Synthesis of 4-(1: H -isochromen-1-yl)isoquinolines through the silver-catalysed homodimerization of ortho -alkynylarylaldehydes and subsequent condensation of the 1,5-dicarbonyl motif with NH3

Article abstract of DOI:10.1039/c8ra09269a

4-(1H-Isochromen-1-yl)isoquinoline derivatives were synthesized in high yields via the AgBF₄-catalyzed self-reaction of ortho-alkynylarylaldehydes to give isochromene intermediates, followed by the dehydration of the 1,5-dicarbonyl motif with NH₃. Compared with electron-rich aromatic substituents, this strategy can provide the desired isochromene products with an electron-deficient isoquinoline unit. The reactions feature simple experimental operations, mild reaction conditions and high product yields.

Full text of DOI:10.1039/c8ra09269a

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Synthesis of 4-(1H-isochromen-1-yl)isoquinolines
through the silver-catalysed homodimerization of
ortho-alkynylarylaldehydes and subsequent
condensation of the 1,5-dicarbonyl motif with
NH3†
Cite this: RSC Adv., 2019, 9, 2703
a
a
a
a
a
ab
*
*
Minghui Guo, Xin Meng, Yang Zhao, Yuexia Dong, Xuejun Sun, Laijin Tian
ab
*
and Ziping Cao
4-(1H-Isochromen-1-yl)isoquinoline derivatives were synthesized in high yields via the AgBF4-catalyzed
self-reaction of ortho-alkynylarylaldehydes to give isochromene intermediates, followed by the
dehydration of the 1,5-dicarbonyl motif with NH3. Compared with electron-rich aromatic substituents,
this strategy can provide the desired isochromene products with an electron-deficient isoquinoline unit.
The reactions feature simple experimental operations, mild reaction conditions and high product yields.
Received 9th November 2018
Accepted 7th January 2019
DOI: 10.1039/c8ra09269a
rsc.li/rsc-advances
isochromene derivatives starting from ortho-alkynylar-
ylaldehydes, with a series of nucleophilic reagents.8 Recently,
Introduction
electron-rich (hetero)arenes, such as alkoxylbenzenes and
indoles, have been utilized as nucleophiles leading to the
synthesis of functionalized 1H-isochromene compounds with
high efficiency (Scheme 1(a)).17 However, electron-decient
heteroarene-substituted 1H-isochromenes could not be
synthesized via direct methods due to weak nucleophilic abili-
ties. In this context, and following our ongoing interest in the
reactions of enynal substrates,17a,18,21a,c we envisaged that these
heteroarene-substituted 1H-isochromenes could be obtained
via indirect ways involving the late-stage synthesis of the cyclic
skeletons. Herein, we provide an efficient strategy to achieve the
synthesis of isoquinoline-substituted 1H-isochromenes
through a two-step route, which contains the AgBF4-catalyzed
self-reaction of ortho-alkynylarylaldehydes to give intermediate
The 1H-isochromene skeleton is the core structure of many
biologically active molecules possessing important pharma-
ceutical activities, such as the those involved in the inamma-
tory activation of microglia,1 antimicrobial activity against the
Gram-positive bacteria Staphylococcus aureus and Streptococcus
pneumoniae,2 selective receptor antagonists of neurokinin-1
(NK1),3 and antagonists of Mycobacterium bovis BCG.4 Iso-
quinoline derivatives are also a class of important heterocycles
having acetylcholinesterase inhibitory activities,5 murine tumor
cell cytotoxicity,6 antiplasmodial activities,7 and so on. Thus,
compounds with a combination of these two structural motifs
could possess important potential bioactivity properties.
Therefore, the synthesis of these kinds of product is of great
signicance.
Ortho-alkynylarylaldehydes are a class of important organic
intermediates that can be converted into products possessing
polycyclic skeletons.8,9 In particular, 1H-isochromenes can be
readily constructed through metal- or non-metal-catalyzed
reactions.10–17 Pioneering work by Yamamoto and co-workers
revealed a Pd(OAc)2-catalyzed reaction of enynals with alco-
hols to afford alkoxyl-substituted 1H-isochromenes.10i From
that time on, many methods were developed to access 1H-
aSchool of Chemistry and Chemical Engineering, Qufu Normal University, Qufu
273165, P. R. China. E-mail: caozp_qfnu@163.com; mengxin1108@163.com;
laijintian@163.com
bShandong Key Laboratory of Life-Organic Analysis, Key Laboratory of Pharmaceutical
Intermediates and Analysis of Natural Medicine, Qufu 273165, P. R. China
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. See DOI: 10.1039/c8ra09269a
Scheme 1 Access to (hetero)aromatic substituted 1H-isochromene
derivatives.
