Microwave enhanced palladium catalysed coupling reactions: A diversity-oriented synthesis approach to functionalised flavones

Article abstract of DOI:10.1039/b610734f

Microwave enhanced diversity-oriented synthesis (MEDOS) using palladium catalysed protocols is introduced as a powerful new strategy for the synthesis of systematically modified small molecules and is highlighted by application to functionalised flavones. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b610734f

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Microwave enhanced palladium catalysed coupling reactions: A
diversity-oriented synthesis approach to functionalised flavones{
Richard J. Fitzmaurice,a Zac C. Etheridge,a Emelie Jumel,a Derek N. Woolfsonb and Stephen Caddick*a
Received (in Cambridge, UK) 26th July 2006, Accepted 11th September 2006
First published as an Advance Article on the web 29th September 2006
DOI: 10.1039/b610734f
Microwave enhanced diversity-oriented synthesis (MEDOS)
using palladium catalysed protocols is introduced as a powerful
new strategy for the synthesis of systematically modified small
molecules and is highlighted by application to functionalised
flavones.
Diversity-oriented synthesis (DOS) has become accepted as an
important strategy for chemical biology and has been exploited in
a number of important chemical and biological problems.1
Underpinning the DOS approach is a requirement for generic
synthetic methods that enable the elaboration of a functional
group into a variety of different molecular structures. Palladium
catalysed organic transformations offer a platform for DOS,
because of the wide range of transformations mediated by
palladium.2 Thus, an aryl halide can act as a ‘chemical code’ for
a variety of valuable functional groups, including pharmaco-
phores, recognition motifs etc. Judicious choice of catalyst and
coupling agent are required to convert the aryl halide into the
target structure (Scheme 1).
Scheme 1 Palladium chemistry as a platform for diversity.
palladium mediated cross-couplings.7,14,–21 We concluded, there-
fore, that the biological importance of this class of compounds
made them an ideal candidate for development of the MEDOS
approach using palladium catalysis. Here, we describe the
realisation of the strategy and its applicability to functionalised
flavones.
A further advantage of basing a DOS approach on palladium
chemistry is that such reactions are known to be significantly
enhanced by microwave heating.3 Therefore microwave-enhanced
diversity oriented synthesis approach (MEDOS) based on
palladium chemistry may be particularly useful. The present paper
describes this strategy and demonstrates its applicability to a
biologically relevant class of small-molecule structures.
In selecting a small-molecule template to illustrate the potential
of the strategy, we wished to identify a class of molecule of
widespread importance in biology, but which had not been
extensively elaborated using palladium catalysis. We chose the
flavones, a key class of flavonoids that occur naturally in a wide
range of sources and exhibit a plethora advantageous biological
effects.4–9 Recently, the flavone motif has been incorporated into
a number of synthetic constructs with resulting interesting
biological properties.10–12 In our own programme we have
identified flavones as an entirely new class of ligand for the
protein apo-Neocarzinostatin.13
Many routes have been described for the de novo synthesis of
flavones.7,10,12,16,22–26 Our own initial investigations toward the
synthesis of haloflavones have been conducted using protocols
based upon the classical Baker–Ventakaraman O-acylation
approach.22,25 However, reactions proved to be relatively low
yielding and slow to perform. Application of a C-acylation
methodology described by Cushman23 for the synthesis of
hydroxylated flavones is more successful and results in generally
good yields of flavones 2–10 (Scheme 2). The 5-Br and 7-Br
flavones were restricted due to lack of availability of the
corresponding brominated acetophenones. In order to study
palladium-based elaborations at all positions, triflates 11 and 13
were readily accessed via microwave-assisted triflation with
Tf2NPh of the corresponding alcohols 6 and 12 in excellent yields
(Scheme 3).27 It is noteworthy that reaction of 11 under thermal
conditions with Tf2O in NEt3–DCM or pyridine provided
disappointing yields, 20–25%.
Although a range of synthetic strategies are available for the
