Synthesis of indoles via electron-catalyzed intramolecular C?N bond formation

Article abstract of DOI:10.1021/acs.orglett.8b02784

A new protocol for the preparation of N-substituted indole-3-carboxylates has been developed. The key C?N bond formation occurs under transition-metal-free conditions employing a t-BuOK/DMF system without special initiators or additives. Across a number o

Full text of DOI:10.1021/acs.orglett.8b02784

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Indoles via Electron-Catalyzed Intramolecular C−N
Bond Formation
Dmitry I. Bugaenko, Anastasia A. Dubrovina, Marina A. Yurovskaya, and Alexander V. Karchava*
Department of Chemistry, Moscow State University, Moscow 119234, Russia
S
* Supporting Information
ABSTRACT: A new protocol for the preparation of N-substituted
indole-3-carboxylates has been developed. The key C−N bond
formation occurs under transition-metal-free conditions employing
a t-BuOK/DMF system without special initiators or additives.
Across a number of substrates, indoles were afforded in yields
higher or comparable to those obtained under transition-metal-
catalyzed conditions. While demonstrating high functional group
tolerance, new conditions are particularly attractive for manufactur-
ing halogenated indoles that cannot be made in a pure form using
other metal-based catalytic methods.
eveloped over the past century, transition-metal-
catalyzed cross-coupling reactions have revolutionized
The indole structural motif is widespread in natural and
synthetic biologically active compounds.8 For decades, this
foundational heterocycle remains a privileged scaffold in drug
discovery research. It is important to note that among the
FDA-approved drugs currently in the market, 17 are indole-
containing compounds.9 Many methods for preparing
indoles,10 especially those recently developed, involve the use
of palladium-11 and copper-catalyzed reactions12 and have the
above shortcomings. Another approach based on oxidative
cyclizations mediated by hypervalent iodine compounds13
suffers from the use of toxic reagents, generation of a large
amount of waste, and low regioselectivity. Therefore,
alternative pathways to construct biologically relevant indole
targets are highly appealing.
Previously, we disclosed an efficient strategy toward N-
functionalized 1H-indole-3-carboxylates 1 via a Cu-14 or Fe-
catalyzed15 intramolecular cyclization of 3-amino-2-(2-
bromophenyl)acrylates 2 (Figure 1A). Compound 2 is easily
accessed from (2-bromophenyl)acetate, methyl formate, and
primary amine (Figure 1B).14a Several years later, this
disconnection was used for the synthesis of 2-substituted
analogues, employing a Pd catalyst.16 Substituted indole-3-
carboxylic acids are common building blocks for the synthesis
of biologically relevant indole compounds such as CPI-1205,17
a highly potent and selective inhibitor EZH2, that is currently
in clinical trial as an anticancer agent, and SPD 304,18 an
inhibitor of tumor necrosis factors α (Figure 1C). Compared
to other approaches,19 our strategy is advantageous due to its
modular character and wide scope, which enables the
systematic variations of N(1) and C(2) substituents. Utilizing
the same disconnection, herein we present the first electron-
catalyzed indole synthesis and a comparative analysis of
D
organic synthesis and incredibly expanded our opportunities to
construct complex valuable organic molecules. These greatly
efficient synthetic methodologies are currently in high demand
in everyday synthetic practice, including on an industrial scale.1
Despite their preeminent status among modern synthetic
methods, the transition-metal-catalyzed reactions are associ-
ated with several drawbacks: high cost and toxicity of transition
metals and ligands and trace metal contaminations in the final
products. The latter represents a serious practical concern in
the pharmaceutical industry and organic electronics and
require extra metal-removing steps, which are usually time-
demanding and expensive.2 Moreover, transition-metal-cata-
lyzed cross-coupling reactions of polyhalogenated substrates
often suffer from a partial dehalogenation.3
To address the above-mentioned shortcomings, much
attention has been paid recently to the development of
transition-metal-free cross-coupling reactions, especially those
employing the same starting materials (usually haloarenes) and
giving the same products as the transition-metal-catalyzed
reactions.2a Remarkably attractive protocols for the formation
of carbon−carbon4 and carbon−heteroatom5 bonds in a
transition-metal-free manner have been developed over the
past several years.
