Radical cascade cyanomethylation of activated alkenes to construct cyano substituted oxindoles

Article abstract of DOI:10.1039/c4cc07667b

The cyanomethyl radical was easily generated from acetonitrile by using DTBP, which was applied to a cascade alkene addition and cyclization reaction to construct useful oxindole derivatives. This protocol features simple manipulation, cheap reagents and a broad substrate scope. In addition, nitro substituted oxindoles were also synthesized for the first time. This journal is

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ARTICLE TYPE
Radical Cascade Cyanomethylation of Activated Alkenes to Construct
Cyano Substituted Oxindoles
Juan Li, Zhigang Wang, Ningjie Wu, Ge Gao* and Jingsong You*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Table 1 Optimization of the reaction conditions.a
Cyanomethyl radical was easily generated from acetonitrile
by using DTBP, which was applied to a cascade alkene
addition and cyclization reaction to construct useful oxindole
derivatives. This protocol features simple manipulation,
10 cheap reagent and a broad substrate scope. In addition, nitro
substituted oxindoles were also synthesized for the first time.
40
Entry
1c
Oxidant
DTBP
TBHP
PIDA
H2O2
Additive
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
-
CuCl
CuCl
Cu(OAc)2
ZnCl2
IrCl3
Yield (%)b
32
Cyanomethylation is a synthetically useful reaction because
cyano group can easily convert to amino, carboxyl, alkyl,
aldehyde and ester groups.1 An attractive approach is to use
15 acetonitrile directly through C–H activation due to the highly
efficient atom economy and the avoidance of prefunctionalization.
Early efforts on the C–H activation of acetonitrile by using
stoichiometric amounts of transition metals such as Fe, Rh, Ru, Ir,
Ni, and Au have been well documented.2 A recent advance is the
20 catalytic C–H activation, which is still rare.3 An elegant example
is the oxidative dicarbonation of N-aryl acrylamides 1 to
construct cyano substituted oxindole derivatives 3 through a
cascade Pd-catalyzed C(sp2)–H and C(sp3)–H activation reported
by Liu group (Eq. 1).4 However, the drawbacks are also apparent:
25 the use of precious Pd catalyst with nitrogen-containing ligand as
well as the requirement of an oxidant PhI(OPiv)2 (1.1 equiv) and
a key additive AgF (4 equiv). A more concise synthesis is highly
desirable.
2c
N. R.
Trace
N. R.
N. R.
N. R.
50
80
82
80
34
45
76
78
30
80
77
76
3c
4c
5c
K2S2O8
DDQ
6c
7d
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
8e
9
10f
11
12g
13h
14
15
16
17
18i
FeCl3
CuCl
a
Reaction conditions: 1a (0.25 mmol), oxidant (3.0 equiv), additive (10
mol%) and MeCN (2.0 mL) at 120 oC under nitrogen atmosphere for 24 h.
b Isolated yield. c Oxidant (2.0 equiv), MeCN (1.0 mL). d MeCN (1.0 mL).
e
f
g
o
h
o
i
MeCN (1.5 mL). MeCN (2.5 mL). At 100 C. At 130 C. CuCl (5
45 mol%). N. R. = no reaction.
Due to our continuous interests in C(sp3)–H activation for
coupling reactions,7 we initialize a reaction involving N-methyl-
N-phenylmethacrylamide 1a (0.25 mmol) as the starting material
in the presence of 2 equiv. of DTBP (Table 1). The blank reaction
50 in 1 mL MeCN at 120 ˚C for 24 hours afforded compound 3a in
32% yield (entry 1), which was fully characterized by HRMS, 1H
and 13C NMRs. Other oxidant such as TBHP, H2O2, K2S2O8,
DDQ and PhI(OAc)2 resulted in either no reaction or only trace
amount of 3a (entries 2-6). Increasing the amount of DTBP
55 promoted the yield to 50% (entry 7). Varying the amount of
MeCN showed that the best yield of 82% was obtained in 2 mL
MeCN (entries 8-10). Without CuCl, 3a was also obtained in 32%
yield (entries 11). These results indicated a possible radical
process and a Lewis acid role of CuCl.6f,8 The dramatic
30 Oxindoles are ubiquitous heterocyclic scaffolds existing in a
wide variety of natural products, pharmaceuticals, and bioactive
molecules.5 Over the past few years, substantial substituted
oxindoles have been synthesized via radical cascade reactions of
alkenes with simple reagents such as azide, ether, aldehyde,
35 cycloalkane, dichloromethane and alcohol, etc.6 Herein, we
would like to present
a practical and efficient radical
cyanomethylation of alkenes to construct cyano substituted
oxindoles by simply using DTBP as the radical initiator.
