Cu-Catalyzed Cyanation of Arylboronic Acids with Acetonitrile: A Dual Role of TEMPO

Article abstract of DOI:10.1002/chem.201501823

The cyanation of arylboronic acids by using acetonitrile as the "CN" source has been achieved under a Cu(cat.)/TEMPO system (TEMPO=2,2,6,6-tetramethylpiperidine N-oxide). The broad substrate scope includes a variety of electron-rich and electron-poor arylboronic acids, which react well to give the cyanated products in high to excellent yields. Mechanistic studies reveal that TEMPO-CH₂CN, generated in situ, is an active cyanating reagent, and shows high reactivity for the formation of the CN^- moiety. Moreover, TEMPO acts as a cheap oxidant to enable the reaction to be catalytic in copper. The cyanation of arylboronic acids by using acetonitrile as the "CN" source has been achieved under a Cu(cat.)/TEMPO system. Electron-rich and electron-poor arylboronic acids react well to give the cyanated products in high to excellent yields. Mechanistic studies reveal that TEMPO-CH₂CN, generated in situ, is an active cyanating reagent. Moreover, TEMPO, a cheap oxidant, enables the reaction to be catalytic in copper (see scheme; TEMPO=2,2,6,6-tetramethylpiperidine N-oxide).

Full text of DOI:10.1002/chem.201501823

DOI: 10.1002/chem.201501823
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&
CÀC activation |Hot Paper|
Cu-Catalyzed Cyanation of Arylboronic Acids with Acetonitrile:
A Dual Role of TEMPO**
Yamin Zhu, Linyi Li, and Zengming Shen*[a]
Abstract: The cyanation of arylboronic acids by using aceto-
nitrile as the “CN” source has been achieved under
a Cu(cat.)/TEMPO system (TEMPO=2,2,6,6-tetramethylpiperi-
dine N-oxide). The broad substrate scope includes a variety
of electron-rich and electron-poor arylboronic acids, which
react well to give the cyanated products in high to excellent
yields. Mechanistic studies reveal that TEMPOÀCH2CN, gener-
ated in situ, is an active cyanating reagent, and shows high
reactivity for the formation of the CNÀ moiety. Moreover,
TEMPO acts as a cheap oxidant to enable the reaction to be
catalytic in copper.
Introduction
The activation of CÀC bonds is an appealing, yet challenging,
strategy in modern organic chemistry that provides a novel
and direct process for cross-coupling.[1] Acetonitrile is
a common solvent that shows weak coordination to metal cen-
ters and is typically inert in transition-metal-catalyzed coupling
reactions owing to a high CH3ÀCN bond dissociation energy
(133 kcalmolÀ1), relative to alkane CÀC bonds (ca. 83 kcal
molÀ1) (Scheme 1). Consequently, catalytic activation of the
acetonitrile CÀCN bond by transition metals has rarely been
explored.[2] A few examples of cyanation by employing the rel-
atively safe acetonitrile as the cyano source have been docu-
mented by Cheng, Li, Zhu, Shen, and others.[3,4] Recently, we
disclosed the Cu-catalyzed cyanation of aromatic CÀH bonds
through CH3ÀCN bond cleavage, in which disilane plays a cru-
cial role in promoting acetonitrile cleavage.[4] Herein, we de-
scribe the catalytic cyanation of boronic acids by using aceto-
nitrile as an attractive cyano source. This strategy avoids the
use of highly toxic metal cyanides and occurs through a novel
mechanism for cross-coupling.
Scheme 1. Catalytic cyanation strategy using acetonitrile as the “CN” source.
anides (e.g., TMSCN, BnCN, NCTS, RSCN) were used as the cy-
anating agent. Identifying ways to generate “CN” in situ from
simple and readily available reagents by a combination process
is a highly attractive strategy. Since Chang’s pioneering discov-
ery, there have been notable advances in this area;[8d,11–14] how-
ever, the main problem with these procedures is that super-
stoichiometric amounts of copper species were required. In
2012, Chang and co-workers developed a procotol for the cy-
anation of arylboronic acids by using a NH4I/DMF combina-
tion;[10c] wherein, stoichiometric amounts of Cu(NO3)2·3H2O
were needed (Scheme 1). More recently, advances have been
made by Li,[3b] Zhu,[3c] and Chang,[11d] in the catalytic cyanation
of aryl iodides and arenes by using a catalytic Cu species com-
bined with a stoichiometric oxidant, Ag2O or Ag2CO3. Al-
though, silver salts are generally more expensive than copper
species.
