Synthesis of ketones by palladium-catalysed desulfitative reaction of arylsulfinic acids with nitriles

Article abstract of DOI:10.1039/c1cc13352g

Palladium-catalysed desulfitative addition of arylsulfinic acids to aryl and alkyl nitriles with 2,2′-bipyridine as a ligand afforded a variety of aryl ketones via hydrolysis of ketimine intermediates.

Full text of DOI:10.1039/c1cc13352g

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COMMUNICATION
Synthesis of ketones by palladium-catalysed desulfitative reaction of
arylsulfinic acids with nitrilesw
Tao Miaoa and Guan-Wu Wang*ab
Received 6th June 2011, Accepted 5th July 2011
DOI: 10.1039/c1cc13352g
Palladium-catalysed desulfitative addition of arylsulfinic acids to
aryl and alkyl nitriles with 2,20-bipyridine as a ligand afforded a
variety of aryl ketones via hydrolysis of ketimine intermediates.
Nevertheless, at least one ortho substituent was necessary for
the decarboxylative addition to occur successfully and this
method was mainly suitable for aliphatic nitriles. We recently
reported the Pd-catalyzed desulfitative Heck-type reaction of
arylsulfinic acids with alkenes initiated by a palladium(II)
species.8 Herein, we disclose the efficient synthesis of aryl
ketones by palladium-catalyzed desulfitative reaction of aryl-
sulfinic acids with nitriles (Scheme 1, eqn (2)).
Aryl ketones are common structural motifs in functional
molecules and natural products,1 and are important precursors
for many elaborate organic compounds. The traditional synthesis
of aryl ketones employs Friedel–Crafts acylation of aromatic
compounds,2 yet involves the usage of corrosive AlCl3 and
generation of hard-to-separate isomeric mixtures due to
limited regioselectivity. In recent years, increasing attention
has been paid to transition-metal-catalysed synthesis of aryl
ketones from nitriles through the hydrolysis of ketimine
intermediates. For example, Larock’s group reported the
novel Pd-catalysed reactions of arenes and arylboronic acids
with nitriles.3 Subsequently, the Lu group,4 Cheng group5 and
others6 developed various catalytic systems for the synthesis of
aryl ketones from arylboronic acids and nitriles. In these
reactions, arylboronic acids were transmetallized to organo-
metallic compounds by palladium,4 nickel5 or rhodium.6 The
synthesis of aryl ketones from palladium-catalyzed decarboxy-
lative addition of benzoic acids to nitriles was described
last year by Larhed and co-workers (Scheme 1, eqn (1)).7
In our initial study, we investigated the desulfitative reaction
of benzenesulfinic acid (1a) with benzonitrile (2a) in the
presence of a palladium catalyst (10 mol%), H2O (1 equiv.)
under an argon atmosphere to optimize the reaction conditions
with different additives, ligands and solvents. When 20 mol%
of 2,20-bipyridine was used as the ligand, the reaction of 1a
with 2a in isobutyl alcohol was promising and gave aryl ketone
3aa in 42% yield (Table 1, entry 1). Various acids were chosen
as additives to examine the effect on the product yield. While
AcOH, TFA and H3PO4 were not beneficial for the catalytic
reaction (Table 1, entries 2–4), HCl and HNO3 were improper
additives and prohibited the reaction (Table 1, entries 5 and 6).
Much to our pleasure, when concentrated H2SO4 were
employed, 3aa was obtained in 89% yield (Table 1, entry 7).
Other bidentate nitrogen ligands and a phosphine ligand, i.e.
triphenylphosphine (Ph3P), were also screened. Replacing
2,20-bipyridine with 1,10-phenanthroline (Phen) afforded a
slightly lower yield (Table 1, entry 8 vs. entry 7). Tetramethyl-
ethylenediamine (TMEDA) and Ph3P were detrimental to this
transformation (Table 1, entries 9 and 10). Further screening
of solvents revealed that isobutyl alcohol was the optimal
solvent (Table 1, entries 11–18 vs. entry 7). An isolated yield of
61% was obtained when n-butyl alcohol was chosen as the
solvent, whereas only a trace amount of 3aa was detected with
tert-butyl alcohol (Table 1, entries 11 and 12). Other polar
solvents such as ethanol, dioxane, DMF and DMSO were
harmful to this reaction (Table 1, entries 13–16). Low-polar
solvents including dichloroethane (DCE) and toluene were
infeasible (Table 1, entries 17 and 18).
Scheme 1 Palladium-catalysed synthesis of ketones from nitriles.
a Hefei National Laboratory for Physical Sciences at Microscale,
CAS Key Laboratory of Soft Matter Chemistry, Joint Laboratory of
Green Synthetic Chemistry and Department of Chemistry,
University of Science and Technology of China, Hefei,
Anhui 230026, P. R. China. E-mail: gwang@ustc.edu.cn;
Fax: +86 551 3607864; Tel: +86 551 3607864
With the optimized reaction conditions (10 mol% of Pd(OAc)2,
20 mol% of 2,20-bipyridine, 2 equiv. of concentrated H2SO4,
1 equiv. of H2O, 2.0 mL of isobutyl alcohol, 100 1C, Ar, 6 h) in
hand, this Pd-catalyzed desulfitative addition reaction was
then extended to a wide array of arylsulfinic acids and
nitriles to explore the scope and limitation of the reaction
(Table 2). Benzenesulfinic acid (1a) reacted efficiently with
b State KeyLaboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou, Gansu 730000, PR. China
w Electronic supplementary information (ESI) available: Experimental
procedures for the synthesis, spectral data and NMR spectra of
products 3. See DOI: 10.1039/c1cc13352g
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9501–9503 9501

