An efficient synthesis of novel tetrahydrochromeno[2,3-b]chromenes

Article abstract of DOI:10.1016/j.tetlet.2010.05.025

A series of novel tetrahydrochromeno[2,3-b]chromenes is synthesized via the acid-catalyzed dimerization reactions of 5-methoxy- or 6-methoxyflavenes. A rational mechanism for the observed rearrangement is proposed.

Full text of DOI:10.1016/j.tetlet.2010.05.025

Tetrahedron Letters 51 (2010) 3636–3638
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Tetrahedron Letters
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An efficient synthesis of novel tetrahydrochromeno[2,3-b]chromenes
*
Ruth Devakaram, David StC. Black, Naresh Kumar
School of Chemistry, The University of New South Wales, UNSW, Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel tetrahydrochromeno[2,3-b]chromenes is synthesized via the acid-catalyzed dimeriza-
tion reactions of 5-methoxy- or 6-methoxyflavenes. A rational mechanism for the observed rearrange-
ment is proposed.
Received 16 March 2010
Revised 27 April 2010
Accepted 7 May 2010
Available online 12 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Flavene dimers
Acid-catalyzed dimerization
Tetrahydrochromeno[2,3-b]chromenes
MeO
OMe
OMe
Phytoestrogens are naturally occurring, non-steroidal com-
pounds present in legumes, grains and seasonings. The daily con-
OMe
OMe
H
O
MeO
sumption of phytoestrogens has been suggested to play
a
H
H
protective role against cancer growth.1 Flavonoids are a particu-
larly widely studied class of phytoestrogens that are found
throughout the plant kingdom.
O
H
Many flavonoids exist as dimers, comprising identical or non-
identical units joined symmetrically or non-symmetrically through
various linkages.2 Despite their interesting range of biological
activities, their use as therapeutic agents has been limited by their
low abundance in nature, tedious extraction and purification pro-
cedures and scarce availability of biological data. Thus, there exists
a need for the development of efficient synthetic methodologies for
these compounds.
Dependensin (1) is a typical example of a dimeric flavonoid iso-
lated from the root bark of the Tanzanian medicinal plant, Uvaria
dependens, whose crude extract shows potent anti-malarial activ-
ity.3 The heterocyclic ring system present in dependensin, a benzo-
pyrano[4,3-b]benzopyran, is quite unique and contains an
assortment of functionality and stereochemistry, including two
fused benzopyran ring systems, four stereocentres and one trans
double bond.3
Dependensin (1)
As part of our study on the synthesis of these dimeric systems,
we have investigated the acid-catalyzed reactions of 5-methoxy-,
6-methoxy- and 7-methoxyflavenes. Interestingly, instead of the
expected dependensin analogues, a series of novel tetrahydrochro-
meno[2,3-b]chromenes was obtained from the acid-catalyzed
dimerization reactions of 5-methoxy- and 6-methoxyflavenes.
The Claisen–Schmidt condensation of 20-hydroxy-50-methoxy-
acetophenone or 20-hydroxy-60-methoxyacetophenone with para-
substituted benzaldehydes using sodium hydroxide as the base
in ethanol furnished the intermediate chalcones 2a–i in moderate
to good yields. These chalcones were then subjected to sodium
Biosynthetically, dependensin was suggested by Nkunya et al.
to originate from the acid-catalyzed dimerization of 5,7,8-trimeth-
oxyflavene, but they were unable to verify this experimentally,
obtaining a ring-opened product instead of dependensin.3 How-
ever, our group has recently demonstrated the synthesis of depen-
densin via this route.4
R2
O
R2
R1
NaBH4, IPA, 12 h, rt
R1
OH
65-80%
R
O
R
2a-i
3a-i
* Corresponding author. Tel.: +61 2 9385 4698; fax: +61 2 9385 6141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.025

R. Devakaram et al. / Tetrahedron Letters 51 (2010) 3636–3638
3637
borohydride reduction5 in isopropanol to yield the desired 5-meth-
oxy- or 6-methoxyflav-3-enes (3a–i) in 65–80% yield (Scheme 1).6
In general, we observed that flavenes 3a, 3d, 3e, 3h and 3i bear-
ing electron-donating or electronically neutral groups were formed
in better yields when compared to the flavenes 3b, 3c, 3f and 3g
bearing electron-withdrawing groups (Table 1). The flavenes so ob-
tained were either low melting white solids or yellow oily residues.
Previous research in our group has demonstrated the acid-cata-
lyzed reaction of 40,7-diacetoxyflav-3-ene to yield the benzopyr-
ano[4,3-b]benzopyran ring system present in the natural product,
dependensin.4 Similar reactions of 7-methoxyflavenes also yielded
the same ring system, but the related 40,5-diacetoxy- and 40,6-
diacetoxyflavenes did not. However, it has been observed that
the 6-methoxyflavenes 3a–d underwent a completely different
reaction to yield the tetrahydrochromeno[2,3-b]chromenes 4a–d.
The 1H NMR spectrum of compound 4b showed the presence of
four aliphatic protons corresponding to H11, H11a and H12 be-
tween d 2.84 and d 3.46. The protons on the trans double bond,
Figure 1. ORTEP diagram of compound 4b.
H
a
and Hb appeared as a doublet of doublets and a doublet at d
6.24 (J = 9.8 Hz, 15.8 Hz) and d 6.47 (J = 15.8 Hz), respectively.7
The HMBC experiment showed two-bond and three-bond proton
to carbon couplings from the four aliphatic protons to C5a at d
100.4. DEPT-135 along with a broadband decoupled 13C NMR spec-
trum indicated the presence of one CH2 group in the structure.
A single crystal of compound 4b was obtained for X-ray crystal-
lographic analysis8 (Fig. 1), further confirming the structure
indicated.
R
H+/MeOH
O
O
MeO
5a
This unique structure consists of two symmetrically fused benz-
opyran units, flanked by the two aromatic rings on either side of
the fused ring system together with an exocyclic trans double
bond.
H
11a
MeO
OMe
O
11
H
α
H
H
12
β
R
3a-d
By correlation of the 1H NMR and 13C NMR spectra, the other di-
meric products 4a, 4c and 4d resulting from the acid-catalyzed
reactions of 6-methoxyflavenes 3a, 3c and 3d were concluded to
contain the same structure (Scheme 2).
4a-d
R
Scheme 2.
The reaction mechanism for the formation of this new dimeric
system is thought to involve the protonation of the flavene 5, fol-
lowed by ring-opening and formation of the stabilized benzylic
carbocation intermediate 6. A second molecule of the flav-3-ene
can isomerize in situ to the corresponding flav-2-ene 7 under
acidic conditions and attack the carbocation intermediate 6 giving
another stable benzylic intermediate 8, which can then undergo
cyclization to give the dimer 4b (Scheme 3).
MeO
MeO
H+
O
O
H
MeOH
3b
Br
Br
In a similar fashion, the acid-catalyzed reactions of 5-methoxy-
flav-3-enes 3e–i gave the tetrahydrochromeno[2,3-b]chromenes
9a–e (Scheme 4). The dimerization reaction mechanism is believed
to be similar to the pathway taken by the 6-methoxyflavenes.
The dimeric flavonoids 4a–d and 9a–e were obtained in moder-
ate to good yields (Table 2). The identity and purity of all com-
pounds were confirmed by 1H and 13C NMR spectroscopy, IR
spectroscopy, mass spectrometry, thin layer chromatography and
elemental analyses.
5
HO
OMe
OMe
O
6
7
Br
Br
Br
Br
Table 1
Synthesis of 5-methoxy- and 6-methoxyflavenes
Chalcone
R1
R2
R
Flavene
Yielda (%)
H
O
O
O
O
2a
2b
2c
2d
2e
2f
2g
2h
2i
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
H
Br
Cl
Me
H
Br
Cl
OMe
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
72
65
68
74
77
70
70
80
79
MeO
OMe
MeO
OMe
4b
8
Br
Br
a
Yield of isolated pure product.
Scheme 3.

3638
R. Devakaram et al. / Tetrahedron Letters 51 (2010) 3636–3638
2. Ma, X.; Liua, Y.; Shi, Y. Chem. Biodivers. 2007, 4, 2172–2181.
R
3. Nkunya, M. H. H.; Waibel, R.; Achenbach, H. Phytochemistry 1993, 34, 853–856.
4. Deodhar, M.; Black, D. StC.; Kumar, N. Tetrahedron 2007, 63, 5227–5235.
5. Clark-Lewis, J. W.; Jemison, R. W. Aust. J. Chem. 1968, 21, 2247–2254.
6. Representative procedure for 5-methoxy- and 6-methoxy-flav-3-enes 3b: The
chalcone 2b (1.0 g, 3.00 mmol) was dissolved in isopropanol (25 mL) at 50 °C,
and NaBH4 (9.00 mmol) was slowly added. The reaction mixture was then
cooled to room temperature and allowed to stir overnight. The solvent was
evaporated, ice was added and the resulting solution was acidified using 10%
glacial AcOH to pH 5. The solution was extracted with CH2Cl2, and the organic
layer was washed with brine, dried over anhydrous Na2SO4 and evaporated.
Purification of the residue by column chromatography over silica gel (20%
CH2Cl2/hexane) eluted the flavene 3b as a white solid (0.62 g, 65%); mp 98–
OMe
H+/MeOH
O
H
O
H
O
H
H
OMe
R
OMe
R
3e-i
100 °C; UV (MeOH): kmax 202 (
nm; IR (KBr): max 3441, 3006, 2958, 2931, 2831, 1608, 1580, 1490, 1462, 1427,
1271, 1219, 1152, 1028, 971, 821 cmꢀ1 1H NMR (300 MHz, CDCl3): 3.76 (s, 3H,
e
34,171 cmꢀ1 Mꢀ1), 232 (39,101), 330 (4329)
9a-e
m
;
CH3O), 5.80 (dd, J = 3.0, 10.9 Hz, 1H, H3), 5.83 (dd, J = 1.5 Hz, 3.0 Hz, 1H, H2),
6.52 (dd, J = 1.5 Hz, 10.9 Hz, 1H, H4), 6.61 (d, J = 3.0 Hz, 1H, H5), 6.68 (dd,
J = 3.0 Hz, 8.7 Hz, 1H, H7), 6.74 (d, J = 8.7 Hz, 1H, H8), 7.32 (d, J = 8.3 Hz, 2H, H20,
H60), 7.49 (d, J = 8.3 Hz, 2H, H30, H50); 13C NMR (75.6 MHz, CDCl3): d 55.6 (CH3O),
76.0 (C2), 111.8 (C5), 114.6 (C7), 116.5 (C8), 121.8 (C4a), 122.2 (C40), 124.5 (C4),
125.1 (C3), 128.7 (C20, C60), 131.7 (C30, C50), 139.6 (C10), 146.7 (C8a), 154.1 (C6);
MS (ESI) m/z [M+1]+ 316.95 (100%); Anal. Calcd for C16H13BrO2: C, 60.59; H, 4.13.
Found: C, 60.82; H, 4.26.
Scheme 4.
Table 2
Dimerization products of 5-methoxy- and 6-methoxyflavenes
Flavene
R
Chromeno-chromene
Yielda (%)
7. Representative procedure for the synthesis of dimer 4b: The flavene 3b (0.10 g,
0.32 mmol) was dissolved in MeOH (20 mL), 10 drops of acid (10 M HCl, TFA or
glacial AcOH) were added and the solution was heated to 60–70 °C for 12 h. The
solvent was partially removed under reduced pressure, and EtOAc was added.
The organic layer was washed with saturated NaHCO3 solution, dried over
anhydrous Na2SO4 and evaporated. Purification of the crude product by column
chromatography over silica gel (50% CH2Cl2/hexane) eluted the dimer 4b as a
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
Br
Cl
Me
H
Br
Cl
OMe
Me
4a
4b
4c
4d
9a
9b
9c
9d
9e
70
73
74
72
75
69
72
58
56
white solid (0.15 g, 73%); mp 212–214 °C; UV (MeOH): kmax 203
(e
61,384 cmꢀ1 Mꢀ1), 220 (35,949), 230 (28,486), 263 (34,167), 291 (17,870), 299
(12,616) nm; IR (KBr): mmax 3444, 3006, 2929, 2833, 1615, 1489, 1464, 1427,
1275, 1230, 1200, 1154, 1041, 971, 951, 803 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
a
Yield of isolated pure product.
2.84 (s, 3H, H11a, H12), 3.46 (dd, J = 3.4 Hz, 9.8 Hz, 1H, H11), 3.70 (s, 3H, CH3O),
3.73 (s, 3H, CH3O), 6.24 (dd, J = 9.8 Hz, 15.8 Hz, 1H, H ), 6.47 (d, J = 15.8 Hz, 1H,
a
Hb), 6.55 (d, J = 2.3 Hz, 1H, H10), 6.60 (d, J = 3.0 Hz, 1H, H1), 6.72 (dd, J = 3.0 Hz,
8.6 Hz, 1H, H3), 6.80 (dd, J = 2.3 Hz, 8.3 Hz, 1H, H8), 6.87 (d, J = 8.6 Hz, 1H, H4),
6.96 (d, J = 8.3 Hz, 1H, H7), 7.24 (d, J = 8.6 Hz, 2H, H200, H600), 7.37 (d, J = 8.3 Hz,
2H, H30, H50), 7.41 (d, J = 8.3 Hz, 2H, H20, H60), 7.44 (d, J = 8.6 Hz, 2H, H300, H500);
13C NMR (75.6 MHz, CDCl3): d 23.6 (C12), 37.8 (C11a), 42.3 (C11), 55.5 (CH3O),
55.6 (CH3O), 100.4 (C5a), 113.6 (C1), 113.7 (C10), 114.0 (C3), 114.4 (C8), 117.2
(C7), 117.5 (C4), 121.3 (C40), 121.6 (C12a), 122.1 (C10a), 123.1 (C400), 125.8 (C200,
In summary, an efficient methodology for the synthesis of a ser-
ies of tetrahydrochromeno[2,3-b]chromenes has been developed
via the acid-catalyzed dimerization reactions of 6-methoxy- and
5-methoxyflavenes.
C600), 127.8 (C20, C60), 128.5 (C ), 131.6 (C30, C50), 131.7 (C300, C500), 133.2 (Cb),
a
135.4 (C10), 139.5 (C100), 145.5 (C4a), 145.9 (C6a), 154.2 (C9), 154.3 (C2); HRMS
(ESI) m/z calcd for C32H26Br2O4Na (M+Na)+ 655.0098. Found 655.0086; Anal.
Calcd for C32H26Br2O4: C, 60.59; H, 4.13. Found: C, 60.32; H, 4.13.
8. Crystallographic data for the structure of compound 4b have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 769425. The X-ray crystal structure was obtained by Don Craig,
Crystallography Laboratory, Analytical Centre, The University of New South
Wales, Sydney, Australia.
Acknowledgements
We thank the University of New South Wales and the Australian
Research Council for their financial support.
References and notes
1. Adlercreutz, H. Lancet Oncol. 2002, 3, 364–373.