A concise approach to indoles via oxidative C-H amination of 2-alkenylanilines using dioxygen as the sole oxidant

Article abstract of DOI:10.1039/c6ra03378d

A novel synthetic method to prepare indole derivatives from N-Ts-2-alkenylanilines has been achieved. This reaction is through an oxidative intramolecular C-H amination by using molecular oxygen as the sole oxidant. This protocol is operationally simple a

Full text of DOI:10.1039/c6ra03378d

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Journal Name
ARTICLE
A concise approach to the indoles via oxidative C–H amination of
2-alkenylanilines using dioxygen as the sole oxidant
Received 00th January 20xx,
Accepted 00th January 20xx
Ai-Lun Ma, Yin-Long Li, Jian Li and Jun Deng*
A novel synthetic method to prepare indole derivatives from N-Ts-2-alkenylanilines has been achieved. This reaction
through an oxidative intramolecular C-H amination by using molecular oxygen as sole oxidant. This protocol is
operationally simple and environmental friendly, and provides a diverse range of substrate scope.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Indoles are important and valuable heterocycles because their
wide application in chemistry, biology, and material sciences.1
Therefore the synthesis of indole derivatives have long been of
great interest in organic synthesis.2 A great number of superior
methods have been established, and a large portion of these
methods employ transition metal catalysts.3 These protocols
are efficient and have been widely applied in organic synthesis.
While to be more friendly to the environment and economic,
developing a metal-free methodology to prepare indole
derivatives is an attractive goal.4
The intramolecular amination reaction of alkenes is a
direct approach to indole synthesis and these approaches are
known in the literature.5 The different oxidants were utilized
for the metal-free version (Scheme 1), for example, Muñiz
reported a sulfonic acid-catalyzed synthesis of indoles using
iodosobenzene as the oxidant.4a Later on, Youn reported a
synthesis of indoles through oxidative C–H amination of 2-
alkenylanilines by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) at 120 oC.4b Recently, Ortgies and Zhao successively
demonstrated the protocols involving the use N-
fluorobenzenesulfonimide as the terminal oxidant catalyzed by
selenium via the intramolecular amination of C(sp2)-H bonds.4c,
d Our laboratory is engaged in developing transition-metal-free
methods for the synthesis of heterocycles, especially through
new C–N, C–O bond formation.6 Although we have achieved
the synthesis of indoles by N-Iodosuccinimide (NIS) mediated
cascade C-N bond formation/aromatization of 2-
alkenylanilines under temperate conditions,6a we became
interested in the design of the novel method to replace these
oxidants by more environmentally friendly and economical
reagent. Since dioxygen is very cheap and produces no
Scheme 1: Metal-free indole synthesis from 2-alkenylanilines.
environmentally hazardous byproduct, and has been
extensively applied in organic synthesis.7 Consequently we
wish to communicate here our success in achieving the
practical and novel synthesis of indole derivatives using
molecular oxygen as the terminal oxidant.
Results and discussion
We began our investigation with the anilide 1a as the model
substrate to search for the optimal reaction conditions (Table
1). First, we evaluated the solvent effect on this reaction.
Various solvents were tested, only dimethyl sulfoxide (DMSO)
and 1,4-dioxane showed relatively high yield (Table 1, entries 1,
2).
School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug
Delivery & High-Efficiency, Tianjin University, Tianjin, 300072 P. R. China.
E-mail: jdeng@tju.edu.cn
Electronic Supplementary Information (ESI) available: [copies of 1H and 13C spectra of
all products.]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1. Optimization of reaction conditionsa
additive for this reaction, the correspondingVieinwdAortilcele Ownlianse
obtained in good yield (Table 1, entry 14), however, poorer
DOI: 10.1039/C6RA03378D
yields were obtained when we use acetic acid and p-
toluenesulfonic acid (Table 1, entries 12, 13). Base such as
potassium carbonate and sodium tert-butoxide proved to be
ineffective for this transformation and resulted in no reaction
(Table 1, entries 10, 11). Subsequently, we examined benzoic
acid derivatives and delightfully find that the 3,5-
dichlorobenzoic acid appeared preferable with regard to
product yield (Table 1, entry 16). We attempted to increase
the amount of 3,5-dichlorobenzoic acid to 1 equiv and it led to
decrease the yield to 46% (Table 1, entry 20). We changed the
ratio of DMSO and 1,4-dioxane, and the yield is decreasing
(Table 1, entries 18, 19). Alteration of key operating
parameters was also examined, e.g., neither lower nor raise
the temperature could increase the yield (Table 1, entries 21,
22). Last but not the least, we examined the concentration of
this reaction and it turned out the 0.1 M is appropriate (Table
1, entries 23, 24). After all above experiments, the optimal
conditions for the synthesis of indole derivatives using
molecular oxygen as the sole oxidant were established [0.2
equiv 3,5-dichlorobenzoic acid, DMSO/1,4-dioxane (1/1, 0.1 M),
O2, 120 oC].
