One-Pot Domino Friedel-Crafts Acylation/Annulation between Alkynes and 2-Methoxybenzoyl Chlorides: Synthesis of 2,3-Disubstituted Chromen-4-one Derivatives

Article abstract of DOI:10.1021/acs.joc.8b01357

A highly regioselective synthesis of 2,3-disubstituted chromen-4-one derivatives is accomplished from readily available internal alkynes and 2-methoxybenzoyl chlorides. The reaction proceeds via a domino intermolecular Friedel-Crafts acylation/intramolecular vinyl carbocation trapping (or oxa-Michael addition)/demethylation reaction sequence. This Lewis acid promoted method features relatively mild reaction conditions to synthesize a variety of 2,3-disubstituted chromen-4-one derivatives in one pot with up to 93% yield. The chromen-2-one (coumarin) product was obtained when 2,6-dimethoxybenzoyl chloride was used as a starting material via an electrophilic aromatic substitution/rearrangement process.

Full text of DOI:10.1021/acs.joc.8b01357

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Article
One-pot Domino Friedel-Crafts Acylation/Annulation
between Alkynes and 2-Methoxybenzoyl Chlorides:
Synthesis of 2,3-Disubstituted Chromen-4-one Derivatives
Radha Bam, and Wesley A. Chalifoux
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01357 • Publication Date (Web): 05 Jun 2018
Downloaded from http://pubs.acs.org on June 5, 2018
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One-pot Domino Friedel-Crafts Acylation/Annulation between Alkynes and 2-
Methoxybenzoyl Chlorides: Synthesis of 2,3-Disubstituted Chromen-4-one
Derivatives
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Radha Bam and Wesley A. Chalifoux*
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Department of Chemistry, University of NevadaꢀReno, 1664 N. Virginia Street, Reno, NV
89557, USA
ABSTRACT: A highly regioselective synthesis of 2,3ꢀdisubstituted chromenꢀ4ꢀone derivatives is
accomplished from readily available internal alkynes and 2ꢀmethoxybenzoyl chlorides. The
reaction proceeds via a domino intermolecular FriedelꢀCrafts acylation/intramolecular vinyl
carbocation trapping (or oxaꢀMichael addition)/demethylation reaction sequence. This Lewis acid
promoted method features relatively mild reaction conditions to synthesize a variety of 2,3ꢀ
disubstituted chromenꢀ4ꢀone derivatives in oneꢀpot with up to 93% yield. Chromenꢀ2ꢀone
(coumarin) product was obtained when 2,6ꢀdimethoxybenzoyl chloride was used as a starting
material via an electrophilic aromatic substitution/rearrangement process.
INTRODUCTION
Chromenꢀ4ꢀones and their derivatives are secondary metabolites that are ubiquitous in nature.1
The rigid chromenꢀ4ꢀone structure has been identified as an important structure in drug discovery
due to its pharmacologically active properties, such as antiviral,2 antimicrobial,3 anticancer,4 antiꢀ
oxidative,5 cardioprotective,6 and many other biological properties.1a, 7 The prenylated flavonoid,
kuwanon C, isolated from the root bark of Morus lhou, inhibits the activity of βꢀsecretase, which
is a potential target for the treatment of Alzheimer's disease (Figure 1).8 The chromenꢀ4ꢀone
alkaloid schumannificine, isolated from root bark of Schumanniophyton magnificum, was found
to be active against the human immunodeficiency virus (HIV) and herpes simplex virus (HSV).9
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It has been found that the baicalein (5,6,7ꢀtryhydrooxyflavone) is active against a variety of
cancer cells, especially human breast cancer cells.10
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Figure 1. Examples of some biologically active chromenꢀ4ꢀone derivatives.
Chromenꢀ4ꢀone derivatives can be prepared from salicylic acids,11 phenols12 and oꢀ
hydroxyaryl ketones.13 The most common synthetic approaches to make chromenꢀ4ꢀone
derivatives includes BakerꢀVenkatamaran,14 KostaneckiꢀRobinson15 and VilsmeierꢀHaack
reactions.1a,16 More recently, microwave irradiation has been used for the synthesis of several
chromenꢀ4ꢀone derivatives.17 Although several methods have been established for the
construction of simple chromenꢀ4ꢀone derivatives, most of them suffer from serious
disadvantages such as harsh conditions, multiꢀstep procedures, long reaction times, unexpected
sideꢀreactions and poor yields.
The FriedelꢀCrafts reaction is an important tool to form CꢀC bonds.18 FriedelꢀCrafts acylation
of trialkylsilylꢀsubstituted alkynes has been used in the preparation of ynones.19 These high
energy ynones are very important intermediates for the synthesis of oligoynes, molecules that
have been used to study the properties of the elusive spꢀhybridized carbon allotrope, carbyne.20
They can also serve as useful substrates for multicomponent and domino cyclizations to afford
terpenoid scaffolds.21 Recently, our group reported the synthesis of 1ꢀacylꢀ2ꢀalkynylꢀ1,4ꢀ
cyclohexadienes via a regioselective Diels–Alder cycloaddition of conjugated 2,4ꢀdiynones and a
variety of dienes.22 During that study, the formation of an interesting annulated side product was
observed when attempting to make a 2ꢀmethoxyphenyl ynone derivative. Interestingly, the side
reaction of the FriedelꢀCrafts acylation reaction turned out to be annulation to give a chromenꢀ4ꢀ
one. A very convenient method to make substituted chromenꢀ4ꢀones is via a Lewis acid catalyzed
FriedelꢀCrafts acylation of alkynes with suitable benzoyl chlorides. For example, a SnCl4ꢀ
catalyzed synthesis of 2ꢀsubstituted aminochromenꢀ4ꢀones via an annulation reaction of ynamides
with 2ꢀmethoxybenzoyl chlorides was recently reported by Chang and coꢀworkers (Scheme 1a).23
Oh and coꢀworkers recently reported the synthesis of (thio)chromenꢀ4ꢀones via a FriedelꢀCrafts
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acylation/cyclization (Scheme 1b).24 A TMS group is a very useful functional handle that can
easily be converted to other functionalities.25 However, to date, TMSꢀsubstituted internal alkynes
have rarely been used to make TMSꢀfunctionalized chromenꢀ4ꢀones.25 Thus, the development of
new methods for the direct synthesis of TMSꢀfunctionalized chromenꢀ4ꢀones would be of
significant value in terms of probing chemical space. Herein, we report a oneꢀpot synthesis of
various 2,3ꢀdisubstituted chromenꢀ4ꢀones via the annulation reaction between 2ꢀmethoxybenzoyl
chlorides and internal alkynes, including terminal TMSꢀsubstituted alkynes, under relatively mild
conditions.26
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Scheme 1: One-pot Synthesis of Chromen-4-ones
RESULTS AND DISCUSSION
2ꢀMethoxybenzoyl chloride 1a and (4ꢀmethoxyphenylethynyl)trimethylsilane 2a were used as
substrates to optimize the reaction conditions (Table 1). As expected, neither desired product 3a
nor ketone 4a were observed in the absence of Lewis acid at room temperature (entry 1). When
Lewis acids such as EtAlCl2, SnCl4, Sc(OTf)3, and FeCl3 were used in the reaction, only ynone 4a
was observed as a product (entries 2ꢀ5). Neither 3a nor 4a were observed in the presence of
BF3·OEt2 (entry 6) or BBr3 (entry 7). A 1:3 ratio of 3a:4a was obtained when TiCl4 was used as a
Lewis acid at low temperature (entries 8). When AlCl3 was employed at low temperature, a
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significant increase in the formation of 3a was observed (entry 9). Increasing the temperature
resulted in a slight decrease in the amount of 3a formed (entry 10). We hypothesized that
switching to AlBr3 would increase the amount of 3a being formed in the reaction relative to 4a.
