Cooperative Palladium/Lewis Acid-Catalyzed Transfer Hydrocyanation of Alkenes and Alkynes Using 1-Methylcyclohexa-2,5-diene-1-carbonitrile

Article abstract of DOI:10.1021/jacs.8b10651

Catalytic transfer hydrocyanation represents a clean and safe alternative to hydrocyanation processes using toxic HCN gas. Such reactions provide access to pharmaceutically important nitrile derivatives starting with alkenes and alkynes. Herein, an efficient and practical cooperative palladium/Lewis acid-catalyzed transfer hydrocyanation of alkenes and alkynes is presented using 1-methylcyclohexa-2,5-diene-1-carbonitrile as a benign and readily available HCN source. A large set of nitrile derivatives (>50 examples) are prepared from both aliphatic and aromatic alkenes with good to excellent anti-Markovnikov selectivity. A range of aliphatic alkenes engage in selective hydrocyanation to provide the corresponding nitriles. The introduced method is useful for chain walking hydrocyanation of internal alkenes to afford terminal nitriles in good regioselectivities. This protocol is also applicable to late-stage modification of bioactive molecules.

Full text of DOI:10.1021/jacs.8b10651

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Article
Cooperative palladium/Lewis acid-catalyzed transfer hydro-cyanation of
alkenes and alkynes using 1-methylcyclohexa-2,5-diene-1-carbonitrile
Anup Bhunia, Klaus Bergander, and Armido Studer
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 Nov 2018
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Journal of the American Chemical Society
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Cooperative palladium/Lewis acid-catalyzed transfer
hydrocyanation of alkenes and alkynes using 1-
methylcyclohexa-2,5-diene-1-carbonitrile
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Anup Bhunia,a Klaus Bergandera and Armido Studer*a
aOrganisch-Chemisches Institut, Westfalische Wilhelms-Universität, Corrensstraβe 40, 48149 Münster, Germany
Supporting Information Placeholder
ABSTRACT: The catalytic transfer hydrocyanation represents a clean and safe alternative to hydrocyanation processes using
the toxic HCN gas. Such reactions provide access to pharmaceutically important nitrile derivatives starting with alkenes
and alkynes. Herein, an efficient and practical cooperative palladium/Lewis acid catalyzed transfer hydrocyanation of
alkenes and alkynes is presented using 1-methylcyclohexa-2,5-diene-1-carbonitrile as a benign and readily available HCN
source. A large set of nitrile derivatives (> 50 examples) are prepared from both aliphatic and aromatic alkenes with good
to excellent anti-Markovnikov selectivity. A range of aliphatic alkenes engage in selective hydrocyanation to provide the
corresponding nitriles. The introduced method is useful for chain walking hydrocyanation of internal alkenes to afford
terminal nitriles in good regioselectivities. This protocol is also applicable to late stage modification of bioactive molecules.
has introduced silylated CHD reagents, which have been
successfully used in radical transfer hydrosilylations
(Scheme 1b).6b-c Notably, these reagents have also found
application in tin-free radical dehalogenations,
deselanations and deoxygenations.6a The same conceptual
approach has later been successfully applied to the radical
transfer hydroamidation using aminated CHDs as
reagents.7 These cascades proceed via cyclohexadienyl
radical intermediates A and B.
INTRODUCTION
The development of practically applicable catalytic
transfer processes that enable in situ transfer of an atom or
a functional group from one molecule to another, which is
also relevant in biological systems, is of great importance
in organic synthesis.1 Transfer hydrogenation using 1,4-
cyclohexadiene (CHD) or alcohols as H2-equivalents has
been used widely for reduction of -systems.2 Along with
the “simple” H2-transfer, the conceptual approach is also
applicable to the transfer of functional moieties. In such
processes, two distinct compounds undergo facile
Scheme 1. 1-Susbtituted cyclohexa-2,5-dienes as
reagents for functional group transfer reactions
defunctionalization/functionalization
through
a
a. Cardellini, Walton & co-workers
R
CO2R1
R
CO2R1
transmitting functional group.3 The successful realization
of the transfer functionalization strategy relies on several
key factors: i) the nature of the interchanging functional
group; ii) the stability of the residual part of the donor,
which provides the thermal driving force; iii) the nature of
the acceptor compound, and the thermodynamic as well as
kinetic stability of the resulting product. Importantly,
transfer or shuttle catalysis helps avoiding the use of
gaseous/hazardous and/or unstable starting materials. In
this context, the cyclohexadiene core structure has proved
to be a highly efficient platform for the design of donors in
such functional group transfer processes.
