Synthesis of benzoylacetonitriles from Pd-catalyzed carbonylation of aryl iodides and trimethylsilylacetonitrile

Article abstract of DOI:10.1021/ol300035u

Palladium-catalyzed carbonylation of aryl iodides and trimethylsilylacetonitrile to produce benzoylacetonitrile derivatives through a one-pot, three-component reaction is described. This preparation method provides good yields of the carbonylated products without any additional ligands. It has a broad substrate scope with a high tolerance for a variety of functional groups.

Full text of DOI:10.1021/ol300035u

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1118–1121
Synthesis of Benzoylacetonitriles from
Pd-Catalyzed Carbonylation of Aryl
Iodides and Trimethylsilylacetonitrile
Ahbyeol Park and Sunwoo Lee*
Department of Chemistry, Chonnam National University, Gwangju, 500-757,
Republic of Korea
sunwoo@chonnam.ac.kr
Received January 7, 2012
ABSTRACT
Palladium-catalyzed carbonylation of aryl iodides and trimethylsilylacetonitrile to produce benzoylacetonitrile derivatives through a one-pot,
three-component reaction is described. This preparation method provides good yields of the carbonylated products without any additional
ligands. It has a broad substrate scope with a high tolerance for a variety of functional groups.
Benzoylacetonitrile analogues, namely 3-oxo-3-arylpro-
panenitriles, have been used as starting materials for the
synthesis of various biologically and pharmacologically
active compounds, such as nonsteroidal anti-inflamma-
tory drugs and inhibitors against HIV.1 Moreover, they
have been employed as precursors for the synthesis of
optically active β-hydroxy carboxylic nitriles,2 which are
the key building blocks for the synthesis of 1,3-amino
alcohol moieties and a variety of heterocyclic structures,
including aminopyrazoles,3 aminoisoxazoles,4 imidazoles,5
furanes,6 and triazoles.7 The classical preparation methods
for benzoylacetonitriles involve the coupling of acetonitriles
and esters in the presence of a strong base8 and a cyanide
displacement reaction with R-bromoketones9 (Scheme 1a
and b respectively). Recently, several new methods have
been developed, such as the C-arylation of resin-bound
cyanoacetates and indium-mediated coupling of bromoa-
cetonitriles with acyl cyanides.10 These methods have draw-
backs such as the need for a preparation step for the starting
materials, low functional group tolerance, and low yields.
Since Heck reported the palladium-catalyzed carbonylation
of aryl halides with carbon monoxide and nucleophiles,11
(1) (a) Yadav, M. R.; Pawar, V. P.; Marvaniya, S. M.; Halen, P. K.;
Giridhar, R.; Mishra, A. K. Bioorg. Med. Chem. 2008, 16, 9443.
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(b) Andreu, I.; Morera, I. M.; Bosca, F.; Sanchez, L.; Camps, P.; Miranda,
M. A. Org. Biomol. Chem. 2008, 6, 860. (c) Norinder, J.; Bogar, K.;
Kanupp, L.; Baeckvall, J.-E. Org. Lett. 2007, 9, 5095. (d) Herschhorn,
A.; Lerman, L.; Weitman, M.; Gleenberg, I. O.; Nudelman, A.; Hizi, A.
J. Med. Chem. 2007, 50, 2370.
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(2) (a) Soltani, O.; Arger, M. A.; Vazquez-Villa, H.; Carreira, E. M.
(5) Laufer, S. A.; Zimmermann, W.; Ruff, K. J. J. Med. Chem. 2004,
47, 6311.
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Eur. J. 2011, 17, 3584.
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(b) Long, R. S. J. Am. Chem. Soc. 1947, 69, 990. (c) Ji, Y.; Trenkle, W. C.;
Vowles, J. V. Org. Lett. 2006, 8, 1161.
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Y.; Biehl, E. R.; Hua, L. Org. Lett. 2007, 9, 2561. (c) Ankatik, H.; Zhu,
D.; Yang, Y.; Biehl, E. R.; Hua, L. J. Org. Chem. 2009, 74, 1658.
