Nickel-Catalyzed Highly Regioselective Hydrocyanation of Terminal Alkynes with Zn(CN)2 Using Water as the Hydrogen Source

Article abstract of DOI:10.1021/jacs.8b02542

The first efficient and general nickel-catalyzed hydrocyanation of terminal alkynes with Zn(CN)₂ in the presence of water has been developed. The reaction provides a regioselective protocol for the synthesis of functionalized vinyl nitriles with a range of structural diversity under mild reaction conditions while obviating use of the volatile and hazardous reagent of HCN. Deuterium-labeling experiments confirmed the role of water as the hydrogen source in this hydrocyanation reaction.

Full text of DOI:10.1021/jacs.8b02542

Subscriber access provided by University of Massachusetts Amherst Libraries
Communication
Nickel-Catalyzed Highly Regioselective Hydrocyanation of Terminal
Alkynes with Zn(CN)2 Using Water as the Hydrogen Source
Xingjie Zhang, Xin Xie, and Yuanhong Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02542 • Publication Date (Web): 31 May 2018
Downloaded from http://pubs.acs.org on May 31, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Nickel-Catalyzed Highly Regioselective Hydrocyanation of Terminal
Alkynes with Zn(CN)2 Using Water as the Hydrogen Source
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
Xingjie Zhang, Xin Xie and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Orꢀ
ganic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai
200032 (P. R. China).
Supporting Information Placeholder
selectivity.9 However, the efficient Markovnikov hydrocyanation
ABSTRACT: The first efficient and general nickelꢀcatalyzed
of alkynes have not been reported yet. During our recent work on
nickelꢀcatalyzed cyanation of aryl/heteroaryl chlorides using less
toxic Zn(CN)2 as the cyanide source,10 we discovered that
Zn(CN)2 could also be used for hydrocyanation of alkynes. In this
report, we disclosed the first general and efficient nickelꢀcatalyzed
hydrocyanation of terminal alkynes with less toxic Zn(CN)2 in a
mixed solvent of CH3CN/H2O. Remarkably, the method provides
the alkenyl nitriles with excellent Markovnikov selectivity for
aromatic as well as aliphatic substrates under extremely mild reacꢀ
hydrocyanation of terminal alkynes with Zn(CN)2 in the presence
of water has been developed. The reaction provides a novel and
regioselective protocol for the synthesis of functionalized vinyl
nitriles with a wide range of structural diversity under mild reacꢀ
tion conditions while obviating the use of the volatile and hazardꢀ
ous reagent of HCN. Deuteriumꢀlabeling experiments confirmed
the role of water as the hydrogen source in this hydrocyanation
reaction.
o
tion conditions (25 to 50 C) while obviating the use of the volaꢀ
tile and hazardous reagent of HCN. In addition, the competitive
alkyne cyclotrimerization pathway11 could be minimized to a
large extent. Deuteriumꢀlabeling experiments confirmed the role
of water as the hydrogen source in the hydrocyanation reaction.
