Ex situ generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: Evidence for a transmetallation step between two oxidative addition Pd-complexes

Article abstract of DOI:10.1039/c7sc03912c

A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of ex situ generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts. Cyanation was achieved employing the Pd(0) precatalyst, P(tBu)₃-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable for the synthesis of ¹³C-labelled benzonitriles with ex situ generated ¹³C-hydrogen cyanide. Stoichiometric studies with the metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)₃)₂ with H¹³CN in THF provided two Pd-hydride complexes, (P(tBu)₃)₂Pd(H)(¹³CN), and [(P(tBu)₃)Pd(H)]₂Pd(¹³CN)₄, both of which were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was performed in a THF : water mixture in the presence of KOAc, only (P(tBu)₃)₂Pd(H)(¹³CN) was formed. Subjection of this cyano hydride metal complex with the oxidative addition complex (P(tBu)₃)Pd(Ph)(Br) in a 1 : 1 ratio in THF led to a transmetallation step with the formation of (P(tBu)₃)₂Pd(H)(Br) and ¹³C-benzonitrile from a reductive elimination step. These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(ii)-species from the oxidative addition of L_nPd(0) into HCN and an aryl bromide followed by a transmetallation step to L_nPd(Ar)(CN) and L_nPd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and L_nPd(0).

Full text of DOI:10.1039/c7sc03912c

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Ex situ generation of stoichiometric HCN and its application in the
Pd-catalysed cyanation of aryl bromides: Evidence for a
transmetallation step between two oxidative addition Pd-
complexes
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Steffan K. Kristensen,a Espen Eikeland,b Esben Taarning,c Anders T. Lindhardt*,d and Troels
Skrydstrup*,a
www.rsc.org/
A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is
reported for the first time. A two-chamber reactor was adopted for the safe liberation of ex situ generated HCN in a closed
environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this
setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding
benzonitriles in high yields, without the need for cyanide salts. Cyanation was achived employing the Pd(0) precatalyst,
P(tBu)3-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable
for the synthesis of 13C-labelled benzonitriles with ex situ generated 13C-hydrogen cyanide. Stoichiometric studies with the
metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)3)2
with H13CN in THF provided two Pd-hydride complexes, (P(tBu)3)2Pd(H)(13CN), and [(P(tBu)3)Pd(H)]2Pd(13CN)4, both of which
were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was
performed in a THF:water mixture in the presence of KOAc, only (P(tBu)3)2Pd(H)(13CN) was formed. Subjection of this
cyano hydride metal complex with the oxidative addition complex (P(tBu)3)Pd(Ph)(Br) in a 1:1 ratio in THF led to a
transmetallation step with the formation of (P(tBu)3)2Pd(H)(Br) and 13C-benzonitrile from a reductive elimination step.
These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(II)-species from the
oxidative addition of LnPd(0) into HCN and an aryl bromide followed by a transmetallation step to LnPd(Ar)(CN) and
LnPd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and LnPd(0).
for the instalment of a cyanide group onto an aromatic ring
include the Rosenmund-von Braun or Sandmeyer reactions
applying stoichiometric CuCN with aryl halides or diazonium
salts.3 Yet, in the last decade, transition metal catalysed
Introduction
Benzonitriles are a valuable class of compounds with a broad
range of applications serving as important substructures in
many agrochemicals, pharmaceuticals, dyes, polymers and
other organic materials.1 The nitrile group is also a precursor
to a variety of important functionalities such as aldehydes,
ketones, carboxamides and carboxylates.2 Conventional means
cyanations of aromatic halides with metal complexes based on
copper,4 nickel5 and palladium6,7 has held a key position. In
particular, the protocols based on Pd-catalysis through the
extensive work by Beller,7 Grushin8 and Buchwald9 are
characterised by relatively mild reaction conditions and good
functional group tolerance. A variety of different cyanide
sources have been applied including salts or derivatives such
as NaCN,8,10 KCN,6a,c,d,11 (Me)3SiCN,12 acetone cyanohydrin,13
K4Fe(CN)6,9a,14 Zn(CN)2,9b,15 CuCN,16 etc. (Scheme 1). However,
many of these sources also have their disadvantages. For
example, metal contaminants can become an issue with the
use of potassium ferrocyanide, whereas with the cyanohydrin
of acetone, this chemical must be stored carefully and is
approx. 20 times more costly than potassium cyanide.§
Furthermore, considering the fact that all of these cyanide
precursors originate from hydrogen cyanide (HCN), which is
produced on a million-ton scale size via the Andrussow17 and
BMA-Degussa processes18 from natural gas and ammonia or as
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a byproduct in acrylonitrile production,18,19 there could be an by specific water/organic solvents mixtures or by use of
interest in the development of a cyanation process of aryl cyanide complexes with low solubilities.8,9b,13,14 Grushin and
halides exploiting this original source of cyanide, namely co-workers have published impressive and detailed studies on
gaseous HCN.20
the mechanism of cyanide induced catalyst deactivation in the
Pd-catalysed cyanation of aromatic halides. In their work, they
report that addition of an excess of 13C-labelled potassium
cyanide (K13CN) to different intermediates of the catalytic cycle
in the Pd-catalysed cyanation of iodobenzene led to
coordinatively saturated and catalytically inactive palladium
Established methods: Pd-catalysed cyanation of aryl halides with
different cyanide sources
Pd cat.
Ar CN
Ar–X
Cyanide source
2–
2– 25
complexes such as [Pd(CN)4] , [HPd(CN)3] [ArPd(CN)3] .
