A Homogeneous Method for the Conveniently Scalable Palladium- and Nickel-Catalyzed Cyanation of Aryl Halides

Article abstract of DOI:10.1021/acs.oprd.6b00229

Homogeneous conditions for the palladium-catalyzed cyanation of aryl halides were developed. This new system features a broad scope of aryl chlorides and bromides, uses 2-propanol or 1-butanol as solvent, and is readily scalable. The same conditions can also provide simple benzonitriles using the recently developed (TMEDA)NiCl(o-tolyl) precatalyst in conjunction with 1,1′-bis(diphenylphosphino)ferrocene (dppf) as a ligand.

Full text of DOI:10.1021/acs.oprd.6b00229

Communication
pubs.acs.org/OPRD
A Homogeneous Method for the Conveniently Scalable Palladium-
and Nickel-Catalyzed Cyanation of Aryl Halides
Finn Burg,† Julian Egger, Johannes Deutsch, and Nicolas Guimond*
Chemical Development Department, Bayer Pharma AG, Friedrich-Ebert-Str. 217-333, 42096 Wuppertal, Germany
S
* Supporting Information
ABSTRACT: Homogeneous conditions for the palladi-
um-catalyzed cyanation of aryl halides were developed.
This new system features a broad scope of aryl chlorides
and bromides, uses 2-propanol or 1-butanol as solvent, and
is readily scalable. The same conditions can also provide
simple benzonitriles using the recently developed
(TMEDA)NiCl(o-tolyl) precatalyst in conjunction with
1,1′-bis(diphenylphosphino)ferrocene (dppf) as a ligand.
ryl nitriles are highly versatile building blocks widely used
Ain the chemical industry as intermediates or functional
entities in final products.1 Catalytic approaches starting from
aryl halides, whether they are Ni-,2 Cu-,3 or Pd-catalyzed,4 now
constitute the state-of-the art approach to this coveted
functional group. Even though these catalytic methods show
very broad scope on small scale, their ready application on
larger scale remains challenging. This is in part due to the
cyanide sources typically employed. Given the propensity of
cyanide ions toward poisoning palladium,5 chemists have
traditionally used cyanide sources that are only slightly soluble
in common reaction solvents. This makes for heterogeneous
reaction mixtures where physicochemical parameters such as
the particle size of the cyanide source6 and presence of
impurities7 can have a dramatic impact on the reaction
outcome, thus complicating scale-up campaigns.
As an important advance, Beller reported that the nontoxic
K3Fe(CN)6 could also be used as a cyanide transfer agent.8
Besides its low toxicity, it has the advantage of preventing easy
catalyst poisoning. It however typically requires a high
temperature for the transmetalation of the cyanide from iron
to palladium. Further improvements from the laboratories of
Huang, Buchwald, and Kwong4e−h showed that Pd-catalyzed
cyanation reactions could be conducted at somewhat lower
temperature in mixtures of dioxane, acetonitrile, or t-BuOH and
water. These reports seem to showcase the broadest scope
elaborated so far with regard to aryl chlorides. Despite these
advances, most reactions are heterogeneous or biphasic
mixtures that may cause reproducibility and scaling issues
depending on physical factors such as vessel size, stirring speed,
and substrate solubility (Figure 1). One strategy that
intrinsically addresses these issues was reported with palladium
by Beller in 2003.9 In this example, instead of “controlling” the
cyanide delivery through its solubility or speed of trans-
metalation, acetone cyanohydrin was used as cyanide source
and was slowly added to the reaction mixture at a rate slower
than the catalytic turnover. This allowed for some of the
Figure 1. General methods for aryl halide cyanation.
highest turnover numbers observed for Pd-catalyzed aryl
cyanation. Although this method showed great potential with
palladium, nickel,2a and copper,3c,10 it never benefited from the
latest advancements in ligand design.
Herein we report the discovery of homogeneous conditions
allowing aryl halide cyanation reactions to be run reliably with a
broad scope of aryl chlorides and aryl bromides. As opposed to
most previous reports employing either DMF, NMP, DMAc, or
aqueous solvent mixtures, these reactions are run in alcoholic
solvents at temperatures ranging from 80 to 100 °C.
Remarkably, the same conditions can also accommodate the
nickel-catalyzed cyanation of simple aryl halides. Of note, the
choice of using either i-PrOH (water miscible) or n-BuOH
(nonwater miscible) in these reactions provides the highest
degree of flexibility for isolation of the desired aryl nitrile.
