Synthesis of 4H-Chromen-4-one Derivatives by Intramolecular Palladium-Catalyzed Acylation of Alkenyl Bromides with Aldehydes

Article abstract of DOI:10.1021/acs.joc.7b00640

The palladium-catalyzed intramolecular acylation of alkenyl bromides and aldehydes was developed for an efficient synthesis of 4H-chromen-4-ones. With Pd(PPh₃)₄/Xphos as the catalyst and K₂CO₃ as the base, this protocol was applied to synthesize a small library of diversely functionalized flavonoids in moderate to good yields in 1,4-dioxane.

Full text of DOI:10.1021/acs.joc.7b00640

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Note
Synthesis of 4H-Chromen-4-one Derivatives by Intramolecular
Palladium-Catalyzed Acylation of Alkenyl Bromides with Aldehydes
Yixia Yue, Jinsong Peng, Deqiang Wang, Yunyun Bian, Peng Sun, and Chunxia Chen
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 May 2017
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Synthesis of 4H-Chromen-4-one Derivatives by Intramolecular
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Palladium-Catalyzed Acylation of Alkenyl Bromides with Aldehydes
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Yixia Yue, Jinsong Peng,* Deqiang Wang, Yunyun Bian, Peng Sun and Chunxia Chen*
Department of Chemistry and Chemical Engineering, College of Science, Northeast
Forestry University, Harbin, 150040, P. R. China
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ABSTRACT
The palladium-catalyzed intramolecular acylation of alkenyl bromides and aldehydes
has been developed for an efficient synthesis of 4H-chromen-4-ones. With
Pd(PPh3)4/Xphos as the catalyst and K2CO3 as the base, this protocol was applied to
synthesize a small library of diversely functionalized flavonoids in moderate to good
yields in 1,4-dioxane.
Chromone frameworks are frequently found in a diverse array of compounds,
including natural flavone and isoflavone products, biologically and therapeutically
active drugs such as anti-inflammatory, antiplatelet, antimicrobial, antiobesity and
anticancer agents, and drug candidates for neurodegenerative diseases and
adenosine receptors.1 Chromones as a privileged scaffold in drug discovery have
received considerable attention over the past years; consequently, much effort has
been focused on the development of new synthetic methods.
The main classical synthetic routes enclose the following approaches: (a) Claisen
condensation (classic Claisen condensation,2 Baker-Venkatamaran,3 and
Kostanecki−Robinson reaction4), benzopyrylium salts5 and Vilsmeier−Haack reaction6
from ortho-hydroxyarylalkylketones; (b) Simonis7 and Ruhemann reaction8 from
phenols; (c) synthesis of chromones from salicylic acid and derivatives.9 Although
these processes are widely used, there remain many drawbacks to overcome such as
the use of strong acids or bases, high temperature, long reaction time, unexpected
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side-products and unsatisfactory yields.10 The design and development of mild, novel,
and efficient methods for the assembly of the chromone ring is still highly imperative.
Organo-catalyzed,11 base-mediated,12 hypervalent iodine or iodine-promoted,13 and
one-pot cascade syntheses14 have been recently developed. During the last decades,
transition-metal-catalyzed reactions provide one of the most attractive
methodologies for C−C and C-heteroatom formation. The application of these
reactions in the construction of polycyclic structures nowadays has increased
tremendously.15 Following this tendency, several attractive palladium-catalyzed
protocols have been discovered for the synthesis of chromones (Scheme 1, paths
a-d). Despite the significant progress made in the Pd-catalyzed synthesis of
chromones, novel synthetic approaches, with enhanced reaction efficiency, milder
reaction conditions as well as improved availability of starting materials, are still
desirable.
