Gold-catalyzed intramolecular hydroamination of terminal alkynes in aqueous media: efficient and regioselective synthesis of indole-1-carboxamides

Article abstract of DOI:10.1039/b904044g

Using [Au(PPh₃)]Cl/Ag₂CO₃-catalyzed 5-endo-dig cyclization in water under microwave irradiation, we developed a fast and green route to prepare indole-1-carboxamides from N′-substituted N-(2-alkynylphenyl)ureas. The descri

Full text of DOI:10.1039/b904044g

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PAPER
www.rsc.org/greenchem | Green Chemistry
Gold-catalyzed intramolecular hydroamination of terminal alkynes in
aqueous media: efficient and regioselective synthesis of
indole-1-carboxamides†
Deju Ye,a Jinfang Wang,a Xu Zhang,a,b Yu Zhou,a Xiao Ding,a Enguang Feng,a Haifeng Sun,a
Guannan Liu,a Hualiang Jianga and Hong Liu*a
Received 27th February 2009, Accepted 30th April 2009
First published as an Advance Article on the web 28th May 2009
DOI: 10.1039/b904044g
Using [Au(PPh3)]Cl/Ag2CO3-catalyzed 5-endo-dig cyclization in water under microwave
irradiation, we developed a fast and green route to prepare indole-1-carboxamides from
N¢-substituted N-(2-alkynylphenyl)ureas. The described method is tolerant to a variety of
functional groups, including N¢-aryl, alkyl, heterocyclic, various N-(substituted-2-ethynylphenyl)
and N-(2-ethynylpyridin-3-yl)ureas and affords moderate to high yields of the desired products.
amides to alkynes to form polyfunctionlized indoles have been
Introduction
developed.12 The synthesis of 2-substituted indoles through Cu-
Over recent years great efforts have been made in the field
or Pd-catalyzed domino reactions of N-protected o-iodoaniline
of green chemistry to adopt methods and processes that use
derivatives with 1-alkynes has been also reported.13 Additionally,
less toxic chemicals, produce smaller amounts of by-products
Yamamoto and co-workers reported tandem cyclization of
and use less energy.1 As part of this green concept, water and
2-alkynylaniline in the presence of certain nucleophiles to give
microwave irradiation have become very popular and received
the nucleophile incorporated indoles.14
substantial interest.2 Water is environmentally benign, abundant
On the other hand, indole-1-carboxamide compounds have
and cheap solvent. In addition, it often exhibits unique reactivity
been used for the treatment of inflammatory diseases15 and
and selectivity that cannot be attained in conventional organic
diabetes.16 However, so far, only a few methods for the syn-
solvents.3 Microwave-assisted organic synthesis (MAOS) is time-
thesis of indole-1-carboxamides have been described.17 These
and energy-saving, and compound libraries can be rapidly
procedures use anhydrous conditions, toxic organic solvents (e.g.
synthesized either in a parallel or sequential format. Meanwhile,
ether17a,b or THF17c), and are limited in scope and selectivity. Re-
it often facilitates the discovery of novel reaction pathways.4
cently, a PdCl2-catalyzed cyclization of 2-alkynylbenzenamines
Indole derivatives are found in many natural and synthetic
with isocyanates to form 2-substituted indole-1-carboxamides
products that exhibit a wide range of biological activities.5
was developed.18 This reaction is performed in THF at 80 ◦C
The development of efficient methods for their synthesis has
for 20 h, and is only limited to the internal alkynes and
continuously attracted the attentions of many chemists. Besides
classical methods (e.g. Fischer, Reissert, Madelung, and Larock
aryl isocyanates. Consequently, the development of faster and
greener protocols to assemble indole-1-carboxamides, especially
reactions),5a,6 catalytic transformation by using transition-metal
2-unsubstituted indole-1-carboxamides, is still a synthetic chal-
catalysts is one of the modern approaches for forming indoles.7,8
lenge.
In particular, intramolecular cyclizations of functionalized
In recent times, gold-catalyzed intramolecular hydroamina-
o-alkynylaniline derivatives are some of the most efficient
tions of alkynes for the preparation of various N-heterocycles,
approaches. Pd- or Cu-catalyzed cyclization of o-alkynylanilines
in the presence of alkyl, vinyl, or aryl halides has been reported
to give various 2-substituted and 2,3-disubstituted indoles.9,10
Rh-catalyzed reactions of o-alkynylaniline to 2,3-unsubstituted
indoles11 and Pt-catalyzed intramolecular C–N bond addition of
such as indoles,19 pyrroles,20 quinolines,21 and isoquinolines,22
have received much attention. Some Au-catalyzed procedures
that performed in water or under neat conditions were also
reported.23 In addition, we have previously found that N¢-
substituted N-(2-halophenyl)ureas can be efficiently trans-
formed to N-substituted 1,3-dihydrobenzimidazol-2-ones.24
Prompted by these results, here we would like to describe
a green protocol for the synthesis of indole-1-carboxamides
mediated by Au-catalyzed intramolecular hydroamination of N-
(2-ethynylphenyl)ureas in water under microwave irradiation.
aDrug Discovery and Design Centre, State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, Chinese Academy of Sciences, 555 Zu chong zhi
Road, Shanghai, 201203, P. R. China. E-mail: hliu@mail.shcnc.ac.cn
bDepartment of Medicinal Chemistry, China Pharmaceutical University,
24 Tong jia Xiang, Nanjing, 210009, P. R. China
Results and discussion
† Electronic supplementary information (ESI) available: Labeling stud-
ies experimental details, 1H and 13C NMR spectra. CCDC reference
numbers 721328 for 2a. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b904044g
We initiated our studies by examining catalyst and reaction
conditions using N¢-benzyl-N-(2-ethynylphenyl)ureas (1a) as
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Table 1 Optimization of the reaction conditionsa
Catalyst B
(mol%)
Yield
[%]b
Entry Catalyst A (mol%)
T/◦C
t
Fig. 1 X-Ray structure of compound 2a.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16e
17e
—
—
—
—
—
100
120
150
150
150
150
30 min
0
Au(PPh3)]Cl to other Au(I) catalysts, such as [Au(IPr)]Cl26
or [tris(2,4-di-tert-butylphenyl)phosphite]gold chloride,27 led to
slightly decreased yields (Table 1, entries 9 and 10). In addition,
several other Ag salts with low pKa values, such as AgOTf,
AgSbF6 and AgBF4, proved to be less effective synergists than
Ag2CO3 (Table 1, entries 11–13). We also found that compound
2a was obtained in a lower yield (82% yield Table 1, entry
14) when decreasing the [Au(PPh3)]Cl/Ag2CO3 catalyst loading
from 10 to 5 mol%. Finally, we performed the reactions at 100 ◦C
for 4 h to compare the results using MAOS and the classical
method, which gave 89% and 69% yields, respectively (Table 1,
entries 15 and 16). An 89% yield was obtained when the reaction
was carried out at 90 ◦C for 16 h using classical method (Table 1,
entry 17). From the results, the MAOS method is more effective
as it has a significant effect on the increase in the yield and the
decrease in the reaction time. Therefore, we chose to employ
MAOS method in the next investigation.
