An enantioselective approach toward 3,4-dihydroisocoumarin through the bromocyclization of styrene-type carboxylic acids

Article abstract of DOI:10.1021/jo202221c

A facile and enantioselective approach toward 3,4-dihydroisocoumarin was developed. The method involved an amino-thiocarbamate catalyzed enantioselective bromocyclization of styrene-type carboxylic acids, yielding 3-bromo-3,4-dihydroisocoumarins with good yields and ee's. 3-Bromo-3,4- dihydroisocoumarins are versatile building blocks for various dihydroisocoumarin derivatives in which the Br group can readily be modified to achieve biologically important 4-O-type and 4-N-type 3,4-dihydroisocoumarin systems. In addition, studies indicated that, by refining some parameters, the synthetically useful 5-exo phthalide products could be achieved with good yields and ee's.

Full text of DOI:10.1021/jo202221c

Article
pubs.acs.org/joc
An Enantioselective Approach toward 3,4-Dihydroisocoumarin
through the Bromocyclization of Styrene-type Carboxylic Acids
Jie Chen, Ling Zhou, Chong Kiat Tan, and Ying-Yeung Yeung*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
S
* Supporting Information
ABSTRACT: A facile and enantioselective approach toward 3,4-dihydroisocoumarin was developed. The method involved an
amino-thiocarbamate catalyzed enantioselective bromocyclization of styrene-type carboxylic acids, yielding 3-bromo-3,4-
dihydroisocoumarins with good yields and ee's. 3-Bromo-3,4-dihydroisocoumarins are versatile building blocks for various
dihydroisocoumarin derivatives in which the Br group can readily be modified to achieve biologically important 4-O-type and 4-
N-type 3,4-dihydroisocoumarin systems. In addition, studies indicated that, by refining some parameters, the synthetically useful
5-exo phthalide products could be achieved with good yields and ee's.
Over the past decades, significant efforts have been devoted
to the construction of isocoumarin systems.3 Their asymmetric
variants, however, are scattered. A well-known approach is the
asymmetric lithiation process, which involved the use of
stoichiometric amounts of chiral amine.4 Other methods,
including Sharpless asymmetric dihydroxylation,5 rhodium-
catalyzed intermolecular [4 + 2] annulation,6 and enzymatic
catalysis,7 were also applied to construct the 3,4-dihydroiso-
coumarin skeletons. Despite the attractive biological properties
of 3,4-dihydroisocoumarins, a general and versatile approach
toward the enantioselective synthesis of this class of
compounds, however, is still in its infancy. Herein, we report
a diversified approach toward the enantioselective synthesis of
3,4-dihydroisocoumarin 1 and its related skeletons.
INTRODUCTION
■
3,4-Dihydroisocoumarin is the fundamental unit of many
compounds that possess a wide spectrum of biological activity.
Of particular interest, 3-substitiuted 3,4-dihydroisocoumarin
(e.g., 3-aryl) core 1 (R1 = H) has attracted much attention since
this structural motif is present in many natural products and
bioactive molecules.1 The related frameworks of 1, which
include the 4-O-type (R1 = O) and the 4-N-type (R1 = N) 3,4-
dihydroisocoumarins, are also attractive targets for synthetic
chemists as they constitute a number of important
pharmaceuticals (Scheme 1).2
Scheme 1. Biologically Important 3,4-Dihydroisocoumarins
We rationalized that 3,4-dihydroisocoumarin 1 could be
originated from 4-bromo-3,4-dihydroisocoumarin 2, which
could be furnished by the catalytic asymmetric bromocycliza-
tion of styrene-type carboxylic acid 3. Although bromocycliza-
tion of 3 seems routine based on the history of bromolacto-
nization over the past decades, the breakthrough of the
asymmetric variants only appeared recently. The scopes were
rather limited, and to date, the enantioselective halocyclization
of 3 remains unknown.8
In addition, there are two other challenges that exist in the
halocyclization of the styrene-type carboxylic acid 3: (1) The
rigidity of the skeleton due to the aryl ring significantly reduced
Received: November 4, 2011
Published: December 16, 2011
© 2011 American Chemical Society
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a
Table 1. Optimization of the Bromocyclization of 3a
b
c
entry
catalyst
solvent
CH2Cl2
time (d)
% yield (4a:5a)
% ee 4a
1
2
3
4
6
5
5
5
5
6
6
6
6
6
trace (ND)
trace (ND)
75 (5:1)
ND
ND
86
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8a
9
96 (5.5:1)
96 (5.5:1)
30 (5:1)
92
d
5
9
92
6
7
8
9
8b
8c
9
60
29 (5:1)
63
hexane/CHCl3 (1:1)
PhMe/CHCl3 (2:1)
73 (3:1)
73
9
65 (3:1)
84
a
Reactions were carried out with olefinic acid 3a (0.1 mmol), catalyst (0.01 mmol), and NBS (0.12 mmol) in solvent (3.5 mL) in the absence of
b
c
d
1
light. Isolated yield. Determined by H NMR. Reaction was conducted on a 4.0 mmol scale.
the cyclization efficiency. In fact, at room temperature, the
bromocyclization of 3a (Table 1) using NBS was sluggish even in
the presence of a Lewis base catalyst.9 (2) Both 6-endo (product 4)
and 5-exo (product 5) cyclization pathways (Scheme 2) may
happen depending on various factors (vide infra).10
catalysts that contain 2,4-dimethoxyphenyl units were investigated
initially. After a round of catalyst screening, it was surprising to
find that cinchonidine- and quinine-derived amino-thiocarbamates
6 and 7 were unable to promote the reaction (Table 1, entries
1 and 2). In sharp contrast, cinchonine- and quinidine-derived
amino-thiocarbamates 8a and 9 were able to promote the desired
reaction and furnished isocoumarin 4a with appreciable ee's and
yields (Table 1, entries 3 and 4). This is quite unusual since
cinchonidine and quinine are commonly regarded as the
pseudoenantiomeric catalyst skeletons of cinchonine and
quinidine, respectively.11 This drastic difference implies that the
vinyl substituent may play a crucial role in this type of reaction.
Next, examinations on the methoxylated phenyl unit of the
thiocarbamate showed that the 2,4-dimethoxyphenyl unit appeared
to be critical for the reaction (Table 1, entries 6 and 7). Other
halogen sources, including N-chlorosuccinimide (NCS) and N-
iodosuccinimide (NIS), were examined, and the reactions were
sluggish with low enantioselectivities (Scheme 3).12
Scheme 2. 6-endo and 5-exo Cyclization
Scheme 3. Halocyclization of 3a Using NCS and NIS
RESULTS AND DISCUSSION
■
6-endo Cyclization of Styrene-type Carboxylic Acids
3. Previously, we have reported the use of amino-thiocarbamate
as the catalyst in the enantioselective bromocyclization.8d,j−m In
this context, we attempted to apply this catalytic protocol to the
cyclization of styrene-type carboxylic acid. Thus, the bromocycliza-
tion of 3a was selected as a model reaction and NBS was used as
the stoichiometric brominating agent. The amino-thiocarbamate
A survey on the solvent effect was also performed.
Interestingly, solvent blends, including hexane/chloroform and
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a
Table 2. Asymmetric Bromocyclization of 3
b
c
entry
substrate, R1, R2
T (°C), time (d)
% yield (4:5)
% ee 4
1
2
3b, H, 4-FC6H4
3c, H, 4-ClC6H4
3d, H, 4-BrC6H4
3e, H, 4-CH3C6H4
3f, H, 2-naphthyl
3g, H, 4-AcOC6H4
3h, H, 4-CH3OC6H4
3i, H, 3-CH3C6H4
3j, 3-CH3, C6H5
3k, 4-F, C6H5
−50, 4
−60, 4
−60, 4
−78, 3
−60, 5
−60, 5
−78, 3
−65, 4
−78, 5
−60, 4
−60, 7
−60, 4
98 (9:1)
91
95
95
83
88
80
24
90
84
90
89
93
95 (3.2:1)
94 (2.5:1)
95 (15:1)
95 (10:1)
87 (2.5:1)
99 (40:1)
97 (7.4:1)
97 (50:1)
98 (8.5:1)
91 (8.4:1)
97 (12:1)
3
4
5
6
7
8
9
10
11
12
3l, 4-Cl, C6H5
3m, 5-F, C6H5
a
Reactions were carried out with olefinic acid 3 (0.1 mmol), catalyst 9 (0.01 mmol), and NBS (0.12 mmol) in solvent (3.5 mL) in the absence of
b
c
1
light. Isolated yield. Determined by H NMR.
toluene/chloroform, which were proven to be useful in a number
of organocatalytic enantioselective halogenation systems,8 had a
deteriorated effect on the reaction rate, ee, and the 6-endo/5-exo
selectivity (Table 1, entries 8 and 9).
Scheme 4. Conversion of 4a into Derivatives 10−12
With the optimized conditions in hand (Table 1, entry 4), a
variety of styrene-type carboxylic acids were subjected to
investigation. In general, excellent reaction yields were achieved
(Table 2). For the substrates with electron-deficient R2 aryl
substituents, good to excellent ee's were obtained (Table 2,
entries 1−3). Other R2 substituents, including 4-methylphenyl,
2-naphthyl, 4-acetoxyphenyl, and 3-methylphenyl groups, were
also examined, which returned with high ee's and high endo/
exo ratios (Table 2, entries 4−6, 8). For the substrates with R2
as a 4-methoxyphenyl group, although an excellent endo/exo
ratio was observed, a relatively low ee was obtained (Table 2,
entry 7).13 Other than the R2 group, some substrates with
different substituents in the benzoic acid moiety were also
investigated, and good yields, ee's, and high endo/exo ratios
were observed (Table 2, entries 9−12). The absolute
configuration of isocoumarins 4 were assigned based on the
X-ray crystallographic structure of 4f.