Through screening of cyanation conditions we discovered
that n-BuOH provided a good replacement solvent in the most
common systems for cyanation reactions. Having some
reproducibility problems with reported heterogeneous or
biphasic methods, we decided to embark on the optimization
of the strategy reported by Beller in 2003 whereby a slow
addition of acetone cyanohydrin was performed. From our first
attempts, we were glad to observe the full conversion of a
model substrate (2-chlorotoluene) yielding the desired cyanide
with an addition time of 2 h of the acetone cyanohydrin
Received: July 1, 2016
© XXXX American Chemical Society
A
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a
solution using XPhos as a ligand and [Pd(cinnamyl)Cl]2 as a
catalyst. While screening for different bases, it was found that
DIPEA was well-suited for the reaction. This thus makes for
homogeneous, easily reproducible, and readily scalable reaction
conditions. While using this method for different projects, we
noticed that some ligands were more useful than others
depending on the substrate. Based on these results, we
established that one of the four ligands showed in Figure 2
usually provides the desired product in good to high yield,
XPhos being the best ligand in the vast majority of cases.
Scheme 1. Palladium-Catalyzed Cyanation of Aryl Halides
Figure 2. Ligands for aryl cyanation.
Having established a first set of conditions, we were curious
to explore the scope of the reaction. Scheme 1 summarizes the
results obtained on a 1.5 mmol scale with various aryl and
heteroaryl halides. These new conditions were found to be on
par with the best palladium-catalyzed aryl cyanation reported so
far. Both electron-withdrawing and donating substituents do
not pose any problem to the reaction. In addition, sterically
hindered as well as unprotected alcohols, amines, and
carboxylic acids react smoothly to provide the desired
benzonitrile. Regarding the heteroaryl halides, pyridines bearing
a halide at the 2-, 3-, or 4- position are all compatible. Of note,
we found that 1,1′-bis(diphenylphosphino)ferrocene (dppf)
was a good ligand to perform the reaction on 2-halopyridine
(3k). In some cases, the use of higher temperature (100 °C) in
n-BuOH provided better conversion (see 3c, 3g, and 3m). Five-
membered heterocycles were also compatible, as exemplified by
the successful cyanation of 3-bromo-N-methylindazole (3r) and
2-chloro-5-methylthiophene (3s).
a
Conditions: Aryl halide (1.5 mmol), acetone cyanohydrin (1.2 equiv
in 2 mL of solvent added over 2 h), [Pd(cinnamyl)Cl]2 (1 mol %),
XPhos (3 mol %), DIPEA (2 equiv) in i-PrOH (4 mL), 80 °C. Yields
b
of isolated product are given. Reaction ran in n-BuOH at 100 °C.
c
d
Reaction ran using dppf (3 mol %) as ligand. Reaction ran using t-
Having developed a homogeneous system where no major
issues associated with a solid reagent particle size, stirring
speed, or substrate solubility were expected, we were confident
to test it on larger scale. Aryl bromide 1u needed to be
converted to the corresponding benzonitrile 3u. A first test on
small scale revealed that our newly developed method provided
full conversion of the substrate to the desired product. The
reaction also worked just as well using the inexpensive base
triethylamine. We then ran some experiments on multigram
scale while monitoring other reaction parameters more
carefully. Measuring the pH of the reaction over time revealed
an immediate decline upon initial addition of acetone
cyanohydrin (see the Supporting Information). This pH
decrease can be well-explained by the formation of HBr upon
release of acetone and coupling of the cyanide. This then
generates a buffered system with the trialkylamine base. After
addition of about one-sixth of the cyanide source, the pH
decreased at a much slower rate. Based on this observation, we
hypothesized that the decomposition rate of acetone
cyanohydrin to deliver the required cyanide would be faster
at the beginning of the reaction. Therefore, we assumed the
sensitivity toward the initial acetone cyanohydrin addition rate
would also be much greater. Upon performing the cyanation on
400 g scale, we decided to add the first third of acetone
BuXPhos (3 mol %) as ligand.
cyanohydrin solution at a slower rate (3.3 g/min) (Scheme 2).
The remaining two-thirds was then added at a rate
Scheme 2. Reaction on a 400 g Scale
corresponding to a 5 h total addition time (6.1 g/min). Once
the starting material was fully converted, a simple cool down of
the reaction mixture caused the desired product to crystallize at
58 °C. Water was added to ensure no salt would crystallize and
the product could be obtained in excellent purity (see the
Supporting Information) by simple filtration. This highlights
another advantage of this method: a product can be obtained
by direct crystallization from the reaction mixture. The
B
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miscibility of i-PrOH with water is very practical in this respect.
In addition, if an extractive workup is needed, n-BuOH can be
employed as solvent, thus allowing extraction without the
addition of other organic solvents or great excess of water.
Nickel-catalyzed aryl cyanation reactions are significantly
underdeveloped in the literature compared to their palladium
counterparts. They were however shown to exhibit similar
reactivity in many cases.2 In fact, as early as 1974, Cassar et al.2a
showed that acetone cyanohydrin could be used to convert aryl
halides into benzonitriles. Considering the important economic
advantage of using nickel catalysis on large scale, we decided to
try our new cyanation conditions using this abundant transition
metal. Being aware that the initial reduction of Ni(II) to Ni(0)
is more difficult than with palladium catalysis, we opted to use
the newly developed air-stable precatalyst reported simulta-
neously by the Doyle group as well as Pfizer.11 This made for a
simpler reaction setup where ligands can be easily screened
without the need for additional reductant. To our delight, using
this new precatalyst in conjunction with dppf as ligand allowed
us to perform a homogeneous nickel-catalyzed aryl cyanation
without modification of the reaction conditions developed for
palladium. The scope obtained with this system is shown in
Scheme 3. Most electron-deficient simple aryl bromides are
successfully on 400 g scale and were able to obtain the desired
product by simple crystallization from the reaction mixture.