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Scheme 1. Pathways for the Synthesis of Chromones via Palladium-Catalyzed Reactions
(a) Kalinin (1990), Yang (2000), Capretta (2009)
Alper (2010) and Zhuo (2013)16
X
R1
H
R2
+
+
CO
(c) Jafarpour and Shafiee (2012),
Kim (2012), Hong (2012), Kim (2016)18
OR
X = I, Br; R =H, Ac
one-pot carbonylation
Sonogashira/annulation
O
O
(b) Wu and Beller (2012)17
R2
R2
or
+
O
O
O
O
R
Pd(II)/Oxidant
Pd(OAc)2/DPPB
R2
+
CO +
Br
R2
R
R
DBU, DMSO
OH
O
O
R1
or
H
(HO)2B
(d) Lei (2015)19
R1
O
R1
R2
H
K2CO3
DMF
(e) this work
Pd(OAc)2/S=PPh3
H
R2
+
R2
Br
R1
+
O
Cl
Cl
Pd(PPh3)4/Xphos
OH
TEBAC/NMP/Na2CO3
OH
CHO
Br
K2CO3, 1,4-dioxane
Among various Pd-catalyzed cross-coupling processes, the nucleophilic additions of
σ-arylpalladium intermediates to unsaturated carbon−heteroatom bonds have been
emerging as powerful synthetic methodologies for the construction of ring systems
in recent years.20 In a continuation of our efforts to develop Pd-catalyzed new
synthetic protocols for building valuable heterocyclic frameworks,21 herein we report
on a new and efficient entry to 4H-chromen-4-ones through Pd-catalyzed
intramolecular acylation of ether-tethered alkenyl bromides and aldehydes, readily
accessible starting material from regio- and stereoselective nucleophilic addition of
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salicylaldehydes to alkynyl bromides (Scheme 1, path e).22
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(Z)-Alkenyl bromide 1a was selected as a model substrate for a palladium-catalyzed
intramolecular acylation. We first tested the reaction conditions previously used for
cross-coupling of aryliodides with aldehydes.23 However, a combination of Pd2(dba)3,
dtpf, and Cs2CO3/Et3N (1:2) can not efficiently promote the reaction in toluene, and
2a was obtained in low yields. Benzofuran by-product, formed through Pd-catalyzed
direct aromatic C-H vinylation,22 can be isolated in 24% yield. To suppress this
competitive reaction, a judicious choice of catalysts, ligands, bases, solvents and
temperatures is needed. The data from that study are summarized in Table 1.
Investigation of the effect of temperature on reaction yields showed that with the
reaction temperature increasing, higher yields were obtained (entries 1-3). A survey
of reaction media showed that 1,4-dioxane provided better results (34% yield, entry
8) than toluene, DMF, DMA, DMSO, and THF (entries 3-7). The effect of palladium
sources on the reaction was next investigated, Pd(PPh3)4 was found to give the best
result (entries 9-12). To increase the yield of 2a, different bases such as Cs2CO3,
K2CO3, K3PO4, Na2CO3, NaOtBu, and NaOH were then tested (entries 12-17).
Compared to other bases, K2CO3 provided a better result, and the acylation product
2a can be obtained in 61% yield (entry 13). Finally, the effect of different ligands,
including bulky monodentate phosphines, biaryl monodentate phosphines, and
bidentate phosphines, was investigated (entries 13, and 18-24). Sterically hindered
biaryl phosphine Xphos proved to be a highly efficient ligand for the acylation,
providing 2a in 72% yield (entry 21). A higher ratio of ligand to Pd is preferable to
afford a better result [58% (1:1), 72% (2:1), and 80% (3:1), entry 12]. It is worth
noting that Et3N as the additive led to an inferior result (51% vs 72%, entries 21 and
22). In addition, the reaction can be carried out on a 1.0 mmol scale without
compromising the yield (entries 21 and 25).
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With the optimized reaction conditions in hand, the scope of this acylation process
was then examined. A variety of diversely substituted chromone derivatives was
obtained in moderate to good yields (schemes 2 and 3). As shown in scheme 2, for
the olefin-linked aryl moiety, a variety of substituents (Me, OMe, F, Cl, and Br) were
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applicable, affording products 2b-2i in 31-80% yields. The electronic nature of the
aromatic motifs did not seem to affect the efficiency, both electron-donating (2b-2e)
and electron-withdrawing (2f-2i) substituents can be incorporated at either the
para- or meta-position. In addition, a wide array of alkenyl bromides with simple
linear alkyl substitutions (1j-1l) was amenable to the protocol, delivering
chromen-4-ones 2j-2l in 60-78% yields. Alkenyl bromide 1m that contained a
protected alcohol functionality is also tolerated, and provide the corresponding
product 2m in 41% yield.
