Sterically Controlled Ru(II)-Catalyzed Divergent Synthesis of 2-Methylindoles and Indolines through a C-H Allylation/Cyclization Cascade

Article abstract of DOI:10.1021/acs.joc.8b01034

A ruthenium-catalyzed synthesis of 2-methylindole was accomplished via a C-H allylation/oxidative cyclization cascade. Strategically, β-hydride elimination from the σ-alkyl-Ru intermediate has been suppressed by steric hindrance from a remote position. Hence, 2-methylindolines from the corresponding ortho-substituted anilines were achieved via protodemetalation in lieu of β-hydride elimination under a modified reaction condition. This mild intermolecular annulation cascade proceeds smoothly by a redox-neutral ruthenium catalyst without stoichiometric metal oxidants, such as silver(I) or copper(II) salts, providing excellent functional group tolerance.

Full text of DOI:10.1021/acs.joc.8b01034

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Article
Sterically Controlled Ru(II)-Catalyzed Divergent Synthesis of 2-
Methylindoles and Indolines through a C-H Allylation/Cyclization Cascade
Manash Kumar Manna, Gurupada Bairy, and Ranjan Jana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01034 • Publication Date (Web): 06 Jun 2018
Downloaded from http://pubs.acs.org on June 6, 2018
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Sterically Controlled Ru(II)-Catalyzed Divergent Synthesis
of 2-Methylindoles and Indolines through a C-H
Allylation/Cyclization Cascade
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†
,‡
†,‡
†,‡
Manash Kumar Manna, Gurupada Bairy, and Ranjan Jana*
†
Organic and Medicinal Chemistry Division, CSIRꢀIndian Institute of Chemical Biology
4
Raja S. C. Mullick Road, Jadavpur, Kolkataꢀ700032, West Bengal, India
‡
Academy of Scientific and Innovative Research (AcSIR), Kolkataꢀ700032, West Bengal, India
R = H
DCE
Me
H
N
N
-hydride
elimination
N
H
N
RuII
RuIILn
N
C-H allylation/cyclization cascade
steric-controlled chemoselectivity
redox-neutral Ru(II)-catalyst
R
OAc
R
N
X
X
R = FG
TFE
H
no stoichiometric metal oxidant
steric-controlled
N
protodemetalation
FG
N
N
ABSTRACT: A Rutheniumꢀcatalyzed synthesis of 2ꢀmethylindole was accomplished via CꢀH
allylation, oxidative cyclization cascade. Strategically, βꢀhydride elimination from the σꢀalkylꢀRu
intermediate has been suppressed by steric hindrance from a remote position. Hence 2ꢀ
methylindolines from the corresponding orthoꢀsubstituted anilines were achieved via
protodemetalation in lieu of βꢀhydride elimination under a modified reaction condition. This
mild intermolecular annulation cascade proceeds smoothly by redoxꢀneutral ruthenium catalyst
without stoichiometric metal oxidants such as silver(I) or copper(II) salts providing excellent
functional group tolerance.
INTRODUCTION
Indole and indoline core structures are ubiquitously found in medicinal scaffolds, natural
1
products, agrochemicals, and functionalized materials. By taking advantage of facile
2
electrophilic ortho metalation of protected anilines, an impressive array of CꢀH activation
3
methodology has been developed for the synthesis of indoles. Direct synthesis of indoline
4
5
nucleus was also achieved with norbornene that lacks syn βꢀhydrogen, πꢀallyl stabilization,
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nucleophilic addition of Rhꢀalkyl species to N=N bond, or intramolecular CꢀH amination.
However, divergent synthesis of indole and indoline from aniline derivatives via CꢀH activation
is underdeveloped. Hypothetically, it is plausible by intercepting the incipient Heck intermediate
which is formed through migratory alkene insertion.
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In this vein, previously, we reported a palladiumꢀcatalyzed divergent synthesis of 2ꢀ
arylindole and indolines merging CꢀH activation and alkene difunctionalization manifolds
8
(Scheme 1a). Recently, we have also demonstrated the synthesis of indoline with electronically
unbiased styrenes by Ruꢀcatalyst which is reluctant to undergo βꢀhydride elimination compared
9
to palladium catalyst. Although, synthesis of 2ꢀarylindoles via CꢀH activation has been studied
extensively, the synthesis of 2ꢀalkylindoles are less attended. The Saá group has reported an
expensive Rh(III)ꢀcatalyzed synthesis of 2ꢀmethylindoles where shoichiometric copper(II) was
10
used as an oxidant (Scheme 1b). To the best of our knowledge, there is no report for the direct
intermolecular synthesis of 2ꢀmethylindolines. We report herein, a ruthenium(II)ꢀcatalyzed
synthesis of 2ꢀmethylindole from 2ꢀpyridineꢀprotected aniline and allyl acetate via CꢀH
allylation/oxidative cyclization cascade. Furthermore, a hitherto unknown sterically controlled
indoline formation for orthoꢀsubstituted anilines was also achieved via protodemetalation in lieu
of βꢀhydride elimination (Scheme 1c). Besides, inexpensive ruthenium(II)ꢀcatalyst, no
stoichiometric copper, silver salt or base was essential since an unprecedented redoxꢀneutral
catalytic cycle has been explored for this reaction manifold.
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Scheme 1. Divergent Synthesis of Indole and Indoline
RESULTS AND DISCUSSION
We chose an inexpensive rutheniumꢀcatalyst, Nꢀarylpyrimidine and allyl acetate for initial
o
screening (entry 1, Table 1). To our delight, after heating the reaction mixture at 120 C in DCE,
the desired 2ꢀmethylindole (3a) was obtained in 22% yield along with 7% Cꢀ3 allylation of 2ꢀ
methylindole (3a’) product as an inseparable mixture (entry 1, table 1). Although, yield of 3a
increased to 43% with the addition of NaOAc, the yield of 3a’ was also increased
commensurately (entry 2, table 1). Gratifyingly, by changing the directing group from
pyrimidine to pyridine, the formation of unexpected 3ꢀallylꢀ2ꢀmethylindole (3a’) was suppressed
completely and the desired 2ꢀmethylindole (3a) was obtained exclusively in 82% yield (entry 5,
table 1). Among various silver salts such as AgSbF , AgBF , AgOTf, AgNTf , AgSbF (20 mol
6
4
2
6
%) was found to be most effective to generate the active catalyst. Since acetate ion is required to
generate active catalyst, several acetate ion sources such as LiOAc, NaOAc, KOAc, CsOAc,
AgOAc, Cu(OAc) were examined and among them NaOAc was found to be optimal. Finally, 5
2
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o
mol % [Ru(pꢀcymene)Cl ] , 20 mol % AgSbF and 50 mol % NaOAc in DCE at 120 C provided
2
2
6
82% yield of the desired indole (Table 1).
Table 1. Optimization of the Reaction Conditions
a
0
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b
entry X
Ag(I)
salts
additive solvent yield
3
a/3a’
1
2
3
4
5
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7
8
9
1
N
N
N
N
AgSbF6
ꢀ
DCE
22/7
43/13
36/11
22/53
82/0
67/0
79/0
43/0
48/0
AgSbF6 NaOAc DCE
AgSbF6 PivOH DCE
AgSbF6 NaOAc TFE
CH AgSbF6 NaOAc DCE
CH AgSbF6 PivOH DCE
CH AgSbF6 NaOAc TFE
CH AgBF4 NaOAc DCE
CH AgOTf NaOAc DCE
0
CH AgSbF6 NaOAc Toluene 45/0
11
CH AgSbF6 NaOAc 1,4ꢀ
dioxane
ND
c
1
2
3
CH AgSbF6 NaOAc DCE
56/0
37/0
d
1
CH AgSbF6 NaOAc DCE
a
b
All reactions were carried out in 0.1 mmol scale. Yields refer to here are overall isolated yields
c
and the product distribution was measured from NMR . Allyl methyl carbonate was used instead
d
of allyl acetate. Allyl alcohol was used instead of allyl acetate.
