2-Substituted-2,3-dihydro-1H-quinolin-4-ones via Acid-Catalyzed Tandem Rupe Rearrangement-Donnelly-Farrell Ring Closure of 2-(3′-Hydroxy­propynyl)anilines

Abstract

A range of 2-substituted 2,3-dihydro-1H-quinolin-4-ones have been synthesized from anilines by a two-step process involving Sonogashira coupling with a propargyl alcohol then acid-catalyzed cyclization of the resulting 2-(3′-hydroxypropynyl)anilines. The cyclization reaction appears to proceed via re­gioselective rearrangement of the propargyl alcohol to an α,β-unsaturated ketone (Rupe rearrangement) and then 6-endo-trig ring closure (Donnelly-Farrell cyclization). The isolation of the α,β-­unsaturated ketone intermediate in one example supports this pathway.

quinolinone - Sonogashira coupling - Rupe rearrangement - cyclization - alkaloids - alkynes

References and Notes

1 Michael JP. Nat. Prod. Rep.  2008,  25:  166 

2 Sable D. Murakawa GJ. Dis. Mon.  2004,  50:  381 

3 Atwal MS. Bauer L. Dixit SN. Gearien JE. Morris RW. J. Med. Chem.  1965,  8:  566 

4 LaMontagne MP. Blumbergs P. Smith DC. J. Med. Chem.  1989,  32:  1728 

5 Xia Y. Yang Z.-Y. Xia P. Bastow KF. Tachibana Y. Kuo S.-C. Hamel E. Hackl T. Lee K.-H. J. Med. Chem.  1998,  41:  1155 

6 Zhang S.-X. Feng J. Kuo S.-C. Brossi A. Hamel E. Tropsha A. Lee K.-H. J. Med. Chem.  2000,  43:  167 

7 Ahmed N. van Lier JE. Tetrahedron Lett.  2006,  47:  2725 

8 Gong Y. Kato K. J. Fluorine Chem.  2004,  125:  767 

9 Nemoto T. Fukuda T. Hamada Y. Tetrahedron Lett.  2006,  47:  4365 

10 Shintani R. Yamagami T. Kimura T. Hayashi T. Org. Lett.  2005,  7:  5317 

11 Donnelly JA. Farrell DF. Tetrahedron  1990,  46:  885 

12 Donnelly JA. Farrell DF. J. Org. Chem.  1990,  55:  1757 

13 Grigg R. Liu A. Shaw D. Suganthan S. Woodall DE. Yoganathan G. Tetrahedron Lett.  2000,  41:  7125 

14 Kundu NG. Mahanty JS. Das P. Das B. Tetrahedron Lett.  1993,  34:  1625 

15 Clarke IP. Meth-Cohn O. ARKIVOC  2000,  (iii):  372 

16 Majumdar KC. Taher A. Ponra S. Synlett  2010,  735 

17 Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  16:  4467 

18 Chinchilla R. Nájera C. Chem. Rev.  2007,  107:  874 

19 Ames DE. Bull D. Takundwa C. Synthesis  1981,  364 

20 Mal’kina AG. Brandsma L. Vasilevsky SF. Trofimov BA. Synthesis  1996,  589 

21 Melissaria AP. Litt MH. J. Org. Chem.  1992,  57:  6998 

22 Although we did not explore this, it is also possible to synthesize 2-alkynylanilines directly from anilines by C-H activation at the 2-position, see: Tobisu M. Ano Y. Chatani N. Org. Lett.  2009,  9:  3250 

23 Swaminathan S. Narayanan KV. Chem. Rev.  1971,  429 

24 Jacubert M. Provot O. Peyrat J.-F. Hamze A. Brion J.-D. Alami M. Tetrahedron  2010,  66:  3775 

25 Muthukrishnana M. Mujahida M. Punitharasua V. Dnyaneshwara DA. Synth. Commun.  2010,  40:  1391 

26 Lord MD. Negri JT. Paquette LA. J. Org. Chem.  1995,  60:  191 

27 Liu HJ. Shia KS. Shang X. Zhu BY. Tetrahedron  1999,  55:  3803 

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General Procedure for the Sonogashira Couplings with 2-Methylbut-3-yn-2-ol (2a)
The iodo-, bromo-, or triflate-substituted aniline was dissolved in Et₃N-pyridine (1:1, 0.1 M), and nitrogen was bubbled through for 10 min at r.t. 2-Methylbut-3-yn-2-ol (2a 1.5 equiv) was added, and the solution was stirred for 10 min with nitrogen bubbling through. CuI (0.05 equiv), Ph₃P (0.5 equiv), and (PPh₃)₂PdCl₂ (0.05 equiv) were then added, and the resulting suspension was heated at 90 ˚C for 1.5-3 h (see Table  [¹] ). The reaction mixture was cooled to r.t. and quenched with a sat. solution of NaCl. The mixture was then extracted twice with EtOAc, and the combined organic phases were dried over MgSO₄, filtered, and concentrated in vacuo. The desired products were purified by flash chromatography.
N -[2-(3-Hydroxy-3-methylbut-1-ynyl)phenyl]acetamide (3a)
Colorless oil (76% yield). ESI-HRMS: m/z calcd for C₁₃H₁₅NO₂Na: 240.1000; found: 240.1001 (Δ = 0.4 ppm). ESI-MS: m/z (%) = 240 (95) [MNa⁺], 200(100). ^¹H NMR (400 MHz, CDCl₃): δ = 8.29 (d, J = 8.3 Hz, 1 H, 6-H), 7.81 (br s, 1 H, NH), 7.31 (dd, J = 7.7, 1.3 Hz, 1 H, 3-H), 7.26 (td, J = 8.3, 1.5 Hz, 1 H, 5-H), 6.96 (t, J = 7.4 Hz, 4-H), 2.15 (s, 3 H, CH ₃CONH), 1.61 [s, 6 H, C(CH ₃)₂OH]. ^¹³C NMR (101 MHz, CDCl₃): δ = 168.4 (s, CO), 138.9 (s, Ar), 131.5 (d, Ar), 129.7 (d, Ar), 123.4 (d, Ar), 119.4 (d, Ar), 111.4 (s, Ar), 101.5 (s, 2 C, Cº), 65.7 [s, C(CH ₃)₂OH], 31.5 [q, 2 C, C(CH ₃)₂OH], 24.8 (q, CH ₃CO). IR: ν_max = 3360, 2924, 2853, 2400, 1662, 1523, 1447 cm^-¹.

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General Procedure for the Acid-Catalyzed Cyclization
Sonogashira coupling product 3a-h was dissolved in concd HCl-H₂O (1:1, v/v; 0.1 M) and heated at 120 ˚C for 1.5-8 h (see Table  [²] ). The reaction mixture was then concentrated in vacuo. Water was then added followed by K₂CO₃ up to pH = 11. The mixture was extracted twice with EtOAc, and the combined organic phases were dried over MgSO₄, filtered, and concentrated in vacuo. Final quinolinones were purified by flash chromatography.
2,2-Dimethyl-2,3-dihydro-1 H -quinolin-4-one (4a)
Yellow oil (70% yield). ESI-HRMS: m/z calcd for C₁₁H₁₄NO: 176.1075; found: 176.1071 (Δ = -2.3 ppm). ESI-MS: m/z (%) = 176 (78) [MH⁺], 120 (100). ^¹H NMR (400 MHz, CDCl₃): δ = 7.83 (dd, J = 7.9, 1.4 Hz, 1 H, Ar), 7.35-7.27 (m, 1 H, Ar), 6.71 (m, 1 H, Ar), 6.63 (d, J = 8.2 Hz, 1 H, Ar), 4.18 (s, 1 H, NH), 2.61 (s, 2 H, 3-H), 1.35 [s, 6 H, NC(CH₃)₂]. ^¹³C NMR (100 MHz, CDCl₃): δ = 194.0 (s, CO), 149.8 (s, Ar), 135.4 (d, Ar), 127.2 (d, Ar), 118.1 (d, Ar), 117.5 (d, Ar), 115.8 (s, Ar), 53.6 (s, 2-C), 50.6 (t, 3-C), 27.7 (q, 2 C, CH₃). IR: ν_max = 3333, 2924, 2853, 1659, 1613, 1481 cm^-¹.