Arylboronic acids are readily available and easy-to-handle
coupling partners in metal-catalyzed coupling reactions.[5–8]
However, to the best of our knowledge, there are only a few
examples regarding the transformation of arylboronic acids
into aryl nitriles, which use Pd,[9a–b] Rh,[9c] or Cu[10] catalysts or
stoichiometric promoters. In these procedures, metal cyanides
(e.g., Zn(CN)2, K4[Fe(CN)6], CuCN, CuSCN) or specific organic cy-
[a] Y. Zhu, L. Li, Prof. Dr. Z. Shen
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai, 200240 (P.R. China)
Fax: (+86)21-54741297
As an alternative to metal oxidants, TEMPO (2,2,6,6-tetra-
methylpiperidine N-oxide) is a persistent nitroxide radical that
has found widespread application in organic synthesis. Along
with its use as a radical trapping reagent, TEMPO has been
used as a mild oxidant in transition-metal-catalyzed coupling
reactions.[15] Recently, we revealed that TEMPO can be used as
E-mail: shenzengming@sjtu.edu.cn
[**] TEMPO=2,2,6,6-tetramethylpiperidine N-oxide
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501823.
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an oxidant in the cyanation reaction to allow the use of cata-
lytic amounts of the Cu species.[4b] All of these studies inspired
us to achieve the Cu-catalyzed cyanation of arylboronic acids
by using CH3CN as the “CN” source. Subsequent mechanistic
studies have gained insight into the activation of the CÀC
bond in acetonitrile.
such as Cs2CO3, TMEDA, DBU, and H2O, also efficiently gave the
product 2a in 59–80% yield (Table 1, entries 10, 12–14). When
iPr2NH and H2O were used as additives, we considered that
they might combine with the boronic compound that is re-
leased from substrate 1a, which would drive the cyanation re-
action forward and result in a higher yield of the product. By
varying the ligand, we found that the use of catalyst Cu(OAc)2/
1,10-phenanthroline (1,10-phen, L4) in acetonitrile afforded op-
timal results (Figure 1). Under these conditions, the cyanated
product 2a was formed in quantitative yield. Other copper
complexes, such as Cu(ClO4)2·6H2O, Cu(NO3)2·3H2O, and
Cu(OTf)2, also worked well as catalysts for this transformation,
which gave 2a in 88, 92, and 78% yields, respectively. In addi-
tion, a series of control experiments were carried out, which
suggest that disilane is essential for the CÀCN cleavage (see
the Supporting Information, Table S1).
Results and Discussion
To test the Cu-catalyzed cyanation of arylboronic acids with
acetonitrile, we used 2-naphthyl boronic acid (1a) as a model
substrate. Based on conditions that we previously optimized
for the cyanation of CÀH bonds by using CH3CN,[4] compound
1a was first treated with Cu(OAc)2/bathophenanthroline (L2)
(20 mol%) and (Me3Si)2 (2 equiv) in CH3CN under an oxygen at-
mosphere at 1508C, but none of the desired product 2a was
observed (Table 1, entry 1). In contrast, the fast protonolysis of
1a occurred to yield the deboronated naphthalene product. To
avoid this side reaction, we envisioned a strategy that involved
a sequential iodination/cyanation of arylboronic acids in one
pot. Therefore, a wide range of oxidants were examined in the
presence of I2.[16] To our delight, TEMPO was the best oxidant,
which gave the corresponding cyanated product 2a in 50%
yield (Table 1, entry 8). In contrast, Ag2CO3 only gave 19% yield
of 2a (Table 1, entry 2), and oxone, BQ, TBHP, and benzoic per-
oxyanhydride showed even poorer reactivity (Table 1, en-
tries 3–6). With TEMPO as an oxidant, we switched from I2 to