Conversion of 3-Bromo-3,4-dihydroisocoumarin 4a
into Other Useful Building Blocks. To demonstrate the
practicality of this approach toward the enantioenriched 3,4-
dihydroisocoumarin system, we attempted to scale up the
reaction to 4.0 mmol, in which the efficiency and the
enantioselectivity were maintained (Table 1, entry 5). The
derivatization of bromoisocoumarin 4 was then performed. It
was found that the Br atom in 4a could be removed by the
Ph3SnH/AIBN reduction, yielding 3-phenyl-3,4-dihydroisocou-
marin (10), which is a very important core of many drug
molecules (Scheme 4).1 The Br unit in 4a could readily be
converted to other functional groups. For instance, a
nucleophilic acetate displacement of 4a allowed us to obtain
the 4-oxygenated 3,4-dihydroisocoumarin core 11, which is the
fundamental unit of a proinflammatory cytokines tumor
necrosis factor-alpha (TNF-alpha) and an enzyme cyclo-
oxygenase-2 (COX-2) inhibitor.2f In addition, an azide
substitution of 4a using sodium azide gave the nitrogen-
substituted core 12, which resembles the structures of an
aldosterone synthase inhibitor that is used for the treatment of
disease mediated by an aldosterone synthase (CYP11B2).2a
On the other hand, 4a is manipulated with a two-step sequence:
(1) reduction of the lactone in 4a to form the epoxy alcohol 13
and (2) an acid-promoted epoxide opening, followed by an
intramolecular etherification, yielding enantioenriched alcohol 14,
which is a useful skeleton for natural product synthesis (Scheme 5).14
The structure of 14 was confirmed by an X-ray study.
Investigation of the Factors That Favor the Formation
of 5-exo Cyclized Product 5. In the studies of
dihydrocoumarin 4 synthesis, it was found that many substrates
have a bias in favor of the formation of 6-endo product 4,15
which could be attributed to the following reason(s): (1) the
skeleton rigidity restricted the formation of 5-exo product 5
and/or (2) the electron-withdrawing property of the carboxylic
acid group destabilized the 5-exo cyclization pathway. Despite
our success in the catalytic approach toward the enantioen-
riched 6-endo product 4, understanding the factors that can
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product was obtained when using the 3,5-bis(trifluoromethyl)-
phenyl substrate 3p (Table 3, entry 3); the substrates with a
relatively more electron-deficient R2 group returned with more 5-
exo product 5, preferentially due to the destabilization of the 6-
endo cyclization pathway (Scheme 2). For the R2 as a 2-substituted
aryl group, the product returned with high 5-exo selectivity; the 6-
endo/5-exo ratio was 1:15.4 when R2 was a 2-chlorophenyl group
(Table 3, entry 5). Other than some specific aryl systems, R2 as a
hydrogen or other alkyl substituents also returned with good 5-exo
selectivity (Table 3, entries 6−8).
Scheme 5. Conversion of 4a into 14
Although we have identified some features of the substrates
that might be responsible for the higher 5-exo selectivity, the
enantioselectivities of phthalide 5 in these reaction were
generally not very satisfactory. Thus, we further investigated
other parameters that could favor the phthalide product 5
formation with a higher enantioselectivity.
Studies showed that reaction in chloroform favored a better
5-exo product yield (Table 3, entry 10 vs 11).17 Moreover, a
better ee of the 5-exo product was obtained when changing the
quinidine-derived catalyst 9 to cinchonine-derived catalyst 8a
(Table 3, entry 11 vs 13). Additionally, the ee of phthalide 5 could
further be improved by using the 2,4,6-trimethoxyphenyl
thiocarbamate catalyst 8d (Table 3, entry 13 vs 15). Attempts
to apply these modifications to some electron-deficient substrates,
favor the formation of 5-exo product 5 is equally important
since the phthalide 5 is also a useful building block.16
During the substrate investigation, it appears that the 5-exo/
6-endo ratio is partly dependent on the nature of the substrates
in which typically a more electron-rich R2 group favored the 6-
endo product. For instance, the electron-deficient R2, in
particular, the 3-substituted aryl system, gave higher 5-exo
selectivity (Table 3, entries 1−4). A 1:4.5 ratio of 6-endo/5-exo
a
Table 3. Studies on Optimizing the Formation of 5
b
c
entry
substrate, R2
cat.
solvent
temp (°C), time (d)
% yield (4:5)
% ee (4, 5)
1
2
3n, 3-ClC6H4
3o, 3-NO2C6H4
3p, 3,5-(CF3)2C6H3
3q, 4-CF3C6H4
3r, 2-ClC6H4
3s, H
9
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
CHCl3
CH2Cl2
CHCl3
CHCl3
CHCl3
CH2Cl2
−60, 6
−30, 4
−30, 6
−45, 5
−45, 5
−60, 4
−78, 4
−78, 4
−78, 5
−60, 5
−60, 5
−78, 5
−60, 5
−78, 5
−60, 5
−50, 4
−45, 5
−78, 5
89 (1.5:1)
96 (1:3.8)
84 (1:4.5)
90 (1:2)
96, −41
98, −47
93, −17
88, −44
33, −32
NA, −34
53, −12
58, −28
92, −16
88, −13
77, 18
3
9
4
9
5
9
92 (1:15.4)
6
9
90 (only exo)
95 (1:7)
7
3t, nPr
9
8
3u, cyclohexyl
3a, C6H5
9
96 (1:8)
9
9
96 (5.5:1)
93 (4.5:1)
97 (2.1:1)
75 (5:1)
10
11
12
13
14
15
16
17
18
3a, C6H5
9
3a, C6H5
9
3a, C6H5
8a
8a
8d
8d
8d
8d
15
86, 24
3a, C6H5
90 (2.7:1)
92 (3.1:1)
91 (2:1)
82, 51
3a, C6H5
77, 70
3a, C6H5
73, 79
3n, 3-ClC6H4
3q, 4-CF3C6H4
3a, C6H5
89 (1:2.3)
90 (1:4)
73, 66
58, 53
93 (5.3:1)
91, −25
a
b
Reactions were carried out with acid 3 (0.1 mmol), catalyst (0.01 mmol), and NBS (0.12 mmol) in the absence of light. Isolated yield.
Determined by H NMR.
c
1
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such as 3n and 3q, allowed us to obtain better yields and
enantioselectivities of the phthalides 5n and 5q (Table 3, entries
1 vs 16, 4 vs 17). The absolute configuration of 5-exo products 5
was assigned by converting 5q to the corresponding debrominated
phthalide 5q′, which was compared with the literature known
compound (Scheme 6).18,19
the 6-alkoxy substituent of quinoline in catalyst 9 (i.e., catalyst 15)
gave more ent-5 product, as reflected by the higher, but
negative, ee value (Table 3, entry 9 vs 18). On the basis of our
previous mechanistic picture (Scheme 7, complex A),8j
a
possible explanation is that the 6-methoxy group of quinoline in
the quinidine-derived catalyst 9 may serve as a steric-screening
group, which suppresses the formation of 5-exo product 5
(Scheme 7, B → 5, pathway b) and favors the formation of
more ent-5 (Scheme 7, C → ent-5, pathway c), that is, reduce
the ee of 5. Although the roles of the solvent and
thiocarbamate’s aryl group on the 5-exo/6-endo selectivity
remain unclear and are subjected to further investigation, the
above-mentioned results suggest that, in addition to the selec-
tion of a suitable substrate, further refinement of other param-
eters might open an avenue toward the nonclassical, but syn-
thetically useful, 5-exo cyclized phthalide product 5.
Scheme 6. Debromination of 5q
It is important to note that, apart from the solvent effect, it
seems that the catalyst structure is also responsible to the 5-exo
product selectivity. For this type of cyclization, potentially there
are three different pathways (Scheme 7): (1) 6-endo cyclization
of conformer 3 (pathway a), (2) 5-exo cyclization of conformer
3 (pathway b), and (3) 5-exo cyclization of conformer 3′
(pathway c). The formation of more 5-exo product 5 could be
attributed to the more favorable cyclization (pathway b) when
using the cinchonine-derived catalyst; an increase in ee's of 5
was observed when changing the catalyst from 9 to 8 (Table 3,
entries 10 vs 13, 12 vs 14). In fact, increasing the bulkiness of
CONCLUSION
■
In summary, we have developed a facile, efficient, and enantio-
selective approach toward 4-bromo-3-aryl-3,4-dihydroisocoumarins
4 through an amino-thiocarbamate-catalyzed bromocyclization
process. 4 is a versatile building block for the synthesis of
biologically important 3-substituted 3,4-dihydroisocoumarins and
its related cores. Studies indicate that, other than the substrate
selection, adjusting some parameters, such as solvent and catalyst
structure, may allow us to obtain the synthetically useful 5-exo
phthalide product 5 with good yield and ee. Further investigation
on other applications and studies of the mechanism are underway.
Scheme 7. Plausible Pathways toward 5 and ent-5
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128.5 (d, J = 7.5 Hz), 127.3, 127.1, 115.6 (d, J = 21.5 Hz); HRMS
(ESI) Calcd for C15H10FO2 m/z [M − H]−: 241.0670; found,
241.0671.
EXPERIMENTAL SECTION
■
General. All reactions that required anhydrous conditions were
carried by standard procedures under a nitrogen atmosphere.
Commercially available reagents were used as received. The solvents
were dried by distillation over the appropriate drying reagents. Infrared
spectra were recorded on an FT-IR spectrophotometer and reported
in wavenumbers (cm−1). Melting points were determined on a melting
1
(E)-2-(4-Chlorostyryl)benzoic Acid (3c). White solid: H NMR
(300 MHz, CDCl3): δ 11.0 (brs, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.05
(d, J = 16.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H),
7.48 (d, J = 8.2 Hz, 2H), 7.41−7.32 (m, 3H), 6.97 (d, J = 16.4 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ 173.2, 139.9, 135.8, 133.6, 133.2,
131.7, 130.4, 128.9, 128.15, 128.06, 127.5, 127.3, 127.2; MS (ESI) m/z
[M − H]−: 257.2.
point apparatus and are uncorrected. H NMR and 13C NMR spectra
1
were recorded on a 300 MHz and a 500 MHz spectrometer. Chemical
shifts (δ) are reported in parts per million relative to TMS (δ 0.00) for
the 1H NMR and to chloroform (δ 77.0) for the 13C NMR
measurements. Low-resolution mass spectra were obtained on a mass
spectrometer in ESI mode. High-resolution mass spectra were
obtained from EI or ESI mass spectrometers. Enantiomeric excesses
were determined by HPLC analysis using analytical chiral columns.
