Transition-metal-free synthesis of multisubstituted N-arylindoles via reaction of arynes and α-amino ketones

Article abstract of DOI:10.1016/j.tet.2014.02.028

A simple transition-metal-free protocol for the synthesis of indoles has been developed using aryne cycloaddition. The in situ-generated arynes couple with α-amino ketones through a one-step N-arylation-nucleophilic addition process under mild conditions and efficiently produce multisubstituted N-arylindoles.

Full text of DOI:10.1016/j.tet.2014.02.028

Tetrahedron 70 (2014) 2400e2405
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Transition-metal-free synthesis of multisubstituted N-arylindoles
via reaction of arynes and a-amino ketones
*
Lin He , Ji-Xin Pian, Jun-Feng Shi, Guang-Fen Du, Bin Dai
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University,
Xinjiang Uygur Autonomous Region 832000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A
simple transition-metal-free protocol for the synthesis of indoles has been developed using
Received 12 December 2013
Received in revised form 23 January 2014
Accepted 13 February 2014
Available online 18 February 2014
aryne cycloaddition. The in situ-generated arynes couple with -amino ketones through a one-step
N-arylationenucleophilic addition process under mild conditions and efficiently produce multi-
substituted N-arylindoles.
a
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Arynes
Cross-coupling reaction
a
-Amino ketones
1. Introduction
the Fischer-cycloaddition. Wang12 also developed an improved
Hemetsberger-indole reaction using arynes and azides, but the
The indole skeleton is a privileged structure found in bi-
ologically active natural products and pharmaceutically active
compounds.1 Continuous efforts have been exerted to develop al-
ternative methods for the synthesis of this ubiquitous aromatic
heterocycle structure.2 Despite the well-established Fischer indole
synthesis,3 in the past decades, numerous methods based on
transition-metal-catalyzed CeC and CeN bond formation reactions
have been developed and have provided facile access to indoles and
their derivatives.4 However, the construction of this heterocyclic
structure faces a number of challenges, such as the requirement of
a stoichiometric amount of transition-metal catalysts or additives,
relatively high reaction temperature, and limited scope of the re-
actions. Hence, the development of an environmentally benign and
efficient approach for the synthesis of these compounds is of high
importance.
products are limited to 2-carboxylated free indoles. We hypothe-
sized that the coupling of arynes with the readily available
a
-
amino ketones would lead to the formation of an indole ring. In
this paper, we report an alternative method for the synthesis of
multisubstituted N-arylindoles.13 The procedure involves a one-
step tandem reaction of arynes under transition-metal-free
conditions.
2. Results and discussion
Our study commenced with a cascade reaction of the commer-
cially available aryne precursor 1a and a-amino ketone 2a in the
presence of 3.0 equiv CsF. The reaction proceeded smoothly in
acetonitrile at room temperature and produced N-arylindole 3a in
60% yield (Table 1, entry 1). KF and Bu4NF were also tested for the
reaction, but they only catalyzed the reaction in low efficiency
(Table 1, entries 2 and 3). When 3.0 equiv 18-crown-6 was added as
a co-additive with 3.0 equiv KF or CsF, the yield of 3a increased
dramatically (Table 1, entries 4 and 5). The suitability of other re-
action media, such as THF, toluene, and DCM, was also evaluated.
The results indicate that CH3CN is the optimal solvent in terms of
yield (Table 1, entries 6e8). Reducing the additive loading resulted
in a dramatic decrease in the reaction yield (Table 1, entries 9e11).
The generality of the reaction was then determined under op-
Arynes5 are highly active intermediates that are widely used in
synthetic chemistry; in particular, the annulation of arynes pro-
vides convenient access to various pharmaceutically active het-
erocycles, such as benzisoxazoles,6 indolines,7 carbazoles,8
coumarines,9 and others.10 Greaney11 reported that arynes can
undergo a Fischer indole reaction with N-tosyl hydrazones to
produce N-tosylindoles efficiently via
a two-step procedure.
However, excess BF3$OEt2 and reflux conditions are required for
timized reaction conditions. As shown in Table 2, various
a-amino
* Corresponding author. E-mail address: helin@shzu.edu.cn (L. He).
ketones can couple with arynes to produce the desired
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.028

L. He et al. / Tetrahedron 70 (2014) 2400e2405
2401
Table 1
be conducted on gram-scale and high yield maintained (Table 2,
entry 22).
Evaluation of reaction conditionsa
Substituted arynes were also successfully used in the cascade
reaction (Table 3). The symmetric arynes derived from pre-
cursors 1b, 1c, and 1d efficiently underwent the coupling re-
action to afford the corresponding multisubstituted indoles in
high yields (Table 3, entries 1e3). Notably, the asymmetric aryne
derived from precursor 1e coupled with
a-amino ketone with
Entry
Additives
Solvent
t (h)
Yieldb (%)
high regioselectivity and yielded 3x as the sole product (Table 3,
1
2
3
4
5
6
7
8
CsF 3.0 equiv
KF 3.0 equiv
Bu4NF 3.0 equiv
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
toluene
CH2Cl2
CH3CN
CH3CN
CH3CN
16
16
13
1
1
4
4
4
6
26
16
60
12
32
93
97
87
13
41
90
entry 4).14
CsFþ18-crown-6 (3.0 equiv)
KFþ18-crown-6 (3.0 equiv)
KFþ18-crown-6 (3.0 equiv)
KFþ18-crown-6 (3.0 equiv)
KFþ18-crown-6 (3.0 equiv)
KFþ18-crown-6 (2.0 equiv)
KFþ18-crown-6 (1.0 equiv)
No additives
Table 3
Evaluation of substituted arynesa
9
10
11
68
<10
a
Reaction conditions: 1a (1.5 equiv), 2a (0.1 M, 1.0 equiv), room temperature.
