Synthesis and conjugate additions of 2,3,4,9-tetrahydro-1H-xanthene-1,9-diones

Article abstract of DOI:10.1039/a700375g

An efficient two step procedure for the synthesis of 2,3,4,9-tetrahydro-1H-xanthene-1,9-diones is described. A study of their conjugate additions has shown them to be efficient Michael acceptors. Reaction of 2,3,4,9-tetrahydro-1H-xanthene-1,9-dione with t

Full text of DOI:10.1039/a700375g

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Synthesis and conjugate additions of 2,3,4,9-tetrahydro-1H-
xanthene-1,9-diones
Christopher D. Gabbutt,a John D. Hepworth,*,a Michael W. J. Urquhart a and
Luis Millan Vazquez de Miguelb
a
Department of Chemistry, University of Central Lancashire, Preston, UK PR1 2HE
b Departamento de Quimica Organica, Universidad de Extremadura, 06071 Badajoz, Spain
An efficient two step procedure for the synthesis of 2,3,4,9-tetrahydro-1H -xanthene-1,9-diones is
described. A study of their conjugate additions has shown them to be efficient M ichael acceptors.
Reaction of 2,3,4,9-tetrahydro-1H -xanthene-1,9-dione with tris(methylthio)methyllithium, followed by
mercury(II) catalysed methanolysis, gave methyl 1-hydroxy-9-oxo-3,4,4a,9-tetrahydro-2H -xanthene-4a-
carboxylate, the nucleus of the secalonic acids and other natural products
A number of natural products contain the reduced xanthone
Discussion
unit 3,4,4a,9-tetrahydro-2H-xanthen-9-one, of which secalonic
Reactions of cyclohexane-1,3-diones 7a–f with 2-fluorobenzoyl
acid 1 is typical. First isolated in 1906,1 seven diastereoisomers
have now been isolated from natural sources.2 This tetrahydro-
xanthone moiety 2 also features in the lactone ergochrisin,3 the
chlorides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) proceeded smoothly at Ϫ10 ЊC in acetonitrile to give the
corresponding enol esters 8a–f (Scheme 2). Whilst pyridine has
been widely used as solvent and catalyst in acylation reactions,
we found DBU to be superior to pyridine giving higher yields
(82 to 93%) of purer products. It was essential to employ short
reaction times, typically 40 min, and rapid aqueous work-up
was necessary in order to minimise hydrolysis of the product.
A characteristic alkenyl signal was present at ca. 6 ppm in the
1H NMR spectrum of the enol esters 8 and the ester and carb-
Me
OH
O
HO
MeO2C
O
OH
OH
O
OH
OH
O
OH
onyl stretching bands occurred around 1740 and 1670 cmϪ1
respectively.
Attempts to effect the Fries rearrangement of 8a with two
equivalents of aluminium chloride in dichloromethane at 25 ЊC
,
O
Me
O
MeO2C
CO2Me
1
2
1
for 16 h gave a sticky orange solid in moderate yield. The H
eumetrin pigments,4 the beticolin toxins5 and the antibiotic,
xanthoquinodin A1.6 Previous attempts to obtain compounds
of type 2 which relied on the reaction of 7-oxabicyclo-
[2.2.1]heptane-2,3-dicarboxylic anhydride with aryllithiums did
not proceed as expected.7 Prior to this, Franck et al.8 prepared a
desmethoxycarbonylhemisecalonic acid in low overall yield in a
multi-step sequence from a tetrahydroxybenzophenone. More
recently,9 the tetrahydroxanthenedione system has been
obtained from the cyclocondensation of 2-acryloyl-2Ј-hydroxy-
acetophenone with 1-pyrrolidinocycloalkenes. We envisaged
that compounds of type 2 could be synthesised by conjugate
addition to 2,3,4,9-tetrahydro-1H-xanthene-1,9-dione 3a. We
now report a facile route to this α,β-unsaturated diketone and
related molecules and discuss their behaviour as Michael
acceptors.
NMR spectrum of this crude material was complex, but sug-
gested the presence of both the Fries product 9a and cyclised
O
O
S
OH
4
i
O
O
S
O
O
OH
R
The dione 3a has been synthesised 10 from the β-keto sulf-
oxide 411 through condensation with glutaraldehyde and sub-
sequent thermal elimination of methanesulfenic acid from 5.
Oxidation of the reduced xanthone 6 using Jones’ reagent com-
pleted the sequence (Scheme 1). However, a low overall yield
of 7% together with the foul smelling nature of the β-keto
sulfoxide prompted a search for an alternative route.
O
O
CHO
5 R = SOMe
ii
O
O
OH
A simple procedure for the preparation of 2-acylcyclo-
hexane-1,3-diones has been described,12 which is based on the
Fries rearrangement 13 of enol esters derived from the acylation
of cyclohexane-1,3-dione. Chromones have been prepared by
the intramolecular nucleophilic displacement of fluoride from
ethyl 2-(2-fluorobenzoyl)-2-acylacetates,14 and a combination
of these two protocols was considered to offer a viable entry to
the xanthone 3a.
iii
O
O
3a
6
Scheme 1 Reagents and conditions: i, OHC(CH2)3CHO (aq.), piperi-
dine, DMF, 50 to 80 ЊC; ii, 110 to 140 ЊC, 33%; iii, CrO3, conc. H2SO4,
H2O, AcMe, 23%
J. Chem. Soc., Perkin Trans. 1, 1997
1819

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O
O
O
O
OH
O
O
NaBH4, py
i
O
F
R4
R4
R4
R4
R2
R3
O
OH
O
R5
R5
R5
R5
3
10
R1
R4
R5
Yield (%)
7
R2
a
b
c
H
H
H
100
85
78
8
CH3
CH3 CH3
ii
Scheme 3
R1
O
O
R1
O
O
acetyl-2-methylchromanone19 in which the peri proton at ca.
7.8 ppm is separated from the other signals. A prominent car-
bonyl stretching band is apparent at ca. 1610 cmϪ1 for the di-
R2
R3
R2
iii
R4
R4
O
R3
F
1
R5
OH
R5
ketone; although inspection of the H NMR spectra suggests
R2
R2
that these compounds are fully enolised, no OH stretching band
was seen when their IR spectra were recorded in Nujol. Arom-
atisation of 10a to 1-hydroxyxanthone occurred on treatment
with o-chloranil in refluxing dioxane.
