Perfluorobutyl iodide-assisted direct cyanomethylation of azoles and phenols with acetonitrile

Article abstract of DOI:10.1039/c5ra02242h

A perfluorobutyl iodide-assisted transition-metal-free cyanomethylation of azoles and phenols with acetonitrile in the presence of NaH has been developed. The reaction proceeded smoothly under mild reaction conditions to give the cyanomethylated products in moderate to high yields. A mechanism involving the cyanomethyl radical through C-H bond cleavage in acetonitrile was proposed. This journal is

Full text of DOI:10.1039/c5ra02242h

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Perfluorobutyl iodide-assisted direct
cyanomethylation of azoles and phenols with
Cite this: RSC Adv., 2015, 5, 20562
acetonitrile†
Received 7th January 2015
Accepted 10th February 2015
*
Juan Zhang, Wei Wu, Xinfei Ji and Song Cao
DOI: 10.1039/c5ra02242h
www.rsc.org/advances
A perfluorobutyl iodide-assisted transition-metal-free cyanomethy-
Nowadays, transition-metal-catalyzed C–H bond activation
lation of azoles and phenols with acetonitrile in the presence of NaH of acetonitrile has become a straightforward and viable alter-
has been developed. The reaction proceeded smoothly under mild native approach to cyanomethylated compounds.11 To date,
reaction conditions to give the cyanomethylated products in most of the research in this area focuses on the cyanomethy-
moderate to high yields. A mechanism involving the cyanomethyl lation of carbonyl compounds,12 activated alkenes (N-phenyl-
radical through C–H bond cleavage in acetonitrile was proposed.
acrylamides)13 and imines.14 However, direct N- and
O-cyanomethylation of azole and phenol with acetonitrile still
remains challenging.
The cyanomethylation of organic compounds is an important
chemical transformation due to the wide utility of the nitrile
group as a potent synthetic block for the construction of diverse
complex molecules.1 Recently, extensive efforts have been made
toward the development of methods for introducing the cya-
nomethyl group to different substrates.2 As a consequence,
various novel cyanomethylation reactions have increasingly
emerged such as the photoassisted direct cyanomethylation of
benzene with acetonitrile in the presence of Pd/TiO2,3 the cya-
nomethylation of aromatic alcohols with acetonitrile using
CuCl2 as the catalyst and O2 as the oxidant4 and the nickel
cyanomethyl complex-catalyzed the coupling of aldehydes and
acetonitrile.5
In addition, peruoroalkyl iodides are usually utilized as
peruoroalkyl radical precursors.15 However, the formation of
radicals from these peruoroalkyl radical sources is oen
initiated by precious metal photocatalysts,16 radical initiators,17
peroxides,18 heat and light irradiation.19 In 2014, Zhang and
Studer reported the Rf–I bond in peruoroalkyl iodide could be
homolytically cleaved to generate a peruoroalkyl radical with
the assistance of Cs2CO3 in the absence of metal salt initiator.20
Herein, we report the rst example of NaH-mediated direct
N- and O-cyanomethylation of azole and phenol via per-
uorobutyl iodide-assisted cleavage of C–H bond of acetonitrile
without transition metal catalyst (Scheme 1).
The methods for the preparation of cyanomethylated
compounds typically require the use of prefunctionalized
acetonitrile,
including
haloacetonitrile,6
Me3SiCH2CN
(TMSAN)7 and isoxazole-4-boronic acid pinacol ester (acetoni-
trile anion equivalent).8 The direct use of acetonitrile as starting
material to undergo cyanomethylation reaction has attracted
much interest in organic chemistry since it avoids substrate
prefunctionalization.9 Traditionally, the deprotonation of
acetonitrile could proceed smoothly in the presence of strong
bases (such as sodium amide) at very low temperature,10 but the
harsh reaction conditions limit this method.
Scheme 1 Cyanomethylation of azoles and phenols with acetonitrile.
At the start of our investigations, we chose the reaction
between benzimidazole 2a and acetonitrile in the presence of
peruorobutyl iodide as a model reaction to survey the reaction
conditions (Table 1). Among the bases tested, NaH proved to be
the most effective base for this reaction, affording product 3a in
90% yield (entry 7). The use of other bases led to decreased
yields (entries 1–6). No detectable amount of N-cyanomethy-
lated benzimidazole 3a was formed in the absence of base (entry
8). It was found that three equivalents of NaH were necessary to
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology (ECUST), Shanghai 200237, China. E-mail:
scao@ecust.edu.cn; Fax: +86-21-64252603; Tel: +86-21-64253452
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra02242h
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Table 1 Optimization of the reaction conditionsa
Entry
CH3CN (mL)
RfI (equiv.)
Temp (ꢀC)
Base (equiv.)
Yield of 3ab(%)
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.5
3.5
4.0
2.5
2.5
2.5
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (0.5)
C4F9I (1.0)
C4F9I (1.5)
None
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
25
65
50
NaOH (3.0)
KOH (3.0)
K2CO3 (3.0)
K3PO4 (3.0)
tBuOK (3.0)
Cs2CO3 (3.0)
NaH (3.0)
None
NaH (1.5)
NaH (2.0)
NaH (2.5)
NaH (3.5)
NaH (3.0)
NaH (3.0)
NaH (3.0)
NaH (3.0)
NaH (3.0)
NaH (3.0)
NaH (3.0)
NaH (3.0)
NaH (3.0)
NaH (3.0)
10
25
45
50
66
70
90
0
70
83
85
74
50
76
88
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
C4F9I (1.2)
CF3(CF2)7I (1.2)
73
85
83
70
45
85
a
b
Reaction conditions: 2a (0.25 mmol), 24 h. Yields determined by GC analysis and based on 2a.
achieve this transformation (entries 7 and 9–11), but if the present or not. The optimized conditions were also suitable
amount of NaH was increased to 3.5 equiv., the yield of 3a for the N-cyanomethylation of benzo-fused pyrazole (1H-inda-
decreased obviously (entry 12).
zole, 2g) and pyrazole derivative 2h, however, the yields
The addition of 1.2 equiv. of peruorobutyl iodide was decreased appreciably. 1H-Benzo[d][1,2,3]triazole 2i could
required to obtain satisfactory yield (entry 7 and entries 13–15). react with acetonitrile, but the desired product 3i was
The reaction did not proceed in the absence of peruorobutyl obtained in low yield. It is noteworthy that quinazolin-4(3H)-
iodide (entry 16). The acetonitrile was used as both substrate one 2j is also compatible with this reaction and the cyano-
and solvent. Increasing or decreasing the amount of CH3CN methylated product was obtained in moderate yield. Unfor-
slightly diminished the yield of 3a (entries 17–19). The use of 2.5 tunately, when 1H-indole was used as substrate, less than 20%
mL of CH3CN could provide a good yield. The effect of the of the expected product was detected (GC-MS). It appears that
temperature on the reaction was also examined (entries 20–21). the basicity of the azoles played a crucial role in the reaction.
The results indicated that 50 ꢀC was the optimal temperature for With a decrease in the basicity, benzoimidazole or imidazole
this reaction. Finally, no obvious difference was observed by derivatives, 1H-indazole or 1H-pyrazole, 1H-benzo[d][1,2,3]tri-
replacing peruorobutyl iodide with peruorooctyl iodide azole and 1H-indole led to sharply descending reaction effi-
(entry 22).
ciency. The order of reactivity, imidazole > pyrazole >
To survey the generality of this transformation, a variety of 1H-benzo[d][1,2,3]triazole > 1H-indole, is in accordance with
azoles were allowed to react with acetonitrile under the opti- the order of their basicities.
mized conditions as in entry 7 in Table 1. The results are
To expand the scope of this novel transformation, the reac-
summarized in Table 2. Most azoles could afford the N-cya- tions of acetonitrile 1 with various substituted phenols 2k–t
nomethylated products in moderate to high yields. Both were carried out under identical reaction conditions as outlined
benzoimidazole derivatives (2a, 2d, 2e and 2f) and imidazole above and representative results were summarized in Table 3.
derivatives (2b and 2c) underwent the cyanomethylation Phenol derivatives with electron donating group such as CH3
reaction smoothly irrespective of whether benzene ring is and OCH3 (2l and 2m) at para position afforded excellent yields
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Table 2 Cyanomethylation of various azoles with acetonitrileab
In addition, when aniline, amino pyridine or benzyl alcohol
was used as substrate, only trace amount of cyanomethylation
product was detected. Furthermore, the replacement of aceto-
nitrile with propionitrile or phenylacetonitrile led to the failure
of this novel reaction. It might be due to steric effect of ethyl and
phenyl group.
To gain possible insights into the reaction mechanism,
several control experiments were conducted. Under the
optimized reaction conditions, a radical scavenger such as
hydroquinone (0.5 equiv.), TEMPO (2.0 equiv.) and galvinoxyl
(2.0 equiv.) was added separately, the yields of the reactions
between benzimidazole 2a and acetonitrile 1 decreased signif-
icantly (7%, 56% and 35%, respectively). These studies indi-
cated that the reaction may proceed via a radical pathway. In
addition, when the reaction was performed in the absence of
benzimidazole 2a in the model reaction, 2-iodoacetonitrile was
detected (19%, GC-MS). This result clearly revealed that the
reaction involved the formation of the key intermediate ICH2CN
in the earlier stage of the reaction.
Based on the above observations, a plausible reaction
mechanism is depicted in Scheme 2 (with 2a as the example).
It has been reported that Cs2CO3,20,21a Na2CO3,21b enamines21c,d
could be used as a radical initiator for the cleavage of C–I
bond in peruoroalkyl iodide to produce peruoroalkyl radical
a
Reaction conditions: 1 (10 mL), azoles (1.0 mmol), n-C4F9I (1.2 mmol),
b
NaH (3.0 mmol), 50 ꢀC, 24 h. Isolated yields.
(R ). In the course of optimization of the reaction conditions,
f
c
Table
3 Cyanomethylation of various substituted phenols with
we found that other base such as Cs2CO3, tBuOK, K3PO4 and
K2CO3 could also provide moderate yield of desired product.
Therefore, we assume that NaH worked as radical initiator.22 In
initiation step, the cleavage of C–I bond in peruoroalkyl
iodide with the assistance of NaH resulted in the formation of
acetonitrileab
peruoroalkyl radical (R f). The Rf radical can undergo
c
hydrogen abstraction from the CH3CN to generate the cyano-
methyl radical (cCH2CN) and RfH. Subsequently, the cyano-
methyl radical attacks peruoroalkyl iodide to produce the key
intermediate, ICH2CN along with peruoroalkyl radical. Finally,
the reaction of ICH2CN with sodium salt of benzimidazole
afforded the cyanomethylated product 3a.
a
Reaction conditions: 1 (10 mL), substituted phenols (1.0 mmol),
b
n-C4F9I (1.2 mmol), NaH (3.0 mmol), 50 ꢀC, 12 h. Isolated yields.
Scheme 2 Possible mechanism for the reaction of benzimidazole 2a
with acetonitrile.
of aryloxyacetonitriles, whereas those with electron donating
group at meta or ortho position provided the corresponding
cyanomethylated products in moderate to good yields (3n–p).
Phenols bearing relatively weak electron-withdrawing substitu-
ents such as ester and halogen were also tolerated, providing
the products in moderate yields (3q–t). The reactions of
4-nitrophenol and 4-hydroxybenzonitrile with acetonitrile
hardly proceeded and no desired products were observed due to
the presence of strong electron-withdrawing group on the
benzene ring.
In summary, we have developed the rst peruoroalkyl
iodide-promoted cyanomethylation of azoles and phenols with
acetonitrile in the presence of NaH through a cyanomethyl
radical pathway. The transformation proceeded efficiently in
the absence of transition metal catalyst or other additional
radical initiator. The main advantage of this method is that the
acetonitrile could be used directly without prefunctionalization
of it with halogen. Further studies to expand the scope of the
C–H bond cleavage of CH3CN with the assistance of per-
uorobutyl iodide are underway in our laboratory.
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