Optical rotations were recorded on a polarimeter equipped with a
sodium lamp source (589 nm). Analytical thin-layer chromatography
(TLC) was performed with precoated TLC plates (silica gel 60 F254
on aluminum sheets). Flash chromatography separations were
performed on 60 (0.040−0.063 mm) mesh silica gel. Amino-
thiocarbamate catalysts 6−98d and carboxylic acid 320 were prepared
according to the literature proceudures.
General Procedure for the Preparation of Racemic 4 and 5.
To a mixture of 3 (0.1 mmol, 1.0 equiv) and Ph3PS (5.9 mg, 0.02
mmol, 0.2 equiv) in CH2Cl2 (3.5 mL) at low temperature in the dark
under N2 was added N-bromosuccinimide (26.7 mg, 0.15 mmol,
1.5 equiv). After the reaction mixture was continued for 24 h, the
reaction was quenched with saturated Na2SO3 (4.0 mL) at the reaction
temperature and then was warmed to 25 °C. The solution was diluted
with water (4.0 mL) and extracted with CH2Cl2 (3 × 6 mL). The
combined extracts were washed with brine (10.0 mL), dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography (hexane/EtOAc, 5:1) to yield (50−70%) of
the corresponding racemic isocoumarins 4 and 5.
(E)-2-(4-Bromostyryl)benzoic Acid (3d). White solid, mp
1
179.8−181.3 °C: H NMR (300 MHz, CDCl3): δ 8.10 (d, J = 7.6
Hz, 1H), 8.06 (d, J = 16.3 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.58 (dt,
J = 7.6, 1.3 Hz, 1H), 7.51−7.36 (m, 5H), 6.95 (d, J = 16.3 Hz, 1H);
13C NMR (75 MHz, CDCl3): δ 172.7, 139.9, 136.3, 133.2, 131.8,
131.7, 130.5, 128.4, 128.3, 127.5, 127.3, 127.2, 121.8; MS (ESI) m/z
[M − H]−: 301.1.
1
(E)-2-(4-Methylstyryl)benzoic Acid (3e). White solid: H NMR
(300 MHz, CDCl3): δ 8.11 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 16.1 Hz,
1H), 7.76 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.9
Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H), 7.03 (d, J =
16.1 Hz, 1H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 173.2,
140.4, 137.9, 134.6, 133.1, 131.8, 131.6, 129.4, 127.2, 127.1, 127.0,
126.9, 126.5, 21.3; MS (ESI) m/z [M − H]−: 237.1.
2-[(E)-2-(2-Naphthyl)ethenyl]carboxylic Acid (3f). White solid:
1H NMR (300 MHz, DMSO-d6): δ 8.08 (d, J = 16.4 Hz, 1H), 8.00−
7.88 (m, 6H), 7.78 (d, J = 8.5 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.55−
7.47 (m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 16.4 Hz, 1H); 13
C
NMR (75 MHz, DMSO-d6): δ 168.6, 137.8, 134.7, 133.2, 132.7, 131.9,
130.7, 130.3, 129.8, 128.3, 127.9, 127.6, 127.5, 126.7, 126.5, 126.1,
123.6; MS (ESI) m/z [M − H]−: 273.2.
(E)-2-(4-Acetoxystyryl)benzoic Acid (3g). White solid, mp
179.8−181.7 °C: IR (KBr): 2991, 2870, 2670, 2548, 1758, 1671,
1504, 1300, 1194, 971, 912 cm−1; 1H NMR (300 MHz, CDCl3): δ 8.11
(d, J = 7.9 Hz, 1H), 8.03 (d, J = 16.1 Hz, 1H), 7.73 (d, J = 7.6 Hz,
1H), 7.60−7.55 (m, 3H), 7.37 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 8.5 Hz,
2H), 7.01 (d, J = 16.1 Hz, 1H), 2.32 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 172.7, 169.5, 150.3, 140.0, 135.1, 133.1, 131.7, 130.7, 127.9,
127.8, 127.3, 127.2, 121.8, 21.1; HRMS (ESI) Calcd for C17H13O4 m/z
[M − H]−: 281.0819; found, 281.0815.
Representative Procedure for the Enantioselective Bromo-
cyclization of 3. To a solution of acid 3a (0.1 mmol, 1.0 equiv),
catalyst 9 (6.0 mg, 0.01 mmol, 0.1 equiv) in CH2Cl2 (3.5 mL) at low
temperature in the dark under N2 was added N-bromosuccinimide
(21.2 mg, 0.12 mmol, 1.2 equiv). The resulting mixture was stirred at
−78 °C for 5 days. The reaction was quenched with saturated Na2SO3
(2.0 mL) at the reaction temperature and then was warmed to 25 °C.
The solution was diluted with water (3.0 mL) and extracted with
CH2Cl2 (3 × 5 mL). The combined extracts were washed with brine
(5.0 mL), dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography (hexane/EtOAc,
5:1) to yield the corresponding isocoumarin 4a. White solid, mp
130.7−132.5 °C: [α]D26 −70.2 (c 1.0, CHCl3, 92% ee); IR (KBr): 3013,
(E)-2-(4-Methoxystyryl)benzoic Acid (3h). White solid: 1H
NMR (300 MHz, MeOD): δ 7.89−7.84 (m, 2H), 7.77 (d, J = 8.0 Hz,
1H), 7.54−7.45 (m, 3H), 7.30 (dt, J = 7.7, 1.1 Hz, 1H), 7.04 (d, J =
16.3 Hz, 1H), 6.91 (dd, J = 6.9 Hz, 2.0 Hz, 2H), 3.80 (s, 3H); 13C
NMR (75 MHz, MeOD): δ 171.2, 161.1, 140.5, 133.1, 131.8, 131.7,
130.4, 129.1, 127.8, 127.5, 126.1, 115.1, 55.7; MS (ESI) m/z [M −
H]−: 253.1.
1
2361, 1712, 1385, 1242, 1119, 962, 698 cm−1; H NMR (300 MHz,
1
(E)-2-(3-Methylstyryl)benzoic Acid (3i). White solid: H NMR
(300 MHz, CDCl3): δ 8.11 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 16.4 Hz,
1H), 7.75 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.40−7.35 (m,
3H), 7.27 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H), 7.02 (d, J =
16.1 Hz, 1H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 172.8,
140.3, 138.2, 137.3, 133.1, 132.0, 131.6, 128.8, 128.6, 127.7, 127.34,
127.30, 127.2, 124.1, 21.4; MS (ESI) m/z [M − H]−: 237.1.
CDCl3): δ 8.15 (d, J = 7.3 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.50−
7.45 (m, 2H), 7.33−7.25 (m, 5H), 5.91 (d, J = 4.4 Hz, 1H), 5.57 (d,
J = 4.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 163.1, 137.7,
136.3, 134.6, 130.4, 129.8, 128.9, 128.8, 128.3, 126.4, 124.1, 84.1,
46.1; HRMS (EI) Calcd for C15H11O2 m/z [M − Br]+: 223.0754;
found, 223.0765; HPLC (Daicel Chiralpak IC, i-PrOH/hexane =
30/70, 0.6 mL/min, 230 nm): t1 = 18.4 min (minor), t2 = 19.8 min
(major).
1
(E)-3-Methyl-2-styryl Benzoic Acid (3j). White solid: H NMR
(300 MHz, CDCl3): δ 7.85 (d, J = 7.7 Hz, 1H), 7.55−7.45 (m, 4H),
7.38 (t, J = 7.4 Hz, 2H), 7.33−7.29 (m, 2H), 6.57 (d, J = 16.5 Hz, 1H),
2.47 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 173.8, 139.2, 137.4,
137.3, 134.6, 133.7, 129.5, 128.6, 128.5, 127.7, 126.9, 126.6, 126.5,
21.1; MS (ESI) m/z [M − H]−: 237.0.
(E)-2-Styryl Benzoic Acid (3a). White solid: 1H NMR (300 MHz,
CDCl3): δ 11.43 (brs, 1H), 8.13−8.08 (m, 2H), 7.77 (d, J = 7.9 Hz,
1H), 7.59−7.57 (m, 3H), 7.41−7.27 (m, 4H), 7.05 (d, J = 16.1 Hz,
1H); 13C NMR (75 MHz, CDCl3): δ 173.3, 140.1, 137.3, 133.1, 131.8,
131.6, 128.7, 127.9, 127.5, 127.3, 127.2, 126.9; MS (ESI) m/z
[M − H]−: 223.2.
(E)-4-Fluoro-2-styryl Benzoic Acid (3k). White solid, mp 182.2−
1
182.6 °C: IR (KBr): 3082, 2820, 1682, 1489, 1238, 826 cm−1; H
NMR (300 MHz, CDCl3): δ 8.17 (dd, J = 7.3, 2.5 Hz, 1H), 8.09 (d,
J = 16.5 Hz, 1H), 7.57 (d, J = 7.4 Hz, 2H), 7.44−7.29 (m, 4H), 7.08−
7.01 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 172.1, 165.65 (d, J =
252.7 Hz), 143.6 (d, J = 8.6 Hz), 136.9, 134.6 (d, J = 9.7 Hz), 133.0,
128.8, 128.3, 127.1, 126.5, 123.2, 114.4 (d, J = 22.1 Hz), 113.9 (d, J =
22.6 Hz); HRMS (ESI) Calcd for C15H10FO2 m/z [M − H]−:
241.0670; found, 241.0671.