3
9
a R1 = R2 = R3 = R4 = R5 = H
b R1 = R2 = R3 = R4 = H, R5 = Me
c R1 = R2 = R3 = H, R4 = R5 = Me
d R1 = F, R2 = R3 = R4 = R5 = H
e R1 = R2 = H, R3 = F, R4 = R5 = H
f R1 = R2 = R3 = F, R4 = R5 = H
Chromones with an activating group in the 3-position have
been converted to the corresponding 2-methylchromanones on
treatment with lithium dimethylcuprate(),19 and this chemistry
was extended to provide a route to unsymmetrical 2,2-dialkyl-
chromanones and -thiochromanones.20 In marked contrast to
the behaviour of simple 3-acylchromones, when 3a was added
to a solution of a homocuprate R2CuLi, where R = Me, Bun or
Ph, in THF under conditions reported by Wallace,19 only medi-
ocre quantities of the corresponding 1,4-adducts 11 were
obtained. Employing higher order cuprates derived from cop-
per() iodide,21 the copper() bromide–dimethyl sulfide com-
plex19 and copper() cyanide22 in either THF or diethyl ether led
to extensive substrate decomposition and consequently low
yields of 11. Lower order cyanocuprates, RCu(CN)Li, have
been used for the regiospecific ring opening of α,β-unsaturated
epoxides23 and recently their addition to α,β-enals and -enones
has been accomplished.24 In similar fashion, the reaction of 3a
with a five-fold excess of lithium methylcyanocuprate() in
diethyl ether gave an excellent yield of 11a, without the need
for chromatographic purification. THF is known to retard
cuprate complex formation 25 and was not a suitable solvent in
this work. Similarly, BunCu(CN)Li gave an essentially quanti-
Scheme 2 Reagents and conditions: i, ArCOCl, DBU, MeCN, Ϫ10 ЊC;
ii, AlCl3, DCE, Ϫ10 to 25 ЊC; iii, EtOH, heat
material 3a. Cyclisation ensued during recrystallisation from
ethanol, with the loss of hydrogen fluoride, and pure 3a was
obtained exclusively, although the yield after recrystallisation
was only moderate (ca. 40%). The insolubility of 3a in dichloro-
methane rendered isolation difficult and consequently low
recoveries of product were usual, but yields were markedly
increased when 1,2-dichloroethane was used as the solvent. A
range of substituted derivatives 3b–f was prepared in good to
excellent yield (72 to 87%) under these conditions (Scheme 2).
Several of these compounds exhibited wide melting ranges, but
chromatographic, spectroscopic and analytical data confirm
their purity and support the assigned structures. In none of the
Fries reactions was any uncyclised product 9 isolated in a
pure state, since the elimination of hydrogen fluoride proceeds
relatively smoothly under the reaction conditions. The aromatic
1
region of the H NMR spectra of the xanthenediones 3a,b,c
O
O
O
OH
and e clearly showed a signal at 8.2 ppm for H-8, typical of a
proton peri to the carbonyl function in a chromone. The 13C
NMR spectra confirmed the presence of the two carbonyl
groups which absorbed at ca. 193 ppm (C-1) and 178 ppm
(C-9). In the IR spectra νC᎐O moved to 1710–1690 and 1645–
1630 cmϪ1 for the C-1 and C-9 ketone functions, respectively.
With efficient access to large quantities of the tetrahydroxan-
thenedione 3a, its behaviour as a Michael acceptor was investi-
gated. It is known that reduction of acylchromones with
sodium borohydride in alcoholic solvents is indiscriminate and
leads to complex mixtures of products,15 and the same proved
true for the reduction of 3a under these conditions when the
diketone 10a could only be obtained in 22% yield. The solvent
plays an important role in the reduction of α,β-unsaturated
ketones by sodium borohydride and it is reported that in pyri-
dine conjugate reduction is favoured and only the saturated
ketones are produced.16 In like manner, 3-benzoyl-coumarin 17
and -thiocoumarin 18 are converted into the corresponding 3,4-
dihydro compounds, but no examples of analogous behaviour
of chromones have been reported. We now find that under these
conditions, the xanthenedione 3a is reduced to 10a in quantita-
tive yield. A similar result was observed with the 3-substituted
analogues 3b and 3c which were converted in high yield to the
corresponding xanthones 10b and 10c respectively (Scheme 3).
Following conjugate reduction, the aromatic signals in the
1H NMR spectra are comparable with those reported for 3-
i
O
O
R
3a
11
R
Yield (%)
a
CH3
Bun
Bus
Ph
93
98
34
21a
51
24
b
c
d
e
f
Et
4-CH3C6H4CH2
Scheme 4 Reagents and conditions: i, RCu(CN)Li (5 equiv.), Et2O,
Ϫ50 ЊC or a Ph2CuLi (1.5 equiv.), Et2O–PhH, Ϫ40 to 0 ЊC
tative yield of 11b on reaction with xanthenedione 3a, but reac-
tion with the cyanocuprate derived from sec-butyllithium gave a
substantially lower yield of 11c. These results indicate that
increasing the steric bulk of the nucleophile hinders the conju-
gate reaction with substrate 3a. It is noteworthy that whilst 1,4-
addition appeared unfavourable in the latter case, no direct 1,2-
attack was observed and unchanged 3a was recovered at the end
of the reaction. Furthermore, no reaction occurred with the
tert-butylcuprate. Problems were encountered in trying to form
the phenylcuprate from copper() cyanide and phenyllithium
and the alternative reagent Ph2CuLi was used in this case, but
1820
J. Chem. Soc., Perkin Trans. 1, 1997

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only a low conversion to the 4a-phenyl derivative 11d was
observed (Scheme 4). The failure of homo and higher order
cuprates to add to 3a is attributed to their greater basicity rela-
tive to that of the lower order cyanocuprates. It appears that
lower order cyanocuprates offer significant advantages in the
conjugate addition reactions of acidic α,β-unsaturated systems
which have so far been unappreciated. The 1H NMR spectra of
11a–d exhibited an aromatic proton pattern similar to that of a
chroman-4-one and the appropriate signals appeared for the 4a-
substituent. In particular, the 4a-methyl signal for 11a (1.48
ppm) compared favourably with that for the 4a-methyl group in
hemisecalonic acid (1.46 ppm).8 We were unable to obtain satis-
factory elemental analysis for 11c even though it was chroma-
tographically homogeneous (TLC). However, the similarity of
NMR spectrum, the methylthio groups absorbed at 15.8 ppm
and the orthothioester carbon at 89.0 ppm. The signals for C-1
(174.8 ppm) and C-9 (192.0 ppm) are appreciably different from
the corresponding absorptions in 11a (181.6 and 182.4 ppm,
respectively). The HgII catalysed oxidative methanolysis of 15
gave the ester 2 in quantitative yield (Scheme 5). This approach
O
O
O
OH
i
O
O
R
3a
15 R = C(SCH3)3
2 R = CO2CH3
ii
1
its H NMR spectrum with the spectra of 11a–b and 11d–f
firmly established its constitution.
