Nickel-Catalyzed Markovnikov Transfer Hydrocyanation in the Absence of Lewis Acid

Article abstract of DOI:10.1021/acs.orglett.0c01454

Hydrocyanation in the absence of toxic HCN gas is highly desirable. Addressing that challenge, transition-metal-catalyzed transfer hydrocyanation using safe HCN precursors has been developed, but these reagents generally require a Lewis acid for activation, and the control of regioselectivity often remains problematic. In this Letter, a Ni-catalyzed highly Markovnikov-selective transfer hydrocyanation that operates in the absence of any Lewis acid is reported. The readily prepared pro-aromatic 1-isopropylcyclohexa-2,5-diene-1-carbonitrile is used as the HCN source, and the reaction shows a broad substrate scope and high functional group tolerance. Terminal styrene derivatives, dienes, and internal alkynes are converted with good to excellent selectivities. Mechanistic studies provide insights into the origin of the regioselectivity.

Full text of DOI:10.1021/acs.orglett.0c01454

pubs.acs.org/OrgLett
Letter
Nickel-Catalyzed Markovnikov Transfer Hydrocyanation in the
Absence of Lewis Acid
Nils L. Frye,† Anup Bhunia,† and Armido Studer*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01454
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Hydrocyanation in the absence of toxic HCN gas is highly desirable.
Addressing that challenge, transition-metal-catalyzed transfer hydrocyanation using
safe HCN precursors has been developed, but these reagents generally require a
Lewis acid for activation, and the control of regioselectivity often remains
problematic. In this Letter, a Ni-catalyzed highly Markovnikov-selective transfer
hydrocyanation that operates in the absence of any Lewis acid is reported. The
readily prepared pro-aromatic 1-isopropylcyclohexa-2,5-diene-1-carbonitrile is used
as the HCN source, and the reaction shows a broad substrate scope and high
functional group tolerance. Terminal styrene derivatives, dienes, and internal alkynes
are converted with good to excellent selectivities. Mechanistic studies provide insights into the origin of the regioselectivity.
Scheme 1. Transition-Metal-Catalyzed Transfer
Hydrocyanation of Alkenes
he nitrile functional group is an important moiety in
Tsynthesis that can be readily transformed into various
other functional groups.1 Moreover, the nitrile entity is also
found in natural products.2 Such alkyl nitriles are generally
accessed by substitution reactions using the cyanide anion as
the nucleophile1 and by the transition-metal-catalyzed hydro-
cyanation of alkenes.3 The latter important strategy has been
successfully applied in industry to the preparation of
adipodinitrile.4 However, a problem in alkene hydrocyanation
lies in the necessity of using poisonous HCN gas. To address
that critical issue, reagents that generate HCN in situ have been
introduced. Precursors such as (Me)3SiCN or acetone
cyanohydrin are also not perfect due to their volatility because
high reaction temperatures are mostly applied in alkene
hydrocyanations.5 Morandi recently showed that isovaleroni-
trile can be used as a cheap HCN source in the Ni-catalyzed
transfer hydrocyanation of terminal alkenes (Scheme 1A).6
These hydrocyanations are reversible under the applied
conditions, and the formation of gaseous, readily removable
isobutylene as the byproduct drives the process. Considering
the reversible hydrocyanation of terminal alkenes, control of
the regioselectivity is a challenge because the Markovnikov
(branched) and anti-Markovnikov (linear) alkyl nitriles show
similar energies, and accordingly, thermodynamic product
control will lead to regioisomeric mixtures.6
We have recently introduced 1-methylcyclohexa-2,5-diene-1-
carbonitrile 1a, which is easily prepared via the reductive Birch
methylation of benzonitrile, as a valuable HCN donor in Pd-
catalyzed anti-Markovnikov transfer hydrocyanations (Scheme
1B).7 Oestreich and coworkers used the same type of reagents
in Lewis-acid-catalyzed HCN transfers.8 Both the Morandi Ni-
catalyzed6 and our Pd-catalyzed transfer hydrocyanation work
only in the presence of a Lewis acid for reagent activation,9 and
Received: April 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01454
Org. Lett. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Organic Letters
pubs.acs.org/OrgLett
Letter
in some cases, the Ni variant delivers only moderate
regioselectivity.
simplifying the process. Xantphos (10 mol %) turned out to be
the ideal ligand, in combination with Ni(COD)2 (5 mol %) as
the catalyst in benzene at 90 °C (18 h), and nitrile 3a was
obtained in 51% isolated yield with complete Markovnikov
selectivity (>98:2; for the full reaction optimization, see the
Supporting Information). DPEphos as the ligand provided a
similar result, and the yield could be further improved to 82%
upon switching to reagent 1b using Xantphos as the ligand
without compromising regioselectivity.10 In addition, we
conducted the reaction on a 1.0 mmol scale, increasing the
yield to 93%.