2– or
X = Cl, Br, I
More interestingly, the same group revealed that traces of
water in the reaction mixture combined with K13CN forms
H13CN that immediately undergoes oxidative addition with
Pd(0) leading to the same coordinatively saturated and off-
cycle palladium complexes with concurrent formation of
hydrogen gas.26
Cyanide source: NaCN, KCN, (Me)3SiCN, acetone cyanohydrin,
CuCN, K4Fe(CN)6, Zn(CN)2
This work: Pd-catalysed cyanation of aryl bromides
with gaseous HCN
Industrial source
of cyanide
Weak base
Pd cat., KOAc, HCN
In this paper, we report on the direct use of industrially
important hydrogen cyanide in the palladium-catalysed
cyanation of (hetero)aromatic bromides (Scheme 1). These
results deviate from conventional wisdom, since Grushin’s
earlier work demonstrated the propensity of palladium(0) to
undergo fast oxidative addition into the H–CN bond shutting
down the catalytic cycle. And yet, our results demonstrate that
conditions can be identified whereby the presence of HCN
does not terminate the cyanation reaction, but enhances the
reactivity vis-à-vis cyanide salts. Secondly and most important,
we describe a simple and safe setup whereby HCN is delivered
in stoichiometric amounts by ex situ generation in a two-
chamber reactor, thereby providing a simple and safe setting
for handling gaseous HCN in small-scale reactions. We
demonstrate the usefulness of this setup not only for the Pd-
catalysed cyanation of aryl bromides, but also for the Ni-
mediated hydrocyanation of styrenes as a test reaction. With
respect to the cyanation reactions good functional group
tolerance was obtained, and the method proved amenable to
scale-up, but also to carbon-13 isotope labelling applying
H13CN. Surprisingly, the developed conditions proved to be
dependent on water as the co-solvent and the presence of a
weak base, KOAc. In their absence, catalytic shutdown was
observed, thereby indicating the operation of an alternative
mechanism to Pd-catalysed cyanations applying cyanide salts.
Studies and isolation of the oxidative addition complexes
suggest a mechanism involving the transmetallation between
two palladium(II) species, both formed by the oxidative
addition of palladium(0) into either HCN or the aryl bromide
electrophile.
Ar–Br
Ar CN
H2O:Dioxane
Aqueous
conditions
Successful approach
High yields
Broad substrate scope
Safe generation of HCN
Scheme
1 Previous developments in Pd-catalysed cyanation
protocols and our new approach applying gaseous HCN.
Only three reports are found in the literature applying HCN
directly or by its in situ formation. In 2015, Buchwald and
Hooker reported a 11C-cyanation study for the synthesis of
aromatic cyanides with applications for positron emission
tomography (PET).21 Here, submicromolar amounts of gaseous
H11CN dissolved in THF were introduced to a 1000-fold excess
of preformed oxidative addition palladium(II) complex,
affording the desired 11C-benzonitriles nearly instantaneously.
A follow-up paper by the same two groups demonstrated the
possibilities of this approach for the 11C-labelling of
unprotected peptides.22 Alternatively, Beller and co-workers
reported the in situ release of HCN from acetone cyanohydrin
although this was carried out in the presence of sodium
carbonate, which undoubtedly leads to the direct formation of
the reactive cyanide anion species.13
Nevertheless, there is a reluctance to apply HCN (b.p. 27
ᵒ
C) as a cyanation reagent in an academic setting or an R&D
laboratory, which is undoubtedly linked to the high toxicity
and explosive nature of this gaseous one-carbon reagent,
thereby
complicating
its
handling,
storage
and
transportation.23 Another challenge in the use of hydrogen
cyanide as a cyanation reagent is how to control its dosage in
stoichiometric amounts as Pd-catalysed cyanations of aryl
halides are particularly sensitive to the cyanide concentrations.
The strong binding of cyanide anion to transition metals can
lead to catalyst deactivation if present in elevated
concentrations.7,24 With other cyanide reagents, this
complication is normally addressed by their slow addition to
the reaction mixture, slow mass transport of the cyanide anion
Results and discussion
Hydrogen cyanide releasing studies. In order to provide a
system for the controlled dosage of hydrogen cyanide in
stoichiometric quantities, we envisioned that the two-chamber
system previously utilised for the ex situ liberation of carbon
monoxide,27 hydrogen28 and ethylene29 from specific
nongaseous precursors could be exploited. Such an approach
would provide a simple and safe setup without the direct
2 | J. Name., 2012, 00, 1-3
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Scheme 2 Ni-Catalysed hydrocyanation of styrenes employing a
two-chamber system with ex situ generated HCN.a
weak base such as KOAc, and a solvent mixture of water and
dioxane could generate 4-methoxybenzonitrile (8) with a
conversion of 78% according to the 1H NMR analysis of the
crude reaction mixture (Table 1, entry 1). P(tBu)3 as a ligand
proved to be superior to other monodentate and bidentate
ligands (entries 2–6; see Supporting Information section for
full optimisation studies), which is in accord with earlier results
reported by Grushin and co-workers.8,26 In general, weak bases
such as KOAc and NaOAc provided better conversions to the
desired 4-methoxybenzonitrile, whereas stronger bases
including Cy2NMe, DBU and Et3N all proved inferior (entries
7−9). Increasing to three equivalents of KOAc provided a slight
increase in the conversion to 82% (entry 10). The efficiency of
the reaction could also be increased further exploiting the
Buchwald pre-catalyst, P(tBu)3-Pd-G3, providing a 90% isolated
HCN Consuming Chamber
Ni(COD)2 (5.0 mol%)
HCN Producing Chamber
KCN (1.5 equiv).
XantPhos (7.5 mol%)
CPME (2 mL), 60 oC, 18 h
AcOH (9.0 equiv).
Ethylene glycol, 60 o
C
CN
R
R
1–7
CN
CN
CN
CN
O
O
yield of benzonitrile
8 after column chromatography (entry
1 92%
2 90%
3 93%
CN
4 95%
11). Control experiments with omission of either base or
palladium precursors resulted in low or no conversion, resp.
Different water:solvent combinations were tested and
dioxane proved to be the solvent of choice (entries 12 and 13,
see also Supporting Information). Notably, the presence of
CN
CN
O
HO
F
O
O
5 95%
6 91%
7 92%
a Chamber A: Styrene (1 mmol), Ni(COD)2 (5.0 mol%), XantPhos (7.5 mol%) and
CME (2 mL). Chamber B: KCN (1.5 mmol), Ethylene glycol (1 mL), AcOH (9.0
mmol). Isolated yields are given as an average of 2 runs.
