A silver(I) triflate-catalyzed reaction of 1-((cyclopropylidenemethyl)-2- alkynyl)arene with 2-alkynylbenzaldoxime

Article abstract of DOI:10.1039/c4cc00691g

A silver(I)-catalyzed reaction of 1-((cyclopropylidenemethyl)-2-alkynyl) arene with 2-alkynylbenzaldoxime leads to 1-((1,3-dihydroisobenzofuran-1-yl) methyl)isoquinolines in good to excellent yields. A radical process is believed to be involved in the transformation. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00691g

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A silver(I) triflate-catalyzed reaction of
1-((cyclopropylidenemethyl)-2-alkynyl)arene
with 2-alkynylbenzaldoxime†
Jie Sheng,a Congbin Fan,a Yechun Ding,b Xiaona Fan*b and Jie Wu*ac
Cite this: Chem. Commun., 2014,
50, 4188
Received 26th January 2014,
Accepted 28th February 2014
DOI: 10.1039/c4cc00691g
www.rsc.org/chemcomm
A silver(I)-catalyzed reaction of 1-((cyclopropylidenemethyl)-2-alkynyl)-
arene with 2-alkynylbenzaldoxime leads to 1-((1,3-dihydroisobenzofuran-
1-yl)methyl)isoquinolines in good to excellent yields. A radical process is
believed to be involved in the transformation.
Fig. 1 2-Alkynylaryl methylenecyclopropane.
As we know, chemists are focusing on the pursuit of efficient and
facile routes for the rapid generation of small molecules with
In the meantime, 2-alkynylbenzaldoxime has continuously
molecular complexity and diversity, especially in the field of drawn our attention since it can easily undergo 6-endo cycliza-
chemical biology and in the drug discovery process.1 Among the tion in the presence of an electrophile or a catalytic amount of a
strategies utilized, the tandem reaction has demonstrated its Lewis acid.7 The following [3+2] cycloaddition or nucleophilic
efficiency.2 In the past few years, the attractiveness of tandem addition could afford various N-heterocycles with molecular
reactions has also prompted us to explore new pathways for the complexity starting from 2-alkynylbenzaldoximes.8 Combined with
construction of natural product-like compounds.3 For example, the reactivity of 2-alkynylaryl methylenecyclopropane, we conceived
fused indolines could be synthesized via a tandem reaction of that 2-alkynylbenzaldoxime could be involved in the reaction of
2-ethynylaryl methylenecyclopropane with sulfonyl azide catalyzed 2-alkynylaryl methylenecyclopropane under suitable conditions for
by copper(I) iodide.3a From this transformation, we recognized that the assembly of complex small molecules. In the presence of a
2-alkynylaryl methylenecyclopropane4 was a useful building block catalytic amount of silver triflate, 2-alkynylbenzaldoxime 1 would
for the formation of polycyclic compounds. The two active sites undergo 6-endo cyclization to produce isoquinoline N-oxide. We
(Fig. 1, alkynyl moiety and methylenecyclopropane) would be anticipated that the following [3+2] cycloaddition of 2-alkynylaryl
helpful in the rational design of complex small molecules. methylenecyclopropane would occur to generate an isoquinoline-
So far, the transformation of methylenecyclopropanes has been based compound.
well documented due to their diverse reactivity driven by the relief
The initial studies are summarized in Table 1. A silver(I)-
of ring strain.5 A variety of carbocycles and heterocycles could be catalyzed reaction of 2-alkynylbenzaldoxime 1a with 1-((cyclo-
formed via the ring-opening reactions of methylenecyclopropanes.6 propylidenemethyl)-2-alkynyl)arene 2a was selected as the model.
Encouraged by these results, we envisioned that 2-alkynylaryl In the beginning, the reaction was performed at 75 1C in DMF. To
methylenecyclopropane (Fig. 1) could be used in our approach our delight, a product was obtained and isolated in 31% yield
for the construction of natural product-like compounds.
(Table 1, entry 1). The structural illustration using X-ray diffraction
analysis (Fig. 2) revealed that the compound was 1-((1,3-dihydroiso-
benzofuran-1-yl)methyl)isoquinoline 3a. Upon this transformation,
the core structures of isoquinoline and 1,3-dihydroisobenzofuran
