C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles by tuning Pd catalytic modes: Pd(i)-Pd(ii) catalysisvs.Pd(ii) catalysis

Article abstract of DOI:10.1039/d0sc05409g

Efficient C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles have been developed. The former route enables C4-arylation in a highly efficient and mild manner and the latter route provides an alternative straightforward protocol for synthesis of C2/C4 disubstituted indoles. The mechanism studies imply that the different reaction pathways were tuned by the distinct acid additives, which led to either the Pd(i)-Pd(ii) pathway or Pd(ii) catalysis.

Full text of DOI:10.1039/d0sc05409g

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C4-arylation and domino C4-arylation/3,2-
carbonyl migration of indoles by tuning Pd catalytic
Cite this: Chem. Sci., 2021, 12, 3216
modes: Pd(I)–Pd(II) catalysis vs. Pd(II) catalysis†
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
a
Yaohang Cheng,a Shijie Yu,a Yuhang He,a Guanghui An,
Guangming Li
*
*
b
*
and Zhenyu Yang
Efficient C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles have been developed.
The former route enables C4-arylation in a highly efficient and mild manner and the latter route provides
an alternative straightforward protocol for synthesis of C2/C4 disubstituted indoles. The mechanism
studies imply that the different reaction pathways were tuned by the distinct acid additives, which led to
either the Pd(I)–Pd(II) pathway or Pd(II) catalysis.
Received 30th September 2020
Accepted 7th January 2021
DOI: 10.1039/d0sc05409g
rsc.li/chemical-science
mode tuned C4-arylation/directing group migration. With
different acidic additives, the different pathways were tuned to
Introduction
either the Pd(I)–Pd(II) pathway or Pd(II) catalysis (Scheme 1C).
Multi-substituted-indoles are key building blocks in a large
number of natural products, pharmaceuticals and agrochemi-
cals.1 Transition-metal-catalyzed directed C–H activation at the
benzene moiety has emerged as a powerful synthetic approach
to streamline the synthesis of highly substituted indoles.2 It
normally requires an adjacent directing group to the C–H
functionalization sites, which leads to the generation of vicinal
disubstituted indoles. However, direct formation of non-vicinal
disubstituted indoles via the directing group's assistance
remains challenging.
To achieve this goal, several directed remote C–H function-
alization strategies have been developed recently (Scheme 1A).
C6-selective olenation of indoles has successfully been ach-
ieved by groups of Yu using a combination of a monoprotected
amino acid ligand and the nitrile template attached at the
indole nitrogen via a sulfonamide linkage (Scheme 1B).3 Frost
developed an N-pyrimidinyl group assisted cycloruthenation
pathway to achieve remote C6-selective alkylation.4 Shi reported
a Cu(II)-diaryliodonium triate salt catalytic system for N–
P(O)tBu2 directed C6-selective arylation and C3-pivaloyl directed
C5-selective arylation.5 Despite this impressive progress, the
scope is limited to the synthesis of 3,5- and N,6-disubstituted
indoles and strategies other than directed remote C–H activa-
tion have been elusive. Herein, we reported the rst catalysis
aKey Laboratory of Functional Inorganic Material Chemistry (MOE), School of
Chemistry and Materials Science, Heilongjiang University, No. 74, Xuefu Road,
Nangang District, Harbin 150080, People's Republic of China. E-mail: chemagh@
163.com; gmli@hlju.edu.cn
bSchool of Pharmaceutical and Materials Engineering, Taizhou University, 1139 Shifu
Avenue, Taizhou 318000, China. E-mail: zhyyang@aliyun.com
† Electronic supplementary information (ESI) available. CCDC 2031280 (3a) and
2031282 (4a). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/d0sc05409g
Scheme
1 Transition-metal-catalyzed synthesis of non-vicinal
disubstituted indoles via C–H functionalization.
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Table 1 Optimization of the reaction conditionsa
Entry
HFIP/acid
Pd catalyst
Yield% (3a)b
Yield% (4a)b
1c
2d
3
HFIP/AcOH (3 : 1, v/v)
TsOH$H2O (3.75 equiv.)
ClCH2COOH (3.75 equiv.)
HFIP/TFA (3 : 1, v/v)
—
TsOH$H2O (3.75 equiv.)
TsOH$H2O (3.75 equiv.)
TsOH$H2O (3.75 equiv.)
