Synthesis of Flavanones via Palladium(II)-Catalyzed One-Pot β-Arylation of Chromanones with Arylboronic Acids

Article abstract of DOI:10.1021/acs.joc.9b01162

A total of 47 flavanones were expediently synthesized via one-pot β-arylation of chromanones, a class of simple ketones possessing chemically unactivated β sites, with arylboronic acids via tandem palladium(II) catalysis. This reaction provides a novel route to various flavanones, including natural products such as naringenin trimethyl ether, in yields up to 92percent.

Full text of DOI:10.1021/acs.joc.9b01162

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Article
Synthesis of Flavanones via Palladium(II)-Catalyzed One-
Pot #-Arylation of Chromanones with Arylboronic Acids
Hyung-Seok Yoo, Seung Hwan Son, Yang Yil Cho, Soo Jin Lee, Hyu Jeong Jang, Young Min
Kim, Dong Hwan Kim, Nam Yong Kim, Boyoung Y. Park, Yong Sup Lee, and Nam-Jung Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01162 • Publication Date (Web): 19 Jul 2019
Downloaded from pubs.acs.org on July 19, 2019
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Synthesis of Flavanones via Palladium(II)-Catalyzed One-Pot β-
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Arylation of Chromanones with Arylboronic Acids
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Hyung-Seok Yoo,† Seung Hwan Son,† Yang Yil Cho,† Soo Jin Lee,† Hyu Jeong Jang,† Young Min
Kim,† Dong Hwan Kim,† Nam Yong Kim,‡ Boyoung Y. Park,† Yong Sup Lee,†,‡ and Nam-Jung Kim*,†,‡
†College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447,
Republic of Korea.
‡Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro,
Dongdaemun-gu, Seoul 02447, Republic of Korea.
O
O
O
Pd(TFA)2, bpy
DMSO/dioxane, O2

R1
R1
(HO)2B
then TFA
R2
O
R2
Chemically
Unactivated
Chromanones
47 examples of flavanones
up to 92% yield
Abstract: A total of 47 flavanones were expediently synthesized via one-pot β-arylation of
chromanones, a class of simple ketones possessing chemically unactivated β sites, with arylboronic
acids via tandem palladium(II) catalysis. This reaction provides a novel route to various flavanones,
including natural products such as naringenin trimethyl ether, in yields up to 92%.
INTRODUCTION
Flavonoids, which feature 15-carbon skeleton including 2 phenyl rings and 1 oxacycle, are a
class of natural products from medicinal plants and their synthetic analogues.1 For the past decades,
flavonoids have been considered a privileged repository of various drug candidates due to their
biological activities such as anti-oxidative, anti-inflammatory and anti-cancer effects.2 Among
flavonoids, flavanones, which are also known as 2-arylchroman-4-ones and include natural
compounds such as naringenin trimethyl ether, have recently been identified as novel privileged
structures with potent anti-cancer activity (Figure 1).3 To date, the Claisen-Schmidt condensation of 2-
hydroxyacetophenones and corresponding benzaldehydes has generally been used to provide
chalcone intermediates that can be transformed into flavanones under acidic or basic refluxing
conditions.4 However, such conditions are harsh and not compatible with acid/base-labile compounds.
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Therefore, novel synthetic routes for flavanones have been pursued.
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Figure 1. Examples of natural flavanones
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O
O
OMe O
O
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MeO
MeO
OMe
Liquiritigenin dimethyl ether
OMe
Naringenin trimethyl ether
OH
O
OH
O
MeO
O
HO
O
Pinocembrin
Pinostrobin
Recently, nucleophilic 1,4-addition to the electrophilic β sites of chromones, a class of enones,
were reported for the synthesis of flavanones (Scheme 1).5 These methods provided flavanones in
good yields under mild conditions, mainly involving transition metal catalysis. In particular, they did not
require acidic or basic refluxing conditions which were generally used in the Claisen-Schmidt
condensation. Therefore, they showed good to excellent functional group compatibility and the
feasibility of late-stage functionalization which has been central focus in the medicinal chemistry and
chemical biology fields. However, chromones are sometimes prepared from chromanones,6 a class of
simple ketones, via additional oxidation processes7 and generally not unmanageable because they
possess reactive α,β-unsaturated carbonyl and enol ether which chromanones do not have.
Therefore, chromanones might be applicable substrates to the synthesis of flavanones if it is possible
to use them.
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Scheme 1. One-Pot β-Arylation Strategy for Flavanones
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Reported Works : Pd(II) catalyzed -Arylation of Chromones
M
8
9
O
O
R2
R1
R1

O
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Pd(II)-Catalyzed
Conjugate Addition
O
R2
Chemically
Activated
Chromones
Flavanones
M: metal species
This Work : One-Pot -Arylation of Chromanones to Flavanones
O
O
(HO)2B
O
R2
R1

R1
Pd(II), O2, [H+]
O
R2
Flavanones
Chromanones
Chemically
Unactivated
O
O
R1
Conjugate
Addition
Dehydrogenation
Thus, direct β-arylation of chromanones with aryl synthons would be a versatile approach to
functionalized flavanones although a direct and transformative arylation of the chemically unactivated
β-sites of various chromanones has not been reported. Recently, the MacMillan group and Dong
group reported catalytic β-arylation of ketones with aryl synthons in the metal catalysis, respectively.8
Furthermore, Li group reported palladium catalyzed β-arylation of ketones using arylboronic acid with
o-iodoxybenzoic aicd (IBX) as an oxidant.9 Inspired by these pioneering works, we aimed to develop
novel methodologies that provide a diversity of privileged flavanones by one-pot arylation of
chromanones via metal catalysis. In particular, an efficient transformation of a broad scope of
substrates with high yields in the reaction would be expected to be desirable for the methodology
towards flavanones. Herein, we report palladium(II)-catalyzed one-pot β-arylation of chromanones
with arylboronic acids for the synthesis of flavanones.
RESULTS AND DISCUSSION
To obtain flavanones via β-arylation of chromanones in a one-pot sequence, we speculated that
the overall reaction would involve oxidative chromone formation and sequential nucleophilic conjugate
addition. Recently, preliminary reports suggested the potential of palladium(II) catalysis to enable
dehydrogenation as well as conjugate addition of organoboron reagents, respectively.5c, 5f, 8d, 10 Based
on this speculation, we chose 4-chromanone 1a and phenylboronic acid as the model compounds to
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investigate the feasibility of a reaction in which they could be assembled into flavanones via
palladium(II)-catalyzed dehydrogenation and sequential conjugate addition (Table 1). In our previous
report on the synthesis of flavones from chromanones via a palladium(II) catalysis, we observed that
the reaction with Pd(TFA)2, 5-nitro-1,10-phenanthroline and DMSO solvent under an O2 provided
flavanone 3a as a minor product (25%) along with flavone 4a in 42% yield (entry 1).11 For the
successful conversion from chromanone to flavanone, we speculated that dehydrogenation would
precede conjugate addition; however, formation of the flavone and arylboronic acid-derived
byproducts should be avoided in the reaction.12 For this purpose, we tried to screen many conditions
and found that the yield of flavanone 3a was significantly increased to 46% and that the yield of
flavone, the oxidative boron-Heck product, was lowered to 14% (entry 2) when adding phenylboronic
acid (conjugate addition) after complete conversion of chromanone into chromone 2a
(dehydrogenation). Given recent reports that protonolysis could induce conjugate addition rather than
oxidative boron-Heck coupling in palladium(II) catalysis,11, 13 we tried to add an acid in the conjugate
addition step. In the presence of TFA, the yield of flavanone was increased to 60%, whereas the yield
of flavone was lowered (14% to 10%), as anticipated (entry 3). Next, ligands were screened,10a, 12d, 14
and 2,2′-bipyridine (bpy) was found to be superior to other ligands, providing flavanone in 65%
isolated yield (entry 8). On the other hand, in the absence of ligand or with monodentate ligands such
as DMAP, the reactions produced only trace amounts of the desired flavanones (entries 4-6). When
TFA was changed to AcOH, the yield of the reaction was slightly reduced (entry 9).
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Table 1. Optimization of the Reaction Conditiona
O
O
O
O
O
Pd(TFA)2, ligand
solvent, O2
+
+
TFA
then
O
O
O
(HO)2B
2a
3a:
4a: Flavone
1a
Flavanone
Yield (%)b
Entry
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
Ligand
Acid
2a
1
3a
25
46
60
1
4a
42
14
10
7
1c
2
5-Nitro phen
5-Nitro phen
5-Nitro phen
-
-
-
1
3
TFA
TFA
TFA
4
4
86
85
5
DMAP
0
0
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DMSO
DMSO
Pyridine
Phendione
bpy
TFA
TFA
TFA
AcOH
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
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3
1
1
1
11
65
56
4
8
DMSO
3
9
DMSO
bpy
1
5
10
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10
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16d
17
18
19
20
21
22e
23
AcOH
bpy
26
1
0
Toluene
bpy
35
50
55
48
63
63
76
80
81
82
85
73
80
8
NMP
bpy
1
26
10
10
2
DMA
bpy
1
DMF
bpy
9
1,4-Dioxane
i-PrOH
bpy
26
1
bpy
3
DMSO/i-PrOH(1:1)
DMSO/dioxane(1:1)
DMSO/dioxane(1:2)
DMSO/dioxane(1:3)
DMSO/dioxane(1:4)
DMSO/dioxane(1:4)
DMSO/dioxane(1:8)
bpy
4
2
bpy
3
3
bpy
3
4
bpy
1
3
bpy
1
3
bpy
1
2
bpy
1
2
aReaction conditions: 1a (0.34 mmol), Pd(TFA)2 (15 mol%), ligand (30 mol%), and solvent (0.5 mL) at
100 °C under O2, 24-48 h; then phenylboronic acid (1.02 mmol), acid (0.34 mmol) and solvent (0.5
mL) at 80 °C under O2, 4-48 h. bIsolated yield. c1a and phenylboronic acid were added simultaneously
and the reaction was done at 100 °C. d80 °C. ePd(TFA)2 (10 mol%), bpy (20 mol%) and phenylboronic
acid (0.51 mmol).
