Enantioselective α-benzoyloxylation of ketones promoted by primary amine catalyst

Article abstract of DOI:10.1021/jo2024976

A mixture of 9-amino-(9-deoxy)epi-dihydroquinidine and salicylic acid was able to promote the direct reaction of various cyclohexanones with dibenzoyl peroxide, thus affording the corresponding protected α-hydroxy carbonyl compounds in high yield and enantioselectivity. Interestingly the same catalytic salt was found to be active when 1-indanones derivatives were directly employed in the reaction with dibenzoyl peroxide furnishing chiral 1-oxo-2,3-dihydro-1H- inden-2-yl benzoates in high yields and enantioselectivity. Furthermore their treatment with NaBH₄ gives easy access to the corresponding enantioenriched 1,2-diols in high yields and without any loss of stereoselectivity.

Full text of DOI:10.1021/jo2024976

Article
pubs.acs.org/joc
Enantioselective α-Benzoyloxylation of Ketones Promoted by
Primary Amine Catalyst
Milind S. Jadhav,†,‡ Paolo Righi,† Enrico Marcantoni,‡ and Giorgio Bencivenni*,†
†Department of Organic Chemistry “A. Mangini”, Alma Mater Studiorum-University of Bologna, viale Risorgimento 4, I-40136
Bologna, Italy
‡School of Science and Technology, Chemistry Division, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy
S
* Supporting Information
ABSTRACT: A mixture of 9-amino-(9-deoxy)epi-dihydroqui-
nidine and salicylic acid was able to promote the direct reaction
of various cyclohexanones with dibenzoyl peroxide, thus
affording the corresponding protected α-hydroxy carbonyl
compounds in high yield and enantioselectivity. Interestingly
the same catalytic salt was found to be active when 1-indanones
derivatives were directly employed in the reaction with
dibenzoyl peroxide furnishing chiral 1-oxo-2,3-dihydro-1H-
inden-2-yl benzoates in high yields and enantioselectivity.
Furthermore their treatment with NaBH4 gives easy access to
the corresponding enantioenriched 1,2-diols in high yields and without any loss of stereoselectivity.
Scheme 1. Proposed Catalytic Cycle for the α-
Benzoyloxylation of Cyclohexanone
INTRODUCTION
■
The development of catalytic methods that furnish enantioen-
riched α-functionalized ketones starting from the commercially
available precursors, thus avoiding the preparation of reactive
metal enolates, are highly required.1 In this field the
construction of enantiomerically active α-hydroxy or protected
α-hydroxy carbonyl compounds represents an important goal
for asymmetric organocatalysis principally because of the
important role that this class of substrates play as natural
products or fundamental building blocks for the construction of
more elaborated structures.2
During the past years chiral primary amines derived from
commercially available cinchona alkaloids3 were revealed to be
among the most powerful catalysts able to promote the
functionalization of sterically demanding carbonyl compounds
such as ketones and branched aldehydes via iminium ion,4
enamine,5 and dienamine6 activation modes. Because of the
great ability to impart a unique reaction pathway and elevated
enantioselectivity,7 we believed that this class of catalysts could
efficiently promote the reaction between diverse cyclic
saturated ketones and dibenzoyl peroxide in order to furnish
enantioenriched α-benzoyloxylated carbonyl compounds. Our
idea is to exploit the capability of primary amine to condense
with the cyclic ketone and furnish a sufficiently stable and
reactive enamine with the required nucleophilicity8 to react
with the electrophilic dibenzoyl peroxide (Scheme 1).
RESULTS AND DISCUSSION
■
Our screening started by comparing the reactivity of different
primary amine-based organocatalysts (Figure 1) for the
reaction of cyclohexanone and dibenzoyl peroxyde.
As outlined in Table 1, among the various chiral primary
amines tested, those based on the scaffold of cinchona alkaloid,
in combination with salicylic acid as co-catalyst were revealed to
be the most active for the enantioselective α-functionalization
of cyclohexanone albeit with low amount of isolated product
(Table 1, entry 1−5). We screened other acids, but no
In this report we would like to present our results for the
reaction of α-benzoyloxylation of cyclic ketones under enamine
catalysis using 9-amino(9-deoxy)epi-hydroquinidine as catalyst
and dibenzoyl peroxide as oxidizing agent.9
Received: December 5, 2011
Published: February 16, 2012
© 2012 American Chemical Society
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the presence of various undefined byproducts was observed in
the crude mixture of the reaction. Also the use of more polar
solvents such as methanol (MeOH), ethyl acetate (EtOAc),
and tetrahydrofuran (THF) did not furnish satisfying results so
that toluene was revealed to be the best compromise in term of
yield and enantioselectivity (Table 3, entries 3−6).
We next carried out the reaction with different molar
amounts of ketone and at different concentrations of benzoyl
peroxide because as already observed in Table 1, an excess of
cyclohexanone could increase the yield of the reaction (entry
13). For this reason we believed that a further study on the
effect of the different ratio between ketone and peroxide was
necessary once the screening of solvents and bases was
completed. We found that a good compromise between yield
(80%) and enantioselectivity (96.5% ee) could be achieved in a
0.4 M solution of toluene at 0 °C (Table 4, entry 5). The α-
benzoyloxylation was performed using a 10 mol % of catalyst
loading thus highlighting the efficiency of the process.
With the optimized condition in hand we explored the scope
of the benzoyloxylation of cyclic ketones with different
substituents and heteroatoms (Table 5). As outlined in Table
5 the reaction furnished the desired 2-oxocyclohexyl benzoates
3a−i in high yields and excellent enantioselectivities. In any
case the presence of the ketone functionalized at both α-
positions has never been observed. Interestingly when 9-
amino(9-deoxy)epi-hydroquinine (ent-F), the pseudoenan-
tiomer of catalyst F, was employed, the opposite enantiomers
of the α-functionalized ketones were obtained with good level
of yields and enantioselectivities for almost all entries (Table 5,
entries 3, 5, 8, and 10). The absolute configuration of
compounds 3a was assigned to be R by comparison with the
previously reported literature data,10 and by analogy it was
assigned to be the same for compounds 3b−i.11 When racemic
ketone 1b was used, the reaction resulted to be highly
enantioselective and regioselective; however, poor diastereose-
lectivity was observed for the corresponding product 3b (Table
Figure 1. Primary amine tested for the α-functionalization of cyclic
ketone.
improvements, especially of yields, were observed (Table 1,
entry 6−13).