R
radical initiator
-CO2
H
+
R1
+
A
CN
CN
intermediate
H
H
driving force
aromatization
pro-aromatic
b. Studer & co-workers
R
R
FG
R FG
R2
R2
FG
R1
radical initiator
FG = SiR3, NR2
R3
R3
H
R1
+
+
R4
R4
B
intermediate
H
H
c. Oestreich & co-workers
R
FG
R
R
FG
R2
R2
FG
R1
R3
R3
H
cat. Lewis acid
+
R1
+
+
C
R4
R4
Compounds comprising the CHD core (Scheme 1) act as
intermediate
FG = SiR3, GeR3, H
H
H
pro-aromatic
compounds
and
upon
transfer
d. Present work, transfer hydrocyanation
defunctionalization they gain 33-36 kcal/mol arene
resonance stabilization energy, that is harvested to drive
the targeted transfer reaction.4 In 1995, Walton, Cardellini
and co-workers demonstrated the radical alkene hydro-
alkylation using cyclohexa-2,5-diene-1-carboxylates as
reagents with di-tert-butylperoxide as a radical initiator
(Scheme 1a).5 Building on this seminal study our laboratory
HCN free nitrile synthesis
anti-Markonikov selectivity
broad scope
late stage hydrocyanation
chain walking
R2
R
CN
R2
cat. Pd(0)
cat. Lewis acid
CN
R1
R3
H
R3
R1
+
R4
R4
H
H
cooperative palladium/Lewis acid catalysis
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More recently, a significant advance has been achieved by
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15% yield, documenting the advantage of the CHD-system
over isovaleronitrile in these Pd-catalyzed transfer
hydrocyanations. We found that CHD 2a can also be used
in combination with Ni-catalysis, albeit with lower
efficiency as compared t0 the Pd-mediated process (34%
yield, for the detailed optimization study, see SI). Note that
activation of nitriles by LA cocatalysis was previously
demonstrated by Tolman, Jones, Nakao and Hiyama.14
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Oestreich and co-workers, who developed Lewis acid
(electron-deficient triarylboranes) catalyzed ionic transfer
hydrosilylation,8a
hydrogermylation8b
and
hydrogenation8c-d of alkenes using CHD reagents (Scheme
1c). These LA-catalyzed processes proceed through the
Wheland intermediate C.
In a continuation of our program, we sought to further
explore and expand the synthetic utility of CHD-based
functional group transfer chemistry. While taking the
advantage of pro-aromaticity, we envisaged that 1-
methylcyclohexa-2,5-diene-1-carbonitrile (2a), that is
readily prepared in large scale by reductive Birch
methylation of benzonitrile with NH3, Li, and
iodomethane (see the Supporting Information, SI), can act
as an easily stored, non-toxic HCN donor in transfer
hydrocyanation reactions (Scheme 1d). Notably,
hydrocyanation of alkenes with zero-valent palladium and
nickel complexes are highly attractive from both an
industrial and academic perspective.9 However, these
reactions currently suffer limitations such as the necessity
of using poisonous HCN gas. Considering the generally
high reaction temperatures required, volatile reagents like
acetone cyanohydrin and (Me)3SiCN applied are also not
ideal.10 Moreover, reported methods give mostly the
branched alkyl nitriles and the selective synthesis of the
linear congeners remains challenging.11 Along these lines,
Morandi and co-workers recently developed an elegant Ni-
catalyzed transfer hydrocyanation of terminal alkenes
using alkylnitriles as a HCN donors.12 These Ni-catalyzed
transfer hydrocyanations are reversible and the product
nitriles can be reverted back to the starting alkenes. This
problem was successfully addressed by using
isovaleronitrile as the donor leading to the gaseous
isobutylene as the side product, which is readily removed
from the reaction mixture to drive the equilibrium.