We also screened several solvents ranging from nonpolar to aprotic polar systems (entries 10-
16). The reaction worked moderately in aprotic polar solvents while it did not in nonpolar toluene.
Other solvents were not as good as DMSO, but 1,4-dioxane was similarly effective. i-PrOH was also
moderate for the reaction (63%), but AcOH was not. Upon screening for the optimal condition, we
observed that dehydrogenation from chromanone to chromone occurred faster and more smoothly in
DMSO than in 1,4-dioxane and i-PrOH, while the conjugate addition in 1,4-dioxane and i-PrOH
progressed well, compared that in DMSO. Based on this observation, we tried to screen the reaction
conditions using co-solvents such as DMSO/dioxane. To our delight, compared to those in single
solvents, the yields of flavanone in the reactions using co-solvent conditions were significantly
increased (entries 17-23). Notably, the use of DMSO/dioxane (1:4) as a co-solvent system enables
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the reaction to provide the desired flavanone 3a with the highest yield of 85% within a shorter reaction
time than those required under other conditions. In the case of decreasing loading amounts of
catalyst, ligand, and phenylboronic acid, the yield for desired flavanone was slightly decreased.
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Under the optimized condition, the reactions of chromanone 1a with a series of arylboronic acids
were performed to investigate the functional group tolerance of the reaction (Table 2). The reactions
were successfully applied to synthesize a series of flavanones from 1a with arylboronic acids
possessing either electron-donating aryl or alkyl groups (3b-g) or electron-withdrawing groups (3h-o).
Hydroxy (3p and 3q) and methoxy (3r-v) flavanones mimicking natural flavanones were also readily
synthesized using corresponding arylboronic acids. Furthermore, thiophene group (3x), a kind of
heteroaryl group, was also tolerated in the reaction although the yield was slightly decreased. In
particular, the highest yield of 92% was obtained for trimethoxy flavanone 3s, while a relatively lower
yield was obtained for nitro flavanone 3o.
Table 2. Scope of Reactions Using Arylboronic Acidsa, b
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O
O
O
Pd(TFA)2, bpy
DMSO/dioxane, O2
then TFA
(HO)2B
O
R
R
8
1a
3
9
O
O
O
O
O
O
O
O
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3c
3g
3d
3b
(74%)
O
(90%)
O
3a
3e
(84%)
O
(85%)
O
Ph
O
O
O
O
F
Ph
3h
(68%)
O
(65%)
O
(69%)
O
3f
(89%)
O
O
O
O
O
Br
CF3
TMS
Cl
3j
(77%)
O
3k
3l
(67%)
O
3i
(79%)
O
(77%)
O
OH
NO2
O
O
O
O
OMe
CHO
3p
3m
(61%)
O
(45%)
O
3n
3o
(21%)
O
(16%)
O
O
OMe
OMe
OH
O
O
O
O
OMe
3t
(74%)
O
3s
(83%)
O
3r
(71%)
O
3q
3u
(71%)
O
OMe
OMe
OMe
OMe
O
O
O
O
S
OBn
3x
(33%)
3v
(92%)
3w
(59%)
(87%)
OMe
aReaction conditions: 1a (0.34 mmol), Pd(TFA)2 (15 mol%), bpy (30 mol%), and DMSO/dioxane (1:4)
(0.5 mL) at 100 °C under O2, 16 h; then arylboronic acid (1.02 mmol), TFA (0.34 mmol) and
DMSO/dioxane (1:4) (0.5 mL) at 80 °C under O2, 4-24 h. bIsolated yield.
Subsequently, to further broaden the scope of the reaction, phenylboronic acid was reacted with
a variety of chromanones under the optimized condition (Table 3). In the case of using chromanones
with both electron-donating alkyl groups (3y and 3z) and electron-withdrawing halogen substituents
(3aa and 3bb), the reactions progressed well. Hydroxy (3cc and 3dd), methoxy (3ee-ii), and
benzyloxy (3jj) flavanones were also expediently synthesized under the condition. In addition, OH−-
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labile ester functional groups, such as those in (3kk-mm), and H+-labile acetal group 3nn were also
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tolerated in the reaction.
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9
Table 3. Scope of Reactions Using Chromanonesa, b
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11
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O
O
O
Pd(TFA)2, bpy
DMSO/dioxane, O2
R
R
then TFA
(HO)2B
O
1
3
O
O
O
O
O
O
O
F
Cl
O
3bb
3aa
(76%)
O
(80%)
3z
3y
(84%)
O
(78%)
O
OMe O
MeO
HO
O
O
O
HO
O
3ff
(87%)
O
3ee
3dd
(64%)
O
(70%)
3cc
3gg
(79%)
O
OMe O
BnO
MeO
MeO
O
MeO
PivO
O
MeO
PivO
O
O
3jj
(85%)
O
(77%)
O
3hh
3ii
(71%)
(76%)
O
O
AcO
O
O
O
O
O
O
3nn
(72%)
3kk
(71%)
3ll
(65%)
3mm
(80%)
aReaction conditions: 1 (0.34 mmol), Pd(TFA)2 (15 mol%), bpy (30 mol%), and DMSO/dioxane (1:4)
(0.5 mL) at 100 °C under O2, 12-24 h; then phenylboronic acid (1.02 mmol), TFA (0.34 mmol) and
DMSO/dioxane (1:4) (0.5 mL) at 80 °C under O2, 4-24 h. bIsolated yield.
To further confirm the utility of our methodology, we tried to synthesize natural flavanones via the
reaction (Scheme 2a).15 First, we attempted to synthesize liquiritigenin dimethyl ether16 7 and butin
trimethyl ether17 8 from 7-methoxy-4-chromanone 5, and successfully obtained the desired flavanones
in good yields of 82% and 80%, respectively. Furthermore, 3 natural flavanones (9-11),18 were also
obtained from 5,7-dimethoxy-4-chromanone 6 as a common intermediate. Among these natural
compounds, compound 7 and 9 have been known to exhibit potent anti-cancer activity through cell
cycle arrest, indicating that our methodology can be useful for further pharmacological studies by
providing anti-cancer flavanones.19 In addition, pinocembrin 12 and pinostrobin 13,20 natural hydroxyl
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flavanones were readily converted from a common intermediate, 3hh.21 A scaled-up one-pot β-
arylation using 5 and 4-methoxyphenylboronic acid as starting materials was also successfully
performed, providing the desired anti-cancer flavanone 7 in 80% yield (Scheme 2b). Also, to expand
the scope our methodology, we tried to synthesize α- or β-substituted flavanone (Scheme S2, ESI†).
However, only trace amount of β-substituted product was isolated in the reaction with 2-
methylchroman-4-one and no conjugate addition product was obtained with α-substituted
chromanone, 3-methylchroman-4-one.
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Scheme 2. Synthesis of Natural Flavanones and Scaled-Up Reaction
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O
Pd(TFA)2, bpy
DMSO/dioxane, O2, 21 h
a)
6
7
8
9
(HO)2B
then TFA,
MeO
O
4 h
OMe
OMe
7
O
Liquiritigenin dimethyl ether ( )
82%
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MeO
O
O
5
Pd(TFA)2, bpy
DMSO/dioxane, O2, 21 h
OMe
MeO
O
(HO)2B
OMe
OMe
OMe
then TFA,
15 h
8
Butin trimethyl ether ( )
80%
OMe O
Pd(TFA)2, bpy
DMSO/dioxane, O2, 18 h
MeO
O
(HO)2B
then TFA,
OMe
9
4 h
OMe
Naringenin trimethyl ether ( )
56%
OMe O
OMe O
Pd(TFA)2, bpy
DMSO/dioxane, O2, 18 h
OMe
MeO
O
(HO)2B
OMe
OMe
then TFA,
7 h
MeO
O
OMe
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5,7,3',4'-tetramethoxyflavanone (
43%
)
OMe O
Pd(TFA)2, bpy
DMSO/dioxane, O2, 18 h
OMe
MeO
O
MeO
(HO)2B
MeO
OMe
then TFA,
20 h
11
5,7,2',5'-tetramethoxyflavanone (
45%
)
OH
O
ref. 21a
77%
HO
O
OMe O
12
Pinocembrin (
OH
)
O
MeO
O
ref. 21b
44%
3hh
MeO
O
13
Pinostrobin (
O
)
b)
O
O
Pd(TFA)2, bpy
DMSO/dioxane, O2, 21 h
then TFA, 6 h
MeO
O
MeO
(HO)2B
5
OMe
OMe
3.0 mmol
534 mg
7
Liquiritigenin trimethyl ether ( )
80%
Next, to investigate the detailed mechanism of our methodology, we performed kinetic analysis of
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the reaction by monitoring the time-dependent conversion of chromanone to chromone
(dehydrogenation), eventually resulting in the formation of the flavanone (conjugate addition) under
the optimal condition (Scheme 3a and Table S2, ESI†). During the first step of the reaction,
chromanone 1a was smoothly converted into chromone 2a. Within 16 hours, chromanone was
completely consumed, and chromone was concurrently produced in quantitative yield. After adding
phenylboronic acid and TFA dropwise, chromone was subsequently converted into the desired
flavanone 3a by conjugate addition in a yield of 85% within 8 hours, along with a small amount of
flavone 4a. In addition, we confirmed whether an acid is beneficial in the reaction. In the
dehydrogenation step, acidic condition resulted slightly lower conversion of chromanone to chromone
with the yield of 84%, compared to 92% of optimized condition (Table S3, ESI†). Furthermore, in the
absence of an acid, chromone was slowly converted to flavanone, and complete consumption of
chromone took more than 16 hours with a decreased yield of 78% as a final output (Table S4, ESI†).
These results suggested that acid is beneficial for the conjugate addition but not for dehydrogenation,
compared to its absence. In this study, when chromanone, phenylboronic acid and TFA were reacted
simultaneously, it was observed that a small amount of chromanone was converted into chromone,
leading to only a trace amount of flavanone (Table S1 and S5, ESI†). Based on previous reports that
arylboronic acid is undesirably transformed into arene through protodeboronation under acidic
palladium(II) catalysis,12a, 12b we presumed that the all-in-one reaction would be sluggish due to the
competitive protodeboronation of arylboronic acid. To validate our speculation, all-in-one β-arylation
was executed, and its progress was analyzed by monitoring the conversion of chromanone into
flavanone and byproducts (Scheme 3b). As anticipated, 1,2-dimethoxy benzene, the
protodeboronated compound, was detected as a major product in yields up to 60% with little
chromone and flavanone. Thus, tandem Pd(II) catalysis involving dehydrogenation and sequential
conjugate addition would be more favorable than simultaneous catalysis for the conversion of
chromanones into flavanones in the reaction.
