Ligand-free palladium catalysis of aryl coupling reactions facilitated by grinding

Article abstract of DOI:10.1016/S0040-4039(02)02645-X

Ligand-free palladium-catalysed Suzuki coupling reactions and homo-couplings of boronic acids have been facilitated by grinding. The reactions are rapid (10-30 min) and can be performed without the need to exclude air and moisture.

Full text of DOI:10.1016/S0040-4039(02)02645-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 765–768
Ligand-free palladium catalysis of aryl coupling reactions
facilitated by grinding
Liane M. Klingensmith and Nicholas E. Leadbeater*
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
Received 8 October 2002; revised 15 November 2002; accepted 22 November 2002
Abstract—Ligand-free palladium-catalysed Suzuki coupling reactions and homo-couplings of boronic acids have been facilitated
by grinding. The reactions are rapid (10–30 min) and can be performed without the need to exclude air and moisture. © 2003
Elsevier Science Ltd. All rights reserved.
Biaryl units constitute important building blocks in
catalysed Suzuki reaction using ball-milling has been
investigated previously. The authors report that the
1,2
8
natural products and advanced materials. The palla-
dium-mediated cross-coupling reaction between aryl
halides and arylboronic acids (the Suzuki reaction) has
proven to be a versatile and highly useful method for
formation of the Suzuki-coupled product is often
accompanied by a significant quantity of biphenyl, gen-
erated by homo-coupling of phenylboronic acid. As a
result they use two equiv. of boronic acid for their
Suzuki coupling reactions to stop the homo-coupling
being a limiting factor. In addition, the reaction condi-
tions used work well only for a limited number of
substrates. We wanted to explore the possibility of
forming exclusively either Suzuki coupled product or
boronic acid homo-coupled product. Secondly, we
wanted to increase the substrate scope of the Suzuki
reaction using grinding and reduce the stoichiometric
ratio of aryl halide to boronic acid from 1:2 to 1:1.
3
the preparation of biaryl-containing molecules. A vari-
ety of catalysts have been prepared and screened for
activity in the reaction including palladium N-hetero-
4
cyclic carbene complexes and a wide range of palla-
5
dium phosphine compounds. There have been a
6
,7
number of recent reports on ligand-free,
solvent-
7
,8
6,9,10
11
free,
aqueous-phase
and microwave-assisted
Suzuki coupling reactions. Another biaryl-forming
reaction of interest is the palladium catalysed homo-
coupling of boronic acids to form symmetrical biaryls.
Again, as well as using phosphine-ligated palladium
1
2,13
catalysts
there have been a number of recent reports
1
3–15
Table 1. Optimisation of conditions for Suzuki coupling
on developments of ligand-free
and aqueous-
a,22
of 4-bromotoluene and phenylboronic acid
1
4,15
phase
methods.
We report here the ligand-free palladium-mediated
Suzuki coupling of aryl halides, in particular bromides,
and the homocoupling of boronic acids. We show that
it is possible to perform these reactions rapidly by using
triethylamine as a base and grinding the reaction mix-
ture. The reactions are performed without the need to
use dry reagents or anaerobic conditions. The use of
grinding as a synthetic tool is a topic of increasing
interest within the chemistry community, this being
Entry
Reaction conditions
Yield (%)b
1
2
3
4
5
6
7
Pd(OAc) , b=Na CO , g.t.=30 min
12
9
2
2
3
PdCl , b=Na CO , g.t.=30 min
2
2
3
Pd(OAc) , b=Na CO , g.t.=1 h
14
95
79
95
60
2
2
3
Pd(OAc) , b=NEt , g.t.=30 min
2
3
PdCl , b=NEt , g.t.=30 min
2
3
16
Pd(OAc) , b=NEt , g.t.=10 min
reflected in the number of recent reviews
and
2
3
c
1
7–20
Pd(OAc) , b=NEt , t=16 h
2 3
communications
on the subject. The Pd(PPh3)4
a
1
mmol aryl halide, 1 mmol PhB(OH) , 3 mmol base, 4.5 mol% Pd
2
salt. b=base, g.t.=grind time, t=reaction time.
Isolated yields.