synthesis and modification of flavones 1, relatively scant attention
has been given to the elaboration of functionalised flavones using
aDepartment of Chemistry, University College London, Christopher
Ingold Laboratories, 20 Gordon Street, London, UK WC1H 0AJ.
E-mail: s.caddick@ucl.ac.uk
bSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol,
UK BS8 1TS and Department of Biochemistry, School of Medical
Sciences, University Walk, Bristol, UK BS8 1TD
{ Electronic supplementary information (ESI) available: experimental
details. See DOI: 10.1039/b610734f
4814 | Chem. Commun., 2006, 4814–4816
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Table 1 Suzuki–Miyaura reactions with POPd–CsF
Substrate
5Ar
Yield (%)
98a
–Ph
Scheme 2 Synthesis of functionalised flavones.
–Ph
89
Initial investigations in the Suzuki–Miyuara reaction on flavone
2 identified Li’s28 POPd catalyst with CsF as optimum and
furnished the desired arylated flavone in 83% yield via conven-
tional heating at 85 uC for 5 h. Use of microwave heating at 85 uC
reduced the reaction time to 15 min and improved the yield to
98%.
–Ph
–Ph
0
0
Application of the optimised POPd based protocol to the range
of flavone bromides and triflates is described in Table 1. Reactions
generally proceeded smoothly across the substrate range with the
best yields obtained for the most electron poor bromides 2, 3, and
9. Reactions with both triflated flavone substrates 11 and 13 also
proceeded smoothly in high yield. As expected, reactions with
relatively electron rich bromide 7 were less successful with both
electron-rich and electron-poor boronic acids. Reaction of
bromoflavone 5 afforded only a low yield of the desired arylated
flavone on reaction with phenylboronic acid. This can in part be
attributed to the hindered nature of the bromide substrate and in
part to difficulty in separating the desired arylated compound from
the simple reduction product. Use of the more electron poor
3-nitrophenyl boronic acid afforded a crystalline product to aid
purification.
44
64
–Ph
–Ph
–Ph
–Ph
89
60b
53
82
Arylation of flavone 4 was wholly unsuccessful using POPd–
CsF catalyst regime. However, use of Pd(PPh3)4–K3PO4 with
microwave heating afforded the arylated product in 86% yield.
Attempts to selectively mono arylate bishaloflavones 9 and 10
using POPd–CsF protocol were unsuccessful and provided
inseparable mixtures of monoarylated, via displacement of both
bromine and chlorine, and bis arylated products.
84c
57
a
b
c
83% yield with 5 h conventional heating 2 6 30 min 3 6
30 min.
Imidazolium salts have been successfully used as ligands in a
wide range of Buchwald–Hartwig amination reactions on aryl
halides. However, use of a Pd2(dba)3–SIMES.HCl catalyst regime
on flavone 2required high temperature microwave heating, 165 uC,
to achieve reasonable reaction rates and gave only moderate yields,
51%.29 Application of Buchwald’s Pd2(dba)3–BINAP–NaOtBu
catalyst was considerably more effective at lower temperatures
(Table 2).30 Employing these conditions with microwave heating
afforded a range of functionalised flavones in good to moderate
yield. Reaction of sterically hindered flavone 5did not generate any
of the required aminated product with only direct haloflavone
reduction observed. Attempts to aminate triflate 13 were low
yielding compared to the bromides and the catalyst mixture was
completely inactive towards triflate 11. Attempts to apply POPd as
an amination catalyst were unsuccessful with both POPd–CsF and
POPd–Cs2CO3 proving completely inactive as catalysts for
amination of 2 with hexylamine. Monoamination of bromo-
chloroflavones 9 and 10 was achieved readily using only one
equivalent of amine, with Pd2(dba)3–BINAP–NaOtBu
Scheme 3 Triflation of hydroxylated flavones.
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from the corresponding bromochloroflavones without intermedi-
ate purification, save filtration, with no loss of overall yield.
In summary, we have successfully demonstrated the power of
the MEDOS strategy by application to a variety of systematically
modified and functionalised flavones, We anticipate this approach
finding widespread applicability in small molecule synthesis and
the development of small molecules as tools for chemical biology.
We thank BBSRC, EPSRC and CEM for support.
Table 2 Buchwald–Hartwig aminations on bromoflavones
Substrate
Yield (%)
83
Substrate
Yield (%)
42
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4816 | Chem. Commun., 2006, 4814–4816
This journal is ß The Royal Society of Chemistry 2006