Ni-Mediated Generation of "cN" Unit from Formamide and Its Catalysis in the Cyanation Reactions

Article abstract of DOI:10.1021/acscatal.8b05111

The in situ generation of a "cyano" unit from readily available organic precursors is of high interest in synthetic chemistry. Herein, we report the first example of Ni-mediated dehydration of formamide to form "CN" and its subsequent catalytic applications in the hydrocyanation of alkynes and cyanation of aryl halides. Formamide can serve as a convenient source for the nitrile unit, in that it releases water as the only byproduct.

Full text of DOI:10.1021/acscatal.8b05111

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Letter
Ni-Mediated Generation of “CN“ Unit from Formamide
and Its Catalysis in the Cyanation Reactions
Luo Yang, Yu-Ting Liu, Yoonsu Park, Sung-Woo Park, and Sukbok Chang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b05111 • Publication Date (Web): 14 Mar 2019
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Ni-Mediated Generation of “CN“ Unit from Formamide and Its
Catalysis in the Cyanation Reactions
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Luo Yang,†,* Yu-Ting Liu,† Yoonsu Park,‡,§ Sung-Woo Park,§,‡ and Sukbok Chang§,‡,*
†
Key Laboratory for Green Organic Synthesis and Application of Hunan Province, College of Chemistry, Xiangtan
University, Hunan 411105, PR China
‡
Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 34141, Republic of
Korea
§Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of
Korea
KEYWORDS: cyano source, formamide, Ni catalyst, hydrocyanation, alkynes, aryl halides
ABSTRACT: The in situ generation of a “cyano” unit from readily available organic precursors is of high interest in synthetic
chemistry. Herein we report the first example of Ni-mediated dehydration of formamide to form “CN” and its subsequent
catalytic applications in the hydrocyanation of alkynes and cyanation of aryl halides. Formamide can serve as a convenient
source for the nitrile unit in that it releases water as the only by-product.
C
N
H2
H
O
[Ni]
H
[Ni/Co]
[Ni/Al]
Ar
(X: Br, I)
R
CN
"
"
CN
Ar
CN
X
R
R
R



Formamide as a convenient cyano source
Ni-mediated dehydration of formamide to genertae "CN"
Applied in the hydrocyantion of alkynes and cyanation of aryl bromides
Nitrile constitutes a prevalent unit in numerous natural
products, pharmaceuticals, and agrochemicals.1 It also
serves as a versatile precursor to a range of synthetic
functional groups such as amines, amides, aldehydes,
amidines, ketones, and carboxylic acids.2 Therefore, a
handful of preparative procedures of introducing the
nitrile group onto organic compounds has been developed
by employing various cyano sources. Aryl nitriles can
readily be obtained by classical methods, such as the
Sandmeyer reaction or the Rosenmund-von Braun
protocol using copper(I) cyanide.3 Coupling partners
frequently employed in the transition metal-catalyzed
cyanation reactions are metal- or metalloid cyanides such
as KCN, NaCN, Zn(CN)2, TMSCN or K4[Fe(CN)6] (Scheme
1A).4 An another array of organic cyano precursors that do
not contain metal elements has been scrutinized in recent
years. Representative examples include cyanohydrin, N-
cyanosuccinimide, N-cyano-p-toluenesulfonamide, N-
bromide, and acetonitrile (Scheme 1B).5 Isovaleronitrile
has also been proved to be a versatile “CN” source in a
reversible transfer hydrocyanation of alkenes.6 While each
approach bears its own merits, most procedures have
intrinsic drawbacks in that the cyano sources are often
toxic and/or produce stoichiometric byproducts. In
addition, a careful control of cyanide concentration is often
required to obtain satisfactory catalytic reactivity.7
An alternative approach is to generate the cyano group
in situ from readily available non-toxic organic precursors.
One of the authors previously developed a procedure of
generating “CN” from “combined” cyano precursors
mediated by Cu or Pd catalyst systems.8 In this protocol, a
combination of two compounds was employed to generate
cyano under oxidative conditions. For instance,
dimethylformamide and ammonia or its halide salts were
found to work cooperatively to serve carbon and nitrogen
of the “CN”, respectively (Scheme 1C, left). This approach
was successfully utilized in the chelation-assisted CH
cyanoimindazole,
aryl(cyano)iodonium,
cyanogen
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cyanation of arenes and indoles as well as in the cyanation
observed a color change from yellow to red in a picrate
impregnated indicator paper, which implied the formation
of cyanide anion.9b,10c At the same time, reductive
formation of ammonium formate was also monitored by
13C NMR, which would be generated from a reaction of
formamide with water that is produced from the
formamide dehydration.12 DFT calculations of the putative
pathway suggested that HCN generation, indeed, is
facilitated by the coordination of formamide to the ligated
nickel metal center (Scheme 3). Upon binding of
formamide to the metal center, deprotonation of an amide
of aryl boronic acids and aryl halides.9 Subsequently,
Cheng, Yu, Sakai, and Jiao groups independently showed
that an additional array of organic compounds can also
serve as cyano precursors, including DMSO, TMEDA,
nitromethane, or sodium azide.10a-i Bhanage and co-
workers reported a Pd-catalyzed cyanation of aryl iodides
with formamide as the cyano source in the presence of
POCl3, wherein an Ar-Pd intermediate was proposed to
insert into the C=N bond of a Vilsmer intermediate
generated from a reaction of formamide with POCl3.10j-k
Herein, we report the first example of in situ generation of
“CN” unit from formamide via nickel catalysis (Scheme 1C,
right). This precursor is especially noteworthy as a cyano
source in that it generates water as a single byproduct. This
new procedure was further leveraged to catalyze
hydrocyanation of alkynes and cyanation of aryl halides.
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moiety
by
acetylacetonate
base
becomes
thermodynamically accessible (I to II), and a reasonable
kinetic barrier for this dehydration process was also
calculated (31.9 kcal/mol, II to III-TS).
Ni(acac)2 (0.01 mmol)
bpy (0.06 mmol)
O
CN
+
C
- N
H O2 H4
+
C
H
2
145 oC, 12 h
N
H
H2
detected by detected by
picrate paper
A. Cyanation with metal- or metalloid-"CN" sources
13C NMR
cat. Pd, Ni, or Cu
+
MCN
Ar
X
Ar CN
Scheme 2. Proof of principle: generation of HCN at
mild temperature. The color of picrate impregnated
indicator paper changed from yellow (left, blank) to red
(right, after absorbing HCN.). bpy, 2,2’-bipyridine.
G
X = N2+, I, Br, Cl, OTf
MCN
= CuCN, KCN, NaCN, Zn(CN)2, TMSCN, K4[Fe(CN)6] etc.
B. Cyanation with organic "CN" sources
cat. Pd, Ni, or Cu
H
(kcal/mol)
O
N
+
R-CN
Ar
X
Ar CN
Ni
C
H
N
N
X = H, B(OH)2, I, Br
O
III-TS
OH
III-TS
(-32.58)
III
Ts
CN
,
R-CN
=
I
N
Ph
N CN
N CN
Br-CN CH3-CN
,
CN
(-36.49)
,
,
,
N
(0.0)
acac
acacH
O
31.93
kcal/mol
C. Cyanation with organic precursors
(our contributions)
O
2+ N
Ni
N
C
H
IV
(-48.11)
"CN" from two C and N sources
"CN" from formamide
N
H
cat.
[Pd] or [Cu]
II
(-64.51)
H
I
CHO
O
cat. [Ni]
H3C
N
NH3
+
CN
"
"
C
H
[O]
N
H
H2
CH3
HO
O
N
+
O
N
+
Ni
N
+
Ni
C
H
Ni
N
C
H
current study
N
N
N
N
N
C
H
H
II
III
IV
Scheme 1. Cyanation with various “CN” sources.
Scheme 3. Potential energy profile for HCN formation
Dehydration of formamide to hydrocyanic acid was
previously known to proceed at high temperatures in the
Intrigued by the initial results, we tried to leverage the
reactivity of nickel catalysis for valuable organic
transformations. Specifically, a direct hydrocyanation of
alkynes was first examined to afford vinyl nitriles, which
are a versatile synthetic building unit (Table 1).13 Indeed,
the desired product, 2,3-diphenylacrylonitrile (3a), was
obtained in 18% yield (Z-/E-isomers, 1:1) from a reaction of
diphenylacetylene in formamide and anisole when
Ni(acac)2 was employed (5 mol %) in the presence of
o
range of ~500 C.11 We were curious to see whether the
same transformation would be facilitated by transition
metal catalysts, and, moreover, the in situ generated “CN”
unit could be subsequently incorporated into organic
compounds eventually to make nitrile products. Based on
this initial working hypothesis, we screened a series of late
transition metal-based catalytic conditions, and
discovered that a nickel catalyst system is capable of
generating hydrocyanic acid at lower temperature (Scheme
2). Upon heating formamide and catalytic amounts of
Ni(acac)2 species and bipyridyl ligand at 145 oC, we
o
Xanphos (15 mol %) at 150 C for 12 h (entry 1). While an
increase of catalyst loading improved the product yield to
some extent (entry 2), we found that additives displayed
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significant influence on the reactivity. Inspired by Konwar
(1r) substituted ethynes were also viable for this Ni-
catalyzed cyanation reaction. It is noteworthy that while
an almost equal mixture of stereoisomers (E/Z) was
produced from the reaction of diarylacetylenes, E-isomeric
product (E-3r) was formed exclusively from the
hydrocyanation of dibutylacetylene (1r) although the exact
pathway is not understood at the present stage.
and Maffioli’s finding that Lewis acids can facilitate the
dehydration of amides,14 an array of additives was
examined subsequently. While aluminum or tin species (10
mol %) improved product yields moderately (entries 35),
a reaction in the presence of Co(acac)2 additive gave much
higher efficiency, leading to 3a in 90% yield (entry 6).
While the nature of cobalt species was crucial in this
catalytic reaction (entry 7), cobalt alone did not mediate
the cyanation (entry 8). Reaction at lower temperature
resulted in a sharp decrease in product yield (entry 9).
Nickel catalysts other than Ni(acac)2 were less effective for
the current transformation (entries 1012). While a similar
ligand effect of bipyridine was observed when it compared
to Xantphos in the absence of additives (entry 13), the latter
one was much more effective in combination with cobalt
species (entry 14).
Table 2. Scope of the alkynes for the hydrocyanation a
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Ni(acac)2 (5 mol %)
Co(acac)2 (10 mol %)
O
CN
Xantphos (15 mol %)
R
R
+
C
R
PhOCH3
150 oC, 24 h
N
H
H2
R
1a 1r
-
3a 3r
-
R1 = H
4-Me
, 89% (1:1.2)
, 96% (1:1.3)
, 93% (1:1)
3a
3b
3c
3d
3-Me
Table 1. Optimization of the alkyne hydrocyanation a
2-Me
, 76% (11:1)
, 91% (1.2:1)
3e
3f
4-Et
Ni catalyst
4-nBu
, 85% (1:1)
Xantphos (15 mol %)
4-tBu
, 88% (1.4:1)
, 90% (1.3:1)
, 85% (1.1:1)
, 90% (1.3:1)
O
3g
3h
CN
CN
R1
additive (10 mol %)
Ph
Ph
+
C
2,4-(Me)2
3,5-(Me)2
3,4-(Me)2
4-OMe
3-OMe
2-OMe
4-OEt
Ph
N
H
H2
PhOCH3
150 oC, 24 h
Ph
R1
3i
3j
1a
2
3a
3k
, 86% (1.2:1)
, 81% (1:1.3)
entry
[Ni] (mol %) additive (mol %) yield of 3a
3l
3m
(%)
, 77% (1:1)
, 85% (1.2:1)
, 70% (1:1.6)
1
2 b
3
4
5
6
7
8
Ni(acac)2 (5)
Ni(acac)2 (25)
Ni(acac)2 (5)
Ni(acac)2 (5)
Ni(acac)2 (5)
Ni(acac)2 (5)
Ni(acac)2 (5)
-
-
-
18
50
31
3n
3o
4-OCF3
2-Cl
AlCl3 (10)
3p
, 77% (1.4:1)
Al(iBu)3 (10)
SnCl2·2H2O (10)
Co(acac)2 (10)
CoCl2 (10)
52
37
90
60
<5
<5
85
63
81
CN
CN
3q
3r
E- , 92% (>99:1)
, 87% (1:1:1)
Co(acac)2 (10)
Co(acac)2 (10)
Co(acac)2 (10)
Co(acac)2 (10)
Co(acac)2 (10)
-
9 c
10
11
12
13 d
Ni(acac)2 (5)
a Reaction conditions: 1 (0.2 mmol), Ni(acac)2 (5 mol %),
NiSO4·6H2O (5)
Ni(COD)2 (5)
NiCl2 (5)
Co(acac)2 (10 mol %), Xantphos (15 mol %), HCONH2 (1.0
o
mL) and anisole (0.6 mL) were reacted at 150 C for 24 h
under argon atmosphere; Ratios of E/Z-isomers
determined by GC analysis are in parenthesis; See SI for
details.
Ni(acac)2 (5)
Ni(acac)2 (5)
22
26
14 d
Co(acac)2 (10)
a
Reaction conditions: 1a (0.2 mmol), Ni catalyst,
Xantphos (15 mol %), and additive in HCONH2 (1.0 mL) and
anisole (0.6 mL) at 150 oC for 24 h under argon atmosphere.
Overall yields of (E) and (Z) isomers determined by GC
Encouraged by the above results on the hydrocyanation
of alkynes, the Ni-catalyst system of generating the cyano
unit from formamide was next attempted to the cyanation
of aryl halides (Table 3). Extensive optimization studies
revealed that the use of AlCl3 additive and 2,2’-bipyridine
(bpy) ligand instead of cobalt and Xanphos, which were
employed for the hydrocyanation of acetylenes, was more
effective in the presence of ZnO in this case (see
Supporting Information for details). The role of ZnO is
assumed to work as a base to neutralize HX (X = Br or I,
vide infra).15 Cyanation of 4-methoxyphenyl bromide and
its iodo analog gave rise to 5a in high yields. The position
of substituents did not much alter the cyanation efficiency
(5b5c). Moreover, the type of substituents in regard to the
b
analysis with n-dodecane as an internal standard.
Xantphos (25 mol %) was added. c Run at 130 C. d bpy (15
o
mol %) was employed instead of Xantphos as a ligand.
Under the optimized conditions, an array of 1,2-
diphenylethynes bearing various substituents (1a1p) was
observed to undergo the desired hydrocyanation to afford
the corresponding acrylonitriles (3a3p) in moderate to
high yields (Table 2). Indeed, substrates with alkyl (1a1l),
alkoxy (1k1o), and halo (1p) substituents could readily be
employed. Furthermore, naphthalen-1-yl (1q) and n-butyl
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electronic and/or steric variation was not a critical factor
this Ni catalysis. An additional application of this
cyanation protocol was conducted for the efficient
synthesis of cyanopromazine (7o), an antipsychotic drug of
a phenothiazine class (Scheme 4).
in the cyanation. The optimized conditions were
compatible with various functional groups such as anilide
(5d5f), primary amide (5m), or olefin (5n). Chlorophenyl
iodides (4k4l) were selectively cyanated to afford
chlorobenzonitriles (5k5l). In addition, naphthalenyl
bromides were readily cyanated without difficulty
(5r5t).16 It should be mentioned that the present
cyanation of (hetero)aryl halides was not found to proceed
via the ArCONH2 intermediacy followed by dehydration
based on control experiments (see Scheme S1 for details).
Table 4. Scope of hetero-aromatic bromides for the
cyanation a
Ni(acac)2 (5 mol %)
AlCl3 (10 mol %)
9
O
bpy (30 mol %)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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Het
C
Br
Het
+
CN
N
H
H2
ZnO (1.0 equiv)
1.2-Dimethoxyethane
145 oC, 12 h
X
X
6a-6n
7a 7n
-
Table 3. Scope of benzene and naphthalene halides for
CN
the cyanation a
NC
NC
Ni(acac)2 (5 mol %)
N
Ph
NC
N
N
Me
AlCl3 (10 mol %)
bpy (30 mo l%)
R
R
O
CN
N
H
X
H
+
C
N
7a
7b
7c
7d
H
H2
,78%
, 79%
, 83%
, 82%
ZnO (1.0 equiv)
1.2-Dimethoxyethane
145 oC, 12 h
4a-4t
5a-5t
CN
CN
N
N
H
CN
CN
CN
CN
MeO
NC
H
N
N
CN
MeO
OMe
AcHN
5d
7e
7f
7g
7h
, 73%
, 84%
CN
, 74%
, 76%
NC
5a
5b
5c
, X = Br, 85%
X = I, 90%
,
X = I, 83%
, X = Br, 89%
X = I, 85%
, X = Br, 92%
X = I, 90%
NC
N
Me
CN
CN
CN
CN
O
S
S
S
tBu
N
H
Me2N
5f
Me
tBu
5h
7i
7j
7k
, 70%
, 72%
, 75%
5e
, X = I, 91%
5g
, X = Br, 88%
, X = Br, 67%
X = I, 76%
, X = Br, 80%
X = I, 82%
CN
X = I, 94%
NC
CN
CN
CN
CN
NC
N
N
N
Cl
5l
Cl
Ph
5i
7l
7m
7n
, 67%
, 71%
, 69%
5j
5k
, X = I, 81%
, X = Br, 85%
X = I, 88%
, X = I, 73%
,
X = I, 72%
a Reaction conditions: 6 (0.2 mmol), Ni(acac)2 (5 mol %),
AlCl3 (10 mol %), bpy (30 mol %), ZnO (1.0 equiv), HCONH2
(1.0 mL) and 1,2-DME (1.5 mL) were reacted at 145 oC for 12 h
under air atmosphere unless otherwise noted: isolated yields.
CN
CN
CN
MeO
MeO
CN
H2N
F3C
5o
Ph
O
5n
, X = Br, 70%
5m
5p
, X = Br, 88%
, X = Br, 91%
,
X = Br, 66%
S
S
N
optimized
conditions
CN
MeO
NC
N
Br
CN
CN
CN
N
N
MeO
OMe
, X = Br, 83%
75% yield
7o
, cyanopromazine
5q
5r
5s
5t
6o, bromopromazine
, X = Br, 73%
, X = Br, 74%
, X = Br, 90%
a
Reaction conditions: 4 (0.2 mmol), Ni(acac)2 (5 mol %),
Scheme 4. Synthesis of cyanopromazine.
AlCl3 (10 mol %), bpy (30 mol %), ZnO (1.0 equiv), HCONH2
o
(1.0 mL) and 1,2-DME (1.5 mL) at 145 C for 12 h under air
In conclusion, we have developed a new protocol of
generating hydrocyanic acid in situ from formamide.
Nickel species can mediate this dehydration process with
the help of Lewis acid additives to release water as a single
byproduct. Significantly, this Ni-catalyzed procedure was
successfully utilized for the efficient hydrocyantion of
alkynes and cyanation of (hetero)aryl halides. Mechanistic
details on the formation of cyano unit from formamide and
additional synthetic applications are currently underway
in our laboratory.
atmosphere: isolated yields.
To extend the synthetic scope of the reactions, cyanation
of heteroaryl bromides with formamide was also examined
(Table 4). Under the optimal conditions, substrates
derived from indoles (6a6f), isoquinolines (6g6h),
benzothiophenes (6i6j) benzothiazole (6k) and
quinolines (6l6n) were all smoothly cyanated.
Significantly, cyanation at the various positions took place
in satisfactory yields. Both N-H and N-phenyl
bromoindoles could readily be employed as substrates for
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Recent Advances in the Synthesis of Aryl Nitrile Compounds. Adv.
Synth. Catal. 2017, 359, 4068-4105.
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures, detailed optimization, mechanistic
studies, compound characterization and NMR spectra.
(5) (a) Arai, S.; Amako, Y.; Yang, X.F.; Nishida, A. Hydrocyanative
Cyclization and Three-Component Cross-Coupling Reaction
between Allenes and Alkynes under Nickel Catalysis. Angew.
Chem., Int. Ed. 2013, 52, 8147–8150. (b) Ye, F.; Chen, J. T.; Ritter, T.
Rh-Catalyzed Anti-Markovnikov Hydrocyanation of Terminal
Alkynes. J. Am. Chem. Soc. 2017, 139, 7184–7187. (c) Ma, H.; Sui, F.;
Zhao, Q.-H.; Zhang, N.; Sun, Y.; Xian, J.; Jiao, M.; Liu, Y.; Wang,
Z.-M. Lewis base-catalyzed cyanation of Morita-Baylis-Hillman
carbonates. Synthesis of allylamine derivatives. Tetrahedron Lett.
2017, 58, 3410–3414. (d) Pawar, A. B.; Chang, S. Cobalt-Catalyzed
C–H Cyanation of (Hetero)arenes and 6-Arylpurines with N-
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Nagata, T.; Kiyokawa, K.; Minakata, S. Catalytic Activation of 1-
AUTHOR INFORMATION
Corresponding Author
* Luo Yang, E-mail: yangluo@xtu.edu.cn.
* Sukbok Chang, E-mail: sbchang@kaist.ac.kr.
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ORCID
* Luo Yang, 0000-0002-0061-0816
* Sukbok Chang, 0000-0001-9069-0946
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21772168), Hunan Provincial Natural
Science Foundation (2016JJ2122), Key Foundation of Education
Bureau of Hunan Province (17A208) and the Project of
Innovation Team of the Ministry of Education (IRT_17R90),
and Institute for Basic Science (IBS-R010-D1) in Republic of
Korea.
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be replaced by other inorganic bases such as CaO, MgO, K2CO3,
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details). For relevant references on the utilization of ZnO as a base,
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conditions.
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Table of Contents
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Ni-Mediated Generation of “CN“ Unit from Formamide and Its Catalysis in the Cyanation
Reactions
Luo Yang,* Yu-Ting Liu, Yoonsu Park, Sung-Woo Park and Sukbok Chang*
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C
N
H2
H
O
[Ni]
H
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[Ni/Co]
[Ni/Al]
Ar
(X: Br, I)
R
CN
"
"
CN
Ar
CN
X
R
R
R



Formamide as a convenient cyano source
Ni-mediated dehydration of formamide to genertae "CN"
Applied in the hydrocyantion of alkynes and cyanation of aryl bromides
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