Catalyst and additive free 6-endo-dig cyclization of ortho-alkynylarylaldimines in water: An environmentally friendly access to isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2019.151454

A novel and sustainable route for the synthesis of isoquinoline was developed by reacting 2-ethynylbenzaldehyde with ammonium hydroxide in water. This method provides a convenient, atom-economical, and catalyst-free access to diversely substituted isoquinolines with moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2019.151454

Journal Pre-proofs
Catalyst and additive free 6-endo-dig cyclization of ortho-alkynylarylaldimines
in water: An environmentally friendly access to isoquinolines
Jin Yang, Xinyu Wei, Yajun Yu, Yeting Zhu, Yun-Hui Zhao, Wenlin Xie, Lang
Zhao
PII:
S0040-4039(19)31253-5
DOI:
https://doi.org/10.1016/j.tetlet.2019.151454
TETL 151454
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 September 2019
22 November 2019
25 November 2019
Please cite this article as: Yang, J., Wei, X., Yu, Y., Zhu, Y., Zhao, Y-H., Xie, W., Zhao, L., Catalyst and additive
free 6-endo-dig cyclization of ortho-alkynylarylaldimines in water: An environmentally friendly access to
isoquinolines, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151454
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Catalyst and additive free 6-endo-dig
cyclization of ortho-alkynylarylaldimines in
water: An environmentally friendly access to
isoquinolines
Leave this area blank for abstract info.
Jin Yang, a Xinyu Wei, a Yajun Yu, a Yeting Zhu, a Yun-Hui Zhao,* a,b,c Wenlin Xiea and Lang, Zhaoa
N
O
catalyst free
H2O
R1
+
R1
NH3H2O
R2
R2
Catalyst and additive free
high atom economy
water as the sole byproduct
Water as solvent

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Catalyst and additive free 6-endo-dig cyclization of ortho-alkynylarylaldimines
in water: An environmentally friendly access to isoquinolines
Jin Yang, a† Xinyu Wei, a† Yajun Yu,a Yeting Zhu,a Yun-Hui Zhao,*1 a,b,c Wenlin Xiea, and Lang Zhaoa
aSchool of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan, 411201, P. R. China
bKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai, 200032, P. R. China
cHunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan University of Science
and Technology, Xiangtan,411201, P. R. China
†These authors contributed equally to this work.
1
ARTICLE INFO
ABSTRACT
Corresponding author: zhao_yunhui@163.com (Y.-H. Zhao)
Article history:
Received
Received in revised form
Accepted
A novel and sustainable route for the synthesis of isoquinoline was developed by reacting 2-
ethynylbenzaldehyde with ammonium hydroxide in water. This method provides a convenient,
atom-economical, and catalyst-free access to diversely substituted isoquinolines with
moderate to good yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
catalyst free
green chemistry
isoquinoline
cyclization
With the increasing demand for pharmaceuticals and chemical products, increasing amounts of solvents are used in the chemical
industry for fine chemical and pharmaceutical production. Due to growing environmental concerns, organic solvents, especially low-boiling-
point volatile organic solvents, have become one of the major sources of pollution by the chemical industry. Therefore, the development of
highly efficient chemical synthetic methodologies to provide maximum structural complexity and diversity with a minimum number of
synthetic procedures and maximum atom efficiency for providing compounds with special structures and properties is an important task in
green chemistry [1]. One powerful way to achieve the goal is to adopt “green” solvents, such as ionic liquids [2], poly(ethylene glycol) (PEG)
[3] and water [4]. Other potential methods are to improve atomic economy, and reduce additive use and by-product emissions.
Transition metals play a very important role in the construction of colorful organic compounds.[5] For example, the four famous coupling
reactions—Suzuki coupling [6] Negishi coupling, [7] Kumada coupling [8], and Stille coupling [9]—as well as transition metal catalyzed C-H
activation [10] have become powerful tools for constructing C-C bonds in recent years. However, some metals are very expensive, while
others are very toxic, which is problematic for organic synthesis and environmental pollution. Recently, non-metal mediated oxidative
coupling reactions have been developed, which have gradually become a powerful method for forming C-C bonds and carbon-heteroatom
bonds.[11] Of course, if it is possible to develop a reaction without needing catalyst or promoter, or a reaction in which the catalyst can be
recycled, environmental stress will be reduced. The exploration of new, environmentally-friendly and atomically-economical reactions is a
challenging goal for organic chemists.
Continue our interest in the development of new strategies with high synthetic efficiency and atom economy,[12] we wish to report a
novel method for preparation of isoquinolines via 6-endo-dig cyclization of o-alkynylarylaldehyde with ammonia without catalysts or
additives in water (Scheme 1a). In view of their extensive biological activity and significant role in organic synthesis, great efforts have been
made to explore new methods for the synthesis of isoquinolines and their derivatives.[13] Traditional methods for synthesizing
isoquinolines are mainly based on the cyclization of o-alkynylarylaldehydes and amines catalyzed by metal cations or electrophiles in
organic solvent (Scheme 1b).[14] In recent years, due to the development of C-H activation, noble metal-catalyzed direct C-H bond
functionalization of aromatic aldehydes has been used to form an orthynyl aldehyde, which is then condensed with amines and cyclized to
provide isoquinolines (Scheme 1c).[15] In the current era of global pollution, our method appears to be highly atomically economical and
avoids chemical wastage.

