A facile approach to 2-substituted isoflav-3-enes via isoflavylium salts

Article abstract of DOI:10.1055/s-0028-1087523

A compact and regioselective approach to 2-substituted isoflav-3-enes based on a preformed 2-unsubstituted isoflavene is described. Isoflavene oxidation by hydride ion abstraction to the corresponding isoflavylium salt using trityl hexafluorophosphate fol

Full text of DOI:10.1055/s-0028-1087523

306
LETTER
A Facile Approach to 2-Substituted Isoflav-3-enes via Isoflavylium Salts
A
pproach
a
to 2-Substi
n
tuted
I
soflav
e
-
3-enes Faragalla,a Andrew Heaton,b Renate Griffith,c John B. Bremner*a
a
School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
Fax +61(2)42214287; E-mail: john_bremner@uow.edu.au
b
c
Novogen Ltd., 140 Wicks Road, North Ryde, NSW 2113, Australia
School of Medical Sciences/Pharmacology, University of NSW, Sydney, NSW 2052, Australia
Received 4 September 2008
OR
Abstract: A compact and regioselective approach to 2-substituted
isoflav-3-enes based on a preformed 2-unsubstituted isoflavene is
described. Isoflavene oxidation by hydride ion abstraction to the
corresponding isoflavylium salt using trityl hexafluorophosphate
followed by nucleophilic addition to the 2-position resulted in the
introduction of a range of substituent groups in generally moderate
to good yields.
1a R = H
1b R = Ac
1c R = TBS
RO
O
Figure 1 The structure of dehydroequol 1a, together with the pro-
tected analogues 1b and 1c
Key words: nucleophilic additions, isoflavonoid, isoflavylium,
isoflavene, trityl salts
Previous approaches to 2-substituted isoflav-3-enes have
included a number based on 3-arylcoumarins. For exam-
ple,3 DIBAL reduction of the protected 3-arylcoumarin 2
gave the hemiacetal 3, which on reaction with phenol af-
forded the 2-substituted isoflav-3-ene 4 in high yield;
reaction of 4 with various Grignard reagents, which in
most cases gave the 1,2-product over the 1,4-product, fol-
lowed by desilylation provided access to 5 (Scheme 1). It
was proposed that displacement with the Grignard reagent
proceeded via a magnesium-coordinated intermediate
rather than a free oxonium ion (isoflavylium ion) interme-
diate.
Isoflavonoids have gained increasing attention in recent
years because of the range of biological activities they dis-
play. These activities include estrogen-receptor antago-
nism,1a anticancer (protein kinase inhibition),1b
antiplatelet aggregation,1c anti-inflammatory,1c,d antialler-
gy,1c antifungal,1e peroxisome proliferator-activated re-
ceptor binding,1f and diuretic properties.1g Isoflav-3-ene
(1a) (haginin E,2a dehydroequol, phenoxodiol), is of great
interest as it has been shown to possess significant anti-
cancer activity.2b Additionally, 1a acts as a chemosensi-
tizer to current cancer therapies.2c
In a somewhat similar way, Cook and co-workers access-
ed 2,4-disubstituted isoflav-3-enes4a from 4-substituted 3-
arylcoumarins but in this case the Grignard reagent was
added to the DIBAL-H reduction product in situ; acid-
catalyzed cyclization then gave the isoflavenes. Direct
Grignard addition to coumarins results in 2,2-disubstitut-
ed analogues.4b,c
As part of a general SAR program with compounds of
type 1, we were interested in developing a facile and flex-
ible route to 2-substituted derivatives based on the isoflav-
3-ene derivatives 1a–c (Figure 1).
OTBS
DIBAL
OTBS
TBSO
O
O
TBSO
O
OH
2
3
PhOH
OTBS
OH
RMgBr
TBSO
O
OPh
TBAF
HO
O
R
4
5
Scheme 1 A coumarin-based route to 2-substituted isoflav-3-enes3
SYNLETT 2009, No. 2, pp 0306–0309
x
x.
x
x.
2
0
0
8
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087523; Art ID: D31908ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Approach to 2-Substituted Isoflav-3-enes
307
–
Isoflavones can also serve as precursors for unsymmetri- PF6 anion acting as a source of fluoride.12 In view of these
cally substituted 2,4-dialkylisoflav-3-enes via sequential results, and taking into account environmental issues as-
reaction with an alkyl lithium followed by a trialkylalumi- sociated with the stannate salt, trityl hexafluorophosphate
num reagent.5
and 1b were subsequently used to explore the generality
of the addition reactions of the isoflavylium salt interme-
diate.
