Synthesis of Quinolone-Fused Multi-ring-Sized Heterocycles via Combined Claisen Rearrangement/Ring-Closing Metathesis Reactions

Abstract

Synthetic strategy on 4-quinolone nucleus coupling aza-Claisen rearrangement and ring-closing metathesis was developed. Thus, quinolone-fused multiring-sized oxygen heterocycles 5a-c were prepared from 5-hydroxy-7-methoxy-3-(4-methoxyphenyl)-4(1H)-quinolone (1). According to the same strategy, azepino[2,3-f]quinolone derivative 9 was synthesised from triflate 6.

Key words

quinolone - Claisen rearrangement - olefin - ring-closing metathesis

References

• 1a Grubbs RH. Chang S. Tetrahedron  1998,  54:  4413 
• 1b Armstrong SK. J. Chem. Soc., Perkin Trans. 1  1998,  371 
• 1c Phillips AJ. Abell AD. Aldrichimica Acta  1999,  32:  75 
• 1d Fürstner A. Angew. Chem. Int. Ed.  2000,  39:  3012 
• 1e Trnka TM. Grubbs RH. Acc. Chem. Res.  2001,  34:  18 
• 1f Blechert S. Connon SJ. Angew. Chem. Int. Ed.  2003,  42:  1900 
• 2a Bertinato P. Sorensen EJ. Meng D. Danishefsky SJ. J. Org. Chem.  1996,  61:  8000 
• 2b Nicolaou KC. He Y. Vourloumis D. Vallberg H. Roschangar F. Sarabia F. Ninkovic S. Yang Z. Trujillo JI. J. Am. Chem. Soc.  1997,  119:  7960 
• 2c Fürstner A. Langemann K. J. Am. Chem. Soc.  1997,  119:  9130 
• 2d Stefinovic M. Snieckus V. J. Org. Chem.  1998,  63:  2808 
• 2e Fürstner A. Thiel OR. Kindler N. Bartkowska B. J. Org. Chem.  2000,  65:  7990 
• 2f Labrecque D. Charron S. Rej R. Blais C. Lamothe S. Tetrahedron Lett.  2001,  42:  2645 
• 3a Fürstner A. Langemann K. Synthesis  1997,  792 
• 3b Goldring WPD. Hodder AS. Weiler L. Tetrahedron Lett.  1998,  39:  4955 
• 3c Dirat O. Vidal T. Langlois Y. Tetrahedron Lett.  1999,  40:  4801 
• 3d Hunt JCA. Laurent P. Moody CJ. Chem. Commun.  2000,  1771 
• 3e Crimmins MT. King BW. Zuercher WJ. Choy AL. J. Org. Chem.  2000,  65:  8499 
• 3f Lane C. Snieckus V. Synlett  2000,  1294 
• 3g Boyer F.-D. Hanna I. Nolan SP. J. Org. Chem.  2001,  66:  4094 
• 3h Chatterjee AK. Toste FD. Goldberg SD. Grubbs R. Pure Appl. Chem.  2003,  75:  421 
• 4a Joseph B, Darro F, Guillaumet G, Kiss R, and Frydman A. inventors; PCT Int. Appl. WO  0112607.  ; Chem. Abstr. 2001, 134, 193348
• 4b Joseph B. Béhard A. Lesur B. Guillaumet G. Synlett  2003,  1542 
• 5 Chattopadhyay SK. Maity S. Panja S. Tetrahedron Lett.  2002,  43:  7781 
• 6a Ziegler FE. Chem. Rev.  1988,  88:  1423 
• 6b Frauenrath H. In Methods of Organic Chemistry (Houben-Weyl), Stereoselective Synthesis   Vol. E21d:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Thieme; Stuttgart: 1995.  p.3301-3756  

7

Typical RCM Procedure: Under argon atmosphere, Grubb’s reagent (19.6 mg, 0.02 mmol) was added to a solution of 4a (93 mg, 0.24 mmol) in dry CH₂Cl₂ (10 mL). The final solution was stirred at r.t. for 2 h. The solvent was evaporated. The residue was purified by column chromatography (petroleum ether-EtOAc, 2:8; then EtOAc) to give 70 mg (81%) of 5a.