Nitriles are versatile intermediates in organic synthesis since they
can be used in the preparation of a large number of pharmaceutiꢀ
cals, pesticides, and functional materials which are widely used in
daily life.1 They also serve as precursors for amides, amines, carꢀ
boxylic acids, esters, aldehydes, ketones and alcohols etc.2 Transiꢀ
tionꢀmetalꢀcatalyzed addition of hydrogen cyanide to alkynes
(hydrocyanation) offers a straightforward way for the synthesis of
vinyl nitriles3,4 These reactions generally proceed via oxidative
addition of HCN followed by syn addition of both H and CN
groups to the carbonꢀcarbon triple bond (Scheme 1). Unfortunateꢀ
ly, these methods still suffer from the following major drawbacks:
Scheme 1. Transition-metal-catalyzed hydrocyanation reac-
tions of alkynes
Known reaction: oxidative addition of HCN
HCN
H
CN
R2
cat. [Ni0]
H
Ni CN
extremely toxic reagent
Low regioselectivity
limited scope
R1
R2
R1
R2
R1
Ritter et al: Rh-catalyzed anti-Markovnikov hydrocyanation
o
(1) the highly toxic and volatile hydrogen cyanide (bp 26 C) was
cat. TpRh(COD)
R
employed. In addition, a careful control of the HCN concentration
is usually required to avoid catalyst poisoning during the reaction
process. Although acetone cyanohydrin has been employed as a
source of HCN, it still poses a significant risk; (2) The scope of
the possible substrates were quite limited; (3) The regioselectivity
was not good. For example, in Niꢀcatalyzed hydrocyanation of
terminal alkynes with HCN or acetone cyanohydrin, a mixture of
linear and branched vinyl nitriles were usually formed. For phenyl
acetylene, the linear product was strongly favored,5a,b whereas for
aliphatic alkynes with small and moderately sized substituents,
branched nitriles were predominant.3a,5 Hydrocyanation reactions
of alkynes without the use of HCN have been accomplished by
HO CN
ligand
+
H
R
CH3CN, 110 oC, 12 h
CN
This work: Ni-catalyzed Markovnikov hydrocyanation assisted by water
Zn(CN)2
without the use of HCN
water as the hydrogen source
high regioselectivity and mild conditions
new reaction pattern for hydrocyanation
cat. [NiII]/Mn/(L)
R
R
H
CH3CN/H2O, 25-50 o
C
CN
H
R = aryl, heteroaryl, alkyl
We initially investigated the nickelꢀcatalyzed hydrocyanation
of 1ꢀethynylꢀ4ꢀmethylbenzene 1a with Zn(CN)2. Upon optimizaꢀ
tion of a variety of reaction parameters such as nickel catalysts,
ligands, reducing agents, additives etc. we were pleased to find
that the hydrocyanation of 1a proceeded smoothly to afford
6
using stoicheiometric amount of [Co(CN)5]3ꢀ and H2 or subꢀ
stoicheiometric amount of [Ni(CN)4]2ꢀ (0.5 equiv) in the presence
of excess KCN with excess NaBH4 or Zn as the reducing agents
in ethylene glycol or water.7 However, in most of these cases,7a
the hydrocyanation is accompanied by a hydrogenation reaction
leading to saturated nitriles. Morandi et al. have reported an eleꢀ
gant nickelꢀcatalyzed transfer hydrocyanation reaction through
reversible alkeneꢀnitrile interconversion for the synthesis of alkyl
nitriles, and the reaction could be extended to internal alkynes.8
However, the reactivity of terminal alkynes has not been reported
by this method. Recently, a nice Rhꢀcatalyzed hydrocyanation of
terminal alkynes with acetone cyanohydrin was reported by Ritter
et al., which afforded the alkenyl nitriles with anti-Markovnikov
o
branched nitrile 2a exclusively in 85% yield at 25 C in the presꢀ
ence of 5 mol% Ni(acac)2 and 20 mol% Mn in CH3CN/H2O withꢀ
out adding additional ligands (Table 1, entry 1).12 The linear
product 3a was not observed according to 1H NMR analysis of the
crude reaction mixture. These results indicated that the reaction
proceeds with high regioselectivity via Markovnikov addition.
The regioselectivity of arylalkynes observed in our reaction is in
contrast to those reported in previous hydrocyanation events.5a,b
We have also examined the effects of the ligands on the reaction
efficiency. Among these ligands, neocuproine gave the best reꢀ
sults, and bipyridine or Nꢀheterocyclic carbene (IPr) ligand
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
showed comparative activity with that of neocuproine (entries 2, 6
reaction at 25 oC, leading to branched nitrile 2e in 50% yield after
24 h. However, high yield of 2e (77%) could be achieved by inꢀ
creasing the reaction temperature to 50 C and using 50 mol% of
and 10). The use of C4, C4’ꢀsubstituted bipyridine led to a slightly
lower yield (entry 3). Other 1,10ꢀphenanthrolineꢀtype ligands of
L3, L4 and L6 resulted in trace or low yields of 2a (entries 4ꢀ5,
7). The high efficiency of neocuproine L5 is likely due to the
enhanced stability of the nickelꢀcontaining intermediates with this
ligand. Interestingly, the reaction was not interfered severely by
the addition of PPh3 as the ligand, leading to 2a in 72% yield
(entry 9). Other nickel catalysts such as NiCl2·6H2O, NiI2, and
NiBr2(diglyme) gave 2a in low yields under ligandless conditions
(entries 11ꢀ13). The reaction could also proceed effectively in
THF. Inferior results were found when other solvents such as
DMF or reducing agents were employed (entries 14ꢀ16). Imꢀ
portantly, with 2 equiv water or without water there was no reacꢀ
tion, indicating a crucial role of water (entry 17). The results indiꢀ
cate that water may also play a role in improving the solubility of
Zn(CN)2. Control experiments indicated that the nickel catalyst
and Mn were essential for the reaction to occur (entries 18). Only
14% and 24% of 2a were detected after 6 h and 12 h, respectively,
indicating a longer induction period was involved in this reaction
(entry 19).
