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Transient Directing Group-Assisted Palladium-Catalyzed C4-

Alkynylation of Indoles
Shuqi Guo, Huanfeng Jiang, Shaorong Yang, and Wanqing Wu*
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ABSTRACT: Pd-catalyzed C4-selective alkynylation of indoles

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was established by employing glycine as a transient directing group.

This reaction exhibits high regioselectivity with the tolerance of a
wide scope of functional groups to afford diverse alkynylated
indoles in moderate to good yields. Moreover, the readily accessible
scale-up synthesis and further decorations to achieve multi-
functionalized indoles demonstrate the synthetic potential of this
protocol.

A lkynylindoles constitute one of the most crucial

heterocyclic skeletons, which are widely used in many
pharmaceuticals and materials science.1−5 With the develop-
Scheme 1. C4-Alkynylations of Indoles

ment of transition-metal-catalyzed C−H activation, regiose-

lective C−H alkynylation has been regarded as an efficient and
powerful approach to constructing alkynylindoles.6−9 Because
of the electronically rich nature of the pyrrole, alkynylation at
the C2- and C3-positions of indoles via both direct and
directed C−H activation is well established.10,11 To access the
direct C4-functionalization of indoles, the C2 and C3 positions
are usually exclusively blocked in advance.12,13 Consequently,
the synthesis of C4-alkynylated indoles has drawn great
attention. However, there are few examples of synthesizing
C4-alkynylated indoles, which could be divided into two
categories: (i) Traditionally, the C4-alkynylated indoles are
prepared through Leimgruber-Batcho indole synthesis and
later Sonogashira coupling (Scheme 1a).14,15 (ii) By installing
a directing group at the C3 position and utilizing its weak
coordination properties, selective alkynylation at the C4
position can be achieved (Scheme 1b).16−19 Despite the
progress in this field, the precursors need to be carefully
prepared, or the appropriate directing group must be
preinstalled at position C3 for subsequent alkylation. There-
fore, the quest for novel and convenient methods to selectively strategy has been rarely used for the alkynylation of heteroaryl
introduce alkynyl groups at the C4 position of indoles remains rings.31
both intriguing and challenging. Therefore, we envisioned that using a TDG strategy to
Haloalkynes are readily available and highly versatile generate a stable [5,6]-bicyclic palladium intermediate would
structural motifs, which are also admirable alkynylation afford C4-selective alkynylation (Scheme 1).32−34 Based on
reagents.20−24 Recently, we developed palladium-catalyzed
alkynylation of indoles with haloalkynes at C2 and C7 sites,
using di-tert-butylphosphinoyl and primary amine as the Received: October 5, 2024
directing groups, respectively.25,26 In the past few years, the Revised: December 26, 2024
newly emerged transient directing group (TDG) strategy has Accepted: January 3, 2025
witnessed significant advances.27,28 By the judicious choice of a Published: January 10, 2025
transient directing group, selective alkylation of the benzene
ring has been developed recently.29,30 Nevertheless, this

© 2025 American Chemical Society https://doi.org/10.1021/acs.joc.4c02478

1455 J. Org. Chem. 2025, 90, 1455−1459
The Journal of Organic Chemistry pubs.acs.org/joc Note

our continuous interest in haloalkyne chemistry, herein, we With the optimized reaction conditions in hand, a systematic
report directing-group-assisted C4-selective alkynylation of investigation of the substrate scope was implemented (Table
indoles. In this chemistry, glycine was used as the TDG ligand, 2). We initiated our study by screening a variety of N-tosyl 3-
and high regioselectivity was achieved. Additionally, the
remaining aldehyde group allows for further modification Table 2. Substrate Scope of Indoles and Benzoheterocyclesa
and diversification.
We commenced our studies by selecting 1-tosyl-1H-indole-
3-carbaldehyde (1a) as the model substrate and TIPS-
protected bromoacetylene (2a) as the coupling partner. The
reaction was initially performed in the presence of Pd(OAc)2
(10 mol %), AgOAc (0.5 equiv), Gly (2.0 equiv), and AcOH/
H2O (v/v = 10/1, 1 mL) at 100 °C for 12 h. First, a series of
catalysts were tested, and Pd(OAc)2 showed the best catalytic
effect, giving a 28% yield of 3a (Table 1, entries 1−5).

