Cerium-catalyzed α-hydroxylation reactions of α-cyclopropyl β-dicarbonyl compounds with molecular oxygen

Article abstract of DOI:10.1002/ejoc.200600061

Three α-cyclopropyl β-dicarbonyl compounds have been used as probes for α-radicals as electrophilic reaction intermediates in a cerium-catalyzed α-hydroxylation reaction with molecular oxygen. Since the cyclopropyl group did not ring-open to products with a butenyl moiety, but was retained in the products, a localized unpaired electron at the α position can be excluded during the course of the reaction. The α-cyclopropyl- substituted substrates were prepared by aldol or Claisen reactions. Other substrates with α-methyl, α-isopropyl, and α-tert-butyl substituents were prepared and converted under the α-hydroxylation conditions in order to estimate steric influences on the yield of the reaction. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600061

FULL PAPER
DOI: 10.1002/ejoc.200600061
Cerium-Catalyzed α-Hydroxylation Reactions of α-Cyclopropyl β-Dicarbonyl
Compounds with Molecular Oxygen
Jens Christoffers,*[a][‡] Thomas Kauf,[a] Thomas Werner,[a][‡‡] and Michael Rössle[a][‡]
Keywords: Cerium / Catalysis / Dicarbonyl compounds / Oxidation / Dioxygen / Cyclopropane derivatives
Three α-cyclopropyl β-dicarbonyl compounds have been
used as probes for α-radicals as electrophilic reaction inter-
mediates in a cerium-catalyzed α-hydroxylation reaction
with molecular oxygen. Since the cyclopropyl group did not
ring-open to products with a butenyl moiety, but was re-
tained in the products, a localized unpaired electron at the α
position can be excluded during the course of the reaction.
The α-cyclopropyl-substituted substrates were prepared by
aldol or Claisen reactions. Other substrates with α-methyl, α-
isopropyl, and α-tert-butyl substituents were prepared and
converted under the α-hydroxylation conditions in order to
estimate steric influences on the yield of the reaction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
We have recently reported on a new α-hydroxylation re-
action of β-dicarbonyl compounds 1 catalyzed by cerium
chloride in 2-propanol (Scheme 1).[1] The key feature of this
reaction is the utilization of dioxygen as oxidant, which can
be regarded as optimal in terms of economic and ecological
considerations. Moreover, the precatalyst CeCl3·7H2O is in-
expensive and nontoxic. We have meanwhile further devel-
oped this method towards oxidative C–C bond forming re-
actions yielding 1,2-dioxane[2] derivatives or 1,4-dike-
tones.[3] This development was actually based on the as-
sumption that an α-radical species was formed as a reactive
intermediate.
The exact stoichiometry of this reaction could be estab-
Scheme 1. Cerium-catalyzed α-hydroxylation of β-dicarbonyl com-
lished from oxygen-uptake measurements with half an pounds 1, possible reaction intermediates 3a–3c (co-ligands at ce-
rium cannot be specified and are omitted for clarity), and chlori-
nated byproducts 4.
equivalent of O2 taken up per equivalent of product 2
formed. In some cases the formation of α-chlorinated by-
products 4 was observed, presumably resulting from a nu-
cleophilic attack of the chloride counterion of the catalyst
CeIV ions, for example, as hydrate or chloro complexes in
on an electrophilic reaction intermediate. With regard to
solution, readily form CeIV–diketonate species 3a
the mechanism of the catalysis we have made the following
(Scheme 1) under the reaction conditions. As known from
proposal: The role of dioxygen might only be to oxidize
the stoichiometric use of CeIV reagents, for example, CAN,
the CeIII species to CeIV under the reaction conditions. The
for the formation of α-radicals,[4] we propose ligand-to-
hydroxy group in product 2 could result from a nucleophilic
metal electron transfer generating species 3b. In this com-
attack of water on an electrophilic reaction intermediate.
plex the central metal formally has the oxidation state +
and a neutral β-diketone ligand with an unpaired electron
localized in the α-position. This radical species might then
[a] Institut für Organische Chemie der Universität Stuttgart,
be the electrophilic reaction intermediate[5] that forms the
Pfaffenwaldring 55, 70569 Stuttgart, Germany
[‡] New address: Institut für Reine und Angewandte Chemie der
Universität Oldenburg,
hydroxylation products 2 or the byproducts 4 upon reaction
with water or chloride as nucleophiles.
As a probe for spin density at the α-position and, thus,
to support our mechanistic proposal, we decided to prepare
α-cyclopropyl-substituted β-dicarbonyl compounds and
Carl-von-Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
Fax: +49-441-798-3873
E-mail: jens.christoffers@uni-oldenburg.de
[‡‡] New address: Chemistry Department, Imperial College Lon-
don,
Exhibition Road, South Kensington, London, SW7 2AZ, UK study them under the conditions of α-hydroxylation. If an
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J. Christoffers, T. Kauf, T. Werner, M. Rössle
FULL PAPER
unpaired electron is localized in this α-position, rapid frag- Table 1. α-Hydroxylation of β-dicarbonyl compounds 1a–1i.[a]
mentation to a butenyl radical species 3c will occur. Hence,
the cyclopropane ring should not be retained in any isolable
reaction product. This “radical clock” concept has proved
to be very effective in studies of radical intermediates in
oxygenation[6] and other reactions described in the litera-
ture.[7]
Results and Discussion
Hydroxylation Reactions
Three cyclopropane derivatives 1a–1c were prepared as
radical probes. These were then allowed to react for 16 h
under standard conditions for α-hydroxylation reactions,
employing 2-propanol as the solvent and 5 mol-%
CeCl3·7H2O as the catalyst under oxygen (1 atm). In the
case of acetylacetone derivative 1a and benzoyl acetate (1c)
the respective acyloins 2a and 2c were isolated by
chromatography on silica as the major components of the
reaction mixtures in 47 and 45% yields, respectively
(Table 1). With the β-keto ester 2c the chloro compound
4c was obtained as a byproduct in 15% yield. In contrast,
dibenzoylmethane derivative 1b was not oxidized to the re-
spective alcohol 2b. The only isolable material in this case
was the chloro compound 4b (5%). However, the crude re-
action mixture contained several species with an intact cy-
clopropane moiety, as clearly indicated by characteristic sig-
nals in the 13C (Ͻ12 ppm) and 1H NMR spectra (Ͻ1 ppm).
The total integral of cyclopropane protons is about 4 H
relative to the aromatic protons (10 H), indicating, that in
approx. 80% of the material the cyclopropane rings were
retained. We presume decomposition of the β-dicarbonyl
[a] Reagents and conditions: Approx. 3 moldm–3 iPrOH, 5 mol-%
CeCl3·7H2O, 23 °C, 16 h. [b] Reagents and conditions: 10 mol-%
CeCl3·7H2O, 22 h. [c] Yield determined by GC-MS.
unit of compounds 1b, 2b, or 4b occurs by a retro-Claisen
reaction before or after α-oxidation due to the high steric
congestion of these compounds.