Isolated yield.
Entry
1
1
Product
Yieldb (%)
b
3v, 87
Table 2
Indole synthesis via aryne cyclizationa
2
3
3w, 88
3x, 90
Entry
R1
R2
R3
3, Yieldb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
p-Cl-Ph
Ph
Ph
Ph
p-MeO-Ph
p-Me-Ph
p-MeO-Ph
Ph
3a, 97
3b, 73
3c, 74
3d, 82
3e, 83
3f, 91
3g, 85
3h, 93
3i, 86
3j, 92
3k, 89
3l, 88
3m, 86
3n, 74
3o, 88
3p, 99
3q, 99
3r, 63
3s, 66
3t, 72
3u, 51
3a, 95
p-Cl-Ph
p-Br-Ph
Ph
p-Br-Ph
p-Me-Ph
p-MeO-Ph
p-Me-Ph
Ph
p-Cl-Ph
p-Br-Ph
Ph
Ph
p-Me-Ph
p-MeO-Ph
p-Me-Ph
Ph
9
4
3y, 95
10
11
12
13
14
15
16
17
18
19
20
21
22c
Ph
Ph
Ph
p-MeO-Ph
p-MeO-Ph
p-Cl-Ph
p-Br-Ph
p-CF3-Ph
m-Br-Ph
o-MeO-Ph
Ph
p-Br-Ph
p-Cl-Ph
p-Br-Ph
Ph
m-MeO-Ph
m-Br-Ph
2-Furan
2-Furan
p-Cl-Ph
Me
Ph
p-MeO-Ph
p-MeO-Ph
a
Reaction conditions: 1 (0.45 mmol), 2a (0.3 mmol), KF (0.9 mmol), 18-crown-6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(0.9 mmol), anhydrous acetonitrile 3.0 mL, room temperature.
b
Isolated yield.
p-MeO-Ph
Me
Et
A plausible mechanism (Scheme 1) was proposed for the cou-
pling reaction of arynes based on the experimental results and
Ph
Ph
pioneering studies.7 The amino group of the
a-amino ketone
a
Reaction conditions: 1a (0.45 mmol), 2 (0.3 mmol), KF (0.9 mmol), 18-crown-6
reacted with the aryne via an insertion reaction and subsequently
underwent nucleophilic addition to the ketone to yield
a substituted indoline, which was also successfully isolated in high
yield.15 Hydrolysis of indoline under acidic conditions produced the
target multisubstituted N-arylindole product.
(0.9 mmol), anhydrous acetonitrile 3.0 mL, room temperature.
b
Isolated yield.
c
Compound 1a (5.0 mmol), compound 2a (4.0 mmol), KF (4.0 mmol), 18-crown-6
(4.0 mmol), anhydrous acetonitrile 5.0 mL, room temperature, 13 h.
multisubstituted N-arylindoles in moderate to high yield (50e99%).
3. Conclusions
Both electron-withdrawing and electron-donating substituents at
different positions of the
a-amino ketones were suitable for these
In conclusion, we have demonstrated a fluoride-mediated
processes (Table 2, entries 1e17). Interestingly, heteroaryl-
substituted N-arylindoles can also be obtained in good yield via
cascade annulation reaction of arynes and a-amino ketones.
The efficient, transition-metal-free and extremely mild condi-
tions provide a novel and conscious approach for the synthesis of
multisubstituted N-arylindoles from readily available sub-
strates.16 Furthermore, the reaction can be readily scaled up
without reducing the reaction yield. Further investigations on the
this coupling reaction (Table 2, entries 17 and 19).
substituted -amino ketones could be employed as suitable sub-
strates to provide -alkyl substituted N-arylindoles in moderate to
good yield (Table 2, entries 20 and 21). The coupling reaction could
a-Alkyl
a
a

2402
L. He et al. / Tetrahedron 70 (2014) 2400e2405
Scheme 1. Proposed mechanism.
detailed reaction mechanism and applications of this coupling
reaction in synthetic chemistry are ongoing within the research
group.
with CH2Cl2 (15.0 mLꢂ3). The combined organic phase was dried
over anhyd Na2SO4, filtered, and concentrated. The crude product
was purified by flash column chromatography on silica gel (PE/
EtOAc, 150:1 to 100:1) to give the desired product.
