Modular Synthesis of Polysubstituted Quinolin-3-amines by Oxidative Cyclization of 2-(2-Isocyanophenyl)acetonitriles with Organoboron Reagents

Article abstract of DOI:10.1021/acs.orglett.1c02373

Polysubstituted quinolin-3-amines are vital structural motifs because of their broad biological activities as well as versatile transformational abilities. However, they are not easily accessible. We disclose a protocol with Mn(III) acetate as a mild one-

Full text of DOI:10.1021/acs.orglett.1c02373

pubs.acs.org/OrgLett
Letter
Modular Synthesis of Polysubstituted Quinolin-3-amines by
Oxidative Cyclization of 2‑(2-Isocyanophenyl)acetonitriles with
Organoboron Reagents
Shihui Wang, Jian Xu, and Qiuling Song*
Cite This: https://doi.org/10.1021/acs.orglett.1c02373
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Polysubstituted quinolin-3-amines are vital struc-
tural motifs because of their broad biological activities as well as
versatile transformational abilities. However, they are not easily
accessible. We disclose a protocol with Mn(III) acetate as a mild
one-electron oxidant promoting a radical process to construct
polysubstituted quinolin-3-amines. 2-(2-Isocyanophenyl)-
acetonitriles and organoboron reagents are suitable substrates for
this reaction. The remarkable advantages of this protocol are the
practical method, mild approach, high reaction efficiency, and good
compatibility of functional groups, providing straightforward access
to functional quinoline derivatives.
cyclization of 2-(2-isocyanophenyl)acetonitriles can break
eterocyclic compounds occupy a considerable position
1
Hin the design of pharmaceutical applications. Among through the restrictions mentioned above by introducing aryl
and alkyl groups along with the construction of quinoline
skeletons and amine motifs, aryl radicals, and alkyl that can be
generated from the corresponding aryl- or alkylborons upon
suitable oxidations.11 As part of our ongoing interests in
organoboron chemistry12 and being inspired by our previous
works on isocyanides12a,b,13 and the works of Studer,11a
Nagib,10c Chatani,10d and Lei,14 we envisioned that with 2-
(2-isocyanophenyl)acetonitrile as a radical acceptor and
organoboron as a radical donor, an intermolecular radical
addition to isocyanide would lead to an imidoyl radical,10
which could subsequently intramolecularly attack the cyanide
group in 2-(2-isocyanophenyl)acetonitrile to render the
desired quinolin-3-amines. There are several challenges in
our conjecture: (1) An appropriate condition should be found
to promote the radical from organoboron compounds, which
could not interrupt the following cyclization. (2) A sufficiently
fast reaction rate should be maintained to keep the efficiency of
the overall process; otherwise, multiside reactions might occur
to lead to byproducts. Herein, we report a Mn-mediated
cascade reaction from 2-(2-isocyanophenyl)acetonitrile and
organoboron to construct polysubstituted quinolin-3-amines.
To the best of our knowledge, this is the first case of the
them, the quinoline skeleton is an attractive platform for
natural compounds and bioactive molecules,2 especially the C3
nitrogen-containing quinolines,3 for example, AZD2624,3a
MALT1 inhibitors,3b the AKR1B1 inhibitor,3c Jusbetonin,3d
Imiquimod,3e and Neocryptolepine3f (Figure 1A). In addition,
when it comes to glycans on a matrix-assisted laser desorption
ionization (MALDI) target, quinolin-3-amines could be
sensitive labelings.3g Generally, quinolin-3-amines can be
prepared from a condensation reaction between 2-amino-
benzaldehydes and 1-(2-ethoxycarbonyl-2-oxoethyl)-pyridi-
nium bromide salt4 or reaction between nitroarenes and
protected ethyl aminocrotonate.5 Another strategy is amination
of 3-bromoquinolines6 or 3-nitroquinolines.7 When it comes to
2-alkylquinolin-3-amines, the construction was usually started
from quinolin-3-amine with tBuLi.8 In most instances,
amination occurs on preformed aromatics for reaction. This
paper contains the preparation of polysubstituted quinolin-3-
amines by a conceptually original means of constructing the
quinoline core during the process of radical cyclization. In
comparison to the reported ways, which occurred through the
formation of a single C−C bond, our methodology comprises
one amino group and two C−C bond formations. The possible
regioselectivity in the process of radical cyclization is not a
problem in this pathway.
