Construction of medium-ring oxacycloalkenones. Extension towards benzo-fused cyclic ethers

Article abstract of DOI:10.1039/b307289b

A study was done on the construction of medium-ring oxacycloalkenones. The synthetic protocol consisted of the intramolecular Kulinlovich cyclopropanation on oxa-esters bearing a terminal double bond, followed by oxidative cleavage of the cyclopropanol mo

Full text of DOI:10.1039/b307289b

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Construction of medium-ring oxacycloalkenones.
Extension towards benzo-fused cyclic ethers
Frédéric Lecornué and Jean Ollivier*
Laboratoire des Carbocycles, UMR 8615,
Institut de Chimie Moléculaire et des Matériaux d’Orsay Bât. 420, Université de Paris-Sud,
91405 ORSAY, France. E-mail: jollivie@icmo.u-psud.fr; Fax: ϩ33 1 69 15 62 78;
Tel: ϩ33 1 69 15 72 52
Received 25th June 2003, Accepted 3rd September 2003
First published as an Advance Article on the web 23rd September 2003
Application of the intramolecular Kulinkovich cyclopropanation of oxa-ω-alkenoic esters followed by Saegusa
oxidation and dehydrohalogenation led to simple or benzo-fused oxacycloalkenones, basic structural elements in a
wide range of naturally occurring compounds.
significant improvement was observed using chlorotitanium
Introduction
triisopropoxide) and four equivalents of Grignard reagent.13
Cyclohexylmagnesium chloride, normally a poor nucleophile
towards esters,14 appeared a very efficient reagent in such an
intramolecular Kulinkovich reaction.15
The discovery of a large number of biologically active natural
products containing medium-sized oxacycloalkenones in their
structure has spurred efforts to enhance this challenge. Such
skeletons are encountered, for example, in helivypolide B1 1 or
(ϩ)-heliannuol F2 2, active allelopathic agents isolated from
sunflower leaves. Another example is brazilone 3, an anti-
coagulant isolated from the leguminous plant Caesalpinia
sappan3 (Scheme 1).
The resulting cis-fused cyclopropanols 5a–g, isolated with
acceptable yields (see Table 1), were firstly treated with ferric()
chloride, then underwent subsequent dehydrochlorination
(sodium acetate, MeOH) to lead to the expected cycloalkenones
6a–g of (Z) configuration. Formation of fused cyclopropanols
5a–g and cycloalkenones 6a–g is summarized in Table 1.
Excepting oxacycloalkenones 6a16 (recently obtained by ring
closing metathesis) and 6d17 (prepared by oxidation of the
corresponding oxacycloalkanone) for which, however, no
spectral data were reported, the new cyclopropanols 5a–g and
enones 6b, c, e, eЈ, f and g were characterized by their spectral
data and their purities were checked by gas chromatography;
starting compounds 4b, 4c and 4d were also original.
The moderate yield observed in the formation of 5a could be
explained by the more strained structure of this compound. It
must be underlined that in spite of efforts to improve the yields
of cyclopropanol 5f, only small amounts were obtained in order
to perform the preparation of cycloalkenone 6f; such difficul-
ties with conjugated esters in the Kulinkovich cyclopropanation
have been previously related in the literature.18
From the cyclopropanol 5e, two products of dehydrochlor-
ination were obtained. The isolation of the intermediate chlor-
ide showed the presence of only one regioisomer 7e which led to
the two benzo-fused oxacycloalkenones: the kinetic product 6e
and the thermodynamic product 6eЈ (see evolution in entries b
and c in Scheme 2). In fact, the selective formation of the
products was highly dependent on the experimental procedure.
Scheme 1
Results and discussion
We report here a general method that provides easy access to
oxacycloalkenones of different sizes, as an extension of meth-
odology previously developed by Cha4 in the synthesis of
seven- and eight-membered carbocycles. The synthetic protocol
consists of the intramolecular Kulinkovich cyclopropanation5
on oxa-esters bearing a terminal double bond, followed by
oxidative cleavage of the cyclopropanol moiety6 and base-
induced dehydrochlorination. We have applied this strategy to
the synthesis of different medium-sized oxacycloalkenones
such as oxepinone, tetrahydrooxocinone and oxoninone.
Moreover, benzo-fused 7-, 8- and 9-membered cyclic ethers,
challenging synthetic targets in the unusual structure of some
bioactive natural products, have been achieved by our
approach.
