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Synlett 2009(7): 1162-1166  
DOI: 10.1055/s-0028-1088115
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Assembly of 1,3-Dihydro-2H-3-benzazepin-2-one Conjugates via Ugi Four-Component Reaction and Palladium-Catalyzed Hydroamidation [¹]

Jinlong Wua, Yong Jianga, Wei-Min Dai*a,b
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, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
Fax: +85223581594; e-Mail: chdai@ust.hk;
Further Information

Publication History

Received 2 February 2009
Publication Date:
26 March 2009 (online)

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Abstract

The Ugi four-component reaction (U-4CR) of a number of 2-aminophenols was carried out with 2-alknylbenzaldehydes, benzyl isocyanide, and 2-chloro-5-nitrobenzoic acid in MeOH under microwave heating (MW, 80 ˚C, 20 min). The reaction mixture was then directly treated with aqueous K2CO3 (MW, 100 ˚C, 10 min) to promote an intramolecular nucleophilic aromatic substitution (SNAr), resulting in the formation of highly functionalized dibenz[b,f][1,4]oxazepin-11(10H)-ones. The N-benzyl amide and arylalkynyl moieties, derived from benzyl isocyanide and 2-alkynylbenzaldehydes, allow for further assembly of 1,3-dihydro-2H-3-benzazepin-2-one scaffold via an intramolecular 7-endo-dig hydroamidation catalyzed by 10 mol% Pd(PhCN)2Cl2 (THF, 60 ˚C, 24 h, 61-74%). This new post-Ugi annulation enables an expeditious access to the C-N bond-linked conjugates of two benzannulated seven-membered-ring heterocycles.

Key words

alkynes - hydroamidation - microwaves - palladium - Ugi four-component reaction

1

Part 12. Chemistry of Aminophenols. For part 11, see ref. 9d.

