Synthesis of Highly Substituted 2-Arylindoles via Copper-Catalyzed Coupling of Isocyanides and Arylboronic Acids

Article abstract of DOI:10.1021/acs.orglett.8b01132

Highly functionalized 2-arylindoles were synthesized from 2-alkenylarylisocyanides and arylboronic acids using a simple, inexpensive copper catalyst. The reaction exhibits excellent functional group tolerance for both the arylisocyanide and boronic acid coupling partners. To avoid the direct handling of the pungent arylisocyanide starting materials, continuous flow chemistry is further demonstrated to provide safe and effective access to 2-arylindoles through in situ dehydration and cyclization of easy-to-handle 2-alkenyl-N-formylanilines.

Full text of DOI:10.1021/acs.orglett.8b01132

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Highly Substituted 2‑Arylindoles via Copper-Catalyzed
Coupling of Isocyanides and Arylboronic Acids
Laurel M. Heckman, Zhi He,† and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: Highly functionalized 2-arylindoles were synthe-
sized from 2-alkenylarylisocyanides and arylboronic acids using
a simple, inexpensive copper catalyst. The reaction exhibits
excellent functional group tolerance for both the arylisocyanide
and boronic acid coupling partners. To avoid the direct
handling of the pungent arylisocyanide starting materials,
continuous flow chemistry is further demonstrated to provide safe and effective access to 2-arylindoles through in situ
dehydration and cyclization of easy-to-handle 2-alkenyl-N-formylanilines.
cycles.8,9 In the case of 2-arylindoles, the two current methods
he 2-arylindole motif is found in a variety of natural
1
employing arylisocyanides provide modest yields, require
Tproducts, therapeutics, and drug candidates.
Key
examples include bazedoxifene,1e a treatment for postmeno-
stoichiometric amounts of palladium, or utilize difficult to
handle 2-alkynylarylisocyanides (Scheme 1a).10,11 Alternatively,
pausal osteoporosis, and the natural product cladoniamide G,2
which demonstrates antibreast cancer activity. In addition, 2-
arylindoles form the core of several medicines currently in
development. Specifically, Kenpaullone has shown anticystic
fibrosis activity,3 2-phenylindole-3-carboxaldehydes have shown
high antiproliferative activity in breast cancer cell lines,4 and 2-
pyridylindole has potential application as an antidepressant
(Figure 1).5 Despite the vast array of methods to synthesize 2-
arylindoles,1c,6 new methods that efficiently access highly
decorated indoles remain desirable.7
Scheme 1. (A) Current Methods To Synthesize 2-
Arylindoles from Arylisocyanides; (B) Two-Step Synthesis of
2-Arylindoles from Arylisocyanides; (C) Synthesis of 2-
Arylindoles via Copper-Catalyzed Cyclization of 2-
Alkenylarylisocyanides
Recently, the amphoteric nature of arylisocyanides has been
exploited in the preparation of nitrogen-containing hetero-
2-iodo, 2-stannyl, and 2-boryl-substituted indoles have been
synthesized from isocyanides (Scheme 1b).12−14 Subsequent
cross-coupling has provided access to a variety of 2-arylindoles.
A general, one-step catalytic approach to highly substituted 2-
arylindoles directly from arylisocyanides has yet to be
developed.
Figure 1. Representative examples of highly substituted 2-arylindole-
containing molecules: current therapeutics, natural products, and
drugs in development.
Received: April 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of a Copper-Catalyzed Cyclization of Arylisocyanides with Arylboronic Acids
b
b
entry
boron reagent
base
copper cat.
additive
conversion (%)
yield (%)
c
1
2
3
4
5
6
7
8
Ar−BMIDA
Ar−Bpin
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
−
CuCl2
CuCl2
CuCl2
CuOTf2
−
CuCl2
CuCl2
CuCl2
−
−
−
−
−
−
−
air
87
72
93
93
42
68
49
89
<5
6
56
55
Ar−B(OH)2
Ar−B(OH)2
Ar−B(OH)2
Ar−B(OH)2
Ar−B(OH)2
Ar−B(OH)2
d
<1
d
<1
LiOt-Bu
14
39
KOt-Bu
a
Reaction conditions: aryl isocyanide 1a (0.1 mmol), 4-cyanophenylboronic acid (1.5 equiv), potassium tert-butoxide (1.3 equiv), and CuCl2 (0.1
b
equiv) were stirred in THF (2 mL) for 24 h at 65 °C under an inert atmosphere. Conversion and yield were determined using HPLC with
naphthalene as an internal standard. Trace product detected. No product detected.
c
d
Despite their unique and promising reactivity, arylisocyanides
remain underutilized owing to their offensive odor.15,16
Arylisocyanides are generally synthesized from the correspond-
ing aniline via formylation followed by dehydration. These
precursors to arylisocyanides, namely N-formylaniline and
anilines, are bench-stable, easy to handle, and frequently
commercially available. Thus, developing a telescoped
procedure in which the arylisocyanides can be synthesized in
situ from a benign precursor and immediately reacted would
enable their use in organic synthesis.
