Nickel-Catalyzed Cyanation of Aryl Halides and Hydrocyanation of Alkynes via C-CN Bond Cleavage and Cyano Transfer

Article abstract of DOI:10.1021/acscatal.9b04586

We report nickel-catalyzed cyanation and hydrocyanation methods to prepare aryl nitriles and vinyl nitriles from aryl halides and alkynes, respectively. Using inexpensive and nontoxic 4-cyanopyridine N-oxide as the cyano shuttle, the methods provide an efficient approach to prepare aryl cyanides and vinyl nitriles under mild and operationally simple reaction conditions with a broad range of functional group tolerances. In hydrocyanation of alkynes, the method demonstrated good regioselectivity, producing predominantly E- or Z-alkenyl nitriles in a controlled manner and exclusively Markovnikov vinyl nitriles when internal diaryl alkynes and terminal alkynes were applied as the substrates, respectively. The preliminary mechanistic investigation indicated that the C-CN bond cleavage process is promoted by oxidative addition to the nickel(I) complex in the cyanation of aryl halides, and further studies via a series of deuterium exchange experiments indicated that water serves as the hydrogen source for the hydrocyanation of alkynes.

Full text of DOI:10.1021/acscatal.9b04586

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Article
Nickel-Catalyzed Cyanation of Aryl Halides and Hydrocyanation
of Alkynes via C-CN Bond Cleavage and Cyano Transfer
Hui Chen, Shuhao Sun, Yahu A. Liu, and Xuebin Liao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04586 • Publication Date (Web): 20 Dec 2019
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ACS Catalysis
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Nickel-Catalyzed Cyanation of Aryl Halides and Hydrocyanation of
Alkynes via C-CN Bond Cleavage and Cyano Transfer
Hui Chen,† Shuhao Sun,† Yahu A. Liu,‡ and Xuebin Liao*†
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†School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of
Education), Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China
‡ Discovery Chemistry, Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA
Supporting Information Placeholder
ABSTRACT: We report nickel-catalyzed cyanation and hydrocyanation methods to prepare aryl nitriles and vinyl nitriles from aryl
halides and alkynes, respectively. Using inexpensive and non-toxic 4-cyanopyridine N-oxide as the cyano shuttle, the methods provide
an efficient approach to prepare aryl cyanides and vinyl nitriles under mild and operationally simple reaction conditions with a broad
range of functional group tolerance. In hydrocyanation of alkynes, the method demonstrated good regioselectivity, producing
predominantly E or Z-alkenyl nitriles in a controlled manner and exclusively Markovnikov vinyl nitriles when internal diaryl alkynes
and terminal alkynes were applied as the substrates, respectively. The preliminary mechanistic investigation indicated that C-CN
bond cleavage process is promoted by oxidative addition to the nickel(I) complex in the cyanation of aryl halides, and further studies
via a series of deuterium exchange experiments indicated that water serves as the hydrogen source for the hydrocyanation of alkynes.
KEYWORDS： Nickel catalysis, cyanation, hydrocyanation, C-CN bond cleavage, Z/E selectivity, Markovnikov addition
1. INTRODUCTION
alkynes. Replacing toxic cyano resources by alternative sources
through activation of C-CN bonds in less toxic reagents would
be a valuable approach for the synthesis of such organic nitriles.
The reported work in this direction includes the oxidative
addition of C-CN to stoichiometric metal complexes by
Yamamoto’s and Jones’ groups,6 the intramolecular aryl
cyanation by Nakao’s group,7 as well as the investigation
described by a few other research groups. Nonetheless, regio-
selectivity or configuration selectivity in most cases still
troubled chemists in their synthesis of alkenyl nitriles through
hydrocyanation of alkynes 8 (Scheme 1A).
The nitrile is an important structural moiety in natural products
and pharmaceuticals.1 In medicinal chemistry, nitrile groups
often play a key role as a hydrogen bond accepter which is
employed to form a hydrogen bond with serine or arginine.
Among nitriles, aryl nitriles and alkenyl nitriles are particularly
attractive to medicinal chemists as they are metabolically
robust. Over 50 aryl nitrile- and vinyl nitrile-containing
pharmaceuticals are marketed drugs or in clinical development
for treatment of a diverse variety of diseases (Figure 1).
Moreover, nitriles serve as versatile intermediates for a vast
array of transformations into other functional groups, such as
amines, acids, aldehydes, amides, isocyanates, ketones, esters
as well as heterocycles. 2
N
N
O
S
O
OH
O
H
• HCl
N
N
CF3
CN
CN
O
F
Me
N
H
CN
Aryl nitriles can be made by transition-metal-catalyzed
couplings of aryl halides with cyanide derivatives. Cyanide
salts, such as KCN, NaCN, Zn(CN)2 and K4[Fe(CN)6],3 have
been widely employed as cyano sources. More recently, acetone
cyanohydrin (ACH) and TMSCN have been adopted as cyano
sources in the formation of nitriles (Scheme 1A).4 The transfer
of a cyano group (CN) to the catalyst in such a reaction is
usually smooth, but the catalyst could be easily deactivated as a
result of strong interaction between the cyanide anion and the
catalyst. Furthermore, all of these reactions suffer from the high
toxicity or low solubility of their cyano sources. Consequently,
because of the drawbacks of these cyano sources, the research
groups of Yu, Chang, and Jiao all developed new strategies
which allow CN be generated in situ from readily available
reagents (Scheme 1A).5 However, these methods required
elevated temperatures and the presence of oxidants, which
limited the substrate scope as many functional groups contained
in the substrates could be quite fragile under such conditions. In
general, vinyl nitriles could be made through hydrocyanation of
Fadrozole (Afema)
Nonsteoidal aromatase inhibitor
Breast cancer
Bicalutamide
Nonsteoidal androgen receptor antagonist
Advanced prostate cancer
Milrinone (Primacor)
Hosphodiesterase inhibitor
Heart failure
N
CN
CN
O
OH
N
HN
H
Cl
N
CN
O
N
NH
N
S
CN
N
O
N
O
N
Br
Etravirine
Non-nucleoside reverse
transcriptase inhibitor
HIV
NH2
Neratinib (Nerlyn)
EGFR inhibitor
Early-stage breast cancer
Pericyazine
Antipsychotic
Cl
Cl
O
NC
N
Cl
S
HO
CN
S
S
CN
HO
N
N
S
NO2
N
N
Lanoconazole
Sterol 14R-methylase
Antifungal
Entacapone
Catechol-O-methyltransferase inhibitor
Parkinson’s disease
Luliconazole
Tterol 14R-methylase
Antifungal
Figure 1. Selected examples of arylnitrile- and vinylnitrile-
containing pharmaceuticals
Herein, we report a nickel-catalyzed cyanation method which
involves C-CN activation along with CN group transfer under
ACS Paragon Plus Environment

ACS Catalysis
mild and operationally simple conditions (Scheme 1B). The
Page 2 of 9
oxide (2b) and 2-cyanopyridine N-oxide (2c), as the cyano
shuttles. It was found that the former did not afford any desired
product, and the reaction using the latter proceeded in a lower
yield than the one when 2a was used (entry 17, 18). Thus, we
opted to use N-oxide 2a as the CN source.
