Direct C-2 acylation of indoles with toluene derivatives via Pd(II)-catalyzed C-H activation

Article abstract of DOI:10.1039/c7ra06004a

A simple and efficient Pd-catalyzed method for the C2-acylation of indoles is described. Less toxic, stable, and commercially available toluene derivatives were used as acyl sources, with tert-butylhydroperoxide (TBHP) as oxidant and pivalic acid as addit

Full text of DOI:10.1039/c7ra06004a

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Direct C-2 acylation of indoles with toluene
derivatives via Pd(II)-catalyzed C–H activation†
Cite this: RSC Adv., 2017, 7, 32559
c
a
a
a
*
Yaping Zhao, Upendra K. Sharma, Felix Schrӧder, Nandini Sharma,
Gonghua Songc and Erik V. Van der Eycken
*
ab
Received 29th May 2017
Accepted 16th June 2017
A simple and efficient Pd-catalyzed method for the C2-acylation of indoles is described. Less toxic, stable,
and commercially available toluene derivatives were used as acyl sources, with tert-butylhydroperoxide
(TBHP) as oxidant and pivalic acid as additive, providing moderate to good yields.
DOI: 10.1039/c7ra06004a
rsc.li/rsc-advances
pyrimidyl indoles with a-diketones10a and ethyl glyoxylate10b was
reported. Despite the signicant progress made in the area of
Introduction
C2-acylation of indoles, there are no reports on the formation of
a C–C bond directly from the more challenging and inert Csp3–
H bond.11,12 In continuation of our efforts to develop facile
methods for the C–H functionalization via radical addition,13 we
were interested to use substrates without prefunctionalization
for the creation of a new Csp2–Csp3 bond between the indole
ring and an unactivated methyl substituent. Considering that
readily available toluene derivatives are easy to handle, inex-
pensive, quite stable, with low toxicity,11 and could be used as
ideal in situ generated acylating reagents, we sought to develop
a complementary method for the preparation of 2-acylindoles
(Scheme 1).
We began to investigate the feasibility for oxidative cross-
coupling between N-pyrimidyl indole and toluene by the iden-
tication of suitable reaction conditions. To this end, the model
reaction between 1-(pyrimidin-2-yl)-1H-indole (1a) with toluene
(2a) was systematically examined (Table 1). As the use of
a transition-metal catalyst is generally needed both for acti-
vating the alkyl C–H bond and for the subsequent coupling to
form the C–C bond, we screened various Pd-catalysts with tert-
butyl hydroperoxide (TBHP) as oxidant in toluene (entries 1–4).
Acylated indoles are important structural motifs present in
a number of biologically active natural products and serve as
valuable intermediates in the synthesis of various dyes and
pharmaceuticals.1 Thus, the efficient construction of function-
alized acyl indole analogues has been the focus of intense
research efforts of synthetic chemists. With the advent of
transition metal-catalyzed C–H bond functionalization,2 this
methodology has become the most straightforward one leading
to functionalized indoles.3 However, the regioselective C-2
functionalization of the indole nucleus in the presence of the
electron rich C-3 position, still remains a challenging proposi-
tion for organic chemists.4 To override this inherent selectivity,
the introduction of a suitable N-protecting group would change
the regioselectivity from C-3 to the more electrophilic C-2
position of the indole nucleus.5 Towards this end, consider-
able progress has been achieved in recent years via metal-
catalyzed oxidative cross-couplings (Scheme 1). These
processes allow the use of less functionalized starting materials
in a minimum number of operational steps.6 In 2012, Li and co-
workers developed a Rh-catalyzed oxidative direct C2-acylation
of indoles with alkyl and aryl aldehydes through Csp2–H acti-
vation.7 Following this work, the group of Zhu disclosed
a palladium-catalyzed decarboxylative C2-acylation of indoles
with a-oxocarboxylic acids.8 Subsequently, Liang and co-
workers described
a palladium-catalyzed C2-acylation of
indoles with aryl and alkyl aldehydes via C–H functionaliza-
tion.9 Very recently, a palladium-catalyzed C2-acylation of N-
aLaboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of
Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven,
Belgium. E-mail: n_sharma023@yahoo.co.in; erik.vandereycken@chem.kuleuven.be;
Web: http://chem.kuleuven.be/en/research/mds/lomac
bPeoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya
street, Moscow, 117198, Russia
cShanghai Key Laboratory of Chemical Biology, East China University of Science and
Technology, Shanghai 200237, People's Republic of China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra06004a
Scheme 1 Previous reports towards C-2 acylation of N-pyrimidyl
indoles.
