Silver-mediated radical cyclization of alkynoates and α-keto acids leading to coumarins via cascade double c-c bond formation

Article abstract of DOI:10.1021/jo502474z

A novel and convenient silver-mediated radical cyclization method for the synthesis of coumarin derivatives via the direct difunctionalization of alkynoates with α-keto acids through double C-C bond formation under mild conditions has been developed. This new method is highly efficient and practical, and the starting materials are readily prepared. The present method should provide a useful strategy for the construction of coumarin motifs.

Full text of DOI:10.1021/jo502474z

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Article
Silver-Mediated Radical Cyclization of Alkynoates and alpha-Keto
Acids Leading to Coumarins via Cascade Double C-C Bond Formation
Kelu Yan, Daoshan Yang, Wei Wei, Fen Wang, Yuanyuan Shuai, Qiannan Li, and Hua Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502474z • Publication Date (Web): 06 Jan 2015
Downloaded from http://pubs.acs.org on January 12, 2015
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SilverꢀMediated Radical Cyclization of Alkynoates and αꢀKeto
Acids Leading to Coumarins via Cascade Double CꢀC Bond
Formation
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Kelu Yan, Daoshan Yang,* Wei Wei, Fen Wang, Yuanyuan Shuai, Qiannan Li, and
Hua Wang*
The Key Laboratory of LifeꢀOrganic Analysis and Key Laboratory of Pharmaceutical
Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical
Engineering, Qufu Normal University, Qufu 273165, Shandong, P. R. China.
* Eꢀmail: huawang_qfnu@126.com; yangdaoshan@tsinghua.org.cn
ABSTRACT: A novel and convenient silverꢀmediated radical cyclization method for
the synthesis of coumarin derivatives via the direct difunctionalization of alkynoates
with αꢀketo acids through double CꢀC bond formation under mild conditions has been
developed. This new method is highly efficient and practical, and the starting
materials are readily prepared. The present method should provide a useful strategy
for the construction of coumarin motifs.
INTRODUCTION:
The coumarin nucleus is a key core structure that widely occurs in natural products,
biological molecules and they are also widely used in material chemistry.1 Importantly,
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coumarin derivatives are well documented as therapeutic agents and possess a variety
of pharmacological properties, such as antitumour,2 antimalarial,3 anticoagulant,4
antimicrobial,5 and antiꢀHIV properties6 (Scheme 1). Thus, development of novel and
efficient methods for construction of these compounds will be great value for the
screening of novel biologically active molecules. The conventional methods for the
preparation of coumarins typically involve three approaches, including the Pechmann
reaction,7 the Wittig reaction,8 and the Knoevenagel condensation.9 In 2008, Gabriele
and coꢀworkers developed a palladiumꢀcatalyzed dicarbonylation process to construct
coumarins using 2ꢀ(1ꢀhydroxypropꢀ2ꢀynyl)phenols as substrates.10 Despite these
methods have made various successes, the harshness of strong acid conditions and the
uneasily available precursors could limit their wide applications. Therefore, more
effective processes are needed. Transitionꢀmetalꢀcatalyzed transformations are useful
tools in organic chemistry. Recently, Heck crossꢀcouplings,11 Suzuki
crossꢀcouplings,12 and Pdꢀcatalyzed siteꢀselective crossꢀcoupling reactions13 have
emerged as attractive methods for the synthesis of coumarin derivatives. However,
challenges still remain, it is still highly desirable to develop new strategies to prepare
functionalized coumarins that are utilizing inexpensive substrates and proceeding
under mild conditions.
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As one of the promising synthesis strategies, direct difunctionalization of
alkynes has attracted considerable attention, due to its high efficiency in the cascade
formation of carbonꢀcarbon or carbonꢀheteroatom bonds. In this field, some excellent
difunctionalization reactions such as halosulfonylation,14 ipsoꢀCarboacylation,15
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arylphosphorylation,16 and oxyvinylcyclization17 have been significantly disclosed.
Also, as a valuable functional group, carbonyl functionality is widely used in organic
chemistry. Consequently, the introduction of carbonyl group into organic framework
strongly attracts synthetic pursuit of chemists.18 Nevertheless, up to date, very few
strategies for the fabrication of carbonyl compounds have been developed via the
difunctionalization of alkynes.15a, 15c, 15d In addition, recent years have witnessed
significant efforts devoted to the development of decarboxylative reactions using
carboxylic acids as the coupling partners, owing to that those substrates are readily
available and stable, and besides that, CO2 is the sole waste product from the
transformation.19 For example, Jafarpour and coꢀworkers developed an elegant work
for the synthesis of coumarins via palladiumꢀcatalyzed decarboxylative arylation and
alkenylation of coumarinꢀ3ꢀcarboxylic acids.20 Among all the carboxylic acids, αꢀketo
acids have been emerging as appealing coupling partners in decarboxylative reactions.