Stirred in a test tube.
b
c
*
Corresponding author. Tel.: +44 (0)20 7848 1147; fax: +44 (0)20
848 2810; e-mail: nicholas.leadbeater@kcl.ac.uk
7
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02645-X

7
66
L. M. Klingensmith, N. E. Leadbeater / Tetrahedron Letters 44 (2003) 765–768
Our starting point was to develop a set of working
conditions for the Suzuki coupling reaction. Using 4-
bromotoluene as the aryl halide and phenylboronic acid
as the coupling partner, we screened a range of palla-
dium compounds (Pd(OAc) , PdCl and Pd (dba) ) and
Under our conditions aryl chlorides could not be cou-
pled and aryl iodides gave incomplete conversion, even
with extended grinding times. Similar problems with
aryl iodides have been reported in the literature previ-
10,21
ously.
AgBF
Fu and co-workers show that addition of
can speed up Suzuki couplings involving aryl
4
2
2
2
3
mineral bases (Na CO , NaOH, KF) in the reaction
2
3
using a grinding time of 30 min. Reactions were per-
formed in a hardened-steel vial with steel shot-ball
cones. Working on a 1 mmol scale of aryl halide and
boronic acid, 4.5 mol% catalyst and 3 mmol base, we
found that it was possible to generate up to 12% of the
desired biaryl (Table 1, entries 1–3). The yield did not
improve on extending the grinding time, increasing the
catalyst loading or varying the intensity of the grinding.
a,23
Table 2. Suzuki cross-couplings facilitated by grinding
We decided to change the base from an inorganic salt
to a liquid organic base, choosing triethylamine. We
wanted to maintain the threefold molar excess of the
base as compared to the aryl halide and boronic acid
but this meant that the reaction mixture was now
liquid. In order to be able to use a grinding methodol-
ogy we needed to bulk-up the mixture with an inert
solid to make a paste. We chose as this bulking agent
NaCl, addition of which to the mixture of 4-bromo-
toluene and phenylboronic acid (1 mmol of each), 4.5
mol% Pd(OAc) and 3 equiv. NEt to make a paste,
2
3
followed by 30 min grinding resulted in an isolated
yield of 4-phenyltoluene of 95%. The reaction was
performed in a hardened-steel vial with one large ball.
Variation of reaction conditions showed us that the
grinding time could be reduced from 30 min to 10 min
with no drop in product yield (Table 1, entries 4–6). We
wanted to compare the results obtained by grinding the
reaction mixture with those obtained by simply stirring
the mixture. We performed a control experiment, stir-
ring a mixture of 4-bromotoluene, phenylboronic acid,
Pd(OAc) and NEt in a flask for 10 min and found
2
3
that there was little product formed. However, if the
mixture is stirred overnight then a 60% yield of product
is obtained (Table 1, entry 7). This result is interesting
in itself and shows that the use of triethylamine as a
base has potential for application in room temperature
Suzuki reactions simply using stirring. Clearly one of
the key roles of the grinding is simply to mix the
reagents thoroughly and rapidly, speeding up the reac-
tion. Concomitant with this will be localised heating of
the reaction mixture, this perhaps also accelerating the
reaction. Of interest is that heating the stirred reaction
mixture results in a decrease in product yield. We term
our methodology as being facilitated by grinding rather
than invoking a mechanical activation effect.
Having found suitable conditions for the reaction, we
screened a range of aryl bromides in the Pd(OAc)2-
mediated Suzuki coupling reaction with phenylboronic
acid (Table 2, entries 1–10). The data shows that the
methodology is general, a variety of bromides reacting
with phenylboronic acid in good yields. Sterically hin-
dered aryl bromides can be coupled using this method
but the yields are lower than their non-hindered ana-
logues. We also screened representative aryl iodides and
chlorides in the reaction (Table 2, entries 11–13).
a
1
.0 equiv. ArX, 1.0 equiv. PhB(OH) , 3.0 equiv. NEt , 4.5 mol%
2 3
Pd(OAc) , NaCl added to form a damp paste, grinding for 10 min.
Isolated yields of compounds, characterised by comparison of
and C NMR spectra with authentic samples or literature data.
Grinding time of 30 min.
With 3 equiv. AgBF added.