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2
3
4
5
6
7
8
method allows smooth formation of aryl nitriles from aryl
halides. Also reported is a configurationally selective insertion
of CN groups to diaryl internal alkynes which gave either Z or
E isomers predominantly, depending on the controlled reaction
conditions; the insertions to the terminal alkynes produced
Markovnikov hydrocyanated products exclusively.
Table 1. Optimization of Ni-Catalyzed Cyanation of 4-
Iodobiphenyl a
Scheme 1. Methods for the Cyanation of Aryl Halides and
Hydrocyanation of Alkynes
"Standard" conditions A:
NiCl2 (15 mol%), L1 (16 mol%)
KF (1.2 equiv), NaI (3.0 equiv)
Zn (6.0 equiv), TFAA (3.0 equiv)
I
CN
CN
+
N
A
Conventional cyanation strategies:
9
Ph
O
Ph
(84% isolated yield)
CN
DMAc, 50 °C, 36 h
"CN" source
1a
2a
3a
(1.0 equiv)
(1.3 equiv)
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CN
R1
or
R
or
"CN" precursor
deviation from above yield (%)
entry
entry deviation from above
yield (%)
Drawbacks:
low solubility and high toxicity
low solubility
"CN" source
KCN, NaCN, ZnCN2, or TBACN
L2
L3
1
2
3
4
5
6
7
8
9
69
52
10
11
12
13
14
15
16
17
18
NiI2
Ni(PPh3)4
Ni(PCy3)2Cl2
no nickel or ligand
no NaI
no Zn
no TFAA
2b
70
76
80
0
57
trace
0
K4[Fe(CN)6]
L4
62
TMSCN or ACH
high toxicity
L5
42
"CN" precursor
L6
51
elevated temperature, oxidants required
and limited functional group tolerance
poor regioselectivity
MeNO2, or DMF
L7
61
L8
36
L9
trace
76
0
78
This work:
2c
NiBr2
B
C-CN bond
cleavage
R
R
R1
R1
CN
CN
N
N
CN
R
R2
R2
L8
R
N
N
N
N
aryl halides
diaryl
aromatic or
aliphatic
terminal alkynes
L
NC
O
R = Me,
L
R1 = R2 = H,
1
5
N
O
R = t-Bu, L2
R1 = R2 = Me,
L
6
H
N
N
alkynes
L
7
R1 = Phenyl, R2 = H,
P(Cy)2
L
R = OMe,
O
CN
CN
3
CN
R
L
2b
2c
R = H,
4
L9
R
(Cy)2P
Ni
R
a
Reactions were run on 0.5 mmol scale. Yields were
determined by GC except as indicated otherwise. DMAc = N,
N-dimethylacetamide.
cyano shuttle
cyano source
nontoxic, cheap
high solube
reaction
mild conditions
broad substrate scope
good regioselectivity
non-volatile powder, easy to weigh
Table 2. Substrate Scope of Ni-Catalyzed Cyanation of
Aryl Iodides a
2. RESULTS AND DISCUSSION
"Standard" conditions A:
I
CN
NiCl2 (15 mol%), L1 (16 mol%)
KF (1.2 equiv), NaI (3.0 equiv)
Zn (6.0 equiv), TFAA (3.0 equiv)
CN
CN
CN
+
R
In searching for an alternative cyano source or shuttle, 4-
cyanopyridine N-oxide (2a), a commercially available and
inexpensive reagent, was initially attempted owing to its non-
toxicity and superb solubility.9-15 We postulated that if the rate
of transferring CN to the catalyst would be moderate,
deactivation of the catalyst resulting from excessive cyanide
anions could be avoided. In our initial exploration of cyanation
of aryl halide using N-oxide 2a, 4-iodobiphenyl (1a) was
chosen as a model substrate (Table 1) to screen ligands,
including bipyridines (entries 1-3), phenanthrolines (entries 4-
6), biquinoline (entry 7) and phosphine (entry 8), with 4,4’-
dimethyl-2,2’-bipyridine (L1) being found to be the most
efficient. Next, through examining a range of nickel catalysts
(entries 9-12), we found that inexpensive inorganic salt NiCl2
performed the best, and surrogating it with a variety of other
nickel complexes (Ni0 or NiII) led to lower yields. The reactions
without either catalyst or ligand resulted in no product,
indicating that both catalyst and ligand are required for the
cyanation (entry 13). The presence of NaI was found to be
critical to the reaction since the absence of NaI resulted in
significantly decreased yield together with formation of
hydrodehalogenated side product (entry 14). Thus, it implied
that the role of NaI was to reduce the hydrodehalogenated
product of aryl halides.16 Zinc powder was required as being a
reductant to the nickel catalyst (entry 15). In addition,
trifluoroacetic anhydride (TFAA) also played critical roles in
the activation of C-CN bonds (entry 16). In the absence of KF,
the yield was decreased to 78%, but the role of KF in the
cyanation reaction was not quite clear. Finally, we examined the
possibility of the two regioisomers of 2a, 3-cyanopyridine N-
N
R
O
1
2a
(1.0 equiv)
(1.3 equiv)
3
DMAc, 50 °C, 36 h
CN
CN
t-Bu
3b
3e
3c
, 92 %
, 76 %
3d
, 70 %
CN
CN
O
EtO
N
H
O
3f
3g
3j,
, 61 %
, 93 %
, 82 %
CN
, 65 %
CN
CN
O
O
BnO
3h
, 93 %
CN
3i
66 %
CN
O
CN
O
O
HO
3k
3l
, 73 %
3m, 67 %
, 66 %
CN
CN
CN
N
N
N
N
Ph
3n
Ph
, 66 %
, 64 %
3p
, 85 %
3o
a Reactions were run on 0.5 mmol scale. Yield is that of the
isolated product.