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Table 1. Optimization of Intramolecular Acylation Reaction Conditionsa
entry
1
catalyst
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
PdCl2
ligand
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
dtpf
base/additiveb
Cs2CO3/Et3N
Cs2CO3/Et3N
Cs2CO3/Et3N
Cs2CO3/Et3N
Cs2CO3/Et3N
Cs2CO3/Et3N
Cs2CO3/Et3N
solvent
Toluene
Toluene
Toluene
DMF
temp(℃)
80
yieldc
16
2d
110
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
21
3
27
4
15
5
DMA
20
6
DMSO
THF
25
7
30
8
Cs2CO3/Et3N 1,4-dioxane
34
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
21
10
11
12
13d
14d
15d
16d
17d
18d
19d
20d
21d
22
23d
24d
25
23
22
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
27
61
K3PO4
22
Na2CO3
NaOtBu
NaOH
48
49
trace
44
Pd(PPh3)4 (tBu)3P·HBF4
K2CO3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cy3P·HBF4
Davephos
Xphos
K2CO3
66
K2CO3
49
K2CO3
72/58e/80f
Xphos
K2CO3/ Et3N
K2CO3
51
DPEphos
Xantphos
Xphos
50
K2CO3
61
77g
K2CO3
a
Reaction conditions: 1a (0.2 mmol), base (0.4 mmol), Pd (5 mol %), ligand (10 mol % ), solvent
(2 mL), 24 h. b Et3N (1.2 mmol). c Isolated yield. d base (0.6 mmol). e ligand (5 mol%). ligand (15
f
mol%). g 1.0 mmol scale.
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Scheme 2. Variation of the Alkenyl Bromidesa,b
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a Reaction conditions: 1 (0.2 mmol), K2CO3 (0.6 mmol), 5 mol % of Pd(PPh3)4, 15 mol % of Xphos,
1,4-dioxane (2 mL), 140 ℃, 24 h. c Isolated yield after chromatography.
The generality of the aryl aldehydes 1 were then examined (Scheme 3). A variety of
substituents (Me, OMe, F, Cl, and Br) were tolerated, affording the corresponding
products in 20-91% yields. The electronic nature of the aryl aldehyde motifs affected
the outcome to some extent. The incorporation of electron-donating substituents
(Me and OMe) at either the para- or meta-position did not seem to hamper the
reaction, and the flavonoids 2n, 2o, 2r, 2u, and 2v could be obtained in good yields
(61-91%). When electron-withdrawing substituents (Cl and Br) are introduced to the
aryl aldehyde moiety, the corresponding products 2q, 2t, and 2x were obtained in
low yields (20-41%). However, when fluoro-substituted aryl aldehydes 1p, 1s, and
1w were used, the corresponding chromones can be obtained in good yields
(50-77%). In addition, β-naphthyl aldehyde substrate 1y can also be efficiently
transformed into 2y in 48% yield. The capacity to perform nucleophilic addition and
Pd-catalyzed acylation together in one pot potentially makes this method more
versatile and valuable. Consequently, one-pot approach was finally explored. As
shown in scheme 4, the reaction of salicylaldehyde and arylethynyl bromides can
smoothly proceed to generate the corresponding products 2a-c in 42%, 36% and
56% yield, respectively.
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Scheme 3. Variation of the Aromatic Aldehydesa, b
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a
Reaction conditions: 1 (0.2 mmol), K2CO3 (0.6 mmol), 5 mol % of Pd(PPh3)4, 15 mol % of Xphos,
1,4-dioxane (2 mL), 140 ℃, 24 h. c Isolated yield after chromatography.
Scheme 4. One-Pot synthesis of 4H-chromen-4-onesa
O
CHO
(1) K2CO3, DMF, 110 ℃, 12 h
R
Br
O
R
OH
(2) Pd2(PPh3)4, Xphos, K2CO3
1,4-dioxide, 140 ℃, 24 h
one-pot reaction
yieldb
R
C6H5
2a, 42%
p-Me-C6H4
2b, 36%
2c, 56%
p-MeO-C6H4
a Conditions: salicylaldehyde (0.5 mmol), alkynyl bromides (0.6 mmol), K2CO3 (2.5 mmol), DMF (1
mL), 110 ℃, 12 h; then Pd(PPh3)4 (5 mol%), Xphos (15 mol%), 1,4-dioxane (2 mL), 140 ℃, 24 h. b
Isolated yield.
Scheme 5. Proposed catalytic mechanism
On the basis of the results obtained by Miura,24 and Solé,23,25 two competitive
catalytic cycles have been proposed. The first one (Scheme 5A), describes the
nucleophilic addition of the alkenyl-Pd(II) intermediate to the carbonyl group, while
the second one (Scheme 5B), shows direct C-H vinylation at the formyl group of aryl
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aldehyde. The initial step involved the oxidative addition of alkenyl bromide 1 by
Pd(0) to generate 3. Carbopalladation of the alkenyl-Pd(II) intermediate 3 across the
C=O bond26 provided nucleophilic addition intermediate 4, which was followed by
β-hydride elimination would afford the ketone 2 and regenerate the Pd(0) catalyst
(mechanism A). Alternatively, the alkenyl-Pd(II) 3 underwent C-H activation of the
aldehyde to provide intermediate 6. After loss of HX from the resulting Pd(IV)
intermediate 6 by the base and reductive elimination from the acyl-Pd complex 7
would also form the ketone 2 and regenerate the catalyst (mechanism B).27
In summary, we have developed a practical protocol for the synthesis of flavonoids
through Pd-catalyzed intramolecular acylation of alkenyl bromides and aldehydes.
The success of the reaction heavily relies on the careful selection of proper base and
solvent. K2CO3 as the base in 1,4-dioxane was found to be essential for the efficient
formation of chromenones. The result presented here should be of considerable
interest for valuable synthetic targets for medicinal chemistry.
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EXPERIMENTAL SECTION
General Experimental Methods. Chemicals were all purchased from commercial
supplies and used without further purification unless otherwise stated. Solvents
were dried and purified according to the standard procedures before use. Reactions
were monitored by analytical thin-layer chromatography (TLC). All reactions were
conducted in dried glassware. Purification of reaction products was done by flash
chromatography with 230-400 mesh silica gel. Alkenyl bromide substrates were
prepared according to the literature methods.22 Melting points were determined on
1
a melting point apparatus in open capillaries and are uncorrected. H NMR spectra
were recorded on a 400 or 600 MHz spectrometer, and 13C NMR spectra were
recorded at 100 or 150 MHz. Unless otherwise stated, deuterochloroform (CDCl3)
was used as a solvent. Chemical shifts (δ) are given in parts per million downfield
relative to residual CHCl3 (δ = 7.26 ppm). Chemical shifts for carbon resonances are
reported in parts per million and are referenced to the carbon resonance of the
solvent CHCl3 (δ = 77.16 ppm). The splitting patterns are reported as s (singlet), d
(doublet), dd (double doublet), t (triplet), and m (multiplet). Coupling constants are
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given in hertz. High-resolution mass spectra were recorded on a BIO TOF Q mass
spectrometer.
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General Procedures for Synthesis of Chromenone derivatives.
9
A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with alkenyl
bromides (0.2 mmol, 1.0 equiv), K2CO3 (82.5 mg, 0.6 mmol, 3.0 equiv), and then
Pd(PPh3)4 (0.01 mmol, 12 mg) and Xphos (0.03 mmol, 14 mg) were added. Finally,
1,4-Dioxane (2.0 mL) was added to the mixture via syringe at room temperature
under air. The tube was sealed and put into a preheated oil bath at 140 ℃ for 24 h.
The mixture was cooled to room temperature, quenched with water (5 mL), and
diluted with ethyl acetate (8 mL). The layers were separated, and the aqueous layer
was extracted with 2 × 8 mL of ethyl acetate. The combined organic extracts were
dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude
product was then purified by flash chromatography on silica gel (H), eluting with
5−10% ethyl acetate/petroleum ether.
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2-Phenyl-4H-chromen-4-one (2a). Yield, 80% (35.5 mg). Yellow solid, Mp: 94-97 ℃
(Lit.14b mp 97 ℃). ¹H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 5.8
Hz, 2H), 7.70 (t, J = 7.7 Hz, 1H), 7.58-7.53 (m, 4H), 7.42 (t, J = 7.5 Hz, 1H), 6.83 (s, 1H).
