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15.3.1.1.1.6.3.1 Method 1: From β-(Arylamino)-α,β-unsaturated Ketones and Aldehydes; the Beyer–Combes Synthesis

DOI: 10.1055/sos-SD-015-00689

Larsen, R. D.; Cai, D.Science of Synthesis, (200515440.

The BeyerCombes or Combes synthesis entails the cyclization of an intermediate β-aryl­enaminone 210, generally prepared from a diketone 209 and an aniline 208, to the 2,4-disubstituted quinoline 211 by heating in an acidic medium (Scheme 67).[‌290‌,‌473‌‌475‌] Concentrated sulfuric acid is often used as the medium,[‌32‌,‌476‌] but other acids are also effective, such as polyphosphoric acid,[‌477‌‌479‌] hydrochloric acidacetic acid,[‌480‌] and aluminum trichloride.[‌481‌] The formation of the β-arylenaminone is quite general for a variety of substrates; however, the cyclization is very dependent upon the electronic factors of the ring and steric environment at the site of ring closure.[‌475‌,‌482‌,‌483‌] A study of the ring closure versus hydrolysis of the azomethine in aqueous sulfuric acid of varying acid strengths led to the understanding that the cyclization proceeds via a diprotonated azomethine, whereas the hydrolysis proceeds via the neutral azomethine.[‌484‌] The cyclization of azomethines of 2-substituted malonaldehydes is an effective means for preparing the corresponding 3-substituted quinolines. The acids polyphosphoric acid,[‌481‌,‌485‌] aluminum trihalide (chloride, bromide),[‌481‌,‌486‌,‌487‌] sulfuric acid,[‌481‌,‌486‌] 4-toluenesulfonic acid,[‌488‌] or neat zinc(II) chloride at 200300°C[‌489‌] are suitable catalysts for the cyclization. Addition of an arylamino hydrochloride to the azomethine of methazonic acid (the dimer of nitromethane) facilitates the cyclization in refluxing acetic acid.[‌490‌] On the other hand, the cyclization of β-arylaminoenones 212[‌491‌] of α-formyl ketones to quinolines 213 in concentrated sulfuric acid is not straightforward.[‌481‌,‌492‌] The failure[‌492‌] to cyclize is attributed to the trans configuration of the intermediate not being in position for ring closure.[‌493‌,‌494‌] The successful cyclization of these substrates is achieved with zinc(II) chloride.[‌495‌‌497‌]

Meeeee 88 Mee-Meee MeeeeMeeeee Meeeeeeee[‌88‌,‌888‌,‌888‌,‌888‌]

Meeee eee eeeeeeeeeee eeee eee eeee eeeee ee eee eeeeee eeeeeeee ee eeeeee eee 8,8-eeeeeeeeeeeee eeeeeeeee, eee eeeeee ee eee eeeeeeee eeeeeeee. Mee eeee eeeeeeee ee eeeeeeee eeee eeeeeeeeee eeeeeeee ee eee eeeeeeeeee eeeee.[‌888‌] Meeeeee, eee eeeeeee ee eee eeeeee eeeeee ee eee β-eeeeeeeeeeeee ee eeeeeee ee eeeeeeee eeee eeeeeeeeeeeeee eeee[‌888‌] ee eeeeee eeee[‌888‌] ee eee eeeeeeeeeee eeeee.[‌888‌,‌888‌] Meeeee eeee eeeee eeee eeeeee ee eee eeeeeeee.[‌888‌,‌888‌] Meeeeeeeeeeee, eeeeeeee eeeeeeeeeee eeeeeeee eeeeeeee eeeeee ee 8-eeeeeeeeeeeeeeee eeee β-eeeeeeeeeeee-8-ee-8-eee.[‌888‌] Me ee eeeeeeee eeeeeeee ee eee eeeeeeeeeee eeee ee eee eee eeeeeeeeee eeee eeee eeeeeeee, eee eeeeeeeee ee eeeeeeeeeeee eee-eeeeeeeeeee ee eeeeee.[‌888‌] Meeeeee eeeeee eeeeeeeeeee eeee e eeeeee eeeeeeeee eeee eeeeeeeee eeeeeeeeeeee eeee eee eeee ee eee eeeeeeeeee, eeeeeeee ee eeeeeeee eee eeeeeeee.[‌888‌] Mee eee-eeeeeeeeee eeeeeee eeeeeee eeeeeeeeeee eeeeee eeeeeeeeeee, eee ee eee eeeeeee-ee-eeeeeeeee eeeee ee eeeeeeeee ee 88:8 eee eeeeeee eeeee eeee eeeeeeeee ee 88:88. Meeeeee eeeee eeee eee eeeeeeeeeee eeeee eeeee eeeeeee eee eeeeeeeee ee e eee-eeeeeeeeee eeeeeeeeeeee ee eeeeeeeee ee eee eeeeeee ee eee eeee-eeeeeeeeee ee eeeeeee ee eeeeee eeee ee 888°M, eeeeeee eee eee-eeeeeeeeee eeeeeeee eeeeeeeeeee.[‌888‌]

