Aniline, 3- -, EMME

In 1939, Gould and Jacobs reported the condensation of aniline with acetyl malonic ester (AME) and ethoxymethylenemalonate (EMME), respectively, followed by cyclization of anilinomethylenemalonic ester 13 and 14 in mineral oil to afford the esters 15 and 16. Saponification of the esters gave the known acids 17 and 18, respectively. 

A mixture of aniline 131 (20 mmols) and EMME (22 mmols) was warmed to 100 °C for 80 min with a light N2 flow to remove the ethanol which was formed. Hexanes was added and the reaction mixture warmed and allowed to cool to rt to give malonate 132 as a slightly pink solid in 85% yield. For malonate 132 mp = 76-77 °C IR (KBr) 1739... 

In 1897, Claisen and Haase prepared amino- and A-phenylaminomethy-lenemalonates (9, R1 = H, Ph R2 = H) in the reactions of diethyl ethoxy-methylenemalonate (EMME) with ammonia and aniline (1897LA75). This reaction and its one-pot version later became the basic synthetic methods for preparing aminomethylenemalonates (1) (see Sections IV,A,1 and IV,A,2). 

Fluoro-3-(2-methyl-l,3-dithian-2-yl)aniline was reacted successfully with EMM E in toluene. Toluene was distilled off until the head temperature reached 120-125°C (84EUP106489 85EUP153163 87JHC1509). 

Af-EthyI-/V-[3-(4-pyridyl)phenyl]aminomethylenemalonate was prepared in the reaction of /V-ethyl-3-(4-pyridyl)aniline and EMME at 165°C for 0.5 hr (85USP4537735) (Scheme 19). In the reactions of N-alkyl-yV-arylamines (105) and EMME at 120-140°C for 20 min, /V-alkyl-AA-arylaminomethylenemalonates (106) were prepared in 54-81% yields (72HCA1319). 

Substituted anilines were reacted with EMME in diphenyl ether by heating to 185°C, with distillation of the ethanol formed. The temperature of the reaction mixture was then raised to 245°C and the reaction mixture was heated at 245°C for 1 hr to give ethyl 6-substituted quinoline-3-carboxylates in good yields (85USP4560692). 

The reaction follows the same course when one of the alkoxy groups in the starting material is replaced by alkyl. Thus, condensation of aniline (23-4) with EMME... 

A somewhat different approach is used for the preparation of the analogue that contains a trifluoromethyl group. The scheme involves first the conversion of ort/zo-trifluoromethyl aniline (27-1) to a quinolol. The compound is thus condensed with EMME and cyclized thermally (27-2). That intermediate is then saponified the resulting acid is decarboxylated and finally converted to the 4-chloroquinoline (27-3) by reaction with phosphorus oxychloride. The displacement of chlorine with methyl anthranilate (27-4) then affords the coupled intermediate (27-5). An ester interchange of that product with glycerol leads to the glyceryl ester. There is thus obtained the NSAID flocatfenine (27-6) [31]. 

The same scheme affords a true quinolone when applied to an aniline. Condensation of piperonylamine (38-7) with EMME followed by cyclization of... 

---