Iridium(III)-catalyzed direct C-7 amination of indolines with organic azides

Article abstract of DOI:10.1021/jo5018475

Iridium-catalyzed regioselective C-7 amination of indolines has been achieved with organic azides as a facile nitrogen source. The developed procedure is convenient to perform even at room temperature and applicable to a wide range of substrates with high catalytic activity. Various types of organic azides (sulfonyl, aryl, and alkyl derivatives) were all successfully reacted under the present conditions as the viable reactant. Furthermore, indoline substrates bearing easily removable N-protecting groups such as N-Boc or N-Cbz could readily be employed, highlighting the synthetic utility of this methodology. (Chemical equation presented).

Full text of DOI:10.1021/jo5018475

Note
pubs.acs.org/joc
Iridium(III)-Catalyzed Direct C‑7 Amination of Indolines with Organic
Azides
Kwangmin Shin†,‡ and Sukbok Chang*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejon 307-701, Republic of Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejon 307-701, Republic of Korea
S
* Supporting Information
ABSTRACT: Iridium-catalyzed regioselective C-7 amination
of indolines has been achieved with organic azides as a facile
nitrogen source. The developed procedure is convenient to
perform even at room temperature and applicable to a wide
range of substrates with high catalytic activity. Various types of
organic azides (sulfonyl, aryl, and alkyl derivatives) were all successfully reacted under the present conditions as the viable
reactant. Furthermore, indoline substrates bearing easily removable N-protecting groups such as N-Boc or N-Cbz could readily
be employed, highlighting the synthetic utility of this methodology.
Scheme 1
mong various nitrogen-containing heterocycles, indole
Aand indoline derivatives have been recognized especially as
privileged core structures owing to their ubiquity in numerous
biologically active compounds and natural products.1 In
particular, C7-substituted indole and indoline scaffolds have
received great attention due to their prevalence in important
pharmaceutical agents.2 For this reason, synthetic methods for
the introduction of functional groups at the C-7 position of
indoles or indolines are in high demand. However, the
development of synthetic routes allowing this transformation
has been less explored. Indeed, whereas procedures for the
selective C2- and C3-functionalization of indoles have been
actively investigated,3−5 approaches to access C7-functionalized
indole derivatives are relatively rare, especially with respect to
the transition-metal-catalyzed C−H bond functionalization.6,7
Moreover, while examples of the direct C7-functionalization of
indolines via chelation-assisted C−H activation have been
disclosed,8−11 most of those methods allowed for C−C bond
formation in reaction with alkenes8 or arylating reagents9
(Scheme 1a). Very recently, an elegant example of the Ru-
catalyzed C-7 amidation of indolines using sulfonyl azides has
been reported,11 although this procedure requires a somewhat
elevated temperature with limited scope (Scheme 1b).
scope of azides is highly broad, including sulfonyl, aryl, and
alkyl variants as an efficient amino source; and (3) the present
reaction can be applicable to indolines bearing readily
removable N-protecting groups (e.g., Boc or Cbz), thus
enabling subsequent transformations of the obtained aminated
products.
At the outset of the present investigation, we sought the
optimal amidation conditions in a model reaction of N-
acetylindoline (1a) with p-toluenesulfonyl azide (2a, Table 1).
In a few recent years, our group has been engaged in
developing selective and efficient C−N bond-forming reac-
tions12 leading to the Rh- and Ru-catalyzed direct C(sp2)−H
amination procedures by the use of organic azides working both
as an amino source and as an internal oxidant via N−N2 bond
cleavage.13−15 In addition, we also disclosed an iridium catalyst
system that offers milder amination reaction conditions with
enhanced activity and broader substrate scope.16 In this context,
we report herein a new procedure for the Ir-catalyzed C-7
amination of indolines with a wide range of organic azides
(Scheme 1c). The significance of the present direct C−H
amination route is 3-fold: (1) the reaction proceeds under mild
reaction conditions at room temperature in most cases; (2) the
Special Issue: Mechanisms in Metal-Based Organic Chemistry
Received: August 10, 2014
© XXXX American Chemical Society
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Note
a
Table 1. Optimization of Ir-Catalyzed Amidation
b
entry
catalyst (mol %)
additive (mol %)
AgSbF6 (16)
solvent
yield (%)
1
2
3
4
[IrCp*Cl2]2 (4)
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
toluene
75
AgSbF6 (16)
N.R.
N.R.
N.R.
N.R.
<5
[IrCp*Cl2]2 (4)
[RhCp*Cl2]2 (4)
[RhCp*Cl2]2 (4)
[Ru(p-cymene)Cl2]2 (4)
[IrCp*Cl2]2 (4)
[IrCp*Cl2]2 (4)
[IrCp*Cl2]2 (4)
[IrCp*Cl2]2 (4)
[IrCp*Cl2]2 (2)
[IrCp*Cl2]2 (2)
[IrCp*Cl2]2 (1)
[IrCp*Cl2]2 (2)
[IrCp*Cl2]2 (2)
[IrCp*Cl2]2 (2)
AgSbF6 (16)
c
5
AgSbF6 (16)
6
7
AgSbF6 (16)
AgNTf2 (16)
98
8
AgOAc (16)
N.R.
60
9
AgPF6 (16)
10
11
12
13
14
15
16
AgBF4 (16)
46
AgNTf2 (8)
85
AgNTf2 (8) + NaOAc (30)
AgNTf2 (4) + NaOAc (30)
AgNTf2 (8) + NaOAc (30)
AgNTf2 (8) + NaOAc (30)
AgNTf2 (8) + NaOAc (30)
95
90
90
1,4-Dioxane
92
THF
65
a
b
Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv), catalyst and additive in solvent (0.5 mL) at 25 °C for 6 h. Yield was determined by 1H NMR
c
spectroscopy by using dibromomethane as an internal standard. At 80 °C.
a b c d e
, , , ,
Scheme 2. Scope of Indolines and Sulfonyl Azides
a
Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv), [IrCp*Cl2]2 (2 mol %), AgNTf2 (8 mol %), and NaOAc (30 mol %) in 1,2-dichloroethane (0.5
b
c
d
e
mL) at 25 °C for 6 h. [IrCp*Cl2]2 (4 mol %), AgNTf2 (16 mol %) were used. At 50 °C. At 80 °C. 5 mmol scale (with 5 mmol of 1i).
We were pleased to see that a high yield of the desired product
(3aa) was obtained when [IrCp*Cl2]2 was applied as a catalyst
and AgSbF6 as an additive at ambient temperature (entry 1).
