Microwave-assisted C-3 selective oxidative radical alkylation of flavones

Article abstract of DOI:10.1039/c2ob25249j

Flavones were directly alkylated at the C-3 position in moderate yields using a xanthate-based oxidative radical addition procedure. This methodology is a suitable synthetic tool for the direct substitution of the vinylic and unactivated C-H bond of the C ring of the flavone by an alkyl functionality under neutral conditions. The Royal Society of Chemistry 2012.

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Microwave-assisted C-3 selective oxidative radical alkylation of flavones†
Marco V. Mijangos,a Joaquin González-Marrero,*b Luis D. Miranda,*a Paulette Vincent-Ruz,a
Armando Lujan-Montelongo,a Diana Olivera-Díaz,a Elhiu Bautista,a Alfredo Ortega,a
María de la Luz Campos-Gonzálezb and Rocio Gamez-Montañoc
Received 2nd February 2012, Accepted 13th February 2012
DOI: 10.1039/c2ob25249j
considerable quantities and with demonstrated pharmacological
activity, is of increasing importance in the search for drug leads
with improved biological activity. In this context, several syn-
thetic approaches for the construction of the flavone ring system
with a wide range of functionalities have been developed over
the last decade.10 In contrast, the direct functionalization of an
already prepared or isolated flavonoid has been less studied.11
Functionalization of a flavone ring system entails special impor-
tance because several flavonoids could be extracted in gram
scale from their natural sources, and might give rapid access to
libraries of diverse flavonoid scaffolds. Toward this goal, various
methodologies for the alkylation at C-3 have been described in
the literature. A direct alkylation at C-3 could be achieved via
lithiation with lithium diisopropylamide (LDA) and subsequent
trapping of the anion with an appropriate electrophile.11g–i In
addition to the strongly basic conditions required for this
method, its main disadvantage is that flavones containing
methoxy groups or other directing substituents might not afford
good regioselectivity. Additionally, the introduction of an alkyl
substituent at C-3 could also be achieved using a palladium-
mediated cross coupling process using 3-haloflavones as starting
materials.11e,l,m The scope of this latter process is limited by the
availability of 3-haloflavones. Thus, a process that avoids the use
of strong basic conditions, expensive transition metal complexes,
and prefunctionalized starting material would therefore be a
Flavones were directly alkylated at the C-3 position in mod-
erate yields using a xanthate-based oxidative radical addition
procedure. This methodology is a suitable synthetic tool for
the direct substitution of the vinylic and unactivated C–H
bond of the C ring of the flavone by an alkyl functionality
under neutral conditions.
Flavones are natural products of the benzopyran type (i.e. neva-
densin 1 and flavone 2, Fig. 1) and are widely distributed in
nature as secondary metabolites in fruits and vegetables.1 This
family of molecules possesses a wide variety of biological activi-
ties, including anxiolytic,2 antiviral,3 antiprotozoal,4 anticarcino-
genic,5 antioxidant6 and antihyperglycemic properties,7 among
others.1
In addition to the basic common natural flavonoids that
exhibit a C-3 unsubstituted framework, many members of this
family are alkylated or oxygenated at this position (Fig. 1). For
instance, 3-prenyl derivatives of primuletin (5-hydroxyflavone) 3
and chrysin (5,7-dihydroxyflavone) 4, can be found in the aerial
parts of Sida cordifolia (Malvaceae), and both have shown
analgesic and anti-inflammatory activities.8 Furthermore, apigen-
inyl-(I-3,II-3)-naringenin 5 and related natural products were iso-
lated from the crude extract of the root of Ormocarpum kirkii
S. Moore (Papilionaceae).9 These molecules were found to
display antiplasmodial activity, a property suspected to contrib-
ute to the antimalarial use of O. kirkii in Tanzanian traditional
medicine.9
In medicinal chemistry, transforming or simply modifying
natural products, especially those that may be obtained in
aInstituto de Química, Universidad Nacional Autónoma de México,
Circuito Exterior, Ciudad Universitaria, Coyoacán, México, D.F. 04510,
México. E-mail: lmiranda@servidor.unam.mx
bUnidad Profesional Interdisciplinaria de Ingeniería, Instituto
Politécnico Nacional, Av. Mineral de Valenciana, No. 200, Col. Fracc.