were incorporated into one molecule with the formation of four new
bonds. Therefore, we proposed a possible mechanism, which is
shown in Scheme 1. As mentioned above, 2-alkynylbenzaldoxime 1
would undergo 6-endo cyclization to produce isoquinoline N-oxide A
in the presence of a catalytic amount of silver triflate. Then
2-alkynylaryl methylenecyclopropane 2 would react with isoquino-
line N-oxide A through [3+2] cycloaddition to afford compound B.
The cleavage of the N–O bond would generate the radical species C,
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6564 1740;
Tel: +86 21 6510 2412
b School of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi 341000, China
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, 1H and 13C NMR spectra of compounds 3. CCDC 973694.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4cc00691g
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Table 1 Initial studies for the reaction of 1-((cyclopropylidenemethyl)-2-
alkynyl)arene 2a with 2-alkynylbenzaldoxime 1a
Entry
T (1C)
Solvent
Yielda (%)
1
75
75
75
DMF
DMF
DMA
31
Trace
44
2b
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17d
18e
75
75
75
75
75
75
25
50
DMSO
THF
53
Trace
24
Trace
NR
NR
NR
Trace
54
67
60
58
76
Scheme 1 A possible mechanism for the silver-catalyzed reaction of
1-((cyclopropylidenemethyl)-2-alkynyl)arene with 2-alkynylbenzaldoxime.
MeCN
Toluene
CF3CH2OH
(CF3)2CHOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
product (Table 1, entry 2). When the reaction occurred in other
solvents, it was found that the transformation worked efficiently
in DMSO leading to the corresponding product 3a in 53% yield
(Table 1, entry 4). The result could be improved when the reaction
temperature was changed (Table 1, entries 10–15). Compound 3a
could be obtained in 67% yield when the reaction was performed
at 100 1C (Table 1, entry 13). The yield could be increased to 76%
90
100
110
120
100
100
100
69
NR
a
b
Isolated yield based on 2-alkynylbenzaldoxime 1a. In the presence of
c
2,2,6,6-tetramethylpiperidin-1-olate (TEMPO). In the presence of
Table 2 Scope investigation for the reaction of 1-((cyclopropylidene-
methyl)-2-alkynyl)arene 2a with various 2-alkynylbenzaldoximes 1a
1.5 equivalent of 2-alkynylbenzaldoxime 1a. d In the presence of 1.5 equiva-
e
lent of 1-((cyclopropylidenemethyl)-2-alkynyl)arene 2a. Without the
addition of AgOTf.
Fig. 2 X-ray ORTEP illustration of compound 3a (30% probability ellipsoids).
which would then proceed through intramolecular addition of
triple bond to furnish the intermediate D. The subsequent
transformation would produce the corresponding 1-((1,3-dihydro-
isobenzofuran-1-yl)methyl)isoquinolines 3.
With this interesting result in hand, we further investigated
its optimized conditions. To verify the radical process, 2,2,6,6-
tetramethylpiperidin-1-olate (TEMPO) was added to the reac-
tion. As expected, the reaction failed to give rise to the desired
a
Isolated yield based on 1-((cyclopropylidenemethyl)-2-alkynyl)arene 2a.
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Table 3 Scope investigation for the reaction of 2-alkynylbenzaldoxime 1a
with various 1-((cyclopropylidenemethyl)-2-alkynyl)arenes 2a
the standard conditions (Scheme 2). As expected, the reaction
worked well to generate the corresponding product 3u in
80% yield.
In summary, we have described a facile route to prepare
1-((1,3-dihydroisobenzofuran-1-yl)methyl)isoquinolines via
a
silver(I)-catalyzed reaction of 1-((cyclopropylidenemethyl)-2-
alkynyl)arene with 2-alkynylbenzaldoxime. The reaction pro-
ceeds through a radical process to provide the corresponding
products in good to excellent yields. Currently, the library
construction of 1-((1,3-dihydroisobenzofuran-1-yl)methyl)iso-
quinolines is ongoing in our laboratory.
Financial support from the National Natural Science Founda-
tion of China (No. 21032007, 21372046) is gratefully acknowledged.
Notes and references
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alkynyl)arene 2a.
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