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R. V. H. Jones et al. / Tetrahedron Letters 46 (2005) 8695–8697
Table 1. Palladium-catalyzed carbonylationa of arylmethyl halides in methanol
Substrate
Catalyst
Temp (°C)
Productsb (%)
Unreacted starting material (%)
ArCH2CO2Me
ArCH2OMe
PhCH2Cl
PhCH2Br
PhCH2Br
4-MeC6H4CH2Br
4-MeC6H4CH2Br
2
2
4
2
4
55
35
55
34
50
99
99
74
93
59
0
0
11
7
0
0
15
0
36
5
a See Ref. 13 for the general experimental procedure.
b Products from reactions catalyzed by 2 are contaminated by 1,4-dihydro-3H-2-benzopyran-3-one (3-isochromanone) derived from the catalyst (cf.
Ref. 11).
Table 2. Palladium-catalyzed carbonylationa of benzyl halides in an aqueous (biphasic) medium
Substrate
Catalyst
Temp. (°C)
Productsb (%)
Unreacted starting material (%)
PhCH2CO2H
PhCH2CO2CH2Ph
PhCH2Cl
PhCH2Cl
PhCH2Br
PhCH2Br
2
4
2
4
6191
7160
50
4
5
9
5145
65
30
4
53
32
1
a See Ref. 14 for the general experimental procedure.
b Products from reactions catalyzed by 2 are contaminated by 1,4-dihydro-3H-2-benzopyran-3-one (3-isochromanone) derived from the catalyst (cf.
Ref. 11).
20 atm;1 R = H, X = Cl, [cat. PdCl2(PPh3)2], n-Bu4NI,
95 °C, 5 atm.10 Also, the formation of by-products is
observed in certain cases [e.g., PhCH2OCH2Ph, cf.
Ref. 7; PhCH2CO2Ph cf. Ref. 9]; see also examples from
the present work described below.
gradually afforded a homogeneous pale yellow solution;
formation of Pd-black was not observed. The transfor-
mation (PhCH2Br ! PhCH2CO2Me) was also achieved
quantitatively using catalysts 3a–c under identical condi-
tions to those described above using 2. Furthermore, all
four catalysts (2, 3a–c) proved to be equally efficient for
the carbonylation of a series of benzyl halide derivatives
[viz: XC6H4CH2Br; X = 2-Br; 2-CH2Br {affording
C6H4(CO2Me)2}; 2-NO2; 4-Me; and 2-(bromomethyl)-
naphthalene]. In general, the desired methyl esters were
formed in quantitative yields except for one example
[viz. 2-(bromomethyl)naphthalene using catalyst 3c gave
an 88% yield of the ester but also two by-products,
[2-C10H7CH2OMe (4%) and 2-C10H7CHO (4%)].
In this letter, we describe the use of new catalysts for
this type of transformation in which lower tempera-
tures and low pressures (1–4 bar) of carbon monoxide
are employed; yields are almost quantitative and the
formation of by-products is generally avoided. Cata-
lysts 211, 3a,11 3b12 and 3c11 are equally effective and
were initially evaluated in methanol solution for the
syntheses of methyl arylacetates in comparison with
[PdCl2(PPh3)2] 4 under 3.45 bar CO pressure (e.g., see
Table 1 for use of 2). Catalyst 2 mediates almost
quantitative conversion of benzyl chloride or bromide
into methyl phenylacetate by comparison with the use
of [PdCl2(PPh3)2]; the latter catalyst requires higher
working temperatures, effects lower conversions and
by-products are formed. Catalyst 2 is also efficient
for the 3.45 bar CO pressure carbonylation of benzyl
chloride in an aqueous (biphasic) system, but benzyl
bromide is an unsatisfactory substrate with the forma-
tion of benzyl phenylacetate being a competing path-
way (see Table 2).
We have recently shown that compounds 2, 3a,b and 3c
react rapidly with carbon monoxide to form labile acyl
complexes (probably 5, 6a,b and 6c, respectively) with
short lifetimes (ca. 0.5 h) in solution at ambient temper-
ature.11 It is probable that complexes 2, 3a,b and 3c are
Ôpre-catalystsÕ, serving to generate active catalytic species
through the acyl intermediates (5, 6a,b and 6c) under rel-
atively mild conditions.
The high yields and selectivity achievable with catalysts
2, 3a–c together with the use of low pressures (1–4 bar)
of carbon monoxide provide incentives for investigation
of industrial-scale syntheses of phenylacetic acid and
derived esters through this route.
Experiments were then conducted at atmospheric pres-
sure in a glass vessel fitted with a coarse sinter and a
gas inlet. Carbon monoxide was introduced to generate
a fine stream of bubbles such that additional stirring was
unnecessary. Using methanol as solvent, the carbonyl-
ation of benzyl bromide afforded methyl phenylacetate
quantitatively [catalyst 2 (5 mol %), i-PrNEt2 (1.1 mol
equiv), Ph3P (10 mol %), 60 °C, 2 h]. Almost immedi-
ately the colourless mixture became deep orange and
Acknowledgements
We thank Zeneca Ltd (latterly Syngenta) and Heriot-
Watt University for support through a Postgraduate
Studentship (to D.D.P.).