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A wide variety of anilines containing functional groups such as methoxy (3q, 3v, 3v’),
OTBDMS (3u), trifluoromethoxy (3t), methyl (3f, 3l, 3p, 3q), tertꢀbutyl (3s), trifluoromethyl
(3h, 3n, 3o), aryl (3m) etc. were compatible under these mild reaction conditions. Notably, the
annulation reaction took place regioselectively at the ortho position of ꢀNHPy group while ꢀ
NHPiv (3e) remains inert suggesting a strong, electronꢀrich directing group is necessary for
1
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electrophilic ortho metalation. Other weakly coordinating groups such as ꢀCO Me (3d), ꢀNO2
2
(
3j), ꢀCH CO Me (3k), ꢀCOMe (3r) that have the potential to competitively direct ortho CꢀH
2 2
activation were found to compatible and did not direct CꢀH allylation under these conditions.
Halogens such as fluoro (3b, 3g) and chloro (3c, 3o, 3p) are compatible under the reaction
conditions. Interestingly, electronꢀdeficient pꢀnitro aniline also produced the desired product with
good yield (3j). Electronꢀrich mꢀmethoxy aniline furnished a mixture of two regioꢀisomeric
products through ortho metallation from both ortho positions (3v, 3v’). Electron withdrawing
and neutral functional groups give a single product through ortho metalation from the sterically
less hindered side. Reaction with αꢀmethyl allyl acetate furnished 2ꢀethylindole in lower yield
(3w). Interestingly, no double allylation followed by singular cyclization to provide 7ꢀallyl,2ꢀ
methylindole was observed (Table 2).
a,b
Table 2. Substrate Scope of Indoles
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a
b
All reactions were carried out in 0.2 mmol scale. Yields refer to the average of isolated yields
c
of at least two experiments. From mꢀmethoxy aniline.
During the synthesis of 2ꢀmethylindoles, we observed that ortho methyl anilines
furnished a mixture of 2ꢀmethylindoles and indolines in 17% and 36% yield respectively. We
assumed that the βꢀhydride elimination of the rutheniumꢀalkyl species which leads to the indole
formation may be perturbed in the case of ortho substituted aniline, furnishing corresponding
indoline product through protodemetalation. Although sterically controlled remote CꢀH
1
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functionalization is reported,
to the best of our knowledge stericꢀinduced scaffold
diversification through CꢀH activation is unknown. Being encouraged by this exciting result we
started further optimization to get indoline product exclusively. As expected indoline formation
was favoured in protic solvent via protodemetalation. Therefore, when the solvent was changed
from DCE to TFE the yield of the indoline product increased to 54% with a trace amount of
indole product. Switching from pyridine to pyrimidine directing group, the yield of the reaction
was further improved to 82%. Since no effect of NaOAc was observed, it was omitted to
simplify the reaction condition further (Table 3).
a
Table 3. Optimization of the Reaction Conditions
b
entry X
Ag(I)
salts
additive solvent yield
5
c/5c’
1
2
3
4
5
CH2 AgSbF6 NaOAc DCE
CH2 AgSbF6 NaOAc TFE
36/17
54/8
N
N
N
AgSbF6 NaOAc DCE
AgSbF6 NaOAc TFE
43/26
82/trace
82/trace
AgSbF6
ꢀ
TFE
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5
6
a
b
All reactions were carried out in 0.1 mmol scale. Yields refer to here are overall isolated yields
and the product distribution was measured from NMR .
Although, sterically less hindered fluorine substitution at the ortho position of aniline
yielded indole as predominant product (3g), other larger halogens such as ortho chloro (5a) and
bromo (5b) substituted anilines provided exclusive indoline products in high yields. Besides
halogen, methyl (5c, 5d, 5e), methoxy (5f), isopropyl (5g) substituted aniline at ortho position
produces the corresponding indoline products in good yield. Presumably, syn βꢀhydrogen may
not be accessible for elimination instead protoderuthenation occurs in protic solvent to furnish
indoline. This is an unprecedented example of divergent indole and indoline synthesis where
steric hindrance from a remote position inhibits the βꢀhydride elimination. As expected, even
larger ortho substituents on aniline, such as tertꢀbutyl (6a) and phenyl (6b) provided CꢀH
allylation product which do not undergo further cyclization due to steric hindrance.
0
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0
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5
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8
9
0
a,b
Table 4. Substrate Scope of Indolines
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H
N
Me
[
Ru(p-cymene)Cl ] (5 mol %)
2 2
H
N
N
OAc
R
R
+
AgSbF (20 mol %)
6
N
TFE, 16 h
N
N
o
2
equiv
120 C
4
2
5a-5i
1
1
1
1
1
1
1
1
1
1
2
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2
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Me
Me
Me
N
N
N
Cl
N
Br
N
Me
N
N
N
N
5
a: 82%
5b: 78%
5c: 82%
CCDC:1817992
Me
Me
Me
Me
Me
N
N
N
N
Cl
Me
N
Me
N
OMe
N
N
Et
N
N
N
N
5d: 80%
5e: 56%
5f: 70%
5g: 63%
Me
Me
N
N
NH
NH
nPr
iPr
tBu
Ph
N
N
N
N
N
N
N
N
5
h: 35%
5i: 65%
6a: 65%
6b: 35%
a
b
All reactions were carried out in 0.2 mmol scale. Yields refer to the average of isolated yields
of at least two experiments.
When deuterated 1aꢀd was subjected under standard reaction condition in the absence of
5
olefin 70% ortho DꢀH exchange was observed (Scheme 2, a). Whereas, in the absence of metal
catalyst no DꢀH exchange was observed, suggesting the involvement of a reversible directed
ortho metalation step. A similar experiment in the presence of allyl acetate provided desired
product in 80% yield with a 83% DꢀH exchange at the Cꢀ7 position (Scheme 2, b). This suggests
that although a reversible ortho metalation is feasible at both ortho positions, allylationꢀ
cyclization takes place exclusively in one of the ortho positions. From a competitive experiment
1
by taking an equimolecular mixture of 1a and 1a-d k /k = 1.2 was determined from H NMR
5
H
D
(Scheme 2, c). This low value indicates that the CꢀH activation may not be involved in the rate
determining step. To know the role of NaOAc, when the annulation was performed with a
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combination of Ru(pꢀcymene)(OAc) and NaSbF , the desired product was isolated in 76% yield
2
6
(Scheme 2, d) and no product formation was observed in the absence of NaSbF . This
6
experiment suggests that the catalytic silver ion is necessary to remove the chloride ion and
ꢀ
NaOAc and SbF ions are necessary to generate the active catalyst. A preformed allylation
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product was separately prepared and subjected to the standard reaction condition to form the
annulation product in 84% yield (Scheme 2, e). This experiment indicates that CꢀH allylation
take place during the course of the reaction. No indoline to indole oxidation was observed under
the standard reaction condition with a preformed indoline substrate, indicating that
protodemetalation followed by oxidation may not be involved. Instead, a concerted βꢀhydride
elimintion/isomerization sequences may be involved for the indole formation (Scheme 2, e).
When 4c was subjected to the indoline formation in DCE in the presence of 10 equiv of D O,
2
3
2% deuterium incorporation was observed at the 2ꢀmethyl group (Scheme 2, f) suggesting a
protodemetalation step is involved for the indoline formation.
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Scheme 2. Control Experiments
12
From the control experiments and previous reports, the active catalyst is generated from [Ru(pꢀ
cymene)Cl ] in presence of AgSbF and NaOAc through the removal of silver chloride which
2
2
6
undergoes directed ortho metalation to the substrate in reversible manner to generate the
intermediate B. Migratory insertion of the intermediate B to alkene generates an alkyl ruthenium
intermediate C which undergoes rapid βꢀacetoxy elimination to generate a CꢀH allylation
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intermediate D. The ruthenium catalyst further coordinates with the aniline nitrogen atom and
undergoes a migratory alkene insertion to the allyl group that results in the intermediate F
through intramolecular CꢀN bond formation. In case of ortho unsubstituted anilines the
intermediate F undergoes a rapid βꢀhydride elimination and double bond isomerization to
produce the desired indole product. But in case of ortho substituted anilines the βꢀhydride
elimination is perturbed due to steric interaction with the directing pyrimidine group which
stabilizes the alkylꢀRu species through coordination. Thus it prefers a protodemetalation in protic
solvent e.g. TFE to produce the indoline product. The active catalyst is regenerated for
subsequent runs from the generated ruthenium hydride species presumably by the formation of
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hydrogen gas reacting with AcOH generated in the reaction medium (Scheme 3).
Scheme 3. Plausible Catalytic Cycle
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Finally, to remove the pyridine directing group, the indole was treated with MeOTf
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followed by alkali to furnish the deprotected 2ꢀmethylindole in 87% yield. However, all of our
7
attempts to deprotect pyrimidine from the indoline moiety were in vain.