Entry
Reagent (0.2 equiv)
Solvent
1,4-dioxane
DMSO
toluene
THF
ClCH2CH2Cl
CCl4
HOCH2CH2OH
EtOH
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
DMSO/1,4-
dioxane
Yield (%)b
30
1
2
3
4
5
6
7
8
9
―
―
―
―
―
―
―
―
―
22
<10
0
<10
<10
15
<10
32
10
11
K2CO3
t-BuONa
0
0
12
CH3COOH
44
50
58
61
73
58
61
37
46
ND
20
47
29
13
TsOH
Table 2. Effects of protecting groupsa
14
benzoic acid
3-chlorobenzoic acid
15
Yield (%)b
73 (2a
11 (2b
44 (2c
25 (2d)
Trace
16
3,5-dichlorobenzoic
Entry
R
acid
3,5-difluorobenzoic
acid
3,5-dichlorobenzoic
acid
3,5-dichlorobenzoic
acid
3,5-dichlorobenzoic
acid
3,5-dichlorobenzoic
acid
3,5-dichlorobenzoic
acid
3,5-dichlorobenzoic
acid
3,5-dichlorobenzoic
acid
1
2
3
4
5
6
7
8
9
Ts (1a
)
)
)
)
17
C6H5SO2 (1b
p-ClC6H4SO2 (1c
p-NO2C6H4SO2 (1d
p-MeOC6H4SO2 (1e
Ms (1f
Ac (1g
Cbz (1h
H (1i
)
)
18c
19d
20e
21f
22g
23h
24i
)
)
)
)
63 (2f
)
ND
Trace
ND
)
)
aReaction conditions: Substrate
1
(0.1 mmol), 3,5-
dichlorobenzoic acid (0.2 equiv), DMSO/1,4-dioxane (1:1,
o
b
1.0 mL), 120 C under O2 (balloon), 24 h. Isolated yield.
ND = Not detected.
With optimized conditions in hand, a brief survey of the
effect of N-protecting groups including sulfonyl (entries 1-6),
acyl (entry 7) reconfirmed the effectiveness of p-
aReaction conditions: 1a (0.1 mmol), additive (0.2 equiv), toluenesulfonyl as the preferred group for this reaction
(Table
solvent (1.0 mL), 120 oC under O2 (balloon). bIsolated yield, ND 2). These observations proved that the pKa of the N-H units
= Not detected. cDMSO/Dioxane (3:7). dDMSO/1,4-dioxane (7:3) plays a significant role in the reaction.
eUsing 1.0 equiv additive. fAt 100 o C. gAt 150 o C. h0.05 M. i0.15
M.
To probe the flexibility of this methodology, we
proceeded to explore the substituent effect at the alkene
moiety (Table 3, entries 1-14). We tested the substrates with
various ortho-, meta- and para-, substitution on the phenyl
ring at the alkene moiety. The results reveal that there is a
certain influence on the substitution pattern of the substituent
on the phenyl ring of the substrates. The electron-donating
Combination of these two solvents and gratifyingly provided a
higher yield (Table 1, entry 9). Next, we then turned our
attention to screen the additives. When the benzoic acid as
2 | J. Name., 2012, 00, 1-3
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Table 3. Scope of 2-alkenylanilinesa
ring, the target products cannot be formed (Table 3, entry 14).
This result was probably caused by the strong electron-
View Article Online
DOI: 10.1039/C6RA03378D
withdrawing characteristic of the nitro group.
Subsequently we also investigated the effect of the
substitution pattern of aniline. As shown in Table 3 (entries 15-
23), the reaction exhibited poor tolerance to various
substituents on the aromatic ring. Substituents (R1) residing on
the aromatic moiety of N-Ts-2-styrylanilines showed fair yields.
When it is electron-donating group, the reaction took place
smoothly to provide the desired indoles in better yields (Table
3, entries 15, 16). When it is electron-withdrawing group such
as F, Cl and CF3, the lower yields were obtained (Table 3,
entries 17-19). The substituents (R2) residing on the aromatic
moiety of N-Ts-2-styrylanilines showed relatively lower yields
(Table 3, entries 20, 21). Apparently, this reaction is affected
by the position of the substituents on the aromatic ring of
anilines. We then tested substrates with two substituents on
the aromatic ring of the alkene and aniline. When both of
them are electron-donating group, the reaction took place
smoothly to provide a higher yield than electron-withdrawing
group was involved (Table 3, entries 22, 23).
Entry
R1
R2 R3
R4
Time
(h)
24
36
36
Yield
(%)b
73(2a
1
2
3
4
5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph(1a
2-MeC6H4(1j
3-MeC6H4(1k
4-MeC6H4(1l
)
)
)
)
)
70(2j
)
50(2k
)
24
24
64(2l
)
2-
69(2m)
MeOC6H4(1m
)
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
3-
24
5
45(2n
72(2o
53(2p
51(2q
)
MeOC6H4(1n
)
4-
)
MeOC6H4(1o
4-tert-
ButylC6H4(1p
)
24
36
)
)
)
cyclopropyl
After successfully synthesized
a series of Indole
(
1q
2-naphthyl(1r)
H(1s
4-FC6H4(1t
4-ClC6H4(1u
4-NO2C6H4(1v
Ph(1w
)
derivatives by oxidative C–H amination of 2-alkenylanilines. To
gain more insight about the mechanism of above reaction,
several control experiments were conducted (Scheme 2). First,
TEMPO as a radical scavenger was added into the reaction
with optimized conditions. However, there is no desired
product was obtained only recovered the starting material.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
H
H
H
H
Me
MeO
F
Cl
CF3
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
17
48
36
36
48
48
36
36
36
36
24
36
48
36
76(2r)
)
37(2s
44(2t
)
)
)
)
36(2u)
ND
55(2w)
64(2x
50(2y
47(2z)
36(2aa
30(2ab
)
)
)
)
)
)
)
)
The fact might suggest
a radical initiation pathway.
