Copper-catalyzed cyanation of aryl iodides with α-cyanoacetates via C-CN bond activation

Article abstract of DOI:10.1039/c5ob01675d

A Cu(i)-catalyzed cyanation reaction of aryl iodides with α-cyanoacetates is reported herein, which uses α-cyanoacetates as the nontoxic and easy-handling CN source through copper-mediated C-CN bond cleavage. This reaction enables access to aryl nitriles with an array of functional groups on the aromatic ring in good to excellent yields.

Full text of DOI:10.1039/c5ob01675d

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ARTICLE TYPE
Copperꢀcatalyzed cyanation of aryl iodides with αꢀcyanoacetates via Cꢀ
CN bond activation†
SongꢀLin Zhang* and Lu Huang
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A Cu(I)ꢀcatalyzed cyanation reaction of aryl iodides with αꢀcyanoacetates is reported herein, which uses
αꢀcyanoacetates as the nontoxic and easyꢀhandling CN source through copperꢀmediated CꢀCN bond
cleavage. This reaction enables access to aryl nitriles with an array of functional groups on the aromatic
ring in good to excellent yields.
due to the prevalence of CꢀC bond in organic molecules.16
Among them, the activation of CꢀCN bond of nitriles by a
10
1
Introduction
transition metal complex (typically a Ni(0) or Rh(I) complex) has
50 been well studied to yield TMꢀCN (TM denotes a transition metal
complex) intermediates.17 These TMꢀCN intermediates are
known to be much less toxic than common cyanide salts that are
extremely dangerous. Therefore, nitrile activation by a transition
metal complex followed by coupling with aryl halides may
55 provide an alternative and friendly route for the preparation of
aryl nitriles (Scheme 1).
Aryl nitriles are important structural motifs in numerous
compounds ranging from pharmaceuticals, agrochemicals,
materials to dyes.1 Aryl nitriles are also synthetic intermediates
for an array of valuable functionalized compounds, e.g., amines,
15 imines, ketones and Nꢀheterocycles, taking advantage of the
versatile conversion of cyano functional group.2 Therefore, the
search for efficient aromatic cyanation reactions has been a
longstanding interest. Classic methods for the preparation of aryl
nitriles are illustrated by Sandmeyer reaction3 (Scheme 1a) and
20 Rosenmundꢀvon Braun reaction4 (Scheme 1b) which exploit the
cyanation of aryldiazonium salts or aryl halides by stoichiometric
amounts of CuCN. In recent years, transition metal (typically Pd
and Cu) catalyzed cyanation reactions have been developed to
produce aryl nitriles by coupling of aryl halides with inorganic
25 cyanide salts such as NaCN, KCN, CuCN, Zn(CN)2, K4Fe(CN)6
etc (Scheme 1c).5,6 For example, one breakthrough in this area is
reported in 2003 by Buchwald et al. who achieved the efficient
cyanation of aryl and heteroaryl bromides by NaCN in the
Previous work:
CuCN
(a) ArN2+X-
Ar-CN
ꢀ
CuCN
Ar-CN
(b) Ar-X
ꢀ
cat. M
(c)
Ar-X + m-CN
X = I, Br, Cl, OTf
Ar-CN
m-CN: KCN, Zn(CN)2, TMSCN, K4[Fe(CN)6] etc.
presence
of
catalytic
amount
of
KI
under
cat. M
(d)
+
CN-precursors
Ar-X
30 CuI/dimethylethylenediamine catalyst sytem.6b The use of
relatively less toxic K4Fe(CN)6 as the CN source for cyanation
also achieved impressive progress.6f,6i However, in these reports,
the cyanide salts are highly toxic and hard to handle which
greatly limits their widespread applications. The search for
35 methods using safer and easily handling CN sources remains
highly desirable. To this end, a number of CNꢀcontaining small
organic molecules such as cyanohydrin,7 CH3CN,8 as well as
molecules without a CN group such as formamide,9 DMF10 and
nitromethane,11 have been shown to be effective CN sources for
40 aromatic cyanation reactions (Scheme 1d).5 In addition, more
complicated strategies for generating CN group from combined
sources have been reported to achieve aromatic cyanation
reactions, e.g., DMF + NH3,12 DMF + NH4I,13 DMF + NH4HCO3
14 and etc.15
Ar-CN
cyanohydrin, CH3CN, DMF, MeNO2, formamide etc.
