Overcoming Selectivity Issues in Reversible Catalysis: A Transfer Hydrocyanation Exhibiting High Kinetic Control

Article abstract of DOI:10.1021/jacs.0c03184

Reversible catalytic reactions operate under thermodynamic control, and thus, establishing a selective catalytic system poses a considerable challenge. Herein, we report a reversible transfer hydrocyanation protocol that exhibits high selectivity for the thermodynamically less favorable branched isomer. Selectivity is achieved by exploiting the lower barrier for C-CN oxidative addition and reductive elimination at benzylic positions in the absence of a cocatalytic Lewis acid. Through the design of a novel type of HCN donor, a practical, branched-selective, HCN-free transfer hydrocyanation was realized. The synthetically useful resolution of a mixture of branched and linear nitrile isomers was also demonstrated to underline the value of reversible and selective transfer reactions. In a broader context, this work demonstrates that high kinetic selectivity can be achieved in reversible transfer reactions, thus opening new horizons for their synthetic applications.

Full text of DOI:10.1021/jacs.0c03184

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Communication
Overcoming Selectivity Issues in Reversible Catalysis – A
Transfer Hydrocyanation Exhibiting High Kinetic Control
Benjamin N. Bhawal, Julia C Reisenbauer, Christian Ehinger, and Bill Morandi
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Jun 2020
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Journal of the American Chemical Society
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Overcoming Selectivity Issues in Reversible Catalysis – A Transfer
Hydrocyanation Exhibiting High Kinetic Control
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Benjamin N. Bhawal,†,‡ Julia C. Reisenbauer,†,‡ Christian Ehinger,† Bill Morandi*,†,‡
†ETH Zürich, Vladimir-Prelog-Weg 3, HCI, 8093 Zürich, Switzerland
‡Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Supporting Information. Detailed experimental procedures and characterization data.
One fundamental drawback of metathesis and shuttle
catalysis reactions is that, due to their inherent reversibility,
they operate under thermodynamic control. This often leads
to mixtures of products being formed such as in the case for
alkene metathesis wherein the ratio of E:Z products is
determined by their relative stability (Scheme 1A).1 In a
similar manner, the transfer hydrocyanation reported by our
group also leads to mixtures of products, with the reaction of
styrene affording an 81:19 mixture of linear and branched
products, respectively.8d Again, this ratio reflects the relative
thermodynamic stability of the two regioisomers.12
ABSTRACT: Reversible catalytic reactions operate under
thermodynamic control and thus establishing a selective
catalytic system poses a considerable challenge. Herein, we
report a reversible transfer hydrocyanation protocol that
exhibits high selectivity for the thermodynamically less
favorable branched isomer. Selectivity is achieved by
exploiting the lower barrier for C–CN oxidative addition and
reductive elimination at benzylic positions in the absence of
co-catalytic Lewis acid. Through the design of a novel type
of HCN donor, a practical, branched-selective, HCN-free
transfer hydrocyanation was realized. The synthetically
useful resolution of a mixture of branched and linear nitrile
isomers was also demonstrated to underline the value of
reversible and selective transfer reactions. In a broader
context, this work demonstrates that high kinetic selectivity
can be achieved in reversible transfer reactions, thus opening
new horizons for their synthetic applications.
Scheme 1. Context of the work.
Reversible catalytic reactions such as alkene metathesis1
and transfer hydrogenation2 have found a plethora of
applications in diverse fields of chemistry.3,4,5 Given their
value to the synthetic practitioner, our group and others have
investigated expanding these transformations to include the
metathesis of other bonds and the transfer of functionality
other than H2.6,7,8 These reaction paradigms offer numerous
advantages such as implementing safer protocols avoiding
the use of highly toxic reagents or unlocking previously
unknown transformations. Our group applied a shuttle
catalysis strategy to achieve transfer hydrocyanation whilst
avoiding the use of highly toxic and volatile HCN.8d Notably,
this strategy also enabled the first example of
dehydrocyanation of aliphatic nitriles. These results have
subsequently spurred the development of other transfer
hydrocyanation protocols that circumvent the use of HCN9
as well as opening new approaches for other cyanation
reactions using relatively non-toxic cyanide sources.10,11
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A. Selectivity challenges in reversible catalytic reactions
Instead, most reversible transfer reactions proceed to form
the more thermodynamically stable products.
Grubbs 2nd
1
2
Me
OBz
Me
OBz
generation catalyst
AcO
+
+
AcO
4
Alkene
Inspired by the precedent set by Z-selective alkene
metathesis to obtain a selective and reversible metathesis
manifold,13 we sought to develop a protocol that would
enable a selective and reversible transfer hydrocyanation of
styrenes by manipulating the difference in the barrier for the
formation of the branched and linear nitrile isomers to
selectively form the less stable branched isomer (Scheme 1C).
This would be complementary to the linear selectivity
obtained in previous transfer hydrocyanation reactions.8d,9a
Several groups have demonstrated that co-catalytic Lewis
acids help facilitate both C–CN oxidative addition and
reductive elimination,14,15 resulting in a thermodynamic
mixture of products in transfer hydrocyanation because both
the linear and branched isomers are accessible. We surmised
that in the absence of a Lewis acid co-catalyst a benzylic
stabilization effect could lead to a markedly lower barrier for
both the cleavage and formation of the branched nitrile
4
metathesis
3
4
5
6
7
8
9
E/Z = 91:9
Ni-catalysis
Lewis acid
co-catalysis
H
CN
+
+
CN
Ph
Me
Me
Ph
Transfer
hydrocyanation
l:b = 81:19
Reversible reactions
thermodynamic control
Product ratio determined by