Not surprisingly, the amidated product 3aa was not formed in
the absence of either [IrCp*Cl2]2 or AgSbF6 (entries 2 and 3),
implying that a cationic iridium species is crucial in the current
transformation. It should be noted that the present amidation
did not proceed at all when [RhCp*Cl2]2 catalyst was
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Note
ab c
, ,
Scheme 3. Scope of Indolines and Aryl Azides
a
Reaction conditions: 1 (0.2 mmol), 4 (1.5 equiv), [IrCp*Cl2]2 (2 mol %), AgNTf2 (8 mol %), and NaOAc (30 mol %) in 1,2-dichloroethane (0.5
b
c
mL) at 25 °C for 6 h. [IrCp*Cl2]2 (4 mol %), AgNTf2 (16 mol %) were used. At 50 °C.
a
Scheme 4. Scope of Alkyl Azides
a
Reaction conditions: 1a (0.2 mmol), 6 (1.5 equiv), [IrCp*Cl2]2 (4 mol %), AgNTf2 (16 mol %), and NaOAc (30 mol %) in 1,2-dichloroethane
(0.5 mL) at 50 °C for 12 h.
employed even at elevated temperature 80 °C (entries 4 and 5).
Interestingly, a ruthenium catalyst system was found to be
almost ineffective at 25 °C (entry 6).11 These results clearly
demonstrate the superior catalytic activity of the iridium species
toward the C-7 amidation of indolines when compared to the
rhodium and ruthenium catalyst systems. On the other hand,
among various silver additives screened, AgNTf2 was especially
efficient, leading to an almost quantitative product yield (entry
7), whereas others were inferior (entries 8−10). In addition,
loading of the iridium catalyst precursor could be reduced
down to 1 mol % without much affecting the reaction efficiency
when sodium acetate (30 mol %) was added as a coadditive
(entries 11−13).17 The use of solvents other than 1,2-
dichloroethane resulted in decreased product yields (entries
14−16).
irrespective of electronic variation at the arene part of indolines
(3aa−3da).19 N-Acetylindolines possessing halogen substitu-
ents at the C-5 position (1e−1f) were well-tolerated to afford
the desired products 3ea and 3fa, respectively, in excellent
yields, thus allowing for the possibility of further trans-
formations. Substitution at the C-2 or C-3 position of the
indoline did not hamper the reaction efficiency (3ga−3ha). In
addition, we were pleased to observe that synthetically versatile
groups such as N-Boc-,20 Cbz-, and carbamoyl-protected
indolines (1i−1k) underwent the current amidation to afford
3ia−3ka in good yields, albeit at slightly higher reaction
temperatures. It is also worth mentioning that the present
reaction could be performed on a gram scale without much
difficulty, as demonstrated in the production of 3ia. In regard to
the scope of sulfonyl azides, it was observed that arenesulfonyl
azides bearing electron-donating, electron-withdrawing, or
halogen functional groups readily participated in the amidation
with excellent efficiency (3ab−3ae). Moreover, additional
derivatives, such as naphthyl, benzyl, and aliphatic sulfonyl
Having established the optimized conditions for the C-7
amidation of indolines, we set out to explore the scope of this
transformation in reactions of substituted indolines with
sulfonyl azides (Scheme 2).18 The amidation proceeded
smoothly to give the corresponding amidated products
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Note
azides, underwent the amidation also in almost quantitative
yields (3af−3ah).
Scheme 5. Isolation of an Iridacycle (9) and Its Amidation
Reaction
During the course of our studies, it was found that a series of
aryl azides reacted readily with indolines under the present
reaction conditions to yield the desired C-7 aminated indolines
(Scheme 3).18 It should be noted that the use of aryl azides as a
nitrogen source in the Ir(III)-catalyzed C−N bond formation
was of limited success in our previous studies: indeed 3,5-
bis(trifluoromethyl)phenyl azide (4b) was the only viable
reactant in the Ir(III)-catalyzed C−N bond formation of
benzamides.16b In the current study, however, 4-(trifluoro-
methyl)phenyl azide (4a) also readily participated in the
amination reaction with substituted indolines (5aa−5ea).
Moreover, a range of phenyl azides bearing electron-with-
drawing groups underwent the desired amination in excellent
yields (5ab−5ae). A phenyl azide substituted with a bromo
group at the para position smoothly reacted under the
developed conditions (5af). However, amination with a phenyl
azide substituted with an electron-neutral alkyl group was
rather sluggish to give the desired product in a moderate yield
(5ag).
Generality of the current C−H amination method was
further investigated by examining the scope of alkyl azides. To
our delight, alkyl azides including a benzyl derivative were
found to be an efficient amino source for the present
transformation, although slightly more forcing conditions
were applied when compared to sulfonyl and aryl azides
(Scheme 4).18 Benzyl azide was facile in this amination, leading
to the desired product in good yield (7aa). An array of
phenethyl azides reacted with indoline 1a to provide the
aminated products in moderate to good yields (7ab−7ae). In
addition, more hydrophobic derivatives, such as 3-phenyl-
propyl, 4-phenylbutyl, and n-hexyl azides, were also aminated,
albeit in slightly lower product yields (7af−7ah).
One of the major concerns in the application of the
chelation-assisted C−H activation approaches lies in the facile
removal of the initially installed directing groups after the
targeted C−H functionalizations.21 To address this issue in the
present amination protocol, we were able to prove the
feasibility of readily removable N-substituents of indoline
substrates, as shown in Scheme 2. In fact, not only N-acetyl but
also N-Boc and N-Cbz groups were successfully employed to
guide the regioselective C-7 amination. As a proof of the
concept of facile removal of chelating groups, N-directing
groups in the aminated products were examined to be
deprotected (eq 1). As anticipated, the deprotection processes
were highly smooth under the conventional conditions to
furnish C-7 amidated indoline compound 8 in high yields.
amidated product 3aa in high yield, thus indicating the
intermediacy of a cyclometalated iridacyclic intermediate in
the catalytic cycle.
In summary, we have developed an iridium-catalyzed direct
C−H amination of indolines exclusively at the C-7 position
using diverse organic azides as an amino source. A broad range
of N-substituted indolines were regioselectively aminated under
the present amination procedure even at room temperature in
high efficiency. In addition, the nitrogen source for the reaction
was not limited to sulfonyl azides: aryl and alkyl azides also
participated in the amination reaction as an amino source.
Synthetic utility of the current approach was highlighted by the
use of Boc- and Cbz-protecting groups as a directing group,
thus allowing for the facile removal of those chelating groups
after the targeted amination. We believe that the above features
of the present method will offer a practical route to the
synthesis of pharmaceutically relevant C7-aminated indoline
derivatives.
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise stated, all commercial
reagents and solvents were used without additional purification.
Analytical thin-layer chromatography (TLC) was performed on
precoated silica gel 60 F254 plates. Visualization on TLC was achieved
by the use of UV light (254 nm). Column chromatography was
undertaken on silica gel (400−630 mesh) using a proper eluent
system. The NMR data were recorded with 0.1 Hz resolution.
Chemical shifts were quoted in parts per million (ppm) referenced to
the appropriate solvent peak or 0.0 ppm for tetramethylsilane. The
following abbreviations were used to describe peak splitting patterns
when appropriate: br (broad), s (singlet), d (doublet), t (triplet), q
(quartet), dd (doublet of doublet), td (triplet of doublet), ddd
(doublet of doublet of doublet), m (multiplet). Coupling constants, J,
were reported in hertz unit (Hz). 13C{1H} NMR was fully decoupled
by broad band proton decoupling. Chemical shifts were reported in
ppm referenced to the center of a triplet at 77.0 ppm of chloroform-d.
Infrared (IR) spectra were recorded on an FT-IR spectrometer using a
diamond ATR module. Frequencies are given in reciprocal centimeters
(cm−1), and only selected absorbance is reported. High-resolution
mass spectra were obtained by using the EI method (analyzer type:
Magnetic Sector − Electric Sector, MS/MS) or by using the ESI
method (analyzer type: Quadrupole − TOF, MS/MS). Unless
otherwise stated, all commercial reagents and solvents were used
without additional purification.
To understand the mechanistic aspects of the present
amination reaction, a plausible iridacyclic intermediate was
isolated and subjected to the amidation conditions (Scheme 5).
When N-acetylindoline (1a) was treated with a dimeric iridium
complex in the presence of AgOTFA and Li2CO3, a labile
iridacycle (9) was isolated, albeit in low yield.16e Whereas a
single-crystal structure of 9 could not be obtained, it was clearly
characterized by NMR and mass spectroscopy. A subsequent
stoichiometric reaction of 9 with sulfonyl azide 2a afforded the
Preparation of Substrates. N-Acetylindolines 1,9d N-Boc-indo-
line 1i,22 N-CBz-indoline 1j,23 N,N-diethylcarbamoylindoline 1k,8b
and organic azides 2,13a 4,13b and 613c were prepared according to the
previously reported procedures.
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General Procedure for the C-7 Amination of Indolines with
Sulfonyl and Aryl Azides. To a screw-capped vial with a spinvane
triangular-shaped Teflon stir bar were added N-protected indoline (1,
0.2 mmol), sulfonyl or aryl azide (2 or 4, 0.3 mmol), [IrCp*Cl2]2 (3.2
mg, 0.004 mmol, 2 mol %), AgNTf2 (6.2 mg, 0.016 mmol, 8 mol %),
NaOAc (4.9 mg, 0.06 mmol, 30 mol %), and 1,2-dichloroethane (0.5
mL) under atmospheric conditions. The reaction mixture was stirred
at 25 °C for 6 h, filtered through a pad of Celite, and then washed with
dichloromethane (10 mL × 3). Organic solvents were removed under
reduced pressure, and the residue was purified by chromatography on
silica gel (n-hexane/EtOAc) to give the desired product 3 or 5.
N-(1-Acetyl-5-methylindolin-7-yl)-4-methylbenzenesulfonamide
(dd, J = 7.4, 1.5 Hz, 1H), 3.04 (t, J = 7.9 Hz, 2H), 2.67 (t, J = 7.9 Hz,
2H), 1.66 (s, 3H); 13C{1H} NMR (150 MHz, CD2Cl2) δ 169.1, 135.7,
135.4, 135.1, 133.9, 133.8, 129.4, 128.6, 128.2, 127.6, 126.6, 126.3,
126.2, 125.6, 124.7, 124.1, 122.6, 50.6, 28.3, 23.5; IR (diamond) 2962,
2855, 1625, 1581, 1460, 1421, 1243, 1165, 1118, 1088, 1005, 806
cm−1; HRMS (EI) m/z calcd. for C20H18N2O3S [M]+: 366.1038,
found: 366.1039; Rf (n-hexane/EtOAc, 1:1): 0.17.
N-(1-Acetylindolin-7-yl)-1-phenylmethanesulfonamide (3ag).
White solid (63.4 mg, 96%); mp 137−138 °C; 1H NMR (600
MHz, CDCl3) δ 10.14 (s, 1H), 7.37 (dd, J = 8.1, 1.3 Hz, 1H), 7.32−
7.28 (m, 3H), 7.23−7.22 (m, 2H), 7.08 (dd, J = 8.1, 8.1 Hz, 1H), 6.99
(dd, J = 8.1, 1.3 Hz, 1H), 4.21 (s, 2H), 3.98 (t, J = 8.0 Hz, 2H), 3.07 (t,
J = 8.0 Hz, 2H), 2.09 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
169.6, 135.3, 133.2, 130.5, 129.1, 128.4, 127.0, 126.7, 121.2, 121.2,
57.9, 51.3, 28.7, 24.4; IR (diamond) 2954, 2923, 1625, 1582, 1424,
1327, 1149, 1120, 1012, 916, 888, 764 cm−1; HRMS (EI) m/z calcd.
for C17H18N2O3S [M]+: 330.1038, found: 330.1039; Rf (n-hexane/
EtOAc, 1:1): 0.18.
1
(3ba). White solid (64.1 mg, 93%); mp 175−176 °C; H NMR (600
MHz, CDCl3) δ 9.85 (s, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2
Hz, 2H), 7.11 (d, J = 1.1 Hz, 1H), 6.83 (d, J = 1.1 Hz, 1H), 3.57 (t, J =
7.8 Hz, 2H), 2.90 (t, J = 7.8 Hz, 2H), 2.37 (s, 3H), 2.30 (s, 3H), 2.03
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.5, 142.9, 137.4,
136.7, 134.8, 133.1, 129.0, 127.0, 126.0, 125.9, 123.3, 51.2, 28.6, 23.9,
21.4, 20.9; IR (diamond) 2917, 2882, 1632, 1589, 1478, 1417, 1383,
1165, 1134, 1091, 949, 860 cm−1; HRMS (EI) m/z calcd. for
C18H20N2O3S [M]+: 344.1195, found: 344.1192; Rf (n-hexane/EtOAc,
1:1): 0.28.
