Electroreductive intermolecular coupling of phthalimides with aldehydes: Application to the synthesis of alkylideneisoindolin-1-ones

Article abstract of DOI:10.1016/j.tet.2012.07.094

The electroreduction of N-methyl, N-p-anisyl, and N-unsubstituted phthalimides with aldehydes in the presence of chlorotrimethylsilane and triethylamine gave intermolecularly coupled products, 3-hydroxy-3-(1- hydroxyalkyl)isoindolin-1-ones. The coupling p

Full text of DOI:10.1016/j.tet.2012.07.094

Tetrahedron 68 (2012) 8805e8816
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Tetrahedron
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Electroreductive intermolecular coupling of phthalimides with aldehydes:
application to the synthesis of alkylideneisoindolin-1-ones
*
Naoki Kise , Shinsaku Isemoto, Toshihiko Sakurai
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-cho Minami, Tottori 680-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 April 2012
Received in revised form 28 July 2012
Accepted 29 July 2012
Available online 14 August 2012
The electroreduction of N-methyl, N-p-anisyl, and N-unsubstituted phthalimides with aldehydes in the
presence of chlorotrimethylsilane and triethylamine gave intermolecularly coupled products, 3-hydroxy-
3-(1-hydroxyalkyl)isoindolin-1-ones. The coupling products were reduced with Et3SiH/BF3$Et2O to 3-(1-
hydroxyalkyl)isoindolin-1-ones, which were dehydrated to alkylideneisoindolin-1-ones. From N-un-
substituted phthalimides, Z-isomers of alkylideneisoindolin-1-ones were obtained stereospecifically.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Electroreduction
Reductive coupling
Chlorotrimethylsilane
Phthalimides
Alkylideneisoindolin-1-ones
1. Introduction
(Scheme 2). We found that Z-isomers of 4 were stereospecifically
formed from N-unsubstituted 2. The synthesis of alkylidenei-
The reductive cross coupling of phthalimides with carbonyl
compounds is promising method for the synthesis of 3-
soindolin-1-ones has attracted much attention from synthetic
chemists,5 since a lot of natural products6 and pharmaceutically
active compounds7 possessing an alkylideneisoindolin-1-one
structure have been reported.
a
substituted isoindoline-1-ones. To date, the intermolecular cou-
pling of N-substituted phthalimides with aliphatic aldehydes and
ketones,1 and the intramolecular coupling of phthalimides with
aldehydes,2a ketones,2b oxime ethers,2c nitrones,2c and Michael
accepters2c have been realized using samarium(II) iodide as a re-
ducing agent. Recently, we have also reported the electroreductive
intramolecular coupling of phthalimides with ketones and alde-
OH
R
1) +2e
TMSCl-Et3N
O
O
HO
n
n
N
R
N
2) Bu4NF
hydes3 (Scheme 1) and -unsaturated esters4 in the presence of
a,b
O
O
R = Me, n = 1,2
R = H, n = 1~3
chlorotrimethylsilane (TMSCl) and triethylamine (TEA). In this pa-
per, we report the electroreductive intermolecular coupling of
phthalimides with aldehydes in the presence of TMSCl and TEA
(Scheme 2). It is noted that not only N-methyl (X¼Me) and N-p-
anisyl (p-methoxyphenyl, X¼An) phthalimides, but also N-unsub-
stituted phthalimides (X¼H) reacted with aldehydes to give effec-
tively 3-hydroxy-3-(1-hydroxyalkyl)isoindolin-1-ones 2. Although
the N-unsubstituted 2 are more versatile than N-substituted 2 for
synthetic use, the reductive coupling of N-unsubstituted phthali-
mides with carbonyl compounds has not so far been reported. In
addition, the diols 2 were transformed to alkylideneisoindolin-1-
ones 4 by reduction with Et3SiH/BF3$Et2O and subsequent de-
HO
HO
OHC
1) +2e
TMSCl-Et3N
O
N
N
n
n
2) Bu4NF
n = 1~3
O
O
Scheme 1. Electroreductive intramolecular coupling of phthalimides with aldehydes
and ketones.
2. Results and discussion
hydration of resulting 3-(1-hydroxyalkyl)isoindolin-1-ones
3
The electroreduction of N-methylphthalimide 1a and benzal-
dehyde in the presence of TMSCl and TEA was performed according
to our method.3 The product was obtained as disilyl ether 2a0 (70%
* Corresponding author. E-mail address: kise@bio.tottori-u.ac.jp (N. Kise).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.094

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N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
R
1) +2e
TMSCl-Et3N
O
HO
O
OH
N-X
+
N-X
R
H
2) Bu4NF
Y
Y
Y
O
O
Y
2
Y
1
X = Me, An, H
Y = H, OMe, -OCH2O-
R
H
R
cat. PPTS
Et3SiH
BF3 Et2O
OH
toluene
reflux
N-X
N-X
CH2Cl2
Y
O
Y
4
O
Y
3
Scheme 2. Electroreductive intermolecular coupling of phthalimides 1 with aldehydes
and subsequent transformation to alkylideneisoindolin-1-ones 4.
yield), which was desilylated with TBAF in THF to give 3-hydroxy-3-
(hydroxy(phenyl)methyl)-2-methylisoindolin-1-one 2a in a 67%
yield from 1a with a 60:40 diastereomeric ratio (Scheme 3). The
major isomer of 2a was determined to be erythro by X-ray crys-
tallographic analysis (Fig. 1). The results of the electroreduction of
1a and N-p-anisylphthalimide 1b with a variety of aldehydes and
subsequent desilylation with TBAF are summarized in Table 1. Ar-
omatic aldehydes reacted with 1a and 1b to give the corresponding
diols 2beh (X¼Me) and 2keo (X¼An) in moderate to good yields
(runs 2e8 and 11e15). In contrast to 2a, the major isomers of 2k
Fig. 1. X-ray crystal structures of erythro-2a, threo-2k, and threo-2n.
+2e
Ph
Ph
O
TMSO
HO
TMSCl
O
OTMS
N-Me
OH
N-Me
Bu4NF
-Et3N
+
N-Me
Ph
H
O
O
O
1a
2a' 70%
2a 67% (60:40 dr)
Scheme 3. Electroreductive intermolecular coupling of 1a with benzaldehyde and subsequent desilylation to 2a.
Table 1
Electroreductive coupling of 1a,b with aldehydes and subsequent desilylation to 2aeo
R
R
O
1) +2e
TMSCl-Et3N
HO
HO
O
OH
N-X
OH
N-X
+
R
N-X
H
2) Bu4NF
O
O
O
threo-2a-o
1a
X = Me
1b X = An (p-MeOC6H4)
erythro-2a-o
run
1
R
2
Yielda (%)
drb
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
67
62
78
52
68
45
71
57
44
20
60:40c
70:30
50:50
50:50
80:20
50:50
50:50
50:50
50:50
50:50
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-FC6H4
1-Naphthyl
2-Naphthyl
3,4-Methylenedioxyphenyl
CH3CH2CH2
(CH3)2CH
10
2j
11
12
13
14
15
1b
1b
1b
1b
1b
Ph
2k
2l
2m
2n
2o
54
46
58
40
34
80:20d
80:20
67:33
80:20d
60:40
m-MeOC6H4
p-FC6H4
2-Naphthyl
3,4-Methylenedioxyphenyl
a
Isolated yield.
b
c
Diastereomeric ratio determined by 1H NMR analysis.
The major isomer was determined to be erythro by X-ray crystallography.
The major isomer was determined to be threo by X-ray crystallography.
d

N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
8807
and 2n were assigned to be threo by X-ray crystallography (Fig. 1).
Although aliphatic aldehydes afforded diols 2i and 2j, the yields
were relatively low (runs 9 and 10).
It is noteworthy that N-unsubstituted phthalimides 1cee (X¼H)
could be employed as the substrates for the electroreductive cou-
pling with aldehydes. As shown in Table 2, N-unsubstituted diols
2pew were obtained in moderate to good yields. In addition, the
reaction proceeded regiospecifically at the 1-position on 4,5-
dimethoxy- and 4,5-methylenedioxy substituted phthalimides 1d
and 1e to give 2uew (runs 6e8).
obtained in moderate to high yields as mixtures of two di-
astereomers (runs 1e9 and 15e22). The major isomers of 3a, 3b, 3d,
and 3g were determined to be threo, whereas the minor isomer of
3a was confirmed to be erythro by X-ray crystallography (Fig. 2). On
the other hand, N-p-anisyl substituted 3keo (X¼An) were obtained
stereospecifically, although the yields somewhat lowered (runs
10e14). The stereostructures of the obtained 3meo were con-
firmed to be threo by X-ray crystallography and, therefore, it is
likely that those of 3k and 3l were also threo. The stereospecific
formation of threo isomers of 3meo seems to be due to the bulky
anisyl group, since it has been reported that increasing the bulki-
ness of the N-protecting group in phthalimides leads to an increase
in threo-selectivity.1
Table 2
Electroreductive coupling of 1cee with aldehydes and subsequent desilylation to
2pew
R
O
Table 3
Reduction of 2 to 3
1) +2e
TMSCl-Et3N
HO
O
1
OH
N-H
+
5
R
4
R
R
N-H
R
H
2) Bu4NF
HO
H
H
Y
Et3SiH
BF3 Et2O
Y
O
OH
OH
OH
Y
O
Y
+
N-X
N-X
N-X
1c Y = H
2p-w
CH2Cl2
1d Y = OMe
1e Y = -OCH2O-
Y
Y
Y
O
O
O
Y
Y
threo-3
Y
erythro-3
2
run
1
R
2
Yielda (%)
drb
1
2
3
4
5
6
7
8
1c
1c
1c
1c
1c
1d
1d
1e
Ph
2p
2q
2r
2s
2t
2u
2v
2w
65
61
66
40
54
56
53
49
50:50
55:45
67:33
70:30
50:50
65:35
60:40
60:40
run
2
X
Y
R
3
Yield (%)a drb
m-MeOC6H4
p-FC6H4
2-Naphthyl
3,4-Methylenedioxyphenyl
Ph
3,4-Methylenedioxyphenyl
3,4-(MeO)2C6H3
1
2
3
4
5
6
7
8
9
2a Me
2b Me
2c Me
2d Me
2e Me
2f Me
2g Me
2h Me
2i Me
H
H
H
H
H
H
H
H
H
Ph
3a 82
3b 67
3c 78
3d 55
3e 85
3f 76
3g 80
80:20c
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-FC6H4
1-Naphthyl
2-Naphthyl
80:20d
75:25
90:10d
80:20
60:40
70:30d
90:10
85:15
a
Isolated yield.
3,4-Methylenedioxyphenyl 3h 56
CH3CH2CH2
b
Diastereomeric ratio determined by 1H NMR analysis.
3i 85
10
11
2k An
2l An
H
H
H
H
H
Ph
3k 58
3l 52
3m 56
3n 55
100:0
The cyclic voltammograms of 1a, 1b, 1c, and benzaldehyde in
m-MeOC6H4
p-FC6H4
2-Naphthyl
100:0
0.03 M Bu4NClO4/DMF on a platinum cathode showed a first re-
duction peak at ꢀ1.53 V, ꢀ1.48 V, ꢀ1.54 V, and ꢀ1.96 V versus SCE,
respectively. These results show that phthalimides 1aec can be
reduced easily than benzaldehyde. Hence, the plausible mechanism
of the electroreductive coupling of 1a with benzaldehyde is illus-
trated in Scheme 4. Carbanion A is formed by the two-electron
transfer to 1a followed by O-silylation with TMSCl. The nucleo-
philic attack of A to benzaldehyde and following silylation of
resulting O-anion B gives disilyl ether 2a0. Subsequent O-desilyla-
tion of 2a0 with TBAF affords diol 2a.
12 2m An
13 2n An
14
100:0d
100:0d
100:0d
2o An
3,4-Methylenedioxyphenyl 3o 51
15
16
17
18
19
20 2u
21 2v
22 2w
2p
2q
2r
2s
2t
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
Ph
3p 87
3q 85
3r 83
3s 85
65:35
63:37
60:40
60:40
67:33
60:40
55:45
60:40
m-MeOC6H4
p-FC6H4
2-Naphthyl
3,4-Methylenedioxyphenyl 3t 61
Ph 3u 80
3,4-Methylenedioxyphenyl 3v 65
3w 57
eOCH2Oe 3,4-(MeO)2C6H3
a
b
c
Isolated yield.
Diastereomeric ratio determined by 1H NMR analysis.
The major and minor isomers were determined to be threo and erythro, re-
Ph
O
OTMS
NMe
O
+2e
TMSCl
TMSO
PhCHO
O
spectively, by X-ray crystallography.
NMe
d
NMe
The major isomer was determined to be threo by X-ray crystallography.
O
O
1a
A
B
Dehydration of 3 in refluxing toluene containing a catalytic
amount of PPTS gave alkylideneisoindolin-1-ones 4 and the results
are summarized in Table 4. N-Substituted 4a, 4b, 4h (X¼Me), and
4n (X¼An) were produced as mixtures of two geometric isomers
(runs 1e4). The major isomers of 4a and 4b were confirmed to be E-
form by X-ray crystallography (Fig. 3). In contrast, N-unsubstituted
4pew (X¼H) were obtained stereospecifically (runs 5e12). The
geometries of the obtained 4peu were determined to be Z-form by
1H NMR analysis and X-ray crystallography (Fig. 3). The stereo-
specific formation of Z-isomers of 4pew suggests that Z-isomers
are much more thermodynamically stable than their E-isomers.5f
This assumption is also supported by the results of the DFT calcu-
lations of Z- and E-4p at the B3LYP/6-311þG(2d,p) level. As shown
in Fig. 4, Z-4p is much more stable (3.54 kcal/mol in gas phase
and 3.55 kcal/mol in toluene) than E-4p. Although the
Ph
Ph
TMSO
HO
OTMS
OH
NMe
TMSCl
TBAF
NMe
O
O
2a'
2a
Scheme 4. Reaction mechanism of electroreductive coupling of 1a with benzaldehyde.
Next, the diols 2 were reduced to 3-(1-hydroxyalkyl)isoindolin-
1-ones 3 with Et3SiH/BF3$Et2O in dichloromethane according to the
reported method1 and the results are shown in Table 3. N-Methyl
substituted 3aei (X¼Me) and N-unsubstituted 3pew (X¼H) were

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N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
Fig. 3. X-ray crystal structures of E-4a, E-4b, Z-4q, and Z-4r.
Fig. 2. X-ray crystal structures of threo-3a, erythro-3a, threo-3b, threo-3d, and threo-3g.
Fig. 4. Optimized structures and relative energies of Z- and E-4p calculated at the
B3LYP/6-311þG(2d,p) level.
Table 4
Dehydration of 3 to 4
6,7-unsubstituted 4pet (Y¼H) were obtained in moderate to good
yields (runs 5e9), the yields of the 6,7-disubstituted alkylidenei-
soindolone-1-ones 4uew lowered (runs 10e12).
R
R
R
H
cat. PPTS
toluene
OH
N-X
N-X
+
N-X
6
6
7
7
reflux
Y
Y
Y
3. Conclusion
O
O
O
Y
Y
Y
Z-4
3
E-4
The electroreduction of N-methyl, N-p-anisyl, and N-unsub-
stituted phthalimides 1 with aldehydes in the presence of TMSCl
and TEA and following desilylation with TBAF gave the adducts,
run
3
X
Y
R
4
Yielda (%) Z/Eb
1
2
3
4
5
6
7
8
9
3a Me
3b Me
3h Me
3n An
3p
3q
3r
3s
3t
H
H
H
H
H
H
H
H
H
Ph
4a 70
4b 50
33:67c,d
15:85c
33:67
3-hydroxy-3-(1-hydroxyalkyl)isoindolin-1-ones 2. The diols
2
p-MeOC6H4
3,4-Methylenedioxyphenyl 4h 65
3,4-Methylenedioxyphenyl 4n 54
were transformed to alkylideneisoindolin-1-ones 4 by reduction
with Et3SiH/BF3$Et2O and subsequent dehydration of resulting
3-(1-hydroxyalkyl)isoindolin-1-ones 3 in refluxing toluene in the
presence of PPTS. From N-unsubstituted phthalimides 1cee,
Z-isomers of 4pew were obtained stereospecifically.
33:67
H
H
H
H
H
H
H
H
Ph
4p 56
4q 58
4r 57
4s 68
100:0d
100:0e
100:0e
100:0d
100:0d,e
100:0e
100:0
m-MeOC6H4
p-FC6H4
2-Naphthyl
3,4-Methylenedioxyphenyl 4t 45
Ph 4u 24
3,4-Methylenedioxyphenyl 4v 22
4w 30
10 3u
11 3v
12 3w
OMe
OMe
4. Experimental section
4.1. General
eOCH2Oe 3,4-(MeO)2C6H3
100:0
a
Isolated yield.
b
c
Z/E ratio determined by 1H NMR analysis.
Column chromatography was performed on silica gel 60. CH3CN,
TMSCl, TEA, DMF, and CH2Cl2 were distilled from CaH2. THF was
distilled from sodium benzophenone ketyl radical.
The major isomer was determined to be E-form by X-ray crystallography.
d
e
The geometry was determined by 1H NMR.
The geometry was determined to be Z by X-ray crystallography.

