Azo-compound-mediated cyanoalkylation of alkenes by copper catalysis: General access to cyano-substituted oxindoles

Article abstract of DOI:10.1055/s-0034-1379902

Abstract A practical and highly efficient azo-compound-mediated/ promoted radical cyanoalkylation of activated alkenes by copper catalysis was developed, which allowed for general synthesis of oxindoles bearing various nitrile moieties, especially the rarely reported 3° nitrile moiety via cascade radical addition/C(sp²)-H cyclization. This protocol demonstrates that DIAD served for a new promoter instead of usual Ag salts or bases in the C(sp³)-H functionalization of acetonitrile for the first time. The use of readily available AIBN and beyond as the radical sources, and inexpensive copper as the catalyst, as well as the simplicity of operation and handling, make this protocol an attractive access to therapeutically important cyano-substituted oxindoles.

Full text of DOI:10.1055/s-0034-1379902

SYNTHESIS
0
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©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 1567–1580
1567
paper
Synthesis
S. Tang et al.
Paper
Azo-Compound-Mediated Cyanoalkylation of Alkenes by Copper
Catalysis: General Access to Cyano-Substituted Oxindoles
6
R5
R
Shi Tang*a
Dong Zhoua
CN
N
NC
N
R5
R6
5 R6
R
R3
Zhi-Hao Lia,b
Mei-Jun Fua
Jie Lia
Me
CN
O
CuI, DTBP
R1
80 °C
N
R2
NH
R3
4
R
= H
N
H
R1
3° nitrile
Me
Rui-Long Sheng*b
Shu-Hua Lia
N
O
O
CN
R4
R2
R3
N
+
R4
N
Oi-Pr
i-PrO
N
O
R1
O
CN
CuI, DTBP
5 °C
H
a
R2
College of Chemistry and Chemical Engineering, Jishou University,
9
Jishou 416000, P. R. of China
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
1° or 2° nitrile
b
°
°
°
general incorporation of 1 , 2 , and 3 nitrile
Cu catalysis
345 Lingling Road, Shanghai 200032, P. R. of China
stang@jsu.edu.cn
rlsheng@sioc.ac.cn
broad substrate scope (42 examples)
Received: 07.01.2015
Accepted after revision: 15.02.2015
Published online: 26.03.2015
whereas direct addition of electrophilic radical produced by
AIBN onto the double bond of an electron-poor alkene (e.g.,
acrylamides) was usually slow and thus less commonly en-
countered.4c Moreover, despite significant advances in
alkene difunctionalization research (including Heck-type
and free radical reactions), the direct construction of α-
functionalized quaternary carbon center via simple alkene
DOI: 10.1055/s-0034-1379902; Art ID: ss-2015-h0011-op
Abstract A practical and highly efficient azo-compound-mediated/
promoted radical cyanoalkylation of activated alkenes by copper cataly-
sis was developed, which allowed for general synthesis of oxindoles
bearing various nitrile moieties, especially the rarely reported 3° nitrile
moiety via cascade radical addition/C(sp )–H cyclization. This protocol
demonstrates that DIAD served for a new promoter instead of usual Ag
2
5
biscarbonation step remains rare and challenging. It can be
expected that this strategy would undoubtedly represent a
highly interesting approach to oxindole scaffold with an α-
cyano quaternary carbon center. Nevertheless, the alkylary-
3
salts or bases in the C(sp )–H functionalization of acetonitrile for the
first time. The use of readily available AIBN and beyond as the radical
sources, and inexpensive copper as the catalyst, as well as the simplicity
of operation and handling, make this protocol an attractive access to
therapeutically important cyano-substituted oxindoles.
2
lation of activated alkenes with AIBN involving C(sp )–H
bond activation has, to our best knowledge, rarely been re-
ported.6
Key words azo compounds, cyanoalkylation, alkenes, radical, copper
catalysis
In earlier studies, the C–H bond activation of acetoni-
trile by a stoichiometric amount of transition metal (e.g., Ir,
7
Rh, Ni, Fe, etc.) has been well documented. Recent years
The efficient construction of multiple C–C bonds in a
cascade process is a perennial topic of interest for organic
chemists. In this regard, inexpensive metal-catalyzed radi-
have also witnessed considerable advances on catalytic α-
C–H functionalization of acetonitriles. Nevertheless, suc-
8
1
cess in this field is limited mainly to those cases requiring a
strong base for the deprotonation [pKa (MeCN) ~31.3] or
stoichiometric Lewis acid AgF as an activator. Therefore, the
development of alternative environment-friendly activators
instead of commonly encountered strong bases or Ag re-
agents for α-C–H functionalization of nitriles is still well-
desired. Due to economic and environmental benefits, cop-
per has recently gained much popularity as a catalyst in ox-
cal biscarbonation of alkenes to form dual C–C bond simul-
taneously attracted increasing attention, where various
aryl/alkyl radical precursors, such as aryl diazonium salts,
carbazates, diaryliodonium salts, CF3 reagents, C–H reac-
tants, etc. were successfully utilized to involve the tandem
2
addition/interception process. Aliphatic azo compounds
(e.g., AIBN and DEAD), a type of widespread reagent in or-
ganic and polymer synthesis, decompose softly to give radi-
cal species that can be applied for C–H functionalization.3
Therefore, we envisaged that the difunctionalization of
alkenes with 2,2′-azobisisobutyronitrile (AIBN) is, by judi-
cious design, possible to generate oxindoles bearing a ter-
tiary-alkyl nitrile moiety via tandem radical addi-
idative cross-dehydrogenative coupling and difunctional-
9,10
ization of alkenes.
However, base-free copper-catalyzed
3
difunctionalization of alkenes via C(sp )–H functionaliza-
tion of acetonitrile was developed later.8 Oxindoles are
common structural motifs in pharmaceutical agents and
natural products,11 and, given that cyano-containing mole-
cules exhibit important functions in materials, synthetic in-
termediates and pharmaceuticals, the incorporation of cya-
no-substituted groups into oxindole scaffold via simple
d,e
2
tion/C(sp )–H cyclization (Scheme 1, eq. 1). Remarkably,
AIBN in combination with Bu SnH was commonly used as
3
an initiator for radical addition of alkyl halide onto alkene,4
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Synthesis
S. Tang et al.
Paper
this work: cyanoalkylation via radical addition/C–H cyclization
R6
R5
CN
N
R5
R6
NC
N
R6
R3
N
R5
CN
O
CuI, DTBP
0 °C
R4 = H
R1
(1)
8
R3
R2
3° nitrile
R1
N
R2
O
O
CN
R4
N
N
Oi-Pr
R3
N
+
i-PrO
R4
O
R1
O
CN
CuI, DTBP
5 °C
(2)
H
R2
9
1° or 2° nitrile
Scheme 1 Azo compound-mediated cyanoalkylation of alkenes; DTBP = di-tert-butyl peroxide.
alkene difunctionalization is still of great interest, which is
an oxidant improved the reaction and using DTBP is opti-
mal. Other oxidants, such as TBHP, K S O , PhI(OAc) , and
12
still rare (only a few examples to date). For example, Liu
2
2
8
2
12a
and co-workers, in early stage, reported a pioneering Pd-
catalyzed oxidative alkylarylation of alkene with the aid of
a stoichiometric AgF (4 equiv). Just recently, You and co-
PhI(OTF) resulted in unparallel yields (entries 9–13). Se-
2
quential screening of solvents revealed MeCN as the best
choice (entries 14–16). The optimal temperature effect for
the current reaction was 80 °C (entries 17 and 18).
12b
workers developed an elegant copper-catalyzed oxidative
radical cyanomethylation of activated alkenes using a cata-
lytic combination of CuCl and t-BuOOt-Bu (3 equiv). Re-
gardless of substantial achievements in this regard, appar-
ent limitations remain: (1) requirement of either the com-
bination of Pd catalyst with stoichiometric AgF or an
After establishing the optimal reaction conditions, the
scope of N-arylacrylamides was investigated in the difunc-
tionalization reaction using AIBN as α-cyanoalkyl radical
source (Scheme 2). Initial screening revealed that N-substit-
uents of acrylamides had obvious effect on the reaction. For
example, N-arylacrylamides with a benzyl or ethyl group
on the N-atom were found to be well compatible with the
reaction conditions, whereas unprotected N-arylacryl-
12b,c
elevated temperature (≥120 °C)
and (2) in general ineffi-
ciency for the incorporation of 3° nitrile moiety into oxin-
3
dole via α-C(sp )–H functionalization of the 3° nitrile (pos-
2
sibly due to steric hindrance or lower reactivity of α-
amide (R = H) was less efficient in the cyclization (3b and
3
12a
C(sp )–H bond of 3° nitriles). As a continuation of our in-
3c vs 3d). Next, the substitution effect on the N-aryl moiety
in the reaction was investigated. Gratifyingly, a wide array
1
3
terest in oxindole synthesis, we herein demonstrate an al-
ternative AIBN and beyond-mediated/promoted oxidative
cyanoalkylation reaction of N-arylacrylamides by copper
catalysis, which could allow for general incorporation of 1°,
of substituents including Me, MeO, Cl, F, and CF at the 4-,
3
3- or 2-position of the aromatic ring displayed good reac-
tivity, and the reactive order is: poor electron-withdrawing
and electron donating groups > strong electron-withdraw-
ing groups (3e–o). Notably, the halo groups, such as Cl and
F on the 3- or 4-position of the N-aryl moiety, were intact in
the reaction, whereas Br substituent at 2-position was very
reactive and lead to unidentified by-products. The reaction
of meta-methyl-substituted N-arylacrylamide afforded a
mixture of two regioselective products 3j and 3j′. Ortho-
substituted N-arylacrylamides were also tolerated, but the
yield decreased to some extent possibly owing to the steric
hindrance (3k and 3i). Remarkably, a polycyclic oxindole
derivative was successfully synthesized by this protocol,
and the N-containing ligand (1,10-phenanthroline) was
found to be useful to achieve good yield (3p). Sequential in-
2
°, and 3° alkyl nitrile moieties into oxindoles through cas-
2
cade radical addition/C(sp )–H cyclization (Scheme 1, eq. 1)
or double C–H cleavage of an arene and acetonitrile
(Scheme 1, eq. 2).
