Ni-Catalyzed hydrocyanation of alkenes with formamide as the cyano source

Article abstract of DOI:10.1039/c9gc04275j

CN generation from formamide dehydration! A novel Ni-catalyzed hydrocyanation of various alkenes to provide aliphatic nitriles is developed by generating hydrocyanic acid in situ from safe and readily available formamide. Excellent linear or branched regio-selectivity, wide substrate scope, cheap and stable nickel salt as a pre-catalyst, a safe cyano source, slow generation of CN to obviate catalyst deactivation and convenient experimental operation would render this hydrocyanation attactive for laboratory synthesis of aliphatic nitriles.

Full text of DOI:10.1039/c9gc04275j

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DOI: 10.1039/C9GC04275J
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Ni-catalyzed hydrocyanation of alkenes with formamide as the
cyano source
Received 00th January 20xx,
Accepted 00th January 20xx
Xiao Shu, Yuan-Yuan Jiang, Lei Kang* and Luo Yang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
a) Classic hydrocyanation of alkenes
“CN” Generation from formamide dehydration! A novel Ni-catayzed
hydrocyanation of various alkenes to provide aliphatic nitriles is
developed, by generating hydrocyanic acid in situ. from safe and
readily available formamide. Excellent linear or branched regio-
selectivity, wide substrate scope, cheap and stable nickel salt as pre-
catalyst, safe cyano source, slow generation of “CN” to obviate
catalyst deactivation and convenient experimental operation would
render this hydrocyanation attactive for laboratory synthesis of
aliphatic nitriles.
CN
Ni0/Ligand
CN
HCN
+
+
R
+
R
R
b) Morandi's transer hydrocyanation from isovaleronitrile
Ni(COD)2
R1
R1
DPEphos
CN
CN
+
R2
R2
Me2AlCl
c) Studer's transfer hydrocyanation from cyclohexa-2,5-diene-1-carbonitrile
Pd(PPh3)4
R1
R1
Nitrile constitutes a prevalent unit in numerous natural
products, pharmaceuticals, and agrochemicals.1 It’s also
particularly useful in organic synthesis as a versatile precursor
to a range of functional groups such as amines, amides,
aldehydes, amidines, ketones, and carboxylic acids.2 Therefore,
various procedures for introducing the nitrile group onto
organic compounds has been developed by employing
different cyano sources. Among them, hydrocyanation of
alkenes (addition of HCN to C=C bond) provides a concise and
atom-economical access to alkyl nitriles, by benefiting from
the readily available alkenes as substrate (Scheme 1a).3 The by
far most prominent application is the production of
adiponitrile from 1,3-butadiene (>1000 000 tons per year).4
This hydrocyanation process requires an expensive Ni(0)
catalyst and an excess amount of hydrogen cyanide as the
cyano source. However, the Ni(0) catalyst is difficult to handle
due to its sensitivity to moisture and oxygen, while hydrogen
cyanide is extremely toxic and volatile; which limits the
application of alkene hydrocyanation in the multistep
synthesis of more complex organic compounds. Therefore,
more convenient method for the hydrocyanation of alkenes is
required.
DPEphos
CN
+
+
R2
R2
CN
BPh3
CN
d) This work: formamide as a convenient and safer " " source
C
N
H2
H
O
LA
NiII/Xantphos
Zn0
CN
CN
Alkyl
Aryl
Alkyl
Aryl
or
or
+
CN
"
"



HCN-free hydrocyanation
slow "CN" generation via dehydration
avoiding "CN" accumulation


cheap NiII pre-catalyst
linear or branched selectivity
Scheme 1. Ni or Pd catalyzed hydrocyanation of alkenes with
different cyano source.
For seeking safer cyano source, Morandi et al. reported an
elegant Ni-catalyzed transfer hydrocyanation of alkenes with
isovaleronitrile as the HCN donor, where the air sensitive
Ni(COD)2 and AlMe2Cl (as a Lewis acidic additive) were used as
the effective catalyst combination (Scheme 1b).5 Similarly,
Studer and co-workers developed a Pd-catalyzed transfer
hydrocyanation of alkenes with anti-Markovnikov selectivity,
using 1-methylcyclohexa-2,5-diene-1-carbonitrile as the HCN
source instead (Scheme 1c).6 Besides the “CN” containing
reagent as potential cyano source, an alternative approach is
generating the cyano unit in situ. from readily available non-
toxic organic precursors. Chang’s group pioneered in the
“combined cyano source” mediated by Cu or Pd catalyst
systems,7 where a combination of two compounds was
employed to generate cyano under oxidative conditions. For
a
Key Laboratory for Green Organic Synthesis and Application of Hunan Province,
College of Chemistry, Xiangtan University, Hunan, 411105, PR China.