Scheme 5 Reagents and conditions: i, LiC(SMe)3 (1.1 equiv.), THF,
Ϫ50 ЊC, 35%; ii, HgCl2, HgO, MeOH, H2O, 25 ЊC, 100%
For comparative purposes, the reactivity of 3a with Grignard
reagents was also investigated. Reaction of 3a with methylmag-
nesium bromide in diethyl ether gave a mixture of 11a (40%)
and the alcohol 12 (24%). The latter compound arises from
direct nucleophilic addition to the substrate. The balance of
material was identified as unreacted 3a, and it is likely that
competitive deprotonation of 3a by the basic Grignard reagent
is also a factor in this reaction. The alcohol is interesting
because it is structurally similar to the naturally occurring
aphloiol 13,26 and to the physiologically active compounds
represents the first successful synthetic route to the secalonic
acid half unit. Not surprisingly, the 13C NMR data for 2 corres-
pond closely to the 13C shifts reported for the xanthone subunit
of beticolin. 5 In particular, signals for the ester function appear
at 52.8 and 172.7 ppm, whilst C-1, C-4a, C-9 and C-9a absorb
at 179.5, 85.7, 185.1 and 104.6 ppm, respectively. There was
evidence in the 1H and 13C NMR spectra of a trace of an impur-
ity in the product, but this did not show in either the elemental
analysis or chromatographically. However, the sample softened
at 123 ЊC before melting at 126–129 ЊC.
It was thought that the modest yield of the adduct 15 could
be attributed to the acidic nature of the C-4 proton in 3a,
and therefore the major pathway was deprotonation by LiC-
(SMe)3. For this reason it was decided to decrease the acidity
of 3a by temporarily removing one of the ketone functions. Of
the two carbonyls in 3-acylchromones, the exocyclic carbonyl
group can be selectively protected as the ketal,31 and 3a should
react in a similar fashion. Although a variety of conditions exist
for ketalisation, the particularly mild conditions developed by
Chan et al.32 seemed appropriate for this reactive substrate.
Reaction of 3a with ethylene glycol and trimethylchlorosilane
in 1,2-dichloroethane at reflux gave the mono-ketal 14 in excel-
lent yield. However, the reaction of 14 with tris(methylthio)-
methyllithium was unsuccessful and only unchanged starting
material was recovered. Evidently, removal of one of the car-
bonyl functions in 3a not only decreases the acidity of the C-4
position but also deactivates the ring towards conjugate
addition.
O
OH
O
OH
O
O
O
CH3
CH3
OH
O
O
OH
O
OH
12
13
14
reported by von Strandtmann and co-workers.10 However, only
the 1,4-adducts 11e and 11f were isolated when 3a was reacted
with EtCu(CN)MgBr and the cyanocuprate derived from 4-
methylbenzylmagnesium bromide, respectively.
The conjugate addition of tris(methylthio)methyllithium, a
sulfur stabilised carbanion, to 3a is of particular interest
because it is an ester anion equivalent and would allow the
introduction of the 4a-carboxy function found in the secalonic
acids and related compounds. The reaction of sulfur stabilised
carbanions with α,β-unsaturated ketones generally results in
1,2-addition, but conjugate addition to cyclohexenone has been
achieved and the process is favoured by unhindered substrates.27
Other workers have reported that 1,4-addition results under
thermodynamic control, but that kinetic conditions lead to the
1,2-product.28 Furthermore, the addition of hexamethylphos-
phoramide (HMPA) to the carbanion prior to addition of the
substrate is reported to favour the conjugate reaction.29 How-
ever, no reaction was observed when 3a was treated with
tris(methylthio)methyllithium in a 4:1 mixture of THF and
HMPA. Omission of HMPA proved beneficial and the conju-
gate product 15 was obtained in 20% yield with no evidence for
the formation of the 1,2-product. Initial experiments involved
addition of the substrate at Ϫ80 ЊC followed by warming to
ambient temperature to achieve the thermodynamic conditions
reported to favour conjugate reaction. Prolonged reaction at
room temperature caused decomposition of both the organo-
lithium reagent and the product; the instability of tris(methyl-
thio)methyllithium has been noted previously.30 Optimisation
of the conjugate addition was achieved by strict temperature
control throughout the reaction and maintaining an internal
temperature of below Ϫ50 ЊC ensured only limited decom-
position of the reagent and increased the yield of the yellow
conjugate product to 35%. Incorporation of the C(SMe)3 unit
into the product was confirmed by a signal at 2.1 ppm in the 1H
NMR spectrum which integrated for 9 protons. In the 13C
Experimental
Reactions requiring anhydrous conditions were performed
using oven-dried glassware and conducted under nitrogen.
