A novel reaction of the 'Huisgen zwitterion' with benzofuran-2,3-diones: An efficient strategy for the synthesis of spirocyclic benzofuran-2-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.07.129

The nitrogen-based nucleophile generated from azodicarboxylate and triphenylphosphine displayed good reactivity toward benzofuran-2,3-diones to generate a variety of spirocyclic benzofuran-2-one derivatives. The reactions accommodate a number of benzofuran-2,3-diones and different dialkylazodicarboxylates to give the enriched functionalized 3-spirooxadiazole benzofuran-2-ones with moderate to good yields (up to 93%).

Full text of DOI:10.1016/j.tetlet.2013.07.129

Tetrahedron Letters 54 (2013) 5473–5476
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel reaction of the ‘Huisgen zwitterion’ with benzofuran-2,3-
diones: an efficient strategy for the synthesis of spirocyclic
benzofuran-2-one derivatives
⇑
⇑
Ze-Dong Wang, Nan Dong, Feng Wang, Xin Li , Jin-Pei Cheng
Department of Chemistry and State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071,China
a r t i c l e i n f o
a b s t r a c t
Article history:
The nitrogen-based nucleophile generated from azodicarboxylate and triphenylphosphine displayed
good reactivity toward benzofuran-2,3-diones to generate a variety of spirocyclic benzofuran-2-one
derivatives. The reactions accommodate a number of benzofuran-2,3-diones and different dialkylazodi-
carboxylates to give the enriched functionalized 3-spirooxadiazole benzofuran-2-ones with moderate
to good yields (up to 93%).
Received 7 May 2013
Revised 18 July 2013
Accepted 26 July 2013
Available online 2 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Huisgen zwitterion
Benzofuran-2,3-diones
Spirocyclic benzofuran-2-ones
The importance of spirocycles is clear, not only because of their
unique structural properties, but also because of their presence in
countless natural products and clinically valuable compounds.
Moreover, the unique structural features of spirocyclic compounds
have been used for the synthesis of ligands and catalysts.1 The
search for efficient methods for the construction of these com-
pounds is therefore interesting in organic synthesis, and significant
efforts have been directed toward the development of synthetic
methodology to this challenging area.2 In particular, the construc-
tion of spirocyclicoxindoles has been widely studied in recent
years.3 However, corresponding synthesis of the spirocyclic benzo-
furan-2-ones, whose structures are very close to spirocyclicoxin-
doles, has been rarely investigated. Esmaeili et al., reported the
reaction of benzofuran-2,3-dione derivatives with the zwitterions
generated from dialkylacetylenedicarboxylates with isoquinoline
and pyridine to form highly substituted spiro[1,3]oxazino[2,3-
a]isoquinoline4a and pyrido[2,1-b][1,3]oxazines,4b respectively.
Very recently, our group developed a phosphine-containing Lewis
base catalyzed regioselective [3+2] cycloaddition of benzofuranone
type olefins with allenoates, in which functionalized spiro-
cyclicbenzofuran-2-ones were obtained.5 In addition, there are
only a few examples of the synthesis of chiral 3,30-substituted ben-
zofuran-2-ones by asymmetric catalysis. 6 It should be pointed out
that spirocyclic benzofuran-2-ones are ubiquitous in a number of
natural products and biologically active heterocyclic compounds.7
In this context, discovering a methodology for the synthesis of
diversely structured spirocyclic benzofuran-2-ones is strongly
desired.
The facile reaction of triphenylphosphine with azodicarboxylate
leading to the formation of zwitterion 3 and the nucleophilic reac-
tivity of the latter was established by Huisgen et al., (Scheme 1).8
This zwitterion is the nucleophilic trigger in the Mitsunobu reac-
tion, which is a powerful and widely used protocol for the inver-
sion of the configuration of alcohols.9 Furthermore, the reaction
of zwitterions 3 is also a versatile synthetic method involved in
the transformation of the C–X bond (X = O, N, S, C) with either
inversion or retention of stereochemistry.10 Apart from the men-
tioned pivotal role, the chemistry of Huisgen zwitterion 3 has re-
ceived limited attention. Recently, Lee and co-workers have
reported that the reaction of the zwitterion 3 with carbonyl com-
pounds affords various products.11 Contemporaneous investiga-
tions in Nair’s laboratory disclosed interesting reactivity patterns
exhibited by zwitterion 3 in a series of reactions with differently
active double bond compounds.12 These transformations culmi-
nated in a facile synthesis of highly functionalized heterocyclic
derivatives. Ground on the above highlighted work, and in view
of our general interest in the construction of the structural core
including 3,3-substituted benzofuran-2-ones,5,13 herein we were
intrigued by the reaction of the employment of the zwitterion de-
rived from triphenylphosphine and a dialkylazodicarboxylate with
benzofuran-2,3-diones, in which we hope a new synthetic strategy
was found to construct spirocyclic benzofuran-2-ones.
Our investigations were initiated by treating the benzofuran-
2,3-dione 4a with diisopropylazodicarboxylate (DIAD) 2a in the
presence of triphenylphosphine in CH2Cl2 at room temperature.
⇑
Corresponding authors. Fax: +86 22 23499147.
E-mail address: xin_li@nankai.edu.cn (X. Li).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.129

