In Situ Preparation of Palladium Nanoparticles for C-2 Selective Arylation of Indoles in Agro-Waste Extract Based Mixed Solvents

Article abstract of DOI:10.1002/ejoc.202100331

An efficient and practical method for the in situ generation of palladium nanoparticles was successfully established in a water extract of pomelo peel ash. The produced palladium nanoparticles were characterized by energy-dispersive X-ray spectroscopy elemental mapping, field emission scanning electron microscopy, high-resolution transmission electron microscope, X-ray powder diffraction, and showed high catalytic activity for selective C-2 arylation of indoles. A series of 2-arylindoles were smoothly installed in moderate to good yields through the direct palladium-catalyzed cross-coupling reactions of indoles and iodoarenes without external ligand, base, oxidant, and preinstallation directing group.

Full text of DOI:10.1002/ejoc.202100331

Communications
doi.org/10.1002/ejoc.202100331
In Situ Preparation of Palladium Nanoparticles for C-2
Selective Arylation of Indoles in Agro-Waste Extract Based
Mixed Solvents
Yajun Sun,[a] Rui Wang,[a] Tianxiang Liu,[a] Weiwei Jin,*[a] Bin Wang,[a] Yonghong Zhang,[a]
Yu Xia,[a] and Chenjiang Liu*[a]
mechanochemistry,[7] and microwave chemistry[8] also have
An efficient and practical method for the in situ generation of
successfully showed their considerable potential in the direct C-
2 selective arylation of indoles. However, there still exist some
intrinsic drawbacks, such as the installation of directing group,
poor C2/C3 selectivity, and addition of external ligand, base,
additive, and equivalent oxidant, need to be solved.
palladium nanoparticles was successfully established in a water
extract of pomelo peel ash. The produced palladium nano-
particles were characterized by energy-dispersive X-ray spectro-
scopy elemental mapping, field emission scanning electron
microscopy, high-resolution transmission electron microscope,
X-ray powder diffraction, and showed high catalytic activity for
selective C-2 arylation of indoles. A series of 2-arylindoles were
smoothly installed in moderate to good yields through the
direct palladium-catalyzed cross-coupling reactions of indoles
and iodoarenes without external ligand, base, oxidant, and
preinstallation directing group.
Resource utilization and recycling of bulky organic solid
wastes, which mainly come from agricultural production and
comprise abundant lignin and cellulose, have attracted increas-
ing attention from governments and scientists all over the
world during the past few years. The conversion of agricultural
organic solid wastes to biofuels and high-value-added fine
chemicals are the two most preferential developing directions.[9]
Recently, using water extract of agro-waste ash (AWEs) as a
source of agro-based biosolvents has been demonstrated and
opened a new application.[10] As a kind of novel green reaction
medium, many elegant studies in organic synthetic chemistry
including transition-metal catalyzed cross-coupling reactions,[11]
Dakin reaction,[12] Henry reaction,[13] peptide synthesis,[14] ipso-
hydroxylation,[15] biodiesel synthesis,[16] have been realized in
AWEs. These studies have suggested that AWEs played more
than the role of solvents.
As the extension of our research on the resourcing of
organic agriculture waste[17] and environmentally friendly chem-
ical transformations of indoles,[18] we present herein our
preliminary study about the construction of 2-arylindoles via
in situ generation of palladium nanoparticles catalyzed direct
sp2 CÀ H functionalization of indoles with iodoarenes in agro-
waste extract based mixed solvents. To the best of our
knowledge, this is the first report on the palladium-catalyzed C-
2 selective direct CÀ H arylation of indoles in AWEs.
Introduction
Arylated indole compounds are the core structures in many
natural products and biologically active molecules, and have
been widely used in the manufacture of pharmaceuticals,
pesticides, and fine chemicals.[1] Many classical and reliable
approaches for the formation of arylindole derivatives through
transition metal-catalyzed cross-coupling reactions have been
well developed.[2] However, these procedures often require
prefunctionalization indole and arene substrates as the cou-
pling partners and do not conform to the basic principle of
atomic and step economy of chemical reaction and process. In
recent years, transition metal-catalyzed CÀ H activation reac-
tions, which do not need preactivation substrates, have
emerged as an important alternative way to traditional
transition metal-catalyzed cross-coupling reactions.[3] The devel-
opment of highly regioselective catalytic systems for the
arylation of indoles at different CÀ H bonds is the key and hot
point in this field.[4] At present, directing group strategy is one
of the most commonly used technique to control the reaction Results and Discussion
site and regioselectivity.[5] In addition, heterogeneous catalysis,[6]
The water extract of pomelo peel ash (WEPPA) used in this
study was firstly prepared according to our reported
procedure.[17] Then, the reaction of N-methylindole 1a and
iodobenzene 2a was selected as the model reaction to screen
the best conditions (Table 1). This cross-coupling reaction
preferred to occur at C-2 position of indole and formed 1-
methyl-2-phenyl-1H-indole 3a as the major product in WEPPA
(entry 1). Comprehensive considering the reaction efficiency
and C2/C3 regioselectivity of products, the three-component
mixed solvents behaved better reaction efficiency and regiose-
lectivity than single or two-component mixed solvent. After the
[a] Y. Sun, R. Wang, T. Liu, Prof. Dr. W. Jin, B. Wang, Prof. Dr. Y. Zhang,
Prof. Dr. Y. Xia, Prof. Dr. C. Liu
Urumqi Key Laboratory of Green Catalysis and Synthesis Technology,
State Key Laboratory of Chemistry and Utilization of Carbon Based Energy
Resources,
Key Laboratory of Advanced Functional Materials, Autonomous Region,
College of Chemistry, Xinjiang University,
Urumqi 830046, P. R. China
E-mail: wwjin0722@xju.edu.cn
pxylcj@126.com
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100331
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Table 1. Optimization of reaction conditions.[a]
Table 2. Substrate scope of iodoarenes 2.[a,b]
Entry
[Pd]
[10 mol%]
Solvent
Yield of
3a:3a’[b]
3a [%][b]
1
2
3
4
PdCl2
PdCl2
Pd(OAc)2
Pd(TFA)2
Pd(PPh3)4
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
WEPPA
14
87
80
63
59
80
49
96:4
91:9
88:12
88:12
93:7
96:4
92:8
92:8
84:16
0:0
DMSO/CH3CN/WEPPA
DMSO/CH3CN/WEPPA
DMSO/CH3CN/WEPPA
DMSO/CH3CN/WEPPA
DMSO/CH3CN/WEPPA
DMSO/CH3CN/WEPPA
DMSO/CH3CN/WEPPA
DMSO/CH3CN/WEPPA
DMSO/CH3CN
5
6[d]
7[e]
8[f]
91 (88)[c]
48
9[f,g]
10[f,h]
11[f]
12[f,i]
13[f,j]
14[f,k]
n.r.
14
43
22
50
PdCl2
PdCl2
PdCl2
PdCl2
DMSO/CH3CN/H2O
96:4
86:14
84:16
96:4
DMSO:CH3CN:K2CO3 aq
DMSO:CH3CN:Cs2CO3 aq
DMSO:CH3CN:NaOH aq
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), Pd catalyst
°
(10 mol%), solvent (2.0 mL, v:v:v=0.5:0.5:1.0), 100 C, air, 12 h. [b]
Determined by GC analysis. [c] Isolated yield of 3a in parentheses. [d]
°
°
80 C. [e] 120 C. [f] 8 h. [g] PdCl2 (5 mol%) [h] DMSO/CH3CN (1.0 mL, v:v=
0.5:0.5). [i] pH=11.7. [j] pH=12.4. [k] pH=13.6. WEPPA: water extract of
pomelo peel ash. n.r.=no reaction.
[a] Reaction conditions: 1a (0.25 mmol), 2 (0.5 mmol), PdCl2 (10 mol%),
°
DMSO/CH3CN/WEPPA (2.0 mL, v:v:v=0.5:0.5:1.0), 100 C, air, 8–24 h. [b]
Isolated yield. [c] 5 mmol scale reaction. For 3b–3c, and 3e, 12 h; 3g, 3i,
and 3m, 16 h; 3d, 3f, 3h, 3j–3l, and 3n, 24 h.
systematic screening, the three-component mixed solvents
DMSO/CH3CN/WEPPA seemed to be the best combination and
formed the best-isolated yield of 3a in 88% (entry 8). Decreas-
ing or increasing the reaction temperature had an adverse
effect on the reaction activities (entries 6–7). Lowering the PdCl2
to 5 mol%, the yield of 3a diminished to 48% (entry 9). Control
experiments demonstrated that AWEs were a crucial factor,
which enable the model reaction to proceed smoothly
(entry 10). Replacing WEPPA with water or other aqueous
solutions of inorganic bases, the desired product 3a was only
obtained in 14–50% yields, this further demonstrated the and
not only functioned as the solvent (entries 11–14). Other N-
protected indoles were also tested under standard conditions.
Only N-ethylindole furnished the desired product in the yield of
51%, while N-benzylindole and N-Boc-indole did not work.
Replacement of N-methylindole 1a with free NÀ H indole
afforded the corresponding arylation product in 44% yield.
With the optimized conditions established, the generality of
this protocol was firstly explored by the reaction of N-meth-
ylindole 1a with a range of iodoarenes 2 at 0.25 mmol scale
(Table 2). In general, this methodology behaved high functional
group compatibility with various electron-donating groups
(EDG) and electron-withdrawing groups (EWG) substituted
iodoarenes 1 and afforded the desired 2-arylindoles 3a–3n in
good yields. The steric hindrance and electronic effect of the
substituents had no obvious influence on the reaction
efficiency. Methyl, tert-butyl, methoxyl, and methylthio could be
well tolerated as EDG groups on the aromatic rings of
iodoarenes, and the corresponding products 3b–3f were
obtained in good yields. Interestingly, the presence of fluoro,
chloro, and bromo atoms on the 4-position of the iodobenzene
also reacted smoothly with 1a to assemble the desired
products 3g–3i in 64–80% yields and kept these halogen
atoms untouched. The starting materials with strong electron-
deficient groups such as À CF3, À COCH3, and À CO2Et underwent
the arylation reaction, generating the target products 3j–3l in
satisfactory yields. The fused ring compounds α- and β-
iodonaphthalene both were suitable substrates, producing the
arylation products 3m and 3n in 69% and 61% yields,
respectively.
Subsequently, the substrate scope of indole derivatives 1
were further investigated. As shown in Table 3, it was observed
that substituted indoles with À Me, À MeO, À F, À Cl, and À Br at C-
5, C-6, and C-7 positions worked well with iodobenzene under
optimal conditions to deliver the cross coupling products 4a–
4h in 59–89% yields. However, the reaction of 1-methyl-5-nitro-
1H-indole and iodobenzene only led to the desired product 4i
in 33% yield, possibly due to the strong electron withdrawing
property of nitro group at C-5 location. What is more, this
protocol could be successfully extended to 7-azaindole as well
in good yield (83%).
Considering that the in situ generated palladium nano-
particles during the organic chemical reactions catalyzed by
homogeneous palladium catalysts was known.[19] So, the
resulted solid residue of this protocol was characterized by
various means. Energy dispersive X-ray (EDX) spectrum showed
the existence of O and Pd elements (Figure 1), and EDX
mapping identified the chemical composition of the in situ
produced catalyst (Figure 2a). Field emission scanning electron
microscopy (FESEM) was used to observed the morphology of
the catalyst (Figure 2b).[20]
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Table 3. Substrate scope of indoles 1.[a,b]
Figure 3. HRTEM images of Pd NPs.
X-ray diffraction (XRD) was conducted to investigate the
size and structure of Pd NPs, as shown in Figure 4. Three peaks
°
°
°
[a] Reaction conditions: 1 (0.25 mmol), 2a (0.5 mmol), PdCl2 (10 mol%),
were observed at 2θ=39.9 (111), 46.6 (200), and 67.9 (220),
corresponding to the Pd metals in comparison to the data from
JCPDS file, No.46-1043, respectively. The broadening of the
peak further manifested the nano size of the in situ produced
Pd catalyst.[11f]
°
DMSO/CH3CN/WEPPA (2.0 mL, v:v:v=0.5:0.5:1.0), 100 C, air, 12–24 h.
Isolated yield. For 4j, 12 h; 4a–4g, 16 h; 4h–4i, 24 h.
Conclusion
In summary, a novel method for the regioselective synthesis of
2-arylindoles through the direct CÀ H arylation of indoles with
iodoarenes in AWEs has been well developed. This catalytic
system features wide substrate scope, good functional group
tolerance, excellent regioselectivity, and external ligand, base,
directing group, and oxidant-free conditions. Preliminary evi-
dence suggests that palladium nanoparticles are generated
in situ in the assistant of the water extract of pomelo peel ash
Figure 1. EDX spectrum of Pd NPs.
Figure 2. EDX mapping (a) and FESEM (b) patterns of Pd NPs.
High-resolution transmission electron microscopy (HRTEM)
was also used to observed the morphology of the catalyst.
HRTEM images highlighted a typical metallic Pd NPs with a
lattice space of 0.22 nm, which was assigned to the (111) plane
of metallic Pd (Figure 3).[21]
Figure 4. XRD pattern of Pd NPs.
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Experimental Section
General Procedure for the Synthesis of 3a: Under atmosphere, 1-
methyl-1H-indole 1a (0.25 mmol, 31 μL), iodobenzene 2a
(0.50 mmol, 56 μL), PdCl2 (10 mol%, 4.4 mg) and DMSO/CH3CN/
WEPPA (0.5:0.5:1.0, v:v:v, 2.0 mL) were added to a 10 mL reaction
tube equipped with a stir bar. Then the reaction mixture was stirred
°
in an oil bath at 100 C for 8 h. After cooling to ambient temper-
ature, the resulting mixture was extracted with ethyl acetate (3×
5 mL). The combined organic phase was dried over anhydrous
Na2SO4, filtered, and all the volatiles were evaporated under
reduced pressure. The resultant residue was purified by silica gel
°
column chromatography (eluent: petroleum ether (35–60 C)/
EtOAc=20:1 to 5:1, v/v) to afford the desired 1-methyl-2-phenyl-
1H-indole 3a in 88% yield.
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Supporting Information
(see footnote on the first page of this article): Experimental
details, compound characterization, NMR spectra.
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We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21572195, 21702175, and 21961037) for
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Conflict of Interest
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Keywords: Agro-waste extract · CÀ H activation · Indoles ·
Nanoparticles · Palladium
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Manuscript received: March 18, 2021
Revised manuscript received: April 6, 2021
Accepted manuscript online: April 14, 2021
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