Initially, the reaction between N-methyl-N-phenylacryl-
amide (1a) and AIBN was employed as the model reaction
to explore the optimal conditions to prepare oxindoles with
a 3° nitrile moiety (Table 1). Delightedly, we observed the
formation of the desired cyclization product 3a in a 23%
yield when the reaction was conducted without the use of
metal catalyst (Table 1, entry 1). Encouraged by this result,
various inexpensive copper(I) and iron(II) salts were subse-
quently used as the catalyst to enhance the yield (entries 2–
8). Among the metals examined, CuI turned out to be the
vestigations revealed that several groups (Ph and CH OAc)
2
most effective one, and afforded 3a in a yield of 78% when
at the 2-position of the acrylamide moiety were compatible
using DTBP as an oxidant (entry 4). In this process, adding
with the optimal conditions to afford 3q and 3s, respective-
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Synthesis
S. Tang et al.
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3
ly, whereas hydroxymethyl (R = CH OH) and mono-substi-
hexyl ring underwent the C–H cyclization to yield corre-
sponding oxindoles in good to excellent yields (3u–v). How-
ever, azo compound 2c [CAS Reg. No. 2638-94-0] bearing
carboxylic group failed to give the desired oxindole (3y).
Our initial attempt to introduce the ethoxylcarbonyl
moiety into oxindole scaffold using diethyl azodicarboxyl-
ate (DEAD) under the above standard conditions unexpect-
2
3
tuted olefins (R = H) were inefficient for the cyclization
process (3r and 3t). Unfortunately, the β-phenyl substituted
acrylamides failed to be tolerated in our current reaction
conditions (3u).
Table 1 Optimization of Reaction Conditionsa
2a
edly did not result in the desired product 5 efficiently, but
3
led to the oxindole 4a via C(sp )–H functionalization of ace-
tonitrile (Table 2). With these results in mind, we wondered
whether the DEAD was really involved in this cyclization re-
action through dual C–H bond cleavage of an arene and ace-
tonitrile. After brief screenings, the dialkyl azodicarboxylate
was observed to be crucial for this transformation, and the
use of diisopropyl azodicarboxylate (DIAD) was optimal.
Notably, the reaction failed to lead to desired oxindole 4a in
the absence an azodicarboxylate reagent under current
temperature conditions (95 °C),14 which might be attribut-
ed to the fact that azodicarboxylate could serve as a radical
initiator to promote the C–H activation of acetonitrile (for
detail screenings see Supporting information).
Entry
Metal
Oxidant
Solvent
Yield (%)b
Subsequently, the substrate scope in this reaction in-
volving C–H cleavage of acetonitrile were investigated
1
2
3
4
5
6
7
8
9
none
CuCl
CuBr
CuI
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1,4-dioxane
toluene
DCE
23
53
74
78
65
45
57
46
61
51
46
42
14
62
55
39
42
64
(Scheme 4). Rewardingly, a series of substituents, such as p-
Me, o-Me, Cl, F, CF displayed good reactivity in most cases
3
to yield various oxindoles with 1° nitrile moiety irrespec-
tive of steric and electronic character of the substituent
groups (4a–f). Of more importance, this protocol could also
be utilized to prepare complex and pharmaceutically inter-
esting oxindoles. For example, the polycyclic oxindole 4r
could be synthesized through the C–H cyclization of N-aryl-
acrylamide 1r. In addition, the N-pyridylacrylamide 1s was
also a viable substrate for the reaction, and afforded syn-
thetically important heterocycle 4s. Next, the compatibility
of other nitriles as C–H reactant under the standard condi-
tions was examined. n-Butyl nitrile was also a viable C–H
reactant for the cyanoalkylation to N-methyl-N-phenyl-
acrylamide (1a), but the yield decreasing to some extent
CuCN
FeSO
4 2
·7H O
FeBr
2
Fe(NH
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
4 2 4 2 2
) (SO ) ·6H O
1
1
1
1
1
1
1
1
0
1
2
3
4
5
2 2 8
K S O
PhI(OAc)
2
PhI(OTFA)
2
none
DTBP
DTBP
(
4t). Nevertheless, the 3° nitrile proved to be an inefficient
6
DTBP
reactant to be involved in the cyanoalkylation promoted by
DIAD (4u).
7c
DTBP
MeCN
MeCN
8d
To investigate the mechanism of the cascade addi-
1
DTBP
2
tion/C(sp )–H cyclization process, the inter- and intra-mo-
a
Reaction conditions: 1a (0.5 mmol), AIBN (2 equiv), oxidant (2 equiv),
metal (5 mol%), and solvent (2 mL) at 80 °C for 12 h. TBHP: tert-Butyl hy-
drogen peroxide (70% aq solution); DCE: 1,2-Dichloroethane.
Yield of the isolated product.
Reaction conducted at 60 °C.
Reaction conducted at 100 °C.
lecular kinetic isotope control experiments were per-
formed (Scheme 5). For the cyanopropylation using AIBN,
small kinetic isotopic effects (the intramolecular
K /K = 1.3 and intermolecular K /K = 1.0) were observed.
b
c
d
H
D
H
D
Comparative kinetic isotopic effects (the intramolecular
Next, the scope of α-cyanoazo compounds was investi-
gated. Besides AIBN, other α-cyanoazo compounds could
serve as viable substrate for the alkylarylation reaction to
give the desired oxindoles with various 3° nitrile moieties
K /K = 1.3 and intermolecular K /K = 1.0) were also ob-
served in the DIAD-promoted cyanomethylation involving
C–H activation of acetonitrile, which suggested that either
H
D
H
D
the S Ar mechanism or the free radical mechanism was in-
E
(Scheme 3). Notably, irrespective of electronic and steric
volved in the two reactions.15 Interestingly, when the reac-
character of the substituent groups on the aromatic ring of
tion of 1a was conducted in a 1:1 mixture of MeCN–CD CN
3
acrylamides, the α-cyanoazo compound 2b bearing a cyclo-
using DIAD, a large primary isotope effect (K /k = 4.5) was
H
D
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R3
N
R3
CuI (5 mol%)
R1
N
CN
CN
O
DTBP (2 equiv)
MeCN, 80 °C
12 h
+
O
NC
N
R1
N
R2
1
2
3
R2
3° nitrile
CN
O
R
CN
O
CN
O
N
N
N
Me
R
Me
3
b R = Et, 84%
3
3
3
3
3
e R = OMe, 83%
f R = F, 69%
g R = Cl, 72%
h R = CF3, 57%
i R = NO2, < 5%
3
a, 75%a
3c R = Bn, 70%
3d R = H, <5%
CN
CN
O
+
O
N
N
Me
Me
3j + 3j' (2:1), 73%
CN
CN
Cl
Cl
CN
O
O
O
+
N
Cl
N
N
Me
Me
Me
Cl
R
3n + 3n' (1:3), 43%
3
3
3
k R = Me, 68%
l R = OMe, 51%
m R = Br, < 5%
Ph
CN
O
Cl
N
O
NC
CN
O
N
Me
N
p, 58%b
3
3q, 73%
Me
3o, 60%
AcO
HO
H
CN
O
CN
O
CN
O
N
N
N
Me
Me
3s, 66%
Me
3r, < 5%
3t, < 5%
Ph
H
CN
O
N
Me
3
u, < 5%
Scheme 2 Scope of N-arylacrylamines. Reaction conditions: 1 (0.5 mmol), AIBN (2 equiv), DTBP (2 equiv), CuI (5 mol%), and MeCN (2 mL) at 80 °C for
2 h. Reaction was carried out on a 2 mmol scale. b 1,10-phenanthroline (10 mol%) was added.
a
1
3
obtained (Scheme 5, eq. 1). A similar KIE value (3.0) was
also observed in individual reaction in CH CN and CD CN,
which suggested that a C(sp )–H bond cleavage of acetoni-
trile contributed to the rate-determining step. Notably, the
3
3
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Synthesis
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4
5
R R
R3
N
R3
R4 R5
CuI (5 mol%)
DTBP ( 2 equiv)
CN
O
R1
R1
N
CN
+
NC
N
N
R2
O
MeCN, 80 °C
12 h
R4 R5
R2
1
2
3
F
CN
O
CN
O
CN
O
N
N
N
Me
Me
Me
3x, 75%a
3w, 95%
3v, 92%
CO2H
O
CN
O
CN
O
O
N
N
Me
Me
3y, 66%
3z, < 5%
Scheme 3 Scope of α-cyanoazo compounds. Reaction conditions: 1 (0.5 mmol), 2 (2 equiv), DTBP (2 equiv), CuI (5 mol%), and MeCN (2 mL) at 80 °C for
a
1
2 h. Reaction was carried out on a 2 mmol scale.
free radical mechanism was supported by the control ex-
periment: a stoichiometric amount of TEMPO (4 equiv), a
well-known radical inhibitor, was used in the reactions of
Finally, to utilize the copper-catalyzed difunctionaliza-
tion of alkene for the modification of pharmaceutically in-
teresting scaffold, diverse synthetic transformations of the
above-obtained cyano-containing oxindoles were explored
(Scheme 7). Delightedly, the product 3w could be reduced
1a with either AIBN or DIAD, and the formation of the cor-
responding oxindoles was suppressed seriously (Scheme 5,
eq. 2 and 3).