HFIP/TFA (3 : 1, v/v)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OTs)2(MeCN)2
A
50
90
20
3
6
—
3
75
—
—
—
—
75
4e,f
5
8
6d
7d
8d
9e
15
88
91
3
B
Pd(TFA)2
a
Reaction conditions: 1a (0.2 mmol), 2a (3.0 equiv.), AgTFA (2.0 equiv.), Pd catalyst (10 mol%), HFIP/acid ¼ 3 : 1 (v/v, 1.0 mL), 100 ꢀC, 13 h.
b
e
c
d
Isolated yields. C2-arylation products obtained in 20% yields. The reaction was carried out with 1.0 mL HFIP at 60 ꢀC in 40 minutes.
f
HFIP : TFA ¼ 3 : 1 (v/v, 1.1 mL). C2-arylation products obtained in 6% yields. HFIP ¼ 1,1,1,3,3,3-hexauoro-2-propanol, TsOH$H2O ¼ p-
toluenesulfonic acid monohydrate, TFA ¼ triuoroacetate.
The Pd(I)–Pd(II) pathway enables the rapid and mild C4- (Tables S1 in the ESI†). The structures of 3a and 4a were
arylation and the latter Pd(II) catalysis undergoes an unprece- conrmed unambiguously by X-ray crystallography (Schemes 5
dented domino C4-arylation/3,2-carbonyl migration of indoles, and 6, and crystallographic data in the ESI†). Extensive
which provides a straightforward protocol for synthesis of C2/ screening of TDGs and solvent revealed that the acid is crucial
C4 disubstituted indoles.
for the promotion of the reaction (Tables S1 and S2 in the ESI†).
Therefore, further investigation was carried out without TDGs.
Surprisingly, replacing acetic acid with TsOH$H2O signicantly
enabled C4-arylation in a highly efficient and mild manner,
providing 3a as a sole product in 90% yield within 40 minutes
(Table 1, entry 2). Notably, with triuoroacetic acid as a co-
solvent, the product 4a was selectively obtained in 75% yield
(Table 1, entry 4). Further screening of other factors didn't
improve the reaction efficiency. Thus, TsOH$H2O is the best
acidic additive for 3a and TFA/HFIP is an optimal cosolvent for
4a.
Results and discussion
Optimization of reaction conditions
Shi5a and Zou2u reported C4/C5-arylation of a N–Bn protected
indole, and C2/C4-regioselective heteroarylation of N–Me pro-
tected indoles has successfully been achieved by You's groups.2v
Until now, direct C4-arylation of unprotected indoles has not
been reported. Thus, we employed unprotected indoles as the
starting material. As transient directing group strategies would
enhance coordination between Pd catalysts and weak-
coordinating directing groups,6 we commenced our investiga-
tion by evaluation of several transient directing groups (TDGs)
Mechanism studies: tuning the catalytic mode via acids
in C4-arylation of 1-(1H-indol-3-yl)ethan-1-one (1a) with methyl To probe the role of TsOH$H2O in C4-arylation, several control
4-iodobenzoate (2a) using Pd(OAc)2 as the catalyst and AgTFA as experiments were carried out. According to previous reports, the
the additive. Interestingly, both C4-arylation product 3a and role of TsOH$H2O in the Pd-catalyzed reactions can be catego-
unexpected 4a were obtained when using glycine as a transient rized into two aspects: combination of Pd(OAc)2 with
directing group in the cosolvent of HFIP/HOAc (3/1, v/v, 1.0 mL) TsOH$H2O would afford either electrophilic Pd(OTs)2(MeCN)2
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Fig. 1 (a) Time-dependent formation of 3a using various Pd(I) and Fig.
2
The X-ray photoelectron spectroscopy (XPS) data of the
Pd(II) catalysts. (b) Time-dependent formation of 3a and 4a using reaction mixture.
Pd(OAc)2 and Pd(TFA)2 catalysts.
