Highly regioselective Friedländer annulations with unmodified ketones employing novel amine catalysts: Syntheses of 2-substituted quinolines, 1,8-naphthyridines, and related heterocycles

Journal of Organic Chemistry

Volumn 68, Issue 2, 2003, Pages 467-477

  Dormer, Peter G ^a   Eng, Kan K ^a   Farr, Roger N ^a   Humphrey, Guy R ^a   McWilliams, J Christopher ^a   Reider, P J ^a   Sager, Jess W ^a   Volante, R P ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

REGIOSELECTIVITY;

AMINES; CATALYST ACTIVITY; SUBSTRATES;

KETONES;

1,8 NAPHTHYRIDINE DERIVATIVE; ALDEHYDE; AMINE; AROMATIC COMPOUND; CHROMONE DERIVATIVE; HETEROCYCLIC COMPOUND; KETONE; PYRROLIDINE DERIVATIVE; QUINOLINE DERIVATIVE;

ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; CATALYST; CHEMICAL REACTION; CHEMICAL STRUCTURE; ENANTIOMER; PROTON NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; SYNTHESIS; TEMPERATURE SENSITIVITY;

EID: 0037462413     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo026203i     Document Type: Article

References (59)

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32. A recent report describes the reaction of methyl ketones with 2-aminobenzyl alcohol in the presence of KOH and a ruthenium catalyst, providing the 2-substituted quinolines as products. Two examples of aliphatic methyl ketones are reported to yield the 2-substituted quinolines in excess of the 2,3-disubstituted quinolines (ratios ranged from 70:30 to 80:20). The mechanism has not been discerned as yet, but is believed to proceed by way of oxidation of the 2-aminobenzyl alcohol to 2-aminobenzaldehyde, followed by a Friedländer reaction sequence. Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Chem. Commun. 2001, 2576.
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39. A description of the automated discovery procedure can be found in the Experimental Section.
40. Adamantylamine and tert-butylamine were also evaluated in a screening run. At 23 °C, less than 0.5 mol % product was observed. After 24 h at 70 °C, the major products were the corresponding imines. A small amount (< 5mol %) of Friedländer products was observed after aging at 70 °C, with regioselectivity of 40:60 and 33:66 in favor of 4a for adamantylamine and t-butylamine, respectively.
41. An independent examination of the reaction with catalytic amounts of azetidine (5%) indicated that this was the most reactive of the amine catalysts. The regioselectivity remained essentially the same as with 1.1 equivalents of catalyst. The substituted azetidine, L-azetidine 2-carboxylic acid, did not catalyze the Friedländer reaction at room temperature, but provided an 87 mol % conversion after 23 h at 70 °C, albeit with only a 67:33 ratio of 3a:4a, respectively.
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