Meeeeeeeeee ee eee Meeeee eeeeeeeee ee eee eeeeeeeeeeeeeee eeeeeeeee ee 8- ee 8-eeeeeeeeeeeeeee ee eeeee eeeeeeeeeee eeeee ee eeeeeeeeee ee eee eeeeeeeeeeee eeeeeee ee eee eeeeeeee.[‌888‌] Meee eeeeeeeeeeeeeee eee ee eeee eeeee eee eeeeeeeeee ee eee eeeeeeeee ee eeee eee 8-(eeeeeeeeeeeeeee) eeeeeee. Mee eeeeeeee ee eee β-eeeeeeeeeeeee ee eeeee-eeeeeeee,[‌888‌] eeeeeeeeee,[‌888‌] ee eeeeeeeeeeee ee eee eeeeeee eeee eee eeee eeeee ee eeeeeee[‌888‌] eeeee 8-(eeeeeeeeeeeeeee)eeeeeeeeee. Mee eeeeeeee eeeeeeeeeee 888 eee 8-(eeeeeeeeeeeeeee)-eeeeeeeeeee eeeeeee 888 ee eeeeee eeeeee eeeeeeee (Meeeee 88).[‌888‌‌888‌] Mee eeee eeee eeeee eeee eeee eee eeeee ee eeee 8-(eeeeeeeeeeeeeeeeee)-8,8,8,8,8,8-eeeeeeeeeeeeeeeee-8,8-eeeee, eeeee eeeeeeee eeee eeeeee ee eee 8-(eeeeeeeeeeeeeee)eeeeeeeee eeee eeeeeeee(MM) eeeeeeee.[‌888‌] Meee eeeeeeeeeeeeee eeee, 8-(eeeeeeeeeeeeee)eeeeeeeeee eee eeeeeeee eeee ee eeeeeeeeee.[‌888‌] Meee eee 8-eeeeee eeeee ee 888 eee 8-(eeeeeeeee­eeeeee)eeeeeeeee 888 ee eeeeeeee ee eeee eeeee. M eeeeeee ee eeee eeeeeeeee eee eeeeeeeee eee eeee eeeeeeee, eeee ee eeeeeeeeeeeeee eeee,[‌888‌,‌888‌,‌888‌] eeeeeeee(MM) eeeeeeee,[‌888‌] eeee(MM) eeeeeeee,[‌888‌] eee eeeeeeeeee eeeeeeee.[‌888‌,‌888‌] Meeeeeeeeee ee 8-eeeeeeeeeeeeeeeeeee eeee eeeeeeeeeeeeee eeee eeeeee eeeee[e]eeeeeeeeee.[‌888‌]

Meeeee 88 Meeeeeeee Meeeeeeeeee ee Meeeeeeeeeeeeeeeeeeeeeee[‌888‌,‌888‌‌888‌]

Meeeeeeeeeee Meeeeeeee

8,8-Meeeeeeee-8-eeeeee-8-eeeeeeeeeeeeeee (888, M8=M8=MMe; M8=Me); Meeeeee Meeeeeeee: [‌88‌]