relative stability of products


B. Model for selectivity
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With co-catalytic Lewis acid
(previous work - Ref. 8d)
Without co-catalytic Lewis acid
(this work)
G‡
G‡
B'


B
G‡
G‡
G‡
G‡
A
G‡
G‡
A


B
B'
A'


A'
CN
H
CN
H
CN
H
H
H
CN
CN
H
[Ni]
CN
[Ni]
[Ni]
Minor
[Ni]
[Ni]
[Ni]
Not
product compared to the linear isomer, unlocking
branched selective transfer hydrocyanation of styrenes.
a
Major
Major
product
product
product
formed
G‡A' accessible

G‡
,
G‡
,
G‡ and G‡

B B'
G‡
&
We verified this hypothesis experimentally through the
reaction of 2-phenylpropionitrile 1a with 4-tert-butylstyrene
2b and found that a mixture of the starting materials with
styrene 2a and branched nitrile 1b was obtained while the
linear isomers (3a and 3b) were not observed (Scheme 2a).
This confirms that both the oxidative addition and reductive
elimination can occur at the benzylic position in the absence
of co-catalytic Lewis acid, whereas the formation of the linear
product is considerably more challenging. Performing the
reaction in reverse, gave an identical ratio of the two
branched nitriles, a strong indicator that the reaction has
reached equilibrium. The high barrier to oxidative addition
of non-benzylic nitriles with the Lewis acid free system is
also implicated by the lack of reactivity observed between 3-
phenylpropionitrile 3a and 4-tert-butylstyrene 2b (Scheme
2b). Furthermore, hydrocyanation of norbornadiene was not
observed upon reaction with 2-phenylpropionitrile 1a
(Scheme 2c). This truly underlines the challenging C–CN
reductive elimination at non-benzylic positions with this
transfer hydrocyanation manifold, as norbornadiene is
typically a potent acceptor for transfer reactions.6d,8c-e
Collectively, these results show that, in the absence of co-
catalytic Lewis acid, the reaction is still reversible and
kinetically controlled toward selective formation and
cleavage of the branched isomer, leaving other positions
unreacted.



A
A'

A
all accessible
reversible reaction

both products formed
& reversible reaction

G‡
&
G‡B' are not accessible


B
less stable product formed

more stable product

& linear isomer does not react
predominantly formed
C. This work - reversible, kinetically selective transfer hydrocyanation
CN
Ni-catalysis
CN
+
+
H
H
Reversible &
selective
HCN transfer
CN
H
NC
Me
NC
Me
Ni-catalysis
CN
+
+
H
Selective
transfer
hydrocyanation
Me
Me
Highly selective
Less stable isomer favored