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1999, 1, 1879. (e) Hammond, R. J.; Poston, B. W.; Ghiviriga, I.; Feske,
B. D. Tetrahedron Lett. 2007, 48, 1217. (f) Nowill, R. W.; Patel, T. J.;
Beasley, D. L.; Alvarez, J. A.; Jackson, E., III; Hizer, T. J.; Ghiviriga, I.;
Mateer, S. C.; Feske, B. D. Tetrahderon Lett. 2011, 52, 2440.
(9) Gakhar, H. K.; Gill, G. S.; Multani, J. S. J. Indian Chem. Soc.
1971, 48, 953.
(3) (a) Ranatunge, R. R.; Garvey, D. S.; Janero, D. R.; Letts, L. G.;
Martino, A. M.; Murty, M. G.; Richardson, S. K.; Young, D. V.;
Zemetseva, I. S. Bioorg. Med. Chem. 2004, 12, 1357. (b) Kordik, C. P.;
Luo, C.; Zanoni, B. C.; Dax, S. L.; McNally, J. J.; Lovenberg, T. W.;
Wilson, S. J.; Reitz, A. B. Bioorg. Med. Chem. Lett. 2001, 11, 2283.
(4) Eddington, N. D.; Cox, D. S.; Roberts, R. R.; Butcher, R. J.;
Edafiogho, I. O.; Stables, J. P.; Cooke, N.; Goodwin, A. M.; Smith,
C. A.; Scott, K. R. Eur. J. Med. Chem. 2002, 37, 635.
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1974, 39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39,
3327.
r
10.1021/ol300035u
Published on Web 02/09/2012
2012 American Chemical Society

through a one-pot three-component reaction for the first
time (Scheme 1c).
Scheme 1. Synthetic Methods of Benzoylacetonitrile
Because of its functional group tolerance and mild
conditions, we used an activated nitrile such as trimethyl-
silylacetonitrile as the nitrile source. To find the optimized
conditions, the coupling reaction of iodobenzene, tri-
methylsilylacetonitrile, and carbon monoxide was chosen
as a model.
Table 1 shows the yields under various conditions of the
desired carbonylated compound 2a and the noncarbony-
lated coupling product 3a.
Table 1. Optimization of the Bases and the Solvents for the
Carbonylationa
a variety of carbonylation methodologies have been
reported.12 The use of alcohols and amines as nucleophiles
has produced carboxylic acid derivatives.13 Carbonylative
cross-coupling reactions such as the Stille, Suzuki, Sonoga-
shira, and Heck carbonylations have produced a variety of
aryl ketones.14 Recently, the use of reductive carbonylation
to produce aromatic aldehydes under milder conditions
using CO/H2 (synthesis gas) has been reported.15 Similarly,
carbonylative CꢀH activation has been used to produce
aryl ketones.16 In addition, a variety of sp3 carbon nucleo-
philes have been used as coupling partners in the palladium-
catalyzed carbonylation.17 However, there have been no
reports on the use of aliphatic nitrile anions in the transition-
metal-catalyzed carbonylation of aryl halides including aryl
iodides, though they have been employed in direct coupling
reactions with aryl halides in the R-arylation of nitriles.18
Here, we report the use of palladium-catalyzed carbonyla-
tion for the synthesis of benzoylacetonitrile derivatives
yield (%)c
entry
Pd
Pd2(dba)3
ligand
additiveb 2a
3a
1
2c
3
4
5
6
7
8
9
Xantphosd
dppfe
ꢀ
0
0
0
0
0
Pd2(dba)3
Pd(OAc)2
Pd(PPh3)4
ꢀ
0
Xantphos
Xantphos
ꢀ
0
ꢀ
0
{(cinnamyl)PdCl}2 Xantphos
{(allyl)PdCl}2 Xantphos
ꢀ
9
13
ꢀ
21
43
trace
28
41
56
32
45
trace
{(2-Me-allyl)PdCl}2 Xantphos
{(2-Me-allyl)PdCl}2 dppf
{(2-Me-allyl)PdCl}2 tBu3P HBF4
ꢀ
trace
ꢀ
0
ꢀ
0
3
10 {(2-Me-allyl)PdCl}2
11 {(2-Me-allyl)PdCl}2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
0
CuCl
CuBr
CuCl2
14
8
12 {(2-Me-allyl)PdCl}2
13 {(2-Me-allyl)PdCl}2
14 {(2-Me-allyl)PdCl}2
(12) (a) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011,
0
€
40, 4986. (b) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem.,
CuBr2 82
CuBr2
6
Int. Ed. 2009, 48, 4114. (c) Shibata, T. Adv. Synth. Catal. 2006, 348, 2328.
