Direct C-2 Carboxylation of 3-Substituted Indoles Using a Combined Br?nsted Base Consisting of LiO-tBu/CsF/18-crown-6

Article abstract of DOI:10.1002/ejoc.202000272

Herein, we report that a combination of LiO-tBu, CsF, and 18-crown-6 can be used to carry out the carboxylation of indole derivatives at the C-2 position under an ambient CO₂ atmosphere. Substrates bearing an electrophilic substituent (i.e., cyano, formyl, benzoyl, phenylsulfonyl, phenylsulfinyl, and chloride) at the C-3 position are smoothly converted into their corresponding carboxylated products with high functional group compatibility.

Full text of DOI:10.1002/ejoc.202000272

A Journal of
Accepted Article
Title: Direct C-2 carboxylation of 3-substituted-indoles using a
combined Brønsted base consisting of LiO-t-Bu/CsF/18-crown-6
Authors: Masanori Shigeno, Itsuki Tohara, Kanako Nozawa-Kumada,
and Yoshinori Kondo
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000272
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000272
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10.1002/ejoc.202000272
European Journal of Organic Chemistry
COMMUNICATION
Direct C-2 carboxylation of 3-substituted-indoles using a
combined Brønsted base consisting of LiO-t-Bu/CsF/18-crown-6
Masanori Shigeno,*[a] Itsuki Tohara,[a] Kanako Nozawa-Kumada,[a] and Yoshinori Kondo*[a]
[a]
Dr. M. Shigeno, I. Tohara, Dr. K. Nozawa-Kumada, Prof. Dr. Y. Kondo
Department of Biophysical Chemistry
Graduate School of Pharmaceutical Science, Tohoku University
6-3 Aoba, Sendai 980-8578 (Japan)
E-mail: masanori.shigeno.e5@tohoku.ac.jp (MS), yoshinori.kondo.a7@tohoku.ac.jp (YK)
http://www.pharm.tohoku.ac.jp/~henkan/lab/henkan_top.html
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, we report that a combination of LiO-t-Bu, CsF, and
18-crown-6 can be used to carry out the carboxylation of indole
derivatives at the C-2 position under an ambient CO2 atmosphere.
Substrates bearing an electrophilic substituent (i.e., cyano, formyl,
benzoyl, phenylsulfonyl, phenylsulfinyl, and chloride) at the C-3
position are smoothly converted into their corresponding carboxylated
products with high functional group compatibility.
Indoles constitute the core motif of a wide range of natural
compounds, pharmaceuticals, and functional organic materials.1
Indole 2-carboxylic acid derivatives are a particularly important
family among them, which find widespread use in biologically
active compounds and as synthetic precursors for their
synthesis.2 Accordingly, the development of competent synthetic
methodology is highly desirable. C–H bond carboxylation of
indoles at the C-2 position using CO2 as a low-cost, abundant, and
non-toxic C1 unit has been used for this purpose.3 Conventionally,
strong Brønsted bases such as BuLi, i-Pr2NLi, and (i-Pr2N)2Mg
have been used in the reaction, which consists of a two-step
protocol including the deprotonation of the C–H bond at the C-2
position and subsequent carboxylation of the resulting 2-lithio-
and 2-magnesio-indole intermediates (Table 1a).4 However, the
functional group tolerance of this reaction is rather limited, owing
to the use of these strong bases and the preparation of the
reactive carbanion intermediates. Transition metal catalysis has
been employed for direct carboxylation using a one-step reaction
(Table 1b). Takaya, Iwasawa, et al. have reported that rhodium
catalyzes the carboxylation of 1-methylindole in the presence of
AlMe1.5(OEt)1.5, however, the scope of the indole substrate used
in the reaction was not demonstrated.5 Thus, further development
of an efficient and practical carboxylation reaction with high
functional group compatibility is of great interest in organic
chemistry.6–9
Figure 1. C–H carboxylation of indoles at the C-2 position and those related to
this study.
