Direct C?H Arylation of Indole-3-Acetic Acid Derivatives Enabled by an Autonomous Self-Optimizing Flow Reactor

Article abstract of DOI:10.1002/adsc.202001217

Described herein is a continuous-flow strategy for the palladium-catalyzed direct C?H arylation of indole-3-acetic acid derivatives with arenediazonium salts. A fully autonomous self-optimizing flow platform was used to efficiently optimize the coupling reaction in a three-dimensional space. The flow methodology developed is experimentally simple, mild, broad in scope, and safer than traditional batch approaches. Our continuous-flow approach is particularly convenient to prepare precursors of pharmaceutically relevant compounds. (Figure presented.).

Full text of DOI:10.1002/adsc.202001217

Title: Direct C-H arylation of indole-3-acetic acid derivatives enabled by
an autonomous self-optimizing flow reactor
Authors: N Vasudevan, Eric Wimmer, Elvina Barré, Daniel Cortés-
Borda, Mireia Rodriguez-Zubiri, and François-Xavier Felpin
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001217
Link to VoR: https://doi.org/10.1002/adsc.202001217

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Direct C-H Arylation of Indole-3-acetic Acid Derivatives
Enabled by an Autonomous Self-Optimizing Flow Reactor
N. Vasudevan,a Eric Wimmer,a Elvina Barré,a Daniel Cortés-Borda,a Mireia Rodriguez-
Zubiri,a and François-Xavier Felpina,*
a
Université de Nantes, CNRS, CEISAM UMR 6230, 2 rue de la Houssinière, 44322 Nantes, France
E-Mail: fx.felpin@univ-nantes.fr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Described herein is a continuous-flow strategy for
the palladium-catalyzed direct C-H arylation of indole-3-
acetic acid derivatives with arenediazonium salts. A fully
autonomous self-optimizing flow platform was used to
efficiently optimize the coupling reaction in a three-
dimensional space. The flow methodology developed is
experimentally simple, mild, broad in scope, and safer than
traditional batch approaches. Our continuous-flow approach
is particularly convenient to prepare precursors of
pharmaceutically relevant compounds.
Keywords: Self-optimizing flow reactor; Flow chemistry;
Direct C-H arylation; Autonomous synthesis; Indole
pre-functionalize the indole moiety at the C2 position
with either a halogen atom or a metal (Sn or B). A
more step- and atom-efficient approach consists of the
direct C-H arylation of indole acetic acids with aryl
Introduction
The 2-aryl-3-carbonylmethyl indole skeleton is a
ubiquitous moiety in compounds of pharmaceutical
relevance (Figure 1). For instance, paullone 1 and
kenpaullone 2 exhibit potent biological activities as
ATP-competitive inhibitors of cyclin-dependent
kinases (CDKs), glycogen-synthase kinases-3 (GSKs
3) and mitochondrial malate dehydrogenase
(mMDH).[1] FS-554 3 is a potent trypanothione
synthetase inhibitor with promising activity against
parasites.[2] Compound 4 is the most active member of
a large family of farnesyl pyrophosphate-competitive
inhibitors of farnesyl protein transferase.[3] FGIN-1-27
5 is a well-known potent and selective ligand for
mitochondrial diazodiazepine receptors, producing
anxiolytic effects.[4] Because these compounds are
frequently used by biologists as biochemical tools and
references in drug discovery, they are occasionally
commercially available from specialized sellers but
only on milligram scale and at a very prohibitive cost.
Therefore, the development of methodologies
allowing a straightforward and efficient access to 2-
aryl-3-carbonylmethyl indole derivatives is of huge
interest for biologists and medicinal chemists.
halides
using
palladium-catalyzed
coupling
reactions.[7] While generally high yielding, this batch
approach suffers from extensive reaction times and
high temperatures. Our long standing experience in
diazonium chemistry associated with pioneering
works from Correia,[8] Noël,[9] and Fairlamb[10]
describing the arylations of indoles with
arenediazonium salts in batch, prompted us to propose
our own flow-based strategy. Indeed, with the
objective of developing an efficient arylation strategy
of indole acetic acid derivatives, we acknowledged
that the use of arenediazonium salts as highly reactive
aryl halides surrogates would allow mild experimental
conditions and fast reaction rates. However,
considering the high reactivity and hazardous behavior
of arenediazonium salts, we envisioned the
development of a flow-based strategy to mitigate the
safety concerns. In this contribution, we describe our
efforts toward the development of an efficient, safe
and operationally simple palladium-catalyzed direct
C-H arylation strategy of indole acetic acid derivatives,
assisted by an autonomous self-optimizing flow
reactor. The methodology shows a broad substrate
scope and is applied to the preparation of a key
intermediate of farnesyl pyrophosphate-competitive
inhibitors of farnesyl protein transferase 4.
The traditional approach to access the 2-arylindole-
3-acetic acid motif involves the arylation of indole
acetic acid derivatives through Suzuki-Miyaura or
Stille cross-coupling reactions.[5, 6] While versatile and
efficient, these strategies suffer from the necessity to
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
Figure 1. Pharmaceutically relevant 2-aryl-3-carbonylmethyl indoles.
Based on our experience in autonomous self-
Results and Discussion
optimizing reactors, we designed an automated two-
stream flow setup integrating an online HPLC unit for
the benchmark arylation of indole 6a with
tolyldiazonium tosylate 7a under palladium catalysis
(Figure 2). Before starting an optimization campaign
with the flow platform, a careful assessment of the
solubility profile of all known chemicals involved in
the reaction is an important pre-requisite as any
precipitate formed during the process would inevitably
clog the flow reactor. This is particularly true when
using arenediazonium tosylates which are poorly
soluble in many organic solvents and generate
inorganic salts. Arenediazonium tosylates are often
ideally handled in MeOH or EtOH in which they are
generally well soluble and stable over hours.[38] By
contrast, Pd(OAc)2 is rapidly reduced by MeOH and
EtOH into Pd nanoparticles which precipitate within
minutes. Considering these features, we used a
solution of diazonium 7a in MeOH in the first stream
while in the second stream indole 6a, Pd(OAc)2 and
naphthalene 9 (used as internal standard for HPLC
analysis) were solubilized in DMF. Therefore, a
solution of diazonium salt 7a was continuously
pumped (0.1 M) and meet, in a T-shaped mixer, a
DMF solution of indole 6a (0.1 M), Pd(OAc)2 (5 × 10-
3 M) and naphthalene 9 (0.1 M). The reaction occurred
in a stainless steel reactor coil (0.75 mm i.d., 10 mL)
placed in an oven. The outlet of the reactor was
connected to an automatic 2-way 6-port switch valve
which injected an aliquot of the crude mixture into the
HPLC line. An automated data processing allowed to
integrate the chromatogram and to calculate the
reaction yield. The value was automatically sent to the
algorithm which proposed a new set of experimental
conditions and the process control software modified
the variables accordingly. The machine autonomously
continues this iterative process until it reaches an
optimum. The reaction yield was optimized in a 3-
dimensional space where three variables, i.e.,
equivalent of 7a, residence time and temperature, were
considered in the range of 1-2 equiv, 15-90 min, and
25-60 °C, respectively. The temperature was limited to
60 °C to preserve the diazonium salt integrity. The
initial experiment X0 was fixed at 1 equiv of 7a, 15 min
of residence time and 25 °C with d value of 0.2 equiv,
15 min and 7 °C, respectively.