E-mail: yangluo@xtu.edu.cn; Fax: +86-731-58292251; Tel: +86-731-59288351
† Electronic Supplementary Information (ESI) available: Experimental details and
characterisation of products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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instance, dimethylformamide and ammonia (or ammonium supplementary role, which was more effective than other
View Article Online
salts) were found to work cooperatively to serve carbon and reductive additives, such as metallic Mn,DMOgI: 1o0r.1o0r3g9a/Cn9icGHC0C4O227H5J,
nitrogen of the “CN”, respectively.8 Subsequently, Cheng, Yu, HCO2NH4 (entries 3, 11-14). It’s a pity that a relatively high
o
Sakai, and Jiao groups independently showed that an temperature of 150 C was required to realize an acceptable
additional array of organic compounds can also serve as cyano conversion, due to the inertness of formamide dehydration
precursors, including DMSO, TMEDA, nitromethane, or sodium (entry 15). It’s worth noting that in the absence of any
azide.9 Bhanage and co-workers reported a Pd-catalyzed reductive additives (entry 3), the model reaction could also
amidation of aryl iodides with formamide, which could be provide a medium yield of 52%, which might imply that the
dehydrated by POCl3 to provide aryl cyanides.10 However, this formamide was able to act as a potential reductant for this
“combined cyano source” strategy mainly confined to the reaction. 14b
cyanation of Ar-X (X= halo, H and B) to prepare the
corresponding aromatic nitriles, and relatively complex Table 1. Optimization of reaction conditions a
oxidative reaction conditions were required.
CN
10 mol% Ni(acac)2
15 mol% Xantphos
O
The challenges for the hydrocyanation of alkenes concludes:
1) the highly toxic and volatile hydrogen cyanide (with a low
boiling point of 26 °C) was required, making it difficult to
+
C
N
H
H2
20 mol% Zn powder
150 oC, 24 h
3a
1a
2
handle in
a
normal laboratory; although acetone
11c,d
cyanohydrin,11a,b Zn(CN)2
and TMSCN11e have been
entry
1
Change from the “standard conditions”
none
3a (%)b 1a (%)b
employed as a surrogates for HCN, it still poses a significant
risk. 2) Careful control of cyanide concentration is often
required to obtain satisfactory catalytic reactivity, due to the
possible coordinating saturation of transition-metal (such as Ni)
by the cyanide anion.12 3) The requirement of expensive and
sensitive Ni(0) catalyst. We speculated that the former two
requirements for convenient and safe cyano source and low
concentration of cyanide might be ideally achieved by the
steady generation of cyano unit by the Lewis acid catalyzed
dehydration of formamide, which was proposed and
confirmed in our previous studies on the cyanation of aryl
halides.14a While the third challenge might be realized by the in
situ. preparation of an active metal species (such as Ni0-
phosphorous ligand complexes) from the cheap and stable
metal salts (such as NiII), assisted by a suitable reductant;
which was proved to be a successful strategy, as exhibited by
Liu et. al. in the hydrocyanation of alkenes and alkynes, by
using Zn0 and Mn0 as additive to reduce the NiII salts (as pre-
catalyst), respectively.11c,d Herein, we report a novel Ni-
catalyzed hydrocyanation of alkenes with formamide as a
green cyano source, dehydrant, reductant and solvent, by
generating the “CN” unit from the dehydration of formamide
(Scheme 1d).
81
8
2
no Ni(acac)2
0
56
3
no Zn
52 30
20 50
30 32
66 18
53 33
40 41
10 51
22 42
4
no Xantphos
5
5 mol% Ni(acac)2
6
10 mol% Ni(OAc)2 instead of Ni(acac)2
10 mol% NiCl2 instead of Ni(acac)2
10 mol% Xantphos
7
8
9
15 mol% DPEphos instead of Xantphos
15 mol% BINAP instead of Xantphos
20 mol% Mn powder instead of Zn
20 mol% Mg powder instead of Zn
20 mol% HCO2H instead of Zn
20 mol% HCO2NH4 instead of Zn
140 oC instead of 150 oC
10
11
12
13
14
15
40
45
34 48
54 22
48 25
44 36
a
Conditions: Styrene (1a, 0.2 mmol), Ni(acac)2 (0.02 mmol, 10 mol%), Zn
powder (0.04 mmol, 20 mol%), Xantphos (0.03 mmol, 15 mol%), formamide
(1.0 mL) were reacted at 150 °C (oil bath temperature) for 24 h under argon
b
atmosphere. Yields and recovered 1a were tested by GC with an internal
standard.
Based on the above speculation and our recent work,
styrene (1a) was chose as the model substrate to test our
hydrocyanation strategy. Detailed optimization was performed
focusing on NiII pre-catalysts, phosphorus ligands, reductive
additives and their dosage, which revealed the combination of
10 mol% Ni(acac)2 / 15 mol% Xantphos / 20 mol% Zn proved to
be the most effective one, to afford the branched
hydrocyanation product 3a (with Markovnikov selectivity) in
81% GC yield (Table 1, entry 1). The control experiments
showed that the NiII pre-catalyst was crucial for this
hydrocyanation; besides Ni(acac)2, Ni(OAc)2 and NiCl2 could
also be used, albeit resulted in lower yields (entries 5-7).
Different phosphorus ligands also caused obvious influence on
this reaction (entries 8-10), and Xantphos with a large bite
angle of 114o was found to be the best one to match the
Ni(acac)2 catalyst. In contrast, the Zn powder played a
With formamide as the green cyano source, the generality of
this Ni-catalyzed hydrocyanation of alkenes was subsequently
investigated. Gratifyingly, a wide range of alkenes were
suitable for this reaction, including mono-substituted aromatic
alkenes (Table 2, entries 1-8), mono-substituted aliphatic
alkenes (entries 9-13), di-substituted aromatic alkenes (entries
14-21) and di-substituted aliphatic alkenes (entries 22 and 23).
The effect of substituents on the styrene moiety is studied and
various styrene derivatives bearing electron donating or
withdrawing substituents on the phenyl moiety (1a-1g)
smoothly underwent this hydrocyanation to afford the desired
benzyl nitriles (3a-3g) in good yields. For these mono-
substituted aromatic alkenes, the branched regio-isomers
(with Markovnikov selectivity) were generated in excellent
selectivity (>98:2), possibly due to the formation of 3-benzyl
nickel intermediate.13a In sharp contrast, the mono-substituted
2 | J. Name., 2012, 00, 1-3
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a Conditions: alkene (1, 0.2 mmol), Ni(acac)2 (0.02 mmol, 10 mol%), Zn
Table 2. Substrate scope for the hydrocyanation of alkene a
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powder (0.04 mmol, 20 mol%), Xantphos (0.03 mmol, 15 mol%),
DOI: 10.1039/C9GC04275J
10 mol% Ni(acac)2
15 mol% Xantphos
O
CN
formamide (1.0 mL) were reacted at 150 °C (oil bath temperature) for
CN
+
R
+
C
R
24
h under argon atmosphere. Isolated yield. The ratios of
N
H
H2
R
20 mol% Zn powder
150 oC, 24 h
linear/branched isomers were detected by GC of the reaction mixture,
1
2
3a'
yield (ratio)
3a
b
and confirmed by the 1H NMR.
temperature) for 36 h.
Reacted at 155 °C (oil bath
entry
1-7
substrate
product
CN
aliphatic alkenes 1i and 1j switched to produce the linear
regio-isomers (with anti-Markovnikov selectivity), and the
reversal of regio-selectivity likely stems from the reversible
nature of hydrocyanation to produce the thermodynamically
R1
R1
1, R1 = H
, 78% (>98:2)
3a
1a 1g
-
2,
3,
4,
5,
6,
7,
4-tBu
, 73% (>98:2)
, 75% (>98:2)
, 72% (>98:2)
, 70% (>98:2)
, 58% (>98:2)
more stable linear isomers at elevated temperature.13a,
3b
5
3c
3d
4-Me
Interestingly, for the terminal alkenes (1k-1m), where the C=C
bond and phenyl group were separated by more than one
methylene unit (CH2), the Ni-catalyzed alkenes isomerization
would occur to transform the terminal alkenes to the
corresponding conjugated alkenes, which then participate in
the hydrocyanation to provide the cyanated products with the
cyano group connecting to the benzyl position. What’s more,
the optimized reaction conditions were also compatible with
the di-substituted aromatic and aliphatic alkenes (1n-1u),
affording the corresponding nitriles in moderate yields.