No co-catalytic Lewis
acid present

HCN-free
Novel HCN donor


These reactions are reversible because the products
possess the same functionality as the starting materials and
thus are roughly ergoneutral (Scheme 1B). Hence, in most
cases, the barrier for both the forward and reverse reaction is
similar. In reactions where the formation of more than one
isomer is kinetically accessible, the selectivity is determined
by their relative stability. To override this thermodynamic
bias in selectivity, the barrier for one of the isomers must be
kinetically inaccessible. In this scenario, the reaction will
remain reversible but restricted to a smaller subset of
isomers. This is the case in Z-selective alkene metathesis,
wherein the intricate design of the catalysts lead to a
significantly higher activation barrier for the formation and
reaction of E-alkenes.13 As a result, Z-alkenes are exclusively
formed and, conversely, if a mixture of Z- and E-alkenes are
present, then only the Z-alkenes will react. To date, there are
no analogous examples of a transfer reaction that has been
demonstrated to be reversible and kinetically selective.
Next, we considered how to develop a practical, HCN-free
transfer hydrocyanation process exhibiting such selectivity.
While 2-phenylpropionitrile 1a is a competent HCN donor
under the reaction conditions, it is not ideal for use in transfer
hydrocyanation as an excess would be required to ensure
good conversion of the substrate. Aside from being highly
wasteful, this would also present problems with regards to
purification and, therefore, an alternative HCN donor was
devised. Desirable features include being able to donate
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Journal of the American Chemical Society
HCN in the absence of a Lewis acid and it should also ideally
form a stable alkene by-product that would be unsusceptible
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8
to hydrocyanation itself. We reasoned that malononitrile
derivatives bearing an aliphatic group could fulfill these
criteria while also being simply synthesized from
inexpensive starting materials.16,17 It was anticipated that
these species should be activated toward donating HCN to
the Ni-catalyst18,19 and the conjugated alkenyl nitrile by-
product
should
be
recalcitrant
to
undergoing
9
hydrocyanation. Gratifyingly, we discovered that
malononitriles bearing a secondary aliphatic substituent (4a–
4d) afforded high yields of product, although those bearing
bulkier substituents (4e) failed in the reaction (Scheme 3). A
simple isofunctional experiment confirmed that the
dehydrocyanation of the reagent is irreversible under the
reaction conditions. These results are also supported by
comparison of the ground state free energies of reactants and
products in the hydrocyanation of styrene 2a with
malononitrile 4a, which suggests that the reaction is
distinctly exergonic (ΔG = –12.9 kcal/mol at 298 K, see SI for
details).
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Scheme 2. Experiments to compare relative ease of C–
CN oxidative addition and reductive elimination at
benzylic and non-benzylic positions.
A. Proof of concept – reversible and
selective transfer hydrocyanation
Ni(cod)2, Xantphos
No Lewis acid
o-xylene, 120 °C, 48 h
Forward reaction
CN
1a
CN
1b
+
+
Ar
Ph
2a
H
H
Ph
Ar
Reverse reaction
2b
Ar = 4-t-BuC6H4
Forward reaction
Reverse reaction
1a
1b
1a
1b
Yield
Yield
= 43%
= 49%
Yield
Yield
= 41%
= 51%
Interconversion of branched nitriles 1a and 1b

oxidative addition AND reductive elimination

at benzylic position in absence of Lewis acid
H
H
Linear isomers 3a and 3b not observed
high barrier for reductive elimination at
non-benzylic position in absence of Lewis acid


CN
CN
Ph
Ar
3a
3b
B. High barrier for C–CN oxidative addition at non-benzylic position
Ni(cod)2
Xantphos
No Lewis acid
H
CN
1b
+
+
Ar
Ph
CN
H
Ph
Ar
PhMe
120 °C, 24 h
3a
2b
Ar = 4-t-BuC6H4
2a
not observed
not observed
C. High barrier for C–CN reductive elimination at non-benzylic position
Ni(cod)2
Xantphos
No Lewis acid
CN
1a
NC
H
+
+
Ph
H
Ph
PhMe
120 °C, 24 h
2a
traces
not observed
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position. Excitingly, even simple, unprotected alcohols (e.g.
11) afforded the linear product 12, suggesting that alcohols
can also act as directing groups.
Scheme 3. Development of novel HCN donors for
regioselective transfer hydrocyanation.
1
2
3
4
5
6
7
 Malononitrile derivative donates
HCN under Lewis-acid free
conditions
Ni(cod)2
Xantphos
CN
H
X
X
CN
+
+
Ph
H
R1
R1
R2
PhMe (0.5 M)
120 °C, 24 h
Ph
R2
Hydrocyanation of alkenyl-nitrile
by-product not possible

