Design and applications of new phosphine-free tetradentate Pd-catalyst: Regioselective C–H activation on 1-substituted 1,2,3-triazoles and indoles(NH-Free)

Article abstract of DOI:10.1080/00397911.2017.1381260

This article describes the synthesis of a new phosphine free tetradentate Pd catalyst using dl-2,3-diaminopropionic acid. The complex was characterized by Mass, IR, and ¹H NMR. The catalyst is air stable at room temperature and non-hygroscopic. Application of this new catalyst to regioselective C–H activation on 1-substituted 1,2,3-triazole and indoles with aryl iodides to get corresponding C-5 and C-2 arylated products with satisfactory yields. All the products were characterized by spectroscopic studies.

Full text of DOI:10.1080/00397911.2017.1381260

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Design and applications of new Phosphine-free
tetradentate Pd-catalyst: Regioselective C-H
activation on 1-substituted 1,2,3-triazoles and
Indoles(NH-free)
Sarma V. Markandeya, Ch. Renuka, Parvathi K. Lakshmi, A. Rajesh, Chidara
Sridhar & Dr. Korupolu Raghu Babu
To cite this article: Sarma V. Markandeya, Ch. Renuka, Parvathi K. Lakshmi, A. Rajesh, Chidara
Sridhar & Dr. Korupolu Raghu Babu (2017): Design and applications of new Phosphine-free
tetradentate Pd-catalyst: Regioselective C-H activation on 1-substituted 1,2,3-triazoles and
Indoles(NH-free), Synthetic Communications, DOI: 10.1080/00397911.2017.1381260
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1381260
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Date: 23 October 2017, At: 21:44

Design and applications of new phosphine-free tetradentate
Pd-catalyst: Regioselective C-H activation on 1-substituted
1,2,3-triazoles and indoles(NH-free)
Sarma V. Markandeya
Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd, IDA, Hyderabad, Telangana,
India
Department of Engineering Chemistry, Andhra University, Visakhapatnam, AP, India
Ch. Renuka
Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd, IDA, Hyderabad, Telangana,
India
Department of Engineering Chemistry, Andhra University, Visakhapatnam, AP, India
Parvathi K. Lakshmi
Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd, IDA, Hyderabad, Telangana,
India
Department of Engineering Chemistry, Andhra University, Visakhapatnam, AP, India
A. Rajesh
Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd, IDA, Hyderabad, Telangana,
India
1

Department of Engineering Chemistry, Andhra University, Visakhapatnam, AP, India
Chidara Sridhar*
Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd, IDA, Hyderabad, Telangana,
India
Dr. Korupolu Raghu Babu
Department of Engineering Chemistry, Andhra University, Visakhapatnam, AP, India
*Address corresponding to Chidara Sridhar, Department of Medicinal Chemistry, GVK
Biosciences Pvt. Ltd, IDA, Nacharam, Hyderabad, Telangana 500076, India. Tele: + 91-40-
6748-3459. Fax: + 91-40 67483400. E-mail: Sridhar.chidara@gvkbio.com
Supplementary data (general experimental details, characterization data) copies of the 1H NMR
and LC-MS of all synthesized compounds associated with this article can be found, in the online
version
ABSTRACT
This article describes the synthesis of a new phosphine free tetradentate Pd catalyst by
1
using DL-2,3-diaminopropionic acid. The complex was characterized by Mass, IR, and HNMR.
The catalyst is air stable at room temperature and non-hygroscopic. Application of this new
catalyst to regioselective C-H activation on 1-substituted 1,2,3-triazole and indoles with aryl
iodides to get corresponding C-5 and C-2 arylated products with satisfactory yields. All the
products were characterized by spectroscopic studies.
GRAPHICAL ABSTRACT
2

KEYWORDS
Introduction
C-H activation of aromatic and hetero aromatics became area of interest as it has many
advantages to achieve new C-C bonds without the requirement of halo groups or any other
leaving groups. So far, many metals have been used for the C-H activation[1–6] like Ru, Pd, Ni,
Cu & Fe and also developed several ligands (phosphine and non-phosphine) to enhance the
reactivity as well as to increase the scope of the reactions. The wide range of significance of C-C
bond construction in organic and material synthesis induced to work on highly active and stable
Pd catalyst which is very versatile and effective. Since last few years several research groups
have worked on the Pd with different ligands such as phosphines,[7] nitrogen and carbon
containing ligands.[8] By adding these ligands, increasing the bulkiness and electron donating
functional groups will help to proceed both oxidative and reductive elimination steps in catalytic
cycle and achieve desire product formation.
Till date, a number of phosphine free ligands,[8,9] were invented to avoid phosphine
ligands as they are very toxic, air sensitive and expensive. Common ligands used to complex
with Pd are monodentate, bidentate, tri and tetradentate donors by using various substrates
3