Table 1 Optimisation of the Pd-catalysed cyanation of aryl bromides
using gaseous HCN.a
HCN (1.5 equiv)
Pd(dba)2 (2.5 mol%)
P(tBu)3 (5.0 mol%)
KOAc (2.0 equiv)
Br
CN
handling of HCN gas. Hence, our focus was first directed to
identifying a suitable system for the generation of HCN gas
under a closed environment, and the well-established nickel-
catalysed hydrocyanation of olefins was exploited as a test
system for the optimisation.30–32 After considerable
experimentation on the hydrocyanation of styrene (see
Supporting Information), we finally adopted the following
conditions as illustrated in Scheme 2. A combination of KCN,
ethylene glycol and AcOH provided the desired release of
gaseous HCN. Ethylene glycol serves a dual purpose acting
both as solvent while simultaneously ensuring separation of
the AcOH from KCN until stirring is initiated. By utilising this
setup for the HCN producing chamber in combination with the
Ni-catalysed hydrocyanation conditions in the second chamber
(Ni(COD)2, XantPhos), a range of different styrenes bearing
both electron donating and withdrawing groups could
H2O:Dioxane (1:1, 2 mL)
60 oC, 16 h
O
O
8
Deviation from lead
conditions
Entry
Conversionb (%)
1
2
None
78
0
Ligand: PCy3
3
Ligand: XPhos
Ligand: tBu-XPhos
Ligand: DPPF
60
74
0
4
5
6
Ligand: XantPhos (2.5 mol%)
Base: Cy2NMe
0
7
38
5
8
Base: DBU
successfully be hydrocyanated to products
1–7 in near
9
Base: Et3N
67
82
quantitative yields. Full conversion of all styrene derivatives
was attained applying only 1.5 equivalents of KCN for the
production of HCN, indicating the effectiveness of this gas
generator.
10
Base: KOAc (3.0 equiv)
Pd/Ligand: P(tBu)3-Pd-G3
KOAc (3.0 equiv)
11
12
13
90 (90)c
Pd/Ligand: P(tBu)3-Pd-G3
Solvent: THF
77
Studies on the cyanation of (hetero)aryl bromides. With a
simple and convenient system for the release of gaseous HCN
in hand, we next turned our attention towards the Pd-
catalysed cyanation of (hetero)aryl bromides. As depicted in
the scheme of Table 1, initial optimisation results were carried
out with 4-bromoanisole. This study revealed that reaction
conditions consisting of a catalyst formed from Pd(dba)2 with
P(tBu)3, in the presence of hydrogen cyanide (1.5 equiv), a
Pd/Ligand: P(tBu)3-Pd-G3
Solvent: Toluene
61
a
Chamber A: 4-Bromoanisole (1.0 mmol), Pd(dba)2 (2.5 mol%), P(tBu)3 (5.0
mol%), KOAc (2.0 mmol) in dioxane (1 mL) and H2O (1 mL). Chamber B: KCN (1.5
mmol), ethylene glycol (1 mL) and AcOH (9.0 mmol). Determined by 1H NMR
b
using mesitylene as an internal standard. P(tBu)3-Pd-G3
Buchwald precatalyst with the tri-tert-butylphosphine ligand. c Isolated yield.
= third generation
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water as the co-solvent is of key importance as similar Scheme 3 Pd-Catalysed cyanation of aryl bromides.a
experiments applying only dioxane as the solvent resulted in
HCN Consuming Chamber
P(tBu)3-Pd-G3 (2.5 mol%)
complete catalytic shutdown. In our scope studies, we later
discovered that a 2:1 mixture of water and dioxane provided
KOAc (3.0 equiv)
H2O:Dioxane (2:1, 3 mL), 60 oC, 16 h
Br
CN
higher yields for certain substrates, and hence this ratio was
used for all subsequent cyanations. Not surprisingly and in
accord with Grushin’s previous results, carrying out the Pd-
catalysed cyanation in a single chamber reactor applying KCN
directly with or without the addition of acetic acid under the
Ar
Ar
R
R
HCN Producing Chamber
KCN or K13CN (1.5 equiv), AcOH (9.0 equiv)
8–28
Ethylene glycol (1 mL), rt
CN
CN
CN
CN
CN
conditions developed led to no formation of
shown).
8 (result not
O
HO
tBu
Ph
With the optimised reaction conditions in hand, we set out
to explore the scope of the Pd-catalysed cyanation using
gaseous HCN. All yields are reported as an average of two runs
and the results are depicted in Scheme 3. Aryl bromides
carrying electron donating substituents were initially
examined. Methoxy-, hydroxy-, alkyl- and aryl-substituted aryl
bromides provided the desired compounds in high yields
8 90%
9 93%
10 92%
11 97%
10-13C 92%
11-13C 99%
CN
HO
CN
CN
EtO
NC
O
O
O
15 86%b,c
12 98%
13 92%
14 99%
12-13C 92%
ranging from 90% to 97% (compounds
withdrawing substituents such as cyano, acyl and carboxylate
afforded compounds 12 13 and 14 in yields attaining
8−11). Electron
CN
CN
CN
CN
H2N
,
O
quantitative. Even p-bromobenzoic acid underwent successful
coupling affording p-cyanobenzoic acid (15) in an 86% yield,
using 4 equiv of KOAc combined with 5 mol% of Buchwald’s
precatalyst. The use of phenol and benzoic acid derivatives in
the Pd-catalysed cyanation with NaCN were previously shown
by Ushkov and Grushin to lead to catalyst deactivation due to
the formation of HCN.8 p-Bromobenzaldehyde also proved
reactive with the isolation of 16 in a somewhat lower yield.