(E)-2-(4-Fluorostyryl)benzoic Acid (3b). White solid, mp
149.0−150.3 °C: IR (KBr): 3069, 2972, 2863, 2632, 1683, 1507,
1
1402, 1229, 829, 748 cm−1; H NMR (300 MHz, CDCl3): δ 12.54
(brs, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 16.1 Hz, 1H), 7.73
(d, J = 7.9 Hz, 1H), 7.61−7.51 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H),
7.10−6.07 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 173.4, 162.5
(d, J = 246.3 Hz), 140.1, 133.3 (d, J = 19.4 Hz), 133.2, 131.7, 130.6,
1004
dx.doi.org/10.1021/jo202221c | J. Org. Chem. 2012, 77, 999−1009

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1
(E)-4-Chloro-2-styryl Benzoic Acid (3l). White solid: H NMR
(300 MHz, DMSO-d6): δ 7.93−7.86 (m, 3H), 7.57 (d, J = 7.3 Hz,
2H), 7.45−7.41 (m, 3H), 7.38−7.27 (m, 2H); 13C NMR (75 MHz,
DMSO-d6): δ 167.7, 140.0, 136.8, 132.3, 132.1, 128.7, 128.2, 128.1,
127.1, 126.7, 126.1, 125.5; MS (ESI) m/z [M − H]−: 257.0.
140.9, 140.0, 132.8, 131.2, 127.4, 126.9, 126.5, 126.2, 41.2, 32.8, 26.2,
26.0; MS (ESI) m/z [M − H]−: 229.1.
(3S,4R)-4-Bromo-3,4-dihydro-3-phenylisochromen-1-one
(4a).21 White solid, mp 130.7−132.5 °C: [α]D26 −70.2 (c 1.0, CHCl3,
92% ee); IR (KBr): 3013, 2361, 1712, 1385, 1242, 1119, 962, 698 cm−1;
1H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 7.3 Hz, 1H), 7.59 (t, J = 7.6
(E)-5-Fluoro-2-styryl Benzoic Acid (3m). White solid, mp
182.8−184.7 °C: IR (KBr): 2972, 2812, 1680, 1573, 1412, 1254,
1134, 984 cm−1; 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J = 16.1 Hz,
1H), 7.80 (dd, J = 9.4, 2.9 Hz, 1H), 7.73 (dd, J = 8.8, 5.6 Hz, 1H), 7.55
(d, J = 7.3 Hz, 2H), 7.41−7.26 (m, 4H), 6.98 (d, J = 16.1 Hz, 1H); 13C
NMR (75 MHz, CDCl3): δ 171.5, 161.5 (d, J = 246.8 Hz), 137.2,
136.6, 132.0, 129.3 (d, J = 7.5 Hz), 128.7, 128.5, 128.1, 126.9, 126.4,
120.5 (d, J = 21.5 Hz), 118.2 (d, J = 23.7 Hz); HRMS (ESI) Calcd for
C15H10FO2 m/z [M − H]−: 241.0670; found, 241.0680.
Hz, 1H), 7.50−7.45 (m, 2H), 7.33−7.25 (m, 5H), 5.91 (d,
J = 4.4 Hz, 1H), 5.57 (d, J = 4.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 163.1, 137.7, 136.3, 134.6, 130.4, 129.8, 128.9, 128.8, 128.3,
126.4, 124.1, 84.1, 46.1; HRMS (EI) Calcd for C15H11O2 m/z [M − Br]+:
223.0754; found, 223.0765; HPLC (Daicel Chiralpak IC,
i-PrOH/hexane = 30/70, 0.6 mL/min, 230 nm): t1 = 18.4 min (minor),
t2 = 19.8 min (major).
(R)-3-[(S)-Bromo(phenyl)methyl]isobenzofuran-1(3H)-one
(5a). White solid: 79% ee; 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J =
7.5 Hz, 1H), 7.65 (dt, J = 7.8, 1.1 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H),
7.53 (dt, J = 7.4, 0.5 Hz, 1H), 7.41 (dd, J = 8.0, 1.4 Hz, 2H), 7.34−7.28
(m, 3H), 5.94 (d, J = 6.0 Hz, 1H), 5.23 (d, J = 6.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 169.2; 146.2, 135.9, 133.8, 129.9, 129.0, 128.61,
128.57, 126.7, 125.7, 123.8, 82.5, 53.4; HPLC (Daicel Chiralpak IC, i-
PrOH/hexane = 30/70, 0.6 mL/min, 230 nm): t1 = 26.9 min (minor),
t2 = 33.4 min (major).
1
(E)-2-(3-Chlorostyryl)benzoic Acid (3n). White solid: H NMR
(300 MHz, CDCl3): δ 8.13 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 16.1 Hz,
1H), 7.72 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.52 (s, 1H),
7.45−7.24 (m, 4H), 6.95 (d, J = 16.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 172.7, 139.8, 139.2, 134.6, 133.3, 131.8, 130.4, 129.9, 129.1,
127.8, 127.6, 127.5, 127.3, 126.9, 125.0; MS (ESI) m/z [M − H]−:
257.0.
1
(E)-2-(3-Nitrostyryl)benzoic Acid (3o). Light yellow solid: H
(3S,4R)-4-Bromo-3-(4-fluorophenyl)-3,4-dihydroisochro-
men-1-one (4b). White solid, mp 113.2−115.0 °C: [α]D28 −34.6
(c 1.0, CHCl3, 91% ee); IR (KBr): 3425, 2958, 1727, 1514, 1266,
1118, 1085 cm−1; 1H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 7.9 Hz,
1H), 7.65−7.60 (m, 1H), 7.53−7.47 (m, 2H), 7.31−7.26 (m, 2H),
7.05−7.00 (m, 2H), 5.84 (d, J = 5.6 Hz, 1H), 5.51 (d, J = 5.3 Hz, 1H);
13C NMR (75 MHz, CDCl3): δ 163.0, 162.8 (d, J = 247.4 Hz), 137.7,
134.7, 132.2, 130.5, 129.9, 128.6 (d, J = 7.0 Hz), 128.5, 123.9, 115.8
(d, J = 22.1 Hz), 83.5, 46.2; HRMS (EI) Calcd for C15H10O2F m/z
[M − Br]+: 241.0659; found, 241.0655; HPLC (Daicel Chiralpak IC,
i-PrOH/hexane = 5/95, 0.6 mL/min, 230 nm): t1 = 47.7 min (minor),
t2 = 49.5 min (major).
NMR (300 MHz, DMSO-d6): δ 8.37 (s, 1H), 8.15−8.00 (m, 3H),
7.90−7.84 (m, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H),
7.43 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 16.4 Hz, 1H); 13C NMR (75
MHz, DMSO-d6): δ 168.4, 148.3, 139.1, 137.3, 132.6, 132.0, 130.4,
130.3, 130.1, 129.9, 128.4, 128.0, 127.0, 122.2, 120.9; MS (ESI) m/z
[M − H]−: 268.1.
(E)-2-[3,5-Bis(trifluoromethyl)styryl]benzoic Acid (3p). White
solid, mp 197.1−198.5 °C: IR (KBr): 3089, 2887, 2656, 1687, 1573,
1142, 1254, 984 cm−1; 1H NMR (300 MHz, acetone-d6): δ 8.34 (d, J =
16.4 Hz, 1H), 8.21 (s, 2H), 8.05 (d, J = 7.6 Hz, 1H), 7.93−7.87 (m,
2H), 7.64 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 16.4
Hz, 1H); 13C NMR (75 MHz, acetone-d6): δ 168.5, 141.5, 139.1,
133.2, 132.6 (q, J = 32.8 Hz), 131.8, 130.4, 129.1, 128.6, 128.2, 127.7,
124.5 (q, J = 270.5 Hz), 121.5; HRMS (ESI) Calcd for C17H9F6O2
m/z [M − H]−: 359.0512; found, 359.0509.
(3S,4R)-4-Bromo-3-(4-chlorophenyl)-3,4-dihydroisochro-
men-1-one (4c). White solid, mp 112.5−114.3 °C: [α]D28 −51.0
(c 1.0, CHCl3, 95% ee); IR (KBr): 3437, 3082, 2910, 2362, 1732, 1255,
1
1081, 998 cm−1; H NMR (300 MHz, CDCl3): 8.12 (d, J = 7.7 Hz,
(E)-2-(4-Trifluoromethylstyryl)benzoic Acid (3q). White solid,
mp 148.6−149.6 °C: IR (neat): 3068, 2986, 2876, 2650, 1686, 1415,
1H), 7.59 (dt, J = 7.6, 1.3 Hz, 1H), 7.49−7.44 (m, 2H), 7.30−7.19 (m,
4H), 5.81 (d, J = 5.3 Hz, 1H), 5.47 (d, J = 5.3 Hz, 1H); 13C NMR (75
MHz, CDCl3): δ 162.9, 137.6, 135.0, 134.81, 134.76, 130.5, 129.9,
129.0, 128.5, 127.9, 123.9, 83.4, 46.0; HRMS (EI) Calcd for
C15H10O2BrCl m/z [M]+: 335.9547; found, 335.9568; HPLC (Daicel
Chiralpak IA, i-PrOH/hexane = 5/95, 0.6 mL/min, 230 nm): t1 = 33.1
min (minor), t2 = 36.4 min (major).
1
1332, 1111, 1069, 821 cm−1; H NMR (300 MHz, CDCl3): δ 8.20−
8.14 (m, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.66−7.58 (m, 5H), 7.42 (t, J =
7.6 Hz, 1H), 7.03 (d, J = 16.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
δ 173.1, 140.8, 139.6, 133.4, 131.8, 130.2, 129.6 (q, J = 32.3 Hz),
127.9, 127.5, 127.3, 127.0, 125.65, 125.60, 124.2 (q, J = 269.9 Hz);
HRMS (ESI) Calcd for C16H10F3O2 m/z [M − H]−: 291.0638; found,
291.0641.
(3S,4R)-4-Bromo-3-(4-chlorophenyl)-3,4-dihydroisochro-
men-1-one (4d). White solid, mp 130.3−132.3 °C: [α]D28 −64.5
(c 1.0, CHCl3, 95% ee); IR (KBr): 3428, 2910, 2363, 1730, 1257, 1079,
1
(E)-2-(2-Chlorostyryl)benzoic Acid (3r). White solid: H NMR
(300 MHz, CDCl3): δ 8.13 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 16.4 Hz,
1H), 7.79 (t, J = 8.5 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.45−7.39 (m,
3H), 7.31−7.20 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 172.9,
140.0, 135.4, 133.6, 133.3, 131.7, 130.1, 129.7, 128.8, 127.81, 127.77,
127.7, 127.3, 127.1, 127.0; MS (ESI) m/z [M − H]−: 257.1.
2-Vinylbenzoic Acid (3s). White solid: 1H NMR (300 MHz,
CDCl3): δ 8.07 (d, J = 7.6 Hz, 1H), 7.65−7.53 (m, 3H), 7.38 (t, J =
7.6 Hz, 1H), 5.68 (d, J = 16.8 Hz, 1H), 5.40 (d, J = 10.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3): δ 173.0, 140.7, 136.1, 133.1, 131.3, 127.7,
127.5, 127.1, 116.8; MS (ESI) m/z [M − H]−: 147.0.
1
997, 740 cm−1; H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 7.6 Hz,
1H), 7.62 (t, J = 8.2 Hz, 1H), 7.52−7.45 (m, 4H), 7.18 (d, J = 8.5 Hz,
2H), 5.83 (d, J = 5.3 Hz, 1H), 5.50 (d, J = 5.3 Hz, 1H); 13C NMR (75
MHz, CDCl3): δ 162.9, 137.6, 135.3, 134.8, 132.0, 130.5, 129.9, 128.4,
128.2, 123.9, 123.2, 83.4, 45.9; HRMS (ESI) Calcd for C15H10O2Br2
m/z [M]+: 379.9042; found, 379.9046; HPLC (Daicel Chiralpak IA,
i-PrOH/hexane = 5/95, 0.6 mL/min, 230 nm): t1 = 35.5 min (minor),
t2 = 40.4 min (major).
(3S,4R)-4-Bromo-3,4-dihydro-3-p-tolylisochromen-1-one
(4e). White solid, mp 104.6−106.2 °C: [α]D28 −73.4 (c 1.0, CHCl3,
83% ee); IR (KBr): 3033, 1717, 1599, 1264, 1119, 987 cm−1; 1H NMR
(300 MHz, CDCl3): δ 8.15 (d, J = 7.7 Hz, 1H), 7.59 (dt, J = 7.6, 1.5
Hz, 1H), 7.47 (t, J = 7.9 Hz, 2H), 7.17−7.10 (m, 4H), 5.88 (d, J = 4.4
Hz, 1H), 5.54 (d, J = 4.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 163.2, 138.9, 137.8, 134.5, 133.4, 130.4, 129.8, 129.5, 128.3,
126.3, 124.2, 84.1, 46.2, 21.1; HRMS (ESI) Calcd for C16H13BrO2 m/z
[M − Br]+: 237.0910; found, 237.0912; HPLC (Daicel Chiralpak IA,
i-PrOH/hexane = 5/95, 0.6 mL/min, 230 nm): t1 = 26.7 min (minor),
t2 = 29.4 min (major).
1
2-[(E)-pent-1-enyl] Benzoic Acid (3t). Colorless oil: H NMR
(300 MHz, CDCl3): δ 11.19 (brs, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.58
(d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.33−7.26 (m, 2H), 6.13
(dt, J = 15.9 Hz, 6.8 Hz, 1H), 2.27 (dt, J = 7.1 Hz, 2H), 1.55 (tq, J =
7.4 Hz, 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 173.5, 140.7, 134.2, 132.9, 131.2, 128.7, 127.5, 126.8, 126.5,
35.2, 22.4, 13.7; MS (ESI) m/z [M − H]−: 189.1.
1
2-[(E)-2-Cyclohexylvinyl] Benzoic Acid (3u). Colorless oil: H
NMR (300 MHz, CDCl3): δ 11.10 (brs, 1H), 8.04 (d, J = 7.7 Hz, 1H),
7.59 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.33−7.24 (m, 2H),
6.13 (dd, J = 15.8 Hz, 6.7 Hz, 1H), 2.24−2.17 (m, 1H), 1.89−1.69 (m,
4H), 1.42−1.18 (m, 5H); 13C NMR (75 MHz, CDCl3): δ 173.6,
(3S,4R)-4-Bromo-3,4-dihydro-3-(naphthalen-2-yl)isochromen-1-
one (4f). White solid, mp 145.0−146.5 °C: [α]D28 −95.3 (c 1.0, CHCl3,
88% ee); IR (KBr): 3439, 2910, 1732, 1459, 1255, 1113, 1003 cm−1;
1005
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Article
cm−1; 1H NMR (300 MHz, CDCl3): δ 8.09 (d, J = 8.2 Hz, 1H), 7.48−
7.28 (m, 7H), 5.88 (d, J = 5.0 Hz, 1H), 5.49 (d, J = 5.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3): δ 162.3, 141.0, 139.4, 136.0, 132.0, 130.3,
129.2, 128.9, 128.5, 126.4, 122.5, 84.0, 45.1; HRMS (EI) Calcd for
C15H10O2Cl m/z [M − Br]+: 257.0364; found, 257.0358; HPLC
(Daicel Chiralpak IC, i-PrOH/hexane = 30/70, 0.6 mL/min, 230 nm):
t1 = 15.9 min (minor), t2 = 17.2 min (major).
1H NMR (300 MHz, CDCl3): δ 8.19 (d, J = 7.3 Hz, 1H), 7.83−7.73
(m, 4H), 7.60−7.45 (m, 5H), 7.39 (dd, J = 8.5, 1.7 Hz, 1H), 6.08 (d,
J = 4.4 Hz, 1H), 5.69 (d, J = 4.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 163.2, 137.7, 134.6, 133.6, 133.1, 132.8, 130.4, 129.9, 128.8,
128.3, 128.2, 127.6, 126.8, 126.7, 126.1, 124.1, 123.3, 84.2, 46.0;
HRMS (EI) Calcd for C19H13O2Br m/z [M]+: 352.0093; found,
352.0104; HPLC (Daicel Chiralpak IA, i-PrOH/hexane = 5/95, 0.6
mL/min, 230 nm): t1 = 37.3 min (minor), t2 = 40.3 min (major).
(3S,4R)-4-Bromo-3-(4-acetoxyphenyl)-3,4-dihydroisochro-
men-1-one (4g). White solid, mp 136.6−138.5 °C: [α]D25 −58.6
(c 1.0, CHCl3, 80% ee); IR (KBr): 3445, 2951, 1755, 1705, 1511, 1212,
(3S,4R)-4-Bromo-7-fluoro-3,4-dihydro-3-phenylisochromen-
1-one (4m). White solid, mp 120.0−121.3 °C: [α]D27 −75.9 (c 1.0,
CHCl3, 93% ee); IR (KBr): 3422, 3082, 2958, 1716, 1486, 1274, 1064,
1
982 cm−1; H NMR (300 MHz, CDCl3): δ 7.83 (dd, J = 8.2, 2.3 Hz,
1
1118, 985 cm−1; H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 7.6 Hz,
1H), 7.47 (dd, J = 8.5, 5.0 Hz, 1H), 7.34−7.25 (m, 6H), 5.93 (d, J =
4.4 Hz, 1H), 5.55 (d, J = 4.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
δ 162.9 (d, J = 250.1 Hz), 162.1, 136.1, 133.8, 130.7 (d, J = 7.5 Hz),
129.1, 128.9, 126.3, 122.0 (d, J = 22.0 Hz), 117.0 (d, J = 23.7 Hz),
84.4, 45.1; HRMS (EI) Calcd for C15H10O2F m/z [M − Br]+:
241.0659; found, 241.0659; HPLC (Daicel Chiralpak IC, i-PrOH/
hexane = 30/70, 0.6 mL/min, 230 nm): t1 = 13.5 min (minor), t2 =
14.6 min (major).
(3S,4R)-4-Bromo-3-(3-chlorophenyl)-3,4-dihydroisochro-
men-1-one (4n). White solid, mp 119.0−121.0 °C: [α]D26 −25.4
(c 1.0, CHCl3, 96% ee); IR (KBr): 3420, 2923, 1719, 1599, 1373, 1239,
1118, 1049 cm−1; 1H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 7.3 Hz,
1H), 7.63 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.32−7.24 (m,
3H), 7.18 (d, J = 7.0 Hz, 1H), 5.83 (d, J = 5.3 Hz, 1H), 5.52 (d, J = 5.3
Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 162.8, 138.3, 137.5, 134.8,
130.5, 130.1, 129.9, 129.3, 128.5, 126.8, 124.8, 123.9, 83.3, 45.8;
HRMS (EI) Calcd for C15H10O2Cl m/z [M − Br]+: 257.0364; found,
257.0360; HPLC (Daicel Chiralpak IB, i-PrOH/hexane = 25/75, 0.6
mL/min, 230 nm): t1 = 14.4 min (minor), t2 = 16.2 min (major).
(S)-3-[(R)-Bromo(3-chlorophenyl)methyl]isobenzofuran-
1(3H)-one (5n). White solid, mp 101.1−103.1 °C: [α]D25−24.3 (c 1.0,
CHCl3, 66% ee); IR (KBr): 3486, 1759, 1472, 1286, 1078, 982 cm−1;
1H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 7.6 Hz, 1H), 7.71−7.67
1H), 7.62 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 8.8
Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 5.90 (d, J = 4.4 Hz, 1H), 5.53 (d,
J = 4.4 Hz, 1H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 169.1,
162.9, 150.9, 137.6, 134.7, 133.8, 130.5, 129.9, 128.5, 127.7, 124.0,
122.0, 83.6, 45.9, 21.1; HRMS (EI) Calcd for C17H13O4Br m/z [M]+:
359.9992; found, 359.9986; HPLC (Daicel Chiralpak IB, i-PrOH/
hexane = 30/70, 0.6 mL/min, 230 nm): t1 = 19.7 min (minor), t2 =
22.1 min (major).
(3S,4R)-4-Bromo-3-(4-methoxyphenyl)-3,4-dihydroisochro-
men-1-one (4h). White solid, mp 108.0−109.8 °C: 24% ee; IR
(KBr): 3402, 2962, 1704, 1607, 1518, 1256, 1121, 1022, 980 cm−1; 1H
NMR (300 MHz, CDCl3): δ 8.14 (d, J = 8.5 Hz, 1H), 7.61 (dt, J = 7.4,
1.3 Hz, 1H), 7.48 (dt, J = 7.4, 1.2 Hz, 2H), 7.18 (dt, J = 8.5, 2.8 Hz,
2H), 6.83 (dt, J = 8.9, 2.8 Hz, 2H), 5.84 (d, J = 5.0 Hz, 1H), 5.53 (d,
J = 4.8 Hz, 1H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 163.2,
159.9, 137.9, 134.6, 130.4, 129.8, 128.43, 128.36, 127.9, 124.1, 114.1,
83.9, 55.2, 46.4; HRMS (EI) Calcd for C16H13O3Br m/z [M]+:
332.0043; found, 332.0045; HPLC (Daicel Chiralpak IC, i-PrOH/
hexane = 30/70, 0.6 mL/min, 230 nm): t1 = 26.5 min (major), t2 =
29.4 min (minor).
(3S,4R)-4-Bromo-3-(3-methylphenyl)-3,4-dihydroisochro-
men-1-one (4i). White solid, mp 124.6−126.3 °C: [α]D27 −71.2 (c 1.0,
CHCl3, 90% ee); IR (KBr): 3421, 3014, 2919, 1722, 1376, 1242, 1114,
(m, 2H), 7.60−7.53 (m, 1H), 7.40 (s, 1H), 7.33−7.27 (m, 3H), 5.91
(d, J = 6.4 Hz, 1H), 5.09 (d, J = 6.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 168.9, 146.1, 138.2, 134.5, 134.0, 130.2, 129.9, 129.3, 128.7,
126.8, 126.6, 125.9, 123.8, 82.1, 52.1; HRMS (EI) Calcd for
C15H10O2Cl m/z [M − Br]+: 257.0364; found, 257.0369; HPLC
(Daicel Chiralpak IC, i-PrOH/hexane = 30/70, 0.6 mL/min, 230 nm):
t1 = 22.2 min (minor), t2 = 23.4 min (major).
1
1050, 695 cm−1; H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 7.3 Hz,
1H), 7.59 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.3 Hz, 2H), 7.19 (t, J = 7.9
Hz, 1H), 7.12−7.10 (m, 2H), 7.04 (d, J = 7.6 Hz, 1H), 5.88 (d, J = 4.4
Hz, 1H), 5.57 (d, J = 4.4 Hz, 1H), 2.31 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 163.2, 138.6, 137.8, 136.2, 134.5, 130.4, 129.8, 129.7, 128.6,
128.3, 127.0, 124.1, 123.4, 84.1, 46.1, 21.4; HRMS (EI) Calcd for
C16H13O2 m/z [M − Br]+: 237.0910; found, 237.0906; HPLC (Daicel
Chiralpak IC, i-PrOH/hexane = 15/85, 0.6 mL/min, 254 nm): t1 =
29.8 min (major), t2 = 31.6 min (minor).
(3S,4R)-4-Bromo-3,4-dihydro-5-methyl-3-phenylisochro-
men-1-one (4j). White solid, mp 133.4−135.1 °C: [α]D26 −111.8
(c 1.0, CHCl3, 84% ee); IR (KBr): 3409, 3024, 1712, 1447, 1377, 1263,
1126, 1077 cm−1; 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J = 8.6 Hz,
1H), 7.40−7.24 (m, 5H), 7.16 (d, J = 7.6 Hz, 2H), 6.10 (s, 1H), 5.63
(d, J = 0.6 Hz, 1H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3):
δ 163.2, 136.8, 136.2, 135.7, 135.4, 129.6, 128.9, 128.6, 128.3, 125.6,
124.6, 83.7, 42.7, 17.9; HRMS (EI) Calcd for C16H13O2 m/z [M −
Br]+: 237.0910; found, 237.0909; HPLC (Daicel Chiralpak IC,
i-PrOH/hexane = 30/70, 0.6 mL/min, 230 nm): t1 = 16.7 min (major),
t2 = 20.8 min (minor).
(3S,4R)-4-Bromo-3-(3-nitrophenyl)-3,4-dihydroisochromen-
1-one (4o). White solid, mp 125.0−127.0 °C: [α]D25 +23.4 (c 0.5,
CHCl3, 98% ee); IR (KBr): 3421, 3074, 2950, 1714, 1525, 1350, 1263,
1114, 1082, 996, 737 cm−1; 1H NMR (300 MHz, CDCl3): δ 8.26−8.16
(m, 3H), 7.74−7.51 (m, 5H), 5.89 (d, J = 6.4 Hz, 1H), 5.56 (d, J = 6.7
Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 162.6, 148.3, 138.4, 137.4,
135.0, 132.9, 130.7, 130.1, 130.0, 128.7, 124.2, 122.0, 82.9, 45.9;
HRMS (EI) Calcd for C15H10NO4 m/z [M − Br]+: 268.0604; found,
268.0600; HPLC (Daicel Chiralpak IA, i-PrOH/hexane = 30/70, 0.6
mL/min, 230 nm): t1 = 18.3 min (major), t2 = 21.0 min (minor).
3-[Bromo(3-nitrophenyl)methyl]isobenzofuran-1(3H)-one
(5o). White solid, mp 142.4−144.1 °C: [α]D25 +12.8 (c 1.0, CHCl3,
−47% ee); IR (KBr): 3500, 3079, 1760, 1529, 1349, 1073, 980, 692
1
cm−1; H NMR (300 MHz, CDCl3): δ 8.22 (s, 1H), 8.17 (d, J = 8.2
Hz, 1H), 7.86−7.80 (m, 3H), 7.72 (t, J = 7.2 Hz, 1H), 7.61−7.52 (m,
2H), 6.00 (d, J = 7.0 Hz, 1H), 5.14 (d, J = 6.7 Hz, 1H); 13C NMR (75
MHz, CDCl3): δ 168.7, 148.1, 145.9, 138.5, 134.7, 134.3, 130.4, 129.8,
126.3, 126.1, 123.9, 123.8, 123.4 81.8, 50.9; HRMS (EI) Calcd for
C15H10NO4 m/z [M − Br]+: 268.0604; found, 268.0610; HPLC
(Daicel Chiralpak IA, i-PrOH/hexane = 50/50, 0.6 mL/min, 230 nm):
t1 = 26.6 min (minor), t2 = 32.4 min (major).
3-{[3,5-Bis(trifluoromethyl)phenyl]bromomethyl}-
isobenzofuran-1(3H)-one (5p). White solid, mp 98.7−100.7 °C:
[α]D27 −3.7 (c 1.0, CHCl3, −34% ee); IR (KBr): 3492, 1758, 1283,
1189, 1126, 985 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.85−7.80 (m,
5H), 7.73 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.3 Hz, 1H), 5.99 (d, J = 7.0
Hz, 1H), 5.14 (d, J = 7.0 Hz, 1H); 13C NMR (75 MHz, CDCl3):
δ 168.5, 145.7, 139.2, 134.3, 132.2 (q, J = 33.9), 130.5, 128.8, 126.3,
126.2, 123.8, 123.0, 122.8 (q, J = 271.0), 81.5, 50.5; HRMS (EI) Calcd
(3S,4R)-4-Bromo-6-fluoro-3,4-dihydro-3-phenylisochromen-
1-one (4k). White solid, mp 122.0−124.0 °C: [α]D25 −18.6 (c 1.0,
CHCl3, 90% ee); IR (KBr): 3415, 2921, 1713, 1612, 1260, 1107, 985
cm−1; 1H NMR (300 MHz, CDCl3): δ 8.18 (dd, J = 8.8, 5.6 Hz, 1H),
7.36−7.27 (m, 5H), 7.20 (dd, J = 8.8, 2.3 Hz, 1H), 7.14 (dd, J = 8.5,
2.3 Hz, 1H), 5.86 (d, J = 5.3 Hz, 1H), 5.50 (d, J = 5.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3): δ 166.1 (d, J = 256.5 Hz), 162.2, 140.9 (d,
J = 9.1 Hz), 136.0, 133.6 (d, J = 9.7 Hz), 129.2, 128.9, 126.5, 120.5,
117.4 (d, J = 22.1 Hz), 115.6 (d, J = 23.7 Hz), 84.0, 45.4; HRMS (EI)
Calcd for C15H10O2F m/z [M − Br]+: 241.0659; found, 241.0657;
HPLC (Daicel Chiralpak IC, i-PrOH/hexane = 30/70, 0.6 mL/min,
230 nm): t1 = 16.0 min (minor), t2 = 17.4 min (major).
(3S,4R)-4-Bromo-6-chloro-3,4-dihydro-3-phenylisochromen-
1-one (4l). White solid, mp 121.1−123.0 °C: [α]D26 −27.2 (c 1.0,
CHCl3, 89% ee); IR (KBr): 3412, 3027, 1712, 1596, 1376, 1259, 1104
1006
dx.doi.org/10.1021/jo202221c | J. Org. Chem. 2012, 77, 999−1009

The Journal of Organic Chemistry
Article
for C17H9O2F6 m/z [M]+: 359.0501; found, 359.0496; HPLC (Daicel
Chiralpak IA, i-PrOH/hexane = 5/95, 0.6 mL/min, 230 nm): t1 = 22.5
min (minor), t2 = 27.6 min (major).
i-PrOH/hexane = 25/75, 0.6 mL/min, 254 nm): t1 = 20.1 min (minor),
t2 = 24.1 min (major).