4. Experimental section
4.1. General methods
4.4. Experimental data
4.4.1. 1,2,3-Triphenyl-1H-indole (3a).19 Yield: 97%; white solid; mp
Unless otherwise indicated, all reactions were conducted under
nitrogen atmosphere in an oven-dried glassware with magnetic
stirring bar. Column chromatography was performed with silica gel
(200e300 mesh) and analytical TLC on silica gel 60-F254. 1H NMR
(400 MHz, CDCl3), 13C NMR (100 MHz, CDCl3) spectra were recor-
ded on 400 MHz spectrometer using deuterated chloroform as
solvent, with tetramethylsilane as an internal standard and re-
190e191 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.83e7.77 (m, 1H),
7.40e7.35 (m, 4H), 7.34e7.28 (m, 4H), 7.25e7.18 (m, 5H), 7.17e7.06
(m, 5H); 13C NMR (100 MHz, CDCl3)
138.1, 137.9, 137.1, 134.9, 131.6,
131.2, 130.2, 129.1, 128.3, 128.3, 127.9, 127.6, 127.3, 127.1, 125.9, 122.7,
120.9, 119.6, 116.7, 110.7. IR (KBr, cmꢀ1
3059, 3043, 1594, 1495,
d
)
n
1448, 1375, 1229, 1077, 746, 699; HRMS (ESI): calcd for C26H19N:
345.1512; found: 345.1511.
ported in parts per million (d ppm). Infrared spectra were recorded
on an FT/IR spectrophotometer and reported as wave number
(cmꢀ1). High-resolution mass spectra (HRMS) were recorded on
FTICRMS. 2-(Trimethylsilyl) aryl triflate 1a, 1c, 1d, 1e, KF, and 18-
crown-6 were obtained from commercial supplies and used with-
4.4.2. 2,3-Bis(4-chlorophenyl)-1-phenyl-1H-indole (3b). Yield: 73%;
light yellow solid; mp 199e200 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.75e7.70 (m, 1H), 7.42e7.33 (m, 3H), 7.32e7.25 (m, 5H),
7.25e7.23 (m, 1H), 7.22e7.17 (m, 3H), 7.14e7.10 (m, 2H), 7.01e6.96
(m, 2H); 13C NMR (100 MHz, CDCl3)
138.0, 137.7, 135.8, 133.7,
133.2, 132.3, 132.0, 131.4, 129.8, 129.3, 128.7, 128.4, 128.2, 127.5,
127.2, 123.2, 121.2, 119.4, 115.9, 110.8. IR (KBr, cmꢀ1
3047, 3039,
out purification. Aryne precursor 1b17 and -aminoketone18 were
a
d
prepared according to literature. Anhydrous THF, toluene were
distilled from sodium and benzophenone. CH2Cl2 and CH3CN were
distilled from calcium hydride. Petroleum ether (PE), where used,
has a boiling range of 60e90 ꢁC.
)
n
1593, 1500, 1448, 1361, 1242, 1109, 1083, 1017, 837, 765, 692. HRMS
(ESI): calcd for [C26H18Cl2N]þ [MþH]þ 414.0811; found: 414.0802.
4.2. General procedure
4.4.3. 2,3-Bis(4-bromophenyl)-1-phenyl-1H-indole (3c). Yield: 90%;
white solid; mp 223e224 ꢁC; 1H NMR (400 MHz, CDCl3)
d 7.75e7.70
To a solution of
0.9 mmol), 18-crown-6 (238 mg, 0.9 mmol) in anhydrous acetoni-
trile (3.0 mL) was added 2-(trimethylsilyl) aryl triflate
(0.45 mmol). The mixture was stirred at room temperature until
full consumption of the starting -aminoketone as indicated by TLC.
a-aminoketone 2 (0.3 mmol), KF (52 mg,
(m, 1H), 7.49e7.44 (m, 2H), 7.43e7.33 (m, 3H), 7.33e7.25 (m, 4H),
7.24e7.18 (m, 5H), 6.94e6.90 (m, 2H); 13C NMR (100 MHz, CDCl3)
1
d
138.0, 137.7, 135.8, 133.6, 132.5, 131.7, 131.6, 131.4, 130.2, 129.3,
128.2, 127.5, 127.1, 123.2, 122.0, 121.3, 120.2, 119.3, 115.9, 110.8. IR
(KBr, cmꢀ1
) n 3043, 3038, 1596, 1540, 1494, 1448, 1368, 1249, 1096,
a
1070, 1003, 818, 745, 692. HRMS (ESI): calcd for [C26H17N1Br2]þ
500.9722; Found: 500.9724 and calcd for [C26H17N1Br811Br1]þ
502.9702; Found: 502.9702.
HCl (2.0 mL, 1.0 mol/L) was added to the reaction mixture and after
it was stirred for 3.0 h at room temperature, neutralized by satd
aq NaHCO3, and extracted with CH2Cl2 (5.0 mLꢂ3). The combined
organic phase was dried over anhyd Na2SO4, filtered, and concen-
trated. The crude product was purified by flash column chroma-
tography on silica gel (PE/EtOAc, 150:1 to 100:1) to give the desired
product.
