Rh(I)-catalyzed asymmetric synthesis of 3-substituted isoindolinones through co gas-free aminocarbonylation

Article abstract of DOI:10.1021/jo300201g

A highly efficient and accessible synthesis of chiral 3-substituted isoindolinone frameworks is described. The synthesis involved the Rh(I)-catalyzed asymmetric arylation of boronic acids to 2-halobenzaldimines and the subsequent Rh(I)-catalyzed intramolecular aminocarbonylation of the resulting 2-halobenzylamines using an aldehyde as the carbonyl source. The method tolerates a variety of functional groups, yielding isoindolinone derivatives in moderate to high yields with high ee-values. In addition, two Rh(I)-catalyzed transformations could be efficiently accomplished in a one-pot sequence to give chiral isoindolinones by the simple addition of a ligand and an aldehyde after the Rh(I)-catalyzed asymmetric arylation.

Full text of DOI:10.1021/jo300201g

Article
pubs.acs.org/joc
Rh(I)-Catalyzed Asymmetric Synthesis of 3-Substituted
Isoindolinones through CO Gas-Free Aminocarbonylation
Masahiko Fujioka, Tsumoru Morimoto,* Takayuki Tsumagari, Hiroki Tanimoto, Yasuhiro Nishiyama,
and Kiyomi Kakiuchi
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), Ikoma, Nara 630-0192, Japan
S
* Supporting Information
ABSTRACT: A highly efficient and accessible synthesis of chiral 3-substituted
isoindolinone frameworks is described. The synthesis involved the Rh(I)-
catalyzed asymmetric arylation of boronic acids to 2-halobenzaldimines and the
subsequent Rh(I)-catalyzed intramolecular aminocarbonylation of the resulting
2-halobenzylamines using an aldehyde as the carbonyl source. The method
tolerates a variety of functional groups, yielding isoindolinone derivatives in moderate to high yields with high ee-values. In addition,
two Rh(I)-catalyzed transformations could be efficiently accomplished in a one-pot sequence to give chiral isoindolinones by the simple
addition of a ligand and an aldehyde after the Rh(I)-catalyzed asymmetric arylation.
If the method is to be applied to the asymmetric synthesis of
3-chiral isoindolinones, chiral 2-halobenzylamines, which can
be prepared by the rhodium(I)-catalyzed asymmetric addition
of boronic acids to 2-haloarylaldimines, are required.10 We
describe herein a new concise synthesis of chiral 3-substituted
isoindolinones based on the above rhodium(I)-catalyzed
aminocarbonylation, which can be carried out in conjunction
with the rhodium(I)-catalyzed asymmetric addition of arylboronic
acids to 2-haloarylaldimines, and on the one-pot sequence of these
rhodium(I)-catalyzed reactions (Scheme 2). In the one-pot syn-
thesis, the loaded rhodium complex plays three sequential catalytic
roles, asymmetric arylation/decarbonylation/aminocarbonylation.
The present method reported here affords a more accessible route
for the synthesis of chiral 3-substituted isoindolinones compared
with the conventional methods from the following aspects: (i) the
ready availability of the substrates, N-tosyl-2-bromoarylaldimines,
and their synthetic precursors, 2-bromoarylaldehydes, and (ii) no
need for the use of carbon monoxide.
INTRODUCTION
■
Chiral 3-substituted isoindolinone frameworks are frequently found
in bioactive molecules. Examples include the anxiolytic drug can-
didate pagoclone (1),1 a sedative-hypnotic drug candidate JM-1232
(2),2 a dopamine D4 receptor antagonist PD-172938 (3),3 and a
NK2 antagonist ZD7944 (4)4 (Figure 1). In addition, the chiral 3-
methyl analogues 5a or b, which contain a dienophile5a or diene,5b,c
have been used as a chiral auxiliary in asymmetric Diels−Alder reac-
tions. Because of this, interest has focused on the development of an
efficient synthetic method for the synthesis of such a framework.6
The rhodium(I)-catalyzed reaction of 2-(N-tosylimino)-
benzoates with arylboronic acids has been reported to be an
effective approach for the construction of a chiral 3-substituted
isoindolinone framework.7 The reaction involves the asymmetric
arylation of the imino group and the subsequent, spontaneous
ester-amide exchange, leading to the complete formation of
isoindolinones, accompanied by the production of a new chiral
center at the 3-position. This method has a major disadvantage, in
that the substrates, 2-(N-tosylimino)benzoates, and their synthetic
materials, 2-formylbenzoates, are not readily available.
On the other hand, the palladium-catalyzed aminocarbonylation
of aryl halides that contains a nitrogen-nucleophile at the ortho-
position also represents a convenient synthesis of isoindolinones.8
However, the method suffers from the need for the use of toxic,
gaseous carbon monoxide. In constrast, we recently reported on a
concise synthesis of isoindolinones by the rhodium(I)-catalyzed
intramolecular aminocarbonylation of aryl halides having a
nitrogen-nucleophile at the ortho-position, using aldehydes as a
carbonyl source (Scheme 1).9 The method can be operationally
simply substituted for the original aminocarbonylation using
carbon monoxide. Thus, two rhodium-catalyzed processes, namely,
the abstraction of a carbonyl moiety from an aldehyde by the
rhodium catalyst (decarbonylation) and the introduction of the
abstracted carbonyl moiety into 2-bromobenzylamine (amino-
carbonylation), function cooperatively, resulting in a simple,
straightforward aminocarbonylation procedure.
RESULTS AND DISCUSSION
■
We first examined the rhodium(I)-catalyzed aminocarbonyla-
tion reaction of an enantioenriched 2-halobenzylamine with an
aldehyde. Enantioenriched N-tosyl-2-bromobenzylamine (7a),
prepared in 99% ee (S) from 2-bromobenzaldimine (6a) using
the method described by Hayashi, was used as the substrate
(Scheme 3i).11 When (S)-7a was treated with 5 equiv of penta-
fluorobenzaldehyde in the presence of 5 mol % of [RhCl(cod)]2,
10 mol % of dppp, and 2 equiv of K2CO3 in xylene at 130 °C,8 the
aminocarbonylation proceeded to give the desired 3-phenyl-
isoindolinone (8a) in 89% isolated yield, along with 10% of the
hydrogenated starting material (9a) in 10% yield (Scheme 3i-b).
Although it is known that the deprotonation of isoindolinone at
the C-3 position can lead to epimerization under strongly basic
Received: January 26, 2012
Published: February 23, 2012
© 2012 American Chemical Society
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Figure 1. Representative chiral 3-substituted isoindolinone.
Scheme 1. Rh(I)-Catalyzed Isoindolinone Synthesis from
2-Halobenzylamines with Aldehydes through CO Gas-Free
Aminocarbonylation
consumed within 8 h to give 8a in a lower yield (77% with 98%
ee (S)). In the case of this transformation, paraformaldehyde, a
low-cost C1 feedstock, could also be used as the carbonyl
source.9,13,14 The use of paraformaldehyde (10 equiv) in the
transformation resulted in the production of the carbonylated
product 8a in 68% yield; however, the yield of the unfavorable
product 9a was increased to 30% (Scheme 3ii-b).
The reverse enantiomer, (R)-8a, was synthesized via the
rhodium(I)-catalyzed aminocarbonylation of the (R)-enan-
tiomer of N-tosyl-2-chlorobenzylamine (12), which can be
readily prepared by the asymmetric addition of 2-chlorophe-
nylboronic acid to N-tosylbenzaldimine (11) using the same
rhodium catalyst ([RhCl((R)-10)]2) with Scheme 3i.15 When
(R)-12 (99% ee) was reacted with pentafluorobenzaldehyde in
the presence of the rhodium catalyst, the desired isoindolinone,
(R)-8a, was obtained with 99% ee, although in low yield (24%)
(Scheme 4). The use of KI (1 equiv) as an additive increased
the chemical yield to 67% with the ee maintained.
Scheme 2. A New Strategy for the Convenient Synthesis of
Chiral 3-Substituted Isoindolinones
Scheme 4. Synthesis of Reverse Enantiomer, (R)-8a
conditions,6d,12 the enantiomeric excess and the absolute
configuration of 8a (99% ee (S)) were not diminished under
the present basic conditions, compared with those of 7a. When
7a was reacted with 1 atm of carbon monoxide, instead of
C6F5CHO, under otherwise identical conditions, 7a was completely
We next explored the scope of the reaction with respect to
the substituents on the aromatic ring of the arylboronic acids.
Reactions using pentafluorobenzaldehyde as a carbonyl source
Scheme 3. Rh(I)-Catalyzed Aminocarbonylation of Chiral Benzylamine (S)-7a with Aldehydes
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are general and high-yielding and usually do not involve the
degradation of the optical purity of the substrates. The results
are summarized in Table 1. Substrates containing an electron-
donating group such as methoxy and methyl groups reacted
a
Table 1. Rh(I)-Catalyzed Aminocarbonylative Cyclization of Various Chiral Bromobenzylamines
b
c
d
entry
substrate
aldehyde (R)
time (h)
product
yield (%)
ee (%) (config)
1
7b (99% ee (S))
C6F5
H
7
7
8b
84
73
93
71
88
64
86
54
80
58
81
53
87
73
75
51
90
68
84
53
91
55
99 (S)
99 (S)
98 (S)
99 (S)
95 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
98 (S)
96 (S)
99 (S)
99 (S)
99 (S)
97 (S)
99 (S)
97 (S)
2
3
7c (99% ee (S))
7d (99% ee (S))
7e (99% ee (S))
7f (99% ee (S))
7g (99% ee (S))
7h (99% ee (S))
7i (99% ee (S))
7j (99% ee (S))
7k (99% ee (S))
71 (99% ee (S))
C6F5
H
8
8c
8d
8e
8f
4
6
5
C6F5
H
8
6
6
7
C6F5
H
10
8
8
9
C6F5
H
5
10
11
12
13
14
15
16
17
18
19
20
21
22
5
C6F5
H
5
8g
8h
8i
5
C6F5
H
48
18
60
18
20
15
16
15
17
16
C6F5
H
C6F5
H
8j
C6F5
H
8k
81
C6F5
H
a
Reaction conditions: N-tosyl-2-bromobenzylamine (0.25 mmol), aldehyde, [RhCl(cod)]2 (0.0125 mmol), dppp (0.025 mmol), K2CO3 (0.5 mmol),
b
c
d
and xylene (2 mL) at 130 °C. C6F5: C6F5CHO (1.25 mmol); H: paraformaldehyde (2.5 mmol). Isolated yield. Products' ee-values were measured
by HPLC analysis. Their absolute configurations were determined from specific optical rotation measurement or X-ray crystallographic analysis. See
the Supporting Information.
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smoothly with pentafluorobenzalehyde to afford 8b and 8c in
84 and 93%, respectively (Table 1, entries 1 and 3). 7d,
containing a 2-methyl phenyl group also reacted readily, despite
the steric hindrance close to the reaction site (Table 1, entry 5).
The reaction of 7e gave the corresponding 8e without the loss
of the Cl group (Table 1, entry 7). Compounds 7f and 7g,
which contain electron-withdrawing groups, such as F and CF3,
also reacted smoothly to yield 8f and 8g in 80 and 81%,
respectively (Table 1, entries 9 and 11). The use of para-
formaldehyde instead of pentafluorobenzaldehyde as a carbonyl
source also afforded the corresponding isoindolinones with
their ee-values maintained, but the yields were lower than when
pentafluorobenzaldehyde was used (Table 1, entries 2, 4, 6, 8,
10, and 12). We further examined the effect of various sub-
stituents on the aromatic ring of 2-bromoarylaldimines on the
carbonylation reaction. Irrespective of the electronic nature of
the substituent introduced, the reaction proceeded slightly
more slowly than that of the substrates of entries 1−12 (Table 1),
but the corresponding isoindolinones were obtained in good to
high yields with 96−99% ee (Table 1, entries 13−22).
The fact that the synthesis of 7a, as well as the above
aminocarbonylation of 7a, can be catalyzed by a rhodium(I)
complex encouraged us to further investigate the rhodium(I)-
catalyzed one-pot arylation−aminocarbonylation sequence
from aldimine 6a to isoindolinone 8a. The asymmetric arylation
of aldimines catalyzed by a rhodium(I)-chiral diene complex was
chosen as the first step, the in situ formation of enantiomerically
enriched 2-bromobenzylamines, because it is well-known that the
use of chiral diene ligands leads to a more smooth reaction with
higher enantioselectivity than chiral phosphine ligands in the
rhodium(I)-catalyzed arylation of aldimines.16 Aldimine 6a was
first reacted with 1.1 equiv of PhB(OH)2 in the presence of
5 mol % [RhCl((R)-10)]2 and 0.4 equiv of KOH as a base in
xylene at 60 °C for 2 h. After completion of this reaction,
5 equiv of pentafluorobenzaldehyde, 10 mol % of dppp, and
2 equiv of K2CO3 were added to the reaction mixture, and the
resulting mixture was stirred at 130 °C until the intermediate
7a had been completely consumed (7 h). The desired
isoindolinone 8a was obtained in 82% yield with 97% ee (S)
(Scheme 5a). This result shows that the one-step sequence is
intermediate 7a (13 h) and a lower chemical yield of 8a (58%)
with 98% ee (S). Unfortunately, a one-pot procedure in which
all the reagents are introduced simultaneously afforded no
phenylation product 7a, and no carbonylated product 8a.17
The results for the one-pot reactions using various aryl-
boronic acids and aldimines are listed in Table 2. Reactions of
6a with various arylboronic acids containing electron-donating
or -withdrawing groups on the aromatic ring proceeded smoothly
to give the corresponding 3-arylisoindolinones 8b−g in high yields
and ee-values. The introduction of substituents into the aromatic
ring of aldimines had only negligible effects, and one-pot
asymmetric synthesis of 3-arylisoindolinones 8h−l also
proceeded smoothly.
The synthesis of the reverse enantiomer (R)-8a was examined
under the developed one-pot conditions. The rhodium(I)-
catalyzed reaction of N-tosylbenzaldimine (11) with 2-
chlorophenylboronic acid, followed by reaction with penta-
fluorobenzaldehyde, afforded (R)-8a in 56% isolated yield with
98% ee. Compared to that of Scheme 4, this is slightly more
efficient (Scheme 6).
Finally, we applied the one-pot procedure to the construction
of a chiral 3-arylphthalide framework, which is also found in a
variety of bioactive molecules.18 When 2-bromobenzaldehyde
(13) was exposed to conditions similar to those described in
Table 2, except for the base used (K3PO4), the reaction led to
the formation of the desired phthalide 14 in 73% yield with
62% ee (S) (Scheme 7). As in the other cases described above,
no decrease in chemical yield and enantiomeric excess was
detected for the one-pot operation because, in the case of two-
step synthesis of phthalide 14, the first step gave the primary
product 15 in 93% with 62% ee (S) and the second step resulted
in the production of 14 in 75% yield. Although some optimization
will still be required for higher yield and higher enantioselectivity,
it was found that the present one-pot method appears to be
a convenient synthetic tool for producing enantioenriched
3-substituted phthalides.
CONCLUSION
■
We report on a new protocol for the synthesis of chiral 3-
substituted isoindolinones through Rh(I)-catalyzed asymmetric
arylation and the subsequent aminocarbonylative cyclization
using an aldehyde as the carbonyl source. Enantioenriched 3-
substituted isoindolinones containing a wide range of sub-
stituents on the aromatic ring could be obtained from readily
available substrates in moderate to high yields with high ee-
values. The two Rh(I)-catalyzed processes can be carried out
efficiently in a one-pot operation without any detectable loss of
enantioselectivity. Furthermore, the present one-pot protocol is
applicable to the asymmetric arylation-alkoxycarbonylation
sequence of 2-bromobenzaldehyde leading to the synthesis of
enantioenriched 3-arylphthalides.
Scheme 5. One-Pot Procedure for Synthesis of Chiral
Isoindolinone 8a from Aldimine 6a
EXPERIMENTAL SECTION
General Considerations. Nuclear magnetic resonance spectra
were recorded on a 500 MHz spectrometer. Chemical shifts of H
■
1
more efficient than the two-step one, which yields the same
product 8a in 73% combined yield as shown in Scheme 3.
Paraformaldehyde could also work well to give 8a in 68% yield
with 99% ee (S) (Scheme 5b). As for the aminocarbonylation
of 7a mentioned above, these aldehydes were superior to
carbon monoxide as a carbonyl source in this sequential cata-
lysis. Thus, the use of atmospheric carbon monoxide instead of
pentafluorobenzaldehyde in the second step resulted in a longer
reaction time for the complete consumption of the synthetic
NMR spectra are given in ppm using the solvent signal as the internal
standard (CDCl3, δ = 7.26 ppm). Data are reported as follows: multi-
plicity (s = singlet, d = doublet, t = triplet, q = quartet, and m =
multiplet), coupling constant in Hz, and integration. 13C NMR chemical
shifts are given in ppm using deuteriochloroform (77.0 ppm) as the
internal standard. Infrared absorption peaks are reported in reciprocal
centimeters with the following relative intensities: s (strong), m
(medium), or w (weak). Mass spectra were obtained with ioniza-
tion voltages of 70 eV. High performance liquid chromatography was
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a
Table 2. One-Pot Synthesis of Various Chiral Isoindolinone from Aldimines
b
c
d
entry
aldimine
Ar
aldehyde (R)
time (h)
product
yield (%)
ee (%) (config)
1
6a
4-OMeC6H4
C6F5
H
17
10
14
10
14
12
7
8b
79
66
85
59
82
56
74
51
24
38
79
55
87
70
85
71
89
65
78
50
79
51
99 (S)
99 (S)
97 (S)
97 (S)
96 (S)
97 (S)
99 (S)
99 (S)
99 (S)
97 (S)
99 (S)
95 (S)
90 (S)
94 (S)
99 (S)
99 (S)
94 (S)
99 (S)
95 (S)
85 (S)
95 (S)
96 (S)
2
3
6a
6a
6a
6a
6a
6h
6i
4-MeC6H4
2-MeC6H4
4-CIC6H4
4-FC6H4
4-CF3C6H4
Ph
C6F5
H
8c
8d
8e
8f
4
5
C6F5
H
6
7
C6F5
H
8
6
9
C6F5
H
9
10
11
12
13
14
15
16
17
18
19
20
8
C6F5
H
7
8g
8h
8i
11
14
12
16
10
17
16
26
11
16
12
C6F5
H
Ph
C6F5
H
6j
Ph
C6F5
H
8j
6k
61
Ph
C6F5
H
8k
81
e
21
Ph
C6F5
H
e
22
a
Reaction conditions: aldimine 6 (0.50 mmol), arylboronic acid (0.55 mmol), [RhCl((R)-10)]2 (0.025 mmol), KOH (0.20 mmol), and xylene
b
(2 mL) at 60 °C for 2 h; then, aldehyde, dppp (0.050 mmol), and K2CO3 (1.0 mmol) at 130 °C. C6F5: C6F5CHO (2.5 mmol); H: paraformaldehyde
(5 mmol). Isolated yield. Products' ee-values were measured by HPLC analysis. Their absolute configurations were determined from specific
optical rotation measurement or X-ray crystallographic analysis. See the Supporting Information. In step (i), K2CO3 was used as a base instead of KOH.
c
d
e
Scheme 6. One-Pot Synthesis of (R)-3-Phenylisoindolinone (8a)
Scheme 7. Application for the Synthesis of (S)-3-
Phenylphthalide (14)
conducted using an ultraviolet detector. Optical rotations were measured
on a digital polarimeter. Chrystal of suitable for X-ray structural deter-
mination was mounted on a glass fiber. The structure was solved by
direct methods and refined on F by full-matrix least-squares using all
unique data. Hydrogen atoms have been included in calculated positions
(riding model) for the structure.
reported methods, respectively. N-Tosyl-benzaldimines, 6a−l and 11
were prepared from the corresponding benzaldehydes and p-
toluenesulfonamide using the reported procedure.21 Racemic and
chiral benzylamines 7 and 12 were prepared using the reported
procedure11 with [RhCl(cod)]2 and [RhCl((R)-10)]2, respectively,
with minor modifications.
Materials. All commercial reagents were used as supplied or
purified by standard techniques where necessary. [RhCl(cod)]2,19
chiral diene (R)-10,11 and [RhCl((R)-10)]2 were prepared using
20
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Determination of Absolute Configuration. The absolute
configurations of 7b−k were determined from specific optical rotation
data of the known compounds 9b−k, which were prepared by the
hydrogenation of 7b−k using a Pd-catalyst.22 The absolute con-
figurations of 7l and 8c−l were determined from X-ray crystallographic
analysis.23
N-[(2S)-(2-Bromophenyl)(4-methylphenyl)methyl]-4-methylben-
zenesulfonamide (7c). White solid: mp 151.7−153.1 °C; Rf 0.23
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.28 (s, 3H), 2.39 (s,
3H), 5.17 (d, J = 6.7 Hz, 1H), 5.85 (d, J = 6.7 Hz, 1H), 6.92 (d, J =
7.9 Hz, 2H), 7.03 (d, J = 7.9 Hz, 2H), 7.07 (td, J = 7.6, 1.5 Hz, 1H),
7.18 (d, J = 7.9 Hz, 2H), 7.20 (td, J = 7.6, 1.5 Hz, 1H), 7.38 (dd, J =
7.6, 1.5 Hz, 1H), 7.42 (dd, J = 7.6, 1.5 Hz, 1H), 7.63 (d, J = 7.9 Hz,
2H); 13C NMR (CDCl3) δ 20.9, 21.4, 60.0, 122.9, 127.1, 127.2, 127.5,
128.7, 129.1, 129.2, 129.3, 132.8, 136.2, 136.8, 137.3, 139.3, 143.1; IR
(KBr) 3292 m, 3247 m, 2923 w, 1597 w, 1511 w, 1494 w, 1440 m,
1321 s, 1152 s, 1123 m, 1094 s, 1076 m, 1022 m, 950 m, 931 m, 873 w,
837 w, 814 m, 782 w, 752 m, 719 m, 705 w, 681 m, 662 s, 576 s, 547
m, 487 w; MS m/z (relative intensity, %) 277 (13), 276 (84), 275
(16), 274 (M+ − Ts, 100), 207 (11), 194 (31), 180 (13), 179 (10),
165 (25), 155 (15), 118 (18), 92 (11), 91 (75), 77 (11), 65 (23);
exact mass-ESI calcd for C21H20BrNNaO2S 452.0296 [M + Na]+,
found 452.0295; [α]17D = +31.5° (c 1.00, CHCl3) for 99% ee (S); HPLC
(Chiralpak OD-H, n-hexane/2-propanol = 90/10, flow = 1.0 mL/min,
detection at 254 nm) Rt = 9.3 min (R), Rt = 13.3 min (S). The absolute
configurations of 7c was determined from specific optical rotation of the
known compound 9c,25 which was prepared by the hydrogenation of 7c
using a Pd-catalyst.
Substrates for Schemes 3 and 4 and Table 1: N-
Tosylbenzylamines 7 and 12. N-[(2S)-(2-Bromophenyl)-
phenylmethyl]-4-methylbenzenesulfonamide (7a).24 White solid:
mp 173.5−174.6 °C; Rf 0.22 (hexane/AcOEt = 4/1); 1H NMR
(CDCl3) δ 2.38 (s, 3H), 5.28 (d, J = 6.7 Hz, 1H), 5.90 (d, J =
6.7 Hz, 1H), 7.05−7.09 (m, 3H), 7.17 (d, J = 8.6 Hz, 2H),
7.19−7.23 (m, 4H), 7.36 (dd, J = 7.6, 1.5 Hz, 1H), 7.43 (dd, J =
7.6, 1.5 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ
21.5, 60.4, 123.0, 127.2, 127.4, 127.5, 127.8, 128.6, 128.9, 129.3,
129.4, 133.0, 136.8, 139.0, 139.2, 143.3; IR (KBr) 3291 m, 3237
m, 1597 w, 1494 w, 1467 m, 1439 m, 1321 s, 1305 m, 1152 s,
1093 s, 1045 w, 1022 m, 941 m, 906 w, 830 w, 813 m, 755 s,
697 s, 680 m, 663 m, 606 w, 574 s, 547 s, 504 w; MS m/z
(relative intensity, %) 263 (11), 262 (85), 261 (16), 260 (M+ −
Ts, 100), 207 (24), 182 (11), 180 (29), 166 (20), 165 (29),
155 (24), 104 (18), 92 (12), 91 (68), 77 (29), 65 (15), 51
(12); exact mass-ESI calcd for C20H18BrNNaO2S 438.0139
[M + Na]+, found 438.0140; [α]17D = +24.5° (c 0.77, CHCl3) for
99% ee (S); HPLC (Chiralpak AD-H, n-hexane/2-propanol =
90/10, flow = 0.7 mL/min, detection at 254 nm) Rt = 27.1 min
(S), Rt = 29.9 min (R). The absolute configuration was assigned
as S from the comparison with the reported HPLC retention
(2R)-N-[(4-Methylphenyl)phenylmethyl]-4-methylbenzenesulfo-
namide (9c).25 White solid: mp 112.6−114.1 °C; Rf 0.30 (hexane/
1
AcOEt = 4/1); H NMR (CDCl3) δ 2.28 (s, 3H), 2.38 (s, 3H), 5.36
(d, J = 7.3 Hz, 1H), 5.52 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 8.6 Hz, 2H),
7.01 (d, J = 8.6 Hz, 2H), 7.10−7.13 (m, 4H), 7.18−7.21 (m, 3H), 7.56
(d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ 21.0, 21.4, 61.0, 127.1,
127.2, 127.3, 127.4, 128.4, 129.1, 129.3, 137.2, 137.3, 137.6, 140.6,
143.1; IR (KBr) 3853 w, 3734 w, 3649 w, 3261 w, 2922 w, 2360 w,
1599 w, 1558 w, 1541 w, 1508 w, 1491 w, 1434 m, 1321 m, 1163 s,
1093 m, 1043 m, 932 w, 843 w, 811 m, 777 w, 722 m, 701 m, 678 m,
561 m, 543 m; MS m/z (relative intensity, %) 197 (15), 196 (M+ −
Ts, 100), 194 (17), 181 (16), 180 (28), 165 (11), 118 (10), 104 (12),
91 (41), 77 (10), 65 (11); exact mass-ESI calcd for C21H21NNaO2S
time and specific optical rotation (lit. [α]20 = +14.5° (c 0.77,
D
CHCl3) for 84% ee (S)).
N-[(2S)-(2-Bromophenyl)(4-methoxyphenyl)methyl]-4-methyl-
benzenesulfonamide (7b). White solid: mp 144.7−145.9 °C; Rf 0.19
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.37 (s, 3H), 3.72 (s,
3H), 5.77 (d, J = 6.7 Hz, 1H), 5.88 (d, J = 6.7 Hz, 1H), 6.72 (d, J = 8.6
Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 7.04 (t, J = 7.6 Hz, 1H), 7.14 (d, J =
7.9 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.41 (d,
J = 7.6 Hz, 1H), 7.61 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.4,
55.1, 59.9, 113.8, 122.9, 127.1, 127.5, 128.7, 128.8, 129.1, 129.3, 131.2,
132.9, 136.8, 139.3, 143.2, 158.9; IR (KBr) 3251 m, 1609 m, 1512 s,
1439 m, 1332 m, 1307 m, 1255 s, 1156 s, 1093 m, 1068 m, 1024 m,
945 w, 922 w, 842 w, 816 m, 782 w, 752 w, 728 w, 680 m, 663 m,
572 m, 546 m; MS m/z (relative intensity, %) 293 (12), 292 (79), 291
(41), 290 (M+ − Ts, 100), 289 (33), 288 (18), 260 (16), 258 (16),
211 (11), 210 (63), 196 (14), 195 (18), 181 (10), 167 (12), 165 (12),
155 (14), 153 (12), 152 (16), 134 (31), 109 (10), 92 (13), 91 (71), 77 (18),
65 (23); exact mass-ESI calcd for C21H20BrNNaO3S 468.0245 [M + Na]+,
374.11907 [M + Na]+, found 374.11909; [α]26 = +12.5° (c 0.70,
D
CHCl3) for 99% ee (R) (lit. [α]20D = +11.0° (c 0.7, CHCl3) for 94% ee
(R)); HPLC (Chiralpak OD-H, n-hexane/2-propanol = 95/5, flow =
1.0 mL/min, detection at 254 nm) Rt = 17.5 min (S), Rt = 25.7 min (R).