3-[Bromo(cyclohexyl)methyl]isobenzofuran-1(3H)-one (5u).
White solid, mp 137.0−139.0 °C: −28% ee; IR (KBr): 3444, 2926,
2852, 1764, 1471, 1295, 1078, 977 cm−1; 1H NMR (300 MHz,
CDCl3): δ 7.93 (t, J = 8.2 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.69 (t, J =
7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 5.70 (d, J = 8.8 Hz, 1H), 3.95
(dd, J = 8.5 Hz, 3.8 Hz, 1H), 2.07−2.00 (m, 2H), 1.83−1.54 (m, 4H),
1.50−1.18 (m, 5H); 13C NMR (75 MHz, CDCl3): δ 169.5, 147.8,
133.9, 129.8, 126.3, 125.7, 124.4, 79.5, 62.5, 40.2, 31.5, 28.1, 26.1, 25.9,
25.5; HRMS (EI) Calcd for C15H17O2 m/z [M − Br]+: 229.1223;
found, 229.1225; HPLC (Daicel Chiralpak IB, i-PrOH/hexane =
25/75, 0.6 mL/min, 230 nm): t1 = 17.5 min (major), t2 = 26.3 min
(minor).
(3S,4R)-4-Bromo-3-[4-(trifluoromethyl)phenyl]-3,4-dihydroi-
sochromen-1-one (4q). White solid, mp 101.7−103.2 °C: [α]D28
−84.2 (c 0.5, CHCl3, 88% ee); IR (KBr): 3424, 2957, 2361, 1727,
1
1327, 1166, 1109 cm−1; H NMR (300 MHz, CDCl3): δ 8.17 (d, J =
7.6 Hz, 1H), 7.66−7.60 (m, 3H), 7.53−7.44 (m, 4H), 5.92 (d, J = 5.3
Hz, 1H), 5.54 (d, J = 5.3 Hz, 1H); 13C NMR (75 MHz, CDCl3):
δ 162.7, 140.1, 137.4, 134.9, 131.2 (q, J = 32.8 Hz), 130.6, 130.0, 128.5,
127.0, 125.8 (q, J = 3.8 Hz), 123.8, 123.6 (J = 271.0 Hz), 83.3, 45.7;
HRMS (EI) Calcd for C16H10O2BrF3 m/z [M]+: 369.9811; found,
369.9815; HPLC (Daicel Chiralpak IC, i-PrOH/hexane = 5/95, 0.6
mL/min, 230 nm): t1 = 31.8 min (minor), t2 = 33.3 min (major).
(S)-3-{(R)-Bromo[4-(trifluoromethyl)phenyl]methyl}-
isobenzofuran-1(3H)-one (5q) (From Table 3, Entry 17).
Colorless oil: [α]D28 −11.1 (c 0.9, CHCl3, 53% ee); IR (KBr): 3474,
3037, 1756, 1450, 1280, 1180, 985 cm−1; 1H NMR (300 MHz,
CDCl3): δ 7.84 (d, J = 7.6 Hz, 1H), 7.72−7.52 (m, 7H), 5.96 (d, J =
6.4 Hz, 1H), 5.17 (d, J = 6.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
δ 168.8, 146.0, 140.1, 134.1, 130.9 (q, J = 32.3 Hz), 130.2, 129.1,
126.5, 126.0, 125.7 (q, J = 3.9 Hz), 123.69, 123.65 (q, J = 271.0 Hz),
82.1, 51.8; HRMS (EI) Calcd for C16H10O2BrF3 m/z [M]+: 369.9811;
found, 369.9819; HPLC (Daicel Chiralpak IC, i-PrOH/hexane = 5/95,
0.6 mL/min, 230 nm): t1 = 61.1 min (minor), t2 = 69.0 min (major).
(R)-3-[4-(Trifluoromethyl)benzyl]isobenzofuran-1(3H)-one
(5q′).18 To a solution of 5q (from Table 3, entry 17) (37 mg, 0.1
mmol, 1.0 equiv) in toluene (1.5 mL) was added AIBN (1.6 mg, 0.01
mmol, 0.1 equiv) and Ph3SnH (77 μL, 0.3 mmol, 3.0 equiv). The
mixture was refluxed for 2 h, then cooled to 25 °C, and concentrated
in vacuo. The residue was purified by flash column chromatography
(hexane/EtOAc, 3:1) to give phthalide 10r′ (27 mg, 92%) as a white
Amino-Thiocabamate 8b. 71%, light yellow solid, mp 82.6−84.6 °C:
[α]D28 −112.2 (c 1.2, CHCl3); IR (KBr): 2942, 1622, 1510, 1359, 1231,
1
991 cm−1; H NMR (the compound existed as a mixture of rotamers,
and the major rotamer was assigned) (300 MHz, CDCl3): δ 8.88
(d, J = 4.6 Hz, 1H), 8.69 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.12 (d,
J = 8.4 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.60−7.57 (m, 2H), 7.43−
7.40 (m, 2H), 7.16−7.00 (m, 2H), 6.89 (d, J = 8.1 Hz, 1H), 6.13−5.90
(m, 1H), 5.09 (d, J = 16.8 Hz, 2H), 3.82 (s, 3H), 3.52−3.32 (m, 1H),
2.93−2.69 (m, 4H), 2.27−2.24 (m, 1H), 1.99−1.74 (m, 2H), 1.56−
1.52 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 149.9, 149.3, 148.5,
145.4, 140.4, 130.3, 129.1, 126.6, 126.4, 125.7, 124.0, 120.6, 119.2,
114.9, 110.6, 60.6, 55.7, 49.7, 49.2, 40.0, 37.5, 27.9, 26.4, 12.0; HRMS
(ESI) Calcd for C27H30N3O2S m/z [M + H]+: 460.2053; found,
460.2059.
Amino-Thiocabamate 8d. 82%, white solid, mp 191.0−192.6 °C:
[α]D28 +6.0 (c 1.0, CHCl3); IR (KBr): 2931, 1623, 1511, 1247, 1166,
1033 cm−1; 1H NMR (the compound existed as a mixture of rotamers,
and the major rotamer was assigned) (300 MHz, CDCl3): δ 8.83 (d,
J = 4.4 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H),
7.68−7.62 (m, 2H), 7.47−7.42 (m, 1H), 7.32 (d, J = 4.4 Hz, 1H), 7.20
(d, J = 8.7 Hz, 1H), 6.09 (s, 2H), 5.82−5.70 (m, 1H), 5.05−4.97 (m,
2H), 3.86 (s, 3H), 3.57 (s, 6H), 3.24−3.15 (m, 1H), 2.86−2.82 (m,
2H), 2.64−2.59 (m, 2H), 2.17−2.14 (m, 2H), 1.88−1.80 (m, 1H),
1.66 (br, 1H), 1.53−1.42 (m, 2H); 13C NMR (75 MHz, CDCl3):
δ 190.4, 160.7, 156.5, 149.7, 148.6, 145.2, 140.5, 130.1, 128.7, 126.3,
126.1, 124.3, 119.8, 114.7, 90.4, 81.4, 60.0, 55.4, 49.5, 49.1, 40.7, 28.3,
26.3, 23.3; HRMS (ESI) Calcd for C29H34N3O4S m/z [M + H]+:
520.2265; found, 520.2274.
solid: [α]D26 +44.0 (c 0.89, CHCl3, 53% ee); H NMR (400 MHz,
1
CDCl3): δ 7.85 (d, J = 7.6 Hz, 1H), 7.68−7.64 (m, 1H), 7.55−7.51
(m, 3H), 7.35−7.30 (m, 3H), 5.71 (t, J = 6.1 Hz, 1H), 3.33 (dd, J =
14.3, 5.4 Hz, 1H), 3.24 (dd, J = 14.3, 6.9 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 169.9, 148.6, 139.1, 134.0, 130.0, 129.7, 129.5, 129.3,
126.2, 125.9, 125.41 (q, J = 3.6 Hz), 124.1 (q, J = 269.8 Hz), 80.5,
40.6. (The data are in full accordance with the literature in all
respects.)18
(3S,4R)-4-Bromo-3-(2-chlorophenyl)-3,4-dihydroisochro-
men-1-one (5r). White solid, mp 114.2−116.2 °C: −32% ee; IR
(KBr): 3445, 1762, 1468, 1285, 1057, 960 cm−1; 1H NMR (300 MHz,
CDCl3): δ 7.86 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.68−
7.40 (m, 3H), 7.35−7.25 (m, 3H), 6.00 (d, J = 6.1 Hz, 1H), 5.80 (d,
J = 6.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 169.1, 146.0, 133.8,
132.9, 131.1, 130.2, 130.1, 129.7, 127.4, 126.7, 125.8, 124.0, 81.3, 48.4;
HRMS (EI) Calcd for C15H10O2Cl m/z [M − Br]+: 257.0364; found,
257.0364; HPLC (Daicel Chiralpak IB, i-PrOH/hexane = 5/95,
0.6 mL/min, 230 nm): t1 = 22.3 min (major), t2 = 26.2 min (minor).
3-(Bromomethyl)isobenzofuran-1-(3H)-one (5s). White solid,
mp 60.2−62.2 °C: [α]D27 −27.2 (c 1.0, CHCl3, −34% ee); IR (KBr):
Amino-Thiocabamate 15. 76%, light yellow solid: 1H NMR (the
compound existed as a mixture of rotamers, and the major rotamer
was assigned) (400 MHz, CDCl3): δ 8.72 (d, J = 4.5 Hz, 1H), 8.38 (s,
1H), 7.98 (d, J = 9.3 Hz, 1H), 7.58 (s, 1H), 7.44−7.33 (m, 3H), 6.48
(d, J = 2.4 Hz, 1H), 6.46 (s, 1H), 6.09−5.92 (m, 1H), 5.29−5.05 (m,
2H), 4.15−4.05 (m, 2H), 3.82 (s, 6H), 3.44−3.41 (m, 1H), 2.90−2.71
(m, 4H), 2.25−2.10 (m, 3H), 2.02−1.74 (m, 4H), 1.56−1.49 (m, 3H),
0.99 (d, J = 6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 188.0,
157.3, 151.4, 147.2, 144.7, 143.4, 140.3, 131.4, 127.6, 124.1, 122.4,
119.5, 114.8, 104.0, 102.7, 98.8, 80.6, 66.9, 60.0, 55.5, 49.2, 40.3, 37.8,
27.9, 26.4, 25.1, 24.4, 22.6.