The corresponding benzonitrile was thus obtained with high
yield and high purity. Using analogous conditions, it was found
that nickel catalysis is also viable with simple substrates, offering
a cost-effective and operationally convenient method for
preparative-scale cyanation reactions.
EXPERIMENTAL SECTION
■
Safety Considerations. Acetone cyanohydrin is a highly
toxic compound that should be handled extremely carefully.
Small-scale experiments should always be conducted in a well-
ventilated fume hood. The use of larger vessels should always
be fitted with appropriated basic scrubber. The reaction mixture
or the work up phases should never be acidic as the evolution
of HCN can occur.
All reactions were conducted under nitrogen atmosphere.
Nitrogen was bubbled through the solvent for 30 min before
each experiment. All reagents were used as received from
1
commercial sources. H NMR experiments were recorded on
either a Bruker 400, 500, or 600 MHz spectrometer. The
chemical shifts are reported in parts per million (ppm) relative
to tetramethylsilane. High-resolution mass spectra were
obtained on LTQ Orbitrap XL instrument. Low-resolution
MS was obtained using a DSQII-GCMS instrument. Thin layer
chromatography analysis was performed using Alugram Xtra
SIL precoated TLC aluminum sheets. Flash column chroma-
tography was done on a Biotage Isolera One using Puriflash
cartridges (Interchim PF-50SIHP-JP) packed with 50 μm
particle size silica gel. See below for elution conditions.
a
Scheme 3. Nickel-Catalyzed Cyanation of Aryl Halides
General Procedure A (Pd-Catalyzed). A 20 mL vial was
charged with the aryl halide (1.5 mmol), [Pd(cinnamyl)Cl]2
(7.8 mg, 0.015 mmol, 1.0 mol %), and Xphos (21 mg, 0.045
mmol, 3.0 mol %) and flushed with N2. i-PrOH (4.0 mL) was
then added followed by DIPEA (0.39 g, 3.0 mmol, 2.0 equiv).
The reaction mixture was heated to 80 °C and acetone
cyanohydrin (0.15 g, 1.8 mmol, 1.2 equiv) dissolved in 2 mL i-
PrOH was added via syringe pump over 2 h (very important).
Subsurface addition in the reaction mixture is required to avoid a
too-fast addition of cyanide through big drops. After addition of
the acetone cyanohydrin, the reaction mixture was cooled down
to room temperature and diluted with sat. NaHCO3 solution
and water and extracted three times with EtOAc. The
combined organic layers were washed with sat. NaCl solution
and dried over magnesium sulfate. After removal of all volatiles
in vacuo, the crude material was subjected to Biotage flash
column chromatography (see below for elution conditions).
2-Cyano-4-fluoroaniline (3a). 3a is an off-white solid
obtained in 99% (204 mg) yield from 2-chloro-4-fluoroaniline
(0.22 g, 1.5 mmol) following general procedure A. The product
was isolated by column chromatography using 25% EtOAc in
heptane as eluent. 1H NMR (500 MHz, DMSO-d6): δ 7.32 (dd,
J = 8.8, 3.2 Hz, 1H), 7.23 (td, J = 8.8, 8.8, 3.2, 1H), 6.80 (dd, J
= 9.3, 4.6 Hz, 1H), 5.95 (br s, 2H). 13C NMR (100 MHz,
DMSO-d6): 152.5 (d J = 232.6 Hz), 148.8 (d, J = 1.4 Hz),
122.2 (d, J = 23.1 Hz), 117.3 (d, J = 25.0 Hz), 117.0 (d, J = 2.8
Hz), 116.8 (d J = 8.0 Hz), 92.9 (d, J = 9.4 Hz) HRMS
calculated for C7H5FN2 [M + H]+: 137.0510, found 137.0505.
2-(2,6-Dimethoxyphenyl)-benzonitrile (3b). 3b is a white
solid obtained in 94% (339 mg) yield from 2′-bromo-2,6-
dimethoxy-1,1′-biphenyl (0.44 g, 1.5 mmol) following general
procedure A. The product was isolated by column chromatog-
a
Conditions: Aryl halide (1.5 mmol), acetone cyanohydrin (1.2 equiv
in 2 mL of solvent added over 2 h), (TMEDA)NiCl(o-tolyl) (5 mol
%), dppf (7.5 mol %), DIPEA (2 equiv) in i-PrOH (4 mL), 80 °C.
Yields of isolated product are given. Calculated yield by HPLC using
b
1,3,5-trimethoxybenzene as an internal standard.
well-tolerated, including 3-halopyridine systems, which under-
went smooth transformation. The use of aryl chlorides as well
as electron-rich aryl bromides gave low to no conversion.
Although the scope of nickel-catalyzed cyanation is to date not
as elaborated compared to palladium methods, we are confident
that the operational simplicity (no need for preformation of
Ni(0) using reductants, easily performed ligand screening)
coupled with the low cost of nickel will facilitate the
development of this method for the production of simple aryl
nitriles on an industrial scale.
In summary, we have developed homogeneous conditions
allowing cyanation reactions to be run reproducibly with a
broad scope of aryl chlorides and aryl bromides. These
reactions are run in alcoholic solvent using DIPEA as a base
at temperatures between 80 and 100 °C, leading to reaction
completion typically within 2 h. We used this method
1
raphy using 10% EtOAc in heptane as eluent. H NMR (600
C
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MHz, CDCl3): δ 7.71 (dd, J = 7.5, 1.1 Hz), 7.59 (td, J = 7.7,
7.7, 1.5 Hz, 2H), 7.42−7.37 (m, 2H), 7.34 (t, J = 8.4, 8.4 Hz,
1H), 6.66 (d, J = 8.4 Hz), 3.75 (s, 6H). The 1H NMR spectrum
is in accord with literature precedent.12
DMSO-d6): 149.3, 139.0, 132.6 (q, J = 5.0 Hz), 126.2, 121.5 (q,
J = 274 Hz), 122.1 (q, J = 34.4 Hz), 116.2, 116.1. HRMS
calculated for C8H3F3N2O2: 216.0147. It did not ionize using
our LC-HRMS instrument. The GCMS was found to be 215.9.
3,5-Dimethoxybenzonitrile (3i). 3i is a white solid obtained
in 93% (227 mg) yield from 1-chloro-3,5-dimethoxybenzene
(0.26 g, 1.5 mmol) following general procedure A. The product
was isolated by column chromatography using 20% EtOAc in
heptane as eluent. 1H NMR (600 MHz, CDCl3): δ 6.76 (d, J =
2.4 Hz, 2H), 6.65 (t, J = 2.3, 2.3 Hz, 1H), 3.81 (s, 6H). The 1H
NMR spectrum is in accord with literature precedent.18
3-Aminobenzonitrile (3c). 3c is a brown solid obtained in
73% (129 mg) yield from 3-chloroaniline (0.19 g, 1.5 mmol)