Recently, the direct carboxylation of (hetero)aromatic
substances using Brønsted bases, wherein the (hetero)aromatic
carbanion species generated via deprotonation is trapped in situ
with CO2, has been thoroughly investigated (Figure 1c).10–12 This
methodology is attractive in terms of its potential to expand the
substrate scope and functional group tolerance, and also benefits
from its operational simplicity. Among these reactions, Kobayashi
et al. demonstrated that the carboxylation of NH-indoles takes
place at the C-3 position in the presence of LiO-t-Bu via
deprotonation of the N–H bond (Figure 1, i).11 However, no reports
have described the application of this system to the carboxylation
of indoles at the C-2 position.
We previously reported that a combined Brønsted base
system consisting of LiO-t-Bu/CsF/18-crown-6 can be
successfully used for the carboxylation of electron-rich
heteroarenes, such as benzothiophene and benzofuran
derivatives (Figure 1, i).12 Herein, we found that this system can
efficiently carry out the C-2 carboxylation of indole substrates
bearing an electron-withdrawing group (i.e., cyano, aldehyde,
ketone, sulfonyl, sulfinyl, and chloride) at the C-3 position (Figure
1, ii). Substituents on the benzene ring of the indole are
1
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10.1002/ejoc.202000272
European Journal of Organic Chemistry
COMMUNICATION
compatible in the reaction, which include methyl, methoxy,
methylthio, fluorine, chlorine, bromine, iodine, and nitro groups.
This study began by optimizing the carboxylation conditions
using 3-cyano-1-methylindole 1a as a model substrate (Table 1).
A mixture of 1a (0.30 mmol), alkoxide base (0.90 mmol), and
additive(s) (0.90 mmol) in 1,3-dimethyl-2-imidazolidinone (DMI)
(1.5 mL) was stirred at 100 C under an ambient CO2 atmosphere.
After 15 h, the reaction mixture was treated with methyl iodide at
60 C. A standard extractive work-up afforded the crude product,
which was used to determine the yield of the target carboxylated
product 2a using NMR spectroscopy. The use of LiO-t-Bu
afforded 2a, albeit in 7% yield (entry 1). The addition of CsF
improved the product yield to 28% (entry 2). Furthermore,
employing 18-crown-6 in the reaction provided 2a in 82% yield
(entries 3–5). The use of LiO-t-Bu/CsF/18-crown-6 was essential
in the reaction (entries 6 and 7). Moreover, decreasing the amount
of these reactants (2 equiv.) reduced the product yield (entry 8),
while the use of other alkoxide bases (NaO-t-Bu, KO-t-Bu, and
LiOMe) or alkali-metal halides (RbF, CsCl, and CsI) was not as
effective (entries 9–14).13 Finally, when the reaction temperature
was increased to 120 C, product 2a was isolated in 97% yield
(entry 15). When the reaction was scaled up to 1.0 mmol, a high
yield of 2a was still observed (entry 16).
With the optimized conditions for the carboxylation reaction in
hand, we next examined the substrate scope using 3-
cyanoindoles (Figure 2). Substrates 1b–d bearing electron-
donating methyl, methoxy, and methylthio groups, were used in
the reaction and their corresponding carboxylated products were
prepared in 85, 95, and 87% yields, respectively. Halogen-
substituted indoles 1e–h with F, Cl, Br, and I in the 5-position also
yielded their corresponding carboxylated products in excellent
yields (90, 92, 99, and 96%, respectively). The reactions of 1i and
1j, which contain a chloride atom at the 6- and 7-positions,
respectively, also proceeded in high yields. Substrates 1k–n
containing benzyl, methoxymethyl, phenyl, and 2-pyridyl groups
on the nitrogen atom were investigated in the reaction and
afforded the desired products in high yields (91, 94, 90, and 88%,
respectively).
Table 1. Optimization of the reaction conditions used in the carboxylation of 1a.a,
b
Entry
Alkoxide base
Additive(s)
Yield of 2a
(%)b
1
2
3
4
5
6
7
8
LiO-t-Bu
LiO-t-Bu

7
CsF
28
21
51
82
6
LiO-t-Bu
CsF, 12-crown-4
CsF, 15-crown-5
CsF, 18-crown-6
18-crown-6
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu

CsF, 18-crown-6
0
LiO-t-Bu (2 equiv.)