N-(1-Acetyl-5-methoxyindolin-7-yl)-4-methylbenzenesulfon-
amide (3ca). White solid (67.0 mg, 93%); mp 169−170 °C; 1H NMR
(600 MHz, CDCl3) δ 10.18 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.17 (d,
J = 8.2 Hz, 2H), 6.85 (d, J = 2.5 Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H),
3.76 (s, 3H), 3.63 (t, J = 7.8 Hz, 2H), 2.91 (t, J = 7.8 Hz, 2H), 2.37 (s,
3H), 2.07 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.3, 158.3,
143.1, 137.3, 136.1, 129.0, 128.4, 127.2, 127.0, 108.8, 108.8, 55.7, 51.3,
28.9, 23.8, 21.4; IR (diamond) 2926, 2843, 1628, 1592, 1458, 1337,
1322, 1285, 1218, 1164, 1040, 807 cm−1; HRMS (EI) m/z calcd. for
C18H20N2O4S [M]+: 360.1144, found: 360.1143; Rf (n-hexane/EtOAc,
1:1): 0.13.
N-(1-Acetylindolin-7-yl)methanesulfonamide (3ah). White solid
1
(48.8 mg, 96%); mp 110−111 °C; H NMR (600 MHz, CDCl3) δ
10.09 (s, 1H), 7.38 (dd, J = 7.9, 1.1 Hz, 1H), 7.14 (dd, J = 7.9, 7.9 Hz,
1H), 7.04 (dd, J = 7.9, 1.1 Hz, 1H), 4.12 (t, J = 8.0 Hz, 2H), 3.14 (t, J
= 8.0 Hz, 2H), 2.92 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 169.9, 135.4, 133.7, 127.2, 126.9, 121.9, 121.4, 51.4, 39.9,
28.8, 24.5; IR (diamond) 3016, 2924, 1629, 1584, 1462, 1377, 1308,
1149, 1012, 967, 811, 787 cm−1; HRMS (EI) m/z calcd. for
C11H14N2O3S [M]+: 254.0725, found: 254.0721; Rf (n-hexane/
EtOAc, 1:2): 0.25.
1-[7-{4-(Trifluoromethyl)phenylamino}indolin-1-yl]ethanone
(5aa). Light yellow solid (57.7 mg, 90%); mp 102−103 °C; 1H NMR
(600 MHz, CDCl3) δ 8.33 (s, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.27 (d, J
= 7.9 Hz, 1H), 7.09 (dd, J = 7.9, 7.9 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H),
6.87 (d, J = 7.9 Hz, 1H), 4.08 (t, J = 7.7 Hz, 2H), 3.09 (t, J = 7.7 Hz,
2H), 2.31 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.1, 146.8,
135.9, 132.9, 132.3, 127.5, 126.5, 126.5, 126.5, 126.5, 126.4, 125.7,
123.9, 122.1, 121.2, 121.0, 120.7, 120.5, 118.8, 118.1, 115.3, 51.6, 29.4,
24.2; IR (diamond) 3208, 2924, 1642, 1616, 1527, 1396, 1318, 1242,
1157, 1099, 1062, 834 cm−1; HRMS (EI) m/z calcd. for C17H15F3N2O
[M]+: 320.1136, found: 320.1133; Rf (n-hexane/EtOAc, 2:1): 0.48.
1-[5-Methyl-7-{4-(trifluoromethyl)phenylamino}indolin-1-yl]-
ethanone (5ba). Light brown solid (62.9 mg, 94%); mp 111−112 °C;
1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H),
7.08 (s, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.68 (s, 1H), 4.06 (t, J = 8.1 Hz,
2H), 3.04 (t, J = 8.1 Hz, 2H), 2.29 (s, 3H), 2.28 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 168.8, 146.9, 136.5, 136.0, 136.0, 131.8,
130.6, 127.5, 126.5, 126.5, 126.5, 126.4, 125.7, 123.9, 122.1, 121.0,
120.8, 120.6, 120.4, 119.0, 118.9, 115.3, 51.6, 29.3, 24.1, 21.1; IR
(diamond) 2923, 2855, 1643, 1590, 1531, 1418, 1396, 1313, 1239,
1161, 1114, 826 cm−1; HRMS (EI) m/z calcd. for C18H17F3N2O [M]+:
334.1293, found: 334.1291; Rf (n-hexane/EtOAc, 2:1): 0.50.
tert-Butyl 7-(4-Methylphenylsulfonamido)indoline-1-carboxylate
1
(3ia). White solid (51.3 mg, 66%); mp 145−146 °C; H NMR (600
MHz, CDCl3) δ 9.83 (s, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.34 (dd, J =
7.5, 1.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.03 (dd, J = 7.5, 7.5 Hz,
1H), 6.98 (dd, J = 7.5, 1.3 Hz, 1H), 3.56 (t, J = 8.2 Hz, 2H), 2.86 (t, J
= 8.2 Hz, 2H), 2.37 (s, 3H), 1.53 (s, 9H); 13C{1H} NMR (150 MHz,
CDCl3) δ 153.7, 142.8, 137.4, 135.4, 134.3, 129.0, 126.9, 125.9, 125.1,
125.0, 122.5, 82.4, 49.7, 28.3, 28.2, 21.4; IR (diamond) 2985, 2933,
1659, 1467, 1391, 1329, 1308, 1250, 1153, 1132, 1090, 789 cm−1;
HRMS (EI) m/z calcd. for C20H24N2O4S [M]+: 388.1457, found:
388.1454; Rf (n-hexane/EtOAc, 5:1): 0.22.
Benzyl 7-(4-Methylphenylsulfonamido)indoline-1-carboxylate
1
(3ja). White solid (59.1 mg, 70%); mp 110−111 °C; H NMR (600
MHz, CDCl3) δ 9.67 (s, 1H), 7.45−7.38 (m, 5H), 7.35−7.32 (m, 3H),
7.06−7.03 (m, 1H), 6.99−6.97 (m, 3H), 5.19 (s, 2H), 3.62 (t, J = 8.2
Hz, 2H), 2.87 (t, J = 8.2 Hz, 2H), 2.29 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 154.0, 142.9, 137.1, 135.6, 135.0, 134.3, 129.0, 128.7,
128.7, 128.6, 126.9, 126.0, 125.5, 125.1, 122.6, 68.3, 49.5, 28.3, 21.4; IR
(diamond) 3039, 2956, 1676, 1595, 1446, 1323, 1256, 1241, 1165,
1155, 1024, 823 cm−1; HRMS (EI) m/z calcd. for C23H22N2O4S [M]+:
422.1300, found: 422.1298; Rf (n-hexane/EtOAc, 3:1): 0.30.