In 2008, Gooβen and coꢀworkers firstly reported a Cu/Pdꢀcatalyzed decarboxylative
crossꢀcoupling of αꢀketo carboxylate salts with aryl bromides to afford diaryl
ketones.21 Since then, about the αꢀketo acids decarboxylative reaction has been
extensively studied.22 Meanwhile, about the αꢀketo acids decarboxylative reactions
via radical pathways have also been widely explored, such as difunctionalization of
activated alkenes,23 acylfluorination of styrenes,24 and acyloxylation of sp3 C–H
Bond.25 Inspired and encouraged by these excellent works and with our interest in
heterocycles synthesis via radical pathways,26 we herein describe a new
silverꢀmediated direct carbonylation of alkynes with αꢀketo acids towards
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3ꢀcarbonylated coumarins under mild conditions.
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Scheme 1. Some representative compounds containing the coumarin motif
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RESULTS AND DISCUSSION
Initially, phenyl 3ꢀphenylpropiolate (1a) and 2ꢀoxoꢀ2ꢀphenylacetic acid (2a) were
chosen as the model substrates to optimize reaction conditions including the catalysts,
oxidants and solvents under nitrogen atmosphere. As shown in Table 1, five oxidants
o
such as Na2S2O8, K2S2O8, (NH4)2S2O8, TBHP and O2 were investigated at 60 C by
using 1.0 equiv of AgNO3 (relative to amount of 2a) in 2 mL CH3CN/H2O (v1/v2=1:1),
and K2S2O8 gave the highest yield (75%) (entries 1ꢀ5, Table 1). Furthermore, the
silver salts, including AgNO3, Ag2O, Ag2CO3 and AgOAc were tested in CH3CN/H2O
(entries 5ꢀ8, Table 1) using K2S2O8 as the oxidant at 60 oC, and AgNO3 was found to
be the most effective catalyst (entries 5ꢀ9, Table 1). We attempted to use different
solvents, and CH3CN/H2O was superior to the others (compare entries 5, 10ꢀ12, Table
1). Various reaction temperatures were attempted (entries 5, 13 and 14, Table 1), and
60 oC was found to be suitable for this reaction (entry 5, Table 1). Notably, elevated
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temperature didn’t obviously enahance the yield (entry 15, Table 1). Additionally,
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Table 1. Silverꢀmediated synthesis of 3ꢀbenzoylꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone via
cascade reaction of phenyl 3ꢀphenylpropiolate with 2ꢀoxoꢀ2ꢀphenylacetic acid:
optimization of the catalysis conditionsa
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entry
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catalyst
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
Ag2O
Ag2CO3
AgOAc
None
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
oxidant
Na2S2O8
(NH4)2S2O8
TBHP
solvent
yield b (%)
57
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
DMSO :H2O
H2O
DMF: H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
CH3CN:H2O
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20
trace
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O2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
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trace
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38 c
58 d
76 e
39 f
56 g
a
Reaction conditions: under nitrogen atmosphere, 1a (0.3mmol), 2a (0.6 mmol), catalyst (0.3
mmol), oxidant (4.0 equiv.), solvent 2 mL CH3CN/H2O (v1/v2=1:1), 60oC and reaction time (24 h).
TBHP= tertꢀbutyl hydroperoxide solution 5.5M in decane. b Isolated yield. c Reaction temperature
d
d
e
(30oC). Reaction temperature (50oC). Reaction temperature (50oC). Reaction temperature
(70oC). f AgNO3 (0.06mmol). gAgNO3 (0.18 mmol).
the amount of AgNO3 was rationally changed (compare entries 5, 17 and 18, Table 1),
and 1.0 equiv of AgNO3 provided the highest yield. After the optimization process for
catalysts, oxidants, solvents and temperature, the various coumarin derivatives were
synthesized under our standard conditions: 1.0 equiv of AgNO3 as the promoter, 4.0
equiv of K2S2O8 as the oxidant, and 2 mL CH3CN/H2O(v1/v2=1:1) as the solvent at
60oC under nitrogen atmosphere.
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Table 2. Sliverꢀmediated synthesis of coumarin derivatives via radical cyclization
of alkynoates with αꢀketo acids a,b,c
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a Reaction conditions: under nitrogen atmosphere, substituted alkynoates (0.3 mmol), αꢀketo acids
b
(0.6 mmol), AgNO3(0.3 mmol), K2S2O8 (1.2 mmol), CH3CN/H2O(v1/v2=1:1) (2.0 mL), 60oC.
Isolated yield. c Reaction time (24 h).
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With the optimum reaction conditions in hand, we investigated the scope of
substrates for the silverꢀmediated radical cyclization of substituted alkynoates (1) with
αꢀketo acids (2) leading to coumarin derivatives (3). As shown in Table 2, the tested
substrates afforded moderate to good yields. For the substituted αꢀketo acids which
bearing electron withdrawing group, such as ꢀCl and ꢀBr (Table 2, 3d, 3h, 3o and 3t)
could give slight good yields as compared to the αꢀketo acids with the electron
donating substituents (Table 2, 3g, 3n and 3r). For the substituted alkynoates, the
electronꢀwithdrawing as well as electronꢀdonating substituents did not significantly
affect the catalytic activity. With a strong electronꢀwithdrawing substituent (CF3) on
the phenoxy ring, the corresponding product (3qꢀ3t) were obtained in good yield.