This slight reduction in isolated yield can possibly be explained
by competing benzoin condensation of both starting material
and product. The substitution pattern of bromoanilines
interfered significantly with the developed conditions and
installment of the cyano-functionality onto 2-, 3-, and 4-
bromoaniline was achieved in yields of 95%, 77% and 47%
17 o: 95%
18 m: 77%
19 p: 47%
16 86%
20 92%
21 96 %b
O
CN
CN
NC
O
O
OH
Cl
NC
23 88%d
24 84%b
22 95%
25 93%
CN
H
CN
NC
N
O
N
O
28 75%b
N
26 98%
27 95%
28-13C - 79%b
a Chamber A: Aryl bromide (1.0 mmol), P(tBu)3-Pd-G3 (2.5 mol %) and KOAc (3.0
mmol) in dioxane (1 mL) and H2O (2 mL). Chamber B: KCN (1.5 mmol) or K13CN
(1.5 mmol) ethylene glycol (1 mL) and AcOH (9 mmol). Isolated yields are given as
an average of 2 runs. b 5.0 mol% catalyst used. c 4.0 equiv. of KOAc used. dHCN
consuming chamber only heated to 45 ᵒC.
respectively (compounds 17
ortho-substitutions were also effective for these substitution
reactions as illustrated with compounds 17 and 20 22, all
−19). Aryl bromides displaying
−
isolated in yields between 92% and 96%. However, 2-bromo-
1,3-dimethylbenzene did require an increase of the catalyst
loading to achieve the high 96% isolated yield of 21. Lowering
the reaction temperature of the HCN consuming chamber,
applying the developed protocol, were non-rewarding with no
conversion observed for this electrophile.
Next, attention was directed to implementing this
developed protocol for 13C-labelling. By simply substituting
KCN with its 13C-labelled counterpart under otherwise
unchanged conditions, direct access to isotopically labeled
benzonitrile derivatives were achieved. Four entries from
Scheme 3 were selected for labelling, and all compounds were
isolated in near identical yields to the unlabeled compounds
from 60 °C to 45 °C, ensured a chemoselective activation of
the aromatic bromide in the presence of the p-chloride
affording 23 in an 88% isolated yield. Subsequently, an aryl
bromide possessing
a
benzylic alcohol, and five
heteroaromatic bromides were tested under the developed
conditions. All underwent successful cyanation to afford the
desired target molecules in yields ranging from 75% to 95%
(compounds 10-13C 11-13C 12-13C and 28-13C).
, ,
(compounds 22, 24–28). It should be mentioned though that
Finally, the developed protocol was tested for the synthesis
of three active pharmaceutical ingredients, namely dapivirine
(reverse transcriptase inhibitor), citalopram (serotonin
reuptake inhibitor) and letrozole (non-steroidal aromatase
inhibitor), the results of which are depicted in Scheme 4.33
despite the successful coupling of these handful of heteroaryl
bromides, two other heterocycles tested such as
2-acetyl-5-bromothiophene and 3-bromobenzothiophene
failed to provide the corresponding nitrile product. The
reasons for this catalytic shutdown are not completely
understood (see discussion in next section). Finally, attempts
to perform catalytic cyanation on 4-phenylphenyl triflate,
Dapivirine
(29) and citalopram (30) were obtained in
satisfactory 96% and 86% isolated yields, respectively, from
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Scheme
4 Synthesis of pharmaceuticals by Pd-catalysed indication why certain heteroaryl bromides were successful
cyanation and scale up studies.a
coupling partners with HCN, whereas others were not. With
the exception of the protocol developed by Buchwald and
HCN (1.5 equiv)
P(tBu)3-Pd-G3
(5.0 mol%)
Oxidative addition
LnPd0
Ar CN
HN
N
HN
N
Ar
X
KOAc (3.0 equiv)
CN
Br
N
H2O:Dioxane
(1:1, 4 mL)
60 oC, 16 h
N
Reductive
Elimination
N
N
H
H
29a
Dapivirine (29) - 96%
Ar
Ar
X
LnPdII
LnPdII
CN
NC
Br
O
O
Same conditions
as above
N
N
Nucleophilic
Displacement
X
CN
F
F
Scheme 5 Accepted mechanism for the cyanation of aryl halides
with cyanide salts.
30a
Citalopram (30) - 86%
HCN (3.0 equiv)
P(tBu)3-Pd-G3
(5.0 mol%)
Hooker, in which H11CN is used to form PET tracers, no reports
are found on palladium-catalysed cyanation of aryl halides
using gaseous HCN as the reactant.21 Although it should be
noted under the conditions used for 11C-isotope-labelling, the
Pd(II)-aryl complex is in an approx. 1,000-fold excess compared
to the H11CN generated. With this in mind it was decided to
take a closer look at the possible mechanism for the developed
protocol.
N
N
N
N
N
N
KOAc (4.0 equiv)
H2O:Dioxane (2:1)
60 oC, 16 h
Br
Br
NC
CN
31a
Letrozole (31)
1 mmol - 97%
5 mmol - 95%
10 mmol - 85%
a For reactions on 1.0 mmol scale, yields are an average of two runs.
the corresponding bromide precursors applying 5.0 mol% of
the Buchwald precatalyst. For the synthesis of letrozole (31) a
double cyanation is required with the dibromide 31a. Doubling
the loading of KCN for HCN release to 3 equivalents combined
with an increase in KOAc to 4 equivalents, gratifyingly afforded
the dicyanide 31 in an excellent 97% isolated yield again with 5
mol% precatalyst. The synthesis of letrozole was then
attempted on a fivefold scale combined with a 100 mL two-
chamber reactor to afford a near identical isolated yield of
95%. Finally, scaling up to 10 mmol in a 200 mL two-chamber
reactor, with an HCN release from 30 mmol of KCN,
corresponding to more than 700 mL of gaseous HCN, afforded
the desired pharmaceutical in a good 85% isolated yield.