4
(1.2 equiv)
 Excess of HCN donor not required
HCN donors
8
9
CN
NC
CN
H
CN
H
CN
H
CN
H
NC
NC
NC
Et
NC
H
Me
Me
i-Pr
Et
i-Pr
4e
no reaction
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Scheme 4. Substrate scope for the regioselective, HCN-
free transfer hydrocyanation.a,b
4a
4b
4c
4d
, 60% yield
b:l = 95:5
, 90% yield
b:l > 95:5
, 80% yield
b:l = 94:6
, 88% yield
b:l = 91:9
CN
H
EtO2C
CN
CN
H
CN
NC
NC
MeO2C
H
CN
NC
Me
CN
Ni(cod)2 (10 mol%)
Xantphos (10 mol%)
Me
Me
CN
NC
H
H
H
Et
4f
Ph
Ph
CN
1
+
Ar
H
4g
4h
no reaction
4i
no reaction
4j
no reaction
4k
no reaction
, 37% yield
b:l = 95:5
, 31% yield
b:l = 95:5
Me
H
PhMe (0.5 M)
120 °C, 24 h
Ar
Me
4a
(1.2 equiv)
2
Dehydrocyanation of malononitrile derivative is irreversible
Ni(cod)2 (10 mol%)
Xantphos (10 mol%)
CN
H
NC
NC
CN
H
NC
NC
Styrenes
+
+
PhMe (0.5 M)
120 °C, 24 h
CN
CN
1a
; R = H
90% yield; b:l > 95:5
1b
H
H
CN
4c
5b
4b
not observed
5c
14% GC yield
H
; R = t-Bu
94% yield; b:l = 94:6
1c
MeO
Me2N
1e
; R = i-Pr
R
1d
; 77% yield
b:l > 95:5
; 69% yield
b:l > 95:5
73% yield; b:l = 91:9
Following further optimization of the reaction conditions,
the applicability of this HCN-free, branched-selective
transfer hydrocyanation was examined (Scheme 4). A variety
of functional groups were well tolerated in the reaction
including both electron donating and electron withdrawing
moieties. The reaction also affords high yields and
selectivities when performed with lower catalyst loadings
(1o). Besides the high branched selectivity of this new
reaction, which is complementary to previous protocols, we
were also interested to see if it exhibits greater functional
group tolerance, given that the current reaction conditions
do not require co-catalytic Lewis acid. Indeed, substrates
possessing acidic protons (1q–1v) or a Boc-protected amine
(1u) were well tolerated. Finally, common heterocyclic cores
(1w–1y) were found to successfully undergo transfer
hydrocyanation with high selectivity. In cases with reduced
yields, this was primarily due to low conversion.
CN
CN
CN
CN
H
H
H
H
MeS
1f
F
F3C
NC
1g
1h
1i
; 57% yield
b:l > 95:5
; 50% yield
b:l = 93:7
; 83% yield
b:l = 95:5
; 99% yield
b:l > 95:5
CN
CN
CN
CN
H
H
H
H
MeO
MeO2C
AcO
OHC
1j
1k
1l
1m
; 64% yield
; 76% yield
; 66% yield
; 54% yield
b:l > 95:5
b:l > 95:5
b:l > 95:5
b:l > 95:5
CN
CN
CN
H
H
H
PhthN
c
1n
1o
1p
; 34% yield
b:l = 91:9
; 94% (89%) yield
b:l > 95:5
; 31% yield
b:l > 95:5
Styrenes with acidic protons or acid sensitive functionality
CN
CN
H
H
CN
H
i-Pr
HO
OH
1r
OH
1s
d
1q
; 45% yield
; 98% yield
b:l > 95:5
; 82% yield
b:l > 95:5
Interestingly, while studying vinylheteroarenes as
complete switch in
regioselectivity was observed with 2-vinylpyridine
b:l > 95:5
CN
H
CN
CN
substrates in the reaction,
a
H
H
OH
CbzHN
MeO2C
6
BocHN
(Scheme 5). In this case, exquisite selectivity for the linear
isomer 7 was observed. This is most likely due to a directing
group effect, by the N atom of the pyridine, lowering the
otherwise inaccessible energy barrier for C–CN reductive
elimination at non-benzylic positions.20 To further probe this
coordinating effect, reaction of 6-methyl-2-vinylpyridine 8
was attempted and this was found to afford a mixture of both
the linear (9) and branched (10) isomers, with the latter
preferred. This lack of selectivity likely arises from the
methyl group interfering with the ligation of the pyridine
ring to the metal catalyst, allowing for the normal benzylic
stabilization-controlled selectivity to compete with the
directing group effect. In addition, linear isomer 7 could act
as a HCN donor for hydrocyanation of simple styrenes (see
SI for details), suggesting that the pyridine directing group
also facilitates C–CN oxidative addition at the non-benzylic
1t
1u
1v
; 85% yield
b:l = 90:10
; 66% yield
b:l = 94:6
; 88% yield
b:l > 95:5
Vinyl heteroarenes
CN
N
CN
H
H
H
O
N
CN
1w
; 48% yield
b:l > 95:5
1x
; 57% yield
b:l > 95:5
1y
; 85% yield
b:l > 95:5
aYields are given for isolated and purified material.
Reactions were conducted on
a
0.5 mmol scale.
bRegioselectivity was determined by 1H NMR analysis of the
c
crude reaction mixture. Yield in parentheses for reaction
performed on 2.0 mmol scale with 2.5 mol% Ni(cod)2 and
Xantphos. dAldehyde 1j was also isolated in 33% yield.
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Having found that directing groups could be used to
1
2
3
4
5
6
7
8
control the selectivity of the reaction, we recognized that this
provided an opportunity to explore less well-documented
directing group effects.21 In particular, we were attracted to
vinylsilanes as we reasoned that the silyl groups ability to
stabilize both α-anions and β-cations could provide another
mechanism to lower the energy barrier for reductive
elimination through inductive effects (Scheme 5).
Accordingly, phenyldimethylvinylsilane 13 afforded the
linear nitrile product 14 in high yields and selectivity,
possibly hinting at the build-up of a positive charge at the β-
position to the silicon during the C‒CN reductive
elimination.
9
10
11
12
13
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insignificant compared to the barrier for C–CN reductive
Scheme 5. Control of regioselectivity by directing
groups.a,b
1
2
3
4
5
6
7
8
elimination. Thus, a rapid scrambling of the hydrogens at the
branched and linear positions can occur. This result further
verifies that selectivity in our reaction arises from the
insurmountable barrier for C–CN reductive elimination at
the linear position in the absence of co-catalytic Lewis acid.
Pyridine directing group
Ni(cod)2 (10 mol%)
Xantphos (10 mol%)
CN
H
NC
Me
Me
4a
(1.2 equiv)
H
N
+
N
PhMe (0.5 M)
120 °C, 24 h
CN
This observation, combined with the results shown in
Schemes 2 and 3, allows us to understand the origins of the
7
6
68% yield
l:b > 95:5
Complete switch in regioselectivity