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Scheme 3. Mechanism Study by Kinetic Analysis
a)
O
O
Pd(TFA)2, bpy
DMSO/dioxane, O2
then TFA
(HO)2B
O
O
3a
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b)
(HO)2B
OMe
OMe
O
O
O
Pd(TFA)2, bpy, TFA
DMSO/dioxane
OMe
OMe
OMe
OMe
+
O
O2
1,2-Dimethoxy
benzene
1a
3u
Based on mechanistic analysis, a plausible mechanism of the reaction is depicted in Scheme 4.
In the first step, Pd(II) enolate A might be initially formed, followed by sequential β-hydride
elimination.10a, 10b, 22 As a result, enone intermediate chromone 2a is formed, and its electrophilic β-site
could be assembled with palladated intermediate B transformed from phenylboronic acid via
transmetallation in the next step, resulting in intermediate C.23 Finally, this intermediate is converted
into the desired flavanone 3a through concurrent protonolysis, along with the formation of a small
amount of flavone 4a as a byproduct by competitive β-hydride elimination.24 During dehydrogenation,
Pd(0) species formed in the reaction would be regenerated into Pd(II) via the [O] process, where O2
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works as the main oxidant in the reoxidation process.25
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Scheme 4. A Plausible Mechanism of the Reaction
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[O] Process
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O
OH
O
H2O2
(1/2 O2 + H2O)
PdIIX2
O
1a
2HX
O
O
PdII
PdX
O
O
O
PdIIX
H
H
O2
O
Pd0
A
Protodeboronation
O
O
(HO)2B
H
PdII
Dehydrogenation
X
XPdII
HX
2a
B
Conjugate Addition
PdIIX
O
O
O
PdIIX
PdIIX2
O
C
Protonolysis
O
-H elimination
O
HX
O
4a
H
O
3a
CONCLUSION
In conclusion, we developed a novel and efficient method to access a variety of flavanones via
palladium(II)-catalyzed one-pot β-arylation of chromanones, possessing chemically unactivated β-
sites, with arylboronic acids. This methodology has various advantages, including providing products
in high yields (up to 92%), using easily accessible reagents, and offering good compatibilities with a
wide range of functional groups. It also provides novel synthetic routes to diverse biologically active
natural flavanones, such as liquiritigenin dimethyl ether. Further investigations on the biological
studies of flavanones synthesized by our methodology are ongoing.
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Experimental Section
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General information. Unless noted otherwise, all starting materials and reagents were obtained
from commercial suppliers (Aldrich, Acros Organics, Alfa Aesar, and TCI) and were used without
further purification. All solvents used for routine isolation of products and chromatography were
reagent grade. Reaction flasks were dried at 80 °C. Analytical thin-layer chromatography (TLC) was
performed using Merck silica gel glass plates with F-254 indicator, visualized by UV light (254 nm,
365 nm), in some cases stained with Hanessian’s or p-anisaldehyde followed by heating. Flash
column chromatography was performed using silica gel 60 (230-400 mesh) with the indicated
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1
solvents. NMR spectra were recorded and obtained using a Bruker 400 (400 MHz for H-NMR) and
Varian VNMRS500 (125 MHz for 13C{1H}-NMR and 470 MHz for 19F-NMR) spectrometer,
1
respectively. H, 13C, and 19F-NMR chemical shifts are reported in parts per million (ppm) relative to
TMS (tetramethylsilane), with the residual solvent peak used as an internal reference. Signals are
reported as m (multiplet), s (singlet), d (doublet), t (triplet), q (quartet), bs (broad singlet), bd (broad
doublet), dd (doublet of doublets); the coupling constants (J) are reported in Hertz (Hz). High-
resolution mass spectrometry (HRMS) data were obtained with a JEOL JMS-700 instrument (EI-
quadrupole). 4-Chromanone derivatives 1, starting materials for the synthesis of flavanones, were
prepared, according to the reported procedures.3e, 6c All of the spectral data of the synthesized 4-
chromanones were in accordance with the reported ones. The representative scheme for 4-
chromanone synthesis was described in the supporting information.
General procedure for palladium(II)-catalyzed β-arylation to flavanones. To a 10 mL two
neck round bottom flask, 4-chromanone 1 (0.337 mmol, 1.0 equiv.), Pd(TFA)2 (0.051 mmol, 15 mol%),
and 2,2′-bipyridine (0.102 mmol, 30 mol%) were added and then dissolved with anhydrous
DMSO/dioxane (1:4) (0.5 mL). Under an oxygen (balloon) atmosphere, the reaction mixture was
stirred at 100 °C in oil bath with reflux condenser until complete conversion of the starting material to
chromone on TLC. Then, the reaction temperature was lowered to 80 °C and a solution of arylboronic
acid (1.011 mmol, 3.0 equiv.) and TFA (0.337 mmol, 1.0 equiv.) in anhydrous DMSO/dioxane (1:4)
(0.5 mL) was added dropwise to flask. The reaction mixture was stirred until complete consumption of
chromone. Then, the reaction mixture was cooled to room temperature. 2N aq. HCl was added and
the resulting mixture was extracted with EtOAc. The combined organic layers were dried with MgSO4,
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filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography.
2-phenylchroman-4-one (3a). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
phenylboronic acid using the general procedure described above. The residue was purified by silica
gel column chromatography (EtOAc : n-hexane = 1 : 60) to afford 64.2 mg (85%) of compound 3a as
a white solid; mp 75-76 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.95 (dd, 1H, J = 7.9, 1.3 Hz), 7.57-7.35 (m,
6H), 7.11-7.01 (m, 2H), 5.49 (dd, 1H, J = 13.3, 2.7 Hz), 3.10 (dd, 1H, J = 16.8, 13.4 Hz), 2.90 (dd, 1H,
J = 16.9, 2.8 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 192.1, 161.7, 138.9, 136.3, 129.0, 128.9, 127.2,
126.3, 121.7, 121.0. 118.3, 79.7. 44.8; HR-MS (EI+) calcd for C15H12O2 224.0837, found 224.0837.
2-(p-tolyl)chroman-4-one (3b). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and 4-
methylphenylboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (EtOAc : n-hexane = 1 : 40) to afford 67.5 mg (84%) of compound
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3b as a white needle; mp 61-63 °C; H-NMR (DMSO-d6, 400 MHz) δ 7.79 (dd, 1H, J = 8.0, 1.7 Hz),
7.59 (m, 1H), 7.43 (d, 2H, J = 8.0 Hz), 7.24 (d, 2H, J = 7.9 Hz), 7.12-7.06 (m, 2H), 5.63 (dd, 1H, J =
12.8, 2.8 Hz), 3.25 (dd, 1H, J = 16.8, 12.9 Hz), 2.80 (dd, 1H, J = 16.8, 2.9 Hz), 2.32 (s, 3H); 13C{1H}-
NMR (CDCl3, 125 MHz) δ 192.3, 161.8, 138.9, 136.3, 135.9, 129.6, 127.2, 126.3, 121.7, 121.1, 118.3,
79.7, 44.7, 21.4; HR-MS (EI+) calcd for C16H14O2 238.0994, found 238.0994.
2-(2,4-dimethylphenyl)chroman-4-one (3c). Prepared from 4-chromanone (50.0 mg, 0.34 mmol)
and 2,4-dimethylphenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 60) to afford 63.1 mg (74%) of
compound 3c as a white solid; mp 82-83 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.97 (dd, 1H, J = 7.7, 0.9
Hz), 7.55-7.42 (m, 2H), 7.13 (d, 1H, J = 7.8 Hz), 7.10-7.02 (m, 3H), 5.66 (dd, 1H, J = 13.7, 2.2 Hz),
3.10 (dd, 1H, J = 16.8, 13.8 Hz), 2.83 (dd, 1H, J = 16.9, 2.5 Hz), 2.37 (s, 3H), 2.36 (s, 3H); 13C{1H}-
NMR (CDCl3, 125 MHz) δ 192.6, 162.1, 138.6, 136.3, 135.3, 133.9, 131.8, 127.3, 127.2, 125.9, 121.7,
121.1, 118.3, 76.9, 43.7, 21.2, 19.1; HR-MS (EI+) calcd for C17H16O2 252.1150, found 252.1148.
2-(4-(tert-butyl)phenyl)chroman-4-one (3d). Prepared from 4-chromanone (50.0 mg, 0.34 mmol)
and 4-tert-butylphenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 60) to afford 85.4 mg (90%) of
compound 3d as a white solid; mp 99-100 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 7.80 (dd, 1H, J = 8.0,
1.7 Hz) 7.59 (m, 1H), 7.50-7.42 (m, 4H), 7.13-7.06 (m, 2H), 5.64 (dd, 1H, J = 12.8, 2.8 Hz), 3.27 (dd,
1H, J = 16.8, 12.9 Hz), 2.83 (dd, 1H, J = 16.9, 3.0 Hz), 1.29 (s, 9H); 13C{1H}-NMR (CDCl3, 125 MHz)
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δ 192.4, 161.8, 152.1, 136.3, 135.8, 127.2, 126.2, 125.9, 121.7, 121.1, 118.3, 79.7, 44.6, 34.8, 31.4;
HR-MS (EI+) calcd for C19H20O2 280.1463, found 280.1467.