In a quite different strategic approach, 2-amino substitut-
ed isoflav-3-enes have been prepared through microwave-
assisted assembly of the substituted pyran ring from sub- Various nucleophiles could be added via C–C and C–O
stituted o-hydroxybenzaldehydes and enamine precur- bond formation to the 2-position of the salt generated in
sors, and a subsequent Knoevenagel reaction;6 2-aryl- situ (Table 2).13 With the C–C bond formation, TMS- or
isoflav-3-enes have been prepared similarly from a trihy- tin-based reagents were used to deliver the nucleophilic
droxydeoxybenzoin precursor.7
component in good to modest yields. Alcohols could also
be added readily, as expected, to give the 2-alkoxy deriv-
atives. The structures of the products were confirmed
through NMR spectroscopy, and high-resolution mass
spectrometry data or elemental analytical data were con-
sistent with the molecular formulae.14 The regioselectivity
of nucleophilic attack at the 2-position over the 4-position
in the salt was confirmed by HMBC analysis with a key
correlation being observed between a vinylic H4 and C5.
This regioselectivity is consistent with the greater double-
bond stabilization possible with a stilbenyl moiety com-
pared to the styryl moiety, which would be present from
4-substitution.
Explicit production of an isoflavylium salt precursor for
further 2-substituted isoflav-3-ene formation is an alterna-
tive and potentially more versatile route, which we have
explored. In particular, we investigated direct formation
of such salts by hydride ion removal from readily avail-
able 2-unsubstituted isoflav-3-ene precursors using trityl
salts8 and then nucleophilic addition to the 2-position. The
results are now reported in this paper.
A number of trityl salts was investigated for the hydride
abstraction step using the phenol-protected isoflav-3-ene
derivatives 1b and 1c. These derivatives were formed in
turn from 1a9a,b using acetic anhydride and pyridine, or
TBS chloride in the presence of imidazole, respectively.
Table 2 Synthesis of the Isoflav-3-enes 8
OAc
OAc
Table 1 Synthesis of Isoflav-3-enes 7
OR
OR
Ph3CPF6
Ph3CPF6
AcO
O
AcO
O
X
[6b, X = PF6
]
1b
RO
O
RO
RO
O
OAc
6
1
X
OR
AR
8
[6b, X = PF6
]
AcO
O
R
TMSCN
a R = H
b R = Ac
c R = TBS
Entry AR
Compound R
Yield(%)
of 8a–g
O
CN
7
Entry
Isoflavylium ion 6b,c Counterion (X–) Yield of 7b,c (%)
1
2
3
4
5
6
7
2-TMS-thiazole
TMSC≡CH
8a 2-thiazolyl
8b C≡CH
76
7
–
1
2
3
4
6b
6b
6b
6c
BF4
43
76
80
0
–
SnCl5
TMSCH2N(Boc)2
8c CH2NHBoc
45
68
63
63
66
–
PF6
(Bu)3SnCH2CH=CH2
MeOH
8d CH2CH=CH2
8e OMe
–
PF6
EtOH
8f OEt
With the protected isoflavenes in hand, reaction optimiza-
tion was explored utilizing TMS cyanide as the nucleo-
phile source for attack on the salts 6b and 6c (Table 1).10
Such nucleophilic addition with TMS cyanide (and other
nucleophiles) to related 1-benzopyrylium salts had been
demonstrated previously,11 but these salts were derived
from a 2-substituted acetal precursor on treatment with
BF3·OEt2. With 1b, the best yields of 7b were obtained
with the hexafluorophosphate and pentachlorostannate
trityl salts, while 1c failed to give any of the desired prod-
uct 7c with trityl hexafluorophosphate salt presumably
due to desilylation of the phenolic silyl ether groups by
HOCH2CH2CH2Br
8g OCH2CH2CH2Br
The poor yield of the ethynyl isoflav-3-ene 8b was due to
the formation of the dimeric product 9, which was isolated
in 67% yield. This dimer could arise from fluoride-medi-
ated ethynyl group addition to the isoflavylium ion
(Scheme 2).
In conclusion, a new and concise one-pot procedure has
been developed for the synthesis of 2-substituted isoflav-
3-enes from a readily available isoflav-3-ene precursor
utilizing in situ generation of an isoflavylium salt interme-
Synlett 2009, No. 2, 306–309 © Thieme Stuttgart · New York

308
J. Faragalla et al.
LETTER
OAc
O
OAc
AcO
O
AcO
O
OAc
8b
H
O
OAc
9
AcO
6b
AcO
Scheme 2 Proposed mechanism for the formation of the dimeric product 9
Leblanc, G.; Martel, C.; Simard, J.; Merand, Y.; Belanger,
A.; Labrie, C.; Labrie, F. J. Med. Chem. 1997, 40, 2117.
(8) (a) Trityl perchlorate has been used previously to access
chromylium salts from the dihydro precursors8b but not, as
far as we can ascertain, from 2-unsubstituted isoflav-3-enes.
Isoflavylium salts can also be made, for example, by ring
construction8c or by trityl salt mediated elimination of 2-
substituted isoflav-3-enes8d (b) Canalini, G.; Degani, I.;
Fochi, R.; Spunta, G. Ann. Chim. (Rome) 1967, 57, 1045.
(c) Bouvier, P.; Andrieux, J.; Molho, D. Tetrahedron Lett.
1974, 1033. (d) Dean, F. M.; Varma, R. S. J. Chem. Soc.,
Perkin Trans. 1 1982, 1193.
(9) (a) Compound 1a is accessible from the commercially
available precursors daidzein9c or daidzein diacetate9d,e
(b) Faragalla, J. E. PhD Thesis; University of Wollongong:
Australia, 2005. (c) Heaton, A.; Jeoffreys, G. WO
2005103025, 2005; Chem. Abstr. 2005, 143, 422198.
(d) Heaton, A.; Kumar, N. WO 2000049009, 2000; Chem.
Abstr. 2000, 133, 177059. (e) Liepa, A. J. Aust. J. Chem.
1981, 34, 2647.
diate. This is a flexible approach, which allows for the
ready introduction of a range of synthetically versatile
substituents in this heterocyclic system.
Acknowledgment
J.B.B. thanks the University of Wollongong and Novogen Ltd for
financial contribution to the project. A University of Wollongong-
Novogen scholarship to J.F. is also gratefully acknowledged.
References and Notes
(1) (a) Jain, N.; Kanojia, R. M.; Xu, J.; Jian-Zhong, G.; Pacia,
E.; Lai, M.-T.; Du, F.; Musto, A.; Allan, G.; Hahn, D.;
Lundeen, S.; Sui, Z. J. Med. Chem. 2006, 49, 3056.
(b) Sarkar, F. H.; Li, Y. Cancer Metastasis Rev. 2002, 25,
265. (c) Fwu, S.-Y.; Chang, C.-Y.; Huang, L.-J.; Teng,
C.-M.; Wang, J.-P.; Chen, S.-C.; Kuo, S.-C. Chin. Pharm. J.
(Taipei) 1999, 34, 255. (d) Emmanuel, T.; Dieudonne, N.;
Tanyi, M. J.; Tanee, F. Z.; Albert, K.; Jean-Claude, M.;
Rosa, G. M.; Carmen, R. M.; Salvador, M.; Luis, R. J. J. Nat.
Prod. 2003, 66, 891. (e) Lozovaya, V. V.; Lygin, A. V.;
Zernova, O. V.; Li, S.; Hartman, G. L.; Widholm, J. M. Plant
Phys. Biochem. 2004, 42, 671. (f) Kuroda, M.; Mimaki, Y.;
Sashida, Y.; Mae, T.; Kishida, H.; Nishiyama, T.;
Tsukagawa, M.; Konishi, E.; Takahashi, K.; Kawada, T.;
Nakagawa, K.; Kitahara, M. Bioorg. Med. Chem. Lett. 2003,
13, 4267. (g) Martinez, R. M.; Gimenez, I.; Lou, J. M.;
Mayoral, J. A.; Alda, J. O. Am. J. Clin. Nutr. 1998, 68 (S1),
1354S.
(2) (a) Miyase, T.; Sano, M.; Nakai, H.; Muraoka, M.;
Nakazawa, M.; Suzuki, M.; Yoshino, K.; Nishihara, Y.;
Tanai, J. Phytochemistry 1999, 52, 303. (b) Gamble, J. R.;
Xia, P.; Hahn, C. N.; Drew, J. J.; Drogemuller, C. J.; Brown,
D.; Vadas, M. A. Int. J. Cancer 2006, 118, 2412.
(c) Alvero, A. B.; O’Malley, D.; Brown, D.; Kelly, G.; Garg,
M.; Chen, W.; Rutherford, T.; Mor, G. Curr. Oncol. Rep.
2006, 8, 104.
