Catalytic enantioselective synthesis of a 3-Aryl-3-benzyloxindole (=3-Aryl-3-benzyl-1,3-dihydro-2H-indol-2-one) exhibiting antitumor activity

Article abstract of DOI:10.1002/hlca.201200477

A palladium-catalyzed intramolecular α-arylation of an amide in the presence of a bulky chiral N-heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)-6-chloro-3-(3-chlorobenzyl)-1,3-dihydro-3-(3- methoxyphenyl)-2H-indol-2-one ((R)-5). This oxindole, in racemic form, had been shown previously to be an anticancer agent. (R)-5 was obtained with an overall yield of 45% and with 96% enantioselectivity.

Full text of DOI:10.1002/hlca.201200477

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Catalytic Enantioselective Synthesis of a 3-Aryl-3-benzyloxindole (¼ 3-Aryl-
3-benzyl-1,3-dihydro-2H-indol-2-one) Exhibiting Antitumor Activity
by Dmitry Katayev and E. Peter Kꢀndig*
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva, 4
(fax: þ 41-22-379-3215; email: peter.kundig@unige.ch)
Dedicated to Prof. Dieter Seebach on the occasion of his 75th birthday
A palladium-catalyzed intramolecular a-arylation of an amide in the presence of a bulky chiral N-
heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)-6-chloro-3-(3-
chlorobenzyl)-1,3-dihydro-3-(3-methoxyphenyl)-2H-indol-2-one ((R)-5). This oxindole, in racemic
form, had been shown previously to be an anticancer agent. (R)-5 was obtained with an overall yield
of 45% and with 96% enantioselectivity.
Introduction. – Oxindoles (¼1,3-dihydro-2H-indol-2-ones) containing a quaternary
stereogenic center at the C(3) position are found in a growing number of natural and
synthetic products presenting biological activities of interest [1]. Spiro[oxindole-3,3’-
pyrrolidines], in particular, constitute a large family of natural products. Examples are
the spirooxindole alkaloids 1 – 4 (Fig. 1) [2]. Spirocyclic compounds apart, oxindoles
having a quaternary stereogenic center at the C(3) position have also shown
pharmaceutical activity. Examples include a large range of compounds that were
contained in a patent by F. HoffmannꢀLa Roche AG as anticancer agents with rac-5
showing particularly high activity [3]. We also note that SSR-149415 (6) [4] is in clinical
trials for treatment of anxiety and depression, and SM-130686 (7) [5], containing a 3-
aryl-3-hydroxyoxindole skeleton, is a highly potent and orally active nonpeptidic
growth hormone secretagogue.
Not surprisingly, a large number of synthesis methods has been developed to
provide access to oxindoles [1d][1e][6]. Increasingly, attention has also focused on
asymmetric catalytic methods. One powerful route is the palladium-catalyzed intra-
molecular a-arylation of amides developed by Hartwig and co-workers in 2001 as a
simple and useful method for the synthesis of 3,3-disubstituted oxindoles. Bulky chiral
N-heterocyclic carbene (NHC) ligands worked best for the asymmetric transformation,
but enantioselectivities were modest (50 – 70% ee) [7].
We, and subsequently others, have developed bulky NHC ligands that brought
largely improved asymmetric inductions in this reaction [8][9]. With the chiral ligands
reported from our laboratory1), highly enantiomer-enriched 3,3-disubstituted oxin-
doles are now accessible in excellent yields (Scheme 1). X-Ray crystal structures of
borane adducts of these ligands and applications of [Pd(L1)] and [Pd(L4)] in
1
)
(S,S)-[L1H]I and (S,S)-[L4H]I will be available commercially shortly (Aldrich).