18
by LiAlH to afford spirocyclic indoline 6 in 73% yield. In
4
Based on the experimental results and previously re-
ported mechanism, a possible mechanism is proposed as
addition, aliphatic carboxylic acid 7 resulted by the hydro-
lysis of 3a under alkaline conditions was an interesting syn-
thetic precursor for the construction of an interesting bis-
oxindole scaffold 8 via an additional cyclization process de-
2–8
outlined in Scheme 6 for this alkylarylation process of N-
II
arylacrylamides. First, the copper(II) alkoxide [Cu ]Ot-Bu
•
I
2k
and t-BuO were generated by the reaction of [Cu ] with t-
veloped by Zhu.
1
6
BuOOt-Bu. For the C–H cyclization using AIBN, at first, the
AIBN decomposes to give the nitrile-stabilized radical A,
followed by its addition onto the C=C bond of N-methyl-N-
phenylacrylamide (1a) generating an alkyl radical B. Intra-
molecular cyclization of intermediate B with an aryl ring
forms radical intermediate C, and then abstraction of an
In summary, we have developed a highly practical azo
compound-mediated radical cyanoalkylation of activated
alkenes by inexpensive CuI, which allowed for general
preparation of various oxindoles bearing various nitrile
moieties, especially the rare-reported ones bearing an α-
cyano quaternary carbon center. In addition, this protocol
discovered that DIAD could be used as a novel promoter in-
stead of commonly encountered Ag reagents or strong base
II
aryl hydrogen in the intermediate C by [Cu ]-species takes
place to afford desired oxindole 3a. Regarding the cycliza-
3
tion involving C–H functionalization of acetonitrile, at first
for the α-C(sp )–H functionalization of acetonitrile, which
•
the DIAD decomposes to generate radical i-PrO C under
would open a new door for the application of azo com-
pound in the C–H functionalization of nitriles. The use of
environment-friendly and readily available azo compound
and inexpensive copper as the catalyst, as well as the sim-
plicity of preparation and handling, make this protocol a
highly attractive complement for the construction of phar-
maceutically interesting cyano-substituted oxindoles. The
detailed mechanism and application of the novel reaction
to more complex targets are currently under investigation
in our laboratory.
2
•
heat, and then i-PrO C abstracts a hydrogen from acetoni-
2
•
17
•
trile to generate CH CN. The resulting CH CN adds onto
2
2
C=C bond of 1a to give intermediate D, followed by cycliza-
tion of intermediate D generating E. Finally, the abstraction
II
of an aryl hydrogen by the [Cu ] species produced by the
I
oxidative reaction of [Cu ] salt with t-BuOOt-Bu takes place
to give the corresponding oxindole 4a.
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3-(1-Ethyl-3-methyl-2-oxoindolin-3-yl)-2,2-dimethylpropane-
nitrile (3b)
All manipulations of oxygen- and moisture-sensitive materials were
conducted with a Schlenk technique or in a dry box under a N or ar-
Yield: 107.5 mg (84%); colorless solid; mp 71–72 °C.
2
gon atmosphere. Flash column chromatography was performed using
EM Silica gel 60 (300―400 mesh). Visualization was accomplished
IR (KBr): 2247, 1713, 1611, 1431. 1376, 1337 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.31 (m, 2 H), 7.09 (t, J = 7.2 Hz, 1
3
with UV light (254 nm) and/or an aqueous alkaline KMnO solution
4
1
13
H), 6.90 (d, J = 8.0 Hz, 2 H), 3.90–3.70 (m, 2 H), 2.32 (d, J = 14.4 Hz, 1
H), 2.16 (d, J = 14.4 Hz, 1 H), 1.32 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.20
(s, 3 H), 1.05 (s, 3 H).
followed by heating. H and C NMR spectra were recorded on a Vari-
an Mercury 400 ( H NMR, 400 MHz; C NMR 101 MHz) spectrometer
with solvent resonance as the internal standard ( H NMR, CHCl at
.26 ppm; C NMR, CDCl at 77.0 ppm). Unless otherwise noted, re-
1
13
1
3
13
13C NMR (101 MHz, CDCl
7
3
): δ = 179.2, 142.1, 131.0, 128.5, 125.0,
3
agents were commercially available and were used without further
124.2, 122.2, 108.6, 46.0, 46.1, 30.8, 29.8, 27.9, 26.1, 25.8, 12.2.
purification. N-Arylacrylamides 1 were prepared according to litera-
ture procedures.
+
MS (EI, 70 eV): m/z (%) = 256 ([M ], 27), 174 (100).
12a
+
HRMS (ESI): m/z calcd for C16H21N O [M + H] : 257.1649; found:
2
257.1653.
Oxindoles Bearing 3° Nitrile Moiety; General Procedure
To a mixture of N-arylacrylamide 1 (0.5 mmol), AIBN or its analogue
3
-(1-Benzyl-3-methyl-2-oxoindolin-3-yl)-2,2-dimethylpropane-
(2.0 equiv), CuI (5 mol%) in MeCN (2.0 mL) was added t-BuOOt-Bu
nitrile (3c)
(2.0 equiv) dropwise, and then the resulting solution was stirred at
Yield: 111.3 mg (70%); yellow solid; mp 80–81 °C.
IR (KBr): 2233, 1701, 1610, 1432, 1376, 1332 cm–1
the indicated temperature for 12 h. The solvent was evaporated under
reduced pressure and the resulted mixture was filtered through a Flo-
risil pad, diluted with Et O (50 mL), and the Et O layer was washed
.
1
2
2
H NMR (400 MHz, CDCl ): δ = 7.40–7.20 (m, 7 H), 7.05 (t, J = 7.2 Hz, 1
3
with H O (10 mL) and then brine (10 mL). The organic layer was dried
H), 6.83 (d, J = 8.0 Hz, 2 H), 5.12 (d, J = 15.6 Hz, 1 H), 4.72 (d, J = 15.6
2
(
MgSO ) and concentrated in vacuo. The residue was purified by flash
Hz, 1 H), 2.36 (d, J = 14.8 Hz, 1 H), 2.22 (d, J = 14.4 Hz, 1 H), 1.40 (s, 3
4
chromatography on silica gel to afford the corresponding oxindole
with 3° alkyl nitrile moiety in a yield listed in Scheme 1 and 2.
H), 1.19 (s, 3 H), 1.03 (s, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 179.7, 142.3, 130.8, 128.7, 128.5,
3
1
27.7, 127.6, 124.8, 124.1, 122.4, 119.9, 109.5, 47.0, 46.2, 44.1, 30.8,
3
(
-(1,3-Dimethyl-2-oxoindolin-3-yl)-2,2-dimethylpropanenitrile
3a)
Yield: 94.0 mg (78%); colorless solid; mp 100–101 °C.
29.7, 28.1, 26.3.
+
MS (EI, 70 eV): m/z (%) = 318 ([M ], 22), 236 (100).
+
HRMS: m/z (ESI) calcd for C21H23N O [M + H] : 319.1805; found:
2
IR (KBr): 2234, 1716, 1610, 1432, 1378, 1335 cm–1
.
319.1801.
1
H NMR (500 MHz, CDCl ): δ = 7.40–7.25 (m, 2 H), 7.09 (t, J = 7.5 Hz, 1
3
H), 6.90 (d, J = 8.0 Hz, 1 H), 3.23 (s, 3 H), 2.32 (d, J = 14.4 Hz, 1 H), 2.16
3
-(1-Ethyl-5-methoxy-3-methyl-2-oxoindolin-3-yl)-2,2-diethyl-
(d, J = 14.5 Hz, 1 H), 1.34 (s, 3 H), 1.13 (s, 3 H), 1.08 (s, 3 H).
propanenitrile (3e)
13
C NMR (101 MHz, CDCl ): δ = 179.5, 143.1, 130.9, 128.6, 124.6,
Yield: 118.6 mg (83%); yellow solid; mp 111–112 °C.
3
1
23.9, 122.4, 108.5, 47.0, 46.5, 30.7, 29.6, 27.4, 26.8, 26.4.
IR (KBr): 2237, 1702, 1596, 1431, 1384, 1337 cm–1
.
+
MS (EI, 70 eV): m/z (%) = 242 ([M ], 32), 160 (100).
1
H NMR (400 MHz, CDCl ): δ = 6.95 (s, 1 H), 6.86–6.79 (m, 2 H), 3.84–
3
+
HRMS (ESI): m/z calcd for C15H19N O [M + H] : 243.1492; found:
3.67 (m, 2 H), 3.80 (s, 3 H), 2.30 (d, J = 14.8 Hz, 1 H), 2.17 (s, J = 14.8
2
243.1495.
Hz, 1 H), 1.31 (s, 3 H), 1.29–1.20 (m, 6 H), 1.04 (s, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 178.9, 166.7, 135.5, 132.3, 124.3,
3
113.2, 112.4, 108.9, 55.9, 47.3, 46.0, 30.8, 29.8, 29.7, 28.0, 25.8, 12.2.
Table 2 Screening of Azodicarboxylic Reagentsa
CN
2
CO R
RO2CN=NCO2R
CuI, DTBP
N
O
O
O
+
Me
MeCN
N
N
Me
Me
1
a
4a
5
Entry
RO
2
CN=NCO
2
R
Yield of 4a(%)b
Yield of 5 (%)c
1
2
3
none
<5
35
43
85
0
R = Me (DMAD)
R = Et (DEAD)
R = i-Pr (DIAD)
trace
trace
trace
4
a
Reaction conditions: 1a (0.5 mmol), RO
Yield of the isolated product.