The arylation of indole 6 with tolyldiazonium tosylate
7a, in the presence of Pd(OAc)2 as catalyst, was
selected as benchmark transformation to be optimized
for the development of a continuous flow strategy
(Scheme 1).
Scheme 1. Benchmark reaction for the direct C-H arylation
of
2-arylindole-3-acetic
acid
derivatives
with
arenediazonium salts in flow.
As our objective was to develop a simple, robust
and environmentally acceptable methodology, we
excluded the use of additives such as ligand, base,
oxidant and stabilizing agent (ammonium salt).
Traditionally, the optimizations of chemical
transformations conducted either in batch or in flow,
are mainly based on the (often biased) know-how of
chemists through one-variable-at-a-time optimizations.
Whilst this popular optimization method is easily set
up, it is generally poorly efficient for multi-
dimensional optimizations as it neglects interactions
between variables. The use of design-of-experiment
(DoE) methods partially addresses these drawbacks,
but the high number of experiments required to locate
a satisfactory optimum associated to the absence of
feedback are strong handicaps to develop efficient
automations. The development and optimization of
continuous flow processes can be greatly speeded-up
with the use of autonomous self-optimizing flow
[11-26]
reactors.
These powerful automated devices
combine flow reactors with process control
instrumentations, in-line/online analyses and
optimization algorithms to assist the decision-making
process of chemists.[27-34] Our lab also recently
contributed to this emerging field of research with the
development of a reconfigurable flow platform for the
screening of reagents and the autonomous
optimization of chemical transformations including
natural product synthesis.[35-37]
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
Figure 2. Autonomous self-optimizing flow reactor for the optimization of 8a. The red dashed lines indicate the units
controlled by the computer via MATLAB.
The optimization progressed rapidly until reaching a
maximum reaction yield of 62% after 17 experiments
at 1.2 equiv of 7a, 65 min of residence time and 48 °C
(Figure 3a, blue curve). The algorithm reached a
stopping criteria in experiment 20 after 5 consecutive
simplexes without improvement (see Table S1 in
Supporting Information for details on experimental
conditions). A close examination of the crude mixture
showed the presence of a significant amount of toluene
which likely arose from a rapid proto-dediazotization
of 7a. We suspected that this unwanted behavior was,
at least partially, favored in DMF which has been
reported to promote proto-dediazotization of
arenediazonium salts.[39] We, therefore, reconsidered
the selection of solvents and reasoned that the volume
of DMF, which is required to solubilize Pd species,
should be significantly reduced through the use of a
co-solvent. After having evaluated various
combinations of DMF/co-solvent in different ratios,
we selected a mixture of DMF/EtOAc in a 1/4 ratio.
This choice was justified by the fact that
tolyldiazonium tosylate 7a is stable in EtOAc (no
degradation observed after 30 min at room
temperature) which is, in turn, considered as a
sustainable solvent. The DMF/EtOAc ratio (1/4,
respectively) was adjusted in order to reduce the
volume of DMF to a minimum while keeping a clear
solution with a complete dissolution of Pd species. We
re-started the optimization process with this new
solvent system while conserving the same search space
and starting parameters. A spectacular effect was
observed on the initial simplex since the reaction
yields, ranging from 5 to 14% in MeOH/DMF,
increased from 19 to 41% in MeOH/DMF/EtOAc
(Figure 3b, red curve).
Figure 3. (a) Maximization of the yield of indole 8a. The
blue curve corresponds to the MeOH/DMF solvent system
while the red curve corresponds to the MeOH/DMF/EtOAc
solvent system. (b) Representation of the three-dimensional
experimental conditions for the maximization of the yield
for indole 8a in the MeOH/DMF/EtOAc solvent system.
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
After the initial simplex, the algorithm smoothly
salts and indoles, using the continuous flow setup
depicted in Figure 4. The first stream, equipped with a
5 mL injection loop 1 and loaded with a solution of
arenediazonium salts in MeOH (0.1 M, 82 µL/min),
progressed by increasing the value of all variables until
reaching an optimum in the 15th experiment at 44 °C,
74 min of residence time and 1.6 equivalents of 7a,
corresponding to 90% HPLC yield (88% isolated yield, met in a T-shaped piece a second stream equipped with
see Figure S1 in supporting information for the HPLC
chromatogram). The algorithm was unable to improve
the reaction yield in the subsequent 5 simplexes and,
a 2 mL injection loop 2 and loaded with a solution of
indole (0.1 M) and Pd(OAc)2 (5 × 10-3 M) in
DMF/EtOAc (1/4, 51 µL/min). The merged streams
(133 µL/min) entered in a stainless steel reactor coil
(0.75 mm id, 10 mL, 74 min residence time) heated at
44 °C, and the resulting 2-arylindole-3-acetic acid
derivatives 8a-8q were collected in vials.
therefore, reached
a
stopping criterion after
experiment 28 (see Table S2 in Supporting
Information for details on experimental conditions).
With the optimized conditions in hand, the reaction
scope was examined with various arenediazonium
Figure 4. Scope of the C2-arylation of indole-3-acetic acid derivatives. The yields are averages of two runs.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
The arylation of indole-3-acetic acid alkyl esters
transformations, we applied our process to the
synthesis of Methyl 2-(2-phenyl-1-methyl-1H-indol-
3-yl)acetate 8r which was isolated with 81% yield
(Scheme 2). Continuous use of the flow platform over
a period of 10 hours allowed the isolation of ca. 0.5 g
of indole 8r (79%), showing the facile scalability of
our methodology in flow. Indole 8r is a key
intermediate in the synthesis of farnesyl
pyrophosphate-competitive inhibitor of farnesyl
protein transferase 4.[3]
was explored with a broad set of arenediazonium salts.