The idea here is that increasing the bromide ion concentration in the reaction would increase the
rate of demethylation and favor the formation of product 3a. This is because the bromide anion is
a better nucleophile for the demethylation step of the mechanism (vide infra) relative to
chloride.27 At the same time, the rate of desilylation would decrease, disfavoring the alternate
reaction pathway leading to 4a, since bromide is slower than chloride for desilylation.28 To our
delight, the annulated product 3a was formed exclusively in the presence of AlBr3 in 56% yield
(entry 11). This result suggests that one of these steps demethylation or desilylation is the rate
determining step under these reaction conditions.
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Table 1. Reaction Optimization for 3a
temperature
yield 3a (%) 3a:4aa
entry Lewis acid
(°C)
1
-
–78 to r.t
–78
–78
–78
–78
–78
–78
–78
–78
r.t.
0
0
2
EtAlCl2
SnCl4
Sc(OTf)3
FeCl3
BF3•OEt2
BBr3
0
0:1
0:1
0:1
0:1
0
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0
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TiCl4
N/Ab
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N/Ab
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1:3
3:2
1:1
1:0
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AlCl3
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11
AlCl3
AlBr3
–78
aDetermined by 1H NMR. bNot isolated.
With optimized conditions in hand, a series of TMSꢀsubstituted alkynes were studied, and the
results are summarized in Scheme 2. Alkynes substituted with electronꢀrich and electronꢀpoor
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aryl groups (R2) as well as heteroaryl groups provided desired products (3a-g). The very electronꢀ
poor 2ꢀ(pꢀnitrophenyl)ꢀ1ꢀ(TMS)acetylene failed to provide either 3h or 4h. The reaction is fast
and clean when an electronꢀdonating group is para to the methoxy substituent, providing 3i in
84% yield. Placing an electronꢀwithdrawing trifluoromethyl group para to the methoxy group
gave only ketone product 4j. Having an electronꢀdonating methoxy group para to the carbonyl
resulted in the formation of many spots, by TLC, with no desired product 3k or acyclic ketone 4k
being isolated. Interestingly, other ortho/para directing groups in this position – such as a fluoro,
chloro or bromo – produced the respective ketone products 4l, 4m, and 4n but failed to provide
any desired chromenꢀ4ꢀone products 3l, 3m and 3n. Having a weakly electronꢀdonating methyl
group para to the carbonyl did give desired product 3o, albeit in modest yield. Having an
electronꢀwithdrawing CF3 group para to the carbonyl group did not provide 3p but did produce
ketone 4p as the major product. It seems from these results that increasing the nucleophilicity of
the methoxy group that is participating in the cyclization step (i.e., placing an electronꢀdonating
substituent para to it), improves the formation of the cyclic chromenꢀ4ꢀone product 3. However,
deactivating the methoxy group by substituting the with inductively withdrawing substituents
para to the methoxy group, such as in 3j, seems to retard the cyclization step, leading to larger
amounts of ketone product 4 being observed. Placing the electronꢀwithdrawing group para to the
carbonyl group, such as in 3p, would increase the rate of the FriedelꢀCrafts step but it likely slows
down the cyclization step by inductively deactivating the methoxy group leading to desilylation
being favored. It was found that a conjugated enyne was tolerated to provide 3q, albeit in low
yield. We were excited that the larger naphthyl derivative worked to provide benzochromone
derivative 3r in good yield. Neither bis(TMS)acetylene or 1ꢀ(TMS)ꢀ1ꢀhexyne gave desired
products 3s or 3t, respectively. This may be attributed to a less stabilized vinyl cation
intermediate. Single crystals of 3g and 3r, suitable for Xꢀray crystallographic analysis, were
obtained and their structures unambiguously confirmed (Scheme 2).
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Scheme 2: Scope of Reaction with TMS-alkynes
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After demonstrating that TMSꢀsubstituted alkynes worked well for this transformation,
various symmetrical tolans were explored. To our delight, tolan gave compound 3u in 72% yield
(Scheme 3). Further, electronꢀrich tolans provided products 3v and 3w in 39% and 65% yields,
respectively. It was found that the substituents on the benzoyl chloride significantly affected its
reactivity, following a similar trend as seen in Scheme 2. For instance, having an electronꢀ
donating group para to the methoxy substituent resulted in formation of desired chromenꢀ4ꢀone
product 3x in 82% yield; whereas, having an electronꢀwithdrawing group in this position
significantly slowed down the reaction and gave only 33% yield of product 3y, along with an
intractable mixture of other side products. However, placing the CF3 group para to carbonyl
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resulted in a fast reaction and provided 3z in 93% yield. This result would seem to contrast the
analogous result seen for 3p (Scheme 2); however, since tolans are now being used in the Friedelꢀ
Crafts step, there is no option for desilylation to afford ketone 4 as an alternative pathway, thus
chromenꢀ4ꢀone 3z is favored. Having a methoxy group para to carbonyl resulted in no desired
product 3aa (as was also seen for 3j, Scheme 2), whereas the weakly electronꢀdonating methyl
group para to the carbonyl gives moderate yield of the desired product 3bb. In contrast to the
results when using alkyne 2a (Scheme 2), the halogenꢀsubstituted (Br, Cl and F) benzoyl
chlorides did react with tolan to give moderate yields of chromenꢀ4ꢀone products 3ccꢀ3ff. The
lower yield could be attributed to these groups being ortho/para directors (via their lone pairs)
and thus they will retard the FriedelꢀCrafts step in a similar way as seen in 3aa (although to a
lesser extent).
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Scheme 3: Scope of the Reaction with Internal Alkynes
Interestingly, when 2,6ꢀdimethoxybenzoyl chloride and tolan were used under the optimized
reaction conditions, we observed in the 13C{1H} NMR spectrum that the carbonyl peak of the
isolated product was significantly shifted upfield (δ=161.2 ppm) relative to the other chromenꢀ4ꢀ
one products (176ꢀ183.5 ppm) and the predicted value of 180.5 ppm.29 Xꢀray crystallographic
analysis of the product showed that a rearrangement had occurred to provide compound 6 as the
major product (Scheme 4). We propose that this alternate reaction pathway is the result of steric
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inhibition of resonance,30 where the carbonyl group in intermediate A is forced to be outꢀofꢀplane
relative to the aryl group due to the steric repulsion of the two orthoꢀmethoxy groups. This results
in the methoxy group being further away from the vinyl cation. However, the highly activated
ipsoꢀcarbon of the dimethoxy aryl group in intermediate A is poised to capture the vinyl cation to
form a spirocyclic intermediate B.31 This strained 4ꢀmembered spirocyclic intermediate would
undergo ring opening to generate the more conjugated intermediate C. This intermediate can then
participate in a cyclization/demethylation step to form 3,4ꢀdiphenylcoumarin 6.
