Trifluoroacetaldehyde

Chemically, 2,2,2-trifluoroethanol behaves as a typical alcohol. It can be converted to trifluoroacetaldehyde [75-90-1] or trifluoroacetic acid [76-05-1] by various oxidi2iag agents such as aqueous chlorine solutions (51) or oxygen ia the preseace of a vanadium pentoxide catalyst (52). Under basic conditions, it adds to tetrafluoroethylene and acetylene to give, respectively, 1,1,2,2-tetrafluoroethyl 2/2/2 -trifluoroethyl ether [406-78-0] (53) and... 

Fluoroalkjiations are frequentiy performed indirectly using tandem reactions. Arenes react with sodium borohydride in trifluoroacetic acid to afford otherwise difficult to obtain l,l,l-trifluoro-2,2-diarylethanes. Presumably sodium borohydride reacts initially with the trifluoroacetic acid to produce the trifluoroacetaldehyde or its equivalent, which rapidly undergoes Friedel-Crafts-type condensation to give an intermediate carbinol. The carbinol further alkylates ben2ene under the reaction conditions giving the observed product. The reaction with stericaHy crowded arenes such as mesitylene and durene... 

Indole has also been demonstrated to undergo a thermally induced condensation with trifluoroacetaldehyde ethyl hemiacetal to give a variety of products depending on the reaction conditions, e.g., the 6,12-dihydroindolo[3,2-f)]carbazole 172, which could be isolated in low yield from the mixture originating from the heating of equimolar amounts of the reactants in the absence of solvent. The formation of an intermediate indolenine species was suggested to account for the outcome (88JFC47). 

It has been shown to metabolize trifluoroethene to glyoxylate, difluoroacetate, and the rearranged product trifluoroacetaldehyde (Fox et al. 1990). The last reaction is analogous to the formation of trichloroacetaldehyde from trichloroethene by the same strain (Oldenhuis et al. 1989). 

The soluble MMO from Methylsosinus trichosporium OB3 produced difluoroacetate as one of the main products from the oxidation of trifluoroethene and a low yield of trifluoroacetaldehyde by rearrangement (Fox et al. 1990). 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

Reaction of 2-cyanomethylpyridine with iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)-iV -(4-methylphenyl)carbodiimides, and with (1,1,2,2,2-pentachloro- and l,l-dichloro-2,2,2-trifluoroethyl)isocyanates or A-methoxycarbonyl-l,2,2,2-tetrachloro-, — l-chloro-2,2-trifluoroacetaldehyde imines afforded 3-aryl-4-cyano-l-(4-methylphenyl)imino-3-trifluoromethyl-2,3-dihydro-17/-pyrido[l,2-f]pyrimidines and 4-cyano-3-trichloro-, 4-cyano-3-trifluoro-17/-pyrido[l,2-4pyrimidin-l-ones, respectively <2004CHE47>. Refluxing 2-cyanomethylpyridine and iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)isocyanates in benzene furnished l-aryl-4-cyano-l-trifluoromethyl-l,2-dihydro-3//-pyrido[l,2-4pyrimidin-3-ones. However, when the solution of the isocyanate was added dropwise to the solution of 2-cyanomethylpyridine, and the reaction mixture was then treated with NEt at room temperature, the isomeric 3-aryl-4-cyano-3-trifluoromethyl-2,3-dihydro-l//-pyr-ido[l,2-dpyrimidin-l-ones were obtained. Reaction of l-(acetyl- and benzoylmethylene)-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinolines with PhCONCS yielded 1-acetyl-, 1 -benzoyl-9,10-dime thoxy-3-pheny 1-6,7-dihydro-2//-pyrimido[6,l- ]isoquinoline-2-thiones <2003SL2369>. 

Diketones are reductively cyclized in a TFA-catalyzed reaction. The cycliza-tion of the cage structure shown in Eq. 236 illustrates this ring closure in the formation of an acetal of trifluoroacetaldehyde.409 The organosilane reduction of triketone 69 followed by Jones oxidation gives the cyclic ketoether in fair yield (Eq. 237).410... 