While the optimization was conducted with indole-3-
acetic acid ethyl ester 6a, the reaction scope was
extended to the methyl ester derivative 6b-f to avoid
any unwanted transesterification process with MeOH.
The arylation of indoles 6a-b was found to be
compatible with arenediazonium salts bearing alkyl
substituents at either para- or ortho-positions (8a-e).
The excellent yield obtained for the ortho, ortho’-
substituted indole 8c suggests that the transformation
was poorly sensitive to steric hindrance. Switching an
alkyl group for an aryl substituent on the diazonium
salt, did not significantly affect the reaction outcome
(compounds 8g). One of the salient advantages of
using arenediazonium salts as super-electrophile is the
possibility to introduce very electron-rich substituents
such as methoxy groups which usually significantly
deactivate aryl halides and compromise the C-H
arylation efficiency. Another unique advantage of
arenediazonium salts is the possibility to work without
any base, resulting in a high chemoselectivity at the
diazonium group in the presence of halogen positions
and the compatibility of base-sensitive functional
groups such as esters. For instance the coupling of 4-
chloro- and 4-bromophenyl diazonium tosylates
provided indoles 8h-i with no evidence for a
competing electrophilic reactivity of the halide atoms.
Interestingly, we did not observe any significant
difference in reactivity of 1-methylindole 6c and N-
Boc indole 6d which behaved similarly than free NH-
indoles (see 8l-n versus 8d, 8k and 8b, respectively).
Decorating the indole skeleton with substituents (OMe
and Br) significantly extended the reaction scope of
the process (8o-q). Despite the lower yields observed
with bromo-indoles, no evidence for a competing
electrophilic reactivity of the bromine atom was
observed and the drop in reactivity was instead
attributed to a lower solubility of the starting indole 6e.
The inertness of halogen atoms in the reaction
Conclusion
In summary, we developed a mild, base-free, ligand-
free and safe continuous-flow protocol for the
palladium-catalyzed direct C-H arylation of indole-3-
acetic acid derivatives with arenediazonium salts.
Highlights of this work include (i) the development of
a fully autonomous self-optimizing flow platform, (ii)
the use of arenediazonium salts as super-electrophiles,
and (iii) the synthesis of a key intermediate in the
synthesis of a farnesyl pyrophosphate-competitive
inhibitor of farnesyl protein transferase. The capability
of our autonomous self-optimizing flow platform to
simultaneously screen several continuous variables
without a priori knowledge of the optimal objective
function is an indisputable attractive feature to
optimize chemical transformations in a short time
frame and reliable experimental conditions. While
arenediazonium salts are often considered as
hazardous reagents, our continuous-flow approach
mitigates the risk associated with these attractive
electrophiles which allow high reaction rates and mild
experimental conditions. We believe that this work is
a representative contribution in the area of machine-
assisted chemistry which should become the standard
of chemical laboratories 4.0.
conditions
might
allow
further
chemical
Experimental Section
functionalizations through standard transition-metal
catalyzed reactions.
General Information. All commercially available
chemicals were used as received unless otherwise noted.
High-field 1H and 13C NMR spectra were recorded at 300 or
1
400 and 75 or 100 MHz, respectively. H and 13C NMR
spectra were referenced to the residual signal of the internal
deuterated solvent (CDCl3) at 7.26 and 77.16 ppm,
respectively, and coupling constants were measured in
Hertz. The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad. FT-IR spectra were recorded in
the ATR mode. Wavelengths of maximum absorbance
(νmax) are quoted in wave numbers (cm−1). High resolution
mass spectrometry (HRMS) was recorded on a microTOF
spectrometer equipped with orthogonal electrospray
interface (ESI). Reactions were monitored by thin layer
chromatography (TLC) with pre-coated silica gel plates (60
F254), and visualization was accomplished with either a UV
lamp at 254 nm or by immersion in ethanolic solution of
Scheme 2. Synthesis of the key intermediate 8r of
FPTase inhibitor 4.
phosphomolybdic
acid
(PMA).
Flash
column
chromatography was performed using silica gel 60 (40−63
μm). To remove any traces of waste (Pd particles, inorganic
salts, etc.) which progressively deposits on the wall of the
reactor coil, the tubing was washed every 100 hours of use
with an aqueous solution of nitric acid (1 M, 50 mL)
followed by a thorough washing with water (100 mL) and
CH3CN (100 mL).
To further confirm the efficiency of the
methodology developed herein and, if this should
prove necessary, highlight the importance of such
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
Details of the experimental setup of the self-
129.1, 128.1, 122.3, 119.9, 119.2, 115.0, 110.8, 105.3, 60.8,
31.2, 21.3, 14.2. HRMS (ESI) m/z [M + H]+ Calcd for
C19H20O2N 294.1494; Found 294.1493.
optimizing reactor. HPLC pumps (JASCO PU2080 and
JASCO PU4185) equipped with a RS-232 port were
employed to flow the solution through the system. The
reactor coil was heated with a heating plate (Heidolph, MR
Hei-Connect) equipped with a RS-232 port. A 2-way 6-port
valve (VICI, Cheminert C2-3006D) equipped with a RS-
232 port was used to inject an aliquot of the crude mixture
within the on-line HPLC unit. The HPLC column (Agela
Promosil C18, 3.5 mm × 150mm, 5 µm) outlet was
connected to a UV detector (JASCO, UV 2075) equipped
with a RS-232 port. The flow outlet was connected to a
programmable fraction collector (Advantec, CHF 1225C).
All units equipped with a RS-232 port were autonomously
controlled with MATLAB® through the use of
communication protocols provided by the manufacturers.
Experimental procedure of the self-optimization for
compound 8a. The experimental setup consisted of two
streams as depicted in Figure 2. The first stream contained
a solution of tolyldiazonium tosylate 7a (0.1 M) in MeOH
while the second stream contained a solution of indole 6a
(0.1 M), Pd(OAc)2 (5 × 10-3 M) and naphthalene 9 (0.1 M)
as the internal standard in DMF. Each solution was
continuously pumped with two independent pumps at the
required flow rate, and met in a stainless steel T-shaped
piece (internal volume: 0.57 μL). The resulting mixture was
introduced in a PEEK reactor coil (10 mL, 0.75 mm i.d.)
heated at the desired temperature. The reactor outlet was
connected to an automatic 2-way 6-port switch valve which
injected 0.2 µL of the crude mixture in the HPLC unit while
the remaining stream was collected in a fraction collector. A
mixture of MeOH/H2O (60/40, v/v) was used as mobile
phase for the HPLC analysis at a flow rate of 0.4 mL/min.