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Scheme 4: Proposed Rearrangement Pathway towards Compound 6
The reaction of phenylacetylene 7 required a higher temperature (25 °C) but also gave desired
annulation product 8 in 67% yield (Scheme 5a). Using the optimized reaction conditions, the
reaction between 2ꢀmethoxybenzoyl chloride and 1,4ꢀbis(trimethylsilyl)butaꢀ1,3ꢀdiyne 9 provided
a 4:1 mixture of the 2ꢀethynyl(TMS)ꢀsubstituted product 10 and acyclic ketone 11, respectively
(Scheme 5b). These could be easily separated to provide 10 and 11 in 68% and 16% yields,
respectively. Unsymmetrical internal alkynes with nꢀhexyl and cyclopentyl substituents were also
investigated and shown to work, providing 13 and 15 in 80% and 67% yields, respectively.
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Scheme 5: Regioselective Annulation Reaction of Benzoyl Chloride Derivatives and other
Alkynes
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To demonstrate the utility of TMSꢀfunctionalized chromenꢀ4ꢀone derivatives, product 3a was
converted into the iodochromenone intermediate 16 by iododesilylation with ICl (Scheme 6).
Alkyne functionalized chromenꢀ4ꢀone derivative 17 was obtained in a very good yield (90%) via
a Sonogashira crossꢀcoupling reaction. In addition to that, iodochromenone intermediate 16 was
utilized to obtain the 1,2ꢀdisubstituted chromenꢀ4ꢀone derivatives 18 in good yield (88%) by a
Suziki crossꢀcoupling reaction. This demonstrates that this method provides an easy route to
desirable unsymmetrical and highly functionalized disubstituted chromenꢀ4ꢀone derivatives.
Scheme 6: Synthetic Utility of TMS-functionalized Chromen-4-one Products
We propose that the formation of the chromenꢀ4ꢀone product proceeds by way of initial
acylium ion D formation followed by nucleophilic attack by internal alkyne 2 to form vinyl
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carbocation intermediate E (Scheme 7). This carbocation is stabilized by resonance via the aryl
substituent (R2) and by the trimethylsilyl group (R3), via the βꢀsilyl effect, when alkyne substrates
2 and 9 are used. We propose that there are two possible pathways from here that the reaction can
follow. In path i, there can be a direct intramolecular nucleophilic attack of the carbocation by the
methoxy substituent to provide intermediate F. Demethylation of F by the bromide anion would
result in compound 3. Although the formation of vinyl bromide intermediates G was not
observed,24 path ii cannot be ruled as a plausible route to chromenꢀ4ꢀone product 3. This would
involve an oxaꢀMichael addition on intermediate G followed by demethylation and halogen
elimination.
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Scheme 7: Proposed Reaction Pathway of Annulation Reaction to Chromen-4-ones
CONCLUSION
In summary, highly functionalized chromenꢀ4ꢀone derivatives have been synthesized in moderate
to high yields by a domino FriedelꢀCrafts acylation/oxaꢀMichael addition/elimination pathway. A
wide scope of both benzoyl chloride and internal alkyne substrates were studied, and the
regioselectively was unambiguously determined by Xꢀray crystallography. The regiochemistry
observed in the final annulated products can be rationalized by the resonance stabilization of the
vinyl carbocation intermediate. In addition, electronic effects played a vital role on benzoyl
chloride substrate, particularly when the substituents were para relative to the methoxy group or
the carbonyl group. Moreover, an interesting rearrangement reaction was observed when
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employing 2,6ꢀdimethoxybenzoyl chlorides in the reaction, resulting in the formation of a
functionalized coumarin product. Additionally, this method would allow the synthesis of
regiocontrolled 2,3ꢀdisubstituted chromenꢀ4ꢀone derivatives through crossꢀcoupling. Overall, this
oneꢀpot synthetic methodology provides an effective way to synthesize biologically relevant
chromenꢀ4ꢀones and coumarin derivatives from inexpensive starting materials.
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EXPERIMENTAL SECTION
General Experimental Methods
2ꢀMethoxybenzoyl chloride was purchased from commercial suppliers and used without
further purification. Dichloromethane was purified using a PureSolv MD 5 solvent purification
system. Evaporation and concentration in vacuo was performed using rotary evaporation. Where
appropriate, reactions were performed in standard, dry glassware under an inert atmosphere of
N2. Column chromatography: Silica gel irregular 60 Å (40ꢀ60 micron) from VWR International.
Thinꢀlayer chromatography (TLC): glass sheets covered with silica gel 60 F254 from Millipore a
Corporation; visualization by UV light. Mp: MelꢀTemp apparatus; uncorrected. IR spectra
(cmꢀ1): Thermo Nicolet 6700 FTꢀIR (diamond ATR), data are reported as cm–1. 1H and C{1H}
13
NMR (Varian NMR 400 MHz and 500 MHz) spectra were recorded in deuterated chloroform
(CDCl3). Tetramethylsilane (TMS, set to 0 ppm) was used as an internal standard for chemical
1
shifts or referenced to the residual protioꢀsolvent peaks (7.26 ppm for H and 77.16 ppm for
13C{1H}, respectively). ESIꢀTOF MS: Agilent G6230A instrument with purine and HPꢀØ921 as
internal calibrants.
General Procedure A
To a solution of benzyol chloride 1 (1.1 equiv) in dichloromethane (20 mL) at –78 ºC under N2
atmosphere was added aluminum bromide (1.0 equiv) followed by addition of alkyne 2 (1.0
equiv). After stirring for 1ꢀ1.5 hours at –78 ºC, the reaction was quenched with saturated aqueous
NaHCO3 at –78 ºC, then warmed to room temperature. The reaction mixture was extracted with
Et2O (100 mL × 2). The layers were separated, the organic phase was washed with H2O, brine,
and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the
crude product was purified by column chromatography.
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General Procedure B
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The carboxylic acid (1.0 ~ 1.6 equiv) was dissolved in SOCl2 (2 mL). After refluxing for two
hours, the excess SOCl2 was removed by vacuum distillation. The resulting crude acid chloride
was used without further purification. To a solution of crude acid chloride in dichloromethane
(20 mL) at –78 ºC under N2 atmosphere was added aluminum bromide (1.0 equiv) and alkyne 2
(1.0 equiv). The reaction was quenched after 1ꢀ1.5 hours at –78 ºC with saturated aqueous
NaHCO3, then warmed to room temperature. The reaction mixture was extracted with Et2O (100
mL × 2). The organic layer was washed with H2O, brine, and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure and the crude product was purified by column
chromatography.
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2-(4-Methoxyphenyl)-3-(trimethylsilyl)-4H-chromen-4-one (3a) was prepared following the
general procedure A using 2ꢀmethoxybenzoyl chloride 1a (274 mg, 1.60 mmol) and alkyne 2a
(300 mg, 1.47 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc =
5:1, v/v) yielded pure 3a as a white solid (219 mg, 56%). Rf = 0.20 (hexane:EtOAc = 10:1); Mp
= 110ꢀ111 ºC; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.8 Hz, 1H), 7.61 (dd, J = 9.6, 6.8 Hz,
1H), 7.49 – 7.41 (m, 2H), 7.40 – 7.31 (m, 2H), 7.01 – 6.93 (m, 2H), 3.87 (s, 3H), 0.05 ppm (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.7, 169.3, 161.5, 156.4, 133.5, 131.0, 128.4, 125.8,
125.0, 123.0, 118.2, 117.8, 113.7, 55.6, 0.8 ppm; IR (film): 3008, 2953, 2891, 1627, 1614, 1503,
1463 cm–1; HRMS (ESIꢀTOF) m/z calcd for C19H21O3Si [M+H]+ 325.1254; found 325.1252.
2-(2-Methoxyyphenyl)-3-(trimethylsilyl)-4H-chromen-4-one (3b) was prepared following
general procedure A using 2ꢀmethoxybenzoyl chloride 1a (137 mg, 0.810 mmol) and alkyne 2b
(150 mg, 0.735 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc
1
= 10:1, v/v) yielded pure 3b as a yellow oil (85 mg, 36%). Rf = 0.20 (hexane:EtOAc = 8:1); H
NMR (400 MHz, CDCl3) δ 8.18 (d, J = 9.0 Hz, 1H), 7.66 – 7.58 (m, 1H), 7.54 – 7.41 (m, 1H),
7.40 – 7.34 (m, 2H), 7.30 (d, J = 7.3 Hz, 1H), 7.08 – 7.01 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.82
(s, 3H), ꢀ0.02 ppm (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.4, 166.3, 157.4, 156.8,
133.4, 131.8, 130.9, 125.8, 125.0, 124.9, 123.2, 120.3, 120.2, 118.0, 111.1, 55.6, ꢀ0.1 ppm; IR
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(film): 2951, 1631, 1613, 1464, 1348, 1245 cm–1; HRMS (ESIꢀTOF) m/z calcd for C19H21O3Si
[M+H]+ 325.1254; found 325.1241.
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2-(2-Furanyl)-3-(trimethylsilyl)-4H-chromen-4-one (3c) was prepared following general
procedure A using 2ꢀmethoxybenzoyl chloride 1a (228 mg, 1.34 mmol) and alkyne 2c (200 mg,
1.22 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 15:1, v/v)
yielded pure 3c as a colorless crystalline solid (150 mg, 53%). Rf = 0.39 (hexane:EtOAc = 10:1);
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Mp = 137ꢀ138 ºC; H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.64 –
13
7.59 (m, 1H), 7.53 (s, 1H), 7.38 – 7.33 (m, 2H), 6.66 (s, 1H), 0.17 ppm (s, 9H); C{1H} NMR
(100 MHz, CDCl3) δ 181.4, 160.7, 155.3, 142.7, 142.4, 132.6, 124.8, 124.1, 122.1, 120.6, 118.7,
116.7, 110.1, ꢀ0.1 ppm; IR (film): 2946, 1613, 1603, 1543, 1461, 1352 cm–1; HRMS (ESIꢀTOF)
m/z calcd for C16H17O3Si [M+H]+ 285.0941; found 285.0929.
2-(4-Bromoyphenyl)-3-(trimethylsilyl)-4H-chromen-4-one (3d) was prepared following
general procedure A using 2ꢀmethoxybenzoyl chloride 1a (148 mg, 0.868 mmol) and alkyne 2d
(200 mg, 0.790 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc
= 6:1, v/v) yielded pure 3d as a light yellow solid (184 mg, 63%). Rf = 0.20 (hexane:CH2Cl2 =
1:1); Mp = 169ꢀ171 ºC; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 1H), 7.67 – 7.61 (m,
13
3H), 7.43 – 7.35 (m, 4H), 0.05 ppm (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 182.3, 167.9,
156.3, 134.7, 133.7, 131.6, 131.0, 125.8, 125.2, 125.1, 122.9, 119.0, 117.8, 0.7 ppm; IR (film):
3062, 2950, 1628, 1611, 1464, 1347 cm–1; HRMS (ESIꢀTOF) m/z calcd for C18H18BrO2Si
[M+H]+ 373.0254; found 373.0245.
2-(2-Bromoyphenyl)-3-(trimethylsilyl)-4H-chromen-4-one (3e) was prepared following
general procedure A using 2ꢀmethoxybenzoyl chloride 1a (370 mg, 2.17 mmol) and alkyne 2e
(500 mg, 1.97 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc =
1
10:1, v/v) yielded pure 3e as a yellow oil (540 mg, 73%). Rf = 0.20 (hexane: EtOAc = 8:1); H
NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 7.72 – 7.57 (m, 2H), 7.50 – 7.27 (m, 5H),
13
0.00 ppm (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 182.1, 166.9, 156.5, 136.7, 133.7, 132.8,
131.5, 131.1, 127.2, 125.7, 125.2, 123.2, 123.1, 119.9, 117.9, ꢀ0.2 ppm; IR (film): 2979, 1626,
1611, 1558, 1461, 1340 cm–1; HRMS (ESIꢀTOF) m/z calcd for C18H18BrO2Si [M+H]+ 373.0254;
found 373.0234.
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2-Phenyl-3-(trimethylsilyl)-4H-chromen-4-one (3f) was prepared following general procedure
A using 2ꢀmethoxybenzoyl chloride 1a (188 mg, 1.10 mmol) and alkyne 2f (174 mg, 1.00
mmol). Purification by flash column chromatography (silica gel, hexane:CH2Cl2 = 4:1, v/v)
yielded pure 3f as a colorless crystalline solid (250 mg, 85%). Rf = 0.20 (hexane:CH2Cl2 = 3:1);
Mp = 136ꢀ137 ºC; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.4 Hz, 1H), 7.63 (dd, J = 8.8, 6.7
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Hz, 1H), 7.58 – 7.45 (m, 5H), 7.43 – 7.34 (m, 2H), 0.05 ppm (s, 9H); C{1H} NMR (100 MHz,
CDCl3) δ 182.5, 169.3, 156.4, 135.9, 133.6, 130.6, 129.4, 128.4, 125.8, 125.1, 123.0, 118.7,
117.8, 0.6 ppm; IR (film): 2944, 1623, 1607, 1546 cm–1; HRMS (ESIꢀTOF) m/z calcd for
C18H19O2Si [M+H]+ 295.1149; found 295.1135.
2-(4-Cyanophenyl)-3-(trimethylsilyl)-4H-chromen-4-one (3g) was prepared following general
procedure A using 2ꢀmethoxybenzoyl chloride 1a (141 mg, 0.830 mmol) and alkyne 2g (149 mg,
0.750 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 15:1,
v/v) yielded pure 3g as a white solid (106 mg, 44%). Rf = 0.20 (hexane:EtOAc = 10:1); Mp =
1
161ꢀ163 ºC; H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.8 Hz, 1H), 7.83– 7.75 (m, 2H), 7.70 –
7.57 (m, 3H), 7.50 – 7.34 (m, 2H), 0.03 ppm (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 180.0,
164.6, 154.3, 137.8, 132.0, 130.2, 128.2, 123.9, 123.5, 120.9, 117.7, 116.2, 115.8, 112.4, ꢀ1.4
ppm; IR (film): 2957, 2917, 2849, 2230, 1629, 1602, 1464 cm–1; HRMS (ESIꢀTOF) m/z calcd for
C19H18NO2Si [M+H]+ 320.1101; found 320.1085.
6-Methoxy-2-(4-methoxyphenyl)-3-(trimethylsilyl)-4H-chromen-4-one (3i) was prepared
following general procedure B using 2,5ꢀdimethoxybenzoic acid (250 mg, 1.37 mmol) and
alkyne 2a (150 mg, 0.734 mmol). Purification by flash column chromatography (silica gel,
hexane:EtOAc = 8:1, v/v) yielded pure 3i as a light yellow solid (219 mg, 84%). Rf = 0.20
1
(hexane:EtOAc = 10:1); Mp = 126ꢀ127 ºC; H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 3.1 Hz,
1H), 7.48 – 7.42 (m, 2H), 7.32 (d, J = 9.1, Hz, 1H), 7.22 (dd, J = 9.1, 3.1 Hz, 1H), 7.03 – 6.95
(m, 2H), 3.887 (s, 3H), 3.878 (s, 3H), 0.05 ppm (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ
182.6, 169.2, 161.4, 156.8, 151.2, 130.9, 128.4, 123.6, 123.4, 119.3, 117.1, 113.7, 104.8, 56.0,
55.5, 0.8 ppm; IR (film): 3005, 2967, 1625, 1609, 1503, 1481 cm–1; HRMS (ESIꢀTOF) m/z calcd
for C20H23O4Si [M+H]+ 355.1360; found 355.1371.