With the optimized reaction conditions in hand, we explored
the scope of aryl iodides as substrates (Table 2). We were
delighted to find that the reaction encompassed aryl iodides
containing a range of functional groups, including electron
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ACS Catalysis
neutral, donating and withdrawing ones (3b-3p). Various
functional groups, such as ester (3f), amide (3g), ethers (3h-l),
and even hydroxy (3m), were all compatible with our reaction
conditions. Substituents at the ortho- position (3j, 3l) did not
significantly impact reaction yields. Notably, heteroaryl iodides
(3n, 3o) afforded their corresponding cyanation products in
good yields.
selectivity in most cases still remains to be improved. Thus, we
first chose diaryl alkynes as substrates in the screening of the
reaction conditions. Through arduous screening effort (See SI),
we identified the optimal conditions that did not require the
presence of NaI, with L3 instead of L1 being the best performer
under the conditions. A vast range of diaryl alkynes having
electron-neutral, -rich or -withdrawing groups on the arenes
could be transformed into hydrocyanation products in good to
excellent yields and with good E-selectivity (Table 4, 8a-8h).
Functional groups, including methoxy (8d), fluorine (8e),
trifluoromethyl (8f), chlorine (8g, 8h) and ester (8i), were all
compatible with the conditions. It was worth noting that the
reaction conditions tolerated heterocyclic arenes: the
hydrocyanation of di(thiophenyl)ethyne (7j) proceeded in a
good yield, albeit the configuration selectivity was not very
satisfactory. Intriguingly, although all of the above reactions
afforded hydrocyanation product E-selectively, we were able to
obtain thermodynamic products, Z configuration nitriles (8k,
8l), under modified reaction conditions (See Supporting
Information (SI)).
1
2
3
4
5
6
We next investigated this cyanation reaction with a variety of
aryl bromides (Table 3). The reaction temperature was
increased to 60 ℃, given that the aryl bromide’s activity is
usually lower than that of the corresponding iodide. Aryl
bromides containing electron-rich or electron-neutral groups
(5a-5f), such as PhO-, MeO- and t-Bu, were transformed into
the corresponding products in high yields. The nitriles could
also be made from those eletron-poor aryl bromides, albeit in
modest yields (5g-5l). Notably, the unprotected indole moiety
was not affected under the reaction conditions (5l). Of particular
note, aryl triflates were also borne with standard conditions,
affording their corresponding cyanation products in good yields.
Aryl chlorides could undergo cyanation to generate the cyanide
product, but in much lower yields even under harsh conditions.
The further exploration of cyanation with acryl chlorides is
ongoing in our group now.
7
8
9
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60
Table 4. Substrate Scope of Hydrocyanation of Diaryl
Alkynes a
"Standard" conditions C:
CN
R
R
L
NiCl2 (15 mol%), 3 (16 mol%)
CN
H
Table 3. Substrate Scope of Ni-Catalyzed Cyanation of
Aryl Bromides, Triflates and Chloride a
KF (1.2 equiv), Zn (6.0 equiv)
TFAA (3.0 equiv)
+
N
R
O
R
DMAc
"Standard" conditions B:
7 (1.0 equiv)
2a (3.0 equiv)
8
NiCl2 (15 mol%), L1 (16 mol%)
KF (1.2 equiv), NaI (3.0 equiv)
Zn (6.0 equiv), TFAA (3.0 equiv)
X
CN
CN
CN
CN
CN
H
+
R
H
H
R
N
O
DMAc, 60 °C, 36 h
t-Bu
4
2a
5
(1.0 equiv)
(1.3 equiv)
X = Br
t-Bu
8c
E:Z>20:1
MeO
CN
CN
CN
8a
, 95%
8b
E:Z>20:1
, 86%
, 98%
(E:Z=13:1)
Ph
O
MeO
5c,
CN
CN
CN
OMe
H
a
H
H
a
5a,
94%
a
5b,
5e,
71%
73%
CN
CF3
F
OMe
CN
CN
CN
O
tBu
CF3
8f
F
O
OMe
8d
O
8e
, 78%
, 97%
, 62%
a
a
a
E:Z>20:1
E:Z=10:1
E:Z>20:1
5d,
64%
5f,
5i,
92%
81%
CN
CN
CN
CN
H
CN
CN
H
H
Cl
EtO
OEt
Cl
O
NC
O
F
a
5g,
a
Cl
53%
a
67%
5h,
45%
Cl
EtO
O
O
8h
E:Z=11:1
, 70%
8g, 90%
8i
, 43%
NC
CN
E:Z=15:1
E:Z=92:8
O
CN
N
t-Bu
CN
H
X = Cl
NC
H
H
H
a
a
a
S
5j,
5k,
5l,
93%
38%
47%
CN
CN
X = OTf
t-Bu
CN
S
CN
CN
b
b
8j
8k,
8l,
82%
88%
E:Z=85:15
73%
BnO
S
Z:E>20:1
Z:E>20:1
O
O
O
a
a
b
5m,
5n,
5o
, 46%
a Reactions were run on 0.5 mmol scale at 70 ℃ for 10 h
except as indicated otherwise. b Reactions were run on 0.5 mmol
scale at 50 ℃ for 36 h. a, b Yield is that of the isolated product.
53%
62%
a
b
Reactions were run on 0.5 mmol scale.
Reaction
temperature 100 ℃. a, b Yield is that of the isolated product.
Encouraged by the successful hydrocyanation of internal aryl
alkynes, we extended our exploration to terminal alkynes. After
an extensive screening of reactions conditions (See SI), the
optimal reaction conditions were identified under which the
hydrocyanation afforded the Markovnikov products in high
yields exclusively. Under such reaction conditions, ligand was
not needed, but adding water to the reaction system was critical.
