Decarboxylative acylation of: N -free indoles enabled by a catalytic amount of copper catalyst and liquid-assisted grinding

Article abstract of DOI:10.1039/c9ob00622b

A facile decarboxylative acylation of N-free indoles with α-ketonates via liquid-assisted grinding was reported. The reaction requires only a catalytic amount of Cu(OAc)₂·H₂O in combination with O₂ as the terminal oxidant to give various 3-acylindoles with high efficiency. Additionally, this new methodology was applicable to a gram-scale synthesis.

Full text of DOI:10.1039/c9ob00622b

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Decarboxylative acylation of N-free indoles enabled by catalytic
amount of copper catalysis and liquid-assisted grinding
Received 00th January 20xx,
Accepted 00th January 20xx
Jingbo Yu,* Chao Zhang, Xinjie Yang, Weike Su*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A facile decarboxylative acylation of N-free indoles with α-
ketonates via liquid-assisted grinding was reported. The reaction
requires only a catalytic amount of Cu(OAc)2·H 2O in combination
with O2 as the terminal oxidant to give various 3-acylindoles in
high efficiency. Additionally, this new methodology was applicable
to a gram-scale synthesis.
Transition-metal decarboxylative C–H cross coupling offers an
atom- and step-economical alternative for C–C bond formation.1
This strategy has attracted considerable interest in the past decade
due to the merit integration of inexpensive, accessible and
environmentally benign properties of carboxylic acids with
circumvented prefunctionalized coupling partner.2 Extensive studies
have been accomplished in this area since the first Pd catalyzed
decarboxylative C–H arylation was reported by Crabtree et al.3
Among the investigated carboxylic acids, α-keto acids4 were also
used as decarboxylative coupling partners for direct acylation,
which provided a new approach to ketones. Representative
examples are Ge’s works5 of Pd-catalyzed decarboxylative
acylations of 2-phenylpyridines, acetanilides, potassium
aryltrifluoroborates and benzoic acids with α-keto acid derivatives;
and Kim’s reports6 of Pd-catalyzed decarboxylative acylation of o-
methyl ketoximes, phenylacetamides and o-phenyl carbamates with
α-keto acids. Besides, azoxybenzenes, azobenzenes,
tetrahydroquinolines and N-nitrosoanilines were also amenable
substrates to be acylated by α-keto acids.7 However, albeit
heteroaromatics ketones are ubiquitous among biologically active
natural products and pharmaceutical compounds,8 transition-metal-
catalyzed decarboxylative acylation on aromatic heterocyclic
Scheme 1. Approaches to heteroaromatics ketones via transition-
compounds is still less explored (Scheme 1). In 2013, Zhu9 and metal-catalyzed decarboxylative acylation
Wang10 et al. independently reported expedient access to 2- and 3-
acylindoles via Pd(II)/Ag and stoichiometric Cu catalyzed
acylation of azoles with α-keto acids was achieved under novel
decarboxylative acylation of N-substituted indoles. N-free indoles
could also be involved in the Cu catalyzed decarboxylative acylation
by using excessive silver salt as oxidant.11 Later, decarboxylative 2-
Ni/Ag and Co/Ag catalysis by Ge’s12 and Lu’s group13, respectively.
Very recently, a direct acylation for 2H-indazoles using Ag-catalyzed
decarboxylative cross-coupling of α-keto acids was developed by
Oh’s group.14 Besides the conventional reaction way, visible light
photoredox catalysis was also explored for C3-acylation of indoles.15
Despite undisputable advances, the deficiency of these methods
can be shared given the required expensive catalyst, stoichiometric
metal oxidant and some harsh reaction conditions. Therefore,
developing a modern strategy enabling facile decarboxylative C-H
National Engineering Research Center for Process Development of Active
Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta
Region Green Pharmaceuticals, Zhejiang University of Technology. Hangzhou
310014, PR China. E-mail: yjb@zjut.edu.cn, Pharmlab@zjut.edu.cn
† Electronic Supplementary Information (ESI) available: mechanical parameters
screening, characterization and 1H, 13C and 19F NMR spectra of the synthesized
compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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acylation by catalytic amounts of low-cost metal is highly desired.