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7-Methyl-2-(4-methoxyphenyl)-3-(trimethylsilyl)-4H-chromen-4-one (3o) was prepared
following general procedure B using 2ꢀmethoxyꢀ4ꢀmethylbenzoic acid (250 mg, 1.51 mmol) and
alkyne 2a (200 mg, 0.980 mmol). Purification by flash column chromatography (silica gel,
hexane:EtOAc = 8:1, v/v) yielded pure 3o as a yellow solid (106 mg, 32%). Rf = 0.20
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(hexane:EtOAc = 10:1); Mp = 138ꢀ139 ºC; H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz,
1H), 7.50 – 7.39 (m, 2H), 7.21 – 7.11 (m, 2H), 7.04 – 6.92 (m, 2H), 3.88 (s, 3H), 2.46 (s, 3H),
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0.05 ppm (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 182.5, 169.0, 161.4, 156.5, 144.7, 130.9,
128.5, 126.4, 125.5, 120.8, 117.9, 117.5, 113.7, 55.5, 21.9, 0.8 ppm; IR (film): 2959, 2923, 1652,
1607, 1504, 1245 cm–1; HRMS (ESIꢀTOF) m/z calcd for C20H23O3Si [M+H]+ 339.1411; found
339.1393.
2-(1-Cyclohexen-1-yl)-3-(trimethylsilyl)-4H-chromen-4-one (3q) was prepared following
general procedure A using 2ꢀmethoxybenzoyl chloride 1a (263 mg, 1.55 mmol) and alkyne 2i
(250 mg, 1.40 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc =
10:1, v/v) yielded pure 3q as a brown sticky solid (80 mg, 19%). Rf = 0.20 (hexane:EtOAc =
15:1); 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 7.9, 1.4 Hz, 1H), 7.59 (ddd, J = 8.8, 7.2, 1.7,
1H), 7.34 (d, J = 8.5, 1H), 7.32 (ddd, J = 8.1, 7.1, 1.0, 1H), 5.96 (tt, J = 3.72, 1.75 Hz, 1H), 2.46
– 2.29 (m, 2H), 2.29 – 2.10 (m, 2H), 1.83 – 1.73 (m, 2H), 1.72 – 1.64 (m, 2H), 0.28 ppm (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 183.1, 172.3, 156.1, 134.3, 134.1, 133.4, 125.7, 124.7,
123.1, 117.6, 116.5, 26.7, 25.4, 22.1, 21.5, 1.2 ppm; IR (film): 2933, 2858, 1629, 1610, 1544 cm–
1; HRMS (ESIꢀTOF) m/z calcd for C18H23O2Si [M+H]+ 299.1462; found 299.1456.
2-(4-Methoxyphenyl)-3-(trimethylsilyl)-Naphtho[2,3-b]-4H-chromen-4-one
(3r)
was
prepared following general procedure B using 3ꢀmethoxyꢀ2ꢀnaphthoic acid (296 mg, 1.46 mmol)
and alkyne 2a (250 mg, 1.22 mmol). Purification by flash column chromatography (silica gel,
hexane:CH2Cl2 = 1:1, v/v) yielded pure 3r as a white solid (274 mg, 60%). Rf = 0.20
(hexane:CH2Cl2 = 2:1); Mp = 149ꢀ151 ºC; 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 8.04 (d, J
= 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.57 (dd, J = 8.4, 6.8 Hz, 1H), 7.54 – 7.51
(m, 2H), 7.49 (dd, J = 8.4, 6.9 Hz, 1H), 7.08 – 6.98 (m, 2H), 3.90 (s, 3H), 0.10 ppm (s, 9H);
13C{1H} NMR (125 MHz, CDCl3) δ 183.5, 170.2, 161.6, 152.9, 136.0, 131.0, 130.5, 129.9,
128.6, 128.5, 127.3, 126.8, 125.7, 122.2, 116.3, 113.8, 113.7, 55.6, 0.9 ppm; IR (film): 3054,
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2839, 1644, 1612, 1452, 1244 cm–1; HRMS (ESIꢀTOF) m/z calcd for C23H23SiO3 [M+H]+
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375.1411; found 375.1391.
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2,3-Diphenyl-4H-chromen-4-one (3u) was prepared following general procedure A using 2ꢀ
methoxybenzoyl chloride 1a (210 mg, 1.24 mmol) and alkyne 2l (200 mg, 1.12 mmol).
Purification by flash column chromatography (silica gel, hexane:EtOAc = 6:1, v/v) yielded pure
3u as a white solid (240 mg, 72%). Rf = 0.30 (hexane:EtOAc = 8:1); Mp = 146ꢀ147 ºC; 1H NMR
(500 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 1H), 7.69 (dd, J = 9.3, 6.3 Hz, 1H), 7.53 (d, J = 8.4 Hz,
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1H), 7.46 – 7.36 (m, 3H), 7.36 – 7.19 ppm (m, 8H); C{1H} NMR (100 MHz, CDCl3) δ 177.4,
161.6, 156.2, 133.8, 133.4, 133.0, 131.3, 130.2, 129.7, 128.4, 128.2, 127.7, 126.5, 125.2, 123.7,
123.1, 118.1 ppm; IR (film): 3052, 1632, 1615, 1599, 1560 cm–1; HRMS (ESIꢀTOF) m/z calcd
for C21H15O2 [M+H]+ 299.1067; found 299.1055.
2,3-Bis(4-methoxyphenyl)-4H-chromen-4-one (3v) was prepared following general procedure
A using 2ꢀmethoxybenzoyl chloride 1a (150 mg, 0.880 mmol) and alkyne 2m (150 mg, 0.630
mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 5:1, v/v)
yielded pure 3v as a white solid (87 mg, 39%). Rf = 0.20 (hexane:EtOAc = 8:1); Mp = 157ꢀ158
ºC; 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 9.4 Hz, 1H), 7.68 (dd, J = 9.2, 6.3 Hz, 1H), 7.52
(d, J = 8.4 Hz, 1H), 7.44 – 7.35 (m, 3H), 7.21 – 7.13 (m, 2H), 6.92 – 6.84 (m, 2H), 6.84 – 6.76
(m, 2H), 3.82 (s, 3H), 3.81 ppm (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 177.6, 161.2,
160.9, 159.0, 156.0, 133.5, 132.4, 131.3, 126.4, 125.7, 125.5, 124.9, 123.5, 121.7, 117.9, 114.0,
113.6, 55.4, 55.3 ppm; IR (film): 2933, 2837, 1637, 1607, 1506 cm–1; HRMS (ESIꢀTOF) m/z
calcd for C23H19O4 [M+H]+ 359.1278; found 359.1257.
