Iron(II)-catalyzed direct cyanation of arenes with aryl(cyano)iodonium triflates

Article abstract of DOI:10.1002/anie.201309791

A direct oxidative cyanation of arenes under Fe^II catalysis with 3,5-di(trifluoromethyl)phenyl(cyano)iodonium triflate (DFCT) as the cyanating agent has been developed. The reaction is applicable to wide range of aromatic substrates, including polycyclic structures and heteroaromatic compounds. Copyright

Full text of DOI:10.1002/anie.201309791

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Angewandte
Communications
DOI: 10.1002/anie.201309791
Synthetic Methods
Iron(II)-Catalyzed Direct Cyanation of Arenes with Aryl(cyano)-
iodonium Triflates**
Zhibin Shu, Wenzhi Ji, Xi Wang, Yujing Zhou, Yan Zhang, and Jianbo Wang*
Dedicated to Professor Max Malacria on the occasion of his 65th birthday
Abstract: A direct oxidative cyanation of arenes under FeII
catalysis with 3,5-di(trifluoromethyl)phenyl(cyano)iodonium
triflate (DFCT) as the cyanating agent has been developed. The
reaction is applicable to wide range of aromatic substrates,
including polycyclic structures and heteroaromatic com-
pounds.
alternative cyano sources, such as ammonium salts, DMSO,
and DMF, has attracted considerable attention, and signifi-
cant progress has been made.[10,11]
As an alternative to nucleophilic cyanation, electrophilic
cyanation has become a promising strategy for the synthesis
of aromatic nitriles. So far, electrophilic cyanation reactions
of reactive aryl nucleophiles, such as aryl stannanes and
Grignard, zinc, and lithium reagents, have been documen-
ted.[11b,12] However, in most of the established electrophilic
cyanation processes, highly toxic cyanogen halides are
unavoidable: They are used either to prepare the cyanating
T
he aromatic cyano group is widely applied in functional-
group transformations, including the formation of aromatic
acids, aldehydes, amines, amides, and heterocycles.[1] Aryl
nitriles are also found as integral parts of many dyes,
herbicides, agrochemicals, pharmaceuticals, and natural prod-
ucts.[2] Consequently, the development of efficient methods
for the synthesis of aryl nitriles has been pursued for many
decades.
À
reagent or as a direct cyano source. Moreover, direct C H
bond cyanation of arenes without a directing group is still very
limited.[13] Recently, Ohe and co-workers reported an inter-
esting GaCl3-catalyzed electrophilic cyanation of electron-
rich aromatic compounds with cyanogen bromide as the
cyano source.[13c]
The Sandmeyer and Rosenmund–von Braun reactions are
two classical functional-group transformations for the syn-
thesis of aromatic nitriles.[3] However, both reactions require
toxic copper(I) cyanide as the cyano source and occur under
rather harsh reaction conditions. The nucleophilic cyanation
of aryl halides under the catalysis of transition metals with
KCN or NaCN,[4] Zn(CN)2,[5] acetone cyanohydrin,[6] trime-
thylsilyl cyanide,[7] and K4[Fe(CN)6][8] as cyanating agents has
emerged as an alternative route to aryl nitriles. Moreover,
We recently reported a BF3·OEt2-catalyzed cyanation of
indoles and pyrroles with N-cyano-N-phenyl-para-toluene-
sulfonamide (NCTS) as the electrophilic cyano source.[14]
However, this reaction system failed when applied to
substituted benzene derivatives. In our continued search for
new and efficient cyanation systems,[15] we noticed that
hypervalent iodine(III) reagents have been widely applied
to direct oxidative nucleophilic substitution reactions of
À
directing-group-assisted transition-metal-catalyzed C H
À
bond functionalization has enabled the direct cyanation of
aromatic compounds with various nucleophiles, such as
[9]
[16]
À
À
À
À
aromatic C H bonds.
CN, N3, OAc, and SCN, under mild conditions.
In
Although much effort and remarkable progress has been
made in this area, some drawbacks remain with these
reactions. The major drawback is the high affinity of the
cyanide ion for the transition metal, which often results in
rapid deactivation of the catalyst. Moreover, most of the
cyano sources, in particular KCN, CuCN, Zn(CN)2, and
TMSCN, have notorious toxicity. Recently, the search for
particular, Kita and co-workers reported the direct cyanation
of aromatic compounds in a reaction mediated by hypervalent
iodine(III) reagents generated in situ.[17] However, this direct
cyanation system is only compatible with electron-rich
heteroaromatic compounds. Herein, we demonstrate an
efficient iron(II)-catalyzed direct cyanation of arenes under
mild conditions with aryl(cyano)iodonium triflates as the
cyano source.
The aryl(cyano)iodonium triflates C1–4 (Scheme 1) were
developed by Stang and co-workers.[18,19] These reagents,
which are prepared by the treatment of ArI(CO2CF3)2 with
[*] Z. Shu, W. Ji, X. Wang, Y. Zhou, Prof. Dr. Y. Zhang, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of the Ministry of Education, College of Chemistry, Peking University
Beijing 100871 (China)
E-mail: wangjb@pku.edu.cn
Prof. Dr. J. Wang
The State Key Laboratory of Organometallic Chemistry, SIOC
Chinese Academy of Sciences
Shanghai 200032 (China)
[**] This project was supported by the 973 Program (2012CB821600)
and the NSFC (grants 21272010, 21172005, and 21332002).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309791.
Scheme 1. Aryl(cyano)iodonium triflates and NCTS. Tf=trifluorome-
thanesulfonyl, Ts=p-toluenesulfonyl.
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Me3SiOTf and Me3SiCN, are relatively stable and can be
stored for months in a refrigerator without evident decom-
position. These reagents have found application as useful
iodonium-transfer reagents in the synthesis of various alkynyl
iodonium and alkenyl iodonium salts.[18a] To the best our
knowledge, they have not been used as electrophilic cyanating
agents.
At the outset, the hypervalent iodine(III) reagent C1 was
tested for the direct cyanation of p-xylene (1; Table 1). A
series of catalysts, including BF3·Et2O, CuBr, CuCl, CoCl2,
Table 1: Cyanation reaction of p-xylene (1).[a]
Entry
Catalyst (mol%)
Cyanating agent (equiv)
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CuBr (10)
CuCl (10)
CoCl2 (10)
SnCl2 (10)
FeCl2 (5)
C1 (2)
C1 (2)
C1 (2)
C1 (2)
C1 (2)
C1 (2)
C1 (2)
C1 (2)
C1 (2)
C2 (2)
C3 (2)
C4 (2)
C4 (4)
C4 (4)
0
0
0
0
trace[c]
trace[c]
trace
trace
trace
20
FeBr2 (5)
FeF2 (5)
Fe(OTf)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (10)
none
trace
47
73
N.R.[d]
[a] Reaction conditions: 1 (0.2 mmol), catalyst, cyanating agent, 1,2-
dichloroethane (DCE; 2 mL), 12 h. [b] Yield of the isolated product.
[c] The main products were halogenated arenes. [d] N.R.: no reaction.
and SnCl2, were examined; however, no expected cyanation
product 2 could be identified (Table 1, entries 1–4). When FeII
catalysts were examined, we observed the formation of a trace
amount of the desired product (Table 1, entries 5–9). With
Fe(OAc)2 (5 mol%) as the catalyst, other cyanating agents
C2–4 were then examined. To our delight, the cyanation
product 2 could be isolated in improved yield with these
cyanating agents (Table 1, entries 10–12). With 3,5-
Scheme 2. Scope of the cyanation of arenes. [a] The ratio was deter-
mined by 1H NMR spectroscopy. [b] The starting material was m-tolyl
di(trifluoromethyl)phenyl(cyano)iodonium
triflate
(C4,
acetate.
DFCT) as the cyanating agent, the yield was further improved
by increasing the loading of the catalyst from 5 to 10 mol%
(Table 1, entry 13). A control experiment indicated that in the
absence of a metal catalyst, no reaction occurred (Table 1,
entry 14). Finally, for comparison, NCTS (C5) was also
examined. No desired cyanation product was identified with
NCTS under otherwise identical conditions, or under our
previous conditions for indole cyanation with BF3·OEt2
(100 mol%).[14]
Having optimized the reaction conditions, we next
proceeded to explore the scope of the reaction. The cyanation
of benzene derivatives with various electron-donating sub-
stituents proceeded smoothly (Scheme 2), whereby the reac-
tion temperature and the amount of DFCT required varied
depending on the reactivity of the arene substrate.[20] The
cyanation of toluene gave a mixture of three regioisomers
(product 4a). Similar results were observed for the cyanation
of o-xylene (product 4b). The regioselectivity of the cyana-
tion reaction is governed by both electronic and steric effects
of the substituents, in a similar manner to the hypervalent-
iodine-induced nucleophilic substitution reactions reported
by Kita and co-workers.[16] The reaction with electron-rich
mesitylene afforded the product 4g in nearly quantitative
yield. The cyanation was also successful with methoxy-
substituted benzene derivatives (products 4h–m) and a hy-
droxy-substituted substrate (4n).
Notably, the cyanation reaction with polycyclic aromatic
substrates, such as naphthalene derivatives (products 4o–s),
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anthracene derivatives (4t,u), and phenanthrene (product
4v), all proceeded well and afforded the corresponding
cyanation products as single regioisomers in moderate to
high yields. The results are in accordance with the high
reactivity of these positions for electrophilic substitution.
Next, we extended the cyanation reaction to heteroaro-
matic compounds (Scheme 3). Heteroaromatic compounds
Scheme 4. Radical-trapping experiments. TEMPO=2,2,6,6-tetramethyl-
piperidin-1-oxyl.
We carried out experiments to elucidate the reaction
mechanism (Scheme 4). When the reaction of mesitylene and
DFCT was conducted in the presence of a stoichiometric
amount of TEMPO, the transformation of mesitylene was
almost completely inhibited, but no adduct derived from the
trapping of cyano radical by TEMPO could be observed.
When the reaction of DFCT and TEMPO was carried out in
the absence of mesitylene and with stoichiometric Fe(OAc)2,
the TEMPO–CN adduct was also not observed.
On the basis of these preliminary experiments and the
studies by Kita and co-workers,[17] we propose a reaction
mechanism which involves a single-electron-transfer (SET)
sequence (Scheme 5). The highly reactive radical species A is
Scheme 3. Cyanation of heteroarenes. [a] The ratio was determined by
1H NMR spectroscopy. [b] The ratio was determined by GC. Bn=ben-
zyl, dtbpy=2,6-di-tert-butylpyridine, TIPS=triisopropylsilyl.
Scheme 5. Proposed reaction mechanism.
were generally more reactive toward electrophilic cyanation,
although the regioselectivity was significantly affected by the
structure of the substrate. The amount of the cyanating agent
DFCTrequired also varied depending on the substrate, and in
most cases 2,6-di-tert-butylpyridine was needed to optimize
the yield.[20] In the case of pyrroles, it was possible to control
the cyanation to occur at either the C2 or the C3 position
through fine-tuning of the substituent on the nitrogen atom
(products 6a,b). The control of regioselectivity can be
interpreted in terms of steric effects of the substituent.
Interestingly, benzofuran and benzothiophene showed differ-
ent selectivities for C2 and C3 cyanation (products 6d,e). For
indole derivatives, the C2 cyanation showed high reactivity;
however, the selectivity could be controlled by the substituent
on the nitrogen atom (products 6j–l).
initially produced through single-electron transfer from FeII
to DFCT. A pathway via a free cyano radical can be ruled out
because cyano radical was not trapped by TEMPO. Instead,
we suggest SET from the radical species A to the arene
substrate to form intermediate B; nucleophilic addition of
cyanide ion to B then generates radical intermediate C.
Finally, SET occurs to give cation intermediate D, the
deprotonation of which affords the final product.[17]
In summary, we have developed a direct oxidative
cyanation of arenes under FeII catalysis by using DFCT as
the cyanating agent. The procedure has been successfully
applied to the direct cyanation of a wide range of aromatic
substrates, including polycyclic structures and heteroaromatic
compounds. Further studies are ongoing to expand the
reaction scope and identify more reactive cyanating agents.
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Typical procedure: Under a nitrogen atmosphere, a mixture of p-
xylene (1; 32.0 mg, 0.3 mmol), DFCT (618 mg, 1.2 mmol, 4.0 equiv),
and iron(II) acetate (2.6 mg, 0.015 mmol, 0.05 equiv) in 1,2-dichloro-
ethane (3 mL) was stirred at 708C for 12 h. After cooling, the reaction
mixture was diluted with CH2Cl2 (10 mL) and washed with aqueous
saturated NaHCO3 and then aqueous FeCl3. The aqueous layer was
further extracted with CH2Cl2 (10 mL), and the combined organic
phases were dried with anhydrous MgSO4 and then concentrated in
vacuo. Purification of the crude residue by column chromatography
afforded pure 2 (29 mg, 73% yield) as a solid.
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Received: November 11, 2013
Revised: December 27, 2013
Published online: January 22, 2014
Keywords: aromatic substitution · aryl nitriles · cyanation ·
.
hypervalent iodine · iron catalysis
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