Access to β-Ketonitriles through Nickel-Catalyzed Carbonylative Coupling of α-Bromonitriles with Alkylzinc Reagents

Article abstract of DOI:10.1002/chem.201902206

Herein, we report a nickel-catalyzed carbonylative coupling of α-bromonitriles and alkylzinc reagents with near stoichiometric carbon monoxide to give β-ketonitriles in good yields. The reaction is catalyzed by a readily available and stable nickel(II) pincer complex. The developed protocol tolerates substrates bearing a variety of functional groups, which would be problematic or incompatible with previous synthetic methods. Additionally, we demonstrate the suitability of the method for carbon isotope labeling by the synthesis of ¹³C-labeled β-ketonitriles and their transformation into isotopically labeled heterocycles.

Full text of DOI:10.1002/chem.201902206

A Journal of
Accepted Article
Title: Access to β-Ketonitriles via Nickel-Catalyzed Carbonylative
Coupling of α-Bromonitriles with Alkylzinc Reagents
Authors: Troels Skrydstrup, Aske Donslund, Karoline Neumann,
Nicklas Corneliussen, Ebbe Grove, Domenique Herbstritt, and
Kim Daasbjerg
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201902206
Link to VoR: http://dx.doi.org/10.1002/chem.201902206
Supported by

10.1002/chem.201902206
Chemistry - A European Journal
COMMUNICATION
b
Access to -Ketonitriles via Nickel-Catalyzed Carbonylative
a
Coupling of -Bromonitriles with Alkylzinc Reagents
Aske S. Donslund, Karoline T. Neumann, Nicklas P. Corneliussen, Ebbe K. Grove,
Domenique Herbstritt, Kim Daasbjerg and Troels Skrydstrup*
Abstract: Herein, we report a nickel-catalyzed carbonylative
coupling of α-bromonitriles and alkylzinc reagents with near
stoichiometric carbon monoxide to obtain β-ketonitriles in
good yields. The reaction is catalyzed by a readily available
and stable nickel(II) pincer complex. The developed protocol
tolerates substrates bearing a variety of functional groups,
which would be problematic or incompatible with previous syn-
thetic methods. Additionally, we demonstrate the suitability of
the method for carbon isotope labeling by the synthesis of 13C-
labeled β-ketonitriles and their transformation into isotopically
labeled heterocycles.
that methyl cyanoacetate and aryl iodides could be used for the
synthesis of b-ketonitriles through a carbonylation-decarboxyla-
tion sequence.[13] In 2016, we reported a similar carbonylation-
decarboxylation sequence using (hetero)aryl bromides and tert-
butyl cyanoacetate as the coupling partners.[14] Common for these
protocols is the limitation to aryl electrophiles generating 3-oxo-3-
arylpropanenitriles, and all the obtained b-ketonitriles were un-
substituted on the a-position. With regard to the a-substitution,
the group of Beller developed a carbonylative coupling of aryl io-
dides and alkyl nitriles yielding a,a-disubstituted products
(Scheme 1b).[15] Conversely, due to the strong anionic conditions
the functional group tolerance is diminished.
