Ni-Catalyzed Reductive Cyanation of Aryl Halides and Phenol Derivatives via Transnitrilation

Article abstract of DOI:10.1021/jacs.9b11208

Herein, we report a Ni-catalyzed reductive coupling for the synthesis of benzonitriles from aryl (pseudo)halides and an electrophilic cyanating reagent, 2-methyl-2-phenyl malononitrile (MPMN). MPMN is a bench-stable, carbon-bound electrophilic CN reagent that does not release cyanide under the reaction conditions. A variety of medicinally relevant benzonitriles can be made in good yields. Addition of NaBr to the reaction mixture allows for the use of more challenging aryl electrophiles such as aryl chlorides, tosylates, and triflates. Mechanistic investigations suggest that NaBr plays a role in facilitating oxidative addition with these substrates.

Full text of DOI:10.1021/jacs.9b11208

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Communication
Ni-Catalyzed Reductive Cyanation of Aryl Halides
and Phenol Derivatives via Transnitrilation
Leo Reginald Mills, Joshua Graham, Purvish Patel, and Sophie A.L. Rousseaux
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11208 • Publication Date (Web): 11 Nov 2019
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Ni-Catalyzed Reductive Cyanation of Aryl Halides and Phenol
Derivatives via Transnitrilation
L. Reginald Mills, Joshua Graham,‡ Purvish Patel,‡ and Sophie A. L. Rousseaux*
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Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George St., Toronto, ON, M5S
3H6, Canada
Supporting Information Placeholder
one-step synthesis of benzonitriles (Scheme 1a, bottom
arrow). The reaction uses 2-methyl-2-
ABSTRACT: Herein, we report a Ni-catalyzed reductive
coupling for the synthesis of benzonitriles from aryl
(pseudo)halides and an electrophilic cyanating reagent,
2-methyl-2-phenyl malononitrile (MPMN). MPMN is a
bench-stable, carbon-bound electrophilic CN reagent
that does not release cyanide under the reaction
phenylmalononitrile (MPMN), a non-toxic, C-bound
source of electrophilic CN, which is thus safer to use
than the metal cyanide salts typically used in metal-
catalyzed cyanation reactions and avoids catalyst
poisoning challenges associated with their use.12,13
While alkylnitriles have been employed as reagents for
Ni-catalyzed cyanation of aryl bromides, these
previously reported protocols either treat these reagents
as mere cyanide surrogates and generate anionic CN or
metal–CN intermediates in situ,14,15 or else require
highly
conditions.
A
variety of medicinally relevant
benzonitriles can be made in good yields. Addition of
NaBr to the reaction mixture allows for the use of more
challenging aryl electrophiles such as aryl chlorides,
tosylates, and triflates. Mechanistic investigations
suggest that NaBr plays a role in facilitating oxidative
addition with these substrates.
Scheme 1. Cyanation of aryl halides
Ni-catalyzed reductive cross-coupling is a powerful
tool for creating C–C bonds between two electrophilic
coupling partners.1 The coupling of organic halides with
π-type electrophiles like alkenes,2 CO2,3 and carbonyl
derivatives4,5 has emerged as a convenient strategy that
circumvents the extra synthetic steps and lack of
chemoselectivity typical of conventional Grignard-type
addition chemistry. Thus, the development of new
coupling partners and mechanisms for this reactivity
regime is of significant interest to chemists working in
the fields of catalysis and Ni chemistry.