N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
8809
4.2. Typical procedures for electroreduction and subsequent
desilylation
white solid; Rf 0.3 (hexanes/ethyl acetate¼1:2); mp 162e165 ꢂC; 1H
NMR (CDCl3)
d 2.86 (s, 2.1H), 2.91 (s, 0.9H), 3.64 (s, 2.1H), 3.72 (s,
0.9H), 5.04 (s, 0.7H), 5.14 (s, 0.3H), 6.50e6.55 (m, 1.4H), 6.63e6.68
(s, 0.6H), 6.74e6.79 (m, 1.4H), 6.92e6.97 (m, 0.6H), 7.15e7.56 (m,
3H), 7.69e7.73 (m, 0.7H), 7.99e8.04 (m, 0.3H); 13C NMR (CDCl3,
A 0.3 M solution of Et4NOTs in CH3CN (15 mL) was placed in the
cathodic chamber of a divided cell (40 mL beaker, 3 cm diameter,
6 cm height) equipped with a lead cathode (5ꢁ5 cm2), a platinum
anode (2ꢁ1 cm2), and a ceramic cylindrical diaphragm (1.5 cm di-
ameter). A 0.3 M solution of Et4NOTs in DMF (4 mL) was placed in
the anodic chamber (inside the diaphragm). N-Methylphthalimide
1a (161 mg, 1 mmol), benzaldehyde (318 mg, 3 mmol), TMSCl
(0.64 mL, 5 mmol), and TEA (0.70 mL, 5 mmol) were added to the
cathodic chamber. After 300 C of electricity was passed at a con-
stant current of 100 mA at room temperature, the catholyte was
evaporated in vacuo. The residue was dissolved in ethyl acetate
(20 mL) and insoluble solid was filtered off. After removal of the
solvent, the residue was purified by column chromatography on
silica gel (hexanes/ethyl acetate) to give 2a0 in a 70% yield with an
80:20 dr.
DMSO-d6)
d 24.2 (q), 24.7 (q), 54.5 (q), 54.6 (q), 75.3 (d), 75.5 (d),
90.9 (s), 91.1 (s), 112.2 (d), 112.3 (d), 121.7 (d) 121.9 (d), 122.9 (d),
124.0 (d), 127.5 (d), 128.0 (d), 128.6 (d), 128.7 (d), 129.4 (s), 130.3 (s),
130.5 (d), 130.6 (d), 131.7 (s), 132.2 (s), 144.5 (s), 144.7 (s), 158.4 (s),
166.8 (s), 167.0 (s); HRMS (ESI) calcd for C17H18NO4 (MþH)þ
300.1236, found 300.1234.
4.2.5. 3-Hydroxy-3-(hydroxy(3-methoxyphenyl)methyl)-2-
methylisoindolin-1-one (2c). Diastereomeric mixture (50:50);
white solid; Rf 0.25 (hexanes/ethyl acetate¼1:2); mp 160e162 ꢂC;
1H NMR (CDCl3, DMSO-d6)
d 3.11 (s, 1.5H), 3.14 (s, 1.5H), 3.51 (s,
1.5H), 3.64 (s, 1.5H), 4.47 (br s, 0.5H), 4.71 (br s, 0.5H), 5.11 (s, 0.5H),
5.18 (s, 0.5H), 6.03 (br s, 0.5H), 6.28 (br s. 0.5H), 6.42 (br s, 0.5H),
6.54e6.63 (m, 1H), 6.65 (br s, 0.5H), 6.69e6.74 (m, 1H), 6.93e6.99
(m, 0.5H), 7.03e7.09 (m, 0.5H), 7.19e7.25 (m, 0.5H), 7.35e7.54 (m,
2.5H), 7.59e7.63 (m, 0.5H), 7.82e7.87 (m, 0.5H); 13C NMR (CDCl3,
To a solution of the crude 2a0 in THF (10 mL) was added 1 M TBAF
in THF (1 mL) at 0 ꢂC and the mixture was stirred for 15 min. After
addition of acetic acid (60 mg, 1 mmol), the solvent was removed in
vacuo. The crude product was purified by column chromatography
on silica gel (hexanes/ethyl acetate) to give 2a in a 67% yield with
a 60:40 dr. Recrystallization of the diastereomeric mixture of 2a
from ethyl acetate gave erythro-2a (major) as a crystalline solid.
DMSO-d6)
d 24.4 (q), 24.7 (q), 54.7 (q), 55.0 (q), 73.7 (d), 75.5 (d),
91.2 (s), 91.6 (s), 112.2 (d), 112.8 (d), 113.4 (d), 113.6 (d), 119.6 (d),
120.4 (d), 121.7 (d) 121.9 (d), 123.9 (d), 124.9 (d), 128.07 (d), 128.13
(d), 129.1 (d), 130.5 (d), 131.1 (d), 132.3 (s), 132.9 (s), 141.3 (s), 142.1
(s), 145.1 (s), 145.8 (s), 158.26 (s), 158.29 (s), 166.4 (s), 166.7 (s);
HRMS (ESI) calcd for C17H18NO4 (MþH)þ 300.1236, found 300.1233.
4.2.1. 2-Methyl-3-(phenyl(trimethylsilyloxy)methyl)-3-(trimethylsi-
lyloxy)isoindolin-1-one (2a0). Diastereomeric mixture (80:20); col-
orless paste; Rf 0.5 (hexanes/ethyl acetate¼5:1); 1H NMR (CDCl3)
4.2.6. 3-Hydroxy-3-(hydroxy(2-methoxyphenyl)methyl)-2-
methylisoindolin-1-one (2d). Diastereomeric mixture (50:50);
white solid; Rf 0.6 (hexanes/ethyl acetate¼1:2); mp 172e175 ꢂC; 1H
d
ꢀ0.22 (s, 7.2H), ꢀ0.14 (s, 1.8H), ꢀ0.02 (s, 7.2H), 0.04 (s, 1.8H), 2.93
(s, 0.6H), 3.08 (s, 2.4H), 5.02 (s, 1H), 6.53e6.58 (m, 0.8H), 6.89e6.94
(m, 0.2H), 7.00e7.58 (m, 7H), 7.68e7.73 (m, 0.8H), 7.75-7.79 (m,
NMR (CDCl3)
d
3.02 (d, 0.5H, J¼5.5 Hz), 3.08 (s, 1.5H), 3.11 (s, 1.5H),
0.2H); 13C NMR (CDCl3)
d
(major) 0.0 (q), 0.7 (q), 24.7 (q), 76.7 (d),
3.22 (d, 0.5H, J¼4.1 Hz), 3.67 (s, 1.5H), 3.78 (br s,1.5H), 3.93 (s, 0.5H),
4.58 (s, 0.5H), 5.51 (d, 0.5H, J¼5.5 Hz), 5.57 (d, 0.5H, J¼4.1 Hz),
6.67e6.73 (m, 1H), 6.86e6.89 (m, 0.5H), 6.91e6.94 (m, 0.5H),
6.96e7.02 (m, 1H), 7.12e7.16 (m, 0.5H), 7.19e7.22 (m, 0.5H),
7.29e7.33 (m, 0.5H), 7.37e7.48 (m, 2H), 7.50e7.53 (m, 0.5H),
7.56e7.59 (m, 0.5H), 7.67e7.70 (m, 0.5H); 13C NMR (DMSO-d6)
93.0 (s), 122.4 (d), 124.3 (d), 126.7 (d), 127.46 (d), 128.1 (d), 129.1 (d),
129.9 (d),133.1 (s), 139.0 (s),143.4 (s),167.4 (s); (minor) ꢀ0.2 (q), 0.8
(q), 25.3 (q), 78.5 (d), 92.6 (s), 122.3 (d), 125.0 (d), 126.8 (d), 127.0
(d),127.50 (d), 127.9 (d),129.3 (d), 130.6 (d),132.6 (s),138.4 (s),144.1
(s), 167.1 (s); HRMS (ESI) calcd for C22H32NO3Si2 (MþH)þ 414.1921,
found 414.1917.
d
24.9 (q), 25.8 (q), 55.2 (q), 55.3 (q), 68.6 (d), 68.7 (d), 91.5 (s), 91.8
(s), 110.3 (d), 110.4 (d), 119.4 (d) 119.7 (d), 121.5 (d), 121.7 (d), 124.1
(d), 125.1 (d), 128.0 (s), 128.1 (d), 128.4 (d), 128.5 (s), 128.6 (d), 128.7
(s), 128.9 (d), 129.2 (d), 130.3 (d) 131.0 (d), 132.2 (s), 132.4 (s), 145.87
(s), 145.94 (s), 156.1 (s), 156.5 (s), 166.5 (s), 167.1 (s); HRMS (ESI)
calcd for C17H18NO4 (MþH)þ 300.1236, found 300.1230.
4.2.2. 3-Hydroxy-3-(hydroxy(phenyl)methyl)-2-methylisoindolin-1-
one (2a). Diastereomeric mixture (60:40); white solid; Rf 0.3
(hexanes/ethyl acetate¼1:2); mp 152e155 ꢂC; 1H NMR (CDCl3)
d
2.95 (s, 1.8H), 2.97 (s, 1.2H), 2.98 (br s, 0.4H), 3.21 (br s, 0.6H), 4.23
(br s, 0.4H), 4.31 (br s, 0.6H), 5.13 (s, 0.6H), 5.24 (s, 0.4H), 6.87-6.92
(m, 1H), 7.00e7.50 (m, 5.4H), 7.71e7.75 (m, 0.6H); 13C NMR (CDCl3,
4.2.7. 3-((4-Fluorophenyl)(hydroxy)methyl)-3-hydroxy-2-
methylisoindolin-1-one (2e). Diastereomeric mixture (80:20);
white solid; Rf 0.25 (hexanes/ethyl acetate¼1:2); mp 216e218 ꢂC;
DMSO-d6)
d 24.1 (q), 24.2 (q), 74.8 (d), 75.5 (d), 90.6 (s), 90.9 (s),
121.3 (d), 121.5 (d), 122.9 (d), 123.8 (d), 126.2 (d), 126.5 (d), 126.6 (d),
126.7 (d), 126.9 (d), 128.3 (d), 128.4 (d), 130.1 (d), 130.4 (d), 131.4 (s),
132.1 (s),137.5 (s),138.5 (s),144.36 (s),144.39 (s),166.6 (s),166.7 (s);
HRMS (ESI) calcd for C16H16NO3 (MþH)þ 270.1130, found 270.1128.
1H NMR (CDCl3, DMSO-d6)
d 3.12 (s, 1.05H), 3.14 (s, 1.95H), 5.09 (d,
0.65H, J¼2.8 Hz), 5.12 (d, 0.65H, J¼2.8 Hz), 5.14 (d, 0.35H, J¼4.6 Hz),
5.26 (d, 0.35H, J¼4.6 Hz), 6.36 (s, 0.35H), 6.58 (s, 0.65H), 6.68e6.74
(m, 1.3H), 6.86e6.96 (m, 2.7H), 6.88e6.96 (m, 2.0H), 7.14e7.19 (m,
1.6H), 7.29e7.33 (m, 0.8H), 7.39e7.45 (m, 1H), 7.18e7.23 (m, 1H),
7.36e7.63 (m, 3.35H), 7.83e7.87 (m, 0.65H); 13C NMR (DMSO-d6)
24.4 (q), 24.8 (q), 72.9 (d), 74.8 (d), 91.2 (s), 91.6 (s), 113.89 (d,
JCCF¼21.4 Hz), 113.92 (d, JCCF¼20.9 Hz), 121.8 (d), 122.0 (d), 123.8 (d),
124.7 (d), 129.0 (d, JCCCF¼8.4 Hz), 129.2 (d), 129.3 (d), 129.9 (d,
JCCCF¼8.4 Hz), 130.7 (d), 131.3 (d), 132.2 (s), 133.0 (s), 136.0 (s,
JCCCCF¼2.8 Hz), 136.7 (s, JCCCCF¼2.8 Hz), 145.0 (s), 145.6 (s), 161.5 (s,
JCF¼242.8 Hz), 161.6 (s, JCF¼242.8 Hz), 166.6 (s), 166.8 (s); HRMS
(ESI) calcd for C16H15FNO3 (MþH)þ 288.1036, found 288.1038.
4.2.3. (R
*
)-3-Hydroxy-3-((R )-hydroxy(phenyl)methyl)-2-
*
methylisoindolin-1-one (erythro-2a). White solid; Rf 0.3 (hexanes/
ethyl acetate¼1:2); mp 191e192 ꢂC (recryst from ethyl acetate); IR
(KBr) 3389, 3300, 1655, 1614, 1601, 1483, 802, 783, 716, 694 cmꢀ1
;
1H NMR (CDCl3, DMSO-d6)
(d, 1H, J¼3.7 Hz), 6.20 (s, 1H), 7.05e7.09 (m, 1H), 7.15e7.20 (m, 5H),
7.38e7.44 (m, 2H), 7.58e7.62 (m, 1H); 13C NMR (DMSO-d6)
24.3
d
3.16 (s, 3 H), 4.94 (d, 1H, J¼3.7 Hz), 5.18
d
(q), 73.5 (d), 91.5 (s), 121.8 (d), 123.8 (d), 127.0 (d), 127.2 (d), 127.9
(d), 129.0 (d), 130.5 (d), 132.9 (s), 140.5 (s), 145.1 (s), 166.6 (s). Anal.
Calcd for C16H15NO3: C, 71.36%; H, 5.61%; N, 5.20%. Found: C, 71.40%;
H, 5.62%; N, 5.15%.
4.2.8. 3-Hydroxy-3-(hydroxy(naphthalen-1-yl)methyl)-2-
methylisoindolin-1-one (2f). Diastereomeric mixture (50:50); white
solid; Rf 0.4 (hexanes/ethyl acetate¼1:2); mp 183e186 ꢂC; 1H NMR
4.2.4. 3-Hydroxy-3-(hydroxy(4-methoxyphenyl)methyl)-2-
methylisoindolin-1-one (2b). Diastereomeric mixture (70:30);
(CDCl3) d 2.87e2.91 (m, 3H), 3.04 (br s, 0.5H), 3.53 (br s. 0.5H), 3.95

8810
N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
(br s, 0.5H), 4.74 (br s, 0.5H), 5.82e5.86 (m, 0.5H), 5.96e6.00 (m,
0.5H), 6.88e7.86 (m, 10.5H), 8.13e8.18 (m, 0.5H); 13C NMR (CDCl3,
168.0 (s), 168.1 (s); HRMS (ESI) calcd for C13H18NO3 (MþH)þ
236.1287, found 236.1283.
DMSO-d6)
d 24.2 (q), 25.3 (q), 69.5 (d), 72.4 (d), 91.1 (s), 92.3 (s),
121.88 (d),121.91 (d),122.6 (d),124.07 (d),124.10 (d) 124.3 (d),124.4
(d), 124.5 (d), 124.7 (d), 124.8 (d), 125.0 (d), 125.3 (d), 125.9 (d), 127.9
(d), 128.0 (d), 128.1 (d), 128.3 (d), 128.7 (d), 128.8 (d), 130.0 (d),130.6
(s), 131.1 (s), 131.7 (s), 132.0 (s),132.5 (s), 132.7 (s), 132.9 (s), 134.8 (s),
135.7 (s), 144.8 (s), 144.9 (s), 167.1 (s), 167.5 (s); HRMS (ESI) calcd for
C20H18NO3 (MþH)þ 320.1287, found 320.1281.
4.2.13. (R
*
)-3-Hydroxy-3-((R )-hydroxy(phenyl)methyl)-2-(4-
*
methoxyphenyl)isoindolin-1-one (threo-2k). White solid; Rf 0.45
(hexanes/ethyl acetate¼1:2); mp 178e179 ꢂC (recryst from ethyl
acetate); IR (KBr) 3518, 3239, 1676, 1611, 1584, 1514, 1470, 872, 826,
787, 733, 721, 700 cmꢀ1 1H NMR (CDCl3, DMSO-d6)
; d 3.86 (s, 3H),
4.65 (d, 1H, J¼2.8 Hz), 5.04 (d, 1H, J¼2.8 Hz), 6.70e6.74 (m, 2H),
6.93e7.01 (m, 5H), 7.04e7.08 (m, 1H), 7.45e7.49 (m, 1H), 7.58e7.66
4.2.9. 3-Hydroxy-3-(hydroxy(naphthalen-2-yl)methyl)-2-
methylisoindolin-1-one (2g). Diastereomeric mixture (50:50);
white solid; Rf 0.4 (hexanes/ethyl acetate¼1:2); mp 173e176 ꢂC; 1H
(m, 4H), 7.99e8.02 (m, 1H); 13C NMR (CDCl3, DMSO-d6)
d 54.9 (q),
76.2 (d), 93.1 (s), 113.1 (d), 122.2 (d), 124.3 (d), 126.7 (d), 127.3 (d),
127.4 (d), 128.8 (s), 128.9 (d), 131.0 (s), 131.4 (d), 136.9 (s), 144.3 (s),
157.2 (s), 166.1 (s). Anal. Calcd for C22H19NO4: C, 73.12%; H, 5.30%; N,
3.88%. Found: C, 73.16%; H, 5.24%; N, 3.69%.
NMR (CDCl3) d 2.83 (s, 1.5H), 2.86 (s, 1.5H), 3.60 (br s, 1H), 4.82 (br s,
0.5H), 5.03 (br s, 0.5H), 5.17 (s, 0.5H), 5.28 (s, 0.5H), 6.89e6.92 (m,
0.5H), 6.99e7.03 (m, 0.5H), 7.11e7.15 (m, 1H), 7.16e7.21 (m, 0.5H),
7.22e7.27 (m, 1H), 7.30e7.46 (m, 4H), 7.51e7.56 (m, 1H), 7.57e7.60
(m, 0.5H), 7.60e7.65 (m, 1H), 7.67e7.70 (m, 0.5H), 7.72e7.75 (m,
4.2.14. 3-Hydroxy-3-(hydroxy(3-methoxyphenyl)methyl)-2-(4-
methoxyphenyl)isoindolin-1-one
(80:20); white solid; Rf 0.5 (hexanes/ethyl acetate¼1:2); mp
132e135 ꢂC; 1H NMR (CDCl3)
(major) 3.01 (s, 1H), 3.47 (s, 3H), 3.86
(2l). Diastereomeric
mixture
0.5H); 13C NMR (CDCl3, DMSO-d6)
d 23.5 (q), 23.8 (q), 73.6 (d), 75.2
(d), 90.4 (s), 90.8 (s), 120.9 (d), 121.0 (d), 122.7 (d), 123.6 (d), 123.9
(d) 124.6 (d), 124.65 (d), 124.67 (d), 124.69 (d), 125.2 (d), 125.3 (d),
125.55 (d),125.58 (d),126.3 (d),126.4 (d),126.8 (d),126.9 (d),127.95
(s), 127.97 (d), 129.5 (d), 130.0 (d), 131.1 (s), 131.3 (s), 131.4 (s),131.57
(s), 131.62 (s), 131.9 (s), 135.4 (s), 136.5 (s), 144.0 (s), 144.4 (s), 166.0
(s), 166.2 (s); HRMS (ESI) calcd for C20H18NO3 (MþH)þ 320.1287,
found 320.1284.
d
(s, 3H), 4.45 (s, 1H), 5.02 (s, 1H), 6.19e6.21 (m, 1H), 6.27e6.30 (m,
1H), 6.62e6.65 (m, 1H), 6.87e6.93 (m, 3H), 7.36e7.40 (m, 1H),
7.42e7.45 (m, 1H), 7.46e7.50 (m, 2H), 7.55e7.59 (m, 1H), 7.82e7.85
(m, 1H); 13C NMR (CDCl3)
d (major) 54.6 (q), 55.1 (q), 76.2 (d), 93.3
(s), 112.0 (d), 113.5 (d), 114.4 (d), 120.3 (d), 122.7 (d), 124.4 (d), 127.6
(d), 127.9 (d), 128.9 (s), 129.2 (d), 131.4 (s), 131.6 (d), 138.2 (s), 144.5
(s), 157.2 (s), 158.3 (s), 166.4 (s); HRMS (ESI) calcd for C23H22NO5
(MþH)þ 392.1498, found 392.1494.
4.2.10. 3-(Benzo[d][1,3]dioxol-5-yl(hydroxy)methyl)-3-hydroxy-2-
methylisoindolin-1-one (2h). Diastereomeric mixture (50:50);
white solid; Rf 0.3 (hexanes/ethyl acetate¼1:2); mp 177e180 ꢂC; 1H
4.2.15. 3-((4-Fluorophenyl)(hydroxy)methyl)-3-hydroxy-2-(4-
methoxyphenyl)isoindolin-1-one (2m). Diastereomeric mixture
(67:33); white solid; Rf 0.7 (hexanes/ethyl acetate¼1:2); mp
NMR (DMSO-d6)
d 2.85 (s, 1.5H), 2.97 (s, 1.5H), 4.92 (d, 0.5H,
J¼5.0 Hz), 4.93 (d, 0.5H, J¼4.1 Hz), 5.66 (d, 0.5H, J¼5.0 Hz), 5.76 (d,
0.5H, J¼4.1 Hz), 5.82e5.85 (m, 1H), 5.93e5.98 (m, 1H), 6.28 (br s.
0.5H), 6.43e6.47 (m, 0.5H), 6.56e6.61 (m, 1H), 6.64e6.77 (2.5H),
7.34e7.46 (m, 2H), 7.50e7.54 (m, 0.5H), 7.55e7.60 (m, 0.5H),
184e185 ꢂC; 1H NMR (CDCl3)
d 3.75 (s, 1H), 3.81 (s, 2H), 4.67 (s,
0.33H), 4.87 (s, 0.67H), 6.40e8.00 (m, 12H); 13C NMR (CDCl3)
(major) 55.1 (q), 75.8 (d), 93.5 (s), 113.5 (d), 113.90 (d,
d
7.78e7.82 (m, 0.5H); 13C NMR (DMSO-d6)
d
24.2 (q), 24.6 (q), 73.2
JCCF¼22.8 Hz), 122.8 (d), 124.11 (d), 127.2 (d), 128.3 (s), 129.2 (d,
JCCCF¼8.4 Hz), 129.6 (d), 130.6 (s), 131.88 (s, JCCCCF¼3.6 Hz), 131.94
(d), 143.4 (s), 157.6 (s), 162.2 (s, JCF¼245.9 Hz), 166.9 (s); (minor)
55.2 (q), 72.6 (d), 93.8 (s), 113.88 (d, JCCF¼22.8 Hz), 114.2 (d), 122.7
(d), 123.8 (d), 127.4 (s), 128.89 (d), 129.4 (d), 129.5 (d, JCCCF¼7.2 Hz),
131.2 (d), 131.8 (s), 134.2 (s), 142.9 (s), 158.2 (s), 162.2 (s,
JCF¼245.9 Hz), 168.0 (s); HRMS (ESI) calcd for C22H19FNO4 (MþH)þ
380.1298, found 380.1295.
(d), 75.2 (d), 91.1 (s), 91.5 (s), 100.6 (t), 100.7 (t), 107.0 (d), 107.3 (d),
108.3 (d), 120.6 (d), 121.1 (d), 121.6 (d), 121.7 (d), 123.8 (d) 124.7 (d),
128.9 (d), 129.1 (d), 130.5 (d), 131.1 (d), 132.2 (s), 132.9 (s),133.8 (s),
134.4 (s), 145.1 (s), 145.7 (s), 146.13 (s), 146.15 (s), 146.16 (s), 146.2
(s), 166.3 (s), 166.5 (s); HRMS (ESI) calcd for C17H16NO5 (MþH)þ
314.1028, found 314.1023.
4.2.11. 3-Hydroxy-3-(1-hydroxybutyl)-2-methylisoindolin-1-one
(2i). Diastereomeric mixture (50:50); white solid; Rf 0.35 (hexanes/
4.2.16. (R
*
)-3-Hydroxy-3-((S )-hydroxy(naphthalen-2-yl)methyl)-2-
*
ethyl acetate¼1:2); mp 115e116 ꢂC; 1H NMR (CDCl3)
d
0.60e1.53
(4-methoxyphenyl)isoindolin-1-one (threo-2n). White solid; Rf 0.45
(hexanes/ethyl acetate¼1:2); mp 199e201 ꢂC (recryst from ethyl
acetate); IR (KBr) 3489, 3144, 1665, 1609, 1508, 1466, 856, 820, 789,
(m, 7H), 2.67 (s, 1.5H), 2.81 (s, 1.5H), 3.03 (br s, 1H), 4.01e4.11 (m,
1H), 4.94 (br s, 0.5H), 5.04 (br s, 0.5H), 7.33e7.54 (m, 3.5H),
7.72e7.76 (m, 0.5H); 13C NMR (CDCl3)
d
13.68 (q), 13.70 (q), 19.1 (t),
766, 746, 731, 718, 695 cmꢀ1; 1H NMR (CDCl3)
d 2.99 (br s, 1H), 3.89
19.3 (t), 23.7 (q), 25.3 (q), 31.7 (t), 32.2 (t), 73.0 (d), 74.6 (d), 91.0 (s),
91.1 (s), 122.1 (d), 122.6 (d), 122.9 (d), 124.0 (d), 129.3 (d), 129.5 (d),
130.9 (s), 131.4 (s), 131.9 (d), 144.5 (s), 144.9 (s), 168.00 (s), 168.03
(s); HRMS (ESI) calcd for C13H18NO3 (MþH)þ 236.1287, found
236.1286.
(s, 3H), 4.11 (br s, 1H), 5.26 (s, 1H), 6.79e6.82 (m, 1H), 6.94e6.98 (m,
2H), 7.17 (br s, 1H), 7.35e7.54 (m, 9H), 7.57e7.61 (m, 1H), 7.65e7.69
(m, 1H), 7.86e7.89 (m, 1H); 13C NMR (CDCl3, DMSO-d6)
d 54.9 (q),
76.3 (d), 93.4 (s), 113.1 (d), 122.1 (d), 124.6 (d), 124.9 (d), 125.3 (d),
125.4 (d), 126.0 (d), 126.9 (d), 127.0 (d), 127.2 (d), 127.3 (d), 129.0 (d),
129.1 (s), 131.1 (s), 131.5 (d), 131.7 (s), 132.3 (s), 135.2 (s), 144.7 (s),
157.2 (s), 165.9 (d). Anal. Calcd for C26H21NO4: C, 75.90%; H, 5.14%;
N, 3.40%. Found: C, 75.95%; H, 5.17%; N, 3.30%.
4 . 2 .12 . 3 - Hy d ro x y- 3 - ( 1- hy d ro x y- 2 - m e t hyl p ro p yl ) - 2 -
methylisoindolin-1-one (2j). Diastereomeric mixture (50:50); white
solid; Rf 0.4 (hexanes/ethyl acetate¼1:2); mp 151e153 ꢂC; 1H NMR
(CDCl3)
d
0.39 (d, 1.5H, J¼6.8 Hz), 0.52 (d, 1.5H, J¼6.8 Hz), 0.76 (d,
4.2.17. 3-(Benzo[d][1,3]dioxol-5-yl(hydroxy)methyl)-3-hydroxy-2-
(4-methoxyphenyl)isoindolin-1-one (2o). Diastereomeric mixture
(60:40); white solid; Rf 0.5 (hexanes/ethyl acetate¼1:2); mp
1.5H, J¼6.9 Hz), 0.84 (d, 1.5H, J¼6.8 Hz), 1.22e1.41 (m, 1H), 2.71 (s,
1.5H), 2.89 (s, 1.5H), 3.08 (br s, 0.5H), 3.20 (br s, 0.5H), 3.87 (d, 0.5H,
J¼4.2 Hz), 3.95 (d, 0.5H, J¼5.4 Hz), 4.92 (br s, 0.5H), 5.09 (br s, 0.5H),
180e182 ꢂC; 1H NMR (CDCl3, DMSO-d6)
d
3.62 (d, 0.4H, J¼4.2 Hz),
7.34e7.54 (m, 3H), 7.76e7.80 (m, 1H); 13C NMR (CDCl3)
d
17.0 (q),
3.85 (s, 1.2H), 3.86 (s, 1.8H), 4.10 (d, 0.6H, J¼1.8 Hz), 4.81 (d, 0.4H,
J¼4.2 Hz), 4.97 (d, 0.6H, J¼1.8 Hz), 5.78e5.84 (m, 1H), 5.92e5.97 (m,
0.8H), 6.16e6.29 (m, 1.4H), 6.43e6.48 (m, 0.4H), 6.67e6.85 (m,
2.4H), 6.94e7.01 (m, 2H), 7.40e7.74 (m, 4.2H), 7.81e7.85 (m, 0.4H),
17.1 (q), 21.1 (q), 21.4 (q), 24.1 (q), 26.1 (q), 28.2 (d), 29.0 (d), 77.7 (d),
79.9 (d), 90.7 (s), 122.2 (d), 122.8 (d), 123.2 (d), 124.6 (d), 129.5 (d),
129.6 (d), 130.9 (s), 131.2 (s), 131.9 (d), 132.0 (d), 144.9 (s), 145.7 (s),

N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
8811
7.94e7.98 (m, 0.4H); 13C NMR (CDCl3, DMSO-d6)
d
55.2 (q), 73.6 (d),
0.5H), 4.36 (br s, 0.5H), 4.81 (s, 0.5H), 5.09 (s, 0.5H), 5.18 (br s, 0.5H),
5.33 (br s, 0.5H), 5.78 (s, 1H), 5.87 (s, 1H), 6.44e6.50 (m, 1H),
6.57e6.64 (m, 1H), 6.73 (s, 0.5H), 6.81 (s, 0.5H), 7.12e7.16 (m, 0.5H),
7.23e7.54 (m, 3.5H), 7.91 (br s, 0.5H), 8.05 (0.5H); 13C NMR (CDCl3)
76.4 (d), 93.4 (s), 93.7 (s), 100.6 (t), 100.7 (t), 106.9 (d), 107.7 (d),
108.7 (d), 113.6 (d) 113.9 (d), 121.1 (d), 121.7 (d), 122.86 (d), 122.93
(d), 124.2 (d), 124.4 (d), 127.6 (d), 128.2 (s), 128.9 (s),129.2 (d), 129.3
(d), 129.4 (d), 130.5 (s), 131.1 (d), 131.4 (s), 131.8 (d), 132.7 (s), 133.0
(s), 143.9 (s), 144.4 (s), 146.5 (s), 144.6 (s), 146.7 (s), 147.0 (s), 157.6
(s), 166.6 (s), 167.4 (s); HRMS (ESI) calcd for C23H20NO6 (MþH)þ
406.1291, found 406.1283.
d
77.2 (d), 77.8 (d), 89.8 (s), 90.1 (s), 100.7 (t), 100.8 (t), 107.19 (d),
107.24 (d), 107.9 (d), 108.4 (d), 121.3 (d), 121.9 (d), 122.7 (d), 123.1
(d), 123.3 (d), 124.1 (d), 129.4 (d), 130.8 (s), 131.0 (s), 131.1 (s), 131.8
(s), 132.0 (s), 132.2 (s), 145.1 (s), 145.9 (s), 146.6 (s), 146.78 (s), 146.83
(s), 147.1 (s), 170.3 (s), 170.5 (s); HRMS (ESI) calcd for C16H14NO5
(MþH)þ 300.0872, found 300.0870.
4.2.18. 3-Hydroxy-3-(hydroxy(phenyl)methyl)isoindolin-1-one
(2p). Diastereomeric mixture (50:50); colorless paste; Rf 0.45
(ethyl acetate); 1H NMR (CDCl3, DMSO-d6)
d
4.98 (br s, 0.5H), 5.08
4 . 2 . 2 3 . 3 - H y d r o x y - 3 - ( h y d r o x y ( p h e n yl ) m e t h yl ) - 6 , 7 -
dimethoxyisoindolin-1-one (2u). Diastereomeric mixture (65:35);
colorless paste; Rf 0.65 (ethyl acetate/ethanol¼10:1); 1H NMR
(br s, 0.5H), 5.33 (br s, 0.5H), 5.52 (br s, 0.5H), 6.42e6.46 (m, 1H),
7.07e7.27 (m, 5H), 7.33e7.42 (m,1.5H), 7.45e7.53 (m, 2.5H), 7.97 (br
s, 0.5H), 8.06 (br s, 0.5H); 13C NMR (CDCl3, DMSO-d6)
d
76.1 (d), 76.4
(CDCl3) d 3.66 (s, 1.95H), 3.75 (s, 1.05H), 3.78 (s, 1.05H), 3.79 (s,
(d), 88.2 (s), 88.6 (s), 121.3 (d), 121.5 (d), 122.4 (d), 123.1 (d), 126.05
(d), 126.11 (d), 126.2 (d), 126.4 (d), 126.7 (d), 127.0 (d), 127.9 (d),
128.0 (d), 130.5 (d), 131.0 (s), 131.1 (s), 138.0 (s), 138.2 (s), 145.6 (s),
145.7 (s), 167.9 (s), 168.1 (s); HRMS (ESI) calcd for C15H14NO3
(MþH)þ 256.0974, found 256.0969.
1.95H), 4.91 (s, 0.35H), 5.14 (s, 0.65H), 6.80 (d, 0.35H, J¼8.0 Hz), 6.86
(d, 0.35H, J¼8.0 Hz), 6.95 (d, 0.65H, J¼8.0 Hz), 7.04e7.25 (m, 5.65H),
7.75 (br s, 0.65H), 7.89 (br s, 0.35H); 13C NMR (CDCl3)
d 56.1 (s),
62.15 (q), 62.17 (q), 77.7 (d), 78.1 (d), 88.4 (s), 89.0 (s),115.8 (d),115.9
(d), 118.4 (d), 119.9 (d), 122.8 (s), 123.1 (s), 127.1 (d), 127.2 (d), 127.3
(d), 127.4 (d), 127.6 (d), 128.0 (d), 137.6 (s), 137.9 (s), 138.0 (s), 138.9
(s), 145.7 (s), 145.9 (s), 152.7 (s), 152.8 (s), 168.1 (s), 168.3 (s); HRMS
(ESI) calcd for C17H18NO5 (MþH)þ 316.1185, found 316.1182.
4.2.19. 3-Hydroxy-3-(hydroxy(3-methoxyphenyl)methyl)isoindolin-
1-one (2q). Diastereomeric mixture (55:45); colorless paste; Rf 0.45
(ethyl acetate); 1H NMR (CDCl3)
d 3.33 (br s, 0.45H), 3.61 (s, 1.65H),
3.66 (br s, 0.55H), 3.67 (s, 1.45H), 4.24 (br s, 0.45H), 4.41 (br s,
0.55H), 4.95 (s, 0.45H), 5.12 (s, 0.55H), 6.67e6.87 (m, 3H), 7.01e7.05
(m, 0.55H), 7.13e7.18 (m, 0.45H), 7.20 (br s, 0.55H), 7.31 (br s,
0.45H), 7.32e7.41 (m, 1.9H), 7.45e7.50 (m, 1H), 7.53e7.57 (m,
4.2.24. 3-(Benzo[d][1,3]dioxol-5-yl(hydroxy)methyl)-3-hydroxy-6,7-
dimethoxyisoindolin-1-one (2v). Diastereomeric mixture (60:40);
colorless paste; Rf 0.65 (ethyl acetate/ethanol¼10:1); 1H NMR
(CDCl3) d 3.74 (s, 1.8H), 3.798 (s, 2.4H), 3.804 (s, 1.8H), 4.81 (s, 0.4H),
0.55H), 7.62e7.66 (m, 0.55H); 13C NMR (CDCl3)
d
77.3 (d), 78.0 (d),
5.04 (s, 0.6H), 5.82 (s, 1.2H), 5.87e5.89 (m, 0.8H), 6.50e6.54 (m,
1.2H), 6.62 (d, 0.4H, J¼8.0 Hz), 6.64e6.67 (m, 0.4H), 6.74 (s, 0.6H),
6.82 (br s, 0.4H), 6.84 (d, 0.4H, J¼8.0 Hz), 6.89 (d, 0.4H, J¼8.0 Hz),
6.97 (d, 0.6H, J¼8.0 Hz), 7.16 (d, 0.6H, J¼8.0 Hz), 7.70 (br s, 0.6H),
89.7 (s), 90.1 (s), 112.9 (d), 113.2 (d), 113.5 (d), 113.9 (d), 120.0 (d),
120.6 (d), 122.8 (d), 123.0 (d), 123.2 (d), 124.2 (d), 128.3 (d), 128.4
(d), 129.3 (d), 130.9 (s), 131.1 (s), 131.9 (d), 132.1 (d), 138.8 (s), 139.3
(s), 145.2 (s), 145.9 (s), 158.5 (s), 158.6 (s), 170.3 (s), 170.5 (s); HRMS
(ESI) calcd for C16H16NO4 (MþH)þ 286.1079, found 286.1074.
7.90 (br s, 0.4H); 13C NMR (CDCl3)
d 56.1 (q), 62.0 (q), 77.3 (d), 77.9
(d), 88.4 (s), 88.8 (s), 100.6 (t), 107.1 (d), 107.9 (d), 108.4 (d), 115.8 (d),
116.0 (d), 118.2 (d), 119.7 (d), 121.2 (d), 121.8 (d), 122.8 (s), 123.1 (s),
131.5 (s), 132.0 (s), 138.1 (s), 139.0 (s), 145.8 (s), 146.0 (s), 146.5 (s),
146.6 (s), 146.9 (s), 152.86 (s), 152.92 (s), 168.1 (s), 168.3 (s); HRMS
(ESI) calcd for C18H18NO7 (MþH)þ 360.1083, found 360.1078.
4.2.20. 3-((4-Fluorophenyl)(hydroxy)methyl)-3-hydroxyisoindolin-
1-one (2r). Diastereomeric mixture (67:33); colorless paste; Rf 0.45
(ethyl acetate); 1H NMR (CDCl3)
d 3.90 (br s, 0.33H), 4.94 (s, 0.33H),
5.06 (br s, 0.67H), 5.20 (s, 0.67H), 6.73e6.78 (m, 1.33H), 6.85e6.91
(m, 0.67H), 7.05e7.09 (m, 1.33H), 7.14e7.32 (m, 3H), 7.41e7.44 (m,
0.33H), 7.49e7.55 (m, 1.33H), 7.93 (br s, 0.67H), 7.98 (br s, 0.33H);
4.2.25. 6-((3,4-Dimethoxyphenyl)(hydroxy)methyl)-6-hydroxy-
6,7-dihydro-[1,3]dioxolo[4,5-e]isoindol-8-one (2w). Diastereomeric
mixture (60:40); colorless solid; Rf 0.45 (ethyl acetate/
13C NMR (CDCl3)
d
76.7 (d), 90.3 (s), 114.2 (d, JCCF¼20.4 Hz), 122.7
(d), 123.2 (d), 129.1 (JCCCF¼7.2 Hz), 129.5 (d), 130.7 (s), 132.3 (d),
132.9 (s), 145.6 (s),162.0 (s, JCF¼247.1 Hz),170.7 (s); (minor) 77.4 (d),
89.8 (s), 114.3 (d, JCCF¼20.1 Hz), 123.0 (d), 124.0 (d), 129.5 (d), 129.6
(d, JCCCF¼7.8 Hz), 130.9 (s), 132.1 (d), 133.5 (s), 145.0 (s), 162.3 (s,
JCF¼246.2 Hz), 170.5 (s); HRMS (ESI) calcd for C15H13FNO3 (MþH)þ
274.0879, found 274.0871.
ethanol¼10:1); mp 152e155 ꢂC; 1H NMR (CDCl3)
d 3.67 (s, 1.8H),
3.72 (s, 1.2H), 3.78 (s, 1.8H), 3.83 (s, 1.2H), 4.51 (br s, 0.4H), 4.58 (br s,
0.6H), 4.90 (s, 0.4H), 5.07 (s, 0.6H), 5.95e6.01 (m, 2H), 6.60e6.94
(m, 0.44H), 7.03 (d, 0.6H, J¼7.2 Hz), 7.45 (br s, 0.6H), 7.52 (br s,
0.4H); 13C NMR (CDCl3, DMSO-d6)
d 55.50 (q), 55.53 (q), 55.60 (q),
55.63 (q), 77.0 (d), 77.1 (d), 89.4 (s), 89.9 (s), 102.4 (t), 102.5 (t),
109.98 (d), 110.05 (d), 110.7 (d), 111.3 (d), 111.4 (d), 114.1 (s), 114.3 (s),
116.2 (d), 117.3 (d), 120.3 (d), 120.7 (d), 131.6 (s), 131.8 (s), 140.1 (s),
140.4 (s), 142.4 (s), 142.5 (s), 147.5 (s), 147.6 (s), 147.9 (s), 148.0 (s),
148.97 (s), 149.03 (s), 166.2 (s), 166.5 (s); HRMS (ESI) calcd for
C18H18NO7 (MþH)þ 360.1083, found 360.1077.
4.2.21. 3-Hydroxy-3-(hydroxy(naphthalen-2-yl)methyl)isoindolin-1-
one (2s). Diastereomeric mixture (70:30); colorless paste; Rf 0.55
(ethyl acetate); 1H NMR (CDCl3)
d 3.55 (br s, 0.3H), 3.83 (br s, 0.7H),
4.36 (br s, 0.3H), 4.52 (br s, 0.7H), 5.08 (s, 0.3H), 5.28 (s, 0.7H),
7.12e7.15 (m, 0.3H), 7.23e7.54 (m, 8H), 7.55e7.59 (m, 0.7H),
7.60e7.64 (m, 2H), 7.67e7.72 (m, 1.7H), 7.76e7.80 (m, 0.3H); 13C
NMR (CDCl3)
d
77.5 (d), 90.3 (s), 122.9 (d), 123.2 (d), 125.1 (d), 125.6
4.3. Typical procedure of reduction of 2 to 3
(d), 125.74 (d), 127.0 (d), 127.3 (d), 128.0 (d), 129.3 (d), 130.7 (s),
132.1 (d), 132.39 (s), 132.7 (s), 134.9 (s), 145.8 (s), 170.6 (s); (minor)
78.2 (d), 89.9 (s), 123.1 (d), 124.1 (d), 125.68 (d), 125.8 (d), 125.9 (d),
127.1 (d), 127.4 (d), 128.1 (d), 129.3 (d), 131.0 (s), 131.9 (d), 132.44 (s),
133.0 (s), 135.4 (s), 145.1 (s), 170.5 (s); HRMS (ESI) calcd for
C19H16NO3 (MþH)þ 306.1130, found 306.1126.
To a solution of 2a (180 mg, 0.67 mmol) in CH2Cl2 (10 mL) were
added Et3SiH (0.24 mL, 1.5 mmol) and BF3$Et2O (0.20 mL, 1.5 mmol)
at 0 ꢂC, and the mixture was stirred for 1.5 h at this temperature.
After removal of the solvent in vacuo, the residue was purified by
column chromatography on silica gel (hexanes/ethyl acetate) to
give 3a in an 82% yield with an 80:20 dr. Recrystallization of the
diastereomeric mixture of 3a from ethyl acetate gave threo-3a
(major) as a crystalline solid. The mother liquor was recrystallized
to give erythro-3a (minor) as a crystalline solid.
4.2.22. 3-(Benzo[d][1,3]dioxol-5-yl(hydroxy)methyl)-3-
hydroxyisoindolin-1-one (2t). Diastereomeric mixture (50:50);
colorless paste; Rf 0.45 (ethyl acetate); 1H NMR (CDCl3)
d 4.12 (br s,

8812
N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
4.3.1. (R
*
)-3-((R
*
)-Hydroxy(phenyl)methyl)-2-methylisoindolin-1-
6.88e6.95 (m, 3H), 7.18e7.21 (m, 1H), 7.30e7.42 (m, 3H), 7.76e7.78
(m, 1H). Anal. Calcd for C17H17NO3: C, 72.07%; H, 6.05%; N, 4.94%.
Found: C, 72.09%; H, 6.05%; N, 4.84%.
one (threo-3a). White solid; Rf 0.4 (hexanes/ethyl acetate¼1:2); mp
168e169 ꢂC (recryst from ethyl acetate); IR (KBr) 3204, 1663, 1618,
1478, 756, 706, 698 cmꢀ1; 1H NMR (CDCl3)
d
2.19 (d, 1H, J¼3.4 Hz),
3.22 (s, 3H), 4.77 (d, 1H, J¼5.6 Hz), 5.05 (dd, 1H, J¼3.4, 5.6 Hz),
4.3.7. 3-((4-Fluorophenyl)(hydroxy)methyl)-2-methylisoindolin-1-
7.00e7.04 (m, 1H), 7.16e7.20 (m, 2H), 7.25e7.29 (m, 3H), 7.35e7.41
one (3e). Diastereomeric mixture (80:20); colorless paste; Rf 0.3
(m, 2H), 7.69e7.73 (m, 1H); 13C NMR (DMSO-d6)
d
29.0 (q), 66.3 (d),
(hexanes/ethyl acetate¼1:2); 1H NMR (CDCl3, DMSO-d6)
d 3.16 (s,
72.2 (d), 122.2 (d), 124.4 (d), 126.7 (d), 127.3 (s), 127.5 (d), 128.1 (d),
130.7 (d), 132.6 (s), 140.3 (s), 143.1 (s), 167.9 (s). Anal. Calcd for
C16H15NO2: C, 75.87%; H, 5.95%; N, 5.53%. Found: C, 75.83%; H,
5.96%; N, 5.44%.
2.4H), 3.19 (s, 0.6H), 4.77e4.82 (m, 1H), 5.16e5.18 (m, 0.8H),
5.30e5.33 (m, 0.2H), 6.81e6.88 (m, 1.6H), 6.97e7.09 (m, 2H),
7.22e7.28 (m, 0.4H), 7.32e7.59 (m, 3.8H), 8.03e8.08 (m, 0.2H); 13C
NMR (CDCl3, DMSO-d6) d (major) 28.9 (q), 66.3 (d), 71.8 (d),114.0 (d,
JCCF¼21.1 Hz), 122.2 (d), 124.3 (d), 127.9 (d), 128.3 (d, JCCCF¼7.7 Hz),
130.6 (d), 132.4 (s), 136.0 (s, JCCCCF¼2.9 Hz), 142.7 (s), 161.4 (s,
JCF¼243.8 Hz), 168.1 (s); HRMS (ESI) calcd for C16H15FNO2 (MþH)þ
272.1087, found 272.1084.
4.3.2. (R
*
)-3-((S )-Hydroxy(phenyl)methyl)-2-methylisoindolin-1-
*
one (erythro-3a). White solid; Rf 0.4 (hexanes/ethyl acetate¼1:2);
mp 209e210 ꢂC (recryst from ethyl acetate); IR (KBr) 3316, 1655,
1616, 1591, 1499, 1481, 787, 739, 708 cmꢀ1; 1H NMR (CDCl3)
d 2.09
(d, 1H, J¼3.7 Hz), 3.18 (s, 3H), 4.76 (d, 1H, J¼3.7 Hz), 5.31 (t, 1H,
J¼3.7 Hz), 6.77e6.81 (m, 1H), 7.30e7.44 (m, 7H), 7.75e7.79 (m, 1H).
Anal. Calcd for C16H15NO2: C, 75.87%; H, 5.95%; N, 5.53%. Found: C,
75.80%; H, 5.99%; N, 5.46%.
4.3.8. 3-(Hydroxy(naphthalen-1-yl)methyl)-2-methylisoindolin-1-
one (3f). Diastereomeric mixture (60:40); white solid; Rf 0.45
(hexanes/ethyl acetate¼1:2); mp 137e139 ꢂC; 1H NMR (CDCl3)
d
3.13 (s, 1.2H), 3.25 (s, 1.8H), 4.93 (d, 0.6H, J¼3.7 Hz), 5.04 (d, 0.4H,
J¼6.0 Hz), 5.61 (d, 0.4H, J¼6.0 Hz), 6.06 (d, 0.6H, J¼3.7 Hz), 6.43 (d,
4.3.3. 3-(Hydroxy(4-methoxyphenyl)methyl)-2-methylisoindolin-1-
one (3b). Diastereomeric mixture (80:20); white solid; Rf 0.3
(hexanes/ethyl acetate¼1:2); mp 139e142 ꢂC; 1H NMR (CDCl3,
0.6H, J¼7.3 Hz), 6.45 (d, 0.4H, J¼7.3 Hz), 7.15e8.11 (m, 10H); 13C
NMR (DMSO-d6) d 27.6 (q), 30.4 (q), 65.5 (d), 66.5 (d), 66.7 (d), 72.0
(d), 122.29 (d), 122.32 (d), 122.9 (d), 123.6 (d), 123.8 (d), 123.9 (d),
125.09 (d), 125.14 (d), 125.2 (d), 125.5 (d), 125.7 (d), 125.8 (d), 126.2
(d), 126.6 (d), 127.9 (d), 128.08 (d) 128.14 (d), 128.3 (d), 128.8 (d),
129.0 (d), 129.7 (s), 130.0 (d), 130.5 (s),130.7 (d), 132.6 (s),133.27 (s),
133.34 (s), 133.5 (s), 136.7 (s), 137.8 (s), 142.1 (s), 143.5 (s), 168.0 (s),
168.4 (s); HRMS (ESI) calcd for C20H18NO2 (MþH)þ 304.1338, found
304.1336.
DMSO-d6)
d 3.20 (s, 0.6H), 3.26 (s, 2.4H), 3.74 (s, 2.4H), 3.80 (s,
0.6H), 4.71e4.76 (m, 1H), 5.00 (dd, 1H, J¼3.8, 5.7 Hz), 5.24 (t, 0.2H,
J¼4.0 Hz), 5.33 (d, 0.2H, J¼4.0 Hz), 5.53 (d, 0.8H, J¼3.8 Hz),
6.67e6.72 (m, 1.6H), 6.80e6.84 (m, 0.4H), 6.92e6.96 (m, 0.2H),
6.99e7.04 (m, 1.6H), 7.15e7.19 (m, 0.4H), 7.22e7.26 (m, 0.8H),
7.33e7.42 (m, 2.2H), 7.58e7.62 (m, 1H); 13C NMR (CDCl3, DMSO-d6)
d
(major) 29.1 (q), 54.7 (q), 66.5 (d), 73.1 (d), 112.6 (d), 122.0 (d),
124.2 (d), 127.2 (s), 127.59 (d), 127.64 (d) 130.2 (d), 131.9 (s), 132.3
(s), 142.5 (s), 158.5 (s), 168.3 (s); HRMS (ESI) calcd for C17H18NO3
(MþH)þ 284.1287, found 284.1283.
4.3.9. 3-(Hydroxy(naphthalen-2-yl)methyl)-2-methylisoindolin-1-
one (3g). Diastereomeric mixture (70:30); white solid; Rf 0.5
(hexanes/ethyl acetate¼1:2); mp 141e144 ꢂC; 1H NMR (CDCl3,
DMSO-d6)
d
3.24 (s, 0.9H), 3.27 (s, 2.1H), 4.85 (d, 0.3H, J¼3.3 Hz),
4.3.4. (R
*
)-3-((R
*
)-Hydroxy(4-methoxyphenyl)methyl)-2-
4.87 (d, 0.7H, J¼5.4 Hz), 5.23 (d, 0.7H, J¼5.4 Hz), 5.40 (br s, 0.3H),
5.47 (d, 0.3H, J¼3.3 Hz), 5.58 (br s, 0.7H), 7.23e7.50 (m, 5.7H),
7.55e7.86 (m, 5H), 6.78e6.82 (m, 0.3H); 13C NMR (DMSO-d6)
methylisoindolin-1-one (threo-3b). White solid; Rf 0.3 (hexanes/
ethyl acetate¼1:2); mp 181e182 ꢂC (recryst from ethyl acetate); IR
(KBr) 3325, 1670, 1613, 1514, 1474, 1460, 831, 808, 762, 746, 696,
d
(major) 29.1 (q), 66.3 (d), 72.4 (d), 122.2 (d), 124.5 (d), 124.9 (d),
653 cmꢀ1; 1H NMR (CDCl3)
d
2.21 (d, 1H, J¼3.2 Hz), 3.24 (s, 3H), 3.78
125.5 (d), 125.9 (d), 126.1 (d), 126.8 (d), 127.5 (d), 127.8 (d) 128.1 (d),
130.8 (d), 132.3 (s), 132.4 (s), 132.5 (s), 138.1 (s), 143.2 (s), 167.9 (s);
HRMS (ESI) calcd for C20H18NO2 (MþH)þ 304.1338, found
304.1334.
(s, 3H), 4.73 (d, 1H, J¼6.0 Hz), 4.97 (dd, 1H, J¼3.2, 6.0 Hz), 6.76e6.81
(m, 2H), 6.99e7.03 (m, 1H), 7.05e7.09 (m, 2H), 7.35e7.41 (m, 2H),
7.69e7.73 (m,1H). Anal. Calcd for C17H17NO3: C, 72.07%; H, 6.05%; N,
4.94%. Found: C, 72.02%; H, 6.00%; N, 4.88%.
4.3.10. (R )-(Hydroxy(naphthalen-2-yl)methyl)-2-methylisoindolin-
*
4.3.5. 3-(Hydroxy(3-methoxyphenyl)methyl)-2-methylisoindolin-1-
one (3c). Diastereomeric mixture (75:25); colorless paste; Rf 0.3
1-one (threo-3g). White solid; Rf 0.5 (hexanes/ethyl acetate¼1:2);
mp 197e198 ꢂC (recryst from ethyl acetate); IR (KBr) 3248, 1665,
(hexanes/ethyl acetate¼1:2); 1H NMR (DMSO-d6)
d
3.05 (s, 2.25H),
1479, 748, 696, 669 cmꢀ1; 1H NMR (CDCl3)
d
2.45 (d, 1H, J¼3.6 Hz),
3.12 (s, 0.75H), 3.54 (s, 2.25H), 3.66 (s, 0.75H), 4.78e4.83 (m, 1H),
5.08e5.13 (m, 0.75H), 5.24e5.28 (m, 0.25H), 5.65e5.69 (m, 0.25H),
5.92e5.97 (m, 0.75H), 6.57 (br s, 0.75H), 6.11e6.86 (m, 2.5H),
6.99e7.04 (m, 0.75H), 7.14e7.20 (m, 0.25H), 7.30e7.37 (m, 1.25H),
3.21 (s, 3H), 4.86 (d, 1H, J¼5.6 Hz), 5.19 (dd, 1H, J¼3.6, 5.6 Hz),
6.98e7.02 (m, 1H), 7.30e7.38 (m, 3H), 7.46e7.51 (m, 2H), 7.65e7.70
(m, 2H), 7.73e7.79 (m, 2H), 7.80e7.84 (m, 1H). Anal. Calcd for
C20H17NO2: C, 79.19%; H, 5.65%; N, 4.62%. Found: C, 79.15%; H,
5.67%; N, 4.53%.
7.42e7.55 (m, 2.5H); 13C NMR (DMSO-d6)
d (major) 28.9 (q), 54.7
(q), 66.2 (d), 72.3 (d), 111.9 (d), 113.0 (d), 119.0 (d), 122.1 (d), 124.4
(d), 127.9 (d), 128.3 (d), 130.5 (d), 132.5 (s), 141.9 (s), 143.1 (s), 158.5
(s), 167.9 (s); (minor) 28.2 (q), 54.9 (q), 67.0 (d), 70.8 (d), 111.8 (d),
112.7 (d), 118.5 (d), 122.2 (d), 123.5 (d), 127.8 (d), 128.8 (d), 130.3 (d),
132.2 (s),142.2 (s), 142.5 (s),158.9 (s),166.0 (s); HRMS (ESI) calcd for
C17H18NO3 (MþH)þ 284.1287, found 284.1284.
4.3.11. 3-(Benzo[d][1,3]dioxol-5-yl(hydroxy)methyl)-3-hydroxy-2-
methylisoindolin-1-one (3h). Diastereomeric mixture (90:10); col-
orless paste; Rf 0.25 (hexanes/ethyl acetate¼1:2); 1H NMR (CDCl3)
d
3.15 (s, 0.3H), 3.22 (s, 2.7H), 4.69 (d, 0.1H, J¼3.4 Hz), 4.71 (d, 0.9H,
J¼5.7 Hz), 4.94 (d, 0.9H, J¼5.7 Hz), 5.18 (br s, 0.1H), 5.93 (s, 1.8H),
5.97e5.99 (m, 0.2H), 6.58e6.82 (m. 3H), 6.96e7.00 (m, 0.1H),
7.06e7.71 (m, 0.9H), 7.36e7.43 (m, 2H), 7.69e7.76 (m, 1H); 13C NMR
4.3.6. (R
*
)-3-((R )-Hydroxy(2-methoxyphenyl)methyl)-2-
*
methylisoindolin-1-one (threo-3d). White solid; Rf 0.25 (hexanes/
ethyl acetate¼1:2); mp 192e194 ꢂC (recryst from ethyl acetate); IR
(KBr) 3298, 1657, 1616, 1601, 1493, 1470, 800, 772, 754, 745, 700,
(CDCl3, DMSO-d6) d (major) 29.0 (q), 66.4 (d), 72.9 (d), 100.5 (t),
106.9 (d), 107.0 (d), 119.9 (d), 122.1 (d), 124.2 (d), 127.7 (d), 130.3 (d),
132.4 (s), 133.9 (s), 142.5 (s), 146.4 (s), 146.6 (s), 168.2 (s); (minor)
28.4 (q), 67.2 (d), 71.1 (d), 100.6 (t), 106.6 (d), 107.3 (d), 119.3 (d),
122.2 (d), 123.3 (d), 127.7 (d), 130.2 (d), 132.6 (s), 134.2 (s), 142.0 (s),
683, 656 cmꢀ1; 1H NMR (CDCl3)
d
2.61 (d, 1H, J¼6.9 Hz), 3.12 (s, 3H),
3.84 (s, 3H), 4.91 (d, 1H, J¼5.5 Hz), 5.18 (dd, 1H, J¼5.6, 6.9 Hz),

N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
8813
146.3 (s), 147.0 (s), 168.3 (s); HRMS (ESI) calcd for C17H16NO4
(d), 132.1 (s), 132.3 (s), 132.5 (s), 135.7 (s),141.6 (s), 156.7 (s), 166.9
(s). Anal. Calcd for C26H21NO3: C, 78.97%; H, 5.35%; N, 3.54%. Found:
C, 79.05%; H, 5.39%; N, 3.57%.
(MþH)þ 298.1079, found 298.1075.
4.3.12. 3-(1-Hydroxybutyl)-2-methylisoindolin-1-one (3i). Diastereo-
meric mixture (85:15); white solid; Rf 0.5 (hexanes/ethyl
4.3.17. (R
*
)-3-((R )-Benzo[d][1,3]dioxol-5-yl(hydroxy)methyl)-2-(4-
*
acetate¼1:2); mp 115e118 ꢂC; 1H NMR (CDCl3)
d
0.76e1.56 (m, 7H),
methoxyphenyl)isoindolin-1-one (threo-3o). White solid; Rf 0.7
(hexanes/ethyl acetate¼1:2); mp 241e243 ꢂC (recryst from ethyl
acetate); IR (KBr) 3198, 1653, 1609, 1585, 1508, 1487, 1470, 932, 874,
3.13 (s, 2.6H), 3.24 (s, 0.4H), 4.17e4.23 (m, 1H), 4.55e4.59 (m, 1H),
7.41e7.47 (m, 1H), 7.48e7.53 (m, 1H), 7.71e7.75 (m, 1H), 7.76e7.81
(m, 1H); 13C NMR (DMSO-d6)
d
(major) 14.1 (q), 18.8 (t), 28.0 (q), 32.1
808, 758, 729, 706, 677 cmꢀ1 1H NMR (CDCl3)
; d 2.16 (d, 1H,
(t), 65.4 (d), 68.8 (d), 122.5 (d), 124.3 (d), 128.1 (d), 131.1 (d), 132.6 (d),
143.8 (s), 167.9 (s); HRMS (ESI) calcd for C13H18NO2 (MþH)þ
220.1338, found 220.1333.
J¼2.9 Hz), 3.86 (s, 3H), 5.10 (dd, 1H, J¼2.9, 5.0 Hz), 5.55 (d, 1H,
J¼5.0 Hz), 5.81e5.82 (m, 1H), 5.83e5.84 (m, 1H), 6.20e6.24 (m, 2H),
6.48 (d, 1H, J¼8.0 Hz), 6.99e7.02 (m, 2H), 7.44e7.52 (m, 3H),
7.55e7.59 (m, 1H), 7.73e7.75 (m, 1H), 7.77e7.98 (m, 1H); 13C NMR
4.3.13. (R
*
)-3-((R
*
)-Hydroxy(phenyl)methyl)-2-(4-methoxyphenyl)
(CDCl3, DMSO-d6) d 55.0 (q), 64.4 (d), 71.2 (d), 100.2 (t), 106.5 (d),
isoindolin-1-one (threo-3k). White solid; Rf 0.25 (hexanes/ethyl
acetate¼2:1); mp 210e211 ꢂC (recryst from ethyl acetate); IR (KBr)
3300, 1649, 1611, 1512, 1468, 833, 808, 773, 756, 706, 681 cmꢀ1; 1H
106.7 (d), 113.8 (d), 119.7 (d), 122.6 (d), 123.9 (d), 124.5 (d) 127.9 (d),
130.1 (s), 130.8 (d), 132.1 (s), 132.2 (s), 141.6 (s), 146.07 (s), 146.09 (s),
156.4 (s), 166.5 (s). Anal. Calcd for C23H19NO5: C, 70.94%; H, 4.92%;
N, 3.60%. Found: C, 70.88%; H, 4.95%; N, 3.49%.
NMR (CDCl3)
d
2.26 (d, 1H, J¼3.0 Hz), 3.87 (s, 3H), 5.19 (dd, 1H,
J¼3.0, 4.7 Hz), 5.59 (d, 1H, J¼4.7 Hz), 6.74e6.79 (m, 2H), 6.99e7.13
(m, 5H), 7.40e7.45 (m, 1H), 7.50e7.58 (m, 3H), 7.66e7.70 (m, 1H),
4.3.18. 3-(Hydroxy(phenyl)methyl)isoindolin-1-one (3p). Diastereo-
meric mixture (65:35); colorless paste; Rf 0.4 (ethyl acetate); 1H
7.74e7.79 (m, 1H); 13C NMR (CDCl3)
d 55.4 (q), 64.4 (d), 71.2 (d),
114.3 (d), 122.7 (d), 124.3 (d), 124.9 (d), 126.4 (d), 127.0 (d), 127.2 (d),
128.4 (d), 130.5 (s), 131.4 (d), 132.2 (s), 138.9 (s), 142.2 (s), 156.5 (s),
166.2 (s). Anal. Calcd for C22H19NO3: C, 76.50%; H, 5.54%; N, 4.06%.
Found: C, 76.39%; H, 5.54%; N, 3.83%.
NMR (CDCl3, DMSO-d6)
d
4.49 (d, 0.65H, J¼7.5 Hz), 4.78 (d, 0.65H,
J¼7.5 Hz), 4.86 (d, 0.35H, J¼5.2 Hz), 4.90 (d, 0.35H, J¼5.2 Hz), 5.64
(br s, 0.35H), 5.71 (br s, 0.65H), 6.45e6.49 (m, 0.65H), 7.20e7.52 (m,
7.7H), 7.63e7.66 (m, 0.35H), 7.68e7.71 (m, 0.65H), 8.00 (br s,
0.65H); 13C NMR (CDCl3, DMSO-d6)
d (major) 62.2 (d), 75.6 (d),
4.3.14. (R
*
)-3-((R
*
)-Hydroxy(3-methoxyphenyl)methyl)-2-(4-
122.5 (d), 124.1 (d), 126.7 (d), 127.3 (d), 127.7 (d), 130.6 (d), 132.8 (s),
140.6 (s), 143.6 (s), 169.9 (s); (minor) 62.1 (d), 74.0 (d), 122.6 (d),
123.9 (d), 127.2 (d), 127.5 (d), 127.8 (d), 130.8 (d), 132.3 (s), 140.4 (s),
144.4 (s), 170.2 (s); HRMS (ESI) calcd for C15H14NO2 (MþH)þ
240.1025, found 240.1023.
methoxyphenyl)isoindolin-1-one (threo-3l). White solid; Rf 0.6
(hexanes/ethyl acetate¼1:2); mp 198e200 ꢂC (recryst from ethyl
acetate); IR (KBr) 3258, 1649, 1611, 1584, 1508, 1485, 1472, 878, 835,
810, 775, 756, 737, 708, 689, 660 cmꢀ1 1H NMR (CDCl3)
; d 2.23 (d,
1H, J¼3.0 Hz), 3.54 (s, 3H), 3.86 (s, 3H), 5.17 (dd, 1H, J¼3.0, 4.6 Hz),
5.58 (d, 1H, J¼4.6 Hz), 6.27e6.29 (m, 1H), 6.34e6.37 (m, 1H),
6.63e6.66 (m, 1H), 6.93e6.97 (m, 1H), 6.98e7.02 (m, 2H), 7.42e7.46
(m, 1H), 7.50e7.54 (m, 2H), 7.54e7.58 (m, 1H), 7.69e7.73 (m, 1H),
4.3.19. 3-(Hydroxy(3-methoxyphenyl)methyl)isoindolin-1-one
(3q). Diastereomeric mixture (63:37); colorless paste; Rf 0.45
(ethyl acetate); 1H NMR (CDCl3)
d
2.93 (d, 0.37H, J¼3.1 Hz), 3.15 (d,
7.78e7.82 (m, 1H); 13C NMR (CDCl3)
d
54.7 (q), 55.3 (q), 64.5 (d),
0.63H, J¼3.5 Hz), 3.77 (s, 1.11H), 3.81 (s, 1.89H), 4.54 (dd, 0.63H,
J¼3.5, 7.6 Hz), 4.72 (dd, 0.37H. J¼3.1, 6.7 Hz), 4.80 (d, 0.37H,
J¼6.7 Hz), 4.81 (d, 0.63H, J¼7.6 Hz), 6.32 (br s, 0.37H), 6.51e6.55 (m,
0.63H), 6.83e6.87 (m, 0.37H), 6.89e6.98 (m, 2.63H), 7.19 (br s,
0.63H), 7.22e7.61 (3.37H), 7.75e7.84 (m, 1H); 13C NMR (CDCl3,
72.2 (d), 111.4 (d), 113.8 (d), 114.1 (d), 119.1 (d), 123.1 (d), 124.2 (d),
124.7 (d), 127.9 (d), 128.1 (d), 130.3 (s), 130.9 (d), 132.5 (s), 139.6 (s),
141.7 (s), 156.7 (s), 158.4 (s), 167.0 (s). Anal. Calcd for C23H21NO4: C,
73.58%; H, 5.64%; N, 3.73%. Found: C, 73.45%; H, 5.72%; N, 3.59%.
DMSO-d6) d 54.9 (q), 62.4 (d), 75.9 (d), 112.6 (d), 113.5 (d), 119.7 (d),
4.3.15. (R
*
)-3-((R
*
)-(4-Fluorophenyl)(hydroxy)methyl)-2-(4-
122.7 (d), 124.1 (d), 127.9 (d), 128.9 (d), 130.7 (d), 132.7 (s), 142.2 (s),
143.4 (s), 159.1 (s), 170.3 (s); (minor) 54.8 (q), 62.1 (d), 74.2 (d), 112.1
(d), 113.0 (d), 119.0 (d), 122.7 (d), 124.0 (d), 127.8 (d), 128.6 (d), 130.9
(d), 132.5 (s), 142.0 (s), 144.5 (s), 158.9 (s), 170.5 (s); HRMS (ESI)
calcd for C16H16NO3 (MþH)þ 270.1130, found 270.1125.
methoxyphenyl)isoindolin-1-one (threo-3m). White solid; mp
245e246 ꢂC (recryst from ethyl acetate); Rf 0.75 (hexanes/ethyl
acetate¼1:2); IR (KBr) 3264, 1655, 1614, 1603, 1506, 1472, 833, 800,
781, 766, 746, 723, 696, 679 cmꢀ1; 1H NMR (CDCl3)
d 2.22 (br s, 1H),
3.87 (s, 3H), 5.20 (d, 1H, J¼4.6 Hz), 5.58 (d, 1H, J¼4.6 Hz), 6.69e6.75
(m, 4H), 6.99e7.05 (m, 2H), 7.42e7.48 (m, 1H), 7.50e7.59 (m, 3H),
4.3.20. 3-((4-Fluorophenyl)(hydroxy)methyl)isoindolin-1-one
(3r). Diastereomeric mixture (60:40); colorless paste; Rf 0.45
7.68e7.72 (m, 1H), 7.79e7.83 (m, 1H); 13C NMR (DMSO-d6)
d
55.0
(q), 64.2 (d), 70.7 (d), 113.3 (d, JCCF¼20.4 Hz), 113.9 (d), 122.5 (d),
123.6 (d), 124.5 (d), 127.9 (d, JCCCF¼8.4 Hz), 130.0 (s) 130.8 (d), 132.0
(s), 133.9 (s), 141.4 (s), 156.3 (s), 161.3 (s, JCF¼244.6 Hz), 166.4 (s).
Anal. Calcd for C22H18FNO3: C, 72.72%; H, 4.99%; N, 3.85%. Found: C,
72.69%; H, 4.52%; N, 3.80%.
(hexanes/ethyl acetate¼1:5); 1H NMR (CDCl3, DMSO-d6)
d 4.49 (dd,
0.6H, J¼4.0, 8.0 Hz), 4.75 (d, 0.6H, J¼8.0 Hz), 4.86 (d, 0.4H, J¼5.2 Hz),
4.92 (t, 0.4H, J¼5.2 Hz), 5.52 (d, 0.4H, J¼5.2 Hz), 5.59 (d, 0.6H,
J¼4.0 Hz), 6.46e6.49 (m, 0.6H), 6.89e6.95 (m, 0.8H), 7.02e7.09 (m,
1.2H), 7.19e7.27 (m, 1H), 7.29e7.35 (m, 1.8H), 7.37e7.43 (m, 1H),
7.45e7.54 (m, 1H), 7.65e7.68 (m, 0.4H), 7.72e7.75 (m, 0.6H), 7.80
4.3.16. (R
*
)-3-((R
*
)-Hydroxy(naphthalen-2-yl)methyl)-2-(4-
(br s, 0.6H); 13C NMR (CDCl3, DMSO-d6)
d (major) 62.2 (d), 74.9 (d),
methoxyphenyl)isoindolin-1-one (threo-3n). White solid; Rf 0.75
(hexanes/ethyl acetate¼1:2); mp 218e219 ꢂC (recryst from ethyl
acetate); IR (KBr) 3327, 1668, 1599, 1585, 1508, 1466, 827, 810, 779,
114.4 (d, JCCF¼20.4 Hz), 122.6 (d), 124.1 (d), 127.85 (d), 129.0 (d,
JCCCF¼8.4Hz), 130.7 (d), 132.7 (s), 136.4 (s, JCCCCF¼3.6 Hz), 143.4 (s),
161.6 (s, JCF¼244.7 Hz), 170.1 (s); (minor) 62.1 (d), 73.6 (d), 114.1 (d,
JCCF¼21.6 Hz), 122.7 (d), 123.7 (d), 127.80 (d), 128.5 (d, JCCCF¼7.2 Hz),
130.9 (d), 132.5 (s), 136.0 (s, JCCCCF¼2.4 Hz), 144.2 (s), 161.9 (s,
JCF¼244.6 Hz), 170.4 (s); HRMS (ESI) calcd for C15H13FNO2 (MþH)þ
258.0930, found 258.0927.
760, 746, 725, 692 cmꢀ1
;
1H NMR (CDCl3)
d
2.32 (d, 1H, J¼2.9 Hz),
3.85 (s, 3H), 5.36 (dd, 1H, J¼2.9, 4.6 Hz), 5.66 (d, 1H, J¼4.6 Hz),
4.86e6.90 (m, 1H), 6.98e7.02 (m, 2H), 7.21 (br s, 1H), 7.36e7.43 (m,
3H), 7.48e7.59 (m, 5H), 7.63e7.66 (m, 1H), 7.67e7.70 (m, 1H),
7.81e7.84 (m, 1H); 13C NMR (CDCl3, DMSO-d6)
d 55.2 (q), 64.6 (d),
72.4 (d), 114.0 (d), 123.0 (d), 124.3 (d), 124.7 (d), 125.39 (d), 125.43
(d), 125.9 (d), 126.4 (d) 127.1 (d), 127.5 (d), 128.1 (d), 130.3 (s), 130.9
4.3.21. 3-(Hydroxy(naphthalen-2-yl)methyl)isoindolin-1-one
(3s). Diastereomeric mixture (60:40); colorless paste; Rf 0.55 (ethyl

8814
N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
acetate); 1H NMR (CDCl3)
d
4.40 (br s, 1H), 4.67 (d, 0.6H, J¼7.7 Hz),
62.6 (d), 74.2 (d), 75.5 (d), 102.4 (t), 110.6 (d), 110.67 (d), 110.70 (d),
110.9 (d), 115.3 (s), 115.4 (s), 116.7 (d), 117.2 (d), 119.4 (d), 120.1 (d),
132.6 (s), 133.1 (s), 137.3 (s), 138.0 (s), 142.8 (s), 147.99 (s), 148.04 (s),
148.1 (s), 148.3 (s), 148.4 (s), 167.8 (s), 168.2 (s); HRMS (ESI) calcd for
C18H18NO6 (MþH)þ 344.1134, found 344.1130.
4.91 (d, 0.6H, J¼7.7 Hz), 4.96 (d, 0.4H, J¼5.5 Hz), 5.04 (d, 0.4H,
J¼5.5 Hz), 6.42e6.47 (m, 0.6H), 7.21e7.27 (m, 0.6H), 7.34e7.56 (m,
5H), 7.63e7.67 (m, 0.4H), 7.70e7.83 (m, 3.6H), 7.85e7.90 (m, 1.2H),
7.94 (br s, 0.6H); 13C NMR (CDCl3)
d 62.4 (d), 62.6 (d), 74.6 (d), 76.1
(d), 123.0 (d), 124.3 (d), 125.0 (d), 125.4 (d), 125.9 (d), 126.00 (d),
126.04 (d), 126.1 (d), 126.2 (d), 126.6 (d), 127.4 (d), 127.6 (d), 127.7
(d), 127.8 (d), 127.96 (d), 128.01 (d), 128.1 (d), 128.2 (d), 131.1 (d),
131.3 (d), 132.7 (s), 132.76 (s), 132.81 (s), 132.9 (s),133.0 (s),138.1 (s),
138.4 (s), 143.8 (s), 144.8 (s), 170.7 (s), 170.9 (s); HRMS (ESI) calcd for
C19H16NO2 (MþH)þ 290.1181, found 290.1178.
4.4. Typical procedure of dehydration of 3 to 4
A mixture of 3a (139 mg, 0.55 mmol) and PPTS (10 mg) in toluene
(10 mL) was refluxed using DeaneStark apparatus until 3a was
completely consumed (6 h). After the solvent was removed in vacuo,
the residue was purified by column chromatography on silica gel
(hexanes/ethyl acetate) to give 4a in a 70% yield (Z/E¼33:67). Re-
crystallization of the diastereomeric mixture of 4a from hexanes/
ethyl acetate (2:1) gave E-4a (major) as a white solid. E-4a,5a,d
Z-4a,5a,c Z-4p,5b,c,e,i,k,l Z-4s,5i and Z-4t,5i were known compounds.
4.3.22. 3-(Benzo[d][1,3]dioxol-5-yl(hydroxy)methyl)isoindolin-1-one
(3t). Diastereomeric mixture (67:33); colorless paste; Rf 0.45 (ethyl
acetate); 1H NMR (CDCl3, DMSO-d6)
d
4.40 (d, 0.67H, J¼8.0 Hz), 4.72
(d, 0.67H, J¼8.0 Hz), 4.78e4.82 (m, 0.67H), 5.61 (br s, 0.33H), 5.66
(br s, 0.67H), 5.91e5.93 (m, 0.67H), 5.98e6.01 (m,1.33H), 6.59e6.78
(m, 2.67H), 6.86e6.87 (m, 0.33H), 6.90e6.92 (m, 0.67H), 7.33e7.72
4.4.1. (E)-3-Benzylidene-2-methylisoindolin-1-one
(E-4a). White
(m, 3.67H), 8.05 (br s, 0.67H); 13C NMR (CDCl3, DMSO-d6)
d
(major)
solid; mp 118 ꢂC (lit.5a 120e122 ꢂC).
62.1 (d), 75.0 (d), 100.8 (t), 107.3 (d), 107.5 (d), 120.8 (d), 122.56 (d),
124.3 (d), 127.9 (d), 130.7 (d), 133.0 (s), 134.7 (s), 143.9 (s), 146.7 (s),
146.9 (s), 169.8 (s); (minor) 62.2 (d), 73.9 (d), 100.7 (t), 107.2 (d),
107.4 (d), 120.2 (d), 122.59 (d), 124.0 (d), 127.8 (d), 130.9 (d), 132.8
(s),134.6 (s), 144.5 (s),146.4 (s),146.8 (s), 170.2 (s); HRMS (ESI) calcd
for C16H14NO4 (MþH)þ 284.0923, found 284.0919.
4.4.2. (E)-3-(4-Methoxybenzylidene)-2-methylisoindolin-1-one (E-
4b). White solid; Rf 0.7 (hexanes/ethyl acetate¼1:2); Mp
145e146 ꢂC (recryst from hexanes/ethyl acetate¼2:1); IR (KBr) 1695,
1649, 1605, 1574, 1510, 1466, 1460, 837, 829, 814, 772, 743, 692,
683 cmꢀ1
;
1H NMR (CDCl3)
d
3.37 (s, 3H), 3.88 (s, 3H), 6.47 (s, 1H),
6.95e6.99 (m, 2H), 7.30e7.34 (m, 1H), 7.36e7.43 (m, 4 H), 7.81e7.85
(m,1 H); 13C NMR (CDCl3)
26.1 (q), 55.3 (q),110.3 (d),114.1 (d),122.9
4.3.23. 3-(Hydroxy(phenyl)methyl)-6,7-dimethoxyisoindolin-1-one
d
(3u). Diastereomeric mixture (60:40); colorless paste; Rf 0.45
(d), 123.1 (d), 127.3 (s), 128.6 (s), 129.0 (d), 130.5 (s), 130.8 (d), 131.4
(d),134.9 (s),136.9 (s),159.3 (s). Anal. Calcd for C17H15NO2: C, 76.96%;
H, 5.70%; N, 5.28%. Found: C, 76.94%; H, 5.74%; N, 5.22%.
(ethyl acetate); 1H NMR (CDCl3)
d 3.82 (s, 1.8H), 3.86 (s, 1.2H), 3.90
(s, 1.2H), 3.97 (s, 1.8H), 4.41 (d, 0.6H, J¼7.9 Hz), 4.64 (d, 0.6H,
J¼7.9 Hz), 4.73 (d, 0.4H, J¼5.4 Hz), 4.82 (d, 0.4H, J¼5.4 Hz), 6.01 (d,
0.6H, J¼8.0 Hz), 6.84 (d, 0.6H, J¼8.0 Hz), 6.96 (br s, 0.4H), 7.06 (d,
0.4H, J¼8.0 Hz), 7.11 (d, 0.4H, J¼8.0 Hz), 7.20e7.41 (m, 5H), 7.60 (br
4 . 4 . 3 . ( E ) - 3 - ( B e n z o [ d ] [ 1, 3 ] d i o x o l - 5 - yl m e t hyl e n e ) - 2 -
methylisoindolin-1-one (E-4h). Pale yellow solid; Rf 0.4 (hexanes/
ethyl acetate¼2:1); mp 144e145 ꢂC (recryst from hexanes/ethyl
acetate¼2:1); IR (KBr) 1705, 1636, 1605, 1499, 1472, 922, 862, 849,
s, 0.6H); 13C NMR (CDCl3, DMSO-d6)
d 55.0 (q), 55.1 (q), 59.9 (d),
60.1 (d), 60.56 (d), 60.62 (d), 73.3 (d), 75.1 (d), 114.7 (d), 114.9 (d),
118.0 (d), 118.3 (d), 118.4 (d), 123.5 (s), 123.6 (s), 125.7 (d), 126.1 (d),
126.3 (d), 126.4 (d), 126.7 (d), 135.6 (s), 136.5 (s), 139.0 (s), 139.5 (s),
144.9 (s), 145.0 (s), 150.7 (s),150.8 (s),167.5 (s),167.9 (s); HRMS (ESI)
calcd for C17H18NO4 (MþH)þ 300.1236, found 300.1230.
835, 806, 762, 745, 691 cmꢀ1; 1H NMR (CDCl3)
d 3.36 (s, 3H), 6.04 (s,
2H), 6.41 (s, 1H), 6.86e6.89 (m, 1H), 6.90e6.95 (m, 2H), 7.32e7.37
(m, 1H), 7.40e7.45 (m, 2H), 7.82e7.85 (m, 1H); 13C NMR (CDCl3)
d
26.1 (q), 101.3 (t), 108.6 (d), 109.7 (d), 110.0 (d), 123.0 (d), 123.1 (d),
123.2 (d), 128.8 (s), 129.1 (d), 130.6 (s), 131.4 (d), 134.8 (s), 137.3 (s),
147.3 (s), 147.9 (s), 166.5 (s). Anal. Calcd for C17H13NO3: C, 73.11%; H,
4.69%; N, 5.02%. Found: C, 73.06%; H, 4.71%; N, 4.90%.
4.3.24. 3-(Benzo[d][1,3]dioxol-5-yl(hydroxy)methyl)-6,7-
dimethoxyisoindolin-1-one (3v). Diastereomeric mixture (55:45);
colorless paste; Rf 0.3 (ethyl acetate); 1H NMR (CDCl3, DMSOed6)
d
3.84 (s, 1.65H), 3.87 (s, 1.35H), 3.90 (s, 1.35H), 3.94 (s, 1.65H), 4.35
4 . 4 . 4 . ( Z ) - 3 - ( B e n z o [ d ] [ 1, 3 ] d i o x o l - 5 - yl m e t hyl e n e ) - 2 -
(dd, 0.55H, J¼3.4, 8.0 Hz), 4.58 (d, 0.55H, J¼8.0 Hz), 4.67 (d, 0.45H,
J¼5.2 Hz), 4.75 (t, 0.45H, J¼5.2 Hz), 5.55 (d, 0.45H, J¼5.2 Hz), 5.61 (d,
0.55H, J¼3.4 Hz), 5.92 (s, 0.9H), 5.98e6.01 (m, 1.1H), 6.25 (d, 0.55H,
J¼8.0 Hz), 6.64e6.68 (m, 0.9H), 6.71 (dd, 0.55H, J¼1.7, 8.0 Hz), 6.76
(d, 0.55H, J¼8.0 Hz), 6.85 (s, 0.45H), 6.89 (d, 0.55H, J¼1.7 Hz), 6.93 (d,
0.55H, J¼8.0 Hz), 7.09 (d, 0.45H, J¼8.0 Hz), 7.16 (d, 0.45H, J¼8.0 Hz),
7.51 (br s, 0.45H), 8.00 (br s, 0.55H); 13C NMR (CDCl3, DMSO-d6)
methylisoindolin-1-one (Z-4h). Pale yellow paste; Rf 0.5 (hexanes/
ethyl acetate¼2:1); 1H NMR (CDCl3)
d 3.10 (s, 3H), 6.02 (s, 2H), 6.69
(s, 1H), 6.80e6.86 (m, 3H), 7.46e7.51 (m, 1H), 7.57e7.61 (m,1 H),
7.70e7.73 (m, 1H), 7.84e7.87 (m, 1H).
4.4.5. 3-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-(4-methoxyphenyl)
isoindolin-1-one (4n). Z/E¼33:67; pale yellow paste; Rf 0.4
d
56.1 (q), 56.2 (q), 61.0 (d), 61.2 (d), 61.68 (q), 61.72 (q), 74.5 (q), 76.1
(hexanes/ethyl acetate¼2:1); 1H NMR (CDCl3)
d 3.75 (s, 1H), 3.87 (s,
(d),100.6 (t), 100.8 (t),107.2 (d), 107.3 (d), 107.48 (d), 107.53 (d),115.7
(d), 116.0 (d), 119.3 (d), 119.5 (d), 120.2 (d), 121.0 (d), 124.6 (s), 124.8
(s), 134.4 (s), 134.8 (s), 136.6 (s), 137.8 (s), 145.96 (s), 146.00 (s), 146.5
(s), 146.9 (s), 147.0 (s), 147.2 (s), 151.8 (s), 151.9 (s), 168.7 (s), 169.0 (s);
HRMS (ESI) calcd for C18H18NO6 (MþH)þ 344.1134, found 344.1128.
2H), 5.82 (s, 0.67H), 6.02 (s, 1.33H), 6.22 (s, 0.67H), 6.29 (s, 0.33H),
6.40e6.47 (m, 0.67H), 6.67e6.73 (m, 1H), 6.82e6.91 (m, 2H),
6.99e7.08 (m, 2H), 7.30e7.35 (m, 1.33H), 7.40e7.44 (m, 0.67H),
7.67e7.58 (m, 1.67H), 7.62e7.67 (m, 0.33H), 7.79e7.83 (0.33H),
7.91e7.95 (m, 1H); HRMS (ESI) calcd for C23H18NO4 (MþH)þ
372.1236, found 372.1235.
4.3.25. 6-((3,4-Dimethoxyphenyl)(hydroxy)methyl)-6,7-dihydro-
[1,3]dioxolo[4,5-e]isoindol-8-one (3w). Diastereomeric mixture
(60:40); colorless paste; Rf 0.5 (ethyl acetate/ethanol¼10:1); 1H
4.4.6. (Z)-3-Benzylideneisoindolin-1-one (Z-4p). White solid; mp
185e186 ꢂC (lit.5i 183e184 ꢂC).
NMR (CDCl3, DMSO-d6) d 3.80 (s, 1.2H), 3.84 (s, 1.2H), 3.85 (s, 1.8H),
3.90 (s, 1.8H), 4.39 (d, 0.6H, J¼8.2 Hz), 4.71 (d, 0.6H, J¼8.2 Hz),
4.80e4.83 (m, 0.8H), 5.91 (d, 0.6H, J¼8.0 Hz), 6.06e6.10 (m, 2H),
6.12 (d, 0.4H, J¼8.0 Hz), 6.66e6.96 (m, 4H), 6.99 (br s, 0.4H), 7.59 (br
4.4.7. (Z)-3-(3-Methoxybenzylidene)isoindolin-1-one (Z-4q). White
solid; Rf 0.45 (hexanes/ethyl acetate¼2:1); mp 150 ꢂC (recryst from
ethyl acetate); IR (KBr) 3177, 3046, 1692, 1649, 1612, 1584, 1489,
s, 0.6H); 13C NMR (CDCl3, DMSOed6)
d
55.67 (q), 55.72 (q), 62.5 (d),
858, 756, 744, 691, 681 cmꢀ1; 1H NMR (CDCl3)
d 3.86 (s, 3H), 6.52 (s,