Figure 1 1H NMR (JH-C = 53.0 Hz, JH–P = 4.7 Hz) and 31P NMR (JP–C
11.7 Hz) of compound 32 in THF-d8.
=
Mechanistic investigations. Having established the scope of
the Pd-catalysed cyanation of (hetero)aryl bromides with
hydrogen cyanide, some questions still remained. Given a pKa
difference in water for acetic acid (4.76) and HCN (9.21) of
almost 4.5 units, indicates that HCN is potentially the reactive
species in solution and not the free cyanide anion. However,
previous reports by Grushin and co-workers clearly
demonstrated that the presence of free HCN formed from the
protonation of KCN with trace amounts of water, quickly leads
to shutdown of the catalytic activity.8,26 Still this deactivation is
a combined result of Pd(0) undergoing oxidative addition into
the H–CN bond followed by trapping of this species with
excess cyanide anion to generate off-cycle palladium(II)
cyanide complexes. Furthermore, there was not a clear
The overall accepted mechanism for the Pd-catalysed
cyanation using sodium or potassium cyanide is believed to go
through an initial oxidative addition of the Pd(0) complex into
the aryl halide, nucleophilic displacement by cyanide on the
formed palladium(II) centre, and lastly a reductive elimination
furnishing the desired benzonitrile (Scheme 5).6h,7,8,26 When
metal complexes such as Zn(CN)2 are utilised, a change in
mechanism occurs, whereby nucleophilic substitution is
replaced with a transmetallation step.9b,34
During the optimisation of the catalytic system, different
bases were tested (Table 1, entries 7–10). A clear trend can be
abstracted from this base screening, where an increase in base
strength leads to a decrease in conversion. This can be
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equivalent phosphine ligands.§§§ The 31P NMR analysis of 32
reveals a doublet at 93.1 ppm arising from P–C coupling with
the 13C-labelled cyanide. Due to disturbance in the crystal
structure, the hydride could not be located. However, in view
of the combined data obtained from the NMR and the X-ray
crystal structural analysis, we are confident that the structure
of 32 is as indicated in Figure 2.
P1
N1
C1
Pd1
H1
P2
N1
C1
P1
Pd1
Figure 2 ORTEP representation of complex 32.
Pd2
C2
H1
N2
explained by the higher degree of deprotonation of HCN with
strong bases leading to catalytic shutdown. The effect is
highest for the strong base DBU affording a mere 5%
P2
conversion to product 8. The optimum conditions found in this
work applies KOAc as base, suggesting that HCN is the reactive
species and not cyanide itself.
Initially, the oxidative addition of Pd(P(t
Bu)3)2 to H13CN in
Figure 4 ORTEP representation of complex 33.
THF as the solvent was investigated using the two-chamber
reactor (See Supporting Information for reaction details).§§
To our surprise, the X-ray crystal structure analysis of the
This afforded two palladium-hydride species in roughly a 6:1 palladium-hydride complex 33 revealed it to be a tri-metallic
1
ratio, as observed by H NMR analysis of the reaction mixture, species as illustrated in the ORTEP representation of Figure 4.
1
with the hydride signals residing at –11.42 and –16.82 ppm In the H NMR spectrum a hydride signal is located at –16.79
(Figures 1 and 3).35 Careful manipulation of the reaction ppm as a multiplet (Figure 3), whereas for the 31P NMR
mixture allowed for the isolation and crystallisation of both spectrum, a singlet at 84.7 ppm can be found. A closer look at
hydride species 32 and 33, the structures of which were this Pd3-complex, shows its resemblance to K2[Pd(13CN)4],
confirmed by X-ray crystal structural analysis (Figures 2 and 4). which can also be produced from the reaction of Pd(0) with
H13CN in turn formed from the hydrolysis of K13CN with
Table 2 Mechanistic evaluation of the reaction between H13CN and
a
Pd(P(tBu)3)2
13CN
Pd
(tBu)3P
P(tBu)3
H
H13CN
32
13CN
Pd(P(tBu)3)2
Solvent (2 mL)
rt, 3 h
P(tBu)3
H Pd N13
P(tBu)3
P(tBu)3
Pd 13CN Pd
C
H
13CN
33
P(tBu)3
H13CN
(equiv)
KOAc
(equiv)
Entry Solvent
Ratio 32:33b
Figure 3 1H NMR and 31P NMR of compound 33 in CDCl3.
1
2
3
4
5
6
THF
1.0
3.0
1.0
1.0
3.0
3.0
ꢀ
ꢀ
85:15 (100%)
84:16 (100%)
86:14 (100%)
>95:5 (29%)
>95:5 (92%)
>95:5 (97%)
Compound 32 was identified as the oxidative addition
t
complex with H13CN, (P( Bu)3)2Pd(H)(13CN). While others have
THF
THF:H2O
THF:H2O
THF:H2O
THF:H2O
ꢀ
reported the corresponding HBr and HCl adducts,36,37 it is to
the best of our knowledge the first time compound 32 has
been isolated. The hydride signal is located at –11.42 ppm as a
2.0
2.0
6.0
1
double triplet in the H NMR spectrum (Figure 1), whereby the
multiplicity originates from a large trans-coupling with the 13-
carbon of the cyanide, and small cis-coupling with the two
a Reactions performed on a 0.1 mmol scale. Reactions stopped after 3 h. b Values
in brackets are given as conversions.
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water.26 In structure 33, the anionic core, [Pd(13CN)4]2–, carries end, we examined the reaction between 4-bromobiphenyl and
two cationic counter ions in the form of [(P( 32 in THF-d8 at room temperature with mesitylene as an
Bu)3)Pd(H)]+.
t
To investigate the importance of the reaction conditions internal standard (Scheme 7). The reaction progress was
and influence on the formation of 32 and 33, a series of followed by both 1H- and 31P NMR. From the 1H NMR spectrum
experiments were performed the results of which are shown in it was clear that as the reaction progressed a build-up of the
Table 2. As can be seen from entries 1–3, neither the amount palladium-hydride species 35 in addition to the formation of
of H13CN nor the presence of water appears to influence the the aromatic nitrile 11-13C was observed. The reaction turned
distribution between 32 and 33. However, the addition of out to be relatively slow at 25 ᵒC despite a 1:1 relationship
KOAc and water resulted in the exclusive formation of the Pd- between complex 32 and 4-bromobiphenyl. Nevertheless,
hydride complex 32 (entry 4).§§§§ Increasing the H13CN loading after 12 h, the conversion into 11-13C had reached 55%.
