Regioselective Synthesis of Quinolin-4-ones by Pyrolysis of Anilinomethylene Derivatives of Meldrum’s Acid

Abstract

Electron-rich and electron-deficient anilinomethylene derivatives of Meldrum’s acid cyclize equally efficiently to quinolin-4-ones via imidoylketene intermediates under flash vacuum pyrolysis (FVP) conditions.

Key words

quinolin-4-ones - Meldrum’s acid - flash vacuum pyrolysis

References and Notes

• 1a Sterling Drug Inc. Brit.; 1,147,760 Chem. Abstr.  1969,  71:  49967a 
• 1b Cassis R. Tapia R. Valderrama JA. Synth. Commun.  1985,  15:  125 
• 1c Rotzoll S. Reinke H. Fischer C. Langer P. Synthesis  2009,  69 
• 2 Gordon HJ. Martin JC. McNab H. J. Chem. Soc., Chem. Commun.  1983,  957 
• 3 Briehl H. Lukosch A. Wentrup C. J. Org. Chem.  1984,  49:  2772 
• 4 Review: Gaber AM. McNab H. Synthesis  2001,  2059 
• 5 Al-Awadi NA. Abdelhamid IA. Al-Etaibi AM. Elnagdi MH. Synlett  2007,  2205 
• 6 Ramana Rao VV. Wentrup C. J. Chem. Soc., Perkin Trans. 1  1998,  2583 
• 7 McNab H. Aldrichimica Acta  2004,  37:  19 
• 8 George L. Netsch K.-P. Penn G. Kollenz G. Wentrup C. Org. Biomol. Chem.  2006,  4:  558 
• 9 McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 1  1988,  863 
• 11 Hirano J. Hamase K. Zaitsu K. Tetrahedron  2006,  62:  10065 
• 13 Lauer WM. Arnold RT. Tiffany B. Tinker J. J. Am. Chem. Soc.  1946,  68:  1268 
• 14 For example, see: Harrison AG. Honnen LR. Dauben HJ. Lossing FP. J. Am. Chem. Soc.  1960,  82:  5593 
• 16 Reported by: Margolis BJ. Long KA. Laird DLT. Ruble JC. Pulley SR. J. Org. Chem.  2007,  72:  2232 
• 17 Reported by: Price CC. Snyder HR. Bullitt OH. Kovacic P. J. Am. Chem. Soc.  1947,  69:  374 
• 18 Sashida H. Kaname M. Tsuchiya T. Chem. Pharm. Bull.  1990,  38:  2919 
• 19 For example, see: Fields EK. Meyerson S. Acc. Chem. Res.  1969,  2:  273 
• 21 Heindel ND. Kennewell PD. Fish VB. J. Heterocycl. Chem.  1969,  6:  77 
• 22 Frisch MJ. Trucks GW. Schlegel HB. Scuseria GE. Robb MA. Cheeseman JR. Montgomery JA. Vreven T. Kudin KN. Burant JC. Millam JM. Iyengar SS. Tomasi J. Barone V. Mennucci B. Cossi M. Scalmani G. Rega N. Petersson GA. Nakatsuji H. Hada M. Ehara M. Toyota K. Fukuda R. Hasegawa J. Ishida M. Nakajima T. Honda Y. Kitao O. Nakai H. Klene M. Li X. Knox JE. Hratchian HP. Cross JB. Bakken V. Adamo C. Jaramillo J. Gomperts R. Stratmann RE. Yazyev O. Austin AJ. Cammi R. Pomelli C. Ochterski JW. Ayala PY. Morokuma K. Voth GA. Salvador P. Dannenberg JJ. Zakrzewski VG. Dapprich S. Daniels AD. Strain MC. Farkas O. Malick DK. Rabuck AD. Raghavachari K. Foresman JB. Ortiz JV. Cui Q. Baboul AG. Clifford S. Cioslowski J. Stefanov BB. Liu G. Liashenko A. Piskorz P. Komaromi I. Martin RL. Fox DJ. Keith T. Al-Laham MA. Peng CY. Nanayakkara A. Challacombe M. Gill PMW. Johnson B. Chen W. Wong MW. Gonzalez C. Pople JA. Gaussian 03   Gaussian, Inc.; Wallingford CT: 2004. 
• 24 Dunwell DW. Evans D. J. Chem. Soc., Perkin Trans. 1  1973,  1588 

10

Prior isolation of 1 provides much cleaner products 2 (³ 95% yield) than the one-pot method reported in ref. 5.

