Synthesis of 9-substituted-l,8-dioxooctahydroxanthenes by an efficient Iodine-catalyzed cyclization

Article abstract of DOI:10.1002/ejoc.200801233

New 1,8-dioxooctahydroxanthenes with substituents in the 2-, 3-, and 9-positions were obtained by cyclization with iodine from tandem. Michael/Michael, adducts. The X-ray molecular structure of the methyl 2-(l,8-dioxo-2,3,4,5,6,7,8,9-octahydro-lH-xanthen-

Full text of DOI:10.1002/ejoc.200801233

FULL PAPER
DOI: 10.1002/ejoc.200801233
Synthesis of 9-Substituted-1,8-Dioxooctahydroxanthenes by an Efficient
Iodine-Catalyzed Cyclization
Liliana E. Luna,[a] Raquel M. Cravero,*[a] Ricardo Faccio,[b,c] Helena Pardo,[b,c]
Álvaro W. Mombrú,[b,c] and Gustavo Seoane[d]
Keywords: Oxygen heterocycles / Iodine / Cyclization / Alkynes / Fused-ring systems
New 1,8-dioxooctahydroxanthenes with substituents in the
2-, 3-, and 9-positions were obtained by cyclization with io-
the parallel laminae packing of these molecules. Further-
more, we reported the structure of intermediate 4 isolated
dine from tandem Michael/Michael adducts. The X-ray mo- from this reaction.
lecular structure of the methyl 2-(1,8-dioxo-2,3,4,5,6,7,8,9-oc-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tahydro-1H-xanthen-9-yl)acetate (3a) was solved and shows
Germany, 2009)
between 1,3-cyclohexanediones 1a,c with methyl propiolate
and butynone.[1] The detailed study of this reaction and
structural features of 2 allowed us to discover the perform-
ance of 1,3-cyclohexadiones in the intramolecular amino-
Introduction
Compounds 2a–d were recently obtained by our research
group as products of tandem Michael/Michael additions
Scheme 1. Synthesis of octahydroxanthenes 3a–f by sequential tandem Michael–iodine-catalyzed cyclization. Reaction conditions:
ϵ–C(O)R5, -proline, DMSO, room temp., 3 d; then I2 cat., room temp., 5 h.
[a] IQUIR (Instituto de Química Rosario), Facultad de Ciencias
catalyzed 1,4-additions with acetylenic acceptors. The taut-
Bioquímicas y Farmacéuticas, Universidad Nacional de Rosa-
omerism associated with the chirality around the Csp2–Csp3
rio-Suipacha 531,
S2002LRK Rosario, Argentina
bond sets off these atropisomers as a portion present in
the antimalarial natural products cordypyridones A and B
(Scheme 1).[2]
A number of synthetic and natural products have the
xanthene unit in their molecular structures. The biological
Fax: +54-341-4370477
E-mail: rcravero@fbioyf.unr.edu.ar
[b] Crystallography, Solid State and Materials Laboratory
(Cryssmat-Lab), DETEMA, Facultad de Química, Universidad
de la República,
CC 1157, 11800 Montevideo, Uruguay
[c] Centro NanoMat, Polo Tecnológico de Pando, Facultad de activities of many oxoxanthene derivatives have been tested.
Química, Universidad de la República,
Some of these derivatives received considerable attention in
91000 Canelones, Uruguay
the bioorganic and medicinal areas, as they exhibited anti-
[d] Departamento de Química Orgánica, Facultad de Química,
Universidad de la República,
tumoral, fungicidal, and bactericidal properties.[3–5]
CC 1157, Montevideo, Uruguay
Compounds related to octahydroxanthene have been syn-
thesized from the Knoevenagel reaction between 5,5-di-
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
3052
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3052–3057

9-Substituted-1,8-Dioxooctahydroxanthenes by an I2-Catalyzed Cyclization
methyl-1,3-cyclohexanedione (dimedone) and aromatic al- discovered the sequential, tandem Michael–iodine-cata-
dehydes, promoted by dodecilbenzenesulfonic acid,[6] PPA/ lyzed cyclization (Table 1, Entry 9).
