Synthesis of 3-(2-Olefinbenzyl)-4H-chromen-4-one through Cyclobenzylation and Catalytic C-H Bond Functionalization Using Palladium(II)

Article abstract of DOI:10.1021/acs.joc.7b01626

An efficient strategy for synthesizing 3-(2-olefinbenzyl)-4H-chromen-4-one in two steps was developed. The first step is a cyclobenzylation reaction between (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one and benzyl bromide to produce homoisoflav

Full text of DOI:10.1021/acs.joc.7b01626

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Article
Synthesis of 3-(2-Olefinbenzyl)-4H-chromen-4-one through Cyclobenzylation
and Catalytic C–H Bond Functionalization Using Palladium (II)
Yu-Feng Lin, Chi Fong, Wan-Ling Peng, Kuei-Chien Tang, Yi-En Liang, and Wen-Tai Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01626 • Publication Date (Web): 21 Sep 2017
Downloaded from http://pubs.acs.org on September 22, 2017
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Synthesis of 3-(2-Olefinbenzyl)-4H-chromen-4-one through
Cyclobenzylation and Catalytic C–H Bond Functionalization
Using Palladium (II)
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YuꢀFeng Lin, Chi Fong, WanꢀLing Peng, KueiꢀChien Tang, YiꢀEn Liang, and WenꢀTai
Li*
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei
11221, Taiwan, R.O.C.
*Email: wtli@nricm.edu.tw
Cyclobenzylationreaction
π-Chelating assisted C-H bond olefination
O
O
O
O
Pd catalyst
R1
BnBr
N
R1
R1
NaI
H
R2
OH
O
R3
R2
R3
24 examples
71-84% yield
34 examples
66-84% yield
ABSTRACT
An efficient strategy for synthesizing 3ꢀ(2ꢀolefinbenzyl)ꢀ4Hꢀchromenꢀ4ꢀone in two
steps was developed. The first step is a cyclobenzylation reaction between
(E)ꢀ3ꢀ(dimethylamino)ꢀ1ꢀ(2ꢀhydroxyphenyl)propꢀ2ꢀenꢀ1ꢀone and benzyl bromide to
produce homoisoflavonoid. The second step involves intermolecular Pdꢀcatalyzed
πꢀchelatingꢀassisted C−H bond olefination. Using the Cꢀ2/Cꢀ3 double bond of chromone,
palladiumꢀcatalyzed aryl C−H bond activation can be functionalized to generate
orthoꢀolefination derivatives in moderate to high yields.
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INTRODUCTION
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The directed activation of C−H bonds catalyzed by transition metal complexes into
useful functional groups has proven extremely valuable, and the versatility and
practicality of this strategy in organic synthesis has been demonstrated.1 The
methodology involved in the directed activation of CꢀH bonds is attractive to synthetic
chemists because the transformation is simple and the synthetic route is efficient (i.e.
does not include extra steps). The C−H bond functionalization between arenes and olefins
can be achieved through the introduction of a directing group, and this is commonly
known as the Fujiwara−Moritani reaction.2 The directing group comprises an Nꢀ or
Oꢀcontaining functional group, such as an acylamino, carboxylic acid, oxazoline, or
Nꢀheteroaryl group.3ꢀ5 Most directing groups involve the σꢀcoordination of metal catalysts;
however, few researchers have reported on C=C double bond (πꢀchelating)ꢀassisted C−H
bond olefination using a palladium catalyst.6ꢀ7 Moreover, a small number of studies have
reported intermolecular C−H olefination reactions assisted by πꢀchelating C=C bonds,
most of which have limited their focus to reactions involving an allylbenzene substrate.
Chromone forms the core structure of several flavonoids, and chromone and its
derivatives are found in numerous natural products.8 Chromone fragments are highly
versatile building blocks that are used in the construction of various heterocyclic
compounds. Furthermore, chromone is classified as a “privileged structure” and is found
in a wide variety of pharmacologically active compounds (e.g. homoisoflavonoids) that
are used in the treatment of angiogenesisꢀmediated diseases and in the development of
anticancer agents.9ꢀ10 Recently, allylic groups have been successfully employed in the
orthoꢀalkenylation of arenes, which prompted us to explore whether the Cꢀ2/Cꢀ3 double
bond of chromone could be used as a directing group in intermolecular C−H activation
and olefination reactions. Herein, we report an efficient process that can be applied to
synthesize 3ꢀ(2ꢀolefinbenzyl)ꢀ4Hꢀchromenꢀ4ꢀone for use as a biologically active
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compound. The olefin reduction products of 3ꢀ(2ꢀolefinbenzyl)ꢀ4Hꢀchromenꢀ4ꢀones have
been shown to inhibit aldose reductase, which is a potential target in the treatment of
diabetes complications.11 Our proposed synthesis method involves a twoꢀstep reaction, as
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follows:
(E)ꢀ3ꢀ(dimethylamino)ꢀ1ꢀ(2ꢀhydroxyphenyl)propꢀ2ꢀenꢀ1ꢀone using benzyl bromide to
produce homoisoflavonoid, followed by (2) Pdꢀcatalyzed ꢀchelatingꢀassisted C−H bond
(1)
the
cyclobenzylation
of
π
olefination. We found that employing the Cꢀ2/Cꢀ3 double bond of chromone allows
palladiumꢀcatalyzed aryl C−H bonds to be functionalized efficiently to generate
orthoꢀolefination derivatives in moderate to high yields (Scheme 1).
Scheme 1. Strategy for synthesis of 3ꢀ(2ꢀolefinbenzyl)ꢀ4Hꢀchromenꢀ4ꢀone
Cyclobenzylationreaction
O
O
O
O
O
Pd catalyst
R3
BnBr
NaI
N
3
3
2
R1
R1
R1
2 H
R2
OH
R2
R3
O
3
R1
O
2 Pd
R2
π
-Chelating assisted C-H bond olefination
RESULTS AND DISCUSSION
Synthesis was
initiated
by
directly
converting
(E)ꢀ3ꢀ(dimethylamino)ꢀ1ꢀ(2ꢀhydroxyphenyl)propꢀ2ꢀenꢀ1ꢀone 1a and benzyl bromide into
homoisoflavonoid 2a through electrophilic cyclobenzylation.12 To achieve this, 1a was
heated with benzyl bromide in DMF to produce cyclobenzylation product 2a and
cyclization product 2a’ at a ratio of approximately 2:1. Additive(s) (listed in Table 1)
were then used to optimize the reaction (i.e. to increase the yield of cyclobenzylation
product 2a and to reduce the yield of cyclization product 2a’). To elucidate the effects of
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various additives, NaI and KI were individually examined under the same reaction
conditions. We determined that 2a was produced in satisfactory yields when NaI was used
as an additive in acetone under heating conditions. The presence of alkaline metal iodide
might undergo the Finkelstein reaction, which results in a halide exchange involving
benzyl bromide. This further improved the yield of the cyclobenzylation product. We next
sought to determine whether using an additive of NaI combined with silver salt or TMSCl
as an activator could further optimize reaction conditions; however, the presence of silver
salt was found to hamper cyclobenzylation and cyclization, and the addition of TMSCl
did not improve the cyclobenzylation yield. Results of these evaluations are summarized
in Table 1.
