Angewandte
Chemie
ing ethyl and hexyl ester derivatives, respectively (Table 1,
entries 2 and 3). In a similar manner, the combination of the
CuII compounds Cu(OAc)2, Cu(OTf)2, and CuCl2 or CuI
halides CuX (X = I, Br, Cl) with N-heterocyclic carbene
ligands such as IPr·HCl, SIPr·HCl (SIPr= 1,3-bis(2,6-diiso-
propylphenyl)imidazolin-2-ylidene), IMes·HCl (IMes = 1,3-
bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), or SIMes·HCl
(SIMes = 1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene)
were also effective for the carboxylation of benzoxazole, with
CuCl and CuBr seeming to give the most efficient reactions
(Table 1, entries 4–12). Other ligands such as PPh3,
1,10-phenanthroline, l-proline, and tetramethylethylenedi-
amine (TMEDA) were less effective (Table 1, entries 9–16).
In the absence of a copper source, only a trace amount of the
carboxylation product was observed under the same reaction
conditions (Table 1, entries 17 and 18). The use of CuCl alone
afforded the expected product in only 8% yield (Table 1,
entry 19). Of the catalysts surveyed, [Cu(IPr)Cl] proved to be
the best. In addition to KOtBu, other bases such as K2CO3,
K3PO4, LiOtBu, and NaOtBu were also examined, but these
were less effective. The use of THF and toluene as solvent
gave better results than DMF, dioxane, or acetonitrile.
in 87% and 85% yield, respectively. The reaction of
4-methylbenzoxazole under the same conditions gave a
lower yield of the corresponding ester 2b (50%), probably
because of the steric influence of the methyl group on the
heterocyclic ring.
Various 5-arylated benzoxazole derivatives bearing either
electron-donating (e.g., OMe) or electron-withdrawing
(e.g., CF3 and CN) functional groups at the aryl unit could
be used in the carboxylation reaction to give the correspond-
ing functionalized esters, such as 2h, 2i, and 2j, selectively
and in high yields. In the case of 5-(methylbenzoate)-
substituted benzoxazole, the expected straightforward reac-
tion product 2k was isolated in 52% yield, along with a by-
product 2kꢀ (25%), which was formed by transesterification
with the tBuOH generated in situ. Chloride, bromide, and
nitro groups could survive the reaction conditions to give the
corresponding functionalized ester products such as 2e, 2 f,
and 2g. In comparison with benzoxazoles, N-methylbenzoi-
midazole (pKa = 32.5) afforded the corresponding ester 2l in
14% yield, while 1,3,4-oxadiazole afforded the expected
product 2m in 38% yield; the low yield of these products is
probably due to their weaker acidity.[10] Similarly, only a trace
amount of the carboxylation products was observed in the
reactions of substrates with higher pKa values such as
benzothiazole (pKa = 27.3), 4-phenyloxazole, and benzofuran
(pKa = 33.2).
The carboxylation of other heterocyclic compounds was
then examined by using [Cu(IPr)Cl] as the catalyst and
n-C6H13I as an alkylating agent. Some representative results
are summarized in Scheme 2. The reactions of 6- and
5-methylbenzoxazoles with CO2 took place smoothly to give
the corresponding hexyl esters 2a and 2c, which were isolated
Several stoichiometric reactions were examined to eluci-
date the mechanism of the current catalytic process,
(Scheme 3). As reported previously,[3d,11] the alkoxide Cu
Scheme 3. Stoichiometric reactions of copper complexes.
complex [Cu(IPr)(OtBu)] could be easily obtained by the
reaction of [Cu(IPr)Cl] with tBuOK. The reaction of
[Cu(IPr)(OtBu)] with 1.0 equivalent of benzoxazole gave
the benzoxazolylcopper complex 3, which was isolated in
93% yield. Colorless single crystals of 3 were obtained by
recrystallization from THF/toluene (1:1). X-ray crystallo-
graphic analysis revealed that the benzoxazolyl group is
bound to the Cu atom in an h1 fashion, with an almost linear
C(1)-Cu(1)-C(2)
configuration
(]C(1)-Cu(1)-C(2) =
174.4(2)8; Figure 1). The carboxylate complex 4 was isolated
in 93% yield after exposure of 3 to 1 atm of CO2 in THF at
room temperature. X-ray crystallographic analysis estab-
lished that the benzoxazolylcarboxylate unit in 4 is bound to
the Cu atom in a chelating fashion through a carboxylate
oxygen atom and the nitrogen atom to form a five-membered
Scheme 2. Copper-catalyzed carboxylation of aromatic heterocycles
with carbon dioxide. Reaction conditions: [Cu(IPr)Cl] (5 mol%), sub-
strate (1.0 mmol), KOtBu (1.1 mmol), CO2 (1 atm), THF (5 mL), 808C,
14 h, then THF was evaporated, DMF (5 mL), RI (2.0 mmol), 808C,
5 h. Yield of the isolated product. THF=tetrahydrofuran.
Angew. Chem. Int. Ed. 2010, 49, 8670 –8673
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