Tandem cyclization-[3+3] cycloaddition reactions of 2-alkynylbenzaldoxime: synthesis of fused 1,2-dihydroisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2008.10.121

Tandem cyclization-[3+3] cycloaddition of 2-alkynylbenzaldoximes with dimethyl cyclopropane-1,1-dicarboxylate co-catalyzed by AgOTf and Yb(OTf)₃ is described, which provides an useful method for the synthesis of tetrahydro-1,2-oxazine fused 1,2

Full text of DOI:10.1016/j.tetlet.2008.10.121

Tetrahedron Letters 50 (2009) 198–200
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Tetrahedron Letters
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Tandem cyclization-[3+3] cycloaddition reactions of 2-alkynylbenzaldoxime:
synthesis of fused 1,2-dihydroisoquinolines
Qiuping Ding a,c, Zhiyong Wang a, Jie Wu a,b,
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
c Analytical Centre for Physics and Chemistry, Jiangxi Normal University, 437 West Beijing Road, Nanchang 330027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Tandem cyclization-[3+3] cycloaddition of 2-alkynylbenzaldoximes with dimethyl cyclopropane-1,1-
dicarboxylate co-catalyzed by AgOTf and Yb(OTf)3 is described, which provides an useful method for
the synthesis of tetrahydro-1,2-oxazine fused 1,2-dihydroisoquinolines.
Received 4 September 2008
Revised 10 October 2008
Accepted 24 October 2008
Available online 30 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
2-Alkynylbenzaldoxime
Dimethyl cyclopropane-1,1-dicarboxylate
1,2-Dihydroisoquinoline
Silver triflate
Yetterbium triflate
The increasing significance of combinatorial chemistry in phar-
maceutical sciences demands the development of new strategies to
synthesize a collection of natural product-like compounds.1 As a
privileged fragment, the 1,2-dihydroisoquinoline skeleton is an
important substructure in both natural products and therapeutic
agents, as well as the wide application of 1,2-dihydroisoquinolines
in pharmaceutical research.2 Typical examples include papaverine
(smooth muscle relaxant),2e saframycin-B (antitumor agent),2f
indenoisoquinoline (topoisomerase I inhibitor),2g and narciclasine
(antitumor agent).2h Thus, significant effort continues to be given
to the development of new 1,2-dihydroisoquinoline-based struc-
tures and new methods for their construction.3–5 As part of a pro-
gram in our laboratory for synthesis of biologically relevant
heterocyclic compounds,5,6 we became interested in developing
novel and efficient methods to construct the new 1,2-dihydroiso-
quinoline-based structures, with a hope of finding active hits for
our particular biological assays. Herein, we present our recent
efforts for the synthesis of tetrahydro-1,2-oxazine-fused 1,2-dihy-
droisoquinoline derivatives via AgOTf and Yb(OTf)3 co-catalyzed
tandem cyclization-[3+3] cycloaddition reaction of 2-alkynylbenz-
aldoximes with dimethyl cyclopropane-1,1-dicarboxylates.
the development of tandem reactions has been a fertile area in
organic synthesis.7 In particular, the development of tandem reac-
tions for the efficient construction of small molecules is an impor-
tant goal in combinatorial chemistry from the viewpoints of
operational simplicity and assembly efficiency. Recently, we
and others discovered that in the presence of electrophiles (such
as iodine or bromine) or Lewis acids, 2-alkynylbenzaldoxime could
be transferred to isoquinoline-N-oxide via electrophilic cycliza-
tion.6b,8 Prompted by these results, we envisioned that the tandem
cyclization-cycloaddition reaction might occur since the generated
isoquinoline-N-oxide could undergo further dipolar cycloaddition
in the presence of dipolarophiles, leading to the fused 1,2-dihydro-
isoquinoline derivatives. Recently, donor–acceptor cyclopropanes
as dipolarophiles have been successfully applied in the [3+3] cyclo-
addition of nitrones developed by Kerr and others.9,10 The gener-
ated tetrahydro-1,2-oxazine core is also found in many natural
products and pharmaceuticals that exhibit remarkable biological
activities.11 They also serve as valuable synthetic intermediates
in total synthesis.12,13 Based on these results, we started to inves-
tigate the possibility of this tandem reaction of 2-alkynylbenzal-
doxime with dimethyl cyclopropane-1,1-dicarboxylate.
Among the strategies used for the construction of small
molecules, design and synthesis of natural product-like com-
pounds via tandem reactions have attracted much attention, and
The reaction was initially studied with 2-alkynylbenzaldoxime
1a and dimethyl cyclopropane-1,1-dicarboxylate 2a, which were
selected as suitable substrates for reaction development (Scheme
1). As described above, in the presence of Lewis acid, 2-alkyn-
ylbenzaldoxime could be transferred to isoquinoline-N-oxide via
electrophilic cyclization. At the outset, various Lewis acids were
* Corresponding author. Tel.: +86 21 5566 4619; fax: +86 21 6510 2412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.121