N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
8815
1H), 6.84e6.88 (m, 1H), 6.98e7.00 (m, 1H), 7.04e7.07 (m, 1H),
7.33e7.37 (m, 1H), 7.49e7.54 (m, 1H), 7.61e7.65 (m, 1H), 7.76e7.79
structure was solved by direct methods with SIR-97 and refined
with SHELXL-97. The non-hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were refined isotropically. All calcula-
tions were performed with the YADOKARI-XG software package.
Crystal data are as follows: CCDC 875188e875204 contain the
supplementary crystallographic data. These data can be obtained
free of charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
(m, 1H), 7.86e7.89 (m, 1H), 8.54 (br s, 1H); 13C NMR (CDCl3)
d 55.3
(d), 105.9 (d), 113.3 (d), 114.0 (d), 119.8 (d), 120.9 (d), 123.5 (d), 128.7
(s), 129.2 (d), 130.2 (d), 132.2 (d), 133.2 (s), 136.3 (s), 138.1 (s), 160.1
(s), 169.0 (s). Anal. Calcd for C16H13NO2: C, 76.48%; H, 5.21%; N,
5.57%. Found: C, 76.57%; H, 5.28%; N, 5.41%.
4.4.8. (Z)-3-(4-Fluorobenzylidene)isoindolin-1-one (Z-4r). Pale yel-
low solid; Rf 0.5 (hexanes/ethyl acetate¼2:1); mp 242 ꢂC (recryst
from ethyl acetate); IR (KBr) 3181, 1682, 1655, 1601, 1589, 1508,
4.5.1. Crystal data of erythro-2a (CCDC 875194). C16H15NO3,
FW¼269.29, mp 191e192 ꢂC, triclinic, Pꢀ1 (no. 2), colorless block,
1476, 862, 816, 781, 754, 704, 691 cmꢀ1; 1H NMR (CDCl3)
d 6.52 (s,
ꢀ
ꢀ
ꢀ
a
a¼7.6098(16) A, b¼8.6193(12) A, c¼11.0551(18) A,
¼71.592(9),
3
ꢀ
1H), 7.12e7.17 (m, 2H), 7.40e7.45 (m, 2H), 7.52e7.56 (m, 1H),
7.63e7.67 (m, 1H), 7.77e7.80 (m, 1H), 7.87e7.80 (m, 1H), 7.87e7.90
b¼81.395(11),
g
¼86.486(9), V¼680.2(2) A , T¼298 K, Z¼4,
Dcalcd¼1.315 g/cm3,
m
¼0.91 cmꢀ1, GOF¼1.049.
(m, 1H), 8.05 (br s, 1H); 13C NMR (CDCl3)
d 104.6 (d), 116.3 (d,
JCCF¼18.1 Hz), 119.7 (d), 123.7 (d), 128.8 (s), 129.3 (d), 130.2 (d,
JCCCF¼7.1 Hz), 131.2 (s), 132.3 (d), 133.2 (s), 138.3 (s), 162.1 (s,
JCF¼248.6 Hz), 169.0 (s). Anal. Calcd for C15H10FNO: C, 75.30%; H,
4.21%; N, 5.85%. Found: C, 75.37%; H, 4.22%; N, 5.69%.
4.5.2. Crystal data of threo-2k (CCDC 875196). C22H19NO4,
FW¼361.38, mp 178e179 ꢂC, monoclinic, P21/n (no. 14), colorless
ꢀ
ꢀ
ꢀ
b
block, a¼12.014(6) A, b¼7.956(3) A, c¼19.650(10) A, ¼106.45(4),
3
V¼1801.4(5) A , T¼298 K, Z¼4, Dcalcd¼1.333 g/cm3,
m
¼0.92 cmꢀ1
,
ꢀ
GOF¼1.038.
4.4.9. (Z)-3-(Naphthalen-2-ylmethylene)isoindolin-1-one (Z-4s). Pale
yellow solid; mp 227 ꢂC (lit.5i 215e216 ꢂC).
4.5.3. Crystal data of threo-2n (CCDC 875197). C26H21NO4,
FW¼411.44, mp 199e201 ꢂC, monoclinic, P21/c (no. 14), colorless
ꢀ
ꢀ
ꢀ
4.4.10. (Z)-3-(Benzo[d][1,3]dioxol-5-ylmethylene)isoindolin-1-one
block, a¼19.629(3) A, b¼13.414(3) A, c¼19.267(2) A,
(Z-4t). Pale yellow solid; mp 225e226 ꢂC (lit.5i 226e227 ꢂC).
3
ꢀ
b
¼23.3340(12), V¼2009.5(5) A , T¼298 K, Z¼4, Dcalcd¼1.360 g/cm3,
m
¼0.92 cmꢀ1, GOF¼1.063.
4.4.11. (Z)-3-Benzylidene-6,7-dimethoxyisoindolin-1-one (Z-4u). Pale
yellow solid; Rf 0.3 (hexanes/ethyl acetate¼2:1); mp 246e247 ꢂC
(recryst from ethyl acetate); IR (KBr) 3256,1694,1684,1647,1495, 935,
914, 901, 835, 812, 802, 777, 758, 750, 734, 696, 688, 674, 663 cmꢀ1; 1H
4.5.4. Crystal data of threo-3a (CCDC 875195). C16H15NO2,
FW¼253.29, mp 168e169 ꢂC, monoclinic, P21/n (no. 14), colorless
ꢀ
ꢀ
ꢀ
block, a¼7.8612(13) A, b¼12.085(3) A, c¼14.386(2) A,
3
ꢀ
b
¼101.774(10), V¼1337.9(5) A , T¼298 K, Z¼4, Dcalcd¼1.257 g/cm3,
NMR (CDCl3)
J¼8.2 Hz), 7.25e7.29 (m, 1H), 7.39e7.42 (m, 4H), 7.44 (d,1H, J¼8.2 Hz),
8.09 (br s,1H); 13C NMR (CDCl3)
56.9 (q), 62.4 (q),103.7 (d),115.0 (d),
d 3.94 (s, 3H), 4.12 (s, 3H), 6.38 (s, 1H), 7.17 (d, 1 H,
m
¼0.83 cmꢀ1, GOF¼1.057.
d
117.4 (d), 120.8 (s), 127.3 (d), 128.2 (d), 129.2 (d), 132.2 (s), 132.6 (s),
135.4 (s), 147.4 (s), 153.4 (s), 167.0 (s). Anal. Calcd for C17H15NO3: C,
72.58%; H, 5.37%; N, 4.98%. Found: C, 72.48%; H, 5.40%; N, 4.84%.
4.5.5. Crystal data of erythro-3a (CCDC 875198). C16H15NO2,
FW¼253.29, mp 209e210 ꢂC, monoclinic, P21/c (no. 14), colorless
ꢀ
ꢀ
ꢀ
b
block, a¼9.902(2) A, b¼12.299(2) A, c¼10.867(3) A, ¼96.826(7),
3
V¼1314.1(5) A , T¼298 K, Z¼4, Dcalcd¼1.280 g/cm3,
m
¼0.85 cmꢀ1
,
ꢀ
4.4.12. (Z)-3-(Benzo[d][1,3]dioxol-5-ylmethylene)-6,7-dimethox-
yisoindolin-1-one (Z-4v). Pale yellow solid; Rf 0.45 (hexanes/ethyl
acetate¼1:1); mp 222e223 ꢂC (recryst from ethyl acetate); IR (KBr)
GOF¼1.039.
4.5.6. Crystal data of threo-3b (CCDC 875199). C17H17NO3,
FW¼283.32, mp 181e182 ꢂC, monoclinic, P21/c (no. 14), colorless
3265, 1701, 1655, 1497, 926, 856, 804, 797, 658 cmꢀ1 1H NMR
;
ꢀ
ꢀ
ꢀ
b
(CDCl3)
6.85e6.90 (m, 2H), 7.17 (d, 1H, J¼8.0 Hz), 7.43 (d, 1H, J¼8.0 Hz), 7.85
(br s, 1H); 13C NMR (CDCl3)
56.8 (q), 62.4 (q), 101.3 (t), 103.8 (d),
d 3.94 (s, 3H), 4.12 (s, 3H), 6.01 (s, 2H), 6.31 (s, 1H),
block, a¼10.632(3) A, b¼9.482(3) A, c¼15.278(5) A, ¼97.803(12),
V¼1526.0(8) A , T¼298 K, Z¼4, Dcalcd¼1.233 g/cm3,
m
¼0.85 cmꢀ1
,
3
ꢀ
d
GOF¼1.063.
108.2 (d), 109.1 (d), 114.9 (d), 117.2 (d), 120.6 (s), 122.2 (d), 129.4 (s),
131.6 (s), 132.1 (s), 147.0 (s), 147.1 (s), 148.4 (s), 153.1 (s), 167.1 (s).
Anal. Calcd for C18H15NO5: C, 66.46%; H, 4.65%; N, 4.31%. Found: C,
66.51%; H, 4.67%; N, 4.25%.
4.5.7. Crystal data of threo-3d (CCDC 875200). C17H17NO3,
FW¼283.32, mp 192e194 ꢂC, monoclinic, P21/c (no. 14), colorless
ꢀ
ꢀ
ꢀ
b
block, a¼8.464(2) A, b¼10.591(3) A, c¼16.181(3) A, ¼96.638(10),
V¼1440.9(6) A , T¼298 K, Z¼4, Dcalcd¼1.306 g/cm3,
m
¼0.90 cmꢀ1
,
3
ꢀ
4.4.13. (Z)-6-(3,4-Dimethoxybenzylidene)-6,7-dihydro-[1,3]dioxolo
[4,5-e]isoindol-8-one (Z-4w). Pale yellow solid; Rf 0.45 (hexanes/
ethyl acetate¼1:1); mp 223e225 ꢂC (recryst from ethyl acetate); IR
(KBr) 3219,1686, 1647, 1599, 1516, 1499, 1462, 916, 868, 802, 785,
GOF¼1.069.
4.5.8. Crystal data of threo-3g (CCDC 875201). C20H17NO2,
FW¼303.35, mp 197e198 ꢂC, monoclinic, P21/c (no. 14), colorless
770, 758, 718, 694 cmꢀ1
;
1H NMR (CDCl3)
d
3.927 (s, 3H), 3.930 (s,
ꢀ
ꢀ
ꢀ
block, a¼8.0257(14) A, b¼14.723(2) A, c¼13.1975(18) A,
3
ꢀ
b
¼98.658(6), V¼1541.7(4) A , T¼298 K, Z¼4, Dcalcd¼1.307 g/cm3,
3H), 6.20 (s, 2H), 6.38 (s, 1H), 6.87 (d, 1H, J¼2.3 Hz), 6.92 (d, 1H,
m
¼0.84 cmꢀ1, GOF¼1.038.
J¼8.0 Hz), 6.98 (dd, 1H, J¼2.3, 8.0 Hz), 7.07 (d, 1H, J¼8.0 Hz), 7.26 (d,
1H, J¼8.0 Hz), 7.88 (br s, 1H); 13C NMR (CDCl3)
d 55.95 (q), 56.02 (q),
103.1 (t), 104.8 (d), 111.0 (s), 111.4 (d), 111.7 (d), 112.1 (d), 112.9 (d),
120.9 (d), 127.9 (s), 131.9 (s), 132.3 (s), 143.5 (s), 148.7 (s), 149.2 (s),
149.5 (s), 166.3 (s). Anal. Calcd for C18H15NO5: C, 66.46%; H, 4.65%;
N, 4.31%. Found: C, 66.56%; H, 4.72%; N, 4.16%.
4.5.9. Crystal data of threo-3m (CCDC 875202). C22H18NO3,
FW¼363.37, mp 245e246 ꢂC, monoclinic, Cc (no. 9), colorless block,
ꢀ
ꢀ
ꢀ
b
a¼25.162(6) A, b¼7.9512(14) A, c¼19.334(3) A,
¼110.917(8),
V¼3613.3(12) A , T¼298 K, Z¼8, Dcalcd¼1.336 g/cm3,
m
¼0.96 cmꢀ1
,
3
ꢀ
GOF¼0.925.
4.5. X-ray crystallographic analysis
4.5.10. Crystal data of threo-3n (CCDC 875203). C26H21NO3,
FW¼395.44, mp 218e219 ꢂC, triclinic, Pꢀ1 (no. 2), colorless block,
All measurements were made on a Rigaku RAXIS imaging plate
area detector with graphite monochromated Mo Ka radiation. The
ꢀ
ꢀ
ꢀ
a¼9.551(5) A, b¼13.879(6) A, c¼16.073(9) A,
a¼105.00(2),

8816
N. Kise et al. / Tetrahedron 68 (2012) 8805e8816
3
ꢀ
b
¼91.521(19),
g
¼97.62(2), V¼2035.7(17) A , T¼298 K, Z¼4,
level. The optimized structures were verified by the vibrational
analysis at the same level and their energies were thermally cor-
rected to 298 K based on the frequencies. In addition, single point
calculations were carried out for the optimized structures using the
IEFPCM model in toluene at 408 K to take the solvent effect into
consideration.
Dcalcd¼1.290 g/cm3,
m
¼0.84 cmꢀ1, GOF¼0.975.
4.5.11. Crystal data of threo-3o (CCDC 875204). C23H19NO5,
FW¼389.39, mp 241e243 ꢂC, triclinic, Pꢀ1 (no. 2), colorless block,
ꢀ
ꢀ
ꢀ
a¼7.635(9) A, b¼11.86(3) A, c¼18.61(2) A,
a¼89.856(3),
3
ꢀ
b¼88.68(4),
g
¼88.36(5), V¼1684(5) A , T¼298 K, Z¼4,
Dcalcd¼1.536 g/cm3,
m
¼1.09 cmꢀ1, GOF¼0.985.
References and notes
4.5.12. Crystal data of E-4a (CCDC 875188). C16H13NO, FW¼235.27,
1. Yoda, H.; Matsuda, K.; Nomura, H.; Takabe, K. Tetrahedron Lett. 2000, 41,
1775.
ꢂ
ꢀ
mp 118 C, triclinic, Pꢀ1 (no. 2), colorless block, a¼8.28(3) A,
ꢀ
ꢀ
2. (a) Yoda, H.; Nakahama, A.; Koketsu, T.; Takabe, K. Tetrahedron Lett. 2002,
43, 4667; (b) Chiara, J. L.; Garcia, A.; Cristobal-Lumbroso, G. J. Org. Chem.
b¼9.27(2) A, c¼9.304(12) A,
a
¼66.220(15),
b
¼78.74(11),
3
ꢀ
g
m
¼74.00(13), V¼625(3) A , T¼298 K, Z¼2, Dcalcd¼1.249 g/cm3,
ꢁ
2005, 70, 4142; (c) Vacas, T.; Alvarez, E.; Chiara, J. L. Org. Lett. 2007, 9,
¼0.78 cmꢀ1, GOF¼1.063.
5445.
3. (a) Kise, N.; Sakurai, T. Tetrahedron Lett. 2010, 51, 70; (b) Kise, N.; Isemoto, S.;
Sakurai, T. J. Org. Chem. 2011, 76, 9856.
4. Kise, N.; Isemoto, S.; Sakurai, T. Org. Lett. 2009, 11, 4902.
4.5.13. Crystal data of E-4b (CCDC 875189). C17H15NO2, FW¼265.30,
mp 145e146 ꢂC, triclinic, Pꢀ1 (no. 2), colorless block,
5. Recent syntheses of alkylideneisoindoline-1-ones, see: (a) Couture, A.; Deniau,
E.; Grandclaudon, P. Tetrahedron 1997, 53, 10313; (b) Wu, M.-J.; Chang, L.-J.; Wei,
L.-M.; Lin, C.-F. Tetrahedron 1999, 55, 13193; (c) Kundu, N. G.; Khan, M. W. Tet-
rahedron 2000, 56, 4777; (d) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau,
C.; Rys, V. Tetrahedron Lett. 2002, 43, 2207; (e) Lu, W.-D.; Lin, C.-F.; Wang, C.-J.;
Wang, S.-J.; Wu, M.-J. Tetrahedron 2002, 58, 7315; (f) Rys, V.; Couture, A.; Deniau,
E.; Grandclaudon, P. Tetrahedron 2003, 59, 6615; (g) Couty, S. C.; Liegault, B.;
Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511; (h) Yao, T.; Larock, R. C. J. Org. Chem.
2005, 70, 1432; (i) Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P. Syn-
thesis 2006, 1333; (j) Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008, 10, 5281; (k)
Sun, C.; Xu, B. J. Org. Chem. 2008, 73, 7361; (l) Li, L.; Wang, L.; Zhang, X.; Jiang, Y.;
Ma, D. Org. Lett. 2009, 11, 1309; (m) Belluau, V.; Noeureuil, P.; Ratzke, E.;
ꢀ
ꢀ
ꢀ
a¼7.959(13) A, b¼9.170(18) A, c¼10.191(14) A,
a
¼107.33(4),
3
ꢀ
b
¼93.86(7),
g
¼102.00(6), V¼688(2) A , T¼298 K, Z¼2,
Dcalcd¼1.281 g/cm3,
m
¼0.84 cmꢀ1, GOF¼1.076.
4.5.14. Crystal data of Z-4q (CCDC 875190). C16H13NO2, FW¼251.27,
mp 150 ꢂC, orthorhombic, Pbca (no. 61), colorless block,
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼14.5008(13) A, b¼7.2341(5) A, c¼24.6711(19) A, V¼2588.0(4) A ,
T¼298 K, Z¼8, Dcalcd¼1.290 g/cm3,
m
¼0.86 cmꢀ1, GOF¼1.004.
€
Skvortsov, A.; Gallagher, S.; Motti, C. A.; Olegemoller, M. Tetrahedron Lett. 2010,
4.5.15. Crystal data of Z-4r (CCDC 875191). C16H10FNO, FW¼251.25,
51, 4738.
ꢂ
ꢀ
3
ꢀ
6. (a) Hussain, S. F.; Minard, R. D.; Freyer, A. J.; Shamma, M. J. Nat. Prod. 1981, 44,
mp 242 C, monoclinic, P21/a (no.14), colorless block, a¼13.009(4) A,
ꢁ
169; (b) Blasko, G.; Gula, D. J.; Shamma, M. J. Nat. Prod. 1982, 45, 105; (c)
ꢀ
ꢀ
b¼7.247(3) A, c¼13.404(4) A,
b
¼113.794(15), V¼1156.3(7) A ,
Rucker, G.; Breitmater, E.; Zhang, G.-L.; Mayer, R. Phytochemistry 1994, 36,
519; (d) Chia, Y.-C.; Chang, F.-R.; Teng, C.-M.; Wu, Y.-C. J. Nat. Prod. 2000, 63,
1160.
T¼298 K, Z¼4, Dcalcd¼1.443 g/cm3,
m
¼1.02 cmꢀ1, GOF¼0.953.
7. (a) Kato, Y.; Ebiike, H.; Achiwa, K.; Ashizawa, N.; Kurihara, T.; Kobayashi, F.
Chem. Pharm. Bull. 1990, 38, 2060; (b) Kato, Y.; Takemoto, M.; Achiwa, K. Chem.
Pharm. Bull. 1993, 41, 2003; (c) Kato, Y.; Takemoto, M.; Achiwa, K. Chem. Pharm.
Bull. 1999, 47, 529; (d) Botero Cid, H. M.; Trankle, C.; Baumann, K.; Pick, R.;
Mies-Klomfass, E.; Kostenis, E.; Mohr, K.; Holzgrabe, U. J. Med. Chem. 2000, 43,
2155.
4.5.16. Crystal data of Z-4t (CCDC 875192). C16H11NO3, FW¼265.26,
mp 225e226 ꢂC, monoclinic, P21/a (no. 14), colorless block,
ꢀ
ꢀ
ꢀ
b
€
a¼15.332(2) A, b¼14.3613(19) A, c¼14.8335(15) A,
¼48.159(4),
3
V¼2433.3(5) A , T¼298 K, Z¼8, Dcalcd¼1.448 g/cm3,
m
¼1.01 cmꢀ1
,
ꢀ
GOF¼0.951.
8. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi,
R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J.
B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R.
L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg,
J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision B.01; Gaussian, Inc:
Wallingford, CT, 2010.
4.5.17. Crystal data of Z-4u (CCDC 875193). C17H15NO3, FW¼281.30,
mp 246e247 ꢂC, monoclinic, P21/c (no. 14), colorless block,
ꢀ
ꢀ
ꢀ
b
a¼12.9567(17) A, b¼15.711(2) A, c¼13.882(2) A,
¼96.670(9),
V¼2806.8(7) A , T¼298 K, Z¼8, Dcalcd¼1.331 g/cm3,
m
¼0.92 cmꢀ1
,
3
ꢀ
GOF¼0.929.
4.6. Computational methodology
All calculations were carried out with the Gaussian 09 program.8
Geometry optimization was performed at the B3LYP/6-311þG(2d,p)