On account of the importance of alkenyl nitrile
pharmaceuticals, we then turned our attention to exploring
hydrocyanation of alkynes on the basis of the cyanation method
we developed. Metal‐catalyzed hydrocyanation of alkynes
using HCN or in‐situ generation of HCN from cyano sources is
a direct and economical approach to preparing vinyl nitriles, 17
however the cyano sources are toxic, and regioselectivity or E/Z
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ACS Catalysis
In addition, the hydrocyanation reaction was accelerated by KF
Page 4 of 9
With the successful hydrocyanation method, we envisioned
that saturated nitriles could be made in one-pot if vinyl nitrile
formed in hydrocyanation were reduced without isolation from
the reaction system. To our delight, with adding NaBH4 to the
MeOH-diluted reaction mixtures after the hydrocyanation,
saturated nitrile products were obtained in fair to good yields
(Table 7, 13a-13c).
1
2
3
4
5
6
7
8
as it required much longer time to consume the alkyne starting
materials in absence of KF. We subsequently investigated the
substrate scope of this hydrocyanation of terminal alkynes. Aryl
alkynes bearing electron neutral or donating groups could be
hydrocyanated to form Markovnikov nitrile products in
moderate to good yields (Table 5, 10a-10f). Surprisingly, when
4-ethynylaniline was used as the substrate, trifluoroacetamide
10g’, instead of aniline 10g, was obtained as the product due to
the reaction of the aniline with TFAA. Electron-withdrawing
substituents on arenes were tolerated, and the cyanations were
achieved in modest to good yields (10h-10k). Functional
groups, including fluorine (10h, 10i), chlorine (10j), amide
(10k), ketal (10l) and protected-amine (10m) all tolerated the
reaction conditions. Interestingly, reaction of the terminal
alkyne containing unprotected indole proceeded in an excellent
yield (10n). It is worth mentioning that a synthetic precursor of
ibuprofen (10o) could be made straightforwardly using this
method.
Table 6. Substrate Scope of Hydrocyanation of Aliphatic
Terminal Alkynes a
"Standard" conditions E:
9
NiCl2 (15 mol%), KF (1.2 equiv)
CN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Zn (6.0 equiv), TFAA (5.0 equiv)
R
+
CN
H2O (4 equiv)
N
O
R
DMAc, 30 °C, 24 h
11
2a
12
(1.0 equiv)
(3.0 equiv)
CN
CN
CN
9
12a
6
12b
12c
, 90%
, 82%
, 68%
O
Table 5. Substrate Scope of Hydrocyanation of Aryl
Terminal Alkynes a
O
O
O
CN
S
O
CN
N
CN
OEt
12f, 89%
"Standard" conditions D:
NiCl2 (15 mol%), KF (1.2 equiv)
O
12d, 79%
12g, 86%
12e, 42%
CN
Zn (6.0 equiv), TFAA (5.0 equiv)
H2O (4 equiv)
+
CN
R
R
N
O
DMAc, 30 °C, 10 h
NC
HO
Cl
9
2a
10
, 66%
, 72%
(1.0 equiv)
(3.0 equiv)
CN
CN
O
O
CN
CN
12i, 46 %
12h, 52%
CN
CN
CN
Me
t-Bu
Ph
HO
Ph
CN
10c
10b
10e
, 85%
HO
10a
10d
, 76%
CN
3
Ph
Me
CN
CN
CN
CN
CN
12j, 92%
12k, 63%
12l, 54%
O
BnO
F
a Reactions were run on 0.5 mmol scale. Yield is that of the
isolated product.
, 77%
10f
, 74%
O
CN
Table 7. One-Pot Process Synthesis of Saturated Nitriles
and Synthetic Applications a
F3C
N
H
F
"Standard" conditions D:
NiCl2(15 mol%), KF(1.2 equiv)
Zn (6.0 equiv),TFAA (5.0 equiv)
DMAc, 30 °C, 10 h
1)
10h
, 75%
10g'
, 82%
, 64%
10i
10l
, 70%
CN
CN
+
R
R
Cl
N
O
O
CN
O
O
CN
CN
,
2) NaBH4 MeOH
2a
(3.0 equiv)
9
13
(1.0 equiv)
N
H
One-pot Process:
10j
, 65%
10k
, 45%
CN
CN
CN
CN
N
H
Ph
S
13a
13b
13c
, 82%
, 61%
, 55%
CN
CN
N
H
N
Applications:
Ph
OH
1) "standard"
conditions D
CN
10n
, 90%
10m
, 66%
10o
, 58%
HCl (12 M)
95 °C
O
2) NaBH4
MeOH
Ibuprofen,
a Reactions were run on 0.5 mmol scale. Yield is that of the
isolated product.
9o
13o
14o
, 54%
, 80%
O
Na2CO3, H2O2 (30%)
Acetone, 0 °C to rt
NH2
CN
We then applied the above aromatic terminal alkynes’
hydrocyanation conditions to aliphatic terminal alkynes. It was
found that the hydrocyanation proceeded in good yields with
excellent regioselectivity, forming Markovnikov products
exclusively (Table 6, 12a-12c). Functional groups including
sulfonate (12d), imide (12e), ester (12f), cyano (12g), chloride
(12h), ketal (12i) were all compatible with the reaction
conditions. Of particular note, hydroxyl group in alkyne
compounds was well tolerated as vinyl nitriles (12j-12l) were
formed from the hydrocyanation in good to excellent yields.
O
Ph
Ph
10a
15a
, 88%
a Reactions were run on 0.5 mmol scale. Yield is that of the
isolated product.
To exemplify potential application of the hydrocyanation
method, we synthesized ibuprofen, a nonsteroidal anti-
inflammatory drug. Commercially available 1-ethynyl-4-
isobutylbenzene (9o) underwent the above-described one-pot
reaction to afford the nitrile compound 13p which was then
ACS Paragon Plus Environment

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ACS Catalysis
hydrolyzed to afford ibuprofen in 43% overall yield. Another
interesting example is the oxidation of vinyl nitrile 10a which
afforded epoxide amide 15a in very good yield.
surrogate albeit the reaction in DMF is in a lower yield than in
DMAc (Scheme 2g). No deuterium products were detected
from the reaction in DMF-d7 indicating that there was no
deuterium exchange between the solvent and the substrate
(Scheme 2h). When deuterated water (D2O) was used, the ratio
of the deuterated products to the total hydrocyanated products
was increasing as escalation of equivalents of D2O added to the
reaction system (Scheme 2i), which confirmed that water is the
proton source (See SI).