A UV detector was connected to the outlet of the HPLC
column (Agela Promosil C18, 3.5 mm × 150 mm, 5 µm) to
follow the absorbance at a wavelength of 254 nm. Peak
integration and yield calculation were under full MATLAB
automation. The calculated yield was automatically sent to
the algorithm which set new experimental conditions to the
units via RS-232 ports. A 3-D optimization of the reaction
yield was conducted using the temperature, residence time
and stoichiometry as the variables. The initial experiment of
the simplex was: 25 °C, 15 min and 1 equivalent of
diazonium salt 7a. The d values were 7 °C, 15 min and 0.2
equivalent. The lower and upper boundaries of the research
space were the following: 25-70 °C, 10-90 min and 1-2
equiv for the temperature, residence time and stoichiometry,
respectively. The details of the 28 experiments carried out
with the autonomous flow reactor are given in supporting
information (Table S2). An optimum giving 90% HPLC
yield was found in experiment 15 at 44 °C, 74 min of
residence time and 1.60 equiv. of diazonium salt 7a. An
analytical sample of ethyl 2-(2-(p-tolyl)-1H-indol-3-yl)
acetate 8a was obtained by flash chromatography (10%
AcOEt-petroleum ether) as a white solid (51.6 mg, 88%).
General experimental setup for the synthesis of
indoles 8b-r. The experimental setup consisted of two
streams as depicted in Figure 4. The first stream (flow rate:
82 µL/min), equipped with a PEEK injection loop (5 mL)
loaded with a solution of arenediazonium tolylate in MeOH
(0.1 M), meet in a stainless steel T-shaped piece (internal
volume 0.57 μL) a second stream (flow rate: 51 µL/min)
consisting of a solution of indoles (0.1 M) and Pd(OAc)2 (5
× 10-3 M) in DMF/EtOAc (1/4) loaded in a second PEEK
loop (2 mL). The merged streams entered in a PEEK reactor
coil (10 or 15 mL, 0.75 mm id, 44 °C) at a flow rate of 0.133
mL/min and the resulting indoles 8b-r were collected in
vials. Volatiles were removed under reduced pressure and
the crude indoles 8b-r were purified by flash
chromatography on silica gel.
Methyl
2-(2-(p-tolyl)-1H-indol-3-yl)acetate
8b.
Purification by flash chromatography on silica gel (5%
EtOAc-petroleum ether) gave 8b as a colorless oil (48 mg,
1
86%). IR (ATR) ν 3373, 1723, 1456, 740 cm–1. H NMR
(CDCl3, 400 MHz) δ 8.14 (br s, 1H), 7.66 (d, 1H, J = 7.7
Hz), 7.54 (d, 2H, J = 8.1 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.30
(d, 2H, J = 8.2 Hz), 7.22 (dt, 1H, J = 1.1, 7.1 Hz), 7.17 (dt,
1H, J = 0.9, 7.0 Hz), 3.85 (s, 2H), 3.72 (s, 3H), 2.43 (s, 3H).
13C NMR (CDCl3, 100 MHz) δ 172.7, 138.0, 136.3, 135.6,
129.6, 129.5, 129.1, 128.1, 122.4, 120.0, 119.1, 110.8, 105.2,
52.0, 30.9, 21.3. HRMS (ESI) m/z [M + H]+ Calcd for
C18H18O2N 280.1338; Found 280.1336.
Methyl
2-(2-(o-tolyl)-1H-indol-3-yl)acetate
8c.
Purification by flash chromatography on silica gel (5%
EtOAc-petroleum ether) gave 8c as a white solid (44.1 mg,
79%). mp 98 °C [Lit.[40] 102 °C]. IR (ATR) ν 3362, 1719,
1
1167, 694 cm–1. H NMR (CDCl3, 300 MHz) δ 8.03 (br s,
1H), 7.66 (dd, 1H, J = 0.9, 8.0 Hz), 7.42 - 7.28 (m, 5H), 7.24
(dt, 1H, J = 1.4, 7.0 Hz), 7.18 (dt, 1H, J = 1.2, 7.1 Hz), 3.65
(s, 2H), 3.63 (s, 3H), 2.27 (s, 3H). 13C NMR (CDCl3, 75
MHz) δ 172.4, 137.8, 136.0, 135.5, 131.6, 131.1, 130.3,
128.8, 128.1, 125.7, 122.2, 119.8, 119.0, 110.8, 106.3, 51.8,
30.6, 19.9. HRMS (ESI) m/z [M + H]+ Calcd for C18H18O2N
280.1338; Found 280.1341.
Methyl
2-(2-(4-isopropylphenyl)-1H-indol-3-
yl)acetate 8d. Purification by flash chromatography on
silica gel (5% EtOAc-petroleum ether) gave 8d as a white
solid (54.6 mg, 89%). mp 124 °C. IR (ATR) ν 3309, 1703,
1343, 738 cm–1. 1H NMR (CDCl3, 300 MHz) δ 8.10 (br s,
1H), 7.66 (dt, 1H, J = 0.6, 7.7 Hz), 7.58 (dt, 2H, J = 2.0, 8.3
Hz), 7.40-7.34 (m, 3H), 7.22 (dt, 1H, J = 1.4, 7.1 Hz), 7.16
(dt, 1H, J = 1.2, 7.1 Hz), 3.85 (s, 2H), 3.72 (s, 3H), 2.98
(sept, 1H, J = 6.9 Hz), 1.30 (d, 6H, J = 6.9 Hz). 13C NMR
(CDCl3, 75 MHz) δ 172.8, 148.9, 136.3, 135.6, 129.8, 129.0,
128.2, 127.0, 122.4, 120.0, 119.1, 110.8, 105.1, 52.0, 33.9,
31.0, 23.9. HRMS (ESI) m/z [M + H]+ Calcd for C21H24O2N
308.1651; Found 308.1663.