branched
selectivity
(Scheme
7).
Irreversible
9
Pyridine ligation enables C–CN

dehydrocyanation of the malononitrile generates the
corresponding H–Ni–CN intermediate. Rapid and reversible
alkene insertion into the Ni–H bond allows for an
equilibrium to be established between the branched and the
linear alkyl nickel intermediates. Finally, reversible
reductive elimination to form the desired branched isomer
occurs with high kinetic control over formation of the linear
isomer.
reductive elimination at non-benzylic
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positions
Probing directing effect - methyl group interferes with pyridine ligation
CN
H
NC
H
CN
H
+
N
N
N
Me
Me
Me
+
Me
Me
4a
CN
8
9
10
(1.2 equiv)
Both isomers observed by 1H NMR
Ratio of 9:10 = 1:2.5
Alcohol directing group
Ni(cod)2 (10 mol%)
Xantphos (10 mol%)
H
CN
NC
Me
Me
Scheme 6. Resolution of a regioisomeric mixture by
selective dehydrocyanation.
Me
Me
CN
+
Me
H
PhMe (0.5 M)
120 °C, 24 h
OH
11
Me
4a
(1.2 equiv)
OH
12
27% yield
l:b > 95:5
MeO
Ni(cod)2 (20 mol%)a
Xantphos (20 mol%)a
Silyl directing group
+
H
Ref. 8d
Ni(cod)2 (10 mol%)
dppp (10 mol%)
CN
CN
NC
Me
+
Ph
2a
CN
CN
H
Ph
Ph
PhMe
+
PhMe2Si
13
H
CN
PhMe2Si
14
H
PhMe (0.5 M)
120 °C, 24 h
l:b = 81:19
120 °C, 24 h
3a
Me
4a
(1.2 equiv)
96% yieldb
MeO
75% yield
l:b = 95:5
l:b > 50:1
Silyl group lowers barrier for C–CN reductive elimination