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Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Oxidant
Solvent
Additive
Yieldb (%)
1
2
3
4
Pd(OAc)2
PdCl2
PdCl2(PPh3)2
PdBr2
TBHP
TBHP
TBHP
TBHP
DCP
Toluene
Toluene
Toluene
Toluene
—
—
—
—
7
33
33
45
5
PdBr2
Toluene
—
27
6
7
8
9
10
11
12
13c
14d
15c,e
16c,e
17c,f
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
DTBP
TBPB
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Toluene
Toluene
—
—
—
—
—
—
—
—
39
Trace
32
17
47
46
50
57 (50)
51
— (73)
nd
Toluene/EtOAc (1 : 1)
Toluene/DCE (1 : 1)
Toluene/PhCl (1 : 1)
Toluene/PhCl (2 : 1)
Toluene/PhCl (3 : 1)
Toluene/PhCl (3 : 1)
Toluene/PhCl (3 : 1)
Toluene/PhCl (3 : 1)
Toluene/PhCl (3 : 1)
Toluene/PhCl (3 : 1)
—
PivOH
CF3COOH
PivOH
70 (63)
a
b
Reaction conditions: 1a (0.1 mmol), oxidant (3 equiv., 0.3 mmol), catalyst (10 mol%), solvent (1 mL), sealed tube, 120 ꢀC, 24 h. NMR yields
(isolated yields in parentheses). c TBHP 5 equiv. TBHP 10 equiv. Additive 0.5 equiv. Additive 1 equiv. TBHP ¼ tert-butyl hydroperoxide, DCP
d
e
f
¼ dicumyl peroxide, DTBP ¼ di-tert-butyl peroxide, TBPB ¼ tert-butyl peroxybenzoate, PivOH ¼ pivalic acid. nd ¼ not detected.
The results revealed the superior catalytic activity of Pd catalysts
having halide ions with PdBr2 providing a better yield (entry 4).
Subsequently, we investigated the effect of various oxidants on
Table 2 Optimization of directing group
this transformation and found that TBHP was the most suitable
oxidant (45% yield), with other oxidants affording poorer reac-
tivities (entries 5–7 vs. 4, also see ESI Table S1†). The above-
obtained positive results encouraged us to explore co-solvents
with toluene for achieving satisfying yields (entries 8–12).
Using chlorobenzene as a co-solvent with toluene in a 3 : 1 ratio
Entry DG
Product
Entry DG
Product
(v/v) led to a slightly higher yield (entry 12). Increasing the
stoichiometry of TBHP to 5 equiv. resulted in higher yield (57%)
of the desired product (entry 13). However a further increase led
to a decrease in yield (entry 14). A signicant inuence of the
additive on reaction was observed as the use of 0.5 equiv. of
PivOH resulted in a relatively high yield of 73% (entry 15).
However, either increasing the amount of PivOH or adding
another acid additive (CF3COOH) was relatively ineffective
(entries 16 and 17).
1
4
A survey of other directing groups (Table 2) established that
besides the N-2-pyrimidyl group (1a, entry 1) only the N-2-pyr-
idyl group (1b, entry 2) is effective, albeit to a lower extent. The
other reported directing groups for C-2 functionalization of
indoles failed to yield any product under the optimized condi-
tions (entries 3–6). Under the optimized reaction conditions
(Table 1, entry 15), the substrate scope of this synthetic meth-
odology was examined. As summarized in Table 3, a number of
toluene derivatives were employed as acylation reagents to react
with N-pyrimidyl indole (1a) to generate the desired acylation
products (3a–o).