1
mp 97 °C. IR (ATR) ν 3346, 1719, 764 cm-1. H NMR
Methyl
2-(2-(4-(tert-butyl)phenyl)-1H-indol-3-
(CDCl3, 300 MHz) δ 8.10 (brs, 1H), 7.67 (dd, 1H, J = 0.7,
7.6 Hz), 7.56 (d, 2H, J = 8.1 Hz), 7.37 (dm, 1H, J = 6.4 Hz),
7.32 (d, 2H, J = 7.8 Hz), 7.22 (dt, 1H, J = 1.3, 7.1 Hz), 7.15
(dt, 1H, J = 1.2, 7.1 Hz), 4.18 (q, 2H, J = 7.2 Hz), 3.82 (s,
2H), 2.42 (s, 3H), 1.26 (t, 3H, J = 7.1 Hz). 13C NMR (CDCl3,
75 MHz,) δ 172.3, 137.9, 136.3, 135.6, 130.0, 129.6, 129.5,
yl)acetate 8e. Purification by flash chromatography on
silica gel (5% EtOAc-petroleum ether) gave 8e as a white
solid (54.6 mg, 85%). mp 138 °C. IR (ATR) ν 3316,1704,
1008, 700 cm–1. 1H NMR (CDCl3, 300 MHz) δ 8.15 (br s,
1H), 7.67 (dm, 1H, J = 7.6 Hz), 7.59 (app dt, 2H, J = 1.6,
8.1 Hz), 7.52 (app dt, 2H, J = 2.1, 8.7 Hz), 7.37 (dm, 1H, J
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
= 7.6 Hz), 7.23 (dt, 1H, J = 1.4, 7.1 Hz), 7.17 (dt, 1H, J =
1.2, 7.1 Hz), 3.87 (s, 2H), 3.73 (s, 3H), 1.39 (s, 9H). 13C
NMR (CDCl3, 75 MHz) δ 172.7, 151.1, 136.2, 135.6, 129.4,
129.1, 127.9, 125.9, 122.4, 120.0, 119.2, 110.8, 105.2, 52.0,
34.7, 31.3, 31.0. HRMS (ESI) m/z [M + H]+ Calcd for
C21H24O2N 322.1807; Found 322.1807.
159.6, 136.2, 135.6, 129.5, 129.0, 124.8, 122.3, 120.0, 119.0,
114.4, 110.7, 104.8, 55.3, 52.0, 30.9. HRMS (ESI) m/z [M
+ H]+ Calcd for C18H18O3N 296.1287; Found 296.1291.
Methyl
2-(2-(3,4-dimethoxyphenyl)-1H-indol-3-
yl)acetate 8k. Purification by flash chromatography on
silica gel (30% EtOAc-petroleum ether) gave 8k as a pale
yellow solid (49.4 mg, 76%). mp 128 °C. IR (ATR) ν 3324,
Methyl
2-(2-phenyl-1H-indol-3-yl)acetate
8f.
1
Purification by flash chromatography on silica gel (5%
EtOAc-petroleum ether) gave 8f as a white solid (44.1 mg,
83%). mp 108 °C [Lit.[40] 106 °C]. IR (ATR) ν 3326, 1703,
1722, 1010, 738 cm–1. H NMR (CDCl3, 300 MHz) δ 8.20
(s, 1H), 7.68 (dm, 1H, J = 7.2 Hz), 7.36 (dd, 1H, J = 1.2, 6.6
Hz), 7.32 (d, 1H, J = 2.1 Hz), 7.24-7.14 (m, 3H), 6.97 (d, 1h,
J = 8.4 Hz), 3.95 (s, 3H), 3.93 (s, 3H), 3.84 (s, 2H), 3.72 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 172.8 149.2, 149.0,
136.3, 135.5, 129.1, 125.1, 122.3, 120.5, 120.0, 119.1, 111.8,
111.5, 110.7, 104.8, 56.0, 55.9, 52.0, 31.0. HRMS (ESI) m/z
[M + H]+ Calcd for C19H20O4N 326.1406; Found 326.1392.
Methyl 2-(2-(4-isopropylphenyl)-1-methyl-1H-indol-
3-yl)acetate 8l. Purification by flash chromatography on
silica gel (5% EtOAc-petroleum ether) gave 8l as a colorless
oil (52.6 mg, 82%). IR (ATR) ν 1733, 1506, 1148, 739 cm–
1
1274, 740 cm–1. H NMR (CDCl3, 300 MHz) δ 8.18 (br s,
1H), 7.70-7.63 (m, 3H), 7.52-7.47 (m, 2H), 7.43-7.36 (m,
2H), 7.24-7.15 (m, 2H), 3.87 (s, 2H), 3.73 (s, 3H). 13C NMR
(CDCl3, 75 MHz) δ 172.7, 136.2, 135.7, 132.3, 129.0, 128.9,
128.2, 128.1, 122.6, 120.1, 119.2, 110.9, 105.5, 52.0, 30.9.
HRMS (ESI) m/z [M + H]+ Calcd for C17H16O2N 266.1181;
Found 266.1185.
Methyl
2-(2-([1,1'-biphenyl]-4-yl)-1H-indol-3-
yl)acetate 8g. Purification by flash chromatography on
silica gel (5% EtOAc-petroleum ether) gave 8g as a white
solid (53.4 mg, 78%). mp 126 °C. IR (ATR) ν 3359, 1723,
1168, 733 cm–1. 1H NMR (CDCl3, 300 MHz) δ 8.22 (s, 1H),
7.72-7.64 (m, 7H), 7.48 (app tm, 2H, J = 7.1 Hz), 7.43-7.36
(m, 2H), 7.25 (dt, 1H, J = 1.4, 7.1 Hz), 7.19 (dt, 1H, J = 1.2,
7.1 Hz), 3.92 (s, 2H), 3.75 (s, 3H). 13C NMR (CDCl3, 75
MHz) δ 172.7, 140.7, 140.4, 135.8, 131.2, 129.1, 128.9,
128.5, 127.6, 127.0, 122.6, 120.1, 119.2, 110.9, 105.7, 52.0,
31.0. HRMS (ESI) m/z [M + H]+ Calcd for C21H24O2N
342.1492; Found 342.1494.
1
1. H NMR (CDCl3, 300 MHz) δ 7.65 (d, 1H, J = 7.8 Hz),
7.42-7.34 (m, 5H), 7.27 (app dt, 1H, J = 1.1, 6.9 Hz), 7.18
(app dt, 1H, J = 1.1, 7.9 Hz), 3.70 (s, 2H), 3.69 (s, 3H), 3.64
(s, 3H), 3.01 (quin, 1H, J = 7.0 Hz), 1.34 (d, 6H, J = 7.0 Hz).
13C NMR (CDCl3, 75 MHz) δ 172.9, 149.0, 139.5, 137.1,
130.6, 128.5, 127.6, 126.5, 121.8, 119.6, 119.0, 109.4, 105.5,
51.9, 34.0, 31.0, 31.0, 23.9. HRMS (ESI) m/z [M + H]+
Calcd for C21H24O2N 322.1807; Found 322.1819.
