NiH-Catalyzed Hydroamination/Cyclization Cascade: Rapid Access to Quinolines

Article abstract of DOI:10.1021/acscatal.1c02055

Despite the significant success of metal-H-catalyzed hydroamination methodologies, considerable limitations still exist in the selective hydroamination of alkynes, especially for terminal alkynes. Herein, we develop a highly efficient NiH catalytic system that activates readily available alkynes for a cascade hydroamination/cyclization reaction with anthranils. This mild, operationally simple protocol is amenable to a wide array of alkynes including terminal and internal, aryl and alkyl, electron-deficient and electron-rich ones, delivering structurally diverse quinolines in useful to excellent yields (>80 examples, up to 93% yield). The utility of this procedure is exhibited in the late-stage functionalization of several natural products and in the concise synthesis of an antitumor molecule graveolinine and a triplex DNA intercalator. Preliminary mechanistic experiments suggest an alkenylnickel-mediated alkyne hydroamination and an intramolecular cyclization/aromatization of putative enamine intermediates.

Full text of DOI:10.1021/acscatal.1c02055

pubs.acs.org/acscatalysis
Research Article
NiH-Catalyzed Hydroamination/Cyclization Cascade: Rapid Access to
Quinolines
Yang Gao,* Simin Yang, Yanping Huo, Qian Chen, Xianwei Li, and Xiao-Qiang Hu*
Cite This: ACS Catal. 2021, 11, 7772−7779
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Despite the significant success of metal-H-catalyzed
hydroamination methodologies, considerable limitations still exist
in the selective hydroamination of alkynes, especially for terminal
alkynes. Herein, we develop a highly efficient NiH catalytic system
that activates readily available alkynes for a cascade hydro-
amination/cyclization reaction with anthranils. This mild, opera-
tionally simple protocol is amenable to a wide array of alkynes
including terminal and internal, aryl and alkyl, electron-deficient and electron-rich ones, delivering structurally diverse quinolines in
useful to excellent yields (>80 examples, up to 93% yield). The utility of this procedure is exhibited in the late-stage functionalization
of several natural products and in the concise synthesis of an antitumor molecule graveolinine and a triplex DNA intercalator.
Preliminary mechanistic experiments suggest an alkenylnickel-mediated alkyne hydroamination and an intramolecular cyclization/
aromatization of putative enamine intermediates.
KEYWORDS: NiH catalysis, hydroamination, alkynes, anthranils, quinolines
ithin the field of synthetic organic chemistry, the
efficient and selective construction of C−N bonds is of
reported by Lu et al.12a Miura and Hirano et al. developed Zr/
Cu sequential catalysis for the formal hydroamination of
terminal aryl alkynes in two steps.12b
W
critical importance because of the presence of nitrogen-
containing compounds in many natural products,1 medicinally
relevant molecules,2 and functional materials.3 Apart from the
state-of-the-art C−N cross-coupling,4 traditional hydroamina-
tion of alkenes and alkynes enabled by rare-earth and noble
metals has been extensively investigated for decades (Scheme
1a, method A).5 In recent years, a polarity-reversed strategy
that utilizes metal hydrides in combination with an electro-
philic aminating reagent has emerged as a powerful means to
prepare complex amines because of attractive advantages such
as low cost, mild conditions, as well as high regio- and
stereoselectivity (Scheme 1a, method B).6 Pioneered by
Buchwald,7 Miura,8 Hirano, and others,9 CuH-catalyzed
hydroamination of alkenes has been developed for the
formation of sp3 C−N bonds. However, to the best of our
knowledge, metal-H-mediated alkyne hydroamination for sp2
C−N bond formation has been largely unsuccessful and
remains as a challenging task in this field. This is probably
attributed to the fast protodemetalation of the in-situ-
generated alkenylcopper intermediate, which may result in
the semireduction of alkynes to alkenes.10 Moreover, the
instability of enamine products is also a crucial issue that
hinders the advancement on alkyne hydroamination. The
group of Buchwald has achieved an interesting CuH-catalyzed
hydroamination of internal aryl alkynes (Scheme 1b, path A).11
However, in this catalytic system, alkylamines are competitively
formed via a sequential semireduction/hydroamination of
alkynes (Scheme 1b, path B). A similar chemoselectivity has
also been recently observed in a cobalt-catalyzed system
Compared with the widespread success of CuH catalytic
systems in alkene functionalization, NiH catalysis is more
commonly used in the hydrofunctionalization of alkynes
probably due to the slow protodemetalation of alkenylnickel
intermediates.13 Recently, Chang and Seo achieved the first
NiH-catalyzed hydroamidation of alkynes with dioxazolones
for the selective synthesis of enamides.14 Given the intrinsic
reactivity of NiH complexes,15 we recently questioned whether
a NiH catalytic system could be applied to further expand the
research on hydroamination of simple alkynes which is a long-
standing challenge in Cu or Co catalytic systems. The rational
choice of an appropriate electrophilic amine reagent is critical
for the success of this type of reaction. On the one hand, the
aminating reagent should be stable under reductive conditions.
On the other hand, the reaction of the aminating reagent with
alkenylnickel intermediates should completely outcompete the
protodemetalation process. In addition, the in-situ-generated
enamine product should also be stable, or it can be rapidly
trapped by electrophiles for the assembly of other high-value
N-containing molecules.
Received: May 6, 2021
Revised: June 3, 2021
Published: June 13, 2021
https://doi.org/10.1021/acscatal.1c02055
© 2021 American Chemical Society
ACS Catal. 2021, 11, 7772−7779
7772

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Scheme 1. Hydroamination Reaction for C−N Bond
Formation and Reaction Design
Table 1. Summary of the Effects of Reaction Parameters
a
Standard conditions: 1a (0.2 mmol), 2a (0.22 mmol), Ni(BF4)2·
6H2O (5 mol %), L1 (5.5 mol %), Me(OEt)2SiH (3.0 equiv), DMA
(1.0 mL) under an argon atmosphere at room temperature for 12 h.
b
1
DMA refers to N,N-dimethylacetamide. Yields determined by H
NMR analysis with 1,3,5-trimethoxybenzene as the internal standard.
c
d
The yield in parentheses is the isolated yield. 0.2 mmol proton
source was added.
key alkenylnickel species A. The resulting intermediate A is
expected to couple with anthranils to produce enamine
intermediates B with an adjacent carbonyl group. Subsequent
intramolecular cyclization/aromatization of enamine B would
afford the desired quinoline products. The key challenges for
this cascade reaction can be attributed to the following points:
(1) the compatibility of anthranils in the NiH catalytic system;
(2) semihydrogenation of alkynes (Scheme 1c, path A);10−12
(3) the reduction of the carbonyl group by the NiH species
before intramolecular cyclization (Scheme 1c, path B).18 We
believe that the rational combination of the Ni catalyst and
reductant may provide a solution to these challenges.
Quinolines are one of the most prevalent N-heterocycles in
pharmaceuticals, natural products, and materials (Figure 1).20
Traditional methods often rely on harsh reaction conditions
and specialized substrates,21 which largely limits their
applications in practical synthesis. We developed a novel
NiH catalytic system that activates readily available alkynes for
a cascade hydroamination/cyclization reaction with anthranils,
furnishing a wide range of quinolines in good yields. The
remarkable features of this protocol include mild conditions,
simple operation, excellent regioselectivity, and broad substrate
scope, providing a general and convenient platform for the
construction of quinolines.
Figure 1. Representative biologically important quinolines.
Anthranils are stable and readily available, which have been
used as versatile aminating reagents in many C−N formation
reactions.16 Moreover, they are usually regarded as polarity-
reversed 2-carbonyl anilines, which may provide a possibility
for the trapping of enamine intermediates by the carbonyl
group.17 For instance, Knochel et al. have recently disclosed a
convenient Co-catalyzed cross-coupling of alkenylzinc pivalates
and anthranils for the synthesis of quinolines.17b In addition,
anthranils were successfully applied in a copper-catalyzed
hydroamination of vinylarenes.18 Inspired by these precedents
and our ongoing interests in anthranil chemistry16,17a and N-
heterocycle synthesis,19 herein, we envisaged to develop a new
alkyne hydroamination strategy based on an efficient NiH-
catalyzed polarity-reversed reaction mode with the use of
anthranils as electrophilic aminating sources. The specific
mechanistic details of our proposed NiH-catalyzed hydro-
amination/cyclization cascade are outlined in Scheme 1c. In
the presence of hydrosilane, the reactive NiH-catalyst is in-situ-
generated, which would readily react with alkynes to form the
To test the feasibility of this hydroamination/cyclization
reaction, phenylacetylene (1a) and benzo[c]isoxazole (2a)
were chosen as the model substrates, and various catalysts,
ligands, hydrosilanes, and solvents were systematically
7773
https://doi.org/10.1021/acscatal.1c02055
ACS Catal. 2021, 11, 7772−7779

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
a
Scheme 2. Scope of Alkynes
a
Reactions were run with 1 (0.3 mmol) and 2 (0.33 mmol) under standard reaction conditions at room temperature (for terminal alkynes) or 40
b
c
°C (for internal alkynes) for 12 h. Reported yields are the isolated ones. Trimethyl(arylethynyl)silane was used as the substrate. 3-Alkyl
substituted isomer was detected by crude H NMR, and the ratio of 2-alkyl quinoline 3z:3-alkyl quinoline 3z′ is 20:1.
1
investigated (Table 1). We first tested the commonly used
copper catalysts to promote the proposed reaction. However,
these copper catalysts were found to be ineffective for this
reaction (see Table S1 for the screening of copper catalysts). In
CuH catalytic systems, byproducts 2-aminobenzaldehyde and
styrene were observed via the competitive reduction of
anthranil 2a and phenylacetylene, respectively. To our delight,
nickel catalysts exhibit remarkable activity for the formation of
quinoline product 3a. The yield of 3a can be achieved in 90%
using Ni(BF4)2·6H2O (5 mol %) as the catalyst, 6,6′-dimethyl-
2,2′-bipyridine (L1) as the ligand, and Me(OEt)2SiH as the
hydride source in dimethylacetamide (DMA) at room
7774
https://doi.org/10.1021/acscatal.1c02055
ACS Catal. 2021, 11, 7772−7779

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
a
groups such as fluoro (3b), chloro (3c), bromo (3d), methoxy
(3e), methylthio (3g), amino (3h), ester (3k), trifluoromethyl
(3l), cyano (3m), sulfone (3n), and even free hydroxyl group
(3as) were tolerated well. A series of valuable bis(hetero)aryls
(3p−3v) can be obtained in good yields, which are privileged
π-conjugated structural cores in biologically active molecules
and organic functional materials.22 Remarkably, terminal
aliphatic alkynes reacted smoothly with anthranils to give the
desired 2-alkyl quinolines in moderate yields (3w−3z). The
high regioselectivity of aliphatic alkynes is probably attributed
to the stability of the α-alkenyl nickel species.13e Ethyl
propiolate afforded the desired ethyl quinoline-2-carboxylate
(3aa) in 46% yield with excellent regioselectivity. Diary-
lacetylenes are successfully converted into expected products in
generally good to excellent yields (3ab−3am). Oct-4-yne
(3an) and cyclododecyne (3ao and 3ap) participated in this
transformation with a high reaction efficiency. For unsym-
metrical internal alkynes bearing an aryl substituent (3aq−
3at), these reactions proceed in high regioselectivity with C−N
bond formation occurring adjacent to the aryl group.11a The
electron-deficient alkynes including alkynyl esters (3au and
3av), alkynamide (3aw), alkynone (3ax−3az), and electron-
rich ones such as alkynyl ether (3ba) and ynamide (3bb) are
compatible with this catalytic system, producing the corre-
sponding quinolines in good yields (58−84%). Significantly,
1,3-diethynylbenzene and 1,3,5-triethynylbenzene also proved
to be suitable, furnishing the expected products 3bc and 3bd in
80% and 67% yields, respectively.
Scheme 3. Scope of Anthranils
a
Reactions were run with 1 (0.3 mmol) and 2 (0.33 mmol) under
standard reaction conditions. Reported yields are the isolated ones.
temperature (entry 1). Notably, 2-phenylquinoline was formed
with exclusive regioselectivity presumably because of the
stabilization of the alkenylnickel species by an adjacent phenyl
group.11a The screening of reaction solvents indicated that
other solvents such as N, N′-dimethylpropyleneurea (DMPU),
N-methyl-2-pyrrolidone (NMP), or dimethylformamide
(DMF) led to diminished yields (entry 2). The counter
anion of nickel salt has a significant influence on the reaction
outcome. Ni(BF4)2·6H2O proved to be the optimal catalyst,
while NiBr2, Ni(acac)2·2H2O, or Ni(OAc)2 resulted in
decreased yields (entry 4). The strong cationic nickel center
in Ni(BF4)2·6H2O may promote the initial NiH formation step
because of the weak coordination of BF4− anions. Although the
ligand is not indispensable for this reaction to proceed, the use
of 6,6′-dimethyl-2,2′-bipyridine (L1) as a supporting ligand can
improve the yield (entries 5 and 6). Me(OEt)2SiH (3.0 equiv)
proved to be the most efficient hydride source, and other
tested silanes resulted in decreased yields (entry 8). Base
additives were found to have detrimental influence on the
reaction (entry 9). As expected, control experiments
demonstrated that the nickel catalyst and silane were essential
for this reaction (entries 3 and 7). In addition, the influence of
proton sources has been investigated. This cascade reaction
proceeded smoothly when 1.0 equivalent of H2O, EtOH, or
iPrOH was added to the reaction mixture (entry 10).
Moreover, product 3a can be obtained in good yields even
with the addition of 10 equiv H2O in the system (entry 11).
These results strongly support that the expected hydro-
amination completely outcompetes the semireduction process
in this NiH catalytic system. Compared with the easy
protonation of well-established alkenylcopper intermediates,
the protodemetalation of the alkenylnickel species is
unfavorable because of the relatively high energy barrier.14
As shown in Scheme 2, a large variety of alkynes including
terminal and internal, electron-deficient and electron-rich, aryl
and alkyl ones were compatible in this reaction. Under the
optimized conditions, alkynes bearing different functional
We next turned our attention to the scope of anthranils in
this new NiH catalytic system. As shown in Scheme 3, various
substituents including F (3be), Cl (3bf), Br (3bg), OMe
(3bh), benzyl (3bi), CF3 (3bj), and acetal (3bm) were well
tolerated, giving rise to the desired polysubstituted quinolines
in good yields (61−88%). Notably, 3-aryl- and alkyl-
substituted anthranils were found to participate readily in
this transformation (3bn−3bp, 3bu, and 3bv).
To further exemplify the utility of this protocol, we applied
this NiH-catalyzed hydroamination/cyclization cascade reac-
tion in the late-stage modification of several readily available
natural products and pharmaceutical derivatives. As outlined in
Scheme 4a, the alkynes derived from some bioactive molecules
such as estrone (3bw), vitamin E (3bx), nerol (3by), menthol
(3bz), cholesterol (3ca), ibuprofen (3cb), and galactose (3cc)
reacted smoothly with anthranils, delivering high-function-
alized quinolines in synthetically useful yields. The success of
these reactions demonstrated the synthetic potential of this
methodology in organic chemistry and industrial applications.
Alkynes can be easily accessed from aryl bromide via
Sonogashira coupling.23 The gram-scale experiment involving
2-bromo-9H-fluoren-9-one as the starting material proceeded
efficiently, furnishing the corresponding quinoline 3cd in 72%
(0.92 g) yield (Scheme 4b). In addition, transition-metal-
catalyzed C−H alkynylation has been well established to
prepare alkynes.24 We can start from the commercially
available acetophenone to synthesize the bioactive quinoline
3ce via a sequential iridium-catalyzed ortho-C−H alkynylation
and NiH-mediated hydroamination/cyclization cascade
(Scheme 4c). Moreover, this mild NiH catalytic system can
be successfully applied to the concise synthesis of biologically
active compounds. For instance, graveolinine, which exhibits
antibacterial, spasmolytic, and antitumor activities, can be
concisely synthesized from 3o (Scheme 4d).25 2-(2-Naphthyl)-
quinoline derivative 3ci, that has been designed to target
7775
https://doi.org/10.1021/acscatal.1c02055
ACS Catal. 2021, 11, 7772−7779

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Scheme 4. Late-Stage Modification of Natural Products and Pharmaceutical Derivatives and Synthetic Applications
Scheme 5. Lewis Acid-Catalyzed Pathway (a), Testing the
Possible Intermediate (b), and Hydroamination of Styrene
(c)
Scheme 6. Deuteration with Ph2SiD2 (a), Kinetic Isotope
Effect (b), and Stepwise Stoichiometric Reaction (c)
triplex DNA, was efficiently constructed from product 3v via
To understand the mechanism, a series of control experi-
ments were conducted (Scheme 5). Anthranils have been
two simple operations (Scheme 4e).26
7776
https://doi.org/10.1021/acscatal.1c02055
ACS Catal. 2021, 11, 7772−7779

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
oxidative insertion into the N−O bond of anthranils, giving
rise to species B′ and its resonance structure C′.28 The
subsequent reductive elimination of B′ affords the key enamine
intermediate D′. The resulting intermediate D′ then reacts
with Me(OEt)2SiH to deliver intermediate E′ with the
regeneration of an active NiH catalyst for the next catalytic
cycle. It should be noted that the presence of H2O may help
release the Ni catalyst from intermediate D′ and enhance the
generation of the active NiH species.14 Finally, the
intermediate E′ undergoes intramolecular cyclization to deliver
the desired quinoline product.
Scheme 7. Proposed Mechanism
In summary, an efficient NiH-catalyzed hydroamination/
cyclization cascade of alkynes and anthranils has been
developed, which opens up a convenient route for the
synthesis of various highly substituted quinolines. This new
protocol features good regioselectivity, mild reaction con-
ditions, simple operation, and broad substrate scope. Beyond
the synthetic application displayed herein, we anticipate that
this protocol can be widely used in a concise synthesis of other
valuable targets. Moreover, the success of NiH catalysis in
alkyne hydroamination may stimulate the rapid development
of new catalytic systems for the transformation of simple
alkynes into various high-value compounds.
reported to undergo Diels−Alder (DA) reaction with
enamines in the presence of TiCl4 as a catalyst.27 To probe
this possibility, Lewis acids including TiCl4, Zn(OAc)2, and
In(OTf)3 were tested; however, all of these catalysts turned
out to be ineffective for this reaction in the presence or
absence of a ligand (Scheme 5a). Therefore, a tandem process,
involving a Lewis-acid-catalyzed DA reaction of anthranils and
alkynes, and subsequent reduction by silane, could be
excluded. Although a small amount of 2-aminobenzaldehyde
(6) can be detected in the reaction, it is not likely an
intermediate for this reaction because no desired product was
detected when 2-aminobenzaldehyde was subjected to the
reaction system (Scheme 5b). Notably, under the current
conditions, the reaction of styrene 7 and anthranil 2a
proceeded smoothly to give the hydroamination product 8a
in good yields (Scheme 5c). This important result confirms
that anthranils can serve as efficient electrophilic aminating
reagents in NiH-catalyzed hydroamination reactions. In
addition, the aldehyde group is left intact in the reductive
system, opening an opportunity for the NiH-catalyzed
hydroamination/cycloisomerization cascade reaction of al-
kynes with anthranils.
Moreover, an isotope labeling experiment was conducted
with the use of Ph2SiD2 as the reductant (Scheme 6a). As a
result, 56% deuterium incorporation at the 3-position of
compound 3a was observed, which indicated that deuterium is
provided by silyldeuteride from the generated NiD species.
The partly loss of deuterium may occur in the intramolecular
condensation step in which a hydrogen or deuterium is
eliminated. In addition, there are no significant kinetic isotope
effects in parallel experiments, which indicates that the Si-H
bond cleavage is not likely to be involved in the rate-
determining step (Scheme 6b). The intermediary of the
alkenylnickel species was demonstrated by the success of a
stepwise reaction of 1aa and 2a (Scheme 6c) (see the
Supporting Information for details).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c02055.
Detailed experimental procedures and 1H and 13C NMR
spectra for all the compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Yang Gao − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China; orcid.org/0000-0001-9513-6899;
Email: gaoyang@gdut.edu.cn
Xiao-Qiang Hu − Key Laboratory of Catalysis and Energy
Materials Chemistry of Ministry of Education & Hubei Key
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China; orcid.org/
0000-0001-9094-2357; Email: huxiaoqiang@
mail.scuec.edu.cn
Authors
Simin Yang − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China
Yanping Huo − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China
Qian Chen − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China; orcid.org/0000-0002-0818-6028
Xianwei Li − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China; orcid.org/0000-0002-4014-6712
According to the above mentioned results and previous
studies, a plausible NiH-catalytic cycle is proposed in Scheme
7. First, a LNiH species is generated from the reaction of
Ni(BF4)2·6H2O, Me(OEt)2SiH, and ligand.14,15 Then, alkyne
insertion occurs with high regioselectivity to give reactive
alkenylnickel intermediate A′13,14 that further undergoes
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c02055
7777
https://doi.org/10.1021/acscatal.1c02055
ACS Catal. 2021, 11, 7772−7779

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
(8) (a) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed
Intermolecular Regioselective Hydroamination of Styrenes with
Polymethylhydrosiloxane and Hydroxylamines. Angew. Chem., Int.
Ed. 2013, 52, 10830−10834. (b) Nishikawa, D.; Hirano, K.; Miura,
M. Asymmetric Synthesis of α-Aminoboronic Acid Derivatives by
Copper-Catalyzed Enantioselective Hydroamination. J. Am. Chem.
Soc. 2015, 137, 15620−15623.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Natural Science
Foundation of China (21901045 and 21901258) and the
Technology Plan of Guangdong Province (2018A030310570)
for financial support. The authors thank Prof. Wenbo Liu
(SYU), Dr. Zhihang Qiu, and Dr. Maoping Pu (Schenzhen Bay
Laboratory) for helpful discussion. The authors also thank the
anonymous referees for helpful suggestions.
(9) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F. Regioselective,
Asymmetric Formal Hydroamination of Unactivated Internal Alkenes.
Angew. Chem., Int. Ed. 2016, 55, 776−780.
(10) (a) Semba, K.; Fujihara, T.; Xu, T.; Terao, J.; Tsuji, Y. Copper-
Catalyzed Highly Selective Semihydrogenation of Non-Polar Carbon-
Carbon Multiple Bonds Using a Silane and an Alcohol. Adv. Synth.
Catal. 2012, 354, 1542−1550. (b) Whittaker, A. M.; Lalic, G.
Monophasic Catalytic System for the Selective Semireduction of
Alkynes. Org. Lett. 2013, 15, 1112−1115.
(11) (a) Shi, S.-L.; Buchwald, S. L. Copper-Catalysed Selective
Hydroamination Reactions of Alkynes. Nat. Chem. 2015, 7, 38−44.
(b) Tobisch, S. CuH-Catalysed Hydroamination of Arylalkynes with
Hydroxylamine Esters − a Computational Scrutiny of Rival
Mechanistic Pathways. Chem. Sci. 2017, 8, 4410−4423.
(12) (a) Chen, J.; Shen, X.; Lu, Z. Cobalt-Catalyzed Markovnikov
Selective Sequential Hydrogenation/Hydrohydrazidation of Aliphatic
Terminal Alkynes. J. Am. Chem. Soc. 2020, 142, 14455−14460.
(b) Sakae, R.; Hirano, K.; Satoh, T.; Miura, M. Formal Anti-
Markovnikov Hydroamination of Terminal Aryl Alkynes with
Pinacolborane and Hydroxylamines via Zr/Cu Sequential Catalysis.
Chem. Lett. 2013, 42, 1128−1130.
(13) (a) Gao, F.; Hoveyda, A. H. α-Selective Ni-Catalyzed
Hydroalumination of Aryl- and Alkyl-Substituted Terminal Alkynes:
Practical Syntheses of Internal Vinyl Aluminums, Halides, or
Boronates. J. Am. Chem. Soc. 2010, 132, 10961−10963. (b) Li, S.;
Yuan, W.; Ma, S. Highly Regio- and Stereoselective Three-
Component Nickel-Catalyzed Syn-Hydrocarboxylation of Alkynes
with Diethyl Zinc and Carbon Dioxide. Angew. Chem., Int. Ed. 2011,
50, 2578−2582. (c) Wang, X.; Nakajima, M.; Martin, R. Ni-Catalyzed
Regioselective Hydrocarboxylation of Alkynes with CO2 by Using
Simple Alcohols as Proton Sources. J. Am. Chem. Soc. 2015, 137,
8924−8927. (d) Wang, X.; Nakajima, M.; Serrano, E.; Martin, R.
Alkyl Bromides as Mild Hydride Sources in Ni-Catalyzed Hydro-
amidation of Alkynes with Isocyanates. J. Am. Chem. Soc. 2016, 138,
15531−15534. (e) Zhang, X.; Xie, X.; Liu, Y. Nickel-Catalyzed Highly
Regioselective Hydrocyanation of Terminal Alkynes with Zn(CN)2
Using Water as the Hydrogen Source. J. Am. Chem. Soc. 2018, 140,
7385−7389.
REFERENCES
■
(1) (a) Blair, L. M.; Sperry, J. Natural Products Containing a
Nitrogen−Nitrogen Bond. J. Nat. Prod. 2013, 76, 794−812.
(b) Petkowski, J. J.; Bains, W.; Seager, S. Natural Products Containing
a Nitrogen−Sulfur Bond. J. Nat. Prod. 2018, 81, 423−446.
(2) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals: Mini-
perspective. J. Med. Chem. 2014, 57, 10257−10274. (b) Taylor, A. P.;
Robinson, R. P.; Fobian, Y. M.; Blakemore, D. C.; Jones, L. H.;
Fadeyi, O. Modern Advances in Heterocyclic Chemistry in Drug
Discovery. Org. Biomol. Chem. 2016, 14, 6611−6637.
(3) (a) Yang, Z.; Mao, Z.; Xie, Z.; Zhang, Y.; Liu, S.; Zhao, J.; Xu, J.;
Chi, Z.; Aldred, M. P. Recent Advances in Organic Thermally
Activated Delayed Fluorescence Materials. Chem. Soc. Rev. 2017, 46,
915−1016. (b) Gao, H.; Zhang, Q.; Shreeve, J. M. Fused Heterocycle-
Based Energetic Materials (2012−2019). J. Mater. Chem. A 2020, 8,
4193−4216.
(4) (a) Bariwal, J.; Van der Eycken, E. C−N Bond Forming Cross-
Coupling Reactions: An Overview. Chem. Soc. Rev. 2013, 42, 9283.
(b) Ma, D.; Cai, Q. Copper/Amino Acid Catalyzed Cross-Couplings
of Aryl and Vinyl Halides with Nucleophiles. Acc. Chem. Res. 2008, 41,
1450−1460. (c) Ruiz-Castillo, P.; Buchwald, S. L. Applications of
Palladium-Catalyzed C−N Cross-Coupling Reactions. Chem. Rev.
2016, 116, 12564−12649. (d) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Rational Development of Practical Catalysts for
Aromatic Carbon−Nitrogen Bond Formation. Acc. Chem. Res. 1998,
31, 805−818.
(5) (a) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J.
Late Transition Metal-Catalyzed Hydroamination and Hydroamida-
̈
tion. Chem. Rev. 2015, 115, 2596−2697. (b) Muller, T. E.; Hultzsch,
(14) Lyu, X.; Zhang, J.; Kim, D.; Seo, S.; Chang, S. Merging NiH
Catalysis and Inner-Sphere Metal-Nitrenoid Transfer for Hydro-
amidation of Alkynes. J. Am. Chem. Soc. 2021, 143, 5867−5877.
(15) (a) Jeon, J.; Lee, C.; Seo, H.; Hong, S. NiH-Catalyzed
Proximal-Selective Hydroamination of Unactivated Alkenes. J. Am.
Chem. Soc. 2020, 142, 20470−20480. (b) Xiao, J.; He, Y.; Ye, F.; Zhu,
S. Remote Sp3 C−H Amination of Alkenes with Nitroarenes. Chem
2018, 4, 1645−1657.
K. C.; Yus, M.; Foubelo, F.; Tada, M. Hydroamination: Direct
Addition of Amines to Alkenes and Alkynes. Chem. Rev. 2008, 108,
3795−3892. (c) Patel, M.; Saunthwal, R. K.; Verma, A. K. Base-
Mediated Hydroamination of Alkynes. Acc. Chem. Res. 2017, 50, 240−
254.
(6) (a) Liu, R. Y.; Buchwald, S. L. CuH-Catalyzed Olefin
Functionalization: From Hydroamination to Carbonyl Addition.
Acc. Chem. Res. 2020, 53, 1229−1243. (b) Pirnot, M. T.; Wang, Y.-
M.; Buchwald, S. L. Copper Hydride Catalyzed Hydroamination of
Alkenes and Alkynes. Angew. Chem., Int. Ed. 2016, 55, 48−57.
(c) Deutsch, C.; Krause, N.; Lipshutz, B. H. CuH-Catalyzed
Reactions. Chem. Rev. 2008, 108, 2916−2927.
(7) (a) Guo, S.; Yang, J. C.; Buchwald, S. L. A Practical Electrophilic
Nitrogen Source for the Synthesis of Chiral Primary Amines by
Copper-Catalyzed Hydroamination. J. Am. Chem. Soc. 2018, 140,
15976−15984. (b) Niu, D.; Buchwald, S. L. Design of Modified
Amine Transfer Reagents Allows the Synthesis of α-Chiral Secondary
Amines via CuH-Catalyzed Hydroamination. J. Am. Chem. Soc. 2015,
137, 9716−9721. (c) Yang, Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald,
S. L. Catalytic Asymmetric Hydroamination of Unactivated Internal
Olefins to Aliphatic Amines. Science 2015, 349, 62−66. (d) Zhu, S.;
Niljianskul, N.; Buchwald, S. L. Enantio- and Regioselective CuH-
Catalyzed Hydroamination of Alkenes. J. Am. Chem. Soc. 2013, 135,
15746−15749.
(16) Gao, Y.; Nie, J.; Huo, Y.; Hu, X.-Q. Anthranils: Versatile
Building Blocks in the Construction of C−N Bonds and N-
Heterocycles. Org. Chem. Front. 2020, 7, 1177−1196.
(17) (a) Gao, Y.; Nie, J.; Li, Y.; Li, X.; Chen, Q.; Huo, Y.; Hu, X.-Q.
Rh-Catalyzed C−H Amination/Annulation of Acrylic Acids and
Anthranils by Using −COOH as a Deciduous Directing Group: An
Access to Diverse Quinolines. Org. Lett. 2020, 22, 2600−2605. (b) Li,
J.; Tan, E.; Keller, N.; Chen, Y.-H.; Zehetmaier, P. M.; Jakowetz, A.
C.; Bein, T.; Knochel, P. Cobalt-Catalyzed Electrophilic Aminations
with Anthranils: An Expedient Route to Condensed Quinolines. J.
Am. Chem. Soc. 2019, 141, 98−103.
(18) Xie, F.; Shen, B.; Li, X. Enantioselective Copper-Catalyzed
Hydroamination of Vinylarenes with Anthranils. Org. Lett. 2018, 20,
7154−7157.
(19) (a) Hu, X.-Q.; Chen, J.-R.; Wei, Q.; Liu, F.-L.; Deng, Q.-H.;
Beauchemin, A. M.; Xiao, W.-J. Photocatalytic Generation of N-
7778
https://doi.org/10.1021/acscatal.1c02055
ACS Catal. 2021, 11, 7772−7779

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Centered Hydrazonyl Radicals: A Strategy for Hydroamination of β,γ-
Unsaturated Hydrazones. Angew. Chem., Int. Ed. 2014, 126, 12359−
12363. (b) Hu, X.-Q.; Qi, X.; Chen, J.-R.; Zhao, Q.-Q.; Wei, Q.; Lan,
Y.; Xiao, W.-J. Catalytic N-Radical Cascade Reaction of Hydrazones
by Oxidative Deprotonation Electron Transfer and TEMPO
Mediation. Nat. Commun. 2016, 7, No. 11188. (c) Hu, X.-Q.;
Chen, J.-R.; Xiao, W.-J. Synergistic CO2 Mediation and Photo-
catalysis for α-Alkylation of Primary Aliphatic Amines. Chem 2018, 4,
2274−2277.
(20) (a) Chuang, T.-H.; Yang, C.-H.; Kao, P.-C. Efficient Red-
Emitting Cyclometalated Iridium(III) Complex and Applications of
Organic Light-Emitting Diode. Inorg. Chim. Acta 2009, 362, 5017−
5022. (b) Fröhlich, T.; Tsogoeva, S. B. In Vivo and In Vitro
Optimization of Screening Antimalarial Hits toward Lead Molecules
for Preclinical Development. J. Med. Chem. 2016, 59, 9668−9671.
(c) Michael, J.; Quinoline, P. Quinazoline and Acridonealkaloids. Nat.
Prod. Rep. 2008, 25, 166−187. (d) Weissbuch, I.; Leiserowitz, L.
Interplay Between Malaria, Crystalline Hemozoin Formation, and
Antimalarial Drug Action and Design. Chem. Rev. 2008, 108, 4899−
4914.
(21) (a) Marco-Contelles, J.; Pérez-Mayoral, E.; Samadi, A.;
̈
Carreiras, M. D. C.; Soriano, E. Recent Advances in the Friedlander
Reaction. Chem. Rev. 2009, 109, 2652−2671. (b) Quinolines; Jones,
G., Ed.; The Chemistry of heterocyclic compounds; Wiley: London;
New York, 1977.
(22) (a) Boldi, A. M. Libraries from Natural Product-like Scaffolds.
Curr. Opin. Chem. Biol. 2004, 8, 281−286. (b) Yang, Y.; Lan, J.; You,
J. Oxidative C−H/C−H Coupling Reactions between Two (Hetero)-
Arenes. Chem. Rev. 2017, 117, 8787−8863.
(23) Chinchilla, R.; Nájera, C. Recent Advances in Sonogashira
Reactions. Chem. Soc. Rev. 2011, 40, 5084.
(24) (a) Li, X.; Ouyang, W.; Nie, J.; Ji, S.; Chen, Q.; Huo, Y. Recent
Development on Cp*Ir(III)-Catalyzed C−H Bond Functionalization.
ChemCatChem 2020, 12, 2358−2384. (b) Wang, M.; Wang, Z.;
Shang, M.; Dai, H. Transition-Metal-Catalyzed CH Alkynylation.
Chin. J. Org. Chem. 2015, 35, 570. (c) Li, X.; Wu, G.; Liu, X.; Zhu, Z.;
Huo, Y.; Jiang, H. Regioselective C−H Bond Alkynylation of
Carbonyl Compounds through Ir(III) Catalysis. J. Org. Chem. 2017,
82, 13003−13011.
(25) (a) An, Z.-Y.; Yan, Y.-Y.; Peng, D.; Ou, T.-M.; Tan, J.-H.;
Huang, S.-L.; An, L.-K.; Gu, L.-Q.; Huang, Z.-S. Synthesis and
Evaluation of Graveoline and Graveolinine Derivatives with Potent
Anti-Angiogenesis Activities. Eur. J. Med. Chem. 2010, 45, 3895−
3903. (b) Luo, W.; Lv, J.-W.; Wang, T.; Zhang, Z.-Y.; Guo, H.-Y.;
Song, Z.-Y.; Wang, C.-J.; Ma, J.; Chen, Y. Synthesis, in Vitro and in
Vivo Biological Evaluation of Novel Graveolinine Derivatives as
Potential Anti-Alzheimer Agents. Bioorg. Med. Chem. 2020, 28,
No. 115190.
(26) Chaires, J. B.; Ren, J.; Henary, M.; Zegrocka, O.; Bishop, G. R.;
Strekowski, L. Triplex Selective 2-(2-Naphthyl)Quinoline Com-
pounds: Origins of Affinity and New Design Principles. J. Am.
Chem. Soc. 2003, 125, 7272−7283.
(27) Ohta, K.; Shimizu, H.; Nomura, Y. Reaction of Anthranils with
Enamines Novel Synthesis of Quinolines. Nippon Kagaku Kaishi 1989,
5, 846−854.
(28) (a) Baum, J. S.; Condon, M. E.; Shook, D. A. Nickel-catalyzed
transformations of 2,1-benzisoxazoles with organozinc reagents. J. Org.
Chem. 1987, 52, 2983−2988. (b) Gao, Y.; Yang, S.; Li, Y.; Huo, Y.;
Huang, Z.; Chen, Z.; Hu, X.-Q. Copper-Catalyzed Electrophilic
Amination of Arylboronic Acids with Anthranils: An Access to N-
Aryl-2-aminophenones. J. Org. Chem. 2020, 85, 10222−10231.
7779
https://doi.org/10.1021/acscatal.1c02055
ACS Catal. 2021, 11, 7772−7779