2
3
5
6
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Table 3 Scope of toluene derivativesa,b
Table 4 Scope of indolesa,b
a
Reaction conditions: 1 (0.2 mmol), toluene (1.5 mL), TBHP (5 equiv.),
PdBr2b(10 mol%), PhCl (0.5 mL), PivOH (0.5 equiv.), sealed tube, 120 ꢀC,
24 h. Isolated yield.
a
Reaction conditions: 1a (0.2 mmol), toluene derivatives (1.5 mL),
TBHP (5 equiv.), PdBr2 (10 mol%), PhCl (0.5 mL), PivOH (0.5 equiv.),
b
sealed tube, 120 ꢀC, 24 h. Isolated yield. nd ¼ not detected.
reaction was observed with benzimidazole derivatives even aer
prolonged reaction time.
To enhance the synthetic utility of this process, facile
removal of the N-pyrimidyl group, was carried out in a traceless
fashion using sodium ethoxide in DMSO for 24 h at 100 ꢀC, with
an overall yield of 73% 3cc (Scheme 2).
Based on the previous research about C2-acylation of indoles
with toluene as acylation reagent,11,12 we proposed a plausible
reaction mechanism as shown in Scheme 3. First, Pd(II)Br2
reacted with the C2 position of the indole (1a) directed by the
pyrimidin-2-yl to generate the ve-membered cyclopalladated
intermediate A. Subsequently, intermediate A would react with
the benzoyl radical (formed in situ from the oxidation of toluene
by TBHP), to produce the reactive Pd(IV)14 or dimeric Pd(III)15
species B. Finally, the cyclopalladated intermediate B under-
went reductive elimination to give the desired product 3a.
Meanwhile, the Pd(II) species was regenerated for the next
catalytic cycle.
In general, reaction of 1a with toluene derivatives bearing
electron-donating groups (such as CH3, OCH3) or weakly
electron-withdrawing groups (such as Cl, Br, I) in para-position
gave moderate to good yields (3b–f). However, the reaction was
completely hampered in the presence of strongly electron-
withdrawing groups such as acetyl (3g) and nitro (3h). In case
of o-xylene (3i) and mesitylene (3j), the reaction took place on
only one methyl group while the others remained untouched.
This could be due to the fact that aer oxidation of one of the
methyl groups to the carbonyl group, its electron-withdrawing
property renders the subsequent oxidations unfavorable.12a 1-
Methylnaphthalene was also found to be a suitable coupling
partner for the reaction (3k). Furthermore, the presence of
a methyl group or a halo group in the meta-position of the
aromatic ring was well tolerated (3l–3o).
Next, the substituent effect on the indole ring was investi-
gated using toluene as coupling partner (Table 4). The reaction
worked well with a variety of functional groups at the 3-, 4-, 5-, 6-
and 7-position of the indole, such as F, Br, CH3, and CH3O (3p–
3w) with moderate yields. Interestingly, it was observed that
indoles bearing a substitution at the 5- or 6-position provide the
corresponding products with slightly higher yields (3q–s, 3v)
while moderate yields were observed for 4- or 7-substituted
indoles (3t, 3w). However, a sterically hindering 3-substitution
(3p) or the presence of a strongly electron-withdrawing group
such as cyano on the indole ring (3u) gave an inferior yield. No Scheme 2 Traceless removal of the directing group.
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Scheme 3 Plausible reaction mechanism.
Conclusions
We have developed an operationally simple and efficient Pd-
catalyzed method for the synthesis of C2-acylated indoles.
Low toxic, stable, and commercially available toluene deriva-
tives were used as acyl source, with TBHP as oxidant and PivOH
as additive. The reaction exhibited a satisfying functional group
tolerance. The generality and operational simplicity of this
method make it attractive for the alternative construction of 2-
acylindoles.
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YZ is grateful to the China Scholarship Council (CSC) for
providing a visiting doctoral fellowship. UKS and NS are
thankful to University of Leuven (KU Leuven) for a postdoctoral
fellowship. FS is grateful to Flanders Innovation & Entrepre-
neurship (VLAIO) for providing
a PhD scholarship. We
acknowledge the support by COST (European Cooperation in
Science and Technology) Action (CA15106) CH-Activation in
Organic Synthesis. The research was nancially support by The
Ministry of Education and Science of the Russian Federation
(the Agreement number 02.a03.0008).
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