having electron donating nature. The Palladium catalyst having multifunctional donor ligands
may provide stability and active Pd species. From the literature, N4-tetradentate
dicarboxyamidate/dipyridyl palladium (II) and Amido/Pyridyl Carboxylate Palladium (II) were
used for heck reactions.[10] N -donor ligands shows significant catalytic activity with aryl halides
and anionic amides (deprotonated amides) ligands strongly donate to metal center and stabilizing
various oxidation states of metal center. This type of Pd complex impart thermodynamic stability
to active metal species. Most of these complexes are applied for C-C bond formation and a very
few reports are available on C-H activation. Therefore, these factors are motivated towards
designing of a new phosphine free Pd catalyst and application in C-C bond formation by C-H
activation.
1, 2, 3-triazole and indole based heterocycles are the corner stone of medicinal chemistry
due to their important biological activities and their wide applications in the synthesis of
pharmaceuticals, receptors, fluorinated hydrogels, antibiotics, antitubercular agents, ligands,
surfactants, nucleosides, and their applications in radiochemistry.[11–15] So far, there are only a
few references are available on Palladium catalyzed regioselective C-H activation on 1,2,3-
triazoles and indoles by using phosphine ligands or additives.[16] Gevorgyan group has first
developed a method for direct Pd-catalyzed arylation on 1,2,3-triazoles by using
Pd(PPh3)2Cl2/Bu4NOAc and later Oshima team has developed same transformation in
o
microwave at 250 C by using Pd(OAc)2/PCy3 catalytic system. Recently, Banerjee team
reported same transformation by using Pd(OAc)2 with the combination of (o-tolyl)3P as ligand.
Whereas C-H activation on indoles at C-2 position in presence of Pd catalyst and phosphine
ligands also been reported. To avoid phosphine ligands and additives, we have designed and
developed a new tetradentate phosphine free Pd catalyst and applied for the regioselective C-H
4

activation on 1,2,3-triazoles without using any other additives under relatively mild reaction
conditions.
In this article, we describe the synthesis of Pd (II) complex of tetradentate
imino/hydroxyl methyl carboxylate and found the catalytic activity for C-C bond formation on
1,2,3-triazoles and Indoles. Herein, imino nitrogen atoms acts as donor ligands and anionic
oxygen atoms coordinate with Pd towards oxidative addition. As we have previous experience
with Co-Salen complexes which are prepared by using this 2,3-diamino propionic acid for chiral
cycloaddition reactions,[17] same here we used it for making Pd- salen complex to achieve
regioselective C-H activation.
New Pd catalyst (5) was synthesized from DL-2,3-diaminopropionic acid
monohydrochloride in 3 steps (Scheme 1). Esterification of compound 1 was performed with
thionyl chloride in methanol at 80 °C for 16h to offered compound 2, which further treated with
2-hydroxy benzaldehyde, in dichloromethane for 16h to get di imine (compound 4). The purified
compound 4 was reacted with Pd(OAc)2in THF at rt to obtain Pd(0) complex (compound 5) as
yellow solid after washings with diethyl ether. The obtained Pd complex is soluble in polar
solvents such as acetonitrile, methanol, dimethylsulphoxide, dimethylformamide etc. and found
1
to be non-hygroscopic and air stable at room temperature. It was characterized by IR, H-NMR
1
and Mass spectroscopy. H NMR of compound-4 indicates two phenolic hydrogens appears at
δ12.966ppm to δ12.985ppm and which were absent after formation of Pd complex (5). Also,
imine attached protons were shifted to up filed to δ8.308ppm from δ8.658in ligand 4. The
elemental analysis of compound 5 is in good agreement with the molecular formula proposed
and it appears that compound 4 coordinates to the Pd metal. It was confirmed by mass analysis
5

(M-1 = 428.9; exact mass of complex is 430.01). These results indicate that Pd was coordinated
with two imine and hydroxyl functional groups to act as tetradentate ligand.
Result and discussion
Activity of Pd catalyst initially, we examined for C-C coupling between 1-substituted-
1,2,3-triazoles[16,18] and aryl iodides through C-H activation. To achieve ideal reaction conditions
screened different parameters such as temperature, solvent, bases and catalyst loading (Table 1).
In case of DMSO, 1, 4-Dioxane, NMP, H2O and toluene as solvents achieved minor amount of
product (8-12%; entries 1-7) by LCMS. In case of bases, mostly focused on K2CO3 and Cs2CO3
because these are mild and water soluble. Organic bases (Et3N; entry 9) did not initiate the
reaction. Combination of DMF with Cs2CO3 works much better than the entry 8 (DMF/K2CO3).
Finally, better yields were achieved by taking 3mol % of Pd catalyst in DMF by using Cs2CO3 as
base (entry-12). Here (Tabel-1) arylation was observed exclusively at C-5 position of 1,2,3-
triazole because of its electrophilic nature of C-5 carbon and it was supported by NOE analysis.
Irradiation on H-4 at δ8.33ppm giving signal enhancement of H-13, 17 at δ7.56ppm . This spatial
interaction indicating that 4 –nitro benzene group attacked on 5th position. The arylation was
occurs at C-5 position of triazole because of the energy of the transition state of C-5 is less than
the C-4 transition state as reported in the literature.[16]
After establishing the optimal reaction conditions, the C-H activation of 1-subsituted-
1,2,3-trizoles bearing electron donating, withdrawing and neutral functional groups with various
aryl iodides to determine the generality of this catalytic method (Table 2). All the reactions with
different aryl iodides and various 1-subsituted-1,2,3-trizoles proceeded to satisfactory yields
indicating less effect of electronic properties of substituents presence on both the reactants. Also
6

tested 1,4-substituted-1,2,3-trizoles towards C-H activation and found same reactivity compared
to 1-subsituted-1,2,3-trizoles (entries: 5a, 8a, 11a, 13a & 14a). And also we tried with aryl
bromide (bromo benzene) and aryl triflate (phenyl triflate) in place of aryl iodides with same
optimized conditions, we observed that traces of desired product ( < 5%) and major unreacted
starting material. Instead of 2,3-diamino propionic acid we replaced with simple 1,2-
diaminoethane treated with compound 3 for the preparation of Pd catalyst 6 and found the same
regioselectivity but less yields compared to the Catalyst 5 (entries 13 and 21). So here we
focused more on preparation of catalyst 5 because chelated or bulky groups plays an important
role in reductive elimination steps in Pd catalytic cyclic.
Result and discussion: C-H activation on Indoles at C-2 arylation
The optimization for suitable reaction conditions was initiated with model reaction using
Indole (0.5 mmol) and iodobenzene (1 mmol) using different additives in presence of Pd catalyst
(5mol %). Reaction solvent plays very crucial role in selectivity as well as overall yield. So we
started our investigation with solvent screening. The product formation was poor in aprotic
solvents such as toluene (etntry-6, 21%), DMF (entry 5 & 8, traces), THF (entry-9, 10%) and
DMSO (32 to 50%). In aprotic solvents, we have found good yield with AgOAc (66%) as
additive compare to oxone (32%), H2O2 (traces) and KOAc (no reaction) in DMSO.
7

Whereas in polar protic solvent such as PEG we obtained same yield (~50%) as in
DMSO and AgOAc as additive, which forced us to screen more oxidizing reagents in PEG.
Under identical conditions other additives such as PIDA, NaIO4, H2O2 and KOAc gave well to
moderate yield (entry 11 to 17). However, we noticed that when we used KOAc in DMSO and
PEG we didn’t observed any conversion, whereas in the mixture of solvent PEG and H2O, KOAc
shows promising conversion, which lead us to conclusion that may be water is playing crucial
role for co-ordination of tetradentate catalyst, which results in good yields. Obviously another
aspect is eco-friendly and economical reaction condition. In a parallel study, when we reduced
catalyst loading to 2.5%, the reaction was not completed even after 48h, it shows only 30-40% of
conversion. We also spent our time to optimize equivalence of aryl iodide. After some attempts,
it was found that by adjusting the substrate ratio (1:2), increasing the catalyst loading (5mol %),
100 °C and prolonging the reaction time (12h ), the yield was drastically elevate to 76% (entry
20).
With optimized reaction condition in hand, the substrate scope of this C-2 arylation
reaction was investigated. The indole derivatives bearing electron donating groups such as 5,6-
dimetoxy (entry 8) or mild electron withdrawing groups such as chloro indole (entry 10 and 12)
reacts very well with aryl iodides and provide the products in good yields. In the case of iodo
aryl derivatives with both electron donating (4-methyl, 3-methyl, 3-Br, 4-Cl, 4-isopropyl;
entries-1, 2,3,4,8,10,11and 12), neutral and electron withdrawing (4-CF3, entry 5) as well as
bulkier groups on the aromatic ring (naphthalene; entry 9) participated smoothly in this reaction
with an average to good yield of 3. Particularly, this reaction also works well with bromo
substituted aryl iodide (entry 3) which can function as handle for further transformations.
Experimental
8

