When Ethyl Isocyanoacetate Meets Isatins: A 1,3-Dipolar/Inverse 1,3-Dipolar/Olefination Reaction for Access to 3-Ylideneoxindoles

Article abstract of DOI:10.1021/acs.orglett.8b00217

A new CuI/1,10-phen-catalyzed reaction for the synthesis of 3-ylideneoxindoles from readily available isatins and ethyl isocyanoacetate, in which ethyl isocyanoacetate acts as a latent two-carbon donor like the Wittig reagent, is reported. A tandem procedure including 1,3-dipolar cycloaddition/inverse 1,3-dipolar ring opening/olefination allows the preparation of 3-ylideneoxindoles with broad functional group tolerance.

Full text of DOI:10.1021/acs.orglett.8b00217

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
When Ethyl Isocyanoacetate Meets Isatins: A 1,3-Dipolar/Inverse 1,3-
Dipolar/Olefination Reaction for Access to 3‑Ylideneoxindoles
†
†
‡
,†
,†
Wen-Kui Yuan, Tao Cui, Wei Liu, Li-Rong Wen,* and Ming Li*
†State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of
Science & Technology, Qingdao 266042, China
‡
University and College Key Lab of Natural Product Chemistry and Application in Xinjiang, Yili Normal University, Yining 835000,
China
*
S Supporting Information
ABSTRACT: A new CuI/1,10-phen-catalyzed reaction for the synthesis of 3-ylideneoxindoles from readily available isatins and
ethyl isocyanoacetate, in which ethyl isocyanoacetate acts as a latent two-carbon donor like the Wittig reagent, is reported. A
tandem procedure including 1,3-dipolar cycloaddition/inverse 1,3-dipolar ring opening/olefination allows the preparation of 3-
ylideneoxindoles with broad functional group tolerance.
3
-Ylideneoxindole is a prominent skeleton of pharmacological
Scheme 1. Reported Synthetic Strategies of 3-
Ylideneoxindoles
importance; it appears as the core structural motif in a variety of
bioactive molecules exhibiting potent antifungal, antiprolifer-
1
2
3
4
ative, antiviral, and anti-inflammatory activities. Furthermore,
-ylideneoxindoles as key intermediates and versatile building
3
blocks have also been applied in the synthesis of diverse
5
spirocyclic oxindoles. Thus, the development of novel efficient
strategies for the assembly of 3-ylideneoxindoles is one of the
most active areas in modern synthetic organic chemistry.
The reported synthetic methods for 3-ylideneoxindoles can
be typically classified into two classes. The first class mainly
focuses on the utility of isatins as building blocks through the
6
,7
Wittig reaction (Scheme 1a,b). Another class involves base-
mediated phenoxide cyclization or palladium-catalyzed aro-
8
,9
matic C−H functionalization (Scheme 1c,d). Although these
methods are efficient, they suffer from some difficulties such as
use of hazardous or toxic reagents, generating much waste and
poor atom economy, or the use of expensive palladium catalysts
and requirement of elaborately designed or inaccessible
substrates, which limit their application.
1
0
11
Isocyanoacetates
and isatins
are two classes of
give optically active spirooxindole oxazolines at room temper-
commercially available starting materials. Isocyanoacetates are
a useful building block for tandem reactions due to their
unusual reactivity for generating multiple bonds in a one-pot
15
ature. A careful survey of the literature revealed that the
application of the reactive spirooxindole oxazolines to form 3-
ylideneoxindole in organic synthesis is largely unexplored. In
our study, when we conducted the reactions of ethyl
isocyanoacetate with isatins by copper catalysis at a higher
temperature (110 °C), an unexpected 3-ylideneoxindole
compound 3 was obtained, which might be converted via
inverse 1,3-dipolar process at elevated temperature from
1
2
process. Directing this tunable reactivity with metal or
nonmetal catalysts provides rapid access to a large array of
complex structures ideally functionalized for medicinal
1
3
applications.