2,3-Bis(4-methylphenyl)-4H-chromen-4-one (3w) was prepared following general procedure A
using 2ꢀmethoxybenzoyl chloride 1a (455 mg, 2.68 mmol) and alkyne 2n
(500 mg, 2.43 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc =
6:1, v/v) yielded pure 3w as a white solid (510 mg, 65%). Rf = 0.30 (hexane:EtOAc = 8:1); Mp =
145ꢀ146 ºC; 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.9 Hz, 1H), 7.71 – 7.66 (dd, J =7.8, 6.3
Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 7.5, 7.5 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.16 –
13
7.06 (m, 6H), 2.35 (s, 3H), 2.34 ppm (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 177.6, 161.5,
156.1, 140.4, 137.3, 133.6, 131.1, 130.7, 130.1, 129.6, 129.2, 128.9, 126.5, 125.0, 123.6, 122.6,
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118.0, 21.54, 21.45 ppm; IR (film): 2918, 1640, 1609, 1462 cm–1; HRMS (ESIꢀTOF) m/z calcd
for C23H19O2 [M+H]+ 327.1380; found 327.1363.
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6-Methoxy-2,3-diphenyl-4H-chromen-4-one (3x) was prepared following general procedure B
using 2ꢀmethoxyꢀ5ꢀmethoxybenzoic acid (100 mg, 1.64 mmol) and alkyne 2l (100 mg, 0.561
mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 10:1, v/v)
yielded pure 3x as a white solid (151 mg, 82%). Rf = 0.20 (hexane:EtOAc = 10:1); Mp = 181ꢀ
182 ºC; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 3.1 Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.41 –
7.36 (m, 2H), 7.34 – 7.19 (m, 9H), 3.92 ppm (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 177.3,
161.5, 157.1, 151.1, 133.6, 133.2, 131.4, 130.1, 129.7, 128.4, 128.2, 127.7, 124.3, 123.9, 122.4,
119.6, 105.6, 56.1 ppm; IR (film): 3054, 2971, 1627, 1601, 1566, 1482, 1437 cm–1; HRMS (ESIꢀ
TOF) m/z calcd for C22H17O3 [M+H]+ 329.1172; found 329.1166.
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6-(Trifluoromethyl)-2,3-diphenyl-4H-chromen-4-one (3y) was prepared following general
procedure B using, 2ꢀmethoxyꢀ5ꢀ(trifluoromethyl)ꢀbenzoic acid (429 mg, 1.95 mmol) and alkyne
2l (250 mg, 1.40 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc
= 12:1, v/v) yielded pure 3y as a white solid (169 mg, 33%). Rf = 0.40 (hexane:EtOAc = 10:1);
Mp = 144ꢀ146 ºC; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.89 (d, J = 10.7 Hz, 1H), 7.63 (d,
13
J = 8.8 Hz, 1H), 7.42 – 7.17 ppm (m, 10H); C{1H} NMR (100 MHz, CDCl3) δ 176.5, 162.0,
157.6, 132.7, 132.3, 131.2, 130.6, 130.1 (q, J = 3.3 Hz), 129.7, 128.5, 128.3, 128.0, 127.6 (q, J =
33.7 Hz), 124.6 (q, J = 4.0 Hz), 123.7 (q, J = 272.4 Hz), 123.52, 123.46, 119.3 ppm; IR (film):
3062, 1638, 1621, 1562 cm–1; HRMS (ESIꢀTOF) m/z calcd for C22H14F3O2 [M+H]+ 367.0940;
found 367.0934.
7-(Trifluoromethyl)-2,3-diphenyl-4H-chromen-4-one (3z) was prepared following general
procedure B using 2ꢀmethoxyꢀ4ꢀ(trifluoromethyl)ꢀbenzoic acid (150 mg, 0.682 mmol) and
alkyne 2l (110 mg, 0.617 mmol). Purification by flash column chromatography (silica gel,
hexane:EtOAc = 15:1, v/v) yielded pure 3z as a white solid (210 mg, 93%). Rf = 0.40
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(hexane:EtOAc = 10:1); Mp = 145ꢀ146 ºC; H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 7.9 Hz,
1H), 7.85 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.44 – 7.15 ppm (m, 10H); 13C{1H} NMR (100 MHz,
CDCl3) δ 176.6, 162.3, 155.6, 135.4 (q, J = 33.0 Hz), 132.8, 132.4, 131.2, 130.6, 129.7, 128.5,
128.3, 128.1, 127.9, 125.8, 123.7, 123.3 (q, J = 271.0 Hz), 121.5 (q, J = 3.0 Hz), 116.1 ppm (q, J
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= 4.0 Hz); IR (film): 3056, 1639, 1629, 1554, 1435 cm–1; HRMS (ESIꢀTOF) m/z calcd for
C22H14F3O2 [M+H]+ 367.0940; found 367.0937.
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7-Methyl-2,3-diphenyl-4H-chromen-4-one (3bb) was prepared following general procedure B
using 2ꢀmethoxyꢀ4ꢀmethylbenzoic acid (300 mg, 1.80 mmol) and alkyne 2l (61 mg, 0.195
mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 10:1, v/v)
yielded pure 3bb as a white solid (61 mg, 35%). Rf = 0.30 (hexane:EtOAc = 10:1); Mp = 241ꢀ
243 ºC; 1H NMR (500 MHz, CDCl3) δ 8.17 (dd, J = 8.1, 0.8 Hz, 1H), 7.40 – 7.37 (m, 2H), 7.35 –
7.19 (m, 12H), 2.51 ppm (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 177.3, 161.3, 156.3, 145.1,
133.6, 133.1, 131.4, 130.1, 129.7, 128.3, 128.2, 127.6, 126.7, 126.3, 123.0, 121.4, 117.8, 22.0
ppm; IR (film): 3055, 2923, 1706, 1604, 1442 cm–1; HRMS (ESIꢀTOF) m/z calcd for C22H17O2
[M+H]+ 313.1223; found 313.1221.
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7-Bromo-2,3-diphenyl-4H-chromen-4-one (3cc) was prepared following general procedure B
using 2ꢀmethoxyꢀ4ꢀbromobenzoic acid (190 mg, 0.757 mmol) and alkyne 2l (100 mg, 0.562
mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 8:1, v/v)
yielded pure 3cc as a white solid (87 mg, 41%). Rf = 0.30 (hexane:EtOAc = 10:1); Mp = 129ꢀ131
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ºC; H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 7.52 (d, J = 9.8 Hz,
1H), 7.41 – 7.16 ppm (m, 10H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 161.5, 156.1, 132.8,
132.5, 131.1, 130.3, 129.5, 128.7, 128.3, 128.1, 127.9, 127.82, 127.79, 123.2, 122.4, 121.1 ppm;
IR (film): 3054, 1640, 1599, 1559, 1420 cm–1; HRMS (ESIꢀTOF) m/z calcd for C21H14BrO2
[M+H]+ 377.0172; found 377.0164.
7-Chloro-2,3-diphenyl-4H-chromen-4-one (3dd) was prepared following general procedure B
using 2ꢀmethoxyꢀ4ꢀchlorobenzoic acid (250 mg, 1.34 mmol) and alkyne 2l (150 mg, 0.843
mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 8:1, v/v)
yielded pure 3dd as a white solid (112 mg, 40%). Rf = 0.20 (hexane:EtOAc = 10:1); Mp = 110ꢀ
111 ºC; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.40 –
7.17 ppm (m, 11H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 161.6, 156.2, 139.7, 132.9,
132.5, 131.2, 130.3, 129.6, 128.4, 128.2, 127.9, 127.8, 126.0, 123.2, 122.1, 118.1 ppm; IR (film):
2924, 1639, 1595 cm–1; HRMS (ESIꢀTOF) m/z calcd for C21H14ClO2 [M+H]+ 333.0677; found
333.0671.
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7-Fluoro-2,3-diphenyl-4H-chromen-4-one (3ee) was prepared following general procedure B
using 4ꢀfluoroꢀ2ꢀmethoxyꢀbenzoic acid (300 mg, 1.76 mmol) and alkyne 2l (200 mg, 1.12
mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 8:1, v/v)
yielded pure 3ee as a white solid (114 mg, 32%). Rf = 0.35 (hexane:EtOAc = 10:1); Mp = 155ꢀ
157 ºC; 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 8.9, 6.3 Hz, 1H), 7.42 – 7.08 ppm (m, 12H);
13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 165.9 (d, J = 253.3 Hz), 161.8, 157.1 (d, J = 13.4
Hz), 133.0, 132.6, 131.3, 130.3, 129.6, 129.1 (d, J = 10.5 Hz), 128.4, 128.3, 127.9, 123.2, 120.5
(d, J = 2.4 Hz), 114.0 (d, J = 22.7 Hz), 104.7 ppm (d, J = 25.0 Hz); IR (film): 3058, 2920, 1732,
1709, 1644, 1606, 1559 cm–1; HRMS (ESIꢀTOF) m/z calcd for C21H14FO2 [M+H]+ 317.0972;
found 317.0964.
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6-Fluoro-2,3-diphenyl-4H-chromen-4-one (3ff) was prepared following general procedure B
using 5ꢀfluoroꢀ2ꢀmethoxybenzoic acid (300 mg, 1.76 mmol) and alkyne 2l (280 mg, 1.57 mmol).
Purification by flash column chromatography (silica gel, hexane:EtOAc = 8:1, v/v) yielded pure
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3ff as a white solid (330 mg, 66%). Rf = 0.20 (hexane:EtOAc = 10:1); Mp = 169ꢀ170 ºC; H
NMR (400 MHz, CDCl3) δ 8.59 (s 1H), 7.91 (dd, J = 8.8, 2.3 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H),
7.44 – 7.15 ppm (m, 10H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.7, 161.9, 159.7 (d, J = 245.0
Hz), 152.4 (d, J = 1.6 Hz), 133.1, 132.6, 131.3, 130.3, 129.7, 128.4, 128.2, 127.9, 124.8 (d, J =
7.3 Hz), 122.4, 122.1 (d, J = 25.5 Hz), 120.2 (d, J = 8.0 Hz), 111.2 ppm (d, J = 23.6 Hz); IR
(film): 3059, 1626, 1528, 1563, 1480 cm–1; HRMS (ESIꢀTOF) m/z calcd for C21H14FO2 [M+H]+
317.0972; found 317.0965.
3,4-Diphenyl-2H-chromen-2-one (6) was prepared following general procedure A using 2,6ꢀ
dimethoxybenzoyl chloride 1a (124mg, 0.37 mmol) and alkyne 2l (100 mg, 0.67 mmol).
Purification by flash column chromatography (silica gel, hexane:EtOAc = 10:1, v/v) yielded pure
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6 as a crystalline solid (109 mg, 50%). Rf = 0.10 (hexane:EtOAc = 10:1); Mp = 201ꢀ204 ºC; H
NMR (400 MHz, CDCl3) δ 7.48 – 7.43 (m, 1H), 7.18 – 7.10 (m, 6H), 7.08 – 6.96 (m, 5H), 6.73 –
6.55 (m, 1H), 3.34 ppm (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.2, 157.8, 154.5, 151.2,
138.6, 134.1, 132.0, 130.6, 128.0, 127.6, 127.3, 127.2, 127.1, 126.8, 110.5, 109.8, 107.1, 55.9
ppm; IR (film): 3097, 3054, 3027, 2928, 1712, 1590, 1466, 1263 cm–1; HRMS (ESIꢀTOF) m/z
calcd for C22H17O3 [M+H]+ 329.1172; found 329.1154.
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2-Phenyl-4H-chromen-4-one (8): To a solution of 2ꢀmethoxybenzoyl chloride 1a (230 mg, 1.35
mmol) in dichloromethane (20 mL) at room temperature under N2 atmosphere, aluminum
bromide (330 mg, 1.24 mmol) was added, which was followed by addition of phenylacetylene 7
(128 mg, 1.25 mmol). After stirring for 1.5 hours, the reaction was quenched by saturated
aqueous NaHCO3 and extracted with Et2O (100 mL x 2). The layers were separated, the organic
phase was washed with H2O, brine, and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue was purified by column chromatography (silica gel,
hexane:EtOAc = 6:1, v/v) yielded pure 8 as a white solid (187 mg, 67%). Rf = 0.20
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(hexane:EtOAc = 8:1); Mp = 97ꢀ98 ºC; H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 7.9 Hz, 1H),
7.98 – 7.90 (m, 2H), 7.72 – 7.69 (m, 1H), 7.63 – 7.48 (m, 4H), 7.46 – 7.40 (m, 1H), 6.84 ppm (s,
1H); 13C{1H} NMR (125 MHz, CDCl3) δ 178.6, 163.6, 156.4, 133.9, 131.9, 131.8, 129.2, 126.5,
125.9, 125.4, 124.1, 118.2, 107.7 ppm; IR (film): 3053, 1640, 1607, 1465 cm–1; HRMS (ESIꢀ
TOF) m/z calcd for C15H11O2 [M+H]+ 223.0754; found 223.0755.
3-(Trimethylsilyl)-2-[2-(trimethylsilyl)ethynyl]-4H-chromen-4-one (10) was prepared
following general procedure A using 2ꢀmethoxybenzoyl chloride 1a (483 mg, 2.83 mmol) and
1,4ꢀbis(trimethylsilyl)butaꢀ1,3ꢀdiyne 9 (500 mg, 2.57 mmol). Purification by flash column
chromatography (silica gel, hexane:EtOAc = 10:1, v/v) yielded pure 10 as a brown sticky solid
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(549 mg, 68%). Rf = 0.30 (hexane:EtOAc = 15:1); H NMR (500 MHz, CDCl3) δ 8.07 (d, J =
8.1, Hz, 1H), 7.64 – 7.57 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.35 – 7.30 (m, 1H), 0.40 (s, 9H),
13
0.30 ppm (s, 9H); C{1H} NMR (125 MHz, CDCl3) δ 181.6, 156.6, 149.8, 133.8, 125.8, 125.2,
123.4, 123.3, 117.7, 104.7, 98.3, 0.6, ꢀ0.6 ppm; IR (film): 2961, 2900, 2099, 1626, 1611, 1534
cm–1; HRMS (ESIꢀTOF) m/z calcd for C17H23Si2O2 [M+H]+ 315.1231; found 315.1215.
3-Hexyl-2-(4-methoxyphenyl)-4H-chromen-4-one (13) was prepared following general
procedure A using 2ꢀmethoxybenzoyl chloride 1a (147 mg, 0.865 mmol) and alkyne 12 (170 mg,
0.785 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 6:1, v/v)
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yielded pure 13 as a colorless oil (210 mg, 80%). Rf = 0.30 (CH2Cl2); H NMR (500 MHz,
CDCl3) δ 8.24 (d, J = 8.0, Hz, 1H), 7.65 – 7.6 (m, 1H), 7.59 – 7.52 (m, 2H), 7.45 – 7.40 (m, 1H),
7.39 – 7.34 (m, 1H), 7.06 – 7.00 (m, 2H), 3.89 (s, 3H), 2.60 – 2.50 (m, 2H), 1.62 – 1.52 (m, 2H),
13
1.36 – 1.18 (m, 6H), 0.85 ppm (t, J = 6.7 Hz, 3H); C{1H} NMR (125 MHz, CDCl3) δ 178.6,
161.7, 161.1, 156.2, 133.3, 130.3, 126.2, 126.0, 124.7, 123.1, 122.1, 117.9, 114.0, 55.6, 31.6,
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29.6, 29.2, 26.0, 22.7, 14.2 ppm; IR (film): 2955, 2926, 1619, 1609, 1510 cm–1; HRMS (ESIꢀ
TOF) m/z calcd for C22H25O3 [M+H]+ 337.1798; found 337.1776.
