Synthesis of oxygenated 4-arylisoflavans and 4-arylflavans

Article abstract of DOI:10.1016/j.tetlet.2012.09.117

Oxygenated 4-arylisoflavans and 4-heteroarylisoflavans were synthesized in good yields via BF₃·OEt₂ catalyzed arylation reactions of 4′,7-diacetoxyisoflavan-4-ol 8 with activated aryl and heteroaryl compounds. These reactions were found to produce stereoselectively the trans isomers. Similar reactions of 4′,7-diacetoxyflavan-4-ol 16 afforded the corresponding 4-arylflavans and 4-heteroarylflavans as mixtures of cis/trans isomers.

Full text of DOI:10.1016/j.tetlet.2012.09.117

Tetrahedron Letters 53 (2012) 6697–6700
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of oxygenated 4-arylisoflavans and 4-arylflavans
⇑
Mandar Deodhar, Kasey Wood, David StC Black, Naresh Kumar
School of Chemistry, The University of New South Wales, 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:
Received 12 July 2012
Revised 7 September 2012
Accepted 25 September 2012
Available online 2 October 2012
Oxygenated 4-arylisoflavans and 4-heteroarylisoflavans were synthesized in good yields via BF3ꢀOEt2 cat-
alyzed arylation reactions of 40,7-diacetoxyisoflavan-4-ol 8 with activated aryl and heteroaryl com-
pounds. These reactions were found to produce stereoselectively the trans isomers. Similar reactions of
40,7-diacetoxyflavan-4-ol 16 afforded the corresponding 4-arylflavans and 4-heteroarylflavans as mix-
tures of cis/trans isomers.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
4-Arylisoflavans
4-Arylflavans
The flavonoids are a very well known family of natural prod-
ucts.1–3 They are found extensively throughout the plant kingdom
and play a vital role in the ecology of plants. They have received
considerable attention on account of their medicinal properties,4
such as antioxidant,5 anti-inflammatory,6 gastroprotective,7 antivi-
ral,8 antimutagenic,9 topoisomerase II inhibitory,10 protein kinase
C inhibitory,11 and cytotoxic activities.12–14 Kumar and Heaton
have demonstrated that dimeric isoflavonoid compounds with
the general formulae as depicted in 1 show potent anticancer
activity toward a variety of cancer cell lines.15 Similar biologically
active compounds can be found in the 4-arylflavan series as well.
For example, Hecht et al.16 have described compound 2 and its
atropisomer as potent DNA polymerase b inhibitors.
Although there are several examples of naturally occurring di-
meric flavonoids with potent activity against various pathogenic
conditions, their use as medicaments has been severely limited
due to their low abundance in plant material, tedious methods of
extraction and purification, and unavailability of appropriate bio-
logical data. The development of efficient synthetic methodologies
to generate these systems is therefore necessary in order to exploit
fully their medicinal potential.
4-Arylflavanoids have been previously synthesized17–19 by
condensation of isoflavanols with phenols in the presence of
aluminum trichloride, through treatment of isoflavanones with
Grignard reagents and subsequent hydrogenation, through the
reaction of 4-haloflavans with potassium salts of phenolic
compounds and by reactions of flavans with 4-benzylthioflavans
in the presence of silver tetrafluoroborate. However, these method-
ologies cannot be easily adopted for the synthesis of highly
oxygenated flavones or isoflavones due to their low yields, and
structure activity studies have shown that the oxygenation pattern
is very important for biological activity.
OH
OH
O
Ph
8
O
Herein we report the efficient synthesis of oxygenated
4-arylisoflavans and 4-arylflavans via the acid-catalyzed reaction
of isoflavonols and flavanols with activated aromatic and heteroar-
omatic compounds.
HO
OH
OH
HO
HO
O
The precursor to the targeted 4-arylisoflavones, diacetoxyisof-
lavanol 8, was synthesized in four steps using standard isoflavone
synthetic methods20 as outlined in Scheme 1. Resorcinol (3) was
reacted with 4-hydroxyphenylacetic acid (4) in the presence of
boron trifluoride-diethyl etherate (BF3ꢀOEt2) to give deoxybenzoin
5 in 73% yield. Deoxybenzoin 5 was then cyclized by heating with
triethyl orthoformate in the presence of pyridine and piperidine to
give daidzein (40,7-dihydroxyisoflavone) (6) in 67% yield. Daidzein
(6) was acetylated using acetic anhydride/pyridine prior to cata-
lytic hydrogenation with palladium on carbon in order to prevent
2
OH
HO
O
1
⇑
Corresponding author. Tel.: +61 293854698; fax: +61 293856141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.117

6698
M. Deodhar et al. / Tetrahedron Letters 53 (2012) 6697–6700
OAc
OH
HC(OEt)3
R
OH
O
O
O
HO
HO
OH
BF3·OEt2
H2, Pd/C
3
4
EtOH, 90%
110 °C, 73 %
Pyridine,
Piperidine
67%
AcO
HO
OH
R
O
COOH
8
5
Ac2O
Pyridine
90%
6 R = OH
cis:trans
2:1
7
R = OAc
Scheme 1.
OAc
R
Ar
OH
BF3·OEt2
CH2Cl2, r.t.
+ ArH
AcO
O
8
R
O
9
R = OAc
R = OH
1 M KOH
MeOH
10
Scheme 2.
Table 1
Synthesis of 4-aryl and 4-heteroarylisoflavans
Entry Ar
Isoflavan
Yield (%) 10
9
Yield (%)
O
OMe
OH
1
2
3
4
9a 67
9b 28
9c 29
9d 46
9e 81
10a 84
HO
O
10b 95
10c 94
10d 64
10e 68
Figure 1. ORTEP diagram of 4-heteroarylisoflavan 10 g.
MeO
OH
self coupling of the isoflavanol when later preparing the 4-aryl sys-
tems. 40,7-Diacetoxyisoflavan-4-ol 8 was obtained in 90% yield as a
2:1 cis:trans mixture of isomers, which was not separated, as deter-
mined by 1H NMR spectroscopy.
Isoflavanol 8 was then reacted with 2-hydroxy-6-methoxyace-
tophenone in the presence of BF3ꢀOEt2 at room temperature for
1 h.21 After aqueous work-up, the crude product was column chro-
matographed to give isoflavan 9a in 67% yield (Scheme 2, Table 1,
entry 1). The trans stereochemistry of the product was established
on the basis of the coupling constant of 7.2 Hz between the H3 and
H4 protons, and there was a noted absence of any NOE correlation
between the H3 and H4 protons. Substitution of the acetophenone
ortho to the hydroxyl group was established through the presence
of an NOE correlation between the methoxy group and its adjacent
aromatic proton, indicating a C4–C300 connection between the
isoflavan and 2-hydroxy-6-methoxyacetophenone units. The cor-
responding 40,7-dihydroxy analogue 10a was subsequently
prepared in 84% yield by hydrolyzing the acetoxy groups using
1 M KOH solution.
Exclusive formation of the trans product was an interesting
outcome because it was expected that the incoming nucleophile
could possibly attack from either side of the carbocation interme-
diate, and as a result produce a mixture of cis and trans isomers.
Formation of the trans product only is therefore rationalized by
the presence of the C3 aryl group, which directs the attack of the
incoming nucleophile to the opposite side of the intermediate
carbocation due to steric hindrance. Thus the BF3ꢀEt2O-catalyzed
arylation reaction was found to be stereoselective and although a
mixture of cis and trans isomers of the starting isoflavanol 8 was
employed, only the trans product was obtained in good yield.
OMe
OMe
MeO
OH
OH
MeO
MeO
5
6
7
9f
65
10f
80
OH
OMe
Br
MeO
9g 43
10g 83
10h 80
O
OMe
Ph
8
9
9h 75
Ph
N
H
MeO
MeO
O
9i
77
10i
74
OMe

M. Deodhar et al. / Tetrahedron Letters 53 (2012) 6697–6700
6699
O
O
O
OH
O
aq. KOH
HO
HO
OH
O
Conc. HCl, MeOH
H2, Pd/C
11
12
HO
OH
100 °C, 65%
R
O
reflux, 62%
EtOH, 90%
AcO
OH
H
R
16
13
OAc
Ac2O
Pyridine
90%
14
15
R = OH
R = OAc
Scheme 3.
obtained as the trans isomers in 74–83% yields (Table 1, entries
7–9).
OH
Ar
O
BF3·OEt2
CH2Cl2, r.t.
The trans 4-arylisoflavans and 4-heteroarylisoflavans were sub-
sequently hydrolyzed using 1 M KOH to give the corresponding
40,7-dihydroxyisoflavans in 64–95% yields. The stereochemistry of
compound 10g was further confirmed by X-ray crystallography
as shown in Figure 1.22
+ ArH
OAc
AcO
O
R
16
R
17
R = OAc
1 M KOH
MeOH
With these encouraging results, this methodology was
extended to the synthesis of 4-arylflavans. The diacetoxyflavanol
precursor 16 was synthesized in 4 steps starting from resacetoph-
enone (11) (Scheme 3). 4,20,40-Trihydroxychalcone 13 was
synthesized by the condensation of resacetophenone (11) with
4-hydroxybenzaldehyde (12) in the presence of excess KOH.23
Chalcone 13 was then cyclized by heating under reflux in concen-
trated HCl before being acetylated using acetic anhydride/pyridine
to give diacetoxyflavanone 15. Finally, catalytic hydrogenation
using Pd/C in THF gave cis-diacetoxyflavanol 16 in 90% yield.
Flavanol 16 was condensed with 2-hydroxy-6-methoxyaceto-
phenone and 2-hydroxy-4-methoxyacetophenone in the presence
of BF3ꢀOEt2 at room temperature for 1 h. (Scheme 4, Table 2, entries
1 and 2). However, in this case the reactions were not found to be
stereoselective and gave almost equal mixtures of both cis and
trans isomers of compounds 17a and 17b. The cis/trans isomers
had the same Rf value on TLC and were very difficult to separate
18 R = OH
Scheme 4.
Isoflavanol 8 underwent acid-catalyzed substitution reactions
with other activated phenolic compounds to give similarly only
the trans isomers of 4-arylflavans 9b and 9c in good yields (Table 1,
entries 2 and 3). Phenols with bulky substituents ortho to the most
activated position gave the corresponding 4-arylisoflavans 9d–f as
a mixture of atropisomers due to restricted rotation around the
C4–C100 bond (Table 1, entries 4–6). This caused broadening of
some peaks in the 1H NMR spectra and additional peaks for some
of the carbon atoms in the 13C NMR spectra. With these results
in hand, the reaction of isoflavanol 8 with activated heterocyclic
compounds such as benzofurans, indoles, and isoflavenes was
investigated. The resulting 4-heteroarylisoflavans 9g–i were
Table 2
Synthesis of 4-aryl and 4-heteroarylflavans
Entry
Ar
Flavan
17
Yield (%)
67
18
Yield (%)
18a trans
18b cis
97
85
O
OMe
OH
1
2
3
4
5
17a
HO
18c trans
18d cis
87
100
O
17b
17c
17d
17e
37
24
69
73
MeO
MeO
OMe
Br
18e trans
18f trans
18g trans
83
95
92
O
OMe
Ph
Ph
N
H
MeO
MeO
O
OMe

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M. Deodhar et al. / Tetrahedron Letters 53 (2012) 6697–6700
8. Meyer, N. D.; Haemers, A.; Mishra, L.; Pandey, H.-K.; Pieters, L. A. C.; Berghe, D.
A. V.; Vlietinck, A. J. Med. Chem. 1991, 34, 736–746.
9. Wall, M. E.; Wani, M. C.; Manikumar, G.; Abraham, P.; Taylor, H.; Hughes, T. J.;
Warner, J.; McGivney, R. J. Nat. Prod. 1988, 51, 1084–1091.
10. Yamashita, Y.; Kawada, S.; Nakano, H. Biochem. Pharmacol. 1990, 39, 737–744.
11. Ferriola, P.; Cody, V.; Middleton, E., Jr. Biochem. Pharmacol. 1989, 38, 1617–
1624.
12. Hayashi, T.; Uchida, K.; Hayashi, K.; Niwayama, S.; Morita, N. Br. J. Cancer 1988,
54, 595–600.
13. Double, J. A.; Bibby, M. C.; Loadman, P. M. Br. J. Cancer 1986, 3, 581–584.
14. Beutler, J. A.; Cardellina, J. H.; Lin, C. M., II; Hamel, E.; Cragg, G. M.; Boyd, M. R.
Bioorg. Med. Chem. Lett. 1993, 3, 581–584.
15. Heaton, A.; Kelly, G. E.; Kumar, N.; (Novogen Research Pty. Ltd., Australia).
Application: WO WO, 2002070502; Chem. Abstr. 2002, 137, 232488.
16. Maloney, D. J.; Deng, J. Z.; Starck, S. R.; Gao, Z.; Hecht, S. M. J. Am. Chem. Soc.
2005, 127, 4140–4141.
17. Carney, R. W. J.; Bencze, W. L.; Wojtkunski, J.; Renzi, A. A.; Dorfman, L.;
DeStevens, G. J. Med. Chem. 1966, 9, 516–520.
18. Brown, B. R.; Guffogg, S.; Kahn, M. L.; Smart, J. W.; Stuart, I. A. J. Chem. Soc.,
Perkin Trans. 1 1983, 1825–1829.
using flash column chromatography. Small quantities of the pure
isomers were eventually obtained after repeated column chroma-
tography purification and were subsequently hydrolyzed using
1 M KOH to give corresponding 40,7-dihydroxyflavans 18a–d.
The lack of stereoselectivity observed in the flavan system can
be rationalized by the fact that the C2 phenyl group is further away
from the intermediate cationic carbon than in the previously de-
scribed isoflavan system. As a result, the incoming nucleophile is
free to attack from either face of the carbocation, which leads to
a mixture of cis and trans isomers being produced.
Flavanol 16 was similarly condensed with an activated benzofu-
ran, indole, and isoflavene in the presence of BF3ꢀOEt2 to give 4-
heteroaryl analogues 17c–e as 1:1 mixtures of cis and trans isomers
(Table 2, entries 3–5). However, in these cases only the trans iso-
mer could be isolated in pure form after column chromatography.
With the slightly lower Rf value, the cis isomer could not ade-
quately be separated from the trans isomeric product to allow for
complete characterization. Hydrolysis of the trans isomers using
1 M KOH afforded the corresponding trans 40,7-dihydroxyflavans
18e–g in good yields.
19. Steynberg, P. J.; Nel, R. J.; Van Rensburg, H.; Bezuidenhoudt, B. C. B.; Ferreira, D.
Tetrahedron 1998, 54, 8153–8158.