2
1
H
1
3
b
c
4

L. M. Klingensmith, N. E. Leadbeater / Tetrahedron Letters 44 (2003) 765–768
767
iodides. To see if this would increase the rate of cou-
plings in our reaction we screened a range of silver salts
as additives using 4-iodotoluene and phenylboronic
acid as substrates. We found that the yield of biaryl
could be increased from 20 to 67% by addition of 1.5
equiv. of AgBF . When using 3 equiv. of AgNO , we
silver nitrate as an additive. Work to extend the scope
of the reactions is currently underway.
Acknowledgements
4
3
found that together with formation of the Suzuki
product, we also obtained significant quantities of
homo-coupled product deriving from the phenylboronic
acid. We believed that this may open up the possibility
of preparing symmetrical biaryls from boronic acids
and so repeated the reaction in the absence of aryl
halide, this giving biphenyl in 72% yield. We then
The Royal Society is thanked for a University Research
Fellowship (N.E.L.) and Alfred University, New York,
USA thanked for an International Internship Scholar-
ship (L.M.K.). Funding from the Royal Society and
King’s College London is acknowledged.
screened other boronic acids in the Pd(OAc) -mediated
2
homo-coupling reaction (Table 3). The data show that
moderate to good yields of the desired products were
obtained. De-activated boronic acids can be coupled
using the methodology but only in low yields. Again it
is possible to perform the reaction by stirring the
mixture instead of grinding but yields are lower even
after extended reaction times.
References
1
. Hassan, J.; S e´ vignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359–1469.
. Stanforth, S. P. Tetrahedron 1998, 54, 263–303.
. (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168;
b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–
483.
. For a review on the area, see: Jafarpour, L.; Nolan, S. P.
2
3
(
2
In summary, Suzuki coupling and boronic acid homo-
coupling reactions facilitated by grinding have been
reported. Good yields of biaryls have been formed from
phenylboronic acid and a range of aryl bromides. The
reactions are rapid, the catalyst used simple, and they
are performed without the need to exclude air and
moisture. A number of boronic acids have been homo-
coupled using the same reaction conditions but with
4
5
Adv. Organomet. Chem. 2001, 46, 181–222.
. See for example: (a) Liu, S.-Y.; Choi, M. J.; Fu, G. C.
Chem. Commun. 2001, 2408–2409; (b) Wolfe, J. P.;
Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550–9561.
6
. Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53,
1
4437–14450.
7
. (a) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R.
Org. Lett. 2001, 3, 1555–1557; (b) Kabalka, G. W.;
Namboodiri, V.; Wang, L. Chem. Commun. 2001, 775–
Table 3. Boronic acid homo-couplings facilitated by
a,24
grinding
776; (c) Kabalka, G. W.; Pagni, R. M.; Hair, C. M. Org.
Lett. 1999, 1, 1423–1425.
8. Nielsen, S. F.; Peters, D.; Axelsson, O. Synth. Commun.
2000, 30, 3501–3509.
9
. For selected examples see: (a) Sakurai, H.; Tsukuda, T.;
Hirao, T. J. Org. Chem. 2002, 67, 2721–2722; (b)
Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999,
64, 3384–3388; (c) Botella, L.; N a´ jera, C. Angew. Chem.,
Int. Ed. 2002, 41, 179–181.
1
1
0. Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.;
Guzzi, U. J. Org. Chem. 1997, 62, 7170–7173.
1. (a) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4,
2973–2976; (b) Blettner, C. G.; Konig, W. A.; Stenzel,
W.; Schotten, T. J. Org. Chem. 1999, 64, 3885–3890; (c)
Hallberg, A.; Larhed, M. J. Org. Chem. 1996, 61, 9582–
9584; (d) Kabalka, G. W.; Pagni, R. M.; Wang, L.;
Namboodiri, V.; Hair, C. M. Green Chem. 2000, 2,
120–122; (e) Villemin, D.; Caillot, F. Tetrahedron Lett.
2001, 42, 639–642.
1
1
2. (a) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001,
2, 4087–4089; (b) Song, Z. Z.; Wong, H. N. C. J. Org.
Chem. 1994, 59, 33–41.
3. Moreno-Ma n˜ as, M.; P e´ rez, M.; Pleixats, R. J. Org.
4
Chem. 1996, 61, 2346–2351.
a
14. Kabalka, G. W.; Wang, L. Tetrahedron Lett. 2002, 43,
067–3068.
Reaction conditions: 1.0 equiv. R-B(OH) , 3.0 equiv. NEt , 4.5
2
3
3
mol% Pd(OAc) , 3.0 equiv. AgNO , NaCl added to form a damp
2
3
1
5. Smith, K. A.; Campi, E. M.; Jackson, W. R.; Marcuccio,
S.; Naeslund, C. G. M.; Deacon, G. B. Synlett 1997,
131–132.
paste, grinding for 30 min. Isolated yields of compounds, character-
1
13
ised by comparison of H and C NMR spectra with authentic
samples or literature data.

7
68
L. M. Klingensmith, N. E. Leadbeater / Tetrahedron Letters 44 (2003) 765–768
1
6. (a) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem.
NaCl. A grinding ball was then added, the jar closed and
placed into the mixer mill and the reaction mixture
ground for 10 min. After grinding, the jar was then
opened cautiously to avoid loss of material attached to
the lid. All the material inside the jar was scraped into a
conical flask and the jar rinsed with water and then ether
and the washings placed with the scrapings. Water (30
ml) and ether (30 ml) were added to the flask and the
entire contents transferred to a separating funnel. HCl
Commun. 2001, 2159–2169; (b) Tanaka, K.; Toda, F.
Chem. Rev. 2000, 100, 1025–1074.
1
7. (a) Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky,
V. K. J. Am. Chem. Soc. 2002, 124, 6244–6245; (b)
Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V.
K. Chem. Commun. 2002, 724–725.
1
8. (a) Cave, G. W. V.; Raston, C. L. J. Chem. Soc., Perkin
Trans. 1 2001, 3258–3264; (b) Cave, G. W. V.; Hardie,
M. J.; Roberts, B. A.; Raston, C. L. Eur. J. Org. Chem.
(
40 ml, 2 M) was added and after agitation, the organic
2
001, 3227–3231.
layer was separated, dried over anhydrous MgSO4,
1
2
2
2
9. Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J.
filtered and concentrated by rotary evaporation. In initial
L. J. Am. Chem. Soc. 2001, 123, 8701–8708.
1
screening experiments yields were determined by
H
0. Komatsu, K.; Fujiwara, K.; Murata, Y. Chem. Commun.
NMR analysis using 1,2-dichloroethene as an internal
standard. For isolation of products, in the cases where
the starting aryl halide was a liquid unreacted aryl halide
was firstly removed by heating the crude residue whilst
under a vacuum on a Schlenk line. Products were purified
by recrystallization, or flash chromatography on silica gel
using hexane or hexane/ethyl acetate as eluent.
2
000, 1583–1584.
1. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
22, 4020–4028.
2. Grinding experiments were performed using a Retsch
1
®
Mixer Mill Type MM 200 (http://www.retsch.de/
index.php). Samples were loaded into 10 ml capacity
screw cap stainless steel grinding jars. The vibration
frequency of the mixer mill was set to 30 Hz (1800 rpm).
Stirring experiments were performed in small test tubes
which, after loading with the reagents, were sealed with a
septum to prevent evaporation.
2
4. General procedure for homo-couplings of boronic acids: A
grinding jar was loaded with boronic acid (1 mmol),
Pd(OAc)2 (10 mg, 0.045 mmol, 4.5 mol %), AgNO3 (3
mmol, 510 mg) and triethylamine (300 mg, 0.41 ml, 3
mmol). NaCl was added slowly to the reaction mixture
with agitation with a spatula until a damp paste was
formed. The consistency of the paste was such that no
liquid remained in the grinding jar but the granules of
NaCl clung to the spatula when lifted from the mixture.
A grinding ball was then added, the jar closed and placed
into the mixer mill and the reaction mixture ground for
2
3. General procedure for Suzuki couplings of aryl bromides
and phenylboronic acid: A grinding jar was loaded with
aryl bromide (1 mmol), phenylboronic acid (122 mg, 1
mmol), Pd(OAc) (10 mg, 0.045 mmol, 4.5 mol %) and
2
triethylamine (300 mg, 0.41 ml, 3 mmol). NaCl was
added slowly to the reaction mixture with agitation with
a spatula until a damp paste was formed. The consistency
of the paste was such that no liquid remained in the
grinding jar but the granules of NaCl clung to the spatula
when lifted from the mixture, this taking roughly 2 g
30 min. The grinding jar was then opened and the
contents worked up in an identical manner to the Suzuki
reactions.