Metal-free arylalkylation of N -aryl acrylamides with azobisalkylnitriles

Article abstract of DOI:10.1055/s-0034-1379888

A novel metal-free arylalkylation of N-aryl acrylamides with readily available azobisalkylnitriles leading to cyano-containing oxindoles has been developed. The use of readily available azobisalkylnitriles and DTBP as oxidant makes this protocol environmentally benign and practical.

Full text of DOI:10.1055/s-0034-1379888

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 681–687
letter
681
Q. Tian et al.
Letter
Synlett
Metal-Free Arylalkylation of N-Aryl Acrylamides with Azobisalkyl-
nitriles
Qingshan Tiana
Ping Hea
Chunxiang Kuang*a,b
CN
R4
R3
R3
CN
ligand-free
metal-free
R1
R4
N
+
R1
N
R4
O
a Department of Chemistry, Tongji University, Siping Road 1239,
Shanghai 200092, P. R. of China
kuangcx@tongji.edu.cn
b Key Laboratory of Yangtze River Water Environment, Ministry of
Education, Siping Road 1239, Shanghai 200092, P. R. of China
N
R2
O
N
CN
R2
Received: 28.10.2014
Accepted after revision: 14.12.2014
Published online: 29.01.2015
Oxindoles derivatives are very important compounds in
organic synthesis because they are frequently found in the
core structure of natural alkaloids and bioactive com-
pounds.9 As a result, considerable efforts have been direct-
ed to the development of efficient methods for their syn-
thesis. Recently, transition-metal-catalyzed (such as Fe,10
Cu,11 Ag,12 and Pd13) difunctionalization of activated alkenes
provides some versatile strategies for the synthesis of vari-
ous functional oxindoles. For example, the Jiao group re-
ported iron-catalyzed aerobic difunctionalization of
alkenes to construct sulfone-containing oxindoles under
mild reaction conditions.9b In 2011, the Liu group estab-
lished a useful access to cyano-containing oxindoles by pal-
ladium-catalyzed oxidative difunctionalization of alkenes
using acetonitrile as nitrile source (Scheme 1, a).14 More re-
cently, metal-free difunctionalization of alkenes has at-
tracted more attention due to the economic and environ-
mental viewpoint.15 To the best of our knowledge, the reac-
tion of azobisalkylnitriles with activated alkenes in the
synthesis of cyano-containing oxindoles has not been re-
ported. Herein, we report a novel metal-free arylalkylation
of activated alkenes with azobisalkylnitriles leading to cya-
no-containing oxindoles through a radical process (Scheme
1, b).
In an initial study, N-methyl-N-phenylmethacrylamide
(1a) and AIBN were chosen as the model substrates, and
various oxidants were tested in different solvents at differ-
ent temperatures. To out delight, this reaction occurred in
the presence of K2S2O8 as oxidant in DCE at 80 °C under ar-
gon atmosphere for 16 hours, the desired product 2a was
isolated in 30% yield (Table 1, entry 1). Inspired by this re-
sult, the effect of various oxidants on this transformation,
such as BQ, AgNO3, PhI(OAc)2, TBHP, and DTBP (Table 1, en-
tries 2–6) were further investigated; DTBP was found to be
the most efficient for this reaction (Table 1, entry 6). In ad-
dition, decreasing the temperature resulted in a decrease in
DOI: 10.1055/s-0034-1379888; Art ID: st-2014-w0893-l
Abstract A novel metal-free arylalkylation of N-aryl acrylamides with
readily available azobisalkylnitriles leading to cyano-containing oxin-
doles has been developed. The use of readily available azobisalkylni-
triles and DTBP as oxidant makes this protocol environmentally benign
and practical.
