Copper-promoted decarboxylative direct C3-acylation of N-substituted indoles with α-oxocarboxylic acids

Article abstract of DOI:10.1039/c3cc40389k

A novel and efficient Cu-promoted decarboxylative direct C3-acylation of N-substituted indoles with α-oxocarboxylic acids for the synthesis of 3-acylindoles was developed. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc40389k

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Copper-promoted decarboxylative direct C3-acylation
of N-substituted indoles with a-oxocarboxylic acids†
Lin Yu,a Pinhua Lia and Lei Wang*ab
Cite this: Chem. Commun., 2013,
49, 2368
Received 17th January 2013,
Accepted 4th February 2013
DOI: 10.1039/c3cc40389k
www.rsc.org/chemcomm
A novel and efficient Cu-promoted decarboxylative direct C3-acylation
Acylated indoles are ubiquitous among biologically active
of N-substituted indoles with a-oxocarboxylic acids for the synthesis of natural products and pharmaceutical compounds like anti-
3-acylindoles was developed.
diabetic, anticancer, and inhibitor of HIV-1 integrase.18 Additionally,
related indoles have even been employed as fulgides and optical
Transition-metal-catalyzed decarboxylative coupling has attracted a switches,19 and 3-acylindoles are valuable intermediates in a variety
considerable interest in the past decade.1 It is an effective synthetic of functional group transformations.20 The synthesis of 3-acylindoles
method for C–C bond formations because the carboxyl group can has thus got considerable attention for over a century since the
direct the regioselectivity and the only waste product from the reaction 3-position of indole is the premier site for electrophilic sub-
is CO2.2 Extensive studies have been accomplished in this area since stitution.21–26 The most classic methods for the preparation of
Pd-catalyzed decarboxylative Heck-type reactions of benzoic acids of 3-acylindoles are Friedel–Crafts reaction,21 Vilsmeier–Haack
olefination were reported by Meyers et al.3 and Su et al.4 Representa- reaction,22 and indole Grignard reaction.23 The other significant
tive examples are Pd-catalyzed decarboxylative coupling of aryl halides approaches include Ru-catalyzed formylation and Fe-catalyzed
with benzoic acids by Goossen et al.,5 Wagner et al.6 and biaryl acylation of indoles by using anilines as the carbonyl source,24
coupling of aromatic carboxylic acids by Forgione et al.;7 Cu-catalyzed N-(2-haloacyl)pyridinium salt with indole,25 Pd-catalyzed acyl
decarboxylative coupling of potassium polyfluorobenzoates with aryl chloride with 3-indolyzinc chloride.26 These classic reactions
halides by Liu et al.;8 propiolic acids with aryl halides or amines by Lee require strict exclusion of moisture, stoichiometric Lewis acid
et al.,9 You et al.,10 and Jiao.11 Recently, alternative approaches for promoters,21c or a protecting functional group on nitrogen,21b or
decarboxylative acylations of aromatic C–H bonds with a-oxo- large number of environmental unfriendly POCl3 used.22a,b And,
carboxylic acids used as acyl sources were reported.12–14 Goossen they cannot tolerate the sensitive functional group under harsh
et al. first described Pd-catalyzed decarboxylative acylation of aryl conditions in some cases.23
bromides with potassium a-oxocarboxylates to afford diaryl ketones.12
Herein, we wish to report a novel and mild Cu-promoted
Shortly thereafter, Ge demonstrated a Pd-catalyzed decarboxylative decarboxylative direct acylation of C(3)–H of N-substituted
ortho-acylation of acetanilides and phenylpyridines with a-oxo- indoles with a-oxocarboxylic acids. The protocol has a broad
carboxylic acids via C–H bond activation.13 Duan also reported a substrate scope, simple reaction conditions, and good yields
Pd-catalyzed decarboxylative acylation of cyclic enamides with a-oxo- (Scheme 1).
carboxylic acids.14 Most recently, Kim proposed a Pd-catalyzed
Our initial efforts focused on the decarboxylation coupling
decarboxylative acylation of o-methyl ketoximes and phenylacetamides between N-methylindole (1a) and benzoylformic acid (2a) to
with a-oxocarboxylic acids via sp2 C–H bond activation.15 Meanwhile, examine suitable reaction conditions, and the screening results
Tan et al. developed a Pd-catalyzed decarboxylative ortho-acylation of are compiled in Table 1. When Cu(OAc)2ÁH2O was used as the
o-methyl oximes with phenylglyoxylic acids.16 However, transition- oxidant, Ag2CO3 exhibited the higher reactivity than Pd(OAc)2
metal-catalyzed decarboxylative acylation on aromatic heterocyclic (Table 1, entries 1 and 2). According to C-3 arylation of indoles
compounds or C-heteroatom bond formation is rarely explored.17
with benzoic acids,2b a Pd–Ag catalytic system was used for the
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000,
P. R. China. E-mail: leiwang@chnu.edu.cn; Fax: +86-561-309-0518;
Tel: +86-561-380-2069
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc40389k
Scheme 1
c
2368 Chem. Commun., 2013, 49, 2368--2370
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Table 1 Effect of catalyst and oxidant on the model reactiona
Entry
Catalyst
Oxidant
Yieldb (%)
1
2
3
4
5
6
7
8
Ag2CO3
Pd(OAc)2
PdCl2
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Ag2CO3
TBHP
H2O2
DTBP
K2S2O8
(NH4)2S2O8
PhI(OAc)2
DDQ
68
64
43
40
38
35
31
26
NR
NR
NR
75
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
—
9
10
11
12
BQ
Cu(OAc)2ÁH2O
a