This work:
Ar-X
O
Cu
NC
Ar-CN
ArX
+
O
Cu(I)
″
″
LnCu(I)
CN
Scheme 1 Synthetic methods for the preparation of aryl nitriles
We set out our study by coupling of aryl halides with
60 commercially readily available ethyl αꢀcyanoacetate as the CN
source under copper catalysis. We anticipate that αꢀcyanoacetate
may undergo more facile CꢀCN bond activation due to the
stabilizing resonance of enolate structure in the inꢀsitu generated
(CN)Cu(CH2CO2Et) type of intermediate. Additional advantages
45
In recent years, transition metalꢀmediated CꢀC bond activation
reactions have emerged as a promising tool for organic synthesis
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for the use of cyanoacetate are the ready availability, nontoxicity 25 led to the discovery that in the presence of 20 mol% Cu2O and 40
and easily handling characters. These properties are especially
attractive from synthetic viewpoint compared to commonly used
cyanide salts in cyanation chemistry. The selection of copper
catalyst is attributed to two reasons. First, the classic Rosenmundꢀ
mol% PPh3 ligand reaction of ethyl αꢀcyanoacetate (2a) with
paraꢀmethoxyphenyl iodide (1a) gave the desired benzonitrile 3a
in 53% yield in Nꢀmethylpyrrolidinone (NMP) at 130oC under air
(entry 4). NMP is a preferred solvent compared to other common
5
von Braun reaction demonstrated the feasibility of CuꢀCN as the 30 solvents such as DMF, DMA, DMSO and toluene (entries 2ꢀ6),
cyanation reagent to react with aryl halides. Second, copper salts
are also readily available, nonꢀtoxic and operationally simple. To
our knowledge, there is no precedent of aryl nitrile preparation
possibly due to the better solubility of the inꢀsitu formed CuꢀCN
intermediate in NMP.5a Notably, oxygen is necessary for the
reaction to occur; performing the reaction under N2 atmosphere
led to no reaction at all (entry 7). When an oxygen balloon was
10 using copperꢀcatalyzed coupling of aryl halides with αꢀ
cyanoacetates although a Pdꢀcatalyzed variant has been reported 35 used, the reaction yield can increase significantly to 70% (entry
recently.18
8). Furthermore, change of the catalyst precursors to other copper
salts did not result in improved yields compared to Cu2O (entries
9ꢀ13). A number of other ligands such as phenanthroline, Lꢀ
proline, Xantphos, Xphos and PCy3 etc were also examined, but
40 gave reduced yields compared to PPh3 (entries 14ꢀ19). The
optimal reaction temperature was 130 oC; reaction at 100 oC
largely reduced the yield to only 18% (entry 20). Interestingly,
reducing the amount of PPh3 ligand from 40 mol% to 20 mol%
further improved the reaction yield to 80% (entry 21). Finally,
45 addition of one equivalent AgNO3 additive led to a 74% yield
which may act as a coꢀoxidant assisting oxygen to achieve good
catalytic turnovers (entry 22). This beneficial effect of coꢀoxidant
is further demonstrated for some substrates in reaction scope
study as discussed in Table 2 (vida infra). Other additives were
50 also examined to show good promotion effect, including TBHP,
H2O2 and DTBP, but they were slightly less effective than
AgNO3 (entries 23ꢀ25). However, for practical largeꢀscale
applications, they may be potential substitutes for AgNO3 due to
the low price.
2 Results and Discussion
2.1 Reaction development
15 Table 1 Optimization of the reaction conditions a
I
CN
O
catalyst, ligand
+
NC
OEt
solvent, oxidant
OCH3
OCH3
1a
2a
Ligand
3a
oxidant
entr Catalyst
y
Solvent
Yield
(%)b
35
44
45
53
30
0
0
70
64
56
45
35
12
29
48
1
2
3
4
5
6
7
8
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
DMF
DMF
DMA
NMP
DMSO
toluene
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
air
air
air
air
air
air
N2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Phen
55 2.2 Substrate scope
9
(CH3COO)2Cu·H2O
Cu(NO3)2·3H2O
(CuSO4)·5H2O
CuO
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
With the optimized reaction conditions in hand, we next studied
the substrates scope for this cyanation reaction (Table 2). Various
substituted aryl iodides with either electronꢀrich or ꢀdeficient
substituents on the aryl ring were compatible with the optimized
LꢀProline NMP
DPPE NMP
Xantphos NMP
60 reaction
conditions.