SiO2,[7] Dowex-50W,[8] and 1-methylimidazolium trifluoro-
1
All products were structurally confirmed by IR and H
acetate, a Brønsted acidic ionic liquid.[9] The condensation
of dimedone with sugars catalyzed by scandium-cation-ex-
changed montmorillonite has been accomplished in aque-
ous solution.[10] The NMR spectra of representative exam-
ples of the various adducts have been also examined.[11]
The behavior of molecular iodine as a mild Lewis acid
and its nontoxic properties are the benefits to its role as a
catalyst in many organic transformations. In most cases, the
reactions proceed smoothly with good yields and high selec-
tivity.[12] Even though there are many good methods in the
literature for the preparation of xanthenes derivatives, there
are few reports on the employment of an inexpensive cata-
lyst such as iodine in the sequential synthesis of substituted
compounds 3, with ester and methyl ketone chain function-
alities, short reaction times, and excellent yields.
and 13C NMR spectroscopy, and in particular, adduct 3a
1
was also studied by X-ray crystallography. In the H NMR
spectra of 3a we observed that the coupling of the triplet
for the methine hydrogen at 3.95 ppm with the doublet for
the methylene hydrogen of the side chain at 2.61 ppm has a
3
value of J = 4.4 Hz and a torsion angle of 58.11(21)° with
a rotation restricted along its bond axis. Therefore, the pre-
dominant conformer in solution (alternate conformation) is
what situates this methine hydrogen with the ester group in
the anti position, as we corroborated by X-ray analysis.
Because there is asymmetry in the ring of 2e as a result
1
of the position of the gem-dimethyl group, the H NMR
spectrum showed two enol protons. The keto–enol taut-
omerism is also reflected in the duplicity of the signals of
the ring C-3 (34.8, 34.5 ppm), C-5 (35.4, 35.3 ppm), and C-
6 (204.1, 203.7 ppm) carbon atoms and the geminal methyl
groups (26.2, 26.1 and 24.2, 24.1 ppm). Of all synthesized
compounds, 2e is the only example of this series in which,
for the carbonyl group, two chemical shift values appear at
204.1 and 203.7 ppm and a single value appears for C=C–
OH at 115.1 ppm due to a fast tautomeric equilibrium.
The reverse reaction was investigated by monitoring the
transformation of 3a in [D6]DMSO by 1H NMR spec-
troscopy at temperatures of 50, 80, 100, 110, and 130 °C as
proof of the stability of these heterocycles. For the CH3
group, a downfield chemical shift from 3.58 ppm (50 °C) to
3.63 ppm (100 °C) was observed. Above 80 °C, 3a suffers
spontaneous ring opening followed by the first retro-
Michael reaction to generate the corresponding monoad-
duct, which was confirmed by the two signals for the ole-
finic protons at 6.73 and 7.67 ppm (d, J = 16.1 Hz, Ha–
Hb trans; Scheme 2). The second retro reaction occurred at
130 °C leading to starting material 1a.
Results and Discussion
With the realization of previous work on the double
Michael reaction, compounds 2a–d were obtained from 1a–
c, methyl propiolate, and butynone through -proline-cata-
lyzed addition in DMSO at room temperature.[1] This
method could be further developed for the preparation of
new compounds 2e,f.
In the presence of a catalytic amount of iodine (3 mol-
%), compounds 2a–f (in ethanol, room temperature) can be
transformed into new octahydroxanthenes 3a–f by cycload-
dition of the ring fragments (Table 1, Entry 5).[13]
This method when applied to the reaction of 2 without
catalyst and CH2Cl2 as solvent, showed no reaction pro-
gress (Table 1, Entry 2), and a long reaction time was neces-
sary to achieve products when the condensation was carried
out in a DMSO or EtOAc (Table 1, Entries 3 and 4).
