Pd-PEPPSI-IPentCl: A new highly efficient ligand-free and recyclable catalyst system for the synthesis of 2-substituted indoles: Via domino copper-free Sonogashira coupling/cyclization

Article abstract of DOI:10.1039/c7nj01544e

A pyridine-containing decidedly resourceful Pd-N-heterocyclic carbene complex, Pd-PEPPSI-IPent^Cl (PEPPSI = pyridine enhanced precatalyst preparation, stabilization, and initiation), is used as a first class recyclable catalytic system for the synthesis of 2-substituted indoles via domino copper-free Sonogashira coupling/cyclization. The catalyst showed a greater performance in the cascade reaction of various 2-bromo anilines with different terminal acetylenes under mild (60 °C) and green conditions (ethanol:water) even in the absence of a copper catalyst and an inert atmosphere. The catalyst is used for the first time in these reactions. The findings suggest that 0.1 mol% of the catalyst is sufficient, and that the catalyst is recyclable and can be reused for up to six cycles.

Full text of DOI:10.1039/c7nj01544e

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Pd-PEPPSI-IPentCl: A new highly efficient ligand-free and
recyclable catalyst system for the synthesis of 2-substituted
indoles via domino copper-free Sonogashira coupling/cyclization
Murali Krishna Kollia,c,#, Nagul Meera Shaikb,c,#, Govindasamy Chandrasekara,*, Sridhar Chidarab,c
and Ragu Babu Korupolub
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pyridine containing decidedly resourceful Pd-N-heterocyclic carbene complex, Pd-PEPPSI-IPentCl
(PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and initiation) is being used as a first
class recyclable catalytic system for the synthesis of 2-substituted indoles via domino copper-free
Sonogashira coupling/cyclization. The catalyst showed a greater performance in the cascade reaction
of various 2-bromo anilines with different terminal acetylenes under mild (60 °C) and green conditions
(ethanol: water) even in the absence of copper catalyst and inert atmosphere. The catalyst is used for
the first time in these reactions. The findings suggest that 0.1 mol% of catalyst is sufficient, recyclable
and can be reused up to six cycles.
Sonogashira reaction attained a greater degree of importance in the
synthetic organic chemistry for synthesizing industrially important
Introduction
Indole derivatives are recognized as important synthetic
intermediates commonly found in pharmaceutically active agents
and natural products1a-e. Numerous methods have been developed
thus far for the synthesis of indole derivatives by using non-metal
mediated approaches including Fischer, Madelung, Reissert,
Leimgruber-Batcho, and Gassman indole syntheses2a-d. Other side
applications include the use of metal/metal complex catalysts such
as Au, Cu, Pd, Rh, Sb, Ru, Pt, Fe, and Nb2e-m. N-heterocyclic carbene
(NHC) complexes play a vital role in catalysis and synthetic organic
chemistry. More particularly Pd-N-heterocyclic carbene (Pd-NHC)
complexes are playing a very important role in cross coupling
reactions for C-C, C-O and C-N bond formations3.
compounds of heterocycles, arylated compounds, natural products,
polymers and organic nanostructured materials. Sonogashira
reaction offers a simple and straight forward coupling of aryl
halides with terminal acetylenes using palladium catalyst and
copper cocatalyst in basic medium. The utility of the reaction
required inert atmosphere and moisture free conditions, since trace
amounts of oxygen could lead to homo-coupled products by Glaser
coupling15 as the copper–acetylide intermediate is extremely
sensitive to aerobic conditions.16a-g Therefore, achieving copper-
free conditions that would provide a tolerance in aerobic conditions
would be a greater challenge in the Sonogashira coupling reactions.
While the copper free conditions would ensure the coupling being
tolerant to aerobic conditions, the amine-free conditions would
circumvent the toxicity issues associated with the use of some of
the amines.17
Capretta et al.4 first reported the cross coupling reaction catalysed
by Pd-N-heterocyclic carbene (Pd-NHC) in 2004. Several N-
heterocyclic carbenes5a-f (NHC) with nitrogen atoms substituted
with bulkier aromatic rings such as mesityl,6a-e 2,6-
diisopropylphenyl,7a-j 2,6-diisopentylphenyl,8 2,6,-diisopropyl-4-
Pd-PEPPSI-IPent Cl
,
Br
tritylphenyl,9
calixarenyl,10
resorcinarenyl11a-b
and
2,6-
Cs2CO3, EtOH, H2O,
60 °C, 45-70 min
R1
R1
di(diphenylmethyl)-4-methoxyphenyl12a-b showed a greater catalytic
activities12c-f in cross coupling reactions compared to the analogs
bearing smaller substituents due to the steric effect. Glorius et
al.13a-b have explored the beneficial role of bulky N-substituents that
display structure flexibility and thereby enabling the steric
requirements of each individual step of the catalytic cycle in these
reactions.14
R2
NH2
N
R2
2a-2m
H
75-91%
1a-1h
3a-3t
R1, R2: Various aryl/hetero aryl groups and electron-donating/
withdrawing groups
Scheme 1. Synthesis of 2-substituted indoles using Pd-PEPPSI-
IPentCl catalyst
Bolm and co-workers explained the significance of copper catalysed
Sonogashira reactions in the presence of chelating diamines.18
Surprisingly in 2014, Lu et al.,19 synthesized a new Pd-NHC(II)
catalyst for Sonogashira coupling reaction in aerobic and copper-
free conditions. Organ et al.,20a-c developed a versatile Pd-NHC
complexes through PEPPSI (Pyridine-Enhanced Precatalyst
Preparation Stabilization and Initiation) method with Pd(II) species
a.Department of Chemistry, SAS Division, VIT University, Chennai-600127,
Tamilnadu, India. Tel.: +91 44 39931237; fax: +91 44 3993 2555; E-mail:
gc_sekar78@yahoo.co.in, chandrasekar.g@vit.ac.in (G. Chandrasekar)
b.Department of Engineering Chemistry, Andhra University, Visakhapatnam, A.P.,
India-530003
c. Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd, IDA Nacharam,
Hyderabad, Telangana, India-500076
#. Equal contribution
bearing an NHC ligand, two halides and 3-chloro pyridyl group20d
.
† Electronic Supplementary Informaꢀon (ESI) available: General experimental
section characteristic data and copies of (1H, D2O exchange & 13C NMR), LCMS, IR
and HRMS specta see DOI: 10.1039/x0xx00000x
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The striking catalyst, Pd-PEPPSI-IPentCl (Fig. 1) is one such Pd-NHC using Pd-PEPPSI-IPentCl catalyst in ethanol : water as the green
based complex, which is air and moisture stable even for longer reaction medium under mild reaction conditions.
times.
Results and Discussion
Here our interest is to develop a new and highly efficient ligand-free
and recyclable Pd-PEPPSI-IPentCl catalytic (synthesized and used)
system for one pot synthesis of 2-substituted indoles via
Sonogashira coupling (without copper catalyst) followed by
cyclization under green approach. Sonogashira coupling under
copper/amine free conditions were first reported by the Ghosh
et.,21 and observed that PEPPSI type precatalysts with a more
electron-rich metal centre show better activity.22 N-heterocyclic
carbenes for the highly desirable copper-free and amine-free
Sonogashira coupling in air and mixed-aqueous medium is
reported.14 Specifically, the PEPPSI themed (NHC)PdCl2(pyridine)
type precatalysts, efficiently carried out the highly convenient
copper-free and amine free Sonogashira coupling of aryl bromides
with terminal acetylenes in air and mixed aqueous medium.
One pot synthesis of various 2-substituted indoles
The 2-substituted indoles synthesized from various 2-bromo
anilines (1a-1h) and terminal acetylenes (2a-2m) are shown in Table
3 as outlined in scheme 1. There are 20 compounds (3a-3t) were
prepared by various successive substitutions with aryl/heteroaryl
moieties through Sonogashira coupling followed by cyclization using
a common Pd-PEPPSI-IPentCl catalyst system. To accomplish the
desired results, we optimized the reaction conditions by changing
the reaction parameters such as catalyst, ligand, solvent and
temperature.
Table 1. Screening on the effect of various palladium catalysts for
the synthesis of 2-phenyl indole
Br
N
H
NH2
1j
2j
3j
Entry Catalyst
Ligand
None
TPP
Time
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
3 h
Yielda (%)
1
0
0
PdCl2
2
PdCl2
3
0
PdCl2
Dppf
TPP
Fig. 1 Pd-PEPPSI-IPentCl
4
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(Ph3P)4
PdCl2(dppf)2
PdCl2(TPP)2
5
0
Xphos
Dppf
None
None
None
None
Binap
Hence a remarkable challenge is faced in Sonogashira coupling
reaction was overcome and it has been carried out in copper-free,
amine-free and air atmosphere conditions. Synthesis of 2-
substituted indoles starting from 2-bromoaniline, is generally
carried out in two steps by using various palladium catalysts23a-b
under inert conditions. In contrast to the stepwise synthesis, one
pot transformations save time and resources, as they require only a
single isolation and purification step. Furthermore, one pot
synthetic methodologies are attractive since they produce highly
functionalized products in one single synthetic procedure, often
circumventing unwanted wastes. Initially, we have examined the
preparation of Pd-PEPPSI-IPentCl by following the reported
literature24 with some modifications in order to improve the yields.
So far solvents such as, acetone, toluene, tetrahydrofuran,
acetonitrile, 1, 4-dioxane and dimethylformamide25 are most
frequently used for Sonogashira coupling reactions. But these are
expensive, toxic, and difficult to recycle. Development of
inexpensive and environmentally acceptable method for the
synthesis of 2-substitued indoles is therefore highly desirable.
6
0
7
<5
5
8
9
11
14
18
19
62
61
65
72
91
81b
85c
71d
10
11
12
13
14
15
16
17
18
19
20
PdCl2(CH3CN)2
Pd2(dba)3
Pd(H2NCH2CH2NH2)Cl2 None
PEPPSI-iPr
None
None
None
None
None
None
None
None
PEPPSI-iPent
3 h
PEPPSI-SIPr
3 h
PEPPSI-SONO-SP2
PEPPSI-IPentCl
PEPPSI-IPentCl
PEPPSI-IPentCl
PEPPSI-IPentCl
1.5 h
50 min
50 min
50 min
50 min
Reaction conditions : 2-bromo aniline (3 mmol), Phenyl acetylene (3
mmol), Cs2CO3 (6 mmol), PEPPSI-IPentCl (0.5 mol%) in EtOH : H2O (1
: 1, 10 mL) medium at 60 ˚C for 50 min. a = Isolated yield after
column purification. b = Reaction temperature at 100 ˚C. c =
Reaction carried out in a microwave apparatus (Anton paar,
monowave). d = Reaction carried out in a sealed tube.
As part of our interest taking into consideration the immense
biological importance, synthesis, separation and purification of
compounds, expensiveness and recyclability of catalyst and also
looking into environmentally friendly reaction conditions, we now
report ligand-free one pot synthesis of 2-substituted indoles via
Sonogashira coupling (copper/amine free) followed by cyclization
2 | J. Name., 2012, 00, 1-3
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In order to establish the optimal condition for Sonogashira coupling that 0.1 mol% of catalyst is adequate to complete the reaction
reaction, we have selected the model reaction between 2- within 50 min.
bromoaniline and phenyl acetylene in the presence of various
palladium based catalysts, ligand, Cs2CO3 in EtOH : H2O (1 : 1)
medium at 60 °C and the products yield are depicted in Table 1. It is
very clear from the experimental results that the reaction did not
proceed with PdCl2 and Pd(OAc)2 even in the presence and absence
of the ligand (Table 1, entries 1-6). When the reaction was carried
out with Pd(PPh3)4 in the absence of ligand, the product obtained
was less than 5% in yield (Table 1, entry 7). Very less amount of
product yield was observed in the reactions catalyzed by various
palladium catalysts (Table 1, entry 8-12). However, interestingly a
competitive product yield of 62% was observed using Pd-PEPPSI-iPr
(Table 1, entry 13) and this triggered us to screen various Pd-PEPPSI
catalysts to enhance the product yield for the convenient catalytic
use. Catalysts such as Pd-PEPPSI- iPent, SIPr, SONO-SP2, IPentCl are
used for this reaction and observed increasing product yields
accordingly (Table 1, entry 14-17). On the other hand increase in
Fig. 2 Time course for the formation of compound 3ja at variable
temperature from 60 to 100 ˚C did not contribute to any increase in
concentrations of Pd-PEPPSI-IPentCl
yield (Table 1, entry 18). Therefore, 60 ˚C was opted as an optimal
Reaction conditions: 2-bromo aniline (3 mmol), Phenyl acetylene (3
temperature for further experiments. Moderate yields were
mmol), Cs2CO3 (6 mmol), Pd-PEPPSI-IPentCl in EtOH : H2O (1 : 1, 10
observed when reaction was carried out under Microwave and in
mL) medium at 60 ˚C for 50 min. a = isolated yield after column
sealed tube (Table 1, entry 19-20). Note worthily, Pd-PEPPSI-IPentCl
purification
was found to give superior results among other catalysts studied at
this temperature even in the absence of ligand and without copper
The scope and the limitations of this reaction methodology were
catalyst (Table 1, entry 17).
studied using various electron-donating and electron-withdrawing
substituted 2-bromoaniline and aryl/heterocyclic acetylene and
Table 2. Screening on effect of various solvents
found that all compounds were successfully isolated in high yields
Entry
Solvent
Time
8 h
Yielda (%)
(Table 3). Table 3 clearly shows that the reaction time for the
synthesis of compounds from 3a to 3t varies from 45 to 70 min. The
electron-donating groups present on amine/acetylene facilitate the
reaction to complete at a shorter reaction time compared to the
electron-withdrawing groups present on amine/acetylene
compounds. The rate determining step of cyclization (Fig. 5) is
based on the nucleophilicity of the amine derivative (Sonogashira
coupled product). Hence when the electron-donating group is
present on the amine, it increases the nucleophilicity, which further
enhances the cyclization thereby resulting in a shorter reaction
time. But on the other hand when the electron-withdrawing group
is present on the amine, it decreases the nucleophilicity of the
amine, thereby decreasing the rate of cyclization that results in a
longer reaction time.
1
2
3
4
5
Tetrahydrofuran
N,N-Dimethylformamide
1,4-Dioxane
55
73
71
77
91
6 h
6 h
1,4-Dioxane : water
Ethanol : water
6 h
0.5 h
Reaction conditions: 2-bromo aniline (3 mmol), Phenyl acetylene (3
mmol), Cs2CO3 (6 mmol), PEPPSI-IPentCl (0.5 mol%) in EtOH : H2O
(1:1, 10 mL) medium at 60 ˚C for 50 min. a = isolated yield after
column purification.
We required a low loading catalyst ratio to carry out the reaction in
economical large scale synthesis. Hence we studied the
effectiveness of our catalyst with different mole percentage of Pd-
PEPPSI-IPentCl catalyst on the above model reaction. Fig.
2
Represents the product yield of 3j with different reaction time on
different mole percentage of Pd-PEPPSI-IPentCl. The increase in
product yield with respect to the reaction time was observed in
different mole percentage of Pd-PEPPSI-IPentCl catalysts used from
0.05 and 0.5. The reaction completes after 70 min with the product
yield of 65 % and 75 % using 0.05 mol% and 0.08 mol% of Pd-
PEPPSI-IPentCl catalyst, respectively. When the catalyst amount is
increased to 0.1, 0.3 and 0.5 mol%, the reaction completes at a
shorter reaction time of 50 min with 91 % product yield. There is no
increase in the product yield when the catalyst amount was
increased from 0.1 to 0.5 mol%. From the above results, it is clear
We studied the possibility of this method for a convenient scale-up
process for the preparation of 2-substituted indoles (Table 2, entry
10) on 5 g and 10 g scale and the results showed 90% and 91% of
product yield, respectively. This study clearly indicates that the
methodology is convenient for a scale-up process and there is no
remarkable product yield difference between R&D scale and scale
up process.
Optimized conditions in hand, we endeavoured to catalyze the
Sonogashira coupling reactions followed by cyclization for
compounds (1a-1h) with terminal acetylenes (2a-2m). All the
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reactions were carried out under the non-inert atmosphere and To clarify the catalytic role, reaction pathway and rate of the
without use of copper/amine to obtain various 2-substituted reaction in one-pot synthesis, we analysed the crude samples
indoles (3a-3t) at different rates and variable yields. The obtained at various time intervals of 20, 30, 40 and 50 min using 1H
synthesized compounds were characterized by IR, (1H, 1H-D2O Ex. & NMR (DMSO-d6, 500 MHz) and the spectra are shown in Fig 4. The
13C) NMR, LCMS, HRMS and IR spectra.
1H NMR spectrum (a) showed that our catalyst promoted the
In the next study, we have examined the recovery of catalyst for the conversion of aryl bromide and acetylene to the Sonogashira
Sonogashira coupling reaction followed by cyclization of compound coupled product within 20 min and corresponding peaks due to –
3j with phenyl acetylene over six consecutive reaction cycles. After NH2 group and aryl group were observed peaks at 5.5 ppm and at
completion of reaction (monitored through TLC), the catalyst was 7.4 ppm, respectively. The cyclization reaction is also confirmed by
recovered from the reaction mixture by simple filtration, followed the peak observed at 11.5 ppm due to indole –NH group. The 1H
by hexane washings and then dried under vacuum at RT for 1 h. The NMR spectra of crude obtained at 30 and 40 min showed a
recovered catalyst maintained a high catalytic activity with the decrease in peak intensity at 5.5 and 7.4 ppm and the
product yield of 91 % for three runs without any loss in its corresponding increase in peak intensity at 11.5 ppm with increase
performance. After three cycles the catalyst was recovered from in reaction time. This clearly indicates that the conversion of
the reaction medium and it is washed with hexane, dried and then Sonogashira product in to the desired product formation. The 1H
analysed by 1H NMR spectroscopic method. The 1H NMR analysis NMR spectrum is showing the complete conversion and formation
showed that the recovered catalyst is very much stable even after of 2-phenyl indole after 50 min. This study also proves that the
three cycles. This is of much significance for the exploitation of the reaction path way going via Sonogashira coupled product followed
catalyst for different coupling reactions. The catalytic activity is by cyclization and also evidence with respect to the rate of the
decreased in fourth, fifth and sixth run cycle to the product yield of reaction, the Sonogashira coupled product formed within 20 min
84 %, 75 % and 65 %, respectively (Fig. 3).
and cyclization taking little longer time ~30 min.
Fig. 3 Recyclability test of the catalyst Pd-PEPPSI-IPentC
Reaction conditions: 2-bromo aniline (3 mmol), Phenyl acetylene (3
mmol), Cs2CO3 (6 mmol), Pd-PEPPSI-IPentCl (0.1 mol %) in EtOH :
H2O (1 : 1, 10 mL) medium at 60 ˚C for 50 min
4 | J. Name., 2012, 00, 1-3
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(d)
1H NMR at 50 min.
(c)
1H NMR at 40 min.
(b)
H2N
1H NMR at 30 min.
(a)
H2N
1H NMR at 20 min.
Fig. 4 1H NMR spectrums (crude) at various time intervals of (a) 20 min, (b) 30 min, (c) 40 min and (d) 50 min
Reaction condition: 2-Bromo aniline (10 mol), phenyl acetylene (10 mol), Cs2CO3 (20 mol), Pd-PEPPSI-IPentCl (0.1 %), EtOH : H2O (2
mL, 1:1), 60 ˚C and 50 min
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Table 3. Synthesis of various 2-substituted indoles using Pd-PEPPSI-IPentCl catalyst
Entry
Bromo aniline
acetylene
Product
Time (Min) Yielda (%)
Mp (°C)
215-217
O
O
Br
N
N
O
1.
45
45
90%
N
H
N
N
NH2
1a
2a
O
3a
N
O
Br
O
2.
3.
4.
176-180
234-238
168-172
85%
NH2
1a
N
H
N
2b
3b
O
O
O
Br
N
N
Cl
50
50
86%
90%
N
H
N
N
N
NH2
1a
2c
Cl
3c
O
Br
N
CF3
3d
N
H
NH2
1a
2d
CF3
O
Br
O
N
N
O
N
Boc
NHBoc
1b
5.