Continuous flow is uniquely suited to enable the safe use of
toxic, reactive, and dangerous reagents.17 Unlike traditional
batch chemistry, continuous flow reactors utilize narrow
diameter tubing that enables improved heat transfer during
exothermic reactions, improved mixing, and smaller quantities
of dangerous reagents at any given time.18 Additionally,
reactions can be telescoped, allowing the safe generation and
use of toxic or unstable intermediates.19 Herein, we describe a
facile copper-catalyzed cyclization of 2-alkenylarylisocyanides
and readily available boronic acids to access highly substituted
2-arylindoles and demonstrate the safe use of 2-alkenylaryl-
isocyanides via a continuous flow setup (Scheme 1c).
Inspired by the copper-catalyzed borylation of 2-alkenylaryl-
isocyanides,14 we began our studies by investigating the copper-
catalyzed reaction between arylisocyanide 1a and a variety of
arylboron reagents to generate 2-arylindole 2a (Table 1). Initial
reactions using easy to handle BMIDA and Bpin reagents
demonstrated the viability of the transformation, albeit with low
yields of 2a, <5% and 6%, respectively (Table 1, entries 1 and
2). Utilizing the more reactive 4-cyanophenylboronic acid gave
indole 2a in good yield (56%; Table 1, entry 3). Of note, these
reactions were heterogeneous in nature, with the copper
catalyst being incompletely solubilized. A more soluble
copper(II) triflate was tested and showed no improvement in
yield (Table 1, entry 4). As such, the inexpensive copper(II)
chloride (CuCl2) catalyst was used throughout. In the absence
of a copper catalyst, product formation was not observed
(Table 1, entry 5). Similarly, in the absence of a base, product
formation was not observed (Table 1, entry 6). We hypothesize
that, in solution, the alkoxide base activates the boronic acid,
forming a nucleophilic aryl boronate salt, which more readily
undergoes transmetalation with the copper catalyst. Consistent
with this proposal, use of lithium tert-butoxide (LiOt-Bu),
which is known to form a less activated boronate species,
resulted in a significantly lower yield of 2a (11%, Table 1, entry
7). Finally, we were pleased to find that the reaction is only
marginally air-sensitive, with only a modest reduction in yield
when the reaction is set up in the absence of air-sensitive
techniques (Table 1, entry 8).
Encouraged by these promising results, we explored the
scope of this copper-catalyzed cyclization of arylisocyanide 1a
with a variety of commercially available arylboronic acids to
afford the corresponding 2-arylindoles (Scheme 2). We
observed that both electron-donating and -withdrawing
substituents on the arylboronic acids were tolerated (2a−h).
Substrates containing a free amino group (2i) do not provide
an indole product. However, nitro-substituted boronic acids (an
amine surrogate) provided the corresponding indole in good
yield (2c). Indoles containing functional handles capable of
further elaboration, such as alkene, alkyne, bromide, and methyl
ketone, were synthesized in modest to good yield (2j−m).
Notably, our method allowed the synthesis of molecules
containing multiple heterocycles in a single step (2n and 2o).
A variety of 2-alkenylarylisocyanides were synthesized to
explore the scope of this method (Scheme 3). Both electron-
donating and -withdrawing groups on the 5, 6, and 7 positions
of the aryl ring of isocyanide 1 were tolerated, affording the
corresponding indole in good yield (3a−g). To expand the
scope of this method further, orthogonal electrophilic vinyl
components of aryl isocyanide 1 were explored. Both the
vinylogous nitrile 1i and, more interestingly, the poor Michael
acceptor, enamide 1h, proved competent in the reaction.
Unsurprisingly, isocyanide 1j containing the nonelectrophilic
styrenyl functional group was not transformed to the desired
indole 3j, and a mixture of 1j and decomposition were
observed.