CONCLUSION
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In conclusion, we have developed an unprecedented sterically controlled synthesis of 2ꢀ
methylindoles and indolines. Mechanistically, the 2ꢀmethylindole nucleus is obtained through Cꢀ
H allylation/carboamination/βꢀhydride elimination/double bond isomerization cascade whereas
for ortho substituted sterically hindered anilines, the indolines are obtained through CꢀH
allylation/carboamination/protodemetalation cascade in protic solvent. This mild intermolecular
annulation cascade proceeds smoothly by redoxꢀneutral ruthenium catalyst without
stoichiometric metal oxidants such as silver(I) or copper(II) salts with exceptional functional
group tolerance. This divergent synthetic approach through CꢀH activation cascade will be a
valuable tool in organic and medicinal chemistry.
EXPERIMENTAL SECTION
General Information. All manipulations with airꢀsensitive reagents were carried out under a dry
nitrogen atmosphere. Unless otherwise stated, all commercial reagents were used without
additional purification. Solvents were dried using standard methods and distilled before use. The
14,15
3g
starting material Nꢀaryl pyridines,
Nꢀaryl pyrimidines and deuterated Nꢀphenyl pyridine
1
5
(
1a-d5) were prepared using literature reported method. TLC was performed on silica gel
plates (Merck silica gel 60, f ), and the spots were visualized with UV light (254 and 365 nm)
254
1
or by charring the plate dipped in KMnO or vanillin charring solution. H NMR was recorded at
4
3
00 MHz (BrukerꢀDPX), 400 MHz (JEOLꢀJNMꢀECZ400S/L1) and 600 MHz (BrukerꢀAvance)
1
3
frequency and C NMR spectra were recorded at 75 MHz (BrukerꢀDPX) and 150 MHz
1
9
(
BrukerꢀAvance) frequency in CDCl solvent using TMS as the internal standard. F NMR
3
spectra were recorded in CDCl solvent using hexafluorobenzene as the internal standard.
3
Chemical shifts were measured in parts per million (ppm) referenced to 0.0 ppm for
tetramethylsilane. The following abbreviations were used to explain multiplicities: s = singlet, d
=
doublet, t = triplet, q = quartet, m = multiplet, br. = broad. Coupling constants, J were reported
in Hertz unit (Hz). HRMS (m/z) were measured using EI and ESI techniques (JEOLꢀJMS 700
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and QꢀTof Micro mass spectrometer respectively). Infrared (IR) spectra were recorded on
Fourier Transform Infrared Spectroscopy (Bruker Tensor 27), only intense peaks were reported.
General Experimental Procedure for Ruthenium-Catalyzed 2-Methylindole Synthesis from
the Corresponding N-aryl pyridines and Allyl acetates. A mixture of Nꢀaryl pyridine (0.2
mmol), [Ru(pꢀcymene)Cl ] (0.01 mmol, 5 mol %), AgSbF (0.04 mmol, 20 mol %) and NaOAc
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(0.1 mmol, 0.5 equiv) was taken in a 15ꢀmL pressure tube. To this reaction mixture, DCE (2.0
mL) and the corresponding allyl acetate (0.4 mmol) were added via micro syringe and the closed
o
reaction mixture was allowed to stir at 120 C for 16 h. After completion as indicated by TLC,
the reaction the reaction mixture was cooled to ambient temperature. After dilution with
dichloromethane the reaction mixture was completely transferred to a RB flask and concentrated
under reduced pressure. The crude product was purified by column chromatography using ethyl
acetate/hexane as eluent to afford the desired indole product.
2
-Methyl-1-(pyridin-2-yl)-1H-indole, 3a, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
product as a colorless liquid, (34 mg, 82%). The same reaction was performed in 1.0 mmole
1
scale and the desired product obtained in 68% yield. H NMR (600 MHz, CDCl ): δ 8.69 (dd, J
3
1
=
4.8 Hz, J = 1.8 Hz, 1H), 7.90 (td, J = 7.2 Hz, J = 1.8 Hz, 1H), 7.58ꢀ7.60 (m, 1H), 7.45 (d, J =
2 1 2
8.4 Hz, 1H), 7.41ꢀ7.42 (m, 1H), 7.32ꢀ7.34 (m, 1H), 7.15ꢀ7.17 (m, 2H), 6.46 (s, 1H), 2.50 (s, 3H);
1
3
C NMR (150 MHz, CDCl ): δ 151.4, 149.6, 138.2, 137.1, 136.8, 128.7, 121.9, 121.5, 120.8,
3
ꢀ1
1
20.6, 119.7, 110.2, 103.3, 14.0; IR (neat): υmax 2922, 1691, 1582, 1461, 742 cm ; HRMS (ESI,
+
m/z) calcd. for C H N [M+H] : 209.1079; found: 209.1075.
1
4
13
2
5
-Fluoro-2-methyl-1-(pyridin-2-yl)-1H-indole, 3b, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow liquid, (29 mg, 64%). H NMR (600 MHz, CDCl ): δ 8.68 (dd, J = 4.8 Hz,
3
1
J = 1.8 Hz, 1H), 7.90 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.30ꢀ7.35 (m,
2
1
2
2
2
1
H), 7.21 (dd, J = 9.6 Hz, J = 3.0 Hz, 1H), 6.87 (td, J = 9.0 Hz, J = 3.0 Hz, 1H), 6.40 (s, 1H),
1 2 1 2
13
.47 (s, 3H); C NMR (150 MHz, CDCl ): δ 158.4 (d, J = 233.4 Hz), 151.2, 149.6, 138.4, 138.3,
3
33.6, 129.1 (d, J = 10.4 Hz), 122.0, 120.7, 110.0 (d, J = 9.5 Hz), 109,4 (d, J = 25.7 Hz), 140.7
19
(
d, J = 23.4 Hz), 103.2 (d, J = 4.1 Hz), 14.1; F NMR (376 MHz, CDCl ): δ ꢀ124.0 (s, 1F); IR
3
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ꢀ1
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(
neat): υmax 2921, 1585, 1466, 1179, 780 cm ; HRMS (ESI, m/z) calcd. for C H N F [M+H] :
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2
227.0985; found: 227.0979.
5
-Chloro-2-methyl-1-(pyridin-2-yl)-1H-indole, 3c, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
2
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5
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product as a yellow liquid, (39 mg, 80%). H NMR (600 MHz, CDCl ): δ 8.67 (dd, J = 4.8 Hz,
3
1
J = 1.8 Hz, 1H), 7.90 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 7.8
2
1
2
Hz, 1H), 7.33ꢀ7.36 (m, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.08 (dd, J = 9.0 Hz, J = 2.4 Hz, 1H),
1
2
1
3
6
1
1
.38 (s, 1H), 2.46 (s, 3H); C NMR (150 MHz, CDCl ): δ 151.0, 149.6, 138.4, 138.2, 135.5,
3
29.8, 126.1, 122.2, 121.6, 120.7, 119.1, 111.3, 102.8, 14.0; IR (neat): υmax 2923, 1582, 1455,
ꢀ1
+
378, 786 cm ; HRMS (ESI, m/z) calcd. for C H N Cl [M+H] : 243.0689; found: 243.0693.
1
4
12
2
Methyl 2-methyl-1-(pyridin-2-yl)-1H-indole-5-carboxylate, 3d, Table 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (50 mg, 94%), mp 64ꢀ66 ºC. H NMR (600 MHz, CDCl ): δ 8.70 (dd, J
3
1
=
4.8 Hz, J = 1.8 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 7.94 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.84
2 1 2
(
dd, J = 9.0 Hz, J = 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.38ꢀ7.40 (m, 1H), 7.36 (d, J = 9.0
1 2
1
3
Hz, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 2.47 (s, 3H); C NMR (150 MHz, CDCl ): δ 168.1, 150.9,
3
1
49.7, 139.6, 138.5, 138.4, 128.2, 123.1, 122.6, 122.5, 122.4, 121.0, 110.0, 104.1, 51.8, 13.9; IR
ꢀ1
(
neat): υmax 2923, 1712, 1578, 1441, 1299, 775 cm ; HRMS (EI, m/z) calcd. for C H N O
16
14
2
2
+
[M] : 266.1055; found: 266.1055.
