MnO2-Catalyzed Oxidative Alkylation of Enamides with Ethers via C(sp3)-H/C(sp2)-H Cross-Dehydrogenative Coupling and Hydrolysis Sequence

Article abstract of DOI:10.1055/s-0035-1560180

A new MnO₂-catalyzed oxidative alkylation of enamides with a C(sp³)-H bond adjacent to an oxygen atom is described. This method achieves a C(sp³)-H/C(sp²)-H cross-dehydrogenative coupling and hydrolysis, thus pr

Full text of DOI:10.1055/s-0035-1560180

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2557–2560
letter
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Z. Hu et al.
Letter
Synlett
MnO2-Catalyzed Oxidative Alkylation of Enamides with Ethers via
C(sp3)–H/C(sp2)–H Cross-Dehydrogenative Coupling and Hydroly-
sis Sequence
Zhiyan Hua,b
Yucai Tanga
Shan Zhanga
Xiaoqing Lia
Xiaohua Dua
Xiangsheng Xu*a
O
MnO2 (20 mol%)
TBHP (4.0 equiv)
NHAc
H
+
H
Ar
O
O
Ar
100 °C
18 examples
22–79% yield
C(sp3)–H/C(sp2)–H CDC
and hydrolysis sequence
a College of Chemical Engineering, Zhejiang University of Technology,
Hangzhou 310014, P. R. of China
future@zjut.edu.cn
b Key Laboratory of Chemical Ultilization of Forestry Biomass of
Zhejiang Province, School of Science Zhejiang Agriculture and Forestry
University, Lin’an 311300, P. R. of China
Received: 25.05.2015
Accepted after revision: 23.07.2015
Published online: 02.09.2015
reaction between N-vinylacetamides and carbazates, which
provided an efficient strategy for the preparation of useful
highly substituted (β-acylamino)acrylates.6 A valuable ap-
proach to arylvinyl sulfides via silver-mediated oxidative
vinylic C–H sulfenylation of enamides with diaryl disulfides
has been developed by Deng and co-workers.7 Very recent-
DOI: 10.1055/s-0035-1560180; Art ID: st-2015-w0396-l
Abstract A new MnO2-catalyzed oxidative alkylation of enamides with
a C(sp3)–H bond adjacent to an oxygen atom is described. This method
achieves a C(sp3)-H/C(sp2)-H cross-dehydrogenative coupling and hy-
drolysis, thus providing efficient and general access to a variety of β-oxo
ketones.
Table 1 Optimization of Reaction Conditionsa
Key words C(sp3)–H/C(sp2)–H
ethers, enamides, β-oxo ketones, radicals
cross-dehydrogenative
coupling,
O
O
NHAc
O
O
O
cat. (20 mol%)
oxidant
+
H
The direct functionalization of C–H bonds has proved to
be one of the most powerful tools for the construction of C–
C and C–X bonds.1 In particular, great progress has been
achieved with respect to the functionalization of C(sp3)–H
bonds of ethers via radical process.2 However, the function-
alization of C(sp3)–H bond of ethers via cross-dehydrogena-
tive coupling (CDC) with a C(sp2)–H bond gained less atten-
tion.2g
Enamides, which can be readily prepared by the reduc-
tive acylation of ketoximes, are powerful building blocks in
organic synthesis.3 Great progress has been achieved with
respect to the palladium(II)-catalyzed functionalization of
vinylic Cβ–H bond of enamides, such as arylation with orga-
noboron,4a organosilane reagents,4b or arenes,4c and nucleo-
philic addition to isocyanates.5 Recently, palladium-free
functionalization of vinylic Cβ–H bond of enamides via radi-
cal process have attracted much attention. Loh and co-
workers reported a iron(II)-catalyzed alkoxycarbonylation
1a
3a
2a
Entry
Catalyst
–
Oxidant
Yield (%)b
1
2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBPB
DTBP
BPO
50
FeCl3·6H2O
FeCl2·4H2O
Cu(OAc)2
CuI
n.d.
26
3
4
57
5
38
6
TBAI
trace
20
7
NiCl2·6H2O
Co(OAc)2·4H2O
Co(acac)2
MnO2
8
56
9
48
10
11
12
13
14c
71
MnO2
25
MnO2
10
MnO2
31
MnO2
TBHP
17
O
NHAc
MnO2, TBHP
a Reaction conditions: 1a (0.25 mmol), 2 (1.5 mL), catalyst (20 mol%), oxi-
H
H
+
Ar
O
Ar
O
dant (4.0 equiv), 100 °C, 6 h.
b Isolated yield.
Scheme 1 Oxidative cross-coupling of ethers with enamides
c 80 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2557–2560

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Z. Hu et al.
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ly, we also developed a facile synthetic route towards phar-
maceutically interesting β-keto sulfones by tetrabutylam-
monium iodide (TBAI)/tert-butyl hydroperoxide (TBHP)
mediated sulfonylation of vinylic Cβ–H bond of enamides
with sulfonylhydrazides.8 However, to the best of our
knowledge, examples of functionalization of vinylic Cβ–H
bond of enamides via C(sp3)–H/C(sp2)–H CDC have been
rarely studied. Herein, we report the first radical C(sp3)–H/
C(sp2)–H CDC of enamides with ethers (Scheme 1). The re-
action proceeds with TBHP oxidation using MnO2 as cata-
lyst, thereby providing a general and straightforward means
of accessing various β-oxo ketones.
under catalyst-free conditions. To our delight, the desired
product 3a was obtained in 50% yield (Table 1, entry 1). In-
spired by the initial result, we first tested different cata-
lysts. We found that the oxidative coupling occurs with a
higher yield of 3a when using MnO2 (71% yield) as catalyst
(Table 1, entry 10), while the use of other catalysts, includ-
ing FeCl3·6H2O, FeCl2·4H2O, Cu(OAc)2, CuI, TBAI,
Co(OAc)2·4H2O, and Co(acac)2 was less efficient (Table 1, en-
tries 2–9). A number of other oxidants, including tert-butyl
peroxybenzoate (TBPB), di-tert-butyl peroxide (DTBP), ben-
zoyl peroxide (BPO), were subsequently investigated (Table
1, entries 11–13), and they were found to be less effective
than TBHP. When the reaction was carried out at 80 °C, the
yield of 3a decreased to 17%.
Our investigation started with N-vinylacetamide 1a and
1,4-dioxane (2a) at 100 °C using TBHP (70% aq) as oxidant
O
MnO2 (20 mol%)
NHAc
+
Ar
R1
O
H
TBHP (4.0 equiv )
100 °C , 6 h
O
Ar
R2
2
1
3
O
O
O
O
O
O
O
O
O
R
R
3a: R = H, 71%
3k: R = MeO, 46%
3l: R = Cl, trace
3h: R = MeO, 61%
3i: R = Br, 42%a
3j: R = CF3, 41%
R
3b: R = Me, 56%
3c: R = MeO, 36%
3d: R = F, 52%
3e: R = Cl, 70%
3f: R = Br, 79%
3g: R = CF3, 56%
O
O
O
O
O
O
O
O
X
O
3n: X = S, 40%
3o: X = O, n.d.
3p: <5%
3m: 22%
O
O
O
O
O
O
O
3q: n.d.
3r: 58%
3s: 69%
O
O
O
OEt
O
O
+
3u: 52%
3t/3t': 63% (3:1)b
OMe
O
OMe
3v: 45%
Scheme 2 Reaction of enamides with ethers. Reagents and conditions: 1 (0.25 mmol), 2 (1.5 mL), MnO2 (20 mol%), TBHP (4.0 equiv) at 100 °C for 6 h.
Isolated yields are given. a 10 h. b Determined by the 1H NMR spectra of the isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2557–2560

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MnO2
t-BuO or t-BuOO
t-BuOOH
NHAc
H
O
O
t-BuO or t-BuOO
NHAc
O
O
O
1a
O
H
I
II
t-BuOH or t-BuOOH
[O]
NHAc
O
O
O
O
NHAc
O
O
+
O
hydrolysis
III
IV
3a
Scheme 3 Proposed preliminary mechanism
After the optimal reaction conditions were established,
the scope of this oxidative alkylation with regard to enam-
ides as well as the C(sp3)–H bonds adjacent to an oxygen
atom was exploited (Scheme 2).9 First, substitution effects
of enamides were examined. The reaction proceeded
smoothly not only for the enamides bearing an electron-
donating group (products 3b,c,h,k) but also for those sub-
strates having halides (products 3d–f,i) or strong electron-
withdrawing CF3 substituent (3g,j). Surprisingly, attempt to
carry out the corresponding oxidative alkylation of 2-Cl-
substituted enamide was unsuccessful. The application of
polysubstituted enamide provided the desired product 3m
as well. The oxidative alkylation with enamide containing
the thiophene delivered the desired product 3n in 40%
yield, while the enamide containing furan and benzofurans
was unreactive and resulted in no formation of 3o. The
enamides derived from propiophenone and dihydronaph-
thalene failed in the reaction to give the desired products
3p and 3q due to the steric effect. We next set out to inves-
tigate the scope of the C(sp3)–H bonds adjacent to an oxy-
gen atom. When using tetrahydro-2H-pyran and tetrahy-
drofuran, the reaction afforded 58% and 69% yields of the
corresponding 3r and 3s. To investigate the regioselectivity
of the transformation, 2-methyltetrahydrofuran was also
treated with N-vinylacetamide under the optimized condi-
tions, and a mixture of two regioisomers (products 3t/3t′)
was generated in the ratio of 3:1. Importantly, this proce-
dure is not limited to the cyclic ethers. For example,
ethoxyethane and dimethoxyethane afforded the desired
products 3u and 3v in 52% and 45% yields, respectively.
According to the above experimental results and previ-
ous reports, a plausible mechanism is proposed (Scheme 3).
Initially, MnO2-assisted decomposition of TBHP generated
tert-butoxyl and tert-butylperoxy radicals,10 which ab-
stracted the α-H of ether and generated radical intermedi-
ate (I).2 The addition of the resultant radical intermediate
(I) to a C–C double bond in the enamide furnished carbon-
centered radical intermediate (II), followed by oxidation
with TBHP to afford carbocation intermediate (III). The in-
termediate (III) then eliminated a proton to form enamide
intermediate (IV). Finally, hydrolysis reaction of enamide
intermediate (IV) afforded the product 3a.
In conclusion, we have developed a novel MnO2-cata-
lyzed oxidative alkylation of enamides with a C(sp3)–H
bonds adjacent to a oxygen atom. The process involves a
C(sp3)–H/C(sp2)–H CDC and hydrolysis sequence. This reac-
tion provided a simple and practical protocol for the syn-
thesis of β-oxo ketones.
Acknowledgment
Financial support from the National Natural Science Foundation of
China (21102130), the Natural Science Foundation of Zhejiang Prov-
ince (LY14B020005), and the 863 Program (2013AA065005) is greatly
appreciated.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560180.
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References and Notes
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Oxidative Cross-Coupling of Ethers with Enamides
To a suspension of N-vinylacetamides 1 (0.25 mmol), MnO2
(0.05 mmol), and 1,4-dioxane (2) (1.5 mL) was added TBHP (70%
aq solution, 1.0 mmol), and the mixture was stirred at 100 °C
for 6 h. After the solvent was removed under reduced pressure,
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2557–2560