talysis is reported starting from tert-butyl acetoacetate and
different R-haloketones (Scheme 2). A further alkylation with
Table 1. 3-Acetyl-2-hydroxyfuran Derivatives
Scheme 2a
a (a) NaH (1.1 equiv) in THF, 30 min at 0 °C, then 1 (1.1 equiv),
2 h at 0 °C and overnight at rt; (b) TFA, 1 h at rt or CH2Cl2/THF
(10:1) overnight at rt.
different bromoalkanes previous to the acidic treatment gives
access to disubstituted 2-methylfurans (Scheme 3). This is
a straightforward synthesis for electron-rich trisubstituted
furans.
the acid treatment is involved in the formation of the furan
ring. In the case of compounds 4a-c, the attack of the keto
function by the carboxylic acid leading to the formation of
a cyclic intermediate can be assumed though no experimental
identification of such species was achieved. The intermedi-
ates would be the alkylated analogues of the intermediates
obtained with compounds 2a-c. However, the â-ketoester
moiety of the alkylated intermediates lacks the ability to
tautomerize, consequently they would revert to their open
form to lose carbon dioxide.
Scheme 3a
As one can expect, deprotection of the tert-butyl group
and cyclization are both catalyzed by TFA. Cyclization could
not be observed either starting from the tert-butyl 2-meth-
oxycarbonyl-4-oxo-4-phenylbutyrate or from the methyl
3-tert-butyloxycarbonyl-4-oxopentanoate by standard TFA
treatment. The carbonyl of the keto function should be
electrophilic enough to allow attack of the carboxylic acid.
The enolizability of the â-ketoester moiety is also an
important factor stabilizing the cyclic intermediate formed
by the attack of the carboxylic acid on the keto function.
Simple 1,4-diketones as 2,5-hexanedione or methyl 4,7-
dioxodecandioate are not converted into furans by TFA
a (a) NaH (1.1 equiv) in THF, 1 h at 0 °C, then BrBn or
BrCH2CO2Me (1.1 equiv), 2 h at 0 °C and overnight at rt; (b)
CH2Cl2/THF (10:1) overnight at rt.
The alkylation of tert-butyl acetoacetate was achieved by
deprotonation with sodium hydride in THF at 0 °C and
treatment of the resulting anion with methyl 5-bromolevuli-
nate (1a), phenacyl bromide (1b), chloroacetone (1c), and
R-bromopropiophenone (1d) to yield the racemic intermedi-
ates 2a-d. Treatment of the intermediates 2a-d for 1 h at
rt with TFA (97%) yields the 3-acetyl-2-hydroxyfuran
derivatives 3a-d in good yields (Scheme 2).
The racemic intermediate 2a was further alkylated with
benzyl bromide and the racemic intermediates 2b,c were
alkylated with methyl bromoacetate to give the intermediates
4a-c. Overnight treatment of the intermediates 4a-c by a
TFA (10%) solution in CH2Cl2 gives access to 2-methylfuran
derivatives 5a-c (Scheme 3).
Table 2. Electron-Rich 2-Methylfuran Derivatives
The synthesized intermediates 2a-d and the corresponding
furans 3a-d are listed in Table 1.
The synthesized intermediates 4a-c and the corresponding
furans 5a-d are listed in Table 2.
In the case of the racemic dialkylated tert-butyl aceto-
acetate 4a-c, the acid treatment leads to a decarboxylation
whereas in the case of the monosubstituted tert-butyl
acetoacetate 2a-d, the carboxylic acid function liberated by
3536
Org. Lett., Vol. 2, No. 23, 2000