Introduction

Fluorine-containing compounds have been utilized in diverse fields due to their special character originating from unique fluorine atoms or fluorinated groups . During our study in this area, ethyl 4,4,4-trifluorobut-2-enoate (1a) has been frequently employed as a potent and convenient Michael acceptor towards a variety of enolates as well as organometallic species . At least in part, its high reactivity was considered to be due to the significantly lower-lying LUMO energy level by the attachment of electron-withdrawing trifluoromethyl (CF3) and ethoxycarbonyl groups . As we previously pointed out , the effective intramolecular interaction between fluorine and metals would also facilitate the smooth progress of these reactions. Such high potential of 1a allowed us to apply it to nucleophilic epoxidation because the resultant epoxyester 2a is recognized as an intriguing building block (Scheme 1).

Scheme 1: Expectation of the regio- as well as stereoselective reactions of 2.

Another expectation to 2a is the high regio- and stereoselectivities of its epoxy ring opening specifically occurring at the 2 position in an SN2 manner, when it is treated with appropriate nucleophiles (Nu), leading to the formation of the 2-substituted 3-hydroxyesters with 2,3-anti stereochemistry. These characteristic outcomes would stem from a result of the electronically repulsive interaction between the incoming nucleophiles and an electronically strongly negative CF3 group, and the anticipated clean SN2 mechanism of epoxides in general, respectively. This is interestingly compared with the case of 2a with nonfluorinated Rf groups which sometimes suffered from the contamination of the regioisomers as a consequence of the regiorandom attack of nucleophiles .

Despite such significant advantage, compound 2a was previously prepared only by 1) the LDA-mediated iodination-intramolecular ring closure sequence from the corresponding chiral 4,4,4-trifluoro-3-hydroxybutyrate at low temperature , and 2) t-BuO2Li-mediated transformation of the enoates like 1g at −78 °C and, to the best of our knowledge, no report has appeared on the convenient methods applicable to the larger scale synthesis to get access to the synthetically quite useful compounds like 2a .

Under such situations, we envisaged that the high electrophilicity of compound 1a would permit the usage of the extraordinarily convenient and mild reagent NaOCl which opens the promising route for the preparation of 2a. Moreover, the fact that only very limited examples are known for their synthetic application except for the synthesis of 4,4,4-trifluorothreonine , stereoselective ring opening with organometallic species , and so on also stimulated our interest. In this article, we would like to describe in detail the results of the preparation of epoxyesters 2 with various Rf groups as well as their reactivity with diverse nucleophiles .

Results and Discussion Preparation of (E)-2,3-epoxypropanoates 2 with Rf groups at the 3 position

Because the urea·H2O2 complex proved its usefulness for the epoxidation of the β-CF3-α,β-unsaturated ketones , we applied this method at first for the epoxidation of 1b. However, contrary to our anticipation, only a total recovery of the substrate was observed, and further search for an oxidant reached the usage of a NaClO aqueous solution with its convenient handling and availability at a low cost. Following to the reported protocol , although a catalytic amount of Al2O3 and MgO worked nicely (entries 1 and 2 in Table 1), it was clarified that these additives were not necessary for the attainment of the same level of chemical yields (entries 3 vs 1 and 2). The drawback of this sequence was the isolated yield of 2b no more than 70% which was, at least in part, due to the production of the undesired hydrolyzed products from 1b and/or 2b under the alkaline conditions of this epoxidation reagent. This was experimentally proved by the detection of benzaldehyde which was considered to be formed by the NaClO-mediated oxidation of benzyl alcohol generated by hydrolysis. Changing the oxidizing reagent to crystalline NaClO·5H2O nicely solved the problem with the realization of 86% isolated yield of 2b by the utilization of this oxidant (2 equiv) at 0 °C with 6 h stirring (entry 8 in Table 1). We also tried to apply these conditions to other fluorine-containing substrates 1c–f and successfully obtained good to high yields of the desired products 2c–f, respectively (entries 10–13 in Table 1). The requirement of longer reaction time and higher temperature especially in the case of compounds 1e and 1f as well as the high loading of the oxidant in the latter might be due to their higher oleophobicity by possessing longer Rf chains. For all instances, epoxyesters 2 were obtained as single E-isomers, and based on the result obtained by the t-BuO2Li reagent , we speculated that NaClO·5H2O would similarly work for the corresponding Z-1 with retention of stereochemistry.

Table 1: Optimization of epoxidation conditions of 1.

Entry Sub. NaClOa (equiv) Conditions Isolated yieldb (%) 1c 1b AQ 1.0 25 °C, 6 h 59 (67) 2d 1b AQ 1.0 25 °C, 5 h (69) 3 1b AQ 1.0 25 °C, 4.5 h 60 (63) 4 1b S 1.0 20 °C, 3 h (65) 5 1b S 1.5 20 °C, 3 h (83) 6 1b S 1.5 20 °C, 6 h (84) 7 1b S 1.5 0 °C, 6 h (89) 8 1b S 2.0 0 °C, 6 h 86 (94) 9 1b S 3.0 0 °C, 6 h (83) 10 1c S 2.0 0 °C, 6 h 79 11 1d S 2.0 0 °C, 6 h 78 12 1e S 2.0 0 °C, 6 h: 20 °C, 12 h 73 13 1f S 5.0 20 °C, 48 h 61

aAQ: a 5% aqueous solution, S: solid of NaClO·5H2O; bthe yields determined by 19F NMR were described in the parentheses; c10 mol % of Al2O3 was added; d20 mol % of MgO was added.

The procedure found here was also applied to the three representative CF3-containing α,β-unsaturated esters,1h–j with different substitution patterns (Scheme 2).

Scheme 2: Attempts of the present epoxidation to other α,β-unsaturated esters, 1h–j.

The subjection of the compounds 1h and 1i to the standard conditions described above resulted in high recovery of the substrates, which could be explained by their higher LUMO + 1 energy levels responsible for the epoxidation . Extensive decomposition was observed in the case of 1j even in a shorter period possibly because of its significantly high electrophilicity by the attachment of three strongly electron-withdrawing moieties.

Reactions of (E)-3-Rf-2,3-epoxypropanoates 2 with amines, thiols, and metal halides

Because the epoxide ring opening is known to occur in an SN2 fashion, compounds 2 were recognized as versatile building blocks for the construction of 2-amino-3-hydroxypropanoates with 2,3-anti stereochemistry, if appropriate amines work nicely in a nucleophilic manner .

After the brief optimization of the conditions for the reaction of 2b and p-anisidine, good yields with high stereoselectivity were similarly recorded for the other substrates 2c and 2d possessing different Rf groups at the 3 position (Table 2, entries 1–3). Mixing of 2b with different primary (entries 4–7 in Table 2) and secondary (entries 8 and 9) amines led to the formation of the respective products in high to excellent yields without detection of any regio- as well as stereoisomers. The chirality contained in amines did not work efficiently for the stereochemical induction of the products (entries 6 and 7 in Table 2). In the case of secondary amines, the sterically demanding dibenzylamine failed in this transformation and recovery of 2b was observed (Table 2, entry 10). As was pointed out in the introductory section, the highly regioselective epoxy ring opening is well compared with the case when the nonfluorinated substrate (Ph instead of CF3 in 2b) was employed .

Table 2: Reactions of 2 with a variety of amines.

Entry Rf R1 R2 Time (h) Isolated yield (%) 1a CF3 4-MeOC6H4 H 19 78 (3ba) 2a CHF2 4-MeOC6H4 H 19 59 (3ca) 3a CClF2 4-MeOC6H4 H 19 76 (3da) 4 CF3 PhCH2 H 7 86 (3bb) 5 CF3 n-Bu H 7 48 (3bc) 6 CF3 PhCH(CH3) H 18 77c (3bd) 7b CF3 EtCH(Me)CH(CO2Bn) H 24 72c (3be) 8 CF3 Et Et 7 83 (3bf) 9 CF3 (CH2)4 7 56 (3bg) 10 CF3 Bn Bn 7 –d

aEtOH was used as the solvent and the reaction temperature was 50 °C; breaction was performed with 2.5 equiv of benzyl isoleucinate·TsOH and Et3N; cconsisted of 53:47 diastereomers in both cases; dno reaction was observed.

With the successful employment of amines as nucleophiles for the epoxy ring opening in a highly stereoselective fashion, we next turned our attention to thiols. Optimization of the reaction conditions based on the ones for amines clarified the tendency that the longer reaction time and the higher temperature decreased the chemical yields as well as the diastereomeric ratios (Table 3, entries 1–4). The higher pKa values of the carbonyl α-proton of 4 (for example, the pKa values of the protons of X-CH2C(O)Ph in DMSO were reported to be 17.1 (X: PhS) and 20.3 (X: Ph2N) ) would result in the contamination of the stereoisomers when compared with the case of the compounds 3 . Because control of the amount of PhCH2SH to 1.0 equiv did not give a positive effect, the conditions in entry 4 (Table 3) were eventually determined as the best.

Table 3: Reactions of 2 with a variety of thiols.

Entry Rf R1 Time (h) Isolated yield (%) dra 1b CF3 PhCH2 3 92 (4ba) 87:13 2b CF3 PhCH2 12 75 (4ba) 75:25 3c CF3 PhCH2 3 80 (4ba) 61:39 4 CF3 PhCH2 5 90 (4ba) 94:6 5d CF3 PhCH2 5 90 (4ba) 94:6 6 CHF2 PhCH2 48 76 (4ca) >99:1 7 CClF2 PhCH2 24 87 (4da) 90:10 8 C2F5 PhCH2 81 72 (4ea) 69:31 9 CF3 CH3(CH2)9 10 59e (4bb) 95:5 10 CF3 Ph 5 92 (4bc) 93:7 11 CF3 CH3OC(O)CH2 5 94 (4bd) 95:5

aDetermined by 19F NMR; breaction at 40 °C; creaction at 60 °C; dutilization of 1.0 equiv of PhCH2SH resulted in the observation of 9% recovery of 2b by 19F NMR; e7% recovery of 2a was observed by 19F NMR.

The different epoxyesters 2c–e were also applied for this ring-opening reaction with the same thiol (entries 6–8 in Table 3). It is interesting to note that a longer reaction time was required for these substrates which would be the major reason for the relatively low diastereomeric ratio (especially in the case of entry 8 in Table 3) while the CHF2-possessing epoxyester 2b furnished a single stereoisomer (entry 6) whose reason was not clear yet. Other thiols like decanethiol, thiophenol, and thioglycolate all worked nicely to furnish the corresponding products 4bb–bd in good to excellent chemical yields with high stereoselectivities (Table 3, entries 9–11).

The stereostructure of the products was confirmed by X-ray crystallographic analysis using the minor diastereomer of 3bd, nicely separated from the major isomer by recrystallization, and the major product 4ba. As was our expectation, these compounds possess the anti relationship between the 2 and 3 positions which clearly proved the epoxy ring opening taking place at the 2 position in an SN2 fashion (Figure 1).

Figure 1: Crystallographic structure of the epoxy ring-opening products by PhCH(NH2)Me (3bd) and PhCH2SH (4ba).

The introduction of an additional halogen atom was considered to be possible by treatment of 2b with an appropriate metal salt, and actually, similar results to the case of amines and thiols were obtained by using the corresponding MgX2. It was proved that a larger amount of nucleophiles, higher temperature, and longer time all led to a decrease in the diastereomeric ratio of the products 5 (ca 10%) like the case of thiols described above. This is the reason why the three examples shown in Scheme 3 stopped before completion, and, for example, 24 h stirring in the case of the Cl atom entry furnished 67% yield of 5ba and 19% recovery of 2b with the diastereomeric ratio of the former of 97:3. Contamination by the deiodinated 3-hydroxyester was noticed during the synthesis of 5bc using LiI.

Scheme 3: Introduction of additional halogen atoms at the 2-position of the compound 2b.

Reactions of (E)-4,4,4-trifluoro-2,3-epoxybutanoate 2b with compounds possessing an acidic proton

It was very interesting to know that there were scarce examples in the literature on the ring opening of 2,3-epoxyesters in general by the stabilized anionic species from, for example, malonate. One reason could be because of the formation of the less stable alkoxide by the progress of the nucleophilic addition. If this is really the case, the presence of the strongly electron-withdrawing fluorine-containing groups in our instance should nicely affect the characteristics of the resultant intermediate which could lead to the realization of the addition of such nucleophilic species.

First of all, as shown in Table 4, we started to investigate the reactivity of 2b toward sodium malonate as the representative nucleophile. Because a brief solvent search indicated DMSO as the best for the attainment of high yields and diastereoselectivity (entries 1–5 vs 6 in Table 4), we further examined bases in this solvent to find out that t-BuOK behaved nicely, and the reaction of 2b with 2.0 equiv of diethyl malonate for 0.5 h at room temperature furnished 93% yield of the product (Table 4, entry 15). During this optimization process, the obtained product was uncovered not to be a single component but a mixture of two compounds, anti,syn-7a and anti,syn-7b, the latter of which seemed to be produced from the former by the attack of the ethoxide ion released during the lactone-forming process. Their close structural resemblance led to a significant peak overlap both in the 1H and 19F NMR spectra which made it difficult to obtain their exact ratio and thus, the combined 19F NMR yields were shown in Table 4. Separation of these two compounds was eventually succeeded by the usual hydrogenolysis to furnish the carboxylic acid anti,syn-8a in 79% isolated yield and the lactone anti,syn-7b was recovered in 13% yield (Scheme 4) which was considered to be the reflection of the original composition of anti,syn-7a and -7b. The relative stereochemistry of anti,syn-8a was confirmed as 2,3-anti-3,4-syn by its X-ray crystallographic analysis (Figure 2) whose construction could be readily understood as the result of a highly stereoselective SN2-type epoxy ring opening of 2a, followed by the intramolecular lactone formation with the pro-R ethoxycarbonyl group possibly due to the higher steric congestion by the selection of the other CO2Et moiety.

Table 4: Reactions of 2b with the anionic species from diethyl malonate.

Entry Base Solvent Yielda (%) dr Recovery (%) 1b NaH THF 20 >99:1 0 2b NaH Toluene 6 >99:1 13 3b NaH Et2O 12 >99:1 13 4b NaH MeCN 45 98:2 7 5b NaH DMF 75 96:4 0 6 NaH DMSO 78 99:1 0 7 Et3N DMSO 0 – 83 8 TMG DMSO 22 14:86 3 9 DBU DMSO 13 23:77 2 10 CsF DMSO 34 91:9