Interestingly salicylic acid was revealed to be the best choice
probably because of a fruitful hydrogen bond interaction
between the hydroxyl group of the acid and the carbonyl
groups of the benzoyl peroxide. We then decided to study the
effect of an inorganic base5a that might increase the reaction
rate and maintain the good level of enantioselectivity by
quenching the benzoic acid generated during the course of the
reaction (Scheme 1). The addition of 1.2 equiv of solid
Na2CO3 had a negative effect on the yield of the process when
catalyst D and salicylic acid were used (Table 1, entry 14) but
gave a better yield after 24 h of reaction time and furnished
high enantiocontrol when catalyst F was used (Table 1, entry
15). Indeed as outlined in Table 2 the use of weaker or stronger
inorganic bases did not furnish significant improvements if
compared to those obtained using Na2CO3.
The effects of different solvents were then considered.
Interestingly, as shown in Table 3 (entries 1 and 2), the
reaction can be performed in water as well as in absence of
solvent with relevant results. However, under these conditions,
a
Table 1. Catalyst and Acid Screening for the α-Benzoyloxylation of Cyclohexanone
c
d
entry
cat.
acid
base
none
yield (%)
ee (%)
1
A
2-OH-PhCOOH
2-OH-PhCOOH
2-OH-PhCOOH
2-OH-PhCOOH
2-OH-PhCOOH
TFA
none
none
<5
nd
nd
nd
86
84
nd
88
nd
nd
nd
90
95
95
95
96
2
B
none
none
none
none
none
none
none
none
none
none
none
none
Na2CO3
Na2CO3
3
C
D
E
4
35
5
17
6
D
D
D
D
D
D
D
D
D
F
none
5
7
DCA
8
PTSA
<5
9
PhCOOH
<5
10
11
12
(PhO)2PO2H
D-NBocPhGlyOH
2-F-PhCOOH
2-F-PhCOOH
2-OH-PhCOOH
2-OH-PhCOOH
none
20
9
b
13
16
14
15
15
30
a
b
Unless otherwise noted, the reactions were performed with 0.1 mmol of 1a and 0.12 mmol of 2 at room temperature for 24 h. Reaction performed
c
d
using 0.2 mmol of 1a. Isolated yield. Determined by HPLC analysis on a chiral stationary phase.
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a
Table 2. Base Screening for the α-Benzoyloxylation of Cyclohexanone
b
d
entry
cat.
acid
base
yield (%)
ee (%)
1
2
3
F
F
F
2-OH-PhCOOH
2-OH-PhCOOH
2-OH-PhCOOH
Na2CO3
NaHCO3
K2CO3
30
35
48
96
93
90
a
b
Unless otherwise noted, the reactions were performed with 0.1 mmol of 1a and 0.12 mmol of 2 at room temperature for 24 h. Isolated yield.
Determined by HPLC analysis on a chiral stationary phase.
d
a
Table 3. Solvent Screening for the α-Benzoyloxylation of Cyclohexanone
b
d
entry
solvent
yield (%)
ee (%)
1
2
3
4
5
6
H2O
29
65
77
90
nd
nd
88
96
neat
MeOH
AcOEt
THF
none
<5
25
toluene
30
a
b
Unless otherwise noted, the reactions were performed with 0.1 mmol of 1a and 0.12 mmol of 2 at room temperature for 24 h. Isolated yield.
Determined by HPLC analysis on a chiral stationary phase.
d
a
Table 4. Optimization Study for the α-Benzoyloxylation of Cyclohexanone
c
d
entry
1a:2
T [°C]/time [h]
concn [M]
yield (%)
ee (%)
1
2
3
4
10:1
10:1
5:1
25/24
25/24
25/24
25/24
0/80
1
85
83
60
82
80
83
0.1
0.1
0.1
0.4
96
95.5
90
2:1
b
5
2.5:1
96.5
a
b
Unless otherwise noted, the reactions were performed on a 0.1 mmol scale at room temperature for 24 h. Reaction performed using 10 mol % of
c
d
catalyst F and 20 mol % of salicylic acid. Isolated yields. Determined by HPLC analysis on a chiral stationary phase.
5, entry 2). Using 4-phenylcyclohexanone 1c, the desymmet-
rization pathway resulted to be efficient especially for the
diastereoisomer cis-3c, which was obtained with ee of 99%
(Table 5, entries 4 and 5). The same asymmetric desymmet-
rization pathway has been observed for the α-aminoxylation of
4-substituted ketone catalyzed by proline.2f
The presence of two methyl groups in the 4 position of the
cyclohexanone was well tolerated in the reaction and furnished
the corresponding α-benzoyloxylated carbocycle in high yield
and excellent enantioselectivity (Table 5, entry 6). Heter-
oatoms such as oxygen and sulfur as part of the cyclic
framework of the ketone could be employed maintaining the
same level of enantioselection observed so far (Table 5, entries
7−10). However in the case of sulfur yields are not good using
both catalyst F and its pseudoenantiomer ent-F. This negative
result could be ascribed to parasitic reactions that totally
consumed the peroxide and a large amount of the cyclic ketone.
In this case the desired products 3f and ent-3f were obtained as
a part of a highly complex reaction mixture, where unidentified
tars and plausible polymeric materials were the main products.
The good results observed in term of yields and enantiose-
lectivity using cycloheptanone 1g and cyclooctanone 1h extend
the applicability of our methodology to medium ring-sized
ketones, which generally are challenging substrates for
enamine-activation catalysis (Table 5, entries 11 and 12).9
Also in the presence of a carbamate as substituent the reaction
can be performed with good efficiency and stereoselection
(Table 5, entry 13). In this last case the low value recorded of
both enantioselectivity and yields were probably due to the
presence of Boc moiety that could obstruct the catalyst salt
during the enamine formation thus reducing the reaction rate
and at the same time the stereocontrol.