from 1.0 to 3.0 equiv provided a 92% conversion to 32. Full
conversion to 32 was obtained with 3 equiv of H13CN in
combination with 6 equiv. of KOAc (entry 6). Finally, direct
formation of 33 from 32 can also be achieved by heating 32 in
THF at 60 ᵒC, and after 3 h, a 3:1 ratio between 32 and 33 is
achieved. This result could be explained by the slow
transmetallation between two Pd-hydride species 32 leading
to
the
formation
of
(P(
t
Bu)3)2Pd(H)2
and
(P(
t
Bu)3)2Pd(13CN)2.35,38 Whereas, the former can reductively
eliminate generating Pd(0) and dihydrogen, we speculate that
(P(
Bu)3)2Pd(13CN)2 could abstract cyanide from two Pd-
hydride complexes 32 ultimately leading to the formation of
t
the Pd3-complex 33
.
Figure 5 1H NMR (JH–P = 7.2 Hz) and 31P NMR (J = 1.9 Hz) of
compound 35 in THF-d8.
H13CN (3.0 equiv)
13CN
Pd
Ph3P
N13
Pd(PPh3)4
(0.1 mmol)
PPh3
C
THF (2 mL), rt, 3 h
34
Scheme 6 Reaction between Pd(PPh3)4 and H13CN.a
a
Reaction performed on a 0.1 mmol scale with a two-chamber system. The reaction
was stopped after 3 h.
To further probe the necessity of the bulky and electron
P1
rich P(tBu)3 ligand, Pd(PPh3)4 was dissolved in THF and treated
Br1
with H13CN (Scheme 6). This resulted in the sole formation of
(PPh3)2Pd(13CN)2 (34), the structure of which was confirmed by
both NMR and X-ray analysis (see Supporting Information).§§§§§
Possibly, the transmetallation event involving two
(PPh3)2Pd(H)(13CN) species is significantly faster than that for
Pd1
H1
complex 32, and therefore cyanide abstraction from
(PPh3)2Pd(H)(13CN) with complex 34 cannot compete as with
similar palladium species bearing the P(tBu)3 ligand.
13CN
4-bromobiphenyl
(1.0 equiv)
Figure 6. ORTEP representation of complex 35.
13CN
Br
(tBu)3P
(tBu)3P
Pd
Pd
+
P(tBu)3
P(tBu)3
H
H
To verify that the structure of the new Pd-hydride species
formed indeed is as proposed for compound 35, a sample of
this complex was prepared according to a known literature
THF-d8, rt
Ph
11-13
C
32
35
Scheme 7 Reactivity studies between complex 32 with 4-bromo-
procedure involving the treatment of Pd(P(tBu)3)2 with
pyridinium bromide in toluene.39 As can be seen in Figure 5,
1
complex 35 produced a triplet at –15.63 ppm in the H NMR
biphenyl.a
a 0.02 mmol of both 32 and 4-bromobiphenyl were added to a NMR-tube. Mesitylene
spectrum arising from the coupling to the two equivalent
phosphorus atoms. In the 31P NMR spectrum, 35 gives rise to a
doublet located at 83.5 ppm. These spectroscopic data were in
accord with those observed from the reaction of 32 with 4-
was used as an internal standard.
Next, we addressed the question whether complex 32
represents an active participant in the catalytic cycle. To this
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bromobiphenyl. Finally, by dissolving 35 in a small amount of reformed through two reductive elimination events involving
CH2Cl2 layered with heptane resulted in crystals that were both LnPd(Ar)(CN) and LnPd(H)(Br). In the latter case, base is
suitable for X-ray analysis (Figure 6).
The formation of aryl nitrile 11-13C is only possible if presence of aqueous KOAc should be sufficient for promoting
complex 32 can reductively eliminate generating Pd(P( Bu)3)2 this reduction step at the metal centre. Whereas stronger
required to initiate the regeneration of LnPd(0), and the
t
and H13CN, thereby implying that the addition of HCN to Pd(0) bases would be able to carry out this step as well, they would
is a reversible process.40 The Pd(0) species produced from this also lead to the deprotonation of HCN resulting in increased
reductive elimination step can then either undergo an concentrations of cyanide anion in solution. Subsequently, this
oxidative addition to H13CN again or alternatively to the aryl cyanide would trap the active species in the catalytic cycle as
bromide generating (P(t
Bu)3)Pd(Ar)(Br).41 With the presence in multi-cyano palladium complexes and as such lead to catalytic
solution of both this complex and 32, a transmetallation event shutdown.
could take place between these two species leading to the
formation of the Pd-hydride 35 and (P(t
Bu)3)Pd(Ar)(13CN),
a)
13CN
Pd
13CN
which subsequently undergoes reductive elimination to the
desired benzonitrile 11-13C and Pd(0).§§§§§§
(tBu)3P
Br
(tBu)3P
Pd
P(tBu)3
H
P(tBu)3
H
32
35
37 53%
P(tBu)3
H Pd N13C Pd 13CN Pd H
Br
Ar–Br + HCN
(tBu)3P Pd
THF-d8, rt
13CN
P(tBu)3
LnPd
Ar CN
(1.0 equiv)
13CN
P(tBu)3
P(tBu)3
Oxidative addition
36
33 11%
H
Ar
Br
PdII
Ln
LnPdII
b)
Base
13CN
P(tBu)3
P(tBu)3
CN
Reductive
Elimination
13
CN
H Pd N13C Pd 13CN Pd H
13CN
P(tBu)3
P(tBu)3
H
LnPdII
33
Transmetallation
37 61%
Br
Ar
Br
CDCl3, rt
(tBu)3P Pd
Br
(tBu)3P
PdII
Ln
Pd
CN
P(tBu)3
H
(1.0 equiv)
35
36
Scheme 8 A proposed mechanism for the Pd-catalysed cyanation of
aryl bromides with HCN.
c)
The progress of the reaction between 32 and
-bromobiphenyl was monitored by 31P NMR spectroscopy,
Br
p
K2Pd(CN)4
CN
(tBu)3P Pd
Br
(tBu)3P
Pd
the results of which are shown in Figure 7. Within the first 10
minutes Pd(P( Bu)3)2 (85.5 ppm) and free P( Bu)3 (63.4 ppm)
were formed, which is consistent with the observations by Fu
and coworkers when a P(
Bu)3/Pd(0) ration of 2:1 is used.42
P(tBu)3
H
THF-d8, D2O
rt
(1.0 equiv)
t
t
35
36
t
Scheme 9 Transmetallation studies with complexes 36 in THF-d8.
