Copper-catalyzed alkylarylation of activated alkenes using isocyanides as the alkyl source: An efficient radical access to 3,3-dialkylated oxindoles

Article abstract of DOI:10.1039/c6cc02024k

A novel and efficient protocol for the synthesis of 3,3-dialkylated oxindoles is described. The method involves a copper-catalyzed tandem radical addition/cyclization of N-arylacrylamides with the alkyl radicals generated from isocyanides. Two C-C bonds are formed in a single step.

Full text of DOI:10.1039/c6cc02024k

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DOI: 10.1039/C6CC02024K
Journal Name
COMMUNICATION
Copper-catalyzed alkylarylation of activated alkenes using
isocyanides as the alkyl source: An efficient radical access to 3,3-
dialkylated oxindoles
Received 00th January 20xx,
Accepted 00th January 20xx
ab
a
a
a
b
DOI: 10.1039/x0xx00000x
Yaping Zhao,‡ Zhenghua Li,‡ Upendra K. Sharma, Nandini Sharma,* Gonghua Song, and Erik
a
V. Van der Eycken*
www.rsc.org/
A novel and efficient protocol for the synthesis of 3,3-dialkylated co-workers reported an efficient organo-catalytic strategy for
oxindoles is described. The method involves a copper-catalyzed the tandem radical addition/cyclization of N-arylacrylamides
tandem radical addition/cyclization of N-arylacrylamides with the with the tert-butyl radical generated via the thermal
7
alkyl radicals generated from isocyanides. Two C−C bonds are decomposition of bis(pivaloyloxy)iodo]benzene. In 2013, Zhu
formed in a single step.
and co-workers have described a visible-light-promoted access
to alkyl radicals from aliphatic carboxylic acids. Similarly, the
8
3
,3-Disubstituted oxindoles are one of the most prominent N-
synthesis of 3-ethyl-3-substituted oxindole derivatives have
containing heterocyclic scaffolds, widely present in bioactive
natural products and pharmaceuticals. As a consequence,
numerous synthetic strategies have been developed during
the past few decades to construct oxindoles.
years, free radical chemistry has become an effective tool in
organic synthesis and has contributed significantly in the
evolution of chemistry. Because of their simplicity and
relatively high synthetic efficiency, free radical tandem
reactions have been frequently utilized for constructing
9c
been reported where di-tert-butyl peroxide or dicumyl
1
9d
peroxide have been used as methyl radical precursor. Also,
1a,2
(hetero)arylmethanes, phenylethane, and cumene can act as
alkyl radical precursors in tandem radical addition/cyclizations
Over the
9
a
with N-arylacrylamides under Lewis acidic conditions.
9
b
9e
Similarly, toluene
and simple alkanes
have been
successfully employed as radical precursors for the efficient
synthesis of alkyl-substituted oxindoles under Cu-catalysis. In
3
3
addition to this, C(sp )–H bonds adjacent to the heteroatom
complex (hetero)polycyclic skeleton. Towards this end, the
direct difunctionalization of N-arylacrylamides by sequential have also been employed as radical precursors to access
intermolecular addition of radicals followed by intramolecular functionalized oxindoles via oxidative alkene 1,2-alkylarylation
10
cyclization has proven to be an efficient approach to generate of N-arylacrylamides. In a recent report, Duan and co-
4
,5
3
,3-disubstituted oxindoles.
Alkyl groups are one of the most commonly occurring
workers have utilized unactivated alkyl halides containing a β-
hydrogen as alkylating reagents in a palladium-catalyzed
11
structural features in numerous bioactive natural products and
are known to exert significant influence on drug metabolism.
difunctionalization of activated alkenes. However, increasing
6
Thus, exploring efficient strategies for the incorporation of
alkyl groups into bioactive organic molecules, such as
oxindoles, is challenging and highly desirable. In the past few
years, several elegant works have been reported for the
successful incorporation of different alkyl groups into the C3-
position of the oxindole scaffold (Scheme 1). In 2012, Liu and
Scheme 1: Some previous strategies towards 3,3-dialkylated oxindoles.
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Journal Name
the diversity of the available synthetic methods in this area bases such as Et N and DBU as additives failed to afford better
3
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would be interesting.
results (entries 6, 7). Among the differ
O gave the best result (entries 8-10). Also, CuCl was
synthesis and have profound applications in multicomponent found effective for the above transformation, albeit providing
D
e
O
n
I:
t
10
c
.
a
1
t
0
a
3
l
9
y
/
t
C
ic6C
s
C
y
0
s
2
t
0
e
2
m
4K
s
Isocyanides are irreplaceable building blocks in organic tested, Cu
2
12
13
14
reactions and as versatile C1 synthons in transition metal 3a in lower yield (entry 8). Further, optimization focused on
catalysis. It is well known that addition of a free radical initiator the molar ratio of the reactants (entries 11, 12), catalyst
to an aliphatic isocyanide leads to the formation of an imidoyl (entries 13, 14) and oxidant (entry 15). This did not result in an
radical species, which undergoes unimolecular β-scission to amelioration of the conditions. When the reaction time was
yield the corresponding alkyl radical. This could be trapped by reduced to 12 h, a considerable decrease in product yield was
a suitable reactive moiety. Therefore, we envisaged that the observed (entry 16). Without the addition of a Cu-salt a
difunctionalization of alkenes with isocyanides through a considerably diminished yield was obtained (entry 17). The
1
5
2
tandem radical addition/C(sp )–H cyclization process could reaction was also found feasible with iron catalysts but in
result in a highly interesting approach to oxindoles containing comparatively lower yield (entries 18-20).
a quaternary carbon center. To the best of our knowledge, the
Having optimized the reaction conditions (Table 1, entry
present study is the first report on the employment of 10), we evaluated the scope and limitations with substituted
isocyanides for the alkylarylation of activated alkenes to N-arylacrylamides. To our satisfaction, the optimized
incorporate a 3,3-dialkyl moiety into an oxindole scaffold.
First we examined the reaction of N-arylacrylamide 1a (0.1 substituents having different electronic properties on the
mmol) and tert-butyl-isocyanide 2a (0.5 mmol) under various aromatic ring (3b 3l). However, a substrate bearing a strong
conditions were found to be generally applicable for
-
reaction conditions (Table 1). Using CuCl (15 mol%) as catalyst electron-withdrawing group like NO
and DCP (3 equiv) as oxidant in EtOAc at 120 C for 24 h, the result (3k). In the case of N-arylacrylamides bearing a meta-
gave an unsatisfactory
2
2
o
desired product 3a was obtained in 70% yield (entry 1). substitutent, a mixture of isomers was observed (3f
, 3g and 3l).
Subsequently, the effect of different oxidants (entries 2, 3) and Also, different alkyl, phenyl or benzyl substituents on nitrogen
solvents (entries 4, 5) was investigated. However a significant
lower yield was observed in each case. Employing organic
a, b
Table 2 Scope of N-arylacrylamides.
a
Table 1 Optimization of the reaction conditions.
a
Conditions: 1a (0.1 mmol), oxidant (0.3 mmol), catalyst (15 mol%), 2a (0.5
o
b
mmol), solvent (1 mL) at 120 C for 24 h. NMR yields; isolated yield in
parentheses. Et
mmol). 2a (0.7 mmol). Cu
c
d
e
a
3
N (10 mol%) as additive. DBU (10 mol%) as additive. 2a (0.3
2
Reaction conditions: 1b-s (0.2 mmol), 2a (5 equiv), DCP (3 equiv), Cu O (15
f
g
h
i
j
o
b
c
2
O (5 mol%). Cu
2
O (10 mol%). DCP (0.2 mmol).
mol%), EtOAc (2 mL) at 120 C for 24 h. Isolated yield. Ratio of isomers
reaction time =12 h. DCP = Dicumyl peroxide. DTBP = Di-tert-butyl peroxide. TBHP determined by H-NMR; nd = not detected.
1
=
tert-Butyl hydroperoxide.
2
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were well tolerated (3m
electron withdrawing tosyl group was found to be bulky adamantyl isocyanide (3x) while DaOqI:u1i0t.e10l3o9w/C6yCieCl0d20w24aKs
incompatible with these conditions (3q 3r). It turned out that observed in case of benzylic isocyanide (3y). Also, ethyl 2-
acrylamide derived from atropic acid (3s) gave a relatively low isocyanoacetate (3z) proved to be an effective substrate for
yield, which might be attributed to steric factors. the above reaction. However, the protocol failed to deliver the
-3p). On the contrary, a free –NH or of linear isocyanide (3w). A moderate yield was oVbietwaiAnrteicdle Ownilitnhe
,
Further, the above protocol was successfully extended to a desired product in case of aromatic isocyanides.
domino reaction starting from 1-(3,4-dihydroquinolin-1(2H)- To deduce the plausible reaction mechanism for this copper-
yl)-2-methylprop-2-en-1-one 4a (derived from 1,2,3,4- catalyzed alkylation/cyclization of N-acrylamides with
tetrahydroquinoline) delivering compound 5a in 57% yield isocyanides, a series of control experiments were performed
(
Scheme 2). However, use of cinnamamide derived from (Scheme 3). The presence of BHT or TEMPO hampered the
cinnamic acid 4b delivered 6-membered dihydroquinolinone reaction to a great extent, suggesting that a radical
, instead of oxindole, in 25% yield (Scheme 2). intermediate is involved in the catalytic cycle of the reaction
Scheme 3, eq. 1). Further, a series of deuteration reactions
5
b
(
were carried out (Scheme 3, also see supporting information),
where a kinetic isotope effect (KIE) of 1.0 was observed
(Scheme 3, eq. 2 and 3).
Scheme 2. Expansion of scope to a tetrahydroquinoline and a phenylcinnamamide
derivative.
To further demonstrate the catalytic efficacy, we expanded
the scope of this protocol to other isocyanide derivatives
(
Table 3). Various primary, secondary and tertiary aliphatic
isocyanides were found compatible, furnishing the desired
oxindoles in moderate to good yields (3a 3t 3w). Remarkably,
,
-
Scheme 3 Control experiments and KIE studies.
tertiary aliphatic isocyanides showed better reactivity than
primary or secondary isocyanides probably due to the effect of
the stability of the corresponding carbon centered radicals.
Moreover, the reaction showed good regio-selectivity in case
4a,16
On the basis of the above results and previous reports
plausible route has been proposed (Scheme 4). The first step
a
involves the copper-assisted homolysis of DCP to generate the
a, b
Table 3 Scope of isocyanides.
9b,9e
cumyloxyl radical.
Subsequently, attack of the cumyloxyl
radical on the isonitrile generates another radical intermediate
, which is followed by homolytic cleavage affording and
tert-butyl radical . Thereafter, addition of to the C=C bond
of N-acrylamide 1a delivers D. The intramolecular cyclization
of followed by copper-assisted deprotonation generates the
A
B
C
C
D
a
2
Reaction conditions: 1a (0.2 mmol), 2 (5 equiv, 1 mmol), DCP (3 equiv), Cu O (15
o
b
c
mol%), EtOAc (2 mL) at 120 C for 24 h. Isolated yields. 10 equiv of isocyanide
used.
Scheme 4 Plausible mechanism.
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Commun., 2014, 50, 4115; (i) W. W. J. Wen, D. VYiaewngA,rtiJc.leDOun,linJe.
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7
8
Conclusions
We
have
developed
a
novel
copper-catalyzed
for the
9
alkylarylation/cyclization cascade
approach
construction of alkyl substituted 3,3-disubstituted oxindoles
via trapping of the alkyl radical generated from the isocyanide.
The protocol shows remarkable regio-selectivity for the linear
isocyanides and tolerates a series of functional groups,
providing the desired products in moderate to high yields.
Support was provided by the Research Fund of the
University of Leuven (KU Leuven) and the FWO (Fund for
Scientific Research Flanders (Belgium). Y.Z. and Z.L. are
grateful to the China Scholarship Council (CSC) for providing a
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