Improved Substrate Scope in the Potassium Hexacyanoferrate(II)-Based Cyanation for the Synthesis of Benzonitriles and Their Heterocyclic Analogues

Article abstract of DOI:10.1021/acs.joc.8b00515

The use of Pd(DPEPhos)Cl₂ (P26) as a catalyst for the formation of benzonitriles and their heterocyclic analogues provides excellent complementarity to existing catalysts, allowing highly electron-deficient heterocyclic aryl halides to be effic

Full text of DOI:10.1021/acs.joc.8b00515

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Improved Substrate Scope in the Potassium Hexacyanoferrate (II) based
Cyanation for the Synthesis of Benzonitriles and their Heterocyclic Analogs.
Jeffery Richardson, and Simon P. Mutton
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00515 • Publication Date (Web): 09 Apr 2018
Downloaded from http://pubs.acs.org on April 9, 2018
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Improved Substrate Scope in the Potassium Hexacyanoferrate (II) based Cyanation for the
Synthesis of Benzonitriles and their Heterocyclic Analogs.
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Jeffery Richardsona* and Simon P. Muttonb
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a Eli Lilly and Company, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH,
United Kingdom.
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b AMRI UK Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, United
Kingdom.
richardson_jeffery@lilly.com
Abstract
The use of Pd(DPEPhos)Cl2 (P26) as a catalyst for the formation of benzonitriles and their
heterocyclic analogs provides excellent complementarity to existing catalysts, allowing highly
electron deficient heterocyclic aryl halides to be efficiently converted to the corresponding nitriles
using K4[Fe(CN)6]) as cyanide source. This catalyst significantly enhances the scope of this reaction
to include a number of substrates that are highly relevant for pharmaceutical and agrochemical
applications. Importantly, not only does this cyanation method employ a nonꢀtoxic cyanide source,
simple semiꢀquantitative testing suggests that, unlike many other methods, no free cyanide is present
in the reaction mixture or during a variety of potential workꢀups, thus improving the safety aspects of
this method from initial setꢀup through to product isolation. Finally, developing and testing a series of
convenient cyanation kits, has allowed facile application and broader adoption of this method in our
labs.
Introduction
Benzonitriles are versatile intermediates in organic synthesis that undergo a wide variety of
transformations as well as being key structural motifs in some highly important substances.1 There are
many methods for their synthesis and one of the most attractive disconnections is the conversion of an
aryl halide or pseudohalide to the aryl nitrile. This is typically achieved using a transition metal
catalyst and a cyanide source. Since the first report of Pd catalyzed methods for the synthesis of
benzonitriles2ꢀ3 these have superseded more traditional Cu mediated methods. The Pd catalyzed
variants generally operate under milder conditions and are more tolerant of functional groups, but
ultimately suffer from a common drawback; these methods rely on cyanide sources, such as metal
cyanide salts KCN,4ꢀ8 NaCN,5, 9ꢀ10 and Zn(CN)2,11ꢀ16 which are highly toxic both to humans and the
environment, as well as posing additional risk during handling and workꢀup. These metal cyanides
are, by design, insoluble under the reaction conditions to maintain a low concentration of “dissolved
cyanide” since it is a known catalyst poison and limiting its concentration allows these reactions to be
performed catalytically.10, 16ꢀ20 This effect has led to cyanation reactions being amongst the least
efficient of the myriad of Pd catalyzed CꢀC bond forming reactions in terms of catalyst turnover and
the insoluble salts can also blight the product isolation.21 The addition of reducing agents has been
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employed to convert catalytically inactive Pd cyanide species back to Pd(0), but these reductants can
further complicate workꢀup operations.
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While many other reagents have been developed for Pd catalyzed cyanation of aryl halides, many of
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them ultimately generate cyanide in situ and thus must be treated with the same precautions,
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especially during workꢀup. For example, TMSCN
and acetone cyanohydrin
are both
effective cyanation reagents, but they are readily hydrolyzed to HCN and must be added slowly
throughout the course of the reaction to avoid catalyst poisoning due to their high solubility and thus
high cyanide concentration. To overcome this, methods that do not employ cyanide sources have been
developed, for example tertꢀbutyl isocyanide,25 ethyl nitro acetate/dimethylfumarate,26 butyronitrile27
and CuSCN28 based methods have been used to effect this transformation. Another noteworthy
method involves metalation of the aryl halide, reaction with dimethylmalononitrile and subsequent
rearrangement to form benzonitriles.29 While these methods avoid the use of cyanide, they are each
subject to their own specific challenges.