Determined by GC/MS.
2 2
CN=NCO R (2 equiv), DTBP (4 equiv), CuI (20 mol%), and MeCN (2 mL) at 95 °C for 24 h.
b
c
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intermolecular KIE experiment
D
intramolecular KIE experiment
D
+
D
N
O
N
O
Me
Me
D
N
O
Me
D
D
D5]-1a
1a
[D ]-1a
[
1
7% yield (2 h), KH/KD = 1.0a
2% yield (2 h), KH/KD = 1.0b
67% yield (12 h), KH/KD = 1.3a
73% yield (24 h), KH/KD = 1.0b
3
4
CN
CN
D
CuI (20 mol%)
DIAD (2 equiv)
DTBP (4 equiv)
D
O+
O
(1)
N
O
MeCN–CD3CN (1:1)
5 °C, 24 h
N
N
Me
9
Me
Me
1a
H D
K /K = 4.5
4a
2
[D ]-4a
(KIE = 3.0 in individual reaction)
CuI (5 mol%), DTBP (2 equiv)
CN
O
TEMPO (4 equiv), AIBN (2 equiv)
MeCN, 80 °C, 12 h
(2)
N
Me
3a, <10%
N
O
CN
Me
CuI (20 mol%), DTBP (4 equiv)
TEMPO (4 equiv), DIAD (2 equiv)
1
a
O
(3)
MeCN, 95 °C, 24 h
N
Me
4
a, <10%
Scheme 5 Control experiments. a Under standard conditions using AIBN. b Under standard conditions using DIAD.
+
1
MS (EI, 70 eV): m/z (%) = 286 ([M ], 17), 204 (100).
H NMR (400 MHz, CDCl ): δ = 7.31–7.25 (m, 2 H), 6.81 (d, J = 8.0 Hz, 1
3
+
H), 3.21 (s, 3 H), 2.32 (d, J = 14.4 Hz, 1 H), 2.10 (d, J = 14.4 Hz, 1 H),
HRMS (ESI): m/z calcd for C17H23N O [M + H] : 287.1755; found:
2
2
1
.34 (s, 3 H), 1.15 (s, 3 H), 1.10 (s, 3 H).
287.1752.
13
C NMR (101 MHz, CDCl ): δ = 179.0, 141.7, 132.7, 127.9, 125.0,
3
1
23.9, 123.6, 109.4, 47.2, 46.6, 30.5, 29.6, 27.3, 27.1, 26.5.
3
-(5-Fluoro-1,3-dimethyl-2-oxoindolin-3-yl)-2,2-dimethylpro-
+
panenitrile (3f)
MS (EI, 70 eV): m/z (%) = 276 ([M ], 12), 194 (100).
Yield: 89.75 mg (69%); pale yellow solid; mp 107–108 °C.
+
HRMS (ESI): m/z calcd for C15H18ClN O [M + H] : 277.1103; found:
277.1106.
2
IR (KBr): 2234, 1718, 1617, 1435, 1383, 1335 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.10–7.00 (m, 2 H), 6.60–6.71 (m, 1 H),
3
3
-(1,3-Dimethyl-2-oxo-5-(trifluoromethyl)indolin-3-yl)-2,2-di-
3
3
.21 (s, 3 H), 2.32 (d, J = 14.8 Hz, 1 H), 2.11 (d, J = 14.8 Hz, 1 H), 1.34 (s,
H), 1.16 (s, 3 H), 1.10 (s, 3 H).
methylpropanenitrile (3h)
1
3
Yield: 88.3 mg (57%); yellow solid; mp 114–115 °C.
IR (KBr): 2235, 1715, 1624, 1432, 1385, 1327 cm–1
.
C NMR (101 MHz, CDCl ): δ = 179.2, 159.2 (d, J = 204.4 Hz), 139.1,
3
1
32.6, 123.7, 114.8 (d, J = 23.4 Hz), 112.7 (d, J = 24.5 Hz), 109.0, 47.4,
4
6.5, 30.6, 29.1, 23.3, 26.9, 26.5.
1
H NMR (400 MHz, CDCl ): δ = 7.60 (d, J = 8.4 Hz, 1 H), 7.52 (s, 1 H),
3
+
MS (EI, 70 eV): m/z (%) = 260 ([M ], 17), 178 (100).
6.96 (d, J = 8.4 Hz, 1 H), 3.26 (s, 3 H), 2.33 (d, J = 14.8 Hz, 1 H), 2.15 (d,
J = 14.8 Hz, 1 H), 1.37 (s, 3 H), 1.11 (s, 6 H).
+
HRMS: m/z (ESI) calcd for C15H18FN O [M + H] : 261.1397; found:
2
13
261.1399.
C NMR (101 MHz, CDCl ): δ = 179.4, 146.1, 131.6, 126.3 (q, J = 3.9
3
Hz), 124.0 (q, J = 32.8 Hz), 123.4, 121.6 (q, J = 3.5 Hz), 120.2, 108.3,
4
7.0, 46.5, 30.5, 29.5, 27.2, 27.1, 26.6.
3
-(5-Chloro-1,3-dimethyl-2-oxoindolin-3-yl)-2,2-dimethylpro-
+
panenitrile (3g)
MS (EI, 70 eV): m/z (%) = 310 ([M ], 32), 228 (100).
Yield: 99.3 mg (72%); pale yellow solid; mp 128–129 °C.
+
HRMS (ESI): m/z calcd for C16H18F N O [M + H] : 311.1366; found:
311.1367.
3
2
IR (KBr): 2233, 1715, 1610, 1432, 1383, 1345 cm–1
.
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t-BuOOt-Bu + Cu(I)
t-BuO-Cu(II) + t-BuO
a) path for C–H cyclization using AIBN
1a
CN
CN
N
CN
NC
N
N
O
O
2
a
N2
Me
B
A
Cu(II)
H
CN
3a
N
Cu(I)
Me
C
b) path for C–H cyclization using DIAD
O
N2
N
Oi-Pr
O
MeCN
i-PrO
N
Oi-Pr
CH2CN
O
DIAD
t-BuOOt-Bu
1a
CN
Cu(I)
Cu(II)
H
CN
O
4a
N
N
Me
O
Me
E
D
Scheme 6 Proposed mechanism for the formation of oxindoles
R2
R3
CN
F
R1
CO2H
O
a
b
NH
O
R1 = F
1
2
N
N
H
R
= H
N
Me
Me
3
2
3
Me
R = R = Me
R = R
=
6, 73%
7, 68%
cf. ref. 2k
O O
N
N
Me
Me
8
Scheme 7 Synthetic transformation of cyano-containing oxindoles. Reagent and conditions: (a) LiAlH (4 equiv), THF, 1 h, then reflux, 0.5 h; (b) NaOH (5
4
equiv), ethylene glycol, 110 °C, 12 h, then aq 1 M HCl, 0 °C to r.t.
1
2,2-Dimethyl-3-(1,3,6-trimethyl-2-oxoindolin-3-yl)propane-
H NMR (400 MHz, CDCl ): δ = 7.26–7.15 (m, 3 H), 6.90–6.83 (m, 3 H),
3
nitrile (3j) and 2,2-Dimethyl-3-(1,3,4-trimethyl-2-oxoindolin-3-
yl)propanenitrile (3j′)
6.74–6.70 (m, 3 H), 2.20 (s, 9 H), 2.42 (s, 6 H), 2.36 (s, 3 H), 2.36–2.22
(m, 5 H), 2.12 (d, J = 14.8 Hz, 1 H), 2.39 (s, 6 H), 2.30 (s, 3 H), 1.15 (s, 6
H), 1.13 (s, 3 H), 1.07 (s, 6 H), 1.05 (s, 3 H).
Yield 3j/3j′ (2:1): 93.4 mg (73%).
IR (KBr): 2233, 1702, 1610, 1434, 1372, 1327 cm–1
.
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13
CN
C NMR (101 MHz, CDCl ): δ = 180.0, 179.6, 143.3, 143.1, 138.7,
3
CuI (20 mol%)
DTBP (4 equiv)
DIAD (3 equiv)
1
35.8, 128.5, 128.1, 125.3, 124.4, 123.4, 122.9, 109.4, 106.2, 46.8, 46.4,
R2
R2
45.1, 44.2, 30.8, 30.7, 30.5, 30.3, 29.6, 29.1, 27.5, 26.6, 26.4, 24.7.
R1
R1
+
O
O
+
H
MS (EI, 70 eV): m/z (%) = 256 ([M ], 26), 174 (100).
CN
N
95 °C, 24 h
N
Me
HRMS (ESI): m/z calcd for C16H21N O [M + H] : 257.1649; found:
+
Me
2
4
1
257.1654.
1
° or 2° nitrile
CN
CN
2,2-Dimethyl-3-(1,3,7-trimethyl-2-oxoindolin-3-yl)propane-
nitrile (3k)
CN
R
Yield: 87.0 mg (68%); yellow solid; mp 84–85 °C.
O
O
O
IR (KBr): 2232, 1702, 1600, 1432, 1363, 1327 cm–1
.
N
N
N
Et
Me
1
Me
a, 85%
H NMR (400 MHz, CDCl ): δ = 7.12 (d, J = 7.6 Hz, 1 H), 7.04 (d, J = 7.6
3
4
4
4
b R = Et, 75%
c R = Bn, 63%
d R = H, < 5%
Hz, 1 H), 6.99 (t, J = 7.6 Hz, 1 H), 3.51 (s, 3 H), 2.59 (s, 3 H), 2.21 (d.
