Synthesis of 2-Amino-3-hydroxy-3H-indoles via Palladium-Catalyzed One-Pot Reaction of Isonitriles, Oxygen, and N-Tosylhydrazones Derived from 2-Acylanilines

Article abstract of DOI:10.1021/acs.joc.7b01195

A cyanide-free one-pot procedure was developed to access 2-amino-3-hydroxy-3H-indoles, which involved: (1) in situ formation of ketenimines by the reaction of N′-(1-(2-aminophenyl)ethylidene)-p-tosylhydrazones with isonitriles; (2) the intramolecular nucleophilic attack of ketenimines by the amino in phenyl furnishing the ring closure leading to 2-aminoindoles; (3) the oxidation of 2-aminoindoles by O₂ leading to 2-amino-3-hydroxy-3H-indoles. This strategy represents not only a key compliment to the sporadic synthetic methods toward 2-amino-3-hydroxy-3H-indoles but also progress in N-tosylhydrazone, isonitrile, and ketenimine chemistry.

Full text of DOI:10.1021/acs.joc.7b01195

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Note
Synthesis of 2-Amino-3-Hydroxy-3H-Indoles via Palladium-
catalyzed One-Pot Reaction of Isonitriles, Oxygen
and N-tosylhydrazones Derived from 2-Acylanilines
Haoke Chu, Qiang Dai, Yan Jiang, and Jiang Cheng
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 13 Jul 2017
Downloaded from http://pubs.acs.org on July 13, 2017
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Page 1 of 15
The Journal of Organic Chemistry
Synthesis of 2ꢀAminoꢀ3ꢀHydroxyꢀ3HꢀIndoles via Palladiumꢀ
catalyzed OneꢀPot Reaction of Isonitriles, Oxygen and Nꢀ
tosylhydrazones Derived from 2ꢀAcylanilines
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Haoke Chu, Qiang Dai, Yan Jiang and Jiang Cheng*
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School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangꢀ
su Province Key Laboratory of Fine Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R.
China
jiangcheng@cczu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the
journal that you are submitting your paper to)
ABSTRACT
A cyanideꢀfree oneꢀpot procedure was developed to access 2ꢀaminoꢀ3ꢀhydroxyꢀ3
in situ formation of ketenimines by the reaction of N'ꢀ(1ꢀ(2ꢀaminophenyl)ethylidene)ꢀ
isonitriles; 2) the intraꢀmolecular nucleophillic attack of ketenimines by the amino in phenyl furnishing the ring
closure leading to 2ꢀaminoindoles; 3) the oxidation of 2ꢀaminoindoles by O2 leading to 2ꢀaminoꢀ3ꢀhydroxyꢀ3
indoles. This strategy represents not only a key compliment to the sporadic synthetic methods towards 2ꢀaminoꢀ3ꢀ
hydroxyꢀ3 ꢀindoles but also a progress in Nꢀtosylhydrazone, isonitrile and ketenimine chemistry.
H
ꢀindoles, which involved: 1)
p
ꢀtosylhydrazones with
H
ꢀ
H
2ꢀAminoꢀ3ꢀhydroxyꢀ3Hꢀindoles possess activity against plasmodium falciparum, serving as antimalarials with poꢀ
tent in vivo activity.1 However, its biological activity is virtually unexplored, which is at least partly due to sporadic
synthetic methodologies.2 To date, only two practical methods were reported. One is the annulation of 2’ꢀ
aroylacylanilides with cyanide developed by Bell (Scheme 1, Eq 1).3 Mazitschek demonstrated the other procedure
involving the addition of aryl boronic acids to isatins followed by treatment with tertꢀbutyldimethylsilyl amine (Scheme
1, Eq 2).4 Therefore, further development of practical methods involving either new reaction partners or pathways toꢀ
wards such frameworks kept highly desired goal for organic chemists.
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Meanwhile, ketenimines are versatile intermediates in organic synthesis.5 Cai pioneered the study on in situ forꢀ
mation of ketenimines6 whereby direct reaction between isonitriles7,8,9 and Nꢀtosylhydrazones10,11,12 as the carbene preꢀ
cursors. Afterwards, interꢀmolecular nucleophillic attack of the in situ formed ketenimines by H2O produced amides
(Scheme 1, Eq 1).6a This strategy was further developed by us in a palladiumꢀcatalyzed MCRs to access amidines,
where amines served as nucleophiles (Scheme 1, Eq 3).13 We expect the intraꢀmolecular nucleophillic attack on the in
situ formed ketenimines, albeit no reports before, could furnish ring closure towards 2ꢀaminoindoles, which, subseꢀ
quently, is oxidized by O2 allowing to access 2ꢀaminoꢀ3ꢀhydroxyꢀ3Hꢀindoles quickly (Scheme 1, Eq 4).14 Herein, we
wish to report such a synthetic pathway, which represents not only a key compliment to the sporadic synthetic methods
towards 2ꢀaminoꢀ3ꢀhydroxyꢀ3Hꢀindoles but also a progress in Nꢀtosylhydrazone, isonitrile and ketenimine chemistry.
