Hypoiodite-catalysed oxidative cyclisation of Michael adducts of chalcones with 1,3-dicarbonyl compounds: A facile and versatile approach to substituted furans and cyclopropanes

Article abstract of DOI:10.1039/c6cc06624k

Through hypoiodite catalysis, oxidative cyclisation of Michael adducts of chalcones with 1,3-dicarbonyl compounds for divergent synthesis of either furans or cyclopropanes is developed. The selective synthesis of major products is achieved depending on the use of different reaction conditions or substrates.

Full text of DOI:10.1039/c6cc06624k

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Hypoiodite-Catalysed Oxidative Cyclisation of Michael Adducts of
Chalcones with 1,3-Dicarbonyl compounds: A Facile and Versatile
Approach to Substituted Furans and Cyclopropanes
Received 00th January 20xx,
Accepted 00th January 20xx
Wen-Chao Gao,* Fei Hu, Jun Tian, Xing Li, Wen-Long Wei and Hong-Hong Chang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Through hypoiodite catalysis, the oxidative cyclisation of Michael
adducts of chalcones with 1,3-dicarbonyl compounds for divergent
synthesis of either furans or cyclopropanes is developed. The
selective synthesis of major products is achieved depending on the
use of different reaction conditions or substrates.
(1) Pr evious wor k
R4
O
O
O
R1
transition-metal
catalyst
R4 (R5)
+
R1
R2
R1
H
R3
CO2R
R2
R3
O
R4 = H, CHO, CO2R
Catalytic functionalization reactions of C−H bond adjacent to a
carbonyl group have aroused considerable attention with
much progress achieved.1 Apart from the use of transition
metal catalysis and hypervalent iodine compounds, C-H
oxidation catalysed by hypoiodite generated in situ from
iodine source with peroxide compounds has become an
efficient and environmentally benign alternative for diverse
transformations in recent years.2 Ishihara and co-workers
reported the seminal work of asymmetric oxidative
cycloetherification by in situ generated hypoiodite catalyst,
and chiral dihydrobenzofuran and tetrahydrobenzopyran cores
could be constructed with high efficiency and
enantioselectivity.3 This catalytic oxidation system has been
also applied to the synthesis of various other heterocycles,
RO2C
CO2R
Iodine or
R1
hypervalent iodine reagent
O
CO2R
stoichometric amount
O
R2
R1
R1
(2) This work
O
R3
NIS(cat.), DBU, TBHP
O
R1
O
O
Hypoiodite
catalyst
R3
CO2R4
R2
CO2R4
COR3
R4O2C
R2
TBAI (cat.), TBHP
O
R2
R1
Scheme 1. Strategies for furan and cyclopropane construction from 1,3-
dicarbonyl compounds
benzoxazoles,4
aziridines,5
oxazoles,6
skeletons led to numerous synthetic strategies being
developed over the years.14 Among these methods, 1,3-
dicarbonyl compounds or their derivatives were usually
utilized as raw materials to construct both furans and
cyclopropanes [Scheme 1 (1)]. For example, Ag-mediated or
Au-catalysed dehydrogenative cross-coupling reaction of 1,3-
dicarbonyl compounds with terminal alkynes,15 Pd(II)-catalysed
oxidative difunctionalisation of enol ethers with 1,3-diones16
and Cu(I)-Catalysed addition/oxidation cyclisation from
alkynoates and 1,3-diones17 could efficiently offer access to
substituted furans. As for the cyclopropanation reaction, one
of the most promising methods focused on directly oxidative
cyclisation of Michael adducts of 1,3-diesters with chalcones
by using stoichiometric or excess amount of iodine or
hypervalent iodine reagents.13a,18 The efficient synthesis of
either furans or cyclopropanes with metal-free catalyst from
the same substrate, however, to the best of our knowledge,
remains elusive and would bring much advantages over
existing methods. As part of our continuing interest in iodine
catalysis,19 herein, we report a transition metal-free protocol
such
as
imidazopyridines,7 and lactones.8 These reactions were
believed to proceed through the hypoiodite-catalysed
activation of C-H bond, which can be attacked by a nucleophile
to form new C-O or C-N bond. Despite these achievements, the
hypoiodite catalysis for oxidative C-C bond formation has been
rarely reported.9
Furans and cyclopropanes are ubiquitous and privileged
frameworks in nature. In particular, substituted furans and
cyclopropanes not only appear in many pharmaceuticals,10
organic functional materials11 and natural products,12 but also
perform various transformations to produce many useful
building blocks.13 Therefore, the significance of these two
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to yield either substituted furans or cyclopropanes as major and desired products were afforded in moderate yields (2b
products through hypoiodite catalysed oxidative C-O or C-C and 2c). Chloride substituent could be tolerated in this
bond formation from Michael adducts of
β-keto esters by transformation, and the reaction proceeded to give the
tuning the reaction conditions[Scheme 1(2)], and these two desired product 2d and 2i in 53% and 68% yields respectively.
skeletons can be also selectively produced by using adducts of Additionally, the exact structure of 2i was also unequivocally
chalcone with 1,3-diketones or 1,3-diesters as substrates confirmed by single-crystal X-ray analysis (See the ESI
under the same metal-free conditions. details). Substrates bearing thienyl, furyl, and naphthyl groups
Initially, a set of experiments were carried out to evaluate were well-suited for this transformation, and gave the
the reaction conditions using Michael adduct 1a, derived from corresponding furans in moderate yields (2e-g 2j and 2k).
the FeCl3-catalysed addition of ethyl benzoyl-acetate to Furthermore, we also varied the -keto ester moiety of
† for
,
β
chalcone,20 as the model substrate. The best result for furan Michael adducts for the cyclisation reaction. For example, the
construction (66%) was obtained using the combination of NIS adducts of ethyl 4-methoxylbenzoylacetate or ethyl 3-(2-furyl)-
(10 mol %), DBU (2 equiv) and TBHP (70% in water, 3 equiv) in 3-oxopropanoate with chalcone gave furan derivatives as
2 mL of 1,4-dioxane, along with cyclopropane 3a produced in major products (2l and 2m), while the substrate derived from
30% yield with excellent stereoselectivity21 (See the ESI
† for the addition of ethyl pivaloylacetate with chalcone only
details). After getting the optimized reaction conditions, we furnished the furan product 2n in 41% yield along with
firstly investigated the functional group tolerance of NIS- cyclopropane product in 53% yield. Moreover, we also
catalysed etherification/dehydrogenation for the synthesis of investigated the oxidative cyclisation by using adducts of
substituted furans (Table 1). As anticipated, the variation of chalcone with 1,3-diketones or 4-hydroxycoumarin, to our
substituents on the phenyl ring of chalcones did not hamper delight, furan derivatives were exclusively produced in good to
the catalytic progress, and cyclopropane derivatives were high yields (2o-q).
produced as byproducts in most cases. Electron-rich methyl
Table 2 Substrate scope of substituted cyclopropane constructiona
and methoxyl groups were suitable for this reaction,
R3
R4
TBAI (10 mol %)
TBHP (3 equiv)
THF, reflux
Table 1 Substrate scope of substituted furan constructiona
O
R2
O
O
O
R1
R3
O
R2
O
R4
R1
1 or 4
3 or 5
O
O
O
Ph
Ph
Ph
Ph
O
S
Ph
R
EtO2C
EtO2C
Ph
EtO2C
O
O
O
R = H, 3a, 2 h, 76 %
R = Me, 3b, 2 h, 74%
3e, 2 h, 61%
3f,1.5 h, 58%
R
R = OMe, 3c, 1.5 h, 70%
R = Cl, 3d, 2 h, 69%
O
O
O
O
Ph
Ph
Ph
EtO2C
Ph
EtO2C
Ph
O
O
EtO2C
Ph
3j, 5 h, 52%
R = Me, 3h, 1h, 79%
R = Cl, 3i, 1h, 72%
O
3g, 1.5 h, 62%
O
O
S
O
Ph
Ph
Ph
EtO2C
Ph
Ph
EtO2C
O
EtO2C
Ph
OMe
O
O
O
3m, 6 h, 50%
3k, 2 h, 63%
3l, 1.5 h, 66%
R2
O
O
O
Ph
Ph
Ph
RO2C
Ph
EtO2C
CO2R
R1
EtO2C
CO2Et
O
R = Et, 5a, 2 h, 94%b
R = Me, 5b,3 h, 93%b
R1 = H, R2 = OMe, 5c, 2 h, 93%b
R1 = Cl, R2 = H, 5d, 2.5 h, 96%b
3n, 4 h, 53%b
a Conditions unless specified otherwise: 1 (0.1 mmol), TBAI (0.01 mmol), TBHP (5-
6 M in decane, 0.3 mmol) stirred at reflux in 2 mL of THF. b Reaction conditions: 4
(0.1 mmol), NIS (0.01 mmol), TBHP (70% in water)(0.2 mmol), DBU (0.2 mmol),
stirred at 50 oC in 2 mL of 1,4-dioxane.
a Reaction conditions: 1 (0.1 mmol), NIS (0.01 mmol), DBU (0.2 mmol), TBHP (70%
in water, 0.3 mmol); reaction time and isolated yields were shown; yields of
cyclopropanes were given in parentheses.
In view of our success in the synthesis of substituted furans,
we envisioned that the yields of byproduct cyclopropanes with
excellent diastereoselectivity could be able to be improved by
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tuning the reaction conditions. We thus explored the the attack of enol carbon in enol-ketone equilibrium to form
possibility of selectively oxidative C-C bond formation using 1a cyclopropane 3a (Path b).25 The high diastereoselectivity of 3a
as the substrate, and the best result (76% yield of 3a) was is probably attributed to the intermediate
obtained in the presence of TBAI (10 mol %), TBHP (5-6 M in equilibrate to the thermodynamically more stable
decane, 3 equiv) in 2 mL of THF at reflux, with furan product conformation ( ), whereby the benzoyl group and the phenyl
being not observed (See the ESI for details). Subsequently, we group adopt the opposite position to avoid the unfavourable
C being long-lived to
F
†
further studied the substrate scope by treating various Michael interaction. After cyclisation, the released iodide ion could
adducts under optimal reaction conditions (Table 2). regenerate hypoiodite species for the next catalytic cycle.
Substrates with different functional groups on chalcone
moiety, regardless of their electro-rich or deficient properties,
were all suitable for this oxidative C-C bond formation, and
gave their corresponding cyclopropanes in moderate to good
yields (3b-d, 3h, and 3i). Other aromatic systems like furyl and
thienyl rings were also well tolerated, and heterocyclic
substituted cyclopropanes were obtained in moderate yields
(
3e
chalcone with ethyl benzoylacetate, substrates derived from
ethyl 4-methoxyl-benzoylacetate, ethyl 3-(2-furyl)-3-
, 3f, 3j and 3k). Compared with standard Michael adducts of
oxopropanoate and ethyl pivaloylacetate showed a decreased
reactivity for this transformation (3l-n). It was worth noting
that the reactions using the utilization of Michael adducts of
1,3-diesters with chalcones proceeded well and gave the
desired cyclopropane products in excellent yields (5a-d).
Furthermore, to demonstrate the practicability of this catalytic
system, we tried to reduce the loading of catalyst and expand
the reaction scale. Fortunately, although the reaction was
performed with 3 mmol of Michael adduct 4a (1.1 g) and 1 mol
% of NIS [turnover number (TON) of the catalyst = 100], the
product 5a was obtained in 84% yield. This result suggested
that the catalytic cyclopropanation would provide convenient
and practical access to the synthesis of a serious of heterocycle
derivatives.13
To gain the insight of the reaction mechanism, several
control experiments were subsequently conducted (See the
ESI† for details). NIS used to serve as an iodine radical reagent
for various transformations, while the addition of 1 equiv of
radical-trapping reagent TEMPO did not inhibit the present
reaction progress and no TEMPO-bound adduct was detected
under standard reaction conditions despite a slight change in
the ratio of 2a to 3a. Therefore, the iodine-radical mechanism
was not likely involved in the furan construction. Besides, no
furan or cyclopropane product was detected by using a
stoichiometric amount of iodine as the oxidant, which implied
that the oxidation involving iodine could also be excluded.
Scheme 2. A tentative mechanism
Oligofuran-based materials are biodegradable and have
been extensively investigated as organic electronic devices
owning to their superior electronic properties.11 With three
bifuran derivatives 2f
properties were determined by fluorescence measurements
(See the ESI for details). In the photoluminescence spectra, 2f
, 2j and 2m in hands, their photophysical
Based on these observations and literature reports,2-8
a
†
and 2m had an emission maximum at 385 nm and 337 nm,
while the fluorescent of 2j had a vibronically split band at
around 328 nm and 440 nm. These results indicated that the
resulted bifuran derivatives had potential applications in
organic electronic materials.
tentative mechanism was proposed in Scheme 2. The oxidation
of iodide with TBHP3b or the reaction of NIS with water in the
presence of DBU22,23 would probably produce hypoiodite
species, which activated the α-position of 1a to form the
intermediate . Subsequently, different reaction conditions
A
In summary, we have developed a metal-free method for
selective synthesis of furans or cyclopropanes involving
hypoiodite catalysis. The product selectivity was achieved
depending on the use of different reaction conditions or
led to distinctively reaction pathways to form either C-O or C-C
bond. Under basic conditions, the enolate anion of
intermediate
position to form dihydrofuran
further oxidative dehydrogenation with
combination to give 2a 24
In contrast, under neutral conditions,
the activated -carbon of intermediate tended to receive
A
would be generated and attack the activated
(Path a), which underwent a
DBU/I-/TBHP
D
substrates: for adducts of β-keto esters, furan products were
obtained as the major products through NIS-catalysed
a
.
oxidative cycloetherification/dehydrogenation in the presence
α
A
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11 (a) O. Gidron, Y. Diskin-Posner and M. Bendikov, J. Am.
of DBU base, while cyclopropanes with excellent
diastereoselectivity were exclusively produced using TBAI as
the catalyst under neutral conditions; besides, under the same
catalytic oxidation system (NIS/DBU/TBHP), adducts of 1,3-
diketones preferred to give furan products, whereas adducts
of 1,3-diesters favoured to form cyclopropanes via C-C bond
formation. Synthetically, this catalytic system for
cyclopropanation could be scaled up to gram scale and catalyst
loading could be reduced to 1 mol % with high efficiency.
Moreover, the prepared bifuran derivatives showed notable
photophysical properties. Further studies on the application of
the method are in progress in our laboratory and will be
reported in due course.
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Scientific and Technological Innovation Programs of Higher
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3
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