Merging C-H activation and alkene difunctionalization at room temperature: A palladium-catalyzed divergent synthesis of indoles and indolines

Article abstract of DOI:10.1021/ol5036968

A palladium-catalyzed 1,2-carboamination through C-H activation at room temperature is reported for the synthesis of 2-arylindoles, and indolines from readily available, inexpensive aryl ureas and vinyl arenes. The reaction initiates with a urea-directed electrophilic ortho palladation, alkene insertion, and ?2-hydride elimination sequences to provide the Fujiwara-Moritani arylation product. Subsequently, aza-Wacker cyclization, and ?2-hydride elimination provide the 2-arylindoles in high yields. Intercepting the common -alkyl-Pd intermediate, corresponding indolines are also achieved. The indoline formation is attributed to the generation of stabilized, cationic -benzyl-Pd species to suppress ?2-hydride elimination.

Full text of DOI:10.1021/ol5036968

Letter
pubs.acs.org/OrgLett
Merging C−H Activation and Alkene Difunctionalization at Room
Temperature: A Palladium-Catalyzed Divergent Synthesis of Indoles
and Indolines
Manash Kumar Manna, Asik Hossian, and Ranjan Jana*
Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal,
India
*
S Supporting Information
ABSTRACT: A palladium-catalyzed 1,2-carboamination
through C−H activation at room temperature is reported for
the synthesis of 2-arylindoles, and indolines from readily
available, inexpensive aryl ureas and vinyl arenes. The reaction
initiates with a urea-directed electrophilic ortho palladation,
alkene insertion, and β-hydride elimination sequences to
provide the Fujiwara−Moritani arylation product. Subse-
quently, aza-Wacker cyclization, and β-hydride elimination
provide the 2-arylindoles in high yields. Intercepting the
common σ-alkyl-Pd intermediate, corresponding indolines are also achieved. The indoline formation is attributed to the
generation of stabilized, cationic π-benzyl-Pd species to suppress β-hydride elimination.
itrogen-containing heterocycles, particularly indoles and
indolines, are prevalent in numerous pharmaceuticals1,
dimerization was reduced but not diminished. Therefore, we
turned our attention to optimize this cascade reaction at room
temperature. Cationic palladium complexes are known to
undergo facile electrophilic palladation to aryl urea derivatives
N
natural products, agrochemicals, and functionalized materials.
Therefore, a significant effort has been devoted to their
synthesis, and sustained progress has been made through
1
0d,g−i
at room temperature.
N′-phenylurea and commercially available electrophilic Pd-
(tfa) , Pd(CH CN) (BF complexes, the yield of the desired
Gratifyingly, using N,N-dimethyl-
2
3
4
5
Fisher, Larock, Buchwald, and Hegedus indole synthesis. In
the past decade, the transition-metal-catalyzed C−H activation
strategy has enabled the generation of indole moiety directly
from anilines or protected anilines obviating rigorous
prefunctionalizations. In this vein, two distinct strategies have
been well explored: (a) intramolecular cyclization of N-
)
4 2
2
3
4
product was improved at room temperature. Palladium(II)
acetate, in the presence of excess TsOH, is known to generate
highly electrophilic palladium mono- or bistosylate species in
11
situ. Interestingly, ubiquitous Pd(OAc)
TsOH and inexpensive 1,4-benzoquinone (BQ) was found to
be optimal for the catalytic turnover. Other oxidants such as O
N-ligands/O , Cu(OAc) , AgOAc, and even DDQ were
in combination with
2
6
arylenamines or -imines and (b) intermolecular cyclization
7
of anilines and alkynes. We hypothesized that annulation of
,
2
aniline derivatives with readily available and inexpensive olefins
such as styrenes to afford 2-arylindoles and 2-arylindolines in
intermolecular fashion will be synthetically attractive but
challenging due to the facile β-hydride elimination. In fact,
the potential of simple olefins was realized in the synthesis of
2
2
ineffective. Presumably, BQ has a dual role as ligand as well
as oxidant in palladium(II) catalysis, and the redox process is
12
anticipated to be accelerated under acidic conditions. Other
directing/protecting groups such as pivalate, tosylate, N,N-
diethyl-N′-phenylurea, N-methyl, etc. were less effective in this
case. After a rigorous screening (for details, see the Supporting
Information), we found that 10 mol % of Pd(OAc)2 in
combination with 1.0 equiv of TsOH and 2.0 equiv of 1,4-
benzoquinone as terminal oxidant provided 2-phenylindole in
8
N-arylindoles from diarylamines. However, this methodology
is limited due to the formation of inseparable mixture of
regioisomers from unsymmetrical diarylamines and requires
high temperature to occur. To exploit the full potential of C−H
9
functionalization in the complex molecule synthesis, develop-
8
2% yield at room temperature from 1.0 equiv of phenylurea
ment of expedient methods under mild conditions, particularly
10
and 1.5 equiv of styrene (entry 10, Table 1). During
optimization, it was also found that water is detrimental to
the reaction outcome, but dioxygen has little or no effect.