1
2
3
4
5
6
7
8
9
To gain preliminary insight into the mechanism of the
cyanation reactions, we examined possibility of the formation
of organozinc intermediates. Aryl iodide and aryl bromide were
subjected to the standard conditions but in the absence of Ni
catalyst and ligands, and then quenched by adding aqueous HCl
solution (1.0 M). Hydrodehalogenation of aryl iodide was
minimal (Scheme 2a), while aryl bromide remained unreacted
(Scheme 2b). No detectable organozinc formation implied that
direct insertion of zinc into organic iodide or bromide did not
occur, so the role of organozinc intermediate was excluded.
Scheme 3. Plausible Mechanisms of the Cyanation of Aryl
Halides (A) and Hydrocyanation of Alkynes (B).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A
Ni(II)X2
N
Zn
= L1
N
Scheme 2. Mechanistic Investigation
1/2 ZnX2
N
R
1. KF (1.2 equiv), NaI (3.0 equiv)
Zn (6.0 equiv), TFAA (3.0 equiv)
DMAc, 50 °C, 36 h
I
CN
H
I
Ni(0)
X
1/2 Zn
+
+
(a)
N
N
Ph
O
Ph
Ph
Ph
2. HCl (aq., 1.0 M)
I
N
1a
2a
14 %
86 %
(1.0 equiv)
Br
(1.3 equiv)
CN
R
Ni(I)
X
1. KF (1.2 equiv), NaI (3.0 equiv)
Zn (6.0 equiv), TFAA (3.0 equiv)
DMAc, 60 °C, 36 h
H
Br
N
V
+
+
N
N
(b)
(c)
N
Ph
O
Ph
2. HCl (aq., 1.0 M)
Ni(II)
X
II
R
> 99 %
4a
2a
(1.0 equiv)
(1.3 equiv)
0 %
O
CN
OEt
1/2 Zn
I
THF
-30 °C to rt
N
N
O
Ni(cod)2
+
N
+
Ni
N
OEt
I
6
1f
, 86%
N
Ni(I)
N
CN
Ni(III)
1/2 ZnX2
R
6
(15 mmol%)
I
CN
CN
R
N
N
KF (1.2 equiv), NaI (3.0 equiv)
Zn (6.0 equiv), TFAA (3.0 equiv)
+
(d)
EtO
EtO
N
O
III
IV
O
DMAc, 50 °C, 36 h
O
N
O
1f
2a
3f
, 50%
(1.0 equiv)
(1.3 equiv)
O
O
N
F3C
KF (1.2 equiv), NaI (3.0 equiv)
Zn (6.0 equiv)
CF3
O
2a (1.3 equiv)
(e)
(f)
NC
6
(1.0 equiv)
+
3f
, 41%
DMAc, 50 °C, 36 h
CF3CO2
I
CN
"standard" conditions A
TEMPO (3.0 equiv)
+
no reaction
Ni(II)X2
Zn, Ln
N
O
B
Ph
R1
1a
2a
(1.0 equiv)
(1.3 equiv)
NiCl2(15 mol%), KF(1.2 equiv)
Zn (6.0 equiv), TFAA (5.0 equiv)
H2O (4 equiv)
R2
(R2 = H or R1)
CN
CN
1/2 ZnX2
+
(g)
(h)
Ni(0)L
N
Ph
O
Ph
DMF, 30 °C, 36 h
1/2 Zn
9a
2a
10a
(1.0 equiv)
(3.0 equiv)
, 65%
D/H
I'
D/H
CN
NiCl2(15 mol%), KF(1.2 equiv)
Zn (6.0 equiv), TFAA (5.0 equiv)
H2O (4 equiv)
L
CN
Ni
CN
Ni(0)L
R2
+
+
Ni(I)LX
N
O
O
Ph
CN
R1
R1
R2
H2O
R1
Ph
DMF-d7, 30 °C, 36 h
VI'
Ph
10a
/
H
-d1 d2, 0%
9a
2a
10a
10a
(1.0 equiv)
(1.0 equiv)
(3.0 equiv)
, 42%
O
II'
CF3
N
R2
D/H
D/H
CN
NiCl2(15 mol%), KF(1.2 equiv)
Zn (6.0 equiv), TFAA (5.0 equiv)
D2O (x equiv)
CN
CN
+
+
(i)
N
O
OH
Ph
Ph
DMF-d7, 30 °C, 36 h
H
Ph
Ni(III)L
10a
/
Ni(II)L
-d1 d2
9a
2a
(3.0 equiv)
H
CN
R1
R2
V'
R1
1/2 Zn
1/2 Zn(OH)2
R2
III'
R2
H
To elucidate the roles of catalyst and ligand, an organonickel
complex 6 was synthesized (Scheme 2c and SI). It was found
that when complex 6 was used as the catalyst, nitrile product
was obtained in modest yield (Scheme 2d). Stoichiometric
reaction of 6 with N-oxide 2a under the established reaction
condition (Scheme 2e) afforded the product in modest yield.
Both results indicated that 6 was a key intermediate in the
catalytic cycle. In addition, complete suppression of the
reaction by the presence of a strong oxidant, 2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO), indicated the
reaction possibly involved single electron reduction (SER)
process as TEMPO could prevent the Ni catalyst from being
reduced by Zn (Scheme 2f).
CF3CO2
O
O
R1 Ni(I)L
IV'
N
CF3
NC
On the basis of our studies, a plausible mechanism for the
formation of aryl nitriles was proposed (Scheme 3A).18-20 We
believed that precatalyst NiIIX2 could be first reduced by zinc to
generate bipyridine ligand-chelated Ni0 I, and oxidative
addition of aryl halide generates NiII complex II, which was
then reduced by zinc to give aryl nickelI complex III.
Subsequent oxidative addition of cyano source 2a with the
assistance from TFAA results in NiIII species IV,18-19 which then
undergoes reductive elimination to afford cyanation product
and NiI complex V. At this point, NiI could be reduced by zinc
powder to give the Ni0.19
In order to have further insight into the mechanism, we
performed deuterium exchange experiments. Since DMAc-d9
were not commercially accessible, DMF-d7 was used a
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 9
Conversion of Nitriles to NH2-amines. Science, 2019, 364, 45-51. (b)
Liskey, C. W.; Liao, X.; Hartwig, J. F. Cyanation of Arenes via Iridium-
Catalyzed Borylation. J. Am. Chem. Soc. 2010. 132. 11389-11391.
We also proposed a mechanism for the formation of alkene
nitriles through hydrocyanation of alkynes (Scheme 3B). Pre-
catalyst NiIIX2 was first reduced by zinc to generate Ni0 species
I’ which was coordinated by the alkyne to generate intermediate
II’. Oxidative addition of water to II resulted in NiII complex
III’, which was then reduced by zinc to give alkenylnickelI
complex IV’. Subsequent oxidative addition of 4-
cyanopyridinium-1-olate with the assistance of trifluoroacetic
anhydride furnished the NiIII species V’ which underwent
reductive elimination to afford hydrocyanation product along
with NiI complex VI’. Complex VI’ was reduced by zinc
powder to regenerate active Ni0 species I’ which was then
brought in the next catalytic cycle (See SI for detailed
information).
1
2
3
4
5
6
7
8
(3) Selected examples of using Mm(CN)n (M = K, Na, Zn, Cu, etc.) as
reagent: (a) Senecal, T. D.; Shu, W.; Buchwald. S. L. A General, Practical
Palladium-Catalyzed Cyanation of (Hetero)Aryl Chlorides and Bromides.
Angew. Chem., Int. Ed. 2013. 52, 10035-10039. (b) Zanon, J.; Klapars, A.;
Buchwald, S. L. Copper-Catalyzed Domino Halide Exchange-Cyanation of
Aryl Bromides. J. Am. Chem. Soc. 2003. 125. 2890-2891. (c) Ratani, T. S.;
Bachman, S.; Fu, G. C.; Peters, J. C. Photoinduced, Copper-Catalyzed
Carbon-Carbon Bond Formation with Alkyl Electrophiles: Cyanation of
Unactivated Secondary Alkyl Chlorides at Room Temperature. J. Am.
Chem. Soc. 2015, 137, 13902-13907. (d) Cohen, D. T.; Buchwald, S. L.
Mild Palladium-Catalyzed Cyanation of (Hetero)aryl Halides and Triflates
in Aqueous Media. Org. Lett. 2015, 17, 202-205. (e) Percec, V.; Bae, J. Y.;
Hill, D. H. Aryl Mesylates in Metal Catalyzed Homo- and Cross-Coupling
Reactions. Scope and Limitations of Aryl Mesylates in Nickel Catalyzed
Cross-Coupling Reactions. J. Org. Chem. 1995, 60, 6895-6903. (f) Ellis, G.
P.; Romney-Alexander, T. R. Cyanation of Aromatic Hatides. Chem. Rev.
1987, 87, 779-794. (g) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y.
A Mild and Efficient Palladium-Catalyzed Cyanation of Aryl Mesylates in
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. CONCLUSIONS
In summary, we have developed novel and efficient methods
to synthesize aryl and alkenyl nitriles from aryl halides and
alkynes, respectively, through C-CN bond activation using
nickel-catalysis under mild conditions. The insertion of CN to
alkynes could proceed in excellent E/Z-selectivity for di-aryl
alkynes and in exclusive Markovnikov selectivity for terminal
alkynes. With their broad substrate scopes, non-toxic cyano
source, mild reaction conditions, E/Z selectivity and
regioselectivity, the cyanation and hydrocyanation methods
described in this report provided a valuable and safe approach
to access nitrile-containing compounds. Further investigations
to elucidate the detailed mechanism are underway in this
laboratory, and the progress will be reported in due course.
t
Water or BuOH/Water. Angew. Chem. Int. Ed. 2010, 49, 8918-8922. (h)
Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Palladium-Catalyzed Direct
Cyanation of Indoles with K4[Fe(CN)6]. Org. Lett. 2010, 12, 1052-1055.
(i) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Chelation-Assisted Palladium-
Catalyzed Direct Cyanation of 2-Arylpyridine C-H Bonds. Org. Lett., 2009,
20, 4716-4719. (j) Cristau, H. J.; Ouali, A.; Spindler, J. F.; Taillefer, M.
Mild and Efficient Copper-Catalyzed Cyanation of Aryl Iodides and
Bromides. Chem. Eur. J. 2005, 11, 2483-2492. (k) Mariampillai, B.;
Alberico, D.; Bidau, V.; Lautens, M. Synthesis of Polycyclic Benzonitriles
via a One-Pot Aryl Alkylation/Cyanation Reaction. J. Am. Chem. Soc. 2006,
128, 14436-14437. (l) Anbarasan, P.; Schareina, T.; Beller, M. Recent
Developments and Perspectives in Palladium-Catalyzed Cyanation of Aryl
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(m) Lu, Z.; Hu, C.; Guo, J.; Li, J.; Cui, Y.; Jia, Y. Water-Controlled
Regioselectivity of Pd-Catalyzed Domino Reaction Involving a C-H
Activation Process: Rapid Synthesis of Diverse Carbo- and Heterocyclic
Skeletons. Org. Lett., 2010, 12, 480-483. (n) Do, H. Q.; Daugulis, O.
Copper-Catalyzed Cyanation of Heterocycle Carbon-Hydrogen Bonds. Org.
Lett., 2010, 12, 2517-2519. (o) Heravi, M. M.; Panahi, F.; Iranpoor, N.
Nickel-Catalyzed Deoxycyanation of Activated Phenols via Cyanurate
Intermediates with Zn(CN)2: A Route to Aryl Nitriles. Org. Lett., 2018, 20,
2753-2756. (p) Chatupheeraphat, A.; Liao, H. H.; Lee, S. C.; Rueping, M.
Nickel-Catalyzed C-CN Bond Formation via Decarbonylative Cyanation of
Esters, Amides, and Intramolecular Recombination Fragment Coupling of
Acyl Cyanides. Org. Lett. 2017, 19, 4255-4258. (q) Yu, H.; Richey, R. N.;
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ASSOCIATED CONTENT
Supporting Information
The supporting information (SI) is available free of charge on ACS
Publications website.
Detail experimental procedures and characterization data
(1H NMR, 13C NMR, MS, and HRMS) for the
compounds.
AUTHOR INFORMATION
Corresponding Author
*E-mail: liaoxuebin@mail.tsinghua.edu.cn
Using
a Microwave-Assisted, Copper-Catalyzed Concurrent Tandem
Catalysis Methodology. Organometallics, 2013, 32, 3537-3543. (s) Zhang,
X.; Xie, X.; Liu, Y. Nickel-Catalyzed Highly Regioselective
Hydrocyanation of Terminal Alkynes with Zn(CN)2 Using Water as the
Hydrogen Source. J. Am. Chem. Soc. 2018, 140, 7385-7389. (t) Zhao, D.;
Xu, P.; Ritter, T. Palladium-Catalyzed Late-Stage Direct Arene Cyanation.
Chem, 2019, 5, 97-107. (u) Chen, H.; Mondal, A.; Wedi, P.; Gemmeren, M.
V. Dual Ligand-Enabled Nondirected C-H Cyanation of Arenes. ACS Catal.
2019, 9, 1979-1984. (v) Louafi, F.; Hurvois, J. P.; Chibani, A.; Roisnel, T.
Synthesis of Tetrahydroisoquinoline Alkaloids via Anodic Cyanation as the
Key Step. J. Org. Chem. 2010, 75, 5721-5724. (w) Schareina, T.; Zapf, A.;
Magerlein, W.; Muller, K.; Beller, M. A New Palladium Catalyst System
for the Cyanation of Aryl Chlorides with K4[Fe(CN)6]. Tetrahedron Lett.
2007, 48, 1087-1090. (x) Ooi, T.; Uematsu, Y.; Maruoka, K. Asymmetric
Strecker Reaction of Aldimines Using Aqueous Potassium Cyanide by
Phase-Transfer Catalysis of Chiral Quaternary Ammonium Salts with a
Tetranaphthyl Backbone. J. Am. Chem. Soc. 2006, 128, 2548-2549. (y)
Jaegli, S.; Vors, J. P.; Neuville, L.; Zhu, J. P. Palladium-Catalyzed Domino
Heck/Cyanation: Synthesis of 3-Cyanomethyloxindoles and Their
Conversion to Pirooxoindoles. Tetrahedron, 2010, 66, 8911-8921. (z) Roy,
T.; Kim, M. J.; Yang, Y.; Kim, S.; Kang, G.; Ren, X. Y.; Kadziola, A.; Lee,
H. Y.; Baik, M. H.; Lee, J. W. Carbon Dioxide-Catalyzed Stereoselective
Cyanation Reaction. ACS Catal. 2019, 9, 6006-6011. (aa) Shi, S. C.;
Szostak, M. Decarbonylative Cyanation of Amides by Palladium Catalysis.
Org. Lett. 2017, 19, 3095-3098. (ab) Zhang, X. J.; Xia, A. Y.; Chen, H. Y.;
Liu, Y. H. General and Mild Nickel-Catalyzed Cyanation of
ORCID
Xuebin Liao: 0000-0002-0290-894X
Yahu A. Liu: 0000-0002-9434-6453
ACKNOWLEDGMENTS
We are grateful for financial support from the Collaborative
Innovation Center for Diagnosis and Treatment of Infectious
Disease, Tsinghua-Peking Centre for Life Science. We thank Dr.
Daniel Raymond (Genomics Institute of the Novartis Research
Foundation) for critical reading of the manuscript.
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1
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6
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8
(4) Selected examples of using TMSCN or acetone cyanohydrin as a reagent:
(a) Tsuji, Y., Kusui, T.; Kojima, T.; Sugiura, Y.; Yamada, N.; Tanaka, S.;
Ebihara, M.; Kawamura, T. Palladium-Complex-Catalyzed Cyanation of
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(8) Other selected examples to install cyano groups: (a) Fang, X.; Yu, P.;
Activation. ACS Catal. 2016, 6, 5989-6005. (ac) Sun, M. X.; Wang, Y. F.;
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Mashima, K. Nickel-Catalyzed Cyanation of Aryl Halides and Triflates
Using Acetonitrile via C–CN Bond Cleavage Assisted by 1,4-
bis(trimethylsilyl)-2,3,5,6- tetramethyl-1,4-dihydropyrazine. Chem. Sci.,
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J.; Bora, U. An Insight into Nitromethane as an Organic Nitrile Alternative
Source towards the Synthesis of Aryl Nitriles. Eur. J. Org. Chem. 2019, 36,
6211–6216.
(9) Luo, F. H.; Chu, C. I.; Cheng, C. H. Nitrile-Group Transfer from
Solvents to Aryl Halides. Novel Carbon-Carbon Bond Formation and
Cleavage Mediated by Palladium and Zinc Species. Organometallics 1998,
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from the Complexes (Diphosphine)Pd(R)(CN). J. Am. Chem. Soc. 1998,
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(11) Liu, B.; Wang, Y.; Chen, Y.; Wu, Q.; Zhao, J.; Sun, J. Stereoselective
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Electron-Rich Alkynes. Org. Lett, 2018, 20, 3465-3468.
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Coupling of Boronic Acids and Benzylthiocyanate. A Cyanide-Free
Cyanation of Boronic Acids. Org. Lett. 2006, 8, 4331-4333.
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with Aminoacetonitriles by Nickel Catalysis. Org. Lett. 2016, 18, 4428-
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(14) (a) Patra, T.; Agasti, S.; Akanksha, Maiti, D. Nickel-Catalyzed
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Auxiliary. Angew. Chem. Int. Ed., 2017, 129, 12712-12716.
(15) Souillart, L.; Cramer, N. Catalytic C-C Bond Activations via Oxidative
Addition to Transition Metals. Chem. Rev. 2015, 115, 9410-9464.
Morandi, B. Catalytic Reversible Alkene-Nitrile Interconversion through
Controllable Transfer Hydrocyanation. Science, 2016, 315, 832-836. (b) Yu,
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Using Butyronitrile: Merging Retro-hydrocyanation with Cross-Coupling.