5474
Z.-D. Wang et al. / Tetrahedron Letters 54 (2013) 5473–5476
Ph3P
CO2R
CO2R
PPh3
+
N N
N
N
RO2C
RO2C
1
2
3
R = Et, i-Pr, t-Bu, Bn
Scheme 1. Formation of Huisgen zwitterion.
Purification of the reaction mixture by SiO2 column chromatogra-
phy afforded the functionalized 5a as a colorless solid in 90% yield
(Table 1, entry 1).
The product was assigned the structure 5a on the basis of spec-
troscopic analysis. In the IR spectrum, the ester isopropyl was seen
at 1754 cmꢀ1 and the lactone at 1827 cmꢀ1. The 1H NMR spectrum
showed different sets of signals for carbo-isopropyl ether and iso-
propyl ether protons. The two tertiary carbon protons resonated at
d 4.71–5.03. This may be due to the intramolecular C–Hꢁ ꢁ ꢁO inter-
actions between the exocyclic C–H bond and the ester group. The
ester carbonyls were discernible at d 168.4 and 156.3 in the 13C
NMR spectrum. Unambiguous evidence confirming the structure
and stereochemistry of 5a was obtained from a single-crystal
Figure 1. X-ray crystal structure of 5a.
14
X-ray analysis (Fig. 1).
Then other three phosphines such as PBu3, P(p-MeOPh)3, and
P(p-MePh)3 were screened in the current model reaction at room
temperature. To our delight, all of the phosphines exhibited good
reactivity. As a result, the spirocyclic benzofuran-2-ones were
cleanly isolated with moderate yields (entries 1–4 in Table 1).
The examination of the phosphines revealed that PPh3 was the best
reagent for this reaction, in which 90% yield of product was
obtained within 10 min (entry 1 in Table 1).
Having confirmed PPh3 as the optimum phosphine for the reac-
tion, other factors, such as solvent and reagent ratio, influencing
the reaction were thoroughly investigated. The results are listed
in Table 1. The reactions generally proceeded smoothly in chlori-
nated solvents, such as CH2Cl2, CHCl3, and ClCH2CH2Cl (entries 1,
5, and 6 in Table 1). Furthermore, strong polar solvents, such as
THF (entry 7 in Table 1), Acetone (entry 8 in Table 1), Ethyl acetate
(entry 9 in Table 1) and CH3CN (entry 12 in Table 1), were also
propitious to the reaction. It should be pointed out that ether type
solvent was an inapplicable solvent leading to poor to moderate
yields (entries 10 and 13 in Table 1). Among a number of solvents
examined, the initially used CH2Cl2 was the optimal one, furnishing
the best yield. Further studies indicated that changing the ratio of
the initial three reactants display little influence on the spirocyclic
reaction (entries 14 and 15 in Table 1).
With the optimal conditions in hand, the substrate scopes were
next explored. Firstly, seven different substituted benzofuran-2,3-
diones were examined. As revealed in Table 2 (entries 1–7), the
reactions were shown to work well with a range of benzofuran-
2,3-diones bearing different substituted groups to give the desired
products with moderate to very good yields (5a–5g, 56–93%).
Table 1
Optimization of reaction conditionsa
O
OiPr
iPrO
O
N
O
iPrO2C
N
N
3 mL solvent
rt, <10 min
O
+
+
PR3
O
N
O
i
O
CO2 Pr
-R3P
O
4a
2a
5a
Entry
PR3
Solvent
4a:2a:PR3
Yieldb (%)
1
2
3
4
5
6
7
8
PPh3
PBu3
P(p-MeOPh)3
P(p-MePh)3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.5:1.5
1:1.2:1.2
1:2:2
90
48
85
83
85
82
76
64
80
40
73
80
0
DCE
THF
Acetone
Ethyl acetate
Ether
Toluene
CH3CN
DME
9
10
11
12
13
14
15
CH2Cl2
CH2Cl2
82
90
a
Unless noted, the reaction was conducted with 0.1 mmol 4a, 0.15 mmol 2a, and 0.15 mmol PR3 in 3 mL solvent.
Isolated yield.
b

Z.-D. Wang et al. / Tetrahedron Letters 54 (2013) 5473–5476
5475
Table 2
Substrate scopea
O
OR5
R1
R4
N
O
O
R5O
R1
R2
R3
N
R5O2C
PPh3
O
R2
R3
N
N
O
+
O
CH2Cl2, rt, <10 min
O
CO2R5
R4
4
2
5
Entry
R1
R2
R3
R4
Azodicarboxylate
Yieldb (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
H
H
H
H
Cl
Br
Me
t-Bu
H
H
H
H
H
H
H
H
H
Me
H
Me
Me
Me
H
Me
Me
H
H
H
t-Bu
t-Bu
Me
Me
Me
Me
Me
Me
H
2a: R5 = i-Pr
2a: R5 = i-Pr
2a: R5 = i-Pr
2a: R5 = i-Pr
2a: R5 = i-Pr
2a: R5 = i-Pr
2a: R5 = i-Pr
2b: R5 = Et
2c: R5 = t-Bu
2d: R5 = Bn
2b: R5 = Et
2c: R5 = t-Bu
2d: R5 = Bn
2b: R5 = Et
5a: 90
5b: 88
5c: 93
5d: 62
5e: 58
5f: 66
5g: 56
5h: 83
5i: 75
5j: 70
5k: 76
5l: 72
5m: 68
5n: 82
5o: 70
5p: 69
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
Me
Me
Me
9
10
11
12
13
14
15
16
H
H
2c: R5 = t-Bu
2d: R5 = Bn
a
The reaction was conducted with 0.1 mmol 4, 0.15 mmol 2, and 0.15 mmol PPh3 in 3 mL CH2Cl2.
Isolated yield.
b
O
Ph3P
O
N
N
OR
RO2C
CO2R
RO2C
O
N
N
+
R'
O
O
PPh3
N N
+
Ph3P
CO2R
O
RO2C
R'
O
O
2
1
3
4
6
Ph3P
Ph3P
O
OR
O
OR
N
N
N
N
RO2C
N
RO2C
RO2C
OR
N
O
O
Ph3P
O
R'
R'
R'
O
O
O
O
O
O
5
Scheme 2. Proposed mechanism for the reaction.
Next, other substituted azodicarboxylates, 2b–2d, were investi-
multifunctional spirooxadiazoline compounds. This methodology
substantially broadens the benzofuranone chemistry and offers
more functionalized spirocyclic products.
gated in this study. From the results in Table 2 (entries 8–16 in Ta-
ble 2), we found that 2b–2d put up very good activities, in which
the spirooxadiazoline type products 5h–5p were obtained in
68–83% yields.
Acknowledgments
Although the mechanism of the reaction between the benzofu-
ran-2,3-dione and dialkylazodicarboxylate in the presence of
triphenylphosphine has not been established experimentally, a
possible pathway is proposed in Scheme 2. On the basis of the
well-established chemistry of ‘Huisgen zwitterions’, it is reason-
able to assume initial formation of the 1,3-dipolar intermediate 3
from triphenylphosphine 1 and azodicarboxylate 2. This can add
to the ketone of benzofuran-2,3-dione 4, forming 6, which gives
the spirooxadiazoline 5 presumably by the elimination of triphen-
ylphosphine oxide via a process resembling the Wittig reaction.
In conclusion, we have discovered a novel synthetic strategy of
spirocyclic benzofuran-2-ones by a triphenylphosphine-mediated
reaction of benzofuran-2,3-diones with dialkylazodicarboxylate
that proceeds with high yields. The reaction scope is substantial,
and a number of substituted benzofuran-2,3-diones and different
dialkylazodicarboxylates could be successfully applied to give
The project was supported by National Natural Science Founda-
tion of China (Grant Nos. 21172112 and 21172118), the National
Basic Research Program of China (973 Program, No.
2010CB833300 and 2012CB821600), and the State Key Laboratory
on Elemento-organic Chemistry (Nankai University, China). X. Li
also thanks the Program for New Century Excellent Talents in the
University for support (NCET-12-0279).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.
129. These data include MOL files and InChiKeys of the most
important compounds described in this article.

5476
Z.-D. Wang et al. / Tetrahedron Letters 54 (2013) 5473–5476
Washington, DC, 1994; p 62; (b) Huisgen, R.; Blaschke, H.; Brunn, E. Tetrahedron
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