Modular Catalytic Synthesis of 3-Amino-3-aryl-2-oxindoles: Rh Catalysis with Isatin-Derived N-Boc-Protected Ketimines

Article abstract of DOI:10.1002/ejoc.201501399

Chiral 3-amino-3-aryloxindoles are important biologically active compounds. Using a catalytic modular approach, 31 new 3-amino-3-aryl-2-oxindoles were prepared by a simple Rh-catalysed addition of arylboronic acids to isatin-derived N-Boc-protected ketimines (Boc = tert-butoxycarbonyl). A low catalyst loading of 3 mol-% was used, and the reaction showed a wide scope with high functional-group compatibility, and gave good yields. We report the first catalytic enantioselective reactions with this substrate. Deprotection of the Boc group was easily accomplished in good yields.

Full text of DOI:10.1002/ejoc.201501399

DOI: 10.1002/ejoc.201501399
Full Paper
Modular Oxindole Synthesis
Modular Catalytic Synthesis of 3-Amino-3-aryl-2-oxindoles: Rh
Catalysis with Isatin-Derived N-Boc-Protected Ketimines
[a]
[a,b]
Carolina S. Marques* and Anthony J. Burke*
Abstract: Chiral 3-amino-3-aryloxindoles are important bio- low catalyst loading of 3 mol-% was used, and the reaction
logically active compounds. Using a catalytic modular ap- showed a wide scope with high functional-group compatibility,
proach, 31 new 3-amino-3-aryl-2-oxindoles were prepared by a and gave good yields. We report the first catalytic enantio-
simple Rh-catalysed addition of arylboronic acids to isatin-de- selective reactions with this substrate. Deprotection of the Boc
rived N-Boc-protected ketimines (Boc = tert-butoxycarbonyl). A group was easily accomplished in good yields.
Introduction
Some examples include: SSR-149415 (Figure 1), an orally ac-
The oxindole skeleton is a privileged framework that is found
[
3]
tive nonpeptide vasopressin-receptor antagonist; AG-041R, a
gastrin/CCK-B-receptor antagonist also effective in the repair of
in a variety of natural products and biologically active com-
[
1a]
pounds.
tant,
3,3-Disubstituted derivatives are particularly impor-
and 3-substituted-3-amino-2-oxindole frameworks (Fig-
[
4]
[
1b]
cartilage defects;
3.2′′]-5,6-dimethoxy-1′′-indanone-4-aryl-substituted
idine, which was identified as an acetylcholinesterase (AChE)
an N-methyl-spiro[2.3′]oxindolespiro-
[
pyrrol-
ure 1) bearing a tetrasubstituted stereogenic centre at the 3-
position are of considerable interest as promising drug candi-
[
5]
[
2]
inhibitor; and NITD609 (Figure 1), an antimalarial drug candi-
dates.
[
6]
date. Thus the development of efficient methods to access
these scaffolds is important. Several methods have been re-
Figure 1. Some representative examples of biologically active 3-substituted
-amino-2-oxindole derivatives.
3
[
[
a] Centro de Química de Évora, University of Évora, Institute for Research
and Advanced Training, CLAV,
Rua Romão Ramalho 59, 7000 Évora, Portugal
b] Department of Chemistry, School of Science and Technology, University of
Évora, CLAV,
Rua Romão Ramalho 59, 7000 Évora, Portugal
E-mail: ajb@dquim.uevora.pt
carolsmarq@uevora.pt
http://www.burkegroup.uevora.pt/
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
ejoc.201501399.
Figure 2. Some routes to 3-substituted 3-amino-2-oxindoles.
806 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2016, 806–812

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ported to date.[2] One very convenient approach is through a enormous scope by the synthesis of 31 new 3-substituted 3-
transition-metal-catalysed cyclization onto activated imine amino-2-oxindole derivatives.
[
7a]
groups. For example, Tolstoy et al.
based on (R)-DiFluorPhos with α-ketimino amide substrates
Figure 2a), but this approach has the disadvantage that the
used a chiral Pd catalyst
Results and Discussion
As a model reaction,[11] we attempted the addition of phenyl-
boronic acid to ketimine 1a using several commercially sourced
Rh catalysts (Scheme 1).
(
synthesis of the imine substrate is difficult. In fact, as part of
our research into the development of small-molecule AChE and
butyrylcholinesterase (BuChE) inhibitors, using our experience
[
8]
in the area of catalytic arylations, we have developed a
cyclization method using in situ generated arylboronic ester
[
7b,7c]
N-tert-butanesulfinyl aldimines,
and these results will be
reported in due course.
The other common approach to these targets is through a
[
9]
catalytic nucleophilic addition to isatin-ketimines. This ap-
proach is also straightforward and powerful, considering the
cheapness and availability of isatin (Figure 2b and c). The down-
side is that until now, toxic and environmentally unfriendly met-
als like Ti and Zn have been used in stoichiometric quantities.
With this in mind, and prompted by a report from Ellman's
[
10b]
group
on the reaction of N-trityl-protected imine substrates
Scheme 1. Rh-catalysed addition of phenylboronic acid to ketimine 1a.
with arylboroxines (Figure 2, b), we conducted a study using N-
Boc protected isatin-ketimines (Figure 2, c). The improvements
Of all the catalysts tested, only Rh(COD) BF (COD = 1,5-cy-
2
4
that our route gives over Ellman's lie in the fact that an expen- clooctadiene), [Rh(COD)Cl] , and [Rh(COD)OH] gave the desired
2
2
sive tert-butylsufinylamide group is not required, and neither is 3-amino-3-phenyl-2-oxindole (i.e., 2a) in moderate to good
an arylboroxine required (these compounds have limited com- yield (Scheme 1). The reaction failed when [Rh(nbd)Cl] (nbd =
2
mercial availability). Thus our approach is more economically norbornadiene), [Rh(C H ) Cl] , Rh(acac)(C H ) (acac = acetyl-
2
4 2
2
2 4 2
appealing. We also have demonstrated that the reaction has an acetone), [Rh(Cp*)Cl ] , or Rh (OAc) was used, which demon-
2
2
2
4
Scheme 2. Reaction of 1a with arylboronic acids. Reaction conditions: ketimine 1a (0.4 mmol), ArB(OH)
0.8 mmol), toluene (2 mL), 60 °C, 24 h.
2 2 4 3
(0.8 mmol), Rh(COD) BF (0.012 mmol, 3 mol-%), NEt
(
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strates the importance of the 1,5-cyclooctadiene (COD) ligand.
Table 1. Substrate scope in the Rh-catalysed arylation of isatin-derived ket-
imines 1b and 1c using arylboronic acids.
Ru(p-cymene)Cl2]2[ and Pd(OAc) /bpy (2,2′-bipyridine) cat-
8h]
[8i]
[
2
alysts were also tested in this arylation reaction, but only the
Pd(OAc) /bpy system gave 2a in 18 % yield. We then evaluated
2
the scope of the reaction using a range of boronic acid deriva-
tives bearing electron-donating and -withdrawing substituents
with Rh(COD) BF as catalyst. The results are shown in
2
4
Scheme 2.
In general, moderate to good results were obtained, and
good functional group tolerance was observed for the boronic
acids. Both electron-deficient and -rich boronic acids were used
successfully, which is consistent with previous reports on analo-
Entry[a]
Yield[b] [%]
Ketimine
Ar
Product 3 or 4
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1b
1b
1b
C
6
H
5
74
36
80
71
44
78
84
54
49
3a
3b
3c
3d
3e
3f
3g
3h
3i
6 4
3-AcC H
4-MeC6H4
1-naphthyl
6 4
2-MeC H
4-MeOC
3-MeOC
2-naphthyl
4-BrC
[
10b,12]
gous systems.