structures indicate the presence of two distinct oxidation
(ref. 7) or complex A.8 Pd(OTs)2(MeCN)2 instead of Pd(OAc)2
delivered lower yields with an induction period (Table 1,
entry 6 and Fig. 1a). In contrast, complex A8 provided 3a in
88% yield without the induction period (Table 1, entry 7 and
Fig. 1a), suggesting that complex A would be a competent
catalyst. As Bedford and coworkers revealed that complex A
would be readily converted to unstable Pd(I) species C (see
Table 1),8 an investigation of the possible involvement of
Pd(I) species in this catalysis process was carried out. A stable
dinuclear Pd(I) complex B9 was employed, providing 91%
yield without the induction period (Table 1, entry 8 and
Fig. 1a).10 This result is in contrast to that for a previously
reported DAF-Pd(I) species, which reduces the catalytic
activity in allylic C–H acetoxylation of terminal alkenes and
intramolecular aza-Wacker cyclization.11 These results indi-
cated that TsOH$H2O together with Pd(OAc)2 would form
a reported Pd(I) catalyst C in situ via complex A, which is
involved in the catalytic cycle. To explore Pd species in the
catalytic cycle, the X-ray photoelectron spectroscopy (XPS)
measurement of the reaction mixture using the Pd(OAc)2/
TsOH$H2O system was carried out. The observed peak
states of Pd species (Fig. 2). These peaks can be attributed to
Pd(I) (49.77 at%) and Pd(II) (50.23 at%) without apparent
Pd(0) signals,12 which shows that the C4-arylation reaction
may proceed through a Pd(I)–Pd(II) mechanism. In the Pd(I)–
Pd(II) catalytic pathway, involvement of silver salts is
uncommon. Owing to the halogenophilicity of silver,13 Ag(I)
was reported to abstract halogen during a reported Pd(I)-
involved cross-coupling of enamides with a-bromocarbonyls
by Loh.14 In our case, we indeed detected Ag(I) as the only
silver species in XPS (Fig. 2),15 further conrming that Ag(I)
acts as a halogen abstractor for aryl iodides instead of an
oxidant.16 To our knowledge, this Pd(I)–Pd(II) catalytic
pathway would be the rst report of the Pd(I) involved C–H
arylation process.8,9,11,12,14,17,18
To elucidate the pathway of domino C4-arylation/3,2-
carbonyl migration of indoles, several tests were carried out.
Pd(TFA)2 instead of Pd(OAc)2 provided 4a in 75% yield, sug-
gesting that Pd(OAc)2 would be readily converted to Pd(TFA)2 to
catalyze reactions (Table 1, entry 9 and Fig. 1b). As we moni-
tored the reaction for 4a, 3a was formed before the generation of
4a and the rate for 4a formation decreased aer maximum
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indicate that TFA might be crucial to trigger this reverse
Friedel–Cras reactions via protonation of 3a. Notably,
a signicant improvement of efficiency was achieved by using
TFA and Pd(OAc)2 (89% yield in 4 h), indicating that coop-
eration of TFA with Pd(OAc)2 prompted the efficient 3,2-
carbonyl migration process. Further efforts towards key
intermediate trapping were carried out as well. Aer reacting
3a with Pd(OAc)2 in HFIP : TFA ¼ 3 : 1 (v/v, 1.1 mL) at 100 ꢀC
for 2 h, the 19F NMR spectrum indicated generation of
anhydride E (Fig. S4 in the ESI†) and D was isolated with 6%
yield (Scheme 2d). We hypothesized that E would react with D
to afford the product 4a. Indeed, when D was subjected to the
reaction with E, migration product 4a was obtained in 90%
yield without 3a (Scheme 2e). These outcomes suggest that
reverse Friedel–Cras reactions of species 3a might generate
intermediates D and E. Next, Friedel–Cras reactions of D
selectively occurred at the C2 position with E as an inter-
molecular reaction, which provided product 4a. TFA would
promote the Friedel–Cras reaction of D with E via proton-
ation of E, which is consistent with results from Scheme 2e:
the reaction between D and E failed in the absence of TFA;
addition of TFA delivered 4a with 30% yield in 0.5 h.
Furthermore, comparing the different results in Scheme 2e
with or without Pd species, addition of Pd species would
increase the reaction rate: a signicant improvement of effi-
ciency was achieved by using TFA and Pd(OAc)2 (90% yield in
0.5 h). Thus, we proposed that either Pd(TFA)2 as a Lewis acid
or TFA as a Bronsted acid would activate E for Friedel–Cras
reaction of D.
When 1a was subjected to C4-arylation conditions using
1,1,1,3,3,3-hexauoro-2-propanol-d2 as solvent and TsOD$D2O
as acid additive in the presence of D2O, no D/H exchange was
detected by NMR (Scheme 3). It implies that in the reaction (1)
the C–H bond cleavage is an irreversible process and (2) Pd
catalysts may undergo oxidative addition with iodobenzenes
before C–H activation. In the C4-arylation/3,2-carbonyl migra-
tion reaction, D/H exchange was detected by NMR at C4 as well
as Me, C5 and C7. It implies that in the domino reaction Pd
catalysts may undergo oxidative addition with iodobenzenes
aer C–H activation.