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Table 1. Optimization studies for the cyclobenzylation reaction of 1a and benzyl bromidea
entry
additive(s)
solvent
2a yield (%)b
2a’ yield (%)b
1
2
ꢀ
DMF
CH3CN
CH2Cl2
acetone
DMF
54c
46
26c
35
29
25
12c
14
ꢀ
10c
13
34
20
ꢀ
3
ꢀ
48
4
ꢀ
NaI
57
72c
5
6
NaI
CH2Cl2
acetone
DMF
69
7
NaI
80c
68c
64
8
KI
9
NaI + TMSCl
NaI + AgNO3
NaI + AgOTf
DMF
10
DMF
42
11
DMF
51
aUnless otherwise mentioned, all reactions were carried out using 1a (1.0 mmol), benzyl
o
bromide (1.0 mmol), additive(s) (3.0 mmol), 4Å molecular sieves, and solvent at 80 C
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b
1
for 5 h. Yields were determined by the H NMR integration method using mesitylene as
the internal standard. cIsolated yield.
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Results of both the current study (shown in Table 1) and previous studies suggest a
plausible mechanism for the cyclobenzylation of 1a and benzyl bromide, which is shown
in Scheme 2.12 In brief, intramolecular cycloaddition of a hydroxy group with iminium
generates intermediate A, and intermediate A is then benzylated with benzyl iodide to
produce intermediate B. Finally, elimination of dimethyl amine generates the desired
homoisoflavone 2a.
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Scheme 2. Proposed mechanism underlying cyclobenzylation reaction
O
O
I
O
+
Ph
O
O
O
O
O
O
N
N
O
H
OH
O
N
1a
A
I
O
O
O
H
HNMe2+I-
O
O
O
Ph
Ph
O
O
N
B
2a
Having obtained the cyclobenzylation product 2a, we next sought to perform
πꢀchelatingꢀassisted C−H bond catalytic olefination in Pd. This reaction was initiated by
adding homoisoflavonoid 2a and nꢀbutyl acrylate to dichloromethane in the presence of
Pd(OAc)2 (10 mol%) and TFA (20 equiv). We then evaluated the ability of various
combinations of oxidants and solvents to increase the reaction yield of 3a. Among the
oxidants, O2 and K2S2O8 were found to be most effective. The other oxidants were far less
effective, leading to the production of 3a in the following yields: Cu(OAc)2 (22%), Ag2O
(15%), AgOAc (trace), PhI(OAc)2 (0%), and O2 + Cu(OAc)2 (41%). Using DCE as a
cosolvent achieved yields that were similar to those obtained when DCM was used (Table
2, entries 7 and 8), whereas other cosolvents (DMF, ACN, toluene, and THF) reduced
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reaction yields. The structure of 3a was confirmed by 1H and 13C NMR spectra as well as
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by mass data.13
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Table 2. Screening conditions for Pdꢀcatalyzed olefination of homoisoflavonoid 2a with
nꢀbutyl acrylatea
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entry
1
Pd catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
PdCl2
oxidant
O2
solvent
TFA/DCM
TFA/DCM
TFA/DCM
TFA/DCM
TFA/DCM
TFA/DCM
TFA/DCM
TFA/DCE
temp oC/time h yield %c
25/36
80/36
80/36
80/36
80/36
80/36
80/36
80/36
80/36
80/36
80/36
80/36
80/36
80/36
80/36
80/12
80/24
80/48
80/48
80/36
80/36
80/36
80/36
80/36
76b,d
22
15
trace
ꢀ
41b
83d
82d
18
ꢀ
2
Cu(OAc)2
Ag2O
3
4
AgOAc
PhI(OAc)2
O2 + Cu(OAc)2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
ꢀ
5
6
7
8
9
TFA/DCM
TFA/DCM
AcOH/DCM
PivOH/DCM
TFA/DCM
TFA
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11
12
13
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15
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20
21
22
23
24
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
ꢀ
62d,e
ꢀ
TFE/DCM
TFA/DCM
TFA/DCM
TFA/DCM
TFA/DCE
trace
44
72
76
69
ꢀ
TFA/DCM
TFA(30 eq)/DCM
TFA(10 eq)/DCM
TFA(5 eq)/DCM
DCM
K2S2O8
K2S2O8
K2S2O8
K2S2O8
67
78
58
ꢀ
aUnless otherwise mentioned, all reactions were carried out using 2a (1.0 mmol), nꢀbutyl
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acrylate (1.0 mmol), Pd catalyst (10 mol %), oxidant (2.0 mmol), TFA (20 eq), and
b
c
solvent (6.0 mL). Reaction was performed under one atmosphere of O2. Yields were
determined by the 1H NMR integration method using mesitylene as the internal standard.
dIsolated yield. e4Å molecular sieves were added.
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Results of these tests revealed that the highest yield of 3a (83%) was obtained when
the reaction was conducted in TFA/DCM in the presence of the oxidant K2S2O8 at a
temperature of 80 oC. However, when the reaction was conducted under mild conditions
and molecular oxygen was employed as the terminal oxidant, the yield was only slightly
lower. Moreover, a higher concentration of TFA resulted in a slight decrease in the yield
of 3a, whereas weaker acids (AcOH or PivOH) greatly inhibited 3a formation. We also
investigated the efficiency of various Pd catalysts, including PdCl2, Pd(PPh3)2Cl2, and
Pd(OH)2/C. Of these, only Pd(PPh3)2Cl2 presented catalytic activity, resulting in an 18%
yield of 3a. The other catalysts were completely inactive. In addition, the olefination
process was observed to be largely insensitive to the presence of water, and the yield was
not improved when the reaction was performed using molecular sieves (Table 2, entry 7
vs. entry 13). Considering all screening tests, the best results were obtained when 2a was
treated with 10 mol% of Pd(OAc)2 and 2 equiv. of K2S2O8 in TFA/DCM under heating
(80 °C) over a period of 36 h. Nonetheless, molecular oxygen was only slightly less
efficient than K2S2O8 as a terminal oxidant. Oxygen is more environmentally friendly, and
it also provides milder reaction conditions. Therefore, oxygen was employed as the
terminal oxidant in subsequent reactions.
Having determined the optimal reaction conditions, we next investigated the ability
of various olefins to facilitate the olefination of homoisoflavonoids 2. Olefins including
methyl acrylate, ethyl acrylate, nꢀbutyl acrylate, phenyl acrylate, acrylic acid,
3ꢀbutenꢀ2ꢀone, and phenyl vinyl sulfone all produced the desired products at satisfactory
yields
(Table
3).
However,
other
olefins,
such
as
styrene,
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1,2,3ꢀtrimethoxyꢀ5ꢀvinylbenzene, and methyl 2ꢀ((tertꢀbutoxycarbonyl)amino)acrylate,
failed to produce the corresponding orthoꢀolefination products under the same reaction
conditions. The substitution effect of this reaction with respect to the Pd catalytic
πꢀchelatingꢀassisted reaction was then investigated. Incorporating an additional methoxy
group on the benzyl ring was found to slightly reduce the yield compared with
compounds 3l, 3m and 3r, 3s (Table 3). Conversely, a substitution in the sixth or seventh
position of 4Hꢀchromenꢀ4ꢀone had almost no effect on product yield (3p to 3x). Notably,
incorporating an additional fluoro or chloro atom on the 4Hꢀchromenꢀ4ꢀone ring
(compounds 3j, 3k, 3n, and 3o) did not alter the yield; however, 3n and 3o, both of which
contained a 3,4ꢀdimethoxy group on the benzyl ring, delivered a higher yield than did 3j
or 3k. Furthermore, 3ꢀbenzylꢀ4Hꢀchromenꢀ4ꢀones that contained an electronꢀwithdrawing
NO2 group (i.e. compound 2ai) or a halogen F (i.e. compound 2aj) at the paraꢀposition of
the benzyl ring failed to undergo orthoꢀolefination. The methyl ester group and other
halogens (Cl and Br) on the benzyl ring were given in trace amounts of olefination
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products. Generally, we found that chromone πꢀbond directed CꢀH bond functionalization
was able to generate the olefination products of a broad variety of homoisoflavonoids in
good yields. However, it is worth noting that, when the reaction was carried out with
excessive ethyl acrylate (up to 5 equiv.), no difunctionalization products were observed.
