Tetrahedron Letters 55 (2014) 12711280

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Tetrahedron Letters
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Digest Paper

Copper-mediated cyanation reactions

Qiaodong Wen, Jisong Jin, Lianpeng Zhang, Yan Luo, Ping Lu , Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, China

a r t i c l e i n f o a b s t r a c t

Article history: Aryl nitriles can be efciently synthesized through transition-metal-mediated cyanation of aryl halides,
Received 29 October 2013 arenes, aryl boronic acids, and so on. Among those most commonly used transition-metals, copper cata-
Revised 30 December 2013 lysts are surely much more inexpensive and easier to handle, compared to any other metal catalysts. Con-
Accepted 8 January 2014
sidering the high-efciency of copper catalysts in the activation of CX, CH, and CB bond as well as in
Available online 15 January 2014
the formation of CCN bond, this Letter summarizes various copper-mediated cyanations based on the
different kinds of cyanide reagents, such as metal cyanides, potassium hexacyanoferrate(II), acetone cya-
Keywords:
nohydrins, DDQ, AIBN, benzyl cyanide, malononitrile, nitromethane, and DMF. Our groups recent contri-
Aryl nitriles
Copper catalysis
butions to this area are also demonstrated.
Cyanations 2014 Elsevier Ltd. All rights reserved.
Aryl halides
Arenes

Introduction
Aryl nitriles are an important class of organic compounds. They
are present as a key motif of natural products, pharmaceuticals,
agrochemicals, dyes, and herbicides.1 Moreover, aryl nitriles are
well-known as versatile intermediates for the preparation of
amines, amidines, amides, aldehydes, carboxylic acids, and tetra-
zoles.2 Take the synthesis of losartan, which is an angiotensin II
receptor antagonist, for example.3 Losartan is a tetrazole derivative
like many other sartans drugs. The part of tetrazole structure can
be synthesized from aryl nitrile and sodium azide. Hence, 40 -
methyl-[1,10 -biphenyl]-2-carbonitrile is the key precursor in this
conversion (Scheme 1).
Undoubtedly, the preparation of aryl nitriles shows great
importance in organic synthesis. Among these preparation pro-
cesses, the most popular synthetic strategies are the classical
Rosenmund-von Braun reaction and Sandmeyer reaction, starting
from aryl halides and aryl diazonium salts, respectively
(Scheme 2).4 However, both of them utilize stoichiometric
amounts of CuCN as cyanating reagent under relatively high tem-
perature, which indicates equal amounts of metal waste and
pollution.
The transition metal-mediated cyanation reactions have been
more and more attractive in these years, among which palladium
and copper are most commonly involved.5 Researchers have estab-
lished lots of cyanation methods based on these metal catalysts
and also disclosed a series of cyanating reagents.6,7 While compar-
ing to Cu-catalyzed cyanation reactions, Pd-catalyzed cyanation
Corresponding authors. Tel./fax: +86 571 87952543.
E-mail addresses: pinglu@zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. Wang).
reactions suffer from several drawbacks, in spite of their high ef-
ciencies. The most obvious disadvantage is that many palladium
catalysts are relatively expensive, as are their corresponding li-
gands. Moreover, in some cyanation reactions, excess dissociative
cyanide anion (CN) would poison the palladium catalyst and re-
strain the reactions, owing to the high afnity of CN to
palladium.8
Given the unfavorable factors mentioned above, copper cata-
lysts show several distinctive advantages in cyanation reactions.
Cheap and commercially available copper sources make various
cyanations possible under much milder reaction conditions,
including copper-mediated cyanation of aryl halides, arenes, as
well as aryl boronic acids. Most of them show great efciency in
each reaction. Although several recent reviews about cyanation
reactions mainly discussed palladium-catalyzed cyanation of aryl
halides,5b,c synthesis of aryl nitriles using nonmetallic cyano-
sources,5d and transition-metal-catalyzed CCN bonds couplings,5e
there are no specic reviews focused on the copper-mediated cya-
nation reactions. Herein, we describe recent developments in cop-
per-mediated cyanations, classied by the cyanide source.
Metal cyanides
Metal cyanide (MCN) has been commonly used in direct cyana-
tion reactions, such as KCN, NaCN, CuCN, Zn(CN)2, AgCN, TMSCN,
etc. A serious issue in common with all is their high toxicity. How-
ever, such drawback has not limited their wide applications in
transition metal-mediated cyanation reactions. Besides palla-
dium-catalyzed cyanations with these cyanides, copper-catalyzed
cyanations are also universal.

0040-4039/$ - see front matter 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.032
1272 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280

Cl Table 1
Me N Cyanation of aryl bromides with NaCN
OH
N N N 10 mol% CuI, 20 mol% KI
Me N NH 1.0 equiv ligand 1
CN Ar Br Ar CN Me(H)N N(H)Me
1.2 equiv NaCN
Toluene, 110-130 o C, 24 h 1

Losartan CN NC
MeO CN
0 0
Scheme 1. Preparation of Losartan from 4 -methyl-[1,1 -biphenyl]-2-carbonitrile.
MeO
91% (110 o C) 90% (130 o C) 98% (130 o C)
CN
CN OEt H
CuCN N Me
Ar X Ar CN (Rosenmund-von Braun reaction)
150-250 o C HO O
X = I, Br NC O
Me
CuCN 80% (110 o C, 20 h) 70% (130 o C) 70% (130 o C)
Ar N 2 +X - o
Ar CN (Sandmeyer reaction)
60-100 C

Scheme 2. Classical Rosenmund-von Braun reaction and Sandmeyer reaction.