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Table 1 Palladium-catalysed desulfitative reaction of benzenesulfinic
acid with benzonitrile under various conditionsa
Table 2 Palladium-catalysed desulfitative reaction of arylsulfinic
acids with nitrilesa
Entry Ligand
Additive Solvent (1C)
Yieldb (%)
1
2
3
4
5
6
7
8
2,20-Bipyridine —
Isobutyl alcohol (100) 42
Isobutyl alcohol (100) 25
Isobutyl alcohol (100) 49
2,20-Bipyridine AcOH
2,20-Bipyridine TFA
c
2,20-Bipyridine H3PO4 Isobutyl alcohol (100) 44
d
2,20-Bipyridine HNO3
2,20-Bipyridine HCle
Isobutyl alcohol (100) Trace
Isobutyl alcohol (100)
0
f
2,20-Bipyridine H2SO4 Isobutyl alcohol (100) 89
f
Phen
TMEDA
Ph3P
H2SO4f Isobutyl alcohol (100) 78
9
H2SO4f Isobutyl alcohol (100)
H2SO4f Isobutyl alcohol (100)
7
8
61
10
11
12
13
14
15
16
17
18
2,20-Bipyridine H2SO4f n-Butyl alcohol (100)
2,20-Bipyridine H2SO4 tert-Butyl alcohol (82)g Trace
f
2,20-Bipyridine H2SO4 EtOH (78)g
34
30
19
14
Trace
0
f
2,20-Bipyridine H2SO4f Dioxane (100)
2,20-Bipyridine H2SO4f DMF (100)
2,20-Bipyridine H2SO4f DMSO (100)
2,20-Bipyridine H2SO4f Toluene (100)
2,20-Bipyridine H2SO4 DCE (83)g
a
Unless otherwise specified, all reactions were carried out using 1a
(0.8 mmol), 2a (0.5 mmol) and Pd(OAc)2 (10 mol%) in a solvent
b
c
(2.0 mL) under different conditions for 6 h. Isolated yield. 85%
d
H3PO4 was used. 65% HNO3 was used. 37% HCl was used. 98%
e
f
g
H2SO4 was used. Refluxing temperature of the solvent.
both electron-rich and -deficient aryl nitriles, giving aryl ketones
3ab–3ak in good to excellent yields. 4-Tolylnitrile (2b) and
3-tolylnitrile (2c) underwent addition with 1a to give 3ab and
3ac in 92% and 95% yields, respectively. However, when the
2-position of aryl nitrile was substituted with a methyl group,
the yield of product 3ad decreased dramatically to 61%,
probably due to the ortho steric hindrance. Substrate 2e, a
disubstituted benzonitrile, afforded 3ae in good yield (87%).
Gratifyingly, this reaction is also tolerant with bromo, chloro,
and fluoro substituents on the aromatic ring of aryl nitriles 2,
3-bromo-, 4-chloro-, and 4-fluorobenzonitriles reacted with 1a
to generate addition products 3af, 3ag and 3ah in 84%, 88% and
75% yields, respectively. Substrate 2i bearing a strong electron-
withdrawing nitro group could be used and provided 3ai in 71%
yield. It is worth noting that alkyl nitriles were also applicable to
this catalytic system to furnish alkyl aryl ketones 3aj and 3ak in
96% and 92% yields. To further expand the scope of this
reaction, we next examined the reaction of several other arylsulfinic
acids including 4-methylbenzenesulfinic acid (1b), 4-chloro-
benzenesulfinic acid (1c), 4-fluorobenzenesulfinic acid (1d),
4-methoxybenzenesulfinic acid (1e), 1-naphthylsulfinic acid
(1f), 2-naphthylsulfinic acid (1g), 3-methylbenzenesulfinic acid
(1h) and 2-methylbenzenesulfinic acid (1i) with different
nitriles. Arylsulfinic acids bearing a methyl, chloro or fluoro
group at the para postion provided the addition products with
either aryl nitriles (2a, 2b, 2g) or alkyl nitrile (2j) in high yields
(80–95%). Arylsulfinic acid 1e, which contains a para strong
electron-donating methoxy group, gave 3ea in 70% yield at a
slightly higher catalyst loading. In comparison, the reaction of
1e proceeded well with benzylnitrile to produce 3ej in 81%
a
Unless otherwise specified, all reactions were carried out using 1a
(0.8 mmol), 2a (0.5 mmol) and Pd(OAc)2 (10 mol%), 2,20-bipyridine
(20 mol%), H2SO4 (1.0 mmol), H2O (0.5 mmol), Ar in isobutyl alcohol
b
(2.0 mL) at 100 1C for 6 h. 15 mol% of Pd(OAc)2 was used.
yield under our optimized conditions. The reaction of 1- or
2-naphthylsulfinic acid was also effective to give the corres-
ponding aryl ketones 3fa, 3fj, 3ga, 3gb, 3gg and 3gj in good to
excellent yields (84–93%). Moreover, arylsulfinic acids with a
substituent at the meta (1h) or ortho (1i) position reacted with
c
9502 Chem. Commun., 2011, 47, 9501–9503
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2,20-bipyridine as a ligand. This method provides a new venue
for the rapid synthesis of various biaryl ketones and alkyl aryl
ketones in one pot, broadening the scope of Pd-catalysed
coupling reactions. The halo group in the aryl ketones could
be utilized in further chemical reactions. The investigation of
arylsulfinic acids as the aryl source in other coupling reactions
is underway.
We are grateful for the financial support from National
Natural Science Foundation of China (No. 20972145 and
91021004) and National Basic Research Program of China
(2011CB921402).
Scheme 2 Possible reaction mechanism for the formation of aryl
ketones from palladium-catalysed reaction of arylsulfinic acids with
nitriles.
Notes and references
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Soc., 1999, 121, 2471; (b) K. R. Romines, G. A. Freeman,
L. T. Schaller, J. R. Cowan, S. S. Gonzales, J. H. Tidwell,
C. W. Andrews, D. K. Stammers, R. J. Hazen, R. G. Ferris,
S. A. Short, J. H. Chan and L. R. Boone, J. Med. Chem., 2006,
49, 727.
2 (a) N. O. Calloway, Chem. Rev., 1935, 17, 392; (b) P. H. Gore,
Chem. Rev., 1955, 55, 229.
3 (a) C. X. Zhou and R. C. Larock, J. Am. Chem. Soc., 2004,
126, 2302; (b) C. X. Zhou and R. C. Larock, J. Org. Chem., 2006,
71, 3551.
4 (a) B. W. Zhao and X. Y. Lu, Tetrahedron Lett., 2006, 47, 6765;
(b) B. W. Zhao and X. Y. Lu, Org. Lett., 2006, 8, 5987.
5 Y. Wong, K. Parthasarathy and C. Cheng, Org. Lett., 2010,
12, 1736.
6 (a) K. Ueura, S. Miyamura, T. Satoh and M. Miura, J. Organomet.
Chem., 2006, 691, 2821; (b) H. Shimizu and M. Murakami, Chem.
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nitrile 2a to afford 3ha and 3ia in 87% and 60% yields,
respectively. The yield of 3ia was lower than those of 3ba and
3ha, but was almost the same as that of 3ad due to the steric effect.
Based on the previously proposed reaction mechanisms, a
possible pathway leading to the formation of aryl ketones 3
from arylsulfinic acids 1 with nitriles 2 is shown in Scheme 2.
Reaction of Pd(OAc)2 with arylsulfinic acid provides palladium
salt A. Elimination of SO2 from A generates a ArPd(II) species,
which inserts into the C–N triple bond of nitrile 2 to give
intermediate B. Protonation of intermediate
B affords
ketimine C and a Pd(II) species. Hydrolysis of ketimine C
under acidic conditions produces aryl ketone 3.
In conclusion, we have developed an efficient protocol for
the palladium(II)-catalysed desulfitative addition reaction of
arylsulfinic acids with nitriles to afford a variety of aryl ketones
in good to excellent yields in the presence of inexpensive
7 J. Lindh, P. Sjoerg and M. Larhed, Angew. Chem., Int. Ed., 2010,
¨
49, 7733.
8 G.-W. Wang and T. Miao, Chem.–Eur. J., 2011, 17, 5787.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9501–9503 9503