Ph(1x
Ph(1y
Ph(1z
Ph(1aa
Ph(1ab
)
)
Furthermore, this oxidation was completely inhibited under
nitrogen. A control study using hydrogen peroxide as the
oxidant did not lead to the desired indole. This result indicates
that the reaction is not mediated by hydrogen peroxide.
)
)
H
Me
CF3
Cl
H
H
Ph(1ac
37(2ac)
64(2ad
32(2ae
4-MeC6H4(1ad
4-MeC6H4(1ae
)
)
)
)
aReaction conditions: Substrate
1
(0.1 mmol), 3,5-
dichlorobenzoic acid (0.2 equiv), DMSO/1,4-dioxane (1:1, 1.0
mL), 120 oC under O2 (balloon). bIsolated yield. ND = Not
detected.
groups at different positions furnished the corresponding
products in moderate to good yields. For example, substrates
with a methyl or methoxyl group at ortho-, meta- and para-
substitution on the phenyl ring provided the desired products
with 45-72% yields (Table 3, entries 2-7). Both tert-
butylbenzene alkene and cyclopropyl alkene only can obtain
about 50% yields (Table 3, entries 8, 9). The alkene without
any substitutions is also suitable under the reaction conditions
(Table 3, entry 11). It is noted that the naphthyl alkene formed
the desired product in best yield (76% yield, Table 3, entry 10).
While the electron-withdrawing groups at different positions
obtained the corresponding products in lower yields. Such as
substrates with F, Cl substituents on the phenyl ring provided
the desired products in 44% and 36% yields respectively (Table
3, entries 12, 13). When the substrates with NO2 on the phenyl
Scheme 2. Control experiments.
Although the reaction mechanism has not been fully
established at the present stage,8,9 a plausible mechanism for
this reaction was outlined in Scheme 3. Under thermal
condition, anilide was oxidized into nitrogen radical cation by
singlet oxygen, then electrophilic addition of this radical cation
to alkene to generate benzylic radical, which was oxidated to
its corresponding benzylic cation. During this process, 3,5-
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dichlorobenzoate anion was formed and it can assist the purified by column chromatography on silica geVlietwoArgtiicvleeOntlhinee
DOI: 10.1039/C6RA03378D
following aromatization to provide the product.
corresponding product.
o
N-Ts-2-Phenylindole (2a).4b White solid, mp: 145-148 C (Lit.
o
1
142-144 C); Rf = 0.59 (10% EtOAc/Petroleum Ether); H NMR
(600 MHz, CDCl3) δ 2.27 (s, 3H), 6.54 (s, 1H), 7.03 (d, J = 7.8 Hz,
2H), 7.27 (d, J = 7.7 Hz, 3H), 7.35 (t, J = 7.7 Hz, 1H), 7.43 - 7.44
(m, 4H), 7.49 - 7.50 (m, 2H), 8.31 (d, J = 8.3 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 21.5, 113.6, 116.6, 120.7, 124.3, 124.8,
126.8, 127.5, 128.6, 129.2, 130.3, 130.5, 132.4, 134.6, 138.2,
142.1, 144.5; HRMS (ESI): m/z calcd for C21H17NO2S (M+Na)+
370.0878, found 370.0891.
N-(Benzenesulfonyl)-2-Phenylindole (2b). 4b White solid, mp:
91-93 oC (Lit. 98-101 oC); Rf = 0.42 (10% EtOAc/Petroleum
1
Ether); H NMR (600 MHz, CDCl3) δ 6.53 (s, 1H), 7.23 (t, J = 7.8
Scheme 3. A proposed mechanistic pathway.
Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.34 - 7.49 (m, 10H), 8.32 (d, J
= 8.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 112.7, 115.6, 119.7,
123.4, 123.8, 125.7, 126.5, 127.5, 127.7, 129.3, 129.5, 131.3,
132.5, 137.5, 139.2, 142.1; HRMS (ESI): m/z calcd for
C20H15NO2S (M+Na)+ 356.0721, found 356.0729.
Conclusions
In conclusion, we have demonstrated a synthetic method to
prepare the indole derivatives via an oxidative intramolecular
C-H amination of 2-alkenylanilines by using molecular oxygen
as sole oxidant. In comparison to other oxidants mediated
reactions, this method was an environmentally friendly
process. Furthermore, our discovery provides a possibility to
design more new reactions in the field of aerobic oxidation of
alkene.
N-(4-Chlorophenylsulfonyl)-2-phenylindole (2c).4b White solid,
mp: 155-157 oC (Lit. 152-158 oC); Rf
= 0.59 (10%
1
EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 6.56 (s,
1H), 7.21 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 8.4 Hz, 3H), 7.36 (t, J =
7.8 Hz, 1H), 7.42 - 7.49 (m, 6H), 8.29 (d, J = 8.4 Hz, 1H). 13C
NMR (150 MHz, CDCl3) δ 113.1, 115.7, 119.9, 123.7, 124.0,
126.6, 127.2, 127.8, 127.9, 129.2, 129.6, 131.1, 134.7, 137.2,
139.2, 141.0; HRMS (ESI): m/z calcd for C20H14ClNO2S (M+Na)+
390.0331, found 390.0333.
Experimental
o
N-Ns-2-phenylindole (2d).4b Light yellow solid, mp: 142-144 C
o
1
(Lit. 140-147 C); Rf = 0.37 (10% EtOAc/Petroleum Ether); H
NMR (600 MHz, CDCl3) δ 6.60 (s, 1H), 7.30 (t, J = 7.2 Hz, 1H),
7.39 (t, J = 8.4 Hz, 1H), 7.44 - 7.50 (m, 6H), 7.53 (d, J = 9.0 Hz,
1H), 8.08 (d, J = 9.0 Hz, 2H), 8.29 (d, J = 8.4 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 114.8, 116.7, 121.2, 123.8, 125.2, 125.4,
127.8, 128.1, 129.1, 130.2, 130.8, 131.7, 138.1, 141.9, 142.3,
150.4; HRMS (ESI): m/z calcd for C20H14N2O4S (M+Na)+
401.0572, found 401.0581.
General Information
All reactions were performed in standard glassware. Solvents
were distilled prior to use. All commercially available reagents
were used as purchased without further purification. H and
1
13C NMR spectra were obtained on 600 MHz (150 MHz for 13C
NMR) spectrometer at 25 °C, using CDCl3 with TMS or residual
solvent as standard unless otherwise noted. Chemical-shift
values were given in ppm and referenced to the internal
standard TMS (tetramethylsilane). The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q,
quadruplet; m, multiplet; dd, doublet of doublets, and br s,
broad singlet. The coupling constants (J) are reported in hertz
(Hz). Melting points were determined with a micromelting
point apparatus without corrections. High-resolution mass
o
N-Ms-2-Phenylindole (2f).4b White solid, mp: 100-102 C (Lit.
o
1
107-108 C); Rf = 0.38 (10% EtOAc/Petroleum Ether); H NMR
(600 MHz, CDCl3) δ 2.71 (s, 3H), 6.70 (s, 1H), 7.35 (t, J = 7.4 Hz,
1H), 7.38 (t, J = 7.6 Hz, 1H), 7.41 - 7.42 (m, 3H), 7.54 - 7.55 (m,
2H), 7.59 (d, J = 7.4 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 38.4, 112.0, 114.8, 120.0, 123.5, 124.1,
126.7, 127.9, 129.1, 129.3, 131.0, 137.0, 141.0; HRMS (ESI):
m/z calcd for C15H13NO2S (M+Na)+ 294.0565, found 294.0570.
spectrometry (HRMS) was obtained on
microspectrometer. Flash column chromatography was
performed over silica gel 200−300 mesh.
a
Q-TOF
o
N-Ts-2-o-Tolylindole (2j).4b White solid, mp: 90-92 C (Lit. 82-
o
1
89 C); Rf = 0.54 (10% EtOAc/Petroleum Ether); H NMR (600
MHz, CDCl3) δ 2.21 (s, 3H), 2.31 (s, 3H), 6.46 (s, 1H), 7.08 - 7.10
(m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 8.1 Hz, 2H), 7.35 -
General Procedure for the Indole Synthesis
.
7.37 (m, 4H), 7.49 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H). 13
C
To a solution of substrate (0.1 mmol) in DMSO/1,4-dixoane
(1:1, 1.0 mL) was added 3,5-dichlorobenzoic acid (4 mg, 0.02
mmol) under oxygen (balloon). The resulting mixture was
NMR (150 MHz, CDCl3) δ 19.5, 20.5, 111.3, 114.7, 119.6, 122.8,
123.5, 123.6, 125.9, 128.1, 128.3, 128.6, 129.0, 129.8, 131.1,
134.6, 136.3, 138.3, 139.3, 143.6; HRMS (ESI): m/z calcd for
C22H19NO2S (M+Na)+ 384.1034, found 384.1049.
o
stirred at 120 C for the reported time, and then the mixture
o
N-Ts-2-m-Tolylindole (2k).4b White solid, mp: 144-147 C (Lit.
was concentrated under reduced pressure. The residue was
o
1
140-144 C); Rf = 0.43 (10% EtOAc/Petroleum Ether); H NMR
4 | J. Name., 2012, 00, 1-3
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(600 MHz, CDCl3) δ 2.28 (s, 3H), 2.41 (s, 3H), 6.52 (s, 1H), 7.03 N-Ts-2-Cyclopropylindole (2q).6b light yellow oil. Rf = 0.43 (5%
View Article Online
1
DOI: 10.1039/C6RA03378D
(d, J = 7.7 Hz, 2H), 7.24 - 7.30 (m, 7H), 7.34 (t, J = 8.0 Hz, 1H), EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 0.59 (d, J
7.43 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H). 13C NMR (151 = 5.1 Hz, 2H), 0.95 (d, J = 8.0 Hz, 2H), 2.34 (s, 2H), 2.42 - 2.46
MHz, CDCl3) δ 21.4, 21.6, 113.4, 116.6, 120.7, 124.3, 124.7, (m, 1H), 6.17 (s, 1H), 7.19 - 7.20 (m, 3H), 7.25 (t, J = 7.6 Hz, 1H),
126.8, 127.4, 129.1, 129.4, 130.5, 131.1, 132.3, 134.7, 137.0, 7.38 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H), 8.21 (d, J = 8.3
138.2, 142.3, 144.5; HRMS (ESI): m/z calcd for C22H19NO2S Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 7.33 8.40, 20.5, 105.0,
(M+Na)+ 384.1034, found 384.1016.