NIS, and observed the yield 2a increase to 65% (Table 1,
entry 9). To further enhance the yield, various additives were
tested. Gratifyingly, an 88% yield of 2a was observed when
using iPr2NH as an additive (Table 1, entry 11). Other additives,
Next, we investigated the scope of the reaction by varying
the substituent on the arylboronic acid (Table 2). A variety of
arylboronic acids 1b–g with electron-donating groups (R=Me,
OMe, OBn, tBu, respectively) on the aryl ring furnished the cor-
responding products 2b–g in 71–97% yields (Table 2, en-
tries 1–6). More electron-rich boronic acids 1o–1q, which con-
tained two electron-donating substituents, worked more effi-
ciently to give the products 2o–q in 81–99% yields (Table 2,
entries 14–16). Additionally, it was observed that electron-with-
drawing substituents (R=4-OCF3, 4-CF3, 4-COOMe, 4-F) were
tolerated under the reaction conditions; however, the corre-
sponding products 2j–l,r were afforded in lower yields
(Table 2, entries 9–11 and 17). Notably, the substrate 1n, which
contained a strongly electron-withdrawing NO2 group, per-
Table 1. Optimization of conditions for arylboronic acid cyanation using
CH3CN.[a]
Entry
[I] source
Additive
(1 equiv)
Oxidant
t
[h]
Yield
[%][b]
1
2
3
4
5
6
none
–
–
–
–
–
–
–
48
72
72
72
72
72
–
I2 (0.6 equiv)
I2 (0.6 equiv)
I2 (0.6 equiv)
I2 (0.6 equiv)
I2 (0.6 equiv)
Ag2CO3 (1 equiv)
oxone (1 equiv)
BQ (1 equiv)
19
13
33
2
TBHP (1 equiv)
benzoic peroxy
anhydride (1 equiv)
TEMPO (2 equiv)
TEMPO (2 equiv)
TEMPO (2 equiv)
TEMPO (2 equiv)
TEMPO (2 equiv)
TEMPO (2 equiv)
TEMPO (2 equiv)
TEMPO (2 equiv)
3
7[c]
8
I2 (0.6 equiv)
I2 (0.6 equiv)
–
–
–
72
72
58
48
48
48
48
48
34
50
65[d]
59
88
78
78
80
9
NIS (1.1 equiv)
NIS (1.1 equiv)
NIS (1.1 equiv)
NIS (1.1 equiv)
NIS (1.1 equiv)
NIS (1.1 equiv)
10
11
12
13
14
Cs2CO3
iPr2NH
TMEDA
DBU
H2O
[a] Conditions: 1a (0.2 mmol), Cu(OAc)2 (20 mol%), L2 (20 mol%), iodine
source, (Me3Si)2 (2 equiv), TEMPO (2 equiv), additive, O2, 1508C. [b] Yield
of isolated product 2a. [c] Using L1 as the ligand (20 mol%). [d] GC yield
using dodecane as internal standard.
Figure 1. Effect of ligands in the cyanation of arylboronic acids by using
CH3CN.
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Table 2. Scope of substrates in the Cu-catalyzed arylboronic acid cyana-
tion using CH3CN.[a]
Table 3. Scope of heteroarylboronic acids in the Cu-catalyzed cyanation
using CH3CN.[a,b]
[a] Conditions:
4 (0.2 mmol), Cu(OAc)2 (20 mol%), L4 (20 mol%), NIS
(1.1 equiv), (Me3Si)2 (2 equiv), TEMPO (2 equiv), iPr2NH (1 equiv), O2,
1508C, 2–3 days. [b] Yield of isolated product 5.
yields. In addition, alkenyl boronic acid 4j could smoothly re-
acted to give the cinnamonitrile 5j in 62% yield.
Besides arylboronic acids, arylboronic esters and borate salts,
such as potassium trifluoroborates, are both attractive classes
of air-stable and easy-to-handle coupling reagents.[5] Under the
optimal reaction conditions, widely-used boronic ester 4k and
borate salt 4l were smoothly transformed into the correspond-
ing cyanated products 2a and 5l in 92 and 83% yields, respec-
tively [Eq. (1)–(2)]. In addition, 2-iodonaphthalene 3a was sub-
jected to the standard reaction conditions to test the reactivity
of aryl iodide substrates in this cyanation reaction, and the cor-
responding cyanated product 2a was afforded in 92% yield
[Eq. (3)]. Overall, these results demonstrate that this methodol-
ogy is a general and suitable approach for the cyanation of ar-
ylboronic acids, arylboronic esters, borate salts, and aryl io-
dides.