Established Methods:
b-Ketonitriles serve as useful reactive precursors in organic syn-
thesis.[1] Due to the relative position of the ketone and nitrile func-
tionalities, this class of organic compounds has been exploited for
the synthesis of numerous heterocycles, including isoxazoles,[2]
pyrazoles,[3] pyrimidines,[4],[5] pyrans,[6] and thiazolidines,[7] repre-
senting important structural fragments of biologically active mole-
cules. Furthermore, the enantioselective reduction of b-ketoni-
triles yields b-hydroxynitriles[8] that are common intermediates for
the preparation of various pharmaceuticals, e.g. the antiparasitic
agent, levamisole.[9]
a) Acylation of Metalated Nitriles
O
O
M CN
Conditions
CN
+
R
R
X
R2 R3
R2 R3
X = Cl, OR, N(OMe)Me. M: Li, Na, K, Mg+, R2/R3 = H, alkyl or aryl
b) Palladium-Catalyzed Carbonylative Coupling
i) Lee (2012, 2016), Skrydstrup (2016)
[Pd], additive
O
CO
Y
CN
+
Ar
I
CN
or Mo(CO)6
Ar
Y = TMS, CO2Me or CO2tBu
ii) Beller (2014)
no α-Substitution
Numerous protocols for the synthesis of b-ketonitriles have
been developed, which still remains an active research area, in-
cluding substitution of α-haloketones with cyanide or the electro-
philic cyanation with nucleophilic carbon species.[10] The most di-
rect approach relies on the acylation of metalated nitriles (Scheme
1a).[11] Nevertheless, a drawback of this well-established acylation
method is the incompatibility of various electrophilic functionalities
with the harsh anionic conditions, which is clearly reflected in the
substrate scope. To achieve higher functional group tolerance,
palladium-catalyzed carbonylative couplings have been devel-
oped as an alternative approach to β-ketonitriles. As reported by
Lee and coworkers in 2012, the carbonylative coupling of aryl io-
dides and (trimethylsilyl)acetonitrile tolerates a number of sensi-
tive functionalities including nitrile, carboxylate and ketone func-
tionalities (Scheme 1b).[12] Additionally, the same group reported
Pd(OAc)/Xantphos
CO (5–10 bar)
O
CN
CN
Ar
I
+
Ar
R1 R2
NaHMDS
R1 R2
R1= alkyl, R2= alkyl or aryl
α,α-Substitution
c) This work: Nickel-Catalyzed Carbonylative Coupling
ex situ
generated
*COgen
O
[Ni]
*CO
R
Br
CN
*
C
CN
Alk
Alk
ZnBr
+
THF
R
(2 equiv.)
30 oC, 4.5 h
α-Substitution
R
= C(sp3)
= H, 1o- or 2o-alkyl
*CO = 12CO or 13CO
Scheme 1. Established methods for the synthesis of b-ketonitriles via a) acyla-
tion of metalated nitriles, b) palladium-catalyzed carbonylative cross couplings
and c) nickel-catalyzed carbonylative cross coupling.
[ ]
*
Aske S. Donslund, Dr. Karoline T. Neumann, Nicklas P. Cornelius-
sen, Ebbe K. Grove, Domenique Herbstritt and Prof. Dr. Troels
Skrydstrup
Carbon Dioxide Activation Center (CADIAC), Department of Chem-
istry and the Interdisciplinary Nanoscience Center (iNANO), Aarhus
University
During the last 20 years, a plethora of Ni-catalyzed cross cou-
pling protocols applying alkyl electrophiles have been reported.[16]
Nevertheless, the corresponding three-component carbonylative
version is rare, which can be ascribed to the possibility for gener-
ating the toxic and volatile Ni(CO)4, or catalytically inactive nickel
carbonyl species. Such difficulties were earlier observed by the
groups of Ogoshi, Troupel and Weix, requiring slow CO release
Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
Supporting information and the ORCID identification number(s) for
the author(s) can be found under http://dx.doi.org/XXXX.
This article is protected by copyright. All rights reserved.

10.1002/chem.201902206
Chemistry - A European Journal
COMMUNICATION
from carbon monoxide releasing molecules for successful car-
bonylative couplings.[17] Recently, the group of Hu published a
nickel-catalyzed reductive carbonylation of alkyl halides using
ethyl chloroformate as the CO source.[18]
Preliminary stoichiometric and catalytic reactions indicated
that a-bromonitriles were suitable electrophiles for the nickel(II)-
catalyzed carbonylative coupling. Optimization using a-bromoni-
trile 1 with n-propylzinc bromide and 1.5 equivalents of CO gen-
erated from COgen, led initially to ketone 2a formation accompa-
nied by the debromination adduct 2b as the only two products.
From a control experiment without the nickel catalyst and CO, 2b
was observed as the only product, possibly arising from a zinc-
halide exchange between 1 and n-propylzinc bromide, followed
by protonation during workup. A similar metal halide exchange
with a-bromonitriles was reported by the group of Knochel with
organomagnesium, -copper and -lithium species.[11e],[11f]
In 2018, we reported the nickel(II)-catalyzed carbonylative
coupling of benzyl bromides with alkylzinc reagents to produce
benzyl alkyl ketones.[19] The method relies on the use of a
nickel(II) pincer complex, which we proposed was essential for
avoiding multiple CO binding to the metal center. Mechanistic in-
vestigations provided evidence for a radical based mechanism,
and a Ni(II/III/I) catalytic cycle involving bimetallic oxidative addi-
tion.[20] Furthermore, for successful carbonylation, the system
proved to be highly dependent on the pressure and release rate
of CO, originating from COgen in the two chamber system
COware,[21] which confirms the aforementioned sensitivity of
nickel towards CO poisoning. In order to expand this chemistry,
we envisioned that the nickel-catalyzed carbonylative protocol
could be applied for the carbonylative coupling between a-bro-
monitriles and alkylzinc reagents to obtain 3-oxo-3-alkylpropane-
nitrile products (Scheme 1c). In this case, substitution on the a-
position would be feasible and due to the mild conditions, it should
be possible to tolerate a broader range of functionalities com-
pared to the anionic acylation approach (Scheme 1a).
