An efficient synthesis of embelin derivatives through domino Knoevenagel hetero Diels-Alder reactions under microwave irradiation

Article abstract of DOI:10.1016/j.tet.2008.06.057

The synthesis of novel pyrano embelin derivatives has been achieved through domino Knoevenagel hetero Diels-Alder reactions of embelin (1) with paraformaldehyde and electron rich alkenes. This synthetic approach is highly efficient when microwave irradiat

Full text of DOI:10.1016/j.tet.2008.06.057

Tetrahedron 64 (2008) 8938–8942
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journal homepage: www.elsevier.com/locate/tet
An efficient synthesis of embelin derivatives through domino Knoevenagel
hetero Diels–Alder reactions under microwave irradiation
a
,
b
a
,
c
a
,
b
,
a,b,
*
*
´
´
´
´
Sandra Jimenez-Alonso , Haydee Chavez , Ana Estevez-Braun
, Angel G. Ravelo
,
Gabriela Feresin d, Alejandro Tapia d
a
´
´
´
´
Instituto Universitario de Bio-Organica ‘Antonio Gonzalez’, Universidad de La Laguna, Avda. Astrofısico Francisco Sanchez No 2, 38206, La Laguna, Tenerife, Spain
b Hospital Universitario de La Candelaria, 38010, Tenerife, Spain
c Facultad de Farmacia y Bioqu´ımica, Universidad San Luis Gonzaga de Ica, Peru
d
´
´
Instituto de Biotecnolog´ıa-Instituto de Ciencias Basicas, Universidad Nacional de San Juan. Av. Libertador General San Martın 1109, CP 5400, San Juan, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 April 2008
Received in revised form 13 June 2008
Accepted 16 June 2008
Available online 20 June 2008
The synthesis of novel pyrano embelin derivatives has been achieved through domino Knoevenagel
hetero Diels–Alder reactions of embelin (1) with paraformaldehyde and electron rich alkenes. This
synthetic approach is highly efficient when microwave irradiation is used.
Ó 2008 Published by Elsevier Ltd.
Keywords:
Quinones
Multicomponent reactions
Knoevenagel heteroDiels–Alderreactions
MW irradiation
1. Introduction
In addition, recent studies have shown that embelin is a fairly
potent, nonpeptidic, cell-permeable inhibitor of XIAP (X-linked
Quinonic compounds are ubiquitous in nature. They are impli-
cated in numerous cellular functions and are involved in mecha-
nisms of electron and hydrogen transfers. Quinones form a large
class of antitumor agents approved for clinical use, and many other
antitumor quinones are in different stages of clinical and preclinical
development.1 The efficiency of the quinonic compounds in
inhibiting cancer cell growth is believed to stem from their par-
ticipation in key cellular redox mechanisms with consequent gen-
eration of highly reactive oxygen species (ROS). The ROS turn out to
modify and degrade nucleic acids and proteins within the cells.2
One of the most simple 1,4-benzoquinonic compound isolated
from natural sources is embelin (1). Embelin (1) is isolated as the
main secondary metabolite from species of the Myrsinaceae3 and
Oxalidaceae4 families. Compound 1 shows a diversity of relevant
biological activities such as chemopreventive effect against DENA/
PB-induced hepatocarcinogenesis in Wistar rats,5 anti-fertility ef-
fects,6 and in vitro cytotoxic activity against B16 and XC cell lines.7
inhibitor of apoptosis protein), and it represents a promising lead
compound for designing an entirely new class of anticancer agents
that target the BIR3 domain of XIAP.8 These antecedents justify the
interest in evolving newer synthetic methods for the construction
of embelin derivatives.
We have recently published the preparation of several bis-pyr-
ano-1,4-benzoquinones following a double domino Knoevenagel
hetero Diels–Alder reaction.9 We thought that embelin is a suitable
substrate for a similar approach and, in one pot reaction in the
presence of electron rich alkenes and paraformaldehydes, a variety
of pyrano derivatives can be obtained.
2. Results and discussion
The domino Knoevenagel hetero Diels–Alder reaction (DKHDA)
is a powerful weapon in organic synthesis, especially in the area of
heterocycles and natural products.10 The most widely used hetero-
dienes are usually those where the olefinic bond is flanked between
symmetrical 1,3-dicarbonyl compounds.11 In the present work, we
were interested in the mode of cycloaddition of a heterodiene
obtained from unsymmetrical 2,5-dihydroxy-1,4-benzoquinone.
As it is illustrated in Scheme 1, there are two possible hetero-
dienesfromtheintermediate, whichwillgeneratethecorresponding
* Corresponding authors.
´
´
E-mail addresses: aestebra@ull.es (A. Estevez-Braun), agravelo@ull.es (A.G.
Ravelo).
URL: http://www.icic.es
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.06.057

S. Jime´nez-Alonso et al. / Tetrahedron 64 (2008) 8938–8942
8939
Table 2
Synthesized embelin adducts
ortho and para-pyranobenzoquinones. We found out that the
reactionofembelin,paraformaldehyde, andalkenesisregioselective,
since only 1,4-benzoquinone derivatives were obtained from the
more electron-poor heterodiene (a). These reactions are inverse
electron demand hetero Diels–Alder, and the dominating orbital
interaction (corresponding to the lowest LUMO–HOMO energy
separation) is the LUMO heterodiene–HOMO dienophile.12
Entry
Dienophile
Adduct
Yield (%)
O
O
OEt
SPh
Ph
10
HO
OEt
1
100
O
O
O
O
(a)
X
O
X
OH
O
10
10
3
O
10
(CH2O)n
HO
HO
HO
O
O
10
O
1
O
(b)
HO
SPh
Ph
2
3
89
O
O
O
10
4
HO
O
O
O
10
X
HO
81
Scheme 1.
O
The first reaction that we carried out was the reaction of
5
embelin, paraformaldehyde, and ethyl vinyl ether in dioxane as
solvent. After 24 h and reflux conditions, the corresponding adduct
was obtained in only 8% yield. Microwave irradiation has been
applied with success to cycloaddition reactions.13 Under classical
heating conditions, these reactions usually require long reaction
times, high temperatures, and/or Lewis acid catalyst resulting
in partial or total decomposition of sensitive compounds.
These problems have been conveniently overcome by the use of
microwave irradiation. The short reaction time associated with
microwave activation avoids decomposition of reagents and prod-
ucts, and prevents polymerization of the diene or dienophiles. For
all these reasons and with the aim of improving the yields, we
explored the possibility of using microwaves.
First we optimized the synthesis of the pyrano-1,4-benzoqui-
none derivative (3) from embelin (1), paraformaldehyde (2), and
ethyl vinyl ether as a model. Optimized results for this reaction are
shown in Table 1. The reaction only works with large excess of
paraformaldehyde. The ratio of reagents that produced the highest
yields was 1 equiv of embelin/3 equiv of ethyl vinyl ether/8 equiv
(CH2O)n. Different solvents were used, from good microwave
absorbers like EtOH or MeOH to solvents more or less transparent
to the microwave irradiation as toluene or dioxane. The power and
temperature were also optimized for a Discover-CEM focused mi-
crowave. We also carried out the reaction without the solvent (neat
media) (entry 8) but 3 was obtained in low yield. The best result
was achieved with EtOH (entry 3).
O
O
O
10
HO
4
83
6
O
Ph
Ph
O
O
O
10
5
50
HO
O
7
O
H
H
O
O
O
10
HO
6
7
57
76
O
O
O
8
10
HO
H
O
9
The optimized conditions described above were applied to
prepare a set of dihydropyran–embelin derivatives using several
dienophiles. The structures of the adducts (3–10) and the obtained
yields are detailed in Table 2.
The reaction proceeds normally in good yields, and tolerates
several types of electron-releasing groups in the alkene component.
O
H
H
O
10
8
74
HO
O
10
Table 1
Optimized yields and conditions for compound 3
Entry
Solvent
Power (W)
Temperature (ꢀC)
Time (min)
Yield (%)
In fact, the bicyclic pyrano-1,4-benzoquinones (3–6) were
obtained in high yield from ethyl vinyl ether, phenyl vinyl
sulfide, styrene, and 2,4,6-trimethylstyrene, respectively. The
resulting adducts present substituents of different nature (oxy-
gen, sulfur, and carbon-based substituents) at the contiguous
carbon of the heterocyclic oxygen, which will allow to examine
its influence in the biological activity when these compounds
will be tested. A moderate yield (50%) was obtained with the
1
2
3
4
5
6
7
8
DCM
DCE
185
80
110
150
123
90
150
150
150
150
150
150
150
150
20
20
20
20
20
20
20
20
50
42
99
8
56
58
27
9
EtOH
Dioxane
Toluene
MeOH
MeCN
d
200
94

8940
S. Jime´nez-Alonso et al. / Tetrahedron 64 (2008) 8938–8942
the appropriate residual solvent peak. EIMS and EIHRMS were
O
O
H
H
recorded at VG Micromass ZAB-2F. All compounds were named
using ACD40 Name-Pro program, which is based on IUPAC rules. IR
spectra were taken on a Bruker IFS28/55 spectrophotometer. The
embelin (1) used in the reactions was obtained from Oxalis eryth-
rorhiza following the procedure described in Ref. 4.
O
10
HO
H
H
Figure 1. HMBC-key correlations for 10.