[Au(PPh3)]Cl (10)
[Au(PPh3)]Cl (10)
AuCl (10)
AuCl3 (10)
—
30 min 20
10 min 75
10 min 35
10 min 74
10 min 23
10 min 75
10 min 90
10 min 83
10 min 85
10 min 85
10 min 84
10 min 80
10 min 82
—
AgOTf (10)
—
Ag2CO3 (10) 150
Ag2CO3 (10) 150
Ag2CO3 (10) 150
Ag2CO3 (10) 150
AgOTf (10)
AgSbF6 (10)
AgBF4 (10)
Ag2CO3 (5)
[Au(PPh3)]Cl (10)
[Au(IPr)]Cl (10)c
Au catalyst X (10)d
[Au(PPh3)]Cl (10)
[Au(PPh3)]Cl (10)
[Au(PPh3)]Cl (10)
[Au(PPh3)]Cl (5)
[Au(PPh3)]Cl (10)
[Au(PPh3)]Cl (10)
[Au(PPh3)]Cl (10)
150
150
150
150
Ag2CO3 (10) 100
Ag2CO3 (10) 100
Ag2CO3 (10)
4 h
4 h
16 h
89
69
89
90
a Reaction conditions: 1a (0.2 mmol), catalyst
catalyst B (0.02 mmol), H2O (3 mL). b Yield of isolated prod-
A (0.02 mmol),
ucts based on 1a. c [Au(IPr)]Cl
=
1,3-bis(2,6-diisopropylphenyl-
imidazol-2-ylidene)gold(I) chloride. d Au catalyst X = [tris(2,4-di-tert-
butylphenyl)phosphite]gold chloride. e The classical method using oil
bath heating was adopted.
After determining the optimized conditions (10 mol%
[Au(PPh3)]Cl, 10 mol% Ag2CO3, H2O, MW, 150 ◦C, 10 min), we
examined the generality of the process. First, we demonstrated
that a variety of N¢-substituted-N-(2-ethynylphenyl)ureas, in-
cluding N¢-aliphatic, N¢-aromatic, and N¢-heterocyclic substi-
tuted ureas can provide the desired products 2a–o in mod-
erate to good yields (40–91%) (Table 2, entries 1–15). The
electron-withdrawing substituents on the N¢-R1 group of 1
gave lower yields in the cases of N¢-4-cyanophenyl and N¢-
naphthyl substituted ureas, presumably due to the significantly
decreased nucleophilicity of the N atom of the substrates. We
did observe the hydrolytic decomposition of the corresponding
materials (Table 2, entries 7 and 13).28 It is worth noting that
the corresponding product yields increased greatly when the
reactions were performed at 90 ◦C for 24 h using classical
method (81% for 2g and 76% for 2m). The ortho-, meta-,
and para-substituents had no significant steric effects (Table 2,
entries 9–11). Nevertheless, the introduction of a bulky 2,6-
diisopropylphenyl group to the N¢-R1 led to strongly decreased
reactivity, with only a 40% yield of 2n along with 51% recovered
starting material. Carrying out the reaction at 90 ◦C with oil bath
heating and prolonging the time to 48 h did not improve the yield
(Table 2, entry 14). This contrasts with the substrates 1g and
1m bearing an electron-withdrawing substituent, as described
above. Additionally, N¢-heterocyclic groups such as pyridin-4-yl
produced 2o in good yield (Table 2, entry 15).
a model substrate. The results are shown in Table 1. Under
catalyst-free conditions, no reaction took place and only the
starting material 1a was recovered (Table 1, entry 1). However,
◦
in the presence of [Au(PPh3)]Cl (10 mol%) in water at 120 C
under microwave heating for 30 min, we observed the formation
of a product in 20% yield (Table 1, entry 2). When the reaction
temperature increased to 150 ◦C, the yield improved to 75%
(Table 1, entry 3). In principle, there are three possible
mechanisms for cyclization: 5-endo, leading to structure A, 7-
endo, leading to sturcture B and 6-exo, leading to struture C
(Scheme 1).25 Structure elucidation by 1H, 13C NMR, mass spec-
troscopy, and X-ray crystallography proved that our product has
the desired structure A and no other products were detected by
TLC (Fig. 1).† Further screening of metal catalysts revealed
that AuCl and AgOTf were less effective, while AuCl3 and
Ag2CO3 were as effective as [Au(PPh3)]Cl (Table 1, entries 4–7).
Surprisingly, the yield improved significantly in the presence of
catalytic amounts of both [Au(PPh3)]Cl and Ag2CO3 (90% yield
Table 1, entry 8), in which the synergistic effect of the two metals
makes the catalytic cycle operative. Subsequently switching
We next explored the substrate scope in variation of N¢-
benzyl-N-(substituted-2-ethynylphenyl)ureas (Table 2, entries
16–20). Our investigations revealed that the reaction was signifi-
cantly affected by the electronic properties of R3 substituents. N¢-
benzyl-N-(substituted-2-ethynylphenyl)ureas with substituents
Scheme 1 5-endo, 7-endo and 6-exo hydroamination of terminal
alkynes.
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Table 2 Synthesis of N-substituted indole-1-carboxamides in watera
Entry
1
Substrate 1
Product 2: yield (%)b
2a: 90
Entry
9
Substrate 1
Product 2: yield (%)b
2i: 82
2
3
2b: 91
2c: 80
10
11
2j: 84
2k: 83
4
5
2d: 83
2e: 86
12
13
2l: 81
2m: 41c 76 d
6
2f: 83
14
15
2n: 40 e 48 f
7
8
2g: 62 c 81 d
2o: 52c 75 d
2h: 89
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Table 2 (Contd.)
Entry
16
Substrate 1
Product 2: yield (%)b
2p: 85
Entry
20
Substrate 1
Product 2: yield (%)b
2t: 83
17
2q: 86
21
22
2u: 0 h
18
19
2r: 51
2s: 0g
2v: 0 h
a Reaction conditions: 1 (0.2 mmol), [Au(PPh3)]Cl (0.02 mmol), Ag2CO3 (0.02 mmol), H2O (3 mL). b Yield of isolated products based on 1.
c Decomposition occurred. d The reactions were performed at 90 ◦C for 24 h using classical method. e 51% of starting material was recovered. f The
◦
reaction was carried out at 90 C for 48 h using classical method. g No desired product 2s but the 1,2-unsubstituted indole product was observed.
h 100% of starting material was recovered.
R3 bearing a fluorine meta or an electron-rich methyl para to
the urea group are tolerant of the cyclization (Table 2, entries
16 and 17). However, relatively lower yields were obtained in
the case of substrates with substituents R3 bearing an electron-
neutral Cl or an electron-deficient CF3 para to the urea group
(Table 2, entries 18 and 19).29 Besides N¢-benzyl-N-(substituted-
2-ethynylphenyl)ureas 1p–s, N¢-benzyl-N-(2-ethynylpyridin-3-
yl)urea 1t was also a good substrate for this kind of transforma-
tion (83% yield, Table 2, entry 20). Lastly, we also realized the
limitation of the reaction. We did not obtain any of the desired
products 2u or 2v under the optimized conditions when the
internal alkyne substrates 1u and 1v, respectively, were used and
Scheme 2 Labeling studies with D2O or deuterated starting material.
100% of the starting materials were recovered (Table 2, entries
21 and 22).
leads to a vinylidene intermediate I.30 The key intermediate
To gain insight into the mechanism of the reaction, we
performed labeling studies with deuterated starting materials
or solvents. The reaction of 1a in D2O under the standard
conditions afforded the 2,3-bideuterated compound [D2]-2a.
Reaction of the deuterated alkyne [D1]-1a in H2O led to the
formation of non-deuterated product 2a (Scheme 2).
On the basis of these observations, we proposed a reaction
mechanism (Scheme 3). Coordination of the alkyne substrate
1 with transition metal-catalyst, followed by rearrangement,
may undergo nucleophilic capture by the adjacent atom N1 to
generate carbene complex II, which is followed by tautomer-
ization and reductive elimination of the metal hydride complex
to form the desired product 2 and regenerate the active catalyst.
Labeling experiments discussed previously revealed that both the
vinyl hydrogen atoms of [D2]-2a and 2 came from the solvent.
The formation of [D2]-2a directly from D2O is consistent with
existing literature, in that hydrogen atoms in the position a to the
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0.00 ppm, CHCl3 at 7.24 ppm 13C NMR: CDCl3 at 77.0 ppm) or
were recorded using tetramethylsilane (TMS) in the solvent of
DMSO-d6 as the internal standard (1H NMR: TMS at 0.00 ppm,
DMSO at 2.50 ppm 13C NMR: DMSO at 40.0 ppm). Low-
and high-resolution mass spectra (LRMS and HRMS) were
measured on Finnigan MAT 95 spectrometer. All melting points
are uncorrected.
General experimental procedure for the synthesis of
2,3-unsubstituted indole-1-carboxamides in water
Microwave method. A mixture of N¢-substituted N-(2-
alkynylphenyl)ureas 1 (0.2 mmol), [Au(PPh3)]Cl (0.02 mmol)
and Ag2CO3 (0.02 mmol) was stirred in water (3–5 mL) under
Ar atmosphere. The vial was sealed and the mixture was then
irradiated for 10 min at 150 ◦C. After the reaction was cooled to
ambient temperature, the crude reaction mixture was extracted
three times with ethyl acetate (EA) (3 ¥ 15 mL). The combined
organic phase was washed with saturated NaHCO3 solution,
brine, dried with Na2SO4 and concentrated. The residue was
Scheme 3 Proposed mechanism.
carbene group can be exchanged with D2O (Scheme 2).23a,31 More
support for this reaction mechanism proposal can be found
in the comparison of terminal and internal alkyne substrates
(Table 2). Since only terminal alkynes can yield such vinylidene
intermediates, no reaction occurred for the internal alkyne
substrates (Table 2, entries 21 and 22). An alternative mechanism
involving the formation of p-complex via coordination of the
catalyst to the alkyne to induce nucleophilic attack by the amino
group in endo mode was proposed as well.18,19a However, this
mechanism can not explain the lack of reactivity of internal
alkynes and the formation of the 2,3-bideuterated compound.
R
purified by column chromatography on CombiFlashꢀ to provide
the desired product.
Classical method using a thermostatted oil bath. A mix-
ture of N¢-substituted N-(2-alkynylphenyl)ureas 1 (0.2 mmol),
[Au(PPh3)]Cl (0.02 mmol) and Ag2CO3 (0.02 mmol) was stirred
in water (3–5 mL) under Ar atmosphere. The vial was sealed
and the mixture was then stirred at 90 ◦C or 100 ◦C with
oil heating for 3–48 h. After the reaction was cooled to
ambient temperature, the crude reaction mixture was extracted
three times with EA (3 ¥ 15 mL). The combined organic phase
was washed with saturated NaHCO3 solution, brine, dried with
Na2SO4 and concentrated. The residue was purified by column
chromatography on combiflash to provide the desired product.
Conclusion
In summary, we have developed an Au(I)-catalyzed regioselective
cyclization reaction for the preparation of 2,3-unsubstituted
indole-1-carboxamides under microwave irradiation in water.
Substrates are readily available and functional-group tolerance is
high for this atom-economical reaction. A mechanism involving
a metal vinylidene intermediate was proposed based on the
labeling studies which distinguishes this process from other gold-
catalyzed cyclization methods. Collectively, the present method
is a simple, fast, efficient and green route to assemble biologically
interesting indoles.
N-Benzyl-1H-indole-1-carboxamide 2a. Compound 2a was
obtained as a white solid after purification by flash chromatog-
raphy (SiO2, 300–400 mesh EA:PE, 1:15 to 1:9) (yield, 90%),
◦
1
mp 85–86 C. H NMR d (300 MHz, CDCl3, ppm) 4.650 (d,
J = 5.7 Hz, 2H, CH2 of Bn), 5.921 (br, s, 1H, NH), 6.620 (d,
J = 3.6 Hz, 1H, C5-H), 7.207–7.416 (m, 7H), 7.450 (d, J =
3.9 Hz, 1H, C4-H), 7.605 (d, J = 7.8 Hz, 1H, ArH), 8.105 (d,
J = 8.1 Hz, 1H, ArH) 13C NMR d (75 MHz, CDCl3, ppm): 44.9
(CH2), 107.2 (C5), 114.1 (CAr), 121.2 (CAr), 122.3 (CAr), 123.9
(CAr), 124.2, 127.8, 128.9, 130.2 (CAr), 135.1 (CAr), 137.7 (CAr),
Experimental
+
=
152.1 (C O) ESI-MS m/z 251 [M + H] 100% HRMS (ESI)
calcd for C16H14N2ONa [M + Na]+ 273.1004, found 273.1000.
General experimental procedures
The reagents were purchased from commercial sources and
used without further purification. Analytical thin layer chro-
matography (TLC) was HSGF 254 (0.15–0.2 mm thickness,
Yantai Huiyou Company, China). All of the microwave-assisted
reactions were performed in an InitiatorTM EXP microwave
system (Biotage, Inc.) at the specified temperature using the
standard mode of operation. Column chromatography was
N-Octyl-1H-indole-1-carboxamide 2b. Compound 2b was
obtained as a white foam after purification by flash chromatog-
raphy (SiO2, 300–400 mesh EA:PE, 1:15 to 1:8) (yield, 91%) 1H
NMR d (300 MHz, CDCl3, ppm) 0.897 (t, J = 6.6 Hz, 1H, CH3),
1.289–1.415 (br, m, 10H), 1.602–1.705 (m, 2H), 3.424–3.490 (m,
NCH2, 1H), 5.718 (br, s, 1H, NH), 6.610 (d, J = 3.9 Hz, 1H,
C5-H), 7.199–7.349 (m, 2H, ArH), 7.480 (d, J = 3.6 Hz, 1H,
C4-H), 7.600 (d, J = 7.8 Hz, 1H, ArH), 8.105 (d, J = 8.1 Hz,
1H, ArH) 13C NMR d (75 MHz, CDCl3, ppm): 14.1 (CH3), 22.6
(CH2), 26.9 (CH2), 29.1 (CH2), 29.2 (CH2), 29.7 (CH2), 31.7
R
performed with CombiFlashꢀ Companion system (Teledyne
Isco, Inc.). All reactions were carried out under Ar atmosphere.
Proton and carbon magnetic resonance spectra (1H NMR and
13C NMR) were recorded using tetramethylsilane (TMS) in the
solvent of CDCl3 as the internal standard (1H NMR: TMS at
(CH2), 40.9 (CH2), 106.7, 113.9, 121.1, 122.1, 124.0, 124.1, 130.1,
+
=
135.0, 152.1 (C O) ESI-MS m/z 273 [M + H] 100% HRMS
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(ESI) calcd for C17H24N2ONa [M + Na]+ 295.1786, found
295.1806.
8.045 (d, J = 3.6 Hz, 1H, C4–H), 8.230 (d, J = 7.8 Hz, 1H,
ArH), 10.461 (s, 1H, NH) 13C NMR d (75 MHz, d6-DMSO,
ppm): 105.4, 106.9, 115.1, 119.1, 120.3, 121.0, 122.6, 124.0,
N-Allyl-1H-indole-1-carboxamide 2c. Compound 2c was
obtained as yellow oil after purification by flash chromatography
(SiO2, 300–400 mesh EA:PE, 1:12 to 1:8) (yield, 80%) 1H NMR
d (300 MHz, CDCl3, ppm) 4.089–4.128 (m, 2H, N-CH2), 5.219–
=
125.7, 129.8, 133.2, 135.3, 143.1, 149.6 (C O) ESI-MS m/z
260 [M - H]- 100% HRMS (ESI) calcd for C16H11N2ONa [M +
Na]+ 284.0800, found 284.0790.
=
5.350 (m, 2H, CH2), 5.713 (br, s, 1H, NH), 5.921–6.051 (m,
N-(4-Fluorophenyl)-1H-indole-1-carboxamide
2h. Com-
=
1H, CH), 6.630 (d, J = 3.9 Hz, 1H, C5-H), 7.209–7.357 (m,
pound 2h was obtained as a white solid after purification by
2H, ArH), 7.480 (d, J = 3.6 Hz, 1H, C4-H), 7.600 (d, J = 7.2 Hz,
1H, ArH), 8.100 (d, J = 7.5 Hz, 1H, ArH) 13C NMR d (75 MHz,
flash chromatography (SiO2, 300–400 mesh EA:PE, 1:14 to 1:10)
◦
1
(yield, 89%), mp 170–172 C. H NMR d (300 MHz, CDCl3,
ppm) 6.680 (dd, J = 0.9, 3.6 Hz, 1H, C5-H), 7.049–7.106 (m,
2H), 7.244–7.298 (m, 1H), 7.330–7.409 (m, 2H), 7.463–4.509
(m, 2H), 7.545 (d, J = 3.6 Hz, 1H, C4-H), 7.652 (dd, J = 0.9,
8.4 Hz, 1H, ArH), 8.110 (dd, J = 0.9, 8.1 Hz, 1H, ArH) 13C
NMR d (75 MHz, CDCl3, ppm): 107.9, 114.0, 115.8, 116.0,
121.4, 122.5, 122.6, 122.7, 123.9, 124.5, 130.3, 132.9, 135.1,
=
CDCl3, ppm): 43.3 (N–CH2), 107.1, 114.0, 117.1 ( CH2), 121.2,
=
122.3, 124.0, 124.2, 130.1, 133.7, 135.0, 151.9 (C O) ESI-MS
m/z 201 [M + H]+ 100% HRMS (ESI) calcd for C12H12N2ONa
[M + Na]+ 223.0847, found 223.0847.
N-Cyclohexyl-1H-indole-1-carboxamide 2d. Compound 2d
was obtained as a light yellow oil after purification by flash
chromatography (SiO2, 300–400 mesh EA:PE, 1:15 to 1:10)
=
149.8 (C O), 158.5(C–F), 160.9 (C–F) ESI-MS m/z 255 [M +
H]+ 100% HRMS (ESI) calcd for C15H11N2OFNa [M + Na]+
277.0753, found 277.0760.
1
(yield, 83%) H NMR d (300 MHz, CDCl3, ppm) 1.214–1.517
(m, 5H), 1.643–1.827 (m, 3H), 2.089–2.176 (br, m, 2H), 3.889–
3.933 (m, 1H), 5.451 (br, 1H, NH), 6.610 (d, J = 3.9 Hz, 1H,
C5-H), 7.198–7.350 (m, 2H, ArH), 7.482 (d, J = 3.6 Hz, 1H,
C4-H), 7.600 (d, J = 8.1 Hz, 1H, ArH), 8.030 (d, J = 8.4 Hz,
1H, ArH) 13C NMR d (75 MHz, CDCl3, ppm): 24.8 (CH2), 25.4
N-(4-Methoxyphenyl)-1H-indole-1-carboxamide 2i. Com-
pound 2i was obtained as a white solid after purification by
flash chromatography (SiO◦2, 300–400 mesh EA:PE, 1:14 to 1:9)
1
(yield, 82%), mp 148–150 C. H NMR d (300 MHz, CDCl3,
(CH2), 33.3 (CH2), 49.9 (N–CH), 106.6, 113.7, 121.2, 122.1,
ppm) 3.807 (s, 3H, OMe), 6.650 (dd, J = 0.9, 3.6 Hz, 1H, C5–
H), 6.890 (dd, J = 2.4, 6.6 Hz, 2H), 7.255–7.421 (m, 5H), 7.550
(d, J = 3.6 Hz, 1H, C4–H), 7.620 (d, J = 7.5 Hz, 1H, ArH),
8.116 (d, J = 7.2 Hz, 1H, ArH) 13C NMR d (75 MHz, CDCl3,
ppm): 55.4, 107.5, 114.1, 114.3, 121.3, 122.5, 122.8, 124.0, 124.3,
+
=
124.0, 124.3, 134.9, 151.2 (C O) ESI-MS m/z 243 [M + H]
100% HRMS (ESI) calcd for C15H18N2ONa [M + Na]+ 265.1317,
found 265.1331.
N-p-Tolyl-1H-indole-1-carboxamide 2e. Compound 2e was
obtained as a white solid after purification by flash chromatogra-
phy (SiO2, 300–400 mesh EA:PE, 1:15 to 1:11) (yield, 86%), mp
119–120 ◦C. 1H NMR d (300 MHz, CDCl3, ppm) 2.349 (s, 3H),
6.650 (d, J = 3.6 Hz, 1H, C5-H), 7.170 (d, J = 8.1 Hz, 2H, ArH),
7.240–7.412 (m, 5H), 7.545 (d, J = 3.6 Hz, 1H, C4-H), 7.630
=
129.7, 130.2, 135.1, 150.1 (C O), 156.9 ESI-MS m/z 267 [M +
H]+ 100% HRMS (ESI) calcd for C16H14N2O2Na [M + Na]+
289.0953, found 289.0969.