The one-pot transformation of 1Ǟ3 in DMSO/CH2Cl2
Colorless crystals of 3a were obtained by slow crystalli-
with stirring at room temperature for several weeks led to zation from xylene. Single-crystal X-ray diffraction studies
recovery of the starting material (Table 1, Entry 8). How- revealed an orthorhombic geometry, abnormal for organic
ever, exposure of a DMSO solution of 2a,c to ultrasonic compounds with high symmetrical content (Figure 1;
irradiation at room temperature gave 3a,c, although in low Table S1, Supporting Information). They were macroscopi-
yield (25–45%; Table 1, Entries 6 and 7). Increasing the cally visualized during the crystallization tests with the ob-
amount of iodine did not improve the yield. Finally, we servation of rhombic shapes 3–4 mm in size. As observed
Table 1. Study on the preparation of octahydroxanthenes 3.
Entry
Starting material
Reaction conditions[a]
Reaction time
Product
%Yield
1
2
3
4
5
6
7
8
2
EtOH, room temp.
CH2Cl2, room temp.
DMSO, room temp.
EtOAc
cat. I2, EtOH, room temp.
cat. I2, DMSO, room temp.
cat. I2, DMSO, room temp.
cat. -proline, alkyne, cat. I2,
DMSO/CH2Cl2 (1:1), room temp.
cat. -proline, alkyne, DMSO, 3 d, room temp.,
then cat. I2, 5 h, room temp.
5 h
5 h
7–15 d
7–15 d
5 h
6 h
6 h
no reaction
no reaction
2
2
3
3
3
3a
3c
Ͻ 10
Ͻ 15
quantitative
30
2
2
2a
2c
40
1 (one-pot reaction)
several weeks
no reaction
9
1 (one-pot sequential
Michael–cyclization)
77 h
3
85
[a] Entries 1–5, 8, and 9 magnetic stirring; Entries 6 and 7 ultrasonic irradiation.
Eur. J. Org. Chem. 2009, 3052–3057
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L. E. Luna, R. M. Cravero R. Faccio, H. Pardo, Á. W. Mombrú, G. Seoane
FULL PAPER
Scheme 2. Study of the retrocyclization and retro-tandem Michael reactions of 3a in [D6]DMSO by 1H NMR spectroscopy at programmed
temperatures.
in Figures 1 and 2, this molecule is packed in parallel lami-
nae with an inverted disposition of the side chain on C9
with weak hydrogen-bond interactions through C2–
H2···O1i (symmetry code, i = 1/2 + x, y, 1/2 – z; Tables S2
and S3, Supporting Information).
Figure 2. A view of the packing scheme for 3a normal to the [100]
direction (crystalline a axis direction).
Intermediate 4 was isolated and characterized by NMR
spectroscopy ([D6]acetone). Examination of its 13C NMR
spectrum showed that the signals at 51.8 and 197.1 ppm
correspond to the C-9a and C-1 carbon atoms, whereas C-
4a (O–C–OH) resonated at 101.8 ppm. All assignments
Figure 1. The structure 3a with the labeling scheme. Displacement
ellipsoids are drawn at the 30% probability level. Because a crystal-
lographic mirror plane at the middle of the molecule exists, gener-
ated atoms are labeled with i (symmetry code: i = 1/2 + x, y, 1/2 –
z]. The relationship between chemical and crystallographic no-
were thus in accord with both the enol and hemiketal por-
tions of 4. Crystallization from absolute ethanol afforded 4
as crystals suitable for X-ray analysis (Figures 3 and 4).
The molecular structure clearly shows a spatial disposi-
menclature is as follows: C1i = C8, C2i = C7, C3i = C6, C4i = C5, tion of the atoms that requires attack of the hydroxy group
C4ai = C4b; C9ai = C8a.
on the activated carbonyl group from the opposite face of
the methyl ester. Intermediate 4 also has a space group that
For the formation of the tricycle we propose a plausible is lower in symmetry than that of 3a (Table S1, Supporting
mechanism that involves nucleophilic attack of the enol Information). The location of the H9a hydrogen and the
moiety of 2a to the carbonyl group that is activated by hydroxy group on C4a of 4 is clearly indicative of an annu-
iodine of other moiety. Resulting hemiketal 4 undergoes eli- lar junction with syn stereochemistry (selected bond lengths
mination of a water molecule to form dehydrated octahyd- are given in Table S4, Supporting Information). The pack-
roxanthene 3a (Scheme 3).
ing is stabilized through many hydrogen bonds (Table S5,
Scheme 3. Cyclization pathways for the formation of 3a through hemiketal 4.