Analogously, the reaction of trifluoroacetaldehyde dimethylhydrazone 249 with TFAA gave 250, which condensed in situ with o-phenylenediamine to afford quinoxaline 251 in good yield <00TL9267>. 

A related catalyst 20 was used in the diastereoselective carbonyl-ene reaction between ethylidenecyclohexane, ethylidenecycloheptane, or 2-methyl-2-butene and trifluoroacetaldehyde (21, R = CF3, Equation (ll))19 or methyl glyoxylate (R = C02Me).20 The best results were obtained when X = Br 63-85% yields are obtained with syn/anti ratios of 95 5 or better, and ee s of the. qw-isomer of 74-89%. 

Formylation can be also achieved when DMF is used as an electrophile. Thus, the cathodic reduction of CF3Br in DMF using an aluminum anode provides trifluoroacetaldehyde in good yield (Eq. 8) [21]. 

By the way, trifluoroacetaldehyde is a versatile fluoro building block. However the chemical or electrochemical oxidative transformation of trifluoro-ethanol to trifluoroacetaldehyde has been unsuccessful. Trifluoroacetaldehyde is therefore generally produced by the reduction of trifluoroacetic acid ester or acid chloride using an excess of LAH. The anodic substitution at fluoroaikyl phenyl sulfides is a useful alternative because it realizes the transformation of economical trifluoroethanol to highly valuable trifluoroacetaldehyde equivalents as shown in Scheme 6.5. 

In fact, 3 is easily converted into trifluoroacetaldehyde phenylhydrazone without any defluorination by alkali hydrolysis (Eq. 22). 

The carbon-fluorine bond is relatively resistant to metabolism. In vitro studies with rabbit, rat, and human hepatic microsomes and rat hepatocytes (Olson and Surbrook 1991 Olson et al. 1990a, 1990b) identified the major route of metabolism of HFC-134a as oxidation by P-450 2E1 to 2,2,2,1-tetrafluoroethanol elimination of hydrogen fluoride or fluoride ion yields 2,2,2-trifluoroacetaldehyde, which is further oxidized to trifluoroacetic acid. 

The reduction of aldehydes is not usually apparent because aldehydes are generally rapidly oxidized and oxidation to carboxylic acids is basically an irreversible process. Aldehydes with electron-withdrawing groups, however, such as trifluoroacetaldehyde, are more readily reduced since they are less readily oxidized and therefore this pathway is more evident. 

When trifluoroacetaldehyde ethyl hemiacetal [F3CCH(OH)OEt] is treated with enamines in hexane at room temperature, it provides a source of the aldehyde under mild conditions. Subsequent reaction with the enamine can be used to prepare -hydroxy-/ -trifluoromethyl ketones, F3CCH(OH)CH2COR. The enamine plays successive roles as base, ammonium counterion, and then carbon nucleophile as the sequence proceeds. 

Starting from Fluoral Fluoral (trifluoroacetaldehyde) is an unstable gas that must be prepared before use by dehydration of the corresponding hydrate (commercially available). In spite of this limitation, fluoral itself has been used as a substrate in various reactions. Among the most recent examples, carbonyl-ene and hetero-Diels-Alder reactions deserve mention. The use of chiral Lewis acid... 

Irradiation of hexafluorobiacetyl in the vapor phase produces a 2 1 mole ratio of carbon monoxide and hexafluoroethane, products consistent with an initial carbon-carbon bond cleavage.62 However, vapor phase irradiation of hexafluorobiacetyl in the presence of a large excess of 2,3-dimethylbutane vapor or in 2,3-dimethylbutane solution gave less than 1% carbon monoxide and trifluoromethane. No trifluoroacetaldehyde or hexafluoroacetone was produced in the latter reaction. Instead a complex mixture of products, which was not separated and identified but whose infrared showed the presence of a hydroxyl band and a diminished carbonyl band, was obtained. This observation is consistent with product formation via hydrogen abstraction. 