8
9
Scheme 2. Palladium/Lewis acid cocatalyzed transfer
hydrocyanation of 1a
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Pd(PPh3)4 (4 mol%)
DPEPhos (8 mol%)
BPh3 (20 mol%)
CN
CN
+
+
Ph
(1.0 equiv)
1a
dioxane, 110 °C
20 h
Ph
(1.5 equiv)
2a
3a 89%
CN
Et CN
i-Pr CN
CN
CN
2f (15%)
2b (53%)
2d (22%)
2e (0%)
2c (39%)
To study the scope and limitations of the new
hydrocyanation method, various alkenes were reacted with
the reagent 2a under the optimized conditions. As shown
in table 1, the transfer hydrocyanation can be extended to
a range of other -substituted styrenes, giving the
corresponding linear nitriles in 59-92% yield (3a-3i).
Various substituents at the phenyl ring and at the -
position were tolerated. Less activated 2-substituted
aliphatic alkenes such as (2-methylallyl)benzene and 2-(2-
methylallyl)naphthalene gave 3j and 3k in reasonable
yields. In all these cases, the reaction proceeded with high
regioselectivity (linear:branched
≥
20:1). Styrene
derivatives bearing an iodo or a bromo-substituent at the
aryl moiety did not work. Transfer hydrocyanation of
styrenes lacking the -substituent gave the desired
products in high yields with good linear to branched
selectivity (3l-3t). The high regioselectivity toward
formation of the linear nitriles with aryl alkenes as
substrates is worth noting.15 In general, branched nitriles
are favored for most reported hydrocyanation processes.
Vinyl silane and 9-vinyl-9H-carbazole also afforded the
cyanated products 3u and 3v in high yields. However,
heteroaryl-alkenes such as 2-vinyl pyridine or 4-vinyl
pyridine did not engage in this sequence.
RESULTS AND DISCUSSION
To explore the possibility of HCN transfer from 1-
methylcyclohexa-2,5-diene-1-carbonitrile 2a to -methyl
styrene (1a), radical and ionic processes were tested first.
Disappointingly, we found that both the radical approach
and also Lewis acid (LA) catalysis failed to deliver the
targeted transfer hydrocyanation product 3a. However,
switching to transition metal catalysis, we realized that
cooperative Pd/LA catalysis allows forming the desired
nitrile product along with toluene as the by-product. The
best result was achieved by using Pd(PPh3)4 (4 mol
%)/DPEphos (8 mol%) in combination with BPh3 (20
mol%) as a co-catalyst in dioxane at 110 °C for 20 h to
deliver the targeted 3a in 89% yield (Scheme 2). DPEphos
has a bite angle of around 105° and other commonly used
bisphosphine ligands like dppe, dppp, binap all having
smaller bite angles resulted in lower conversions.13 BPh3
can be replaced by B(C6F5)3 but LA-cocatalysis with BF3,
AlMe2Cl, AlMe3 and AlCl3 gave worse results. Other
sterically and electronically diverse CHDs 2b-2e led to
inferior results. Notably, replacing the CHD 2a with
isovaleronitrile (2f) as the HCN donor afforded 3a in only
The hydrocyanation was also effective for terminal
aliphatic alkenes lacking any -substituent. The
corresponding linear nitriles were isolated in good to
excellent yields (3w-3ag). Notably, the hydrocyanation of
1-hexene and 1-octene afforded the terminal nitriles 3w and
3x with complete regioselectivities in high yields.16 These
results were particularly remarkable taking into
consideration the low selectivity profiles found in related
hydrocyanation processes using existing methodology,
specifically employing Ni-catalysis. The significantly
improved l/b ratios as compared to those obtained for the
complementary Ni-catalyzed transfer hydrocyanations
using isovaleronitrile12 is an important point considering
the higher cost of the CHD-type reagent 2a. The presence
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of various functional groups did not suppress the reaction
and non-conjugated dienes participated in the transfer
hydrocyanation (3ah).