Q. Ding et al. / Tetrahedron Letters 50 (2009) 198–200
199
Table 1
MeO2C
Tandem cyclization/[3+3] cycloaddition of 2-alkynylbenzaldoximes with dimethyl
OH
+
Lewis acid
(10 mol %)
cyclopropane-1,1-dicarboxylate14
MeO2C
N
CO2Me
CO2Me
O
MeO2C
N
R3
OH
R3
solvent
AgOTf (5 mol %)
N
MeO2C
R1
R1
CO2Me Yb(OTf)3 (10 mol %)
Ph
Ph
+
O
N
1a
2a
3a
toluene
CO2Me
R2
R2
Scheme 1.
1
2
3
Entry
1
2-Alkynyl benzaldoxime
R3
Product
Yielda (%)
MeO2C
MeO2C
screened, and AgOTf (5 mol %) was demonstrated as the best
choice for isoquinoline-N-oxide formation.8b However, this cata-
lyst was not effective for the subsequent [3+3] cycloaddition reac-
tion. Thus, additional Lewis acid catalyst was added to the reaction
system. To our delight, we observed the formation of the desired
fused 1,2-dihydroisoquinoline 3a, when the reaction was per-
formed in toluene co-catalyzed by AgOTf (5 mol %) and Yb(OTf)3
(10 mol %) at 80 °C (77% yield). Following an extensive investiga-
tion, we observed that the yields were inferior when other solvents
(THF, CH3CN, DMF, CH2Cl2, and DCE) were employed in the reac-
tion. Decreasing the amount of catalyst diminished the yield of
product 3a.
To test the effectiveness of this catalytic system, a range of 2-
alkynylbenzaldoximes 1 were examined using the preliminary
optimized reaction conditions [toluene as the solvent, 5 mol % of
AgOTf, 10 mol % of Yb(OTf)3, 80 °C], and the results are summa-
rized in Table 1. 2-Alkynylbenzaldoxime 1b reacted with dimethyl
cyclopropane-1,1-dicarboxylate 2a, leading to the formation of 1,2-
dihydroisoquinoline 3b in 74% yield (Table 1, entry 2). Complete
conversion and excellent isolated yield (92%) were observed, when
fluoro-substituted 2-alkynylbenzaldoxime 1c was employed in the
reaction (Table 1, entry 3). Reaction of 2-alkynylbenzaldoxime 1d
with dimethyl cyclopropane-1,1-dicarboxylate 2a also furnished
the desired product 3d in good yield (78% yield, Table 1, entry 4).
However, inferior results were displayed, when substrates with
electron-donating groups attached on the aromatic ring of 2-al
kynylbenzaldoxime were employed. For instance, substrate 1e
reacted with dimethyl cyclopropane-1,1-dicarboxylate 2a, which
gave rise to the corresponding product 3e in 38% yield (Table 1, en-
try 5). Similar yields were observed when 2-alkynylbenzaldoxime
1f or 1g was utilized in the reaction (36% or 42% yield, respectively,
Table 1, entries 6 and 7). We also found that, in this kind of trans-
formation, the R2 group attached on the triple bond is crucial.
When R2 was replaced by aliphatic group, such as butyl (1h) and
cyclopropyl groups (1j), the reaction was complicated and no de-
sired product was isolated (Table 1, entries 8 and 9). We also tested
