Nickel-Catalyzed β-Regioselective Amination/Cyclization of Ynamide-Nitriles with Amines: Synthesis of Functionalized 3-Aminoindoles and 4-Aminoisoquinolines

Article abstract of DOI:10.1021/acs.orglett.0c04278

A highly regioselective nickel/Lewis acid catalyzed amination/cyclization of ynamide-nitriles with amines involving β-addition has been developed. The reaction offers an attractive and efficient route for the synthesis of 3-aminoindoles and 4-aminoisoquinoline derivatives. The Ts-group on the ynamide acts as a directing group to produce the alkenyl nickel species with high regioselectivity.

Full text of DOI:10.1021/acs.orglett.0c04278

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Letter
Nickel-Catalyzed β‑Regioselective Amination/Cyclization of
Ynamide-Nitriles with Amines: Synthesis of Functionalized
3‑Aminoindoles and 4‑Aminoisoquinolines
Xiaoping Hu, Xin Xie, Yi Gan, Gaonan Wang, and Yuanhong Liu*
Cite This: Org. Lett. 2021, 23, 1296−1301
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ABSTRACT: A highly regioselective nickel/Lewis acid catalyzed amination/cyclization of ynamide-nitriles with amines involving β-
addition has been developed. The reaction offers an attractive and efficient route for the synthesis of 3-aminoindoles and 4-
aminoisoquinoline derivatives. The Ts-group on the ynamide acts as a directing group to produce the alkenyl nickel species with
high regioselectivity.
namides have emerged as versatile and important building
hand, hydroamination of alkynes is a well-known process for
Yblocks in organic chemistry during the past two decades. the synthesis of imines, enamines, and heterocycles.11 Early
transition metals, rare earth metal complexes, and palladium
and gold complexes are often used in hydroamination
reactions. There are few examples using inexpensive late-
transition-metals such as nickel as the catalyst in the
hydroamination of alkynes, and the reported reactions usually
require harsh reaction conditions and limited scope.12 Only a
few reports on metal-catalyzed intermolecular hydroamina-
tion13 or amination/cyclizations14 of ynamides with anilines
are known, and most of the studies rely on gold-based systems
via α-addition (e.g., Scheme 1c13). In this paper, we describe a
nickel-catalyzed cyclization of ynamide-nitriles with primary
anilines involving β-regioselective addition, which provides an
efficient and attractive route for the synthesis of highly
functionalized 3-aminoindoles and 4-aminoisoquinolines
(Scheme 1d). To the best of our knowledge, this is the first
example which involves nickel-catalyzed amination of ynamide
derivatives.15
They have been shown to engage in a wide range of
transformations due to their high reactivity caused by the
polarizing effect of the nitrogen on the alkyne, such as in
transition-metal-catalyzed cyclizations, cycloadditions, carbo-
metalation, ring-closing metathesis, rearrangements, radical
reactions, etc.1 Usually, α-addition to the triple bond in
ynamides occurs due to the polarity of the ynamides (Scheme
1a), whereas the β-addition has much less been explored,
especially in intermolecular processes.2 In this context, most of
the studies related to the intermolecular β-additions con-
centrated on the chelation controlled regioselective reactions
(Scheme 1b). That is, the reaction is directed by chelation of
the metal with the electron-withdrawing group, usually, an
oxazolidinone group, to give a β-addition intermediate I, which
can undergo further transformations to furnish the function-
alized products. This includes carbocupration,3 Rh-4 or Cu5-
catalyzed carbozincation, Rh-catalyzed arylation with arylbor-
onic acids, arylboronates, and triarylboroxines,6 Cu-catalyzed
addition of Grignard reagents,7 silyl-7a,8 and boryl-metalation,9
etc.10 Although much progress has been achieved, stoichio-
metric amounts of organometallic reagents were usually
required as the nucleophiles in these reactions, and some of
them are air- and moisture-sensitive and suffer from low
stability and low functional-group tolerance. Ideally, the use of
nonmetallic reagents such as amines as the nucleophiles to
initiate the β-additions would be of high interest since these
nucleophiles are easily available and inexpensive. On the other
To test the feasibility, we initially investigated the nickel-
catalyzed reaction of ynamide-nitrile 1a16 with 4-fluoroaniline
(Table 1). After evaluation of the reaction parameters such as
Received: December 28, 2020
Published: February 3, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04278
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1296−1301
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Scheme 1. Transition-Metal-Catalyzed Amination of
Ynamides
Table 1. Optimization Studies for the Formation of 3a
ligand
(mol %)
Lewis acid
(mol %)
yield
a
entry
catalyst
(%)
1
2
3
4
NiCl2 (DME)
(10)
NiCl2 (DME)
(10)
NiCl2 (DME)
(10)
NiCl2 (DME)
(10)
dppp (10)
dppp (10)
PMePh2 (20)
Zn(OTf)2 (20)
77
−
38 (6)
20 (7)
− (72)
Zn(OTf)2 (20)
Xantphos (10) Zn(OTf)2 (20)
5
6
7
8
9
10
NiI2 (10)
dppp (10)
−
−
−
−
−
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Sc(OTf)3 (20)
Al(OTf)3 (20)
BPh3 (20)
77
78
63 (3)
48 (7)
16 (11)
NiCl2(dppp) (10)
NiCl2(dppp) (10)
NiCl2(dppp) (10)
NiCl2(dppp) (10)
NiCl2(dppp) (10)
Zn(OTf)2 (100) 78
11 NiCl2(dppp) (5)
−
−
−
−
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
−
81
b
12
13
14
15
16
17
18
19
20
NiCl2(dppp) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (5)
−
NiCl2(DME) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (10)
NiCl2(dppp) (10)
71
c
68 (12)
d
35 (37)
dppp (5)
− (70)
− (81)
−
−
−
−
−
e
− (61)
25 (35)
f
nickel catalysts, ligands, additives and solvents (the detailed
results are shown in the Supporting Information), we found
that the addition of a Lewis acid played an important role for
this reaction. For example, the 3-aminoindole 3a was formed in
77% yield by the use of NiCl2(DME) (10 mol %), dppp (10
mol %), Zn powder (1.0 equiv, alfa, 100 mesh) and Zn(OTf)2
(20 mol %) in dioxane at 80 °C (Table 1, entry 1). Without
Zn(OTf)2, only 38% of 3a was formed (entry 2). The structure
of 3a was confirmed by X-ray crystallographic analysis.17
Interestingly, the results indicated that the Ts-group was
eliminated during the reaction. Other ligands such as PMePh2
or Xantphos are much less effective (entries 3−4). NiI2 also
showed high catalytic performance for this reaction (entry 5).
A preassembled nickel phosphine complex NiCl2(dppp)
catalyzed the reaction also efficiently (entry 6). When
Sc(OTf)3 or Al(OTf)3 were used instead of Zn(OTf)2, 3a
could be formed in 48−63% yields, whereas low yield was
observed with BPh3 (entries 7−9). We suggested that Lewis
acid might play a role by increasing the electrophilicity of the
cyano group through coordination, thereby accelerates the
nucleophilic addition process. Increasing the amount of
Zn(OTf)2 did not give a significant effect on the product
yield (entry 10). The catalyst loading could be reduced to 5
mol %, resulting in a comparable yield of 3a to that obtained
using 10 mol % nickel catalyst (entry 11). The reaction also
progressed smoothly in THF (entry 12). Decreasing the
temperature to 50 °C or lowering the amount of Zn to 50 mol
% reduced the yield of 3a (entries 13−14). As expected, no
products were formed without Ni catalyst, dppp, or Zn powder
(entries 15−17). It was noted that when Zn powder derived
from another chemical company (Admas, 325 mesh) was used,
1.0 equiv of Lewis acid was required to consume the starting
material completely (entries 19−20). 3-Aminoindole deriva-
tives are of high interest in pharmaceutical development, which
Zn(OTf)2 (20)
Zn(OTf)2 (100) 78
31 (25)
f
a
NMR yields using 1,3,5-trimethoxybenzene as an internal standard.
b
The yields of the unreacted 1a are shown in parentheses. THF was
used. 50 °C. 50 mol % Zn was used. Without Zn powder. 1.0
equiv Zn (Adamas 325 mesh) was used.
c
d
e
f
exhibit a wide range of biological activities.18 However, the
synthetic route for 3-aminoindole is limited;19 our method
provides a straightforward route for these heterocycles.
With the optimized reaction conditions established, the
substrate scope of this nickel-catalyzed cascade amination/
cyclization was explored. The scope of the anilines was
evaluated first using 1a as the reaction partner (Scheme 2).
During this process, we found that the 5 mol % catalyst loading
was not effective in some cases, thus 10 mol % NiCl2(dppp)
was used in most of the cases (the conditions shown in Table
1, entry 6) to achieve the better results. A wide variety of
anilines bearing either electron-donating or electron-with-
drawing groups was suitable for this transformation. For
example, anilines bearing an electron-deficient o-F, p-Cl, p-
COPh, p-CO2Et, or p-CN group were converted into the
corresponding products 3b−f in 35−54% yields. The use of
electron-neutral aniline resulted in the formation of 3g in 76%
yield. Anilines with an electron-donating group such as p-Me,
p-OMe, or p-tBu group gave higher yields of 3h−j (76−81%)
than those with electron-deficient groups, possibly due to the
stronger nucleophilicity of these amines. Introduction of a
N,N-dimethyl at the para-position of the aryl ring resulted in a
lower yield of 3k (28%), possibly due to the competitive
coordination of this amino group with the nickel catalyst or a
Lewis acid. The 3,5-dimethylaniline and 4-phenylaniline gave
the corresponding product 3l and 3m in 40−45% yields. When
the sterically bulkier 1-naphthylamine was employed, the
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a
a
Scheme 2. Scope of Anilines
Scheme 3. Scope of the Ynamides
a
Isolated yields.
a
b
Scheme 4. Synthesis of Isoquinolin-4-amine Derivative
Isolated yields. 5 mol % NiCl2(dppp) was used.
corresponding product 3n was formed in a lower yield (34%),
indicating that the reaction is sensitive to the steric effects. In
this case, most of the substrate 1a was consumed, and the
reaction was not clean. Heteroaryl amines such as 2-
aminothiazole were also compatible (3o). However, no
apparent product or trace product was observed with
TsNH2, benzyl amine, or o-methylaniline, respectively.
4-amine derivatives have recently been found to be an efficient
NRF2 activator.21 Unlike the product 3, the imine part in 6
was reduced to an amine, indicating that possibly a Ni−H
species was generated during the reaction.
Next, the scope of ynamides was investigated by the
reactions with 4-fluoroaniline (Scheme 3). The effect of the
electron-withdrawing group of the ynamide was first examined.
The N-Ms substrate afforded 3a in 58% yield, which is lower
than that obtained from the N-Ts-substituted one. N-p-
Fluorobenzenesulfonyl or N-p-methoxybenzenesulfonyl-substi-
tuted ynamides were all suitable for this reaction, furnishing 3p
in 58−59% yields. Substrates with an electron-donating group
such as p-Me, p-OMe, or 3,5-dimethyl on the terminal aryl ring
underwent the cyclization reactions smoothly, furnishing 3q,
3p, and 3r in 58−67% yields. Ynamides with a variety of
electron-withdrawing groups such as p-Cl, o-F, p-F, or p-CO2Et
on the aryl ring reacted smoothly with 2a, furnishing 3s−3v in
39−68% yields. Notably, a chlorine substituent was tolerated
in this reaction (3s). Thienyl-substituted ynamide gave 3w in
58% yield. As for the alkyl-substituted ynamide such as methyl-
substituted one, the desired product 3x could be formed in
21% yield, along with a byproduct 420 derived from [2 + 2 + 2]
cycloaddition of alkyne-nitrile with alkyne.16
To understand the reaction mechanism, we carried out the
following experiments. First, we examined the reaction of 1a
and 2a using a catalytic amount of Ni(cod)2. Only a trace of 3a
was observed (Scheme 5, eq 1). However, in the presence of
1.0 equiv of Zn, 3a could be formed in 21% yield. The results
indicate that Zn may promote the regeneration of the Ni(0)
catalyst. The use of a stoichiometric amount of Ni(cod)2 and
dppp gave the desired 3a in 50% yield within 1 h. The yield
was improved to 60% by adding 1.0 equiv of Zn(OTf)2
(Scheme 5, eq 2). The results suggest that both the cyclization
and desulfonylation processes can be catalyzed by a Ni(0)
species.
Interestingly, preliminary results indicated that a highly
efficient hydroamination of alkyl-substituted ynamide 5 could
occur using 20% Zn(OTf)2 as the catalyst, leading to 7 via α-
addition (Scheme 5, eq 3). Such unwanted side reaction might
compete with the main pathway, resulting in a lower yield of 6.
Although the detailed mechanistic discussions should await
further studies, we tentatively propose the following reaction
mechanism for these reactions (Scheme 6). Initially, the in situ
generated Ni(0) species coordinates with alkyne to form a π-
The reaction was also successfully expanded to ynamide-
nitrile 5 linked by an alkylaryl group (Scheme 4). Interestingly,
isoquinolin-4-amine 6 was obtained in 57% yield. Isoquinolin-
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Scheme 5. Control Experiments
Scheme 7. Possible Mechanism for the Formation of 6
the imine to form an amino-nickel(II) complex 20, which
undergoes reduction with Zn to provide zinc complex 21 and
regenerates the Ni(0) catalyst.
Scheme 6. Possible Mechanism for the Formation of 3
In summary, a highly regioselective nickel-catalyzed
cyclization of ynamide-nitriles with amines has been
developed. The catalyst system, featured on the nickel and
Lewis acid dual catalysis, offers an attractive and efficient route
for the synthesis of 3-aminoindoles and 4-aminoisoquinoline
derivatives which may have the potential utility in medicinal
chemistry. The Ts-group on the ynamide acts as a directing
group to produce the alkenyl nickel species with high
regioselectivity. Further mechanistic studies and the develop-
ment of the Ni-catalyzed transformations of ynamides are
currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04278.
Experimental details and spectroscopic characterization
of all products and new substrates, Crystal data and
structural refinement for compounds 3g, 4, S-5 (2-
tosylisoindolin-1-imine), 5, 6, and 7 (PDF)
complex 8. Regioselective addition of amine to the alkyne-
complex 8 affords a zwitterion complex 9′ via syn- or anti-
addition.12d The detailed mechanism and the stereochemistry
for this addition process were not clear yet. The regioselectivity
of this step might be ascribed to the chelation of the nickel
catalyst with the tosyl group. The cyano group may also
coordinate with nickel and direct the subsequent nucleophilic
attack via 9 to give the cyclized intermediate 10. Proton
dissociation from the amino group and protonation of the
iminium nickel species deliver intermediate 11, which
tautomerizes to afford intermediate 12. Oxidative addition of
N-Ts group in 12 to Ni(0) followed by reduction regenerates
the Ni(0) species and forms the zinc intermediate 14, which
leads to the final product 3 upon protonation.22 Alternatively,
as suggested by a reviewer, the reaction might be initiated
through N−H bond activation.23 In this pathway, oxidative
addition of the N−H bond in aniline by Ni(0) followed by Ni-
amido bond addition to the alkyne affords a syn-alkenyl-Ni(II)
species, or an anti-alkenyl-Ni(II) species via isomerization24 of
the syn-species. The subsequent step is similar to that shown in
Scheme 6. The reaction pathway involving the azanickela-
cycle16 could also not be excluded.
Accession Codes
CCDC 2048276−2048278, 2056793, and 2057425−2057426
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Yuanhong Liu − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China; orcid.org/
0000-0003-1153-5695; Email: yhliu@sioc.ac.cn
Authors
For the formation of 6 (Scheme 7), after cyclization, the
oxidative addition of N-Ts to Ni(0) in 17 occurs followed by
β-hydride elimination to give 19. Then the hydride can reduce
Xiaoping Hu − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
1299
https://dx.doi.org/10.1021/acs.orglett.0c04278
Org. Lett. 2021, 23, 1296−1301

Organic Letters
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China
Xin Xie − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, People’s Republic of China
Yi Gan − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, People’s Republic of China
Gaonan Wang − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China
pubs.acs.org/OrgLett
Letter
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The authors declare no competing financial interest.
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Sanchez, A.; Canavera-Buelvas, F.; Barrios-Francisco, R.; Cifuentes-
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Amines As Hydrogen Donors. Organometallics 2011, 30, 3340−3345.
We thank the National Key R&D Program of China
(2016YFA0202900), the National Natural Science Foundation
of China (21772217), the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB20000000), Science
and Technology Commission of Shanghai Municipality
(18XD1405000) for financial support.
́
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(c) Reyes-Sanchez, A.; Garcia-Ventura, I.; GarcIa, J. J. Easily available
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(17) CCDC-2048276 (for 3g), -2056793 (for 4), -2057425 (for S-5,
2-tosylisoindolin-1-imine), -2057426 (for 5), -2048277 (for 6), and
-2048278 (for 7) contain the supplementary crystallographic data for
this paper.
(18) (a) Pews-Davtyan, A.; Tillack, A.; Schmole, A. C.; Ortinau, S.;
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amidoindole derivatives and their evaluation as potential GSK-3β
1300
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Org. Lett. 2021, 23, 1296−1301

Organic Letters
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Org. Lett. 2021, 23, 1296−1301