With the optimized conditions in hand, the reaction scope
was investigated. The transfer hydrocyanation of styrene
derivatives was not very sensitive toward electronic effects
because yields obtained for substrates bearing electron-
donating substituents such as alkyl (2b), methoxy (2c),
methylthiyl (2d), dimethylaminyl (2e), and dioxole (2g) as
well as electron-accepting substituents such as fluoro (2h) and
trifluoromethyl (2i) at the para position did not vary to a large
extent with a clear trend. The corresponding products 3b−i
were isolated in 80−99% yields with excellent regioselectivity
(>98:2; the linear isomer could not be detected by GC analysis
on the crude reaction mixture). Substrates with hydroxyl (2f)
and cyano (2j) substituents at the para position reacted
moderately, giving the corresponding products 3f and 3j, each
in 53% yield. Meta-substituted styrenes also engaged in the
reaction (3k,l), but ortho-substituted congeners turned out to
be unreactive toward the hydrocyanation. (See the SI.) para-
Phenylstyrene (2m) and β-vinyl naphthalenes 2n,o reacted
highly efficiently, and the product nitriles 3n,o were isolated in
80−99% yields. Heteroarenes were also tolerated, as
documented by the successful transformation of the pyrazole
derivative (3p), 2-vinylbenzofuran (3q), and a 3-vinylated
indole (3r).
Herein we show that cyclohexadienes of type 1 can also be
applied to the Ni-catalyzed transfer hydrocyanation of styrene
derivatives (Scheme 1C). In contrast with the Pd variant that
delivers the linear nitrile, a Lewis acid is not required, and the
branched Markovnikov product is obtained with excellent
regioselectivity. Mechanistic studies will provide insights into
the origin of the high regioselectivity.
Reaction optimization was conducted with styrene (2a) as
the substrate (Scheme 2). We were pleased to find that the Ni-
catalyzed transfer hydrocyanation of 2a with reagent 1a can be
conducted in the absence of any Lewis acid, significantly
Scheme 2. Ni-Catalyzed Transfer Hydrocyanation of
Various Styrene Derivatives and Alkynes with Reagent 1b
Surprisingly, 2-vinylpyridine (2s) gave the anti-Markovnikov
product 4s as a major regioisomer in 79% isolated yield (4s/3s
9:1). We assumed that the N atom of the pyridine ring
interacts with the Ni catalyst, leading to a reversal of the
regioselectivity. This assumption could be supported by the
reaction of 3-vinylpyridine (2t), where coordination during
hydrocyanation is not likely. As a result, the Markovnikov
product 3t was obtained with high regioselectivity (>98:2) in
91% isolated yield. Hydrocyanation could also be achieved on
more complex natural-product-derived alkenes. (See 3u and
3v.) Unfortunately, unactivated aliphatic alkenes did not react
under the optimized conditions. (See the SI.)
Dienes 2w−y turned out to be eligible HCN acceptors, and
the products 3w−y were obtained in moderate to good yields.
In all of these transformations, the linear products were not
identified, but in two cases, we found isomerization of the
double bond to give the corresponding acrylonitrile derivative.
For example, the hydrocyanation of diene 2w occurred with
high regioselectivity to afford the desired allylic nitrile 3w.
However, (E)-2-methyl-4-phenylbut-2-enenitrile (3w′) was
formed as a side product, likely via the isomerization of the
targeted 3w (ratio 3w/3w′ 3:1; see the SI for more details). A
similar reactivity was found for the fluoro-substituted diene 2x.
In contrast, the more electron-rich methoxy congener 2y
afforded the allylic nitrile 3y with excellent regioselectivity in
71% yield, and isomerization did not occur.
a
b
Reaction was conducted on a 0.5 mmol scale. Reaction was
c
conducted on a 1.0 mmol scale. Reaction was conducted on a 0.2
mmol scale. Ratio of product to its double-bond isomer is given in
d
e
We next tested alkynes in the transfer hydrocyanation with
reagent 1b because acrylonitrile derivatives are valuable
substrates in synthesis. Internal alkynes, even unactivated
parentheses. Minor isomer 3w′: (E)-2-methyl-4-phenylbut-2-eneni-
f
trile. Minor isomer 3x′: (E)-4-(4-fluorophenyl)-2-methylbut-2-
g
enenitrile. Minor isomer: (E)-2-phenylbut-2-enenitrile.
