Access to flavones via a microwave-assisted, one-pot sonogashira- carbonylation-annulation reaction

Article abstract of DOI:10.1021/ol901043q

Palladium complexes of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6- phosphaadamantane are shown to be effective catalytic systems facilitating the sequential application of a microwave-assisted Sonogashira and carbonylative annulation reaction for the preparation of substituted flavones.

Full text of DOI:10.1021/ol901043q

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3210-3213
Access to Flavones via a
Microwave-Assisted, One-Pot
Sonogashira-Carbonylation-Annulation
Reaction
Emelia Awuah and Alfredo Capretta*
Department of Chemistry, McMaster UniVersity, Hamilton, Ontario, Canada L8S 4M1
capretta@mcmaster.ca
Received May 20, 2009
ABSTRACT
Palladium complexes of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane are shown to be effective catalytic systems facilitating
the sequential application of a microwave-assisted Sonogashira and carbonylative annulation reaction for the preparation of substituted flavones.
Flavones1 are a major group of secondary metabolites found
throughout the plant kingdom and have been shown to
possess a wide variety of biological activity.2 A number of
classical synthetic approaches to this family of compounds
exist. The Baker-Venkataraman3 method involves the
conversion of 2-hydroxyacetophenones into benzoyl esters,
rearrangement in base to 1,3-diphenylpropane 1,3-diones,
followed by cyclization in acid to yield the flavone ring
system.4 Alternatively, treatment of a 2-hydroxyacetophenone
and benzaldehyde under Claisen-Schmidt conditions yields
a 2-hydroxychalcone that can be oxidatively cyclized to yield
the flavone system.5 Both approaches utilize harsh conditions
such as strong bases, acid, and elevated temperatures. A
particularly attractive alternate approach involves the Pd-
catalyzed carbonylation6/cyclization reaction between 2-io-
dophenols and terminal alkynes.7 Given our work with
palladium complexes of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-
phenyl-6-phosphaadamantane (PA-Ph)8 and their ability to
(4) (a) Lee, K. S.; Seo, S. H.; Lee, Y. H.; Kim, H. D.; Son, M. H.;
Chung, B. Y.; Lee, J. Y.; Jin, C.; Lee, Y. S. Bioorg. Med. Chem. Lett.
2005, 15, 2857–2860. (b) Zembower, D. E.; Zhang, H. J. Org. Chem. 1998,
63, 9300–9305.
(1) Andersen, Ø. M.; Markham, K. R. FlaVonoids: Chemistry, Bio-
chemistry, and Applications; CRC Press: Boca Raton, FL, 2006.
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Choi, J.; Min Lim, K.; Hoon Lee, C.; Chung, S. Bioorg. Med. Chem. Lett.
2003, 13, 413–417. (f) Yang, X.; Sun, Y.; Xu, Q.; Guo, Z. Org. Biomol.
Chem. 2006, 4, 2483–2491.
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Castellano, E. E.; Vidal, A.; Azqueta, A.; Monge, A.; de Cera´in, A. L.;
Sagrera, G.; Seoane, G.; Cerecetto, H.; Gonza´lez, M. Bioorg. Med. Chem.
2007, 15, 3356–3367. (b) Hemanth Kumar, K.; Perumal, P. T. Tetrahedron
2007, 63, 9531–9535. (c) Yao, N.; Song, A.; Wang, X.; Dixon, S.; Lam,
K. S. J. Comb. Chem. 2007, 9, 668–676.
(6) Barnard, C. F. J. Organometallics 2008, 27, 5402–5422.
(7) (a) Ciattini, P. G.; Morera, E.; Ortar, G.; Rossi, S. S. Tetrahedron
1991, 47, 6449–6456. (b) Liang, B.; Huang, M.; You, Z.; Xiong, Z.; Lu,
K.; Fathi, R.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 6097–6100. (c)
Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765–1768. (d) Torii, S.; Okumoto,
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Venkataraman, K. J. Chem. Soc. 1934, 1767–1769.
(8) Available from Cytec Canada Inc., PO Box 240, Niagara Falls,
Ontario, L2E 6T4, Canada.
10.1021/ol901043q CCC: $40.75
Published on Web 07/06/2009
 2009 American Chemical Society