4.4.4. 1-(4-Chlorophenyl)-2,3-diphenyl-1H-indole (3d). Yield: 82%;
white solid; mp 155e156 ꢁC; 1H NMR (400 MHz, CDCl3)
d 7.82e7.76
(m, 1H), 7.38e7.35 (m, 1H), 7.35e7.31 (m, 5H), 7.30e7.28 (m, 1H),
7.27e7.25 (m, 1H), 7.24e7.20 (m, 2H), 7.20e7.13 (m, 5H), 7.09e7.05
4.3. Scale-up experiment
(m, 2H); 13C NMR (100 MHz, CDCl3)
d
137.8, 136.9, 136.7, 134.7,
132.8, 131.3, 131.2, 130.2, 129.4, 129.3, 128.3, 128.1, 127.7, 127.6, 126.1,
123.0, 121.1, 119.8, 117.2, 110.4. IR (KBr, cmꢀ1
3045, 2919, 1494,
To a solution of
a
-aminoketone 2a (1.148 g, 4.0 mmol), KF
) n
(232 mg, 4.0 mmol), 18-crown-6 (1.06 g, 4.0 mmol) in anhydrous
acetonitrile (5.0 mL) was added 2-(trimethylsilyl) aryl triflate
(1.2 mL, 5 mmol). The mixture was stirred for 13 h at room tem-
perature under a nitrogen atmosphere. Then HCl (6.0 mL, 1.0 mol/L)
was added to the reaction mixture and after it was stirred for 3.0 h
at room temperature, neutralized by satd aq NaHCO3, and extracted
1448, 1368, 1229, 1169, 1010, 818, 738, 698. HRMS (EI): calcd for
[C26H18NCl]þ 379.1128; found: 379.1130.
4.4.5. 3-(4-Bromophenyl)-1,2-diphenyl-1H-indole (3e). Yield: 83%;
white solid; mp 168e169 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.78e7.72
(m, 1H), 7.44 (d, J¼8.32 Hz, 2H), 7.40e7.28 (m, 5H), 7.26e7.23

L. He et al. / Tetrahedron 70 (2014) 2400e2405
2403
(m, 4H), 7.21e7.14 (m, 4H), 7.09e7.04 (m, 2H); 13C NMR (100 MHz,
CDCl3) 137.9, 137.3, 134.0, 131.7, 131.4, 131.3, 131.1, 129.1, 128.2,
128.0, 127.6, 127.3, 127.2, 122.9, 121.1, 119.83, 119.2, 115.4, 110.8. IR
119.4, 116.2, 113.4, 110.6, 55.1. IR (KBr, cmꢀ1
2827, 1600, 1500, 1448, 1361, 1292, 1250, 1173, 1034, 837, 786, 756,
702, 694. HRMS (EI): calcd for [C27H22NO]þ [MþH]þ 376.1696;
found: 376.1685.
)
n
3039, 2959, 2926,
d
(KBr, cmꢀ1
) n 3059, 2920, 1594, 1534, 1501, 1455, 1362, 1229, 1170,
1063,1004, 819, 746, 693, 653. HRMS (ESI): calcd for [C26H18N1Br1]þ
423.0617; Found: 423.0625 and calcd for [C26H18N811Br1]þ
425.0597; found: 425.0604.
4.4.12. 3-(4-Bromophenyl)-2-(4-methoxyphenyl)-1-phenyl-1H-in-
dole (3l). Yield: 88%; light yellow solid; mp 171e172 ꢁC; 1H NMR
(400 MHz, CDCl3) d 7.76e7.72 (m, 1H), 7.46e7.42 (m, 2H), 7.41e7.35
4.4.6. 1-Phenyl-2,3-di-p-tolyl-1H-indole (3f). Yield: 91%; light yel-
(m, 2H), 7.34e7.28 (m, 2H), 7.25e7.22 (m, 4H), 7.22e7.20 (m, 2H),
low solid; mp 176e177 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.79e7.75
(m, 1H), 7.39e7.34 (m, 2H), 7.32e7.27 (m, 3H), 7.24e7.16 (m, 4H),
7.15e7.12 (m, 2H), 6.98e6.91 (m, 4H), 2.36 (s, 3H), 2.26 (s, 3H); 13
NMR (100 MHz, CDCl3) 138.3, 137.8, 137.0, 136.9, 135.3, 132.0,
131.0, 130.0, 129.0, 128.6, 128.6, 128.3, 127.7, 127.0, 122.5, 120.7,
119.5, 116.3,110.5, 21.3, 21.2. IR (KBr, cmꢀ1
3025, 2913, 1494, 1448,
6.99e6.96 (m, 2H), 6.71e6.67 (m, 2H), 3.75 (s, 3H); 13C NMR
(100 MHz, CDCl3)
131.4, 129.1, 128.3, 127.2, 127.2, 123.5, 122.7, 121.0, 119.7, 119.1, 114.9,
113.6, 110.7, 55.1. IR (KBr, cmꢀ1
3039, 2946, 2827, 1593, 1547, 1507,
d 158.9, 138.0, 137.8, 137.2, 134.2, 132.3, 131.7,
C
d
) n
1454, 1368, 1242, 1169, 1030, 844, 745, 692. HRMS (EI): calcd for
[C27H20ONBr]þ 453.0723; found: 453.0718 and calcd for
[C27H20ON81Br]þ 455.0702; found: 455.0705.
)
n
1361, 1235, 1096, 1016, 818, 738, 692, 652. HRMS (EI): calcd for
[C28H23N1]þ 373.1825; found: 373.1822.