Our method featuring a copper-catalyzed cyclization of
arylisocyanides with arylboronic acids demonstrates the
potential of arylisocyanides in the synthesis of nitrogen-
containing heterocycles. However, given their odor and variable
toxicity, we have additionally developed a telescoped,
continuous flow setup for their safe handling. The improved
setup consists of synthesizing the arylisocyanide 1a via
dehydration of arylformamide 4 and then accessing the highly
substituted aryl indole in a single step using the method
described herein (Table 2). Initially, we explored conditions to
B
DOI: 10.1021/acs.orglett.8b01132
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Scheme 2. Preparation of 2-Arylindoles from Various
Commercially Available Arylboronic Acids
Table 2. Development of a Two-Step Continuous Flow
a
a b
,
Synthesis of Indole 2a from N-Formylaniline 4
a
Yields were determined using HPLC with naphthalene as an internal
standard.
decrease the reaction time of the copper-catalyzed cyclization of
arylisocyanide 1a to increase throughput and decrease reactor
size in the continuous flow setup. Copper flow reactors have
been utilized to decrease reaction times compared to their
batch reaction counterparts.20 Our continuous flow system
consists of mixing three streams containing arylisocyanide 1a,
arylboronic acid, and potassium tert-butoxide in a continuous
stirred tank reactor (CSTR) containing copper beads heated to
65 °C for 30 min (Scheme 4). We were pleased to observe
a
Reaction conditions: aryl isocyanide 1a (1 mmol), aryl boronic acid
(1.5 equiv), potassium tert-butoxide (1.3 equiv), and CuCl2 (0.1
equiv) were stirred in THF (15 mL) for 24 h at 65 °C under an inert
Scheme 4. Copper-Catalyzed Cyclization of Arylisocyanide
a
1a to Indole 2a in a CSTR
b
atmosphere. All yields in parentheses are the isolated product after
silica gel chromatography.
Scheme 3. Preparation of 2-Arylindoles from Various 2-
ab
,
Alkenylarylisocyanides
a
Yields were determined using HPLC with naphthalene as an internal
standard.
indole 2a in 56% yield, providing similar yields to our isolated
batch reactions (55% yield). NMP was added to increase
solubility and reaction rate.21,22
We then developed the dehydration of N-formylaniline in
continuous flow. Streams of 4, phosphorus oxychloride
(POCl3), and diisopropylethylamine (DIPEA) were mixed for
2.5 min, providing isocyanide 1a in 94% yield (Table 4, Module
1; see Supporting Information (SI) for details, Scheme S-3).
Dichloromethane (DCM) was chosen as the ideal solvent for
the dehydration of formamide 4 due to its compatibility with
the subsequent copper-catalyzed cyclization step, solubility of
starting materials, and its good separation from the aqueous
streams.
a
Reaction conditions: aryl isocyanide 1 (1 mmol), 4-cyanophenyl-
boronic acid (1.5 equiv), potassium tert-butoxide (1.3 equiv), and
CuCl2 (0.1 equiv) were stirred in THF (15 mL) for 24 h at 65 °C
b
under an inert atmosphere. All yields in parentheses are the isolated
product after silica gel chromatography.
Telescoping the dehydration of N-formylaniline 4 directly
into the copper-catalyzed cyclization yielded no indole product
(Table 2, entry 1; see SI for details). The acidic and amine
C
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byproducts formed in the dehydration step are not compatible
with the subsequent cyclization. The addition of liquid−liquid
membrane separators helped to remove the byproducts of the
dehydration through an aqueous extraction. After the addition
of a single in-line basic separation with 0.5 M K3PO4, a 9% yield
of indole 2a was observed (Table 2, entry 2). After a single
extraction, a stream of 1a retained water, so a drying column
consisting of a packed bed of 4 Å molecular sieves was added,
resulting in an increased, yet modest yield of 19% (Table 2,
entry 3). Finally, a slightly acidic separation with ammonium
chloride was added after the basic separation to remove any
remaining acid or amine byproducts. After two separations and
a drying column, indole 2a was observed in 51% yield over two
steps, a comparable yield to both the batch isolated yield of
55% and the single step CSTR yield of 56% (Table 2, entry 4).
