Palladium-catalyzed arylation of sulfonyl CH-acids

Article abstract of DOI:10.1016/S0040-4039(02)00321-0

A method for the palladium-catalyzed monoarylation of a series of functionalized sulfones by aryl halides is described. The reaction proceeds in the presence of 2 mol% of Pd₂dba₃·CHCl₃ (dba=dibenzylideneacetone), PPh₃ and NaH as a base, only with relatively strong CH-acids and gives monoarylated products in moderate to high yields.

Full text of DOI:10.1016/S0040-4039(02)00321-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2539–2542
Palladium-catalyzed arylation of sulfonyl CH-acids
Alexander N. Kashin, Anton V. Mitin, Irina P. Beletskaya * and Richard Wife
a
a
a,
b
a
Chemistry Department, Moscow State University, 119899, Leninskie Gory, Moscow, Russia
b
SPECS and BioSPECS, Fleminglaan 16, 2289 CP Rijswijk, The Netherlands
Received 2 January 2002; revised 5 February 2002; accepted 15 February 2002
Abstract—A method for the palladium-catalyzed monoarylation of a series of functionalized sulfones by aryl halides is described.
The reaction proceeds in the presence of 2 mol% of Pd dba ·CHCl (dba=dibenzylideneacetone), PPh and NaH as a base, only
2
3
3
3
with relatively strong CH-acids and gives monoarylated products in moderate to high yields. © 2002 Elsevier Science Ltd. All rights
reserved.
NaH, dioxane(dme)
SO2Ph
Y
SO Ph
Sulfones are an important type of organic synthon, widely
used in the total synthesis of useful organic compounds
such as natural products and bioactive substances. The
2
Ar(Het)X
+
Ar(Het)
1
Y
.
Pd dba CHCl /PPh
2
3
3
3
1
auxiliary sulfonyl group enables the deprotonation of a
neighboring carbon atom and the resulting carbanions
can enter into various transformations after which the
1
1
a: Y=CO Et 1c: Y=COPh
2
b: Y=SO Ph 1d: Y=NO2
1b
2
group can be removed by reductive desulfonylation.
Several synthetic routes to (arylmethyl)-sulfones have
been reported, but these are not of general applicability
and involve complex multi-step procedures.
side reaction leading to biaryl formation was observed,
and the yield of the main product decreased. Weaker bases
1
c
(
K PO , Cs CO ) turned out to be ineffective. It is
3 4 2 3
necessary to use at least a twofold excess of the base. A
Here we report on the synthesis of a-functionalized
arylmethylphenylsulfones by palladium-catalyzed aryla-
tion of the related phenylmethylsulfones with aryl halides.
We followed a synthetic approach based on the palla-
dium-catalyzed arylation of CH-acids. It is known that
number of phosphines (PPh , dppf, BINAP, xanphos)
3
have similar effectiveness, therefore, we used the common
triphenylphosphine as the ligand. Pd dba was used as a
2
3
palladium source because other sources such as PdCl2,
2
and [Pd (m-Cl) (o-dimethylaminomethylphenyl) ] turned
a-functionalized nitriles, YCH CN, can be monoaryl-
2
2
2
2
out to be less effective.
ated by a Pd-catalyzed reaction with a conventional PPh3
ligand. However, in the majority of cases including the
arylation of ketones and many other CH-acids such as
3
We performed the reaction of 1b and 1a with various aryl,
6
4
5a,b
5b
heteroaryl and vinyl halides using the optimized condi-
amides, diethyl malonate,
cyclic 1,3-diketones,
the reactions demand the
5
b
5c,d
tions above. The reaction proceeds smoothly with aryl
bromides and iodides both with electron-donating and
electron-withdrawing substituents and results in high to
moderate yields of the monoarylated products.
nitroalkanes and esters,
application of a Pd-catalyst with bidentate or specific
bulky, electron-rich phosphines.
We have found that the compounds 1a–d react smoothly
with various aryl, heteroaryl and vinyl halides in the
presence of the catalyst-Pd dba /3 PPh and NaH as the
The reaction with the aryl chloride stopped with incom-
plete conversion and led to a low yield of the product
2
3
3
(
Table 1, entry 10). This result was the same even when
base.
we used donating and bulky phosphines such as PCy and
3
2
-di-t-butylphosphinobiphenyl which are efficient in
The above mentioned conditions were developed in the
investigation of the reaction of 1a with p-bromoben-
zotrifluoride (dioxane, 70°C). It was found that sodium
hydride was a suitable base. When t-BuOK was used, a
5b
other reactions of aryl chlorides. Heterocyclic bromides
Table 1, entries 4, 5 and 13) also undergo this reaction
(
and give monoarylated products in moderate to high
yields. A vinylation reaction of 1a with b-bromostyrene
also proceeds under the above mentioned conditions
(Table 1, entry 14). To the best of our knowledge, this
is the first example of intermolecular vinylation of
CH-acids.
Keywords: palladium; sulfones; CH-acids; catalysis; aryl halides; aryl-
ation; carbanions.
*
Corresponding author. E-mail: beletska@org.chem.msu.ru
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00321-0

2
540
A. N. Kashin et al. / Tetrahedron Letters 43 (2002) 2539–2542
a
Table 1. Palladium-catalyzed arylation of bis-(phenylsulfonyl)methane and ethylphenylsulfonylacetate
The reaction was found to be accompanied by a side
process resulting in aryl halide reduction to the corre-
sponding arene, reducing the yield of the main product.
The competition between these processes depends on
the sulfones used:

A. N. Kashin et al. / Tetrahedron Letters 43 (2002) 2539–2542
2541
a
Table 2. Palladium-catalyzed reactions of p-bromobenzotrifluoride and a-functionalized phenylmethylsulfones
We have also observed the reduction of aryl bromides
in the absence of the CH-acids.
Thus, in this report we suggest a method of functional-
ized (arylmethyl)sulfone synthesis based on palladium
catalyzed arylation of strongly CH-acidic sulfones. In
our opinion, the unusual dependence of the CH-acid
7
In order to clarify the scope of the method we per-
formed the palladium-catalyzed reaction of p-bro-
mobenzotrifluoride with a number of a-functionalized
reactivity on the pK could be related to the mechanism
a
of the reaction which is a subject of our present studies.
phenylmethylsulfones with a wide pK range.
a
The results shown in Table 2 prompted us to consider
the following reaction features: Firstly, weak CH-acids
being the precursors of highly nucleophilic carbanions
are unreactive (Table 2, entries 1 and 2). It is notewor-
thy that the reaction does not proceed even when
n-BuLi was used as the base and the CH-acid was
completely transformed to the corresponding carban-
ions; Secondly, the reaction proceeds only in the case of
relatively strong CH-acids. The most notable is the
Acknowledgements
The financial support of this work by the Russian
Foundation for Basic Research (Grants 00-03-32766,
01-03-06132) is gratefully acknowledged.
References
arylation of the strong CH-acid 1d (pK =7.1) (Table 2,
a
entry 7), the anion of which is apparently a very weak
nucleophile; Thirdly, the reactions proceed as a selec-
tive monoarylation of CH-acids. The CH-acids contain-
ing a tertiary a-carbon were demonstrated to be
inactive in the reaction (Table 2, entries 8 and 9). This
is an essential difference from the results reported with
the donating bulky phosphines, when both mono- and
1
. (a) Simpkins, N. S. Sulphones in Organic Synthesis; Perga-
mon Press: Oxford, 1993; (b) N a´ jera, C.; Yus, M. Tetra-
hedron 1999, 55, 10546–10658; (c) Houben-Weyl,
Methoden Der Organic Chemie, E11; Georg Thieme Ver-
lag: Stuttgart, New York, 1985.
2. (a) Uno, M.; Seto, K.; Takahashi, S. J. Chem. Soc., Chem.
Commun. 1984, 932–933; (b) Uno, M.; Seto, K.; Ueda, W.;
Masuda, M.; Takahashi, S. Synthesis 1985, 506–508; (c)
9
diarylation of CH-acids were possible.

2
542
A. N. Kashin et al. / Tetrahedron Letters 43 (2002) 2539–2542
Sakamoto, T.; Katoh, E.; Kondo, Y.; Yamanaka, H.
thaw cycles and the reactor was filled with argon. The
reaction was carried out with stirring at 70°C under posi-
tive argon pressure. After 3 h, GLC showed the absence of
the starting p-bromobenzotrifluoride. The reaction mixture
was cooled to room temperature, mixed with brine,
extracted with ether three times (30 ml), and the extract
was evaporated. The residue was chromatographed on
silica gel 40–100 mm, eluting with light petroleum
ether:ethyl acetate mixture (v/v 4:1), to give 153 mg (83%)
Chem. Pharm. Bull. 1988, 36, 1664–1668; (d) Sakamoto,
T.; Katoh, E.; Kondo, Y.; Yamanaka, H. Chem. Pharm.
Bull. 1990, 38, 1513–1517.
. See for example: (a) Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1740;
3
(
1
b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997,
19, 12382–12383; (c) Palucki, M.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 11108–11109.
. Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J.
Org. Chem. 1998, 63, 6546–6553.
. (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
4
5
of
ethyl(p-trifluoromethylphenyl)phenylsulfonylacetate
(
mp=95–96°C). All substances were purified by column
chromatography on silica gel 40–100 mm and were charac-
1
21, 1473–1478; (b) Fox, J. M.; Huang, X.; Chieffi, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–1370;
c) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc.
001, 123, 7996–8002; (d) Lee, S.; Beare, N. A.; Hartwig,
1
terized by elemental analysis, and H NMR and IR spec-
troscopy.
(
2
7
. The reduction of aryl halides by sodium hydride in the
absence of palladium complexes has been reported: Nel-
son, R. B.; Gribble, G. W. J. Org. Chem. 1974, 39,
J. F. J. Am. Chem. Soc. 2001, 123, 8410–8411.
6
. Typical procedure for the reaction of aryl or heteroaryl
halides and sulfones. A mixture of ethylphenylsulfonylac-
etate (148 mg, 0.65 mmol), NaH (1.5 mmol), p-bromoben-
zotrifluoride (112 mg, 0.5 mmol), Pd dba ·CHCl (10.4
1425–1426.
8
9
. Bordwell, F. G.; Vanier, W. S.; Matthews, W. S.; Hen-
drickson, J. B.; Skipper, P. L. J. Am. Chem. Soc. 1975, 97,
2
3
3
7160–7162.
mg, 2 mol%) and PPh (15.8 mg) in dioxane (4 ml), purged
3
. Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J.
F. J. Am. Chem. Soc. 2001, 123, 4641–4642.
with argon, was placed into an argon filled reactor. The
reaction mixture was degassed by several freeze–pump–