Bell's work
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COCHCl2
NHCOCHCl2
NHCOCHCl2
N
NH
KCN
O
CN
OH
Ph
OH
Ph
Ph
N
NH2
OH
further functionalization
Eq 1
Ph
Mazitschek's work
R
O
R
OH
TBDMSNH2
SnCl4, NMM
OH
RB(OH)2
or
O
O
NH2
Eq 2
THF, uwave
120 oC, 1 h
RMgX
N
N
N
H
H
R = 1-naphthyl
intermolecular
R1
R1
R2-NC
Nu
+
NNHTs
NuH = H2O, ref 6a
NuH = R4NH2, ref 11
Ar
Ar
NuH
N
R2
Eq 3
intramolecular
R1
R1
R1
OH
O2
NHR2
NNHTs
NHR2
Ar
Ar
Ar
This work
+ R2-NC
N
N
NH2
H
Eq 4
Scheme 1. The nucleophillic attack on in situ formed ketenimine via reaction of Nꢀtosylhydrazone and isonitrile.
Initially, we tested the reaction of N'ꢀ(1ꢀ(2ꢀaminophenyl)ethylidene)ꢀpꢀtosylhydrazone (1a, 1.0 equiv.), 2,6ꢀ
diisopropylphenyl isonitrile (2a, 1.2 equiv.) in the presence of Pd(OAc)2 (5 mol%), PPh3 (10 mol%) and LiOH (3.0
o
equiv.) in dioxane under N2 at 120 C for 5 h (Table 1, entry 1). To our delight, 2ꢀ((2,6ꢀdiisopropylphenyl)amino)ꢀ3ꢀ
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methylꢀ3ꢀhydroxyꢀ3Hꢀindole 3aa was isolated in 44% yield after further heating the reaction mixture under O2 at 60 oC
for 1 h (Table 1, entry 1). Pd(acac)2 provided a comparable yield (50%, Table 1, entry 2). Pleasingly, Pd(MeCN)2Cl2
increased the yield to 70% (Table 1, entry 3) and PdCl2(dppe) was the best (73%, Table 1, entry 4).
PdCl2(dppf)•CH2Cl2 and Pd(cod)Cl2 slightly decreased the reaction efficiency to 62% and 58%, respectively (Table 1,
entries 5 and 6). The ligands, such as tri(4ꢀmethylphenyl)phosphine (36%, Table 1, entry 7), tri(2ꢀfuryl)phosphine
(68%, Table 1, entry 8) and tricyclohexylphosphine (45%, Table 1, entry 9) were inferior to PPh3. In the absence of
PPh3, the yield dramatically decreased to 33% (Table 1, entry 10); while no reaction took place in the absence of both
palladium and PPh3 (Table 1, entry 11). Replacing dioxane with THF slightly decreased the reaction efficiency (65%,
Table 1, entry 12); while DMF and toluene resulted in no reaction (Table 1, entries 13 and 14). The reaction was
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inhibited when LiOH was replaced with Cs2CO3 or LiOtBu (Table 1, entries 15 and 16)
Table 1. Selected results for screening the optimized reaction conditions a
.
Catalyst
Pd(OAc)2
Pd(acac)2
Ligand
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Solvent
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
Yield (%)b
44
Entry
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15c
16d
50
70
73
62
58
36
68
45
33
NR
65
<5
<5
Pd(MeCN)2Cl2
PdCl2(dppe)
PdCl2(dppf)·CH2Cl2
Pd(cod)Cl2
PdCl2(dppe)
PdCl2(dppe)
PdCl2(dppe)
PdCl2(dppe)
ꢀꢀ
P(pꢀtolyl)3 dioxane
P(2ꢀfuryl)3 dioxane
PCy3
ꢀꢀ
ꢀꢀ
PPh3
PPh3
PPh3
PPh3
PPh3
dioxane
dioxane
dioxane
THF
PdCl2(dppe)
PdCl2(dppe)
PdCl2(dppe)
PdCl2(dppe)
PdCl2(dppe)
DMF
toluene
dioxane
dioxane
27
<5
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Pd catalyst (0.01 mmol, 5 mol%), ligand (0.02 mmol, 10 mol%) and LiOH (0.6
o
b
c
mmol, 3.0 equiv.) in solvent (2 mL) under N2, 120 C for 5 h in a sealed tube, then under O2, 60 oC for 1 h Cs2CO3. Isolated yield.
Cs2CO3 instead of LiOH. d LiOtBu instead of LiOH.
