Pd-Catalyzed One-Pot Borylation/Intramolecular Asymmetric Arylation on α-Ketiminoamides: Innovative Approach to Chiral 3-Amino-2-oxindoles

Article abstract of DOI:10.1055/s-0036-1590940

3-Amino-2-oxindole derivatives are a common framework found in many natural products and medicinal compounds and thus their synthesis is of significant importance. We report for the first time a one-pot approach for the synthesis of these compounds, using a bory-lation/intramolecular asymmetric arylation sequence starting from -ortho -bromo-α-ketimino amide derivatives. Pd(OAc) ₂ was used as the pre-catalyst along with (R)-BINAP as the chiral source. We successfully obtained a family of 3-phenyl-3-(aryl-amino)-indolin-2-one derivatives (11 in total) with excellent yields (up to 98%) and enantioselectivities of up to 76% ee. The reaction is versatile and tolerant of a wide range of functional groups.

Full text of DOI:10.1055/s-0036-1590940

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
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C. S. Marques et al.
Letter
Synlett
Pd-Catalyzed One-Pot Borylation/Intramolecular Asymmetric
Arylation on α-Ketiminoamides: Innovative Approach to Chiral
3-Amino-2-oxindoles
Carolina S. Marques*a
Simon E. Lawrenceb
Anthony J. Burke*a,c
0
0
0
0
0-
0
0
3
1-
6
9
7
7-
8
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1
R3
O
O
O
O
R2
0
0
0
0
0-
0
0
1
9-
4
3
0
7-
9
8
3
B
B
N
R1
R3
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N
O
0
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0
0
0-
0
0
1
8-
2
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8
1-
1
1
6
(S)
[Pd], (R)-BINAP
NH
a Centro de Química de Évora, University of Évora, Institute for
Research and Advanced Training, CLAV, Rua Romão Ramalho 59,
7000 Évora, Portugal
R1
KOAc, 1,4-dioxane
100 °C, 18 h
O
Br
R2
carolsmarq@uevora.pt
ajb@dquim.uevora.pt
3-phenyl-3-(aryl-amino)-indolin-2-one
derivatives
ortho-bromo-α-ketimino amide
derivatives
b School of Chemistry, Analytical and Biological Chemistry
Research Facility, Solid State Pharmaceutical Centre,
University College Cork, Cork, Ireland
11 new compounds
up to 98% yield
up to 76% ee
c Department of Chemistry, School of Science and Technology,
University of Évora, CLAV, Rua Romão Ramalho 59, 7000 Évora,
Portugal
Received: 30.08.2017
Accepted after revision: 04.10.2017
Published online: 03.11.2017
Very recently we reported an interesting Rh-catalyzed ad-
dition of arylboronic acids to isatin-derived N-Boc-protect-
ed ketimines to afford novel 3-amino-3-aryl-2-oxindoles in
very good yields. Notably, this was the first catalytic enanti-
oselective procedure with this substrate type.3 Although
some methods have been described in the literature,4,5 we
have investigated a novel one-pot borylation/intramolecu-
lar cyclization to give 3-amino-2-oxindoles. Although
transition-metal-catalyzed (Rh, Pd) arylation of protected
ketimines using arylboron reagents is a well-established
methodology for obtaining chiral amines, particularly tetra-
substituted quaternary centers;6 there has been very little
reported on the intramolecular version. Besides our own re-
port, the only other report is that of Ley and co-workers
who disclosed an intramolecular arylation on a ketimine to
afford oxindoles with an α-tertiary amine at the 3-posi-
tion.7 The methodology is interesting but limited to one
type of ketimine substrate and also to one chiral phosphane
ligand, namely (R)-DifluorPhos.
