Aqueous copper nitrate catalyzed synthesis of 3-alkylideneoxindoles from α-diazo-ketoanilides

Article abstract of DOI:10.1002/ejoc.201402206

An economical, practical, and green protocol with which to synthesize 3-alkylideneoxindoles from α-diazo-ketoanilides has been developed. The approach employs inexpensive Cu(NO₃)₂·3H ₂O as catalyst and environmentally friendly water as solvent, and achieves moderate to excellent yields. The method has good tolerance to a range of N-alkyl and N-aryl groups, including electron-withdrawing and electron-donating groups on the aromatic ring, ortho-, meta-, and para-substituents, and -aliphatic and -aromatic keto groups. A plausible mechanism involving intramolecular aromatic metal carbene electrophilic addition as the key step is proposed. Inexpensive Cu(NO₃)₂· 3H₂O catalyst and environmentally friendly water solvent are employed for the transformation of α-diazo-ketoanilides into 3-alkylidene- oxindoles. The process is easily handled, economical, environmentally friendly, and can be used to convert a broad range of substrates in moderate to excellent yields. An intramolecular aromatic metal carbene electrophilic addition mechanism is proposed. Copyright

Full text of DOI:10.1002/ejoc.201402206

FULL PAPER
DOI: 10.1002/ejoc.201402206
Aqueous Copper Nitrate Catalyzed Synthesis of 3-Alkylideneoxindoles from
α-Diazo-β-ketoanilides
Shanyan Mo,[a] Zhanhui Yang,[a] and Jiaxi Xu*[a]
Keywords: Synthetic methods / Waste prevation / Green chemisty / Electrophilic addition / Cyclization / Copper / Carbenes
An economical, practical, and green protocol with which to
N-aryl groups, including electron-withdrawing and electron-
synthesize 3-alkylideneoxindoles from α-diazo-β-ketoanil- donating groups on the aromatic ring, ortho-, meta-, and
ides has been developed. The approach employs inexpensive
Cu(NO3)2·3H2O as catalyst and environmentally friendly
water as solvent, and achieves moderate to excellent yields.
The method has good tolerance to a range of N-alkyl and
para-substituents, and β-aliphatic and β-aromatic keto
groups. A plausible mechanism involving intramolecular aro-
matic metal carbene electrophilic addition as the key step is
proposed.
Because of the significance of 3-alkylideneoxindoles,
their syntheses have attracted extensive attention over the
past decades.[3f,4,6–9] In general, synthetic approaches to 3-
alkylideneoxindoles can be divided into five categories
(Scheme 1): (Method i) direct acylation of oxindoles with
active acyl derivatives or orthoesters;[4,6] (Method ii) intra-
molecular arylation of β-keto-2-iodoanilides catalyzed by
CuI/(l)-proline;[7] (Method iii) Ag2O-mediated oxidized
coupling of acetoacetanilides;[8] (Method iv) catalytic oxi-
dation and C–H functionalization of N-arylpropiolamides
involving gold carbenoid intermediates;[3f] (Method v) in-
Introduction
The economical and practical synthesis of biologically
active compounds or their intermediates is a challenging
objective for organic chemists. Generally, it is important to
develop methods with inexpensive starting materials and/or
reagents. Alternatively, substantial progress can also be
made by modifying existing methods so that they become
economical, practical, and green-chemistry versions.[1,2]
3-Alkylideneoxindoles are important intermediates in
organic synthesis.[3] In addition, 3-alkylideneoxindoles are
common structure motifs in pharmaceuticals. Representa-
tive compounds include a GSK3 kinase inhibitor 1,[4] anti-
rheumatic drug 2 (Tenidap),[5] and influenza endonuclease
inhibitor 3[5c] (Figure 1).
Figure 1. Pharmaceuticals containing 3-alkylideneoxindole motifs.
[a] State Key Laboratory of Chemical Resource Engineering,
Department of Organic Chemistry, Faculty of Science, Beijing
University of Chemical Technology,
Beijing 100029, People’s Republic of China
E-mail: jxxu@mail.buct.edu.cn
http://sci.buct.edu.cn/szll/jsml/yjhxx/9746.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402206.
Scheme 1. Synthetic methods used for the production of 3-alkyl-
ideneoxindoles.
Eur. J. Org. Chem. 2014, 3923–3929
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S. Mo, Z. Yang, J. Xu
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tramolecular cyclization through metal-catalyzed aromatic studies on the replacement of precious metals in carbene
C–H insertion of α-diazo-β-ketoanilides.[9] Among these reactions, we decide to explore the use of inexpensive cupric
five methods, Methods (i) and (ii) require functionalized salts to catalyze the cyclization reaction of α-diazo-β-
precursors, so their applications and scope are limited. This ketoanilides.