N-(3-Methoxyphenyl)-1H-indole-1-carboxamide 2j. Com-
pound 2j was obtained as a white solid after purification by
flash chromatography (SiO◦2, 300–400 mesh EA:PE, 1:14 to 1:9)
(d, J = 6.6 Hz, 1H, ArH), 8.120 (d, J = 8.1 Hz, 1H, ArH) 13
C
NMR d (75 MHz, CDCl3, ppm): 20.8 (CH3), 107.5, 114.0, 120.7,
1
(yield, 84%), mp 111–112 C. H NMR d (300 MHz, CDCl3,
121.3, 122.5, 124.1, 124.3, 129.7, 130.3, 134.3, 134.6, 135.0, 149.7
ppm) 3.823 (d, J = 1.2 Hz, 3H, OMe), 6.660 (dd, J = 0.9, 3.9 Hz,
1H, C5–H), 6.730 (dt, J = 1.2, 8.4 Hz, 1H), 7.045 (dt, J = 0.9,
8.1 Hz, 1H), 7.241–7.384 (m, 4H), 7.443 (br, s, 1H, NH), 7.550
(d, J = 3.6 Hz, 1H, C4-H), 7.630 (d, J = 7.2 Hz, 1H, ArH), 8.110
(d, J = 8.4 Hz, 1H, ArH) 13C NMR d (75 MHz, CDCl3, ppm):
55.3, 106.1, 107.7, 110.5, 112.5, 114.0, 121.4, 122.6, 122.8, 124.0,
+
=
(C O) ESI-MS m/z 251 [M + H] 100% HRMS (ESI) calcd for
C16H14N2ONa [M + Na]+ 273.1004, found 273.1005.
N-(4-Bromophenyl)-1H-indole-1-carboxamide
2f. Com-
pound 2f was obtained as a white solid after purification by
flash chromatography (SiO2, 300–400 mesh EA:PE, 1:14 to
1:11) (yield, 83%), mp 124–126 ◦C. 1H NMR d (300 MHz,
CDCl3, ppm) 6.710 (d, J = 3.6 Hz, 1H, C5–H), 7.268–7.560
(m, 8H), 7.652 (d, J = 7.8 Hz, 1H, ArH), 8.110 (d, J = 8.4 Hz,
1H, ArH) 13C NMR d (75 MHz, CDCl3, ppm): 108.1, 114.0,
=
124.4, 129.9, 130.3, 135.0, 138.2, 149.5 (C O), 160.3 ESI-MS
m/z 267 [M + H]+ 100% HRMS (ESI) calcd for C16H14N2O2Na
[M + Na]+ 289.0953, found 289.0965.
N-(2-Methoxyphenyl)-1H-indole-1-carboxamide 2k. Com-
pound 2k was obtained as a white solid after purification by
flash chromatography (SiO2, 300–400 mesh EA:PE, 1:14 to 1:9)
(yield, 83%), mp 81–83 ◦C. 1H NMR d (300 MHz, CDCl3, ppm)
3.958 (s, 3H, OMe), 6.710 (d, J = 3.3 Hz, 1H, C5–H), 6.970 (dd,
J = 1.5, 7.5 Hz, 1H), 7.067–7.135 (m, 2H), 7.261–7.421 (m, 2H),
7.644–7.675 (m, 2H), 8.169 (br, s, 1H, NH), 8.190 (dd, J = 0.9,
8.4 Hz, 1H, ArH), 8.340 (dd, J = 1.8, 8.1 Hz, 1H, ArH) 13C NMR
d (75 MHz, CDCl3, ppm): 55.8, 107.4, 110.0, 113.7, 119.4, 121.2,
117.5, 121.5, 121.9, 122.8, 124.0, 124.6, 130.4, 132.2, 135.1,
-
=
136.2, 149.7 (C O) ESI-MS m/z 313 [M - H] 100% HRMS
(ESI) calcd for C15H11N2OBrNa [M + Na]+ 336.9952, found
336.9959.
N-(4-Cyanophenyl)-1H-indole-1-carboxamide
2g. Com-
pound 2g was obtained as a white solid after purification by
flash chromatography (SiO2, 300–400 mesh EA:PE, 1:8 to 1:5)
(yield, 62% under microwave irradiation and 81% under oil
heating for 24 h), mp 200–202 ◦C. 1H NMR d (300 MHz,
d6-DMSO, ppm) 6.801 (d, J = 3.6 Hz, 1H, C5–H), 7.225–7.358
(m, 2H), 7.650 (d, J = 7.5 Hz, 1H, ArH), 7.839–7.911 (m, 4H),
121.4, 122.5, 123.9, 124.3, 124.4, 126.9, 130.4, 134.8, 148.1, 149.0
+
=
(C O) ESI-MS m/z 267 [M + H] 100% HRMS (ESI) calcd for
C16H14N2O2NaF3 [M + Na]+ 289.0953, found 289.0961.
1206 | Green Chem., 2009, 11, 1201–1208
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N-(2-(Trifluoromethyl)phenyl)-1H-indole-1-carboxamide 2l.
Compound 2l was obtained as a light yellow solid after purifi-
cation by flash chromatography (SiO2, 300–400 mesh EA:PE,
1:10 to 1:8) (yield, 81%), mp 125–127 ◦C. 1H NMR d (300 MHz,
CDCl3, ppm) 6.750 (d, J = 3.6 Hz, 1H, C5–H), 7.267–7.419 (m,
3H), 7.515 (d, J = 3.6 Hz, 1H, C4–H), 7.638–7.709 (m, 4H),
8.200 (d, J = 8.4 Hz, 1H, ArH), 8.270 (d, J = 8.7 Hz, 1H, ArH)
13C NMR d (75 MHz, CDCl3, ppm): 108.7, 114.3, 121.4, 122.9,
123.4, 124.3, 124.8, 126.2, 126.3, 130.3, 133.1, 134.9, 135.3, 149.2
5.1, 8.1 Hz, 1H), 7.955 (dd, J = 2.1, 10.2 Hz, 1H) 13C NMR d
(75 MHz, CDCl3, ppm): 44.9, 101.7 (C-8), 102.0 (C-8), 107.3,
110.7, 111.1, 121.6, 121.7, 123.6, 126.1, 127.8, 127.9, 128.9,
=
135.6, 137.5, 151.8 (C O), 159.7 (C-9), 162.1 (C-9) ESI-MS
m/z 269 [M + H]+ 100% HRMS (ESI) calcd for C16H13N2ONaF
[M + Na]+ 291.0910, found 291.0912.
3-Benzyl-5-methyl-1H-indole-1-carboxamide
2q. Com-
pound 2q was obtained as a white solid after purification by
+
flash chromatography (SiO◦2, 300–400 mesh EA:PE, 1:13 to 1:8)
=
(C O) ESI-MS m/z 305 [M + H] 100% HRMS (ESI) calcd for
1
(yield, 86%), mp 100–101 C. H NMR d (300 MHz, CDCl3,
C16H11N2OF3Na [M + Na]+ 327.0721, found 327.0728.
ppm) 2.435 (s, 3H), 4.660 (d, J = 5.7 Hz, 2H, CH2), 5.791 (br, s,
1H, NH), 6.640 (d, J = 3.0 Hz, 1H, C5-H), 7.120 (dd, J = 1.8,
8.4 Hz, 1H), 7.319–7.423 (m, 7H), 7.940 (d, J = 8.7 Hz, 1H)
13C NMR d (75 MHz, CDCl3, ppm): 21.3, 44.9, 106.9, 113.6,
N-(Naphthalen-1-yl)-1H-indole-1-carboxamide 2m. Com-
pound 2m was obtained as a white solid after purification by
flash chromatography (SiO2, 300–400 mesh EA:PE, 1:15 to 1:10)
(yield, 41% under microwave irradiation and 76% under oil
heating for 24 h), mp 204–205 ◦C. 1H NMR d (300 MHz, CDCl3,
ppm) 6.755 (d, J = 4.2 Hz, 1H, C5–H), 7.296–7.414 (m, 2H),
7.518–7.592 (m, 3H), 7.668 (br, s, 1H, NH), 7.690 (d, J = 3.6 Hz,
121.0, 124.0, 125.6, 127.9, 128.9, 130.5, 131.8, 133.3, 137.7,
+
=
152.0 (C O) ESI-MS m/z 265 [M + H] 100% HRMS (ESI)
calcd for C17H16N2ONa [M + Na]+ 287.1160, found 287.1151.
2H), 7.795–7.968 (m, 4H), 8.220 (d, J = 8.4 Hz, 1H, ArH) 13
C
3-Benzyl-5-chloro-1H-indole-1-carboxamide 2r. Compound
2r was obtained as a white solid after purification by flash
chromatography (SiO2, 300–400 mesh EA:PE, 1:13 to 1:9) (yield,
NMR d (75 MHz, CDCl3, ppm): 107.9, 114.2, 120.8, 121.4,
121.7, 122.7, 124.1, 124.6, 125.7, 126.3, 126.7, 126.8, 127.9,
◦
1
=
51%), mp 170–172 C. H NMR d (300 MHz, CDCl3, ppm):
4.640 (d, J = 6.3 Hz, 2H, CH2), 5.841 (br, s, 1H, NH), 6.440
(d, J = 3.6 Hz, 1H, C5-H), 7.247–7.428 (m, 7H), 7.550 (d, J =
2.1 Hz, 1H), 8.100 (d, J = 9.0 Hz, 1H) 13C NMR d (75 MHz,
CDCl3, ppm): 44.9, 106.7, 115.6, 120.5, 124.5, 124.7, 127.9,
128.9, 130.4, 131.7, 134.2, 135.2, 150.4 (C O) ESI-MS m/z
287 [M + H]+ 100% HRMS (ESI) calcd for C19H14N2ONa [M +
Na]+ 309.1004, found 309.0994.
N-(2,6-Diisopropylphenyl)-1H-indole-1-carboxamide
2n.
Compound 2n was obtained as a white solid after purification
by flash chromatography (SiO2, 300–400 mesh EA:PE, 1:15 to
1:11) (yield, 40% under microwave◦irradiation and 48% under
=
128.0, 128.9, 130.5, 131.1, 133.7, 137.5, 151.6 (C O) ESI-MS
m/z 285 [M + H]+ 100% HRMS (ESI) calcd for C16H13N2ONaCl
[M + Na]+ 307.0614, found 307.0639.
1
oil heating for 48 h), mp 204–205 C. H NMR d (300 MHz,
CDCl3, ppm) 1.240 (d, J = 7.2 Hz, 12H), 3.212 (m, 2H), 6.715
(d, J = 3.3 Hz, 1H, C5-H), 6.863 (s, 1H, NH), 7.252–7.417 (m,
5H), 7.625 (d, J = 3.0 Hz, 1H, C4–H), 7.670 (d, J = 7.8 Hz, 1H),
8.150 (d, J = 8.4 Hz, 1H, ArH) 13C NMR d (75 MHz, CDCl3,
ppm): 32.7, 28.8, 107.4, 114.1, 121.3, 122.5, 123.8, 124.2, 124.6,
N-benzyl-1H-pyrrolo[2,3-b]pyridine-1-carboxamide
Compound 2r was obtained as a white solid after purification
2t.
by flash chromatography (SiO2, 300–400 mesh EA:PE, 1:8
◦
1
to 1:5) (yield, 83%), mp 100–101 C. H NMR d (300 MHz,
CDCl3, ppm): 4.750 (d, J = 6.0 Hz, 2H, CH2), 6.550 (d, J =
4.2 Hz, 1H, C5-H), 7.180 (dd, J = 5.1, 8.4 Hz, 1H), 7.285–7.453
(m, 5H), 7.930 (dd, J = 1.2, 8.4 Hz, 1H), 8.030 (d, J = 3.9 Hz,
1H), 8.260 (dd, J = 1.5, 4.8 Hz, 1H), 10.177 (br, s, 1H, NH)
13C NMR d (75 MHz, CDCl3, ppm): 44.1, 102.9, 117.9, 123.5,
=
128.8, 130.1, 130.3, 135.2, 146.5, 151.1 (C O) ESI-MS m/z
321 [M + H]+ 100% HRMS (ESI) calcd for C21H24N2ONa [M +
Na]+ 343.1786, found 343.1769.
N-(Pyridin-4-yl)-1H-indole-1-carboxamide 2o. Compound
2o was obtained as a light yellow solid after purification by flash
chromatography (SiO2, 300–400 mesh CH3OH:CH2Cl2, 1:30 to
1:15) (yield, 52% under microwave irradiation and 75% under oil
heating for 24 h), mp 73–74 ◦C. 1H NMR d (300 MHz, CDCl3,
ppm) 6.645 (d, J = 3.6 Hz, 1H, C5-H), 7.245 (dt, J = 0.9,
7.5 Hz, 1H), 7.360 (dt, J = 0.9, 8.1 Hz, 1H), 7.452 (br, 1H, NH),
7.573–7.610 (m, 3H), 7.640 (d, J = 3.9 Hz, 1H, C4-H), 8.169 (d,
J = 8.1 Hz, 1H), 8.460 (dd, J = 1.2, 4.8 Hz, 2H) 13C NMR d
(75 MHz, CDCl3, ppm): 108.4, 114.1, 114.6, 121.3, 123.0, 123.9,
126.3, 127.3, 127.5, 128.6, 129.9, 138.4, 142.4 146.6, 151.8
+
=
(C O) ESI-MS m/z 262 [M + H] 100% HRMS (ESI) calcd
for C15H13N3ONa [M + Na]+ 274.0956, found 274.0971.
Procedures for labeling studies see in ESI.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grants 20721003 and 20872153), In-
ternational Collaboration Projects (Grants 2007DFB30370 and
20720102040) and the 863 Hi-Tech Program of China (Grants
2006AA020602)
=
124.7, 130.2, 135.3, 145.7, 149.3 (C O), 150.2 ESI-MS m/z 238
[M + H]+ 100% HRMS (ESI) calcd for C14H12N3O [M + H]+
230.3980, found 230.0989.
N-Benzyl-6-fluoro-1H-indole-1-carboxamide
pound 2p was obtained as a light yellow solid after the
2p. Com-
References
purification by flash chromatography (SiO2, 300–400 mesh
1 (a) P. Anastas, L. G. Heine, T. C. Williamson, in Green Chemical
Syntheses and Processes, Oxford University Press, New York, 2000;
(b) A. Matlack, Green Chem., 2003, 5, G7–G12; (c) S. K. Hota, A.
Chatterjee, P. K. Bhattacharya and P. Chattopadhyay, Green Chem.,
2009, 11, 169–176; (d) F. F. Jian, J. Zheng, Y. F. Li and J. Wang, Green
Chem., 2009, 11, 215–222.
◦
1
EA:PE, 1:11 to 1:6) (yield, 85%), mp 100–102 C. H NMR
d (300 MHz, CDCl3, ppm): 4.630 (d, J = 5.4 Hz, 2H, CH2),
5.859 (br, s, 1H, NH), 6.588 (d, J = 3.6 Hz, 1H, C5–H), 6.995
(dt, J = 2.4, 9.3 Hz, 1H), 7.324–7.393 (m, 6H), 7.500 (dd, J =
This journal is
The Royal Society of Chemistry 2009
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©

View Article Online
2 (a) D. Dallinger and C. O. Kappe, Chem. Rev., 2007, 107, 2563–2591;
(b) M. A. Herrero, J. M. Kremsner and C. O. Kappe, J. Org. Chem.,
2008, 73, 36–47; (c) Y. Kabri, A. Gellis and P. Vanelle, Green Chem.,
2009, 11, 201–208.
3 (a) C.-J. Li and T.-H. Chan, in Organic Reactions in Aqueous
Media, Wiley, New York, 1997; (b) Organic Synthesis in Water, ed.
P. A. Grieco, Blackie Academic and Professional, London, 1998;
(c) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751–2722; (d) C. J. Li,
Chem. Rev., 2005, 105, 3095–3165; (e) S. Bhadra, A. Saha and B. C.
Ranu, Green Chem., 2008, 10, 1224–1230.
Ed., 2002, 41, 3230–3256; (c) S. Kamijo and Y. Yamamoto, J. Org.
Chem., 2003, 68, 4764–4771.
15 (a) M. L. Curtin, S. K. Davidsen, H. R. Heyman, R. B. Garland,
G. S. Sheppard, A. S. Florjancic, L. Xu, G. M. Jr Carrera, D. H.
Steinman, J. A. Trautmann, D. H. Albert, T. J. Magoc, P. Tapang
and D. A. Rhein, J. Med. Chem., 1998, 41, 74–95; (b) H. Matsumoto
and A. Fujii, J. Pharmacol. Exp. Ther., 2002, 300, 668–672.
16 W. Holger, L. Elke, E. Matthias, S. Ru¨diger, S. Corinna, S.-M.
Annette and P. Alexander, WO Pat., 2008, 113, 760.
17 (a) D. L. Boger and M. Patel, J. Org. Chem., 1987, 52, 3934–3936;
(b) W.-H. Fan, M. Parikh and J. K. Snyder, Tetrahedron Lett., 1995,
36, 6591–6594; (c) J. E. Macor, A. Cuff and L. Cornelius, Tetrahedron
Lett., 1999, 40, 2733–2736.
4 C. O. Kappe and D. Dallinger, Nat. Rev. Drug Discovery, 2006, 5,
51–64.
5 (a) R. L. Sundberg, Indoles, Academic, London, 1996; (b) M.
Lounasmaa and A. Tolvanen, Nat. Prod. Rep., 2000, 17, 175–191;
(c) M. F. Zheng, M. Y. Zheng, D. J. Ye, Y. M. Deng, S. F. Qiu, X. M.
Luo, K. X. Chen, H. Liu and H. L. Jiang, Bioorg. Med. Chem. Lett.,
2007, 17, 2414–2420.
6 (a) R. C. Larock, J. Organomet. Chem., 1999, 576, 111–124; (b) D. Y.
Yue and R. C. Larock, Org. Lett., 2004, 6, 1037–1040.
7 For recent reviews, see: (a) G. R. Humphrey and J. T. Kuethe, Chem.
Rev., 2006, 106, 2875–2911; (b) S. Patil and J. K. Buolamwini, Curr.
Org. Chem., 2006, 3, 477–498; (c) S. Patil and R. Patil, Curr. Org.
Chem., 2007, 4, 201–222.
8 (a) H. Kusama, J. Takaya and N. Iwasawa, J. Am. Chem. Soc., 2002,
124, 11592–11593; (b) H. Kusama, Y. Suzuki, J. Takaya and N.
Iwasawa, Org. Lett., 2006, 8, 895–897; (c) Y. Terada, M. Arisawa
and A. Nishida, Angew. Chem., Int. Ed., 2004, 43, 4063–4067; (d) A.
Saito, S. Oda, H. Fukaya and Y. Hanzawa, J. Org. Chem., 2009, 74,
1517–1524.
9 For examples of Pd-catalyzed reactions, see: (a) G. Battistuzzi, S.
Cacchi and G. Fabrizi, Eur. J. Org. Chem., 2002, 2671–2681, and
references cited therein; (b) A. Arcadi, S. Cacchi, G. Fabrizi, F.
Marinelli and L. M. Parisi, J. Org. Chem., 2005, 70, 6213–6217;
(c) A. Yasuhara, Y. Takeda, N. Suzuki and T. Sakamoto, Chem.
Pharm. Bull., 2002, 50, 235–238; (d) Z. Shen and X. Lu, Tetrahedron,
2006, 62, 10896–10899; (e) A. Takeda, S. Kamijo and Y. Yamamoto,
J. Am. Chem. Soc., 2000, 122, 5662–5663; (f) R. C. Larock and E. K.
Yum, J. Am. Chem. Soc., 1991, 113, 6689–6690; (g) R. C. Larock,
E. K. Yum and M. D. Refvik, J. Org. Chem., 1998, 63, 7652–7662;
(h) R. C. Larock, Pure Appl. Chem., 1999, 71, 1435–1449; (i) M.
Shen, G. Li, B. Z. Lu, A. Hossain, F. Roschanger, V. Farina and
C. H. Senanayake, Org. Lett., 2004, 6, 4129–4132; (j) C.-Y. Chen,
D. R. Lieberman, R. D. Larsen, R. A. Reamer, T. R. Verhoeven and
P. J. Reider, Tetrahedron Lett., 1994, 35, 6981–6984; (k) J. Yu, X. Z.
Wearing and M. Cook, J. Org. Chem., 2005, 70, 3963–3979; (l) N.