CsF (2 equiv.), 18-
crown-6 (2 equiv.)
65
9
NaO-t-Bu
KO-t-Bu
LiOMe
CsF, 18-crown-6
CsF, 18-crown-6
CsF, 18-crown-6
RbF, 18-crown-6
CsCl, 18-crown-6
CsI, 18-crown-6
CsF, 18-crown-6
CsF, 18-crown-6
38
10
11
12
13
14
15
16
43
1
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
67
8
1
quant. (97)c,d
(95)d,e
aCarboxylation: 1a (0.30 mmol), CO2 (1 atm), alkoxide base (0.90 mmol),
additive(s) (0.90 mmol), DMI (1.5 mL), 100 C, 15 h. Methyl esterification: MeI
(0.90 mmol), 60 C, 2 h. bThe yield of 2a was determined using 1H NMR
spectroscopy with 1,1,2-trichloroethane as an internal standard. cThe reaction
was conducted at 120 C. dThe yield reported in the parenthesis denotes the
isolated yield. eCarboxylation: 1a (1.0 mmol), CO2 (1 atm), LiO-t-Bu (3.0 mmol),
CsF (3.0 mmol), 18-crown-6 (3.0 mmol), DMI (5.0 mL), 120 C, 15 h. Methyl
esterification: MeI (3.0 mmol), 60 C, 2 h.
Figure 2. Scope of 3-cyanoindoles used in the carboxylation reaction.a, b aThe
reactions were conducted on a 0.3 mmol scale. bThe isolated yields are reported.
cThe reaction was conducted at 140 C. dThe reaction was conducted at 130 C.
2
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10.1002/ejoc.202000272
European Journal of Organic Chemistry
COMMUNICATION
The reaction system was then extended to the reaction of 3-
substituted-indoles bearing an electron-withdrawing group other
than a cyano group (Figure 3). 1-Methyl-3-formylindole 3a was
used in the carboxylation and furnished the target product 4a with
the formyl moiety tolerated in the reaction. Its derivatives 3b–f,
which comprise methoxy, chloro, bromo, iodo, and nitro groups,
underwent the carboxylation reaction to give their corresponding
products in good yields (91, 94, 97, 94, and 93%, respectively). 3-
Formyl-7-azaindole 3g was also used in the reaction and
produced its corresponding carboxylated product in 82% yield. In
these reactions, side reaction of self-condensation, wherein the
deprotonatively formed indoyl carbanion species adds onto the
formyl moiety of another molecule, was not observed. This is
presumably ascribed to the relatively low reactivity
(electrophilicity) of the formyl group compared to that of CO2,
owing to the presence of the electron-rich indoyl substituent,14
and/or ascribed to the protection of the formyl moiety as a
hemiacetal form in the reaction with the tert-butoxide base.15 Then,
the reaction of 3-benzoyl-1-methylindole 3h was carried out and
afforded product 4h in 66% yield. When substrates 3i and 3j
bearing phenylsulfonyl and phenylsulfinyl groups were examined,
the target products were obtained in 77 and 91% yields,
respectively. 3-Chloro-substituted indole 3k also furnished the
carboxylated product in 81% yield.16
Figure 4. Carboxylations of 3-formyl-substitued-heteroarenes other than the
indole.a, b aThe reactions were conducted on a 0.3 mmol scale. bThe isolated
yields are reported. cThe reaction was conducted at 80 C. dThe reaction was
conducted at 130 C.
5a–c were employed in the reactions, the desired carboxylated
products were produced in 93, 86, and 52% yields, respectively.
The reaction was confirmed to proceed via the formation of a
tert-butyl carbonate species (Scheme 1). When the reaction of 1a
was carried out in the presence of [LiOCO2-t-Bu], CsF, and 18-
crown-6 under an Ar atmosphere, the carboxylated product 2a
was obtained in 92% yield. The compatibility of the weak aromatic
carbon–halogen bonds (i.e., C–Br and C–I)17 in substrates 1g, 1h,
3d, and 3e was a result of the in situ generation of the weaker
Brønsted base of the carbonate base derived from tert-butoxide.18
Scheme 1. Carboxylation of 1a using [LiOCO2-t-Bu], CsF, and 18-crown-6
under an Ar atmosphere.a, b aThe reaction was conducted on a 0.3 mmol scale.
bIsolated yield.