catalyze the coupling of aryl halides with terminal acety-
lenes,9 we envisioned a reaction sequence wherein the
product of a Sonogashira reaction could then undergo Pd-
catalyzed carbonylative annulation with a 2-iodophenol to
yield a flavone scaffold. The present paper describes a
microwave-assisted, one-pot method that allows the efficient
and mild preparation of flavones from aryl halides and
2-iodophenol derivatives.
Table 2. Flavones and Chromones via a Pd-Catalyzed
Carbonylation-Cyclization Reactiona
Our initial effort focused on the Pd-catalyzed carbonylation
annulation reaction between 2-iodophenol and 1-hexyne
using the PA-Ph ligand. The screening of various Pd sources,
solvents, temperatures, and bases is presented in Table 1.
Table 1. Optimization of Pd-Catalyzed
Carbonylation-Annulation Conditionsa
Pd
temp (°C)/
entry source
solvent
H2O
base
Et3N
(iPr)2NEt
Et3N
Cs2CO3
time (h) % yield
1
PdCl2
25/2
25/2
25/2
25/2
25/2
25/2
25/2
25/14
25/2
25/2
25/14
25/14
50/4
50/4
0
42
0
54
0
0
2
Pd2(dba)3 MeCN
Pd2(dba)3 MeCN
Pd2(dba)3 MeCN
Pd2(dba)3 dioxane
Pd2(dba)3 toluene
Pd2(dba)3 THF
3
4
5
(iPr)2NEt
(iPr)2NEt
(iPr)2NEt
Cs2CO3
6
7
20
40
0
8
Pd2(dba)3 THF
Pd2(dba)3 toluene/THF
9
(iPr)2NEt
a Reactions were carried out using 0.50 mmol of the substituted
2-iodophenol and 0.75 mmol of the alkyne. b Isolated yield. c 50 °C, 4 h.
d 50 °C, 12 h.
10
11
12
13
14
Pd2(dba)3 toluene/MeCN (iPr)2NEt
0
Pd2(dba)3 DMSO
Pd2(dba)3 DMF
Pd2(dba)3 DMF
Pd2(dba)3 DMF
Cs2CO3
Cs2CO3
Cs2CO3
DBU
20
76
91
93
a Reactions were carried out using 0.50 mmol of 2-iodophenol and 0.75
mmol of 1-hexyne.
h). The lower yield observed for entry 8 was not due to
desilylation as might be expected; rather, under the conditions
employed, significant amounts of starting material remain
unreacted. It is likely that the electron-donating substituents
on the aryl iodide slow the rate of oxidative addition with
the Pd-catalyst system.
Microwave-assisted organic synthesis has demonstrated
itself to be superior in many instances when compared to
reactions carried out using conventional heating.10 The use
of microwave irradiation often helps to reduce reaction times,
minimize side products, increase yields, and improve repro-
ducibility. A number of examples of microwave-assisted
carbonylation reactions have been described in the litera-
ture.11 These previous approaches have generally utilized
Mo(CO)6 and, as a result, require elevated temperatures to
induce the decomposition of the molybdenum reagent and
Reagents were combined in a reaction vessel, and the reaction
was carried out under 1 atm of CO gas. These experiments
quickly revealed that using DMF as the solvent with Cs2CO3
or DBU as the base at 50 °C resulted in 91% and 93%
isolated yield, respectively, of the desired flavone (Table 1,
entries 13 and 14). Under these conditions we produced the
flavone products exclusively and did not observe any of the
aurone byproduct. The relatively low catalyst loading (1.5
mol % equivalent of Pd2(dba)3 and 3 mol % equivalent of
PA-Ph), short reaction time, high conversion, and mild
temperatures render our catalytic system more efficient than
previously reported protocols.7
With the optimal set of conditions in hand, we proceeded
to generate a small library of flavones (Table 2). Overall,
the method works well and tolerates a variety of functional
groups. With entries 2 and 5, desilylation during the
annulation step proceeds without the need for any additional
reagents. Entries 8 and 9 required longer reaction times (12
(10) (a) Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical
MicrowaVe Synthesis for Organic Chemists-Strategies, Instruments, and
Protocols; Wiley-VCH: Weinheim, 2009. (b) MicrowaVes in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002.
(11) (a) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750–5753.
(b) Wannberg, J.; Kaiser, N.-F. K.; Vrang, L.; Samuelsson, B.; Larhed,
M.; Hallberg, A. J. Comb. Chem. 2005, 7, 611–617. (c) Gremmen, C.;
Willemse, B.; Wanner, M. J.; Koomen, G. J. Org. Lett. 2000, 2, 1955–
1958. (d) Lagerlund, O.; Larhed, M. J. Comb. Chem. 2006, 8, 4–6. (e) Wu,
X.; Ekegren, J. K.; Larhed, M. Organometallics 2006, 25, 1434–1439.
(9) Adjabeng, G.; Brenstrum, T.; Frampton, C. S.; Robertson, A. J.;
Hillhouse, J.; McNulty, J.; Capretta, A. J. Org. Chem. 2004, 69, 5082–
5086.
Org. Lett., Vol. 11, No. 15, 2009
3211