Industrial Puerto Interior, C.P. 36275 Silao de la Victoria, Guanajuato,
México. E-mail: jgonzalezm@ipn.mx
cDepartamento de Química, Universidad de Guanajuato, Noria Alta
S/N, Guanajuato, C.P. 36050, México
†Electronic supplementary information (ESI) available: Experimental
details, characterization data, X-ray CIF file of 6a and copies of the
1H NMR spectra for all the products. CCDC 869563. For ESI and crys-
tallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25249j
Fig. 1 Leading examples of natural flavonoids.
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Table 1 Optimization for the oxidative radical addition to flavones
Scheme 1 Proposed mechanism for the oxidative radical addition to
flavones.
Entry Conditions
% Yield 14 % Conv.a
1
2
3
DLP/DCE/reflux/5 h
DLP/DCE/MW/reflux/30 min
DLP/solventless/MW/105 °C/30 min 39
39
40
58
62
50
valuable and straightforward synthetic strategy for preparing
flavone derivatives.
a % Conversion based on recovered starting flavone.
In the search for milder and more versatile reaction conditions
and new patterns of reactivity, the use of free radicals has gained
importance in synthetic organic chemistry.12 In particular,
xanthate-based radical addition processes developed by Zard and
coworkers are powerful tools for constructing C–C bonds under
metal-free conditions.13 Taking all these observations into con-
sideration, we wondered if the flavone ring system (1) could be
selectively alkylated at C-3 using a xanthate-based radical
addition process to obtain the corresponding alkylated flavones
(Scheme 1). Preliminary results of our endeavors in this field are
presented herein.
The mechanism proposed for the addition process is depicted
in Scheme 1. The oxygen-stabilized benzyl radical 9 would be
generated upon the addition of the radical 7, formed from the
xanthate 8, to the flavone 6. In principle, the radical intermediate
9 would be prone to oxidize to the benzyl oxonium ion 10, par-
ticularly in the presence of a stoichiometric quantity of dilauroyl
peroxide (DLP).14 Deprotonation would furnish the expected
alkylated product 11.
Several flavones were prepared according to a known two-step
sequence.15 We first examined the reaction of the 4′-methoxyfla-
vone 12a15 with xanthate 13a to evaluate the viability and
efficiency of the reaction. Relevant observations are reported in
Table 1. Heating a 1,2-dichloroethane (DCE) solution of 12a
with 2.0 equivalents of xanthate 13a and 1.5 equivalents of DLP
at reflux temperature for 5 h afforded the desired 3-alkylsubsti-
tuted flavone 14 in 39% yield as the only product (found by
TLC analysis), with the recovery of a considerable amount of
starting flavone 12a (Table 1, entry 1). Because of the long reac-
tion time, we elected to examine the process under microwave
(MW) irradiation conditions. Thus, microwave irradiation (250
W) of a DCE solution of 12a produced 14 in 41% yield (62%
based on the recovered starting flavone 12a) within 30 min
(Table 1, entry 2). In addition, when the reaction was performed
without solvent,16 compound 14 was formed in a similar 39%
yield, but with a lower conversion yield. The structure of 14 was
confirmed by X-ray crystallography (Fig. 2).
Fig. 2 X-Ray crystal structure of alkylated flavone 14.
CEM apparatus).17 The temperature was maintained at 73 °C, by
power modulation from 200 to 250 W and with simultaneous
cooling of the flask with pressurized air.
By and large, we obtained moderate yields of the 3-alkylsub-
stituted flavones along with considerable amounts of recovered
starting flavones. Remarkably, the substituent at the aromatic B
ring had no drastic effect on the yield of the reaction. We also
isolated generally good product yields with the ethyl ester-
derived xanthate 13a (Table 2, 15, 16, 19, 29). The use of benzo-
phenone-derived xanthates 13b and 13c afforded slightly lower
yields of the alkylated flavones 20–23 and 25–27, respectively
(Table 2). When we subjected the highly oxygenated (A-ring)
natural nevadensin 118 to the same alkylating process using the
xanthate 13a, we observed only a complex mixture of products.