Anhydrous solvents were prepared according to published pro-
cedures33 and stored over activated 4 Å molecular sieves. Melt-
ing points are uncorrected. IR spectra were recorded on a Matt-
son Galaxy 3000 FT-IR spectrometer. NMR spectra were
recorded on a Bruker WM250 instrument for CDCl3 solutions;
coupling constants J are given in Hz. Distillations were per-
formed using a bulb-to-bulb (Kügelrohr) apparatus (Büchi
GKR-50 glass tube oven) and all boiling points quoted relate to
the oven temperature at which distillation commenced. Flash
chromatography was performed on silica gel (Sorbsil C60,
MPD 60 Å, 40–60 µm) according to the published procedure.34
General method for the preparation of 3-oxocyclohex-1-enyl
benzoates 8
To a stirred suspension of the appropriate cyclohexane-1,3-
dione (85 mmol) in dry acetonitrile (100 cm3) was added a
solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (102 mmol) in
acetonitrile (20 cm3) in one portion. Dissolution of the dione
was almost instantaneous. The resulting brown solution was
cooled to Ϫ10 ЊC and then treated dropwise with an equimolar
J. Chem. Soc., Perkin Trans. 1, 1997
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quantity of the aroyl chloride (85 mmol) in acetonitrile (40
cm3), maintaining the temperature below 0 ЊC. Within minutes
after completion of this addition the reaction was judged com-
plete from TLC inspection. Dilution with ethyl acetate (200
cm3), washing with saturated aqueous sodium chloride (2 × 200
cm3), 2  hydrochloric acid (2 × 200 cm3) and finally with satur-
ated aqueous sodium hydrogen carbonate (2 × 200 cm3), fol-
lowed by evaporation of the dried organic extracts (Na2SO4)
provided the crude product. Distillation under reduced pressure
gave the ester in an analytically pure state. The following com-
pounds were prepared by this protocol.
3-Oxocyclohex-1-enyl 2-fluorobenzoate 8a. From 2-fluoro-
benzoylchlorideand cyclohexane-1,3-dioneascolourlessneedles
(88%) after crystallisation from ethyl acetate and hexane, mp
58–60 ЊC; νmax(Nujol)/cmϪ1 1738, 1667 and 1611; δH 2.16 (2H,
m, H-5Ј), 2.48 (2H, dt, J 1.2, 6.8, H-4Ј), 2.69 (2H, dt, J 1.2, 6.8,
H-6Ј), 6.06 (1H, t, J 1.2, H-2Ј), 7.24 (2H, m, Ar-H), 7.61 (1H,
m, Ar-H), 8.00 (1H, m, Ar-H) (Found: C, 66.6; H, 4.7.
C13H11FO3 requires C, 66.7; H, 4.7%).
cm3), water (100 cm3) and ice (ca. 200 g) and then extracted with
chloroform (3 × 80 cm3). Evaporation of the dried organic
extracts (Na2SO4) provided the crude product as a red–brown
oil or solid. Recrystallisation provided the pure product. The
following compounds were obtained by this procedure.
2,3,4,9-Tetrahydro-1H-xanthene-1,9-dione 3a. From ester 8a
as colourless needles (75%) after recrystallisation from ethyl
acetate, mp 170–200 ЊC (decomp.); νmax(Nujol)/cmϪ1 1693, 1634
and 1615; δH 2.18 (2H, m, H-3), 2.60 (2H, t, J 6, H-2), 3.00 (2H,
t, J 6, H-4), 7.40 (2H, m, Ar-H), 7.65 (1H, m, Ar-H), 8.23 (1H,
dd, J 1.7, 7.8, H-8) (Found: C, 72.9; H, 4.6. C13H10O3 requires
C, 72.9; H, 4.7%).
2,3,4,9-Tetrahydro-3-methyl-1H-xanthene-1,9-dione 3b. From
ester 8b as colourless needles (72%) after crystallisation from
ethanol and ethyl acetate, mp 158 ЊC; νmax(Nujol)/cmϪ1 1692,
1633 and 1613; δH 1.50 (3H, d, J 7.0, Me), 1.80–3.20 (5H, m, H-
2, H-3, H-4), 7.40 (2H, m, Ar-H), 7.66 (1H, m, Ar-H), 8.22 (1H,
dd, J 1.7, 7.8, H-8) (Found: C, 74.0; H, 5.3. C14H12O3 requires
C, 73.7; H, 5.3%).
5-Methyl-3-oxocyclohex-1-enyl 2-fluorobenzoate 8b. From 2-
fluorobenzoyl chloride and 5-methylcyclohexane-1,3-dione as a
colourless oil (86%), bp 165 ЊC at 0.04 mbar;† νmax(Nujol)/cmϪ1
1746, 1670 and 1612; δH 1.09 (3H, d, J 6.1, Me), 2.12 (1H, m, H-
5Ј), 2.52 (4H, m, H-4Ј, H-6Ј), 5.99 (1H, s, H-2Ј), 7.16 (2H, m,
Ar-H), 7.58 (1H, m, Ar-H), 7.93 (1H, m, Ar-H) (Found: C,
67.9; H, 5.5; F, 7.6. C14H13FO3 requires C, 67.7; H, 5.3; F, 7.6%).
5,5-Dimethyl-3-oxocyclohex-1-enyl 2-fluorobenzoate 8c. From
2-fluorobenzoyl chloride and 5,5-dimethylcyclohexane-1,3-
dione as a colourless oil (93%), bp 165 ЊC at 0.04 mbar, which
crystallised on standing, mp 40–43 ЊC; νmax(Nujol)/cmϪ1 1737,
1667 and 1612; δH 1.15 (6H, s, Me), 2.32 (2H, s, H-6Ј), 2.55 (2H,
s, H-4Ј), 6.05 (1H, s, H-2Ј), 7.20 (2H, m, Ar-H), 7.59 (1H, m,
Ar-H), 8.00 (1H, m, Ar-H) (Found: C, 68.7; H, 5.9; F, 7.4.
C15H15FO3 requires C, 68.7; H, 5.87; F, 7.2%).