The chemistry of trifluoroacetaldehyde is more extensive. Inhibitors of Human Leukocyte Elastase [153-155] and antagonists of Leukotrienes D4 and E4 [156] were prepared recently using trifluoral chemistry. 

Male Fischer 344 rats were exposed by inhalation to 1% 2-chloro-1,1,1 -trifluoroethane for 2 h and then urine was collected for 24 h. Urinary metabolites identified by 19F nuclear magnetic resonance and gas chromatography/mass spectrometry were 2,2,2-trifluoroethyl glucuronide (16%), trifluoroacetic acid (14%), trifluoroacetaldehyde hydrate (26%), trifluoroacetaldehyde-urea adduct (40%) and inorganic fluoride (3%). A minor, unidentified metabolite was also detected. No covalent binding of fluorine-containing metabolites was observed in the liver and kidney from the exposed rats (Yin et al., 1995). In-vitro incubation of 2-chloro-1,1,1-trifluoroethane with rat liver microsomes and an NADPH-generating system has been shown to involve a dechlorination reaction (Salmon et al., 1981) that produced trifluoroacetaldehyde hydrate as the only metabolite (Yin et al., 1995). 

The photolysis of trifluoroacetaldehyde at a wavelength of 3130 A. has been shown by Dodd and Smith68 to follow a reaction scheme... 

A series of halogenated ethanes 1 containing the trifluoromethyl group has been oxidized under various conditions.5-7 When water is present in the reaction mixture, the acid 3 is usually formed during the reaction when water is absent, the acid halide 2 formed can be hydrolyzed in a trap with water. Trifluoroacetaldehyde hydrate 4 is formed6 as a minor product in addition to the acid when 2-chloro-l,l,l-trifluoroethane is treated with oxygen and chlorine under UV irradiation with subsequent reflux of the mixture with hydrogen peroxide. 

The results of the oxidations of polyfluoropropanes and higher alkanes are strongly dependent both on the structure of the substrate and the oxidation agent. Shorter chain compounds formed by degradative oxidation are usually present in the reaction mixture as byproducts. Thus, 1,1,1 -trifluoropropanecan be converted by nitric acid and oxygen into a mixture of trifluoroacetaldehyde (5) and l,l,l-trifluoro-3-nitropropane (6).8... 

Trifluoroacetaldehyde (5) Fraction 1 (a 20-g aliquot) was extracted with H20 (20 mL) at rt the remaining insoluble liquid (7.6 g) was combined with Fraction 2. The aqueous extract (12.5 g aliquot) was added dropwise to P205 (50 g) and a colorless gas was evolved which solidified in a condenser immersed in liquid N2. Considerable decomposition of the mixture occurred during the dehydration. Redistillation of the condensate yielded the product as a colorless hygroscopic liquid yield 3 g bp — 18.8 to — 17.5 C/748 Torr. 

A third approach to the preparation of allyl lluorovinyl ethers is the reaction of an allylic alcohol with trifluoroacetaldehyde, as illustrated by an alternative synthesis of 37a.17 Cinnamyl alcohol (47) forms with trifluoroacetaldehyde a hemiacetal, which is converted into bromide 48 via the mesy late. Reductive elimination affords 37a, which undergoes Claisen rearrangement within one hour in refluxing carbon tetrachloride to give 2,2-difluoro-3-phenylpent-4-enal (38a).17... 

Table 1. Thermal Condensation of Substituted Imidazoles with Trifluoroacetaldehyde Ethyl Hemiacetal [5]...

Trifluoroacetaldehyde hydrate (5.4 g, 47 mmol) and anhyd K2C03 (0.1 g, 0.7 mmol) were added at rt to 2-nitro-l-phenylethane (5.9 g, 39 mmol), and the mixture was heated at 50 °C for 12 h. The mixture was cooled and dissolved in Et20 (100 mL), washed with H20, the organic layer separated, dried, and concentrated, giving a viscous oil yield 9.5 g (98%). 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

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