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Potassium hexacyanoferrate (II) (K4[Fe(CN)6]) has been employed as an inexpensive and nonꢀtoxic
reagent for the cyanation of aryl halides since its first disclosure by Beller20, 30 and Weissman31 and
numerous key developments have been made in terms its convenience and substrate scope.32ꢀ37 These
reactions are most commonly catalyzed by palladium complexes, although copper catalyzed methods
are also known for relatively simple substrates at high temperature.38
During a Lilly drug discovery program where several benzonitriles were prepared, the method
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developed by Buchwald
was found to be highly effective for the cyanation of a range of aryl
bromides and chlorides. Despite the practicality, broad scope and attractive reagents, other conditions
were frequently employed in other discovery chemistry efforts that suffered from the drawbacks
outlined above. This is a general challenge for high value, well established transformations in early
discovery projects. When faced with hundreds of hits from a literature database, one strategy is to
refine the search criteria to make the query closer to the substrate of interest, but for more recently
developed methodologies there is a significant probability that the relative lack of exemplification
versus older methods will result in the older, potentially less desirable method being retrieved from
the database preferentially.39 If these conditions perform sufficiently for the first substrate tested, then
they are likely to become the method of choice for that library or discovery project. In many instances
this would not be an issue, but when newer methods exist that extend the scope and overcome the
inherent safety or practicality issues of the older methods then this represents a missed opportunity at
best. Lowering the “barrier to use” for this chemistry would result in more efficient and safe
chemistry being broadly employed and formed a significant component of the work described here.
During these projects the conditions described by Buchwald using XPhos and tBuXPhos precatalysts
had performed well across a broad range of substrates, but were unsuccessful for some electron
deficient heteroarenes such as haloꢀpyrimidines. Given that such heterocycles are common in
pharmaceuticals and intermediates, identification of conditions that address this limitation and allow
these substrates to be successfully employed would be of significant value. We began by screening a
series of Pd complexes under the conditions described by Buchwald in a small set of potentially
challenging substrates to understand whether any differentiation occurred between the various
complexes and also if any would allow us to obtain electron deficient pyrimidine 4. (Scheme 1).36 In
general, the complexes of Buchwald monodentate phosphines (P1-7) performed well, forming
products 1-3 starting from both the corresponding aryl chlorides and bromides. Complexes of XPhos
(P2) and tBuXPhos (P4) performed well for nitriles 1-3, but were unsuccessful for nitrile 4 as had
previously been observed. Other ligand classes performed less broadly and relatively few worked well
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for 2ꢀchloroanisole. Many of the complexes tested performed significantly better for the aryl bromides
than the corresponding chlorides, presumably in most instances due to inefficient oxidative addition
into the CꢀCl bond with those catalysts.
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The formation of 4 was largely unsuccessful, and this could potentially be attributed to the difficulty
of the product forming reductive elimination step in the catalytic cycle. Buchwald had demonstrated
that using ligands that were more sterically demanding at phosphorus, such as L4, helped in some
instances to facilitate the key reductive elimination,36 but clearly for these highly electron deficient
arenes this was not sufficient since P2 and P4 were unable to afford 4 in good yield.40 Presumably
reductive elimination is prohibitively difficult in these very electron deficient heteroarenes.
Interestingly, the Pd complexes of bidentate ligands (P12, P13, P17) were uniquely effective catalysts
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for cyanation of the electron deficient pyrimidine to afford 4. This is consistent with the observation
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that a wide bite angle in bidentate ligands may facilitate reductive elimination.
Since oxidative
addition of Pd complexes to electron deficient arenes is typically facile, these complexes bearing less
electron rich ligands were anticipated to work well across a series of electron deficient heterocycles.
These bidentate ligands did not perform as well as P2 or P4 for the electronꢀneutral and electronꢀrich
aryl chlorides and so we felt that these catalysts offered excellent complementarity to the Buchwald
ligands.
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Scheme 1: Screening of challenging aryl halides in cyanation reactions with K4[Fe(CN)6]. a) X = Br,
b) X = Cl
A series of electron deficient arenes with bidentate ligands were studied to better understand exactly
when the complexes P2 or P4 would not suffice and which of the bidentate ligands would be most
useful (Scheme 2). The preparation of a series of cyano (hetero)arenes (4-13) was studied using P2,
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P4 and complexes containing bidentate ligands (P12, P13, P17 and P26). As expected, for simple
arenes bearing a single electron withdrawing group P4 was successful in all cases and P2 worked for
some. This is in good agreement with the observations made by Buchwald, where the synthesis of 8
had shown this catalyst preference. Interestingly, only when a methoxy group was present (7) on the
pyrimidine was P4 successful, however the bidentate ligands were successful for all such substrates.
Highly electron deficient pyrimidine 5 appeared to be unstable to the reaction conditions, presumably
as a result of the nitriles being readily hydrolysed or displaced and so for the catalysts where starting
materials were consumed, multiple unidentified products were obtained. Again, this substrate was not
converted by catalysts P2 or P4 and these reactions returned mostly starting aryl bromide. A similar,
but somewhat attenuated trend was observed for compound 8, although the extent of hydrolysis
seemed to be dependent on the catalyst and it may be possible to modulate this by adjustment of the
amount of water used.42
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Scheme 2: Screening of electron deficient arenes and pyrimidines. a) X=Br, b) X=Cl, c) 100%
conversion of 8 to primary amide d) 50% conversion of 8 to primary amide e) 16% 2ꢀ
hydroxyquinoline formed f) 8% 2ꢀhydroxyquinoline formed g) 10% 2ꢀhydroxyquinoline h) 3 % 2ꢀ
hydroxyquinoline formed i) 5 % 2ꢀhydroxyquinoline formed j) mostly recovered aryl halide k)
complex mixture of products.