B
https://dx.doi.org/10.1021/acs.orglett.0c01454
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
bisalkylalkynes, engaged in the transformation, whereas
terminal alkynes did not react under the optimized conditions.
(See the SI.) Hence, 1-phenyl-1-propyne (2z) provided nitrile
3z with a 4.5:1 regioselectivity and excellent trans-selectivity
(cis-hydrocyanation) for both regioisomers. The symmetric
dec-5-yne (2aa) afforded the hydrocyanation product 3aa in
90% yield with excellent trans-selectivity. Propyne protected
with the bulky triisopropylsilyl group reacted with excellent
regioselectivity to nitrile 3ab (70% yield, trans/cis > 98:2).
Next, we addressed the mechanism of the transfer
hydrocyanation of styrene 2k by using the perdeuterated
reagent 1b-d5 (Scheme 3). Nitrile 3k-d was isolated in 81%
Scheme 4. Proposed Mechanism
Scheme 3. Mechanistic Studies
revealed that a ring methylene H atom gets transferred to the
alkene. Hence B can react via direct δ-hydride elimination,
considering a boat-shaped conformation with the isopropyl
group located in the equatorial position, to C.12 Alternatively, a
1,3-metallotropic shift in B followed by β-hydride elimination
will also lead to complex C.13 Ligand exchange then affords D,
which can undergo migratory insertion to complex E.
Reversible reductive elimination will eventually lead to the
final product 3.
Because the oxidative addition of Ni(0) to the linear product
4a did not occur (see Scheme 3), linear products of type 4
should never be formed during transfer hydrocyanation.
Deuterium incorporation at the benzylic position (see 3a-d)
indicates that the migratory insertion does not proceed with
perfect regioselectivity. We therefore assume that the
migratory insertion is reversible and that reductive elimination
proceeds only for the benzylic Ni complex E, leading to the
branched product 3, whereas the primary alkyl−Ni(II)CN
complex E′ does not engage in reductive elimination to give 4.
In contrast, Schmalz and coworkers observed no deuterium
scrambling in their enantioselective hydrocyanation of styrene-
d8 using HCN at room temperature.3i Thus the formation of
E′ seems to be possible only at higher temperatures.
yield with 35% D incorporation at the β-position and 7% D
incorporation at the α-position. Upon switching to reagent 1b-
d7 using styrene as the acceptor, nitrile 3a was isolated in 69%
yield without any deuterium incorporation, and GCMS
analysis showed the mass of (propan-2-yl-d7)benzene as the
byproduct. (See the SI for details.) These observations indicate
that the H atom that gets transferred to the alkene is derived
from the ring methylene group of reagent 1b and not from the
isopropyl group.
In an additional mechanistic experiment, a 1:1 mixture of
nitrile 3a and its regioisomer 4a was subjected to the reaction
conditions in the absence of reagent 1b. After 18 h, the ratio of
3a/4a remained nearly the same, indicating that the linear
regioisomer 4a is stable under the reaction conditions. To
check whether a benzylic nitrile is also stable, we ran the
reaction of 3a with alkene 2k (1 equiv of each) in the absence
of reagent 1b, and 3k was identified as product along with 3a
(ratio 3a/3k 84:16). This result clearly shows that the benzylic
C−CN bond in 3a gets activated by the Ni catalyst.
Finally, we tested whether regioselectivity for the transfer
hydrocyanation of styrenes using reagent 1a can be reversed
upon running the reaction in the presence of a Lewis acid
(Scheme 5).14 We were pleased to find that with 20 mol % of
AlMe2Cl, the hydrocyanation of 4-vinyl-benzonitrile (2j)
worked under very mild conditions, and the linear anti-
Markovnikov product 4j was isolated in 64% yield with 14:1
regioselectivity. In contrast with previous protocols on Lewis-
acid-mediated transfer hydrocyanations that operate at 100−
130 °C,6 the current transformation proceeds at room
temperature. A lower but still good selectivity (5:1 to 6:1)
was noted for styrene and its para-fluoro congener (4a and
4h), whereas for the more electron-rich 4-vinylanisole, the
regioselectivity dropped to 3:1 (4c). Notably, reagent 1b
showed lower efficiency than 1a in the Lewis-acid-mediated
reaction.
Considering these mechanistic investigations and literature
reports,11 the following mechanism is suggested for the alkene
transfer hydrocyanation with 1b (Scheme 4). The catalytic
cycle starts by complexation of the nitrile functionality of
reagent 1b with the Ni(0) catalyst to give A, which reacts via
oxidative addition to complex B. The deuteration experiments
In summary, we have presented Ni-catalyzed transfer
hydrocyanation of styrenes, dienes, and alkynes using cyclo-
hexadiene 1b as a readily accessible and storable HCN source.
A Lewis acid is not required to activate the cyano functionality
in 1b, and reactions proceed under comparable mild
C
https://dx.doi.org/10.1021/acs.orglett.0c01454
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
51. (b) Larock, R. C. In Comprehensive Organic Transformations: A
Guide to Functional Group Preparations, 3rd ed.; Wiley-VCH, 2018.
(c) Fatiadi, A. J. In Preparation and Synthetic Application of Cyano
Compounds; Patai, P., Rappaport, Z., Eds.; Wiley: New York, 1983.
(2) (a) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B.
C. Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile
Pharmacophore. J. Med. Chem. 2010, 53, 7902−7917. (b) Fleming, F.
F. Nitrile-containing natural products. Nat. Prod. Rep. 1999, 16, 597−
606. (c) Scheuer, P. J. Isocyanides and cyanides as natural products.
Acc. Chem. Res. 1992, 25, 433−439.
Scheme 5. anti-Markovnikov-Selective Transfer
Hydrocyanation
a
(3) (a) Zhang, H.; Su, X.; Dong, K. Recent progress in transition-
metal-catalyzed hydrocyanation of nonpolar alkenes and alkynes. Org.
Biomol. Chem. 2020, 18, 391−399. (b) Huthmacher, K.; Krill, S.
Reactions with Hydrogen Cyanide (Hydrocyanation). In Applied
Homogeneous Catalysis with Organometallic Compounds; Cornils, B.,
Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, Germany, 1996; Vol.
I; p 465. (c) Casalnuovo, A. L.; Rajan Babu, T. V. Transition Metal-
Catalyzed Alkene and Alkyne Hydrocyanations. In Transition Metals
for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; p 149. For representative examples of
hydrocyanation, see: (d) Chen, H.; Sun, S.; Liu, Y. A.; Liao, X. Nickel-
Catalyzed Cyanation of Aryl Halides and Hydrocyanation of Alkynes
via C−CN Bond Cleavage and Cyano Transfer. ACS Catal. 2020, 10,
1397−1405. (e) Xing, Y.; Yu, R.; Fang, X. Synthesis of Tertiary
Benzylic Nitriles via Nickel-Catalyzed Markovnikov Hydrocyanation
of α-Substituted Styrenes. Org. Lett. 2020, 22, 1008−1012. (f) Wang,
G.; Xie, X.; Xu, W.; Liu, Y. Nickel-catalyzed highly regioselective
hydrocyanation of alkenes with Zn(CN)2. Org. Chem. Front. 2019, 6,
2037−2042. (g) 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. (h) Ye, F.; Chen, J.; Ritter, T. Rh-Catalyzed Anti-
Markovnikov Hydrocyanation of Terminal Alkynes. J. Am. Chem. Soc.
2017, 139, 7184−7187. (i) Falk, A.; Cavalieri, A.; Nichol, G. S.; Vogt,
D.; Schmalz, H.-G. Enantioselective Nickel-Catalyzed Hydrocyana-
tion using Chiral Phosphine-Phosphite Ligands: Recent Improve-
ments and Insights. Adv. Synth. Catal. 2015, 357, 3317−3320.
a
Reaction was performed on a 0.2 mmol scale. The ratio of linear to
b
branched product is given in parentheses. Reaction with 40 mol % of
AlMe2Cl. The GC yield is reported.
conditions at 90 °C. For styrene derivatives, excellent
Markovnikov selectivity is obtained. In the presence of
AlMe2Cl (20 mol %), transfer hydrocyanation can be
conducted at room temperature using this type of reagent,
and the anti-Markovnikov product is formed as a major
regioisomer with good to very good selectivity.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01454.