1-[5-Methoxy-7-{4-(trifluoromethyl)phenylamino}indolin-1-yl]-
1
ethanone (5ca). Brown solid (64.5 mg, 92%); mp 118−119 °C; H
NMR (600 MHz, CDCl3) δ 8.59 (s, 1H), 7.43 (d, J = 8.3 Hz, 2H),
7.09 (d, J = 8.3 Hz, 2H), 6.79 (s, 1H), 6.44 (s, 1H), 4.07 (t, J = 7.7 Hz,
2H), 3.74 (s, 3H), 3.06 (t, J = 7.7 Hz, 2H), 2.30 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 168.4, 158.7, 146.4, 137.1, 133.0, 127.4,
126.5, 126.5, 126.5, 126.4, 126.3, 125.6, 123.8, 122.0, 121.4, 121.2,
121.0, 120.8, 115.8, 104.1, 103.0, 55.6, 51.7, 29.7, 24.0; IR (diamond)
3005, 2951, 1636, 1593, 1317, 1260, 1147, 1101, 1063, 940, 925, 818
cm−1; HRMS (EI) m/z calcd. for C18H17F3N2O2 [M]+: 350.1242,
found: 350.1239; Rf (n-hexane/EtOAc, 2:1): 0.38.
N,N-Diethyl-7-(4-methylphenylsulfonamido)indoline-1-carbox-
amide (3ka). White solid (53.5 mg, 69%); mp 118−119 °C; 1H NMR
(600 MHz, CDCl3) δ 8.02 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.24 (dd,
J = 7.7, 1.5 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.02−6.97 (m, 2H), 3.71
(t, J = 8.2 Hz, 2H), 3.09−3.03 (m, 6H), 2.36 (s, 3H), 1.17 (t, J = 7.1
Hz, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 160.5, 142.8, 138.4,
138.1, 133.4, 129.2, 126.7, 125.5, 124.8, 124.2, 122.4, 52.5, 41.6, 30.0,
21.4, 13.1; IR (diamond) 2971, 2874, 1617, 1584, 1460, 1353, 1317,
1195, 1156, 1091, 1051, 788 cm−1; HRMS (EI) m/z calcd. for
C20H25N3O 3S [M]+: 387.1617, found: 387.1615; Rf (n-hexane/
EtOAc, 2:1): 0.19.
N-(1-Acetylindolin-7-yl)naphthalene-1-sulfonamide (3af). Gray
solid (66.7 mg, 91%); mp 183−184 °C; 1H NMR (600 MHz,
CD2Cl2) δ 9.90 (bs, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.2 Hz,
1H), 7.90 (m, 2H), 7.54 (ddd, J = 8.2, 6.9, 1.4 Hz, 1H), 7.49 (ddd, J =
8.2, 6.9, 1.4 Hz, 1H), 7.37−7.33 (m, 2H), 7.12−7.10 (m, 1H), 6.96
1-[5-Nitro-7-{4-(trifluoromethyl)phenylamino}indolin-1-yl]-
1
ethanone (5da). Yellow solid (67.2 mg, 92%); mp 133−134 °C; H
NMR (600 MHz, CDCl3) δ 8.43 (s, 1H), 8.14 (d, J = 1.4 Hz, 1H),
7.64 (d, J = 1.4 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.3 Hz,
2H), 4.23 (t, J = 8.0 Hz, 2H), 3.20 (t, J = 8.0 Hz, 2H), 2.38 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 170.2, 146.2, 145.2, 137.3, 137.1,
133.0, 127.2, 126.9, 126.8, 126.8, 126.8, 125.4, 123.6, 123.1, 122.9,
122.7, 122.5, 121.8, 116.9, 112.9, 112.3, 51.9, 28.9, 24.4; IR (diamond)
3204, 2924, 1651, 1604, 1579, 1516, 1406, 1311, 1250, 1180, 1111,
E
dx.doi.org/10.1021/jo5018475 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1064 cm−1; HRMS (EI) m/z calcd. for C17H14F3N3O3 [M]+:
365.0987, found: 365.0985; Rf (n-hexane/EtOAc, 2:1): 0.33.
1-[5-Bromo-7-{4-(trifluoromethyl)phenylamino}indolin-1-yl]-
ethanone (5ea). Light brown solid (48.7 mg, 61%); mp 114−115 °C;
1H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H),
7.38 (d, J = 1.6 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 1.6 Hz,
1H), 4.10 (t, J = 7.8 Hz, 2H), 3.08 (t, J = 7.8 Hz, 2H), 2.32 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 169.3, 145.8, 137.7, 133.7, 131.7,
127.3, 126.7, 126.7, 126.6, 126.6, 125.5, 123.7, 122.3, 122.0, 121.9,
121.8, 121.6, 120.5, 120.4, 119.2, 116.3, 51.6, 29.2, 24.2; IR (diamond)
3237, 2923, 1645, 1616, 1584, 1522, 1186, 1146, 1102, 1065, 941, 869
cm−1; HRMS (EI) m/z calcd. for C17H14BrF3N2O [M]+: 398.0242,
found: 398.0239; Rf (n-hexane/EtOAc, 2:1): 0.40.
4.08 (t, J = 7.7 Hz, 2H), 3.07 (t, J = 7.7 Hz, 2H), 2.31 (s, 3H), 1.30 (s,
9H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.7, 143.4, 140.6, 135.5,
134.9, 131.4, 126.3, 126.0, 117.9, 116.7, 115.8, 51.6, 34.1, 31.5, 29.5,
24.2; IR (diamond) 3225, 2958, 1644, 1592, 1515, 1438, 1411, 1310,
1240, 1189, 1112, 825 cm−1; HRMS (EI) m/z calcd. for C20H24N2O
[M]+: 308.1889, found: 308.1886; Rf (n-hexane/EtOAc, 2:1): 0.46.
Analytic data of C-7 amidated indoline products [3aa, 3da−3ha,
3ab−3ae] have been already reported.11
General Procedure for the C-7 Amination of N-Acetylindo-
line with Alkyl Azides. To a screw-capped vial with a spinvane
triangular-shaped Teflon stir bar were added N-acetylindoline (1a,
32.2 mg, 0.2 mmol), alkyl azide (6, 0.3 mmol), [IrCp*Cl2]2 (6.4 mg,
0.008 mmol, 4 mol %), AgNTf2 (12.4 mg, 0.032 mmol, 16 mol %),
NaOAc (4.9 mg, 0.06 mmol, 30 mol %), and 1,2-dichloroethane (0.5
mL) under atmospheric conditions. The reaction mixture was stirred
in a preheated heating block at 50 °C for 12 h, filtered through a pad
of Celite, and then washed with dichloromethane (10 mL × 3).