aCatalyst loadings are reported with respect to the amount
Silyl group unlikely to ligate to the metal

b
of the branched isomer in the regioisomeric mixture. The
yield was calculated by reference to an internal standard by
GC-FID analysis and is given with respect to the amount of
the linear isomer in the regioisomeric mixture.
inductive effect

aYields are given for isolated and purified material.
Reactions were conducted on
a
0.5 mmol scale.
bRegioselectivity was determined by 1H NMR analysis of the
crude reaction mixture.
Scheme 7. Labeling studies and proposed catalytic
cycle.
Finally, to further illustrate the value of this reversible and
selective reaction, we used this new protocol to resolve the
mixture of linear and branched isomers (l:b = 81:19) obtained
upon transfer hydrocyanation of styrene 2a using our
previous, thermodynamically controlled protocol (Scheme
6).8d By using an excess of commercially available 4-
methoxystyrene, selective dehydrocyanation of the branched
isomer was achieved while the linear isomer 3a could be
recovered quantitatively with exquisite linear purity. In this
manner, the linear nitrile can be obtained in high regiopurity
through successive transfer hydrocyanations. This process is
analogous to the resolution of a mixture of E- and Z-alkenes
by Z-selective ethenolysis to afford enrichment of the E-
alkene content .22
Ni(cod)2 (10 mol%)
Xantphos (10 mol%)
D
CN
CN
NC
H2.34D0.66
C
H0.78D0.22
+
Me
H
PhMe (0.5 M)
120 °C, 24 h
Me
4a
(1.2 equiv)
Statistical redistribution of D
- indicative of rapid and
reversible hydride insertion
Proposed catalytic cycle
CN
H
NC
Irreversible
dehydrocyanation of
malononitrile derivative
Me
Me
[Ni0]
[Ni0]
H
CN
H
CN
Ph
Ph
Branched
selective
hydrocyanation
Linear
selective
hydrocyanation
Fast, reversible
reductive elimination
at benzylic
Very slow
H
CN
[NiII]
reductive elimination
at non-benzylic
position
position
H
[NiII] CN
H
[NiII] CN
Ph
Ph
Ph
Reversible hydride insertion
- establishes rapid equilibrium
Preliminary deuterium labeling studies resulted in a
statistical distribution of deuterium at both the branched and
linear positions (Scheme 7). This suggests that a rapid pre-
equilibrium has been reached and that the barrier for hydride
insertion and β-hydride elimination is likely to be
In conclusion, we have discovered a HCN-free transfer
hydrocyanation manifold that exhibits high kinetic
selectivity for the thermodynamically less stable, branched
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isomer but, significantly, also remains reversible. Key to this
selectivity is the lower barrier for C–CN oxidative addition
and reductive elimination at the benzylic position in the
absence of co-catalytic Lewis acid. This manifold was
1
2
3
4
5
6
7
8
exploited to achieve
a
highly selective transfer
hydrocyanation of styrenes by using a novel design of HCN
donor. To date, no other transfer reactions have been
demonstrated to be both kinetically selective and reversible.
Extending this concept could have enormous potential in
organic synthesis, opening new strategies to both selectively
functionalize multiple bonds and, through the reverse
reaction, selectively defunctionalize complex molecules.
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Corma, A.; Navas, J.; Sabater, M. J. Advances in One-Pot Synthesis
ASSOCIATED CONTENT
Supporting Information
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2
3
4
5
6
7
8
through Borrowing Hydrogen Catalysis. Chem. Rev. 2018, 118, 1410.
(6) For reviews, see: (a) Bhawal, B. N.; Morandi, B. Catalytic
Isofunctional Reactions—Expanding the Repertoire of Shuttle and
Metathesis Reactions. Angew. Chem. Int. Ed. 2019, 58, 10074. (b)
Becker, M. R.; Watson, R. B.; Schindler, C. S. Beyond Olefins: New
Metathesis Directions for Synthesis. Chem. Soc. Rev. 2018, 47, 7867. (c)
