Rhodium(III)-catalyzed direct oxidative cross coupling at the C5 position of chromones with alkenes

Article abstract of DOI:10.1021/ol303067f

An atom-economical, Rh(III)-catalyzed, direct oxidative cross-coupling at the C5 position of chromones and flavones with a broad range of alkenes was developed. The products were formed in a highly regioselective manner in good to excellent yields. The developed method was applied in the cross-coupling of natural products for the synthesis of hybrid molecules.

Full text of DOI:10.1021/ol303067f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Catalyzed Direct Oxidative
Cross Coupling at the C5 Position of
Chromones with Alkenes
Rajarshi Samanta, Rishikesh Narayan, and Andrey P. Antonchick*
Max-Planck-Institut fu€r Molekulare Physiologie, Abteilung Chemische Biologie,
Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
andrey.antonchick@mpi-dortmund.mpg.de
Received November 7, 2012
ABSTRACT
An atom-economical, Rh(III)-catalyzed, direct oxidative cross-coupling at the C5 position of chromones and flavones with a broad range of alkenes
was developed. The products were formed in a highly regioselective manner in good to excellent yields. The developed method was applied in the
cross-coupling of natural products for the synthesis of hybrid molecules.
Transition-metal-catalyzed carbonÀcarbon or carbonÀ
heteroatom bond-forming transformations via CÀH bond
functionalization reactions have gained significant atten-
tion from the entire chemical community due to their ex-
tensive application in straightforward formation of com-
plex molecular structures.1 Over the past decades, varieties
of processes were developed for the coupling of prefunc-
tionalized building blocks in high yields and with predict-
ableregioselectivity. However, direct methodsfor coupling
of nonprefunctionalized partners can avoid the prepara-
tion of activated coupling partners, and make the synthetic
strategy more atom-economic.2 Cross-dehydrogenative
coupling (CDC) often requires a directing group contain-
ing substrate, a coupling partner with a transition metal,
and a terminal oxidant to furnish the desired regioselec-
tivity and catalytic turnover.2b Among CDC reactions,
oxidative arene olefination3 catalyzed by transition
metals,4 especially rhodium,5,6 have been intensively stu-
died in recent times. Unfortunately, the choice of olefins in
these transformations is typically limited to styrenes and
(1) For recent reviews, see: (a) Dyker, G. Handbook of CÀH Trans-
formations; Wiley-VCH: Weinheim, 2005. (b) Zeni, G.; Larock, R. C. Chem.
Rev. 2006, 106, 4644. (c) Godula, K.; Sames, D. Science 2006, 312, 67and
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Synthesis 2009, 4087. (g) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.;
Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (h) Chen, X.; Engle, K. M.;
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(k) Liu, C.; Zhang, H.; Shi, W.; Lei, A.-W. Chem. Rev. 2011, 111, 1780.
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41, 3381.
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Asian J 2010, 5, 436. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev.
2002, 102, 1731. (e) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318. (f) Yu, D.-G.; Li, B.-J.;
Shi, Z.-J. Tetrahedron 2012, 68, 5130. (g) Li, B.-J.; Shi, Z.-J. Chem. Soc.
Rev. 2012, 41, 5588. (h) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun.
2010, 46, 677. (i) Li, B.; Yang, S.; Shi, Z.-J. Synlett 2008, 7, 949.
(5) For reviews on Rh-catalyzed oxidative coupling reactions, see: (a)
Satoh, T.; Miura, M. Synthesis 2010, 3395. (b) Colby, D. A.; Tsai, A. S.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (c) Song,
G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (d) Satoh, T.;
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R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (f) Patureau, F. W.;
WincelÀDelord, J.; Glorius, F. Aldrichimica Acta 2012, 45, 31.
(2) For selected reviews on CÀH activation, see: (a) Cho, S. H.; Kim,
J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (b) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Xu, L. M.; Li, B. J.;
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r
10.1021/ol303067f
XXXX American Chemical Society

acrylates. This fact has also been highlighted in the recent
review by Glorius et al.5f and others.5aÀe
structural domains having different biological functions.12b
The hybrid approach is a promising direction for medicinal
drugs that can effectively target multifactorial diseases.
Herein, we report a Rh(III)-catalyzed highly regioselective
dehydrogenative cross coupling of a large variety of
chromone derivatives with a broad range of olefins.
Recently Hong et al. developed a direct cross-coupling
between chromones and electron-deficient olefins at the
most electron-rich C3 position of chromone using Pd(OAc)2
as catalyst,7 and Jeganmohan et al. showed that the C5
position of chromone can be alkenylated using a chelation-
assisted ruthenium-catalyzed transformation (Figure 1).8
However, these two methodologies also suffer from limita-
tions in terms of the scope of olefins that can be efficiently
used.
In the wake of these reports and their associated limita-
tions and as part of our studies on the direct functionaliza-
tion of unactivated CÀH bonds,9 we planned to establish a
relatively general methodology for the direct regioselective
functionalization of chromone derivatives at the C5 posi-
tion with a variety of olefins using the keto group of
chromone as directing group.
Moreover, regioselective introduction of chemically ver-
satile alkene moieties to chromone, having multiple reac-
tive sites, is of immense importance as chromones are
present in many biologically active scaffolds.10 We also
thought that the coupling of chromones, if possible, with
quinone derivatives11 which themself are present in many
bioactive scaffolds could provide ready access to a new
class of so-called “hybrid molecules”.12 Hybrid molecules
can be defined as chemical entities with two or more
Figure 1. Dehydrogenative cross-coupling with chromones.
We started our optimization using the simple natural
products chromone13 (1a) and 1,4-naphthoquinone14 (2a)
for Rh(III)-catalyzed CDC. Our initial attempt based on
reported conditions6i,s using stoichiometric amounts of
anhydrous copper acetate as oxidant, 2 mol % of bis-
(pentamethylcyclopentadienylrhodium dichloride) and
8 mol % of AgSbF6 as an additive in tert-amyl alcohol at
100°C led toselective formation of thedesired product(3a)
with an impressive 70% yield (Table 1, entry 1). It is
remarkable; there are six CÀH bonds (two CÀH bonds in
chromone and four in 1,4-naphthoquinone) that can be
activated by transition metal and lead to different regioiso-
meric and dimerized products. Nevertheless, selective for-
mation of only one product was observed. Further screening
of various solvents resulted in the improved isolated yield
of 3a (77%) in 1,4-dioxane (Table 1, entries 1À6). Applica-
tionof copper(II) triflateasoxidant was notabletoprovide
the desired product in detectable amount (Table 1, entry 8).
Among other oxidants tested, Ag2O provided the best
yield with 73% in 17 h (Table 1, entry 10). Unfortunately,
the attempt to use air as an oxidant in the presence of
substoichiometric amounts of anhydrous copper acetate
was not successful (Table 1, entry 7). In further control
experiments, it was revealed that in the absence of Rh(III)
catalyst or additive (AgSbF6) the reaction did not provide
the desired product 3a (Table 1, entries 13 and 14). In
further optimization, it was found that the decrease of the
amount of copperacetate to1.2 equiv or 2ato1.5 equivstill
provided the desired product in comparable isolated yield
(77À79%) after 22 h (Table 1, entry 15 and 16) at 120 °C.
However, a decrease of both substances to 1.2 and 1.5 equiv
led to decreased yields of product (68%) (Table 1, entry 17).
It is important to note that the use of [RuCl2(p-cymene)]2 as
(6) For Rh-catalyzed important recent progress in oxidative cou-
€
pling, see: (a) Schroder, N.; Wincel-Delord, J.; Glorius, F. J. Am. Chem.
Soc. 2012, 134, 8298. (b) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou,
K. Angew.Chem., Int. Ed. 2011, 50, 1338. (c) Rakshit, S.; Grohmann, C.;
Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (d) Stuart,
D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,
18326. (e) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc.
2010, 132, 9585. (f) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2010, 12, 2068. (g) Wang, F.; Song, G.; Li, X. Org. Lett. 2010,
12, 5430. (h) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
9982. (i) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed.
2011, 50, 1064. (j) Xu, X.; Liu, Y.; Park, C.-M. Angew. Chem., Int. Ed.
2012, 51, 9372. (k) Wang, C.; Chen, H.; Wang, Z.; Chen, J.; Huang, Y.
Angew. Chem., Int. Ed. 2012, 51, 7242. (l) Muralirajan, K.; Parthasar-
athy, K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2011, 50, 4169. (m) Wang,
H.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 7318. (n) Li, B.-J.;
Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem., Int. Ed. 2012, 51,
€
3948. (o) Shi, Z.; Schroder, N.; Glorius, F. Angew. Chem., Int. Ed. 2012,
51, 8092. (p) Zheng, L.; Wang, J. Chem.;Eur. J. 2012, 18, 9699. (q)
Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc.
2011, 133, 2154. (r) Song, G.; Chen, D.; Pan, C.-L.; Crabtree, R. H.; Li,
X. J. Org. Chem. 2010, 75, 7487. (s) Stuart, D. R.; Bertrand-Laperle, M.;
Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
(7) For Pd-catalyzed oxidative cross-coupling between the C-3 posi-
tion of chromone with quinone and the electron-deficient double bond,
see: (a) Moon, Y.; Hong, S. Chem. Commun. 2012, 48, 7191. (b) Kim, D.;
Hong, S. Org. Lett. 2011, 13, 4466.