The depletion of complex 32 then occurred with concurrent
build-up of the Pd-hydride 35 residing at 83.5 ppm. No signal
a
0.02 mmol of either 32, 33 or K2[Pd(CN)4] with 36 were added to a NMR-tube.
from the oxidative addition complex (P(
t
Bu)3)Pd(Ar)(Br) was
Bu)3)
Mesitylene was used as an internal standard.
observed, suggesting that the oxidative addition of Pd(P(
t
to 4-bromobiphenyl is the rate-determining step in this setup.
From these initial experiments, a possible mechanistic
scenario for the Pd-catalysed cyanation of aryl bromides with
gaseous HCN is depicted in Scheme 8, which accounts for the
above observations. After formation of the catalytically active
palladium(0) species, two reversible oxidative addition events
take place forming LnPd(H)(CN) and LnPd(Ar)(Br). The necessity
for the oxidative addition steps to be reversible at least for the
latter complex may explain why aryl triflates are not
competent electrophiles for this catalytic protocol. The two
complexes can then undergo transmetallation providing
LnPd(Ar)(CN) and LnPd(H)(Br). Similar transmetallative events
have previously been reported for two Pd(II)-aryl species.43
Finally, the benzonitrile and the active LnPd(0) species are
The mechanism depicted in Scheme 8 also supports the
findings made by Buchwald and Hooker.21,22 In their setup,
H11CN is introduced to a large excess of the oxidative addition
complex of the same type as 36. Only a small portion of this
Ar-Pd(II) complex would have to undergo reductive elimination
to afford a Pd(0) species that could trap the added H11CN
leading to product formation.
In order to investigate the viability of such
a
transmetallation step between two Pd(II) species of the
proposed catalytic cycle in Scheme 8, we investigated the
reaction between Pd-hydride 32 and the preformed oxidative
addition complex 36 (Scheme 9a). The aryl-Pd complex 36 was
prepared in a 79% isolated yield via the oxidative addition of
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Figure 7 31P NMR spectra of the reaction between complex 32 and p-bromobiphenyl.
Pd(P(
procedure.44 Complexes 32 and 36 were dissolved in THF-d8, hydride 35
and using mesitylene as the internal standard, their
tBu)3)2 to bromobenzene according to a literature seen from the absence of signals for benzonitrile and Pd-
.
Next, we examined whether the different Pd-cyanide
transformation was followed by 31P NMR spectroscopy. From species are catalytically competent species and can promote
this experiment, three species were formed as the reaction the catalytic conversion of aryl bromides to aryl nitriles with
progressed, being 13C-benzonitrile (37), (P(
t
Bu)3)2Pd(H)(Br) (35
)
HCN. By using 32 as the palladium source we could isolate
and the Pd3-complex 33. The transformation was completed in biphenyl nitrile 11-13C in quantitative yield (Scheme 10). On
less than 30 min, and applying the internal standard, 37 was the other hand, with 33 as the palladium source no conversion
formed in a 53% yield while most of the remaining 13C-labelled to product was observed. This is in perfect accordance with
cyanide could be accounted for from the formation of 33 (11% the observations shown in Table 2, demonstrating that the
yield).
presence of aqueous KOAc prevents formation of Pd3-complex
Given the undoubtedly strong binding mode of cyanide to 33 and that K2[Pd(CN)4], which is most likely produced from 33
palladium(II), the possibility of free cyanide in solution is most under these conditions, is inactive as
likely absent, thereby eliminating the possibility for the precursor.§§§§§§§
a
catalyst
formation of 35 through a nucleophilic displacement pathway.
This in turn indicates that 35 forms as a result of
transmetallation step between 36 and one or both of heteroaryl bromides provided low or even no conversion to
complexes 32 and 33 product. One of these inactive bromides,
Finally, while the substrate scope of the Pd-catalysed
a
cyanation of aryl bromides using HCN proved broad, some
.
As mentioned above, the Pd3-complex 33 is presumably 2-acetyl-5-bromothiophenyl bromide, was added to the
not formed under the optimised conditions. Nevertheless, we cyanation reaction of 4-bromophenol, which under our
investigated whether 33 could also promote benzonitrile standard condition with HCN and in the absence of the
formation alone. The trinuclear complex 33 was mixed with 36 heteroaryl bromide provided the corresponding 4-
in a 1:1 relationship in CDCl3, and followed by 1H NMR cyanophenol in high yield as depicted in Scheme 3.45,§§§§§§§§
spectroscopy. Surprisingly, complete formation of 13C- However, under the exact same conditions but with the
benzonitrile (37) and Pd-hydride 35 was achieved after only 2 addition of this inactive heteroaryl bromide, the formation of
h
(Scheme 9b). To evaluate the importance of the
t
Bu)3)2Pd(H)]+ cation in 33, the direct reaction between
13CN
Pd
[(P(
(tBu)3P
K2[Pd(CN)4] and 36 was tested (Scheme 9c). However,
following the reaction by 1H NMR spectroscopy, no conversion
was observed between these two palladium complexes as
P(tBu)3
H
HCN (1.5 equiv)
KOAc (3.0 equiv)
32
(2.5 mol%)
CN
Br
H2O:Dioxane (2:1, 3 mL)
60 oC, 16 h
Ph
Ph
11 99%
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Scheme 10 Pd-Catalysed cyanation of aryl bromides using 32
instead of P(tBu3)-Pd-G3.
shutdown, but instead provided a robust and reproducible
method.