The best yield was achieved using 1-
naphthylboronic acid (Scheme 2, compound 2f, 81 % yield).
Apparently the reaction yield improved when an electron-do-
nating group was present (compounds 2e, 2f, 2k, Scheme 2),
with the exception of compound 2c (71 % yield, Scheme 2),
which contained a Cl atom. Steric effects were also noted, as
the yield for the formation of 2e was higher than that for 2g
6
H
H
4
6
4
6 4
H
1
0
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
C
6
H
5
84
63
21
76
72
25
54
48
69
44
71
4a
4b
4c
4d
4e
4f
4g
4h
4i
[
13]
(
Scheme 2). The aliphatic boronic acids
methylboronic acid,
11
3-AcC
4-ClC
4-FC
4-MeC
1-naphthyl
2-MeC
4-MeOC
3-MeOC
2-naphthyl
4-BrC
6 4
H
1
1
1
1
2
3
4
5
6 4
H
1-dodecylboronic acid, and ethylboronic acid were also tested
6 4
H
in this catalytic transformation, but failed to give any product.
6 4
H
Due to the availability of the isatin derivatives 5-methylisatin
and 5-bromoisatin, we decided to extend the scope of the reac-
tion. We synthesized the corresponding ketimine derivatives
16
6
H
4
17
18
19
20
6
H
H
4
6
4
(
i.e., 1b and 1c, see Figure 2, c) and tested these compounds
4j
4k
under the optimized conditions described above using the
same range of boronic acid derivatives. The results are shown
in Table 1.
6
H
4
[
a] Reaction conditions: ketimine 1 (0.4 mmol), ArB(OH)
Rh(COD) BF (0.012 mmol), NEt (0.8 mmol), toluene (2 mL), 60 °C, 24 h.
[b] Isolated yield.
2
(0.8 mmol),
2
4
3
Using a commercially available Rh catalyst, 20 new com-
pounds were synthesized (Table 1). When ketimine 1b was
used, owing to the electron-donating group (Me) in the 5-posi-
tion of the phenyl ring, no product was obtained with 4-chloro-
or 4-fluorophenylboronic acid. However, surprisingly, with 4-
bromophenylboronic acid, 3i was obtained in 49 % yield
Table 2. Rh-catalysed asymmetric arylation of ketimine 1a with phenylboronic
acid.
(
Table 1, entry 9). Very good yields were obtained when aryl-
boronic acid derivatives bearing electron-donating groups were
used (see, for instance, Table 1, entries 3, 4, 6, and 7). Once
again, due to steric effects, compound 3c was obtained in a
higher yield (80 %) than compound 3e (44 %; Table 1, compare
entries 3 and 5). The best yield using ketimine 1b was obtained
for compound 3g (Table 1, entry 7).
Entry[a]
[Rh]
Chiral ligand
Yield[b] [%] ee[c] [%]
(S,S)-Diene 5[d]
(R)-MonoPhos
(S,S)-Diene 5[
(R)-BINAP
1
2
3
4
5
6
7
[RhCl(C
[Rh(COD)OH]2
[Rh(COD)OH]
[Rh(COD)OH]
[Rh(COD)OH]
2
H
4
)
2
]
2
30
70
82
80
68
0
39
<5
rac
rac
<5
–
d]
2
2
2
When ketimine 1c [with an electron-withdrawing substituent
(
Br) in the 5-position of the isatin phenyl ring] was used to-
(R,R)-ChiraPhos
(R)-MOP
gether with the various arylboronic acid reagents, no significant
difference was observed in the yields of the products compared
to when 1b or 1a was used. The best yield was obtained for
compound 4a, with no substituents on the aryl ring (Table 1,
entry 10). Steric effects were again observed, since boron rea-
gents bearing para substituents in the aryl ring gave better
yields than their ortho-substituted analogues (Table 1, compare
entries 14 and 16).
Rh(acac)(C
Rh(COD) BF
2 4 2
H )
(S,S)-Diene 5[
d]
45
13
2
4
[
2
a] Reaction conditions: ketimine 1a (0.4 mmol), PhB(OH) (0.8 mmol), [Rh]
(0.012 mmol), chiral ligand (0.013 mmol), NEt3 (0.8 mmol), toluene (2 mL),
room temp., 24 h. [b] Isolated yield. [c] Determined by chiral stationary phase
HPLC (see Supporting Information for further details). [d] See structure in
Supporting Information; (R)-BINAP = (R)-2,2′-bis(diphenylphosphino)-1,1′-bi-
naphthyl; (R,R)-ChiraPhos = (2R,3R)-2,3-bis(diphenylphosphino)butane; (R)-
MOP = (R)-2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl.
Encouraged by these results, we decided to evaluate the
asymmetric version of this reaction. The preliminary results can
be seen in Table 2.
tested chiral diene ligand 5[11] (see Table 2, entry 1 and Sup-
porting Information for structure information), and despite the
Several commercially available chiral ligands were tested us- fact the yield was only moderate, an encouraging enantiose-
ing different Rh precatalysts. In the first catalytic reaction, we lectivity of 39 % ee was obtained. Such ligands have already
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proved their applicability in other imine arylations.[11] When we General Procedure for the Synthesis of Isatin-Derived N-Boc
[
18]
Ketimines 1a–c:
6
Butyllithium (2.5 M solution in hexane; 2.5 mL,
screened [Rh(COD)OH] (which gave good results in the non-
2
.2 mmol) was added to a stirred solution of tert-butyl (trimethyl-
asymmetric reaction, see Scheme 1) with a series of phosphane
[
14]
silyl)carbamate (see Supporting Information; 1.17 g, 6.2 mmol) in
THF (10 mL) at –78 °C. The mixture was stirred for 1 h, then N-
protected isatin (see Supporting Information; 6.2 mmol) in THF
10 mL) was added dropwise. The reaction mixture was stirred for
a further 5 h, and then chlorotrimethylsilane (0.59 mL, 6.8 mmol)
was added to the reaction mixture. The reaction mixture was then
ligands [(R)-BINAP, (R,R)-ChiraPhos, and (R)-MonoPhos ], good
yields were obtained, but the enantioselectivities were very
poor. The combination of [Rh(COD)OH] with diene ligand 5
2
(
was also unsuccessful in terms of the enantioselectivity
(
Table 2, entry 3). Following on from the work of the Hayashi
[
15]
group,
we tested the (R)-MOP ligand in combination with gradually warmed to room temperature over 2 h. The mixture was
Rh(acac)(C H ) as a precatalyst, but unfortunately there was no poured into saturated aqueous NaHCO , and extracted with ethyl
2
4 2
3
reactivity whatsoever (Table 2, entry 6). Rh(COD) BF was also acetate. The combined organic layers were dried with anhydrous
2
4
MgSO , and concentrated under reduced pressure. The crude mix-
ture was purified by column chromatography on silica gel using
tested together with chiral diene ligand 5 (Table 2, entry 7).
Although the yield was better than that obtained with
4
hexane/Et O (1:1) as eluent to give the product.
2
[
RhCl(C H ) ] , the enantioselectivity was lower (13 % ee).
2 4 2 2
[
16]
The Boc group of 2a was successfully deprotected to give tert-Butyl (Z)-1-Methyl-2-oxoindolin-3-ylidenecarbamate (1a):
[
18a]
1
Yellow solid (0.82 g, 52 %).
m.p. 98.4–99.7 °C. H NMR (CDCl ,
3
the free amine (i.e., 6) in 42 % yield (Scheme 3).