(d) Strubing, D.; Beller, M. Top. Organomet. Chem. 2006, 18, 165.
(e) Trzeciak, A. M.; Ziolkowski, J. J. Coord. Chem. Rev. 2005, 249, 2308.
15
ꢀ
0
0
a Reaction conditions: 1a (0.30 mmol), trimethylsilylacetonitrile
(0.36 mmol), Pd (0.024 mmol), ZnF2 (0.18 mmol), and CO (10 atm)
were reacted in DMF (N,N-dimethylformamide) at 80 °C for 12 h.
b 0.03 mmol was added. c Determined by gas chromatography with
internal standard. d 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
e 1,10-Bis(diphenylphosphino)ferroecene.
€
(13) (a) Hu, Y.; Liu, J.; Lu, Z.; Luo, X.; Zhang, H.; Lan, Y.; Lei, A.
J. Am. Chem. Soc. 2010, 132, 3153. (b) Brennfuhrer, A.; Neumann, H.;
Pews-Davtyan, A.; Beller, M. Eur. J. Org. Chem. 2009, 38. (c) Munday,
R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130,
2754. (d) Jimenez-Rodriquez, C.; Eastham, G. R.; Cole-Hamilton, D. J.
Dalton Trans. 2005, 1826.
(14) (a) Park, A.; Park, K.; Kim, Y.; Lee, S. Org. Lett. 2011, 13, 944.
(b) Yang, Q.; Alper, H. J. Org. Chem. 2010, 75, 948. (c) Wu, X.-F.;
Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 5284. (d) Wu,
X.-F.; Neumann, H.; Spannenberg, A.; Schulz, T.; Jiao, H.; Beller, M.
J. Am. Chem. Soc. 2010, 132, 14596. (e) Lindh, J.; Fardost, A.; Almeida,
M.; Nilsson, P. Tetrahedron Lett. 2010, 51, 2470. (f) Neumann, H.;
Employing ZnF2 as an activator, the model reaction was
conducted in the presence of Pd2(dba)3 and Xantphos,
which had shown good activity in coupling reactions with
aryl halides and trimethylsilylacetonitrile in studies by the
Hartwig group.18g No product was formed in the presence
of carbon monoxide (entry 1), by using dppf as a ligand
(entry 2), or in the presence of Pd(OAc)2 and Pd(PPh3)4
(entries 3 and 4). In carbonylation, and when used as a Pd
source, {(cinnamyl)PdCl}2 showed limited activity, yield-
ing 9% of product 2a and 13% of product 3a (entry 5).
Both {(allyl)PdCl}2 and {(2-Me-allyl)PdCl}2 yielded only
a trace amount of product 3a but yielded, respectively,
21% and 43% of product 2a (entries 6 and 7). With {(2-
Me-allyl)PdCl}2 as a palladium source, both dppf and
€
Brennfuhrer, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2437.
(g) Zheng, S.; Xu, L.; Xia, C. Appl. Organomet. Chem. 2007, 21, 772.
(h) Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125, 15292.
(i) Ahmed, M. S. M.; Mori, A. Org. Lett. 2003, 5, 3057.
€
€
(15) Klaus, S.; Neumann, H.; Zapf, A.; Strubing, D.; Hubner, S.;
Almena, J.; Riermeier, T.; Gross, P.; Sarich, M.; Krahnert, W.-R.;
Rossen, K.; Beller, M. Angew. Chem., Int. Ed. 2006, 45, 154.
(16) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2010, 49, 7316.
(17) (a) Lee, P. H.; Lee, S. W.; Lee, K. Org. Lett. 2003, 5, 1103.
(b) Miura, K.; Tojino, M.; Fujisawa, N.; Hosomi, A.; Ryu, I. Angew.
Chem., Int. Ed. 2004, 43, 2423.
(18) (a) Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J. F.
J. Am. Chem. Soc. 2001, 123, 4641. (b) Beare, N. A.; Hartwig, J. F.
J. Org. Chem. 2002, 67, 541. (c) Culkin, D. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 9330. (d) Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234. (e) You, J.; Verkade, J. G. Angew. Chem., Int. Ed.
2003, 42, 5051. (f) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003.
(g) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
tBu3P HBF4 were used as a ligand; however, the yields
3
ofthe desired product were unsatisfactory(entries 8 and 9).
Org. Lett., Vol. 14, No. 4, 2012
1119

Interestingly, the reaction conditions in the absence of a
ligand showed a similar yield to that in the presence of
Xantphos (entry 10). We also took into account cost
effectiveness by testing the reaction conditions without
ligands. To increase the yield of 2a, we used copper
complexes CuCl, CuBr, CuCl2, and CuBr2 as cocatalysts.
CuBr2 gave the best result, yielding 82% of carbonylated
compound 2a and a small amount of 3a (entry 14). No
coupled product formed using CuBr2 as a catalyst (entry 15)
in the absence of Pd.
Table 3. Synthesis of Benzoylacetonitrile from Aryl Iodidea
Table 2 shows the results of the effect of changing the
base, additive, or solvent in the carbonylation reaction to
study the role of fluorides.
Table 2. Effect of Base, Additive, and Solventa
yield (%)b
entry
base
KF
additive
solvent
2a
3a
1
ꢀ
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMSO
DMF
0
0
0
0
0
5
3
20
0
2
CsF
ꢀ
3
CsF
CuBr2
ꢀ
0
4
CuBr2
CuCl2
FeF2
CoF2
NiF2
CuF2
ZnF2
ZnF2
ZnF2
0
5
ꢀ
0
6
CuBr2
CuBr2
CuBr2
ꢀ
0
7
0
8
trace
69
12
19
0
9
10
11
12c
CuBr2
CuBr2
CuBr2
32
33
0
38
2
a Reaction conditions: 1a (0.30 mmol), trimethylsilylacetonitrile
(0.36 mmol), {(2-Me-allyl)PdCl}2 (0.012 mmol), base (MF = 0.36
mmol, MF2 = 0.18 mmol), CO (10 atm), and additive (0.03 mmol) were
reacted in DMF at 80 °C for 12 h. b Determined by gas chromatography
with internal standard. c CO (5 atm).
KF, used as a fluoride source to activate trimethylsily-
lacetonitrile, gave20%ofthe noncarbonylatedproduct, 3a
(entry 1). Whether CuBr2 was added or not, CsF did not
give any coupled product (entries 2 and 3), nor did CuBr2
or CuCl2 (entries 4 and 5). Using late transition metal
fluorides such as FeF2, CoF2, and NiF2 instead of ZnF2
produced a very low yield of 2a (entries 6ꢀ8).
The use of CuF2 as a base afforded 69% of 2a and 19% of
3a. Among the tested solvents, NMP and DMSO yielded,
respectively, 32% and 33% of 2a and no 3a (entries 10 and
11).19 By decreasing the pressure of carbon monoxide to
5 atm, the yield decreased to 38% (entry 12). From these re-
sults, we found that the combination of ZnF2 and CuBr2 is
essential to obtain the desired benzoylacetonitrile in good yield.
With the optimized conditions defined, we examined the
scope of the carbonylativecoupling reactions using various
a Reaction conditions: aryl iodides (3.0 mmol), trimethylsilylaceto-
nitrile (3.6 mmol), {(2-Me-allyl)PdCl}2 (0.12 mmol), ZnF2 (1.8 mmol),
and CuBr2 (0.3 mmol) were reacted under CO (10 atm) in DMF at 80 °C
for 12 h. b Isolated yield.
aryl iodides. As shown in Table 3, most aryl iodides
produced the corresponding benzoylacetonitrile in mod-
erate to good yields. Notably, benzoylacetonitrile (2a) was
(19) No product was formed in diglyme and toulene.
1120
Org. Lett., Vol. 14, No. 4, 2012

successfully isolated in 80% yield (entry 1). Aryl iodides
bearing an alkyl group at the ortho, meta, or para position
produced a 65ꢀ75% yield (entries 2ꢀ5). Dimethyl-sub-
stituted phenyl iodides led to good yields (entries 6 and 7),
but iodoanisole derivatives produced slightly lower yields
(entries 8ꢀ10). Aryl iodides bearing a halo group, viz.
fluoro, chloro, and bromo, which are electron-withdrawing
groups, produced yields of 65%, 74%, and 82%, res-
pectively (entries 11ꢀ13). The yield from aryl iodides
with nitrile, ester, ketone, and amine groups, which are
sensitive to a base, ranged from 41% to 83% (entries
15ꢀ18). In addition, 2-iodonaphthalene and heteroaryl
iodides such as 2-iodothiophene also gave good yields
(entries 19 and 20).
Scheme 3. Proposed Mechanism
product was formed in the presence of high-pressure
carbon monoxide. In the transmetalation step, two path-
ways might exist: Path A as direct transmetalation, and
Path B as copper-catalyzed transmetalation from the
reaction with trimethylsilylacetonitrile and ZnF2. We did
not observe any change when ZnF2 and trimethylsilylace-
tonitrile were reacted in DMF-d7, as Hartwig reported.18g
However, the amount of trimethylsilylacetonitrile was
Taking atom economy into consideration, we attempted
to employ acetonitrile instead of trimethylsilylaceto-
nitrile in the synthesis of benzoylacetonitrile. As shown
in Scheme 2, none of the desired product was obtained when
iodobenzene and acetonitrile were reacted with carbon
monoxide under the optimized conditions (Scheme 2,
condition a). We used a strong base to activate the R-
proton of acetonitrile. In the presence of {(cinnamyl)PdCl}2
and Xantphos, NaHMDS (HMDS = hexamethyldisilane)
did not produce benzoylacetonitrile. However, benzoyl-
acetonitrile was obtained in 10% yield when the reaction
was carried out with NaOtBu in the presence of Pd(OAc)2
and dppf.20
decreased and trimethylsilylfluoride was identified in 19
F
NMR (ꢀ159.0 ppm, J HꢀF = 7.3 Hz),21 when ZnF2 and
trimethylsilylacetonitrile were reacted in the presence of
CuBr2 (10 mol %) in DMF-d7. Based on the experimental
results, path B would be predominant over path A. Finally,
the reductive elimination of complex III affords the desired
product.
Scheme 2. Synthesis of Benzoylacetonitrile from Acetonitrilea
In summary, we developed a novel method of synthesiz-
ing benzoylacetonitriles from the palladium-catalyzed car-
bonylation of aryl iodides and trimethylsilylacetonitrile.
This method provides a broad scope and good yields of the
carbonylated products without any additional ligands.
In addition, it shows high functional group tolerance.
To the best of our knowledge, this is the first report on
the construction of benzoylacetonitriles from palladium-
catalyzed carbonylation. Mechanistic studies are ongoing in
our laboratory.
a Reaction conditions: iodobenzene (3.0 mmol), acetonitrile (6.0
mmol), and carbon monoxide (10 atm) were reacted at 80 °C for 12 h
in the following conditions: (a) {(2-Me-allyl)PdCl}2 (0.12 mmol), ZnF2
(1.8 mmol), and CuBr2 (0.3 mmol) were used in DMF; (b)
{(cinnamyl)PdCl}2 (0.12 mmol), Xantphos (0.30 mmol), and NaHMDS
(6.0 mmol) were used in toluene; (c) Pd(OAc)2 (0.15 mmol), dppf (0.15
mmol), and NaOtBu (6.0 mmol) were used in toluene.
Acknowledgment. This work was supported by the Na-
tional Research Foundation of Korea Grant funded by the
Korean Government (2009-0072357).
Scheme 3 shows our proposed mechanism for the
palladium-catalyzed carbonylation of aryl iodides and
Me3SiCH2CN to produce benzoylacetonitriles.
The oxidative addition of aryl iodides to Pd(0) form the
palladium complex I. Next, the insertion of carbon mon-
oxide into the aryl palladium iodide complex I occurs. This
process might be reversible because the noncarbonylated
Supporting Information Available. Reaction proce-
dures and spectral and analytical data for reaction pro-
ducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) For reference of the chemical shift of 19F NMR H, see: Burger;
Moritz, P. J. Organomet. Chem. 1992, 427, 293.
(20) The yield of product was not improved even in the presence of
CuBr2.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1121