Table 1. Optimization of Reaction Conditionsa

Entry Catalyst Additive Solvent Yield (%)b

1 PdCl2 AgOAc AcOH/H2O (10/1) 16
2 Pd(dppp)Cl2 AgOAc AcOH/H2O (10/1) n.d.
3 Pd(PhCy3)2 AgOAc AcOH/H2O (10/1) 18
4 Pd(dba)2 AgOAc AcOH/H2O (10/1) 20
5 Pd(OAc)2 AgOAc AcOH/H2O (10/1) 28
6 Pd(OAc)2 Ag2CO3 AcOH/H2O (10/1) n.d.
a
7 Pd(OAc)2 AgNO3 AcOH/H2O (10/1) n.d. Yields referred to isolated yields. Reaction was carried out with 1
8 Pd(OAc)2 Ag2O AcOH/H2O (10/1) trace (0.1 mmol), 2a (0.3 mmol), Pd(OAc)2 (10 mol %), AgOAc (0.5
9 Pd(OAc)2 AgTFA AcOH/H2O (10/1) 14 equiv), Gly (2 equiv), and 18-crown-6 (1.5 equiv) in HFIP (1 mL) 90
10 Pd(OAc)2 AgOAc DCE n.r. °C for 12 h. n.d. = not detected.
11 Pd(OAc)2 AgOAc isopropyl alcohol n.r.
12 Pd(OAc)2 AgOAc dioxane n.r. formyl indoles bearing electron-donating and electron-with-
13 Pd(OAc)2 AgOAc HFIP 46 drawing substituents. First, 3-formyl indoles comprising the
14c Pd(OAc)2 AgOAc HFIP 60 electron-rich groups (−Me, −MeO, and −BnO) at the C6-
15d Pd(OAc)2 AgOAc HFIP 82 (75e) position were transformed into the corresponding products
a
Reaction was carried out with 1a (0.1 mmol), 2a (0.3 mmol), Pd 3b−3d in moderate to good yields. Introducing a weakly
catalyst (10 mol %), additive (0.5 equiv), TDG (2 equiv) in solvent electron-withdrawing group such as MeCOO−, −CF3, and
(1 mL) 100 °C for 12 h. Gly = glycine. HFIP = 1,1,1,3,3,3-hexafluoro-
2-propanol. bDetermined by 1H NMR using CH2Br2 as the internal
halogen at C6-site was feasible, albeit with a lower yield (3e
standard. c90 °C. d18-crown-6 (1.5 equiv). eIsolated yield. n.d. = not and 3g−3j). It is noteworthy to mention that C5-substitutional
detected. n.r. = no reaction. substrates that had a bulkier steric hindrance to C4-
functionalization were also found to be effective in giving the
expected products 3k and 3l. However, the reaction did not
occur when the substrate contained a cyano group at the C5-
Additionally, an extensive TDG survey revealed that product position (3m), possibly due to the poor solubility.
3a could be obtained with the best result when glycine was Gratifyingly, 7-methyl-1-tosyl-1H-indole-3-carbaldehyde
used (Table S3). The examination of various additives could transform to 3n in a slightly increased yield. Moreover,
suggested that AgOAc was the optimal choice (Table 1, the substrates with substituents at the C2-site, such as phenyl
entries 5−9). It was found that the solvent played a crucial role
and ester groups, were also tested, giving 3p and 3q in 50 and
in this reaction, and HFIP was demonstrated to be the best
solvent, increasing the yield of 3a from 28% to 60% (Table 1, 41% yields, respectively. This reaction also allowed for the
entries 10−13). Furthermore, the temperature screening selective alkynylation of benzofuran-3-carbaldehyde and
revealed that 90 °C turned out to be the most suitable benzo[b]sthiophene-3-carbaldehyde to afford the desired
temperature for this transformation. Delightfully, with the products 3r and 3s.
addition of 1.5 equiv of 18-crown-6, the yield of 3a increased Next, N-protected 3-formylindoles were investigated (Table
to 82%. Finally, the optimal reaction conditions were as 3). The substrates with arylsulfonyl protecting groups such as
follows: 1a (0.1 mmol), 2 (0.3 mmol), Pd(OAc)2 (10 mol %), naphthylsulfonyl and 4-chlorophenylsulfonyl delivered the
Gly (2 equiv), AgOAc (0.5 equiv), and 18-crown-6 (1.5 equiv) desired products 3t and 3u in 76 and 72% yields, respectively.
in HFIP (1.0 mL) at 90 °C for 12 h (entry 16). N-Alkylsulfonyl-protected indoles converted to the corre-
1456 https://doi.org/10.1021/acs.joc.4c02478
J. Org. Chem. 2025, 90, 1455−1459
The Journal of Organic Chemistry pubs.acs.org/joc Note

Table 3. Substrate Scope of N-Protected 3-Formyl Indolesa Scheme 2. Gram-Scale Synthesis and Functionalization

mmol scale with an isolated yield of 72%. Additionally, tosyl

a
Yields referred to isolated yields. Reaction was carried out with 1 could be easily removed under the treatment of KOH in
(0.1 mmol), 2a (0.3 mmol), Pd(OAc)2 (10 mol %), AgOAc (0.5 EtOH/H2O. The carbaldehyde group of product 3a could be
equiv), Gly (2 equiv), and 18-crown-6 (1.5 equiv) in HFIP (1 mL) 90 further transformed into alkenyl and oxazole via a Wittig
°C for 12 h. n.d. = not detected. reaction32,33 and Van Leusen oxazole synthesis.35 In addition,
reduction36 of the carbonyl group of 3a was carried out with
sponding products 3v and 3w in good yields. However, N- NaBH4 to give the corresponding alcohol product 3ag. The
alkyl-protected indoles converted into 3x−3aa in lower yields. retention and transformation of aldehyde groups demonstrate
A range of haloalkynes was also investigated (Table 4). No the potential applications of this method in synthetic and
reaction occurred with (bromoethynyl)triethylsilane as the pharmaceutical chemistry.
Several control experiments were then carried out to shed
Table 4. Substrate Scope of Haloalkynesa light on the reaction mechanism (Scheme 3). First, when this
C4-alkynylation was respectively carried out in the presence of
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) or BHT (2,6-
di-tert-butyl-p-cresol), the yields of 3a were not affected

Scheme 3. Plausible Reaction Mechanism

Entry R X Yield (%)b

1 TES Br n.r.
2 OTBS Br 3ab, 22
3 TIPS Br 3a, 75
4 TIPS Cl 3a, 80
5 TIPS I 3a, trace
a
Reaction was carried out with 1a (0.1 mmol), 2 (0.3 mmol),
Pd(OAc)2 (10 mol %), AgOAc (0.5 equiv), Gly (2 equiv), and 18-
crown-6 (1.5 equiv) in HFIP (1 mL) 90 °C for 12 h. bIsolated yields
were given. TES = triethylsilyl, OTBS = tert-butyldimethylsilyl. n.r. =
no reaction.

substrate (entry 1). Pleasingly, the desired product could be

obtained when using OTBS-substituted haloalkyne as the
alkynylation reagent (entry 2). Among all of the TIPS-
protected haloalkynes, (chloroethynyl)triisopropylsilane was
demonstrated as the most effective coupling partner, furnishing
3a in 80% isolated yield, while (iodoethynyl)triisopropylsilane
almost hardly involved alkylation of indole (entries 4 and 5).
To highlight the efficiency and practicality of this reaction
(Scheme 2), product 3a could be readily prepared at the 3
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J. Org. Chem. 2025, 90, 1455−1459
The Journal of Organic Chemistry pubs.acs.org/joc Note

obviously, indicating that a radical pathway should not be

involved in this process (Scheme 3a). The H/D exchange
■ ASSOCIATED CONTENT
Data Availability Statement
experiment was also conducted, which suggested that the initial The data underlying this study are available in the published
C−H cleavage was irreversible (Scheme 3b). Then, a parallel article and its Supporting Information.
KIE of kH/kD = 2.12 revealed that C4−H bond cleavage of
substrate 1a plausibly was not the rate-determining step in this
*
sı Supporting Information

alkynylation reaction (Scheme 3c). In addition, the substrate The Supporting Information is available free of charge at
with an acetyl at the C3-position of indole could also be https://pubs.acs.org/doi/10.1021/acs.joc.4c02478.
transformed to the alkylated product 3ah in 28% yield Optimization table; mechanistic investigation; synthetic
(Scheme 3d). This demonstrated that the carbonyl group procedures; NMR spectra for all new compounds; and
reacted with glycine to form an imine intermediate, followed crystallographic data for 3a (PDF)
by TDG-directed C4−H activation. Accession Codes
Based on mechanistic studies and literature precedent,37−40 Deposition Number 2376664 contains the supplementary
a plausible mechanism for C4-alkynylation is outlined in crystallographic data for this paper. These data can be obtained
Scheme 4. First, 3-formylindole reacts with glycine, leading to free of charge via the joint Cambridge Crystallographic Data
Centre (CCDC) and Fachinformationszentrum Karlsruhe
Scheme 4. Mechanistic Studies Access Structures service.

■ AUTHOR INFORMATION
Corresponding Author
Wanqing Wu − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, China; orcid.org/0000-0001-5151-
7788; Email: [email protected]
Authors
Shuqi Guo − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of
Technology, Guangzhou 510640, China
Huanfeng Jiang − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of
Technology, Guangzhou 510640, China; orcid.org/
0000-0002-4355-0294
Shaorong Yang − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of
Technology, Guangzhou 510640, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.4c02478
imine intermediate A with liberation of H2O. Subsequently,
Notes
the imine and carboxyl group could coordinate with the Pd
The authors declare no competing financial interest.
catalyst to generate B. Subsequently, preferential formation of
[5,6]-bicyclic palladium intermediate B occurs via regioselec-
tive C4−H activation of indoles over the undesired C2−H
activation, which would involve [5,5]-bicyclic palladium. The
■ ACKNOWLEDGMENTS
The authors thank the National Youth Talent Support
succeeding oxidative addition of a haloalkyne to intermediate Program, Guangdong Basic and Applied Basic Research
C generates Pd(IV) species D. Then, the reductive elimination Foundation (2021B1515020058 and 2024B1515040027),
of D regenerates the active Pd(II) catalyst and the imine F. and Guangzhou Science and Technology Projects
Finally, imine F is hydrolyzed to generate the C4-alkylated (2024A04J6248) for financial support.
indole and releases Gly.
In conclusion, we have developed a Pd-catalyzed C4-
selective alkynylation between indoles and haloalkynes via a
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