The olefination of 4ꢀchromanone 4 was also investigated using ethyl acrylate and the
Pd catalyst under the same reaction conditions as those described earlier. However,
olefination product 5 was not obtained (Scheme 3). This finding as well as findings
related to the Pdꢀcatalyzed olefination of homoisoflavonoids 2 indicate that the chromone
C=C πꢀbond is an influential directing group in the olefination reactions. Therefore, we
posit that the reaction pathway associated with the olefination of homoisoflavonoids 2 is
likely similar to the pathway associated with the olefination of allyl benzene, as outlined
in previous reports.
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Table 3. Scope of the Pd(II)ꢀcatalyzed olefination of homoisoflavonoidsa
R
6
7
8
9
O
O
R"
Pd(OAc)2 (0.1eq)
R
R'
+
R'
O2 (1 atm)
O
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O
TFA/CH2Cl2
rt, 36 h
R"
3
2
O
O
O
O
O
X
OMe
OMe
O
O
O
O
O
nBuO2C
R
R
3a R = CO2nBu; 76%
3d R = CO2Me; 81%
3e R = CO2Et; 84%
3f R = CO2nBu; 78%
3g R = SO2Ph; 71%
3h R = CO2Ph; 73%
3i R = CO2H; 66%
O
3j X = F; 75%
3k X = Cl; 78%
3b R = CO2Ph; 73%
OMe O
O
O
O
OMe
OMe
OMe
OMe
MeO
MeO
X
O
O
nBuO2C
R'
R
3c 81%
O
3p R = CO2Me, R' = OMe; 71%
3q R = CO2Et, R' = OMe; 73%
3r R = CO2nBu, R' = OMe; 78%
3s R = CO2nBu, R' = H; 72%
3t R = CO2Et, R' = H; 77%
nBuO2C
O
3n X = F; 77%
3o X = Cl; 80%
OMe
OMe
O
MeO
BnO
O
OMe
OMe
MeO
R'
O
O
nBuO2C
O
3l R' = H; 71%
3m R' = OMe; 67%
R
R'
O
O
OMe
R
O
O
O
3y R = CO2Me; 76%
3z R = CO2nBu; 72%
OMe
OMe
EtO2C
3aa R = Me, R' = H; 76%
3ab R = Cl, R' = H; 74%
3ac R = H, R' = H; 70%
3ad R = H, R' = Me; 77%
3ae R = H, R' = OMe; 72%
3af R, R' = -OCH2O-; 69%
OMe O
O
R'
R
O
3u R = CO2Me, R' = OMe; 72%
3v R = CO2Et, R' = OMe; 74%
3w R = CO2nBu, R' = OMe; 76%
3x R = CO2nBu, R' = H; 73%
O
O
nBuO2C
3ag 81%
O
O
O
OMe
O
O
Me
O
NO2
O
F
Me
O
OMe
MeOC
nBuO2C
nBuO2C
3ai 0%b
3aj 0%b
3ah 74%
aUnless otherwise mentioned, all reactions were performed using 2 (1.0 mmol), olefin (1.0
b
mmol), Pd catalyst (10 mol %), O2 (1 atm), TFA (20 eq), and solvent (6.0 mL). Starting
material was recovered.
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Scheme 3. Pd(II)ꢀcatalyzed olefination of 4ꢀchromanone
O
6
7
8
9
O
OMe
OMe
Pd(OAc)2 (0.1eq)
CO2Et
OMe
OMe
+
O2, rt,
O
O
TFA/CH2Cl2
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EtO2C
4
5
One possible mechanism underlying the πꢀassisted olefination reaction is outlined in
Scheme 4. Based on the results obtained in the current study and known Pdꢀcatalyzed
C−H activation reactions, we posit that electrophilic [Pd(TFA)]+ species should form in
the presence of Pd(OAc)2 and TFA.7,14ꢀ15 Indeed, the highly electrophilic Pd(II) species
generated from this reaction for the coordination of the C=C πꢀbond in 2 leads to the
formation of the intermediate A’. Subsequently, metalation of the aryl C−H bond forms
the Pd(II) σꢀaryl complex B’. The oxidative addition of the activated olefin to
Pd(II)ꢀcomplex B’ followed by the elimination of βꢀhydride then yields the corresponding
product 3 as well as the Pd(0) species. Finally, Pd(0) is reoxidized to form the
catalytically active [Pd(TFA)]+ species using molecular oxygen, which completes the
catalytic cycle.
Conversely, olefination of the chromanone 4 product was not observed under the
same reaction conditions. This indicates that the carbonyl group of
3ꢀbenzylꢀ4Hꢀchromenꢀ4ꢀone did not act as the directing group in the orthoꢀmetalation of
the benzylic ring (through a sevenꢀmemberedꢀring palladacycle) (Scheme 3).16
Scheme 4. Proposed mechanism underlying the Pdꢀcatalyzed olefination of
homoisoflavonoids
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CONCLUSIONS
This study demonstrated the synthesis of 3ꢀ(2ꢀolefinbenzyl)ꢀ4Hꢀchromenꢀ4ꢀone in a
twoꢀstep process involving cyclobenzylation and Pdꢀcatalyzed ꢀchelatingꢀassisted C−H
π
bond olefination. Specifically, a homoisoflavonoid scaffold was constructed through the
cyclobenzylation of (E)ꢀ3ꢀ(dimethylamino)ꢀ1ꢀ(2ꢀhydroxyphenyl)propꢀ2ꢀenꢀ1ꢀone and
benzyl bromide. Subsequently, with the assistance of the Cꢀ2/Cꢀ3 double bond of
chromone
πꢀchelation, the Pdꢀcatalyzed benzyl C−H bonds were functionalized to
generate orthoꢀolefination derivatives.
EXPERIMENTAL SECTION
General information. All reagents were used as received from commercial suppliers
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unless otherwise stated. Dichloromethane (DCM) and N,N’ꢀdimethylformamide (DMF)
were dried over calcium hydride for 48 h prior to distillation. The proton NMR spectra
were obtained on Varian Unity Inova 500 (500 MHz) and Varian VNMRS 600 (600 MHz)
spectrometers. All NMR chemical shifts were reported as δ values in parts per million
(ppm), and coupling constants (J) were given in hertz (Hz). The splitting pattern
abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; br, broad; m,
unresolved multiplet due to the field strength of the instrument; dd, doublet of doublet;
and dt, doublet of triplet. Melting points were measured on a Yanaco MPꢀS3 micro
melting point apparatus and are uncorrected. Fourier transform infrared spectra were
collected with an Avatar 320 spectrometer. Highꢀresolution mass spectra were obtained
by using electrospray ionization (ESI-Quadrupole). Purification was performed using
preparative separations in flash column chromatography (Merck silica gel 60, particle size
of 230-400 mesh). Analytical TLC was carried out on precoated plates (Merck silica gel
60, F254). The compounds analyzed on the TLC plates were visualized using a UV light,
I2 vapor, or basic aqueous potassium permanganate (KMnO4) with heating.
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General procedure for the synthesis of 3-benzyl-4H-chromen-4-one 2a-2ai
through
cyclobenzylation
of
(E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one and benzyl bromide.
