[3 + 3] Formal Cycloadditions of Nitrones from Isatins and Azaoxyallyl Cations for Construction of Spirooxindoles

Article abstract of DOI:10.1002/cjoc.201600864

A [3 + 3] formal cycloaddition reaction between in situ formed azaoxyallyl cations and nitrones from isatins has been developed, furnishing a spectrum of spiro[1,2,4-oxadiazinan-5-one]oxindoles in good to excellent yields with excellent diastereoselectivity. This method provides direct and efficient access to potentially bioactive spirooxindoles incorporating a six-membered heterocyclic scaffold.

Full text of DOI:10.1002/cjoc.201600864

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DOI: 10.1002/cjoc.201600864
[3＋3] Formal Cycloadditions of Nitrones from Isatins and
Azaoxyallyl Cations for Construction of Spirooxindoles
Weijia Lin,a Gu Zhan,a Minglin Shi,a Wei Du,*,a and Yingchun Chen*,a,b
a Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University,
Chengdu, Sichuan 610041, China
b College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
A [3＋3] formal cycloaddition reaction between in situ formed azaoxyallyl cations and nitrones from isatins has
been developed, furnishing a spectrum of spiro[1,2,4-oxadiazinan-5-one]oxindoles in good to excellent yields with
excellent diastereoselectivity. This method provides direct and efficient access to potentially bioactive spirooxin-
doles incorporating a six-membered heterocyclic scaffold.
Keywords cycloaddition, spirooxindoles, azaoxyallyl cations, nitrones, 1,3-dipoles
Introduction
mal cycloadditions with nitrones from isatins for the
synthesis of valuable spirooxindoles (Scheme 1, d).
The spirooxindole scaffolds are a unique type of core
structures encountered in abundant natural products and
pharmaceutics.[1] The potentially biological properties
of these structural features, such as antimalarial,[2] anti-
convulsant[3] and antiandrogen activities,[4] have led to a
great demand for efficient synthetic methods to con-
struct such skeletons. A single-step synthesis of spiro-
oxindoles incorporating a heterocyclic framework from
unsaturated oxindole derivatives has attracted much
attention because of its high efficiency.[5] In particular,
nitrones derived from isatins have been applied as
1,3-dipoles in [3＋2] cycloaddition reactions with al-
kenes, constructing spiro[isoxazolidine]oxindoles in
moderate to good yields (Scheme 1, a).[6] In addition,
we reported a regioselective asymmetric [3＋2] formal
cycloaddition reaction of nitrone ylides from isatins and
enals via iminium ion catalysis, furnishing an array of
1'-hydroxy-3,2'-pyrrolidinylspirooxindoles (Scheme 1,
b).[7] The Shi group also presented an interesting [3＋3]
cycloaddition reaction of nitrones from isatins to con-
struct spirooxindoles incorporating a six-membered
heterocycle (Scheme 1, c).[8]
Experimental
Nitrone 1 (0.1 mmol), α-chlorohydroxamate 2 (0.14
mmol), diisopropylethylamine (DIPEA, 0.2 mmol) and
4 Å MS (30 mg) were added into an oven-dried vial
equipped with a magnetic stirbar. Then hexafluoroiso-
propanol (HFIP, 0.5 mL) and CH2Cl2 (0.1 mL) were
added. The mixture was stirred at room temperature for
4 h. The resulting crude residue was purified by column
chromatography on silica gel eluting with a mixture of
petroleum ether and ethyl acetate (10∶1 to 5∶1) to
afford product 3.
Results and Discussion
Initially, we investigated the model reaction between
nitrone 1a and α-chlorohydroxamate 2a in HFIP in the
presence of 2.0 equiv. of Na2CO3 and 4 Å molecular
sieves (MS) at room temperature. To our delight, the
desired [3＋3] adduct 3a was obtained in 83% yield
with excellent diastereoselectivity (Table 1, Entry 1).
Different bases were tested, and it was found that an
organic base DIPEA gave a higher yield compared to
those of inorganic carbonates (Table 1, Entries 2 and 3).
Further screenings on solvents showed that toluene,
THF and CH3CN were not suitable for the cycloaddition,
while CH2Cl2 provided inferior results (Table 1, Entries
4－7). Subsequently, a mixture of HFIP/CH2Cl2 was
tested, as better solubility of the nitrone 1a was
On the other hand, azaoxyallyl cations, readily in
situ generated from α-halohydroxamates in the presence
of bases, have been discovered as another type of valu-
able 1,3-dipoles, providing efficient access to various
heterocycles via [3＋4],[9] [3＋3],[10] [3＋2][11] and even
[3＋1][12] annulation reactions. The rapid application of
azaoxyallyl cations prompted us to consider them to be
ideal 3-unit synthons, which might undergo [3＋3] for-
*
E-mail: duweiyb@scu.edu.cn, ycchen@scu.edu.cn
Received December 5, 2016; accepted January 3, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600864 or from the author.
In Memory of Professor Enze Min.
Chin. J. Chem. 2017, XX, 1—4
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Lin et al.
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Scheme 1 Different cycloaddition reactions of nitrones from
isatins to access diverse spirooxindoles
observed in CH2Cl2. The yield of 3a was further im-
proved, and the best results were obtained with
HFIP/CH2Cl2 in a 5∶1 ratio (Table 1, Entries 8 and 9).
Consequently, the substrate scope and limitations of
nitrones and α-chlorohydroxamates for the [3＋3] for-
mal cycloadditions were explored under the optimized
reaction conditions. At first, a variety of nitrones de-
rived from isatins were tested with α-chlorohydro-
xamate 2a. The nitrones with various N-alkyl substitu-
ents, including linear and branched ones, afforded the
corresponding products 3a－3e in high yields with ex-
cellent diastereoselectivity (Table 2, Entries 1－5). The
N-aryl substituted nitrones, together with the 2-styryl
substituted one, proceeded smoothly as well (Table 2,
Entries 6－8). In addition, the nitrones with both elec-
tron-poor and -rich substituents on the oxindole ring, as
well as the one derived from 7-azaisatin, were also in-
vestigated, providing the desired products 3i－3n in
excellent yields (Table 2, Entries 914). In addition, the
N-Boc protected nitrone substrate, even that with a free
NH group, exhibited good reactivity, delivering 3o and
3p in good results, respectively (Table 2, Entries 15 and
16). On the other hand, α-chlorohydroxamates 2 with
different aryl groups were compatible with the cycload-
ditions (Table 2, Entries 17－22). Besides, 3w and 3x
were obtained in good yields when the gem-dimethyl
substituted α-chlorohydroxamate was employed (Table
2, Entries 23 and 24). Unfortunately, all attempts to
conduct the potential asymmetric [3＋3] formal cy-
cloadditions failed when a few chiral hydrogen-bonding
donor catalysts or phase transfer catalysts were em-
ployed, probably because both dipole substrates could
direct participate in the observed reaction without any
interaction with the catalysts.[13]
The relative configuration of product 3a was unam-
biguously determined by X-ray analysis (Figure 1).[14]
Furthermore, the reaction mechanism was proposed ac-
cordingly, as shown in Scheme 2. Under basic condi-
tions, azaoxyallyl cation I was generated from substrate
2a, followed by a [3＋3] formal cycloaddition with
nitrone 1a, producing 3a with high diastereoselectivity.
Table 1 Screening studies on [3＋3] formal cycloadditiona
Ph
-
O
base
(2.0 equiv.)
Bn
O
O
N
Ph
N+
O
Bn
NHOBn
+
NOBn
O
Cl
4 Å MS
solvent, r.t.
4 h
O
N
N
2a
1a
> 19:1 dr
3a
Scheme 2 Proposed mechanism for the [3＋3] cycloaddition
reaction
Entry Base
Solvent
HFIP
Yield/%b
83
1
2
3
4
5
6
7
8
Na2CO3
K2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
HFIP
79
HFIP
85
Toluene
THF
－
－
CH3CN
CH2Cl2
－
36
HFIP/CH2Cl2 (5/1)
HFIP/CH2Cl2 (1/5)
94
9
92
a
Reaction conditions: nitrone 1a (0.1 mmol) and α-chlorohy-
droxamate 2a (0.14 mmol), 4 Å MS (30 mg), base (0.4 mmol) in
solvent (0.6 mL) at r.t. for 4 h. b Isolated yield.
2
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[3＋3] Formal Cycloadditions of Nitrones from Isatins and Azaoxyallyl Cations
Table 2 Substrate scope of [3＋3] formal cycloadditionsa
Entry R, R1,R2
R3, R4
Yieldb/%
1
2
3
H, Bn, CH3
Ph, H
Ph, H
Ph, H
3a, 95c
3b, 86
3c, 91
H, Me, CH3
H, Et CH3
4
5
Ph, H
Ph, H
3d, 85
3e, 87
H,
, CH3
, CH3
Ph
O
N
O
Bn
NOBn
O
H,
6
7
8
9
H, Ph, CH3
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
3f, 83
3g, 95
3h, 92
3i, 89
3j, 92
3k, 88
3l, 97
3m, 95
3n, 90
N
H, 1-naphthyl, CH3
H, 2-styryl, CH3
5-F, Bn , CH3
3a
Figure 1 X-ray structure of 3a.
10
11
12
13
5-Br, Bn, CH3
6-Br, Bn, CH3
5-Me, Bn, CH3
5-MeO, Bn, CH3
H, Bn, CH3
protocol to access the potentially bioactive spirooxin-
doles incorporating a six-membered heterocyclic skele-
ton.
Acknowledgement
14d
We are grateful for financial support from the NSFC
(Nos. 21602143 and 21125206) and the Starting Foun-
dation for Young Teachers of Sichuan University (No.
2016SCU11009).
15
Ph, H
3o, 91
H,
, Boc
16
17
18
19
20
21
22
23
24
H, Bn, H
Ph, H
3p, 89
3q, 92
3r, 90
3s, 93
3t, 95
3u, 97
3v, 91
3w, 88
3x, 94
H, Bn, CH3
H, Bn, CH3
H, Bn, CH3
H, Bn, CH3
H, Bn, CH3
H, Bn, CH3
H, Bn, CH3
H, Me, CH3
4-ClC6H4, H
2-BrC6H4, H
3-BrC6H4, H
4-MeC6H4, H
2-MeOC6H4, H
4-MeOC6H4, H
CH3, CH3
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4
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