113.5, 119.1, 122.3, 122.8, 125.6, 128.2, 128.6, 135.5, 136.3,
N-Ts-2-p-Tolylindole (2l).4b White solid, mp: 98-101 C (Lit. 99- 143.0, 143.5; HRMS (ESI): m/z calcd for C18H18NO2S (M+H)+
o
o
1
103 C); Rf = 0.46 (10% EtOAc/Petroleum Ether); H NMR (600 312.1058, found 312.1049.
o
MHz, CDCl3) δ 2.27 (s, 3H), 2.43 (s, 3H), 6.50 (s, 1H), 7.04 (d, J = N-Ts-2-(1-Naphthyl)indole (2r).4b White solid, mp: 139-143 C
o
1
7.7 Hz, 2H), 7.23-7.28 (m, 5H), 7.33 (t, J = 7.7 Hz, 1H), 7.40 (t, J (Lit. 138-142 C); Rf = 0.45 (10% EtOAc/Petroleum Ether); H
= 8.9 Hz, 3H), 8.30 (d, J = 8.3 Hz, 1H). 13C NMR (150 MHz, CDCl3) NMR (600 MHz, CDCl3) δ 2.25 (s, 3H), 6.65 (s, 1H), 6.96 (d, J =
δ 21.4, 21.5, 113.3, 116.7, 120.6, 124.3, 124.6, 126.8, 128.3, 7.8 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.40
129.2, 129.5, 130.2, 130.7, 134.7, 138.2, 138.6, 142.3, 144.4; - 7.46 (m, 3H), 7.51 (t, J = 7.7Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H),
HRMS (ESI): m/z calcd for C22H19NO2S (M+Na)+ 384.1034, 7.64 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2
found 384.1024.
Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ
N-Ts-2-(2-Methoxyphenyl)indole (2m).4b White solid, mp: 72- 21.5, 113.7, 115.8, 120.8, 123.9, 124.4, 124.8, 125.8, 126.1,
75 oC(Lit. 77-80 oC); Rf = 0.50 (10% EtOAc/Petroleum Ether); H 126.2, 126.9, 128.0, 129.3, 129.4, 129.5, 129.8, 130.0, 133.0,
1
NMR (600 MHz, CDCl3) δ 2.29 (s, 3H), 3.77 (s, 3H), 6.53 (s, 1H), 133.4, 135.3, 137.6, 138.8, 144.5; HRMS (ESI): m/z calcd for
6.95 (d, J = 8.2 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 7.9 C25H19NO2S (M+Na)+ 420.1034, found 420.1035.
o
o
Hz, 2H), 7.20 - 7.24 (m, 2H), 7.31 (t, J = 7.7 Hz, 1H), 7.39 (d, J = N-Ts-Indole (2s).4b White solid, mp: 57-60 C (Lit. 68-71 C); Rf
1
7.8 Hz, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 8.22 = 0.45 (10% EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3)
(d, J = 8.3 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 21.5, 55.5, δ 2.33 (s, 3H), 6.65 (d, J = 2.9 Hz, 1H), 7.20 - 7.28 (m, 3H), 7.30
110.5, 112.4, 115.6, 119.6, 120.7, 121.9, 123.6, 124.4, 126.8, (t, J = 7.7 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 3.0 Hz,
129.2, 130.2, 130.6, 131.8, 135.8, 137.4, 138.0, 144.3, 158.6; 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.99 (d, J = 8.3 Hz, 1H). 13C NMR
HRMS (ESI): m/z calcd for C22H19NO3S (M+Na)+ 400.0983, (150 MHz, CDCl3) δ 20.5, 108.0, 112.5, 120.3, 122.2, 123.5,
found 400.0978.
125.3, 125.8, 128.8, 129.7, 133.8, 134.3, 143.9; HRMS (ESI):
N-Ts-2-(3-Methoxyphenyl)indole (2n).4b White solid, mp: 100- m/z calcd for C15H13NO2S (M+Na)+ 294.0565, found 294.0598.