All starting esters were prepared using reported literature or
adapted procedures. Thus, buten-3-ol was used as precursor for
the synthesis of esters 4a7 and 4b,8 pent-4-enol for 4c8 while
ether 4d was obtained by basic condensation of ethyl bromo-
acetate on 2-vinylphenol acetate;9 likewise, the esters 4e,10 4f11
and 4g11 were prepared from the corresponding phenolic deriv-
atives. It must be underlined that the allylic ethers were found
unsuitable for such reactions.12
The cyclopropanations were performed using one or two
equivalents of titanium tetraisopropoxide (in some cases, a
Scheme 2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 0 0 – 3 6 0 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Cyclopropanation and oxidation–dehydrochlorination of oxa-ω-alkenoic esters 4a–g
Entry
1
Oxa-esters
Cyclopropanols (%)
Oxacycloalkenones (%)
2
3
4
5
6
7
Thus, dehydrochlorination effected in standard conditions
(sodium acetate in methanol or treatment with triethylamine or
DBU in ether) yielded only alkenone 6eЈ while the reaction
promoted with sodium acetate in methanol at low temperature,
furnished a mixture of the alkenones 6e and 6eЈ. Aqueous
sulfuric acid in THF19 gave no reaction (Scheme 2).
This result was in agreement with calculated energies of
respectively Ϫ2547.38 and Ϫ2545.90 kcal molϪ1 20 for products
6e and 6eЈ; the difference of 1.48 kcal molϪ1 appears to be
sufficiently important to explain the favoured formation of the
benzo-conjugated product 6eЈ.
mesh) or on Fluka neutral alumina 507c (100–200 mesh). Melt-
ing points (uncorrected) were determined with a Mettler FP51
1
apparatus. H (200, 250 and 360 MHz) and 13C (50 and 63
MHz) NMR spectra were recorded in CDCl3 or C6D6 on
Bruker AM360, AM250, AC250 and AM200 spectrometers
and the data are reported in δ (ppm) from CDCl3 (1H = 7.27 and
13C = 77) and C6D6 (1H = 7.17). Coupling constant (J) values are
given in Hz. Infrared (IR) spectra were recorded as thin films on
an FT-IR Perkin Elmer Spectrum One spectrometer. Electron
impact (EI) mass spectra were obtained using a Nermag R-10
apparatus coupled with an OKI DP 125 gas chromatograph.
Relative percentages are shown in brackets; high-resolution
mass spectra were recorded with a Finnigan MAT 95S.
Conclusion
We have developed an interesting pathway to the synthesis of
varying medium-sized cyclic ethers. This synthetic study should
allow the synthesis of bioactive benzo-fused cyclic ethers, while
further applications of this methodology are under current
investigation.
4b: Ethyl 3-(3-buten-1-yloxy)propanoate. To a solution of
3-(3-buten-1-yloxy)propanoic acid (5.855 g, 40.6 mmol) in
30 ml of absolute ethanol was added thionyl chloride (5 ml,
0.068 mmol). After stirring and refluxing for 60 h, the solution
was evaporated and diluted with 150 ml of pentane. The
organic phase was washed with water (3 × 40 ml), dried over
magnesium sulfate and concentrated to give the pure ester 4b
(5.3 g, 30.4 mmol).
Experimental
General
Colourless liquid; yield 75%; HRMS calcd. for C9H16O3:
172.1099. Found: 172.1102; νmax/cmϪ1 (neat) 2981, 1738, 1642;
δH (250 MHz, CDCl3) 5.91–5.71 (1 H, m), 5.08 (1 H, d, J 17.1),
Preparative column chromatography was performed on SDS
normal silica gel (70–230 mesh), on SDS flash silica gel (35–70
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 0 0 – 3 6 0 4
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5.03 (1 H, d, J 10.5), 4.16 (2 H, q, J 7.1), 3.72 (2 H, t, J 6.6), 3.51
(2 H, t, J 6.8), 2.57 (2 H, t, J 6.6), 2.33 (2 H, qt, J 6.8, 1.5), 1.26
(3 H, t, J 7.1); δC (63 MHz, CDCl3) 171.4, 134.9, 116.1, 70.1,
65.9, 60.2, 34.9, 33.8, 14.0; m/z (EI) 172 (0.1, Mϩ), 131 (100),
101 (37), 73 (65), 59 (92), 55 (41).
was added over four hours at room temperature under argon
4 ml (6.4 mmol) of a solution of cyclohexylmagnesium chloride
(1.6 M in diethyl ether). After stirring one additional hour at
room temperature, the black solution was cooled at 0 ЊC and
40 ml of diethyl ether was added. The mixture was quenched by
addition of 10 ml of a saturated ammonium chloride solution
and the white precipitate was filtered off through a plug of
Celite, washed with 50 ml of ether and the filtrate was dried
over magnesium sulfate. After evaporation, the pure products
were isolated by column chromatography.