However, alkynoates containing NO2 group did not work in the reaction. The steric
hindrance in the αꢀketo acids did not significantly affect the catalytic efficiency (Table
2, 3b and 3r). Although aromatic αꢀketo acids showed high reactivity, unfortunately,
aliphatic ones were poor substrates. If aliphatic αꢀketo acids such as 2ꢀoxopropanoic
acid and 3,3ꢀdimethylꢀ2ꢀoxobutanoic acid were used as the substrates under the
optimal reaction conditions, only a trace of product was obtained (Table 2, 3u and 3v).
As expected, metaꢀsubstituent group of the phenoxy ring gave two regioselective
products (3aa/3aa’). Unfortunately, alkylpropiolate such as methylpropiolate was not
tolerated in the transformation (3ab).The silverꢀmediated domino reactions could
tolerate some functional groups such as alkyl group, CꢀCl bonds, CꢀBr bonds and
CꢀCF3 bonds which could be used for further modifications at the substituted positions.
The structure of 3a was unambiguously confirmed by Xꢀray crystallographic analysis
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(Figure 1 see Supporting Information).
,
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Scheme 2. Control experiments
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According to the previous report that acyl radicals were easily generated from the
Ag(I)/K2S2O8 system,26 which implies that the transformation should proceed through
a freeꢀradical mechanism. As shown in Scheme 2, when 2.0 equiv of TEMPO
(2,2,6,6ꢀtetramethylpiperidine 1ꢀoxy, a wellꢀknown radical inhibitor) was added in the
standard reaction condtions, the formation of 2a was completely inhibited as expected.
In addition, another radical scavenger such as BHT ( butylated hydroxytoluene) was
also proven to inhibit the transformation. Furthermore, the cyclization product 4a was
not obtained when 1a was performed only under the standard conditions.
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Scheme 3. A proposed mechanism for the direct transformation
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On the basis of these preliminary results above, a possible mechanism for the
silverꢀmediated radical cyclization reactions for the synthesis of coumarin derivatives
is suggested in Scheme 3. Firstly, a acyl radical (A) is generated from αꢀketo acids (2)
by Ag(I)/K2S2O8 with releasing one molecular CO2.27 Selectivie addition of the acyl
radical (A) to the alkynoates (1) gives the vinyl radical (B) stabilized by the phenyl
group. Subsequently, the vinyl radical (B) undergoes an intramolecular cyclization to
generate radical intermediate C. Finally, an Ag(II)ꢀmediated hydrogen abstraction of
radical intermediate C take place, releasing the product 3, H+ and Ag(I).
In summary, a novel and useful protocol has been developed for the synthesis of
coumarin derivatives via silverꢀmediated tandem radical cyclization of readily
prepared alkynoates and αꢀketo acids. A series of potentially biological coumarin
frameworks could be conveniently and efficiently obtained in moderate to good yields
with excellent functional group tolerance. The easy and efficient method for the
synthesis of coumarin compounds should attract much attention in synthetic and
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pharmaceutical chemistry.
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EXPERIMENTAL SECTION
General.
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All commercially available reagent grade chemicals were purchased from chemical
suppliers and used as received without further purification unless otherwise stated.
Alkynoates were prepared according to previous literatures.28 All solvents were dried
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according to standard procedures. H NMR and C NMR spectra were recorded in
CDCl3 on a 400 MHz spectrometer with TMS as internal standard (400 MHz 1H, 100
MHz 13C) at room temperature, the chemical shifts (δ) were expressed in ppm and J
values were given in Hz. The following abbreviations are used to indicate the
multiplicity: singlet (s), doublet (d), triplet (t) and multiplet (m). All first order
splitting patterns were assigned on the basis of the appearance of the multiplet.
Splitting patterns that could not be easily interpreted were designated as multiplet (m).
Mass analyses and HRMS were obtained by ESI on a TOF mass analyzer. Column
chromatography was performed on silica gel (200ꢀ300 mesh).
General experimental procedures.
A 25 ml Schlenk tube equipped with a magnetic stirring bar was charged with AgNO3
(51 mg, 0.3 mmol), potassium persulfate(324mg, 1.2 mmol), substituted various
alkynoates (1) (0.3 mmol) and αꢀketo acids (2) (0.6 mmol). The tube was evacuated
twice and backfilled with nitrogen, and 2 mL CH3CN/H2O(v1/v2=1:1) was added to
the tube under nitrogen atmosphere. The tube was sealed with a balloon and then the
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mixture was allowed to stir under nitrogen atmosphere at 60 C for 24 h. After
completion of the reaction, the resulting solution was cooled down to room
temperature, and the solvent was removed with the aid of a rotary evaporator. The
residue was purified by column chromatography on silica gel using petroleum
ether/ethyl acetate as eluent to provide the desired product (3).
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3ꢀbenzoylꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3a): Compound 3a was obtained in 75%
yield (74 mg) according to the general procedure. Eluent petroleum ether/ethyl acetate
(20:1). mp 100ꢀ101oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.81 (d, 2H, J = 8.0 Hz),
7.66ꢀ7.62 (m, 1H), 7.50 (t, 2H, J = 8.0 Hz), 7.38ꢀ7.35 (m, 5H), 7.30ꢀ7.27 (m, 4H). 13C
NMR (CDCl3, 100 MHz, ppm) δ 192.1, 158.8, 153.8, 153.0, 136.3, 133.8, 132.7,
132.3, 129.5, 129.3, 128.7, 128.6, 128.0, 126.0, 124.7, 119.5, 117.2. HRMS m/z calcd.
for C22H14O3 [M+Na]+: 349.0841, found: 349.0827.
3ꢀ(2ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3b): Compound 3b was
obtained in 67% yield (68 mg) according to the general procedure. Eluent petroleum
1
ether/ethyl acetate (30:1). mp 177ꢀ179oC. H NMR (CDCl3, 400 MHz, ppm) δ
7.64ꢀ7.58 (m, 2H), 7.48 (d, 2H, J = 8.0 Hz), 7.36ꢀ7.32 (m, 4H), 7.26ꢀ7.23 (m, 4H),
13
7.17ꢀ7.12 (m, 2H), 2.41 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 193.8, 158.8,
153.7, 152.3, 140.2, 136.0, 132.6, 132.5, 132.4, 132.0, 131.1, 129.3, 128.6, 128.5,
127.9, 127.5, 125.5, 124.6, 119.6, 117.2, 21.3. HRMS m/z calcd. for C23H16O3
[M+Na]+: 363.0997, found: 363.0996.
3ꢀ(3ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3c): Compound 3c was obtained
in 72% yield (73 mg) according to the general procedure. Eluent petroleum
ether/ethyl acetate (20:1). mp 154ꢀ156oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.72 (d,
2H, J = 8.0 Hz), 7.65ꢀ7.61 (m, 1H), 7.48 (d, 1H, J = 8.0 Hz), 7.37ꢀ7.35 (m, 3H), 7.18
13
(d, 1H, J = 8.0 Hz), 2.38 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 191.7, 158.6,
153.7, 152.7, 144.9, 133.8, 132.6, 132.4, 129.4, 129.3, 128.7, 128.6, 128.0, 126.2,
124.6, 119.5, 117.2, 21.8. HRMS m/z calcd. for C23H16O3 [M+Na]+: 363.0997, found:
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3ꢀ(3ꢀbromobenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3d): Compound 3d was
obtained in 78% yield (95 mg) according to the general procedure. Eluent petroleum
ether/ethyl acetate (20:1). mp 150ꢀ152oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.91 (s,
1H), 7.43 (d, 1H, J = 8.0 Hz), 7.66ꢀ7.63 (m, 2H), 7.50 (d, 1H, J = 8.0 Hz), 7.40ꢀ7.36
(m, 3H), 7.34ꢀ7.24 (m, 5H). 13C NMR (CDCl3, 100 MHz, ppm) δ 190.6, 158.5, 153.8,
153.5, 138.0, 136.5, 132.9, 132.2, 132.0, 130.1, 129.7, 128.7, 128.1, 127.7, 125.3,
124.7, 122.9, 119.3, 117.3. HRMS m/z calcd. for C22H13BrO3 [M+Na]+: 426.9946,
428.9925 found: 426.9947, 428.9925.
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3ꢀbenzoylꢀ6ꢀmethylꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3e): Compound 3e was obtained
in 57% yield (58 mg) according to the general procedure. Eluent petroleum
ether/ethyl acetate (20:1). mp 167ꢀ169oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.81 (d,
2H, J = 8.0 Hz), 7.51 (t, 1H, J = 8.0 Hz), 7.40ꢀ7.33 (m, 5H), 7.29ꢀ7.26 (m, 3H), 7.19
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(d, 1H, J = 8.0 Hz), 7.08 (d, 1H, J = 8.0 Hz), 7.51 (t, 3H). C NMR (CDCl3, 100
MHz, ppm) δ 192.4, 159.1, 153.9, 153.1, 144.3, 133.7, 132.6, 129.4, 129.3, 128.7,
128.6, 128.5, 127.7, 125.9, 117.3, 117.0, 21.7. HRMS m/z calcd. for C23H16O3
[M+Na]+: 363.0997 found: 363.0992.
