Cyanomethylation of alkenes with C-H bond activation of acetonitrile: In situ generated diazonium salts as promoters without transition-metals

Article abstract of DOI:10.1039/c5ra23471a

Diazonium salts, which were in situ generated from p-anisidine and tert-butyl nitrite, could be used as a novel radical promoter for the C_sp³-H functionalization of acetonitrile. The cyanomethylation of alkenes could be performed wit

Full text of DOI:10.1039/c5ra23471a

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Cyanomethylation of alkenes with C–H bond
activation of acetonitrile: in situ generated
diazonium salts as promoters without transition-
metals†
Cite this: RSC Adv., 2016, 6, 522
Received 7th November 2015
Accepted 15th December 2015
*
Zhangqin Ni, Xin Huang, Jichao Wang and Yuanjiang Pan
DOI: 10.1039/c5ra23471a
www.rsc.org/advances
Diazonium salts, which were in situ generated from p-anisidine and (Fig. 1, eqn (3)).10 Sheng developed DIAD as a promoter for
tert-butyl nitrite, could be used as a novel radical promoter for the cyanomethylation of alkenes by Cu catalyst (Fig. 1, eqn (4)).11
3
C
sp –H functionalization of acetonitrile. The cyanomethylation of Nevertheless, catalytic or stoichiometric amount of transition
alkenes could be performed without the use of transition-metal salts metals are still required in forementioned examples. Metal
or photocatalyst and the functionalized oxindoles could be obtained contamination is a serious issue in the pharmaceutical
with simple operation in moderate to good yields. This process industry. Transition-metal-free reactions are of great interest in
tolerates a variety of functional groups and provides an alternative terms of atom economy, environmental impact, and cost
procedure for the synthesis of functionalized oxindoles.
reduction. It would still be highly desirable to develop a method
for cyanomethylation of alkenes using environmental-friendly
condition. As our continuing interests in the researches
involving the in situ generated diazonium salts,12 we describe
a novel cyanomethylation of alkenes using in situ generated
diazonium salts as promoter without transition-metals or pho-
tocatalyst (Fig. 1, eqn (5)).
Nitriles and alkenes are essential materials in the chemical
industry and also widely exist in nature.1 The functionalization
of alkenes, the C–H bond activation of acetonitrile and many
important chemical transformations of these compounds have
achieved much attention from chemists.2–5 A wide range of
transition metals, such as Ir, Rh, Ni, Fe, etc. have been applied
to the C–H bond activation of acetonitrile while stoichiometric
amounts of these transition metals are needed in most cases.6
Although several examples of a-C–H functionalization of
acetonitrile using a catalytic amount of transition-metal have
been developed, there are still some limitations. As acetonitrile
has a high pKa value [pKa (MeCN) z 31.3, DMSO], a strong base
is required for the deprotonation.7 Therefore, it is of great
interest to develop new environment-benign method for the
C–H functionalization of acetonitrile. In previous studies, Liu
reported a Pd-catalyzed oxidative alkylarylation of alkene
involving a-C–H activation of acetonitrile with the aid of stoi-
chiometric amount of PhI(OCOtBu)2 and AgF (Fig. 1, eqn (1)).8
Very recently, the alkylarylation of alkene with the C–H activa-
tion of acetonitrile through a radical process have been well
documented. Li used diazonium salts as a promoter for cya-
nomethylation of alkenes by visible-light catalyst (Fig. 1,
eqn (2)).9 Zhao and Tang reported cascade arylalkylation of
activated alkene using phenylboronic acid as radical initiator
Department of Chemistry, Zhejiang University, Hangzhou, 310027, China. E-mail:
cheyjpan@zju.edu.cn; Tel: +86 571 87951269
Fig. 1 Oxidative cyanomethylation of alkene with C–H bond activa-
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra23471a
tion of acetonitrile.
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Table 1 The optimization of the reaction conditionsa
acetates were screened to improve the yield (Table 1, entries
5–8). Among the acetates tested, KOAc provided the best yield
with 43%. Further optimizations were focused on the ratio
and the concentration of reactants, while the reaction
temperature was also optimized (Table 2). When 1a
(0.5 mmol), p-anisidine (0.75 mmol), t-BuONO (0.75 mmol)
were used, the yield decreased obviously (Table 2, entry 1).