1
2
3
4
5
6
7
8
o
Mn. Sterically hindered 1ꢀnaphthylꢀsubstituted alkyne afforded
nitrile 2f in 73% yield by further adding 6 mol% neocuproine as
the ligand. These results also indicated that the regioselectivity
was not affected by the steric effects on the alkyne substituents.
Fluoro, chloro and bromo substituents on the aryl rings were also
well tolerated (2gꢀ2i). Although the ArꢀX bonds are susceptible to
undergo oxidative addition by lowꢀvalent nickel species, we did
not observe the corresponding products derived from dehalogenaꢀ
tion or cyanation reactions. Moderate yields were observed for
aryl alkynes bearing electronꢀwithdrawing groups such as pꢀCF3
(2j) and pꢀCONH2 (2k). The results might be ascribed to the conꢀ
sumption of the nitrile products through oligomerization or
polymerization catalyzed by lowꢀvalent nickel species.13 In fact,
the nitrile such as 2j was consumed almost completely upon subꢀ
jection to the standard reaction conditions. Notably, the vinyl or
internal alkynyl groups remained intact in the cases of 2m and 2n,
indicating that the reaction is highly chemoselective. Lower yield
of 2o (39%) was obtained when 3ꢀethynylpyridine was employed
as the substrate. Internal alkynes such as 1,2ꢀdiphenylethyne was
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
Table 1. Optimization of the reaction conditionsa
o
also well suited, furnishing 2p in 78% yield at 80 C. However,
1,3ꢀbutadiynes, ynamides or allenes were not suitable under the
Me
Me
+
0.8 equiv Zn(CN)2
5 mol% Ni(acac)2
20 mol% Mn
current reaction conditions.12
Me
Table 2. Scope of Ni-catalyzed hydrocyanation of aryl alkynesa
CH3CN/H2O (5/1), 25 oC, 24 h
NC
CN
5 mol% Ni(acac)2
20 mol% Mn
standard conditions
Ar
1a
2a
3a
Yield (%)b
+
Zn(CN)2
Ar
CH3CN/H2O = 5/1, 25 oC, 24 h
NC
0.8 equiv
Entry
Deviation from standard conditions
1
2
2a
3a
85 (83c)
none
0
0
0
0
0
0
Me
MeO
CbzHN
1
2
3
4
5
6
with 6 mol% L1
with 6 mol% L2
with 6 mol% L3
with 6 mol% L4
with 6 mol% L5
with 6 mol% L6
with 6 mol% L7
with 12 mol% PPh3
with 6 mol% IPr
82
74
1
H2N
Me
7
88
NC
NC
NC
NC
NC
2a, 83%
2b, 79%
2c, 85%b
2d, 83%
2e, 77%c
1
7
27
20
72
84
O
10 (6c)
X
8
F
F3C
H2N
0
0
9
10
0
0
0
NiCl2 6H2O instead of Ni(acac)2
NiI2 instead of Ni(acac)2
11
12
13
3
NC
18
7
NC
NC
NC
NC
X = Cl, 2h, 77%
X = Br, 2i, 72%
NiBr2(diglyme) instead of Ni(acac)2
THF instead of CH3CN
2f, 50 oC, 73%d
2k, 54%e
2g, 79%
2j, 51%
14
15
83
2
2
0
Ph
DMF instead of CH3CN
Ph
0
0
0
0
16
17
18
19
Zn instead of Mn
5
0
0
with 2 equiv H2O or without H2O
without either Ni(acac)2 or Mn
1 h, 3 h, 6 h or 12 h instead of 24 h
N
0, 1, 14, 24
NC
NC
NC
2p, 80 oC, 78%d
NC
NC
R2
R2
L3: R1 = R2 = H
R
R
2m, 75%f
2n, 68%f
2l, 74%
2o, 50 oC, 39%d
L4: R1 = H, R2 = Ph
L5: R1 = Me, R2 = H
L6: R1 = Me, R2 = Ph
O
aIsolated yields. b25 h. c50 oC, 5 mol% Ni(acac)2 and 50 mol% Mn were used. d5 mol%
Ni(acac)2, 6 mol% neocuproine and 50 mol% Mn were used. e36 h. f22 h.