8

Physical data of compound 5a: mp 175-176 °C (EtOAc). IR (KBr): ν = 1626, 1609, 1584, 1511 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 7.52 (d, 2 H, J = 8.8 Hz, Ar-H), 7.42 (s, 1 H, =CH), 6.89 (d, 2 H, J = 8.8 Hz, Ar-H), 6.36 (s, 1 H, Ar-H), 5.89-5.77 (m, 1 H, CH=), 5.51-5.45 (m, 1 H, CH=), 4.80-4.77 (m, 2 H, CH₂), 3.90 (s, 3 H, OCH₃), 3.80 (s, 3 H, OCH₃), 3.69 (s, 3 H, NCH₃), 3.58-3.54 (m, 2 H, CH₂). ¹³C NMR (62.90 MHz, CDCl₃): δ = 175.6 (CO), 159.7 (C), 158.7 (C), 158.6 (C), 141.6 (C), 140.4 (CH), 130.1 (2 CH), 128.6 (CH), 128.2 (C), 125.7 (CH), 124.4 (C), 123.1 (C), 115.9 (C), 113.7 (2 CH), 91.7 (CH), 70.2 (CH₂), 55.7 (CH₃), 55.4 (CH₃), 41.4 (CH₃), 21.5 (CH₂). MS (IS): m/z = 364
(M + H⁺). Anal. Calcd for C₂₂H₂₁NO₄: C, 72.71; H, 5.82; N, 3.85. Found: C, 73.03; H, 5.94; N, 3.77.

9

All new compounds gave satisfactory spectroscopic (¹H-, ¹³C NMR, MS and IR) and analytical data.

10

Physical data of compound 7: mp 119-120 °C (EtOAc). IR (KBr): ν = 3460, 1630, 1610, 1570, 1560, 1512 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 10.18 (broad s, 1 H, NH), 7.49 (d, 2 H, J = 7.8 Hz, Ar-H), 7.43 (s, 1 H, =CH), 6.93 (d, 2 H, J = 7.8 Hz, Ar-H), 6.06 (s, 1 H, Ar-H), 6.17-5.89 (m, 2 H, =CH), 5.34-5.25 (m, 1 H, =CH₂), 5.08-4.95 (m, 3 H, =CH₂), 3.90-3.82 (m, 5 H, OCH₃ + CH₂), 3.79 (s, 3 H, OCH₃), 3.61 (s, 3 H, NCH₃), 3.44-3.42 (m, 2 H, CH₂). ¹³C NMR (62.90 MHz, CDCl₃): δ = 178.7 (CO), 162.0 (C), 158.6 (C), 154.9 (C), 142.1 (C), 140.2 (C), 137.9 (C), 137.2 (C), 130.1 (2 CH), 128.1 (CH), 121.8 (CH), 115.1 (CH₂), 114.4 (CH₂), 113.6 (2 CH), 112.0 (CH), 110.7 (C), 86.1 (CH), 55.4 (CH₃), 55.3 (CH₃), 51.4 (CH₂), 41.5 (CH₃), 30.2 (CH₂). MS (IS):
m/z = 391 (M + H⁺). Anal. Calcd for C₂₄H₂₆N₂O₃: C, 73.82; H, 6.71; N, 7.17. Found: C, 73.95; H, 6.60; N, 7.08.

11

Physical data of compound 9: mp 245-246 °C (EtOAc). IR (KBr): ν = 1671, 1635, 1612, 1575, 1513 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 7.54 (s, 1 H, =CH), 7.50 (d, 2 H, J = 8.7 Hz, Ar-H), 6.88 (d, 2 H, J = 8.7 Hz, Ar-H), 6.69 (s, 1 H, Ar-H), 5.75-5.68 (m, 1 H, =CH), 5.52-5.40 (m, 2 H, CH₂ + =CH), 3.98 (s, 3 H, OCH₃), 3.81 (s, 3 H, OCH₃), 3.78 (s, 3 H, NCH₃), 3.63-3.43 (m, 3 H, CH₂), 1.74 (s, 3 H, COCH₃). ¹³C NMR (62.90 MHz, CDCl₃): δ = 174.9 (CO), 169.5 (CO), 158.9 (C), 158.6 (C), 142.9 (C), 141.8 (C), 140.8 (CH), 130.1 (2 CH), 128.2 (C+CH), 127.7 (C), 124.2 (CH), 123.3 (C), 117.0 (C), 113.8 (2 CH), 95.6 (CH), 56.0 (CH₃), 55.4 (CH₃), 43.6 (CH₂), 41.6 (CH₃), 21.8 (CH₃), 21.5 (CH₂). MS (IS): m/z = 405 (M + H⁺). Anal. Calcd for C₂₄H₂₄N₂O₄: C, 71.27; H, 5.98; N, 6.93. Found: C, 70.99; H, 6.12; N, 6.89.