8,8-Meeeeeeeeeeeeeee (888, M8=M8=MMe; 8.8e, 88eeee) eee eeeeeeeeeeeeee (888, M8=Me; 8.8e, 88eeee) eeee eeeeee eeeeeeee ee e eeeeeeeeeee eeeeee ee e eeeeeee eeeee eeee. Mee eeeee eeee ee 8M ee MMe eee eeee eeeee. M8M eeeeeeeee ee eeeeeeee eeeeee e eee eeeeeee eee eee eeeeeeee eee eeeeeeee eeeeee 8e. Me eeeeeee eee eeeeeeee ee eeeee, eee eee eeeeeeeeeeee. Meeee eee eeeeeeeeeeeeeeeeee (eee MeMM), eee β-eeeeeeeeeeeee 888 eee eeeeeeee ee eeee eeeee eeeeee eeeeee, ee 888°M; eeeee: 8.8e (eeeee).

Mee β-eeeeeeeeeeeee 888 (8e, 88eeee) eee eeeeeeeee eeeeeeeee ee eeee eeeee M8MM8 (88eM). Mee eeeee eeeeee eeeeeee eeeeee ee eeeeeee eeee eee eeee eee eeee eeee eeee eeee eeee eeeeeeeee ee eeee, eeeeee ee e eeee eeeeee eeeee eeee eeeeeeeeeee ee e eeee eeeeeeeeeeee. Meeee eeeeeeee eeeeeeeee eee ee eeeeeee eeee eee, eee eeee eee eeeeee eeee M8M eee eee eeee eee eeeeeeee eeee eeeeee MeMM eeee. M eeee eeee eeeeee eee eeeeeeeee, eeeee eee eeeeeee ee eeeeeeeeeee. Meeee eeeeeeeeee ee e eeeeee eee eeeeeee eeee M8M ee eee eeeeeeeeeeeeee (MeMM) ee e eeeeeee. Meeeeee eeee MeMM eeeeeeeeee eee eeeeeeeee, eeeee eeeeeeeee eeee eee eeeeeee ee eeee eeeeeeee eeeeee; eeeee: 8.88.8e (8888%); ee 888°M.

8-Meeee-8,8-eeeeeeeeeeeeeeeee (888, M8=M; M8=Me; M8=Me); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee 8-eeeeeeeeeeee (888, M8=M; M8=Me; 8e, 88eee) eee eeeeeee-8,8-eeeee (888, M8=Me; 8e, 88eeee) eee eeeeeeee eee 8e. Mee eeeee eeeeeeeeee eee eeeeeeeee eeee eeeeeee (MMMMMMM: eeeeeeeeee) eee eeeee (MeMM8). Meeee M8MM8 (88eM) eee eeeeee ee e eeeee eeee eee eee eeeee eeeeeeeeee eee eeeee eeeeeeee eeee 88eee eee eee eeeeeee eee eeeeee eee e eeeeeee 88eee. Mee eeeeeee eee eeeeee, eeee eeeeeeee eeee ee MM8, eee eee eeeee eeeeeee eee eeeeeeeee eeee eeeeeee eee eeeee (MeMM8). Meeeee eeeeeeee eeeeeeee eee eeeeeee ee eeeeeeeeeeeee. Mee eeeee eeeeeee eee eeeeeeee ee eeeee eeeeeeeeeeee, eeeeeeeee eeee Me8M, eee eeeee (MeMM8). Meeeeee ee eeeeeee eeee eee eeeeeeeee ee e eeeeee eee; eeeee: 8.8e (88%); ee 888888°M/888Meee.

8-(Meeeeeeeeeeeeee)eeeeeeeee (888, M8=M); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee eee eeeee eeeeee 888 (M8=M; 8.8e, 88eeee), MMMe8 (8.8eM, 8.8e, 88eeee), eee eeeeeee (88eM) eee eeeeee ee 888°M eee 8e. Mee eeeeeeeee eeeeeeeeee eee eeeeee eeee eee. ee Me8MM8. Mee eeeeeee eee eeeeeeeee eeee Me8M (8 × 88eM), eeeeeeee ee eeeeee eee, eee eeeeee eeee MM8Me8/eeeeee ee Me8M/eeeeee (8:8) ee eeeeee eee eeeeeeeee ee eeeeeeeee eeeeeee; eeeee: 8.8e (88%); ee 88.888.8°M.

References


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