Direct synthesis of arylketones by nickel-catalyzed addition of arylboronic acids to nitriles

Article abstract of DOI:10.1021/ol1003252

A convenient and efficient method for the synthesis of various arylketones by nickel-catalyzed addition of arylboronic acids to nitriles is described. A catalytic cycle involving Ni(II) species as the catalytic intermediates is proposed to account for the present catalytic reaction.

Full text of DOI:10.1021/ol1003252

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1736-1739
Direct Synthesis of Arylketones by
Nickel-Catalyzed Addition of Arylboronic
Acids to Nitriles
Ying-Chieh Wong, Kanniyappan Parthasarathy, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received February 7, 2010
ABSTRACT
A convenient and efficient method for the synthesis of various arylketones by nickel-catalyzed addition of arylboronic acids to nitriles
is described. A catalytic cycle involving Ni(II) species as the catalytic intermediates is proposed to account for the present catalytic
reaction.
Arylketones are important building blocks in both natural
products and functional materials.1 The classical routes
to the synthesis of arylketones rely on the oxidation of
the corresponding secondary alcohols by chromium re-
agents,2 Friedel-Crafts3a-e acylation of aromatic com-
pounds in the presence of AlCl3, in addition to a few other
methods.3f-i
In recent years, the transition-metal-catalyzed addition
reactions provide great opportunities for the synthesis of
arylketones from nitriles.4 Larock’s group observed a
palladium-catalyzed annulation reaction of 2-iodoben-
zonitriles with internal alkynes5a-c and the addition of an
arene C-H bond to nitriles and arylboronic acids to
nitriles.5d,e Later, Lu et al. developed a Pd(II)-catalyzed
intramolecular addition of vinylpalladium species to nitriles6a
and a cationic palladium-catalyzed addition of arylboronic
acids to nitriles.6b,c In 2006, Miura and co-workers reported
a rhodium-catalyzed addition of arylboronic acids to nitriles
that led to the formation of arylketone derivatives.7 Recenly
Murakami et al. showed a rhodium-catalyzed synthesis of
R-keto esters by the reaction of cyanoformate with arylbo-
ronic acids.8 However, the methods described above for
synthesizing arylketones generally require long reaction time,
expensive catalyst, or harsh reaction conditions.
(4) (a) Ishiyama, T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N.
J. Org. Chem. 1998, 63, 4726. (b) Ishiyama, T.; Kizaki, H.; Miyaura, N.;
Suzuki, A. Tetrahedron Lett. 1993, 34, 7595. (c) Hirao, T.; Misu, D.; Agawa,
T. J. Am. Chem. Soc. 1985, 107, 7179. (d) Satoh, T.; Itaya, T.; Miura, M.;
Nomura, M. Chem. Lett. 1996, 823. (e) Ishiyama, T.; Hartwig, J. F. J. Am.
Chem. Soc. 2000, 122, 12043. (f) Liebeskind, L. S.; Srogl, J. J. Am. Chem.
Soc. 2000, 122, 11260. (g) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am.
Chem. Soc. 2004, 126, 15356, and references therein.
(1) For reviews, see: (a) Tsuji, J. Transition Metal Reagents and
Catalysts; Wiley: New York, 2004. (b) Diederich, F.; Stang, P. J. Metal-
Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim, Germany,
1998. (c) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; John Wiley & Sons: Weinheim, Germany, 2004.
(2) (a) Hudlicky, M. In Oxidations in Organic Chemistry; ACS
Monograph 186; American Chemical Society: Washington, DC, 1990. (b)
Larock, R. C. ComprehensiVe Organic Transformations; VCH: New York,
1989; p 591.
(5) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999,
121, 3238. (b) Pletnev, A. A.; Larock, R. C. Tetrahedron Lett. 2002, 43,
2133. (c) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67,
9276. (d) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302. (e)
Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551.
(3) (a) Olah, G. Friedel-Crafts and Related Reactions; Interscience
Publishers: New York, 1964; Vol. III, p 1259. (b) Osman, M. HelV. Chim.
Acta 1982, 65, 2448. (c) Zimmerman, H. E.; Paskovich, D. H. J. Am. Chem.
Soc. 1964, 86, 2149. (d) Heitzler, F. R.; Hopf, H.; Jones, P. G.;
Bubenitschek, P.; Lehne, V. J. Org. Chem. 1993, 58, 2781. (e) Ianni, A.;
Waldvogel, S. R. Synthesis 2006, 5, 2103. (f) Savari, M. H.; Sharghi, H. J.
Org. Chem. 2004, 69, 6953. (g) Savari, M. H.; Sharghi, H. Synthesis 2004,
3, 2165. (h) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F. Tetrahedron 2004,
60, 10843. (i) Bensari, A.; Zaveri, N. T. Synthesis 2003, 2, 267.
(6) (a) Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343. (b)
Zhao, B.; Lu, X. Tetrahedron Lett. 2006, 47, 6765. (c) Zhao, B.; Lu, X.
Org. Lett. 2006, 8, 5987.
(7) Ueura, K.; Miyamura, S.; Satoh, T.; Miyaura, M. J. Organomet.
Chem. 2000, 595, 31.
(8) Shimizu, H.; Murakami, M. Chem. Commun. 2007, 2855.
10.1021/ol1003252  2010 American Chemical Society
Published on Web 03/24/2010

Up to now, there has been no example of using first-
row transition metal complexes as catalyst for the addition
of arylboronic acids to nitriles. Our continued interest in
nickel-catalyzed addition reactions9 and the activation of
nitrile groups10 prompted us to explore the possibility of
using low-cost nickel complexes as catalysts for addition
reactions. Herein, we wish to report a nickel-catalyzed
addition of arylboronic acids to nitriles, providing a very
convenient and efficient method for the synthesis of
arylketones.
Our initial attempt to find an effective nickel catalyst
system for the addition of phenylboronic acid (1a) to
2-phenylacetonitrile 2a using nickel complexes11a with
monodentate phosphine ligand PPh3 in 1,4-dioxane in the
presence of ZnCl2 and H2O at 80 °C for 8 h was not
successful (Table 1, entries 2 and 3). Fortunately, when
used on the yield of the reaction of 1a with benzylnitrile
(2a) was further investigated. Other bidentate phosphine
nickel(II) complexes Ni(dppb)Br2, Ni(dppe)Br2, and Ni(d-
ppe)Cl2 are also effective for the addition reaction (Table
1, entries 4-7). Among these complexes examined,
Ni(dppe)Cl2 is most active, furnishing 3a in 95% yield as
determined by an NMR integration method (Table 1, entry
7) or 90% isolated yield (Table 2, entry 1). The solvent
chosen for the present catalytic reaction also showed
profound effect on the yield of product 3a. The best
solvent is 1,4-dioxane in which 3a was obtained in 95%
yield. THF is also effective, giving 3a in 68% yield (Table
1, entry 8). Other solvents such as toluene, DCE, DMF,
and nitromethane were ineffective for the catalytic reaction
(Table 1, entries 9-12).
The presence of a Lewis acid was crucial to the reaction.
Various Lewis acids were examined to understand the
effect on the product yield. Among them, ZnCl2 gave the
best results and afforded 3a in 95% yield. Other Lewis
acids including ZnI2, ZnBr2, ZnCl2, Zn(OAc)2, CuI, CuBr,
and CuCl are less effective for the catalytic reaction (see
the Supporting Information for detailed studies). It is
noteworthy that the present catalytic reaction required
water for hydrolysis of the imine intermediate; without
adding extra water, 3a was obtained in only 62% yield.
The use of 1.0 equiv of H2O gave 3a in nearly quantitative
yield. On the basis of the above optimization studies, we
choose the conditions in entry 7, boronic acid 1 (1.0
mmol), nitrile 2 (0.50 mmol), Ni(dppe)Cl2 (5 mol %),
ZnCl2 (0.75 mmol), and H2O (0.50 mmol) in 1,4-dioxane
(1.0 mL) at 80 °C with a reaction time of 8 h as the
standard reaction conditions for the following studies.
Table 1. Effect of Catalyst and Solvent on the Addition
Reaction of Phenylboronic Acid (1a) to Phenylacetonitrile 2aa
entry
catalyst
solvent
yield (%)b
1c
2
3
4
5
6
7
8
9
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
toluene
DCE
DMF
CH3NO2
0
0
0
Ni(PPh3)2Br2
Ni(PPh3)2Cl2
Ni(dppp)Br2
Ni(dppb)Br2
Ni(dppe)Br2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
Ni(dppe)Cl2
16
22
75
95
68
trace
0
Under the standard reaction conditions, various arylbo-
ronic acids reacted smoothly with benzylnitrile (2a) to
give the corresponding arylketones. Thus, 4-tolyl- and
4-anisylboronic acids (1b and 1c) underwent addition with
2a to give 3b and 3c in 81 and 80% yield, respectively
(entries 2 and 3). Similarly, the reaction of 3-nitrophe-
nylboronic acid 1d with 2a gave 3d in 77% yield (entry
4). The above results indicate that electron-withdrawing
and -donating arylboronic acids work equally well. In
addition, this reaction is also compatible with fluoro,
chloro, and bromo substituents on the aromatic ring of
arylboronic acid 1. Thus 3-fluoro-, 3-chloro-, and 4-bro-
mophenylboronic acids 1e-g reacted with 2a to give
addition products 3e, 3f, and 3g in 93, 90, and 84% yield,
respectively (entries 5-7). In addition, sterically bulkier
1-naphthyl- and 1-pyrenylboronic acids 1h,i also reacted
smoothly with 2a to give the corresponding arylketones
in excellent yields (entries 8 and 9).
10
11
12
0
0
a All reactions were carried out using boronic acid 1a (1.0 mmol), nitrile
2a (0.50 mmol), Ni complex (5 mol %), ZnCl2 (0.75 mmol), H2O (0.50
mmol), and solvent (1.0 mL) at 80 °C for 8 h under N2. b Yields were
measured by 1H NMR, using mesitylene as an internal standard. c Reaction
time was 12 h.
we switched to nickel complex Ni(dppe)Br2, we started
to observe product 3a in 16% yield (entry 4). Product 3a
was thoroughly characterized by its 1H and 13C NMR and
mass data.
To understand the nature of this nickel-catalyzed
addition reaction, the effect of nickel complex and solvent
(9) (a) Kong, K.-C.; Cheng, C.-H. J. Chem. Soc., Chem. Commun. 1991,
423. (b) Kong, K.-C.; Cheng, C.-H. Organometallics 1992, 11, 1972. (c)
Feng, C.-C.; Nandi, M.; Sambaiah, T.; Cheng, C.-H. J. Org. Chem. 1999,
64, 3538. (d) Sambaiah, T.; Li, L. P.; Huang, D. J.; Lin, C. H.; Rayabarapu,
D. K.; Cheng, C.-H. J. Org. Chem. 1999, 64, 3663. (e) Sambaiah, T.; Huang,
D. J.; Cheng, C.-H. J. Chem. Soc., Perkin Trans. 1 2000, 195. (f) Majumdar,
K. K.; Cheng, C.-H. Org. Lett. 2000, 2, 2295. (g) Huang, Y.-C.; Majumdar,
K. K.; Cheng, C.-H. J. Org. Chem. 2002, 67, 1682.
The present nickel-catalyzed addition reaction is suc-
cessfully extended to various substituted arylnitriles 2b-d.
Thus, benzonitrile (2b) reacted well with 1a to afford
benzophenone (3j) in 78% yield (entry 10). In a similar
manner, the reaction of methyl 4-cyanobenzoate (2c) and
4-acetylbenzonitrile (2d) with 1a gave arylketones 3k and
3l in 82 and 76% yield, respectively (entries 11 and 12).
Alkyl nitriles also worked well for this reaction. Thus,
(10) (a) Luo, F.-H.; Chu, C.-I.; Cheng, C.-H. Organometallics 1998,
17, 1025. (b) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2007,
9, 505. (c) Hsieh, J.-C.; Cheng, C.-H. Chem. Commun. 2008, 2992.
Org. Lett., Vol. 12, No. 8, 2010
1737

butyronitrile (2e) and isobutyronitrile (2f) reacted smoothly
with 1a to give 3m and 3n in 69 and 63% yield,
respectively (entries 13 and 14). Similarly, both cyclo-
propane and cyclohexanecarbonitriles 2g and 2h reacted
with 1a to provide the expected arylketone derivatives 3o
and 3p in 82 and 85% yield, respectively (entries 15 and
16).
Table 2. Results of the Reaction of Arylboronic Acids with Nitrilesa
On the basis of known metal-catalyzed addition reac-
tions of organometallic reagents with nitriles,4-9 a possible
reaction mechanism is proposed to account for the present
nickel-catalyzed reaction (Scheme 1). The catalytic reaction
Scheme 1
.
Proposed Mechanism for the Addition Reaction of
Arylboronic Acids with Nitriles
is probably initiated by the formation of NiII(OH) species 4
through substitution of a coordinated chloride in [Ni(PP)Cl2]
by water with the assistance of Lewis acid ZnCl2. Intermedi-
ate 4 then undergoes transmetalation with arylboronic acid
(1a) to give arylnickel(II) intermediate 5. Coordination of
phenylacetonitrile 2 to the nickel center gives intermediate
6 or 6′.11e Then 1,2-addition of the coordinated aryl group
to the nitrile group gives intermediate 7. Hydrolysis of 7
afforded the final arylketone 3 and regenerates the active
NiII(OH) species 4 for the next catalytic cycle.
In the catalytic reaction, ZnCl2 likely acts as a Lewis
acid to remove chloride from the nickel(II) species (see
Scheme 1), providing a coordination site for the water
and nitrile substrate. Another possible role of ZnCl2 is as
an activator for a nitrile substrate, promoting the addition
of aryl to the nitrile group in 6′. It is interesting to note
that no extra base is necessary for the transmetalation of
arylboronic acid to the nickel center. The presence of a
metal hydroxide11,12 such as NiII(OH) species 4 in the
catalytic cycle accounts well for this observation.
(11) (a) Lin, P.-S.; Jeganmohan, M.; Cheng, C.-H Chem. Asian J. 2007,
2, 1409. (b) Rayabarapu, D. K.; Cheng, C.-H. Acc. Chem. Res. 2007, 40,
971. (c) Lin, P. -S.; Jeganmohan, M.; Cheng, C.-H. Chem.sEur. J. 2008,
14, 11296. (d) Mannathan, S.; Jeganmohan, M.; Cheng, C.-H. Angew.
Chem., Int. Ed. 2009, 48, 2192. (e) Najera, C.; Sansano, J. M. Angew. Chem.,
Int. Ed. 2009, 48, 2452
.
a Unless otherwise mentioned, all reactions were carried out with boronic
acid 1a (1.0 mmol), nitrile 2a (0.50 mmol), Ni(dppe)Cl2 (5 mol %), ZnCl2
(0.75 mmol), H2O (0.50 mmol), and 1,4-dioxane (1.0 mL) at 80 °C for 8 h
under N2. b Isolated yields.
(12) (a) Suginome, M.; Yamamoto, A.; Murakami, M. J. Am. Chem.
Soc. 2003, 125, 6358. (b) Miura, T.; Nakazawa, H.; Murakami, M. Chem.
Commun. 2005, 2855. (c) Miura, T.; Shimada, M.; Murakami, M. J. Am.
Chem. Soc. 2005, 127, 1094. (d) Miura, T.; Sasaki, T.; Harumashi, T.;
Murakami, M. J. Am. Chem. Soc. 2006, 128, 2516
.
1738
Org. Lett., Vol. 12, No. 8, 2010

In conclusion, we have demonstrated that low-cost nickel
complexes, instead of novel metal complexes, can also
effectively catalyze the addition of arylboronic acids to
nitriles to afford substituted arylketones in good to excellent
yields. This method provides an opportunity for the synthesis
of various unsymmetrical biarylketones and arylketones in
one pot. Further extension of the reaction to an intramolecular
version and a detailed mechanistic investigation are in
progress.
Acknowledgment. We thank the National Science Council
of the Republic of China (NSC-96-2113-M-007-020MY3)
for support of this research.
Supporting Information Available: General experimen-
tal procedure and characterization details. This material
isavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
OL1003252
Org. Lett., Vol. 12, No. 8, 2010
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