Aryl
iodides
with
methoxyl,
42
41
0
45
methoxycarbonyl, chloride, nitro, amide and cyano were shown
to be reactive and afford the desired coupling products in good to
excellent yields (entries 1ꢀ8). Notably, phenyl iodide with paraꢀ
chloride (1c) gave selectively the desired product 3c at the CꢀI
65 position with the CꢀCl bond intact, which provides a handle for
further functionalization of the product (entry 3).19 Aryl iodides
with a nitro group at either ortho, meta or para position were all
reactive to produce the desired CꢀI cyanation products (entries 4ꢀ
6). This is particularly significant considering that nitro group can
70 hardly be tolerated in many crossꢀcoupling reactions due to its
unique electronic properties and that it is often difficult for aryl
halides with ortho substituents to undergo crossꢀcoupling reaction
due to steric repulsion. Aryl iodide 1h with a cyano group at the
paraꢀposition gave the desired terephthalonitrile 3h in good
75 yields, which can be synthetic intermediate for biologically active
compounds and materials with conjugated aromatic rings.
Additionally, biaryl iodides and other fused aryl iodides such as
1i, 1j, 1k and 1l can be compatible with the reaction conditions,
giving the desired aryl nitriles in good to excellent yields (entries
80 9ꢀ12).
Xphos
PCy3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
18[c]
80[d]
74[d,e]
53[d,e]
69[d,e]
68[d,e]
AgNO3,O2
TBHP,O2
DTBP,O2
H2O2, O2
a
Reaction conditions: 4ꢀiodoanisole (0.5 mmol), ethyl cyanoacetate (1.0
mmol), copper catalyst (0.1 mmol), ligand (0.2 mmol), and solvent (2
mL) stirred at 130oC under air or oxygen overnight. b Isolated yields after
silica gel column chromatography. c Reaction performed at 100oC. PPh3
d
20 (0.1 mmol).e Coꢀoxidant (0.5 mmol); TBHP, tertbutylhydroperoxide;
DTBP, ditertbutyl peroxide.
PCy2
i-Pr
i-Pr
HO
O
Ph2P
PPh2
O
N
H
PPh2
PPh2
i-Pr
L-proline
Xantphos
DPPE
XPhos
.
Initial screening of the reaction conditions (entries 1ꢀ4, Table 1)
| Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C5OB01675D
a
Table 2 Substrate scope for copperꢀcatalyzed aromatic cyanation a
Reaction conditions: aryl halide (0.5 mmol), ethyl cyanoacetate (1.0
mmol), Cu2O (0.1 mmol), PPh3 (0.1 mmol), AgNO3 (0.5 mmol) and NMP
(2 mL), 130 C, under O2 atmosphere. Isolated yields using silica gel
column chromatography. c without AgNO3 salt. d Cu2O (0.5 mmol).
o
b
Cu2O 20 mol%
O
PPh3 20 mol%
5
X
+
NC
CN
OEt
AgNO3 1 eq.
NMP, O2, 130 o
R
R
C
X=I, Br, Cl, OTf
In addition to aryl iodides, aryl bromides can also react with αꢀ
cyanoacetate to deliver the desired aryl nitrile products. However,
stoichiometric amounts of Cu2O were generally required and
1
entry
1[c]
2a
3
ArX
Product
Yield(%)b
MeO
CN
10 much lower yields were obtained (entries 13ꢀ16). Aryl chlorides
and triflates were also examined for this cyanation reaction, but
no appreciable amounts of products could be obtained (entries
17,18). The reactivity of aryl halides follows an apparent trend of
ArI > ArBr > ArCl. This strongly implies that aryl halide
15 activation should be rateꢀlimiting under the reaction conditions
for this reaction. Further efforts are still required for these
challenging substrates.
To further demonstrate the compability of this cyanation
reaction, several commercially available cyanoacetates were
20 examined to react with iodide 1i under the optimized reaction
conditions (Table 3). It was pleased to find that methyl
cyanoacetate (2b) gave the desired product 3i in 80% yield,
which is a little lower than ethyl cyanoacetate (2a). Additionally,
cyanoacetates 2c and 2d with either one phenyl or two methyls
25 substituents at the αꢀC position were also reactive to give the
desired 3i in very good yields. These results demonstrate that an
array of cyanoacetates are feasible CN sources for this cyanation
reaction.
MeO
I
80
3a
1a
2[c]
H3CO
O
H3CO
O
I
CN
76
1b
1c
3b
3c
3d
3[c]
4[c]
5
Cl
CN
Cl
I
70
75
O2N
I
O2N
CN
1d
I
CN
66
50
90
O2N
O2N
3e
NC
1e
I
6
7
O2N
O2N
1f
3f
O
O
HN
CN
HN
I
3g
1g
1h
Table 3 Substrate scope for cyanoacetate sources a
8
9
NC
CN
NC
I
61
89
Cu2O 20 mol%
3h
3i
O
PPh3 20 mol%
NC
I
+
CN
I
CN
OR''
AgNO3 1 eq.
NMP, O2, 130 o
R
R'
C
1i
NC
I
10
1i
entry
2
3i
Cyanoacetate
Product
Yield (%)b
51
96
86
3j
O
1j
CN 3i
CN 3i
1
2
89
80
NC
11
12
O2N
CN
OEt
O2N
I
2a
3k
O
1k
I
CN
NC
OMe
OEt
2b
O
NC
1l
3l
3i
CN 3i
3
76
75
13[d]
14[d]
CN
CN
Br
45
24
2c
1m
O
O
O
NC
Br
CN 3i
4
OEt
H3CO
H3CO
O2N
Me Me
2d
3b
1n
1o
15[d]
16[d]
17[d]
18[d]
30 a Reaction conditions: aryl halide (0.5 mmol), cyanoacetate (1.0 mmol),
Cu2O (0.1 mmol), PPh3 (0.1 mmol), AgNO3 (0.5 mmol) and NMP (2 mL),
130 oC, under O2 atmosphere. b Isolated yields using silica gel column
chromatography.
Br
O2N
CN
CN
31
24
0
3d
3a
MeO
MeO
O2N
O2N
Br
Cl
1p
1q
35
Finally, the synthetic potential of this reaction is further shown
by the ready scale up of this reaction to gram levels. For example,
reaction of 8 mmol 1i with 16 mmol 2a under the optimized
reaction conditions gave the desired 3i in a yield of 1.03 g (72%
yield). This should be particularly attractive for practical
O2N
O2N
CN
CN
3d
3d
OTf
0
1r
40 synthetic applications because it is not practical to prepare aryl
nitriles at gram levels using large quantity of common toxic
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cyanide salts as the CN source.
cyanation of aryl iodides has been reported, which uses readily
50 available and friendly αꢀcyanoacetate as the CN source via CꢀCN
bond cleavage. It provides an alternative and safe choice for the
preparation of aryl nitriles to currently known methods using
toxic cyanides salts. This reaction is operationally simple, free of
manipulating toxic cyanide salts and can tolerate an array of
55 functional groups on the aromatic ring, which render it very
attractive for the practical synthesis of functionalized aryl nitriles.
Further studies on the expansion of the substrate scope and
understanding the mechanism of this reaction are ongoing in our
laboratory.
2.3 Mechanistic aspects
To shed insights into the mechanistic aspects of this reaction,
especially the fate of the CH2CO2Et and halide anion counterparts
of the reactants, GC analyses of the crude product mixture were
performed for the reaction in Table 1. GC analyses showed that
aside from the desired products and the reactants recovered, there
were no signals of organic compounds containing CH2CO2Et or
10 halide anion counterparts, such as ICH2CO2Et conceived from
reaction stoichiometry (please refer to ESI for details).