The impact of various reaction parameters and the final opti-
mization is depicted in Table 1. The conditions displayed (entry 1)
result in full conversion into the products 2a and 2b in a 71:29
ratio and 2a was isolated in a 63% yield. Using NiL2 instead of
NiL1 led to a complete shutdown of the catalytic reaction (entry
2), which might be the result of the increased bulk on the datively
coordinating amine. NiL4 with a pyridine instead of the quinoline
motif proved to be an active catalyst, but produced a lower prod-
uct selectivity compared to NiL1. If the addition rate of the bro-
mide was doubled, the yield diminished (entry 4), whereas de-
creasing the addition rate resulted in an unaltered ratio of prod-
ucts (entry 5). Lowering the catalyst loading (entry 6) or increasing
the reaction temperature (entry 7) only led to reduced yields. Un-
fortunately, access to 3-oxo-3-arylpropanenitrile products using
PhZnBr proved ineffective (entry 8). It was discovered that the
amount of n-propylzinc bromide added could be reduced to 2.0
equiv., which marginally improved the product ratio, and as such
2a could be isolated in a 72% yield (entry 9). Switching to NiL3
under similar conditions gave a slightly poorer ratio of 2a:2b (entry
10). Other solvents were examined including, butyronitrile, tolu-
ene, ethyl acetate and DMF (entries 11–14), but no improvements
in the selectivity of the reaction was observed. Lastly, it was
shown that secondary alkylzinc reagents are not compatible with
the optimized conditions. Employing cyclohexylzinc bromide only
afforded the corresponding β-ketonitrile in a 5% isolated yield
(see Supporting Information).
Table 1. Effect of reaction parameters and final optimization.[a]
Chamber B
Chamber A
COgen
(1.5 equiv.)
NiL1 (10 mol%)
n-PrZnBr (0.5 M in THF)
(2.5 equiv.)
n-Pr
O
Pd(0)
catalysis
C
THF, 30 oC, 4.5 h
CN
Br
2a
CN
+
CO
+
CN
1 - 0.4 mmol
Slow add. (4 h)
2b
2a:2b ratio[b]
(isolated
yield%)
Deviation from
shown conditions
Entry
1
2
3
4
5
6
7
8
None
71(63):29
0:100
37:63
41:59
71:29
65:35
60:40
0:100
NiL2
N
With acceptable reaction conditions in hand, we examined the
scope and limitations of this Ni-catalyzed carbonylative cross cou-
pling. Various unfunctionalized aliphatic a-bromonitriles were tol-
erated, leading to the formation of the corresponding b-ketonitriles
2a–4a, 6a and 7a in modest to high yields. The difference in yields
between entries 6a and 7a, 36% and 81% respectively, could be
attributed to different putative radicals formed from 2-bromoace-
tonitrile and 2-bromopropionitrile. The a-bromonitrile containing
an internal alkene underwent smooth transformation to the de-
sired product 5a. Additionally, the thio- and benzylether contain-
ing substrates were tolerated leading to the b-ketonitriles 8a and
9a in good isolated yields. A few aryl (pseudo)halides endured the
reaction conditions, providing b-ketonitriles displaying an aryl flu-
oride (10a), aryl bromide (11a) and aryl tosylate (12a), allowing
for further synthetic manipulation. Utilizing an acetal containing
alkylzinc reagent and 2-bromopropionitrile as coupling reagents
produced the intended b-ketonitrile 13a in an acceptable 50%
yield. A substrate containing a terminal alkyl bromide also proved
NiL4
NiII
N
Cl
Slow add. 2 h
Slow add. 6 h
5 mol% NiL1
50 oC
O
=
=
=
NMe2 (NiL1)
(NiL2)
N
O
Sn-Pr (NiL3)
PhZnBr in THF
9
2.0 equiv. n-PrZnBr
NiL3
74(72):26
65:35
N
10[c]
11
NiII
n-PrCN
68:32
N
Cl
O
12
13
14
Toluene
EtOAc
DMF
23:77
49:51
68:32
NMe2
NiL4
[a] All reactions were set up using a two-chamber reactor, COware® (See Sup-
porting Information). [b] The ratio of 2a and 2b was determined by 1H-NMR
spectroscopy. Full conversion of 1 was observed for all entries. [c] 2.0 equiv. of
n-PrZnBr were used. THF = Tetrahydrofuran. DMA = N,N-Dimethylacetamide.
