A silver(I)-catalyzed tandem reaction of 2-alkynylbenzaldoxime with alkylidenecyclopropane

Article abstract of DOI:10.1021/ol301393f

A silver(I)-catalyzed tandem reaction of 2-alkynylbenzaldoxime with alkylidenecyclopropane gives rise to benzo-7-azabicyclo[4.2.2]dec-7-en-4-ones in moderate to good yields. The complexity and diversity could be easily incorporated with the formation of three bonds during the process.

Full text of DOI:10.1021/ol301393f

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3430–3433
A Silver(I)-Catalyzed Tandem Reaction of
2-Alkynylbenzaldoxime with
Alkylidenecyclopropane
Qian Xiao,†,‡ Shengqing Ye,† and Jie Wu*,†,§
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China, Department of Chemistry, Nanchang University, 999 Xuefu Road, Nanchang,
Jiangxi 330031, China, and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
jie_wu@fudan.edu.cn
Received May 20, 2012
ABSTRACT
A silver(I)-catalyzed tandem reaction of 2-alkynylbenzaldoxime with alkylidenecyclopropane gives rise to benzo-7-azabicyclo[4.2.2]dec-7-en-4-
ones in moderate to good yields. The complexity and diversity could be easily incorporated with the formation of three bonds during the process.
Continuous efforts to develop efficient approaches have
been underway for the generation of nitrogen-containing
heterocycles because of their remarkable biological and
physical properties.1 Recently, intense interest has been
directed toward the strategy of diversity-oriented
synthesis2 for the concise assembly of structurally complex
compounds. During studies of chemical genetics, we were
interested in tandem reactions3 for the preparation of
natural product-like compounds with diversity and com-
plexity using diversity-oriented synthesis. Recently, we and
others identified that 2-alkynylbenzaldoxime was a useful
building block for accessing N-heterocycles.4,5 In the pres-
ence of a suitable metal salt or electrophile, isoquinoline
N-oxide as the key intermediate could be easily formed
from 2-alkynylbenzaldoxime, which would undergo sub-
sequent nucleophilic addition or a [3 þ 2] cycloaddition
reaction. In the meantime, strained alkylidenecyclopro-
paneshavebeenwidely usedfor the synthesisof avariety of
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† Fudan University.
‡ Nanchang University.
§ Shanghai Institute of Organic Chemistry.
€
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(1) Recent reviews for the synthesis of heterocycles: (a) Armstrong,
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A. R.; Rachwal, S. Chem. Rev. 2010, 110, 1564. (c) Martins, M. A. P.;
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r
10.1021/ol301393f
Published on Web 06/12/2012
2012 American Chemical Society

temperature. However, no reaction took place at all. A
trace amount of product was detected when the reaction
temperature was elevated to 60 °C. Interestingly, a product
was isolated in 15% yield when the reaction occurred in
toluene. However, structure elucidation revealed that the
product was benzo-7-azabicyclo[4.2.2]dec-7-en-4-one 3a
instead of the expected one. The structure of compound
3a was unambiguously demonstrated by X-ray diffraction
analysis (Figure 1, also see the Supporting Information).
This unexpected result prompted us to investigate
suitable conditions (Table 1). Solvent screening led to
Scheme 1. Unexpected Silver(I)-Catalyzed Reaction of 2-Alky-
nylbenzaldoxime 1a with 1-Bromo-4-(cyclopropylidenemethyl)-
benzene 2a
carbocyclesand heterocycleswithincomplex molecules.6ꢀ8
Encouraged by the chemistry of 2-alkynylbenzaldoxime
and the advancement of alkylidenecyclopropanes, we
envisioned that the fused 1,2-dihydroisoquinolines would
be generated via a reaction of 2-alkynylbenzaldoxime
with alkylidenecyclopropane. As outlined in Scheme 1,
we anticipated that treatment of 2-alkynylbenzaldoxime 1
in the presence of a catalytic amount of silver triflate would
lead to isoquinoline-N-oxide A. Then alkylidenecyclopro-
pane would be involved through a [3 þ 2] cycloaddition to
provide access to 1,2-dihydroisoquinoline framework B.
In order to efficiently access the designed 1,2-dihydro-
isoquinoline scaffold, we first evaluated the proposed reac-
tion using select 2-alkynylbenzaldoxime 1a with 1-bromo-
4-(cyclopropylidenemethyl)benzene 2a in the presence
of 10 mol % of silver triflate (Scheme 1, eq 2). Initially,
the reaction was performed in 1,2-dichloroethane at room
Figure 1. X-ray ORTEP illustration of benzo-7-azabicyclo-
[4.2.2]dec-7-en-4-one 3a (30% probability ellipsoids).
Table 1. Initial Studies for the Silver Triflate-Catalyzed
Reaction of 2-Alkynylbenzaldoxime 1a with 1-Bromo-
4-(cyclopropylidenemethyl)benzene 2a
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entry
additive
solvent
toluene
temp (°C)
yielda (%)
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1
25
60
25
60
60
60
60
60
60
60
60
60
60
60
45
75
90
NR
15
2
toluene
DCE
3
NR
trace
18
4
DCE
5
MeCN
DMF
6
52
7
1,4-dioxane
THF
23
8
30
9
Au(PPh3)Cl
Sc(OTf)3
Bi(OTf)3
DMF
25
10
11
12
13
14b
15b
16b
17b
DMF
21
DMF
30
Zn(OTf)2
Cu(OTf)2
DMF
18
DMF
22
DMF
73
DMF
49
DMF
83
DMF
82
a Isolated yield based on 2-alkynylbenzaldoxime 1a. b In the presence
of 2.5 equiv of 1-bromo-4-(cyclopropylidenemethyl)benzene 2a.
Org. Lett., Vol. 14, No. 13, 2012
3431