3ꢀbenzoylꢀ6ꢀmethylꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3f): Compound 3f was obtained
in 69% yield (73 mg) according to the general procedure. Eluent petroleum
ether/ethyl acetate (30:1). mp 131ꢀ132oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.57 (d,
1H, J = 8.0 Hz), 7.34ꢀ7.28 (m, 5H), 7.23ꢀ7.20 (m, 2H), 7.16ꢀ7.11 (m, 3H), 7.05 (d, 1H,
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J = 8.0 Hz), 2.50 (s, 3H) , 2.40 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 194.0,
159.0, 153.8, 152.5, 144.1, 140.1, 132.7, 132.3, 131.9, 131.0, 129.2, 128.5, 128.4,
127.7, 125.8, 125.5, 117.3, 117.2, 21.7, 21.2. HRMS m/z calcd. for C24H18O3
[M+Na]+: 377.1154 found: 377.1149.
6ꢀmethylꢀ3ꢀ(2ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3g): Compound 3g
was obtained in 61% yield (65 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (20:1). mp 124ꢀ126oC. 1H NMR (CDCl3, 400 MHz, ppm)
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δ 7.63ꢀ7.60 (m, 2H), 7.36ꢀ7.32 (m, 4H), 7.29ꢀ7.24 (m, 4H), 7.19 (d, 1H, J = 8.0 Hz),
7.08 (d, 1H, J = 8.0 Hz), 2.51 (s, 3H) , 2.34 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm)
δ 192.5, 159.1, 153.9, 153.0, 144.2, 134.6, 129.6, 129.4, 128.7, 128.5, 128.4, 127.7,
126.7, 125.9, 117.3, 117.1, 21.7, 21.3. HRMS m/z calcd. for C24H18O3 [M+Na]+:
377.1154 found: 377.1149.
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3ꢀ(4ꢀchlorobenzoyl)ꢀ6ꢀmethylꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3h): Compound 3h
was obtained in 73% yield (82 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (30:1). mp 155ꢀ156oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.66 (t, 1H, J = 4.0 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.38ꢀ7.35
(m, 3H), 7.34ꢀ7.25 (m, 4H), 7.19 (d, 1H, J = 8.0 Hz), 7.09 (d, 1H, J = 8.0 Hz), 2.52 (s,
13
3H). C NMR (CDCl3, 100 MHz, ppm) δ 191.1, 158.9, 153.9, 153.7, 144.6, 134.9,
133.6, 129.9, 129.6, 129.1, 128.6, 127.8, 127.3, 126.0, 117.4, 116.9, 21.7. HRMS m/z
calcd. for C23H15ClO3 [M+Na]+: 397.0607 found: 397.0612.
3ꢀ(3ꢀbromobenzoyl)ꢀ6ꢀmethylꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3i): Compound 3i was
obtained in 73% yield (89 mg) according to the general procedure. Eluent petroleum
ether/ethyl acetate (20:1). mp 147ꢀ149oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.91 (t,
1H, J = 4.0 Hz), 7.72 (d, 1H, J = 8.0 Hz), 7.63 (d, 1H, J = 8.0 Hz), 7.38ꢀ7.35 (m, 3H),
7.30ꢀ7.25 (m, 4H), 7.22 (d, 1H, J = 8.0 Hz), 7.09 (d, 1H, J = 8.0 Hz), 2.52 (s, 3H). 13C
NMR (CDCl3, 100 MHz, ppm) δ 191.1, 158.9, 153.9, 153.8, 144.7, 136.5, 132.0,
130.1, 129.6, 128.6, 127.8, 126.0, 117.4, 116.9, 21.9. HRMS m/z calcd. for
C23H15BrO3 [M+Na]+: 441.0102, 443.0082 found: 441.0111, 443.0076.
3ꢀbenzoylꢀ6ꢀchloroꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3j): Compound 3i was obtained
in 72% yield (67 mg) according to the general procedure. Eluent petroleum
ether/ethyl acetate (20:1). mp 148ꢀ150oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.79 (d,
2H, J = 8.0 Hz), 7.54ꢀ7.49 (m, 2H), 7.40ꢀ7.34 (m, 5H), 7.27ꢀ7.24 (m, 4H). 13C NMR
(CDCl3, 100 MHz, ppm) δ 191.7, 158.2, 154.0, 152.4, 138.8, 136.1, 134.0, 132.0,
129.7, 129.3, 128.9, 128.7, 128.6, 125.9, 125.3, 118.1, 117.4. HRMS m/z calcd. for
C22H13ClO3 [M+Na]+: 383.0451 found: 383.0449.
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3ꢀbenzoylꢀ6ꢀchloroꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3k): Compound 3k was obtained
in 65% yield (73 mg) according to the general procedure. Eluent petroleum
ether/ethyl acetate (30:1). mp 142ꢀ144oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.56 (d,
2H, J = 8.0 Hz), 7.47 (d, 2H, J = 4.0 Hz), 7.37ꢀ7.30 (m, 4H), 7.22ꢀ7.19 (m, 4H), 7.15
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(d, 2H, J = 8.0 Hz), 2.40 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 193.3, 158.2,
153.9, 151.7, 140.2, 138.7, 132.6, 132.0, 131.0, 129.5, 128.9, 128.6, 128.5, 125.6,
125.2, 118.3, 117.4, 21.3. HRMS m/z calcd. for C23H15ClO3 [M+Na]+: 397.0607
found: 397.0603.
3ꢀbenzoylꢀ6ꢀbromoꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3l): Compound 3l was obtained
in 52% yield (63 mg) according to the general procedure. Eluent petroleum
ether/ethyl acetate (20:1). mp 185ꢀ187oC. 1H NMR (CDCl3, 400 MHz, ppm) δ 7.80 (d,
2H, J = 8.0 Hz), 7.65 (d, 2H, J = 4.0 Hz), 7.53 (t, 1H, J = 8.0 Hz), 7.40ꢀ7.35 (m, 6H),
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7.27ꢀ7.25 (m, 2H), 7.17 (d, 2H, J = 8.0 Hz). C NMR (CDCl3, 100 MHz, ppm) δ
191.7, 158.1, 153.9, 152.4, 136.1, 134.0, 131.9, 129.7, 129.2, 129.0, 128.7, 128.1,
126.9, 126.1, 120.4, 118.5. HRMS m/z calcd. for C22H13BrO3 [M+Na]+: 426.9946,
428.9925 found: 426.9941, 428.9927.
6ꢀbromoꢀ3ꢀ(3ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3m): Compound 3m
was obtained in 58% yield (73 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (20:1). mp 145ꢀ146oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.66 (d, 1H, J = 4.0 Hz), 7.61ꢀ7.58 (m, 2H), 7.41ꢀ7.34 (m, 5H), 7.29ꢀ7.25 (m, 3H),
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7.17 (d, 2H, J = 8.0 Hz), 2.35 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 191.9,
158.1, 153.8, 152.3, 138.5, 134.8, 132.0, 129.7, 129.5, 129.0, 128.7, 128.5, 128.1,
126.7, 120.4, 118.5, 21.2. HRMS m/z calcd. for C23H15BrO3 [M+Na]+: 441.0102,
443.0082 found: 441.0113, 443.0081.
6ꢀbromoꢀ3ꢀ(4ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3n): Compound 3n
was obtained in 61% yield (76 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (20:1). mp 203ꢀ204oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.70 (d, 2H, J = 8.0 Hz), 7.65 (s, 1H), 7.40ꢀ7.36 (m, 4H), 7.29ꢀ7.25 (m, 2H),
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7.19ꢀ7.15 (m, 3H), 2.38 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 191.3, 158.2,
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153.8, 152.1, 145.1, 133.7, 132.0, 129.7, 129.4, 128.9, 128.7, 128.6, 128.1, 126.7,
126.3, 120.4, 118.6, 21.8. HRMS m/z calcd. for C23H15BrO3 [M+Na]+: 441.0102,
443.0082 found: 441.0112, 443.0081.
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6ꢀbromoꢀ3ꢀ(3ꢀbromobenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3o): Compound 3o
was obtained in 66% yield (95 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (20:1). mp 138ꢀ140oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.89 (t, 1H, J = 2.0 Hz), 7.70 (d, 1H, J = 8.0 Hz), 7.67 (d, 1H, J = 4.0 Hz), 7.62 (d,
1H, J = 8.0 Hz), 7.42ꢀ7.36 (m, 4H), 7.26ꢀ7.22 (m, 3H), 7.18 (d, 1H, J = 8.0 Hz). 13C
NMR (CDCl3, 100 MHz, ppm) δ 190.4, 157.9, 153.9, 153.0, 137.8, 136.7, 131.9,
131.7, 130.2, 129.9, 129.4, 129.1, 128.8, 128.6, 128.3, 127.7, 127.2, 122.9, 120.5,
118.3. HRMS m/z calcd. for C22H12Br2O3 [M+Na]+: 504.9051, 506.9030 found:
504.9049, 506.9033.
6ꢀbromoꢀ3ꢀ(4ꢀchlorobenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3p): Compound 3p
was obtained in 55% yield (72 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (20:1). mp 164ꢀ166oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.74 (d, 2H, J = 8.0 Hz), 7.67 (d, 1H, J = 4.0 Hz), 7.43ꢀ7.35 (m, 6H), 7.26ꢀ7.23 (m,
2H), 7.17 (d, 1H, J = 8.0 Hz). 13C NMR (CDCl3, 100 MHz, ppm) δ 190.5, 158.0,
153.9, 152.8, 140.5, 130.5, 129.9, 129.1, 129.0, 128.8, 128.6, 120.5, 118.4. HRMS
m/z calcd. for C22H12BrClO3 [M+Na]+: 460.9556, 462.9536 found: 504.9049,
506.9033.