In most instances P17 gave product but the reaction yields were somewhat variable across the
substrates. However XantPhos (P12), NꢀXantPhos (P13) and DPEphos (P26) complexes all worked
well across the range of electron deficient substrates. The wide bite angles of these ligands (L12 =
111 °, L13 = 114 ° and L26 = 102 °, compared to L17 = 93 °)43 presumably result in more facile
reductive elimination to the benzonitriles. Both L17 and L26 (DPEPhos) were used in the original
21, 30
disclosure by Beller
but did not possess suitably broad substrate scope under mild conditions to
be considered general catalysts. However, under these conditions P26 has excellent complimentary
with P2 for this transformation and plugs a significant gap in the scope of this transformation.
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In order to encourage the use of these conditions as a standard method for cyanation of aryl halides in
both discovery chemistry laboratories and automated settings (such as the Lilly Automated Synthesis
Lab44) the use of premixed “Cat Kits” was investigated, having met with some success for other Pd
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catalyzed reactions.
By mixing the inorganic reagent and catalyst, these kits minimise weighing
operations and also reduce the weighing error associated with dispensing small quantities of catalyst.
A “cyanation kit”, if successful, would achieve both of these goals.
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Having established that by using P26 and one of either P2 or P4 substantial substrate generality was
obtained, we felt that these would represent excellent choices for development as cyanation kits. Kits
were prepared in the fumehood by combining all of the solid components. To test robustness, the kits
were split in half with half stored under air and half in a glovebox under nitrogen. The catalyst was
incorporated into the kit at a level such that when 0.5 equivalents of K4[Fe(CN)6] was employed the
catalyst loading would be 5 mol%. In many cases this loading could be lowered, but the 5 mol% kit
serves as a practical 1st pass option for small scale applications.
The kits containing P2 and P4 were periodically tested in the formation of 1 from the corresponding
aryl bromide (Table 1). In all instances the kits were stable to long term storage, giving very good
conversion in the test reaction even after 6 months storage in air. Some kits (C,E,F &H) contained
additional ligand to examine whether this conferred any long term catalyst stability, but it was found
that this was not necessary as the kits without additional ligand performed equally well over a long
period. Full details of kit contents can be found in supporting information. There was no difference
observed between P2 and P4 in terms of durability over 6 months.
Test Reaction conversionb
Entry
Kit
Kit Contentsa
Storage
1 week 1 month 6 months
100%
1
2
3
4
A
A
B
B
KOAc, K4[Fe(CN)6].3H2O
KOAc , K4[Fe(CN)6].3H2O
Glovebox 100%
100%
100%
98%
100%
100%
100%
99%
Air
100%
P2, KOAc, K4[Fe(CN)6].3H2O Glovebox 100%
P2, KOAc, K4[Fe(CN)6].3H2O
Air
100%
86%
P2, L2, KOAc,
K4[Fe(CN)6].3H2O
P2, L2, KOAc,
5
6
C
C
Glovebox 100%
100%
100%
100%
Air
100%
K4[Fe(CN)6].3H2O
100%
100%
100%
7
8
D
D
P4, KOAc , K4[Fe(CN)6].3H2O Glovebox 100%
100%
100%
P4, KOAc , K4[Fe(CN)6].3H2O
P4, L4, KOAc,
Air
100%
9
E
E
Glovebox 100%
100%
100%
K4[Fe(CN)6].3H2O
P4, L4, KOAc,
K4[Fe(CN)6].3H2O
P4, L4, K4[Fe(CN)6].3H2O
100%
10
Air
Glovebox 100%
Air 100%
100%
100%
100%
11
12
F
F
100%
100%
P4, L4, K4[Fe(CN)6].3H2O
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100%
100%
100%
100%
100%
100%
13
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G
G
H
H
I
P4, K4[Fe(CN)6].3H2O
Glovebox
Air
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
100%
100%
100%
100%
100%
100%
P4, K4[Fe(CN)6].3H2O
P2, L2, K4[Fe(CN)6].3H2O
P2, L2, K4[Fe(CN)6].3H2O
P2, K4[Fe(CN)6].3H2O
P2, K4[Fe(CN)6].3H2O
Glovebox
Air
Glovebox
Air
I
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Table 1: Long term stability testing for cyanation kits of catalysts P2 and P4. a) full details of kit
contents and preparation can be found in supporting information. b) conversion assessed by LCMS.