20. Wahala, K.; Hase, T. A. J. Chem. Soc., Perkin Trans. 1 1991, 3005–3008.
21. Representative procedure for compound 9a: To a stirred solution of isoflavanol 8
(500 mg, 1.46 mmol) and 2-hydroxy-6-methoxyacetophenone (242 mg,
1.61 mmol) in CH2Cl2 (25 ml) was added BF3ꢀOEt2 (10 drops). The mixture
was stirred at r.t. for 2 h then quenched with H2O (25 ml). The aqueous layer
was extracted with CH2Cl2 (25 ml). The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated under vacuum. Chromatography
(SiO2, 25% EtOAc/hexane) gave the title compound 9a as a white solid (480 mg,
67%). mp 138–140 °C; Found: C, 68.36; H, 5.64. Anal. Calculated for C28H26O8:
C, 68.56; H, 5.34. 1H NMR (300 MHz, CDCl3): d 2.26 (s, 3H, CH3COO), 2.60 (s, 3H,
CH3COO), 2.68 (s, 3H, CH3CO), 3.42 (m, 1H, H3), 3.83 (s, 3H, CH3O), 4.23 (m, 2H,
H2), 4.69 (d, J = 7.2 Hz, 1H, H4), 6.27 (d, J = 8.6 Hz, 1H, H500, 6.54 (dd, J = 8.3,
2.3 Hz, 1H, H6), 6.66 (d, J = 2.3 Hz, 1H, H8), 6.75 (d, J = 8.3 Hz, 1H, H5), 6.96 (d,
J = 8.7 Hz, 2H, H30, H50), 6.97 (d, J = 8.6 Hz, 1H, H600), 7.30 (d, J = 8.7 Hz, 2H, H20,
H60), 13.77 (s, 1H, OH); 13C NMR (75.6 MHz, CDCl3): d 20.9, 21.0, 33.6, 39.9,
43.0, 55.4, 68.6, 100.7, 109.6, 110.7, 114.0, 121.6, 122.0, 128.7, 130.7, 136.4,
138.3, 149.4, 149.9, 155.2, 160.3, 162.1, 169.2, 169.3, 205.3; UV (MeOH): kmax
In conclusion, BF3ꢀOEt2-catalyzed reactions of 40,7-diacetoxyi-
soflavan-4-ol 8 with activated aryl and heteroaryl compounds gave
trans 4-arylisoflavans and 4-heteroarylisoflavans in good yields in
a single step. The related reaction of 40,7-diacetoxyflavan-4-ol 16
under similar conditions gave the corresponding 4-arylflavans
and 4-heteroarylflavans as mixtures of cis/trans isomers.
References and notes
1. Bohm, B. A. Introduction to Flavonoids; Harwood Academic Publishers:
Amsterdam, 1998.
2. The Flavanoids: Advances in Research; Harborne, J. B., Mabry, T. J., Eds.; CRC Press
Inc, 1982.
3. The Flavanoids; Harborne, J. B., Mabry, T. J., Mabry, H., Eds.; CRC Press Inc, 1975.
4. Jordan, V. C. Cancer 1992, 70, 977–982.
5. Simpson, T. H.; Uri, N. Chem. Ind. 1956, 956–957.
6. Ito, M.; Ishimoto, S.; Nishida, Y.; Shiramizu, T.; Yunoki, H. Agric. Biol. Chem.
1986, 50, 1073–1074.
206 nm (e
49509 cm-1Mꢁ1), 275 (14429), 344 (4233); IR (KBr): mmax 3452,
2930, 1760, 1613, 1496, 1463, 1428, 1368, 1317, 1244, 1207, 1146, 1111, 1088,
1035, 1017, 911, 801 cmꢁ1; MS (TOF-ESI) m/z Calcd for C28H26O8Na (M + Na)+
513.15. Found 513.12.
22. Crystallographic data for the structure in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 882494 (10g). The X-ray crystal structure was obtained by Donald Craig,
Crystallography Laboratory, UNSW Analytical Centre, Sydney, Australia.
23. Al-Ani, H. A. M.; Dewick, P. M. J. Chem. Soc., Perkin Trans. 1 1984, 2831–2838.
7. Ares, J. J.; Outt, P. E.; Randall, J. L.; Murray, P. D.; Weisshaar, P. S.; O’Brien, L. M.;
Ems, B. L.; Kakodkar, S. V.; Kelm, G. R.; Kershaw, W. C.; Werchowski, K. M.;
Parkinson, A. J. Med. Chem. 1995, 38, 4937–4943.