3ꢀbenzoylꢀ4ꢀphenylꢀ6ꢀ(trifluoromethyl)ꢀ2Hꢀchromenꢀ2ꢀone (3q): Compound 3q
was obtained in 71% yield (84 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (20:1). mp 206ꢀ208oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.80 (d, 2H, J = 8.0 Hz), 7.74 (s, 1H), 7.52 (t, 2H, J = 8.0 Hz), 7.46ꢀ7.44 (m, 1H),
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7.41ꢀ7.36 (m, 5H), 7.29ꢀ7.25 (m, 2H). C NMR (CDCl3, 100 MHz, ppm) δ 191.4,
157.9, 153.4, 151.7, 135.8, 134.1(q, 2J = 32.3 Hz), 131.6, 129.9, 129.2 (q, 1J = 271.2
Hz), 128.9, 128.8, 128.7, 128.6, 127.9, 121.1, 121.0, 114.6, 114.5, 114.4. HRMS m/z
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calcd. for C23H13F3O3 [M+Na]+: 417.0714 found: 417.0716.
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3ꢀ(2ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ6ꢀ(trifluoromethyl)ꢀ2Hꢀchromenꢀ2ꢀone
(3r):
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Compound 3r was obtained in 62% yield (76 mg). according to the general procedure.
Eluent petroleum ether/ethyl acetate (30:1). mp 111ꢀ113oC. 1H NMR (CDCl3, 400
MHz, ppm) δ 7.73ꢀ7.30 (m, 3H), 7.52ꢀ7.44 (m, 2H), 7.40ꢀ7.37 (m, 3H), 7.30ꢀ7.26 (m,
2H), 7.19 (d, 2H, J = 8.0 Hz), 2.38 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ
190.9, 158.0, 153.3, 151.4, 145.3, 133.4 (q, 2J = 33.0 Hz), 131.7, 129.5 (q, 1J = 270.2
Hz), 128.8, 128.6, 127.9, 121.0, 114.6, 114.5, 21.8. HRMS m/z calcd. for C24H15F3O3
[M+Na]+: 431.0871 found: 431.0874.
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3ꢀ(3ꢀbromobenzoyl)ꢀ4ꢀphenylꢀ6ꢀ(trifluoromethyl)ꢀ2Hꢀchromenꢀ2ꢀone
(3s):
Compound 3r was obtained in 75% yield (106 mg) according to the general procedure.
Eluent petroleum ether/ethyl acetate (30:1). mp 176ꢀ178oC. 1H NMR (CDCl3, 400
MHz, ppm) δ 7.90 (t, 1H, J = 2.0 Hz), 7.74 (s, 1H), 7.71 (d, 1H, J = 8.0 Hz), 7.66 (d,
1H, J = 8.0 Hz), 7.51ꢀ7.46 (m, 2H), 7.42ꢀ7.39 (m, 3H), 7.30ꢀ7.26 (m, 3H). 13C NMR
(CDCl3, 100 MHz, ppm) δ 190.1, 157.7, 153.4, 152.3, 137.5, 136.9, 131.9, 131.4,
130.2, 130.1, 128.9 (q, 1J = 270.0 Hz), 127.3, 123.0, 121.2, 114.7, 114.6. HRMS m/z
calcd. for C24H15F3O3 [M+Na]+: 431.0871 found: 431.0874.
3ꢀ(3ꢀbromobenzoyl)ꢀ4ꢀphenylꢀ6ꢀ(trifluoromethyl)ꢀ2Hꢀchromenꢀ2ꢀone
(3t):
Compound 3t was obtained in 76% yield (98 mg) according to the general procedure.
Eluent petroleum ether/ethyl acetate (20:1). mp 162ꢀ164oC. 1H NMR (CDCl3, 400
MHz, ppm) δ 7.75ꢀ7.72 (m, 3H), 7.51ꢀ7.45 (m, 2H), 7.41ꢀ7.35 (m, 5H), 7.29ꢀ7.25 (m,
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2H). C NMR (CDCl3, 100 MHz, ppm) δ 190.2, 157.8, 153.4, 152.0, 140.7, 134.2,
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131.5, 130.5, 130.1, 129.1(q, J = 270.0 Hz), 128.9, 128.6, 114.7, 114.6. HRMS m/z
calcd. for C23H12ClF3O3 [M+Na]+: 451.0325 found: 451.0320.
3ꢀ(3ꢀbromobenzoyl)ꢀ4ꢀ(4ꢀbromophenyl)ꢀ2Hꢀchromenꢀ2ꢀone (3x): Compound 3w
was obtained in 72% yield (104 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (20:1). mp 121ꢀ123oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.92 (s, 1H), 7.74 (d, 1H, J = 8.0 Hz), 7.69ꢀ7.64 (m, 2H), 7.52ꢀ7.48 (m, 3H),
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7.32ꢀ7.25 (m, 3H), 7.17 (d, 2H, J = 8.0 Hz). C NMR (CDCl3, 100 MHz, ppm) δ
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127.8, 125.5, 125.0, 124.3, 123.1, 119.0, 117.4. HRMS m/z calcd. for C22H12Br2O3
[M+Na]+: 504.9051, 506.9030 found: 504.9049, 506.9033.