3-Oxocyclohex-1-enyl 2,6-difluorobenzoate 8d. From 2,6-
difluorobenzoyl chloride and cyclohexane-1,3-dione as a col-
ourless oil (82%), bp 155 ЊC at 0.04 mbar which crystallised on
standing, mp 36–40 ЊC; νmax(Nujol)/cmϪ1 1750, 1680 and 1610;
δH 2.12 (2H, m, H-5Ј), 2.44 (2H, t, J 6.7, H-6Ј), 2.67 (2H, dt, J
1.0, 6.7, H-4Ј), 6.05 (1H, apparent s, H-2Ј), 7.00 (2H, m, Ar-H),
7.49 (1H, m, Ar-H) (Found: C, 61.8; H, 3.9; F, 15.3. C13H10F2O3
requires C, 61.9; H, 4.0; F, 15.1%).
2,3,4,9-Tetrahydro-3,3-dimethyl-1H-xanthene-1,9-dione 3c.
From ester 8c as colourless needles (82%) after crystallisation
from ethyl acetate and hexane, mp 135.5–136 ЊC; νmax(Nujol)/
cmϪ1 1691 and 1630; δH 1.16 (6H, s, 2 × Me), 2.46 (2H, s, H-2),
2.85 (2H, s, H-4), 7.38 (2H, m, Ar-H), 7.64 (1H, m, Ar-H), 8.21
(1H, dd, J 1.7, 7.8, H-8) (Found: C, 74.5; H, 5.8. C15H14O3
requires C, 74.4; H, 5.8%).
8-Fluoro-2,3,4,9-tetrahydro-1H-xanthene-1,9-dione 3d. From
ester 8d as pale brown needles (74%) after recrystallisation from
ethanol, mp 217.5–218 ЊC (decomp.); νmax(Nujol)/cmϪ1 1707,
1645 and 1622; δH 2.16 (2H, m, H-3), 2.59 (2H, t, J 6.5, H-2),
2.96 (2H, t, J 6.5, H-4), 7.03 (1H, m, Ar-H), 7.20 (1H, m, Ar-
H), 7.57 (1H, m, Ar-H) (Found: C, 67.1; H, 3.8; F, 8.1.
C13H9FO3 requires C, 67.2; H, 3.9; F, 8.2%).
6-Fluoro-2,3,4,9-tetrahydro-1H-xanthene-1,9-dione 3e. From
ester 8e as colourless needles (86%) after recrystallisation from
ethyl acetate and hexane, mp 151–171 ЊC (decomp.);
νmax(Nujol)/cmϪ1 1704, 1639 and 1613; δH 2.17 (2H, m, H-3),
2.59 (2H, t, J 6.5, H-2), 2.99 (2H, t, J 6.5, H-4), 7.10 (2H, m, Ar-
H), 8.21 (1H, m, Ar-H) (Found: C, 66.9; H, 3.8; F, 8.3.
C13H9FO3 requires C, 67.2; H, 3.9; F, 8.2%).
5,6,7,8-Tetrafluoro-2,3,4,9-tetrahydro-1H-xanthene-1,9-dione
3f. From ester 8f as colourless plates (87%) after recrystallis-
ation from ethyl acetate, mp 180–210 ЊC (decomp.); νmax(Nujol)/
cmϪ1 1704, 1642 and 1585; δH 2.17 (2H, m, H-3), 2.55 (2H, t, J
6.5, H-2), 3.02 (2H, t, J 6.5, H-4) (Found: C, 54.6; H, 2.0; F,
26.6. C13H6F4O3 requires C, 54.6; H, 2.1; F, 26.6%).
3-Oxocyclohex-1-enyl 2,4-difluorobenzoate 8e. From 2,4-
difluorobenzoyl chloride and cyclohexane-1,3-dione as a col-
ourless oil (82%), bp 150 ЊC at 0.04 mbar; νmax(Nujol)/cmϪ1
1750, 1680 and 1613; δH 2.10 (2H, m, H-5Ј), 2.44 (2H, t, J 6.7,
H-6Ј), 2.65 (2H, t, J 6.7, H-4Ј), 6.01 (1H, s, H-2Ј), 6.94 (2H, m,
Ar-H), 8.01 (1H, m, Ar-H) (Found: C, 61.8; H, 3.9; F, 15.1.
C13H10F2O3 requires C, 61.9; H, 4.0; F, 15.1%).
General method for the preparation of 3,4,4a,9-tetrahydro-1-
hydroxy-2H-xanthen-9-ones 10
3-Oxocyclohex-1-enyl 2,3,4,5,6-pentafluorobenzoate 8f. From
2,3,4,5,6-pentafluorobenzoyl chloride and cyclohexane-1,3-
dione as a colourless oil (91%), bp 160 ЊC at 0.04 mbar;
νmax(CCl4)/cmϪ1 1739, 1650 and 1604; δH 2.10 (2H, m, H-5Ј),
2.45 (2H, t, J 6.5, H-6Ј), 2.62 (2H, dt, J 1.0, 6.5, H-4Ј), 6.01 (1H,
s, H-2Ј). Satisfactory elemental analysis could not be obtained
for this compound; its constitution was verified by conversion
to 3f.
A stirred suspension of the xanthenedione 3 (56 mmol) in
anhydrous pyridine (150 cm3) was treated with sodium borohy-
dride (56 mmol) in portions. The suspension dissolved and the
resulting dark solution was stirred at room temperature for 3 h.
After pouring onto ice (ca. 200 g) and 2  hydrochloric acid
(200 cm3), the mixture was extracted with ethyl acetate (3 × 100
cm3). The combined organic extracts were washed with 2 
hydrochloric acid (4 × 200 cm3) and brine (200 cm3). After dry-
ing (Na2SO4), evaporation of the solvent provided the crude
product. The following compounds were prepared according to
this method.
General method for the preparation of 2,3,4,9-tetrahydro-1H-
xanthene-1,9-diones 3
A stirred suspension of aluminium chloride (40 mmol) in dry
1,2-dichloroethane (100 cm3) at Ϫ8 ЊC (ice–ethanol) was treated
dropwise with a solution of the appropriate ester 8 (19.8 mmol)
in 1,2-dichloroethane (40 cm3). During the addition the alu-
minium chloride dissolved giving a pale brown solution. After
stirring at this temperature for 1 h, the mixture was kept at
room temperature until the reaction was adjudged complete by
TLC. The mixture was poured into 2  hydrochloric acid (100
3,4,4a,9-Tetrahydro-1-hydroxy-2H-xanthen-9-one 10a. From
chromone 3a as pale yellow crystals (100%) after sublimation,
mp 71.5–73.5 ЊC; νmax(Nujol)/cmϪ1 1608; δH 1.96 (3H, m, H-3,
H-4), 2.39 (3H, m, H-2, H-4), 5.05 (1H, m, H-4a), 6.91 (1H, m,
Ar-H), 7.03 (1H, m, Ar-H), 7.42 (1H, m, Ar-H), 7.84 (1H, dd, J
1.7, 7.8, H-8), 14.97 (1H, s, OH) (Found: C, 72.1; H, 5.5.