Table 2
Cyanation of heteroaryl bromides with NaCN
In 2003, Buchwald demonstrated copper-catalyzed cyanation of
10 mol% CuI, 20 mol% KI
aryl bromides via a halide exchange (Scheme 3).9 They disclosed 1.0 equiv ligand 1
that CuI worked much better than CuBr or CuCN in the cyanation Het Br
1.2 equiv NaCN
Het CN Me(H)N N(H)Me
of aryl bromides. The result was explained as copper-catalyzed Toluene, 110 o C, 24 h 1
conversion of aryl bromide into aryl iodide, which was more reac-
NC CN
tive in cyanation reaction. Thus, by addition of 20 mol % KI to the CN
Ph N CN
reaction, the efciency of this cyanation reaction was improved. N
S
N
H N
Moreover, addition of ligand seemed to be very benecial for this 95% 74% 78% 80%
cyanation. This reaction had a wide substrate scope with a great
tolerance of functional groups (Table 1). And various heteroaryl
bromides also preformed excellently via this cyanation, including
some indoles, benzothiophenes, quinolines, and pyrazoles
(Table 2).
Table 3
In 2010, Daugulis and co-workers reported a copper-catalyzed
CuCN-catalyzed cyanation with NaCN
cyanation of heterocycles using copper cyanide as catalyst, NaCN CuCN (10 mol%)
as the cyanide source, and iodine as an oxidant (Table 3).10 The phenanthroline (20 mol%)
Ar H Ar CN
cyanation was thought to be a stepwise reaction. Benzothiazole I 2 , NaCN, tBuOLi
was rstly iodinated to 2-iodobenzothiazole under the help of t- dioxane/m-xylene, 110 o C
BuOLi, followed by a copper-catalyzed cyanation with NaCN as Me Ph
cyanating reagent. In relation to the substrate scope, many hetero- O S N
CN CN N N
CN CN
cycles were cyanated smoothly in good yields. Furthermore, by N N N N
minor modications of general conditions, N-methylindole and 63% 72% 51% 71%
azulene could be cyanated via this method. CN CN
F
CuCN can function as both copper catalyst and cyanating
reagent.11 One classical example is the Rosenmund-von Braun Ph N CN
N CN N
O
reaction, which is both catalyzed and cyanated by CuCN at a high Me
temperature (150250 C). As a modication of Rosenmund-von 71% 53% 90% 36%
Braun reaction, Ding and co-workers reported L-proline-promoted
CuCN-mediated cyanation of aryl halides in 2008 (Table 4).12
Employing L-proline as ligand, the reaction occurred at a lower
temperature (80120 C) than in its absence. Table 4
Cheng and co-workers also reported a copper-mediated cyana- Cyanation of aryl halides with CuCN
tion with CuCN in the cyanation of boronic acids (Table 5).13 Here, 2.0 equiv CuCN
1.0 equiv L-proline CN
X
CuCN activated the CB bond and served as a cyanide source. Reac- DMF
R R
tions were conducted under much milder reaction conditions, o
X = I, 80 C, 24 h
which were run in DMF solution at 60 C for 2 h. Various boronic X = Br, 120 o C, 45 h

acids, with different functional groups, afforded the corresponding CN CN CN

aryl nitriles in good yields.
In the same report,13 TMSCN, AgCN, and Zn(CN)2 were also MeO O2 N
examined as cyanide sources (Table 6). 0.55 equiv of CuI was X = I, 98% X = I, 92% X = I, 90%
X = Br, 81% X = Br, 56% X = Br, 76%

CN
CN CN
MCN MI
MI
Ar Br Ar I Ar CN MeO N
MBr HO
X = Br, 85% X = Br, 87% X = Br, 78%
Scheme 3. Halide exchange in cyanation.
 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280 1273

Table 5 Table 9
Cyanation of aryl boronic acids with CuCN Cyanation of aryl bromides with K4[Fe(CN)6]
K2 CO 3 (3.0 equiv) Cu(BF4) 26H2 O (0.1 equiv)
R B(OH) 2 CuCN R CN KI (0.2 equiv)
DMF, 60 o C, air, 2 h Na 2CO3 (0.2 equiv)
1.5 equiv 1.0 equiv K4 [Fe(CN) 6]
Br CN
R DMEDA (1.0 equiv) R
CN 0.2 equiv
DMAc, 140 oC, 16 h
MeO CN Cl CN DMEDA = N,N-dimethyl ethylenediamine
CN MeO CN CN CN
95% 96% 79%
H MeO Me MeO MeO
CN CN CN
85% 91% 85% 96%
O O
CN CN CN CN
74% 96% 93%
O2 N
F3C Ac S N
HO CN MeS CN CN
73% 61% 90% 67%
86% 83% 42%

Table 10
Table 6 Cyanation of heteroaryl bromides with K4[Fe(CN)6]
Cyanation of aryl boronic acids with TMSCN, AgCN, and Zn(CN)2
CuI (10 mol%)
CuI (0.55 equiv) K4 [Fe(CN)6 ] (20 mol%)
K2 CO3 (3.0 equiv) Het Br Het CN
R B(OH) 2 [CN] source R CN A: 1-n-butylimidazole (200 mol%)
DMF, 60 o C, air, 2 h toluene (2 mL), 160 oC
1.25 equiv 1.0 equiv
or B: 1-methylimidazole (2 mL), 140 o C
CN
CN CN CN NC F
Cl CN CN