DOI: 10.1055/s-0036-1590940; Art ID: st-2017-d0656-l
Abstract 3-Amino-2-oxindole derivatives are a common framework
found in many natural products and medicinal compounds and thus
their synthesis is of significant importance. We report for the first time
a one-pot approach for the synthesis of these compounds, using a
borylation/intramolecular asymmetric arylation sequence starting from
ortho-bromo-α-ketimino amide derivatives. Pd(OAc)2 was used as the
pre-catalyst along with (R)-BINAP as the chiral source. We successfully
obtained a family of 3-phenyl-3-(aryl-amino)-indolin-2-one derivatives
(11 in total) with excellent yields (up to 98%) and enantioselectivities of
up to 76% ee. The reaction is versatile and tolerant of a wide range of
functional groups.
Key words oxindoles, intramolecular, bis(pinacolate)diboron, palladi-
um, arylation, α-ketimines
The oxindole framework, bearing a tetrasubstituted
quaternary carbon stereocenter in the 3-position, is a privi-
leged and common substructure found in numerous natu-
ral products and biologically active molecules.1 Our group
has particular interest in the synthesis of 3-amino-2-oxin-
doles due to their presence in promising drug candidates,
particularly for cancer and neurodegenerative diseases.2
With our interest in this field,8 we decided to use our
experience to develop a new efficient methodology to ac-
cess enantiomerically pure 3-amino-2-oxindole derivatives
2 (Scheme 1).
R3
R2
1. (COCl)2, DMF (cat), CH2Cl2
N
R3
N
N
NH2
R1
O
R1
Borylation
Cyclization
O
, NEt3, 0 °C to rt
Br
OH
R1
NH
R2
O
"one-pot"
O
Br
2. NaHCO3, 4 Å MS,
toluene, 100 °C
R2
H2N
1
2
3. NaH, THF, 0 °C to rt
X-R3, 50 °C
Scheme 1 Intramolecular borylation/arylation of ortho-bromo-α-ketimino amides 1 to give 3-amino-2-oxindoles 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
C. S. Marques et al.
Letter
Synlett
ortho-Bromo-α-ketimino amides 1 were synthesized
according to the literature,7,9 from cheap and easily accessi-
ble phenylglyoxylic acid (Scheme 1). Our first approach was
to borylate substrate 1a folllowing the well-established
conditions reported by Miyaura and co-workers,10a using
bis(pinacolate)diboron (B2Pin2) as the boron source, and
1,4-dioxane instead of dimethylsulfoxide (DMSO) as sol-
vent. Gratifyingly we obtained the corresponding cyclic ox-
indole product 2a in 86% yield (Scheme 2) and presume that
the boronic ester was formed in situ and then underwent
cyclization.
We also tested the borylation conditions reported by
Colobert and co-workers,10b using Pd(OAc)2 and DPEPhos li-
gand, pinacolborane (HBPin) and NEt3 as base, and the cy-
clic compound 2a was obtained in 64% yield, with only the
presence of vestigial amounts of the borylated intermedi-
ate. We decided to study in depth this interesting reaction,
where apparently the same Pd catalyst was able to catalyze
the borylation of the C–Br bond carbon and the cyclization
O
O
O
O
Me
B
B
N
O
Me
N
N
PdCl2dppf (3 mol%)
NH
O
KOAc (3 equiv), 1,4-dioxane
100 °C, overnight
Br
1a
2a, 86% yield
O
O
B
Me
N
N
O
Not detected
Scheme 2 One-pot borylation of 1a to 2a
onto the C=N unit.11 We then decided to optimize the reac-
tion conditions and study the reaction scope. The results
can be seen in Table 1.
Table 1 Chiral Ligand Screening in the One-Pot Borylation/Intramolecular Arylation Reaction of Substrate 1aa
Me
N
Me
N
N
O
Pd(OAc)2 (5 mol%)
Chiral Ligand (10 mol%)
+ B2Pin2
NH
2a
O
KOAc (3 equiv), 1,4-dioxane
100 °C, overnight
Br
(1.1 equiv)
1a
Entry
Chiral ligand
Conversion (%)b
ee (%)b,c
1
(R)-BINAP
>99
>99
72
68 (S)
37 (S)
29 (S)
18 (S)
15 (R)
16 (R)
<10
2
(R)-Tol-BINAP
(R)-SegPhos
3
4
(R,R)-ChiraPhos
(S)-iPr-MeOBIHEP
(S,S)-BDPP
83
5
99
6
98
7
(R)-PhanePhos
(R)-DifluorPhos
(S)-JosiPhos
65
8
>99
67
23 (S)
<5
9
10
11
12
13
14
15
16
JosPOPhos
14
23 (R)
21 (S)
<5 (S)
58 (R)
<10
(R,R,S,S)-DuanPhos
(R)-MonoPhos
(R)-Diox-MonoPhos
(R,R)(+)-Box
33
<10
93
14
(R)(+)-PyBox
(S,S)-diene
<10
<10
<10
<5
a Reaction conditions: Pd(OAc)2 (5 mol%), chiral ligand (10 mol%; see Supporting Information for structure details), and 1,4-dioxane (1 mL) were stirred for 30
min at room temperature. After that, 1a (0.25 mmol), B2Pin2 (0.28 mmol), and KOAc (0.76 mmol) were added sequentially to the reaction vessel. Additional 1,4-
dioxane (1 mL) was added, and the reaction mixture stirred at 100 °C for 18 h.
b Determined by chiral stationary phase HPLC (see Supporting Information for further details).
c The absolute configuration of 2a was determined using X-ray crystallography (see Supporting Information for further details).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
C. S. Marques et al.
Letter
Synlett
Several chiral phosphane ligands were screened (Table
1, entries 1–11) and, in general, excellent to moderate con-
versions were achieved. Almost full conversion into 2a was
obtained using BINAP ligands,12 (S)-iPr-MeOBIHEP, (S,S)-
BDPP, and (R)-DifluorPhos7 (Table 1, entries 1, 2, 5, 6, and 8,
respectively). Very low conversion was obtained with the
phosphane-oxide ligand JosPOPhos (Table 1, entry 11).
Phosphoramidite-type ligands13 were also screened (Table
1, entries 12 and 13), but despite (R)-MonoPhos giving very
poor results, the analogous phosphane ligand (R)-Diox-
MonoPhos gave much better results (Table 1, entry 13). We
also screened bisoxazoline ligands14 (Table 1, entries 14 and
15), but these were not very efficient. A chiral diene li-
gand15 containing a bicyclo[2,2,2]octa-2,5-diene core gave
the product in only trace quantities (Table 1, entry 16). Re-
garding the enantioselectivity, the best values were ob-
tained using (R)-BINAP ligand (68% ee, Table 1, entry 1) and
the phosphoramidite type (R)-Diox-MonoPhos (58% ee, Ta-
ble 1, entry 13). An X-ray crystal-structure determination
on compound 2a16 (see Supporting Information), showed
that it had the S absolute configuration, which is in agree-
ment with the results of Ley’s group7 for an analogous sys-
tem. We decided to run further reaction screenings using
Pd(OAc)2 and (R)-BINAP to optimize the conditions further.
Boron reagent, base, and solvent were screened in this new
one-pot borylation/intramolecular arylation reaction using
substrate 1a. The results are shown in Table 2.
Table 2 Boron Reagent, Base and Solvent Screening in the One-Pot Borylation/Intramolecular Arylation of 1aa
Me
N
Me
N
N
O
(S)
Pd(OAc)2 (5 mol%)
(R)-BINAP (10 mol%)
PPh2
PPh2
+ [Boron
Reagent]
NH
Base, Solvent
60 °C and 100 °C, 18 h
O
Br
1a
2a
(R)-BINAP
Entry
Boron reagent
Base
Solvent
Conversion (%)b
ee (%)b
1
HBPin
B2(cat)2
B2(npg)2
B2(OH)4
HBPin
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
B2Pin2
KOAc
KOAc
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
CH2Cl2
toluene
CH3CN
DME
54
77
97
63
99
90
<10
99
91
87
53
<1
86
12
45
<1
19
31
24
99
76
68
68
57
60
47
67
30
18
15
44
n.d.
36
26
75
n.d.g
38
10
44
21
2
3
KOAc
KOAc
KOAc
Cs2CO3
NEt3
4
5c
6
7
8
KOtBu
K2CO3
K3PO4
DIPEA
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
9
10
11
12d
13
14
15
16
17
18d,e
19d,f
20f
DCE
THF
MeOH
dioxane
toluene
a Reaction conditions: Pd(OAc)2 (5 mol%), (R)-BINAP (10 mol%), and solvent (1 mL) were stirred for 30 min at room temperature. After that, 1a (0.25 mmol),
Boron reagent (0.28 mmol), and base (0.76 mmol) were added sequentially to the reaction vessel. Additional solvent (1 mL) was added and the reaction mixture
stirred at 100 °C for 18 h.
b Determined by chiral stationary phase HPLC (see Supporting Information for further details).
c Reaction run with 0.53 mmol of HBPin.
d Reaction run at 60 °C.
e Pd(OAc)2 and (R)-BINAP were pre-stirred in CH2Cl2.
f Pd(OAc)2 and (R)-BINAP were pre-stirred in DME.
g n.d. = not determined.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
C. S. Marques et al.
Letter
Synlett
As HBPin had already been shown to be successful in this
reaction by Colobert and co-workers,10b we decided to test
this boron reagent with the chiral (R)-BINAP ligand (Table 2,
entries 1 and 5). Gratifyingly, we obtained a higher enantiose-
lectivity (76% ee, compared with 68% using B2Pin2, compare
Table 2, entry 1 with Table 1, entry 1), although the conver-
sion was lower. We decided to increase the quantity of HBPin
to 2.1 equivalents and almost full conversion of 2a was ob-
tained, despite a slight decrease in ee (Table 2, entry 5). Other
commercially available diboron reagents, such as arylboro-
nate esters and acids,17 were also evaluated (Table 2, entries
2–4). We speculated that the steric bulk of the
tetra(alkoxy)diboron reagent might play an important role in
the reaction, but no significant alterations in conversion and
enantioselectivity were noted when the less sterically hin-
dered bis(neopentyl glycolato)diboron (B2(npg)2) was used
(Table 2, entry 3). Less expensive tetrahydroxydiboron
(B2(OH)4) was also tested, but lower conversions were
achieved (Table 2, entry 4). The same happened with bis(cate-
cholato)diboron (B2(cat)2). There was no change in the
enantioselectivity but the conversion only reached a maxi-
mum of 77% (Table 2, entry 2). We decided to conduct a base-
screening study, maintaining the other reagents, i.e.,
(Pd(OAc)2 and (R)-BINAP) and B2Pin2 (Table 2, entries 6–11).
Generally, organic bases such as NEt3 and N,N-diisopropyl-
ethylamine (DIPEA) are not the best choice for this reaction,
since low conversions of 2a were obtained (Table 2, entries 7
and 11). High conversions were obtained with the inorganic
bases Cs2CO3, KOtBu, and K2CO3 (Table 2, entries 6, 8, and 9,
respectively). Unfortunately, there was no improvement in
the reaction enantioselectivity. Finally, we decided to evaluate
the effect of the solvent (Table 2, entries 12–20). None of the
desired product 2a was obtained using chlorinated solvents
such as CH2Cl2 and 1,2-dichloroethane (DCE, Table 2, entries
12 and 16). We conducted the same reaction with CH2Cl2 in a
sealed tube at 100 °C and again no product 2a was obtained.
For good conversions, apolar aprotic solvents were the best.
For example, toluene afforded the product with a conversion
of 86% (Table 2, entry 13), albeit with low enantioselectivity.
However, upon using 1,2-dimethoxyethane (DME) as solvent,
an enantioselectivity of 75% ee was obtained, despite a low
conversion (Table 2, entry 15). So, we decided to use DME in
the pre-complexation step between the Pd(OAc)2 and (R)-
BINAP and then run the reaction in dioxane and toluene, after
evaporation of the DME (Table 2, entries 19 and 20, respec-
tively). No significant variations were observed in the conver-
sions and enantioselectivities. At this point we established
the following conditions to be the optimized conditions for
this reaction: Pd(OAc)2 and (R)-BINAP as ligand, B2Pin2 as the
boron source, KOAc as base, and dioxane as the solvent (see
Table 1, entry 1).18 The next step was to study the reaction
scope and this study is shown in Scheme 3.
