Ruthenium-Catalyzed Enantioselective Hydrogenation/Lactonization of 2-Acylarylcarboxylates: Direct Access to Chiral 3-Substituted Phthalides

Article abstract of DOI:10.1002/cctc.201700695

Highly enantioselective tandem hydrogenation/lactonization of various 2-acylarylcarboxylates including 2-aroylarylcarboxylates were realized by using [RuCl(benzene)(S)-SunPhos]Cl as the catalyst under mild reaction conditions. Excellent enantioselectivities (up to 99.6 % ee) and activities (S/C=1000) were obtained. This convenient and practical method enables a direct access to a series of highly optically pure 3-substituted phthalides that are very important molecules as valuable pharmacological compounds and diversified synthons for medicinal chemistry. Moreover, a gram-scale reaction was performed to further demonstrate the practicality of this approach.

Full text of DOI:10.1002/cctc.201700695

Accepted Article
Title: Ruthenium-Catalyzed Enantioselective Hydrogenation/
Lactonization of 2-Acylarylcarboxylates：Direct Access to Chiral
3-Substituted Phthalides
Authors: Bin Lu, Mengmeng Zhao, Guangni Ding, Xiaomin Xie, Lili
Jiang, Virginie Ratovelomanana-Vidal, and Zhao-Guo Zhang
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10.1002/cctc.201700695
ChemCatChem
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Ruthenium-Catalyzed Enantioselective
Hydrogenation/Lactonization of 2-Acylarylcarboxylates：Direct
Access to Chiral 3-Substituted Phthalides
Bin Lu,[a] Mengmeng Zhao,[a] Guangni Ding,[a] Xiaomin Xie,[a] Lili Jiang,[a] Virginie Ratovelomanana-
Vidal,[c] and Zhaoguo Zhang*[a,b]
Abstract:
hydrogenation/lactonization of various 2-acylarylcarboxylates
including 2-aroylarylcarboxylates were realized using
Highly
enantioselective
tandem
catalytic
asymmetric
reduction/lactonization
of
2-
acylarylcarboxylate compounds represents an attractive and
elegant strategy for optically pure phthalide synthesis.
Nevertheless to date, only a handful of relevant reports including
asymmetric hydroboration,[4c, 4d] and transfer hydrogenation[4j, 4k,
4m, 4n] followed by lactonization have been realized. Among these
two direct reduction/lactonization routes, the asymmetric
hydroboration aforementioned suffered from limited range of
substrates and poor efficiency (catalyst loading was 50 mol%).
Although excellent enantioselectivity was obtained through
transfer hydrogenation, the catalytic activity was need to be
further improved for its practical application. Accordingly, there
still remains a significant need for a more effective and highly
enantioselective reduction/lactonization process to optically pure
3-substituted phthalides.
[RuCl(benzene)(S)-SunPhos]Cl as catalyst under mild reaction
conditions. Excellent enantioselectivities (up to 99.6% ee) and
activities (S/C = 1000) were obtained. This convenient and practical
method enables a direct access to a series of highly optically pure 3-
substituted phthalides that are very important molecules as valuable
pharmacological compounds and diversified synthons for medicinal
chemistry. Moreover, a gram-scale reaction was performed to further
demonstrate the practicality of this approach.
Introduction
Optically
active
3-substituted
phthalides
(1(3H)-
isobenzofuranones) are not only very useful molecules as
precious pharmacological compounds, but also key structural
motif in many natural products and biologically active
compounds (Figure 1).[1] Over the past decades，a variety of
approaches have been developed for the asymmetric synthesis
of chiral 3-substituted phthalides, including nucleophilic
addition/cyclization,[2] intramolecular ketone hydroacylation,[3]
5]
asymmetric reduction/lactonization,[4] and other methods.[1g,
Among them, catalytic methods seem to be the most atom
economic and therefore are of particular interest. Consequently,
[a]
B. Lu, M. Zhao, G. Ding, Dr. X. Xie, L, Jiang, Prof. Z. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (P.R. China)
Fax: (+86)21-5474-8925
E-mail: zhaoguo@sjtu.edu.cn
Figure 1. Selected examples of natural occurring chiral 3-substituted
[b]
[c]
Prof. Z. Zhang
Shanghai Institute of Organic Chemistry
Chines Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
Dr. V. Ratovelomanana-Vidal
Institut de Recherche de Chimie Paris
PSL Research University, Chimie ParisTech–CNRS
11 rue Pierre et Marie Curie
phthalides.
Asymmetric hydrogenation of prochiral ketones using
clean dihydrogen and small amount of chiral transition metal
complex is considered as one of the most direct, efficient and
economical strategies to produce various optically active
alcohols both from academic and industrial points of view.[6]
Because of its great significance, much effort has been devoted
75005 Paris, (France)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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to this important transformation and some catalytic systems
have been investigated to achieve high efficiency and
enantioselectivity.[7] For the Ru-catalyzed enantioselective
hydrogenation of functionlized ketones, the evolutionary
breakthrough was achieved by Noyori and co-workers in 1980s
using the chiral Ru-BINAP catalytic system.[8] Subsequently,
numerous efficient chiral ruthenium-diphosphines catalysts have
been emerged for the important transformation over the last
decades, which not only provide abundant choices of catalytic
systems, but also improve the activity and enantioselectivity of
catalyzed asymmetric hydrogenation/lactonization of 2-
acylarylcarboxylates.
Results and Discussion
Considering that previous example regarding the asymmetric
hydrogenation
of
ethyl
4-oxopentanoate
using
the
[NH2Me2][{RuCl[(R)-SegPhos]}2(µ-Cl)3] catalytic system reported
by Saito and co-workers, firstly we applied the
[NH2Me2][{RuCl[(S)-SunPhos]}2(µ-Cl)3] as catalyst for the
asymmetric hydrogenation of methyl 2-acetylbenzoate (1a)
serving as the model substrate. The reaction was initially carried
out in MeOH containing 0.5 mol% of [NH2Me2][{RuCl[(S)-
SunPhos]}2(µ-Cl)3] under 40 atm of H2 at 50 °C for 12 h.
Unfortunately, incomplete conversion and poor yield was
obtained in the reaction albeit of good enantioselectivity (Table 1,
entry 1). However, when the [RuCl(benzene)(S)-SunPhos]Cl
was employed as the catalyst, to our great delight, full reduction
and subsequent in situ lactonization were realized affording
optically pure 2a with little amount of by-product 2a′ (Table 1,
entry 2). The result was superior to that obtained by using other
two Ru-diphosphines catalytic systems (Table 1, entry 2 vs.
entries 3, 4). It is noteworthy that the reaction condition is much
mild compared to that (100 atm, for 165 h) reported by Noyori
using Ru(BINAP)(OAc)2-HCl catalytic system. Additionally, a
number of commercially available chiral diphosphines ligands
(shown in Figure 2) were also tested under the same reaction
conditions and the results are revealed in Table 1.
9]
the hydrogenation of various functionlized ketones.[7a-d,
Consequently, the efficiency of this transformation has promoted
greatly and the substrate scope has been expanded extensively
today. However, to the best of our knowledge, only three
examples regarding asymmetric hydrogenation of 2-
acylarylcarboxylates have been reported, which can be
attributed to the much lower reactivity of γ-ketoacid derivatives in
a hydrogenation reaction compared to that of α- and β-ketoacid
10]
derivatives.[4g-i,
In 1988, Noyori and co-workers firstly
described the asymmetric hydrogenation of the o-acetylbenzoic
acid using Ru-BINAP catalyst followed by lactonization in situ to
afford the 3-methylisobenzofuran-1(3H)-one with 92% ee.[4g]
Two years later, this group also successfully realized the
enantioselective hydrogenation/lactonization of the ethyl o-
acetylbenzoate with 97% ee, catalyzed by 0.4 mol%
Ru(OCOCH3)2[(S)-BINAP] in the presence of HCl at 100 atm for
165 h.[4h] In 2011, Zhou et al. applied the Ir-SpiroPAP catalyzed
highly effective enantioselective hydrogenation/cyclization of
ethyl 2-pentanoylbenzoate to synthesize 3-butylisobenzofuran-
1(3H)-one with 99% ee at S/C = 10000.[4i] All three above were
limited to a sole substrate, so there is still no more general and
effecient catalytic system reported for the asymmetric
hydrogenation of various 2-acylarylcarboxylates, especially for
much less reactive 2-aroylarylcarboxylates. Therefore, using
asymmetric hydrogenation to synthesize diversified chiral 3-
substituted phthalides is still a significant and challenging work.
Our group has been focusing on the studies of the
asymmetric hydrogenation and has designed some biaryl
diphosphine ligands-SunPhos family which showed high
efficiency and enantioselectivity for the hydrogenation of various
functionlized ketones and simple ketones.[9d, 11] Herein, we report
a convenient and efficient synthetic method for the synthesis of
optically pure 3-substituted phthalides by the Ru-SunPhos
Figure 2. Structures of chiral bidentate ligands.
All the screened ligands showed excellent activity, and similar
enantiomeric excess were obtained by using (S)-BINAP, (S)-
SegPhos, (S)-SynPhos and (S)-4-MeO-BIPHEP as ligand (Table
1, entries 5-8, 99.0%-99.4% ee), which were higher than that of
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(S)-C3-TunePhos (Table 1, entry 9, 85.8% ee). Based on the
above results, the catalytic system [RuCl(benzene)(S)-
SunPhos]Cl was the choice for this transformation.
7, 8), while lower temperature dramatically reduced the reaction
rate and moderately decreased the enantiomeric excess (Table
2, entry 6). Performing the reaction at a lower pressure resulted
in slightly lower yields of the desired product 2a, though high
enantioselectivities were remained (Table 2, entry 1 vs. entries
10, 11). On the basis of the above results, the optimized reaction
Table 1. Effects of Ligands in Asymmetric Hydrogenation of 1a.[a]
conditions were using 0.5 mol
% of [RuCl(benzene)(S)-
SunPhos]Cl as the catalyst, MeOH as the solvent with a
substrate concentration of 0.5 M under 40 atm of H2 at 50°C for
12 h.
2a/2a′[b]
4/39
99/1
99/1
92/8
99/1
98/2
99/1
99/1
ee [%][c]
83.8
99.6
99.2
97.0
99.0
99.2
99.2
99.4
Entry
1[d]
2[e]
3[f]
Ligand
Table 2. Optimization of Solvent, Temperature, Pressure.[a]
(S)-SunPhos
(S)-SunPhos
(S)-SunPhos
(S)-SunPhos
(S)-BINAP
T/°C
P/atm
Conv.
[%][b]
ee
[%][c]
Entry
Solvent
4[g]
5[e]
6[e]
7[e]
8[e]
1
MeOH
EtOH
50
50
50
50
50
30
70
90
50
50
50
40
40
40
40
40
40
40
40
60
20
10
100
100
100
0
99.6
99.2
99.0
n.a.
2
(S)-SegPhos
(S)-SynPhos
3
iPrOH
CH2Cl2
Toluene
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
4[d]
5[d]
6
(S)-4-MeO-
BIPHEP
0
n.a.
57
98.4
99.4
99.0
99.9
99.4
99.6
9[e]
(S)-C3-TunePhos
98/2
85.8
7
100
100
100
100
100
[a] Unless otherwise stated, all reactions were carried out with a substrate
(0.5 mmol) concentration of 0.5 M in MeOH under 40 atm of H2 at 50°C for
12 h, substrate/catalyst = 200:1. Conversion: 100%. [b] Ratios were
calculated from the NMR spectra. [c] Determined by HPLC on a Chiralpak
OJ-H column. [d] [NH2Me2][{RuCl[(S)-SunPhos]}2(µ-Cl)3]. Conversion:
43%. [e] [RuCl(benzene)L]Cl. [f] [RuCl(cymene)(S)-SunPhos]Cl. [g]
RuCl2[(S)-SunPhos](DMF)n
8
9
10[e]
11[e]
[a] All reactions were carried out with a substrate (0.5 mmol) concentration
of 0.5 M in a specified solvent for 12 h, substrate/catalyst = 200:1. [b]
Determined by NMR analysis and the ratio of 2a/2a′ = 99/1 without
otherwise stated. [c] Determined by HPLC on a Chiralpak OJ-H column.
[d] Starting material was recovered completely. [e] The ratio of 2a/2a′ =
95/5.
Next, the effect of solvent, temperature and hydrogenation
pressure was explored and the results were summarized in
Table 2. It has been known that solvent has a significant
influence on the activity and enantioselectivity of the asymmetric
hydrogenation. Changing the solvent from MeOH to other protic
solvents including EtOH and iPrOH resulted in slightly
decreased enantioselectivity (Table 2, entry 1 vs. entries 2, 3).
When aprotic solvents such as CH2Cl2 and toluene were used,
the reaction could hardly proceed (Table 2, entries 4, 5). The
reactivity and enantioselectivity of the hydrogenation were also
dependent on the reaction temperature. Higher reaction
temperature led to a slight drop of the ee value (Table 2, entries
With the optimized reaction established, the substrate
scope and limitations of the methodology were investigated and
the results are depicted in Table 3. A variety of alkyl 2-
acetylbenzoates and even the o-acetylbenzoic acid were
hydrogenated smoothly followed by in situ lactonization to afford
the corresponding phthalide with high yield and excellent
enantioselectivity (Table 3, entries 1−4). The result
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19[i]
20[h]
21
1p
1q
1r
100
100
0
89
98
0
33.8 (S)
99.4 (S)
n.a.
demonstrated that the bulkiness of the alcohol had no significant
effect on the activity and enantioselectivity of the reaction.
Moreover, it is notable that when the catalyst loading was further
reduced to 0.1 mol%, the reaction also proceeded smoothly on
gram-scale with excellent enantiofacial discrimination (Table 3,
entries 5−6).
22
1s
0
0
n.a.