Based on previous literature9 and our results, we proposed
two catalytic cycles for the aforementioned reactions (Scheme
Scheme 2 Pathway of domino C4-arylation/3,2-carbonyl migration
of indoles.
production of 3a (Fig. 1b), indicating a plausible generation of
4a from 3a as path 2 (Scheme 2a). Furthermore, 1-(1H-indol-2-yl)
ethan-1-one (6a) was subjected to the standard reaction condi-
tions and failed to give the desired 4a (Scheme 2b), which ruled
out path 1 and suggested a domino C4-arylation/3,2-carbonyl
immigration.19
To probe the role of acid in the 3,2-carbonyl migration
process, several parallel experiments were conducted
(Scheme 2c). HFIP as solvent with or without Pd(OAc)2 only
afforded 3a in 8% or 7% yield, respectively. Addition of TFA
delivered 4a with 40% yield in 4 h and 88% yield of 4a was
obtained by extending the reaction time to 12 h. These results
Scheme 3 H/D exchange experiments.
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and CF3COOꢁ, and regenerates Pd(TFA)2. Finally, the process of
deprotonation–rearomatization of L affords product 4a and
TFA.
Substrate scope
We next explored the scope of C4-arylation under the opti-
mized conditions (Scheme 5). Arylation of indole 1a with
diverse aryl iodides was rst examined. A series of aryl
iodides with electron-withdrawing or electron-donating
groups at the ortho, meta or para position successfully
provided arylation products with moderate to good yields in
40 minutes (Scheme 5A). 4-Iodobenzonitrile with a labile
cyano group also provided arylation products (3g and 3l)
successfully. Although 4-iodobenzaldehyde and 40-iodoace-
tophenone were not compatible with basic coupling con-
ditions,5a they afforded the products 3h and 3i under these
optimal conditions. These C4-arylations were previously
inaccessible (3g and 3i). Lower aryl iodide loading (1.2 equiv.)
also afforded good to excellent yields. Methyl 4-bromo-
benzoate provided arylation product 3a in 12% yield as well
(Table S11 in the ESI†). With iodobenzene (2a) as the
coupling partner, diverse indole derivatives were explored
(Scheme 5B). In contrast to previous reports, various carbonyl
directing groups at the C3 position proved to be viable for
directed arylation (3o–3s), which provides an alternative
route for direct synthesis of 3,4-disubstituted indoles.
Furthermore, reactions of indoles with methyl (3t and 3u),
esters (3v and 3z), uoro (3w), chloro (3x), and bromo
substituents (3y and 3aa) afforded the corresponding 4-aryl
indoles in moderate to excellent yields. Although aza-indole
derived 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one failed
to give C4-arylation products (Table S13 in the ESI†), other
heterocyclic substrates, such as 1-(benzo[b]thiophen-3-yl)
ethan-1-one, were compatible with this reaction (3ab).
Pleasingly, the robustness of this protocol can also be proven
by application to highly functionalized indoles in 40 minutes
(Scheme 5C). Tri-substituted indoles, such as a lilolidine
derivative and bioactive 4-oxocarbazoles, afforded the
desired product in excellent yields (5a–5c). Notably, this
approach didn't afford arylation at the N of pyrrole, which
clearly enables the rapid and modular construction of highly
substituted indoles (5e) from simple and available indole
substrates with minimal prefunctionalization.2c,20 Further
screening of the reaction scope revealed that methyl 1H-
Scheme 4 Proposed mechanism.
4). In the C4-arylation catalysis cycles, Pd(OAc)2 reacts with
TsOH$H2O to afford Pd(I) catalytic species C,8 which then
readily undergoes oxidative addition with aryl iodides to form
Pd(II) species F. Subsequent C–H activation of 1a with F affords
G, which undergoes reductive elimination to give C4-arylation
products 3a and regenerate Pd(I) species C. In the domino C4-
arylation and 3,2-carbonyl migration of indole catalysis cycles,
Pd(OAc)2 reacts with TFA to afford Pd(TFA)2, which undergoes
C–H activation with substrate 1a to afford species H. Oxidative
addition of H with aryl iodides forms I, which undergoes
reductive elimination to give species J. Reverse Friedel–Cras
reactions of J begin with the protonation at the C3 positions of
indoles, providing K. K reacts with CF3COOꢁ to generate species
D and E. Friedel–Cras reaction of species D and E releases L
indole-3-carboxylate
and
(1H-indol-3-yl)(morpholino)
methanone failed to give C4-arylation products (Table S13
in the ESI†).
