Electrocatalytic intramolecular oxidative annulation of: N -aryl enamines into substituted indoles mediated by iodides

Article abstract of DOI:10.1039/c7cc00410a

An electrocatalytic reaction protocol is developed for achieving intramolecular dehydrogenative annulation of N-aryl enamines. It offers a simple and efficient way for the synthesis of indoles in an undivided cell. Good to excellent yields are obtained un

Full text of DOI:10.1039/c7cc00410a

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Electrocatalytic intramolecular oxidative annulation of N-aryl
enamines into substituted indoles mediated by iodides
Shan Tang,‡a Xinlong Gao,‡a and Aiwen Lei*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An electrocatalytic reaction protocol is developed for achieving decided to study iodine-promoted oxidative annulation
intramolecular dehydrogenative annulation of N-aryl enamines. It reactions under electrochemical conditions. In this work, we
offers a simple and efficient way for the synthesis of indoles in an would like to communicate our development on an external
undivied cell. Good to excellent yields are obtained under oxidant- chemical oxidant-free electrocatalytic oxidative annulation of
free and transition-metal-free conditions. Moreover, imidazo[1,2- N-aryl indoles for the synthesis of indoles (Scheme 1b).
a]pyridines could also be produced when N-pyridyl enamines were
R3
used as the substrates.
H H
R3
catalysts
R1
R1
2
R2
a)
H [O]
+
[O]
Indoles are important structure moieties, which widely
N
H
R2
N
H
distributed
in
natural
products,
pharmaceuticals,
agrochemicals and materials.1 Continuous efforts have been
devoted to developing efficient methods regarding their
synthesis.2 One of most straightforward strategies is the
intramolecular oxidative cyclization of N-aryl enamines.3 Such
transformations have been previously accomplished by using
stoichiometric or excess amount of oxidants such as Cu(II)
R3
H H
R3
R2
electricity
R1
b)
R2
R1
H
+
↑
2
N
H
N
H
Scheme 1. Intramolecular dehydrogenative C-H/C-H cross-coupling for
salts,4 hypervalent iodine reagents,5 N-bromosuccinimide the synthesis of indoles.
(NBS)6 and oxygen7 (Scheme 1a). From the viewpoint of atom-
Ethyl 3-phenyl-3-(phenylamino)acrylate (1a) was used as the
economic and sustainable chemistry, direct oxidative
annulation of N-aryl enamines under oxidant-free conditions
with hydrogen evolution is more appealing.8
model substrate to test the reaction conditions. By using KI as
the electrolyte under 7 mA constant current, the desired
indole 2a was obtained in 72% yield in an undivided four-
necked bottle (Table 1, entry 1). Further optimization was
carried out by adding co-solvents into the reaction system.
Acetonitrile and 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP)
suppressed the oxidative annulation process (Table 1, entries 2
and 5). Alcohols such as methanol and isopropanol promoted
the formation of indole (Table 1, entries 3 and 4) while water
gave the best result, which afforded 2a in an excellent yield
(Table 1, entry 6). The effect of electrolyte was also explored.
Iodide salts such as NaI and tetrabutylammonium iodide gave
similar results with KI (Table 1, entries 7 and 8). Only 30% yield
of 2a could be obtained by using NaBr instead of KI (Table 1,
entry 9) In this transformation, KI not only served as the
electrolyte but also acted as redox mediator for this oxidative
annulation (Table 1, entry 10). As was expected, no desired
product could be obtained by using tetrafluoroborate or
perchlorate as the electrolyte (Table 1, entries 10 and 11).
Carbon anode and nickel cathode can be used for this
Electrosynthesis is recognized as
a
versatile and
environmentally friendly synthetic tool and attracted
continuous interests.9 Over the past decade, application of
electrochemical anodic oxidation to replace chemical oxidants
in dehydrogenative cross-coupling reactions has received
increasing attention.10 Moreover, redox mediators have been
widely used to achieve indirect anodic oxidation processes.11
Recently, our group was interested in iodine-catalysed
oxidative annulation for the synthesis of heterocycles.12
However, these reactions required the use of strong oxidants
especially peroxides. Since iodide salts have been reported to
act as redox mediators under electrochemical conditions,13 we
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transformation while with decreased reaction efficiency (Table,
entries 12 and 13).
Table 1. Condition optimization.
a Reaction conditions: Pt plate anode, Pt plate cathode, constant current = 7
