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.

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

References and Notes

1

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

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 

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.

20 Larhed M. Moberg C. Hallberg A. Acc. Chem. Res.  2002,  35:  717 

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.