(E)ꢀ3ꢀ(Dimethylamino)ꢀ1ꢀ(2ꢀhydroxyphenyl)propꢀ2ꢀenꢀ1ꢀone was synthesized in
previously reported method.17 To
accordance with
a
a
solution of
(E)ꢀ3ꢀ(dimethylamino)ꢀ1ꢀ(2ꢀhydroxyphenyl)propꢀ2ꢀenꢀ1ꢀone (191 mg, 1.0 mmol), NaI
(450 mg, 3.0 mmol) and 4Å molecular sieves in acetone (15 mL) was added benzyl
bromide (0.12 mL, 1.0 mmol) dropwise. The reaction mixture was then heated to reflux
over a period of 5 h, as verified using thin layer chromatography (TLC). The reaction was
then quenched by addition of water, and the reaction mixture was filtered and extracted
with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine
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solution (15 mL), dried over MgSO4, and concentrated in vacuo. Finally, the residue was
purified by flash column chromatography (EtOAc/hexanes =1:4) to yield the desired
3ꢀbenzylꢀ4Hꢀchromenꢀ4ꢀone.
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General
procedure
for
the
Pd-catalyzed
olefination
of
3-benzyl-4H-chromen-4-ones 2a-2ai with alkenes.
In a 100 mL twoꢀnecked flask was placed 3ꢀbenzylꢀ4Hꢀchromenꢀ4ꢀone 2a-2aj (1.0
mmol) and Pd(OAc)2 (10 mol%), which was evacuated and then filled with oxygen gas.
Dichloromethane (6.0 ml) and trifluoroacetic acid (TFA) (1.5 mL, 20 equiv) were then
sequentially added to the flask. Following the addition of alkene (1.0 mmol), the mixture
was stirred under an oxygen atmosphere until the reaction had completed. The mixture
was then filtered through a Celite pad and washed with CH2Cl2 (20 mL). Finally, the
filtrate was concentrated, and the residue was purified by flash column chromatography
(EtOAc/hexanes = 1/4) to yield the desired olefination product. All the compounds shown
in Table 3 were prepared according to this procedure.
7-Benzyl-8H-[1,3]dioxolo[4,5-g]chromen-8-one (2a). Yellow solid; yield: 224 mg
(80%); Rf = 0.55 (EtOAc/hexanes = 1:4); mp 155ꢀ157 oC; IR (KBr) νmax 3064, 2909, 1639,
1611, 1473, 1390, 1131, 1039 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.51 (s, 1H), 7.49 (s,
1H), 7.30ꢀ7.26 (m, 4H), 7.21ꢀ7.18 (m, 1H), 6.77 (s, 1H), 6.05 (s, 2H), 3.77 (s, 2H); 13C
NMR (150 MHz, CDCl3) δ 176.4, 153.8, 152.5, 152.4, 146.0, 138.7, 129.0, 128.6, 126.5,
123.9, 118.8, 102.4, 102.3, 97.8, 31.6; HRMS (ESIꢀquadrupole) m/z: [M + 23]+ calcd for
C17H12O4Na 303.0633; Found 303.0624.
3-(3,4-Dimethoxybenzyl)-5,7-dimethoxy-4H-chromen-4-one (2c). Yellow solid; yield:
o
288 mg (81%); Rf = 0.45 (EtOAc/hexanes = 1:4); mp 133ꢀ135 C; IR (KBr) νmax 2936,
2360, 1610, 1513, 1207, 1082 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.32 (s, 1H), 6.80ꢀ6.76
(m, 3H), 6.34 (d, J = 2.4 Hz, 1H), 6.30 (d, J = 2.4 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.82
(s, 3H), 3.82 (s, 3H), 3.65 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 176.2, 163.7, 161.1,
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160.0, 150.5, 148.9, 147.5, 131.4, 125.8, 121.1, 112.4, 111.2, 109.3, 95.9, 92.4, 56.2, 55.9,
55.8, 55.6, 31.0; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C20H21O6 357.1333;
Found 357.1321.
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7-(3,4-Dimethoxybenzyl)-8H-[1,3]dioxolo[4,5-g]chromen-8-one (2d). Yellow solid;
o
yield: 272 mg (80%); Rf = 0.45 (EtOAc/hexanes = 1:4); mp 141ꢀ143 C; IR (KBr) νmax
1
3003, 1463, 1257, 1030 cmꢀ1; H NMR (600 MHz, CDCl3) δ 7.52 (s, 1H), 7.48 (s, 1H),
6.81ꢀ6.78 (m, 4H), 6.06 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.72 (s, 2H); 13C NMR (150
MHz, CDCl3) δ 176.4, 153.8, 152.5, 152.4, 149.0, 147.7, 146.0, 131.2, 124.2, 120.9,
118.8, 112.3, 111.3, 102.4, 102.3, 97.8, 55.9, 55.8, 31.2; HRMS (ESIꢀquadrupole) m/z: [M
+ 1]+ calcd for C19H17O6 341.1020; Found 341.1010.
3-Benzyl-6-fluoro-4H-chromen-4-one (2j). Yellow solid; yield: 195 mg (77%); Rf =
o
0.60 (EtOAc/hexanes = 1:4); mp 200ꢀ202 C; IR (KBr) νmax 3069, 2921, 1634, 1476,
1393, 1132 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.84 (dd, J = 7.8, 3.0 Hz, 1H), 7.59 (s,
1H), 7.40 (dd, J = 9.0, 4.2 Hz, 1H), 7.36ꢀ7.33 (m, 1H), 7.31ꢀ7.26 (m, 4H), 7.21 (dt, J =
4
6.6, 1.8 Hz, 1H), 3.80 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 176.7 (d, JC-F = 2.3 Hz),
1
3
159.4 (d, JC-F = 245.5 Hz), 153.3, 152.6, 138.3, 129.0, 128.6, 126.6, 124.8 (d, JC-F = 6.9
2
2
Hz), 124.1, 121.7 (d, JC-F = 25.2 Hz), 120.2, 110.7 (d, JC-F = 23.6 Hz), 31.6; HRMS
(ESIꢀquadrupole) m/z: [M + 1]+ calcd for C16H12O2F 255.0816; Found 255.0814.
3-Benzyl-6-chloro-4H-chromen-4-one (2k). Colorless solid; yield: 216 mg (80%); Rf
= 0.65 (EtOAc/hexanes = 1:4); mp 97ꢀ99 oC; IR (KBr) νmax 3023, 2926, 1638, 1465, 1381,
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1315, 1153 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.17 (d, J = 3.0 Hz, 1H), 7.57ꢀ7.54 (m,
2H), 7.35 (d, J = 9.0 Hz, 1H), 7.30ꢀ7.26 (m, 4H), 7.23ꢀ7.20 (m, 1H), 3.79 (s, 2H); 13C
NMR (150 MHz, CDCl3) δ 176.3, 154.7, 153.2, 138.2, 133.7, 130.9, 129.0, 128.7, 126.6,
125.4, 124.8, 124.7, 119.8, 31.6; HRMS (ESIꢀquadrupole) m/z: [M + 23]+ calcd for
C16H11O2ClNa 293.0340; Found 293.0335.
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3-(3,4-Dimethoxybenzyl)-7,8-dimethoxy-4H-chromen-4-one (2l). Yellow solid; yield:
o
277 mg (78%); Rf = 0.45 (EtOAc/hexanes = 1:4); mp 106ꢀ108 C; IR (KBr) νmax 2923,
1
1600, 1454, 1284, 1171, 1078 cmꢀ1; H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 9.0 Hz,
1H), 7.59 (s, 1H), 7.00 (d, J = 9.0 Hz, 1H), 6.81ꢀ6.77 (m, 3H), 3.95 (s, 3H), 3.91 (s, 3H),
3.83 (s, 3H), 3.82 (s, 3H), 3.72 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 177.0, 156.2,
152.8, 150.8, 149.0, 147.7, 136.5, 131.1, 124.2, 121.3, 120.9, 118.7, 112.3, 111.3, 110.0,
61.5, 56.4, 55.9, 55.8, 31.2; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C20H21O6
357.1333; Found 357.1329.