N H 2N N H 2N N
TMS-CN: 90% TMS-CN: 80% TMS-CN: 61% O
Zn(CN)2 : 58% A, 82% A, 49% B, 53% B, 93%
H
AgCN: 62% CN HO CN CN CN
MeO O N
CN TMS-CN: 73% TMS-CN: 76% CN CN
S N N S
O H
TMS-CN: 77% MeS CN Ac CN B, 67% A, 68% B, 58% B, >99%
Zn(CN)2 : 52%
AgCN: 67% TMS-CN: 84% TMS-CN: 80%

needed as catalyst under the same reaction conditions. A variety of

substrates afforded the corresponding aryl nitriles in good yields.
Table 7
Cyanation of aryl boronic acids with Zn(CN)2 Hartwig and co-workers reported a Cu(II)-mediated oxidative
Cu(NO 3) 23H2 O (2 equiv) cyanation of aryl bronic esters/acids using Zn(CN)2 as cyanide
B(OH) 2 CN
Zn(CN) 2 (3 equiv), CsF (1 equiv) source (Table 7).14 Reactions were conducted in aqueous methanol
R R
MeOH/H2 O (2.5:1), 80 C, 2 h o solution at 80 C for 2 h. Arylboronic acids, with chloro, bromo, or
iodo substituents, produced corresponding aryl nitriles in moder-
CN CN Cl CN
ate yields without the detection of dehalogenation. If iridium-cat-
Me MeO alyzed CH borylation was added in the sequence, a one-pot
Me Me Cl operational process was realized (Table 8). Because iridium-cata-
68% 70% 69% lyzed CH borylation regioselectively occurred on the meta posi-
O2 N CN CN CN tion of 1,3-disubstituted arenes, this methodology provided 1-
cyano-3,5-disubstituted arene products with excellent
X Br N
X = Br, 58% regioselectivity.
67% 61%
X = I, 62%

Potassium hexacyanoferrate(II)

Potassium hexacyanoferrate(II) has been widely introduced as a

Table 8 low toxic cyanating agent in many cyanation reactions, which was
Iridium-catalyzed borylation and copper-mediated cyanation with Zn(CN)2 rstly reported by Bellers group in 2004 and used in the palla-
1. [Ir(cod)OMe] 2 (0.1 mol %)
dium-catalyzed cyanation of aryl halides.6n In opposite to its initial
dtbpy (0.2 mol %), THF, 80 oC, 18 h
O O evaporation of volatile materials
targeting at palladium, its application in copper-catalyzed cyana-
Ar H B B Ar CN
tion reactions has been largely described.
O O 2. Cu(NO3 )2 3H 2O (2 equiv)
Zn(CN)2 (3 equiv), CsF (1 equiv) In 2005, Beller and co-workers developed a Cu-catalyzed syn-
B 2 pin 2 MeOH/H 2O (2.5:1), 100 o C, 3-6 h thesis of aryl nitriles from aryl bromides and K4[Fe(CN)6]
dtbpy = di-ter t-butylbipyridine (Table 9).15 After screening the reaction conditions, Cu(BF4)26H2O
and N,N-dimethyl ethylenediamine were selected as the best cata-
CN CN CN CN CN
lyst and ligand, respectively. This procedure showed a wide sub-
strate scope for aryl and heteroaryl halides with good yields.
Me Me Me OMe Me Cl Me Br Me Br In 2007, Beller and co-workers discovered a novel copper
60% 55% 63% 67% 57% catalyst system containing imidazole ligands and applied it for
1274 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280

Table 11 Table 13
Cyanation of aryl bromides and chlorides with K4[Fe(CN)6] Cyanation of aryl bromides with acetone cyanohydrin
Cu(OAc) 2H 2 O (30 mol%) a) CuI (10 mol%), (1) (20 mol%)
EDA (90 mol%) R KI (50 mol%), DMF, 110 oC, 6 h R
Ar Br K4 [Fe(CN) 6] Ar CN Br CN
Na 2CO3 (20 mol%) b) (CH 3) 2C(OH)CN (1.1 equiv)
0.2 equiv
KI (50 mol %), NMP, 155 o C NBu 3 (1.2 equiv), 110 oC, 60 h

CN (1): 1,10-phenanthroline
CN CN CN
CN CN CN CN
Ph O 2N tBu
N
F3 C H2 N
85% (8 h) 98% (8 h) 92% (5 h) 90% (32 h)
88% 87% 98% 70%
NO2 CN CN
MeO CN CN
CN CN CN NO2
Me Ac
Cl
N O 2N NO2 Ac CN 80% 96% 79% 86%
S
X = Cl X = Cl
65% (8 h) 91% (8 h) 72% (23 h) 57% (36 h)

