Acetonitrile as a cyanating reagent: Cu-catalyzed cyanation of arenes

Article abstract of DOI:10.1021/acs.orglett.5b00886

A novel approach to the Cu-catalyzed cyanation of simple arenes using acetonitrile as an attractive cyano source has been documented. The C-H functionalization of arenes without directing groups involves a sequential iodination/cyanation to give the desired aromatic nitriles in good yields. A highly efficient Cu/TEMPO system for acetonitrile C-CN bond cleavage has been discovered. TEMPO is used as a cheap oxidant and enables the reaction to be catalytic in copper. Moreover, TEMPOCH₂CN 6 has been identified as the active cyanating agent and shows high reactivity for forming the -CN moiety.

Full text of DOI:10.1021/acs.orglett.5b00886

Letter
pubs.acs.org/OrgLett
Acetonitrile as a Cyanating Reagent: Cu-Catalyzed Cyanation of
Arenes
Yamin Zhu,† Mengdi Zhao,† Wenkui Lu, Linyi Li, and Zengming Shen*
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
S
* Supporting Information
ABSTRACT: A novel approach to the Cu-catalyzed cyanation of simple arenes using acetonitrile as an attractive cyano source
has been documented. The C−H functionalization of arenes without directing groups involves a sequential iodination/cyanation
to give the desired aromatic nitriles in good yields. A highly efficient Cu/TEMPO system for acetonitrile C−CN bond cleavage
has been discovered. TEMPO is used as a cheap oxidant and enables the reaction to be catalytic in copper. Moreover,
TEMPOCH2CN 6 has been identified as the active cyanating agent and shows high reactivity for forming the −CN moiety.
Scheme 1. Strategies for Cyanation of Arenes
romatic nitriles are versatile functional units in many dyes,
Aherbicides, agrochemicals, pharmaceuticals, and natural
products.1 Furthermore, the cyano group serves as a valuable
intermediatefortransformationintoaldehydes, amines,amidines,
tetrazoles, amides, and their carboxyl derivatives.2 In recent
decades, significant progress has been achieved in the transition-
metal catalyzed synthesis of benzonitriles.3 Notably, the
cyanations of aryl (pseudo)halides,3 activated arenes,4,6f and
arenes with directing groups5 have been elegantly developed. In
most cases, metal cyanides were often used as cyanating reagents.
A significant problem 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 investigation of combined cyano sources as an
alternative strategy, such as ammonium salts in combination with
DMF or DMSO, has attracted considerable attention.6
that a Cu/TEMPO system plays a crucial role in the activation of
acetonitrile.
Fromthe viewpointof safetyand atom-economy, acetonitrile is
a rather attractive “CN” source, avoiding the employment of toxic
metal cyanides and structurally complex electrophilic “CN”
sources. However, thistypeofC−Cbondactivationischallenging
due to a high CH3−CN bond dissociation energy (133 kcal/mol)
relative to alkane C−C bonds (ca. 83 kcal/mol).8 Given our
interest in cyanation studies, our group recently disclosed the Cu-
catalyzed cyanation of aromatic C−H bonds bearing a directing
group using acetonitrile as the “CN” source.9 Notably, the
identification of (Me3Si)2 as a suitable Lewis acid was crucial for
activating the relatively inert acetonitrile C−CN bond. Based on
this work, we envisioned a strategy for the cyanation of simple
arenes by using CH3CN as a “CN” source (Scheme 1, eq 3). This
strategy involves a sequential process to activate simple arenes via
initial iodination followed by cyanation. However, the iodination
The cyanation of simple arenes, that is arenes without a
directing group, is an attractive and modern approach to making
benzonitriles. This strategy avoids the need for prefunctionaliza-
tion of substrates, and importantly, simple arenes are abundant
starting materials. Thus far, few examples have been reported in
this field due to their low reactivity. In 2010, Hartwig and co-
workers documented an elegant example of the cyanation of
unactivated arenes (Scheme 1, eq1).7a In this case, an Ir-catalyzed
C−H borylation is followed by a stoichiometric Cu-promoted
cyanaton using Zn(CN)2 as the cyano source. Recently, Wang
and co-workers reported the Fe-catalyzed direct cyanation of
arenes using aryl(cyano)iodonium triflate (DFCT) as a cyano
source (Scheme 1, eq 2).7b In considering this challenge, our
laboratorywas interestedindevelopingacomplementary method
that exploits the common solvent, acetonitrile, as the cyano
source. Herein, we report a copper-catalyzed cyanation of simple
arenes using acetonitrile via an initial iodination. Studies reveal
Received: March 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00886
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Parameters for Cyanation of Arenes
b
b
entry
LA (10 mol %)
2a (%)
[Cu] (20 mol %)
oxidant
none
3a (%) (o:p)
1
2
3
4
5
6
7
none
−
31
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
none
−
AlCl3
TEMPO
9 (1:1)
BF3·Et2O
Bi(OTf)3
97
TEMPO
31 (1.8:1)
67 (1.4:1)
77 (1:1)
49 (1.3:1)
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
TEMPO
Sc(OTf)3
Fe(OTf)3
Yb(OTf)3
Cu(ClO4)2·6H2O
Cu(OTf)2
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Cu(ClO4)2·6H2O
TEMPO
TEMPO
c
TEMPO
94 (1:1.1)
d
c
8
e
TEMPO
91 (1.1:1)
c
9
none
TEMPO
83 (1.1:1)
10
11
12
13
14
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(OAc)2
none
Ag2CO3 (1 equiv)
Oxone (1 equiv)
BQ (1 equiv)
TBHP (1 equiv)
TEMPO
40 (1.3:1)
−
−
−
77 (1.3:1)
f
15
TEMPO
29 (1.2:1)
a
Conditions: the first step: Lewis acid (10 mol %), NIS (1.05 equiv), CH3CN, 150 °C, O2, 2 h; the second step: [Cu] catalyst (20 mol %), 1,10-
b
phenanthroline (20 mol %), (Me3Si)2 (1 equiv), TEMPO (2,2,6,6-tetramethylpiperidinyloxy, 2 equiv), 150 °C, O2, 2−2.5 d. GC yield using
dodecane as an internal standard. Isolated yield. Cu(ClO)4 (20 mol %). Cu(OTf)2 (20 mol %). Without (Me3Si)2.
c
d
e
f
of simple arenes is normally carried out under harsh conditions
such as the use of strong acids, excess amounts of oxidants, and
special reagents.10 Therefore, the one-pot cyanation using
CH3CN as a cyanating reagent via a iodination process would
be a challenging strategy.
sequential iodination/cyanation in a one-pot process are entry
8 (conditions A) and entry 7 (conditions B).
With the optimal conditions in hand, the generality and
limitations of this Cu-catalyzed cyanation of simple arenes with
acetonitrile were explored, as shown in Table 2. Pleasingly,
benzene smoothly underwent cyanation under the standard
conditions, giving benzonitrile 3b (39% yield under conditions A,
47% yield under conditions B) (entry 2). A variety of substituents
on the arene, from Me to the bulky t-Bu group (1a, 1c−1e), were
well tolerated, furnishing the corresponding products in 76−96%
yields (entries 2−5). Interestingly, a trend was observed where
selectivity for para-substitution increased as the bulk of the
substituent increases. For simple disubstituted arenes such as o-,
m-, and p-xylene, these reactions performed well to provide the
desired cyanated products 3f−h under both conditions A and B
(75−95% yields) (entries 6−8). The cyanation in products 3f−g
occurred primarily at the less hindered and electron-rich
positions. p-Xylene 1h exclusively provided 2,5-dimethylbenzo-
nitrile 3h in high yield (entry 8). The electron-withdrawing fluoro
substituent on the aryl ring did not influence the reactivity to give
3i in 56% and 81% yields under system A and B, respectively
(entry 9). Besides phenyl rings, fused aromatic rings such as
phenanthrene 1j could also smoothly transfer to 1-naphthonitrile
3j in 74% and 82% yields under conditions A and B (entry 10).
The reactions of analogous methyl substituted phenanthrenes
1k−1l produced the corresponding cyanated products 3k and 3l
ingoodyieldswithahighlevelofregioselectivity (entries11−12).
Encouraged by the positive results of simple arenes, we next
focused on the scope of functional groups on aromatic rings
(Scheme 2). Note that arenes (4a−e) with an electron-donating
OMe group resulted in fast iodination within 30 min and
efficiently furnished the cyanated products 5a−e with predom-
inant para selectivity to the OMe group in excellent yields (85−
97%). In particular, we found that 4-cyano-2,6-dimethylphenol
5ee deprotected from 5e (5ee: 83% yield) is a valuable
intermediate that can be used for the preparation of
pharmaceutical etravirine for the treatment of HIV.13 Unexpect-
We chose readily available toluene as a test substrate. To
identify conditions for this transformation, a series of Lewis acids,
copper catalysts, and oxidants were examined (Table 1). First, we
found that no product was formed under Cu(NO3)2·3H2O/
(Me3Si)2 catalytic conditions(Table1, entry1), whileacetonitrile
C−CN cleavage successfully proceeded to release the CN− anion
with this system,11 showing acetonitrile is an effective cyano
source in the presence of (Me3Si)2. Accordingly, various Lewis
acidswerescreened forthecyanationof tolueneinthepresence of
an iodinating agent. Pleasingly, Yb(OTf)3 showed good reactivity
forthesequentialiodination/cyanationusingNISasaniodinating
source, giving the desired cyanated product 3a in 94% yield with
1:1.1 regioselectivity for ortho and para substitution (entry 7).
Other M(OTf)3 salts (M = Bi, Sc, Fe) can efficiently promote the
iodination of toluene, whereas these triflate salts had an inferior
effect on the cyanation process (Table 1, entries 4−6). It is worth
notingthattheuseofCu(ClO)4 (10mol%)orCu(OTf)2 (10mol
%) as a Lewis acid facilitated not only the iodination but also the
cyanation reaction to provide 3a in 91% and 83% yields,
respectively (Table 1, entries 8−9). No other Cu catalysts were
required in the cyanation step, making this system simple and
efficient. These results mean that Cu(ClO4)2 and Cu(OTf)2
could efficiently serve three roles: a Lewis acid for iodination, a
catalystforC−CNbondcleavage, andapromoter fornewC−CN
bond formation. By varying oxidants (entries 10−13), we found
that TEMPO is the best oxidant for this sequential trans-
formation. Ag2CO3, a good oxidant in previous reports,6e,12 gave
3a in moderate yield (entry 10). In the absence of (Me3Si)2, the
yield of 3a dramatically decreased to 29%, indicating disilane is
still important for acetonitrile C−CN bond scission (Table 1,
entry 15). Consequently, the optimal conditions for this
B
DOI: 10.1021/acs.orglett.5b00886
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Scope of Simple Arenes in the Sequential Iodination/
Cyanation Using Acetonitrile as Cyano Unit
Scheme 2. Scope of Substrates
a
a
b
Isolated yield. s1 means the first step; s2 means the second step. A
c
5:1 ratio of 4-methoxybenzonitrile and 2-methoxybenzonitrile. Trace
3-methoxy-2,4-dimethylbenzonitrile was isolated. KOH (1 equiv) was
d
added into the first step.
Table 3. Using 6 instead of TEMPO for Cyanation
entry
6 instead of TEMPO
2 equiv of 6 under 02
time
3a (%)
1
2
3
41 h
2 d
90
62
38
2 equiv of 6 under N2
2 equiv of 6 using 1,4-dioxane as sol. under O2
2 d
proceeded. However, chlorobenzene (4l) could undergo
cyanation albeit with a 36% yield.
a
Conditions A: the first setp: substrate 1 (0.5 mmol), Cu(ClO4)2·
6H2O (15−20 mol %), NIS (1.05 equiv), CH3CN (1.2 mL), O2, 150
°C; the second step: 1,10-phen (15−20 mol %), TEMPO (2 equiv),
(Me3Si)2 (1 equiv), 150 °C, O2. Conditions B: the first step: Yb(OTf)3
(10 mol %), NIS (1.05 equiv), CH3CN (1.2 mL), O2, 150 °C; the
second step: Cu(NO3)2·3H2O (15−20 mol %), 1,10-phen (15−20
The Cu/TEMPO system efficiently allowed access to the
catalytic cyanation of simple arenes via a tandem process. For the
catalytic cyanation, TEMPO acted as an important oxidant.
Fortunately, a key intermediate, TEMPO−CH2CN 6, was
observed by GC during the course of reaction, and this species
was confirmed by NMR and HRMS. Interestingly, when
TEMPO−CH2CN 6 was used in place of TEMPO under an
oxygen or nitrogen atmosphere, the reaction of 1-iodo-4-
methylbenzene p-2a with acetonitrile still proceeded to give the
cyanated product p-3a in 90% and 62% yields, respectively (Table
3, entries 1 and 2). Next, an experiment was designed to test the
hypothesis that 6 is the active cyanating agent: the reaction was
carried out in 1,4-dioxane as solvent using 6 instead of TEMPO
(Table 3, entry 3). Incredibly, a 38% yield of cyanated product p-
3a was obtained. These studies support the proposal that
intermediate 6 is indeed the direct supplier of the “CN” unit and
oxidant for catalytic cyanation, and oxygen most likely enables
formation of TEMPO−CH2CN 6. Consequently, a tentative
mechanismforCu-catalyzedsequentialiodination/cyanation was
outlined in Scheme 3. TEMPO−CH2CN 6 might be formed by
the reaction of TEMPO and acetonitrile in the presence of a Cu
species and oxygen, which acts as a “CN” supplier by C−CN
cleavage promoted by (Me3Si)2 and the Cu catalyst. The in situ
generated cyanide anion would subsequently take part in the
b
mol %), TEMPO (2 equiv), (Me3Si)2 (1 equiv), 150 °C, O2. Isolated
yield.
