Conversions of aryl carboxylic acids into aryl nitriles using multiple types of Cu-mediated decarboxylative cyanation under aerobic conditions

Article abstract of DOI:10.1039/d0ob01945c

Here, we used malononitrile or AMBN as a cyanating agent to develop efficient and practical protocols for Cu-mediated decarboxylative cyanations, under aerobic conditions, of aryl carboxylic acids bearing nitro and methoxyl substituents at the ortho position as well as of heteroaromatic carboxylic acids. These protocols involved economical methods to synthesize value-added aryl nitriles from simple and inexpensive raw materials. Further diversification of the 2-nitrobenzonitrile product was performed to highlight the practicality of the protocols. This journal is

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DOI: 10.1039/D0OB01945C
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Conversion of aryl carboxylic acids into aryl nitriles through multi-
versions of Cu-mediated decarboxylative cyanation under aerobic
conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Zhengjiang Fu,*a,b Xihan Cao,b Shuiliang Wang,b Shengmei Guo,b and Hu Cai*a
DOI: 10.1039/x0xx00000x
Using malononitrile or AMBN as cyanating agent, efficient and NH4 /DMF,5c NH4 /DMSO,5d etc) have been employed as
practical protocols for Cu-mediated decarboxylative cyanation of attractive alternatives for the synthesis of aromatic cyanides.4-
aryl carboxylic acids bearing nitro and methoxyl substituents at 5 Despite major progress in the field for user-friendly cyanating
the ortho position as well as heteroaromatic carboxylic acids have agents, a close investigation of previous studies4-5 revealed a
been well established under aerobic conditions, which are few challenges associated with cyanation conversion: (1) as in
obviously economical methods to synthesize value-added aryl the case of selected aryl source, there are drawbacks for
nitriles from simple and cheap raw materials. Further prefunctionalization of substrate using aryl halide as aryl
diversification of 2-nitrobenzonitrile product has been performed source and selectivity of C-H bond employing arene as aryl
+
+
to highlight practicality of the protocols.
source; (2) as in the case of chose cyanation catalyst, the use
of noble metal mediators led to high reaction cost; (3) as in the
case of used oxidant, metal salts and organic oxidants have
environmental and cost disadvantages over oxygen.
The incorporation of a cyano group into the structure of
aromatic compounds can dramatically modify their properties,
which is reflected in that aryl nitriles are key structural motifs
in a wide spectrum of pharmaceuticals, natural products and
function materials, moreover, nitrile group can serve as a
versatile synthetic intermediate that can be easily transformed
into various functional groups including amide, amine, ketone,
aldehyde, carboxylic acid and heterocycle.1 As a result, the
development of practical and efficient approaches for the
synthesis of aryl nitriles has been a longstanding goal in
synthetic methodology.
Traditionally, the general strategies for cyanation mainly
involve classical synthetic methods, such as Sandmeyer
transformation of aryldiazonium salts and Rosenmund-von
Braun conversion of aryl halides with stoichiometric amounts
of CuCN.2 Over the past decades, extensive investigation has
been made in transition metal-promoted formation of aryl
nitriles with various metal cyanides M-CN (CuCN,3a NaCN,3b
KCN,3c Zn(CN)2,3d K4Fe(CN)6,3e etc) as cyano source.3 To
overcome notorious drawback associated with toxicity of some
metal cyanides, organic R-CN (BnCN,4a TMSCN,4b TBACN,4c
CH3CN,4d NCTS,4e butyronitrile,4f and acetone cyanohydrins,4g
etc) and the combined cyano group (AIBN,5a DMF,5b
In recent decade, the emergence of decarboxylative
coupling has enabled the use of benzoic acids as aryl sources,
furthermore, the generated aryl-metal intermediate under
decarboxylation can serve as either electrophile or nucleophile
depending on the nature of employed transition-metal
mediator.6 Thus, transition metal-catalyzed decarboxylative
functionalization of aryl carboxylic acids has emerged as a
powerful tool to build carbon-carbon/hetero bonds.7 Recently,
we have reported Ag/Cu-promoted decarboxylative cyanation
+
of benzoic acids with K4Fe(CN)6 or NH4 /DMF as cyano source
to synthesize aryl nitriles (Scheme 1, a and b).8 In view of our
continuing research pursuit in the realms of functionalization
of carboxylic acids,9 we describe herein two protocols for
preparing aryl nitriles through Cu-promoted decarboxylative
cyanation of aryl carboxylic acids with malononitrile or AMBN
(2,2'-azodi(2-methylbutyronitrile)) as cyanating agent under
aerobic conditions (Scheme 1, c and d).
As we have established CuI-promoted decarboxylative
cyanation of benzoic acids with K4Fe(CN)6 as cyanide reagent
K4Fe(CN)6
CN
NC
CN
CN
c
Ref. 8a
a
COOH
this work!
R
R
R
Ref. 8b
NH4+/DMF
d
b
a. College of Chemistry, Nanchang University, Nanchang 330031, China. E-
mail: fuzhengjiang@ncu.edu.cn, caihu@ncu.edu.cn.
AMBN
Scheme
1 The established and desired decarboxylative
b. State Key Laboratory of Coordination Chemistry, Nanjing University,
Nanjing, Jiangsu 210023, China
cyanation transformations in our group
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Journal Name
Table 1 Optimization of the reaction conditions with malononitrile Table 2 The scope of aryl carboxylic acids in decarboxylative
View Article Online
DOI: 10.1039/D0OB01945C
as cyano sourcea
cyanation
COOH
CN
NC
CN
condition A
[Cu], base
O2
DMF, 160 °C
R
or
R
+
NO2
NO2
CN
condition B
AMBN
1
14
1 14p
-
-
+
CN
NC
CN
CN
CN
Me
CN
COOH
O2N
O2N
O2N
O2N
7
7p
2 equiv
OMe
Yieldb (%)
Entry [Cu] (equiv.)
Base (equiv.)
_
OMe
OMe
OMe
, 61%a,c (45%b)
, 42%a (19%b)
, 53%a (48%b)
, 71%a,c (40%b)
1p
2p
3p
4p
1
2
CuI (0.5)
CuI (1.0)
CuI (1.0)
CuI (1.2)
CuBr (1.2)
CuCl (1.2)
26%
38%
46%
55%
31%
13%
20%
59%
75%
80%
38%
71%
63%
43%
75%
32%
CN
_
CN
CN
O2N
O2N
Me
O2N
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
KOAc (1)
KOtBu (1)
K3PO4 (1)
K2HPO4 (1)
K3PO4 (0.5)
K3PO4 (2)
K3PO4 (1)
K3PO4 (1)
K3PO4 (1)
3
4
5
6
7
8
9
NH2
, 22%a (0%b)
, 80%a (52%b)
O2N
, 70%a,c (53%b)
6p
7p
CN
5p
CN
CN
CN
O2N
O2N
O2N
CuOAc (1.2)
Cl
, 42%a (0%b)
CF3
, 39%a (0%b)
Cl
F
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
CuI (1.2)
, 43%a (21%b)
9p
, 28%a,d (25%b)
8p
11p
10p
Me
MeO
Me
10
11
12
13
14c
15d
16e
CN
CN
, 33%a,c (65%b,f
CN
, 48%a (47%b,f
14p
S
O
MeO
OMe
, 39%a (50%b,e
)
)
12p
13p
)
aCondition A: acid (0.2 mmol), malononitrile (2 equiv), CuI (1.2
equiv), K3PO4 (1 equiv), DMF (2 mL), O2, 160 oC, 20 h.
bCondition B: acid (0.2 mmol), AMBN (4 equiv), CuBr (1.2
equiv), K2CO3 (1 equiv), DMSO (2 mL), O2, 160 oC, 20 h. c170 oC
aConditions: 7 (0.2 mmol), malononitrile (2 equiv), DMF (2 mL),
instead of 160 oC. dDMSO instead of DMF. The addition of
e
o
b
c
O2, 160 C, 20 h. Yield of the isolated product. Malononitrile
(1 equiv). dMalononitrile (3 equiv). e140 oC.
Pd(OAc)2 (0.1 equiv). fCuI (1.2 equiv), K3PO4 (1 equiv) and DMF
(2 mL) instead of CuBr (1.2 equiv), K2CO3 (1 equiv) and DMSO
(2 mL).