Gathergood and P. J. Scammells, Org. Lett., 2003, 5, 921–923.
10 For examples of Cu-catalyzed reactions, see: (a) K. Hiroya, S. Itoh
and T. Sakamoto, J. Org. Chem., 2004, 69, 1126–1136; (b) K. Hiroya,
S. Itoh, M. Ozawa, Y. Kanamori and T. Sakamoto, Tetrahedron Lett.,
2002, 43, 1277–1280; (c) C. G. Batse, P. Saejueng, J. M. Murphy and
D. Venkataraman, Org. Lett., 2002, 4, 4727–4729; (d) B. C. J. Van
Esseveldt, F. L. van Delft, J. M. M. Smits, R. de Gelder, H. E.
Schoemaker and F. P. Z. J. T. Rutjes, Adv. Synth. Catal., 2004, 346,
823–834; (e) For an example of an Ir-catalyzed reaction, see: X.
Li, A. R. Chianese, T. Vogel and R. H. Crabtree, Org. Lett., 2005, 7,
5437–5440; (f) For an example of In-catalyzed reaction, see: N. Sakai,
K. Annaka and T. Konakahara, Org. Lett., 2004, 6, 1527–1530.
11 B. M. Trost and A. McClory, Angew. Chem., Int. Ed., 2007, 46,
2074–2077.
18 S. Ye, Q. Ding, Z. Wang, H. Zhou and J. Wu, Org. Biomol. Chem.,
2008, 6, 4406–4412.
19 (a) A. Arcadi, G. Bianchi and F. Marinelli, Synthesis, 2004, 610–618;
(b) I. Nakamura, U. Yamagishi, D. Song, S. Konta and Y. Yamamoto,
Angew. Chem., Int. Ed., 2007, 46, 2284–2287; (c) Y. Zhang, J. P.
Donahue and C.-J. Li, Org. Lett., 2007, 9, 627–630.
20 (a) D. J. Gorin, N. R. Davis and F. D. Toste, J. Am. Chem. Soc., 2005,
127, 11260–11261; (b) N. Morita and N. Krause, Org. Lett., 2004,
6, 4121–4123; (c) F. M. Istrate and F. Gagose, Org. Lett., 2007, 9,
3181–3184.
21 X.-Y. Liu, P. Ding, J.-S. Huang and C.-M. Che, Org. Lett., 2007, 9,
2645–2648.
22 Q. P. Ding, Y. Ye, R. H. Fan and J. Wu, J. Org. Chem., 2007, 72,
5439–5442.
23 (a) X.-Y. Liu and C.-M. Che, Angew. Chem., Int. Ed., 2008, 47,
3805–3810; (b) H. H. Jung and P. E. Floreancig, Org. Lett., 2006, 8,
1949–1951; (c) X. Yao and C.-J. Li, Org. Lett., 2006, 8, 1953–1955;
(d) B. Yan and Y. Liu, Org. Lett., 2007, 9, 4323–4326; (e) A. Arcadi,
G. Bianchi, S. Di, Giuseppe and F. Marinelli, Green Chem., 2003, 5,
64–67.
24 Z. G. Li, H. B. Sun, H. L. Jiang and H. Liu, Org. Lett., 2008, 10,
3263–3266.
25 Y. Yu, G. A. Stephenson and D. Mitchell, Tetrahedron Lett., 2006,
47, 3811–3814.
26 N. Marion, R. S. Ramo´n and S. P. Nolan, J. Am. Chem. Soc., 2009,
131, 448–449.
27 C. H. M. Amijs, V. Lo´pez-Carrillo, M. Raducan, P. Pe´rez-Gala´n,
C. Ferrer and A. M. Echavarren, J. Org. Chem., 2008, 73, 7721–
7730.
28 The material ureas were decomposed to 2-ethynylaniline and 4-
cynaoaniline or 1-naphthylamine.
29 1s was totally transformed to the 5-(trifluoromethyl)-1H-indole prod-
1
uct which was determined by LC-MS and H NMR: d (300 MHz,
CDCl3, ppm): 6.660 (t, J = 2.4 Hz, 1H, H-3), 7.321 (t, J = 3.3 Hz,
1H), 7.406–7.492 (m, 2H), 7.961 (s, 1H), 8.364 (br, 1H, NH) LC-
MS m/z 186 [M + H]+ 100%. For structure verification see: J.-G.
Parmentier, G. Poissonnet and S. Goldstein, Heterocycles, 2002, 57,
465–476.
30 For reviews on vinylidene complexes, see: (a) C. Bruneau and P. H.
Dixneuf, Acc. Chem. Res., 1999, 32, 311–323; (b) B. M. Trost and
A. McClory, Chem.–Asian J., 2008, 3, 164–194; (c) F. E. McDonald,
Chem.–Eur. J., 1999, 5, 3103–3106; (d) For synthetic use of vinylidene
intermediates, see for examples: F. E. McDonald and C. C. Schultz,
J. Am. Chem. Soc., 1994, 116, 9363–9364; (e) F. E. McDonald,
Chem.–Eur. J., 1999, 5, 3103–3106; (f) K. Maeyama and N. Iwasawa,
J. Am. Chem. Soc., 1998, 120, 1928–1928; (g) N. Iwasawa, K.
Maeyama and H. Kusama, Org. Lett., 2001, 3, 3871–3873; (h) H.
Kusama, H. Yamabe and N. Iwasawa, Org. Lett., 2002, 4, 2569–
2751; (i) N. Iwasawa, M. Shido, K. Maeyama and H. Kusama, J. Am.
Chem. Soc., 2000, 122, 10226–11027; (j) T. Miura and N. Iwasawa,
J. Am. Chem. Soc., 2002, 124, 518–519; (k) K. Miki, F. Nishino, K.
Ohe and S. Uemura, J. Am. Chem. Soc., 2002, 124, 5260–5267.
31 J. Barluenga, A. Die´guez, A. Ferna´ndez, F. Rodr´ıguez and F. J.
Fan˜ana´s, Angew. Chem., 2006, 118, 2145–2147, (Angew. Chem. Int.
Ed., 2006, 45, 2091–2093).
12 (a) T. Shimada, I. Nakamura and Y. Yamamoto, J. Am. Chem. Soc.,
2004, 126, 10546–10547; (b) I. Nakamura, Y. Mizushima and Y.
Yamamoto, J. Am. Chem. Soc., 2005, 127, 15022–15023.
13 (a) S. Cacchi, G. Fabrizi and L. M. Parisi, Org. Lett., 2003, 5, 3843–
3846; (b) K. B. Hong, C. W. Lee and E. K. Yum, Tetrahedron Lett.,
2004, 45, 693–697; (c) Q. Huang and R. C. Laroch, J. Org. Chem.,
2003, 68, 7342–7344.
14 (a) S. Kamijo and Y. Yamamoto, J. Am. Chem. Soc., 2002, 124,
11940–11945; (b) S. Kamijo and Y. Yamamoto, Angew. Chem., Int.
1208 | Green Chem., 2009, 11, 1201–1208
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