Organocatalyzed Enantioselective Synthesis of Quaternary Carbon-Containing Isoindolin-1-ones

Article abstract of DOI:10.1002/ejoc.201100163

3,3′-Triphenylsilyl-substituted (S)-BINOL-based (1,1′-bi-2- naphthol phosphoric acid has proven to be an effective organocatalyst for the asymmetric Friedel-Crafts alkylation of indoles with 3-substituted 3-hydroxyisoindolin-1-ones, affording the correspo

Full text of DOI:10.1002/ejoc.201100163

FULL PAPER
DOI: 10.1002/ejoc.201100163
Organocatalyzed Enantioselective Synthesis of Quaternary Carbon-Containing
Isoindolin-1-ones
Xiaolei Yu,[a] Youming Wang,*[a] Guiping Wu,[a] Haibin Song,[a] Zhenghong Zhou,*[a] and
Chuchi Tang[a]
Keywords: Synthetic methods / Asymmetric catalysis / Enantioselectivity / Nitrogen heterocycles / Alkylation
3,3Ј-Triphenylsilyl-substituted (S)-BINOL-based (1,1Ј-bi-2-
naphthol) phosphoric acid has proven to be an effective or-
ganocatalyst for the asymmetric Friedel–Crafts alkylation of
indoles with 3-substituted 3-hydroxyisoindolin-1-ones, af-
fording the corresponding quaternary carbon-containing 3,3-
disubstituted isoindolin-1-ones in good yields (up to 99%)
with good to excellent enantioselectivities (up to 95%ee).
The optical purity of the product was further improved after
a single recrystallization. This protocol provides a convenient
method for the catalytic asymmetric synthesis of valuable
3,3-disubstituted isoindolin-1-ones in high yields and
enantioselectivities.
Introduction
Although 2,3-dihydro-1H-isoindol-1-ones (isoindolin-1-
ones) are the key skeleton in a number of synthetic and
naturally occurring bioactive molecules, the methodology
for the asymmetric synthesis of simple substituted isoindoli-
nones with a high ee was rarely explored, and only a few
diastereoselective processes were developed during the past
two decades.[1–6] The main drawback of these protocols is
that stoichiometric amounts of a chiral controller derived
from the natural chiral pool are required. Recently, we have
developed the first catalytic asymmetric process for the
preparation of enantiomerically enriched 3-substituted iso-
indolinones.[7] In the presence of chiral phosphoric acid[8,9]
catalyst 2b, a variety of 3-indolyl-substituted isoindolin-1-
ones were obtained with moderate to good enantio-
selectivity by Friedel–Crafts (F–C) alkylation[10] of ind-
oles[11] with 3-hydroxyisoindolin-1-one. However, this
catalytic system failed to provide quaternary carbon-con-
taining isoindolin-1-ones with a satisfactory ee value. For
example, the asymmetric F–C alkylation of indole with 3-
ethyl 3-hydroxyisoindolin-1-one, instead of 3-hydroxyiso-
indolin-1-one, led to the corresponding 3-ethyl 3-(1H-indol-
3-yl)isoindolin-1-one with an enantioselectivity of only
24%ee (Scheme 1).
Scheme 1. Phosphoric acid 2b-catalyzed asymmetric F–C alkyl-
ation of indole with 3-ethyl 3-hydroxyisoindolin-1-one.
synthesis of quaternary carbon-containing isoindolin-1-
ones appeared to be of great importance.[13] We report
herein our further efforts on the development of an enantio-
selective synthesis of 3,3-disubstituted isoindolin-1-ones
starting from the corresponding 3-substituted 3-hydroxyiso-
indolin-1-ones, which can easily be prepared from the reac-
tion of phthalimide with various Grignard reagents.[14]
Results and Discussion
Based on the previous result, the influence of the steric
and electronic properties of the 3 and 3Ј substituents as well
as the backbone on the catalytic performance of the chiral
phosphoric acids was systematically investigated. Thus, a
series of 3,3Ј-substituted (S)-BINOL-based phosphoric
Since the construction of chiral quaternary carbons rep-
resents one of the most challenging and demanding topics
in the synthesis of natural products and chiral drugs,[12] the
development of such a new catalytically enantioselective
acids
1a–e,
3,3Ј-substituted
(R)-H8-BINOL-based
[a] State Key Laboratory of Elemento-Organic Chemistry, Institute
of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
(5,5Ј,6,6Ј,7,7Ј,8,8Ј-octahydro-1,1Ј-bi-2-naphthol) phosphor-
ic acids 2a–d, and the corresponding N-triflylphosphor-
amides 3, 4a, and 4b were employed as the catalyst candi-
dates in the model reaction for the F–C alkylation of indole
(5a) with 3-ethyl 3-hydroxyisoindolin-1-one (6b). All the
Fax: +86-22-23508939
E-mail: z.h.zhou@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100163.
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Organocatalyzed Enantioselective Synthesis of Isoindolin-1-ones
catalytic tests were conducted at room temperature in chlo- formance in the nucleophilic substitution of γ-hydroxylac-
roform using 5 mol-% of catalyst, and the results are listed tams with indole (Table 1, Entry 10).[15] Similarly, H8-BI-
in Table 1.
NOL-based N-triflylphosphoramides 4 also exhibited poor
stereoselectivities (Table 1, Entries 11 and 12).
Further optimization of reaction conditions by changing
the solvent, reaction temperature, or substrate concentra-
tion, or providing an additive to the reaction mixture, was
performed with catalyst 1e. As shown in Table 2, both the
catalytic efficiency and enantioselectivity are strongly de-
pendent on the choice of solvent (Table 2, Entries 1–7). The
same level of stereocontrol was almost obtained for other
chlorohydrocarbons (Table 2, Entries 2 and 3 versus En-
try 1). The use of toluene as an apolar solvent resulted in
marked decrease in both the reaction rate and selectivity
(Table 2, Entry 4). The reaction was sluggish to some extent
especially using ethereal solvents (Table 2, Entries 6 and 7).
Although an improved enantioselectivity of 74%ee was ob-
served with THF (tetrahydrofuran), the corresponding al-
kylation product was obtained in only 35% yield, even with
a prolonged reaction time of 5 d. Performing the reaction
in ethyl acetate favored the stereocontrol of the reaction,
affording product 7ab with 70%ee. The highest ee value of
76% was achieved when the reaction was run in acetonitrile,
but using other nitrile solvents such as propiononitrile and
benzonitrile led to a significant erosion of enantioselectivity
The results in Table 1 clearly demonstrated that all the
phosphoric acids and N-triflylphosphoramides catalyzed
the reaction at 20 °C, affording 3-ethyl-3-(1H-indol-3-yl)iso-
indolin-1-one (7ab) with variable degrees of enantiomeric
excess. Enantioselectivities ranging from 16% to 23%ee
were obtained when 3,3Ј-aryl-substituted BINOL-based
phosphoric acids (S)-1a–c were used (Table 1, Entries 1–3).