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2
3
4
Table 1. Transfer hydrocyanation of various alkenes and alkynesa
5
6
-Substituted alkenes
A 
7
8
9
CN
Cl
CN
CN
CN
CN
CN
CN
CN
Me
Ph
Me
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3a 89% (87%)b
3b 80%
3c 86%
3d 92%
B. Styrenesd
3e 81%
3f 87%
3g 78%
3h 59%
CN
CN
CN
CN
CN
CN
CN
F3C
O
3i 74%c
3j 86%
3k 90%
3l 90% (90:10)
3m 84%
3n 87% (91:9)
3o 94% (90:10)
Me
C. Activated alkenes
CN
CN
CN
CN
CN
CN
N
Si
CN
Me
Me
Me
Me
F5
OMe
3p 82% (89:11)
3r 75%
3t 95% (90:10)
3u 96%
3s 85% (92:8)
3q 90%
3v 83%
D. Aliphatic alkenesd
CN
Me
CN
CN
CN
CN
CN
CO2Et
3w 99%e
3x 80%e
3y 78% (85:15)
3z 88% (94:6)
3aa 81% (90:10)
3ab 84% (90:10)
CN
O
O
O
EtO2C
EtO2C
O
Me
S
O
O
N
CN
N
O
O
O
CN
CN
3af 77% (90:10)
CN
CN
O
CN
3ac 85% (90:10)
3ae 90% (90:10)
3ag 86% (90:10)
3ad 93% (92:8)
3ah 68%
E. Chain walking hydrocyanation of internal alkenesf
Ph
Ph
CO2Me
Ph
Ph
Ph
CN
Ph
3al 67% (84:16)
CN
CN
CN
NC
CN
Ph
CN
CN
3aj 73% (78:22)
3ak 77% (82:18)
3am 70% (80:20)
3an 68% (85:15)
3ao 79% (90:10)
3ai 75% (86:14)
F. Diastereoselective hydrocyanationd
CN
CN
MeO
Me
tBu
CN
H
H
CN
H
H
+
H
H
O
CN
H
H
OMe
CN
MeO
tBu
CN
Ph
H
3ap 63% dr 20:1
3aq 91% rr 2:1 dr 20:1 3ar 84% dr 20:1
3at 78% 3:1
3au 73% dr 5:1
dr
3av 66% dr 1:1
3as 90% dr 20:1
G. Alkynes
S
H
CN
H
H
CN
Ph
H
H
O
CN
TMS
TMS
TMS
CN
CN
TMS
5b 33%
5c 62%g
5d 72%
3aw 75% dr 1:1
5a 87% (96:4)
aStandard conditions: Pd(PPh3)4 (4 mol %), DPEphos (8 mol%) and BPh3 (20 mol%), dioxane (3.0 mL), 110 °C, 20 h, Isolated yield
on a 0.5 mmol scale. bReaction performed in 2.0 mmol scale. cReaction performed in 1.0 mmol scale. dIn parenthesis ratio of linear
to branched product and reaction performed with B(C6F5)3 (15 mol%) instead of BPh3. eGC yield reported fReaction performed with
B(C6F5)3 (15 mol%) instead of BPh3 and Xantphos in place of DPEphos for 40 h. 15% of the other regioisomer isolated. The
highlighted red -bond indicates the former double bond in the substrate alkene.
g
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Interestingly, internal alkenes afforded mainly the
Page 4 of 8
both branched and linear nitriles are active HCN donors.21
Moreover, in this experiment unreacted nitrile 3x (8 C
atoms) was not converted to its branched isomer 3x’ and
accordingly branched 3ax (9 C atoms) not to its
corresponding linear nitrile 3ax’. A similar result was also
noted with nitriles 3l and 3l’, where both nitriles were
consumed in equal amounts (Scheme 3, eq 2). However, as
compared to the reaction with the couple 3ax/3ax’, a
higher conversion was achieved in the latter case. To
address the reversibility of the hydrocyanation, we reacted
in two separate experiments 3ax and 3ax’ under optimized
conditions in the absence of 1-nonene. Interestingly, in
both cases the starting nitriles could be recovered without
formation of the other regioisomer (Scheme 3, eqs 3 and 4).