J = 14.4 Hz, 1 H), 2.11 (d, J = 14.4 Hz, 1 H), 1.31 (s, 3 H), 1.14 (s, 3 H),
1.10 (s, 3 H).
4
4
4
e R = Me, 87%
f R = MeO, 83%
g R = F, 77%
4
CN
CN
4h R = Cl, 81%
4
4
13
C NMR (101 MHz, CDCl ): δ = 180.3, 140.9, 132.3, 131.6, 123.9,
3
i R = CH3, 71%
j R = EtO2C, 52%
122.5, 122.3, 120.1, 46.7, 46.3, 30.7, 29.7, 29.6, 27.8, 26.8, 19.1.
+
MS (EI, 70 eV): m/z (%) = 256 ([M ], 22), 174 (100).
O
O
+
+
N
N
HRMS (ESI): m/z calcd for C16H21N O [M + H] : 257.1649; found:
2
Me
Me
257.1652.
4
k + 4k', 82%
CN
O
CN
CN
3-(7-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)-2,2-dimethylpro-
panenitrile (3l)
Yield: 69.4 mg (51%); yellow solid; mp 93–94 °C.
IR (KBr): 2233, 1700, 1612, 1439, 1365, 1333 cm–1
.
O
O
N
Me
N
N
Me
Me
Cl
1
OMe
H NMR (400 MHz, CDCl ): δ = 7.01 (t, J = 8.4 Hz, 2 H), 6.90–6.71 (m, 2
3
4n, 63%
H), 3.85 (s, 3 H), 3.49 (s, 3 H), 2.28 (d, J = 14.8 Hz, 1 H), 2.12 (d, J = 14.8
Hz, 1 H), 1.30 (s, 3 H), 1.17 (s, 3 H), 1.08 (s, 3 H).
4l, 73%
4m, 79%
CN
CN
H
13
C NMR (101 MHz, CDCl ): δ = 179.8, 146.6, 132.6, 130.9, 123.9,
CN
3
122.9, 117.3, 112.2, 55.8, 46.9, 46.5, 30.7, 29.7, 27.7, 26.4, 25.8.
Cl
Cl
O
+
O
MS (EI, 70 eV): m/z (%) = 272 ([M ], 35), 190 (100).
N
N
O
+
Me
HRMS (ESI): m/z calcd for C16H21N O [M + H] : 273.1598; found:
Me
2
2
N
273.1603.
Me
4
o, 51%
4q, < 5%
4p, 77%
3
-(5,6-Dichloro-1,3-dimethyl-2-oxoindolin-3-yl)-2,2-dimethyl-
Pr
CN
CN
propanenitrile (3n) and 3-(4,5-Dichloro-1,3-dimethyl-2-oxoindo-
lin-3-yl)-2,2-dimethylpropanenitrile (3n′)
N
O
Yield 3n/3n′ (1:3): 66.7 mg (43%).
IR (KBr): 2235, 1723, 1602, 1473, 1376, 1325 cm–1
O
N
N
N
.
Me
O
Me
NC
1
H NMR (400 MHz, CDCl ): δ = 7.45 (d, J = 8.4 Hz, 1 H), 7.36 (s, 0.3 H),
3
4t, 43% (1:1.1)a,b
4r, 62%
4s, 49%
6.98 (s, 0.3 H), 6.77 (d, J = 14.4 Hz, 1 H), 3.21 (s, 3 H), 3.20 (s, 1 H), 2.68
(d, J = 14.4Hz, 1 H), 2.31 (d, J = 14.4 Hz, 0.3 H), 2.21 (d, J = 14.4 Hz, 1
H), 2.10 (d, J = 14.4 Hz, 0.3 H), 1.48 (s, 3 H), 1.33 (s, 1 H), 1.18 (s, 4 H),
1
.12 (s, 3 H), 1.09 (s, 1 H).
CN
O
13
C NMR (101 MHz, CDCl ): δ = 178.9, 178.4, 143.3, 142.7, 130.9,
3
N
130.4, 130.3, 129.7, 126.5, 123.9, 123.6, 121.5, 123.1, 110.9, 107.8,
Me
47.0, 46.4, 44.2, 43.4, 30.6, 30.5, 30.4, 30.3, 29.7, 28.2, 28.0, 27.3, 26.9,
26.6, 25.8.
4
u, < 5%
+
MS (EI, 70 eV): m/z (%) = 310 ([M ], 35), 227 (100).
Scheme 4 Scope of N-arylacrylamides. Reaction conditions: 1 (0.5
mmol), DIAD (2 equiv), DTBP (4 equiv), CuI (20 mol%), and MeCN (2
mL) at 95 °C for 24 h. n-Butyl nitrile (2 mL) instead of MeCN. b The ra-
tio in the parentheses is the diasteroselectivity of the reaction as deter-
+
HRMS (ESI): m/z calcd for C15H17Cl N O [M + H] : 311.0713; found:
2
2
a
311.0717.
1
mined by H NMR spectroscopy.
3-(4-Chloro-1,3,7-trimethyl-2-oxoindolin-3-yl)-2,2-dimethylpro-
panenitrile (3o)
Yield: 87.0 mg (60%); yellow solid; mp 78–79 °C.
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IR (KBr): 2231, 1717, 1636, 1457, 1384 1337 cm–1
.
IR (KBr): 2231, 1701, 1614, 1471 cm–1
.
1
1
H NMR (400 MHz, CDCl ): δ = 6.98 (d, J = 8.4 Hz, 1 H), 6.88 (d, J = 8.4
H NMR (400 MHz, CDCl ): δ = 7.32–7.28 (m, 2 H), 7.06 (t, J = 7.6 Hz, 1
3
3
Hz, 1 H), 3.5 (s, 3 H), 2.60 (d, J = 14.4 Hz, 1 H), 2.57 (s, 3 H), 2.19 (d,
J = 14.4 Hz, 1 H), 1.47 (s, 3 H), 1.18 (s, 3 H), 1.13 (s, 3 H).
H), 6.87 (d, J = 8.0 Hz, 1 H), 3.21 (s, 3 H), 2.39 (d, J = 14.4 Hz, 1 H), 2.14
(d, J = 14.4 Hz, 1 H), 1.64–1.03 (m, 10 H), 1.31 (s, 3 H).
13
13
C NMR (101 MHz, CDCl ): δ = 179.6, 142.7, 123.5, 129.8, 129.1,
C NMR (101 MHz, CDCl ): δ = 179.8, 143.0, 131.3, 128.5, 124.6,
3
3
1
28.5, 128.1, 118.8, 47.6, 44.1, 30.7, 29.7, 28.2, 28.0, 23.8, 19.0.
122.4, 122.1, 108.5, 46.7, 46.6, 38.1, 37.0, 35.0, 27.7, 26.4, 24.8, 22.8,
22.5.
+
MS (EI, 70 eV): m/z (%) = 290 ([M ], 23), 208 (100).
+
+
MS (EI, 70 eV): m/z (%) = 282 ([M ], 15), 160 (100).
HRMS (ESI): m/z calcd for C16H20ClN O [M + H] : 291.1259; found:
2
+
291.1256.
HRMS (ESI): m/z calcd for C18H23N O [M + H] : 283.1805; found:
2
283.1808.
2,2-Dimethyl-3-(1-methyl-2-oxo-2,4,5,6-tetrahydro-1H-pyrro-
lo[3,2,1-ij]quinolin-1-yl)propanenitrile (3p)
1-[(1,3,5-Trimethyl-2-oxoindolin-3-yl)methyl]cyclohexanecarbo-
nitrile (3w)
Yield: 77.7 mg (58%); yellow oil.
IR (neat): 2232, 1710, 1608, 1473, 1372, 1341 cm–1
Yield: 140.6 mg (95%); yellow solid; mp 145–146 °C.
.
IR (KBr): 2233, 1706, 1617, 1496 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.20 (d, J = 7.2 Hz, 1 H), 7.13 (d, J = 7.6
3
1
Hz, 1 H), 7.04 (t, J = 7.6 Hz, 1 H), 3.85–3.74 (m, 2 H), 2.93–2.79 (m, 2
H), 2.38 (d, J = 14.4 Hz, 1 H), 2.19 (d, J = 14.4 Hz, 1H), 2.11–2.09 (m, 2
H), 1.41 (s, 3 H), 1.22 (s, 3 H), 1.18 (s, 3 H).
H NMR (400 MHz, CDCl ): δ = 7.11 (s, 1 H), 7.07 (d, J = 7.6 Hz, 1 H),
3
6.74 (d, J = 8.0 Hz, 1 H), 3.17 (s, 3 H), 2.31 (s, 3 H), 2.25 (d, J = 14.8 Hz,
1 H), 2.11 (d, J = 14.8 Hz, 1 H), 1.28–1.09 (m, 10 H), 1.28 (s, 3 H).
13
13
C NMR (101 MHz, CDCl ): δ = 179.3, 139.8, 130.3, 128.1, 124.8,
C NMR (101 MHz, CDCl ): δ = 179.8, 140.6, 131.8, 131.2, 128.6,
3
3
1
23.3, 122.6, 121.4, 49.1, 47.2, 31.6, 30.4, 27.9, 27.7, 25.4, 21.9.
125.5, 122.2, 108.1, 46.7, 46.5, 38.1, 37.0, 34.8, 27.8, 26.4, 24.8, 22.7,
22.5, 21.2.
+
MS (EI, 70 eV): m/z (%) = 268 ([M ], 29), 186 (100).
+
+
MS (EI, 70 eV): m/z (%) = 296 ([M ], 15), 174 (100).
HRMS (ESI): m/z calcd for C17H21N O [M + H] : 269.1649; found:
2
+
269.1653.
HRMS (ESI): m/z calcd for C19H25N O [M + H] : 297.1962; found:
2
297.1965.