Intriguingly, using phosphoric acids 1d [R = P(O)Ph2] and
1e (R = SiPh3) significantly improved the enantioselectivity
of 7ab to 51 and 66%ee, respectively, with a reverse in the
absolute stereochemistry (Table 1, Entries 4 and 5). No su-
perior results were obtained by changing the backbone
from the BINOL-based to H8-BINOL-based skeleton
(Table 1, Entries 6–9). Surprisingly, N-triflylphosphoramide
3 led to a nearly racemic product in spite of its good per-
Table 2. Optimization of reaction conditions.[a]
Table 1. Catalyst evaluation.[a]
Entry
Solvent
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CHCl3
8
12
36
66
66
80
5 d
12
20
45
26
52
60
3
95
99
95
91
82
87
35
89
98
85
91
89
91
94
99
91
98
66
63
63
50
70
64
74
76
62
60
70
10
66
68
60
78
75
CH2Cl2
ClCH2CH2Cl
PhCH3
EA
Et2O
THF
CH3CN
CH3CH2CN
PhCN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Entry Catalyst
Time [h] Yield [%][b] ee [%][c]
9
1
2
3
4
5
6
7
8
1a (R = 4-ClC6H4)
1
1
0.5
10
8
94
82
96
92
95
99
Ͼ99
92
89
97
23
16
17
–51
–66
–35
–24
31
53
–2
20
9
10
11[d]
12[e]
13[f]
14[g]
15[h]
16[i]
17[j]
1b (R = 4-PhC6H4)
1c (R = 2-naphthyl)
1d [R = P(O)Ph2]
1e (R = SiPh3)
2a (R = 4-ClC6H4)
2b (R = 2-naphthyl)
2c (R = 9-phenanthryl)
2d (R = SiPh3)
3 (R = SiPh3)
4a (R = 2-naphthyl)
4b (R = 9-phenanthryl)
1
45
11
20
0.5
0.5
24
0.5
0.5
0.5
9
[a] Reagents and conditions: 5a (0.3 mmol) and 6b (0.2 mmol) in
the presence of catalyst 1e (5 mol-%) in 1 mL of solvent (0.2 m solu-
tion of 6b). [b] Isolated yield. [c] Determined by chiral HPLC
analysis. [d] 4 Å molecular sieves (MS) were added as an additive.
[e] 0.1 mL of water was added. [f] The reaction was performed at
10 °C. [g] The reaction was carried out at 40 °C. [h] Using 2 mol-%
1e. [i] Using 0.1 m solution of 6b. [j] Using 0.05 m solution of 6b.
10
11
12
98
99
[a] Reagents and conditions: 5a (0.3 mmol) and 6b (0.2 mmol) in
the presence of catalyst (5 mol-%) in chloroform (1 mL). [b] Iso-
lated yield. [c] Determined by chiral HPLC analysis.
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X. Yu, Y. Wang, G. Wu, H. Song, Z. Zhou, C. Tang
FULL PAPER
(Table 2, Entries 9 and 10 versus Entry 8). The addition of Table 3. Substrate scope of indoles in the 1e-catalyzed F–C reac-
tion.[a]
4 Å molecular sieves as an additive to remove the trace
amount of water generated from the reaction resulted in
decreasing both the reaction rate and stereoselectivity
(Table 2, Entry 11), which was consistent with our previous
report.[7] The addition of water as an additive also had a
negative effect on the outcome of the reaction (Table 2, En-
try 12). The effect of temperature was also remarkable.
Conducting the reaction at either a lower or higher tem-
perature led in both cases to an obvious loss of stereocon-
trol (Table 2, Entries 13 and 14). Moreover, it is noteworthy
that the concentration of the reaction mixture also played
an important role in the reaction. Dilution of the reaction
mixture (from a 0.2 to a 0.1 m solution of 6a) led to a slight
increase in enantioselectivity, furnishing the product 7ab in
91% yield and 78%ee (Table 2, Entry 16). Decreasing the
concentration of 6b further from a 0.1 to a 0.05 m solution
did not lead to further improvement in the enantio-
selectivity, but rather to the slight loss of catalytic efficiency
(Table 2, Entry 17 versus Entry 16).
The scope of the substrate in the reaction was initially
explored by subjecting various 3-hydroxyisoindolin-1-ones
bearing different substituents at the three-position to the
optimized reaction conditions with indole (5a). Both ali-
phatic and aromatic substituents for R1 were tolerated with
the 3-hydroxyisoindolin-1-ones (Table 3, Entries 1–5). Al-
though moderate enantioselectivities were observed with
methyl- and phenyl-substituted 3-hydroxyisoindolin-1-ones,
the use of ethyl-, allyl-, and butyl-substituted ones led to
a significant improvement in stereocontrol, generating the
corresponding alkylation product with enantioselectivities
of 78%, 79% and 77%ee, respectively.
Entry Product 7 (R,R1) Time [h] Yield [%][b]
ee [%][c]
1
7aa (H, Me)
7ab (H, Et)
12
11
48
72
12
29
48
30
30
20
24
21
30
20
34
37
25
88
74
66
42
66
60
24
24
99
91 (70)[d]
92
56
78 (99.8)[d]
79
2
3
7ac (H, allyl)
4[e]
5
7ac (H, allyl)
85
93
90
76
76
77
58
68
79
68
79
66
81
90
80
86
87
95
79
66
7ad (H, Bu)
6
7
8
9
7ae (H, Ph)
7bb (5-F, Et)
7cb (6-F, Et)
75
79
66
80
95
72
90
94
80
83
59
66
63
80
62
74
7db (5-Cl, Et)
7eb (6-Cl, Et)
7fb (5-Br, Et)
7gb (5-MeO, Et)
7hb (7-MeO, Et)
7ib (5-BnO, Et)
7jb (6-BnO, Et)
7kb (7-BnO, Et)
7lb (7-Me, Et)
7cc (6-F, allyl)
7ec (6-Cl, allyl)
7hc (7-MeO, allyl)
7jc (6-BnO, allyl)
7kc (7-BnO, allyl)
7lc (7-Me, allyl)
7hd (7-MeO, Bu)
7ld (7-Me, Bu)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
86
76
83
94
85
95
82
91
[a] Reagents and conditions: 5 (0.3 mmol) and 6 (0.2 mmol) in the
presence of catalyst 1e (5 mol-%) in acetonitrile (2 mL). [b] Isolated
yield. [c] Determined by chiral HPLC analysis. [d] Data in the pa-
rentheses were obtained through a single recrystallization from
methanol. [e] The reaction was carried out using a 2 mmol-scale.
To further demonstrate the scope of this organocatalytic
F–C alkylation, a plethora of indoles 5 were evaluated for
the reaction with 3-ethyl 3-hydroxyisoindolin-1-one (6b) un-
der the optimal reaction conditions. As shown in Table 3, a
wide range of indoles bearing either an electron-with-
drawing or electron-donating substituent at various posi-
tions on the indole ring were included as the reaction part-
ners, leading to the formation of the desired products in
good to excellent yields (Table 3, Entries 6–16). Generally,
electron-rich indoles exhibited a higher enantioselectivity
than those of electron-poor ones. In fact, the stereocontrol
was particularly favored by the introduction of an electron-
donating group on the seven-position of the indole ring.
The highest value of 95%ee was obtained with 7-methyl-
substituted indole 5l (Table 3, Entry 17). The same phe-
nomenon was also observed when 3-allyl 3-hydroxyisoindo-
lin-1-one (6c), instead of 6b, was employed (Table 3, En-
tries 18–23). Similarly, 7-methyl-substituted indole 5l was
proven to be the best substrate, affording the alkylation
product 7lc with an ee value of 94%. Moreover, the reaction
between 3-butyl 3-hydroxyisoindolin-1one (6d) and elec-
tron-rich indoles, such as 5h and 5l, also ran smoothly to
afford the desired products with 85% and 95%ee, respec-
tively. In addition, the reaction was repeated on a larger
scale. For instance, both a comparable ee value and yield
performed on a 2 mmol-scale. As all the F–C alkylation
products were solids with a high melting point, there was
an opportunity to further improve the optical purity of the
Figure 1. X-ray crystal structure determination of the F–C alk-
ylation product 7ab. The solvent and most of the hydrogen atoms
were observed for compound 7ac when the reaction was have been omitted for clarity.
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Organocatalyzed Enantioselective Synthesis of Isoindolin-1-ones
for C17H14N2O [M – H]– 261.1033; found 261.1035. HPLC analysis
(Chiralpak AD-H column; hexane/2-propanol, 70:30; flow rate:
1.0 mL/min; wavelength: 220 nm): Rt (retention time) = 5.46
(minor) and 10.53 min (major).
products through recrystallization. For example, the optical
purity of 7ab was dramatically improved by a single
recrystallization from methanol, affording an almost op-
tically pure alkylation product in an acceptable yield
(Table 3, Entry 2, 99.8%ee). An X-ray crystal structure de-
termination of enantiopure 7ab was obtained, which en-
abled the absolute configuration of the product to be as-
signed as R (Figure 1).[16] The stereochemistry of the other
products was assigned by analogy.
(R)-3-Ethyl-3-(1H-indol-3-yl)isoindolin-1-one (7ab): White solid,
50.3 mg, 91% yield, m.p. 195–197 °C, [α]2D0 = +39.8 (c = 1.0,
MeOH), 78%ee (99.8%ee after a single recrystallization from
methanol). 1H NMR (400 MHz, [D6]DMSO): δ = 0.65 (t, J =
7.2 Hz, 3 H, CH3), 2.33–2.47 (m, 2 H, CH2), 6.80 (t, J = 7.2 Hz, 1
H, Ar-H), 6.99–7.01 (m, 2 H, Ar-H), 7.33 (t, J = 7.2 Hz, 2 H, Ar-
H), 7.41–7.49 (m, 3 H, Ar-H), 7.72 (d, J = 6.8 Hz, 1 H, Ar-H),
8.90 (s, 1 H, NH), 11.09 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz,
[D6]DMSO): δ = 7.7, 30.4, 63.5, 111.6, 115.9, 118.5, 119.2, 120.9,
122.3, 122.5, 123.0, 124.8, 127.8, 131.7, 132.1, 136.7, 151.2,
169.1 ppm. HRMS (ESI): calcd. for C18H16N2O [M – H]– 275.1190;
found 275.1192. HPLC analysis (Chiralpak AD-H column; hexane/
2-propanol, 75:25; flow rate: 1.0 mL/min; wavelength: 220 nm): Rt
= 6.00 (minor) and 12.13 min (major).
Similar to Rueping’s[15] and our previous report,[7] the
reaction is believed to occur by an in situ generated cyclic
acyl iminium ion upon treatment of 3-substituted 3-hy-
droxyisoindolin-1-ones with the chiral phosphoric acid.
Conclusions
In conclusion, we have successfully developed the first
organocatalytic enantioselective synthesis of quaternary
carbon-containing isoindolin-1-ones through a chiral phos-
phoric acid-catalyzed asymmetric F–C alkylation of indoles
with 3-substituted 3-hydroxyisoindolin-1-ones. The corre-
sponding products were obtained in excellent chemical
yields with good to excellent enantioselectivities. Moreover,
almost enantiomerically pure isoindolin-1-ones was at-
tained through a simple recrystallization. The protocol de-
scribed herein provides an efficient access to biologically
valuable quaternary carbon-containing isoindolin-1-ones in
high yields and enantioselectivities.
(R)-3-Allyl-3-(1H-indol-3-yl)isoindolin-1-one (7ac): White solid,
53.1 mg, 92% yield, m.p. 173–175 °C, [α]2D0 = +52.6 (c = 1.0,
1
MeOH), 79%ee. H NMR (400 MHz, [D6]DMSO): δ = 3.13–3.24
(m, 2 H, CH2), 4.94 (d, J = 10.0 Hz, 1 H, vinyl), 5.05 (d, J =
17.2 Hz, 1 H, vinyl), 5.37–5.47 (m, 1 H, vinyl), 6.79 (t, J = 7.6 Hz,
1 H, Ar-H), 6.94 (d, J = 7.6 Hz, 1 H, Ar-H), 7.00 (t, J = 7.6 Hz, 1
H, Ar-H), 7.35 (d, J = 8.4 Hz, 2 H, Ar-H), 7.43 (t, J = 7.2 Hz, 1
H, Ar-H), 7.49 (t, J = 7.2 Hz, 1 H, Ar-H), 7.55 (s, 1 H, Ar-H), 7.70
(d, J = 7.2 Hz, 1 H, Ar-H), 8.96 (s, 1 H, NH), 11.12 (s, 1 H,
NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 42.0, 62.7,
111.6, 115.5, 118.5, 119.0, 119.2, 121.0, 122.5, 122.6, 123.3, 124.7,
127.8, 131.6, 132.0, 132.5, 136.7, 150.9, 168.8 ppm. HRMS (ESI):
calcd. for C19H16N2O [M – H]– 287.1190; found 287.1190. HPLC
analysis (Chiralpak AD-H column; hexane/2-propanol, 70:30; flow
rate: 1.0 mL/min; wavelength: 220 nm): Rt = 5.55 (minor) and
112.57 min (major).
Experimental Section
General Methods: All reagents and solvents were commercial grade
and purified prior to use when necessary. NMR spectra were re-
corded with a Varian 400 MHz instrument. Chemical shifts are
measured relative to the residual solvent peaks with an internal
standard set to δ = 2.50 and δ = 39.43 ([D6]DMSO). Specific rota-
tions were measured with a Perkin–Elmer 341MC polarimeter. En-
antiomeric excesses were determined using a HP-1100 instrument
(chiral column; mobile phase, hexane/iPrOH). HRMS was per-
formed with a Varian QFT-ESI instrument. Melting points were
measured with a Taike X-4 melting point apparatus.
(R)-3-Butyl-3-(1H-indol-3-yl)isoindolin-1-one (7ad): White solid,
56.6 mg, 93% yield, m.p. 202–204 °C, [α]2D0 = +48.0 (c = 1.0,
1
MeOH), 77%ee. H NMR (400 MHz, [D6]DMSO): δ = 0.80 (t, J
= 6.8 Hz, 3 H, CH3), 1.20–1.25 (m, 4 H, 2 CH2), 2.30–2.46 (m, 2
H, CH2), 6.80 (t, J = 7.6 Hz, 1 H, Ar-H), 7.00 (t, J = 7.6 Hz, 2 H,
Ar-H), 7.34 (d, J = 7.6 Hz, 2 H, Ar-H), 7.41–7.49 (m, 3 H, Ar-H),
7.70 (d, J = 7.2 Hz, 1 H, Ar-H), 8.92 (s, 1 H, NH), 11.09 (s, 1 H,
NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 13.9, 22.2,
25.2, 37.4, 63.1, 111.6, 116.0, 118.5, 119.2, 120.9, 122.3, 122.5,
123.0, 124.7, 127.7, 131.7, 131.9, 136.7, 151.6, 169.0 ppm. HRMS
(ESI): calcd. for C20H20N2O [M + Na]+ 327.1468; found 327.1468.
HPLC analysis (Chiralpak AD-H column; hexane/2-propanol,
70:30; flow rate: 1.0 mL/min; wavelength: 220 nm): Rt = 5.72
(minor) and 12.00 min (major).
General Procedure for 1e-Catalyzed Asymmetric F–C Alkylation of
Indoles with 3-Substituted 3-Hydroxyisoindolin-1-one: In a dry
Schlenk tube, indoles 5 (0.30 mmol), 3-substituted 3-hydroxyiso-
indolin-1-ones 6 (0.20 mmol) and phosphoric acid (S)-1e (8.7 mg,
0.01 mmol) were dissolved in CH3CN (2.0 mL) at room tempera-
ture under a nitrogen atmosphere. The solution was stirred after
the total consumption of 7 (monitored by TLC). After removal of
the solvent under reduced pressure, the residue was purified by
flash chromatography (ethyl acetate/dichloromethane, 1:8) to af-
ford the desired product.
(R)-3-(1H-Indol-3-yl)-3-phenylisoindolin-1-one (7ae): White solid,
58.4 mg, 90% yield, m.p. 237–239 °C, [α]2D0 = –35.0 (c = 1.0,
1
MeOH), 58%ee. H NMR (400 MHz, [D6]DMSO): δ = 6.77–6.83
(m, 2 H, Ar-H), 6.88 (d, J = 2.4 Hz, 1 H, Ar-H), 7.02–7.06 (m, 1
H, Ar-H), 7.27–7.35 (m, 3 H, Ar-H), 7.38 (d, J = 8.0 Hz, 1 H, Ar-
(R)-3-(1H-Indol-3-yl)-3-methylisoindolin-1-one (7aa): White solid, H), 7.47–7.53 (m, 3 H, Ar-H), 7.55–7.63 (m, 2 H, Ar-H), 7.75 (d,
51.9 mg, 99% yield, m.p. 209–210 °C, [α]2D0 = +7.8 (c = 1.0, MeOH),
56%ee. H NMR (400 MHz, [D6]DMSO): δ = 1.92 (s, 3 H, CH3),
J = 7.2 Hz, 1 H, Ar-H), 9.65 (s, 1 H, NH), 11.08 (d, J = 2.0 Hz, 1
H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 66.2, 111.7,
116.7, 118.6, 119.9, 121.3, 123.1, 124.1, 124.2, 125.1, 126.4, 127.4,
128.3, 131.0, 131.9, 137.0, 142.7, 150.8, 168.5 ppm. HRMS (ESI):
calcd. for C22H16N2O [M – H]– 323.1190; found 323.1195. HPLC
analysis (Chiralpak AD-H column; hexane/2-propanol, 70:30; flow
rate: 1.0 mL/min; wavelength: 220 nm): Rt = 14.08 (major) and
21.00 min (minor).
1
6.74–6.84 (m, 2 H, Ar-H), 6.99 (t, J = 7.2 Hz, 1 H, Ar-H), 7.31–
7.35 (m, 2 H, Ar-H), 7.47 (t, J = 7.2 Hz, 2 H, Ar-H), 7.54 (s, 1 H,
Ar-H), 7.74 (d, J = 6.8 Hz, 1 H, Ar-H), 8.98 (s, 1 H, NH), 11.10
(s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 26.9,
59.8, 111.6, 116.0, 118.5, 119.0, 120.9, 122.2, 122.7, 123.3, 124.6,
127.8, 131.2, 130.8, 136.8, 153.0, 168.3 ppm. HRMS (ESI): calcd.
Eur. J. Org. Chem. 2011, 3060–3066
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3063

X. Yu, Y. Wang, G. Wu, H. Song, Z. Zhou, C. Tang
FULL PAPER
(R)-3-Ethyl-3-(5-fluoro-1H-indol-3-yl)isoindolin-1-one (7bb): White
solid, 44.7 mg, 76% yield, m.p. 217–219 °C, [α]2D0 = +21.6 (c = 1.0,
MeOH), 68%ee. H NMR (400 MHz, [D6]DMSO): δ = 0.64 (t, J
AD-H column; hexane/2-propanol, 70:30; flow rate: 1.0 mL/min;
wavelength: 220 nm): Rt = 5.42 (minor) and 7.74 min (major).
1
(R)-3-(5-Bromo-1H-indol-3-yl)-3-ethylisoindolin-1-one (7fb): White
solid, 56.8 mg, 80% yield, m.p. 155–156 °C, [α]2D0 = –14.0 (c = 1.0,
= 7.2 Hz, 3 H, CH3), 2.30–2.39 (m, 1 H, one proton of CH2), 2.41–
2.48 (m, 1 H, one proton of CH2), 6.63 (dd, J = 2.0 and 10.8 Hz,
1 H, Ar-H), 6.86 (dt, J = 2.0 and 9.2 Hz, 1 H, Ar-H), 7.33 (d, J =
6.0 Hz, 2 H, Ar-H), 7.45 (t, J = 7.2 Hz, 1 H, Ar-H), 7.51 (t, J =
7.2 Hz, 1 H, Ar-H), 7.58 (d, J = 2.0 Hz, 1 H, Ar-H), 7.72 (d, J =
7.2 Hz, 1 H, Ar-H), 8.90 (s, 1 H, NH), 11.21 (s, 1 H, NH) ppm.
13C NMR (100.6 MHz, [D6]DMSO): δ = 7.6, 30.3, 63.3, 103.7 (d,
J = 23.7 Hz), 109.1 (d, J = 26.1 Hz), 112.5 (d, J = 9.9 Hz), 116.1
(d, J = 4.6 Hz), 122.3, 122.5, 124.7 (d, J = 10.1 Hz), 125.1, 127.8,
131.8, 132.0, 133.3, 150.9, 156.3 (d, J = 231.0 Hz), 169.0 ppm.
HRMS (ESI): calcd. for C18H15FN2O [M – H]– 317.1061; found
317.1064. HPLC analysis (Chiralpak AD-H column; hexane/2-pro-
panol, 70:30; flow rate: 1.0 mL/min; wavelength: 220 nm): Rt = 5.17
(minor) and 8.64 min (major).
1
MeOH), 66%ee. H NMR (400 MHz, [D6]DMSO): δ = 0.63 (t, J
= 7.2 Hz, 3 H, CH3), 2.29–2.38 (m, 1 H, one proton of CH2), 2.40–
2.47 (m, 1 H, one proton of CH2), 7.09 (s, 1 H, Ar-H), 7.12 (d, J
= 8.4 Hz, 1 H, Ar-H), 7.31 (d, J = 8.8 Hz, 2 H, Ar-H), 7.46 (t, J
= 7.2 Hz, 1 H, Ar-H), 7.52 (t, J = 7.2 Hz, 1 H, Ar-H), 7.58 (d, J
= 2.4 Hz, 1 H, Ar-H), 7.72 (d, J = 7.2 Hz, 1 H, Ar-H), 8.94 (s, 1
H, NH), 11.33 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 7.6, 30.5, 63.2, 111.2, 113.6, 115.7, 121.3, 122.3, 122.5,
123.4, 124.8, 126.5, 127.9, 131.8, 131.9, 135.3, 150.8, 169.0 ppm.
HRMS (ESI): calcd. for C18H15BrN2O [M + Na]+ 377.0260; found
377.0261. HPLC analysis (Chiralpak AD-H column; hexane/2-pro-
panol, 70:30; flow rate: 1.0 mL/min; wavelength: 220 nm): Rt = 4.85
(minor) and 9.08 min (major).
(R)-3-Ethyl-3-(6-fluoro-1H-indol-3-yl)isoindolin-1-one (7cb): White
solid, 44.1 mg, 75% yield, m.p. 220–221 °C, [α]2D0 = +29.8 (c = 1.0,
MeOH), 79%ee. H NMR (400 MHz, [D6]DMSO): δ = 0.62 (t, J
(R)-3-Ethyl-3-(5-methoxy-1H-indol-3-yl)isoindolin-1-one
(7gb):
White solid, 58.2 mg, 95% yield, m.p. 269–271 °C, [α]2D0 = –32.0 (c
= 0.2, MeOH), 81%ee. 1H NMR (400 MHz, [D6]DMSO): δ = 0.64
(t, J = 6.8 Hz, 3 H, CH3), 2.33–2.37 (m, 1 H, one proton of CH2),
2.44–2.47 (m, 1 H, one proton of CH2), 3.53 (s, 3 H, CH3), 6.40 (s,
1 H, Ar-H), 6.67 (d, J = 8.4 Hz, 1 H, Ar-H), 7.21 (d, J = 8.4 Hz,
1 H, Ar-H), 7.33 (d, J = 7.2 Hz, 1 H, Ar-H), 7.43–7.46 (m, 2 H,
Ar-H), 7.51 (t, J = 7.2 Hz, 1 H, Ar-H), 7.72 (d, J = 7.2 Hz, 1
H, Ar-H), 8.90 (s, 1 H, NH), 10.95 (s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 7.7, 30.2, 55.0, 63.4, 101.6, 110.5,
112.1, 115.4, 122.5, 123.7, 125.1, 127.8, 131.8, 131.9, 132.3, 151.0,
152.6, 169.0 ppm. HRMS (ESI): calcd. for C19H18N2O2 [M +
Na]+ 329.1260; found 329.1268. HPLC analysis (Chiralpak AD-H
column; hexane/2-propanol, 70:30, flow rate: 1.0 mL/min; wave-
length: 220 nm): Rt = 7.05 (minor) and 29.76 min (major).
1
= 7.2 Hz, 3 H, CH3), 2.27–2.38 (m, 1 H, one proton of CH2), 2.40–
2.47 (m, 1 H, one proton of CH2), 6.68 (dt, J = 2.0 and 9.2 Hz, 1
H, Ar-H), 6.92 (dd, J = 5.6 and 8.8 Hz, 1 H, Ar-H), 7.10 (dd, J =
2.0 and 10.0 Hz, 1 H, Ar-H), 7.31 (d, J = 7.6 Hz, 1 H, Ar-H), 7.44
(t, J = 7.6 Hz, 1 H, Ar-H), 7.45–7.52 (m, 2 H, Ar-H), 7.70 (d, J =
7.2 Hz, 1 H, Ar-H), 8.88 (s, 1 H, NH), 11.15 (s, 1 H, NH) ppm.
13C NMR (100.6 MHz, [D6]DMSO): δ = 7.6, 30.3, 63.2, 97.4 (d, J
= 25.3 Hz), 107.0 (d, J = 24.1 Hz), 116.1, 120.0 (d, J = 10.0 Hz),
122.3, 122.5, 123.7 (d, J = 2.9 Hz), 127.8, 131.7, 132.0, 136.6 (d, J
= 12.6 Hz), 151.0, 158.5 (d, J = 234.8 Hz), 168.9 ppm. HRMS
(ESI): calcd. for C18H15FN2O [M
+
Na]+ 317.1061; found
317.1068. HPLC analysis (Chiralpak AD-H column; hexane/2-pro-
panol, 70:30; flow rate: 1.0 mL/min; wavelength: 220 nm): Rt = 5.49
(minor) and 7.39 min (major).
(R)-3-Ethyl-3-(7-methoxy-1H-indol-3-yl)isoindolin-1-one
(7hb):
White solid, 44.1 mg, 72% yield, m.p. 234–236 °C, [α]2D0 = +64.0 (c
= 1.0, MeOH), 90%ee. 1H NMR (400 MHz, [D6]DMSO): δ = 0.63
(t, J = 7.2 Hz, 3 H, CH3), 2.29–2.38 (m, 1 H, one proton of CH2),
2.41–2.48 (m, 1 H, one proton of CH2), 3.86 (s, 3 H, CH3), 6.58 (t,
J = 8.0 Hz, 2 H, Ar-H), 6.72 (t, J = 8.0 Hz, 1 H, Ar-H), 7.32 (t, J
= 8.0 Hz, 1 H, Ar-H), 7.35 (s, 1 H, Ar-H), 7.42 (t, J = 7.2 Hz, 1
H, Ar-H), 7.48 (t, J = 7.2 Hz, 1 H, Ar-H), 7.68 (d, J = 7.2 Hz, 1
H, Ar-H), 7.72 (d, J = 7.2 Hz, 1 H, Ar-H), 8.84 (s, 1 H, NH), 11.16
(s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 7.7,
30.4, 55.0, 63.4, 101.4, 112.5, 116.5, 119.1, 122.2, 122.4, 126.3,
126.8, 127.6, 131.6, 132.0, 151.2, 169.0 ppm. HRMS (ESI): calcd.
for C19H18N2O2 [M + Na]+ 329.1260; found 329.1261. HPLC
analysis (Chiralpak AD-H column; hexane/2-propanol, 70:30; flow
rate: 1.0 mL/min; wavelength: 220 nm): Rt = 7.92 (minor) and
41.49 min (major).
(R)-3-(5-Chloro-1H-indol-3-yl)-3-ethylisoindolin-1-one (7db): White
solid, 49.1 mg, 79% yield, m.p. 157–159 °C, [α]2D0 = +15.0 (c = 1.0,
MeOH), 68%ee. H NMR (400 MHz, [D6]DMSO): δ = 0.63 (t, J
1
= 6.8 Hz, 3 H, CH3), 2.31–2.37 (m, 1 H, one proton of CH2), 2.42–
2.47 (m, 1 H, one proton of CH2), 6.95 (s, 1 H, Ar-H), 7.01 (d, J
= 8.4 Hz, 1 H, Ar-H), 7.32 (d, J = 7.2 Hz, 1 H, Ar-H), 7.36 (d, J
= 8.8 Hz, 1 H, Ar-H), 7.45 (t, J = 7.2 Hz, 1 H, Ar-H), 7.51 (t, J =
7.2 Hz, 1 H, Ar-H), 7.60 (s, 1 H, Ar-H), 7.73 (d, J = 7.2 Hz, 1
H, Ar-H), 8.94 (s, 1 H, NH), 11.32 (s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 7.6, 30.5, 63.2, 113.1, 115.8, 118.3,
120.9, 122.3, 122.6, 123.1, 124.9, 125.8, 127.9, 131.8, 131.9, 135.1,
150.8, 169.0 ppm. HRMS (ESI): calcd. for C18H15ClN2O [M +
Na]+ 333.0765; found 333.0768. HPLC analysis (Chiralpak AD-H
column; hexane/2-propanol, 70:30; flow rate: 1.0 mL/min; wave-
length: 220 nm): Rt = 4.87 (minor) and 8.89 min (major).
(R)-3-(5-Benzyloxy-1H-indol-3-yl)-3-ethylisoindolin-1-one
(7ib):
(R)-3-(6-Chloro-1H-indol-3-yl)-3-ethylisoindolin-1-one (7eb): White
solid, 41.0 mg, 66% yield, m.p. 219–220 °C, [α]2D0 = +18.4 (c = 1.0,
White solid, 68.8 mg, 90% yield, m.p. 215–216 °C, [α]2D0 = –10.0 (c
= 0.5, MeOH), 80%ee. 1H NMR (400 MHz, [D6]DMSO): δ = 0.64
(t, J = 6.8 Hz, 3 H, CH3), 2.29–2.34 (m, 1 H, one proton of CH2),
1
MeOH), 79%ee. H NMR (400 MHz, [D6]DMSO): δ = 0.63 (t, J
= 6.8 Hz, 3 H, CH3), 2.30–2.36 (m, 1 H, one proton of CH2), 2.41– 2.42–2.47 (m, 1 H, one proton of CH2), 4.87 (d, J = 18.8 Hz, 1 H,
2.48 (m, 1 H, one proton of CH2), 6.84 (d, J = 8.8 Hz, 1 H, Ar-
H), 6.96 (d, J = 8.4 Hz, 1 H, Ar-H), 7.32 (d, J = 7.2 Hz, 1 H, Ar-
H), 7.38 (s, 1 H, Ar-H), 7.44 (t, J = 7.2 Hz, 1 H, Ar-H), 7.50 (t, J
= 7.2 Hz, 1 H, Ar-H), 7.54 (s, 1 H, Ar-H), 7.70 (d, J = 7.2 Hz, 1
H, Ar-H), 8.91 (s, 1 H, NH), 11.23 (s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 7.6, 30.4, 63.2, 111.1, 116.2, 118.8,
120.4, 122.2, 122.5, 123.5, 124.2, 125.8, 127.8, 131.8, 131.9, 137.1,
150.9, 169.0 ppm. HRMS (ESI): calcd. for C18H15ClN2O
[M + Na]+ 333.0765; found 333.0768. HPLC analysis (Chiralpak
one proton of CH2), 4.91 (d, J = 18.4 Hz, 1 H, one proton of CH2),
6.61 (s, 1 H, Ar-H), 6.74 (d, J = 7.6 Hz, 1 H, Ar-H), 7.22 (d, J =
8.4 Hz, 1 H, Ar-H), 7.31–7.36 (m, 7 H, Ar-H), 7.43–7.51 (m, 2 H,
Ar-H), 7.71 (d, J = 6.8 Hz, 1 H, Ar-H), 8.85 (s, 1 H, NH), 10.89
(s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 7.7,
30.4, 63.5, 69.5, 103.2, 111.4, 112.1, 115.5, 122.3, 122.5, 123.6,
125.0, 127.5, 127.6, 127.7, 128.3, 131.6, 132.0, 132.1, 137.4, 151.0,
151.5, 169.0 ppm. HRMS (ESI): calcd. for C25H22N2O2 [M +
Na]+ 405.1573; found 405.1568. HPLC analysis (Chiralpak AD-H
3064
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3060–3066

Organocatalyzed Enantioselective Synthesis of Isoindolin-1-ones
column; hexane/2-propanol, 70:30; flow rate: 1.0 mL/min; wave-
length: 220 nm): Rt = 8.96 (minor) and 25.01 min (major).
(R)-3-Allyl-3-(6-chloro-1H-indol-3-yl)isoindolin-1-one (7ec): White
solid, 42.6 mg, 66% yield, m.p. 220–222 °C, [α]2D0 = +36.2 (c = 1.0,
MeOH), 66%ee. H NMR (400 MHz, [D6]DMSO): δ = 3.10–3.20
1
(R)-3-(6-Benzyloxy-1H-indol-3-yl)-3-ethylisoindolin-1-one
(7jb):
(m, 2 H, CH2), 4.93 (d, J = 10.0 Hz, 1 H, vinyl), 5.04 (d, J =
17.2 Hz, 1 H, vinyl), 5.33–5.43 (m, 1 H, vinyl), 6.83 (d, J = 8.4 Hz,
1 H, Ar-H), 6.88 (d, J = 8.4 Hz, 1 H, Ar-H), 7.35 (t, J = 7.2 Hz, 2
H, Ar-H), 7.44 (d, J = 7.2 Hz, 1 H, Ar-H), 7.50 (t, J = 7.2 Hz, 1
H, Ar-H), 7.59 (s, 1 H, Ar-H), 7.68 (d, J = 7.2 Hz, 1 H, Ar-H),
8.97 (s, 1 H, NH), 11.25 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz,
[D6]DMSO): δ = 42.0, 62.5, 111.2, 115.9, 118.9, 119.2, 120.4, 122.6,
123.5, 124.5, 125.9, 127.9, 131.8, 131.9, 132.3, 137.1, 150.6,
168.8 ppm. HRMS (ESI): calcd. for C19H15ClN2O [M + Na]+
345.0765; found 345.0759. HPLC analysis (Chiralpak AD-H col-
umn; hexane/2-propanol, 70:30; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 5.44 (minor) and 7.80 min (major).
White solid, 71.9 mg, 94% yield, m.p. 191–192 °C, [α]2D0 = +25.2 (c
= 0.5, MeOH), 86%ee. 1H NMR (400 MHz, [D6]DMSO): δ = 0.62
(t, J = 7.2 Hz, 3 H, CH3), 2.27–2.39 (m, 1 H, one proton of CH2),
2.40–2.46 (m, 1 H, one proton of CH2), 5.05 (s, 2 H, CH2), 6.56
(dd, J = 1.6 and 8.8 Hz, 1 H, Ar-H), 6.85–6.88 (m, 2 H, Ar-H),
7.28–7.51 (m, 9 H, Ar-H), 7.69 (d, J = 7.2 Hz, 1 H, Ar-H), 8.86 (s,
1 H, NH), 10.87 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 7.7, 30.4, 63.4, 69.3, 95.9, 109.3, 115.9, 119.3, 119.8,
121.7, 122.2, 122.5, 127.3, 127.5, 127.7, 128.3, 131.6, 132.0, 137.3,
137.4, 151.2, 154.2, 169.0 ppm. HRMS (ESI): calcd. for
C25H22N2O2 [M + Na]+ 405.1573; found 405.1573. HPLC analysis
(Chiralpak AD-H column; hexane/2-propanol, 70:30; flow rate:
(R)-3-Allyl-3-(7-methoxy-1H-indol-3-yl)isoindolin-1-one
(7hc):
1.0 mL/min; wavelength: 220 nm): Rt
=
11.36 (minor) and
White solid, 40.1 mg, 63% yield, m.p. 216–218 °C, [α]2D0 = +66.0 (c
= 0.5, MeOH), 86%ee. 1H NMR (400 MHz, [D6]DMSO): δ =
3.10–3.20 (m, 2 H, CH2), 3.86 (s, 3 H, CH3), 4.92 (d, J = 10.0 Hz,
1 H, vinyl), 5.03 (d, J = 16.8 Hz, 1 H, vinyl), 5.34–5.44 (m, 1 H,
vinyl), 6.51 (d, J = 8.0 Hz, 1 H, Ar-H), 6.57 (d, J = 7.6 Hz, 1 H,
Ar-H), 6.70 (t, J = 7.6 Hz, 1 H, Ar-H), 7.35 (d, J = 7.2 Hz, 1 H,
Ar-H), 7.40 (s, 1 H, Ar-H), 7.42 (t, J = 7.2 Hz, 1 H, Ar-H), 7.48
(t, J = 7.2 Hz, 1 H, Ar-H), 7.66 (d, J = 7.6 Hz, 1 H, Ar-H), 8.91
(s, 1 H, NH), 11.19 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz,
[D6]DMSO): δ = 42.0, 55.0, 62.6, 101.4, 112.0, 116.1, 118.9, 119.1,
122.4, 122.5, 122.8, 126.2, 126.8, 127.7, 131.6, 132.0, 132.5, 146.1,
150.9, 168.8 ppm. HRMS (ESI): calcd. for C20H18N2O2 [M +
Na]+ 341.1261; found 341.1257. HPLC analysis (Chiralpak AD-H
column; hexane/2-propanol, 65:35; flow rate: 1.0 mL/min; wave-
length: 220 nm): Rt = 6.63 (minor) and 44.91 min (major).
23.15 min (major).
(R)-3-(7-Benzyloxy-1H-indol-3-yl)-3-ethylisoindolin-1-one
(7kb):
White solid, 61.2 mg, 80% yield, m.p. 112–113 °C, [α]2D0 = +44.6 (c
= 1.0, MeOH), 87%ee. 1H NMR (400 MHz, [D6]DMSO): δ = 0.63
(t, J = 7.2 Hz, 3 H, CH3), 2.29–2.38 (m, 1 H, one proton of CH2),
2.41–2.47 (m, 1 H, one proton of CH2), 5.22 (s, 2 H, CH2), 6.60
(d, J = 7.6 Hz, 1 H, Ar-H), 6.64–6.71 (m, 2 H, Ar-H), 7.30–7.54
(m, 9 H, Ar-H), 7.68 (d, J = 7.2 Hz, 1 H, Ar-H), 8.87 (s, 1 H, NH),
11.20 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
7.7, 30.5, 63.5, 69.0, 102.8, 112.3, 116.5, 119.0, 122.3, 122.5, 122.7,
126.5, 127.1, 127.5, 127.8, 128.3, 131.7, 132.1, 137.3, 145.0, 151.3,
169.0 ppm. HRMS (ESI): calcd. for C25H22N2O2 [M + Na]+
405.1573; found 405.1564. HPLC analysis (Chiralpak OD-H col-
umn; hexane/2-propanol, 70:30; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 15.46 (minor) and 42.03 min (major).
(R)-3-Allyl-3-(6-benzyloxy-1H-indol-3-yl)isoindolin-1-one
(7jc):
White solid, 63.1 mg, 80% yield, m.p. 188–190 °C, [α]2D0 = +38.0 (c
= 1.0, MeOH), 76%ee. 1H NMR (400 MHz, [D6]DMSO): δ =
3.08–3.18 (m, 2 H, CH2), 4.92 (d, J = 10.0 Hz, 1 H, vinyl), 5.03 (d,
J = 17.2 Hz, 1 H, vinyl), 5.05 (s, 2 H, OCH2), 5.34–5.44 (m, 1 H,
vinyl), 6.55 (dd, J = 2.0 and 8.8 Hz, 1 H, Ar-H), 6.80 (d, J = 8.8 Hz,
1 H, Ar-H), 6.88 (d, J = 1.6 Hz, 1 H, Ar-H), 7.29–7.50 (m, 9 H,
Ar-H), 7.67 (d, J = 7.2 Hz, 1 H, Ar-H), 8.92 (s, 1 H, NH), 10.89
(s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 41.9,
62.7, 69.3, 96.0, 109.4, 115.6, 118.9, 119.3, 119.7, 122.0, 122.5,
127.3, 127.5, 127.7, 128.3, 131.6, 132.0, 132.5, 137.3, 137.4, 150.9,
154.2, 168.8 ppm. HRMS (ESI): calcd. for C26H22N2O2 [M +
Na]+ 417.1573; found 417.1575. HPLC analysis (Chiralpak AD-H
column; hexane/2-propanol, 70:30; flow rate: 1.0 mL/min; wave-
length: 220 nm): Rt = 11.94 (minor) and 22.21 min (major).
(R)-3-Ethyl-3-(7-methyl-1H-indol-3-yl)isoindolin-1-one (7lb): White
solid, 48.2 mg, 83% yield, m.p. 212–214 °C, [α]2D0 = +50.8 (c = 1.0,
MeOH), 95%ee. H NMR (400 MHz, [D6]DMSO): δ = 0.65 (t, J
1
= 6.8 Hz, 3 H, CH3), 2.33–2.48 (m, 2 H, CH2), 2.42 (s, 3 H, CH3),
6.71 (t, J = 7.6 Hz, 1 H, Ar-H), 6.80–6.85 (m, 2 H, Ar-H), 7.32 (d,
J = 7.2 Hz, 1 H, Ar-H), 7.41–7.48 (m, 3 H, Ar-H), 7.70 (d, J =
7.2 Hz, 1 H, Ar-H), 8.91 (s, 1 H, NH), 11.07 (s, 1 H, NH) ppm.
13C NMR (100.6 MHz, [D6]DMSO): δ = 7.7, 16.8, 30.5, 63.5,
116.3, 116.9, 118.7, 120.7, 121.4, 122.3, 122.5, 122.7, 124.5, 127.8,
131.7, 132.6, 136.2, 151.3, 169.1 ppm. HRMS (ESI): calcd. for
C19H18N2O [M + Na]+ 313.1311; found 313.1315. HPLC analysis
(Chiralpak AD-H column; hexane/2-propanol, 70:30; flow rate:
1.0 mL/min; wavelength: 220 nm): Rt = 5.38 (minor) and 13.23 min
(major).
(R)-3-Allyl-3-(7-benzyloxy-1H-indol-3-yl)isoindolin-1-one
(7kc):
(R)-3-Allyl-3-(6-fluoro-1H-indol-3-yl)isoindolin-1-one (7cc): White
solid, 36.1 mg, 59% yield, m.p. 199–200 °C, [α]2D0 = +50.2 (c = 1.0,
MeOH, 79%ee). H NMR (400 MHz, [D6]DMSO): δ = 3.10–3.20
White solid, 48.9 mg, 62% yield, m.p. 90–92 °C, [α]2D0 = +54 (c =
1
1
1.0, MeOH), 83%ee. H NMR (400 MHz, [D6]DMSO): δ = 3.11–
3.21 (m, 2 H, CH2), 4.93 (d, J = 10.4 Hz, 1 H, vinyl), 5.04 (d, J =
16.4 Hz, 1 H, vinyl), 5.22 (s, 2 H, OCH2), 5.35–5.45 (m, 1 H, vinyl),
6.53 (d, J = 7.2 Hz, 1 H, Ar-H), 6.64–6.70 (m, 2 H, Ar-H), 7.30–
7.54 (m, 9 H, Ar-H), 7.67 (d, J = 7.2 Hz, 1 H, Ar-H), 8.91 (s, 1 H,
NH), 11.21 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 42.0, 62.6, 69.0, 102.9, 112.2, 116.1, 118.8, 119.0,
122.4, 122.5, 122.8, 126.3, 127.0, 127.4, 127.6, 127.7, 128.2, 131.5,
132.0, 132.5, 137.2, 145.0, 150.9, 168.7 ppm. HRMS (ESI): calcd.
for C26H22N2O2 [M + Na]+ 417.1573; found 417.1571. HPLC
analysis (Chiralpak OD-H column; hexane/2-propanol, 65:35; flow
rate: 1.0 mL/min; wavelength: 220 nm): Rt = 10.73 (minor) and
30.29 min (major).
(m, 2 H, CH2), 4.93 (d, J = 10.0 Hz, 1 H, vinyl), 5.03 (d, J =
17.2 Hz, 1 H, vinyl), 5.33–5.43 (m, 1 H, vinyl), 6.68 (t, J = 9.2 Hz,
1 H, Ar-H), 6.84 (dd, J = 6.0 and 8.4 Hz, 1 H, Ar-H), 7.10 (d, J =
9.6 Hz, 1 H, Ar-H), 7.34 (d, J = 7.2 Hz, 1 H, Ar-H), 7.43 (t, J =
7.2 Hz, 1 H, Ar-H), 7.48 (t, J = 7.2 Hz, 1 H, Ar-H), 7.54 (s, 1 H,
Ar-H), 7.68 (d, J = 7.2 Hz, 1 H, Ar-H), 8.97 (s, 1 H, NH), 11.19
(s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 41.9,
62.5, 97.4 (d, J = 26.9 Hz), 107.1 (d, J = 25.7 Hz), 115.7, 119.0,
120.0 (d, J = 10.2 Hz), 121.5, 122.5, 124.0, 127.9, 131.7, 131.9,
132.3, 136.6 (d, J = 13.4 Hz), 150.7, 158.5 (d, J = 249.3 Hz),
168.7 ppm. HRMS (ESI): calcd. for C19H15FN2O [M + Na]+
329.1061; found 329.1059. HPLC analysis (Chiralpak AD-H col-
umn; hexane/2-propanol, 70:30; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 5.46 (minor) and 7.25 min (major).
(R)-3-Allyl-3-(7-methyl-1H-indol-3-yl)isoindolin-1-one (7lc): White
solid, 44.8 mg, 74% yield, m.p. 215–216 °C, [α]2D0 = +90.2 (c = 1.0,
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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X. Yu, Y. Wang, G. Wu, H. Song, Z. Zhou, C. Tang
FULL PAPER
MeOH), 94%ee. H NMR (400 MHz, [D6]DMSO): δ = 2.41 (s, 3
1
H, 3 H, CH3), 3.12–3.23 (m, 2 H, CH2), 4.93 (d, J = 10.0 Hz, 1 H,
vinyl), 5.04 (d, J = 17.2 Hz, 1 H, vinyl), 5.35–5.45 (m, 1 H, vinyl),
6.68 (t, J = 7.6 Hz, 1 H, Ar-H), 6.74 (d, J = 7.6 Hz, 1 H, Ar-H),
6.79 (d, J = 6.4 Hz, 1 H, Ar-H), 7.33 (d, J = 7.2 Hz, 1 H, Ar-H),
7.42 (t, J = 7.2 Hz, 1 H, Ar-H), 7.48 (t, J = 7.2 Hz, 1 H, Ar-H),
7.52 (s, 1 H, Ar-H), 7.67 (d, J = 7.2 Hz, 1 H, Ar-H), 8.94 (s, 1 H,
NH), 11.07 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 16.7, 42.0, 62.8, 115.9, 116.9, 118.8, 119.0, 120.7,
121.5, 122.5, 122.6, 123.0, 124.4, 127.8, 131.6, 132.1, 132.6, 136.2,
151.0, 168.9 ppm. HRMS (ESI): calcd. for C20H18N2O [M + Na]+
325.1311; found 325.1311. HPLC analysis (Chiralpak AD-H col-
umn; hexane/2-propanol, 70:30; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 5.29 (minor) and 17.30 min (major).
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(R)-3-Butyl-3-(7-methoxy-1H-indol-3-yl)isoindolin-1-one
(7hd):
White solid, 54.8 mg, 82% yield, m.p. 253–255 °C, [α]2D0 = +51.0 (c
= 0.2, MeOH), 85%ee. 1H NMR (400 MHz, [D6]DMSO): δ = 0.79
(t, J = 7.2 Hz, 3 H, CH3), 1.14–1.28 (m, 4 H, 2 CH2), 2.25–2.32
(m, 1 H, one proton of CH2), 2.39–2.46 (m, 1 H, one proton of
CH2), 3.86 (s, 3 H, CH3), 6.57 (d, J = 8.0 Hz, 1 H, Ar-H), 6.59 (d,
J = 8.0 Hz, 1 H, Ar-H), 6.72 (t, J = 8.0 Hz, 1 H, Ar-H), 7.32–7.34
(m, 2 H, Ar-H), 7.42 (t, J = 7.2 Hz, 1 H, Ar-H), 7.48 (t, J = 7.2 Hz,
1 H, Ar-H), 7.67 (d, J = 7.2 Hz, 1 H, Ar-H), 8.86 (s, 1 H, NH),
11.15 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
13.8, 22.1, 25.2, 37.4, 55.0, 63.1, 101.4, 112.1, 116.6, 119.0, 122.2,
122.3, 122.4, 126.2, 126.8, 127.6, 131.6, 131.8, 146.0, 151.6,
168.8 ppm. HRMS (ESI): calcd. for C21H22N2O2 [M – H]–
333.1609; found 333.1614. HPLC analysis (Chiralpak AD-H col-
umn; hexane/2-propanol, 65:35; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 6.01 (minor) and 30.43 min (major).
(R)-3-Butyl-3-(7-methyl-1H-indol-3-yl)isoindolin-1-one (7ld): White
solid, 58.0 mg, 91% yield, m.p. 233–235 °C, [α]2D0 = +70.6 (c = 1.0,
1
MeOH), 95%ee. H NMR (400 MHz, [D6]DMSO): δ = 0.80 (t, J
= 7.2 Hz, 3 H, CH3), 1.16–1.30 (m, 4 H, 2 CH2), 2.27–2.34 (m, 1
H, one proton of CH2), 2.40 (s, 3 H, CH3), 2.44–2.48 (m, 1 H, one
proton of CH2), 6.70 (t, J = 7.2 Hz, 1 H, Ar-H), 6.79 (d, J = 6.8 Hz,
1 H, Ar-H), 6.83 (d, J = 8.0 Hz, 1 H, Ar-H), 7.33 (d, J = 7.6 Hz,
1 H, Ar-H), 7.40–7.44 (m, 2 H, Ar-H), 7.48 (dt, J = 0.8 and 7.2 Hz,
1 H, Ar-H), 7.68 (t, J = 7.2 Hz, 1 H, Ar-H), 8.86 (s, 1 H, NH),
11.01 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
13.8, 16.6, 22.1, 25.2, 37.4, 63.1, 116.4, 116.9, 118.6, 120.6, 121.3,
122.2, 122.4, 122.5, 124.4, 127.6, 131.6, 131.9, 136.2, 151.6,
168.9 ppm. HRMS (ESI): calcd. for C21H22N2O [M + Na]+
341.1624; found 341.1625. HPLC analysis (Chiralpak AD-H col-
umn; hexane/2-propanol, 65:35; flow rate: 1.0 mL/min; wavelength:
220 nm): Rt = 4.44 (minor) and 9.95 min (major).
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR and HRMS spectra as well as the chiral
HPLC chromatograms of the prepared quaternary carbon-contain-
ing optically active isoindolin-1-ones.
Acknowledgments
[15] M. Rueping, B. J. Nachtsheim, Synlett 2010, 119–122.
[16] CCDC-813725 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
We are grateful to the National Natural Science Foundation of
China (grant numbers 20772058 and 20972070), the National Basic
Research Program of China (973 program, grant 2010CB833300),
and the Key Laboratory of Elemento-Organic Chemistry for gener-
ous financial support of our programs.
Received: February 4, 2011
Published Online: April 12, 2011
3066
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3060–3066