Benzonitriles are found in a range of pharmaceuticals
(Scheme 1b) and their preparation via a simple reductive
coupling of aryl halides with an electrophilic cyanating
reagent would be convenient.6 Such a procedure
represents a catalytic version of conventional stepwise
electrophilic cyanation,7,8 in which the aryl halide is first
converted to a reactive organometallic intermediate
(Scheme 1a, top arrow).9 The addition of arylnickel
intermediates to nitriles is precedented, however ketones
are generally produced in these reactions.10 A related
process that would ultimately release a benzonitrile
product has been underdeveloped in the context of Ni
chemistry.11
In this communication, we report the first reductive
cross-electrophile coupling of wide range of aryl
(pseudo)halides with a malononitrile derivative for a
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specialized reagents.16 The use of MPMN facilitates a
safe, cyanide-free transnitrilation mechanism, which has
not been employed in the context of Ni catalysis.17
Namely, a key pathway of this new protocol is the 1,2-
migratory insertion of a Ni(I)-aryl species across the
nitrile, followed by β-carbon elimination at Ni to form
the desired benzonitrile (Scheme 1a).11
Page 2 of 8
observed in the presence of Zn,22,23 making its use as a
reducing agent preferable. Other transnitrilating reagents
like DMMN (entry 5) or 2,2-dibenzylmalononitrile
(DBMN; see Table S2) were less efficient
transnitrilating reagents. Removing Ni from the reaction
mixture (entry 6) resulted in low conversion of 1a and
no detectable formation of benzonitrile 2a. Iodoarenes
also participated in transnitrilation (entry 7), however
gave greater amounts of homocoupled and reduced side-
products (see Table S1).
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8
Additionally, NaBr can be used as a halide additive to
enable functionalization of otherwise inert aryl–X bonds
including aryl chlorides, mesylates, tosylates and aryl
triflates. The addition of NaBr provides a literal on/off
reactivity switch with no other change to the reaction
conditions, which has little precedence in Ni catalysis.18
The optimized reaction conditions for the reductive
cyanation of aryl bromides are shown in Table 1. Using
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A summary of substrates that can be made with this
protocol is shown in Table 2. The reaction tolerates
arenes with substituents of varying electronic and steric
properties, including ortho substituents (2p). The
reaction is compatible with alkenes (2l); products
resulting from migratory insertion across the alkene
were not detected. (Pseudo)halide handles like chloride
(2m), fluoride (2n), and tosylate (2aj, Table S10) are
unreactive under these conditions; very little (<5%)
functionalization of the corresponding C–X bond is
observed. Substrates with protecting groups such as an
acetal (2o) reacted without detectable amounts of the
deprotected products. Arenes with multiple C–Br bonds
can be dicyanated if excess MPMN and Zn are
employed (2p, 2q); in the presence of 1 equiv of MPMN
the second C–Br bond is reduced to C–H. The reaction
is compatible with both electron-rich (2r, 2aa) and
electron-poor (2t, 2u) arenes. Other compatible
functional groups include free alcohols (2s), esters (2t),
and amides (2u). Notably, free alcohols and esters are
functional groups not typically compatible with
Grignard chemistry, which is an advantage of this Ni-
catalyzed protocol over typical, stoichiometric
electrophilic cyanation protocols (Scheme 1a). For all
reactions in Table 2, full conversion of starting material
was observed. For low-yielding reactions, the remaining
mass balance went predominantly to reduced product.
A wide range of heteroaryl bromides could also be
converted to the corresponding heteroaryl nitriles using
this procedure (Table 2). The reaction scope includes
electron-rich heteroarenes like indole (2v), carbazole
(2w), dibenzofuran (2x), benzothiophene (2y, 2z), and
pyrazole (2aa). Electron-deficient arenes are also
compatible, including quinoline (2ae), pyridine (2ab)
and pyrimidine (2ad, 2ae). Pyridines and pyrimidines
without bulky blocking groups ortho to the nitrogen
resulted in very little conversion, suggesting that catalyst
poisoning by these substrates may be occurring (see
Figure S3 for representative examples). N-protecting
groups are compatible with the reaction conditions,
including benzyl (2v, 2ad) and TBS (2w).24 For
supplemental examples of heteroarenes, see Table S10.
The reaction is also applicable to late-stage cyanation,
as demonstrated by the synthesis of biologically relevant
substrates, including the antipsychotic cyanopromazine
(2af, 49%), and an intermediate from the synthesis of
antimigraine therapeutic donitriptan (2ag, 68%).