    References and Notes

  • 2a Modern Acetylene Chemistry   Stang PJ. Diederich F. VCH; Weinheim: 1995. 
    Google Scholar
  • 2b Enediynes Antibiotics as Antitumor Agents   Borders DB. Doyle TW. Marcel Dekker; New York: 1995. 
    Google Scholar
  • 3a Nicolaou KC. Dai W.-M. Angew. Chem., Int. Ed. Engl.  1991,  30:  1387 
    Google Scholar
  • 3b Dai W.-M. Curr. Med. Chem.  2003,  10:  2265 ; and references cited therein
    Google Scholar
  • For reviews, see:
  • 4a Cacchi S. J. Organomet. Chem.  1999,  576:  42 
    Google Scholar
  • 4b Alonso F. Beletskaya IP. Yus M. Chem. Rev.  2004,  104:  3079 
    Google Scholar
  • For formation of five-membered-ring heterocycles, see:
  • 5a Koseki Y. Kusano S. Nagasaka T. Tetrahedron Lett.  1998,  39:  3517 
    Google Scholar
  • 5b Koseki Y. Kusano S. Ichi D. Yoshida K. Nagasaka T. Tetrahedron  2000,  56:  8855 
    Google Scholar
  • 5c Kozawa Y. Mori M. J. Org. Chem.  2003,  68:  8068 
    Google Scholar
  • 5d Hiroya K. Itoh S. Sakamoto T. J. Org. Chem.  2004,  69:  1126 
    Google Scholar
  • 5e Sun L.-P. Huang X.-H. Dai W.-M. Tetrahedron  2004,  60:  10983 ; and references cited therein
    Google Scholar
  • 5f Yeom H.-S. Lee E.-S. Shin S. Synlett  2007,  2292 
    Google Scholar
  • 5g Lai R.-Y. Surekha K. Hayashi A. Ozawa F. Liu Y.-H. Peng S.-M. Liu S.-T. Organometallics  2007,  26:  1062 
    Google Scholar
  • 5h Martín R. Rivero MR. Buchwald SL. Angew. Chem. Int. Ed.  2006,  45:  7079 
    Google Scholar
  • For microwave-assisted solid-phase synthesis, see:
  • 5i Dai W.-M. Guo D.-S. Sun L.-P. Huang X.-H. Org. Lett.  2003,  5:  2919 
    Google Scholar
  • 5j Sun L.-P. Dai W.-M. Angew. Chem. Int. Ed.  2006,  45:  7255 
    Google Scholar
  • For formation of six-membered-ring heterocycles, see:
  • 6a Enomoto T. Obika S. Yasui Y. Takemoto Y. Synlett  2008,  1647 
    Google Scholar
  • 6b Obika S. Yausi Y. Yanada R. Takemoto Y. J. Org. Chem.  2008,  73:  5206 
    Google Scholar
  • 6c Patil NT. Huo Z. Bajracharya GB. Yamamoto Y. J. Org. Chem.  2006,  71:  3612 ; see also ref. 7a
    Google Scholar
  • For formation of seven-membered-ring heterocycles, see:
  • 7a Tsubakiyama M. Sato Y. Mori M. Heterocycles  2004,  64:  27 
    Google Scholar
  • 7b Yu Y. Stephenson GA. Mitchell D. Tetrahedron Lett.  2006,  47:  3811 
    Google Scholar
  • 8 Dai W.-M. Shi J. Comb. Chem. High Throughput Screening  2007,  10:  837 
    CrossrefGoogle Scholar
  • 9a Xing X. Wu J. Feng G. Dai W.-M. Tetrahedron  2006,  62:  6774 
    Google Scholar
  • 9b Xing X. Wu J. Luo J. Dai W.-M. Synlett  2006,  2099 
    Google Scholar
  • 9c Feng G. Wu J. Dai W.-M. Tetrahedron Lett.  2007,  48:  401 
    Google Scholar
  • 9d Dai W.-M. Shi J. Wu J. Synlett  2008,  2716 
    Google Scholar
  • For recent reviews, see:
  • 10a Akritopoulou-Zanze I. Djuric SW. Heterocycles  2007,  73:  125 
    Google Scholar
  • 10b Sunderhaus JD. Martin SF. Chem. Eur. J.  2009,  15:  1300 
    Google Scholar
  • 11 Wu J. Nie L. Luo J. Dai W.-M. Synlett  2007,  2728 
    Article in Thieme ConnectGoogle Scholar
  • 12 For a recent review on benzannulated medium-ring heterocycles, see: Majhi TP. Achari B. Chattopadhyay P. Heterocyles  2007,  71:  1011 
    CrossrefGoogle Scholar
  • 13 For a report on U-4CR and gold-catalyzed intramolecular hydroamination sequence, see: Kadzimirsz D. Hildebrandt D. Merz K. Dyker G. Chem. Commun.  2006,  661 
    CrossrefGoogle Scholar
  • For recent reviews on enamides, see:
  • 14a Matsubara R. Kobayashi S. Acc. Chem. Res.  2008,  41:  292 
    Google Scholar
  • 14b Carbery DR. Org. Biomol. Chem.  2008,  6:  3455 
    Google Scholar
  • 15a Dai W.-M. Wang X. Ma C. Tetrahedron  2005,  61:  6879 
    Google Scholar
  • 15b Feng G. Wu J. Dai W.-M. Tetrahedron  2006,  62:  4635 
    Google Scholar
  • 15c Xing X. Wu J. Dai W.-M. Tetrahedron  2006,  62:  11200 
    Google Scholar
  • Selected examples of heterocycle synthesis using 2-alknylbenzaldehydes, see:
  • 16a Tanaka K. Tanaka R. Nishida G. Noguchi K. Hirano M. Chem. Lett.  2008,  37:  934 
    Google Scholar
  • 16b Ding Q. Wu J. Org. Lett.  2007,  9:  4959 ; and references cited therein
    Google Scholar
  • 16c Dyker G. Stirner W. Henkel G. Eur. J. Org. Chem.  2000,  1433 
    Google Scholar
  • 19 For a review, see: Walsh DP. Chang Y.-T. Chem. Rev.  2006,  106:  2476 
    CrossrefGoogle Scholar
1

Part 12. Chemistry of Aminophenols. For part 11, see ref. 9d.