Once the optimized conditions were established, the scope and limitation of substituted N'ꢀ(1ꢀ(2ꢀ
aminophenyl)ethylidene)ꢀpꢀtosylhydrazones were studied (Scheme 2). As expected, the procedure ran smoothly to
access 2ꢀaminoꢀ3ꢀmethylꢀ3ꢀhydroxyꢀ3Hꢀindole derivatives with various substitutents at the 5ꢀ and 6ꢀ position in
moderate to good yields (3baꢀ3ia). A series of functional groups, such as methyl, bromo, chloro and fluoro were
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compatible with the reaction conditions, which provided handles for potentially further functionalization. Notably, the
diversity was further increased as the 3ꢀalkyl in 2ꢀaminoꢀ3ꢀhydroxyꢀ3Hꢀindoles was not limited to methyl. The 3ꢀethyl
(3ja, 68%), cyclohexyl (3ka, 62%), tꢀbutyl (3la, 76%) and nꢀbutyl (3ma, 80%) analogues were all isolated in good
yields, while 3ꢀaryl products was isolated in trace disappointedly. The structure of 3aa was established by Xꢀray
crystallographic analysis (see Supporting Information).15
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Scheme 2. The substrate scope of substituted Nꢀtosylhydrazones a
R1
R1
N
(1) PdCl2(dppe) (5 mol%)
PPh3 (10 mol%), LiOH (3.0 equiv)
dioxane, 120 oC
OH
NHAr'
NNHTs
Ar'-NC
+
Ar
Ar
(2) O2, 60 oC
NH2
Ar' = 2,6-diisopropylphenyl
3ba-3ma
1b-1m
2a
OH
Br
OH
NHAr'
OH
Me
Cl
NHAr'
N
NHAr'
N
N
3ba, 52%
3ca, 60%
3da, 67%
OH
OH
OH
F
Ph
NHAr'
NHAr'
NHAr'
N
N
N
3ga, 50%
Et
Me
3ea, 73%
3fa, 66%
OH
NHAr'
OH
NHAr'
OH
NHAr'
N
N
N
Cl
Ph
3ha, 56%
3ia, 45%
3ja, 68%
Cy
tBu
nBu
OH
NHAr'
OH
NHAr'
OH
NHAr'
N
N
N
3ka, 62%
3la, 76%
3ma, 80%
a Reaction conditions: 1b-1m (0.2 mmol), 2a (0.24 mmol), PdCl2(dppe) (0.01 mmol, 5 mol%), PPh3 (0.02 mmol, 10 mol%) and LiOH (0.6
mmol, 3.0 equiv.) in dioxane (2 mL) under N2, 120 oC for 5 h in a sealed tube, then under O2, 60 oC for 1 h.
Afterwards, the scope of isonitriles was studied (Scheme 3). The hindrance on the phenyl of isonitrile was benefiꢀ
cial for this transformation. For example, phenyl isonitrile provided 3ab in 45% yield; while the 2,6ꢀdimethyl, 2,4,6ꢀ
trimethyl and 2,6ꢀdiethyl analogues produced the corresponding 2ꢀaminoꢀ3ꢀhydroxyꢀ3Hꢀindoles in 53% (3ac), 64%
(3ad) and 68% (3ae) yields, respectively. Notably, tꢀbutyl isonitrile took part in this transformation, and 2ꢀtꢀ
butylaminoꢀ3ꢀmethylꢀ3ꢀhydroxyꢀ3Hꢀindole 3af was isolated in 47% yield. nꢀHexylisonitrile did not work under the
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procedure. The structure of 3ab was established by Xꢀray crystallographic analysis (see Supporting Information).16
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3
Notably, in this case, the C=N bond in NꢀC=N linkage located in out of the ring.
4
5
6
Scheme 3. The substrate scope of isonitriles a
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a Reaction conditions: 1a (0.2 mmol), 2b-2f (0.24 mmol), PdCl2(dppe) (0.01 mmol, 5 mol%), PPh3 (0.02 mmol, 10 mol%) and LiOH (0.6
mmol, 3.0 equiv.) in dioxane (2 mL) under N2, 120 oC for 5 h in a sealed tube, then under O2, 60 oC for 1 h.
Some experiments were conducted to get some insights into this procedure. In the competitive experiments, under
either the standard procedure or the procedure in ref 11, 2ꢀ((2,6ꢀdiisopropylphenyl)amino)ꢀ3ꢀmethylꢀ3ꢀhydroxyꢀ3Hꢀ
indole 3aa was isolated as the sole product and no product whereby the interꢀmolecular nucleophilic attack was
detected at all (Scheme 4, Eq 1). This may be ascribed to the hindrance of the presumed ketenimine intermediate
(Scheme 4, Eq 1). During the transformation, 2ꢀaminoindoles were occasionally detected, which were not stable
enough to be isolated. The product 3aa could not be detected when the reaction was conducted in oneꢀpot under
oxygen atmosphere (Scheme 4, Eq 2). Moreover, no 18O was detected in the final product by adding H218O to the
standard procedure. However, 18O was totally incorporated in the hydroxy group of the product when the reaction was
conducted under 18O2 atmosphere (Scheme 4, Eq 3).
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PhN
NHAr'
1
2
3
4
5
NNHTs
PhNH2
+
3aa
+
N Ar'
NH2
NH2
3'
6
7
CH3
Ar' = 2,6-diisopropylphenyl
8
9
standard procedure, 3aa (70%), 3' (< 1%);
procedure in ref 11, 3aa (64%), 3' (< 1%);
NH2Ph
NH2
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N
PhNH2
Ar'
the hindrance of ketenimine
Eq 1
PdCl2(dppe) (5 mol%)
PPh3 (10 mol%)
OH
NNHTs
NHAr'
Eq 2
+
N Ar'
LiOH (3.0 equiv)
dioxane, O2, 120 oC
Ar' = 2,6-diisopropylphenyl
N
NH2
not detected
18OH
standard procedure
18O2 instead of O2
NNHTs
+
N Ar
NHAr'
Eq 3
N
NH2
Ar' = 2,6-diisopropylphenyl
Scheme 4. Preliminary mechanism study.
Based on the experimental results, a proposed mechanism was outlined in Scheme 5. Firstly, the coordination of
palladium with isonitrile formed complex A. Then, under basic conditions, sequential deprotonation and detosylation
of N'ꢀ(1ꢀ(2ꢀaminophenyl)ethylidene)ꢀpꢀtosylhydrazone took place to produce a diazo compound, which reacted with
palladium complex A towards a palladium carbene B, along with the extrusion of N2. Secondly, B converted to the
palladium complex C via migratory insertion. After the dissociation of palladium to enter the catalytic cycle, the intraꢀ
molecular attack of ketenimine 4 by the amino in the phenyl ring furnished the ring closure leading to 2ꢀaminoindole 5.
Finally, the oxidation of 5 by O2 produced the final product 2ꢀaminoꢀ3ꢀhydroxyꢀ3Hꢀindole via the formation of 2ꢀ
aminoꢀ3ꢀperoxyꢀ3Hꢀindole.14
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Scheme 5. A tentative mechanism.
In conclusion, we have developed
a
palladiumꢀcatalyzed cascade oneꢀpot reaction of N'ꢀ(1ꢀ(2ꢀ
aminophenyl)ethylidene)ꢀpꢀtosylhydrazones, isonitriles and O2 towards 2ꢀaminoꢀ3ꢀhydroxyꢀ3Hꢀindoles. This procedure
involved: the sequential in situ formation of ketenimines; intraꢀmolecular nucleophillic attack of ketenimines by amino;
and oxidation by O2. It represents a practical synthetic method towards 2ꢀaminoꢀ3ꢀhydroxyꢀ3Hꢀindoles, rendering a
progress in Nꢀtosylhydrazone, isonitrile and ketenimine chemistry.
EXPERIMENTAL SECTION
General Information: Unless otherwise noted, all chemicals were purchased from commercial suppliers and used
without further purification. H NMR and 13C NMR spectra were recorded at ambient temperature on a 300 or 400
1
MHz (75 or 100 MHz for 13C) NMR spectrometer. NMR experiments are reported in δ units, parts per million (ppm),
and were referenced to CDCl3 (δ δ δ 2.50 or 39.50
7.26 or 77.0 ppm), acetoneꢀd6 ( 7.26 or 77.0 ppm) or DMSOꢀd6 (
ppm) as the internal standard. The coupling constants J are given in Hz. Column chromatography was performed using
EM Silica gel 60 (300ꢀ400 mesh). Highꢀresolution mass spectra (HRMS) were obtained using a micro TOF II focus
spectrometer (ESI).
Experimental Procedure:
General Procedure for 2-Amino-3-hydroxy-3H-indoles.
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A 20 mL Schlenk tube equipped with a stir bar was charged with 1 (0.2 mmol), 2 (0.24 mmol, 1.2 equiv.),
PdCl2(dppe) (5.8 mg, 5 mol%), PPh3 (5.2 mg, 10 mol%), LiOH (48.0 mg, 0.6 mmol) and dioxane (2 mL). The tube
was sealed with a Teflon lined cap. The reaction mixture was stirred under N2 at 100 oC in oil bath. After 5 h, the tube
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3
4
5
6
7
o
was cooled to room temperature, and poured with O2. The mixture was stirred at 60 C for another 1 h. After
8
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completion, 5 mL of brine was added, and the mixture was extracted with EtOAc (3 × 2mL). The organic layer was
collected and concentrated in vacuum. The residue was purified by flash column chromatography on silica gel with
petroleum etherꢀEtOAc as the eluent to give the desired product.
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2-((2,6-Diisopropylphenyl)amino)-3-methyl-3-hydroxy-3H-indole (3aa):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3aa (47.0 mg, 73% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.2 Hz, 1H), 7.22ꢀ7.15 (m, 4H), 6.99 (t, J = 7.4 Hz, 1H) 6.62
(d, J = 7.7 Hz, 1H), 6.52 (s, 1H), 4.09 (s, 1H), 3.12ꢀ3.02 (m, 2H), 1.83 (s, 3H), 1.25ꢀ1.16 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 163.6, 143.0, 141.3, 139.6, 139.1, 132.2, 129.4, 124.1, 123.8, 123.6, 123.3, 121.8, 109.0, 75.4, 28.2,
27.7, 27.3, 23.8, 23.8, 23.6, 23.2; GCMS (EI) calcd for C21H26N2O 322, found 322; HRMS (ESI) m/z calcd for
C21H27N2O (M + H)+ 323.2118, found 323.2119; IR (KBr) 3414, 3060, 2962, 2926, 2867, 1687, 1620, 1588, 1484,
1471, 1384, 1362, 1325 cmꢀ1.
2-((2,6-Diisopropylphenyl)amino)-3,5-dimethyl-3-hydroxy-3H-indole (3ba):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ba (35.1 mg, 52% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.22ꢀ7.16 (m, 3H), 7.00 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 7.7
Hz, 1H), 6.40 (s, 1H), 3.76 (s, 1H), 3.11ꢀ3.02 (m, 2H), 2.34 (s, 3H), 1.84 (s, 3H), 1.25ꢀ1.15 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 163.7, 143.2, 139.5, 139.0, 139.0, 132.1, 131.4, 129.7, 124.5, 124.0, 123.5, 123.3, 108.7, 75.4, 28.2,
27.7, 27.3, 23.7, 23.7, 23.6, 23.2, 20.9; GCMS (EI) calcd for C22H29N2O 336, found 336; HRMS (ESI) m/z calcd for
C22H29N2O (M + H)+ 337.2274, found 337.2274; IR (KBr) 3474, 3415, 2961, 1637, 1617, 1458, 1384, 1339 cmꢀ1.
5-Bromo-2-((2,6-diisopropylphenyl)amino)-3-methyl-3-hydroxy-3H-indole (3ca):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ca (48.2 mg, 60% yield) as
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yellow solid: H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.20ꢀ7.13 (m, 4H), 6.56 (d, J = 8.1 Hz, 1H), 6.47 (s, 1H),
3.94 (s, 1H), 3.05ꢀ2.95 (m, 2H), 1.80 (s, 3H), 1.22ꢀ1.12 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 163.2, 142.7, 139.8,
139.4, 138.9, 133.8, 129.3, 127.1, 124.4, 124.3, 123.6, 123.4, 110.0, 75.4, 29.7, 28.2, 27.8, 27.3, 23.7, 23.6, 23.2;
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GCMS (EI) calcd for C21H25BrN2O 400, found 400; HRMS (ESI) m/z calcd for C21H26BrN2O (M + H)+ 401.1223,
found 401.1212; IR (KBr) 3416, 2962, 2926, 2868, 1685, 1638, 1618, 1560, 1459, 1384, 1326 cmꢀ1.
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5-Chloro-2-((2,6-diisopropylphenyl)amino)-3-methyl-3-hydroxy-3H-indole (3da):
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Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3da (47.7 mg, 67% yield) as
yellow solid: 1H NMR (300 MHz, DMSOꢀd6) δ 9.12 (s, 1H), 7.45 (s, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.12ꢀ7.04 (m, 3H),
6.72 (d, J = 7.2 Hz, 1H), 6.09 (s, 1H), 3.11ꢀ2.97 (m, 1H), 2.96ꢀ2.76 (m, 1H), 1.61 (s, 3H), 1.12ꢀ1.08 (m, 12H); 13C
NMR (75 MHz, DMSOꢀd6) δ 131.4, 123.1, 122.7, 74.8, 27.8, 27.0, 23.9, 23.6, 23.3, 23.0; GCMS (EI) calcd for
C21H25ClN2O 356, found 356; HRMS (ESI) m/z calcd for C21H26ClN2O (M + H)+ 357.1728, found 357.1730; IR (KBr)
3547, 3474, 3414, 3235, 2958, 2866, 1668, 1638, 1616, 1478, 1457, 1436, 1384, 1322 cmꢀ1.
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2-((2,6-Diisopropylphenyl)amino)-5-fluoro-3-methyl-3-hydroxy-3H-indole (3ea):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ea (49.6 mg, 73% yield) as
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yellow solid: H NMR (400 MHz, CDCl3) δ 7.20ꢀ7.12 (m, 4H), 6.86 (t, J = 8.7 Hz, 1H), 6.56ꢀ6.53 (m, 1H), 6.48 (s,
1H), 3.09ꢀ2.98 (m, 2H), 2.03 (s, 1H), 1.81 (s, 3H), 1.23ꢀ1.13 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 163.8, 158.7 (d,
JCꢀF = 239.0 Hz), 142.8, 139.3 (d, JCꢀF = 53.0 Hz), 137.2, 133.6, 124.3, 123.6, 123.4, 115.8, 115.6, 111.8, 111.6, 109.5
(d, JCꢀF = 7.0 Hz), 75.6, 28.2, 27.7, 27.3, 23.7, 23.6, 23.2, 21.0; GCMS (EI) calcd for C21H25FN2O 340, found 340;
HRMS (ESI) m/z calcd for C21H26FN2O (M + H)+ 341.2024, found 341.2022; IR (KBr) 3436, 2963, 2928, 2868, 1691,
1629, 1488, 1438, 1384, 1362, 1327 cmꢀ1.
