Palladium-catalyzed carbonylative α-arylation to β-ketonitriles

Article abstract of DOI:10.1002/chem.201402893

A carbonylative α-arylation process employing unactivated nitriles for the first time is described. The reaction tolerates a range of (hetero)aryl iodides and several nitrile coupling partners. No prefunctionalization of the nitriles is necessary and the resulting β-ketonitriles are obtained in good to excellent yields. The methodology also allows for a convenient ¹³C-labelling of the generated carbonyl moiety. Three COmponent α-arylation: A carbonylative α-arylation process employing nitriles for the first time is described (see scheme). The reaction tolerates a range of (hetero)aryl iodides and several nitrile coupling partners. No prefunctionalization of the nitriles is necessary and the resulting β-ketonitriles are obtained in good to excellent yields. In addition, the methodology allows for a ¹³C-labelling of the generated carbonyl moiety.

Full text of DOI:10.1002/chem.201402893

DOI: 10.1002/chem.201402893
Communication
&
Synthetic Methods
Palladium-Catalyzed Carbonylative a-Arylation to b-Ketonitriles
Johannes Schranck,[a] Mia Burhardt,[b] Christoph Bornschein,[a] Helfried Neumann,[a]
Troels Skrydstrup,*[b] and Matthias Beller*[a]
Thus, an extension of the carbonylative a-arylation towards
nitriles as easily available coupling partners constitutes a worth-
Abstract: A carbonylative a-arylation process employing
unactivated nitriles for the first time is described. The re-
while goal for further developments. The resulting b-ketoni-
triles are useful difunctional intermediates for the synthesis of
many biologically active compounds.[7] Since the derived b-hy-
action tolerates a range of (hetero)aryl iodides and several
nitrile coupling partners. No prefunctionalization of the ni-
droxy nitriles are important optically active intermediates in
triles is necessary and the resulting b-ketonitriles are ob-
the preparation of g-amino alcohols, the diversity of the b-ke-
tained in good to excellent yields. The methodology also
allows for a convenient 13C-labelling of the generated car-
tonitriles available has a significant impact on the range of
structures that can be accessed.[8] In this context, conventional
bonyl moiety.
methods for the synthesis of b-ketonitriles through acylation
of acetonitriles or carbonylative coupling of trimethylsilylaceto-
nitrile are limited to the formation of b-ketones that are unsub-
stituted at the a-position (Scheme 1).[9]
In the past few decades, the application of activated carbon
nucleophiles has emerged as a key technology for the devel-
opment of palladium-catalyzed (hetero)arylation reactions of
esters, ketones, nitriles, and related a-CH-acidic substrates.[1]
Stemming from the groundbreaking work of Miura, Buchwald,
Hartwig, and others, catalytic a-arylation procedures have
found multiple synthetic applications.[2] Careful mechanistic
studies led to the development of efficient catalyst systems for
a-arylations, which in turn have been utilized in the formation
of allylic and benzylic carbonyl compounds through C(sp2)–
C(sp3) bond formation starting from various a-CH-acidic com-
pounds (i.e., ketones, esters, malonates, amides, aldehydes, ni-
triles).[3,4]
As an important extension of such methodologies, carbony-
lative a-arylations have been studied as well. Various efforts
have been made in this area; however, initial protocols were
Scheme 1. (Carbonylative) a-arylation of nitriles.
mostly limited to the use of malonate derivatives as starting
materials.[5] Recently, our groups developed catalyst systems
that allow for the intermolecular carbonylative a-arylation of
ketones, thereby preventing the alkoxycarbonylation of the
enolate derivative to an acylated enol.[6] Unfortunately, these
carbonylative a-arylation reactions were limited to the use of
carbonyl-containing compounds as C-nucleophiles.
More recent approaches have provided access to a-substi-
tuted b-ketonitriles through the base-mediated, direct acyla-
tion of nitrile anions with unactivated esters or N-acylbenzo-
triazoles, although these protocols do not allow for the gener-
ation of a quaternary a-carbon center.[10] In addition, the direct
a-arylation of nitriles has only been reported in a few proto-
cols by Hartwig, Verkade, and co-workers (Scheme 1).[11] There-
fore, the direct synthesis of b-ketonitriles from aryl halides,
carbon monoxide, and nitriles as a simple and abundant feed-
stock would represent a desirable achievement. Herein, we
report the first examples of such carbonylative a-arylation re-
actions. A commercially available catalyst system is employed
(Pd(OAc)2/4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(xantphos)) that allows for the selective formation of a-disub-
stituted b-ketonitriles under a low pressure of gaseous CO
with the use of unactivated nitriles.