7,8-Dimethoxy-3-(3,4,5-trimethoxybenzyl)-4H-chromen-4-one (2m). Yellow solid;
o
yield: 274 mg (71%); Rf = 0.30 (EtOAc/hexanes = 1:4); mp 119ꢀ121 C; IR (KBr) νmax
2929, 1641, 1601, 1507, 1454, 1400, 1285, 1126 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.93
(d, J = 9.0 Hz, 1H), 7.61 (s, 1H), 7.0 (d J = 9.0 Hz, 1H), 6.48 (s, 2H), 3.95 (s, 3H), 3.91 (s,
3H), 3.80 (s, 6H), 3.78 (s, 3H), 3.70 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 176.9, 156.2,
153.2, 152.8, 150.8, 136.5, 136.5, 134.3, 123.8, 121.3, 118.6, 109.9, 105.9, 61.5, 60.8,
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56.4, 56.0, 31.8; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C21H23O7 387.1438;
Found 387.1434.
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3-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-fluoro-4H-chromen-4-one (2n). Yellow solid;
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o
yield: 241 mg (81%); Rf = 0.55 (EtOAc/hexanes = 1:4); mp 127ꢀ129 C; IR (KBr) νmax
2921, 2852, 1642, 1478, 1321, 1245, 1177, 1037 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.83
(dd, J = 8.4, 3.0 Hz, 1H), 7.61 (s, 1H), 7.40 (dd, J = 9.6, 4.2 Hz, 1H), 7.36ꢀ7.32 (m, 1H),
6.73 (d, J = 13.2 Hz, 1H), 6.72 (s, 2H), 5.90 (s, 2H), 3.70 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 176.7 (d, 4JC-F = 2.4 Hz), 160.2, 158.6, 153.2, 152.6 (d, 4JC-F = 1.2 Hz), 147.0 (d,
1JC-F = 232.8 Hz), 132.0, 124.9 (d, JC-F = 7.5 Hz), 124.1, 121.8, 121.7, 120.1 (d, JC-F
=
3
3
2
8.0 Hz), 110.6 (d, JC-F = 23.6 Hz), 109.4, 108.3, 100.9, 31.3; HRMS (ESIꢀquadrupole)
m/z: [M + 1]+ calcd for C17H12O4F 299.0714; Found 299.0712.
3-(Benzo[d][1,3]dioxol-5-ylmethyl)-6-chloro-4H-chromen-4-one (2o). Yellow solid;
o
yield: 264 mg (84%); Rf = 0.55 (EtOAc/hexanes = 1:4); mp 133ꢀ135 C; IR (KBr) νmax
2922, 1643, 1500, 1464, 1245, 1145, 1036 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.16 (d, J
= 3.0 Hz, 1H), 7.59 (t, J = 1.2 Hz, 1H), 7.55 (dd, J = 9.0, 2.4 Hz, 1H), 7.35 (d, J = 9.0 Hz,
13
1H), 6.74ꢀ6.72 (m, 3H), 5.90 (s, 2H), 3.70 (s, 2H); C NMR (150 MHz, CDCl3) δ 176.3,
154.7, 153.2, 147.8, 146.3, 133.7, 131.9, 130.9, 125.3, 124.9, 124.7, 121.9, 119.8, 109.4,
108.4, 100.9, 31.3; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C17H12O4Cl
315.0419; Found 315.0414.
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7-Methoxy-3-(3,4,5-trimethoxybenzyl)-4H-chromen-4-one (2p). White solid; yield:
5
6
7
8
o
274 mg (77%); Rf = 0.35 (EtOAc/hexanes = 1:4); mp 109ꢀ111 C; IR (KBr) νmax Yield:
9
2938, 2838, 1637, 1608, 1440, 1239, 1125 cmꢀ1; 1H NMR (600 MHz, CDCl3) 8.12 (d, J =
9.0 Hz, 1H), 7.53 (s, 1H), 6.95 (dd, J = 9.0, 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.49 (s,
2H), 3.87 (s, 3H), 3.82 (s, 6H), 3.80 (s, 3H), 3.72 (s, 2H); 13C NMR (150 MHz, CDCl3)
176.8, 163.9, 158.2, 153.3, 152.7, 136.6, 134.5, 127.4, 124.3, 117.8, 114.5, 106.0, 100.1,
60.8, 56.1, 55.8, 31.9. HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C20H21O6
357.1333; Found 357.1330.
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3-(3,4-Dimethoxybenzyl)-7-methoxy-4H-chromen-4-one (2s). Yellow solid; yield:
o
248 mg (76%); Rf = 0.38 (EtOAc/hexanes = 1:4); mp 100ꢀ102 C; IR (KBr) νmax 2956,
2360, 1607, 1514, 1440, 1240, 1139, 1027 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.11 (d, J
= 9.0 Hz, 1H), 7.49 (s, 1H), 6.94 (dd, J = 9.0, 2.4 Hz, 1H), 6.81ꢀ6.79 (m, 3H), 6.76 (d, J =
2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.72 (s, 2H); 13C NMR (150 MHz,
CDCl3) δ 176.9, 163.9, 158.2, 152.6, 149.0, 147.7, 131.2, 127.4, 124.7, 121.0, 117.8,
114.4, 112.4, 111.3, 100.0, 55.9, 55.8, 55.7, 31.2; HRMS (ESIꢀquadrupole) m/z: [M + 1]+
calcd for C19H19O5 327.1227; Found 327.1227.
6-(Benzyloxy)-3-(3,4,5-trimethoxybenzyl)-4H-chromen-4-one (2u). Yellow solid;
o
yield: 350 mg (81%); Rf = 0.52 (EtOAc/hexanes = 1:4); mp 114ꢀ116 C; IR (KBr) νmax
3481, 2937, 1637, 1482, 1322, 1240, 1162, 1009 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.68
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(d, J = 3.0 Hz, 1H), 7.61 (s, 1H), 7.44 (d, J = 7.2 Hz, 2H), 7.38ꢀ7.30 (m, 3H), 7.33ꢀ7.29
(m, 2H), 6.50 (s, 2H), 5.13 (s, 2H), 3.82 (s, 6H), 3.81 (s, 3H), 3.74 (s, 2H); 13C NMR (150
MHz, CDCl3) δ 177.2, 155.9, 153.3, 153.0, 151.4, 136.6, 136.2, 134.4, 128.6, 128.2,
127.7, 124.4, 124.2, 123.6, 119.6, 106.2, 106.0, 70.6, 60.8, 56.1, 32.1; HRMS
(ESIꢀquadrupole) m/z: [M + 1]+ calcd for C26H25O6 433.1646; Found 433.1640.
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6-(Benzyloxy)-3-(3,4-dimethoxybenzyl)-4H-chromen-4-one (2x). Yellow solid; yield:
305 mg (76%); Rf = 0.57 (EtOAc/hexanes = 1:4); mp 95ꢀ97 oC; IR (KBr) νmax 2925, 1639,
1482, 1451, 1322, 1261, 1139, 1027 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 3.0
Hz, 1H), 7.56 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.34ꢀ7.27 (m, 3H),
6.83ꢀ6.77 (m, 3H), 5.10 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.74 (s, 2H); 13C NMR (150
MHz, CDCl3) δ 177.2, 155.8, 152.9, 151.3, 148.9, 147.6, 136.2, 131.1, 128.6, 128.1,
127.6, 124.3, 124.0, 123.9, 120.9, 119.4, 112.2, 111.2, 106.0, 70.5, 55.8, 55.7, 31.3;
HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C25H23O5 403.1540; Found 403.1538.
