Iron-Catalyzed Benzylation of 1,3-Dicarbonyl Compounds
COMMUNICATIONS
The calibration of spectra was carried out on solvent signals
To our delight dehydro-b-amino acid derivatives
can be benzylated to a reasonable extent in the pres-
ence of FeCl3·6H2O. Hence, methyl 3-acetamidobut-
2-enoate in the reaction with 1-phenylethanol (2a)
yielded 38% of the corresponding product 4f
(Table 3, entry7). To the best of our knowledge these
are the first benzylations involving this class of enam-
ides.
1
1
(CDCl3: d H=7.25, d 13C=77.0; acetone-d6: d H=2.05, d
13C=29.8).
IR spectra are taken as nujol mulls (using KBr plates) or
KBr pellets or as capillaryfilms. MS were obtained on an
AMD 402/3 (EI, 70 eV). HR-MS analyses were recorded on
a high resolution magnetic sector spectrometer. GC analyses
were performed on an HP 6890 equipped with an HP-5 ca-
pillarycolumn ( l=30 m, d=250 mm) and an FID detector.
Quantitative GC analyses were referenced to decane as in-
ternal standard.
Finally, the benzylation of 4-hydroxycoumarin to
give
4-hydroxy-3-(1-arylalkyl)-2H-chromen-2-ones
was investigated. The resulting products constitute
important building blocks for potentiallynew phar-
maceuticals, especiallyanticoagulants. Actual exam-
ples of this class of compounds are Warfarin (Couma-
dinꢁ) and Phenprocoumon (Marcumarꢁ, Falithromꢁ,
Phenpro Ratiopharmꢁ). Furthermore, this motif is
widelypresent in rodenticides such as Bromadiolon
Representative Procedure
In a pressure tube, catalyst (5 mol%, 0.025 mmol), 1-phenyl-
ethanol (0.5 mmol), and methyl 3-oxobutanoate (2 mmol)
were dissolved in 2 mL CH3NO2. After stirring for 4 h at
508C decane (50 mL) was added as internal GC standard.
Aliquots were taken from the reaction mixture and subject-
and Difenacoum.[15] Indeed, the reaction of 4-hydroxy- ed to GC analyses for determination of yield and conver-
sion. For product isolation, the reaction was quenched with
water followed byextraction with dichloromethane. The
combined organic layers were dried over MgSO4 and the
solvents were distilled off. Then, the product was purified by
column chromatography( n-heptane/ethyl acetate, 1:1).
coumarin with 1-phenylethanol (2a) proceeded with
81% yield of the desired product 5a. The benzylation
with 1-phenyl-1-propanol was even more successful
yielding Phenprocoumon (5b) in excellent 94% yield
(Scheme 3).[16]
Acknowledgements
This work has been financed by the State of Mecklenburg-
Vorpommern, the Bundesministerium für Bildung und For-
schung (BMBF), and the Deutsche Forschungsgemeinschaft
(Leibniz-price). We thank Dr. W. Baumann, Dr. C. Fischer,
Mrs. S. Buchholz, Mrs. A. Lehmann, Mrs. C. Mewes, and
Mrs. S. Schareina (all Leibniz-Institut für Katalyse e.V.) for
their excellent analytical support.
Scheme 3. Benzylation of 4-hydroxycoumarin – synthesis of
Phenprocoumon (5b).
In summary, we have developed novel catalysts for
convenient and effective benzylations of 1,3-dicarbon-
yl compounds and similar substrates. Best results have
been obtained employing FeCl3·6H2O as a non-ex-
pensive and disposable catalyst. When applying ben-
zylic alcohols as electrophiles, water is the only by-
product in these reactions and excellent product
yields under mild reaction conditions (508C, 4 h) are
achieved. The usefullness of this procedure is shown
bya one-step synthesis of Phenprocoumon, a current
pharmaceutical drug.
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Experimental Section
General Remarks
All reactions were performed in ACE pressure tubes.
Unless specified, commercial solvents were used directly
without further purification. Column chromatographywas
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1
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