13C NMR (151 MHz, CDCl3) δ 178.5, 163.4, 156.3, 133.8, 131.8, 131.6, 129.1, 126.3,
125.7, 125.3, 124.0, 118.1, 107.6.
2-(p-Tolyl)-4H-chromen-4-one (2b). Yield, 78% (36.8 mg). Yellow solid, Mp:
100-102 ℃(Lit.14b,28a mp 100-102 ℃). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.9 Hz,
1H), 7.83 (d, J = 8.0 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.42 (t, J =
7.5 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 6.80 (s, 1H), 2.45 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 178.5, 163.7, 156.3, 142.3, 133.7, 129.8, 129.0, 126.3, 125.7, 125.2, 124.0,
118.1, 107.0, 21.6.
2-(4-Methoxyphenyl)-4H-chromen-4-one (2c). Yield, 80% (40.3 mg). Yellow solid. Mp:
1
157-158 ℃ (Lit.14b,28a mp 155-156 ℃). H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.0
Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.69 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.41 (t,
J = 7.4 Hz, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 3.90 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 178.4, 163.4, 162.4, 156.2, 133.6, 128.0, 125.7, 125.1, 124.0, 123.9, 118.0,
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114.5, 106.2, 55.5.
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2-(3-Methoxyphenyl)-4H-chromen-4-one (2d). Yield, 71% (35.8 mg). Yellow solid. Mp:
1
132-134 ℃ (Lit.28a mp 128-129 ℃). H NMR (400 MHz, CDCl3) δ 8.23 (dd, J = 8.0,
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1.2 Hz 1H), 7.74-7.66 (m, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H),
7.45-7.40 (m, 3H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 6.82 (s, 1H), 3.90 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ 178.5, 163.2, 160.0, 156.2, 133.8, 133.1, 130.1, 125.7, 125.3,
124.0, 118.7, 118.1, 117.2, 111.7, 107.8, 55.5.
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2-(m-Tolyl)-4H-chromen-4-one (2e). Yield, 48% (31.0 mg). Yellow solid. Mp:
105-107 ℃ (Lit.17 mp 128-129 ℃). 1H NMR (600 MHz, CDCl3) δ 8.21 (dd, J = 7.9, 1.5
Hz, 1H), 7.67 (m, 3H), 7.54 (d, J = 8.4 Hz, 1H), 7.38 (m, 2H), 7.31 (d, J = 7.4 Hz, 1H),
6.78 (s, 1H), 2.43 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 178.4, 163.6, 156.2, 138.8,
133.7, 132.4, 131.6, 128.9, 126.8, 125.6, 125.2, 123.9, 123.5, 118.1, 107.5, 21.5.
2-(3-Fluorophenyl)-4H-chromen-4-one (2f). Yield, 45% (21.6 mg). Yellow solid. Mp:
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97-99 ℃ (Lit.18b mp 96-98 ℃). H NMR (600 MHz, CDCl3) δ 8.24 (d, J = 7.8 Hz, 1H),
7.74-7.71 (m, 2H), 7.65 (d, J = 9.6 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.53-7.49 (m, 1H),
7.45 (t, J = 7.4 Hz, 1H), 7.27-7.24 (m, 1H), 6.82 (s, 1H). 13C NMR (151 MHz, CDCl3) δ
178.4, 163.1 (d, J = 246 Hz), 161.92, 161.91, 156.2, 134.0, 133.9, 130.8 (d, J = 9 Hz),
125.6 (d, J = 48 Hz), 123.9, 122.0 (d, J = 3 Hz), 118.6 (d, J = 21 Hz), 118.1, 113.4 (d, J =
24 Hz), 108.2.
2-(4-Fluorophenyl)-4H-chromen-4-one (2g). Yield, 80% (55.5 mg). Yellow solid. Mp:
143-145 ℃ (Lit.28d mp 148-150 ℃). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.9 Hz,
1H), 7.94 (m, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.5 Hz,
1H), 7.22 (m, 2H), 6.77 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 178.4, 164.8 (d, J = 246
Hz), 162.4, 156.2, 133.9, 128.5 (d, J = 9 Hz), 128.0 (d, J = 3 Hz), 125.8, 125.4, 123.9,
118.1, 116.3 (d, J = 21 Hz), 107.4.
2-(4-Chlorophenyl)-4H-chromen-4-one (2h). Yield, 57% (29.2 mg). Yellow solid. Mp:
188-189 ℃ (Lit.28a mp 185-187 ℃). ¹H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.8 Hz,
1H), 7.96-7.87 (m, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.60-7.50 (m, 3H), 7.44 (t, J = 7.6 Hz,
1H), 6.80 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 178.3, 162.3, 156.2, 133.9, 131.7,
130.3, 129.4, 127.6, 125.8, 125.4, 123.9, 118.1, 107.7.
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2-(4-Bromophenyl)-4H-chromen-4-one (2i). Yield, 31% (18.6 mg). Yellow solid. Mp
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163-165 ℃ (Lit.28d mp 164-166 ℃). H NMR (600 MHz, CDCl3) δ 8.25 (dd, J = 7.9,
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1.4 Hz, 1H), 7.95 (dd, J = 7.7, 1.7 Hz, 2H), 7.73-7.70 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H),
7.57-7.52 (m, 3H), 7.44 (t, J = 7.5 Hz, 1H), 6.85 (s, 1H); 13C NMR (151 MHz, CDCl3) δ
178.5, 163.4, 156.3, 133.8, 131.8, 131.6, 129.1, 126.3, 125.7, 125.3, 123.9, 118.1,
107.6.
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2-Butyl-4H-chromen-4-one (2j).16c,28b Yield, 63% (63.7 mg). Yellow oil. H NMR (400
MHz, CDCl3) δ 8.18 (d, J = 7.9 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H),
7.36 (t, J = 7.6 Hz, 1H), 6.17 (s, 1H), 2.62 (t, J = 7.6 Hz, 2H), 1.73 (m, 2H), 1.43 (m, 2H),
0.96 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 178.5, 169.9, 156.5, 133.4, 125.6,
124.9, 123.7, 117.9, 109.8, 34.0, 28.9, 22.1, 13.8.
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2-Hexyl-4H-chromen-4-one (2k).16c Yield, 60% (55.2 mg). Yellow oil. H NMR (600
MHz, CDCl3) δ 8.17 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H),
7.35 (t, J = 7.5 Hz, 1H), 6.17 (s, 1H), 2.60 (t, J = 7.7 Hz, 2H), 1.76-1.68 (m, 2H), 1.38 (m,
2H), 1.31 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 178.3, 169.8,
156.4, 133.4, 125.5, 124.8, 123.6, 117.8, 109.6, 34.2, 31.4, 28.6, 26.7, 22.4, 14.0.
2-Decyl-4H-chromen-4-one (2l).28c Yield, 78% (89.3mg). Yellow oil. 1H NMR (600 MHz,
CDCl3) δ 8.18 (d, J = 7.9 Hz, 1H), 7.66-7.58 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 (t, J =
7.5 Hz, 1H), 6.17 (s, 1H), 2.61 (t, J = 7.6 Hz, 2H), 1.76-1.71 (m, 2H), 1.41-1.37 (m, 2H),
1.35-1.31 (m, 2H), 1.31-1.24 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 178.3, 169.8, 156.5, 133.4, 125.6, 124.8, 123.7, 117.8, 109.8, 34.3, 31.9, 29.5,
29.4, 29.3, 29.2, 29.0, 26.8, 22.7, 14.1.
4-(4-Oxo-4H-chromen-2-yl)butyl benzoate (2m). Yield, 41% (27.7 mg). Yellow solid.
Mp: 122-124 ℃. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.2
Hz, 2H), 7.61-7.51 (m, 2H), 7.42-7.32 (m, 4H), 6.17 (s, 1H), 4.36 (br, 2H), 2.68 (br, 2H),
1.88 (br, 4H). 13C NMR (151 MHz, CDCl3) δ 178.2, 168.9, 166.5, 156.4, 133.5, 133.0,
130.1, 129.5, 128.4, 125.6, 125.0, 123.7, 117.8, 110.0, 64.2, 33.9, 28.1, 23.4.
HRMS-ESI: [M + Na]+ calcd for C20H18NaO4 m/z 345.1103, found m/z 345.1112.
6-Methyl-2-phenyl-4H-chromen-4-one (2n). Yield, 63% (59.5 mg). Yellow solid. Mp:
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119-121 ℃ (Lit.14b,17 mp 112-114 ℃). H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H),
7.93-7.91 (m, 2H), 7.53-7.45 (m, 5H), 6.81 (s, 1H), 2.46 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 178.6, 163.2, 154.5, 135.2, 135.0, 131.9, 131.5, 129.0, 126.3, 125.0, 123.6,
117.8, 107.4, 20.9.
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6-Methoxy-2-phenyl-4H-chromen-4-one (2o). Yield, 80% (79.7 mg). Yellow solid. Mp:
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163-165 ℃ (Lit.14b,17 mp 165-167 ℃). H NMR (600 Hz, CDCl3) δ 7.95-7.89 (m, 2H),
7.59 (d, J = 3.1 Hz, 1H), 7.56-7.47 (m, 4H), 7.29 (dd, J = 9.1, 3.1 Hz, 1H), 6.82 (s, 1H),
3.91 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 178.3, 163.2, 157.0, 151.1, 131.9, 131.5,
129.0, 126.2, 124.6, 123.8, 119.5, 106.8, 104.8, 55.9.
6-Fluoro-2-phenyl-4H-chromen-4-one (2p). Yield, 71% (68.2 mg). Yellow solid. Mp:
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100-102 ℃ (Lit.28c mp 99-103 ℃). H NMR (400 MHz, CDCl3) δ 7.94-7.83 (m, 3H),
7.60-7.50 (m, 4H), 7.44-7.39 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H). 13C NMR (151 MHz,
CDCl3) δ 177.6 (d, J = 1.5 Hz), 163.7, 159.6 (d, J = 246 Hz), 152.4, 131.8, 131.5, 129.1,
126.3, 125.1 (d, J = 7.5 Hz), 121.9 (d, J = 24 Hz), 120.2 (d, J = 9 Hz), 110.6 (d, J = 22.5
Hz), 106.9.
6-Chloro-2-phenyl-4H-chromen-4-one (2q). Yield, 20% (20.5 mg). Yellow solid. Mp:
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183-184 ℃ (Lit.14b,17 mp 184-186 ℃). H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 4.0
Hz, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.64 (dd, J = 8.8, 1.9 Hz, 1H), 7.58-7.51 (m, 4H), 6.83
(s, 1H). 13C NMR (151 MHz, CDCl3) δ 177.2, 163.7, 154.6, 134.0, 131.9, 131.4, 131.2,
129.2, 126.4, 125.2, 124.9, 119.9, 107.5.
7-Methyl-2-phenyl-4H-chromen-4-one (2r). Yield, 67% (31.6 mg). Yellow solid. Mp:
126-128 ℃ (Lit.17,28g mp 122-124 ℃). 1H NMR (600 MHz, CDCl3) δ 8.09 (d, J = 8.1 Hz,
1H), 7.89 (dd, J = 7.6, 1.6 Hz, 2H), 7.54–7.48 (m, 3H), 7.34 (s, 1H), 7.21 (d, J = 8.0 Hz,
1H), 6.77 (s, 1H), 2.49 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 178.4, 163.0, 156.3, 145.1,
131.8, 131.5, 129.0, 126.7, 126.2, 125.4, 121.7, 117.8, 107.5, 21.8.
7-Fluoro-2-phenyl-4H-chromen-4-one (2s). Yield, 50% (36 mg). Yellow solid. Mp:
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100-102 ℃ (Lit.28b,g mp 100-101 ℃). H NMR (600 MHz, CDCl3) δ 8.25 (dd, J = 8.8,
6.3 Hz, 1H), 7.91 (dd, J = 8.0, 1.4 Hz, 2H), 7.58-7.53 (m, 3H), 7.28-7.26 (m, 1H),
7.18-7.15 (m, 1H), 6.81 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 177.5, 165.7 (d, J = 254
Hz), 163.8, 157.3 (d, J = 13.5 Hz), 131.8, 131.4, 129.1, 128.3 (d, J = 10.5 Hz), 126.3,
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120.8, 114.0 (d, J = 22.5 Hz), 107.7, 104.8 (d, J = 25.5 Hz).
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7-Bromo-2-phenyl-4H-chromen-4-one (2t). Yield, 80% (49.2 mg). White solid. Mp:
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163-165 ℃ (Lit.28b,g mp 164-165 ℃). H NMR (600 MHz, CDCl3) δ 8.25 (dd, J = 7.9,
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1.5 Hz, 1H), 7.95 (dd, J = 7.7, 1.7 Hz, 2H), 7.73-7.70 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H),
7.58-7.52 (m, 3H), 7.44 (t, J = 7.5 Hz, 1H), 6.85 (s, 1H). 13C NMR (151 MHz, CDCl3) δ
178.5, 163.4, 156.3, 133.8, 131.8, 131.6, 129.1, 126.3, 125.7, 125.3, 124.0, 118.1,
107.6.
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8-Methyl-2-phenyl-4H-chromen-4-one (2u). Yield, 80% (66.1 mg). White solid. Mp:
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168-170 ℃ (Lit.28d mp 170 °C). H NMR (600 MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 1H),
7.94 (d, J = 7.5 Hz, 2H), 7.57-7.52 (m, 4H), 7.31 (t, J = 7.5 Hz, 1H), 6.84 (s, 1H), 2.61 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 178.9, 162.9, 154.7, 134.7, 132.0, 131.6, 129.1,
127.5, 126.2, 124.8, 123.8, 123.3, 107.3, 15.9.
8-Methoxy-2-phenyl-4H-chromen-4-one (2v). Yield, 80% (45.9 mg). Yellow solid. Mp:
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199-200 ℃ (Lit.28e mp 199-200 ℃). H NMR (600 MHz, CDCl3) δ 8.00-7.96 (m, 2H),
7.78 (d, J = 8.0 Hz, 1H), 7.54-7.51 (m, 3H), 7.33 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 7.9 Hz,
1H), 6.85 (s, 1H), 4.03 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 178.5, 163.0, 149.1, 146.7,
131.8, 131.6, 129.1, 126.4, 125.0, 124.8, 116.4, 114.4, 107.4, 56.4.
8-Fluoro-2-phenyl-4H-chromen-4-one (2w). Yield, 77% (73.9 mg). White solid. Mp:
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125-126 ℃. H NMR (400 MHz, CDCl3) δ 8.00-7.96 (m, 3H), 7.59-7.52 (m, 3H),
7.51-7.45 (m, 1H), 7.38-7.33 (m, 1H), 6.86 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 177.5,
163.1, 151.4 (d, J = 252 Hz), 145.0 (d, J = 12 Hz), 131.9, 131.2, 129.2, 126.4, 125.9,
124.8 (d, J = 7.5 Hz), 120.7 (d, J = 3 Hz), 119.6 (d, J = 16.5 Hz), 107.6.
8-Bromo-2-phenyl-4H-chromen-4-one (2x). Yield, 24% (14.4 mg). Yellow solid. Mp:
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173-175 ℃. H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.8 Hz, 1H), 8.10-7.99 (m, 2H),
7.93 (d, J = 7.7 Hz, 1H), 7.61-7.52 (m, 3H), 7.31 (t, J = 7.8 Hz, 1H), 6.88 (s, 1H). 13C
NMR (151 MHz, CDCl3) δ 177.9, 163.4, 152.8, 137.2, 132.0, 131.3, 129.2, 126.5, 125.9,
125.3, 125.1, 112.0, 107.2.
2-Phenyl-4H-benzo[g]chromen-4-one (2y). Yield, 48% (52.2 mg). Yellow solid. Mp:
129-131 ℃ (Lit.28f mp 129−130 ℃). 1H NMR (600 MHz, CDCl3) δ 10.06 (d, J = 7.9 Hz,
1H), 8.09-8.05 (m, 1H), 7.95-7.89 (m, 2H), 7.88-7.86 (m, 1H), 7.75-7.73 (m, 1H),
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7.60-7.56 (m, 2H), 7.52 (br, 3H), 6.96-6.94 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 180.3,
160.8, 157.3, 135.5, 131.4, 131.3, 130.6, 130.4, 129.2, 129.0, 128.1, 127.1, 126.6,
126.0, 117.5, 117.2, 110.3.
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Supporting Information
1H and 13C NMR spectra of the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: jspeng1998@163.com
ccx1759@163.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National Natural Science
Foundation of China (31400294 and 31300286), the Fundamental Research Funds for
the Central Universities (2572015EB02).
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