4
8
7
2
1
00 MHz): δ = 1.62 (s, 9 H, CH ), 3.21 (s, 3 H, CH ), 6.82–6.84 (d, J =
3 3
Hz, 1 H, Ar), 7.07–7.11 (t, J = 8 Hz, 1 H, Ar), 7.47–7.50 (t, 1 H, Ar),
.63–7.64 (m, 1 H, Ar) ppm. 13C NMR (CDCl , 100 MHz): δ = 26.2,
3
8.1, 83.6, 109.3, 119.5, 123.3, 123.6, 124.4, 129.9, 135.4, 148.2,
60.5 ppm.
tert-Butyl
1b): Pale orange solid (1.43 g, 82 %).
NMR (CDCl , 400 MHz): δ = 1.62 (s, 9 H, CH ), 2.30 (s, 3 H, CH ), 3.17
(Z)-1,5-Dimethyl-2-oxoindolin-3-ylidenecarbamate
[
18a]
1
(
m.p. 123.5–125.0 °C. H
Scheme 3. Deprotection of 2a to give 6; TFA = trifluoroacetic acid.
3
3
3
(
s, 3 H, CH ), 6.70–6.72 (d, J = 8 Hz, 1 H, Ar), 7.26–7.28 (d, J = 8 Hz,
3
13
1
2
1
H, Ar), 7.42 (br. s, 1 H, Ar) ppm. C NMR (CDCl , 100 MHz): δ =
3
0.9, 28.0, 29.7, 83.3, 109.1, 119.3, 124.7, 130.8, 133.2, 135.8, 145.9,
53.4, 160.6 ppm.
Conclusions
We have developed an efficient Rh-catalysed arylation of isatin- tert-Butyl (Z)-5-Bromo-1-methyl-2-oxoindolin-3-ylidenecarbam-
[
18b,18c]
1
ate (1c): Orange solid (1.31 g, 61 %).
m.p. 155.0–155.9 °C. H
derived N-Boc ketimines to give important 3-aryl-3-amino-2-ox-
indoles using commercially available arylboronic acid deriva-
tives. We also have reported the first asymmetric catalytic aryl-
ation – requiring no chiral auxiliary – of isatin-containing ket-
imines to give 3-amino-3-aryl-2-oxindoles. We are currently test-
ing these compounds for AChE and BuChE inhibition.
NMR (CDCl , 400 MHz): δ = 1.60 (s, 9 H, CH ), 3.17 (s, 3 H, CH ),
3
3
3
6
.72–6.74 (d, J = 8 Hz, 1 H, Ar), 7.56–7.58 (d, J = 8 Hz, 1 H, Ar), 7.68
(
br. s, 1 H, Ar) ppm. 13C NMR (CDCl , 100 MHz): δ = 26.3, 28.0, 83.8,
3
1
10.9, 116.2, 120.9, 127.0, 137.7, 146.8, 152.1, 156.7, 159.9 ppm.
General Procedure for the Rh-Catalysed Addition of Arylboronic
Acids to Ketimines: In a Radley's® 12-position carousel reactor
under a nitrogen atmosphere, Rh(COD) BF4 (4.7 mg, 0.012 mmol,
2
3
mol-%), ketimine 1a–1c (100 mg, 0.4 mmol), ArB(OH) (0.8 mmol),
3
Experimental Section
2
NEt (0.11 mL, 0.8 mmol), and toluene (2 mL) were mixed. The reac-
General Remarks: Reagents were obtained from Sigma–Aldrich
and Acros, and were used as received. The solvents used were dried
using current laboratory techniques.[17] Reactions with transition
metals (Rh) were conducted in a Radley's® 12-position carousel reac-
tor under a nitrogen atmosphere, and nonaqueous reactions and
manipulations were carried out using standard Schlenk techniques.
Column chromatography was carried out on silica gel (SDS, 70–
tion mixture was stirred at 60 °C for 24 h. After that, the solvent
was evaporated under reduced pressure. The crude product was
purified by column chromatography on silica gel using hexane/Et O
2
(1:1) as eluent to give the desired compounds.
tert-Butyl 1-Methyl-2-oxo-3-phenylindolin-3-ylcarbamate (2a):
White solid (0.114 g, 73 %). m.p. 120.9–122.1 °C. 1H NMR (CDCl3,
4
00 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.19 (s, 3 H, CH ), 5.49 (br. s, 1
3 3
2
00 mm). Thin-layer chromatography (TLC) was carried out on alu-
H, NH), 6.86–6.88 (d, J = 8 Hz, 1 H, Ar), 7.12–7.16 (t, J = 8 Hz, 1 H,
minium-backed Kieselgel 60 F254 plates (Merck). Plates were visual-
ized either by UV light or with phosphomolybdic acid in ethanol.
Melting points were determined with a Barnstead Electothermal
1
3
Ar), 7.29–7.30 (m, 3 H, Ar), 7.34–7.43 (m, 4 H, Ar) ppm. C NMR
CDCl , 100 MHz): δ = 26.8, 28.1, 64.9, 80.6, 108.4, 122.8, 124.5,
(
3
1
26.8, 128.9, 129.0, 129.2, 138.1, 144.0, 154.0, 175.9 ppm. HRMS
9
100 apparatus. NMR spectra were recorded with a Bruker Avance
+
(ESI): calcd. for C H N O [M] 339.16640; found 339.17068.
20 22 2 3
III instrument (400 MHz). Chemical shifts are quoted in parts per
million (ppm) relative to δ = 0.0 ppm for tetramethylsilane, and
were referenced to the appropriate non-deuterated solvent peak.
Coupling constants (J) are reported in Hz, and refer to apparent
peak multiplicities. Splitting patterns are reported as s, singlet; d,
doublet; t, triplet; m, multiplet; br., broad. Mass spectra (MS) were
recorded with a Waters-Micromass instrument using the ESI-TOF
technique. High-performance liquid chromatographic (HPLC) analy-
sis was carried out with a Hitachi Primaide instrument, equipped
with a 1410 series UV detector.
tert-Butyl 3-(3-Acetylphenyl)-1-methyl-2-oxoindolin-3-ylcarb-
1
amate (2b): Yellow solid (0.0754 g, 50 %). m.p. 118.0–119.7 °C. H
NMR (CDCl , 400 MHz): δ = 1.28 (br. s, 9 H, CH ), 2.55 (s, 3 H, CH ),
3
3
3
3.20 (s, 3 H, CH ), 5.45 (br. s, 1 H, NH), 6.89–6.91 (d, J = 8 Hz, 1 H,
3
Ar), 7.16–7.19 (t, 1 H, Ar), 7.38–7.46 (m, 3 H, Ar), 7.59–7.61 (d, J =
8 Hz, 1 H, Ar), 7.88–7.90 (d, J = 8 Hz, 1 H, Ar), 8.02 (s, 1 H, Ar) ppm.
13
C NMR (CDCl , 100 MHz): δ = 26.8, 26.9, 28.2, 64.7, 80.9, 108.7,
3
123.2, 124.8, 126.8, 128.7, 129.3, 129.6, 130.0, 131.5, 137.8, 138.9,
+
143.9, 154.0, 175.5, 197.7 ppm. MS (ESI-TOF): m/z = 381.18 [M] .