N
N
N
N
PPh2
PPh2
L1: R = H
L2: R = tBu
R1
R1
L7
a1a (0.5 mmol), Zn(CN)2 (0.4 mmol), Ni(acac)2 (0.025 mmol), Mn (0.1 mmol), in
CH3CN/H2O (5:1, total 3.0 mL). bDetermined by 1H NMR of the crude reaction
mixture using 1,3,5-trimethoxybenzene as an internal standard. cIsolated yields.
Next, we examined the hydrocyanation reactions of terminal alꢀ
iphatic alkynes with Zn(CN)2. During this process, we found that
the alkynes could not be consumed completely under the standard
reaction conditions for aryl alkynes. We then made an effort to reꢀ
optimize the reaction conditions for alkylꢀsubstituted alkynes.
After some trials, it was found that the desired reactions proceedꢀ
ed smoothly with also excellent Markovnikov selectivity cataꢀ
lyzed by 5 mol% Ni(acac)2 and 6 mol% neocuproine in the presꢀ
Encouraged by these results, we next turned our attention to inꢀ
vestigate the generality of this hydrocyanation reaction. The scope
of aryl alkynes 1 was first studied under the standard reaction
conditions (Table 2). It was found that the method was applicable
to a wide range of substituted terminal aryl alkynes, and in all
cases, the reaction proceeded with excellent Markovnikov selecꢀ
tivity as no linear nitriles were observed. The electronꢀrich aryl
alkynes bearing pꢀMe, pꢀMeO, free amino and amide groups were
well tolerated, furnishing 2aꢀ2d in 79ꢀ85% yields. The presence
of an orthoꢀsubstituent on the aryl ring resulted in a less efficient
o
ence of 50 mol% Mn at 50 C. A large variety of nonꢀactivated
alkylꢀsubstituted alkynes were cyanated efficiently under these
modified reaction conditions (Table 3). For example, the common
alkynes such as 1ꢀdodecyne or 1ꢀoctyne transformed to vinyl niꢀ
triles 5a and 5b in 62% and 87% yields, respectively. Alkyl side
chains bearing phenyl, ester, cyano, Cl or unprotected OH funcꢀ
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
Cl
tional groups were also suitable for this reaction, furnishing 5cꢀ5h
Gram scale study: 10 mmol
in 60ꢀ85% yields. In the case of 5d, a saturated nitrile of 2ꢀ
methylꢀ4ꢀphenylbutanenitrile was also isolated in 6% yield, indiꢀ
cating further hydrogenation of 5d occurred during the process. In
particular, good products yields were observed for propargyl alꢀ
cohols, and not only secondary propargyl alcohols, but also steriꢀ
cally hindered tertiary propargyl alcohols worked well to afford
1
2
3
4
5
6
7
8
5 mol% Ni(acac)2
20 mol% Mn
+
Zn(CN)2
0.8 equiv
Cl
CH3CN/H2O = 5/1, 25 oC, 24 h
NC
2h, 1.22g, 74%
1h
Late-stage hydrocyanation of complicated drug molecules
0.8 equiv Zn(CN)2
5 mol% Ni(acac)2
20 mol% Mn
Ph
Ph
tBu
tBu
N
N
CH3CN/H2O = 5/1
50 oC, 24 h
N
NC
N
Table 3. Scope of Ni-catalyzed hydrocyanation of alkyl alkynesa
6
7, 74%
5 mol% Ni(acac)2
0.8 equiv Zn(CN)2
5 mol% Ni(acac)2
6 mol% Neocuproine
50 mol% Mn
6 mol% Neocuproine
50 mol% Mn
OH
OH
alkyl
9
+
Zn(CN)2
alkyl
CN
CH3CN/H2O = 5/1, 50 oC, 24 h
H
H
NC
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
0.8 equiv
CH3CN/H2O = 5/1, 50 oC, 24 h
4
5
H
H
H
H
O
O
8
9, 80%
Ph
Ph
Me
Me
CN
CN
CN
CN
tion proceeds predominantly in a synꢀaddition manner. Employing
TMSCN/MeOH as an in situ source of HCN17 resulted in no forꢀ
