Kazutaka
Shibatomi
*,
Kazumasa
Kitahara
,
Takuya
Okimi
,
Yoshiyuki
Abe
and
Seiji
Iwasa
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan. E-mail: shiba@ens.tut.ac.jp
First published on 16th November 2015
The highly enantioselective fluorination of α-branched aldehydes was achieved using newly developed chiral primary amine catalyst 1. Furthermore, the C–F bond cleavage of the resulting α-fluoroaldehydes proceeded smoothly under alcoholic alkaline conditions to yield the corresponding α-hydroxyacetals in a stereospecific manner. Accordingly, the one-pot conversion of α-branched aldehydes into α-hydroxyacetals was achieved for the first time in high enantioselectivity.
The structure of the new chiral primary amine catalyst 1 is shown in Scheme 2.10 An ester moiety and substituents at the 3,3′-positions on the binaphthyl backbone are expected to influence the chirality of the resulting products. Catalyst 1 was synthesized according to the procedure shown in Scheme 2. First, (R)-3,3′-diaryl-2,2′-bis(bromomethyl)-1,1′-binaphthyl (2) was prepared from commercially available (R)-BINOL via a reported procedure.11 Compound 2 was then converted into the desired amino ester 1via alkylative cyclization with ethyl isocyanoacetate and subsequent acid hydrolysis of the isocyano group.
Next, 1 was applied in the enantioselective fluorination of α-branched aldehydes (Table 1). Fluorination of 2-phenylpropanal (3a) was carried out with N-fluorobenzenesulfonimide (NFSI) in the presence of 10 mol% 1a to yield 2-fluoro-2-phenylpropanal (4a) in a high conversion. The fluorinated product was isolated after reduction to primary alcohol 5a, due to difficulties in the purification of 4a. Thus, 5a was isolated in a sufficiently high chemical yield, but with poor enantioselectivity (entry 1). To our delight, the enantioselectivity of the fluorination dramatically improved to 90% ee by employing catalyst 1b, which has bulky aryl substituents at the 3,3′-positions (entry 2). As expected, the use of catalyst 1c without aryl substituents in the 3,3′-positions yielded a nearly racemic product (entry 3). The optimal solvent for the reaction was found to be toluene (entries 4–7). The enantioselectivity and reaction rate were slightly increased by adding 10 mol% 3,5-dinitrobenzoic acid as a co-catalyst (entry 10). We also confirmed that chiral primary amines 6 and 7, which were reported to induce high enantioselectivity in the amination of α-branched aldehydes,12 were ineffective in the fluorination of 3a (entries 11 and 12). The absolute configuration of 5a was determined to be S, by comparison of its optical rotation with that of the reported value.6
Entry | Catalyst | Solvent | Time (h) | Yieldb (%) | eec (%) |
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a Reactions were carried out with 1.5 equiv. of rac-3a based on NFSI in the presence of 10 mol% 1 unless otherwise noted. b Isolated yield of 5a. c Absolute configuration of the major enantiomer is specified in parenthesis. d 1.5 equiv. of NFSI was used based on rac-3a. e At 0 °C. f 10 mol% 3,5-(NO2)2C6H3CO2H was used as a co-catalyst. g 5 mol% catalyst was used with 15 mol% TFA. h 20 mol% catalyst. | |||||
1 | 1a | Toluene | 24 | 79 | 51 (S) |
2 | 1b | Toluene | 2 | 97 | 90 (S) |
3 | 1c | Toluene | 24 | 71 | 3 |
4 | 1b | CH2Cl2 | 18 | 86 | 74 (S) |
5 | 1b | EtOAc | 4 | 99 | 82 (S) |
6 | 1b | t BuOMe | 3 | 97 | 86 (S) |
7 | 1b | MeOH | 48 | <10 | n.d. |
8d | 1b | Toluene | 6 | 82 | 88 (S) |
9e | 1b | Toluene | 48 | 73 | 93 (S) |
10e,f | 1b | Toluene | 48 | 86 | 95 (S) |
11g | 6 | CHCl3 | 24 | 76 | 13 (R) |
12h | 7 | THF | 2 | 98 | 13 (S) |
Encouraged by the results obtained with amine catalyst 1b, we attempted to expand the substrate scope of the fluorination reaction. As summarized in Table 2, various α-alkyl-α-aryl aldehydes were successfully fluorinated to afford the corresponding α-fluoroaldehydes in high yields with high enantioselectivities. On the other hand, the reaction with α,α-dialkyl aldehyde 3o yielded the product with good enantioselectivity but in poor yield, while the reaction with 3p showed disappointingly low enantioselectivity. Although it was observed that the reaction with 3f yield the corresponding fluoroaldehyde 4f in good conversion by NMR measurement of the reaction mixture, reduction of 4f to 5f gave a complicated mixture, thus we could not determine those enantiopurity.