2
Tetrahedron
This work
(a)
R1
Preparation of isoquinolines via 6-endo-dig cyclization of o-alkynylarylaldehyde
with ammonia without catalysts in water
N
O
catalyst free
R1
NH3H2O
+
H2O
R2
R2
Catalyst and additive free
high atom economy
water as the sole byproduct
Water as solvent
previous work
(b) The cyclization of o-alkynylarylaldehydes and amines catalyzed by metal cations
R3
N
O
metal cations
R1
+
R1
H2N R3
solvent
R2
R2
(c) Noble metal-catalyzed cascade reaction for preparation of isoquinolines
R3
N
O
R1
R1
noble metal
solvent
R2
H2N R3
+
+
R2
H
Scheme 1 Synthetic routes of isoquinolines.
In order to reduce chemical waste, inorganic ammonium and ammonia water were chosen as the ammonia sources. In our initial study,
reactions of o-alkynylarylaldehyde [16] with NH4HCO3 were conducted in the presence of I2 at 100 oC in a sealed tube. A 20% yield of target
product was obtained in 1,2-dichloroethane (DCE; entry 1, Table 1). However, performing the reaction in green solvent EtOH or H2O did not
produce the required product after 10 h (entries 2 and 3). Using N-bromosuccinimide (NBS) instead of I2, the product was obtained at a
yield of 26% (entry 4). A significant improvement in yield was observed when ammonia water was used in the reaction, with the desired
product isolated at 78% yield (entry 5). Then, an optimum catalyst concentration investigation was carried out with an NBS concentration
of 150 mol% and 50 mol%. Increasing the NBS concentration to 150 mol% or lowering the catalyst concentration to 50 mol% did not
provide any significant improvement in product yield (entries 6, 7). Next, the effect of temperature on the efficiency of this reaction under
similar conditions and duration was investigated. On conducting the reaction at 80 °C, product 2a was observed at 52% yield, while a
negative effect was observed on product yield with further increases in reaction temperature (entries 8-9). Then, the influence of other
electrophiles on reaction efficiency was evaluated (entries 10-11). The reaction offered the desired isoquinoline at 49% yield in the
presence of N-chlorosuccinimide (NCS), while trace product was observed under the presence of N-iodosuccinimide (NIS). Next, the
necessity of catalyst was checked by performing the reaction in its absence. Unexpectedly, in the absence of NBS, an 80% yield of the
product was obtained (entry 13). However, the reaction time needed be extended to 24h (65% yield for 10h, entry 12). This is the first
example of catalyst- and additive-free reaction for the preparation of isoquinolines in the aqueous phase.
Table 1 Optimisation of reaction conditions for synthesis of isoquinolinesa
N
O
catalyst
+ ammonia source
OMe
OMe
2a
1a
Ammonia resource
(equiv.)
Catalyst
(equiv.)
Entry
Solvent
T/ oC
Yield %b
1
2
NH4HCO3 (300%)
NH4HCO3 (300%)
NH4HCO3 (300%)
NH4HCO3 (300%)
NH3•H2O (1 mL)
NH3•H2O (1 mL)
NH3•H2O (1 mL)
NH3•H2O (1 mL)
NH3•H2O (1 mL)
NH3•H2O (1 mL)
NH3•H2O (1 mL)
I2(100%)
I2(100%)
I2(100%)
DCE
EtOH
H2O
H2O
--
100
100
100
100
100
100
100
80
20
trace
trace
26
3
4
NBS(100%)
NBS(100%)
NBS(150%)
NBS(50%)
NBS(100%)
NBS(100%)
NCS(100%)
NIS(100%)
5
78
6
--
58
7
--
67
8
--
52
9
--
120
100
100
65
10
11
--
49
--
trace
12
NH3•H2O (1 mL)
--
--
100
65
13c
NH3•H2O (1 mL)
--
--
100
80
a reaction conditions: the reaction was performed with 0.3 mmol 1a and ammonia source in a sealed tube for 10h.
b isolated yields.

3
c 24h.
After the optimized reaction conditions were established, we next explored the application scope of this green reaction with a variety of
o-alkynylarylaldehydes. A series of o-alkynylarylaldehydes bearing electron-donating and -withdrawing groups at different positions of the
benzaldehyde ring were well tolerated for cyclization with ammonia for the synthesis of corresponding isoquinolines in moderate to good
yields (Scheme 2). Generally, the method well tolerated the presence of electron-withdrawing groups (EWGs) and electron-donating groups
(EDGs) on the phenyl substituent R2. The electron-donating group produced a better positive effect on the reaction yield than the electron-
withdrawing group. Reaction of the substrate with n-butyl attached to the triple bond provided the corresponding product with 42% yield.
In addition, the electronic effect of R1 was studied and found to have no obvious influence on the reaction. Only in the case of strong
electron withdrawing-groups, such as nitro, did the reaction provide the desired product in 26% yield (not show). This approach appeared
to provide better results, in terms of reducing reaction temperatures and solvent emissions, than existing methods.[17]
O
R1
N
R1
NH3·H2O
+
100 oC
R2
R2
N
N
N
N
N
n-Bu
Cl
OMe
2a
, 80%
2e
2b
, 58%
, 64%
2c
2d
, 58%
, 69%
MeO
N
N
N
N
N
F
Cl
2i
, 45%
2j
, 50%
2h
2g
, 45%
, 72%
Cl
2f
, 41%
N
Cl
Cl
N
N
N
N
F
n-Bu
2o
, 42%
2n
, 66%
2m
, 76%
2k
, 55%
2l,
75%
Cl
Scheme 2 Substrate scope of different 2-alkynylbenzaldehydes with ammonium hydroxide.
To explore the reaction mechanism, several control experiments were performed, as shown in Scheme 3. When ammonia-methanol was
substituted for aqueous ammonia, the reaction provided isoquinoline at a 63% yield under the optimized conditions (Scheme 3-1). Only
trace product was observed when the reaction was carried out under open conditions. Interestingly, the reaction of o-alkynylarylaldehyde
with NH4HCO3 in water also afforded the target product in 52% yield (Scheme 3-2). In addition, a new isoquinolinium salt was obtained with
53% yield when benzyl amine was used in this reaction.
N
O
(1)
+ NH3MeOH
OMe
100 o
C
OMe
2a,
2a,
63%
1a
N
O
(2)
H2O
100 o
+ NH4HCO3
OMe
C
OMe
52%
OH
1a
N
Ph
O
H2O, Na2CO3
100 o
(3)
+
H2N
Ph
C
OMe
3a
, 46%
1a
OMe
Scheme 3 Control experiments.
Based on the above results, it can be concluded that the reaction may proceed smoothly without a promoter. The driving force for the
intramolecular cyclization of the imine is derived from a certain pressure in the reaction system. Therefore, the probable reaction pathway
is as follows (Scheme 4): the first step of the reaction sequence is the formation of the imine A from o-alkynylarylaldehyde and amine. The

imine intermediate A subsequently undergoes annulation via the addition of a C=N bond to the C-C triple bond to afford the required
compound isoquinoline.
NH
O
NH
NH3
B
A
1a
OMe
OMe
OMe
N
OMe
2a
Scheme 4 Plausible reaction pathway.
In summary, an environmental-friendly, catalyst-free method has been explored for the preparation of isoquinolines. A series of
isoquinolines with different substituent was obtained with moderate to good yields. This method has several advantages over other
reported methods: (a) the reaction works smoothly without any catalyst and additives; (b) a renewable solvent, such as water, cab be used;
(c) it has high atom economy with only one mole of water loss; and (d) there are no toxic byproducts.
Acknowledgments
The generous financial support from the National Natural Science Foundation of China (Nos. 51773057, 21571058 and
21877034), the Hunan Provincial Education Department Scientific Research Fund (Nos. 18B221 and 18A192) are gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
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Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
Catalyst and additive free 6-endo-dig
cyclization of ortho-alkynylarylaldimines in
water: An environmentally friendly access to
isoquinolines
Jin Yang, a† Xinyu Wei, a† Yajun Yu, a Yeting Zhu, a Yun-Hui Zhao,* a,b,c Wenlin Xiea and Lang, Zhaoa
N
O
catalyst free
H2O
R1
+
R1
NH3H2O
R2
R2
Catalyst and additive free
high atom economy
water as the sole byproduct
Water as solvent
The reaction worked smoothly without any catalyst and additives.
A renewable solvent, such as water was used.
High atom economy and no toxic byproducts.

Conflicts of interest
There are no conflicts to declare.