4c: Ethyl 3-(4-penten-1-yloxy)propanoate. To a solution of
3-(4-penten-1-yloxy)propanoic acid8 (6.5 g, 41.1 mmol) in 75
ml of ethanol was added thionyl chloride (3 ml, 0.041 mmol).
After refluxing and stirring for 60 h, the solution was evapor-
ated and purified by column chromatography to furnish the
expected ester 4c (4.59 g, 24.7 mmol).
Eluent for column chromatography: pentane–Et2O 9 : 1;
colourless liquid; yield 60%; HRMS calcd. for C10H18O3:
186.1255. Found: 186.1245; νmax/cmϪ1 (neat) 2938, 1739, 1641;
δH (250 MHz, CDCl3) 5.92–5.71 (1 H, m), 5.01 (1 H, d, J 17.1),
4.96 (1 H, d, J 11.5), 4.16 (2H, q, J 7.2), 3.69 (2H, t, J 6.3), 3.45
(2H, t, J 7.1), 2.57 (2H, t, J 6.3), 2.10 (2H, q, J 7.1), 1.66 (2H, q,
J 7.1), 1.27 (3H, t, J 7.2); δC (63 MHz, CDCl3) 171.4, 137.9,
114.5, 70.1, 65.9, 60.2, 35.0, 30.0, 28.5, 14.0; m/z (EI) 186 (0.6,
Mϩ), 131 (93), 119 (30), 101 (40), 73 (65), 69 (62), 68 (40), 59
(100).
5a: 3-Oxabicyclo[4.1.0]heptan-1-ol. Eluent for flash chrom-
atography: pentane–EtOAc 2.5 : 7.5; colourless oil; yield 35%;
HRMS calcd. for C6H10O2: 114.0680. Found: 114.0676; νmax
/
cmϪ1 (neat) 3385, 2931, 1450; δH (360 MHz, CDCl3) 4.05 (1 H,
d, J 10.7), 3.73 (1 H, d, J 10.7), 3.61 (1 H, ddd, J 11.3, 6.5, 2.6),
3.33 (1 H, ddd, J 11.3, 11.2, 4.9), 2.30 (1 H, s), 2.00–1.91 (1 H,
m), 1.69–1.60 (1 H, m), 1.33–1.26 (1 H, m), 0.99 (1 H, dd,
J 10.4, 5.2), 0.63 (1H, dd, J 5.8, 5.7; δC (63 MHz, CDCl3) 69.7,
64.8, 51.4, 24.3, 18.4, 16.4; m/z (EI) 114 (25, Mϩ), 95 (20), 84
(69), 83 (100), 71 (26), 70 (28), 69 (43), 60 (17), 58 (57), 57 (23),
55 (86), 43 (40), 41 (52).
4d: Ethyl (2-vinylphenoxy)acetate. To a solution of 2-vinyl-
phenol acetate9 (6 g, 37 mmol) and ethyl bromoacetate (6.15
ml, 55.5 mmol) in 120 ml of ethanol was added under argon at
room temperature a solution of freshly prepared sodium
ethylate (5.1 g, 74 mmol) in 115 ml of ethanol. After refluxing
for 2 h, the mixture was concentrated under reduced pressure
and to the residue, ether (200 ml) and water (50 ml) were added.
The aqueous phase was extracted with ether (50 ml) and the
combined organic layers were dried on magnesium sulfate,
evaporated and chromatographed on silica gel to obtain the
ester 4d (6.33 g, 30 mmol).
5b: 4-Oxabicyclo[5.1.0]octan-1-ol. Eluent for flash chromato-
graphy: pentane–EtOAc 2.5 : 7.5; colourless oil; yield 62%;
HRMS calcd. for C7H12O2: 128.0837. Found: 128.0834; νmax
/
cmϪ1 (neat) 3391, 2943, 1465; δH (360 MHz, CDCl3) 3.85 (1 H,
ddd, J 12.5, 8.5, 1.5), 3.73–3.60 (3 H, m), 2.39 (1 H, dd, J 15.4,
6.6), 2.28–2.21 (1 H, m), 2.00 (1 H, s), 1.86 (1 H, dd, J 15.4, 8.5),
1.37–1.20 (2 H, m), 0.99 (1 H, dd, J 9.8, 5.5), 0.66 (1 H, dd,
J 5.8, 5.5); δC (63 MHz, CDCl3) 71.0, 68.7, 58.0, 40.4, 32.8, 23.6,
20.5; m/z (EI) 128 (17, Mϩ), 100 (53), 83 (77), 70 (89), 56 (47), 55
(100), 43 (90), 41 (99).
Eluent for flash chromatography: pentane–CH2Cl2 6 : 4 then
3 : 7; yellow oil; yield 83%; HRMS calcd. for C12H14O3:
206.0942. Found: 206.0943; νmax/cmϪ1 (neat) 1759, 1733, 1599;
δH (250 MHz, CDCl3) 7.50 (1 H, d, J 7.7), 7.21 (1 H, dd, J 7.7,
7.6), 7.13 (1 H, dd, J 17.4, 10.9), 6.99 (1 H, dd, J 7.7, 7.6), 6.77
(1 H, d, J 7.7), 5.81 (1 H, d, J 17.4), 5.31 (1 H, d, J 10.9), 4.66
(2 H, s), 4.28 (2 H, q, J 7.2), 1.31 (3 H, t, J 7.2); δC (63 MHz,
CDCl3) 168.7, 155.0, 135.5, 131.3, 127.3, 126.7, 121.7, 114.9,
112.2, 65.9, 61.2, 14.0; m/z (EI) 206 (100, Mϩ), 133 (89), 119
(31), 105 (92), 91 (40), 77 (32).
5c: 4-Oxabicyclo[6.1.0]nonan-1-ol. Eluent for flash chrom-
atography: pentane–EtOAc 2.5 : 7.5; colourless oil; yield 49%;
HRMS calcd. for C8H14O2: 142.0993. Found: 142.0990; νmax
/
cmϪ1 (neat) 3390, 2924, 1472; δH (250 MHz, CDCl3) 3.92–3.61
(4 H, m), 2.18–1.94 (2 H, m), 1.80–1.45 (4 H, m), 1.02–0.80 (3
H, m), 0.23–0.12 (1 H, m); δC (63 MHz, CDCl3) 70.5, 66.9, 55.1,
35.9, 29.1, 27.4, 24.0, 19.0; m/z (EI) 142 (6, Mϩ), 114 (13), 84
(13), 83 (25), 71 (100), 70 (33), 69 (13), 55 (32), 43 (27), 41 (40).
5d: 1,7b-Dihydrocyclopropa[c]chromen-1a(2H)-ol. Eluent for
flash chromatography: CH2Cl2–Et2O 9 : 1; colourless oil; yield
46%; HRMS calcd. for C10H10O2: 162.0680. Found: 162.0673;
νmax/cmϪ1 (neat) 3550, 3029, 1491; δH (360 MHz, CDCl3) 7.20
(1 H, d, J 7.7), 7.07 (1 H, ddd, J 7.7, 7.6, 1.5), 6.91 (1 H, ddd,
J 7.7, 7.6, 1.5), 6.83 (1 H, d, J 7.7), 4.40 (1 H, d, J 10.1), 3.89
(1 H, d, J 10.1), 2.39 (1 H, br s), 2.18 (1 H, dd, J 9.8, 5.3), 1.41
(1 H, dd, J 9.8, 5.5), 1.34 (1H, dd, J 5.5, 5.3); δC (63 MHz,
CDCl3) 151.7, 128.0, 126.4, 121.9, 117.0, 121.3, 64.6, 59.4, 21.6,
18.8; m/z (EI) 162 (33, Mϩ), 147 (29), 131 (23), 120 (100), 103
(20), 91 (31), 77 (15).
4e: Ethyl (2-allylphenoxy)acetate. To a solution of 2-allyl-
phenol (9.14 g, 68 mmol), anhydrous potassium carbonate
(20 g, 145 mmol), and ethyl bromoacetate (12.1 g, 72.5 mmol) in
130 ml of acetone was added potassium iodide (140 mg, 0.86
mmol). The mixture was refluxed for 16 h, then cooled to room
temperature, filtered off and the resulting cake was washed with
acetone. The filtrate was evaporated and isolated by column
chromatography to give the expected product 4e (14.8 g, 67.5
mmol).
Eluent for column chromatography: pentane–Et2O 9 : 1;
colourless oil; yield 99%; HRMS calcd. for [C13H16O3 ϩ Na]ϩ:
243.09971. Found: 243.09959; νmax/cmϪ1 (neat) 1736, 1760,
1638; δH (250 MHz, CDCl3) 7.17 (2 H, dd, J 7.0, 6.9), 6.95 (1 H,
dd, J 7, 6.9), 6.74 (1 H, d, J 6.9), 6.14–5.92 (1 H, m), 5.16–4.95
(2 H, m), 4.64 (2 H, s), 4.27 (2 H, q, J 7.1), 3.48 (2 H, d, J 6.8),
1.30 (3 H, t, J 7.1); δC (63 MHz, CDCl3) 168.7, 155.3, 136.6,
129.9, 129.0, 127.0, 121.3, 111.1, 115.2, 65.3, 60.9, 34.1, 13.9;
m/z (EI) 220 (100, Mϩ), 133 (89), 131 (52), 115 (50), 105 (42),
91 (66), 77 (25).
5e: 8,8a-Dihydro-1H-benzo[b]cyclopropa[c]oxepin-1a(2H)-ol.
Eluent for flash chromatography: pentane–EtOAc 7.5 : 2.5;
white solid; yield 47%; mp 55–57 ЊC; HRMS calcd. for
C11H12O2: 176.0837. Found: 176.0829; νmax/cmϪ1 (neat) 3368,
3017, 1487; δH (360 MHz, CDCl3) 7.12 (1 H, dd, J 7.7, 7.6), 6.97
(1 H, d, J 7.6), 6.87 (1 H, d, J 7.6), 6.83 (1 H, dd, J 7.7, 7.6), 4.57
(1 H, d, J 13.4), 4.46 (1 H, d, J 13.4), 3.00 (1 H, dd, J 16.2, 8.6),
2.83 (1 H, dd, J 16.2, 8.6), 2.74 (1 H, s), 1.75–1.66 (1H, m), 1.16
(1 H, dd, J 9.0, 5.8), 0.73 (1H, dd, J 5.8, 5.6); δC (63 MHz,
CDCl3) 157.0, 131.3, 127.8, 126.2, 120.9, 119.6, 74.5, 57.1, 36.5,
24.4, 20.8; m/z (EI) 176 (25, Mϩ), 134 (25), 133 (22), 119 (51),
118 (100), 115 (21), 107 (72), 91 (69), 77 (20), 51 (10).
General procedure for the synthesis of the cyclopropanols 5a–g
To a solution of oxa-ω-alkenoic esters 4a–g (1.6 mmol) and
titanium tetraisopropoxide (0.48 ml, 1.6 mmol for 4a, 4b, 4d
and 0.96 ml, 3.2 mmol for 4c) or chlorotitanium triisopropoxide
(0.42 g, 1.6 mmol for 4e, 4f and 4g) in anhydrous THF (40 ml)
5f:
1,1a,2,3-Tetrahydro-8bH-benzo[b]cyclopropa[d]oxepin-
8b-ol. Eluent for flash chromatography: pentane–EtOAc 7.5 :
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 0 0 – 3 6 0 4
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2.5; colourless oil; yield 9%; HRMS calcd. for C11H12O2:
176.0837. Found: 176.0834; νmax/cmϪ1 (neat) 3392, 3074, 1603;
δH (200 MHz, CDCl3) 7.58 (1 H, d, J 7.4), 7.32–7.12 (2 H, m),
7.01 (1 H, d, J 7.4), 4.29 (1 H, ddd, J 12.1, 11.0, 4.1), 3.94 (1 H,
ddd, J 11.0, 5.8, 2.0), 2.5 (1 H, br s), 2.17 (1 H, dddd, J 15.3, 4.5,
4.1, 2.0), 1.52–1.26 (2 H, m), 1.01–0.83 (1 H, m), 0.56 (1H, dd, J
5.2, 4.8); δC (63 MHz, CDCl3) 153.2, 134.9, 131.1, 129.3, 124.7,
122.0, 70.4, 55.5, 29.2, 20.5, 19.0; m/z (EI) 176 (45, Mϩ), 147
(100), 145 (56), 132 (83), 131 (46), 121 (91), 120 (49), 77 (22).
