Microwave-Assisted Copper-Catalyzed Oxidative Cyclization of Acrylamides with Non-Activated Ketones

Article abstract of DOI:10.1002/chem.201504776

An operationally simple and efficient microwave-assisted protocol for the oxidative cyclization of acrylamide derivatives with non-activated ketones to generate 3,3-disubstituted oxindoles is described. The reaction proceeds by a copper-catalyzed tandem radical addition/cyclization strategy and tolerates a series of functional groups with moderate to excellent yields. From a kitchen to the lab! An efficient Cu-catalyzed microwave-assisted oxidative addition of non-activated ketones to acrylamides is described for the construction of 3,3-disubstituted oxindoles (see scheme). This simple transformation demonstrates a high functional group tolerance, providing good to excellent product yields under mild reaction conditions.

Full text of DOI:10.1002/chem.201504776

DOI: 10.1002/chem.201504776
Communication
&
Cyclization
Microwave-Assisted Copper-Catalyzed Oxidative Cyclization of
Acrylamides with Non-Activated Ketones
Yaping Zhao,[a, b] Nandini Sharma,*[a] Upendra K. Sharma,[a] Zhenghua Li,[a] Gonghua Song,[b]
and Erik V. Van der Eycken*[a]
tions have been developed to introduce functional groups,
Abstract: An operationally simple and efficient micro-
such as cyano, alkoxyl, and hydroxyl, into the oxindole skele-
wave-assisted protocol for the oxidative cyclization of
ton.[7] In comparison, the direct oxidative 1,2-alkylarylation of
acrylamide derivatives with non-activated ketones to
an activated alkene with non-activated ketones still remains
generate 3,3-disubstituted oxindoles is described. The
challenging and is confined to only one report. In 2013, Duan
reaction proceeds by a copper-catalyzed tandem radical
and co-workers developed the silver-catalyzed oxidative cou-
addition/cyclization strategy and tolerates a series of
pling/cyclization of acrylamides with 1,3-dicarbonyl com-
functional groups with moderate to excellent yields.
pounds providing b-diketones and b-keto esters in good
yields.[8] However, except for acetone, the yields were poor
when non-activated ketones were tried as coupling partners,
With a growing awareness about the environment, the devel-
opment of new, sustainable, and highly efficient synthetic ap-
proaches has been taken more seriously by chemists.[1] In the
last few decades, the construction of CÀC bonds by metal-cat-
alyzed direct CÀH bond functionalization has acquired signifi-
cant importance among modern organic synthetic strategies.[2]
Among these reactions, the sequential formation of multiple
CÀC bonds in one pot, especially through activation of the
C(sp3)ÀH bond for the synthesis of useful and structurally di-
verse heterocyclic molecules is highly desirable.[3] Among the
various N-heterocycles, oxindoles are privileged heterocyclic
scaffolds in various natural products and exhibit significant bio-
logical activities.[4,11b] In addition, functionalized oxindoles have
been widely used as versatile starting materials to synthesize
other heterocyclic compounds and natural products.[5] Thus,
numerous strategies are devised for obtaining this valuable
framework, the most common one being the intramolecular
Heck reaction of ortho-functionalized anilides.[6] However,
owing to their expensive and commercially nonviable nature,
the direct oxidative coupling of ortho nonfunctionalized acryla-
mides and unactivated C(sp3)ÀH bonds provides an appealing
approach for the synthesis of oxindoles. Through this strategy,
various metal-catalyzed cyclizations as well as metal-free reac-
which could be ascribed to their lower activity. Also, the reac-
tion time needed was quite long (28 h). Therefore, there is still
a need for the development of a simple, convenient, efficient,
and alternative strategy to access more diverse alkylated oxin-
doles by direct difunctionalization of alkenes. In the context of
green chemistry, microwave-assisted chemistry has brought
a paradigm shift in organic synthesis by drastically reducing re-
action times and enhancing yields.[9] Additionally, the use of in-
expensive and less toxic copper salts for CÀH functionalization
reactions has gained significant attraction, and a range of
these methodologies relating to the construction of heterocy-
cles have been successfully developed.[10] As part of our contin-
ued interest in the synthesis of oxindole motifs,[11] we describe
a simple and convenient microwave-assisted approach to pro-
vide 3,3-dialkylated oxindoles with high efficiency (Scheme 1).
For the optimization studies, N-arylacrylamide 1a (0.1 mmol)
and acetophenone (2a; 0.5 mL) were chosen as model sub-
strates (Table 1). The reaction was carried out in the presence
of di-tert-butyl peroxide (DTBP; 2.0 equiv) and Cu2O (5 mol%)
under microwave irradiation at 1208C for 1 h to give the de-
sired 2-oxindole 3a in 32% yield (based on NMR; entry 1). Un-
fortunately, there was no significant improvement in yield with
other copper salts or oxidants (entries 2–7). Among all, the
combination of copper(II)chloride with dicumyl peroxide (DCP)
was found better (entry 6) and hence was used for further
optimization. Increasing or decreasing the amount of aceto-
phenone led to a reduced product yield (entries 8 and 9). Also,
any change in reaction temperature led to a negative outcome
(entries 10–12). Interestingly, the use of Et3N (10 mol%) as an
additive increased the yield to 78% (entry 13). Here small
amount of Et3N might be working as a promoter to assist the
copper to catalyze the reaction.[5b] Other organic and inorganic
bases, such as DIPEA, DABCO, and NaHCO3, proved to be less
efficient than Et3N (entries 14–16). However, there was no fur-
ther increase in product yield by either increasing or decreas-
ing the amount of Et3N (entries 17 and 18). After several per-
[a] Y. Zhao, Dr. N. Sharma, Dr. U. K. Sharma, Z. Li, Prof. Dr. E. V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC)
Department of Chemistry, University of Leuven (KU Leuven)
Celestijnenlaan 200F, 3001 Leuven (Belgium)
E-mail: n_sharma023@yahoo.co.in
erik.vandereycken@chem.kuleuven.be
Homepage: http://chem.kuleuven.be/en/research/mds/lomac
[b] Y. Zhao, Prof. Dr. G. Song
Shanghai Key Laboratory of Chemical Biology
East China University of Science and Technology
Shanghai 200237 (People’s Republic of China)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under http://dx.doi.org/10.1002/
chem.201504776.
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arylacrylamides. As depicted in Table 2, the optimized
conditions can be applied to a wide range of N-aryla-
crylamides providing the corresponding products in
moderate to high yields. In general, electron-donat-
ing substituents afforded slightly higher yields com-
pared to electron-withdrawing substituents (3a–3e).
Importantly, F- and Cl-substituted N-arylacrylamides
were also compatible and gave the desired products
3 f and 3g in 75 and 64% yield, respectively. A good
Scheme 1. Difunctionalization of alkenes with non-activated ketones.
Table 1. Optimization of reaction conditions.[a]
Table 2. Scope of N-arylacrylamides.[a,b]
Entry
Catalyst (mol%)
Oxidant
Additive [mol%]
Yield [%][b]
1
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu(OAc)2 (5)
CuBr2 (5)
CuCl2 (5)
CuCl (5)
DTBP
TBHP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP[i]
DCP[j]
DCP[i]
DCP[i]
DCP[i]
DCP[i]
–
–
–
–
–
–
–
–
–
–
–
–
32
trace
36
39
38
44
43
34
41
trace
28
39
78 (69)
74
65
48
50
71
82
2[c]
3
4
5
6
7
8[d]
9[e]
10[f]
11[g]
12[h]
13
14
15
16
17
18
19
20
21
22
23
24[k]
25
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (15)
CuCl2 (20)
CuCl2 (15)
CuCl (15)
Et3N (10)
DIPEA (10)
DABCO (10)
NaHCO3 (10)
Et3N (5)
Et3N (20)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
85
80
88 (80)
76
56
– (80)
[a] N-methyl-N-phenylmethacrylamide (1 equiv, 0.1 mmol), acetophenone
(0.5 mL), catalyst (5 mol%, 0.005 mmol), oxidant (2 equiv, 0.2 mmol), addi-
tive (10 mol%, 0.01 mmol), MW, 1208C, 1.0 h. [b] NMR yields using 3,4,5-
trimethoxy benzaldehyde as the internal standard; isolated yields in the
parentheses. [c] TBHP in 70% H2O. [d] 2a=0.2 mL. [e] 2a (1.0 mL).
[f] 1008C. [g] 110 8C. [h] 1408C. [i] 3Equiv. [j] 4Equiv. [k] Conventional
heating, 1208C, 48 h. TBHP=tert-butyl hydroperoxide; DIPEA=N,N-di-
isopropylethylamine; DABCO=1,4-diazobicyclo[2.2.2]octane.
[a] Reaction conditions: 1a-u (1 equiv, 0.2 mmol), 2a (1.0 mL), CuCl2
(15 mol%, 0.03 mmol), DCP (3 equiv, 0.60 mmol), Et3N (10 mol%,
0.02 mmol), MW (Pmax =100 W), 1208C, 1 h. [b] Isolated yields. nd=not
determined.
yield was also obtained with a halogen at ortho-position of the
aryl ring (3h). For N-arylacrylamides bearing a meta-substitu-
ent, a mixture of isomers was obtained (3j, 3k, and 3l). Addi-
tionally, the reaction with disubstituted methyl groups (3i) and
naphthyl substrate (3m) worked equally well, affording the
corresponding products in good yields. Also, N-ethyl-, N-
benzyl-, N-phenyl-, and N-phenacyl-substituted acrylamides all
gave the desired products in moderate to high yields under
the optimal conditions (3o–3q, 3t). However, no product was
found with unsubstituted acrylamide 3r, whereas the tosyl
substitution provided only traces of the product 3s. Also, the
fused N-heterocyclic 3u was obtained from 1-(3,4-dihydroqui-
mutations and combinations (entries 19–23), the optimized
conditions (entry 22) were found to be: CuCl2 (15 mol%), DCP
(3 equiv), and Et3N (10 mol%). It is worth noting that a conven-
tional heating was less effective for the above reaction under
similar conditions giving a maximum yield of 56% after 48 h
(entry 24). Also, CuCl was found to be equally effective for the
above transformation, giving the desired product in 80% yield
(entry 25).
With the optimized reaction conditions established, we stud-
ied the scope of the reaction of acetophenone with various N-
Chem. Eur. J. 2016, 22, 5878 – 5882
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nolin-1(2H)-yl)-2-methylprop-2-en-1-one in 67% yield under
the optimal conditions.
We subsequently tested the substrate scope for different
ketones (Table 3). Moderate yields were obtained by using
p-methylacetophenone and p-ethylacetophenone as coupling
Table 3. Scope of ketones.[a,b]
Scheme 3. Concise synthesis of heterocycles up to 1 mmol scale.
Table 4. control experiments.
Entry
Catalyst
Oxidant
Additive
Yield [%][a]
1
2
3
4
5
6
7
CuCl2
CuCl2
–
CuCl2
–
DCP
–
DCP
–
DCP
–
DCP
–
44
19
27
<10
22
NR
80
Et3N
Et3N
–
–
Et3N
Et3N
–
CuCl2
[a] Isolated yield
[a] Reaction conditions: 1a (1 equiv, 0.2 mmol),
2 (1.0 mL), CuCl2
(15 mol%, 0.03 mmol), DCP (3 equiv, 0.6 mmol), Et3N (10 mol%,
0.02 mmol), MW (Pmax =100 W), 1208C, 1 h. [b] Isolated yields. [c] Yield of
benzylarylation product. [d] 2j (10 equiv), EtOAc (1 mL). d.r. calculated
from the 1H NMR of crude mixture.
Scheme 4. Control experiments with TEMPO and BHT. TEMPO=2,2,6,6-tetra-
methylpiperidine N-oxide; BHT=butylated hydroxytoluene.
partners (4a, 4b), whereas good to moderate yields were ob-
tained by using halogen-bearing substituents in different
positions of the acetophenone (4c–4g). We were pleased to
observe that polysubstituted acetophenones also reacted
successfully with N-arylacrylamide (4h, 4i). Similarly, 1-(4-fluo-
rophenyl)propan-1-one and 1-phenylbutan-1-one also provid-
ed the desired products in 69% (4j) and 79% (4k) yield.
Gratifyingly, acetone and cyclohexanone also produced the
corresponding products 4l and 4m in 72 and 70% yield,
respectively. Also, MeNO2 (4n) and MeCN (4o), containing acti-
vated C(sp3)ÀH bonds, proved to be effective substrates for
the above reaction (Scheme 2). The practical applicability of
the process was successfully demonstrated by upscaling the
reaction to 1 mmol scale for 3a, 3b, and 3i (Scheme 3).
of a catalyst, oxidant, or an additive, a reduced or no yield of
3a was observed (Table 4, entries 1–6). Moreover, the presence
of TEMPO and BHT hampered the reaction to a great extent,
suggesting that a radical intermediate is involved in the cata-
lytic cycle of the reaction (Scheme 4). Further, to shed some
light on the catalytic procedure, a series of deuteration reac-
tions were carried out (Scheme 4, also see the Supporting In-
formation). When [D1]-1a and [D5]-1a were subjected to inter-
and intramolecular competition experiments, a kinetic isotope
effect (KIE) of 1.0 was observed (Scheme 5a and 5b), indicating
that an electrophilic substitution or a free-radical substitution
occurs during this transformation.[5b,12] The intermolecular com-
petition reaction between a 1:1 mixture of 2a and its deuterat-
ed analogue [D3]-2a and 1a demonstrated a KIE of 4.1
(Scheme 5c). However, parallel experiments between 2a and
[D3]-2a with acrylamide revealed a kinetic isotope effect of
1.12 (see Figure S1 in the Supporting Information), which indi-
cates that the cleavage of the CÀH bond from acetophenone
may or may not be involved in the rate-limiting step.
For mechanistic investigations, a series of control experi-
ments were conducted (Table 4 and Scheme 4). In the absence
Based on these observations and literature reports,[13] we
propose a plausible catalytic cycle (Scheme 6). The first step in-
Scheme 2. Substrates containing activated C(sp3)ÀH bonds.
Chem. Eur. J. 2016, 22, 5878 – 5882
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cavity of a CEM discover microwave reactor for 1 h at 1208C using
a maximum power of 100 W. After completion of the reaction
(monitored by TLC analysis), the mixture was filtered, concentrated,
and the crude product was purified by column chromatography
on silica gel using heptane/EtOAc as eluent. The products were
further identified by 1H, 13C NMR, and HRMS, which were all in
good agreement with the assigned structures.
Acknowledgements
Support was provided by the Research Fund of the University
of Leuven (KU Leuven) and the FWO Fund for Scientific Re-
search Flanders (Belgium). U.K.S. and N.S. are thankful to KU
Leuven for providing a post-doctoral fellowship. Y.Z. and Z.L.
are grateful to the China Scholarship Council (CSC) for provid-
ing a doctoral exchange and doctoral scholarship, respectively.
Scheme 5. Deuterium labelling experiments.
Keywords: alkenes · copper · ketones · oxindoles · radical
addition
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Experimental Section
General procedure for the synthesis of 3,3-disubstituted
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