Silver Nitrate Mediated Cyclization/N-N Bond-Cleavage Reaction for the Synthesis of 3-Arylisoquinolines

Article abstract of DOI:10.1055/s-0035-1562609

An unprecedented silver nitrate mediated novel transformation of aromatic hydrazones into various isoquinolines has been developed. This method involves a silver nitrate promoted cyclization of aromatic hydrazones followed by N-N bond cleavage, and has wide substrate scope under mild conditions.

Full text of DOI:10.1055/s-0035-1562609

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
Y.-H. Zhao et al.
Letter
Synlett
Silver Nitrate Mediated Cyclization/N–N Bond-Cleavage Reaction
for the Synthesis of 3-Arylisoquinolines
Yun-Hui Zhao*a,b
Yubo Lia
Mingjian Luoa
Zilong Tangc
Keqin Denga,c
NH2
N
N
O
R1
R1
R1
NH2NH2
EtOH
AgNO3 (1 equiv)
DMSO, 100 °C
R2
R2
R2
1 = H, Me, Cl, F, MeO
R2 = H, Me, Cl, F, OMe, Bu
readily available substrates
cheap silver promoter without co-catalyst
mild conditions and simple operations
16 examples
39–65% yield
R
a Hunan Province College Key Laboratory of QSAR/QSPR,
School of Chemistry and Chemical Engineering, Hunan
University of Science and Technology, Xiangtan, Hunan,
411201, P. R. of China
zhao_yunhui@163.com
b Key Laboratory of Synthetic Chemistry of Natural
Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai, 200032, P. R.
of China
c Key Laboratory of Theoretical Chemistry and Molecular
Simulation, Ministry of Education, Xiangtan, Hunan, 411201, P. R. of China
Received: 03.06.2016
Accepted after revision: 12.07.2016
Published online: 03.08.2016
catalysts are usually required to achieve C–H functionaliza-
tion (Scheme 1).2f,8 On the other hand, Ag salts have also
proved to be efficient catalysts for the formation of isoquin-
olines.9 As part of our long-term interest in the develop-
ment of methods for heterocycle synthesis,10 we report
here an efficient AgNO3-mediated isoquinoline synthesis
from aromatic hydrazones through cyclization and N–N
bond cleavage. This approach has several advantages, in-
cluding readily available substrates that can be prepared by
simple condensation of ortho-alkynyl benzaldehydes with
inexpensive hydrazine, a cheap silver promoter with no re-
quirement for an external additive, mild conditions, and
simple operations.
DOI: 10.1055/s-0035-1562609; Art ID: st-2016-w0377-l
Abstract An unprecedented silver nitrate mediated novel transforma-
tion of aromatic hydrazones into various isoquinolines has been devel-
oped. This method involves a silver nitrate promoted cyclization of aro-
matic hydrazones followed by N–N bond cleavage, and has wide
substrate scope under mild conditions.
Key words isoquinolines, bond cleavage, hydrazones, silver nitrate,
alkynals, domino reactions
The isoquinoline skeleton, as a privileged substructure,
is a key motif found in numerous natural products and
pharmaceuticals with many biological activities.1 Efficient
constructions of functionalized isoquinoline motifs play
critical roles in many syntheses toward natural products
and pharmaceuticals.2 Consequently, numerous efforts
have been made to develop new synthetic approaches to
isoquinolines.3 Of these, transition-metal-catalyzed inter-
or intramolecular cyclization/(hetero)annulation reactions
are among the most popular strategies.4 For example, iso-
quinoline derivatives can be obtained by silver-catalyzed
cyclization of ortho-alkynylaryl aldimines.5 Recently, transi-
tion-metal-catalyzed direct C–H bond functionalization of
arenes bearing nitrogen-containing directing groups, fol-
lowed by cyclization with the resulting internal alkynes,
has been developed as a highly efficient method for con-
structing diverse isoquinolines with a wide range of func-
tional groups.6 The hydrazone group is widely used as a di-
recting group, and cyclization to isoquinolines can be fol-
lowed by hydrazone N–N bond cleavage, as demonstrated
by elegant works from Cheng and Knochel and their respec-
tive co-workers.7 In these reactions, noble-metal rhodium
Previous work
R2
H
N
[RhCp*Cl2]2
co-catalyst
R1
N
N
+
R2
R3
R3
This work
NH2
R1
N
AgNO3
N
R1
readily available substrates
cheap silver promoter without co-catalyst
mild conditions and simple operations
Scheme 1 Synthesis of isoquinolines by cleavage of N–N bonds
Initially, we used [2-(phenylethynyl)benzylidene]hydra-
zine as a model substrate to screen the reaction parameters
(Table 1). On the basis of our previous study on isoquinoline
synthesis, we first tested CuI in the reaction (Table 1, entry
1), and we obtained the desired isoquinoline product 2a in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
Y.-H. Zhao et al.
Letter
Synlett
moderate yield by heating with a catalytic amount of CuI in
DCE at 80 °C for 12 hours. Although the reaction with PdCl2
gave a similar result (entry 2), further studies revealed that
AgNO3 is a superior catalyst, affording product 2a in 36%
isolated yield (entry 3). With AgNO3 as the catalyst, we next
examined the effects of a wide range of solvents (entries 4–
12), and the reaction in DMSO as the solvent gave the best
yield (entry 12). To further improve the yield, we studied
the effect of catalyst loading on the reaction. The reaction
efficiency was improved by increasing the catalyst loading
to 30 mol% (entry 13). The yield increased to 53% on further
increasing the AgNO3 loading to 50 mol% (entry 14). The
yield of the isoquinoline product increased markedly to 57%
with one equivalent of AgNO3 (entry 15), but no further im-
provement was observed when more catalyst was used (en-
try 16).
Having identified the optimal reaction conditions
[AgNO3 (100 mol%), DMSO, 100 °C], we next examined the
scope of the reaction (Table 2). Generally, the domino reac-
tions provided substituted isoquinolines in moderate to
good yields. Various substitutions on the aryl rings, includ-
ing chloro, methyl, fluoro, and methoxy groups, were well
tolerated. Better results were usually observed with sub-
strates bearing electron-donating groups at the para-posi-
tion of the phenyl ring (Table 2, entries 11 and 12), whereas
those with electron-withdrawing groups at the same posi-
tion gave slightly lower yields (entries 13 and 14). A sub-
strate bearing chloro substituents on both aryl rings
showed poor reactivity, and the corresponding product 2g
was isolated in only 39% yield (entry 7). Furthermore, when
the reaction was tested with a substrate bearing an alkyl-
terminated alkyne, none of the desired product was ob-
tained under the standard conditions (entry 16).
On the basis of these experiment results and reported
precedents for silver-catalyzed cyclization of ortho-alkynyl-
aryl aldimines,11 we propose a possible mechanism for the
present cyclization reaction, shown in Scheme 2. First, acti-
vation of the alkyne triple bond by silver(I) facilitates a 6-
endo-dig cyclization of the hydrazine and alkyne groups in
1a to afford intermediate I. Protonation of intermediate I
then gives intermediate II, which undergoes N–N bond
cleavage to afford product 2a. The strong tendency toward
aromatization is possibly the driving force for the critical
N–N bond cleavage. The byproduct NH2OH might form a
stable silver–amine complex, thereby hampering catalyst
recycling; a stoichiometric amount of AgNO3 is therefore
required to promote the reaction.
Table 1 Optimization of the Reaction Conditionsa
NH2
N
O
N
NH2NH2
Lewis acid
solvent
EtOH
1a
3a
2a
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1
2
CuI (10%)
DCE
80
80
12
12
0.5
12
12
12
10
10
0.5
12
12
12
12
10
0.5
0.2
21
24
36
36
35
25
33
34
41
35
32
44
47
53
57
56
PdCl2 (10%)
DCE
3
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (10%)
AgNO3 (30%)
AgNO3 (50%)
AgNO3 (100%)
AgNO3 (400%)
DCE
80
4
CHCl3
CCl4
80
5
80
6
toluene
THF
80
7
80
8
MeCN
MeOH
DMF
80
9
80
10
11
12
13
14
15
16
80
H2O
80
DMSO
DMSO
DMSO
DMSO
DMSO
100
100
100
100
100
a Reaction conditions: 1a (0.3 mmol), solvent (3.0 mL).
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
Y.-H. Zhao et al.
Letter
Synlett
NH2
OH
N
NH2
NH2
N
N
N
6-endo-dig
+ H2O
– Ag+, – OH–
protonation
– NH2OH
Ag
3a
Ag
H
I
II
2a
Scheme 2 Proposed mechanism for the AgNO3-promoted cyclization/N–N bond-cleavage reaction
Table 2 Substrate Scopea
Supporting Information
Supporting information for this article is available online at
R1
R1
R2
http://dx.doi.org/10.1055/s-0035-1562609.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
O
N
1. NH2NH2, EtOH
R2
R3
2. AgNO3, DMSO, 100 °C
R3
References and Notes
1
2
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Entry
Product
R1
R2
R3
Ph
Yieldb (%)
1
2
2a
2b
2c
2d
2e
2f
H
H
57
56
48
51
60
55
39
61
60
62
56
52
56
50
65
–
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Me
Cl
H
H
H
H
H
H
H
H
H
H
H
F
Ph
3
Ph
4
Me
Me
Cl
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-BuC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
Ph
5
6
7
2g
2h
2i
Cl
8
H
9
H
10
11
12
13
14
15
16
2j
H
2k
2l
H
H
2m
2n
2o
2p
H
MeO
H
H
F
Ph
4-MeC6H4
Bu
H
H
a Reaction conditions: o-alkynyl aldehyde 1 (0.3 mmol), solvent (3.0 mL).
b Isolated yield.
In summary, we have developed a convenient domino
reaction for synthesizing various substituted isoquinolines
in moderate to good yields.12 This method involves a silver
nitrate promoted cyclization/N–N bond cleavage in the ab-
sence of an external additive.
(6) (a) He, R.; Huang, Z.-T.; Zheng, Q.-Y.; Wang, C. Angew. Chem. Int.
Ed. 2014, 53, 4950. (b) Zhou, B.; Chen, H.; Wang, C. J. Am. Chem.
Soc. 2013, 135, 1264. (c) Dell’Acqua, M.; Abbiati, G.; Rossi, E.
Synlett 2010, 2672.
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7785. (b) Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel, P. Eur. J.
Org. Chem. 2007, 4166.
Acknowledgment
(8) (a) Han, W.; Zhang, G.; Li, G.; Huang, H. Org. Lett. 2014, 16, 3532.
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2014, 79, 1025. (c) Chuang, S.-C.; Gandeepan, P.; Cheng, C.-H.
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Muralikrishna, A.; Reddy, K. V. J. Heterocycl. Chem. 2014, 51,
1045.
We gratefully acknowledge generous financial support from the Na-
tional Natural Science Foundation of China (Nos. 21372070 and
21471052), the Hunan Provincial Education Department Scientific
Research Fund (No. 14k035).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
Y.-H. Zhao et al.
Letter
Synlett
(9) (a) Verma, A. K.; Kotla, S. K. R.; Choudhary, D.; Patel, M.; Tiwari,
R. K. J. Org. Chem. 2013, 78, 4386. (b) Verma, A. K.; Choudhary,
D.; Saunthwal, R. K.; Rustagi, V.; Patel, M.; Tiwari, R. K. J. Org.
Chem. 2013, 78, 6657.
(10) (a) Zhao, Y.-H.; Li, Y.; Guo, T.; Tang, Z.; Deng, K.; Zhao, G. Synth.
Commun. 2016, 46, 355. (b) Zhao, Y.-H.; Li, Y.; Guo, T.; Tang, Z.;
Xie, W.; Zhao, G. Tetrahedron Lett. 2016, 57, 2257. (c) Li, Y.;
Zhao, Y.; Luo, M.; Tang, Z.; Cao, C.; Deng, K. Chin. J. Org. Chem.
2016, DOI: 10.6023/cjoc201604031.
further purification. The crude aromatic hydrazones 3a was dis-
solved in DMSO (3 mL) and AgNO3 (51.0 mg, 0.3 mmol) was
added. The mixture was stirred at 100 °C until all starting mate-
rial was consumed. The solvent was evaporated and the residue
was purified by column chromatography, eluting with
hexanes/EtOAc (5:1) to give a white solid; yield: 35 mg (57%);
mp 97–99 °C; 1H NMR (500 MHz, CDCl3): δ = 9.37 (s, 1 H), 8.16
(d, J = 7.5 Hz, 2 H), 8.10 (s, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.91–
7.89 (d, J = 8.0 Hz, 1 H), 7.75–7.70 (m, 1 H), 7.63–7.60 (m, 1 H),
7.56–7.53 (m, 2 H), 7.47–7.44 (m, 1 H); 13C NMR (125 MHz,
CDCl3): δ = 152.5 , 151.3, 139.6, 136.7, 130.6, 128.8, 128.6,
127.8, 127.6, 127.1, 127.0, 126.9, 116.6. The NMR data agreed
with those previously reported.
(11) Ghavtadze, N.; Fröhlich, R.; Würthwein, E.-U. Eur. J. Org. Chem.
2010, 1787.
(12) 3-Phenylisoquinolines (2a);13 Typical Procedure
To a solution of 2-(phenylethynyl)benzaldehyde (1a; 62.0 mg,
0.3 mmol) in EtOH (5 mL) was added N2H4·HCl (30.6 mg, 0.45
mmol), and the mixture was stirred at r.t. for 3 h. The solid was
then collected by filtration and used in the next step without
(13) Niu, Y.-N.; Yan, Z.-Y.; Gao, G.-L.; Wang, H.-L.; Shu, X.-Z.; Ji, K.-G.;
Liang, Y.-M. J. Org. Chem. 2009, 74, 2893.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D