7-(3,4,5-Trimethoxybenzyl)-8H-[1,3]dioxolo[4,5-g]chromen-8-one (2y). Yellow
o
solid; yield: 299 mg (81%); Rf = 0.37 (EtOAc/hexanes = 1:4); mp 189ꢀ191 C; IR (KBr)
ν
max 2938, 1641, 1590, 1464, 1256, 1125 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.52 (s, 1H),
7.51 (s, 1H), 6.79 (s, 1H), 6.48 (s, 2H), 6.07 (s, 2H), 3.82 (s, 6H), 3.80 (s, 3H), 3.71 (s,
2H); 13C NMR (150 MHz, CDCl3) δ 176.4, 153.8, 153.3, 152.6, 152.4, 146.1, 136.6,
134.4, 123.8, 118.8, 106.0, 102.4, 102.3, 97.8, 60.8, 56.1, 31.9; HRMS (ESIꢀquadrupole)
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m/z: [M + 1]+ calcd for C20H19O7 371.1125; Found 371.1115.
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3-(Benzo[d][1,3]dioxol-5-ylmethyl)-5-methoxy-4H-chromen-4-one (2ag). Yellow
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o
solid; yield: 232 mg (75%); Rf = 0.53 (EtOAc/hexanes = 1:4); mp 115ꢀ117 C; IR (KBr)
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νmax 2895, 1646, 1475, 1360, 1246, 1159, 1075 cmꢀ1; H NMR (600 MHz, CDCl3) δ
7.50ꢀ7.47 (m, 2H), 6.94 (dd, J = 9.0, 0.6 Hz, 1H), 6.77ꢀ6.70 (m, 4H), 5.89 (s, 2H), 3.97 (s,
3H), 3.65 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 177.0, 160.0, 158.5, 151.0, 147.6, 146.0,
133.5, 132.6, 125.8, 122.0, 114.6, 110.0, 109.6, 108.2, 105.9, 100.8, 56.3, 31.3; HRMS
(ESIꢀquadrupole) m/z: [M + 1]+ calcd for C18H15O5 311.0914; Found 311.0907.
3-(3,4-Dimethoxybenzyl)-7-methyl-4H-chromen-4-one (2ah). Yellow solid; yield:
o
220 mg (71%); Rf = 0.20 (EtOAc/hexanes = 1:4); mp 142ꢀ145 C; IR (KBr) νmax 3070,
1
2933, 2834, 1643, 1513, 1426, 1352, 1261, 1139 cmꢀ1; H NMR (600 MHz, CDCl3) δ
8.07 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 1.2 Hz, 1H), 7.17ꢀ7.15 (m, 2H), 6.81ꢀ6.78 (m, 3H),
3.83 (s, 3H), 3.82 (s, 3H), 3.72 (s, 2H), 2.43 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 177.3,
156.5, 152.8, 149.0, 147.6, 144.7, 131.2, 126.4, 125.6, 124.6, 121.6, 120.9, 117.6, 112.3,
111.3, 55.9, 55.8, 31.2, 21.7; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C19H19O4
311.1278; Found 311.1278.
3-(3-Chlorobenzyl)-4H-chromen-4-one (2ak). Yellow solid; yield: 189 mg (70%); Rf
o
= 0.67 (EtOAc/hexanes = 1:4); mp 105ꢀ107 C; IR (KBr) νmax 3067, 2922, 1643, 1609,
1466, 1350, 1141 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.15 (dd, J = 8.0, 1.2 Hz, 1H), 7.63
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(s, 1H), 7.57 (dt, J = 8.4, 1.2 Hz, 1H), 7.35ꢀ7.28 (m, 2H), 7.24 (s, 1H), 7.17ꢀ7.12 (m, 3H),
3.72 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 176.9, 156.2, 152.9, 140.7, 134.1, 133.3,
129.6, 128.7, 127.0, 126.5, 125.6, 124.8, 123.6, 123.5, 117.9, 31.2; HRMS
(ESIꢀquadrupole) m/z: [M + 23]+ calcd for C16H12O2Cl 271.0519; Found 271.0520.
3-(4-Bromobenzyl)-4H-chromen-4-one (2al). Yellow solid; yield: 226 mg (72%); Rf
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= 0.65 (EtOAc/hexanes = 1:4); mp 157ꢀ159 C; IR (KBr) νmax 3065, 2921, 1635, 1486,
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1465, 1351, 1141 cmꢀ1; H NMR (500 MHz, CDCl3) δ 8.19 (dd, J = 8.0, 2.0 Hz, 1H),
7.65ꢀ7.61 (m, 2H), 7.41ꢀ7.35 (m, 4H), 7.16 (d, J = 6.5 Hz, 2H), 3.74 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 177.3, 156.4, 153.0, 137.7, 133.5, 131.6, 130.7, 125.9, 125.0, 124.0,
123.8, 120.4, 118.0, 31.2. HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C16H12O2Br
315.0015; Found 315.0014.
Methyl 4-((4-oxo-4H-chromen-3-yl)methyl)benzoate (2am). Yellow solid; yield: 229
o
mg (78%); Rf = 0.45 (EtOAc/hexanes = 1:4); mp 174ꢀ176 C; IR (KBr) νmax 3060, 2952,
1710, 1633, 1609, 1467, 1282, 1106 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 8.20 (dd, J = 8.0,
1.5 Hz, 1H), 7.95 (d, J = 6.5 Hz, 2H), 7.66ꢀ7.62 (m, 2H), 7.42ꢀ7.34 (m, 4H), 3.88 (s, 3H),
3.85 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 177.3, 166.7, 156.5, 153.1, 144.2, 133.6,
129.9, 128.9, 128.5, 126.0, 125.1, 123.8, 118.1, 110.0, 52.0, 31.8; HRMS (ESIꢀquadrupole)
m/z: [M + 1]+ calcd for C18H15O4 295.0965; Found 295.0965
Butyl (E)-3-(2-((8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)methyl)phenyl)acrylate
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(3a). White solid; yield: 308 mg (76%); Rf = 0.50 (EtOAc/hexanes = 1:4); mp 156ꢀ158 oC;
IR (KBr) νmax 3065, 2910, 1612, 1475, 1391, 1262, 1199, 1132, 1040 cmꢀ1; 1H NMR (600
MHz, CDCl3) 7.92 (d, J = 15.6 Hz, 1H), 7.59 (dd, J = 7.2, 1.2 Hz, 1H), 7.53 (s, 1H),
7.33ꢀ7.27 (m, 4H), 6.77 (s, 1H), 6.35 (d, J = 15.6 Hz, 1H), 6.06 (s, 2H), 4.15 (t, J = 6.6 Hz,
2H), 3.93 (d, J = 1.2 Hz, 2H), 1.64ꢀ1.60 (m, 2H), 1.38ꢀ1.34 (m, 2H), 0.90 (t, J = 7.2 Hz,
3H); 13C NMR (150 MHz, CDCl3) 176.2, 166.8, 153.7, 152.6, 152.6, 146.1, 141.6, 137.5,
133.7, 131.0, 130.3, 128.8, 127.4, 126.8, 123.0, 120.3, 118.7, 102.4, 97.8, 64.5, 30.7, 29.0,
19.2, 13.7; HRMS (ESIꢀquadrupole) m/z: [M + 23]+ calcd for C24H22O6Na 429.1309;
Found 429.1308.
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Phenyl
(E)-3-(2-((8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)methyl)phenyl)acrylate (3b). White
o
solid; yield: 311 mg (73%); Rf = 0.25 (EtOAc/hexanes = 1:4); mp 190ꢀ192 C; IR (KBr)
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νmax 2922, 1462, 1257, 1137 cmꢀ1; H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 16.2 Hz,
1H), 7.67 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.38ꢀ7.30 (m, 5H), 7.21 (t, J = 7.2 Hz, 2H),
7.12 (d, J = 5.4 Hz, 2H), 6.78 (s, 1H), 6.54 (d, J = 16.2 Hz, 1H), 6.06 (s, 2H), 3.96 (s, 2H);
13C NMR (150 MHz, CDCl3) δ 176.2, 165.1, 153.8, 152.7, 152.6, 150.7, 146.1, 143.6,
137.9, 133.4, 131.1, 130.7, 129.4, 127.5, 127.0, 125.8, 123.0, 121.6, 119.3, 118.7, 102.4,
97.8, 97.8, 29.0; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C26H19O6 427.1176;
Found 427.1177.