Methyl
indol-3-yl)acetate
2-(2-(3,4-dimethoxyphenyl)-1-methyl-1H-
8m. Purification by flash
Methyl 2-(2-(4-chlorophenyl)-1H-indol-3-yl)acetate
8h. Purification by flash chromatography on silica gel (5%
EtOAc-petroleum ether) gave 8h as a white solid (28.7 mg,
48%). mp 94 °C. IR (ATR) ν 3364, 1716, 1435, 749 cm–1.
1H NMR (CDCl3, 300 MHz) δ 8.18 (br s, 1H), 7.66 (dt, 1H,
J = 0.6, 7.7 Hz), 7.57 (dt, 2H, J = 2.4, 8.7 Hz), 7.44 (dt, 2H,
J = 2.4, 8.7 Hz), 7.35 (dm, 1H, J = 8.1 Hz), 7.23 (dt, 1H, J
= 1.4, 7.0 Hz), 7.17 (dt, 1H, J = 1.2, 7.1 Hz), 3.82 (s, 2H),
3.72 (s, 3H). 13C NMR (CDCl3, 75 MHz,) δ 172.6, 135.8,
chromatography on silica gel (30% EtOAc-petroleum ether)
gave 8m as a colorless oil (56.3 mg, 83%). IR (ATR) ν 3002,
2941, 1727, 1509, 1465, 1247, 1025 cm–1. 1H NMR (CDCl3,
300 MHz) δ 7.67 (dt, 1H, J = 1.0, 7.7 Hz), 7.35 (d, 1H, J =
8.0 Hz), 7.27 (ddd, 1H, J = 1.0, 1.2, 6.9 Hz), 7.18 (ddd, 1H,
J = 1.0, 1.2, 7.0 Hz), 7.10 (brs, 1H), 7.02 (m, 2H), 3.97 (s,
3H), 3.93 (s, 3H), 3.70 (s, 2H), 3.70 (s, 3H), 3.65 (s, 3H).
13C NMR (CDCl3, 75 MHz) δ 172.8, 149.1, 148.7, 139.3,
137.0, 127.5, 123.6, 123.2, 121.9, 119.7, 118.9, 114.0, 111.0,
135.0, 134.1, 130.8, 129.4, 129.2, 128.9, 122.9, 120.3, 119.3, 109.4, 105.4, 55.9, 55.9, 51.8, 31.0, 30.9. HRMS (ESI) m/z
116.6, 110.9, 106.0, 52.1, 30.8. HRMS (ESI) m/z [M + H]+
Calcd for C17H15O2NCl 300.0791; Found 300.0793.
[M + H]+ Calcd for C2H22O4N 340.1549; Found 34
tert-Butyl 3-(2-methoxy-2-oxoethyl)-2-(p-tolyl)-1H-
Methyl 2-(2-(4-bromophenyl)-1H-indol-3-yl)acetate
8i. Purification by flash chromatography on silica gel (5%
EtOAc-petroleum ether) gave 8i as a white solid (35.0 mg,
51%). mp 119 °C [Lit.[40] 121 °C]. IR (ATR) ν 3360, 1721,
indole-1-carboxylate
chromatography on silica gel (10% EtOAc-petroleum ether)
8n.
Purification
by
flash
gave 8n as a colorless oil (75.8 mg, 85%). IR (ATR) ν 2979,
2950, 1726, 1454, 1358, 1322, 1144, 1071, 748 cm−1. H
1
1
1168, 639 cm–1. H NMR (CDCl3, 300 MHz) δ 8.14 (br s,
NMR (CDCl3, 400 MHz) δ 8.23 (d, 1H, J = 8.2 Hz), 7.55
(dm, 1H, J = 7.6 Hz), 7.35 (ddd, 1H, J = 1.3, 7.2, 8.5 Hz),
7.30-7.23 (m, 5H), 3.68 (s, 3H), 3.54 (s, 2H), 2.42 (s, 3H),
1.27 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ 171.9, 150.1,
137.8, 137.6, 136.4, 130.5, 129.7, 129.2, 128.6, 124.5,
1H), 7.65 (dd, 1H, J = 0.7, 7.7 Hz), 7.60 (dt, 2H, J = 2.1, 8.7
Hz), 7.51 (dt, 2H, J = 2.2, 8.6 Hz), 7.35 (d, 1H, J = 7.6 Hz),
7.24 (dt, 1H, J = 1.2, 7.7 Hz), 7.17 (dt, 1H, J = 1.1, 7.1 Hz),
3.82 (s, 2H), 3.72 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ
172.5, 135.8, 134.9, 132.1, 131.2, 129.7, 128.9, 122.9, 122.3, 122.8, 118.8, 115.3, 113.2, 83.1, 52.0, 30.6, 27.5, 21.3.
120.3, 119.3, 110.9, 106.1, 52.1, 30.8. HRMS (ESI) m/z [M
HRMS (ESI) m/z [M + Na]+ Calcd for C23H25NO4Na
402.1681; Found 402.1671.
+ H]+ Calcd for C17H15O2NBr 344.0286; Found 344.0285.
Methyl
2-(2-(4-methoxyphenyl)-1H-indol-3-
Methyl
2-(5-methoxy-2-(p-tolyl)-1H-indol-3-
yl)acetate 8j. Purification by flash chromatography on
silica gel (20% EtOAc-petroleum ether) gave 8j as a pale
yellow solid (46.6 mg, 79%). mp 89 °C. IR (ATR) ν 3334,
yl)acetate 8o. Purification by flash chromatography on
silica gel (10% EtOAc-petroleum ether) gave 8o as a yellow
oil (31.5 mg, 51%). IR (ATR) ν 3367, 2949, 2830, 1729,
1624, 1485, 1452, 1434, 1216, 1197, 1169, 1113, 1022, 821
cm−1. 1H NMR (CDCl3, 300 MHz) δ 7.97 (br s, 1H), 7.43 (d,
2H, J = 8.1 Hz), 7.20 (d, 2H, J = 7.9 Hz), 7.16 (d, 1H, J =
9.2 Hz), 7.02 (d, 1H, J = 2.4 Hz), 6.78 (dd, 1H, J = 2.5, 8.8
Hz), 3.80 (s, 3H), 3.73 (s, 2H), 3.64 (s, 3H), 2.33 (s, 3H).