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2-([1,1′-biphenyl]-4-yl)chroman-4-one (3e). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
4-biphenylboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (DCM : methanol = 1 : 100) to afford 69.7 mg (69%) of compound
3e as a white solid; mp 115-116 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.96 (d, 1H, J = 7.8 Hz), 7.71-7.35
(m, 10H), 7.11-7.04 (m, 2H), 5.55 (dd, 1H, J = 13.3, 2.3 Hz), 3.15 (dd, 1H, J = 16.8, 13.4 Hz), 2.95
(dd, 1H, J = 16.8, 2.7 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 192.1, 161.7, 142.0, 140.6, 137.8,
136.4, 129.0, 127.8, 127.7, 127.3, 127.2, 126.8, 121.8, 121.1, 118.3, 79.6, 44.7; HR-MS (EI+) calcd
for C21H16O2 300.1150, found 300.1150.
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2-([1,1′′-biphenyl]-3-yl)chroman-4-one (3f). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
3-biphenylboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (EtOAc : n-hexane = 1 : 50) to afford 90 mg (89%) of compound 3f
1
as a colorless oil; H-NMR (CDCl3, 400 MHz) δ 7.97 (m, 1H) 7.76-7.35 (m, 10H), 7.14-7.04 (m, 2H),
5.55 (dd, 1H, J = 13.4, 2.6 Hz), 3.16 (dd, 1H, J = 16.9, 13.5 Hz), 2.95 (dd, 1H, J = 16.9, 2.8 Hz);
13C{1H}-NMR (CDCl3, 125 MHz) δ 192.0, 161.7, 142.1, 140.8, 139.4, 136.3, 129.4, 129.0, 127.7,
127.7, 127.3, 127.2, 125.1, 125.1, 121.8, 121.1, 118.3, 79.8, 44.9; HR-MS (EI+) calcd for C21H16O2
300.1150, found 300.1149.
2-(naphthalen-2-yl)chroman-4-one (3g). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and 2-
naphtylboronic acid using the general procedure described above. The residue was purified by silica
gel column chromatography (EtOAc : n-hexane = 1 : 70) to afford 72 mg (65%) of compound 3g as a
white solid; mp 106-107 °C; 1H-NMR (CDCl3, 400 MHz) δ 8.01-7.82 (m, 5H), 7.61 (d, 1H, J = 8.4 Hz),
7.58-7.49 (m, 3H), 7.15-7.03 (m, 2H), 5.66 (dd, 1H, J = 13.2, 2.3 Hz), 3.20 (dd, 1H, J = 16.8, 13.3 Hz),
2.99 (dd, 1H, J = 16.9, 2.7 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 192.0, 161.7, 136.4, 136.2, 133.5,
133.3, 128.9, 128.3, 127.9, 127.2, 126.7, 125.5, 123.8, 121.8, 121.1, 118.3, 79.8, 44.8; HR-MS (EI+)
calcd for C19H14O2 274.0994, found 274.0994.
2-(4-fluorophenyl)chroman-4-one (3h). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and 4-
fluorophenylboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (EtOAc : n-hexane = 1 : 50) to afford 55.4 mg (68%) of compound
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3h as a yellow solid; mp 74-75 °C; H-NMR (CDCl3, 400 MHz) δ 7.94 (d, 1H, J = 7.6 Hz), 7.56-7.41
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(m, 3H), 7.17-7.01 (m, 4H), 5.47 (dd, 1H, J = 13.2, 2.1 Hz), 3.07 (dd, 1H, J = 16.7, 13.4 Hz), 2.88 (dd,
1H, J = 16.8, 2.6 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 191.9, 163.0 (d, J = 246.2 Hz), 161.5, 136.4,
134.7 (d, J = 3.2 Hz), 128.2 (d, J = 8.3 Hz), 127.2, 121.9, 121.0, 118.2, 116.0 (d, J = 21.5 Hz), 79.1,
44.8; 19F-NMR (CDCl3, 470 MHz) δ −112.8 (m, 1F); HR-MS (EI+) calcd for C15H11FO2 242.0743,
found 242.0741.
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2-(4-chlorophenyl)chroman-4-one (3i). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and 4-
chlorophenylboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (EtOAc : n-hexane = 1 : 50) to afford 67.5 mg (77%) of compound
3i as a white solid; mp 79-80 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.93 (dd, 1H, J = 7.7, 1.1 Hz), 7.53 (m,
1H), 7.46-7.36 (m, 4H), 7.11-7.02 (m, 2H), 5.47 (dd, 1H, J = 13.1, 2.8 Hz), 3.05 (dd, 1H, J = 16.8, 13.2
Hz), 2.88 (dd, 1H, J = 16.8, 2.9 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 191.7, 161.4, 137.4, 136.4,
134.7, 129.2, 127.7, 127.2, 122.0, 121.0, 118.2, 79.0, 44.7; HR-MS (EI+) calcd for C15H11ClO2
258.0448, found 258.0445.
2-(4-bromophenyl)chroman-4-one (3j). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and 4-
bromophenylboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (EtOAc : n-hexane = 1 : 60) to afford 77.6 mg (77%) of compound
3j as a yellow solid; mp 111-113 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 7.80 (dd, 1H, J = 8.0, 1.6 Hz),
7.67-7.48 (m, 5H), 7.14-7.07 (m, 2H), 5.69 (dd, 1H, J = 12.9, 2.5 Hz), 3.25 (dd, 1H, J = 16.8, 13.0 Hz),
2.85 (dd, 1H, J = 16.8, 2.8 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 191.6, 161.4, 137.9, 136.5, 132.1,
127.9, 127.2, 122.9, 122.0, 121.0, 118.2, 79.0, 44.7; HR-MS (EI+) calcd for C15H11BrO2 301.9942,
found 301.9944.
2-(4-(trimethylsilyl)phenyl)chroman-4-one (3k). Prepared from 4-chromanone (50.0 mg, 0.34
mmol) and 4-trimethylsilylphenylboronic acid using the general procedure described above. The
residue was purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 60) to afford 79 mg
(79%) of compound 3k as a yellow solid; mp 66-68 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.95 (dd, 1H, J =
8.0, 1.7 Hz), 7.62 (d, 2H, J = 7.9 Hz), 7.55-7.46 (m, 3H), 7.10-7.03 (m, 2H), 5.49 (dd, 1H, J = 13.4, 2.8
Hz), 3.12 (dd, 1H, J = 16.8, 13.4 Hz), 2.91 (dd, 1H, J = 16.8, 2.9 Hz), 0.30 (s, 9H); 13C{1H}-NMR
(CDCl3, 125 MHz) δ 192.1, 161.7, 141.6, 139.2, 136.3, 134.0, 127.2, 125.6, 121.7, 121.1, 118.3, 79.8,
44.7, -1.0; HR-MS (EI+) calcd for C18H20O2Si 296.1233, found 296.1231.
2-(4-(trifluoromethyl)phenyl)chroman-4-one (3l). Prepared from 4-chromanone (50.0 mg, 0.34
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mmol) and 4-trifluoromethylphenylboronic acid using the general procedure described above. The
residue was purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 50) to afford 65.8
mg (67%) of compound 3l as a white solid; mp 74-75 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.94 (dd, 1H, J
= 8.1, 1.4 Hz), 7.71 (d, 2H, J = 8.2 Hz), 7.62 (d, 2H, J = 8.1 Hz), 7.54 (m, 1H), 7.13-7.02 (m, 2H), 5.56
(dd, 1H, J = 13.0, 2.9 Hz), 3.05 (dd, 1H, J = 16.8, 13.0 Hz), 2.92 (dd, 1H, J = 16.8, 3.1 Hz); 13C{1H}-
NMR (CDCl3, 125 MHz) δ 191.3, 161.3, 142.8 (d, J = 1.2 Hz), 136.5, 131.0 (q, J = 32.4 Hz), 127.2,
126.5, 126.0 (q, J = 3.8 Hz), 124.0 (q, J = 270.5 Hz), 122.1, 121.0, 118.2, 78.9, 44.8; 19F-NMR
(CDCl3, 470 MHz) δ −62.6 (s, 3F); HR-MS (EI+) calcd for C16H11F3O2 292.0711, found 292.0713.
methyl 4-(4-oxochroman-2-yl)benzoate (3m). Prepared from 4-chromanone (50.0 mg, 0.34 mmol)
and 4-methoxycarbonylphenylboronic acid using the general procedure described above. The residue
was purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 20) to afford 43.0 mg (45%)
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of compound 3m as a white solid; mp 133-134 °C; H-NMR (CDCl3, 400 MHz) δ 8.14-8.08 (m, 2H),
7.94 (dd, 1H, J = 8.0, 1.8 Hz), 7.59-7.49 (m, 3H), 7.10-7.05 (m, 2H), 5.55 (dd, 1H, J = 13.0, 3.1 Hz),
3.94 (s, 3H), 3.05 (dd, 1H, J = 16.9, 13.0 Hz), 2.92 (dd, 1H, J = 16.9, 3.2 Hz); 13C{1H}-NMR (CDCl3,
125 MHz) δ 191.4, 166.7, 161.4, 143.8, 136.5, 130.5, 130.3, 127.2, 126.1, 122.0, 121.0, 118.2, 79.1,
52.4, 44.8; HR-MS (EI+) calcd for C17H14O4 282.0892, found 282.0894.
4-(4-oxochroman-2-yl)benzaldehyde (3n). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
4-formylphenylboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (EtOAc : n-hexane = 1 : 10) to afford 18.2 mg (21%) of compound
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3n as a white solid; mp 101-103 °C; H-NMR (CDCl3, 400 MHz) δ 10.06 (s, 1H), 7.99-7.92 (m, 3H),
7.67 (d, 2H, J = 8.4 Hz), 7.55 (m, 1H), 7.12-7.07 (m, 2H), 5.58 (dd, 1H, J = 12.9, 3.3 Hz), 3.05 (dd,
1H, J = 16.9, 12.9 Hz), 2.94 (dd, 1H, J = 16.8, 3.3 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 191.8,
191.2, 161.3, 145.4, 136.6, 136.6, 130.4, 127.3, 126.7, 122.2, 121.1, 118.2, 79.0, 44.8; HR-MS (EI+)
calcd for C16H12O3 252.0786, found 252.0772.