The integrated flow setup with increased throughput (550
mg/h) consists of one PEEK cross-mixer, one perfluoroalkox-
yalkane (PFA) tubing reactor, two liquid−liquid membrane
separators, a packed bed containing 4 Å molecular sieves, a
surge tank, and a CSTR (35 mL) with copper beads (Scheme
5). This setup provided 2a in 49% yield over two steps,
a safe and effective approach to the synthesis of 2-arylindoles
from readily available 2-alkenyl-N-formylanilines in continuous
flow. We have shown that multiple incompatible reaction steps
can be telescoped through the use of liquid−liquid separators
and a drying column, which has the potential to be adapted to a
variety of sensitive isocyanide chemistry conducted in
continuous flow.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01132.
Experimental procedures and spectral data for isocya-
nides 1a−j, indoles 2a−o, and indoles 3b−j and
experimental procedures for the continuous flow system
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tfj@mit.edu.
ORCID
Scheme 5. Two-Step Continuous Flow Synthesis of Indole
a
2a from Simple N-Formylaniline 4
Timothy F. Jamison: 0000-0002-8601-7799
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Novartis-MIT Center for Continuous
Manufacturing for financial support. We thank several
colleagues at Novartis (Dr. Berthold Schenkel, Dr. Gerhard
Penn, Dr. Benjamin Martin, Dr. Francesco Venturoni, Dr.
Julien Haber, and Dr. Jorg Sedelmaier) for insightful
̈
discussions.
DEDICATION
■
†Dedicated to Dr. Zhi He, deceased September 24, 2016.
REFERENCES
■
(1) For recent reviews: (a) Sravanthi, T. V.; Manju, S. L. Indoles - A
promising scaffold for drug development. Eur. J. Pharm. Sci. 2016, 91,
1. (b) Zhang, M. Z.; Chen, Q.; Yang, G. F. A review on recent
developments of indole-containing antiviral agents. Eur. J. Med. Chem.
2015, 89, 421. (c) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.;
Kim, C. H.; Verma, A. K.; Choi, E. H. Biomedical importance of
indoles. Molecules 2013, 18, 6620. (d) Johansson, H.; Jørgensen, T. B.;
Gloriam, D. E.; Brauner-Osborne, H.; Pedersen, D. S. 3-Substituted 2-
̈
a
Yield of indole 2a (1.8 mmol) is isolated product after silica gel
phenyl-indoles: privileged structures for medicinal chemistry. RSC Adv.
2013, 3, 945. (e) Lal, S.; Snape, T. J. 2-Arylindoles: A Privileged
Molecular Scaffold with Potent, Broad-Ranging Pharmacological
Activity. Curr. Med. Chem. 2012, 19, 4828. (f) Welsch, M. E.;
Snyder, S. A.; Stockwell, B. R. Privileged scaffolds for library design
and drug discovery. Curr. Opin. Chem. Biol. 2010, 14, 347.
(2) Williams, D. E.; Davies, J.; Patrick, B. O.; Bottriell, H.; Tarling,
T.; Roberge, M.; Andersen, R. J. Cladoniamides A-G, tryptophan-
derived alkaloids produced in culture by Streptomyces uncialis. Org.
Lett. 2008, 10, 3501.
(3) Tolle, N.; Kunick, C. Paullones as inhibitors of protein kinases.
Curr. Top. Med. Chem. 2011, 11, 1320.
(4) Kaufmann, D.; Pojarova, M.; Vogel, S.; Liebl, R.; Gastpar, R.;
Gross, D.; Nishino, T.; Pfaller, T.; von Angerer, E. Antimitotic
activities of 2-phenylindole-3-carbaldehydes in human breast cancer
cells. Bioorg. Med. Chem. 2007, 15, 5122.
chromatography.
demonstrating the scalability of the system. Additionally, we
explored adding the formylation of a simple ortho-alkenylaniline
to our two-step continuous flow setup. However, a low yield of
12% of indole 2a was observed due to the increased complexity
of the impurity profile (see the SI for details). Given that the
batch preparation of 4 is straightforward, further inline
purification modules were not explored after the formylation
step.
In conclusion, we have developed a catalytic method for the
synthesis of highly substituted 2-arylindoles from 2-alkenyliso-
cyanides and arylboronic acids. Additionally, we have developed
D
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Organic Letters
Letter
(5) Dinnell, K.; Chicchi, G. G.; Dhar, M. J.; Elliott, J. M.;
Hollingworth, G. J.; Kurtz, M. M.; Ridgill, M. P.; Rycroft, W.; Tsao,
K. L.; Williams, A. R.; Swain, C. J. 2-Aryl indole NK1 receptor
antagonists: optimization of the 2-Aryl ring and the indole nitrogen
substituent. Bioorg. Med. Chem. Lett. 2001, 11, 1237.