C13H12O3 requires C, 72.2; H, 5.6%).
3,4,4a,9-Tetrahydro-1-hydroxy-3-methyl-2H-xanthen-9-one
10b. From chromone 3b as a yellow solid (85%), distilled at
130 ЊC at 0.04 mbar, mp 49–63 ЊC; νmax(Nujol)/cmϪ1 1609; δH
† 1 bar = 105 Pa.
1822
J. Chem. Soc., Perkin Trans. 1, 1997

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1.10 (3H, m, Me), 1.64 (1H, m, H-4), 2.19 (4H, m, H-2, H-3, H-
4), 5.06 (1H, m, H-4a), 6.95 (1H, m, Ar-H), 7.03 (1H, m, Ar-H),
7.42 (1H, m, Ar-H), 7.86 (1H, m, H-8), 14.55–14.95 (1H, br s,
OH) (Found: C, 73.0; H, 6.0. C14H14O3 requires C, 73.0; H,
6.1%).
3,4,4a,9-Tetrahydro-1-hydroxy-3,3-dimethyl-2H-xanthene-9-
one 10c. From chromone 3c as orange prisms (78%) after crys-
tallisation from ethyl acetate and hexane, mp 92.5–93.5 ЊC;
νmax(Nujol)/cmϪ1 1606; δH 0.99 (3H, s, Me), 1.12 (3H, s, Me),
1.79 (1H, dd, J 10.2, 12.3, H-4), 2.06 (1H, m, H-4), 2.16 (1H,
dd, J 1.4, 18.5, H-2), 2.38 (1H, dd, J 1.4, 18.5, H-2), 5.06 (1H,
m, H-4a), 6.92 (1H, m, Ar-H), 7.04 (1H, m, Ar-H), 7.43 (1H, m,
Ar-H), 7.86 (1H, dd, J 1.8, 7.8, H-8), 14.86 (1H, s, OH) (Found:
C, 73.8; H, 6.6. C15H16O3 requires C, 73.8; H, 6.6%).
benzene (21.0 cm3, 42 mmol) was added to a stirred suspension
of copper() iodide (4.01 g, 21 mmol) in dry diethyl ether (100
cm3) at Ϫ5 ЊC under nitrogen, keeping the internal temperature
below 0 ЊC. The resulting dark solution was stirred below 0 ЊC
for 15 min, cooled to Ϫ80 ЊC and treated with 3a (3.0 g, 14
mmol) in portions via a powder funnel. After stirring below
Ϫ40 ЊC for 100 min, the reaction mixture was allowed to warm
to 0 ЊC and then stirred at 0 ЊC for a further 6 h. The usual
work-up gave a sticky brown solid. Purification by column
chromatography (ethyl acetate–hexane, 1:9) and recrystallis-
ation from light petroleum (bp < 40 ЊC) gave the title com-
pound 11d as golden yellow crystals (0.86 g, 21%), mp 140–
143 ЊC; νmax(Nujol)/cmϪ1 3401, 1648 and 1606; δH 1.34 (1H, m,
H-3), 1.67 (1H, m, H-3), 2.26 (2H, m, H-4), 2.46 (2H, m, H-2),
6.79 (1H, m, Ar-H), 6.88 (1H, m, Ar-H), 7.20 (4H, m, Ar-H),
7.39 (2H, m, Ar-H), 7.70 (1H, dd, J 1.7, 7.8, H-8), 15.56 (1H, s,
OH) (Found: C, 78.1; H, 5.5. C19H16O3 requires C, 78.1; H,
5.5%).
4a-Ethyl-3,4,4a,9-tetrahydro-1-hydroxy-2H-xanthen-9-one
11e. From chromone 3a and magnesium ethylcyanocuprate()
bromide as yellow crystals (51%) after elution from silica with
ethyl acetate–hexane (1:9) and crystallisation from diethyl
ether, mp 70–80 ЊC; νmax(Nujol)/cmϪ1 1607; δH 0.85 (3H, t, J 7.3,
Me), 1.57 (1H, m, CH2Me), 1.71 (1H, m, H-3), 1.89 (2H, m,
H-3, H-4), 2.05 (1H, m, CH2Me), 2.30 (1H, m, H-4), 2.46 (2H,
m, H-2), 6.89 (1H, m, Ar-H), 7.00 (1H, m, Ar-H), 7.41 (1H, m,
Ar-H), 7.83 (1H, dd, J 1.7, 7.8, H-8), 15.30 (1H, s, OH) (Found:
C, 73.9; H, 6.5. C15H16O3 requires C, 73.8; H, 6.6%).
3,4,4a,9-Tetrahydro-1-hydroxy-4a-(4-methylbenzyl)-2H-
xanthen-9-one 11f. From chromone 3a and magnesium (4-
methylbenzyl)cyanocuprate() bromide as colourless prisms
(24%) after elution from silica with ethyl acetate–hexane (1:9)
and crystallisation from ethyl acetate–hexane, mp 121–123 ЊC;
νmax(Nujol)/cmϪ1 1606; δH 1.90 (3H, m, H-3, H-4), 2.10 (1H, m,
H-4), 2.33 (3H, s, Me), 2.49 (2H, m, H-2), 2.79 (1H, d, J 14.7,
CH2Ar), 3.35 (1H, d, J 14.7, CH2Ar), 6.96 (3H, m, Ar-H), 7.06
(3H, m, Ar-H), 7.51 (1H, m, Ar-H), 7.90 (1H, dd, J 1.7, 7.8, H-
8), 15.48 (1H, s, OH) (Found: C, 78.8; H, 6.5. C21H20O3 requires
C, 78.7; H, 6.3%).
1-Hydroxy-9H-xanthen-9-one
A mixture of 3,4,4a,9-tetrahydro-1-hydroxy-2H-xanthen-9-one
10a (0.5 g), o-chloranil (1.14 g) and 1,4-dioxane (40 cm3) was
refluxed for 5 h. The residue remaining after filtration and
evaporation of the cooled filtrate was eluted from silica with
ethyl acetate–hexane (1:9) and recrystallised from hexane to
give the title compound (77%), mp 148.5–149 ЊC as a yellow
solid (lit.,35 mp 148–149 ЊC).
General method for the preparation of 4a-substituted 3,4,4a,9-
tetrahydro-1-hydroxy-2H-xanthen-9-ones 11
To a stirred suspension of copper() cyanide (116.7 mmol) in
dry diethyl ether (150 cm3) at Ϫ50 ЊC was added a solution of
the alkyllithium (116.8 mmol), maintaining the temperature
below Ϫ25 ЊC at all times. Towards the end of the addition the
copper() cyanide dissolved. The homogeneous solution of the
cuprate was cooled to Ϫ70 ЊC and stirred for 30 min. The
chromone 3a (5.0 g, 23.35 mmol) was added in portions via a
powder funnel. An initial red colouration was apparent. The
mixture was stirred below Ϫ50 ЊC until the reaction was com-
plete. The resulting mixture was poured into water (300 cm3)
and hydrochloric acid (50 cm3), and filtered through Celite.
The filter cake was washed with ethyl acetate (2 × 100 cm3) and
the organic layer was separated. After drying (Na2SO4),
removal of the solvent gave the conjugate addition product.
The following compounds were prepared in this way.
2,3,4,9-Tetrahydro-1-hydroxy-1-methyl-1H-xanthen-9-one 12
A solution of methylmagnesium bromide in diethyl ether (15.0
mmol) was added dropwise to a stirred suspension of 3a (1.5 g,
7.01 mmol) in dry diethyl ether (80 cm3) at Ϫ18 ЊC. Gradual
dissolution of the substrate occurred giving an orange–red
solution. After stirring for 30 min, the mixture was poured onto
ice (ca. 50 g) and 1  hydrochloric acid (100 cm3), and extracted
with ethyl acetate (2 × 100 cm3). The combined organic extracts
were washed with aqueous ammonium chloride (2 × 200 cm3),
dried (Na2SO4) and evaporated to yield an orange–yellow oil.
Column chromatography (ethyl acetate–hexane, 1:5) gave the
1,4-adduct 11a followed by the title compound 12, obtained as
a yellow solid (0.64 g, 40%) and a yellow oil (0.38 g, 24%)
respectively. The latter solidified and was crystallised from ethyl
acetate and hexane as yellow–brown crystals, mp 75–77 ЊC;
νmax(Nujol)/cmϪ1 3531, 3483, 3417, 1626 and 1600; δH 1.64 (3H,
s, Me), 1.95 (4H, m, H-2, H-3), 2.73 (2H, m, H-4), 5.39 (1H, s,
OH), 7.37 (2H, m, Ar-H), 7.63 (1H, m, Ar-H), 8.16 (1H, dd, J
1.4, 8.4, H-8) (Found: Mϩ, 230.093 99. C14H12O3 requires M,
230.094 29).
3,4,4a,9-Tetrahydro-1-hydroxy-4a-methyl-2H-xanthen-9-one
11a. From chromone 3a and lithium methylcyanocuprate() as
golden yellow crystals (93%) after crystallisation from light pet-
roleum (bp 40–60 ЊC), mp 91–93.5 ЊC; νmax(Nujol)/cmϪ1 1607;
δH 1.48 (3H, s, Me), 1.83 (1H, m, H-3), 2.04 (3H, m, H-3, H-4),
2.47 (2H, m, H-2), 6.88 (1H, m, Ar-H), 7.00 (1H, m, Ar-H),
7.42 (1H, m, Ar-H), 7.85 (1H, dd, J 1.3, 7.8, H-8), 15.27 (1H, s,
OH) (Found: C, 72.9; H, 6.1. C14H14O3 requires C, 73.0; H,
6.1%).
4a-Butyl-3,4,4a,9-tetrahydro-1-hydroxy-2H-xanthen-9-one
11b. From chromone 3a and lithium n-butylcyanocuprate() as
a pale yellow solid (98%) after distillation at 160 ЊC at 0.04
mbar, mp 66–68 ЊC; νmax(Nujol)/cmϪ1 1607; δH 0.79 (3H, t, J 7.1,
Me), 1.23 (4H, m, H-2Ј, H-3Ј), 1.60 (2H, m, H-3), 1.89 (3H, m,
H-1Ј, H-4), 2.30 (1H, m, H-4), 2.43 (2H, m, H-2), 6.87 (1H, m,
Ar-H), 6.98 (1H, m, Ar-H), 7.40 (1H, m, Ar-H), 7.84 (1H, dd, J
1.3, 7.7, H-8), 15.34 (1H, s, OH) (Found: C, 75.1; H, 7.4.
C17H20O3 requires C, 75.0; H, 7.4%).
4a-(Butan-2-yl)-3,4,4a,9-tetrahydro-1-hydroxy-2H-xanthen-
9-one 11c. From chromone 3a and lithium sec-butylcyano-
cuprate() as a yellow–brown oil (34%) after column chroma-
tography (ethyl acetate–hexane, 1:9) and distillation at 160 ЊC
at 0.04 mbar as a yellow oil; νmax(Nujol)/cmϪ1 1607; δH 0.82 (6H,
m, 2 × Me), 1.00 (1H, m, H-3Ј), 1.30 (1H, m, H-3Ј), 1.84 (3H, m,
H-2Ј, H-3), 2.02 (2H, m, H-4), 2.32 (2H, m, H-2), 6.87 (1H, m,
Ar-H), 6.98 (1H, m, Ar-H), 7.41 (1H, m, Ar-H), 7.84 (1H, m,
H-8), 14.99 (1H, br s, OH).