Table 3. Microwave-Assisted Sonogashira Reactionsa
Table 4. Flavones via a Microwave-Assisted
Sonogashira-Carbonylation-Cyclization Reactiona
a Reactions were carried out using 1.0 mmol of aryl halide and 1.5
mmol of alkyne. b Isolated yield.
a Reactions were carried out using 1.0 mmol of aryl halide, 1.5 mmol
of alkyne, and 0.5 mmol of substituted 2-iodophenol. b Isolated yield over
two steps based on starting amount of substituted 2-iodophenol used.
liberation in situ of CO gas. Given the relatively mild
temperatures used above and the efficacy of the PA-Ph
ligand, we examined the effect of microwave heating on our
reaction conditions. We determined, ultimately, that com-
parable yields for the carbonylation-annulation reaction
could be obtained when the reaction mixture was irradiated
in a microwave at 90 °C using a shortened reaction time of
only 30 min. However, a much improved yield of 68% was
obtained when the microwave-assisted conditions were
applied to preparation of the TBDMS-protected flavone
(Table 2, entry 8). While the use of a CEM gas addition
unit12 greatly facilitated the introduction of CO into the
reaction vessel, we also found that simply bubbling CO gas
into the reaction prior to microwave irradiation allowed an
equally efficient reaction and avoided the need for Mo(CO)6.
so as to integrate with those developed for the carbonylation-
annulation reaction. In this way, we found that the optimal
conditions (1.5% Pd2(dba)3; 3% PA-Ph, DMF, DBU) using
microwave irradiation allowed a reduction in reaction times
and the elimination of the CuI co-catalyst generally required
by the Sonogashira reaction (see Table 3). For example, the
coupling of p-iodotoluene with phenylacetylene (entry 2)
could be achieved at 90 °C in 30 min in 96% yield. When
aryl bromides were used (entries 6-9) as coupling partners,
an increase in temperature (to 120 °C) allowed excellent
yields with comparable reaction times.
Having established the conditions and scope of both the
microwave-assisted, Pd-catalyzed carbonylative-annulation
and the Sonogashira reaction, a natural extension of the work
involves a sequential combination of the two reactions
effectively allowing a one-pot flavone synthesis.
The alkyne required for the Pd-catalyzed carbonylative
annulation developed above could be generated via a
Sonogashira reaction. Using our previously developed pro-
tocol as a starting point,9 we modified the reaction conditions
In all cases, the initial microwave-mediated Sonogashira
reaction involved an aryl halide and TMS acetylene. The
products from this reaction were then introduced into a
reaction vessel containing the iodophenol, fresh Pd/PA-Ph
(12) Available from CEM Corporation, P. O. Box 200, 3100 Smith Farm
Road, Matthews, NC 28106, USA.
3212
Org. Lett., Vol. 11, No. 15, 2009

catalyst system, solvent, and base. Introduction of CO
followed by microwave irradiation allowed the preparation
of the flavones listed in Table 4. It should be noted that
addition of TBAF in the second step allowed deprotection
of the TMS group and permitted a smoother, more reproduc-
ible annulation reaction. The yields of the isolated flavone
range from moderate to very good with the entire sequence
completed in approximately 1 h.
iodides and bromides as well as substituted o-iodophenols),
the method should prove valuable in the preparation of
combinatorial libraries of flavones.
Acknowledgment. The authors thank the Natural Sciences
and Engineering Research Council of Canada for their
financial support.
Overall, the synthetic method developed above for the
preparation of substituted flavones involves mild reaction
conditions and relatively short reaction times and provides
good yields of the desired products. Given the range of
commercially available components for this protocol (aryl
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901043Q
Org. Lett., Vol. 11, No. 15, 2009
3213