Metal-free oxidative hydroxyalkylarylation of activated alkenes by direct sp3 C-H functionalization of alcohols

Article abstract of DOI:10.1039/c3cc44055a

A metal-free tandem radical addition/cyclization reaction of activated alkenes and alcohols has been developed. The process provides an efficient and atom economical access to various valuable hydroxyl-containing oxindoles through the direct sp³ C-H functionalization of alcohols.

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Metal-free oxidative hydroxyalkylarylation of activated alkenes by
direct sp3 C-H functionalization of alcohols
Yuan Meng, Li-Na Guo,* Hua Wang and Xin-Hua Duan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
H
A metal-free tandem radical addition/cyclization reaction of
O
activated alkenes and alcohols has been developed. The
process provides an efficient and atom economical access to
various valuable hydroxyl-containing oxindoles through the
10 direct sp3 C-H functionalization of alcohols.
N
HO
O
HO
R1
R2
R1
R2
TBHP
1a
HO
R1
N
N
O
H
R2
2
I
3
Direct catalytic functionalization of the a sp3 C-H bond of
Scheme 1 Metal-free tandem oxidative cyclization reaction of activated
alkenes with alcohols
alcohols has proved to be
a reliable method for the
construction of a new C-C bond.1 This new protocol offers the
advantages of retaining an active hydroxyl functional group in
15 the product and the use of simple aliphatic alcohols as starting
materials. Pioneering work by Minisci in the 1980s
demonstrated that the oxidant promoted couplings of alcohols
with electron-deficient heterocycles.2 The recent progress on
the direct a-functionalization of alcohols included transition
20 metal catalyzed cross-coupling of alcohols with olefins,3
heterocycles,4 cinnamic acids,5 and H-phosphonates.6 In
addition, A few metal-free catalytic systems on this subject
have also been reported.7 However, this kind of transformation
50 using di-tert-butyl peroxide (DTBP) or dicumyl peroxide
(DCP) as the oxidant (entries 2 and 3). To our delight, tert-
butyl hydroperoxide (TBHP, 70% aqueous) exhibited good
catalytic activity and the 3a was achieved in 86% yield (entry
5). A screening of the reaction temperature revealed that 100
55 oC was the best one (entries 5-7). In the absence of oxidant,
the reaction did not work at all (entry 9).
Table 1 Optimization of the reaction conditionsa
HO
using simple alcohols as the reactant still remains
a
Oxidant
+
EtOH
25 challenging to chemists, and the C-H functionalization of
alcohols in a tandem addition/cyclization reaction has scarcely
been investigated.1
o
100
C
N
O
N
O
1a
3a
2a
Entry
Oxidant (equiv)
Yield b (%)
In
recent
years,
the
catalytic
intramolecular
difunctionalization of activated alkenes has emerged as a
30 powerful method for the synthesis of biologically active
heterocyclic compounds.8 For example, a range of Pd-, Fe-,
and Ag-catalyzed difunctionalization of acrylamides for the
synthesis of functionalized oxindoles have been developed.9
Among these reports, many functional groups have been
35 successfully introduced into the oxindoles. However, direct
introduction of a hydroxyl group in such a process is quite
rare so far. Herein, we report a novel metal-free tandem
oxidative cyclization reaction of activated alkenes with
alcohols (Scheme 1).10 This approach would provide a new
40 entry to more valuable hydroxyl-containing oxindoles with
high atom economy and high efficiency.11
Initially, the reaction of N-methyl-N-phenylmethacrylamide
(1a) and ethanol (2a) was chosen as a model reaction for the
optimization investigation (Table 1). Gratifyingly, treatment
45 of 1a with tert-butyl peroxybenzoate (TBPB) in 1 mL of
ethanol at 100 oC for 24 h led to the desired product 3a in
65% yield (Table 1, entry 1). However, no reaction observed
1
2
3
4
5
6
7
8
9
TBPB (2)
DTBP (2)
DCP (2)
TBHPd (2)
TBHPe (2)
TBHPe (2)
TBHPe (2)
TBHPe (1.2)
-
65
n.r.c
n.r.c
76
86
28f
74g
73
n.r.c
Reaction conditions: 1a (0.2 mmol, 1 equiv), ethanol (1 mL), oxidant (2
d
o
b
c
equiv), 100 C, 24 h. Yield of isolated product. n.r. = no reaction.
e
60 TBHP (tert-butyl hydroperoxide, 5-6 M in decane).
TBHP (70%
aqueous). f at 80 oC. g at 120 oC.
Subsequently, we examined the scope of alcohols in the
tandem oxidative cyclization reaction under the optimized
reaction conditions (Scheme 2). In addition to ethanol, n-
65 propyl alcohol is also effective (3b). However, when
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propargyl alcohol was used, only a trace amount of the desired
HO
R3
R3
product 3c was observed. It is noteworthy that ethylene glycol
was also successfully applied in this transformation, albeit in
somewhat low yield (3d). The reaction also worked with
secondary alcohols, such as isopropanol, cyclohexanol and 2-
butanol gave the corresponding oxindoles in good to moderate
yields (3e-g). Finally, the reaction of 1a with methanol
afforded 3i in 24% yield after 24 h due to the low conversion.
40
45
50
55
60
65
R1
OH
R1
TBHP (2 equiv)
View Article Online
+
100 o
C
DOI: 10.1039/C3CC44055A
N
R2
O
N
O
R2
5
2e
MeO
1
4
Me
F
HO
HO
O
HO
O
N
N
N
O
10
4a, 80%
HO
4b, 62%
HO
4c, 79%
HO
HO
O
I
NC
1
2
Cl
R
R
OH
TBHP (2 equiv)
o
+
2
1
100
C
N
O
R
R
N
N
N
N
O
O
O
2
1a
3
4f, 63%
4d, 91%
4e, 67%
HO
HO
HO
HO
EtO2C
HO
O
HO
N
N
N
O
O
O
N
N
N
O
O
Me
F
3a, 86% (d.r.=2.7:1)
3b, 83% (d.r.=1:1)
3c, trace
4g, 82%
4h, 60%
4i, 65%
HO
HO
HO
HO
HO
HO
AcO
OH
N
N
N
O
O
O
N
N
N
O
O
O
H
Bn
4j, 62%
3d, 41%
3e, 82%
3f, 40%
4l, 80%
4k, mixture
HO
OH
HO
Bn
HO
Ph
HO
HO
N
N
O
O
N
O
N
N
O
O
3h, 24%
3g, 64% (d.r.=2:1)
Scheme 2 Scope of alcohols 2
4n, trace
4m, 55%
4o, mixture
70 Scheme 3 Scope of acrylamides 1
We then evaluated the scope of substituted N-
arylacrylamides 1 with isopropanol 2e and the results are
radical-trapping reagent, was added. Interestingly, a large KIE
(kH/kD = 6.7) of the competitive experiment involving 1:1
mixture of methanol and [D4]-methanol was obtained (eq. 3),
implying that the cleavage of a C-H bond of alcohol
75 contributed to the rate-determing step. Based on the previous
mechanistic studies9d,9e,10 and our current data, we proposed
that the reaction is initiated by the TBHP promoted oxidation
summarized in Scheme 3. N-arylacrylamides
1 bearing
15 electron-donating or -withdrawing substituents on aniline
moieties could be successfully converted into the desired
products in moderate to good yields (4a-g). Notably, the
chloro- and iodo-substituted N-arylacrylamides provided the
corresponding oxindoles 4d and 4e in good yields with
20 retaining the halo groups intact. o-substituted N-
arylacrylamides also proceeded smoothly to afford the
corresponding products in moderate yields (4h and 4i).
Additionally, changing the protecting group on the N tether
from methyl group to benzyl also gave the desired product 4j
25 in 62% yield. Unfortunately, unprotected N-H acrylamide was
not tolerated in this transformation (4k). Finally, acrylamides
having acetoxymethyl and benzyl groups at the a-position
also reacted well with isopropanol (4l-m). However, phenyl
and hydroxymethyl substituted acrylamides were inefficient
30 under the optimization conditions (4n and 4o).
to form the a-hydroxyethyl radical
I A
(Scheme 4).7
subsequent radical addition process to generate intermediate
80 II,9d,9e,10 followed by intramolecular radical substitution
(radical III), would produce the corresponding oxindole 3a.
HO
standard
conditions
O
(1)
+
2e
3e
+
N
kH/kD = 1.0
N
O
D
D
[D1]-1a
[D1]-3e
82% yield
In order to get insight into the mechanism of the reaction,
the intra- and intermolecular competition experiments were
performed (eqs. 1 and 2). No kinetic isotope effects (KIE,
kH/kD = 1.0) were observed with isopropanol and [D1]-1a or
35 [D5]-1a. This clearly indicated that the reaction proceeded
through free-radical substitution which was similar to
mechanisms proposed in previously reports.9d,9e,10 In addition,
the reaction was also suppressed remarkably when TEMPO, a
1a
D
D
D
HO
O
standard
conditions
kH/kD = 1.0
+
2e
(2)
3e
+
D
D
D
D
N
D
O
[D4]-3e
N
72% yield
D
[D5]-1a
1a/[D5]-1a = 1:1
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 3
ChemComm
40 6
Z. Zhao, W. Xue, Y. Gao, G. Tang and Y. Zhao, Chem. Asian J.,
2013, 8, 713.
CH3OH
7
(a) Z.-Q. Liu, L. Sun, J.-G. Wang, J. Han, Y.-K. ZhVaioewanAdrtBicl.eZOhnoliun,e
DOI: 10.1039/C3CC44055A
Org. Lett., 2009, 11, 1437; (b) T. He, L. Yu, L. Zhang, L. Wang and
M. Wang, Org. Lett., 2011, 13, 5016.
D
2h
D
standard
conditions
kH/kD = 6.7
OH
OD
1a
(3)
+
+
45 8
For reviews, see: (a) J. P. Wolfe, Eur. J. Org. Chem., 2007, 571; (b)
J. P. Wolfe, Synlett, 2008, 2913; (c) D. M. Schultz, J. P. Wolfe,
Synthesis, 2012, 351.
N
N
O
O
CD3OD
3h
[D3]-3h
[D4]-2h
20% yield
9
For the Pd-catalyzed difunctionalization of activated alkenes
reactions, see: (a) S. Jaegli, J. Dufour, H.-L. Wei, T. Piou, X.-H.
Duan, J.-P. Vors, L. Neuville and J. Zhu, Org. Lett., 2010, 12, 4498;
(b) T. Wu, X. Mu and G. Liu, Angew. Chem., Int. Ed., 2011, 50,
12578; (c) X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo and G. Liu, J. Am.
Chem. Soc., 2012, 134, 878; Fe-catalyzed reaction, see: (d) W.-T.
Wei, M.-B. Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P.
Xie and J.-H. Li, Angew. Chem., Int. Ed., 2013, 52, 3638; Ag-
catalyzed reaction, see: (e) Y.-M. Li, M. Sun, H.-L. Wang, Q.-P.
Tian and S.-D. Yang, Angew. Chem., Int. Ed., 2013, 52, 3972; For
the related copper-catalyzed allylamines difunctionalization reaction,
see: (f) H. Egami, R. Shimizu, S. Kawamura and M. Sodeoka,
Angew. Chem., Int. Ed., 2013, 52, 4000; (g) H. Egami, S. Kawamura,
A. Miyazaki and M. Sodeoka, Angew. Chem., Int. Ed., 2013, 52,
asap, DOI: 10.1002/anie.201303350.
2h/[D4]-2h = 1:1
50
H
O
HO
N
H
TBHP
1a
N
H
H C
3
H
H C
3
55
60
OH
O
OH
2a
I
II
HO
O
HO
H
N
TBHP
10 For the metal-free oxidative difunctionalization of alkenes leading
to oxindoles via radical process, see: (a) T. Wu, H. Zhang and G.
Liu, Tetrahedron, 2012, 68, 5229; (b) M.-B. Zhou, R.-J. Song, X.-H.
Ouyang, Y. Liu, W.-T. Wei, G.-B. Deng and J.-H. Li, Chem. Sci.,
2013, 4, 2690.
11 (a) A. Ashimori, B. Bachand, L. E. Overman and D. J. Poon, J. Am.
Chem. Soc., 1998, 120, 6477; (b) A. Ashimori, B. Bachand, M. A.
Calter, S. P. Govek, L. E. Overman and D. J. Poon, J. Am. Chem.
Soc., 1998, 120, 6488; (c) S. Akai, T. Tsujino, E. Akiyama, K.
Tanimoto, T. Naka and Y. Kita, J. Org. Chem., 2004, 69, 2478; (d)
L. E. Overman and M. D. Rosen, Tetrahedron, 2010, 66, 6514; (e)
X.-L. Liu, Y.-H. Liao, Z.-J. Wu, L.-F. Cun, X.-M. Zhang and W.-C.
Yuan, J. Org. Chem., 2010, 75, 4872.
N
O
t
+
H O
2
BuO
3a
III
65
70
75
Scheme 4 Proposed mechanism
In summary, we have demonstrated an efficient metal-free
oxidative hydroxyalkylarylation of activated alkenes by direct
sp3 C-H functionalization of alcohols. This methodology
provides the simplest way to construct hydroxyl-containing
oxindoles which are important synthetic intermediates in
biologically active compounds and medicinal chemistry.
10 Further applications of this transformation to other simple
substrates and the synthesis of more valuable compounds are
underway in this group.
5
Acknowledgements
Financial support from National Natural Science Foundation
15 of China (Nos. 21102111, 21102110), and the Fundamental
Research Funds of the Central Universities are greatly
appreciated.
Notes and references
Department of Chemistry, School of Science and MOE Key Laboratory
20 for Nonequilibrium Synthesis and Modulation of Condensed Matter,
Xi’an Jiaotong University, Xi’an 710049, China.
E-mail: guoln81@mail.xjtu.edu.cn; duanxh@mail.xjtu.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
25 DOI: 10.1039/b000000x/
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30
35
3
4
5
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