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3-Cyclopentyl-2-(4-methoxyphenyl)-4H-chromen-4-one (15) was prepared following general
procedure A using 2ꢀmethoxybenzoyl chloride 1a (190 mg, 1.12 mmol) and alkyne 14 (215 mg,
1.08 mmol). Purification by flash column chromatography (silica gel, hexane:EtOAc = 10:1, v/v)
yielded pure 15 as a white solid (230 mg, 67%). Rf = 0.20 (hexane:EtOAc = 15:1); Mp = 123ꢀ124
ºC; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.0 Hz, 1H), 7.61– 7.56 (m, 1H), 7.53 – 7.49 (m,
2H), 7.39 – 7.30 (m, 2H), 7.03 – 6.98 (m, 2H), 3.87 (s, 3H), 3.01 – 2.88 (m, 1H), 2.25 – 2.14 (m,
2H), 1.99 – 1.97 (m, 2H), 1.72 – 1.63 (m, 2H), 1.59 – 1.49 ppm (m, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 178.3, 162.0, 161.0, 155.9, 133.1, 130.5, 126.4, 125.7, 124.6, 123.9, 123.4,
117.8, 113.9, 55.5, 39.3, 30.7, 27.2 ppm; IR (film): 2952, 2930, 2872, 2833, 1690, 1625, 1611,
1509 cm–1; HRMS (ESIꢀTOF) m/z calcd for C21H21O3 [M+H]+ 321.1485; found 321.1481.
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3-Iodo-2-(4-methoxyphenyl)-4H-chromen-4-one (16): A procedure in the literature was
modified.32 A solution of ICl in dry CH2Cl2 (1.00 g, 6.16 mmol) was added dropwise to a
solution of 3a (1.60 g, 4.90 mmol) in dry CH2Cl2 (40 mL) at 0 °C. After stirring for 1 h, the
reaction was quenched with aqueous Na2S2O3. The organic layer was extracted using
CH2Cl2/water, and dried using Na2CO3. Purification by flash chromatography on silica gel to
afford the compound 16 as a light yellow solid (1.5g, 83%); Rf = 0.30 (hexane:EtOAc = 15:1);
Mp = 127ꢀ129 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 8.0, 1.7 Hz, 1H), 7.81 – 7.76 (m,
2H), 7.69 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 7.53 – 7.37 (m, 2H), 7.06 – 6.96 ppm (m, 2H), 3.89 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.8, 164.5, 161.8, 156.0, 134.2, 131.5, 127.3, 126.9,
125.9, 120.1, 117.7, 113.7, 87.8, 55.6 ppm; IR (film): 3069, 3014, 2841, 1657, 1608, 1558, 1504,
1465 cm–1; HRMS (ESIꢀTOF) m/z calcd for C16H11IKO3 [M+K]+ 416.9384; found 416.9366.
2-(4-Methoxyphenyl)-3-(2-phenylethynyl)-4H-chromen-4-one (17): Compound 16 (210 mg,
0.555 mmol), and phenylacetylene (68 mg, 0.67 mmol) were dissolved in dry THF (2 mL) and
Et3N (5 mL). Then (Ph3P)2PdCl2 (20 mg, 0.028 mmol), CuI (10 mg, 0.053 mmol) were added to
the solution after degassing the reaction mixture via bubbling nitrogen for 30 min. The solution
was allowed to stir at room temperature overnight. The reaction mixture was concentrated under
reduced pressure. The residue was purified by flash chromatography on silica gel to afford the
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compound 17 as a light yellow solid (179 mg, 90%); Rf = 0.20 (hexane:EtOAc = 10:1); Mp =
142ꢀ144 °C; 1H NMR (500 MHz, CDCl3) δ 8.31 – 8.26 (m, 3H), 7.69 (ddd, J = 8.6, 7.1, 1.7 Hz,
1H), 7.57 – 7.50 (m, 3H), 7.43 (dd, J = 8.1, 7.1 Hz, 1H), 7.37 – 7.31 (m, 3H), 7.09 – 7.03 (m,
2H), 3.92 ppm (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.8, 165.4, 162.3, 155.5, 134.0,
131.7, 131.0, 128.5, 128.4, 126.3, 125.5, 124.9, 123.5, 122.4, 118.0, 113.8, 106.1, 97.9, 82.6,
55.7 ppm; IR (film): 3060, 2935, 2838, 2361, 1647, 1604, 1576, 1510 cm–1; HRMS (ESIꢀTOF)
m/z calcd for C24H17O3 [M+H]+ 353.1172; found 353.1201.
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3-[4-(1,1-Dimethylethyl)phenyl]-2-(4-methoxyphenyl)-4H-chromen-4-one (18): Compound
16 (300 mg, 0.970 mmol), 4ꢀtertꢀbutylphenylboronic acid pinacol ester (379 mg, 1.46 mmol) and
K2CO3 (340 mg, 2.50 mmol) were dissolved in the mixture of toluene (9 mL), EtOH (6 mL), and
H2O(3 mL). Then Pd(OAc)2 (22.0 mg, 0.097 mmol) and XPhos (92.0 mg, 0.193 mmol) were
added to the solution after degassing the reaction mixture via bubbling nitrogen for 30 min. The
resulting mixture was stirred under a N2 atmosphere at 80 °C overnight. The reaction mixture
was concentrated under reduced pressure. The residue was purified by flash chromatography on
silica gel to afford the compound 18 as a white solid (310 mg, 88%); Rf = 0.20 (hexane:EtOAc =
1
10:1); Mp = 148ꢀ150 °C; H NMR (400 MHz, CDCl3) δ 8.28 (dd, J = 8.0, 1.7 Hz, 1H), 7.68
(ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.52 (dd, J = 8.5, 1.2 Hz, 1H), 7.41 (dd, J = 8.1, 7.1 Hz, 1H), 7.38
– 7.32 (m, 4H), 7.19 – 7.14 (m, 2H), 6.87 – 6.72 (m, 2H), 3.80 (s, 3H), 1.32 ppm (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 160.2, 159.9, 155.1, 149.4, 132.5, 130.4, 129.8,
129.2, 125.5, 124.8, 124.4, 124.0, 122.6, 121.1, 116.9, 112.5, 54.4, 33.7, 30.5 ppm; IR (film):
2960, 2867, 2838, 1637, 1606, 1578, 1503 cm–1; HRMS (ESIꢀTOF) m/z calcd for C26H25O3
[M+H]+ 385.1798; found 385.1797.
AUTHOR INFORMATION
Corresponding Author
*Email: wchalifoux@unr.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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WAC thanks the National Science Foundation (NSF) for supporting this work through a
CAREER Award (CHEꢀ1555218). We would also like to thank Dr. Wenlong Yang for assisting in
Xꢀray crystallographic data collection.
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ASSOCIATED CONTENT
Supporting Information
NMR spectra, crystallographic data, and CIF files. This material is available free of charge via
the Internet at http://pubs.acs.org.
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