Cs2CO3-promoted defluorination and functionalization of α-CF3 carbonyl compounds in the presence of N-, O-, and/or S-nucleophiles

A simple, efficient, and mild method for defluorination and functionalization of 3,3,3-trifluoro carbonyl compounds has been developed. In the present method, Cs2CO3 can easily convert α-trifluoromethyl esters, amides, and ketones into β,β-S-, O- and/or N-substituted α,β-unsaturated carbonyl compounds in the presence of N-, O-, and S-nucleophiles with moderate to excellent yields, and furthermore, this transformation with α-trifluoromethyl ester and a series of 2-aminophenols can result in benzooxazoles in good yields.


Introduction
In the past six decades, hydrouorocarbons have been widely used in pharmaceuticals, agrochemicals, materials, refrigeration, and air conditioning. Introduction of C-F bonds into pharmaceuticals or materials can modify the acidity, lipophilicity, conformation and metabolism of pharmaceuticals, [1][2][3] improve the hydrophobic properties, chemical inertness, and elasticity of materials, 4,5 and sometimes enhance their special water-/stain-resistant and non-sticky characteristics. 6,7 This "uorine effect" or "uorine magic" stems from a very short bond length, low polarizability, being fairly inert and the strong inductive effects of the C-F bond. 8,9 Logically, chemical inertness of C-F bond will make hydro-uorocarbons resistent to biotransformation or biodegradation. 10,11 Thus, continual and increasing use of hydrouorocarbons in modern life has implications for the environment and human health that urgently require attention. 12,13 In light of the environmental concerns associated with organouorine compounds, 14,15 the development of novel synthetic methods for the C-F cleavage and subsequent functionalization is highly required. 16 3,3,3-Triuoropropanoic acid derivatives are one of the very important building blocks to incorporate one CF 3 group into organic molecules. The exploitation of their a-CF 3 enolates as active nucleophiles for the introduction of a CF 3 group have been achieved (Fig. 1, path a), 17-21 but their deuorination and functionization are only scarcely explored, 22 because their direct deuorinations usually require strong basic conditions 23 and the resultant b,b-diuoro-a,b-unsaturated carbonyl compounds are prone to subsequent decomposition even at a low temperature (path b). 24 Recently, deuorination and functionization of 3,3,3-triuoropropanoic acid derivatives have been reported at À78 C to prepare monouoroalkenes via elimination and addition with organolithium or Grignard reagents as C-nucleophiles (path c). 25 These results prompted us to examine deuorination and functionization of a-CF 3 carbonyl compounds with other nucleophiles such as S-, O-, and Nnucleophiles. Herein, we described an efficient and mild deuorinated and functionized method of a-CF 3 carbonyl compounds via a Cs 2 CO 3 -promoted elimination/addition in the presence of a series of N-, O-, S-nucleophiles.

Results and discussion
We initiated our work by studying the reaction of ethyl 3,3,3-triuoropropanoate (1a) and 4-mercaptotoluene (2a) under the basic conditions. As shown in Table 1, in the presence of NaHMDS, the reaction was run at rt for 2 h, and expectedly, 2a was not consumed because of the almost quantitative recovery of 2a. When the reaction was run at 0 C, only a small amount of deuorinated product could be isolated (entry 1, 37%), and its structure was subsequently determined as 3aa. Decreasing reaction temperature to À78 C, only 3aa could be isolated in a higher yield (entry 2, 46%), but the partial-deuorinated product, such as 4aa, was still not isolated. Increasing the amount of 2a did not improve the reaction (entry 3, 47%), instead, increasing the amount of NaHMDS could increase the yield of 3aa up to 88%, albeit without 4aa. LDA had a similar performance to NaHMDS (entry 5, 64%). The above results implied that those bases might rapidly transform the ester into active b,b-diuoro-a,b-unsaturated carbonyl compounds, and then this unstable intermediate could be trapped by 2a to some extent while it was prone to decompose.
Based on the facts that only the trace partial-deuorinated product was observed and the major full-deuorinated product, as one kind of a-oxoketene-S,S-acetals, might be one potentially versatile three-carbon building blocks for the construction of various heterocyclic systems, 26 we turned to optimize the full-deuorinated reaction by screening a variety of other bases for the reaction.
As shown in Table 1, t-BuOK gave a moderate yield (entry 6, 54%) at 0 C, but a higher or lower temperature led to a poorer yield (at rt or À78 C). Similarly, MeONa could give the almost same result (entry 7, 56%). The weaker bases, such as Na 2 CO 3 , AcONa and Et 3 N, could not initiate the reaction (entry 8, 10, 11) while K 2 CO 3 just resulted in a very low yield (entry 9, 15%). To our delight, Cs 2 CO 3 gave the almost quantitative yield and its amount could be reduced from 3.0 to 2.0 equivalents (entry 12, 98% vs. 96%). Subsequently, the solvent screening demonstrated that neither DMF nor EtOH was good to the reaction (entry 13, 15), and DMSO just gave a slightly decreased yield (entry 14, 74%). As a result, THF was chosen as the optimized solvent for the reaction, but therein, elevating the temperature seemed to have an adverse effect on the reaction (entry 16).
With the optimized condition in hand, we subsequently examined the nucleophile scope with a variety of mono-dentate S-, O-, and N-nucleophiles, and the results were depicted in Table 2. For the S-containing nucleophiles, aryl thiols generally gave their deuorinated products in good to excellent yields (3aa-3af, 46-96%), and the substituent electronic effect in the Table 1 The optimization on the reaction condition for the defluorination and functionization of 3,3,3-trifluoropropanoic acid derivatives  aryl ring may have little inuence on the reaction, instead, the bulkier nucleophile seems to have a slight effect on the reaction (3ac, 46%). This reaction could successfully be expanded to the aliphatic thiol (3ag, 89%). On the other hand, for the different 3,3,3-triuoropropanoyl esters, the reaction also gave the similar results in the case of benzyl ester and b-naphthalenyl ester (3ba, 43%; 3ca, 71%). N,Nsubstituted 3,3,3-triuoropropanamide was able to carry out this transformation with a lower yield (3da, 34%). In contrast, the N-monosubstituted amide only produced a trace amount of the desired product at 0 C, but could afford the product at 45 C in DMSO (3fa, 79%).
Furthermore, the O-and N-containing nucleophiles were tested in the reaction, for example, p-cresol successfully afforded the deuorinated product at a higher temperature (3ai, 90% at 45 C). However, in terms of the N-containing nucleophile, ptoluidine did not afford the desired compound (3aj, trace) under Cs 2 CO 3 -, NaHMDS-, or t-BuOK-promoted conditions, possibly due to poor nucleophilicity of the amine or instability of 3aj. In contrast, the amide was able to produce the partial-deuorinated product (4ak, 61%) with Z-conguration. To our surprise, a-CF 3 ketone was also proved exible in the reaction, for example, 3,3,3-triuoro-1-phenylpropan-1-one could react with 2a under the standard condition, and then gave 3ga in 53% yield.
Next, this deuorinative functionalization was switched from those mono-dentate nucleophiles to the bidentate nucleophiles, the results were depicted in Table 3. When one equivalent of catechol was used as one O,O-bidentate nucleophile, the reaction did not occur at 0 C, but at a higher temperature (45 C) the cyclized compound was smoothly produced (5am, 83%). Similarly, 2-mercaptophenol, one O,S-bidentate nucleophile, could smoothly afford the corresponding product (5an, 66%), and interestingly, the single crystal X-ray diffraction experiment demonstrated that the stereo conguration between H atom at the olen and O atom at the heterocycle was syn-conguration, 27 indicating there evidently existed bulkier repulse between H atom and S atom.
Unexpectedly, 2-aminothiophenol, as one N,S-bidentate nucleophile, did not give the desired product, instead, it resulted in the undesired product (3ao, 71%), possibly due to the weaker nucleophilicity of amine than that of thiol. Furthermore, the reaction using benzene-1,2-diamine as one N,N-bidentate nucleophile led to complicated products (5ap, trace).
To understand the reaction mechanism, the control experiments were performed, as shown in Scheme 1. If the reaction was run in absence of Cs 2 CO 3 , the reaction did not occur (Scheme 1a). Meanwhile the triuoropropanoylate ester was not decomposed by Cs 2 CO 3 in the absence of nucleophile (Scheme 1b), although decomposition occurred with a strong base (such as NaHMDS). On the other hand, if methyl 3,3-diuoroacrylate was subjected to the same basic condition, the desired compound (3ha) could be produced (Scheme 1c), strongly Table 3 Defluorination and functionization of ethyl 3,3,3-trifluoropropanoylate with some bidentate nucleophiles a a Reaction conditions: a solution of 1a (1.0 mmol), 2 (1.0 mmol) and Cs 2 CO 3 (2.0 mmol)in anhydrous THF (10 mL) was stirred at 45 C for 2 h under Ar. The isolated yield based on 1a.
indicating the 3,3-diuoroacrylate was the intermediate. Although we attempted to isolate the corresponding 3,3-diuoroacrylamide or monitor other uoro organic compounds by 19 F NMR in the case of 4ka, unfortunately we did not succeed (Scheme 1d).
Together with the above results, we proposed a plausible mechanism (Scheme 2). 22-24 At rst, Cs 2 CO 3 promoted the dehydrouorinative elimination of triuoropropanoylate ester in the presence of one suitable nucleophile, and the resultant 3,3-diuoroacrylate ester was rapidly added by the nucleophile, then the adduct continued to rapidly undergo elimination to afford a,b-unsaturated monouorinated carbonyl compound, and in general, the further addition and dehydrouorinative elimination continued to occur and nally resulted in the full-deuorinated product.

Conclusions
In conclusion, we have developed an efficient deuorinated and functionized method of 3,3,3-triuoropropanoic acid derivatives, and in this method, a mild base (Cs 2 CO 3 ) enables to promote deuorination and functionalization of the b,b,b-tri-uoro carbonyl compounds in the presence of a series of N-, O-, S-nucleophiles. By the current method, the a-triuoromethyl carbonyl compounds easily afford b,b-N-, O-, and/or Ssubstituted a,b-unsaturated products in moderate to excellent yields, and a-triuoromethyl ester can also be transformed into the corresponding benzooxazoles in good yields when 2-aminophenols were used as nucleophiles.

Conflicts of interest
There are no conicts to declare.