2-(3-nitrophenyl)chroman-4-one (3o). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and 3-
nitrophenylboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (EtOAc : n-hexane = 1 : 10) to afford 14.7 mg (16%) of compound
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3o as a white solid; mp 137-138 °C; H-NMR (CDCl3, 400 MHz) δ 8.42 (t, 1H, J = 1.8 Hz), 8.26 (m,
1H), 7.95 (dd, 1H, J = 8.2, 1.8 Hz), 7.81 (d, 1H, J = 7.7 Hz), 7.64 (t, 1H, J = 8.0 Hz), 7.56 (m, 1H),
7.14-7.07 (m, 2H), 5.61 (dd, 1H, J = 12.9, 3.3 Hz), 3.07 (dd, 1H, J = 16.8, 12.9 Hz), 2.96 (dd, 1H, J =
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16.8, 3.4 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 190.9, 161.1, 148.8, 141.1, 136.7, 132.0, 130.1,
127.3, 123.7, 122.3, 121.3, 121.0, 118.2, 78.4, 44.8; HR-MS (EI+) calcd for C15H11NO4 269.0688,
found 269.0680.
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2-(2-hydroxyphenyl)chroman-4-one (3p). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
2-hydroxyphenylboronic acid using the general procedure described above. The residue was purified
by silica gel column chromatography (EtOAc : n-hexane = 1 : 12) to afford 49.2 mg (61%) of
compound 3p as a yellow solid; mp 158-159 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 9.84 (bs, 1H), 7.80
(d, 1H, J = 7.6 Hz), 7.60 (t, 1H, J = 7.2 Hz), 7.48 (d, 1H, J = 7.5 Hz), 7.20 (t, 1H, J = 7.3 Hz), 7.14-7.05
(m, 2H), 6.92-6.83 (m, 2H), 5.79 (dd, 1H, J = 13.1, 2.3 Hz), 3.21 (dd, 1H, J = 16.6, 13.4 Hz), 2.78 (dd,
1H, J = 16.7, 2.3 Hz); 13C{1H}-NMR (CD3OD, 125 MHz) δ 194.9, 163.7, 155.3, 137.5, 130.3, 127.8,
127.6, 126.9, 122.4, 122.0, 120.7, 119.2, 116.2, 76.4, 43.9; HR-MS (EI+) calcd for C15H12O3
240.0786, found 240.0786.
2-(3-hydroxyphenyl)chroman-4-one (3q). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
3-hydroxyphenylboronic acid using the general procedure described above. The residue was purified
by silica gel column chromatography (EtOAc : n-hexane = 1 : 5) to afford 57.5 mg (71%) of compound
3q as a yellow solid; mp 135-136 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 7.79 (dd, 1H, J =
8.1, 1.5 Hz), 7.59 (m, 1H), 7.21 (t, 1H, J = 8.1 Hz), 7.12-7.06 (m, 2H), 6.95-6.90 (m, 2H), 6.76 (m, 1H),
5.59 (dd, 1H, J = 12.6, 2.9 Hz), 3.19 (dd, 1H, J = 16.7, 12.6 Hz), 2.82 (dd, 1H, J = 16.8, 3.0 Hz);
13C{1H}-NMR (CD3OD, 125 MHz) δ 194.1, 163.1, 158.8, 141.9, 137.5, 130.8, 127.7, 122.5, 122.0,
119.2, 118.3, 116.4, 114.1, 80.7, 45.4; HR-MS (EI+) calcd for C15H12O3 240.0786, found 240.0786.
2-(2-methoxyphenyl)chroman-4-one (3r). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
2-methoxyphenylboronic acid using the general procedure described above. The residue was purified
by silica gel column chromatography (EtOAc : n-hexane = 1 : 20) to afford 61.2 mg (71%) of
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compound 3r as a yellow oil; H-NMR (CDCl3, 400 MHz) δ 7.95 (dd, 1H, J = 7.8, 1.6 Hz), 7.65 (dd,
1H, J = 7.6, 1.3 Hz), 7.51 (m, 1H), 7.35 (m, 1H), 7.10-7.03 (m, 3H), 6.93 (d, 1H, J = 8.1 Hz), 5.86 (dd,
1H, J = 12.4, 3.8 Hz), 3.84 (s, 3H), 3.02-2.86 (m, 2H); 13C{1H}-NMR (CDCl3, 125 MHz) δ 192.8, 162.1,
155.9, 136.1, 129.5, 127.6, 127.2, 126.5, 121.5, 121.1, 121.0, 118.2, 110.6, 74.8, 55.4, 43.8; HR-MS
(EI+) calcd for C16H14O3 254.0943, found 254.0943.
2-(3-methoxyphenyl)chroman-4-one (3s). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
3-methoxyphenylboronic acid using the general procedure described above. The residue was purified
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by silica gel column chromatography (DCM : methanol = 1 : 400) to afford 71.5 mg (83%) of
compound 3s as a white solid; mp 72-73 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.93 (dd, 1H, J = 8.1, 1.6
Hz), 7.51 (m, 1H), 7.35 (t, 1H, J = 8.2 Hz), 7.10-7.01 (m, 4H), 6.92 (dd, 1H, J = 8.2, 1.9 Hz), 5.45 (dd,
1H, J = 13.3, 2.8 Hz), 3.84 (s, 3H), 3.08 (dd, 1H, J = 16.8, 13.4 Hz), 2.87 (dd, 1H, J = 16.8, 2.9 Hz);
13C{1H}-NMR (CDCl3, 125 MHz) δ 192.0, 161.6, 160.0, 140.4, 136.3, 130.0, 127.1, 121.7, 121.0,
118.4, 118.2, 114.1, 112.0, 79.5, 55.4, 44.8; HR-MS (EI+) calcd for C16H14O3 254.0943, found
254.0943.
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2-(4-methoxyphenyl)chroman-4-one (3t). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and
4-methoxyphenylboronic acid using the general procedure described above. The residue was purified
by silica gel column chromatography (EtOAc : n-hexane = 1 : 5) to afford 63.6 mg (74%) of compound
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3t as a yellow solid; mp 82-83 °C; H-NMR (CDCl3, 400 MHz) δ 7.93 (dd, 1H, J = 7.7, 0.9 Hz), 7.51
(m, 1H), 7.42 (d, 2H, J = 8.6 Hz), 7.08-7.01 (m, 2H), 6.96 (d, 2H, J = 8.6 Hz), 5.44 (dd, 1H, J = 13.3,
2.4 Hz), 3.84 (s, 3H), 3.11 (dd, 1H, J = 16.8, 13.4 Hz), 2.86 (dd, 1H, J = 16.8, 2.7 Hz); 13C{1H}-NMR
(CDCl3, 125 MHz) δ 192.4, 161.8, 160.1, 136.3, 130.9, 127.9, 127.2, 121.7, 121.0, 118.3, 114.3, 79.5,
55.5, 44.6; HR-MS (EI+) calcd for C16H14O3 254.0943, found 254.0943.
2-(3,4-dimethoxyphenyl)chroman-4-one (3u). Prepared from 4-chromanone (50.0 mg, 0.34 mmol)
and 3,4-dimethoxyphenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 5) to afford 57.8 mg (87%) of
compound 3u as a yellow solid; mp 118-119 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.93 (dd, 1H, J = 7.9,
1.2 Hz), 7.51 (m, 1H), 7.09-6.95 (m, 4H), 6.91 (d, 1H, J = 7.9 Hz), 5.43 (dd, 1H, J = 13.3, 2.3 Hz),
3.92 (s, 3H), 3.90 (s, 3H), 3.12 (dd, 1H, J = 16.8, 13.4 Hz), 2.87 (dd, 1H, J = 16.8, 2.6 Hz); 13C{1H}-
NMR (CDCl3, 125 MHz) δ 192.2, 161.7, 149.6, 149.4, 136.3, 131.3, 127.2, 121.7, 121.0, 118.9, 118.3,
111.3, 109.5, 79.7, 56.1, 56.1, 44.7; HR-MS (EI+) calcd for C17H16O4 284.1049, found 284.1051.
2-(3,4,5-trimethoxyphenyl)chroman-4-one (3v). Prepared from 4-chromanone (50.0 mg, 0.34
mmol) and 3,4,5-trimethoxyphenylboronic acid using the general procedure described above. The
residue was purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 6) to afford 97.4 mg
(92%) of compound 3v as a white solid; mp 98-100 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.92 (dd, 1H, J =
8.1, 1.6 Hz), 7.51 (m, 1H), 7.09-7.02 (m, 2H), 6.70 (s, 2H), 5.40 (dd, 1H, J = 13.4, 2.7 Hz), 3.89 (s,
6H), 3.86 (s, 3H), 3.09 (dd, 1H, J = 16.9, 13.4 Hz), 2.87 (dd, 1H, J = 16.8, 2.8 Hz); 13C{1H}-NMR
(CDCl3, 125 MHz) δ 191.9, 161.5, 153.6, 138.3, 136.3, 134.4, 127.1, 121.8, 120.9, 118.2, 103.3, 79.9,
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60.9, 56.2, 44.9; HR-MS (EI+) calcd for C18H18O5 314.1154, found 314.1156.
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2-(4-(benzyloxy)phenyl)chroman-4-one (3w). Prepared from 4-chromanone (50.0 mg, 0.34 mmol)
and 4-benzyloxyphenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 50) to afford 65.2 mg (59%) of
compound 3w as a white solid; mp 105-106 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.95 (dd, 1H, J = 7.7,
1.5 Hz), 7.51 (m, 1H), 7.49-7.32 (m, 7H), 7.09-6.99 (m, 4H), 5.43 (dd, 1H, J = 13.4, 2.7 Hz), 5.10 (s,
2H), 3.11 (dd, 1H, J = 16.8, 13.4 Hz), 2.87 (dd, 1H, J = 16.8, 2.8 Hz); 13C{1H}-NMR (CDCl3, 125 MHz)
δ 192.3, 161.7, 159.2, 136.8, 136.2, 131.1, 128.7, 128.1, 127.8, 127.5, 127.1, 121.6, 121.0, 118.2,
115.2, 79.4, 70.1, 44.5; HR-MS (EI+) calcd for C22H18O3 330.1256, found 330.1259.