4-MeO
2-MeO
4-F
3e
3f
3g
4-Cl
, 50% (>98:2)
CN
8
3h
, 72% (>98:2)
1h
1i
CN
CN
nC5H11
nC6H13
nC5H11
nC6H13
3i
3j
, 67% (<2:98)
, 64% (<2:98)
9
To extend the synthetic scope of this hydrocyanation, and
considering the important and famous industrial
transformation of 1,3-butadiene to adiponitrile (as the
10
1j
CN
CN
precursor
to
the polymer nylon-6,6),
the
mono-
hydrocyanation of 1,3-butadiene and 4-pentenenitrile with
formamide as the green cyano source was also examined,
under the optimized reaction conditions (Scheme 2). When
1,3-butadiene (1v, dissolved in toluene) was used as the
substrate, the mono-hydrocyanation of 1,3-butadiene
proceeded smoothly, to provide the 4-pentenenitrile (3v) as
the single product in 82% yield (determined by GC due to the
low boiling point), avoiding the formation of the other 3-
pentenenitrile or 2-methylbutenenitrile regio-isomers, which
demonstrates the excellent selectivity of this method. For the
second hydrocyanation of 4-pentenenitrile to adiponitrile, the
reaction became sluggish, and currently only a low yield of
28% (4v, isolated yield) was realized; since part of the 4-
pentenenitrile was reduced to pentanenitrile, which waits for
3k
3l
, 64% (>98:2)
1k
11
12
, 76% (>98:2)
1l
MeO
MeO
CN
3m
, 76% (>98:2)
R2
1m
13
CN
R2
14-19b
R2
R2
14, R2 = H
1n 1s
-
3n
, 78%
, 73%
, 72%
3o
15,
16,
17,
18,
19,
4-Me
4-MeO
further improvement.
3p
3q
10 mol% Ni(acac)2
4-F
, 70%
, 66%
O
NC
15 mol% Xantphos
+
NC
3r
1-naph
3,4-(Me)2
C
N
H
H2
20 mol% Zn powder
150 oC, 24 h
3s
, 66%
CN
1v
3v
2
3v
, 82%
CN
10 mol% Ni(acac)2
15 mol% Xantphos
3k
, 62% (>98:2)
20
O
CN
+
C
NC
NC
1k'
1l'
1t
N
H
H2
20 mol% Zn powder
150 oC, 24 h
CN
4v
, 28%
2
3l
, 76% (>98:2)
21
22
23
Scheme 2. Ni-catalyzed hydrocyanation for adiponitrile synthesis
with formamide as the green cyano source
MeO
MeO
CN
3t,
68%
63%
To understand the reaction mechanism of this
hydrocyanation with formamide as the green cyano source,
several control experiments were performed. Firstly, the
dehydration of formamide to produce hydrocyanic acid (HCN)
was detected by the picrate impregnated indicator paper
CN
nC4H9
1u
nC4H9
nC4H9
n
3u,
C4H9
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under the optimized conditions; at the same time, the water NiIILn to form Ni0Ln (L = ligand), with or without the assistance
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released from this dehydration step would hydrolyze another of Zn powder.11c,d Then, oxidative addition of hydrocyanic acid
DOI: 10.1039/C9GC04275J
formamide molecule to generate an ammonium formate to Ni0Ln generates NiII intermediate I, followed by coordination
(Scheme 3a). Considering the control reaction using Zn(CN)2 as of the alkene 1a and cis-addition of Ni-H bond to C=C bond to
the cyano source (also catalyzed by NiII/Xantphos) was able to produce intermediate III, which underwent reductive
o
proceed at a lower temperate of 80 C,11d the dehydration of elimination to provide the hydrocyanation product 3a and
formamide might be the rate-determining-step for this regenerate the Ni0Ln catalyst.
hydrocyanation. Secondly, by shorting the reaction time from
In conclusion, we have developed a new protocol for the
24 h to 8 h, the hydrocyanation of alkene 1l afforded the hydrocyanation of various alkenes by generating hydrocyanic
desired cyanated product 3l in 45% yield, accompanied by a acid in situ. from safe and readily available formamide. The
by-product (1l’) coming from the migrative isomerization of slow and steady generation of cyano unit by the Ni-catalyzed
C=C bond (Scheme 3b), which not only revealed that the Ni- dehydration of formamide, provided a low concentration of
catalyzed migrative isomerization was faster than the cyanide for hydrocyanation to obviate the possible catalyst
hydrocyanation, but also supported the generation of nickel- deactivation due to coordination saturation between Ni and
hydride [Ni-H] intermediate.13b Thirdly, the amide 5a could not the cyanide anion. Besides as the cyano source, formamide
be transformed into the nitrile 3a under the same reaction also acted as the dehydrating agent, reductant and co-solvent
conditions (Scheme 3c), this result and the high reactivity for for this reaction. Excellent branched selectivity for aromatic
the oxidative addition of Ni0 with HCN to yield [H-NiII-CN] alkenes, and linear selectivity for aliphatic alkenes were
intermediate, might be able to exclude the pathway consisting realized. Wide substrate scope, cheap and stable nickel salt as
of the hydroamidation of C=C bond to form amide 5a and pre-catalyst, safe cyano source and convenient experimental
subsequent dehydration.
operation would render this hydrocyanation practical for
laboratory synthesis of aliphatic nitriles.