From these results we can conclude that a localized un-
paired electron at the α position, as depicted in structure
3b, can definitely be excluded. Therefore, we need to revise
our mechanistic picture of the overall reaction.
cally with a tert-butyl group, as in compound 1i, completely
prevents conversion under the standard reaction conditions.
Since the yields of products 2a and 2c were relatively low,
we investigated the reactions of other aliphatic β-dicarbonyl
compounds 1d–1i under α-hydroxylation conditions in or-
der to obtain an estimate of the influence of the steric bulk
Synthesis of Cyclopropane Derivatives
Since compounds 1a, 1b (Scheme 2), and 1c (Scheme 3)
of the α-substituent on the yield of the respective product. were not accessible by direct α-alkylation of β-dicarbonyl
In particular, we investigated α-methyl-, α-isopropyl-, and compounds, we decided to build up the β-dicarbonyl moiety
α-tert-butyl substitution. In the cases of an α-methyl resi- by Claisen or aldol reactions. For this purpose, homoallylic
due, oxidation products 2d[8] and 2e[9] were isolated in mod- alcohols 5a[10] and 5b[11] were prepared by the reaction of
erate yields, similar to those of cyclopropyl derivatives 2a vinyl Grignard reagents with the corresponding aldehydes
and 2c. For the isopropyl congeners 2f and 2h the yields according to literature procedures and subsequently cyclo-
drop significantly to about 10% and some starting materials propanated[12] by the Simmons–Smith protocol[13] or its
1f and 1h could be reisolated. Therefore, we conclude that Furukawa modification[14] to furnish the alcohols 6a[15]
the steric requirement of a cyclopropyl group is comparable and 6b,[16] respectively (Scheme 2). Oxidation with PCC[17]
[18]
to that of a methyl group, which are both smaller than an or Na2Cr2O7/H2SO4
gave ketones 7a[15,19] and
isopropyl group. Similar to the cyclopropyl derivative 1b, 7b.[16a,19a,19b,20] Lewis acid mediated Claisen condensa-
the isopropylated dibenzoylmethane 1g partly decomposed tion[21] of methyl ketone 7a with Ac2O regioselectively gave
under the reaction conditions. The amount of starting ma- the new β-diketone 1a in a good yield. Claisen condensation
terial reisolated was 88%. Bulking up the substrate steri- of phenyl ketone 7b was more problematic, but could be
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Ce-Catalyzed α-Hydroxylations with Molecular Oxygen
FULL PAPER
Scheme 2. Preparation of α-cyclopropyl β-diketones 1a and 1b. Reagents and conditions: a) Zn, CuCl, CH2I2, Et2O, 35 °C, 16 h; 25%
(6a), 91% (6b); b) Et2Zn, CH2I2, toluene, 23 °C, 1.5 h; 83% (6b); c) PCC, CH2Cl2, 23 °C, 1.5 h; 48% (7a); d) Na2Cr2O7, H2SO4/H2O,
Et2O, 23 °C, 5 h; 76 % (7b); e) Ac2O, BF3·OEt2, 50 °C, 16 h; 74% (1a); f) 1. LDA, THF, –78 °C, 0.5 h; 2. (PhCO)2O, THF, 60 °C, 5 h;
66% (8), 20% (1b); g) NaOH, cat. H2O2, MeOH/H2O, 16 h, 50 °C; 82% (7b).
achieved with benzoic anhydride after stoichiometric depro- isomers, which were oxidized according to the Ley pro-
tonation with LDA.[22] However, O-acylation was the pre- cedure[26] to give cyclopropane derivative 1c in 52% yield
dominant process and enol ester 8 was isolated as the major over three steps.
product, which could be recycled to the starting material
7b in 82% yield by saponification[23]. The new C-acylation
product 1b was obtained in preparatively useful amounts
by repeated conversion of ketone 7b.
α-Alkylation of β-Dicarbonyl Compounds
α-Isopropylation of acetylacetone (1j)[27] and dibenzo-
ylmethane (1k)[28] was achieved only in moderate yields in
acetone at higher temperatures and with an excess of iso-
propyl iodide and K2CO3 (Scheme 4). Acetylacetone (1j)
was alkylated with tert-butyl alcohol and sulfuric acid to
give β-diketone 1i; the still moderate yield of this process
was significantly increased compared with the literature
procedure by changing the solvent to CH2Cl2.[29] Com-
Scheme 3. Synthesis of α-cyclopropyl β-keto ester 1c. Reagents and
conditions: a) CH2N2, cat. Pd(OAc)2, Et2O, 23 °C, 5 h; 71 % (10);
b) 1. LDA, THF, –78 °C, 40 min; 2. PhCHO, –78 °C, 15 min; 90%
(11), dr = 4:1; c) NMO, cat. TPAP, CH2Cl2, mol. sieves (4 Å),
23 °C, 45 min; 81% (1c).
In order to synthesize β-keto ester 1c, vinylacetic acid 9
was first cyclopropanated[24] and esterified with diazometh-
ane[25] in a Pd-catalyzed reaction (Scheme 3) to furnish
compound 10. Subsequent aldol reaction of the ester enol-
ate of 10, prepared by stoichiometric deprotonation with
Scheme 4. α-Alkylation of β-dicarbonyl compounds. Reagents and
conditions: a) iPrI, K2CO3, acetone, 120 °C, 2.5 d; 45% (1f); b)
iPrI, K2CO3, acetone, 60 °C, 16 h; 40% (1g), 51% (starting material
1k); c) tBuOH, H2SO4, CH2Cl2, 23 °C, 16 h; 33% (1i); d) MeI,
DBU, Et2O, 16 h, 23 °C; 50% (1e); e) NaOMe, iPrI, MeOH, 65 °C,
LDA, gave hydroxy ester 11 as a mixture of two diastereo- 16 h; 28% (1h).
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J. Christoffers, T. Kauf, T. Werner, M. Rössle
FULL PAPER
pounds 1e[30] and 1f[27] were prepared by α-alkylation of
acetoacetate 1l with MeI/DBU and iPrI/NaOMe, respec-
tively.
keto: δ = 4.42 (CH2), 10.23 (CH), 29.06 (CH3), 72.97 (CH), 204.90
(C=O) ppm; enol: δ = 8.58 (CH), 8.92 (CH2), 23.68 (CH3), 112.92
(C), 192.92 (C=O) ppm. IR (ATR): ν = 3413 (s, br), 1710 (m), 1687
˜
(s), 1463 (m), 1252 (m), 1097 (s) cm–1. HRMS (EI, 70 eV): calcd.
for C8H12O2: 140.0837; found 140.0837 [M]+.
Conclusion
2-Cyclopropyl-1,3-diphenyl-1,3-propanedione (1b): A solution of
LDA (4.2 mL, 8.4 mmol, c = 2.0 moldm–3 in THF) was added at
–78 °C to a stirred solution of ketone 7b (1.22 g, 7.62 mmol) in
THF (5 mL). After stirring the mixture for 30 min at –78 °C, ben-
zoic anhydride (2.58 g, 11.4 mmol) was added, the mixture was
stirred for a further 5 h at 60 °C, and then diluted with a saturated
aqueous NH4Cl solution (5 mL). The aqueous layer was extracted
with THF (4×20 mL), the combined organic layers dried with
Na2SO4, and after filtration, concentrated in vacuo. The product
mixture was separated by column chromatography (SiO2, PE/EA,
10:1) to give enol ester 8 (Rf = 0.30, 1.49 g, 5.66 mmol, 66%) in
the first fraction as a brown oil and the title compound 1b (Rf =
0.15, 439 mg, 1.66 mmol, 20%) in the second fraction as a brown-
ish oil. 1H NMR (500 MHz, CDCl3): δ = 0.33–0.36 (m, 2 H), 0.69–
0.75 (m, 2 H), 1.61–1.70 (m, 1 H), 4.34 (d, J = 9.7 Hz, 1 H), 7.42–
7.45 (m, 4 H), 7.53–7.56 (m, 2 H), 7.94–7.99 (m, 4 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 4.85 (2 CH2), 11.36 (CH),
63.67 (CH), 128.82 (8 CH), 133.46 (2 CH), 136.32 (2 C), 195.99 (2
An electrophilic reaction intermediate with an unpaired
electron was proposed in the cerium-catalyzed α-hydroxyla-
tion of β-dicarbonyl compounds. Three α-cyclopropyl β-di-
carbonyl compounds 1a–1c were prepared by aldol or
Claisen condensation reactions as probes for this α-radical.
However, under the standard reaction conditions of the oxi-
dation process, the cyclopropyl moieties of these substrates
were retained rather than being converted to the ring-
opened product with a butenyl moiety. Therefore we con-
clude that the spin density in a long-lived paramagnetic in-
termediate cannot be localized at the α position, but must
be highly delocalized among the six-membered chelate ring.
For comparison of steric influences on the yields of this
α-hydroxylation process, six β-dicarbonyl compounds with
α-methyl, α-isopropyl, or α-tert-butyl substituents were pre-
pared and exposed to the conditions of the α-hydroxylation
reaction.
C) ppm. IR (ATR): ν = 1721 (m), 1694 (s), 1659 (s), 1595 (m), 1580
˜
(m), 1447 (m), 1320 (m), 1270 (s), 1204 (m), 1021 (m), 1001 (m),
946 (m) cm–1. HRMS (EI, 70 eV): calcd. for C18H16O2: 264.1150;
found 264.1142 [M]+.
Experimental Section
Methyl 2-Cyclopropyl-3-oxo-3-phenylpropanoate (1c): Molecular si-
eves (6.7 g, 4 Å) and NMO (2.300 g, 17.02 mmol) were added at
23 °C to a solution of alcohol 11 (2.500 g, 11.35 mmol) in CH2Cl2
(23 mL). After stirring for 8 min at 23 °C, TPAP (597 mg,
1.70 mmol) was added and the reaction mixture was stirred for a
further 45 min, then filtered through a pad of SiO2 to yield the title
compound 1c (1.997 g, 9.150 mmol, 81%) as a brown oil. Rf (SiO2,
PE/EA, 5:1) = 0.32. 1H NMR (300 MHz, CDCl3): δ = 0.16–0.24
(m, 1 H), 0.36–0.46 (m, 1 H), 0.60–0.77 (m, 2 H), 1.62–1.50 (m, 1
H), 3.54 (d, J = 9.9 Hz, 1 H), 3.70 (s, 3 H), 7.45–7.51 (m, 2 H),
7.56–7.62 (m, 1 H), 7.94–7.98 (m, 2 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): δ = 3.95 (CH2), 4.51 (CH2), 10.61 (CH), 52.51
(CH3), 59.12 (CH), 128.62 (CH), 128.78 (CH), 133.54 (CH), 136.29
(C), 170.30 (C=O), 194.79 (C=O) ppm. MS (CI, CH4): m/z (%) =
General Methods: Procedures using Grignard reagents, Et2Zn,
CuCl, LDA, BF3·Et2O, TPAP–NMO, or NaOMe were performed
in flame-dried glassware and with absolute solvents under nitrogen.
Column chromatography was carried out using Merck SiO2 60 with
hexanes (= PE, boiling range 40–60 °C) and ethyl acetate (= EA)
as eluents. 1H NMR spectra were recorded with a Bruker ARX
500 (500 MHz), Bruker ARX 300 (300 MHz), or Bruker AC 250
(250 MHz) spectrometer. 13C NMR spectra were recorded with a
Bruker ARX 500 (125 MHz), Bruker ARX 300 (75 MHz) or
Bruker AC 250 (62 MHz) instrument. Multiplicities were deter-
mined by DEPT experiments. IR spectra were recorded with a
Bruker Vector 22 instrument with a Diamond ATR unit. Mass
spectra were recorded with Varian MAT 711 (EI, HRMS) and Fin-
nigan MAT 95 (EI, CI) instruments. Melting points were measured
with a Büchi 510 and are uncorrected. The starting material 1d was
commercially available. Compounds 5a,[10] 5b,[11] and diazometh-
ane[25] were prepared according to literature procedures.
219 (5) [MH]+, 187 (5) [M – MeOH]+, 105 (100). IR (ATR): ν =
˜
1743 (vs), 1686 (vs), 1442 (m), 1290 (m) cm–1. C13H14O3 (218.25):
calcd. C 71.54, H 6.47; found C 71.24, H 6.50.
Methyl 2-Methyl-3-oxobutanoate (1e): MeI (4.31 g, 30.4 mmol) was
added to a suspension of keto ester 1l (2.89 g, 24.9 mmol) and
DBU (3.79 g, 24.9 mmol) in Et2O (35 mL). The reaction mixture
was stirred for 16 h at 23 °C and then diluted with H2O (20 mL).
The aqueous layer was extracted with CH2Cl2 (3×15 mL). The
combined organic layers were dried with MgSO4. After filtration,
the solvent was removed in vacuo. The residue was purified by
chromatography (SiO2, PE/EA, 2:1, Rf = 0.33) to give the title com-
pound 1e (1.61 g, 12.4 mmol, 50%) as a colorless oil. 1H NMR
(500 MHz, CDCl3): δ = 1.38 (d, J = 7.5 Hz, 3 H), 2.27 (s, 3 H),
3.55 (q, J = 7.3 Hz, 1 H), 3.77 (s, 3 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 12.20 (CH3), 28.48 (CH3), 52.47 (CH3),
3-Cyclopropyl-2,4-pentanedione (1a): BF3·Et2O (0.66 mL, 0.74 g,
5.6 mmol) was added dropwise to a solution of the ketone 7a
(200 mg, 2.04 mmol) in Ac2O (0.42 g, 4.1 mmol). The reaction mix-
ture was then stirred for 16 h at 50 °C, a solution of NaOAc (0.67 g,
8.2 mmol) in H2O (6 mL) was added, and the mixture refluxed for
3 h. After cooling to ambient temperature the organic layer was
separated and the aqueous phase extracted with Et2O (3×20 mL).
The combined organic layers were washed with saturated NaHCO3
solution, dried with MgSO4, filtered, and the solvent removed in
vacuo. The residue was purified by chromatography (SiO2, PE/EA,
5:1, Rf = 0.51) to provide compound 1a (212 mg, 1.51 mmol, 74%)
as a colorless oil as a mixture of keto-enol tautomer (keto:enol =
2:1, determined by 1H NMR). 1H NMR (500 MHz, CDCl3),
ketone: δ = 0.25–0.28 (m, 2 H), 0.70–0.74 (m, 2 H), 1.30–1.35 (m,
1 H), 2.26 (s, 6 H), 2.72 (d, J = 10.5 Hz, 1 H) ppm; enol: δ = 0.36–
0.39 (m, 2 H), 0.87–0.92 (m, 2 H), 1.36–1.43 (m, 1 H), 2.25 (s, 6
53.46 (CH), 171.02 (C=O), 203.66 (C=O) ppm. IR (ATR): ν = 2990
˜
(m), 2954 (m), 1746 (s), 1718 (s), 1456 (m), 1436 (m), 1360 (m),
1210 (m) cm–1. HRMS (EI, 70 eV): calcd. for C6H10O3: 130.0629;
found 130.0628 [M]+.
3-Isopropyl-2,4-pentanedione (1f): A mixture of diketone 1j (7.34 g,
H), 16.45 (s, 1 H, OH) ppm. 13C{1H} NMR (125 MHz, CDCl3), 73.3 mmol), 2-iodopropane (37.4 g, 220 mmol), and K2CO3 (30.4 g,
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220 mmol) in acetone (30 mL) was stirred in an autoclave for 2.5 d
at 120 °C. After cooling to ambient temperature and filtration the
solvent was removed in vacuo and the residue purified by
chromatography [SiO2, PE/EA, 10:1, Rf = 0.21] to give the title
compound 1f as a colorless oil (4.66 g, 32.8 mmol, 45%). 1H NMR
(500 MHz, CDCl3): δ = 0.92 (d, J = 6.6 Hz, 6 H), 2.16 (s, 6 H),
2.48 (dsept, J = 10.5, J = 6.6 Hz, 1 H), 3.41 (d, J = 10.5 Hz, 1
removed under reduced pressure and the residue purified by distil-
lation (b.p. 80 °C, 20 mbar) to give the title compound 1i (20.5 g,
131 mmol, 33%) as a yellowish oil. Rf (PE/EA, 2:1) = 0.55. 1H
NMR (CDCl3, 500 MHz): δ = 1.08 (s, 9 H), 2.22 (s, 6 H), 3.65 (s,
1 H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): δ = 28.42 (3 CH3),
32.44 (2 CH3), 35.42 (C), 76.45 (CH), 204.59 (2 C) ppm. IR (ATR):
ν = 2959 (m), 1720 (s), 1693 (vs), 1356 (s), 1148 (s) cm–1. MS (EI,
˜
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 20.54 (CH3), 70 eV): m/z (%) = 156 (1) [M]+, 114 (8) [M – C2H3O]+, 99 (100)
29.28 (CH), 29.60 (CH3), 77.80 (CH), 204.49 (C=O) ppm. IR [M – C4H9]+. C9H16O2 (156.22): calcd. C 69.20, H 10.32; found C
(ATR): ν = 1690 (s), 1098 (m) cm–1. HRMS (EI, 70 eV): calcd. for
68.90, H 10.11.
˜
C8H14O2: 142.0994; found 142.0994 [M]+.
General Procedure for the α-Hydroxylation Reaction: The respective
β-dicarbonyl compound 1 (1 equiv.) was added to a suspension of
CeCl3·7H2O (5 mol-%) in iPrOH (approx. 3 moldm–3 of 1). The
flask was evacuated twice to approx. 500 mbar, each time flushed
with O2, and the mixture then stirred for 16 h at 23 °C while a slow
stream of O2 (approx. 50 cm3 h–1) was passed through. Finally, the
solvent was evaporated and the residue purified by column
chromatography (SiO2, PE/EA) to yield the products 2 and 4 as
specified below.
2-Isopropyl-1,3-diphenyl-1,3-propanedione (1g): A mixture of dike-
tone 1k (245 mg, 1.09 mmol), 2-iodopropane (537 mg, 3.28 mmol),
K2CO3 (435 mg, 3.28 mmol), and acetone (1 mL) was heated for
16 h at 60 °C and then cooled to ambient temperature, filtered, and
the residue washed with acetone. The filtrate was concentrated in
vacuo and purified by chromatography (SiO2, PE/EA, 10:1) to give
the starting material 1k (44 mg, 0.20 mmol, 18%) in the first frac-
tion (Rf = 0.41), while the second fraction was a mixture, which
was submitted to another chromatography (SiO2, PE/EA, 10:1) to
yield again the starting material 1k (96 mg, 0.36 mmol, 33%) in the
first fraction and the title compound 1g (118 mg, 0.44 mmol, 40%)
in the second fraction [Rf(PE/EA, 10:1) = 0.21] as a colorless solid,
3-Cyclopropyl-3-hydroxy-2,4-pentanedione (2a): Diketone 1a
(250 mg, 1.78 mmol) and CeCl3·7H2O (33 mg, 0.088 mmol) were
converted in iPrOH (1 mL) according to the general procedure.
Chromatography (SiO2, PE/EA, 10:1, Rf = 0.32) furnished the α-
hydroxy compound 2a (131 mg, 0.840 mmol, 47%) as a colorless
oil. 1H NMR (500 MHz, CDCl3): δ = 0.40 (d, J = 6.9 Hz, 4 H),
1.64 (quint, J = 6.7 Hz, 1 H), 2.32 (s, 6 H), 4.25 (s, 1 H, OH) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = –0.23 (CH), 15.34 (CH2),
1
m.p. 80 °C. H NMR (500 MHz, CDCl3): δ = 1.02 (d, J = 6.6 Hz,
6 H), 2.92 (dsept, J = 9.3, J = 6.6 Hz, 1 H), 5.06 (d, J = 9.3 Hz, 1
H), 7.41–7.45 (m, 4 H), 7.51–7.56 (m, 2 H), 7.98–8.01 (m, 4
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 21.35 (CH3),
30.29 (CH), 65.13 (CH), 128.72 (CH), 128.79 (CH), 133.38 (CH),
25.49 (CH ), 86.82 (C), 207.68 (C=O) ppm. IR (ATR): ν = 3435
˜
3
137.14 (C), 195.65 (C=O) ppm. IR (ATR): ν = 2963 (m), 1692 (s),
˜
(w), 3011 (m), 1702 (s), 1418 (m), 1353 (m), 1236 (m), 1191 (m),
1154 (s), 1050 (s), 1025 (s), 971 (s) cm–1. HRMS (CI, CH4): calcd.
for C8H13O3: 157.0865; found 157.0856 [MH]+.
1655 (s), 1594 (m), 1579 (m), 1447 (m), 1330 (m), 1307 (s), 1278
(s), 1202 (s), 1178 (s), 1158 (m), 1119 (m), 995 (m) cm–1. MS (EI,
70 eV): m/z (%) = 266 (2) [M]+, 105 (100) [PhCO]+. C18H18O2
(266.34): calcd. C 81.17, H 6.81; found C 81.31, H 6.80.
Methyl 2-Cyclopropyl-2-hydroxy-3-oxo-3-phenylpropanoate (2c):
The keto ester 1c (251 mg, 1.15 mmol) and CeCl3·7H2O (45 mg,
0.12 mmol) were converted in iPrOH (0.5 mL) according to the ge-
neral procedure. After chromatography (SiO2, PE/EA, 10:1) the
chloro compound 4c [46 mg, 0.18 mmol, 15%, Rf (PE/EA, 5:1) =
0.42] was obtained in the first fraction as a colorless oil (data vide
infra). In the second fraction [Rf (SiO2, PE/EA, 5:1) = 0.28] the
title compound 2c (120 mg, 0.512 mmol, 45%) was obtained as a
colorless oil. 1H NMR (500 MHz, CDCl3): δ = 0.33–0.40 (m, 2 H),
0.53–0.59 (m, 1 H), 0.68–0.73 (m, 1 H), 1.65–1.70 (m, 1 H), 3.78
(s, 3 H), 4.28 (s, 1 H, OH), 7.45–7.49 (m, 2 H), 7.58–7.61 (m, 1 H),
8.01–8.04 (m, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ =
0.12 (CH2), 0.99 (CH2), 15.40 (CH), 53.28 (CH3), 79.82 (C), 128.69
(CH), 129.53 (CH), 133.35 (C), 133.75 (CH), 172.48 (C=O), 195.66
(C=O) ppm. MS (CI, CH4): m/z (%) = 235 (4) [MH]+, 217 (62)
Methyl 2-Isopropyl-3-oxobutanoate (1h): NaOMe (0.930 g,
17.2 mmol) and 2-iodopropane (4.39 g, 25.8 mmol) were added to
a stirred solution of keto ester 1l (2.00 g, 17.2 mmol) in MeOH
(12 mL) and the resulting mixture was refluxed for 16 h. Then the
solvent was mostly evaporated under reduced pressure and the resi-
due dissolved in water (8 mL) and extracted with Et2O (4×10 mL).
The combined organic layers were dried with MgSO4. After fil-
tration, the solvent was removed in vacuo. The residue was purified
by chromatography [SiO2, PE/EA, 5:1 gradient to 2:1, Rf (PE/EA,
2:1) = 0.54] to give the title compound 1h (757 mg, 4.79 mmol,
1
28%) as a colorless liquid. H NMR (500 MHz, CDCl3): δ = 0.86
(d, J = 6.7 Hz, 3 H), 0.90 (d, J = 6.7 Hz, 3 H), 2.15 (s, 3 H) 2.40
(dsept, J = 9.5, J = 6.7 Hz, 1 H), 3.13 (d, J = 9.5 Hz, 1 H) 3.66 (s,
3 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 20.47 (CH3),
20.48 (CH3), 28.75 (CH3), 29.26 (CH), 52.21 (CH3), 67.47 (CH),
[MH – H O]+, 203 (5) [MH – MeOH]+, 105 (100). IR (ATR): ν =
˜
2
3064 (w), 3010 (w), 2954 (w), 1741 (s), 1694 (s), 1274 (m), 1235
(m), 1170 (m) cm–1. C13H14O4 (234.25): calcd. C 66.66, H 6.02;
found C 66.46, H 6.04.
169.72 (C=O), 203.24 (C=O) ppm. IR (ATR): ν = 2963 (m), 2876
˜
(m), 1736 (s), 1709 (s), 1434 (m), 1358 (m), 1284 (m), 1197 (s), 1144
(s) cm–1. MS (EI, 70 eV): m/z (%) = 158 (2) [M]+, 127 (15) [M –
CH3]+, 116 (70) [M – C3H6]+, 101 (100). C8H14O3 (158.20): calcd.
C 60.74, H 8.92; found C 60.64, H 8.84.
3-Hydroxy-3-methyl-2,4-pentanedione (2d): Diketone 1d (300 mg,
2.62 mmol) and CeCl3·7H2O (48 mg, 0.13 mmol) were converted in
iPrOH (0.9 mL) according to the general procedure. Chromatog-
raphy (SiO2, PE/EA, 2:1, Rf = 0.38) furnished the α-hydroxy com-
3-tert-Butyl-2,4-pentanedione (1i): Conc. H2SO4 (76.4 g, 779 mmol)
was slowly added to a cooled (ice/water bath) and stirred solution
of acetylacetone (1j) (40.0 g, 400 mmol) in CH2Cl2 (80 mL). During
this addition the reaction temperature should not rise above 10 °C.
Then tBuOH (47.4 g, 639 mmol) was added dropwise and the mix-
ture stirred for 16 h at 23 °C. Water (200 mL) was added slowly and
the mixture extracted with PE (5×200 mL). The combined organic
layers were washed with a saturated aqueous MgSO4 solution
(480 mL) and dried with MgSO4. After filtration, the solvent was
1
pound 2d (115 mg, 0.884 mmol, 34%) as a colorless oil. H NMR
(500 MHz, CDCl3): δ = 1.54 (s, 3 H), 2.24 (s, 6 H), 4.70 (br. s, 1
H, OH) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 22.59 (CH3),
24.72 (CH ), 87.61 (C), 207.43 (C=O) ppm. IR (ATR): ν = 3351
˜
3
(m), 2973 (m), 2925 (m), 2854 (m), 1708 (s), 1417 (m), 1356 (m),
1237 (m), 1148 (m) cm–1. HRMS (CI, CH4): calcd. for C6H11O3:
131.0708; found 131.0708 [MH]+.
Eur. J. Org. Chem. 2006, 2601–2608
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2605

J. Christoffers, T. Kauf, T. Werner, M. Rössle
FULL PAPER
Methyl 2-Hydroxy-2-methyl-3-oxobutanoate (2e): Dicarbonyl com-
(CH3), 74.12 (C), 128.50 (CH), 129.40 (CH), 133.34 (CH), 133.66
pound 1e (200 mg, 1.54 mmol) and CeCl3·7H2O (29 mg, (C), 168.96 (C=O), 189.33 (C=O) ppm. MS (CI, CH4): m/z (%) =
0.078 mmol) were converted in iPrOH (0.5 mL) according to the
general procedure. Chromatography (SiO2, PE/EA, 5:1, Rf = 0.38)
furnished the acyloin 2e (117 mg, 0.802 mmol, 52%) as a colorless
oil in the second fraction and the remaining starting material 1e
253 (4) [MH]+, 217 (12) [MH – HCl]+, 193 (8), 185 (10), 105 (100).
IR (ATR): ν = 3056 (w), 3017 (w), 2954 (w), 1759 (vs), 1730 (vs),
˜
1697 (s), 1258 (m), 1221 (m) cm–1. C13H13ClO3 (252.70): calcd. C
61.79, H 5.19; found C 61.85, H 5.29.
1
(Rf = 0.49, 49 mg, 0.38 mmol, 25%) in the first fraction. H NMR
1-Cyclopropyl-2-propanol (6a): A suspension of Zn dust (15.9 g,
242 mmol) and CuCl (24.0 g, 242 mmol) in Et2O (47 mL) was
stirred for 30 min at 35 °C. The olefin 5a (8.04 g, 93.4 mmol) and
CH2I2 (50.0 g, 187 mmol) were added and the mixture stirred for a
further 16 h at 35 °C. After filtration and washing of the residue
with 5% hydrochloric acid (2×50 mL), the filtrate was washed with
a saturated aqueous NaHCO3 solution (50 mL) and brine (50 mL).
The organic layer was dried with MgSO4, filtered, and the solvent
evaporated under reduced pressure. Chromatography (SiO2, PE/
EA, 5:1, Rf = 0.11) afforded the product 6a (1.40 g, 13.9 mmol,
(CDCl3, 500 MHz): δ = 1.61 (s, 3 H), 2.29 (s, 3 H), 3.81 (s, 3 H),
4.21 (br. s, 1 H, OH) ppm. 13C{1H} NMR (CDCl3, 125 MHz): δ =
21.97 (CH3), 24.18 (CH3), 53.40 (CH3), 81.04 (C), 171.76 (C=O),
204.90 (C=O) ppm. IR (ATR): ν = 3460 (m, br), 1726 (s), 1438
˜
(m), 1360 (m), 1269 (m), 1156 (m) cm–1. HRMS (CI, CH4): calcd.
for C6H11O4: 147.0657; found 147.0657 [MH]+.
3-Hydroxy-3-isopropyl-2,4-pentanedione (2f): Diketone 1f (303 mg,
2.13 mmol) and CeCl3·7H2O (40 mg, 0.11 mmol) were converted in
iPrOH (0.7 mL) according to the general procedure. Chromatog-
raphy (SiO2, PE/EA, 10:1, Rf = 0.35) furnished the α-hydroxy com-
pound 2f (37 mg, 0.23 mmol, 11%) as a colorless oil in the first
fraction and the starting material 1f (115 mg, 0.809 mmol, 38%) in
1
25%) as a brown oil. H NMR (500 MHz, CDCl3): δ = 0.03–0.08
(m, 1 H), 0.09–0.13 (m, 1 H), 0.43–0.52 (m, 2 H), 0.68–0.77 (m, 1
H), 1.22 (d, J = 6.2 Hz, 3 H), 1.36 (t, J = 6.6 Hz, 2 H), 1.66 (s, 1 H,
OH), 3.91 (sext, J = 6.2 Hz, 1 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ = 3.74 (CH2), 4.36 (CH2), 7.48 (CH), 23.19 (CH3), 44.07
1
the second fraction (Rf = 0.21). H NMR (500 MHz, CDCl3): δ =
0.80 (d, J = 6.7 Hz, 6 H), 2.24 (s, 6 H), 2.76 (sept, J = 6.7 Hz, 1
H), 4.55 (s, 1 H, OH) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ
= 16.31 (CH3), 25.84 (CH), 34.73 (CH), 94.28 (C), 208.22
(CH ), 68.71 (CH) ppm. IR (ATR): ν = 3343 (s, br), 2967 (m), 2914
˜
2
(m), 1460 (m), 1372 (m), 1119 (m), 1085 (s), 1041 (m), 1015 (m),
929 (m) cm–1. HRMS (EI, 70 eV): calcd. for C6H12O: 100.0888;
found 100.0890 [M]+.
(C=O) ppm. IR (ATR): ν = 3448 (s, br), 2668 (m), 2937 (m), 2879
˜
(m), 1700 (s), 1416 (m), 1388 (m), 1353 (s), 1190 (m), 1173 (m),
1147 (s), 1043 (s) cm–1. HRMS (EI, 70 eV): calcd. for C8H14O3:
158.0943; found 158.0948 [M]+.
2-Cyclopropyl-1-phenyl-1-ethanol (6b): a) Simmons–Smith protocol:
A suspension of CuCl (14.7 g, 148 mmol) and Zn dust (9.66 g,
148 mmol) in Et2O (84 mL) was refluxed for 30 min. The olefin 5b
(8.44 g, 56.9 mmol) and CH2I2 (39.7 g, 148 mmol) were added and
the mixture was stirred for 16 h at 35 °C. After filtration through
Florisil (Et2O) the solvent was evaporated in vacuo and after
chromatography (bas. Al2O3, PE/EA, 10:1) the product 6b (8.39 g,
52.4 mmol, 91%) was obtained as a yellowish oil. b) Furukawa
modification: A solution of Et2Zn (33.3 mL, 36.7 mmol, c =
1.1 moldm–3 in toluene) was quickly dropped at 0 °C into a mixture
of the alcohol 5b (1.81 g, 12.2 mmol) and CH2I2 (9.82 g,
36.7 mmol). The mixture was warmed to room temperature and
stirred for 1.5 h. Subsequently, air was blown through the mixture
(15 min) which was then stirred overnight at ambient temperature.
Toluene (20 mL) was added and the mixture washed with an aque-
ous NaOH solution (3 moldm–3, 20 mL). The aqueous layer was
separated and extracted with Et2O (3×50 mL). The combined or-
ganic extracts were dried with Na2SO4 and filtered. After evapora-
tion of the solvent under reduced pressure, chromatography (SiO2,
PE/E, 10:1, Rf = 0.10) yielded the product 6b (1.65 g, 10.1 mmol,
83%) as a yellowish oil. 1H NMR (300 MHz, CDCl3): δ = 0.01–
0.07 (m, 1 H), 0.09–0.19 (m, 1 H), 0.36–0.55 (m, 2 H), 0.64–0.79
(m, 1 H), 1.59–1.75 (m, 2 H), 1.93 (s, 1 H), 4.79 (dd, J = 7.4, J =
5.9 Hz, 1 H), 7.24–7.39 (m, 5 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ = 3.92 (CH2), 4.50 (CH), 7.65 (CH2), 44.18 (CH2), 75.05
(CH), 125.89 (CH), 127.44 (CH), 128.36 (CH), 144.68 (C) ppm. IR
Methyl 2-Hydroxy-2-isopropyl-3-oxobutanoate (2h): Diketone 1h
(300 mg, 1.90 mmol) and CeCl3·7H2O (35 mg, 0.094 mmol) were
converted in iPrOH (0.6 mL) according to the general procedure.
Chromatography (SiO2, PE/EA, 10:1, Rf = 0.14) furnished the acy-
loin 2h (28 mg, 0.16 mmol, 8%) as a colorless oil in the second
fraction and the starting material 1h (Rf
= 0.25, 208 mg,
1.31 mmol, 69%) in the first fraction. 1H NMR (CDCl3,
250 MHz): δ = 0.78 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H),
2.33 (s, 3 H), 2.72 (sept, J = 6.8 Hz, 1 H), 3.81 (s, 3 H), 4.13 (s, 1
H, OH) ppm. 13C{1H} NMR (CDCl3, 62 MHz): δ = 15.87 (CH3),
16.92 (CH3), 25.09 (CH), 34.01 (CH3), 53.32 (CH3), 87.90 (C),
171.34 (C=O), 205.74 (C=O) ppm. IR (ATR): ν = 3467 (s, br), 2966
˜
(m), 1720 (vs), 1357 (m), 1263 (m), 1154 (m) cm–1. HRMS (EI,
70 eV): calcd. for C8H14O4: 174.0892; found 174.0892 [M]+.
2-Chloro-2-cyclopropyl-1,3-diphenyl-1,3-propanedione (4b): Dike-
tone 1b (296 mg, 1.12 mmol) and CeCl3·7H2O (20 mg, 0.054 mmol)
were converted in iPrOH (1.0 mL) according to the general pro-
cedure. Chromatography (SiO2, PE/EA, 10:1, Rf = 0.40) furnished
the α-chloro compound 4b (18 mg, 0.060 mmol, 5%) as a colorless
oil. 1H NMR (500 MHz, CDCl3): δ = 0.74–0.77 (m, 4 H), 1.90–
1.94 (m, 1 H), 7.34–7.39 (m, 4 H), 7.46–7.49 (m, 2 H), 7.92–7.97
(m, 4 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 3.31 (CH2),
13.31 (CH2), 17.46 (CH), 81.22 (C), 128.59 (CH), 130.17 (CH),
133.47 (CH), 191.73 (C=O) ppm. IR (ATR): ν = 3062 (w), 3012
˜
(ATR): ν = 3219 (m), 3076 (m), 2999 (m), 2905 (m), 1491 (s), 1454
˜
(w), 2929 (w), 1766 (w), 1678 (s), 1596 (m), 1580 (m), 1448 (m),
1218 (s) cm–1. GCMS (CI, CH4): m/z (%) = 299 (3) [MH]+, 263
(66) [MH – Cl]+, 176 (21), 105 (100). HRMS (EI, 70 eV): calcd. for
C18H15ClO2: 298.0761; found 298.0775 [M]+.
(m), 1335 (s), 1064 (s), 1040 (m), 1012 (s), 964 (m) cm–1. MS (EI,
70 eV): m/z (%) = 162 (10) [M]+, 107 (100). C11H14O (162.23):
calcd. C 81.44, H 8.70; found C 80.94, H 8.85.
Methyl 2-Chloro-2-cyclopropyl-3-oxo-3-phenylpropanoate (4c): The
title compound 4c (46 mg, 0.18 mmol, 15%) was obtained as a col-
orless oil as a byproduct in the synthesis of acyloin 2c. Rf (SiO2,
1-Cyclopropyl-2-propanone (7a): A solution of the alcohol 6a
(1.77 g, 17.8 mmol) and PCC (5.73 g, 26.6 mmol) in CH2Cl2
(35 mL) was stirred at 23 °C for 1.5 h, then diluted with Et2O
PE/EA, 5:1) = 0.42. 1H NMR (300 MHz, CDCl3): δ = 0.59–0.84 (26 mL), and decanted from the solid. The solid was extracted with
(m, 4 H), 1.78–1.87 (m, 1 H), 3.75 (s, 3 H, CH3), 7.42–7.47 (m, 2
H), 7.51–7.59 (m, 1 H), 7.95–7.99 (m, 2 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 1.53 (CH2), 2.95 (CH2), 16.80 (CH), 53.76
Et2O (4×50 mL) and the combined organic extracts were filtered
(SiO2, Et2O, Rf = 0.65). After removing the solvent in vacuo ketone
7a (839 mg, 8.55 mmol, 48%) was obtained as a brownish oil. H
1
2606
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2601–2608

Ce-Catalyzed α-Hydroxylations with Molecular Oxygen
FULL PAPER
NMR (500 MHz, CDCl3): δ = 0.11–0.14 (m, 2 H), 0.55–0.59 (m, 2
H), 0.94–1.02 (m, 1 H), 2.18 (s, 3 H), 2.30 (d, J = 7.0 Hz, 2 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 4.50 (CH2), 6.43 (CH),
was removed in vacuo and the residue purified by distillation (b.p.
93–95 °C, 304 mbar) to yield the title compound 10 (3.743 g,
32.79 mmol, 71%) as a colorless liquid. 1H NMR (300 MHz,
CDCl3): δ = –0.06 to +0.08 (m, 2 H), 0.32–0.48 (m, 2 H), 0.83–
0.97 (m 1 H), 2.06 (d, J = 7.1 Hz, 2 H), 3.54 (s, 3 H, CH3) ppm.
29.61 (CH ), 48.98 (CH ), 209.15 (C=O) ppm. IR (ATR): ν = 3410
˜
3
2
(s, br), 2953 (m), 2857 (m), 1686 (s), 1463 (s), 1406 (m), 1251 (m),
1218 (s), 1098 (s), 1004 (m), 905 (m) cm–1. HRMS (EI, 70 eV): 13C{1H} NMR (75 MHz, CDCl3): δ = 4.39 (CH2), 6.89 (CH), 39.22
calcd. for C6H10O: 98.0731; found 98.0727 [M]+.
(CH2), 51.55 (CH3), 173.73 (C=O) ppm. MS (EI, 70 eV): m/z (%)
= 114 (18) [M]+, 99 (9) [M – Me]+, 83 (24) [M – OMe]+. IR (ATR):
2-Cyclopropyl-1-phenyl-1-ethanone (7b): a) By oxidation of alcohol
6b: A solution of Na2Cr2O7 (24.0 g, 80.7 mmol) in conc. H2SO4
(18.3 mL) and H2O (120 mL) was added over a period of 5 h to a
solution of alcohol 6b (14.5 g, 89.5 mmol) in Et2O (40 mL). The
organic layer was separated and the aqueous layer was extracted
with Et2O (5×50 mL). The combined organic layers were washed
with a saturated aqueous NaHCO3 solution, dried (Na2SO4), fil-
tered, and all volatile materials were removed in vacuo. The residue
was purified by chromatography (SiO2, PE/EA, 10:1, Rf = 0.36) to
afford the diketone 7b (11.0 g, 68.7 mmol, 76%) as a colorless oil.
b) By saponification of enol ester 8: Solid NaOH (3.10 g,
77.4 mmol) and one drop of H2O2 (30%) was added to a solution
of ester 8 (1.84 g, 6.96 mmol) in MeOH (15.5 mL) and H2O
(12.5 mL). The mixture was heated to 50 °C for 16 h, then diluted
with a saturated aqueous NaHCO3 solution (25 mL), and extracted
with Et2O (4×50 mL). The combined organic layers were dried
with MgSO4 and filtered. The solvent was evaporated to give a
residue, which was purified by chromatography (SiO2, PE/EA, 10:1,
Rf = 0.36) to give diketone 7b as a colorless oil (0.980 g, 6.14 mmol,
82%). 1H NMR (300 MHz, CDCl3): δ = 0.17–0.22 (m, 2 H), 0.57–
0.64 (m, 2 H), 1.11–1.24 (m, 1 H), 2.89 (d, J = 6.8 Hz, 2 H), 7.42–
7.52 (m, 2 H), 7.52–7.59 (m, 1 H), 7.91–7.98 (m, 2 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 4.53 (CH2), 6.64 (CH),
43.78 (CH2), 128.12 (CH), 128.55 (CH), 132.91 (CH), 136.96 (C),
ν = 1737 (vs), 1193 (m), 1173 (m) cm–1. C H O (114.14): calcd.
˜
6
10
2
C 63.14, H 8.83; found C 63.13, H 8.93.
Methyl 2-Cyclopropyl-3-hydroxy-3-phenylpropanoate (11): A solu-
tion of ester 10 (608 mg, 5.33 mmol) in THF (2.0 mL) was added
dropwise to a solution of LDA (3.0 mL, 6.0 mmol, c = 2 moldm–3
in THF, heptane, and ethylbenzene) diluted with THF (10 mL) at
–78 °C. The reaction mixture was stirred for 40 min at –78 °C, then
benzaldehyde (585 mg, 5.51 mmol) was added, and the mixture was
stirred for a further 15 min at –78 °C. A saturated NH4Cl solution
(5.0 mL) was added, the mixture warmed to 23 °C, then H2O
(20 mL) was added, and the mixture extracted with Et2O
(3×20 mL). The combined organic layers were dried with NaSO4.
After filtration, all volatiles were removed in vacuo and the residue
purified by chromatography (SiO2, PE/EE = 5:1) to yield the title
compound 11 (1.051 g, 4.771 mmol, 90%) in two fractions as two
diastereomers (A/B, 80:20). The first fraction (Rf = 0.22) contained
isomer A as a yellow oil, the second fraction contained isomer B
(Rf = 0.14) as a yellow solid, m.p. 72–73 °C. The relative configura-
1
tion was not assigned. H NMR (300 MHz, CDCl3), isomer A: δ
= –0.09 to –0.01 (m, 1 H), 0.15–0.27 (m, 1 H), 0.43–0.53 (m, 2 H),
1.07–1.89 (m, 1 H), 2.00 (dd, J = 10.0, J = 5.4 Hz, 1 H), 3.18 (d,
J = 2.9 Hz, 1 H; OH), 3.63 (s, 3 H), 5.09 (dd, J = 5.4, J = 2.9 Hz,
1 H), 7.27–7.38 (m, 5 H) ppm; isomer B: δ = –0.36 to –0.25 (m, 1
H), 0.18–0.31 (m, 2 H), 0.37–0.48 (m, 1 H), 0.87–0.99 (m, 1 H),
1.99 (dd, J = 9.0, J = 8.0 Hz, 1 H), 3.04 (d, J = 4.9 Hz, 1 H, OH),
3.70 (s, 3 H), 4.94 (dd, J = 7.8, J = 4.5 Hz, 1 H), 7.27–7.37 (m, 5
H) ppm. 13C{1H} NMR (125 MHz, CDCl3), isomer A: δ = 2.16
(CH2), 5.42 (CH2), 9.91 (CH), 51.75 (CH3), 57.59 (CH), 74.69
(CH), 126.27 (CH), 127.65 (CH), 128.11 (CH), 141.31 (C), 174.82
(C=O) ppm; isomer B: δ = 2.87 (CH2), 5.20 (CH2), 11.14 (CH),
51.79 (CH3), 57.86 (CH), 75.74 (CH), 126.48 (CH), 127.78 (CH),
128.24 (CH), 142.40 (C), 175.17 (C=O) ppm. MS (EI, 70 eV): m/z
200.03 (C=O) ppm. IR (ATR): ν = 3078 (w), 3003 (w), 1680 (s),
˜
1448 (m), 1286 (m), 1211 (s), 1178 (m), 1101 (m), 1070 (m), 1047
(m), 1018 (m), 964 (m) cm–1. MS (EI, 70 eV): m/z (%) = 160 (8)
[M]+, 105 (100). C11H12O (160.21): calcd. C 82.46, H 7.55; found
C 82.06, H 7.57.
(Z)-2-Cyclopropyl-1-phenyl-1-ethenyl Benzoate (8): Compound 8
was obtained as the major product in the preparation of diketone
1b [Rf (PE/EA, 10:1) = 0.30]. 1H NMR (500 MHz, CDCl3): δ =
0.55–0.60 (m, 2 H), 0.81–0.88 (m, 2 H), 1.58–1.68 (m, 1 H), 5.37
(d, J = 9.9 Hz, 1 H), 7.22–7.25 (m, 1 H), 7.27–7.31 (m, 2 H), 7.40–
7.42 (m, 2 H), 7.51–7.54 (m, 2 H), 7.62–7.66 (m, 1 H), 8.24–8.29
(m, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 7.36 (CH2),
9.26 (CH), 122.71 (CH), 123.88 (CH), 127.78 (CH), 128.51 (CH),
128.63 (CH), 129.43 (C), 130.22 (CH), 133.54 (CH), 134.91 (C),
(%) = 220 (3) [M]+, 202 (1) [M – H O]+, 114 (100). IR (ATR): ν =
˜
2
1719 (vs), 1329 (m), 1250 (m), 1194 (m), 1191 (m), 1021 (m) cm–1.
C13H16O3 (220.27): calcd. C 70.89, H 7.32; C 70.62, H 7.41.
Acknowledgments
145.80 (C), 164.55 (C=O) ppm. IR (ATR): ν = 1734 (s), 1243 (s),
˜
1088 (m), 1067 (m) 1025 (m), 989 (s), 955 (s) cm–1. MS (EI, 70 eV):
m/z (%) = 264 (3) [M]+, 212 (3) [M – C4H4]+, 159 (12) [M –
C7H5O]+, 143 (10), 105 (100) [M – C11H11O]+, 77 (29). C18H16O2
(264.32): calcd. C 81.79, H 6.10; found C 81.33, H 6.15.
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (Normalverfahren and SFB 706) and by the Fonds
der Chemischen Industrie (fellowship for M.R.). Thanks to Dipti
and Doro for their assistance.
Methyl 2-Cyclopropylacetate (10): A solution of diazomethane (ap-
prox. 13.5 g, approx. 321 mmol) in Et2O (1200 mL) was slowly
added dropwise to a solution of vinylacetic acid (9) (4.000 g,
46.46 mmol) in Et2O (30 mL) until the reaction mixture became
yellow. Then the speed of addition was increased. Subsequently, a
suspension of Pd(OAc)2 (200 mg, 0.891 mmol) in Et2O (10 mL) was
added carefully (CAUTION: vigorous gas evolution). The mixture
was stirred for 10 min and further Pd(OAc)2 (100 mg, 0.445 mmol)
was added. After stirring the reaction mixture for 5 h at 23 °C,
brine (300 mL) was added and the aqueous layer extracted with
Et2O (2×200 mL). The combined organic layers were washed with
brine (200 mL) and dried with MgSO4. After filtration, the solvent
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Received: January 24, 2006
Published Online: March 27, 2006
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Eur. J. Org. Chem. 2006, 2601–2608