Highly Regioselective Isoquinoline Synthesis via Nickel-Catalyzed Iminoannulation of Alkynes at Room Temperature

Article abstract of DOI:10.1002/ejoc.201800341

A simple and cost-efficient nickel catalytic system for the annulation of 2-haloaldimines with alkynes to synthesize 3,4-disubstituted and 3-substituted isoquinolines at room temperature has been developed. The air-stable and inexpensive Ni(dppe)Cl₂ was employed as a precatalyst, and Et₃N was found to be an essential additive for obtaining high yields. By using this nickel catalytic system one-pot three-component direct synthesis of isoquinolines starting with simple 2-halobenzaldehydes, tert-butylamine, and alkynes were also achieved. These reactions occur in moderate to excellent yields with complete regioselectivity. Moreover, these reactions feature a broad substrate scope, easy scalability, operational simplicity, and excellent practicality.

Full text of DOI:10.1002/ejoc.201800341

A Journal of
Accepted Article
Title: Highly Regioselective Isoquinoline Synthesis via Nickel-
Catalyzed Iminoannulation of Alkynes at Room Temperature
Authors: Jian-Guo Sun, Xiao-Yu Zhang, Hua Yang, Ping Li, and Bo
Zhang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800341
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800341
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10.1002/ejoc.201800341
European Journal of Organic Chemistry
COMMUNICATION
Highly Regioselective Isoquinoline Synthesis via Nickel-
Catalyzed Iminoannulation of Alkynes at Room Temperature
Jian-Guo Sun, Xiao-Yu Zhang, Hua Yang, Ping Li, and Bo Zhang*[a]
Abstract: A simple and cost-efficient nickel catalytic system for the
annulation of 2-haloaldimines with alkynes to synthesize 3,4-
disubstituted and 3-substituted isoquinolines at room temperature
has been developed. The air-stable and inexpensive Ni(dppe)Cl2
was employed as a precatalyst, and Et3N was found to be an
essential additive for obtaining high yields. By using this nickel
catalytic system one-pot three-component direct synthesis of
isoquinolines starting with simple 2-halobenzaldehydes, tert-butyl
amine, and alkynes were also achieved. These reactions occur in
moderate to excellent yields with complete regioselectivity. Moreover,
these reactions feature a broad substrate scope, easy scalability,
operational simplicity, and excellent practicality.
Introduction
Scheme 1. Synthesis of substituted isoquinolines via transition-metal-
catalyzed iminoannulation of alkynes.
Heterocyclic compounds, especially nitrogen heterocycles, are
among the most important structural classes of chemical
substances in the pharmaceutical, agrochemical, and chemical
In recent years, considerable attention has been paid to
industries.[1] Among them, isoquinolines are very common
conditions for a facile access to diverse isoquinolines is highly
warranted.
develop cross-coupling reactions that were facilitated by nickel
structural motifs that are frequently found in numerous natural
catalysis.[8] In comparison to palladium, nickel is much less
products, bioactive molecules, and functional materials.[2] Wide
expensive and significantly more abundant. In light of these
applications trigger continued interest in the preparative
advantages offered by nickel, a variety of elegant nickel-
chemistry of isoquinolines.[3] Traditional methods for the
catalyzed cross-coupling reactions have been established to
preparation of isoquinolines rely on the Bischler-Napieralski
form C-C[9] and C-heteroatom bonds.[10] It was however
reaction, the Pomeranz-Fritsch reaction, and the Pictet-Spengler
surprising to note that investigations on building the isoquinoline
moiety via a nickel-catalyzed Larock-type annulation reaction is
very rare. In 2005, Cheng and co-workers reported a nickel-
catalyzed cyclization of 2-iodobenzaldimines with alkynes to
synthesize substituted isoquinolines (Scheme 1c).[11,12] However,
this method require high temperatures and the use of a
stoichiometric metal reducing agent (Zn), thus limiting the further
application of such a method.