Received: July 16, 2021
Arylisonitriles are undisputed radical acceptors in cascade
reactions for constructing heteroarenes.9 Unfortunately, the
sequential additions of aryl and alkyl radicals to 2-(2-
isocyanophenyl)acetonitriles have not been investigated to
date in contrast to FG-arylisonitriles.10 The radical cascade
https://doi.org/10.1021/acs.orglett.1c02373
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry arylboron
initiator
additive (equiv)
yield (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
3
4
Mn(OAc)3·2H2O
Mn(acac)3
−
−
18
32
57
66
49
84
53
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O
Na2CO3
CsF
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
c
d
e
no reaction
a
Unless otherwise specified, all reactions were performed at 80 °C for
8 h in toluene (2 mL) with 1 (0.2 mmol, 1 equiv), 2 (0.4 mmol, 2
equiv), Mn(OAc)3·2H2O (2 equiv), and an additive (0.2 mmol, 1
b
c
equiv) under an argon atmosphere. Isolated yield. Cs2CO3 (0.2
d
e
mmol, 1 equiv). 3 (0.4 mmol, 2 equiv). 4 (0.4 mmol, 2 equiv).
To corroborate the practicability of these transformations, we
performed gram scale reactions. Product 5 was provided with a
separation yield of 79%, and there was no obvious loss of
efficiency. We are pleased that arylboronic acids bearing
halides and a trifluoromethyl group provided the desired
products (17−23) in good yields. Notably, heteroarylboronic
acids, including pyrazol (24), thiophene (25), dibenzo[b,d]-
furan (26), 1-methyl-1H-indole (27), and benzofuran (28),
were also compatible. It is noteworthy that the reaction was
sensitive to the spatial volume of the substrates; for instance,
compound 21, with an o-chloro group, gave a moderate yield.
Next, the scope with respect to the 2-(2-isocyanophenyl)-
acetonitriles was studied [the synthetic method of the starting
2-(2-isocyanophenyl)acetonitriles is provided in the Support-
ing Information]. As shown in Scheme 1 (bottom), electronic
effects do not significantly affect the outcomes of the reaction.
Both electron-rich (29) and electron-deficient (30−33)
functional groups were quite compatible under the modified
conditions. According to the previous literature, it is difficult to
synthesize fully substituted quinoline compounds. To our great
surprise, regardless of whether an aryl group or an alkyl group
is at the benzyl position of 2-(2-isocyanophenyl)acetonitriles,
we can obtain fully substituted 3-aminoquinoline compounds
under the standard conditions (34−37). In addition,
arylboronic acids derived from clofibrate were smoothly
converted into the commensurable product, showing good
functional group tolerance to the reaction conditions (38).
Encouraged by the success of the oxidative cyclization of 2-
(2-isocyanophenyl)acetonitriles with arylboronic acids, we next
explored the more challenging alkyl radicals formed by
alkylboronic acids or alkyl-BF3K other than aryl radicals
(Scheme 2). Pleasingly, the reaction was not limited to
arylboronic acids, as primary alkylboronic acids (39−45) were
also competent radical donors. Furthermore, we found that
ether was also within reach (45). The cyclizations with
secondary alkylboronic acids (46) and cyclopentyl (47) and
-hexyl (48) were used, proceeded smoothly, and produced the
corresponding products with good efficiency (54−85% yields)
under the standard conditions. With iso-butyl-BF3K, the
quinolin-3-amine product (49) was obtained in 71% yield. It
is worth noting that an amide moiety (50) remained
Figure 1. Mn(III) enabled divergent synthesis of quinolin-3-amine
from 2-(2-isocyanophenyl)acetonitrile.
application of 2-(2-isocyanophenyl)acetonitriles to a radical
acceptor to construct quinolin-3-amine via a well-organized
and good regional selectivity electron transfer process. This
reaction features high reaction efficiency, valuable products,
mild reaction conditions, ease of execution, good functional
group compatibility, a broad substrate scope, and synthetic
applications.
We initiated our research with the reaction of 2-(2-
isocyanophenyl)acetonitrile (1) and (4-methoxyphenyl)-
boronic acid (2) using Mn(OAc)3·2H2O as an initiator in
toluene (Table 1). We focused on arylboronic acids as the
radical precursors because of their easy availability and air and
moisture stability; they are ideal arylation reagents. To our
delight, cyclization product 5 was successfully obtained in 18−
32% yield (Table 1, entries 1 and 2). The addition of Na2CO3
(1.0 equiv) led to a 57% yield of 5 after 8 h at 80 °C (Table 1,
entry 3). Encouraged by this result, we further investigated
bases, and the results showed that Cs2CO3 was the best one
compared to Na2CO3, K3PO4, and CsF, which led to a
significant increase in yield from 57% to 85% (Table 1, entries
4−6, respectively). 4-Methoxyphenyl-BF3K (3) and 2-(2-
isocyanophenyl)acetonitrile (1) could successfully undergo
oxidative cyclization to produce product 5 in 53% yield (Table
1, entry 7). It is noteworthy that arylborate 4 did not react in
this reaction (Table 1, entry 8).
With the optimized reaction conditions in hand, we next
examined the range of arylboronic acids that are amenable to
this oxidative cyclization reaction (Scheme 1, top). Various
electron-neutral and electron-rich substituents on the aromatic
ring of arylboronic acids have been shown to be effective for
this transformation (5−16); furthermore, the structure of 5
was explicitly proven by X-ray single-crystal diffraction analysis.
B
https://doi.org/10.1021/acs.orglett.1c02373
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Substrate Scope for the Arylboronic Acid and
Isocyanide
Scheme 2. Substrate Scope for the Alkylboronic Acids and
a,b
a,
b
Alkyltrifluoroborates
a
Unless otherwise specified, all reactions were performed at 80 °C for
8 h in toluene (2 mL) with 1 (0.2 mmol, 1 equiv), an alkylboronic
acid (0.4 mmol, 2 equiv), Mn(OAc)3·2H2O (2 equiv), and Cs2CO3
b
c
(0.2 mmol, 1 equiv) under an argon atmosphere. Isolated yield. tert-
Butyl-BF3K.
a
Scheme 3. Synthetic Applications
a
Unless otherwise specified, all reactions were performed at 80 °C for
8 h in toluene (2 mL) with isocyanide (0.2 mmol, 1 equiv), an
arylboronic acid (0.4 mmol, 2 equiv), Mn(OAc)3·2H2O (2 equiv),
and Cs2CO3 (0.2 mmol, 1 equiv) under an argon atmosphere.
a
Derivatizations of primary amine 5: (a) 5 (0.2 mmol, 1 equiv),
B2pin2 (1.1 equiv), BPO (2 mol %), tBuONO (1.5 equiv), CH3CN (2
mL), rt, 3 h; (b) 5 transformed isonitrile (0.2 mmol, 1 equiv), 4-
methoxyphenylboronic acid (2 equiv) and Mn(OAc)3·2H2O (2
equiv), Cs2CO3 (1 equiv), PhMe (2 mL), 80 °C, N2; (c) 5 (0.2
mmol, 1 equiv), 37% HCl (0.1 mL), NaNO2 (1.5 equiv), H2O (2
mL), KI (4 equiv), 0−100 °C; (d) 5 (0.2 mmol, 1 equiv),
Pd(PhP3)2Cl2 (2 mol %), CuI (2 mol %), phenylacetylene (1.5
equiv), Et3N (2 mL), rt; (e) 53 (0.2 mmol, 1 equiv), imidazole (1.5
mmol), Cu2O (0.1 mmol), KOH (2 mmol), DMSO (2 mL) under an
Ar atmosphere; (f) 5 (0.2 mmol, 1 equiv), Pd(OAc)2 (5 mol %),
PhI(OAc)2 (2 equiv), DMF (2 mL), 24 h, rt; (g) 5 (0.2 mmol, 1
equiv), BrCF2COOEt (3 equiv), Cu(OTf)2 (10 mol %), 1,10-phen
(12 mol %), Na2CO3 (3 equiv), 120 °C, 20 h, CH3CN (2 mL), N2;
(h) 5 (0.2 mmol, 1 equiv), BrCF2COOEt (1.2 equiv), Cu(OAc)2·
H2O (10 mol %), B2pin2 (30 mol %), 4,4′-di-tert-butyl-2,2′-bipyridine
(10 mol %), NaOAc (2 equiv), 100 °C, 16 h, DCE (2 mL), N2.
b
Isolated yield.
undamaged under this reaction condition, offering more
opportunities for subsequent transformations, confirming the
mild nature of the conversion conditions, and providing the
handling for the further structural elaborations.
Further transformations of 5 demonstrate its potential to
serve as a versatile building block (Scheme 3). As expected, a
borylation reaction of 5 with B2pin2 under transition-metal-free
conditions15 delivered valuable pinacol boronate 51 in good
yields (a). Conversion of the primary amino group in
compound 5 into isocyanide and then a subsequent oxidative
radical cyclization under standard conditions led to naphthyr-
idine 52 (b). The Sandmeyer reaction16 with CuI yielded
iodine product 53 (c), which was subjected to a Sonogashira
reaction17 that afforded compound 54 (d). To reveal the
transformability and applicability of the product, we tried to
synthesize a drug molecule. It should be noted that quinolin-3-
amine 5 can be converted into the 2-argio-3-(1H-imidazol-1-
yl)quinoline (55) in 49% yield.18 The compound has good
inhibitory activity against citrus green mold, wheat blight,
wheat fusarium, and wheat stand blight and can be used as a
fungicide.19 This feasible process may furnish a new method
C
https://doi.org/10.1021/acs.orglett.1c02373
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Accession Codes
for the discovery of new bioactive molecules from a wealth of
raw materials. Pd-catalyzed C−H amination reaction20
smoothly delivered indole 56, a significant building block
that is widespread in a series of systems (f). In addition,
following our own research, when compound 5 was treated
with BrCF2COOEt under the Cu(OTf)2/1,10-phen catalytic
system13a or upon Cu/B2pin2-catalyzed C−H difluoroacetyla-
tion cycloamidation21 of anilines, 2-difluoro-naphthyridin 57
(g) and 3,3-difluoro-2-oxindole 58 (h) were obtained in good
yields accordingly.
CCDC 2034500 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Several control experiments were carried out (Scheme 4) to
gain some mechanistic insights into the cyclization process
Qiuling Song − Institute of Next Generation Matter
Transformation, College of Material Sciences Engineering at
Huaqiao University, Xiamen, Fujian 361021, China;
Guangdong Provincial Key Laboratory of Catalysis, Southern
University of Science and Technology, Shenzhen 518055
Guangdong, China; orcid.org/0000-0002-9836-8860;
Email: qsong@hqu.edu.cn
Scheme 4. Control Experiments
Authors
Shihui Wang − Institute of Next Generation Matter
Transformation, College of Material Sciences Engineering at
Huaqiao University, Xiamen, Fujian 361021, China
Jian Xu − Institute of Next Generation Matter Transformation,
College of Material Sciences Engineering at Huaqiao
University, Xiamen, Fujian 361021, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02373
Notes
The authors declare no competing financial interest.
presented here. Radical capture experiments upon addition of
3.0 equiv of TEMPO/BHT under the standard conditions had
an adverse effect on the acquisition of product 5 (Scheme 4, eq
1); a notable decrease in the yield of 5 was observed, which
indicated that the reaction of 2-(2-isocyanophenyl)-
acetonitriles and arylboronic acid may involve a radical
process. After that, the control experiment using 1,1-diphenyl-
ethylene (Scheme 4, eq 2) as a radical scavenger delivered an
adduct product (60), demonstrating that the alkyl radical was
generated under the standard cyclization conditions. Never-
theless, the reaction of phenylboronic acid 2 with 2′-
isocyano(1,1′-biphenyl)-2-carbonitrile (61) gave 6-(4-
methoxyphenyl)phenanthridine-10-carbonitrile (62) unexpect-
edly rather than the prospective product (Scheme 4, eq 3).
In summary, we have developed an innovative bimolecular
coupling of 2-(2-isocyanophenyl)acetonitriles with organo-
boron reagents under mild reaction conditions. This method
offers an efficient approach to the rapid divergent synthesis of
polysubstituted quinolin-3-amine derivatives, featuring ease of
operation, atomic economy, excellent functional group
compatibility, a broad substrate scope, and useful products.
One amino group and two C−C bonds could be constructed
simultaneously in this single-vessel reaction. Further bioactive
or drug molecule modifications demonstrated the usefulness of
this reaction.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21772046 and 2193103) is gratefully
acknowledged. The authors also thank the Instrumental
Analysis Center of Huaqiao University for analysis support.
This work was sponsored by the Guangdong Provincial Key
Laboratory of Catalysis (2020B121201002).
REFERENCES
■
(1) (a) Bogart, J. W.; Kramer, N. J.; Turlik, A.; Bleich, R. M.; Catlin,
D. S.; Schroeder, F. C.; Nair, S. K.; Williamson, R. T.; Houk, K. N.;
Bowers, A. A. Interception of the Bycroft−Gowland Intermediate in
the Enzymatic Macrocyclization of Thiopeptides. J. Am. Chem. Soc.
2020, 142, 13170−13179. (b) Song, L.; Ni, D.; Jia, S.; Pi, R.; Dong,
S.; Yang, F.; Tang, J.; Liu, S. C(sp2)−H Bond Multiple
Functionalization in Air for Construction of Tetrahydrocarbazoles
with Continuous Quaternary Carbons and Polycyclic Diversification.
Org. Lett. 2020, 22, 1846−1851.
(2) (a) Jeong, J.; Heo, J.; Kim, D.; Chang, S. NHC-Catalyzed 1,2-
Selective Hydroboration of Quinolines. ACS Catal. 2020, 10, 5023−
5029. (b) Jo, W.; Baek, S.-y.; Hwang, C.; Heo, J.; Baik, M.-H.; Cho, S.
H. ZnMe2-Mediated, Direct Alkylation of Electron-Deficient N-
Heteroarenes with 1,1-Diborylalkanes: Scope and Mechanism. J. Am.
Chem. Soc. 2020, 142, 13235−13245.
(3) (a) Yamamoto, K.; Okazaki, S.; Ohno, H.; Matsuda, F.; Ohkura,
S.; Maeda, K.-i.; Fujii, N.; Oishi, S. Development of Novel NK3
Receptor Antagonists with Reduced Environmental Impact. Bioorg.
Med. Chem. 2016, 24, 3494−3500. (b) Scott, D. A.; Hatcher, J. M.;
Liu, H.; Fu, M.; Du, G.; Fontán, L.; Us, I.; Casalena, G.; Qiao, Q.;
Wu, H.; Melnick, A.; Gray, N. S. Quinoline and Thiazolopyridine
Allosteric Inhibitors of MALT1. Bioorg. Med. Chem. Lett. 2019, 29,
1694−1698. (c) Crespo, I.; Giménez-Dejoz, J.; Porté, S.; Cousido-
Siah, A.; Mitschler, A.; Podjarny, A.; Pratsinis, H.; Kletsas, D.; Parés,
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02373.
General experimental procedures, crystallographic data,
and spectroscopic data for the products (PDF)
D
https://doi.org/10.1021/acs.orglett.1c02373
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
X.; Ruiz, F. X.; Metwally, K.; Farrés, J. Design, Synthesis, Structure-
activity Relationships and X-ray Structural Studies of Novel 1-
Oxopyrimido[4,5-c]quinoline-2-acetic Acid Derivatives as Selective
and Potent Inhibitors of Human Aldose Reductase. Eur. J. Med. Chem.
2018, 152, 160−174. (d) Zhang, Z.; Wang, S.; Wan, S.; Ren, S.; Li,
W.; Jiang, T. Efficient Synthesis of Jusbetonin, an indolo[3,2-
b]quinoline Glycoside, and its Derivatives. Carbohydr. Res. 2009,
344, 291−297. (e) Izumi, T.; Sakaguchi, J.; Takeshita, M.; Tawara,
H.; Kato, K.-i.; Dose, H.; Tsujino, T.; Watanabe, Y.; Kato, H. 1H-
Imidazo[4,5-c]quinoline Derivatives as Novel Potent TNF-α
Suppressors: Synthesis and Structure−activity Relationship of 1-, 2-
and 4-Substituted 1H-imidazo[4,5-c]quinolines or 1H-imidazo[4,5-
c]pyridines. Bioorg. Med. Chem. 2003, 11, 2541−2550. (f) Arzel, E.;
Rocca, P.; Grellier, P.; Labaeïd, M.; Frappier, F.; Guéritte, F.;
Gaspard, C.; Marsais, F.; Godard, A.; Quéguiner, G. New Synthesis of
Benzo-δ-carbolines, Cryptolepines, and Their Salts: In Vitro
Cytotoxic, Antiplasmodial, and Antitrypanosomal Activities of δ-
Carbolines, Benzo-δ-carbolines, and Cryptolepines. J. Med. Chem.
2001, 44, 949−960. (g) Fukuyama, Y.; Funakoshi, N.; Takeyama, K.;
Hioki, Y.; Nishikaze, T.; Kaneshiro, K.; Kawabata, S.-i.; Iwamoto, S.;
Tanaka, K. 3-Aminoquinoline/p-Coumaric Acid as a MALDI Matrix
for Glycopeptides, Carbohydrates, and Phosphopeptides. Anal. Chem.
2014, 86, 1937−1942.
(4) Wang, Y. D.; Boschelli, D. H.; Johnson, S.; Honores, E. A facile
One-pot Synthesis of 2-Substituted-3-aminoquinolines: Preparation of
Benzo[b]naphthyridine-3-Carbonitriles. Tetrahedron 2004, 60, 2937−
2942.
(5) Bujok, R.; Kwast, A.; Cmoch, P.; Wróbel, Z. Novel Approach to
Synthesis of Substituted 3-Aminoquinolines from Nitroarenes and
Protected Ethyl Aminocrotonate. Tetrahedron 2010, 66, 698−708.
(6) Trabanco, A. A.; Vega, J. A.; Fernández, M. A. Fluorous-Tagged
Carbamates for the Pd-Catalyzed Amination of Aryl Halides. J. Org.
Chem. 2007, 72, 8146−8148.
(7) Magnus, P.; Eisenbeis, S. A.; Fairhurst, R. A.; Iliadis, T.; Magnus,
N. A.; Parry, D. Synthetic and Mechanistic Studies on the
Azabicyclo[7.3.1]enediyne Core and Naphtho[2,3-h]quinoline Por-
tions of Dynemicin A. J. Am. Chem. Soc. 1997, 119, 5591−5605.
(8) Dade, J.; Provot, O.; Moskowitz, H.; Mayrargue, J.; Prina, E.
Synthesis of 2-Substituted Trifluoromethylquinolines for the Evalua-
tion of Leishmanicidal Activity. Chem. Pharm. Bull. 2001, 49, 480−
483.
(9) (a) Xia, Z.; Huang, J.; He, Y.; Zhao, J.; Lei, J.; Zhu, Q. Arylative
Cyclization of 2-Isocyanobiphenyls with Anilines: One-Pot Synthesis
of 6-Arylphenanthridines via Competitive Reaction Pathways. Org.
Lett. 2014, 16, 2546−2549. (b) Liu, Y.; Chen, X.-L.; Li, X.-Y.; Zhu, S.-
S.; Li, S.-J.; Song, Y.; Qu, L.-B.; Yu, B. 4CzIPN-tBu-Catalyzed Proton-
Coupled Electron Transfer for Photosynthesis of Phosphorylated N-
Heteroaromatics. J. Am. Chem. Soc. 2021, 143, 964−972. (c) Tobisu,
M.; Koh, K.; Furukawa, T.; Chatani, N. Modular Synthesis of
Phenanthridine Derivatives by Oxidative Cyclization of 2-Isocyano-
biphenyls with Organoboron Reagents. Angew. Chem., Int. Ed. 2012,
51, 11363−11366.
(10) (a) Song, B.; Xu, B. Metal-catalyzed C−H functionalization
involving isocyanides. Chem. Soc. Rev. 2017, 46, 1103−1123.
(b) Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.;
Novellino, E.; Tron, G. C.; Zhu, J. To each his own: isonitriles for
all flavors. Functionalized isocyanides as valuable tools in organic
synthesis. Chem. Soc. Rev. 2017, 46, 1295−1357. (c) Zhang, B.;
Studer, A. Recent advances in the synthesis of nitrogen heterocycles
via radical cascade reactions using isonitriles as radical acceptors.
Chem. Soc. Rev. 2015, 44, 3505−3521. (d) Mitamura, T.; Iwata, K.;
Ogawa, A. (PhTe)2-Mediated Intramolecular Radical Cyclization of o-
Ethynylaryl Isocyanides Leading to Bistellurated Quinolines upon
Visible-Light Irradiation. Org. Lett. 2009, 11, 3422−3424. (e) Sun, X.;
Wang, W.; Li, Y.; Ma, J.; Yu, S. Halogen-Bond-Promoted Double
Radical Isocyanide Insertion under Visible-Light Irradiation: Synthesis
of 2-Fluoroalkylated Quinoxalines. Org. Lett. 2016, 18, 4638−4641.
(f) Xu, J.; Song, Q. Radical Promoted Difunctionalization of
Unsaturated Carbon-Carbon Bonds in the Presence of Dioxygen.
Youji Huaxue 2016, 36, 1151−1162.
(11) (a) Dickschat, A.; Studer, A. Radical Addition of Arylboronic
Acids to Various Olefins under Oxidative Conditions. Org. Lett. 2010,
12, 3972−3974. (b) Huang, Z.; Tang, S.; Lei, A. Oxidative cross-
coupling: an alternative way for C−C bond formations. Sci. Bull.
2015, 60, 1391−1394. (c) Wang, F.; Wei, T.-Q.; Xu, P.; Wang, S.-Y.;
Ji, S.-J. Mn(III)-mediated radical cascade reaction of boronic acids
with isocyanides: Synthesis of diimide derivatives. Chin. Chem. Lett.
̈
2019, 30, 379−382. (d) Demir, A. S.; Reis, O.; Emrullahoglu, M.
Generation of Aryl Radicals from Arylboronic Acids by Manganese-
(III) Acetate: Synthesis of Biaryls and Heterobiaryls. J. Org. Chem.
2003, 68, 578−580. (e) Zhu, J. L.; Laws, S. W.; Rourke, M. J.;
Scheidt, K. A. Radical coupling of β-ketoesters and amides promoted
by Brønsted/Lewis acids. Green Synth. Catal. 2020, 1, 70−74.
(12) (a) Yang, K.; Zhang, F.; Fang, T.; Li, C.; Li, W.; Song, Q.
Passerini-type Reaction of Boronic Acids enables α-Hydroxyketones
Synthesis. Nat. Commun. 2021, 12, 441. (b) Yang, K.; Hu, X.; Li, W.;
Qiu, J.; Feng, Q.; Wang, S.; Zhang, G.; Kuang, Z.; Yu, P.; Song, Q.
Transition-Metal-free Double-Insertive Coupling of Isocyanides with
Arylboronic Acids Enabled Diarylmethanamines. Cell. Rep. Phys. Sci.
2020, 1, 100268−100283. (c) Yang, K.; Zhang, F.; Fang, T.; Zhang,
G.; Song, Q. Stereospecific 1,4-Metallate Shift Enables Stereo-
convergent Synthesis of Ketoximes. Angew. Chem., Int. Ed. 2019, 58,
13421−13426. (d) Feng, Q.; Ma, X.; Bao, W.; Li, S.-J.; Lan, Y.; Song,
Q. Catalytic Atroposelective Catellani Reaction Enables Construction
of Axially Chiral Biaryl Monophosphine Oxides. CCS Chem. 2021, 3,
377−387. (e) Kuang, Z.; Chen, H.; Qiu, J.; Ou, Z.; Lan, Y.; Song, Q.
Cu-Catalyzed Regio- and Stereodivergent Chemoselective sp2/sp3
1,3- and 1,4-Diborylations of CF3-Containing 1,3-Enynes. Chem.
2020, 6, 2347−2363. (f) Kuang, Z.; Mai, S.; Yang, K.; Song, Q.
Synthesis of anti-vicinal diboronates from diarylethynes and B2pin2.
Sci. Bull. 2019, 64, 1685−1690. (g) Yang, K.; Kuang, Z.; Song, Q.
Radical-Induced 1,2-Boron Shift, Enabling 1,3-Difunctionalization of
Allylboronic Esters. Chem. 2020, 6, 330−331. (h) Wang, C.; Zhou, L.;
Yang, K.; Zhang, F.; Song, Q. Photoinduced NaI-Promoted Radical
Borylation of Alkyl Halides and Pseudohalides. Chin. J. Chem. 2021,
39, 1825−1830. (i) Gao, C.; Xuan, Q.; Song, Q. Cu-Catalyzed
Chemoselective Reduction of N-Heteroaromatics with NH3·BH3 in
Aqueous Solution. Chin. J. Chem. 2021, DOI: 10.1002/
cjoc.202100259.
(13) (a) Ma, X.; Mai, S.; Zhou, Y.; Cheng, G.-J.; Song, Q. Dual Role
of Ethyl BromodiFluoroacetate in the Formation of Fluorine-
containing Heteroaromatic Compounds. Chem. Commun. 2018, 54,
8960−8963. (b) Ma, X.; Song, Q. Recent Progress on Selective
Deconstructive Modes of Halodifluoromethyl and Trifluoromethyl-
containing Reagents. Chem. Soc. Rev. 2020, 49, 9197−9219.
(14) Niu, L.; Jiang, C.; Liang, Y.; Liu, D.; Bu, F.; Shi, R.; Chen, H.;
Chowdhury, A. D.; Lei, A. Manganese-Catalyzed Oxidative Azidation
of C(sp3)−H Bonds under Electrophotocatalytic Conditions. J. Am.
Chem. Soc. 2020, 142, 17693−17702. (b) Yuan, Y.; Zheng, Y.; Xu, B.;
Liao, J.; Bu, F.; Wang, S.; Hu, J.-G.; Lei, A. Mn-Catalyzed
Electrochemical Radical Cascade Cyclization toward the Synthesis
of Benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one Derivatives. ACS
Catal. 2020, 10, 6676−6681. (c) Wang, S.; Tang, S.; Lei, A. Tuning
radical reactivity for selective radical/radical cross-coupling. Sci. Bull.
2018, 63, 1006−1009.
(15) Mo, F.; Jiang, Y.; Qiu, D.; Zhang, Y.; Wang, J. Direct
Conversion of Arylamines to Pinacol Boronates: A Metal-Free
Borylation Process. Angew. Chem., Int. Ed. 2010, 49, 1846−1849.
(16) (a) He, Z.; Huang, Y. Diverting C−H Annulation Pathways:
Nickel-Catalyzed Dehydrogenative Homologation of Aromatic
Amides. ACS Catal. 2016, 6, 7814−7823. (b) Isaad, J. Acidic Ionic
Liquid Supported on Silica-coated Magnetite Nanoparticles as a
Green Catalyst for One-pot Diazotization−halogenation of the
Aromatic Amines. RSC Adv. 2014, 4, 49333−49341. (c) Huang, S.-
H.; Keith, J. M.; Hall, M. B.; Richmond, M. G. Ortho-Metalation
Dynamics and Ligand Fluxionality in the Conversion of
Os3(CO)10(dppm) to HOs3(CO)8[μ-PhP(C6H4-μ2, η1)CH2PPh2]:
E
https://doi.org/10.1021/acs.orglett.1c02373
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Experimental and DFT Evidence for the Participation of Agostic C−
H and π-Aryl Intermediates at an Intact Triosmium Cluster.
Organometallics 2010, 29, 4041−4057.
(17) Wilson, K. L.; Kennedy, A. R.; Murray, J.; Greatrex, B.;
Jamieson, C.; Watson, A. J. B. Scope and limitations of a DMF bio-
alternative within Sonogashira cross-coupling and Cacchi-type
annulation. Beilstein J. Org. Chem. 2016, 12, 2005−2011.
(18) Huang, Y.-Z.; Miao, H.; Zhang, Q.-H.; Chen, C.; Xu, J. Cu2O: a
Simple and Efficient Reusable Catalyst for N-arylation of Nitrogen-
containing Heterocycles with Aryl Halides. Catal. Lett. 2008, 122,
344−348.
(19) Beltran-Hortelano, I.; Alcolea, V.; Font, M.; Pérez-Silanes, S.
The Role of Imidazole and Benzimidazole Heterocycles in Chagas
Disease: A Review. Eur. J. Med. Chem. 2020, 206, 112692.
(20) Huang, Y.-Z.; Miao, H.; Zhang, Q.-H.; Chen, C.; Xu, J. Cu2O: a
Simple and Efficient Reusable Catalyst for N-arylation of Nitrogen-
containing Heterocycles with Aryl Halides. Catal. Lett. 2008, 122,
344−348.
(21) Ke, M.; Song, Q. Copper/B2pin2-catalyzed C−H Difluor-
oacetylation−cycloamidation of Anilines Leading to the Formation of
3,3-Difluoro-2-oxindoles. Chem. Commun. 2017, 53, 2222−2225.
F
https://doi.org/10.1021/acs.orglett.1c02373
Org. Lett. XXXX, XXX, XXX−XXX