Reaction conditions: 1a (0.25 mmol), 2a (0.50 mmol), catalyst (10 mol%),
b
oxidant (1.2 equiv.), CH3CN (2.0 mL), 110 1C, 10 h. Isolated yields.
reaction; however, the result was not satisfactory (Table 1, entry 3).
Subsequently, further exploration of a number of oxidants indicated
that TBHP was superior to the others when Cu(OAc)2ÁH2O was used
as catalyst, as is shown in Table 1, entry 4. Other oxidants, H2O2,
di-tert-butyl peroxide (DTBP), K2S2O8 and (NH4)2S2O8 showed lower
efficiency (Table 1, entries 5–8). No desired product was obtained
with PhI(OAc)2, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and
1,4-benzoquinone (BQ) used as oxidants (Table 1, entries 9–11). It is
delighted to find that 1.2 equiv. of Cu(OAc)2ÁH2O could promote the
reaction efficiently without other transition metal as catalyst
(Table 1, entry 12).
Then, various promoters were tested for the reaction and the
results are listed in Table S1 (ESI†). The promoter plays an important
role in the reaction. Optimization of the promoters demonstrated
that Cu(OAc)2ÁH2O was most effective, providing the desired product
3a in the highest yield. Lower yields of 3a were obtained by using
Cu(NO3)2Á3H2O, (NH4)2S2O8, Ag2CO3 and CuSO4Á5H2O as promoters.
Trace amount of 3a was obtained in the presence of CuBr2 or
Cu(acac)2. No desired product was detected by using Cu(OH)2,
CuCl2Á2H2O, Cu, K2S2O8, and TBHP (Table S1, ESI,† entries 1–12).
Of the solvents tested on the model reaction, CH3CN proved parti-
cularly suitable. Chlorobenzene, methanol, dioxane, DMSO, toluene,
p-xylene, CH3CH2OH and EtOAc were subsequently inferior. Only a
trace amount of 3a was observed when the reaction was carried out in
CH3NO2 or DCE. No desired product was found in THF, NMP or H2O
(Table S1, ESI,† entries 13–25). Increasing the amount of Cu(OAc)2Á
H2O did not increase the yield of 3a. The effect of temperature on
the reaction was also surveyed and the results showed that the yield
of 3a was not improved when the reaction temperature was increased
to 120 1C, but a lower yield was observed when the reaction was
performed at less than 100 1C. After surveying a variety of parameters,
we found that 1.2 equiv. Cu(OAc)2ÁH2O in CH3CN at 110 1C for 10 h is
the optimal condition (see Table S1, ESI† for details).
Scheme 2 The reactions of N-substituted indoles with 2-oxo-2-arylcarboxylic acids.a
the desired products in good yields. A wide range of indoles bearing
substituents on the N-atom and aromatic rings were investigated.
The results demonstrated that both electron-donating and electron-
withdrawing groups were tolerated. N-Methylindole, N-ethylindole,
N-allylindole, N-n-butylindole and N-benzylindole coupled with 2a
smoothly and gave the desired products in 58–75% yields (Scheme 2,
3a–e). Notably, the N-methylindoles with a methyl group in the C-2 or
C-7 position were well tolerated and the desired products (3f and 3g)
were obtained in 74% and 81% yields, respectively. 5-Methoxy-N-
methylindole, 6-fluoro-N-methylindole, 5-chloro-N-methylindole, and
5-bromo-N-methylindole could also couple with 2a to give the
desired products (3h–k) in 57–73% yields. It is important to note
that N-methyl-pyrrolo[2,3-b]pyridine gave the corresponding product
3l in 58% yield. However, a high electron-deficient N-methyl-5-
cyanoindole was ineffective in the reaction. Notably no desired
product was observed when free NH-indole was used under the
present reaction conditions.
To examine the scope of the substrates, the reactions of
N-substituted indoles with benzoylformic acid (2a) were performed
under the optimized reaction conditions. The results are summar-
ized in Scheme 2. As can be seen from Scheme 2, the reactions of 2a
with different N-substituted indoles could proceed well and offered
The reactions of various 2-oxo-2-arylacetic acids with N-methyl-
indole (1a) are also presented in Scheme 2. 2-Oxo-2-arylacetic
acids with an electron-donating group, such as Me or t-Bu on the
para-position of the benzene ring could react with 1a and afford
the corresponding decarboxylative acylation products 3m and 3n
c
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Although the exact mechanism of this decarboxylative coupling
is still not clear, on the basis of our results and literature,2b,27
a plausible mechanism is proposed and shown in Scheme 3.
a-Oxocarboxylic acid initially reacts with Cu(OAc)2ÁH2O to form a
Cu(II) carboxylate A, and then an acyl Cu(II) species B is generated via
a decarboxylation process. The obtained B can undergo attack at
the C3-position of indole to generate C, which is followed by a
rearomatization via C–H bond cleavage to D. The reductive elimina-
tion of D affords the C3-acylation product and Cu(0).
In summary, we have demonstrated a novel and efficient
Cu-promoted decarboxylative direct acylation of indoles with
a-oxocarboxylic acids. In the presence of Cu(OAc)2ÁH2O, a variety of
a-oxocarboxylic acids reacted with N-substituted indoles to generate
the corresponding C-3 acylated indoles exclusively in good yields.
The protocol has a broad substrate scope and simple reaction
conditions. The detailed reaction mechanism and further applica-
tions are currently under way.
This work was financially supported by the National Science
Foundation of China (No. 21172092).
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c
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