N-[(2S)-(2-Bromophenyl)(2-methylphenyl)methyl]-4-methylben-
zenesulfonamide (7d). White solid: mp 187.4−188.2 °C; Rf 0.23
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.24 (s, 3H), 2.38 (s,
3H), 4.85 (d, J = 6.1 Hz, 1H), 6.09 (d, J = 6.1 Hz, 1H), 6.83 (d, J =
7.9 Hz, 1H), 7.01 (br s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.14−7.18 (m,
5H), 7.31 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.9
Hz, 2H); 13C NMR (CDCl3) δ 19.0, 21.5, 57.6, 123.4, 126.1, 127.1,
127.3, 127.6, 128.1, 128.9, 129.4, 129.5, 130.8, 133.0, 136.8, 136.9,
137.1, 138.7, 143.4; IR (KBr) 3288 m, 3062 w, 1597 w, 1494 w, 1435 m,
1346 m, 1327 m, 1304 w, 1185 w, 1157 s, 1092 m, 1054 m, 1018 m,
947 w, 904 w, 881 m, 837 w, 810 m, 791 w, 756 s, 723 m, 682 m, 665
m, 617 w, 578 m, 546 m, 499 w, 453 w; MS m/z (relative intensity, %)
276 (17), 274 (M+ − Ts, 23), 260 (13), 258 (13), 194 (14), 180 (20),
179 (100), 178 (18), 165 (15), 155 (16), 91 (55), 65 (20); exact mass-
ESI calcd for C21H20BrNNaO2S 452.02958 [M + Na]+, found
found 468.0246; [α]17 = +41.3° (c 1.00, CHCl3) for 99% ee (S);
D
HPLC (Chiralpak AD-H, n-hexane/2-propanol = 90/10, flow =
0.7 mL/min, detection at 254 nm) Rt = 40.1 min (R), Rt = 44.8 min
(S). The absolute configuration of 7b was determined from specific
optical rotation of the known compound 9b,25 which was prepared
by the hydrogenation of 7b using a Pd-catalyst.
(2R)-N-[(4-Methoxyphenyl)phenylmethyl]-4-methylbenzenesulfo-
namide (9b).25 White solid: mp 125.7−127.0 °C; Rf 0.28 (hexane/
1
452.02959; [α]17 = +83.4° (c 1.00, CHCl3) for 99% ee (S); HPLC
AcOEt = 4/1); H NMR (CDCl3) δ 2.37 (s, 3H), 3.74 (s, 3H), 5.33
D
(d, J = 7.3 Hz, 1H), 5.52 (d, J = 7.3 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H),
7.00 (d, J = 8.6 Hz, 2H), 7.10−7.13 (m, 4H), 7.18−7.20 (m, 3H), 7.55
(d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.4, 55.2, 60.7, 113.8,
127.1, 127.2, 127.4, 128.4, 128.5, 129.3, 132.7, 137.3, 140.7, 143.0,
158.9; IR (KBr) 3239 s, 3007 m, 2952 s, 2833 m, 1885 w, 1609 s, 1510 s,
1494 s, 1433 s, 1378 w, 1322 s, 1252 s, 1159 s, 1114 s, 1092 s, 1033 s,
932 m, 905 m, 873 m, 843 s, 804 s, 776 m, 745 s, 728 s, 703 s, 672 s,
632 m, 581 s, 559 s, 540 s, 488 m; MS m/z (relative intensity, %) 213
(15), 212 (M+ − Ts, 100), 211 (44), 210 (56), 197 (31), 181 (11),
180 (55), 165 (11), 155 (10), 153 (11), 134 (19), 104 (15), 91 (50),
77 (17), 65 (14); exact mass-ESI calcd for C21H21NNaO3S 390.11398
(Chiralpak OD-H, n-hexane/2-propanol = 95/5, flow = 0.6 mL/min,
detection at 254 nm) Rt = 23.7 min (S), Rt = 25.8 min (R). The
absolute configuration of 7d was assigned as S from the specific optical
rotation of 9d,25 which was prepared by the hydrogenation of 7d using
a Pd-catalyst.
(2R)-N-[(2-Methylphenyl)phenylmethyl]-4-methylbenzenesulfo-
namide (9d).25 White solid: mp 166.0−167.5 °C; Rf 0.30 (hexane/
1
AcOEt = 4/1); H NMR (CDCl3) δ 2.16 (s, 3H), 2.37 (s, 3H), 5.38
(d, J = 7.3 Hz, 1H), 5.80 (d, J = 7.3 Hz, 1H), 7.03−7.07 (m, 4H),
7.09−7.14 (m, 4H), 7.17−7.20 (m, 3H), 7.54 (d, J = 8.6 Hz, 2H); 13C
NMR (CDCl3) δ 19.3, 21.4, 58.0, 126.1, 127.0, 127.2, 127.3, 127.4,
127.5, 128.5, 129.2, 130.5, 135.4, 137.4, 138.2, 139.9, 143.1; IR (KBr)
3734 w, 3649 w, 3292 m, 3236 m, 2922 w, 1653 w, 1597 w, 1541 w,
1494 m, 1436 m, 1316 s, 1151 s, 1119 m, 1095 s, 1064 m, 940 m, 908
m, 838 m, 815 m, 788 w, 758 m, 723 m, 699 s, 668 s, 640 m, 608 w,
[M + Na]+, found 390.11400; [α]23 = +20.8° (c 1.20, CHCl3) for
D
98% ee (R) (lit. [α]20D = +13.6° (c 0.58, CHCl3) for 93% ee (R)); HPLC
(Chiralpak OD-H, n-hexane/2-propanol = 70/30, flow = 0.7 mL/min,
detection at 254 nm) Rt = 11.9 min (S), Rt = 16.6 min (R).
2916
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Article
572 s, 548 s; MS m/z (relative intensity, %) 197 (16), 196 (M+ − Ts,
100), 194 (40), 181 (20), 180 (49), 179 (29), 178 (11), 166 (13), 165
(19), 155 (19), 118 (13), 104 (12), 91 (65), 77 (15), 65 (17); exact
mass-ESI calcd for C21H21NNaO2S 374.11907 [M + Na]+, found
(2R)-N-[(4-Fluorophenyl)phenylmethyl]-4-methylbenzenesulfo-
namide (9f).25 White solid: mp 108.3−110.2 °C; Rf 0.31 (hexane/
AcOEt = 4/1); 1H NMR (CDCl3) δ 2.39 (s, 3H), 5.01 (d, J = 7.3 Hz,
1H), 5.55 (d, J = 7.3 Hz, 1H), 6.90 (td, J = 8.9, 2.2 Hz, 2H), 7.05−7.10
(m, 4H), 7.16 (d, J = 7.9 Hz, 2H), 7.21−7.23 (m, 3H), 7.56 (d, J =
7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.4, 60.6, 115.3 (d, 2JC−F = 22.1 Hz),
127.2 (d, 3JC−F = 12.5 Hz), 127.7, 128.6, 129.0, 129.1, 129.3, 136.3 (d,
374.11907; [α]27D = −8.8° (c 0.98, CHCl3) for 99% ee (R) (lit. [α]20
=
D
−10.0° (c 0.98, CHCl3) for 95% ee (R)); HPLC (Chiralpak OD-H,
n-hexane/2-propanol = 80/20, flow = 0.5 mL/min, detection at 254 nm)
Rt = 13.9 min (R), Rt = 16.7 min (S).
1
4JC−F = 2.9 Hz), 137.2, 140.3, 143.3, 162.0 (d, JC−F = 246.6 Hz); IR
(KBr) 3853 w, 3735 w, 3649 w, 3274 s, 2925 w, 2363 w, 1603 m, 1158
w, 1506 s, 1456 m, 1322 s, 1225 m, 1155 s, 1092 s, 1064 m, 1016 m,
930 m, 859 m, 814 m, 797 m, 747 m, 701 s, 669 s, 565 s; MS m/z
(relative intensity, %) 201 (14), 200 (M+ − Ts, 100), 198 (21), 185
(13), 122 (13), 91 (35), 77 (11), 65 (10); exact mass-ESI calcd for
N-[(2S)-(2-Bromophenyl)(4-chlorophenyl)methyl]-4-methylben-
zenesulfonamide (7e). White solid: mp 109.0−110.7 °C; Rf 0.24
(hexane/AcOEt = 4/1); 1H NMR (CDCl3) δ 2.35 (s, 3H), 5.94 (d, J =
7.9 Hz, 1H), 6.31 (d, J = 7.9 Hz, 1H), 7.01−7.06 (m, 3H), 7.11 (d, J =
7.9 Hz, 2H), 7.13−7.15 (m, 3H), 7.33 (d, J = 7.9 Hz, 1H), 7.40 (d, J =
7.9 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.3, 59.6,
122.8, 127.0, 127.6, 128.5, 128.7, 129.0, 129.1, 129.3, 132.9, 133.4,
136.7, 137.8, 138.7, 143.3; IR (KBr) 3268 s, 3063 m, 1912 w, 1597 m,
1570 w, 1490 s, 1470 s, 1434 s, 1409 s, 1336 s, 1265 m, 1185 m, 1157
s, 1090 s, 1058 s, 1018 s, 945 m, 910 s, 873 m, 822 s, 809 s, 755 s, 714
s, 685 s, 664 s, 621 m, 572 s, 546 s, 495 m, 455 m, 428 w; MS m/z
(relative intensity, %) 298 (24), 297 (16), 296 (100), 295 (13), 294
(M+ − Ts, 82), 214 (19), 165 (38), 155 (21), 138 (16), 111 (11), 92
(12), 91 (77), 77 (13), 75 (12), 65 (23); exact mass-ESI calcd for
C20H18FNNaO2S 378.09400 [M + Na]+, found 378.09399; [α]20
=
D
−3.9° (c 1.02, CHCl3) for 97% ee (R) (lit. [α]20 = −4.1° (c 1.02,
D
CHCl3) for 93% ee (R)); HPLC (Chiralpak OD-H, n-hexane/2-
propanol = 80/20, flow = 0.8 mL/min, detection at 254 nm) Rt = 9.0
min (S), Rt = 10.7 min (R).
N-[(2S)-(2-Bromophenyl)(4-trifluoromethylphenyl)methyl]-4-
methylbenzenesulfonamide (7g). White solid: mp 126.5−128.1 °C;
1
Rf 0.24 (hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.38 (s, 3H),
5.32 (d, J = 7.3 Hz, 1H), 5.97 (d, J = 7.3 Hz, 1H), 7.11 (td, J = 7.6, 1.5
Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 7.21 (td, J = 7.6, 1.5 Hz, 1H), 7.22−
7.25 (m, 3H), 7.45 (dd, J = 7.6, 1.5 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H),
7.60 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.4, 60.1, 123.0, 123.9
C20H17BrClNNaO2S 471.9750 [M + Na]+, found 471.9749; [α]17
=
D
+20.7° (c 1.00, CHCl3) for 99% ee (S); HPLC (Chiralpak OD-H,
n-hexane/2-propanol = 90/10, flow = 1.0 mL/min, detection at 254 nm)
Rt = 10.5 min (R), Rt = 17.2 min (S). The absolute configuration of 7e
was assigned as S from the specific optical rotation of 9e,26 which was
prepared by the hydrogenation of 7e using a Pd-catalyst.
2
1
(d, JC−F = 272.5 Hz), 125.5 (q, JC−F = 3.5 Hz), 127.1, 127.7, 127.8,
3
129.4, 129.4, 129.5, 129.9 (d, JC−F = 32.6 Hz), 133.3, 136.7, 138.3,
143.2 (d, JC−F = 2.9 Hz), 143.6; IR (KBr) 3260 m, 2361 w, 1619 w,
4
1596 w, 1473 w, 1432 m, 1413 w, 1327 s, 1164 s, 1135 s, 1092 w, 1069 s,
1016 m, 926 w, 850 w, 839 w, 809 w, 752 w, 730 w, 704 w, 684 m, 664
m, 568 m, 541 w, 453 w; MS(EI) m/z (relative intensity) 331 (14),
330 (84), 329 (15), 328 (M+ − Ts, 87), 248 (13), 234 (11), 207 (11),
182 (10), 172 (13), 165 (26), 157 (10), 155 (36), 145 (13), 92 (18), 91
(100), 77 (13), 65 (27); exact mass-ESI calcd for C21H17BrF3NNaO2S
506.00132 [M + Na]+, found 506.00129; [α]17D = +4.9° (c 1.00, CHCl3)
for 99% ee (S); HPLC (Chiralpak AD-H, n-hexane/2-propanol = 95/5,
flow = 0.8 mL/min, detection at 254 nm) Rt = 30.3 min (R), Rt = 33.1
min (S). The absolute configuration of 7g was assigned as S from the
specific optical rotation of 9g,27 which was prepared by the hydrogenation
of 7g using a Pd-catalyst.
(2R)-N-[(4-Chlorophenyl)phenylmethyl]-4-methylbenzenesulfo-
namide (9e).26 White solid: mp 116.3−118.1 °C; Rf 0.36 (hexane/
AcOEt = 4/1); 1H NMR (CDCl3) δ 2.39 (s, 3H), 5.09 (d, J = 6.7 Hz,
1H), 5.53 (d, J = 6.7 Hz, 1H), 7.03−7.07 (m, 4H), 7.14−7.18 (m,
4H), 7.20−7.23 (m, 3H), 7.55 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3)
δ 21.5, 60.7, 127.2, 127.3, 127.9, 128.6, 128.7, 128.8, 129.4, 133.5,
137.1, 138.9, 140.0, 143.5; IR (KBr) 3239 s, 3057 w, 3036 w, 2919 w,
2865 w, 1598 m, 1490 m, 1448 m, 1433 s, 1412 w, 1379 m, 1321 s,
1293 m, 1276 w, 1249 w, 1189 w, 1161 s, 1092 s, 1048 s, 1030 m, 1014 m,
935 m, 904 m, 872 m, 837 s, 804 m, 745 m, 721 m, 701 s, 669 s, 650 w,
629 w, 573 s, 558 s, 539 m; MS m/z (relative intensity, %) 218 (32),
217 (15), 216 (M+ − Ts, 100), 214 (10), 201 (10), 180 (20), 166 (13),
165 (19), 155 (12), 138 (11), 104 (14), 91 (45), 77 (15), 65 (12); exact
mass-ESI calcd for C20H18ClNNaO2S 394.06445 [M + Na]+, found
(2R)-N-[(4-Trifluoromethylphenyl)phenylmethyl]-4-methylbenze-
nesulfonamide (9g).27 White solid: mp 122.6−124.2 °C; Rf 0.33
(hexane/AcOEt = 4/1); 1H NMR (CDCl3) δ 2.36 (s, 3H), 5.57 (d, J =
7.3 Hz, 1H), 5.60 (d, J = 7.3 Hz, 1H), 7.05 (br s, 2H), 7.10 (d, J = 7.9
Hz, 2H), 7.20−7.27 (m, 5H), 7.42 (d, J = 7.3 Hz, 2H), 7.52 (d, J = 7.9
Hz, 2H); 13C NMR (CDCl3) δ 21.4, 61.0, 123.9 (d, 2JC−F = 271.6 Hz),
394.06445; [α]20D = +5.8° (c 0.85, CHCl3) for 92% ee (R) (lit. [α]27
=
D
+6.3° (c 0.85, CHCl3) for 94% ee (R)); HPLC (Chiralpak OD-H,
n-hexane/2-propanol = 70/30, flow = 0.7 mL/min, detection at 254 nm)
Rt = 8.7 min (S), Rt = 10.6 min (R).
1
125.4 (q, JC−F = 3.5 Hz), 127.1, 127.3, 127.7, 128.1, 128.9, 129.4,
129.7 (d, 3JC−F = 32.6 Hz), 137.0, 139.7, 143.5, 144.2; IR (KBr) 3853 w,
3735 w, 3649 w, 3246 m, 3031 w, 2925 m, 2853 w, 2361 w, 1618 w,
1598 w, 1558 w, 1541 w, 1496 m, 1438 m, 1327 s, 1155 s, 1136 s, 1119 s,
1092 m, 1068 s, 1053 m, 1015 m, 927 m, 903 w, 873 m, 847 w, 813 m,
748 m, 696 m, 678 s, 658 m, 633 m, 602 m, 569 m, 543 s; MS m/z
(relative intensity, %) 251 (16), 250 (M+ − Ts, 100), 155 (11), 91
(37), 77 (11); exact mass-ESI calcd for C21H18F3NNaO2S 428.09080
N-[(2S)-(2-Bromophenyl)(4-fluorophenyl)methyl]-4-methylbenze-
nesulfonamide (7f). White solid: mp 109.0−110.7 °C; Rf 0.24
(hexane/AcOEt = 4/1); 1H NMR (CDCl3) δ 2.37 (s, 3H), 5.61 (d, J =
7.3 Hz, 1H), 5.89 (d, J = 7.3 Hz, 1H), 6.90 (t, J = 8.6 Hz, 2H), 7.02−
7.09 (m, 3H), 7.15 (d, J = 7.9 Hz, 2H), 7.18 (td, J = 7.6, 1.5 Hz, 1H),
7.31 (dd, J = 7.6, 1.5 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.9
Hz, 2H); 13C NMR (CDCl3) δ 21.5, 59.9, 115.5 (d, 2JC−F = 21.1 Hz),
3
[M + Na]+, found 428.09076; [α]23 = −9.5° (c 1.00, CHCl3) for
123.0, 127.2, 127.6, 129.1, 129.2, 129.3 (d, JC−F = 12.5 Hz), 129.4,
D
133.2, 135.0 (d, 4JC−F = 2.9 Hz), 136.8, 138.8, 143.5, 162.1 (d, 1JC−F
=
94% ee (R) (lit. [α]20D = −10.1° (c 1.00, CHCl3) for 76% ee (R)); HPLC
(Chiralpak OD-H, n-hexane/2-propanol = 80/20, flow = 0.5 mL/min,
detection at 254 nm) Rt = 14.6 min (S), Rt = 21.1 min (R).
247.6 Hz); IR (KBr) 3283 s, 3238 s, 3070 m, 2876 m, 1919 w, 1604 s,
1670 w, 1509 s, 1467 m, 1440 s, 1317 s, 1234 s, 1184 m, 1148 s, 1125 s,
1095 s, 1078 s, 1019 s, 947 s, 928 s, 871 m, 829 m, 814 s, 797 s, 753 s,
722 m, 705 m, 681 s, 661 s, 574 s, 547 s, 488 m, 420 w; MS m/z
(relative intensity, %) 281 (14), 280 (88), 279 (17), 278 (M+ − Ts,
100), 198 (29), 184 (28), 183 (33), 182 (10), 155 (23), 122 (21), 95
(13), 92 (11), 91 (72), 77 (11), 75 (10), 65 (21); exact mass-ESI calcd
for C20H17BrFNNaO2S 456.00451 [M + Na]+, found 456.00450;
N-[(2S)-(2-Bromo-4-methoxyphenyl)phenylmethyl]-4-methylben-
zenesulfonamide (7h). White solid: mp 178.0−179.2 °C; Rf 0.19
(hexane/AcOEt = 4/1); 1H NMR (CDCl3) δ 2.38 (s, 3H), 3.74 (s, 3H),
5.46 (d, J = 7.3 Hz, 1H), 5.86 (d, J = 7.3 Hz, 1H), 6.72 (dd, J = 8.6,
2.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 7.0, 1.5 Hz, 2H),
7.16 (d, J = 7.9 Hz, 2H), 7.20−7.22 (m, 4H), 7.62 (d, J = 7.9 Hz, 2H);
13C NMR (CDCl3) δ 21.5, 55.5, 60.1, 113.6, 118.2, 123.3, 127.2, 127.3,
[α]17 = +23.8° (c 1.00, CHCl3) for 99% ee (S); HPLC (Chiralpak
D
OD-H, n-hexane/2-propanol = 90/10, flow = 1.0 mL/min, detection
at 254 nm) Rt = 10.1 min (R), Rt = 14.9 min (S). The absolute
configuration of 7f was assigned as S from the specific optical rota-
tion of 9f,25 which was prepared by the hydrogenation of 7f using a
Pd-catalyst.
127.7, 128.6, 129.4, 130.1, 131.1, 136.9, 139.6, 143.3, 159.3; IR (KBr)
3256 s, 3066 m, 2982 m, 2941 m, 1732 w, 1597 s, 1569 m, 1480 s,
1452 m, 1429 s, 1338 s, 1303 m, 1283 s, 1223 s, 1168 s, 1110 m, 1092
m, 1067 s, 1021 s, 938 m, 902 m, 868 m, 844 m, 820 s, 758 m, 698 s,
667 s, 580 s, 541 s; MS m/z (relative intensity, %) 293 (14), 292 (81),
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291 (22), 290 (M+ − Ts, 100), 289 (10), 288 (15), 287 (10), 275
(11), 260 (10), 212 (11), 210 (35), 196 (20), 195 (19), 167 (11), 165
(10), 155 (22), 152 (13), 104 (18), 91 (73), 77 (23), 65 (17); exact mass-
ESI calcd for C21H20BrNNaO3S 468.0245 [M + Na]+, found 468.0246;
[α]23D = −2.5° (c 1.00, CHCl3) for 99% ee (S); HPLC (Chiralpak OD-H,
n-hexane/2-propanol = 95/5, flow = 0.8 mL/min, detection at 254 nm)
Rt = 35.7 min (S), Rt = 40.2 min (R). The absolute configuration of 7h was
assigned as S from the specific optical rotation of 9h26 (the enantiomer of
9b), which was prepared by the hydrogenation of 7h using a Pd-catalyst;
[α]14D = −20.3° (c 0.93, CHCl3) for 99% ee (S) (lit. [α]28D = −19.6°
(c 0.93, CHCl3) for 95% ee (S)).
180 (17), 179 (17), 165 (26), 155 (21), 91 (73), 89 (11), 77 (22), 65
(18); exact mass-ESI calcd for C21H20BrNNaO2S 452.02958 [M + Na]+,
found 452.02961; [α]23 = +7.2° (c 1.00 CHCl3) for 99% ee (S);
D
HPLC (Chiralpak AD-H, n-hexane/2-propanol = 95/5, flow = 0.4
mL/min, detection at 254 nm) Rt = 78.9 min (S), Rt = 82.2 min (R).
The absolute configuration of 7j was assigned as S from the specific
optical rotation of 9j26 (the enantiomer of 9c), which was prepared by the
hydrogenation of 7j using a Pd-catalyst; [α]15D = −12.1° (c 0.97, CHCl3)
for 99% ee (S) (lit. [α]27 = −11.9° (c 0.97, CHCl3) for 91% ee (S)).
D
(2S)-N-[(4-Methylphenyl)phenylmethyl]-4-methylbenzenesulfo-
1
namide (9j) (Enantiomer of 9c). H NMR (CDCl3) δ 2.28 (s, 3H),
(2S)-N-[(4-Methoxyphenyl)phenylmethyl]-4-methylbenzenesulfo-
namide (9h) (Enantiomer of 9b). 1H NMR (CDCl3) δ 2.38 (s, 3H),
3.74 (s, 3H), 5.28 (d, J = 7.3 Hz, 1H), 5.51 (d, J = 7.3 Hz, 1H), 6.72
(d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 7.10−7.14 (m, 4H),
7.18−7.20 (m, 3H), 7.55 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ
21.4, 55.2, 60.8, 113.8, 127.1, 127.2, 127.4, 128.4, 128.6, 129.3, 132.7,
137.3, 140.7, 143.1, 158.9.
2.38 (s, 3H), 5.06 (d, J = 6.7 Hz, 1H), 5.52 (d, J = 6.7 Hz, 1H), 6.97
(d, J = 7.9 Hz, 2H), 7.02 (d, J = 7.9 Hz, 2H), 7.10−7.15 (m, 4H),
7.19−7.21 (m, 3H), 7.56 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ
21.0, 21.5, 61.1, 127.1, 127.2, 127.3, 127.5, 128.5, 129.2, 129.3, 137.2,
137.3, 137.6, 140.6, 143.1.
N-[(2S)-(2-Bromo-4-fluorophenyl)phenylmethyl]-4-methylbenze-
nesulfonamide (7k). White solid: mp 135.1−136.9 °C; Rf 0.22
(hexane/AcOEt = 4/1); 1H NMR (CDCl3) δ 2.40 (s, 3H), 5.57 (br s,
1H), 5.88 (d, J = 6.7 Hz, 1H), 6.92 (td, J = 8.2, 2.2 Hz, 1H), 7.04 (dd,
J = 6.4, 2.7 Hz, 2H), 7.17−7.22 (m, 6H), 7.37 (dd, J = 8.2, 5.8 Hz,
1H), 7.62 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.5, 59.9, 114.7
(d, 2JC−F = 21.1 Hz), 120.1 (dd, 2JC−F = 24.5, 3.4 Hz), 123.0 (d, 3JC−F
= 9.6 Hz), 127.2, 127.3, 128.0, 128.7, 129.5, 130.4 (d, 3JC−F = 8.6 Hz),
135.2 (d, 4JC−F = 3.8 Hz), 136.7, 139.0, 143.6, 161.5 (d, 1JC−F = 251.4
Hz); IR (KBr) 3367 m, 3254 s, 3071 m, 1599 s, 1482 s, 1454 s, 1419 s,
1337 s, 1305 s, 1266 m, 1226 s, 1160 s, 1093 s, 1028 s, 937 s, 904 m,
865 s, 850 m, 828 m, 816 s, 797 m, 753 m, 697 s, 667 s, 628 m, 580 s,
547 s, 474 m, 445 m; MS m/z (relative intensity, %) 281 (13), 280
(90), 279 (15), 278 (M+ − Ts, 100), 198 (22), 184 (23), 183 (32),
155 (22), 104 (13), 92 (11), 91 (69), 77 (23), 65 (19), 51 (10); exact
mass-ESI calcd for C20H17BrFNNaO2S 456.00451 [M + Na]+, found
N-[(2S)-(2-Bromo-5-methoxyphenyl)phenylmethyl]-4-methylben-
zenesulfonamide (7i). White solid: mp 150.5−152.1 °C; Rf 0.20
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.36 (s, 3H), 3.66 (s,
3H), 5.85 (d, J = 7.9 Hz, 1H), 5.91 (d, J = 7.9 Hz, 1H), 6.60 (dd, J =
8.9, 2.7 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1H), 7.11−7.14 (m, 4H), 7.20−
7.22 (m, 3H), 7.28 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 7.9 Hz, 2H); 13C
NMR (CDCl3) δ 21.4, 55.3, 60.4, 113.3, 114.5, 115.1, 127.1, 127.3,
127.7, 128.5, 129.3, 133.5, 136.8, 139.1, 139.8, 143.3, 158.9; IR (KBr)
3275 m, 3244 m, 2959 w, 2359 w, 1734 w, 1593 m, 1573 w, 1463 s,
1320 s, 1291 m, 1240 m, 1150 s, 1093 s, 1050 m, 1016 m, 940 m, 907 w,
876 w, 865 m, 836 w, 810 m, 754 w, 699 m, 670 s, 652 m, 592 m, 540 s;
MS m/z (relative intensity, %) 447 (14), 445 (M+, 13), 366 (22),
293 (10), 292 (71). 291 (19), 290 (M+ − Ts, 82), 260 (17), 213 (13),
211 (14), 210 (71), 196 (20), 195 (16), 181 (17), 167 (15), 155 (35),
153 (11), 152 (15), 104 (21), 92 (12), 91 (100), 77 (28), 65 (22);
exact mass-ESI calcd for C21H20BrNNaO3S 468.0245 [M + Na]+,
456.00446; [α]23 = +27.3° (c 1.00, CHCl3) for 99% ee (S); HPLC
D
(Chiralpak AD-H, n-hexane/2-propanol = 90/10, flow = 1.0 mL/min,
detection at 254 nm) Rt = 14.5 min (S), Rt = 22.9 min (R). The
absolute configuration of 7k was assigned as S from the specific optical
rotation of 9k24 (the enantiomer of 9f), which was prepared by the
hydrogenation of 7k using a Pd-catalyst; [α]22D = +3.7° (c 0.91, CHCl3)
found 468.0246; [α]23 = +30.2° (c 1.00, CHCl3) for 99% ee (S);
D
HPLC (Chiralpak AD-H, n-hexane/2-propanol = 90/10, flow =
0.5 mL/min, detection at 254 nm) Rt = 51.6 min (S), Rt = 53.7 min
(R). The absolute configuration of 7i was assigned as S from the
specific optical rotation of 9i,25 which was prepared by the
hydrogenation of 7i using a Pd-catalyst.
for 99% ee (S) (lit. [α]20 = +3.8° (c 0.91, CHCl3) for 94% (S)).
D
(2S)-N-[(4-Fluorophenyl)phenylmethyl]-4-methylbenzenesulfo-
(2S)-N-[(3-Methoxyphenyl)phenylmethyl]-4-methylbenzenesulfo-
1
namide (9k) (Enantiomer of 9f). H NMR (CDCl3) δ 2.39 (s, 3H),
namide (9i).25 White solid: mp 150.3−151.9 °C; Rf 0.28 (hexane/
5.06 (d, J = 7.3 Hz, 1H), 5.55 (d, J = 7.3 Hz, 1H), 6.90 (td, J = 8.6, 0.6
Hz, 2H), 7.02−7.12 (m, 4H), 7.15 (d, J = 7.9 Hz, 2H), 7.21−7.22 (m,
3H), 7.55 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.5, 60.7, 115.4
1
AcOEt = 4/1); H NMR (CDCl3) δ 2.37 (s, 3H), 3.67 (s, 3H), 5.45
(d, J = 7.3 Hz, 1H), 5.53 (d, J = 7.3 Hz, 1H), 6.62 (s, 1H), 6.68 (d, J =
7.3 Hz, 1H), 6.72 (dd, J = 8.6, 2.4 Hz, 1H), 7.09−7.13 (m, 5H), 7.18−
7.21 (m, 3H), 7.56 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.4,
55.0, 61.2, 112.8, 113.0, 119.6, 127.1, 127.2, 127.5, 128.5, 129.3, 129.5,
137.3, 140.4, 142.0, 143.1, 159.6; IR (KBr) 3853 w, 3735 w, 3649 w,
3283 m, 2930 w, 2360 w, 1654 w, 1596 m, 1558 w, 1541 w, 1491 m,
1457 m, 1411 m, 1324 s, 1268 m, 1161 s, 1092 m, 1041 m, 915 w, 865 w,
818 m, 782 m, 731 m, 705 m, 672 s, 569 m, 553 m, 420 w; MS m/z
(relative intensity, %) 213 (17), 212 (M+ − Ts, 100), 211 (10), 210
(18), 180 (35), 155 (12), 104 (13), 91 (44), 77 (14), 65 (10); exact
mass-EI calcd for C21H21NO3S 367.1242 [M]+, found 367.1240;
[α]18 = −2.5° (c 1.10, CHCl3) for 99% ee (R) (lit. [α]20 = −2.4°
2
3
(d, JC−F = 21.1 Hz), 127.2 (d, JC−F = 8.6 Hz), 127.8, 128.7, 129.0,
4
129.1, 129.4, 136.2 (d, JC−F = 2.9 Hz), 137.2, 140.2, 143.4, 162.1 (d,
1JC−F = 246.6 Hz).
N-[(2S)-(2-Bromo-5-fluorophenyl)phenylmethyl]-4-methylbenze-
nesulfonamide (7l). White solid: mp 167.4−168.5 °C; Rf 0.23
(hexane/AcOEt = 4/1); 1H NMR (CDCl3) δ 2.39 (s, 3H), 5.55 (d, J =
6.7 Hz, 1H), 5.86 (d, J = 6.7 Hz, 1H), 6.80 (td, J = 8.2, 3.1 Hz, 1H),
7.03 (dd, J = 6.4, 3.4 Hz, 2H), 7.15 (dd, J = 9.8, 3.1 Hz, 1H), 7.19 (d,
J = 7.9 Hz, 2H), 7.22−7.23 (m, 3H), 7.39 (dd, J = 8.2, 5.2 Hz, 1H),
7.64 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.4, 60.4, 116.2 (d,
2JC−F = 22.1 Hz), 116.5 (d, 2JC−F = 25.0 Hz), 117.0 (d, 4JC−F = 3.8 Hz),
D
D
(c 1.10, CHCl3) for 91% (R)); HPLC (Chiralpak OD-H, n-hexane/2-
propanol = 95/5, flow = 0.8 mL/min, detection at 254 nm) Rt = 34.4
min (R), Rt = 39.0 min (S).
3
127.2, 127.4, 128.1, 128.8, 129.5, 134.2 (d, JC−F = 7.7 Hz), 136.6,
138.4, 141.3 (d, 3JC−F = 6.7 Hz), 143.6, 161.9 (d, 1JC−F = 247.6 Hz); IR
(KBr) 3248 s, 1583 m, 1495 m, 1467 s, 1434 s, 1328 s, 1265 s, 1220 m,
1149 s, 1093 s, 1027 s, 938 m, 904 m, 879 s, 840 m, 812 s, 747 m, 697 s,
669 s, 647 m, 617 m, 593 s, 577 s, 538 s, 479 m, 438 m; MS m/z
(relative intensity, %) 281 (15), 280 (95), 279 (15), 278 (M+ − Ts,
100), 198 (27), 184 (21), 183 (30), 155 (25), 104 (14), 92 (13),
91 (78), 77 (25), 65 (21), 51 (10); exact mass-ESI calcd for
C20H17BrFNNaO2S 456.00451 [M + Na]+, found 456.00450;
[α]23D = +36.4° (c 1.00, CHCl3) for 99% ee (S); HPLC (Chiralpak
AD-H, n-hexane/2-propanol = 95/5, flow = 0.8 mL/min, detection
at 254 nm) Rt = 34.2 min (S), Rt = 37.4 min (R). The absolute con-
figuration was assigned as the (S)-configuration by X-ray crystallo-
graphic analysis.23
N-[(2S)-(2-Bromo-4-methylphenyl)phenylmethyl]-4-methylben-
zenesulfonamide (7j). White solid: mp 181.2−182.1 °C; Rf 0.20
(hexane/AcOEt = 4/1); 1H NMR (CDCl3) δ 2.27 (s, 3H), 2.39 (s, 3H),
5.24 (d, J = 6.7 Hz, 1H), 5.85 (d, J = 6.7 Hz, 1H), 7.00 (d, J = 7.9 Hz,
1H), 7.05−7.07 (m, 2H), 7.18 (d, J = 7.9 Hz, 2H), 7.20−7.24 (m,
5H), 7.62 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 20.5, 21.4, 60.0,
122.7, 127.1, 127.2, 127.5, 128.3, 128.4, 129.1, 129.2, 133.2, 136.0,
136.8, 139.1, 139.4, 143.1; IR (KBr) 3363 m, 3303 s, 2923 m, 2361 w,
1742 w, 1598 m, 1493 m, 1448 m, 1335 s, 1164 s, 1093 m, 1072 m,
1030 m, 932 m, 901 m, 849 m, 809 m, 753 w, 738 m, 719 w, 696 m,
669 s, 629 w, 580 s, 548 s, 465 m; MS m/z (relative intensity, %) 277
(15), 276 (91), 275 (18), 274 (M+ − Ts, 100), 270 (11), 194 (27),
2918
dx.doi.org/10.1021/jo300201g | J. Org. Chem. 2012, 77, 2911−2923

The Journal of Organic Chemistry
Article
N-[(2R)-(2-Chlorophenyl)phenylmethyl]-4-methylbenzenesulfo-
namide (12). White solid: mp 171.1−172.5 °C; Rf 0.23 (hexane/
AcOEt = 4/1); 1H NMR (CDCl3) δ 2.37 (s, 3H), 5.54 (d, J = 7.3 Hz,
1H), 5.93 (d, J = 7.3 Hz, 1H), 7.07−7.22 (m, 10H), 7.36 (br s, 1H),
7.61 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3) δ 21.4, 58.5, 126.9, 127.1,
127.2, 127.7, 128.6, 128.7, 129.2, 129.3, 129.8, 132.7, 136.8, 137.4,
139.2, 143.3; IR (KBr) 3853 w, 3735 w, 3649 w, 3287 m, 3236 m,
1699 w, 1653 w, 1597 w, 1558 w, 1541 w, 1507 w, 1495 w, 1442 m,
1320 s, 1151 s, 1094 s, 1038 m, 941 m, 906 w, 831 w, 813 m, 755 s,
697 s, 666 s, 607 w, 574 s, 546 s, 419 w; MS m/z (relative intensity, %)
218 (31), 217 (14), 216 (M+ − Ts, 100), 180 (11), 166 (10), 165 (16),
155 (16), 138 (13), 104 (10), 91 (45), 77 (15), 65 (11); exact
mass-ESI calcd for C20H18ClNNaO2S 394.0644 [M + Na]+, found
7.32 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 7.9 Hz,
2H), 7.56 (t, J = 7.9 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H); 13C NMR
(CDCl3) δ 21.6, 65.6, 123.7, 124.7, 128.0, 128.1, 128.6, 128.7, 128.8,
129.0, 129.1, 134.3, 135.8, 136.8, 144.7, 146.4, 166.4; [α]27D = −80.8°
(c 0.95, CHCl3) for 99% ee (R) (lit.7a [α]20D = +86.8° (c 0.95, CHCl3)
for 99% ee (S)); HPLC (Chiralpak AD-H, n-hexane/2-propanol = 90/
10, flow = 0.4 mL/min, detection at 254 nm) Rt = 66.7 min (S), Rt =
69.6 min (R).
(3S)-2,3-Dihydro-3-(4-methoxyphenyl)-2-[(4-methylphenyl)-
sulfonyl]-1H-isoindol-1-one (8b).7a White solid: mp 97.5−98.9 °C; Rf
1
0.18 (hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.35 (s, 3H), 3.80
(s, 3H), 6.19 (s, 1H), 6.77 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz,
2H), 7.13 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6
Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.84 (d, J =
7.6 Hz, 1H); 13C NMR (CDCl3) δ 21.5, 55.3, 65.2, 113.9, 123.7,
124.5, 127.9, 128.6, 128.8, 128.9, 129.1, 129.4, 134.2, 135.9, 144.6,
146.5, 159.7, 166.3; IR (KBr) 2934 m, 2836 m, 1731 s, 1611 m, 1513 s,
1468 m, 1359 s, 1289 s, 1268 m, 1247 s, 1215 m, 1173 s, 1092 s,
1035 s, 903 w, 880 w, 847 s, 812 s, 777 m, 738 s, 724 s, 705 m, 686 m,
666 s, 631 w, 619 m, 576 s, 546 s, 416 w; MS m/z (relative intensity, %)
393 (M+, 10), 329 (M+ − SO2, 28), 328 (10), 239 (16), 238 (M+ − Ts,
100), 195 (14), 130 (28), 91 (28), 77 (12), 65 (11); exact mass-ESI
calcd for C22H19NNaO4S 416.0932 [M + Na]+, found 416.0933;
[α]17 = +42.7° (c 1.00, CHCl3) for 99% ee (S) (lit. [α]20 = +50.0°
394.0645; [α]19 = −16.5° (c 1.00, CHCl3) for 99% ee (S); HPLC
D
(Chiralpak AD-H, n-hexane/2-propanol = 90/10, flow 0.7 mL/min,
detection at 254 nm) Rt = 25.5 min (S), Rt = 29.3 min (R). The
absolute configuration was assigned as S from the comparison with the
repoted HPLC retention time and specific optical rotation data (lit.25
[α]20 = −16.5° (c 0.49, CHCl3) for 95% ee (S)).
D
Typical Procedure for Rhodium-Catalyzed Aminocarbony-
lative Cyclization Using Pentafluorobenzaldehyde (Schemes 3
and 4 and Table 1). In a 5 mL two-necked flask equipped with reflux
condenser were placed [RhCl(cod)]2 (6.2 mg, 0.0125 mmol), dppp
(10.3 mg, 0.025 mmol), and xylene (0.5 mL), and the solution was stirred
at room temperature for 15 min, whereupon a light yellow suspension
occurred. At this point, benzylamine 7a (104.2 mg, 0.25 mmol, 99% ee),
pentafluorobenzaldehyde (245.1 mg, 1.25 mmol), K2CO3 (69.1 mg,
0.50 mmol) (in addition, KI (83.0 mg, 0.50 mmol) for the reaction of
12), and xylene (1.5 mL) were added. The mixture was degassed
through three freeze−pump−thaw cycles and stirred at 130 °C under
N2 until the substrate was completely consumed. The reaction mixture
was filtered, and the filtrate was concentrated in vacuo to give a residue
that was purified by column chromatography on silica gel (eluent: hexane/
AcOEt = 4/1) to give (3S)-2,3-dihydro-3-(4-methoxyphenyl)-2-[(4-
methylphenyl)sulfonyl]-1H-isoindol-1-one (8a) (81.0 mg, 0.223 mmol)
in 89% yield as a white solid, along with the hydrogenated starting material
(9a) in 10% yield as white solid.
D
D
(c 1.01, CHCl3) for 99% ee (S)); HPLC (Chiralpak AD-H, n-hexane/
2-propanol = 80/20, flow = 0.7 mL/min, detection at 254 nm) Rt =
25.1 min (S), Rt = 31.5 min (R).
(3S)-2,3-Dihydro-3-(4-methylphenyl)-2-[(4-methylphenyl)-
sulfonyl]-1H-isoindol-1-one (8c). White solid: mp 147.5−149.1 °C; Rf
1
0.21 (hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.35 (s, 3H), 2.37
(s, 3H), 6.19 (s, 1H), 6.97 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 7.9 Hz,
2H), 7.14 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.46 (t, J =
7.6 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.85 (d,
J = 7.6 Hz, 1H); 13C NMR (CDCl3) δ 21.1, 21.6, 65.4, 123.6, 124.6,
127.9, 128.1, 128.8, 128.9, 129.1, 129.3, 133.9, 134.2, 135.9, 138.5,
144.6, 146.5, 166.4; IR (KBr) 3276 w, 2922 w, 2360 w, 1732 s, 1596 w,
1513 w, 1469 w, 1353 s, 1288 m, 1171 s, 1102 s, 851 m, 814 m, 741 m,
718 w, 703 m, 687 m, 666 s, 619 w, 575 s, 542 m; MS m/z (relative
intensity, %) 314 (23), 313 (M+ − SO2, 99), 312 (57), 223 (17), 222
(M+ − Ts, 100), 206 (10), 182 (10), 165 (14), 130 (38), 105 (17),
102 (10), 91 (70), 77 (17), 76 (11), 65 (34); exact mass-ESI calcd for
(3S)-2,3-Dihydro-2-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-isoin-
dol-1-one ((S)-8a).7a White solid: mp 207.8−209.4 °C; Rf 0.20
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.36 (s, 3H), 6.22 (s,
1H), 7.08 (d, J = 7.3 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 7.9
Hz, 1H), 7.26 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.47 (t, J =
7.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.86 (d,
J = 7.9 Hz, 1H); 13C NMR (CDCl3) δ 21.6, 65.5, 123.7, 124.6, 128.0,
128.1, 128.6, 128.7, 128.8, 128.9, 129.1, 134.3, 135.7, 136.8, 144.7,
146.3, 166.4; IR (KBr) 1723 s, 1595 w, 1494 w, 1455 w, 1372 m, 1350 m,
1292 m, 1189 m, 1169 s, 1091 m, 815 w, 736 w, 701 w, 687 w, 676 w,
664 m, 605 w, 577 m, 546 w; MS m/z (relative intensity, %) 300
(22), 299 (M+ − SO2, 100), 298 (70), 222 (20), 208 (M+ − Ts, 55),
168 (15), 165 (19), 152 (10), 130 (28), 105 (17), 91 (63), 77 (38),76
(13), 65 (24), 51 (15); exact mass-ESI calcd for C21H17NNaO3S
C22H19NNaO3S 400.09833 [M + Na]+, found 400.09825; [α]17
=
D
+61.6° (c 1.00, CHCl3) for 98% ee (S); HPLC (Chiralpak AD-H, n-
hexane/2-propanol = 90/10, flow = 1.0 mL/min, detection at 254 nm)
Rt = 24.3 min (S), Rt = 28.4 min (R). The absolute configuration was
assigned as the (S)-configuration by X-ray crystallographic analysis.23
(3S)-2,3-Dihydro-3-(2-methylphenyl)-2-[(4-methylphenyl)-
sulfonyl]-1H-isoindol-1-one (8d). White solid: mp 175.9−177.3 °C;
1
Rf 0.21 (hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.37 (s, 3H),
2.78 (s, 3H), 6.29 (d, J = 7.3 Hz, 1H), 6.60 (s, 1H), 6.81 (t, J = 7.3 Hz,
1H), 7.11−7.15 (m, 3H), 7.17 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.3 Hz,
1H), 7.44−7.55 (m, 5H), 7.86 (d, J = 7.9 Hz, 1H); 13C NMR (CDCl3)
δ 19.7, 21.6, 61.0, 123.3, 124.8, 126.3, 126.4, 127.8, 128.1, 128.2, 128.8,
129.1, 130.9, 134.3, 135.0, 135.7, 136.5, 144.7, 146.9, 166.7; IR (KBr)
2925 w, 2359 w, 1717 s, 1597 w, 1468 w, 1363 m, 1343 w, 1292 m,
1209 w, 1189 m, 1172 s, 1112 m, 1090 m, 829 w, 813 w, 757 w, 744 m,
724 m, 693 m, 666 m, 610 w, 571 s, 546 m, 452 w; MS m/z (relative
intensity, %) 314 (12), 313 (M+ − SO2, 45), 223 (17), 222 (M+ − Ts,
100), 179 (15), 178 (12), 130 (24), 91 (52), 77 (11), 65 (24); exact
mass-ESI calcd for C22H20NO3S 378.11639 [M + H]+, found 378.11641;
[α]17D = +128.3° (c 1.00, CHCl3) for 95% ee (S); HPLC (Chiralpak AD-
H, n-hexane/2-propanol = 95/5, flow = 0.4 mL/min, detection at 254
nm) Rt = 78.8 min (S), Rt = 82.4 min (R). The absolute configuration was
assigned as the (S)-configuration by X-ray crystallographic analysis.23
(3S)-3-(4-Chlorophenyl)-2,3-dihydro-2-[(4-methylphenyl)-
sulfonyl]-1H-isoindol-1-one (8e). White solid: mp 180.3−181.0 °C; Rf
386.08268 [M + Na]+, found 386.08265; [α]27 = +82.5° (c 0.95,
D
CHCl3) for 99% ee (S); HPLC (Chiralpak AD-H, n-hexane/
2-propanol = 90/10, flow = 0.4 mL/min, detection at 254 nm) Rt =
66.6 min (S), Rt = 69.3 min (R).
N-(Diphenylmethyl)-4-methylbenzenesulfonamide (9a).28 White
1
solid: mp 207.8−209.4 °C; Rf 0.29 (hexane/AcOEt = 4/1); H NMR
(CDCl3) δ 2.37 (s, 3H), 5.57 (d, J = 7.3 Hz, 1H), 5.61 (d, J = 7.3 Hz,
1H), 7.10−7.12 (m, 6H), 7.19−7.20 (m, 6H), 7.56 (d, J = 8.6 Hz,
2H); 13C NMR (CDCl3) δ 21.4, 61.2, 127.1, 127.3, 127.4, 128.4,
129.2, 137.2, 140.5, 143.0; IR (KBr) 3247 m, 1599 w, 1495 w, 1452 m,
1315 s, 1161 s, 1096 m, 1058 w, 1028 w, 940 w, 834 w, 811 w, 734 w,
700 s, 675 m, 571 s; MS m/z (relative intensity, %) 183 (15), 182
(M+ − Ts, 100), 180 (23), 167 (15), 165 (12), 155 (13), 104 (21),
91 (35), 77 (19); exact mass-ESI calcd for C20H19NNaO2S 360.10342
[M + Na]+, found 360.10342.
1
0.22 (hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.37 (s, 3H), 6.18
(3R)-2,3-Dihydro-2-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-iso-
1
indol-1-one ((R)-8a). White solid: 1H NMR (CDCl3) δ H NMR
(s, 1H), 7.02 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 7.3 Hz, 1H), 7.17 (d, J =
8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.54−
7.59 (m, 3H), 7.85 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3) δ 21.6,
(CDCl3) δ 2.36 (s, 3H), 6.22 (s, 1H), 7.07 (d, J = 7.3 Hz, 2H), 7.13
(d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 7.3 Hz, 2H),
2919
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Article
64.8, 123.6, 124.8, 128.0, 128.8, 128.9, 129.2, 129.3, 129.4, 134.4,
134.6, 135.6, 135.8, 145.0, 145.8, 166.2; IR (KBr) 3062 m, 2927 w,
2361 w, 1738 s, 1596 m, 1493 m, 1465 m, 1416 m, 1371 s, 1288 s,
1215 m, 1189 m, 1171 s, 1090 s, 1015 m, 903 w, 850 s, 815 m, 746 s,
717 m, 704 s, 671 s, 662 m, 615 m, 573 s, 549 s, 539 s, 499 m; MS m/z
(relative intensity, %) 335 (32), 334 (40), 333 (M+ − SO2, 100),
332 (61), 244 (19), 242 (M+ − Ts, 62), 222 (17), 207 (22), 202 (17),
165 (11), 152 (11), 130 (30), 111 (10), 105 (20), 102 (11), 92 (11),
91 (81), 77 (23), 76 (18), 75 (12), 65 (34), 51 (13); exact mass-ESI
calcd for C21H17ClNO3S 398.06177 [M + H]+, found 398.06177;
330 (19), 329 (M+ − SO2, 78), 328 (38), 252 (11), 239 (21), 238
(M+ − Ts, 100), 207 (36), 195 (18), 160(12), 155(10), 135 (31), 92
(12), 91 (74), 77 (27), 65 (18), 60 (10); exact mass-ESI calcd for
C22H19NNaO4S 416.0932 [M + Na]+, found 416.0933; [α]17
=
D
+137.3° (c 1.00, CHCl3) for 99% ee (S); HPLC (Chiralpak AD-H,
n-hexane/2-propanol = 90/10, flow = 1.0 mL/min, detection at 254 nm)
Rt = 28.0 min (R), Rt = 32.0 min (S). The absolute configuration was
assigned as the (S)-configuration by X-ray crystallographic analysis.23
(3S)-2,3-Dihydro-5-methoxy-2-[(4-methylphenyl)sulfonyl]-3-phe-
nyl-1H-isoindol-1-one (8i). White solid: mp 208.9−210.2 °C; Rf 0.18
1
[α]17 = +59.5° (c 1.00, CHCl3) for 99% ee (S); HPLC (Chiralpak
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.26 (s, 3H), 3.66 (s,
D
3H), 6.05 (s, 1H), 6.48 (d, J = 1.8 Hz, 1H), 6.88 (dd, J = 8.6, 1.8 Hz,
1H), 7.00 (d, J = 7.3 Hz, 2H), 7.03 (d, J = 7.9 Hz, 2H), 7.17 (t, J =
7.3 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.67 (d,
J = 8.6 Hz, 1H); 13C NMR (CDCl3) δ 21.5, 55.7, 65.2, 107.4, 116.4,
121.0, 126.2, 127.8, 127.9, 128.5, 128.6, 129.0, 135.9, 136.9, 144.4,
148.9, 164.7, 166.0; IR (KBr) 3853 w, 3735 w, 3649 w, 2942 w, 2362 w,
1731 s, 1608 s, 1558 w, 1541 w, 1491 m, 1456 m, 1399 w, 1364 s, 1296 m,
1277 m, 1246 s, 1187 m, 1172 s, 1081 s, 1019 m, 943 m, 869 w, 843 m,
812 m, 765 m, 721 m, 703 m, 678 m, 660 m, 608 w, 575 s, 547 m, 516 m,
465 w, 441 w; MS m/z (relative intensity, %) 330 (23), 329 (M+ −
SO2, 100), 328 (73), 252 (17), 238 (M+ − Ts, 52), 195 (10), 168 (12),
160 (13), 135 (14), 106 (10), 91 (59), 77 (24), 65 (20), 63 (10);
exact mass-ESI calcd for C22H19NNaO4S 416.0932 [M + Na]+, found
OJ-H, n-hexane/2-propanol = 80/20, flow = 1.0 mL/min, detection at
254 nm) Rt = 23.8 min (R), Rt = 28.9 min (S). The absolute configura-
tion was assigned as the (S)-configuration by X-ray crystallographic
analysis.23
(3S)-2,3-Dihydro-3-(4-fluorophenyl)-2-[(4-methylphenyl)-
sulfonyl]-1H-isoindol-1-one (8f). White solid: mp 165.6−166.9 °C; Rf
1
0.22 (hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.37 (s, 3H), 6.21
(s, 1H), 6.95 (t, J = 8.6 Hz, 2H), 7.06 (dd, J = 8.6, 5.5 Hz, 2H), 7.14−
7.17 (m, 3H), 7.48 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.57
(td, J = 7.6, 1.2 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3)
2
δ 21.5, 64.7, 115.6 (d, JC−F = 21.1 Hz), 123.6, 124.7, 127.9, 128.7,
3
4
129.1, 129.2, 129.8 (d, JC−F = 8.6 Hz), 132.7 (d, JC−F = 2.9 Hz),
1
134.4, 135.8, 144.8, 146.1, 162.7 (d, JC−F = 247.6 Hz), 166.2; IR
416.0933; [α]20 = −8.2° (c 0.85, CHCl3) for 99% ee (S); HPLC
(KBr) 3086 m, 3064 m, 2927 m, 2359 w, 1810 w, 1736 s, 1604 s, 1511 s,
1496 m, 1465 s, 1424 m, 1399 m, 1371 s, 1331 m, 1289 s, 1226 s,
1189 s, 1171 s, 1092 s, 1014 m, 954 w, 939 w, 904 m, 851 s, 816 s, 790 s,
738 s, 718 s, 705 m, 687 s, 676 s, 662 s, 617 m, 572 s, 555 s, 539 s,
511 m, 496 m, 471 w, 412 w; MS m/z (relative intensity, %) 317
(M+ − SO2, 100), 316 (72), 227 (10), 226 (M+ − Ts, 58), 222 (15),
186 (20), 183 (20), 130 (25), 105 (17), 91 (62), 77 (19), 76 (13), 65
(29); exact mass-ESI calcd for C21H17FNO3S 382.0913 [M + H]+,
found 382.0914; [α]17D = +89.3° (c 1.00, CHCl3) for 99% ee (S); HPLC
(Chiralpak OJ-H, n-hexane/2-propanol = 70/30, flow = 1.0 mL/min,
detection at 254 nm) Rt = 18.6 min (R), Rt = 23.5 min (S). The absolute
configuration was assigned as the (S)-configuration by X-ray crystallo-
graphic analysis.23
D
(Chiralpak AD-H, n-hexane/2-propanol = 80/20, flow = 1.0 mL/min,
detection at 254 nm) Rt = 21.5 min (S), Rt = 25.2 min (R). The
absolute configuration was assigned as the (S)-configuration by X-ray
crystallographic analysis.23
(3S)-2,3-Dihydro-6-methyl-2-[(4-methylphenyl)sulfonyl]-3-phe-
nyl-1H-isoindol-1-one (8j). White solid: mp 186.5−188.1 °C; Rf 0.23
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.35 (s, 3H), 2.40 (s,
3H), 6.17 (s, 1H), 7.04 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 7.3 Hz, 2H),
7.12 (d, J = 7.9 Hz, 2H), 7.24 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz,
1H), 7.36 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.64 (s, 1H);
13C NMR (CDCl3) δ 21.2, 21.6, 65.4, 123.3, 124.5, 127.9, 128.0, 128.5,
128.6, 128.8, 129.1, 135.5, 135.8, 137.0, 139.2, 143.7, 144.6, 166.5; IR
(KBr) 3252 m, 3064 w, 2361 w, 1717 s, 1594 m, 1507 m, 1492 s, 1455 m,
1442 m, 1375 s, 1352 s, 1308 s, 1266 s, 1232 m, 1189 s, 1166 s, 1112 s,
1091 s, 1069 s, 955 m, 923 m, 881 m, 854 m, 814 s, 783 m, 764 s, 731 m,
702 s, 673 s, 661 s, 619 m, 593 s, 565 s, 545 s, 421 w; MS m/z (relative
intensity, %) 314 (23), 313 (M+ − SO2, 100), 312 (64), 298 (14), 236
(21), 223 (12), 222 (M+ − Ts, 70), 207 (15), 168 (10), 165 (14), 144
(19), 119 (28), 91 (87), 90 (12), 89 (18), 77 (22), 65 (29), 51 (10);
exact mass-ESI calcd for C22H19NNaO3S 400.09833 [M + Na]+, found
(3S)-2,3-Dihydro-2-[(4-methylphenyl)sulfonyl]-3-[4-
(trifluoromethyl)phenyl]-1H-isoindol-1-one (8g). White solid: mp
139.3−141.1 °C; Rf 0.21 (hexane/AcOEt = 4/1); 1H NMR (CDCl3) δ
2.37 (s, 3H), 6.25 (s, 1H), 7.14−7.16 (m, 3H), 7.21 (d, J = 8.6 Hz,
2H), 7.49−7.53 (m, 3H), 7.54 (d, J = 8.6 Hz, 2H), 7.58 (t, J = 7.9 Hz,
1H), 7.89 (d, J = 7.9 Hz, 1H); 13C NMR (CDCl3) δ 21.6, 64.8, 123.6,
2
1
123.7 (d, JC−F = 272.5 Hz), 125.0, 125.7 (q, JC−F = 3.8 Hz), 127.9,
3
128.3, 128.8, 129.3, 129.4, 130.9 (d, JC−F = 32.6 Hz), 134.5, 135.7,
400.09830; [α]23 = +67.9° (c 1.00, CHCl3) for 99% ee (S); HPLC
141.0, 145.1, 145.4, 166.1; IR (KBr) 3439 w, 3068 w, 2956 w, 2361 w,
1925 w, 1727 s, 1597 m, 1494 m, 1468 m, 1423 m, 1372 s, 1328 s,
1290 s, 1212 s, 1170 s, 1109 s, 1067 s, 1018 s, 904 w, 861 s, 813 s,
799 m, 771 m, 748 s, 736 s, 705 m, 695 s, 665 s, 649 s, 622 m, 594 s,
572 s, 542 s, 490 m, 414 w; MS m/z (relative intensity, %) 368 (24),
367 (M+ − SO2, 100), 366 (73), 276 (M+ − Ts, 31), 236 (21), 222
(31), 105 (15), 92 (10), 91 (85), 77 (21), 76 (14), 65 (37); exact
mass-ESI calcd for C22H16F3NNaO3S 454.0701 [M + Na]+, found
D
(Chiralpak OD-H, n-hexane/2-propanol = 90/10, flow = 1.0 mL/min,
detection at 254 nm) Rt = 14.6 min (R), Rt = 17.1 min (S). The absolute
configuration was assigned as the (S)-configuration by X-ray crystallo-
graphic analysis.23
(3S)-2,3-Dihydro-6-fluoro-2-[(4-methylphenyl)sulfonyl]-3-phenyl-
1H-isoindol-1-one (8k). White solid: mp 170.0−172.3 °C; Rf 0.21
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.36 (s, 3H), 6.19 (s,
454.0700; [α]17 = +88.8° (c 1.00, CHCl3) for 99% ee (S); HPLC
1H), 7.06 (d, J = 7.3 Hz, 2H), 7.12−7.15 (m, 3H), 7.23−7.28 (m,
D
3H), 7.33 (t, J = 7.3 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.50 (dd, J =
(Chiralpak AD-H, n-hexane/2-propanol = 95/5, flow = 0.8 mL/min,
detection at 254 nm) Rt = 43.3 min (S), Rt = 46.4 min (R). The absolute
configuration was assigned as the (S)-configuration by X-ray crystallo-
graphic analysis.23
2
7.3, 2.4 Hz, 1H); 13C NMR (CDCl3) δ 21.6, 65.2, 110.9 (d, JC−F
=
24.0 Hz), 122.2 (d, 2JC−F = 24.0 Hz), 125.6 (d, 3JC−F = 7.7 Hz), 127.9,
128.0, 128.7, 128.8, 129.2, 130.8 (d, JC−F = 8.6 Hz), 135.5, 136.3,
3
141.9 (d, 4JC−F = 1.9 Hz), 144.9, 162.9 (d, 1JC−F = 250.5 Hz), 165.3 (d,
4JC−F = 3.8 Hz); IR (KBr) 3853 w, 3735 w, 3649 w, 3067 w, 1909 w,
1747 s, 1596 m, 1558 w, 1541 w, 1488 s, 1456 m, 1441 m, 1400 w,
1364 s, 1290 s, 1260 s, 1231 m, 1189 m, 1170 s, 1090 s, 1069 s, 954 m,
922 w, 880 m, 852 m, 829 m, 813 m, 780 m, 765 s, 734 w, 698 m, 670 s,
618 m, 594 m, 563 s, 546 s, 526 m, 420 w, 406 w; MS m/z (relative
intensity, %) 318 (21), 317 (M+ − SO2, 100), 316 (57), 240 (19), 227
(10), 226 (M+ − Ts, 63), 183 (16), 168 (14), 148 (24), 123 (18), 95
(10), 92 (10), 91 (73), 77 (26), 65 (30), 51 (12); exact mass-ESI calcd
(3S)-2,3-Dihydro-6-methoxy-2-[(4-methylphenyl)sulfonyl]-3-phe-
nyl-1H-isoindol-1-one (8h). White solid: mp 208.9−210.4 °C; Rf 0.18
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.36 (s, 3H), 3.83 (s,
3H), 6.15 (s, 1H), 7.04 (d, J = 9.2 Hz, 1H), 7.06 (d, J = 7.3 Hz, 2H),
7.10−7.14 (m, 3H), 7.25 (t, J = 7.3 Hz, 2H), 7.28 (d, J = 1.8 Hz, 1H),
7.31 (t, J = 7.3 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H); 13C NMR (CDCl3)
δ 21.6, 55.7, 65.2, 106.4, 123.1, 124.6, 127.9, 128.0, 128.5, 128.6, 129.1,
130.0, 135.8, 137.0, 138.9, 144.6, 160.4, 166.5; IR (KBr) 3853 w, 3735 w,
3649 w, 2954 w, 1719 s, 1619 w, 1595 w, 1558 w, 1493 s, 1471 m,
1455 m, 1369 s, 1336 m, 1310 m, 1278 m, 1174 s, 1092 s, 1072 s, 1019
m, 948 m, 913 w, 861 w, 847 m, 814 s, 776 w, 763 m, 722 w, 702 m,
691 m, 664 s, 625 m, 600 m, 568 s, 545 s; MS m/z (relative intensity, %)
for C21H16FNNaO3S 404.0733 [M + Na]+, found 404.0732; [α]23
=
D
+78.3° (c 1.00, CHCl3) for 99% ee (S); HPLC (Chiralpak AD-H, n-
hexane/2-propanol = 90/10, flow = 1.0 mL/min, detection at 254 nm)
2920
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Article
Rt = 19.5 min (R), Rt = 21.8 min (S). The absolute configuration was
assigned as the (S)-configuration by X-ray crystallographic analysis.23
(3S)-2,3-Dihydro-5-fluoro-2-[(4-methylphenyl)sulfonyl]-3-phenyl-
1H-isoindol-1-one (8l). White solid: mp 173.4−173.5 °C; Rf 0.18
(d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 7.45 (s, 1H), 7.88 (d, J =
7.9 Hz, 2H), 8.00 (d, J = 7.9 Hz, 1H), 9.36 (s, 1H); 13C NMR
(CDCl3) δ 21.5, 21.6, 128.0, 128.1, 128.3, 128.9, 129.7, 130.3, 134.1,
134.7, 144.6, 147.6, 168.9; IR (KBr) 3735 m, 3649 m, 2361 w, 1749 w,
1647 w, 1582 s, 1456 w, 1395 w, 1355 w, 1323 s, 1293 m, 1277 m,
1227 m, 1183 m, 1155 s, 1088 s, 1041 m, 878 w, 832 s, 810 m, 774 s,
706 w, 666 s, 589 s, 559 m, 545 m, 531 m, 514 m, 478 w, 448 m; MS
m/z (relative intensity, %) 272 (M+ − Br, 41), 207 (20), 155 (25),
92 (15), 91 (100), 90 (11), 65 (22); exact mass-ESI calcd for
C15H14BrNNaO2S 373.9826 [M + Na]+, found 373.9830.
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.36 (s, 3H), 6.18 (s,
1H), 6.84 (dd, J = 7.9, 1.8 Hz, 1H), 7.07 (d, J = 7.3 Hz, 2H), 7.13 (d,
J = 7.9 Hz, 2H), 7.16 (td, J = 7.9, 1.8 Hz, 1H), 7.28 (t, J = 7.3 Hz, 2H),
7.34 (t, J = 7.3 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.86 (dd, J = 7.9, 4.9
4
Hz, 1H); 13C NMR (CDCl3) δ 21.5, 65.1 (d, JC−F = 1.9 Hz), 111.0
(d, 2JC−F = 24.0 Hz), 117.3 (d, 2JC−F = 24.0 Hz), 124.9 (d, 4JC−F = 1.9
Hz), 127.1 (d, 3JC−F = 9.6 Hz), 127.9, 128.0, 128.8, 128.9, 129.1, 135.6,
136.2, 144.8, 148.9 (d, 3JC−F = 9.6 Hz), 165.2, 166.5 (d, 1JC−F = 256.2
Hz); IR (KBr) 3735 w, 3649 w, 3067 w, 2920 w, 1724 s, 1620 m, 1604
m, 1484 m, 1456 m, 1366 s, 1337 m, 1306 s, 1264 m, 1236 m, 1189 m,
1171 s, 1134 m, 1090 s, 951 m, 918 w, 869 m, 841 m, 814 m, 782 w,
762 m, 721 m, 699 m, 686 s, 669 s, 654 m, 607 w, 577 s, 552 m, 514 m,
469 w, 431 w; MS m/z (relative intensity, %) 318 (21), 317 (M+ −
SO2, 100), 316 (70), 240 (18), 226 (M+ − Ts, 52), 183 (14), 168
(17), 148 (22), 123 (13), 91 (68), 77 (28), 65 (31), 51 (12); exact
mass-ESI calcd for C21H16FNNaO3S 404.07326 [M + Na]+, found
N-[(2-Bromo-4-fluorophenyl)methylene]-4-methylbenzenesulfo-
namide (6k). White solid: mp 143.6−146.9 °C; Rf 0.41 (hexane/
AcOEt = 4/1); 1H NMR (CDCl3) δ 2.43 (s, 3H), 7.09 (td, J = 8.2, 2.0
Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.37 (dd, J = 8.2, 2.0 Hz, 1H), 7.88
(d, J = 8.6 Hz, 2H), 8.17 (dd, J = 8.2, 5.5 Hz, 1H), 9.34 (s, 1H); 13C
2
2
NMR (CDCl3) δ 21.6, 115.8 (d, JC−F = 22.1 Hz), 121.1 (d, JC−F
=
25.0 Hz), 127.6 (d, 4JC−F = 2.9 Hz), 128.2, 129.7 (d, 3JC−F = 10.6 Hz),
129.8, 132.5 (d, 3JC−F = 9.6 Hz), 134.4, 144.9, 165.9 (d, 1JC−F = 263.0
Hz), 167.6; IR (KBr) 3084 m, 1699 w, 1670 w, 1590 s, 1481 s, 1394
m, 1362 m, 1328 s, 1246 s, 1187 m, 1158 s, 1119 m, 1087 s, 1032 m,
973 w, 894 m, 864 s, 833 m, 812 s, 711 s, 704 m, 666 s, 588 s, 553 s, 537
m, 513 s, 478 m, 460 m, 450 m; MS m/z (relative intensity, %) 276
(M+ − Br, 21), 155 (45), 92 (11). 91 (100), 65 (24); exact mass-ESI
calcd for C14H11BrFNNaO2S 377.9576 [M + Na]+, found 377.9575.
N-[(2-Bromo-5-fluorophenyl)methylene]-4-methylbenzenesulfo-
namide (6l). White solid: mp 114.1−116.8 °C; Rf 0.43 (hexane/
AcOEt = 4/1); 1H NMR (CDCl3) δ 2.41 (d, J = 3.7 Hz, 3H), 7.14 (tt,
J = 8.5, 2.5 Hz, 1H), 7.34 (dd, J = 8.2, 2.1 Hz, 2H), 7.58 (dd, J = 8.5,
5.0 Hz, 1H), 7.75 (dd, J = 9.2, 2.5 Hz, 1H), 7.86 (dd, J = 8.2, 2.1 Hz,
2H), 9.30 (dd, J = 4.3, 1.8 Hz, 1H); 13C NMR (CDCl3) δ 21.5, 116.6
404.07328; [α]23 = +86.6° (c 1.00, CHCl3) for 99% ee (S); HPLC
D
(Chiralpak AD-H, n-hexane/2-propanol = 90/10, flow = 1.0 mL/min,
detection at 254 nm) Rt = 23.2 min (S), Rt = 26.7 min (R). The
absolute configuration was assigned as the (S)-configuration by X-ray
crystallographic analysis.23
Substrates for Schemes 3−6 and Table 2: N-Tosylbenzaldi-
mines 6 and 11. N-[(2-Bromophenyl)methylene]-4-methylbenze-
nesulfonamide (6a).29 White solid: mp 144.3−146.3 °C; Rf 0.36
1
(hexane/AcOEt = 4/1); H NMR (CDCl3) δ 2.45 (s, 3H),
7.36−7.39 (m, 3H), 7.43 (td, J = 7.9, 1.8 Hz, 1H), 7.66 (dd, J =
7.9, 1.2 Hz, 1H), 7.90 (d, J = 7.9 Hz, 2H), 8.15 (dd, J = 7.9, 1.8
Hz, 1H), 9.43 (s, 1H); 13C NMR (CDCl3) δ 21.6, 127.9, 128.1,
128.8, 129.8, 130.4, 130.9, 133.7, 134.4, 135.7, 144.8, 169.0; IR
(KBr) 1597 s, 1556 m, 1430 m, 1359 w, 1319 s, 1290 m, 1273
m, 1214 m, 1156 s, 1086 s, 1026 m, 861 m, 807 s, 786 s, 760 s,
705 m, 688 s, 658 m, 613 m, 546 s, 498 m, 449 m, 422 w; MS
m/z (relative intensity, %) 258 (M+ − Br, 39), 155 (40), 92
(12), 91 (100), 65 (22); exact mass-EI calcd for C14H12BrNO2S
336.9772, found 336.9773.
(dd, 2JC−F = 24.5, 3.4 Hz), 122.7 (d, 4JC−F = 2.9 Hz), 123.0 (d, 2JC−F
=
23.0 Hz), 128.1, 129.8, 132.4 (dd, 3JC−F = 7.7, 2.9 Hz), 133.9, 135.1 (d,
1
3JC−F = 7.7 Hz), 145.0, 161.5 (dd, JC−F = 249.5, 1.9 Hz), 167.7 (t,
4JC−F = 1.9 Hz); IR (KBr) 3735 m, 3649 m, 3096 m, 2362 w, 1914 w,
1748 w, 1699 w, 1591 s, 1573 s, 1507 w, 1469 s, 1451 m, 1409 s, 1360
m, 1331 s, 1294 m, 1265 s, 1225 m, 1185 m, 1163 s, 1105 m, 1089 s,
1034 m, 1018 w, 995 w, 980 m, 875 m, 824 s, 806 s, 752 s, 695 m, 672
s, 621 s, 599 m, 579 m, 552 s, 539 s, 521 m, 481 w, 452 m; MS m/z
(relative intensity, %) 276 (M+ − Br, 31), 155 (39), 92 (10), 91 (100),
65 (23); exact mass-ESI calcd for C14H11BrFNNaO2S 377.95756
[M + Na]+, found 377.95758.
N-[(2-Bromo-4-methoxyphenyl)methylene]-4-methylbenzenesul-
fonamide (6h). White solid: mp 122.1−123.6 °C; Rf 0.37 (hexane/
1
AcOEt = 4/1); H NMR (CDCl3) δ 2.42 (s, 3H), 3.85 (s, 3H), 6.87
N-(Phenylmethylene)benzenesulfonamide (11).29 White solid: mp
(dd, J = 8.6, 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 7.9 Hz,
2H), 7.87 (d, J = 7.9 Hz, 2H), 8.09 (d, J = 8.6 Hz, 1H), 9.30 (s, 1H);
13C NMR (CDCl3) δ 21.5, 55.9, 114.5, 118.4, 123.6, 127.9, 129.7,
1
91.0−92.6 °C; Rf 0.35 (hexane/AcOEt = 4/1); H NMR (CDCl3) δ
2.44 (s, 3H), 7.35 (d, J = 7.9 Hz, 2H), 7.49 (t, J = 7.9 Hz, 2H), 7.62 (t,
J = 7.9 Hz, 1H), 7.89 (d, J = 7.9 Hz, 2H), 7.93 (d, J = 7.9 Hz, 2H),
9.03 (s, 1H); 13C NMR (CDCl3) δ 21.5, 127.9, 129.0, 129.7, 131.1,
132.1 134.8, 134.9, 144.5, 170.0; IR (KBr) 3070 w, 1652 w, 1598 s,
1574 s, 1496 w, 1450 s, 1403 w, 1364 m, 1319 s, 1224 m, 1187 m,
1157 s, 1088 s, 1020 w, 999 m, 924 w, 867 s, 783 s, 756 s, 704 w, 689 m,
674 s, 618 s, 554 s, 540 s, 490 m, 473 s; MS m/z (relative intensity, %)
259 (M+, 12), 155 (44), 104 (M+ − Ts, 12), 92 (11) 91 (100), 77 (12),
65 (22), 51 (12); exact mass-EI calcd for C14H13NO2S 259.06670, found
259.06670.
130.6, 132.0, 135.1, 144.4, 165.1, 168.3; IR (KBr) 3853 w, 3735 w,
3648 w, 3006 w, 2359 w, 1924 w, 1699 w, 1684 w, 1653 w, 1584 s,
1559 s, 1538 s, 1653 w, 1584 s, 1559 s, 1538 s, 1491s, 1456 m, 1435 m,
1403 m, 1325 s, 1292 m, 1260 s, 1221 m, 1184 m, 1159 s, 1126 m,
1086 s, 1029 m, 1018 m, 884 m, 849 m, 827 s, 813 s, 801 s, 776 s, 705
w, 671 s, 602 m, 555 m, 542 s, 526 s, 454 m, 424 w; MS m/z (relative
intensity) 288 (M+ − Br, 21), 214 (27), 212 (M+ − Ts, 30), 207 (16),
155 (17), 92 (20), 91 (100), 77 (10), 65 (25), 63 (15); exact mass-ESI
calcd for C15H14BrNNaO3S 389.9776 [M + Na]+, found 389.9777.
N-[(2-Bromo-5-methoxyphenyl)methylene]-4-methylbenzenesul-
fonamide (6i). White solid: mp 144.1−146.1 °C; Rf 0.38 (hexane/
Typical Procedure for the One-Pot Synthesis (Schemes 5
and 6 and Table 2). In a 5 mL two-necked flask equipped with a
reflux condenser were placed N-tosyl-2-bromobenzaldimine (6a)
(169.1 mg, 0.50 mmol), phenylboronic acid (67.1 mg, 0.55 mmol),
[RhCl((R)-10)]2 (23.5 mg, 0.025 mmol), KOH (11.2 mg, 0.20
mmol), and xylene (2 mL). The reaction mixture was then degassed
through three freeze−pump−thaw cycles and stirred at 60 °C for 2 h.
Pentafluorobenzaldehyde (490.2 mg, 2.50 mmol), dppp (11.2 mg,
0.050 mmol) (in addition, KI (83.0 mg, 0.50 mmol) for the reaction of 11),
and K2CO3 (138.2 mg, 1.0 mmol) were then added, and the mixture was
degassed again and stirred at 130 °C until the substrate had been
completely consumed. After filtering the reaction mixture, the filtrate
was concentrated in vacuo, and the residue was purified by column
chromatography on silica gel (eluent: hexane/AcOEt = 4/1) to give
(3S)-2,3-dihydro-2-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-isoindol-
1-one (8a) (148.9 mg, 0.410 mmol) in 82% yield as a white solid.
1
AcOEt = 4/1); H NMR (CDCl3) δ 2.43 (s, 3H), 3.78 (s, 3H), 6.99
(dd, J = 8.6, 3.1 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz,
1H), 7.59 (d, J = 3.1 Hz, 1H), 7.88 (d, J = 8.6 Hz, 2H), 9.34 (s, 1H);
13C NMR (CDCl3) δ 21.6, 55.7, 113.2, 119.7, 123.6, 128.2, 129.8,
131.4, 134.3, 134.4, 144.8, 159.0, 169.1; IR (KBr) 3087 s, 2939 s, 1749 w,
1588 s, 1491 m, 1462 s, 1417 s, 1357 m, 1324 s, 1292 s, 1231 s, 1186 s,
1156 s, 1089 s, 1052 s, 1014 s, 995 m, 945 s, 876 s, 817 s, 749 s, 704 m,
692 m, 673 s, 624 s, 598 s, 566 m, 545 s, 455 s; MS m/z (relative
intensity) 289 (11), 288 (M+ − Br, 58), 155 (16), 139 (18), 92 (11),
91 (100), 65 (19), 63 (12); exact mass-ESI calcd for C15H14BrNNaO3S
389.9776 [M + Na]+, found 389.9775.
N-[(2-Bromo-4-methylphenyl)methylene]-4-methylbenzenesulfo-
namide (6j). White solid: mp 143.6−146.2 °C; Rf 0.39 (hexane/
1
AcOEt = 4/1); H NMR (CDCl3) δ 2.37 (s, 3H), 2.42 (s, 3H), 7.15
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The Journal of Organic Chemistry
Article
Procedure for the One-Pot Synthesis of (3S)-3-Phenyl-1(3H)-
isobenzofuranone (14) (Scheme 7). In a 5 mL two-necked flask
equipped with a reflux condenser were placed 2-bromobenzaldehyde
(13) (53.1 mg, 0.50 mmol), phenylboronic acid (67.1 mg, 0.55
mmol), [RhCl((R)-10)]2 (23.5 mg, 0.025 mmol), K3PO4 (21.2 mg,
1.0 mmol), and xylene (2 mL), and the reaction mixture was degassed
through three freeze−pump−thaw cycles and stirred at 60 °C for 5 h.
Pentafluorobenzaldehyde (490.2 mg, 2.50 mmol), dppp (20.6 mg,
0.050 mmol), and K3PO4 (21.2 mg, 1.0 mmol) were then added, and
the mixture was degassed again and stirred at 130 °C until 13 was had
been completely consumed. The reaction mixture was filtered, the
filtrate was concentrated in vacuo, and the residue was purified by
column chromatography on silica gel (eluent: hexane/AcOEt = 4/1)
to give (3S)-3-phenyl-1(3H)-isobenzofuranone (14)30 (76.7 mg, 0.365
mmol) in 73% yield as a white solid. White solid: mp 113.2−115.3 °C;
(3) (a) Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.;
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Nieuwenhuyzen, M.; Reynolds, K.; Sarma, P. K. S.; Stevenson, P. J.
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J. P.; Nieuwenhuyzen, M.; Reynolds, K.; Sarma, P. K. S.; Stevenson, P.
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1
Rf 0.49 (hexane/AcOEt = 4/1); H NMR (CDCl3) δ 6.41 (s, 1H),
7.28 (dd, J = 6.1, 3.1 Hz, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.36−7.40 (m,
3H), 7.56 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.97 (d, J = 7.6
Hz, 1H); 13C NMR (CDCl3) δ 82.7, 122.8, 125.5, 125.6, 126.9, 128.9,
129.2, 129.3, 134.3, 136.4, 149.6, 170.5; IR (KBr) 3483 m, 3064 m,
3033 m, 2950 m, 2545 w, 2253 w, 2135 w, 2037 w, 1955 w, 1744 s,
1611 s, 1599 s, 1494 s, 1474 m, 1456 s, 1335 s, 1286 s, 1210 s, 1184 s,
1157 m, 1099 s, 1067 s, 1012 s, 966 s, 920 s, 894 s, 841 m, 790 m, 763 s,
742 s, 698 s, 621 s, 569 m, 537 s; MS m/z (relative intensity, %) 210 (M+,
49), 209 (12), 181 (10), 165 (19), 133 (12), 105 (100), 104 (29), 77
(37), 76 (17), 51 (18), 50 (10); exact mass-ESI calcd for C14H10Na1O2
́
2356. (b) Stajer, G.; Csende, F. Curr. Org. Chem. 2005, 9, 1277−1286.
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Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron: Asymmetry
2008, 19, 111−123. (e) Deniau, E.; Couture, A.; Grandclaudon, P.
Tetrahedron: Asymmetry 2008, 19, 2735−2740. (f) Yu, X.; Lu, A.;
Wang, Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C. Eur. J. Org. Chem.
2011, 892−897.
233.0578 [M + Na]+, found 233.0579; [α]28 = +29.0° (c 0.80, CHCl3)
D
for 62% ee (S) (lit. [α]20D = +40.5° (c 0.80, CHCl3) for 93% ee); HPLC
(Chiralpak OD-H, n-hexane/2-propanol = 85/15, flow = 1.0 mL/min,
detection at 225 nm) Rt = 8.0 min (S), Rt = 9.8 min (R).
(7) (a) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem.
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Hu, X.; Xia, C.; Huang, H. Angew. Chem., Int. Ed. 2010, 49, 2728−
2731.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds; HPLC charts by
which enantiomeric excesses of benzylamines 7 and 12, their
hydrogenated derivatives 9, and carbonylated products 8 and
14 were measured; and X-ray crystallographic data and ORTEP
drawings of 7l and 8c−l. This material is available free of charge
via the Internet at http://pubs.acs.org.
(8) For reports on an intramolecular aminocarbonylation reaction
using carbon monoxide for the constructing of the isoindolinone
framework, see: (a) Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978,
43, 1684−1687. (b) Grigg, R.; Sridharan, V.; Suganthan, S.; Bridge,
A. W. Tetrahedron 1995, 51, 295−306. (c) Ryu, I.; Matsu, K.; Minakata,
S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120, 5838−5839. (d) Bocelli,
G.; Catellani, M.; Cugini, F.; Ferraccioli, R. Tetrahedron Lett. 1999, 40,
2623−2624. (e) Anderson, J. C.; Flaherty, A.; Swarbrick, M. E. J. Org.
Chem. 2000, 65, 9152−9156. (f) Grigg, R.; MacLachlan, W. S.;
MacPherson, D. T.; Sridharan, V.; Suganthan, S.; Thornton-Pett, M.;
Zhang, J. Tetrahedron 2000, 56, 6585−6594. (g) Grigg, R.; Zhang, L.;
Collard, S.; Keep, A. Tetrahedron Lett. 2003, 44, 6979−6982. (h) Gai,
X.; Grigg, R.; Khamnaen, T.; Rajviroongit, S.; Sridharan, V.; Zhang, L.;
Collard, S.; Keep, A. Tetrahedron Lett. 2003, 44, 7441−7443. (i) Orito,
K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.; Yuguchi, M.;
Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126, 14342−14343.
(j) Grigg, R.; Zhang, L.; Collard, S.; Ellis, P.; Keep, A. J. Organomet.
Chem. 2004, 689, 170−173. (k) Grigg, R.; Gai, X.; Khamnaen, T.;
Rajviroongit, S.; Sridharan, V.; Zhang, L.; Collard, S.; Keep, A. Can. J.
Chem. 2005, 83, 990−1005. (l) Orito, K.; Miyazawa, M.; Nakamura,
T.; Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.;
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(m) Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008, 10, 5281−5284.
(n) Grigg, R.; Sridharan, V.; Shah, M.; Mutton, S.; Kilner, C.;
MacPherson, D.; Milner, P. J. Org. Chem. 2008, 73, 8352−8356.
(o) Onozaki, Y.; Kurono, N.; Senboku, H.; Tokuda, M.; Orito, K.
J. Org. Chem. 2009, 74, 5486−5495. (p) Kallan, N. C.; Spencer, K. L.;
Blake, J. F.; Xu, R.; Heizer, J.; Bencsik, J. R.; Mitchell, I. S.; Gloor, S. L.;
Martinson, M.; Risom, T.; Gross, S. D.; Morales, T. H.; Wu, W.-I;
Vigers, G. P. A; Brandhuber, B. J.; Skelton, N. J. Bioorg. Med. Chem.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: morimoto@ms.naist.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported, in part, by a Grant-in-Aid
for Scientific Research on Innovative Area “Molecular
Activation Directed toward Straightforward Synthesis” from
MEXT. We wish to acknowledge Prof. Tamio Hayashi and
Dr. Takahiro Nishimura of Kyoto University for the gift of a
sample of [RhCl((R)-10)]2. We thank also Ms. Mika Yamamura
and Ms. Yuriko Nishiyama, and Mr. Shouhei Katao for assistance
in obtaining HRMS and X-ray crystallographic data, respectively.
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