CN-containing cyanide sources

Table 12
Cyanation of alkoxy-substituted benzenes with K3[Fe(CN)6] Acetone cyanohydrin
I 2 (0.5 equiv)
Cu(NO3 )2 3H 2O (0.8 equiv) Acetone cyanohydrin equilibrates with acetone and hydrogen
Ar H + K 3[Fe(CN) 6] Ar CN
CH3 CN, 180 o C, 35 h cyanide (HCN) in solution. In this equilibrium, the formed HCN
0.5 equiv
can be a potential cyanide source (Scheme 4). It is considered to
be inexpensive and soluble cyanide source, and has been widely
MeO CN EtO CN BnO CN
used in cyanation reactions. Among these cyanations with acetone
87% 73% 69% cyanohydrins, copper-catalyzed cyanation has been investigated.
CN Taillefer and co-workers rst used acetone cyanohydrin in cop-
BnO CN n-BuO CN per-catalyzed cyanation of aryl iodides and bromides in 2005
Me
BnO OBn
Cl (Table 13).20 In this reaction, a similar halide exchange was men-
71%
Me
36% 51%
MeO
tioned as an accelerative step for the cyanation of aryl bromides.
However, the deactivation of the catalyst occurred when the con-
n-BuO CN EtO CN MeO centration of dissolved cyanide ions became too large, which nal-
Me Me MeO CN
ly prevented the emergence of halide exchange. To overcome this
72% 23% 71% obstacle, they tried to decrease the addition rate of cyanation re-
agent. Here 1,10-phenanthroline was used as a ligand and tributyl-
amine as a base. Good yields of aryl nitriles were obtained from
both electron-rich and electron-poor aryl bromides.
O
In 2011, Beller and co-workers also developed a copper-cata-
HO CN base
HCN lyzed cyanation of aryl and heteroaryl bromides with acetone cya-
nohydrin (Table 14).21 By screening the reaction conditions, the
Scheme 4. Equilibrium of acetone cyanohydrins. combination of CuI and 1-n-butylimidazole was found to be the
best catalyst system. In order to overcome the deactivation of cop-
per catalyst, acetone cyanohydrin was gradually added by syringe
the cyanation of heteroaryl bromides (Table 10).16 Many sub- pump in a controlled rate. By adjusting the rate of addition, aryl
strates, like nitrogen-, oxygen-, and sulfur-containing bromohet- and heteroaryl bromides reacted smoothly with acetone
erocycles gave the corresponding aryl nitriles in good yields. cyanohydrin.
Later, several similar works were reported by Bellers group, apply-
ing this copper catalyst system in the cyanation of different kinds
of aromatic and heteroaromatic bromides.17
In 2009, Wang and co-workers also described an ethylenedia- Table 14
mine/Cu(OAc)2H2O/KI catalyst system in the cyanation of aryl bro- Cyanation of aryl and heteroaryl bromides with acetone cyanohydrin
mides and some aryl chlorides with K4[Fe(CN)6] (Table 11).18 This CuI (0.05 or 0.1 equiv)
1-n-butylimidazole (0.5 or 1.0 equiv)
reaction was accelerated by addition of KI as well, which was prob- Br
HO CN Na2 CO 3 (1.1 equiv) CN
ably consistent with a mechanism featuring halogen exchange like R R
o-xylene, 150 oC
Buchwalds report.9 0.08 or 0.1 mL/h 21 h or 26 h
In 2012, Wang and co-workers reported a selective para-cyana- CN
tion of alkoxy-substituted benzenes mediated by copper(II) nitrate CN CN CN
and iodine, employing K3[Fe(CN)6] as the cyanation reagent.19
NC O2 N Ph N CN
Most substrates were cyanated with high regioselectivities and in 66% 91%
75%, R = 4-CN 85% 69%
good yields under the standard reaction conditions (Table 12).
The reaction consumed 0.5 equiv of K3[Fe(CN)6] and 0.5 equiv of io- CN CN
CN CN CN
dine which worked for the iodination on the phenyl ring of alkoxy-
substituted benzenes. Thus, a sequential mechanism, including the N OMe Me F3 C H2 N N
iodination of substrates and the copper-mediated cyanations of the 60% 77% 60% 71% 71%

in situ formed aryl iodides, was presented.

 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280 1275

Table 15 Table 17
Cyanation of arylboronic acids with DDQ Cyanation of 2-phenylprydines with benzyl cyanide
O
Cu(OTf) 2 (0.1 equiv) CN
B(OH)2 Cl CN CN
Ag 2CO3 (1.0 equiv) CuBr (1.2 equiv)
R R N N
R R
Cl CN K2CO3 (1.5 equiv) DMF, air
DMF, 100 o C, 20 h CN
O 130o C, 18 h
1.0 equiv 1.0 equiv
R = H, 83% Me
CN OMe CN CN R = OMe, 68% Me
N N N
R = Cl, 61%
R = F, 73%
MeO CN MeS R CN CN CN
R = CF3 , 57%
87% 71% 74% 72% 61% 31%
Me CN
CN
CN CN CN 3
N N
Cl OHC NC 1 N
95%, R = 4-CN CN CN CN 1-CN+3-CN, 63%
72% 70% 91%
59% 66% 1,3-di-CN, 21%
N
N N Me
N N N N

Table 16 CN CN CN CN
42% 43% 39% 51%
Cyanation of 2-phenylpyridine with AIBN

R' R'
Cu(OAc) 2 (0.55 equiv)
N AIBN N
R R
O2 , MeCN
5.0 equiv CN
135 oC, 48 h
R= H, 74%
MeO 3 N
R= Me, 67% 4 Ph CN SET Cu(II) N
N N N
t
R= Bu, 63% 3-OMe, 92% N
Cu(I) Cu(I)
R CN R= OMe, 64% CN 4-OMe, 86% CN
41% O2 Cu(II)
R' OCN -
(1.1 equiv [Cu]) PhCHO A Cu(II)
Me OH
[O]
R= CF3 , 31% CN - B
Ph CN
N R= CN, 44% N N
R= Cl, 58% O2
R' = Me, 72% [O]
R CN R= Br, 52% CN CN R' = Ph, 68%
N Cu(I)
60% O PhCOOH Cu(I)
CN
Ph CN N N
Cu(I)
H
CN
C CN

AIBN O2 -O2 -acetone D

OO CN O CN CN
r
aj o
m

B C Scheme 6. Possible mechanism for the cyanation with benzyl cyanide.