Journal Name
acylated indole product (3aa) in 66% (or 64%) yiVeieldw,AritniclewOhnilicnhe
DOI: 10.1039/C9OB00622B
Mechanosynthesis by ball milling has been developed into a Cu(OAc)2·H 2O seemed to be a better choice (entry 1). Control
valuable technique to conduct organic reactions, of which the experiments highlighted the crucial roles of the assisted liquid (LAGs)
boundaries have been pushed into an elaborated set of synthetic and grinding auxiliary in this transformation (entries 2-3, < 20%).
transformations,16 particularly metal catalyzed cross-couplings.17 In Strong fluctuation of yields was found within the screened LAGs.
recent years, since the finding that adding a small amount of liquid High polarity aprotic solvent like MeCN and DMSO were more
can modify mechanochemical reaction environment, the effective than less-polar dioxane, EtOAc and toluene, which
methodology termed liquid assisted grinding (LAG)18 leads to a probably due to their facile coordination with Cu catalyst that
breakthrough reactivity compared to conventional solution-based helped promote the reaction (entries 1 and 4 vs entries 6-7). It was
reactions, rather than a solvent-less alternative synthetic method.19 interesting to find that polar protic alcohol could also increase the
On the basis of our previous research program on LAG accelerated product yield mildly (entry 5). Subsequently, various grinding
cross-couplings20 as well as our focuses on the construction of auxiliary were examined since the solid additives were always vital
indole derivatives20b, 21, we wish to report herein a novel and mild for the reactivity in mechanosynthesis that feature one or more
decarboxylative acylation of N-free indoles via liquid assisted liquid component.16i Clearly, sodium salts, particularly the non-
grinding in the presence of catalytic amounts of Cu(II) and O2.
adsorptive NaCl, gave better results than others (entries 1, 9-12),
Initial investigation began with the decarboxylative coupling of while silica gel commonly used as grinding auxiliary in our previous
21, 23
indole (1a) and potassium 2-oxo-2-phenylacetate22 (2a) as model works20b,
afforded poor yield (entry 12). A preliminary
reaction (Table 1). We were delighted to find that co-grinding of evaluation of oxidants revealed persulfate was a promising oxidant.
carboxylate and indole in the presence of Cu(OAc)2·H 2O (20 mol%) However, 35% of acylate indole could be afforded when the
or Cu(OAc)2 (20 mol%), K2S2O8 (1.0 equiv.), MeCN (LAGs, η = 0.11) reaction proceeded in the absence of an additional oxidant (entry
and NaCl (grinding auxiliary, 2.0 g) provided the desired 16). Thus, a positive effect was anticipated when the reaction
performed under an atmosphere of dioxygen24 instead of air. This
Table 1. Optimization of the reaction conditionsa
assumption was confirmed, and the utilization of Cu(OAc)2·H 2O (20
mol%), O2 (1 atm), MeCN (η = 0.11) and NaCl (2 g) provided 62%
yield of 3aa (entry 17). Delightedly, the catalyst loading could be
reduced to 15 mol% without significant decrease in product yield
(entry 17). Changing the η value of MeCN to 0.14 or 0.08 proved to
be detrimental to the product yield, result in 50% and 47% of 3aa,
respectively (entries 18 and 19), whereas raising the amount of
NaCl to 3 g improved the product yield to 67% (entry 21).
To the best of our knowledge, the mechanical parameters in
mechanosynthesis usually play an important role in reaction control,
Entry
1
2
3
4
5
6
7
8
Oxidant (eq)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
(NH4)2S2O8 (1)
DDQ (1)
LAGs (μL/mg)
MeCN (0.11)
—
Auxiliary (g)
NaCl (2)
NaCl (2)
—
NaCl (2)
NaCl (2)
NaCl (2)
NaCl (2)
NaCl (2)
NaBr (2)
Na2SO4 (2)
KCl (2)
Silica gel (2)
NaCl (2)
NaCl (2)
NaCl (2)
NaCl (2)
NaCl (2)
NaCl (2)
NaCl (2)
NaCl (3.5)
NaCl (3)
NaCl (2.5)
3aa Yieldb (%)
66, 64c
12
MeCN (0.11)
DMSO (0.11)
EtOH (0.11)
Dioxane (0.11)
EtOAc (0.11)
Toluene (0.11)
MeCN (0.11)
MeCN (0.11)
MeCN (0.11)
MeCN (0.11)
MeCN (0.11)
MeCN (0.11)
MeCN (0.11)
MeCN (0.11)
MeCN (0.11)
MeCN (0.14)
MeCN (0.08)
MeCN (0.11)
MeCN (0.11)
MeCN (0.11)
18
64
49
47
35
28
60
57
35
40
62
0
and the combined evaluation of the reaction parameters may result
25
in a highly efficient synthesis.23e,
As expected, after delicate
adjustment of the synergistic effects of the rotation speed (vrot), the
milling-ball filling degree (ΦMB) and the milling-ball size (dMB), we
were pleased to obtain 3aa in the best yield of 76% (see Figure S1 in
supporting information). In summary, the optimal conditions for the
decarboxylative coupling of 1a and 2a showed unexpectedly good
reactivity, provided that the use of Cu(OAc)2·H 2O (20 mol%), MeCN
(η = 0.11) and NaCl (3 g) at 750 rpm in planet mill for [8(15 min + 1
min break)] under O2 atmosphere.