mation of 2a (Scheme 3, eq 2).18 Importantly, It was found that
Ni(COD)2 could catalyze the reaction leading to 2a in 38% yield,
whereas Ni(I) complex Ni(acac)IPr15 failed to give a clean reacꢀ
tion (Scheme 3, eq 3ꢀ4). The results suggest that the reaction proꢀ
ceeds possibly via a Ni(0) species. Preliminary results implied
that semihydrogenation of 1a could occur in the absence of
Zn(CN)2 with an excess amount of reductant, indicating that a Niꢀ
H species might be involved (Scheme 3, eq 5).19,20 Water is typiꢀ
cally employed as a proton source, but it could also act as a hyꢀ
dride source through the reaction with the lowꢀvalent metals. Altꢀ
hough quite rare, the oxidative addition of water by late transitionꢀ
metal complexes21 leading to the formation of metal hyꢀ
drido(hydroxo) complexes has been proposed in a variety of cataꢀ
lytic processes such as the water gas shift reaction,22 alkyneꢀ
aldehyde coupling,23 semihydrogenation,19 etc. Our results sugꢀ
gested that a process involving oxidative addition of water might
take place in our reaction. To make clear whether the heterogeneꢀ
ous Ni catalysts act as real catalysts, the mercury poisoning experꢀ
iments were carried out.12 It was found that addition of mercury
did not inhibit the reaction. Thus the reaction may not proceed via
heterogeneous system.
5b, 61% (87%b)
5c, 79%
5a, 62%
5d, 78%c
O
MeO
HO
NC
Cl
CN
CN
CN
CN
5g, 60%
5e, 67%d
OH
5h, 85%
5f, 84%
OH
OH
OH
Ph
Ph
CN
5j, 82%
CN
CN
CN
5i, 68%
5k, 82%
5l, 71%
Ac
TIPS
PhHN
N
N
Ph
CN
CN
CN
5p, traced
CN
5m, 54%d
5n, 83%
5o, 80%
aIsolated yields. bNMR yield. c2-Methyl-4-phenylbutanenitrile was also isolated in 6% yield.
d10 mol% Ni(acac)2 and 12 mol% neocuproine were used.
the corresponding 5iꢀ5l in good yields. Especially, in the case of
5l, the vinyl moiety remained intact, highlighting again the excelꢀ
lent chemoselectivity of this method. Propargyl amines were
proved to be also suitable substrates. In the case of Nꢀ(propꢀ2ꢀ
ynyl)benzenamine bearing an αꢀNHPh group, the reaction apꢀ
peared to proceed well by doubling the amounts of Ni(acac)2 and
neocuproine (5m). However, when propargyl amine bearing a
protected amino group was employed, high yield of 83% could be
achieved under the standard reaction conditions (5n). It was noted
that usually low regioselectivity was observed in nickelꢀcatalyzed
hydrocyanation of propargyl alcohols or amines with HCN.5c,d An
indolyl moiety could be successfully incorporated into the product
(5o). However, silyl alkynes such as ethynyltriisopropylsilane
only led to a trace amount of the product (5p).
To demonstrate the practicality of the process, the reaction of
1h with Zn(CN)2 at 10 mmol scale was performed. Gratifyingly,
high yield of 2a (74%) was achieved without further modification
of the optimized reaction conditions. Thus, the protocol represents
a lowꢀcost and convenient route to vinyl nitriles from alkynes. In
addition, alkyne 6 derived from drug Buclizine and Ethisterone 8,
were cyanated in good yields by this Niꢀcatalyzed hydrocyanation
(Scheme 2). Thus, the present method can be used for the lateꢀ
stage functionalization of medicinally relevant compounds.