N-(2-Methyl-1-(pyridin-2-yl)-1H-indol-5-yl)pivalamide, 3e, Table 2
Column chromatography (SiO , eluting with 7:3 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow solid, (39 mg, 64%), mp 128ꢀ130 ºC. H NMR (600 MHz, CDCl ): δ 8.66
3
(
dd, J = 5.4 Hz, J = 1.8 Hz, 1H), 7.89 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.81 (d, J = 2.4 Hz,
1 2 1 2
1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31ꢀ7.33 (m, 2H), 7.16 (dd, J = 9.0 Hz, J = 2.4 Hz, 1H), 6.38 (s,
1
2
1
3
1
1
H), 2.46 (s, 3H), 1.35 (s, 9H); C NMR (150 MHz, CDCl ): δ 176.4, 151.3, 149.5, 138.2,
3
37.7, 134.3, 131.4, 129.0, 121.8, 120.6, 115.3, 111.6, 110.3, 103.5, 39.4, 27.7, 14.1; IR (neat):
ꢀ1
+
υmax 3338, 2920, 1655, 1584, 1471, 1208 cm ; HRMS (EI, m/z) calcd. for C H N O [M] :
19
21
3
307.1685; found: 307.1684.
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,6-Dimethyl-1-(pyridin-2-yl)-1H-indole, 3f, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow liquid, (28 mg, 63%). H NMR (300 MHz, CDCl ): δ 8.69 (dd, J = 4.2 Hz,
3
1
J = 1.8 Hz, 1H), 7.91 (td, J = 7.5 Hz, J = 1.8 Hz, 1H), 7.42ꢀ7.47 (m, 2H), 7.30ꢀ7.35 (m, 1H),
2
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0
1
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3
7.21 (s, 1H), 6.99 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H), 6.39 (s, 1H), 2.46 (s, 3H), 2.44 (s, 3H); C
1
2
NMR (75 MHz, CDCl ): δ 151.5, 149.5, 138.2, 137.5, 136.0, 131.3, 126.5, 122.2, 121.7, 120.9,
3
ꢀ1
1
19.3, 110.3, 10ꢀ3.1, 21.8, 13.9; IR (neat): υmax 2921, 1692, 1582, 1467, 773 cm ; HRMS (EI,
+
m/z) calcd. for C H N [M] : 222.1157; found: 222.1134.
1
5
14
2
7
-Fluoro-2-methyl-1-(pyridin-2-yl)-1H-indole, 3g, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow liquid, (26 mg, 58%). H NMR (600 MHz, CDCl ): δ 8.63 (dd, J = 5.4 Hz,
3
1
J = 2.4 Hz, 1H), 7.87 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.36ꢀ7.41 (m, 2H), 7.34 (d, J = 7.8 Hz,
2
1
2
1
3
1H), 7.02ꢀ7.05 (m, 1H), 6.81ꢀ6.85 (m, 1H), 6.45 (s, 1H), 2.36 (s, 3H); C NMR (150 MHz,
CDCl ): δ 151.7, 149.3 (d, J = 243.8 Hz), 148.7, 138.6, 137.8, 132.5 (d, J = 4.8 Hz), 124.7 (d, J
3
=
8.7 Hz), 122.7, 122.2 (d, J = 4.4 Hz), 120.5 (d, J = 6.9 Hz), 115.5 (d, J = 3.5 Hz), 107.5 (d, J =
1
9
1
8.0 Hz), 103.0 (d, J = 1.5 Hz), 13.5; F NMR (376 MHz, CDCl ): δ ꢀ129.2 (s, 1F); IR (neat):
3
ꢀ1
+
υmax 2924, 1576, 1471, 1174, 767 cm ; HRMS (EI, m/z) calcd. for C H N F [M] : 226.0906;
14
11
2
found: 226.0901.
2-Methyl-1-(pyridin-2-yl)-6-(trifluoromethyl)-1H-indole, 3h, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (34 mg, 62%). H NMR (600 MHz, CDCl ): δ 8.71 (dd, J = 5.4
3
1
Hz, J = 2.4 Hz, 1H), 7.95 (td, J = 7.8 Hz, J = 2.4 Hz, 1H), 7.63ꢀ7.65 (m, 2H), 7.43 (d, J = 8.4
2
1
2
13
Hz, 1H), 7.38ꢀ7.42 (m, 2H), 6.50 (s, 1H), 2.49 (s, 3H); C NMR (150 MHz, CDCl ): δ 150.7,
3
1
49.8, 139.7, 138.6, 136.1, 131.1, 125.2 (q, J = 269.7 Hz), 123.5 (q, J = 31.7 Hz), 122.6, 120.9,
19
119.9, 117.4 (q, J = 3.6 Hz), 107.8 (q, J = 4.4 Hz), 103.3, 14.0; F NMR (376 MHz, CDCl ): δ ꢀ
3
ꢀ1
6
0.3 (s, 3F); IR (neat): υmax 2924, 1585, 1443, 1331, 1114, 823 cm ; HRMS (ESI, m/z) calcd. for
+
C H F N [M+H] : 277.0953; found: 277.0951.
15
12
3
2
2-Methyl-1-(pyridin-2-yl)-1H-indol-5-yl acetate, 3i, Table 2
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Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (46 mg, 87%), mp 74ꢀ76 ºC. H NMR (300 MHz, CDCl ): δ 8.66 (d, J =
3
4
.8 Hz, 1H), 7.89 (td, J = 7.8 Hz, J = 2.1 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.30ꢀ7.35 (m, 2H),
1 2
7
.24 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 6.40 (s, 1H), 2.45 (s, 3H), 2.31
1
2
13
1
1
1
1
1
1
1
1
1
1
2
2
2
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2
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3
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4
4
4
4
4
4
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5
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5
5
5
5
5
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0
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2
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4
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6
7
8
9
0
1
2
3
4
5
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7
8
9
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1
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6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
s, 3H); C NMR (75 MHz, CDCl ): δ 170.4, 151.2, 149.6, 145.0, 138.3, 138.2, 135.0, 129.1,
3
122.1, 120.7, 115.3, 111.9, 110.7, 103.4, 21.2, 14.1; IR (neat): υmax 2922, 1753, 1585, 1465,
ꢀ1
+
1
216, 754 cm ; HRMS (EI, m/z) calcd. for C H N O [M] : 266.1055; found: 266.1052.
16 14 2 2
2-Methyl-5-nitro-1-(pyridin-2-yl)-1H-indole, 3j, Table 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow liquid solid, (37 mg, 74%), mp 142ꢀ144 ºC. H NMR (300 MHz, CDCl ): δ
3
8.71(dd, J = 5.4 Hz, J = 2.1 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 7.94ꢀ8.05 (m, 2H), 7.41ꢀ7.45 (m,
1
2
1
3
2
1
H), 7.35 (d, J = 9.3 Hz, 1H), 6.58 (s, 1H), 2.46 (s, 3H); C NMR (75 MHz, CDCl ): δ 150.2,
3
49.9, 142.3, 140.4, 140.0, 138.7, 128.0, 123.1, 121.0, 117.2, 116.6, 110.2, 104.6, 13.9; IR
ꢀ1
(neat): υmax 2917, 1577, 1512, 1464, 1334, 777 cm ; HRMS (EI, m/z) calcd. for C H N O
2
14
11
3
+
[
M] : 253.0851; found: 253.0855.
Methyl 2-(2-methyl-1-(pyridin-2-yl)-1H-indol-5-yl)acetate, 3k, Table 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (45 mg, 81%). H NMR (600 MHz, CDCl ): δ 8.66 (dd, J = 4.8
3
1
Hz, J = 1.8 Hz, 1H), 7.88 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J = 8.4 Hz,
2
1
2
1
1
1
H), 7.34 (d, J = 8.4 Hz, 1H), 7.30ꢀ7.32 (m, 1H), 7.06 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 6.40 (s,
1 2
13
H), 3.73 (s, 2H), 3.70 (s, 3H), 2.47 (s, 3H); C NMR (150 MHz, CDCl ): δ 172.8, 151.4, 149.5,
3
38.2, 137.3, 136.3, 129.0, 126.2, 122.8, 121.8, 120.6, 120.3, 110.3, 103.2, 51.9, 41.3, 14.0; IR
ꢀ1
(neat): υmax 2920, 1735, 1582, 1470, 1155, 786 cm ; HRMS (EI, m/z) calcd. for C H N O
2
17
16
2
+
[
M] : 280.1212; found: 280.1218.
2,5-Dimethyl-1-(pyridin-2-yl)-1H-indole, 3l, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (34 mg, 76%). H NMR (600 MHz, CDCl ): δ 8.67 (dd, J = 4.8
3
1
Hz, J = 1.8 Hz, 1H), 7.88 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.37 (s,
2
1
2
1
H), 7.29ꢀ7.31 (m, 2H), 6.97 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 6.37 (s, 1H), 2.48 (s, 3H), 2.46
1 2
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5
5
5
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6
13
(
s, 3H); C NMR (150 MHz, CDCl ): δ 151.6, 149.5, 138.1, 136.8, 135.4, 129.9, 129.0, 122.9,
3
ꢀ1
121.6, 120.5, 119.5, 109.9, 103.0, 21.4, 14.1; IR (neat): υmax 2926, 1586, 1378, 1175, 773 cm ;
+
HRMS (EI, m/z) calcd. for C H N [M] : 222.1157; found: 222.1157.
15 14
2
2
-Methyl-5-phenyl-1-(pyridin-2-yl)-1H-indole, 3m, Table 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless solid, (45 mg, 80%), mp 116ꢀ118 ºC. H NMR (600 MHz, CDCl ): δ 8.70
3
(dd, J = 4.8 Hz, J = 1.8 Hz, 1H), 7.93 (t, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.66ꢀ7.68 (m, 2H), 7.44ꢀ
1
2
13
7
.48 (m, 4H), 7.39ꢀ7.40 (m, 1H), 7.31ꢀ7.36 (m, 2H), 6.49 (s, 1H), 2.51 (s, 3H); C NMR (150
MHz, CDCl ): δ 151.4, 149.5, 142.4, 138.3, 137.5, 136.6, 134.1, 129.2, 128.6, 127.3, 126.3,
3
ꢀ1
1
21.9, 121.3, 120.7, 118.3, 110.5, 103.7, 14.1; IR (neat): υmax 2919, 1581, 1466, 1375, 756 cm ;
+
HRMS (EI, m/z) calcd. for C H N [M] : 284.1313; found: 284.1311.
2
0
16
2
2
-Methyl-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-indole, 3n, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (40 mg, 65%). H NMR (600 MHz, CDCl ): δ 8.70 (dd, J = 4.8
3
1
Hz, J = 1.8 Hz, 1H), 7.93 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.86 (s, 1H), 7.36ꢀ7.43 (m, 4H),
2
1
2
1
3
6.51 (s, 1H), 2.48 (s, 3H); C NMR (150 MHz, CDCl ): δ 150.8, 149.8, 138.8, 138.48, 138.46,
3
1
28.1, 125.3 (q, J = 270.0 Hz), 122.9 (q, J = 31.4 Hz), 122.5, 120.9, 118.3 (q, J = 3.6 Hz), 117.3
19
(
q, J = 4.1 Hz), 110.4, 103.6, 13.9; F NMR (376 MHz, CDCl ): δ ꢀ60.3 (s, 3F); IR (neat): υ
3
max
ꢀ1
+
2921, 1582, 1467, 1217, 775 cm ; HRMS (EI, m/z) calcd. for C H N F [M] : 276.0874;
1
5
11
2 3
found: 276.0872.
-Chloro-2-methyl-1-(pyridin-2-yl)-6-(trifluoromethyl)-1H-indole, 3o, Table 2
5
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow solid, (38 mg, 62%), mp 86ꢀ88 ºC. H NMR (600 MHz, CDCl ): δ 8.71 (s,
3
1H), 7.96 (td, J = 7.2 Hz, J = 1.8 Hz, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.39ꢀ7.43 (m, 2H), 6.42
1
2
1
3
(
s, 1H), 2.48 (s, 3H); C NMR (150 MHz, CDCl ): δ 150.3, 149.9, 141.2, 138.7, 134.4, 131.7,
3
1
23.8 (q, J = 270.5 Hz), 123.3, 122.9, 121.9, 120.8, 120.7 (q, J = 30.8 Hz), 110.0 (q, J = 7.35
1
9
Hz), 102.7, 14.0; F NMR (376 MHz, CDCl ): δ ꢀ60.6 (s, 3F); IR (neat): υ 2922, 1585, 1437,
3
max
ꢀ1
+
1288, 1128, 760 cm ; HRMS (EI, m/z) calcd. for C H ClF N [M] : 310.0485; found:
15
10
3
2
3
10.0486.
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-Chloro-2,5-dimethyl-1-(pyridin-2-yl)-1H-indole, 3p, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (32 mg, 62%). H NMR (600 MHz, CDCl ): δ 8.66 (dd, J = 4.8
3
1
Hz, J = 1.8 Hz, 1H), 7.89 (td, J = 7.8 Hz, J = 2.1 Hz, 1H), 7.30ꢀ7.40 (m, 4H), 6.32 (s, 1H),
2
1
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
2.44 (s, 3H), 2.44 (s, 3H); C NMR (150 MHz, CDCl ): δ 151.1, 149.6, 138.4, 137.4, 136.1,
3
1
28.1, 127.9, 127.6, 122.0, 120.9, 120.5, 110.7, 102.8, 20.3, 14.0; IR (neat): υmax 2921, 1584,
ꢀ1
+
1
465, 1376, 754 cm ; HRMS (EI, m/z) calcd. for C H ClN [M] : 256.0767; found: 256.0766.
15
13
2
6
-Methoxy-2,5-dimethyl-1-(pyridin-2-yl)-1H-indole, 3q, Table 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (28 mg, 55%), mp 88ꢀ90 ºC. H NMR (600 MHz, CDCl ): δ 8.69 (dd, J
3
1
=
4.8 Hz, J = 1.8 Hz, 1H), 7.90 (td, J = 7.8 Hz, J = 2.4 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.31ꢀ
2 1 2
1
3
7
.33 (m, 1H), 7.29 (s, 1H), 6.90 (s, 1H), 6.30 (s, 1H), 3.80 (s, 3H), 2.43 (s, 3H), 2.32 (s, 3H); C
NMR (150 MHz, CDCl ): δ 154.6, 151.8, 149.5, 138.2, 136.2, 134.8, 122.1, 121.6, 120.73,
3
1
20.66, 120.5, 102.8, 92.8, 55.6, 16.7, 14.0; IR (neat): υmax 2920, 1583, 1471, 1376, 1202, 779
ꢀ1
+
cm ; HRMS (EI, m/z) calcd. for C H N O [M] : 252.1263; found: 252.1259.
1
6
16
2
1-(2-Methyl-1-(pyridin-2-yl)-1H-indol-5-yl)ethanone, 3r, Table 2
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (37 mg, 74%). H NMR (600 MHz, CDCl ): δ 8.69 (d, J = 3.6 Hz,
3
1
1
H), 8.22 (s, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 7.8 Hz, J =
1 2
13
.2 Hz, 1H), 7.36ꢀ7.39 (m, 2H), 6.53 (s, 1H), 2.67 (s, 3H), 2.46 (s, 3H); C NMR (150 MHz,
CDCl ): δ 198.3, 150.8, 149.7, 139.7, 138.6, 138.5, 130.6, 128.2, 122.5, 122.0, 121.7, 120.9,
3
ꢀ1
110.1, 104.3, 26.7, 14.0; IR (neat): υmax 2921, 1669, 1588, 1469, 1364, 786 cm ; HRMS (ESI,
+
m/z) calcd. for C H N ONa [M+Na] : 273.1004; found: 273.1010.
1
6
14
2
5-(tert-Butyl)-2-methyl-1-(pyridin-2-yl)-1H-indole, 3s, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow liquid, (38 mg, 72%). H NMR (600 MHz, CDCl ): δ 8.66 (dd, J = 4.8 Hz,
3
1
J = 1.8 Hz, 1H), 7.88 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 7.8
2
1
2
Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29ꢀ7.31 (m, 1H), 7.23 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H),
1
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5
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6
13
6
.41 (s, 1H), 2.48 (s, 3H), 1.41 (s, 9H); C NMR (150 MHz, CDCl ): δ 151.6, 149.5, 143.6,
3
138.1, 136.8, 135.2, 128.5, 121.5, 120.4, 119.6, 115.8, 109.7, 103.4, 34.5, 31.9, 14.1; IR (neat):
ꢀ1
+
υmax 2954, 1583, 1473, 1375, 783 cm ; HRMS (ESI, m/z) calcd. for C H N Na [M+Na] :
18 20
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2
87.1524; found: 287.1525.
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4
5
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7
8
9
0
1
2
3
4
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6
7
8
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0
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9
0
2-Methyl-1-(pyridin-2-yl)-5-(trifluoromethoxy)-1H-indole, 3t, Table 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (34 mg, 58%). H NMR (600 MHz, CDCl ): δ 8.68 (dd, J = 5.4
3
1
Hz, J = 1.8 Hz, 1H), 7.92 (td, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.40ꢀ7.42 (m, 2H), 7.34ꢀ7.37 (m,
2
1
2
13
2
H), 7.00 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 6.44 (s, 1H), 2.47 (s, 3H); C NMR (150 MHz,
1 2
CDCl ): δ 151.0, 149.7, 143.6, 138.7, 138.4, 135.4, 128.9, 122.3, 120.8 (q, J = 253.7 Hz), 120.7,
3
1
9
115.2, 112.1, 110.9, 103.3, 14.0; F NMR (376 MHz, CDCl ): δ ꢀ58.0 (s, 3F); IR (neat): υ
3
max
+
ꢀ1
2
924, 1585, 1466, 1262, 1163, 782 cm ; HRMS (EI, m/z) calcd. for C H F N O [M] :
1
5
11
3
2
2
92.0823; found: 292.0822.
-((tert-Butyldimethylsilyl)oxy)-2-methyl-1-(pyridin-2-yl)-1H-indole, 3u, Table 2
5
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (41 mg, 60%). H NMR (600 MHz, CDCl ): δ 8.65 (dd, J = 7.8
3
1
Hz, J = 1.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.26ꢀ7.31 (m, 2H), 7.00 (d, J = 1.8 Hz, 1H), 6.69
2
13
(
dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 6.33 (s, 1H), 2.46 (s, 3H), 1.02 (s, 9H), 0.21 (s, 6H); C NMR
1
2
(150 MHz, CDCl ): δ 151.6, 150.0, 149.4, 138.1, 137.2, 132.7, 129.4, 121.5, 120.4, 115.3, 110.6,
3
ꢀ1
1
09.6, 103.1, 25.8, 18.2, 14.1, ꢀ4.4; IR (neat): υmax 2929, 1583, 1466, 1261, 1198, 864 cm ;
+
HRMS (EI, m/z) calcd. for C H N OSi [M] : 338.1814; found: 338.1804.
2
0
26
2
4-Methoxy-2-methyl-1-(pyridin-2-yl)-1H-indole, 3v, Table 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow liquid, (18 mg, 37%). H NMR (300 MHz, CDCl ): δ 8.66 (dd, J = 4.8 Hz,
3
1
J = 1.2 Hz, 1H), 7.87 (td, J = 7.5 Hz, J = 1.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.28ꢀ7.33 (m,
2
1
2
1
H), 6.98ꢀ7.08 (m, 2H), 6.57 (dd, J = 7.2 Hz, J = 1.2 Hz, 1H), 6.53 (s, 1H), 3.97 (s, 3H), 2.45
1 2
1
3
(
s, 3H); C NMR (150 MHz, CDCl ): δ 152.5, 151.5, 149.5, 138.4, 138.2, 135.2, 122.2, 121.9,
3
120.9, 119.0, 103.8, 100.8, 100.3, 55.4, 13.9; IR (neat): υmax 2926, 1583, 1447, 1254, 1098, 766
ꢀ1
+
cm ; HRMS (EI, m/z) calcd. for C H N O [M] : 238.1106; found: 238.1104.
1
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-Methoxy-2-methyl-1-(pyridin-2-yl)-1H-indole, 3v’, Table 2
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a yellow liquid, (13 mg, 28%). H NMR (300 MHz, CDCl ): δ 8.67 (dd, J = 5.1 Hz,
3
1
J = 1.5 Hz, 1H), 7.89 (td, J = 7.5 Hz, J = 1.8 Hz, 1H), 7.40ꢀ7.43 (m, 2H), 7.29ꢀ7.34 (m, 1H),
2
1
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6.92 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 6.34 (s, 1H), 3.79 (s, 3H), 2.41
1
2
1
3
(s, 3H); C NMR (150 MHz, CDCl ): δ 156.1, 151.5, 149.6, 138.2, 137.8, 135.6, 122.9, 121.8,
3
1
20.7, 120.1, 109.6, 103.0, 94.9, 55.8, 14.0; IR (neat): υmax 2922, 1579, 1440, 1203, 1029, 775
ꢀ1
+
cm ; HRMS (EI, m/z) calcd. for C H N O [M] : 238.1106; found: 238.1084.
1
5
14
2
2
-Ethyl-1-(pyridin-2-yl)-1H-indole, 3w, Table 2
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (12 mg, 28%). H NMR (600 MHz, CDCl ): δ 8.68 (dd, J = 5.4
3
1
Hz, J = 1.8 Hz, 1H), 7.90 (td, J = 7.2 Hz, J = 1.8 Hz, 1H), 7.59ꢀ7.61 (m, 1H), 7.45 (d, J =7.8
2
1
2
Hz, 1H), 7.33ꢀ7.36 (m, 2H), 7.13ꢀ7.16 (m, 2H), 6.48 (s, 1H), 2.88 (q, J = 7.8 Hz, 2H), 1.25 (t,
1
3
3
1
H); C NMR (150 MHz, CDCl ): δ 151.5, 149.6, 143.2, 138.2, 137.3, 128.6, 122.0, 121.5,
3
ꢀ1
21.1, 120.5, 119.9, 110.0, 101.2, 20.9, 12.8; IR (neat): υmax 2922, 1585, 1458, 1374, 756 cm ;
+
HRMS (EI, m/z) calcd. for C H N [M] : 222.1157; found: 222.1157.
1
5
14
2
General Experimental Procedure for Ruthenium-Catalyzed 2-Methylindoline Synthesis
from the Corresponding N-aryl pyrimidines and Allyl acetates. A mixture of Nꢀaryl
pyrimidine (0.2 mmol), [Ru(pꢀcymene)Cl ] (0.01 mmol, 5 mol %), and AgSbF (0.04 mmol, 20
2
2
6
mol %) was taken in a 15ꢀmL pressure tube. To this reaction mixture, trifluoroethanol (TFE) (2.0
mL) and the corresponding allyl acetate (0.4 mmol) were added via micro syringe and the closed
o
reaction mixture was allowed to stir at 120 C for 16 h. After completion as indicated by TLC,
the reaction the reaction mixture was cooled to ambient temperature. After dilution with
dichloromethane the reaction mixture was completely transferred to a RB flask and concentrated
under reduced pressure. The crude product was purified by column chromatography using ethyl
acetate/hexane as eluent to afford the desired indoline product.
7-Chloro-2-methyl-1-(pyrimidin-2-yl)indoline, 5a, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (40 mg, 82%), mp 100ꢀ102 ºC. H NMR (600 MHz, CDCl ): δ 8.49 (d,
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6
J = 4.8 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.99 (t, J = 9.1 Hz, 1H), 6.77
(t, J = 4.8 Hz, 1H), 4.89ꢀ4.94 (m, 1H), 3.54 (dd, J = 15.6 Hz, J = 8.4 Hz, 1H), 2.57 (d, J = 15.6
1
2
1
3
Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H); C NMR (150 MHz, CDCl ): δ 160.3, 157.4, 140.2, 135.7,
3
ꢀ1
1
28.9, 124.5, 124.1, 123.4, 113.2, 61.3, 37.3, 21.6; υmax 2976, 1568, 1458, 1050, 770 cm ;
+
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HRMS (EI, m/z) calcd. for C H N Cl [M] : 245.0720; found: 245.0721.
1
3
12
3
7
-Bromo-2-methyl-1-(pyrimidin-2-yl)indoline, 5b, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (45 mg, 78%), mp 118ꢀ120 ºC. H NMR (600 MHz, CDCl ): δ 8.50 (d,
3
J = 4.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 8.4 Hz, 1H), 6.78
(
t, J = 4.8 Hz, 1H), 4.90ꢀ4.94 (m, 1H), 3.55 (dd, J = 15.0 Hz, J = 7.8 Hz, 1H), 2.57 (d, J = 15.6
1 2
1
3
Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H); C NMR (150 MHz, CDCl ): δ 160.1, 157.4, 142.0, 135.9,
3
ꢀ1
1
31.9, 124.8, 124.0, 113.3, 113.2, 61.4, 37.4, 21.6; υmax 2972, 1564, 1415, 1215, 1049, 769 cm ;
+
HRMS (EI, m/z) calcd. for C H BrN [M] : 289.0215; found: 289.0215.
1
3
12
3
2
,7-Dimethyl-1-(pyrimidin-2-yl)indoline, 5c, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (37 mg, 82%), mp 94ꢀ96 ºC. H NMR (300 MHz, CDCl ): δ 8.43 (d, J =
3
4.5 Hz, 2H), 6.96ꢀ7.10 (m, 3H), 6.68 (t, J = 4.5 Hz, 1H), 4.91ꢀ5.00 (m, 1H), 3.47 (dd, J = 15.3
1
1
3
Hz, J = 8.1 Hz, 1H), 2.50 (d, J = 15.3 Hz, 1H), 2.19 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H); C NMR
2
(
75 MHz, CDCl ): δ 160.8, 157.6, 141.4, 133.1, 129.5, 128.5, 123.9, 122.4, 112.1, 60.5, 37.0,
3
ꢀ1
21.3, 20.8; IR (neat): υmax 2922, 1577, 1429, 1189, 760 cm ; HRMS (EI, m/z) calcd. for
+
C H N [M] : 225.1266; found: 225.1245.
14 15
3
6
-Chloro-2,7-dimethyl-1-(pyrimidin-2-yl)indoline, 5d, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (41 mg, 80%), mp 56ꢀ58 ºC. H NMR (300 MHz, CDCl ): δ 8.43 (d, J =
3
4.8 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.71 (t, J = 4.8 Hz, 1H), 4.94ꢀ
5
1
1
.03 (m, 1H), 3.43 (dd, J = 15.6 Hz, J = 8.4 Hz, 1H), 2.47 (d, J = 15.6 Hz, 1H), 2.14 (s, 3H),
1
2
13
.39 (d, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl ): δ 160.9, 157.6, 143.0, 133.6, 131.7, 127.0,
3
ꢀ1
24.6, 122.7, 112.6, 61.2, 36.7, 21.4, 18.6; υmax 2967, 1572, 1448, 1176, 788 cm ; HRMS (EI,
+
m/z) calcd. for C H N Cl [M] : 259.0876; found: 259.0871.
1
4
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,5,7-Trimethyl-1-(pyrimidin-2-yl)indoline, 5e, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (27 mg, 56%), mp 78ꢀ80 ºC. H NMR (600 MHz, CDCl ): δ 8.43 (d, J =
3
4
.8 Hz, 2H), 6.92 (s, 1H), 6.90 (s, 1H), 6.67 (t, J = 4.8 Hz, 1H), 4.94ꢀ4.99 (m, 1H), 3.45 (dd, J =
1
1
1
1
1
1
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1
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1
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15.6 Hz, J = 8.4 Hz, 1H), 2.46 (d, J = 15.6 Hz, 1H), 2.32 (s, 3H), 2.18 (s, 3H), 1.39 (, J = 6.6
2
1
3
Hz, 3H); C NMR (150 MHz, CDCl ): δ 161.0, 157.6, 139.0, 133.5, 133.2, 130.0, 128.2, 123.1,
3
ꢀ1
1
11.9, 60.6, 37.0, 21.3, 21.0, 20.6; υmax 2951, 1579, 1426, 1191, 793 cm ; HRMS (ESI, m/z)
+
calcd. for C H N [M+H] : 240.1501; found: 240.1494.
1
5
18
3
7
-Methoxy-2-methyl-1-(pyrimidin-2-yl)indoline, 5f, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (34 mg, 72%), mp 142ꢀ144 ºC. H NMR (300 MHz, CDCl ): δ 8.42 (d,
3
J = 4.8 Hz, 2H), 7.01ꢀ7.06 (m, 1H), 6.87ꢀ6.90 (m, 2H), 6.68 (t, J = 4.8 Hz, 1H), 4.85ꢀ4.94 (m,
1H), 3.84 (s, 3H), 3.50 (dd, J = 15.3 Hz, J = 8.4 Hz, 1H), 2.52 (dd, J = 15.3 Hz, J = 1.2 Hz,
1
2
1
2
13
1
1
H), 1.07 (d, J = 6.6 Hz, 3H); C NMR (75 MHz, CDCl ): δ 160.7, 157.3, 150.2, 134.7, 131.4,
3
ꢀ1
24.7, 117.7, 112.3, 112.2, 60.9, 55.9, 37.3, 21.5; υmax 2941, 1561, 1430, 1271, 1078, 768 cm ;
+
HRMS (EI, m/z) calcd. for C H N O [M] : 241.1215; found: 241.1218.
1
4
15
3
7
-Ethyl-2-methyl-1-(pyrimidin-2-yl)indoline, 5g, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (30 mg, 63%). H NMR (300 MHz, CDCl ): δ 8.42 (d, J = 4.8 Hz,
3
2
H), 7.02ꢀ7.15 (m, 3H), 6.67 (t, J = 4.8 Hz, 1H), 4.94ꢀ5.04 (m, 1H), 3.46 (dd, J = 15.0 Hz, J =
1 2
8
.1 Hz, 1H), 2.61 (q, J = 7.5 Hz, 2H), 2.48 (d, J = 15.3 Hz, 1H), 1.37 (d, J = 6.6 Hz, 3H), 1.13 (t,
1
3
J = 7.5 Hz, 3H); C NMR (75 MHz, CDCl ): δ 160.9, 157.5, 140.5, 134.5, 133.3, 127.3, 124.2,
3
+
1
22.4, 112.2, 60.4, 36.8, 26.6, 21.0, 13.3; HRMS (ESI, m/z) calcd. for C H N [M+H] :
1
5
18
3
2
40.1501; found: 240.1496.
2
-Methyl-7-propyl-1-(pyrimidin-2-yl)indoline, 5h, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (18 mg, 35%). H NMR (300 MHz, CDCl ): δ 8.42 (d, J = 4.8 Hz,
3
2
H), 6.99ꢀ7.11 (m, 3H), 6.67 (t, J = 4.8 Hz, 1H), 4.94ꢀ5.04 (m, 1H), 3.44 (dd, J = 15.3 Hz, J =
1 2
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.1 Hz, 1H), 2.45ꢀ2.70 (m, 3H), 1.52ꢀ1.64 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H), 0.77 (t, J = 7.2 Hz,
1
3
3H); C NMR (75 MHz, CDCl ): δ 157.7, 140.9, 133.6, 133.3, 128.5, 124.4, 122.7, 112.3,
3
+
1
00.1, 60.6, 37.0, 36.2, 22.2, 21.1, 14.2; HRMS (ESI, m/z) calcd. for C H N [M+H] :
16 20
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54.1657; found: 254. 1627.
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7-Isopropyl-2-methyl-1-(pyrimidin-2-yl)indoline, 5i, Table 4
Column chromatography (SiO , eluting with 9:1 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (33 mg, 65%). H NMR (600 MHz, CDCl ): δ 8.42 (d, J = 4.8 Hz,
3
2
H), 7.21ꢀ7.28 (m, 1H), 7.10ꢀ7.13 (m, 2H), 6.69 (t, J = 4.8 Hz, 1H), 5.02ꢀ5.07 (m, 1H), 3.44 (dd,
J = 15.6 Hz, J = 8.4 Hz, 1H), 2.93 (m, 1H), 2.49 (d, J = 15.0 Hz, 1H), 1.42 (d, J = 6.6 Hz, 3H),
1
2
13
1
.39 (d, J = 6.6 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H); C NMR (150 MHz, CDCl ): δ 161.5, 157.5,
3
140.0, 139.8, 133.5, 124.8, 124.5, 122.4, 112.3, 60.4, 37.0, 30.1, 24.9, 21.4, 21.1; υmax 2966,
ꢀ1
+
1
2
580, 1435, 1186, 787 cm ; HRMS (EI, m/z) calcd. for C H N [M] : 253.1579; found:
16 19 3
53.1578.
N-(2-Allyl-6-(tert-butyl)phenyl)pyrimidin-2-amine, 6a, Table 4
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (35 mg, 65%). H NMR (300 MHz, CDCl ): δ 8.30 (d, J = 5.1 Hz,
3
2
H), 7.41 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.20ꢀ7.29 (m, 2H), 7.07 (br. s, 1H), 6.57 (t, J = 4.8
1 2
13
Hz, 1H), 5.85ꢀ5.98 (m, 1H), 4.93ꢀ5.04 (m, 2H), 3.22ꢀ3.29 (m, 2H), 1.38 (s, 9H); C NMR (75
MHz, CDCl ): δ 162.1, 158.7, 158.3, 148.3, 140.7, 136.9, 135.1, 128.3, 127.9, 125.5, 116.0,
3
+
1
11.2, 36.8, 35.6, 31.2; HRMS (ESI, m/z) calcd. for C H N [M+H] : 268.1814; found: 268.
17 22
3
1
807.
N-(3-Allyl-[1,1'-biphenyl]-2-yl)pyrimidin-2-amine, 6b, Table 4
Column chromatography (SiO , eluting with 8:2 hexane/ethyl acetate) afforded the desired
2
1
product as a colorless liquid, (17 mg, 35%). H NMR (300 MHz, CDCl ): δ 8.23 (d, J = 4.8 Hz,
3
2
5
1
H), 7.22ꢀ7.34 (m, 8H), 6.54 (t, J = 4.8 Hz, 1H), 6.46 (br. s, 1H), 5.93ꢀ6.06 (m, 1H), 5.03ꢀ
13
.11(m, 2H), 3.40ꢀ3.43 (m, 2H); C NMR (75 MHz, CDCl ): δ 161.5, 158.1, 140.1, 140.0,
3
38.3, 136.6, 133.8, 129.3, 128.9, 128.8, 128.0, 127.2, 127.0, 116.2, 111.5, 36.7; HRMS (ESI,
+
m/z) calcd. for C H N [M+H] : 288.1501; found: 288. 1496.
1
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Deprotection of the directing group of Iodole
Methyl trifluoromethanesulfonate (0.24 mmol, 1.2 equiv) was added dropwise to a solution of 3a
0.20 mmol, 1.0 equiv) in CH Cl (5 mL) at 0 °C, and the resulting solution was stirred for 24 h
(
2
2
at room temperature. Then the solvent was removed under reduced pressure, and the residue was
dissolved in MeOH (2.0 mL). 2M aq. NaOH solution (2.0 mL) was added to it and stirring was
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0
o
continued at 60 C for 10 h. Then, the solvents were removed under reduced pressure and the
resulting residue was extracted with EtOAc. The combined organic layers were washed with
brine, dried over Na SO , and again concentrated under reduced pressure. The residue was
2
4
purified by column chromatography to afford the desired indole 7a.
16
2
-methyl-1H-indole, 7a
Column chromatography (SiO , eluting with 19:1 hexane/ethyl acetate) afforded the desired
2
1
product as a white solid, (23 mg, 87%). H NMR (300 MHz, CDCl ): δ 7.77 (br. s, 1H), 7.55 (dd,
3
J = 6.9 Hz, J = 2.1 Hz, 1H), 7.27ꢀ7.30 (m, 1H), 7.08ꢀ7.18 (m, 2H), 6.25 (s, 1H), 2.44 (s, 3H);
1
2
1
3
C NMR (150 MHz, CDCl ): δ 135.9, 135.1, 128.9, 120.8, 119.5, 110.2, 100.2, 13.5.
3
ASSOCIATED CONTENT
Supporting Information
1
13
Mechanistic study, spectral data of 3a’, crystallographic data of 3m, 5c, H and C NMR
spectra for all synthesized compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*
Eꢀmail: rjana@iicb.res.in
ACKNOWLEDGMENT
This work was supported by DST, SERB, Govt. of India, Ramanujan fellowship; award no.
SR/S2/RJNꢀ97/2012 and extra mural research grant no. EMR/2014/000469. MKM and GB thank
UGC for their fellowships.
REFERENCES
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(
1) For Indole, see: (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996. (b) d’Ischia,
M.; Napolitano, A.; Pezzella, A. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 3, pp 353ꢀ
3
88. For Indoline, see: (c) Takano, S.; Ogasawara, K. Alkaloids 1989, 36, 225ꢀ251.
2) For review, see: (a) WencelꢀDelord, J.; Dröge, T.; Liu, F.; Glorius, F. Towards mild metalꢀ
0
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2
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4
5
6
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8
9
0
1
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5
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7
8
9
0
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2
3
4
5
6
7
8
9
0
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3
4
5
6
7
8
9
0
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3
4
5
6
7
8
9
0
(
catalyzed CꢀH bond activation. Chem. Soc. Rev. 2011, 40, 4740ꢀ4761. For selected examples,
see: (b) Ciana, C. L.; Phipps, R. J.; Brandt, J. R.; Meyer, F. M.; Gaunt, M. J. A Highly Paraꢀ
Selective Copper(II)ꢀCatalyzed Direct Arylation of Aniline and Phenol Derivatives. Angew.
Chem. Int. Ed. 2011, 50, 458ꢀ462. (c) Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Room
Temperature CꢀH Activation and CrossꢀCoupling of Aryl Ureas in Water. Angew. Chem. Int. Ed.
2
010, 49, 781ꢀ784. (d) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. Cationic
Palladium(II) Catalysis: CꢀH Activation/SuzukiꢀMiyaura Couplings at Room Temperature. J.
Am. Chem. Soc. 2010, 132, 4978ꢀ4979. (e) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J.
G.; Tyler, S. N. G.; Gagné, M. R.; LloydꢀJones, G. C.; BookerꢀMilburn, K. I. RoomꢀTemperature
PalladiumꢀCatalyzed CꢀH Activation: orthoꢀCarbonylation of Aniline Derivatives. Angew.
Chem., Int. Ed. 2009, 48, 1830ꢀ1833. (f) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A.
H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. Selective PdꢀCatalyzed
Oxidative Coupling of Anilides with Olefins through CꢀH Bond Activation at Room
Temperature. J. Am. Chem. Soc. 2002, 124, 1586ꢀ1587.
(3) For review, see: (a) Agasti, S.; Dey, A.; Maiti, D. Palladiumꢀcatalyzed benzofuran and indole
synthesis by multiple CꢀH functionalizations. Chem. Commun. 2017, 53, 6544ꢀ6556. For
selected examples, see: (b) Lu, Q.; VásquezꢀCéspedes, S.; Gensch, T.; Glorius, F. Control over
Organometallic Intermediate Enables Cp*Co(III) Catalyzed Switchable Cyclization to
Quinolines and Indoles. ACS Catal. 2016, 6, 2352ꢀ2356. (c) Liu, B.; Song, C.; Sun, C.; Zhou, S.;
Zhu, J. Rhodium(III)ꢀCatalyzed Indole Synthesis Using NꢀN Bond as an Internal Oxidant. J. Am.
Chem. Soc. 2013, 135, 16625ꢀ16631. (d) Wang, C.; Sun, H.; Fang, Y.; Huang, Y. General and
Efficient Synthesis of Indoles through TriazeneꢀDirected CꢀH Annulation. Angew. Chem. Int. Ed.
2
013, 52, 5795ꢀ5798. (e) Zhao, D.; Shi, Z.; Glorius, F. Indole Synthesis by Rhodium(III)ꢀ
Catalyzed HydrazineꢀDirected CꢀH Activation: RedoxꢀNeutral and Traceless by NꢀN Bond
Cleavage. Angew. Chem. Int. Ed. 2013, 52, 12426ꢀ12429. (f) Ackermann, L.; Lygin, A. V.
Cationic Ruthenium(II) Catalysts for Oxidative C–H/N–H Bond Functionalizations of Anilines
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with Removable Directing Group: Synthesis of Indoles in Water. Org. Lett. 2012, 14, 764ꢀ767.
(g) Chen, J.; Song, G.; Pan, C.ꢀL.; Li, X. Rh(III)ꢀCatalyzed Oxidative Coupling of NꢀArylꢀ2ꢀ
aminopyridine with Alkynes and Alkenes. Org. Lett. 2010, 12, 5426ꢀ5429. (h) Stuart, D. R.;
BertrandꢀLaperle, M.; Burgess, K. M. N.; Fagnou, K. Indole Synthesis via Rhodium Catalyzed
Oxidative Coupling of Acetanilides and Internal Alkynes. J. Am. Chem. Soc. 2008, 130, 16474ꢀ
16475.
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