Recently, Franz and co-workers reported a regio- and
stereoselective cyclization between isatins and 5-methoxyox-
azoles to afford spirooxindole oxazolines at room temper-
1
4
ature. In addition, Shi and co-workers developed an efficient
3 + 2] cycloaddition reaction of isocyanoacetates to isatins to
Received: January 22, 2018
[
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00217
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
intermediate spirooxindole oxazolines 4 in situ generated
through 1,3-dipolar cycloaddition (Scheme 2). This approach
Table 1. Optimization of Reaction Conditions for 3a
Scheme 2. Present Synthetic Strategy of 3-Ylideneoxindoles
b
ligand
(equiv)
temp
(°C)
yield
(%)
entry
cat. (equiv)
solvent
1
2
3
toluene
toluene
toluene
110
110
110
41
48
51
Cu(OTf) (0.1)
2
CuSO ·5H O
4
2
(
0.1)
4
5
6
7
8
9
CuI (0.1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
110
110
110
110
110
110
110
110
110
110
110
66
CuCl (0.1)
CuBr (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
52
55
L1 (0.1)
L2 (0.1)
L3 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
L1 (0.1)
83
44
is quite simple and might open a new window for the direct
conversion of isocyanoacetates with isatins into well-known 3-
ylideneoxindoles. In this reaction, ethyl isocyanoacetate serves
as a two-carbon donor like the Wittig reagent, thereby
expanding the reactive mode of isocyanoacetates. Based on
our ongoing interest in isonitriles chemistry, herein we report
a CuI/1,10-phen-catalyzed reaction for the synthesis of 3-
ylideneoxindoles from readily available isatins and ethyl
isocyanoacetate (Scheme 2).
The reaction of 1-methylisatin (1a) with ethyl isocyanoace-
tate (2) was used as the model reaction to optimize reaction
conditions, including catalysts, ligands, bases, solvents, and
temperatures (Table 1).
56
c
1
1
1
1
0
1
2
3
trace
d
NP
trace
trace
55
DMSO
16
14
1,4-
dioxane
1
1
1
1
1
2
5
6
7
8
9
0
CuI (0.1)
CuI (0.1)
CuI (0.05)
CuI (0.15)
CuI (0.1)
CuI (0.1)
L1 (0.1)
L1 (0.2)
CH CN
110
110
110
110
130
100
51
73
57
81
77
66
3
toluene
L1 (0.05) toluene
L1 (0.15) toluene
L1 (0.1)
L1 (0.1)
toluene
toluene
a
Initially, a mixture of 1a and 2 without any additive in
toluene was stirred at 110 °C for 6 h, and only 41% yield of
aimed product 3a was obtained (Table 1, entry 1). Then
various copper salts such as Cu(OTf) , CuSO ·5H O, CuI,
Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), solvent (2 mL) in
b c d
sealed tube. Isolated yield. TEA (2 equiv) was added. Cs
equiv) was added. L1 = 1,10-phen, L2 = L-proline, L3 = 3-
imidazolidin-2-ylidene)pentane-2,4-dione.
CO (2
2
3
(
2
4
2
CuCl, and CuBr were examined, and the results showed that
.1 equiv of CuI worked more efficiently than other catalysts,
0
giving 66% yield of 3a (entries 2−6). Next, ligands were
screened. Delightfully, the addition of 1,10-phen (L1) (0.1
equiv) increased the yield of 3a to 83% (entry 7). Different
ligands such as L-proline (L2) and HKA (heterocyclic ketene
aminal) such as 3-(imidazolidin-2-ylidene)pentane-2,4-dione
1
7
(
L3) were examined, but they were inferior to 1,10-phen
(
entries 8 and 9). The addition of a base such as TEA and
Cs CO was adverse to the reaction (entries 10 and 11).
2
3
Solvent screening with DMF, DMSO, 1,4-dioxane, and CH CN
3
revealed that polar solvents are also unfavorable to the reaction
(
entries 12−15). Changing the amount and ratio of CuI/1,10-
phen did not further improve the reaction yield (entries 16−
8). Finally, the reaction temperature was investigated, and the
1
results showed raising or lowering reaction temperature were
not beneficial to the reaction (entries 19 and 20).
With the optimized reaction conditions in hand, we
evaluated the substrate scope and generality of the reaction,
and the results are summarized in Figure 1. As can be seen from
Figure 1, a wide scope of isatins could be successfully utilized to
afford the desired products 3, including various halogen−
substituted isatins. In particular, unprotected isatins can be well
tolerated (3i−u).
Figure 1. Synthesis of products 3. Reaction conditions: 1 (0.5 mmol),
(0.6 mmol), CuI (0.05 mmol), 1,10-phen (0.05 mmol), toluene (2
mL) in sealed tube, 110 °C. Isolated yield. E/Z = 5.67:1 for 3b.
2
The relative configuration of 3-ylideneoxindoles 3 was
unambiguously determined by X-ray diffraction analysis of 3i
(
Figure S1).
Delightedly, under the same conditions, acenaphthylene-1,2-
smoothly to give rise to ethyl 2-(2-oxoacenaphthylen-1(2H)-
ylidene)acetate 6 (Scheme 3).
dione 5 could also react with ethyl isocyanoacetate (2)
B
DOI: 10.1021/acs.orglett.8b00217
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Reaction of Acenaphthylene-1,2-dione with 2
(7%). Next, two comparative experiments were performed with
4i as the substrate at 110 °C for 4 h to indicate the effect of
copper catalyst on the reaction (Schemes 6b,c). It was found
that in the absence or presence of CuI/1,10-phen intermediate
4i could convert smoothly to the desired product 3i in similar
yields. These two results suggested that copper catalyst does
not work for this ring-opening reaction.
On the basis of the above experimental results and relevant
1
8
reports, a plausible catalytic cycle mechanism for the
formation of 3-ylideneoxindoles 3 is proposed (Scheme 7).
Isocyanoacetamides 7 instead of ethyl isocyanoacetate (2)
were also successfully employed to react with isatins such as 5-
bromo-1-methylindoline-2,3-dione 1f for the synthesis of 3-
ylideneoxindoles; however, the yield was only 36%, suggesting
the reactivity of isocyanoacetamide is inferior to that of
isocyanoacetate (Scheme 4).
Scheme 7. Possible Reaction Mechanism
Scheme 4. Reaction of Isocyanoacetamide 7 with Isatin 1f
With the aim of evaluating the practicality of this catalytic
process, a gram-scale experiment was performed with 1c (1.76
g, 9.0 mmol) and 2 (1.22 g 10.8 mmol), yielding the
corresponding product 3c in 60% (1.43 g) (Scheme 5).
First, the reaction of ethyl isocyanoacetate 2 with CuI in the
presence of a ligand forms the intermediate [I]. Intermediate
Scheme 5. Gram-Scale Synthesis of 3c
[I] takes place a formal [3 + 2] cycloaddition into isatins 1 to
generate the cyclic organocopper intermediate of spirooxindole
oxazolines [II], which is then transformed to spirooxindole
oxazoline intermediate 4 as well as the intermediate [I] for a
new cycle. Finally, 4 undergoes an inverse 1,3-dipolar ring-
opening/olefination reaction to form product 3 at 110 °C with
an elimination of isocyanic acid that can form in situ cyanuric
1
acid (as confirmed by H NMR analysis, see the SI).
Next, our attention was shifted to elucidate a reasonable
mechanism of this transformation. Notably, during the
investigation of this interesting transformation reaction under
the standard conditions, we noticed a trace intermediate by
TLC, which disappeared gradually with time expanding.
In order to obtain the intermediate, the reaction of isatin (1i)
with 2 was conducted at relatively low 80 °C for 1 h (Scheme
In summary, a versatile strategy has been devopled for the
straightforward synthesis of 3-ylideneoxindoles through a
copper(I)-catalyzed [3 + 2] cycloaddition of isocyanoacetates
to isatins and inverse 1,3-dipolar ring-opening/olefination
tandem reaction, in which isocyanoacetates act as a latent
two-carbon donor like the Wittig reagent. This novel method is
complementary to the classical Wittig reaction in that it is well-
suited to the convenient preparation of 3-ylideneoxindoles,
which are widespread in pharmaceutically relevant compounds.
The applications of this reaction in organic synthesis are
currently in progress.
6
a). To our delight, a spirooxindole oxazoline intermediate 4i
was obtained in 43% yield along with 3-ylidene oxindole 3i
Scheme 6. Control Experiments
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00217.
Experimental procedures, characterization, and spectral
data (PDF)
Accession Codes
CCDC 990185 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
C
DOI: 10.1021/acs.orglett.8b00217
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
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AUTHOR INFORMATION
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Corresponding Authors
*
*
E-mail: wenlirong@qust.edu.cn.
E-mail: liming928@qust.edu.cn.
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Li-Rong Wen: 0000-0001-7976-0878
Ming Li: 0000-0003-4906-936X
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Org. Lett. XXXX, XXX, XXX−XXX