Key words metal-free, aryalkylation, acrylamide, AIBN, oxindole
Nitriles are widely used as important building blocks in
the pharmaceutical, fine chemical, dye, and agrochemical
industries.1 They also serve as synthetic scaffolds to a di-
verse array of building blocks such as aldehydes, ketones,
amides, carboxylic acids, amines, and heterocycles.2 Re-
cently, the nitrile group has been used as directing group in
transition-metal-catalyzed C–H bond functionalization re-
actions.3 Traditionally, nucleophilic substitution reaction,
the Sandmeyer reaction, and the Rosenmund–von Braun
reactions have been utilized to synthesize nitriles on a pre-
parative scale.4 Transition-metal-catalyzed cyanation of
aryl halides or their derivatives is considered an important
method for the synthesis of various aryl nitriles.5 Recently,
the use of nonmetallic cyano-group sources as alternatives
for the synthesis of various nitriles has been scrutinized.6 In
the past decades, azobisalkylnitriles (such as AIBN) was the
most widely used as radical initiator in radical reaction and
in polymerization of various alkenes.7 Consequently, re-
ports employing azobisalkylnitriles in C–C bond-forming
reactions to construct cyano-containing compounds were
rare.8 Therefore, it is vital to investigate the direct utiliza-
tion of such simple and readily available azobisalkylnitriles
in C–C bond-forming reactions and the synthesis of valuble
cyano-containing compounds.
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Letter
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a) palladium-catalyzed oxidative arylalkylation of acrylamides (Liu's work)
CN
Pd(OAc)2, ligand
PhI(OPiv)2, AgF
+
H
CN
O
MgSO4, MeCN, 80 °C
N
O
N
b) metal-free oxidative arylalkylation of acrylamides (this work)
R3
NC
R4
R3
ligand-free
metal-free
CN
R1
R4
N
+
R4
O
R1
N
N
O
N
R2
CN
R2
Scheme 1 Difunctionalization of activated alkenes
yield (Table 1, entry 7). Nevertheless, the desired product 2a
was obtained in 69% yield when the reaction was conducted
at 100 °C (Table 1, entry 8). Subsequently, the effect of the
solvent was investigated (MeCN, EtOAc, and DMSO), and the
result showed that DCE was beneficial for this reaction (Ta-
ble 1, entries 9–11).
With the optimized reaction conditions in hand, we
turned our attention to the substrate scope (Scheme 2).16
An investigation into different N-protection of arylacryl-
amides showed that electron-donating groups such as
methyl, ethyl, n-butyl, and benzyl are suitable for the reac-
tion, providing the corresponding oxindoles in good yields
(2a,b,e,f). However, replacement of the methyl substituent
with a hydrogen atom or an electron-withdrawing group
(acetyl group) failed to produce the corresponding products
(2c,d). Hydrogen atom and electron-withdrawing groups
(Ac) might make the reaction intermediate unstable in the
proposed mechanism. A variety of arylacrylamides with
substituents at para, meta, and ortho positions could be
smoothly converted into their corresponding oxindoles in
moderate to good yields. With electron-donating groups in
the para position of the aryl ring in the arylacrylamides, the
reaction worked well and the majority of products were ob-
tained with high yields (2g–j). It was found that substrate
with electron-withdrawing group such as CF3 on the aryl
ring was less reactive, and the corresponding product was
obtained in 39% yield (2k).
Table 1 Optimization of Reaction Conditionsa
NC
AIBN, oxidant
O
solvent, Ar, 80 °C, 16 h
N
O
N
Me
Me
1a
2a
Entry
Oxidant
Solvent
Yield (%)b
1
2
K2S2O8
BQe
DCE
30
19
42
55
41
78
40
63
70
65
58
DCE
Notably, halides on the para position or the ortho posi-
tion of the aryl ring in arylacrylamides were tolerated and
furnished the corresponding products with good yields (2l–
p), thereby facilitating additional modification at the halo-
genated position. In addition, the tetrahydroquinoline de-
rivative furnished the tricyclic oxindole in 65% yield (2q),
and the tetrahydroquinoline structural motifs are com-
monly found in many biologically active compounds. With
the use of substrates with substituents at the meta position
of the aryl ring in arylacrylamide, a mixture of two regiose-
lective products were obtained in good yields but with poor
regioselectivity (2r,r′). Subsequently, various substituted
alkenes were also evaluated. When the substituent on the
alkene moiety was changed from methyl to benzyl, the re-
action still provided the desired product in 60% yield (2s).