2,2-Dimethyl-3-(1-methyl-2-oxo-3-phenylindolin-3-yl)propane-
nitrile (3q)
1-[(5-Fluoro-1,3-dimethyl-2-oxoindolin-3-yl)methyl]cyclohex-
anecarbonitrile (3x)
Yield: 110.9 mg (73%); yellow solid; mp 121–122 °C.
IR (KBr): 2234, 1713, 1611, 1470, 1372, 1341 cm–1
Yield: 450.0 mg (75% on a 2 mmol scale); yellow solid; mp 150–
.
151 °C.
1
H NMR (400 MHz, CDCl ): δ = 7.50–7.48 (m, 7 H), 7.18 (t, J = 8.0 Hz, 1
3
IR (KBr): 2234, 1713, 1621, 1451 cm–1
.
H), 6.96 (d, J = 8.0 Hz, 1 H), 3.22 (s, 3 H), 2.82 (d, J = 14.4 Hz, 1 H), 2.49
1
(d, J = 14.4 Hz, 1 H), 1.23 (s, 3 H), 1.18 (s, 3 H).
H NMR (400 MHz, CDCl ): δ = 7.05–6.97 (m, 2 H), 6.81–6.77 (m, 1 H),
3
1
3
3.20 (s, 3 H), 2.39 (d, J = 14.8 Hz, 1 H), 2.19 (d, J = 14.8 Hz, 1 H), 1.52–
C NMR (101 MHz, CDCl ): δ = 177.4, 144.1, 140.7, 140.4, 129.4,
3
0
.99 (m, 10 H), 1.31 (s, 3 H).
1
2
28.0, 127.5, 125.4, 124.2, 123.8, 122.5, 108.9, 54.6, 46.6, 30.7, 30.2,
9.0, 28.7.
13
C NMR (101 MHz, CDCl ): δ = 179.4, 159.1 (d, J = 241 Hz), 139.0,
3
+
133.0 (d, J = 7.8 Hz), 121.9, 114.6, 112.6 (d, J = 24.5 Hz), 108.9 (d,
J = 7.1 Hz), 47.1, 46.6, 38.1, 36.9, 35.3, 27.6, 26.5, 24.5, 22.7, 22.5.
MS (EI, 70 eV): m/z (%) = 304 ([M ], 35), 222 (100).
+
HRMS (ESI): m/z calcd for C20H21N O [M + H] : 305.1649; found:
2
+
MS (EI, 70 eV): m/z (%) = 300 ([M ], 19), 178 (100).
305.1647.
+
HRMS (ESI): m/z calcd for C18H22FN O [M + H] : 301.1711; found:
2
301.1714.
[
3-(2-Cyano-2-methylpropyl)-1-methyl-2-oxoindolin-3-yl]methyl
Acetate (3s)
Ethyl 3-[(1-Cyanocyclohexyl)methyl]-1,3-dimethyl-2-oxoindoline-
-carboxylate (3y)
Yield: 116.8 mg (66%); yellow solid; mp 140–141 °C.
Yield: 99.0 mg (66%); yellow oil.
IR (neat): 2234, 1732, 1710, 1614, 1491, 1378, 1340 cm–1
5
.
1
H NMR (400 MHz, CDCl ): δ = 7.37 (m, 2 H), 7.07 (t, J = 7.6 Hz, 1 H),
3
IR (KBr): 2235, 1726, 1701, 1612, 1475 cm–1
.
6.90 (d, J = 8.4 Hz, 1 H), 4.34 (d, J = 10.4 Hz, 1 H), 4.00 (d, J = 10.8 Hz, 1
1
H), 3.24 (s, 3 H), 2.28 (s, 2 H), 1.90 (s, 3 H), 1.17 (s, 3 H), 1.10 (s, 3 H).
H NMR (400 MHz, CDCl ): δ = 8.05 (dd, J = 8.4, 1.6 Hz, 1 H), 7.90 (s, 1
3
1
3
H), 6.90 (d, J = 8.4 Hz, 1 H), 4.34 (q, J = 6.8 Hz, 2 H), 3.25 (s, 3 H), 2.32
C NMR (101 MHz, CDCl ): δ = 176.3, 170.2, 143.9, 129.4, 125.9,
3
(
(
1
d, J = 14.4 Hz, 1 H), 2.25 (d, J = 14.4 Hz, 1 H), 1.61–0.98 (m, 10 H), 1.37
t, J = 7.2 Hz, 3 H), 1.35 (s, 3 H).
1
23.7, 122.5, 108.5, 68.5, 50.9, 41.6, 30.3, 27.8, 26.8, 26.5, 20.5.
+
MS (EI, 70 eV): m/z (%) = 300 ([M ], 14), 242 (30), 174 (100).
3
C NMR (101 MHz, CDCl ): δ = 179.9, 166.3, 147.2, 131.5, 131.1,
3
+
HRMS (ESI): m/z calcd for C17H21N O [M + H] : 301.1547; found:
3
2
3
125.4, 124.6, 121.6, 108.0, 60.9, 46.7, 46.6, 37.9, 36.9, 36.1, 27.5, 26.6,
01.1546.
24.8, 22.7, 22.5, 14.3.
+
MS (EI, 70 eV): m/z (%) = 354 ([M ], 13), 232 (100).
1
-[(1,3-Dimethyl-2-oxoindolin-3-yl)methyl]cyclohexanecarboni-
+
HRMS (ESI): m/z calcd for C21H27N O [M + H] : 355.2017; found:
trile (3v)
2
3
355.2019.
Yield: 129.7 mg (92%); yellow solid; mp 158–159 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1567–1580

1
577
Synthesis
S. Tang et al.
Paper
Oxindoles Bearing 1° and 2° Nitrile Moiety; General Procedure
To a mixture of N-arylacrylamide 1 (0.5 mmol), CuI (20 mol%), DIAD
2.0 equiv) in MeCN (2.0 mL) was added t-BuOOt-Bu (4.0 equiv) drop-
3-(5-Fluoro-1,3-dimethyl-2-oxoindolin-3-yl)propanenitrile (4g)12
Yield: 89.3 mg (77%); yellowish oil.
(
1
H NMR (400 MHz, CDCl ): δ = 7.00 (td, J = 8.8, 2.4 Hz, 1 H), 6.93 (dd,
3
wise, and then the resulting solution was stirred at the indicated tem-
perature (Scheme 3) for 24 h. The solvent was evaporated under re-
duced pressure and the resulting mixture was filtered through a Flo-
risil pad. The pad was washed with with Et O (50 mL), and the Et O
J = 7.6, 2.5 Hz, 1 H), 6.78 (dd, J = 8.4, 4.0 Hz, 1 H), 3.18 (s, 3 H), 2.35–
2
.24 (m, 1 H), 2.15–1.89 (m, 3 H), 1.38 (s, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 178.5, 159.4 (d, J = 240.6 Hz), 129.1,
3
2
2
1
1
33.3 (d, J = 7.7 Hz), 118.5, 114.9 (d, J = 23.4 Hz), 110.8 (d, J = 24.5 Hz),
09.0 (d, J = 8.0 Hz), 47.7, 33.2, 26.4, 23.4, 12.8.
layer was washed with H O (10 mL) and brine (10 mL). The Et O layer
2
2
was dried (MgSO ) and concentrated in vacuo. The residue was puri-
4
fied by flash chromatography on silica gel to afford the corresponding
oxindole with 1° and 2° nitrile moiety in a yield listed in Scheme 3.
3
-(5-Chloro-1,3-dimethyl-2-oxoindolin-3-yl)propanenitrile (4h)12
Yield: 100.4 mg (81%); yellowish oil.
-(1,3-Dimethyl-2-oxoindolin-3-yl)propanenitrile (4a)12
1
3
H NMR (400 MHz, CDCl ): δ = 7.29 (dd, J = 8.0, 1.6 Hz, 1 H), 7.16 (s, 1
3
Yield: 90.9 mg (85%); yellowish oil.
H), 6.80 (d, J = 8.4 Hz, 1 H), 3.20 (s, 3 H), 2.37–2.23 (m, 1 H), 2.09–1.97
1
(m, 3 H), 1.39 (s, 3 H).
13C NMR (101 MHz, CDCl
123.2, 118.4, 109.5, 47.5, 33.3, 26.4, 23.4, 12.8.
H NMR (400 MHz, CDCl ): δ = 7.29 (t, J = 7.6 Hz, 1 H), 7.16 (d, J = 7.2
3
Hz, 1 H), 7.09 (t, J = 7.6 Hz, 1 H), 6.85 (d, J = 8.0 Hz, 1 H), 3.19 (s, 3 H),
2
3
): δ = 178.3, 141.7, 133.4, 128.6, 128.5,
.37–2.25 (m, 1 H), 2,12–1.96 (m, 3 H), 1.37 (s, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 178.9, 143.1, 131.6, 128.7, 127.0,
3
3
-(1,3-Dimethyl-2-oxo-5-(trifluoromethyl)indolin-3-yl)propane-
122.6, 118.8, 108.5, 47.3, 33.4, 26.3, 23.4, 12.7.
12
nitrile (4i)
Yield: 100.0 mg (71%); yellow solid; mp 61–62 °C.
1H NMR (400 MHz, CDCl
): δ = 7.61 (d, J = 8.0 Hz, 1 H), 7.42 (s, 1 H),
6.96 (d, J = 8.0 Hz, 1 H), 3.25 (s, 3 H), 2.41–2.30 (m, 1 H), 2.16–2.02 (m,
H), 1.43 (s, 3 H).
13C NMR (101 MHz, CDCl
): δ = 178.3, 148.1, 132.4, 126.5 (q, J = 2.1
3
3
-(1-Ethyl-3-methyl-2-oxoindolin-3-yl)propanenitrile (4b)
Yield: 85.5 mg (75%); yellowish oil.
3
1
H NMR (400 MHz, CDCl ): δ = 7.30 (t, J = 7.2 Hz, 1 H), 7.18 (d, J = 6.4
3
3
Hz, 1 H), 7.09 (t, J = 7.6 Hz, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 5.83–5.68 (m,
2
H), 2.37–2.26 (m, 1 H), 2,14–1.99 (m, 3 H), 1.37 (s, 3 H), 1.25 (t,
J = 7.6 Hz, 3 H).
Hz), 126.3 (q, J = 33 Hz), 119.7 (q, J = 4.1 Hz), 125.2, 118.3, 108.3, 47.2,
13
33.1, 26.5, 23.4, 12.8.
C NMR (101 MHz, CDCl ): δ = 178.4, 142.2, 131.9, 128.6, 127.0,
3
1
22.8, 122.8, 118.8, 108.6, 49.2, 34.7, 33.5, 23.4, 12.7, 12.7.
Ethyl 3-(2-Cyanoethyl)-1,3-dimethyl-2-oxoindoline-5-carboxylate
+
MS (EI, 70 eV): m/z (%) = 228 ([M ], 27), 174 (100).
12
(4j)
+
HRMS (ESI): m/z calcd for C14H17N O [M + H] : 229.1336; found:
2
Yield: 74.3 mg (52%); yellowish oil.
229.1332.
1
H NMR (400 MHz, CDCl ): δ = 8.05 (dd, J = 8.0, 0.8 Hz, 1 H), 7.83 (s, 1
3
H), 6.89 (d, J = 8.4 Hz, 1 H), 4.36 (q, J = 7.6 Hz, 2 H), 3.23 (s, 3 H), 2.38–
3
-(1-Benzyl-3-methyl-2-oxoindolin-3-yl)propanenitrile (4c)12
2
.26 (s, 1 H), 2.14–1.97 (m, 3 H), 1.40 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H).
Yield: 91.3 mg (63%); yellowish oil.
13
C NMR (101 MHz, CDCl ): δ = 179.2, 166.1, 147.2, 131.7, 131.4,
3
1
H NMR (400 MHz, CDCl ): δ = 7.39–7.17 (m, 7 H), 7.07 (t, J = 7.6 Hz, 1
3
125.3, 123.9, 118.5, 108.1, 61.1, 47.2, 33.2, 26.6, 23.5, 14.4, 12.9.
H), 6.79 (d, J = 7.6 Hz, 1 H), 4.90 (d, J = 7.2 Hz, 2 H), 2.43–2.32 (m, 1 H),
2
,22–1.97 (m, 3 H), 1.44 (s, 3 H).
3
-(1,3,6-Trimethyl-2-oxoindolin-3-yl)propanenitrile (4k) and 3-
13
C NMR (101 MHz, CDCl ): δ = 179.0, 142.2, 135.7, 131.6, 128.9,
12
3
(1,3,4-Trimethyl-2-oxoindolin-3-yl)propanenitrile (4k′)
1
1
28.6, 128.0, 127.3, 123.1, 122.7, 118.8, 109.5, 47.3, 43.8, 33.6, 23.8,
2.8.
Yield 4k/4k′ (1:2): 93.4 mg (82%).
1
H NMR (400 MHz, CDCl ): δ = 7.20 (t, J = 7.6 Hz, 2 H), 7.06 (d, J = 7.6
3
Hz, 1 H), 6.94–6.83 (m, 3 H), 6.71–6.66 (m, 3 H), 3.20 (s, 6 H), 3.19 (s, 3
H), 2.38 (s, 6 H), 2.37 (s, 3 H), 2.42–2.23 (m, 3 H), 2.09–1.85 (m, 9 H),
3
-(1,3,5-Trimethyl-2-oxoindolin-3-yl)propanenitrile (4e)12
Yield: 99.1 mg (87%); yellow solid; mp 91–92 °C.
1
.45 (s, 6 H), 1.36 (s, 3 H).
1
H NMR (400 MHz, CDCl ): δ = 7.09 (d, J = 7.6 Hz, 1 H), 6.98 (s, 1 H),
13
3
C NMR (101 MHz, CDCl ): δ = 179.2, 178.9, 143.4, 143.2, 138.9,
3
6.75 (d, J = 7.6 Hz, 1 H), 3.18 (s, 3 H), 2.35 (s, 3 H), 2.55–2.24 (m, 1 H),
1
1
34.4, 128.6, 128.5, 128.1, 125.5, 123.5, 122.3, 118.8, 118.6, 109.4,
06.3, 48.4, 47.1, 32.5, 31.5, 25.4, 25.2, 23.5, 21.8, 18.1, 13.0, 12.8.
2.12–1.93 (m, 3 H), 1.37 (s, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 178.8, 140.7, 132.7, 131.7, 128.9,
3
123.4, 118.9, 108.2, 47.4, 33.5, 26.3, 23.5, 21.1, 12.8.
-(1,3,7-Trimethyl-2-oxoindolin-3-yl)propanenitrile (4l)12
3
Yield: 83.2 mg (73%); yellowish oil.
3
-(5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)propanenitrile
1
H NMR (400 MHz, CDCl ): δ = 7.06–6.95 (m, 3 H), 3.49 (s, 3 H), 2.58
12
3
(4f)
(s, 3 H), 2.36–2.26 (m, 1 H), 2.12–1.91 (m, 3 H), 1.36 (s, 3 H).
Yield: 101.2 mg (83%); yellowish oil.
13
C NMR (101 MHz, CDCl ): δ = 179.6, 140.9, 132.3, 122.9, 120.4,
3
1
H NMR (400 MHz, CDCl ): δ = 6.87–6.72 (m, 3 H), 3.77 (s, 3 H), 3.18
3
120.2, 118.9, 108.2, 46.6, 33.7, 29.6, 23.9, 19.0, 12.9.
(s, 3 H), 2.36–2.23 (m, 1 H), 2.17–1.96 (m, 3 H), 1.36 (s, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 178.5, 156.4, 136.5, 133.1, 118.8,
3
112.6, 110.3, 108.8, 55.8, 47.7, 33.5, 26.4, 23.5, 12.8.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1567–1580

1
578
Synthesis
S. Tang et al.
Paper
1
3
3
-(7-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)propanenitrile
C NMR (101 MHz, CDCl ): δ = 177.7, 163.1, 143.3, 138.3, 123.2,
3
12
(4m)
118.6, 114.6, 43.3, 31.6, 26.1, 21.5, 12.7.
+
Yield: 96.4 mg (79%); yellowish oil.
MS (EI, 70 eV): m/z (%) = 215 ([M ], 27), 161 (100).
1
+
H NMR (400 MHz, CDCl ): δ = 7.03 (t, J = 7.6 Hz, 1 H), 6.84 (d, J = 8.4
HRMS (ESI): m/z calcd for C12H14N O [M + H] : 216.1132; found:
3
3
Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H), 3.84 (s, 3 H), 3.46 (s, 3 H), 2.35–2.23
216.1136.
(m, 1 H), 2.11–1.91 (m, 3 H), 1.34 (s, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 179.1, 145.6, 133.3, 130.8, 123.7,
2-[(1,3-Dimethyl-2-oxoindolin-3-yl)methyl]pentanenitrile (4t)
3
118.9, 115.4, 112.3, 56.9, 47.4, 33.6, 29.6, 23.7, 12.8.
Yield: 52.2 mg (43%); yellow oil.
1
H NMR (400 MHz, CDCl ): δ = 7.38–6.95 (m, 4 H), 3.21 (s, 3 H), 2.37–
3
3-(4-Chloro-1,3,7-trimethyl-2-oxoindolin-3-yl)propanenitrile (4n)
1.89 (m, 3 H), 1.62–1.51 (m, 7 H), 0.85 (t, J = 7.2 Hz, 3 H).
Yield: 82.5 mg (63%); yellowish oil.
13
C NMR (101 MHz, CDCl ): δ = 179.4, 179.2, 143.4, 143.1, 132.2,
3
1
H NMR (400 MHz, CDCl ): δ = 6.96 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 8.0
131.5, 128.5, 123.5, 123.0, 122.6, 122.4, 122.3, 121.0, 108.6, 108.4,
47.6, 46.9, 39.8, 35.2, 27.5, 27.0, 26.3, 24.9, 24.4, 19.9, 13.4.
3
Hz, 1 H), 3.48 (s, 3 H), 2.58–2.49 (m, 4 H), 2.39–2.29 (m, 1 H), 2.05–
1
.90 (m, 3 H), 1.49 (s, 3 H).
+
MS (EI, 70 eV): m/z (%) = 256 ([M ], 27), 160 (100).
13
C NMR (101 MHz, CDCl ): δ = 179.2, 142.8, 133.6, 128.6, 127.8,
+
3
HRMS (ESI): m/z calcd for C16H21N O [M + H] : 257.1649; found:
2
123.7, 118.9, 118.5, 48.4, 30.4, 29.8, 22.0, 21.7, 21.5, 18.9, 13.2.
257.1646.
+
MS (EI, 70 eV): m/z (%) = 262 ([M ], 27), 208 (100).
+
HRMS (ESI): m/z calcd for C14H16ClN O [M + H] : 263.0951; found:
Spirocyclic Indole 6
2
263.0948.