CN
Cu(II)
min

A Me
-e AcO -acetone
or

CN NC OR CN
+e Table 18
Me
Cu (I) D R = Ac or H
Cyanation of aryl halides with benzyl cyanide
X CN
Cu2 O (1.0 equiv)
Scheme 5. Possible mechanism for the formation of cyanide unit from AIBN. R PhCH 2CN R
DMF, air, 130 o C, 12 h

CN CN CN CN
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
MeO AcHN Ph O 2N
X = I, 92% X = I, 95% X = I, 96% X = I, 80%
Interestingly, Cheng and co-workers described copper-cata- X = Br, 41% X = Br, 57%
X = Br, 66%
lyzed cyanation of arylboronic acids, employing DDQ as the cya- CN CN
nide source (Table 15).22 According to the condition-controlled O
CN Me
experiments, they conrmed that the CN unit came from DDQ. Ph
However, the mechanism for the CN transfer was unknown. X = I, 85% X = I, 86% X = I, 92%
X = Br, 40% X = Br, 50% X = Br, 50%

2,20 -Azobisisobutyronitrile (AIBN)

Very recently, Han and co-workers reported a copper-mediated
cyanation of 2-phenylpyridine with a new cyanating agent, which
is AIBN (Table 16).23 They provided a novel protocol for aryl CH
cyanation with a free radical CN source, which was different from
commonly reported CN anion or CN cation sources. Good yields
were obtained with various 2-aryl pyridines. In the mechanistic
study, acetone was detected as the byproduct of reacted AIBN.
Based on the early reports and 18O-labeled experiments, it was
conrmed that the formation of acetone was mainly from the reac-
tion of O2 and AIBN, with a minor amount formed from the inter-
reaction of copper salt Cu(OAc)2 and AIBN. This meant that the
function of Cu(OAc)2 in this reaction was mainly a catalyst. In fact,
0.55 equiv of Cu(OAc)2 could also execute the reaction albeit with a
little longer time (48 h). With some additional experiments, a pos-
sible mechanism was then proposed (Scheme 5).
Benzyl cyanide
In 2012, our group found that the CN unit could be transferred
from benzyl cyanide to the arene ring through Pd-catalyzed activa-
tion of CCN bond.6y Thus benzyl cyanide was rstly disclosed as a
cyanide source. After further investigation, benzyl cyanide was
1276 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280

Table 19
Cyanation of indoles with benzyl cyanide t-BuONa, KF
NC CN Cu(OAc) 2
CN
N N DMF, 120 o C N N
CuI (1.2 equiv) 1 mmol 0.25 mmol 0.5 mmol 48 h Cu
R1 R3 R1 R3 NC CN
PhCH 2CN
N DMF, air, 100 oC, 34 h N [Cu(phen)(CN)2 ]
R2 R2

CN Scheme 7. The immediate in the cyanation with malononitrile.

CN CN CN
Me O2N
Ph
N N N N
H H H H Table 22
80% 53% 93% 48% Cyanation of aryl halides with acetonitrile
CN CN CN CN Cu(OAc)2 (20-30 mol%)
Me O2N X Ph3 PO (40-60 mol%) CN
Me R Me CN R
N N Ag2 O (100 mol%)
N N
Me Me Me Et air, 125 oC, 72 h
86% 86% 96% 65%
OH

CN Me CN MeO CN CN

X = I, 84% X = I, 78% X = I, 78%; X = I, 62%

Table 20 X = Br, 33% CN
Cyanation of aryl boronic acids with benzyl cyanide
CuI (1.0 equiv) Cl CN O2N CN NC CN
B(OH) 2 TBHP (aq. 2.0 equiv) CN
R R = 4-CN
PhCH2 CN R X = I, 94% X = I, 68%; X = I, 72%
DMAc, air, 130 o C, 20 h X = I, 88%;
X = Br, 58%
X = Br, 75% CN
CN CN CN Ph Ac CN N CN
S CN Ph
Ph MeO HO CN X = I, 60% X = I, 89% X = I, 88% X = Br, 62%
82% 72% 72% 76%
CN
CN
CN
Cl O 2N CN X
X = O, 42% [Cu]
76% 74% 62% X = S, 31%
L

CuILn OAc Ar X [Ag]

Ar CN
[Ag]X
Table 21
Cyanation of aryl iodides with malononitrile
Cu(OAc)2 (10 mol%) Ar Ar CuIILn OAc
I CN Cu IIILn OAc
1,10-phenanthroline (20 mol%)
R R CN
NC CN
t-BuONa, KF
DMF, 120 oC, 18 h Me C N
HCOOH AgX Me
C N
CN R = H, 73% CN
L
R= Me, 73% CN R = CH3 , 68% NC O2 /Ag2O L Ar CuIILn-1 OAc
R= OMe, 86% R = OMe, 75%
R= NH 2, 79% R = NH , 60% L = Ph 3PO
R R = NO2 , 47% N
R= NO 2, 49% 2
R R= Cl, 52% 61% 54% Scheme 8. Possible mechanism for the cyanation with acetonitrile.

