a
Table 3 Suzuki reactions with MC-[Pd] in scCO
2
Table 4 Stille couplings with MC-[Pd]
Entry
Method
Transformationa
Yield(%)
Entry
Transformationb
Yield (%)
1
2
3
4
5
6
7
8
a
(i)b
(i)
(i)
(i)
X = Br
X = Br
X = Br
X = Br
X = Br
X = Br
X = Br
X = Cl
R = p-NO
R = p-OMe
R = p-F
R = o-OMe
R = H
R = p-OMe
2
99
88
82
74
50
45
> 34
50
1
2
3
4
5
a
R = H
R = OMe
R = F
X = Br
X = Br
X = Br
X = Br
X = Cl
99
60
98
78
60
c
(ii)
R = NO
R = NO
2
(ii)
(ii)
(ii)
2
R = p-NO
R = p-NO
2
See ESI for representative procedure 4, Suzuki reaction in scCO
Reagents and conditions: scCO
2
.
,
2
b
n
2
, 0.4 mol % MC-[Pd], MePhB(OH)
2
Reagents and conditions: method (i) 2.5 mol % MC-[Pd], IPA–PhMe (1:1,
Bu NOAc, 100 °C
4
n
v/v), Bu
4 3 2
NOAc, Me SnPh, 90 °C; method (ii) scCO , 0.4 mol % MC-[Pd],
Me
3
SnPh, 100 °C. b See ESI for representative procedure 5, Stille reaction.
c
See ESI for representative procedure 6, Stille reaction in scCO
2
(
Table 1, entry 1). Inductively coupled plasma (ICP) analysis of
the crude reaction mixture (after filtration and drying) indicated
7
9 ppm Pd (wt/wt), corresponding to 1% leaching of the
Table 5 Stille couplings: recycling experimentsa
original Pd content of the capsules. The palladium-containing
capsules were removed by a simple filtration and the mixture
purified by being passed through a short silica plug (to remove
triethylamine residues and salts). The scope of this transforma-
tion was established through the generation of a range of
substituted aryl esters in high yields, (Table 1). It was decided
next to investigate whether these palladium microcapsules
could also perform as effective catalysts in Heck type couplings,
Table 2. Treatment of 1-bromo-4-nitrobenzene with n-butyl
Substrate:
Run
1
2
3
4
Yield (%)
Time/h
99
3
98
4.5
99
12
97
24
acrylate in isopropyl alcohol in the presence of MC-[Pd] (2.5
mol%) and Bu
a
Reagents and conditions: 2.5 mol % MC-[Pd], IPA/PhMe (1+1, v/v),
Me SnPh, nBu NOAc, 90 °C.
n
4
NOAc afforded the requisite unsaturated ester
3
4
in an excellent 91% yield (Table 2, entry 1). A range of
substrates were treated under the same conditions to yield the
products in good yields (Table 2, entries 2–4). However,
reaction with 4-bromoanisole was less successful, yielding only
however, yields are generally lower than those observed in
conventional solvents. The feasability of recovery and reuse of
the catalyst in organic solvents was also examined through a
series of sequential Stille couplings of 4-nitrobromobenzene,
Table 5. In all cases, the reactions proceeded to completion
giving excellent isolated yields, although increases in reaction
times were observed.
25% of the desired product. Under these conditions the crude
reaction mixture contained 60 ppm Pd, a loss of 2.8% of the
original Pd content of the capsules.
Supercritical carbon dioxide offers real promise as an
6
alternative solvent for organic synthesis, and there has been
7
considerable interest in hydrogenation and Pd-mediated C–C
In this communication it has been demonstrated that
8
bond forming reactions in this medium. With this in mind, a
2
Pd(OAc) encapsulated in polyurea is an accomplished catalyst
2
range of Heck reactions were carried out in scCO (Table 2,
for cross-coupling reactions in both conventional and super-
critical media that can be removed simply and effectively from
reaction mixtures by a filtration process. The flexibility of the
encapsulation process suggests the prospect of a more rational
design tailored to specific applications.
entries 5–9). Under these conditions, yields were generally
higher than in IPA despite a lower catalyst loading. Separation
of the catalyst was achieved by simple filtration of the ethyl
acetate solution into which the reaction mixture had been
2 2
vented, demonstrating an advantage of using scCO ; CO -
The authors would like to thank Syngenta (to CR), Pembroke
College, Cambridge (to MDS), AstraZeneca (to AJM), the
Novartis Research Fellowship (to SVL) the Isaac Newton Trust,
EPSRC and the Commission of the EU (Brite-Euram Contract
BRRT-CT98-5089 ‘RUCADI’) for support.
soluble products can be extracted from the heterogeneous
reaction mixture while the catalyst remains in the reaction cell.
After the success of the Heck reactions, a range of Suzuki
2
couplings in scCO of tolylboronic acid with aryl halides were
examined, which proceeded in yields comparable to those
5
obtained in organic solvents, Table 3. The general synthetic
applicability of the MC-[Pd] catalyst was further demonstrated
by carrying out a series of Stille coupling reactions between aryl
halides and trimethylphenyltin. The coupling of 1-bromo-
Notes and references
1
S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach, D.
A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor, J. Chem.
Soc., Perkin Trans. 1, 2000, 3815.
4
-nitrobenzene in an IPA–PhMe mixture was initially at-
n
tempted, and proceeded smoothly in the presence of Bu
to afford the biaryl derivative in essentially quantitative yield
Table 4, entry 1). The crude reaction mixture was shown to
4
NOAc
2
G. J. Mars and H. B. Scher, Controlled delivery of crop protecting agents,
ed. R. M. Wilkens, Taylor and Francis, London, 1990, 65.
(
contain 22 ppm Pd, corresponding to leaching of 0.9% of the
initial Pd content of the microcapsules. Reactions in the absence
of the quaternary ammonium salt were found to be exception-
ally slow, leading to very poor conversions. The coupling of
deactivated derivatives was also shown to be possible without
the use of phosphine ligands; 4-bromoanisole (Table 4, entry 2)
was converted to its respective biaryl derivative in 4 h in 88%
yield, and 2-bromoanisole was similarly converted in 74% yield
3 S. Kobayashi, M. Endo and S. Nagayama, J. Am. Chem. Soc., 1999, 121,
11229.
4
5
6
7
R. Akiyama and S. Kobayashi, Angew. Chem., Int. Ed., 2001, 40,
3
469.
C. Ramarao, S. V. Ley, S. C. Smith, I. M. Shirley and N. De Almeida,
Chem. Commun. preceeding paper (DOI:10.1039/b200674j).
P. G. Jessop and W. Leitner, Chemical Synthesis Using Supercritical
Fluids, Wiley-VCH, Weinheim, 1999.
M. Poliakoff, N. J. Meehan and S. K. Ross, Chem. Ind., 1999, 750.
in 24 h. The utility of MC-[Pd] in scCO
2
is further demonstrated
8 R. S. Gordon and A. B. Holmes, Chem. Commun., 2001, 640 and
references contained therein.
by similar Stille reactions (Table 4, entries 5–8). In these cases,
CHEM. COMMUN., 2002, 1134–1135
1135