J 6.6), 2.90 (2 H, t, J 6.8), 2.76 (2H, q, J 6.6); δC (63 MHz,
CDCl3) 201.0, 139.0, 136.0, 65.03, 64.98, 44.2, 29.4; m/z (EI)
126 (21, Mϩ), 99 (29), 96 (14), 81 (11), 68 (100), 54 (50).
6c: 2,3,8,9-Tetrahydro-4(7H)-oxoninone. Eluent for flash
chromatography (alumina): CH2Cl2–Et2O 8.5 : 1.5; colourless
oil; yield 25%; HRMS calcd. for C8H12O2: 140.0837. Found:
140.0835; νmax/cmϪ1 (neat) 2924, 1652; δH (250 MHz, CDCl3)
6.34 (1 H, ddd, J 12.5, 9.2, 9.0), 6.11 (1 H, d, J 12.5), 3.93–3.88
(2 H, m), 3.64–3.54 (2 H, m), 2.88–2.83 (2 H, m), 2.78–2.74 (2H,
m), 1.72–1.64 (2 H, m); δC (63 MHz, CDCl3) 204.3, 141.9,
133.9, 69.9, 68.5, 45.4, 29.4, 24.6; m/z (EI) 140 (65, Mϩ), 139
(49), 113 (45), 111 (34), 99 (45), 95 (32), 82 (34), 81 (61), 71
(100), 67 (34), 54 (41), 53 (33), 41 (39).
5g: 1,1a,2,3-Tetrahydrobenzo[b]cyclopropa[e]oxocin-9a(9H)-
ol. Eluent for flash chromatography: pentane–EtOAc 7.5 : 2.5;
white solid; yield 52%; mp 68–70 ЊC; HRMS calcd. for
C12H14O2: 190.0993. Found: 190.0990; νmax/cmϪ1 (neat) 3409,
2931, 1490; δH (250 MHz, CDCl3) 7.30–7.24 (2 H, m), 7.14–7.07
(2 H, m), 4.52 (1 H, dd, J 11.6, 3.2), 3.68 (1 H, dd, J 11.6, 11.4),
3.09 (1 H, d, J 13.3), 2.89 (1 H, d, J 13.3), 2.28 (1 H, ddd, J 15.9,
5.3, 5.2), 1.94 (1 H, s), 1.61–1.43 (1 H, m), 1.18 (1 H, dd, J 9.7,
5.6), 0.97–0.85 (1 H, m), 0.53 (1 H, dd, J 5.7, 5.6); δC (63 MHz,
CDCl3) 162.8, 133.4, 131.3, 128.3, 123.9, 123.0, 77.0, 60.4, 37.1,
34.7, 24.0, 21.7; m/z (EI) 190 (47, Mϩ), 147 (32), 134 (62), 133
(62), 131 (29), 107 (100), 91 (40), 78 (29), 77 (31), 55(24).
6d: 1-Benzoxepin-3(2H)-one. Eluent for flash chromato-
graphy: pentane–EtOAc 9.2 : 0.8 then 8.7 : 1.3; colourless oil;
yield 76%; HRMS calcd. for C10H8O2: 160.0524. Found:
160.0520; νmax/cmϪ1 (neat) 1667, 1612, 1565; δH (250 MHz,
CDCl3) 7.49–7.43 (2 H, m), 7.33 (1 H, d, J 8.6), 7.29 (1 H, d,
J 12.2), 7.17 (1 H, dd, J 8.6, 7.9), 6.45 (1 H, d, J 12.2), 4.64 (2 H,
s); δC (63 MHz, CDCl3) 196.6, 158.7, 142.1, 133.3, 132.1, 128.9,
127.2, 124.1, 120.5, 77.5; m/z (EI) 160 (95, Mϩ), 132 (84), 131
(100), 119 (23), 103 (41), 102 (51), 91 (26), 76 (28), 63 (20), 51
(38).
General procedure for the synthesis of the ꢀ-chloroketone 7e and
oxacycloalkenones 6a–g
To a solution of ferric() chloride (428 mg, 2.67 mmol) and
pyridine (0.l ml, 1.2 mmol) in 2 ml of anhydrous diethyl ether
cooled at 0Њ under argon was added dropwise cyclopropanols
5a–g (1.2 mmol) in 1 ml of anhydrous diethyl ether. After
stirring for three hours at the same temperature, the reaction
mixture was quenched by addition of water (2 ml). The aqueous
phase was extracted with ether (3 × 5 ml) and the combined
organic layers were dried over anhydrous magnesium sulfate
and evaporated under reduced pressure. The crude residue was
then purified by column chromatography for the chloride 7e or
used directly for the next step.
6e: 2H-1-Benzoxocin-3(6H)-one. Eluent for column chrom-
atography: pentane–CH2Cl2 9.9 : 0.1; white solid; yield from 7e
(NaOAc, MeOH, Ϫ5 ЊC) 42%; mp 40–42 ЊC; HRMS calcd. for
C11H10O2: 174.0680. Found: 174.0675; νmax/cmϪ1 (neat) 3035,
1686; δH (360 MHz, CDCl3) 7.28–7.24 (1 H, m), 7.16–7.03 (3 H,
m), 6.59 (1 H, td, J 13.3, 7.1), 6.05 (1 H, d, J 13.3), 4.74 (2 H, s),
3.67 (2 H, d, J 7.1); δC (50 MHz, CDCl3) 203.0, 158.4, 140.1,
130.8, 129.9, 128.9, 128.6, 124.1, 121.2, 79.7, 33.4, 25.9; m/z
(EI) 174 (66, Mϩ), 159 (24), 145 (36), 131 (86), 119 (80), 118
(100), 115 (73), 91 (67), 68 (46).
To the crude product in 2 ml of anhydrous methanol was
added at room temperature in one portion anhydrous sodium
acetate (502 mg, 6.1 mmol) and the mixture was stirred over-
night. After monitoring by gas chromatography, the resulting
mixture was diluted with water (1 ml) and extracted with
dichloromethane (3 × 5 ml). The organic layers were then dried
over anhydrous magnesium sulfate, evaporated and purified by
column chromatography.
6eЈ: 2H-1-Benzoxocin-3(4H)-one. Eluent for column chrom-
atography: pentane–CH2Cl2 9.9 : 0.1; colourless oil; yield from
7e (DBU, Et2O, Ϫ10 ЊC) 85%; HRMS calcd. for C11H10O2:
174.0680. Found: 174.0681; νmax/cmϪ1 (neat) 3026, 1726, 1601;
δH (250 MHz, CDCl3) 7.30–7.17 (2 H, m), 7.13–7.07 (2 H, m),
6.49 (1 H, d, J 13.7), 5.71 (1 H, td, J 13.7, 7.8), 4.58 (2 H, s), 3.57
(2 H, d, J 7.8); δC (50 MHz, CDCl3) 206.4, 156.4, 133.3, 131.5,
129.7, 125.9, 123.8, 122.0, 121.9, 75.5, 41.4; m/z (EI) 174 (82,
Mϩ), 145 (45), 131 (100), 118 (22), 115 (54).
7e: 5-Chloro-5,6-dihydro-2H-1-benzoxocin-3(4H)-one. Eluent
for column chromatography: pentane–Et2O 9.2 : 0.8 then 8 : 2;
white solid; yield 84%; mp 48–50 ЊC; HRMS calcd. for
C11H11ClO2: 210.0447. Found: 210.0439; νmax/cmϪ1 (neat) 1721,
1492; δH (250 MHz, CDCl3) 7.38–7.32 (1 H, m), 7.26–7.04 (3 H,
m), 4.60 (1 H, d, J 13.1), 4.39 (1 H, d, J 13.1), 4.39–4.31 (1 H,
m), 3.56–3.34 (3 H, m), 3.19 (1 H, dd, J 11.2, 2.9); δC (63 MHz,
CDCl3) 207.1, 157.8, 132.4, 129.7, 129.6, 125.3, 121.8, 81.8,
56.4, 50.5, 41.8; m/z (EI) 212 (32, Mϩ), 210 (100, Mϩ), 175 (43),
131 (33), 121 (79), 115 (35), 91 (56).
6f: 2,3-Dihydro-6H-1-benzoxocin-6-one. Eluent for column
chromatography: CH2Cl2–Et2O 9.5 : 0.5; colourless oil; yield
70%; HRMS calcd. for C11H10O2: 174.0680. Found: 174.0680;
νmax/cmϪ1 (neat) 2875, 1634, 1448; δH (250 MHz, CDCl3) 7.78
(1 H, d, J 7.2), 7.54 (1 H, dd, J 7.2, 7.1), 7.27 (1 H, dd, J 7.2,
7.1), 7.15 (1 H, d, J 7.2), 6.61–6.47 (2 H, m), 4.16 (2 H, t, J 7.1),
2.37 (2 H, q, J 7.1); δH (250 MHz, C6D6) 7.95 (1 H, d, J 7.8),
7.02 (1 H, dd, J 7.8, 7.2), 6.83 (1 H, dd, J 7.8, 7.2), 6.75 (1 H, d,
J 7.2), 6.60 (1 H, d, J 11.8), 5.77 (1 H, td, J 11.8, 8.5), 3.48 (2 H,
t, J 5.8), 1.65–1.52 (2 H, m); δC (63 MHz, CDCl3) 191.7, 156.0,
138.2, 136.9, 135.6, 134.0, 130.5, 125.0, 123.2, 73.2, 25.9; m/z
(EI) 174 (100, Mϩ), 144 (17), 131 (20), 120 (46), 115 (19), 92
(20), 81 (17).
6a: 6,7b-Dihydro-3(2H)-oxepinone. Eluent for flash chrom-
atography: pentane–Et2O 9 : 1; colourless oil; yield 70%;
HRMS calcd. for C6H8O2: 112.0524. Found: 112.0524; νmax
/
cmϪ1 (neat) 2932, 1655; δH (250 MHz, CDCl3) 6.59 (1 H, td,
J 12.4, 4.4), 6.07 (1 H, td, J 12.4, 1.8), 4.33 (2 H, s), 3.96 (2 H, t,
J 5.4), 2.71 (2 H, dq, J 5.4, 1.8); δC (63 MHz, CDCl3) 204.4,
145.2, 130.3, 78.9, 69.6, 35.2; m/z (EI) 112 (43, Mϩ), 84 (83), 83
(43), 81 (54), 55 (20), 54 (100), 53 (41).
6g: 2,3-Dihydro-1-benzoxonin-6(7H)-one. Eluent for flash
chromatography: CH2Cl2–EtOAc 9.5 : 0.5; colourless oil; yield
55%; HRMS calcd. for C12H12O2: 188.0837. Found: 188.0843;
νmax/cmϪ1 (neat) 3021, 1695, 1636; δH (250 MHz, CDCl3) 7.21–
6.94 (4 H, m), 6.01 (1 H, d, J 12.1), 5.90 (1 H, ddd, J 12.1, 7.9,
7.6), 4.24 (2 H, m), 3.71 (2 H, s), 2.51–2.43 (2 H, ddd, J 10.4,
7.6, 5.3); δH (250 MHz, C6D6) 7.01–6.92 (1 H, m), 6.77–6.72
(2 H, m), 6.62 (1 H, d, J 8.3), 5.63 (1 H, d, J 12.0), 5.24 (1 H, td,
J 12.0, 8.2), 3.64 (2 H, dd, J 5.4, 5.3), 3.45 (2 H, s), 2.03–1.95 (2
6b: 2,3,7,8-Tetrahydro-4H-oxocin-4-one. Eluent for flash
chromatography: pentane–EtOAc 1 : 1; colourless oil; yield
73%; HRMS calcd. for C7H10O2: 126.0680. Found: 126.0681;
νmax/cmϪ1 (neat) 2950, 1659; δH (250 MHz, CDCl3) 6.49 (1 H, td,
J 12.1, 8.0), 6.23 (1 H, d, J 12.1), 3.91 (2 H, t, J 6.8), 3.69 (2 H, t,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 6 0 0 – 3 6 0 4
3603

View Article Online
7 R. A. Bunce, E. D. Dowdy, R. S. Childress and P. J. Jones, J. Org.
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H, m); δC (63 MHz, CDCl3) 205.5, 159.2, 135.0, 130.8, 130.4,
128.9, 128.7, 122.8, 119.2, 72.5, 46.7, 27.9; m/z (EI) 188 (43,
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91 (43), 81(99), 78 (38).
10 K. Wünsche, U. Schwaneberg, U. T. Bornscheuer and H. H. Meyer,
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Acknowledgements
This work was financially supported by the CNRS and the Uni-
versity of Paris-Sud (XI), by a grant to F.L. from the Ministère
de la Jeunesse, de l’Education nationale et de la Recherche.
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