While kits AꢀE maintain good performance and seemingly offer greatest convenience since all
components could be dosed simultaneously, the hygroscopic nature of KOAc caused these kits to
become difficult to weigh after 6 months. Additionally, the variable water content over time creates
ambiguity regarding overall potency of the kit. Those kits stored in the glovebox did not suffer this
fate, but storage in the glovebox reduces convenience and accessibility. As such, those kits that did
not include KOAc (kits FꢀI) were preferred since it is operationally no more complex to add aqueous
KOAc to the reaction mixture than it is water. Doing so also overcomes the inherent challenge of
handling and storing a large container of KOAc under air over a long period. Kit I was therefore
selected as the preferred kit for general use with electron neutral and rich susbtrates.
A similar study was performed for those kits containing bidentate ligands (Table 2). While P12 and
P13 provide very similar scope to P26 with respect to the less electron deficient arenes, P26 was
selected as it was a more economical choice and the overall substrate coverage remained the same.47
This kit also performed well with no reduction in performance over 6 months storage in air.
Time point
Kit
Contents
Storage
1 month 6 months
J
J
P26, K4[Fe(CN)6].3H2O
P26, K4[Fe(CN)6].3H2O
Glovebox
Air
100%
100%
100%
100%
Table 2: Cyanation kits for electron deficient systems.
The use of the 6 month old kits I and J for aryl and heteroaryl halides was successful affording
comparable yields to reactions setꢀup using the individual components (Scheme 3). It is worth noting
that these kits perform well on a series of molecules that would be particularly challenging with just
the original Buchwald conditions alone.
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Scheme 3: Comparison of isolated yields for cyanation kits and standard procedure. a) Method A; all
components were charged individually including the catalyst highlighted and K4[Fe(CN)6] (0.5
equiv.). b) Method B: Catalyst and K4[Fe(CN)6] were charged as part of a kit (0.25 g/mmol ArX).
The kit used is denoted next to yield.). c) 2.5 mol% P26, 50 g scale. d) conversion measured by
LCMS.
Another alternative kit could be conceived where the [K4[Fe(CN)6] and KOAc were transferred to the
substrate, catalyst and solvent as an aqueous solution. While this does not reduce the number of
overall dispensing operations, it could be useful in highꢀthroughput catalyst screening to minimise the
number of weighing operations. To ascertain the stability of the aqueous cyanation mix, a 0.5M
solution of [K4[Fe(CN)6] and KOAc was prepared in air and periodically tested in a model reaction
with no reduction in performance over a 3 month period (Scheme 4).
P26 (3 mol%)
aq KOAc/K4Fe(CN)6 mix
1,4-dioxane
90 °C, 1h
Br
F
NC
F
N
S
N
S
1 day:
100% conv
15
1 week: 95% conv
1 month: 100% conv
3 months: 100% conv
Scheme 4: Stability of aqueous cyanation kit (method C) over a 3 month period, stored under air.
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This methodology (method C) would be especially applicable during highꢀthroughput catalyst
screening, where the number of solid dispenses could be kept to a minimum. To demonstrate that this
method could also be employed preparatively, 3 was be prepared using catalyst P2 in 81% yield and
14 using P26 in 69% yield.
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Early methods using K4[Fe(CN)6] required significantly elevated temperatures, and this has been cited
as a disadvantage of the method,41 despite the reduction in temperature achieved by Buchwald. The
effect of temperature was therefore further studied and it was found that for the aqueous cyanation kit
and P2 the reactions went rapidly to completion at as low as 60 °C, but that for P26 full conversion
could only be obtained at 90 °C (see supporting information for full details).
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While these kits provide a simple and rapid method for (hetero)benzonitrile synthesis, a mixed kit
containing both catalysts could potentially provide a single “universal” kit. To test this idea, a 1:1
ratio of kits I and J was combined to afford kit K, which contained 2.5 mol% of catalysts P2 and P26
and tested under the standard conditions (Scheme 5).
Scheme 5: Cyanation with combined cyanation kit K.
In all cases tested, the desired (hetero)benzonitriles were obtained, it was noted that the isolated yields
were typically lower than those where the individual kits were used, although this was likely
attributed to the lower catalyst loading in kit K (2.5 mol%) versus kits I or J (5 mol%).
17, 36
It has been suggested that [K4[Fe(CN)6] has low dissociation to free cyanide
resulting in slow
delivery of cyanide ions to Pd thereby preventing catalyst deactivation even when the cyanide source
is fully dissolved. Beller proposed an alternate, transmetallationꢀtype mechanism shown in scheme 6,
which, if operative, could allow there to be no free cyanide being present during the course of the
reaction.20 This would be a significant safety advantage for this method and so further study was
conducted. It is known that high temperatures are required for transmetallation with [K4[Fe(CN)6]
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suggesting that either this is required to obtain sufficient dissociation of cyanide from Fe or that a
different mechanism, such as that proposed by Beller operates for [K4[Fe(CN)6] versus other cyanide
sources. While [K4[Fe(CN)6] is in itself a safe cyanide source, dissociation to free cyanide during the
reaction would result in many of the drawbacks of other methods still being relevant for these
conditions, especially as pertains to the risk of accidental exposure to cyanide during quenching or
workꢀup. Conversely, a mechanism involving no free cyanide would render this method even more
attractive.