edly, the iodination reaction for more electron-rich arenes (4f−g)
containing two or three OMe groups worked sluggishly under
either system A orB. To solvethis issue, we added KOH(1 equiv)
to the first step to promote the iodination process and observed
the sequential iodination/cyanation reactions proceeded
smoothly, producing the cyanated products 5f−g in 60−90%
yields. The electron-withdrawing COOMe installed in substrate
4h was accommodated and resulted in a moderate yield. To our
delight,notonlytheprotectedAcNH−(4k)butalsothefreeNH2
group in substrate 4i−j was compatible under the standard
conditions, giving the desired products 5i−k in moderate to high
yields. In Hartwig’s report, however, various protected anilines
could not form the corresponding products.7a On the other hand,
the reactions of electron-deficient arenes such as benzonitrile,
benzaldehyde, or methyl benzoate did not take place under the
standard conditions because the initial iodination hardly
C
DOI: 10.1021/acs.orglett.5b00886
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 3. Tentative Reaction Mechanism
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Insummary,wehavedesignedandexecutedanewapproachfor
the Cu-catalyzed cyanation of simple arenes using acetonitriles as
a cyano source via C−CN bond cleavage. This C−H
functionalization strategy involves a sequential iodination/
cyanation process to furnish the corresponding aromatic nitriles
in good to excellent yields. Moreover, we found a highly efficient
Cu/TEMPO system for acetonitrile C−CN bond cleavage.
TEMPO plays a significant role in promoting this cyanation
transformation: (1) TEMPO, a cheap oxidant, allows the reaction
to be catalytic in copper; (2) TEMPOCH2CN is formed in situ
and acts as the active cyanating agent. This system represents a
newavenuetobreaking the relativelyinert C−CN bond. Notably,
in system A, Cu(ClO4)2 is required alone and it serves three roles:
a Lewis acid for initial iodination, a catalyst for C−CN bond
cleavage, and a promoter for new C−CN bond formation. The
development of new cyanation reactions with acetonitrile is in
progress in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
All characterization data, including spectra and GC traces. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b00886.
(7)(a)Liskey, C. W.;Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
11389. (b) Shu, Z.; Ji, W.; Wang, X.; Zhou, Y.; Zhang, Y.; Wang, J. Angew.
Chem., Int. Ed. 2014, 53, 2186.
AUTHOR INFORMATION
Corresponding Author
■
́
(8) For recentreviews forC−CNcleavage, see: (a) Najera, C.;Sansano,
*E-mail: shenzengming@sjtu.edu.cn.
Author Contributions
†Y.Z. and M.Z. contributed equally.
Notes
J. M. Angew. Chem., Int. Ed. 2009, 48, 2452. (b) Kou, X.; Fan, J.; Tong, X.;
Shen, Z. Chin. J. Org. Chem. 2013, 33, 1407 and references therein.
(c) Wen, Q.; Lu, P.; Wang, Y. RSC Adv. 2014, 4, 47806. (d) Luo, F.-H.;
Chu, C.-I.; Cheng, C.-H. Organometallics 1998, 17, 1025. (e) Jiang, Z.;
Huang, Q.; Chen, S.; Long, L.;Zhou, X. Adv. Synth. Catal. 2012, 354, 589.
(f) Xu, W.; Xu, Q.; Li, J. Org. Chem. Front. 2015, 2, 231.
The authors declare no competing financial interest.
(9)Kou,X.;Zhao,M.;Qiao,X.;Zhu,Y.;Tong,X.;Shen,Z. Chem.Eur.
ACKNOWLEDGMENTS
J. 2013, 19, 16880 and references therein.
■
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(11) Cyanide testing paper indicated the cyanide anion is formed in the
reaction. See the Supporting Information for details.
(12) (a) Song, R.-J.; Wu, J.-C.; Liu, Y.; Deng, G.-B.; Wu, C.-Y.; Wei, W.-
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This work was supported by the NSFC (21272001), Shanghai
Education Committee (13ZZ014). We thank Prof. Vy M. Dong
(UCI) and Dr. Peter K. Dornan (CIT) for helpful discussions.
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DOI: 10.1021/acs.orglett.5b00886
Org. Lett. XXXX, XXX, XXX−XXX