Bhawal, B. N.; Morandi, B. Isodesmic Reactions in Catalysis – Only
the Beginning? Isr. J. Chem. 2018, 58, 94. (d) Bhawal, B. N.; Morandi,
B. Catalytic Transfer Functionalization through Shuttle Catalysis.
ACS Catal. 2016, 6, 7528.
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
bill.morandi@org.chem.ethz.ch
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Wang, G.; Xie, X.; Xu, W.; Liu, Y. Nickel-Catalyzed Highly
Notes
A patent application for transfer hydrocyanation has been
filed (US2019031602 (A1)).
ACKNOWLEDGMENT
This project received funding from the European Research
Council under the European Union's Horizon 2020 research
and innovation program (Shuttle Cat, Project ID: 757608). We
also thank the Max-Planck-Society and ETH Zürich for
support. We are also grateful to Prof. B. List for sharing
analytical equipment. B.N.B. acknowledges the Leverhulme
Trust and the ERC for funding. J.C.R. acknowledges a
fellowship of the Stipendienfonds Schweizerische
Chemische Industrie (SSCI). We thank Prof. Z. K. Wickens
(UW–Madison) and Prof. R. H. Grubbs (CalTech) for helpful
discussions.
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Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A
Practical Method for Aryl Nitrile Synthesis. J. Am. Chem. Soc. 2015,
137, 9481. (b) Malapit, C. A.; Reeves, J. T.; Busacca, C. A.; Howell, A.
R.; Senanayake, C. H. Rhodium-Catalyzed Transnitrilation of Aryl
Boronic Acids with Dimethylmalononitrile. Angew. Chem. Int. Ed.
2016, 55, 326. (c) 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.
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Patel, P.; Rousseaux, S. A. L. Ni-Catalyzed Reductive Cyanation of
Aryl Halides and Phenol Derivatives via Transnitrilation. J. Am.
Chem. Soc. 2019, 141, 19257.
see: (a) Nakao, Y.; Yada, A.; Hiyama, T. Heteroatom-Directed
Alkylcyanation of Alkynes. J. Am. Chem. Soc. 2010, 132, 10024. For
reviews on directing group effects, see: (b) Hoveyda, A. H.; Evans,
D. A.; Fu, G. C. Substrate-directable chemical reactions. Chem. Rev.
1993, 93, 1307. (c) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed
Ligand-Directed C−H Functionalization Reactions. Chem. Rev. 2010,
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Organic Synthesis and Catalysis. Angew. Chem. Int. Ed. 2011, 50, 2450.
(e) Sambiagio, C.; Schönbauer, D.; Blieck, R.; Dao-Huy, T.;
Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord,
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Overview of Directing Groups Applied in Metal-Catalysed C–H
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(21) Haines, B. E.; Sarpong, R.; Musaev, D. G. Generality and
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(22) (a) Marinescu, S. C.; Levine, D. S.; Zhao, Y.; Schrock, R. R.;
Hoveyda, A. H. Isolation of Pure Disubstituted E Olefins through
Mo-Catalyzed Z-Selective Ethenolysis of Stereoisomeric Mixtures. J.
Am. Chem. Soc. 2011, 133, 11512. (b) Marx, V. M.; Herbert, M. B.;
Keitz, B. K.; Grubbs, R. H. Stereoselective Access to Z and E
Macrocycles by Ruthenium-Catalyzed Z-Selective Ring-Closing
Metathesis and Ethenolysis. J. Am. Chem. Soc. 2013, 135, 94. (c)
Miyazaki, H.; Herbert, M. B.; Liu, P.; Dong, X.; Xu, X.; Keitz, B. K.;
Ung, T.; Mkrtumyan, G.; Houk, K. N.; Grubbs, R. H. Z-Selective
Ethenolysis with a Ruthenium Metathesis Catalyst: Experiment and
Theory. J. Am. Chem. Soc. 2013, 135, 5848.
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CN
Kinetically
selective
transfer
reaction
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 HCN-free transfer hydrocyanation
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 selective for thermodynamically
 reversible reaction
 new HCN donor
less stable isomer
 resolution of regioisomeric mixture
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