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Scheme 6: Beller’s proposed transmetallation mechanism.
To determine whether a reagent can truly be considered safe, it is important not only to consider the
reagent but also its byꢀproducts and potential reactivity/toxicity during workꢀup and disposal. In order
to demonstrate that these reactions could be run safely with minimal concerns around cyanide
poisoning during setꢀup, reaction or workꢀup we tested these reactions at various points to determine
if cyanide could be detected. By testing for cyanide both during the reaction and under a variety of
workꢀup conditions that could potentially liberate HCN, it was shown that the reactions generate no
detectable cyanide in any of these instances (see supporting information) which is consistent with, but
not proof of, a mechanism such as that shown in scheme 6. The reaction mixtures become a deep blue
colour when they are exposed to air for workꢀup which rendered the cyanide detection more difficult
and so positive control experiments were undertaken to verify these findings. Interestingly, when
NaCN (ca 5 ppm) is added to the reaction mixture at completion and the blue solids removed by
filtration to aid visualization, no cyanide could be detected, even though this falls into the detectable
range for the testing protocol. However, if the blue solids are filtered off before the cyanide is added,
the test strips give a result consistent with the amount of cyanide added. This suggests that the Fe
species present in the complete reaction are capable of efficiently sequestering free cyanide but does
not rule out either the free cyanide or direct transmetallation mechanisms. Either way, the absence of
detectable cyanide in the numerous workꢀup procedures tested makes this method highly attractive
from a safety perspective.
Interestingly, while no cyanide was observed under the reaction conditions, a slight signal was seen
upon storage of the aqueous cyanation kit used in scheme 4, although the signal was sufficiently low
to consider this mixture safe, it should be noted that aged solutions such as this should be tested
periodically to ensure safe handling and storage.
Conclusions
The use of DPEPhos complex P26 significantly enhances the scope of the cyanation of aryl bromides
under Buchwald conditions and thus allows a very broad range of substrates to be cyanated under
operationally simple conditions. The excellent complementarity with the catalysts described by
Buchwald, further enhance the practicality of this method for the synthesis of small molecule
pharmaceuticals and agrochemicals. This method is rendered even more powerful by the fact that
cyanide test strips do not show free cyanide formed at any point through the reaction or its workꢀup
under various conditions. The kits prepared are convenient and stable, avoiding the handling of
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hygroscopic KOAc These kits have been prepared and distributed throughout Lilly’s discovery labs
and represent a first choice for the synthesis of benzonitriles from aryl chlorides and bromides.
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Experimental:
General methods
All reagents were purchased from commercial suppliers and used as received. Solvents were
purchased from Aldrich, anhydrous, SureSeal quality, and used with no further purification. Water was
degassed by evacuation, sonication (30 seconds) and backfilling with N2 (x 5). The ligands and bases
were purchased from commercial sources and stored in a nitrogen filled glovebox. Flash column
chromatography was carried out using silica gel columns with a Teledyne ISCO CombiFlash
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Companion system. H and 13C NMR spectra were recorded on a Bruker AVꢀHD 400 spectrometer.
Signal positions were recorded in δ ppm with the abbreviations s, d, t, q, dd, dt and m denoting
singlet, doublet, triplet, quartet, doublet of doublets, doublet of triplets and multiplet respectively. All
1H NMR chemical shifts were referenced to SiMe4 as an internal standard (0.00 ppm). All 13C NMR
chemical shifts in CDCl3 were referenced to the residual solvent peak at 77.00 ppm. All coupling
constants, J, are quoted in Hz. Infraꢀred spectra were recorded on a Nexus FTꢀIR spectrometer with
Nicolet OMNI sampler using a neat sample. Melting points were obtained using a DSC 1 STARe
system. All LCMS analyses were performed using an Agilent 1200 Infinity Series Liquid
Chromatography (LC) system, consisting of a 1260 HiP degasser (G4225A), 1260 Binary Pump
(G1312B), 1290 autoꢀsampler (G4226A), 1290 thermoꢀstated column compartment (G1316C) and a
1260 Diode Array Detector (G4212B) coupled to an Agilent 6150 single quadrupole mass
spectrometry (MS) detector. The injection volume was set to 1 ꢁL. The UV (DAD) acquisition was
performed at 40 Hz, with a scan range of 190ꢀ400 nm (in 5 nm steps). A 1:1 flow split was used
before the MS detector. The MS was operated with an electroꢀspray ionization source (ESI) in both
positive & negative ion mode. The nebulizer pressure was set to 50 psi, the drying gas temperature
and flow to 350 °C and 12.0 L/min respectively. The capillary voltages used were 4000 V in positive
mode and 3500 V in negative mode. The MS acquisition range was set to 100ꢀ800 m/z with a step size
of 0.2 m/z in both polarity modes. Fragmentor voltage was set to 70 (ESI+) or 120 (ESIꢀ), Gain to
0.40 (ESI+) or 1.00 (ESIꢀ) and the ion count threshold to 4000 (ESI+) or 1000 (ESIꢀ). The overall MS
scan cycle time was 0.15 s/cycle. Data acquisition was performed with Agilent Chemstation software.
Analyses were carried out on a Waters XBridge C18 column of 50 mm length, 2.1 mm internal
diameter and 3.5 ꢁm particle size, eluting from 95:5 to 5:95 of pH 9 adjusted 10 mM NH4HCO3 (aq)
in MeCN over 1.5 min and holding for 0.5 min.
General procedure for the formation of cyanation kits: Cyanation Kit J.
K4[Fe(CN)6].3H2O (98.7 g, 234 mmol) was ground in a pestle and mortar to afford an offꢀwhite fine
powder. The powder was then mixed with Pd(DPEPhos)Cl2 (16.56 g, 23.13 mmol) under air by
rotation until it appeared as a uniform powder.
General Procedure for cyanation using a modification of Buchwald’s procedure (Method A).
A 10 mL vial was charged with aryl halide (1.00 mmol), catalyst (P2 or P26) (5 mol%),
K4[Fe(CN)6].3H2O (213 mg, 0.50 mmol) and potassium acetate (49 mg, 0.50 mmol) and sealed with a
septum cap. The vial was purged with nitrogen and then 1,4ꢀdioxane (1.0 mL) and water (1.0 mL)
were added. The vial was then transferred to a preꢀheated aluminium block at 90 °C for 80 minutes. In
most instances the reactions were complete by LCMS at this point and were then cooled to room
temperature, partitioned between sat. aq. NaCl (20 mL) and EtOAc (20 mL), the layers separated and
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the aqueous was extracted with EtOAc (3 x 20 mL). The combined organics were then washed with
sat. aq. NaCl (10 mL), dried over Na2SO4, filtered and evaporated to afford the aryl nitrile. Products
were further purified by flash chromatography if required, employing a preꢀpacked RediSep Rf
cartridge (12 g), eluting with EtOAc:nꢀheptane (0ꢀ20% over 16 column volumes) unless otherwise
stated.
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General Procedure for Cyanation with 0.5 M KOAc solution (Method B).
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Cyanation Kit (either I or J, 0.25 g/mmol aryl halide) and aryl halide (1 g) were charged to a 20 mL
microwave vial under air. The vessel was then sealed with a septum cap and evacuated and backfilled
with N2 (x 5, 5 sec evacuation time). 1,4ꢀDioxane (1 mL/mmol) and 0.5 M KOAc solution (0.5
equiv.) were charged via syringe and the mixture was then evacuated and backfilled with N2. The
mixture was then heated to 90 °C under a N2 atmosphere with stirring (1000 RPM) and monitored by
LCMS. Reaction mixtures were worked up and purified using the same procedure as method A.
General Procedure for Cyanation with aq cyanation kit (Method C).
Aqueous cyanation kit was prepared by swirling potassium acetate (9.81 g, 100 mmol) and
K4[Fe(CN)6].3H2O (37.2 g, 100 mmol) in a volumetric flask made up to 200 mL volume with water.
This was then stored in a bottle under air.
Aryl halide (100 mg) and catalyst (5 mol%) were charged to a 5 mL microwave vial under air. The
vessel was then sealed and evacuated and backfilled with N2. 1,4ꢀDioxane (1 mL/mmol) and 0.5 M
aq cyanation kit (0.5 equiv) were charged via syringe and the mixture was then evacuated and
backfilled with N2. The mixture was then heated to 90 °C under vented N2 with stirring (1000 RPM)
and monitored by LCMS. Reaction mixtures were worked up and purified using the same procedure
as method A.
tert-butyl 5-cyanoindoline-1-carboxylate (1). Prepared from the ArCl according to Method A (using
catalyst P2, 298 mg, 100%) and according to Method B using cyanation kit I (896 mg, 93%).
Prepared from the ArBr according to Method A (using catalyst P2, 229 mg, 93%) and according to
Method B using cyanation kit I (221 mg, 90%). Obtained as a white solid after trituration with nꢀ
heptane. m.p. 162ꢀ165 °C; 1H NMR (400 MHz, DMSO): 7.95ꢀ7.36 (3H, m), 3.95 (2H, t, J = 8.8 Hz),
3.09 (2H, t, J = 8.8 Hz), 1.51 (9H, s); 13C NMR (100 MHz, CDCl3): 152.1, 132.7, 128.2, 119.6, 104.8,
47.9, 28.3, 26.7; IR (neat, cmꢀ1) 2980, 2220, 1708, 1604, 1489, 1433, 1382, 1369, 1317, 1286, 1251
1165, 1138, 1014; LRMS (ESI) m/z: [M+H]+ 245.0, [MꢀtBu]+189.0.
2-methoxybenzonitrile (2).48 Prepared from the ArBr according to Method A (using catalyst P2, 139
mg, 65%) and according to Method B using cyanation kit I (152 mg, 71%). Also prepared from the
ArCl according to Method A (using catalyst P2, 204 mg, 73%) and Method B using cyanation kit I
1
(148 mg, 53%). Obtained as a colourless oil. H NMR (400 MHz, CDCl3): 7.62ꢀ7.42 (2H, m), 7.08ꢀ
6.85 (2H, m), 3.93 (3H, s); LRMS (ESI) m/z: [M+H]+ 134.4.
4-(dimethylamino)benzonitrile (3).49 Prepared from the ArBr according to Method A(using catalyst
P2, 237 mg, 85%), according to Method B using cyanation kit I (202 mg, 92%) and according to
Method C (using catalyst P2, 237 mg, 81%). Also prepared from the ArCl according to Method A
(272 mg, 97%) and Method B using cyanation kit I (197 mg, 70%). Obtained as white plates. m.p. 74ꢀ
77 °C [lit. 75ꢀ77 °C]50; 1H NMR (400 MHz, CDCl3): 7.53 (2H, d, J = 9.0 Hz), 6.75 (2H, d, J =9.0 Hz),
2.99 (6H, s); 13C NMR (100 MHz, CDCl3): 152.5, 133.4, 120.7, 111.4, 97.4, 39.9; LRMS (ESI) m/z:
[M+H]+ 147.0.+
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methyl 5-cyanopyrimidine-2-carboxylate (4). 51 Prepared from the ArBr according to Method A (using
catalyst P26, 126 mg, 40%) and according to Method B using cyanation kit J (212 mg, 74%).
Obtained as a tan solid. m.p. 129ꢀ132 °C; H NMR (400 MHz, CDCl3): 9.20 (2H, s), 4.11 (3H, s);
LRMS (ESI) m/z: 164.2 [M+H]+.
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Pyrimidine-5-carbonitrile (6). Prepared from the ArBr according to Method A (using catalyst P26,
131 mg, 66%) and according to Method B using cyanation kit J (115 mg, 58%). Obtained as a white
solid. m.p. 84ꢀ87 °C [lit. 83.5ꢀ84 °C (EtOH)]52 1H NMR (400 MHz, CDCl3): 9.41 (1H, s), 9.03 (2H,
s); 13C NMR (100 MHz, CDCl3): 160.5, 159.5, 114.0, 110.2; LRMS (EI) m/z: 104.8 [M]+
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2-methoxypyrimidine-5-carbonitrile (7).53 Prepared from the ArBr according to Method A (using
catalyst P26, 181 mg, 84%) and according to Method B using cyanation kit J (200 mg, 93%).
1
Obtained as white solid. RF = 0.51 (1:1 v/v EtOAc:isoꢀhexane); m.p. 83ꢀ87 °C [lit. 81ꢀ81.5 °C]54; H
NMR (400 MHz, CDCl3): 8.79 (1H, s), 4.11 (3H, s); 13C NMR (100 MHz, CDCl3): 166.1, 162.5,
114.8, 102.9, 56.1; LRMS (ESI) m/z: 136.0 [M+H]+.
Terephthalonitrile (8).55 Prepared from the ArBr according to Method A (using catalyst P26, 179 mg,
85%) and according to Method B using cyanation kit J (197 mg, 93%). Obtained as white crystalline
solid. m.p. 224ꢀ228 °C [lit. 226ꢀ228 °C]56; 1H NMR (400 MHz, CDCl3): 7.80 (4H, s); 13C NMR (100
MHz, CDCl3): 132.8, 117.0, 116.7; LRMS (EI) m/z: 128.0 [M]+ .
Phthalonitrile (9). Prepared from the ArBr according to Method A (using catalyst P26, 193 mg, 91%)
and according to Method B using cyanation kit J (190 mg, 90%). Obtained as white needles. m.p.
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139ꢀ142 °C [lit. 139ꢀ141 °C57]; H NMR (400 MHz, CDCl3): 7.92ꢀ7.80 (2H, m), 7.80ꢀ7.68 (2H, m);
13C NMR (100 MHz, CDCl3): 133.6, 133.1, 116.0, 115.3; LRMS (ESI) m/z: [M+H]+ 129.0.