A suspension of 3w (150 mg, 0.5 mmol) and LiAlH (76 mg, 2.0 mmol)
4
in THF (10 mL) was stirred under a N atmosphere at r.t. for 1 h, and
2
3-(5,6-Dichloro-1,3-dimethyl-2-oxoindolin-3-yl)propanenitrile
then heated at reflux temperature for 0.5 h. The reaction was
(4o)
quenched with THF–H O (10:1, 2 mL) at 0 °C, and the resulting mix-
2
ture was diluted with CH Cl and filtered through a glass filter. The
Yield: 71.9 mg (51%); yellow solid; mp 120–121 °C.
2
2
resulting precipitates were washed thoroughly with CH Cl and the
1
2
2
H NMR (400 MHz, CDCl ): δ = 7.44 (d, J = 8.0 Hz, 1 H), 6.75 (d, J = 8.4
3
filtrate was concentrated in vacuo. The residue was dissolved in EtOAc
10 mL) and added aq 1 M HCl (5 mL). After stirring for 5 min, the
solution was neutralized by adding solid K CO , and then extracted
Hz, 1 H), 3.21 (s, 3 H), 2.57–2.48 (m, 1 H), 2.45–2.345 (m, 1 H), 2.12–
(
1.95 (m, 2 H), 1.52 (s, 3 H).
2
3
13
C NMR (101 MHz, CDCl ): δ = 178.0, 143.3, 120.4, 129.3, 129.3,
3
with EtOAc (3 × 20 mL). The combined organic layers were washed
with brine (10 mL), dried (Na SO ), filtered through a Celite pad, and
127.4, 118.0, 107.7. 49.8, 30.1, 26.6, 21.1, 13.2.
2
4
+
MS (EI, 70 eV): m/z (%) = 282 ([M ], 27), 228 (100).
concentrated in vacuo. The residue was purified by flash column
chromatography to give the title compound as a yellowish oil; yield:
+
HRMS (ESI): m/z calcd for C13H14Cl N O [M + H] : 283.0400; found:
2
2
105.1 mg (73%).
283.0403.
1
H NMR (400 MHz, CDCl ): δ = 6.83–6.73 (m, 2 H), 6.41 (dd, J = 8.0, 4.0
3
-(1-Methyl-2-oxo-3-phenylindolin-3-yl)propanenitrile (4p)12
Hz, 1 H), 3.87 (s, 1 H), 2.77 (s, 3 H), 2.69 (d, J = 12.8 Hz, 1 H), 2.58 (d,
J = 12.8 Hz, 1 H), 1.97 (br, 1 H), 1.70–1.50 (m, 10 H), 1.39 (s, 3 H),
3
Yield: 106.3 mg (77%); yellowish solid; mp 106–107 °C.
1.17–1.04 (m, 2 H).
1
H NMR (400 MHz, CDCl ): δ = 7.41–7.25 (m, 7 H), 7.16 (t, J = 7.6 Hz, 1
3
13
C NMR (101 MHz, CDCl ): δ = 157.4 (d, J = 234.4 Hz), 146.5, 141.4,
3
H), 6.94 (d, J = 8.0 Hz, 1 H), 3.14 (s, 3 H), 2.87–2.76 (m, 1 H), 2.64–2.43
m, 1 H), 2.15 (dt, J = 10.4, 6.0 Hz, 2 H).
113.5 (d, J = 23.4 Hz), 110.1 (d, J = 23.7 Hz), 107.9 (d, J = 7.1 Hz), 87.5,
(
1
49.1, 45.3, 41.4, 38.5, 35.9, 32.8, 32.1, 27.4, 26.9, 22.6, 22.3.
3
C NMR (101 MHz, CDCl ): δ = 177.3, 144.0, 138.7, 130.3, 129.2,
3
+
MS (EI, 70 eV): m/z (%) = 270 ([M ], 100).
1
28.2, 126.9, 125.0, 123.5, 119.0, 10.2, 55.7, 33.5, 26.9, 13.4.
+
HRMS (ESI): m/z calcd for C18H26FN2 [M + H] : 289.2075; found:
89.2079.
2
3
-(1-Methyl-2-oxo-2,4,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quino-
12
lin-1-yl)propanenitrile (4r)
Aliphatic Carboxylic Acid 7
Yield: 74.4 mg (62%); yellow oil.
A solution of 3a (121 mg, 0.5 mmol) and NaOH (100 mg, 2.5 mmol) in
1
H NMR (400 MHz, CDCl ): δ = 7.06–6.93 (m, 3 H), 3.74–3.65 (m, 2 H),
3
ethylene glycol (5 mL) were stirred under a N atmosphere at 110 °C
2
2
3
.77 (t, J = 6.0 Hz, 2 H), 2.52–2.25 (m, 1 H), 2.13–1.95 (m, 5 H), 1.37 (s,
H).
for 12 h. Then, the reaction mixture was treated with aq 1 M
HCl slowly at 0 °C until the pH of solution was between 2 and 3. The
resulting mixture was extracted with EtOAc (3 × 20 mL), and the com-
1
3
C NMR (101 MHz, CDCl ): δ = 177.8, 138.9, 130.2, 127.4, 122.5,
3
1
20.7, 120.5, 118.9, 48.7, 38.9, 33.2, 24.5, 23.2, 21.1, 12.9.
bined organic layers were washed with H O (10 mL) and brine (10
2
mL), and dried (MgSO ). After concentration in vacuo, the residue was
4
3-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-3-
purified by flash chromatography on silica gel to afford the title com-
yl)propanenitrile (4s)
pound as a white solid; yield: 88.7 mg (68%); mp 113–114 °C.
1
Yield: 52.7 mg (49%); yellow oil.
H NMR (400 MHz, CDCl ): δ = 7.25–7.13 (m, 2 H), 6.88 (t, J = 7.6 Hz, 1
3
1
H), 6.80 (d, J = 8.0 Hz, 1 H), 3.19 (s, 3 H), 2.46 (d, J = 14.4 Hz, 1 H), 2.27
H NMR (400 MHz, CDCl ): δ = 8.23 (d, J = 8.8 Hz, 1 H), 7.20 (dd,
3
(d, J = 14.4 Hz, 1 H), 1.30 (s, 3 H), 1.07 (s, 3 H), 0.83 (s, 3 H).
J = 8.0, 5.2 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 1 H), 3.22 (s, 3 H), 2.34–2.10 (m,
4
13
H), 1.42 (s, 3 H).
C NMR (101 MHz, CDCl ): δ = 180.2, 178.0, 140.6, 129.1, 126.4,
3
121.9, 119.4, 105.5, 44.6, 44.2, 38.9, 26.1, 24.9, 23.7, 19.9.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1567–1580

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HRMS (ESI): m/z calcd for C15H20NO3 [M + H] +: 262.1438; found:
62.1437.
(6) For unpredictable addition polymerization of styrene with
AIBN in polymer synthesis, see: (a) Gasanov, R. G.; Tumanskii, B.
L. Russ. Chem Bull. 2002, 51, 240. (b) Ford, W. T.; Nishioka, T.;
Melleskey, S. C.; Mourey, T. H.; Kahol, P. Macromolecules 2000,
2
33, 2413.
Acknowledgment
(
7) (a) Vetter, A. J.; Rieth, R. D.; Jones, W. D. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 6957. (b) Evans, M. E.; Li, T.; Jones, W. D. J. Am.
Chem. Soc. 2010, 132, 16278. (c) Crestani, M.; Steffen, A.;
Kenwright, A.; Batsanov, A.; Howard, J.; Marder, T. Organometal-
lics 2009, 28, 2904. (d) Oertel, A.; Ritleng, V.; Chetcut, M.; Veiros,
L. J. Am. Chem. Soc. 2010, 132, 13588. (e) Derrah, E.; Giesbrecht,
K.; McDonald, R.; Rosenberg, L. Organometallics 2008, 27, 5025.
8) In general, catalytic C–H functionalization of MeCN [pKa
(MeCN) ~31.3 in DMSO] required a strong base for deprotona-
tion, see, Pd/NaN(SiMe ) : (a) Culkin, D. A.; Hartwig, J. F. J. Am.
We acknowledge the financial support from the National Natural Sci-
ence Foundation of China (No.21462017, 21372251), China Postdoc-
toral Science Foundation funded project (No. 2014M560649), and the
Project Sponsored by the Scientific Research Foundation for the Re-
turned Overseas Chinese Scholars, State Education Ministry.
(
Supporting Information
3
2
Supporting information for this article is available online at
Chem. Soc. 2002, 124, 9330. (b) You, J.; Verkade, J. G. Angew.
Chem. Int. Ed. 2003, 42, 5051; Angew. Chem. 2003, 115, 5205.
http://dx.doi.org/10.1055/s-0034-1379902.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
c) Schranck, J.; Burhardt, M.; Bornschein, C.; Neumann, H.;
Skrydstrup, T.; Beller, M. Chem. Eur. J. 2014, 20, 9534. Ru/DBU:
d) Kumagai, N.; Matsunage, S.; Shibasaki, M. J. Am. Chem. Soc.
004, 126, 13632. Base-free copper-oxidative C–H functional-
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1567–1580

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(
14) Although a catalytic combination of CuCl and t-BuOOt-Bu
(17) In view of GC/MS results, DIAD was completely consumed after
the reaction proceeds under standard conditions over 20 h, and
some amount of side-products such as i-PrOCO i-Pr, i-PrOC Ot-Bu
reported by You and co-workers could lead to oxindole 4a effi-
ciently at 120 °C, the comparable combination of CuI and t-
BuOOt-Bu turned out to be less efficient under current tem-
perature conditions (95 °C) in the absence of DIAD, which
resulted in <5% product yield.
2
2
was also observed. These results could suggest that DIAD is
•
subject to decompose to form radical i-PrO C , which is respon-
2
•
sible for the generation of radical CH CN under current reac-
2
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1567–1580