Enantioselective α-Benzoyloxylation of β-Keto Esters by N-Oxide Phase-Transfer Catalysts

Article abstract of DOI:10.1021/acs.joc.7b03150

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.

Full text of DOI:10.1021/acs.joc.7b03150

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Article
Enantioselective #-Benzoyloxylation of #-
keto esters by N-oxide phase-transfer catalysts
Yakun Wang, Qinghe Gao, Zhaomin Liu, Suping Bai, Xiaofei Tang, Hang Yin, and Qingwei Meng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03150 • Publication Date (Web): 23 Jan 2018
Downloaded from http://pubs.acs.org on January 24, 2018
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Enantioselective αꢀBenzoyloxylation of βꢀKeto Esters by NꢀOxide
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PhaseꢀTransfer Catalysts
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Yakun Wang,a,b* Qinghe Gao,a Zhaomin Liu,a Suping Bai,a Xiaofei Tang,b Hang
Yin,b and Qingwei Mengb*
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a School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, Henan, P.
R.China Eꢀmail: 161072@xxmu.edu.cn; Fax: (+86)ꢀ0373ꢀ3029879
b School of Pharmaceutical Science and Technology, Dalian University of Technology,
Dalian 116024, Liaoning, P. R. China. Eꢀmail: mengqw@dlut.edu.cn; Fax:
+86ꢀ0411ꢀ84986201
Abstract
An efficient and enantioselective αꢀbenzoyloxylation of βꢀketo esters has been achieved by phaseꢀtransfer
catalysis. This simple catalytic procedure is applicable to a range of βꢀketo esters with cinchonaꢀderived
Nꢀoxide asymmetric phaseꢀtransfer 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 oxygenꢀcontaining functional group at the αꢀposition of βꢀdicarbonyl compounds.
Introduction
Optically active αꢀoxygenated βꢀdicarbonyl moieties are common structural motifs in a wide range of
natural products and pharmaceuticals1. They have been used for the synthesis of bioactive products, such as
kjellmanianone2, ginkgolide B3 and doxycycline4. Moreover, this functional unit can also serve as versatile
chiral synthon in the synthesis of complex molecules, such as the indoline alkaloid vindoline5 and the
insecticide indoxacarb6 (Scheme 1). Therefore, the asymmetric αꢀoxidation of βꢀdicarbonyl compounds is a
significant transformation. The first example of the enantioselective αꢀoxidation of βꢀketo esters was realized
by Davis in 1981 and required stoichiometric amounts of chiral oxaziridine7. Then, organometallic catalysis8
and organocatalysis9 were rapidly developed for the αꢀoxidation of βꢀdicarbonyl compounds. However, the
available oxygen functionalities were limited to hydroxy, aminoxy10 and oxygenꢀsulfonyl groups11. To the
best of our knowledge, αꢀbenzoyloxylation is a useful oxidative CꢀO coupling technique, and this
oxyfunctionalization is a useful synthetic strategy for introducing an oxygen atom at the αꢀposition of
βꢀdicarbonyl compounds12. Although a number of enantioselective benzoyloxylations have been achived13,
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asymmetric αꢀbenzoyloxylation of βꢀketo esters are scarce. In 2015, Luo reported the first asymmetric
αꢀbenzoyloxylation of αꢀbranched ketones with good enantioselectivities using a primary amine catalyst, and
most of the substrates were acyclic or nonaromatic βꢀketo esters14. Then, Itoh reported the first
enantioselective αꢀbenzoyloxylation of malonic diester using a phaseꢀtransfer catalyst, and this method was
successfully applied to the synthesis of a mineralocorticoid receptor antagonist15. Thus, the development of a
green and highly enantioselective αꢀbenzoyloxylation of βꢀketo esters with a broad substrate scope is
necessary and meaningful.
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Scheme 1. Direct αꢀbenzoyloxylation of βꢀketo esters under phaseꢀtransfer catalysis
Results and discussion
Phaseꢀtransfer catalysis is recognized as an effective and sustainable method, and cinchona alkaloidꢀbased
phaseꢀtransfer catalysts have been applied to many practical asymmetric syntheses16. To develop a new and
convenient method for the chiral αꢀbenzoyloxylation of βꢀketo esters, we investigated the asymmetric
αꢀbenzoyloxylation of 1ꢀindanoneꢀderived βꢀketo ester 1a under phaseꢀtransfer conditions using cinchona
alkaloid derivatives. First, we attempted to use the simplest of the cinchona derivatives, 3a, which contains
an Nꢀbenzyl group as the phase transfer catalyst, and benzoyl peroxide as the oxygen source. The reaction
was performed with 30% K2CO3 in toluene at room temperature, and we were pleased to see that the
αꢀbenzoyloxylation reaction proceeded as expected. Desired product 2a was obtained, but the
enantioselectivity was moderate (43% ee) (Table 1, entry 1). Next, we screened a series of phaseꢀtransfer
catalysts with modifications at the Cꢀ9 and Cꢀ6′ positions. PTC 3b, with a methoxyl group at Cꢀ6′ position,
led to a slightly higher enantioselectivity (Table 1, entry 2). PTC 3c, which has hydroxy groups at both the
Cꢀ9 and Cꢀ6′ positions, showed poor results (Table 1, entry 3). PTC 3d, which has a bulky 1ꢀadamantyl
group at the Cꢀ9 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 5ꢀ6). Nꢀoxides are more polar than the unoxidized
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amines due to the charge separation of the N–O bond, and this molecular feature leads to a decrease in
lipophilicity17a. In our opinion, the Nꢀoxide PTC 3e and nonꢀoxidized 3a have some key differences. First,
the Nꢀoxide PTC is more polar than common PTC, and 3e and 3n are less soluble in toluene, so the Nꢀoxide
PTCs are easier to separate from the product17b. Second, when the quinoline nitrogen atom is oxidized, the
acidity of the Cꢀ9 hydroxy group could be increased17c. Then, we screened the doubly quaternized catalyst
3g18, but the enantioselectivity was poor (Table 1, entry 7). Recently, Cꢀ2′ꢀarylated phase transfer catalysts
were successfully applied in the αꢀfunctionalization of βꢀketo esters19, 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 Nꢀoxide
phaseꢀtransfer catalysts are more suitable for this reaction. Next, a series of Nꢀoxide phaseꢀtransfer catalysts
derived from cinchona alkaloids were screened. Interestingly, PTC 3i, with electronꢀdonating groups (ꢀOMe)
at the 3, 4, and 5ꢀpositions 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 electronꢀwithdrawing groups (ꢀCF3) at the 3ꢀ and
5ꢀpositions, improved the yield (93%) but showed lower enantioselectivity (54% ee) (Table 1, entry 10). A
steady improvement in ee was obtained from the 3,5ꢀ(Br)2 and 3,5ꢀ(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
9ꢀanthracenylmethyl group (Table 1, entry 13). To our delight, PTC 3n, derived from quinidine Nꢀoxide,
afforded 2a in 86% ee and almost quantitative conversion after 12 h (Table 1, entry 14). The classic
nonꢀoxidized catalyst, PTC 3o, was then introduced, but provided 2a in only 78% ee (Table 1, entry 15).