[a] J. Schranck, C. Bornschein, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
[b] M. Burhardt, Prof. Dr. T. Skrydstrup
Center for Insoluble Protein Structures (inSPIN)
Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry
Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
Fax: (+45)8619-6199
E-mail: ts@chem.au.dk
In our initial experiments, Pd(OAc)2/2,2’-bis(diphenylphosphi-
no)-1,1’-binaphthyl (BINAP) was tested as the catalyst system
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402893.
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for the carbonylative coupling of bromobenzene and iso-
butyronitrile, because it had been successfully employed in the
direct a-arylation of nitriles by Hartwig and co-workers.[11a] Un-
fortunately, attempts under different pressures of carbon mon-
oxide (5 and 30 bar) did not lead to the formation of the de-
sired b-ketonitrile, and only direct arylation of isobutyronitrile
was observed. Instead, starting the reaction from iodobenzene
at a CO-pressure of 30 bar enabled the formation of 2,2-di-
methyl-3-oxo-3-phenylpropanenitrile (2) for the first time in
21% yield with a remarkable 21:1 selectivity towards the car-
bonylated product (Table 1, entry 1). Next, further optimiza-
tions were undertaken by using this model system. Changing
the solvent did not lead to any positive effect and only nonpo-
lar aromatic solvents such as toluene and benzene turned out
to be suitable (Table 1, entries 1–6). Testing different bases
showed that only strong ones provide sufficient deprotonation
of the nitrile to enable the coupling process. Thus, organic and
inorganic bases of moderate strength did not lead to any de-
sired product formation, and lithiumdiisopropylamide (LDA)
and sodium hexamethyl disilazide (NaHMDS) gave the desired
product in 14 and 21% yield, respectively (Table 1, entries 1
and 7–12). Surprisingly, similarly basic KHMDS resulted in low
conversion and no product formation.
Next, we turned our attention to determine the influence of
different ligands on our model system. The use of standard
monodentate phosphines, such as triphenylphosphine and
di(1-adamantyl)-n-butylphosphine, as well as bidentate phos-
phine ligands, such as 1,2-bis(diphenylphosphino)ethane
(DPPE), 1,2-bis(diphenylphosphino)butane (DPPB), and 1,1’-
bis(di-phenylphosphino)ferrocene (DPPF), did not promote the
model reaction (Table 1, entries 13–15 and 17–18). However, 2-
bis(diphenylphosphino)propane gave 2 in 10% yield (Table 1,
entry 16). Applying 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene (xantphos) resulted in an enhanced conversion and
yield, albeit a lack of selectivity induced the formation of both
coupling products 1 and 2 in 35 and 27% yield, respectively
(Table 1, entry 19). In further studies by using xantphos,
a higher catalyst loading of 4 mol% was found to be advanta-
geous for the selective formation of the b-ketonitrile in 33%
yield (Table 1, entry 20). Multiple side reactions were account-
ing for the differences between conversion and desired prod-
uct yield; thus, dehalogenation, formylation to benzaldehyde,
as well as formation of benzonitrile and a-(trimethylsilyloxy)-
phenylacetonitrile were observed as side-reactions. Applying
milder reaction conditions (808C, 5 bar of CO) suppressed
these side reactions in favor of the CꢀC-bond formation to-
wards products 1 and 2, which were formed in 26 and 52%
yield, respectively (Table 1, entry 21). Finally, a high selectivity
towards the formation of the b-ketonitrile (73% yield) could be
achieved by using a slight excess of the ligand (5 mol%) with
respect to the palladium precursor (4 mol%; Table 1, entry 21).
This suggests that the loss of ligand owing to the reduction of
PdII to the catalytically active Pd0 species causes a minimal defi-
cit of ligand, which eventually leads to the formation of less-
selective catalyst species.
Table 1. Optimization of the model system.[a]
Entry
Ligand
Solvent
Base
Conv. [%][b]
Yield [%][b]
1
2
Once the optimized reaction conditions had been estab-
lished, we turned our focus on the scope and limitations of
the reaction. The model reaction with iodobenzene led to the
isolation of 2,2-dimethyl-3-oxo-3-phenylpropanenitrile in 71%
yield (Table 2, entry 1). Notably, 4-tert-butyliodobenzene was
converted into the corresponding product in a gratifying yield
of 83% (Table 2, entry 2). Similarly, ortho-, meta- and para-
mono- as well as dimethyl-substitutions were well tolerated,
resulting in good to excellent yields of 75–87% (Table 2, en-
tries 3–6). The bicyclic 1-iodonaphthalene provided a slightly
lower yield of 67% (Table 2, entry 7). Also the presence of
alkoxy substituents on the aryl iodide substrate was tolerated
in the coupling process and resulted in yields ranging from 69
to 78% (Table 2, entries 8 and 9). 4-Chloroiodobenzene proved
to be an excellent substrate, generating the corresponding b-
ketonitrile in 87% yield, and the products of 3- and 4-fluoro-
iodobenzene were obtained in good yields of 71 and 73%, re-
spectively (Table 2, entries 10–12). Electron-deficient trifluoro-
methyl substitution was also tolerated in the ortho-, meta- and
para-positions (63 to 79% yield; Table 2, entries 13–15). Addi-
tionally, we demonstrated that heterocyclic (thiophenyl)aryl io-
dides afforded the desired b-ketonitriles in good to excellent
isolated yields (93 and 71%; Table 2, entries 16 and 17). At-
tempts to apply other aryl halides under similar reaction condi-
tions resulted in consistently lower selectivities towards the
1
2
3
4
5
6
7
8
9
10
11
12
13[c]
14[c]
15
16
17
18
19
20[d]
21[e]
22[f]
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
PPh3
nBuPAd2
DPPE
DPPP
DPPB
DPPF
xantphos
xantphos
xantphos
xantphos
toluene
dioxane
DMF
DMSO
benzene
THF
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
KHMDS
LDA
KOtBu
Cs2CO3
NaOAc
NEt3
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
25
30
59
72
59
73
47
93
60
84
5
1
1
0
3
0
1
0
2
0
0
0
0
0
0
0
0
0
21
0
4
0
15
0
0
14
0
0
0
0
0
0
0
10
0
0
27
33
52
73
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
2
30
58
55
68
42
62
90
90
>99
>99
0
35
7
26
2
[a] General reaction conditions: iodobenzene (1 mmol), isobutyronitrile
(1.2 mmol), Pd(OAc)2 (2 mol%), ligand (2 mol%), base (1.3 mmol), solvent
(2 mL), CO (30 bar), 1008C, 16 h. [b] Conversions and yields were deter-
mined on the basis of calibrated GC data by using hexadecane as an in-
ternal standard. [c] 8 mol% of ligand. [d] Pd(OAc)2 (4 mol%), xantphos
(4 mol%). [e] Pd(OAc)2 (4 mol%), xantphos (4 mol%), CO (5, bar), 808C.
[f] Pd(OAc)2 (4 mol%), xantphos (5 mol%), CO (5, bar), 808C.
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Table 2. Pd-catalyzed carbonylative a-arylation of nitriles with different
aryliodides.[a]
Table 2. (Continued)
Entry
16[c]
Aryl iodide
Product
Yield [%]
93
Entry
1
Aryl iodide
Product
Yield [%]
71
17[b]
71
2
3
83
78
[a] General reaction conditions: aryl iodide (1 mmol), nitrile (1.2 mmol),
Pd(OAc)2 (4 mol%), xantphos (5 mol%), NaHMDS (1.3 mmol), toluene
(2 mL), CO (5 bar), 808C, 16 h; isolated yields. [b] Nitrile (1 mmol), CO
(10 bar), 1008C. [c] Nitrile (1 mmol), CO (10 bar), 808C. [d] Nitrile (1 mmol),
CO (10 bar), 608C.
4[b]
5[b]
6[b]
85
87
75
7[b]
67
8[b]
69
78
87
Scheme 2. Carbonylative a-arylation of different nitriles. General reaction
conditions: 3-iodotoluene (1 mmol), nitrile (1.2 mmol), Pd(OAc)2 (4 mol%),
xantphos (5 mol%), NaHMDS (1.3 mmol), toluene (2 mL), CO (5 bar), 808C,
16 h; isolated yields. [a] Nitrile (1 mmol), CO (10 bar), 1008C.
9[b]
10[b]
carbonylated coupling product (with ArBr) or low conversions
(in the case of ArCl), thus requiring independently comprehen-
sive investigations.
11[b]
12[b]
13[b]
14[c]
73
71
63
79
Next, we examined the scope of the nitrile coupling partners
(Scheme 2). Starting from 3-iodotoluene and isobutyronitrile
yielded the desired b-ketonitrile in 83% yield. By using 2-meth-
ylbutyronitrile, the corresponding product was isolated in 78%
yield. Cyclic nitriles, such as cyclopentanecarbonitrile and cy-
clohexanecarbonitrile, were also well tolerated under these
conditions, affording the b-ketonitriles in similarly high yields
of 86 and 81%, respectively. In addition, aroylation of a-substi-
tuted benzyl cyanide substrates proceeded smoothly to gener-
ate the corresponding products in yields of 72–86%. However,
attempts to convert benzyl nitrile and similar substrates having
a CH2-group in the a-position were not successful under these
conditions, because subsequent aroylation of the products in
their enol form occurred, leading to the corresponding enol-
benzoates. This is in agreement with similar observations
15[d]
68
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(1.3 mmol, 238.5 mg), and a stir bar. All vials were placed into an
alloy plate, sealed with a septum, and locked out of the glove box.