(10) General Procedure (Table 1, Entry 3)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate
(2.2 mmol), and the isoflavene 1b (503 mg, 1.55 mmol) in
freshly distilled, anhyd CH2Cl2 (50 mL, from CaH2) was
stirred at r.t. under nitrogen for 30 min. Trimethylsilyl
cyanide (0.480 g, 4.8 mmol) was then added, and the
reaction mixture was stirred for a further hour at r.t. The
reaction mixture was then filtered, washed with CH2Cl2,
concentrated under vacuum filtration, and subjected to silica
gel chromatography, using CH2Cl2 as the mobile phase to
afford the product as a colorless crystalline solid (431 mg,
80%).
(11) Doodeman, R.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron
Lett. 2000, 41, 5979.
(12) Deprotection of TBS ethers by the related trityl
tetrafluoroborate has been reported with the anion acting as
a fluoride ion source. See: Metcalf, B. W.; Burkhart, J. P.;
Jund, K. Tetrahedron Lett. 1980, 21, 35.
(13) General Procedure (Table 2, Entry 1)
A mixture of powdered 3 Å MS, trityl hexafluorophosphate
(2.2 mmol), and the isoflavene 1b (451 mg, 1.39 mmol) in
freshly distilled, anhyd CH2Cl2 (50 mL, from CaH2) was
stirred at r.t. under nitrogen for 30 min. The commercially
available 2-trimethylsilylthiazole (0.403g, 2.564 mmol) was
then added and the reaction mixture was stirred for a further
hour at r.t. The reaction mixture was then filtered, washed
with CH2Cl2, concentrated under vacuum filtration, and
subjected to silica gel chromatography, using CH2Cl2 as the
mobile phase to afford the product as a creamy white solid
(430 mg, 76%).
(3) Grese, T. A.; Pennington, L. D. Tetrahedron Lett. 1995, 36,
8913.
(4) (a) Cook, C. E.; Twine, C. E. Jr. J. Chem. Soc., Chem.
Commun. 1968, 791. (b) Cook, C. E.; Wall, M. E. J. Org.
Chem. 1968, 33, 2998. (c) Cook, C. E.; Corley, R. C.; Wall,
M. E. J. Org. Chem. 1965, 30, 4114.
(5) Alberola, A.; Andres, C.; Ortega, A. G.; Pedrosa, R.;
Vicente, M. J. Heterocycl. Chem. 1986, 23, 1781.
(6) Varma, R. S.; Dahiya, R. J. Org. Chem. 1998, 63, 8038.
(7) Gauthier, S.; Caron, B.; Cloutier, J.; Dory, Y. L.; Favre, A.;
Larouche, D.; Mailhot, J.; Ouellet, C.; Schwerdtfeger, A.;
Synlett 2009, No. 2, 306–309 © Thieme Stuttgart · New York

LETTER
Approach to 2-Substituted Isoflav-3-enes
309
(14) Data for Selected Compounds
7-Acetoxy-3-p-acetoxyphenyl-2-ethoxy-2H-1-
benzopyran (8f)
7-Acetoxy-3-p-acetoxyphenyl-2-cyano-2H-1-benzopyran
(7b)
Creamy white solid; mp 134–136 °C. 1H NMR (300 MHz,
CDCl3): d = 7.53 (d, J = 9.0 Hz, 2 H, H-2′/6′), 7.23 (d,
J = 8.4 Hz, 1 H, H-5), 7.12 (d, J = 8.4 Hz, 2 H, H-3′/5′), 6.98
(s, 1 H, H-4), 6.82 (d, J = 2.1 Hz, 1 H, H-8), 6.76 (dd,
J = 8.4, 2.1 Hz, 1 H, H6), 5.95 (s, 1 H, H-2), 4.04–3.96 (m,
1 H, OCH2CH3), 3.82–3.74 (m, 1 H, OCH2CH3), 2.32 (s, 3
H, CH3CO), 2.30 (s, 3 H, CH3CO), 1.25 (t, J = 7.2 Hz, 3 H,
CH2CH3). 13C NMR (75 MHz, CDCl3): d = 169.5 (C=O),
169.3 (C=O), 151.4 (C7), 151.1 (C8a), 150.6 (C4¢), 134.6
(C3), 129.7 (C1′), 128.0 (C5), 126.9 (C2), 122.1 (C3′), 121.5
(C4), 119.6 (C4a), 115.4 (C6), 110.4 (C8), 97.2 (C2), 64.1
(CH2CH3), 21.5 (CH3CO), 15.7 (CH2CH3). MS (CI+): m/z
(%) = 323 (100; 2-unsubstituted isoflavylium ion). Anal.
Calcd (%) for C21H20O6: C, 68.40; H, 5.48. Found: C, 68.49;
H, 5.53.
White solid; mp 156–158 °C. 1H NMR (500 MHz, CDCl3):
d = 7.49 (d, J = 8.7 Hz, 2 H, H-2¢/6¢), 7.23 (d, J = 8.0 Hz,
1 H, H-5), 7.18 (d, J = 8.6 Hz, 2 H, H-3¢/5¢), 6.97 (s, 1 H,
H4), 6.85 (dd, J = 2.5, 8.1 Hz, 1 H, H-6), 6.84 (s, 1 H, H-8),
6.01 (s, 1 H, H-2), 2.32 (s, 3 H, CH3), 2.30 (s, 3 H, CH3). 13
NMR (75 MHz, CDCl3): d = 169.1 (C=O), 168.9 (C=O),
151.9 (C7), 151.1 (C8a), 150.3 (C4¢), 131.9 (C3), 128.3
(C5), 126.2 (C2¢), 125.9 (C1¢), 122.4 (C3¢), 122.3 (C4),
C
119.1 (C4a), 117.0 (C6), 110.5 (C8), 64.3 (C2), 21.1 (CH3).
MS (CI+): m/z (%) = 323 (100) [MH+ – HCN]. Anal. Calcd
(%) for C20H15NO5: C, 68.76; H, 4.33; N, 4.01. Found: C,
69.20; H, 4.34; N, 3.67.
7-Acetoxy-3-p-acetoxyphenyl-2-(2-thiazoyl)-2H-1-
benzopyran (8a)
Creamy white solid; mp 136–138 °C. 1H NMR (300 MHz,
CDCl3): d = 7.60 (br d, J = 2.7 Hz, 1 H, H-2¢¢), 7.37 (d,
J = 8.7 Hz, 2 H, H-2¢/6¢), 7.23 (d, J = 6.3 Hz, 1 H, H-5), 7.08
(d, J = 2.7 Hz, 1 H, H-3¢¢), 6.93 (d, J = 8.4 Hz, 2 H, H-3¢/5¢),
6.89 (s, 1 H, H4), 6.57 (dd, J = 2.7, 8.4 Hz, 1 H, H-6), 6.53
(d, J = 2.4 Hz, 1 H,H-8), 6.44 (br s, 1 H, H-2), 2.13 (s, 3 H,
CH3), 2.10 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3):
d = 169.5 (C=O), 169.3 (C=O), 169.3 (C1¢¢), 151.8 (C7),
151.7 (C8a), 150.8 (C4¢), 143.3 (C4¢¢), 134.0 (C3), 131.5
(C1¢), 127.9 (C5), 126.9 (C2¢), 122.2 (C3¢), 121.1 (C3¢¢),
120.9 (C4), 120.2 (C4a), 115.7 (C6), 110.6 (C8), 74.7 (C2),
21.3 (CH3). HRMS (CI+): m/z calcd for [M + H]+
C22H17NO5S + H: 408.0906; found: 408.0887.
7-Acetoxy-3-p-acetoxyphenyl-2-[2-(7-acetoxy-3-p-
acetoxyphenyl-2H-1-benzopyranyl)ethynyl]-2H-1-
benzopyran (9)
Solid; mp 237–238 °C (dec.). 1H NMR (300 MHz, DMF-d6;
integrations and assignments for half dimer): d = 7.11 (d,
J = 9.0 Hz, 2 H, H-2¢/6¢), 7.02 (d, J = 8.4 Hz, 1 H, H-5), 6.98
(s, 1 H, H4), 6.73 (dd, J = 2.4, 0.3 Hz, 1 H, H-8), 6.66 (d,
J = 9.0 Hz, 1 H, H-3¢), 6.53 (s, 1 H, H-2), 6.51 (dd, J = 8.4,
2.4 Hz, 1 H, H6), 1.94 (s, 3 H, CH3), 1.88 (s, 3 H, CH3). 13
C
NMR (75 MHz, DMSO-d6): d = 169.2 (C=O), 169.1 (C=O),
151.8 (C7), 150.8 (C8a), 150.2 (C4¢), 133.0 (C3), 128.4
(C1¢), 128.2 (C5), 126.4 (C2¢), 122.2 (C4), 121.5 (C3¢),
119.4 (C6), 116.3 (C4a), 110.7 (C8), 92.5 (ethynyl C), 91.7
(C2), 20.4 (CH3), 20.3 (CH3). MS (ES+): m/z (%) = 323 (100;
2-unsubstituted isoflavylium ion). Anal. Calcd (%) for
C41H34O10: C, 69.28; H, 4.60. Found: C, 69.27; H, 4.62.
Synlett 2009, No. 2, 306–309 © Thieme Stuttgart · New York

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