1
3492, 3056, 1753, 1466, 1287, 1210, 1061, 966 cm−1; H NMR (300
MHz, CDCl3): δ 7.93 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H),
7.64−7.57 (m, 2H), 5.70 (t, J = 5.0 Hz, 1H), 3.77 (d, J = 5.3 Hz, 1H);
13C NMR (75 MHz, CDCl3): δ 169.3, 147.1, 134.3, 130.0, 126.5,
125.9, 122.4, 78.6, 32.1; HRMS (EI) Calcd for C9H7O2Br m/z [M]+:
225.9624; found, 225.9628; HPLC (Daicel Chiralpak IA, i-PrOH/
hexane = 15/85, 0.6 mL/min, 254 nm): t1 = 15.6 min (minor), t2 =
21.8 min (major).
3-(1-Bromobutyl)isobenzofuran-1(3H)-one (5t). Colorless oil:
−12% ee; IR (KBr): 3453, 2922, 2847, 1774, 1475, 1289, 1076 cm−1;
1H NMR (300 MHz, CDCl3): δ 7.93 (d, J = 7.6 Hz, 1H), 7.75 (d, J =
7.5 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 5.60 (d,
J = 5.9 Hz, 1H), 4.21 (dd, J = 13.4 Hz, 6.2 Hz, 1H), 1.79−1.67 (m,
1H), 1.67−1.45 (m, 1H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 169.4, 146.9, 134.0, 129.9, 126.8, 125.8, 123.6, 82.3,
54.8, 36.0, 20.3, 13.2; HRMS (EI) Calcd for C12H13O2 m/z [M −
Br]+: 189.0910; found, 189.0917; HPLC (Daicel Chiralpak IB,
(R)-3,4-Dihydro-3-phenylisochromen-1-one (10). To a solu-
tion of 4a (61 mg, 0.2 mmol, 1.0 equiv) in toluene (2 mL) was added
AIBN (1.6 mg, 0.01 mmol, 0.05 equiv) and Ph3SnH (153 μL,
0.6 mmol, 3.0 equiv). The mixture was refluxed for 2 h, then cooled to
25 °C, and concentrated in vacuo. The residue was purified by flash
column chromatography (hexane/EtOAc, 7:1) to give lactone 10 (42
mg, 93%) as a white solid, mp 81.5−83.4 °C: [α]D25 +168.5 (c 1.0,
CHCl3, 93% ee); IR (neat): 3434, 2363, 1717, 1275, 1119, 1071 cm−1;
1H NMR (300 MHz, CDCl3): δ 8.15 (d, J = 7.9 Hz, 1H), 7.57 (t, J =
7.5 Hz, 1H), 7.49−7.34 (m, 6H), 7.29 (d, J = 7.6 Hz, 1H), 5.56 (dd,
J = 12.0, 2.9 Hz, 1H), 3.34 (dd, J = 16.4, 12.0 Hz, 1H), 3.13 (dd, J =
16.7, 2.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 165.2, 138.9, 138.6,
133.9, 130.4, 128.6, 127.8, 127.3, 126.1, 125.1, 79.9, 35.5; HRMS (EI)
Calcd for C15H12O2 m/z [M]+: 224.0832; found, 224.0838; HPLC
(Daicel Chiralpak IA, i-PrOH/hexane = 10/90, 0.6 mL/min, 230 nm):
t1 = 21.0 min (major), t2 = 24.6 min (minor).
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The Journal of Organic Chemistry
Article
(3S,4S)-3,4-Dihydro-1-oxo-3-phenyl-1H-isochromen-4-yl Ac-
etate (11). To a stirred solution of 4a (61 mg, 0.2 mmol) in DMSO
(4 mL) was added CH3CO2K (59 mg, 0.6 mmol) at rt. The reaction
mixture was then stirred for 3 days and diluted with water (10 mL)
and extracted with EtOAc (3 × 10 mL). The combined organic layers
were washed with water (3 × 20 mL) and brine (20 mL) and then
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/EtOAc, 5:1) to
give acetate 11 (48 mg, 85%) as a white solid: [α]D28 +265.3 (c 2.0,
CHCl3, 93% ee); 1H NMR (300 MHz, CDCl3): δ 8.23 (dd, J = 8.1, 1.5
Hz, 1H), 7.70−7.57 (m, 3H), 7.51 (dd, J = 8.2, 1.4 Hz, 2H), 7.44−
7.36 (m, 3H), 6.12 (d, J = 2.0 Hz, 1H), 5.73 (d, J = 1.5 Hz, 1H), 1.83
(s, 3H); 13C NMR (75 MHz, CDCl3): δ 169.6, 164.2, 136.3, 134.8,
134.3, 130.4, 129.0, 128.7, 128.4, 126.5, 125.1, 80.7, 67.9, 20.5; HRMS
(ESI) Calcd for C17H14O4Na m/z [M + Na]+: 305.0784; found,
305.0789; HPLC (Daicel Chiralpak IA, i-PrOH/hexane = 10/90,
0.6 mL/min, 230 nm): t1 = 19.8 min (major), t2 = 22.2 min (minor).
(3S,4S)-4-Azido-3,4-dihydro-3-phenylisochromen-1-one
(12). To a solution of 4a (61 mg, 0.2 mmol, 1.0 equiv) in DMF
(2 mL) was added NaN3 (39 mg, 0.6 mmol, 3.0 equiv) at 25 °C. The
mixture was refluxed at 65 °C for 24 h; then water (7 mL) was added.
The mixture was extracted with EtOAc (3 × 6 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography (hexane/EtOAc, 5:1) to give azide
12 (48 mg, 90%) as a white solid, mp 92.4−96.3 °C: [α]D25 +287.1
(c 2.0, CHCl3, 93% ee); IR (neat): 3425, 3066, 2106, 1723, 1268, 1116,
1091 cm−1; 1H NMR (300 MHz, CDCl3): δ 8.28 (d, J = 7.6 Hz, 1H),
7.75 (dt, J = 7.6, 1.2 Hz, 1H), 7.65 (dt, J = 7.6, 0.9 Hz, 1H), 7.54 (d,
J = 7.3 Hz, 2H), 7.50−7.39 (m, 4H), 5.71 (d, J = 1.8 Hz, 1H), 4.69 (d,
J = 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 163.7, 135.9, 135.0,
134.5, 131.2, 130.6, 129.0, 128.6, 127.8, 126.4, 124.5, 80.5 60.8; HRMS
(EI) Calcd for C15H11NO2 [M − N2]+: 237.0784; found, 237.0789;
HPLC (Daicel Chiralpak IA, i-PrOH/hexane = 10/90, 0.6 mL/min,
254 nm): t1 = 21.8 min (major), t2 = 32.6 min (minor).
(3R,4S)-3,4-Dihydro-3-phenyl-1H-isochromen-4-ol (14). To a
solution of lactone 4a (121 mg, 0.4 mmol, 1.0 equiv) in anhydrous Et2O
(6 mL) was added LiAlH4 (38 mg, 1.0 mmol, 2.5 equiv) at −40 °C under
N2. After stirring for 3 h at the same temperature, the reaction was
quenched with water (0.1 mL). The resulting mixture was warmed to
25 °C and filtered through a thin pad of silica gel eluted with EtOAc
(10 mL). The filtrate was concentrated in vacuo and the residue was purified
by flash column chromatography (hexane/EtOAc, 2:1) to give epoxide 13
(41 mg, 45%). A solution of epoxide (34 mg, 0.15 mmol, 1.0 equiv) and
PPTS (7.5 mg, 0.03 mmol, 0.2 equiv) in CH2Cl2 (2 mL) was stirred at 25
°C overnight. The reaction was quenched with saturated NaHCO3 (3 mL)
and extracted with CH2Cl2 (3 × 3 mL). The combined organic fractions
were dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane/EtOAc, 2:1) to give
alcohol 14 (29 mg, 85%) as a white solid, mp 100.6−102.6 °C: [α]D25
−116.1 (c 1.0, CHCl3, 92% ee); 1H NMR (300 MHz, CDCl3): δ 7.62 (d,
J = 6.8 Hz, 1H), 7.50−7.28 (m, 7H), 7.06 (d, J = 6.9 Hz, 1H), 5.01 (d, J =
15.1 Hz, 1H), 4.93 (d, J = 15.1 Hz, 1H), 4.81 (d, J = 8.4 Hz, 1H), 4.44 (d,
J = 8.6 Hz, 1H), 1.85 (brs, 1H); 13C NMR (75 MHz, CDCl3): δ 139.1,
136.4, 134.6, 128.6, 128.5, 127.4, 127.2, 127.1, 126.5, 123.5, 82.0, 70.4, 68.3;
HRMS (EI) Calcd for C15H14O2 m/z [M]+: 226.0988; found, 226.0989;
HPLC (Daicel Chiralpak IA, i-PrOH/hexane = 10/90, 0.6 mL/min,
230 nm): t1 = 21.6 min (minor), t2 = 26.9 min (major).
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National University of
Singapore (Grant No. 143-000-428-112) for the funding of
this research. We also thank Professor Li Deng (Brandeis
University) for a valuable discussion on the mechanism.
REFERENCES
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ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data for compounds 4f and 14 (CIF) and
1
copies of H 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chmyyy@nus.edu.sg. Tel.: +65-6516-7760.
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NOTE ADDED AFTER ASAP PUBLICATION
Compund 8 in Table 3 was corrected and this paper reposted
on January 4, 2012.
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