a Reactions were carried out with 1.5 equiv. of rac-3 based on NFSI in the presence of 10 mol% 1b and 3,5-(NO2)2C6H3CO2H. Isolated yield of 5 are described, except for 4k. b Purified product contained ca. 5% of an inseparable by-product. c At rt. for 2 h. d At rt. for 12–24 h. e 20 mol% catalyst. f 30 mol% catalyst. |
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The resulting fluorides can be converted into a variety of other tertiary fluorides (Scheme 3). First, allyl fluorides 8 were synthesized by Horner–Wadsworth–Emmons reaction of α-fluoroaldehydes 4 in good yield. Next, fluorohydrine 5j was oxidized to carboxylic acid 9,13 which is a fluorinated analogue of a non-steroidal anti-inflammatory agent, flurbiprofen.
We further investigated the synthetic utility of α-fluoroaldehydes 4. Although, in general, the cleavage of carbon–fluorine bonds is not facile due to the strength of the bond, methods for C–F bond activation have recently garnered significant interest.9 The SN2-type nucleophilic substitution of sp3-alkylfluorides is known to be a challenging reaction; in particular, there are very few examples of the substitution of tertiary alkylfluorides.14 We recently reported that the SN2 reaction of α-chloro-α-keto esters with sodium azide and alkylthiols proceeds smoothly, despite the fact that the reaction occurs at a tertiary carbon.15 This finding encouraged us to examine the nucleophilic substitution of α-fluoroaldehydes 4. First, typical nucleophiles such as sodium azide and alkylthiols were surveyed, but the desired product was not obtained. Eventually, we found that treatment of 4a with NaOMe in methonal yielded the corresponding α-hydroxyacetal 10a in a good conversion (Table 3).16 Due to the difficulties in purifying 4a, enantioselective fluorination of 3a and subsequent hydroxyacetalization were performed in a one-pot fashion. Notably, the enantiopurity of 10a was nearly the same as that of 4a. This result indicated that the C–F bond cleavage occurred in a stereospecific manner. As summarized in Table 3, various α-hydroxyacetals 10 were synthesized in good yields with high enantioselectivities via the sequential fluorination–alkaline treatment. When the second step was carried out with NaH in ethylene glycol, the corresponding α-hydroxy cyclic acetal 12 was obtained. The present method would be a good alternative to direct oxidation of α-branched aldehydes.8,17 Our method does not require the use of any explosive oxidant and simultaneously protects the carbonyl group. The resulting 10a could be easily converted into α-hydroxy ester 13 without loss of enantiopurity (Scheme 4). The absolute configuration of 13 was determined to be R, by comparison of reported optical rotation values;18 these results confirmed that this transformation involved the Walden inversion.
a Isolated yields of 10–12 from 3 are described. b The first step was carried out at rt. c es = (ee of 10–12)/(ee of 4). d The second step was carried out at rt. under reflux conditions. Purified product contained ca. 10% of an inseparable by-product. e The second step was carried out with NaH in ethylene glycol instead of NaOR2/R2OH. |
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The proposed reaction mechanism for the formation of hydroxyacetals 10 is shown in Scheme 5. 1H NMR studies revealed that α-fluoroaldehyde 4 is in equilibrium with hemiacetal I in d4-methanol. Upon treatment with NaOMe, epoxide II is formed via intramolecular SN2 displacement, which involves the stereospecific cleavage of C–F bond. Then, regeneration of the carbonyl moiety and subsequent acetalization or direct SN2-type ring opening of II with methoxide affords hydroxyacetal 10.
Footnote |
† Electronic supplementary information (ESI) available: Experimental details including characterization date, copies of 1H, 13C, 19F NMR and HPLC traces. See DOI: 10.1039/c5sc03486h |
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