4.2. Microwave irradiation experiments
chiral enol ether14 (entry 5), because the corresponding adduct
7 turned out to be unstable under purification conditions. We
were also interested in achieving pyrano-1,4-benzoquinones
with structural complexity, since moderately complex structures
are preferable lead compounds and they lead to specific binding
events involving the complete ligand molecule. In this sense,
tricyclic and tetracyclic adducts were obtained with cyclic
All microwave irradiation experiments were carried out in
a DiscoverÒ-CEM monomode microwave apparatus, operating at
a frequency of 2.45 GHz with continuous irradiation power from 0 to
300 W with utilization of the standard absorbance level of 300 W
maximum power. The reactions were carried out in 10 mL glass
tubes, sealed with aluminum/Teflon crimp tops, which can be
exposed up to 250 ꢀC and 20 bar internal pressure. Melting points
were recorded using a Buchi B540 capillary apparatus and are un-
corrected. Temperaturewasmeasured withan IR sensoronthe outer
surface of the process vial. After the irradiation period, the reaction
vessel was cooled rapidly to ambient temperature by air jet cooling.
alkenes such as 3,4-dihydro-2H-pyran (entry 6), (þ)-
a-pinene
(entry 7), and indene (entry 8). These alkenes were selected
because these motifs are present in numerous biological active
compounds.15 The structures of the synthesized compounds
were rigorously characterized by NMR techniques. In particular
the cis stereochemistry of the adducts 8 was determined by the
coupling constant (3J¼2.1 Hz) and the corresponding cis
stereochemistry of 9 was established on the basis of the NOE
4.3. General procedure for the preparation of embelin
adducts (3–10)
effect detected between the methyl group at
d 1.44 and the
multiplet at 1.90–2.72. The cis stereochemistry of the hydro-
d
2,5-Dihydroxy-1,4-benzoquinone (20 mg, 0.068 mmol), 8 equiv
of paraformaldehyde, and 3 equiv of the corresponding alkenes
were suspended in 2 mL of EtOH in a 10 mL reaction glass containing
a stirring magnet. The vial was sealed tightly with an aluminum/
Teflon crimptop. After the irradiationperiod, the reactionvessel was
cooled rapidly to ambient temperature byair jet cooling. The solvent
was removed under reduced pressure then the residue was treated
with a saturated solution of Na2S2O5 and extracted with CH2Cl2. The
combined organic extracts were washed with brine and dried over
MgSO4, filtered, and the solvent was removed under reduced pres-
sure. The residue was purified by preparative-TLC chromatography.
gens implied in the fused rings of 10 was also established by
the value of the coupling constant (3J¼5.6 Hz), as well as by the
NOE effect detected in the ROESY spectrum. The structure of 10
was also ratified on the basis of the HMBC correlations (see
Fig. 1), which established the orientation of the five-membered
ring, with the methylene opposite to the heterocycle oxygen.
3. Conclusions
In short, these findings clearly demonstrate that microwave
irradiation provides an excellent way to induce the generation of o-
quinonemethide intermediates from embelin (1) and para-
formaldehyde. These reactive intermediates give regioselective
hetero Diels–Alder cycloadditions in the presence of electron rich
alkenes to yield pyrano-1,4-benzoquinone adducts in good yields.
Biological assays of the synthesized embelin derivatives are in
progress, and they will be reported elsewhere.
4.3.1. 2-Ethoxy-6-hydroxy-7-undecyl-3,4-dihydro-2H-chromene-
5,8-dione (3)
Following the procedure described above, 20 mg of embelin
(0.068 mmol) in 2 mL of EtOH was treated with 8 equiv of para-
formaldehyde (16.3 mg, 0.54 mmol) and 3 equiv of ethyl vinyl ether
(0.019 mL, 0.20 mmol). The reaction mixture was irradiated for
20 min at a pre-selected temperature of 150 ꢀC, with an irradiation
power of 110 W. The crude was purified by preparative-TLC using
Hex/EtOAc (4:1) to provide 25.7 mg (100%) of 3 as an amorphous
yellow solid. Mp 82–84 ꢀC. Rf (Hex/AcOEt 4:1): 0.46.1H NMR (CDCl3):
4. Experimental section
4.1. General procedures
d
¼0.86 (t, 3J¼6.4 Hz, 3H),1.19 (t, 3J¼7.1 Hz, 3H),1.23 (br s,16H),1.42 (t,
All solvents and reagents were purified by Standard techniques
reported16 or used as supplied from commercial sources when ap-
propriate. Reactions were monitored by TLC (on silica gel POLY-
GRAMÒ SIL G/UV254 foils). Pre-coated TLC plates SIL G-100 UV254
(Machery-Nagel) were used for preparative-TLC purification. 1H
NMR spectra were recorded in CDCl3 or C6D6 at 300 and 400 MHz,
using Bruker AMX300 and Bruker AMX400 instruments. For 1H
spectra, chemical shifts are given in parts per million (ppm) and are
referenced to the residual solvent peak. The following abbreviations
are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. Proton assignments and stereochemistry are supported by
1H–1H COSY and ROESY when necessary. Data are reported in the
following manner: chemical shift (integration, multiplicity, coupling
constant if appropriate). Coupling constants (J) are given in hertz
(Hz) to the nearest 0.5 Hz. 13C NMR spectra were recorded at 75 and
100 MHz using Bruker AMX300 and Bruker AMX400 instruments.
Carbon spectra assignments are supported by DEPT-135 spectra,
13C–1H (HMQC) and 13C–1H (HMBC) correlations when necessary.
Chemical shifts are quoted in parts per million and are referenced to
3J¼7.0 Hz, 2H), 1.78–1.82 (m, 1H), 2.00–2.04 (m, 1H), 2.38–2.48 (m,
4H), 3.70 (dq, 2J¼9.7 Hz, 3J¼7.8 Hz,1H), 3.91 (dq, 3J¼9.1 Hz, 3J¼7.1 Hz,
1H), 5.42 (t, 3J¼2.3 Hz, 1H), 7.23 (s, 1H). 13C NMR (CDCl3):
¼13.2 (t),
d
14.0 (q), 14.9 (q), 22.4 (t), 22.6 (t), 24.9 (t), 28.0 (t), 29.2 (t), 29.3 (t),
29.52 (t), 29.55(t), 29.58(t), 29.6 (t), 31.8(t),65.0(t),98.8(d),114.6 (s),
118.4 (s),151.05 (s),152.6 (s),181.8 (s),182.4 (s). EIMS m/z (%) 378 (Mþ,
100), 350 (MþꢁCO, 39), 333 (MþꢁC2H5O, 25), 306 (MþꢁC4H8O, 8),
278 (MþꢁC4H8OꢁCO, 25), 72 (C4H8O, 41). EIHRMS: 378.2424 (calcd
for C22H34O5 (Mþ) 378.2406). Anal. Calcd for C22H34O5: C, 69.81; H,
9.05. Found: C, 69.46; H, 9.36. IR (CHCl3) nmax (cmꢁ1): 2358, 1733,
1643,1619,1461,1337,1271,1221,1165,1112,1075, 979, 926, 830, 761.
4.3.2. 6-Hydroxy-2-phenylsulfanyl-7-undecyl-3,4-dihydro-2H-
chromene-5,8-dione (4)
Following the procedure described above, 40 mg of embelin
(0.136 mmol) in 2 mL of EtOH was treated with 8 equiv of para-
formaldehyde (32.6 mg, 1.08 mmol) and 3 equiv of phenyl vinyl
sulfide (0.053 mL, 0.41 mmol). The reaction mixture was irradiated
for 20 min at a pre-selected temperature of 150 ꢀC, with an

S. Jime´nez-Alonso et al. / Tetrahedron 64 (2008) 8938–8942
8941
irradiation power of 95 W. The crude was purified by preparative-
TLC using Hex/EtOAc (4:1) to provide 53.5 mg (89%) of 4 as an
amorphous yellow solid. Mp 110–112 ꢀC. Rf (Hex/AcOEt 4:1): 0.43.
paraformaldehyde (32.6 mg, 1.08 mmol) and 3 equiv of (1R,2S)-
vinyl (82.4 mg,
ether14
0.41 mmol). The reaction mixture was irradiated for 20 min at
a pre-selected temperature of 150 ꢀC, with an irradiation power of
90 W. The crude was purified by preparative-TLC using Hex/EtOAc
(ꢁ)-trans-2-phenyl-1-cyclohexyl
1H NMR (300 MHz, CDCl3):
d
¼0.87 (t, 3J¼6.3 Hz, 3H), 1.24 (br s,
16H), 1.45 (t, 3J¼7.5 Hz, 2H), 2.19–2.26 (m, 3H), 2.40–2.45 (m, 2H),
2.54–2.60 (m, 2H), 5.81 (t, 3J¼3.7 Hz, 1H), 7.30–7.37 (m, 3H), 7.53
(dd, 3J¼5.8 Hz, 4J¼2.1 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3):
(7:3) to provide 34.3 mg (50%) of 7 as an amorphous yellow solid.