(8) For Ru-catalyzed oxidative cross-coupling between the C-5 posi-
tion of chromone and acrylate, see: Padala, K.; Jeganmohan, M. Org.
Lett. 2011, 13, 6144.
(9) For the results of our group, see: (a) Samanta, R.; Antonchick,
A. P. Angew. Chem., Int. Ed. 2011, 50, 5217.
(10) For the biological activities of chromone, see: Sharma, S. K.;
Kumar, S.; Chand, K.; Kathuria, A.; Gupta, A.; Jain, R. Curr. Med.
Chem. 2011, 18, 3825.
(11) For the biological activities of 1,4 naphthoquinone, see: Babula,
P.; Adam, V.; Havel, L.; Kizek, R. Ceska Slov. Farm 2007, 56, 114.
(12) For the concept of hybrid molecules, see: (a) Tietze, L. F.; Bell,
H. P.; Chandrasekhar, S. Angew. Chem., Int. Ed. 2003, 42, 3996. (b)
Meunier, B. Acc. Chem. Res. 2008, 41, 69. (c) Decker, M. Curr. Med.
Chem. 2011, 18, 1464. (d) Krettli, A. U.; Adebayo, J. O.; Krettli, L. G.
Curr. Drug Targets 2009, 10, 261. (e) Mehta, G.; Singh, V. Chem. Soc.
Rev. 2002, 31, 324.
(13) Silici, S.; Kutluca, S. J. Ethanopharmacol. 2005, 99, 69.
(14) Binder, R. G.; Benson, M. E.; Flath, R. A. Phytochemistry 1989,
28, 2799.
B
Org. Lett., Vol. XX, No. XX, XXXX

catalyst, which is known as the cheaper alternative for this
kind of coupling, under reported optimized conditions
provided only poor yields of the desired product 3a
(Table 1, entries 18 and 19).8 This clearly proves Rh catalyst
to be a more suitable choice for this important transforma-
tion. Finally, we decided to use 2 mol % of Rh(III) catalyst
along with 8 mol % of AgSbF6 and 1.2 equiv of Cu(OAc)2
as oxidant in 1,4-dioxane at 120 °C as the optimized reaction
conditions. Notably, the use of only 1.2 equiv of Cu(OAc)2
as oxidant represents an advancement as usually at least 2
equiv of oxidant is needed in Rh(III)-catalyzed reactions.5f
Table 1. Screening of Reaction Conditionsa
time
(h)
temp
yieldb
(%)
entry
oxidant (equiv)
solvent
(°C)
1
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (0.25)
Cu(OTf)2 (2.2)
AgOAc (2.2)
t-AmOH
12
12
12
12
12
12
45
17
17
17
17
17
17
17
22
22
19
22
24
100
100
100
100
100
100
120
120
120
120
120
120
120
120
120
120
120
120
110
70
2
1,2-DCE
72
3
1,4-dioxane
1,2-DME
toluene
77
4
69
5
traces
n.d.
17
6
DMF
7
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
8
n.d.
41
9
10
11
12
13c
14d
15e
16
17e
18f
19f,g
Ag2O (2.2)
73
AgOCOCF3 (2.2) 1,4-dioxane
n.d.
49
Ag2CO3 (2.2)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,2-DCE
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (2.2)
Cu(OAc)2 (1.2)
Cu(OAc)2 (1.2)
Cu(OAc)2 (1.2)
Cu(OAc)2 (0.25)
traces
n.d.
77
79
68
Figure 2. Scope of the reaction. Reaction conditions:
chromone 1a (0.2 mmol, 1 equiv), alkene (0.6 mmol, 3 equiv),
[(Cp*Rh(III)Cl2)2] 2 mol %, AgSbF6 (8 mol %), anhydrous
Cu(OAc)2 (0.24 mmol, 1.2 equiv), 1,4 dioxane (0.2 M).
aDimethyl maleate was used as alkene. bReaction conditions:
[(Cp*Rh(III)Cl2)2] 5 mol %, AgSbF6 (20 mol %), anhydrous
Cu(OAc)2 (0.44 mmol, 2.2 equiv), 1,4 dioxane (0.2 M).
12
20
a Conditions: Chromone 1a (0.2 mmol, 1 equiv), 2a (0.6 mmol,
3 equiv), oxidant, solvent (0.2 M). b Isolated yields after column chro-
matography. c No AgSbF6 used. d No Rh(III) catalyst used. e 1.5 equiv of
2a used. f 2 mol % of [RuCl2(p-cymene)]2 used. g 10 mol % of AgSbF6
used, and the reaction was performed in 0.33 M concentration on a 1 mmol
scale.
conditions (Figure 2, products 3e and 3d). When we tested
the transformation on flavones having substituents with
different electronic properties, the products were formed
with good yields (Figure 2, products 3fÀh). Notably,
3-arylchromone (isoflavone) can be regioselectively func-
tionalized at the C5 position of chromone, although there
was a possibility that the keto group of the chromone can
direct the olefin to the aryl ring at its C3 position (Figure 2,
product 3i). Further, alkenylation of chromone at the C5
position is also possible with methylbenzoquinone but
with poor yield (26% in 2:1 regioisomeric mixture, see
the Supporting Information).
Having the optimized reaction conditions in hand, we
started to explore the generality of the reaction. Initially,
the effect of substituents at the different positions of
chromone for the cross-coupling with the highly elec-
tron-deficient 1,4-naphthoquinone was studied. Electron-
donating and electron-withdrawing groups in positions C6
and C7 of chromone were tolerated (Figure 2, products 3b
and 3c).
2-Substituted chromones such as flavone (vitamin P)
and R-naphthoflavone were also coupled with naphtho-
quinone with good yields under the optimized reaction
Org. Lett., Vol. XX, No. XX, XXXX
C

Afterward, we turned our attention to acyclic electron-
deficient alkenes. Dimethyl fumarate provided excellent
yields from the cross-coupling with chromone (Figure 2,
product 3j). When dimethyl maleate was used as coupling
partner, the product turned out to be the same as with
dimethyl fumarate (3j) due to thermal isomerization of the
cis-double bond into the more stable trans-bond. In further
continuation, chromone was coupled with methyl acrylate
in excellent yield (Figure 2, product 3k). However, coupl-
ing with methyl vinyl ketone required increased loading of
Rh(III) catalyst to provide moderate yield (Figure 2, product
3l). Notably, electron-deficient as well as electron-rich
styrenes performed comparably well as coupling partners
with excellent yield in each case (Figure 2, products3mÀp).
As an important result, the inactivated double bond of
diethyl 2-allylmalonate underwent oxidative coupling with
chromone smoothly in a regioselective manner. How-
ever, the formed product was further oxidized to give the
inseparable 1:1 mixture of the desired product with the
corresponding conjugated diene (Figure 2, product 3q).
The over-oxidation of the immediate product can be
rationalized due to its high tendency to undergo oxidation
because the resulting product 3q is highly conjugated.
Mechanistically, we assume that this kind of metal-
catalyzed directing-group assisted dehydrogenative Heck
coupling started via CÀH bond activation (Scheme 1). The
catalytic cycle was initiated by the removal of chloride
ligandsfromthe[(Rh(III)Cp*Cl2)2] byAgSbF6 togenerate
a more active rhodium complex. More likely, this active
rhodium species contains ligands like acetate or solvent in
addition to pentamethylcyclopentadienyl (Cp*) ligands.
Coordination of this active rhodium(III) species with the
keto group of 1a and subsequent ortho CÀH bond activa-
tion via the concerted metalation/deprotonation (CMD
process) offered the five-membered rhodacycle intermedi-
ate A. Insertion of alkene to the rhodiumÀcarbon bond of
A led to the formation of the seven membered rhodacycle
B. β-H elimination from intermediate B offered the desired
product 3 with the reduced inactive [RhICp*] complex.
Thus, the essential task of copper acetate is to reoxidise the
[RhICp*] complex to the [RhIIICp*] species to carry on the
catalytic cycle. Moreover, copper acetate could be the
source of acetate ligand for the active rhodium species.15
Scheme 1. Proposed Mechanism of the Cross Coupling
In conclusion, we have developed a Rh(III)-catalyzed,
highly efficient, atom-economical, oxidative cross-coupling
of chromones and flavones with a variety of olefins having
variable electronic character. The desired products were
formed in a highly regioselective manner. This methodology
works efficiently with one of the broadest known ranges of
olefins reported for similar transformations. This method
also provides a practical way to couple structurally different
natural product scaffolds such as chromone, flavones, and
1,4-naphthoquinone in a single-step transformation.
Acknowledgment. We gratefully acknowledge Prof. Dr.
€
H. Waldmann (MPI fur Molekulare Physiologie and TU
Dortmund) for his generous support.
Supporting Information Available. Experimental pro-
cedures, full characterization of new compounds, and
1
copies of H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(15) (a)Guimond,N.;Gouliaras,C.;Fagnou, K. J. Am. Chem. Soc. 2010,
132, 6908. (b) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX