Ethyl 4,4,4-trifluoroacetoacetate, reaction with

The Knorr pyrrole synthesis was also employed for the synthesis of 3-trifluoropyrroles [91]. Treatment of ethyl trifluoroacetoacetate 267 with sodium nitrite in acetic acid led to the oxime 268. Refluxing with zinc dust and addition of 1,3-dicarbonyl compounds 269 afforded the 3-trifluoromethylpyrroles 270 in moderate yields. Using more acidic trifluoroacetic acid allowed to lower the reaction temperature to 70 °C [92]. Using a similar approach, the tricarboxylic acid ester 273 was prepared starting from the acetone dicarboxylic acid ester 271 and the fluorinated keto ester 272 [93]. 

CuCl/THF followed by catalytic hydrogenation to give the pyrroloquinoline 134. Nitration of the later gave the 9-nitro derivative 135. Reduction of 135 followed by reaction with ethyl trifluoroacetoacetate gave 136 that upon cyclization gave the tetracyclic compound 137 (98JMC623) (Scheme 26). 

Substituents in the pyranone ring are derived from the dicarbonyl component and hence variation in the nature of 3- and 4-substituents is relatively easy. Thus, ethyl benzoylacetate gives 4-phenylcoumarins as for instance in a synthesis of dalbergin (357) (76T2407, 8iiJC(B)9l8) and use of ethyl trifluoroacetoacetate leads to 4-trifluoromethylcoumarins. A study of the reaction of the latter with 3-aminophenol identified the optimum conditions for coumarin formation, but noted the simultaneous formation of the two quinoline derivatives (358) and (359) (80JOC2283). 

The activation of the trifluoromethyl substituent is strong enough to allow the 1,3-dipolar reaction to occur with trisubstituted dipolarophiles, provided a second electron-withdrawing substituent is present in the molecule (Table 11). Under similar conditions non-fluorinated analogs are unreactive (entry 3).5-77-80 The cycloaddition with ethyl trifluoroacetoacetate is a striking example (Table 11, entry 2) in this case, the dipolarophile reacts in its enolic form (Z-isomer). 

Dipolar cycloaddition of ethyl 2-diazo-4,4,4-trifluoroacetoacetate 201 with isobutyl vinyl ether produced dihydrofuran 202 which underwent elimination affording 2-trifluoromethylfuran 203 [130], A related reaction with alkynes directly... 

Reaction of aniline (304) and ethyl trifluoroacetoacetate (305) resulted in formation of 4-trifluoromethylquinolin-2-one (306) from which 2-brom-4-trifluoromethyl-quinoline (307) was synthesized further. Reaction of compound 307 with pyridines 308 at the presence of a palladium complex as the catalyst resulted in quinoline ligands 309 [185] (Scheme 88). 

Acylketene methodology [10] was also developed for the synthesis of 4-pyrones bearing a polyflnoroalkylthio substituent. The reaction of ethyl trifluoroacetoacetate with fluoroalkanesulfenyl chlorides afforded componnds 12 (Scheme 6). 

Ethyl 2-(p-fluorobenzyl)trifluoroacetoacetate reacted with resorcinol in 70 % sulfuric acid at 100 °C to provide coumarin 315a. Upon treatment with N,N-dimethylcarbamoyl chloride in the presence of NaH, this compound was readily converted into the corresponding iV,A -dimethylcarbamate 316a, which was tested as a TNF-a inhibitor [175]. A similar reaction of resorcinol with diethyl... 

Preparation of Fluacrypyrim (301) started with reaction of 0-isopropylisourea hydrochloride and ethyl trifluoroacetoacetate to give pyrimidine 361 (Scheme 80) [292], Alkylation of 361 with bromide 362 (or the corresponding chloride 363 [293,... 

Amino-6,6n,7,8,910-hexahydropyrido[2,l-c][l,4]benzoxazine was reacted with ethyl 4,4,4-trifluoroacetoacetate in boiling benzene for 12-16 h, then the reaction mixture was concentrated in vacuo and the residue was treated with cone. H2SO4 at 100°C to give tetracyclic 11-trifluoromethyl-l,2,3,4,4a,5,8,9-octahydropyrido[l, 2 4,5][l,4]oxazino[3,2-a]quinolin-9-one in 30% yield (OlMIPl). 

A high-yield preparation of 2- and 4-trifluoromethyl-2-quinolinones was sought. Depending on reaction conditions, the condensation of anilines with ethyl 4,4,4-trifluoroacetoacetate <03S2005> led to two different quinolinones as shown. 

CuFc204 nanoparticles are an efficient catalyst for the synthesis of 4-methylcoumarins via Pechmann reaction of phenols with ethyl acetoac-etate in water at room temperature (14SC697). A similar Pechmann reaction of phenols with ethyl 4,4,4-trifluoroacetoacetate catalyzed by molecular iodine affords 4-trifluoromethylcoumarins (14TL6715). Highly functionalized coumarins are formed by an iron(III) chloride-mediated cascade reaction of salicylaldehydes or 2 -hydroxyacetophenones with various activated methylene compounds (14SC1507). 

It was based on an enantioselective domino Michael/hemiketalization reaction of ethyl 4,4,4-trifluoroacetoacetate and other trifluoromethyl-substituted nucleophiles with p,y-unsaturated a-ketoesters catalyzed by a chiral quinine-derived thiourea. 

We found that if 2 equivalents of ethyl 4,4,4-trifluoroacetoacetate (ETFAA) were reacted with one equivalent of an aldehyde and ammonium hydroxide in ethanol under the standard Hantzsch dihydropyridine synthesis conditions, a cis-dihydroxypiperidine 8a was obtained in modest yields after recrystallization. By carefully monitoring the crude reaction mixture with nmr, we were able to identify one of the other products as the trans isomer 8b which is usually more soluble and remains in the mother liquor. The other remaining products were identified as the ammonium salt, enamine, and possibly hydrate, ammonia adduct and hemiketal of ETFAA. We found that better results were obtained if 2 equivalents of ETFAA were reacted with one equivalent of an aldehyde first in a nonprotic solvent followed by passing excess gaseous ammonia into the reaction mixture to form a mixture of cis - and trans-2,6-dihydroxypiperidines 8a and 8b. The nmr shows that, in this manner, the combined yields of cis- and trans-2.6-dihydroxypiperidines 8a and 8b are in excess of 90%. The nmr spectrum also reveals that an isomeric mixture of 2-... 

The classic Hantzsch pyrrole synthesis is based on the reaction of ketones bearing electron-withdrawing group in a-position with a-haloketones or aldehydes in the presence of amine or ammonia. For example, the condensation of the masked bromoacetaldehyde 278 with ethyl 4,4,4-trifluoroacetoacetate (279) and propargyl amine gave the pyrrole 280 [95], The yield of pyrrole 280 was not given. 

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