The vials were then equipped with an inlet needle and flushed
with argon. Toluene (2 mL) and isobutyronitrile (1.2 mmol, 108 ml)
were injected into each vial. After stirring the reaction mixtures for
5 min, iodo benzene (1 mmol, 112 mL) was added to each vial. The
alloy plate with the six vials was then placed in an autoclave
(300 mL; Parr Instruments 4560 series). At room temperature, the
autoclave was flushed with CO (three times) and pressurized to
5 bar. Afterwards, the autoclave was heated to 808C for 16 h, then
cooled to room temperature, and the remaining CO was released
slowly. After discharging, HCl (1.0m; 0.5 mL) was added to each
vial and the product was extracted with ethyl acetate. Then, the
aqueous phase was extracted three times. After drying the com-
bined organic phases over magnesium sulphate and evaporating
the solvent, the crude product was purified by flash chromatogra-
phy using heptane/ethyl acetate (1:0!20:1) to give 2,2-dimethyl-
3-oxo-3-phenylpropanenitrile (2) as a pale yellow oil.
made by us for the carbonylative coupling of deoxybenzoins
generating vinylbenzoates rather than 1,3-diketones.[12]
Making use of the two-chamber system (COware) with the
ex situ generation of CO from 9-methyl-9Hfluorene-9-carbonyl
chloride (COgen), as described earlier,[13] allowed for the use of
a low concentration of carbon monoxide. Thus, starting from
iodobenzene and by using 13COgen, the 13C-labeled b-ketoni-
trile was obtained in 50% yield (Scheme 3).
Scheme 3. Labelling experiments by using COgen.
To prove the usefulness of the synthesized b-ketonitriles as
building blocks, we demonstrated the straightforward synthe-
sis of b-aryl-b-hydroxynitriles. More specifically, we applied
a metal-free selective catalytic hydrosilylation procedure based
on the use of tetrabutylammonium fluoride (TBAF) as catalyst,
which has been reported by our group recently.[14] Thus, after
the palladium-catalyzed coupling process was complete, the
resulting b-ketonitrile was reacted with phenyl silane in the
presence of a catalytic amount of TBAF at room temperature
(Scheme 4). Notably, a selective reduction of the carbonyl
group was observed, whereas the nitrile moiety remained un-
touched. After subsequent hydrolysis, the corresponding b-hy-
droxynitrile could be isolated in a very good yield of 88%.
Acknowledgements
We thank the state of Mecklenburg-Vorpommern and the Bun-
desministerium fꢁr Bildung und Forschung (BMBF) for financial
support. In addition, the research leading to these results has
received funding from the Innovative Medicines Initiative Joint
Undertaking (CHEM21) under grant agreement no. 115360, re-
sources of which are composed of a financial contribution
from the European Union’s Seventh Framework Programme
(FP7/2007–2013) and EFPIA companies in kind contribution.
Generous financial support from the Danish National Research
Foundation (grant no. DNRF59) is also gratefully acknowl-
edged. We also thank Dr. W. Baumann, Dr. C. Fischer, S. Scharei-
na, and S. Buchholz (LIKAT) for analytical support, as well as
Sandra Leiminger and Sçren Hancker (LIKAT) for technical assis-
tance.
Keywords: a-arylation
·
b-ketonitriles
·
carbonylation
·
palladium
Scheme 4. Selective reduction of b-ketonitriles to b-hydroxynitriles.
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a relatively low catalyst loading.
Experimental Section
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In a glove box, six glass vials (4 mL) were charged with Pd(OAc)2
(4 mol%, 8.9 mg), xantphos (5 mol%, 28.9 mg), NaHMDS
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Received: April 1, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Synthetic Methods
J. Schranck, M. Burhardt, C. Bornschein,
H. Neumann, T. Skrydstrup,* M. Beller*
Three COmponent a-arylation: A car-
bonylative a-arylation process employ-
ing nitriles for the first time is described
(see scheme). The reaction tolerates
a range of (hetero)aryl iodides and sev-
eral nitrile coupling partners. No pre-
functionalization of the nitriles is neces-
sary and the resulting b-ketonitriles are
obtained in good to excellent yields. In
addition, the methodology allows for
&& – &&
Palladium-Catalyzed Carbonylative a-
Arylation to b-Ketonitriles
a
13C-labelling of the generated carbon-
yl moiety.
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!