[a] Conditions:
1 (0.2 mmol), Cu(OAc)2 (20 mol%), L4 (20 mol%), NIS
(1.1 equiv), (Me3Si)2 (2 equiv), TEMPO (2 equiv), iPr2NH (1 equiv), O2,
1508C, 2–3 days. [b] Yield of isolated product 2. [c] Using (4-bromophe-
nyl)boronic acid 1t as substrate; 66% yield of 2m was obtained in this
reaction through the change of bromide to iodide. [d] Using (4-iodophe-
nyl)boronic acid as substrate, TEMPO (4 equiv).
formed well and underwent complete conversion to the prod-
uct 2n (>99% yield, Table 2, entry 13). The versatile 4-CN (1m)
and 4-Cl (1s) functional groups were well-tolerated and can be
used as synthetic handles for various applications (Table 2, en-
tries 12 and 18). The compatibility of this reaction was further
extended to free vinyl (1h), NH2 (1u), sulfide (1v), and mor-
pholine (1w) functional groups on the aromatic ring, which
gave the desired products in 48–97% yields (Table 1, entries 7
and 21–23). Fused phenanthrene-based boronic acid 1y pro-
duced the corresponding product 2y in 90% yield (Table 2,
entry 25).
Next, we tested pentanenitrile (18CN), isobutyronitrile
(28CN), and pivalonitrile (38CN) as alternative cyano sources
Encouraged by the broad scope of substituted phenyl bor-
onic acid substrates in this reaction, we tested various hetero-
arylboronic acids under the Cu/TEMPO catalytic conditions
with acetonitrile. As shown in Table 3, 3-pyridyl boronic acids
4a–c, which contain 2-OMe, 6-OMe, and 6-Cl substituents, re-
spectively, gave 3-cyano pyridines 5a–c in good yields. Other
heterocyclic boronic acids, including quinoline (4d), isoquino-
line (4e), pyrimidine (4 f), benzofuran (4g), benzothiophene
(4h), and 9-phenyl-9H-carbazole (4i), reacted under these con-
ditions to furnish the corresponding products in 10-88%
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Table 4. Other alkylnitriles as “CN” source.[a]
Product yield [%]
Other nitriles
53
27
43
75
trace
80
[a] Under the standard conditions.
(Table 4). The experimental results revealed that the long chain
primary nitrile, pentanenitrile, gave the cyanated product 2a
with an efficiency comparable to acetonitrile. Whereas, the sec-
ondary nitrile, isobutyronitrile, had lower efficiency in this
system, and the more bulky tertiary nitrile, pivalonitrile, hardly
reacted under the standard conditions. This trend indicates
that the steric demand of the nitrile has a critical effect on the
CÀCN bond scission.
Figure 2. Reaction profile using 1a as the model substrate.
Investigating the role of TEMPO
A key intermediate, TEMPOÀCH2CN (6), was isolated and con-
firmed by NMR spectroscopy and HRMS. Consequently, a series
of experiments, which employed 6 in place of TEMPO, were
executed. As displayed in Table 5, naphthalen-2-ylboronic acid
1a reacted with 6 smoothly to give the cyanated product 2a
in 98% yield under O2 and 95% yield under N2 (Table 5, en-
tries 1 and 4). In contrast, during optimization of the reaction
conditions (Table S1, entry 7), we found that oxygen was es-
sential for the cyanation of arylboronic acids with acetonitrile.
Therefore, we propose that oxygen most likely enables the for-
mation of 6. Next, an experiment was designed to test the hy-
pothesis that 6 is the active cyanating agent: the reaction was
carried out in 1,4-dioxane, and 6 was used instead of TEMPO
(Table 5, entry 2). Incredibly, a 33% yield of cyanated product
2a was obtained. These studies support the proposal that in-
termediate 6 is indeed the direct supplier of the “CN” unit as
well as being the oxidant for catalytic cyanation. Accordingly,
TEMPO exhibits a dual role in this reaction: firstly, in the gener-
ation of the active cyanating agent, and secondly, as an oxi-
dant in this catalytic cyanation. However, 2 equivalents of 6 are
necessary for this reaction because 6 appears to decompose to
other compounds (Table 5, entry 3).