1
1705, 1241, 741 cm–1. H NMR (CDCl3, 300 MHz) δ 8.11
(br s, 1H), 7.65 (d, 1H, J = 7.3 Hz), 7.58 (dt, 2H, J = 2.9, 8.8
Hz), 7.35 (dm, 1H, J = 7.3 Hz), 7.19 (app dquint, 2H, J =
1.4, 7.1 Hz), 7.01 (dt, 2H, J = 2.9, 8.8 Hz), 3.87 (s, 3H), 3.83
(s, 2H), 3.72 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 172.8,
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
13C NMR (CDCl3, 75 MHz) δ 172.7, 154.4, 137.9, 137.1,
130.7, 129.6, 129.5, 128.0, 112.4, 111.6, 104.9, 101.0, 55.9,
52.0, 31.0, 21.2. HRMS (ESI) m/z [M + H]+ Calcd for
C19H20NO3 310.1443; Found 310.1437.
[3] B. W. Trotter, A. G. Quigley, W. C. Lumma, J. T. Sisko,
E. S. Walsh, C. S. Hamann, R. G. Robinson, H.
Bhimnathwala, D. G. Kolodin, W. Zheng, C. A. Buser,
H. E. Huber, R. B. Lobell, N. E. Kohl, T. M. Williams,
S. L. Graham, C. J. Dinsmore, Bioorg. Med. Chem.
Lett. 2001, 11, 865-869.
[4] M. G. Lima-Maximino, J. Cueto-Escobedo, J. F.
Rodríguez-Landa, C. Maximino, Pharmacol. Biochem.
Behav. 2018, 171, 66-73.
[5] S. Soto, E. Vaz, C. Dell'Aversana, R. Álvarez, L. Altucci,
Á. R. de Lera, Org. Biomol. Chem. 2012, 10, 2101-
2112.
[6] H. F. Roth, M. Li, J. Jiang, D. K. Dulan, M. B. Brendan,
J. Labelled Compd. Radiopharm. 2011, 54, 272-277.
[7] T. Daisuke, Y. Mana, H. Koji, S. Tetsuya, M. Masahiro,
Chem. Lett. 2011, 40, 1015-1017.
Methyl
2-(5-bromo-2-(2-methoxy-4-nitrophenyl)-
1H-indol-3-yl)acetate 8p. Purification by flash
chromatography on silica gel (10% EtOAc-petroleum ether)
gave 8p as an orange solid (34.1 mg, 41%). mp 185 °C. IR
(ATR) ν 3373, 3112, 2920, 2850, 1714, 1588, 1509, 1437,
1337, 1237, 1170, 1058, 1023, 790 cm−1. 1H NMR (CDCl3,
300 MHz) δ 8.80 (br s, 1H), 7.99 (dd, 1H, J = 2.2, 8.4 Hz),
7.88 (d, 1H, J = 2.1 Hz), 7.86 (d, 1H, J = 8.5 Hz), 7.81-7.80
(m, 1H), 7.34 (dd, 1H, J = 1.8, 8.7 Hz), 7.27 (dd, 1H, J =
0.5, 8.6 Hz), 3.99 (s, 3H), 3.77 (s, 2H), 3.75 (s, 3H). 13C
NMR (CDCl3, 75 MHz) δ 171.9, 156.9, 148.4, 134.4, 131.9,
131.4, 129.8, 126.7, 126.3, 122.0, 116.5, 113.4, 112.5,
108.1, 106.5, 56.4, 52.3, 31.0. HRMS (ESI) m/z [M - H]-
Calcd for C18H14N2O5Br 417.0086; Found 417.0083.
[8] A. F. P. Biajoli, E. T. da Penha, C. R. D. Correia, RSC
Adv. 2012, 2, 11930-11935.
Methyl 2-(5-bromo-2-(p-tolyl)-1H-indol-3-yl)acetate
8q. Purification by flash chromatography on silica gel (10%
EtOAc-petroleum ether) gave 8q as a beige solid (41.2 mg,
58%). mp 133 °C. IR (ATR) ν 3339, 2954, 2916, 1715,
1510, 1464, 1436, 1332, 1317, 1197, 1170, 991, 888, 791
[9] H. P. L. Gemoets, I. Kalvet, A. V. Nyuchev, N. Erdmann,
V. Hessel, F. Schoenebeck, T. Noël, Chem. Sci. 2017,
8, 1046-1055.
[10] A. J. Reay, L. A. Hammarback, J. T. W. Bray, T.
Sheridan, D. Turnbull, A. C. Whitwood, I. J. S.
Fairlamb, ACS Catalysis 2017, 7, 5174-5179.
[11] J. P. McMullen, M. T. Stone, S. L. Buchwald, K. F.
Jensen, Angew. Chem. Int. Ed. 2010, 49, 7076-7080.
[12] Z. Amara, E. S. Streng, R. A. Skilton, J. Jin, M. W.
George, M. Poliakoff, Eur. J. Org. Chem. 2015, 6141-
6145.
[13] B. J. Reizman, K. F. Jensen, Chem. Commun. 2015, 51,
13290-13293.
[14] V. Sans, L. Porwol, V. Dragone, L. Cronin, Chem. Sci.
2015, 6, 1258-1264.
[15] D. E. Fitzpatrick, C. Battilocchio, S. V. Ley, Org.
Process Res. Dev. 2016, 20, 386-394.
[16] N. Holmes, G. R. Akien, A. J. Blacker, R. L.
Woodward, R. E. Meadows, R. A. Bourne, React.
Chem. Eng. 2016, 1, 366-371.
[17] N. Holmes, G. R. Akien, R. J. D. Savage, C. Stanetty,
I. R. Baxendale, A. J. Blacker, B. A. Taylor, R. L.
Woodward, R. E. Meadows, R. A. Bourne, React.
Chem. Eng. 2016, 1, 96-100.
1
cm–1. H NMR (CDCl3, 300 MHz,) δ 8.24 (br s, 1H), 7.74
(d, 1H, J = 1.8 Hz), 7.49 (d, 2H, J = 6.5 Hz), 7.27-7.23 (m,
3H), 7.15 (d, 1H, J = 8.6 Hz), 3.78 (s, 2H), 3.74 (s, 3H), 2.41
(s, 3H). 13C NMR (CDCl3, 75 MHz) δ 172.6, 138.3, 137.5,
134.2, 130.7, 129.7, 128.8, 128.0, 125.1, 121.5, 113.2,
112.3, 104.6, 52.1, 30.6, 21.3. HRMS (ESI) m/z [M - H]-
Calcd for C18H15NO2Br 356.0286; Found 356.0286.