The failure of this reaction might be due to the abstraction of the
hydrogen of the phenols by radicals formed in the medium. It is
worth noting that reaction of the dimethylated derivative of 118
with xanthate 13a under the same conditions provided the
expected alkylated product 19 in moderate yield. We observed a
similar result when the p-Cl–benzophenone xanthate derivative
13b was reacted with di-MeO-1 (Table 2, 23). Furthermore
application of the alkylation process to the trimethylated deriva-
tive of 5,6,3′-trihydroxy-7,4′-dimethoxyflavone 219 afforded the
C-3 alkylated flavonoids 28 and 29 in 51% and 29% yields,
To study the versatility, scope, and the synthetic value of the
methodology, we then submitted several flavones to the alky-
lation process with various xanthates (Table 2), setting optimized
conditions as follows: 0.6 mM of flavone in 2 mL of dry DCE,
1.5 eq. of DLP, and 2.0 eq. of xanthate; the mixture was ir-
radiated with microwaves in an open vessel system (Discover,
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Table 2 Scope of the oxidative radical addition to flavones
(%): Yield based on recovered starting material.
respectively. Finally, to further explore the scope of the reaction,
a secondary xanthate 13d was prepared from the corresponding
ethyl-2-chloropropionate. Thus, we established that a secondary
radical could also be added to the C-3 position of the flavonoid
ring system giving 17, 18 and 24 in moderate yields under the
aforementioned conditions (Table 1).
The results in Table 2 convincingly showed that this xanthate-
based oxidative radical addition is a suitable synthetic tool for
2948 | Org. Biomol. Chem., 2012, 10, 2946–2949
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Scheme 2 Synthesis of the flavone–testosterone conjugated 31.
the direct substitution of an alkyl functionality at the vinylic and
unactivated C–H bonds of the C ring of the flavone, under for-
mally neutral conditions. It is important to mention that in most
cases the moderate yields of 3-alkyl flavones did not originate
from a lack of selectivity of the radical addition as indicated by
the considerable amount of recovered starting material. We then
turned our attention to establish that this direct regioselective
radical alkylation may be useful to covalently join flavones with
other synthetic or natural platforms, giving access to more
complex flavone–conjugate scaffolds in the search for enhanced
or diverse biological activities. Accordingly, we were pleased to
find that the testosterone-derived xanthate 30 (see ESI† for the
synthesis) reacted with the flavone 12d and afforded the flavone–
testosterone conjugate 31, albeit in a modest 35% yield
(Scheme 2).
Conclusions
We have developed a convenient synthesis that affords C-3-sub-
stituted flavones in moderate yields through a process that
involves an intermolecular oxidative radical alkylation. To the
best of our knowledge, the synthetic utility of free radicals with
flavones has not been explored previously. This direct method
offers preparative advantages over the established synthesis of
such substituted flavones since it provides a good variety of pro-
ducts and allows the use of mild conditions with great selectivity.
Results presented herein could be useful for accessing the syn-
thesis of naturally occurring 3-alkyl flavones (i.e., apigeninyl-
(I-3,II-3)-naringenin 5) and flavone–conjugate scaffolds. It is
interesting that the flavone’s natural tendency to trap radicals (as
the antioxidant molecules they are) has not been applied for
organic synthesis.20
14 For examples of related oxidative processes using dilauroyl peroxide see:
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We thank CONACYT (J-50922, 82643) for generous financial
support and Dr Joseph M. Muchowski for many helpful discus-
sions. We also thank H. Rios, R. Patiño, J. Pérez, L. Velasco,
N. Zavala, E. Huerta, I. Chavez, A. Peña, S. Hernádez and
A. Toscano for technical support.
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Notes and references
17 Microwave reactions were conducted using a CEM Discover Synthesis™
Unit (CEM Corp., Matthews, NC). http://www.cem.com/page176.html
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Phytochemistry, 1992, 31, 1413–1414. For dimethylations process see:
H.-W. Chu, H.-T. Wu and Y.-J. Lee, Tetrahedron, 2004, 60, 2647–2655.
19 Isolated from Salvia herbacea, see also: A. Bisio, G. Romussi,
G. Ciarallo and N. Tommasi, Pharmazie, 1997, 52, 330–331. For tri-
methylations process see: H.-W. Chu, H.-T. Wu and Y.-J. Lee, Tetrahe-
dron, 2004, 60, 2647–2655.
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