However, no reaction was observed in the case of a mono-
substituented alkene (2t), and the starting material was
consumed completely.
3
AgNO3
PhI(OAc)2
TBHPf
DTBPg
DTBPg
DTBPg
DTBPg
DTBPg
DTBPg
DCE
4
DCE
5
DCE
6
DCE
7c
8d
9
DCE
DCE
MeCN
EtOAc
DMSO
10
11
a Reaction conditions: 1a (0.2 mmol), AIBN (0.2mmol), oxidant (0.3 mmol)
in solvent (2.0 mL), stirred at 80 °C under Ar for 16 h.
b Isolated yields.
c Reaction temp: 60 °C.
d Reaction temp: 100 °C.
e BQ = p-benzoquinone.
f TBHP = tert-butyl hydrogen peroxide (70% in H2O).
g DTBP = di-tert-butyl peroxide.
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NC
R3
a) palladium-catalyzed oxidative arylalkylation of acrylamides (Liu's work)
R3
R1
AIBN(1.0 equiv), DTBP (1.5 equiv)
R1
O
N
R2
O
N
R2
DCE, Ar, 80 °C, 16 h
1
2
NC
NC
NC
NC
O
O
O
O
N
N
N
H
N
Ac
Bn
Me
2a (78%)
2b (67%)
2c (0%)
NC
2d (0%)
NC
NC
NC
t-Bu
O
O
O
O
N
Et
N
N
N
Bu
Me
2g (75%)
NC
Me
2e (71%)
2f (69%)
2h (80%)
NC
NC
NC
MeO
EtO
F3C
F
O
O
O
O
N
N
N
N
Me
Me
Me
Me
2i (69%)
2j (70%)
2k (39%)
2l (64%)
CN
CN
CN
O
CN
O
Cl
Br
I
O
O
N
N
N
N
Me
Me
Me
Me
Br
2m (77%)
2o (61%)
2p (54%)
2n (68%)
CN
NC
NC
NC
Cl
Bn
+
O
O
O
O
N
N
N
N
Cl
Me
Me
Me
2q (65%)
2s (60%)
2r+2r' 75% (2.1:1)
NC
H
O
N
Me
2t (0%)
Scheme 2 Metal-free arylalkylation of 1 with AIBN.a aReaction conditions: 1 (0.2 mmol), AIBN (0.2 mmol), DTBP (0.3 mmol) DCE (2.0 mL), stirred at
80 °C under Ar for 16 h. Isolated yields.
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Moreover, a series of azobisalkylnitriles were also test-
ed.16 As shown in Table 2, we note that 2,2′-azobis-(2-meth-
ylbutyronitrile) was suitable for this reaction, and the de-
sired product was obtained in moderate and low yields (3a–
d). Bulky group on alkene (such as Bn group) could not give
good diasteroselectivity (Table 2, entry 5). Other readily ac-
cessible azobisalkylnitriles [2,2′-azobis(2,4-dimethylvalero-
nitrile) and 1,1′-azobis(cyanocyclohexane)] were not effi-
cient in this reaction (Table 2, entries 6 and 7).
Table 2 Various Azobisalkylnitriles in Reaction with Arylacrylamidea
NC
R3
NC
DTBP (1.5 equiv)
R1
R3
N
+
R1
R3
O
N
N
R2
O
DCE, Ar
80 °C, 16 h
N
CN
R2
1
3
Entry
1
Azo reactant
Product 3
Yield (%)b of 3
CN
Et
NC
N
Et
N
1
62% (1.2:1)
Et
N
O
O
CN
N
Me
Me
3a
CN
Et
NC
N
Et
N
2
56% (1:1)
Et
N
O
O
CN
N
Me
Me
3b
CN
Et
NC
N
Et
N
O
3
39% (1.2:1)
N
O
Et
N
CN
3c
CN
Et
NC
N
Et
N
4
44% (1:1.1)
Et
N
O
O
CN
N
Bu
Bu
3d
CN
Et
NC
N
Et
N
5
1a
54% (1.3:1)
Et
O
CN
N
Bu
3e
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 681–687

685
Q. Tian et al.
Letter
Yield (%)b of 3
trace
Synlett
Table 2 (continued)
Entry
1
Azo reactant
Product 3
CN
NC
6
1a
N
O
N
N
CN
Me
3f
CN
O
CN
N
7
1a
trace
N
CN
N
Me
3g
a Reaction conditions: 1 (0.2 mmol), azo reactant (0.2 mmol), DTBP (0.3 mmol) in DCE (2.0 mL), stirred at 80 °C under Ar for 16 h.
b Isolated yields are given; the ratio in parentheses is the diasteroselectivity of the reaction as determined by 1H NMR spectroscopy.