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 1. Some examples of natural products and bioactive compounds containing the 3,3-disubstituted
oxindole scaffold
Scheme 1. Application of the Developed N-Heterocyclic Carbene (NHC) Ligands to the Synthesis of 3,3-
Disubstituted Oxindoles. Ligand dba ¼ dibenzylideneacetone ¼ 1,5-diphenylpenta-1,4-dien-3-one;
DME ¼ 1,2-dimethoxyethane.
unprecedented asymmetric alkyl chain CꢀH activation shed light on the mechanism of
action and of the potential of these monodentate ligands [10].
Enantiomer-enriched oxindoles synthesized to date have always been model
compounds. They have provided information on scope and limitations of the reaction
but they were neither natural products nor synthetic bioactive agents. In most cases, N-

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methyloxindoles were prepared whereas biologically active compounds contain an
unsubstituted NH moitey. Reactions with N-benzyl protection usually delivered
products with lower enantioselectivity [8]. In this paper, we single out 6-chloro-3-(3-
chlorobenzyl)-1,3-dihydro-3-(3-methoxyphenyl)-2H-indol-2-one (5), one of the most
active compounds contained in the Roche 2006 patent [3] to test the asymmetric
catalytic method developed in our laboratory. The patent reports that 3,3-disubstituted
oxindoles are MDM2 antagonists and disrupt nefarious MDM2-p53 interactions. Since
p53 is a tumor-suppressor protein, MDM2 antagonists can offer a novel approach to
cancer therapy. Oxindole 5 is also mentioned in a recent patent dealing with a method
for improving the production of influenza viruses and vaccine seeds [11]. The reported
synthesis of rac-5 is shown in Scheme 2. To the best of our knowledge, no report of an
enantiomer-enriched oxindole 5 is literature-known.
Scheme 2. F. HoffmannꢀLaRoche Synthesis of rac-5 [3]
Results and Discussion. – The target molecule (R)-5 contains a quaternary
stereogenic center at the benzylic position and also two chloroaryl groups making the
key step of the intramolecular arylation of the precursor amide to give an oxindole
more challenging due to the potential of competition in the transition-metal oxidative
addition process. Our approach to the synthesis of (R)-5 is depicted in Scheme 3. We
envisaged that the requisite amide can easily be prepared from the dihaloaniline and
the carboxylic acid shown in Scheme 3. An asymmetric intramolecular Pd-catalyzed a-
arylation would then generate the sought-after oxindole.
Thus commercially available 3-methoxybenzeneacetic acid was converted to acid 8
by alkylation with 3-chlorobenzyl bromide in the presence of freshly prepared lithium
diisopropylamide (LDA) (Scheme 4). Then 2-bromo-5-chloroaniline (¼2-bromo-5-
chlorobenzenamine) was coupled with acyl chloride 9 producing amide 10 in high yield
(89% over the two steps). Amides 11 and 12 were synthesized by treating 10 with the
corresponding alkoxy chlorides MeOCH2Cl or PhCH2OCH2Cl in the presence of NaH
in THF.

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Scheme 3. Our Retrosynthetic Analysis of 5
Scheme 4. Catalytic Enantioselective Synthesis of (R)-5
Earlier data had shown that the choice of the chiral NHC ligand, the solvent, as well
as the N-protecting group influence both yield and asymmetric induction of the a-
arylation [8]. As shown in the Table, both (benzyloxy)methyl (PhCH2OCH2) and
methoxymethyl (MeOCH2) groups were suitable for the transformation to oxindole:
13 and 14, respectively, the best yields being obtained with 12 and toluene as solvent at
508.

