Copper-Catalyzed Selective N-Vinylation of 3-(Hydroxyimino)indolin-2-ones with Alkenyl Boronic Acids: Synthesis of N-Vinyl Nitrones and Spirooxindoles

Article abstract of DOI:10.1021/acs.joc.7b00620

A copper-catalyzed selective cross-coupling reaction of 3-(hydroxyimino)indolin-2-ones with alkenyl boronic acids to access (E)-N-vinyl oxindole nitrones has been achieved under mild conditions. The studies showed that catalytic copper salt selectively gave mono N-vinylation products, while 2.0 equiv of copper salt provided double N-vinylation products. The control experiments revealed that the carbonyl group in 3-(hydroxyimino)indolin-2-one played important roles on N-vinylation. Furthermore, the prepared N-vinyl oxindole nitrones could be converted to spirooxindoles in good yields under thermal conditions.

Full text of DOI:10.1021/acs.joc.7b00620

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Note
Copper-Catalyzed Selective N-Vinylation of 3-(Hydroxyimino)indolin-2-ones
with Alkenyl Boronic Acids: Synthesis of N-Vinyl Nitrones and Spirooxindoles
Chun-Hua Chen, Qing-Qing Liu, Xiao-Pan Ma, Yu Feng,
Cui Liang, Cheng-Xue Pan, Gui-Fa Su, and Dong-Liang Mo
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 19 May 2017
Downloaded from http://pubs.acs.org on May 19, 2017
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Copper-Catalyzed
Selective
N-Vinylation
of
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3-(Hydroxyimino)indolin-2-ones with Alkenyl Boronic Acids:
Synthesis of N-Vinyl Nitrones and Spirooxindoles
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ChunꢀHua Chen†, QingꢀQing Liu†, XiaoꢀPan Ma, Yu Feng, Cui Liang, ChengꢀXue
Pan, GuiꢀFa Su*, and DongꢀLiang Mo*
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, Ministry of Science and Technology of China; School of Chemistry &
Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin
541004, China
R1
O
(HO)2B
R1
N
2
N
R2
OH
O
R
O
N
R1
R2
R2
heat
R
O
R
1
N
10% Cu(OAc)2
in air
selective N-vinylation
N
O
N
H
H
H
33 examples
29-98% yields
only E-isomer
dr up to 20:1
8 examples
32-80% yields
ABSTRACT:
A
copperꢀcatalyzed selective crossꢀcoupling reaction of
3ꢀ(hydroxyimino)indolinꢀ2ꢀones with alkenyl boronic acids to access (E)ꢀNꢀvinyl
oxindole nitrones has been achieved under mild conditions. The studies showed that
catalytic copper salt selectively gave mono Nꢀvinylation products while 2.0 equiv of
copper salt provided double Nꢀvinylation products. The control experiments revealed
that the carbonyl group in 3ꢀ(hydroxyimino)indolinꢀ2ꢀone played important roles on
Nꢀvinylation. Furthermore, the prepared Nꢀvinyl oxindole nitrones could be converted
to spirooxindoles in good yields under thermal conditions.
Nitrones are a versatile and important type of compounds and can undergo a variety
of reactions.1 Recently, Nꢀvinyl nitrones have attracted much attentions as useful
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synthetic intermediates and showed distinctive characteristics because of the rich
chemistry of the double bond.2 Despite many strategies have been developed to
synthesize Nꢀaryl or Nꢀalkyl nitrones, methods to access Nꢀvinyl nitrones are sparsely
reported.3 In 2006, Denmark and Montgomery reported the first general and practical
method to prepare Nꢀvinyl nitrones from nitroalkenes and aldehydes in four steps
involving 1,4ꢀaddition, reduction, condensation and oxidation (Scheme 1ꢀA).4 In 2015,
Sammakia and coꢀworkers developed an efficient condensation of an αꢀchloroaldhyde
or an αꢀacetoxy ketone with a substituted benzyl hydroxylamine and sequence of
1,4ꢀconjugation elimination in the presence of a base to provide various Nꢀvinyl
nitrones in two steps (Scheme 1ꢀB).5 Although Denmark and Sammakia
independently developed an efficient and general method to afford Nꢀvinyl nitrones,
their methods suffered from some drawbacks, such as multiꢀstep synthesis,
nonꢀcommercial starting materials, and functional groups tolerance. To develop a
more facile method from readily available starting materials, Anderson’s group
recently reported a copperꢀmediated Nꢀvinylation of 9ꢀfluorenone oximes with alkenyl
boronic acids to prepare Nꢀvinyl nitrones in good yields (Scheme 1ꢀC).6 The prepared
Nꢀvinyl nitrones underwent a rearrangement to provide spiroisoxazoles under thermal
conditions. In 2015, Anderson and coꢀworkers continued to report a similar
Nꢀvinylation of chalcone oximes to access corresponding Nꢀvinyl nitrones.7
Anderson’s Nꢀvinylation route is indeed short and efficient. Despite only fluorenone
oximes and chalcone oximes are used, it is the most direct strategy to prepare Nꢀvinyl
nitrones up to now. Therefore, Nꢀvinylation of oximes via the Chan–Lam reaction is
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still desirable.8 In particular, it is more challenging for the controllable selectivity of
coupling reaction of oxime substrates with additional NꢀH or OꢀH groups to
synthesize Nꢀvinyl nitrones. This could improve the efficiency in synthesis of
complex molecules and avoid protection and deprotection procedures.9
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During studies on synthesis of nitrones in our group,10 we hypothesized that a
selective N2ꢀvinylation of 3ꢀ(hydroxyimino)indolinꢀ2ꢀone containing both NꢀH and
OꢀH groups with alkenyl boronic acids would directly afford Nꢀvinyl oxindole
nitrones via the ChanꢀLam reaction (Scheme 1ꢀD). Oxindole nitrones have been
extensively utilized in cycloaddition reactions because of its facile access to
privileged spirooxindoles.11 Herein, we reported a copperꢀcatalyzed selective
Nꢀvinylation of 3ꢀ(hydroxyimino)indolinꢀ2ꢀone with alkenyl boronic acids to
synthesize various (Z)ꢀNꢀvinyl nitrones and sequence of rearragement to afford
spirooxindoleꢀisoxazolines.
A) Denmark and co-workers, synthesis of N-vinyl nitrone in four steps
R3
R3
NO2
NO2
1) Al-Hg
O
m-CPBA
PhSeH
O
N
SePh
N
R1
R1
2) R3CHO
R1
SePh
R2
R2
R1
R2
R2
6 examples
B) Sammakia and co-workers, 1,4-conjugation elimination to synthesize N-vinyl nitrones
OH
R
HN
R
LG
R
LG
O
O
Ar
t-BuOK
O
(H)Me
N
(H)Me
N
(H)Me
THF, -78 °C
H
H
Ar
Ar
60-94% yields
12 examples
LG = X, OR'
C) Anderson and co-workers, copper-mediated N-vinylation of fluorenone oxime
(HO)2B
R1
N
OH
N
R1
R1
R2
O
O
R2
N
Cu(OAc)2 (2.0 equiv)
R2
DCE, rt, air
53-85% yields
16 examples
49-81% yields
10 examples
D) This work, copper-catalyzed selective N-vinylation of isatin oximes
R1
(HO)2B
R1
O
2
OH
O
N
N
R1
R2
R
O
R2
N
R2
R
1
R
O
10% Cu(OAc)2
MeOH
N
N
O
N
H
H
H
selective N-vinylation
dr up to 20:1
in air
only E - nitrone
Scheme 1 An Overview of Synthesis of NꢀVinyl Nitrones
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Initially, the Nꢀvinylation was screened by using 3ꢀ(hydroxyimino)indolinꢀ2ꢀone 1a
and alkenyl boronic acid 2a. No reaction occurred for 24 h in 1,2ꢀdichloroethane
(DCE) when CuCl2 or Cu(OTf)2 was used as catalyst in the presence of pyridine (pyr)
with Na2SO4 as an additive (Table 1, entries 1ꢀ2). To our delight, Nꢀvinyl nitrone 3aa
was isolated in good yield as a major isomer accompanied with nitrone 4aa as a minor
isomer when CuCl or Cu(OAc)2 was used (Table 1, entries 3ꢀ4). Compounds 3aa and
4aa were easily separated by flash chromatography. The structure of nitrone 3 was
further confirmed by the Xꢀray diffraction analysis of nitrone 3ca in Table 2, which
indicates the C=N bond of nitrone 3 is a E–configuration.12 Actually, the yield of 3aa
was a little bit lower without addition of Na2SO4 (Table 1, entry 5). A screen of
solvents revealed that MeOH sharply promoted the formation of 3aa and gave the
best result (Table 1, entries 6ꢀ10). The MeOH perhaps affected the pKa value of NꢀH
group and the nucleophilicity of nitrogen in oxindole so that mono Nꢀvinylation
product was observed as a major isomer. Product 3aa was obtained in 93% yield
when alkenyl boronic acid 2a was decreased to 2.0 equiv (Table 1, entry 11). The base
affected the reaction obviously (Table 1, entries 12ꢀ15). The yield of 3aa was only
afforded in 8% using NEt3 while 57% yield of 3aa was obtained by using Cs2CO3.
The addition of tꢀBuOK or without base inhibited the reaction competely. The yield of
3aa was improved to 95% when the reaction ran at 40 °C, however, decreased yield of
3aa was observed by higher temperature (Table 1, entries 16ꢀ17). The amount of
copper salt played important roles on the yield of 3aa and 4aa (Table 1, entries 18ꢀ19).
Increasing the amount of Cu(OAc)2 decreased the yield of 3aa but improved the yield
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of 4aa (Table 1, entries 11 vs 18ꢀ19). The similar result was also observed in DCE
(Table 1, entries 21ꢀ22). In particular, nitrone 4aa was afforded in 77% yield
accompanied with 3aa in 17% yield in DCE under 2.0 equiv of Cu(OAc)2 with 4.0
equiv of 2a (Table 1, entry 22). But the yield of 4aa was reduced with increasing
temperature (Table 1, entry 23). These results disclosed that Nꢀvinylation process was
controlled by the amount of copper catalyst.
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Table 1. Optimization of the reaction conditionsa,b
O
O
OH
O
N
N
N
n-Bu
n-Bu
(HO)2B
Cu salts, base
Na2SO4, rt, air
+
+
O
O
n-Bu
N
N
N
2a
H
H
1a
n-Bu
3aa
4aa
entry
Cu salt
amount
of Cu
solvent
base
3aa%
4aa%
1
2
3
4
5c
6
7
8
9
CuCl2
10%
10%
10%
DCE
pyr
pyr
pyr
pyr
pyr
pyr
pyr
pyr
pyr
ꢀ
ꢀ
Cu(OTf)2
CuCl
DCE
ꢀ
ꢀ
DCE
73
74
65
75
73
68
65
15
11
6
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
DCE
DCE
toluene
MeCN
DMF
DMSO
6
3
6
8
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Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 10%
Cu(OAc)2 50%
Cu(OAc)2 200%
Cu(OAc)2 200%
Cu(OAc)2 200%
Cu(OAc)2 50%
Cu(OAc)2 200%
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCE
pyr
89
93
8
4
11d
12d
13d
14d
15d
16d,e
17d,f
18d
19d
20d
21g
22g
23e,g
pyr
4
NEt3
tꢀBuOK
Cs2CO3
ꢀ
ꢀ
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ꢀ
ꢀ
57
ꢀ
ꢀ
ꢀ
pyr
95
77
72
44
23
17
47
46
2
pyr
8
pyr
26
54
62
77
43
52
pyr
pyr
DCE
pyr
DCE
pyr
DCE
pyr
aReaction conditions: 1a (0.3 mmol), 2a (0.9 mmol, 3.0 equiv), Cu salts (10 % mmol),
b
base (3.0 equiv), Na2SO4 (6.0 equiv), solvent (3 mL), 25 °C, 2−24 h; Isolated yield;
cwithout Na2SO4; 2a (0.6 mmol, 2.0 equiv) was used; ran at 40 °C; ran at 80 °C;
d
e
f
g2a (1.2 mmol, 4.0 equiv) was used.
To test the scope of formation of Nꢀvinyl nitrone 3, several
3ꢀ(hydroxyimino)indolinꢀ2ꢀones (1a-l) and alkenyl boronic acids (2a-p) were
screened under copperꢀcatalyzed conditions identified in Table 1, entry 11. As shown
in Table 2, various linear and cyclic alkenyl boronic acids were efficiently converted
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into the corresponding Nꢀvinyl oxindole nitrones 3 in good to excellent yields.
Monosubstituted alkenyl boronic acids provided better yields than linear disubstituted
alkenyl boronic acids (3aaꢀag vs 3ahꢀak). However, linear disubstituted alkenyl
boronic acids afforded both isomers of nitrone 3 (3ahꢀak).13 The isomers of nitrone
3ah-ak were the E/Z configuration of the C=C bond, which were derived from the
alkenyl boronic acids. This showed that both E and Z configuration of alkenyl boronic
acids could be coupled to provide Nꢀvinyl nitrones. Cyclic alkenyl boronic acids gave
moderate yields and tolerated five, six, and sevenꢀmembered rings while cyclohexenyl
boronic acid 2m afforded nitrone 3am in 98% yield (3alꢀap). The substituted groups
on the aryl ring of 3ꢀ(hydroxyimino)indolinꢀ2ꢀones were also examined under the
copperꢀcatalyzed conditions. The coupling reaction was compatible with the 5, 6,
7ꢀpositions in the aryl ring of the oximes (3baꢀia). Electronꢀdonating and
electronꢀwithdrawing groups at the 5ꢀposition did not affect the yields of Nꢀvinyl
oxindole nitrones except for 5ꢀNO2 group giving 34% yield (3baꢀfa). When 6ꢀBr
substituted oxime 1g was used, nitrone 3ga was obtained in 29% yield perhaps owing
to the solubility of the oxime in MeOH.14 The coupling reaction did not occur when
the oxime 1j with a 4ꢀbromo group because of the steric hindrance (3ja). When
methylꢀ and phenylꢀprotected oximes 1k and 1l were used, nitrone 3ka and 3la were
afforded in 54% and 84% yields, respectively. In all cases, the Nꢀvinyl nitrone 3 was
obtained as a major isomer while Nꢀvinyl nitrone 4 was always observed in less than 8%
yield. Some sensitive functional groups such as halides, ester, and nitro groups were
compatible, which enables further transformations.
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Table 2. The Scope of Preparing NꢀVinyl Nitrone 3a,b
5
6
7
8
R1
O
O
OH
N
N
R2
(HO)2B
Cu(OAc)2 (10 mmol%)
O
R
+
R
R1
R2
pyr, Na2SO4
N
H
N
H
MeOH, rt, in air
9
1
2
3
R1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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29
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R2 = n-Bu,
R2 = n-Pr,
(93%)
O
3aa
N
R2
O
3ab (79%)
R2 = (CH2)3CO2Me, 3ac (88%)
N
R2
R2 = (CH2)4Cl,
R2 = Ph,
R2 = p-MeOC6H4,
R2 = p-FC6H4,
(76%)
O
3ad
N
O
3ae (85%)
H
N
c
c
R1, R2 = Me,
(64%, 1:0.8)
3ah
3af
(97%)
H
R1 = Ph, R2 = H,
3ai (72%, 20:1)c
3ag (48%)
R1 = Ph, R2 = Et, 3aj (72%, 10:1)c
R1 = Ph, R2 = n-Bu,
(75%, 10:1)
3ak
O
N
O
N
O
O
N
n
O
O
N
O
H
N
H
N
H
n=1, 3al (76%)
n=2, 3am (98%)
3ao (78%)
3ap (58%)
3an
n=3,
(54%)
R = 5-MeO, 3ba (78%)
O
N
3ca
3da
3ea
R = 5-CF3O,
R = 5-Me,
R = 5-F,
(72%)
(78%)
(75%)
n-Bu
O
N
n-Bu
4
7
O
N
5
R
R = 5-NO2, 3fa (34%)
= 6-Br 3ga (29%)
R = 7-F,
O
R
R3
N
H
6
3ha
(77%)
3ia
(88%)
3ja
(<5%)
R3 = Me, 3ka (54%)
R = 7-CF3
R = 4-Br,
,
R3 = Ph,
(84%)
3la
aReaction conditions: 1 (0.3 mmol), alkenyl boronic acid 2 (0.6 mmol, 2.0 equiv),
Cu(OAc)2 (0.03 mmol, 10 %), pyr (0.9 mmol, 3.0 equiv), Na2SO4 (6.0 equiv), MeOH
(3 mL), 25 °C, 2−24 h; bIsolated yield; cE/Z ratio for C=C bond in nitrone.
The scope of double Nꢀvinylation of oxime 1 to prepare Nꢀvinyl nitrone 4 was
further evaluated under the copperꢀmediated conditions identified in Table 1, entry 21.
The reaction tolerated
a
variety of alkenyl boronic acids
2
and
3ꢀ(hydroxyimino)indolinꢀ2ꢀones 1 (Table 3). Linear and cyclic alkenyl boronic acids
gave the corresponding nitrone 4 in good to excellent yields. Compared to formation
of nitrone 3ah, when 2ꢀbutenyl boronic acid 2h with a 2:1 E/Z ratio was used, nitrone
4ah was afforded with a 1:0.5 E/Z ratio at the C=C bond. Most of
3ꢀ(hydroxyimino)indolinꢀ2ꢀones
bearing
either
electronꢀdonating
or
electronꢀwithdrawing groups in the 5, 6, 7–positions could provide corresponding
nitrone 4 in good to excellent yields.
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Table 3. The Scope of Preparing NꢀVinyl Nitrone 4a,b
5
6
7
8
R1
O
O
N
R2
OH
N
(HO)2B
Cu(OAc)2 (2.0 equiv)
R
O
+
R
N
R1
R2
pyr, Na2SO4
DCE, rt, in air
N
H
9
R1
R2
1
2
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
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42
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46
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48
49
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O
Me
Me
O
O
O
N
N
n-Bu
N
O
O
N
N
N
Me
n-Bu
(77%)
Me
c
4ah
4aa
(60%, 1:0.5)
4an
(77%)
O
N
4ba
R = 5-MeO,
(61%)
n-Bu
4
5
R
R = 5-Me, 4da (72%)
R = 5-F, 4ea (86%)
R = 5-NO2, 4fa (58%)
O
N
6
7
4ga
4ha
R = 6-Br,
R = 7-F,
(85%)
(90%)
n-Bu
aReaction conditions: 1 (0.3 mmol), alkenyl boronic acid 2 (1.2 mmol, 4.0 equiv),
Cu(OAc)2 (0.6 mmol, 2.0 equiv), pyr (0.9 mmol, 3.0 equiv), Na2SO4 (6.0 equiv), DCE
(3 mL), 25 °C, 2−24 h; bIsolated yield; cE/Z ratio of C=C bond in nitrone.
Treatment of nitrone 3aa with alkenyl boronic acid 2a under copperꢀmediated
conditions, nitrone 4aa was isolated in 90% yield (Scheme 2ꢀ1). To study the effect
on formation of Nꢀvinyl nitrones from oxime structure, we performed the control
experiments. While methyl protected oxime 1m reacted with 2a, N1ꢀvinylation
product 3ma was afforded in 88% yield (Scheme 2ꢀ2). To our surprise, the oxime 1m
and alkenyl boronic acid 2a were subjected to the optimal conditions, Oꢀ or
N1ꢀvinylation product 3na and 3na’ were observed in 72% yield (Scheme 2ꢀ3). These
results suggested that the carbonyl group in oxime 1 mainly controlled the formation
of nitrones 3 or 4 because it decreased the nucleophilicity of the Nꢀatom.
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O
(HO)2B
N
O
n-Bu
n-Bu
N
2a
n-Bu
O
Cu(OAc)2, pyr
O
1)
2)
3)
N
Na2SO4, DCE, rt, air
90% yield
N
H
n-Bu
3aa
4aa
OMe
N
OMe
N
Cu(OAc)2 (2.0 equiv), pyr
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O
2a
+
O
Na2SO4, DCE, rt, air
88% yield
N
N
H
1m
3ma
n-Bu
OH
N
OH
O
N
N
2a
n-Bu
Me
Me
Me
N
Cu(OAc)2, pyr
Na2SO4, DCE, rt, air
N
N
H
3na
H
1n
3na'
n-Bu
72% yield (3na/3na'=1.2:1)
Scheme 2. The Structural Effect on NꢀVinylation of Oximes
With the two types of Nꢀvinyl nitrones 3 and 4 in hand, we explored their thermal
rearrangements. As shown in Table 4, both nitrones 3 and 4 could be smoothly
converted to corresponding spirooxindole product 5 and 6 in moderate to good yields
in toluene at 120−140 °C. Both disubstituted linear and cyclic Nꢀvinyl nitrones were
compatible for this thermal transformation, while monosubstituted Nꢀvinyl nitrone
such as 3aa-ag in Table 2 decomposed. The disubstituted linear Nꢀvinyl nitrones
required shorter reaction time and provided better yields than cyclic Nꢀvinyl nitrones
(5ah, 5ai, 5aj vs 5am, 5an, 5ap). As expected based on Anderson’s mechanism,6 the
diastereoselectivity of spirooxindoles correlates with the E/Zꢀisomer ratio at C=C
bond in the Nꢀvinyl nitrones. When nitrone 3ah with a 1:0.8 E/Z ratio was heated at
120 °C, a 1:0.8 dr value of spirooxindole 5ah was obtained. Spirooxindole 5aj was
afforded in 10:1 dr by heating nitrone 3aj with 10:1 E/Z ratio at C=C bond. When
nitrone 3am and 3an with a 20:1 E/Z ratio were subjected to the optimal condtions,
the spirooxindole 5am and 5an were furnished with 20:1 dr value. The relative
configuration of the spirooxindole was determined by NOESY spectra of 5aj and 5am,
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which revealed that the proton connected with ethyl group in 5aj or with
sixꢀmembered ring in 5am both had correlation with the proton of the aryl ring.15
Since spirooxindoles and isoxazoles have been identified as bioactive compounds,
this strategy to access these compounds might lead to expand more applications in
pharmaceuticals.16
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Table 4. Thermal Reaction to Form Spirooxindole 5 or 6a,b
R1
O
N
O
R1
R2
O
N
R2
toluene
O
N
R3
120-140 °C
N
R3
3 / 4
5 / 6
NOE
N
NOE
H
H
N
O
N
N
O
O
O
O
O
Me
Ph
Ph
H
H
Me
Et
N
N
N
O
N
O
H
H
H
H
5ah, 74%, 1:0.8c
5aj, 57%, 10:1c
5am, 32%, 20:1c
5ai, 80%
N
O
N
O
Me
N
O
N
O
Me
N
N
O
O
t-Bu
N
N
O
O
H
Me
H
Me
5an, 53%, 20:1c
5ap, 40%, 1:1c
6ah, 75%, 1:0.5c
6am, 50%, 20:1c
aReaction conditions: 3 or 4 (0.2 mmol), toluene (2 mL), 120−140 °C, 10−48 h;
bIsolated yield; cdr value.
In summary, We have developed a copperꢀcatalyzed Nꢀvinylation of
3ꢀ(hydroxyimino)indolinꢀ2ꢀones with alkenyl boronic acids to prepare (E)ꢀNꢀvinyl
oxindole nitrones in good to excellent yields. The reaction tolerated linear and cyclic
alkenyl boronic acids with various functional groups. The Nꢀvinyl nitrones could
undergo a thermal rearrangement to access various spirooxindoles in good yields and
high diastereoselectivity. This coupling strategy provided not only a facile method to
prepare Nꢀvinyl nitrones but also a good entry for spirooxindoles to be further studied
in pharmaceuticals.
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EXPERIMENTAL SECTION
5
6
7
8
9
General Methods. All reactions were performed under an air atmosphere.
Commercially available reagents were used without further purification. The NMR
spectra were recorded in CDCl3 or DMSOꢀd6 on 400, or 500 MHz instrument with
TMS as the internal standard. NMR data are represented as follows: chemical shift
(ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constants in hertz (Hz), and integration. IR spectra were recorded on FTꢀIR
spectrometer, and only major peaks are reported in cm‒1. HRMS were measured in
ESI mode and the mass analyzer of the HRMS was TOF. Flash column
chromatography was performed on silica gel (300ꢀ400 mesh). The oxime 1a17, 1b18,
1c10b, 1d17, 1e17, 1f,19 1g17, 1h20, 1i21, 1j22, 1k23, 1l24, 1m25, and 1n26, the alkenyl
boronic acid 2a-p6,7 were prepared according to literature methods and their spectral
data matched literature values.
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General procedure for preparing N-vinyl nitrone 3: In a 25 mL flask was
charged with 3ꢀ(hydroxyimino)indolinꢀ2ꢀone 1 (0.3 mmol), alkenyl boronic acid 2
(0.6 mmol, 2.0 equiv), Cu(OAc)2 (0.03 mmol, 10%) and anhydrous Na2SO4 (6.0
equiv) under air atmosphere. Then, MeOH (3.0 mL) and pyridine (0.9 mmol, 3.0
equiv) was added via syringe. The reaction flask was then capped with a septum
pierced with a ventilation needle and stirred vigorously at 25 °C for 2−24 h until the
oxime 1 disappeared (monitored by TLC). At this time, the reaction was quenched by
H2O (10 mL) and extracted with DCM (3 × 10 mL). Then, dried over with Na2SO4
and filtered. The solvent was removed under reduced pressure and the crude product
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was purified by flash chromatography (the crude residue was dry loaded on silica gel,
1/10 to 1/6, ethyl acetate/petroleum ether) to provide Nꢀvinyl nitrone 3.
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(1E,NE)-N-(2-Oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3aa), 0.068 g, 93%
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yield, orange solid. mp: 170−171 °C; H NMR (400 MHz, DMSO–d6): δ 10.94 (s,
1H), 8.79 (d, J = 13.2 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.04
(t, J = 7.6 Hz, 1H), 6.96−6.86 (m, 2H), 2.30 (q, J = 7.2 Hz, 2H), 1.47−1.41 (m, 2H),
1.37−1.30 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO–d6): δ
161.8, 140.9, 134.7, 132.8, 132.6, 132.5, 125.3, 122.6, 119.0, 110.4, 30.7, 29.0, 22.3,
14.2; IR (thin film) 3452, 3174, 2926, 1683, 1525, 1459, 1213, 771 cm−1; HRMS (ESI)
m/z calcd for C14H17N2O2 (M+H)+ 245.1290, found 245.1312.
(1E,NE)-N-(2-Oxoindolin-3-ylidene)pent-1-en-1-amine oxide (3ab), 0.055 g, 79%
1
yield, orange solid. mp: 173−174 °C; H NMR (400 MHz, DMSO–d6): δ 10.95 (s,
1H), 8.82 (d, J = 13.2 Hz, 1H), 8.25 (d, J = 13.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H),
7.06 (t, J = 7.6 Hz, 1H), 6.98−6.88 (m, 2H), 2.30 (q, J = 7.6 Hz, 2H), 1.55−1.46 (m, 2
13
H), 0.96 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, DMSO–d6): δ 161.7, 140.8, 134.4,
132.8, 132.6, 132.4, 125.2, 122.5, 118.9, 110.3, 31.2, 21.8, 14.0; IR (thin film) 3396,
3178, 2960, 1714, 1532, 1460, 1205, 657 cm−1; HRMS (ESI) m/z calcd for
C13H15N2O2 (M+H)+ 231.1134, found 231.1128.
(1E,NE)-6-Methoxy-6-oxo-N-(2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide
1
(3ac), 0.076 g, 88% yield, orange solid. mp: 145−146 °C; H NMR (400 MHz,
DMSO–d6): δ 10.94 (s, 1H), 8.79 (d, J = 13.2 Hz, 1H), 8.23 (d, J = 7.2 Hz, 1H), 7.35
(t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.93−6.87 (m, 2H), 3.59 (s, 3H), 2.39 (t, J
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= 7.6 Hz, 2H), 2.33−2.28 (m, 2 H), 1.75 (t, J = 7.2 Hz, 2H); C NMR (100 MHz,
DMSO–d6): δ 173.5, 161.7, 140.9, 133.7, 133.1, 132.7, 132.6, 125.2, 122.5, 118.9,
110.4, 51.7, 33.1, 28.5, 23.9; IR (thin film) 3459, 3179, 2952, 1712, 1530, 1461, 1207,
655 cm−1; HRMS (ESI) m/z calcd for C15H17N2O4 (M+H)+ 289.1188, found 289.1181.
(1E,NE)-6-Chloro-N-(2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3ad),
0.063 g, 76% yield, orange solid. mp: 157−158 °C; 1H NMR (500 MHz, DMSO–d6):
δ 10.94 (s, 1H), 8.80 (d, J = 13.0 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.37 (t, J = 7.5 Hz,
1H), 7.04 (t, J = 7.5 Hz, 1H), 6.96−6.87 (m, 2H), 3.68 (t, J = 7.0 Hz, 2H), 2.34 (t, J =
7.0 Hz, 2H), 1.80 (q, J = 6.5 Hz, 2 H), 1.63 (q, J = 7.5 Hz, 2H); 13C NMR (125 MHz,
DMSO–d6): δ 161.7, 140.9, 134.2, 133.0, 132.7, 132.5, 125.2, 122.5, 118.9, 110.4,
45.5, 32.0, 28.4, 25.8; IR (thin film) 3398, 3161, 2929, 1713, 1533, 1460, 1208, 657
cm−1; HRMS (ESI) m/z calcd for C14H16ClN2O2 (M+H)+ 279.0900, found 279.0898.
(1E,NE)-N-(2-Oxoindolin-3-ylidene)-2-phenylethenamine oxide (3ae), 0.067 g,
85% yield, orange solid. mp: 212−213 °C; 1H NMR (400 MHz, DMSO–d6): δ 11.0 (s,
1H), 9.54 (d, J = 13.6 Hz, 1H), 8.28 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 13.6 Hz, 1H),
7.65 (d, J = 6.8 Hz, 2H), 7.48−7.42 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6
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Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H); C NMR (100 MHz, DMSO–d6): δ 161.9, 141.0,
133.6, 133.4, 132.9, 131.8, 131.2, 130.8, 129.7, 128.7, 125.4, 122.6, 119.1, 110.5; IR
(thin film) 3453, 3175, 2927, 1710, 1525, 1459, 1253, 657 cm−1; HRMS (ESI) m/z
calcd for C16H13N2O2(M+H)+ 265.0977, found 265.0971.
(1E,NE)-2-(4-Methoxyphenyl)-N-(2-oxoindolin-3-ylidene)ethenamine
oxide
1
(3af), 0.085 g, 97% yield, orange solid. mp: 207−208 °C; H NMR (500 MHz,
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DMSO–d6): δ 10.99 (s, 1H), 9.47 (d, J = 13.0 Hz, 1H), 8.28 (d, J = 7.5 Hz, 1H), 7.78
(d, J = 13.0 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 6.5 Hz, 3H), 6.90 (d, J = 6.5
Hz, 1H), 3.81 (s, 3H); 13C NMR (125 MHz, DMSO–d6): δ 161.9, 161.5, 140.7, 132.7,
132.5, 131.2, 130.5, 129.9, 125.8, 125.2, 122.5, 119.2, 115.3, 110.4, 55.9; IR (thin
film) 3398, 3161, 2929, 1713, 1533, 1460, 1208, 657 cm−1; HRMS (ESI) m/z calcd
for C17H15N2O3 (M+H)+ 295.1083, found 295.1082.
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(1E,NE)-2-(4-Methoxyphenyl)-N-(2-oxoindolin-3-ylidene)ethenamine
oxide
1
(3ag), 0.040 g, 48% yield, orange solid. mp: 131−132 °C; H NMR (500 MHz,
DMSO–d6): δ 11.04 (s, 1H), 9.50 (d, J = 13.5 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.83
(d, J = 13.5 Hz, 1H), 7.75−7.72 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 8.5 Hz,
2H), 7.08 (t, J = 8.0 Hz, 1H), 6.9 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz,
DMSO–d6): δ 164.9 ( d, J = 247.1 Hz), 161.9, 141.0, 133.5, 133.0, 131.7, 131.1 (d, J
= 60.5 Hz), 130.1, 130.0 (d, J = 29.0 Hz), 125.4, 122.7, 119.0, 116.9 (d, J = 21.9 Hz),
110.5; IR (thin film) 3430, 3200, 2926, 1705, 1508, 1457, 1231, 655 cm−1; HRMS
(ESI) m/z calcd for C16H12FN2O2 (M+H)+ 283.0883, found 283.0873.
N-(2-Oxoindolin-3-ylidene)but-2-en-2-amine oxide (3ah), E/Z = 1:0.8, 0.041 g,
1
64% yield, orange solid. mp: 128−129 °C; Eꢀisomer: H NMR (400 MHz, CDCl3): δ
10.77 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 8.0 Hz,
1H), 6.91 (d, J = 7.6 Hz, 1H), 5.75 (t, J = 6.4 Hz, 1H), 2.02 (s, 3H), 1.71 (d, J = 7.2
13
Hz, 3H); C NMR (100 MHz, CDCl3): δ 160.6, 143.0, 141.2, 134.0, 132.6, 124.5,
122.6, 122.4, 118.9, 110.4, 19.5, 13.0; Zꢀisomer: 1H NMR (400 MHz, CDCl3): δ 10.71
(s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H),
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6.88 (d, J = 8.0 Hz, 1H), 5.50 (t, J = 6.4 Hz, 1H), 1.99 (s, 3H), 1.43 (d, J = 6.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 160.1, 142.5, 141.0, 133.5, 132.3, 124.4, 122.2,
119.4, 118.2, 110.2, 14.3, 12.5; IR (thin film) 3453, 3074, 2927, 1697, 1518, 1461,
1217, 741 cm−1; HRMS (ESI) m/z calcd for C12H13N2O2 (M+H)+ 217.0977, found
217.0977.
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(2E,NE)-N-(2-Oxoindolin-3-ylidene)but-2-en-2-amine oxide (3ai), 0.057 g, 72%
1
yield, orange solid. mp: 143−144 °C; H NMR (400 MHz, DMSO–d6): δ 10.77 (s,
1H), 8.27 (d, J = 7.2 Hz, 1H), 7.46−7.38 (m, 6H), 7.09 (t, J = 7.6 Hz, 1H), 6.91 (d, J =
13
8.0 Hz, 1H), 6.04 (s, 1H), 5.60 (s, 1H); C NMR (100 MHz, DMSO–d6): δ 160.4,
151.6, 141.6, 135.3, 133.0, 132.8, 129.7, 129.4, 125.8, 124.9, 122.5, 118.5, 111.6,
110.6; IR (thin film) 3454, 3084, 2925, 1708, 1546, 1346, 1197, 696 cm−1; HRMS
(ESI) m/z calcd for C16H13N2O2 (M+H)+ 265.0977, found 265.0976.
(1E,NE)-N-(2-Oxoindolin-3-ylidene)-1-phenylbut-1-en-1-amine oxide (3aj),
0.063 g, 72% yield, orange oil. 1H NMR (500 MHz, DMSO–d6): δ 10.76 (s, 1H), 8.31
(d, J = 7.5 Hz, 1H), 7.43−7.30 (m, 6H), 7.10 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 8.0 Hz,
13
1H), 6.33 (t, J = 7.5 Hz, 1H), 2.10−2.00 (m, 2H), 1.01 (t, J = 3.0 Hz, 3H); C NMR
(125 MHz, DMSO–d6): δ 159.9, 144.9, 141.5, 135.5, 133.5, 133.0, 129.1, 128.7,
126.6, 125.0, 124.8, 122.5, 118.0, 110.5, 21.3, 13.5; IR (thin film) 3435, 3196, 2930,
1713, 1547, 1461, 1192, 697 cm−1; HRMS (ESI) m/z calcd for C18H17N2O2 (M+H)+
293.1290, found 293.1282.
(1E,NE)-N-(2-Oxoindolin-3-ylidene)-1-phenylhex-1-en-1-amine oxide (3ak),
0.072 g, 75% yield, orange oil. 1H NMR (400 MHz, DMSO–d6): δ 10.74 (s, 1H), 8.30
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(d, J = 7.2 Hz, 1H), 7.43−7.29 (m, 6H), 7.10 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.6 Hz,
1H), 6.33 (t, J = 7.6 Hz, 1H), 2.06−2.00 (m, 2H), 1.42−1.36 (m, 2H), 1.29−1.24 (m,
2H), 0.82 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, DMSO–d6): δ 159.9, 145.4, 141.5,
135.5, 133.6, 133.0, 129.2, 128.7, 125.4, 125.1, 124.8, 122.5, 118.0, 110.5, 30.6, 27.3,
22.2, 14.1; IR (thin film) 3252, 2928, 1716, 1617, 1546, 1459, 1196, 747 cm−1;
HRMS (ESI) m/z calcd for C20H21N2O2 (M+H)+ 321.1603, found 321.1595.
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(E)-N-(2-Oxoindolin-3-ylidene)cyclopent-1-enamine oxide (3al), 0.052 g, 76%
1
yield, orange solid. mp: 144−145 °C; H NMR (400 MHz, DMSO–d6): δ 10.76 (s,
1H), 8.19 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.89
(d, J = 8.0 Hz, 1H), 6.12−6.11 (m, 1H), 2.70−2.69 (m, 2H), 2.51−2.50 (m, 2H),
13
2.08−2.01 (m, 2H); C NMR (100 MHz, DMSO–d6): δ 160.4, 146.7, 141.0, 134.8,
132.6, 128.4, 124.5, 122.2, 118.8, 110.2, 31.8, 31.1, 22.4; IR (thin film) 3411, 3176,
2950, 1717, 1549, 1337, 1243, 688 cm−1; HRMS (ESI) m/z calcd for C13H13N2O2
(M+H)+ 229.0977, found 229.0972.
(E)-N-(2-Oxoindolin-3-ylidene)cyclohex-1-enamine oxide (3am), 0.071 g, 98%
1
yield, orange solid. mp: 186−187 °C; H NMR (400 MHz, DMSO–d6): δ 10.69 (s,
1H), 8.15 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.88
(d, J = 7.6 Hz, 1H), 5.95−5.91 (m, 1H), 2.35−2.28 (m, 2H), 2.14−2.13 (m, 2H),
1.77−1.74 (m, 2H), 1.62−1.59 (m, 2H); 13C NMR (100 MHz, DMSO–d6): δ 160.6,
144.9, 141.0, 133.7, 132.3, 124.5, 124.3, 122.1, 118.8, 110.2, 25.9, 24.1, 22.2, 21.2;
IR (thin film) 3452, 3174, 2927, 1683, 1526, 1459, 1214, 771 cm−1; HRMS (ESI) m/z
calcd for C14H15N2O2 (M+H)+ 243.1134, found 243.1131.
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(1E,NE)-N-(2-Oxoindolin-3-ylidene)cyclohept-1-enamine oxide (3an), 0.042 g,
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54% yield, orange solid. mp: 170−171 °C; H NMR (500 MHz, DMSO–d6): δ 10.67
8
9
(s, 1H), 8.13 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H),
6.87 (d, J = 7.5 Hz, 1H), 6.04 (t, J = 6.0 Hz, 1H), 2.48−2.45 (m, 2H), 2.21−2.19 (m,
2H), 1.73−1.71 (m, 4H), 1.64−1.63 (m, 2H); 13C NMR (125 MHz, DMSO–d6): δ
160.7, 148.8, 140.9, 133.3, 132.3, 129.0, 124.3, 122.2, 118.9, 110.2, 31.5, 30.7, 26.8,
26.2, 26.1; IR (thin film) 3456, 3194, 2926, 1621, 1463, 1341, 1193, 752 cm−1;
HRMS (ESI) m/z calcd for C15H17N2O2 (M+H)+ 257.1290, found 257.1285.
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(E)-N-(2-Oxoindolin-3-ylidene)-3,6-dihydro-2H-pyran-4-amine oxide (3ao),
0.057 g, 78% yield, orange solid. mp: 178−179 °C; 1H NMR (500 MHz, DMSO–d6):
δ 10.76 (s, 1H), 8.16 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.0 Hz,
1H), 6.88 (d, J = 8.0 Hz, 1H), 6.14−6.12 (m, 1H), 4.21−4.20 (m, 2H), 3.86 (t, J = 5.5
13
Hz, 2H), 2.44−2.43 (m, 2H); C NMR (125 MHz, DMSO–d6): δ 160.6, 141.5, 141.2,
134.1, 132.6, 124.4, 123.6, 122.2, 118.7, 110.2, 63.9, 63.7, 26.2; IR (thin film) 3450,
3194, 2923, 1705, 1539, 1459, 1121, 659 cm−1; HRMS (ESI) m/z calcd for
C13H13N2O3 (M+H)+ 245.0926, found 245.0920.
(E)-4-tert-Butyl-N-(2-oxoindolin-3-ylidene)cyclohex-1-enamine oxide (3ap),
0.052 g, 58% yield, orange solid. mp: 175−176 °C; 1H NMR (400 MHz, DMSO–d6):
δ 10.70 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.5 Hz,
1H), 6.88 (d, J = 8.0 Hz, 1H), 5.95−5.93 (m, 1H), 2.36−2.33 (m, 2H), 2.19−2.15 (m,
1H), 1.93−1.88 (m, 2H), 1.36−1.31 (m, 2H), 0.89 (s, 9H); 13C NMR (125 MHz,
DMSO–d6): δ 160.5, 144.7, 141.0, 133.8, 132.3, 124.7, 124.3, 122.2, 118.8, 110.2,
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42.9, 32.4, 30.3, 29.5, 27.5, 27.2, 25.8, 23.8; IR (thin film) 3433, 3194, 2964, 1650,
1463, 1341, 1193, 763 cm−1; HRMS (ESI) m/z calcd for C18H23N2O2 (M+H)+
299.1760, found 299.1759.
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(1E,NE)-N-(5-Methoxy-2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3ba),
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0.064 g, 78% yield, orange solid. mp: 170−171 °C; H NMR (400 MHz, CDCl3): δ
8.84 (d, J = 13.2 Hz, 1H), 8.49 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.13−7.06 (m, 1H),
6.92 (t, J = 8.4 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 3.83 (s, 3H), 2.37 (q, J = 7.2 Hz,
2H), 1.57−1.49 (m, 2H), 1.45−1.34 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 162.2, 155.9, 135.5, 132.8, 132.7, 132.6, 119.7, 118.8, 110.5, 110.3,
55.9, 30.7, 29.2, 22.2, 13.8; IR (thin film) 3453, 3193, 2927, 1713, 1526, 1488, 1247,
653 cm−1; HRMS (ESI) m/z calcd for C15H19N2O3 (M+H)+ 275.1396, found 275.1393.
(1E,NE)-N-(2-Oxo-5-(trifluoromethoxy)indolin-3-ylidene)hex-1-en-1-amine
oxide (3ca), 0.071 g, 72% yield, orange solid. mp: 171−172 °C; 1H NMR (400 MHz,
DMSO–d6): δ 11.12 (s, 1H), 8.76 (d, J = 13.2 Hz, 1H), 8.12 (s, 1H), 7.37(d, J = 8.4
Hz, 1H), 7.00−6.94 (m, 2H), 2.32 (q, J = 7.2 Hz, 2H), 1.49−1.42 (m, 2H), 1.38−1.29
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(m, 2H), 0.92 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, DMSO–d6): δ 161.6, 143.4,
139.8, 135.7, 132.7, 132.1, 125.4, 122.0 (d, J = 253.8 Hz), 119.8, 117.6, 112.2, 55.9,
30.5, 28.9, 22.1, 14.1; IR (thin film) 3452, 3174, 2933, 1701, 1517, 1466, 1164, 661
cm−1; HRMS (ESI) m/z calcd for C15H16F3N2O3 (M+H)+ 329.1113, found 329.1097.
(1E,NE)-N-(5-Methyl-2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3da).
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0.060 g, 78%, orange solid. mp: 179−180 °C; H NMR (400 MHz, DMSO–d6): δ
10.82 (s, 1H), 8.79 (d, J = 13.2 Hz, 1H), 8.06−8.05 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H),
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6.95−6.88 (m, 1H), 6.77 (d, J = 7.6 Hz, 1H), 2.30−2.27 (m, 5H), 1.49−1.41 (m, 2H),
1.38−1.31 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO–d6): δ
161.8, 138.6, 134.4, 133.0, 132.7, 132.5, 131.3, 125.6, 119.0, 110.1, 30.6, 28.9, 22.2,
21.2, 14.1; IR (thin film) 3453, 3170, 2927, 1698, 1516, 1481, 1259, 658 cm−1;
HRMS (ESI) m/z calcd for C15H19N2O2 (M+H)+ 259.1447, found 259.1445.
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(1E,NE)-N-(5-Fluoro-2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3ea),
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0.059 g, 75% yield, orange solid. mp: 178−179 °C; H NMR (500 MHz, CDCl3): δ
8.82 (d, J = 13.0 Hz, 1H), 8.25 (s, 1H), 8.17 (dd, J = 8.5, 2.0 Hz, 1H), 7.13−7.03 (m,
2H), 6.82 (t, J = 8.0 Hz, 1H), 2.37 (q, J = 7.0 Hz, 2H), 1.56−1.50 (m, 2H), 1.44−1.37
(m, 2H), 0.96 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 161.8, 160.0 (d, J =
238.8 Hz), 136.4, 134.7, 132.8, 131.9, 120.1 (d, J = 40 Hz), 118.2 (d, J = 98.5 Hz),
113.0 (d, J = 109 Hz), 110.1 (d, J = 33 Hz), 30.6, 29.2, 22.3, 13.8; IR (thin film) 3454,
3175, 2930, 1699, 1517, 1477, 1247, 658 cm−1; HRMS (ESI) m/z calcd for
C14H16FN2O2 (M+H)+ 263.1196, found 263.1198.
(1E,NE)-N-(5-Nitro-2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3fa), 0.030
1
g, 34% yield, yellow solid. mp: 64−65 °C; H NMR (400 MHz, DMSO–d6): δ 11.60
(s, 1H), 8.92 (s, 1H), 8.70 (d, J = 13.2 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.05−6.99 (m,
2H), 2.34 (q, J = 6.8 Hz, 2H), 1.49−1.44 (m, 2H), 1.38−1.32 (m, 2H), 0.93 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, DMSO–d6): δ 161.9, 146.0, 142.6, 136.6, 132.8, 131.5,
128.5, 119.7, 119.2, 110.5, 30.4, 29.0, 22.2, 14.2; IR (thin film) 3434, 2927, 1635,
1528, 1462, 1344, 1122, 747 cm−1; HRMS (ESI) m/z calcd for C14H16N3O4 (M+H)+
290.1141, found 290.1165.
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(1E,NE)-N-(6-Bromo-2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3ga),
0.028 g, 29% yield, yellow solid. mp: 184−185 °C; 1H NMR (400 MHz, DMSO–d6):
δ 11.07 (s, 1H), 8.73 (d, J = 13.2 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz,
1H), 7.02 (s, 1H), 6.98−6.91 (m, 1H), 2.30 (q, J = 6.8 Hz, 2H), 1.49−1.42 (m, 2H),
1.38−1.31 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO–d6): δ
161.5, 142.0, 135.2, 132.8, 131.9, 126.3, 125.2, 124.9, 118.2, 113.1, 30.5, 28.9, 22.2,
14.1; IR (thin film) 3453, 3172, 2927, 1692, 1521, 1443, 1213, 661 cm−1; HRMS (ESI)
m/z calcd for C14H14BrN2O2 (MꢀH)ꢀ 321.0239, found 321.0234.
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(1E,NE)-N-(7-Fluoro-2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3ha),
0.060 g, 77% yield, orange solid. mp: 183−184 °C; 1H NMR (400 MHz, DMSO–d6):
δ 11.47 (s, 1H), 8.79 (d, J = 13.2 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 9.6 Hz,
1H), 7.07 (t, J = 8.0 Hz, 1H), 6.98−6.94 (m, 1H), 2.32 (q, J = 7.2 Hz, 2H), 1.48−1.43
(m, 2H), 1.37−1.31 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
DMSO–d6): δ 161.5, 147.7 (d, J = 240.7 Hz), 135.5, 132.7, 132.2 (d, J = 5.1 Hz),
127.6 (d, J = 13.2 Hz), 123.4 (d, J = 5.7 Hz), 121.8 (d, J = 15.1 Hz), 121.2 (d, J = 2.9
Hz), 119.4 (d, J = 16.8 Hz), 30.6, 28.9, 22.2, 14.2; IR (thin film) 3454, 3219, 2928,
1716, 1525, 1354, 1190, 672 cm−1; HRMS (ESI) m/z calcd for C14H16FN2O2 (M+H)+
263.1196, found 263.1193
(1E,NE)-N-(2-Oxo-7-(trifluoromethyl)indolin-3-ylidene)hex-1-en-1-amine
1
oxide (3ia), 0.083 g, 88% yield, orange solid. mp: 157−158 °C; H NMR (400 MHz,
DMSO–d6): δ 11.39 (s, 1H), 8.79 (d, J = 13.2 Hz, 1H), 8.52 (d, J = 7.2 Hz, 1H), 7.64
(d, J = 7.2 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 6.96−6.95 (m, 1H), 2.32 (q, J = 6.8 Hz,
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2H), 1.49−1.46 (m, 2H), 1.38−1.34 (m, 2H), 0.92 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, DMSO–d6): δ 162.1, 137.6, 135.9, 132.9, 131.1, 128.3, 128.1 (d, J = 14.4 Hz),
125.1, 122.6, 120.7, 111.5 (d, J = 131.2 Hz), 30.5, 29.0, 22.2, 14.1; IR (thin film)
3454, 3170, 2927, 1695, 1528, 1435, 1120, 687 cm−1; HRMS (ESI) m/z calcd for
C15H16F3N2O2 (M+H)+ 313.1164, found 313.1186.
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(1E,NE)-N-(1-Methyl-2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide (3ka),
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0.042 g, 54% yield, orange solid. mp: 55−56 °C; H NMR (400 MHz, DMSO–d6): δ
8.80 (d, J = 13.2 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.08−7.02
(m, 2H), 6.96−6.90 (m, 1H), 3.17 (s, 3H), 2.30 (q, J = 6.8 Hz, 2H), 1.49−1.42 (m, 2H),
1.38−1.29 (m, 2H), 0.92 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, DMSO–d6): δ
160.2, 142.0, 134.9, 132.8, 132.4, 131.9, 124.8, 123.0, 118.1, 109.2, 30.5, 29.0, 26.5,
22.2, 14.2; IR (thin film) 3107, 2955, 2925, 1688, 1529, 1465, 1195, 750 cm−1;
HRMS (ESI) m/z calcd for C15H19N2O2 (M+H)+ 259.1447, found 259.1446.
(1E,NE)-N-(2-Oxo-1-phenylindolin-3-ylidene)hex-1-en-1-amine oxide (3la),
0.081 g, 84% yield, orange solid. mp: 120−121 °C; 1H NMR (400 MHz, DMSO–d6):
δ 8.84 (d, J = 13.2 Hz, 1H), 8.40 (d, J = 7.6 Hz, 1H), 7.61−7.57 (m, 2H), 7.51−7.48
(m, 3H), 7.41 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.04−6.97 (m, 1H), 6.77 (d,
J = 7.6 Hz, 1H), 2.33 (q, J = 6.8 Hz, 2H), 1.51−1.43 (m, 2H), 1.39−1.32 (m, 2H), 0.92
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(t, J = 7.6 Hz, 3H); C NMR (100 MHz, DMSO–d6): δ 159.9, 141.9, 135.3, 134.0,
132.9, 132.6, 131.8, 130.1, 128.9, 127.7, 125.1, 123.6, 118.4, 109.5, 30.5, 28.9, 22.1,
14.2; IR (thin film) 3454, 3097, 2926, 1692, 1496, 1457, 1189, 745 cm−1; HRMS (ESI)
m/z calcd for C20H21N2O2 (M+H)+ 321.1603, found 321.1596.
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General procedure for preparing N-vinyl nitrone 4，3m and 3n: In a 25 mL
flask was charged with indolineꢀ2,3ꢀdione oxime 1 (0.3 mmol), alkenyl boronic acid 2
(1.2 mmol, 4.0 equiv), Cu(OAc)2 (0.6 mmol, 2.0 equiv) and anhydrous Na2SO4 (6.0
equiv) under air atmosphere. Then, DCE (3.0 mL) and pyridine (0.9 mmol, 3.0 equiv)
was added via syringe. The reaction flask was then capped with a septum pierced with
a ventilation needle and stirred vigorously at 25 °C for 2−24 h until the oxime 1
disappeared (monitored by TLC). At this time, the reaction was quenched by H2O (10
mL) and extracted with DCM (3 × 10 mL). Then, dried over with Na2SO4 and filtered.
The solvent was removed under reduced pressure and the crude product was purified
by flash chromatography (the crude residue was dry loaded on silica gel, 1/50 to 1/20,
ethyl acetate/petroleum ether) to provide nitrone 4.
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(1E,NE)-N-(1-((E)-Hex-1-enyl)-2-oxoindolin-3-ylidene)hex-1-en-1-amine oxide
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(4aa), 0.075 g, 77% yield, brown liquid. H NMR (400 MHz, CDCl3): δ 8.82 (d, J =
7.2 Hz, 1H), 8.40 (d, J = 6.0 Hz, 1H), 7.30 (t, J = 6.4 Hz, 1H), 7.06−6.97 (m, 3H),
6.37 (d, J = 7.6 Hz, 1H), 6.19−6.13 (m, 1H), 2.28 (q, J = 5.6 Hz, 2H), 2.18 (q, J = 5.6
Hz, 2H), 1.48−1.36 (m, 4H), 1.35−1.28 (m, 4H), 0.88−0.80 (m, 6H); 13C NMR (100
MHz, CDCl3): δ 159.5, 140.0, 135.5, 132.8, 131.6, 131.5, 125.6, 125.2, 123.5, 119.6,
118.6, 109.0, 31.6, 30.6, 30.5, 29.2, 22.2, 22.1, 13.9, 13.8; IR (thin film) 3091, 2953,
1695, 1602, 1527, 1462, 1183, 743 cm−1; HRMS (ESI) m/z calcd for C20H27N2O2
(M+H)+ 327.2073, found 327.2095.
(2E,NE)-N-(1-((E)-But-2-en-2-yl)-2-oxoindolin-3-ylidene)but-2-en-2-amine
oxide (4ah), E / Z = 1:0.5, 0.049 g, 60% yield, brown liquid. Eꢀisomer: 1H NMR (400
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MHz, CDCl3): δ 8.36 (d, J = 7.0 Hz, 1H), 7.30 (d, J = 11.0 Hz, 1H), 7.04 (d, J = 8.0
Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.71 (q, J = 6.5 Hz, 1H), 5.62−5.61 (m, 1H), 2.08 (s,
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MHz, CDCl3): δ 158.8, 143.2, 141.7, 133.6, 131.7, 128.9, 126.5, 125.0, 123.1, 122.8,
118.1, 109.0, 29.6, 14.6, 13.0, 12.7; Zꢀisomer: 1H NMR (400 MHz, CDCl3): δ 8.31 (d,
J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.04 (q, J = 7.2 Hz, 1H), 6.77 (d, J = 6.4 Hz,
1H), 5.62−5.61 (m, 1H), 5.43−5.41 (m, 1H), 2.05 (s, 3H), 1.89 (s, 3H), 1.73 (d, J =
13
4.8 Hz, 5H), 1.51 (d, J = 6.5 Hz, 1H); C NMR (125 MHz, CDCl3): δ 158.2, 142.7,
141.5, 133.1, 131.6, 128.9, 126.2, 124.9, 122.8, 119.9, 117.6, 108.9, 19.4, 14.1, 13.0,
12.3; IR (thin film) 2922, 2859, 1710, 1604, 1541, 1460, 1185, 748 cm−1; HRMS (ESI)
m/z calcd for C16H19N2O2 (M+H)+ 271.1447, found 271.1445.
(E)-N-(1-Cyclohexenyl-2-oxoindolin-3-ylidene)cyclohex-1-enamine oxide (4an),
0.074 g, 77% yield, brown liquid. 1H NMR (500 MHz, DMSO–d6): δ 8.22 (d, J = 7.5
Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H),
5.94−5.93 (m, 1H), 5.86−5.85 (m, 1H), 2.31−2.30 (m, 2H), 2.20−2.14 (m, 6H),
1.75−1.74 (m, 4H), 1.64−1.61 (m, 4H); 13C NMR (125 MHz, DMSO–d6): δ 158.3,
145.0, 141.7, 132.9, 132.2, 131.8, 128.6, 124.6, 124.2, 122.8, 118.1, 109.4, 26.5, 25.9,
24.7, 24.1, 22.6, 22.2, 21.7, 21.2; IR (thin film) 3055, 2933, 1709, 1603, 1460, 1375,
1189, 747 cm−1; HRMS (ESI) m/z calcd for C20H23N2O2 (M+H)+ 323.1760, found
323.1760.
(1E,NE)-N-(1-((E)-Hex-1-enyl)-5-methoxy-2-oxoindolin-3-ylidene)hex-1-en-1-a
mine oxide (4ba), 0.066 g, 61% yield, brown liquid. 1H NMR (400 MHz, DMSO–d6):
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δ 8.83 (d, J = 13.2 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.04−6.97 (m, 1H), 6.91−6.82
(m, 2H), 6.40−6.36 (m, 1H), 6.14−6.07 (m, 1H), 3.75 (s, 3H), 2.28 (q, J = 6.8 Hz, 2H),
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2.17 (q, J = 6.8 Hz, 2H), 1.47−1.27 (m, 8H), 0.88 (dt, J = 6.8 Hz, 1.2 Hz, 6H); C
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NMR (100 MHz, DMSO–d6): δ 159.4, 156.2, 135.5, 134.0, 132.9, 131.9, 124.0, 119.8,
119.3, 118.1, 110.4, 109.9, 55.8, 31.7, 30.6, 30.5, 29.2, 22.2, 22.1, 13.8, 13.7; IR (thin
film) 3095, 2958, 1694, 1648, 1529, 1482, 1272, 717 cm−1; HRMS (ESI) m/z calcd
for C21H29N2O3 (M+H)+ 357.2178, found 357.2179.
(1E,NE)-N-(1-((E)-Hex-1-enyl)-5-methyl-2-oxoindolin-3-ylidene)hex-1-en-1-am
ine oxide (4da), 0.074 g, 72% yield, brown liquid. 1H NMR (400 MHz, DMSO–d6): δ
8.81 (d, J = 13.2 Hz, 1H), 8.23 (s, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.02−6.97 (m, 1H),
6.86 (d, J = 7.5 Hz, 1H), 6.38 (d, J = 14.5 Hz, 1H), 6.15−6.09 (m, 1H), 2.27−2.23 (m,
5H), 2.16−2.12 (q, J = 5.6 Hz, 2H), 1.48−1.35 (m, 4H), 1.34−1.28 (m, 4H), 0.88 (dt, J
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= 7.5 Hz, 2.5 Hz, 6H); C NMR (100 MHz, DMSO–d6): δ 159.5, 137.9, 135.2, 133.1,
132.8, 132.0, 131.7, 126.1, 124.3, 119.7, 118.6, 108.8, 31.6, 30.6, 30.5, 29.2, 22.2,
22.1, 21.0, 13.8, 13.7; IR (thin film) 3094, 2957, 1696, 1646, 1528, 1461, 1185, 727
cm−1; HRMS (ESI) m/z calcd for C21H29N2O2 (M+H)+ 341.2229, found 341.2229.
(1E,NE)-N-(5-Fluoro-1-((E)-hex-1-enyl)-2-oxoindolin-3-ylidene)hex-1-en-1-ami
ne oxide (4ea), 0.088 g, 86% yield, brown liquid. 1H NMR (500 MHz, CDCl3): δ 8.86
(d, J = 8.5 Hz, 1H), 8.18−8.16 (m, 1H), 7.10−7.01 (m, 2H), 6.96−6.95 (m, 1H), 6.42
(d, J = 14.5 Hz, 1H), 6.20−6.16 (m, 1H), 2.34 (q, J = 7.5 Hz, 2H), 2.23 (q, J = 6.0 Hz,
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2H), 1.54−1.44 (m, 4H), 1.40−1.35 (m, 4H), 0.94 (dt, J = 7.5 Hz, 2.5 Hz, 6H); C
NMR (125 MHz, CDCl3): δ 160.1 (d, J = 239.5 Hz), 159.3, 136.3, 136.0, 132.9, 131.1,
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125.1, 119.6 (d, J = 6.4 Hz), 117.7 (d, J = 24.6 Hz), 112.8, 112.5, 109.6 (d, J = 8.3
Hz), 31.5, 30.5, 30.4, 29.2, 22.2, 22.1, 13.8, 13.7; IR (thin film) 3091, 2956, 1695,
1644, 1530, 1476, 1264, 805 cm−1; HRMS (ESI) m/z calcd for C20H26FN2O2 (M+H)+
345.1978, found 345.1980.
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(1E,NE)-N-(1-((E)-Hex-1-enyl)-5-nitro-2-oxoindolin-3-ylidene)hex-1-en-1-amin
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e oxide (4fa), 0.065 g, 58% yield, brown liquid. H NMR (500 MHz, CDCl3): δ 9.17
(s, 1H), 8.77 (d, J = 13.0 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.11−7.04 (m, 2H), 6.36
(d, J = 14.5 Hz, 1H), 6.23−6.19 (m, 1H), 2.31 (q, J = 7.0 Hz, 2H), 2.22 (q, J = 7.0 Hz,
13
2H), 1.50−1.41 (m, 4H), 1.38−1.31 (m, 4H), 0.88 (dt, J = 6.5 Hz, 5.0 Hz, 6H); C
NMR (125 MHz, CDCl3): δ 159.5, 143.8, 137.9, 132.9, 129.8, 128.2, 127.2, 120.3,
118.9, 118.8, 108.6, 31.3, 30.4, 30.3, 29.6, 29.3, 22.2, 22.1, 13.8, 13.7; IR (thin film)
3089, 2956, 1708, 1520, 1459, 1343, 1178, 745 cm−1; HRMS (ESI) m/z calcd for
C20H26N3O4 (M+H)+ 372.1923, found 372.1926.
(1E,NE)-N-(6-Bromo-1-((E)-hex-1-enyl)-2-oxoindolin-3-ylidene)hex-1-en-1-ami
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ne oxide (4ga), 0.104 g, 85% yield, brown liquid. H NMR (500 MHz, CDCl3): δ
8.83 (d, J = 13.0 Hz, 1H), 8.31 (t, J = 5.5 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.18 (s,
1H), 7.11−7.06 (m, 1H), 6.38 (d, J = 13.0 Hz, 1H), 6.24−6.18 (m, 1H), 2.34 (q, J =
7.0 Hz, 2H), 2.26 (q, J = 7.0 Hz, 2H), 1.55−1.47 (m, 4H), 1.44−1.36 (m, 4H), 0.97 (dt,
J = 16.0 Hz, 7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3): δ 159.3, 140.8, 136.1, 132.9,
130.8, 126.4, 126.3, 126.2, 125.4, 119.2, 117.4, 112.5, 31.5, 30.5, 30.4, 29.4, 22.2,
22.1, 13.8, 13.7; IR (thin film) 3096, 2956, 1698, 1594, 1465, 1375, 1185, 818 cm−1;
HRMS (ESI) m/z calcd for C20H26BrN2O2 (M+H)+ 405.1178, found 405.1181.
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ne oxide (4ha), 0.093 g, 90% yield, brown liquid. H NMR (500 MHz, CDCl3): δ
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8.91 (d, J = 13.0 Hz, 1H), 8.29 (d, J = 4.5 Hz, 1H), 7.12−7.03 (m, 3H), 6.58 (d, J =
14.0 Hz, 1H), 6.40−6.35 (m, 1H), 2.35−2.31 (q, J = 7.0 Hz, 2H), 2.22−2.18 (q, J = 7.0
Hz, 2H), 1.56−1.45 (m, 4H), 1.42−1.36 (m, 4H), 0.95 (dt, J = 14.5 Hz, 7.5 Hz, 6H);
13C NMR (125 MHz, CDCl3): δ 159.4, 148.2 (d, J = 244.1 Hz), 136.2, 132.9, 131.3,
126.6, 126.4 (d, J = 8.3 Hz), 124.2 (d, J = 6.4 Hz), 121.3, 121.0, 120.9 (d, J = 3.6 Hz),
119.9 (d, J = 21 Hz), 31.4, 30.6, 30.4, 29.2, 22.2, 22.1, 13.8, 13.7; IR (thin film) 3092,
2955, 1696, 1527, 1446, 1374, 1190, 785 cm−1; HRMS (ESI) m/z calcd for
C20H26FN2O2 (M+H)+ 345.1978, found 345.1981.
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1-((E)-Hex-1-enyl)-3-(methoxyimino)indolin-2-one (3ma), 0.084 g, 88% yield,
brown liquid. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 4.4 Hz, 1H), 7.33 (d, J = 7.2
Hz, 1H), 7.01−7.00 (m, 2H), 6.40−6.36 (m, 1H), 6.19−6.12 (m, 1H),4.22 (s, 3H), 2.15
(q, J = 6.8 Hz, 2H), 1.42−1.36 (m, 2H), 1.34−1.27 (m, 2H), 0.88−0.84 (t, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 162.3, 143.0, 132.3, 127.9, 124.6, 123.3, 120.9,
119.5, 116.0, 109.6, 64.8, 31.6, 30.5, 22.2, 13.9; IR (thin film) 3053, 2961, 1728, 1606,
1461, 1381, 1003, 748 cm−1; HRMS (ESI) m/z calcd for C15H19N2O2 (M+H)+
259.1447, found 259.1440.
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Mixture of 3na and 3na’, 0.053 g, 72% yield, yellow liquid. 3na: H NMR (400
MHz, CDCl3): δ 7.59 (d, J = 4.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.19−7.15 (m, 1H),
7.10−7.06 (m, 1H), 6.98 (d, J = 14.0 Hz, 1H), 6.56 −6.49 (m, 1H), 5.34 (q, J = 6.8 Hz,
1H), 2.61 (brs, 1H), 1.65 (d, J = 6.8 Hz, 3H), 1.45−1.39 (m, 2H), 1.38−1.29 (m, 2H),
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0.89 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3): δ 148.2, 136.2, 126.9, 124.8,
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121.5, 121.1, 120.3, 117.0, 109.5, 62.7, 31.2, 29.7, 22.9, 22.1, 13.8; 3na’: H NMR
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(400 MHz, CDCl3): δ 7.70 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.35−7.31 (m,
1H), 7.10−7.06 (m, 1H), 6.93 (d, J = 14.0 Hz, 1H), 6.17 −6.10 (m, 1H), 5.27 (q, J =
6.8 Hz, 1H), 2.61 (brs, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.45−1.39 (m, 2H), 1.38−1.29
(m, 2H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 149.7, 139.6, 127.1,
125.6, 123.8, 121.4, 121.2, 119.7, 117.2, 65.5, 31.9, 29.8, 23.4, 22.2, 13.9; IR (thin
film) 2959, 2857, 1672, 1627, 1464, 1383, 1083, 767 cm−1; HRMS (ESI) m/z calcd
for C15H21N2O (M+H)+ 245.1654, found 245.1641.
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General procedure for synthesis of spirooxindole 5 or 6: In a 25 mL seal tube
was charged with Nꢀvinyl nitrone 3 or 4 (0.2 mmol). Then, toluene (2.0 mL) was
added via syringe. The reaction mixture was stirred vigorously at 120−140 °C for
8−65 h until nitrone 3 or 4 disappeared (monitored by TLC). At this time, the solvent
was removed under reduced pressure and the crude product was purified by flash
chromatography (the crude residue was dry loaded on silica gel, 1/4 to 1/1, ethyl
acetate/petroleum ether) to provide spirooxindole 5 or 6.
3',4'-Dimethyl-4'H-spiro[indoline-3,5'-isoxazol]-2-one (5ah), dr = 1:0.8, 0.032 g,
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74% yield, light yellow liquid. major isomer: H NMR (500 MHz, DMSO–d6): δ
10.54 (s, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz,
1H), 6.88 (d, J = 8.0 Hz, 1H), 3.75 (q, J = 7.0 Hz, 1H), 1.93 (s, 3H), 1.10 (d, J = 7.0
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Hz, 3H); C NMR (125 MHz, DMSO–d6): δ 176.9, 159.7, 143.2, 130.9, 128.2, 125.7,
122.9, 110.9, 87.7, 53.6, 12.7, 11.5; minor isomer: 1H NMR (500 MHz, DMSO–d6): δ
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10.43 (s, 1H), 7.25 (d, J = 7.0 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.5 Hz,
1H), 6.85 (d, J = 7.5 Hz, 1H), 3.59 (q, J = 7.5 Hz, 1H), 1.93 (s, 3H), 0.97 (d, J = 7.5
Hz, 3H); 13C NMR (125 MHz, DMSO–d6): δ 174.6, 159.5, 142.8, 130.9, 126.8, 124.9,
122.4, 110.5, 87.6, 51.6, 11.3, 10.8; IR (thin film) 3431, 2926, 1728, 1621, 1471, 1189,
1010, 757 cm−1; HRMS (ESI) m/z calcd for C12H13N2O2 (M+H)+ 217.0977, found
217.0976.
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3'-Phenyl-4'H-spiro[indoline-3,5'-isoxazol]-2-one (5ai), 0.043 g, 80% yield, light
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yellow liquid. H NMR (500 MHz, DMSO–d6): δ 10.66 (s, 1H), 7.75 (d, J = 4.5 Hz,
2H), 7.50−7.49 (m, 3H), 7.41 (d, J = 7.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.04 (t, J =
7.5 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 3.83 (s, 2H); 13C NMR (125 MHz, DMSO–d6):
δ 176.2, 157.0, 143.0, 131.4, 131.1, 129.5, 129.1, 128.6, 127.5, 125.3, 123.3, 110.9,
85.5, 43.7; IR (thin film) 3456, 3199, 2929, 1636, 1472, 1336, 1117, 748 cm−1;
HRMS (ESI) m/z calcd for C16H13N2O2 (M+H)+ 265.0977, found 265.0966.
4'-Ethyl-3'-phenyl-4'H-spiro[indoline-3,5'-isoxazol]-2-one (5aj), dr = 10:1,
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0.034 g, 57% yield, light yellow liquid. H NMR (400 MHz, DMSO–d6): δ 10.67 (s,
1H), 7.74−7.73 (m, 2H), 7.50 (t, J = 6.8 Hz, 3H), 7.43 (d, J = 7.2 Hz, 1H), 7.37 (t, J =
7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 4.12 (dd, J = 10.0 Hz,
3.2 Hz, 1H), 1.73−1.60 (m, 2H), 0.53 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
DMSO–d6): δ 176.9, 160.6, 143.2, 131.3, 130.8, 129.4, 129.1, 127.9, 126.8, 124.6,
122.7, 110.9, 88.4, 55.2, 21.5, 12.1; IR (thin film) 3436, 3197, 2938, 1720, 1621,
1469, 1203, 749 cm−1; HRMS (ESI) m/z calcd for C18H17N2O2 (M+H)+ 293.1290,
found 293.1282.
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