Construction of trisubstituted chromone skeletons carrying electron-withdrawing groups via PhIO-mediated dehydrogenation and its application to the synthesis of frutinone A

Article abstract of DOI:10.3762/bjoc.15.291

The construction of the biologically interesting chromone skeleton was realized by PhIO-mediated dehydrogenation of chromanones under mild conditions. Interestingly, this method also found application in the synthesis of the naturally occurring frutinone A.

Full text of DOI:10.3762/bjoc.15.291

Construction of trisubstituted chromone skeletons
carrying electron-withdrawing groups via PhIO-mediated
dehydrogenation and its application to the synthesis of
frutinone A
Qiao Li1, Chen Zhuang1, Donghua Wang1, Wei Zhang1, Rongxuan Jia1, Fengxia Sun2,
Yilin Zhang3 and Yunfei Du*1,§
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2958–2965.
1Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, China, 2College of Chemical and Pharmaceutical
Engineering, Hebei University of Science and Technology; Hebei
Research Center of Pharmaceutical and Chemical Engineering,
Shijiazhuang 050018, China and 3C. Eugene Bennett Department of
Chemistry, West Virginia University, Morgantown, WV 26506-6045,
United States
doi:10.3762/bjoc.15.291
Received: 09 October 2019
Accepted: 27 November 2019
Published: 12 December 2019
Associate Editor: D. Y.-K. Chen
© 2019 Li et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Yunfei Du* - duyunfeier@tju.edu.cn
* Corresponding author
§ Tel: +86-22-27406121
Keywords:
chromanone; chromone; dehydrogenation; frutinone A; PhIO
Abstract
The construction of the biologically interesting chromone skeleton was realized by PhIO-mediated dehydrogenation of chro-
manones under mild conditions. Interestingly, this method also found application in the synthesis of the naturally occurring fruti-
none A.
Introduction
The chromone system and its derivatives are an important class cidal [12], wound-healing [13], and immune-stimulatory activi-
of heterocyclic compounds, the skeleton of which widely exists ties [14]. For instance, flavoxate [15,16] is a chromone deriva-
in a variety of natural products and medicinal agents [1-3]. It tive that was employed as an anticholinergic agent for its
was found that chromone derivatives exhibit a wide range of antimuscarinic effects [3,17]; apigenin can function as an
pharmacological effects, including antibacterical [4], antifungal antiviral drug for the treatment of HIV [18,19], cancer [20-22],
[5,6], anticancer [7], antioxidant [8], anti-HIV [9], antiulcer, and other viral infections [23]; pranlukast [24] can be used in
immunostimulator [10], anti-inflammatory [11], as well as bio- the treatment of allergic rhinitis [25] and asthma [26]; and
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khellin [27] has been proved to possess antiviral and antispas- (IBX) could also effectively dehydrogenate chromanones to
modic effects (Figure 1) [28]. All of these pharmaceutical chromones (Scheme 1d, method 1) [63]. Moreover, active
agents bear a chromone framework in their respective chemical MnO2 was also found useful in the oxidative dehydrogenation
structure.
of chromanones at a relatively high temperature of 110 °C
(Scheme 1d, method 2) [64,65]. Although all of the above
methods have their respective merits in the preparation of the
corresponding chromone derivatives, it is obvious that some of
them suffer from drawbacks, such as the requirement of a high
reaction temperature, extended reaction time, involvement of
transition metal catalysts, and low yield. In these regards, the
development of alternative approaches that can realize an effi-
cient synthesis of chromones under mild conditions is desirable.
Figure 1: Biologically active chromone derivatives.
Since the chromone derivatives have a variety of biological ac-
tivities, developing synthetic methods for efficient construction
of the chromone skeleton has been a research field of great
interest and long history [2]. Among the numerous synthetic ap-
proaches [29-54], the dehydrogenative oxidation of the readily
available chromanones is a highly efficient method for the syn-
thesis of this privileged class of heterocycles. For example, Kim
and co-workers reported that chromones could be prepared via a
Scheme 1: Methods for the synthesis of chromones via dehydrogena-
tive oxidation of chromanones.
Pd(II)-catalyzed [55-57] dehydrogenation of chromanone deriv- In recent decades, hypervalent iodine reagents have emerged as
atives at 100 °C in DMSO (Scheme 1a) [58]. The synthesis of a class of efficient and environmentally benign nonmetal
chromones could also be realized by DDQ-mediated dehydro- “green” oxidants [66-73]. For instance, iodosobenzene (PhIO)
genation of chromanones under heating in dioxane (Scheme 1b) [74] has been widely used in many synthetic transformations. It
[3,59,60]. In 2005, Yang and co-workers reported that was found that PhIO is efficient in realizing epoxidation of
chromones could be formed by microwave irradiation of the olefins [75-77], converting alkynes and alkenes to ketones [78],
corresponding chromanone reactants and N-bromosuccinimide oxidizing alcohols to aldehydes [79,80], as well as in the direct
(NBS) in the presence of a catalytic amount of azobis(iso- α-hydroxylation of ketones [81]. Furthermore, it could also be
butyronitrile) (AIBN) in CCl4 (Scheme 1c) [61,62]. In 2002, used to realize oxidative C–C [82], C–N [83], and C–O [84]
Nicolaou and co-workers found that ortho-iodoxybenzoic acid bond formations. However, to the best of our knowledge, PhIO
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has never been utilized for the dehydrogenative oxidation reac-
tion. In this letter, we report a facile PhIO-mediated dehydroge-
nation of chromanones, resulting in the efficient synthesis of bi-
ologically interesting chromone compounds under metal-free
conditions.
Table 1: Optimization of reaction conditions.a
Results and Discussion
We initially studied the feasibility of converting chromanone
ethyl 4-oxo-2-phenylchromane-3-carboxylate (1a) to chromone
2a via PhIO-mediated dehydrogenation. To our delight, when
1a was treated with PhIO in DCE at room temperature, the
desired product 2a could be obtained in 66% yield (Table 1,
entry 1), with the generation of some unidentified byproducts.
A solvent screening identified DMF to be the most appropriate
solvent for this transformation (Table 1, entries 1–9). Other
commonly employed oxidants, including phenyliodine(III)
diacetate (PIDA), phenyliodine(III) bis(trifluoroacetate) (PIFA),
and iodylbenzene (PhIO2), were found to be less efficient for
this transformation, as the desired product 2a was generated in
significantly lower yield in each case (Table 1, entries 10–12).
Further studies indicated that the reaction gave the best result if
performed at room temperature, while reduced or elevated tem-
perature (0 or 50 °C) was not beneficial for the reaction
(Table 1, entries 13 and 14). In addition, the amount of PhIO
was proved to be critical for this transformation, as a decreased
yield of the desired product, accompanied with more byprod-
ucts, was observed when increasing the PhIO amount from 2.0
to 3.0 mmol. When the amount of PhIO was reduced to
1.0 mmol, the yield also decreased due to the fact that the
entry
oxidant
solvent
T (°C)
yield
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15c
16d
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PIDA
PIFA
PhIO2
PhIO
PhIO
PhIO
PhIO
DCE
THF
toluene
1,4-dioxane
DMSO
DMF
MeOH
MeCN
EtOAc
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
66
57
42
33
53
89
33
37
35
62
21
46
38
65
64
78
DMF
DMF
DMF
DMF
DMF
DMF
50
rt
rt
aReaction conditions: 1a (1.0 mmol), oxidant (2.0 mmol), solvent
(6 mL). bIsolated yield. c1a (1.0 mmol), PhIO (1.0 mmol), DMF (6 mL).
d1a (1.0 mmol), PhIO (3.0 mmol), DMF (6 mL), 10 min.
starting material could not be completely consumed (Table 1, cally hindered, and heterocyclic groups, all reacted smoothly
entries 15 and 16). Based on the above screening results, the and afforded the desired chromone derivatives 2k–v in accept-
optimal reaction conditions were concluded to be 1.0 mmol of able to good yields. Furthermore, when the ethoxycarbonyl
substrate, 2.0 mmol of PhIO, DMF as solvent, and 10 minutes group R3 was replaced by an acetyl substituent, the resulting
reaction time at room temperature.
substrate was successfully converted to 2w with a high yield.
However, when the substrate bore a strong electron-with-
With the optimized conditions in hand, we explored the scope drawing cyano group, the reaction was less efficient. and the
and generality of the newly established method. As shown in product 2x was produced in a much lower yield. When the elec-
Scheme 2, a wide range of chromanones could be well toler- tron-withdrawing group (R3) in substrate 1 was replaced by
ated under the standard conditions, affording the expected prod- hydrogen, the corresponding product 2y was obtained in a rela-
ucts 2a–x in satisfactory to good yields. Substrates bearing tively low yield. To our disappointment, the method was not
various R1 substituents (F, Cl, Br, CN, NO2, Me, OMe) were all applicable to the synthesis of 4-chromones, as the reaction of
efficiently converted to the corresponding products 2a–i, with 4-chromanones did not occur under the standard conditions
the substrates carrying electron-donating groups affording the (2z). But when R3 was a carbonyl group and R2 was a hydro-
desired products 2h and 2i in noticeably higher yields than gen atom, the corresponding compound 1aa could also be con-
those with electron-withdrawing groups, 2b–g. The product 2g, verted to the desired product with 35% yield. On the basis of
with an electron-withdrawing group in ortho position, was these results, we tentatively proposed that the failure of 1z for-
formed in a much lower yield, most likely due to steric mation might have been caused by the absence of a carbonyl
hindrance. When the phenyl group was replaced by a naphthyl group in its chemical structure [85].
group, less of the corresponding substrate was converted to the
desired product 2j. The substrates bearing various R2 substitu- Control experiments were designed and conducted to elucidate
ents, including electron-withdrawing, electron-donating, steri- the reaction mechanism of this transformation. When 3 equiv of
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Scheme 2: Substrate scope studies. Reaction conditions: 1 (1.0 mmol), PhIO (2.0 mmol), DMF (6 mL), rt. Isolated yields are given.
TEMPO, a radical-trapping reagent, were added to the reaction (Scheme 3, method b). Since the reaction was not greatly
mixture, product 2a was obtained in 55% yield (Scheme 3, suppressed in both cases, we tentatively propose that this dehy-
method a). When another radical-trapping reagent, BHT, was drogenative oxidation reaction may undergo both radical and
used, the reaction gave 50% yield of the desired product 2a nonradical pathways.
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Beilstein J. Org. Chem. 2019, 15, 2958–2965.
One practical application of the obtained chromone derivatives
was their conversion to chromone-derived natural products.
Frutinone A, isolated from the leaves and root bark of Polygala
fruticosa, shows various biological activities, including antibac-
terial, antioxidant, and potent cytochrome P450 1A2 inhibition
(CYP1A2, IC50 = 5.3 nM) properties [90-92]. Treating the ob-
tained chromene-3-carboxylate 2l with LiOH [93] led to the for-
mation of the chromene-3-carboxylic acid G. Heating com-
pound G overnight in the presence of AgNO3 and K2S2O8
Scheme 3: Control experiments for mechanistic studies.
Based on previous reports [63,86] and our own experimental afforded frutinone A in an isolated yield of 45% (Scheme 5).
results, two plausible mechanisms for this dehydrogenation
reaction are proposed (Scheme 4): In pathway a, substrate 1a is
first tautomerized to its enol form A, which would be stabilized
by an internal H-bond. It is highly likely that the enolization is a
necessary process for the reaction to occur, as compound 2z
could not undergo the transformation under the standard condi-
tions. Then, nucleophilic attack on the iodine center of PhIO
[87] by the enol moiety of intermediate A affords the O–I enol
form C (via intermediate B), which is subsequently converted
to I–C intermediate D via radical migration [88]. The homoge-
neous cleavage of the C–I bond in D leads to the stable carbon
radical E and an iodine radical. Finally, the reaction between E
and the iodine radical produces product 2a, with the concomi-
tant release of water and iodobenzene. In pathway b, the O–I
intermediate C is converted to a C–I intermediate D via 1,3-
migration [89]. Then, intermediate D carries through a five-
Scheme 5: Application of the reported method to the synthesis of fruti-
none A.
membered ring transition state F to afford the title product 2a,
accompanied by the release of iodobenzene and water.
Scheme 4: Proposed reaction mechanism.
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In summary, we have developed an efficient metal-free ap-
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Supporting Information
Supporting Information File 1
Synthetic details and compound characterization data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-291-S1.pdf]
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Y. D. acknowledges the National Natural Science Foundation
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