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Conditions used previously with success (5 mol-% of L1 · HI or L4 · HI, 5 mol-% of
[Pd(dba)2], and 1.5 equiv. of tBuONa in 1,2-dimethoxyethane (DME) at r.t.) afforded
13 and 14 with good enantioselectivities but in low yields (Table, Entries 1 – 3). The
reaction was accompanied by decomposition of starting material. Fortunately, changing
the solvent to toluene and increasing the temperature to 508 improved the situation as
shown in Entries 5 – 8. While all four chiral ligands L1 – L4 performed very well, ligand
(R,R)-L3 proved best giving the oxindole 14 in 86% yield and 90% ee. The high yield
shows that the Pd-catalyzed cyclization takes place selectively and without interference
of the chloroaryl moieties present. This procedure was then incorporated into the
synthesis protocol for (R)-5. The MeOCH2 protecting group was chosen for its high
yield of incorporation into 10 and its ready removal from 14. The latter was carried out
with the Fukuyama procedure [12] that consisted of treating 14 with Me3SiCl in the
presence of NaI. The N-(hydroxymethyl) derivative produced, upon heating with Et3N
in MeOH at 558, furnished (R)-5 in 91% yield. Recrystallization from hexane/CH2Cl2
increased the enantiomer purity of (R)-5 to 96% ee (yield 79%). The absolute
configuration of 5 was assigned as (R) by comparison of its circular-dichroism (CD)
spectrum with that of similar oxindole structures described in the literature [8].
Table. Palladium Catalyzed a-Arylation of Substrates 11a) and 12a)
Entry Substrate NHC · HI
Solvent Temp. [8] Time [h] Yield [%]c) ee [%]b)d)
1
2
3
4
5
6
7e)
8
11
11
12
12
12
12
12
12
(S,S)-[L1H][I]
(S,S)-[L4H][I]
(S,S)-[L4H][I]
(S,S)-[L4H][I]
(S,S)-[L4H][I]
(S,S)-[L1H][I]
DME
DME
DME
toluene r.t.
toluene 50
toluene 50
r.t.
r.t.
r.t.
24
24
24
48
48
48
48
48
28
31
30
25
85
86
86
85
ꢀ 84
ꢀ 86
ꢀ 89
ꢀ 89
ꢀ 87
ꢀ 85
90
(R,R)-[L3H][I] toluene 50
(S,S)-[L2H][I] toluene 50
ꢀ 87
a) Substrate 11 or 12 (0.2 mmol) with NHC · HI (0.01 mmol) and [Pd(dba)2] (0.01 mmol). b) Absolute
configurations are assigned by analogy [8] and are tentative. c) Yield isolated of product. d) The
enantiomer excess (ee) ratio was determined by HPLC with a chiral stationary phase (Chiracel-AD-H
column). e) 1 mmol scale.
In conclusion, we have successfully applied the [Pd(NHC)*]-catalyzed asymmetric
a-arylation of amides to the total synthesis of highly enantiomer-enriched (R)-5. The
sequence involves 6 steps with an overall yield of 45%. These studies demonstrate that

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Helvetica Chimica Acta – Vol. 95 (2012)
the [Pd(NHC)*] catalysis can be used in an asymmetric CꢀC bond formation at a late
stage in the synthesis of complex structures.
Experimental Part
General. Chemicals were purchased from Aldrich, Acros, or Alfa Aesar and used without further
purification. Solvents were purified by filtration through drying columns by means of a Solvtecꢀ system or
by distillation over Na/benzophenone. Reactions and manipulations involving organometallic or
moisture sensitive compounds were carried out under N2, and glassware was further dried by heating
t
under vacuum as necessary. BuONa was sublimed and stored in a glove box. Flash chromatography
(FC): silica gel 60 (SiO2, 40 mm). HPLC: Agilent-1100 chromatograph and detection system, Jasco-PU-
980 pump; tR in min. M.p.: Bꢁchi-M-560 apparatus; uncorrected. Optical rotations: PerkinꢀElmer-241
polarimeter, with a quartz cell (l ¼ 10 cm) and a Na high-pressure lamp (l 589 nm); at 208. IR Spectra:
PerkinꢀElmer-Spectrum-One photometer; ˜n in cmꢀ1
.
1H- and 13C-NMR Spectra: Bruker AMX-500,
AMX-400 or AMX-300 spectrometer; d in ppm rel. to Me4Si as internal standard, J in Hz. HR-MS: VG-
7070E analytical instrument; in m/z.
3-(3-Chlorophenyl)-2-(3-methoxyphenyl)propanoic Acid (¼ 3-Chloro-a-(3-methoxyphenyl)benze-
nepropanoic Acid; 8). Lithium diisopropylamide (LDA) was prepared by adding 1.7m BuLi in pentane
(2 equiv., 14 ml, 24.0 mmol) into freshly distilled diisopropylamine (2 equiv., 3.4 ml, 24.0 mmol) in THF
(10 ml) and stirring for 30 min. Then 3-methoxybenzeneacetic acid (1 equiv., 2.0 g, 12.0 mmol) was added
to the magnetically stirred soln. at ꢀ 788, followed by the introduction of 3-chloro benzyl bromide (¼1-
(bromomethyl)-3-chlorobenzene; 1 equiv., 2.46 g, 12 mmol). The mixture was warmed to r.t. and stirred
for 16 h before quenching with 2m aq. HCl (50 ml) followed by extraction with AcOEt (3 ꢁ 20 ml). The
org. layer was dried (MgSO4), and the solvents were evaporated: crude 8 (3.17 g, 91%), which was used
1
in the next step without further purification. H-NMR (400 MHz, CDCl3): 3.03 (dd, J ¼ 6.9, 13.8, 1 H);
3.39 (dd, J ¼ 6.9,13.8, 1 H); 3.82 (s, 3 H); 3.87 (m, 1 H); 6.86 (d, J ¼ 7.5, 1 H); 6.88 (s, 1 H); 6.92 (d, J ¼ 7.5,
1 H); 7.03 (m, 1 H); 7.18 (m, 3 H); 7.28 (d, J ¼ 7.5, 1 H). 13C-NMR (100 MHz, CDCl3): 38.71; 53.11; 55.24;
113.17; 113.85; 120.44; 126.70; 127.10; 129.00; 129.65; 129.81; 134.11; 138.96; 140.64; 159.87.
N-(2-Bromo-5-chlorophenyl)-3-(3-chlorophenyl)-2-(3-methoxyphenyl)propanamide (¼ N-(2-Bro-
mo-5-chlorophenyl)-3-chloro-a-(3-methoxyphenyl)benzenepropanamide; 10). A mixture of 8 (1 equiv.,
2.0 g, 6.88 mmol) and SOCl2 (3 equiv., 2.45 g, 20.6 mmol) was refluxed for 2 h. The excess of SOCl2 was
removed under vacuum. To the crude acyl chloride 9, Et3N (1.5 equiv., 1.04 g, 10.3 mmol) in CH2Cl2
(20 ml) was added at 08 followed by 2-bromo-5-chloroaniline (1 equiv., 1.4 g, 6.88 mmol). The resulting
mixture was stirred for 18 h at r.t. before quenching by the addition of aq. NH4Cl soln. (10 ml).
Extraction with CH2Cl2 (3 ꢁ 40 ml), drying (MgSO4), and evaporation of the volatiles afforded 10
(2.93 g, 89%), which was used in the next step without purification. Colorless oil. IR (neat): 3287m,
3075w, 2933w, 2836w, 1723w, 1655s, 1600s, 1574s, 1519s, 1494s, 1402s, 1355m, 1304m, 1260s, 1233s, 1202s,
1187m, 1156m, 1089s, 1032s, 996m, 872m, 858s, 807s, 787s, 777s, 695s, 653s. 1H-NMR (400 MHz, CDCl3):
3.07 (dd, J ¼ 7.9, 13.8, 1 H); 3.61 (dd, J ¼ 7.9, 13.8, 1 H); 3.79 (m, 1 H); 3.81 (s, 3 H); 6.84 (m, 2 H); 6.92
(m, 1 H); 7.01 (m, 1 H); 7.14 (d, J ¼ 3.4, 3 H); 7.29 (m, 1 H); 7.34 (d, J ¼ 8.5, 1 H), 7.59 (br. s, 1 H); 8.42 (d,
J ¼ 1.7, 1 H). 13C-NMR (100 MHz, CDCl3): 38.30; 55.36; 56.25; 110.83; 113.58; 113.92; 118.63; 118.71;
120.61; 121.38; 125.12; 126.69; 127.28; 129.09; 129.68; 130.42; 132.71; 134.14; 134.25; 136.33; 139.37;
141.19; 160.24; 170.66.