found to be a safe and operational benign cyanide surrogate in cop-
per-catalyzed cyanation of 2-phenylpyridines (Table 17).24 Several
by-products, like benzaldehyde, benzoic acid, N,N-dimethylbenza-
mide, and cis-/trans-2,3-diphenylfumaronitrile were also detected,
accompanied by the detection of cyanide anion in reaction mix-
ture. These facts conrmed that an aerobic CH oxidation of benzyl
cyanide assisted by copper salt occurred in this reaction. Moreover,
a SET process was proposed in the cyanation step (Scheme 6).
With the same cyanide source, aryl halides (Table 18),25 indoles
(Table 19),26 and aryl boronic acids (Table 20)27 were smoothly
changed to the corresponding aryl nitriles in the presence of cop-
per. It is worth mentioning that both the cyanation of indoles
and aryl boronic acids were undertaken with an iodination before-
hand, followed by a copper-catalyzed cyanation with benzyl cya-
nide. For the cyanation of aryl boronic acids, tert-butyl
hydroperoxide (TBHP) was selected as an assistant oxidant in the
CH oxidation of benzyl cyanide. Similarly, cyanation of indoles
and derivatives with benzyl cyanide was also reported by Kwong
and co-workers.28
Malononitrile
In 2012, Zhou and co-workers demonstrated that malononitrile
could be used as a cyanide source in the copper-catalyzed cyana-
tion of aryl iodides (Table 21).29 By screening the reaction condi-
tions, Cu(OAc)2 and 1,10-phenanthroline were effective for the
cyanation. In the mechanistic study, an intermediate, which was
further conrmed to be [Cu(phen)(CN)2], was isolated by conduct-
ing the reaction without aryl iodides under the standard conditions
(Scheme 7). Excellent yield was obtained when [Cu(phen)(CN)2]
reacted directly with the aryl iodide whether in the presence of
KF or not. Thus the procedure seemed to involve the copper-cata-
lyzed CCN bond cleavage of malononitrile assisted by KF, followed
by a copper-catalyzed cyanation of aryl iodides with the in situ
formed coppercyano complex.
Acetonitrile
Acetonitrile was rst reported as a cyanide source for palla-
dium-catalyzed cyanation of aryl halide by Chengs group.6v Later,
 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280 1277

Table 23 (Me3 Si)2

C2-cyanation of indoles and pyrroles with acetonitrile O2 CH 3CN NuH
[CuII]
R R
NuCH 3

X X Cu I
N Cu(OAc)2 (0.5 equiv) N
N
N AgOAc (1.0 equiv) N Cu IICN
CH 3CN CN
O2 , 130 oC CN
N
X = C, N
N H
N N N N Cu III
N N Me N N N
NC OAc
N N N N Cu II
H
CN CN CN CN OAc
NC
Cu I Cu II
70% 52% Me 72% Me 71%
Et
O2
N
N N N N
N N N Scheme 10. Possible mechanism for cyanation of 2-phenylpyridines with
N acetonitrile.
CN N N N
CN CN CN
F Cl
OBn
64% 66% 62% 73% Table 25
F
Cyanation of terminal alkynes with ICN
CuOTf toluene (10 mol%)
N N
N N N N TEMP (1.5 equiv)
R H + I CN R CN
N N N N THF, 60 oC, 17 h
CN CN CN CN 1.0 equiv 2.5 equiv

65% 63% 50% Me 54%

n-C10H 21 CN CN CN

78% 63% 73%

BnO
S
N CN CN CN
N Me
Me
N 58% 51% 62%
H N N
Me C N N
N N
N N C
Cu(OAc)2 CuII CuII Me
OAc OAc Li and co-workers demonstrated copper-catalyzed oxidative cya-
nation reaction with acetonitrile (Table 22).30 By employing
N
Ag2O/air as the oxidant, a variety of aryl iodides afforded aryl ni-
[O] N triles in moderate to good yields. For aryl bromides, more copper
N salts and ligands were needed to increase the conversion rate.
CN N N
AgOAc The reaction proles indicated that the real catalyst was Cu(I) spe-
N N
N N cies. Thus, a possible mechanism was proposed. Ag2O was em-
I
Cu OAc Cu III
CN CuII ployed as a base, as well as an oxidant in this reaction (Scheme 8).
CN
OAc Very recently, Zhu and co-workers reported copper-mediated
C2-cyanation of indoles, also employing acetonitrile as the cyanide
Scheme 9. Possible mechanism for the C2-cyanation of indoles with acetonitrile. source (Table 23).31 N-Pyrimidyl indoles with various substitutions
worked smoothly in this reaction with good yields. The pyrimidi-
Table 24
Cyanation of 2-phenylpyridines with acetonitrile
nyl groups in the substrates were crucial directing grouping in
forming C2-cyanation products. A possible mechanism was pro-
R2
R2 posed (Scheme 9). AgOAc was used as an oxidant in this reaction.
Cu(OAc)2 (30 mol%) More recently, Shen and co-workers also reported a copper-cat-
CN
N TMEDA (30 mol%)
R1 alyzed cyanation of aromatic CH bond by activation of acetonitrile
N
+ (Me3 Si)2 (1.0 eqiuv), H 2 O (1.0 eqiuv) R1 as a cyanide source.32 With the assistance of hexamethyldisilane,
O2 , 150 o C, 10 h or 3-4 d CN
H3 C CN the CCN bond of inert acetonitrile was activated and CN unit
(mono-CN:di-CN)
TMEDA = N,N,N',N'-tetramethylethylenediamine was transferred to aromatic rings catalyzed by Cu(OAc)2. 2-Phenyl-
pyridines with different substituents on the aryl rings could afford
corresponding aryl nitriles, although a long reaction time was
N N N
needed for some substrates (Table 24). The authors hypothesized
Me CN MeO CN F3 C CN that the disilane served as a Lewis acid in the CCN bond cleavage
82%, 10 h 80%, 10 h 78%, 3-4 d
71:9
of acetonitrile, affording the copper cyanide species. And the latter
76:6 62:16
Me Me procedures were copper-catalyzed pyridine-directed cyanation
reactions (Scheme 10).
F
N N N
MeO CN CN CN
Cyanogen iodide (ICN)
68%, 3-4 d 57%, 3-4 d 80%, 3-4 d
71:9 Very recently, Okamoto and coworkers demonstrated a copper-
catalyzed cyanation of terminal alkynes with cyanogen iodide.33 By
1278 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280

Table 28
Cyanation of indoles with DMF and NH4I
(a) R H + I CN + NH R I + NH2 + CN-
Cu(CF 3COO) 2 (1.2 equiv) CN
HOAc (1.2 equiv)
R NH4 I R
L Cu I NH2 + CN- N DMF, O2 (balloon) N
+ L Cu CN + NH2 + I- (1.2 equiv)
Me 130 oC,12 h Me
(b)

L Cu I + I CN L Cu CN + I2 CN CN CN CN
Me F
Ph
(c) L Cu CN + R I L Cu I + R CN N N N N
Me Me Me Me
90% 78% 71% 85%
(d) NH2 + CN- + I2 NH2 + I- + I CN
CN CN CN CN
O 2N

Scheme 11. Possible mechanism for the Cyanation with ICN. N N N N

Me Me Me Bn H
53% 62% 71% 50%

Cu(OAc) 2 (1.0 equiv)

N N
employing 2,2,6,6-tetramethylpiperidine (TEMP) as an efcient
MeNO2 , air
CN base, this cyanation proceeded smoothly via an intermediate alky-
130 oC, 24 h
67% nyl iodide (Table 25). The mechanistic study showed that TEMP
was a sterically congested base in the reaction with cyanogen io-
Scheme 12. Cyanation of 2-phenylprydine with nitromethane. dide, producing ammonium cyanide as a cyanation agent
(Scheme 11).
[Cu]
O O O NH Non-CN-containing cyanide source
Br
CH 3 CuBr2 CH 2 NH 3 CH O2
H N H N H N "CN"
Me SET Me O2 C-N source Nitromethane (CH3NO2)
Me cleavage

Scheme 13. The formation of CN source from DMF and NH3. In 2006, Yu and co-workers reported Cu-catalyzed functionali-
zation of aryl CH bond, in which aryl CH cyanation was
involved.34 Besides normal Cu(OAc)2-catalyzed cyanations of 2-
Table 26
phenylpyridine with TMSCN, the solvent nitromethane (CH3NO2)
Cyanation of aryl boronic acids with DMF and NH4I was also observed as a CN source in affording the same cyanation
B(OH)2
Cu(NO3 )2 3H 2O (2.0 equiv)
CN
product (Scheme 12). The detailed mechanism of this unusual
HOAc (2.0 equiv) transformation remains unknown.
R NH4 I R
DMF, 130 oC, 18 h
O 2 (balloon) The combination of NH4I and DMF
CN R = OMe, 86% MeO CN MeO CN
R = Cl, 60% DMF is often used as a polar solvent in organic reactions. It has
R R = NO 2, 54% MeO also been used as a reagent in many reactions, providing CO, CHO,
85% 81%
CN
NMe2, CONMe2, and so on.35 In 2010, Changs group rst reported
Pd-catalyzed cyanations of 2-phenylpyridine and derivatives,
O CN CN CN
employing DMF as the source of C atom and aqueous ammonia
O N as the source of N atom.7g The combination of aqueous ammonia
60% 80% 75% 54% and DMF was proposed to produce CN with the aid of copper salt
(Scheme 13). However, the cyanation was catalyzed by palladium.
Subsequently, Chang and co-workers demonstrated copper-
mediated cyanation of aryl boronic acids and arenes using the
Table 27 combination of ammonium iodide and DMF.36 Aryl nitriles were
Cyanation of electron-rich arenes with DMF and NH4I obtained in good yields with different aryl boronic acids (Table 26),
Cu(NO3 )2 3H 2O (2.0 equiv)
H
HOAc (2.0 equiv)
CN as well as some electron-rich arenes (Table 27). Aryl iodides were
EDG NH 4 I EDG proposed to be the key intermediates during the reaction. All the
DMF, 130 oC,
18 h
O 2 (balloon)
intermediates involved in this reaction were detected by experi-
CN ments. By replacing aqueous ammonia in the previous work,
OMe Me
CN MeO CN CN
OMe NH4I played a dual role as the origin of iodide and also the nitrogen
atom. Similarly, the copper salt functioned as a catalyst in the acti-
MeO OMe MeO OMe MeO OMe vation of CB or CH bond and an oxidant in the formation of cya-
OMe
92% 72% 82% 99% nide ion (Scheme 14).
Subsequently, Chang and co-workers reported the copper-med-
I2 / CuX n
iated cyanation of indoles with the combination of NH4I and DMF
B(OR) 2 I [- CN] / CuX n CN (Table 28).37 This reaction was largely depending on copper spe-
or CuI

or NH 4I / CuX n or CuCN
cies, in which copper(II) triuoroacetate was the best choice. In-
doles with different functional groups underwent C3-cyanation
Scheme 14. Possible mechanism for the cyanation with DMF and NH4I. with high regioselectivity in good yields. In analogy with cyanation
 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280 1279

