Rhodium(III)-catalyzed internal oxidative coupling of N-hydroxyanilides with alkenes via C-H activation

Article abstract of DOI:10.1016/j.tetlet.2015.07.070

Abstract Described herein is an efficient new method for ortho-olefination of anilides in the presence of AgSbF₆ and NaOAc via rhodium(III)-catalyzed internal oxidative C-H bond activation based on hydroxyl as directing and oxidative group. A range of alkenes and functional groups on acetanilides is supported and a possible mechanism is proposed according to the experimental results.

Full text of DOI:10.1016/j.tetlet.2015.07.070

Accepted Manuscript
Rhodium(III)-catalyzed internal oxidative coupling of N-hydroxyanilides with
alkenes via C−H activation
Jing Wen, An Wu, Pei Chen, Jin Zhu
PII:
S0040-4039(15)01234-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.070
TETL 46559
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
3 June 2015
15 July 2015
22 July 2015
Please cite this article as: Wen, J., Wu, A., Chen, P., Zhu, J., Rhodium(III)-catalyzed internal oxidative coupling of
N-hydroxyanilides with alkenes via C−H activation, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.07.070
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Rhodium(III)-catalyzed internal oxidative
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Jing Wen, An Wu, Pei Chen and Jin Zhu

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Rhodium(III)-catalyzed internal oxidative coupling of N-hydroxyanilides with alkenes
via C−H activation
Jing Wen a , An Wu b, Pei Chen a and Jin Zhu a,*
a
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of Microstructures, Nanjing
University, Nanjing 210093, China.
b
Kuang Yaming Honors School, Nanjing University, Nanjing 210093, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Described herein is an efficient new method for ortho-olefination of anilides in the presence of
AgSbF6 and NaOAc via rhodium(III)-catalyzed internal oxidative C−H bond activation based on
hydroxyl as directing and oxidative group. A range of alkenes and functional groups on
acetanilides is supported and a possible mechanism is proposed according to the experimental
results.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Rhodium
Anilides
Internal oxidation
Alkenes
C-H activation
A new C−C bond directly formed from two simple C−H
bonds is supported by catalytic dehydrogenative cross-coupling
such as oxidative Heck reaction pioneered by Fujiwara and
Moritani, utilizing a C−C instead of a C−H bond.1 This method
has been rapidly developed and widely used in organic synthesis
for the construction of C−X bond with advantages of atom
economy, high selectivity and good toleration of unactivated
substrates.2 With the development in catalytic coupling reaction,
there are lots of literatures involving the access to
transition-metal-catalyzed ortho-functionalization of acetanilides,
which is provided without the need for prefunctionalized
partners.3 Among them, using Rh catalysts, the coupling of
acetanilides with diverse partners has proved to be efficient and
versatile.4 Since acetanilides could be easily hydrolyzed to
anilines, these studies have realistic significance for derivation
and modification of anilines that are the most important organic
intermediates. Nevertheless, all the catalytic oxidative
Moreover, catalytic C−H activation with using hydroxyl as
directing group is seldom reported.
We initiated our investigation with the optimization studies of
the coupling. By the acidity of hydroxyl resulting from
electron-withdrawing effect of N-acetyl and conjugated effect of
phenyl, we predicted that base as additive, which tended to
capture the protons of hydroxyl synergistically with formation of
O-Rh bond, could be effective in catalytic system. Under this, we
examined the effects of various bases as additive (2.0 equiv)
toward the reaction of N-hydroxyacetanilide (1a) and methyl
acrylate (2a, 1.2 equiv) in 1,4-dioxane at 100°C for 12 hours,
using 1:4 [RhCp*Cl2]2 (2.5 mol%)/AgSbF6 (10 mol%) as the
catalyst system. It was found that additive played a crucial role in
the reaction efficiency (Table 1, entries 1-3, 8-13). Notably, the
yields of 3a in the presence of NaOAc and KOAc exceeded 60%
(Table 1, entries 3, 8) compared with that less than 55% in other
additives, and 2.0 equiv of NaOAc was determined to be optimal
(Table 1, entry 3). Among the set of representative solvents,
t-AmOH was found to be optimal as well as 1,4-dioxane (Table 1,
entries 3, 17). The reaction temperature of 100°C was determined
to be the best by the results of that the lower yield of 3a was
obtained at a temperature lower than 100°C and the yield of 3a
did not increase at a temperature higher than 100°C (Table 1,
entries 19-21). The reaction time more than 8 hours was
unhelpful to increasing the yield of 3a (Table 1, entries 23, 24).
Under these conditions, the satisfactory isolated yields of 76%
and 77% were obtained respectively by increasing the
concentration of Rh-catalyst to 3% and 4% (Table 1, entries 6, 7),
and 75% isolated yield of 3a was obtained in t-AmOH as solvent
instead of 1,4-dioxane (Table 1, entry 18). Given all this, the
conditions in entry 6 was determined to be the optimal reaction
ortho-functionalization
of
acetanilides,
even
ortho-functionalization of anilides, occurs based on
directing-acyl, most of which proceeds by external oxidation that
requires additional oxidant such as copper(II) salts.5 Therefore,
developing a new way with novel directing group and internal
oxidation to achieve the ortho-functionalization of anilides
should be attractive. Here we report a study of the internal
oxidative coupling of N-hydroxyanilides with alkenes catalyzed
by [Cp*RhCl2]2 (Cp* = C5Me5) based on hydroxyl as directing
and oxidative group with employing NaOAc and AgSbF6 as
additives. This study also shows broadening of substituted
substrates, a possible mechanism and a kinetic test which
identifies the rate determining step for this transformation.

2
conditions and used as standard conditions in the following
studies.
Table 2
Scope of Alkenesa
Table 1
Reaction Optimizationa
entry additive
solvent
1,4-dioxane 100
Cu(OAc)2 1,4-dioxane 100
temp(°C) Time(h) yield of 3a (%)
1
AgOAc
12
12
12
12
12
8
<5
23
66
41
67
76
77
60
<5
<5
55
19
31
13
42
<5
65
75
<5
45
67
54
67
65
2
3
NaOAc
NaOAcb
NaOAcc
NaOAc
NaOAc
KOAc
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
4
5
6d
7e
8
8
12
12
12
12
12
12
12
12
12
12
8
9
K2CO3
Na2CO3
PivONa
NaOH
10
11
12
13
14
15
16f
17
18d
19
20
21f
22
23
24
PhONa
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
DMF
100
100
100
100
100
a conditions: 1a (0.237 mmol, 1.0 equiv), 2a (1.2 equiv), [RhCp*Cl2]2 (3
mol%), AgSbF6 (12 mol%), NaOAc (2.0 equiv), dioxane (2.0 ml),
100°C.
Toluene
DCE
t-AmOH
t-AmOH
Table 3
1,4-dioxane 60
1,4-dioxane 80
1,4-dioxane 120
1,4-dioxane 100
1,4-dioxane 100
1,4-dioxane 100
20
16
12
6
Scope of N-hydroxyacetanilides
8
16
a Typical conditions: 1a (0.237 mmol, 1.0 equiv), 2a (1.2 equiv), [RhCp*Cl2]2
(2.5 mol%), AgSbF6 (10 mol%), additive (2.0 equiv), solvent (2.0 ml);
Yields (<5%) estimated by TLC; Isolated yields estimated by weighing.
b NaOAc (1.0 equiv). c NaOAc (3.0 equiv).
d [RhCp*Cl2]2 (3 mol%), AgSbF6 (12 mol%).
e [RhCp*Cl2]2 (4 mol%), AgSbF6 (16 mol%).
f Experiment in the pressure tube.
With an optimized catalytic system in hand, we proceeded to
evaluate the generality of the standard reaction conditions with a
variety of alkenes as shown in Table 2. The reactions of alkenes 2
and N-hydroxyacetanilide 1a assessed initially showed that only
terminal alkenes such as acrylates and substituted styrenes could
react with N-hydroxyacetanilide. The standard reaction
conditions, which was optimized for the Rh-catalyzed oxidative
coupling of acrylates affording products 3a-3e in yields of
67-76%, afforded products 3f-3h in lower yields of 25-51% with
substituted styrenes. The electron-donating substituted styrene
did not react with N-hydroxyacetanilide, probably resulted from
that electron-donating group on styrenes is unfavourable to
stabilization for PhC- formed from migratory insertion of double
bond into the Rh-C bond. In all these cases, (E)-configuration of
all products was mainly observed, except that the conversion of
(E)-configuration to (Z)-configuration was observed in products
3b and 3c.

3
Finally, the scope of various
N
-substituents on aniline
was studied under the standard reaction conditions (Table 4).
By comparison, there was no obvious difference on yields of
olefin-products except product 3z. Among them, product 3y
was afforded in highest yield of 82%, compared with
product 3z in the lowest yield of 54%. The results could
revealed that the stronger electron-withdrawing effect of
N
-acyl, caused by conjugated effect from phenyl or furyl,
gave the higher yields such as product 3x and 3y (note that
activity of hydrogen on -hydroxyl, affected by electronic
properties of -acyl, could be understood based on chemical
N
N
shift of hydrogen in NMR). In addition, the substrate with
hydroxyl protected by acetyl could not work in this catalytic
system, illustrating the key role of N-hydroxyl.
Subsequently, the scope of variously substituted
-hydroxyacetanilides 1a 1n with methyl acrylate 2a was
studied under the standard reaction conditions (Table 3). The
electronic properties and position of substituents proved to
have an impact on the yields of products. Evidently, it was
N
-
On the basis of the scope, the chemoselectivity of the
rhodium catalysis in the standard conditions was
preliminarily understood. Intermolecular competition
experiments of different alkenes further revealed that
acrylates as coupling partners were converted preferentially
to products compared with styrenes (Scheme 1a).
found that para-substituted
higher yields than meta-substituted ones and electron-poor
-hydroxyacetanilides were more favorable for coupling
N-hydroxyacetanilides gave
N
reaction than electron-rich ones. With cyan-substituted
substrate, the reaction afforded product 3n in highest yield
of 82%. Notably, meta-substituted substrates exhibited good
regioselectivity that the coupling occurred at a defined
position on aryl. In addition, the reaction mainly delivered
trans-products. The trace of 3s was observed, which was
probably caused by resistance to Rh-catalyzed C−H
activation from acidic property of hydroxyl substituent. No
reaction with ortho-substituted substrates occurred as a
result of steric hindrance. Clearly, all of the coupling
reactions via C-H activation occurred at the ortho-position
on aryl, which demonstrated the key role of directing group.
Additionally,
-hydroxyacetanilides were converted preferentially
(Scheme 1b). The results are essentially in accord with yield
data of products 3a-3r which suggested that
electron-withdrawing groups on aryl as well as -acetyl and
NaOAc could promote the cleavage of O-H bond and C-H
activation probably followed concerted
electron-withdrawing
substituted
N
,
N
metalation-deprotonation rather than electrophilic aromatic
substitution (EAS).6
Table 4
Scope of N-substituents

4
external oxidant 5. However, the product 3a
refutes the proposed mechanism
-
dn (~0% D)
Ⅰ
(Scheme 3b).
a Percentage in bracket estimated by 1H NMR meaning proportion of each
product in total not yield
Scheme 1. Competition Experimenta
Further mechanistic studies showed that the kinetic
isotope effect (KIE) measured by using 1a and 1a-d5 as
substrates revealed a reaction involving a rate-limiting C−H
bond activation (Scheme 2a).7 Additionally, an H/D
exchange was not observed with employing
t-AmOH as the
solvent and deuterated -hydroxyacetanilide 1a
N
-d5 as
substrate, which revealed the irreversibility of C−H
activation and migratory insertion of double bond (Scheme
2b) (note that a trace of H was observed after 24 hours under
the conditions without 2a).
a The structure of compound
5 was not definite.
Scheme 3. Mechanism proposal a
Ⅰ
a Step 1 follows the concerted metalation-deprotonation of hydroxyl.
Scheme 2. Deuterium Experiments
a
Scheme 4. Mechanism proposalⅡ
To understand the conversion of substrate, we did a
pre-study on the side reaction, and observed a certain
Finally, a possible catalytic cycle is proposed in Scheme
4. We hypothesize that the catalytic cycle initiates with
amount of acetanilide
studies showed
-hydroxyacetanilide
4 at the end of the reaction. Further
that
the
translation
from
formation of the rhodacycle intermediate
7
via
N
1a
to
acetanilide
4
via
[RhCp*]-catalyzed C−H activation.8 Immediately, migratory
insertion of double bond into the Rh-C bond works
synergistically with cleavage of O-Rh bond to deliver a
six-membered rhodacycle 9.9 Subsequently, intermediate 10
formed by β-H elimination simultaneously delivers product
oxidation-reduction process occurred under the standard
conditions without alkenes. The above findings are
compatible with the mechanism sketched in Scheme 3a. In
this cycle, the rhodacycle is formed with using acetanilide
4
as the starting reactant and Rh(I) is oxidized to Rh(III) by

5
3918; (j) Shi, Z.; Boultadakis-Arapinis, M.; Glorius, F. Chem. Commun.
2013, 49, 6489.
3
, H2O and Rh(III) derived from internal oxidation by
1
hydroxyl (note that H2O was observed by H NMR; Since
NaOAc can not react with -hydroxyacetanilide 1a to form
a sodium salt of 1a step 1 in the catalytic cycle should
5 (a) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. J. Am. Chem.
Soc. 2010, 132, 4978; (b) Xue, D.; Li, J.; Liu, Y.-X.; Han, W.-Y.; Zhang,
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N
,
follow the concerted metalation-deprotonation of hydroxyl).
In summary, we have developed an efficient new
methodology to achieve the direct ortho-olefination of
acetanilides with acrylates and aryl alkenes via Rh-catalyzed
internal oxidative C-H activation, and brought forth new
hydroxyl as both directing group and internal oxidant. This
methodology, which is attractive with high efficiency of
Rh-catalyst, easily prepared NaOAc, absence of external
oxidant and pollution-free H2O as by-product, supports a
range of differently substituted substrates. The results shows
that electron-withdrawing substrates were more effective
than electron-donating substrates in the coupling reaction
with generation of product 3n in the highest yield of 82%.
The above features in the coupling of acetanilides with
alkenes obtained should lead to many applications,
especially in organic synthesis involving aromatic amines.
8 Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics 2009, 28, 3492.
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Acknowledgements
J.Z. gratefully acknowledges support from the National Natural
Science Foundation of China (21425415, 21274058) and the
National Basic Research Program of China (2015CB856303,
2011CB935801).
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