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suppression of this reaction by the addition of a stoichiometric
amount of radical inhibitors, such as TEMPO and BHT (2,6-di-
tert-butylphenol), confirmed the radical pathway (See SI).
The preliminary results were rather surprising and particular
and electron-donating groups on the phenyl ring afforded the
desired products in moderate to excellent yields (3e-3p). A range
of functional groups, such as methyl, methoxyl, ester, cyano and
halide groups were all tolerated, which provided opportunities for
5
interesting because MeCN is commonly considered as a stable 45 further modification. No steric effect on the phenyl ring was
solvent and widely used in a range of radical reactions.9 Actually,
the C–H bond homolysis of MeCN to generate cyanomethyl
radical is not so easy and seldom presented in the literature.10 For
example, Marks and Lewis et al reported a photocatalyzed
observed in this reaction because the ortho-substituted substrates
gave comparable yields (3e-i). When m-methyl substituted N-
arylacrylamide was employed, two regioisomers 3j and 3j’ were
obtained in a 1:4 ratio.
10 cyanomethylation reaction in 1981. A unique light-absorbing
ground state complex of Ag(I)-norborene cleaved into norborene
cation radical, which then abstracted a hydrogen atom from
MeCN to generate cyanomethyl radical.10a In 2013, The Yoshida
group found that a Pd/TiO2 hybridised catalyst could generate
15 cyanomethyl radical from MeCN under light (405 nm) irradiation,
but the quantum yield was as low as only 0.22%.10c These
processes are far less practical in regard to very limited substrate
scope, expensive transition metal catalysts involved or low yields.
Therefore, we decided to further optimize our reaction conditions.
50 Table 3 Radical cyanomethylation of activated alkenes with nitriles.a,b
20
Lowering the reaction temperature significantly decreased the
yield while elevating the temperature slightly decreased the yield
(entries 12-13). Other metal salts such as Cu(OAc)2, ZnCl2 and
FeCl3 were less effective except that IrCl3 gave a similar yield
(entries 14-17). Cutting the amount of CuCl in half slightly
a Reaction conditions: 1 (0.25 mmol), CuCl (10 mol%), DTBP (3.0 equiv)
25 lowered the yield (entry 18). Finally, the optimal conditions were
set to be in the presence of CuCl (10 mol%) and DTBP (3.0 equiv)
in CH3CN (2.0 mL) at 120 oC for 24 h, and the desired product 3a
was obtained in 82% yield (entry 9).
b
and nitriles (2.0 mL) at 120 oC under nitrogen atmosphere for 24 h.
Isolated yield. c Malononitrile (20 equiv).
55
Next, various substituted alkenes and nitriles were tested and
the results are included in Table 3. For alkenes 1, the mono-
substituted alkene (R3 = H) was ineffective in this reaction and
Table
2
Radical cyanomethylation of activated alkenes with
30 acetonitrile.a,b
gave no product 4a. The gem-disubstituted substrates (R3
phenyl and acetoxymethyl) furnished the corresponding products
=
60 in 48% and 54% yields, respectively (4b and 4c). For nitriles,
propionitrile and phenylacetonitrile performed better than
acetonitrile and afforded oxindoles 4d and 4e in excellent yields.
Finally, malononitrile could also undergo this reaction to provide
dicyanomethyl oxindole 4f in 72% yield.
a
65
Reaction conditions: 1a (0.25 mmol), CuCl (10 mol%), DTBP (3.0
equiv) in CH3CN (2.0 mL) at 120 oC under nitrogen atmosphere for 24 h.
b Isolated yield. c CH3CN (3.0 mL).
