ZnCl₂-Catalyzed Intramolecular Cyclization Reaction of 2-Aminochalcones Using Polymer-Supported Selenium Reagent: Synthesis of 2-Phenyl-4-quinolones and 2-Phenyl-2,3-dihydroquinolin-4(1H)-one

Abstract

A new and efficient method for the synthesis of 2-phenyl-4-quinolones and 2-phenyl-2,3-dihydroquinolin-4(1H)-ones is described. The reaction involves ZnCl₂-mediated polystyrene-supported selenium-induced intramolecular cyclization of 2-amino­chalcones and subsequent traceless or functionalizing cleavage of selenium linker.

polystyrene-supported selenium reagent - intramolecular cyclization - zinc chloride - 2-phenyl-4-quinolones - 2-phenyl-2 - 3-dihydroquinolin-4(1H)-one

References and Notes

1a Osawa T, Ohta H, Akimoto K, Harada K, Soga H, and Jinno Y. inventors; EP  0343574. 

1b Huang L.-J. Hsieh M.-C. Teng C.-M. Lee K.-H. Kuo S.-C. Bioorg. Med. Chem.  1998,  6:  1657 

1c Llinàs-Brunet M. Bailey MD. Ghiro E. Gorys V. Halmos T. Poirier M. Rancourt J. Goudreau N. J. Med. Chem.  2004,  47:  6584 

1d Frutos RP. Haddad N. Houpis IN. Johnson M. Smith-Keenan LL. Fuchs V. Yee NK. Farina V. Faucher A.-M. Brochu C. Haché B. Duceppe J.-S. Beaulieu P. Synthesis  2006,  2563 

Selected references on 2-aryl-4-quinolones as antitumor agents:

2a Hadjeri M. Peiller E.-L. Beney C. Deka N. Lawson MA. Dumontet C. Boumendjel A. J. Med. Chem.  2004,  47:  4964 

2b Ferlin MG. Chiarelotto G. Gasparotto V. Via LD. Pezzi V. Barzon L. Palu G. Castagliuolo I. J. Med. Chem.  2005,  48:  3417 

2c Gasparotto V. Castagliuolo I. Chiarelotto G. Pezzi V. Montanaro D. Brun P. Palu G. Viola G. Ferlin MG. J. Med. Chem.  2006,  49:  1910 

3a Reitsema RH. Chem. Rev.  1948,  43:  43 

3b Katritzky AR. Lagowski JM. In Advances in Heterocyclic Chemistry   Vol. 1:  Katritzky AR. Academic Press; New York: 1963.  p.339-437  

3c Mphahlele MJ. El-Nahas AM. J. Mol. Struct.  2004,  688:  129 

4a Li JJ. Conrad-Limpach Reaction in Name Reactions: A Collection of Detailed Reaction Mechanisms   2nd ed.:  Springer; Berlin: 2003.  p.81 

4b Staskun B. Israelstam SS. J. Org. Chem.  1961,  26:  3191 

For methods utilizing Eaton’s reagent:

4c Zewge D. Chen C.-Y. Deer C. Dormer PG. Hughes DL. J. Org. Chem.  2007,  72:  4276 

Niementowski methods:

4d Fuson RC. Burness DM. J. Am. Chem. Soc.  1946,  68:  1270 

5a Beifuss U. Ledderhose S. Synlett  1997,  313 

5b Strekowski L. Wydra RL. Cegla MT. Czarny A. Harden DB. Patterson SE. Battiste MA. Coxon JM. J. Org. Chem.  1990,  55:  4777 

6 Torii S. Okumoto H. Xu LH. Sadakane M. Shostakovsky MV. Ponomaryov AB. Kalinin VN. Tetrahedron  1993,  49:  6773 

7 Fürstner A. Hupperts A. Ptock A. Janssen E. J. Org. Chem.  1994,  59:  5215 

8 Tollari S. Cenini S. Ragaini F. Cassar L. J. Chem. Soc., Chem. Commun.  1994,  1741 

9 Huang X. Liu ZX. J. Org. Chem.  2002,  67:  6731 

10 Petragnani N. Stefanib HA. Valdugab CJ. Tetrahedron  2001,  57:  1411 

11 Nicolaou KC. Pfefferkorn JA. Cao GQ. Kim S. Kessabi J. Org. Lett.  1999,  1:  807 

12a Yanada K. Fujita T. Yanada R. Synlett  1998,  971 

12b Fujita K. Taka H. Oishi A. Ikeda Y. Taguchi Y. Fujie K. Saeki T. Sakuma M. Synlett  2000,  1509 

12c Nicolaou KC. Pfefferkorn JA. Cao G.-Q. Angew Chem. Int. Ed.  2000,  39:  734 

12d Nicolaou KC. Pfefferkorn JA. Barluenga S. Mitchell HJ. Roecker AJ. Cao G.-Q. J. Am. Chem. Soc.  2000,  122:  9968 

13a Huang X. Tang E. Xu WM. J. Comb. Chem.  2005,  7:  802 

13b Tang E. Huang X. Xu WM. Tetrahedron  2004,  60:  9963 

13c Xu WM. Huang X. Tang E. J. Comb. Chem.  2005,  7:  726 

14a Clémence F. Le Martret O. Collard J. J. Heterocycl. Chem.  1984,  21:  1345 

14b Dubroeucq M.-C, Bains EL, Paris J.-M, Marne VS, and Renault C. inventors; US  5017576. 

