Chiral phosphoric acid catalyzed asymmetric Friedel-Crafts alkylation of indole with 3-hydroxyisoindolin-1-one: Enantioselective synthesis of 3-indolyl-substituted isoindolin-1-ones

Article abstract of DOI:10.1002/ejoc.201001408

Chiral phosphoric acids have been proven to be effective organocatalysts for the asymmetric Friedel-Crafts alkylation of indoles with 3-hydroxyisoindolin-1-ones. The corresponding products were obtained in excellent chemical yields (up to 99%) with modera

Full text of DOI:10.1002/ejoc.201001408

FULL PAPER
DOI: 10.1002/ejoc.201001408
Chiral Phosphoric Acid Catalyzed Asymmetric Friedel–Crafts Alkylation of
Indole with 3-Hydroxyisoindolin-1-one: Enantioselective Synthesis of
3-Indolyl-Substituted Isoindolin-1-ones
Xiaolei Yu,[a] Aidang Lu,[a] Youming Wang,*[a] Guiping Wu,[a] Haibin Song,[a]
Zhenghong Zhou,*[a] and Chuchi Tang[a]
Keywords: Enantioselectivity / Alkylation / Nitrogen heterocycles / Organocatalysis
Chiral phosphoric acids have been proven to be effective or-
ganocatalysts for the asymmetric Friedel–Crafts alkylation of
indoles with 3-hydroxyisoindolin-1-ones. The corresponding
products were obtained in excellent chemical yields (up to
99%) with moderate to excellent enantioselectivities (up to
Ͼ99%ee after a single recrystallization). This is the first ex-
ample of the catalytic asymmetric synthesis of valuable 3-
substituted isoindolin-1-ones in high yields and enantio-
selectivities.
Introduction
Currently, the chemistry of chiral nonracemic 3-substi-
tuted 2,3-dihydro-1H-isoindol-1-ones (isoindolin-1-ones)
has attracted much attention from many research groups,
as they are the key skeleton of a number of synthetic and
naturally occurring bioactive molecules. For example, (S)-
PD172938 (1)[1] is a dopamine D4 receptor antagonist, (R)-
pazinaclone (2)[2] possesses anxiolytic activity and is of
interest as a sedative, hypnotic, and muscle relaxant, and
(+)-lennoxamine (3)[3] is a naturally occurring isoindolo-
benzazepine alkaloid (Figure 1).
Although there are several methods available to make ra-
cemic 3-substituted isoindolinones, in contrast to the great
progress made in asymmetric synthesis during the past
three decades, the methodology for the asymmetric synthe-
sis of simple 3-substituted isoindolinones with high enantio-
selectivity has been rarely explored. These methods involve
an intramolecular Heck reaction of chiral N-vinyl o-iodo-
benzamide,[4] a tandem nucleophilic 1,2-addition/ring-clo-
sure procedure from SAMP or RAMP [(S)- or (R)-1-
amino-2-methoxymethylpyrrolidine] hydrazones,[5] radical
cyclization of allenamide containing a chiral auxiliary,[6] an-
ionic cyclization and re-aromatization of N-benzylbenz-
amide derivatives in the presence of a chiral base,[7] nucleo-
philic addition or hydride reduction of chiral acyliminium
ion,[8] as well as chiral auxiliary mediated carbocation
methods.[9] The main drawback of these protocols is that
Figure 1. Different pyrrolidine-based organocatalysts.
all of them need a chiral auxiliary derived from the natural
chiral pool to control the diastereoselectivity of the reac-
tion. In some cases, the cleavage of the chiral appendage is
quite harsh and tedious. To the best of our knowledge, there
is no catalytic asymmetric process for the preparation of
enantiomerically enriched 3-substituted isoindolinones, and
the development of such a new catalytic enantioselective
synthesis of these compounds appears to be of great impor-
tance.
The formation of new carbon–carbon bonds through the
catalytic asymmetric Friedel–Crafts (F–C) alkylation reac-
tion has recently made a great impact on stereoselective
synthesis.[10] It has potential application in the synthesis of
molecules with the indole framework or pharmacophore,
which is found in a range of natural products and medicinal
compounds of diverse therapeutic actions.[11] On the other
[a] State Key Laboratory of Elemento-Organic Chemistry,
Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China
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.201001408.
892
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 892–897

Enantioselective Synthesis of 3-Indolyl-Substituted Isoindolin-1-ones
hand, in the past few years, chiral phosphoric acids as chiral
Brønsted acids have attracted considerable attention in or-
ganocatalyzed asymmetric organic transformations.[12,13]
These results opened the way for the use of these types of
organocatalysts in asymmetric F–C alkylation reactions. As
part of our ongoing studies on organocatalyzed asymmetric
transformations,[14] we reported herein the first example of
the asymmetric, organocatalytic synthesis of these valuable
enantiopure
3-indolyl-substituted
isoindolin-1-ones
in enantioselectivities ranging from 7 to 39% (Table 1, En-
tries 2–4). Fused aromatic substituents, such as 2-naphthyl
and 9-anthryl, at the 3,3Ј-positions of the phosphoric acids
(i.e., 4e and 4f) are favorable for the stereocontrol of the
reaction, which provide the F–C alkylation product with 47
and 63%ee, respectively (Table 1, Entries 5 and 6). Interest-
ingly, by tuning the 3,3Ј-disubstituents of the phosphoric
acids, the stereochemistry of the F–C alkylation reaction
can be reversed. For instance, chiral phosphoric acids 4b
and 4c, both derived from (S)-binol, led to 8a with opposite
optical rotation (Table 1, Entry 2 vs. 3). Moreover, investi-
gation of the backbone effect of the binaphthyl skeleton
indicated that H8-binol-derived phosphoric acids 5a and 5b
generally demonstrated higher enantioselectivities (Table 1,
Entries 8 and 9) than their corresponding binol-derived an-
alogues (Table 1, Entries 2 and 5). 3-(1H-Indol-3-yl)iso-
indolin-1-one (8a) was obtained in up to 83%ee with cata-
lyst 5b, which bears 2-naphthyl groups at the 3,3Ј-positions
of the catalyst.
through a chiral phosphoric acid catalyzed enantioselective
F–C alkylation of indoles with 3-hydroxyisoindolin-1-
one.[15]
Results and Discussion
We first performed the F–C alkylation of indole (6a) with
3-hydroxyisoindolin-1-one (7) in the presence of binol phos-
phate 4a as the catalyst. Gratifyingly, that the reaction ran
smoothly to give the corresponding F–C alkylation product
3-(1H-indol-3-yl)isoindolin-1-one in excellent yield, albeit
with quite low enantioselectivity. This result prompted us
to improve the catalytic performance of the phosphoric ac-
ids by tuning the steric and electronic properties of the 3,3Ј-
substituents and the backbone of the scaffold. Then, a
series of 3,3Ј-substituted (S)-binol or (R)-H8-binol-based
(H8-binol = 5,5Ј,6,6Ј,7,7Ј,8,8Ј-octahydro-1,1Ј-bi-2-naphth-
ol) phosphoric acids 4b–g and 5a–c was employed to per-
form the F–C alkylation. All the catalytic tests were con-
ducted at room temperature in chloroform by using 5 mol-
% of the catalyst, and the results are listed in Table 1.
Further optimization of the reaction conditions by
changing the solvent, additive, or reaction temperature was
performed with catalysts 5b. The results are listed in
Table 2.
Table 1. Catalyst evaluation.[a]
Table 2. Optimization of reaction conditions.
Entry
Catalyst 4 or 5
Time [d] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
4a (R = H)
4b (R = Ph)
4c (R = 4-MeC6H4)
4d (R = 2,4,6-iPr3C6H2)
4e (R = 2-naphthyl)
4f (R = 9-anthryl)
4g (R = Ph3Si)
5a (R = Ph)
5b (R = 2-naphthyl)
5c (R = 9-phenanthryl)
6.5
5
5.5
7
89
99
73
34
91
65
56
80
99
58
3
39
–33
7
47
63
Entry
Solvent
Time [d]
3.5
3.5
Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
CHCl3
CH2Cl2
ClCH2CH2Cl 2.5
99
96
96
72
66
70
98
64
66
56
27
94
83
71
48
45
42
56
52
19
46
49
49
43
5
5.5
5.5
4
3.5
10
27
THF
PhCH3
Et2O
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
5
5.5
5
4
6
6
6
6
0.71
–47
–83
–42
10
8[c]
9[d]
10[e]
11[f]
12[g]
[a] Reaction conditions: 6a (0.3 mmol) and 7 (0.2 mmol) in the
presence of catalyst (5 mol-%) in chloroform (1 mL). [b] Isolated
yield. [c] Determined by chiral HPLC analysis.
The results in Table 1 clearly show that variation of the
substituents at the 3,3Ј-positions of the binaphthyl scaffold
significantly affect the enantioselectivities of the reaction
(Table 1, Entry 1 vs. Entries 2–7). For example, the intro-
[a] Isolated yield. [b] Determined by chiral HPLC analysis. [c] 3 Å
MS were added as additive. [d] 4 Å MS were added as additive.
[e] 5 Å MS were added as additive. [f] The reaction was carried out
duction of a variety of substituted phenyl moieties resulted at 0 °C. [g] The reaction was at 40 °C.
Eur. J. Org. Chem. 2011, 892–897
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
893

X. Yu, A. Lu, Y. Wang, G. Wu, H. Song, Z. Zhou, C. Tang
FULL PAPER
As shown in Table 2, both the catalytic efficiency and some cases, the optical purity of the product could be dra-
asymmetric induction are strongly dependent on the sol- matically improved by a single recrystallization from meth-
vents used (Table 2, Entries 1–7). Among the variety of sol- anol (Table 3, Entries 1, 5, 6, and 11). An X-ray structure
vents examined for the catalysis, originally chosen chloro- of enantiopure 8a was obtained, which enabled the absolute
form is the best choice in terms of the enantioselectivity. configuration of the product to be assigned as R (Fig-
The effect of temperature on the reaction is also remark- ure 2).[16] The stereochemistry of the other products was as-
able. Both the reaction rate and the enantiomeric excess of signed by analogy.
product 8a were markedly decreased when the reaction tem-
perature was reduced to 0 °C (Table 2, Entry 11). Although
a dramatic rate acceleration was observed, performing the
reaction at 40 °C led to an obvious loss of stereocontrol
(Table 2, Entry 12). Because water is generated during the
F–C reaction with the hydroxy group, the influence of the
addition of molecular sieves as additive to remove the traces
amounts of water generated from the reaction was further
examined (Table 2, Entries 8–10). In general, the presence
of molecular sieves is detrimental to the reaction, which
resulted in sharp decreases in reaction rate and stereoselec-
tivity.
Having established the optimal conditions, we next inves-
tigated the effect of indoles in the reaction with 3-hydroxy-
isoindolin-1-one 7 (Table 3). A wide range of indoles could
be tolerated, leading to the formation of desired adducts in
excellent yields. The highest ee value of 83%ee (Table 3,
Entry 1) was obtained with unsubstituted indole (6a). The
introduction of halogen, alkyl, or alkoxy substituents onto
the indolyl rings all resulted in some loss of stereocontrol,
in which the enantiomeric excess values ranged from 32 to
72% (Table 3, Entries 2–12). Because all of the F–C alk-
ylation products were solids with high melting points, in
Figure 2. X-ray crystal structure of F–C alkylation product 8a.
Most of hydrogen atoms have been omitted for clarity.
The substrate scope of the reaction was also preliminarily
explored by subjecting different 3-hydroxyisoindolin-1-ones
to the optimized reaction conditions with indole (6a)
(Scheme 1). The reaction of 5-bromo-3-hydroxyisoindolin-
1-one (9) was to some extent sluggish and afforded the de-
sired alkylation product in 46% yield with 42%ee. When
using 3-hydroxy-2-methylisoindolin-1-one (11) as the reac-
tant, although the corresponding product could be ob-
tained in quantitative yield, the enantioselectivity eroded
Table 3. Substrate scope of indoles in the 5b-catalyzed F–C reac-
tion.[a]
Entry
R
Time [d]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
H (a)
5-F (b)
3.5
2.5
2.0
2.0
2.5
2.0
3.0
3.0
2.5
4.0
2.0
2.5
3.0
99 (80)[d]
83 (Ͼ99)[d]
98
98
99
97 (77)[d]
96 (75)[d]
90
65
72
59
57 (93)[d]
66 (92)[d]
32
6-F (c)
5-Cl (d)
6-Cl (e)
5-Br (f)
4-OBn (g)
5-OBn (h)
6-OBn (i)
5-MeO (j)
2-Me (k)
7-Me (l)
1-Me (m)
93
90
95
57
43
50
94 (70)[d]
97
68 (97)[d]
51
98
42
[a] Reaction conditions: 6 (0.3 mmol) and 7 (0.2 mmol) in the pres-
ence of catalyst 5b (5 mol-%) in chloroform (1 mL). [b] Isolated
yield. [c] Determined by chiral HPLC analysis. [d] Data in paren-
theses were obtained through a single recrystallization from meth-
anol.
Scheme 1. Reaction of other 3-hydrxoyisoindolin-1-ones.
894
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 892–897

Enantioselective Synthesis of 3-Indolyl-Substituted Isoindolin-1-ones
sure, the residue was purified by flash chromatography (ethyl acet-
ate/dichloromethane, 1:5) to afford the desired product.
dramatically. The reaction of 3-hydroxy-2-phenylisoindolin-
1-one (13) failed to give the F–C alkylation product. 3-Sub-
stituted 3-hydroxyisoindolin-1-one, such as 3-ethyl-3-hy-
droxyisoindolin-1-one (14), exhibited much higher reactiv-
ity under identical conditions relative to 3-hydroxyisoind-
olin-1-one (7). The reaction was complete within 30 min to
provide quantitatively the corresponding product 15 con-
taining a quaternary carbon center with 24%ee (Scheme 1).
The proposed mechanism for the reaction course of this
F–C alkylation is depicted in Scheme 2. The exposure of 3-
hydroxyisoindolin-1-one (7) to the chiral phosphoric acid
leads to the formation of close counterion A, in which the
chiral phosphate anion creates a chiral environment to con-
trol the enantioselectivity of the F–C reaction.
(S)-3-(1H-Indol-3-yl)isoindolin-1-one (8a): Yield: 49 mg, 99%.
White solid, m.p. 225–227 °C. [α]2D0 = +33.6 (c = 1.0, DMSO),
83%ee (Ͼ99%ee after
a
single recrystallization). 1H NMR
(400 MHz, [D6]DMSO): δ = 5.96 (s, 1 H, CH), 6.81 (t, J = 7.2 Hz,
1 H, Ar-H), 6.88 (d, J = 7.2 Hz, 1 H, Ar-H), 7.03 (t, J = 7.2 Hz, 1
H, Ar-H), 7.28–7.36 (m, 2 H, Ar-H), 7.44–7.51 (m, 3 H, Ar-H),
7.74–7.76 (m, 1 H, Ar-H), 8.93 (s, 1 H, NH), 11.07 (s, 1 H,
NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 53.7, 111.7,
118.4, 118.6, 121.2, 122.6, 123.4, 124.3, 125.0, 127.8, 128.6, 131.5,
132.1, 136.7, 148.3, 169.2 ppm. HRMS (ESI): calcd. for
C16H12N2O [M – H]– 247.0877; found 247.0879. HPLC (Chiralpak
AD-H column, hexane/2-propanol = 75:25, flow rate = 1.0 mL/
min, wavelength = 220 nm): tR = 679 (minor), 11.84 min (major).
(R)-3-(5-Fluoro-1H-indol-3-yl)isoindolin-1-one (8b): Yield: 52 mg,
98%. White solid, m.p. 215–217 °C. [α]2D0 = +30.0 (c = 1.0, DMSO),
1
65%ee. H NMR (400 MHz, [D6]DMSO): δ = 5.97 (s, 1 H, CH),
6.59 (d, J = 10.0 Hz, 1 H, Ar-H), 6.89 (dt, J = 9.2, 2.0 Hz, 1 H,
Ar-H), 7.31 (d, J = 7.2 Hz, 1 H, Ar-H), 7.36 (dd, J = 8.8, 4.8 Hz,
1 H, Ar-H), 7.48–7.55 (m, 3 H, Ar-H), 7.77 (d, J = 6.8 Hz, 1 H,
Ar-H), 8.96 (s, 1 H, NH), 11.21 (s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 53.4, 102.8, 103.1, 109.3, 109.6,
112.0, 112.7, 112.8, 122.7, 123.4, 125.1, 125.2, 126.2, 126.3, 128.0,
131.7, 132.0, 133.2, 133.3, 147.9, 155.2, 157.5, 169.2 ppm. HRMS
(ESI): calcd. for C16H11FN2O [M + H]+ 267.0928; found 267.0933.
HPLC (Chiralpak AD-H column, hexane/2-propanol = 70:30, flow
rate = 1.0 mL/min, wavelength = 220 nm): tR = 5.52 (minor),
8.61 min (major).
Scheme 2. Proposed mechanism.
Conclusions
(R)-3-(6-Fluoro-1H-indol-3-yl)isoindolin-1-one (8c): Yield: 52 mg,
98%. White solid, m.p. 224–226 °C. [α]2D0 = +32.3 (c = 1.0, DMSO),
72%ee. H NMR (400 MHz, [D6]DMSO): δ = 5.96 (s, 1 H, CH),
In conclusion, we have successfully developed the first
organocatalytic enantioselective synthesis of 3-substituted
isoindolin-1-ones through the chiral phosphoric catalyzed
asymmetric F–C alkylation of indoles with 3-hydroxyiso-
indolin-1-ones. The corresponding products were obtained
in excellent chemical yields with moderate to good enantio-
selectivities. Enantiomerically pure 3-indolylisoindolin-1-
ones can be attained through simple recrystallization. The
organocatalytic transformation described herein provides
efficient access to valuable 3-substituted isoindolin-1-ones
in high yields and enantioselectivities.
1
6.72 (dt, J = 9.6, 2.4 Hz, 1 H, Ar-H), 6.86 (dd, J = 8.4, 2.4 Hz, 1
H, Ar-H), 7.15 (dd, J = 10.0, 1.6 Hz, 1 H, Ar-H), 7.30 (d, J =
6.8 Hz, 1 H, Ar-H), 7.47 (s, 1 H, Ar-H), 7.49–7.54 (m, 2 H, Ar-H),
7. 76 (d, J = 6.4 Hz, 1 H, Ar-H), 8.99 (s, 1 H, NH), 11.16 (s, 1 H,
NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 53.5, 97.5,
97.8, 107.1, 107.3, 112.0, 119.3, 119.4, 121.8, 122.7, 123.4, 124.9,
125.0, 127.9, 131.6, 132.0, 136.6, 148.1, 157.6, 159.9, 169.2 ppm.
HRMS (ESI): calcd. for C16H11FN2O [M – H]– 265.0783; found
265.0791. HPLC (Chiralpak AD-H column, hexane/2-propanol =
70:30, flow rate = 1.0 mL/min, wavelength = 220 nm): tR = 5.90
(minor), 7.82 min (major).
(R)-3-(5-Chloro-1H-indol-3-yl)isoindolin-1-one (8d): Yield: 56 mg,
99%. White solid, m.p. 214–216 °C. [α]2D0 = +21.6 (c = 1.0, DMSO),
59%ee. H NMR (400 MHz, [D6]DMSO): δ = 5.98 (s, 1 H, CH),
Experimental Section
1
General Methods: All reagents and solvents were commercial grade
and purified prior to use when necessary. NMR spectra were ac-
quired with a Varian 400 MHz instrument. Chemical shifts are
measured relative to residual solvent peaks as an internal standard
set to δ = 2.50 ppm and δ = 39.43 ppm ([D6]DMSO). Specific rota-
tions were measured with a Perkin–Elmer 341MC polarimeter. En-
antiomeric excess values were determined with an HP-1100 instru-
ment (chiral column; mobile phase: hexane/iPrOH). HRMS was
performed with a Varian QFT-ESI instrument. Melting points were
determined with a Taike X-4 melting point apparatus.
6.91 (s, 1 H, Ar-H), 7.05 (dd, J = 8.8, 1.2 Hz, 1 H, Ar-H), 7.31 (d,
J = 6.8 Hz, 1 H, Ar-H), 7.40 (d, J = 8.8 Hz, 1 H, Ar-H), 7.49–7.54
(m, 3 H, Ar-H), 7. 78 (d, J = 7.2 Hz, 1 H, Ar-H), 9.00 (s, 1 H, NH),
11.32 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ
= 53.3, 111.7, 113.3, 117.5, 121.2, 122.7, 123.2, 123.4, 126.1, 126.2,
128.0, 131.7, 131.9, 135.2, 147.9, 169.2 ppm. HRMS (ESI): calcd.
for C16H11ClN2O [M – H]– 281.0487; found 281.0490. HPLC (Chi-
ralpak AD-H column, hexane/2-propanol = 70:30, flow rate =
1.0 mL/min, wavelength = 220 nm): tR = 5.42 (minor), 8.80 min
(major).
General Procedure for 5b-Catalyzed Asymmetric F–C Alkylation of
Indoles with 3-Hydroxyisoindolin-1-one: In a dry Schlenk tube, in-
dole (6; 0.30 mmol), 3-hydroxyisoindolin-1-one (7; 0.20 mmol), and
phosphoric acid (R)-5b (6.0 mg, 0.01 mmol) were dissolved in
CHCl3 (1.0 mL) at room temperature under a nitrogen atmosphere.
The solution was stirred until complete consumption of 7 (moni-
tored by TLC). After removal of the solvent under reduced pres-
(R)-3-(6-Chloro-1H-indol-3-yl)isoindolin-1-one (8e): Yield: 55 mg,
97%. White solid, m.p. 229–231 °C. [α]2D0 = +23.0 (c = 1.0, DMSO),
57%ee (93%ee after
a
single recrystallization). 1H NMR
(400 MHz, [D6]DMSO): δ = 5.97 (s, 1 H, CH), 6.88 (s, 1 H, Ar-
H), 7.29 (d, J = 6.8 Hz, 2 H, Ar-H), 7.42 (s, 1 H, Ar-H), 7.48–7.53
(m, 3 H, Ar-H), 7. 76 (d, J = 6.4 Hz, 1 H, Ar-H), 8.97 (s, 1 H, NH),
Eur. J. Org. Chem. 2011, 892–897
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
895

X. Yu, A. Lu, Y. Wang, G. Wu, H. Song, Z. Zhou, C. Tang
FULL PAPER
11.23 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ
= 53.4, 111.3, 112.1, 119.0, 119.7, 122.7, 123.4, 123.8, 125.5, 126.0,
128.0, 131.6, 132.0, 137.1, 148.0, 169.2 ppm. HRMS (ESI): calcd.
for C16H11ClN2O [M – H]– 281.0487; found 281.0491. HPLC
(Chiralpak AD-H column, hexane/2-propanol = 70:30, flow rate =
1.0 mL/min, wavelength = 220 nm): tR = 6.40 (minor), 8.99 min
(major).
1.0 mL/min, wavelength = 220 nm): tR = 12.28 (minor), 20.93 min
(major).
(R)-3-(5-Methoxy-1H-indol-3-yl)isoindolin-1-one (8j): Yield: 53 mg,
95%. White solid, m.p. 157–159 °C. [α]2D0 = +28.0 (c = 1.0, DMSO),
50%ee. 1H NMR (400 MHz, [D6]DMSO): δ = 3.57 (s, 3 H, OCH3),
5.97 (s, 1 H, CH), 6.44 (s, 1 H, Ar-H), 6.72 (dd, J = 8.8, 1.6 Hz, 1
H, Ar-H), 7.28 (d, J = 8.8 Hz, 1 H, Ar-H), 7.33–7.36 (m, 2 H, Ar-
H), 7.51 (t, J = 6.8 Hz, 2 H, Ar-H), 7.78 (d, J = 6.8 Hz, 1 H, Ar-
H), 8.96 (s, 1 H, NH), 10.94 (s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 53.6, 55.0, 100.7, 110.9, 111.4, 122.5,
123.5, 124.6, 124.7, 125.5, 127.8, 131.5, 131.7, 131.8, 132.1, 148.2,
152.8, 169.2 ppm. HRMS (ESI): calcd. for C17H14N2O2 [M – H]–
277.0982; found 277.0974. HPLC (Chiralpak AD-H column, hex-
ane/2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength =
220 nm): tR = 7.54 (minor), 20.99 min (major).
(R)-3-(5-Bromo-1H-indol-3-yl)isoindolin-1-one (8f): Yield: 63 mg,
96%. White solid, m.p. 191–192 °C. [α]2D0 = +26.9 (c = 1.0, DMSO),
66%ee (92%ee after
a
single recrystallization). 1H NMR
(400 MHz, [D6]DMSO): δ = 5.98 (s, 1 H, CH), 7.07 (s, 1 H, Ar-
H), 7.16 (d, J = 8.8 Hz, 1 H, Ar-H), 7.31 (d, J = 6.8 Hz, 1 H, Ar-
H), 7.35 (d, J = 7.2 Hz, 1 H, Ar-H), 7.49–7.56 (m, 3 H, Ar-H), 7.
78 (d, J = 6.4 Hz, 1 H, Ar-H), 8.99 (s, 1 H, NH), 11.32 (s, 1 H,
NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 53.3, 111.2,
111.6, 113.8, 120.6, 122.7, 123.4, 123.7, 125.9, 126.8, 128.0, 131.7,
131.9, 135.41, 147.9, 169.2 ppm. HRMS (ESI): calcd. for
C16H11BrN2O [M – H]– 324.9982; found 324.9986. HPLC (Chi-
ralpak AD-H column, hexane/2-propanol = 70:30, flow rate =
1.0 mL/min, wavelength = 220 nm): tR = 5.49 (minor), 9.21 min
(major).
(R)-3-(2-Methyl-1H-indol-3-yl)isoindolin-1-one (8k): Yield: 49 mg,
94%. White solid, m.p. 274–276 °C. [α]2D0 = +22.6 (c = 1.0, DMSO),
68%ee (92%ee after
a
single recrystallization). 1H NMR
(400 MHz, [D6]DMSO): δ = 2.46 (s, 3 H, CH3), 6.00 (s, 1 H, CH),
6.59 (s, 1 H, Ar-H), 6.71 (t, J = 6.4 Hz, 1 H, Ar-H), 6.93 (t, J =
6.8 Hz, 1 H, Ar-H), 7.26 (d, J = 6.8 Hz, 2 H, Ar-H), 7.50 (s, 2 H,
Ar-H), 7.78 (s, 1 H, Ar-H), 8.86 (s, 1 H, NH), 11.02 (s, 1 H,
NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 11.3, 52.8,
106.5, 110.6, 117.5, 118.4, 120.2, 122.5, 123.5, 126.1, 127.8, 131.5,
132.4, 134.0, 134.2, 135.1, 135.3, 148.4, 169.3 ppm. HRMS (ESI):
calcd. for C17H14N2O [M + H]+ 263.1179; found 263.1187. HPLC
(Chiralpak AD-H column, hexane/2-propanol = 70:30, flow rate =
1.0 mL/min, wavelength = 220 nm): tR = 5.64 (minor), 10.20 min
(major).
(R)-3-(4-Benzyloxy-1H-indol-3-yl)isoindolin-1-one
(8g):
Yield:
64 mg, 90%. White solid, m.p. 222–224 °C. [α]2D0 = +27.5 (c = 1.0,
1
DMSO), 32%ee. H NMR (400 MHz, [D6]DMSO): δ = 5.20 (d, J
= 4.8 Hz, 2 H, CH2), 6.22 (s, 1 H, CH), 6.59–6.60 (m, 1 H, Ar-H),
6.99–7.00 (m, 3 H, Ar-H), 7.24–7.31 (m, 3 H, Ar-H), 7.41–7.49 (m,
5 H, Ar-H), 7. 67 (d, J = 7.2 Hz, 1 H, Ar-H), 8.85 (s, 1 H, NH),
11.08 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ =
53.9, 69.0, 100.5, 105.2, 113.0, 115.9, 120.8, 120.9, 122.2, 122.5,
123.7, 127.3, 127.5, 128.2, 128.3, 131.3, 131.8, 137.3, 138.1, 138.2,
149.0, 152.3, 169.4 ppm. HRMS (ESI): calcd. for C23H18N2O2 [M –
H]– 353.1296; found 353.1292. HPLC (Chiralpak AD-H column,
hexane/2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength =
220 nm): tR = 12.37 (minor), 25.74 min (major).
(R)-3-(7-Methyl-1H-indol-3-yl)isoindolin-1-one (8l): Yield: 51 mg,
97%. White solid, m.p. 203–205 °C. [α]2D0 = +21.4 (c = 1.0, DMSO),
1
51%ee. H NMR (400 MHz, [D6]DMSO): δ = 2.43 (s, 3 H, CH3),
5.96 (s, 1 H, CH), 6.72 (d, J = 4.4 Hz, 2 H, Ar-H), 6.83 (t, J =
4.0 Hz, 1 H, Ar-H), 7.28 (d, J = 6.4 Hz, 1 H, Ar-H), 7.44 (s, 1 H,
Ar-H), 7.49–7.50 (m, 2 H, Ar-H), 7.74–7.77 (m, 1 H, Ar-H), 8.93
(s, 1 H, NH), 11.05 (s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 16.6, 53.8, 112.1, 116.1, 118.8, 120.8, 121.7, 122.6
123.4, 123.8, 124.0, 124.7, 127.8, 131.5, 132.1, 136.2, 148.3,
169.2 ppm. HRMS (ESI): calcd. for C17H14N2O [M – H]– 261.1033;
found 261.1041. HPLC (Chiralpak AD-H column, hexane/2-pro-
panol = 70:30, flow rate = 1.0 mL/min, wavelength = 220 nm): tR
= 5.77 (minor), 10.02 min (major).
(R)-3-(5-Benzyloxy-1H-indol-3-yl)isoindolin-1-one
(8h):
Yield:
66 mg, 93%. White solid, m.p. 179–181 °C. [α]2D0 = +30.1 (c = 1.0,
1
DMSO), 57%ee. H NMR (400 MHz, [D6]DMSO): δ = 4.91 (d, J
= 4.0 Hz, 2 H, CH2), 5.94 (s, 1 H, CH), 6.57 (s, 1 H, Ar-H), 6.78
(dd, J = 8.8, 2.0 Hz, 1 H, Ar-H), 7.24–7.30 (m, 3 H, Ar-H), 7.34–
7.35 (m, 5 H, Ar-H), 7.49–7.51 (m, 2 H, Ar-H), 7.75–7.77 (m, 1
H, Ar-H), 8.92 (s, 1 H, NH), 10.92 (s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 53.3, 69.5, 102.3, 111.4, 111.7, 112.2
122.6, 123.4, 124.5, 124.7, 125.4, 127.5, 127.6, 127.8, 128.3, 131.5,
131.8, 132.0, 137.4, 148.1, 151.7, 169.2 ppm. HRMS (ESI): calcd.
for C23H18N2O2 [M + Na]+ 377.1260; found 377.1257. HPLC (Chi-
ralpak AD-H column, hexane/2-propanol = 70:30, flow rate =
1.0 mL/min, wavelength = 220 nm): tR = 10.75 (minor), 24.87 min
(major).
(R)-3-(1-Methyl-1H-indol-3-yl)isoindolin-1-one (8m): Yield: 51 mg,
98%. White solid, m.p. 208–210 °C. [α]2D0 = +27.1 (c = 1.0, DMSO),
42%ee. 1H NMR (400 MHz, [D6]DMSO): δ = 3.75 (s, 3 H, NCH3),
5.97 (s, 1 H, CH), 6.89 (t, J = 7.6 Hz, 1 H, Ar-H), 6.99 (d, J =
8.0 Hz, 1 H, Ar-H), 7.12 (t, J = 7.6 Hz, 1 H, Ar-H), 7.30–7.32 (m,
1 H, Ar-H), 7.39–7.41 (m, 2 H, Ar-H), 7.50 (t, J = 3.6 Hz, 2 H,
Ar-H), 7.77–7.79 (m, 1 H, Ar-H), 8.98 (s, 1 H, NH) ppm. 13C NMR
(100.6 MHz, [D6]DMSO): δ = 32.3, 53.4, 109.9, 111.0, 118.6, 121.4,
122.7, 123.4, 125.4, 127.9, 128.4, 131.6, 132.0, 137.1, 148.2,
169.3 ppm. HRMS (ESI): calcd. for C17H14N2O [M + H]+
263.1179; found 263.1177. HPLC (Chiralpak AD-H column, hex-
ane/2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength =
220 nm): tR = 6.73 (minor), 10.54 min (major).
(R)-3-(6-Benzyloxy-1H-indol-3-yl)isoindolin-1-one
(8i):
Yield:
64 mg, 90%. White solid, m.p. 212–214 °C. [α]2D0 = +29.4 (c = 1.0,
1
DMSO), 43%ee. H NMR (400 MHz, [D6]DMSO): δ = 5.06 (s, 2
H, CH2), 5.90 (s, 1 H, CH), 6.58 (dd, J = 8.8, 1.6 Hz, 1 H, Ar-H),
6.74 (d, J = 8.8 Hz, 1 H, Ar-H), 6.91 (d, J = 1.6 Hz, 1 H, Ar-H),
7.28–7.30 (m, 3 H, Ar-H), 7.37 (t, J = 7.6 Hz, 2 H, Ar-H), 7.42 (d,
J = 7.2 Hz, 2 H, Ar-H), 7.50 (t, J = 7.2 Hz, 2 H, Ar-H), 7.74 (d, J
5-Bromo-3-(1H-indol-3-yl)isoindolin-1-one (10): Yield: 30 mg, 46%.
= 6.8 Hz, 1 H, Ar-H), 8.91 (s, 1 H, NH), 10.87 (s, 1 H, NH) ppm. White solid, m.p. 195 °C. [α]2D0 = +24.5 (c = 1.0, DMSO), 42%ee.
13C NMR (100.6 MHz, [D6]DMSO): δ = 53.8, 69.4, 96.3, 109.6,
111.7, 119.1, 119.5, 122.7, 123.2, 123.4, 127.5, 127.6, 127.6, 127.9,
128.4, 131.7, 132.0, 137.5, 148.3, 154.5, 169.4 ppm. HRMS (ESI):
calcd. for C23H18N2O2 [M – H]– 353.1296; found 353.1290. HPLC
(Chiralpak AD-H column, hexane/2-propanol = 70:30, flow rate =
1H NMR (400 MHz, [D6]DMSO): δ = 6.00 (s, 1 H, CH), 6.85 (t,
J = 7.2 Hz, 1 H, Ar-H), 6.93 (d, J = 8.0 Hz, 1 H, Ar-H), 7.05 (t, J
= 7.6 Hz, 1 H, Ar-H), 7.39 (d, J = 8.0 Hz, 1 H, Ar-H), 7.46–7.49
(m, 2 H, Ar-H), 7.67–7.72 (m, 2 H, Ar-H), 9.01 (s, 1 H, NH), 11.16
(s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 53.5,
896
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 892–897

Enantioselective Synthesis of 3-Indolyl-Substituted Isoindolin-1-ones
Page, A. M. Z. Slawin, Tetrahedron Lett. 1999, 40, 141–142; d)
S. M. Allin, C. J. Northfield, M. I. Page, A. M. Z. Slawin, Tet-
rahedron Lett. 1999, 40, 143–146; e) S. M. Allin, C. J. North-
field, M. I. Page, A. M. Z. Slawin, J. Chem. Soc. Perkin Trans.
1 2000, 1715–1721; f) E. Deniau, D. Enders, A. Couture, P.
Grandclaudon, Tetrahedron: Asymmetry 2003, 14, 2253–2258;
g) A. A. Bahajaj, J. M. Vernon, G. D. Wilson, Tetrahedron
2004, 60, 1247–1253; h) M.-D. Chen, X. Zhou, M.-Z. He, Y.-
P. Ruan, P.-Q. Huang, Tetrahedron 2004, 60, 1651–1657; i) E.
Deniau, A. Couture, P. Grandclaudon, Tetrahedron: Asym-
metry 2008, 19, 2735–2740.
110.9, 111.9, 118.3, 121.4, 124.6, 124.7, 124.8, 125.3, 126.4, 131.2,
131.3, 136.7, 150.6, 168.3 ppm. HRMS (ESI): calcd. for
C16H11BrN2O [M – H]– 324.9982; found 324.9987. HPLC (Chi-
ralpak AD-H column, hexane/2-propanol = 75:25, flow rate =
1.0 mL/min, wavelength = 220 nm): tR = 7.70 (minor), 10.27 min
(major).
3-(1H-Indol-3-yl)-2-methylisoindolin-1-one (12): Yield: 33 mg, 63%.
White solid, m.p. 203–205 °C, 2%ee. 1H NMR (400 MHz, [D6]-
DMSO): δ = 2.82 (s, 3 H, CH3), 5.86 (s, 1 H, CH), 6.62 (t, J =
7.2 Hz, 1 H, Ar-H), 6.77 (t, J = 7.60 Hz, 1 H, Ar-H), 7.05 (t, J =
7.6 Hz, 1 H, Ar-H), 7.38 (d, J = 8.0 Hz, 1 H, Ar-H), 7.48–7.50 (m,
2 H, Ar-H), 7.60 (s, 1 H, Ar-H), 7.78–7.80 (m, 1 H, Ar-H), 11.24
(s, 1 H, NH) ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 26.8,
59.3, 109.1, 111.9, 117.9, 118.9, 121.3, 122.4, 123.2, 124.8, 126.1,
128.0, 131.5, 131.8, 136.8, 146.2, 166.9 ppm. HRMS (ESI): calcd.
for C17H14N2O [M – H]– 261.1033; found 261.1041. HPLC
(Chiralpak OD-H column, hexane/2-propanol = 90:10, flow rate =
1.0 mL/min, wavelength = 220 nm): tR = 29.79 (minor), 33.90 min
(major).
[9] a) J. Pérard-Viret, T. Prangé, A. Tomas, J. Royer, Tetrahedron
2002, 58, 5103–5108; b) D. L. Comins, S. Schilling, Y. Zhang,
Org. Lett. 2005, 7, 95–98; c) M. Lamblin, A. Couture, E. De-
niau, P. Grandclaudon, Tetrahedron: Asymmetry 2008, 19, 111–
123.
[10] a) M. Bandini, A. Melloni, S. Tommasi, A. Umani-Ronchi,
Synlett 2005, 1199–1222; b) S.-L. You, Q. Cai, M. Zeng, Chem.
Soc. Rev. 2009, 38, 2190–2201; c) M. Zeng, S.-L. You, Synlett
2010, 1289–1301; d) V. Terrasson, R. M. de Figueiredo, J. M.
Campagne, Eur. J. Org. Chem. 2010, 2635–2655.
[11] a) M. Toyota, N. Ihara, Nat. Prod. Rep. 1998, 15, 327–340; b)
S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–2920; c)
G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875–
2911; d) M. Bandini, A. Eichholzer, Angew. Chem. 2009, 121,
9786; Angew. Chem. Int. Ed. 2009, 48, 9608–9644.
3-Ethyl-3-(1H-indol-3-yl)isoindolin-1-one (15): Yield: 55 mg, Ͼ99%.
White solid, m.p. 195–197 °C. [α]2D0 = –19.0 (c = 1.0, DMSO),
1
24%ee. H 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 (Chiralpak AD-H column, hexane/2-propanol =
75:25, flow rate = 1.0 mL/min, wavelength = 210 nm): tR = 6.73
(minor), 13.88 min (major).
[12] For pioneering work, see: a) T. Akiyama, J. Itoh, K. Yokota,
K. Fuchibe, Angew. Chem. 2004, 116, 1592; Angew. Chem. Int.
Ed. 2004, 43, 1566–1568; b) D. Uraguchi, M. Terada, J. Am.
Chem. Soc. 2004, 126, 5356–5357.
[13] For reviews on phosphoric acid catalysts, see: a) M. Terada,
Synthesis 2010, 1929–1982; b) M. Terada, Chem. Commun.
2008, 4097–4112; c) T. Akiyama, Chem. Rev. 2007, 107, 5744–
5758; d) S. J. Connon, Angew. Chem. 2006, 118, 4013; Angew.
Chem. Int. Ed. 2006, 45, 3909–3912; e) T. Akiyama, J. Itoh, K.
Fuchibe, Adv. Synth. Catal. 2006, 348, 999–1010.
[14] a) H. Y. Tang, G. F. Zhao, Z. H. Zhou, Q. L. Zhou, C. C. Tang,
Tetrahedron Lett. 2006, 47, 5717–5721; b) H. Y. Tang, P. Gao,
G. F. Zhao, Z. H. Zhou, L. N. He, C. C. Tang, Catal. Commun.
2007, 8, 1811–1814; c) H. Y. Tang, G. F. Zhao, Z. H. Zhou, P.
Gao, L. N. He, C. C. Tang, Eur. J. Org. Chem. 2008, 126–135;
d) H. Y. Tang, A. D. Lu, Z. H. Zhou, G. F. Zhao, L. N. He,
C. C. Tang, Eur. J. Org. Chem. 2008, 1406–1410; e) C. G. Wang,
Z. H. Zhou, C. C. Tang, Org. Lett. 2008, 10, 1707–1710; f) P.
Gao, C. G. Wang, Y. Wu, Z. H. Zhou, C. C. Tang, Eur. J. Org.
Chem. 2008, 4563–4566; g) A. D. Lu, X. Y. Xu, P. Gao, Z. H.
Zhou, H. B. Song, C. C. Tang, Tetrahedron: Asymmetry 2008,
19, 1886–1890; h) A. D. Lu, P. Gao, Y. Wu, Y. M. Wang, Z. H.
Zhou, C. C. Tang, Org. Biomol. Chem. 2009, 7, 3141–3147; i)
K. Hu, C. G. Wang, X. P. Ma, Y. M. Wang, Z. H. Zhou, C. C.
Tang, Tetrahedron: Asymmetry 2009, 20, 2178–2184; j) A. D.
Lu, R. H. Wu, Y. M. Wang, Z. H. Zhou, G. P. Wu, J. X. Fang,
C. C. Tang, Eur. J. Org. Chem. 2010, 2057–2061; k) A. D. Lu,
T. Liu, R. H. Wu, Y. M. Wang, Z. H. Zhou, G. P. Wu, J. X.
Fang, C. C. Tang, Eur. J. Org. Chem. 2010, 5777–5781; l) A. D.
Lu, R. H. Wu, Y. M. Wang, Z. H. Zhou, G. P. Wu, J. X. Fang,
C. C. Tang, Eur. J. Org. Chem. 2011, 122–127.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR and HRMS spectra as well as chiral
HPLC traces of the prepared 3-indolyl isoinlolin-1-ones.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 20772058, 20972070), the National Basic Research Pro-
gram of China (973 program 2010CB833301), and the Key labora-
tory of Elemento-Organic Chemistry for generous financial sup-
port of our programs.
[1] T. R. Belliotti, W. A. Brink, S. R. Kesten, Bioorg. Med. Chem.
Lett. 1998, 8, 1499–1502.
[2] T. Wada, N. Fukuda, Psychopharmacology 1991, 103, 314–322.
[3] J. R. Fuchs, R. L. Funk, Org. Lett. 2001, 3, 3923–3925.
[4] R. Grigg, M. J. R. Dorrity, J. F. Malone, T. Mongkolaus-savar-
atana, W. D. J. A. Norbert, V. Sridharan, Tetrahedron Lett.
1990, 31, 3075–3076.
[5] D. Enders, V. Braig, G. Raabe, Can. J. Chem. 2001, 79, 1528.
[6] L. Shen, R. P. Hsung, Org. Lett. 2005, 7, 775–778.
[7] J. Clayden, C. J. Menet, Tetrahedron Lett. 2003, 44, 3059–3062.
[8] a) S. M. Allin, C. J. Northfield, M. I. Page, A. M. Z. Slawin,
Tetrahedron Lett. 1997, 38, 3627–3630; b) S. M. Allin, C. J.
Northfield, M. I. Page, A. M. Z. Slawin, Tetrahedron Lett.
1998, 39, 4905–4908; c) S. M. Allin, C. J. Northfield, M. I.
[15] For a similar enantioselective Brønsted acid catalyzed nucleo-
philic substitution of γ-hydroxylactams with indole providing
disubstituted γ-lactams, see: M. Rueping, B. J. Nachtsheimb,
Synlett 2010, 119–122.
[16] CCDC-800015 (for 8a) contains the supplementary crystallo-
graphic 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.
Received: October 15, 2010
Published Online: December 22, 2010
Eur. J. Org. Chem. 2011, 892–897
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
897