To further evaluate the utility of this chemistry and expand
substrate scope, a few representative enamides were tested. To
our delight, Aza-2-oxindole derivative 3q was obtained in 56%
yield when N-pyridinylacrylamides was used (Eq. 3). With regard
70 to substrate 1r, an interesting six-membered-ring product 3r was
generated (Eq. 4). Notably, this approach was also suitable for
tetrahydroisoquinoline derivative and provided the corresponding
tricyclic product 3s in 73% yield (Eq. 5).
35
With the optimal conditions in hand, the scope of N-
arylacrylamides was investigated (Table 2). While the N-methyl
and N-benzyl N-phenylacrylamides gave the corresponding
oxindoles in good yields (3a-b), the N-H and N-acetyl N-
phenylacrylamides gave only trace amount of the targeted
40 products (3c-d). The substrates with both electron-withdrawing
2
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6948; (c) T. Jinzaki, M. Arakawa, H. Kinoshita, J. Ichikawa and K.
Miura, Org. Lett., 2013, 15, 3750; (d) H. Yi, X. Zhang, C. Qin, Z.
Liao, J. Liu and A. Lei, Adv. Synth. Catal., 2014, 356, 2873.
Based on the above observations and previous mechanistic
studies,6 A plausible mechanism was proposed in Scheme 1. The
homolysis of DTBP by heating initiate the t-butoxyl radical A,
methyl radical B and acetone.11 A or B then abstracted an α-
hydrogen of MeCN to generate the cyanomethyl radical C. The
selective addition of C to C=C double bond of N-arylacrylamide
1a delivered intermediate D, which intramolecularly cyclized to
form E. The hydrogen abstraction on the aryl ring by A or B gave
oxindole 3a as the desired product. CuCl might act as a Lewis
45
50
55
60
65
70
75
80
2
(a) S. D. Ittel, C. A. Tolman, A. D. English and J. P. Jesson, J. Am.
Chem. Soc., 1978, 100, 7577; (b) A. J. Vetter, R. D. Rieth and W. D.
Jones, Proc. Natl. Acad. Sci. USA, 2007, 104, 6957; (c) N. A. Foley, T.
B. Gunnoe, T. R. Cundari, P. D. Boyle and J. L. Petersen, Angew.
Chem. Int. Ed., 2008, 47, 726; (d) M. G. Crestani, A. Steffen, A. M.
Kenwright, A. S. Batsanov, J. A. K. Howard and T. B. Marder,
Organometallics, 2009, 28, 2904; (e) A. M. Oertel, V. Ritleng, M. J.
Chetcuti and L. F. Veiros, J. Am. Chem. Soc., 2010, 132, 13588; (f)
X.-L. Pei, Y. Yang, Z. Lei and Q.-M. Wang, J. Am. Chem. Soc., 2013,
135, 6435.
(a) D. A. Culkin and J. F. Hartwig, J. Am. Chem. Soc., 2002, 124,
9330; (b) J. You and J. G. Verkade, Angew. Chem. Int. Ed., 2003, 42,
5051; (c) N. Kumagai, S. Matsunaga and M. Shibasaki, J. Am. Chem.
Soc., 2004, 126, 13632; (d) S. Chakraborty, Y. J. Patel, J. A. Krause
and H. Guan, Angew. Chem. Int. Ed., 2013, 52, 7523; (e) J. Shen, D.
Yang, Y. Liu, S. Qin, J. Zhang, J. Sun, C. Liu, C. Liu, X. Zhao, C.
Chu and R. Liu, Org. Lett., 2014, 16, 350.
T. Wu, X. Mu and G. Liu, Angew. Chem. Int. Ed., 2011, 50, 12578.
For reviews, see: (a) B. S. Jensen, CNS Drug Rev., 2002, 8, 353; (b)
C. V. Galliford and K. A. Scheidt, Angew. Chem. Int. Ed., 2007, 46,
8748. (c) G. S. Singh and Z. Y. Desta, Chem. Rev., 2012, 112, 6104.
For selected recent radical cascade synthesis of oxindoles, see: (a)
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; (b) Y.-M.
Li, M. Sun, H.-L. Wang, Q.-P. Tian and S.-D. Yang, Angew. Chem.
Int. Ed., 2013, 52, 3972; (c) K. Matcha, R. Narayan and A. P.
Antonchick, Angew. Chem. Int. Ed., 2013, 52, 7985; (d) 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; (e) Y. Meng, L.-N. Guo, H. Wang and X.-
H. Duan, Chem. Commun., 2013, 49, 7540; (f) M.-B. Zhou, C.-Y.
Wang, R.-J. Song, Y. Liu, W.-T. Wei and J.-H. Li, Chem. Commun.,
2013, 49, 10817; (g) J.-H. Fan, W.-T. Wei, M.-B. Zhou, R.-J. Song
and J.-H. Li, Angew. Chem. Int. Ed., 2014, 53, 6650; (h) Z. Li, Y.
Zhang, L. Zhang and Z.-Q. Liu, Org. Lett., 2014, 16, 382; (i) M.-Z.
Lu and T.-P. Loh, Org. Lett., 2014, 16, 4698; (j) T. Shen, Y. Yuan, S.
Song and N. Jiao, Chem. Commun., 2014, 50, 4115.
5
10 acid to stabilize the radical intermediates.6f,8
3
4
5
6
Scheme 1 Proposed mechanism.
It needs to mention that, following the same radical mechanism,
the nitromethylation could also occur under the same reaction
15 conditions to furnish nitromethyl oxindoles, which have
previously not been reported yet. The selective examples are
listed in Scheme 2.
7
(a) K. Li, G. Tan, J. Huang, F. Song and J. You, Angew. Chem. Int.
Ed., 2013, 52, 12942; (b) M. Li, J. Dong, X. Huang, K. Li, Q. Wu, F.
Song and J. You, Chem. Commun., 2014, 50, 3944.
Scheme 2 Nitro substituted oxindoles obtained via radical cascade
20 reaction.
85 8 (a) P. Renaud and M. Gerster, Angew. Chem. Int. Ed., 1998, 37, 2562;
(b) Z. Huang, L. Jin, Y. Feng, P. Peng, H. Yi and A. Lei, Angew.
Chem. Int. Ed., 2013, 52, 7151.
In summary, we have shown
cyanomethylation as well as nitromethylation of N-
phenylacrylamides through radical pathway to construct
substituted oxindoles. The simplicity and the broad substrate
25 scope made this method much more practical than the transition
metal catalyzed reaction. To the best of our knowledge, the C–H
bond activation of MeCN demonstrated in this manuscript is the
most simple and efficient process so far. Exploitation of other
reactions is currently underway in our laboratory.
a concise and practical
9
(a) J. M. Lee, E. J. Park, S. H. Cho and S. Chang, J. Am. Chem. Soc.,
2008, 130, 7824; (b) Z. Shu, Y. Ye, Y. Deng, Y. Zhang and J. Wang,
Angew. Chem. Int. Ed., 2013, 52, 10573; (c) Y.-M. Li, X.-H. Wei, X.-
A. Li and S.-D. Yang, Chem. Commun., 2013, 49, 11701; (d) W.
Kong, E. Merino and C. Nevado, Angew. Chem. Int. Ed., 2014, 53,
5078.
90
a
10 (a) J. W. Bruno, T. J. Marks and F. D. Lewis, J. Am. Chem. Soc., 1981,
103, 3608; (b) T. Yamashita, J. Org. Chem., 1996, 61, 6438; (c) H.
Yoshida, Y. Fujimura, H. Yuzawa, J. Kumagai and T. Yoshida, Chem.
Commun., 2013, 49, 3793.
11 Q. Dai, J. Yu, Y, Jiang, S. Guo, H. Yang and J. Cheng, Chem.
Commun., 2014, 50, 3865.
95
30
We thank the financial support from the National NSF of China
(21025205, 21321061 and 21472127).
Notes and references
a
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, and State Key Laboratory of Biotherapy,
35 West China Medical School, Sichuan University, 29 Wangjiang Road,
Chengdu 610064, PR China. Fax: (+86) 28-85412203; E-mail:
gg2b@scu.edu.cn; jsyou@scu.edu.cn
† Electronic Supplementary Information (ESI) available: [Experimental
procedures, characterization data, and copies of NMR spectra]. See
40 DOI: 10.1039/b000000x/
1
(a) M. Makosza, Chem. Soc. Rev., 2010, 39, 2855; (b) J. Velcicky, A.
Soicke, R. Steiner and H.-G. Schmalz, J. Am. Chem. Soc., 2011, 133,
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