Scheme 3. Control experiments
Me
5 mol% Ni(acac)2
20 mol% Mn
11% D
+
+
D2
(1)
Me
Me
Zn(CN)2
CH3CN/D2O = 5/1
25 oC, 24 h
0.8 equiv
NC
D1
91% D
1a
2a-D, 82%
5 mol% Ni(acac)2
20 mol% Mn
2.0 equiv MeOH
2a
1a
TMSCN
+
(2)
(3)
CH3CN/H2O = 5/1
25 oC, 24 h
97% NMR yield
2.0 equiv
0%
1a
1a
1a
5 mol% Ni(COD)2
Zn(CN)2
0.8 equiv
2a
+
Me
Me
Me
CH3CN/H2O = 5/1, 25 oC, 24 h
38% NMR yield
5 mol% NiI(acac)IPr
Zn(CN)2
complex mixture (4)
+
CH3CN/H2O = 5/1, 25 oC, 24 h
0.8 equiv
10 mol% Ni(acac)2, 2.0 equiv Mn
CH3CN/H2O = 5/1, 80 oC, 24 h
Me
10, 43% NMR yield
(5)
In order to understand the reaction mechanism, a deuterium laꢀ
beling experiment using deuterium oxide (D2O) instead of water
was performed. High deuterium incorporation of D1 (91%) cis to
the cyano group was observed (Scheme 3, eq 1). Complete deuꢀ
teration is not observed possibly due to alkynylic H/D exchange
by D2O14 or the cis to trans double bond isomerization of vinyl
nickel species during the process.15 The results verified that water
acts as the hydrogen source for hydrocyanation7a,16 and the reacꢀ
Scheme 2. Gram scale and modification of drug molecules
1a
Although the detailed mechanistic discussions should await furꢀ
ther studies, we tentatively propose a reaction mechanism for
hydrocyanation of terminal alkynes as depicted in Scheme 4. The
first step involves the formation of Ni(0) species by reduction of
Ni(acac)2 with Mn. Oxidative addition of water to Ni(0) generates
the Ni(II) intermediate 11.21f Alkyne insertion to 11 via cisꢀ
addition of NiꢀH bond (hydronickelation) provides an alkenyl
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(4) For related silylꢀcyanation of alkynes with trimethylsilylcyanide: (a)
nickel complex 12. Possibly, the stability of the alkenyl nickel
species influences the regioselectivity of this step. Transmetaꢀ
lation of 12 with Zn(CN)2 followed by reductive elimination deꢀ
livers the nitriles. Alternatively, reaction of nickel πꢀalkyne comꢀ
plex 14 with H2O may also afford the same intermediate 12 (path
b).20a The detailed process for this transformation is not clear yet,
it may proceed through oxidative addition of water with 1419a or
cleavage of nickelacyclopropene intermediate 15 by water. Howꢀ
ever, the direct attack of the cyanide nucleophile to nickelꢀ
coordinated alkyne followed by protonation could not be excludꢀ
ed.24
Chatani, N.; Hanafusa, T. J. Chem. Soc. Chem. Commun. 1985, 838. (b)
Chatani, N.; Takeyasu, T.; Horiuchi, N.; Hanafusa, T. J. Org. Chem. 1988,
53, 3539. (c) Arai, S.; Nishida, A. Synlett 2012, 23, 2880.
1
2
3
4
5
6
7
8
(5) (a) Jackson, W. R.; Lovel, C. G. J. Chem. Soc. Chem. Commun. 1982,
1231. (b) Jackson, W. R.; Lovel, C. G. Aust. J. Chem. 1983, 36, 1975. (c)
Jackson, W. R.; Lovel, C. G.; Perlmutter, P.; Smallridge, A. J. Aust. J.
Chem. 1988, 41, 1099. (d) Jackson, W. R.; Perlmutter, P.; Smallridge, A. J.