Finally, benzylꢀtrimethylꢀammonium 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 phaseꢀtransfer
catalysts were responsible for both the enantioselectivity and the catalytic activity observed in the
αꢀbenzoyloxylation.
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Table 1. Screening of phase transfer catalysts for the αꢀbenzoyloxylation of βꢀketo ester 1aa.
Entry
Cat.
t [h]
yield [%]b
ee [%]c
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24
24
72
78
43
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3a
3b
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84
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Nd
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3d
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3f
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3k
3l
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3m
3n
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3p
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Trace
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. b Yields shown are of isolated products. c Determined by chiral HPLC (Chiralcel ADꢀH).
Figure 1. Quaternary ammonium salts employed for the αꢀbenzoyloxylation reaction.
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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 1ꢀ8). 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 strong base. To our delight, when weaker
bases (30% Cs2CO3 aq and 30% K2CO3 aq) were used, the ee values and yields of 2a were noticeably
improved (Table 2, entries 3, 4). However, both 50% K2HPO4 aq and 50% EtONa aq provided lower yields
and enantioselectivities than those achieved with 30% K2CO3 aq (Table 2, entries 5 and 6). We believe that
50% K2HPO4 aq and 50% EtONa aq are not strong enough to activate the substrates. The organic base
triethylamine was tested, but only a trace amount of 2a was formed (Table 2, entry 7). Solid K2CO3 provided
a lower yield and enantioselectivity, which indicated that the presence of H2O is necessary for the reactivity
and selectivity (Table 2, entry 8). In the solvent screening, we found that the reaction medium had a
significant effect on the αꢀbenzoyloxylation. Using PhCF3 as the solvent resulted in an excellent yield, but
the enantioselectivity was unsatisfactory (Table 2, entry 9). CHCl3 was then used, but afforded poor results
(45% yield, 11% ee) after 24 h (Table 2, entry 10). It is worth mentioning that the reaction was completed in
6 h when Et2O was used as the solvent, but the enantioselectivity of 2a was very low (Table 2, entry 11).
Next, we investigated the effect of temperature on the reaction. The enantioselectivity decreased when the
reaction temperature was decreased to 0°C (Table 2, entry 12). In contrast, the enantioselectivity improved
when the reaction temperature was increased to 35°C (Table 2, entry 13). Then, we decreased the
temperature to 15°C, and product 2b was obtained in a high enantiomeric excess (92%) and yield (96%)
(Table 2, entry 14). Finally, we found that the enantioselectivity of the reaction could be increased from 92%
to 95% ee by reducing the substrate concentration from 0.02 M to 0.01 M, and that the loading of catalyst 3n
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could be reduced to as low as 2.5 mol% (Table 2, entry 15). We added butylated hydroxytoluene (BHT) as a
radical inhibitor, and the results did not noticeably improve, which indicated a radical process was not
occurring in this reaction system (Table 2, entry 16).
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Table 2. Optimization of the reaction conditions for the αꢀbenzoyloxylation of βꢀketo esters with PTC 3ma.
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Entry
solvent
base
T [°
C
]
t [h]
yield [%]b
ee [%]c
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2
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCF3
CHCl3
Et2O
50% NaOH
50% KOH
30% Cs2CO3
30% K2CO3
50% K2HPO4
50% EtONa
Et3N
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45
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97
95
85
61
Trace
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45
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87
81
96
98
<5
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86
67
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11
<5
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84
92
95
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3
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24
48
48
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24
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6
7d
8d
9
K2CO3
30% K2CO3
30% K2CO3
30% K2CO3
30% K2CO3
30% K2CO3
30% K2CO3
30% K2CO3
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15e
PhCH3
PhCH3
PhCH3
PhCH3
48
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16f
PhCH3
30% K2CO3
15
12
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a Unless otherwise specified, the reactions were performed with 1a (0.1 mmol), BPO (0.15 mmol), PTC 3n (0.005 mmol), and base (0.5
mL) in solvent (5 mL). b Yields shown are of isolated products. c Determined by chiral HPLC (Chiralcel ADꢀH). d Five equivalents of the
base was used. e The reactions were performed with 1a (0.1 mmol), BPO (0.15 mmol), PTC 3n (0.0025 mmol), and 30% K2CO3 (1 mL)
in toluene (10 mL). f Butylated hydroxytoluene (BHT, 0.05 mmol) was added.
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With the optimized conditions in hand, we next explored the substrate scope to demonstrate the generality
of cinchona catalyst 3n in asymmetric αꢀbenzoyloxylation reactions. First, we investigated the steric
influence of the ester group. We found that the enantioselectivities were obviously influenced by the degree
of substitution on the ester group. Tertiary alcoholꢀderived βꢀketo esters 1aꢀ1d gave excellent
enantioselectivities (87ꢀ95% ee), but secondary esters 1eꢀ1i resulted in lower selectivities (59ꢀ81% ee). To
our delight, methyl ester 1j afforded corresponding product 2j with 73% ee and 95% yield, which highlights
the broad substrate scope of this reaction20. Next, a series of 1ꢀindanoneꢀderived adamantly βꢀketo esters
were investigated. A variety of substrates with substituents on the aromatic rings, such as Cl, F, Br and
methyl groups, were nicely converted into the corresponding products (2kꢀ2o) in good yields (93ꢀ97%) with
83ꢀ93% ee. However, when methoxy groups were introduced (1p and 1q), a stronger base (10% KOH) was
needed to afford the desired products (2p, 2q) in 73ꢀ83% yields with 75% ee. The reason why the yields and
ee values of 2p and 2q were noticeably decreased will be discussed in later sections. Compounds 1r and 1s,
which have ꢀF substituents in the 5ꢀposition, afforded 2r and 2s in 95ꢀ96% yields with 90ꢀ91% ee.
Ultimately, such a simple and efficient method for αꢀbenzoyloxylation showed good substrate tolerance for
indanoneꢀderived βꢀketo esters (Scheme 2).
Scheme 2. Substrate scope of the αꢀbenzoyloxylation of indanoneꢀderived βꢀketo esters.
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Reaction conditions (unless otherwise specified): the reactions were performed with βꢀketo ester (0.1 mmol), BPO (0.15 mmol), PTC 3n
(0.0025 mmol), and 30% K2CO3 (1 mL) in toluene (10 mL) at 15°C for 12 h.
To further explore the synthetic utility of the current αꢀbenzoyloxylation reaction, βꢀketo ester 4a derived
from 1ꢀtetralone was examined as shown in Table 3. We found 30% K2CO3 aq. cannot activate this reaction
(Table 2, entry 1). To our surprise, when a stronger base (30% Cs2CO3 aq) was used, αꢀhydroxylation
product 6a was obtained with 51% ee in 15% yield (Table 3, entry 2). Next, 10% NaOH aq and 25% NaOH
aq were tested, and we not only obtained αꢀbenzoyloxylation product 5a (31ꢀ37% yield, 26ꢀ27% ee) but also
αꢀhydroxylation product 6a (48ꢀ51% yield, 84ꢀ87% ee) (Table 3, entries 3 and 4). However, when 50%
NaOH aq was used, only αꢀhydroxylation product 6a was observed (Table 3, entry 5). We also tested Et2O
as the solvent, but it gave poor results (Table 3, entry 6). Then, we use pure oxygen gas instead of BPO as
the oxidant, but very little product was obtained, which indicated that the oxygen source for αꢀhydroxylation
product 6a was BPO (Table 3, entry 7). We also performed this reaction under an argon atmosphere, and the
obtained results were similar to those obtained under air (Table 3, entry 8), which further suggested the
oxygen in the atmosphere has no influence on this reaction.
Table 3. Optimization of the reaction conditions for the αꢀbenzoyloxylation and hydroxylation of
1ꢀtetraloneꢀderived βꢀketo ester 4aa.
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Entry
solvent
base
yield (5a/6a) [%]b
ee (5a/6a) [%]c
5
6
7
8
9
1
2
PhCH3
30% K2CO3
30% Cs2CO3
10% NaOH
25% NaOH
50% NaOH
25% NaOH
25% NaOH
25% NaOH
Nr/Nr
Nd/Nd
Nd/51
26/84
27/87
Nd/61
6/45
PhCH3
PhCH3
PhCH3
PhCH3
Et2O
Trace/15
31/51
10
11
12
13
14
15
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3
4
37/48
5
Trace/31
21/57
6
7[d]
PhCH3
PhCH3
Nr/Nr
Nd/Nd
26/87
8[e]
38/46
a Unless otherwise specified, the reactions were performed with 1a (0.1 mmol), BPO (0.15 mmol), PTC 3n (0.0025 mmol), and base (1
mL) in solvent (10 mL). Yields shown are of isolated products. Determined by chiral HPLC (Chiralcel ADꢀH and ASꢀH). d Pure
b
c
oxygen gas was used as the oxidant instead of BPO. e Performed under an argon atmosphere.
Under the optimized conditions, the scope of sixꢀmembered βꢀketo esters was examined, and the results
are summarized in Scheme 3. Methyl ester 4b afforded αꢀbenzoyloxylation product 5b in 32% ee and 45%
yield, whereas αꢀhydroxylation product 6b was not obtained. Different substituents such as 6ꢀOMe and
7ꢀOMe were investigated. Under mild conditions, the αꢀbenzoyloxylation products (5c and 5d) and
αꢀhydroxylation products (6c and 6d) were all easily obtained in up to 86% ee. Unfortunately,
cyclohexanoneꢀderived βꢀketo ester 4e showed low reactivity, which indicated the aromatic core of the
substrate played an important role in this reaction. Overall, the two αꢀoxygenated products of
1ꢀtetraloneꢀderived βꢀketo esters can be obtained at the same time by this simple method.
Scheme 3. Substrate scope of the αꢀbenzoyloxylation and hydroxylation of βꢀketo esters.
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Reaction conditions (unless otherwise specified): the reactions were performed with βꢀketo ester (0.1 mmol), BPO (0.15 mmol), PTC 3n
(0.0025 mmol), and 25% KOH (1 mL) in toluene (10 mL) at 15°C for 12 h.
To demonstrate the utility of this reaction, we scaled up the reaction to the gram scale. Under
phaseꢀtransfer catalysis, 5 mmol of βꢀketo ester (1a) reacted smoothly with 7.5 mol of BPO and gave 2.09 g
(97% yield) of 2a in 94% ee after 12 h (Scheme 4). It is worth mentioning that Nꢀoxide PTC 3n can be
easily separated from the product because it is nearly insoluble in both the organic phase and water. After
completion of the reaction, the organic layer, which contained product 2a and BPO, was removed. Then,
additional 1a and BPO were added to the toluene, and the reaction was restarted. PTC 3n could be reused
for five runs without any significant loss in reactivity or enantioselectivity (Table 4).
Scheme 4. Gramꢀscale reaction.
Table 4. Reusability of PTC 3n for the asymmetric αꢀ benzoyloxylation of 1a
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Reaction conditions (unless otherwise specified): the reactions were performed with βꢀketo ester (2.5 mmol), BPO (3.8 mmol), PTC 3n,
and 30% K2CO3 (25 mL) in toluene (250 mL) at 15°C.
The absolute configuration of αꢀbenzoyloxylation product 2j was determined to be S by comparison of its
optical rotation with literature data9k. Based on previous studies9c,19b, a plausible transition state was
proposed. An enolate–PTC complex needs to be formed upon deprotonation of 1. Three different types of
interactions could be occurring. (1) An ionꢀpair interaction could be occurring between the substrate and the
PTC. (2) Hydrogen bonds could be forming between the Cꢀ9 hydroxy group and the ester group. The pKa
for quinoline Nꢀoxide is 0.70, whereas the pKa for quinoline is 4.8521. In our opinion, when the quinoline
nitrogen atom of cinchona alkaloid was oxidized, the hydrogen bonding interactions between the Cꢀ9
hydroxy group and the ester group of 1a could be enhanced17c. The stronger hydrogen bonding between
Nꢀoxide PTC and the substrate may be the one reason for the high reactivity of the reaction. (3) Finally, π–π
stacking interactions could be occurring between the PTC and the substrate. An anthracene ring can be
involved in stronger π–π stacking interactions with substrate 1a than a benzene ring. For example, 3o which
has a anthracene ring at Nꢀposition provided better results (91% yield, 78% ee) than that of 3a (72% yield,
43% ee) (Table 1, entries 1, 15). And the Nꢀoxide PTC 3n could provided higher reactivity (95% yield, 86%
ee) than that obtained with 3o (Table 1, entry 14). With this transition state, only the Si face of the enolate is
available for reaction (Scheme 5).
Scheme 5. Model of a possible transition state for the reaction.
OMe
1. An ionꢀpair interaction
Br-
N+
3. Strong ꢀ stacking
-O
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O
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hydrogen
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Based on these experiments, we proposed a possible mechanism for the αꢀbenzoyloxylation and
hydroxylation of βꢀketo esters. First, the deprotonation of 1aꢀ1s occurred quickly in the presence of a base.
Then, the active BPO could react with the ion pair, thereby forming the αꢀbenzoyloxylation product. For the
1ꢀtetraloneꢀderived βꢀketo esters, a stronger base was needed (25% KOH) to complete the reaction. Then,
under the phaseꢀtransfer conditions, 6bꢀ6e can be generated by kinetic resolution of the benzoates, for which
only the R or S product will preferentially to hydrolyze (Scheme 6).
Scheme 6. Proposed mechanism for the αꢀbenzoyloxylation and hydroxylation of βꢀketo esters
To verify this proposed mechanism, we conducted some control experiments. αꢀBenzoyloxylation product
5b (26% ee) can be converted to 6b under the phaseꢀtransfer conditions, and we obtained 6b with a higher
ee (43%). Furthermore, if the reaction was conducted without phaseꢀtransfer catalyst 3n, almost no
αꢀhydroxylation product was obtained. Next, we investigated indanoneꢀderived αꢀbenzoyloxylation product
2a. Almost no αꢀhydroxylation product was obtained when 30% K2CO3 was used as the base. When a
stronger base (25% KOH) was used, the reaction proceeded well, and 2a' was obtained in 51% yield
(Scheme 7). These results might explain the regularity of the substrate scope of indanoneꢀderived βꢀketo
esters. For example, 30% K2CO3 could not promote the hydrolysis of 2a, and 2a was obtained in 98% yield
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and 95% ee. However, some substrates such as 1p and 1q cannot react with BPO in the presence of 30%
K2CO3. When 10% KOH was used, 2p and 2q could be obtained in 73ꢀ81% yield and 75% ee (Scheme 2).
Compared with 2a, the yields and ee values of 2p and 2q were noticeably lower. In our opinion, the
αꢀbenzoyloxylation product of indanoneꢀderived βꢀketo esters can also be hydrolyzed by kinetic resolution
under a strong inorganic base, and this may be the reason why the yields and ee values of 2p and 2q were
lower. Although the scope of βꢀketo esters was limited to the indanone and 1ꢀtetralone derived βꢀketo esters,
we still developed an enantioselective oxidative С–O coupling of βꢀketo esters by phase transfer catalysis,
and this reaction provided an easy and rapid access for potentially valuable precursors for the synthesis of
natural products and pharmaceuticals. Also, it is a good complement for αꢀacyloxylation, especially for
asymmetric system. Developing new methods for derivatization (hydrolysis and reduction) of the
enantioenriched esters has already been in progress.
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Scheme 7. Control experiments
Conclusion
In conclusion, we have developed the first enantioselective αꢀbenzoyloxylation of βꢀketo esters under
phaseꢀtransfer catalysis with commercially available benzoyl peroxide. Under mild conditions, high
enantioselectivities (up to 95%) and good yields (up to 99%) were obtained for a range of substituted
indanone and 1ꢀtetralone derivatives. Moreover, this new methodology was successfully used for a
gramꢀscale reaction, and the cinchonaꢀderived Nꢀoxide phaseꢀtransfer catalysts can be easily separated from
the product and reused in the reaction without any significant loss of reactivity or enantioselectivity. Further
investigations on expanding this enantioselective αꢀbenzoyloxylation to other useful compounds are
currently underway.
Experimental section
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Unless otherwise stated, all commercial reagents and solvents were used without further additional
purification. Analytical TLC was visualized with UV light at 254 nm. Thin layer chromatography was
carried out on TLC aluminum sheets with silica gel 60 F254. Purification of reaction products was carried
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out with chromatography on silica gel (200ꢀ300 mesh). H and 13C NMR spectra were recorded by using a
400 MHz NMR spectrometer. The enantiomeric excesses (ee) were determined by HPLC. Mass spectra are
reported by using electrospray ionization techniques. Optical rotations were measured on a digital
polarimeter with a sodium lamp at 25°C. Cinchona alkaloid catalysts 3a, 3b, 3c, 3d, 3g, 3h were prepared
according to our previous papers9c,19b.The Nꢀoxide catalysts 3eꢀ3f, 3iꢀ3o were prepared according to the
previous paper17a. βꢀketo esters were prepared according to the literature procedures9c.
General proceduce for the asymmetric αꢀbenzoyloxylation of βꢀindanone esters.
The reaction was conducted with βꢀketo esters 1aꢀ1s (0.1 mmol) in the presence of PTC 3n (0.0025 mmol)
and benzoyl peroxide (0.15 mmol) in a mixture containing PhCH3 (10 mL) and 30% K2CO3 (1 mL) at 15°C.
The reaction was stirred at this temperature for 12 h. After the reaction was completed (confirmed by TLC
analysis), the mixture was diluted with EtOAc (30 mL), washed with water (3 × 10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography
(silica gel; petroleum ether/ethyl acetate=30:1–10:1) to afford the αꢀbenzoyloxylation products 2aꢀ2s.
1-Adamantyl 2-benzoyloxy -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2a)
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(Colorless oil, 42.1 mg, 98% yield, 94% ee); [α]D 110.6 (c 0.62, CHCl3); 1H NMR (400 MHz,
Chloroformꢀd) δ 8.21 – 8.08 (m, 2H), 7.88 (d, J = 7.6 Hz, 1H), 7.73 – 7.66 (m, 1H), 7.60 (d, J = 7.4 Hz, 1H),
7.54 – 7.42 (m, 4H), 4.14 (d, J = 17.4 Hz, 1H), 3.47 (d, J = 17.4 Hz, 1H), 2.17 – 2.09 (m, 3H), 2.08 – 1.92
(m, 6H), 1.61 (s, 6H).13C NMR (101 MHz, CDCl3) δ 196.1, 165.5, 165.0, 151.7, 136.0, 133.9, 133.6, 130.12,
129.1, 128.5, 128.0, 126.2, 125.1, 84.6, 83.6, 40.9, 39.0, 35.9, 30.8. .HPLC conditions: Chiralcel ADꢀH
column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR (major) = 12.2 min, τR (minor) =
10.7 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C27H26O5Na 453.1678; Found 453.1671.
1-tert-butyl 2-benzoyloxy -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2b)
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(Colorless oil, 33.4 mg, 95% yield, 91% ee); [α]D 130.6 (c 0.53, CHCl3); 1H NMR (400 MHz,
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Chloroformꢀd) δ 8.14 (dd, J = 8.1, 1.4 Hz, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.76 – 7.57 (m, 2H), 7.58 – 7.38
(m, 4H), 4.16 (d, J = 17.4 Hz, 1H), 3.46 (d, J = 17.4 Hz, 1H), 1.40 (s, 9H).13C NMR (101 MHz, CDCl3) δ
196.0, 165.5, 165.4, 151.7, 136.1, 133.8, 133.6, 130.1, 129.1, 128.5, 128.1, 126.2, 125.1, 84.7, 83.6, 38.9,
27.7. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min,
254 nm, τR (major) = 9.4 min, τR (minor) = 7.8 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C21H20O5Na 375.1208; Found 375.1203.
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(Colorless oil, 35.5 mg, 97% yield, 92% ee); [α]D 123.4 (c 0.56, CHCl3); 1H NMR (400 MHz,
Chloroformꢀd) δ 8.21 – 8.09 (m, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.68 (dd, J = 7.5, 1.2 Hz, 1H), 7.60 (d, J =
7.4 Hz, 1H), 7.55 – 7.41 (m, 4H), 4.14 (d, J = 17.4 Hz, 1H), 3.48 (d, J = 17.4 Hz, 1H), 1.70 – 1.60 (m, 2H),
1.39 (d, J = 9.6 Hz, 6H), 0.70 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 196.0, 165.5, 165.2, 151.7,
136.0, 133.9, 133.6, 130.1, 129.1, 128.5, 128.1, 126.2, 125.1, 86.1, 84.7, 39.0, 33.8, 25.2, 24.9, 7.8. HPLC
conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR
(major) = 8.9 min, τR (minor) = 7.2 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C22H22O5Na 389.1365;
Found 389.1356.