17

General Procedure for the Synthesis of 10a-g A 10 mL pressurized process vial was charged with 0.25 mmol each of 2-aminophenol 5, 2-alknylbenzaldehyde 6, 2-chloro-5-nitrobenzoic acid (7), and benzyl isocyanide (8), and MeOH (2 mL). The loaded vial was then sealed with a cap containing a silicon septum, and put into the microwave cavity, and heated at 80 ˚C for 20 min. Then, an aq soln of K2CO3 (1 mL, 0.30 mmol) was added to the reaction vial through a syringe followed by heating at 100 ˚C for 10 min in the microwave cavity. Water was added to the reaction mixture, and the organic layer was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried over anhyd Na2SO4, and evaporated under reduced pressure. The residue was purified by column chromatography over SiO2 with elution by 20% EtOAc in PE (60-90 ˚C) to afford 10. The structures and yields of the products 10a-g are given in Table  [¹] .
Characterization Data for Compound 10c White crystalline solid; mp 149-151 ˚C (CH2Cl2-hexane). R f  = 0.45 (20% EtOAc-hexane). IR (KBr): 3399, 3322, 2964, 2230, 1651, 1529, 1345, 1272, 1225 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.84 (d, J = 2.4 Hz, 1 H), 8.28 (dd, J = 8.4, 2.4 Hz, 1 H), 7.59-7.55 (m, 1 H), 7.45 (br s, 1 H), 7.37-7.25 (m, 7 H), 7.18-7.12 (m, 2 H), 7.04 (d, J = 8.8 Hz, 1 H), 7.00 (dd, J = 8.8, 2.4 Hz, 1 H), 6.41 (br s, 1 H), 6.35 (t, J = 5.6 Hz, 1 H), 4.66 and 4.59 (ABqd, J = 14.8, 6.0 Hz, 2 H), 2.21 (t, J = 7.2 Hz, 2 H), 1.48-1.37 (m, 2 H), 1.11 (s, 9 H), 0.88 (t, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 168.9, 165.4, 165.2, 151.9, 148.9, 144.7, 137.8, 135.4 (br), 132.4, 129.7 (br), 129.0, 128.6 (2×), 128.4, 128.3, 127.6 (2×), 127.5, 127.4, 127.2, 124.9, 124.2, 121.1, 120.2, 97.4, 77.6, 66.6, 43.9, 34.4, 31.0 (3×), 21.9, 21.4, 13.5 (two aromatic carbons were not seen). MS (+ESI): m/z (%) = 624 (100) [M + Na+]. Anal. Calcd for C37H35N3O5: C, 73.86; H, 5.86; N, 6.98. Found: C, 73.85; H, 5.83; N, 7.01.

18

General Procedure for the Synthesis of 13a-g A 10 mL flask was charged with 10 (0.25 mmol) and Pd(PhCN)2Cl2 (2.5 ¥ 10-² mmol, 10 mol%). The flask was evacuated and backfilled with N2 (repeated three times). To the degassed flask was added degassed anhyd THF (2.5 mL) followed by heating at 60 ˚C for 24 h. Water was added to the reaction mixture, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried over anhyd Na2SO4, and evaporated under reduced pressure. The residue was purified by flash column chromatography over SiO2 with elution by 20% EtOAc in PE (60-90 ˚C) to give 13. The structures and yields of 13a-g are given in Table  [³] . Full characterization data for compounds 13a,b and 13d-g can be found in the Supporting Information.
Characterization Data for Compound 13c White crystalline solid; mp 223-225 ˚C (CH2Cl2-hexane). R f  = 0.47 (20% EtOAc-hexane). IR (KBr) 2961, 1661, 1529, 1346, 1274 cm-¹. ¹H NMR (500 MHz, DMSO-d 6, 80 ˚C): δ = 8.63 (s, 1 H), 8.39 (dd, J = 8.5, 2.0 Hz, 1 H), 7.58 (d, J = 9.0 Hz, 2 H), 7.37-6.90 (m, 9 H), 6.75 (d, J = 7.0 Hz, 2 H), 6.42 (br s, 1 H), 6.27 (br s, 1 H), 5.02 (br s, 1 H), 4.55 (br s, 1 H), 2.30-2.10 (m, 2 H), 1.50-1.30 (m, 2 H), 1.01 (s, 9 H), 0.78 (br s, 3 H). ¹³C NMR (125 MHz, DMSO-d 6, 80 ˚C): δ = 165.1, 164.6, 163.6, 151.8, 148.2, 144.7, 140.0(br), 137.8, 133.5, 130.8, 130.0(br), 129.1, 128.1, 127.9 (3× ), 127.7, 126.6, 126.5 (2×), 126.2, 124.3 (br), 124.0, 121.9, 120.2, 116.6 (br), 67.4 (br), 46.90, 35.9, 34.2, 30.8 (3×), 20.2, 13.7 (two aromatic carbons were not seen). MS (+ESI): m/z (%) = 624 (32) [M + Na+], 602 (100) [M + H+]. Anal. Calcd for C37H35N3O5: C, 73.86; H, 5.86; N, 6.98. Found: C, 73.86; H, 5.91; N, 6.86.