2-((2,6-Diisopropylphenyl)amino)-3-methyl-5-phenyl-3-hydroxy-3H-indole (3fa):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3fa (52.6 mg, 66% yield) as
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yellow solid: H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.56ꢀ7.54 (m, 2H), 7.44ꢀ7.41 (m, 3H), 7.32 (t, J = 7.3 Hz,
1H), 7.22ꢀ7.16 (m, 3H), 6.72 (d, J = 7.8 Hz, 1H), 6.56 (s, 1H), 3.08ꢀ3.02 (m, 2H), 2.04 (s, 1H), 1.87 (s, 3H), 1.24ꢀ1.17
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 163.4, 143.0, 140.9, 140.7, 139.5, 139.0, 135.5, 132.6, 128.8, 128.4, 126.8,
126.8, 124.2, 123.6, 123.4, 122.8, 109.3, 75.4, 28.2, 27.8, 27.3, 23.7, 23.6, 23.6, 23.2; GCMS (EI) calcd for
C21H30N2O 398, found 398; HRMS (ESI) m/z calcd for C27H31N2O (M + H)+ 399.2431, found 399.2437; IR (KBr)
3435, 3060, 2962, 2926, 2867, 1691, 1623, 1600, 1508, 1479, 1464, 1438, 1384, 1362, 1326 cmꢀ1.
2-((2,6-Diisopropylphenyl)amino)-3,6-dimethyl-3-hydroxy-3H-indole (3ga):
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Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ga (33.8 mg, 50% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.5 Hz, 1H), 7.20ꢀ7.11 (m, 3H), 6.81 (d, J = 7.5 Hz, 1H), 6.46
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(s, 1H), 6.43 (s, 1H), 3.39 (s, 1H), 3.04ꢀ2.98 (m, 2H), 2.29 (s, 3H), 1.80 (s, 3H), 1.21ꢀ1.14 (m, 12H); C NMR (100
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MHz, CDCl3) δ 163.5, 143.2, 141.6, 139.8, 139.4, 139.0, 129.1, 124.0, 123.6, 123.5, 123.3, 122.4, 109.8, 75.2, 29.7,
28.2, 27.8, 27.2, 23.6, 23.6, 23.2, 21.7; GCMS (EI) calcd for C22H28N2O 336, found 336; HRMS (ESI) m/z calcd for
C22H29N2O (M + H)+ 337.2274, found 337.2276; IR (KBr) 3463, 2961, 2926, 2867, 1686, 1654, 1630, 1559, 1507,
1458, 1384, 1326 cmꢀ1.
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6-Chloro-2-((2,6-Diisopropylphenyl)amino)-3-methyl-3-hydroxy-3H-indole (3ha):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ha (40.1 mg, 56% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.8 Hz, 1H), 7.18ꢀ7.12 (m, 3H), 6.96 (d, J = 7.9 Hz, 1H), 6.64
(s, 1H), 6.51 (s, 1H), 3.56 (s, 1H), 3.02ꢀ2.94 (m, 2H), 1.79 (s, 3H), 1.21ꢀ1.14 (m, 12H); 13C NMR (100 MHz, CDCl3) δ
162.9, 142.7, 142.5, 139.3, 138.9, 135.1, 130.4, 124.8, 124.4, 123.6, 123.4, 121.9, 109.7, 74.9, 29.7, 28.2, 27.8, 27.2,
23.6, 23.5, 23.2; GCMS (EI) calcd for C21H25ClN2O 356, found 356; HRMS (ESI) m/z calcd for C21H26ClN2O (M +
H)+ 357.1728, found 357.1727; IR (KBr) 3438, 2962, 2926, 2968, 1693, 1617, 1560, 1485, 1458, 1325 cmꢀ1.
2-((2,6-Diisopropylphenyl)amino)-3-methyl-6-phenyl-3-hydroxy-3H-indole (3ia):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ia (36.0 mg, 45% yield) as
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yellow solid: H NMR (400 MHz, CDCl3) δ 7.55ꢀ7.51 (m, 3H), 7.44ꢀ7.40 (m, 2H), 7.37ꢀ7.33 (m, 1H), 7.28ꢀ7.21 (m,
4H), 6.91 (s, 1H), 3.10ꢀ3.00 (m, 2H), 2.08 (s, 1H), 2.07 (s, 1H), 1.90 (s, 3H), 1.24ꢀ1.19 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 143.2, 140.8, 131.3, 128.8, 127.6, 127.1, 125.0, 124.1, 123.8, 123.5, 121.4, 75.6, 29.7, 28.3, 27.8,
27.0, 23.8, 23.5, 23.4; GCMS (EI) calcd for C27H30N2O 398, found 398; HRMS (ESI) m/z calcd for C27H31N2O (M +
H)+ 399.2431, found 399.2427; IR (KBr) 3463, 2961, 2927, 1685, 1626, 1560, 1507, 1458, 1437, 1384, 1339 cmꢀ1.
2-((2,6-Diisopropylphenyl)amino)-3-ethyl-3-hydroxy-3H-indole (3ja):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ja (45.9 mg, 68% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.2 Hz, 1H), 7.20ꢀ7.12 (m, 4H), 6.99 (t, J = 7.4 Hz, 1H), 6.63
(d, J = 7.5 Hz, 1H), 6.48 (s, 1H), 3.37 (s, 1H), 3.10ꢀ3.01 (m, 2H), 2.23ꢀ2.18 (m, 2H), 1.23ꢀ1.12 (m, 12H), 0.91 (t, J =
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8, 142.9, 141.8, 139.1, 138.6, 129.9, 129.1, 124.1, 123.8, 123.2,
123.0, 121.4, 108.6, 76.4, 33.2, 27.7, 27.4, 23.6, 23.3, 23.2, 23.0, 7.5; GCMS (EI) calcd for C22H28N2O 336, found 336;
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HRMS (ESI) m/z calcd for C22H29N2O (M + H)+ 337.2274, found 337.2274; IR (KBr) 3456, 2962, 2918, 2849, 1685,
1637, 1622, 1470, 1384, 1325 cmꢀ1.