3-ethyl 3-pentanyl 2-benzoyloxy -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2d)
(Colorless oil, 39.1 mg, 99% yield, 87% ee); [α]D25 87.5 (c 0.62, CHCl3); 1H NMR (400 MHz, Chloroformꢀd)
δ 8.23 – 8.10 (m, 2H), 7.89 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.62 – 7.57 (m, 1H), 7.54 – 7.42
(m, 4H), 4.13 (d, J = 17.4 Hz, 1H), 3.51 (d, J = 17.4 Hz, 1H), 1.87 – 1.65 (m, 6H), 0.71 (t, J = 7.5 Hz, 9H).
13C NMR (101 MHz, CDCl3) δ 196.1, 165.4, 164.7, 151.7, 136.0, 134.0, 133.6, 130.1, 129.1, 128.4, 128.1,
126.1, 125.1, 91.9, 84.7, 39.2, 26.9, 7.4. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane
/ iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR (major) = 7.6 min, τR (minor) = 6.6 min. HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C24H26O5Na 417.1678; Found 417.1672.
1-isopropyl 2-benzoyloxy -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2e)
(Colorless oil, 31.8 mg, 94% yield, 81% ee); [α]D25 99.3(c 0.61, CHCl3); 1H NMR (400 MHz, Chloroformꢀd)
δ 8.17 – 8.07 (m, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 7.5, 1.3 Hz, 1H), 7.61 (td, J = 7.1, 1.4 Hz, 1H),
7.55 – 7.42 (m, 4H), 5.19 – 5.00 (m, 1H), 4.24 (d, J = 17.5 Hz, 1H), 3.45 (d, J = 17.5 Hz, 1H), 1.24 (dd, J =
6.2, 1.5 Hz, 3H), 1.16 (dd, J = 6.2, 1.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 195.6, 166.0, 165.6, 151.8,
136.3, 133.7, 133.5, 130.1, 128.5, 128.2, 126.3, 125.2, 84.4, 70.6, 38.9, 21.5, 21.3. HPLC conditions:
Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR (major) = 13.0
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min, τR (minor) = 10.1 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C20H18O5Na 361.1052; Found
361.1049.
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(White wax, 38.3 mg, 89% yield, 80% ee); [α]D25 75.1(c 0.83, CHCl3);1H NMR (400 MHz, Chloroformꢀd) δ
8.21 – 8.11 (m, 2H), 7.89 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 7.5, 1.2 Hz, 1H), 7.62 (s, 1H), 7.58 – 7.43 (m,
4H), 5.00 (s, 1H), 4.21 (d, J = 17.4 Hz, 1H), 3.54 (d, J = 17.3 Hz, 1H), 2.01 – 1.91 (m, 2H), 1.85 – 1.61 (m,
9H), 1.53 – 1.32 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 195.7, 165.6, 165.6, 151.5, 136.1, 133.9, 133.7,
130.2, 129.0, 128.5, 128.2, 126.2, 125.2, 84.7, 79.5, 39.1, 37.2, 36.1, 36.1, 31.7, 31.6, 31.5, 31.4, 26.9, 26.8.
HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm,
τR (major) = 15.1 min, τR (minor) = 11.1 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C27H26O5Na
453.1678; Found 453.1672.
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2,4-dimethyl 3-pentanyl 2-benzoyloxy -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2g) (Colorless oil,
36.6 mg, 93% yield, 62% ee); [α]D25 58.2(c 0.64, CHCl3);1H NMR (400 MHz, Chloroformꢀd) δ 8.16 (d, J =
7.0 Hz, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (td, J = 7.5, 1.2 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.56 – 7.42 (m,
4H), 4.65 (dd, J = 6.5, 5.5 Hz, 1H), 4.19 (d, J = 17.4 Hz, 1H), 3.55 (d, J = 17.4 Hz, 1H), 1.96 – 1.64 (m, 2H),
0.89 (d, J = 6.8 Hz, 3H), 0.88 – 0.81 (m, 6H), 0.59 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 195.8,
166.3, 165.4, 151.5, 136.1, 134.0, 133.7, 130.2, 129.0, 128.5, 128.2, 126.2, 125.1, 85.7, 84.7, 39.2, 29.6,
29.4, 19.5, 19.4, 17.3, 16.4. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH =
90 / 10, 1 mL / min, 254 nm, τR (major) = 7.8 min, τR (minor) = 6.3 min. HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C24H26O5Na 417.1678; Found 417.1670.
9-Anthracenemethyl 2-benzoyloxy -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2h) (light yellow oil,
36.4mg, 75% yield, 64% ee); [α]D2589.3 (c 0.78, CHCl3);1H NMR (400 MHz, Chloroformꢀd) δ 8.49 (s, 1H),
8.32 – 8.18 (m, 2H), 8.09 – 7.93 (m, 4H), 7.83 (d, J = 7.7 Hz, 1H), 7.59 (dt, J = 26.1, 7.4 Hz, 3H), 7.50 –
7.34 (m, 8H), 6.25 (q, J = 12.6 Hz, 2H), 4.07 (d, J = 17.5 Hz, 1H), 3.39 (d, J = 17.4 Hz, 1H).13C NMR (101
MHz, CDCl3) δ 195.3, 166.8, 165.4, 151.4, 136.2, 133.6, 133.5, 131.2, 131.0, 130.2, 129.5, 128.9, 128.6,
128.3, 128.1, 126.6, 126.3, 125.3, 125.0, 123.9, 84.5, 61.2, 38.8. HPLC conditions: Chiralcel ASꢀH column
(250 × 4.6 mm), hexane / iꢀPrOH = 80 / 20, 1 mL / min, 254 nm, τR (major) = 9.3 min, τR (minor) =10.4 min.
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C32H22O5Na 509.1365; Found 509.1363.
Benzyl 2-benzoyloxy -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2i)
(Colorless oil, 31.7 mg, 82% yield, 59% ee); [α]D2570.0 (c 0.55, CHCl3); 1H NMR (400 MHz, Chloroformꢀd)
δ 8.13 (dd, J = 8.4, 1.4 Hz, 2H), 7.95 – 7.85 (m, 1H), 7.71 (td, J = 7.5, 1.2 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H),
7.56 – 7.43 (m, 4H), 7.33 – 7.27 (m, 3H), 7.21 (dd, J = 6.6, 3.0 Hz, 2H), 5.24 (s, 2H), 4.25 (d, J = 17.5 Hz,
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1H), 3.50 (d, J = 17.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 195.3, 166.4, 165.6, 151.6, 136.4, 135.0,
133.8, 133.5, 130.2, 128.8, 128.5, 128.5, 128.3, 128.2, 127.7, 126.4, 125.4, 84.5, 67.9, 38.9. HPLC
conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR
(major) = 27.5 min, τR (minor) = 21.4 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C24H18O5Na
409.1052; Found 409.1048.
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Methyl 2-benzoyloxy -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2j)
(light yellow oil, 29.5 mg, 95% yield, 73% ee); [α]D2575.3(c 0.45, CHCl3); 1H NMR (400 MHz,
Chloroformꢀd) δ 8.14 (d, J = 7.8 Hz, 2H), 7.89 (d, J = 7.7 Hz, 1H), 7.79 – 7.59 (m, 2H), 7.58 – 7.40 (m, 4H),
4.27 (d, J = 17.6 Hz, 1H), 3.79 (s, 3H), 3.46 (d, J = 17.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 195.4,
167.1, 165.6, 151.7, 136.4, 133.8, 133.4, 130.2, 128.5, 128.3, 126.4, 125.4, 84.3, 53.5, 38.9. HPLC
conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 80 / 20, 1 mL / min, 254 nm, τR
(major) = 13.0 min, τR (minor) = 9.4 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H14O5Na
333.0739; Found 333.0731.