General experimental procedures, reaction optimization,
mechanistic experiments, and characterization of com-
pounds (PDF)
̈
(j) Falk, A.; Goderz, A.-L.; Schmalz, H.-G. Enantioselective Nickel-
AUTHOR INFORMATION
■
Catalyzed Hydrocyanation of Vinylarenes Using Chiral Phosphine−
Phosphite Ligands and TMS-CN as a Source of HCN. Angew. Chem.,
Int. Ed. 2013, 52, 1576−1580. (k) de Greef, M.; Breit, B. Self-
Assembled Bidentate Ligands for the Nickel-Catalyzed Hydro-
cyanation of Alkenes. Angew. Chem., Int. Ed. 2009, 48, 551−554.
(l) Gaspar, B.; Carreira, E. M. Mild Cobalt-Catalyzed Hydrocyanation
of Olefins with Tosyl Cyanide. Angew. Chem., Int. Ed. 2007, 46,
Corresponding Author
̈
Armido Studer − Organisch-Chemisches Institut, Westfalische
̈
̈
Wilhelms-Universitat, 48149 Munster, Germany; orcid.org/
0000-0002-1706-513X; Email: studer@uni-muenster.de
Authors
Nils L. Frye − Organisch-Chemisches Institut, Westfalische
̈
4519−4522. (m) Backvall, J. E.; Andell, O. S. Stereochemistry and
̈
mechanism of nickel-catalyzed hydrocyanation of olefins and
conjugated dienes. Organometallics 1986, 5, 2350−2355. (n) Saha,
B.; Rajan Babu, T. V. Nickel(0)-Catalyzed Asymmetric Hydro-
cyanation of 1,3-Dienes. Org. Lett. 2006, 8, 4657−4659. (o) Nakao, Y.
Catalytic C−CN Bond Activation. In C−C Bond Activation.; Dong,
G., Ed.; Springer: Berlin, Heidelberg, 2014; Vol. 346, pp 33−58.
(p) Watson, M. P.; Jacobsen, E. N. Asymmetric Intramolecular
Arylcyanation of Unactivated Olefins via C−CN Bond Activation. J.
Am. Chem. Soc. 2008, 130, 12594−12595. For the transfer
hydroiodination reaction using CHDs, see: (q) Chen, W.; Walker,
J. C. L.; Oestreich, M. Metal-Free Transfer Hydroiodination of C−C
Multiple Bonds. J. Am. Chem. Soc. 2019, 141, 1135−1140.
̈
̈
Wilhelms-Universitat, 48149 Munster, Germany
̈
Anup Bhunia − Organisch-Chemisches Institut, Westfalische
̈
̈
Wilhelms-Universitat, 48149 Munster, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01454
Author Contributions
†N.L.F. and A.B. contributed equally.
Notes
The authors declare no competing financial interest.
(4) (a) Kim, J.; Kim, H. J.; Chang, S. Synthesis of Aromatic Nitriles
Using Nonmetallic Cyano-Group Sources. Angew. Chem., Int. Ed.
̈
2012, 51, 11948−11959. (b) Bini, L.; Muller, C.; Vogt, D.
Mechanistic Studies on Hydrocyanation Reactions. ChemCatChem
2010, 2, 590−608.
ACKNOWLEDGMENTS
■
We thank the Deutsche Forschungsgemeinschaft (DFG) for
supporting this work.
(5) (a) Currance, P. L.; Clements, B.; Bronstein, A. C. Emergency
Care for Hazardous Materials Exposure, 3rd ed.; Elsevier Mosby: St.
Louis, MO, 2005; p 432. (b) Haroutounian, S. A. Acetone
Cyanohydrin. In e-EROS Encyclopedia of Reagents for Organic
Synthesis; John Wiley & Sons, 2001. (c) Groutas, W. C.,
REFERENCES
■
(1) (a) Zhang, S.; del Pozo, J.; Romiti, F.; Mu, Y.; Torker, S.;
Hoveyda, A. H. Delayed catalyst function enables direct enantiose-
lective conversion of nitriles to NH2-amines. Science 2019, 364, 45−
D
https://dx.doi.org/10.1021/acs.orglett.0c01454
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Cyanotrimethylsilane. In e-EROS Encyclopedia of Reagents for Organic
Synthesis; John Wiley & Sons, 2001.
(6) (a) Fang, X.; Yu, P.; Morandi, B. Catalytic reversible alkene-
nitrile interconversion through controllable transfer hydrocyanation.