N-[(Benzyloxy)methyl]-N-(2-bromo-5-chlorophenyl)-3-(3-chlorophenyl)-2-(3-methoxyphenyl)pro-
panamide (¼ N-(2-Bromo-5-chlorophenyl)-3-chloro-a-(3-methoxyphenyl)-N-[(phenylmethoxy)methyl]-
benzenepropanamine; 11). A suspension of NaH (1.5 equiv., 0.075 g, 3.13 mmol) in THF (10 ml) at 08 was
treated with 10 (1 equiv., 1.0 g, 2.087 mmol), and the mixture was stirred for 1 h at r.t. Cooling to 08 was
followed by slow addition of PhCH2OCH2Cl ((benzyloxy)methyl chloride; 1.5 equiv., 0.49 g, 3.13 mmol).
The mixture was allowed to warm to r.t. and stirred for 20 h. After the addition of aq. NH4Cl soln.
(30 ml), the mixture was extracted with AcOEt (3 ꢁ 40 ml), the extract dried (MgSO4) and
concentrated, and the residue purified by FC (pentane/AcOEt 7:1): 11 (0.937 g, 75%). Colorless oil.
IR (neat): 2938w, 1674s, 1596m, 1578m, 1464m, 1402m, 1257s, 1147w, 1116w, 1090s, 1049s, 875m, 812m,

Helvetica Chimica Acta – Vol. 95 (2012)
2293
777s, 731s, 693s. 1H-NMR (400 MHz, CDCl3) 2.83 (dd, J ¼ 3.9, 13.5, 1 H); 2.87 (dd, J ¼ 6.7, 13.6, 2 H); 3.34
(t, J ¼ 7.2, 2 H); 3.50 (m, 3 H); 3.58 (dd, J ¼ 3.8, 11.0, 1 H); 3.72 (s, 5 H); 3.78 (s, 3 H); 4.39 (d, J ¼ 6.4,
1 H); 4.50 (d, J ¼ 10.6, 2 H); 4.59 (d, J ¼ 4.7, 3 H); 5.64 (d, J ¼ 10.6, 2 H); 5.72 (d, J ¼ 10.7, 1 H); 6.42 (m,
6 H); 6.70 (m, 2 H); 6.80 (td, J ¼ 2.1, 7.3, 7.9, 3 H); 6.90 (m, 2 H); 7.15 (m, 12 H); 7.35 (m, 22 H); 7.50 (d,
J ¼ 8.6, 1 H); 7.60 (d, J ¼ 8.6, 2 H). 13C-NMR (100 MHz, CDCl3): 40.44; 41.45; 52.07; 53.53; 55.24; 69.93;
70.94; 71.22; 75.82; 76.45; 88.66; 91.62; 113.20; 113.41; 113.78; 120.24; 120.84; 121.85; 122.18; 126.47;
127.09; 127.63; 127.81; 127.95; 128.47; 128.52; 129.45; 129.47; 129.54; 129.81; 129.92; 130.21; 130.41; 132.60;
133.33; 133.52; 133.88; 133.96; 134.35; 134.53; 137.65; 137.67; 139.48; 139.93; 140.01; 140.20; 141.49;
159.68; 159.99; 172.55; 172.79.