4.4.13. 2,3-Bis(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-indole
4.4.7. 2,3-Bis(4-methoxyphenyl)-1-phenyl-1H-indole
85%; light yellow solid; mp 166e167 ꢁC; 1H NMR (400 MHz, CDCl3)
7.78e7.72 (m,1H), 7.40e7.34 (m, 2H), 7.33e7.27 (m, 4H), 7.24e7.16
(3g). Yield:
(3m). Yield: 86%; light yellow solid; mp 185e186 ꢁC; 1H NMR
(400 MHz, CDCl3)
d
7.72 (d, J¼7.6 Hz, 1H), 7.33e7.24 (m, 6H),
d
7.22e7.17 (m, 1H), 7.16e7.09 (m, 4H), 6.99 (d, J¼8.4 Hz, 2H), 6.90 (d,
(m, 4H), 6.99 (d, J¼7.96 Hz, 2H), 6.89 (d, J¼7.84 Hz, 2H), 6.67
J¼8.72 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 158.7,
(d, J¼7.96 Hz, 2H), 3.82 (s, 3H), 3.74 (s, 3H); 13C NMR (100 MHz,
138.3, 136.0, 133.6, 133.3, 132.3, 131.9, 131.3, 130.4, 129.9, 129.3,
128.6, 128.4, 127.0, 123.0, 121.1, 119.3, 115.4, 114.5, 110.8, 55.5. IR
CDCl3)
d 158.7, 157.8, 138.3, 137.7, 136.6, 132.3, 131.2, 129.0, 128.3,
127.8, 127.4, 127.0, 124.0, 122.4, 120.7, 119.4, 115.8, 113.8, 113.4, 110.5,
(KBr, cmꢀ1
) n 3039, 2952, 2833, 1607, 1573, 1514, 1454, 1295, 1242,
55.2, 55.1. IR (KBr, cmꢀ1
)
n
3039, 2999, 2952, 2926, 2827, 1620, 1547,
1169, 1083, 1017, 824, 751. HRMS (EI): calcd for [C27H20ONCl2]þ
1514, 1448, 1361, 1248, 1176, 1023, 845, 836, 752, 744, 698. HRMS
[MþH]þ 444.0916; found: 444.0910.
(EI): calcd for [C28H23NO2]þ 405.1729; found: 405.1728.
4.4.14. 2,3-Bis(4-bromophenyl)-1-(4-methoxyphenyl)-1H-indole
4.4.8. 1-(4-Methoxyphenyl)-2,3-di-p-tolyl-1H-indole
93%; light yellow solid; mp 154e155 ꢁC; 1H NMR (400 MHz, CDCl3)
7.79e7.75 (m,1H), 7.28e7.26 (m, 1H), 7.25e7.21 (m, 2H), 7.20e7.16
(3h). Yield:
(3n). Yield: 74%; light yellow solid; mp 198e199 ꢁC; 1H NMR
(400 MHz, CDCl3)
7.28 (d, J¼8.24 Hz, 2H), 7.24e7.17 (m, 5H), 7.12 (d, J¼8.44 Hz, 2H),
6.95e6.87 (m, 4H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3)
158.7,
d
7.72 (d, J¼7.44 Hz, 1H), 7.45 (d, J¼8.16 Hz, 2H),
d
(m, 2H), 7.15e7.11 (m, 4H), 6.99e6.92 (m, 4H), 6.90e6.86 (m, 2H),
d
3.82 (s, 3H), 2.36 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3)
138.4,136.0,133.7,132.6,131.7,131.6,131.3,130.3,130.3,129.3,126.9,
123.1, 121.9, 121.1, 120.0, 119.2, 115.4, 114.5, 110.8, 55.5. IR (KBr,
d
158.4, 138.2, 137.2, 136.9, 135.2, 132.1, 131.1, 131.0, 130.0, 129.4,
129.0, 128.7, 128.6, 127.5, 122.3, 120.5, 119.5, 115.9, 114.2, 110.6, 55.4,
21.3, 21.2. IR (KBr, cmꢀ1
3045, 3019, 2946, 2913, 1520, 1454, 1295,
cmꢀ1
) n 3039, 2929, 2833, 1514, 1494, 1447, 1288, 1242, 1169, 1010,
)
n
818, 745. HRMS (EI): calcd for [C27H19ONBr81Br]þ 532.9807; found:
532.9803.
1242, 1182, 1103, 1023, 817, 802, 748, 736. HRMS (EI): calcd for
[C29H25ON]þ 403.1931; found: 403.1938.
4.4.15. 1,3-Diphenyl-2-(4-(trifluoromethyl)phenyl)-1H-indole
(3o). Yield: 88%; white solid; mp 146.9e148.8 ꢁC; 1H NMR
4.4.9. 2,3-Diphenyl-1-(p-tolyl)-1H-indole (3i). Yield: 86%; white
solid; mp 177e178 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.82e7.76 (m,
1H), 7.39e7.28 (m, 5H), 7.24e7.18 (m, 3H), 7.18e7.12 (m, 5H),
7.12e7.07 (m, 4H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3)
137.9,
137.2, 134.0, 131.7, 131.4, 131.3, 131.1, 129.1, 128.2, 128.0, 127.6, 127.3,
127.2, 122.9, 121.1, 119.8, 119.2, 115.4, 110.8, 29.7. IR (KBr, cmꢀ1
(400 MHz, CDCl3)
7.29e7.27 (m, 1H), 7.24e7.16 (m, 6H); 13C NMR (100 MHz, CDCl3)
138.2, 137.8, 135.3, 135.1, 134.4, 131.3, 130.2, 129.3, 129.08
d 7.78e7.75 (m, 1H), 7.45e7.30 (m, 10H),
d
d
(q, J¼32.30 Hz), 128.5, 128.2, 127.54, 127.52, 126.4, 124.8
)
n
(q, J¼37.50 Hz), 124.1 (q, J¼260.67 Hz), 123.4, 121.2, 119.9, 118.0,
3052, 2913, 2853, 1492, 1450, 1381, 1355, 1229, 1169, 1103, 1003,
824, 765, 745, 705. HRMS (EI): calcd for [C27H21N]þ 359.1674;
found: 359.1676.
110.7. IR (KBr, cmꢀ1
) n 3048, 2923, 1495, 1455, 1358, 1225, 1168,
1014, 820, 735, 697. HRMS (EI): calcd for [C27H18F3N]þ 413.1391;
found: 413.1389.
4.4.10. 1-(4-Methoxyphenyl)-2,3-diphenyl-1H-indole (3j).20 Yield:
92%; white solid; mp 152e153 ꢁC; 1H NMR (400 MHz, CDCl3)
4.4.16. 2-(3-bromophenyl)-3-(3-methoxyphenyl)-1-phenyl-1H-in-
dole (3p). Yield: 99%; white solid; mp 118e119 ꢁC; 1H NMR
d
7.82e7.78 (m,1H), 7.39e7.35 (m, 2H), 7.34e7.26 (m, 3H), 7.24e7.19
(m, 3H), 7.16e7.12 (m, 5H), 7.11e7.07 (m, 2H), 6.91e6.85 (m, 2H),
3.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
158.5, 138.3, 137.3, 135.1,
131.7, 131.2, 130.9, 130.2, 129.4, 128.2, 127.9, 127.3, 127.3, 125.8,
122.6, 120.7, 119.5, 116.3, 114.3, 110.7, 55.4. IR (KBr, cmꢀ1
3052,
(400 MHz, CDCl3) d 7.83e7.79 (m, 1H), 7.42e7.38 (m, 2H), 7.36e7.29
(m, 3H), 7.29e7.24 (m, 3H), 7.23e7.19 (m, 4H), 7.05e6.97 (m, 2H),
d
6.96e6.91(m, 2H), 6.84e6.80 (m, 1H), 3.72 (s, 3H); 13C NMR
(100 MHz, CDCl3)
130.4, 129.8, 129.4, 129.4, 129.3, 128.3, 127.5, 127.3, 123.2, 122.7,
121.8, 121.1, 119.9, 117.3, 115.5, 112.2, 110.8, 55.2. IR (KBr, cmꢀ1
d 159.6, 138.0, 137.7, 135.7, 135.3, 133.9, 133.8,
)
n
2946, 2926, 2833, 1580, 1514, 1454, 1434, 1249, 1182, 1023, 824, 778,
738, 698.
) n
3059, 2939, 1627, 1587, 1501, 1454, 1341, 1262, 1222, 1156, 1043, 870,
745, 698. HRMS (EI): calcd for [C27H20ONBr]þ 453.0723; found:
453.0724 and calcd for [C27H20ON81Br]þ 455.0702; found:
455.0700.
4.4.11. 2-(4-Methoxyphenyl)-1,3-diphenyl-1H-indole
89%; light yellow solid; mp 175e176 ꢁC; 1H NMR (400 MHz, CDCl3)
7.81e7.76 (m, 1H), 7.40e7.35 (m, 4H), 7.35e7.27 (m, 4H), 7.24e7.16
(m, 5H), 6.99 (d, J¼8.44 Hz, 2H), 6.66 (d, J¼8.48 Hz, 2H), 3.73 (s, 3H);
13C NMR (100 MHz, CDCl3)
158.8, 138.2, 137.8, 137.0, 135.1, 132.3,
130.2, 129.0, 128.3, 128.2, 127.6, 127.1, 125.8, 123.9, 122.5, 120.8,
(3k). Yield:
d
4.4.17. 3-(3-Bromophenyl)-2-(2-methoxyphenyl)-1-phenyl-1H-in-
d
dole (3q). Yield: 99%; white solid; mp 170e171 ꢁC;1 H NMR
(400 MHz, CDCl3)
d 7.86e7.79 (m, 1H), 7.59 (s, 1H), 7.38e7.29

2404
L. He et al. / Tetrahedron 70 (2014) 2400e2405
(m, 4H), 7.28e7.25 (m, 2H), 7.24e7.18 (m, 5H), 7.12 (t, J¼7.76 Hz,1H),
7.04 (d, J¼7.24 Hz, 1H), 6.80 (t, J¼7.36 Hz, 1H), 6.72 (d, J¼8.28 Hz,
7.14e7.07 (m, 3H), 7.05e7.01 (m, 2H), 6.81 (s, 1H), 3.92 (s, 3H), 3.85
(s, 3H); 13C NMR (100 MHz, CDCl3)
147.6, 146.0, 138.4, 135.6, 135.2,
132.4, 131.8, 131.1, 130.1, 129.2, 128.4, 128.2, 127.8, 127.1, 127.0, 125.9,
120.3,116.5, 101.2, 94.0, 56.5, 56.3. IR (KBr, cmꢀ1
3052, 2913,1627,
d
1H), 3.38 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 157.7, 138.1, 137.6,
137.5,134.9,133.1,132.2,130.1,129.6,128.6,128.1,127.5,126.9,122.6,
122.1, 120.8, 120.6, 120.4, 119.2, 115.5, 110.8, 110.6, 54.9. IR (KBr,
) n
1540, 1507, 1388, 1341, 1295, 1129, 1023, 897, 745, 725, 698. HRMS
cmꢀ1
) n 3039, 2966, 2926, 2827, 1593, 1494, 1454, 1369, 1229, 1169,
(EI): calcd for [C28H23NO2]þ 405.1723; found: 405.1716.