Organic solvents were removed under reduced pressure, and the
residue was purified by chromatography on silica gel (n-hexane/EtOAc
or CH2Cl2/acetone) to give the desired product 7.
1-[7-{3,5-Bis(trifluoromethyl)phenylamino}indolin-1-yl]ethanone
1
(5ab). Beige solid (71.4 mg, 92%); mp 143−144 °C; H NMR (600
MHz, CDCl3) δ 8.57 (s, 1H), 7.37 (s, 2H), 7.24−7.22 (m, 2H), 7.14
(dd, J = 7.2, 7.2 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 4.12 (t, J = 7.8 Hz,
2H), 3.13 (t, J = 7.8 Hz, 2H), 2.34 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 169.3, 145.2, 136.2, 133.0, 132.8, 132.5, 132.3, 132.1, 131.5,
126.7, 126.2, 124.4, 122.6, 120.8, 118.8, 118.5, 115.2, 115.2, 115.1,
112.1, 112.1, 112.1, 112.1, 112.0, 51.6, 29.3, 24.2; IR (diamond) 3243,
2977, 1640, 1599, 1417, 1274, 1169, 1123, 1109, 1011, 921, 762 cm−1;
HRMS (EI) m/z calcd. for C18H14F6N2O [M]+: 388.1010, found:
388.1011; Rf (n-hexane/EtOAc, 5:1): 0.16.
1-[7-{3,5-Bis(trifluoromethyl)benzylamino}indolin-1-yl]ethanone
1
(7aa). White solid (51.5 mg, 64%); mp 144−145 °C; H NMR (600
MHz, CDCl3) δ 7.86 (s, 2H), 7.75 (s, 1H), 6.96 (dd, J = 7.9, 7.9 Hz,
1H), 6.85 (s, 1H), 6.63 (d, J = 7.9 Hz, 1H), 6.37 (d, J = 7.9 Hz, 1H),
4.52 (s, 2H), 4.08 (t, J = 7.8 Hz, 2H), 3.06 (t, J = 7.8 Hz, 2H), 2.33 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.3, 142.9, 138.2, 135.1,
132.0, 131.8, 131.6, 131.3, 129.3, 127.3, 127.3, 127.3, 127.2, 126.9,
126.1, 124.3, 122.5, 121.0, 121.0, 120.9, 120.9, 120.9, 120.7, 113.9,
111.4, 51.5, 47.0, 29.4, 24.4; IR (diamond) 3280, 3261, 1638, 1600,
1516, 1449, 1430, 1275, 1183, 1120, 873, 844 cm−1; HRMS (EI) m/z
calcd. for C19H16F6N2O [M]+: 402.1167, found: 402.1165; Rf (n-
hexane/EtOAc, 3:1): 0.29.
1-[7-(4-Nitrophenylamino)indolin-1-yl]ethanone (5ac). Yellow
solid (50.5 mg, 85%); mp 226−227 °C; 1H NMR (600 MHz,
CDCl3) δ 8.89 (s, 1H), 8.06 (d, J = 9.2 Hz, 2H), 7.29 (d, J = 7.9 Hz,
1H), 7.16 (dd, J = 7.9, 7.9 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.94 (d, J
= 9.2 Hz, 2H), 4.14 (t, J = 7.8 Hz, 2H), 3.15 (t, J = 7.8 Hz, 2H), 2.35
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.4, 150.0, 139.2,
136.2, 133.7, 130.5, 126.5, 126.2, 120.3, 119.7, 113.7, 51.6, 29.3, 24.3;
IR (diamond) 3176, 3121, 1633, 1583, 1476, 1301, 1241, 1103, 925,
839, 765, 747 cm−1; HRMS (EI) m/z calcd. for C16H15N3O3 [M]+:
297.1113, found: 297.1110; Rf (n-hexane/EtOAc, 1:1): 0.38.
1-[7-(Phenethylamino)indolin-1-yl]ethanone (7ab). Yellow oil
(27.5 mg, 49%); 1H NMR (600 MHz, CDCl3) δ 7.32−7.20 (m,
5H), 7.05−7.03 (m, 1H), 6.61−6.59 (m, 2H), 6.16 (s, 1H), 4.02 (t, J =
7.7 Hz, 2H), 3.38 (t, J = 7.9 Hz, 2H), 3.03−2.98 (m, 4H), 2.30 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.9, 139.9, 139.3, 134.9,
128.9, 128.7, 128.4, 126.9, 126.2, 113.0, 111.1, 51.6, 45.6, 36.0, 29.6,
24.4; IR (diamond) 3230, 3026, 2928, 1638, 1603, 1473, 1445, 1432,
1357, 1323, 1245, 1182 cm−1; HRMS (EI) m/z calcd. for C18H20N2O
[M]+: 280.1576, found: 280.1575; Rf (n-hexane/EtOAc, 3:1): 0.22.
1-[7-{4-(Trifluoromethyl)phenethylamino}indolin-1-yl]ethanone
1-[7-{4-(Methoxycarbonyl)phenylamino}indolin-1-yl]ethanone
1
(5ad). White solid (60.2 mg, 97%); mp 146−147 °C; H NMR (600
MHz, CDCl3) δ 8.44 (s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.30 (dd, J =
8.1, 1.4 Hz, 1H), 7.10 (dd, J = 8.1, 8.1 Hz, 1H), 6.98 (d, J = 8.7 Hz,
2H), 6.88 (dd, J = 8.1, 1.4 Hz, 1H), 4.09 (t, J = 7.7 Hz, 2H), 3.85 (s,
3H), 3.09 (t, J = 7.7 Hz, 2H), 2.32 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 169.1, 167.1, 148.1, 135.9, 133.0, 131.9, 131.3, 126.4, 120.4,
119.3, 118.3, 114.6, 51.6, 51.6, 29.4, 24.3; IR (diamond) 3004, 2942,
1711, 1642, 1585, 1519, 1433, 1306, 1274, 1170, 1105, 786 cm−1;
HRMS (EI) m/z calcd. for C18H18N2O3 [M]+: 310.1317, found:
310.1314; Rf (n-hexane/EtOAc, 2:1): 0.27.
1
(7ac). Beige solid (43.9 mg, 63%); mp 99−100 °C; H NMR (600
MHz, CDCl3) δ 7.55 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H),
7.04 (dd, J = 7.8, 7.8 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 7.8
Hz, 1H), 6.22 (s, 1H), 4.02 (t, J = 7.7 Hz, 2H), 3.40 (t, J = 7.7 Hz,
2H), 3.06−3.01 (m, 4H), 2.30 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 167.9, 144.1, 139.0, 135.0, 129.1, 129.0, 128.8, 128.6, 128.4,
128.2, 127.1, 126.9, 125.3, 125.3, 125.3, 125.3, 123.5, 121.7, 113.2,
111.1, 51.5, 45.0, 35.7, 29.5, 24.3; IR (diamond) 3192, 2930, 2855,
1642, 1604, 1408, 1322, 1159, 1111, 1065, 1039, 844 cm−1; HRMS
(EI) m/z calcd. for C19H19F3N2O [M]+: 348.1449, found: 348.1448; Rf
(n-hexane/EtOAc, 2:1): 0.22.
1-[7-{4-(Methylsulfonyl)phenylamino}indolin-1-yl]ethanone
1
(5ae). Beige solid (56.8 mg, 86%); mp 186−187 °C; H NMR (600
MHz, CDCl3) δ 8.62 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 7.5
Hz, 1H), 7.13 (dd, J = 7.5, 7.5 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.94
(d, J = 7.5 Hz, 1H), 4.12 (t, J = 7.7 Hz, 2H), 3.13 (t, J = 7.7 Hz, 2H),
3.00 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.3,
148.8, 136.1, 133.4, 131.0, 129.2, 126.4, 119.7, 119.1, 114.6, 51.6, 44.9,
29.3, 24.3; IR (diamond) 3017, 2923, 1646, 1585, 1437, 1393, 1286,
1134, 1088, 956, 827, 765 cm−1; HRMS (EI) m/z calcd. for
C17H18N2O3S [M]+: 330.1038, found: 330.1037; Rf (n-hexane/
EtOAc, 1:1): 0.15.
1-[7-(4-Nitrophenethylamino)indolin-1-yl]ethanone (7ad). Yel-
1
low solid (44.9 mg, 69%); mp 117−118 °C; H NMR (600 MHz,
CDCl3) δ 8.15 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.05 (dd,
J = 7.9, 7.9 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 7.9 Hz, 1H),
6.25 (s, 1H), 4.03 (t, J = 7.8 Hz, 2H), 3.43 (td, J = 7.4, 5.0 Hz, 2H),
3.09 (t, J = 7.4 Hz, 2H), 3.04 (t, J = 7.8 Hz, 2H), 2.30 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 168.0, 147.8, 146.6, 138.9, 135.0,
129.6, 129.0, 126.9, 123.6, 113.4, 111.0, 51.6, 44.6, 35.7, 29.5, 24.4; IR
(diamond) 3184, 2927, 2846, 1629, 1601, 1510, 1401, 1339, 1182,
1127, 1106, 830 cm−1; HRMS (EI) m/z calcd. for C18H19N3O3 [M]+:
325.1426, found: 325.1425; Rf (CH2Cl2/acetone, 100:1): 0.72.
1-[7-(4-Methoxyphenethylamino)indolin-1-yl]ethanone (7ae).
1-[7-(4-Bromophenylamino)indolin-1-yl]ethanone (5af). Brown
solid (33.1 mg, 50%); mp 92−93 °C; 1H NMR (600 MHz, CDCl3) δ
8.04 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.18 (dd, J = 7.9, 1.3 Hz, 1H),
7.04 (dd, J = 7.9, 7.9 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (dd, J =
7.9, 1.3 Hz, 1H), 4.08 (t, J = 7.7 Hz, 2H), 3.08 (t, J = 7.7 Hz, 2H), 2.32
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.9, 142.6, 135.7,
133.6, 132.0, 132.0, 126.4, 119.0, 117.2, 116.9, 111.8, 51.6, 29.4, 24.3;
IR (diamond) 3188, 2925, 1641, 1583, 1473, 1444, 1409, 1303, 1177,
1071, 971, 815 cm−1; HRMS (EI) m/z calcd. for C16H15BrN2O [M]+:
330.0368, found: 330.0367; Rf (n-hexane/EtOAc, 3:1): 0.35.
1-[7-(4-tert-Butylphenylamino)indolin-1-yl]ethanone (5ag).
White solid (23.4 mg, 38%); mp 131−132 °C; 1H NMR (600
MHz, CDCl3) δ 7.87 (s, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.21 (dd, J =
8.0, 1.2 Hz, 1H), 7.02−6.99 (m, 3H), 6.74 (dd, J = 8.0, 1.2 Hz, 1H),
1
Yellow oil (26.7 mg, 43%); H NMR (600 MHz, CDCl3) δ 7.19 (d,
J = 8.4 Hz, 2H), 7.03 (m, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.60 (m, 2H),
6.14 (s, 1H), 4.02 (t, J = 7.7 Hz, 2H), 3.78 (s, 3H), 3.34 (t, J = 7.9 Hz,
2H), 3.02 (t, J = 7.7 Hz, 2H), 2.95−2.92 (m, 2H), 2.30 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 167.8, 158.1, 139.3, 134.8, 132.0,
F
dx.doi.org/10.1021/jo5018475 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
129.6, 128.9, 126.8, 113.9, 112.9, 111.1, 55.2, 51.5, 45.8, 35.1, 29.6,
24.3; IR (diamond) 3232, 2930, 2834, 1638, 1605, 1510, 1471, 1444,
1432, 1245, 1178, 1126 cm−1; HRMS (EI) m/z calcd. for C19H22N2O2
[M]+: 310.1681, found: 310.1678; Rf (CH2Cl2/acetone, 100:1): 0.78.
1-[7-(3-Phenylpropylamino)indolin-1-yl]ethanone (7af). White
solid (24.1 mg, 41%); mp 112−113 °C; 1H NMR (600 MHz,
CDCl3) δ 7.28−7.16 (m, 5H), 7.02 (dd, J = 7.9, 7.9 Hz, 1H), 6.58 (d, J
= 7.9 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 6.13 (s, 1H), 4.02 (t, J = 7.7
Hz, 2H), 3.14 (t, J = 7.1 Hz, 2H), 3.02 (t, J = 7.7 Hz, 2H), 2.78 (t, J =
7.1 Hz, 2H), 2.30 (s, 3H), 2.02 (p, J = 7.2 Hz, 2H); 13C{1H} NMR
(150 MHz, CDCl3) δ 167.8, 142.0, 139.5, 134.8, 128.8, 128.5, 128.3,
126.8, 125.7, 112.8, 111.1, 51.6, 43.0, 33.5, 30.9, 29.6, 24.4; IR
(diamond) 3221, 2933, 2918, 2821, 1626, 1601, 1579, 1480, 1431,
1377, 1126, 923 cm−1; HRMS (EI) m/z calcd. for C19H22N2O [M]+:
294.1732, found: 294.1729; Rf (n-hexane/EtOAc, 3:1): 0.33.