Eur. J. Org. Chem. 2016, 806–812
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tert-Butyl 3-(4-Chlorophenyl)-1-methyl-2-oxoindolin-3-ylcarb-
amate (2c): White solid (0.1025 g, 71 %). m.p. 184.7–185.9 °C. H amate (2j): Yellow solid (0.0669 g, 43 %). m.p. 187.4–188.7 °C. H
tert-Butyl 3-(4-Bromophenyl)-1-methyl-2-oxoindolin-3-ylcarb-
1
1
NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.19 (s, 3 H, CH ),
NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.18 (s, 3 H, CH ),
3
3
3
3
3
3
5
.41 (br. s, 1 H, NH), 6.88–6.90 (d, J = 8 Hz, 1 H, Ar), 7.14–7.17 (t, 1
5.51 (br. s, 1 H, NH), 6.87–6.89 (d, J = 8 Hz, 1 H, Ar), 7.13–7.17 (t, J =
1
3
H, Ar), 7.28 (s, 2 H, Ar), 7.34–7.42 (m, 4 H, Ar) ppm. C NMR (CDCl3, 8 Hz, 1 H, Ar), 7.27–7.29 (d, J = 8 Hz, 2 H, Ar), 7.36–7.43 (m, 2 H, Ar)
1
1
00 MHz): δ = 26.8, 28.1, 64.4, 80.8, 108.6, 123.1, 124.7, 128.4, 129.1,
29.5, 130.1, 135.0, 136.6, 143.9, 153.9, 175.5 ppm. MS (ESI-TOF): 123.0, 123.2, 124.7, 128.7, 129.5, 130.0, 132.0, 137.1, 143.9, 153.9,
ppm. 13C NMR (CDCl , 100 MHz): δ = 26.8, 28.1, 64.4, 80.7, 108.5,
3
+
+
m/z = 373.13 [M] .
175.4 ppm. MS (ESI-TOF): m/z = 419.08 [M] .
tert-Butyl 3-(4-Fluorophenyl)-1-methyl-2-oxoindolin-3-ylcarb-
amate (2d): Pale orange solid (0.0793 g, 48 %). m.p. 147.0–148.1 °C.
tert-Butyl 1-Methyl-3-(naphthalen-2-yl)-2-oxoindolin-3-ylcarb-
amate (2k): White solid (0.1059 g, 64 %). m.p. 88.9–90.1 °C. H NMR
1
1
H NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.19 (s, 3 H,
(CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.19 (s, 3 H, CH ), 5.80
3
3
3
3
3
CH ), 5.37 (br. s, 1 H, NH), 6.87–6.89 (d, J = 8 Hz, 1 H, Ar), 6.97–7.01
(br. s, 1 H, NH), 6.89–6.90 (d, J = 4 Hz, 1 H, Ar), 7.16–7.20 (t, J = 8 Hz,
1 H, Ar), 7.37–7.47 (m, 4 H, Ar), 7.69–7.81 (m, 5 H, Ar) ppm. C NMR
3
1
3
(
t, J = 8 Hz, 2 H, Ar), 7.14–7.18 (t, 1 H, Ar), 7.36–7.42 (m, 4 H, Ar)
13
ppm. C NMR (CDCl , 100 MHz): δ = 26.8, 28.2, 64.3, 80.8, 108.6,
(CDCl , 100 MHz): δ = 26.7, 28.2, 65.0, 79.5, 108.4, 122.9, 124.2,
3
3
1
1
15.7, 115.9, 123.0, 124.6, 128.9, 129.0, 130.1, 129.5, 133.8, 144.0, 124.5, 126.2, 126.4, 126.7, 127.5, 128.4, 128.9, 129.2, 132.9, 133.2,
+
53.9, 161.8, 164.3, 175.8 ppm. MS (ESI-TOF): m/z = 357.16 [M] .
135.2, 144.0, 154.1, 156.5, 175.9 ppm. MS (ESI-TOF): m/z = 389.19
+
[M] .
tert-Butyl 1-Methyl-2-oxo-3-(p-tolyl)indolin-3-ylcarbamate (2e):
White solid (0.0961 g, 71 %). m.p. 167.0–168.1 °C. H NMR (CDCl , tert-Butyl 1,5-Dimethyl-2-oxo-3-phenylindolin-3-ylcarbamate
4
1
3
1
00 MHz): δ = 1.26 (br. s, 9 H, CH ), 2.30 (s, 3 H, CH ), 3.18 (s, 3 H,
(3a): White solid (0.1034 g, 74 %). m.p. 75.1–76.3 °C. H NMR (CDCl ,
3
3
3
CH ), 5.39 (br. s, 1 H, NH), 6.85–6.87 (d, J = 8 Hz, 1 H, Ar), 7.10–7.15
400 MHz): δ = 1.26 (br. s, 9 H, CH ), 2.37 (s, 3 H, CH ), 3.17 (s, 3 H,
3
3
3
(
m, 3 H, Ar), 7.28–7.30 (d, J = 8 Hz, 2 H, Ar), 7.34–7.38 (m, 2 H, Ar)
CH ), 5.43 (br. s, 1 H, NH), 6.75–6.77 (d, J = 8 Hz, 1 H, Ar), 7.15–7.16
3
13
ppm. C NMR (CDCl , 100 MHz): δ = 21.1, 26.7, 28.1, 64.7, 80.5, (d, J = 4 Hz, 1 H, Ar), 7.21 (s, 1 H, Ar), 7.29–7.31 (m, 3 H, Ar), 7.40–
1
1
3
08.3, 122.8, 124.4, 126.7, 129.2, 129.6, 135.1, 138.8, 144.0, 154.0, 7.42 (m, 2 H, Ar) ppm. 13C NMR (CDCl , 100 MHz): δ = 21.3, 26.8,
3
+
76.1 ppm. MS (ESI-TOF): m/z = 353.19 [M] .
28.2, 65.0, 80.5, 108.1, 125.3, 126.8, 128.8, 128.9, 129.5, 130.5, 132.4,
+
1
38.3, 141.6, 154.0, 175.9 ppm. MS (ESI-TOF): m/z = 353.19 [M] .
tert-Butyl 1-Methyl-3-(naphthalen-1-yl)-2-oxoindolin-3-ylcarb-
amate (2f): White solid (0.1215 g, 81 %). m.p. 105.3–106.0 °C. H
1
tert-Butyl 3-(3-Acetylphenyl)-1,5-dimethyl-2-oxoindolin-3-yl-
NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.19 (s, 3 H, CH ),
carbamate (3b): White solid (0.0493 g, 36 %). m.p. 165.2–166.5 °C.
3
3
3
1
5
.74 (br. s, 1 H, NH), 6.89–6.91 (d, J = 8 Hz, 1 H, Ar), 6.99–7.01 (d,
H NMR (CDCl , 400 MHz): δ = 1.28 (br. s, 9 H, CH ), 2.40 (s, 3 H,
3
3
J = 8 Hz, 1 H, Ar), 7.14–7.22 (m, 2 H, Ar), 7.37–7.41 (m, 2 H, Ar),
CH ), 2.58 (s, 3 H, CH ), 3.20 (s, 3 H, CH ), 5.62 (br. s, 1 H, NH), 6.80–
3
3
3
7
.51–7.55 (t, J = 8 Hz, 1 H, Ar), 7.64–7.68 (t, J = 8 Hz, 1 H, Ar), 7.78– 6.82 (d, J = 8 Hz, 1 H, Ar), 7.20–7.22 (d, J = 8 Hz, 1 H, Ar), 7.30 (s, 1
7
(
.80 (d, J = 8 Hz, 1 H, Ar), 7.85–7.87 (d, J = 8 Hz, 1 H, Ar), 9.33–9.35
H, Ar), 7.40–7.44 (t, J = 8 Hz, 1 H, Ar), 7.57–7.59 (d, J = 8 Hz, 1 H,
Ar), 7.90–7.92 (d, J = 8 Hz, 1 H, Ar), 8.07 (s, 1 H, Ar) ppm. C NMR
m, 1 H, Ar) ppm. 13C NMR (CDCl , 100 MHz): δ = 28.1, 67.6, 80.5,
13
3
1
1
08.3, 122.9, 124.6, 124.7, 126.1, 126.3, 126.6, 127.8, 129.2, 129.3, (CDCl , 100 MHz): δ = 21.3, 26.7, 26.8, 28.1, 64.8, 80.7, 108.3, 125.5,
3
30.6, 131.0, 133.4, 135.3, 143.9, 153.7, 175.9 ppm. MS (ESI-TOF): 126.7, 128.6, 129.1, 129.8, 130.1, 131.4, 132.8, 137.7, 139.0, 141.5,
+
+
m/z = 389.19 [M] .
154.1, 175.4, 197.7 ppm. MS (ESI-TOF): m/z = 395.20 [M] .
tert-Butyl 1-Methyl-2-oxo-3-(o-tolyl)indolin-3-ylcarbamate (2g):
tert-Butyl 1,5-Dimethyl-2-oxo-3-(p-tolyl)indolin-3-ylcarbamate
1
1
White solid (0.0756 g, 52 %). m.p. 106.9–108.0 °C. H NMR (CDCl , (3c): Pale yellow solid (0.1026 g, 80 %). m.p. 139.2–141.3 °C. H NMR
3
4
00 MHz): δ = 1.26 (br. s, 9 H, CH ), 2.59 (br. s, 3 H, CH ), 3.20 (s, 3
(CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 2.30 (s, 3 H, CH ), 2.37
3
3
3
3
3
H, CH ), 5.52 (br. s, 1 H, NH), 6.85–6.87 (d, J = 8 Hz, 1 H, Ar), 6.94–
(s, 3 H, CH ), 3.16 (s, 3 H, CH ), 5.40 (br. s, 1 H, NH), 6.74–6.76 (d, J =
3 3
3
6
.96 (d, J = 8 Hz, 1 H, Ar), 7.03–7.05 (m, 1 H, Ar), 7.09–7.13 (t, 1 H,
8 Hz, 1 H, Ar), 7.10–7.12 (d, J = 8 Hz, 2 H, Ar), 7.13–7.15 (d, J = 8 Hz,
13
13
Ar), 7.17–7.18 (m, 2 H, Ar), 7.33–7.36 (m, 2 H, Ar) ppm. C NMR
1 H, Ar), 7.19 (s, 1 H, Ar), 7.28–7.30 (d, J = 8 Hz, 2 H, Ar) ppm.
C
(
CDCl , 100 MHz): δ = 26.7, 28.2, 28.3, 66.3, 80.5, 108.2, 123.0, 126.0, NMR (CDCl , 100 MHz): δ = 21.1, 21.3, 26.8, 28.2, 64.8, 80.5, 108.1,
3
3
1
1
27.8, 128.6, 129.2, 133.5, 135.9, 137.3, 137.6, 144.0, 154.0,
76.0 ppm. MS (ESI-TOF): m/z = 353.19 [M] .
125.2, 126.6, 129.4, 129.6, 130.8, 132.3, 135.3, 138.7, 141.6, 154.0,
176.0 ppm. MS (ESI-TOF): m/z = 367.20 [M] .
+
+
tert-Butyl
3-(4-Methoxyphenyl)-1-methyl-2-oxoindolin-3-yl-
tert-Butyl 1,5-Dimethyl-3-(naphthalen-1-yl)-2-oxoindolin-3-yl-
carbamate (2h): Yellow solid (0.0567 g, 36 %). m.p. 127.1–128.2 °C. carbamate (3d): Pale orange solid (0.1046 g, 71 %). m.p. 156.3–
1
1
H NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.17 (s, 3 H,
157.8 °C. H NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 2.38
3
3
3
3
CH ), 3.74 (s, 3 H, OCH ), 5.44 (br. s, 1 H, NH), 6.80–6.87 (m, 3 H, Ar),
(s, 3 H, CH ), 3.17 (s, 3 H, CH ), 5.70 (br. s, 1 H, NH), 6.77–6.79 (d, J =
3 3
3
3
13
7
.11–7.15 (t, J = 8 Hz, 1 H, Ar), 7.33–7.39 (m, 4 H, Ar) ppm. C NMR 8 Hz, 1 H, Ar), 7.00–7.01 (d, J = 4 Hz, 1 H, Ar), 7.18–7.23 (m, 3 H, Ar),
(
CDCl , 100 MHz): δ = 26.6, 28.1, 55.3, 64.3, 80.4, 108.3, 114.2, 122.7, 7.51–7.55 (t, J = 8 Hz, 1 H, Ar), 7.64–7.68 (t, J = 8 Hz, 1 H, Ar), 7.78–
3
1
24.4, 128.2, 129.1, 129.9, 143.9, 153.9, 160.0, 176.1 ppm. MS (ESI-
7.80 (d, J = 8 Hz, 1 H, Ar), 7.85–7.87 (d, J = 8 Hz, 1 H, Ar), 9.33–9.35
+
13
TOF): m/z = 369.18 [M] .
(d, J = 8 Hz, 1 H, Ar) ppm. C NMR (CDCl , 100 MHz): δ = 21.3, 26.8,
3
2
1
8.2, 67.6, 80.7, 108.1, 124.7, 125.4, 126.0, 126.2, 126.6, 129.2, 128.5,
tert-Butyl
3-(3-Methoxyphenyl)-1-methyl-2-oxoindolin-3-yl-
30.6, 131.0, 131.6, 132.4, 133.6, 135.3, 141.5, 153.8, 175.9 ppm. MS
carbamate (2i): Yellow solid (0.0765 g, 44 %). m.p. 127.5–128.6 °C.
+
(ESI-TOF): m/z = 403.20 [M] .
1
H NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.18 (s, 3 H,
3
3
CH ), 3.75 (s, 3 H, OCH ), 5.53 (br. s, 1 H, NH), 6.81–6.87 (m, 2 H, Ar),
tert-Butyl 1,5-Dimethyl-2-oxo-3-(o-tolyl)indolin-3-ylcarbamate
(3e): Pale yellow solid (0.0578 g, 44 %). m.p. 123.0–124.3 °C. H NMR
3
3
1
6
8
.94–6.96 (d, J = 8 Hz, 1 H, Ar), 7.00 (s, 1 H, Ar), 7.11–7.15 (t, J =
Hz, 1 H, Ar), 7.17–7.21 (t, J = 8 Hz, 1 H, Ar), 7.33–7.39 (m, 2 H, Ar)
(CDCl , 400 MHz): δ = 1.29 (br. s, 9 H, CH ), 2.34 (s, 3 H, CH ), 2.59
3
3
3
13
ppm. C NMR (CDCl , 100 MHz): δ = 26.7, 28.1, 55.3, 64.8, 80.5, (s, 3 H, CH ), 3.17 (s, 3 H, CH ), 5.52 (br. s, 1 H, NH), 6.74–6.76 (d, J =
3
3
3
1
1
08.3, 112.8, 119.0, 122.8, 124.4, 129.2, 129.8, 130.5, 139.6, 143.9, 8 Hz, 1 H, Ar), 6.96–6.98 (d, J = 8 Hz, 1 H, Ar), 7.03–7.07 (m, 1 H, Ar),
+
13
53.9, 159.9, 175.8 ppm. MS (ESI-TOF): m/z = 369.18 [M] .
7.14–7.18 (m, 4 H, Ar) ppm. C NMR (CDCl , 100 MHz): δ = 21.3,
3
Eur. J. Org. Chem. 2016, 806–812
www.eurjoc.org
810
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2
1
1.5, 26.6, 28.2, 66.4, 80.4, 107.9, 126.0, 127.8, 128.5, 129.4, 131.3,
32.5, 133.4, 136.1, 137.6, 141.6, 154.0, 175.9 ppm.
127.7, 128.4, 129.3, 132.1, 132.4, 135.3, 135.8, 143.0, 153.8,
175.0 ppm. MS (ESI-TOF): m/z = 453.04 [M] .
+
tert-Butyl 3-(4-Methoxyphenyl)-1,5-dimethyl-2-oxoindolin-3-yl-
carbamate (3f): Yellow solid (0.1144 g, 78 %). m.p. 165.9–167.4 °C.
tert-Butyl 5-Bromo-3-(4-fluorophenyl)-1-methyl-2-oxoindolin-3-
ylcarbamate (4d): White solid (0.1029 g, 76 %). m.p. 188.4–189.5 °C.
1
1
H NMR (CDCl , 400 MHz): δ = 1.25 (br. s, 9 H, CH ), 2.37 (s, 3 H,
H NMR (CDCl , 400 MHz): δ = 1.27 (br. s, 9 H, CH ), 3.15 (s, 3 H,
3
3
3
3
CH ), 3.15 (s, 3 H, CH ), 3.76 (s, 3 H, OCH ), 5.37 (br. s, 1 H, NH),
CH ), 5.62 (br. s, 1 H, NH), 6.75–6.77 (d, J = 8 Hz, 1 H, Ar), 6.97–7.01
3
3
3
3
6
7
.74–6.75 (d, J = 4 Hz, 1 H, Ar), 6.81–6.83 (d, J = 8 Hz, 2 H, Ar), 7.13–
.15 (d, J = 8 Hz, 1 H, Ar), 7.20 (s, 1 H, Ar), 7.33–7.35 (d, J = 8 Hz, 2
(t, J = 8 Hz, 2 H, Ar), 7.37–7.40 (m, 2 H, Ar), 7.48–7.50 (d, J = 8 Hz,
1 H, Ar), 7.51 (s, 1 H, Ar) ppm. 13C NMR (CDCl , 100 MHz): δ = 26.8,
3
13
H, Ar) ppm. C NMR (CDCl , 100 MHz): δ = 21.3, 26.7, 28.1, 55.4,
28.1, 64.2, 81.0, 110.0, 115.5, 115.8, 116.0, 127.6, 128.7, 128.8, 132.2,
3
6
1
4.4, 80.5, 108.1, 114.2, 125.2, 128.2, 129.4, 130.1, 132.3, 141.5, 154.0, 133.0, 134.0, 143.0, 153.8, 161.8, 164.3, 175.2 ppm. MS (ESI-TOF):
+
+
59.9, 176.1 ppm. MS (ESI-TOF): m/z = 383.20 [M] .
m/z = 435.07 [M] .
tert-Butyl 3-(3-Methoxyphenyl)-1,5-dimethyl-2-oxoindolin-3-yl-
carbamate (3g): White solid (0.1171 g, 84 %). m.p. 137.0–138.3 °C.
tert-Butyl 5-Bromo-1-methyl-2-oxo-3-(p-tolyl)indolin-3-ylcarb-
1
amate (4e): Yellow solid (0.092 g, 72 %). m.p. 149.8–151.0 °C.
H
1
H NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 2.35 (s, 3 H,
NMR (CDCl , 400 MHz): δ = 1.28 (br. s, 9 H, CH ), 2.30 (s, 3 H, CH ),
3
3
3
3
3
CH ), 3.15 (s, 3 H, CH ), 3.74 (s, 3 H, OCH ), 5.55 (br. s, 1 H, NH),
3.16 (s, 3 H, CH ), 5.54 (br. s, 1 H, NH), 6.73–6.75 (d, J = 8 Hz, 1 H,
3
3
3
3
6
6
.73–6.75 (d, J = 8 Hz, 1 H, Ar), 6.80–6.82 (d, J = 8 Hz, 1 H, Ar), 6.93–
.95 (d, J = 8 Hz, 1 H, Ar), 7.00 (s, 1 H, Ar), 7.12–7.14 (d, J = 8 Hz, 1
Ar), 7.11–7.13 (d, J = 8 Hz, 2 H, Ar), 7.26–7.28 (d, J = 8 Hz, 2 H, Ar),
7.46–7.49 (m, 2 H, Ar) ppm. 13C NMR (CDCl , 100 MHz): δ = 21.0,
3
1
3
H, Ar), 7.17–7.20 (m, 2 H, Ar) ppm. C NMR (CDCl , 100 MHz): δ = 26.8, 28.1, 64.6, 80.8, 109.8, 115.4, 126.5, 127.4, 129.7, 131.9, 132.7,
3
2
1
1.2, 26.7, 28.0, 55.2, 64.9, 80.4, 108.0, 112.8, 113.9, 118.9, 125.1,
29.4, 129.7, 130.5, 132.3, 139.7, 141.5, 154.0, 159.8, 175.7 ppm.
134.3, 139.1, 143.0, 153.8, 175.5 ppm.
tert-Butyl 5-Bromo-1-methyl-3-(naphthalen-1-yl)-2-oxoindolin-
3-ylcarbamate (4f): White solid (0.0382 g, 25 %). m.p. 85.2–86.9 °C.
tert-Butyl 1,5-Dimethyl-3-(naphthalen-2-yl)-2-oxoindolin-3-yl-
carbamate (3h): Yellow solid (0.0813 g, 54 %). m.p. 74.5–75.6 °C. H
1
1
H NMR (CDCl , 400 MHz): δ = 1.30 (br. s, 9 H, CH ), 3.18 (s, 3 H,
3
3
NMR (CDCl , 400 MHz): δ = 1.29 (br. s, 9 H, CH ), 2.40 (s, 3 H, CH ),
CH ), 5.77 (br. s, 1 H, NH), 6.77–6.79 (d, J = 8 Hz, 1 H, Ar), 6.98–7.00
3
3
3
3
3
.19 (s, 3 H, CH ), 5.54 (br. s, 1 H, NH), 6.79–6.81 (d, J = 8 Hz, 1 H, (d, J = 8 Hz, 1 H, Ar), 7.22–7.24 (d, J = 8 Hz, 1 H, Ar), 7.51–7.56 (m,
3
Ar), 7.18–7.20 (d, J = 8 Hz, 1 H, Ar), 7.28 (s, 1 H, Ar), 7.43–7.48 (m, 2
3 H, Ar), 7.65–7.69 (t, J = 8 Hz, 1 H, Ar), 7.81–7.83 (d, J = 8 Hz, 1 H,
Ar), 7.87–7.89 (d, J = 8 Hz, 1 H, Ar), 9.27–9.28 (d, J = 4 Hz, 1 H, Ar)
1
3
H, Ar), 7.66–7.83 (m, 5 H, Ar) ppm. C NMR (CDCl , 100 MHz): δ =
3
2
1
1
1.4, 26.8, 28.2, 65.2, 80.6, 108.2, 124.1, 125.4, 126.1, 126.5, 126.7,
27.6, 128.4, 129.0, 129.6, 130.7, 132.5, 133.0, 133.3, 135.5, 141.6, 115.3, 124.6, 126.1, 126.3, 126.4, 127.6, 129.2, 130.7, 132.0, 132.6,
54.1, 175.8 ppm. 133.5, 135.2, 142.9, 153.6, 175.3 ppm. MS (ESI-TOF): m/z = 467.10
ppm. 13C NMR (CDCl , 100 MHz): δ = 26.7, 28.1, 67.3, 80.9, 109.7,
3
+
[
M] .
tert-Butyl 3-(4-Bromophenyl)-1,5-dimethyl-2-oxoindolin-3-yl-
1
carbamate (3i): White solid (0.0836 g, 49 %). m.p. 69.6–70.4 °C. H
tert-Butyl 5-Bromo-1-methyl-2-oxo-3-(o-tolyl)indolin-3-ylcarb-
1
NMR (CDCl , 400 MHz): δ = 1.25 (br. s, 9 H, CH ), 2.36 (s, 3 H, CH ),
amate (4g): White solid (0.0682 g, 54 %). m.p. 177.9–179.1 °C. H
3
3
3
3
.14 (s, 3 H, CH ), 5.57 (br. s, 1 H, NH), 6.75–6.77 (d, J = 8 Hz, 1 H, NMR (CDCl , 400 MHz): δ = 1.31 (br. s, 9 H, CH ), 2.60 (s, 3 H, CH ),
3
3
3
3
Ar), 7.15–7.17 (d, J = 8 Hz, 1 H, Ar), 7.22 (s, 1 H, Ar), 7.26–7.28 (d, 3.17 (s, 3 H, CH ), 5.58 (br. s, 1 H, NH), 6.73–6.75 (d, J = 8 Hz, 1 H,
3
J = 8 Hz, 2 H, Ar), 7.39–7.41 (d, J = 8 Hz, 2 H, Ar) ppm. 13C NMR
Ar), 6.92–6.94 (d, J = 8 Hz, 1 H, Ar), 7.05–7.07 (m, 1 H, Ar), 7.18–7.19
(
1
(
CDCl , 100 MHz): δ = 21.2, 26.8, 28.1, 64.5, 80.7, 108.2, 123.1, 125.4, (d, J = 4 Hz, 2 H, Ar), 7.45 (s, 1 H, Ar), 7.46–7.48 (d, J = 8 Hz, 1 H,
3
28.6, 129.7, 130.1, 131.9, 132.6, 137.3, 141.5, 154.0, 175.3 ppm. MS
ESI-TOF): m/z = 431.10 [M] .
Ar) ppm. 13C NMR (CDCl , 100 MHz): δ = 21.5, 26.7, 28.2, 66.2, 80.8,
3
+
109.6, 115.6, 126.2, 127.6, 128.2, 128.8, 132.0, 133.3, 133.6, 135.2,
37.5, 143.0, 153.8, 175.4 ppm. MS (ESI-TOF): m/z = 431.10 [M] .
+
1
tert-Butyl 5-Bromo-1-methyl-2-oxo-3-phenylindolin-3-ylcarb-
amate (4a): White solid (0.1431 g, 84 %). m.p. 160.3–161.6 °C. H
1
tert-Butyl 5-Bromo-3-(4-methoxyphenyl)-1-methyl-2-oxoindol-
NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.17 (s, 3 H, CH ),
in-3-ylcarbamate (4h): Pale yellow solid (0.0604 g, 48 %). m.p.
3
3
3
1
5
.49 (br. s, 1 H, NH), 6.74–6.76 (d, J = 8 Hz, 1 H, Ar), 7.31–7.33 (m, 3 151.8–153.0 °C. H NMR (CDCl , 400 MHz): δ = 1.29 (br. s, 9 H, CH ),
3
3
13
H, Ar), 7.38–7.41 (m, 2 H, Ar), 7.47–7.50 (m, 2 H, Ar) ppm. C NMR
CDCl , 100 MHz): δ = 26.9, 28.2, 64.8, 80.9, 109.9, 115.5, 126.6,
3.15 (s, 3 H, CH ), 3.75 (s, 3 H, OCH ), 5.45 (br. s, 1 H, NH), 6.73–6.75
3 3
(
(d, J = 8 Hz, 1 H, Ar), 6.82–6.84 (d, J = 8 Hz, 2 H, Ar), 7.31–7.33 (d,
J = 8 Hz, 2 H, Ar), 7.46–7.49 (m, 2 H, Ar) ppm. 13C NMR (CDCl3,
100 MHz): δ = 26.8, 28.1, 55.4, 64.2, 80.8, 109.8, 114.4, 115.3, 127.4,
3
1
27.6, 129.1, 129.2, 132.0, 132.6, 137.4, 143.0, 153.8, 175.4 ppm. MS
+
(ESI-TOF): m/z = 417.08 [M] .
1
28.1, 129.1, 131.9, 143.0, 153.8, 160.1, 175.6 ppm. MS (ESI-TOF):
tert-Butyl 3-(3-Acetylphenyl)-5-bromo-1-methyl-2-oxoindolin-3-
+
m/z = 447.09 [M] .
ylcarbamate (4b): Pale yellow solid (0.0941 g, 63 %). m.p. 113.0–
1
1
14.6 °C. H NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 2.53 tert-Butyl 5-Bromo-3-(3-methoxyphenyl)-1-methyl-2-oxoindol-
3
3
(
8
7
s, 3 H, CH ), 3.15 (s, 3 H, CH ), 5.74 (br. s, 1 H, NH), 6.75–6.77 (d, J =
in-3-ylcarbamate (4i): Pale yellow solid (0.0875 g, 69 %). m.p. 83.5–
3
3
1
Hz, 1 H, Ar), 7.36–7.40 (t, J = 8 Hz, 1 H, Ar), 7.47–7.53 (m, 3 H, Ar),
84.3 °C. H NMR (CDCl , 400 MHz): δ = 1.25 (br. s, 9 H, CH ), 3.16 (s,
3
3
.86–7.87 (d, J = 4 Hz, 1 H, Ar), 8.01 (s, 1 H, Ar) ppm. 13C NMR 3 H, CH ), 3.76 (s, 3 H, OCH ), 5.55 (br. s, 1 H, NH), 6.73–6.75 (d, J =
3
3
(
CDCl , 100 MHz): δ = 26.7, 26.8, 28.1, 64.6, 81.0, 110.1, 115.7, 126.5, 8 Hz, 1 H, Ar), 6.83–6.85 (d, J = 8 Hz, 1 H, Ar), 6.90–6.92 (d, J = 8 Hz,
3
1
1
27.7, 128.8, 129.3, 131.2, 132.1, 132.3, 137.8, 138.1, 142.9, 153.9, 1 H, Ar), 6.97 (s, 1 H, Ar), 7.19–7.23 (t, J = 8 Hz, 1 H, Ar), 7.45–7.49
+
13
75.0, 197.4 ppm. MS (ESI-TOF): m/z = 459.09 [M] .
(m, 2 H, Ar) ppm. C NMR (CDCl , 100 MHz): δ = 26.8, 28.1, 55.4,
3
6
1
4.7, 80.9, 109.8, 112.7, 114.2, 115.4, 118.8, 127.5, 130.0, 132.0, 132.6,
38.8, 143.0, 153.8, 160.0, 175.3 ppm.
tert-Butyl 5-Bromo-3-(4-chlorophenyl)-1-methyl-2-oxoindolin-
-ylcarbamate (4c): White solid (0.0295 g, 21 %). m.p. 138.6–
3
1
1
39.2 °C. H NMR (CDCl , 400 MHz): δ = 1.30 (br. s, 9 H, CH ), 3.17 tert-Butyl 5-Bromo-1-methyl-3-(naphthalen-2-yl)-2-oxoindolin-
3
3
(
7
s, 3 H, CH ), 5.45 (br. s, 1 H, NH), 6.76–6.78 (d, J = 8 Hz, 1 H, Ar), 3-ylcarbamate (4j): Pale yellow solid (0.0462 g, 44 %). m.p. 70.6–
3
13
1
.28–7.35 (m, 4 H, Ar), 7.49–7.52 (d, J = 12 Hz, 2 H, Ar) ppm.
