Efficient Synthesis of Isoquinolines by AgNO3-Catalyzed Sequential Imination-Annulation of 2-Alkynyl Aldehydes with Ammonium Bicarbonate

Article abstract of DOI:10.1002/cjoc.201600277

An operationally simple approach for the tandem synthesis of isoquinolines by the reaction of o-alkynylaldehydes with ammonium bicarbonate via Ag-catalyzed 6-endo-dig ring closure is described. The reaction conditions and the scope of the reaction are examined, and a variety of substituted isoquinolines are prepared in moderate to excellent yields.

Full text of DOI:10.1002/cjoc.201600277

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DOI: 10.1002/cjoc.201600277
Efficient Synthesis of Isoquinolines by AgNO3-Catalyzed
Sequential Imination−Annulation of 2-Alkynyl Aldehydes
with Ammonium Bicarbonate
Yunhui Zhao,*,a,b Mingjian Luo,a Yubo Li,a Xiong Liu,a Zilong Tang,c
Keqin Deng,c and Gang Zhaob
a Hunan Province College Key Laboratory of QSAR/QSPR, School of Chemistry and Chemical Engineering,
Hunan University of Science and Technology, Xiangtan, Hunan 411201, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
c Key Laboratory of Theoretical Chemistry and Molecular Simulation, Ministry of Education, Xiangtan, Hunan
411201, China
An operationally simple approach for the tandem synthesis of isoquinolines by the reaction of o-alkynylalde-
hydes with ammonium bicarbonate via Ag-catalyzed 6-endo-dig ring closure is described. The reaction conditions
and the scope of the reaction are examined, and a variety of substituted isoquinolines are prepared in moderate to
excellent yields.
Keywords isoquinolines, annulation, imination, silver nitrate, o-alkynyl aldehydes
Introduction
stituted isoquinoline.[13] Shin demonstrated that O-alkyl
benzaldoxime derivatives undergo a cyclization-induced
N－O bond cleavage to provide isoquinolines co-cata-
lyzed by AgOTf and TfOH.[14] These two reactions
would undergo a N－N or N－O bond cleavage process
and the residue is waste (Scheme 1). Then Abbiati re-
ported a three-component cascade reaction for the
Isoquinoline derivatives are found in numerous nat-
ural products and pharmaceuticals and display a wide
range of biological activities.[1] Therefor, the isoquino-
line subunits have been employed as the valuable
building block for the preparation of biologically active
compounds including alkaloids, natural products and
pharmaceuticals.[2] Numerous synthetic methods have
been developed to construct the isoquinoline core skel-
Scheme 1 Ag-catalyzed isoquinolines synthesis
eton due to its importance.[3] The Bischler-Napieralski,[4]
Pomeranz-Fritsch,
Previous work
[5]
and Pictet-Spengler[6] reactions
OR3
N
AgOTf
DCE
N
R1
were applied to the preparation of isoquinoline in the
initial years. In order to avoid the harsh conditions or
tedious reaction procedures required in the above reac-
tions, Pfeffer, [7] Heck, [8] and Widdowson[9] reported the
transition metal methodology to synthesize substituted
isoquinolines. And the transition metal catalyzed inter-
or intramolecular cyclization or heteroannulation strat-
egy for preparation of isoquinoline is the most useful
method owing to its efficience and mild conditions.[10]
Among the transition metals, such as Pd, Ag, Cu, Ni, Rh
and Zr, used in synthesizing isoquinolines,[11] the silver
catalyzed protocols have received the most attention due
to the significant role silver plays in annulation reac-
tions of alkynes.[12] Liang utilized Ag-catalyzed cycliza-
tion of 2-alkynyl benzyl azides for the synthesis of sub-
R1
R2
R2
R3
R3
N3
AgSbF6, TFA
DCE
N
R1
R1
R2
R2
Present work
AgNO3
MeCN
O
N
R1
R1
NH3
+
R2
R2
atom economy
cheap catalyst
moderate to excellent yields
*
E-mail: zhao_yunhui@163.com; Tel.: 0086-0731-58290045; Fax: 0086-0731-58290045
Received May 7, 2016; accepted June 20, 2016; published online July 12, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600277 or from the author.
Chin. J. Chem. 2016, 34, 857—860 © 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zhao et al.
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Results and Discussion
synthesis of isoquinolines using aqueous ammonia as
the reagent for the imination step providing product
with low to moderate yields.[15] Consistent with our
former reports,[16] we report here a highly efficient
AgNO3-catalyzed isoquinolines synthesis from o-alky-
nyl aldehydes and ammonium bicarbonate. This ap-
proach has several advantages: a) the ammonia source is
provided by ammonium bicarbonate without other waste
formed; b) the reaction can work well under air condi-
tion without other external co-catalysts or additives; c)
and the catalyst is cheap and easily available.
Initially, we tested the reaction of substrate 2-(phe-
nylethynyl)benzaldehyde 1a with 20 mol% of AgNO3 in
aqueous ammonia (mass percentage 25%－28%) at
80 ℃, and the desired product 2a was obtained in 25%
yield after 12 h (Table 1, Entry 1). By increasing the
temperature to 100 ℃, a higher yield of 40% was ob-
served (Entry 2). No beneficial effect was observed
when using THF as a co-solvent in aqueous ammonia
(Entry 3). Then, NH4Cl, NH4HCO3 and NH4OAc were
investigated instead of aqueous ammonia at 80 ℃ to
provide product 2a in 50%, 65% and 48% yields, re-
spectively (Entries 4－6). Therefore, NH4HCO3 was
chosen as the ammonia source for the following exper-
iments. By further increasing the reaction temperature to
100 ℃, the yield of product was dramatically raised to
79% (Entry 7). Other solvents such as EtOH,
1,2-dichloroethane (DCE) and dimethylsulfoxide
(DMSO) were screened. They afforded the desired
product 2a in lower yields (Entries 8－10). CuI was also
investigated as a catalyst but showed an inferior result
to AgNO3 (Entry 11). Interestingly, the reaction could
provide product 2a with 39% yield without addition of
catalyst (Entry 12). In order to further improve the effi-
ciency of this reaction, changing the conditions to a high-
er reaction temperature (120 ℃) gave the best result of
86% yield (Entry 13). When the catalyst loading was
reduced to 10 mol% of AgNO3, the chemical yield
Experimental
General procedure for Ag-catalyzed sequential imi-
nation-annulation of 2-alkynyl aldehydes
To a solution of 2-(phenylethynyl)benzaldehyde 1a
(62.0 mg, 0.3 mmol) in MeCN (3 mL), NH4HCO3 (79
mg, 1 mmol) and AgNO3 (10 mg, 0.06 mmol) were
added. The mixture was stirred at 120 ℃ until all
starting materials were consumed. The reaction mixture
was diluted with saturated brine and extracted with ethyl
acetate. The organic layers were combined and washed
with water and then dried over anhydrous Na2SO4. The
solvent was removed under vacuum, and the residue
was purified by flash column chromatography on silica
gel to afford the desired product 3-phenylisoquinoline
2a as white solid.[13]
Table 1 Optimization of reaction conditionsa
Entry
1
Catalyst/%
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
CuI (20)
Solvent
—
Ammonium salt
NH3•H2O
NH3•H2O
NH3•H2O
NH4Cl
T/℃
80
t/h
12
12
12
12
12
12
12
12
12
12
12
12
12
12
Yieldb/%
25
2
—
100
100
80
40
3
THF
42
4
MeCN
MeCN
MeCN
MeCN
EtOH
DCE
50
5
NH4HCO3
NH4OAc
80
65
6
80
48
7
NH4HCO3
NH4HCO3
NH4HCO3
NH4HCO3
NH4HCO3
NH4HCO3
NH4HCO3
NH4HCO3
100
100
100
100
100
100
120
120
79
8
16
9
50
10
11
12c
13
14
DMSO
MeCN
MeCN
MeCN
MeCN
42
70
—
39
AgNO3 (20)
AgNO3 (10)
86
75
a The reactions were performed using 0.3 mmol of 2-(phenylethynyl)benzaldehyde 1a and 1 mmol of ammonium salt in 3.0 mL of solvent.
b Isolated yield. c No catalyst was added.
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Chin. J. Chem. 2016, 34, 857—860

Efficient Synthesis of Isoquinolines by AgNO3-Catalyzed Sequential Imination-Annulation
decreased to 75% (Entry 14).
Continued
Yieldb/%
Under the optimized reaction condition [AgNO3 (20
mol%), MeCN, 120 ℃], the scope of the reactions of
o-alkynyl aldehydes 1 was explored. The results are
Entry R1, R2
Product
1
2
summarized in Table 2. Generally, the imination-cycliza-
tion reactions provided substituted isoquinlines in moder-
ate to excellent yields. The results listed in Table 2 showed
that various R1 and R2, including hydrogen, chloro, methyl,
fluoro, methoxyl were well tolerated. Better yields were
observed when electron-donating groups were on the phe-
nyl ring in para-positions in most cases (Table 2, Entries 6,
8, 10). Whereas the phenyl group bearing electron-with-
drawing groups gave inferior results (Table 2, Entries 5, 11,
12). The substituents on the aromatic ring were also in-
vestigated. Introducing electron-withdrawing groups
onto the aromatic ring slightly enhanced the yields (Ta-
ble 2, Entries 3, 6, 7, 13, 15). However, when the elec-
tron-donating groups were used, the yields of target
products were slightly lower (Table 2, Entries 2, 5, 14).
To our disappointment, cyclization could not proceed
when the terminus of the carbon-carbon triple bond was
substituted by an alkyl group. Thus, there was no product
obtained when o-hexynyl aromatic aldehyde reacted un-
der the optimized reaction condition.
7
8
9
7-Cl, 4-Cl
69
87
68
80
75
67
1g
2g
H,
1h
1i
2h
2i
4-Me
N
N
H, 4-n-Bu
Bu-n
10 H, 4-MeO
11 H, 4-F
1j
2j
OCH3
1k
1l
2k
2l
12 H, 4-Cl
13 6-F, H
Table 2 The scope of reaction substratesa
82
66
91
1m
1n
1o
2m
2n
2o
O
R1
N
AgNO3
R1
MeCN
+
NH4HCO3
R2
R2
2
1
14 7-MeO, H
Entry R1, R2
Product
Yieldb/%
86
1
2
1
2
3
4
5
6
H, H
1a
1b
1c
1d
1e
1f
2a
15 6-F, 4-Me
a The reactions were performed using 0.3 mmol of 2-(phenylethy-
nyl)benzaldehyde 1 and 1 mmol of NH4HCO3 in 3.0 mL of
MeCN. b Isolated yield.
7-Me, H
7-Cl, H
67
71
76
66
91
2b
2c
2d
2e
2f
Conclusions
In summary, we have developed a convenient domino
reaction to synthesize various substituted isoquinlines with
moderate to excellent yields. This methodology featured
using NH4HCO3 as the ammonia source catalyzed by silver
nitrate in the absence of an external metal.
7-Me, 4-Me
7-Me. 4-Cl
7-Cl, 4-Me
Acknowledgement
The generous financial support from the National Nat-
ural Science Foundation of China (Nos. 21372070 and
21471052) and the Hunan Provincial Education Depart-
ment Scientific Research Fund (No. 14k035) are gratefully
acknowledged.
Cl
N
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Zhao et al.
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