102 oC (Lit. 98-104 oC); Rf = 0.46 (10% EtOAc/Petroleum Ether); N-Ts-2-(4-Fluorophenyl)indole (2t).6a White solid, mp: 130-132
1H NMR (600 MHz, CDCl3) δ 2.27 (s, 3H), 3.85 (s, 3H), 6.54 (s, oC (Lit. 134-137 oC); Rf = 0.62 (10% EtOAc/Petroleum Ether); H
1
1H), 6.99 (dd, J = 8.2 Hz, 1H), 7.04 (d, J = 8.4 Hz, 3H), 7.09 (d, J NMR (600 MHz, CDCl3) δ 2.28 (s, 3H), 6.52 (s, 1H), 7.04 (d, J =
= 7.4 Hz, 1H), 7.25 - 7.36 (m, 5H), 7.44 (d, J = 7.7 Hz, 1H), 8.31 7.8 Hz, 2H), 7.10 (t, J = 8.3 Hz, 2H), 7.24 - 7.27 (m, 3H), 7.35 (t, J
(d, J = 8.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 21.2, 55.0, = 7.7 Hz, 1H), 7.43 - 7.46 (m, 3H), 8.31 (d, J = 8.4 Hz, 1H). 13C
113.3, 114.2, 115.6, 116.4, 120.4, 122.5, 124.0, 124.5, 126.5, NMR (150 MHz, CDCl3) δ 21.5, 113.6, 114.5 (d, J = 21.7 Hz),
128.2, 128.9, 130.2, 133.3, 134.3, 138.0, 141.6, 144.2, 158.4; 116.6, 120.7, 124.4, 124.9, 126.7, 128.4 (d, J = 3.2 Hz), 129.3,
HRMS (ESI): m/z calcd for C22H19NO3S (M+Na)+ 400.0983, 130.4, 132.1 (d, J = 8.2 Hz), 134.7, 138.2, 140.9, 144.7, 163.9 (d,
found 400.0982.
J = 247 Hz); HRMS (ESI): m/z calcd for C21H16FNO2S (M+Na)+
N-Ts-2-(4-Methoxyphenyl)indole (2o).4b White solid, mp: 131- 388.0783, found 388.0776.
133 oC (Lit. 126-128 oC); Rf = 0.42 (10% EtOAc/Petroleum N-Ts-2-(4-Chlorophenyl)indole (2u).4b Light yellow solid, mp:
1
o
o
Ether); H NMR (600 MHz, CDCl3) δ 2.27 (s, 3H), 3.88 (s, 3H), 134-137 C (Lit. 133-135 C); Rf = 0.61 (10% EtOAc/Petroleum
1
6.47 (s, 1H), 6.94 (d, J = 7.74 Hz, 2H), 7.03 (d, J = 7.4 Hz, 2H), Ether); H NMR (600 MHz, CDCl3) δ 2.29 (s, 3H), 6.54 (s, 1H),
7.25 - 7.26(m, 3H), 7.32 (t, J = 7.3 Hz, 1H), 7.41 (d, J = 7.5 Hz, 7.06 (d, J = 7.7 Hz, 2H), 7.26 (d, J = 5.1 Hz, 3H), 7.35 - 7.40 (m,
3H), 8.30 (d, J = 8.1 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 20.5, 3H), 7.44 (d, J = 7.8 Hz, 3H), 8.30 (d, J = 8.3 Hz, 1H). 13C NMR
55.3, 111.9, 112.0, 115.7, 119.4, 123.2, 123.5, 123.7, 125.7, (150 MHz, CDCl3) δ 20.5, 113.0, 115.7, 119.8, 123.4, 124.0,
128.1, 129.6, 130.6, 133.6, 137.1, 141.0, 143.4, 16059.0; HRMS 125.7, 126.8, 128.2, 129.4, 129.8, 130.5, 133.5, 133.8, 137.3,
(ESI): m/z calcd for C22H19NO3S (M+Na)+ 400.0983, found 139.8, 143.7; HRMS (ESI): m/z calcd for C21H16ClNO2S (M+Na)+
400.0981.
404.0488, found 404.0488.
N-Ts-2-p-tert-butylindole (2p).6a White solid, mp: 140-143 °C N-Ts-5-Methyl-2-phenylindole (2w).4b White solid, mp: 100-
(Lit. 139-143 C); Rf = 0.71 (10% EtOAc/Petroleum Ether); H 103 oC (Lit. 114-115 oC); Rf = 0.50 (10% EtOAc/Petroleum
NMR (600 MHz, CDCl3) δ 1.39 (s, 9H), 2.28 (s, 3H), 6.50 (s, 1H), Ether); H NMR (600 MHz, CDCl3) δ 2.28 (s, 3H), 2.41 (s, 1H),
o
1
1
7.01 (d, J = 7.8 Hz, 2H), 7.23 - 7.27 (m, 3H), 7.33 (t, J = 7.8 Hz, 6.47 (s, 1H), 7.04 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H),
1H), 7.41 - 7.42 (m, 5H), 8.30 (d, J = 8.3 Hz, 1H). 13C NMR (150 7.22 (s, 1H), 7.25 (s, 2H), 7.40 - 7.42 (m, 3H), 7.48 - 7.50 (m,
MHz, CDCl3) δ 21.5, 31.4, 34.7, 113.3, 116.7, 120.6, 124.2, 2H), 8.17 (d, J = 8.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 21.3,
124.4, 124.6, 126.8, 129.1, 129.4, 130.0, 130.6, 134.7, 138.3, 21.5, 113.6, 116.4, 120.6, 126.2, 126.8, 127.5, 128.6, 129.2,
142.3, 144.4, 151.7; HRMS (ESI): m/z calcd for C25H25NO2S 130.3, 130.8, 132.5, 134.0, 134.6, 136.5, 142.3, 144.4; HRMS
(M+Na)+ 426.1504, found 426.1503.