Encouraged by the above results, we then turned our focus on
exploring the generality of this direct acylation reaction. Various
substituted indoles were first reacted with potassium 2-oxo-2-
phenylacetate (2a) under the optimized conditions and the results
are listed in Table 2. Both electron-poor and electron-rich groups on
5-7 positions of indoles were compatible with the decarboxylative
coupling conditions (3da-3oa). Indoles with OMe and OBn on their
4-positions showed unexpectedly good reactivity provided that the
amount of catalyst and the rotation speed were increased (3ba,
3ca). It is worth noting that strong electron-withdrawing NO2 group
was also tolerable when the milling time was extended, giving the
desired product (3ia) in 70% yield. Furthermore, 5,6-dichlor-1H-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
BQ (1)
trace
d
—
35
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
62, 61e, 57f
50
47
62
67
65
a Unless otherwise noted, all reactions were carried out with 1a (1.0 mmol), 2a
(2.0 mmol), Cu(OAc)2·H 2O (20 mol%), oxidant, LAGs [η = V (liquid; µL)/m (reagents;
mg)] and grinding auxiliary at 750 rpm in planet mill [8(15 min + 1 min break)],
using 32 stainless-steel balls (dMB = 6 mm, ФMB = 0.08) in a 45 mL stainless steel
b
c
d
vial. isolated yields. Cu(OAc)2 (20 mol%) was used. the reaction was
e
f
performed under air. Cu(OAc)2·H 2O (15 mol%) was used. Cu(OAc)2·H 2O (10
mol%) was used.
2 | J. Name., 2012, 00, 1-3
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Table 2. Scope of indolesa
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Table 3. Scope of α-ketonatesa
View Article Online
DOI: 10.1039/C9OB00622B
a Unless otherwise noted, all reactions were carried out with 1 (1.0 mmol), 2a (2.0
mmol), Cu(OAc)2·H 2O (20 mol%), MeCN (η = 0.11) and NaCl (3 g) under O2
atmosphere at 750 rpm in planet mill [8(15 min + 1 min break)], using 225
stainless-steel grinding balls (dMB = 4 mm, ФMB = 0.16) in a 45 mL stainless steel
b
vial. Cu(OAc)2·H 2O (30 mol%), 800 rpm [8(15 min + 1 min break)]. c 800 rpm
[11(15 min + 1 min break)]. d 800 rpm [8(15 min + 1 min break)]
a Unless otherwise noted, all reactions were carried out with 1 (1.0 mmol), 2 (2.0
mmol), Cu(OAc)2·H 2O (20 mol%), MeCN (η = 0.11) and NaCl (3 g) under O2
atmosphere at 750 rpm in planet mill [8(15 min + 1 min break)], using 225
stainless-steel grinding balls (dMB = 4 mm, ФMB = 0.16) in a 45 mL stainless steel
vial. b 800 rpm [8(15 min + 1 min break)].
indole, 2-methyl-1H-indole, and 2,5-dimethyl-1H-methylindole
could also be involved in the decarboxylative acylation reactions,
affording good yields of the desired products (86% for 3pa, 68% for
3qa and 89% for 3ra).