12

FVP of 2b (0.600 g, T _f = 600 ˚C, T _i = 170 ˚C, t = 50 min, P = 2.3˙10^-5 bar) gave a yellow solid (0.403 g, quant.), recrystallization from MeOH gave 6-methoxy-1H-quinolin-4-one (3b, 0.234 g, 61%); mp 243-246 ˚C (from MeOH; lit.^¹¹ 251-252 ˚C). ^¹H NMR (360 MHz, DMSO-d ₆): δ = 11.78 (1 H, br s), 7.87 (1 H, d, ^³ J = 7.2 Hz), 7.53-7.52 (2 H, m), 7.30 (1 H, dd, ^³ J = 9.1 Hz, ⁴ J = 2.1 Hz), 6.03 (1 H, d, ^³ J = 7.2 Hz), 3.85 (3 H, s), see Figure  [¹] .
FVP of 2c (0.704 g, T _f = 600 ˚C, T _i = 160 ˚C, t = 1 h, P = 1.9˙10^-5 bar) gave a yellow solid (0.414 g, 93%), in which the ratio 3ca/3cb was 7:93 by ^¹H NMR spectroscopy, and which provided pure 7-methoxy-1H-quinolin-4-one (3cb, 0.277 g, 62%), after recrystallization from MeOH, mp 210-212 ˚C (from MeOH; lit.^¹¹ 219-220 ˚C). ^¹H NMR (360 MHz, DMSO-d ₆): δ = 11.62 (1 H, br s), 8.00 (1 H, dd, ^³ J = 7.6 Hz, ⁴ J = 2.5 Hz), 7.84 (1 H, d, ^³ J = 7.6 Hz), 6.94-6.90 (2 H, m), 5.97 (1 H, d, ^³ J = 7.6 Hz), 3.86 (3 H, s), see Figure  [²] .
FVP of 2d (0.850 g, T _f = 500 ˚C, T _i = 160 ˚C, t = 25 min, P = 3.6˙10^-5 bar) gave 8-methoxy-1H-quinolin-4-one (3da, 0.535 g, 99%); mp 124-126 ˚C [from EtOH; lit.^¹³ 134-135 ˚C(hydrate)]. ^¹H NMR (360 MHz, DMSO-d ₆): δ = 7.82 (1 H, d, ^³ J = 7.2 Hz), 7.70 (1 H, dd, ^³ J = 6.5 Hz, ⁴ J = 2.9 Hz), 7.30-7.28 (2 H, m), 6.12 (1 H, d, ^³ J = 7.6 Hz), 4.30 (3 H, s), see Figure  [³] .

15

FVP of 2e (0.610 g, T _f = 600 ˚C, T _i = 200 ˚C, t = 1.25 h, P = 3.1˙10^-5 bar) gave 6-cyano-1H-quinolin-4-one^¹6 (3e) as an orange solid (0.358 g, 94%); mp 186 ˚C (from MeOH). ^¹H NMR (250 MHz, DMSO-d ₆): δ = 8.47 (1 H, dd, ⁴ J = 1.9 Hz, ⁵ J = 0.5 Hz), 8.06 (1 H, d, ^³ J = 7.6 Hz), 8.02 (1 H, dd, ^³ J = 8.7 Hz, ⁴ J = 1.9 Hz), 7.72 (1 H, dd, ^³ J = 8.7 Hz, ⁵ J = 0.5 Hz), 6.20 (1 H, d, ^³ J = 7.6 Hz).
FVP of 2f (0.306 g, T _f = 650 ˚C, T _i = 210 ˚C, t = 25 min, P = 4.0˙10^-5 bar) gave a ca. 25:75 mixture of 5- and 7-cyano-1H-quinolin-4-ones^¹7 (3fa and 3fb; 0.176 g, 94%). ^¹H NMR (250 MHz, DMSO-d ₆): δ (7-isomer, 250 MHz) = 8.28 (1 H, dd, ^³ J = 8.3 Hz, ⁴ J = 0.4 Hz), 8.06 (1 H, m), 7.81 (1 H, m), 7.71 (1 H, dd, ^³ J = 8.3 Hz, ⁴ J = 1.5 Hz), 6.21 (1 H, d, ^³ J = 7.5 Hz).
FVP of 2g (0.604 g, T _f = 600 ˚C, T _i = 180 ˚C, t = 20 min, P = 3.7˙10^-5 bar) gave 8-cyano-1H-quinolin-4-one (3g, 0.242 g, 64%); mp 234-236 ˚C (from MeOH; lit.^¹8 260-262 ˚C). ^¹H NMR (250 MHz, DMSO-d ₆): δ = 8.43 (1 H, dd, ^³ J = 8.0 Hz, ⁴ J = 1.7 Hz), 8.25 (1 H, dd, ^³ J = 7.4 Hz, ⁴ J = 1.7 Hz), 8.00 (1 H, d, ^³ J = 7.2 Hz), 7.51 (1 H, dd, ^³ J = 8.0, 7.4 Hz), 6.32 (1 H, d, ^³ J = 7.2 Hz).

20

FVP of 2h (0.664 g, T _f = 600 ˚C, T _i = 200 ˚C, t = 1 h, P = 3.2˙10^-5 bar) gave 6-nitro-1H-quinolin-4-one (3h, 0.283 g, 66%); mp >320 ˚C (from MeOH; lit.^²¹ 337-342 ˚C). ^¹H NMR (250 MHz, DMSO-d ₆): δ = 8.88 (1 H, d, ^³ J = 2.8 Hz), 8.46 (1 H, dd, ^³ J = 9.2 Hz, ⁴ J = 2.8 Hz), 8.09 (1 H, d, ^³ J = 7.9 Hz), 7.76 (1 H, dd, ^³ J = 9.2 Hz, ⁵ J = 0.5 Hz), 6.24 (1 H, d, ^³ J = 7.9 Hz).

23

FVP of 7 (0.323 g, T _f = 600 ˚C, T _i = 200 ˚C, t = 1 h, P = 3.3˙10^-5 bar) gave a yellow solid (0.182 g) and recrystalli-zation from MeOH provided 1H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one (8, 0.129 g, 62%); mp 285-287 ˚C (from MeOH; lit.^²4 290 ˚C). ^¹H NMR (250 MHz, DMSO-d ₆): δ = 8.45 (1 H, d, ^³ J = 8.0 Hz), 8.00 (1 H, d, ^³ J = 6.9 Hz), 7.58 (1 H, d, ^³ J = 7.6 Hz), 7.50 (1 H, td, ^³ J = 7.6 Hz, ⁴ J = 1.3 Hz), 7.34 (1 H, td, ^³ J = 8.0 Hz, ⁴ J = 1.3 Hz), 5.99 (1 H, d, ^³ J = 6.9 Hz).