Science 2016, 351, 832−836. (b) Schmalz, H.-G. A molecular shuttle
for hydrogen cyanide. Science 2016, 351, 817.
(7) Bhunia, A.; Bergander, K.; Studer, A. Cooperative Palladium/
Lewis Acid-Catalyzed Transfer Hydrocyanation of Alkenes and
Alkynes Using 1-Methylcyclohexa-2,5-diene-1-carbonitrile. J. Am.
Chem. Soc. 2018, 140, 16353−16359.
(8) Orecchia, P.; Yuan, W.; Oestreich, M. Transfer Hydrocyanation
of α- and α,β-Substituted Styrenes Catalyzed by Boron Lewis Acids.
Angew. Chem., Int. Ed. 2019, 58, 3579−3583.
(9) (a) Tobisu, M.; Chatani, N. Catalytic reactions involving the
cleavage of carbon−cyano and carbon−carbon triple bonds. Chem.
Soc. Rev. 2008, 37, 300−307. (b) Nakao, Y.; Yada, A.; Ebata, S.;
Hiyama, T. A Dramatic Effect of Lewis-Acid Catalysts on Nickel-
Catalyzed Carbocyanation of Alkynes. J. Am. Chem. Soc. 2007, 129,
2428−2429. (c) Brunkan, N. M.; Brestensky, D. M.; Jones, W. D.
Kinetics, Thermodynamics, and Effect of BPh3 on Competitive C−C
and C−H Bond Activation Reactions in the Interconversion of Allyl
Cyanide by [Ni(dippe)]. J. Am. Chem. Soc. 2004, 126, 3627−3641.
(d) Tolman, C. A.; Seidel, W. C.; Druliner, J. D.; Domaille, P. J.
Catalytic hydrocyanation of olefins by nickel(0) phosphite complexes
- effects of Lewis acids. Organometallics 1984, 3, 33−38.
(10) For the role of the ligands in hydrocyanation processes, see:
̈
(a) Bini, L.; Muller, C.; Vogt, D. Ligand development in the Ni-
catalyzed hydrocyanation of alkenes. Chem. Commun. 2010, 46,
8325−8334. (b) Tolman, C. A. Steric effects of phosphorus ligands in
organometallic chemistry and homogeneous catalysis. Chem. Rev.
1977, 77, 313−348.
(11) (a) Murakami, M.; Ishida, N. Potential of Metal-Catalyzed C−
C Single Bond Cleavage for Organic Synthesis. J. Am. Chem. Soc.
2016, 138, 13759−13769. (b) Hirata, Y.; Yukawa, T.; Kashihara, N.;
Nakao, Y.; Hiyama, T. Nickel-Catalyzed Carbocyanation of Alkynes
with Allyl Cyanides. J. Am. Chem. Soc. 2009, 131, 10964−10973.
(12) Rabideau, P. W.; Paschal, J. W.; Patterson, L. E. Stereo-
chemistry of 1,4-cyclohexadienes. Planar vs. boat-shaped conforma-
tions. J. Am. Chem. Soc. 1975, 97, 5700−5704.
(13) (a) Koch, E.; Studer, A. Regioselective Threefold Aromatic
Substitution of Benzoic Acid Derivatives by Dearomatization,
Regioselective Functionalization, and Rearomatization. Angew.
Chem., Int. Ed. 2013, 52, 4933−4936. (b) Chou, C.-M.; Chatterjee,
I.; Studer, A. Stereospecific Palladium-Catalyzed Decarboxylative
C(sp3)−C(sp2) Coupling of 2,5-Cyclohexadiene-1-carboxylic Acid
Derivatives with Aryl Iodides. Angew. Chem., Int. Ed. 2011, 50, 8614−
8617.
(14) (a) Ni, S.-F.; Yang, T.-L.; Dang, L. Transfer Hydrocyanation by
Nickel(0)/Lewis Acid Cooperative Catalysis, Mechanism Investiga-
tion, and Computational Prediction of Shuttle Catalysts. Organo-
metallics 2017, 36, 2746−2754. (b) Huang, J.; Haar, C. M.; Nolan, S.
P.; Marcone, J. E.; Moloy, K. G. Lewis Acids Accelerate Reductive
Elimination of RCN from P2Pd(R)(CN). Organometallics 1999, 18,
297−299.
E
https://dx.doi.org/10.1021/acs.orglett.0c01454
Org. Lett. XXXX, XXX, XXX−XXX