In order to expand the scope of the α-benzoyloxylation
reaction, we tried to focus our attention on 1-indanones as
plausible precursors of new protected α-oxygenated com-
pounds. Although, to the best of our knowledge 1-indanones
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a
Table 5. Direct α-Benzoyloxylation of Various Cyclic Ketones
cyclic ketones 1
compound
oxocyclic benzoates 3
product
b
c
d
entry
X/n
R
R
yield (%)
d.r
ee (%) cis/trans
1
2
CH2/1
CH2/1
CH2/1
CH2/1
CH2/1
C/1
1a
1b
1b
1c
1c
1d
1e
1e
1f
H
3a
H
80
88
87
70
65
80
71
70
22
21
60
96
49
96.5
>99/96.5
>99/82
>99/37
>99/60
96.4
3-Me
3-Me
4-Ph
4-Ph
4,4-Me
H
3b
4-Me
4-Me
5-Ph
5-Ph
5,5-Me
H
1:1
1:1
e
3
ent-3b
3c
4
1:1
e
5
ent-3c
3d
1:1
6
7
none
none
none
none
none
none
none
none
O/1
3e
91
e
8
O/1
H
ent-3e
3f
H
90
9
S/1
H
H
94.5
e
10
S/1
1f
H
ent-3f
3g
H
90
11
12
13
CH2/2
CH2/3
N/1
1g
1h
1i
H
H
>99
H
3h
H
93
4-Boc
3i
5-Boc
80
a
Unless otherwise noted, the reactions were performed for 80 h at 0 °C using 0.2 mmol of 2 and 0.5 mmol of 1a−f, 0.02 mmol of catalyst F, and
b
c
d
0.04 mmol salicylic acid in a 0.4 M toluene solution. Isolated yield. Determined by 1H NMR analysis of the crude reaction mixture. Determined
by HPLC analysis on a chiral stationary phase. Reaction performed using the pseudoenantiomeric form of catalyst F.
e
a
Table 6. Direct α-Benzoyloxylation of 1-Indanones
b
c
entry
R
product
yield (%)
ee (%)
1
2
3
4
5
6
7
H
5a
5b
5c
5d
5e
5f
80
66
55
30
82
68
37
40
77
84
80
79
77
60
76
40
89
84
5-Br
5-F
5-OMe
6-Me
5-Cl
4-CF3
H
5g
5a
5a
d
8
e
9
H
a
Unless otherwise noted, the reactions were performed for 80 h at 0 °C using 0.2 mmol of 2 and 0.5 mmol of 4a−e, 0.04 mmol of catalyst F, and
b
c
d
0.08 mmol salicylic acid in a 0.1 M toluene solution. Isolated yield. Determined by HPLC analysis on a chiral stationary phase. Reaction
performed for 7 days at 0 °C using 2 equiv of 4a. Reaction performed using 10 mol % of 2,6-di-tert-butyl-4-methylphenol (BHT) as radical
scavenger.
e
have never been used for the enantioselective α-oxygenation
performed by means of organocatalytic strategies, we envisaged
that 9-amino(9-deoxy)epi-hydroquinidine F could be efficiently
applied for our purpose. In fact although 1-indanone derivatives
represent a class of bulky aromatic ketones, the almost
complete coplanarity of the five-membered cyclopentanone
with respect to the fused aromatic ring represents an advantage
for the approach of the primary amine catalyst thus promoting
the enamine formation and the subsequent addition to the
dibenzoyl peroxide. As outlined in Table 6 the reaction,
performed under the optimized condition but using 20 mol %
of catalyst loading, proceeded smoothly at 0 °C, furnishing the
desired α-benzoylindanones from moderate to good yields and
good enantioselectivity (Table 6, entries 1−7). Various
substituents that differentiate the stereoelectronic nature of
the starting 1-indanones could be applied with a general good
efficiency of the process. Yields and enantioselectivity are
generally quite good apart from 5-methoxy-1-indanone 4d that
furnished the desired product 5d in 30% isolated yield (Table 6,
entry 4) and 4-trifluoromethyl-1-indanone 4g that allowed us
to isolate the desired α-benzoylindanone 5g in 37% isolated
yield and only 40% enantiomeric excess (Table 6, entry 7).
Interestingly the enantioselectivity could be increased to 89%
ee by performing the reaction with 2 equiv of ketone 4a;
however, the corresponding product 5a was isolated after 7
days of reaction in a lower yield if compared with the reaction
conducted with 2.5 equiv of 4a (Table 6, entry 8). In order to
exclude the presence of a possible radical side pathway that
might affect the stereocontrol of the α-benzoyloxylation, we
performed a test reaction using 10 mol % 2,6-di-tert-butyl-4-
methylphenol (BHT), and compound 5a was isolated without
any decrease of yield and enantiocontrol (Table 6, entry 9).
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procedure. All cyclohexanone and 1-indanone derivatives were
commercially available and used as received. The diastereomeric
ratio was determined by 1H NMR analysis of the crude reaction
mixture and confirmed by HPLC analysis on chiral stationary phase
columns. HPLC analysis on chiral stationary phase were performed
using Chiralpak AD-H column, Chiralcel OD-H column, Chiralcel OJ-
H, and Lux Amylose-2 columns and i-PrOH/hexane as the eluent.
HPLC traces for compounds 3a−i, 5a−g, cis-(1S,2R)-6b, and trans-
(1R,2R)-7b were compared to racemic samples prepared by mixing the
two product antipodes obtained performing the reaction with catalyst
9-amino(9-deoxy)epi-hydroquinidine (F) and the pseudoenantiomer
9-amino(9-deoxy)epi-hydroquinine (ent-F) separately.
To enhance the synthetic utility of this methodology, we
developed a one-pot procedure for the synthesis of 1,2-diols2g
starting from enantioenriched (R)-5-bromo-1-oxo-2,3-dihydro-
1H-inden-2-yl benzoate 5b. The reaction was conducted with 3
equiv of NaBH4 as reducing agent in a 1:3 mixture of MeOH
and THF at 0 °C for 15 min then the solution was placed at 50
°C for 18 h. The crude mixture gave a 4:1 mixture of the
corresponding 1,2-diols in favor of cis-isomer. After purification
cis-(1S,2R)-6b was isolated in a 53% yield and 84% ee and
trans-(1R,2R)-7b in 25% yield and 80% ee12 (Scheme 2).
General Procedure for the Benzoyloxylation of Cyclo-
hexanone. All reactions were carried out in undistilled toluene. In
an ordinary vial equipped with a Teflon-coated stir bar, catalyst F (0.02
mmol, 10 mol %) was dissolved in 500 μL of toluene, and 2 hydroxy-
benzoic acid (0.04 mmol, 20 mol %) was added. The resulting solution
was stirred at 0 °C for 10 min. Cyclohexanone derivative (0.5 mmol,
2.5 equiv) was added, followed by the addition of the dibenzoyl
peroxide (0.2 mmol) and Na2CO3 (1.2 equiv) at 0 °C. Stirring was
continued for 80−84 h. The crude mixture was diluted with CH2Cl2
and flushed through a short plug of silica, using dichloromethane/ethyl
acetate 1:1 as the eluent (20 mL). Solvent was removed in vacuo.
Crude product was purified by flash column chromatography using
hexane/diethyl ether as the eluent mixture.