3054
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Eur. J. Org. Chem. 2009, 3052–3057

9-Substituted-1,8-Dioxooctahydroxanthenes by an I2-Catalyzed Cyclization
Experimental Section
General: Melting points (uncorrected) were measured in open capil-
lary tubes with an Electrothermal 9100 apparatus. NMR spectra
were recorded with Bruker AC-200E and Bruker Avance 300 MHz
spectrometers. FTIR spectra were obtained with a Shimadzu, Pres-
tige 21 Model. X-ray studies were done with a AFC75-Rigaku sin-
gle-crystal diffractometer over recrystallized samples.
General Procedure for the Synthesis of 3: A solution of -proline
(1.5 mol-%), the corresponding alkyne (2 mmol) in DMSO (4 mL),
and dione 1 (2 mmol) was stirred at room temperature for 3 d.
Without isolation of 2, iodine (3 mol-%) was then added to the
solution and it was left to stir at room temperature for 5 h. The
solution was treated with sodium thiosulfate solution (2ϫ10 mL)
until it became colorless. The reaction mixture was taken up in
CH2Cl2 (10 mL) and washed with NH4Cl solution, brine, and
water. The combined organic layer was dried with anhydrous
Na2SO4 and filtered, and the solvent was removed under vacuum
to give 3.
Figure 3. Structure 4 with labeling scheme. Displacement ellipsoids
are drawn at the 30% probability level.
Preparation of 3 by Iodine Cyclization of 2: A solution of 2
(0.2 mmol) and iodine (3 mol-%) in ethanol (0.5 mL) was stirred at
room temperature. The reaction mixture was monitored by TLC
and completed in 5 h. The solvent was removed in vacuo, and the
residue was taken up in CH2Cl2 (10 mL) and washed with sodium
thiosulfate solution (2ϫ10 mL), brine, and water. The combined
organic layer was dried with anhydrous Na2SO4 and filtered, and
the solvent was removed under vacuum to furnish 3.
Compounds 2a–d are known and their characterization is listed in
ref.[1]
Methyl
3,3-Bis(2-hydroxy-3,3-dimethyl-6-oxocyclohex-1-en-1-yl)-
propanoate (2e): Flash chromatography (silica gel; hexane/EtOAc,
60:40) provided 2e as a pure oil. IR (film): ν = 3400 (OH), 2925,
˜
2851, 1760 (C=O ester), 1586 (C=C, 1,3-dicarbonyl enol form),
1384 and 1372 (gem dimethyl), 1247 cm–1. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 13.23, 12.91 (br. s, 1 H), 4.42 (t, J = 7.7 Hz, 1
H), 3.60 (s, 3 H, OMe), 2.99 (d, J = 7.7 Hz, 2 H), 2.46 [br. s, 4 H,
-CH2C(O) keto–enol], 1.73 (m, 4 H, CH2-CH2-C), 1.12 and 1.10
(br. s, 12 H, gem-dimethyl) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 204.1, 203.7 (C=O keto–enol), 172.5 (C=O ester), 115.1
(C=C-OH), 51.5 (OCH3), 35.4, 35.3 (CH2-C=O keto–enol), 34.1
(CH2-C=O side chain), 34.8, 34.5 [C(CH3)2 keto–enol], 24.5 (CH),
26.2, 26.1 and 24.2, 24.1 [C(CH3)2 keto–enol], 24.0 (CH2-CH2-C)
ppm.
Figure 4. A view of the packing scheme for 4 normal to the [100]
direction (crystalline a axis direction), indicating the hydrogen
bonds.
Methyl
3,3-Bis(2-hydroxy-4-methyl-6-oxocyclohex-1-en-1-yl)pro-
Supporting Information), establishing infinite chains along
the [100] direction (crystalline a axis direction) of the crys-
tal.
panoate (2f): Flash chromatography (silica gel; hexane/EtOAc,
50:50) provided 2f as a pure oil. IR (film): ν = 3390 (OH), 2950,
˜
2925, 2875, 1741 (C=O ester), 1590, 1247 cm–1. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 12.90 (br. s, 1 H), 4.50 (t, J = 7.7 Hz,
1 H), 3.62 (s, 3 H, OMe), 3.04 (d, J = 7.7 Hz, 2 H), 2.80 [d, 4 H,
-CH2C(O)], 2.50 (m, 4 H, -CH2C=), 1.22 (m, 2 H, -CH-Me), 1.05
(br. s, 6 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 207.7
(α,β-unsaturated C=O), 172.0 (C=O ester), 163.5 (C=C-O), 117.5
(C=C-O), 51.6 (OCH3), 45.8 (CH2-C=C), 41.1 (CH2-C=O ketone),
34.1 (CH2-C=O ester), 26.3 (CH), 20.7 (CHCH3), 10.0 (CH3CH-
CH2) ppm.
Conclusions
In conclusion, we have developed a simple, practical, and
efficient method for the synthesis of 9-substituted-1,8-di-
oxooctahydroxanthenes 3a–f in high yields by employing a
sequential, tandem Michael–iodine-catalyzed cyclization.
The isolation of 4a-hydroxyxanthene intermediate 4 verified
the mechanistic pathways for the generation of 3a.
The functionalities present in 3 provide access to other
derivatives of interest. The development of this reaction on
solid phase and the preparation of analogs are being investi-
gated.
Methyl (1,8-Dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)ace-
tate (3a): Flash chromatography (hexane/EtOAc, 70:30) provided
3a as a white solid in quantitative yield. M.p. 155–156 °C. IR (film):
ν = 2925, 2853, 1732 (C=O ester), 1660 (α,β-unsaturated C=O),
˜
1622 (C=C), 1471, 1175 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 3.94 (t, J = 4.7 Hz, 1 H, CH), 3.57 (s, 3 H, OCH3), 2.62 (d, J
Eur. J. Org. Chem. 2009, 3052–3057
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L. E. Luna, R. M. Cravero R. Faccio, H. Pardo, Á. W. Mombrú, G. Seoane
2-(3,6-Dimethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-
FULL PAPER
= 4.5 Hz, 2 H, CH2 α-ester), 2.42 [m, 8 H, -CH2C(O), -CH2C=], Methyl
2.05 (m, 4 H, CH2-CH2-CH2) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 197.1 (α,β-unsaturated C=O), 172.2 (C=O ester), 166.0
xanthen-9-yl)acetate (3f): Flash chromatography (hexane/EtOAc,
70:30) provided 3f as a white crystalline solid in 99% yield. M.p.
(C=C-O), 114.2 (C=C-O), 51.2 (OCH3), 37.0 and 36.9 (CH2-C=O 151–152 °C. IR (film): ν = 2956, 2925, 2851, 1733 (C=O ester),
˜
ketone and ester), 27.1 (CH2-C-O), 23.7 (CH), 20.4 (CH2-CH2- 1668 (α,β-unsaturated C=O), 1622 (C=C), 1383, 1190 cm–1. 1H
CH2) ppm. HRMS: calcd. for C16H18O5 290.1154 [M + H]+; found
291.1241.
NMR (300 MHz, CDCl3, 25 °C): δ = 3.92 (br. s, 1 H), 3.62 (s, 3
H, OMe), 2.64 (m, J = 4.3 Hz, 2 H, CH2 α-ester), 2.51 (d, 4 H,
CH2-C=O ketone), 2.18 (m, CH2C-O), 1.22 (m, 2 H, -CH-Me),
1.11 (br. s, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 197.1 (α,β-unsaturated C=O), 172.3 (C=O ester), 165.7 (C=C-
O), 113.9 (C=C-O), 51.2 (OCH3), 45.3 (CH2-C-O), 36.5 (CH2-C=O
ester), 35.3 (CH2-C=O ketone), 23.8 (CH), 20.8 (CHCH3), 14.1
(CH3CH-CH2) ppm. HRMS: calcd. for C20H26O5 [M + H]+
346.1780; found 347.1822.
9-(2-Oxopropyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione
(3b): Flash chromatography (hexane/EtOAc, 60:40) provided 3b as
a white solid in quantitative yield. M.p. 95–96 °C. IR (film): ν =
˜
2950, 1711 (C=O ketone), 1654 (α,β-unsaturated ketone), 1615
1
(C=C), 1379, 1175 cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ =
3.87 (t, J = 4.7 Hz, 1 H, CH), 2.67 (d, J = 4.5 Hz, 2 H, CH2 side
chain), 2.48 [m, 8 H, -CH2C(O) and -CH2C=], 2.10 (s, 3 H, OCH3),
2.00 (m, 4 H, CH2-CH2-CH2) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 208.3 (C=O ketone), 197.5 (α,β-unsaturated C=O,
ketone), 166.1 (C=C-O), 114.8 (C=C-O), 46.9 (CH2-C=O side
chain), 36.9 (CH2-C=O), 30.3 [C(O)CH3], 27.1 (CH2-C-O), 23.4
(CH), 20.3 (CH2-CH2-CH2) ppm. HRMS: calcd. for C16H18O4 [M
+ H]+ 274.1205; found 275.1284.
Methyl 2-[(4aR,9R,9aS)-4a-hydroxy-1,8-dioxo-2,3,4,4a,5,6,7,8,9,9a-
decahydro-1H-xanthen-9-yl]acetate (4): A solution of ester 2a
(60 mg, 0.2 mmol) in EtOH (or EtOH/H2O, 9:1) (5 mL) was kept
at 50 °C for a period of 15 min and then it was slowly left to cool
until crystals were formed. The crystals were filtered and dried to
give compound 4. M.p. 118–119 °C. IR (film): ν = 3383 (OH),
˜
2949, 1734 (C=O ester), 1715 (C=O ketone), 1589 (O=C-CH=CH),
Methyl 2-(3,3,6,6-Tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-
1H-xanthen-9-yl)acetate (3c): Flash chromatography (hexane/
EtOAc, 80:20) provided 3c as white solid in quantitative yield. M.p.
1
1387, 1195 cm–1. H NMR [300 MHz, (CD3)2CO, 25 °C]: δ = 4.48
(t, J = 7.7 Hz, 1 H, H-9), 3.60 (m, 1 H, H-9a), 3.57 (s, 3 H, OCH3),
3.01 (d, J = 7.7 Hz, 2 H, CH2 α-ester), 2.79 [m, 6 H, CH2C(O) and
CH2-C-OH], 2.39 (m, 2 H, CH2C=), 1.85 (m, 4 H, CH2-CH2-CH2)
ppm. 13C NMR [75 MHz, (CD3)2CO, 25 °C]: δ = 197.1 (C=O
ketone), 192.1 (α,β-unsaturated C=O), 173.0 (C=O ester), 168.4
(C=C-O), 117.6 (C=C-O), 101.8 (O-C-OH), 51.8 and 51.4 (C-9a
and OCH3), 40.6 and 37.9 (CH2-C=O), 35.6 and 33.6 (CH2-C-O-
C and CH2-C-OH), 29.4 (CH2 α-ester), 27.4 (C-9), 21.4 and 20.8
(CH2-CH2-CH2) ppm.
151–152 °C. IR (film): ν = 2955, 2872, 1732 (C=O ester), 1660 (α,β-
˜
unsaturated C=O), 1624 (C=C), 1381, 1138 cm–1 1H NMR
.
(300 MHz, CDCl3, 25 °C): δ = 3.91 (t, J = 4.2 Hz, 1 H, CH), 3.55
(s, 3 H, OCH3), 2.72 (d, J = 4.3 Hz, 2 H, CH2 α-ester), 2.39 [s, 4
H, -CH2C(O)], 2.29 (s, 4 H, -CH2C-O), 1.11 [s, 12 H, C(CH3)2]
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 197.1 (α,β-unsatu-
rated C=O), 172.5 (C=O ester), 164.5 (C=C-O), 113.1 (C=C-O),
51.2 (OCH3), 50.8 (CH2-C=O ketone), 36.3 (CH2-C=O ester), 40.9
(CH2-C-O), 32.0 [C(CH3)2], 29.5 and 26.9 [C(CH3)2], 23.8 (CH)
ppm. HRMS: calcd. for C20H26O5 [M + H]+ 346.1780; found
347.1852.