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3-Cyclohexyl-2-((2,6-diisopropylphenyl)amino)-3-hydroxy-3H-indole (3ka):
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Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ka (48.4 mg, 62% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.3 Hz, 1H), 7.20ꢀ7.10 (m, 4H), 6.98 (t, J = 7.4 Hz, 1H), 6.62
(d, J = 7.7 Hz, 1H), 6.44 (s, 1H), 3.11 (hept, J = 6.7 Hz, 1H), 2.95 (hept, J = 6.7 Hz, 1H), 2.87 (s, 1H), 2.17ꢀ2.09 (m,
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2H), 1.86ꢀ1.68 (m, 4H), 1.34ꢀ1.10 (m, 17H); C NMR (100 MHz, CDCl3) δ 163.3, 143.2, 142.4, 139.4, 138.8, 129.8,
129.3, 124.9, 124.0, 123.5, 123.3, 121.5, 108.8, 80.5, 48.3, 28.1, 27.8, 26.9, 26.5, 26.3, 26.1, 26.0, 23.9, 23.6, 23.5,
23.3; GCMS (EI) calcd for C26H34N2O 390, found 390; HRMS (ESI) m/z calcd for C26H35N2O (M + H)+ 391.2744,
found 391.2744; IR (KBr) 3466, 3059, 2960, 2929, 2854, 1725, 1686, 1619, 1470, 1384, 1325 cmꢀ1.
3-(tert-Butyl)-2-((2,6-diisopropylphenyl)amino)-3-hydroxy-3H-indole (3la):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3la (55.5 mg, 76% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.5 Hz, 1H), 7.21ꢀ7.10 (m, 4H), 6.95 (t, J = 7.5 Hz, 1H), 6.59
(d, J = 7.8 Hz, 1H), 6.31 (s, 1H), 3.12 (hept, J = 6.8 Hz, 1H), 3.06 (s, 1H), 2.88 (hept, J = 6.7 Hz, 1H), 1.26ꢀ1.12 (m,
21H); 13C NMR (100 MHz, CDCl3) δ 164.1, 143.3, 142.7, 139.3, 138.6, 130.4, 129.2, 126.1, 124.0, 123.6, 123.3,
121.0, 108.6, 82.5, 38.8, 28.3, 27.7, 24.1, 23.8, 23.7, 23.4, 23.3; GCMS (EI) calcd for C24H32N2O 364, found 364;
HRMS (ESI) m/z calcd for C24H33N2O (M + H)+ 365.2587, found 365.2591; IR (KBr) 3474, 2961, 2929, 2869, 1683,
1638, 1618, 1469, 1384, 1362, 1325 cmꢀ1.
3-(n-Butyl)-2-((2,6-diisopropylphenyl)amino)-3-hydroxy-3H-indole (3ma):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ma (58.3 mg, 80% yield) as
yellow solid: 1H NMR (100 MHz, CDCl3) δ 7.41 (d, J = 7.4 Hz, 1H), 7.20ꢀ7.11 (m, 4H), 6.99 (t, J = 7.4 Hz, 1H), 6.63
(d, J = 7.8 Hz, 1H), 6.49 (s, 1H), 3.09 (s, 1H), 3.07ꢀ2.97 (m, 2H), 2.20ꢀ2.16 (m, 2H), 1.27ꢀ1.12 (m, 16H), 0.89 (t, J =
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.9, 143.2, 142.1, 139.3, 138.9, 130.4, 129.4, 124.3, 124.0, 123.5,
123.3, 121.7, 109.0, 78.3, 40.4, 28.0, 27.8, 25.7, 23.9, 23.5, 23.5, 23.3, 22.9, 13.9; GCMS (EI) calcd for C24H32N2O
364, found 364; HRMS (ESI) m/z calcd for C24H33N2O (M + H)+ 365.2587, found 365.2589; IR (KBr) 3416, 2959,
2931, 2868, 1685, 1638, 1619, 1470, 1384, 1325 cmꢀ1.
3-Methyl-2-(phenylamino)-3-hydroxy-3H-indole (3ab):
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Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ab (21.3 mg, 45% yield) as
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yellow solid: H NMR (300 MHz, acetoneꢀd6) δ 7.93 (s, 1H), 7.36ꢀ7.28 (m, 3H), 7.22ꢀ7.16 (m, 1H), 7.10 (d, J = Hz,
1H), 7.04ꢀ6.99 (m, 1H), 6.97ꢀ6.92 (m, 1H), 5.10 (s, 1H), 1.58 (s, 3H); 13C NMR (75 MHz, acetoneꢀd6) δ 129.9, 129.6,
123.2, 122.8, 122.6, 120.2, 25.9; GCMS (EI) calcd for C15H14N2O 238, found 238; HRMS (ESI) m/z calcd for
C15H15N2O (M + H)+ 239.1179, found 239.1181; IR (KBr) 3450, 3418, 2935, 1642, 1617, 1450, 1380, 1333 cmꢀ1.