the reaction of 2-alkynylbenzaldoxime 1a with phenyl-substituted
dimethyl cyclopropane-1,1-dicarboxylate 2b, which generated the
desired product 3j in 47% yield (Table 1, entry 10).
OH
N
O
H (2a)
77
N
N
Ph
1a
Ph 3a
MeO2C
MeO2C
OH
N
O
2
3
4
H (2a)
H (2a)
H (2a)
74
92
78
PMP
PMP
1b
3b
MeO2C
F
OH
Ph
MeO2C
N
F
O
N
Ph
1c
3c
MeO2C
F
OH
MeO2C
N
F
O
N
PMP
OH
PMP
1d
3d
MeO2C
MeO2C
O
O
N
O
O
5
6
7
H (2a)
H (2a)
H (2a)
N
38
36
42
Ph
O
Ph
1e
3e
MeO2C
MeO2C
OH
O
O
N
O
O
N
PMP
O
PMP
1f
3f
MeO2C
MeO2C
MeO
MeO
OH
N
MeO
MeO
O
N
Ph
OMe
Ph
OMe
1g
3g
MeO2C
MeO2C
OH
In the reaction process, the intermediate isoquinoline-N-oxide
should be formed from 2-alkynylbenzaldoxime in the presence of
silver triflate.8b It was well known that 1,1-cyclopropane diesters
N
N
O
8
9
H (2a)
H (2a)
Ph (2b)
—
N
Bu
1h
Bu 3h
behaved very much like
a,b-unsaturated carbonyl compounds in
their ability to react with nucleophiles,10a–d and the strained bonds
in 1,1-cyclopropane diesters can be polarized and further weak-
ened by coordination of a Lewis acid to one or both of the ester
moieties. Thus, [3+3] cycloaddition of isoquinoline-N-oxide with
1,1-cyclopropane diester occurred, which was similar to the
reports of Kerr and others.9,10
MeO2C
MeO2C
OH
O
—
N
1i
3i
Ph
MeO2C
MeO2C
In summary, we have described a tandem cyclization-[3+3]
cycloaddition reaction of 2-alkynylbenzaldoxime with dimethyl
cyclopropane-1,1-dicarboxylate catalyzed by the combination of
AgOTf and Yb(OTf)3, which provide a facile and useful protocol
for the synthesis of tetrahydro-1,2-oxazine-fused 1,2-dihydroiso-
quinolines. Introducing enantioselectivity in the scaffold and
screening for biological activity of these small molecules are under
OH
Ph
N
O
N
10
47
Ph
1a
3j
a
Isolated yield based on 2-alkynylbenzaldehydes 1.

200
Q. Ding et al. / Tetrahedron Letters 50 (2009) 198–200
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Financial support from National Natural Science Foundation of
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14. General procedure for AgOTf and Yb(OTf)3 co-catalyzed tandem cyclization-[3+3]
cycloaddition reaction of 2-alkynylbenzaldoximes with dimethyl cyclopropane-1,1-
dicarboxylate: 2-Alkynylbenzaldoxime (0.30 mmol) was added to a mixture of
AgOTf (5 mol %) and Yb(OTf)3 (10 mol %) in toluene (2.0 mL) at 80 °C under
nitrogen atmosphere. After 5 min, dimethyl cyclopropane-1,1-dicarboxylate
(0.36 mmol, 1.2 equiv) was added. After completion of the reaction as
indicated by TLC, the reaction mixture was cooled to room temperature,
quenched with water (10 mL), and extracted with EtOAc (2 Â 10 mL).
Evaporation of the solvent followed by purification of the residue on silica
gel afforded fused 1,2-dihydroisoquinoline 3.