1
2
3
4
5
6
7
8
terminal nitriles with good selectivities over all other
possible branched nitriles under slightly modified
conditions (3ai-3ao). Using 5-decene as a starting material,
we observed that under the standard conditions the anti-
Markovnikov product 1-cyanodecane was obtained with
46:54 (l:b) regioselectivity and the branched nitriles were
formed as a mixture of the 4 possible isomers (see SI).17 We
found that with Xantphos as the ligand, the linear to
branched ratio could be further increased to 86:14 (see the
SI). Increased selectivity clearly indicate that Xantphos
supports the β-hydride elimination/migratory insertion
sequence (metal walking) thereby changing the position of
the metal without dissociation of the alkene (chain
walking). The sequence is initiated by the reversible hydro-
palladation of the internal alkene and is driven by the
formation of a thermodynamically more stable terminal
carbo-palladium intermediate and/or by faster reductive
elimination of the primary alkyl-Pd-intermediate over its
secondary congeners18 (see also mechanistic discussion
below).
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Scheme 3. Mechanistic studies
CN
3x (56%)
CN
3ax (59%)
(0.125 mmol) 3x
norbornene
+
(1)
+
CN
optimized
conditions
CN
CN
We next addressed diastereoselective transfer
hydrocyanations. Reaction with the strained norbornene
worked well to provide the cyanated product 3ap with
good yield and very high exo-selectivity. Using cyclic
alkene 1q, we found highly diastereoselective equatorial
cyanide incorporation with 2:1 regioselectivity (3aq).19
Hydrocyanation also proceeded smoothly on (4-
methylenecyclohexyl)benzene to furnish 3ar in 80% yield
with very good diastereoselectivity (20:1). A high selectivity
(20:1) was also noted for the steroid derivative 3as. Late
stage functionalization of more complex alkenes derived
from O-Me-(-)-isopulegol, estrone and dihydrocarvone
gave the corresponding nitriles 3at-3av in moderate
diastereoselectivity. Chemoselective hydrocyanation of
(S)-(+)-carvone afforded 3aw and the enone functionality
remained unreacted.
(0.125 mmol) 3ax
3x' (0%)
3ax' (0%)
CN
(0.125 mmol) 3l
CN
norbornene
3l (8%)
3l' (8%)
(2)
+
+
optimized
conditions
CN
(0.125 mmol) 3l'
optimized
conditions
CN
(3)
+
CN
CN
A: no 1-nonene
B: 1 equiv of
1-nonene
3ax' (0%, A)
3ax' (10%, B)
3ax
3ax (99%, A)
3ax (90%, B)
optimized
conditions
CN
CN
Pleasingly, reaction with aliphatic and aromatic internal
alkynes worked to provide alkenyl nitriles 5a-5d in
moderate to good yields and high regioselectivities.
Whereas the symmetrical non-aromatic alkynes delivered
the expected cis-hydrocyanation products 5a and 5b, the
aromatic congeners provided the trans-product (see 5c and
5d). We assume that in the latter two cases, the initial cis-
product isomerizes under the reaction conditions to the
thermodynamically more stable trans-isomers.12a Notably,
Ni-catalyzed transfer hydracyanation of aryl-TMS-alkynes
(4)
+
CN
A: no 1-nonene
B: 1 equiv of
1-nonene
3ax' (99%, A)
3ax' (99%, B)
3ax'
3ax (0%, A)
3ax (<1%, B)
CD3
D3C CN
optimized
conditions
CN
Ph
(5)
+
+
Ph
Ph
1ab
3ab 76% (0% D)
2a-d3
detected
by GCMS
H3C CN
optimized
conditions
CN
R
R
R
products,12a
further
D-alkenes
detected
by GCMS
provided
the
regioisomeric
Ph
+
(6)
+
documenting the complementary of the herein introduced
method over existing methodology. Unfortunately,
terminal alkynes did not work under the tested conditions.
