Asymmetric proline-catalyzed addition of aldehydes to 3H-indol-3-ones: Enantioselective synthesis of 2,3-dihydro-1H-indol-3-ones with quaternary stereogenic centers

Article abstract of DOI:10.1002/hlca.201200498

The proline-catalyzed addition of various aliphatic aldehydes to sterically hindered 2-aryl-substituted 3H-indol-3-ones affords 2,2-disubstituted 2,3-dihydro-1H-indol-3-one derivatives with excellent enantioselectivities. In addition, the synthesis of a chiral derivative, (S)-2-(2-bromophenyl)-2,3- dihydro-2-(2-hydroxyethyl)-1H-indol-3-one, which can be used as an intermediate for the preparation of the natural product hinckdentine A was accomplished with a high level of enantioselectivity.

Full text of DOI:10.1002/hlca.201200498

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Helvetica Chimica Acta – Vol. 95 (2012)
Asymmetric Proline-Catalyzed Addition of Aldehydes to 3H-Indol-3-ones:
Enantioselective Synthesis of 2,3-Dihydro-1H-indol-3-ones with Quaternary
Stereogenic Centers
by Magnus Rueping*, Ramesh Rasappan, and Sadiya Raja
Institute of Organic Chemistry, RWTH-Aachen University, Landoltweg 1, DE-52074 Aachen
(fax þ 49(241)8092665; e-mail: Magnus.Rueping@rwth-aachen.de)
Meinem verehrten Lehrer, Herrn Prof. Dieter Seebach, zum 75. Geburtstag gewidmet
The proline-catalyzed addition of various aliphatic aldehydes to sterically hindered 2-aryl-
substituted 3H-indol-3-ones affords 2,2-disubstituted 2,3-dihydro-1H-indol-3-one derivatives with
excellent enantioselectivities. In addition, the synthesis of a chiral derivative, (S)-2-(2-bromophenyl)-
2,3-dihydro-2-(2-hydroxyethyl)-1H-indol-3-one, which can be used as an intermediate for the prepara-
tion of the natural product hinckdentine A was accomplished with a high level of enantioselectivity.
Introduction. – The stereoselective construction of CꢀC bonds is a valuable tool in
preparing complex natural products and pharmaceutically important compounds.
However, the synthesis of stereogenic quaternary C-centers with a high level of
enantioselectivity via CꢀC bond-formation is still demanding [1]. In particular, the
preparation of compounds bearing N or other heteroatoms next to the quaternary C-
center constitutes a challenging task in organic chemistry.
Indole derivatives are privileged structures [2] present in numerous pharmaceutical
drugs. Dihydroindol-2- and -3-one derivatives are also found in many natural products
and active compounds against cancer, atherosclerosis, arthritis, and restenosis [3]. 2,3-
Dihydro-1H-indol-3-ones are valuable synthons for the synthesis of more complex
molecules, for example, for the synthesis of the natural product hinckdentine A1)
(Scheme) [5].
Scheme
1
)
For isolation and X-ray characterization of hinckdentine A, see [4].
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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The Mannich reaction is a classic atom economic process for the construction of
CꢀC bonds that has especially been applied in the preparation of amino acids, natural
products, and biologically active compounds [6]. Proline-mediated Mannich reactions
are known to provide excellent enantioselectivities with various aldehydes and ketones
[6][7]. However, the use of acetaldehyde (MeCHO) as a nucleophile is very limited in
organic synthesis due to the rapid self-aldol-condensation reaction which leads to the
formation of polymers. Also, the Mannich product from MeCHO might undergo
further reaction, since the a-C-atom can be further activated by proline [8].
Results and Discussion. – Recently, we showed that the 3H-indol-3-ones can be
utilized to synthesize dihydro-indolone derivatives with a quaternary stereogenic
center bearing a N-atom [9]2). Here, we report our studies on the synthesis of chiral
quaternary 2,2-disubstituted 2,3-dihydro-1H-indol-3-ones via proline-mediated Man-
nich reaction of 3H-indol-3-ones with various aldehydes as efficient nucleophiles.
Moreover, the precursor for the synthesis of hinckdentine A was synthesized with a
good enantioselectivity [10a]3).
With 3H-indol-3-ones 1 in our hands [5c][12], we investigated their usefulness as
substrates in the proline-catalyzed Mannich reactions with MeCHO4). Initial studies
were carried out by varying the catalyst loading, solvent, and temperature. 3H-Indol-3-
one 1a was treated with 6 equiv. of MeCHO (2a) in the presence of l-proline at room
temperature, and the resulting Mannich adduct 3a was reduced with NaBH4 in MeOH
to give 4a. When 20 mol-% of l-proline were used, an excellent enantioselectivity of
96% ee was observed (Table 1, Entry 2). A slightly lower level of enantioselectivity was
observed by decreasing the catalyst loading to 10 mol-% (Table 1, Entry 1). Increasing
the catalyst loading did not improve the enantioselectivity (Table 1, Entry 3).
Interestingly, excellent enantioselectivities were observed in most of the tested
solvents (Table 1, Entries 2 – 7). CH2Cl2 proved to be the most efficient solvent, with
regard to yield and selectivity (Table 1, Entry 6, 56% yield, 98% ee). To improve the
yield of the reaction by suppressing the side-product formation, we carried out
reactions by varying the temperature and the amount of MeCHO (2a). Lowering the
reaction temperature did not improve the reaction yield; however, significant
improvement in the yield was observed when 2a was added in two portions. Under
these conditions, the desired product 4a was obtained in 71% yield with 98% ee
(Table 1, Entry 9).
With the optimized reaction conditions in hand, we explored the scope of 3H-indol-
3-one derivatives as substrates (Table 2). Substrates bearing electron-donating
substituents such as Me, Et, and MeO gave the 2,3-dihydro-1H-indol-3-ones 4a – 4c
with excellent enantioselectivities (Table 2, Entries 1 – 3). Substrates with electron
deficient phenyl rings bearing substituents including F, Cl, and Br afforded the
corresponding products with excellent enantioselectivities as well (Table 2, Entries 4 –
6). Notably, most of the reactions require less than 1 h for completion. Even the bulkier
napthalen-2-yl indol-3-one 1h provided the product in 81% yield and 98% ee (Table 2,
2
)
)
)
For similar studies, see [10].
For achiral Lewis and Brønsted acid catalyzed versions, see [11].
With regard to the mechanism in proline catalysis, see [13].
3
4

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 1. Screening of Catalyst Loading, Various Solvents, and Temperaturea)
Entry
Solvent
Catalyst [mol-%]
Temp. [8]
Time [h]
Yield [%]b)
ee [%]c)
1
2
3
4
5
6
7
8
9d)
10d)
DMSO
DMSO
DMSO
Toluene
CHCl3
CH2Cl2
MeCN
Benzene
CH2Cl2
CH2Cl2
10
20
30
20
20
20
20
20
20
20
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
1
1
1
1
0.75
0.75
1
2
0.75
1
44
46
48
53
51
56
42
44
71
68
87
96
96
97
97
98
97
81
98
98
a) 1 equiv. of 1a, 6 equiv. of MeCHO, l-proline. b) Yields after CC (over two steps). c) Determined by
SFC. d) Addition of 4 equiv. of MeCHO in two portions.
Table 2. Mannich Addition of Acetaldehyde to 3H-Indol-3-onesa)
Entry
Ar
1
Time [h]
4
Yield [%]b)
ee [%]c)
1
2
3
4
5
6
7
8
4-MeꢀC6H4
4-EtꢀC6H4
4-MeOꢀC6H4
4-FꢀC6H4
1a
1b
1c
1d
1e
1f
1g
1h
0.75
0.33
0.5
1
1
1
4a
4b
4c
4d
4e
4f
4g
4h
71
76
74
52
66
51
48
81
98
97
96
94
96
98
95
98
4-ClꢀC6H4
4-BrꢀC6H4
Ph
1
0.5
Naphthalen-2-yl
a) 1 equiv. of 3H-indol-3-one 1, 4 equiv. of MeCHO in two portions. b) Yields after CC (over two steps).
c) Determined by HPLC or supercritical fluid chromatography (SFC).
Entry 8). The absolute configurations of the products 4a – 4h were assigned by
comparison with the literature data [10a].
To extend the scope of the reaction, various aldehydes 2a – 2e were treated with 3H-
indol-3-one 1a, and the results are compiled in Table 3. Propanal (2b) and butanal (2c)
gave products with excellent ee values and very good yields (Table 3, Entries 2 and 3),

Helvetica Chimica Acta – Vol. 95 (2012)
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Table 3. Evaluation of Aldehydes in the Asymmetric Mannich Reactiona)
Entry
R
2
Equiv. (2)
Time [h]
4
Yield [%]b)
dr
ee [%]c)
1
2
3
4
5d)
6
H
2a
2b
2c
2d
2d
2e
4
2
2
1.1
1.1
2
0.75
2
3
1.3
3
3
4a
4i
4j
4k
4k
4l
71
84
91
84
87
72
–
98
98
98
85
85
56
Me
Et
Pr
Pr
iPr
10 : 1
3 : 1
2 : 1
2 : 1
1 : 1
a) 1 equiv. of 3H-indol-3-one, l-proline 20 mol-%, CH2Cl2, r.t. b) Yields after CC (over two steps).
c) Enantioselectivity of the major diastereoisomer, determined by HPLC or SFC. d) Reaction performed
at 08.
but the reactions required longer times compared to the addition of MeCHO (2a). The
products 4i and 4j were obtained with a 10 :1 and a 3 :1 diastereoisomer ratio (dr),
respectively. Extending the alkyl chain of the aldehyde led to a decrease in
enantioselectivity (Table 3, Entries 4 and 5). The branched-chain aldehyde 2e afforded
the corresponding product 4l only with moderate enantioselectivity (Table 3, Entry 6).
The absolute configurations of the products 4i – 4l were assigned by comparison with
the literature data [10a].
The natural product hinckdentine A has a unique structure consisting of a seven-
membered lactam ring fused to a tribromo-indolo[1,2-c]quinazoline with a stereogenic
quaternary and a stereogenic tertiary C-centers (Scheme), which attracted the interest
of several chemists [4][5]. Despite considerable interest in the synthesis of
hinckdentine A, its enantioselective synthesis still remains a challenge due to the
construction of sterically crowded vicinal stereogenic quaternary and tertiary C-centers
present in the structure.
Racemic indolinone 4m was used as an intermediate in the synthesis of 8-debromo-
hinckdentine A derivative [5c]. Hence, our attention was drawn to the enantioselective
synthesis of this molecule. In this particular case, the addition of MeCHO (2a) is more
challenging due to the presence of bulky 2-Br substituent on the phenyl ring. As
anticipated, the product 4m was isolated with a lower level of enantioselectivity (70%
yield, 60% ee), when the reaction was performed under the standard conditions
(Table 4, Entry 2). Use of a stoichiometric amount of l-proline did not improve the
enantioselectivity (Table 4, Entry 3). However, by lowering the reaction temperature,
the enantioselectivity was improved, but the reaction required longer time for the
complete conversion. Accordingly, 2,3-dihydro-1H-indol-3-one 4m was isolated with
75% ee, when the reaction was performed at 08 (Table 4, Entry 4). Lowering the
temperature to –358 afforded the desired product with the best enantioselectivity of

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Table 4. Addition of Acetaldehyde to 2-(4-Bromophenyl)-3H-indol-3-one (1i)a)
Entry
Proline
Loading [mol-%]
Time
Temp [8]
Yield [%]b)
ee [%]c)
1
2
3
4
5
6
7
dl
l
l
l
l
20
20
100
20
20
20
1.3 h
1.3 h
1 h
6 h
4 d
r.t.
r.t.
r.t.
0
65
70
72
70
77
50
10
–
60
55
75
87
87
83
ꢀ 35
l
l
4 d
10 d
ꢀ 78 to ꢀ 30
20
ꢀ 78 to ꢀ 50
a) 1 equiv. of 3H-indol-3-one 1i, 4 equiv. of MeCHO in two portions. b) Yields after CC (over two steps).
c) Determined by SFC.
87% ee and in 77% yield, but the reaction was sluggish and took 4 d for the complete
conversion (Table 4, Entry 5). Decreasing the reaction temperature further to ꢀ 788
did not improve the enantioselectivity, and only traces of the product were observed
even after several days. However, the acetaldehyde Mannich reaction provides access
to a key building block for the synthesis of hinckdentine A.
In conclusion, we have developed an asymmetric synthesis of various 2,2-
disubstituted 2,3-dihydro-1H-indol-3-ones with excellent enantioselectivities. The
reaction is applicable to 3H-indol-3-ones bearing electron-withdrawing as well as
electron-donating groups as electrophiles, and various aldehydes as nucleophiles. More
importantly, a challenging intermediate for the synthesis of hinckdentine A was
synthesized with good enantioselectivity. Further studies are focused on the total
synthesis of hinckdentine A and exploring the scope of 3H-indol-3-ones in other
organocatalyzed reactions.
Experimental Part
General. Solvents were obtained from Fisher Scientific and were purified before use by distillation.
Starting materials were purchased from Acros and Alfa Aesar and were used without further purification.
Optical rotations: Perkin-Elmer 241 polarimeter. IR Spectra: Jasco FT/IR-420 spectrometer, in KBr.
NMR Spectra: Mercury 300 or Inova 400 spectrometer in CD3OD, d in ppm, J in Hz. EI-MS (70 eV): GC/
MS Shimadzu QP2010 (column Equity-5, length ꢁ i.d. 30 m ꢁ 0.25 mm, df 0.25 mm, lot # 28089-U,
Supelco); m/z.
General Procedure. Acetaldehyde (2a; 4 equiv.) was added to the mixture of 3H-indol-3-one 1
(1 equiv.) and l-proline (20 mol-%) in 1.0 ml of CH2Cl2 at r.t. The mixture was stirred vigorously for
20 min. Subsequently, another 4 equiv. of 2a were added. The reaction was monitored by TLC, and upon
completion the solvent was removed, and the crude was taken in 1 ml of MeOH. NaBH4 (2 equiv.) was
added at 08. After stirring for 5 min, the reaction was quenched with H2O, and the mixture was extracted
with AcOEt and washed with brine. The org. layer was dried (Na2SO4), filtered, and the solvent was

Helvetica Chimica Acta – Vol. 95 (2012)
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removed under reduced pressure. Purification of the crude product by column chromatography (CC) on
SiO2 afforded the corresponding product 4.
(2S)-2-(2-Hydroxyethyl)-2-(4-methylphenyl)-2,3-dihydro-1H-indol-3-one (4a). Yellow gummy com-
pound. Yield: 74%. [a]2D5 ¼ þ368 (c ¼ 1.0, CH2Cl2; 98% ee). IR: 3318, 3017, 2924, 2858, 2406, 1674, 1619,
1470, 1327, 1287, 1215, 1042, 1000, 894, 756. 1H-NMR (400 MHz; CD3OD): 7.48 – 7.43 (m, 1 H); 7.42 – 7.39
(m, 3 H); 7.11 (d, J ¼ 8.0, 2 H); 6.97 (d, J ¼ 8.3, 1 H); 6.70 (t, J ¼ 7.4, 1 H); 3.53 – 3.46 (m, 2 H); 2.36 – 2.29
(m, 1 H); 2.26 (s, 3 H); 2.19 (dt, J ¼ 13.7, 7.8, 1 H). 13C-NMR (101 MHz, CD3OD): 203.2; 161.5; 137.6;
136.9; 135.7; 128.7; 125.2; 124.3; 117.8; 117.7; 111.7; 70.4; 57.8; 40.2; 19.7. EI-MS: 268 (15, [M þ H]þ), 267
(69, Mþ), 223 (24), 222 (100).
(2S)-2-(4-Ethylphenyl)-2-(2-hydroxyethyl)-1,2-dihydro-3H-indol-3-one (4b). Yellow gummy com-
pound. Yield: 76%. [a]2D5 ¼ þ265 (c ¼ 1.0, CH2Cl2; 97% ee). IR: 3361, 3012, 2964, 2928, 2876, 1687, 1617,
1488, 1325, 1151, 1098, 1042, 894, 755. 1H-NMR (300 MHz; CD3OD): 7.49 – 7.42 (m, 4 H); 7.15 (d, J ¼ 8.1,
2 H); 6.99 (d, J ¼ 8.3, 1 H); 6.72 (t, J ¼ 7.4, 1 H); 3.59 – 3.45 (m, 2 H); 2.59 (q, J ¼ 7.6, 2 H); 2.40 – 2.31 (m,
1 H); 2.27 – 2.17 (m, 1 H); 1.18 (t, J ¼ 7.6, 3 H). 13C-NMR (75 MHz, CD3OD): 203.4; 161.6; 143.4; 137.6;
136.0; 127.6; 125.4; 124.4; 117.9; 117.7; 111.7; 70.4; 57.8; 40.1; 27.9; 14.7. EI-MS: 281 (60, Mþ), 252 (56), 236
(100).
(2S)-2-(2-Hydroxyethyl)-2-(4-methoxyphenyl)-2,3-dihydro-1H-indol-3-one (4c). Yellow gummy
compound. Yield: 74%. [a]2D5 ¼ þ293 (c ¼ 1.0, CH2Cl2; 96% ee). IR: 3371, 2928, 1690, 1615, 1505,
1324, 1250, 1094, 1036, 756. 1H-NMR (300 MHz; CD3OD): 7.50 – 7.41 (m, 4 H); 6.98 (dt, J ¼ 8.3, 0.8, 1 H);
6.89 – 6.84 (m, 2 H); 6.75 – 6.69 (m, 1 H); 3.74 (s, 3 H); 3.59 – 3.45 (m, 2 H); 2.37 – 2.29 (m, 1 H); 2.25 –
2.15 (m, 1 H). 13C-NMR (75 MHz, CD3OD): 203.6; 161.5; 159.2; 137.6; 130.6; 126.5; 124.4; 117.9; 117.7;
113.5; 111.7; 70.1; 57.8; 54.3; 40.1. EI-MS: 283 (47, Mþ), 254 (51), 238 (100).
(2S)-2-(4-Fluorophenyl)-2-(2-hydroxyethyl)-2,3-dihydro-1H-indol-3-one (4d). Yellow gummy com-
pound. Yield: 52%. [a]2D5 ¼ þ251 (c ¼ 1.0, CH2Cl2, 94% ee). IR: 3370, 2927, 1693, 1617, 1502, 1382, 1325,
1229, 1158, 1091, 1041, 837, 756. 1H-NMR (300 MHz; CD3OD): 7.61 – 7.56 (m, 2 H); 7.51 – 7.43 (m, 2 H);
7.07 – 6.99 (m, 3 H); 6.74 (td, J ¼ 7.4, 0.7, 1 H); 3.59 – 3.44 (m, 2 H); 2.37 – 2.29 (m, 1 H); 2.26 – 2.17 (m,
1 H). 13C-NMR (75 MHz, CD3OD): 202.9; 162.3 (d, J(C,F) ¼ 244.7); 161.4; 137.7; 134.9; 127.4 (d,
J(C,F) ¼ 13.7); 124.4; 117.9; 117.8; 114.7 (d, J(C,F) ¼ 21.5); 111.8; 70.0; 57.7; 40.3. EI-MS: 271 (67, Mþ),
242 (70), 226 (100), 224 (58).
(2S)-2-(4-Chlorophenyl)-2-(2-hydroxyethyl)-2,3-dihydro-1H-indol-3-one (4e). Yellow gummy com-
pound. Yield: 66%. [a]2D5 ¼ þ234 (c ¼ 1.0, CH2Cl2; 96% ee). IR: 3346, 2921, 2851, 2320, 2081, 1904, 1790,
1677, 1616, 1582, 1465, 1386, 1324, 1290, 1152, 1092, 1009, 821, 750. 1H-NMR (300 MHz; CD3OD): 7.59 –
7.57 (m, 1 H); 7.55 – 7.54 (m, 1 H); 7.52 – 7.48 (m, 1 H); 7.47 – 7.43 (m, 1 H); 7.34 – 7.30 (m, 2 H); 7.01 (dt,
J ¼ 8.3, 0.8, 1 H); 6.77 – 6.72 (m, 1 H); 3.59 – 3.43 (m, 2 H); 2.37 – 2.28 (m, 1 H); 2.26 – 2.14 (m, 1 H).
13C-NMR (75 MHz, CD3OD): 202.6; 161.5; 137.7; 133.1; 129.1; 128.1; 127.2; 124.4; 118.0; 117.8; 111.9;
70.1; 57.6; 40.2. EI-MS: 287 (67, Mþ), 258 (64), 244 (46), 242 (100).
(2S)-2-(4-Bromophenyl)-2-(2-hydroxyethyl)-2,3-dihydro-1H-indol-3-one (4f). Yellow gummy com-
pound. Yield: 51%. [a]2D5 ¼ þ222 (c ¼ 1.0, CH2Cl2; 98% ee). IR: 3331, 3018, 2923, 2856, 1677, 1619, 1583,
1471, 1215, 1007, 756. 1H-NMR (300 MHz; CD3OD): 7.52 – 7.43 (m, 6 H); 7.02 – 6.98 (m, 1 H); 6.78 – 6.72
(m, 1 H); 3.59 – 3.44 (m, 2 H); 2.37 – 2.27 (m, 1 H); 2.26 – 2.15 (m, 1 H). 13C-NMR (75 MHz, CD3OD):
202.5; 161.5; 138.4; 137.8; 131.2; 127.5; 124.4; 121.1; 118.0; 117.8; 111.9; 70.1; 57.6; 40.2. EI-MS: 333 (50),
331 (52, Mþ), 288 (79), 286 (100).
(2S)-2-(2-Hydroxyethyl)-2-phenyl-2,3-dihydro-1H-indol-3-one (4g). Yellow gummy compound.
Yield: 48%. 1H-NMR (400 MHz, CD3OD): 7.55 – 7.53 (m, 2 H); 7.49 – 7.41 (m, 2 H); 7.32 – 7.28 (m,
2 H); 7.25 – 7.23 (m, 1 H); 6.99 (d, J ¼ 8.3, 1 H); 6.71 (t, J ¼ 7.4, 1 H); 3.55 – 3.46 (m, 2 H); 2.38 – 2.32 (m,
1 H); 2.26 – .18 (m, 1 H). 13C-NMR (101 MHz, CD3OD): 203.0; 161.5; 138.8; 137.6; 128.1; 127.1; 125.3;
124.3; 117.8; 111.7; 70.5; 57.8; 40.3.
(2S)-2-(2-Hydroxyethyl)-2-(naphthalen-2-yl)-2,3-dihydro-1H-indol-3-one (4h). Yellow gummy com-
pound. Yield: 81%. [a]2D5 ¼ þ223 (c ¼ 1.0, CH2Cl2; 98% ee). IR: 3366, 3057, 3013, 2925, 1687, 1617, 1487,
1325, 1215, 1152, 1040, 754. 1H-NMR (400 MHz; CD3OD): 8.01 – 8.00 (m, 1 H); 7.80 – 7.76 (m, 3 H); 7.68
(dd, J ¼ 8.7, 1.9, 1 H); 7.50 – 7.46 (m, J ¼ 1.3, 1 H); 7.45 – 7.40 (m, 3 H); 7.03 (dt, J ¼ 8.3, 0.8, 1 H); 6.74 –
6.70 (m, J ¼ 0.8, 1 H); 3.60 – 3.48 (m, 2 H); 2.50 – 2.44 (m, J ¼ 4.6, 1 H); 2.35 – 2.28 (m, J ¼ 7.6, 1 H).
13C-NMR (101 MHz, CD3OD): 202.9; 161.5; 137.7; 136.2; 133.3; 132.7; 127.8; 127.6; 127.0; 125.7; 125.6;

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Helvetica Chimica Acta – Vol. 95 (2012)
124.4; 124.1; 123.5; 117.9; 117.8; 111.8; 70.7; 57.9; 40.2. EI-MS: 304 (15, [M þ H]þ), 303 (63, Mþ), 259 (26),
258 (100).
(2S)-2-[(1R)-2-Hydroxy-1-methylethyl]-2-(4-methylphenyl)-2,3-dihydro-1H-indol-3-one (4i). Yel-
low gummy compound. Yield: 84%. [a]2D5 ¼ þ360 (c ¼ 1.0, CH2Cl2, 98% ee). IR: 3396, 3292, 2934,
1
1912, 1673, 1614, 1465, 1379, 1322, 1222, 1035, 892, 752. H-NMR (400 MHz, CD3OD): 7.45 – 7.40 (m,
3 H); 7.38 – 7.36 (m, 1 H); 7.12 – 7.10 (m, 2 H); 6.97 (d, J ¼ 8.3, 1 H); 6.69 – 6.65 (m, 1 H); 3.42 (dd, J ¼
10.6, 5.0, 1 H); 3.27 – 3.24 (m, 1 H); 2.75 – 2.71 (m, 1 H); 2.27 (s, 3 H); 0.85 (d, J ¼ 6.9, 3 H). 13C-NMR
(101 MHz, CD3OD): 203.4; 161.6; 137.3; 136.9; 135.8; 128.7; 125.3; 124.0; 118.8; 117.4; 111.3; 73.9; 62.8;
43.6; 19.5; 11.2. EI-MS: 281 (16, Mþ), 223 (19), 222 (100).
(2S)-2-[(1R)-1-(Hydroxymethyl)propyl]-2-(4-methylphenyl)-2,3-dihydro-1H-indol-3-one (4j). Yel-
low gummy compound. Yield: 91%. [a]2D5 ¼ þ260 (c ¼ 0.9, CH2Cl2; 98% ee). IR: 3350, 3009, 2961, 2930,
1
2878, 1683, 1618, 1470, 1323, 1216, 1034, 893, 756. H-NMR (400 MHz, CD3OD): 7.45 – 7.42 (m, 2 H);
7.41 – 7.36 (m, 2 H); 7.10 (d, J ¼ 8.1, 2 H); 6.97 (d, J ¼ 8.3, 1 H); 6.68 – 6.64 (m, 1 H); 3.52 – 3.43 (m, 2 H);
2.56 – 2.50 (m, 1 H); 1.36 – 1.23 (m, 2 H); 0.83 (t, J ¼ 7.5, 3 H). 13C-NMR (101 MHz, CD3OD): 203.7;
161.6; 137.1; 136.8; 136.2; 128.7; 125.5; 124.1; 118.9; 117.4; 111.4; 74.5; 61.5; 49.9; 20.4; 19.5; 11.8. EI-MS:
295 (16, Mþ), 223 (24), 222 (100).