following general procedure A, but performing the reaction in
n-BuOH at 100 °C instead of i-PrOH at 80 °C. The product
was isolated by column chromatography using 20% EtOAc in
heptane as eluent. 1H NMR (600 MHz, CDCl3): δ 7.13 (t, J =
7.9, 7.9 Hz, 1H), 6.92 (dt, J = 7.6, 1.1, 1.1 Hz, 1H), 6.83−6.81
1
(m, 1H), 6.80−6.77 (m, 1H), 3.86 (br s, 1H). The H NMR
2-Methyl-3-nitrobenzonitrile (3j). 3j is an off-white solid
obtained in 84% (205 mg) yield from 2-chloro-6-nitrotoluene
(0.26 g, 1.5 mmol) following general procedure A. The product
was isolated by column chromatography using 15% EtOAc in
spectrum is in accord with literature precedent.13
3-(Hydroxymethyl)benzonitrile (3d). 3d is an white solid
obtained in 93% (186 mg) yield from 3-chlorobenzyl alcohol
(0.21 g, 1.5 mmol) following general procedure A. The product
was isolated by column chromatography using 20% EtOAc in
1
heptane as eluent. H NMR (600 MHz, CDCl3): δ 8.11 (dd, J
= 8.3, 1.0 Hz, 1H), 7.88 (dd, J = 7.7, 1.1 Hz, 1H), 7.51 (dd, J =
8.0, 8.0 Hz), 2.77 (s, 3H). The 1H NMR spectrum is in accord
with literature precedent.19
1
heptane as eluent. H NMR (600 MHz, CDCl3): δ 7.65−7.63
(m, 1H), 7.60−7.56 (m, 1H), 7.56−7.53 (m, 1H), 7.45 (t, J =
1
7.7, 7.7 Hz, 1H), 4.70 (s, 2H), 2.99 (br s, 1H). The H NMR
2-Methylquinoline-4-carbonitrile (3l). 3l is an off-white
solid obtained in 94% (237 mg) yield from 4-chloro-2-
methylquinoline (0.27 g, 1.5 mmol) following general
procedure A. The product was isolated by column chromatog-
spectrum is in accord with literature precedent.14
4-Acetylbenzonitrile (3e). 3e is a white solid obtained in
98% (214 mg) yield from 4-chloroacetophenone (0.23 g, 1.5
mmol) following general procedure A. The product was
isolated by column chromatography using 20% EtOAc in
heptane as eluent. 1H NMR (600 MHz, CDCl3): δ 8.07−8−04
1
raphy using 15% EtOAc in heptane as eluent. H NMR (600
MHz, CDCl3): δ 8.15−8.07 (m, 2H), 7.82 (ddd, J = 8.4, 7.0,
1.3 Hz, 1H), 7.70−7.66 (m, 1H), 7.62 (s, 1H), 2.80 (s, 3H).
The 1H NMR spectrum is in accord with literature precedent.20
4-Methyl-quinoline-2-carbonitrile (3m). A 20 mL vial was
charged with the 2-chloro-4-methylquinoline (1.5 mmol, 0.27
g), [Pd(cinnamyl)Cl]2 (0.0075 mmol, 3.9 mg, 5.0 mol %
equiv), and Xphos (0.045 mmol, 21 mg, 3.0 mol %) and flushed
with N2. n-BuOH (4 mL) was then added followed by DIPEA
(3.0 mmol, 0.52 mL, 2 equiv). The reaction mixture was heated
to 80 °C, and acetone cyanohydrin (1.8 mmol, 164 μL, 1.2
equiv) dissolved in 2 mL of n-BuOH was added via syringe
pump over 2 h (very important). Subsurface addition in the
reaction mixture is required to avoid a too-fast addition of
cyanide through big drops. After addition of the acetone
cyanohydrin, the reaction mixture was cooled down to room
temperature and diluted with sat. NaHCO3 solution and water
and extracted three times with EtOAc. The combined organic
layers were washed with sat. NaCl solution and dried over
magnesium sulfate. After removal of all volatiles in vacuo, the
crude material was subjected to Biotage flash column
chromatography (8% EtOAc in heptane as eluent). 3m (212
mg) was obtained as an off-white solid in 84% yield. The
product was isolated by column chromatography using 15%
EtOAc in heptane as an eluent. 1H NMR (600 MHz, CDCl3): δ
8.13 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.81 (ddd, J
= 8.4, 7.0, 1.3 Hz), 7.71 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.49 (s,
1
(m, 2H), 7.80−7.77 (m, 2H), 2.66 (s, 3H). The H NMR
spectrum is in accord with literature precedent.15
Terephtalonitrile (3f). 3f is a white solid obtained in 89%
(171 mg) yield from 4-chlorobenzonitrile (0.20 g, 1.5 mmol)
following general procedure A. The product was isolated by
column chromatography using 20% EtOAc in heptane as
1
1
eluent. H NMR (600 MHz, CDCl3): δ 7.74 (s, 4H). The H
NMR spectrum is in accord with literature precedent.16
4-Carboxybenzonitrile (3g). A 20 mL vial was charged with
4-chlorobenzoic acid (0.24 g, 1.5 mmol), [Pd(cinnamyl)Cl]2
(7.8 mg, 0.015 mmol, 1.0 mol %), and Xphos (21 mg, 0.045
mmol, 3.0 mol %) and flushed with N2. n-BuOH (4.0 mL) was
then added followed by DIPEA (0.39 g, 3.0 mmol, 2.0 equiv).
The reaction mixture was heated to 100 °C and acetone
cyanohydrin (0.15 g, 1.8 mmol, 1.2 equiv) dissolved in 2.0 mL
of n-BuOH was added via syringe pump over 2 h (very
important). Subsurface addition in the reaction mixture is required
to avoid a too-fast addition of cyanide through big drops. After
addition of the acetone cyanohydrin, the reaction mixture was
cooled down to room temperature and diluted with 1 M NaOH
solution and EtOAc. The organic layer was then washed twice
with a 1 M NaOH solution. FeSO4·6H2O was then added to
the combined aqueous layer, and conc. HCl was added until pH
0. The now pale green solution was extracted three times with
EtOAc, and the combined organic layers were washed with
brine. The analytically pure desired product 3g was obtained as
1
1H), 2.75 (s, 3H). The H NMR spectrum is in accord with
literature precedent.21
1
a white solid (220 mg) after evaporation of the volatiles. H
3-Quinolinecarbonitrile (3n). 3n is a white solid obtained in
95% (220 mg) yield from 4-bromoisoquinoline (0.31g, 1.5
mmol) following general procedure A. The product was
isolated by column chromatography using 15% EtOAc in
NMR (600 MHz, CDCl3): δ 13.58 (br s, 1H), 8.09 (d, J = 8.1
Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H. The 1H NMR spectrum is in
accord with literature precedent.17
1
4-Nitro-3-trifluoromethylbenzonitrile (3h). 3h is an off-
white solid obtained in 55% (177 mg) yield from 5-chloro-2-
nitrobenzotrifluoride (0.34 g, 1.5 mmol) following general
procedure A. The product was isolated by column chromatog-
heptane as an eluent. H NMR (600 MHz, CDCl3): δ 9.42 (s,
1H), 8.90 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz,
1H), 7.94 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.80 (ddd, J = 8.1, 7.1,
1
1.0 Hz. The H1H NMR spectrum is in accord with literature
raphy using 25% EtOAc in heptane as eluent. H NMR (500
precedent.16
1
MHz, DMSO-d6): δ 8.68 (d, J = 1.0 Hz, 1H), 8.52 (dd, J = 8.4,
1H-Indole-6-carbonitrile (3o). 3o is a brown solid obtained
in 99% (213 mg) yield from 6-chloroindole (0.23 g, 1.5 mmol)
1.4 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz,
D
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following general procedure A, but using t-BuXphos (0.045
mmol, 19 mg, 3.0 mol %) instead of Xphos (3.0 mol %). The
product was isolated by column chromatography using 15%
(3 × 500 mL). An easy-to-filter white powder of excellent
purity was obtained and dried in a vacuum oven for 48 h at 40
°C. 303 g (97% yield) of 3u were obtained. The amount of
residual Pd was determined via XRFS, and a value of 29 ppm
1
EtOAc in heptane as eluent. H NMR (600 MHz, CDCl3): δ
1
8.87 (br s, 1H), 7.77 (s, 1H), 7.69 (d, 8.1 Hz, 1H), 7.42 (dd, J =
2.8, 2.8 Hz, 1H), 7.34 (dd, J = 8.3, 1.3 Hz, 1H), 6.63−6.60 (m,
1H). The 1H NMR spectrum is in accord with literature
precedent.22
1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (3p). 3p is an off-
white solid obtained in 85% (182 mg) yield from 4-chloro-7-
azaindole (0.23 g, 1.5 mmol) following general procedure A.
The product was isolated by column chromatography using
20% EtOAc in heptane as eluent. 1H NMR (400 MHz, DMSO-
d6): δ 12.38 (br s, 1H), 8.42 (d, J = 4.9 Hz, 1H), 7.84 (dd, J =
2.9, 2.9 Hz, 1H), 7.56 (d, J = 4.9 Hz, 1H), 6.66 (dd, J = 3.42,
1.7 Hz, 1H). The 1H NMR spectrum is in accord with literature
precedent.4e
was obtained. H NMR (400 MHz, CDCl3): δ = 7.70 (d, J =
8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.97 (s, 3H), 2.49 ppm
(s, 3H). Spectral data match the one previously reported.23
General Procedure B (Ni-Catalyzed). A 20 mL vial was
charged with the aryl halide (1.5 mmol), NiCl(o-tolyl)
(TMEDA) (23 mg, 0.075 mmol, 5.0 mol %), and dppf (62
mg, 0.11 mmol, 7.5 mol %) and flushed with N2. i-PrOH (4
mL) was then added followed by DIPEA (0.39 g, 3.0 mmol, 2
equiv). The reaction mixture was heated to 80 °C and acetone
cyanohydrin (1.2 equiv) dissolved in 2 mL of i-PrOH was
added via syringe pump over 2 h (very important). Subsurface
addition in the reaction mixture is required to avoid a too-fast
addition of cyanide through big drops. After addition of the
acetone cyanohydrin, the reaction mixture was cooled down to
room temperature and diluted with sat. NaHCO3 solution and
water and extracted three times with EtOAc. The combined
organic layers were washed with sat. NaCl solution and dried
over magnesium sulfate. After removal of all volatiles in vacuo,
the crude material was subjected to Biotage flash column
chromatography (see below for elution conditions).
1-Methyl-1H-indazole-3-carbonitrile (3r). 3r is a white solid
obtained in 88% (208 mg) yield from 3-bromo-1-methyl-
indazole (0.32 g, 1.5 mmol) following general procedure A, but
using t-BuXphos (0.045 mmol, 19 mg, 3.0 mol %) instead of
Xphos (3.0 mol %). The product was isolated by column
1
chromatography using 20% EtOAc in heptane as eluent. H
NMR (500 MHz, DMSO-d6): δ 7.92−7.85 (m, 2H), 7.60 (ddd,
J = 8.4, 7.1, 1.0 Hz, 1H), 7.45−7.40 (m, 1H), 4.21 (s, 3H). 13
C
Methyl-3-cyanobenzoate (3v). 3v is an off-white solid
obtained in 91% (219 mg) yield from methyl-3-bromobenzoate
(0.32 g, 1.5 mmol) following general procedure B. The product
was isolated by column chromatography using 15% EtOAc in
NMR (125 MHz, DMSO-d6): δ 139.7, 127.7, 124.4, 123.8,
118.7, 115.5, 113.8, 111.4, 36.7 HRMS calculated for (C9H7N3
+ H)+: 158.0713, found 158.0707.
1
3-Methyl-2-thiophenecarbonitrile (3s). 3s is a yellow oil
obtained in 67% (124 mg) yield from 2-chloro-3-methylthio-
phene (0.20 g, 1.5 mmol) following general procedure A. The
product was isolated by column chromatography using 5%
heptane as eluent. H NMR (600 MHz, CDCl3): δ 8.32 (dd, J
= 1.4, 1.4 Hz, 1H), 8.28 (ddd, J = 7.9, 1.4, 1.4 Hz, 1H), 7.85
(ddd, J = 7.8, 1.4, 1.4 Hz, 1H), 7.60 (dd, J = 7.8, 7.8 Hz, 1H),
3.97 (s, 3H). The 1H NMR spectrum is in accord with
literature precedent.24
1
EtOAc in heptane as eluent. H NMR (600 MHz, CDCl3): δ
7.47 (d, J = 5.0 Hz, 1H), 6.95 (d, J = 5.0 Hz, 1H), 2.45 (s, 3H).
Spectral data match the one previously reported. The 1H NMR
spectrum is in accord with literature precedent.20
4-Acetylbenzonitrile (3w). 3e is a white solid obtained in
86% (186 mg) yield from 4-bromoacetophenone (0.30 g, 1.5
mmol) following general procedure B. The product was
isolated by column chromatography using 15% EtOAc in
heptane as eluent. 1H NMR (600 MHz, CDCl3): δ 8.07−8−04
6-Methoxy-3-pyridinecarbonitrile (3t). 3t is a white solid
obtained in 88% (177 mg) yield from 5-chloro-2-methoxypyr-
idine (0.22 g, 1.5 mmol) following general procedure A. The
product was isolated by column chromatography using 10%
1
(m, 2H), 7.80−7.77 (m, 2H), 2.66 (s, 3H). The H NMR
spectrum is in accord with literature precedent.15
1
EtOAc in heptane as eluent. H NMR (600 MHz, CDCl3): δ
Terephtalonitrile (3x). 3x is a white solid obtained in 88%
(169 mg) yield from 4-bromobenzonitrile (0.27 g, 1.5 mmol)
following general procedure B. The product was isolated by
column chromatography using 20% EtOAc in heptane as
8.50 (dd, J = 2.4, 0.6 Hz, 1H), 7.78 (dd, J = 8.6, 2.4 Hz, 1H),
1
6.83 (dd, J = 8.6, 0.7 Hz, 1H), 4.00 (s, 3H). The H NMR
spectrum is in accord with literature precedent.18
1
1
2-Nitro-3-methyl-4-cyanoanisole (3u). A 6 L double-walled
glass reactor was charged with aryl bromide (400 g, 1.63 mol, 1
equiv), [Pd(cinnamyl)Cl]2 (8.42 g, 16.25 mmol, 1.0 mol %),
and XPhos (23.2 g, 48.8 mmol, 3.0 mol %) and flushed with N2
for 30 min. In the meantime a mixture of i-PrOH (1610 mL)
and Et3N (453 mL, 3.25 mol, 2 equiv) was degassed for 30 min
with a stream of N2 and then added to the reaction vessel. The
resulting yellow suspension was heated within 30 min to 80 °C
and became a clear solution. To the reaction mixture was added
subsurface a solution of acetone cyanohydrin (179 mL, 1.95
mol, 1.2 equiv) in degassed i-PrOH (1610 mL) with a pump.
The first third was added at a rate of 3.3 g/min, and the
remaining two-thirds were added at a rate of 6.1 g/min. The
total addition time resulted in 5 h 24 min. Upon completion of
the addition the reaction was checked for full conversion and
then cooled to 0 °C over 1 h. At 58 °C the desired product
precipitated. After aging at 0 °C for 16 h, 1 L of water was
added, and the mixture was stirred for another 1 h. Then the
product was filtered, and the filter cake was washed with water
eluent. H NMR (600 MHz, CDCl3): δ 7.74 (s, 4H). The H
NMR spectrum is in accord with literature precedent.16
3-Quinolinecarbonitrile (3y). 3y is a white solid obtained in
85% (195 mg) yield from 3-bromoquinoline (0.31 g, 1.5 mmol)
following general procedure B. The product was isolated by
column chromatography using 15% EtOAc in heptane as
1
eluent. H NMR (600 MHz, CDCl3): δ 9.04 (d, J = 2.0 Hz,
1H), 8.55 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.92−
7.88 (m, 2H), 7.73−7.68 (m, 1H). The 1H NMR spectrum is in
accord with literature precedent.16
4-Isoquinolinecarbonitrile (3z). 3z is a white solid obtained
in 94% (217 mg) yield from 4-bromoisoquinoline (0.31 g, 1.5
mmol) following general procedure A. The product was
isolated by column chromatography using 15% EtOAc in
1
heptane as eluent. H NMR (600 MHz, CDCl3): δ 9.42 (s,
1H), 8.90 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz,
1H), 7.94 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.80 (ddd, J = 8.1, 7.1,
1.0 Hz, 1H). The 1H NMR spectrum is in accord with literature
precedent.16
E
DOI: 10.1021/acs.oprd.6b00229
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
S. L. Angew. Chem., Int. Ed. 2013, 52, 10035−10039. (f) Yeung, P. Y.;
So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2011, 13, 648−651.
(g) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y. Tetrahedron Lett.
2011, 52, 7038−7041. (h) Zhang, J.; Chen, X.; Hu, T.; Zhang, Y.; Xu,
K.; Yu, Y.; Huang, J. Catal. Lett. 2010, 139, 56−60. (i) Cohen, D. T.;
Buchwald, S. L. Org. Lett. 2015, 17, 202−205. (j) Utsugi, M.; Ozawa,
H.; Toyofuku, E.; Hatsuda, M. Org. Process Res. Dev. 2014, 18, 693−
698. (k) Zou, T.; Feng, X.; Liu, H.; Yu, X.; Yamamoto, Y.; Bao, M.
RSC Adv. 2013, 3, 20379−20384. (l) Zhang, D.; Sun, H.; Zhang, L.;
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2909−2911. (m) Tu, Y.; Zhang, Y.; Xu, S.; Zhang, Z.; Xie, X. Synlett
2014, 25, 2938−2942.
Pyridine-3-carbonitrile (3aa). A 20 mL vial was charged
with 3-chloropyridine (0.17g, 1.5 mmol), NiCl(o-tolyl)
(TMEDA) (23 mg, 0.075 mmol, 5.0 mol %), and dppf (62
mg, 0.11 mmol, 7.5 mol %) and flushed with N2. i-PrOH (4.0
mL) was then added followed by DIPEA (0.39 g, 3.0 mmol, 2.0
equiv). The reaction mixture was heated to 80 °C, and acetone
cyanohydrin (0.15 g, 1.8 mmol, 1.2 equiv) dissolved in 2 mL of
i-PrOH was added via syringe pump over 2 h (very important).
The needle has to be plunged in the reaction mixture to avoid a
too-fast addition of cyanide through big drops. After addition of
the acetone cyanohydrin, 1,3,5-trimethoxybenzene (0.25 g, 1.5
mmol, 1.0 equiv) was added as internal standard, and the
HPLC sample was taken. 3aa is obtained in 58% yield based on
the internal standard.
(5) For mechanistic insights, see: (a) Erhardt, S.; Grushin, V. V.;
Kilpatrick, A. H.; Macgregor, S. A.; Marshall, W. J.; Roe, C. J. Am.
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(8) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388−
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(9) (a) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
2003, 42, 1661−1664. For the use of TMSCN, see: (b) Sundermeier,
M.; Mutyala, S.; Zapf, A.; Spannenberg, A.; Beller, M. J. Organomet.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.6b00229.
1
Copies of H and 13C NMR spectra of new compounds
3a, 3h, and 3r and additional information (reaction pH
profile, pictures, XRFS values) about the conversion of
1u to 3u (PDF)
(10) Schareina, T.; Zapf, A.; Cotte,
Synth. Catal. 2011, 353, 777−780.
(11) (a) Magano, J.; Monfette, S. ACS Catal. 2015, 5, 3120−3123.
(b) Shields, J. D.; Gray, E. E.; Doyle, A. G. Org. Lett. 2015, 17, 2166−
2169.
́
A.; Gotta, M.; Beller, M. Adv.
AUTHOR INFORMATION
Corresponding Author
*E-mail: nicolas.guimond@bayer.com.
■
Present Address
(12) Naber, J. R.; Buchwald, S. L. Adv. Synth. Catal. 2008, 350, 957−
961.
†F.B.: Department of Chemistry, Ludwig-Maximilians-Uni-
(13) Rahaim, R. J.; Maleczka, R. E. Org. Lett. 2005, 7, 5087−5090.
(14) Yamamoto, T.; Zhumagazin, A.; Furusawa, T.; Tanaka, R.;
Yamakawa, T.; Oe, Y.; Ohta, T. Adv. Synth. Catal. 2014, 356, 3525−
3529.
(15) Cohen, D. T.; Buchwald, S. L. Org. Lett. 2015, 17, 202−205.
(16) Dutta, U.; Lupton, D. W.; Maiti, D. Org. Lett. 2016, 18, 860−
863.
versitat Munchen, Butenandtstrasse 5−13, 81377, Munich,
̈
̈
Germany.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Steve Weigt for technical support throughout scale
up.
■
(17) Kim, S. M.; Kim, D. W.; Yang, J. W. Org. Lett. 2014, 16, 2876−
2879.
(18) Zhu, Y.; Li, L.; Shen, Z. Chem. - Eur. J. 2015, 21, 13246−13252.
(19) Zheng, S.; Yu, C.; Shen, Z. Org. Lett. 2012, 14, 3644−3647.
(20) Yu, H.; Richey, R. N.; Miller, W. D.; Xu, J.; May, S. A. J. Org.
Chem. 2011, 76, 665−668.
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DOI: 10.1021/acs.oprd.6b00229
Org. Process Res. Dev. XXXX, XXX, XXX−XXX