3-bromoanisole (1a) as
a
model substrate, 3-
methoxybenzonitrile (2a) could be generated in 90%
yield in the presence of MPMN,19 NiBr2(bpy)•xH2O
(10 mol %),20 and Zn(0) dust (2 equiv) after stirring in
DMA at 80 °C for 16 h. Changing the ligand to the more
electron-donating dtbbpy (entry 2) resulted in
diminished yields with increased formation of reduced
arene and homocoupled biaryl side-products. Notably,
the use of dppf (entry 3) or other phosphines (see Table
S1), common ligands for Ni-catalyzed nucleophilic
cyanation protocols,21 resulted in very little conversion
of 1a (ca. 10%), suggesting a mechanistically distinct
reaction pathway. Other reductants like Mn(0) (entry 4)
were also compatible, but gave lower
Table 1. Optimization of the reactiona
aReaction conditions: 3-Bromoanisole 1a (0.10 mmol, 1.0
equiv), 2-methyl-2-phenylmalononitrile (MPMN) (1.2
equiv), NiBr2(bpy) (10 mol %), Zn(0) dust (2.0 equiv),
N,N-dimethylacetamide (DMA) (0.20 M), 80 °C, 16 h. See
b
the SI for full optimization details. GC-MS yield using n-
dodecane as an internal standard. MPMN = 2-methyl-2-
phenylmalononitrile; DMMN = 2,2-dimethylmalononitrile;
dtbbpy = 4,4’-di-tert-butyl-2,2’-dipyridyl.
yields of 2a. Excess MPMN was decomposed by Mn,
implying some formation of metal cyanide salts in situ,
while similar decomposition mechanisms were not
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Table 2. Scope of the reactiona
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aReactions performed on 0.20–0.40 mmol scale. See SI for full details. bUsing MPMN (2.4 equiv), NiBr2(bpy)•xH2O
(20 mol %), and Zn(0) dust (4.0 equiv). For an additional 11 entries, see Table S10.
Next, the reactivity of oxidative addition intermediate
4 with MPMN was evaluated to better understand the
mechanism of transnitrilation (Scheme 2a).25 When 4
was exposed to MPMN at 80 °C, 28% of benzonitrile 2c
was obtained, as well as 65% of 2-bromotoluene (1c)
resulting from C–Br reductive elimination.26,27 The
addition of ZnBr2 (1 equiv) did not affect the product
distribution. However, the addition of Zn(0) dust
(1 equiv) allowed for efficient conversion to 2c, with no
1c detected after 12 h. The presence of Zn(0) may
facilitate reduction of Ni(II)(Br)(aryl) to Ni(I)–aryl,1
suggesting that that Ni(I)–aryl performs 1,2-migratory
insertion with MPMN. In the case without Zn(0) dust,
some Ni(I)–aryl could still be formed via
comproportionation of Ni(II) and Ni(0) intermediates,28
explaining the observed conversion of 4 to 2c in the
absence of Zn(0) dust. Notably, that 2c was observed in
28% in the absence of other metal salts implies that
transnitrilation can be catalyzed by Ni alone.
With these results in mind, our proposed catalytic
cycle is presented in Scheme 2b. Starting with Ni(0)
intermediate 5, reversible oxidative addition to aryl
bromide 1 generates Ni(II) intermediate 6. Reduction
with Zn forms Ni(I)–aryl intermediate 7. 1,2-Migratory
insertion11 with MPMN generates Ni(I)-bound imine 8,29
which can undergo β–C elimination to form benzonitrile
product 2 and α-nickelated intermediate 9.30 Then,
ligand exchange with ZnBr2 can generate Ni(I)–Br
intermediate 10, which can be reduced with Zn to
regenerate the Ni(0) catalyst 5.
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1
2
3
Scheme 2. Mechanistic studies and proposed catalytic
Table 3. Reactivity of aryl chlorides and tosylates
cycle
a) Competence of a pre-transnitrilation Ni(II) species
4
5
6
7
8
9
MPMN (1 equiv)
Me
(bpy)Ni
CN
Br
additive (1 equiv)
+
DMA
80 ºC, 12 h
Me
Me
Br
2c
1c
4
Yield 2c (%) Yield 1c (%)
additive
none
ZnBr2
Zn(0)
28
28
95
65
68
0
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4 [X-ray]
b) Proposed catalytic cycle
ArBr
1/2 ZnBr2
1
LnNi(0)
5
1/2 Zn
LnNiI
ArBr
Ar
Br
LnNiII
Br
CN
10
[Zn]
1/2 Zn
6
Ph
Me
ZnBr2
CN
1/2 ZnBr2
NC CN
LnNiI
LnNiI
Ar
Ph
Me
9
7
LnNiI
N
aReaction conditions: electrophile 1a or 11 (0.10 mmol, 1.0
equiv), MPMN (1.0 equiv), catalyst (0.020–0.10 mmol,
0.20–1.0 equiv), additive (0 or 2.0 equiv), Zn(0) dust (0.20
mmol, 1.0 equiv), DMA, 80 ºC; GC-MS yield using n-
dodecane as an internal standard.
CN
Ar CN
Me
Ph
Ar
2
Me Ph
MPMN
8
b
The apparent reversibility of oxidative addition, and
the necessary reduction of oxidative addition
intermediate 6 to generate pre-transnitrilation Ni(I)–aryl
intermediate 7, led us to further question the importance
of the halide for these elementary steps. We had
observed that aryl chloride (Table 2, substrate 2m) and
aryl tosylate (Table S10, substrate 2aj) do not react
under the standard reaction conditions, leading us to
wonder if this was due to a difference in the oxidative
addition equilibrium with these groups. During reaction
optimization, we also noticed that measurable amounts
(up to 10% by GC-MS) of the ipso-chlorinated product
(11a) were always observed when NiCl2(bpy) or
NiCl2(dme)/bpy were used as precatalysts (Table 3a,
entry 1).31 Indeed, if the reaction was performed with a
stoichiometric amount of NiCl2(bpy) (entry 2), 11a was
obtained as a major product, an apparent dead-end, since
3-chloroanisole is not a viable substrate under standard
conditions (see Table S5). The addition of a bromide salt
additive (2 equiv) like NaBr (entry 3) enabled complete
recovery of the material that had generated 11a in entry
2, with an increased yield of 2a (53% vs. 37% in entries
3 and 2, respectively). Other nucleophilic halide sources
like LiBr, tetrabutylammonium bromide (TBAB), or
tetrabutylammonium chloride (TBAC) had a similar
effect (see Table S8).
Based on this information, 3-chloroanisole (11a) was
used as a substrate for transnitrilation (Table 3b).
Addition of NaBr (2 equiv) leads to 53% yield of 2a,
whereas no conversion to desired product is detected in
the absence of NaBr (entry 1 vs. entry 2). The same is
true for 3-tosylanisole (11b) (entries 3–4). The
significant increase in conversion for these substrates in
the presence of NaBr suggests that NaBr facilitates
oxidative addition. In related Ni-catalyzed reductive
couplings, halide ions have been proposed to i) act as
ligands for Ni(0),32 ii) generate reactive nickelate
intermediates,33 iii) enable halide exchange of Ni(II)
oxidative addition intermediates,34 iv) facilitate
reduction of Ni(II) with Zn,33a,b,35 and v) overcome
catalyst inhibition from ZnX2 salts.5
The generality of the NaBr effect in the context of
other substrates and leaving groups is shown in Table 4.
Under these conditions, aryl chlorides (12c), tosylates
(12a), mesylates (12b), and triflates (2a’), all previously
unreactive substrates, were amenable to reductive
transnitrilation. In all of the above cases, no conversion
was detected without NaBr. The reactivity-enhancing
effect of NaBr was also observed for challenging aryl
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bromides like sterically encumbered 2-bromomesitylene
1
2
3
4
(12d), which saw significantly higher starting material
conversion in the presence of NaBr (ca. 50% vs. 10%
conv. with and without NaBr, respectively).
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
5
*sophie.rousseaux@utoronto.caꢀ
Author Contributions
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Table 4. Scope of alternate aryl electrophiles using
NaBra
‡ These authors contributed equally.
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank NSERC (Discovery Grants and Canada
Research Chair programs), the Canada Foundation for
Innovation (project number 35261), the Ontario
Research Fund and the University of Toronto for
generous financial support of this work. The authors also
wish to acknowledge the Canada Foundation for
Innovation (project number 19119) and the Ontario
Research Fund for funding the Centre for Spectroscopic
Investigation of Complex Organic Molecules and
Polymers. L. R. M. thanks NSERC for a graduate
scholarship (PGS D). Dr. Alan Lough is thanked for X-
ray analysis. Nicholas W. M. Michel is thanked for
insightful discussions.
aReactions performed on 0.20–0.40 mmol scale. Yields are
for isolated material; bWithout NaBr; cUsing
NiBr2(bpy)2•2H2O (20 mol %).
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In conclusion, we have developed a Ni-catalyzed
reductive cyanation of aryl (pseudo)halides using a non-
toxic, carbon-bound source of CN. A wide range of
benzonitriles can be prepared, including substrates
bearing functional groups that are incompatible in
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge
on the ACS Publications website.
Reaction optimization tables, mechanistic and
stoichiometric studies, synthetic procedures, and
characterization data (PDF)
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malononitrile according to the following
Scheme:
(11) For an example of Rh(I)-catalyzed addition of arylboronic acids
to malononitriles, see: 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. 2015, 55, 326–330.
(12) Anbarasan, P.; Schareina, T.; Beller, M.
Recent
developments
and
perspectives
in
palladium-catalyzed cyanation of aryl halides:
synthesis of benzonitriles. Chem. Soc. Rev.
2011, 10, 5049–5067.
(13) The disubstituted malononitrile class of
reagent possesses low toxicity. For instance,
dimethylmalononitrile (DMMN) has a health
rating of 2 in both HMIS and NFPA rating
systems according to the Sigma–Aldrich SDS.
(14) Yu, P.; Morandi, B. Nickel‐Catalyzed Cyanation of Aryl
For full details, see SI. MPMN can also be made in one step from
commercially available reagents: Mills, L. R.; Rousseaux, S. A. L. A
one-pot electrophilic cyanation–functionalization strategy for the
synthesis of disubstituted malononitriles. Tetrahedron 2019, 75,
4298–4306.
(20) See the Supporting Information for details.
(21) (a) Cassar, L. A new nickel-catalyzed synthesis of aromatic
nitriles. J. Organomet. Chem. 1973, 54, C57–C58; (b) Zhang, X.; Xia,
A.; Chen, H.; Liu, Y. General and Mild Nickel-Catalyzed Cyanation
of Aryl/Heteroaryl Chlorides with Zn(CN)2: Key Roles of DMAP.
Org. Lett. 2017, 19, 2118–2121 and references therein; (c) Michel, N.
W. M.; Jeanneret, A. D. M.; Kim, H.; Rousseaux, S. A. L. Nickel-
Catalyzed Cyanation of Benzylic and Allylic Pivalate Esters. J. Org.
Chem. 2018, 83, 11860–11872.
(22) A titration of the reaction mixture to detect the release of cyanide
from MPMN under the reaction conditions gave no detectable amount
of cyanide (<20 mg/L). See the Supporting Information (Section C.3)
for further details.
(23) See Supporting Information (Equation S1)
for details on MPMN decomposition in the
presence of Zn and Ni.
(24) For examples of incompatible protecting groups, see Figure S2.
(25) The reactivity of arylzinc reagents with MPMN was also
evaluated and the results suggest that in situ arylzinc formation does
not significantly contribute to product formation. See the Supporting
Information (Section C.1) for details.
Chlorides
and
Triflates
Using
Butyronitrile:
Merging
Retro‐hydrocyanation with Cross‐Coupling. Angew. Chem. Int. Ed.
2017, 56, 15693–15697.
(15) For examples using alkylnitriles as
cyanating reagents with other metals, see: (a)
Jiang, Z.; Huang, Q.; Chen, S.; Long, L.; Zhou,
X. Copper‐Catalyzed Cyanation of Aryl Iodides
with Malononitrile: An Unusual Cyano Group
Transfer Process from C(sp3) to C(sp2). Adv.
Synth. Catal. 2012, 354, 589–592; (b) Kou, X.;
Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z.
Copper‐Catalyzed Aromatic C–H Bond Cyanation by
C–CN Bond Cleavage of Inert Acetonitrile. Chem.
– Eur. J. 2013, 19, 16880–16886.
(16) A recent mechanistically-distinct example
of reductive cyanation using acetonitrile
employs
tetramethyl-1,4-dihydropyrazine, which is made
from tetramethylpyrazine using
1,4-bis(trimethylsilyl)-2,3,5,6-
(26) Petrone, D. A.; Ye, J.; Lautens, M. Modern
Transition-Metal-Catalyzed Carbon–Halogen Bond Formation.
superstoichiometric K metal over 1 week: Ueda,
Y.; Tsujimoto, N.; Yurino, T.; Tsurugi, H.;
Mashima, K. Nickel-catalyzed cyanation of aryl
halides and triflates using acetonitrile via C–
Chem. Rev. 2016, 116, 8003–8104.
(27) Reversible C(sp2)–X oxidative addition has
been previously proposed in the context of Ni-
catalyzed reductive cross coupling: Biswas, S.;
Weix, D. J. Mechanism and Selectivity in
Nickel-Catalyzed Cross-Electrophile Coupling of
Aryl Halides with Alkyl Halides. J. Am. Chem.
Soc. 2013, 135, 16192–16197.
CN
bond
cleavage
assisted
by
1,4-
bis(trimethylsilyl)-2,3,5,6-tetramethyl-1,4-
dihydropyrazine. Chem. Sci. 2019, 10, 994–999.
See references therein for further examples of
MeCN as a cyanating reagent.
(17) For examples of transnitrilation using
malononitriles and preformed Grignard reagents,
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(28) See Bajo, S.; Laidlaw, G.; Kennedy, A. R.; Sproules, S.; Nelson,
D. J. Oxidative Addition of Aryl Electrophiles to a Prototypical
Nickel(0) Complex: Mechanism and Structure/Reactivity
Relationships. Organometallics 2017, 36, 1662–1672 and references
cited therein.
Chem. 1980, 45, 1930–1937; (d) Evano, G.; Nitelet, A.; Thilmany, P.;
Dewez, D. F. Metal-Mediated Halogen Exchange in Aryl and Vinyl
Halides: A Review. Front. Chem. 2018, 6, article 114 and references
therein.
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(32) (a) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. Aryl Mesylates
in Metal-Catalyzed Homocoupling and Cross-Coupling Reactions. 1.
Functional Symmetrical Biaryls from Phenols via Nickel-Catalyzed
Homocoupling of Their Mesylates. J. Org. Chem. 1995, 60, 176–185;
(b) Hashim, J.; Glasnov, T. N.; Kremsner, J. M.; Kappe, C. O.
Symmetrical Bisquinolones via Metal-Catalyzed Cross-Coupling and
Homocoupling Reactions. J. Org. Chem. 2006, 71, 1707–1710.
(33) (a) Everson, D. A.; Jones, B. A.; Weix, D. J. Replacing
Conventional Carbon Nucleophiles with Electrophiles: Nickel-
Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides. J.
Am. Chem. Soc. 2012, 134, 6146–6159; (b) Colon, I.; Kelsey, D. R.
Coupling of aryl chlorides by nickel and reducing metals. J. Org.
Chem. 1986, 51, 2627–2637; (c) Cassar, L.; Foà, M. Nickel-catalyzed
carbonylation of aromatic halides at atmospheric pressure of carbon
monoxide. J. Organomet. Chem. 1973, 51, 381–393.
(29) It is known that malononitriles can undergo reductive
decyanation in the presence of strong reductants to generate metal
cyanide salts. We believe this mechanism does not have a significant
role in this system based on the following evidence: (1) the
transnitrilation data in Scheme 2a shows that MPMN acts as a
transnitrilating reagent without external reductant; (2) under standard
reaction conditions, excess MPMN is recovered at the end of the
reaction (see Supporting Information, Table S1 for data); (3) exposure
of MPMN to NiBr2(bpy)•xH2O and Zn without ArBr under
catalytically relevant conditions for 16 h yields <5% decomposition of
MPMN, which cannot account for observed product yields if MPMN
is simply generating metal cyanide salts in situ (see Supporting
Information, Equation S1 for details); (4) cyanide salts were not
detected (<20 mg/L) in the reaction mixture (see Section C.3 of the
supporting information for details). For reviews on reductive
decyanation, see: (a) Mattalia, J.-M.; Marchi-Delapierre, C.;
Hazimeh, H.; Chanon, M. The reductive decyanation reaction :
chemical methods and synthetic applications. Arkivok 2006, iv, 90–
118; (b) Mattalia, J.-M. R. The reductive decyanation reaction: an
overview and recent developments. Belstein J. Org. Chem. 2017, 13,
267–284.
(30) It is also possible that 8 can undergo transmetallation with ZnBr2
and that β-carbon elimination occurs at Zn. However, we favour β-
carbon elimination at Ni since this is an intramolecular process, and is
facile and possible (see Scheme 2a, no additive).
(31) (a) Cramer, R.; Coulson, D. R. Nickel-catalyzed displacement
reactions of aryl halides. J. Org. Chem. 1975, 40, 2267–2273; (b)
Takagi, K.; Hayama, N.; Okamoto, T. Synthesis of Aryl Iodides from
Aryl Halides and Potassium Iodide by Means of a Nickel Catalyst.
Chem. Lett. 1978, 7, 191–192; (c) Tsou, T. T.; Kochi, J. K. Nickel
catalysis in halogen exchange with aryl and vinylic halides. J. Org.
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(34) Hofstra, J. L.; Poremba, K. E.; Shimozono, A. M.; Reisman, S.
E. Ni-Catalyzed Conversion of Enol Triflates to Alkenyl Halides.
Angew. Chem. Int. Ed. 2019, 58, 14901–14905.
(35) (a) Zembayashi, M.; Tamao, K.; Yoshida, J.; Kumada, M. Facile
preparation of new unsymmetrical curcumin derivatives by solid-
phase synthesis strategy. Tetrahedron Lett. 1977, 47, 4089–4092; (b)
Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Homocoupling
of Aryl Halides Using Nickel(II) Complex and Zinc in the Presence of
Et4NI. An Efficient Method for the Synthesis of Biaryls and
Bipyridines. Bull. Chem. Soc. Jpn. 1990, 63, 80–87; (c) Ni, S.; Padial,
N. M.; Kingston, C.; Vantourout, J. C.; Schmitt, D. C.; Edwards, J. T.;
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Yang, S.; Perry, M. A.; Gallego, G. M.; Mousseau, J. J.; Collins, M.
R.; Cherney, R. J.; Lebed, P. S.; Chen, J. S.; Qin, T.; Baran, P. S. A
Radical Approach to Anionic Chemistry: Synthesis of Ketones,
Alcohols, and Amines. J. Am. Chem. Soc. 2019, 141, 6726–673.
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