Trifluoromethyl pyruvate

Friedel-Crafts Alkylation Reactions. The activation of glyoxylate esters,trifluoromethyl pyruvate esters, and unsaturated a-ketoesters by catalyst 2 converts these materials into effective electrophiles for asymmetric Friedel-Crafts alkylation reactions with activated arenes (eqs 16 and 17). In fact, bis(triflate) (2) is far superior to tbe bis(hexafluoroantimonate) complex at catalyzing the enantioselective alkylation of benzene derivatives. Aniline and anisole derivatives both give the reaction, as do heterocyclic aromatic compounds such as indole and furan. 

The asymmetric Friedel-Crafts reaction of trifluoromethyl pyruvate 53 with aromatic compounds is catalyzed by cationic Pd(II) complexes with BINAP or SEGPHOS [184]. The reaction proceeded at -30 °C to afford the product 63 in 89% ee with (S)-BINAP and in 82% ee with (S)-SEGPHOS (Scheme 45). In sharp contrast to the situation of the carbonyl-ene reaction, the BINAP ligand provides higher enantioselectivity than the SEGPHOS ligand. 

W-(Methoxycarbonyl)triphenylphosphine imide reacts with methyl trifluoro-pyruvate to form methyl A -methoxycarbonyl 2 immo-3,3,3 trifluoropropionate m 95% yield This convenient building block easily adds nucleophiles such as Gngnard reagents without competing side reactions at the ester group to form trifluoromethylated amino acids [J.S] (equation 31)... 

The 2,2-bis(tnfluoromethyl)-4-methyl-2f/-5-oxazolone, readily available from 2,2-bis(trifluoromethyl)-l,3-oxazolidin-5-one, is a synthetic equivalent of activated pyruvate [90] (equation 16). 

Methyl-1,2-benzenediamine (215, R = Me) with the hydrate of 3,3,3-trifluoro-pyruvic acid gave a mixture of isomers (216, R = Me) and (217, R = Me) (dioxane, reflux, 30 min 98%) from which neither appears to have been isolated in a pure state in contrast, 4-nitro-1,2-benzenediamine (215, R = NO2) and the same synthon gave a mixture of 6-nitro- (216, R = NO2) and 7-nitro-3-trifluoromethyl-2(l//)-quinoxalinone (217, R = NO2) (dioxane, reflux, 4 h 95%), from which both isomers were isolable, albeit with... 

The enantiomeric excess (ee) of the hydrogenated products was determined either by polarimetry, GLC equipped with a chiral column or H-NMR with a chiral shift reagent. Methyl lactate and methyl 3-hydroxybutanoate, obtained from 1 and 2, respectively, were analized polarimetry using a Perkin-Elmer 243B instrument. The reference values of [a]o(neat) were +8.4° for (R)-methyl pyruvate and -22.95° for methyl 3-hydroxybutcinoate. Before GLC analysis, i-butyl 5-hydroxyhexanoate, methyl 5-hydroxyhexanoate, and n-butyl 5-hydroxyhexanoate, obtained from 1, 5, and 6, respectively, were converted to the pentanoyl esters, methyl 3-hydroxybutanoate was converted to the acetyl ester, and methyl 4-methyl-3-hydroxybutanoate obtained from 2 was converted the ester of (+)-a-methyl-a-(trifluoromethyl)phenyl acetic acid (MTPA). 

Nitisinone (59 Qrfadin ) Leptospermone 2-[2-Nitro-4-(trifluoromethyl) benzoyl] cyclohexane-1,3-dione NP-derived Plant Antityrosinaemia Inhibits /5-hydroxyphenyl-pyruvate dioxygenase (HPPD) activity 208-210, 518-524... 

Kavana M, Moran GR. (2003) Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl) benzoyl]- ,3-cyclohexanedione. Biochemistry 42 10238-10245. 

An asymmetric intermolecular carbonyl-ene reaction catalyzed by 1 mol% of chiral A-triflyl phosphoramide (/ )-4t (1 mol%, R = 4-MeO-CgH ) was developed by Rueping and coworkers (Scheme 69) [88], Various a-methyl styrene derivatives 163 underwent the desired reaction with ethyl a,a,a-trifluoropyruvate 164 to afford the corresponding a-hydroxy-a-trifluoromethyl esters 165 in good yields along with high enantioselectivities (55-96%, 92-97% ee). The presence of the trifluoromethyl group was crucial and the use of methyl pyruvate or glyoxylate instead of 164 resulted in lower reactivities or selectivities. 

With regard to carboxylic derivatives, there is generally little difference in chemical shift among the various trifluoroacetic acid derivatives, as exemplified by the examples in Scheme 5.30. Also, the effect of moving the CF3 farther from the carboxylic acid function is similar to that seen with the aldehydes and ketones. Trifluoromethyl ketones will often be in equilibrium with their hydrated form, in which case signals from both the hydrate and water-free ketone will be observed, as is the case for the following pyruvate example. 

In order to reveal the importance of the basic quinuclidine N and the OH group of CD in the enantioselection, the efficiency of CD as chiral modifier of Pt was compared to those of some CD derivatives (Table 3). Two typical trifluoromethyl ketones, 1 and 4, were hydrogenated in an apolar solvent and in acetic acid. Data on ethyl pyruvate 9 hydrogenation are also schown in Table 3 for comparison. 

The group of Baiker also conhibuted significanhy to the Orito reachon. For the classic combinahon of the Pt/CD/pyruvate ester, these authors found that a side (aldol) reaction affected the product ee-value, and that some improvement was observed following its removal [11]. Conhnuous hydrogenahon in a fixed-bed reactor was also demonstrated in supercritical ethane [12] and in acehc acid [13]. The range of applicable substrates was also expanded to P-trifluoromethyl-P-ketoester [14], cyclohexane-1,2-dione [15], aromahc methyl ketones [16], -hydroxyketones [17] and isahn derivatives [18]. Some selected results are shown in Scheme 10.3. 

Thermal and Lewis acid catalyzed ene reactions of electron-deficient ketones proceed in good yield. Dialkyl oxomalonate esters " and pyruvate esters have been most extensively studied. 1,2,3-Tri-ketones, methyl phenylglyoxylate, carbonyl sulfide, carbonyl cyanide, hexafluoroacetone, hexafluorocyclobutanone and 1,1,1-trifluoromethyl ketones have also been developed as enophiles. 

The intrinsic limitation of the previous methods (i.e., exclusive use of 1,3-dimethoxybenzene 9d) was efficiently addressed by Chen under solvent-free conditions [10]. Besides increased reactivity, the absence of solvent positively affected also the stereoselectivity in the FC alkylation of substituted aryl ethers with trifluoromethyl ethyl pyruvate. A range of quaternary benzyhc stereogenic centers was obtained in stereocontrolled manner (ee up to 93%, 99% after recrystaUization). Interestingly, under solvent-free conditions, the loading of the catalyst 12c was reduced up to 0.01 mol%, stiU maintaining a respectable isolated yield (70%) and enantiomeric excess for 14b (85% Scheme 5.4). 

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