(6) For recent reviews: (a) Heravi, M.; Rohani, S.; Zadsirjan, V.;
Zahedi, N. Fischer indole synthesis applied to the total synthesis of
natural products. RSC Adv. 2017, 7, 52852. (b) Inman, M.; Moody, C.
J. Indole synthesis − something old, something new. Chem. Sci. 2013,
4, 29. (c) Soto, S.; Vaz, E.; Dell’Aversana, C.; Alvarez, R.; Altucci, L.;
de Lera, A. R. New synthetic approach to paullones and character-
ization of their SIRT1 inhibitory activity. Org. Biomol. Chem. 2012, 10,
2101. (d) Taber, D. F.; Tirunahari, P. K. Indole synthesis: a review and
proposed classification. Tetrahedron 2011, 67, 7195. (e) Humphrey, G.
R.; Kuethe, J. T. Practical Methodologies for the Synthesis of Indoles.
Chem. Rev. 2006, 106, 2875.
(13) Fukuyama, T.; Chen, X.; Peng, G. A Novel Tin-Mediated Indole
Synthesis. J. Am. Chem. Soc. 1994, 116, 3127.
(14) Tobisu, M.; Fujihara, H.; Koh, K.; Chatani, N. Synthesis of 2-
boryl- and silylindoles by copper-catalyzed borylative and silylative
cyclization of 2-alkenylaryl isocyanides. J. Org. Chem. 2010, 75, 4841.
(15) Pinney, V. R. Malodorant Compositions. USOO6242489 B1
2001.
(16) Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offermann, K.
Isonitrile Syntheses. Angew. Chem., Int. Ed. Engl. 1965, 4, 472.
(17) For recent reviews: (a) Lummiss, J. A. M.; Morse, P. D.;
Beingessner, R. L.; Jamison, T. F. Towards More Efficient, Greener
Syntheses through Flow Chemistry. Chem. Rec. 2017, 17, 667.
(b) Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio,
C.; Ley, S. V.; Stevens, C. V. Taming hazardous chemistry by
continuous flow technology. Chem. Soc. Rev. 2016, 45, 4892.
(c) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-Flow
TechnologyA Tool for the Safe Manufacturing of Active
Pharmaceutical Ingredients. Angew. Chem., Int. Ed. 2015, 54, 6688.
(d) Newman, S. G.; Jensen, K. F. The role of flow in green chemistry
and engineering. Green Chem. 2013, 15, 1456. (e) Baumann, M.;
Baxendale, I. R.; Ley, S. V. The flow synthesis of heterocycles for
natural product and medicinal chemistry applications. Mol. Diversity
2011, 15, 613.
(18) For recent reviews: (a) Morse, P. D.; Beingessner, R. L.;
Jamison, T. F. Enhanced Reaction Efficiency in Continuous Flow. Isr.
J. Chem. 2017, 57, 218. (b) Plutschack, M. B.; Pieber, B.; Gilmore, K.;
Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry parallel.
Chem. Rev. 2017, 117, 11796. (c) Glasnov, T. N.; Kappe, C. O.
Continuous-flow syntheses of heterocycles. J. Heterocyclic Chem. 2011,
48, 11.
(19) For recent reviews: (a) McQuade, D. T.; Seeberger, P. H.
Applying flow chemistry: methods, materials, and multistep synthesis.
J. Org. Chem. 2013, 78, 6384. (b) Webb, D.; Jamison, T. F. Continuous
flow multi-step organic synthesis. Chem. Sci. 2010, 1, 675.
(20) Bao, J.; Tranmer, G. K. The utilization of copper flow reactors in
organic synthesis. Chem. Commun. 2015, 51, 3037.
(21) Cahiez, G.; Marquais, S. Copper-Catalyzed Alkylation of
Organomanganese Chloride Reagents1. Synlett 1993, 1993, 45.
(22) Cahiez, G.; Chaboche, C.; Jezequel, M. Cu-Catalyzed Alkylation
́ ́
of Grignard Reagents: A New Efficient Procedure. Tetrahedron 2000,
56, 2733.
(7) Vicente, R. Recent advances in indole syntheses: new routes for a
classic target. Org. Biomol. Chem. 2011, 9, 6469.
(8) For recent reviews: (a) Sadjadi, S.; Heravi, M. M.; Nazari, N.
