A Wacker-Cook synthesis of isoflavones: formononetine

Article abstract of DOI:10.1016/j.tetlet.2009.01.041

A total synthesis of the isoflavone formononetine 1 by an oxidative Pd-mediated cyclization of α-methylenedeoxybenzoins 4a-c is described. Substrates 4a-c were rapidly assembled using 'protected cyanohydrin' chemistry.

Full text of DOI:10.1016/j.tetlet.2009.01.041

Tetrahedron Letters 50 (2009) 1542–1545
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A Wacker–Cook synthesis of isoflavones: formononetine
*
Evin H. Granados-Covarrubias, Luis A. Maldonado
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, México 04510, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of the isoflavone formononetine 1 by an oxidative Pd-mediated cyclization of a-meth-
ylenedeoxybenzoins 4a–c is described. Substrates 4a–c were rapidly assembled using ‘protected cyano-
hydrin’ chemistry.
Received 17 October 2008
Revised 6 January 2009
Accepted 9 January 2009
Available online 14 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The flavonoids are a group of natural products with interesting
medicinal and biological properties, for example, antioxidant,
enzymatic, estrogenic, insecticidal, and antimicrobial activities.1
Recently, the antileukemic activity of genistein, the major isoflav-
one constituent of soy beans, has been reported and fisetin, a tet-
rahydroxyflavone present in strawberries and other foods, has
been proposed as an oral neurotrophic factor that sustains and en-
hances memory.2,3 Therefore, and despite the large number of
available methods, the development of new synthetic procedures
to efficiently prepare these compounds in the laboratory is an
important issue.4
During their extensive studies concerning the syntheses of com-
plex indole alkaloids of the macroline/sarpagine type, Cook and co-
workers examined the conversion I?II and found that the involved
deprotection–cyclization–oxidation steps can be done in a single
operation with a palladium(II) complex (Na2PdCl4) and an oxidant
(t-BuOOH) in a buffered (AcOH–NaOAc) aqueous dioxane or t-
BuOH media (Scheme 1).5
tone) to remove HCN and HNO2 in the intermediate b-nitro cyano-
hydrin 3 (R = H). However, to our surprise a 1:1 mixture of the
expected a-methylene deoxybenzoin 4a and nitroenone 5 was ob-
tained in 50% yield, which were separated by column chromatog-
raphy and fully characterized by spectroscopy (Scheme 3).9
Since this ratio remained unchanged regardless if the workup is
performed under the rigorous exclusion of air or if oxygen is intro-
duced on purpose, air dehydrogenation of the nitronate adduct can
be discarded as an explanation for the formation of 5. On the other
hand, if in the above reaction (E)-4-methoxy-b-nitrostyrene is
substituted for (E)-b-nitrostyrene, after work up and deprotections
only the ‘normal’ product 6 is obtained in 60% yield. The above
experiments seem to point out that formation of b-nitroenone 5 in-
volves, after lithium nitronate adduct formation, an intramolecular
slow methoxy-assisted benzylic hydride transfer mechanism with
the covalent lithium cation as the hydride acceptor, perhaps
through
a cyclic six-membered intermediate, as depicted in
Scheme 4. To explain, the constant 1:1 ratio of 4a and 5 in the
aforementioned experiments, we propose that, as soon as pro-
tected nitroenone is formed, replaces lithium cation as hydride
acceptor establishing a fast equilibrium with lithium nitronate ad-
duct, which is preserved until quenching.
We wish to report that this elegant Wacker–Cook tandem con-
version can be extended to the synthesis of isoflavones from
a
-methylenedeoxybenzoins. Our results are not trivial since
a-substituted
a
,b-unsaturated ketols are known6 to be inert to
the standard Wacker oxidation and, in our case, phenol intermedi-
ates can potentially be oxidized under these conditions.
To address this issue, we chose the simple isoflavone formo-
nonetine 1 which, in principle, can be prepared by this approach
from an appropriately ortho substituted a-methylenedeoxybenzo-
in 4, and this substrate can, in turn, be obtained by a method re-
ported some time ago from our laboratory7 as indicated in the
retrosynthetic analysis of Scheme 2.
Conjugate addition of the lithium salt of the O-silyl protected
cyanohydrin 28 to commercially available (E)-4-methoxy-b-nitro-
styrene gave a mixture of compounds which without purification
was submitted successively to a mild acid treatment (5% aqueous
H2SO4) to cleave the silyl ether, and a base treatment (Et3N in ace-
Since 5 is, in principle convertible into 4a, we first explored
some reactions on 5, but without success.10 Hence we turned our
attention to the modification of reaction conditions to avoid forma-
tion of 5 and determined that exchanging the lithium base for
more ionic sodium or potassium bases was an attractive, reason-
able alternative. From our point of view, sodium or potassium nitr-
onate adducts could not give analogous cyclic intermediates for
favorable intramolecular hydride transfers as lithium cation did,
and we were pleased to find that with KH as base, the reaction pro-
ceeded without incident affording the ‘normal’ Michael adduct 3
(R = SiMe3, not isolated) as evidenced by the exclusive isolation
(65% overall yield) of 4a under these conditions. Finally, from 4a,
the analogous
a-methylene deoxybenzoins 4b and 4c were ob-
tained by the standard reactions indicated in Scheme 5.
With substrates 4a–c in hand, they were subjected to the Cook
modification of the Wacker oxidation in separate experiments to give
* Corresponding author. Tel.: +52 55 5622 4428; fax: +52 55 5616 2217.
E-mail address: lammg@servidor.unam.mx (L.A. Maldonado).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.041