(ESI): m/z calcd for C22H19NO2S (M+Na)+ 384.1034, found
384.1029.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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ARTICLE
Journal Name
N-Ts-5-Methoxy-2-phenylindole (2x).6a White solid, mp: 114- signal was missing due to peak overlap); HRMS (ESI): m/z calcd
View Article Online
DOI: 10.1039/C6RA03378D
+
117 oC (Lit. 123-125 oC); Rf = 0.48 (10% EtOAc/Petroleum for C21H16ClNO2S (M+Na) 404.0488, found 404.0488.
Ether); H NMR (600 MHz, CDCl3) δ 2.20 (s, 3H), 3.74(s, 3H), N-Ts-5-Methyl-2-p-tolylindole (2ad).6a White solid, mp: 144-
1
6.39 (s, 1H), 6.80 (s, 1H), 6.88 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 7.9 146 oC (Lit. 143-145 oC); Rf = 0.50 (10% EtOAc/Petroleum
1
Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 7.34 - 7.41 (m, 5H), 8.12 (d, J = Ether). H NMR (600 MHz, CDCl3) δ 2.28 (s, 3H), 2.40 (s, 3H),
9.0 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 21.5, 55.6, 103.1, 2.44 (s, 3H), 6.44 (s, 1H), 7.03 (d, J = 7.7 Hz, 2H), 7.15 (d, J = 8.5
113.4, 113.9, 117.7, 126.8, 127.5, 128.6, 129.1, 130.2, 131.7, Hz, 1H), 7.20 (s, 1H), 7.22 - 7.27 (m, 4H), 7.40 (d, J = 7.5 Hz, 2H),
132.4, 132.8, 134.3, 143.1, 144.4, 157.0; HRMS (ESI): m/z calcd 8.16 (d, J = 8.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 21.3, 21.4,
for C22H19NO3S (M+Na)+ 400.0983, found 400.0983.
21.5, 113.2, 116.4, 120.5, 126.0, 126.8, 128.2, 129.1, 129.7,
N-Ts-5-Fluoro-2-phenylindole (2y).6a Light yellow solid, mp: 130.1, 130.9, 133.9, 134.6, 138.5, 144.3; HRMS (ESI): m/z calcd
104-106 C (Lit. 110-112 C); Rf = 0.57 (10% EtOAc/ Petroleum for C23H21NO2S (M+Na)+ 398.1191, found 398.1191.
o
o
Ether); H NMR (600 MHz, CDCl3) δ 2.29 (s, 3H), 6.49 (s, 1H), N-Ts-5-Trifluoromethyl-2-p-tolylindole (2ae).6a White solid,
1
1
7.05 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 7.9 mp: 148-150 oC; Rf = 0.65 (10% EtOAc/Petroleum Ether). H
Hz, 2H), 7.42 - 7.44 (m, 3H), 7.49 (d, J = 7.0 Hz, 2H), 8.26 (dd, J NMR (600 MHz, CDCl3) δ 2.31 (s, 3H), 2.45 (s, 3H), 6.56 (s, 1H),
= 4.4, 8.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 20.5, 105.2 (d, J 7.07 (d, J = 7.7 Hz, 2H), 7.24 - 7.28 (m, 5H), 7.37 (d, J = 7.3 Hz,
= 23.9 Hz), 111.5 (d, J = 24.9 Hz), 112.3 (d, J = 3.4 Hz), 116.9 (d, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 8.41 (d, J = 8.7 Hz, 1H).
J = 9.3 Hz), 125.7, 126.5, 127.9, 128.3, 129.2, 130.6, 131.0, 13C NMR (150 MHz, CDCl3) δ 21.5, 21.6, 112.5, 116.7, 118.0 (d,
133.2, 133.5, 142.9, 143.7, 158.3; HRMS (ESI): m/z calcd for J = 3.77 Hz), 121.2 (d, J = 3.4 Hz), 126.4, 126.6, 126.8, 128.3,
C21H16FNO2S (M+Na)+ 388.0783, found 388.0783.
128.7, 129.4, 130.1, 130.4, 134.7, 139.2, 139.6, 143.9, 145.0;
N-Ts-5-Chloro-2-phenylindole (2z).4b White solid, mp: 138-140 HRMS (ESI): m/z calcd for C23H18F3NO2S (M+Na)+ 452.0908,
oC (Lit. 136-137 oC); Rf = 0.61 (10% EtOAc/Petroleum Ether); H found 452.0917.
1
NMR (600 MHz, CDCl3) δ 2.30 (s, 3H), 6.47 (s, 1H), 7.05 (d, J =
7.9 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 8.8 Hz, 1H), 7.40
- 7.45 (m, 4H), 7.47 (d, J = 7.1 Hz, 2H), 8.23 (d, J = 8.8 Hz, 1H).
Acknowledgements
13C NMR (150 MHz, CDCl3) δ 21.5, 112.6, 117.7, 120.3, 124.9, This project was partially sponsored by the Scientific Research
126.8, 127.6, 129.0, 129.3, 130.0, 130.4, 131.7, 131.9, 134.5, Foundation for the Returned Overseas Chinese Scholars, State
136.6, 143.6, 144.8; HRMS (ESI): m/z calcd for C21H16ClNO2S Education Ministry, the National Basic Research Project (No.
(M+Na)+ 404.0488, found 404.0488.
2014CB932201) and the National Natural Science Foundation
N-Ts-2-Phenyl-5-(trifluoromethyl)indole (2aa).4b White solid, of China (No. 21572154).
mp: 115-118 oC (Lit. 120-124 oC); Rf
= 0.67 (20%
1
EtOAc/Petroleum Ether); H NMR (600 MHz, CDCl3) δ 2.31 (s,
3H), 6.59 (s, 1H), 7.08 (d, J = 7.7 Hz, 2H), 7.26 (d, J = 6.4 Hz, 2H),
7.44 - 7.47 (m, 5H), 7.60 (d, J = 8.7 Hz, 1H), 7.74 (s, 1H), 8.42 (d,
J = 8.7 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 21.6, 112.7, 116.7,
118.1 (q, J = 4.0 Hz), 121.4 (q, J = 3.3 Hz), 125.4, 126.6 (q, J =
32.3 Hz), 126.8, 127.6, 129.1, 129.5, 130.0, 130.5, 131.6, 134.7,
139.6, 143.7, 145.1; HRMS (ESI): m/z calcd for C22H16F3NO2S
(M+Na)+ 438.0752, found 438.0757.
Notes and references
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(b) M. Somei and F. Yamada, Nat. Prod. Rep., 2004, 21, 278;
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S. Takween, S. Akhtar, M. Arif and K. M. Khan, Pak. J.
Pharm. Sci., 2008, 21, 36.
N-Ts-6-Fluoro-2-phenylindole (2ab).6a White solid, mp: 97-100
(2) For selected reviews on indole synthesis, see: (a) B.
Robinson, Chem. Rev., 1963, 63, 373; (b) G. R. Humphrey
and J. T. Kuethe, Chem. Rev., 2006, 106, 2875; (c) M. Shiri,
Chem. Rev., 2012, 112, 3508; (d) K. Kruger, A. Tillack and M.
Beller, Adv. Synth. Catal., 2008, 350, 2153; (e) M.
1
oC (Lit. 103-105 oC); Rf = 0.61 (10% EtOAc/Petroleum Ether); H
NMR (600 MHz, CDCl3) δ 2.30 (s, 3H), 6.50 (s, 1H), 7.02 (t, J =
8.7 Hz, 1H), 7.07 (d, J = 7.9 Hz, 2H), 7.26-7.28 (m, 3H), 7.36 (t, J
= 6.6 Hz, 1H), 7.42-7.47 (m, 4H), 8.06 (d, J = 10.3 Hz, 1H). 13C
NMR (150 MHz, CDCl3) δ 21.6, 104.1 (d, J = 28.5 Hz), 112.6 (d, J
= 23.7 Hz), 121.3 (d, J = 9.7 Hz), 126.7, 126.8, 127.5, 128.8,
129.3, 130.3, 132.1, 134.6, 138.5 (d, J = 12.4 Hz), 142.4, 144.8,
160.1, 161.7; HRMS (ESI): m/z calcd for C21H16FNO2S (M+Na)+
388.0783, found 388.0783.
Inmanand and C. J. Moody, Chem.Sci., 2013, 4, 29; (f) I.
Nakamura and Y. Yamamoto, Chem. Rev., 2004, 104, 2127;
(g) D. F. Taber and P. K. Tirunahari, Tetrahedron, 2011, 67
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7195.
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G. Fabrizi, Chem. Rev., 2005, 105, 2873; (b) S. Cacchi and G.
Fabrizi, Chem. Rev., 2011, 111, PR215; For selected recent
examples of Rh-catalyzed indole synthesis, see: (c) D. Shu,
W. Song, X. Li and W. Tang, Angew. Chem., Int. Ed., 2013,
52, 3237; (d) C. Jones, Q. Nguyen and T. G. Driver, Angew.
Chem., Int. Ed., 2014, 53, 785; (e) C. Wang and Y. Huang,
Org. Lett., 2013, 15, 5294; (f) B. Liu, C. Song, C. Sun, S. Zhou
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Stuart, P. Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc.,
2010, 132, 18326; (h) N. Selander, B. T. Worrell, S.
N-Ts-6-Chloro-2-phenylindole (2ac).4b White solid, mp: 137-
140 oC (Lit. 140-144 oC); Rf = 0.57 (10% EtOAc/Petroleum
1
Ether); H NMR (600 MHz, CDCl3) δ 2.30 (s, 3H), 6.49 (s, 1H),
7.06 (d, J = 7.9 Hz, 2H), 7.24 - 7,26 (m, 3H), 7.35 (d, J = 8.2 Hz,
1H), 7.41 - 7.46 (m, 5H), 8.34 (s, 1H). 13C NMR (150 MHz, CDCl3)
δ 21.6, 112.9, 116.7, 121.3, 124.9, 126.8, 127.5, 128.9, 129.4,
130.4, 130.6, 131.9, 134.5, 138.6, 142.6, 144.9 (One carbon
6 | J. Name., 2012, 00, 1-3
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RSC Advances
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Journal Name ARTICLE
Chuprakov, S. Velaparthi and V. V. Fokin, J. Am. Chem. Soc.,
2012, 134, 14670.
View Article Online
DOI: 10.1039/C6RA03378D
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DOI: 10.1039/C6RA03378D
A novel approach to indole derivatives from N-Ts-2-alkenylanilines has been achieved, which
involves an oxidative intramolecular C-H amination by using molecular oxygen as sole oxidant.
This protocol is operationally simple and environmental friendly, and provides a diverse range of
substrate scope.