Regioselective Cross-Couplings of Coumarins and Flavones with Ethers via C(sp3)-H Functionalization

Article abstract of DOI:10.1021/acs.joc.5b00800

(Chemical Equation Presented) Coumarin and flavone derivatives are highly valuable molecules in drug discovery. Here, two new regioselective cross-dehydrogenation couplings of coumarins and flavones with different ethers via C(sp³)-H functionalization processes were developed, generating new ether-substituted derivatives not previously reported. These reactions proceeded well via radical mechanisms and provided the corresponding products in good yields.

Full text of DOI:10.1021/acs.joc.5b00800

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Note
Regioselective Cross Couplings of Coumarins and
Flavones with Ethers via C(sp3)-H Functionalization
Ben Niu, Wannian Zhao, Yingcai Ding, Zhaogang Bian, Charles U. Pittman, Aihua Zhou, and Haibo Ge
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Jun 2015
Downloaded from http://pubs.acs.org on June 9, 2015
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Regioselective Cross Couplings of Coumarins and
Flavones with Ethers via C(sp3)-H Functionalization
Ben Niu,† Wannian Zhao,† Yingcai Ding,† Zhaogang Bian,† Charles U. Pittman Jr,‡
Aihua Zhou†* and Haibo Ge*§
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† Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang city, Jiangsu, 212013, China
‡ Mississippi State University, Mississippi State, MS 39762, USA.
§ Department of Chemistry and Chemical Biology, Indiana University Purdue University, Indianapolis, Indiana 46202, USA
Abstract: Coumarin and flavone derivatives are highly valuable molecules in drug discovery. Here, two new regioselective cross
dehydrogenation couplings of coumarins and flavones with different ethers via C(sp3)ꢀH functionalization processes were
developed, generating new etherꢀsubstituted derivatives not prviously reported. These reactions proceeded well via radical
mechanisms and provided the corrsponding products in good yields.
Transition metalꢀcatalyzed CꢀH functionalization has become a powerful strategy for the construction of carbonꢀcarbon and
carbonꢀheteroatom bonds.1 One such protocol, the cross dehydrogenation coupling between two different partners has attracted
significant attention in recent years.2 These reactions can annex two partners directly via oxidation of one CꢀH bond from each of
the two coupling partners, thereby providing an efficient and simple way to generate target molecules in minimum synthetic steps
compared with traditional cross couplings which often require the use of preꢀfunctionalized halides and organometallic reagents
as reactants.3 However, cross dehydrogenation couplings are still limited by finding suitable reaction partners and challenged by
the difficulties associated with controlling product regioselectivities.4
Coumarins and flavones are two wellꢀknown natural product classes in drug discovery with carbonylꢀconjugated olefin
functions in their structures.5 They are suitable partners for cross dehydrogenation coupling, where adding new substituents could
create new biological activity worthy of investigation.6 Many coumarin and flavone derivatives with substituents on their α and βꢀ
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positions were achieved via CꢀH bond functionalization using precious Pd, Rh and Ru catalysts.7 However, only a few cross
dehydrogenation couplings were carried out to synthesize these derivatives by using radical mechanisms. Recently, Antonchick,8
Zou,9 and Han10 et al reported cross dehydrogenation couplings of coumarins and flavones with alkanes or sodium
trifluoromethanesulfinate to generate alkyl and trifluoromethylꢀsubstituted derivatives (Scheme1), However, there are no reports
of using ethers as the coupling partners by far.
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Scheme 1. Synthesis of coumarin and flavone derivatives via radical cross dehydrogenation couplings
In this paper, two new cross dehydrogenation couplings of coumarins and flavones with different ethers via C(sp3)ꢀH
functionalization are reported. Ethers are cheap and readily available building blocks, whose αꢀH is easily oxidized to generate a
radical in the presence of peroxide.11 Based on prior literature precedent,12 we first sought suitable reaction conditions for the
couplings of coumarins with ethers. Coumarin and 1,4ꢀdioxane were used as the representative reactants, and different catalysts,
oxidants and solvents were screened (Table 1). First CuCl2 and Cu(OAc)2 were used as catalysts in benzene, and TBHP (tertꢀ
butyl hydroperoxide, 70 wt % in water) was employed as an oxidant. Neither reaction gave the expected product 3a (entries 1 and
2). Using Cu(OAc)2 as a catalyst in benzene with a combination of TBHP/DABCO provided a 51% yield of 3a (entry 3). CuCl2
with TBHP/DBU in benzene only produced a 35% yield of 3a (entry 4). When Cu(OAc)2 was employed with TBHP/DBU or
DTBP/DBU, less than 5% of 3a was observed (entries 5 and 6). The TBHP/DBU combination in the presence of FeCl3 afforded a
trace amount of 3a (entry 7), while the combination of TBHP/DABCO in EtOAc with FeCl3 afforded a 35% yield of 3a (entry 8).
The combination of TBHP/DABCO in a solvent free environment or in toluene with FeCl3 afforded 3a in 50% and 45% yields,
respectively (entries 9 and 10). TBHP/DABCO in benzene with FeCl3 as a catalyst gave a 65% yield (entry 11). When TBHP or
DABCO was used separately, both reactions gave the trace amount of expected product 3a (entries 12 and 13). After screening,
the suitable conditions selected for the coupling of ether and coumarin are: FeCl3 (10.0 mol %), ether (0.5 mL), coumarin (1.0
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equiv.), TBHP (3.0 equiv.), DABCO (1.0 equiv.) in benzene.
Table 1. Optimization of reaction conditions a
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Entry
Catalyst
Oxidant/Ligand
Solvent
Yieldb (%)
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4
5
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10
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12
13
CuCl2
Cu(OAc)2
Cu(OAc)2
CuCl2
Cu(OAc)2
Cu(OAc)2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
TBHP/ꢀꢀꢀ
TBHP/ꢀꢀꢀ
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
ꢀꢀꢀ
EtOAc
ꢀꢀꢀ
Toluene
Benzene
Benzene
Benzene
trace
trace
51
35
<5
trace
trace
35
50
45
TBHP/DABCO
TBHP/DABCO
TBHP/DBU
DTBP/DBU
TBHP/DBU
TBHP/DABCO
TBHP/DABCO
TBHP/DABCO
TBHP/DABCO
TBHP
65
trace
trace
FeCl3
FeCl3
DABCO
a Reaction conditions: catalysts (10 mol%), ether (0.5 mL), coumarin (1 equiv.), TBHP (tertꢀbutyl hydroperoxide 70 wt % in
water, 3.0 equiv.), DTBP (tertꢀbutyl peroxide, 3 equiv.), benzene (0.5 mL), DABCO or DBU (1.0 equiv.), 120 C. b Isolated
o
yield of product was based on the reactant coumarin. These reactions were run for 36 h.
After determining suitable reaction conditions, representative reactions of different ethers with various coumarins were
examined and moderate to good yields of etherꢀsubstituted coumarin derivatives 3a-n were obtained (Table 2) with high
regioselectivities. However, the electronꢀwithdrawing nitroꢀsubstituted coumarin did not react with 1,4ꢀdioxane,failing to give 3i.
Interestingly, a different phenomenon was observed with the use of dibenzylether. As the coupling partner, instead of generating
etherꢀsubstituted derivatives, the benzoylꢀsubstituted product 3j was produced regioselectively in a 67% yield.
Table 2. Syntheses of ether-substituted coumarin derivatives a
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a Reaction conditions: catalyst (10 mol%), ether (0.5 mL), coumarin (1.0 equiv.), TBHP (70 wt % in water, 3.0 equiv.)
and DBU (1.0 equiv.) in benzene (0.5 mL) at 120 C for 36 h. Isolated yields of 3a-n were based on the reactant
coumarin.
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Based on the chemical shifts displayed in the 1H and 13C NMR spectra of each etherꢀsubstituted coumarin derivative, the ether
substrate was bonded to the more electronꢀrich α position of coumarin ester.
To find suitable conditions for ether/flavone coupling, flavone 4a and 1,4ꢀdioxane were used as the representative reactants.
Different catalysts, oxidants and solvents were screened. The coupling conditions used for coumarins and ethers also worked well
for the coupling of flavone with 1,4ꢀdioxane. This reaction gave a 65% yield of product 5a (Table 3, entry 1). Switching from
DABCO to DBU reduced the yield slightly to 60% (entry 2). CuBr2 and CuCl2 were used with the combination of
TBHP/DABCO, but 5a was not observed in either case (entries 3 and 4). When CuI, Cu(OAc)2, CuBr or Cu2O was used with
TBHP/DABCO, only 20%, 10%, 30% or 10% yields of 5a were produced (entries 5, 6, 7 and 8). Surprisingly, using CuO as the
catalyst succeeded, affording a 68% yield of product 5a (entry 9). In addition, a moderate yields of 5a was obtained with FeCl3 in
EtOAc and DCE (entries 10 and 11). When TBHP or DABCO was used separately, both reactions gave the trace amount of
expected product 5a in the presence of CuO catalyst (entries 12 and 13). Based on these screening results, the conditions chosen
for the coupling of ethers with flavones were: CuO (10.0 mol %), flavone (1.0 equiv.), ether (1.0 mL), TBHP (70 wt % in water,
3.0 equiv.) and DABCO (1.0 equiv.) at 120 oC for 36 h.
Table 3. Screening for suitable reaction conditions a
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Entry
Catalyst
Oxidant/Ligand
Solvent
Yield b (%)
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2
3
4
5
6
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8
9
10
11
12
13
FeCl3
FeCl3
CuBr2
CuCl2
CuI
Cu(OAc)2
CuBr
Cu2O
CuO
TBHP, DABCO
TBHP, DBU
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
65
60
trace
trace
20
10
30
10
68
45
43
trace
trace
TBHP, DABCO
TBHP, DABCO
TBHP, DABCO
TBHP, DABCO
TBHP, DABCO
TBHP, DABCO
TBHP, DABCO
TBHP, DABCO
TBHP, DABCO
DABCO
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ꢀꢀꢀ
EtOAc
DCE
ꢀꢀ
FeCl3
FeCl3
CuO
CuO
TBHP
ꢀꢀ
a Reaction conditions: catalysts (10 mol %), ether (1.0 mL), flavone (1.0 equiv.), TBHP (tertꢀbutyl hydroperoxide, 70 wt % in
water, 3.0 equiv.), DABCO or DBU (1.0 equiv.), 120 oC. b Isolated yield of product was based on the reactant flavone. These
reactions were run for 36 h.
Using the optimal reaction conditions found above, some representative flavones were reacted with various ethers (Table 4).
As expected, these cross dehydrogenation couplings gave etherꢀsubstituted flavone derivatives 5a-m in 55% to 79% isolated
yields. Noticeably, one major product was detected and isolated in each reaction, which was the coupling of ethers to the
electronꢀdeficient βꢀposition on the flavones.
Table 4. Syntheses of ether-substituted flavone derivatives a
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a Reaction conditions: CuO (10 mol%), flavone (1.0 equiv.), ether (1.0 mL), TBHP (70 wt % in water, 3.0 equiv.)
and DABCO (1.0 equiv.) at 120 oC for 36 h. b Isolated yield of product was based on the reactant flavones 4.
To explain these results, understanding the reaction mechanism is necessary. To determine if radicals are involved in these two
couplings, TEMPO ((2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxyl) was used as a radical scavenger in these reactions. In the presence
of TEMPO, no coupling products were observed, indicating that radicals are involved in both of these couplings. Based on these
results, a plausible mechanism is proposed (Scheme 2). Heat splits TBHP into two radicals which extract a hydrogen atom from
the α position of ether. The nucleophilic ether radical can attack either the α or βꢀposition of coumarin’s olefin substrate,
Scheme 2. Proposed mechanism for cross dehydrogenation coupling of coumarins and flavones with ethers
generating radical intermediates A or B. The benzylic radical A is more stable than the radical species B, and thus, radical A is
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more easily formed than radical B. Therefore, only α etherꢀsubstituted coumarin derivatives 3 were regiosepecifically obtained
with coumarins.
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The ether radical also has two choices to add to the α or β positions of the flavone’s unsaturated ketone function. The ether
radical is a relatively electronꢀrich radical with some nucleophilicity. Thus, it is more prone to react at the electronꢀdeficient βꢀ
position of the vinylogous ester instead of the relatively electronꢀrich αꢀposition. The αꢀposition is also more electron rich due to
resonance from the ring’s oxygen atom. Also, the ring oxygen’s electronegativity further reduces electron density at the βꢀcarbon.
After the ether radical has added to the βꢀposition, radical C is formed, which is then oxidized to give 5.
To provide some insight into reaction mechanism, couplings of αꢀ or βꢀmethyl substituted coumarins (1k and 1l) or flavones
(4j and 4k) with 1,4ꢀdioxane were also carried out (Scheme 3). In cases of 1k and 4j, in which the preferred reaction sites were
blocked by the methyl group, either no or trace amount of desired products were observed. For coumarin 1l and flavone 4k, in
which the preferred reaction sites are available, the desired products 3l and 5k were obtained in 75% and 50% yield respectively.
These results support the proposed mechanistic explanation in Scheme 2. It should be mentioned that the relatively low yield for
4j is presumably due to the steric effect from the neighboring methyl group.
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Scheme 3. Couplings of coumarin and flavone with 1,4-dioxane.
CONCLUSIONS
In summary, we have developed two regioselective and atom economical cross dehydrogenation couplings of ethers with
coumarins and flavones via C (sp3)ꢀH functionalization. These processes gave two new types of etherꢀsubstituted derivatives with
the ether substituent on αꢀpositions of coumarins and βꢀpositions of flavones, respectively, in good yields and high
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regioselectivities. Both reactions proceeded via radical addition mechanisms. Despite the above advantages, the method is still
limited in scope, the major drawback is that excess ether is used. Investigation of the biological activities of these products is
currently underway.
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EXPERIMENTAL SECTION
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General procedure for the synthesis of compounds 3a-j, 3lꢀ3n. To a dry thickꢀwalled glass pressure tube, coumarin (1.0 mmol,
1.0 equiv.), DABCO (1.0 mmol, 1.0 equiv.), ether (0.5 mL) and benzene (anhydrous, 0.5 mL) were added. Then FeCl3 (0.1 mmol,
10 mol %) and TBHP (3.0 mmol, 3 equiv, 70 wt % in water), were added into the tube. The mixture was stirred at 120 oC for 36
h. After that, the reaction mixture was quenched with brine and extracted with ethyl acetate. The organic layers were combined,
washed with brine, dried (anhydrous Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography
(EtOAc/petroleum ether =1:30) on silica gel to provide the desired product 3a as a colorless oil in a 74% yield, the same
procedure was applied for producing other compounds 3b-h, 3j, 3lꢀ3n.
General procedure for the synthesis of compounds 5a-i, 5k-5m.
Flavone (1.0 mmol, 1.0 equiv.), ether (1.0 mL), and DABCO (1.0 mmol, 1.0 equiv.) were added to a thickꢀwalled pressure tube,
then CuO (0.1mmol, 10 mol %) and TBHP (3.0 mmol, 3.0 equiv., 70 wt % in water) were also added. The mixture was stirred at
120 oC for 36 h. Then reaction was quenched with water and extracted with ethyl acetate. The organic layers were then combined,
washed with brine, dried (anhydrous Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography
(EtOAc/petroleum ether =1:30) on silica gel to give the desired product 5a as a colorless oil in a 68% yield. The same procedure
was applied for producing other compounds 5b-i, 5k-5m.