R
D
H
D
1ab
3ab-D 71% (20% D)
3ab-D 69% (20% D)
R = H, 2a-d1 (dr = 1:1)
R = D, 2a-d5 (dr = 1:1)
To shed light on the mechanism of this transfer
hydrocyanation, additional experiments were conducted
(see Scheme 3). We reacted an equimolecular mixture of
the linear and branched nitriles 3x and 3ax with
norbornene as the limiting substrate in the absence of
reagent 2a under optimized conditions. The branched 3ax
(41%) and linear nitrile 3x (44%) were consumed in almost
equal amounts (Scheme 3, eq 1).20 This result shows that
However, if the experiment with 3ax was repeated in the
presence of 1 equiv of 1-nonene, 10% of the isomeric linear
nitrile 3ax’ was formed. On the other hand, starting with
linear 3ax’, only traces of the branched congener were
formed, even in the presence of 1-nonene. These results
show that the branched nitrile can be transferred to a small
extend to the linear nitrile under the applied conditions, if
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free alkene is present in the reaction mixture. This
substituents still afforded the product 3a, albeit in lower
yields. Oxidative addition to generate A’ will be largely
affected by the bulkier i-Pr and Et-groups and in particular
with the i-Pr group direct oxidative addition to A’ is not
likely. Therefore, we currently favor the pathway via direct
formation of complex A. Complex B then further reacts via
β-hydride elimination to C. Ligand exchange followed by
PdH migratory alkene insertion generates intermediate E,
which finally undergoes reductive elimination to give the
nitrile 3, thereby regenerating the Pd(0) complex. The
driving force of the reaction is the generation of toluene as
the by-product. We assume that the LA remains
complexed to the cyanide during reductive elimination,
since Moloy and Nolan have found that reductive
elimination from RPdCN complexes can be accelerated by
a Lewis acid.25
1
important finding was further supported by a second set of
experiments: reaction of 2-methylbenzylnitrile (3l’) with
the Pd-catalyst under standard conditions (1,4-dioxane, 110
°C, 20 h) did not lead to any isomerization. However,
repeating that experiment in the presence of 1 equiv
styrene provided the linear nitrile 3l in 31% yield along with
69% of the branched isomer 3l’ (see SI).To get insight into
the mechanism of activation of reagent 2a, we ran the
hydrocyanation of 1ab with the deuterium labelled reagent
2a-d3. Nitrile 3ab was isolated in 76% yield without any
deuterium incorporation and GCMS analysis showed the
mass of toluene-d3 (Scheme 3, eq 5). Moreover, the
reagents 2a-d1 and 2a-d5 afforded the nitrile 3ab-D with
20% D incorporation at the β-position in 71% and 69%
yield, respectively (Scheme 3, eq 6). These results show
that the H-atom that gets transferred to the alkene/alkyne
is derived from the methylene group and not from the -
CH3-group in 2a.
2
3
4
5
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The only 20% deuterium labeling of product 3ab-D can
be understood considering that 2a-d1 and 2a-d5 were
prepared as a 1:1 cis/trans diastereoisomeric mixture each.
Hence, the methylene groups are only 50% deuterated and
considering diastereotopic intermediates B, a maximum of
50% deuteration can be achieved in the -hydride
elimination. In the experiments we only found 20%
deuterium incorporation in 3ab, indicating that reductive
elimination in E is slower than -hydride elimination
regenerating complex D. In the -hydride elimination, the
primary kinetic isotope effect will lead to preferable
generation of the corresponding hydrido-Pd-complex D
along with deuterated alkene. In fact, we could identify
deuterated unreacted alkenes (different isomers, see SI).
This explains the low deuteration degree of product 3ab.
Scheme 4. Proposed Mechanism
N
R
Pd(0)
+
LA
LA
H
N
2
3
N
reductive
elimination
-complexation
Pd(0)
R
LA
Pd(ll)
N
LA
oxidative
addition
H
N
LA
E
N
Pd(ll)
Pd(II)
migratory
insertion
The suggested reversibility (D to E to 3) of the
hydrocyanation is supported by experiments depicted in
Scheme 3 (eqs 1 and 2). The remaining issue to be discussed
is the l/b-regioselectivity observed in these reactions.
Regiochemistry is not under thermodynamic control, since
calculations revealed that the branched isopropylnitrile,
considered as a model compound, is even more stable than
the linear n-propylnitrile.21 We therefore assume that the
regiodetermining factor is the hydropalladation step that
occurs with good to high selectivity towards formation of
the terminal alkylPdCN complex E steered by the ligand.
Since the cross over experiments with norbornene show no
significant difference in retro-hydrocyanation for the
linear and branched nitriles,18 the retro-hydrocyanation
step itself, considering microscopic reversibility, should
not change the isomer ratio. Considering that for both the
linear and the branched alkylPd-complex, -hydride
elimination competes with reductive elimination and that
reductive elimination is reversible, the observed l/b-
product ratio can be higher than the kinetic
regioselectivity of the initial hydropalladation step.