This article is protected by copyright. All rights reserved.

10.1002/chem.201902206
Chemistry - A European Journal
COMMUNICATION
to be compatible with the described method yielding the b-ketoni-
trile 16a in a 42% yield. a product, which under conventional ani-
onic conditions, might have cyclized. Furthermore, substrates
possessing electrophilic functional groups including a nitrile, ke-
tone, sulfonamide, carboxylate and carboxamide worked well un-
der the standard conditions leading to compounds 15a and 17a-
21a. The substrate displaying a thiophene ring transformed
smoothly into the desired product 14a, and by employing [13C]-
COgen as the CO source, 13C-labeled 14a could be isolated in a
good yield. This, along with the formation of 13C-3a, demonstrates
the utility of the two-chamber system and the catalytic system for
the convenient 13C-labeling of b-ketonitriles. Some substrates,
also proved to be unsuccessful. This included an aryl iodide con-
taining a-bromonitrile 25, as well as the more substituted and ste-
rically hindered a-bromonitriles 22–24.[22] In the case of com-
pound 25, we believe unproductive iodine abstraction may be tak-
ing place as earlier observed in our work on the Ni(II)-catalyzed
carbonylative coupling of benzyl bromides (see also mechanistic
discussion).[19] To conclude, we examined the possibility for scal-
ing up this Ni-catalyzed transformation. As such in the synthesis
of 7a, the reaction was run on a 2 mmol scale resulting in a 61%
isolated yield of 7a (see Supporting Information).
Br
CO (1.5 equiv.)
NiL1 (10 mol%)
Alkyl
O
R1
C
+
CN
Alkyl ZnBr
R1
R2
THF
CN
[0.5 M in THF]
(2.0 equiv.)
30 oC, 4.5 h
R2
0.4 mmol
2a–21a
O
C
O
O
C
C
CN
CN
CN
2a - 72%
4a - 83%
3a - 66% (d.r. = 1:1)
[
Having illustrated the applicability of the developed method,
we proceeded to determine whether a similar mechanism involv-
ing radical intermediates was operating as that observed for the
preparation of benzyl alkyl ketones.[19] Two radical probe experi-
ments were carried out with a-bromonitriles 26 and 28. Under
standard conditions 26 was converted into b-ketonitrile 27a in a
60% yield (Scheme 3a). No product from 5-exo-trig cyclization
was detected, which is peculiar if a carbon centered radical is
formed. However, the result is in accordance with our previous
mechanistic findings for the nickel-catalyzed carbonylation of ben-
zyl bromides with alkylzinc reagents and can be ascribed to the
stability of the radicals formed. Using the cyclopropyl derivative
28 under standard conditions, led to formation of three different
products (Scheme 3b). b-ketonitrile 29a could be isolated in a
20% yield along with the ring-opened carbonylative adduct 29c in
a 22% yield. In addition, some ring-opened direct coupling prod-
uct 29d was also observed (13% yield). The two latter products
(29c and 29d) suggest a carbon centered radical intermediate is
formed, followed by cyclopropane ring-opening (Scheme 3b). The
two observations that no 5-exo-trig cyclization takes place and
that cyclopropane ring opening is incomplete suggests that the
recombination of the supposed radicals (See proposed mecha-
nism) is faster/or of similar rate to the intramolecular radical probe
reactions, presumably due to the low concentration of alkyl radi-
cals relative to the nickel acyl complex resulting from slow addition
of the electrophile. The addition of 20 mol% of 1,4-dinitrobenzene,
acting as a single electron transfer (SET) inhibitor, to the reaction
13C]3a - 64%
O
C
O
O
C
C
CN
5a - 59% (d.r. = 1:1)
6a - 36%
7a - 81%
CN
(61% on a 2 mmol scale)[a]
CN
O
C
O
C
O
C
S
CN
CN
BnO
CN
F
8a - 63%
9a - 63%
10a - 70%
O
O
C
O
C
O
O
O
C
CN
CN
CN
TsO
Br
S
11a - 58%
12a - 61%
13a - 50%
O
C
O
C
O
C
O
CN
CN
CN
Br
CN
15a - 46%
16a - 42%
14a - 58%
13C]14a - 63%[a]
[
O
O
C
TsN
O
C
CN
CO2Et
C
CN
CN
O
19a - 54%
18a - 47%
17a - 71%
O
C
O
O
C
O
O
O
N
EtO
O
CN
O
a)
NiL1 (10 mol%)
CO (1.5 equiv.)
Br
O
C
20a - 47% CN
21a - 61%
ZnBr
+
CN
26
[0.5 M in THF]
(2.0 equiv.)
THF
CN
27a - 60%
Unsuccessful substrates:
NC Br
30 oC, 4.5 h
Br
Br
Br
O
Ph
CN
CN
CN
b)
O
C
Br
I
Ph
29a - 20%
Ph
NiL1 (10 mol%)
CO (1.5 equiv.)
CN
22
23
24
25
0–45% product formation
reproducibility issues
CN
No product No product
formation formation
28
+
O
C
THF
29c - 22%
Ph E/Z =1:1
30 oC, 4.5 h
Ph
NC
ZnBr
Scheme 2. Scope of the Ni(II)-catalyzed carbonylative coupling . The reactions
were set up in an argon-filled glovebox using a two-chamber system (See Sup-
porting Information for full details). The yields are isolated and are an average
of two separate reactions unless otherwise stated. [a] The reaction was per-
formed once.
CN
[0.5 M in THF]
(2.0 equiv.)
Ph
29d - 13%
E/Z = 1:1
via
NC
Scheme 3. Radical probe experiments.
This article is protected by copyright. All rights reserved.

10.1002/chem.201902206
Chemistry - A European Journal
COMMUNICATION
NH2OH.HCl
Na2CO3
lowered the yield by 16% (from 72% to 56%) of 2a using 1 and n-
propylzinc bromide under optimized conditions.[23]
H2N
O13
(p-F)Ph
(p-F)Ph
n-PrZnBr
F
Br
C
O
The proposed mechanism, depicted in Scheme 4, follows
closely the bimetallic oxidative addition mechanism proposed by
Hu and coworkers for the cross coupling of alkyl substrates cata-
lyzed by Ni(II) pincer complexes.[20] Initially a transmetallation step
is involved with NiL1 followed by CO insertion to form the nickel(II)
acyl complex A. Bromide abstraction from the a-bromonitrile sub-
strate, generates the nickel(III) complex B and the nitrile stabilized
radical 30. Recombination of this carbon-centered radical with an-
other equivalent of complex A leads to the nickel(III) complex C,
which reductively eliminates to the desired b-ketonitrile product
and the Ni(I) complex D. Lastly, comproportionation of B and D
reforms NiL1 and A, thereby completing the catalytic cycle.
N
13C
CN
CN
NiL1 (10 mol%)
13CO (1.5 equiv.)
THF
31 - 60%
30 oC, 4.5 h
Ph
O
Br
13C
N
N
H2N
13C
Ph(CH2)2ZnBr
CN
CN
32 - 54%
Na2CO3
NH2NHPh.HCl
Scheme 5. Post modification of two b-ketonitriles for heterocycle synthesis with
selective carbon isotope labeling. See Supporting information for all details.
1) RZnBr
NiL1
N
2) CO
Br
Acknowledgments
O
C
R1
NiII
CN
N
O
R
We are deeply appreciative of generous financial support from the
Danish National Research Foundation (grant no. DNRF118),
NordForsk (grant no. 85378), the Lundbeck Foundation and Aar-
hus University.
Halide
Abstraction
NMe2
A
NiI/NiIII
Comproportionation
N
N
O
C
R
NiI
NiIII
N
+
N
R1
Keywords: nickel catalysis • carbonylation • alkylzinc reagents •
b-ketonitriles • isotope-labeling
CN
Br
O
O
30
NMe2
NMe2
D
B
Reductive
Elimination
[1]
[2]
M. H. Elnagdi, M. R. H. Elmoghayar, G. E. H. Elgemeie, Synthesis 1984,
1, 1–26.