Scheme 2. Synthesis of 5-Bromo-2,3-dihydro-1H-indene-1,2-
diol
(1R)-2-Oxocyclohexyl Benzoate10 (3a) (Table 5, entry 1). The
reaction was carried out following the general procedure. The title
compound was isolated as a white solid by column chromatography
(hexane/Et2O = 80/20) in 80% yield and 96.5% ee. HPLC analysis on
a Chiralcel OD-H column: 90/10 hexane/i-PrOH, flow rate 1.00 mL/
min, λ = 214 nm: τmajor = 7.186 min, τminor = 10.328 min; ESI-MS: 219
(M + 1)+, 241 (M + Na)+. [α]20D = +15.6 (c 0.77, CHCl3, 96.5% ee).
1H NMR (400 MHz, CDCl3) δ 1.62−1.77(m, 1H), 1.78−1.91 (m,
1H), 1.92−1.99 (m, 1H), 1.99−2.08 (m, 1H), 2.09−2.19 (m, 1H),
2.38−2.52 (m, 2H), 2.54−2.62 (m, 1H), 5.41 (ddd, 1H, J = 12.1 Hz, J
= 7.3 Hz, J = 1.1 Hz), 7.44 (m, 2H), 7.57 (m, 1H), 8.09 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 23.8 (CH2), 27.2 (CH2), 33.2 (CH2),
40.7 (CH2), 76.9 (CH), 128.3 (CH), 129.7 (C), 129.9 (CH), 133.1
(CH), 165.6 (C), 204.3 (C).
CONCLUSION
■
In conclusion we have explored the reactivity of cyclic ketones
for the enantioselective synthesis of their protected α-hydroxy
derivatives using 9-amino(9-deoxy)epi-hydroquinidine (F) in
combination with salicylic acid as catalyst. The reaction
demonstrated to be extremely efficient and highly enantiose-
lective thus furnishing a new and alternative procedure11 for the
synthesis of protected α-hydroxy ketones. The new method-
ology was also effectively applied to the direct enantioselective
synthesis of α-oxygenated 1-indanones derivatives that might be
easily converted into 1,2-diols thus furnishing a new way of
synthesis of this important class of compounds.
(1R,4S)-4-Methyl-2-oxocyclohexyl Benzoate9 (cis-3b) and
(1R,4R)-4-Methyl-2-oxocyclohexyl Benzoate9 (trans-3b) (Table
5, entry 2). The reaction was carried out following the general
procedure to furnish the crude product 3b as 1:1 mixture of cis-isomer
(1R,4S)-3b and trans-isomer (1R,4R)-3b. A white solid was isolated by
column chromatography (hexane/Et2O = 85/15) in 88% yield as a
mixture of cis- and trans- isomers and >99% ee for cis-3b isomer HPLC
analysis on a Chiralcel OD-H column: 99/1 hexane/i-PrOH, flow rate
1.00 mL/min, λ = 254 nm: τmajor = 13.07 min, τminor = 20.64 min; and
96.5% ee for trans-3b isomer HPLC analysis on a Chiralcel OD-H
column: 90/10 hexane/i-PrOH, flow rate 1.00 mL/min, λ = 214 nm:
τmajor = 6.412 min, τminor = 9.837 min; ESI-MS: 233 (M + 1)+, 255 (M
EXPERIMENTAL SECTION
■
General. The 1H and 13C NMR spectra were recorded on 400 and
600 MHz spectrometers. NOE spectra were recorded using the
DPFGSE-NOE sequence,13 using a mixing time of 2.00 s and “rsnob”
20 ÷ 50 Hz wide selective pulses, depending on the crowding of the
spectra region. The chemical shifts (δ) for H and 13C are given in
1
ppm relative to residual signals of the solvents (CDCl3 and CD3CN).
Coupling constants are given in Hz. Carbon types were determined
from DEPT 13C NMR14 experiments. The following abbreviations are
used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q,
quartet; quint, quintet, m, multiplet; bs, broad signal. Purification of
reaction products was carried out by flash chromatography (FC) on
silica gel (230−400 mesh) according to the method of Still.15 Melting
points of solid new samples were determined by melting point
apparatus or by differential scanning calorimetry (DSC) on a DSC
apparatus, adopting a temperature program consisting of two heating
and one cooling ramps starting from room temperature (heating/
cooling rate 2 °C/min under a nitrogen atmosphere). Each sample
(3−5 mg) was heated up to only 150 °C in order to avoid thermal
decomposition. Organic solutions were concentrated under reduced
pressure on a rotary evaporator. Optical rotations are reported as
+ Na)+, 271 (M + K)+. [α]20 cis-3b = +14.5 (c 0.33, CHCl3, >99%
D
ee); [α]20D trans-3b = +13.2 (c 0.11, CHCl3, 96.5% ee). 1H NMR (400
MHz, CDCl3) trans-3b δ 1.09 (d, 3H, J = 6.3 Hz), 1.60 (m, 1H),
1.87−2.05 (m, 3H), 2.21 (td, 1H, J = 12.9 Hz, J = 0.9 Hz), 2.36−2.43
(m, 1H), 2.50−2.56 (m, 1H), 5.40 (ddd, 1H, J = 12.5 Hz, J = 7.1 Hz, J
= 0.9 Hz), 7.44 (m, 2H), 7.57 (m, 1H), 8.1 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 22.0, 31.7, 32.3, 35.0, 48.7, 77.2, 128.3, 129.7 129.9
133.1, 165.7, 203.7.
(1R,5R)-2-Oxo-5-phenylcyclohexyl Benzoate (cis-3c) and
(1R,5S)-2-Oxo-5-phenylcyclohexyl Benzoate (trans-3c) (Table
5, entry 4). The reaction was carried out following the general
procedure to furnish the crude product 3c as a 1:1 mixture of cis-
(1R,5S)-3c and trans-(1R,5R)-3c. The title compound was isolated as a
colorless oil by column chromatography (hexane/Et2O = 80/20) in
70% yield as a mixture of cis- and trans-isomers and >99% ee for cis-3c
isomer HPLC analysis on a Chiralcel AD-H column: 99/1 hexane/i-
follows: [α]rt (c in g per 100 mL, solvent, % ee). All reactions were
D
set up in the air and using undistilled solvent, without any precautions
to exclude moisture. Commercial grade reagents and solvents were
used without further purification; otherwise, where necessary, they
were purified as recommended.16 Commercially available chiral
primary amine catalysts A ((1S,2S)-1,2-diphenylethane-1,2-diamine)
and C ((R)-1,1′-binaphthyl-2,2′-diamine) were used as received.