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Butyl
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(E)-3-(2-((5,7-dimethoxy-4-oxo-4H-chromen-3-yl)methyl)-4,5-dimethoxyphenyl)acrylate
(3c). Yellow solid; yield: 390 mg (81%); Rf = 0.18 (EtOAc/hexanes = 1:2); mp 140ꢀ142
oC; IR (KBr) νmax 2926, 1706, 1609, 1514, 1166 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.83
(d, J = 15.6 Hz, 1H), 7.07 (d, J = 3.0 Hz, 2H), 6.80 (s, 1H), 6.33 (dd, J = 7.8, 2.4 Hz, 2H),
6.24 (d, J = 15.6 Hz, 1H), 4.14 (t, J = 6.6 Hz, 2H), 3.92 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H),
3.84 (s, 3H), 3.83 (s, 3H), 1.63ꢀ1.59 (m, 2H), 1.38ꢀ1.34 (m, 2H), 0.85 (t, J = 6.6 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 176.1, 167.1, 163.8, 161.1, 160.0, 151.0, 150.8, 148.1,
141.2, 131.6, 125.7, 125.0, 117.5, 113.7, 109.1, 108.7, 96.0, 92.4, 64.3, 56.3, 56.0, 55.9,
55.7, 30.7, 29.7, 19.2, 13.7; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C27H31O8
483.2013; Found 483.2012.
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Methyl
(E)-3-(4,5-dimethoxy-2-((8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)methyl)phenyl)acryl
ate (3d). Yellow solid; the Xꢀray structure of this compound was obtained; yield: 343 mg
(81%); Rf = 0.25 (EtOAc/hexanes = 1:2); mp 200ꢀ202 oC; IR (KBr) νmax 2921, 1709, 1641,
1463, 1256, 1168 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 15.6 Hz, 1H), 7.52 (s,
1H), 7.20 (s, 1H), 7.07 (s, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 6.26 (d, J = 15.6 Hz, 1H), 6.06
(s, 2H), 3.89 (s, 6H), 3.86 (s, 2H), 3.74 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 176.3,
167.4, 153.7, 152.7, 152.6, 151.1, 148.2, 146.1, 141.3, 131.4, 125.6, 123.4, 118.6, 117.2,
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113.5, 108.8, 102.4, 102.3, 97.8, 56.0, 55.9, 51.7, 28.5; HRMS (ESIꢀquadrupole) m/z: [M
+ 1]+ calcd for C23H21O8 425.1231; Found 425.1231.
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Ethyl
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(E)-3-(4,5-dimethoxy-2-((8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)methyl)phenyl)acryl
ate (3e). Colorless solid; yield: 368 mg (84%); Rf = 0.45 (EtOAc/hexanes = 1:2); mp
187ꢀ189 oC; IR (KBr) νmax 2922, 1704, 1641, 1463, 1256, 1171 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 7.86 (d, J = 16.2 Hz, 1H), 7.53 (s, 1H), 7.23 (s, 1H), 7.08 (s, 1H), 6.81 (s, 1H),
6.76 (s, 1H), 6.23 (d, J = 16.2 Hz, 1H), 6.06 (d, J = 2.4 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H),
3.90 (s, 3H), 3.89 (s, 3H), 3.86 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 176.2, 167.0, 153.7, 152.6, 152.6, 151.0, 148.2, 146.1, 141.1, 131.4, 125.7,
123.4, 118.7, 117.7, 113.6, 108.6, 102.4, 102.3, 97.8, 60.4, 56.0, 55.9, 29.7, 14.3; HRMS
(ESIꢀquadrupole) m/z: [M + 1]+ calcd for C24H23O8 439.1387; Found 439.1391.
Butyl
(E)-3-(4,5-dimethoxy-2-((8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)methyl)phenyl)acryl
ate (3f). Yellow solid; yield: 363 mg (78%); Rf = 0.58 (EtOAc/hexanes = 1:4); mp
137ꢀ139 oC; IR (KBr) νmax 2927, 2359, 1704, 1463, 1255, 1167 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 7.86 (d, J = 15.6 Hz, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 6.83 (s, 1H),
6.26 (s, 1H), 6.27 (d, J = 15.6 Hz, 1H), 6.07 (s, 2H), 4.15 (t, J = 7.2 Hz, 2H), 3.90 (s, 6H),
3.88 (s, 2H), 1.65ꢀ1.62 (m, 2H), 1.42ꢀ1.37 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR
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(150 MHz, CDCl3) δ 176.1, 167.0, 153.6, 152.6, 151.0, 148.1, 146.0, 141.0, 131.3, 125.6,
123.3, 118.5, 117.5, 113.5, 108.7, 102.3, 102.2, 97.7, 64.3, 55.9, 30.7, 29.6, 19.1, 13.6;
HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C26H27O8 467.1700; Found 467.1704.
7-(4,5-Dimethoxy-2-((E)-2-(phenylsulfonyl)vinyl)benzyl)-8H-[1,3]dioxolo[4,5-g]chr
omen-8-one (3g). Yellow solid; yield: 359 mg (71%); Rf = 0.21 (EtOAc/hexanes = 1:4);
mp 198ꢀ200 oC; IR (KBr) νmax 1640, 1511, 1463, 1142 cmꢀ1; 1H NMR (600 MHz, CDCl3)
δ 7.88ꢀ7.85 (m, 3H), 7.56ꢀ7.52 (m, 2H), 7.47ꢀ7.32 (m, 2H), 7.33 (s, 1H), 6.92 (s, 1H),
6.85 (s, 1H), 6.79 (s, 1H), 6.66 (d, J = 15.0 Hz, 1H), 6.09 (s, 2H), 3.88 (s, 2H), 3.87 (s,
3H), 3.84 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 176.1, 153.7, 152.8, 152.5, 151.7, 148.3,
146.2, 140.8, 139.5, 133.2, 132.5, 129.3, 127.6, 126.3, 123.4, 123.0, 118.7, 113.8, 103.1,
102.4, 102.3, 97.8, 56.1, 56.0, 28.8; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for
C27H23O8S 507.1108; Found 507.1108.
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Phenyl
(E)-3-(4,5-dimethoxy-2-((8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)methyl)phenyl)acryl
ate (3h). Yellow solid; yield: 355 mg (73%); Rf = 0.30 (EtOAc/hexanes = 1:2); mp
o
162ꢀ164 C; IR (KBr) νmax 2923, 1720, 1600, 1462, 1139 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 8.06 (d, J = 15.6 Hz, 1H), 7.51 (s, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.28 (s, 1H),
7.20 (t, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 7.8 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H),
6.45 (d, J = 15.6 Hz, 1H), 6.05 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.88 (s, 2H); 13C NMR
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(150 MHz, CDCl3) δ 176.2, 165.4, 153.7, 152.7, 152.6, 151.4, 150.8, 148.2, 146.1, 143.0,
132.0, 129.3, 125.7, 125.3, 123.3, 121.6, 118.6, 116.4, 113.6, 108.8, 102.3, 102.2, 97.8,
56.0, 55.9, 28.6; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C28H23O8 487.1387;
Found 487.1380.