A broad range of aryl bromides and a few
heteroaromatic bromides afforded the desired benzonitrile
derivatives and given the simple setup, utilising ex situ
generation of HCN, labelling with H13CN was also
straightforward. The presence of water as co-solvent and the
use of the mild base KOAc proved imperative for catalytic
efficiency. In particular, the suitability of this weak base
indicated that possibly the mechanism in operation deviates
from previous catalytic cyanation studies as the concentration
of free cyanide would be virtually non-existent. This led to the
proposal of a mechanism based on a transmetallation between
two Pd-complexes produced from the oxidative addition of
Pd(0) into hydrogen cyanide and an aryl bromide. This
proposal was based on mechanistic indications that co-aligns
with observations reported by Grushin, Beller and others.
Further work is now on-going to examine a similar protocol
under nickel catalysis, as well as examining other electrophiles
than aryl halides. The results of this work will be reported in
due course.
aChamber A: 4-Bromobiphenyl (1.0 mmol), 33 (2.5 mol%) and KOAc (3.0 mmol) in
dioxane (1.0 mL) and H2O (2.0 mL). Chamber B: KCN (1.5 mmol), ethylene glycol (1.0
mL) and AcOH (9 .0mmol)
HCN (1.5 equiv)
P(tBu)3-Pd-G3 (2.5 mol%)
KOAc (3.0 equiv)
2-Acetyl-5-bromothiophene (1.0 equiv)
Br
CN
H2O:Dioxane (2:1, 3 mL)
60 oC, 16 h
HO
HO
9 0%
Scheme 11 Robustness screening on the formation of benzonitrile
9.a
aChamber A: 4-Bromophenol (1.0 mmol), 2-acetyl-5-bromothiophene (1.0 mmol)
P(tBu)3-Pd-G3 (2.5 mol%) and KOAc (3.0 mmol) in dioxane (1.0 mL) and H2O (2.0 mL).
Chamber B: KCN (1.5 mmol), ethylene glycol (1.0 mL) and AcOH (9.0 mmol).
Br
(tBu)3P Pd
Pd P(tBu)3
2-Acetyl-5-bromothiophene
(1.1 equiv)
Br
38
Pd(P(tBu)3)2
O
O
Pentane, rt, 30 min
Acknowledgements
S
S
This study was funded by the BioValue SPIR, Strategic Platform
for Innovation and Research on value added products from
biomass, which is co-funded by The Innovation Fund Denmark,
case no: 0603–00522B. We are also deeply appreciative of
generous financial support from Haldor Topsøe A/S, the Danish
National Research Foundation (grant no. DNRF118) and Aarhus
University.
39
Scheme 12 Formation of Pd2(μ-Br)2(P(tBu)3)2 and 5,5’-diacetyl-2,2’-
bithiophene from Pd(P(tBu)3)2.a
aReaction performed on a 0.1 mmol scale.
benzonitrile
attempted to isolate the oxidative addition complex of
Pd(P( Bu)3)2 and 2-acetyl-5-bromothiophene in order to test
the stoichiometric reaction with Pd-hydride 32 Despite
9 was completely inhibited (Scheme 11). Next, we
Notes and references
t
§ According to the Sigma-Aldrich catalogue,
5 g of acetone
.
cyanohydrin costs the same as approximately 100 g of potassium
cyanide.
extensive experimentation, i.e. different solvents and
temperatures, we only observed the formation of Pd2(μ-
§§ H13CN was used because this isotope eased the spectroscopic
analysis of the complexes formed.
Br)2(P(tBu)3)2 (38) and 5,5’-diacetyl-2,2’-bithiophene (39) in all
cases (Scheme 12).
§§§ In the non-isotopically labelled version, the multiplicity is
seen as a triplet.
Hartwig and co-workers by a similar protocol using Pd(dba)2, §§§§ Complex 33 or the corresponding potassium salt
The Pd-complex 38 has previously been synthesised by
(K2[Pd(13CN)4]) could not be detected by either 31P NMR or 13C
NMR spectroscopic analysis.
P(
formation of 38 is fast at 25
pentane. Given that the developed conditions for the
cyanation of aryl bromides operate at 60 C, production of 38
t
Bu)3 and a tenfold excess of 2-bromothiophene.46 The
ᵒC when using either THF or
§§§§§ Compound 34 has previously been synthesised by Grushin
and co-workers by the reaction of Pd(PPh3)4 with K13CN in the
presence of water. See ref. 25.
°
is fast leading to apparent shutdown of the catalytic system. §§§§§§ During the reaction, no clear phosphine signals are
observed from either the oxidative addition complex (i.e.
(P(tBu)3)Pd(Ar)(Br)) or the complex after transmetallation (i.e.
(P(tBu)3)Pd(Ar)(CN)). This further indicates that the rate
determining step is the oxidative addition into the aryl bromide,
since the generated P(tBu)3)Pd(Ar)(Br) is consumed almost
instantaneously (See J. L. Klinkenberg and J. F. Hartwig, J. Am.
Chem. Soc., 2012, 134, 5748, which studies the reductive
elimination of LnPd(Ar)(CN) complexes.
The formation of complex 38 offers an explanation to why
some heteroaromatic bromides fail under the developed
cyanation protocol, however further investigations are needed
to understand the reasons for this divergence.47,48
Conclusions
§§§§§§§ K2[Pd(CN)4] was also tested. This resulted in no
conversion to benzonitrile 11.
In summary,
a new protocol for the direct use of
§§§§§§§§ Lowering the amount of 2-acetyl-5-bromothiophenyl
bromide to 0.5 equivalents or using other heteroaromatic
bromides, such as 5-bromopyridine, gave the same outcome.
stoichiometric gaseous hydrogen cyanide in the Pd-catalysed
cyanation of aryl bromides has been developed. Contrary to
previous studies, the use of HCN did not lead to catalytic
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Table of contents entry
P1
N1
C1
Pd1
H1
P2
We demonstrate how hydrogen cyanide can be exploited for the cyanation of aryl bromides with Pd-catalysis.
1