To understand the mechanism of this transformation, a
series of control experiments were conducted (Scheme 3).
First, the kinetic isotope experiment was performed, and
no kinetic isotope effect (kH/kD = 1.0) was observed, sug-
gesting that this transformation reaction might involve a
free-radical process. Notably, the free-radical mechanism
was supported by some control experiments in the pres-
ence of radical scavenger: a stoichiometric amount of radi-
cal scavenger (2.5 equiv), such as TEMPO, was added to the
reaction of N-methyl-N-phenylmethacrylamide (1a) with
AIBN, and no desired product was obtained (2a).
NC
NC
D
N
O
D
D
standard reaction
conditions
+
Me
CN
O
N
O
D
D
+
N
N
D
N
NC
D
D
Me
2a–d4
Me
D
2a
N
O
75% yield, kH/kD = 1.0
Me
1a/1a–d5 = 1:1
NC
standard reaction
conditions
CN
N
+
N
O
N
O
NC
TEMPO
Me
N
Me
2a (trace)
1a
Scheme 3 KIE studies and possible mechanism consideration
Although the mechanism is not completely clear yet, a
plausible mechanism is proposed on the basis of our exper-
imental results and previous reports (Scheme 4).10b Initially,
AIBN is readily split into two isobytyronitrile radicals under
heating conditions. Subsequently, the isobutyronitrile radi-
cal adds to the carbon–carbon double bond of 1a affording
radical intermediate A. Intramolecular carbocyclization of
radical intermediate A with an aryl ring gives rise to radical
intermediate B, followed by the oxidation of B into the cor-
responding carbocation C. Finally, abstraction of an aryl hy-
drogen in intermediate C takes place to produce the oxin-
dole (2a).
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In conclusion, we have developed a novel metal-free ox-
idative arylalkylation of N-methyl-N-arylacrylamides with
azobisalkylnitriles for the construction of Csp2–Csp3 and
Csp3–Csp3 bonds. This protocol provides an efficient ap-
proach to synthesize cyano-containing oxindoles with a
quaternary carbon center. The use of readily available azo-
bisalkylnitriles and DTBP as oxidant makes this protocol
environmentally benign and pratical.
(3) (a) Leow, D.; Li, G.; Mei, M.-T.; Yu, J.-Q. Nature (London, U.K.)
2012, 486, 518. (b) Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.;
Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 7567. (c) Yang, Y.-F.; Cheng,
G.-J.; Liu, P.; Leow, D.; Sun, T.-Y.; Chen, P.; Zhang, X.; Yu, J.-Q.;
Wu, Y.-D.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 344.
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J. Am. Chem. Soc. 1955, 77, 6269. (b) Lindley, J. Tetrahedron
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2011, 40, 5049.
(6) (a) Kim, J.; Kim, H. J.; Chang, S. Angew. Chem. Int. Ed. 2012, 51,
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6725. (d) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
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Polym. Chem. 2014, 5, 819. (b) Li, L.; Shu, X.; Zhu, J. Polymer
2012, 52, 5010.
Acknowledgment
Financial support was provided by the National Natural Science Foun-
dation of China (No. 21272174) and the Key Projects of Shanghai in
Biomedicine (No.08431902700). We thank Professor Yanghui Zhang
and Guozhu Zhang (SIOC) for valuable assistance. We also thank the
Center for Instrumental Analysis, Tongji University, P. R. of China.
(8) Xu, H.; Liu, P.-T.; Li, Y.-H.; Han, F.-S. Org. Lett. 2013, 15, 3354.
(9) (a) Jensen, B. S. CNS Drug Rev. 2002, 8, 353. (b) Marti, C.;
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V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748.
(10) For selected examples, see: (a) Xu, X.; Tang, Y.; Li, X.; Hong, G.;
Fang, M.; Du, X. J. Org. Chem. 2014, 79, 446. (b) Shen, T.; Yuan,
Y.; Song, S.; Jiao, N. Chem. Commun. 2014, 50, 4115. (c) Wei, W.
T.; Zhou, M. B.; Fan, J. H.; Liu, W.; Song, R. J.; Liu, Y.; Hu, M.; Xie,
P.; Li, J.-H. Angew. Chem. Int. Ed. 2013, 52, 3638.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379888.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(11) For selected examples, see: (a) Zhou, S. L.; Guo, L. N.; Wang, H.;
Duan, X. H. Chem. Eur. J. 2013, 19, 12970. (b) Yang, F.; Klumphu,
P.; Liang, Y.-M.; Lipshutz, B. H. Chem. Commun. 2014, 50, 936.
(c) Zhou, B.; Hou, W.; Yang, Y.; Feng, H.; Li, Y. Org. Lett. 2014, 16,
1322. (d) Zhou, S. L.; Guo, L. N.; Wang, S.; Duan, X. H. Chem.
Commun. 2014, 50, 3589. (e) Li, Z.; Zhang, Y.; Zhang, L.; Liu, Z. Q.
Org. Lett. 2014, 16, 382.
(12) (a) Yin, F.; Wang, X. Org. Lett. 2014, 16, 1128. (b) Li, Y.; Sun, M.;
Wang, H.; Tian, Q.; Yang, S. Angew. Chem. Int. Ed. 2013, 52, 3972.
(c) Wei, X. H.; Li, Y. M.; Zhou, A. X.; Yang, T. T.; Yang, S. D. Org.
Lett. 2013, 15, 4158.
(1) (a) Schore, N. E. Comprehensive Organic Synthesis; Pergamon
Press: New York, 1991. (b) Bishop, R. Comprehensive Organic
Synthesis; Pergamon Press: New York, 1991.
(2) (a) Fatiadi, A. J. Preparation and Synthetic Applications of Cyano
Compounds; Patai, S.; Rappaport, Z., Eds.; Wiley: New York,
1983. (b) Larock, R. C. Comprehensive Organic Transformations;
VCH: New York, 1989. (c) Miller, J. S.; Manson, J. L. Acc. Chem.
Res. 2001, 34, 563.
NC
N
O
Me
CN
CN
H
1a
CN
N
N
–
N2
O
N
O
CN
N
Me
A
Me
B
[O]
NC
N
NC
N
H
O
+
O
H+
Me
Me
2a
C
Scheme 4 Plausible mechanism
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Letter
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(13) (a) Jaegli, S.; Dufour, J.; Wei, H. L.; Piou, T.; Duan, X. H.; Vors, J.
P.; Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498. (b) An, G.; Zhou,
W.; Zhang, G.; Sun, H.; Han, J.; Pan, Y. Org. Lett. 2010, 12, 4482.
(14) Wu, T.; Mu, X.; Liu, G.-S. Angew. Chem. Int. Ed. 2011, 50, 12578.
(15) For selected examples, see: (a) Li, X.; Xu, X.; Hu, P.; Xiao, X.;
Zhou, C. J. Org. Chem. 2013, 78, 7343. (b) Matcha, K.; Narayan, R.;
Antonchick, A. P. Angew. Chem. Int. Ed. 2013, 52, 7985. (c) Li, L.;
Deng, M.; Zheng, S.; Xiong, Y.; Tan, B.; Liu, X. Y. Org. Lett. 2014,
16, 504.
1349, 1338, 1136, 1021, 774 cm–1. HRMS (ESI-TOF): m/z calcd
for C15H18N2NaO+: 265.1317 [M + Na]+; found: 265.1318.
3-(1-Benzyl-3-methyl-2-oxoindolin-3-yl)-2,2-dimethylpro-
panenitrile (2b)
Clear oil. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.31 (m, 5 H),
7.30–7.24 (m, 2 H), 7.11 (t, d, J = 7.8 Hz, 1 H), 6.87 (d, J = 7.8 Hz,
1 H), 5.16 (d, J = 15.5 Hz, 1 H), 4.76 (d, J = 15.5 Hz, 1 H), 2.39 (d,
J = 14.6 Hz, 1 H), 2.26 (d, J = 14.7 Hz, 1 H), 1.43 (s, 3 H), 1.23 (s, 3
H), 1.06 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 179.75, 142.30,
135.77, 130.87, 128.77, 128.52, 127.69, 127.61, 124.88, 124.17,
122.48, 109.51, 47.05, 46.24, 44.10, 30.80, 29.77, 28.12, 26.36.
IR (thin film): νmax = 2975, 2926, 1708, 1612, 1489, 1468, 1453,
1380, 1357, 1177, 756 cm–1. HRMS (ESI-TOF): m/z calcd for
(16) General Procedure of the Synthesis of Cyano-Containing
Oxindoles 2a–t and 3a–f
An oven-dried 15 mL screw-capped vial containing 1 (0.2
mmol), AIBN (0.4 mmol), and DTBP (0.3 mmol) were evacuated
and purged with Ar gas three times. Then, DCE (2.00 mL) was
added via syringe. The reaction mixture was stirred at 80 °C for
16 h. After cooling to r.t., the solvent was evaporated and then
the residue was purified on a silica gel column using PE–EtOAc
(4:1) as eluent to give the desired product 2 or 3.
Three Representative Examples
3-(1,3-Dimethyl-2-oxoindolin-3-yl)-2,2-dimethylpropane-
nitrile (2a)
C
21H22N2NaO+: 341.1630 [M + Na]+; found: 341.1633.
2-[(1,3-Dimethyl-2-oxoindolin-3-yl)methyl]-2-methylbu-
tanenitrile (3a)
White solid; mp 124 °C. 1H NMR (400 MHz, CDCl3): δ = 7.39–
7.30 (m, 2 H), 7.14 (dd, J = 15.7, 7.8 Hz, 1 H), 6.93 (d, J = 7.7 Hz, 1
H), 3.27 (s, 3 H), 2.45 (d, J = 14.6 Hz, 1 H), 2.27 (q, J = 14.7 Hz, 1
H), 2.07 (d, J = 14.6 Hz, 1 H), 1.59–1.53 (m, 1 H), 1.46–1.33 (m, 4
H), 1.04–0.96 (m, 6 H). 13C NMR (100 MHz, CDCl3): δ = 180.04,
179.52, 143.36, 143.02, 131.47, 130.86, 128.63, 138.56, 124.92,
124.26, 123.28, 122.78, 122.57, 122.27, 108.60, 108.44, 46.94,
46.88, 45.40, 44.46, 35.64, 35.49, 35.30, 33.14, 27.84, 27.59,
26.42, 26.38, 25.82, 22.73, 9.12, 8.98. IR (thin film): νmax = 2986,
2927, 2235, 1710, 1609, 1494, 1470, 1361, 1349, 1338, 1136,
1021, 769 cm–1. HRMS (ESI-TOF): m/z calcd for C16H20N2NaO+:
279.1473 [M + Na]+; found: 279.1474.
White solid; mp 118 °C. 1H NMR (400 MHz, CDCl3): δ = 7.35 (m,
2 H), 7.14 (t, J = 7.5 Hz, 1 H), 6.93 (d, J = 7.7 Hz, 1 H), 3.27 (s, 3
H), 2.35 (d, J = 14.6 Hz, 1 H), 2.19 (d, J = 14.6 Hz, 1 H), 1.38 (s, 3
H), 1.19 (s, 3 H), 1.11 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ =
179.67, 143.16, 130.93, 128.65, 124.70, 123.97, 122.48, 108.52,
47.01, 46.56, 30.72, 29.70, 27.44, 26.65, 26.39. IR (thin film):
νmax = 3059, 2967, 2936, 2233, 1715, 1609, 1493, 1469, 1377,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 681–687

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