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DOI: 10.1002/ejoc.200600061
Introduction
We have recently reported on a new -hydroxylation reaction of -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 CeCl37H2O is inexpensive and nontoxic. We have meanwhile further developed this method towards oxidative CC bond forming reactions yielding 1,2-dioxane[2] derivatives or 1,4-diketones.[3] This development was actually based on the assumption that an -radical species was formed as a reactive
intermediate.
The exact stoichiometry of this reaction could be established from oxygen-uptake measurements with half an
equivalent of O2 taken up per equivalent of product 2
formed. In some cases the formation of -chlorinated byproducts 4 was observed, presumably resulting from a nucleophilic attack of the chloride counterion of the catalyst
on an electrophilic reaction intermediate. With regard to
the mechanism of the catalysis we have made the following
proposal: The role of dioxygen might only be to oxidize
the CeIII species to CeIV under the reaction conditions. The
hydroxy group in product 2 could result from a nucleophilic
attack of water on an electrophilic reaction intermediate.
Scheme 1. Cerium-catalyzed -hydroxylation of -dicarbonyl compounds 1, possible reaction intermediates 3a3c (co-ligands at cerium cannot be specified and are omitted for clarity), and chlorinated byproducts 4.
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unpaired electron is localized in this -position, rapid fragmentation 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 literature.[7]
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Scheme 2. Preparation of -cyclopropyl -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, BF3OEt2, 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 deprotonation with LDA.[22] However, O-acylation was the predominant process and enol ester 8 was isolated as the major
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.
isomers, which were oxidized according to the Ley procedure[26] to give cyclopropane derivative 1c in 52% yield
over three steps.
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keto: = 4.42 (CH2), 10.23 (CH), 29.06 (CH3), 72.97 (CH), 204.90
(C=O) ppm; enol: = 8.58 (CH), 8.92 (CH2), 23.68 (CH3), 112.92
(C), 192.92 (C=O) ppm. IR (ATR): = 3413 (s, br), 1710 (m), 1687
(s), 1463 (m), 1252 (m), 1097 (s) cm1. HRMS (EI, 70 eV): calcd.
for C8H12O2: 140.0837; found 140.0837 [M]+.
Conclusion
Experimental Section
General Methods: Procedures using Grignard reagents, Et2Zn,
CuCl, LDA, BF3Et2O, TPAPNMO, 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 4060 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 determined 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 Finnigan MAT 95 (EI, CI) instruments. Melting points were measured
with a Bchi 510 and are uncorrected. The starting material 1d was
commercially available. Compounds 5a,[10] 5b,[11] and diazomethane[25] were prepared according to literature procedures.
3-Cyclopropyl-2,4-pentanedione (1a): BF3Et2O (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 mixture 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: = 0.250.28 (m, 2 H), 0.700.74 (m, 2 H), 1.301.35 (m,
1 H), 2.26 (s, 6 H), 2.72 (d, J = 10.5 Hz, 1 H) ppm; enol: = 0.36
0.39 (m, 2 H), 0.870.92 (m, 2 H), 1.361.43 (m, 1 H), 2.25 (s, 6
H), 16.45 (s, 1 H, OH) ppm. 13C{1H} NMR (125 MHz, CDCl3),
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Methyl 2-Cyclopropyl-3-oxo-3-phenylpropanoate (1c): Molecular sieves (6.7 g, 4 ) 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): = 0.160.24
(m, 1 H), 0.360.46 (m, 1 H), 0.600.77 (m, 2 H), 1.621.50 (m, 1
H), 3.54 (d, J = 9.9 Hz, 1 H), 3.70 (s, 3 H), 7.457.51 (m, 2 H),
7.567.62 (m, 1 H), 7.947.98 (m, 2 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3): = 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 (%) =
219 (5) [MH]+, 187 (5) [M MeOH]+, 105 (100). IR (ATR): =
1743 (vs), 1686 (vs), 1442 (m), 1290 (m) cm1. 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 compound 1e (1.61 g, 12.4 mmol, 50 %) as a colorless oil. 1H NMR
(500 MHz, CDCl3): = 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): = 12.20 (CH3), 28.48 (CH3), 52.47 (CH3),
53.46 (CH), 171.02 (C=O), 203.66 (C=O) ppm. IR (ATR): = 2990
(m), 2954 (m), 1746 (s), 1718 (s), 1456 (m), 1436 (m), 1360 (m),
1210 (m) cm1. 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,
73.3 mmol), 2-iodopropane (37.4 g, 220 mmol), and K2CO3 (30.4 g,
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removed under reduced pressure and the residue purified by distillation (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): = 1.08 (s, 9 H), 2.22 (s, 6 H), 3.65 (s,
1 H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): = 28.42 (3 CH3),
32.44 (2 CH3), 35.42 (C), 76.45 (CH), 204.59 (2 C) ppm. IR (ATR):
= 2959 (m), 1720 (s), 1693 (vs), 1356 (s), 1148 (s) cm1. MS (EI,
70 eV): m/z (%) = 156 (1) [M]+, 114 (8) [M C2H3O]+, 99 (100)
[M C4H9]+. C9H16O2 (156.22): calcd. C 69.20, H 10.32; found C
68.90, H 10.11.
General Procedure for the -Hydroxylation Reaction: The respective
-dicarbonyl compound 1 (1 equiv.) was added to a suspension of
CeCl37H2O (5 mol-%) in iPrOH (approx. 3 mol dm3 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 h1) 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.
3-Cyclopropyl-3-hydroxy-2,4-pentanedione (2a): Diketone 1a
(250 mg, 1.78 mmol) and CeCl37H2O (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 hydroxy compound 2a (131 mg, 0.840 mmol, 47 %) as a colorless
oil. 1H NMR (500 MHz, CDCl3): = 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.
13
C{1H} NMR (125 MHz, CDCl3): = 0.23 (CH), 15.34 (CH2),
25.49 (CH3), 86.82 (C), 207.68 (C=O) ppm. IR (ATR): = 3435
(w), 3011 (m), 1702 (s), 1418 (m), 1353 (m), 1236 (m), 1191 (m),
1154 (s), 1050 (s), 1025 (s), 971 (s) cm1. HRMS (CI, CH4): calcd.
for C8H13O3: 157.0865; found 157.0856 [MH]+.
Methyl 2-Cyclopropyl-2-hydroxy-3-oxo-3-phenylpropanoate (2c):
The keto ester 1c (251 mg, 1.15 mmol) and CeCl37H2O (45 mg,
0.12 mmol) were converted in iPrOH (0.5 mL) according to the general 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): = 0.330.40 (m, 2 H),
0.530.59 (m, 1 H), 0.680.73 (m, 1 H), 1.651.70 (m, 1 H), 3.78
(s, 3 H), 4.28 (s, 1 H, OH), 7.457.49 (m, 2 H), 7.587.61 (m, 1 H),
8.018.04 (m, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): =
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)
[MH H2O]+, 203 (5) [MH MeOH]+, 105 (100). IR (ATR): =
3064 (w), 3010 (w), 2954 (w), 1741 (s), 1694 (s), 1274 (m), 1235
(m), 1170 (m) cm1. C13H14O4 (234.25): calcd. C 66.66, H 6.02;
found C 66.46, H 6.04.
3-Hydroxy-3-methyl-2,4-pentanedione (2d): Diketone 1d (300 mg,
2.62 mmol) and CeCl37H2O (48 mg, 0.13 mmol) were converted in
iPrOH (0.9 mL) according to the general procedure. Chromatography (SiO2, PE/EA, 2:1, Rf = 0.38) furnished the -hydroxy compound 2d (115 mg, 0.884 mmol, 34 %) as a colorless oil. 1H NMR
(500 MHz, CDCl3): = 1.54 (s, 3 H), 2.24 (s, 6 H), 4.70 (br. s, 1
H, OH) ppm. 13C{1H} NMR (125 MHz, CDCl3): = 22.59 (CH3),
24.72 (CH3), 87.61 (C), 207.43 (C=O) ppm. IR (ATR): = 3351
(m), 2973 (m), 2925 (m), 2854 (m), 1708 (s), 1417 (m), 1356 (m),
1237 (m), 1148 (m) cm1. HRMS (CI, CH4): calcd. for C6H11O3:
131.0708; found 131.0708 [MH]+.
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Methyl 2-Hydroxy-2-methyl-3-oxobutanoate (2e): Dicarbonyl compound 1e (200 mg, 1.54 mmol) and CeCl37H2O (29 mg,
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
(Rf = 0.49, 49 mg, 0.38 mmol, 25 %) in the first fraction. 1H NMR
(CDCl3, 500 MHz): = 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): =
21.97 (CH3), 24.18 (CH3), 53.40 (CH3), 81.04 (C), 171.76 (C=O),
204.90 (C=O) ppm. IR (ATR): = 3460 (m, br), 1726 (s), 1438
(m), 1360 (m), 1269 (m), 1156 (m) cm1. 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 CeCl37H2O (40 mg, 0.11 mmol) were converted in
iPrOH (0.7 mL) according to the general procedure. Chromatography (SiO2, PE/EA, 10:1, Rf = 0.35) furnished the -hydroxy compound 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
the second fraction (Rf = 0.21). 1H NMR (500 MHz, CDCl3): =
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):
= 16.31 (CH3), 25.84 (CH), 34.73 (CH), 94.28 (C), 208.22
(C=O) ppm. IR (ATR): = 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) cm1. HRMS (EI, 70 eV): calcd. for C8H14O3:
158.0943; found 158.0948 [M]+.
(CH3), 74.12 (C), 128.50 (CH), 129.40 (CH), 133.34 (CH), 133.66
(C), 168.96 (C=O), 189.33 (C=O) ppm. MS (CI, CH4): m/z (%) =
253 (4) [MH]+, 217 (12) [MH HCl]+, 193 (8), 185 (10), 105 (100).
IR (ATR): = 3056 (w), 3017 (w), 2954 (w), 1759 (vs), 1730 (vs),
1697 (s), 1258 (m), 1221 (m) cm1. C13H13ClO3 (252.70): calcd. C
61.79, H 5.19; found C 61.85, H 5.29.
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,
25 %) as a brown oil. 1H NMR (500 MHz, CDCl3): = 0.030.08
(m, 1 H), 0.090.13 (m, 1 H), 0.430.52 (m, 2 H), 0.680.77 (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): = 3.74 (CH2), 4.36 (CH2), 7.48 (CH), 23.19 (CH3), 44.07
(CH2), 68.71 (CH) ppm. IR (ATR): = 3343 (s, br), 2967 (m), 2914
(m), 1460 (m), 1372 (m), 1119 (m), 1085 (s), 1041 (m), 1015 (m),
929 (m) cm1. HRMS (EI, 70 eV): calcd. for C6H12O: 100.0888;
found 100.0890 [M]+.
2-Chloro-2-cyclopropyl-1,3-diphenyl-1,3-propanedione (4b): Diketone 1b (296 mg, 1.12 mmol) and CeCl37H2O (20 mg, 0.054 mmol)
were converted in iPrOH (1.0 mL) according to the general procedure. Chromatography (SiO2, PE/EA, 10:1, Rf = 0.40) furnished
the -chloro compound 4b (18 mg, 0.060 mmol, 5 %) as a colorless
oil. 1H NMR (500 MHz, CDCl3): = 0.740.77 (m, 4 H), 1.90
1.94 (m, 1 H), 7.347.39 (m, 4 H), 7.467.49 (m, 2 H), 7.927.97
(m, 4 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): = 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): = 3062 (w), 3012
(w), 2929 (w), 1766 (w), 1678 (s), 1596 (m), 1580 (m), 1448 (m),
1218 (s) cm1. 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]+.
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Acknowledgments
This work was generously supported by the Deutsche Forschungsgemeinschaft (Normalverfahren and SFB 706) and by the Fonds
der Chemischen Industrie (fellowship for M.R.). Thanks to Dipti
and Doro for their assistance.
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T. Mophuang, P. Tuchinda, S. Prabpai, P. Kongsaeree, V. Reutrakul, J. Org. Chem. 2006, 71, 386389; e) for a review, see:
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[2] J. Christoffers, T. Werner, W. Frey, A. Baro, Eur. J. Org. Chem.
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[3] a) M. Rssle, T. Werner, A. Baro, W. Frey, J. Christoffers, Angew. Chem. 2004, 116, 67096711; Angew. Chem. Int. Ed. 2004,
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