This phenomenon indicated that the concentration of reac-
tant had a signicant effect on the reaction. When 2 mL of
acetonitrile was used as the solvent, the target product could
be obtained with only 21% yield (Table 2, entry 2). Once we
increased the amount of acetonitrile to 4 mL, the reaction was
Nitrosating
Entry
reagent
Additive
Base
Yieldb (%)
1
2
3
4
5
6
7
8
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
BPOc
BPOc
BPOc
BPOc
—
—
—
—
NaOAc
K3PO4
K2CO3
NaHCO3
NaOAc
KOAc
27
Trace
Trace
15
37
43
Table 3 The investigation of the reaction scope
LiOAc
CsOAc
29
29
a
Reaction conditions: 1a (0.5 mmol), p-anisidine (1.0 mmol), t-BuONO
b
(1.0 mmol), base (2 equiv.), CH3CN (3 mL), 10 h. Isolated yield.
c
0.05 mmol BPO was added.
We initiated our investigation using N-methyl-N-phenyl-
methacrylamide (1a) and acetonitrile as substrates under
various conditions and the result was summarized in Tables 1
and 2. When we performed the reaction under the following
conditions [1a (0.5 mmol), p-anisidine (2.0 equiv.), benzoyl
peroxide (BPO) (0.1 equiv.), tert-butyl nitrite (t-BuONO)
ꢀ
(2.0 equiv.), NaOAc (2 equiv.), CH3CN (3 mL), 80 C, 10 h], our
desired product 2a could be isolated in 27% yield and the
structure was conrmed by MS and NMR spectra. Then several
different bases were applied to our reaction, a higher yield could
be gained using NaOAc (Table 1, entries 1–4). It was interesting
to nd that a higher yield with 37% was obtained when the
reaction was carried out in the absence of BPO (Table 1, entry 5).
As acetate was more effective than other bases, some other
Table 2 The optimization of the reaction conditionsa
Entry
Ratiob
Concentrationc
Temp
Yieldd (%)
1
2
3
4
5
6
7e
1 : 1.5 : 1.5
1 : 1.5 : 1.5
1 : 1.5 : 1.5
1 : 3 : 3
1 : 3 : 3
1 : 3 : 3
0.167 M
0.250 M
0.125 M
0.125 M
0.125 M
0.125 M
0.125 M
80 ꢀC
80 ꢀC
80 ꢀC
80 ꢀC
75 ꢀC
85 ꢀC
80 ꢀC
24
21
50
70
63
55
22
1 : 3 : 3
a
Reaction conditions: 1a (0.5 mmol), KOAc (2 equiv.), CH3CN (3 mL),
b
10 h. The ratio of N-arylacrylamide, p-anisidine and t-BuONO.
c
d
Concentration refers to 1a. Isolated yield. e Under air.
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promoted to 50% yield (Table 2, entry 3). Fortunately, when we
further increased the ratio of reactants [1a (0.5 mmol), p-
anisidine (1.5 mmol), t-BuONO (1.5 mmol)], the desired
product was isolated in 70% (Table 2, entry 4). The yield could
not be improved when the reaction was performed in either
a higher or lower temperature (Table 2, entries 5–6). The inert
atmosphere was necessary for this transformation as only 22%
could be obtained when the reaction was carried out under air
(Table 2, entry 7).
(8)
(9)
With the optimized reaction condition in hand, we inves-
tigated the scope and limitations of substituted N-arylacryla-
mides 1 with acetonitrile and the results were summarized in
Table 3. It was interesting to nd that the substituted group on
the N atom had an obvious inuence on the yield. The
unprotected N-arylacrylamide (R2 ¼ H) or N-arylacrylamide
with acetyl group were less efficient in the cyclization (2b and
2c). Whereas, N-arylacrylamide substituted with isopropyl, n-
butyl or phenyl groups could afford the desired products in
acceptable yields (2d, 2e and 2f). Then we set out to investigate
the effect of the substituted groups on the phenyl ring. A wide
range of substituents at different positions of the aromatic
ring were discussed. The electronic character of the substit-
uent groups at para-position of aromatic ring had little inu-
ence on this reaction. The substrates with electron-donating or
electron-withdrawing groups could all give the desired prod-
ucts in moderate to good yields (2g–2k). The halogen groups
(Cl, Br, F) could be tolerated in this transformation and they
might be used for further functionalization. It is a pity that
desired product could not be obtained because of the high
reactivity of iodine group (2l). N-Arylacrylamide substituted
with cyano group at para-position could afford the target
product in slightly lower yield (2m). As anticipated, a mixture
of two products were detected when the substrates were
substituted at meta-position of phenyl ring (2n and 2o).
Besides, the steric hindrance decreased the reactivity.
Although the desired products with substituents at ortho-
position of phenyl ring could be obtained in acceptable yields,
they are slightly lower than that with the same substituents at
para-position (2p and 2q). In addition, desired product was
formed in 40% yield when R3 ¼ OMe (2r), but no product could
not be obtained when the R3 ¼ H (2s).
It was interesting to nd that this strategy could also be
applied to synthesize more complex oxindoles. When N-aryla-
crylamide 1t was used as substrate, the desired product poly-
cyclic oxindole 2t could be obtained in 55% yield (eqn (6)). We
also tried to utilize this strategy to other kinds of aliphatic
nitriles. However, it failed to get the target product when n-
butyronitrile was used under the standard reaction condition
(eqn (7)). When we used CH2Cl2 or CHCl3 as the solvent, the
C–H bond of CH2Cl2 or CHCl3 could be activated and the target
product 2u or 2v could be obtained with 35% or 33%, respec-
tively (eqn (8) and (9)).
To investigate the mechanism of this cascade reaction, some
control experiments were performed (Scheme 1). The corre-
sponding oxindole 2a could be obtained with 70% yield when
the reaction was conducted under standard reaction condition.
When radical scavenger 2,2,6,6-tetramethylpoperdine-1-oxyl
Scheme 1 The control experiments.
(6)
(7)
Scheme 2 Proposed mechanism for the synthesis of oxindoles.
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radical (TEMPO) or butylated hydroxytoluene (BHT) were added
to the reaction system, the desired product 2a could not be
obtained. 2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)acetonitrile 3
was obtained with 3% by GC-MS and veried by HRMS. It
indicated that the acetonitrile radical was trapped by TEMPO
and this reaction might go through a radical pathway.
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Based on control experiments and previous literatures,9–13
a possible mechanism for the cyanomethylation of N-arylcar-
ylamides was proposed (Scheme 2). Firstly, the diazonium salt A
is in situ formed by the reaction between p-anisidine and tert-
butyl nitrite. Radical intermediate B is then generated by the
homolysis of diazonium salt A under heat. Radical B can
abstracte a hydrogen atom from acetonitrile to generate
cCH2CN. The resulting cCH2CN adds to the C]C bond of 1a to
give intermediate C. Through the cyclization of intermediate C,
intermediate D is generated. By reacting with another molecule
of diazonium salt A, intermediate E will be given and radical B
will be regenerated. Finally, the nal product can be obtained by
counterion, tert-butoxide, abstracting a proton from the carbo-
cation. An alternative reaction pathway includes a base
promoted homolytic aromatic substitution step is also possible.
Intermediate D is deprotonated by tert-butanolate derived from
tert-butyl nitrite and radical anion F is formed. By reacting with
another molecule of diazonium salt A, nal product is given and
radical B is regenerated.
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Conclusions
We have developed a novel cyanomethylation of alkenes using
in situ generated diazonium salts as promoter. It is interesting
to nd that the in situ generated diazonium salts could be used
as a novel radical promoter without the use of transition-metal
3
salts or photocatalyst for the Csp –H functionalization of
acetonitrile. In most cases, the target products could be ob-
tained with simple operation in moderate to good yields. This
process tolerates a variety of functional groups and provides an
alternative procedure for the synthesis of functionalized oxin-
doles. A radical-involved mechanism was also proposed to give
deeper understanding of the transformation.
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Acknowledgements
We gratefully acknowledge the National Nature Science Foun-
dation of China (21327010).
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