Table 3. Asymmetric Hydrogenation of 2-Acylarylcarboxylate.[a]
[a] Unless otherwise stated, all reactions were carried out with a substrate
(0.5 mmol) concentration of 0.5 M in MeOH under 40 atm of H2 at 50°C for
12 h, substrate/catalyst = 200:1. [b] Determined by NMR analysis. [c]
Isolated yield by column chromatography. [d] Determined by HPLC on a
Chiralpak column. The absolute configuration was determined by
comparison of the specific rotation or HPLC with reported data. [e]
Substrate/catalyst = 1000:1. [f] Substrate/catalyst = 1000:1. Reaction
using 1.23 g of 1d at 40 atm of H2 at 50 °C for 18 h. [g] Substrate/catalyst
= 500:1. [h] Reaction time 15 h. [i] Under 60 atm of H2 at 50°C for 48 h.
Additionally, almost the same enantioselectivities were obtained
by the hydrogenation/cyclization of the substrates 1e-1g
possessing different carbon chain lengths of R2 (Table 3, entries
7−9). This result indicated that the length of the linear alkyl
carbon chain did not obviously affect the reaction activity and
enantioselectivity. It is noteworthy that when the catalyst loading
was lowered to 0.2 mol%, the substate 1g could still be
completely converted to the optically pure 3-n-butylphthalide,
which was isolated from seeds of Apium graveolens and acts as
a medical agent to treat brain-related neurological diseases such
as cerebral ischemia (Table 3, entry 10).[1a-c] However, when R2
was replaced by a larger alkyl group such as isobutyl, even
though the asymmetric hydrogenation and subsequent in situ
lactonization were still happened affording the desired product,
incomplete conversion and obvious erosion of ee value were
observed (58% yield, 91.6% ee, Table 3, entry 11). Moreover,
the reaction failed with further increase of the steric hindrance of
R2 (Table 3, entry 12). It meant that the steric hindrance of the
alkyl group R2 plays an important role in the hydrogenation. To
our delight, both of the substrates 1j and 1k were hydrogenated
in full conversions with high enantiomeric excess, regardless of
electronic properties on the 5-positions of the phenyl moiety
(Table 3, entry 13 vs. entry 14). Surprisingly, the substrate 1l
containing other aromatic ring was also hydrogenated well
providing the corresponding (S)-3-Methylnaphtho[2,3-c]furan-
1(3H)-one (2h) in quantitative yield with 99.4% ee (Table 3,
entry 15). The absolute configuration was unambiguously
confirmed by X-ray analysis of 2h (shown in Figure S1).[12]
Entry
1
1
Conv. [%][b]
100
Yield [%][c]
95
ee [%][d]
99.6 (S)
1a
2
1b
1c
1d
1a
1d
1e
1f
100
100
100
100
100
100
100
100
100
67
98
98
92
98
90
94
94
96
97
58
0
99.6 (S)
99.2 (S)
99.4 (S)
99.0 (S)
98.0 (S)
99.6 (S)
99.2 (S)
99.4 (S)
98.2 (S)
91.6
3
4
5[e]
6[f]
7
8
9
1g
1g
1h
1i
10[g]
11
12
13
14
15
16[h]
17[h]
18[i]
0
n.a.
1j
100
100
100
100
100
83
98
98
98
95
95
75
99.0 (S)
99.4 (S)
99.4 (S)
98.2 (S)
96.2 (S)
99.2 (S)
1k
1l
1m
1n
1o
Encouraged by the promising results above, the first time
we attempted to expand the methodology to the more
challenging 2-aroylarylcarboxylates (R2 = aryl group). Therefore,
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the methyl 2-benzoylbenzoate (1m) was subjected to the
hydrogenation/lactonization reaction under the same catalyst
system. Pleasingly, the desired product 3-phenylisobenzofuran-
1(3H)-one was obtained in 95% yield with 98.2% ee (Table 3,
entry 16). It deserved to be mentioned that the
enantionselectivity is much higher and the reaction time is
reduced greatly compared to the result obtained by the
asymmetric hydroboration of the substrate 1m (10 day, 30% ee
was obtained for 2i).[4b] The 2-benzoylbenzoic acid was also
reactive with excellent enantiofacial discrimination (Table 3,
entry 17). Next, a variety of 2-aroylarylcarboxylates were
prepared and the substituent effect was discussed. The catalytic
system exhibited a good tolerance for diversified substituents
with different electronic properties on the ortho and para
positions of the benzene ring. The substrates 1o possessing an
ortho methyl substituent on the aromatic ring gave a slightly
higher ee value, but incomplete conversion was observed even
when the reaction was conducted under 60 atm of H2 for 48 h
(Table 3, entry 18). The result demonstrated that the reaction
was markedly affected by the steric effect on the ortho position
of the phenyl ring. Substrates bearing para substituent groups
on the phenyl ring showed a distinct effect on both reactivity and
enantioselectivity. Compared with the substrate1p containing an
electron-donating methoxy group on the para position, substrate
1q with an electron-withdrawing trifluoromethyl group not only
was more reactive, but also gave much better enantioselectivity
in the reaction (Table 3, entry 19 vs. entry 20). Electronic
properties of the para substituent groups were presumed to
influence the coplanarity of the phenyl rings with C=O double
bond in the transition state, therefore generating an
unsymmetrical bias.[13] Unfortunately, the analogues 1r and 1s
remained inactive under the [RuCl(benzene)(S)-SunPhos]Cl
catalyst systems (Table 3, entries 21 and 22).
convenient and practical method represents one of the most
general and efficient preparation of highly optically pure 3-
substituted phthalides reported to date, providing valuable
pharmaceutical molecules and important building blocks for
many natural products and biologically active compounds. The
further investigation of the potential applications in medicinal
chemistry and asymmetric catalytic synthesis is underway.
Experimental Section
General Procedures
Commercially available reagents were used throughout without further
purification unless those detailed below. Both MeOH and EtOH were
distilled over magnesium under nitrogen. CH2Cl2, MeCN and iPrOH were
distilled from calcium hydride. Toluene was freshly distilled from Na/
benzophenone under nitrogen. All reactions were conducted under a
nitrogen atmosphere using standard Schlenk techniques, unless
otherwise noted. 1HNMR spectra were recorded at 400 MHz using TMS
as internal standard. 13C NMR spectra were recorded at 100 MHz and
referenced to the central peak of 77.00 ppm for CDCl3. Coupling
constants (J) are reported in Hz and refer to apparent peak
multiplications. HRMS data were collected on an ESI-TOF mass
spectrometer. Flash column chromatography was performed on 300-400
mesh silica gel. [α]D values were obtained in a 0.5 dm cell at 25 °C using
the D-line (589 nm) of a sodium lamp. 2-Acetylbenzoic acid (1d) was
commercially available. Racemates could be prepared by NaBH4
reduction of the corresponding 2-acylarylcarboxylates.
Typical Procedure for the Preparation of 1a-1c.[4d, 14]
A mixture of o-acetylbenzoic acid (2.0 g, 12.2 mmol) and potassium
carbonate (2.5 g, 18.3 mmol) in 10 mL N,N-dimethylformamide was
stirred at room temperature. The corresponding alkyl iodine (36.6 mmol)
in N,N-dimethylformamide (8 mL) was added dropwise within 10 min.
Upon consumption of the starting material (monitored by TLC), DMF was
removed in vacuo and the residue was extracted with CH2Cl2 (8 mL).
Then concentration was carried out under reduced pressure. The crude
product obtained was purified by column chromatography (PE/EA = 12:1)
on silica gel to provide the desired compound
Methyl 2-acetylbenzoate (1a):[15] Rf = 0.32 (PE/EA = 12:1); colorless oil:
2.0 g, 92% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ 7.84 (dd, J = 7.6,
0.8 Hz, 1H), 7.56–7.54 (m, 1H), 7.51–7.49 (m, 1H), 7.41 (dd, J = 7.6, 0.8
Hz, 1H), 3.89 (s, 3H), 2.53 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3,
25 °C): δ 202.1, 167.0, 142.00, 131.5, 129.6, 129.1, 128.4, 126.1, 52.0,
29.3.
Ethyl 2-acetylbenzoate (1b):[4k] Rf = 0.32 (PE/EA = 12:1); colorless oil:
2.2 g, 94% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ 7.84 (dd, J = 7.6,
1.2 Hz, 1H), 7.56–7.51 (m, 1H), 7.49–7.45 (m, 1H), 7.38 (dd, J = 7.6, 1.2
Hz, 1H), 4.33 (q, J = 7.6 Hz, 2H), 2.52 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H);
Conclusions
In conclusion, we have successfully developed a highly efficient
and enantioselective protocol for the synthesis of bioactive chiral
3-substituted phthalides. By means of the Ru-diphosphines
catalyzed asymmetric hydrogenation and subsequent in situ
lactonization, a range of 2-acylarylcarboxylates including 2-
aroylarylcarboxylates were directly converted into the
corresponding optically active 3-substituted phthalides (up to
99.6% ee, S/C = 1000) under mild reaction conditions. This
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13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 202.5, 166.6, 142.3, 131.6,
129.6, 129.3, 128.7, 126.1, 61.2, 30.0, 13.6.
52.3, 51.0, 24.4, 22.5. HRMS-ESI (m/z): (M + Na)+ calcd. for C13H16NaO3,
243.0997; found 243.1000.
Isopropyl 2-acetylbenzoate (1c): Rf = 0.36 (PE/EA = 10:1); colorless oil:
2.4 g, 95% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ 7.85 (dd, J = 7.6,
1.2 Hz, 1H), 7.56–7.52 (m, 1H), 7.49–7.45 (m, 1H), 7.37 (dd, J = 7.6, 1.2
Hz, 1H), 5.22 (hept, J = 6.4 Hz, 1H), 2.53 (s, 3H), 1.34 (d, J = 6.4 Hz,
6H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 202.4, 166.0, 142.3,
131.4, 129.5, 129.2, 129.0, 125.90, 68.9, 29.7, 21.2. HRMS-ESI (m/z):
(M + H)+ calcd. for C12H15O3, 207.1021; found 207.1020.
Methyl 2-isobutyrylbenzoate (1i): Rf = 0.34 (PE/EA = 15:1); colorless
1
oil: 4.5 g, 54% yield; H NMR (400 MHz, CDCl3, 25 °C): δ 7.93 (dd, J =
7.6, 1.2 Hz, 1H), 7.58–7.54 (m, 1H), 7.50–7.46 (m, 1H), 7.30 (dd, J = 7.6,
1.2 Hz, 1H), 3.88 (s, 3H), 3.11–3.00 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H); 13
C
{1H} NMR (100 MHz, CDCl3, 25 °C): δ 209.4, 166.4, 142.6, 131.8, 129.5,
129.1, 127.9, 126.4, 52.0, 40.1, 18.0. HRMS-ESI (m/z): (M + H)+ calcd.
for C12H15O3, 207.1021; found 207.1023.
Typical Procedure for the Preparation of 1e-1i, 1l, 1o-1q.[16]
Methyl 3-acetyl-2-naphthoate (1l): Rf = 0.36 (PE/EA = 15:1); colorless
1
oil: 4.0 g, 43% yield; H NMR (400 MHz, CDCl3, 25 °C): δ 8.34 (s, 1H),
To a stirred mixture of phthalic anhydride (6.0 g, 40.5 mmol), cuprous
iodide (0.6 g, 3.2 mmol) in anhydrous THF (80 mL) under N2 atmosphere
was added dropwise the corresponding Grignard reagent (44.6 mmol in
45 mL THF) over for 1h at -10 °C. The mixture was stirred at this
temperature for 2 h and then allowed to warm to room temperature. Upon
completion of the reaction, the reaction was quenched with aqueous 10%
HCl solution and acidified to pH = 2 at 0°C, then THF was removed in
vacuum and the resulting aqueous solution was extracted with CH2Cl2
(10 mL×3). The combined organic layers were treated with saturated
Na2CO3 solution and the alkaline extracted was acidified with
concentrated HCl. A milky-white colloidal suspension was observed and
the mixture was further kept in refrigerator for several hours. After
filtration, the corresponding acid was obtained as white solid and then
was dried under vacuum. Finally, the desired esterification product was
prepared according to the procedure described above.
7.96 (s, 1H), 7.95–7.90 (m, 2H), 7.67–7.60 (m, 2H), 3.95 (s, 3H), 2.64 (s,
3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 201.4, 167.7, 137.8,
133.3, 132.6, 130.5, 128.5, 128.4, 128.2, 128.0, 127.3, 126.6, 52.2, 29.1.
HRMS-ESI (m/z): (M + Na)+ calcd. for C14H12NaO3, 251.0684; found
251.0685.
Methyl 2-(2-methylbenzoyl)benzoate (1o):[20] Rf = 0.30 (PE/EA = 15:1);
1
colorless oil: 5.1 g, 50% yield; H NMR (400 MHz, CDCl3, 25 °C): δ 7.93
(dd, J = 7.6, 1.2 Hz, 1H), 7.62–7.53 (m, 2H), 7.45 (dd, J = 7.6, 1.2 Hz,
1H), 7.39–7.35 (m, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.20 (dd, J = 7.6, 1.2 Hz,
1H), 7.12 (t, J = 6.8 Hz, 1H), 3.61 (s, 3H), 2.66 (s, 3H); 13C {1H} NMR
(100 MHz, CDCl3, 25 °C): δ 198.0, 166.5, 142.0, 139.2, 136.3, 131.5,
131.4, 131.3, 130.7, 129.6, 129.3, 128.1, 124.9, 51.7, 20.9.
Methyl 2-(4-methoxybenzoyl)benzoate (1p):[21] Rf = 0.38 (PE/EA =
1
7:1); colorless oil: 4.2 g, 38% yield; H NMR (400 MHz, CDCl3, 25 °C): δ
Methyl 2-propionylbenzoate (1e):[17] Rf = 0.30 (PE/EA = 25:1); colorless
8.03 (dd, J = 7.6, 1.2 Hz, 1H), 7.73–7.70 (m, 2H), 7.63–7.59 (m, 1H),
7.56–7.52 (m, 1H), 7.37 (dd, J = 7.6, 1.2 Hz, 1H), 6.92–6.88 (m, 2H),
3.84 (s, 3H), 3.63 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ
195.5, 166.2, 163.3, 141.8, 132.1, 131.4, 130.0, 129.8, 129.1, 128.8,
127.4, 113.5, 55.2, 51.9.
1
oil: 3.5 g, 45% yield; H NMR (400 MHz, CDCl3, 25 °C): δ 7.89 (dd, J =
7.6, 1.2 Hz, 1H), 7.58–7.54 (m, 1H), 7.50–7.46 (m, 1H), 7.33 (dd, J = 7.6,
1.2 Hz, 1H), 3.88 (s, 3H), 2.80 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H).
13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 205.7, 166.6, 142.8, 131.7,
129.3, 129.2, 127.8, 125.7, 51.9, 35.5, 7.7.
Methyl 2-(4-(trifluoromethyl)benzoyl)benzoate (1q): Rf = 0.50 (PE/EA
= 8:1); white solid: 3.7 g, 30% yield; mp 94.8-96.6 °C ; 1H NMR (400 MHz,
CDCl3, 25 °C): δ 8.08 (dd, J = 7.6, 1.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H),
7.71–7.66 (m, 3H), 7.63–7.59 (m, 1H), 7.40 (dd, J = 7.6, 1.2 Hz, 1H),
3.66 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 195.8, 166.0,
141.0, 139.9, 134.5, 134.2, 133.9, 133.6 (q, J = 32.4 Hz), 132.6, 130.2,
129.9, 129.3, 128.9, 127.6, 127.5, 125.52, 125.48, 125.44, 125.41 (q, J =
3.7 Hz), 124.9, 122.2, 119.4 (q, J = 271.0 Hz), 52.2. HRMS-ESI (m/z): (M
+ H)+ calcd. for C16H12F3O3, 309.0739; found 309.0740.
Methyl 2-butyrylbenzoate (1f):[18] Rf = 0.32 (PE/EA = 30:1); colorless
1
oil: 4.3 g, 51% yield; H NMR (400 MHz, CDCl3, 25 °C): δ 7.89 (dd, J =
7.6, 1.2 Hz, 1H), 7.59–7.55 (m, 1H), 7.51–7.47 (m, 1H), 7.36 (dd, J = 7.6,
1.2 Hz, 1H), 3.89 (s, 3H), 2.79 (t, J = 7.6 Hz, 2H), 1.81–1.72 (m, 2H),
1.00 (t, J = 7.6 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 205.3,
167.0, 143.0, 131.8, 129.5, 129.4, 128.3, 126.1, 52.2, 44.3, 17.2, 13.4.
Methyl 2-pentanoylbenzoate (1g):[19] Rf
= 0.32 (PE/EA = 35:1);
1
colorless oil: 4.6 g, 52% yield; H NMR (400 MHz, CDCl3, 25 °C): δ 7.87
(dd, J = 7.6, 1.2 Hz, 1H), 7.56–7.52 (m, 1H), 7.49–7.44 (m, 1H), 7.34 (dd,
J = 7.6, 1.2 Hz, 1H), 3.87 (s, 3H), 2.78 (t, J = 7.6 Hz, 2H), 1.75–1.66 (m,
2H), 1.43–1.32 (m, 2H),0.92 (t, J = 7.6 Hz, 3H); 13C {1H} NMR (100 MHz,
CDCl3, 25 °C): δ 205.2, 166.7, 142.9, 131.7, 129.4, 129.3, 128.1, 125.9,
52.0, 42.0, 25.7, 21.9, 13.5.
Typical Procedure for the Preparation of 1j-1k.[22]
To a suspension of methyl 2-bromo-5-methylbenzoate (2.3 g, 10.0 mmol),
Pd(OAc)2 (0.18 g, 0.80 mmol) and triphenylphosphine (0.42 g, 1.6 mmol)
in degassed acetonitrile (20 mL) was added n-butyl vinyl ether (5.0 g,
50.0 mmol), triethylamine (1.3 g, 13 mmol). The resulting mixture was
heated at reflux for 24 h. After being cooled to room temperature, the
mixture was diluted with water (25 mL) and EtOAc (25 mL), and then
filtered over Celite®, rinsing with EtOAc (30 mL). The filtrate was
concentrated under reduced pressure, then THF (60 mL) and 10% aq.
HCl (60 mL) were added. The mixture was stirred at room temperature
for 2 h and then THF was removed in vacuum. The resulting aqueous
Methyl 2-(3-methylbutanoyl)benzoate (1h): Rf = 0.30 (PE/EA = 22:1);
white solid: 4.1 g, 46% yield; mp 56.7-58.3 °C ; 1H NMR (400 MHz, CDCl3,
25 °C): δ 7.85 (dd, J = 7.6, 1.2 Hz, 1H), 7.57–7.53 (m, 1H), 7.50–7.46 (m,
1H), 7.38 (dd, J = 7.6, 1.2 Hz, 1H), 3.88 (s, 3H), 2.71 (d, J = 6.8 Hz, 2H),
2.31–2.21 (m, 1H), 1.00 (d, J = 6.4 Hz, 6H); 13C {1H} NMR (100 MHz,
CDCl3, 25 °C): δ 204.6, 167.3, 142.9, 131.8, 129.8, 129.7, 128.8, 126.4,
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10.1002/cctc.201700695
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solution was poured into saturated aq. NaHCO3 (100 mL) and extracted
with CH2Cl2 (3 x 50 mL). The combined organic extracts were washed
with brine (50 mL), dried by anhydrous Na2SO4, filtered and concentrated
in vacuo. The crude product obtained was purified by column
Methyl 2-benzoylcyclohexanecarboxylate (1s):[26] Rf = 0.40 (PE/EA =
1
10:1); white solid: 8.1g, 85% yield; mp 28.9-31.0 °C; H NMR (400 MHz,
CDCl3, 25 °C): δ.7.87–7.85 (m, 2H), 7.51–7.55 (m, 1H), 7.47–7.43 (m,
2H), 3.89 (dd, J = 10.0, 5.2 Hz, 1H), 3.62 (s, 3H), 2.75–2.71 (m, 1H),
2.24–2.17 (m, 1H), 2.10–2.05 (m,1H), 1.99–1.92 (m, 1H), 1.84–1.74 (m,
2H), 1.47–1.35 (m, 3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 202.3,
174.2, 136.5, 132.3, 128.3, 127.9, 51.3, 44.1, 42.6, 27.1, 25.3, 24.1, 22.5.
chromatography (PE/EA = 8:1) on silica gel to afford the methyl 2-acetyl-
5-methylbenzoate (1j) as yellow oil. Similarly, compounds (1k) were
prepared from the methyl 2-bromo-5-chlorobenzoate and n-butyl vinyl
ether. The desired product were purified by column chromatography
(PE/EA = 10:1).
Preparation of Methyl 2-(2-phenylacetyl)benzoate (1r).[4k, 27]
To a mixture of benzalphthalide (2.7 g, 12.0 mmol) in 1,4-dioxane (70
mL) and water (10 ml) was added KOH (1.0 g, 18.0 mmol) with magnetic
stirring and the resulting mixture reacted for 3 h at room temperature.
The mixture was acidified with 3N HCl solution to pH = 2, and followed by
extraction with CH2Cl2 (30 mL×3) and concentration. The intermediate
was dissolved in 16 mL DMF directly, and then added anhydrous KF (1.1
g, 18.0 mmol) and MeI (5.1 g, 36.0 mmol). Upon completion of the
reaction (monitored by TLC), DMF was removed in vacuo and the
residue was extracted with CH2Cl2 (8 mL). Then concentration was
carried out by vacuum evaporation process. The crude product obtained
was purified by column chromatography (PE/EA = 15:1) on silica gel to
provide the desired compound.
Methyl 2-acetyl-5-methylbenzoate (1j): Rf = 0.40 (PE/EA = 6:1); yellow
oil: 1.7 g, 88% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ 7.58 (s, 1H),
7.39 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.52 (s,
3H), 2.41 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 201.3,
167.8, 140.6, 138.3, 131.7, 129.5, 129.4, 126.8, 52.1, 28.9, 20.7. HRMS-
ESI (m/z): (M + Na)+ calcd. for C11H12NaO3, 215.0684; found 215.0690.
Methyl 2-acetyl-5-chlorobenzoate (1k): Rf = 0.36 (PE/EA = 8:1); yellow
oil: 1.8 g, 85% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ 7.80 (d, J =
2.0 Hz, 1H), 7.53 (dd, J = 8.0, 2.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.91
(s, 3H), 2.52 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 201.3,
166.4, 140.4, 136.4, 131.9, 130.9, 129.7, 128.1, 52.9, 29.7. HRMS-ESI
(m/z): (M + Na)+ calcd. for C10H9ClNaO3, 235.1038; found 235.1032.
Methyl 2-(2-phenylacetyl)benzoate (1r): Rf = 0.30 (PE/EA = 15:1);
Typical Procedure for the Preparation of 1m-1n, 1s.[23]
1
colorless oil: 2.1 g, 69% yield; H NMR (400 MHz, CDCl3, 25 °C): δ 7.94
To a stirred mixture of benzene (35 mL), phthalic anhydride (6.0 g, 40.5
mmol) was added anhydrous AlCl3 (11.3 g, 85.1 mmol) in portion at 0°C.
The mixture was warmed to room temperature and reacted for 12 h. The
mixture was poured into aqueous 10% HCl solution to acidify to pH = 2 at
0°C. Then redundant benzene was removed in vacuum and the resulting
aqueous solution was extracted with CH2Cl2 (15 mL×3). The combined
organic layers were washed with saturated Na2CO3 solution and the
alkaline extracted was acidified with concentrated HCl. A milky-white
suspension was observed and the mixture was further kept in refrigerator
for 15 h. After filtration, 2-benzoylbenzoic acid 1m was obtained as off-
white solid and then was dried under vacuum. Similarly, compound 2-
(dd, J = 7.6, 1.2 Hz, 1H), 7.52–7.47 (m, 2H), 7.34 – 7.30 (m, 2H), 7.27 –
7.25 (m, 3H), 7.20 (dd, J = 7.6, 1.2 Hz, 1H), 4.12 (s, 2H), 3.90 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 203.1, 166.6, 142.8, 133.6,
132.0, 129.63, 129.60, 129.4, 128.2, 127.8, 126.7, 126.4, 52.3, 49.5.
HRMS-ESI (m/z): (M + Na)+ calcd. for C16H14NaO3, 277.0841; found
277.0844.
Typical Procedure for the Asymmetric Hydrogenation
To a 25 mL Schlenk tube were added [RuCl2(benzene)]2 (5.0 mg,
0.01mmol) and (S)-SunPhos (15.0 mg, 0.022 mmol). The tube was
evacuated and purged with nitrogen three times before addition of freshly
distilled and freeze−thaw−degassed EtOH/CH2Cl2 (1.5 mL/1.5 mL). The
resulting mixture was heated at 50°C for 1 h and then cooled to room
temperature. The solvent was removed by vacuum evaporation process
to give the catalyst as a yellow powder. The catalyst was dissolved in
degassed MeOH (4 mL), and then the solution was equally charged into
eight vials which contained 0.5 mmol of substrates, and 0.5 mL of MeOH.
Then the vials were transferred into 300 mL autoclaves. The autoclaves
were purged five times with H2 and the required pressure of H2 was set.
The contents of autoclaves were stirred under specified reaction
conditions. After being cooled to room temperature and careful release of
the hydrogen, the autoclaves were opened and the solvent was
evaporated. The residue was purified by a silica gel column to provide
the corresponding hydrogenation products and then the enantiomeric
excess was directly determined by HPLC.
benzoylcyclohexanecarboxylic
acid
was
prepared
from
hexahydrophthalic anhydride and benzene. Finally, the desired
esterification product was prepared according to the procedure described
above.
Methyl 2-benzoylbenzoate (1m):[24] Rf = 0.42 (PE/EA = 10:1); white
solid: 7.3g, 75% yield; mp 44.5-46.4 °C; 1H NMR (400 MHz, CDCl3,
25 °C): δ 8.07 (dd, J = 7.6, 0.6 Hz, 1H), 7.76–7.79 (m, 2H), 7.69–7.65 (m,
1H), 7.62–7.55 (m, 2H), 7.48–7.43 (m, 3H), 3.63 (s, 3H); 13C {1H} NMR
(100 MHz, CDCl3, 25 °C): δ 196.3, 165.8, 141.2, 136.7, 132.6, 131.9,
129.5, 129.2, 128.7, 128.0, 127.3, 51.6.
2-Benzoylbenzoic acid (1n):[25] Rf = 0.25 (PE/EA = 1:2); off-white solid:
7.6 g, 83% yield; mp 119.9-121.8 °C; 1H NMR (400 MHz, DMSO, 25 °C):
δ 13.19 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.68–
7.62 (m, 4H), 7.49 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 7.6 Hz, 1H); 13C {1H}
NMR (100 MHz, DMSO, 25 °C): δ 197.1, 167.6, 142.0, 137.5, 133.5,
132.9, 130.3, 130.2, 129.4, 129.1, 127.8.
(S)-3-Methylisobenzofuran-1(3H)-one (2a):[3c] Rf = 0.85 (PE/EA = 2:1);
colorless oil: 70.1 mg, 95% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ
7.90 (d, J = 7.6 Hz, 1H), 7.66–7.60 (m, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.44
(dd, J = 7.6, 0.8 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 1.64 (d, J = 6.8 Hz,
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10.1002/cctc.201700695
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3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 170.4, 151.1, 134.0,
128.9, 125.6, 125.5, 121.5, 77.6, 20.3. HPLC (Chiralcel OJ-H column,
hexane/iPrOH = 90/10, 0.7 mL/min, 230 nm): t1 = 18.2 min, t2 = 20.6 min.
[α]2D5 = –33.0 (c = 1.4 in CHCl3). Lit.[3c] [α]D21 = +37.1 (c = 0.83 in CHCl3) for
(R)-enantiomer with 95% ee.
(S)-3,6-Dimethylisobenzofuran-1(3H)-one (2f):[3a] Rf = 0.32 (PE/EA =
8:1); colorless oil: 79.5 mg, 98% yield; 1H NMR (400 MHz, CDCl3, 25 °C):
δ 7.64 (s, 1H), 7.46 (dd, J = 7.6, 0.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H),
5.50 (q, J = 6.8 Hz, 1H), 2.43 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H). 13C {1H}
NMR (100 MHz, CDCl3, 25 °C): δ 170.5, 148.5, 139.2, 135.1, 125.8,
125.4, 121.2, 77.6, 21.1, 20.4. HPLC (Chiralcel AD-H column,
3-Methoxy-3-methylisobenzofuran-1(3H)-one (2a′):[28] Rf
=
0.36
(PE/EA = 15:1); colorless oil; 1H NMR (400 MHz, CDCl3, 25 °C): δ 7.90–
7.88 (m, 1H), 7.75–7.71 (m, 1H), 7.62–7.58 (m, 1H), 7.51–7.49 (m, 1H),
3.07 (s, 3H), 1.84 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ
168.0, 147.4, 134.6, 130.6, 127.3, 125.5, 122.1, 108.7, 51.2, 25.2.
(S)-3-Ethylisobenzofuran-1(3H)-one (2b):[3c] Rf = 0.80 (PE/EA = 4:1);
colorless oil: 76.2 mg, 94% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ
7.87 (d, J = 7.6 Hz, 1H), 7.68–7.64 (m, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.43
(dd, J = 7.6, 0.8 Hz, 1H), 5.44 (dd, J = 7.2, 4.4 Hz, 1H), 2.16–2.06 (m,
1H), 1.86–1.75 (m, 1H), 0.98 (t, J = 7.6 Hz, 3H); 13C {1H} NMR (100 MHz,
CDCl3, 25 °C): δ 170.6, 149.7, 133.9, 129.0, 126.2, 125.6, 121.7, 82.3,
27.6, 8.8. HPLC (Chiralcel OJ-H column, hexane/iPrOH = 95/5, 0.7
mL/min, 210 nm): t1 = 18.2 min, t2 = 20.6 min. [α]2D5 = –69.9 (c = 1.0 in
CHCl3). Lit.[3c] [α]D22 = +64.1 (c = 0.88 in CHCl3) for (R)-enantiomer with
90% ee.
(S)-3-Propylisobenzofuran-1(3H)-one (2c):[2i] Rf = 0.82 (PE/EA = 4:1);
colorless oil: 83.0 mg, 94% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ
7.89 (d, J = 7.6 Hz, 1H), 7.68–7.64 (m, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.43
(dd, J = 7.6, 0.8 Hz, 1H), 5.48 (dd, J = 8.0, 4.0 Hz, 1H), 2.05–1.97 (m,
1H), 1.78–1.69 (m, 1H), 1.59–1.43 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H); 13C
{1H} NMR (100 MHz, CDCl3, 25 °C): δ 170.7, 150.1, 133.9, 129.0, 126.1,
125.6, 121.7, 81.2, 36.8, 18.2, 13.8. HPLC (Chiralcel AD-H column,
hexane/iPrOH = 95/5, 0.7 mL/min, 210 nm): t1 = 15.7 min, t2 = 17.3 min.
[α]2D5 = –79.0 (c = 0.57 in CHCl3). Lit.[2i] [α]D20 = +49.7 (c = 0.23 in CHCl3)
for (R)-enantiomer with 80% ee.
(S)-3-Butylisobenzofuran-1(3H)-one (2d):[29] Rf = 0.78 (PE/EA = 6:1);
colorless oil: 91.5 mg, 96% yield; 1H NMR (400 MHz, CDCl3, 25 °C): δ
7.84 (d, J = 7.6 Hz, 1H), 7.66–7.62 (m, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.42
(dd, J = 7.6, 0.8 Hz, 1H), 5.44 (dd, J = 8.0, 4.0 Hz, 1H), 2.06–1.97 (m,
1H), 1.77–1.67 (m, 1H), 1.50–1.26 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H); 13C
{1H} NMR (100 MHz, CDCl3, 25 °C): δ 170.5, 150.0, 133.8, 128.9, 126.0,
125.5, 121.6, 81.3, 34.3, 26.7, 22.3, 13.7. HPLC (Chiralcel AD-H column,
hexane/iPrOH = 98/2, 1.0 mL/min, 210 nm): t1 = 14.3 min, t2 = 18.0 min.
[α]2D5 = –64.2 (c = 1.2 in CHCl3). Lit.[29][α]2D5 = +63.3 (c = 0.495 in CHCl3)
for (R)-enantiomer with 94% ee.
hexane/iPrOH = 98/2, 1.0 mL/min, 210 nm): t1 = 16.3 min, t2 = 19.1 min.
[α]2D5 = -45.9 (c = 0.90 in CHCl3). Lit.[3a] [α]2D8 = -35.0 (c = 1.03 in CHCl3) for
(S)-enantiomer with 92% ee.
(S)-6-Chloro-3-methylisobenzofuran-1(3H)-one (2g):[3a] Rf = 0.42
(PE/EA = 5:1); white solid: 89.8 mg, 98% yield; mp 61.8-63.7 °C; 1H NMR
(400 MHz, CDCl3, 25 °C): δ 7.86 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.0,
2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 5.55 (q, J = 6.8 Hz, 1H), 1.63 (d, J =
6.8 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 168.9, 149.2,
135.3, 134.3, 127.5, 125.5, 122.9, 77.6, 20.3. HPLC (Chiralcel OJ-H
column, hexane/iPrOH = 99/1, 0.7 mL/min, 210 nm): t1 = 38.9 min, t2 =
46.5 min. [α]2D5 = -36.7 (c = 0.82 in CHCl3). Lit.[3a] [α]2D8 = -36.1 (c = 0.30 in
CHCl3) for (S)-enantiomer with 95% ee.
(S)-3-Methylnaphtho[2,3-c]furan-1(3H)-one (2h): Rf = 0.45 (PE/EA =
10:1); white solid: 97.3 mg, 98% yield; mp 109.6-111.2 °C; 1H NMR (400
MHz, CDCl3, 25 °C): δ 8.48 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.95 (d, J =
8.4 Hz, 1H), 7.85 (s, 1H), 7.69–7.58 (m, 2H), 5.74 (q, J = 6.8 Hz, 1H),
1.74 (d, J = 6.8Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 170.2,
144.7, 136.1, 132.9, 129.7, 128.8, 128.0, 126.74, 126.67, 123.4, 120.3,
77.7, 20.9. HPLC (Chiralcel OD-H column, hexane/iPrOH = 90/10, 0.8
mL/min, 230 nm): t1 = 16.8 min, t2 = 20.1 min. [α]2D5 = – 90.4 (c = 1.5,
CHCl3). HRMS-ESI (m/z): (M + H)+ calcd. for C13H11O2, 199.0759; found
199.0757.
(S)-3-Phenylisobenzofuran-1(3H)-one (2i):[3c] Rf = 0.80 (PE/EA = 4:1);
light yellow solid: 101.2 mg, 95% yield; mp 110.4-112.2 °C; 1H NMR (400
MHz, CDCl3, 25 °C): δ 7.97 (d, J = 7.6 Hz, 1H), 7.67–7.63 (m, 1H), 7.56
(t, J = 7.6 Hz, 1H), 7.40–7.27 (m, 6H), 6.41 (s, 1H); 13C {1H} NMR (100
MHz, CDCl3, 25 °C): δ 170.3, 149.5, 136.2, 134.2, 129.1, 129.0, 128.7,
126.7, 125.3, 122.7, 82.5; HPLC (Chiralcel OD-H column, hexane/iPrOH
= 85/15, 1.0 mL/min, 210 nm): t1 = 9.1 min, t2 = 11.2 min. [α]2D5 = + 44.5 (c
= 1.0, CHCl3). Lit.[3c] [α]D22 = – 42.1 (c = 1.05, CHCl3) for (R)-enantiomer
with 91% ee.
(S)-3-(o-Tolyl)isobenzofuran-1(3H)-one (2j):[3c] Rf = 0.23 (PE/EA =
15:1); white solid: 84.5 mg, 75% yield; mp 105.3-106.9 °C; 1H NMR (400
MHz, CDCl3, 25 °C): δ 7.98 (d, J = 7.6 Hz, 1H), 7.69–7.65 (m, 1H), 7.57
(t, J = 7.6 Hz, 1H), 7.35 (dd, J = 7.6, 0.4 Hz, 1H), 7.29–7.25 (m, 2H),
7.15–7.11 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 2.50 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 170.5, 149.1, 137.0, 134.1,
134.0, 131.0, 129.2, 129.2, 127.1, 126.3, 125.5, 122.9, 80.4, 19.2. HPLC
(Chiralcel OD-H column, hexane/iPrOH = 85/15, 0.7 mL/min, 210 nm): t1
= 12.2 min, t2 = 15.4 min. [α]2D5 = – 69.2 (c 0.63 = CHCl3). Lit.[3c] [α]2D2 = +
41.6 (c = 0.62, CHCl3) for (R)-enantiomer with 82% ee.
3-Isobutylisobenzofuran-1(3H)-one (2e): Rf
=
0.80 (PE/EA
=
5:1);colorless oil: 55.1 mg, 58% yield; 1H NMR (400 MHz, CDCl3, 25 °C):
δ 7.88 (d, J = 7.6 Hz, 1H), 7.68–7.64 (m, 1H), 7.51 (t, J = 7.6 Hz, 1H),
7.42 (dd, J = 7.6, 0.8 Hz, 1H), 5.50 (dd, J = 10.0, 3.2 Hz, 1H), 2.11–1.98
(m, 1H), 1.80–1.72 (m, 1H), 1.67–1.59 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H),
0.99 (d, J = 6.4 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ 170.6,
150.6, 133.8, 128.9, 125.9, 125.6, 121.6, 80.0, 44.2, 25.2, 23.3, 21.8.
HPLC (Chiralcel AD-H column, hexane/iPrOH = 98/2, 0.5 mL/min, 230
nm): t1 = 23.4 min, t2 = 33.8 min. [α]2D5 = –74.7 (c = 0.9, CHCl3). HRMS-
ESI (m/z): (M + H)+ calcd. for C12H15O2, 191.1072; found 191.1073.
(S)-3-(4-Methoxyphenyl)isobenzofuran-1(3H)-one (2k):[3c] Rf = 0.46
(PE/EA = 5:1); white solid: 107.6 mg, 89% yield; mp 105.8-107.3; 1H
NMR (400 MHz, CDCl3, 25 °C): δ 7.96 (d, J = 7.6 Hz, 1H), 7.67–7.63 (m,
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10.1002/cctc.201700695
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[3] a) D. H. T. Phan, B. Kim, V. M. Dong, J. Am. Chem. Soc. 2009, 131, 15608-
15609; b) S. K. Murphy, V. M. Dong, J. Am. Chem. Soc. 2013, 135, 5553-
5556; c) J. Yang, N. Yoshikai, J. Am. Chem. Soc. 2014, 136, 16748-
16751.
1H), 7.58–7.53 (m, 1H), 7.32–7.30 (m, 1H), 7.19–7.16 (m, 2H), 6.90–6.88
(m, 2H), 6.37 (s, 1H), 3.81 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3,
25 °C): δ 170.5, 160.4, 149.7, 134.22, 129.3, 128.8, 128.3, 125.9, 125.5,
122.9, 114.3, 82.7, 55.3. HPLC (Chiralcel OJ-H column, hexane/iPrOH =
85/15, 1.0 mL/min, 230 nm): t1 = 31.8 min, t2 = 41.1 min. [α]2D5 = – 7.0 (c =
0.8, CHCl3). Lit.[3c] [α]D22 = + 31.0 (c = 0.42, CHCl3) for (R)-enantiomer with
98% ee.
(S)-3-(4-(Trifluoromethyl)phenyl)isobenzofuran-1(3H)-one (2l):[2f] Rf =
0.38 (PE/EA = 8:1); white solid: 136.9 mg, 98% yield; mp 89.8-92.0 °C;
1H NMR (400 MHz, CDCl3, 25 °C): δ 7.99 (d, J = 8.0 Hz, 1H), 7.68–7.65
(m, 3H), 7.59 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.34 (dd, J =
7.6, 0.4 Hz, 1H), 6.45 (s, 1H); 13C {1H} NMR (100 MHz, CDCl3, 25 °C): δ
170.1, 148.9, 140.5, 134.6, 131.8, 131.5, 131.2, 130.8 (q, J = 32.5 Hz),
129.7, 127.8, 127.1, 126.01, 125.97, 125.93, 125.90 (q, J = 3.7 Hz),
125.8, 125.2, 125.1, 122.7, 122.4, 119.6 (q, J = 270.6 Hz), 81.5. HPLC
(Chiralcel OD-H column, hexane/iPrOH = 98/2, 0.5 mL/min, 210 nm): t1 =
41.6 min, t2 = 46.3 min. [α]2D5 = + 68.0 (c = 0.9, CHCl3). Lit.[2f] [α]D27 = + 34.0
(c = 0.50, CHCl3) for (S)-enantiomer with 70% ee.
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Acknowledgements ((optional))
We thank the National Natural Science Foundation of China for
the financial support.
Keywords: ruthenium • asymmetric hydrogenation • 3-
substituted phthalides • enantioselectivity • gram-scale reaction
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Bin Lu,Mengmeng Zhao,Guangni
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Ruthenium-Catalyzed
Text for Table of Contents
Enantioselective
Hydrogenation/Lactonization of 2-
Acylarylcarboxylates：Direct Access
to Chiral 3-Substituted Phthalides
By means of the Ru-diphosphines catalyzed asymmetric hydrogenation and
subsequent in situ lactonization, a series of 2-acylarylcarboxylates including
2-aroylarylcarboxylates were directly converted into the corresponding optically
active 3-substituted phthalides (up to 99.6% ee, S/C = 1000) under mild
reaction conditions.
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