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2-(thiophen-3-yl)chroman-4-one (3x). Prepared from 4-chromanone (50.0 mg, 0.34 mmol) and 3-
thiopheneboronic acid using the general procedure described above. The residue was purified by
silica gel column chromatography (EtOAc : n-hexane = 1 : 40) to afford 25.8 mg (33%) of compound
3x as a brown solid; mp 76-78 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.92 (dd, 1H, J = 8.1, 1.7 Hz), 7.51
(m, 1H), 7.41-7.37 (m, 2H), 7.20 (m, 1H), 7.08-7.02 (m, 2H), 5.60 (dd, 1H, J = 12.1, 3.3 Hz), 3.12 (dd,
1H, J = 16.8, 12.1 Hz), 2.99 (dd, 1H, J = 16.8, 3.3 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 191.9,
161.4, 140.0, 136.3, 127.2, 127.0, 125.8, 123.0, 121.8, 121.2, 118.2, 75.7, 44.0; HR-MS (EI+) calcd
for C13H10O2S 230.0402 found, 230.0401.
6-methyl-2-phenylchroman-4-one (3y). Prepared from 6-methyl-4-chromanone (55.0 mg, 0.34
mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 60) to afford 62.0 mg (78%) of
compound 3y as a white solid; mp 103-104 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.73 (s, 1H), 7.52-7.30
(m, 6H), 6.96 (d, 1H, J = 8.4 Hz), 5.45 (dd, 1H, J = 13.3, 2.7 Hz), 3.07 (dd, 1H, J = 16.9, 13.4 Hz),
2.87 (dd, 1H, J = 17.0, 2.9 Hz), 2.33 (s, 3H); 13C{1H}-NMR (CDCl3, 125 MHz) δ 192.3, 159.7, 139.0,
137.3, 131.1, 128.9, 128.8, 126.7, 126.2, 120.6, 118.0, 79.6, 44.8, 20.5; HR-MS (EI+) calcd for
C16H14O2 238.0994, found 238.0996.
6,7-dimethyl-2-phenylchroman-4-one (3z). Prepared from 6,7-dimethyl-4-chromanone (56.0 mg,
0.32 mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 50) to afford 67.5 mg (84%) of
compound 3z as a white solid; mp 78-79 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 7.51-7.35 (m,
5H), 6.85 (s, 1H), 5.43 (dd, 1H, J = 13.2, 2.8 Hz), 3.04 (dd, 1H, J = 16.9, 13.3 Hz), 2.84 (dd, 1H, J =
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17.0, 2.9 Hz), 2.28 (s, 3H), 2.24 (s, 3H); 13C{1H}-NMR (CDCl3, 125 MHz) δ 192.0, 160.0, 146.8,
139.1, 130.3, 128.9, 128.7, 127.0, 126.2, 118.8, 118.7, 79.6, 44.7, 20.6, 18.9; HR-MS (EI+) calcd for
C17H16O2 252.1150, found 252.1148.
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6-fluoro-2-phenylchroman-4-one (3aa). Prepared from 6-fluoro-4-chromanone (56.0 mg, 0.34
mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 70) to afford 65.6 mg (80%) of
compound 3aa as a yellow solid; mp 71-73 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.58 (dd, 1H, J = 8.2, 3.2
Hz), 7.52-7.36 (m, 5H), 7.24 (m, 1H), 7.04 (m, 1H), 5.47 (dd, 1H, J = 13.4, 2.9 Hz), 3.08 (dd, 1H, J =
17.0, 13.4 Hz), 2.90 (dd, 1H, J = 16.9, 2.9 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 191.2 (d, J = 1.8
Hz), 158.4, 157.8 (d, J = 1.7 Hz), 156.5, 138.5, 129.0, 126.2, 123.8 (d, J = 24.4 Hz), 121.5 (d, J = 6.5
Hz), 119.9 (d, J = 7.1 Hz), 112.1 (d, J = 23.2 Hz), 79.9, 44.4 (d, J = 1.0 Hz); 19F-NMR (CDCl3, 470
MHz) δ −121.0 (m, 1F); HR-MS (EI+) calcd for C15H11FO2 242.0743, found 242.0741.
6-chloro-2-phenylchroman-4-one (3bb). Prepared from 6-chloro-4-chromanone (62.0 mg, 0.34
mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 70) to afford 65.4 mg (75%) of
compound 3bb as a yellow solid; mp 91-92 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.89 (d, 1H, J = 2.6 Hz),
7.50-7.37 (m, 6H), 7.02 (d, 1H, J = 8.8 Hz), 5.47 (dd, 1H, J = 13.2, 3.0 Hz), 3.08 (dd, 1H, J = 16.8,
13.2 Hz), 2.91 (dd, 1H, J = 16.9, 3.0 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 190.9, 160.0, 138.4,
136.1, 129.1, 129.0, 127.3, 126.5, 126.3, 121.8, 120.0, 79.9, 44.4; HR-MS (EI+) calcd for C15H11ClO2
258.0448, found 258.0447.
6-hydroxy-2-phenylchroman-4-one (3cc). Prepared from 6-hydroxy-chroman-4-one (54.0 mg, 0.33
mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (DCM : methanol = 100 : 1) to afford 62.3 mg (79%) of
compound 3cc as a yellow solid; mp 214-216 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 7.54
(s, 1H), 7.52 (s, 1H), 7.46-7.34 (m, 3H), 7.12 (d, 1H, J = 2.9 Hz), 7.04 (dd, 1H, J = 8.8, 3.0 Hz), 6.96
(d, 1H, J = 8.8 Hz), 5.55 (dd, 1H, J = 13.0, 2.6 Hz), 3.17 (dd, 1H, J = 16.8, 13.0 Hz), 2.77 (dd, 1H, J =
16.8, 2.8 Hz); 13C{1H}-NMR (DMSO-d6, 125 MHz) δ 191.7, 154.4, 151.6, 139.2, 128.5, 128.4, 126.6,
124.5, 120.8, 119.0, 109.9, 78.7, 43.7; HR-MS (EI+) calcd for C15H12O3 240.0786, found 240.0782.
7-hydroxy-2-phenylchroman-4-one (3dd). Prepared from 7-hydroxy-chroman-4-one (50.0 mg, 0.30
mmol) and phenylboronic acid using the general procedure described above. The residue was
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purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 5) to afford 51.5 mg (70%) of
compound 3dd as a white solid; mp 185-186 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 10.64 (bs, 1H), 7.66
(d, 1H, J = 8.7 Hz), 7.53 (d, 2H, J = 7.0 Hz), 7.46-7.33 (m, 3H), 6.52 (dd, 1H, J = 8.7, 2.2 Hz), 6.37 (d,
1H, J = 2.2 Hz), 5.59 (dd, 1H, J = 12.7, 2.8 Hz), 3.12 (dd, 1H, J = 16.7, 12.8 Hz), 2.71 (dd, 1H, J =
16.8, 3.0 Hz); 13C{1H}-NMR (CD3OD, 125 MHz) δ 193.0, 166.9, 165.4, 140.7, 129.9, 129.7, 129.6,
127.3, 115.0, 111.9, 103.9, 81.0, 45.1; HR-MS (EI+) calcd for C15H12O3 240.0786, found 240.0786.
5-methoxy-2-phenylchroman-4-one (3ee). Prepared from 5-methoxy-4-chromanone (50.9 mg, 0.29
mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 4) to afford 46.8 mg (64%) of
compound 3ee as a white solid; mp 141-143 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.49-7.33 (m, 6H), 6.66
(d, 1H, J = 8.3 Hz), 6.55 (d, 1H, J = 8.3 Hz), 5.44 (dd, 1H, J = 13.2, 2.8 Hz), 3.94 (s, 3H), 3.07 (dd,
1H, J = 16.4, 13.2 Hz), 2.85 (dd, 1H, J = 16.7, 2.9 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 190.8,
163.3, 160.9, 138.8, 136.1, 128.9, 128.8, 126.2, 111.5, 110.3, 104.1, 79.0, 56.3, 46.0; HR-MS (EI+)
calcd for C16H14O3 254.0943, found 254.0943.
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6-methoxy-2-phenylchroman-4-one (3ff). Prepared from 6-methoxy-4-chromanone (55.0 mg, 0.31
mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 30) to afford 68.5 mg (87%) of
compound 3ff as a pale yellow solid; mp 138-139 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.52-7.32 (m, 6H),
7.13 (dd, 1H, J = 9.0, 3.1 Hz), 7.00 (d, 1H, J = 9.0 Hz), 5.45 (dd, 1H, J = 13.4, 2.6 Hz), 3.82 (s, 3H),
3.08 (dd, 1H, J = 16.9, 13.5 Hz), 2.88 (dd, 1H, J = 16.9, 2.8 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ
192.1, 156.4, 154.3, 139.0, 128.9, 128.8, 126.2, 125.5, 120.9, 119.5, 107.4, 79.8, 55.9, 44.7; HR-MS
(EI+) calcd for C16H14O3 254.0943, found 254.0943.
7-methoxy-2-phenylchroman-4-one (3gg). Prepared from 7-methoxy-4-chromanone (57.0 mg, 0.32
mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 20) to afford 68.9 mg (85%) of
compound 3gg as a white solid; mp 84-86 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.87 (d, 1H, J = 8.8 Hz),
7.50-7.35 (m, 5H), 6.62 (dd, 1H, J = 8.8, 2.4 Hz), 6.50 (d, 1H, J = 2.4 Hz), 5.47 (dd, 1H, J = 13.3, 2.9
Hz), 3.83 (s, 3H), 3.04 (dd, 1H, J = 16.9, 13.3 Hz), 2.83 (dd, 1H, J = 16.9, 2.9 Hz); 13C{1H}-NMR
(CDCl3, 125 MHz) δ 190.6, 166.3, 163.6, 138.9, 128.9, 128.8, 128.8, 126.2, 114.9, 110.3, 101.0, 80.1,
55.7, 44.4; HR-MS (EI+) calcd for C16H14O3 254.0943, found 254.0943.