N-(2-Bromo-5-chlorophenyl)-3-(3-chlorophenyl)-N-(methoxymethyl)-2-(3-methoxyphenyl)propan-
amide (¼ N-(2-Bromo-5-chlorophenyl)-3-chloro-N-(methoxmethyl)-a-(3-methoxyphenyl)benzenepro-
panamine; 12). As described for 11, with 10 (4.17 mmol) and MeOCH2Cl (methoxymethyl chloride;
1.5 equiv., 0.5 g, 6.26 mmol): 12 (1.87 g, 86%). Colorless oil. IR (neat): 2937w, 2833w, 1674s, 1596m,
1577m, 1465s, 1436m, 1400m, 1362m, 1257s, 1113s, 1079s, 1029s, 1003m, 913m, 875m, 814m, 776s, 727m,
693s, 523m. 1H-NMR (400 MHz, CDCl3, mixture of rotamers): 2.82 (m, 1.4 H); 3.22 (s, 1.4 H); 3.29 (t, J ¼
6.7, 1 H); 3.35 (s, 3 H); 3.45 (m, 2 H); 3.71 (s, 3 H); 3.77 (s, 1.4 H); 4.28 (d, J ¼ 10.5, 0.4 H); 4.34 (d, J ¼
10.4, 1 H); 5.52 (d, J ¼ 10.4, 1 H); 5.56 (d, J ¼ 10.5, 0.4 H); 6.30 (d, J ¼ 2.3, 0.4 H); 6.36 (s, 1 H); 6.41 (m,
2 H); 6.67 (d, J ¼ 7.6, 0.4 H); 6.73 (s, 0.4 H); 6.78 (d, J ¼ 8.1, 1.4 H); 6.91 (t, J ¼ 3.8, 1 H); 7.04 (s, 1.4 H);
7.19 (m, 6 H); 7.50 (d, J ¼ 8.6, 0.4 H); 7.58 (d, J ¼ 8.5, 1 H). 13C-NMR (100 MHz, CDCl3): 40.43; 41.44;
52.10; 53.49; 55.22; 56.85; 56.99; 77.64; 78.02; 113.05; 113.19; 113.36; 113.71; 120.16; 126.40; 127.76;
129.39; 129.40; 130.19; 133.27; 133.92; 139.51; 139.94; 139.96; 140.20; 141.40; 141.44; 159.61; 159.91;
172.57; 172.71. HR-EI-MS: 522.0223 ([M þ H]þ, C24H23BrCl2NO3þ ; calc. 522.0232).
(3S)-1-[(Benzyloxy)methyl]-6-chloro-3-(3-chlorobenzyl)-1,3-dihydro-3-(3-methoxyphenyl)-2H-in-
dol-2-one (¼(3S)-6-Chloro-3-[(3-chlorophenyl)methyl]-1,3-dihydro-3-(3-methoxyphenyl)-1-[(phenyl-
methoxy)methyl]-2H-indol-2-one; (S)-13). Under N2, a dried Schlenk tube was charged with [Pd(dba)2]
t
(5 mol-%, 5.7 mg, 0.01 mmol), (S,S)-[L4H]I (5 mol-%, 5.8 mg, 0.01 mmol), and BuONa (1.5 equiv.,
28.8 mg, 0.3 mmol). DME (1 ml) was added, and the mixture was stirred for 10 min at r.t. Then a soln. of
11 (1 equiv., 0.119 g, 0.2 mmol) in DME (3 ml) was added and the mixture stirred at r.t for 48 h. After
addition of sat. aq. NH4Cl soln. (10 ml), the mixture was extracted with AcOEt (3 ꢁ 10 ml), the
combined org. phase washed with H2O (20 ml) and brine (20 ml), dried (MgSO4), and concentrated, and
the crude product purified by FC (pentane/AcOEt 10 :1): (S)-13 (0.032 mg, 31%). Yellow oil. [a]D20
¼