1,3-Dicyanobenzene (10).55 Prepared from the ArBr according to Method A(using catalyst P26, 188
mg, 89%) and according to Method B using cyanation kit J (152 mg, 72%). Obtained as white
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needles. m.p. 160ꢀ162 °C [lit. 161ꢀ163 °C]58; H NMR (400 MHz, CDCl3): 7.96 (1H, m), 7.91 (2H,
dd, J = 8.0, 1.6 Hz), 7.66 (1H, t, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3): 136.0, 135.4, 130.3,
116.6. 114.2; LRMS (EI) m/z: 128.0 [M]+.
methyl 3-cyanobenzoate (11). Prepared from the ArBr according to Method A (using catalyst P2,
187mg, 83%) and according to Method B using cyanation kit I (167 mg, 74%). Also prepared
according to Method A (using catalyst P26, 187 mg, 83%) and according to Method B using
cyanation kit J (191 mg, 85%). Obtained as white needles. RF = 0.51 (1:1 v/v EtOAc:isoꢀhexanes).
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m.p. 59ꢀ63 °C [lit. 61ꢀ62 °C]59; H NMR (400 MHz, CDCl3): 8.33 (1H, s), 8.27 (1H, d, J = 7.8 Hz),
7.84 (1H, d, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 3.96 (3H, s); 13C NMR (100 MHz, CDCl3): 165.1,
136.0, 133.7, 133.3, 131.4, 129.4, 117.9, 113.0, 52.7; LRMS (ESI) m/z: [M+H]+ 162.0.
4-nitrobenzonitrile (12). Prepared from the ArBr according to Method A (using catalyst P26, 175 mg,
80%) and according to Method B using cyanation kit J (199 mg, 91%). Obtained as offꢀwhite needles.
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RF = 0.55 (1:1 v/v EtOAc:isoꢀhexanes). m.p. 148ꢀ151 °C [lit. 149ꢀ151 °C]60; H NMR (400 MHz,
CDCl3): 8.36 (2H, d, J = 8.8 Hz), 7.89 (2H, d, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3): 150.0,
133.5, 124.3, 118.3, 116.8; LRMS (EI) m/z: 148.0 [M]+.
Quinoline-2-carbonitrile (13).61 Prepared from the ArBr according to Method A (using catalyst P26,
247 mg, 87%) and according to Method B using cyanation kit J (234 mg, 83%). Obtained as white
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solid. RF = 0.51 (1:1 v/v EtOAc:isoꢀhexanes) m.p. 94ꢀ97 °C [lit. 94ꢀ96 °C]62; H NMR (400 MHz,
CDCl3): 8.31 (1H, d J = 8.6 Hz), 8.18 (1H, d, J = 8.6 Hz), 7.90 (1H, d, J = 8.0 Hz), 7.85 (1H, td, J =
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8.0, 1.2 Hz), 7.77ꢀ7.65 (2H, m); 13C NMR (100 MHz, CDCl3): 148.2, 137.5, 133.7, 131.3, 130.0,
129.5, 126.7, 127.8, 123.3, 117.6; LRMS (ESI) m/z: [M+H]+ 155.0.
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methyl 5-cyanopyridine-2-carboxylate (14). Prepared from the ArBr according to Method A (using
catalyst P26, 170 mg, 76%), according to Method B using cyanation kit J (539 mg, 72%) and
according to Method C (using catalyst P26, 207 mg, 69%). Obtained as white needles. m.p. 146ꢀ149
°C [lit. 146.6ꢀ147 °C (MeOH)]63; 1H NMR (400 MHz, CDCl3): 9.01 (1H, s), 8.26 (1H, d, J = 8.2 Hz),
8.15 (1H, d, J = 8.2 Hz), 4.05 (3H, s); 13C NMR (100 MHz, CDCl3): 164.2, 152.3, 150.4, 140.7,
124.8, 115.7, 113.0, 53.5; LRMS (ESI) m/z: [M+H]+ 163.2.
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6-fluoro-2-methyl-1,3-benzothiazole-5-carbonitrile (15). Prepared from the ArBr according to method
A (using catalyst P26, 40.9 g, 97%, 93% purity) and according to Method B using cyanation kit J
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(95% conversion by LCMS). Obtained as a beige solid m.p. 124ꢀ130 °C; H NMR (400 MHz,
(CD3)2SO) 8.55 (1H, s), 8.31 (1H, s), 2.83 (3H, s). 19F NMR (376 MHz, (CD3)2SO) ꢀ114.69. 13C NMR
(100 MHz, (CD3)2SO) 20.3, 99.1 (d, J = 21.0 Hz), 110.5 (d, J = 27.1 Hz), 114.7, 127.3, 142.9. 149.7,
159.0 (d, J = 251.6 Hz), 170.8. LRMS (ESI) m/z: [M+H]+ 193.0.
ASSOCIATED CONTENT
Supporting Information. Kit preparation details, reaction temperature studies, cyanide content
determination and copies of spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
Thanks to Iván Collado and Magnus Walter for support of the program and to Peter LindsayꢀScott and
Craig Ruble for helpful discussions during manuscript preparation.
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Cyanation of Aryl Halides. J. Org. Chem. 2011, 76 (2), 665-668.
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