(2S)-2-[(1R)-1-(Hydroxymethyl)butyl]-2-(4-methylphenyl)-2,3-dihydro-1H-indol-3-one (4k). Yel-
low gummy compound. Yield: 87%. [a]D25 ¼ þ225 (c ¼ 1.1, CH2Cl2, 85% ee). 1H-NMR (400 MHz,
CD3OD): 7.46 – 7.43 (m, 2 H); 7.41 – 7.39 (m, 1 H); 7.37 (d, J ¼ 7.8, 1 H); 7.10 (d, J ¼ 8.2, 2 H); 6.97 (d, J ¼
8.3, 1 H); 6.66 (t, J ¼ 7.3, 1 H); 3.50 – 3.42 (m, 2 H); 2.64 – 2.58 (m, 1 H); 2.27 (s, 3 H); 1.41 – 1.30 (m, 1 H);
1.28 – 1.14 (m, 3 H); 0.75 (t, J ¼ 7.1, 3 H ) . 13C-NMR (101 MHz, CD3OD): 203.7; 161.6; 137.1; 136.8; 136.2;
128.7; 125.5; 124.1; 119.0; 117.4; 111.4; 74.5; 62.0; 29.9; 21.1; 19.5; 13.2. EI-MS: 309 (15, Mþ), 223 (24), 222
(100).
(2S)-2-[(1R)-1-(Hydroxymethyl)-2-methylpropyl]-2-(4-methylphenyl)-2,3-dihydro-1H-indol-3-one
(4l). Yellow gummy compound. Yield: 72%. IR: 3387, 2959, 2925, 1689, 1618, 1471, 1384, 1322, 1216,
1149, 1104, 1045, 897, 756. 1H-NMR (400 MHz, CD3OD): 7.45 – 7.42 (m, 2 H); 7.41 – 7.35 (m, 2 H); 7.10 (d,
J ¼ 8.0, 2 H); 7.02 (d, J ¼ 8.3, 1 H); 6.68 – 6.65 (m, 1 H); 3.67 (dd, J ¼ 11.1, 6.3, 1 H); 3.49 (dd, J ¼ 11.1,
6.7, 1 H); 2.74 – 2.70 (m, 1 H); 2.26 (s, 3 H); 1.78 – 1.70 (m, 1 H); 0.97 (d, J ¼ 7.1, 3 H); 0.84 (d, J ¼ 7.0,
3 H). 13C-NMR (75 MHz, CD3OD): 161.7; 136.8; 136.0; 128.7; 125.5; 124.0; 118.6; 117.4; 111.6; 74.8; 58.8;
52.7; 42.4; 26.5; 22.8; 19.5; 16.5. EI-MS: 309 (14, Mþ), 223 (28), 222 (100).
(2S)-2-(2-Bromophenyl)-2-(2-hydroxyethyl)-2,3-dihydro-1H-indol-3-one (4m). Yellow gummy com-
pound. Yield: 77%. [a]2D5 ¼ –312 (c ¼ 0.9, CH2Cl2; 87% ee). IR: 3373, 3063, 3011, 2926, 1690, 1616, 1486,
1436, 1325, 1214, 1152, 1097, 1028, 894, 755. 1H-NMR (400 MHz, CD3OD): 7.62 – 7.57 (m, 2 H); 7.52 (d,
J ¼ 7.8, 1 H); 7.46 (td, J ¼ 7.7, 1.1, 1 H); 7.36 – 7.31 (m, 1 H); 7.19 – 7.14 (m, 1 H); 6.90 (d, J ¼ 8.3, 1 H);
6.78 – 6.74 (m, 1 H); 3.58 – 3.52 (m, 1 H); 3.47 – 3.40 (m, 1 H); 2.65 – 2.58 (m, 1 H); 2.46 – 2.38 (m, 1 H).
13C-NMR (101 MHz, CD3OD): 203.4; 161.2; 137.9; 137.4; 134.8; 129.4; 129.1; 127.0; 123.5; 122.8; 120.6;
118.0; 112.0; 70.6; 57.2; 39.3. EI-MS: 331 (7, Mþ), 252 (100).
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Received August 29, 2012