trifluoroacetate (165.7 mg, 0.75 mmol) was added, and the reaction
mixture was stirred for an additional 12 h at room temperature, filtered
through a pad of Celite with dichloromethane (30 mL), and
concentrated under reduced pressure. A mixture of n-hexane and
EtOAc (5 mL, n-hexane:EtOAc = 2:1) was added to the crude
product, and the resulting yellow precipitate was collected by careful
filtration and washed with a small amount of n-hexane/EtOAc mixture
(10 mL, n-hexane:EtOAc = 2:1). The precipitate was dried under the
reduced pressure to give the desired product as a yellow solid (9):
1
yellow solid (90.1 mg, 20%); mp 191−192 °C; H NMR (600 MHz,
CDCl3) δ 7.82 (dd, J = 7.4, 1.4 Hz, 1H), 6.89 (dd, J = 7.4 Hz, 1H),
6.81 (dd, J = 7.4, 1.4 Hz, 1H), 3.94 (t, J = 8.2 Hz, 2H), 3.08 (t, J = 8.2
Hz, 2H), 2.27 (s, 3H), 1.59 (s, 15H); 13C{1H} NMR (150 MHz,
CDCl3) δ 164.0, 162.1, 161.8, 161.6, 161.4, 138.8, 138.0, 135.7, 127.2,
125.3, 119.3, 118.4, 116.5, 114.5, 112.6, 85.6, 49.2, 27.7, 23.1, 9.1;
19F{1H} NMR (375 MHz, CDCl3) δ −74.5; IR (diamond) 3048,
2967, 2918, 1704, 1693, 1599, 1555, 1475, 1191, 1132, 1031, 838
1-[7-(4-Phenylbutylamino)indolin-1-yl]ethanone (7ag). Yellow
1
oil (24.1 mg, 39%); H NMR (600 MHz, CDCl3) δ 7.28−7.15 (m,
−
cm−1; HRMS (ESI) m/z calcd. for C22H25F3IrNO3 [M − CF3CO2 ]+:
5H), 7.03 (m, 1H), 6.57 (m, 2H), 6.03 (s, 1H), 4.01 (t, J = 7.7 Hz,
2H), 3.14 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 7.4
Hz, 2H), 2.30 (s, 3H), 1.77 (ddddd, J = 17.1, 14.2, 12.0, 7.1, 3.3 Hz,
4H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.8, 142.4, 139.6, 134.8,
128.8, 128.4, 128.2, 126.8, 125.6, 112.7, 111.0, 51.5, 43.5, 35.7, 29.6,
29.1, 29.0, 24.4; IR (diamond) 3025, 2931, 2856, 1638, 1604, 1585,
1495, 1474, 1445, 1432, 1405, 1126 cm−1; HRMS (EI) m/z calcd. for
C20H24N2O [M]+: 308.1889, found: 308.1886; Rf (n-hexane/EtOAc,
3:1): 0.28.
488.1560, found:488.1563.
Stoichiometric Reaction of Iridacycle 9 with Sulfonyl Azide
2a. To a screw-capped vial with a spinvane triangular-shaped Teflon
stir bar were added the iridacyclic complex (9, 60.1 mg, 0.1 mmol), p-
toluenesulfonyl azide (2a, 22.5 μL, 0.15 mmol), and 1,2-dichloro-
ethane (0.3 mL) under atmospheric conditions. The reaction mixture
was stirred at 25 °C for 12 h and filtered through a pad of Celite with
dichloromethane (10 mL × 3), and organic solvents were removed
under reduced pressure. CH2Cl2 (5 mL) and 5 N HCl (2 mL) were
added to the crude mixture and allowed to stir at room temperature
for 12 h and then neutralized by saturated aqueous NaHCO3 solution
and water. The crude mixture was extracted with CH2Cl2 (10 mL ×
3), dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography with
n-hexane/EtOAc (2:1) as an eluent to give the desired product 3aa.
1-[7-(Hexylamino)indolin-1-yl]ethanone (7ah). White solid (18.2
mg, 35%); mp 64−65 °C; 1H NMR (600 MHz, CDCl3) δ 7.04 (dd, J
= 7.7 Hz, 1H), 6.58 (d, J = 7.7 Hz, 2H), 6.01 (s, 1H), 4.03 (t, J = 7.7
Hz, 2H), 3.11 (t, J = 7.3 Hz, 2H), 3.02 (t, J = 7.7 Hz, 2H), 2.31 (s,
3H), 1.69 (p, J = 7.3 Hz, 2H), 1.44 (p, J = 7.1 Hz, 2H), 1.34−1.31 (m,
4H), 0.89 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
167.8, 139.7, 134.7, 128.8, 126.8, 112.6, 111.1, 51.5, 43.8, 31.7, 29.6,
29.4, 27.1, 24.4, 22.6, 14.0; IR (diamond) 3219, 2953, 2921, 2845,
1630, 1602, 1582, 1435, 1408, 1318, 1247, 1160 cm−1; HRMS (EI) m/
z calcd. for C16H24N2O [M]+: 260.1889, found: 260.1884; Rf (n-
hexane/EtOAc, 3:1): 0.38.
Procedure for N-Boc Deprotection of 3ia. To a solution of the
amidated product 3ia (194.2 mg, 0.5 mmol) in dichloromethane (1.5
mL) was added dropwise trifluoroacetic acid (0.4 mL) at 0 °C under a
N2 atmosphere, and the mixture was allowed to stir for 30 min. After
stirring for 6 h at room temperature, the reaction mixture was
quenched with NaHCO3 (5.0 mL). Water (30 mL) was added, and the
crude mixture was extracted with CH2Cl2 (30 mL × 3), dried over
MgSO4, and evaporated under reduced pressure to afford the desired
deprotected product 8 (122.6 mg, 85%).
Procedure for N-Cbz Deprotection of 3ja. To a solution of the
amidated product 3ja (126.7 mg, 0.3 mmol) in ethanol (1.4 mL) and
dichloromethane (0.6 mL) was added Pd/C (3.2 mg, 10%, 10 mol %).
The flask was purged with hydrogen gas for three times, and the
reaction mixture was allowed to stir for 6 h at room temperature under
a H2 atmosphere. The crude product was filtered through a pad of
Celite and then washed with dichloromethane (30 mL × 3). Organic
solvents were removed under reduced pressure to afford the desired
deprotected product 8 (82.2 mg, 95%).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sbchang@kaist.ac.kr (S.C.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the Institute for Basic Science
(IBS). We thank Mr. Hyunggeun Lim for helpful discussions.
■
REFERENCES
■
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