45
85%
130-133
N
N
N
2a
2c
O
3e
O
Br
O
N
N
Cl
NHBoc
1b
N
Boc
6.
7.
70
70
80%
90%
162-164
202-206
N
3f
Cl
F
O2N
Br
O2N
F
F
NH2
N
H
NO2
NO2
1c
2e
3g
N
F
O
O
Br
8.
9.
134-138
202-206
50
70
88%
86%
N
H
N
3h
NH2
1a
N
N
2f
O2N
Br
O2N
CF3
3i
N
H
NH2
1c
NO2
Br
NO2
2g
2h
2i
CF3
186-18726,b
10.
11.
50
50
91%
83%
N
H
NH2
1d
3j
Br
Cl
3k
195-19627,b
N
H
NH2
1d
Cl
6 | J. Name., 2012, 00, 1-3
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Br
76-7828,b
12.
70
80%
83%
N
Boc
NHBoc
1e
3l
2h
2h
O
Br
O
160-16229,b
13.
45
N
H
NH2
1a
1a
3m
O
O
Br
Br
201-20230,b
240-24131,b
100-10132,b
14.
45
84%
82%
82%
N
NH2
H
3n
2j
Br
Br
CF3
50
15.
16.
N
NH2
1d
H
3o
2k
CF3
Br
50
N
H
NH2
1f
2h
3p
O
O
Br
NO2
200-20133,b
17.
50
50
50
75%
83%
79%
N
H
NH2
2l
1a
3q
3r
NO2
Br
18.
Cl
N
180-18134,b
Cl
NH2
1g
H
2h
O
Br
O
213-21435,b
19.
N
H
NH2
1a
2m
2h
3s
3t
O2N
O2N
20.
Br
234-23536,b
70
86%
N
NH2
H
1h
a = Isolated yield.
b = Spectral data (1H, 13C NMR) of known compounds (3j-3t) were found to be identical with those reported in the literature.
Fig. 5 Plausible mechanistic pathway for the one-pot synthesis
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In accordance with previous literature report,37 a plausible reaction
mechanism is proposed (Fig. 5). Initially the oxidative addition of
aryl bromide to Pd(0) leads to formation of Pd-complex (A) followed
by insertion of alkyne to form π-bond mediated new Pd-complex
(B). Deprotonation of alkyne groups of Pd-complex B and bromine
displacement leads to formation of complex (C) followed by
reductive elimination to give the Sonogashira coupled product (D).
Then formation of π-bond mediated new Pd(II)-complex (E),
followed by deprotanation to give the cyclized Pd(II)-complex (F).
Then protonation of Pd(II)-complex (F) gives the desired compound
(G).
Acknowledgments
One of the authors (Murali Krishna Kolli) gratefully acknowledged to
Dr. Gajendrasinh Balvantsinh Raolji and GVK Biosciences Pvt Ltd,
Hyderabad for their support and motivation.
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Journal Name
Graphical Abstract
Pd-PEPPSI-IPentCl: A new highly efficient ligand-free and recyclable catalyst system for
the synthesis of 2-substituted indoles via domino copper-free Sonogashira
coupling/cyclization
Murali Krishna Kollia,c,#, Nagul Meera Shaikb,c,#, Govindasamy Chandrasekara,*, Sridhar Chidarab,c and
Ragu Babu Korupolub
One pot synthesis of 2-substituted indoles via sonogashira coupling (without copper catalyst) followed by
intermolecular cyclization using new competent palladium catalyst Pd-PEPPSI-IPentCl under mild and
greener approach
Pd-PEPPSI-IPentCl
Cl
Cl
N
N
Br
R1
R1
R2
Pd
N
Cl
Cl
N
H
NH2
1. Catalyst recyable
2. Greener protocal
3. Mild condition (60 °C)
4. Short time (45-70 min)
5. High Yield (75-91%)
6. 20 examples
R2
Cl
1
2
3
R1
R2
NH2
R1, R2 = Varies aryl/hetero aryl groups and electron donating/withdrawing groups
10 | J. Name., 2012, 00, 1-3
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