Scheme 2. Scope Investigation for the Silver Triflate-Catalyzed
Tandem Reaction of 2-Alkynylbenzaldoxime 1 with Alkylide-
necyclopropane 2a
Scheme 3. Possible Mechanism for the Silver Triflate-Catalyzed
Tandem Reaction of 2-Alkynylbenzaldoxime 1 with Alkylide-
necyclopropane 2
aromatic backbone. Methyl, methoxy, fluoro, and chloro
functionalities were all tolerated, and the corresponding
benzo-7-azabicyclo[4.2.2]dec-7-en-4-ones 3 were obtained
in moderate to good yields. For instance, 5-chloro-2-
(2-phenylethynyl)benzaldehyde oxime reacted with 1-bro-
mo-4-(cyclopropylidenemethyl)benzene leading to the pro-
duct 3d in 82% yield. Notably, the thiophenyl-incorporated
oxime was a good partner as well in this tandem reaction,
although the final outcome is not as good as expected
(3i, 32% yield). Furthermore, the nature of the substituents
at the R2 position of 2-alkynylbenzaldoximes 1 could not
affect the conversion. Reactions of 2-alkynylbenzaldoximes
1 with a cyclopropyl or n-butyl group attached to the triple
bond also worked well to afford the desired products.
Additionally, various alkylidenecyclopropanes 2 were ex-
amined in the reaction of 2-alkynylbenzaldoxime 1a, which
provided the expected products in good yields.
a Isolated yield based on 2-alkynylbenzaldoxime 1.
A possible mechanism for the formation of this unex-
pected benzo-7-azabicyclo[4.2.2]dec-7-en-4-ones 3 was
proposed in Scheme 3. Based on the previous reports,4,5
we believed that isoquinoline-N-oxide A would be pro-
duced first via a silver triflate-catalyzed 6-endo cyclization
of 2-alkynylbenzaldoxime 1. Subsequently, [3 þ 2] cy-
cloaddition reaction of isoquinoline N-oxide A with alky-
lidenecyclopropanes 2 would occur, leading to a fused
1,2-dihydroisoquinoline compound B. The NꢀO bond
of intermediate B would undergo a cleavage to produce
radical C,4a,9 which then would go through ring-opening
of cyclopropane and intramolecular radical addition to
provide the benzo-7-azabicyclo[4.2.2]dec-7-en-4-one 3.
In summary, we have described an efficient and novel
silver(I)-catalyzedtandem reactionof2-alkynylbenzaldox-
ime with alkylidenecyclopropane, which gives rise to
benzo-7-azabicyclo[4.2.2]dec-7-en-4-ones in moderate to
good yields. Diversity and complexity could be easily
incorporated during the transformation, which proceeded
through 6-endo cyclization, [3 þ 2] cycloaddition, and
identification of DMF as the best choice for the transfor-
mation (Table 1, entry 6). The addition of Lewis acids,
usually found to be effective as additives for activation of
alkylidenecyclopropanes, displayed inferior results in this
reaction (Table 1, entries 9ꢀ13). A control experiment
without the addition of silver triflate resulted in no reac-
tion. The efficiency was retarded when the amount of silver
triflatewasreducedto5mol%(datanotshowninTable1).
The yield was improved (73% yield) when 2.5 equiv of
1-bromo-4-(cyclopropylidenemethyl)-benzene 2a was em-
ployed in the reaction (Table 1, entry 14). Further reaction
optimization revealed that the conversion conducted at
75 °C in DMF afforded optimal result (83% yield, Table 1,
entry 16).
The generality of this silver triflate-catalyzed tandem
reaction of 2-alkynylbenzaldoximes 1 with alkylidenecy-
clopropanes 2 was then explored under the optimized
conditions (10 mol % of AgOTf, DMF, 75 °C). The results
are summarized in Scheme 2. This silver-mediated benzo-
7-azabicyclo[4.2.2]dec-7-en-4-one formation was found
to be workable with 2-alkynylbenzaldoximes 1 bearing
electron-withdrawing and -donating substituents on the
(9) (a) Coskun, N.; Tuncman, S. Tetrahedron 2006, 62, 1345. (b)
Ding, Q.; Wang, Z.; Wu, J. J. Org. Chem. 2009, 74, 921.
3432
Org. Lett., Vol. 14, No. 13, 2012

intramolecular rearrangement. Further exploration using
2-alkynylbenzaldoximes for the construction of other
N-heterocycles is in progress.
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 3, and X-ray data for compound 3a (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support from National
Natural Science Foundation of China (No. 21032007
and 21172038) is gratefully acknowledged.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3433