1-Adamantyl 2-benzoyloxy-5-chloro -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2k) (Colorless oil, 45.0
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mg, 97% yield, 85% ee); [α]D25 89.4(c 0.71, CHCl3); H NMR (400 MHz, Chloroformꢀd) δ 8.13 (d, J = 7.0
Hz, 2H), 7.81 (d, J = 8.2 Hz, 1H), 7.68 – 7.56 (m, 1H), 7.54 – 7.39 (m, 4H), 4.09 (d, J = 17.5 Hz, 1H), 3.45
(d, J = 17.5 Hz, 1H), 2.19 – 2.09 (m, 3H), 2.10 – 2.01 (m, 6H), 1.64 – 1.58 (m, 6H). 13C NMR (101 MHz,
CDCl3) δ 194.7, 165.4, 164.7, 153.0, 142.5, 133.7, 132.5, 130.1, 128.9, 128.5, 126.4, 126.2, 84.5, 84.0, 40.9,
38.7, 35.9, 30.9. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1
mL / min, 254 nm, τR (major) = 12.7 min, τR (minor) = 10.4 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C27H25ClO5Na 487.1288; Found 487.1283.
1-Adamantyl 2-benzoyloxy-5- fluorine -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2l) (Colorless oil,
42.5 mg, 95% yield, 91% ee); [α]D25 99.2(c 0.67, CHCl3); 1H NMR (400 MHz, Chloroformꢀd) δ 8.18 – 8.09
(m, 2H), 7.90 (dd, J = 8.4, 5.3 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.23 – 7.10 (m,
2H), 4.12 (d, J = 17.6 Hz, 1H), 3.46 (d, J = 17.6 Hz, 1H), 2.19 – 2.11 (m, 3H), 2.03 (d, J = 2.8 Hz, 6H), 1.62
(t, J = 3.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 194.2, 169.1, 166.5, 165.5, 164.8, 154.7, 154.6, 133.7,
130.4, 130.1, 129.0, 128.5, 127.6, 84.7, 83.9, 40.9, 38.9, 38.9, 35.9, 30.9. HPLC conditions: Chiralcel ADꢀH
column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR (major) = 12.1 min, τR (minor) =
10.7 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C27H25FO5Na 471.1584; Found 471.1577.
1-Adamantyl 2-benzoyloxy-5- bromine -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2m) (Colorless oil,
47.2 mg, 93% yield, 83% ee); [α]D25 88.9 (c 0.63, CHCl3); 1H NMR (400 MHz, Chloroformꢀd) δ 8.24 – 8.04
(m, 2H), 7.79 – 7.67 (m, 2H), 7.65 – 7.56 (m, 2H), 7.47 (t, J = 7.8 Hz, 2H), 4.09 (d, J = 17.5 Hz, 1H), 3.46
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(d, J = 17.5 Hz, 1H), 2.25 – 1.92 (m, 9H), 1.62 (t, J = 3.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 195.0,
165.4, 164.7, 153.0, 133.7, 132.9, 131.7, 131.4, 130.1, 129.5, 128.9, 128.5, 126.2, 84.4, 84.0, 40.9, 38.6,
35.9, 30.9. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL /
min, 254 nm, τR (major) = 13.5 min, τR (minor) = 10.5 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C27H25BrO5Na 531.0783; Found 531.0773.
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1-Adamantyl 2-benzoyloxy-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2n) (Colorless oil, 42.2
mg, 95% yield, 93% ee); [α]D25 118.0 (c 0.58, CHCl3); 1H NMR (400 MHz, Chloroformꢀd) δ 8.21 – 8.07 (m,
2H), 7.68 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.54 – 7.38 (m, 4H), 4.10 (d, J = 17.3 Hz, 1H), 3.41 (d, J = 17.2
Hz, 1H), 2.45 (s, 3H), 2.08 (dd, J = 39.3, 3.0 Hz, 9H), 1.62 (d, J = 3.0 Hz, 6H). 13C NMR (101 MHz, CDCl3)
δ 196.1, 165.5, 165.2, 149.2, 138.1, 137.3, 134.0, 133.5, 130.1, 129.2, 128.4, 125.8, 125.0, 85.0, 83.6, 40.9,
38.7, 36.0, 30.9, 21.1. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 98 / 2,
1 mL / min, 254 nm, τR (major) = 12.3 min, τR (minor) = 9.8 min. HRMS Calcd. for [C28H28O5+Na]+ requires
m/z 467.1834, found m/z 467.1826. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C28H28O5Na 467.1834;
Found 467.1826.
1-Adamantyl 2-benzoyloxy-4-bromine-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2o) (Colorless oil,
47.2 mg, 93% yield, 87% ee); [α]D25 92.4(c 0.49, CHCl3);1H NMR (400 MHz, Chloroformꢀd) δ 8.17 – 8.08
(m, 2H), 7.89 – 7.78 (m, 2H), 7.61 (d, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1H), 4.06
(d, J = 17.8 Hz, 1H), 3.39 (d, J = 17.8 Hz, 1H), 2.15 – 2.07 (m, 9H), 1.62 (t, J = 3.1 Hz, 6H). 13C NMR (101
MHz, CDCl3) δ 195.6, 165.4, 164.6, 151.3, 138.6, 136.0, 133.8, 130.2, 129.7, 128.8, 128.5, 123.8, 121.5,
84.3, 84.0, 40.9, 40.0, 35.9, 30.9. HPLC conditions: Chiralcel ASꢀH column (250 × 4.6 mm), hexane /
iꢀPrOH = 95 / 5, 1 mL / min, 254 nm, τR (major) = 7.6 min, τR (minor) = 6.9 min. HRMS Calcd. for
[C27H25BrO5+Na]+ requires m/z 531.0783, found m/z 531.0777. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C27H25BrO5Na 531.0783; Found 531.0777.
1-Adamantyl 2-benzoyloxy-5-methoxyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2p) (light yellow oil,
37.3 mg, 81% yield, 75% ee); [α]D25 109.5(c 0.45, CHCl3); 1H NMR (400 MHz, Chloroformꢀd) δ 8.24 – 8.09
(m, 2H), 7.82 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.02 – 6.89 (m, 2H),
4.14 (d, J = 17.4 Hz, 1H), 3.93 (s, 3H), 3.39 (d, J = 17.4 Hz, 1H), 2.21 – 1.95 (m, 9H), 1.61 (t, J = 2.9 Hz,
6H). 13C NMR (101 MHz, CDCl3) δ 193.9, 166.4, 165.7, 165.3, 155.1, 133.5, 130.1, 129.3, 128.4, 127.0,
126.9, 116.2, 109.3, 85.0, 83.5, 55.8, 40.9, 39.1, 36.0, 30.9. HPLC conditions: Chiralcel ADꢀH column (250
× 4.6 mm), hexane / iꢀPrOH = 70 / 30, 1 mL / min, 254 nm, τR (major) = 11.8 min, τR (minor) = 8.3 min.