mA (Janode = 12 mA/cm2), 1a (0.20 mmol), KI (0.15 M), DMF (10.0 mL), co-
b
solvent (0.2 mL), room temperature,
3
h (3.9 F). Yields of 2awere
determined by GC analysis with biphenyl as the internal standard, n.d. = not
c
detected. Graphite rod anode was used instead of Pt anode. d Nickel plate
cathode was used instead of Pt plate cathode.
With the optimized condition in hand, we then turned to
explore the functional group tolerance for the synthesis of
indoles (Table 2). Electron neutral N-phenyl enamines showed
excellent reactivity in the synthesis of indoles (2a-2h). Methyl
groups at the para or ortho position did not affect the reaction
efficiency (2b and 2c while ortho-methyl substituent led to a
slightly decreased reaction efficiency (2d). Halide substituents
including F, Cl, Br and even I were all well tolerated under the
electrochemical conditions (2e-2h). Both strong electron-rich
and electron-deficient N-phenyl enamines were all able to
a Standard conditions: Pt plate anode, Pt plate cathode, constant current = 7
mA (Janode = 12 mA/cm2), 1a (0.20 mmol), KI (1.5 mmol), DMF (10.0 mL), H2O
(1.0 mL), room temperature, 3 h (3.9 F).
furnish corresponding indoles
(2i-2k). Besides N-phenyl
enamines, N-naphthyl and N-pyridyl enamines were also
suitable in this transformation which afforded the desired
indole in good yields (2l and 2m). Replacement of carboxylic
ester by ketone led to decreased reaction efficiency (2n). N-
Phenyl enamines bearing either electron-donating or electron-
withdrawing substituents on the C-2 aryl group all
Scheme 2. Synthesis of imidazo[1,2‑a]pyridine.
Since the method had been established, efforts were paid to
demonstrated good reactivity for the synthesis of indoles (2o- get some insights into the reaction mechanism. Since iodide
2r). Changing the C-2 substituent from phenyl group to was able to be oxidized under electrochemical conditions,
isopropyl group also gave a decreased reaction yield (2o). control experiments were conducted by using 2 equiv of iodine
Importantly, imidazo[1,2-a]pyridine could be synthesized when or N-iodosuccinimide (NIS) as oxidant directly in the reaction
N-pyridyl enamines were applied as the substrates (Scheme 2). of 1a. Without electricity, no desired cyclization product could
be observed by using iodine as the oxidant (Scheme 3a) while
Table 2. Synthesis of indoles.a
a high reaction yield of indole 2a could be obtained by using
NIS as the oxidant (Scheme 3b). In the next step, radical
inhibition experiments were carried out to probe whether the
reaction went through a radical reaction pathway. By adding 1
equiv. of 2,2,6,6-tetramethylpiperidin-1-yl oxyl (TEMPO) or
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butylated hydroxytoluene (BHT) into the reaction system, no pyridyl enamines were used as the substrates. The reactions
desired product could be observed in both cases (Scheme 3c).
proceed in high efficiency and good functional group tolerance
by using KI as the electrolyte under external oxidant-free
conditions. Mechanistically, KI not only acts as the electrolyte
but also participates in the redox processes of the oxidative
annulation.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003), the Ministry of
Science and Technology of China (2012YQ120060), the
Fundamental Research Funds for the Central Universities and
the Program of Introducing Talents of Discipline to Universities
of China (111 Program)
Scheme 3. Mechanistic experiments.
Notes and references
Based on the above experimental results and previous
reports,6 a plausible mechanism was put forward in Scheme 4.
In the first step, hyperiodide intermediate (I+) can be
generated from iodide ion through twice anodic oxidation.
Then N-aryl enamine 1a reacts with in situ generated I+ to form
an N-iodo intermediate. Homolysis of the N-I bond will initiate
the cyclization process. Intramolecular radical addition,
oxidation and deprotonation lead to the formation of indole
2a. Meanwhile, the generated iodine radical can be either
oxidized by anode to regenerate the hyperiodide intermediate.
At the same time, concomitant cathodic reduction of water
releases hydrogen gas during the reaction.
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Scheme 4. Proposed mechanism.
Conclusions
In
conclusion,
an
electrocatalytic
intramolecular
dehydrogenative annulation of N-aryl enamines was
developed for the first time. It provided an environmentally
friendly way for the synthesis of indoles. Moreover,
imidazo[1,2‑a]pyridines could also be produced when N-
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