Copper-mediated cyanation of aryl halides by activation of benzyl cyanide as the cyanide source

Article abstract of DOI:10.1002/ejoc.201300052

Aryl nitriles were efficiently synthesized through copper-mediated cyanation of aryl halides using benzyl cyanide as the cyanide source. Aryl halides with various substituents on the aromatic ring afforded the corresponding aryl nitriles in 32-97 % yields (25 examples). This reaction could also be carried on a gram scale by using commercially available reagents. Additionally, a C-H bond oxidation and a C-CN cleavage are proposed to be involved in this cascade process. An efficient, copper-mediated cascade synthesis of aryl nitriles from aryl halides using benzyl cyanide as the cyanide source is described. Compared with traditional copper-mediated cyanation reactions, this approach effectively avoided the use of toxic MCN and low soluble reagents. Furthermore, C-H oxidation and C-CN cleavage are proposed to be involved in this cascade process. Copyright

Full text of DOI:10.1002/ejoc.201300052

Job/Unit: O30052
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Date: 04-05-13 12:40:21
Pages: 6
FULL PAPER
Cyanation Reactions
An efficient, copper-mediated cascade syn-
thesis of aryl nitriles from aryl halides us-
ing benzyl cyanide as the cyanide source is
described. Compared with traditional cop-
per-mediated cyanation reactions, this ap-
proach effectively avoided the use of toxic
MCN and low soluble reagents. Further-
more, C–H oxidation and C–CN cleavage
are proposed to be involved in this cascade
process.
Q. Wen, J. Jin, Y. Mei, P. Lu,*
Y. Wang* .......................................... 1–6
Copper-Mediated Cyanation of Aryl Hal-
ides by Activation of Benzyl Cyanide as the
Cyanide Source
Keywords: Cyanation / Copper / Aromatic
substitution / Cyanides
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Date: 04-05-13 12:40:21
Pages: 6
Q. Wen, J. Jin, Y. Mei, P. Lu, Y. Wang
FULL PAPER
DOI: 10.1002/ejoc.201300052
Copper-Mediated Cyanation of Aryl Halides by Activation of Benzyl Cyanide
as the Cyanide Source
Qiaodong Wen,[a] Jisong Jin,[a] Yuncai Mei,[a] Ping Lu,*[a] and Yanguang Wang*[a]
Keywords: Cyanation / Copper / Aromatic substitution / Cyanides
Aryl nitriles were efficiently synthesized through copper-me- 97% yields (25 examples). This reaction could also be carried
diated cyanation of aryl halides using benzyl cyanide as the
cyanide source. Aryl halides with various substituents on the
aromatic ring afforded the corresponding aryl nitriles in 32–
on a gram scale by using commercially available reagents.
Additionally, a C–H bond oxidation and a C–CN cleavage
are proposed to be involved in this cascade process.
Introduction
Aryl nitriles are extraordinary important organic com-
pounds that exist wildly in natural products, pharmaceuti-
cals, and agrochemicals.[1] Furthermore, because of the con-
venient transformation of the cyano group into other func-
tional groups,[2] the cyanation reaction has attracted im-
mense interest from many chemists. Traditional methods
towards aryl nitriles include the Sandmeyer reaction and
the Rosenmund von Braun reaction.[3] In addition to these
methods, researchers have explored various kinds of “CN”
sources and thereby established many useful cyanation
methodologies (Scheme 1).
Among these “CN” sources, MCN (M = Na, K, Zn, Cu,
TMS, nBu3Sn) has been widely investigated, however, these
regents are extremely toxic.[4] In 2004, Beller’s group re-
ported a nontoxic cyanide reagent K4[Fe(CN)6], which was
extensively applied in spite of its low solubility in organic
Scheme 1. Reported “CN” sources in cyanation reactions.
solvent.[5] In addition to the use of these “CN” sources, addition to these cyanation reagents, acetone cyanohydrin,
synthetic strategies that derive C and N atoms in the cyano propanedinitrile, and ethyl cyanoacetate could also be used
group from the solvent have been reported; such ap- as organic “CN” sources.[13] Recently, our group found that
proaches include the use of CH3NO2 by Yu’s group,[6] N,N- ArCH2CN is an operator-benign reagent for cyanation re-
dimethylformamide (DMF) by Jiao’s group,[7] and CH3CN actions.[14]
by Cheng’s group.[8] Furthermore, the constituent atoms of
There are two general methods available for the synthesis
“CN” could come from different reactants, such as DMF of aryl nitriles. One is the cyanation of Ar–X [X = I, Br, Cl,
+ NH3,[9] dimethyl sulfoxide (DMSO) + NH4HCO3,[10] and OMs, OTf, B(OR)2],[5c,15] and the second is the cyanation of
DMF + NH4HCO3.[11] Very recently, Chang’s group re- Ar–H through C–H bond activation.[4d,5b,9,16] Most of the
ported that NH4I and DMF could together act as N and cyanation reactions of Ar–X are mediated by metal cata-
C resources in “CN”, respectively, and this system could be lysts, such as Pd and Cu.[17] Compared to expensive palla-
applied for the cyanation of aryl C–B and arene C–H.[12] In dium catalysts, copper catalysts are gaining more attention
because they are relatively inexpensive and easy to obtain.
Transition-metal-catalyzed C–H bond activation,[18] C–X
[a] Department of Chemistry, Zhejiang University,
bond cleavage and C–CN bond cleavage[19] have emerged
Hangzhou 310027, P. R. China
Fax: +86-571-87952543
as hot topics in the field of organic synthesis; as an illustra-
E-mail: pinglu@zju.edu.cn
tion, copper-catalyzed benzylic C–H activation and oxi-
dation has been widely reported.[20] Encouraged by these
blooming methodologies and by our previous report on the
palladium catalyzed C–CN bond cleavage of benzyl cyan-
orgwyg@zju.edu.cn
Homepage: http://mypage.zju.edu.cn/en/pinglu/0.html
http://mypage.zju.edu.cn/en/orgwyg/0.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300052.
2
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Cyanation of Aryl Halides
ide,[14] we describe here a copper-catalyzed cyanation of aryl Table 1. Optimization of reaction conditions for the preparation of
3a.[a]
halides using benzyl cyanide as a cyanation reagent.
Results and Discussion
Our initial experiment was carried out with 4-iodoanisole
(1a), benzyl cyanide (2a), and cuprous iodide (1.5 equiv) in
DMF at 130 °C under air atmosphere. To our delight, the
reaction afforded 4-methoxybenzonitrile (3a) in 51% yield.
We then optimized the reaction conditions and the results
are summarized in Table 1. First, copper sources were scre-
ened. The results showed that both CuI and CuII salts could
be used to conduct the reaction (Table 1, entries 1–7), but
none of the expected product was observed in the absence
of copper sources (Table 1, entry 8). When 1.5 equiv. Cu2O
was selected as the copper source, the cyanation proceeded
quite well with 90% yield. It also worked well under O2
conditions (Table 1, entry 9). However, only a trace amount
of the expected product was detected by TLC when the re-
action was performed under an N2 atmosphere (Table 1, en-
try 10). When the reaction temperature was decreased, a di-
minished yield was obtained (Table 1, entries 11–13). Other
solvents such as N,N-dimethylacetamide (DMA), DMSO,
and N-methyl-2-pyrrolidinone (NMP) also worked for the
reaction, but with slightly decreased yields (Table 1, entries
14–16). In toluene, however, only a trace amount of the
product was detected (Table 1, entry 17). We also attempted
to run the reaction using a catalytic amount of Cu2O; under
these conditions a gradual decrease in yield was observed
as the amount of Cu2O was reduced (Table 1, entries 18–
23). When an equimolar amount of Cu2O to aryl iodide
was used, the optimal yield (92%) was obtained. It is no-
ticeable that the reaction still proceeded well (78% yield)
Entry Cu source (equiv.)
Solvent
T [°C]
Yield [%][b]
1
2
3
4
5
6
7
8
CuI (1.5)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
NMP
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
130
130
130
130
130
130
130
130
130
130
120
100
80
130
130
130
130
130
130
130
130
130
130
130
51
48
47
90
35
39
15
0
90
Ͻ 5
80
78
54
77
48
86
Ͻ 5
92
90
CuBr (1.5)
CuCl (1.5)
Cu2O (1.5)
Cu(OAc)2·H2O (1.5)
CuCl2·2H2O (1.5)
CuBr2 (1.5)
–
9[c]
10[d]
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cu2O (1.5)
Cu2O (1.5)
Cu2O (1.5)
Cu2O (1.5)
Cu2O (1.5)
Cu2O (1.5)
Cu2O (1.5)
Cu2O (1.5)
Cu2O (1.5)
Cu2O (1.0)
Cu2O (0.8)
Cu2O (0.6)
Cu2O (0.4)
Cu2O (0.2)
Cu2O (0.1)
Cu2O (0.05)
89
81
78 (51)[c]
45 (50)[c]
45 (32)[c]
[a] Reaction conditions: 4-iodoanisole (0.5 mmol), benzyl cyanide
(0.75 mmol), Cu source, air, solvent (2 mL), 12 h. [b] Isolated yield.
[c] Under O2. [d] Under N2.
when the amount of Cu2O was reduced to 0.2 equivalent. the yields of products 3n–q was observed, except for the
The reaction was also carried out under O2 with 0.2, 0.1 preparation of 4-acetylbenzonitrile 3n (68% yield). Under
and 0.05 equiv. of Cu2O (Table 1, entries 22–24) and the the same reaction conditions, methyl 3-iodoindole-1-carb-
expected product was obtained in lower yields. Thus, the oxylate afforded 3-cyano-1H-indole (3r; 64% yield) with a
optimal reaction conditions were established (Table 1, en- decarboxylation.[22]
try 18).
Compared with aryl iodides, aryl bromides underwent
With the optimized reaction conditions in hand, we then the reaction with more difficulty because of the higher bond
studied the substrate diversity. Aryl halides with different energy of the C–Br bond (Table 3). 4-Chloroanisole did not
substituents on the aromatic ring were investigated work at all. For 4-bromoaniline, N-(4-bromophenyl)benz-
(Table 2). For substrates with electron-donating groups on amide was obtained in 63% yield, together with the forma-
the aryl iodides, the corresponding aryl cyanides 3a–k were tion of 3d (32% yield). In practice, this method could be
obtained in good to excellent yields. The yield of 4-hydroxy- carried out on gram scales; for example, 1.17 g (5 mmol) of
benzonitrile (3c) was lower than those of the alkyloxy ana- 4-iodoanisole afforded 565 mg of 3a (85% yield).
logues 3a and 3e. A similar situation was observed for 3d
To understand the mechanism in more detail, we tested
and 3g. Steric effects were detected in the preparation of 3f for the presence of free cyanide anion by the use of indi-
and 3h. It is noteworthy that 3k could be obtained in 86% cator paper (Table S1, entries 1–10). As expected, CN– did
yield, which is the key intermediate for the manufacture of cleave from the benzyl cyanide and was found to exist in
Sartan’s medicines.[21] In comparison with our previous the solution. This fact promoted us to investigate the origin
finding, palladium-induced migration of the cyano group of the cyanide anion and the fate of the remaining part of
was effectively avoided in this process.[14a] Moreover, the re- benzyl cyanide. From the CN– detection test, we knew that
action proceeded smoothly for fused aryl iodides and het- the cyanide anion could not be formed without copper
erocyclic compounds 3l and 3m, and double cyanation oc- sources or benzyl cyanide. Under a nitrogen atmosphere,
curred in case of 3m. For substrates with electron-with- cyanide also could not be formed. The combination of cop-
drawing groups on the aryl iodides, no clear decrease in per source, benzyl cyanide, and air released the CN– anion.
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Table 2. Cu-mediated cyanation of various aryl iodides.[a]
Table 3. Cu-mediated cyanation of aryl bromides.[a]
[a] Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), Cu2O
(0.5 mmol), under air, 130 °C, DMF (2 mL), 12 h, isolated yield.
[b] N-(4-Bromophenyl)benzamide was isolated in 63% yield to-
gether with the formation of 3d.
To gain further insight into the mechanism, 2b and 2c
were used for the cyanation of 4-iodoanisole (Table 4); with
these substrates, 4-methoxybenzonitrile (3a) could also be
obtained in 81 and 83% yields, respectively. When 2-phenyl-
propanenitrile (2d) was used, 3a was obtained in 92% yield,
which was comparable to what we observed for the reaction
with benzyl cyanide (2a). However, the yields were de-
creased when a substituent was attached at the para posi-
tion of benzyl cyanides (2e, 2f, and 2g). The nature of the
electron-withdrawing group on the para position of the
benzyl cyanide benefited the benzylic C–H oxidation in the
presence of Cu2O and oxygen, but retarded the rate of re-
lease of the cyanide anion from cyanohydrin. The fact that
the yield of 3a decreased as the reaction temperature de-
creased indicated that a higher reaction temperature was
necessary for the copper-catalyzed cyanation.
[a] Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), Cu2O
(0.5 mmol), under air, 130 °C, DMF (2 mL), 12 h, isolated yield.
[b] The amount of 2a and Cu2O were doubled. [c] The substrate
was methyl 3-iodoindole-1-carboxylate.
Table 4. Cyanation using 2b–g as cyanation reagents.[a]
Tracking the reaction of PhCH2CN, Cu2O, and air in DMF
by GC–MS, we observed the formation of N,N-dimethyl-
benzamide, benzoic acid, and cis-/trans-2,3-diphenyl-
fumaronitrile (Figure S1). The reaction of PhCH2CN,
Cu2O, and air in NMP afforded benzoic acid and cis-/trans-
2,3-diphenylfumaronitrile (Figure S2). Additionally, 4-
MeOC6H4CH2CN (2e), Cu2O, and air in DMF furnished
4-MeOC6H4CONMe2 only (Figure S3). That is to say, as
the cyanide anion was released from benzyl cyanide, benzyl
was transferred into benzoyl through copper-catalyzed oxi-
dation.
In addition, a condition-controlled experiment was un-
dertaken. By increasing the amount of PhCH2CN and
Cu2O to 2 equiv. relative to 4-iodoaniline, and by extending
of reaction time to 18 h, 4-iodoaniline afforded 3d (7%) to-
gether with N-(4-cyanophenyl)benzamide 3s (63%). Taken
together, these observations indicated that the benzyl part
in benzyl cyanide was converted into the benzoyl group.
[a] Reaction conditions: 4-iodoanisole (0.5 mmol), 2b–g
(0.75 mmol), Cu2O (0.5 mmol), under air, 130 °C, DMF (2 mL),
12 h, isolated yield.
4
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Cyanation of Aryl Halides
Furthermore, we employed EPR technology to track the
oxidation state of copper during the reaction of 4-iodo-
anisole and PhCH2CN in DMF (Figure S4). The signal of
CuII clearly appeared at 3300 Gauss when the reaction was
conducted for about three hours, and lasted to the end of
the reaction.
Experimental Section
General Methods: Unless otherwise indicated, NMR spectra were
obtained with a Bruker Avance DMX400 spectrometer operating
1
at 400 MHz for H NMR and 100 MHz for 13C NMR in CDCl3,
or with a Bruker Avance DMX500 spectrometer operating at
1
500 MHz for H NMR and 125 MHz for 13C NMR spectroscopy.
Based on these results, we proposed a possible mecha-
Melting points were recorded with a BÜCHI 535. MS spectra were
nism for the formation of ArCN (Scheme 2). Because of the measured using EI method of ionization. High-resolution mass
spectra (HRMS) were recorded with a GCT Premier CAB170 in-
strument. EPR spectra were obtained with a Bruker A300 EPR
Spectrometer. Flash column chromatography was performed by
employing 300–400 mesh silica gel. Thin-layer chromatography
(TLC) was performed with silica gel HSGF254.
reactivity of the benzylic C–H bond in benzyl cyanide, it is
first activated and oxidized to 2-hydroxy-2-phenylaceto-
nitrile (2b) or benzoyl cyanide (2c) in the presence of oxygen
and CuI. Compound 2b releases the cyanide anion rapidly,
in a similar way to acetone cyanohydrin.[13a,13b] Compound
2c suffers nucleophilic attacked by water and dimethyl-
amine in the solution to form the byproducts benzoic acid
and N,N-dimethylbenzamide, respectively, accompanied by
the release of the cyanide anion. Thus, the C–CN bond in
the benzyl cyanide is activated and cleaved. Meanwhile, the
C–X bond dissociates in the presence of CuI through a SET
process and coordination with cyanide anion. The resulting
CuII complex A undergoes a sequential SET process to
form the CuIII complex B, which could be converted into
ArCN by a final reductive elimination.[23] Thus, the cop-
per(I) catalyst circulates in the system.
Typical Procedure for the Preparation of 4-Methoxybenzonitrile
(3a): A mixture of 1a (117 mg, 0.5 mmol), benzyl cyanide (88 mg,
0.75 mmol), and Cu2O (72 mg, 0.5 mmol) in DMF (2 mL) was
stirred at 130 °C (oil bath) under air atmosphere for 12 h. After
cooling to room temperature, the resultant mixture was added to
water (15 mL), extracted with CH2Cl2 (3ϫ 5 mL), and dried with
anhydrous Na2SO4. The dichloromethane was evaporated under re-
duced pressure and the residue was purified by flash column
chromatography on silica gel (EtOAc/hexane, 1:8, v/v) to give 3a
(61 mg, 92% yield) as a white solid. M. p. 59–60 °C (Lit.[14a] 60–
61 °C). 1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.6 Hz, 2
H), 6.96 (d, J = 8.6 Hz, 2 H), 3.86 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 163.1, 134.2, 119.5, 115.0, 104.2, 55.8 ppm.
MS (EI): m/z = 133 (100) [M+].
2-Butoxybenzonitrile (3f): Yellow liquid. 1H NMR (400 MHz,
CDCl3): δ = 7.59–7.46 (m, 2 H), 7.00–6.94 (m, 2 H), 4.08 (t, J =
6.4 Hz, 2 H), 1.87–1.79 (m, 2 H), 1.60–1.48 (m, 2 H), 0.99 (t, J =
7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.8, 134.2,
133.6, 120.4, 116.5, 112.1, 101.9, 68.6, 30.8, 19.0, 13.7 ppm. MS
(EI): m/z = 175 [M+, 10], 119 (100). HRMS (EI): m/z cacld. for
C11H13NO [M+] 175.0997; found 175.0998.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, characterization data, the
CN– detection test, GC–MS analysis of the by-products, the EPR
test, and copies of 1H and 13C NMR spectra for some of the start-
ing materials and all of the products 3a–s.
Scheme 2. Possible cyanation mechanism.
Acknowledgments
The authors thank the National Nature Science Foundation of
China (NSFC) (grant numbers 21272203, 21032005, and
J1210042).
Conclusions
We have developed a copper-mediated approach to aryl
nitrile from aryl halide using the operator-benign benzyl
cyanide as cyanation reagent. Compared with traditional
copper-mediated cyanation reactions, this approach effec-
tively avoided the usage of toxic MCN and low solubility
reagents such as K4[Fe(CN)6]. During the process, copper-
mediated C–H bond activation and oxidation, C–CN bond
cleavage, and C–X bond dissociation are involved. More-
over, this is a ligand-free reaction. With respect to the Pd-
catalyzed cyanation we previously reported, the present
copper catalyst is undoubtedly much less expensive and,
moreover, can be used in catalytic amounts. Further re-
search on the reaction mechanism for this transformation
and its applications are underway.
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Received: January 12, 2013
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