Methyl 2-(2-phenyl-1-methyl-1H-indol-3-yl)acetate
8r. Purification by flash chromatography on silica gel (10%
EtOAc-petroleum ether) gave 8r as a colorless oil (45.2 mg,
1
81%). IR (ATR) ν 1730, 1466, 1148, 738 cm–1. H NMR
(CDCl3, 300 MHz) δ 7.64 (dt, 1H, J = 1.0, 7.7 Hz), 7.53-
7.41 (m, 5H), 7.35 (d, 1H, J = 7.2 Hz), 7.27 (app dt, 1H, J =
1.2, 6.9 Hz), 7.17 (ddd, 1H, J = 1.0, 1.1, 6.8 Hz), 3.68 (s,
2H), 3.66 (s, 3H), 3.61 (s, 3H). 13C NMR (CDCl3, 75 MHz)
δ 172.7, 139.3, 137.2, 131.2, 130.7, 128.5, 128.3, 127.5,
122.0, 119.7, 119.0, 109.5, 105.7, 51.9, 30.9. HRMS (ESI)
m/z [M + H]+ Calcd for C18H18O2N 280.1338; Found
280.1331.
[18] B. J. Reizman, Y.-M. Wang, S. L. Buchwald, K. F.
Jensen, React. Chem. Eng. 2016, 1, 658-666.
[19] A. Echtermeyer, Y. Amar, J. Zakrzewski, A. Lapkin,
Beilstein J. Org. Chem. 2017, 13, 150-163.
[20] L. M. Baumgartner, C. W. Coley, B. J. Reizman, K. W.
Gao, K. F. Jensen, React. Chem. Eng. 2018, 3, 301-311.
[21] A.-C. Bédard, A. Adamo, K. C. Aroh, M. G. Russell,
A. A. Bedermann, J. Torosian, B. Yue, K. F. Jensen, T.
F. Jamison, Science 2018, 361, 1220-1225.
Acknowledgements
We gratefully acknowledge the University of Nantes, the ‘‘Centre
National de la Recherche Scientifique’’ (CNRS) and the “Région
des Pays de la Loire” in the framework of the SmartCat project for
financial support. N. Vasudevan thanks the UBL for a grant. We
acknowledge Julie Hémez (CEISAM, University of Nantes) for
HRMS analyses and Paul De Bonfils (CEISAM, University of
Nantes) for technical assistance with FTIR.
[22] N. Cherkasov, Y. Bai, A. J. Expósito, E. V. Rebrov,
React. Chem. Eng. 2018, 3, 769-780.
[23] D. E. Fitzpatrick, T. Maujean, A. C. Evans, S. V. Ley,
Angew. Chem. Int. Ed. 2018, 57, 15128-15132.
[24] H.-W. Hsieh, C. W. Coley, L. M. Baumgartner, K. F.
Jensen, R. I. Robinson, Org. Process Res. Dev. 2018,
22, 542-550.
[25] M. I. Jeraal, N. Holmes, G. R. Akien, R. A. Bourne,
Tetrahedron 2018, 74, 3158-3164.
[26] A. D. Clayton, A. M. Schweidtmann, G. Clemens, J. A.
Manson, C. J. Taylor, C. G. Niño, T. W. Chamberlain,
References
[1] D. W. Zaharevitz, R. Gussio, M. Leost, A. M.
Senderowicz, T. Lahusen, C. Kunick, L. Meijer, E. A.
Sausville, Cancer Research 1999, 59, 2566-2569.
[2] O. C. F. Orban, R. S. Korn, D. Benítez, A. Medeiros, L.
Preu, N. Loaëc, L. Meijer, O. Koch, M. A. Comini, C.
Kunick, Biorg. Med. Chem. 2016, 24, 3790-3800.
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
N. Kapur, A. J. Blacker, A. A. Lapkin, R. A. Bourne,
Chem. Eng. J. 2019, 123340.
[27] M. Rasheed, T. Wirth, Angew. Chem. Int. Ed. 2011, 50,
357-358.
[28] B. J. Reizman, K. F. Jensen, Acc. Chem. Res. 2016, 49,
1786-1796.
[29] V. Sans, L. Cronin, Chem. Soc. Rev. 2016, 45, 2032-
2043.
[30] D. C. Fabry, E. Sugiono, M. Rueping, React. Chem.
Eng. 2016, 1, 129-133.
[31] P. Giraudeau, F.-X. Felpin, React. Chem. Eng. 2018, 3,
399-413.
[32] R. A. Skilton, A. J. Parrott, M. W. George, M. Poliakoff,
R. A. Bourne, Appl. Spectrosc. 2013, 67, 1127-1131.
[33] A. D. Clayton, J. A. Manson, C. J. Taylor, T. W.
Chamberlain, B. A. Taylor, G. Clemens, R. A. Bourne,
React. Chem. Eng. 2019, 4, 1545-1554.
[34] C. Mateos, M. J. Nieves-Remacha, J. A. Rincón, React.
Chem. Eng. 2019, 4, 1536-1544.
[35] D. Cortés-Borda, E. Wimmer, B. Gouilleux, E. Barré,
N. Oger, L. Goulamaly, L. Peault, B. Charrier, C.
Truchet, P. Giraudeau, M. Rodriguez-Zubiri, E. Le
Grognec, F.-X. Felpin, J. Org. Chem. 2018, 83, 14286-
14299.
[36] E. C. Aka, E. Wimmer, E. Barré, N. Vasudevan, D.
Cortés-Borda, T. Ekou, L. Ekou, M. Rodriguez-Zubiri,
F.-X. Felpin, J. Org. Chem. 2019, 84, 14101-14112.
[37] E. Wimmer, D. Cortés-Borda, S. Brochard, E. Barré, C.
Truchet, F.-X. Felpin, React. Chem. Eng. 2019, 4,
1608-1615.
[38] V. D. Filimonov, M. Trusova, P. Postnikov, E. A.
Krasnokutskaya, Y. M. Lee, H. Y. Hwang, H. Kim, K.-
W. Chi, Org. Lett. 2008, 10, 3961-3964.
[39] K. S. Nalivela, M. Tilley, M. A. McGuire, M. G. Organ,
Chem. Eur. J. 2014, 20, 6603-6607.
[40] M. Tobisu, H. Fujihara, K. Koh, N. Chatani, J. Org.
Chem. 2010, 75, 4841-4847.
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001217
Advanced Synthesis & Catalysis
FULL PAPER
Direct C-H arylation of indole-3-acetic acid
derivatives enabled by an autonomous self-
optimizing flow reactor
Adv. Synth. Catal. Year, Volume, Page – Page
Natarajan Vasudevan, Eric Wimmer, Elvina Barré,
Daniel Cortés-Borda, Mireia Rodriguez-Zubiri, and
François-Xavier Felpin*
10
This article is protected by copyright. All rights reserved.