The proposed mechanism for the carboxylation reaction is
depicted in Scheme 2. The carbonate base [MOCO2-t-Bu] (M =
Cs coordinated by 18-crown-6) or tert-butoxide [MO-t-Bu], which
are in the equilibrium under a CO2 atmosphere, deprotonates 1a
19
at the C-2 position to form indoyl carbanion species A.18,
Subsequent reaction of A with CO2 occurs to furnish carboxylated
product B.
Figure 3. Scope of 3-substituted indoles bearing an electron-withdrawing group
b
used in the carboxylation reaction.a, aThe reactions were conducted on a
0.3 mmol scale. bThe isolated yields are reported. cThe reaction was conducted
at 150 C. dThe reaction was conducted at 160 C. eThe reaction was conducted
at 180 C.
Scheme 2. Proposed mechanism for the carboxylation reaction.
In summary, direct carboxylation of a variety of indole
derivatives efficiently takes place at the C-2 position using a
combined Brønsted base consisting of LiO-t-Bu, CsF, and 18-
crown-6. An electron-withdrawing substituent at the C-3 position,
Carboxylations
of
3-formyl-substitued-heteroaromatic
substrates, other than the indole, were also tested (Figure 4).
Thus, when benzothiophene, benzofuran, and pyrrole derivatives
3
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10.1002/ejoc.202000272
European Journal of Organic Chemistry
COMMUNICATION
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Acknowledgements
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This work was financially supported by JSPS KAKENHI Grant
Number 19H03346 (YK), JSPS KAKENHI Grant Number
19K06967 (MS), Grand for Basic Science Research Projects from
The Sumitomo Foundation (MS), Yamaguchi Educational and
Scholarship Foundation (MS), NIPPON SHOKUBAI Award in
Synthetic Organic Chemistry, Japan (MS), The Uehara Memorial
Foundation (MS), and also the Platform Project for Supporting
Drug Discovery and Life Science Research funded by Japan
Agency for Medical Research and Development (AMED) (MS,
KNK, and YK).
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Keywords: • Indoles • Carbon dioxide fixation • C1 building
blocks • Brønsted base • CH functionalization
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coworkers
also
reported
that
carboxylation
of
1-(tert-
butoxycarbonyl)indole derivatives occurs by deprotonative alumination at
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4
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10.1002/ejoc.202000272
European Journal of Organic Chemistry
COMMUNICATION
[16] 1-Methyl-3-phenylindole and 1-methylindole were also used as
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[18] Lan and Yu et al. noted that the equilibrium is mainly shifted to the
carbonate side. See: L. Song, L. Zhu, Z. Zhang, J.-H. Ye, S.-S. Yan, J.-
L. Han, Z.-B. Yin, Y. Lan, D.-G. Yu, Org. Lett. 2018, 20, 3776.
[19] Krenske and O’Brien et al. developed the catalytic Wittig reaction using
[NaOCO2-t-Bu] as a weak base, and suggested that [NaOCO2-t-Bu]
slowly releases t-BuONa in situ. See: E. E. Coyle, B. J. Doonan, A. J.
Holohan, K. A. Walsh, F. Lavigne, E. H. Krenske, C. J. O’Brien, Angew.
Chem. Int. Ed. 2014, 53, 12907.
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10.1002/ejoc.202000272
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Key Topic: Indole carboxylation
A combination of LiO-t-Bu, CsF, and 18-crown-6 can be used to carry out the carboxylation of indole derivatives at the C-2 position
under an ambient CO2 atmosphere. Substrates bearing an electrophilic substituent (i.e. CN, formyl, benzoyl, phenylsulfonyl,
phenylsulfinyl, and chloride) at the C-3 position are smoothly converted into their corresponding carboxylated products with high
functional group compatibility.
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