Catalyst B,17 D, E, F,18 and ent-F were prepared from literature
PrOH, flow rate 1.00 mL/min, λ = 254 nm: τmajor = 24.23 min, τminor
=
27.99 min; and 37% ee for trans-3c isomer HPLC analysis on a
Chiralpak AD-H column: 90/10 hexane/i-PrOH, flow rate 0.750 mL/
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min, λ = 214 nm: τmajor = 15.40 min, τminor = 24.51 min; HRMS (ESI+)
30.4 (CH2), 40.7 (CH2), 79.0 (CH), 128.4 (CH), 129.7 (C), 129.8
(CH), 133.1 (CH), 165.9 (C), 207.3 (C).
calcd for C19H19O3 295.1329, found 295.1326; cis-3c: [α]20 = +30.6
D
(R)-2-Oxocyclooctyl Benzoate10 (3h) (Table 5, entry 12). The
reaction was carried out following the general procedure. The title
compound was isolated as a white solid by column chromatography
(pentane/Et2O = 90/10) in 96% yield and 93% ee. HPLC analysis on
a Chiralcel OD-H column: 90/10 hexane/i-PrOH, flow rate 0.750
mL/min, λ = 214 nm: τmajor = 8.15 min, τminor = 9.89 min; ESI-MS:
(c 0.51, CHCl3, 99% ee). trans-3c: [α]20D = −10.7 (c 1.04, CHCl3, 37%
ee). 1H NMR (400 MHz, CDCl3) cis-3c (9:1 mixture of cis:trans
isomers) δ 2.21−2.33 (m, 2H), 2.47−2.58 (m, 3H), 2.75−2.85 (m,
1H), 3.48 (quint, 1H, J = 6.7 Hz), 5.37 (m, 1H), 7.22−7.30 (m, 1H),
7.33−7.40 (m, 4H), 7.44−7.53 (m, 2H), 7.57−7.65 (m, 1H), 8.08−
8.14 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 33.3 (CH2), 37.2
(CH), 37.8 (CH2), 38.3 (CH2), 75.7 (CH), 126.7 (CH), 126.8 (CH),
128.5 (CH), 128.8 (CH), 129.8 (CH), 133.4 (CH), 142.4 (C), 165.4
247 (M + 1)+, 269 (M + Na)+. [α]20 = −30.7 (c 0.95, CHCl3, 93%
D
1
ee). H NMR (400 MHz, CDCl3) δ 1.18−1.33 (m, 2H), 1.49−1.75
1
(m, 4H), 1.80−2.13 (m, 4H), 2.27−2.37 (m, 1H), 2.42 (ddd, J = 14.1
Hz, J = 9.0 Hz, J = 3.5 Hz, 1H), 2.74 (ddd, J = 14.1 Hz, J = 9.4 Hz, J =
3.5 Hz, 1H), 5.42 (dd, J = 8.6 Hz, J = 3.7 Hz, 1H), 7.39−7.48 (m, 2H),
7.53−7.60 (m, 1H), 8.03−8.14 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 22.1, 24.7, 24.8, 27.7, 31.5, 40.7, 77.6, 128.6, 129.8, 130.0,
133.5, 166.2, 211.8.
(C), 206.0 (C). H NMR (400 MHz, CDCl3) trans-3c δ 1.91−2.05
(m, 1H), 2.19−2.36 (m, 2H), 2.56−2.76 (m, 3H), 3.31 (tt, 1H, J =
12.6 Hz, J = 3.4 Hz), 5.64 (ddd, 1H, J = 12.7 Hz, J = 6.3 Hz, J = 0.7
Hz), 7.22−7.30 (m, 3H), 7.32−7.38 (m, 2H), 7.45 (M, 2H), 7.58 (m,
1H), 8.10 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 34.4 (CH2), 39.8
(CH2), 39.9 (CH2), 41.9 (CH), 76.0 (CH), 126.6 (CH), 127.0 (CH),
128.4 (CH), 128.8 (CH), 129.6 (C), 129.9 (CH), 133.2 (CH), 143.1
(C), 165.5 (C), 203.7 (C).
(R)-tert-Butyl 3-(Benzoyloxy)-4-oxopiperidine-1-carboxy-
late9 (3i) (Table 5, entry 13). The reaction was carried out
following the general procedure. The title compound was isolated as a
pale yellow oil by column chromatography (hexane/acetone =
gradient 5%−15% acetone) in 49% yield and 80% ee. HPLC analysis
on a Chiralcel AD-H column: 90/10 hexane/i-PrOH, flow rate 0.700
mL/min, λ = 254 nm: τmajor = 12.65 min, τminor = 14.47 min; ESI-MS:
(R)-5,5-Dimethyl-2-oxocyclohexyl Benzoate10 (3d) (Table 5,
entry 6). The reaction was carried out following the general
procedure. The title compound was isolated as a colorless oil by
column chromatography (pentane/Et2O = 80/20) in 80% yield and
96.4% ee. HPLC analysis on a Chiralpak AD-H column: 80/20
hexane/i-PrOH, flow rate 0.700 mL/min, λ = 214 nm: τmajor = 8.25
320 (M + 1)+, 343 (M + Na)+. [α]20 = +22.1 (c 0.83, CHCl3, 80%
D
ee). 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.49−2.80 (m, 2H),
3.04−3.58 (m, 2H), 4.11−4.79 (m, 2H), 5.36 (dd, J = 10.5 Hz, J = 6.5
Hz, 1H), 7.38−7.50 (m, 2H), 7.53−7.64 (m, 1H), 8.0−8.15 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 28.5, 40.7, 43.9 (broad signal), 48.1
min, τminor = 9.56 min; ESI-MS: 247 (M + 1)+, 269 (M + Na)+. [α]20
= +19.2 (c 0.94, CHCl3, 96.4% ee). H NMR (400 MHz, CDCl3) δ
D
1
1.11 (s, 3H), 1.32 (s, 3H), 1.66−1.83 (m, 2H), 1.90 (t, J = 16.0 Hz,
1H), 2.12 (ddd, J = 12.6 Hz, J = 6.4 Hz, J = 3.3 Hz, 1H,), 2.42 (ddd, J
= 14.3 Hz, J = 4.6 Hz, 2.7 Hz, 1H), 2.64 (td, J = 14.0 Hz, J = 6.4 Hz,
1H), 5.55 (dd, J = 13.0 Hz, J = 6.4 Hz, 1H), 7.39−7.47 (m, 2H), 7.53−
7.59 (m, 1H), 8.04−8.11 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
24.9, 31.6, 32.3, 37.2, 39.8, 45.5, 74.4, 128.5, 129.9, 130.1, 133.3, 165.9,
205.1.