C
72.0 °C. H NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.19 (s,
3 3
NMR (CDCl , 100 MHz): δ = 26.9, 28.2, 64.3, 81.2, 110.12, 115.7, 3 H, CH ), 5.62 (br. s, 1 H, NH), 6.78–6.80 (d, J = 8 Hz, 1 H, Ar), 7.46–
3
3
Eur. J. Org. Chem. 2016, 806–812
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
7
7
.48 (m, 2 H, Ar), 7.51–7.54 (d, J = 12 Hz, 1 H, Ar), 7.58 (s, 1 H, Ar),
.64–7.67 (d, J = 12 Hz, 1 H, Ar), 7.69 (s, 1 H, Ar), 7.76–7.81 (m, 2 H,
Chauhan, S. S. Chimni, Tetrahedron: Asymmetry 2013, 24, 343; c) J. Kaur,
S. S. Chimni, S. Mahajan, A. Kumar, RSC Adv. 2015, 5, 52481.
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Barberis, G. Brossard, P. Soubrié, D. Nisato, M. Pascal, R. Pruss, B. Scatton,
J.-P. Maffrand, G. Le Fur, J. Pharmacol. Exp. Ther. 2002, 300, 1122.
1
3
Ar), 7.83–7.85 (d, J = 8 Hz, 1 H, Ar) ppm. C NMR (CDCl , 100 MHz):
δ = 26.9, 28.2, 65.0, 81.0, 110.0, 115.5, 123.8, 126.1, 126.7, 127.0,
1
1
3
27.6, 128.4, 129.2, 132.2, 132.6, 133.0, 133.3, 134.5, 143.1, 153.9,
75.4 ppm.
[
4] M. Ochi, K. Kawasaki, H. Kataoka, Y. Uchio, H. Nishi, Biochem. Biophys.
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5] M. A. Ali, R. Ismail, T. S. Choon, Y. K. Yoon, A. C. Wei, S. Pandian, R. S.
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tert-Butyl 5-Bromo-3-(4-bromophenyl)-1-methyl-2-oxoindolin-
-ylcarbamate (4k): White solid (0.1205 g, 71 %). m.p. 166.0–
3
1
[6] M. Rottmann, C. McNamara, B. K. S. Yeung, M. C. S. Lee, B. Zou, B. Russell,
P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B. Cohen, K. R. Spencer, G. E.
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WO 2015033261, 2015.
1
68.1 °C. H NMR (CDCl , 400 MHz): δ = 1.26 (br. s, 9 H, CH ), 3.34
3
3
(
s, 3 H, CH ), 5.65 (br. s, 1 H, NH), 6.74–6.76 (d, J = 8 Hz, 1 H, Ar),
3
7
7
.24–7.26 (d, J = 8 Hz, 2 H, Ar), 7.40–7.43 (d, J = 12 Hz, 2 H, Ar),
.47–7.49 (d, J = 8 Hz, 1 H, Ar), 7.51 (s, 1 H, Ar) ppm. 13C NMR
(
CDCl , 100 MHz): δ = 26.9, 28.1, 64.4, 81.1, 110.0, 115.6, 123.4,
3
1
27.6, 128.5, 132.1, 132.3, 136.3, 142.9, 153.8, 174.9 ppm. MS (ESI-TOF):
+
m/z = 496.99 [M] .
-Amino-1-methyl-3-phenylindolin-2-one (6): tert-Butyl 1-
methyl-2-oxo-3-phenylindolin-3-ylcarbamate (2a; 0.114 g,
.34 mmol) was put into a round-bottomed flask containing a stirrer
bar under air. CH Cl (2 mL) was added to the flask, and the mixture
3
[
8] For reviews, see: a) A. J. Burke, C. S. Marques, Catalytic Arylation Methods:
From the Academic Lab to Industrial Processes, John Wiley & Sons, 2015;
b) C. S. Marques, A. J. Burke, ChemCatChem 2011, 3, 635. For relevant
publications, see: c) C. S. Marques, A. J. Burke, Tetrahedron 2013, 69,
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0
2
2
was cooled to 0 °C. TFA (0.1 mL, 1.3 mmol) was added, and the
mixture was stirred for 1 h at 0 °C. The reaction mixture was concen-
trated under reduced pressure. The resulting crude mixture was
purified by silica gel column chromatography to give 3-amino-1-
methyl-3-phenylindolin-2-one (6; 0.0335 g, 42 %) as an orange oil.
2012, 4232; i) C. S. Marques, A. J. Burke, Eur. J. Org. Chem. 2010, 1639.
1
H NMR (CDCl , 400 MHz): δ = 3.16 (s, 3 H, CH ), 6.37 (br. s, 2 H,
3
3
[9] G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104.
NH ), 6.89–6.91 (d, J = 8 Hz, 1 H, Ar), 7.08–7.12 (t, J = 8 Hz, 1 H, Ar),
2
[10] a) G. Lesma, N. Landoni, T. Pilati, A. Sacchetti, A. Silvani, J. Org. Chem.
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7
.30 (m, 3 H, Ar), 7.36–7.40 (m, 3 H, Ar), 7.45–7.47 (d, J = 8 Hz, 1 H,
13
Ar) ppm. C NMR (CDCl , 100 MHz): δ = 26.8, 63.3, 109.2, 124.0,
3
1
25.8, 126.1, 128.3, 129.0, 129.1, 130.6, 136.0, 143.5, 175.5 ppm. MS
+
+
(ESI-TOF): m/z = 222.09 [M – NH ] , 261.10 [M + Na] .
2
[
11] Z.-Q. Wang, C.-G. Feng, M.-H. Xu, G.-Q. Lin, J. Am. Chem. Soc. 2007, 129,
336.
5
Acknowledgments
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12] a) T. Nishimura, A. Noishiki, G. C. Tsui, T. Hayashi, J. Am. Chem. Soc. 2012,
134, 5056; b) R. Shintani, M. Takeda, T. Tsuji, T. Hayashi, J. Am. Chem. Soc.
The authors gratefully acknowledge Fundo Europeu de Desen-
volvimento Regional (FEDER-INALENTEJO) for funding the pro-
gram INMOLFARM – Molecular Innovation and Drug Discovery
2010, 132, 13168.
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13] For the catalytic alkylation of imines with aliphatic boronic acids, see: a)
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(ALENT-07-0224-FEDER-001743) and for financing the acquisi-
tion of the NMR equipment, project LADECA (ALENT-07-0262-
FEDER-001878). The authors are grateful for the award of post-
doc grants to C. S. M. from both ALENT07-0224-FEDER-001743
and from the Fundação para a Ciência e a Tecnologia (FCT)
[
[
14] R. B. C. Jagt, P. Y. Toullec, D. Geerdink, J. G. de Vries, B. L. Feringa, A. J.
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(
SFRH/BPD/92394/2013). LabRMN (University of Évora) is
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acknowledged for recording the NMR spectra.
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014, 16, 2768.
Keywords: Homogeneous catalysis · Rhodium · Nitrogen
heterocycles · Ketimines
[
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Received: November 5, 2015
Published Online: December 23, 2015
Eur. J. Org. Chem. 2016, 806–812
www.eurjoc.org
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim