Copper-catalyzed oxidative benzylarylation of acrylamides by benzylic C-H bond functionalization for the synthesis of oxindoles

Article abstract of DOI:10.1002/chem.201302139

Radically changing benzyls: An efficient method for the benzylarylation of activated alkenes has been developed through a copper-catalyzed tandem radical addition/cyclization strategy (see scheme). This oxidative coupling between acrylamides and benzylic hydrocarbons provides access to diverse alkyl-substituted oxindoles in good to excellent yields. A variety of functional groups were tolerated in this transformation (TBPB=tert-butylperoxy benzoate). Copyright

Full text of DOI:10.1002/chem.201302139

COMMUNICATION
DOI: 10.1002/chem.201302139
Copper-Catalyzed Oxidative Benzylarylation of Acrylamides by Benzylic
À
C H Bond Functionalization for the Synthesis of Oxindoles
Shi-Liu Zhou, Li-Na Guo,* Hua Wang, and Xin-Hua Duan*[a]
Oxindoles, important and representative nitrogen hetero-
cycles, are of great interest to organic synthesis because of
their significant biological activities and wide-ranging appli-
cations in organic synthesis.[1,2] In the past few years, a
number of traditional processes for the synthesis of these
motifs have been established.[3] The groups of Kꢀndig and
À
Taylor have reported the copper-mediated direct Csp2 H/
À
Csp3 H functionalization of anilide to a variety of oxindoles
Scheme 1. Oxidative benzylarylation of activated alkenes.
through a radical process.[3e,f] In addition, palladium-cata-
lyzed intramolecular difunctionalization of alkenes, includ-
Table 1. Optimization of the reaction conditions.[a]
ing aryloxygenation,[4a] arylalkylation,[4b] and aryltrifluoro-
methylation[4c] provides an elegant method for the construc-
tion of the oxindole skeleton. Generally, hypervalent iodine
derivatives have proven to be highly active oxidants in these
transformations. Very recently, a new metal-catalyzed di-
functionalization reaction of alkenes through a radical proc-
ess to form functionalized oxindoles has also been report-
ed.[5] However, there are relatively few methods available
for the preparation of oxindoles through oxidative dicarbo-
nation of alkenes by using unactivated substrates, particular-
À
Entry
Catalyst
([mol%])
Oxidant
ACHTUNGTRENN(UNG [equiv])
Yield
[%][b]
G
1
2
3
4
5
6
7
8
9
–
–
–
–
TBPB (2.0)
TBHP (2.0)
DTBP (2.0)
DCP (2.0)
TBPB (2.0)
TBPB (2.0)
TBPB (2.0)
TBPB (2.0)
TBPB (2.0)
65
24
46
10
87
93
89
96
ly catalytic systems capable of performing direct Csp3
functionalization.[4b,5a]
H
CuN
CuBr2 (5)
CuCl (5)
Cu2O (5)
Cu2O (2)
Recently, metal- or metal-free-catalyzed radical reactions
À
À
have emerged as a powerful tool for C C and C hetero-
ACHTUNGTRENNUNG
95 (93)[c]
atom bond formation.[6] Among these, various benzylic hy-
[a] Reaction conditions: 1a (0.2 mmol, 1.0 equiv), oxidant (2.0 equiv), tol-
uene (1.0 mL), 1208C, 28 h. TBPB=tert-butylperoxy benzoate, TBHP=
tert-butyl hydroperoxide (5–6m in decane), DTBP=di-tert-butyl perox-
ide, DCP=dicumyl peroxide. [b] Yield of the isolated product. [c] Yield
on a 1 mmol scale is given in parentheses.
drocarbons have been used as coupling partners due to their
easily formed active benzyl radicals.[7] Inspired by recent re-
ports on the tandem radical addition/cyclization to form
functionalized oxindoles,[5,8] we envisioned that such a radi-
cal procedure might be applicable to benzylic hydrocarbons,
as shown in Scheme 1. Herein, we report a copper-catalyzed
oxidative benzylarylation of alkenes to form alkyl-substitut-
ed oxindoles by using readily available benzylic hydrocar-
bons as coupling partners.
reaction of 1a with 2a in the presence of 2.0 equivalents of
TBPB as the oxidant at 1208C for 28 h, afforded the desired
product 3a in 65% yield (Table 1, entry 1). The effect of the
oxidant in the reaction was then examined, and TBPB
proved to be better than the other peroxides tested for the
reaction (Table 1, entries 1–4). A brief survey of different
We first investigated the reaction of N-methyl-N-phenyl-
methacrylamide 1a with toluene 2a under various reaction
conditions (for details, see the Supporting Information). The
catalysts, such as CuACHTUNGTRNEUG(N OAc)2, CuBr2, CuCl, and Cu2O, indi-
cated that Cu2O is the best (Table 1, entries 5–8). Finally,
the amount of catalyst could be reduced to 2 mol% and still
lead to an excellent yield (Table 1, entry 9). It should be
noted that the reaction could also be scaled up to 1 mmol,
and the desired product, 3a, was isolated in 93% yield.
With the optimized conditions in hand, the scope of the
reaction towards acrylamides, 1, was examined (Table 2). To
our delight, a variety of acrylamides (1) reacted smoothly
under the oxidative conditions, affording the desired oxin-
[a] S.-L. Zhou, Prof. Dr. L.-N. Guo, H. Wang, Prof. Dr. X.-H. Duan
Department of Chemistry, School of Science and
MOE Key Laboratory for Nonequilibrium Synthesis and
Modulation of Condensed Matter
Xiꢁan Jiaotong University, Xiꢁan 710049 (P.R. China)
E-mail: guoln81@mail.xjtu.edu.cn
duanxh@mail.xjtu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302139.
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Table 2. Scope of the reaction towards acrylamides 1.[a]
Table 3. Scope of the reaction towards benzylic hydrocarbons 2.[a]
[a] Reaction conditions: Cu2O (2 mol%), 1a (0.2 mmol, 1.0 equiv),
TBPB (2.0 equiv), benzylic hydrocarbons (2, 1.0 mL), 1208C, 28 h. [b] 2d
(1.0 mmol, 5.0 equiv), EtOAc (1 mL).
para-tolunitrile and para-methylacetophenone also survived
under the reaction conditions, leading to 4d and 4e in 45
and 63% yields, respectively. meta-Xylene, ortho-xylene,
and mesitylACTHNUGRTNEUNGene, with multiple methyl groups, were trans-
formed into the desired products in excellent yields with
high selectivities (4 f, 4g, and 4i). However, when ethylben-
zene was used as a substrate under the optimized reaction
conditions, only a trace amount of the product, 6a, was de-
tected [Eq. (1)].
[a] Reaction conditions: Cu2O (2 mol%), 1 (0.2 mmol, 1.0 equiv), TBPB
(2.0 equiv), toluene (1.0 mL), 1208C, 28 h.
doles in moderate to good yields. Sensitive functional
groups on the aniline moieties such as ester and cyano
groups were tolerated in this transformation (3c and 3d).
Halo-substituted acrylamides were also compatible and gave
the corresponding products in good yields, which allows fur-
ther functionalization of the oxindoles (3e–g). For ortho-
substituted acrylamides, the corresponding oxindoles, 3h
and 3i, were obtained in 92 and 72% yields, respectively.
The N-arylacrylamide bearing a benzyl protecting group on
the nitrogen atom also reacted smoothly to give the desired
product, 3j, in 88% yield. However, unprotected N-aryl-
To clarify the mechanism of this process, two competition
experiments were performed [Eqs. (2) and (3)]. Firstly,
when [D1]-1a and [D5]-1a were subjected to the reaction
conditions, intra- and intermolecular kinetic isotope effects
(KIE) of 1.0 were observed, demonstrating that electrophilic
aromatic or free-radical substitution occurred in this trans-
formation.[5,8,9] Secondly, a clear KIE of the competitive ex-
periment involving a 1:1 mixture of 2a/[D8]-2a was obtained
ACHTUNGTRENNUNGacrylamide did not react at all under these reaction condi-
À
tions (3k). On the other hand, acrylamides with acetoxy-
methyl, benzyl, and phenyl groups at the a-position led to
the corresponding products, 3l–3n, in good yields. The use
of meta-substituted acrylamide 1o resulted in a mixture of
the products 3o and 3o’ with moderate regioselectivity
(1:3).
[Eq. (4)], indicating that the cleavage of the benzyl C H
bond is the rate-limiting step. Finally, a radical-trapping re-
agent, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), was
added and the reaction was suppressed, suggesting that free-
radical intermediates were involved in the reaction.
Subsequently, our protocol was extended to different ben-
zylic hydrocarbons (Table 3). para-Xylene, para-fluoro-
ACHTUNGTRENNUNG
&
2
&
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Oxidative Benzylarylation of Acrylamides
COMMUNICATION
approach to functionalized oxindoles in terms of atom econ-
omy.
Experimental Section
General procedure for the benzylarylation of acrylamides with benzylic
hydrocarbons: An oven-dried Schlenk tube (10 mL) was charged with
Cu2O (0.6 mg, 2 mol%) and acrylamide (1, 0.2 mmol, 1.0 equiv). The
tube was evacuated and backfilled with nitrogen (three times). TBPB
(0.4 mmol, 2.0 equiv) and the benzylic hydrocarbon (1 mL) were added
by syringe. The tube was then sealed and the mixture was stirred for 28 h
at 1208C. Upon completion of the reaction, the mixture was diluted with
EtOAc. The solvent was then removed under vacuum. The residue was
purified with column chromatography on silica gel (eluent gradient of
EtOAc/petroleum ether, 1:25 to 1:5) to give the corresponding products 3
or 4 in the yields listed in Tables 2 and 3.
Acknowledgements
Financial support from the National Natural Science Foundation of
China (Nos. 21102110 and 21102111), the Doctoral Fund of the Ministry
of Education of China (No. 20110201120076), and the Fundamental Re-
search Funds of the Central Universities is greatly appreciated.
Keywords: activated alkenes · benzylarylation · copper ·
oxindoles · radical addition
Based on these observations, a mechanism can tentatively
be proposed (Scheme 2). Benzyl radical I is formed through
homolytic cleavage of toluene in the presence of TBPB.[7]
Radical I then adds to the double bond of acrylamide (1a)
[1] For reviews, see: a) C. Marti, E. M. Carreira, Eur. J. Org. Chem.
2003, 2209; b) H. Lin, S. J. Danishefsky, Angew. Chem. 2003, 115, 38;
Angew. Chem. Int. Ed. 2003, 42, 36; c) C. V. Galliford, K. A. Scheidt,
Angew. Chem. 2007, 119, 8902; Angew. Chem. Int. Ed. 2007, 46, 8748.
[2] For recent reviews, see: a) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012,
112, 6104; b) K. Shen, X. Liu, L. Lin, X. Feng, Chem. Sci. 2012, 3,
327; c) R. Dalpozzo, G. Bartoli, G. Bencivenni, Chem. Soc. Rev. 2012,
41, 7247; d) N. R. Ball-Jones, J. J. Badillo, A. K. Franz, Org. Biomol.
Chem. 2012, 10, 5165; e) L. Hong, R. Wang, Adv. Synth. Catal. 2013,
355, 1023.
[3] For recent reviews, see: a) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth.
Catal. 2010, 352, 1381; b) J. E. M. N. Klein, R. J. K. Taylor, Eur. J.
Org. Chem. 2011, 6821; for selected examples, see: c) E. J. Hennessy,
S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 12084; d) A. Pinto, Y.
Jia, L. Neuville, J. Zhu, Chem. Eur. J. 2007, 13, 961; e) Y.-X. Jia, E. P.
Kꢀndig, Angew. Chem. 2009, 121, 1664; Angew. Chem. Int. Ed. 2009,
48, 1636; f) A. Perry, R. J. K. Taylor, Chem. Commun. 2009, 3249;
g) S. Ueda, T. Okada, H. Nagasawa, Chem. Commun. 2010, 46, 2462;
h) H.-L. Wei, T. Piou, J. Dufour, L. Neuville, J. Zhu, Org. Lett. 2011,
13, 2244; i) P. Tolstoy, S. X. Y. Lee, C. Sparr, S. V. Ley, Org. Lett.
2012, 14, 4810; j) A. Beyer, J. Buendia, C. Bolm, Org. Lett. 2012, 14,
3948; k) D. C. Fabry, M. Stodulski, S. Hoerner, T. Gulder, Chem. Eur.
J. 2012, 18, 10834; l) T. Piou, L. Neuville, J. Zhu, Angew. Chem. 2012,
124, 11729; Angew. Chem. Int. Ed. 2012, 51, 11561.
[4] a) S. Jaegli, J. Dufour, H.-L. Wei, T. Piou, X.-H. Duan, J.-P. Vors, L.
Neuville, J. Zhu, Org. Lett. 2010, 12, 4498; b) T. Wu, X. Mu, G. Liu,
Angew. Chem. 2011, 123, 12786; Angew. Chem. Int. Ed. 2011, 50,
12578; c) X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo, G. Liu, J. Am.
Chem. Soc. 2012, 134, 878.
[5] a) W.-T. Wei, M.-B. Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M.
Hu, P. Xie, J.-H. Li, Angew. Chem. 2013, 125, 3726; Angew. Chem.
Int. Ed. 2013, 52, 3638; b) Y.-M. Li, M. Sun, H.-L. Wang, Q.-P. Tian,
S.-D. Yang, Angew. Chem. 2013, 125, 4064; Angew. Chem. Int. Ed.
2013, 52, 3972.
Scheme 2. Proposed mechanism for the benzylarylation of alkenes.
to generate the corresponding alkyl radical II.[5,8] Radical II
then undergoes intramolecular attack to give intermediate
III. Abstraction of hydrogen from III by copper(II) affords
oxindole 3a.
In summary, an efficient copper-catalyzed benzylarylation
of activated alkenes to form alkyl-substituted oxindoles has
been developed. This tandem radical addition/cyclization of
acrylamides and benzyl hydrocarbons features operational
simplicity and tolerance of a broad range of functional
groups. This process provides an ideal and straightforward
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

L.-N. Guo, X.-H. Duan et al.
[6] a) Radicals in Organic Synthesis (Eds.: P. Renaud, M. P. Sibi), Wiley-
VCH, Weinheim, 2001; b) Topics in Current Chemistry, Vol. 263, Rad-
icals in Synthesis I: Methods and Mechanisms (Ed.: A. Gansꢃuer),
Springer, Berlin, 2006; c) Topics in Current Chemistry, Vol. 264, Radi-
cals in Synthesis II: Complex Molecules (Ed.: A. Gansꢃuer), Springer,
Berlin, 2006.
[7] a) Z. Li, L. Cao, C.-J. Li, Angew. Chem. 2007, 119, 6625; Angew.
Chem. Int. Ed. 2007, 46, 6505; b) N. Borduas, D. A. Powell, J. Org.
Chem. 2008, 73, 7822; c) C.-X. Song, G.-X. Cai, T. R. Farrell, Z.-P.
Jiang, H. Li, L.-B. Gan, Z.-J. Shi, Chem. Commun. 2009, 6002; d) Q.
Xia, W. Chen, H. Qiu, J. Org. Chem. 2011, 76, 7577; e) H. J. Kim, J.
Kim, S. H. Cho, S. Chang, J. Am. Chem. Soc. 2011, 133, 16382; f) H.
Yang, P. Sun, Y. Zhu, H. Yan, L. Lu, X. Qu, T. Li, J. Mao, Chem.
Commun. 2012, 48, 7847; g) J. Feng, S. Liang, S.-Y. Chen, J. Zhang,
S.-S. Fu, X.-Q. Yu, Adv. Synth. Catal. 2012, 354, 1287; h) Q. Xue, J.
Xie, H. Li, Y. Cheng, C. Zhu, Chem. Commun. 2013, 49, 3700.
[8] For the metal-free difunctionalization of alkenes leading to oxindoles
through a radical process, see: a) T. Wu, H. Zhang, G. Liu, Tetrahe-
dron 2012, 68, 5229; b) M.-B. Zhou, R.-J. Song, X.-H. Ouyang, Y.
Liu, W.-T. Wei, G.-B. Deng, J.-H. Li, Chem. Sci. 2013, 4, 2690.
[9] a) J. A. Tunge, L. N. Foresee, Organometallics 2005, 24, 6440; b) R.
Taylor, Electrophilic Aromatic Substitution, Wiley, New York, 1990,
pp. 25–27.
Received: June 5, 2013
Published online: && &&, 0000
&
4
&
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Oxidative Benzylarylation of Acrylamides
COMMUNICATION
Radical Reactions
S.-L. Zhou, L.-N. Guo,* H. Wang,
X.-H. Duan* .................. &&&& — &&&&
Copper-Catalyzed Oxidative Benzylar-
ylation of Acrylamides by Benzylic
Radically changing benzyls: An effi-
cient method for the benzylarylation
of activated alkenes has been devel-
oped through a copper-catalyzed
tandem radical addition/cyclization
strategy (see scheme). This oxidative
coupling between acrylamides and
benzylic hydrocarbons provides access
to diverse alkyl-substituted oxindoles
in good to excellent yields. A variety
of functional groups were tolerated in
this transformation (TBPB=tert-butyl-
peroxy benzoate).
À
C H Bond Functionalization for the
Synthesis of Oxindoles
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!