We next investigated the scope of C4-arylation and 3,2-
carbonyl migration of indole under the optimal conditions
(Scheme 6). Iodoarenes containing esters (4l), nitriles (4b and
4j), triuoromethyl (4c) and nitro group (4k and 4p) afforded the
desired products in moderate to good yields. Notably, reactive
ketone and aldehyde functionalities on the aryl iodide
remained intact during the reaction (4h and 4i). Aryl iodides
containing uoro, chloro, bromo and iodo substituents are also
compatible in the reaction (4d–4g and 4m–4o), thus
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Scheme 5 C4-arylation of indoles. aReaction conditions: 1 (0.2 mmol), 2 (3.0 equiv.), AgTFA (2.0 equiv.), Pd(OAc)2 (10 mol%), TsOH$H2O (3.75
equiv.), HFIP (1.0 mL), 60 ꢀC, 40 minutes. b2 (1.2 equiv.), 90 minutes. cIsolated yields.
highlighting the potential of this process in combination with removal when
a thiophene derivative was employed as
further conventional cross-coupling transformations. Besides, a substrate (4x). When trisubstituted indole 5d was subjected to
various carbonyl directing groups were tolerated well and gave these domino conditions, a similar directing-group-removal
2,4-disubstituted indole products (4q–4t). Indoles containing product 4y was obtained, which might be attributed to the
halide substituents were compatible providing the corre- bulkiness of the N-protecting group. C2-substituted indoles also
sponding products (4u–4w) in moderate to good yields. Notably, provided 4z and 4aa with directing group removal from their 3-
this approach enables one-pot C4-arylation and directing group carbonyl indole derivatives with generation of intermediate E.
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Scheme 6 C4-arylation and 3,2-carbonyl migration of indoles. aReaction conditions: 1 (0.2 mmol), 2 (3.0 equiv.), AgTFA (2.0 equiv.), Pd(OAc)2
(10 mol%), HFIP : TFA ¼ 3 : 1 (v/v, 1.1 mL), 100 ꢀC. bIsolated yields.
Given that 2,4-disubstituted indoles are important structural methanone failed to give C4-arylation/3,2-carbonyl migration
units in biologically active molecules and drugs,21 this approach products (Table S14 in the ESI†).
would provide an alternative pathway for facile construction of
We next examined the scope of 3,2-carbonyl migration of C3/
diverse bioactive indole building blocks. Further exploring the C4-disubstituted indoles (Scheme 7). 1a without C4-
reaction scope revealed that 1H-indole-3-carbaldehyde, methyl substituents failed to react under migration conditions. A 4-
1H-indole-3-carboxylate
and
(1H-indol-3-yl)(morpholino) methyl indole derivative incorporating C4 electron-donating
substituents was compatible in these conditions, providing
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In summary, we have developed the C4-arylation and domino
C4-arylation/3,2-carbonyl migration of indoles. The former
route enables C4-arylation in a highly efficient and mild manner
employing TsOH$H2O as acid additive and the latter route
provides an alternative straightforward protocol for synthesis of
C2/C4 disubstituted indoles. The different reaction pathways
were tuned by the distinct acid additives, which led to either the
Pd(I)–Pd(II) pathway or Pd(II) catalysis. Given the importance of
3,4- and 2,4-disubstituted indoles in materials science and
active pharmaceutical ingredients, it is expected that the reac-
tions will have wide application in organic chemistry, chemical
materials and pharmaceutical research.
Author contributions
Y. H. C., S. J. Y. and Y. H. H. conducted all the experimental
work. Y. H. C. and G. H. A. collected and analyzed the data. Y. H.
C., G. H. A., G. M. L. and Z. Y. Y. wrote the paper. G. H. A.,
G. M. L. and Z. Y. Y. proposed and supervised the project. All the
authors discussed the results and commented on the manu-
script. All authors have given approval to the nal version of the
manuscript.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
The authors gratefully acknowledge support from the University
Nursing Program for Young Scholars with Creative Talents in
Heilongjiang Province (UNPYSCT-2017124). Associate Professor
Hao Wu is acknowledged for his kind discussion on the XPS
spectrum.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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