Moreover, the hydrocyanation products obtained after
reductive elimination undergo isomerization of the
branched to the linear regioisomer only to a small extent
under the applied conditions, as documented for 3ax (see
Scheme 3, eq 3). Hence, l/b product selectivity can only be
improved slightly upon extending reaction time. Indeed,
this was experimentally documented for hydrocyanation of
R
A'
A
Pd(ll)
N
LA
H
D
ligand
exchange
hydride
Pd(ll)
elimination
B
N
R
LA
Pd(ll)
N
LA
C
H
Based on these studies, we propose the following
mechanism (Scheme 4).22 C−CN bond activation by the LA
and Pd(0) complexation leads to the corresponding -
complex that can further react via two potential pathways.
Oxidative addition generates the carbopalladium(ll)
intermediate A’, which undergoes 1,3-palladium
migration23 via the corresponding π-allyl complex A to
form B. Alternatively, the -complex directly reacts to form
the π-allyl complex A. The coordination of LA with the N
atom of the nitrile group accelerates oxidative addition in
both scenarios.24 The deuterium labelling experiment (see
Scheme 3, eq 5) showed that the H-atom that gets
transferred is not derived from the -CH3-group. This
result indicates that formation of complex A’ is less likely,
since partial -hydride elimination would be expected.
Moreover, reagents 2b and 2c with bulkier ipso-
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2010, 110, 681−703. (c) Guillena, G.; Ramón, D. J.; Yus, M.
alkene 1l, where l/b-selectivity was improved from 9:1 (20
h) to 10:1 (40 h), albeit at the expense of a slightly lower
yield (see SI).
Hydrogen Autotransfer in the N-Alkylation of Amines and
Related Compounds using Alcohols and Amines as Electrophiles.
Chem. Rev. 2010, 110, 1611− 1641. (d) Corma, A.; Navas, J.; Sabater,
M. J. Advances in One-Pot Synthesis through Borrowing
Hydrogen Catalysis. Chem. Rev. 2018, 118, 1410-1459.
1
2
3
4
CONCLUSIONS
5
6
7
8
In summary, we have developed a Pd/LA-cocatalyzed
operationally simple and effective method for highly
regioselective transfer hydrocyanation of alkenes and
alkynes. Various linear nitriles are obtained without using
hazardous and toxic HCN gas. It was found that the ligand
plays an important role in the chain walking
hydrocyanation of internal alkenes. In selected cases, high
diastereoselectivities were obtained. As compared to
known elegant Ni-catalyzed transfer hydrocyanations,12
the Pd-catalyzed processes reported herein deliver
significantly higher linear to branched regioselectivities in
the reaction with terminal alkenes. Whereas the Ni-based
transformations work efficiently with very cheap
isovaleronitrile as the HCN donor,12 the Pd-mediated
processes provide high yields only upon using the
cyclohexadiene-type transfer hydrocyanation reagent 2a.
Pd- as compared to Ni-catalysts are less toxic and it is
important to highlight that reagent 2a can readily be
prepared at low cost in large scale by reductive Birch
methylation using cheap benzonitrile, lithium and methyl
iodide.
(3) (a) Murphy, S. K.; Park, J.-W.; Cruz, F. A., Dong, V. M. Rh-
catalyzed C–C bond cleavage by transfer hydroformylation.
Science 2015, 347, 56−60. (b) Bhawal, B. N.; Morandi, B. Catalytic
Transfer Functionalization through Shuttle Catalysis. ACS. Catal.
2016, 6, 7528-7535. (c) Bhawal, B. N.; Morandi, B. Shuttle
Catalysis-New Strategies in Organic Synthesis. Chem. Eur. J. 2017,
23, 12004-12013. (d) Bhawal, B. N.; Morandi, B. Isodesmic
Reactions in Catalysis – Only the Beginning? Isr. J. Chem. 2018, 58,
94-103.
(4) (a) Walton, J. C.; Studer, A. Evolution of Functional
Cyclohexadiene-Based Synthetic Reagents:ꢀ The Importance of
Becoming Aromatic. Acc. Chem. Res. 2005, 38, 794-802. (b)
Oestreich, M. Transfer Hydrosilylation. Angew. Chem. Int. Ed.
2016, 55, 494-499. (c) Keess, S.; Oestreich, M. Cyclohexa-1,4-
dienes in transition-metal-free ionic transfer processes. Chem. Sci.
2017, 8, 4688-4695.
(5) (a) Binmore, G.; Walton, J. C.; Cardellini, L. L. Radical-chain
decomposition of cyclohexa-1,4-diene-3-carboxylates and 2,5-
dihydrofuran-2-carboxylates. J. Chem. Soc., Chem. Commun. 1995,
27-28. (b) Baguley, P. A.; Walton, J. C. Reductive free-radical
alkylations and cyclisations mediated by 1-alkylcyclohexa-2,5-
diene-1-carboxylic acids. J. Chem. Soc., Perkin Trans 1 1998, 2073-
2082.
(6) (a) Studer, A.; Amrein, S. Silylated Cyclohexadienes: New
Alternatives to Tributyltin Hydride in Free Radical Chemistry.
Angew. Chem. Int. Ed. 2000, 39, 3080-3082. (b) Amrein, S.;
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ASSOCIATED CONTENT
Supporting Information
Timmermann,
A.;
Studer,
A.
Radical
Transfer
Hydrosilylation/Cyclization Using Silylated Cyclohexadienes.
Org. Lett. 2001, 3, 2357-2360. (c) Amrein, S.; Studer, A.
Intramolecular radical hydrosilylation - the first radical 5-endo-
dig cyclisation. Chem. Commun. 2002, 1592-1593.
(7) (a) Kemper, J.; Studer, A. Stable Reagents for the Generation
of N-Centered Radicals: Hydroamination of Norbornene. Angew.
Chem. Int. Ed. 2005, 44, 4914-4917. (b) Guin, J.; Mück-Lichtenfeld,
C.; Grimme, S.; Studer, A. Radical Transfer Hydroamination with
Aminated Cyclohexadienes Using Polarity Reversal Catalysis:ꢀ
Scope and Limitations. J. Am. Chem. Soc. 2007, 129, 4498-4503.
See also: Guin, J.; Fröhlich, R.; Studer, A. Thiol-Catalyzed
Stereoselective Transfer Hydroamination of Olefins with
N-Aminated Dihydropyridines. Angew. Chem. Int. Ed. 2008, 47,
779-782.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental details and characterization data for the
products.
AUTHOR INFORMATION
Corresponding Author
*E-mail: studer@uni-muenster.de.
Notes
The authors declare no competing financial interest.
(8)
(a)
Simonneau,
A.;
Oestreich,
M.
3-Silylated
ACKNOWLEDGMENT
Cyclohexa-1,4-dienes as Precursors for Gaseous Hydrosilanes: The
B(C6F5)3-Catalyzed Transfer Hydrosilylation of Alkenes. Angew.
Chem. Int. Ed. 2013, 52, 11905-11907. (b) Keess, S.; Oestreich, M.
Access to Fully Alkylated Germanes by B(C6F5)3-Catalyzed
Transfer Hydrogermylation of Alkenes. Org. Lett. 2017, 19, 1898-
1901. (c) Chatterjee, I.; Qu, Z.-W.; Grimme, S.; Oestreich, M.
B(C6F5)3-Catalyzed Transfer of Dihydrogen from One
Unsaturated Hydrocarbon to Another. Angew. Chem. Int. Ed.
2015, 54, 12158-12162. (d) Chatterjee, I.; Oestreich, M.
B(C6F5)3-Catalyzed Transfer Hydrogenation of Imines and Related
This work has been supported by the Alexander von
Humboldt Foundation (postdoctoral fellowship to A.B.). We
thank Dr. Christian Mück-Lichtenfeld (Westfälische
Wilhelms-University
calculations.
Münster)
for
conducting
the
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TOC-grafic
CN
R2
R2
CN
R1
R3
H
R3
R1
n
R4
R4
H
H
Pd(0) (cat)
Lewis acid (cat)
R
R
CN
n
53 examples, up to 96% yield
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