10 mol% Ni(acac)2
15 mol% Xantphos
O
+
CN
C
- NH4
O2
C
2
(a)
H
+
H
N
H
H2
20 mol% Zn powder
150 oC, 24 h
Acknowledgments
detected by
13C NMR
detected by
picrate paper
This work was supported by the National Natural Science
Foundation of China (21772168), Key Foundation of Education
Bureau of Hunan Province (17A208), College Student
Innovation Program and Project of Innovation Team of the
Ministry of Education (IRT_17R90).
10 mol% Ni(acac)2
15 mol% Xantphos
CN
+
PMP
PMP
PMP
(b)
(c)
20 mol% Zn powder
150 oC,
8 h
1l
1l'
3l
, 45%
, 50%
10 mol% Ni(acac)2
15 mol% Xantphos
CN
CONH2
The authors declare no competing financial interest.
20 mol% Zn powder
150 oC, 24 h
Ph
Ph
3a
5a
not detected
Notes and references
Scheme 3. Mechanistic experiments.
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.
NiIILn
[Ni]
C
N
H2
2 H
O
+
C
- N
O2 H4
H
CN
3a
or Zn
Ni0Ln
2
3
(a) Z. Rappoport, Chemistry of the Cyano Group, John Wiley
& Sons, London, 1970; (b) R. C. Larock, Comprehensive
Organic Transformations: A Guide to Fucntional Group
Preparations, VCH, New York, 1989.
For reviews, see: (a) M. Beller, J. Seayad, A. Tillack and H.
Jiao, Angew. Chem., Int. Ed., 2004, 43, 3368; (b) L. Bini, C.
Müller and D. Vogt, Chem. Commun., 2010, 46, 8325; (c) L.
Bini, C. Müller and D. Vogt, ChemCatChem, 2010, 2, 590; (d)
T. V. RajanBabu, Org. React., 2011, 75, 1.
CN
H
Ph
H
NiIILn
CN
NiIILn
H
Ph
CN
I
III
Ph
Ph
NiIILn
CN
4
(a) C. A. Tolman, R. J. McKinney,W. C. Seidel, J. D. Druliner
and W. R. Stevens, Adv. Catal., 1985, 33, 1; (b) T. A. Tolman,
J. Chem. Educ., 1986, 63, 19.
H
II
Scheme 4. Proposed mechanism for the hydrocyanation.
5
6
X. Fang, P. Yu and B. Morandi, Science, 2016, 351, 832.
A. Bhunia, K. Bergander and A. Studer, J. Am. Chem. Soc.,
2018, 140, 16353.
Based on these results and literature reports using metal
cyanides as the cyano source, a tentatively mechanism for this
hydrocyanation of alkenes was proposed and depicted in
Scheme 4, with the reaction of styrene (1a) as an example. The
first step involves Ni-catalyzed dehydration of formamide to
form hydrocyanic acid14a and hydrolysis of formamide
molecule to form ammonium formate, 14b which would reduce
7
8
J. Kim, H. J. Kim and S. Chang, Angew. Chem., Int. Ed., 2012,
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9GC04275J
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Green Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C9GC04275J
Abstract for the Contents Pages
Graphic:
Ni-catalyzed hydrocyanation of alkenes with
formamide as the cyano source
C
N
H2
H
O
LA
NiII/Xantphos
Zn0
Xiao Shu, Yuan-Yuan Jiang, Lei Kang* and Luo
Yang*
CN
CN
Alkyl
Aryl
Alkyl
Aryl
or
or
+
CN
"
"
Text:
HCN-free hydrocyanation





“CN” Generation from formamide dehydration!
A novel Ni-catayzed hydrocyanation of various alkenes to provide
aliphatic nitriles is developed, by generating hydrocyanic acid in
situ. from safe and readily available formamide.
slow "CN" generation via dehydration
avoiding "CN" accumulation
cheap NiII pre-catalyst
linear or branched selectivity