A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid

Amines are a fundamentally important class of biologically active compounds and the ability to manipulate their physicochemical properties through the introduction of fluorine is of paramount importance in medicinal chemistry. Current synthesis methods for the construction of fluorinated amines rely on air and moisture sensitive reagents that require special handling or harsh reductants that limit functionality. Here we report practical, catalyst-free, reductive trifluoroethylation reactions of free amines exhibiting remarkable functional group tolerance. The reactions proceed in conventional glassware without rigorous exclusion of either moisture or oxygen, and use trifluoroacetic acid as a stable and inexpensive fluorine source. The new methods provide access to a wide range of medicinally relevant functionalized tertiary β-fluoroalkylamine cores, either through direct trifluoroethylation of secondary amines or via a three-component coupling of primary amines, aldehydes and trifluoroacetic acid. A reduction of in situ-generated silyl ester species is proposed to account for the reductive selectivity observed.

Herein we report a practical and catalyst-free method to access structurally diverse b-fluoroalkylamines using trifluoroacetic acid (TFA), which occurs through reduction of in situ-generated silyl ester intermediates.

Results
Reaction design. Seeking to develop a practical method for the fluoroalkylation of free amines, the direct use of TFA was attractive (Fig. 2), owing to its availability, low cost and stability. To the best of our knowledge reductive fluoroalkylation reactions using TFA have only been carried out in the presence of either platinum 45 or borane 46 catalysts under Schlenk conditions. Therefore, the development of a general and practical method with wide functional group tolerance would constitute a powerful new approach to the synthesis of fluorinated amines.
Trifluoroethylation reactions of secondary amines. Trifluoroethylation reactions were performed in tetrahydrofuran, with 1.75 equivalents of TFA providing optimal results ( Fig. 3; for optimization, see Supplementary Table 1). Importantly, the reactions were carried out in conventional laboratory glassware.
Performing the reaction open to air in non-anhydrous solvent was not detrimental ( Fig. 3; 1) highlighting the practicality of the method. The phenylsilane and TFA were used as supplied without purification. Acyclic and cyclic secondary amines could be trifluoroethylated in good to moderate isolated yields following flash column chromatography (conversions of 70-90% are typical). Additional moderately basic nitrogen atoms (2,5) are tolerated as are silyl-protected alcohols (7) and free alcohols (9). In the case of the latter, the hydroxyl group undergoes silylation under the reaction conditions and the silyl group is cleaved upon workup with aqueous base. Most significantly, esters are not reduced under the reaction conditions (8). This transformation would not be possible using the conventional amidation/reduction protocol using LiAlH 4 (ref. 43); nor could it be achieved using the Pt 45 or borane-catalyzed reactions 46 . Anilines were relatively poor substrates, with N-methyl anilines typically giving less than 40% conversion to the desired amine (not shown).    Three component trifluoroethylation reactions. We anticipated that we might be able to exploit the acidic, reductive conditions to perform a reductive amination of an aldehyde and a primary amine to form a secondary amine ( Fig. 4; brackets), prior to the trifluoroethylation reaction. In this case, a complex, bespoke, b-fluorinated amine core could be generated. As before, these three-component couplings could be carried out in conventional laboratory glassware with moisture exclusion providing small yield gains. The functional group tolerance of this catalyst-free process allows the inclusion of reductively labile, but synthetically valuable, functional groups including alkenes ( Fig. 4; 15,21,25,27,30,31,34), esters (16,26,39), nitro (11), nitrile (12), Boc-protected amines (33), amides (34), azides (see Supplementary Discussion) and aryl bromides (18,26,28,29,33,35). Acid-sensitive functional groups, for example, furans are also tolerated ( Fig. 4; 27, 28). The stereo-integrity of amino acid derivative 26 was preserved. Alkyl chloride 22 was prepared at gram-scale (5.00 mmol) from the HCl salt of the amine. The procedure was also amenable to ketones (36)(37)(38)(39).
Typically, an initial imine-forming period was followed by the standard reaction, with minor timing/temperature adjustments   beneficial for difficult substrates (full details in Supplementary Methods). Alkyl aldehydes (20,23,32,34) gave poorer conversions relative to stabilized analogues. Slightly increased TFA excesses were beneficial in some cases (27)(28)(29). Analysis of the reaction mixtures in these cases revealed competing over-alkylation (double aldehyde addition to the primary amine), with the resulting basic tertiary amines acting to neutralize the required excess acidity. Other competing pathways include amidation of both the initial and alkylated amine.
Mechanistic investigation. The results depicted in Figs 3 and 4 demonstrate that a general trifluoroethylation reaction with wide functional group tolerance is viable in the absence of a catalyst.
To understand the process further and account for the remarkable functional group tolerance, we conducted mechanistic experiments to ascertain the provenance of the amine product. Intuitively, the product might be expected to arise from silane-mediated amidation 47 , followed by amide reduction by an activated silane; however, an activated reductant is not consistent with the high functional group tolerance observed.
Indeed, trifluoroethylation of piperidine in the presence of trifluoroacetamide 40 resulted in the formation of trifluor-oethylamine 41 and complete recovery of amide 40 (Fig. 5a). This result undermines the intervention of an activated reductant/ trifluoroacetamide intermediate and implies a separate trifluoroethylation pathway. Further evidence for a discrete amination pathway was obtained when the stoichiometry of TFA to amine was examined (Fig. 5b). When the amine and TFA are equimolar, amide product 40 was obtained in moderate yield and none of the trifluoroethylated amine 1 was formed. In contrast, increasing the amount of TFA to 1.75 equivalents resulted in 80% of the fluorinated amine 1 and only 6% of amide 40. We next examined a series of carboxylic acids and observed that the product ratio varied as a function of pK a (Fig. 5c), with higher acidities leading to more amine. Synthetically useful amounts of alkylated amines, for which there are few convenient preparative procedures, are produced when other chlorine and fluorine-containing acids are employed (Fig. 5c, 42-44).
Having ruled out amide reduction we next considered the possible in situ reduction of TFA (or a derivative) to trifluoroacetaldehyde. Given the very high reactivity of this aldehyde it is reasonable to assume that it would react rapidly under the reaction conditions and, in practice, we were unable to observe the aldehyde or derivatives during trifluoroethylation reactions. However, we could identify plausible intermediates via 1   typical amine was replaced with substoichiometric (20 mol%) triethylamine (Fig. 5d), which cannot participate in either the amination or amidation reaction. Under these conditions, we observed that phenylsilane reacts with TFA to afford a mixture of silyl ester intermediates (Fig. 5d) was itself also present in smaller amounts. These observations are consistent with silane-mediated reduction of the highly electrophilic TFA-derived silyl ester intermediates. The privileged reactivity of these trifluoroacetoxy silyl esters towards reduction is further apparent from the competition reaction depicted in Fig. 5e. In this case both phenyl and trifluoromethyl-containing silyl esters would be produced leading to amide and amine products respectively. Based upon these data we depict in Fig. 6 a plausible pathway for trifluoroethylation that is congruous with the foregoing experiments. Specifically, we propose that amine-catalysed dehydrogenative silyl ester formation occurs to generate a mixture of silyl esters, from which point it is possible to generate either amide or amine products depending on the stoichiometry of TFA. In the presence of excess acid (and, therefore, low amine concentration) silane-mediated reduction of the silyl ester intermediates occurs to afford silyl acetals and hemiacetals. Related species at this oxidation level are known to participate in reductive amination reactions with amines in the presence of acetic acid and borohydride or borane reductants 43 . Under the acidic conditions, an equilibrium 43 of the silyl acetals with the amine to form highly reactive iminium ions is proposed. Silane-mediated reduction of the iminium species generates the observed trifluoroethylated products. Conversely, when one equivalent of TFA is used, the concentration of free amine is higher and the electrophilic silyl ester intermediates function as activated acids leading to amide products.

Discussion
In summary, we have demonstrated the first catalyst-free trifluoroethylation reactions of amines using TFA as a bench stable and inexpensive fluorine source. The reactions proceed in conventional glassware without rigorous exclusion of either moisture or air. A wide range of functionalized tertiary b-fluoroalkylamines has been prepared either through direct trifluoroethylation of secondary amines or via a three-component coupling of primary amines, aldehydes and TFA. Importantly, the reaction manifold is applicable to other carboxylic acids, opening the door to an extended range of useful alkylated amines. This novel catalyst-free reaction is expected to be a powerful tool for the construction of functionalized tertiary b-fluoroalkylamines, thereby expanding the range of fluorinated organic compounds for applications in drug discovery, agrochemistry, catalysis and materials science.

Methods
General methods. See Supplementary Methods for further details, and Figs 1-136 for additional data, supporting experiments and spectra.
General procedure for trifluoroethylation of secondary amines. To an oven-dried 10 ml round-bottomed flask fitted with a water condenser under an argon atmosphere (balloon) was added tetrahydrofuran (0.5 ml) and the amine (0.50 mmol) as the free base. The reaction flask was heated in an oil bath at 70°C and added immediately by microsyringe was phenylsilane (123 ml, 1.00 mmol) followed by TFA (67.0 ml, 0.875 mmol). The reaction was stirred at reflux for 2-4 h, allowed to cool and was concentrated. After dilution with diethyl ether, the material was washed with saturated aqueous sodium bicarbonate, the organics dried over magnesium sulfate and the material purified by flash column chromatography to give the trifluoroethylated amine product.
General procedure for three-component trifluoroethylation reactions. To an oven-dried 10 ml round-bottomed flask fitted with a water condenser under an argon atmosphere (balloon) was added the amine (0.50 mmol) and aldehyde (0.50 mmol). Toluene was added (0.5 ml), followed by phenylsilane (31 ml, 0.25 mmol). The reaction was stirred at 70°C for 10 min. Then TFA (67.0 ml, 0.875 mmol) and further PhSiH 3 (123 ml, 1.00 mmol) were added and the reaction heated at 70°C for 16 h, and processed as above to yield the trifluoroethylated amine.
Data availability. All data supporting the findings of this study are available within the article and its Supplementary Information file or from the authors on reasonable request. For NMR spectra of the compounds in this article, see Supplementary Figs