ꢀ1.89 (c ¼ 1.0, CH2Cl2). HPLC (Chiralcel AD-H, hexane/iPrOH 95 :5, 1.0 ml/min, 254 nm): tR 17.80
(minor) and 39.38 (major); 86% ee. IR (neat): 2921w, 2852m, 1725s, 1606m, 1488m, 1458m, 1290m, 1259s,
1
1083s, 1021s, 800s, 744m, 696m. H-NMR (400 MHz, CDCl3): 3.49 (d, J ¼ 13.1, 1 H); 3.76 (d, J ¼ 13.0,
1 H); 3.85 (s, 3 H); 3.98 (d, J ¼ 11.6, 1 H); 4.18 (d, J ¼ 11.6, 1 H); 5.02 (d, J ¼ 11.2, 1 H); 5.12 (d, J ¼ 11.2,
1 H); 6.81 (d, J ¼ 6.8, 1 H); 6.90 (m, 2 H); 7.01 (m, 8 H); 7.28 (m, 11 H). 13C-NMR (100 MHz, CDCl3):
43.07; 55.33; 58.17; 69.81; 70.12; 110.83; 112.61; 113.62; 119.30; 123.01; 126.42; 127.28; 127.95; 128.13;
128.39; 128.72; 129.14; 129.85; 130.36; 133.73; 134.55; 136.92; 137.38; 140.63; 143.29; 159.85; 177.62. HR-
EI-MS: 540.1103 ([M þ Na]þ, C30H25Cl2NaNO3þ ; calc. 540.1127).
(3R)-6-Chloro-3-(3-chlorobenzyl)-1,3-dihydro-1-(methoxymethyl)-3-(3-methoxyphenyl)-2H-indol-
2-one (¼(3R)-6-Chloro-3-[(3-chlorophenyl)methyl]-1,3-dihydro-1-(methoxymethyl)-3-(3-methoxy-
phenyl)-2H-indol-2-one; 14). Under N2, a dried Schlenk tube was charged with [Pd(dba)2] (5 mol-%,
t
5.7 mg, 0.01 mmol), (R,R)-[L3H]I (5 mol-%, 7.02 mg, 0.01 mmol), and BuONa (1.5 equiv., 28.8 mg,
0.3 mmol). Toluene (1 ml) was added, and the mixture was stirred for 30 min at r.t. Then a soln. of 12
(1 equiv., 104.6 mg, 0.2 mmol) in toluene (3 ml) was added, and the mixture was stirred at 508 for 48 h.
After addition of sat. aq. NH4Cl soln. (10 ml), the mixture was extracted with AcOEt (3 ꢁ 10 ml), the
combined org. phase washed with H2O (10 ml) and brine (10 ml), dried (MgSO4), and concenrated, and
the crude product purified by FC (pentane/AcOEt 10 :1): (R)-14 (76.0 mg, 86%). Yellow oil. [a]rD:t:
¼
þ1.71 (c ¼ 1.0, CH2Cl2). HPLC (Chiracel AD-H, hexane/iPrOH 99 :1, 1.0 ml/min, 254 nm): tR 39.22
(major) and 65.18 (minor)); 90% ee. CD: Fig. 2. IR (neat): 2933w, 2834w, 1720s, 1604s, 1487s, 1432s,
1394w, 1340s, 1290m, 1240s, 1179m, 1129m, 1081s, 1049s, 971m, 915m, 875m, 781s, 746m, 686s, 658s.
1H-NMR (400 MHz, CDCl3): 2.95 (s, 3 H); 3.42 (d, J ¼ 13.0, 1 H); 3.71 (d, J ¼ 13.0, 1 H); 3.79 (s, 3 H);
4.88 (d, J ¼ 11.0, 1 H); 4.92 (d, J ¼ 11.0, 1 H); 6.72 (d, J ¼ 7.6, 1 H); 6.84 (dd, J ¼ 2.4, 8.2, 1 H); 6.98 (m,

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 2. CD Spectrum of 14 (c ¼ 0.0001m, in CH2Cl2)