Methyl 2,3-diaminopropanoate dihydrochloride (2)
Thionyl chloride (42.8g, 360 mmol) was added drop wise to a stirred suspension of 2, 3-
dimaino propionic acid (5g, 48.07 mmol) in MeOH (75mL ) over a period of 5min . The reaction
mixture was heated to 80 °C for 16h . After that the reaction mixture was cooled and the volatiles
were removed under reduced pressure to obtained compound 2(6.5g, 98%) as an off white solid.
Crude mass complies, Crude compound directly used for next step.
Methyl 2, 3-bis ((E)-2-hydroxybenzylideneamino)propanoate (4)
To a stirred suspension of Diamine hydrochloride salt 2 (1.3g, 3.7 mmol) in
dichloromethane (10mL ), were added triethyl amine (1.3mL, 9.3 mmol) and MgSO4 (1.8g, 14.9
mmol). After stirring for 1.5hours at room temperature a solution of the aldehyde 3(1.57g, 7.46
mmol) in dichloromethane (5mL ) was added. The reaction mixture was stirred at rt for 16h .
After completion of reaction by TLC, the reaction mixture was diluted with dichloromethane and
water separated the layers, organic layer was separated, dried over Na2SO4 concentrated under
reduce pressure. The obtained crude compound was purified by grace system using 10-20% ethyl
1
acetate gave pure compound as pale yellow solid (1.5g, 68%). M.P: 110-114 °C; H NMR
(DMSO, 400MHz ): δ (ppm) 12.98 (d, J = 7.3Hz, 2H), 8.59-8.67 (m, 2H), 7.47 (s, 1H), 7.41-7.48
(m, 1H), 7.30-7.39 (m, 2H), 6.84-6.94 (m, 4H), 4.64 (dd, J = 6.2, 4.8Hz, 1H), 4.03-4.18 (m, 3H),
+
3.73 (s, 3H). LCMS (ESI + ): m/z calcd for C18H18N2O4 [M + H] 326.13; found 327.0. FT-IR
(KBr) υ: 3487, 3053, 2997, 2928, 2908, 2742, 2357, 1732, 1625, 1573, 1489, 1446, 1392, 1274,
1203, 1109, 1055, 979, 889, 823, 750cm -1
Catalyst 5
9

Ligand 4 (391mg, 1.2 mmol) was added to a stirred orange coloured suspension of
palladium acetate (224.49mg, 1 mmol) in tetrahydrofuran (20mL ) in one portion. After the
solution was stirred for 12h at room temperature, a pale yellow precipitate was obtained. The
solvent was removed completely under reduced pressure, and the resulting solid was washed
with excess diethyl ether to obtain pure 5in 74% yield. Pale yellow colour solid; M.P:286-291
1
°C; H NMR (DMSO, 400MHz ): δ (ppm) 8.29 (d, J = 15.9Hz, 2H), 7.45 (dd, J = 7.9, 1.8Hz,
1H), 7.28-7.41 (m, 3H), 6.86 (t, J = 9.4Hz, 2H), 6.55-6.63 (m, 2H), 4.84 (d, J = 6.1Hz, 1H),
4.15-4.24 (m, 1H), 4.08-4.15(m, 1H), 3.73 (s, 3H); 13CNMR (DMSO-d6, 400MHz )
δ169.08,165.44,164.71,163.59,160.87,135.22,135.19,134.75,135.73,134.73,120.99,120.71,120.6
9,120.37,114.66,114.50,70.52,61.96,53.25. LCMS (ESI + ): m/z calcd for C18H16N2O4Pd [M-H]
+
428.90; found FT-IR (KBr) υ: 3016, 2954, 2360, 1735, 1618, 1525, 1444, 1396, 1305, 1222,
1141, 1080, 1014, 900, 852, 752cm -1.
General procedure for the synthesis of compounds C-5 arylation of 1-aryl-1, 2,
3-triazoles
To a stirred solution of N- substituted 1, 2, 3-triazole (1.0 eq), aryl iodide (1.1 eq),
Cs2CO3 (2.0 eq) in DMF (3.0mL ) was added Palladium catalyst 5 (3-5mol %) and the reaction
mixture was stirred at 110 °C for 16h . The progress of reaction was monitored by TLC and after
completion of SM, the reaction mixture was cooled and diluted with EtOAc and water, separated
layers, aqueous layer was extracted with EtOAc(2 x10mL ) combined organic layers were
washed with water(25mL ) followed by brine. The organic layer was dried over Na2SO4,
concentrated under reduced pressure. The obtained crude compound was purified by flash-
column chromatography was performed using silica gel (100-200 mesh) with 5-20% ethyl
acetate in hexane gave pure compound.
10

5-(4-nitrophenyl)-1-phenyl-1H-1,2,3-triazole[19] (1a)
1
Pale yellow solid; Yield: 82%; M.P:140- 144 °C; H NMR (CDCl3, 400MHz ): δ (ppm)
8.31-8.32 (m, 1H), 8.19-8.25 (m, 2H), 8.00 (s, 1H), 7.46-7.54 (m, 3H), 7.40-7.44 (m, 2H), 7.33-
7.38 (m, 2H). LCMS (ESI + ): m/z calcd for C14H10N4O2 [M + H] + 266.08; found 267.10. FT-IR
(KBr)
υ:
3439,
3427,
2924,2852,2362,1734,1595,1531,1454,1346,1111,1053,844,759,682.80,574cm -1
1, 5-diphenyl-1H-1, 2, 3-triazole[20] (2a)
1
Off white solid; Yield: 84%; M.P: 107-111 °C; H NMR (CDCl3, 400MHz ): δ (ppm)
7.87 (s, 1H), 7.42-7.46 (m, 3H), 7.33-7.39 (m, 5H), 7.20-7.24 (m, 2H). LCMS (ESI + ): m/z
+
calcd for C14H11N3 [M + H]
221; found 222.1. FT-IR (KBr) υ: 3442, 2922,
2856,2360,1716,1589,1541,1487,1375,1303,1220,1136,1058,987,912,856,765.74,686,561cm -1
General procedure for synthesis C-2 substuited indoles
A mixture of indole (0.5 mmol), aryl halide (1 mmol), KOAc (1.5 mmol), catalyst 5
(5mol %) and water (10 vol.) were vigorously stirred at 100 °C for 16h . Progress of reaction was
monitored by TLC which shows consumption of SM and formation of new spot. Reaction
mixture was allowed to come at room temperature; the reaction mixture was diluted with ethyl
acetate (5mL ) and filtered. The liquid phase was washed with water and dried over dry sodium
sulfate and evaporated under reduced pressure left behind crude mass. Obtained crude compound
was purified by flash column chromatography on silica gel (mesh size) using 10% ethyl acetate
in pet ether as eluent gave compound 2a as white solid.
2-p-tolyl-1H-indole[21] (3a)
11

1
Off white solid; Yield: 83%; M.P: 130-134 °C; H NMR (CDCl3, 500MHz ): δ (ppm)
8.30 (br s, 1H), 7.60-7.64 (m, 1H), 7.54-7.58 (m, 2H), 7.39 (dd, J = 8.1, 0.8Hz, 1H), 7.23-7.29
(m, 5H), 7.18 (td, J = 7.6, 1.2Hz, 1H), 7.09-7.13 (m, 1H), 6.78 (dd, J = 2.1, 0.9Hz, 1H), 2.40 (s,
+
4H). LCMS (ESI + ): m/z calcd for C15H13N [M + H] 207.10; found 208.1; FT-IR (KBr) υ:
3438.26, 3231.87, 3200.04, 3110.35, 3047.66, 2915.53, 2856.70, 1581.70, 1495.86, 1346.37
1294.29, 1183.38, 1043.53, 926.84, 824.60, 789.88, 609.53, 508.26cm -1
2-m-tolyl-1H-indole[22] (3b)
1
White solid; Yield: 78%; M.P: 137-141 °C; H NMR (CDCl3, 400MHz ): δ (ppm) 8.33
(br s, 1H), 7.63 (d, J = 7.8Hz, 1H), 7.43-7.51 (m, 3H), 7.40 (d, J = 7.8Hz, 1H), 7.34 (t, J =
7.6Hz, 1H), 7.09-7.22 (m, 4H), 6.82 (d, J = 2.2Hz, 1H), 2.43 (s, 4H). LCMS (ESI + ): m/z calcd
+
for C15H13N [M + H] 207.10; found 208.10; FT-IR (KBr) υ: 3421.87, 1610.63, 1540.23,
1502.61, 1432.21, 1329.98, 1236.42, 1176.63, 1117.80, 1064.75,1003.99, 932.62, 843.89,
798.56, 748.41, 692.47, 645.22, 591.21, 509.23cm -1
Conclusion
In conclusion, we have designed and developed a new phosphine free tetradentate Pd (0)
catalyst and its application for regioselective C-H activation of 1-substituted 1,2,3-traizole and
1,4-substituted 1,2,3-traizole at C-5 position and regioselective C-2 arylation of indole (-NH
free) with various aryl iodides. The desired products were obtained in satisfactory isolated yields.
Synthetic applications of this tetradentate catalyst are under investigation in our organization.
Acknowledgments
12

The authors thanks to GVKBIO, Hyderabad, for providing the facilities to do research.
Also thank full to GBR and YSN for continuous support.
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14

Table 1. Optimization conditions between 1-phenyl 1,2,3-triazole & 1-iodo-4-nitrobenzene.
Entry
Solvent
Base
Time (h)
Yield (%)a,b
Temp (C)
100
1
2
DMSO
DMSO
1,4-dioxane
1,4-dioxane
NMP
K2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Et3N
24
24
24
24
16
16
16
16
16
16
16
12
12
5
10
100
3
100
---
4
100
Traces
8
5
150
6
H2O
100
<12
Traces
30
7
Toluene
DMF
100
8
100
9
DMF
100
---
10
11
12
13
DMF
NaHCO3
Na2CO3
Cs2CO3
Cs2CO3
100
trace
<4
DMF
100
DMF
100
82
DMF
100
28 c
15

Reaction conditions: 1-phenyl 1,2,3-traizole(1 mmol), 1-iodo-4-nitro benzene(1mmol), catalyst 5(3-5mol %), base(2 eq) and
solvent (2mL ), aisolated yield, bexclusively 3A . c with Catalyst 6.
16

Table 2. Scope of substratesa.
aReaction conditions:1-phenyl 1,2,3-traizole(1 mmol), aryl halide (1mmol), catalyst 5 (3-5mol %), Cs2CO3(2 eq) and DMF
(2mL ), 100 °C, 12-16h, b Isolated yield after column chromatography, c Calayst used as 3mol %, 12h, d catalyst used as 5mol %,
time 16h.
17

Table 3. Optimization of reaction conditions.
Entry
1
Catalyst (mol %)
Pd(OAc)2(5)
Catalyst-5 (10)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5(5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Solvent
DMSO
DMSO
DMSO
DMSO
Toluene
DMSO
DMF
Additives
AgOAc
AgOAc
Oxone
33% H2O2
AgOAc
KOAc
Yield (%)
22
2
66
3
32
4
--
6
21%
7
No reaction
8
AgOAc
AgOAc
AgOAc
PIDA
Traces
10
9
THF
10
11
12
13
14
16
PEG
62
PEG
42
PEG
NaIO4
42
PEG
H2O2
21
PEG
MgO
42
PEG + H2O
KOAc
56
18

17
18
19
20
21
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-5 (5)
Catalyst-6(5)
PEG
H2O
H2O
H2O
H2O
CsOAc
NMO
52
43
68
76
15
AgOAc
KOAc
KOAc
19

Table 4. Scope of direct C-2 Arylation of indoles with various aryl halides.
Entry
1
R1
H
R2
Product
Yield (%)b
83
4-Me
2
3
H
H
3-Me
3-Br
78
66
4
5
6
7
H
H
H
H
4-Cl
4-CF3
H
72
63
76
62
4-F
8
5,6-OMe
4-isopropyl
65
20

9
H
1-napthalene
56
10
11
12
5-Cl
H
4-Me
4-isopropyl
3-Me
75
62
68
5-Cl
aReaction conditions: Indole (0.5mmol), aryl halide (1 mmol), KOAc (1.5 mmol), Catalyst (5mol %), H2O (10 vol), 100°C,16h; b
Isolated yield.
21

Scheme 1.
22