25
Mp 88–90 ꢀC. [
d
a
]
D
ꢁ6 (c 0.3, CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼13.8 (t),15.0 (q), 22.3 (t), 22.4 (t), 25.7 (t), 27.9 (t), 29.2 (t), 29.2 (t),
¼0.88 (t, 3J¼7.0 Hz, 3H), 1.18–1.22 (m, 16H), 1.36–1.59 (m, 6H),
29.3 (t), 29.39 (t), 29.41 (t), 29.42 (t), 31.6 (t), 85.0 (d), 114.2 (s), 118.5
(s), 128.0 (s) 128.9 (sꢂ2), 132.1 (s), 132.3 (sꢂ2), 150.9 (s), 152.6 (s),
181.0 (s), 182.0 (s) ppm. EIMS m/z (%): 442 (Mþ, 7), 414 (MþꢁCO, 1),
333 (MþꢁC6H5S, 100), 166 (47). EIHRMS: 442.2194 (calcd for
1.74–1.93 (m, 6H), 2.02–2.13 (m, 2H), 2.39–2.49 (m, 4H), 3.90–3.95
(m, 1H), 5.43 (t, 3J¼2.6 Hz, 1H), 7.21–7.36 (m, 5H) ppm. 13C NMR
(75 MHz, CDCl3) d: 13.0 (q),13.8 (t),14.7 (t), 22.2 (t), 22.4 (t), 23.0 (t),
23.8 (t), 24.6 (t), 24.7 (t), 25.8 (t), 27.8 (t), 29.0 (t), 29.1 (t), 29.3 (t),
29.4 (t), 31.6 (t), 33.06 (d), 34.2 (t), 62.9 (d), 74.19 (d), 98.6 (d), 114.4
(s), 118.2 (s), 126.5 (d), 127.6 (dꢂ2), 128.5 (dꢂ2), 151.7 (s), 155.3 (s),
181.6 (s), 182.2 (s) ppm. EIMS m/z (%): 508 (Mþ, 5), 378 (100), 350
(MþꢁC12H16, 40), 308 (MþꢁC14H18O, 14). EIHRMS: 508.3204 (calcd
for C32H44O5 (Mþ) 508.3206). IR (CHCl3) nmax (cmꢁ1): 1727, 1654,
1619, 1494, 1448, 1337, 1271, 1221, 1164, 1111, 1044, 926, 829, 757,
699.
C
26H34O4S (Mþ) 442.2178). Anal. Calcd for C22H34O4S: C, 70.55; H,
7.74. Found: C, 70.03; H, 7.49. IR (CHCl3) nmax (cmꢁ1): 2853, 2360,
1619, 1465, 1352, 1268, 1158, 1118, 1057, 946, 751, 690.
4.3.3. 6-Hydroxy-2-phenyl-7-undecyl-3,4-dihydro-2H-chromene-
5,8-dione (5)
Following the procedure described above, 40 mg of embelin
(0.136 mmol) in 2 mL of EtOH was treated with 8 equiv of para-
formaldehyde (32.5 mg, 1.08 mmol) and 3 equiv of styrene
(0.046 mL, 0.41 mmol). The reaction mixture was irradiated for
20 min at a pre-selected temperature of 150 ꢀC, with an irradiation
power of 67–70 W. The crude was purified by preparative-TLC using
Hex/EtOAc (7:3) to provide 45.2 mg (81%) of 5 an amorphous yel-
low solid. Mp 91–93 ꢀC. Rf (Hex/AcOEt 4:1): 0.43. 1H NMR
4.3.6. 7-Hydroxy-8-undecyl-3,4,4a,10a-tetrahydro-
2H-5H-pyrano[2,3-b]chromene-6,9-dione (8)
Following the procedure described above, 30 mg of embelin
(0.1 mmol) in 2 mL of EtOH was treated with 8 equiv of para-
formaldehyde (24.5 mg, 0.8 mmol) and 3 equiv of 3,4-dihydro-2H-
pyran (0.028 mL, 0.31 mmol). The reaction mixture was irradiated
for 20 min at a pre-selected temperature of 150 ꢀC, with an irra-
diation power of 85 W. The crude was purified by preparative-TLC
using Hex/EtOAc (4:1) to provide 22.8 mg (57%) of 8. Mp 75–77 ꢀC.
(300 MHz, CDCl3):
d
¼0.87 (t, 3J¼6.3 Hz, 3H), 1.26 (br s, 16H), 1.45 (t,
3J¼7.5 Hz, 2H), 1.98–2.03 (m, 1H), 2.23–2.26 (m, 1H), 2.40–2.46 (m,
2H), 2.52–2.55 (m, 2H), 5.15 (dd, 2J¼9.4 Hz, 3J¼2.5 Hz, 1H), 7.30–
7.37 (m, 5H), 7.41 (s,1H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼13.8 (q),
Rf (Hex/AcOEt 4:1): 0.14. 1H NMR (300 MHz, CDCl3):
d
¼0.87
17.2 (t), 22.2 (t), 22.4 (t), 27.9 (t), 29.10 (t), 29.2 (t), 29.33 (t), 29.35
(t), 29.39 (t), 29.43 (t), 29.6 (t), 31.6 (t), 79.3 (d), 113.1 (s), 118.2 (s),
125.5 (sꢂ2), 128.1 (s), 128.4 (sꢂ2), 138.7 (s), 150.9 (s), 155.2 (s), 181.3
(s), 182.1 (s) ppm. EIMS m/z (%): 410 (Mþ,100), 382 (MþꢁCO, 6), 306
(C18H26O4, 23), 104 (C8H8, 48). EIHRMS: 410.2452 (calcd for
(t,3J¼6.2 Hz, 3H), 1.24 (br s, 16H), 1.44 (t, 3J¼5.3 Hz, 2H), 1.62–1.70
(m, 5H), 2.17–2.22 (m, 1H), 2.38–2.44 (m, 4H), 3.74–3.79 (m, 1H),
3.93–3.99 (m, 1H), 5.59 (d, 3J¼2.13 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3):
d
¼13.8 (q), 22.2 (t), 22.4 (t), 23.3 (t), 23.5 (t), 27.9 (t), 29.1 (t),
29.2 (tx2), 29.32 (t), 29.35 (t), 29.38 (t), 29.4 (t), 30.3 (d), 31.6 (t),
65.0 (d), 111.5 (s), 115.0 (s), 118.3 (s), 150.8 (s), 153.0 (s), 181.0 (s),
182.3 (s). EIMS m/z (%): 390 (Mþ, 100), 362 (MþꢁCO, 6), 308
(C18H28O4, 10), 306 (MþꢁC5H8O, 4), 84 (C5H8O, 51). EIHRMS:
390.2405 (calcd for C23H34O5 (Mþ) 390.2406). Anal. Calcd for
C
26H34O4 (Mþ) 410.2457). IR (CHCl3) nmax (cmꢁ1): 1652, 1616, 1496,
1455, 1405, 1351, 1268, 1210, 1121, 1061, 1035, 953, 757, 698.
4.3.4. 6-Hydroxy-2-(2,4,6-trimethyl-phenyl)-7-undecyl-
3,4-dihydro-2H-chromene-5,8-dione (6)
C23H34O5: C, 70.74; H, 8.78. Found: C, 70.96; H, 8.78. IR (CHCl3) nmax
Following the procedure described above, 20 mg of embelin
(0.068 mmol) in 2 mL of EtOH was treated with 8 equiv of para-
formaldehyde (16.3 mg, 0.54 mmol) and 3 equiv of 2,4,6-trime-
thylstyrene (0.032 mL, 0.20 mmol). The reaction mixture was
irradiated for 20 min at a pre-selected temperature of 150 ꢀC, with
an irradiation power of 67–70 W. The crude was purified by pre-
parative-TLC using Hex/EtOAc (4:1) to provide 25.4 mg (83%) of 6 as
an amorphous orange solid. Mp 89–91 ꢀC. Rf (Hex/AcOEt 4:1): 0.51.
(cmꢁ1): 2854, 2360, 1655, 1620, 1464, 1340, 1284, 1255, 1192, 1148,
1122, 1079, 1030, 916, 853, 758.
4.3.7. Adduct obtained from the reaction of 2,5-dihydroxy-
benzoquinone with (þ)-
a-pinene (9)
Following the procedure described above, 30 mg of embelin
(0.10 mmol) in 2 mL of EtOH was treated with 8 equiv of para-
formaldehyde (24.5 mg, 0.82 mmol) and 3 equiv of (1R)-(þ)-
a-
1H NMR (300 MHz, CDCl3):
d
¼0.87 (t, 3J¼6.4 Hz, 3H), 1.25 (br s,
pinene (0.3 mmol, 0.04 mL). The reaction mixture was irradiated
for 20 min at a pre-selected temperature of 150 ꢀC, with an ir-
radiation power of 80 W. The crude was purified by preparative-
16H), 1.44 (t, 3J¼7.4 Hz, 2H), 2.05–2.09 (m, 2H), 2.20 (s, 3H), 2.22 (s,
6H), 2.21–2.30 (m, 3H), 2.74 (dd, J¼17.6, 3.8 Hz, 1H), 5.38 (dd,
J¼11.5, 2.8 Hz, 1H), 6.84 (s, 2H), 7.29 (s, 1H) ppm. 13C NMR (75 MHz,
TLC using Hex/EtOAc (4:1) to provide 34.9 mg (76%) of 9 as an
25
CDCl3):
d
¼13.8 (q), 18.2 (t), 20.1 (qꢂ2), 20.56 (t), 22.2 (t), 22.4 (t),
amorphous yellow solid. Mp 78–80 ꢀC. [
a]
ꢁ250 (c 0.2, CHCl3).
D
24.3 (t), 27.9 (t), 29.1 (t), 29.2 (t), 29.3 (t), 29.38 (t), 29.4 (tꢂ2), 31.6
(t), 78.0 (d), 113.0 (s), 118.1 (s), 130.0 (dꢂ2), 131.3 (s), 135.6 (sꢂ2),
137.4 (s), 151.0 (s), 155.3 (s), 181.2 (s), 182.1 (s). EIMS m/z (%): 452
(Mþ, 85), 424 (MþꢁCO, 9), 308 (C18H28O4, 18), 306 (MþꢁC11H14, 3).
EIHRMS: 452.2946 (calcd for C29H40O4 (Mþ) 452.2927). Anal. Calcd
for C29H40O4: C, 76.95; H, 8.91. Found: C, 76.85; H, 8.55. IR (CHCl3)
nmax (cmꢁ1): 2360, 2338, 1731, 1654, 1575, 1463, 1355, 1283, 1237,
1129, 1009, 962, 858, 759, 670.
1H NMR (300 MHz, CDCl3):
d
¼0.70 (d, 3J¼10.6 Hz, 2H), 0.86 (t,
3J¼6.3 Hz, 3H), 1.08 (s, 3H), 1.23 (br s, 14H), 1.30 (s, 3H), 1.44 (s,
3H), 1.90–2.72 (m, 14H). 13C NMR (75 MHz, CDCl3):
d
¼13.8 (q),
19.2 (t), 22.2 (q), 22.3 (q), 22.4 (t), 27.8 (t), 28.2 (q), 28.7 (t),
29.10 (t), 29.15 (t), 29.3 (tꢂ2), 29.4 (tꢂ3), 31.0 (q), 31.6 (t), 34.7
(t), 39.7 (s), 40.4 (q), 54.4 (q), 87.7 (s), 110.3 (s), 117.6 (s), 151.0
(s), 155.8 (s), 181.2 (s), 182.2 (s). EIMS m/z (%): 422 (Mþ, 80), 427
(MþꢁMe, 8), 399 (427ꢁMe, 9), 308 (C18H28O4, 100). EIHRMS:
442.3068 (calcd for C28H42O4 (Mþ) 442.3083). Anal. Calcd for
4.3.5. 6-Hydroxy-2-(2-phenyl-cyclohexyloxy)-7-undecyl-
3,4-dihydro-2H-chromene-5,8-dione (7)
Following the procedure described above, 40 mg of embelin
(0.136 mmol) in 2 mL of EtOH was treated with 8 equiv of
C28H42O4: C, 75.48; H, 9.56. Found: C, 75.10; H, 9.35; O, 15.55. IR
(CHCl3) nmax (cmꢁ1): 2362, 1728, 1657, 1617, 1461, 1359, 1338,
1301, 1282, 1224, 1151, 1128, 1089, 1010, 962, 864, 833, 759, 722,
663, 631.

8942
S. Jime´nez-Alonso et al. / Tetrahedron 64 (2008) 8938–8942
2. (a) Waris, G.; Ahsan, H. J. Carcinog. 2006, 5, 14; (b) Shiah, S. G.; Chuang, S. E.;
Chau, Y. P.; Shen, S. C.; Kuo, M. L. Cancer Res. 1999, 59, 391–398.
3. (a) Haq, K.; Ali, M.; Siddiqui, A. W. Pharmazie 2005, 60, 69–71; (b) Raja, S.;
Unnikrishnan, K. P.; Ravindran, P. N.; Balachandran, I. Indian J. Pharm. Sci. 2005,
67, 734–736.
4.3.8. 8-Hydroxy-7-undecyl-4b,10,10a,11-tetrahydro-indeno-
[1,2-b]chromene-6,9-dione (10)
Following the procedure described above, 20 mg of embelin
(0.068 mmol) in 2 mL of EtOH was treated with 8 equiv of para-
formaldehyde (16.3 mg, 0.54 mmol) and 3 equiv of indene
(0.023 mL, 0.2 mmol). The reaction mixture was irradiated for
20 min at a pre-selected temperature of 150 ꢀC, with an irradiation
power of 70–76 W. The crude was purified by preparative-TLC using
Hex/EtOAc (7:3) to provide 21.2 mg (74%) of 11 as an amorphous
orange solid. Mp 97–99 ꢀC. Rf (Hex/EtOAc 4:1): 0.44. 1H NMR
4. Ferensin, G. E.; Tapia, A.; Sortino, M.; Zacchino, S.; Rojas de Arias, A.; Inchausti,
´
A.; Yaluff, G.; Rodrıguez, J.; Theoduloz, C.; Schmeda-Hirschmann, G. J. Ethno-
pharmacol. 2003, 88, 241–247.
5. Sreepriya, M.; Bali, G. Fitoterapia 2005, 76, 549–555.
6. Wango, E. O. Acta Biol. Hung. 2005, 56, 1–9.
7. Podolak, I.; Galanty, A.; Janeczko, Z. Fitoterapia 2005, 76, 333–335.
8. (a) Nikolovska-Coleska, Z.; Xu, L.; Hu, Z.; Tomita, Y.; Li, P.; Roller, P. P.; Wang, R.;
Fang, X.; Guo, R.; Zhang, M.; Lippman, M. E.; Yang, D.; Wang, S. J. Med. Chem.
2004, 47, 2430–2440; (b) Chen, J.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.;
Wang, S. Bioorg. Med. Chem. Lett. 2006, 16, 5805–5808.
(300 MHz, CDCl3)
d
: 0.87 (t, 3J¼6.3 Hz, 3H), 1.24 (br s, 16H), 1.42 (t,
3J¼6.9 Hz, 2H), 2.21 (dd, 2J¼17.8 Hz, 3J¼5.3 Hz, 1H), 2.38–2.43 (m,
2H), 2.70–2.88 (m, 3H), 3.09 (dd, 2J¼14.5 Hz, 3J¼5.0 Hz, 1H), 5.63 (d,
´
´
´
9. Jimenez-Alonso, S.; Estevez-Braun, A.; Ravelo, A. G.; Zarate, R.; Lopez, M.
Tetrahedron 2007, 63, 3066–3074.
3J¼5.0 Hz, 1H), 7.22–7.33 (m, 3H), 7.52 (d, 3J¼6.8 Hz, 1H) ppm. 13
C
10. (a) Tietze, L. F.; Brumby, T.; Pretor, M.; Remberg, G. J. Org. Chem. 1988, 53, 810;
(b) Tietze, L. F.; Siegbert, B.; Brumby, T.; Pretor, M.; Remberg, G. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 665; (c) Tietze, L. F.; Bratz, M.; Machinek, R.; Kiedrowski,
G. J. Org. Chem. 1987, 52, 1638–1640; (d) Multicomponent Reactions; Zhu, J.,
Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005; Chapter 5, pp 121-168.
11. (a) Simon, C.; Constantieux, T.; Rodrı´guez, J. Eur. J. Org. Chem. 2004, 4957–4980;
(b) Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 47–69 and references cited therein.
12. (a) Wang, H.; Wang, Y.; Han, K. L.; Peng, X. J. J. Org. Chem. 2005, 70, 4910–4917;
(b) Boger, D. L.; Weinreb, S. N. Hetero Diels–Alder Methodology in Organic Syn-
thesis; Academic: New York, NY, 1987; (c) Carruthers, W. Cycloaddition Reactions
in Organic Synthesis; Pergamon: Oxford, 1990; (d) Fringelli, F.; Taticchi, A. The
Diels–Alder reaction: Selected Practical Methods; John Wiley and Sons: West
Sussex, 2002.
NMR (75 MHz, CDCl3):
d¼13.9 (q), 18.8 (t), 22.3 (t), 22.5 (t), 29.1 (t),
29.2 (t), 29.3 (t), 29.4 (tꢂ3), 29.6 (t), 31.7 (t), 34.9 (d), 36.2 (t), 81.2
(d), 111.2 (s), 117.9 (s), 124.9 (d), 125.4 (d), 126.9 (d), 129.2 (d), 140.6
(s), 141.4 (s), 151.0 (s), 154.8 (s), 181.3 (s), 182.2 (s). EIMS m/z (%): 422
(Mþ, 51), 394 (MþꢁCO, 2), 308 (C18H28O4, 18), 168 (C8H8O3, 19), 84
(C5H8O, 51), 116 (C9H8, 100). HREIMS: 442.2455 (calcd for C27H34O4
(Mþ) 442.2457). Anal. Calcd for C27H34O4: C, 76.74; H, 8.11. Found: C,
76.85; H, 8.55. IR (CHCl3) nmax (cmꢁ1): 2853, 2361, 1652, 1619, 1462,
1352, 1299, 1252, 1222, 1191, 1122, 1070, 1021, 954, 879, 835, 754.
13. (a) Kappe, C. O.; Stadler, A. Methods and Principles in Medicinal Chemistry: Mi-
crowaves in Organic and Medicinal Chemistry; Wiley-VCH: Weinheim, Germany,
2005; Vol. 25; (b) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (c)
De la Hoz, D.; Diaz-Ortiz, A.; Moreno, A. Curr. Org. Chem. 2004, 8, 903–918; (d)
Nu¨chter, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004, 6, 128–
141; (e) Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2002; (f) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225–9283; (g) Varma, R. S. Green Chem. 1999, 1, 43–55; (h) Perreux,
L.; Loupy, A. Tetrahedron 2001, 57, 9199–9346.
14. The chiral enol ether was synthesized as described in the following references:
(a) Denmark, S. E.; Schnute, M. E. J. Org. Chem. 1991, 56, 6738–6739; (b) Clark,
R. C.; Pfeiffer, S. S.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 2587–2593.
15. Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach, 2nd ed.;
Wiley: New York, NY, 2002.
Acknowledgements
This work has been funded by the Spanish MCYT (SAF2006-
06720) and by ICIC. S.J.-A. thanks the MCYT for a predoctoral
fellowship. We thank Dr. Garcıa-Tellado for granting access to the
´
microwave apparatus.
References and notes
16. Perrin, D. D.; Amarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.;
Pergamon: Oxford, 1988.
´
´
´
1. Ravelo, A. G.; Estevez-Braun, A.; Chavez-Orellana, H.; Perez-Sacau, E.; Mesa-
Siverio, D. Curr. Top. Med. Chem. 2004, 4, 241–265.