As shown in Table 3, the present Cu-catalyzed acylation method
also showed good tolerance toward various α-ketoates 2 with
indole (1a). No significant electronic effects and substitution
patterns of the acyl substitute group of α-ketoates were found
except p-OMe and 2-Me (3ab-3aj). Unsurprisingly, heteroaromatic
and aliphatic α-ketoates gave the anticipated product 3ak-3am in
synthetically acceptable yields. It should be noted that a series of α-
ketoates possessing both electron-sufficient and electron-deficient
groups on different (ortho, meta or para) positions of the phenyl
ring reacted smoothly with 5- and 6-substituted indoles to provide
the corresponding cross-coupling products (3gb, 3hd, 3de, 3rg and
3mi) in moderate to good yields. In addition, the protocol’s mild
oxidation aptitude enables the rapid and concise construction of
the potential anticancer drug SCB01A (BPR0L075, phase II trial),
which is generally achieved by Friedel-crafts reaction.26
Scheme 2. Gram-scale reaction
The remarkable advantage of the decarboxylative acylation for N-
free indoles was demonstrated by the gram-scale-reaction with a
relative low catalyst loading and afforded good yield (Scheme 2).
To gain insight into the reaction mechanism, some control
experiments were performed as depicted in Scheme 3. It was found
that the addition of BHT had no obvious influence on the yield of
this reaction27, suggesting that a radical mechanism can be
excluded in the decarboxylative coupling reaction. Comparison
experiments between CuO (1 eq) and CuO/HOAc (1/1 eq) catalyzed
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Journal Name
Acknowledgement
View Article Online
DOI: 10.1039/C9OB00622B
The authors thank the Zhejiang Province Science and Technology
Plan Project (No. LGF18B060004) and National Natural Science
Foundation of China (No. 21406201) for financial support.
Notes and references
1
(a) Y. Wei, P. Hu, M. Zhang and W. Su, Chem. Rev., 2017, 117,
8864; (b) X. Shi, X. Chen, M. Wang, X. Zhang and X. Fan, J.
Org. Chem., 2018, 83, 6524; (c) Y. Yu, X. Chen, Q. Wu, D. Liu,
L. Hu, L. Yu, Z. Tan, Q. Gui and G. Zhu, J. Org. Chem., 2018, 83
8556; (d) S. Mkrtchyan and V. O. Iaroshenko, Eur. J. Org.
Chem., 2018, 6867.
Scheme 3. Control experiment
,
reactions revealed that Cu(OAc)2 was the actual catalyst that could
be formed in situ from the reaction of CuO and HOAc. Exhilarating,
20 mol% freshly prepared copper powder instead of Cu(OAc)2 could
also promote the reaction in the presence of HOAc as additive and
O2 as terminal oxidant to give 3aa in 45% yield, which implied a
Cu0—CuIIO—CuII(OAc)2 oxidative pathway.
2
(a) N. Rodríguez and L. J. Goossen, Chem. Soc. Rev., 2011, 40
,
5030; (b) J. D. Weaver, A. Recio III, A. J. Grenning and J. A.
Tunge, Chem. Rev., 2011, 111, 1846; (c) R. Shang and L. Liu,
Sci. China Chem., 2011, 54, 1670; (d) W. I. Dzik, P. P. Lange
and L. J. Gooßen, Chem. Sci. 2012,
3, 2671; (e) J. Cornella and
On the basis of our results and previous reports10-11, 28, a plausible
catalytic cycle is proposed (Scheme 2). Initially, α-ketonate reacts
with Cu(OAc)2·H 2O to form CuII carboxylate I, which can undergo
decarboxylation to generate acyl CuII species II. Then, a nucleophilic
attack by indole occurs from its C3-position forming the
intermediate III, which is followed by a rearomatization to give
intermediate IV. The reductive elimination of IV provides the C3-
acylation product and a Cu0, which is reoxidized by O2 to afford
CuIIO. Cu(OAc)2 was finally regenerated with the aid of HOAc to
finish the catalytic cycle.
I. Larrosa, Synthesis, 2012, 44, 653.
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In summary, we have developed a mechanochemically (LAG)
induced
3-acylindoles
synthesis
by
copper-catalysed
decarboxylative acylation in a ball mill. In this protocol, only a
catalytic amount of Cu(OAc)2·H 2O is needed by employing O2 as
terminal oxidant. The reaction tolerates a wide range of functional
groups and gives 3-acylindoles in high yields. Moreover, a practical
gram-scale reaction and a facile synthesis of potential anticancer
drug SCB01A (BPR0L075, phase II trial) render the methodology
very efficacious.
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Conflicts of interest
There are no conflicts to declare.
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22 Phenylglyoxylic acid and sodium 2-oxo-2-phenylacetate were
also evaluated in this reaction, but gave lower product yields
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