In the absence of a transition metal, the activation of
carbon−halogen bond can be achieved by a single-electron
transfer (SET) from an electron donor.2a,6 Although transition-
metal-free cross-coupling reactions were proposed to occur by
a way of radical or radical ion species, the true mechanism
sometimes remains unclear and may vary depending on the
substrates and reaction conditions.2a,4−6 In search of a general
mechanistic model, Studer and Curran have introduced a
paradigm “electron is a catalyst”.7 For electron-catalyzed cross-
coupling reactions, an electron formally acts as a catalyst
instead of a transition metal.
Received: August 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02784
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the yield (entries 2 and 3). When the reaction occurred with
less than 2 eqiuv of t-BuOK or at a lower temperature, the
yield of 1a was also decreased (entries 4 and 5). A slighter
lower yield was observed when the reaction time was
shortened (entry 6). Among the other solvents tested, only
DMSO gave a synthetically useful, though considerably lower,
yield (entries 7−10). Remarkably, indole 1a was obtained in
only 24% yield when DMAc was used instead of DMF (entry
8). Unlike published examples of electron-catalyzed intra-
molecular C−N coupling,5 the formation of indole 1a proved
to be effective without the addition of a small-organic-molecule
promoter.6 The use of degassed solvents and inert atmosphere
were, however, crucial to achieving a high efficiency (entry 11).
Having established the optimized conditions (Table 1, entry
1), we set out to investigate the reaction scope. First, we
examined the substrates 2b−q, derived from esters 3a−f and
substituted anilines (Scheme 1). Optimization of the initial
a,b
Scheme 1. Scope of the Reaction: Anilines
Figure 1. Approaches to N-substituted indole-3-carboxylates (A) and
their precursors (B); examples of biologically active compounds (C).
different reaction conditions for an intramolecular C−N bond
formation to afford indoles. The procedure is compatible with
polyhalogenated and sterically congested substrates, which are
challenging under transition-metal-catalyzed conditions.
To optimize the reaction conditions, we selected 2a as a
model substrate, prepared from 4-methoxyaniline and methyl
2-(2-bromophenyl)-2-formylacetate (3a), following our pre-
viously reported procedure.14a The substrate 2a was obtained
as a mixture of Z- and E-isomers; however, as demonstrated
previously,14 both of them can be easily converted to the
indole product. Testing of various base/solvent combinations
and varying of temperatures and reaction times revealed that t-
BuOK (2 equiv) in DMF gave the best result, and after 3 h at
125 °C under an argon atmosphere, the indole 1a was
obtained in almost quantitative isolated yield (Table 1, entry
1). Notably, the use of t-BuONa or K2CO3 led to a decrease in
Table 1. Optimization of the Reaction Conditions for the
a
Synthesis of Indoles
a
b
b
Performed on 0.1 mmol scale as a semione-pot procedure; Yields
entry
deviation from the standard conditions
yields (%)
c
are isolated yields calculated over two steps from 3. Yields under Cu,
Fe, and Pd catalysis were taken for comparison from refs 14a, 15, and
16, respectively. Compound 2h was obtained following ref 16;
cyclization time = 8 h.
1
2
3
4
5
6
7
8
none
100 (94)
24
t-BuONa instead of t-BuOK
K2CO3 instead of t-BuOK
1 equiv of t-BuOK instead of 2 equiv
110 °C instead of 125 °C
2 h instead of 3 h
DMSO instead of DMF
DMAc instead of DMF
NMP instead of DMF
o-xylene instead of DMF
without argon atmosphere
d
56
67
68
87
75
24
60
step revealed that quantitative formation of 2 from 3 and any
amine employed could be achieved by refluxing their mixture
in MeOH for 8 h. The whole process was designed as a
semione-pot procedure; initially, obtained compounds 2b−q
were subsequently used in the cyclization step after simple
removal of the solvent. Yields are calculated over two steps
from esters 3. The method showed generality with respect to
substrates possessing various substitution. The electronic
nature of the substituents in the benzene ring does not affect
the yield (e.g., 1c vs 1l). Also, cyclization of sterically crowded
9
10
11
traces
27
a
b
1
Performed on a 0.1 mmol scale. Yields determined by H NMR
using an internal standard. Yield of isolated product shown in
parentheses. See the SI for details.