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2-((2,6-Dimethylphenyl)amino)-3-methyl-3-hydroxy-3H-indole (3ac):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ac (28.1 mg, 53% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.1 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.09ꢀ7.07 (m, 2H), 6.99ꢀ
6.95 (m, 2H), 6.64 (s, 1H), 6.51 (s, 1H), 4.43 (s, 1H), 2.15 (s, 6H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
163.55, 129.4, 128.3, 123.7, 121.8, 109.0, 75.4, 27.3, 17.7; GCMS (EI) calcd for C17H18N2O 266, found 266; HRMS
(ESI) m/z calcd for C17H19N2O (M + H)+ 267.1492, found 267.1500; IR (KBr) 3457, 2926, 1685, 1621, 1560, 1469,
1384, 1326 cmꢀ1.
2-((2,4,6-Trimethylphenyl)amino)-3-methyl-3-hydroxy-3H-indole (3ad):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ad (35.8 mg, 64% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H),
6.90 (s, 2H), 6.62 (s, 1H), 6.49 (s, 1H), 4.35 (s, 1H), 2.29 (s, 3H), 2.12 (s, 6H), 1.80 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.2, 129.3, 128.9, 123.7, 121.8, 60.4, 21.0, 20.7, 17.6, 14.1; GCMS (EI) calcd for C18H20N2O 280, found
280; HRMS (ESI) m/z calcd for C18H21N2O (M + H)+ 281.1648, found 281.1652; IR (KBr) 3415, 2966, 2924, 2855,
1684, 1637, 1620, 1570, 1470, 1384, 1325 cmꢀ1.
2-((2,6-Diethylphenyl)amino)-3-methyl-3-hydroxy-3H-indole (3ae):
Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3ae (40.0 mg, 68% yield) as
yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.1 Hz, 1H), 7.19ꢀ7.05 (m, 4H), 6.98 (t, J = 7.4 Hz, 1H), 6.61
(d, J = 7.2 Hz, 1H), 6.50 (s, 1H), 3.92 (s, 1H), 2.58ꢀ2.49 (m, 4H), 1.81 (s, 3H), 1.17 (t, J = 7.4 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 163.3, 144.5, 141.3, 134.9, 134.4, 132.1, 129.4, 126.5, 126.3, 123.8, 121.8, 109.0, 75.3, 27.2, 24.6,
24.0, 14.4, 14.2; GCMS (EI) calcd for C19H22N2O 294, found 294; HRMS (ESI) m/z calcd for C19H23N2O (M + H)+
295.1805, found 295.1806; IR (KBr) 3439, 3061, 2966, 2930, 2873, 1686, 1620, 1589, 1471, 1452, 1384, 1326 cmꢀ1.
2-(tert-Butylamino)-3-methyl-3-hydroxy-3H-indole (3af):
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Flash column chromatography on a silica gel (ethyl acetate: petroleum ether, 1: 10) give 3af (20.5 mg, 47% yield) as
yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.20ꢀ7.13 (m, 3H), 6.86 (t, J = 7.2 Hz, 1H), 4.93 (s, 1H), 2.90 (s, 1H), 1.44
(s, 9H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.2, 155.3, 136.8, 129.8, 121.4, 121.2, 117.0, 80.6, 52.0, 28.7,
25.7; GCMS (EI) calcd for C13H18N2O 218, found 218; HRMS (ESI) m/z calcd for C13H19N2O (M + H)+ 219.1492,
found 219.1497; IR (KBr) 3408, 2970, 2928, 1623, 1599, 1574, 1532, 1458, 1384, 1366, 1339 cmꢀ1.
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ASSOCIATED CONTENT
Supporting Information:
The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxx.
1H and 13C NMR spectra for all new compounds (PDF)
Xꢀray crystallographic data for 3aa and 3ab (CIF)
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (nos. 21272028 and 21572025), “Innovation & Enꢀ
trepreneurship Talents” Introduction Plan of Jiangsu Province, the Key University Science Research Project of Jiangsu
Province (15KJA150001), Qing Lan Project of Jiangsu Province, Jiangsu Key Laboratory of Advanced Catalytic Maꢀ
terials &Technology (BM2012110) and Advanced Catalysis and Green Manufacturing Collaborative Innovation Cenꢀ
ter for financial supports. Chu thanks the Research Innovation Program for College Graduates of Jiangsu Province
(Grant No. KYZZ15ꢀ0304) for financial supports.
REFERENCES
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15. The molecular structure of 3aa was determined by Xꢀray crystalloꢀgraphic analysis. CCDC 1497965 contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
16. The molecular structure of 3ab was determined by Xꢀray crystalloꢀgraphic analysis. CCDC 1497966 contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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