Subsequently, we explored the substrate scope under the
optimized reaction conditions. A wide variety of functional
at room temperature, is in high demand. Intrigued by the key
mechanistic features, here we report a palladium-catalyzed
divergent synthesis of 2-arylindole and indoline through a
dehydrogenetive coupling of aryl urea and vinyl arene at room
temperature.
Our initial screening with acetanilide and styrene in acetic
acid at 110 °C was in vain due to the deleterious dimerization
of styrene. Switching to other solvents such as 1,4-dioxane, the
Received: December 23, 2014
©
XXXX American Chemical Society
A
DOI: 10.1021/ol5036968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a,b
Table 1. Optimization of the Reaction Conditions
Scheme 1. Substrate Scope of Indoles
b
temp
(°C)
yield
entry
1
oxidant
Cu(OAc)2
(1 equiv)
solvent
toluene
(%)
110
trace
2
3
4
5
6
7
8
9
AgOAc (1 equiv)
BQ (1 equiv)
BQ (1 equiv)
BQ (1 equiv)
BQ (1 equiv)
BQ (2 equiv)
BQ (2 equiv)
BQ (1 equiv)
BQ (2 equiv)
DDQ (2 equiv)
−
toluene
1,4-dioxane
AcOH
110
110
110
50
8
10
7
AcOH
13
AcOH
25
18
THF
25
58
EtOAc
25
77
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane/AcOH
25
52
1
1
1
1
1
1
0
1
2
25
25
82
trace
12
25
c
3
4
5
BQ (2 equiv)
BQ (3 equiv)
BQ (2 equiv)
25
65
25
80
25
38
(2:1)
a
b
All reactions were carried out in 0.1 mmol scale. Yields refer to here
c
are overall isolated yields. 2.0 equiv of TsOH was used.
groups on aniline as well as styrene were found to be
compatible under this mild reaction protocol. Besides methoxy,
alkyl, and aryl groups, halogens such as bromo (2x, 2ab, 2af,
Scheme 1), chloro (2k, 2t, 2z, 2ah, Scheme 1), and fluoro (2f,
2
u, 2y, 2ag, Scheme 1) remain intact which are useful for
further cross-coupling reactions. Interestingly, the acyl group
2g, 2r, Scheme 1) is well-tolerated under this protocol, which
is a reactive functionality in the Fischer and Yoshikai
(
2
,6f
method. An acid-sensitive −OAc (2j, Scheme 1) group is
also stable, which demonstrates the mild nature of this
protocol. The electronic nature has a prominent influence on
the reaction outcome. In general, a moderate electron-donating
group on the aniline has a positive influence due to the facile
electrophilic palladation. However, highly electron-rich anilines
are too reactive to provide the desired product. Similarly,
neutral or moderately electron-rich and/or electron-defficient
styrenes underwent annulation smoothly. Highly electron-
deficient 3-nitrostyrene and pentafluorostyrene did not furnish
any desired product, presumably due to the alkene deactivation
for migratory palladium insertion. Interestingly, ortho-sub-
stituted anilines (2n−q, 2ah, 2ai, Scheme 1) also afforded good
to high yields of the desired products, which are known to be
a
b
All reactions were carried out in 0.2 mmol scale. Yields refer to the
c
average of isolated yields of at least two experiments. 5 mol % of
Pd(OAc) was used. Reaction time 30 h.
d
2
p-methoxy styrene as a model substrate to explore this
divergent approach to indoline synthesis. Gratifyingly, the
corresponding indoline was obtained in 48% isolated yield
under the same reaction conditions (3a, Scheme 2).
Remarkably, while p-acetoxystyrene (2j, Scheme 1) afforded
indole selectively, the p-methoxy group favors indoline
formation albeit in moderate yield. This subtle change in
electronic nature leads to the generation of two distinct classes
of compounds. This could be attributed to the formation of
stabilized, cationic π-benzyl-Pd species that suppresses β-
hydride elimination. Since naphthalenes have a better ability to
stabilize π-benzyl-Pd species, we decided to examine 1-
vinylnaphthalene under the optimized conditions. As antici-
pated, the corresponding indoline was isolated in high yields
with 1- and 2-vinylnaphthalenes. Remarkably, a number of urea
derivatives with ortho substitution also provided the desired
indolines in high yields (3l−o, Scheme 2).