(broad signal), 74.1, 81.4, 128.7, 129.3, 130.2, 133.7, 154.4, 165.3,
201.7.
General Procedure for the Benzoyloxylation of 1-Inda-
nones. All reactions were carried out in undistilled toluene. In an
ordinary vial equipped with a Teflon-coated stir bar, catalyst F (0.04
mmol, 20 mol %) was dissolved in 1.0 mL of toluene, and 2 hydroxy-
benzoic acid (0.08 mmol, 40 mol %) was added. The resulting solution
was stirred at 0 °C for 10 min. 1-Indanone derivative (2.5 equiv) was
added, followed by the addition of the dibenzoyl peroxide (0.2 mmol)
and Na2CO3 (1.2 equiv) at 0 °C. Stirring was continued for 80 h. The
crude mixture was diluted with CH2Cl2 and flushed through a short
plug of silica, using dichloromethane/ethyl acetate 1:1 as the eluent
(20 mL). Solvent was removed in vacuo. Crude product was purified
by flash column chromatography using dichloromethane/diethyl ether
99:1 as the eluent mixture.
(R)-4-Oxotetrahydro-2H-pyran-3-yl Benzoate19 (3e) (Table 5,
entry 7). The reaction was carried out following the general
procedure. The title compound was isolated as a white solid by
column chromatography (pentane/Et2O = 75/25) in 71% yield and
91% ee. HPLC analysis on a Chiralcel OD-H column: 9/1 hexane/i-
PrOH, flow rate 1.00 mL/min, λ = 254 nm: τmajor = 10.15 min, τminor
=
13.91 min; ESI-MS: 221 (M + 1)+, 243 (M + Na)+. Mp (DSC, 2 °C/
min): 79 °C. [α]20D = +11.9 (c 1.02, CHCl3, 91% ee). 1H NMR (600
MHz, CDCl3) δ 2.60 (m, 1H), 2.84 (m, 1H), 3.73 (m, 2H), 4.31 (m,
1H), 4.46 (m, 1H), 5.52 (m, 1H), 7.45 (m, 2H), 7.58 (m, 1H), 8.07
(m, 2H); 13C NMR (150 MHz, CDCl3) δ 42.2 (CH2), 68.2 (CH2),
70.5 (CH2), 74.0 (CH), 128.4 (CH), 129.0 (C), 129.9 (CH), 133.4
(CH), 165.0 (C), 200.3 (C).
(R)-1-Oxo-2,3-dihydro-1H-inden-2-yl Benzoate (5a) (Table 6,
entry 1). The reaction was carried out following the general
procedure. The title compound was isolated as a white solid by
column chromatography (dichloromethane/diethyl ether = 99/1) in
80% yield and 84% ee. HPLC analysis on a Chiralcel OD-H column:
(S)-4-Oxotetrahydro-2H-thiopyran-3-yl Benzoate20 (3f)
(Table 5, entry 9). The reaction was carried out following the
general procedure. The title compound was isolated as a white solid by
column chromatography (pentane/Et2O = 80/20) in 22% yield and
94.5% ee. HPLC analysis on a Chiralcel OD-H column: 8/2 hexane/i-
PrOH, flow rate 0.750 mL/min, λ = 254 nm: τmajor = 10.41 min, τminor
= 12.08 min; ESI-MS: 259 (M + Na)+, 275 (M + K)+. [α]20D = +17.1
(c 0.23, CHCl3, 94.5% ee). 1H NMR (600 MHz, CDCl3) δ 2.90−3.02
(m, 4H), 3.14−3.23 (m, 2H), 5.61 (dd, 1H, J = 11.2 Hz, J = 5.8 Hz),
7.45 (m, 2H), 7.59 (m, 1H), 8.09 (m, 2H); 13C NMR (150 MHz,
CDCl3) δ 30.04 (CH2), 34.7 (CH2), 44.8 (CH2), 77.1 (CH), 128.4
(CH), 129.3 (CH), 129.9 (CH), 133.4 (CH), 165.1 (C), 201.5 (C).
(R)-2-Oxocycloheptyl Benzoate10 (3g) (Table 5, entry 11).
The reaction was carried out following the general procedure. The title
compound was isolated as a white solid by column chromatography
(hexane/EtOAc = 85/15) in 60% yield and >99% ee. HPLC analysis
on a Chiralcel OD-H column: 95/5 hexane/i-PrOH, flow rate 0.800
mL/min, λ = 254 nm: τmajor = 10.15 min, τminor = 12.96 min; ESI-MS:
233 (M + 1)+, 255 (M + Na)+. [α]20D = −33.7 (c 0.97, CHCl3, >99%
90/10 hexane/i-PrOH, flow rate 0.75 mL/min, λ = 214 nm: τmajor
=
13.48 min, τminor = 14.72 min; HRMS (ESI+) calcd for C16H13O3
253.0859, found 253.0857. Mp (DSC, 2 °C/min): 70 °C. [α]20
=
D
1
−56.1 (c 0.82, CHCl3, 84% ee). H NMR (400 MHz, CDCl3) δ 3.20
(dd, 1H, J = 17.1 Hz, J = 4.7 Hz), 3.77 (dd, 1H, J = 16.9 Hz, J = 8.0
Hz), 5.65 (dd, 1H, J = 8.0 Hz, J = 4.8 Hz), 7.40−7.51 (m, 4H), 7.58
(m, 1H), 7.67 (td, 1H, J = 7.5 Hz, J = 1.2 Hz), 7.84 (bd, 1H, J = 7.7
Hz), 8.10 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 33.6 (CH2), 74.4
(CH), 124.5 (CH), 126.7 (CH), 128.1 (CH), 128.4 (CH), 129.3 (C),
133.4 (CH), 134.6 (C), 135.9 (CH), 150.4 (C), 166.0 (C), 200.4 (C).
(R)-5-Bromo-1-oxo-2,3-dihydro-1H-inden-2-yl Benzoate (5b)
(Table 6, entry 2). The reaction was carried out following the general
procedure. The title compound was isolated as a white solid by column
chromatography (dichloromethane/diethyl ether = 99/1) in 66% yield
and 80% ee. HPLC analysis on a Chiralcel OD-H column: 98/2
hexane/i-PrOH, flow rate 0.850 mL/min, λ = 254 nm: τmajor = 37.63
min, τminor = 33.61 min; HRMS (ESI−) calcd for C16H10BrO3
328.9892, 330.9871, found 328.9890, 330.9869. [α]20 = −3.7 (c
D
1
1
ee). H NMR (400 MHz, CDCl3) δ 1.38−1.51 (m, 1H), 1.65−1.99
1.0, CHCl3, 80% ee). H NMR (400 MHz, CDCl3) δ 3.20 (m, 1H),
(m, 6H), 2.13 (m, 1H), 2.51 (m, 1H), 2.70 (m, 1H), 5.46 (dd, 1H, J =
9.7 Hz, J = 3.5 Hz), 7.45 (m, 2H), 7.57 (m, 1H), 8.08 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 23.0 (CH2), 26.4 (CH2), 28.4 (CH2),
3.75 (m, 1H), 5.60 (dd, 1H, J = 8.0 Hz, J = 4.8 Hz), 7.45 (m, 2H),
7.56−7.62 (m, 2H), 7.66−7.72 (m, 2H), 8.09 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 33.2 (CH2), 74.2 (CH), 125.7 (CH), 128.5
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(CH), 129.1 (C), 130.0 (CH), 131.3 (C), 131.9 (CH), 133.4 (C),
133.5 (CH), 151.9 (C), 166.0 (C), 199.2 (C).
321.0660, found 321.0662. Mp: 92.6−94.0 °C. [α]20D = −13.5 (c 0.66,
1
CHCl3, 40% ee). H NMR (400 MHz, CDCl3) δ 3.34 (dd, J = 17.8
Hz, J = 4.8 Hz, 1H), 3.99 (m, 1H), 5.64 (dd, J = 8.1 Hz, J = 4.8 Hz,
1H), 7.46 (m, 2H), 7.60 (m, 2H), 7.94 (d, J = 8.0 Hz, 1H), 8.03 (d, J =
7.6 Hz, 1H), 8.07−8.12 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
32.3 (CH2), 73.8 (CH), 123.5 (q, JC−F = 273.5 Hz, C), 127.9 (CH),
128.5 (CH), 128.6 (CH), 128.6 (q, JC−F = 32.7 Hz, C), 129.0 (C),
130.1 (CH), 132.3 (q, JC−F = 5.0 Hz, CH), 133.6 (CH), 133.6 (CH),
136.0 (C), 147.7 (C), 165.9 (C), 199.17 (C).
(R)-5-Fluoro-1-oxo-2,3-dihydro-1H-inden-2-yl Benzoate (5c)
(Table 6, entry 3). The reaction was carried out following the general
procedure. The title compound was isolated as a white solid by column
chromatography (dichloromethane/diethyl ether = 99/1) in 55% yield
and 79% ee. HPLC analysis on a Chiralpak AD-H column: 90:10
hexane/i-PrOH, flow rate 0.75 mL/min, λ = 254 nm: τmajor = 20.37
min, τminor = 22.98 min; HRMS (ESI+) calcd for C16H12FO3 271.0765,
found 271.0763. Mp (DSC, 2 °C/min): 119 °C. [α]20 = −40.5 (c
Synthesis of cis-(1S,2R)-6b and trans-(1R,2R)-7b. Compound
5b (40 mg, 0.12 mmol, 80% ee) was dissolved in 2 mL of a 1:3
solution of MeOH/THF and stirred at room temperature for several
minutes. Then 3 equiv (13.7 mg, 0.36 mmol) of solid NaBH4 was
added at 0 °C, and stirring was continued until the disappearance of
5b was observed (15 min, checked by TLC). The reaction was then
placed in an oil bath at 50 °C in a sealed tube for 18 h. The crude
mixture was diluted with dichloromethane and treated with a saturated
aqueous solution of Na2CO3. The organic phase was separated, and
the aqueous phase was extracted two times with dichloromethane.
Organic phases were collected and dried over MgSO4, and the solvent
was removed under reduced pressure. The crude mixture was analyzed
by NMR (dr = 4:1 in favor of cis-6b) and purified by column
chromatography using hexane/acetone 75/25 as the eluent mixture to
give cis-(1S,2R)-6b in 53% yield and 84% ee. HPLC analysis on a
Chiralcel OJ-H column: 90/10 hexane/i-PrOH, flow rate 0.600 mL/
min, λ = 214 nm: τminor = 17.17 min, τmajor = 18.96 min; and trans-
(1R,2R)-7b in a 25% yield and 80% ee HPLC analysis on a Lux
Amylose-2 column: 95/5 hexane/i-PrOH, flow rate 0.700 mL/min, λ
= 230.16 nm: τmajor = 34.66 min, τminor = 32.42 min. [α]20D cis-(1S,2R)-
6b = −5.3 (c 0.57, acetone, 84% ee). HRMS (ESI−) calcd for
C9H8BrO2 226.9713, 228.9693, found 226.9711, 228.9690. Mp cis-
(1S,2R)-6b: 123.0−124.5 °C. Mp trans-(1S,2R)-7b: 187.0−189.4 °C.
1H NMR (400 MHz, CDCl3) cis-(1S,2R)-6b δ 2.84 (dd, 1H, J = 16.5
Hz, J = 3.1 Hz), 3.03 (dd, 1H, J = 16.5 Hz, J = 5.6 Hz), 3022 (d, 1H, J
= 4.6 Hz), 3.55 (d, 1H, J = 7.0 Hz), 4.38 (m, 1H), 4.87 (m, 1H),
7.26−7.31 (m, 2H), 7.37−7.44 (m, 1H); 13C NMR (100 MHz,
CDCl3) cis-(1S,2R)-6b δ 38.9 (CH2), 74.0 (CH), 75.9 (CH), 118.3
(C), 122.1 (C), 127.5 (CH), 129.0 (CH), 130.5 (CH), 143.7 (C),
144.5 (C). 1H NMR (400 MHz, CD3CN, poor solubility) trans-
(1R,2R)-7b δ 2.69 (dd, 1H, J = 16.0 Hz, J = 6.8 Hz), 3.17 (m, 1H),
3.39 (d, 1H, J = 5.0 Hz), 3.60 (d, 1H, J = 6.0 Hz), 4.19 (m, 1H), 4.76
(m, 1H), 7.24 (m, 2H), 7.37−7.43 (m, 3H); 13C NMR (100 MHz,
CD3CN) δ 38.5 (CH2), 81.2 (CH), 82.5 (CH), 118.3 (C), 122.0 (C),
127.1 (CH), 128.7 (CH), 130.6 (CH), 143.4 (C), 143.6 (C).