Isotope labeling study
To understand the mechanism of the Cu/TEMPO system for
catalytic arylboronic acid cyanation, a series of mechanistic
studies were executed. Labeling experiments were performed
with both CH313CN and CH3C15N, and in both cases nearly com-
plete isotopic incorporation into the cyano moiety of the prod-
uct was observed (Scheme 2). This result indicates that the
cyano group in product 2a originates from the acetonitrile
through CÀCN bond cleavage.
Subsequently, we investigated the CÀCN cleavage[17] in
TEMPOÀCH2CN (6) (Table 6). As aforementioned, other copper
salts can be used as efficient catalysts for this transformation.
Scheme 2. Isotope labeling experiments.
Reaction profile
Table 5. Cyanation using 6 instead of TEMPO.
A reaction profile was obtained for the Cu-catalyzed cyanation
of 1a under the standard conditions. We found that the iodi-
nation product 3a was formed in almost quantitative yield
within 30 min.[16] Subsequently, the cyanated product 2a was
gradually produced from 3a over 48 h (Figure 2). Therefore,
the iodination strategy plays a significant role in the cyanation
of arylboronic acids.
Entry
Conditions
Yield 2a [%]
1
2
3
4
2 equiv 6 under O2
2 equiv 6 using 1,4-dioxane as sol. under O2
1 equiv 6 under O2
98
33
55
95
2 equiv 6 under N2
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NMR spectroscopy and HRMS, and we wondered whether it
would act as a cyanating agent because NÀCN compounds are
often used as cyano sources in reported cyanation reactions.[18]
However, by carrying out a control experiment, we excluded
this possibility (see the Supporting Information, Scheme S2).
Accordingly, these results indicated that not only the CÀCN
bond but also the NÀO bond has been cleaved in compound
6. Incidentally, during NÀO bond cleavage, TEMPO might serve
as an oxidant as well.[15,19]
Table 6. Detection of CNÀ by using indicator paper.[a]
Entry
[Cu]/1,10-phen
(Me3Si)2
CNÀ
1[b]
2
3
4
5
6
7
8
none
none
none
none
none
no
Cu(OAc)2/1,10-phen (20 mol%)
Cu(NO3)2·3H2O/1,10-phen (20 mol%)
Cu(OTf)2/1,10-phen (20 mol%)
Cu(ClO4)2·6H2O/1,10-phen (20 mol%)
Cu(OAc)2/1,10-phen (20 mol%)
Cu(ClO4)2·6H2O/1,10-phen (20 mol%)
Cu(ClO4)2·6H2O/1,10-phen (1 equiv)
none
yes
yes
yes
yes
yes
yes
yes
yes
On the basis of the above mechanistic studies, we have pro-
posed a catalytic cycle for the Cu/TEMPO system (Scheme 3).
Two pathways for the formation of TEMPOÀCH2CN (6) are pos-
sible. In path A, TEMPO directly abstracts a hydrogen atom
none
1 equiv
1 equiv
1 equiv
1 equiv
C
from acetonitrile to form the CH2CN radical, which is trapped
9
by a second molecule of TEMPO to yield TEMPOÀCH2CN (6)
and TEMPOH (12)[19,20b] (detected by GC, see the Supporting In-
formation, for details). In path B, owing to the coordination
ability of the nitrile group onto the Cu species, acetonitrile is
selectively activated and deprotonated by base to generate
the active Cu intermediate 10,[21] which reacts with TEMPO to
form TEMPOÀCH2CN (6) and Cu(NCCH2) (11). Species 11 can be
oxidized by O2 to regenerate the CuII complex; thus, oxygen is
crucial for the generation of 6. To the best of our knowledge,
there is only one early report that demonstrated hydrogen ab-
straction from acetonitrile with a photochemically excited
TEMPO to furnish compound 6.[20a] To investigate this process,
two control experiments were carried out in CH3CN at 1508C
under oxygen with and without the copper catalyst
(Scheme 4). Analysis of the two reactions by GC determined
that compound 6 was only formed in the presence of the
copper catalyst (see the Supporting Information, for details).
Therefore, under thermal conditions, we reason that path B is
more likely for the formation of the compound 6.
[a] CNÀ was detected according to the reported procedure by Sukbok
Chang[10c] and Jiang Cheng[11f]. [b] Starting material was stable without any
conversion during 48 h.
Consequently, we tested these copper complexes in the CÀCN
cleavage of 6 and found that catalytic amounts of Cu(OAc)2,
Cu(NO3)2·3H2O, Cu(OTf)2, and Cu(ClO4)2 with 1,10-phenanthra-
line could efficiently cleave the CÀCN bond in compound 6. In
all cases, the cyanide anion derived from 6 could be detected
by indicator paper[10c,11f] (Table 6, entries 2–5). Incidentally, com-
pound 6 was stable in CH3CN under O2 at 1508C in the ab-
sence of the copper salt and silane (Table 6, entry 1); however,
in the presence of disilane alone, the cyanide anion could also
be detected (Table 6, entry 9). These studies suggest that cleav-
age of the CÀCN bond of TEMPOÀCH2CN (6) proceeds easily in
the presence of a CuII complex and/or (Me3Si)2. It should be
mentioned that the reaction in the presence of both the
copper complex and silane pro-
ceeded faster than that with the
CuII complex or (Me3Si)2 alone.
Whilst investigating the CÀCN
bond cleavage step of TEMPOÀ
CH2CN (6), we observed that
these reactions (Table 6, en-
tries 2–8) afforded multiple prod-
ucts, which were detected by
GC. To elucidate their structure,
the reaction in entry 7 was fur-
ther analyzed by GC-MS (see the
Supporting Information, Fig-
ure S8). One product was deter-
mined to be 2,2,6,6-tetramethyl-
piperidine (8) by MS (MW:
141.1). When Cu(ClO4)2·6H2O was
used as the catalyst, compound
8 could be converted into the
R2NH2ClO4 salt 9, which was con-
firmed by single-crystal X-ray
analysis.
2,2,6,6-Tetramethyl-
piperidine-1-carbonitrile (7) (MW:
166.1) was also identified by Scheme 3. Proposed mechanism for Cu(cat.)/TEMPO cyanation.
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Acknowledgements
This work was supported by the National Natural Sciences
Foundation of China (21272001), Shanghai Education Commit-
tee (13ZZ014) and Shanghai Jiao Tong University. We appreci-
ate Prof. Vy M. Dong (UCI) and Dr. Peter K. Dornan (CIT) for
helpful suggestions.
Scheme 4. Control experiments for “TEMPO”.
Keywords: arylboronic acid
cyanides · TEMPO
·
CÀC activation
· copper ·
In the reaction mechanism, TEMPOÀCH2CN (6) may then
react with CuI, with the assistance of (Me3Si)2, to produce the
“CN” species 13 and R2NH 8 through CÀCN and NÀO bond
cleavage. Notably, the R2NH2I salt 14 was also isolated and con-
firmed by single-crystal X-ray analysis. In this cleavage step, 6
also acts as an oxidant. However, the direct cleavage of aceto-
nitrile to form the cyanide anion cannot be ruled out because
the cyanated product was still obtained in the absence of
TEMPO, albeit with low 20% yield (see the Supporting Informa-
tion, Table S1). The cyanide anion 13 can then take part in the
subsequent cyanation as a “CN” source. In cycle C, the initial
iodination of arylboronic acids with NIS occurs. The generated
aryl iodide 3 then reacts with the CuÀCN species to yield the
desired aryl nitrile 2. Accordingly, cheap acetonitrile efficiently
acts as a “CN” source for the cyanation of arylboronic acids,
and TEMPO allows this reaction to be catalytic in copper.
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To probe the generality of this system, we wondered wheth-
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+
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We have reported the Cu(cat.)/TEMPO system for the cyanation
of arylboronic acids by using acetonitrile as the “CN” source.
The reaction has a broad substrate scope: a variety of elec-
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Received: May 9, 2015
Published online on July 31, 2015
Chem. Eur. J. 2015, 21, 13246 – 13252
www.chemeurj.org
13252
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim