Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 2263−2273
Enantioselective α‑Benzoyloxylation of β‑Keto Esters by N‑Oxide Phase-Transfer Catalysts Yakun Wang,*,†,‡ Qinghe Gao,† Zhaomin Liu,† Suping Bai,† Xiaofei Tang,‡ Hang Yin,‡ and Qingwei Meng*,‡ †
School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003 Henan, People’s Republic of China School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, 116024 Liaoning, People’s Republic of China
‡
S Supporting Information *
ABSTRACT: An efficient and enantioselective α-benzoyloxylation of β-keto esters has been achieved by phase-transfer catalysis. This simple catalytic procedure is applicable to a range of β-keto esters with cinchona-derived N-oxide asymmetric phase-transfer catalysts and gives the corresponding products in good enantiopurity (up to 95% ee) and yield (up to 99%). This simple and effective oxyfunctionalization is a useful synthetic strategy for introducing an oxygen-containing functional group at the α position of β-dicarbonyl compounds.
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INTRODUCTION Optically active α-oxygenated β-dicarbonyl moieties are common structural motifs in a wide range of natural products and pharmaceuticals.1 They have been used for the synthesis of bioactive products, such as kjellmanianone,2 ginkgolide B,3 and doxycycline.4 Moreover, this functional unit can also serve as a versatile chiral synthon in the synthesis of complex molecules, such as the indoline alkaloid vindoline5 and the insecticide indoxacarb6 (Scheme 1). Therefore, the asymmetric αoxidation of β-dicarbonyl compounds is a significant transformation. The first example of the enantioselective α-oxidation of β-keto esters was realized by Davis in 1981 and required stoichiometric amounts of chiral oxaziridine.7 Then organometallic catalysis8 and organocatalysis9 were rapidly developed for the α-oxidation of β-dicarbonyl compounds. However, the available oxygen functionalities were limited to hydroxy, aminoxy,10 and oxygen-sulfonyl groups.11 To the best of our knowledge, α-benzoyloxylation is a useful oxidative C−O coupling technique, and this oxyfunctionalization is a useful synthetic strategy for introducing an oxygen atom at the α position of β-dicarbonyl compounds.12 Although a number of enantioselective benzoyloxylations have been achived,13 asymmetric α-benzoyloxylation of β-keto esters are scarce. In 2015, Luo reported the first asymmetric α-benzoyloxylation of α© 2018 American Chemical Society
branched ketones with good enantioselectivities using a primary amine catalyst, and most of the substrates were acyclic or nonaromatic β-keto esters.14 Then Itoh reported the first enantioselective α-benzoyloxylation of malonic diester using a phase-transfer catalyst, and this method was successfully applied to the synthesis of a mineralocorticoid receptor antagonist.15 Thus, the development of green and highly enantioselective αbenzoyloxylation of β-keto esters with a broad substrate scope is necessary and meaningful.
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RESULTS AND DISCUSSION Phase-transfer catalysis is recognized as an effective and sustainable method, and cinchona alkaloid-based phase-transfer catalysts have been applied to many practical asymmetric syntheses.16 To develop a new and convenient method for the chiral α-benzoyloxylation of β-keto esters, we investigated the asymmetric α-benzoyloxylation of 1-indanone-derived β-keto ester 1a under phase-transfer conditions using cinchona alkaloid derivatives. First, we attempted to use the simplest of the cinchona derivatives, 3a, which contains an N-benzyl group as the phase-transfer catalyst and benzoyl peroxide as the Received: December 14, 2017 Published: January 23, 2018 2263
DOI: 10.1021/acs.joc.7b03150 J. Org. Chem. 2018, 83, 2263−2273
Article
The Journal of Organic Chemistry Scheme 1. Direct α-Benzoyloxylation of β-Keto Esters under Phase-Transfer Catalysis
6). N-Oxides are more polar than the unoxidized amines due to the charge separation of the N−O bond, and this molecular feature leads to a decrease in lipophilicity.17a In our opinion, the N-oxide PTC 3e and nonoxidized 3a have some key differences. First, the N-oxide PTC is more polar than common PTC, and 3e and 3n are less soluble in toluene, so the N-oxide PTCs are easier to separate from the product.17b Second, when the quinoline nitrogen atom is oxidized, the acidity of the C-9 hydroxy group could be increased.17c Then we screened the doubly quaternized catalyst 3g,18 but the enantioselectivity was poor (Table 1, entry 7). Recently, C-2′-arylated phase-transfer catalysts were successfully applied in the α-functionalizations of β-keto esters,19 so we screened PTC 3h. To our disappointment, the enantioselectivity of 2a was not noticeably improved (Table 1, entry 8). These results showed that the stereocontrol was sensitive to structural modifications on the quinoline ring, and the N-oxide phase-transfer catalysts are more suitable for this reaction. Next, a series of N-oxide phase-transfer catalysts derived from cinchona alkaloids were screened. Interestingly, PTC 3i, with electron-donating groups (−OMe) at the 3, 4, and 5 positions of the benzyl ring, afforded 2a in 71% ee, although the reaction time was extended to 48 h (Table 1, entry 9). PTC 3j, with electron-withdrawing groups (−CF3) at the 3 and 5 positions, improved the yield (93%) but showed lower enantioselectivity (54% ee) (Table 1, entry 10). A steady improvement in ee was obtained from the 3,5-(Br)2 and 3,5(I)2 derivatives 3k and 3l (Table 1, entries 11 and 12, respectively). Moreover, we found that the ee value was improved to 84% by introducing a 9-anthracenylmethyl group (Table 1, entry 13). To our delight, PTC 3n, derived from quinidine N-oxide, afforded 2a in 86% ee and almost quantitative conversion after 12 h (Table 1, entry 14). The classic nonoxidized catalyst, PTC 3o, was then introduced but provided 2a in only 78% ee (Table 1, entry 15). Finally, benzyltrimethylammonium bromide (BTMAB) was tested, but only a trace amount of 2a was formed (Table 1, entry 16). These results showed that the structural characteristics of the phasetransfer catalysts were responsible for both the enantioselectivity and the catalytic activity observed in the α-benzoyloxylation. After 3n had been identified as a suitable catalyst, further reaction optimization studies were undertaken. Table 2 summarizes the effects of several parameters on this reaction. First, we screened several bases in toluene in the presence of catalyst 3n (Table 2, entries 1−8). The use of 50% NaOH and KOH aqueous solutions provided faster reaction rates, but the enantioselectivities were low (Table 2, entries 1 and 2). We thought 2a might be undergoing hydrolysis in the presence of
oxygen source. The reaction was performed with 30% K2CO3 in toluene at room temperature, and we were pleased to see that the α-benzoyloxylation reaction proceeded as expected. Desired product 2a was obtained, but the enantioselectivity was moderate (43% ee) (Table 1, entry 1). Next, we screened a Table 1. Screening of Phase-Transfer Catalysts for the αBenzoyloxylation of β-Keto Ester 1aa
entry
cat.
t [h]
yield [%]b
ee [%]c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p
24 24 48 24 24 24 24 24 48 12 12 12 12 12 12 48
72 78 35 72 87 88 71 92 65 93 91 93 96 95 91 Trace
43 45 22 39 54 55 12 51 71 54 66 69 84 86 78 Nd
a The reactions were performed with 1a (0.1 mmol), BPO (0.15 mmol), catalyst (0.005 mmol), and 30% K2CO3(0.5 mL) in toluene (4 mL) at room temperature. bYields shown are of isolated products. c Determined by chiral HPLC (Chiralcel AD-H).
series of phase-transfer catalysts with modifications at the C-9 and C-6′ positions. PTC 3b, with a methoxyl group at the C-6′ position, led to a slightly higher enantioselectivity (Table 1, entry 2). PTC 3c, which has hydroxy groups at both the C-9 and the C-6′ positions, showed poor results (Table 1, entry 3). PTC 3d, which has a bulky 1-adamantyl group at the C-9 position, was then screened (Figure 1), but the ee value was slightly lower than that obtained with 3a (Table 1, entry 4). PTCs 3e and 3f, which both contain oxidized quinoline nitrogens, were tested, and we were surprised to find that the reactions proceeded faster (87−88% yield, 12 h) and with higher enantioselectivity (54−55% ee) (Table 1, entries 5 and 2264
DOI: 10.1021/acs.joc.7b03150 J. Org. Chem. 2018, 83, 2263−2273
Article
The Journal of Organic Chemistry
Figure 1. Quaternary ammonium salts employed for the α-benzoyloxylation reaction.
Table 2. Optimization of the Reaction Conditions for the α-Benzoyloxylation of β-Keto Esters with PTC 3ma
entry
solvent
base
T [°C]
t [h]
yield [%]b
ee [%]c
1 2 3 4 5 6 7d 8d 9 10 11 12 13 14 15e 16f
PhCH3 PhCH3 PhCH3 PhCH3 PhCH3 PhCH3 PhCH3 PhCH3 PhCF3 CHCl3 Et2O PhCH3 PhCH3 PhCH3 PhCH3 PhCH3
50% NaOH 50% KOH 30% Cs2CO3 30% K2CO3 50% K2HPO4 50% EtONa Et3N K2CO3 30% K2CO3 30% K2CO3 30% K2CO3 30% K2CO3 30% K2CO3 30% K2CO3 30% K2CO3 30% K2CO3
25 25 25 25 25 25 25 25 25 25 25 0 35 15 15 15
6 6 12 12 24 48 48 12 12 24 6 48 12 12 12 12
45 83 97 95 85 61 Trace 45 97 45 98 87 81 96 98 93