E. H. Granados-Covarrubias, L. A. Maldonado / Tetrahedron Letters 50 (2009) 1542–1545
1543
tBuOOH, Na2PdCl4
Me
OTIPS
O
Me
O
O
N
N
N
Me
N
Me
NaOAc, HOAc,
H2O/dioxane
I
II (55-60% yields)
Scheme 1. The Wacker–Cook cyclization–oxidation of alkaloid d-oxy-
a
-methylene ketones.
OMe
O
OMe
O
?
HO
O
Wacker-Cook
RO
OR
1, formononetine
4
OMe
OMe
CN
MOMO
NC OR
OSiMe3
OMOM
+
MOMO
MOMO
NO2
O2N
3
2
Scheme 2. Retrosynthetic analysis of formononetine based in the Wacker–Cook cyclization as key step.
OMe
OMe
OMe
O
MOMO
O
O2N
+
MOMO
OMOM
MOMO
O2N
4a
50% (1:1 mixture)
5
NC OSiMe3
Li
MOMO
OMOM
O
60%
MOMO
OMOM
O2N
6
Scheme 3. Nitroenone byproduct 5 is formed when the lithium salt of protected cyanohydrin 2 is used.
the isoflavone formononetine 1 in 52–58% yields (Scheme 6). In our
preliminary experiments, we successfully used dioxane as solvent,
buttheacidcatalyzedremovaloftheprotectinggroups(forsubstrates
4a and 4b) was extremely slow. On the other hand, with t-BuOH as
solvent, both the cyclization and acid hydrolysis proceeded at reason-
able rates and was the solvent of choice in these particular cases.13
The remarkable stability of free phenol groups under these
oxidation conditions is noteworthy and allows its use in unpro-
tected form in this reaction. This is very important since hydrox-
ylated isoflavones are common as natural products and also
because free phenol groups usually interfere in the base cata-
lyzed cyclization methods used in isoflavone or isoflavanone

1544
E. H. Granados-Covarrubias, L. A. Maldonado / Tetrahedron Letters 50 (2009) 1542–1545
OSiMe3
Ar
OSiMe3
Ar
NC
H
NC
work up and
deprotections
Li
- LiH
slow
O
OMe
5
NO2
N
O
OMe
lithium nitronate adduct
fast
H:
OSiMe3
Ar
work up and
deprotections
NC
H
Li
4a
O
OMe
N
O
lithium nitronate adduct
Scheme 4. Mechanism proposal for the formation of nitroenone 5. Ar = 2,4-bis-(MOM)phenyl group.
OMe
O
a
b, c
d (89%) or
e (100%)
2
3 : R = SiMe3
4a
65% overall
RO
OH
4b : R = MOM
4c : R = H
Scheme 5. Syntheses of enones 4a–c. Reagents and conditions: (a) KH, DME, rt, then (E)-4-methoxy-b-nitrostyrene, then Na2HPO4 buffer in H2O; (b) 5% H2SO4 in H2O, THF,
50 °C, 14 h; (c) Et3N, Me2CO, rt; (d) BCl3, CH2Cl2, rt; (e) 20% H2SO4 in H2O, THF, 55 °C, 3 h.
OMe
O
Na2PdCl4, t-BuOOH, NaOAc
4a, 4b, 4c
t-BuOH, AcOH, H2O, 80 oC, 18h;
then 10% HCl (for 4a and 4b)
HO
O
1, formononetine
52-58% yields
Scheme 6. Use of the Wacker–Cook method in the synthesis of isoflavones from a-methylene deoxybenzoins.
syntheses. As an example from our laboratory,
a
-methylenede-
genation and acid catalyzed removal of the phenol protecting
group.
We hope that the method reported herein will find ample use in
the synthesis of more complex hydroxylated isoflavones. We are
currently pursuing work along these lines to contribute to this
issue.
oxybenzoin 4c is recovered unchanged when treated with base
reagents (alkaline carbonates, tertiary amines), but 4b cyclizes
quantitatively to isoflavanone 8 in 20 min at rt with Na2CO3 in
EtOH (Scheme 7). For the purpose of comparison, an authentic
sample of formononetine was secured from 8 by DDQ dehydro-