5 H); 7.06 (dd, J ¼ 1.7, 7.9, 1 H); 7.13 (dd, J ¼ 1.8, 7.9, 1 H); 7.20 (d, J ¼ 8.0, 1 H); 7.27 (t, J ¼ 7.8, 1 H).
13C-NMR (100 MHz, CDCl3): 43.06; 55.31; 55.96; 58.18; 71.71; 110.68; 112.60; 113.59; 119.27; 122.92;
126.41; 127.15; 128.43; 128.65; 129.09; 129.82; 130.28; 133.71; 134.47; 137.40; 140.67; 143.21; 159.83;
177.70. HR-EI-MS: 464.0791 (Mþ, C24H21Cl2NaNO3þ ; calc. 464.0790).
(3R)-6-Chloro-3-(3-chlorobenzyl)-1,3-dihydro-3-(3-methoxyphenyl)-2H-indol-2-one (¼(3R)-6-
Chloro-3-[(3-chlorophenyl)methyl]-1,3-dihydro-3-(3-methoxyphenyl)-2H-indol-2-one; (R)-5). To a
soln. of 14 (1 equiv., 76 mg, 0.17 mmol) in MeCN (6 ml) at 08 were added trimethylsilyl chloride
(4.5 equiv., 83 mg, 0.76 mmol) and NaI (4.5 equiv., 114 mg, 0.76 mmol), and the resulting mixture was
stirred at 08 for 1 h. After addition of sat. NaHCO3 soln. (6 ml), the mixture was extracted with AcOEt
(2 ꢁ 15 ml) and the combined org. layer washed with brine (20 ml), dried (Na2SO4), and concentrated.
MeOH (40 ml) at r.t. was added to the residue, followed by Et3N (3 equiv., 52.0 mg, 0.51 mmol). This
mixture was stirred at 608 for 30 min. After cooling to r.t., the reaction was quenched with sat. aq. NH4Cl
soln. (20 ml), and hexane/AcOEt 1:1 (100 ml) was added. The aq. layer was extracted with hexane (2 ꢁ
30 ml), the combined org. phase, washed with brine (100 ml), dried (Na2SO4), and concentrated, and the
residue purified by FC (hexane/AcOEt 5 :1) (R)-5 (61.6 mg, 91%). Recrystallization from CH2Cl2/
hexane gave (R)-5 (53.0 mg, 79%). White solid. M.p. 164.5 – 166.58. [a]2D0 ¼ þ8.7 (c ¼ 1.0, CH2Cl2).
HPLC (Chiracel OD-H, hexane/iPrOH 7:3, 1.0 ml/min, 254 nm): tR 6.98 (minor) and 23.91 (major); 96%
ee. CD: Fig. 3. IR (neat): 3222m, 2930w, 2835w, 1711s, 1612s, 1596s, 1485s, 1454s, 1431s, 1322m, 1255s,
1221m, 1174m, 1069m, 1037m, 859m, 786s, 691s, 635m, 590m.1H-NMR (400 MHz, CDCl3): 3.53 (d, J ¼
12.8, 1 H); 3.64 (d, J ¼ 12.8, 1 H); 3.78 (s, 3 H); 6.74 (d, J ¼ 1.8, 1 H); 6.87 (m, 2 H); 7.05 (m, 6 H);
7.28 (m, 2 H). 13C-NMR (100 MHz, CDCl3): 41.71; 54.29; 58.46; 109.89; 112.28; 112.79; 118.78; 121.67;
126.43; 126.48; 128.27; 128.71; 129.34; 129.77; 130.76; 133.07; 133.61; 137.91; 141.06; 142.93; 159.97;
180.30. HR-EI-MS: 398.0709 (Mþ, C22H17Cl2NO2þ ; calc. 398.0706).
Fig. 3. CD Spectrum of (R)-5 (c ¼ 0.0001m, in CH2Cl2)
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Received August 15, 2012