O
C
A
N
O
R1
CN
β-ketonitrile
M. Krasavin, M. Korsakov, Z. Zvonaryova, E. Semyonychev, T. Tucci-
nardi, S. Kalinin, M. Tanç, C. T. Supuran, Bioorganic Med. Chem. 2017,
25,1914–1925.
C
R
R
NiIII
Recombination
N
CN
O
R1
NMe2
[3]
J. Velcicky, W. Miltz, B. Oberhauser, D. Orain, A. Vaupel, K. Weigand, J.
D. King, A. Littlewood-Evans, M. Nash, R. Feifel, P. Loetscher, J. Med.
Chem. 2017, 60, 3672–3683. .
C
Scheme 4. Proposed Mechanism
[4]
[5]
X. Zhu, M. Zhang, J. Liu, J. Ge, G. Yang, J. Agric. Food Chem. 2015, 63,
3377–3386.
C. Sirichaiwat, C. Intaraudom, S. Kamchonwongpaisan, J. Vanichtanan-
kul, Y. Thebtaranonth, Y. Yuthavong, J. Med. Chem. 2004, 47, 345–354.
Philipp Klahn, Stefan F. Kirsch Eur. J. Org. Chem. 2014, 3149–3155.
R. Markovic´, M. Baranac, Z. Džambaski, M. Stojanovic´, P. J. Steel, Tet-
rahedron 2003, 59, 7803–7810.
Finally, the utility of the synthesized b-ketonitriles was illus-
trated by their employment in the preparation of two 13C-labeled
heterocycles (Scheme 5). Carbonylative couplings applying 13C-
labeled COgen provided the two b-ketonitriles 13C-10a and 13C-
7a. Subsequent transformation of the former into the 13C-labeled
isoxazole 31 proceeded smoothly providing an isolated yield of
60% over two steps. Further conversion of 13C-7a generated the
13C-labeled pyrazole 32 in a 54% yield (two steps).
[6]
[7]
[8]
[9]
M. L. Contente, I. Serra, F. Molinari, R. Gandolfi, A. Pinto, D. Romano,
Tetrahedron 2016, 72, 3974–3979.
A. Kamal, G. B. R. Khanna, T. Krishnaji, R. Ramu, Bioorg. Med. Chem.
Lett. 2005, 15, 613–615.
[10] a) F. F. Fleming, P. S. Iyer, Synthesis 2006, 6, 893–913; b) K. Kiyokawa,
T. Nagata, S. Minakata Synthesis 2018, 50, 485–498; and references
therein.
In conclusion, we have developed a nickel-catalyzed car-
bonylation of b-ketonitriles from a-bromonitriles and alkylzinc re-
agents. The method tolerates functional groups, which are incom-
patible with conventional acylation of metalated nitrile. Addition-
ally, the method gives access to b-ketonitrile products, which can-
not be obtained via the known palladium-catalyzed carbonylative
methods. Furthermore, the method is useful for the synthesis of
13C-labeled b-ketonitriles, which subsequently can be converted
into 13C-labeled heterocycles, as exemplified by 31 and 32. Cur-
rently, we are investigating the use of unactivated alkyl halides as
coupling partner for similar carbonylative transformations.
[11] a) J. B. Dorsch and S. M. McElvain, J. Am. Chem. Soc. 1932, 54, 2960–
2964; b) R. S. Long, J. Am. Chem. Soc. 1947, 69, 990–995; c) Y. Ji, W.
C. Trenkle, J. V. Vowles, Org. Lett. 2006, 8, 1161–1163; d) A. D. Mamuye,
L. Castoldi, U. Azzena, W. Holzer, V. Pace, Org. Biomol. Chem.,
2015,13, 1969–1973; e) F. F. Fleming, Z. Zhang, P. Knochel, Org. Lett.
2004, 6, 501–503; f) F. F. Fleming, Z. Zhang, W. Liu, P. Knochel, J. Org.
Chem. 2005, 70, 2200–2205.
[12]
a) A. Park, S. Lee, Org. Lett., 2012, 14, 1118–1121; b) A. Pyo, A, Park,
H. M. Jung, S. Lee, Synthesis, 2012, 44, 2885–2888.
[13] S. Lee, H. Kim, H. Min, A. Pyo, Tetrahedron Lett., 2016, 57, 239–242.
[14] M. T. Jensen, M. Juhl, D. U. Nielsen, M. F. Jacobsen, A. T. Lindhardt, T.
Skrydstrup, J. Org. Chem. 2016, 81, 1358–1366.
This article is protected by copyright. All rights reserved.

10.1002/chem.201902206
Chemistry - A European Journal
COMMUNICATION
[15] J. Schranck, M. Burhardt, C. Bornschein, H. Neumann, T. Skrydstrup, M.
Beller, Chem. Eur. J. 2014, 20, 9534–9538.
[16] a) S. Z. Tasker, E. A. Standley, T. F. Jamison, Nature 2014, 509, 299–
309; b) J. Choi, G. Fu, Science 2017, 356, 152–160; L. Campeau, N.
Hazari, Organometallics 2019, 38, 3–35.
[17] a) Y. Hoshimoto, T. Ohata, Y. Sasaoka, M. Ohashi, S. Ogoshi, J. Am.
Chem. Soc. 2014, 136, 15877–15880; b) Y. Hoshimoto, K. Ashida, Y.
Sasaoka, R. Kumar, K. Kamikawa, X. Verdaguer, A. Riera, M. Ohashi, S.
Ogoshi, Angew. Chem. Int. Ed. 2017, 56, 8206–8210; Angew. Chem.
2017, 129, 8318–8322; c) A. C. Wotal, R. D. Ribson, D. J. Weix, Organ-
ometallics 2014, 33, 5874–5881; d) M. Oçafrain, M. Devaud, M. Troupel,
J. Perichon, J. Chem. Soc. Chem. Commun. 1995, 2331–2332; e) E.
Dolhem, M. Oçafrain, J. Y. Nédélec, J. M. Troupel, Tetrahedron 1997,
53, 17089–17096.
[18] R. Shi, X. Hu, Angew. Chem. Int. Ed. DOI: 10.1002/anie.201903330; An-
gew. Chem. DOI: 10.1002/ange.201903330.
[19] T. L. Andersen, A. S. Donslund, K. T. Neumann, T. Skrydstrup, Angew.
Chem. Int. Ed. 2018, 57, 800–804; Angew. Chem. 2018, 130, 808–812.
[20] a) J. Breitenfeld, J. Ruiz, M. D. Wodrich, X. L. Hu, J. Am. Chem. Soc.
2013, 135, 12004–12012; b) J. Breitenfeld, M. D. Wodrich,. L. Hu, Or-
ganometallics 2014, 33, 5708–5715. c) R. Shi, Z. Zhang, X. Hu, Acc.
Chem. Res. DOI: 10.1021/acs.accounts.9b00118.
[21] S. D. Friis, A. T. Lindhardt, T. Skrydstrup, Acc. Chem. Res. 2016, 49,
594–605.
[22] We suspect the recombination of the sterically encumbered radicals
formed from the substrates 22 and 24 makes them unviable substrates
for the catalytic transformation. Substrate 23 could form a highly stabi-
lized benzylic radical adjacent to the nitrile, which might be unreactive.
[23] This result contradicts that reported for our nickel-catalyzed carbonyla-
tion to benzyl alkyl ketones, where the addition of 20 mol% 1,4-dinitro-
benzene resulted in a significantly reduced yield (>90% to 20%).
This article is protected by copyright. All rights reserved.

10.1002/chem.201902206
Chemistry - A European Journal
COMMUNICATION
Aske S. Donslund, Karoline T. Neu-
mann, Nicklas P. Corneliussen, Ebbe K.
Grove, Domenique Herbstritt, Kim Daas-
bjerg and Troels Skrydstrup*
N
R’
II
H2N
Br
Cl
Ni
N
R’
O
R
O
(cat.)
NMe2
O
N
Page No. – Page No.
*
C
Alkyl
CN
ZnX
R
13C
F
12CO or 13CO
CN
>20 examples
Alkyl
Access to 13C-labeled
heterocycles
ex situ
generated
*COgen
Good Yields Mild Conditions
Stoichiometric CO Isotope labeling
Squeezing in CO! Herein, we describe the development of a nickel(II)-catalyzed
carbonylative coupling of alkylzinc reagents and a-bromonitriles to afford b-ke-
tonitriles in good yields under mild conditions. Key to the success of this car-
bonylative chemistry is the readily available nickel(II) chloride pincer complex,
which forms stable nickel(II) alkyl and nickel(II) acyl complexes.
This article is protected by copyright. All rights reserved.