E. H. Granados-Covarrubias, L. A. Maldonado / Tetrahedron Letters 50 (2009) 1542–1545
1545
404.1342.The Z configuration of this compound was first established by cycleNOE
NMR experiments and fully confirmed by X-ray crystal analysis.
OMe
O
O
Na2CO3, EtOH
4b
rt, 20 min
100%
8
MOMO
DDQ, dioxane
reflux, 48 h
65%
OMe
O
10% HCl
1
MeOH
reflux, 5 min
84%
formononetine
MOMO
O
10. For instance, 5 does not add the O-ethyl dithiocarbonate anion11 under a
variety of conditions and is remarkably stable to NaBH4 even in boiling MeOH.
However, the acid hydrolysis of 5 proceeds with cyclization to coumaranone 7
in 90% yield, but this compound was also useless because it was recovered
unchanged toward base treatments.12
Scheme 7. Alternative synthesis of formononetine.
Acknowledgments
11. Ouvry, G.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2003, 5, 2907–2909.
12. Coumaranone 7: Pale yellow crystalline solid; mp 177–178 °C (EtOH–hexanes).
IR (KBr): 3178, 1675, 1611, 1557, 1306, 1255, 1169, 1029 cmÀ1 1H NMR
.
We thank Dr. Guillermo E. Delgado L. (Instituto de Química,
UNAM), and Dr. J. Alfredo Vázquez M. (Facultad de Química,
UNAM) members of the Tutorial Committee of EHG-C, for their
valuable suggestions to this research. We also thank Rocío Patiño,
Ángeles Peña, Beatriz Quiroz, Luis Velasco, Francisco J. Pérez, and
Simón Hernández for running spectra. EHG-C thanks a CONACYT
scholarship for graduate studies.
(300 MHz, C3D6O): d 9.98 (broad signal, OH, exchanges with D2O), 7.53 (d,
J = 9 Hz, 2H), 7.52 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 9 Hz, 2H), 6.70 (dd, J = 9, 1.8 Hz,
1H), 6.70 (d, J = 1.8 Hz, 1H), 5.37 (AB system, JAB = 14.4 Hz, 2H), 3.77 (s, 3H). 13
C
NMR (75 MHz, C3D6O):
d 194.81, 174.10, 167.91, 161.23, 127.19, 127.09,
126.44, 115.10, 113.37, 112.98, 99.41, 88.48, 79.29, 55.62. MS (EI, 70 eV): m/z
(%) 315 (M+, 30), 269 (100), 137 (80), 133 (97). HRMS (FAB): [M+1]+ calcd for
C16H14NO6, 316.0821, found 316.0829
O
NO2
7
References and notes
O
HO
1. Rice-Evans, C. A.; Packer, L. Flavonoids in Health and Disease; Marcel Dekker:
New York, USA, 2003.
2. Raynal, N. J.-M.; Momparler, L.; Charbonneau, M.; Momparler, R. L. J. Nat. Prod.
2008, 71, 3–7.
3. (a) Maher, P. Arch. Biochem. Biophys. 2008, 476, 139–144; (b) Maher, P. Free
Radical Res. 2006, 40, 1105–1111; (c) Maher, P.; Akaishi, T.; Abe, K. Proc. Natl.
Acad. Sci. U.S.A. 2006, 103, 16568–16573.
4. Dewick, P. M. In The Flavonoids: Advances in Research Since 1986; Harborne, J. B.,
Ed.; Chapman and Hall: London, 1994.
5. (a) Liao, X.; Zhou, H.; Wearing, X. Z.; Ma, J.; Cook, J. M. Org. Lett. 2005, 7, 3501–
3504; (b) Liao, X.; Zhou, H.; Yu, J.; Cook, J. M. J. Org. Chem. 2006, 71, 8884–8890.
6. Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91–94.
7. Ferriño, S. A.; Maldonado, L. A. Synth. Commun. 1980, 10, 717–723.
8. Protected cyanohydrin 2 was obtained in 83% overall yield from commercial
2,4-dihydroxybenzaldehyde by bis methoxymethylation (ClCH2OMe, NaH,
THF) and cyano O-silylation (Me3SiCN, catalytic KCN and 18-crown-6, C6H6).
See: Greenlee, W. J.; Hangauer, D. G. Tetrahedron Lett. 1983, 24, 4559–4562. for
the cyano O-silylation reaction.
OMe
13. The synthesis of formononetine 1 from
a-methylenedeoxybenzoin 4b is a
representative example. 4b (80 mg, 0.254 mmol), Na2PdCl4 (89 mg,
0.305 mmol), and NaOAc (21 mg, 0.254 mmol) are dissolved in a mixture of
t-BuOH (5.4 mL), AcOH (1.8 mL), and water (5.4 mL) in
a 25 mL round
bottomed flask; a 70% t-BuOOH solution in water (0.05 mL, 0.36 mmol) is
added. The reaction mixture is heated in an oil bath at 80 °C for 18 h, cooled at
rt, diluted with a water-ice mixture (3 mL), and acidified with 10% aqueous HCl
(5 mL). After refluxing for 6 h it was cooled at rt, neutralized with solid
NaHCO3, and the organic solvent removed at reduced pressure (rotary
evaporator). The suspension was diluted with brine and extracted with
AcOEt (3 Â 10 mL), the organic layers dried over Na2SO4 and the solvent
removed at reduced pressure (rotary evaporator). The dark brown semisolid
was purified by silica gel flash chromatography using a 4:1 mixture of hexanes/
AcOEt as eluent to give 32 mg (53% yield) of formononetine as colorless
needles, mp 254–256 °C (EtOH); lit. mp 257 °C: Mahal, H. S.; Rai, H. S.;
Venkataraman, K. J. Chem. Soc. 1934, 1769–1771. Using this procedure, 4a and
4c gave formononetine in 58 and 52% yields, respectively, but it should be
noted that, in the latter case, the HCl treatment is not required.Formononetine
9. Nitroenone 5: Yellow crystalline solid; mp 158–160 °C (EtOH–hexanes). IR (KBr):
1645, 1597, 1505, 1333, 1256, 1158, 1132, 1004 cmÀ1 1H NMR (300 MHz, CDCl3):
.
1. IR (KBr): 1622, 1583, 1446, 1266, 1246, 1177, 1024 cmÀ1 1H NMR (300 MHz,
.
CD3OD + DMSO-d6): d 8.07 (s, 1H), 7.93 (d, J = 9 Hz, 1H), 7.38 (d, J = 9 Hz, 2H),
6.88 (d, J = 9 Hz, 2H), 6.84 (dd, J = 9, 2 Hz, 1H), 6.76 (d, J = 2 Hz, 1H), 3.71 (s, 3H)
d 8.13 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 9 Hz, 2H), 7.36 (s, 1H), 6.89 (d, J = 9 Hz, 2H),
6.80 (dd, J = 8.8, 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 5.19 (s, 2H), 5.0 (s, 2H), 3.81 (s,
3H), 3.46 (s, 3H), 3.17 (s, 3H). 13C NMR (75 MHz, CDCl3): d 189.13, 163.43, 162.40,
158.87, 153.83, 132.81, 130.61, 129.49, 122.85, 119.17, 114.79, 109.59, 102.30,
94.13, 94.02, 56.40, 56.17, 55.44. MS (EI, 70 eV): m/z (%) 403 (M+, 1), 312 (42), 225
(56), 45 (100). HRMS (FAB): [M+1]+ calcd for C20H22NO8, 404.1345, found:
13C NMR (75 MHz, CD3OD + DMSO-d6):
d 176.96, 164.00, 160.61, 159.19,
154.29, 131.16, 128.29, 125.37, 125.05, 117.95, 116.13, 114.58, 103.05, 55.60.
MS (EI, 70 eV): m/z (%) 269 (M+1, 100), 268 (M+, 72), 132 (62).