I CN Table 31
I2 [ -CN] / [CuXn ] Cyanation of vinylsilanes with DMF and NH4I
Si(OEt)3 CN
N Electrophilic N Cyanation N Cu(NO3)23H2O (2.0 equiv)
R Iodination KF (2.0 equiv), DMF
R R NH4I
R o R
(2.0 equiv) O2 (balloon), 140 C, 25 h
Scheme 15. Possible mechanism for the cyanation of indoles with DMF and NH4I.
CN CN CN
MeO Cl
Table 29
67% 62% 71%
Cyanation of 2-phenylprydines with DMF and NH4I E:Z = 82:18 only E only E
Cu(CF3 COO)2 (1.2 equiv)
HOAc (1.2 equiv)
N NH 4 I N
R DMF, O 2 (balloon) R
H (1.2 equiv) CN
130 o C,12 h
Table 32
Me Cyanation of Hiyama silanes with DMF and NH4I
Me
Cu(NO 3) 23H2 O (2.0 equiv)
N N N N HO DMF, O2 (balloon)
NH 4I Ar CN
Me CN CN CN CN Ar Si (2.0 equiv) 140 oC, 35 h
32% 90% 85% 61% Me2
CN CN
MeO CN

MeO
Table 30 67% 65% 80%
Cyanation of arylsilanes with DMF and NH4I
Cu(NO3) 23H2 O (2.0 equiv)
R KF (2.0 equiv), DMF R
Si(OEt) 3 NH 4I CN
(2.0 equiv) O 2 (balloon), 140 oC, 25 h
Table 33
Cyanation of aryl halides with NH4HCO3 and DMF
CN
CN Cu(OAc)2 (1.2 equiv)
CN R = OMe, 81% CN X CN
TMEDA (0.2 equiv)
R = Ph, 94% R NH 4HCO 3 R
R R = CF3 , 54% DMF, 150 o C, air, 22 h
OMe
R = Cl, 60%
91% 97% 93%
CN CN CN CN

of aryl boronic acid using NH4I and DMF, 3-iodoindole was de-
tected to be formed in the early reaction period, followed by a cop-
per-mediated cyanation. Thus with the same process in producing
cyanide anion, indoles proceeded an electrophilic iodination in the
C3-position and a subsequent cyanation mediated by copper
(Scheme 15).
Under presently developed conditions above, 2-phenylpridines
also underwent the copper-mediated cyanation reaction success-
fully (Table 29).37 This reaction could occur in the absence of pal-
ladium catalyst, which was different from Changs previous work
in the cyanation of 2-phenylpridines with aqueous ammonia and
DMF.7g Iodination was also regarded as an initial step via a radi-
cal-cation pathway leading to iodinated intermediate, followed
by a subsequent cyanation step.
Recently, Chang and co-workers reported copper-mediated cya-
nation of organosilanes for the rst time with DMF and ammonium
iodide.38 The uoride additive was essential in this transformation,
instead of acetic acid in the previous work. Both arylsilanes and
vinylsilanes undertook the cyanation smoothly, giving the corre-
sponding nitriles in good yields (Tables 30 and 31). Moreover, Hiy-
ama silanes, which were recently introduced for metal-mediated
coupling reactions without requiring a uoride activator, also pre-
ceded this cyanation in the absence of KF (Table 32). A reaction
prole also showed that arylsilanes underwent an iodination rst
and a copper-mediated cyanation later.
The combination of NH4HCO3 and DMF
In 2011, Cheng and co-workers demonstrated that NH4HCO3
and DMF could be employed as a combined cyanide source in
the copper-mediated cyanation of aryl halides (Table 33).39 After
screening copper sources and ligands, Cu(OAc)2 and N,N,N0 ,N0 -tet-
MeO Ph AcHN Cl
X = I, 85% X = I, 89% X = I, 43% X = I, 54%
X = Br, 62% X = Br, 65% X = Br, 31% X = Br, 42%
CN CN
CN
COOMe N N
CN Me
66% 50% 53% 43%
ramethylethylenediamine (TMEDA) were the optimal choices,
respectively. Aryl iodides and bromides were mostly cyanated
smoothly under the standard conditions. Although the authors
pointed out that the mechanism of releasing cyanide anion from
the combined cyanide source was unclear, the process was likely
to take place similar to Changs proposal (Scheme 13).36
In recent years, transition metal-mediated cyanation reactions
have become more and more popular, providing a series of cyana-
tion strategies commonly used in organic synthesis. Large amounts
of solution were proposed by researchers, aiming to solve ubiqui-
tous metal catalyst deactivation in metal-catalyzed cyanations.
This problem can be overcome by applying suitable solvents with
lower solubility of cyanide sources, like NaCN, KCN, and Zn(CN)2.
Meanwhile, some additives, such as TMEDA, Zn, and Zn salts are
also benecial in solving this problem. Another way is decreasing
the addition rate of cyanide agents (mainly liquid cyanide agents,
like TMSCN, acetone cyanohydrin, etc.) or cyanide-containing solu-
tions, in order to control the cyanide concentration in the reaction
system. While copper catalysts are less expensive and friendlier to
environment compared to other metal catalysts, which make them
as a better choice in cyanation reactions. However, comparatively
lower activity of copper catalysts has limited their applications in
some areas. So the improvement in copper-mediated cyanation
efciency is still challengeable to researches. On the other hand,
1280 Q. Wen et al. / Tetrahedron Letters 55 (2014) 12711280
metal cyanide, such as CuCN, KCN, NaCN, and Zn(CN)2 are toxic and
easily leading to stoichiometric amounts of metal waste. Thus dis-
covery of non-metal and lower toxic cyanide sources is extremely
urgent. Although great developments have been achieved in cop-
per-catalyzed cyanation reactions, long-term efforts should be ta-
ken to realize more practical and efcient cyanation in the future.
Acknowledgment
Ping Lu and Yanguang Wang thank the National Natural Science
Foundation of China (21272203, 21032005).
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