1022, 760, 744, 698. HRMS (EI): calcd for [C27H20ONBr]þ 453.0723;
found: 453.0720 and calcd for [C27H20ON81Br]þ 455.0702; found:
455.0710.
4.4.24. 1,2,3-Triphenyl-1H-benzo[f]indole (3x). Yield: 90%; light
brown solid; mp 202e203 ꢁC; 1H NMR (400 MHz, CDCl3)
d 8.26
(s, 1H), 7.93 (d, J¼8.2 Hz, 1H), 7.82 (d, J¼7.7 Hz, 1H), 7.74 (s, 1H),
4.4.18. 3-(Furan-2-yl)-1,2-diphenyl-1H-indole (3r). Yield: 64%; light
yellow solid; mp 199e200 ꢁC; 1H NMR (400 MHz, CDCl3)
7.49e7.37 (m, 6H), 7.36e7.32 (m, 3H), 7.31e7.25 (m, 3H), 7.20e7.12
(m, 5H); 13C NMR (100 MHz, CDCl3)
d 140.5, 138.7, 138.5, 134.8,
d
8.17e8.12 (m, 1H), 7.44 (dd, J¼1.84, 0.8 Hz, 1H), 7.36e7.28 (m, 3H),
131.4, 131.1, 130.8, 130.3, 129.5, 129.4, 129.2, 128.4, 128.4, 128.2,
127.9, 127.7, 127.5, 127.1, 126.1, 124.0, 122.9, 117.1, 115.9, 105.9. IR
7.28e7.26 (m, 1H), 7.26e7.24 (m, 6H), 7.24e7.22 (m, 1H), 7.21e7.17
(m, 2H), 6.35 (dd, J¼3.32, 1.84 Hz, 1H), 6.02 (dd, J¼3.34, 0.76 Hz,
(KBr, cmꢀ1
) n 3039, 1627, 1500, 1448, 1381, 1355, 1235, 1096, 1030,
1H); 13C NMR (100 MHz, CDCl3)
d
150.5, 140.6, 137.8, 137.7, 137.3,
857, 751, 712, 692. HRMS (EI): calcd for [C30H21N]þ 395.1669;
found: 395.1667.
131.8, 131.1, 129.1, 128.3, 128.1, 127.4, 126.1, 122.9, 121.3, 120.9110.8,
110.7, 107.4, 105.6. IR (KBr, cmꢀ1
)
n
3039, 2827, 1601, 1593, 1500,
1493, 1454, 1385, 1235, 1176, 1023, 887, 798, 764, 737, 698. HRMS
(EI): calcd for [C24H17NO]þ 335.1310; found: 335.1310.
4.4.25. 2,3-Bis(4-bromophenyl)-1-(4-methoxyphenyl)-1H-indole
(3y). Yield: 95%; White solid; mp 149e150 ꢁC; 1H NMR (400 MHz,
CDCl3)
d 7.37e7.32 (m, 4H), 7.30e7.26 (m, 1H), 7.24e7.17 (m, 5H),
4.4.19. 3-(Furan-2-yl)-2-(4-methoxyphenyl)-1-phenyl-1H-indole
7.13 (t, J¼8.2 Hz, 1H), 7.09e7.02 (m, 3H), 6.99e6.92 (m, 3H), 6.60 (d,
(3s). Yield: 50%; light yellow solid; mp 195e196 ꢁC; 1H NMR
J¼7.7, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 154.6, 139.2,
(400 MHz, CDCl3)
d
8.15e8.12 (m, 1H), 7.45e7.43 (m, 1H), 7.37e7.32
138.3, 136.5, 135.7, 131.8, 131.6, 131.3, 129.0, 128.3, 127.6, 127.1, 126.9,
(m, 2H), 7.31e7.23 (m, 3H), 7.23e7.19 (m, 2H), 7.18e7.16 (m, 2H),
7.16e7.14 (m, 1H), 6.80e6.76 (m, 2H), 6.37e6.35(m, 1H), 6.03e6.02
126.9, 125.6, 123.1, 117.1, 116.7, 103.9, 101.4, 55.4. IR (KBr, cmꢀ1
) n
3052, 2936, 2897, 2825, 1597, 1569, 1496, 1437, 1354, 1304, 1271,
1243, 1094, 1071, 922, 736, 703, 664. HRMS (EI): calcd for
[C27H21NO]þ 375.1618; found: 375.1626.
(m, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
159.3, 150.7,
140.5, 137.7, 137.6, 137.2, 132.2, 129.1, 128.3, 127.3, 126.1, 123.9, 122.7,
121.2, 120.8, 113.6, 110.8, 110.6, 107.1, 105.5, 55.1. IR (KBr, cmꢀ1
)
n
4.5. Isolation of indoline 3a0
3032, 2952, 2827,1600,1593,1500,1457,1365,1250,1169,1037, 837,
748, 698. HRMS (EI): calcd for [C25H19NO2]þ 365.1416; found:
365.1415.