under aerobic conditions,8a further inspired by the reports that
readily accessible malononitrile could offer cyano source
under certain conditions,10 thus, Cu-mediated decarboxylative
cyanation between 2-nitrobenzoic acid 7 and malononitrile in
DMF was selected as the model reaction for optimization
studies (Table 1). At the outset, employing 0.5 or 1 equivalent
of CuI as reaction promoter, the model reaction furnished
desired 2-nitrobenzonitrile 7p in moderate yields at 160 °C for
20 hours with malononitrile (2 equiv.) as cyano source under
aerobic conditions (entries 1-2). Interestingly, the additive of
K2CO3 had a beneficial effect on the transformation to increase
yield (entry 3). Fortunately, increasing the loadings of CuI led
to a continuously increased yield, and a careful examination of
different mediators at this stage revealed CuI gave superior
yield than other cuprous salts (entries 4-7). Significantly,
further screening of the counteranion of potassium salt
compound showed K3PO4 was a much better choice than other
tested additives (entries 8-11). It’s found that both decreasing
and increasing the loadings of K3PO4 additive or coupling
partner malononitrile resulted in a drop of reaction efficiency
under otherwise equal condition, thus, the amounts of K3PO4
and malononitrile have an effect on the transformation
(entries 12-15). To our disappointment, lowering the reaction
temperature had a detrimental effect on the conversion to
afford a significantly diminished outcome (entry 16). Finally,
the optimized reaction conditions was obtained as described in
entry 10 of Table 1.
Subsequently, the obtained optimality conditions
encouraged us to evaluate the scope and generality of aryl
carboxylic acids substrates in decarboxylative cyanation
coupling with malononitrile as cyano source. As illustrated in
Table 2 (condition A), moderate to good yields were obtained
for a diverse array of benzoic acids bearing nitro 1-11 and
methoxyl 12 substituents at the ortho position, O- and S-
containing heteroaromatic carboxylic acids 13-14, furthermore,
the isolated yields indicated there was no apparent electronic
effect in the process. For instance, whether there was a
methoxy substituent at C4 or C5 position of o-nitrobenzoic
acid 2-3 or two methoxy groups at C4 and C5 sites of o-
nitrobenzoic acid 1, the conversions furnished mild yields for
corresponding products. Notably, satisfied yields were
observed for decarboxylative cyanation of 2-methyl-4-
nitrobenzoic acid 4 and its isomeric compound 5 with a methyl
substituent at the ortho-position of carboxyl group under
slightly modified conditions, thus, steric hindrance of the
substituent had almost no noticeable effect on the reaction
efficiency. Although 2-nitrobenzoic acid 7 smoothly formed
target product in good yield as high as 80%, significantly, o-
nitrobenzoic acid tolerated an unprotected amino substituent
at the para-position of nitro group 6 were qualified substrate
to deliver expectative product. Besides electron-donating
substituents, electron-withdrawing groups including chloro,
2 | J. Name., 2012, 00, 1-3
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fluoro and trifluoromethyl were well tolerated in this protocol, transition metal and the formed metal cyaniVdieew AgrteicnleeOrnallinlye
DOI: 10.1039/D0OB01945C
restrain the desired reaction, as a matter of fact,
such as o-nitrobenzoic acid bearing a chloro substituent at the
N
Cu
NH
H+
Cu(I)
NO2
base
NC
path a
CN
N
N
Ar-CN
Ar
Ar
B
C
product
Cu(I), O2
CO2, H+
Ar-Cu(II)
A
Ar-COOH
CONH2
path b
Ar-Cu(III)-CN
Ar-CN
product
G
16p
, 80%
CN
F
Cu(I)
Me
Et
CN
Me
MeCOEt
NC
Et
N
N
(AMBN)
b
Et
CN
Me
O
E
Et
CN
Me
N2
NO2
NO2
NH2
CN
D
O2
c
a
CN
CO2H
17p
, 95%
Scheme 2 Proposed mechanism using malononitrile or AMBN as
cyanating agent
7p
15p
, 98%
d
meta-position of carboxyl group 9 and o-nitrobenzoic acid with
an electron-withdrawing group at the para-position of
carboxyl group 8, 10-11 were effective substrates to
conveniently provide hoped-for products, interestingly, the
survived halogen moiety could be used for further
functionalization of the products through traditional cross
coupling. Remarkably, electron-sufficient aryl carboxylic acids
NO2
H
N
N
N
, 79%
N
18p
Scheme 3 Diversification of 2-nitrobenzonitrile (7p)
including
2,4,6-trimethoxybenzoic
acid
12,
3-
3-
methylbenzothiophene-2-carboxylicacid
13
and
stoichiometric amounts of Cu was usually used due to cyanide
poisoning in decarboxylative cyanation coupling reaction.
Following the above radical mechanistic hypothesis, we
envisioned that AMBN would be a feasible cyanating reagent
for decarboxylative cyanation transformation. As outlined in
Table 2 (condition B), it’s found CuBr (1.2 equiv.) as reaction
promoter worked well for a variety of ortho-nitrobenzoic acids
1-5, 7-8 and 10 bearing different substituents including
electron-donating (methoxy and methyl) and -withdrawing
(chloro and fluoro) groups under aerobic conditions, while
smooth decarboxylative cyanation of 2,4,6-trimethoxybenzoic
acid 12 was conveniently realized with the assistance of
Pd(OAc)2 as catalyst under otherwise identical conditions. In
addition, heteroaromatic carboxylic acids 13-14 well
participated in the transformation under slightly modified
conditions.
methylbenzofuran-2-carboxylicacid 14 well proceeded to
undergo the desired conversion. Overall, regardless of the
presence of an electron-withdrawing or -donating substituent
on the position ortho to carboxyl group, a broad range of
aromatic carboxylic acids proved to be suitable substrates for
decarboxylative cyanation with malononitrile as cyanating
agent.
Although the detailed mechanism should await further
investigation, a plausible mechanism for this decarboxylative
cyanation transformation was proposed in Scheme 2. As
reported in the literature,11 initially, aryl carboxylic acid was
swimmingly decarboxylated to aryl-Cu(II) intermediate A in the
presence of Cu(I) mediator under aerobic conditions. As path a
illustrated, employing malononitrile as cyano source, the
reaction between malononitrile and aryl-Cu(II) intermediate A
led to formation of a cupric ketimine intermediate B, followed
by protonation of intermediate B to generate ketimine C, while
the subsequent deprotonation of ketimine C with base
additive resulted into retro-Thorpe fragmentation to give
desired product aryl nitrile.10a
COOH
CN
Cu(OAc)2 (0.5 equiv)
AgOAc (0.2 equiv)
O2N
O2N
+
CH3CN
2 mL
O2, 140 C
7
7p
, 4% yield
by GC-MS
Moreover, if cyano radical •CN existed in reaction mixture,
as path b demonstrated, aryl-Cu(II) intermediate A would trap Scheme 4 Decarboxylative cyanation using CH3CN as cyanating
the cyano radical to form intermediate G through single agent
electron transfer, which finally provided target product aryl
nitrile via reductive elimination. In this regard, using AMBN as
Thereafter, the diversification of 2-nitrobenzonitrile 7p was
cyanating reagent, homolytic cleavage of C-N bond of AMBN performed to exhibit practicality of decarboxylative cyanation
with liberation of N2 formed radical intermediate D which product (Scheme 3). In the case of transformation of nitro
could be further oxidized to radical intermediate E under group, the nitro group could be easily reduced to
aerobic conditions,5a,12 and radical intermediate E could corresponding amine 15p with a combination of B2pin2/KOtBu
produce cyano radical in the following process. Since excess in nearly quantitative yield.13 For the conversion of cyano
dissociative cyano group is prone to coordination with group, it’s found Pd(OAc)2/bipyridyl enabled hydration of aryl
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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nitrile into primary amide 16p in water,14 2-nitrobenzoic acid
17p was successfully obtained in excellent yield when the
compound was heated with a mixture of aqueous HBr/HOAc
under reflux,15 furthermore, [3+2] cycloaddition of nitrile with
sodium azide was readily realized to afford tetrazole 18p
under Cu catalysis.16
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In conclusion, we have developed two novel protocols for
Cu-mediated decarboxylative cyanation of easily available aryl
carboxylic acids with cheap malononitrile or AMBN as
cyanating agent. The methods presented environmentally
benign and cheap complements to conventional methods for
synthesis of valuable aryl nitriles. Efforts are currently
underway to improve reaction efficiency and further explore
other easily accessible cyano soure (Scheme 4), the results will
be reported in due course.
Conflicts of interest
There are no conflicts of interest to declare.
Conflicts of interest
Financial support from the National Natural Science
Foundation of China (NSFC) (21761021 and 21861026) is
gratefully acknowledged.
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Organic & Biomolecular Chemistry
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Journal Name
COMMUNICATION
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View Article Online
DOI: 10.1039/D0OB01945C
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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01945C
COOH
CN
NC
CN
Cu
R
R
AMBN
· Cheap synthetic method
· Up to 80% yield
Two methods for Cu-mediated decarboxylative cyanation of aryl
carboxylic acids with malononitrile or AMBN as cyanating agent have
been well established under aerobic conditions. Obviously, these
approaches have economical advantage in the synthesis of valuable aryl
cyanides from simple and cheap raw materials.