shortcoming is overcome by Methods (iii), (iv), and (v),
Herein, we report the synthesis of 3-alkylideneoxindoles
however, poor yields are obtained by using Method (iii) and from α-diazo-β-ketoanilides with water as solvent and
only acylacetanilides are substrates. Both substrate scope Cu(NO3)2·3H2O as catalyst. The reaction demonstrates the
and yield are extremely good in the Method (iv), but this following advantages: (1) economic – only inexpensive
approach requires abundant oxidants and very expensive cupric catalyst is applied; (2) environmentally friendly –
metal complex catalyst. Method (v) is thus the most com- water is used as solvent; (3) convenient and practical – the
petitive because of its broad substrate scope, its use of a reactions do not require an inert atmosphere or anhydrous
simple catalyst, and the green nature of the process (no conditions.
toxic byproducts released and only nitrogen produced). Sev-
eral groups have reported modifications of Method (v) by
Results and Discussion
using different catalysts and solvents, including Rh2-
(OAc)4/CH2Cl2(benzene),[9a,9b] AgOTf/1,4-dioxane,[9c] and
[Ru(p-cymene)Cl2]2/toluene.[9d] However, all of these groups
used volatile and toxic organic solvents (CH2Cl2, benzene,
and 1,4-dioxane). In addition, they all use precious metal
catalysts [Rh2(OAc)4, AgOTf, and Ru(p-cymene)Cl2], thus
limiting this method to small-scale synthesis. Moreover, the
methods are inconvenient to handle because they require
an inert gas and strictly anhydrous conditions. Thus, a
convenient protocol that does not require precious metal
catalyst and that can be conducted in an environmentally
friendly solvent remains in demand.
α-Diazo-β-ketoanilide 4a was prepared and selected as a
model to optimize the reaction conditions. When 4a was
treated with Cu(acac)2 (5 mol-%) in water heated to reflux
for 18 h, 3-alkylideneoxindole 5a was obtained exclusively
in 51% yield, without the water O–H insertion product, a
secondary alcohol,[9b,13] being observed (Table 1, en-
try 1).[16] Several cupric salts with hydrate(s) were employed
to catalyze the reaction (entries 2–5), and the use of
Cu(NO3)2·3H2O as catalyst was found to be optimal in
terms of both reaction time and yield. From the aqueous
Solvent selection is of increasing concern in both medical
and synthetic organic chemistry. As a guide for solvent se-
lection, there is a principle that solvents that have excellent
assessments for worker and process safety and for environ-
mental and regulatory considerations should be preferen-
tially employed. Among all solvents that are frequently
used, water is clearly the most optimal.[10] However, in con-
trast to the tremendous popularity of water in some syn-
thetic transformations,[11] this solvent has previously been
regarded as the most unlikely solvent in carbene chemistry
because water possesses highly acidic O–H bonds that can
easily react with carbenes; as a result, O–H insertion often
occurs as a side reaction.[9b,12] It was a general understand-
ing that water was disadvantageous for carbenoid reactions
and that carbene reactions should be conducted under
water-free conditions. Therefore, anhydrous conditions are
strictly required in carbenoid reactions, causing great incon-
venience to the experimental operators, especially in indus-
trial production. Yet, surprisingly, in several synthetic trans-
formations involving carbenes, water has been applied as
solvent, and the side reaction of the O–H insertion into
water can be completely avoided.[13] Indeed, water was re-
Table 1. Optimization of cupric catalysts.[a]
Entry Cat.
Cat.
loading
[mol-%]
Time
[h]
Yield
[%][b]
Solubility
[g/100 g][c]
1
2
3
4
5
6
7
8
Cu(acac)2
5
5
5
5
5
–
–
10
2.5
5
18
12
2
1.5
0.7
27
27
0.5
2
51
71
82
80
91
Ͻ1
20
114
120
247
Cu(OAc)2·H2O
CuSO4·5H2O
CuCl2·2H2O
Cu(NO3)2·3H2O
none
52
none
51[d]
85
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
9
91
10
11
12
24
0.7
0.5
trace[e]
92[f]
88[g]
5
5
cently found to be very beneficial in some carbene-mediated [a] Reactions were conducted (unless otherwise noted) on 1 mmol
scale in 10 mL tap water. Diazo compound 4a was added in one
reactions, and its use improved the chemoselectivity and
portion. [b] Isolated yield after extraction with ethyl acetate fol-
simplicity of product isolation;[13] indeed, water can even
lowed by column chromatography on silica gel. [c] Dissolved mass
increase the activity of catalysts.[14] Therefore, we wanted
[g] in 100 g H2O at 100 °C. [d] Deionized water was used as solvent.
to explore the use of water – the least expensive and most
environmentally friendly solvent – as solvent in the cycliza-
tion reaction of α-diazo-β-ketoanilides.
[e] Reaction was performed at 80 °C, most of the starting material
was recovered. [f] Reaction was performed on 10 mmol scale in
100 mL tap water. The product was purified by simple extraction
of the reaction mixture and filtration of the insoluble impurity.
[g] Deionized water was used as solvent. The product was purified
by simple extraction of the reaction mixture and filtration of the
In terms of inexpensive metal catalysts used in water, Hu
and Wang disclosed the use of cupric salts in the formation
of metal carbenes in water.[15] As a continuation of our insoluble impurity.
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Copper Nitrate Catalyzed Synthesis of 3-Alkylideneoxindoles
solubility data of these cupric salts,[17] we found that the Table 2. Aqueous Cu(NO3)2·3H2O-catalyzed intramolecular cycli-
zation of diazo-β-ketoanilides.[a]
efficiency of the catalysts was closely associated with their
solubilities in water: the more soluble the cupric salts, the
higher the efficiency. The reaction also took place in the
absence of any catalyst, but with a long reaction time and
low yields in either tap water or deionized water (entries 6
and 7). Further investigations revealed that both the reac-
tion time and the yield were reduced when the catalyst load-
ing was increased (entry 8), and the required reaction time
increased when the catalyst loading was decreased (entry 9).
Lowering the reaction temperature to 80 °C rendered the
reaction less effective (entry 10). When the reaction was per-
formed on a larger scale (10 mmol), the workup was much
more convenient and faster, because only simple extraction
with ethyl acetate and filtration of the insoluble impurity
were required. After removal of the solvent, the product
1
was obtained in high purity (based on H NMR analysis;
entry 11). A comparable result was obtained in deionized
water, which suggested that the outcome was not influenced
significantly by any dissolved metallic or organic impurity
in the water (entry 12).
We then explored the substrate scope of the reaction
(Table 2). In all cases, the cyclization proceeded smoothly
for 4 even though the substrates were poorly soluble in
water. The reaction time mainly depended on their solubilit-
ies in water. First, the effect of the N-protecting group was
probed. Substrates 4a–d, bearing an N-alkyl, phenyl, or
benzyl group, were successfully converted into 3-alkylid-
eneoxindoles 5a–d in moderate to excellent yields (69–91%).
Second, the electronic effect of the para-substituents on the
aromatic ring was investigated (5e–h). Little difference was
observed in the yields for those substrates with electron-
withdrawing or electron-donating substituents. This phe-
nomenon is consistent with previous reports.[9c,9d] N-
Naphthyl-α-diazo-β-ketoanilide 4i gave the desired product
5i in good yield (73%). Furthermore, the regioselectivity of
the reaction with substrates 4j–l, with the ortho- and meta-
[a] Unless otherwise noted, the reactions were performed on
1 mmol scale in 10 mL tap water under the optimized conditions;
substituents on the N-phenyl group, was studied. The ortho-
methyl-substituted substrate 4j gave a single product, 5j, re-
gioselectively. For meta-substituted substrates 4k and 4l,
only one regioselective product 5k was generated from the
meta-chloro-substituted substrate 4k, but two regioisomeric
products, 5l and 6l, were obtained from the meta-methyl-
substituted substrate 4l. Interestingly, based on its NMR
the reactions were monitored by TLC until complete consumption
of the starting materials was observed. All yields are isolated yields
after column chromatography on silica gel. [b] The reaction was
performed on 2 mmol scale. [c] The reaction was performed on
1.5 mmol scale.
spectral analysis, 6l exists in its ketone form rather than the the structural skeletons of biological compounds 2 and 1,
enolic form. The results indicate that meta-substituted α- respectively.
diazo-β-ketoanilides show different regioselectivity, de-
Considering the reaction mechanism, in the AgOTf-cata-
pending on the nature of the substituents, and the substitu- lyzed system, it was presumed that the free carbene-gener-
ent position also has an impact on the structural features ated carbocation underwent an intramolecular aromatic
of the products.
electrophilic addition as a key step.[9c] Later, Li and Gao
Noting the fact that pharmaceuticals containing 3-(aryl- further proposed that the addition was a Ag-carbene ad-
methylidene)oxindole motifs generally include aromatic dition process on the basis of their computational results.[18]
moieties for R1 (Scheme 1), we attempted to extend our Actually, the Ag-carbene underwent the addition in its ylide
substrate scope to aroyldiazoanilides. To our satisfaction, form. The proposed mechanism is similar to that in the
all aroyldiazoanilides 4m–o were smoothly converted into Rh2(OAc)4-catalyzed system presumed by Doyle.[9a]
A
the desired 3-arylmethylideneoxindoles 5m–o, respectively, strong electron-withdrawing meta-nitro substituted sub-
with good yields under the standard reaction conditions strate, N-benzyl-2-diazo-N-(3-nitrophenyl)-3-oxobutan-
(Table 2). It is noteworthy that products 5n and 5o have amide, failed to give the desired 3-alkylideneoxindole. In-
Eur. J. Org. Chem. 2014, 3923–3929
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S. Mo, Z. Yang, J. Xu
FULL PAPER
stead, a β-lactam product was obtained in low yield resonance structures, 3-acyloxindoles 6, are generated. The
through benzylic C–H insertion (Scheme 2).[13b] The results latter can further tautomerize into their more stable enolic
supports the conclusion that the nature of the electrophilic form, alkylideneoxindoles 5, in most cases.
addition reaction is similar to that of intramolecular Frie-
del–Crafts alkylation. Yu et al. assumed a ruthenium–carb-
Conclusions
ene cyclopropanation process in the [Ru(p-cymene)Cl2]2
catalyzed system based on the results of their H/D kinetic
isotope effect (KIE) study (kH/kD = 1.1).[9d] The KIE result
indeed does not support the carbene C–H insertion mecha-
nism. However, it cannot exclude the intramolecular aro-
matic electrophilic addition mechanism. That is, the KIE
result as a secondary KIE also supports the electrophilic
addition mechanism. Similarly, two regioselective 3-alkylid-
eneoxindoles are generated from the meta-substituted sub-
strate, and electron-donating substituents on the N-phenyl
group are a favorable factor in our Cu(NO3)2·3H2O cata-
We have developed a facile, economical, and green proto-
col with which to synthesize 3-alkylideneoxindoles in mod-
erate to excellent yields from α-diazo-β-ketoanilides under
the catalysis of copper nitrate trihydrate in water. A reaction
mechanism has been proposed. The current methodology
shows broad substrate scope.
Experimental Section
lyzed system. Thus, our catalytic reaction is compatible General Information: Melting points (m.p.) were determined with a
1
Yanaco MP-500 melting point apparatus and are uncorrected. H
and 13C NMR spectra were recorded with a Bruker 400 NMR spec-
trometer at 400 and 100 MHz, respectively, in CDCl3 with TMS as
the internal standard; chemical shifts are reported in ppm. IR spec-
tra were recorded with a Nicolet Avatar 330 FTIR spectrometer in
dichloromethane (CH2Cl2). HRMS spectra were recorded with a
Bruker LC/MSD TOF mass spectrometer. Column chromatog-
raphy was carried out on silica gel (200–300 mesh) with petroleum
ether (PE; 60–90 °C) and ethyl acetate (EtOAc) as eluent. All reac-
tions were followed by thin-layer chromatography (TLC) where
practical, using Silica gel 60 F254 fluorescent treated silica gel
plates, which were visualized under UV light (250 nm). Except for
4d, 4n, 4o, the other synthesized α-diazo-β-ketoanilides 4 are
known compounds and show analytical data identical to those re-
with an intramolecular aromatic copper-carbene electro-
philic addition mechanism.
Scheme 2. Reaction of N-benzyl-2-diazo-N-(3-nitrophenyl)-3-
oxobutanamide under the catalysis of Rh2(OAc)4.
A plausible mechanism for the Cu(NO3)2·3H2O cata-
lyzed transformation of α-diazo-β-ketoanilides 4 into 3-alk-
ylideneoxindoles 5 is proposed in Scheme 3. First, α-diazo- ported.[9]
β-ketoanilides 4 release N2 either under the influence of Cu
General Procedure for the Synthesis of α-Diazo-β-ketoanilides 4a–l:
catalyst or by heating, affording Cu-carbenoids A, which
subsequently undergo intramolecular aromatic electrophilic
addition through their zwitterionic intermediates to give cy-
clized intermediates B. A similar zwitterionic intermediate
has been trapped by Hu et al.[19] The intermediates B can
tautomerize into intermediates C. After an orbital sym-
metry allowed H[1,5] sigmatropic shift and release of the
Cu catalyst, zwitterionic enolic intermediates D and their
Aniline (10 mmol) was added to a solution of diketene (0.78 mL,
840 mg, 10 mmol) in acetonitrile (15 mL) and the resulting solution
was stirred overnight. Then 4-methylbenzenesulfonyl azide
(12 mmol, 2.37 g) and triethylamine (12 mmol, 1.21 g) were added
while stirring. The solution was concentrated under reduced pres-
sure, and the resulting residue was purified by silica gel column
chromatography to give pure 4.
General Procedure for the Synthesis of α-Diazo-β-ketoanilides 4m-
o: To a mixture of Meldrum’s acid (10 mmol, 1.24 g) and DMAP
(20 mmol, 2.44 g) in CH2Cl2 (20 mL) was added aryl chloride
(12 mmol, 1.2 equiv.) dropwise over 10 min at 0 °C. The mixture
was then warmed to room temperature and stirred for 1 h. The
reaction mixture was diluted with CH2Cl2 (20 mL) and washed
with 10% HCl (20 mL), brine (30 mL), and then H2O (30 mL). The
combined organic layers were dried with Na2SO4 and concentrated.
The residue was dissolved in acetonitrile (15 mL), aniline
(10 mmol) was added, and the mixture was heated to reflux for 1 h.
Upon complete consumption of the starting materials, the solvent
was removed under vacuum. The residue was purified by flash col-
umn chromatography to afford the corresponding aroylacetanilide.
The procedure of subsequent diazo transfer reaction was similar
with that used for the preparation of 4a–l, and 4m–o were obtained
as yellow solids or yellow oils.
Analytical Data of α-Diazo-β-ketoanilides 4d, 4n, 4o
N-(4-Chlorobenzyl)-2-diazo-3-oxo-N-phenylbutanamide (4d): Yield
1.49 g (91%); yellow crystals; m.p. 74–75 °C. H NMR (400 MHz,
CDCl3): δ = 7.38–7.30 (m, 3 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.17 (d,
Scheme 3. Proposed mechanism for the preparation of 3-alkylid-
eneoxindoles from α-diazo-β-ketoanilides under the catalysis of
Cu(NO3)2·3H2O.
1
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Copper Nitrate Catalyzed Synthesis of 3-Alkylideneoxindoles
J = 8.4 Hz, 2 H), 7.07–7.02 (m, 2 H), 4.92 (s, 2 H), 2.51 (s, 3 1-(4-Chlorobenzyl)-3-(1-hydroxyethylidene)indolin-2-one (5d):[9c]
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 191.6, 160.9, 141.1,
135.2, 133.5, 130.2, 130.1, 128.7, 128.4, 127.2, 53.4, 28.6 ppm. IR
Yield 208 mg (69 %); purple crystals; m.p. 99–102 °C. 1H NMR
(400 MHz, CDCl3): δ = 13.61 (br. s, 1 H), 7.38 (d, J = 7.1 Hz, 1
H), 7.27 (d, J = 8.3 Hz, 2 H), 7.21 (d, J = 8.3 Hz, 2 H), 7.14–7.06
(m, 2 H), 6.81 (d, J = 7.4 Hz, 1 H), 5.00 (s, 2 H), 2.48 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.4, 171.0, 137.7, 134.6, 133.4,
128.9, 128.6, 125.2, 122.3, 122.3, 119.9, 109.1, 101.6, 42.6,
(CH Cl ): ν = 3062, 2931, 2110, 1643, 1594, 1492, 1431, 1379, 1318,
˜
2
2
1257, 1188, 1091, 965, 851, 797 cm–1. HRMS (ESI): m/z calcd. for
C17H15ClN3O2 [M + H]+ 328.0847; found 328.0845.
N-(4-Chlorophenyl)-2-diazo-N-(4-methoxybenzyl)-3-oxo-3-(thio-
phen-2-yl)propanamide (4n): Yield 2.98 g (70 %); yellow oil. 1H
NMR (400 MHz, CDCl3): δ = 7.58 (dd, J = 4.9, 1.0 Hz, 1 H), 7.49
(dd, J = 3.8, 1.0 Hz, 1 H), 7.18 (d, J = 8.6 Hz, 2 H), 7.16 (d, J =
8.6 Hz, 2 H), 7.03 (dd, J = 4.9, 3.8 Hz, 1 H), 6.85 (d, J = 8.7 Hz,
2 H), 6.80 (d, J = 8.7 Hz, 2 H), 4.90 (s, 2 H), 3.78 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 176.6, 161.2, 159.2, 141.3, 139.9,
133.2, 133.1, 131.5, 130.2, 129.6, 128.2, 128.1, 127.5, 113.9, 55.2,
20.4 ppm. IR (CH Cl ): ν = 2929, 1652, 1604, 1487, 1466, 1436,
˜
2
2
1405, 1302, 1304, 1320, 1293, 1185, 1088, 971, 925, 881, 790, 779,
779, 754, 740, 699 cm–1. HRMS (ESI): m/z calcd. for C17H15ClNO2
[M + H]+ 300.0786; found 300.0789.
1-Benzyl-3-(1-hydroxyethylidene)-5-methoxyindolin-2-one (5e):[9c]
Yield 203 mg (68%); purple crystals; m.p. 145–147 °C (ref.[9c] 142–
144 °C). 1H NMR (400 MHz, CDCl3): δ = 13.67 (br. s, 1 H), 7.31–
7.22 (m, 5 H), 6.95 (d, J = 1.6 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 1 H),
6.64 (dd, J = 8.5, 1.6 Hz, 1 H), 5.00 (s, 2 H), 3.78 (s, 3 H), 2.44 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.4, 171.0, 155.6,
136.1, 132.1, 128.7, 127.5, 127.1, 123.4, 109.6, 109.5, 107.3, 101.8,
55.8, 43.3, 20.3 ppm.
1-Benzyl-3-(1-hydroxyethylidene)-5-methylindolin-2-one (5f):[9c]
Yield 200 mg (71%); purple crystals; m.p. 113–115 °C (ref.[9c] 106–
108 °C). 1H NMR (400 MHz, CDCl3): δ = 13.63 (br. s, 1 H), 7.30–
7.21 (m, 5 H), 7.17 (s, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 6.71 (d, J =
7.8 Hz, 1 H), 5.00 (s, 2 H), 2.46 (s, 3 H), 2.35 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.9, 171.0, 136.1, 135.9, 131.5,
128.7, 127.5, 127.1, 125.7, 122.4, 120.5, 109.0, 101.6, 43.2, 21.4,
20.3 ppm.
53.6 ppm. IR (CH Cl ): ν = 3068, 2934, 2110, 1651, 1613, 1513,
˜
2
2
1492, 1463, 1413, 1379, 1354, 1248, 1176, 1093, 1032, 1011, 881,
836 cm–1. HRMS (ESI): m/z calcd. for C21H17ClN3O3S [M + H]+
426.0674; found 426.0676.
N-(4-Acetylphenyl)-2-diazo-3-(furan-2-yl)-N-(4-methoxybenzyl)-3-
oxopropanamide (4o): Yield 3.12 g (75 %); yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.82 (d, J = 8.6 Hz, 2 H), 7.44 (d, J =
1.7 Hz, 1 H), 7.20 (d, J = 8.6 Hz, 2 H), 7.16 (d, J = 8.6 Hz, 2 H),
6.99 (d, J = 3.6 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 1 H), 6.47 (dd, J =
3.6, 1.7 Hz, 1 H), 5.00 (s, 2 H), 3.77 (s, 3 H), 2.53 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 196.9, 171.0, 161.3, 159.1, 145.2,
135.2, 129.8, 129.7, 129.4, 128.5, 126.5, 126.3, 117.3, 113.9, 112.6,
55.2, 53.6, 26.6 ppm. IR (CH Cl ): ν = 3075, 2921, 2116, 1681,
˜
2
2
1633, 1598, 1573, 1467, 1383, 1304, 1322, 1268, 1178, 1164, 981,
836 cm–1. HRMS (ESI): m/z calcd. for C23H20N3O5 [M + H]+
418.1397; found 418.1399.
1-Benzyl-5-bromo-3-(1-hydroxyethylidene)indolin-2-one (5g):[9c]
Yield 172 mg (50%); purple crystals; m.p. 135–137 °C (ref.[9c] 138–
1
140 °C). H NMR (400 MHz, CDCl3): δ = 13.67 (br. s, 1 H), 7.45
(s, 1 H), 7.33–7.18 (m, 6 H), 6.69 (d, J = 8.2 Hz, 1 H), 5.01 (s, 2
H), 2.46 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.7,
170.7, 136.7, 135.5, 128.8, 127.7, 127.7, 127.1, 124.2, 122.5, 115.1,
110.6, 100.9, 43.3, 20.5 ppm.
General Procedure for Aqueous Cu(NO3)2·3H2O-catalyzed Synthe-
sis of 3-Alkylideneoxindoles 5 from α-Diazo-β-ketoanilides (4): To a
solution of Cu(NO3)2·3H2O (12 mg, 5mol-%) in tap water (10 mL)
was added diazo compound 4 (1 mmol). The suspension was heated
to reflux and the progress of the reaction was monitored by TLC
until complete consumption of the starting materials was observed.
Ethyl acetate (10 mL) was added and the organic layer was sepa-
rated, dried with anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (PE/EtOAc) to give pure 5.
1-Benzyl-3-(1-hydroxyethylidene)-5-iodoindolin-2-one (5h):[9c] Yield
255 mg (65 %); purple crystals; m.p. 138–141 °C (ref.[9c] 148–
1
150 °C). H NMR (400 MHz, CDCl3): δ = 13.57 (br. s, 1 H), 7.63
(s, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.33–7.22 (m, 5 H), 6.59 (d, J =
8.0 Hz, 1 H), 5.00 (s, 2 H), 2.45 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 174.6, 170.5, 137.7, 135.5, 133.6, 128.8, 128.2, 127.7,
127.1, 124.7, 115.0, 111.2, 100.6, 85.2, 43.3, 20.6 ppm.
1-Ethyl-3-(1-hydroxyethylidene)-1H-benzo[g]indol-2(3H)-one (5i):[9a]
Yield 186 mg (73%); green crystals; m.p. 145–147 °C. 1H NMR
(400 MHz, CDCl3): δ = 14.20 (br. s, 1 H), 8.19 (d, J = 8.5 Hz, 1
H), 7.86 (d, J = 8.5 Hz, 1 H), 7.57 (s, 2 H), 7.49 (t, J = 7.6 Hz, 1
H), 7.40 (t, J = 7.6 Hz, 1 H), 4.40 (q, J = 7.0 Hz, 2 H), 2.52 (s, 3
H), 1.47 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 175.1, 170.8, 132.5, 131.3, 129.4, 129.4, 126.1, 124.3, 122.7,
121.1, 120.9, 118.5, 102.0, 36.9, 20.8, 14.8 ppm.
1-Benzyl-3-(1-hydroxyethylidene)-7-methylindolin-2-one (5j):[9c]
Yield 178 mg (63%); purple crystals; m.p. 175–176 °C (ref.[9c] 152–
154 °C). 1H NMR (400 MHz, CDCl3): δ = 13.93 (br. s, 1 H), 7.31–
7.20 (m, 4 H), 7.10 (d, J = 7.4 Hz, 2 H), 6.99 (t, J = 7.6 Hz, 1 H),
6.87 (d, J = 7.6 Hz, 1 H), 5.32 (s, 2 H), 2.49 (s, 3 H), 2.32 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.5, 171.8, 137.9,
136.2, 129.0, 128.8, 127.1, 125.6, 123.0, 122.1, 120.3, 117.8, 101.3,
44.6, 20.5, 19.0 ppm.
3-(1-Hydroxyethylidene)-1-methylindolin-2-one (5a):[9c] Yield
173 mg (91%); purple crystals; m.p. 95–97 °C (ref.[9c] 89–90 °C). 1H
NMR (400 MHz, CDCl3): δ = 13.64 (br. s, 1 H), 7.37 (d, J =
7.5 Hz, 1 H), 7.22 (dd, J = 7.7, 7.5 Hz, 1 H), 7.11 (dd, J = 7.5,
7.5 Hz, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 3.35 (s, 3 H), 2.45 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9, 171.0, 138.9,
125.2, 122.2, 122.1, 119.7, 108.4, 101.8, 25.6, 20.3 ppm.
3-(1-Hydroxyethylidene)-1-phenylindolin-2-one (5b):[9c] Yield
179 mg (71%); purple crystals; m.p. 78–80 °C (ref.[9c] 86–88 °C). 1H
NMR (400 MHz, CDCl3): δ = 13.73 (br. s, 1 H), 7.53 (t, J = 7.4 Hz,
2 H), 7.46–7.40 (m, 4 H), 7.16–7.12 (m, 2 H), 6.97–6.95 (m, 1 H),
2.51 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.1, 170.6,
138.6, 134.0, 129.5, 128.0, 126.7, 125.2, 122.6, 122.2, 119.8, 109.7,
101.6, 20.5 ppm.
1-Benzyl-3-(1-hydroxyethylidene)indolin-2-one (5c):[9c] Yield 184 mg
(69%); purple crystals; m.p. 127–129 °C (ref.[9c] 120–122 °C). 1H
NMR (400 MHz, CDCl3): δ = 13.63 (br. s, 1 H), 7.37 (d, J =
7.2 Hz, 1 H), 7.31–7.23 (m, 5 H), 7.12–7.04 (m, 2 H), 6.84 (d, J = 1-Benzyl-6-chloro-3-(1-hydroxyethylidene)indolin-2-one (5k):[7] Yield
7.4 Hz, 1 H), 5.03 (s, 2 H), 2.47 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 173.2, 171.0, 138.0, 136.0, 128.7, 127.6, 127.2, 125.2,
122.3, 122.1, 119.7, 109.3, 101.6, 43.2, 20.3 ppm.
221 mg (73 %); purple crystals; m.p. 129–131 °C. 1H NMR
(400 MHz, CDCl3): δ = 13.52 (br. s, 1 H), 7.33–7.23 (m, 6 H), 7.03
(dd, J = 8.2, 1.7 Hz, 1 H), 6.82 (d, J = 1.7 Hz, 1 H), 4.99 (s, 2 H),
Eur. J. Org. Chem. 2014, 3923–3929
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3927

S. Mo, Z. Yang, J. Xu
2.44 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.7, 171.1, azoamides 4d, 4n, and 4o and all 3-alkylideneoxindoles 5 and 3-
FULL PAPER
138.8, 135.5, 130.7, 128.9, 127.8, 127.1, 122.1, 120.8, 120.3, 109.7,
101.0, 43.3, 20.4 ppm.
acyloxindole 6l.
1-Benzyl-3-(1-hydroxyethylidene)-6-methylindolin-2-one (5l):[9c]
Yield 98 mg (35%); purple crystals; m.p. 127–129 °C (ref.[9c] 120–
122 °C). 1H NMR (400 MHz, CDCl3): δ = 13.51 (br. s, 1 H), 7.32–
7.22 (m, 6 H), 6.87 (d, J = 7.6 Hz, 1 H), 6.66 (s, 1 H), 5.01 (s, 2
H), 2.43 (s, 3 H), 2.31 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 172.0, 171.3, 138.3, 136.1, 135.3, 128.7, 127.5, 127.1, 122.8,
119.6, 119.5, 110.0, 101.6, 43.1, 21.7, 20.2 ppm.
Acknowledgments
This work was supported in part by The National Basic Research
Program of China (grant number 2013CB328905) and the National
Natural Science Foundation of China (NSFC) (grant numbers
21372025 and 21172017).
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3-[Hydroxy(phenyl)methylene]-1-methylindolin-2-one (5m):[3f] Yield
188 mg (74%); yellow crystals; m.p. 145–147 (ref.:[9c] 147–149 °C).
1H NMR (400 MHz, CDCl3): δ = 13.87 (br. s, 1 H), 7.79–7.76 (m,
2 H), 7.57–7.50 (m, 3 H), 7.20–7.16 (m, 2 H), 6.95–6.87 (m, 2 H),
3.39 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.9, 170.9,
139.1, 134.1, 131.3, 128.6, 128.4, 125.9, 121.8, 121.5, 119.6, 108.3,
101.4, 25.8 ppm.
5-Chloro-3-[hydroxy(thiophen-2-yl)methylene]-1-(4-methoxy-
benzyl)indolin-2-one (5n): Yield 700 mg (88%; 2 mmol scale); yellow
1
crystals; m.p. 130–132 °C. H NMR (400 MHz, CDCl3): δ = 14.15
(br. s, 1 H), 7.86 (d, J = 3.0 Hz, 1 H), 7.70–7.68 (m, 1 H), 7.65 (d,
J = 1.9 Hz, 1 H), 7.24 (dd, J = 10.0, 6.9 Hz, 3 H), 7.07 (dd, J =
8.4, 1.9 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.4 Hz, 1
H), 5.00 (s, 2 H), 3.76 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 171.8, 165.7, 159.2, 136.4, 135.9, 131.4, 131.1, 128.6, 127.7,
127.5, 127.5, 125.5, 123.0, 119.6, 114.2, 110.2, 100.0, 55.2,
43.1 ppm. IR (CH Cl ): ν = 2927, 1644, 1611, 1513, 1473, 1439,
˜
2
2
1409, 1364, 1301, 1279, 1247, 1217, 1176, 1030, 856, 802, 719 cm–1.
HRMS (ESI): m/z calcd. for C21H17ClNO3S [M + H]+ 398.0612;
found 398.0615.
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indolin-2-one (5o): Yield 519 mg (89 %; 1.5 mmol scale); yellow
1
crystals; m.p. 168–169 °C. H NMR (400 MHz, CDCl3): δ = 14.59
(br. s, 1 H), 8.95 (s, 1 H), 7.86 (s, 1 H), 7.79 (dd, J = 8.3, 1.8 Hz, 1
H), 7.37 (d, J = 3.4 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 6.92 (d, J
= 8.3 Hz, 1 H), 6.83 (d, J = 8.5 Hz, 2 H), 6.71 (d, J = 1.8 Hz, 1
H), 5.03 (s, 2 H), 3.75 (s, 3 H), 2.59 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 197.3, 173.2, 159.3, 159.2, 148.5, 146.2,
141.6, 131.7, 128.6, 127.5, 126.9, 122.7, 121.4, 117.8, 114.2, 112.8,
108.5, 98.6, 55.2, 43.1, 26.4 ppm. IR (CH Cl ): ν = 2926, 1673,
˜
2
2
1622, 1540, 1512, 1446, 1402, 1384, 1357, 1282, 1247, 1179, 1141,
1074, 1046, 1015, 883, 815, 753 cm–1. HRMS (ESI): m/z calcd. for
C23H20NO5 [M + H]+ 390.1336; found 390.1339.
3-Acetyl-1-benzyl-4-methylindolin-2-one (6l):[7] Yield 92 mg (33%);
1
[7] B. Lu, D. Ma, Org. Lett. 2006, 8, 6115–6118.
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purple crystals; m.p. 108–109 °C. H NMR (400 MHz, CDCl3): δ
= 7.33–7.24 (m, 5 H), 7.14 (t, J = 7.8 Hz, 1 H), 6.87 (d, J = 7.8 Hz,
1 H), 6.62 (d, J = 7.8 Hz, 1 H), 4.97 (d, J = 15.6 Hz, 1 H), 4.85 (d,
J = 15.6 Hz, 1 H), 4.57 (s, 1 H), 2.29 (s, 3 H), 2.17 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 199.3, 170.7, 143.7, 135.5, 135.4,
129.0, 128.8, 127.7, 127.3, 124.7, 122.3, 107.0, 60.6, 44.1, 28.3,
18.6 ppm.
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Large-Scale Synthesis of 5a: To a solution of Cu(NO3)2·3H2O
(120 mg, 5mol-%) in tap water (100 mL) was added diazo com-
pound 4a (10 mmol), and the suspension was heated to reflux for
40 min. After cooling and addition of ethyl acetate (100 mL), the
organic layer was separated, dried with anhydrous Na2SO4, and
filtered. The resulting solution was concentrated in vacuo to give
5a (1.73 g) in high purity.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of unreported di-
3928
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3923–3929

Copper Nitrate Catalyzed Synthesis of 3-Alkylideneoxindoles
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became colorless. When the reaction finished, part of 5a pre-
cipitated.
[17]
[18]
Data were taken from: J. A. Dean, Lange’s Handbook of Chem-
istry, 15th ed., McGraw-Hill, New York, 1999.
Z. Li, H.-X. Gao, Org. Biomol. Chem. 2012, 10, 6294–6298.
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provides crucial evidence for the involvment of zwitterionic in-
termediates. Although the authors mentioned a C–H insertion
process, they described an intramolecular aromatic metal carb-
ene electrophilic addition mechanism. In our opinion, the aro-
matic electrophilic addition mechanism is reasonable due to the
existence of zwitterionic intermediates. On the other hand, an
orbital symmetry allowed H[1,5] sigmatropic shift is a more
reasonable process than their proposed 1,2-proton transfer for
the proton transfer.
Received: March 12, 2014
Published Online: May 6, 2014
[16] Diazo amide 4a and oxindole 5a can partly dissolve in water.
As the reaction progressed, the yellow solution of 4a in water
Eur. J. Org. Chem. 2014, 3923–3929
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