Isocyanide-based multicomponent reactions in the synthesis of
heterocycles. RSC Adv. 2016, 6, 53203. (b) Chakrabarty, S.;
Choudhary, S.; Doshi, A.; Liu, F. Q.; Mohan, R.; Ravindra Manasa,
P.; Shah, D.; Yang, X.; Fleming Fraser, F. Catalytic Isonitrile Insertions
and Condensations Initiated by RNC−X Complexation. Adv. Synth.
Catal. 2014, 356, 2135. (c) Qiu, G.; Ding, Q.; Wu, J.; Maes, B.; Orru,
R.; Ruijter, E.; Orru, R.; Ruijter, E.; Orru, R. Recent advances in
isocyanide insertion chemistry. Chem. Soc. Rev. 2013, 42, 5257.
(d) Lygin, A. V.; de Meijere, A. Isocyanides in the synthesis of nitrogen
heterocycles. Angew. Chem., Int. Ed. 2010, 49, 9094. (e) Campo, J.;
García-Valverde, M.; Marcaccini, S.; Rojo, M. J.; Torroba, T. Synthesis
of indole derivatives via isocyanides. Org. Biomol. Chem. 2006, 4, 757.
(9) For select recent examples of heterocycle synthesis from
arylisocyanides: (a) Ye, Y.; Cheung, K. P. S.; He, L.; Tsui, G. C.
Synthesis of 2-(Trifluoromethyl)indoles via Domino Trifluoromethy-
lation/Cyclization of 2-Alkynylanilines. Org. Lett. 2018, 20, 1676.
(b) He, Y.; Wang, X.; Xiao, J.-A.; Pang, J.; Gan, C.; Huang, Y.; Huang,
C. Metal-free oxidative isocyanides insertion with aromatic aldehydes
to aroylated N-heterocycles. RSC Adv. 2018, 8, 3036. (c) Gao, Y.; Hu,
Z.; Dong, J.; Liu, J.; Xu, X. Chemoselective Double Annulation of Two
Different Isocyanides: Rapid Access to Trifluoromethylated Indole-
Fused Heterocycles. Org. Lett. 2017, 19, 5292. (d) Xiong, Z.; Wang, J.;
Wang, Y.; Luo, S.; Zhu, Q. Palladium-catalyzed C(sp2)-H amino-
imidoylation of isocyano-containing arenes: synthesis of amino
substituted N-heterocycles. Org. Chem. Front. 2017, 4, 1768. (e) Li,
D.; Mao, T.; Huang, J.; Zhu, Q. Denitrogenative Imidoyl Radical
Cyclization: Synthesis of 2-Substituted Benzoimidazoles from 1-Azido-
2-isocyanoarenes. Org. Lett. 2017, 19, 3223. (f) Evoniuk, C. J.; Gomes,
G. D. P.; Ly, M.; White, F. D.; Alabugin, I. V. Coupling Radical
Homoallylic Expansions with C-C Fragmentations for the Synthesis of
Heteroaromatics: Quinolines from Reactions of o-Alkenylarylisoni-
triles with Aryl, Alkyl, and Perfluoroalkyl Radicals. J. Org. Chem. 2017,
82, 4265. (g) Li, Y.; Chao, A.; Fleming, F. F. Isonitrile alkylations: a
rapid route to imidazo[1,5-a]pyridines. Chem. Commun. 2016, 52,
2111.
(10) Onitsuka, K.; Suzuki, S.; Takahashi, S. A novel route to 2,3-
disubstituted indoles via palladium-catalyzed three-component cou-
pling of aryl iodide, o-alkenylphenyl isocyanide and amine. Tetrahedron
Lett. 2002, 43, 6197.
(11) Nanjo, T.; Yamamoto, S.; Tsukano, C.; Takemoto, Y. Synthesis
of 3-Acyl-2-arylindole via Palladium-catalyzed Isocyanide Insertion and
Oxypalladation of Alkyne. Org. Lett. 2013, 15, 3754.
(12) For recent reviews: (a) Chakrabarty, S.; Choudhary, S.; Doshi,
A.; Liu, F.-Q.; Mohan, R.; Ravindra, M. P.; Shah, D.; Yang, X.;
Fleming, F. F. Catalytic Isonitrile Insertions and Condensations
Initiated by RNC-X Complexation. Adv. Synth. Catal. 2014, 356, 2135.
(b) Tokuyama, H.; Fukuyama, T. Indole synthesis by radical
cyclization of o-alkenylphenyl isocyanides and its application to the
total synthesis of natural products. Chem. Rec. 2002, 2, 37.
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