Co(III)-Catalyzed Coupling-Cyclization of Aryl C-H Bonds with α-Diazoketones Involving Wolff Rearrangement

Article abstract of DOI:10.1021/acscatal.7b03668

An unusual cobalt(III)-catalyzed cross-coupling/cyclization of aryl C-H bonds of N-nitrosoanilines with α-diazo-β-ketoesters has been achieved. This protocol features a unique combination of Csp²-H activation/Wolff rearrangement process, allowing for the rapid assembly of quaternary 2-oxindoles. The empirical evidence and density functional theory (DFT) calculations reveal the trapping process of transient acceptor ketene intermediates by cobalt metallocycles.

Full text of DOI:10.1021/acscatal.7b03668

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Letter
Co(III)-Catalyzed Coupling-Cyclization of Aryl C-H Bonds
with alpha-Diazoketones Involving Wolff Rearrangement
Xinwei Hu, Xun Chen, Youxiang Shao, Haisheng Xie,
Yuanfu Deng, Zhuofeng Ke, Huanfeng Jiang, and Wei Zeng
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03668 • Publication Date (Web): 16 Jan 2018
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Co(III)-Catalyzed Coupling-Cyclization of Aryl C-H Bonds with -
Diazoketones Involving Wolff Rearrangement
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Xinwei Hu, Xun Chen, Youxiang Shao, Haisheng Xie, Yuanfu Deng, Zhuofeng Ke, Huanfeng
Jiang, and Wei Zeng
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R
R
N
R
O
N
O
NO
Co
N
Ar
O
CO2Et Co(III) cat.
-N2
Ar
N
Ar
Ar
+
O
-NO
•
CO2Et
N2
H
Ar
EtO2C
Ar
R = alkyl and aryl
up to 86% yield
30+ examples
Combination of cobalt-catalyzed Csp2-H activation/Wolff rearrangement
Rapid access system for all-carbon quaternary center synthesis
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Co(III)-Catalyzed Coupling-Cyclization of Aryl C-H Bonds with -
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Diazoketones Involving Wolff Rearrangement
Xinwei Hu,a,§ Xun Chen,a,c,§ Youxiang Shao,b Haisheng Xie,a Yuanfu Deng,a Zhuofeng Ke,*,b
Huanfeng Jiang,a and Wei Zeng*,a
a Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engi-
neering, South China University of Technology, Guangzhou 510641, China
b School of Materials Science and Engineering, PCFM Lab, Sun Yat-sen University, Guangzhou 510275, China
c School of Pharmacy, Hainan Medical University, Haikou 571199, China
Supporting Information Placeholder
KEYWORDS: cobalt catalysis, coupling-cyclization, -diazoketones, Wolff rearrangement, quaternary 2-oxindoles.
R
R
N
R
O
N
O
NO
Co
N
Ar
O
CO2Et Co(III) cat.
-N2
Ar
N
Ar
Ar
+
O
-NO
•
CO2Et
N2
H
Ar
Ar
R = alkyl and aryl
EtO2C
up to 86% yield
30+ examples
Combination of cobalt-catalyzed Csp2-H activation/Wolff rearrangement
Rapid access system for all-carbon quaternary center synthesis
ABSTRACT: An unusual cobalt(III)-catalyzed cross-coupling/cyclization of aryl C-H bonds of N-nitrosoanilines with -diazo--
ketoesters has been achieved. This protocol features a unique combination of Csp2-H activation/Wolff rearrangement process, al-
lowing for the rapid assembly of quaternary 2-oxindoles. The empirical evidence and density functional theory (DFT) calculations
reveal the trapping process of transient acceptor ketene intermediates by cobalt metallocycles.
Ketenes are extremely important transient synthons in or-
ganic chemistry.1 Over the past decades, transition metal-
catalyzed cycloaddition and cross-coulping of ketenes with
different reaction partners have been evidenced to enable as-
sembly of complex carbonyl compounds,2 in which most types
of ketenes belong to donor ketenes such as -alkyl ketenes and
-alkylaryl ketenes (generated in situ from acyl chlorides).2j,2k
In comparison, the chemical transformations involving accep-
tor ketenes such as -acyl ketenes have not been well estab-
lished even under the photolysis and high-temperature condi-
tions, possibly due to that acceptor ketenes are frequently un-
available,3 albeit various acceptor ketenes could provide a
potential platform to construct structurally diverse carbonyl
compounds. Therefore, developing new and efficient catalytic
systems to trap transient acceptor ketenes under mild condi-
tions is highly desirable.
zation has aroused great attention due to its low cost and envi-
ronmental benignity.6,7 In this context, Glorius,8 Ackermann9
and Wang10 successively reported the Co(III)-catalyzed cross-
coupling of aryl C-H bonds with diacceptor diazo compounds
through carbene migratory insertion under chelation-assistance
of pyridines, ketamines, amidines, and pyrazoles (Scheme 1a).
However, transition metal-catalyzed Wolff rearrangement of
diazo compounds still remains rather elusive under C-H acti-
vation system. Up to now, only noble metal salts could allow
for the Wolff rearrangement of -diazoketones, resulting in
the formation of donor ketenes (Scheme 1b),11 but earth-
abundant 1st-row transition metal-catalyzed Wolff rearrange-
ment has not been reported yet. As the continuation of our
interest in cobalt-catalyzed C-H functionalization,12 we herein
explored
a
unprecedented cyclic coupling of N-
nitrosoanilines13 (A) with diacceptor diazo compounds, in
which cobalt complex-promoted Wolff rearrangement deli-
vered acceptor -acyl ketenes. This protocol represents a
unique platform to combine C-H activation/Wolff rearrange-
ment for assembling quaternary 2-oxindoles14 (C) (Scheme 1c),
which are the cornerstone of many natural products and medi-
cinal molecules.15
Direct carbenoid functionalization of inert C-H bonds be-
longs to one of the most challenging topics in organic synthe-
sis.4 Recently, chelation-assisted cross-coupling of C-H bonds
with diazo compounds has been extensively investigated for
site-selectively installing a new C-C bond onto a coupling
partner.5 Most particularly, cobalt-catalyzed C-H functionali-
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a) The General reaction pathway about Co(III)-catalyzed chelation-assisted C-H carbenoid insertion
10
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
FeCl3
Cu(OAc)2 DCE
DCE
11d
<5d
21d
22d
51d
64d,e
59d,f
74g
48g
0g
DG
Co
DG
Co
2
DG
H
DG
Co(III)
O
CO R
2
O
Ar
downstream
1
trapping
R
Co(III)
Ar
11
12
13
14
15
16
17
18
19
20
Ar
Ar
+
1
-N
1
2
2
R
N
2
R
R O
C
2
2
R O
C
O
2
B(C6F5)3
Sc(OTf)3
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
DCE
DCE
DCE
DCE
DCE
DCE
TCEh
toluene
DMF
DG = Py, ketamine, amidine and pyrazole
via metal carbene migratory insertion
b) Rh(II)-catalyzed Wolff rearrangement of alpha-diazoketones
2
R
O
O
1
2
cat. Rh (OAc)
1
-Rh(II) cat.
2
4
R
R
= aryl, alkenyl, alkyl
= H, alkyl, aryl
R
N
2
RhL
n
1
1
•
R
R
-N
2
O
2
2
donor ketenes
R
R
c) This work: The combined Co(III)-catalyzed C-H activation/Wolff rearrangement
9
R
R
R
R
2
CO R
2
R
O
N
10
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N
N
N
NO
Co
N
Ar
NO
Co
NO
Co(III)
Ar
O
O
1
Ar
Ar
O
R
N
2
Ar
NO
Co
•
1
2
R
1
H
-N
R
2
CO
R
1
2
R
2
C
2
A
B
R O
C
R O C
2
2
(C, C) complex
via Co-catalyzed Wolff rearangement
all-carbon
quaternary
center
0g
Scheme 1. Transition Metal-Catalyzed Selective Trans-
formations of Diazo Compounds
aUnless otherwise noted, all the reactions were performed
using N-nitroso aniline (1a) (0.20 mmol) and -diazocarbonyl
compound (2a) (0.25 mmol) with catalysts (10 mol %) in the
presence of additives (20 mol %) in 1, 2-dichloroethane (DCE)
(1.0 mL) at 120 ˚C for 24 h under Ar in a sealed tube, followed
by flash chromatography on SiO2. Isolated yield. Cp*CoLn
refers to [Cp*Co(MeCN)3](SbF6)2. AgSbF6 (20 mol %) was
Our initial attempt to construct quaternary 3,3-disubstituted
2-oxindole (3a) involved cyclized coupling of N-nitrosaniline
(1a) with -diazo--ketoester (2a) in the presence of NaOAc
b
c
o
d
(20 mol %) and various cobalt catalysts ( at 120 C for 24 h
e
f
under Ar; Table 1, entries 1-6). To our delight, we quickly
found that Co(acac)2, [Cp*Co(MeCN)3](SbF6)2 and
Cp*Co(CO)I2 could be used to catalyze this transformation in
DCE, but with Cp*Co(CO)I2 the highest yield of the desired
N-methyl-3-phenyl-3-ethoxycarbonyl-2-oxindole (3a) was
obtained (26%, entry 6). However, reactions performed with
other alkali metal salts (NaOAc and NaOPiv) and protonic
acid (PivOH) failed to offer a yield beyond 30% (entries 7-9).
To maximize the conversion of the reaction, we had to switch
to evaluate the effect of different Lewis acids on this transfor-
mation, and we were pleased to finally find that Zn(OAc)2
could significantly increase the yield to 51% (compares entry
14 versus entries 10-13). Moreover, the utilization of 50 mol %
of Zn(OAc)2 in the absence of AgSbF6 could further improve
the reaction conversion with 74% yield (entry 17). We also
tried to optimize the reaction conditions with different solvent
systems including toluene and DMF. Unfortunately, these
solvents did not deliver the desired product 3a at all (entries
19 and 20) [see Supporting Information (SI) for the more de-
tails].
used. 50 mol % of Zn(OAc)2 was used. 100 mol % of
g
Zn(OAc)2 was used. 50 mol % of Zn(OAc)2 was used in the
absence of AgSbF6. hTCE refere to 1,1,2,2-tetrachloroethane.
To explore the scope of the Co(III)-catalyzed 3,3-
disubstituted-2-oxindole synthesis, an array of different func-
tional groups were introduced into the benzene ring of N-
methyl-N-nitrosoaniline 1. As summarized in Scheme 2, subs-
titution at the 2- or 4- position of the phenyl ring did not ob-
viously affect the yield of the 2-oxindoles 3. Electron-donating
substitutents such as methyl and methoxyl group were effec-
tive and provided 74-80% yields of products (3a~3d). Mean-
while, reactions also proceeded smoothly with various halides
such as -F, -Cl, and -Br, affording the corresponding 2-
oxindoles (3e~3i) in good yields (55-81%). However, sub-
strates bearing electron-withdrawing groups (4-CN, 4-NO2, 4-
CO2Me) produced 2-oxindoles in a somewhat lower yields
(56-63%). Among them, N-nitroso-4-ethoxycarbonylaniline
furnished an unexpected acyclic N-aryl amide 4a in 32% yield
possibly due to that ketene intermediates were directly nucleo-
philicaly attacked by N-nitrosoamiline instead of cobaltacycles
species. Besides the mono-substituted N-nitrosoanilines, 3,4-
disubstituted anilines such as N-nitroso-1,3-benzodioxol-5-
amine, and 2,3-dihydro-N-nitroso-1H-Inden-5-amine, etc.
could also be converted into the multi-functional 2-oxindoles
with good yields (3m~3r, 75-82%), in which highly site-
selective coupling-cyclizations resulted from the electron-rich
phenyl rings (3n and 3o), which could more easily lead to a
regioselective electrophilic Csp2-H cyclometalation process.
The substrate scope was further broadened by evaluating the
effect of varying the substituents on the aromatic rings from 2-
diazo-3-aryl ketoesters (2). It was found that electron-donating
group (-Me, -OMe)-substituted phenyl rings could provide
good to excellent yields of cyclized coupling products (3s~3w,
70-86% ), but electron-deficient phenyl rings bearing halides
(-F, -Cl, and -Br) and -CF3 groups made the transformation a
little sluggish and gave moderate to good yields of 2-oxindoles
(3x~3-1a, 55-62%). Of note is that 2-diazo-3-methyl ketoester
could not participate in the reaction system, recovering start-
ing material unaltered (3-1b). Also, when 2-diazo-1,3-
Table 1. Optimization of Reaction Conditionsa
O
catalysts (10 mol %)
additives (20 mol %)
N
O
N
CO Et
N
2
O
Ph
+
o
DCE, Ar, 120 C, 24 h
N
H
CO Et
2
2
1a
2a
Ph
3a
entry
catalysts
CoCl2
additives
KOAc
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
yield (%)b
1
2
3
4
5
6
7
8
9
0
Co(acac)2
Co(OAc)3
Co(acac)3
KOAc
KOAc
KOAc
KOAc
KOAc
NaOAc
NaOPiv
PivOH
13
0
0
c
Cp*CoLn
18
26d
19d
25d
24d
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
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diphenyl-1,3-propanedione was used, only uncyclized amide
give 60% yield of 2-oxindole (3-1g). Most importantly, sever-
al types of nitrogen-heterocycle substrates could still under-
went smooth 2-oxindole formation to assemble fused tricyclic
skeletons regardless of the ring size (3-1h~3-1j, 54-67%),
these complex cycles are commonly encountered in natural
products and bioactive molecules.17 It should be noted that
other substrates bearing oxidizing directing groups such as Nʹ-
phenylacetohydrazide (1y), N-(pivaloxy)benzamide (1z) and
aceto O-povaloyl oxime (1z-a) could not deliver the corres-
ponding coupling-cyclization products, and these substrates
could be almost completely recovered.
4b (57%) was formed partly because of the combined steric
hindrance and electronic effect from the arylketone moiety,
which inhibited the coupling-cyclization with N-nitrosoaniline
1a. Besides all the products were evident by NMR spectrosco-
py, we further univocally assigned the structures of 3f and 3z
by X-ray crystallography.16
Table 2. Substrate Scopea, b
9
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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30
31
32
33
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36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
N
R
O
O
[Cp*Co(CO)I ] (10 mol %)
2
O
N
Zn(OAc) (50 mol %)
2
1
N
3
4
O
R
R
1
R
R
+
R
4
o
DCE, Ar, 120 C, 24 h
N
Pd(PPh3)4 (5 mol %)
NaH (2.0 equiv)
NaH (2.0 equiv)
N
N
2
H
N
N
O
O
3
OsO4/NaIO4
allyl alcohol (5)
O
R
1
2
3
O
O
O
toluene, 25 o
O2, 10 min
C
1,4-dioxane
collidine
allyl alcohol (5)
Ph
toluene, 25 oC, 12 h
Ph
7 (79%)
OH
6 (65%)
Ph
Ph
8 (62%)
O
O
O
O
N
3-1k
N
R1
O
O
Scheme 2. Transformation of Ester Moiety of 2-Oxindoles
CO2Et
CO2Et
Ph
Ph
3m, 82%
3a,R1 = H, 74%
3-Ester-2-oxindoles could be further converted into various
3-substituted 2-oxindole derivatives. Treatment of 2-oxindole
3-1k with allyl alcohol 5 in the presence of NaH afforded 3-
hydroxy-3-phenyl-2-oxindole 6; Moreover, 3-1k could also
successively deliver 3-allyl-3-phenyl-2-oxindole 7 and 3-
acylmethylene-3-phenyl-2-oxindole 8 through allylation and
oxidation (Scheme 2). These 2-oxindoles belong to the key
synthetic precursors of Growth hormone18 and pyrroloindoline
3b, R1 = 5-Me, 75%
3c, R1 = 7-Me, 78%
MeO
N
O
3d, R1 = 5-MeO, 80%
3e, R1 = 5-F, 71%
3f, R1 = 7-F, 67%
3g, R1 = 5-Cl, 81%
3h, R1 = 7-Cl, 55%
3i, R1 = 5-Br, 68%
3j, R1 = 5-CN, 63%
3k, R1 = 5-NO2, 58%
MeO
3n, 82% Ph
CO2Et
N
Cl
N
O
O
Me
CO2Et
Me
CO2Et
Ph
Cl
Ph
3p, 27%
3o, 52% (3o/3p = 2:1)
alkaloids.19
Et
3l, R1 = 5-CO2Me, 56%
Ph
O
H(D)
[Cp*Co(CO)I ] (10 mol %)
2
N
EtO2C
N
N
Zn(OAc) (50 mol %)
2
O
NO
NO
N
O
N
+
CH OD (0.1 mL)
3
(a)
Et
o
DCE, Ar, 120 C, 24 h
CO2Et
H(D)
Ph
3r
3q
1a
MeO2C
4a, 32%
Ph
CO2Et
d2-1a (43% D)
3q + 3r = 75% (3q/3r = 5:8)c
H(D)
N
[Cp*Co(CO)I ] (10 mol %)
2
2a (1.0 equiv)
(D)H
(D)H
N
3
NO
N
R
O
NO
(b)
N
N
+
Zn(OAc) (50 mol %)
2
O
CO Et
2
O
o
d
5
DCE, Ar, 120 C, 8 h
Ph
H(D)
O
4
k
/k = 1.27
H
D
R
CO Et
2
3
d5-1a
1a
d4-3a or 3a
3
4
R
4b,R = R = Ph, 57%
3
3s,R = 4-Me-C H , 76%
2
6
4
R
[Cp*Co(CO)I ] (10 mol %)
2
2a (1.0 equiv)
3
N
N
N
3t, R = 3-Me-C H , 70%
6
4
N
NO
NO
O
3
+
(c)
3u, R = 2-Me-C H , 73%
6
4
1
O
Zn(OAc) (50 mol %)
2
R
CO Et
3
O
O N
2
2
o
3v, R = 4-MeO-C H , 86%
Ph
6
4
DCE, Ar, 120 C, 24 h
CO Et
2
3
1k
3d/3k = 3.4:1
1d
3w, R = 2-naphthyl, 79%
Ph
2
3
3-1c,R = Et, 69%
3x, R = 4-F-C H , 62%
6
4
N
O
[Cp*Co(CO)I ] (10 mol %)
2
2
N
3
3-1d, R = i-Pr, 63%
3y, R = 4-Cl-C H , 58%
6
4
O
Zn(OAc) (50 mol %)
2
2
3
(d)
(e)
3-1e, R = n-Bu, 65%
3z, R = 4-Br-C H , 58%
6
4
o
MeO C
2
Ph
CO Et
2
MeO C
2
DCE, Ar, 120 C, 24 h
2
CO Et
2
3
3-1f, R = Bn, 70%
Ph
3-1a, R = 4-CF -C H , 55%
3
6 4
2
4a
N
3l (0% yield)
3
3-1g, R = Ph, 60%
3-1b, R = Me, 0%
[Cp*RhCl ] (2 mol %)
O
O
2 2
O
N
N
Zn(OAc) (50 mol %)
2
O
+
Ph
OEt
o
DCE, Ar, 120 C, 24 h
N
MeO
N
O
O
H
CO Et
N
2
2
O
CO Et
Ph
N
O
1d
2a
3d (0% yield)
CO Et
2
2
Ph
Ph
O
CO Et
2
N
O
[Cp*Co(CO)I ] (10 mol %)
2
Ph
NH
COOEt
O
(f)
Ph
3-1h, 67%
3-1j, 66%
3-1i, 54%
Zn(OAc) (50 mol %)
2
+
o
Ph
CO Et
2
N
2
DCE, Ar, 120 C, 24 h
10 (37% yield)
9
2a
unsuccessful substrates:
O
OPiv
O
H
N
OPiv
N
O
CoBr (10 mol %)
2
Zn (20 mol %)
O
N
H
N
N
N
N
O
H
H
(g)
+
Ph
OEt
Zn(OAc) (50 mol %)
2
MeO
3d (< 5% yield)
O
o
CO Et
2
N
2
1y
DCE, Ar, 120 C, 24 h
1z-a
1z
Ph
1d
2a
aAll the reactions were carried out using N-nitrosoanilines
(1) (0.20 mmol) and -diazo--ketones (2) (0.25 mmol) with
[Cp*Co(CO)I2] (10 mol %) in the presence of Zn(OAc)2 (50
mol %) in DCE (1.0 mL) at 120 ˚C for 24 h under Ar in a
Scheme 3. Preliminary Mechanism Studies
Designed control experiments were performed to investigate
the reaction mechanism (Scheme 3). The H/D exchange of N-
methyl-N-nitrosoaniline (1a) was firstly conducted in the ab-
sence of diazo compound (2a), 43% deuterium incorporation
at the ortho-position of the aniline ring indicated that an initial
reversible Csp2-H bond activation process was involved in this
reaction (Eq. a and Figure S-1 in SI). Subsequent competitive
cyclized coupling of d5-1a and 1a with diazo compound 2a
b
sealed tube, followed by flash chromatography on SiO2. Iso-
lated yield. cDetermined by 1H NMR spectrum.
Moreover, we evaluated the substitution effects of N-alkyl
groups on this aryl C-H cyclized coupling reaction, and found
different lengths of N-alkyl chains such as (-Et, -iPr, -nBu, -Bn)
were well tolerated, affording 60-70% yields of the desired
products (3-1c~3-1f). Meanwhile, N-phenyl group could also
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(1.0 equiv) did not exhibit a remarkable kinetic isotope effect
rangement or the thermal Wolff rearrangement of 2a needs to
overcome the high activation free energy (see Figure S4 in SI),
but the possibility that the direct coupling-cyclization of in-
termediate B with independently formed ketenes could not be
ruled out (see Scheme 3, Eq f).21 Starting from D, an insertion
of ketene into the Co-C bond leads to a seven-membered ring
intermediate E via transition state TS-DE (G‡ = 16.7
kcal/mol). E undergoes a direct cyclization pathway to yield
five-membered ring product in complex PC1, which finally
releases 3a and HNO with the regeneration of Co(III) catalyst.
The cyclization pathway is exergonic by 50.8 kcal/mol via
transition state TS-E (G‡ = 15.9 kcal/mol, Fingure S3 in SI).
This result is in accord with the mechanism proposed by Zhu
et al.13b and Jiao et al.13c Alternatively, once the Co(III)-
carbenoid complex C is formed, it is also possible that C
yields six-membered F through the traditional carbene migra-
tory insertion (see Figure S3 in SI).8-10 The carbene migratory
insertion (TS-CF, G‡ = 1.1 kcal/mol) is much easier than the
Wolff rearrangement step in Co(III)-carbenoid mechanism
(TS-CD), however, the subsequent transformations through
carbonyl rearrangement, path c (TS-FE) and path d (TS-GH)
are both less feasible with high free energy barriers of 42.8
and 44.8 kcal/mol, respectively (Figure S3 in SI). The proto-
demetallation pathway has also been evaluated (path b, Fig-
ure S3 in SI), which is found to be both kinetically and ther-
modynamically less favored than the direct cyclization me-
chanism. Overall, the Wolff rearrangement through Co(III)-
carbenoid complex (path a, Figure S3 in SI) leading to the
cyclization product is the most plausible mechanism.
(Eq. b and Figure S-2 in SI, kH/kD=1.27). Meanwhile, another
competitive reaction between diazo compound 2a (1.0 equiv)
and N-nitrosoanilines (1d and 1k) differing in electronic ef-
fects implied that an electron-rich aniline tended to easily as-
semble 2-oxindoles at a higher rate (Eq. c), possibly due to
that electron-rich aniline could easily form cobaltacycle inter-
mediate through nucleophilic attack on Co(III) catalysts.
Moreover, uncyclized amide 4a could not further produce the
corresponding 2-oxindole 3l under our standard conditions (Eq.
d), demonstrating that amide 4a was not the reaction interme-
diate of this transformation. More importantly, the treatment
of N-nitrosoaniline (1d) with -diazo--ketoester (2a) under
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o
Rh(III)/Zn(OAc)2 catalyzed system (at 120 C for 24 h) could
not afford the desired 3d (Eq. e),20 indicating that Co(III)-
catalyzed system possibly induced the Wolff rearrangement of
-diazo--ketoesters to deliver ketenes, which were further
trapped by cobaltacycles species. Subsequently, the coupling
reaction of N-methylaniline 9 with diazo compound 2a under
our standard conditions provided 37% yield of N-methyl
amide 10 (Eq. f),21 demonstrating that the Wolff–
rearrangement of 2a possibly proceeded through cobalt-
carbene intermediate to form active ketenes, which could be
further trapped by nucleophilic aniline.22 Finally, considering
that Co(II) could be reduced into Co(I) by Zn powder, 23 we
ran the coupling-cyclization between N-nitrosoaniline 1d and
diazo compound 2a by using CoBr2/Zn system, but only trace
amount of 3d (<5% yield) was observed (Eq. g). This experi-
ment implied that Co(I) salts could not be easily oxidized to
Co(III) species by N-nitrosoanilines in our reaction system,
and Co(III)/Co(I) pathway is also not possibly involved in this
transformation.
In conclusion, we have developed an unprecedented co-
balt(III)-catalyzed coupling cyclization of N-nitrosoanilines
with -diazo--ketoesters through a combined C-H activa-
tion/Wolff rearrangement process. This strategy represents a
valuable and efficient synthetic tool for assembling 3,3-
disubstituted 2-oxindoles with a all-carbon quaternary center
which is derived from acceptor ketenes. Further efforts to
achieving an asymmetric version of this reaction are underway.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publication website.
Detailed experimental procedures, characterization data, crystal-
lographic data for 3f and 3z (CIF), computational details and
structures, copies of 1 H NMR and 13 C NMR spectra for all iso-
lated compounds.
Scheme 4. Proposed Reaction Mechanism
Accession Codes
CCDC 1554109 and 1574420 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: +44 1223 336033.
DFT calculations were performed to further elucidate the
reaction mechanism (see Scheme 4 and Figure S3 in SI). Af-
ter a reversible C-H activation process (TS-AB, G‡ = 4.8
kcal/mol), cobaltacycles species B will be formed. Then the
diazoketoester (2a) reacted with cobaltacycles B to form the
Co(III)-carbenoid specie C with the extrusion of a N2 mole-
cule via transition state TS-BC (17.9 kcal/mol). The Co(III)-
carbenoid C could be transformed into a ketene complex D
through Wolff rearrangement(path a), which needs to over-
come a free energy barrier of 22.2 kcal/mol (TS-CD). It
should be noted that the Cp*Co(OAc)2-catalyzed Wolff rear-
AUTHOR INFORMATION
Corresponding Author
*E-mail for Z. F. Ke: kezhf3@mail.sysu.edu.cn.
*E-mail for W. Zeng: zengwei@scut.edu.cn.
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Int. Ed. 2015, 54, 12121‒12126; (g) Hou, W.; Yang, Y.; Wu, Y.;
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Greies, S.; Glorius, F. Angew. Chem., Int. Ed. 2016, 55, 5577‒5581.
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L. Org. Lett. 2016, 18, 2742‒2745.
(10) Liu, X. –G.; Zhang, S. –S.; Wu, J. –Q.; Li, Q.; Wang, H, Te-
trahedron Lett. 2015, 56, 4093‒4095.
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Lett. 2016, 18, 4742‒4745; (b) Lan, J. Y.; Xie, H. S.; Lu, X. X.; Deng,
Y. F.; Jiang, H. F.; Zeng, W. Org. Lett. 2017, 19, 4279‒4282.
(13) For the selected N-nitroso-directed C-H functionalization
reactions, see: (a) Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J. J.
Am. Chem. Soc. 2013, 135, 468‒473; (b) Liu, B.; Song, C.; Sun, C.;
Zhou, S.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 16625‒16631; (c)
Liang, Y.; Jiao, N. Angew. Chem., Int. Ed. 2016, 55, 4035‒4039; (d)
Wu, Y.; Feng, L. –J.; Lu, X.; Kwong, F. Y.; Luo, H. B. Chem. Com-
mun. 2014, 50, 15352‒15354.
(14) For selected synthetic methodology about quaternary 2-
oxindoles, see: (a) Jia, Y. –X.; Kündig, E. P. Angew. Chem., Int. Ed.
2009, 48, 1636‒1639; (b) Matcha, K.; Narayan, R.; Antonchick, A. P.
Angew. Chem., Int. Ed. 2013, 52, 7985‒7989; (c) Duffey, T. A.; Shaw,
S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14‒15.
(15) For selected reviews, see: (a) Marti, C.; Carriera, E. Eur. J.
Org. Chem. 2003, 2003, 2209‒2219; (b) Trost, B. M.; Brennan, M. K.
Synthesis 2009, 18, 3003‒3025; (c) Galliford, C. V.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2007, 46, 8748‒8758; (d) Dounay, A. B.;
Overman, L. E. Chem. Rev. 2003, 103, 2945‒2964; (e) Oiriel, C.;
Lachia, M.; Wilson, C.; Davies, J. R.; Moody, C. J. J. Org. Chem.
2007, 72, 2978‒2987.
(16) The supplementary crystallographic data for 3f (CCDC
1554109) and 3z (CCDC1574420) can be obtained free of charge
from the Cambridge Crystallographic Data Centre.
3
4
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9
Xinwei Hu: 0000-0002-8476-7158
Xun Chen: 0000-0002-6144-7653
Youxiang Shao: 0000-0002-2777-5258
Haisheng Xie: 0000-0002-2206-7893
Author Contributions
§ These two authors contributed equally to this work.
Notes
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The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors thank the National Key Research and Development
Program of China (No. 2016YFA0602900), NSFC (No. 21372085,
21673301), and Guangdong Natural Science Funds for Distin-
guished Young Scholar (No. 2015A030306027) for financial
support.
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(20) It should be noted that Rh(III)/HOAc/AgSbF6 system-
catalyzed coupling-cyclization of N-nitrosoanilines with diazo com-
pounds could afford indoles through traditional carbene migratory
insertion process, see: Wang, J.; Wang, M.; Chen, K.; Zha, S.; Song,
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(21) It should be noted that the yield of amide 10 would decrease
from 37% to 8% in the absence of [Cp*Co(CO)I2].
(22) It should be noted that the reaction of the diazo compound 2a
with the [Cp*Co(CO)I2] in the presence of Zn(OAc)2 led to formation
of 2-acetoxy-3-oxo-3-phenyl-propionic acid ethyl ester 11 (35%
yield), see SI for more details.
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Co(III)-Catalyzed Coupling-Cyclization of Aryl C-H Bonds with -Diazoketones Involving Wolff Rearrangement
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R
R
N
R
O
N
O
NO
Co
N
Ar
O
CO2Et Co(III) cat.
-N2
Ar
N
Ar
Ar
+
O
-NO
•
CO2Et
N2
H
Ar
EtO2C
Ar
R = alkyl and aryl
up to 86% yield
30+ examples
Combination of cobalt-catalyzed Csp2-H activation/Wolff rearrangement
Rapid access system for all-carbon quaternary center synthesis
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