3-(1,4-Dioxan-2-yl)-2H-chromen-2-one (3a). Following the general procedure, isolated yield (171.7 mg, 74%) as colorless oil;
IR: 2961, 1721, 1635, 1457, 1288, 1058, 756 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.87 (s, 1H), 7.87 (s, 1H), 7.50 (s, 2H), 7.29
(s, 2H), 4.76 (m, 1H), 4.26 (m, 1H),3.96 (m, 2H), 3.83 (m, 1H), 3.68 (m, 1H), 3.25 (m, 1H); 13C-NMR (CDCl3, 100 MHz): δ
159.9, 153.2, 139.2, 131.5, 128.0, 126.1, 124.6, 119.0, 116.5, 72.7, 71.0, 67.3, 66.4; HRMS (ESIꢀTOF) m/z calculated for
C13H12NaO4 255.0633 (M+Na)+, found 255.0624.
3-(1-Ethoxyethyl)-6-methyl-2H-chromen-2-one (3b). Following the general procedure, isolated yield (153.2 mg, 66%) as
colorless oil ;IR: 3148, 2927, 1716, 1399, 1279, 994 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.76 (s, 1H), 7.32ꢀ7.22 (m, 3H), 4.62
(dd, J=12.8, 6.4 Hz, 1H), 3.56ꢀ3.51 (m, 2H), 2.42 (s, 3H), 1.45 (d, J=6.4 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H); 13C-NMR (CDCl3, 100
MHz): δ 161.1, 151.3, 137.1, 134.1, 132.1, 131.5, 127.7, 119.1, 116.2, 72.2, 64.7, 21.6, 20.8, 15.5; HRMS (ESIꢀTOF) m/z
calculated for C14H16NaO3 255.0997 (M+Na)+, found 255.0984.
3-(tetra-Hydrofuran-2-yl)-2H-chromen-2-one (3c). Following the general procedure, isolated yield (140.5 mg, 65%) as
colorless oil; IR: 2972, 1718, 1608, 1457, 1283, 1021, 757 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.81 (s, 1H), 7.51ꢀ7.25 (m, 4H),
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4.98ꢀ4.95 (m, 1H), 4.14ꢀ4.09 (m, 1H), 3.96 (dd, J=15.2, 7.2 Hz), 2.57ꢀ2.48 (m, 1H), 2.05ꢀ1.91 (m, 2H), 1.79ꢀ1.72 (m, 1H); 13C-
NMR (CDCl3, 100 MHz): δ 160.5, 153.1, 136.4, 131.1, 130.9, 127.8, 124.4, 119.3, 116.4, 75.9, 68.9, 32.2, 25.7; HRMS (ESIꢀ
TOF) m/z calculated for C13H12NaO3 239.0684 (M+Na)+, found 239.0679.
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6-Methyl-3-(tetrahydrofuran-2-yl)-2H-chromen-2-one (3d). Following the general procedure, isolated yield (161.1 mg, 70%) as
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colorless oil; IR: 2926, 1716, 1635, 1457, 1281, 1024, 817 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 7.73 (d, J=0.4 Hz, 1H), 7.28ꢀ
7.19 (m, 3H), 4.94 (dd, J=12.8, 6.4 Hz, 1H), 4.13ꢀ4.07 (m, 1H) 3.95 (dd, J=14.8, 7.2 Hz, 1H), 2.55ꢀ2.46 (m, 1H), 2.39 (s, 3H),
2.04ꢀ1.91 (m, 2H), 1.80ꢀ1.73 (m, 1H); 13C-NMR (CDCl3, 100 MHz): δ 160.7, 151.2, 136.4, 134.0, 131.9, 127.6, 119.0, 116.1,
76.0, 68.9, 32.2, 25.6, 20.8; HRMS (ESIꢀTOF) m/z calculated for C14H15O3 231.1021 (M+H)+, found 231.1014.
3-(1-Ethoxyethyl)-2H-chromen-2-one (3e). Following the general procedure, isolated yield (135.2 mg, 62%) as colorless oil; IR:
2975, 2927, 1724, 1635, 1489, 1174, 1072, 782 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.79 (s, 1H), 7.55ꢀ7.50 (m, 2H), 7.37ꢀ7.30
(m, 2H), 4.66ꢀ4.61 (m, 1H), 3.58ꢀ3.52 (m, 2H), 1.44 (d, J=6.4 Hz, 3H), 1.29 (t, J=6.8 Hz, 3H); 13C-NMR (CDCl3, 100 MHz): δ
160.8, 153.1, 137.1, 131.6, 131.1, 127.9, 124.4, 119.3, 116.4, 72.2, 64.7, 21.5, 15.5; HRMS (ESIꢀTOF) m/z calculated for
C13H15O3 219.1021 (M+H)+, found 219.1021.
3-(1,4-Dioxan-2-yl)-6-methyl-2H-chromen-2-one (3f). Following the general procedure, isolated yield (177.2 mg, 72%) as
colorless oil; IR: 2918, 1717, 1636, 1436, 1291, 1035, 818 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.80 (s, 1H), 7.31ꢀ7.27 (m, 2H),
7.19 (d, J=8.4 Hz, 1H), 4.77ꢀ4.74 (m, 1H), 4.25 (dd, J=11.2, 2.4 Hz, 1H), 3.99ꢀ3.89 (m, 2H), 3.82 (t, J=2.4 Hz, 1H), 3.71ꢀ3.64
(m, 1H), 3.22 (t, J=1.6 Hz, 1H), 2.39 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 160.1, 151.3, 139.2, 134.3, 132.5, 127.8, 125.9,
118.7, 116.2, 72.7, 71.0. 67.3, 66.4; HRMS (ESIꢀTOF) m/z calculated for C14H15O4 247.0970 (M+H)+, found 247.0969.
6-Methyl-3-(tetrahydro-2H-pyran-2-yl)-2H-chromen-2-one (3g). Following the general procedure, isolated yield (158.7 mg,
65%) as colorless oil; IR: 2955, 1733, 1616, 1493, 1283, 1054, 813 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.76 (s, 1H), 7.29ꢀ7.19
(m, 3H), 4.46 (d, J=10.8 Hz 1H), 4.19ꢀ4.15 (m, 1H), 3.68ꢀ3.61 (m, 1H), 2.39 (s, 3H), 2.22ꢀ2.19 (m, 1H), 1.93ꢀ1.90 (m, 1H), 1.74ꢀ
1.60 (m, 3H), 1.29ꢀ1.20 (m, 1H); 13C-NMR (CDCl3, 100 MHz): δ 160.5, 151.2, 137.4, 134.0, 132.0, 130.7, 127.7, 119.1, 116.1,
74.6, 69.1, 32.2, 26.0, 23.6, 20.8; HRMS (ESIꢀTOF) m/z calculated for C15H16NaO3 267.0997 (M+Na)+, found 267.0988.
6-Methoxy-3-(tetrahydrofuran-2-yl)-2H-chromen-2-one (3h). Following the general procedure, isolated yield (152.6 mg, 62%)
as colorless oil; IR: 2924, 1716, 1579, 1431, 1262, 1021, 817 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 7.77 (s, 1H), 7.76ꢀ7.27 (m,
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1H), 7.08ꢀ7.05 (m, 1H), 6.94 (d, J=2.8 Hz, 1H), 4.98ꢀ4.95 (m,1H), 4.14ꢀ4.09 (m, 1H), 3.93 (dd, J=14.8, 6.8 Hz, 1H), 3.85 (s, 3H),
2.57ꢀ2.49 (m, 1H), 2.06 (dd, J=12.4, 5.2 Hz, 1H), 1.99ꢀ1.91 (m, 1H), 1.89ꢀ1.78 (m, 1H); 13C-NMR (CDCl3, 100 MHz): δ 160.7,
156.1, 147.5, 136.2, 131.4, 119.6, 118.6, 117.4, 109.9, 76.0, 68.9, 55.8, 32.3, 25.7; HRMS (ESIꢀTOF) m/z calculated for
C14H15O4 247.0970 (M+H)+, found 247.0969.
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3-Benzoyl-2H-chromen-2-one (3j). Following the general procedure, isolated yield (167.5 mg, 67%) as colorless oil; IR: 3063,
1717, 1607, 1493, 1243, 1055, 813 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.11 (s, 1H), 7.90, (d, J=7.2 Hz 2H), 7.70ꢀ7.62 (m, 3H),
7.51 (d, J=7.6 Hz 2H),7.49ꢀ7.36 (m, 2H); 13C-NMR (CDCl3, 100 MHz): δ 160.5, 151.2, 137.4, 134.0, 132.0, 130.7, 127.7, 119.1,
116.1, 74.6, 69.1, 32.2, 26.0, 23.6, 20.8; HRMS (ESIꢀTOF) m/z calculated for C16H10NaO3 273.0528 (M+Na)+, found 273.0519.
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3-(1,4-dioxan-2-yl)-7-hydroxy-4-methyl-2H-chromen-2-one (3l). Following the general procedure, isolated yield (196.5 mg,
75%) as colorless oil; IR : 3261, 2963, 1699, 1617, 1570, 1263, 1110, 923 cmꢀ1; 1H-NMR (MeOD, 400 MHz): δ 7.65 (d, J=8.0
Hz, 1H), 6.82 (dd, J=8.0, 4.0 Hz, 1H), 6.65 (s, 1H), 5.10 (dd, J=8.0, 4.0 Hz, 1H); 3.95ꢀ3.87 (m, 2H); 3.85ꢀ3.81 (m, 2H); 3.79ꢀ
3.70 (m, 2H); 2.66 (s, 3H); 13C-NMR (MeOD, 100 MHz): δ 161.6, 161.4, 154.0, 152.6, 126.4, 116.8, 113.1, 113.0, 101.6, 74.0,
68.0, 67.5, 65.9, 14.5; HRMS (ESIꢀTOF) m/z calculated for C14H14NaO5 285.0739 (M+Na)+, found 285.0740.
6-Bromo-3-(1,4-dioxan-2-yl)-2H-chromen-2-one (3m). Following the general procedure, isolated yield (176.6 mg, 57%) as
colorless oil; IR : 3072, 2932 , 2361, 1745, 1659, 1456, 1244, 1110, 694cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.81 (s, 1H), 7.65
(d, J=2.0 Hz, 1H), 7.61 (dd, J=8.8, 2.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 5.10 (d, J=8.8 Hz, 1H); 4.28 (dd, J=11.2, 2.4 Hz, 1H);
3.99ꢀ3.96 (m, 2H); 3.84 (dd, J = 11.7, 2.5 Hz, 1H), 3.73ꢀ3.67 (m, 1H), 3.23 (dd, J = 10.8, 10.0 Hz, 1H); 13C-NMR (CDCl3, 100
MHz): δ 159.2, 152.0, 137.9, 134.2, 130.3, 127.5, 120.6, 118.3, 117.1, 72.7, 70.9, 67.3, 66.4; HRMS (ESIꢀTOF) m/z calculated
for C13H11BrNaO4 332.9738 (M+Na)+, found 332.9736.
2-(1,4-dioxan-2-yl)-3H-benzo[f]chromen-3-one (3n). Following the general procedure, isolated yield (163.6 mg, 58%) as
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colorless oil; IR : 3161, 2973, 1665, 1587, 1470, 1253, 1150, 823 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.67 (s, 1H), 8.36 (d,
J=8.4 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.71 (dd, J=8.0, 0.8 Hz, 1H); 7.59 (t, J=8.0 Hz, 1H), 7.47 (d,
J=8.8 Hz, 1H), 4.87 (dd, J=9.6, 1.2 Hz, 1H); 4.36 (dd, J=11.6, 2.8 Hz, 1H); 4.09ꢀ3.98 (m, 2H); 3.89 (t, J=2.4 Hz, 1H); 3.79ꢀ3.73
(m, 1H); 3.32 (dd, J=11.2, 10.0 Hz, 1H); 13C-NMR (CDCl3, 100 MHz): δ 160.0, 152.8, 134.9, 132.8, 130.4, 129.1, 129.0, 128.2,
126.1, 125.1, 121.8, 116.7, 113.3, 73.0, 71.1, 67.4, 66.5; HRMS (ESIꢀTOF) m/z calculated for C17H14NaO4 305.0790 (M+Na)+,
found 305.0789.
2-(1,4-Dioxan-2-yl)-4H-chromen-4-one (5a). Following the general procedure, isolated yield (157.8 mg, 68%) as colorless oil;
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IR: 2962, 1654, 1493, 1398, 1115, 911 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.17 (dd, J=7.6, 1.2 Hz, 1H), 7.68ꢀ7.64 (m, 1H),
7.45ꢀ7.38 (m, 2H), 6.48 (d, J=0.8 Hz, 1H), 4.58ꢀ4.55 (m, 1H), 4.16 (dd, J=11.6, 3.2 Hz, 1H), 3.99ꢀ3.96 (m, 1H), 3.91ꢀ3.81 (m,
2H), 3.76ꢀ3.72 (m, 1H), 3.70ꢀ3.60 (m, 1H); 13C-NMR (CDCl3, 100 MHz): δ 178.0, 164.6, 156.1, 133.8, 125.8, 125.3, 124.0,
118.0, 109.1, 73.8, 69.3, 66.6, 66.4; HRMS (ESIꢀTOF) m/z calculated for C13H12 NaO4 255.0633 (M+Na)+, found 255.0624.
6-Methyl-2-(tetrahydrofuran-2-yl)-4H-chromen-4-one (5b). Following the general procedure, isolated yield (181.8 mg, 79%) as
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colorless oil; IR: 2926, 1655, 1485, 1319, 1090, 818 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 7.97 (d, J=0.8 Hz, 1H), 7.47 (dd,
J=28.8, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.41 (d, J=0.8 Hz, 1H), 4.83 (dd, J=8.0, 5.2 Hz, 1H), 4.11ꢀ4.06 (m, 1H), 4.00ꢀ3.94
(m, 1H), 2.41 (s, 3H), 2.40ꢀ2.33 (m, 1H), 2.14ꢀ2.11 (m, 1H), 2.10ꢀ1.98 (m, 2H); 13C-NMR (CDCl3, 100 MHz): δ 178.5, 169.3,
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154.6, 135.0, 134.8, 125.1, 123.7, 117.7, 107.5, 76.9, 69.4, 31.1, 25.4, 20.9; HRMS (ESIꢀTOF) m/z calculated for C14H15O3
231.1021 (M+H)+, found 231.1014.
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2-(1,4-Dioxan-2-yl)-7-hydroxy-4H-chromen-4-one (5c). Following the general procedure, isolated yield (161.2 mg, 65%) as
colorless oil; IR: 3448, 2969, 1649, 1457, 1055, 1008, 823 cmꢀ1; 1H-NMR (DMSOꢀd6, 400 MHz): δ 10.85 (s, 1H), 7.85 (d, J=8.8
Hz, 1H), 6.92 (dd, J= 8.8, 2.0 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.21 (s, 1H), 4.58 (dd, J=9.6, 2.8 Hz, 1H), 4.04 (dd, J=11.2, 2.8
Hz, 1H), 3.90 (d, J=12.8, Hz, 1H), 3.79ꢀ3.73 (m, 1H), 3.63ꢀ3.37 (m, 2H), 2.51ꢀ2.50 (m, 2H); 13C-NMR (DMSOꢀd6, 100 MHz): δ
176.3, 164.3, 163.3, 157.9, 127.1, 116.6, 115.6, 108.7, 102.8, 73.6, 68.7, 66.3, 66.2; HRMS (ESIꢀTOF) m/z calculated for
C13H12NaO5 271.0582 (M+Na)+, found 271.0583.
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6-Chloro-2-(tetrahydrofuran-2-yl)-4H-chromen-4-one (5d). Following the general procedure, isolated yield (197.5 mg, 79%) as
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colorless oil; IR: 2956, 1655, 1437, 1317, 1061, 822 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.14ꢀ8.12 (m, 1H), 7.60 (dd, J=9.2,
2.8 Hz, 1H), 7.41 (d, J=9.2 Hz, 1H), 6.44 (d, J=0.8 Hz, 1H), 4.83 (dd, J=8.0, 4.8 Hz, 1H), 4.11ꢀ4.05 (m, 1H), 4.00ꢀ3.95 (m, 1H),
2.44ꢀ2.35 (m, 1H), 2.15ꢀ2.09 (m, 1H), 2.09ꢀ2.00 (m, 2H); 13C-NMR (CDCl3, 100 MHz): δ 177.0, 169.9, 154.6, 133.8, 131.0,
125.2, 125.0, 119.7, 107.6, 76.7, 69.5, 31.2, 25.4; HRMS (ESIꢀTOF) m/z calculated for C13H11ClNaO3 273.0294(M+Na)+, found
273.0305.
2-(1,3-Dioxolan-2-yl)-4H-chromen-4-one (5e). Following the general procedure, isolated yield (170.1 mg, 78%) as colorless oil;
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IR: 2956, 1655, 1437, 1317, 1101, 762 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.18 (dd, J=8.0, 1.6 Hz, 1H), 7.69ꢀ7.65 (m, 1H),
7.49 (dd, J=8.4, 0.4 Hz, 1H), 7.41ꢀ7.37 (m, 1H), 6.49 (s, 1H), 5.79 (s, 1H), 4.15ꢀ4.07 (m, 4H);13C-NMR (CDCl3, 100 MHz): δ
178.3, 163.2, 156.3, 134.0, 125.7, 125.3, 124.1, 118.3, 109.0, 99.6, 65.6; HRMS (ESIꢀTOF) m/z calculated for C12H10NaO4
241.0477 (M+Na)+, found 241.0469.
2-(1-Ethoxyethyl)-4H-chromen-4-one (5f). Following the general procedure, isolated yield (120.0 mg, 55%) as colorless oil; IR:
2926, 1660, 1465, 1323, 1120, 759 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.22 (dd, J=8.0, 1.6 Hz, 1H), 7.69ꢀ7.65 (m, 1H), 7.47 (d,
J=8.0 Hz,1H), 7.43ꢀ7.39 (m, 1H), 6.43 (s, 1H), 4.29 (dd, J=13.2, 6.8 Hz, 1H), 3.65ꢀ3.50 (m, 2H), 1.56 (d, J=6.4 Hz, 3H), 1.28 (t,
J=7.0 Hz, 3H);13C-NMR (CDCl3, 100 MHz): δ 178.4, 169.5, 156.4, 133.7, 125.8, 125.2, 124.1, 118.1, 108.2, 74.8, 65.4, 20.3,
15.3; HRMS (ESIꢀTOF) m/z calculated for C13H14NaO3 241.0841 (M+Na)+, found 241.0832.
6-Chloro-2-(1,4-dioxan-2-yl)-4H-chromen-4-one (5g). Following the general procedure, isolated yield (186.2 mg, 70%) as
colorless oil; IR: 2923, 1655, 1472, 1374, 1117, 913 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 8.15 (d, J=2.4 Hz, 1H), 7.60 (q, J=8.8,
2.4 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 6.49 (s, 1H), 4.58 (dd, J=9.6, 2.8 Hz, 1H), 4.17 (dd, J=11.2, 2.8 Hz, 1H), 4.00 (d, J=10.8 Hz,
1H), 3.92ꢀ3.82 (m, 2H), 3.77ꢀ3.70 (m, 1H), 3.66ꢀ3.61 (m, 1H);13C-NMR (CDCl3, 100 MHz): δ 176.7, 164.8, 154.4, 134.0, 131.3,
125.3, 125.0, 119.7, 109.1, 73.7, 69.3, 66.6, 66.4; HRMS (ESIꢀTOF) m/z calculated for C13H11 ClNaO4 289.0244 (M+Na)+,
found 289.0252.
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2-(1,4-Dioxan-2-yl)-6-methyl-4H-chromen-4-one (5h). Following the general procedure, isolated yield (167.3 mg, 68%) as
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colorless oil; IR: 2965, 1655, 1485, 1327, 1116, 913 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 7.95 (d, J=1.2 Hz, 1H), 7.46 (dd,
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3.90 (d, J=2.8 Hz, 1H), 3.89ꢀ3.83 (m, 2H), 3.79ꢀ3.71 (m, 1H), 3.69ꢀ3.59 (m, 1H), 2.43 (s, 3H);13C-NMR (CDCl3, 100 MHz): δ
178.0, 164.3, 154.3, 135.3, 135.0, 125.3, 125.1, 123.7, 117.7, 108.9, 73.8, 69.3, 66.6, 66.4, 20.9; HRMS (ESIꢀTOF) m/z
calculated for C14H15O4 247.0970 (M+H)+, found 247.0969.
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2-(1,3-Dioxolan-2-yl)-4H-benzo[h]chromen-4-one (5i). Following the general procedure, isolated yield (193.0 mg, 72%) as
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colorless oil; IR: 3066, 2894, 1655, 1466, 1322, 1125, 941 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.52 (dd, J=8.0, 0.8 Hz, 1H),
8.16 (d, J=8.8 Hz, 1H), 7.93 (t, J=1.6 Hz 1H), 7.78 (d, J=8.8 Hz, 1H), 7.75ꢀ7.67 (m, 2H), 6.67 (s, 1H), 5.98 (s, 1H), 4.25ꢀ4.16 (m,
4H);13C-NMR (CDCl3, 100 MHz): δ 178.1, 162.6, 153.8, 136.0, 129.5, 128.1, 127.2, 125.5, 123.9, 122.4, 120.6, 120.5, 110.4,
99.7, 65.7; HRMS (ESIꢀTOF) m/z calculated for C16H12NaO4 291.0633 (M+Na)+, found 291.0627.
2-(1,4-dioxan-2-yl)-3,6-dimethyl-4H-chromen-4-one (5k). Following the general procedure, isolated yield (130.0 mg, 50%) as
colorless oil; IR : 2922, 1647, 1619, 1490, 1263, 1112, 932 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.98 (s, 1H), 7.48 (dd, J=8.0,
0.4 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 4.88ꢀ4.85 (m, 1H), 4.00ꢀ3.95 (m, 2H), 3.94ꢀ3.90 (m, 2H), 3.85ꢀ3.83 (m, 2H), 2.46 (s, 3H)
2.17 (s, 3H);13C-NMR (CDCl3, 100 MHz): δ 178.3, 157.9, 154.1, 134.9, 134.8, 125.1, 122.1, 118.8, 117.7, 73.8, 67.8, 67.1, 66.3,
20.9, 9.4; HRMS (ESIꢀTOF) m/z calculated for C15H16NaO4 283.0946 (M+Na)+, found 283.0949.
6-Chloro-2-(1-ethoxyethyl)-7-methyl-4H-chromen-4-one (5l). Following the general procedure, isolated yield (159.6 mg, 60%)
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as colorless oil; IR : 2932, 2361, 2334, 1659, 1463, 1112, 952 cmꢀ1; H-NMR (CDCl3, 400 MHz): δ 8.16 (s, 1H), 7.38 (s, 1H),
6.40 (s, 1H), 4.29ꢀ4.24 (m, 1H), 3.62ꢀ3.52 (m, 2H), 2.51 (s, 3H), 1.53 (d, J=6.4 Hz, 3H), 1.26 (t, J=6.8 Hz, 3H); 13C-NMR
(CDCl3, 100 MHz): δ 177.2, 169.5, 154.6, 142.9, 131.8, 125.4, 123.1, 119.9, 108.0, 74.8, 65.4, 20.8, 20.2, 15.3; HRMS (ESIꢀ
TOF) m/z calculated for C14H15ClNaO3 289.0607 (M+Na)+, found 289.0607.
2-(1,4-dioxan-2-yl)-4-oxo-4H-chromene-6-carbonitrile (5m). Following the general procedure, isolated yield (185.0 mg, 72%)
as colorless oil; IR : 3022, 1747, 1619, 1560, 1233, 1212, 862 cmꢀ1; 1H-NMR (CDCl3, 400 MHz): δ 7.94 (d, J=8.8 Hz, 1H), 7.80
(d, J=6.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 6.38 (d, J=6.0 Hz, 1H), 6.32 (dd, J=10.0, 3.2 Hz, 1H), 4.14 (dd, J=11.2, 2.8 Hz, 1H),
4.01 (d, J=8.0 Hz, 1H), 3.99 (dd, J=18.8, 10.4 Hz, 2H), 3.83 (d, J=8.0 Hz, 1H), 3.73 (dd, J=11.2, 10.0 Hz, 1H); 13C-NMR
(CDCl3, 100 MHz): δ 177.5, 158.7, 153.7, 145.9, 138.7, 122.7, 119.3, 117.8, 114.9, 109.4, 73.1, 69.4, 66.7, 65.9; HRMS (ESIꢀ
TOF) m/z calculated for C14H11NNaO4 280.0586 (M+Na)+, found 280.0586.
ASSOCIATED CONTENT
Supporting Information Available
Spectral characterization for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*† Eꢀmail: ahz@ujs.edu.cn, geh@iupui.edu
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Author Contributions
B.N. and W.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Aihua Zhou gratefully acknowledge Jiangsu University for financial support (1281290006).
REFERENCES
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