To a solution of
0.9 mmol), 18-crown-6 (238 mg, 0.9 mmol) in anhydrous acetoni-
trile (3.0 mL) was added 2-(trimethylsilyl) aryl triflate
(0.45 mmol). The mixture was stirred at room temperature until
full consume of the starting -aminoketone as indicated by TLC.
a-aminoketone 2 (0.3 mmol), KF (52 mg,
4.4.20. 3-(4-Chlorophenyl)-2-methyl-1-phenyl-1H-indole
1
(3t). Yield: 72%; white solid; mp 138e139 ꢁC; 1H NMR (400 MHz,
CDCl3)
d
7.67e7.63 (m, 1H), 7.56 (t, J¼7.4 Hz, 2H), 7.51e7.43 (m, 5H),
a
7.39 (d, J¼7.5 Hz, 2H), 7.17e7.12 (m, 3H), 2.32 (s, 3H); 13C NMR
After concentration of the mixture under vacuum, the crude
product was purified through flash column chromatography (silica
gel, PE/EtOAc, 10:1e15:1) to give 3a and indoline 3a0.
(100 MHz, CDCl3)
d 137.7, 137.6, 134.0, 133.7, 131.7, 130.9, 129.6,
128.7,128.1,128.0,127.0,121.9,120.5,118.4,114.2,110.2,12.0. IR (KBr,
cmꢀ1
) n 3052, 2919, 2846, 1586, 1547, 1500, 1461, 1377, 1248, 1169,
1089, 1010, 833, 771, 748, 702. HRMS (EI): calcd for [C21H16NCl]þ
317.0971; found: 317.0971.
4.5.1. 1,2,3-Triphenylindolin-3-ol (3a0). Yield: 88%; white solid; mp
67e68 ꢁC; 1H NMR (400 MHz, CDCl3)
d 7.44e7.39 (m, 2H), 7.37e7.29
(m, 3H), 7.27e7.20 (m, 6H), 7.19e7.10 (m, 5H), 7.07 (d, J¼7.4 Hz, 5H),
4.4.21. 2-Ethyl-3-methyl-1-phenyl-1H-indole (3u).21 Yield: 52%;
6.97 (t, J¼7.2 Hz, 1H), 6.85 (t, J¼7.3 Hz, 1H), 5.30 (s, 1H), 1.99
light brown oil; 1H NMR (400 MHz, CDCl3)
d 7.56e7.48 (m, 3H),
(s, 1H);13C NMR (100 MHz, CDCl3)
d 148.82, 144.33, 142.55, 134.30,
7.45e7.40 (m, 1H), 7.35e7.32 (m, 2H), 7.14e7.01 (m, 3H), 2.68
133.97, 129.66, 129.03, 128.42, 128.39, 128.17, 127.98, 127.30, 126.50,
(q, J¼7.6 Hz, 3H), 2.33 (s, 3H), 0.98 (t, J¼7.6 Hz, 3H); 13C NMR
125.64, 122.94, 121.52, 120.26, 108.85, 82.05, 80.05; IR (KBr, cmꢀ1
)
n
(100 MHz, CDCl3)
d 138.94, 138.44, 137.55, 129.38, 128.75, 128.39,
3543, 3059, 3019, 2860, 1587, 1501, 1474, 1361, 1301, 1169, 1030, 917,
751, 698, 652; HPLCeMS (ESI): m/z 364.1 (Mþ).
127.62, 121.13, 119.41, 117.92, 109.82, 107.27, 18.02, 14.31, 8.73.IR
(KBr, cmꢀ1
) n 3059, 2966, 2926, 2866, 1593, 1507, 1461, 1355, 1215,
1129, 1056, 738, 691. HRMS (EI): calcd for [C23H21N]þ 311.1674;
found: 311.1681.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21162022) and the Team Innovation
Project of Shihezi University (No. 2011ZRKXTD-04, 2012ZRKXJQ06).
4.4.22. 5,6-Dimethyl-1,2,3-triphenyl-1H-indole (3v). Yield: 87%;
light yellow solid; mp 188e189 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.54
(s, 1H), 7.38e7.32 (m, 5H), 7.32e7.27 (m, 2H), 7.24e7.18 (m, 3H),
7.14e7.08 (m, 4H), 7.08e7.04 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H); 13
NMR (100 MHz, CDCl3) 138.5,136.9,136.2, 135.3, 131.9, 131.8, 131.1,
130.2, 129.6, 129.0, 128.2, 128.2, 127.8, 127.1, 126.9, 125.9, 125.7,
119.6, 116.2, 110.9, 20.5, 20.1. IR (KBr, cmꢀ1
3052, 3025, 2959,
C
Supplementary data
d
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.02.028.
)
n
2926, 1600, 1494, 1454, 1375, 1235, 1070, 1017, 851, 758, 718, 692.
HRMS (EI): calcd for [C28H23N]þ 373.1825; found: 373.1824.
References and notes
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d
7.41e7.34
(m, 5H), 7.33e7.25 (m, 3H), 7.23e7.22 (m, 1H), 7.22e7.20 (m, 2H),

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