Considering the fact that oxygen is crucial to this reaction (refer
to discussions related to Table 1), it is possible that the
CH2CO2Et part might be oxidized by oxygen to get oxalate
15 derivatives, which may easily sublime from the reaction solution
or further decompose to release CO2 under the reaction
conditions.20 Additional evidence supporting this hypothesis is
that the reaction mixture shown in Table 1 exhibits significant
acidity (pH~5) while the reaction solution is basic (pH~9) before
20 the reaction.21
5
60 Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Nos. 21472068, 21202062) and the Natural
Science Foundation of Jiangsu Province (No. BK2012108).
Notes and references
65 The Key Laboratory of Food Colloids and Biotechnology, Ministry of
Education, School of Chemical and Material Engineering, Jiangnan
University, Wuxi 214122, Jiangsu Proince, China. Fax: +86-510-
85917763; Tel: +86-510-85917763; E-mail: slzhang@jiangnan.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental
70 details, characterization data, 1H, 13C NMR spectra for all the products
and GC analyses. See DOI: 10.1039/b000000x/
O
"
"
L
nCu CN
HO
+
HX
OR
B
ArX
O
(i) Transmetalation
(ii) Cyanation
O
1
(a) A. Kleemann, J. Engel, B. Kutscher and D. Reichert,
Pharmaceutical Substance: Synthesis Patents, Applications, 4th ed.,
Georg Thieme, Stuttgart, 2001; (b) J. S. Miller and J. L. Manson,
Acc. Chem. Res., 2001, 34, 563; (c) F. F. Fleming and Q. Wang,
Chem. Rev., 2003, 103, 2035.
NC
R
O
+
O2
LnCu(I)
X
Ar-CN
75
80
A
Scheme 2 Plausible mechanism for this cyanation reaction
2
(a) Z. Rappoport, Chemistry of the Cyano Group, Wiley, London,
1970; (b) R. C. Larock, Comprehensive Organic Transformations: A
Guide to Functional Group Preparations, VCH, New York, 1989.
T. Sandmeyer, Ber. Dtsch. Chem. Ges., 1884, 17, 1633.
K.W. Rosenmund and E. Struck, Ber. Dtsch. Chem. Ges., 1919, 2,
1749.
As a result, a plausible mechanism profile is suggested as
shown in Scheme 2 for this copperꢀcatalyzed cyanation reaction.
25 A key LnCuꢀCN intermediate B is generated initially via
transmetalation of CN group from αꢀcyanoacetate to Cu center
through CꢀCN bond cleavage which may probably be
accompanied by oxidation of the methylene group (Scheme 2).
Complex B reacts with aryl halide to produce the desired ArꢀCN
30 product and intermediate A. This step may possibly be rateꢀ
limiting because our experiments clearly show a reactivity trend
of ArI > ArBr > ArCl. Aryl iodides are much more reactive than
aryl bromides and chlorides and can achieve catalytic reactions in
good to excellent yields. In contrast, aryl bromides need
35 stoichiometric amount of copper to produce the desired products
in low yields while aryl chlorides led to no reaction at all under
either catalytic or stoichiometric amounts of copper. Finally, the
regeneration of B from A via transfer of CN group from αꢀ
cyanoacetate to copper center completes the catalytic cycle. At
40 present, it is unclear about the detailed mechanism for the
reaction of intermediate B with aryl halide. Possible oxidative
addition/reductive elimination, nucleophilic aromatic substitution,
σꢀbond metathesis, and single electron transfer mechanisms22,23
may be operative. Additional efforts including computational
45 studies may be required to obtain more information to distinguish
between these candidates.
3
4
5
For reviews on transition metalꢀcatalyzed cyanation reactions, see:
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Luo, P. Lu and Y. Wang, Tetrahedron Lett., 2014, 55, 1271.
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85
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6
M. Taillefer, Chem.－Eur. J., 2005, 11, 2483; (d) T. Schareina, A.
95
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100
105
110
7
8
F.ꢀH. Luo, C.ꢀI. Chu and C.ꢀH. Cheng, Organometallics, 1998, 17,
1025.
5
Conclusions
In summary, a reaction protocol for copperꢀcatalyzed aromatic
4
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9
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