C. J. Med. Chem.  1999,  42:  5120 
• 3c Sun L. Tran N. Liang C. Hubbard S. Tang F. Lipson K. Schreck R. Zhou Y. McMahon G. Tang C. J. Med. Chem.  2000,  43:  2655 
• 3d Sun L. Liang C. Shirazian S. Zhou Y. Miller T. Cui J. Fukuda JY. Chu J.-Y. Nematalla A. Wang X. Chen H. Sistla A. Luu TC. Tang F. Wei J. Tang C. J. Med. Chem.  2003,  46:  1116 
• 3e Andreani A. Burnelli S. Granaiola M. Leoni A. Locatelli A. Morigi R. Rambaldi M. Varoli L. Kunkel MW. J. Med. Chem.  2006,  49:  6922 
• 3f Andreani A. Burnelli S. Granaiola M. Leoni A. Locatelli A. Morigi R. Rambaldi M. Varoli L. Calonghi N. Cappadone C. Farruggia G. Zini M. Stefanelli C. Masotti L. J. Med. Chem.  2007,  50:  3167 
• 3g Yang T.-M. Liu G. J. Comb. Chem.  2007,  9:  86 
• 4 For 3-monosubstituted methyleneindolin-2-ones prepared by HWE olefination, see: Teichert A. Jantos K. Harms K. Studer A. Org. Lett.  2004,  6:  3477 
• For a tandem Heck carbocyclization-Suzuki cross-coupling approach to 3-disubstituted methyleneindolin-2-ones, see:
• 5a Cheung WS. Patch RJ. Player MR. J. Org. Chem.  2005,  70:  3741 
• 5b Yanada R. Obika S. Inokuma T. Yanada K. Yamashita M. Ohta S. Takemoto Y. J. Org. Chem.  2005,  70:  6972 
• 5c Yanada R. Obika S. Oyama M. Takemoto Y. Org. Lett.  2004,  6:  2825 
• For a tandem Heck carbocyclization-Sonogashira cross-coupling approach to 3-disubstituted methyleneindolin-2-ones and the related domino sequence, see:
• 6a D’Souza DM. Rominger F. Müller TJJ. Angew. Chem. Int. Ed.  2005,  44:  153 
• 6b D’Souza DM. Kiel A. Herten D.-P. Rominger F. Müller TJJ. Chem. Eur. J.  2008,  14:  529 
• For intermolecular amino-, carbo-, and carboxy-palladation, C-H activation, and C-C bond-formation sequences to 3-diarylmethyleneindolin-2-ones, see:
• 7a Pinto A. Neuville L. Retailleau P. Zhu J. Org. Lett.  2006,  8:  4927 
• 7b Pinto A. Neuville L. Zhu J. Angew. Chem. Int. Ed.  2007,  46:  3291 
• 7c Tang S. Peng P. Pi S.-F. Liang Y. Wang N.-X. Li J.-H. Org. Lett.  2008, 10, 1179 
• 7d Tang S. Peng P. Wang Z.-Q. Tang B.-X. Deng C.-L. Li J.-H. Zhong P. Wang N.-X. Org. Lett.  2008,  10, 1875 
• 8a Sun L.-P. Huang X.-H. Dai W.-M. Tetrahedron  2004,  60:  10983 ; and references cited therein
• 8b For microwave-assisted solid-phase heteroannulation, see: Dai W.-M. Guo D.-S. Sun L.-P. Huang X.-H. Org. Lett.  2003,  5:  2919 
• 8c Sun L.-P. Dai W.-M. Angew. Chem. Int. Ed.  2006,  45:  7255 
• For a palladium-catalyzed carbonylative annulation to 3-disubstituted methyleneindolin-2-ones, see:
• 9a Tang S. Yu Q.-F. Peng P. Li J.-H. Zhong P. Tang R.-Y. Org. Lett.  2007,  9:  3413 
• 9b For related annulations of 2-alky-nylaryl isocyanates, see: Kamijo S. Sasaki Y. Kanazawa C. Schüsseler T. Yamamoto Y. Angew. Chem. Int. Ed.  2005,  44:  7718 
• 9c Miura T. Takahashi Y. Murakami M. Org. Lett.  2008,  10, 1743 
• 9d For a palladium-catalyzed cyclization-anion-capture approach to 3-substituted methyleneindolin-2-ones, see: Fielding MR. Grigg R. Urch CJ. Chem. Commun.  2000,  2239 
• 10a Arumugam V. Routledge A. Abell C. Balasubramanian S. Tetrahedron Lett.  1997,  38:  6473 
• 10b Inoue M. Furuyama H. Sakazaki H. Hirama M. Org. Lett.  2001,  3:  2863 
• 10c Lin S. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  1967 
• 11a Negishi E. Copéret C. Ma S. Liou S.-Y. Liu F. Chem. Rev.  1996,  96:  365 
• 11b Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 ; and early reviews cited therein
• 11c Dounay AB. Overman LE. Chem. Rev.  2003,  103:  2945 
• For examples of U-4CR-intramolecular Heck reaction sequences, see:
• 12a Gracias V. Moore JD. Djuric SW. Tetrahedron Lett.  2004,  45:  417 
• 12b Xiang Z. Luo T. Lu K. Cui J. Shi X. Fathi R. Chen J. Yang Z. Org. Lett.  2004,  6:  3155 
• 12c Umkehrer M. Kalinski C. Kolb J. Burdack C. Tetrahedron Lett.  2006,  47:  2391 
• 12d Kalinski C. Umkehrer M. Schmidt J. Ross G. Kolb J. Burdack C. Hillerb W. Hoffmann SD. Tetrahedron Lett.  2006,  47:  4683 
• For U-4CR of 2-aminophenols, see:
• 13a Xing X. Wu J. Feng G. Dai W.-M. Tetrahedron  2006,  62:  6774 
• 13b Xing X. Wu J. Luo J. Dai W.-M. Synlett  2006,  2099 
• For use of 2-carboamidoaryl triflates in indole synthesis, see:
• 14a Dai W.-M. Guo D.-S. Sun L.-P. Tetrahedron Lett.  2001,  42:  5275 
• 14b Dai W.-M. Sun L.-P. Guo D.-S. Tetrahedron Lett.  2002,  43:  7699 ; and references cited in refs. 8a,b
• 15 Dai W.-M. Shi J. Comb. Chem. High Throughput Screening  2007,  10:  837 
• 16 For a recent review on post-Ugi transformations, see: Akritopoulou I. Djuric SW. Heterocycles  2007,  73:  125 
• For microwave-assisted synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines from 2-aminophenols, see:
• 17a Dai W.-M. Wang X. Ma C. Tetrahedron  2005,  61:  6879 
• 17b Feng G. Wu J. Dai W.-M. Tetrahedron  2006,  62:  4635 
• 17c Feng G. Wu J. Dai W.-M. Tetrahedron Lett.  2007,  48:  401 
• 17d Wu J. Nie L. Luo J. Dai W.-M. Synlett  2007,  2728 
• 17e For microwave-assisted 3CR-aza-DA of 2-aminophenols, see: Xing X. Wu J. Dai W.-M. Tetrahedron  2006,  62:  11200 
• 20 Larhed M. Moberg C. Hallberg A. Acc. Chem. Res.  2002,  35:  717 

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.