Angew. Chem. Int. Ed. 2017, 56, 15693-15697. (c) Song, R. J.; Wu, J. C.;
Liu, Y.; Deng, G. B.; Wu, C. Y.; Wei, W. T.; Li, J. H. Copper-Catalyzed
Oxidative Cyanation of Aryl Halides with Nitriles Involving Carbon–
Carbon Cleavage. Symlett, 2012, 23, 2491-2496. (d) Zheng, S.; Yu, C.;
Shen, Z. Ethyl Cyanoacetate: A New Cyanating Agent for the Palladium-
Catalyzed Cyanation of Aryl Halides. Org. Lett. 2014, 14, 3644-3647. (e)
Pan, Z.; Pound, S. S.; Rondla, N. R.; Douglas, C. J. Intramolecular
Aminocyanation of Alkenes by N-CN Bond Cleavage. Angew. Chem. Int.
Ed. 2014, 126, 5270-5274. (f) Rondla, N. R.; Levi, S. S.; Ryss, J. M.;
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for Intramolecular Cyanoesterification of Alkynes. Org. Lett. 2011, 13,
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Jia, T.; Smith, M. J.; Pulis, A. P.; Perry, G. J. P.; Procter, D, J.
Enantioselective and Regioselective Copper-Catalyzed Borocyanation of
1-Aryl-1,3-Butadienes. ACS Catal. 2019, 9, 6744-6750. (i) Alazet, S.; West,
M. S.; Patel, P.; Rousseaux, S. A. L. Synthesis of Nitrile-Bearing
Quaternary Centers by an Equilibrium-Driven Transnitrilation and Anion-
Relay Strategy. Angew. Chem. Int. Ed. 2019, 58, 10300-10304. (j) Li, X.
D.; Golz, C.; Alcarazo, M. 5-(Cyano) dibenzothiophenium Triflate: A
Sulfur-Based Reagent for Electrophilic Cyanation and Cyanocyclizations.
Angew. Chem. Int. Ed. 2019, 58, 9496-9500. (k) Donald, J. R.; Berrell, S.
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Sci., 2019, 10, 5832-5836. (l) Kanda, T.; Naraoka, A.; Naka, H. Catalytic
Transfer Hydration of Cyanohydrins to α-Hydroxyamides. J. Am. Chem.
Soc. 2019, 141, 825-830. (m) Lundgren, S.; Wingstrand, E.; Penhoat, M.;
Moberg, C. Dual Lewis Acid-Lewis Base Activation in Enantioselective
Cyanation of Aldehydes Using Acetyl Cyanide and Cyanoformate as
Cyanide Sources. J. Am. Chem. Soc. 2005, 127, 11592-11593. (n) Zhang,
L.; Lu, P.; Wang, Y. G. Cu(NO3)23H2O-Mediated Cyanation of Aryliodides
and Bromides Using DMF as a Single Surrogate of Cyanide. Chem.
Commun., 2015, 51, 2840-2843. (o) Kawamoto, T.; Geib, S. J.; Curran, D.
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Nitriles: Cyanation of NHC-Boranes and Reductive Decyanation of
Malononitriles. J. Am. Chem. Soc. 2015, 137, 8617-8622. (p) Li, X.; You,
C.; Yang, J.; Li, S.; Zhang, D.; Lv, H.; Zhang, X. M. Asymmetric
Hydrocyanation of Alkenes without HCN. Angew. Chem. Int. Ed., 2019, 58,
10928-10931. (q) Li, H.; Zhang, S.; Yu, X.; Feng, X.; Yamamoto, Y.; Bao,
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(16) Everson, D. A.; Jones, B. A.; Weix, D. J. Replacing Conventional
Carbon Nucleophiles with Electrophiles: Nickel-Catalyzed Reductive
Alkylation of Aryl Bromides and Chlorides. J. Am. Chem. Soc. 2012, 134,
6146−6159.
(17) Rajanbabu, T. V. Hydrocyanation of Alkenes and Alkynes Org.
React. 2011, 75, 1-69.
(18) Liu, J.; Ren, Q.; Zhang, X.; Gong, H. Preparation of Vinyl Arenes by
Nickel-Catalyzed Reductive Coupling of Aryl Halides with Vinyl Bromides.
Angew. Chem. Int. Ed. 2016, 55, 15544-15548.
(19) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Catalytic Asymmetric
Reductive Acyl Cross-Coupling: Synthesis of Enantioenriched Acyclic α,α-
Disubstituted Ketones. J. Am. Chem. Soc. 2013, 135, 7442-7445.
(20) Amatore, C.; Jutand, A. Rates and Mechanism of Biphenyl Synthesis
Catalyzed by Electrogenerated Coordinatively Unsaturated Nickel
Complexes. Organometallics, 1988, 7, 2203-2214.
M.
Rhodium(III)-Catalyzed
Aromatic
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Makha, M.; Li, Y. H. Catalytic Cyanation Using CO2 and NH3, Chem, 2018,
4, 2883-2893. (s) Wang, H. N.; Mi, P. B.; Zhao, W. J.; Kumar, R.; Bi, X.
H. Silver-Mediated Direct C−H Cyanation of Terminal Alkynes with
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Nagata, T.; Matsubara, H.; Kiyokawa, K.; Minakata, S. Catalytic Activation
of 1‑Cyano-3,3-dimethyl-3-(1H)‑1,2-benziodoxole with B(C6F5)3 Enabling
the Electrophilic Cyanation of Silyl Enol Ethers. Org. Lett. 2017, 19, 4672-
4675. (u) Vaillant, F. L.; Wodrich, M. D.; Waser, J. Room Temperature
Decarboxylative Cyanation of Carboxylic Acids Using Photoredox
Catalysis and Cyanobenziodoxolones: a Divergent Mechanism Compared
to Alkynylation. Chem. Sci., 2017, 8, 1790-1800. (v) Zhao, W. X.;
Montgomery, J. Cascade Copper-Catalyzed 1,2,3-Trifunctionalization of
Terminal Allenes. J. Am. Chem. Soc. 2016, 138, 9763-9766. (w) Zeng, X.
P.; Zhou, J. Me2(CH2Cl)SiCN: Bifunctional Cyanating Reagent for the
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ACS Catalysis
C-CN bond
cleavage
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aryl halides
diaryl
alkynes
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CN
R
Ni
R
R
cyano source
nontoxic, cheap
high solube
reaction
mild conditions
broad substrate scope
good regioselectivity
non-volatile powder, easy to weigh
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