On the other hand, most of these reported transition-metal-
catalyzed methods suffer from the use of 2-halobenzaldimine
substrates.[5-7a-c,11] Examples of direct construction of
isoquinolines starting with simple 2-halobenzaldehydes, tert-
butyl amine, and alkynes have rare precedents,[7d] although it
can provide a straightforward and step-economical route to
isoquinolines. This approach presents two main challenges that
need to be addressed: 1) amination of 2-halobenzaldehydes
with tert-butyl amine might occur when a transition-metal
catalyst was employed;[13] 2) 2-halobenzaldehydes undergo the
annulation reaction easily with alkynes to produce indenones
II.[6c,14] These issues and challenges mentioned above reinforce
the need for the development of a general, cost-efficient, and
practical catalytic system to realize the construction of important
isoquinolines.
reaction.[4] Nevertheless, the harsh acidic conditions, high
temperatures, as well as tedious reaction procedures and poor
regioselectivity during ring closure remain impediments of these
approaches. Since the pioneering work of Larock and co-
workers in 1998,[5] a palladium-catalyzed annulation reaction of
2-halobenzaldimines with internal alkynes has become
a
powerful and efficient synthetic tool for the construction of 3,4-
disubstituted isoquinolines (Scheme 1a).[6] Later, a palladium-
and copper-catalyzed coupling and annulation reaction of 2-
halobenzaldimines with terminal alkynes has been developed to
prepare 3-substituted isoquinolines (Scheme 1b).[7] Despite
significant advances, these procedures are associated with one
or more limitations such as the use of an expensive palladium
catalyst, the need for specialized ancillary ligands, high
temperatures, superfluous usage of alkynes, and so on.
Therefore, seeking new and efficient synthetic methods that
employ inexpensive metal catalytic systems and mild reaction
[a]
J.-G. Sun, X.-Y. Zhang, H. Yang, Prof. P. Li, Prof. Dr. B. Zhang
State Key Laboratory of Natural Medicines
China Pharmaceutical University
24 Tongjia Xiang, Nanjing 210009, China
E-mail: zb3981444@cpu.edu.cn
Herein, we present a simple and cost-efficient nickel catalytic
system that can efficiently catalyze the formation of substituted
isoquinolines from 2-haloaldimines and alkynes. This nickel
Supporting information for this article is given via a link at the end
of the document.
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10.1002/ejoc.201800341
European Journal of Organic Chemistry
COMMUNICATION
catalytic system employs air-stable and inexpensive Ni(dppe)Cl2
as a precatalyst and Et3N as a mild base. Moreover, we also
showed that this nickel catalytic system is capable of achieving
direct preparation of isoquinolines starting with readily available
2-halobenzaldehydes, tert-butyl amine, and alkynes in one step.
These reactions proceed at room temperature with complete
regioselectivity, and a variety of substituted isoquinolines can be
readily obtained in high yields (Scheme 1d).
3aa was obtained in 44% yield (Table 1, entry 3). Encouraged
by this result, we surveyed a range of bases. Some bases, such
as KOtBu, DBU, 2,6-lutidine, and DABCO were shown to be
ineffective for this transformation (Table 1, entries 4-7). iPrNEt
resulted in a low yield due to the incomplete conversion of 1a
(Table 1, entry 8). Surprisingly, the greatest improvement came
from Et3N, which gave 3aa in 91% yield (Table 1, entry 9). With
Et3N as base, other nickel(II) sources, such as Ni(dppf)Cl2,
Ni(dppp)Cl2, and Ni(PPh3)Cl2, provided poorer results (Table 1,
entries 10-12). The annulation reaction did not proceed in the
absence of ligand (Table 1, entry 13). Solvent screening showed
that CH3CN was optimal (Table 1, entries 14-20). Notably,
decreasing the Ni(dppe)Cl2 loading to 5 mol-% still provided 3aa
in good yield (Table 1, entry 21). However, no product was
observed in the absence of the nickel catalyst (Table 1, entries
22 and 23).
Results and Discussion
We began our investigations by finding mild catalytic conditions
for the annulation of 2-iodobenzaldimine 1a and 1,2-
diphenylethyne 2a. We first surveyed various Ni(II) salts as
precatalysts in the presence of Cs2CO3 as base in CH3CN at
room temperature for 12 h. Unfortunately, the isoquinoline 3aa
was not formed in the presence of NiCl2, Ni(acac)2,
Ni(NO3)2·6H2O, Ni(OTf)2, or Ni(OAc)2·4H2O (Table 1, entry 1).
As for other nickel-catalyzed coupling reactions,[8-10] we
anticipated that ligands would play a key role for success. Thus,
the influence of ligands on this annulation reaction was next
examined. Reactions conducted in the presence of some nickel
complexes with phosphine ligands, including Ni(dppe)Cl2,
Ni(dppp)Cl2, Ni(dppf)Cl2, and Ni(PPh3)Cl2 did not afford 3aa.
Exemplary, the result obtained with Ni(dppe)Cl2 is depicted in
Table 1 (entry 2; for full list of results, see the Supporting
Information). Intriguingly, upon switching to Na2CO3 as base,
With the optimal conditions established, we then explored the
scope of this nickel-catalyzed annulation reaction. As shown in
Scheme 2, the reaction tolerates various electron-donating and
electron-withdrawing substituents at the 4- or 5-positions of 2-
iodobenzaldimines, and the corresponding products 3ba-ia were
obtained in moderate to excellent yields. Substrates with ortho
substituents also gave good yields (see 3ja and 3ka). Besides 2-
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
Base
Solvent
Yield[b] [%]
1[c]
2
3
4
5
6
7
8
NiX2
Cs2CO3
Cs2CO3
Na2CO3
KOtBu
DBU
2,6-lutidine
DABCO
iPrNEt
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
DCE
DMSO
DMF
MeOH
EtOAc
toluene
CH3CN
CH3CN
CH3CN
0
0
44
0
0
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppf)Cl2
Ni(dppp)Cl2
Ni(PPh3)Cl2
NiX2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
dppe
0
0
20
91
10
44
trace
0
trace
trace
trace
trace
trace
0
9
10
11
12
13[c]
14
15
16
17
18
19
20
21[d]
22
23
0
84
0
0
Et3N
Et3N
none
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (10 mol-%),
and base (0.4 mmol) in solvent (2.0 mL) at r.t. under N2 for 12 h. [b] Isolated
yields. [c] Using NiCl2, Ni(acac)2, Ni(NO3)2·6H2O, Ni(OTf)2, or Ni(OAc)2·4H2O
as
bis(diphenylphosphino)ethane, dppf = 1,1'-bis(diphenylphosphino)ferrocene,
dppp 1,3-bis(diphenylphosphino)propane, DBU 1,8-
diazabicyclo[5.4.0]undec-7-ene, DABCO = 1,4-diazabicyclo[2.2.2]octane.
a precatalyst. [d] Using 5 mol-% of Ni(dppe)Cl2. dppe = 1,2-
Scheme 2. Scope of the nickel-catalyzed annulation reaction of 2-
haloaldimines with alkynes. Reaction conditions: see entry 9, Table 1. Yields
of isolated products are given. [a] The reaction was conducted for 24 h.
=
=
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10.1002/ejoc.201800341
European Journal of Organic Chemistry
COMMUNICATION
iodobenzaldimines, the corresponding bromo species exhibited
excellent reactivity. Moreover, the corresponding chloro species
reacted smoothly with 2a to form 3aa in 73% yield, albeit a much
longer reaction time for 24 h. It is noteworthy that the current
methodology can be applied to the construction of pyridine
derivatives. For example, aldimines 1l and 1m were successfully
converted to the desired products 3la and 3ma in moderate to
excellent yields.
From a practical viewpoint, one-pot three-component direct
synthesis of isoquinolines starting with readily available 2-
halobenzaldehydes, tert-butyl amine, and alkynes is highly
desirable. Next, we turned out attention to three-component
assembly of isoquinolines (Scheme 3). Gratifyingly, under this
nickel catalytic system, both 2-iodobenzaldehyde and 2-
bromobenzaldehyde reacted readily with tert-butyl amine and
1,2-diphenylethyne 2a to give the targeted product 3aa in high
yields. However, when 2-chlorobenzaldehyde was used as
substrate, only traces of 3aa were obtained. 2-
Iodobenzaldehydes carrying different substituents consistently
provided the expected products in good to excellent yields
regardless of their electronic properties (see 3ba-ia).
Furthermore, three-component assembly of pyridine derivative is
also proved to be viable (see 3ma). Both internal alkynes and
terminal alkynes underwent this transformation smoothly to give
the desired products 3ac-ay in moderate to excellent yields. For
unsymmetrical alkynes, products are all formed as the exclusive
regioisomers (see 3aj-ay). In all cases, byproducts I and II were
not observed.
Next, the scope of alkyne coupling partners was investigated
(Scheme 2). Symmetrical diaryl-substituted alkynes bearing
electron-donating or electron-withdrawing substituents were
readily converted in high yields to the corresponding products
3ab-ae. An internal alkyne with a heterocycle such as thiophene
afforded the product 3af in 95% yield. Moreover, symmetrical
dialkyl-substituted alkynes are also compatible with this protocol,
leading to the products 3ag-ai in excellent yields. To investigate
the regioselectivity of this reaction, we studied unsymmetrical
alkynes. The regiochemistry of these products was determined
by comparing their NMR spectral data with those reported or by
NOE experiments (see the Supporting Information).
Unsymmetrical phenyl-substituted alkynes 2j-n reacted under
optimized conditions with complete regioselectivity to 3aj-an in
up to 98% yield. The phenyl group in these products is placed at
the C3 position of the isoquinoline products. For unsymmetrical
dialkyl-substituted alkyne 1o, only product 3ao with the larger
substituent attached to the carbon adjacent to the nitrogen atom
was obtained. Intriguingly, the insertion of terminal alkynes
occurs regioselectivity with the substituents (e.g., aryl, heteoaryl,
alkyl, and alkenyl group) being installed at the C3 position of the
products (see 3ap-ay). The low yields for 3ao and 3ax were due
to the incomplete conversions of substrates.
To show the practical usefulness of this method, we carried
out a preparative scale reaction of 4a' with 2a and tert-butyl
amine to produce 3aa in 82% yield (Scheme 4a). Moreover, the
utility of the current methodology is further demonstrated by
applying it toward the total synthesis of CWJ-a-5 (free base),
which was the representative compound identified as
topoisomerase
inhibitor.[15] In the key step, 3-
phenylisoquinoline 3ap could be easily prepared in 99% yield
from commercially available 2-iodobenzaldehyde 4a,
a
1
ethynylbenzene 2p, and tert-butyl amine, which was converted
to 1-chloro-3-phenylisoquinoline 5 by N-oxidation and sequential
chlorination. Amination of 5 with 1-methylpiperazine delivered
CWJ-a-5 (free base) in total yield of 48% (Scheme 4b).
Scheme 4. Large-scale synthesis and synthetic application.
Several experiments were conducted to shed light on the
mechanism of this transformation. We found that the reaction
was completely inhibited by the addition of TEMPO (radical
scavenger) or nitrobenzene (electron acceptor). The addition of
BHT resulted in a sharp decrease in the yield (Scheme 5a).
These observations indicate that single electron transfer
processes might come into play. Next, we conducted a radical
Scheme 3. Scope of the nickel-catalyzed one-pot three-component assembly
of isoquinolines. Reaction conditions: 4 (0.2 mmol), 2 (0.3 mmol), tBuNH2 (0.6
mmol), Ni(dppe)Cl2 (10 mol-%), and Et3N (0.4 mmol) in CH3CN (2.0 mL) at r.t.
under N2 for 12 h. Yields of isolated products are given. [a] The reaction was
conducted for 24 h.
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10.1002/ejoc.201800341
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COMMUNICATION
clock experiment. Starting with olefin 6 containing a radical clock
cyclopropane moiety, no ring-opening product 7 was obtained
(Scheme 5b). Meanwhile, radical trapping experiment with 1,1-
diphenylethylene as the radical trapper on 1a did not give radical
adduct (for details see the Supporting Information). These
results imply that aryl radicals are not likely involved in the
current reaction. Moreover, we found that this reaction did not
work in the absence of Et3N, thus indicating that Et3N is key for a
successful outcome (Scheme 5c). When the reaction was
initiated with a catalytic amount of Ni(cod)2 (cod = 1,5-
cyclooctadiene) and dppe, 3aa was obtained in 98% yield, thus
suggesting that Ni(0) may be the active catalyst in the current
transformation (Scheme 5d). Based on these experimental
observations and previous reports,[6,11] we believe that the
reaction is triggered by an in situ reduction of Ni(II) to the active
Ni(0) catalyst with the aid of Et3N[16] upon SET processes,
followed by oxidative addition into the corresponding C-X bond.
Subsequently, coordinative insertion of alkyne, followed by
reductive elimination would produce the corresponding tert-
butylcarbolinium salt with concomitant regeneration of the active
Ni(0) catalyst. Finally, the tert-butyl group on the tert-
butylcarbolinium salt was removed by the attack of halide ion
generated during the reaction process to give the expected
product.
available starting materials. These reactions are characterized
by a broad substrate scope, good functional group tolerance,
easy scalability, operational simplicity, and complete
regioselectivity. We expect that this simple and cost-efficient
nickel catalytic system will provide a practical, operationally
simple, and user-friendly tool for the construction of various
important nitrogen heterocycles.
Experimental Section
General procedure for the synthesis of isoquinolines via
nickel-catalyzed annulation reaction of 2-haloaldimines with
alkynes: 2-Haloaldimine 1 (0.2 mmol, 1.0 equiv), alkyne 2 (0.3
mmol, 1.5 equiv), Ni(dppe)Cl2 (0.02 mmol, 0.1 equiv), and Et3N
(0.4 mmol, 2.0 equiv) were placed in a dry 10 mL Schlenk tube
under a nitrogen atmosphere. Dry CH3CN (2.0 mL) was added
with a syringe and the reaction mixture was stirred at room
temperature for 12 h monitored with TLC. After completion of the
reaction, it was transferred to a round-bottomed flask after
dilution with CH2Cl2. The solvent was removed under reduced
pressure and the residue was purified by flash column
chromatography on silica gel to afford the product.
General procedure for the synthesis of isoquinolines via
nickel-catalyzed one-pot three-component reaction of 2-
halobenzaldehydes, alkynes, and tert-butyl amine: 2-
Halobenzaldehyde 4 (0.2 mmol, 1.0 equiv), alkyne 2 (0.3 mmol,
1.5 equiv), tBuNH2 (0.6 mmol, 3.0 equiv), Ni(dppe)Cl2 (0.02
mmol, 0.1 equiv), and Et3N (0.4 mmol, 2.0 equiv) were placed in
a dry 10 mL Schlenk tube under a nitrogen atmosphere. Dry
CH3CN (2.0 mL) was added with a syringe and the reaction
mixture was stirred at room temperature for 12 h monitored with
TLC. After completion of the reaction, it was transferred to a
round-bottomed flask after dilution with CH2Cl2. The solvent was
removed under reduced pressure and the residue was purified
by flash column chromatography on silica gel to afford the
product.
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (21702230), the Natural Science
Foundation of Jiangsu Province (BK20160743), the Program for
Jiangsu Province Innovative Research Team, and the 111
Project (B16046).
Scheme 5. Mechanistic studies.
Keywords: alkynes • isoquinolines • annulation • nickel •
Conclusions
regioselectivity
In summary, we have described a highly efficient, simple, and
mild nickel-catalyzed annulation reaction of 2-haloaldimines with
alkynes to prepare 3,4-disubstituted and 3-substituted
isoquinolines in high yields. The air-stable and inexpensive
Ni(dppe)Cl2 was employed as a precatalyst, and we discovered
that Et3N play an important role for obtaining high yields.
Importantly, we also showed that this simple but robust nickel
catalytic system is capable of achieving three-component
assembly of isoquinolines in a single step starting with readily
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European Journal of Organic Chemistry
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10.1002/ejoc.201800341
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Nickel Catalysis
Jian-Guo Sun, Xiao-Yu Zhang, Hua
Yang, Ping Li, Bo Zhang*
Page No. – Page No.
Highly Regioselective Isoquinoline
Synthesis
via
Nickel-Catalyzed
Iminoannulation of Alkynes at Room
Temperature
The air-stable and inexpensive Ni(dppe)Cl2 along with Et3N efficiently catalyzes the
iminoannulation of alkynes at room temperature, allowing for the preparation of important
3,4-disubstituted and 3-substituted isoquinolines in high yields with complete
regioselectivity. These annulation reactions feature a broad substrate scope, easy scalability,
operational simplicity, and excellent practicality.
This article is protected by copyright. All rights reserved.