HRMS Calcd. for [C28H28O6+Na]+ requires m/z 483.1784, found m/z 483.1777. HRMS (ESIꢀTOF) m/z: [M
+ Na]+ Calcd for C28H28O6Na 483.1784; Found 483.1777.
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(light yellow oil, 37.4 mg, 73% yield, 75% ee); [α]D 139.3(c 0.62, CHCl3);1H NMR (400 MHz,
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Chloroformꢀd) δ 8.27 – 8.10 (m, 2H), 7.59 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.28 (s, 1H), 6.92 (s,
1H), 4.10 (d, J = 17.2 Hz, 1H), 3.98 (d, J = 24.3 Hz, 6H), 3.35 (d, J = 17.2, 1H), 2.21 – 1.97 (m, 9H), 1.68 –
1.55 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 194.4, 165.7, 165.4, 156.6, 149.9, 147.8, 133.5, 130.1, 129.3,
128.4, 128.2, 126.4, 125.3, 107.0, 105.4, 85.0, 83.5, 56.4, 56.2, 40.9, 38.8, 36.0, 30.9. HPLC conditions:
Chiralcel ASꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 95 / 5, 1 mL / min, 254 nm, τR (major) = 7.4
min, τR (minor) = 6.4 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C29H30O7Na 513.1889; Found
513.1887.
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1-tert-butyl 2-benzoyloxy5- fluorine -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2r) (Colorless oil, 35.5
mg, 96% yield, 90% ee); [α]D25 120.2(c 0.51, CHCl3);1H NMR (400 MHz, Chloroformꢀd) δ 8.22 – 8.05 (m,
2H), 7.90 (dd, J = 8.4, 5.2 Hz, 1H), 7.69 – 7.55 (m, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.24 – 7.10 (m, 2H), 4.14
(d, J = 17.6 Hz, 1H), 3.45 (d, J = 17.6 Hz, 1H), 1.41 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 194.1, 169.1,
166.6, 165.5, 165.2, 154.7, 133.7, 130.1, 128.9, 128.5, 127.6, 127.5, 116.6, 116.4, 113.2, 112.9, 84.7, 83.9,
38.8, 27.7. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL /
min, 254 nm, τR (major) = 10.5 min, τR (minor) = 8.3 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C21H19FO5Na 393.1114; Found 393.1109.
1- tert-pentyl 2-benzoyloxy5- fluorine -1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2s) (Colorless oil,
36.7 mg, 95% yield, 91% ee); [α]D25 108.5(c 0.44, CHCl3);1H NMR (400 MHz, Chloroformꢀd) δ 8.19 – 8.06
(m, 2H), 7.90 (dd, J = 8.4, 5.3 Hz, 1H), 7.65 – 7.56 (m, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.24 – 7.10 (m, 2H),
4.12 (d, J = 17.6 Hz, 1H), 3.46 (d, J = 17.6 Hz, 1H), 1.72 – 1.60 (m, 2H), 1.39 (d, J = 8.7 Hz, 6H), 0.72 (t, J
= 7.5 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 194.1, 169.1, 166.5, 165.5, 165.0, 154.7, 133.7, 130.4, 130.1,
128.9, 128.5, 127.6, 116.6, 113.2, 86.4, 84.7, 38.9, 38.9, 33.7, 25.2, 24.9, 7.8. HPLC conditions: Chiralcel
ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR (major) = 10.4 min, τR
(minor) = 7.9 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C22H21FO5Na 407.1271; Found 407.1265.
Gramꢀscale reaction and reusability of the phase transfer catalyst 3n
The reaction was conducted with substrate 1a (5 mmol, 1.55 g), benzoyl peroxide (7.5 mmol, 2.25g )
(BPO) in the presence of PTC 3n (2.5 mol%) in a mixture containing PhCH3 (250 mL) and K2CO3 (25 mL,
30% aq.) at 15°C,. After completion of the reaction (confirmed by TLC analysis ), the organic layer and the
aqueous phase was separated, the αꢀbenzoyloxylation product and BPO were dissolved in the organic base,
and the PTC 3n was suspended in the water phase. The organic phase was diluted with EtOAc (150 mL),
washed with water (3× 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
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residue was purified by flash chromatography(PE/EA =25 :1) to give 2a (2.09g, 97% yield, 94% ee). The ee
of the product was determined by chiral ADꢀH. The the aqueous phase was collected (including PTC 3n and
30% K2CO3) for reuse. The reaction for reusability of the phase transfer catalyst 3n was conducted with
substrate 1a (2.5 mmol, 0.78 g), benzoyl peroxide (3.8 mmol, 1.23 g ) (BPO) in the presence of PhCH3 (250
mL) and the reused aqueous phase (including PTC 3n and 30% K2CO3) at 15°C. After completion of the
reaction (confirmed by TLC analysis), the organic layer and the aqueous phase was separated, the
αꢀbenzoyloxylation product and BPO were dissolved in the organic base, and the PTC 3n was suspended in
the aqueous phase. The organic phase was diluted with EtOAc (150 mL), washed with water (3× 50 mL),
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash
chromatography (PE/EA =25 :1) to give 2a.
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General proceduce for the asymmetric αꢀbenzoyloxylation and hydroxylation of 1ꢀtetralone derived
βꢀketo esters
Unless otherwise specified, the reactions were performed with 4aꢀ4e (0.1 mmol), BPO (0.15 mmol), PTC
3n (0.0025 mmol), and 25% KOH(1 mL) in PhCH3 (10 mL) at 15°C. After completion of the reaction
(confirmed by TLC analysis ), the mixture was diluted with EtOAc (30 mL), washed with water (3× 20 mL),
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash
chromatography to give 5aꢀ5e and 6aꢀ6e. The ee of the products were determined by chiral HPLC.
1-Adamantyl 2- benzoyloxy -1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (5a) (Colorless oil, 16.4
mg, 37% yield, 27% ee); [α]D25 ꢀ15.5 (c 0.25, CHCl3); 1H NMR (400 MHz, Chloroformꢀd) δ 8.22 – 7.99 (m,
3H), 7.63 – 7.43 (m, 4H), 7.38 (d, J = 7.6 Hz, 1H), 7.31 – 7.25 (m, 1H), 3.29 – 3.02 (m, 2H), 2.85 – 2.74 (m,
2H), 2.23 – 1.94 (m, 9H), 1.62 (d, J = 3.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 190.1, 166.5, 165.1,
141.9, 133.5, 133.3, 132.7, 130.1, 129.5, 128.4, 128.3, 127.9, 127.0, 83.7, 83.6, 40.9, 36.0, 32.3, 30.8, 26.0.
HPLC conditions: Chiralcel ASꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm,
τR (major) = 7.7 min, τR (minor) = 6.4 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C28H28O5Na
467.1834; Found 467.1830.