Aust. J. Chem. 1988, 41, 1201. (e) Jackson, W. R.; Perlmutter, P.; Smallꢀ
ridge, A. J. Aust. J. Chem. 1988, 41, 251. (f) Jackson, W. R.; Perlmutter,
P.; Smallridge, A. Tetrahedron Lett. 1988, 29, 1983. Although high regiꢀ
oselectivity could be observed for several terminal alkynes such as pentꢀ1ꢀ
yne (5:95, 40%) or phenylacetylene (98:2, 48%), the yields of the prodꢀ
ucts were not good. See Ref. 5b.
(6) (a) Funabiki, T.; Yamazaki, Y.; Tarama, K. J. Chem. Soc. Chem.
Commun. 1978, 63. (b) Funabiki, T.; Yamazaki, Y.; Sato, Y.; Yoshida, S.
J. Chem. Soc. Perkin Trans. II 1983, 1915.
(7) (a) Funabiki, T.; Yamazaki, Y. J. Chem. Soc. Chem. Commun. 1979,
1110. One example of phenylacetylene hydrocyanation giving up to 50%
yield of the branched product was reported in this reference. (b) Funabiki,
T.; Sato, H.; Tanaka, N.; Yamazaki, Y.; Yoshida, S. J. Mol. Catal. 1990,
62, 157.
(8) (a) Fang, X.; Yu, P.; Morandi, B. Science 2016, 351, 832. (b) Fang,
X.; Yu, P.; Cerai, G. P.; Morandi, B. Chem. Eur. J. 2016, 22, 15629.
(9) Ye, F., Chen, J.; Ritter, T. J. Am. Chem. Soc. 2017, 139, 7184.
(10) Zhang, X.; Xia, A.; Chen, H.; Liu, Y. Org. Lett. 2017, 19, 2118.
(11) (a) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307. (b)
Galan, B. R.; Rovis, T. Angew. Chem. Int. Ed. 2009, 48, 2830.
(12) See Supporting Information for details.
(13) For a review on nickelꢀcatalyzed oligomerization of acetylenes and
related reactions, see: Jolly, P. W. Comprehensive Organometallic Chem-
istry; Wilkinson, G.; Stone, G. A.; Abel, E. W. Eds.; Pergamon: Oxford,
1982; Vol. 8, pp 649ꢀ670.
(14) For H/D exchange of terminal alkynes with D2O under basic condiꢀ
tions, see: Bew, S. P.; HiattꢀGipson, G. D.; Lovell, J. A.; Poullain, C. Org.
Lett. 2012, 14, 456.
(15) Zhang, X.; Xie, X.; Liu, Y. Chem. Sci. 2016, 7, 5815.
(16) For a recent work related to nickelꢀcatalyzed carboxylation of alꢀ
kenes or alkynes using water as a hydrogen source, see: Gaydou, M.;
Moragas, T.; JuliáꢀHernández, F.; Martin, R. J. Am. Chem. Soc. 2017, 139,
12161.
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
Scheme 4. Possible reaction mechanism
Ni(acac)2
Mn, L
CN
Mn(acac)2
OH
LnNII
LnNiII
R
H
OH
H
R
Zn(CN)2
H2O
H
LnNII
LnNi0
13
LnNi0
path a
R
11
12
LnNi0
CN
H
LnNi
H2O
R
path b
R
R
R
2 or 5
14
15
In summary, we have developed the first Niꢀcatalyzed regioseꢀ
lective hydrocyanation of terminal alkynes using Zn(CN)2 as the
cyanide source and water as a hydrogen source. The reaction proꢀ
vides a novel and efficient protocol for the synthesis of functionꢀ
alized vinyl nitriles with a wide range of structural diversity under
extremely mild reaction conditions. Further mechanistic studies
and the extension to internal alkynes and other πꢀsystems are
currently ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting Information
(17) (a) Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153. (b) Falk, A.;
Göderz, A. L.; Schmalz, H. G. Angew. Chem. Int. Ed. 2013, 52, 1576. (c)
Arai, S.; Hori, H.; Amako, Y.; Nishida, A. Chem. Commun. 2015, 51,
7493.
Experimental procedures, Xꢀray crystallography of compound 9
and spectral data. This material is available free of charge via the
internet at http://pubs.acs.org.
(18) For hydrolysis of readily ionizable sources of cyanide such as KCN
and NaCN to generate HCN, see: Erhardt, S.; Grushin, V. V.; Kilpatrick,
A. H.; Macgregor, S. A.; Marshall, W. J.; Roe, D. C. J. Am. Chem. Soc.
2008, 130, 4828.
(19) (a) BarriosꢀFrancisco, R.; García, J. J. Inorg. Chem. 2009, 48, 386.
(b) BarriosꢀFrancisco, R.; BenítezꢀPáez, T.; FloresꢀAlamo, M.; Arévalo,
A.; García, J. J. Chem. Asian, J. 2011, 6, 842.
(20) For metalꢀcatalyzed semihydrogenation of alkynes involving oxidaꢀ
tive addition of an acid, see: (a) Shen, R.; Chen, T.; Zhao, Y.; Qiu, R.;
Zhou, Y.; Yin, S.; Wang, X.; Goto, M.; Han, L. J. Am. Chem. Soc. 2011,
133, 17037. For in situꢀgenerated HOAc, see: (b) Chen, Y.; Shuai, B.; Ma,
C.; Zhang, X.; Fang, P.; Mei, T. Org. Lett. 2017, 19, 2969.
(21) For a review, see: (a) Ozerov, O. V. Chem. Soc. Rev. 2009, 38, 83.
For the isolation of metal complexes prepared via oxidative addition of
water, see: (b) Burn, M. J.; Fickes, M. G.; Hartwig, J. F.; Hollander, F. J.;
Bergman, R. G. J. Am. Chem. Soc. 1993, 115, 5875. (c) Dorta, R.; Togni,
A. Organometallics 1998, 17, 3423. (d) Tani, K.; Iseki, A.; Yamagata, T.
Angew. Chem. Int. Ed. 1998, 37, 3381. (e) Blum, O.; Milstein, D. J. Am.
Chem. Soc. 2002, 124, 11456. (f) Formation of [Ni(CN)3H]2ꢀ using water
as the hydrogen source has been proposed: Bingham, D.; Burnett, M. G. J.
Chem. Soc. (A), 1970, 2165.
AUTHOR INFORMATION
Corresponding Author
yhliu@sioc.ac.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Key R&D Program of China
(2016YFA0202900), the National Natural Science Foundation of
China (21772217), the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB20000000), Science and
Technology
Commission
of
Shanghai
Municipality
(18XD1405000) and Shanghai Institute of Organic Chemistry
(sioczz201807) for financial support.
REFERENCES
(22) (a) Yoshida, T.; Ueda, Y.; Otsuka, S. J. Am. Chem. Soc. 1978, 100,
3941. (b) Taqui Khan, M. M.; Halligudi, S. B.; Shukla, S. Angew. Chem.
Int. Ed. 1988, 27, 1735.
(23) Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003, 5, 653.
(24) Manan, R. S.; Kilaru, P.; Zhao, P. J. Am. Chem. Soc. 2015, 137,
6136.
(1) Pollak, P.; Romeder, G.; Hagedorn, F.; Gelbke, H. “Nitriles”, in
Ullman’s Encyclopedia of Industrial Chemistry, 5th ed.; WileyꢀVCH,
Weinheim, Germany, 1985; Vol. A17, p 363.
(2) Larcok, R. C. Comprehensive Organic Transformations: A Guide to
Functional Group Preparations. 2nd ed. VCH: New York, U.S.A, 1999.
(3) For reviews, see: (a) Rajanbabu, T. V. 2011. Hydrocyanation of Al-
kenes and Alkynes. Organic Reactions. Volume 75, chapter 1, pp. 1–74. (b)
Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004,
43, 3368 and the references therein.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
Insert Table of Contents artwork here
4
5
6
7
8
cat. Ni/Mn
R
with or without ligands
+
H
Zn(CN)2
R
CH3CN/H2O, 25-50 oC
CN
H
9
R = aryl, heteroaryl, alkyl
34 examples, up to 85% isolated yield
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
avoiding the use of HCN
air stable Ni(II) precatalyst
new reaction pattern for hydrocyanation
high regioselectivity and mild conditions
5
ACS Paragon Plus Environment