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3ꢀ(3ꢀbromobenzoyl)ꢀ4ꢀ(4ꢀchlorophenyl)ꢀ2Hꢀchromenꢀ2ꢀone (3y): Compound 3x
was obtained in 70% yield (92 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (20:1). mp 103ꢀ104oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.93 (s, 1H), 7.74 (d, 1H, J = 8.0 Hz), 7.69ꢀ7.64 (m, 2H), 7.49 (d, 1H, J = 8.0 Hz),
7.38 (d, 2H, J = 8.0 Hz), 7.31ꢀ7.26 (m, 3H), 7.23 (d, 2H, J = 8.0 Hz). 13C NMR
(CDCl3, 100 MHz, ppm) δ 190.6, 158.4, 153.8, 152.5, 137.8, 136.9, 136.1, 133.2,
132.0, 130.5, 130.4, 130.1, 128.1, 127.8, 125.6, 125.0, 123.1, 119.1, 117.4. HRMS
m/z calcd. for C22H12BrClO3 [M+Na]+: 460.9556, 462.9536 found: 460.9551,
462.9532.
3ꢀ(3ꢀbromobenzoyl)ꢀ4ꢀ(4ꢀbromophenyl)ꢀ6ꢀmethylꢀ2Hꢀchromenꢀ2ꢀone
(3z):
Compound 3y was obtained in 68% yield (101 mg) according to the general
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procedure. Eluent petroleum ether/ethyl acetate (20:1). mp 126ꢀ127oC. H NMR
(CDCl3, 400 MHz, ppm) δ 7.92 (s, 1H), 7.73 (d, 1H, J = 8.0 Hz), 7.67 (d, 1H, J = 8.0
Hz), 7.53 (d, 2H, J = 8.0 Hz), 7.30ꢀ7.26 (m, 2H), 7.16ꢀ7.11 (m, 4H), 2.52 (s, 3H). 13C
NMR (CDCl3, 100 MHz, ppm) δ 190.7, 158.7, 153.9, 152.7, 144.9, 136.8, 136.7,
132.0, 131.2, 130.3, 130.2, 130.1, 127.7, 127.5, 126.2, 124.1, 123.0, 111.5, 116.5,
21.8. HRMS m/z calcd. for C23H14Br2O3 [M+Na]+: 518.9207, 520.9187 found:
518.9201, 520.9185.
7ꢀmethylꢀ3ꢀ(2ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3aa): Compound 3aa
was obtained in 44% yield (47 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (50:1). mp 139ꢀ141oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.59 (d, 1H, J = 8.0 Hz), 7.42 (d, 1H, J = 8.0 Hz), 7.37ꢀ7.29 (m, 4H), 7.22ꢀ7.20 (m,
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2H), 7.16ꢀ7.10 (m, 2H), 7.00 (s, 1H), 2.39 (s, 3H), 2.32 (s, 3H). C NMR (CDCl3,
100 MHz, ppm) δ 194.0, 159.1, 152.4, 151.8, 141.1, 136.1, 134.5, 133.7, 132.5, 132.4,
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131.9, 131.1, 129.3, 128.5, 128.4, 127.9, 127.3, 125.5, 119.2, 116.9. HRMS m/z calcd.
for C24H18O3 [M+Na]+: 377.1154 found: 377.1150.
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5ꢀmethylꢀ3ꢀ(2ꢀmethylbenzoyl)ꢀ4ꢀphenylꢀ2Hꢀchromenꢀ2ꢀone (3aa’): Compound
3aa was obtained in 40% yield (43 mg) according to the general procedure. Eluent
petroleum ether/ethyl acetate (50:1). mp 131ꢀ133oC. 1H NMR (CDCl3, 400 MHz, ppm)
δ 7.59 (d, 1H, J = 8.0 Hz), 7.47 (d, 1H, J = 8.0 Hz), 7.34ꢀ7.28 (m, 4H), 7.22ꢀ7.20 (m,
2H), 7.16ꢀ7.07 (m, 4H), 2.39 (s, 3H), 2.32 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm)
δ 194.0, 159.0, 152.0, 140.0, 136.1, 133.9, 132.8, 132.4, 132.0, 131.1, 129.2, 128.6,
128.4, 126.6, 125.7, 125.5, 124.0, 119.4, 21.3. HRMS m/z calcd. for C24H18O3
[M+Na]+: 377.1154 found: 377.1150.
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ASSOCIATED CONTENT
Supporting Information
13
1H and C NMR spectra for all compounds and ORTEP structures of compound 3a,
and CIF files giving spectroscopic data for 3a; Xꢀray results. This information is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: huawang_qfnu@126.com
* Eꢀmail: yangdaoshan@tsinghua.org.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEGEMENTS
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The authors gratefully acknowledge the financial support from the National Natural
Science Foundation of China (Nos. 21302110, 21302109 and21375075), the Taishan
Scholar Foundation of Shandong Province, the Natural Science Foundation of
Shandong Province (ZR2013BQ017), the Project of Shandong Province Higher
Educational Science and Technology Program (J13LD14).
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