1
1
difficult for electrophilic ortho palladation. The meta-
substituted anilines provided single regioisomeric indoles
through ortho palladation from the sterically less hindered
side (2k−m, 2ae, 2af, Scheme 1). All compounds are new
13
entities and adequately characterized.
From a mechanistic perspective, we realized that migratory
insertion to the alkene results in an unstable σ-alkyl-Pd
intermediate that could be intercepted for further functionaliza-
16
1
4
tion. The direct 1,2-carboamination strategy to generate
15
indoline moiety was reported using norbornene where β-
hydride elimination is not feasible or using 1,3-dienes via π-
1
1
allyl-Pd formation. However, direct synthesis of 2-arylindo-
lines through π-benzyl-Pd stabilization is not known. We chose
B
DOI: 10.1021/ol5036968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 2. Substrate Scope of Indolines
Scheme 3. Mechanistic Possibilities and Elucidations
a
b
All reactions were carried out on a 0.2 mmol scale. Yields refer to
equiv of Pd(OAc) /TsOH without 1,4-benzoquinone. There-
c
2
the average of isolated yields of at least two experiments. Reaction
fore, BQ may act as a ligand and oxidant to the palladium for
catalytic turnover but may not be involved in the oxidation of
indoline to indole directly.
time 30 h.
From all these control experiments it is speculated that the
reaction proceeds through a C−H insertion/carbopalladation/
cyclization/aromatization cascade. The indolines are formed in
a convergent manner from the σ-alkyl-Pd intermediate through
π-benzyl-Pd stabilization as depicted in Scheme 4.
Mechanistically, the reaction may proceed in two distinct
pathways. In path a, an electrophilic ortho palladation followed
by migratory β-alkene insertion may lead to the intermediate
2
a′ (Scheme 3, a). Subsequently, reductive elimination to yield
indolines and oxidation sequences may provide the desired 2-
arylindoles. Alternatively, an initial aza-Wacker reaction
followed by C−H arylation and oxidation cascade may lead
to the desired product as shown in path b (Scheme 3, a). To
understand the plausible mechanism, we performed several
control experiments. From TLC, we observed that initially a
polar, transient intermediate is formed which is converted into
product during the reaction course. Therefore, the reaction was
arrested after 2 h and the intermediate was isolated as
Fujiwara−Moritani Heck arylation product 2a″. Subsequently,
this intermediate was subjected to the standard reaction
conditions, and the desired 2-arylindole was obtained in 78%
yield (Scheme 3, b). Therefore, the reaction may initiate
through path a. To note, depending upon the π-benzyl-Pd
stabilization ability, 8−12% corresponding indoles were also
obtained along with the indolines (Scheme 2). Therefore, in
the subsequent steps, either a concerted aza-Wacker cyclization
followed by β-hydride elimination or initial 1,2-carboamination
of styrenes to yield 2-arylindoline followed by oxidation to yield
Scheme 4. Plausible Catalytic Cycle
8
the desired product is plausible. To probe this, 2-phenylindo-
line was synthesized separately and subjected to the standard
conditions. The indoline remained intact, which eliminates the
possibility of indoline formation/oxidation route (Scheme 3, c).
It also demonstrates that indoles are kinetic in their origin
through concerted β-hydride elimination. From the stoichio-
metric experiment it was observed that the Heck intermediate is
converted to the corresponding indole in 65% yield with 1.0
Finally, the corresponding indole and indoline urea were
hydrolyzed with saturated solution of potassium hydroxide in
refluxing ethanol to afford the 2-arylindole and indoline in 85%
and 80% yield, respectively.
In conclusion, we have developed a mild reaction protocol
for the synthesis of 2-arylindole and indoline derivatives from
arylureas and -styrenes at room temperature. The indoles are
C
DOI: 10.1021/ol5036968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formed through C−H insertion/1,2-carboamination/ β-hydride
elimination cascade, whereas the indolines are obtained through
C−H insertion and 1,2-carboamination via π-benzyl-Pd
stabilization. The present intermolecular technique incorpo-
rates a wide range of starting materials using a ubiquitous and
inexpensive catalytic combination. The catalytic conversion is
also reproducible on a gram scale with lower catalyst loading.
Therefore, we anticipate that this methodology will find many
applications in academia as well as in industrial processes.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectroscopic data, and H and 13C
NMR spectra for all synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Corresponding Author
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was supported by DST, award no. SR/S2/RJN-97/
012, Government of India. M.K.M. and A.H. thank UGC and
CSIR, respectively, for their fellowships. We thank Dr. R.
Natarajan for analyzing the crystal data.
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DOI: 10.1021/ol5036968
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