D
1
0.89, CHCl3, 79% ee). H NMR (400 MHz, CDCl3) δ 3.19 (m, 1H),
3.76 (m, 1H), 5.62 (dd, 1H, J = 8.0 Hz, J = 4.7 Hz), 7.11−7.19 (m,
2H), 7.45 (m, 2H), 7.59 (m, 1H), 7.86 (m, 1H), 8.09 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 33.5 (d, CH2, J = 1.7 Hz), 74.3 (CH),
113.5 (d, CH, JC−F = 22.7 Hz), 116.6 (d, CH, JC−F = 23.7 Hz), 127.0
(d, CH, JC−F = 10.6 Hz), 128.4 (CH), 129.2 (C), 130.0 (CH), 131.1
(d, C, JC−F = 1.6 Hz), 133.5 (CH), 153.3 (d, C, JC−F = 10.5 Hz), 166.0
(C), 166.5 (C), 169.1 (C), 198.6 (C).
(R)-5-Methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl Benzoate
(5d) (Table 6, entry 4). The reaction was carried out following the
general procedure. The title compound was isolated as a white solid by
column chromatography (dichloromethane/diethyl ether = 99/1) in
30% yield and 77% ee. HPLC analysis on a Chiralpak AD-H column:
80/20 hexane/i-PrOH, flow rate 1.00 mL/min, λ = 254 nm: τmajor
14.88 min, τminor = 22.27 min; HRMS (ESI+) calcd for C17H15O4
283.0965, found 283.0963. Mp (DSC, 2 °C/min): 140 °C. [α]20
=
=
D
−6.4 (c 0.45, CHCl3, 77% ee).1H NMR (400 MHz, CDCl3) δ 3.13
(dd, 1H, J = 17.0 Hz, J = 4.5 Hz), 3.73 (dd, 1H, J = 16.9 Hz, J = 7.7
Hz), 3.91 (s, 3H), 5.63 (dd, 1H, J = 7.8 Hz, J = 4.5 Hz), 6.90 (bs, 1H),
6.97 (m, 1H), 7.45 (m, 2H), 7.58 (m, 1H), 7.78 (d, 1H, J = 8.5 Hz),
8.10 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 33.9 (CH2), 55.8
(CH3), 74.5 (CH), 109.8 (CH), 116.2 (CH), 126.6 (CH), 127.9 (C),
128.4 (CH), 129.4 (CH), 130.0 (CH), 133.4 (CH), 153.6 (C), 166.1
(C), 166.2 (C), 198.5 (C).
(R)-6-Methyl-1-oxo-2,3-dihydro-1H-inden-2-yl Benzoate (5e)
(Table 6, entry 5). The reaction was carried out following the general
procedure. The title compound was isolated as a white solid by column
chromatography (dichloromethane/diethyl ether = 99/1) in 82% yield
and 60% ee. HPLC analysis on a Chiralcel OD-H column: 90/10
hexane/i-PrOH, flow rate 0.75 mL/min, λ = 254 nm: τmajor = 12.19
min, τminor = 14.38 min; HRMS (ESI+) calcd for C17H15O3 267.1016,
found 267.1014. Mp (DSC, 2 °C/min): 85 °C. [α]20D = −53.3 (c 0.97,
1
CHCl3, 60% ee). H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 3.14
(dd, 1H, J = 16.9 Hz, J = 4.8 Hz), 3.72 (dd, 1H, J = 17.0 Hz, J = 8.2
Hz), 5.64 (dd, 1H, J = 8.0 Hz, J = 4.8 Hz), 7.34−7.39 (m, 1H), 7.41−
7.51 (m, 3H), 7.58 (m, 1H), 7.64 (bs, 1H), 8.09 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.1 (CH3), 33.2 (CH2), 74.7 (CH), 124.4
(CH), 126.3 (CH), 128.4 (CH), 129.4 (C), 130.0 (CH), 133.3 (CH),
134.7 (C), 137.1 (CH), 138.2 (C), 147.7 (C), 166.0 (C), 200.5 (C).
(R)-5-Chloro-1-oxo-2,3-dihydro-1H-inden-2-yl Benzoate (5f)
(Table 6, entry 6). The reaction was carried out following the general
procedure. The title compound was isolated as a white solid by column
chromatography using dichloromethane as the eluent in 68% yield and
76% ee. HPLC analysis on a Chiralcel AD-H column: 80/20 hexane/i-
PrOH, flow rate 0.750 mL/min, λ = 254 nm: τmajor = 15.99 min, τminor
= 20.12 min; HRMS (ESI+) calcd for C16H12ClO3 287.0397, found
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental procedures, H and 13C NMR spectra,
1
characterization data, and HPLC traces for compounds 3a−i,
5a−g, 6b, and 7b. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: giorgio.bencivenni2@unibo.it.
287.0395. Mp: 162.1−163.2 °C. [α]20 = −10.5 (c 0.78, CHCl3, 76%
D
ee). 1H NMR (400 MHz, CDCl3) δ 3.18 (dd, J = 17.4 Hz, J = 4.9 Hz,
1H), 3.74 (dd, J = 17.4 Hz, J = 8.2 Hz, 1H), 5.6 (dd, J = 8.1 Hz, J = 4.8
Hz, 1H), 7.39−7.51 (m, 1H), 7.56−7.63 (m, 1H), 7.77 (d, J = 8.5 Hz,
2H), 8.07−8.11 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 33.5, 74.5,
125.9, 127.9, 127.1, 128.7, 129.3, 129.4, 130.2, 133.3, 133.7, 142.7,
152.0, 166.1, 199.2.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. Giuseppe Bartoli on the
occasion of his 70th birthday. We acknowledge Prof. Francesco
Gasparrini and Dr. Alessia Ciogli for the HRMS analysis. We
acknowledge Dr. Tiziana Benelli for the DSC analysis. We
acknowledge financial support from Bologna University and
from MIUR National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni”.
(R)-1-Oxo-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl
Benzoate (5g) (Table 6, entry 7). The reaction was carried out
following the general procedure. The title compound was isolated as a
pale yellow solid by column chromatography (hexane/Et2O = 9:1) in
37% yield and 40% ee. HPLC analysis on a Chiralcel AD-H column:
92/8 hexane/i-PrOH, flow rate 0.700 mL/min, λ = 254 nm: τmajor
=
13.03 min, τminor = 14.29 min; HRMS (ESI+) calcd for C17H12F3O3
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The Journal of Organic Chemistry
Article
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NOTE ADDED AFTER ASAP PUBLICATION
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The toc/abstract graphic and Figure 1 contained errors in the
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