CCDC-708841 (for 3a) and -708845 (for 4) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
3,3,6,6-Tetramethyl-9-(2-oxopropyl)-3,4,5,6,7,9-hexahydro-1H-
xanthene-1,8(2H)-dione (3d): Flash chromatography (hexane/
EtOAc, 70:30) provided 3d as a white solid in 99% yield. M.p. 98–
Supporting Information (see footnote on the first page of this arti-
cle): Crystallographic data and selected bond lengths and angles.
99 °C. IR (film): ν = 2950, 1712 (C=O ketone), 1655 (α,β-unsatu-
˜
rated C=O), 1610 (C=C), 1379, 1175 cm–1. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 3.83 (t, J = 4.4 Hz, 1 H, CH), 2.79 (d, J =
4.7 Hz, 2 H, CH2 side chain), 2.38 [s, 4 H, -CH2C(O)], 2.25 (s, 4
H, -CH2C-O), 2.08 (s, 3 H, CH3), 1.09 and 1.05 [s, 12 H,
C(CH3)2] ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 208.4
(C=O ketone), 197.4 (α,β-unsaturated C=O), 164.7 (C=C-O), 113.6
(C=C-O), 50.9 (CH2-C=O ring), 45.7 (CH2-C=O side chain), 40.9
(CH2-C-O), 32.0 [C(CH3)2], 30.4 [C(O)CH3], 29.3 and 27.1
[C(CH3)2], 23.3 (CH) ppm. HRMS: calcd. for C20H26O4 [M +
H]+ 330.1831; found 331.1897.
Acknowledgments
We are grateful to the Consejo Nacional de Investigaciones Científ-
icas y Técnicas (CONICET) and Agencia Nacional de Promoción
Científica y Tecnológica (ANPCYT) for financial support, and we
also thank Lic. M. C. Lecuona for technical assistance. G.S. and
A.W.M. acknowledge Programa de Desarrollo de las Ciencias
Básicas (PEDECIBA) (UN Project URU/97/016), Consejo Supe-
rior de Investigaciones Científicas (CSIC) and Dirección de Innov-
ación, Ciencia y Tecnología para el Desarrollo (DICyT), Uru-
guayan organizations, for financial support.
Methyl 2-(2,2,7,7-Tetramethyl-1,8-dioxo-3,4,5,6,8,9-hexahydro-1H-
xanthen-9-yl)acetate (3e): Flash chromatography (hexane/EtOAc,
85:15) provided 3e as a white solid in quantitative yield. M.p. 149–
151 °C. IR (film): ν = 2965, 2869, 1733 (C=O ester), 1661 (α,β-
˜
unsaturated C=O), 1627 (C=C), 1377, 1166 cm–1. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 3.92 (t, J = 4.2 Hz, 1 H, CH), 3.55
(s, 3 H, OCH3), 2.57 (d, J = 4.3 Hz, 2 H, CH2 α-ester), 2.50 (m, 4
H, -CH2C-O), 1.85 (dd, 4 H, CH2-CH2-C), 1.14 and 1.11 [s, 12 H,
C(CH3)2] ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 201.9 (α,β-
unsaturated C=O), 172.4 (C=O ester), 163.8 (C=C-O), 112.1 (C=C-
O), 51.1 (OCH3), 40.5 [(CH3)2C-C=O ketone], 36.8 and 34.1 (CH2-
C=O ester, CH2-C=C), 24.6 and 24.0 [C(CH3)2], 24.4 (CH), 24.1
(CH2-CH2-C) ppm. HRMS: calcd. for C20H26O5 346.1780 [M + H]
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Received: December 12, 2008
Published Online: April 29, 2009
Eur. J. Org. Chem. 2009, 3052–3057
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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