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5,7-dimethoxy-2-phenylchroman-4-one (3hh). Prepared from 5,7-dimethoxy-4-chromanone (62.6
mg, 0.3 mmol) and phenylboronic acid using the general procedure described above. The residue
was purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 3) to afford 61.0 mg (71%)
of compound 3hh as a yellow solid; mp 140-141 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.47-7.32 (m, 5H),
6.15 (d, 1H, J = 2.1 Hz), 6.08 (d, 1H, J = 2.1 Hz), 5.39 (dd, 1H, J = 13.1, 2.8 Hz), 3.88 (s, 3H), 3.80 (s,
3H), 3.00 (dd, 1H, J = 16.5, 13.2 Hz), 2.78 (dd, 1H, J = 16.6, 2.9 Hz); 13C{1H}-NMR (CDCl3, 125 MHz)
δ 189.4, 166.1, 165.1, 162.4, 138.9, 128.9, 128.8, 126.2, 106.1, 93.7, 93.3, 79.4, 56.3, 55.7, 45.7;
HR-MS (EI+) calcd for C17H16O4 284.1049, found 284.1049.
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6,7-dimethoxy-2-phenylchroman-4-one (3ii). Prepared from 6,7-dimethoxy-4-chromanone (70.0
mg, 0.34 mmol) and phenylboronic acid using the general procedure described above. The residue
was purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 6) to afford 73.1 mg (76%)
1
of compound 3ii as a yellow solid; mp 170-171 °C; H-NMR (CDCl3, 400 MHz) δ 7.52-7.36 (m, 5H),
7.32 (s, 1H), 6.53 (s, 1H), 5.46 (dd, 1H, J = 13.5, 2.9 Hz), 3.91 (s, 3H), 3.90 (s, 3H), 3.04 (dd, 1H, J =
16.9, 13.5 Hz), 2.82 (dd, 1H, J = 16.9, 3.0 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 190.6, 158.0, 156.3,
144.7, 138.9, 128.9, 128.8, 126.2, 113.2, 106.7, 100.3, 80.3, 56.3, 56.2, 44.2; HR-MS (EI+) calcd for
C17H16O4 284.1049, found 284.1049.
6-(benzyloxy)-2-phenylchroman-4-one (3jj). Prepared from 6-(benzyloxy)chroman-4-one (80.0 mg,
0.31 mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 60) to afford 79.7 mg (77%) of
compound 3jj as a yellow solid; mp 103-104 °C; 1H-NMR (DMSO-d6, 400 MHz) δ 7.54 (d, 2H, J = 7.2
Hz), 7.47-7.26 (m, 10H), 7.08 (d, 1H, J = 8.7 Hz), 5.61 (dd, 1H, J = 12.9, 2.5 Hz), 5.13 (s, 2H), 3.23
(dd, 1H, J = 16.8, 13.1 Hz), 2.82 (dd, 1H, J = 16.7, 2.8 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 192.0,
156.5, 153.4, 138.9, 136.7, 128.9, 128.8, 128.7, 128.2, 127.7, 126.2, 126.0, 120.9, 119.6, 108.9, 79.8,
70.6, 44.6; HR-MS (EI+) calcd for C22H18O3 330.1256, found 330.1257.
4-oxo-2-phenylchroman-6-ylpivalate (3kk). Prepared from 4-oxochroman-7-yl pivalate (77.0 mg,
0.31 mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 40) to afford 65.9 mg (65%) of
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compound 3kk as a white solid; mp 106-107 °C; H-NMR (CDCl3, 400 MHz) δ 7.59 (d, 1H, J = 2.7
Hz), 7.50-7.37 (m, 5H), 7.21 (dd, 1H, J = 8.9, 2.8 Hz), 7.07 (d, 1H, J = 8.9 Hz), 5.49 (dd, 1H, J = 13.3,
2.5 Hz), 3.09 (dd, 1H, J = 16.9, 13.5 Hz), 2.90 (dd, 1H, J = 16.9, 2.7 Hz), 1.36 (s, 9H); 13C{1H}-NMR
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(CDCl3, 125 MHz) δ 191.4, 177.3, 159.2, 145.3, 138.6, 130.1, 129.0, 129.0, 126.2, 121.3, 119.3,
119.2, 79.9, 44.5, 39.2, 27.2; HR-MS (EI+) calcd for C20H20O4 324.1362, found 324.1363.
4-oxo-2-phenylchroman-7-ylpivalate (3ll). Prepared from 4-oxochroman-7-ylpivalate (76.6 mg, 0.31
mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 40) to afford 65.9 mg (65%) of
compound 3ll as a colorless oil; 1H-NMR (CDCl3, 400 MHz) δ 7.96 (d, 1H, J = 8.6 Hz), 7.50-7.36 (m,
5H), 6.84-6.72 (m, 2H), 5.50 (dd, 1H, J = 13.3, 2.8 Hz), 3.08 (dd, 1H, J = 16.9, 13.3 Hz), 2.89 (dd, 1H,
J = 16.9, 2.9 Hz), 1.35 (s, 9H); 13C{1H}-NMR (CDCl3, 125 MHz) δ 191.0, 176.3, 162.5, 157.3, 138.6,
128.9, 128.9, 128.5, 126.2, 118.8, 115.8, 111.2, 80.0, 44.5, 39.3, 27.1, 27.1, 27.1; HR-MS (EI+) calcd
for C20H20O4 324.1362, found 324.1360.
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4-oxo-2-phenylchroman-6-yl acetate (3mm). Prepared from 6-acetoxy-chroman-4-one (69.5 mg,
0.34 mmol) and phenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 30) to afford 76.0 mg (80%) of
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compound 3mm as a yellow solid; mp 99-101 °C; H-NMR (CDCl3, 400 MHz) δ 7.63 (d, 1H, J = 2.7
Hz), 7.51-7.36 (m, 5H), 7.24 (dd, 1H, J = 9.1, 2.9 Hz), 7.08 (d, 1H, J = 9.0 Hz), 5.48 (dd, 1H, J = 13.4,
2.5 Hz), 3.08 (dd, 1H, J = 16.9, 13.5 Hz), 2.89 (dd, 1H, J = 17.0, 2.9 Hz), 2.30 (s, 3H); 13C{1H}-NMR
(CDCl3, 125 MHz) δ 191.2, 169.6, 159.3, 144.8, 138.5, 130.0, 129.0, 126.2, 121.2, 119.4, 119.3, 79.9,
44.4, 21.0; HR-MS (EI+) calcd for C17H14O4 282.0892, found 282.0892.
6-phenyl-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one
(3nn)
Prepared
from
6,7-
methylenedioxy-chromanone (58.7 mg, 0.31 mmol) and phenylboronic acid using the general
procedure described above. The residue was purified by silica gel column chromatography (EtOAc :
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n-hexane = 1 : 30) to afford 58.7 mg (72%) of compound 3nn as a yellow solid; mp 114-115 °C; H-
NMR (CDCl3, 400 MHz) δ 7.51-7.36 (m, 5H), 7.30 (s, 1H), 6.51 (s, 1H), 6.00 (d, 2H, J = 2.4 Hz), 5.43
(dd, 1H, J = 13.4, 2.5 Hz), 3.01 (dd, 1H, J = 16.8, 13.6 Hz), 2.82 (dd, 1H, J = 16.9, 2.7 Hz); 13C{1H}-
NMR (CDCl3, 125 MHz) δ 190.4, 159.7, 154.5, 143.3, 138.8, 128.9, 128.8, 126.2, 114.7, 104.1, 102.1,
98.7, 80.2, 44.1; HR-MS (EI+) calcd for C16H12O4 268.0736, found 268.0740.
Liquiritigenin dimethyl ether (7). Prepared from 7-methoxy-4-chromanone (60.0 mg, 0.34 mmol)
and 4-methoxyphenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 15) to afford 79.0 mg (82%) of
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compound 7 as a white solid; mp 87-88 °C; H-NMR (CDCl3, 400 MHz) δ 7.85 (d, 1H, J = 8.8 Hz),
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7.39 (d, 2H, J = 8.6 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.59 (dd, 1H, J = 8.8, 2.3 Hz), 6.46 (d, 1H, J = 2.2),
5.39 (dd, 1H, J = 13.2, 2.7 Hz), 3.81 (s, 3H), 3.80 (s, 3H), 3.03 (dd, 1H, J = 16.8, 13.3 Hz), 2.77 (dd,
1H, J = 16.8, 2.8 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 190.9, 166.3, 163.7, 160.1, 130.9, 128.8,
127.9, 114.9, 114.3, 110.3, 101.0, 79.9, 55.7, 55.5, 44.2; HR-MS (EI+) calcd for C17H16O4 284.1049,
found 284.1050.
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Butin trimethyl ether (8). Prepared from 7-methoxy-4-chromanone (60.0 mg, 0.34 mmol) and 3,4-
dimethoxyphenylboronic acid using the general procedure described above. The residue was purified
by silica gel column chromatography (EtOAc : n-hexane = 1 : 6) to afford 85.2 mg (80%) of compound
8 as a yellow solid; mp 114-115 °C; 1H-NMR (CDCl3, 400 MHz) δ 7.86 (d, 1H, J = 8.8 Hz), 7.03-6.97
(m, 2H), 6.90 (d, 1H, J = 8.6 Hz), 6.61 (dd, 1H, J = 8.8, 2.4 Hz), 6.49 (d, 1H, J = 2.3 Hz), 5.41 (dd, 1H,
J = 13.3, 2.7 Hz), 3.92 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H), 3.06 (dd, 1H, J = 16.8, 13.3 Hz), 2.80 (dd,
1H, J = 16.8, 2.8 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 190.1, 166.2, 163.6, 149.5, 149.3, 131.3,
128.8, 118.9, 114.9, 111.2, 110.3, 109.5, 101.0, 80.0, 56.0, 56.0, 55.7, 44.3; HR-MS (EI+) calcd for
C18H18O5 314.1154, found 314.1157.
Naringenin trimethyl ether (9). Prepared from 5,7-dimethoxy-4-chromanone (70.0 mg, 0.34 mmol)
and 4-methoxyphenylboronic acid using the general procedure described above. The residue was
purified by silica gel column chromatography (EtOAc : n-hexane = 1 : 1) to afford 59.7 mg (56%) of
compound 9 as a yellow solid; mp 86-87 °C 1H-NMR (DMSO-d6, 400 MHz) δ 7.43 (d, 2H, J = 8.4 Hz),
6.96 (d, 2H, J = 8.5 Hz), 6.20 (d, 2H, J = 3.8 Hz), 5.45 (dd, 1H, J = 12.5, 2.2 Hz), 3.79 (s, 3H), 3.77 (s,
3H), 3.76 (s, 3H), 3.06 (dd, 1H, J = 16.2, 12.8 Hz), 2.58 (dd, 1H, J = 16.3, 2.5 Hz); 13C{1H}-NMR
(CDCl3, 125 MHz) δ 189.6, 166.0, 165.2, 162.4, 160.0, 130.9, 127.8, 114.2, 106.1, 93.6, 93.2, 79.1,
56.3, 55.7, 55.4, 45.5; HR-MS (EI+) calcd for C18H18O5 314.1154, found 314.1157.
2-(3,4-dimethoxyphenyl)-5,7-dimethoxychroman-4-one (10). Prepared from 5,7-dimethoxy-4-
chromanone (56.0 mg, 0.27 mmol) and 3,4-dimethoxyphenylboronic acid using the general procedure
described above. The residue was purified by silica gel column chromatography (EtOAc : n-hexane =
2 : 1) to afford 40.1 mg (43%) of compound 10 as a yellow solid; mp 152-153 °C 1H-NMR (CDCl3, 400
MHz) δ 7.02-6.95 (m, 2H), 6.88 (d, 1H, J = 8.7 Hz), 6.15 (d, 1H, J = 2.2 Hz), 6.09 (d, 1H, J = 2.1 Hz),
5.35 (dd, 1H, J = 13.2, 2.7 Hz), 3.92 (s, 3H), 3.90 (s, 6H), 3.82 (s, 3H), 3.04 (dd, 1H, J = 16.4, 13.3
Hz), 2.77 (dd, 1H, J = 16.5, 2.8 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 189.5, 166.1, 165.1, 162.4,
149.5, 149.3, 131.3, 118.9, 111.2, 109.5, 106.1, 93.7, 93.3, 79.3, 56.3, 56.1, 56.1, 55.7, 45.6; HR-MS
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(EI+) calcd for C19H20O6 344.1260, found 344.1262.
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2-(2,5-dimethoxyphenyl)-5,7-dimethoxychroman-4-one (11). Prepared from 5,7-dimethoxy-4-
chromanone (70.0 mg, 0.34 mmol) and 2,5-dimethoxyphenylboronic acid using the general procedure
described above. The residue was purified by silica gel column chromatography (EtOAc : n-hexane =
1 : 1) to afford 52.2 mg (45%) of compound 11 as a yellow solid; mp 117-118 °C 1H-NMR (CDCl3, 400
MHz) δ 7.17 (d, 1H, J = 1.5 Hz), 6.86-6.79 (m, 2H), 6.18 (d, 1H, J = 2.3 Hz), 6.09 (d, 1H, J = 2.3 Hz),
5.75 (dd, 1H, J = 11.9, 4.2 Hz), 3.90 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 2.91-2.77 (m,
2H); 13C{1H}-NMR (CDCl3, 125 MHz) δ 190.0, 165.9, 165.5, 162.4, 153.9, 150.1, 128.7, 113.7, 112.6,
111.7, 106.2, 93.7, 93.2, 77.4, 56.3, 56.0, 55.9, 55.7, 44.9; HR-MS (EI+) calcd for C19H20O6 344.1260,
found 344.1259.
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Pinocembrin (12).21a Yield 21.1 mg (47%) from 50.0 mg (0.18 mmol) of 3hh as a brown solid; mp
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195-197 °C; H-NMR (DMSO-d6, 400 MHz) δ 12.14 (s, 1H), 10.85 (s, 1H), 7.56-7.47 (m, 2H), 7.47-
7.34 (m, 3H), 5.97-5.85 (m, 2H), 5.59 (dd, 1H, J = 12.5, 2.5 Hz), 3.27 (dd, 1H, J = 17.1, 12.7 Hz), 2.78
(dd, 1H, J = 17.1, 2.8 Hz); 13C{1H}-NMR (CD3OD, 125 MHz) δ 197.3, 168.4, 165.5, 164.7, 140.4,
129.7, 129.6, 127.3, 103.4, 97.2, 96.2, 80.4, 44.2; HR-MS (EI+) calcd for C15H12O4 256.0736, found
256.0735.
Pinostrobin (13).21b Yield 16.9 mg (77%) from 23.0 mg (0.08 mmol) of 3hh as a yellow solid; mp 96-
1
97 °C; H-NMR (CDCl3, 400 MHz) δ 12.03 (s, 1H), 7.50-7.35 (m, 5H), 6.08 (d, 1H, J = 2.0 Hz), 6.08
(d, 1H, J = 3.9 Hz), 5.42 (dd, 1H, J = 13.0, 2.7 Hz), 3.81 (s, 3H), 3.09 (dd, 1H, J = 17.1, 13.1 Hz), 2.82
(dd, 1H, J = 17.1, 2.9 Hz); 13C{1H}-NMR (CDCl3, 125 MHz) δ 195.9, 168.1, 164.3, 162.9, 138.5,
129.0, 126.3, 103.3, 95.3, 94.4, 79.4, 55.8, 43.5; HR-MS (EI+) calcd for C16H14O4 270.0892, found
270.0895.
General procedure for scaled up palladium(II)-catalyzed β-arylation to 7. To a 25 mL two
neck round bottom flask, 7-methoxy-4-chromanone 5 (535.0 mg, 3.0 mmol, 1.0 equiv.), Pd(TFA)2
(150.0mg, 0.45 mmol, 15 mol%), and 2,2′-bipyridine (141.0mg, 0.90 mmol, 30 mol%) were added and
then dissolved with anhydrous DMSO/dioxane (1:4) (4.0 mL). Under an oxygen (balloon) atmosphere,
the reaction mixture was stirred at 100 °C in oil bath with reflux condenser until complete conversion
of the starting material to chromone on TLC. Then, the reaction temperature was lowered to 80 °C
and a solution of 4-methoxyphenylboronic acid (1.37 g, 9.0 mmol, 3.0 equiv.) and TFA (230.0 μL, 3.0
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mmol, 1.0 equiv.) in anhydrous DMSO/dioxane (1:4) (4.0 mL) was added dropwise to flask. The
reaction mixture was stirred until complete consumption of chromone. Then, the reaction mixture was
cooled to room temperature. 2N aq. HCl was added and the resulting mixture was extracted with
EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography to give liquiritigenin dimethyl ether 7 (679.7
mg, 80%).
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General procedure for kinetic analysis of palladium(II)-catalyzed dehydrogenation of 4-
chromanone in acidic condition. To a 10 mL two neck round bottom flask, 4-chromanone 1a (50.0
mg, 0.337 mmol, 1.0 equiv.), Pd(TFA)2 (17.0 mg, 0.051 mmol, 15 mol%), 2,2′-bipyridine (15.9 mg,
0.102 mmol, 30 mol%), and TFA (26.0 μL, 0.337 mmol, 1.00 equiv.) were added and then dissolved
with anhydrous DMSO/dioxane (1:4) (1.0 mL). Under an oxygen (balloon) atmosphere, the reaction
mixture was stirred at 100 °C in oil bath with reflux condenser for the indicated time. Then, the
reaction mixture was cooled to room temperature. 2N aq. HCl was added and the resulting mixture
was extracted with EtOAc. The combined organic layers were dried with MgSO4 and concentrated in
vacuo. The residue was purified by silica gel column chromatography.
General procedure for kinetic analysis of palladium(II)-catalyzed β-arylation to flavanone
3a. To a 10 mL two neck round bottom flask, 4-chromanone 1a (50.0 mg, 0.337 mmol, 1.0 equiv.),
Pd(TFA)2 (17.0 mg, 0.051 mmol, 15 mol%), and 2,2′-bipyridine (15.9 mg, 0.102 mmol, 30 mol%) were
added and then dissolved with anhydrous DMSO/dioxane (1:4) (0.5 mL). Under an oxygen (balloon)
atmosphere, the reaction mixture was stirred at 100 °C in oil bath with reflux condenser for the
indicated time. After 960 minutes, the reaction temperature was lowered to 80 °C and a solution of
phenylboronic acid (123.3 mg, 1.011 mmol, 3.0 equiv.) and TFA (26.0 μL, 0.337 mmol, 1.0 equiv.) in
anhydrous DMSO/dioxane (1:4) (0.5 mL) was added dropwise to flask with stirring for the indicated
time. Then, the reaction mixture was cooled to room temperature. 2N aq. HCl was added and the
resulting mixture was extracted with EtOAc. The combined organic layers were dried with MgSO4,
filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography.
General procedure for kinetic analysis of all-in-one palladium(II)-catalyzed β-arylation to
flavanone 3u. To a 10 mL two neck round bottom flask, 4-chromanone 1a (50.0 mg, 0.337 mmol, 1.0
equiv.), Pd(TFA)2 (17.0 mg, 0.051 mmol, 15 mol%), 2,2′-bipyridine (15.9 mg, 0.102 mmol, 30 mol%),
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The Journal of Organic Chemistry
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3,4-dimethoxyphenylboronic acid (183.8 mg, 1.01 mmol, 3.00 equiv.), and TFA (26.0 μL, 0.337 mmol,
1.00 equiv.) were added and then dissolved with anhydrous DMSO/dioxane (1:4) (1.0 mL). Under an
oxygen (balloon) atmosphere, the reaction mixture was stirred at 100 °C in oil bath with reflux
condenser for the indicated time. Then, the reaction mixture was cooled to room temperature. 2N aq.
HCl was added and the resulting mixture was extracted with EtOAc. The combined organic layers
were dried with MgSO4 and concentrated in vacuo. The residue was purified by silica gel column
chromatography.
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ASSOCIATED CONTENT
Supporting Information
Reaction optimization and reaction profiles (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: kimnj@khu.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the Basic Science Research Program through the National Research
Foundation of Korea (NRF), which was funded by the Ministry of Science, ICT & Future Planning
(NRF-2016R1A2B4015169).
References
(1) Nijveldt, R. J.; van Nood, E.; van Hoorn, D. E.; Boelens, P. G.; van Norren, K.; van Leeuwen, P. A.
Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr.
2001, 74, 418.
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