1-Methyl 2- benzoyloxy -1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (5b) (Colorless oil, 14.6 mg,
45% yield, 32% ee); [α]D25 ꢀ14.3 (c 0.23, CHCl3);1H NMR (400 MHz, Chloroformꢀd) δ 8.20 – 8.02 (m, 3H),
7.65 – 7.51 (m, 2H), 7.50 – 7.35 (m, 3H), 7.32 – 7.25 (m, 1H), 3.82 (s, 3H), 3.23 – 3.04 (m, 2H), 3.00 – 2.73
(m, 2H).13C NMR (101 MHz, CDCl3) δ 189.5, 168.5, 165.2, 142.3, 133.9, 133.5, 131.8, 130.1, 128.6, 128.4,
128.4, 127.2, 83.2, 53.0, 31.8, 25.7. HPLC conditions: Chiralcel ASꢀH column (250 × 4.6 mm), hexane /
iꢀPrOH = 90 / 10, 0.8 mL / min, 254 nm, τR (major) = 18.4 min, τR (minor) = 17.6 min. HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C19H16O5Na 347.0895; Found 347.0891.
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1-Adamantyl 2-benzoyloxy-6-methoxyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (5c) (light
yellow oil, 17.5 mg, 37% yield, 42% ee); [α]D25 ꢀ26.3 (c 0.21, CHCl3);1H NMR (400 MHz, Chloroformꢀd) δ
8.19 – 8.01 (m, 3H), 7.69 – 7.53 (m, 1H), 7.45 (t, J = 7.5 Hz, 2H), 6.89 (dd, J = 8.8, 2.5 Hz, 1H), 6.73 (d, J =
2.4 Hz, 1H), 3.89 (s, 3H), 3.24 – 2.97 (m, 2H), 2.93 – 2.63 (m, 2H), 2.20 – 2.02 (m, 9H), 1.69 – 1.58 (m,
6H).13C NMR (101 MHz, CDCl3) δ 188.7, 166.6, 165.2, 163.7, 144.6, 133.2, 130.5, 130.1, 129.6, 128.3,
125.9, 113.5, 112.4, 83.6, 55.5, 41.0, 36.0, 32.1, 30.8, 26.2. HPLC conditions: Chiralcel ADꢀH column (250
× 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR (major) = 17.8 min, τR (minor) = 19.0 min.
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C29H30O6Na 497.1940; Found 497.1933.
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(light yellow oil, 14.7 mg, 31% yield, 34% ee); [α]D ꢀꢀ17.4 (c 0.23, CHCl3); H NMR (400 MHz,
Chloroformꢀd) δ 8.16 – 8.07 (m, 2H), 7.68 – 7.53 (m, 2H), 7.47 (dd, J = 8.4, 7.1 Hz, 2H), 7.19 (d, J = 8.4
Hz, 1H), 7.11 (dd, J = 8.4, 2.8 Hz, 1H), 3.85 (s, 3H), 3.18 – 3.00 (m, 2H), 2.82– 2.74 (m, 2H), 2.10 (dd, J =
31.7, 3.0 Hz, 9H), 1.65– 1.59 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 190.2, 166.5, 165.1, 158.5, 134.6,
133.4, 133.3, 130.1, 129.6, 128.3, 122.0, 109.7, 83.7, 83.6, 55.5, 40.9, 36.0, 32.6, 30.8, 25.2. HPLC
conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR
(major) = 14.5 min, τR (minor) = 12.6 min. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C29H30O6Na
497.1940; Found 497.1935.
1-Adamantyl 2-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (6a) (Colorless oil, 16.3 mg,
48% yield, 87% ee); [α]D25 ꢀ8.5 (c 0.18, CHCl3); 1H NMR (400 MHz, Chloroformꢀd) δ 8.06 (dd, J = 7.8, 1.4
Hz, 1H), 7.54 (td, J = 7.5, 1.5 Hz, 1H), 7.36 (td, J = 7.6, 1.1 Hz, 1H), 7.31 – 7.23 (m, 1H), 4.26 (s, 1H), 3.14
(dd, J = 7.5, 5.2 Hz, 2H), 2.76 – 2.61 (m, 1H), 2.24 (dt, J = 13.5, 7.5 Hz, 1H), 2.15– 2.03 (m, 9H), 1.62 (t, J
= 3.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 194.9, 169.7, 143.8, 134.1, 130.7, 128.8, 127.9, 126.9, 83.5,
41.0, 35.9, 32.9, 30.8, 25.8. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH =
90 / 10, 1 mL / min, 254 nm, τR (major) = 12.1 min, τR (minor) = 18.3 min. The spectral data for the
compound were consistent with that reported in the literature 17a
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1-Adamantyl 2-hydroxy-6-methoxyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (6c) (light yellow
oil, 17.7 mg, 48% yield, 74% ee); [α]D25 ꢀ11.2; (c 0.24, CHCl3); 1H NMR (400 MHz, Chloroformꢀd) δ 8.03
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(d, J = 8.8 Hz, 1H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 4.30 (s, 1H), 3.88 (s, 3H), 3.15 –
3.07 (m, 2H), 2.63 (dt, J = 13.4, 5.1 Hz, 1H), 2.25 – 2.10 (m, 5H), 2.04 (d, J = 2.9 Hz, 6H), 1.63 (t, J = 3.2
Hz, 6H).13C NMR (101 MHz, CDCl3) δ 193.5, 169.9, 164.2, 146.5, 130.5, 124.1, 113.6, 112.6, 83.3, 55.5,
45.3, 41.0, 36.1, 36.0, 32.8, 30.8, 26.1. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane /
iꢀPrOH = 90 / 10, 1 mL / min, 254 nm, τR (major) = 22.7 min, τR (minor) = 31.6 min. The spectral data for
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the compound were consistent with that reported in the literature17a
.
1-Adamantyl 2-hydroxy-7-methoxyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (6d) (light yellow
oil, 20.0 mg, 54% yield, 86% ee); [α]D25 ꢀ14.3 (c 0.25, CHCl3); 1H NMR (400 MHz, Chloroformꢀd) δ 7.52 (d,
J = 2.8 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 8.5, 2.8 Hz, 1H), 4.25 (s, 1H), 3.86 (s, 3H), 3.06 (dd,
J = 7.4, 5.2 Hz, 2H), 2.63 (dt, J = 13.5, 5.2 Hz, 1H), 2.29 – 2.11 (m, 4H), 2.08 – 2.01 (m, 6H), 1.68 – 1.59
(m, 6H).13C NMR (101 MHz, CDCl3) δ 194.9, 169.8, 158.4, 136.5, 131.4, 130.0, 122.7, 109.6, 83.5, 55.5,
41.0, 35.9, 33.1, 30.8, 25.0. HPLC conditions: Chiralcel ADꢀH column (250 × 4.6 mm), hexane / iꢀPrOH =
90 / 10, 1 mL / min, 254 nm, τR (major) = 14.0 min, τR (minor) = 22.6 min. The spectral data for the
compound were consistent with that reported in the literature 17a
.
Acknowledgments
We would likely to thank the National Natural Science Foundation of China (No. 21176041, No. 21476041 )
and the innovation and technology team of Xinxiang (CXTD17004) for their support.
Supplementary Material
Characterization data (including 1H NMR, 13C NMR, and HPLC spectra) for all αꢀbenzoyloxy and
αꢀhydroxy products.
References and notes
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