Ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylates by a tandem addition‐elimination‐S_NAr reaction

Abstract

The ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate ring structure, important in several drug compounds, has been prepared in two steps from ethyl 2‐(2‐fluorobenzoyl)acetate. Treatment of this β‐ketoester with N,N‐dimethylformamide dimethyl acetal gives a 97% yield of the 2‐dimethylaminomethylene derivative. Reaction of this β‐enaminone with primary amines in N,N‐dimethylformamide at 140°C for 48 h then affords the 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate esters in 60–74% yields by a tandem addition‐elimination‐SNAr reaction. The synthesis of the starting material as well as procedural details and a mechanistic scenario are presented. J. Heterocyclic Chem., (2011).

Ethyl 1,4‐Dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylates by a Tandem SNAr‐Addition‐Elimination Reaction

“…In fact, the target heterocycles were produced in similar yields from all amines when the R group was primary, secondary or aromatic. Our previous work indicated that primary amines incorporating a tertiary R group reacted poorly, and this was borne out in this study where tert ‐butylamine (entry g ) gave the lowest yield. Nevertheless, hindered aromatic amines, such as 2‐methylaniline ( o ‐toluidine, entry o ), afforded dihydronaphthyridine 7o in a respectable 78% yield, despite the steric congestion created by the ortho methyl group.…”

“…, entries d and f ) gave the carboxylic acids rather than the ester products. This anomaly was not encountered in our previous work to prepare 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate esters , or from any other amine in this study. Attempts to suppress this process by running the reaction at lower temperature (90–100°C) were unsuccessful and gave ester‐acid mixtures.…”

“…We recently reported a two‐step synthesis of 1‐alkyl‐ and 1‐aryl‐1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate esters from ethyl 2‐(2‐fluorobenzoyl)acetate involving conversion to a β‐enaminone followed by reaction with a primary amine (e.g., RNH 2 ) . This strategy avoided the intermediacy of an alkoxymethylene derivative and afforded the final products in higher yields (by 5–15%) over previous preparations.…”

“…The current project sought to extend this method to the synthesis of 1‐alkyl‐ and 1‐aryl‐1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylates, which would feature a tandem S N Ar‐addition‐elimination reaction with a 2‐chloropyridine moiety as the acceptor in the S N Ar step. Like the dihydroquinolines described previously , the target dihydronaphthyridines have high potential as antibiotics as well as anti‐HIV and anti‐inflammatory drugs . Thus, improved access to these structures is highly desirable.…”

New Synthesis ofN-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide

“…To a stirred suspension of 18 (200 g, 0.75 mol) in toluene (2.3 L) was added DMF-DMA (401 mL, 3.02 mol). The mixture was stirred at 90-100 C for 24 h and then cooled to » 10 C. The resulting yellow solid was collected, washed with cooled toluene (115 mL £ 3), and dried under reduced pressure to give 19 (214 g, 89%) as a bright-yellow powder, which was used directly at the next step, mp: 174-175 C. 1 N-(7-Ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (20). Compound 19 (180 g, 0.56 mol) and Raney-Ni (wet, 20 g) were added to DME (4.6 L), and stirred for 12 h at rt under 1 atm of hydrogen.…”