14c Hadjeri M. Mariotte A.-M. Boumendjel A. Chem. Pharm. Bull.  2001,  49:  1352 

14d Ding D. Li X. Wang X. Du Y. Shen J. Tetrahedron Lett.  2006,  47:  6997 

15 Nicolaou KC. Pastor J. Barluenga S. Winssinger N. Chem. Commun.  1998,  1947 

16

Benzeneselenenyl bromide was prepared by the reaction of diphenyldiselenide (1.0 equiv) and bromine (1.0 equiv) in CH₂Cl₂ at r.t. for 1 hour.

17

General Procedure for Obtaining 4-Quinolone 4 via Route A
An oven-dried 50 mL round-bottomed flask was charged with a suspension of the swollen polystyrene-supported selenenyl bromide (Br: 0.99 mmol/g) resin (1.0 g) in dry CH₂Cl₂ (20 mL). ZnCl₂ (40 mol%) was added. After stirring for 0.5 hour at r.t., substituted 2-aminochalcone 5 (5.0 mmol) was added, and the reaction was stirred for another 12 hours. The resin 3 was collected by filtration, washed with H₂O (4 × 20 mL), THF-H₂O (v/v = 3:1; 2 × 20 mL), THF (2 × 15 mL), MeOH (2 × 15 mL) and CH₂Cl₂ (2 × 15 mL) and dried in vacuo. To a flask containing the suspension of the swollen resin 3 in THF (20 mL) was added 30% H₂O₂ aq (1.0 mL), and the mixture was stirred for 1 hour at 0 ˚C, followed by 20 min at r.t. After the reaction, the mixture was filtered, and the resin was washed with CH₂Cl₂ (2 × 20 mL). The filtrate was washed with H₂O (2 × 10 mL), dried over MgSO₄, and evaporated to dryness in vacuo.
1-Benzyl-2-phenyl-4-quinolone (4a) ^¹H NMR (500 MHz, CDCl₃): δ = 8.53 (1 H, d, J = 7.8 Hz), 7.56 (1 H, m), 7.45-7.26 (10 H, m), 6.98 (2 H, d, J = 7.3 Hz), 6.56 (1 H, s), 5.33 (2 H, s). ^¹³C NMR (125 MHz, CDCl₃): δ = 176.81, 155.64, 140.94, 135.98, 135.21, 132.57, 129.74, 128.98, 128.64, 128.01, 127.64, 126.65, 126.49, 125.34, 125.22, 124.09, 117.30, 112.59, 52.36. IR (KBr): ν_max = 1608, 1486, 763 cm^-¹. HRMS: m/z calcd for C₂₂H₁₈NO [M + H]⁺: 312.1388; found: 312.1385.

18

General Procedure for the Preparation of 2-Phenyl-2,3-dihydroquinolin-4 (1 H )-one (9)
An oven-dried schlenk tube was charged with a suspension of the swollen resin 7 (0.5 g) in dry toluene (10 mL) under nitrogen atmosphere, and tributyltin hydride (0.291 g, 1.0 mmol) or allyltributylstannane (0.331 g, 1.0 mmol) and 2,2′-azobisisobutyronitrile (AIBN, 0.082 g, 0.5 mmol) were added after which the reaction mixture was heated to 90 ˚C for 2 hours. After cooling, the suspension was poured into a fritted funnel, and the resin was washed with CH₂Cl₂ (2 × 10 mL). The filtrate was then concentrated and 10% HCl (5 mL) was added, and the resulting solution was washed with hexanes (3 × 10 mL). The aqueous phase was then neutralized with 10% NaOH and extracted with Et₂O (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO₄, and concentrated to afford the product 9.
1-Acetyl-2-phenyl-2,3-dihydroquinolin-4 (1 H )-one (9a) ^¹H NMR (400 MHz, CDCl₃): δ = 2.43 (3 H, s), 3.22-3.28 (1 H, m), 3.35-3.40 (1 H, m), 6.47 (1 H, br), 7.15-7.22 (7 H, m), 7.44-7.48 (1 H, m), 7.93 (1 H, d, J = 7.6 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 193.1, 170.0, 141.7, 137.9, 134.3, 128.5, 127.5, 127.2, 126.7, 126.0, 125.4, 125.0, 54.6, 42.5, 23.3. IR (film): ν_max = 1693, 1682, 1663, 1601, 1461, 694 cm^-¹. HRMS: m/z calcd for C₁₇H₁₅NO₂: 265.1103; found: 265.1100.