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isochromenes with a 1,5-dicarbonyl motif followed by dehy- AgNO3 couldn't afford product 2 at all, whereas the use of an
dration with NH3 to form the isoquinoline skeleton (Scheme AgOTf catalyst could lead to the formation of 2 in 66% yield
1(b)). It should be mentioned that the homodimerization of (Table 1, entries 2–4). Copper(I) and zinc(II) catalysts showed no
ortho-alkynylarylaldehydes was discovered by Porco Jr et al. in catalytic reactivity under the presented conditions (Table 1,
2007, while only one example was provided for forming the entries 5–7). Notably, Pd(OAc)2 could promote the formation of
isochromene efficiently.13c The present study exhibited better product 2, albeit with a slightly lower yield (Table 1, entry 8).
substrate compatibility and the efficient synthesis of Subsequently, several solvents were investigated, revealing that
isoquinoline-substituted 1H-isochromenes. Furthermore, the tetrahydrofuran (THF) was suitable for the present trans-
reactions feature mild reaction conditions, simple operation formation and the yield of 2 could be improved to 89% (Table 1,
procedures and high efficiency.
entries 9–12). Furthermore, the temperature effects indicated
that the homodimerization product 2 could be readily obtained
in 91–93% yield when the reaction was carried out at room
temperature or under heating (Table 1, entries 14–16), while
lowering the temperature to 0 ꢀC led to a slightly lower yield
(Table 1, entry 13). In order to consider the water effect, control
experiments were carried out. The use of completely dry THF led
to a low yield of 2 under an N2 atmosphere (Table 1, entry 17).
The addition of water (such as 1.0 equiv.) into dry THF did not
obviously inuence the reaction (Table 1, entry 18). In addition,
the reaction couldn't proceed at 100 ꢀC in the absence of AgBF4
(Table 1, entry 19). So, the nal conditions were established as
those shown by entry 14 in Table 1.
To achieve the cyclization of the 1,5-dicarbonyl motif of
compound 2 to an isoquinoline skeleton, different nitrogen
sources and reaction conditions were investigated, and these
are shown in Table 2. It could be found that the use of NH3
solution in MeOH proved to be suitable, affording the desired
product 3a in 62% yield with the decomposed product 4 present
in 20% yield (Table 2, entry 3). Other nitrogen sources such as
NH4OAc and NH3$H2O could lead to the formation of 3a but
with more side-product 4 (Table 2, entries 1 and 2). Tempera-
ture studies showed that the cyclized product 3a could be
Results and discussion
We started from a dimerized product 2, which has a 1H-iso-
chromene ring and a 1,5-dicarbonyl motif. Compound 2 can be
obtained in 80% yield as a mixture of two diastereoisomers (dr
¼ 1/1 (ref. 19)) through the self-reaction of the ortho-alky-
nylbenzaldehyde 1a under conditions involving the presence of
silver salt (AgBF4; 10 mol%) with 1,2-dichloroethane (DCE) as
the solvent (Table 1, entry 1). Notably, the two isomers of 2 can
be isolated carefully via column chromatography. In order to
further improve the yield of 2, a series of metal salts were
screened (Table 1, entries 2–8). The results showed that AgBF4
was the optimal catalyst. Other silver salts such as AgSbF6 and
Table 1 Optimization of the conditions for the homodimerization of
1aa
Table 2 Optimization of the conditions for the condensation of 1,5-
a
dicarbonyl 2 with NH3
Entry
Catalyst
Solv.
Temp. (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
AgBF4
AgSbF6
AgNO3
AgOTf
CuI
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
CH3CN
1,4-Dioxane
THF
THF
THF
THF
15
15
15
15
15
15
15
15
15
15
15
15
0
80
0
0
66
0
0
ZnCl2
ZnBr2
Pd(OAc)2
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
—
0
Yieldb (%)
71
73
89
76
84
85
93
91
91
68
92
0
9
Entry
“N” source (equiv.)
Temp. (ꢀC)
3a
4
10
11
12
13
14
15
16
17c
18c,d
19
1
2
3
4
5
6
7
8
NH4OAc (3)
NH3$H2O (3)
50
50
50
40
25
0
32
47
62
75
87
82
93
75
73
50
20
14
7
7
—
8
25
45
60
25
25
NH3 in CH3OH (3)
NH3 in CH3OH (3)
NH3 in CH3OH (3)
NH3 in CH3OH (3)
NH3 in CH3OH (1.5)
NH3 in CH3OH (1.0)
Dry THF
Dry THF
THF
25
25
100
a
a
All reactions were carried out with 1a (0.4 mmol) and catalyst
All reactions were carried out with 2 (0.2 mmol) and the nitrogen
(0.04 mmol, 0.1 equiv.) in the indicated solvent (1.6 mL) under air for source (0.2–0.6 mmol, 1.0–3.0 equiv.) in methanol (1.6 mL) at the
b
c
b
about 7 and 8 hours. The yield of isolated products. Under an N2 indicated temperature for about 12 hours. The yield of isolated
atmosphere. d 1 equiv. of H2O was added.
products based on 2.
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Table 3 Scope of substratesa,b
Scheme 2 The convenient synthesis of the 4-(1H-isochromen-1-yl)
isoquinoline 3a.
obtained in 87% yield with a lower amount of 4 under room
temperature conditions (Table 2, entry 5). In addition, lowering
the loading of NH3 solution in MeOH could also add to the yield
of 3a to 93%, with trace amounts of side-product 4 (Table 2,
entry 7).
The one-pot synthesis of the isoquinoline 3a with an iso-
chromene unit was also subsequently examined. The AgBF4-
catalyzed self-reaction was accomplished and the NH3 source
was then injected in a straightforward manner, affording the
nal product 3a in only 31% yield. To our delight, aer the
ltration of the metal salt and the evaporation of solvent
following the rst reaction, the residue was dissolved in meth-
anol and the NH3 source was then added to provide the iso-
quinoline 3a with higher efficiency (Scheme 2). The low yield for
the direct one-pot reaction may be owing to the use of an
improper solvent for the second step.
With the optimal process for the synthesis of 3a in hand, the
scope of ortho-alkynylarylaldehyde substrates was next investi-
gated (Table 3). It could be found that a variety of ortho-alky-
nylbenzaldehyde derivatives could be applied to the present
reaction, leading to the synthesis of the 4-(1H-isochromen-1-yl)
isoquinolines 3a–p in 31–91% yields. The substrates 1b–c,
having an electron-rich group at the para-position of the alky-
nylaryl part, were suitable for this transformation, giving the
corresponding products 3b–c with good efficiency. The halo-
substituted (F, Cl and Br) phenylethynylbenzaldehydes 1d–f
could be also converted to the desired isoquinolines 3d–f effi-
ciently. The substrate 3g, with an electron-decient cyano
group, could afford the desired isoquinoline 3g, albeit with
a low yield. The meta-substituted-phenylethynylbenzaldehydes
1h–j were also good substrates, leading to the formation of
the 4-(1H-isochromen-1-yl)isoquinolines 3h–j in 70–86% yields.
In addition, the alkynylarylaldehydes 1k–p, having groups with
different electronic natures in the arylaldehyde part, could
generate efficiently the cyclized products 3k–p under the
current conditions. Alkyl-substituted-alkynylbenzaldehydes
such as 1q were also examined. However, the synthesis of the
desired polycycle 3q was not observed.
a
See the Experimental section. b The yield of isolated products.
A possible mechanism for the synthesis of the isoquinoline
3a is proposed in Scheme 3.13c The coordination of the alkyne
motif of 1a to a silver(I) cation could give complex A, which then
undergoes 6-endo-dig cycloisomerization to form the vinyl metal
benzopyrylium B. The exo[3+2]-cycloaddition of B could afford
the polycyclic intermediate D via C.20,21 The isomerization of the
double bonds of D with the departure of Ag(I)+ (or H+) leads to
the formation of intermediate E, followed by fragmentation to
yield the oxonium species F.22 The addition of water to the
oxonium F and its protodemetalation could form the hemiketal
G, which could be converted to the ketoaldehyde product 2 via
Scheme 3 The proposed mechanism for the formation of 3a.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
We are grateful to the NSFC (21402106), the Shandong Natural
Science Foundation (ZR2018JL013 and ZR2014BQ024), and the
Research Start-up Foundation of Qufu Normal University
(bsqd20130115).
Scheme 4 The proposed mechanism for the formation of the side-
product 4.
Notes and references
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Experimental
Representative procedure for the synthesis of 4-(1H-
isochromen-1-yl)isoquinolines
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To a stirred solution of the ortho-alkynylbenzaldehyde 1a
(82.5 mg, 0.4 mmol, 1.0 equiv.) in THF (1.6 mL), AgBF4 (7.8 mg,
0.04 mmol, 0.1 equiv.) was added at room temperature. The
reaction proceeded for about 8 hours. The mixture was ltered
using a short silica gel column and volatiles were then evapo-
rated off. The resulting crude 1,5-dicarbonyl 2 was dissolved in
methanol (1.6 mL), followed by the injection of a solution of
NH3 in methanol (0.15 mL, 2.0 mol Lꢁ1, 1.5 equiv.). The mixture
was then stirred at room temperature for about 12 hours. Aer
the evaporation of the solvent, the residue was then subjected to
column chromatography to afford the desired isoquinoline 3a.
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isochromen-1-yl)isoquinoline derivatives in high yields. This
method contains two reactions involving the silver-catalyzed
self-reaction of ortho-alkynylarylaldehydes and the subsequent
´
˜
´
´
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