B
DOI: 10.1021/acs.orglett.8b02784
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Organic Letters
Letter
substrates proceeded effectively, delivering the 7-substituted
indoles 1p,q in excellent yields. The process can employ
differently substituted anilines, including those containing
ortho-substituents and being considered as sterically demand-
ing (indoles 1m−o,q). Importantly, using the chloro-, bromo-,
and even iodo-substituted substrates allowed the preparation
of the corresponding halogenated indoles 1i,j,l−n in excellent
yields with no traces of dehalogenation products. Indoles
bearing fluoro substituents (1b,f,k) were also obtained. Despite
the appeal of halogenated products, their preparation leaves a
significant gap in the scope of most Pd-catalyzed reactions.3
For instance, cyclization of a Cl analogue of 2 under Pd-
catalyzed conditions was accompanied by a partial dechlori-
nation.16 While Cu- and electron-catalyzed conditions
normally are compatible with chloro substituents, reactions
of bromo and iodo substrates occur with a pronounced
decrease of yields.5,12,14 Thus, the formation of halogenated
indoles without loss of yield is an attractive feature of our new
conditions. Finally, cyclization of substrates containing the
base-sensitive acetyl group allowed us to obtain 1e, though in a
modest yield. Using our new protocol, N-arylindoles 1a,f,h,o
were afforded in better or comparable yields to those reported
using the same substrates under Cu-,14 Fe-,15 and Pd-
catalyzed16 conditions (Scheme 1).
the preparation of nonracemic chiral indoles as demonstrated
by the synthesis of 1w from (S)-(−)-α-methylbenzylamine
without the loss of ee.20 Utilizing highly bulky tert-butylamine
proved problematic: 1aa was obtained in only 37% yield.21
The developed conditions have been applied in a gram-scale
preparation of a PDG2 inhibitor 422 (Scheme 3A). Starting
Scheme 3. Transition-Metal-Free Preparation of Indoles
Based on Indole-3-carboxylates
Unfortunately, when these conditions were applied to 2
derived from alkylamines, N-alkylindoles were formed in low
yields with most of the starting materials being recovered.
Therefore, an additional screening of the reaction conditions
was performed.20 When 3 equiv of t-BuOK was employed at a
higher temperature and for a prolonged reaction time, indoles
1r−aa were obtained in moderate but still synthetically useful
yields (Scheme 2). Indoles containing tertiary amine (1s) and
hydroxy (1z) functionalities as well as the cyclopropyl moiety
(1x,y) were tolerated. Remarkably, the protocol is suitable for
from methyl o-(bromophenyl)acetate, formation of the acid 4
was accomplished in four steps in an overall 69% yield.20 The
key step afforded a 76% yield of the ester 1bb. Standard
reduction/oxidation and hydrolysis/decarboxylation sequen-
ces20 and the Larrosa decarboxylative iodination23 applied to
esters 1f,m,w provided transition-metal-free routes for indoles
5−7 of high synthetic value24 (Scheme 3B). Aldehyde 5, the
key intermediate for the preparation of SPD 304, was
previously obtained via a Cu-catalyzed N-arylation.18
a,b
Scheme 2. Scope of the Reaction: Alkylamines
Having developed new cyclization conditions, we com-
pared20 them to those previously disclosed.14−16 Neither
conditions are ideal, and their ranges of applicability
complement each other. While the electron-catalyzed con-
ditions are perfect for the preparation of N-aryl and particularly
halogenated indole-3-carboxylates, they proved less effective
for N-alkylated counterparts. Synthesis of indoles with tert-
alkyl substituents is especially difficult.
To test other halogenated substrates and provide some
insight into the mechanism of cyclization, additional experi-
ments were carried out.20 While an iodine-substituted substrate
gave the corresponding indole quantitatively, only a trace
amount of the product was obtained with its F and Cl
analogues. The addition of TEMPO, a common trapping
reagent for free radicals, completely inhibited the cyclization.
Similarly, 7,7′,8,8′-tetracyanoquinodimethane, a single-electron
scavenger, deactivates the reaction. Although several possible
mechanistic scenarios can be envisioned,20 the above features,
as well as the fact that oxygen-free solvent and atmosphere are
mandatory, allow us to presume that a single-electron-transfer
process and/or a formation of radical species might be
involved in this transformation. The radical nature of the
reaction was also supported by EPR experiments.20
a
b
Performed on a 0.1 mmol scale as a semione-pot procedure. Yields
c
are isolated yields calculated over two steps from 3. Yields under Cu,
Fe, and Pd catalysis were taken for comparison from refs14a, 15, and
16, respectively. See the SI for details. Compound 2y was obtained
following ref 16.
On the basis of the Studer−Curran proposal,7 the following
tentative catalytic cycle has been proposed for the indole
formation (Scheme 4). The reaction begins with the initial
d
e
C
DOI: 10.1021/acs.orglett.8b02784
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Organic Letters
Letter
Scheme 4. Proposed Mechanistic Cycle
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: karchava@org.chem.msu.ru.
ORCID
Dmitry I. Bugaenko: 0000-0002-5028-7244
Alexander V. Karchava: 0000-0001-9008-644X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.I.B. and A.A.D. thank the Russian Foundation of Basic
Research (Grant No. 18-33-01100) for partial support of this
work. The NMR equipment used in this research was
purchased under the Moscow State University Program of
Development. Thermo Fisher Scientific, MS Analytica
(Moscow, Russia), and Professor A. Makarov (Thermo Fisher
Scientific) are acknowledged for providing the MS equipment.
We thank Dr. A. V. Bogdanov (MSU) for the EPR experiments
and Dr. M. M. Ilyin (INEOS RAS, Moscow) for the
chromatographic determination of the ee values.
injection of an electron providing the actual catalyst, the
electron. Either the t-BuOK/DMF system25 or an azaallyl
anion derived from 2 upon deprotonation can serve as the
electron donor to initiate the process. Next, the reduction of 2
via a single-electron transfer generates the corresponding
radical anion A, which upon fragmentation delivers the radical
B alongside with bromide-ion. The following intramolecular
trapping of B with the N-nucleophilic moiety generates the
radical anion C. Finally, C acts as an electron donor for the
next molecule of substrate 2, thus giving the product 1 and
liberating the electron back to the catalytic cycle. This
sequence is like the SRN1 mechanism.26 Alternatively, C can
be formed from A via a concerted pathway without the
generation of B, which is similar to the SRN2 mechanism.26b
Although the mechanism of this cyclization remains to be
elucidated, the high selectivity observed for polyhalogenated
substrates suggests the latter pathway to be the more likely.
Moreover, the conversion of A to C appears to be a rate-
determining step in the whole cyclization.
In summary, we have disclosed a new synthetic strategy for
N-functionalized indole-3-carboxylates, based on electron-
catalyzed intramolecular C−N bond formation. The protocol
uses the t-BuOK/DMF system for the cyclization of 3-amino-
2-(2-bromphenyl)acrylate, affording the corresponding indoles
in moderate to excellent yields. Unlike the transition-metal-
based methods, the electron-catalyzed conditions are suitable
for the synthesis of halogenated indoles without traces of
dehalogenation products. While avoiding the use of expensive
catalysts, this method is appealing for rapid generation of
diverse libraries of indole containing compounds in drug
discovery. The extension of this transition-metal-free method-
ology of indole synthesis and further mechanistic study are
currently ongoing in our laboratory.
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(20) See the Supporting Information for details.
(21) A similar negative effect of steric hindrance on the cyclization
to indoles employing Cu and Pd catalysts was observed previously:
(a) Reference 14a. (b) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem.
Commun. 2007, 4764−4766.
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E
DOI: 10.1021/acs.orglett.8b02784
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