3,4,4a,9-Tetrahydro-1-hydroxy-4a-[tris(methylthio)methyl]-2H-
xanthen-9-one 15
A 2.3  solution of n-butyllithium in hexane (3.1 cm3, 7.71
mmol) was added dropwise to a stirred solution of tris(methyl-
thio)methane (1.03 ml, 7.71 mmol) in dry tetrahydrofuran (50
cm3) at Ϫ60 ЊC over 30 min, maintaining the internal temper-
ature below Ϫ55 ЊC. After stirring below Ϫ60 ЊC for 50 min, the
mixture was treated with 3a (1.50 g, 7.01 mmol) in portions via
a powder funnel. The resulting red solution was stirred below
3,4,4a,9-Tetrahydro-1-hydroxy-4a-phenyl-2H-xanthen-9-one
11d. A 2.0  solution of phenyllithium in 25% diethyl ether–
J. Chem. Soc., Perkin Trans. 1, 1997
1823

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Ϫ70 ЊC for 12 h, poured carefully onto water (200 cm3) and ice
(ca. 100 g) and extracted with ethyl acetate (3 × 100 cm3). The
solvent was removed from the dried (Na2SO4) organic extracts
to give a yellow–brown oil. Purification by column chroma-
tography (ethyl acetate–hexane, 1:9) and recrystallisation from
ethyl acetate and hexane yielded yellow crystals (0.90 g, 35%),
mp 97–99 ЊC; νmax(Nujol)/cmϪ1 1607; δH 1.77 (1H, m, H-3), 2.13
(1H, m, H-3), 2.15 [9H, s, (SMe)3], 2.48 (2H, m, H-4), 2.61 (1H,
m, H-2), 2.90 (1H, m, H-2), 6.79 (1H, m, Ar-H), 7.00 (1H, m,
Ar-H), 7.41 (1H, m, Ar-H), 7.81 (1H, dd, J 1.6, 7.8, H-8), 15.12
(1H, s, OH); δC 15.8, 19.7, 32.8, 36.6, 84.4, 89.0, 103.2, 115.7,
119.2, 120.9, 125.1, 134.7, 158.1, 174.8 and 192.0 (Found: C,
55.3; H, 5.4; S, 25.9. C17H20S3O3 requires C, 55.4; H, 5.5; S,
26.1%).
References
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Methyl 3,4,4a,9-tetrahydro-1-hydroxy-9-oxo-2H-xanthene-4a-
carboxylate 2
A solution of 15 (0.51 g, 1.38 mmol), mercuric chloride (1.53 g,
5.62 mmol) and mercuric oxide (0.50 g, 2.33 mmol) in
methanol–water (34 cm3, 12:1) was stirred at room temperature
for 6 h. The resulting white suspension was filtered through
Celite, and the residue was washed with dichloromethane
(2 × 70 cm3). The filtrate was diluted with water (100 cm3),
extracted with dichloromethane (2 × 500 cm3), the combined
organic extracts were washed with 60% aqueous ammonium
acetate (2 × 50 cm3), followed by saturated aqueous ammonium
chloride (2 × 50 cm3). The solvent was removed in vacuo from
the dried (Na2SO4) organic extracts to give the title compound 2
(0.38 g, 100%). Recrystallisation from ethyl acetate and hexane
yielded very pale red–brown crystals, mp 123–129 ЊC;
νmax(Nujol)/cmϪ1 1744, 1682 and 1605; δH 1.90 (2H, m, H-3),
2.17 (1H, m, H-4), 2.46 (3H, m, H-2, H-4), 3.62 (3H, s, OMe),
7.04 (2H, m, Ar-H), 7.43 (1H, m, Ar-H), 7.81 (1H, dd, J 1.6,
7.6, H-8), 15.31 (1H, s, OH); δC 17.4, 30.4, 33.1, 52.8, 85.7,
104.6, 117.6, 120.5, 122.3, 126.5, 135.3, 158.5, 172.7, 179.5 and
185.1 (Found: C, 65.7; H, 5.1. C15H14O5 requires C, 65.7; H,
5.1%).
8 B. Franck, J. Stockigt, U. Ziedler and G. Franckowiack, Chem. Ber.,
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Spiro[[1,3]dioxolane-2,1Ј-(2Ј,3Ј,4Ј,9Ј-tetrahydro-1ЈH-xanthen)]-
9-one 14
Chlorotrimethylsilane (14.4 cm3, 46.75 mmol) was added in one
portion to a stirred solution of 3a (10.0 g, 46.7 mmol) and
ethylene glycol (3.60 g, 58.0 mmol) in dry 1,2-dichloroethane
(150 cm3) under an argon atmosphere and the mixture was
heated to reflux. After 100 h, a wine-red solution was obtained.
The mixture was cooled to room temperature, diluted with
chloroform (400 cm3) and washed with 5% aqueous sodium
hydrogen carbonate (2 × 200 cm3). Evaporation of the dried
(Na2SO4) organic phase provided an orange–brown oil. Purifi-
cation by passage through a short path of silica (ethyl acetate–
hexane, 1:1) and recrystallisation from ethyl acetate and hexane
gave the title compound 14 as colourless crystals (10.86 g, 90%),
mp 93–97.5 ЊC; νmax(Nujol)/cmϪ1 1752, 1673, 1642 and 1595; δH
1.83 (4H, m, H-2, H-3), 2.59 (2H, m, H-4), 3.96–4.39 [4H, m,
(CH2)2], 7.23 (2H, m, Ar-H), 7.47 (1H, m, Ar-H), 8.05 (1H, dd,
J 1.9, 7.8, H-8) (Found: C, 70.0; H, 5.5. C15H14O4 requires C,
69.8; H, 5.5%).
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Acknowledgements
We thank the SERC for a studentship (to M. W. J. U.) and
for access to the mass spectrometry service at the University
College of Swansea, the British Council for support under the
Acciones Integradas scheme and the ERASMUS bureau for
supporting the exchange between the Universities of Central
Lancashire and Extremadura.
Paper 7/00375G
Received 15th January 1997
Accepted 6th March 1997
1824
J. Chem. Soc., Perkin Trans. 1, 1997