R3
N
R2
R3
N
N
Pd(OAc)2 (5 mol%)
(R)-BINAP (10 mol%)
R1
O
(S)
PPh2
PPh2
+ B2Pin2
R1
KOAc, 1,4-dioxane
100 °C, 18 h
NH
O
Br
R2
1
2
(R)-BINAP
Br
Me
Br
Me
Me
Me
N
N
N
F3C
N
O
O
(S)
O
(S)
(S)
O
(S)
F
Br
Br
N
N
H
Cl
NH
NH
NH
O
O
(S)
HN
Br
+
(S)
0% isolated yield
N Me
2b
NH
43% isolated yield
10% ee
2c
2d + 2e
63% isolated
yield (mixture)
98% isolated yield
22% ee
Br
2f
Me
30% ee and 13% ee
87% isolated yield
31% ee
Me
N
Me
N
Me
N
O
Me
(S)
O
Me
(S)
Me
N
N
O
(S)
O
NH
(S)
O
NH
(S)
NC
Me
NH
HO
NH
NH
2i
MeO
91% isolated yield
43% ee
2h
2g
2j
80% isolated yield
31% ee
75% isolated yield
34% ee
2k
59% isolated yield
29% ee
83% isolated yield
<10% ee
Scheme 3 One-pot borylation/intramolecular asymmetric arylation reaction on ortho-bromo-α-ketimino amide substrates 1–k affording 3-amino-
2-oxindoles 2–k
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
C. S. Marques et al.
Letter
Synlett
In general, moderate to very good yields were obtained
using substrates containing both electron-rich and elec-
tron-deficient substituents. The best yield was obtained
with 1c – containing a CF3 electron-withdrawing group – to
give 2c, in a yield of 98% (Scheme 3). The yield decreased
slightly, when halogen substituents were present as the R1
substituent in the substrate (see, for example, compounds
2b,d,e). When several halogen substituents (C, F, Br) were
present in the same ring no reaction occurred. We believe
that in the borylation step, there is competition between
these sites and the ortho-Br site for the boron unit.19 When
we conducted the reaction with 1e it gave a mixture of 2d
and 2e, which would be expected (Scheme 3). Unfortunate-
ly, it was impossible to separate the two isomers by silica
gel chromatography. Low enantioselectivities were ob-
served for compounds 2b,d,e,i,j,k, the best being 43% ee (2i,
Scheme 3). Unfortunately, the only R2 substituents that we
could introduce into the imine phenyl unit were the elec-
tron-donating 4-OMe and 4-OH groups (as in 1g and 1h).
However, gratifyingly both 2g and 2h were obtained in very
good yields, despite giving low enantioselectivities (Scheme
3). In the case of functionalization of the amide (substituent
R3) we could only manage to introduce a benzyl group as is
the case for 1f (Scheme 3). The product 2c was obtained in
high yield and low enantioselectivity (87% and 31% ee, re-
spectively). Since the absolute configuration of 2a was de-
termined, all of our products 2b–k are expected to have the
same S configuration.
References and Notes
(1) (a) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381.
(b) Rudrangi, S. R. S.; Bontha, V. K.; Manda, V. R.; Bethi, S. Asian J.
Res. Chem. 2011, 4, 335. (c) Trost, M.; Brennan, M. K. Synthesis
2009, 3003.
(2) For several examples, see: (a) Gal, C. S.-L.; Wagnon, J.; Simiand,
J.; Griebel, G.; Lacour, C.; Guillon, G.; Barberis, C.; Brossard, G.;
Soubrié, P.; Nisato, D.; Pascal, M.; Pruss, R.; Scatton, B.;
Maffrand, J.-P.; Le Fur, G. J. Pharmacol. Exp. Ther. 2002, 300,
1122. (b) Ochi, M.; Kawasaki, K.; Kataoka, H.; Uchio, Y.; Nishi, H.
Biochem. Biophys. Res. Commun. 2001, 283, 1118. (c) Ali, M. A.;
Ismail, R.; Choon, T. S.; Yoon, Y. K.; Wei, A. C.; Pandian, S.;
Kumar, R. S.; Osman, H.; Manogaran, E. Bioorg. Med. Chem. Lett.
2010, 20, 7064. (d) Rottmann, M.; McNamara, C.; Yeung, B. K. S.;
Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia,
N. V.; Tan, J.; Cohen, S. B.; Spencer, R.; González-Páez, G. A.;
Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.;
Schmitt, E. K.; Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois,
V.; Keller, T. H.; Fidock, D. A.; Winzeler, E. A.; Diagana, T. T.
Science 2010, 329, 1175.
(3) Marques, C. S.; Burke, A. J. Eur. J. Org. Chem. 2016, 806.
(4) For some examples, see: (a) Kaur, J.; Chimni, S. S.; Mahajan, S.;
Kumar, A. RSC Adv. 2015, 5, 52481. (b) Lesma, G.; Landoni, N.;
Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74, 4537.
(c) Shen, K.; Liu, X.; Lin, L.; Feng, X. Chem. Sci. 2012, 3, 327.
(5) (a) Kumagai, N.; Shibasaki, M. Bull. Chem. Soc. Jpn. 2015, 88, 503.
(b) Burke, A. J. Tetrahedron Lett. 2016, 57, 1197.
(6) Catalytic Arylation Methods: From the Academic Lab to Industrial
Processes; Burke, A. J.; Marques, C. S., Eds.; Wiley-VCH: Wein-
heim, 2015.
(7) Tolstoy, P.; Lee, S. X. Y.; Sparr, C.; Ley, S. V. Org. Lett. 2012, 14,
4810.
In conclusion, we have developed a catalytic approach to
the synthesis of chiral 3-amino-2-oxindoles in high yields
and good enantioselectivities using a hitherto unknown
one-pot borylation/intramolecular asymmetric arylation
sequence.
(8) (a) Marques, C. S.; Peixoto, D.; Burke, A. J. RSC Adv. 2015, 5,
20108. (b) Peixoto, D.; Viana, H.; Goth, A.; Marques, C. S.; Burke,
A. J. WO 2015033261, 2015. (c) Marques, C. S.; Burke, A. J. Chem-
CatChem 2011, 3, 635. (d) Marques, C. S.; Burke, A. J. Tetrahedron
2013, 69, 10091. (e) Marques, C. S.; Locati, A.; Ramalho, J. P. P.;
Burke, A. J. Tetrahedron 2015, 71, 3314. (f) Marques, C. S.; Burke,
A. J. Tetrahedron: Asymmetry 2013, 24, 628. (g) Marques, C. S.;
Dindaroglu, M.; Schmalz, H.-G.; Burke, A. J. RSC Adv. 2014, 4,
6035. (h) Marques, C. S.; Burke, A. J. Eur. J. Org. Chem. 2012,
4232. (i) Marques, C. S.; Burke, A. J. Eur. J. Org. Chem. 2010, 1639.
(j) Marques, C. S.; Burke, A. J. Tetrahedron 2012, 68, 7211.
(k) Marques, C. S.; Burke, A. J. ChemCatChem 2016, 8, 3518.
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(10) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
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Colobert, F. Org. Lett. 2004, 6, 4419.
(11) For examples of arylation reactions in ketimines with boronic
acids, see: (a) Jiang, C.; Lu, Y.; Hayashi, T. Angew. Chem. Int. Ed.
2014, 53, 9936. (b) Yang, G.; Zhang, W. Angew. Chem. Int. Ed.
2013, 52, 7540.
Funding Information
We are grateful for the award of a post-doctoral grant to C.S.M.
(FRH/BPD/92394/2013) from the Fundação para a Ciência e a Tecnolo-
gia (FCT). The authors gratefully acknowledge Fundo Europeu de
Desenvolvimento Regional (FEDER)-INALENTEJO for funding the pro-
gram INMOLFARM – Molecular Innovation and Drug Discovery
(ALENT-07-0224-FEDER-001743) and for financing the acquisition of
the NMR equipment, project LADECA (ALENT-07-0262-FEDER-
001878). S.E.L. thanks University College Cork 2013 Research Fund
and Science Foundation Ireland under grant no. 05/PICA/B802/EC07.
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Supporting Information
(12) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(b) Akutagawa, S. Appl. Catal., A 1995, 128, 171.
(13) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Teichert, J. F.;
Feringa, B. L. Angew. Chem. Int. Ed. 2010, 49, 2486.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590940.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(14) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106,
3561.
(15) (a) Glorius, F. Angew. Chem. Int. Ed. 2004, 43, 3364. (b) Shintani,
R.; Hayashi, T. Aldrichimica Acta 2009, 42, 31.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
C. S. Marques et al.
Letter
Synlett
(16) CCDC 1571646 contains the supplementary crystallographic
vessel. The reaction was left stirring at 100 °C during 18 h. After
cooling to room temperature, the crude mixture was purified by
silica gel chromatography using hexane/AcOEt (5:1) as eluent to
afford the desired 3-phenyl-3-(aryl-amino)-indolin-2-one
derivatives 2.
data for 2a. The data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
(17) For selected examples, see: (a) Fang, H.; Kaur, G.; Yan, J.; Wang,
B. Tetrahedron Lett. 2005, 46, 1671. (b) Chow, W. K.; Yuen, O. Y.;
Choy, P. Y.; So, C. M.; Lau, C. P.; Wong, W. T.; Kwong, F. Y. RSC
Adv. 2013, 3, 12518. (c) Takaya, J.; Iwasawa, N. ACS Catal. 2012,
2, 1993. (d) Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J. Am.
Chem. Soc. 2010, 132, 17701.
Compound 2a: Pale yellow solid; mp 86.2–87.8 °C. 1H NMR (400
MHz, CDCl3) δ = 3.26 (s, CH3, 3 H), 6.34–6.36 (d, Ar, 2 H, J = 8 Hz),
6.67–6.71 (t, Ar, 1 H, J = 8 Hz), 6.92–6.94 (d, Ar, 1 H, J = 8 Hz),
6.98–7.02 (t, Ar, 2 H, J = 8 Hz), 7.08–7.12 (t, Ar, 1 H, J = 8 Hz),
7.33–7.42 (m, Ar, 5 H), 7.55–7.57 (d, Ar, 2 H, J = 8 Hz). 13C NMR
(100 MHz, CDCl3) δ = 26.80, 68.08, 108.90, 115.54, 119.40,
123.32, 125.42, 126.73, 128.73, 129.07, 129.12, 129.51, 130.37,
140.19, 143.28, 145.09, 177.05. FTIR: 1499, 1722, 3055, 3373
cm–1. ESI-HRMS: m/z calcd for C21H18N2O: 314.14191; found for
(18) General Procedure for the Asymmetric Synthesis of Chiral 3-
Amino-2-oxindoles
In a Radley’s® 12 position carousel reactor under a nitrogen
atmosphere was added Pd(OAc)2 (0.0125 mmol, 5 mol%), chiral
ligand (0.025 mmol, 10 mol%), and 1,4-dioxane (1 mL). The
mixture was stirred for 30 min at room temperature, then the
C
21H18N2ONa: 337.13113 [M+ + Na]. HPLC: Daicel Chiralpak IA
column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 220 nm; tR
32.447 min (R, minor), 38.080 min (S, major).
=
corresponding ortho-bromo-α-ketimino amide substrate
1
(0.25 mmol), B2Pin2 (0.28 mmol, 1.1 equiv), KOAc (0.76 mmol),
and 1,4-dioxane (1 mL) were added sequentially to the reaction
(19) Lam, K. C.; Marder, T. B.; Lin, Z. Organometallics 2010, 29, 1849.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F