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(E)-3-(4,5-Dimethoxy-2-((8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)methyl)phenyl
)acrylic acid (3i). Yellow solid; yield: 270 mg (66%); Rf = 0.45 (EtOAc/hexanes = 2:1);
o
mp 150ꢀ152 C; IR (KBr) νmax 2936, 1712, 1636, 1482, 1390, 1129, 1044 cmꢀ1; 1H NMR
(600 MHz, CD3OD) δ 7.85 (d, J = 15.6 Hz, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 7.23 (s, 1H),
6.97 (s, 1H), 6.95 (d, J = 15.6 Hz, 1H), 6.85 (s, 1H), 6.11 (s, 2H), 4.57 (br, 1H), 3.88 (s,
3H), 3.86 (s, 3H), 3.83 (s, 2H); 13C NMR (150 MHz, CD3OD) δ 178.4, 155.6, 155.5,
152.3, 149.7, 148.6, 141.6, 132.5, 130.3, 129.4, 127.4, 124.6, 119.4, 115.0, 114.5, 110.7,
104.3, 102.1, 98.9, 56.5, 56.4, 29.3; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for
C22H19O8 411.1074; Found 411.1075.
Butyl
(E)-3-(2-((6-fluoro-4-oxo-4H-chromen-3-yl)methyl)phenyl)acrylate
(3j).
o
Orange solid; yield: 285 mg (75%); Rf = 0.25 (EtOAc/hexanes = 1:8); mp 64ꢀ66 C; IR
(KBr) νmax 3446, 2924, 1646, 1480, 1316, 1173 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.92
(d, J = 15.6 Hz, 1H), 7.86 (dd, J = 8.4, 3.0 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41ꢀ7.27 (m,
6H), 6.35 (d, J = 15.6 Hz, 1H), 4.15 (t, J = 6.6 Hz, 2H), 3.95 (s, 2H), 1.65ꢀ1.60 (m, 2H),
1.38ꢀ1.33 (m, 2H), 0.91 (t, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 176.5, 166.8,
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159.4 (d, 1JC-F = 245.6 Hz), 153.5, 152.6, 141.4, 137.1, 133.7, 131.0, 130.3, 127.5, 126.9,
124.7 (d, 3JC-F = 7.5 Hz), 123.1, 121.9 (d, 2JC-F = 25.8 Hz), 120.5, 120.2 (d, 3JC-F = 8.1 Hz),
110.7 (d, 2JC-F = 23.6 Hz), 64.5, 30.7, 29.0, 19.2, 13.7; HRMS (ESIꢀquadrupole) m/z: [M +
1]+ calcd for C23H22O4F 381.1497; Found 381.1492.
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Butyl
(E)-3-(2-((6-chloro-4-oxo-4H-chromen-3-yl)methyl)phenyl)acrylate
(3k).
o
Yellow solid; yield: 309 mg (78%); Rf = 0.30 (EtOAc/hexanes = 1:8); mp 83ꢀ85 C; IR
(KBr) νmax 2920, 2360, 1711, 1646, 1465, 1313, 1172 cmꢀ1; 1H NMR (600 MHz, CDCl3)
δ 8.19 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 12.0 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.56 (dd, J
= 9.0, 2.4 Hz, 1H), 7.35ꢀ7.27 (m, 5H), 6.35 (d, J = 12.0 Hz, 1H), 4.15 (t, J = 6.6 Hz, 2H),
3.95 (s, 2H), 1.64ꢀ1.60 (m, 2H), 1.39ꢀ1.32 (m, 2H), 0.90 (t, J = 6.6 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 176.1, 166.8, 154.7, 153.5, 141.4, 137.0, 133.8, 133.7, 131.0, 130.3,
127.6, 126.9, 125.4, 124.5, 123.9, 120.5, 119.8, 64.5, 31.9, 29.0, 19.1, 13.7; HRMS
(ESIꢀquadrupole) m/z: [M + 1]+ calcd for C23H22O4Cl 397.1201; Found 397.1198.
Butyl
(E)-3-(2-((7,8-dimethoxy-4-oxo-4H-chromen-3-yl)methyl)-4,5-dimethoxyphenyl)acrylate
(3l). Yellow solid; yield: 342 mg (71%); Rf = 0.25 (EtOAc/hexanes = 1:2); mp 115ꢀ117
oC; IR (KBr) νmax 2957, 1704, 1602, 1514, 1429, 1284 cmꢀ1; 1H NMR (600 MHz, CDCl3)
δ 7.92 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 15.6 Hz, 1H), 7.29 (s, 1H), 7.07 (s, 1H), 6.99 (d, J
= 9.0 Hz, 1H), 6.80 (s, 1H), 6.25 (d, J = 15.6 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.93 (s,
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3H), 3.87 (s, 6H), 3.86 (s, 3H), 3.84 (s, 2H), 1.62ꢀ1.57 (m, 2H), 1.36ꢀ1.32 (m, 2H), 0.85 (t,
J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 176.7, 167.0, 156.2, 153.0, 150.9, 150.7,
148.1, 141.0, 136.4, 131.2, 125.6, 123.3, 121.2, 118.4, 117.6, 113.5, 109.9, 108.7, 64.3,
61.4, 56.3, 55.9, 55.8, 30.6, 28.3, 19.0, 13.6; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd
for C27H31O8 483.2013; Found 483.2008.
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Butyl
(E)-3-(6-((7,8-dimethoxy-4-oxo-4H-chromen-3-yl)methyl)-2,3,4-trimethoxyphenyl)acrylat
e (3m). Yellow solid; yield: 343 mg (67%); Rf = 0.43 (EtOAc/hexanes = 1:2); mp 113ꢀ115
oC; IR (KBr) νmax 2958, 2926, 1735, 1167 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 7.94 (d, J
= 9.0 Hz, 1H), 7.70 (d, J = 16.2 Hz, 1H), 7.39 (s, 1H), 7.01 (d, J = 9.0 Hz, 1H), 6.66 (d, J
= 9.0, 1H), 6.58 (d, J = 16.2 Hz, 1H), 4.12 (t, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.90 (s, 3H),
3.84 (s, 9H), 3.83 (s, 2H), 1.63ꢀ1.57 (m, 2H), 1.36ꢀ1.31 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 176.7, 167.9, 156.3, 154.4, 153.9, 153.1, 150.8, 141.3,
137.8, 136.5, 134.3, 122.9, 121.4, 121.3, 121.2, 120.4, 118.4, 109.9, 64.2, 61.5, 60.9, 60.5,
56.4, 56.0, 30.7, 29.7, 19.1, 13.7; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for
C28H33O9 513.2119; Found 513.2116.
Butyl
(E)-3-(6-((6-fluoro-4-oxo-4H-chromen-3-yl)methyl)benzo[d][1,3]dioxol-5-yl)acrylate
(3n). Colorless solid; yield: 326 mg (77%); Rf = 0.38 (EtOAc/hexanes = 1:4); mp 156ꢀ158
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oC; IR (KBr) νmax 3443, 2923, 2360, 1646, 1480, 1259, 1173, 1038 cmꢀ1; 1H NMR (600
MHz, CDCl3) δ 7.86ꢀ7.83 (m, 2H), 7.40ꢀ7.34 (m, 3H), 7.07 (s, 1H), 6.78 (s, 1H), 6.22 (d,
J = 15.6 Hz, 1H), 5.97 (s, 2H), 4.14 (t, J = 6.6 Hz, 2H), 3.87 (s, 2H), 1.64ꢀ1.59 (m, 2H),
1.37ꢀ1.32 (m, 2H), 0.89 (t, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 176.5, 167.0,
159.4 (d, 1JC-F = 245.4 Hz), 153.5, 152.6, 152.5, 149.6, 147.3, 140.8, 132.4, 127.1, 124.7,
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124.6, 123.2, 121.8 (d, JC-F = 25.2 Hz), 120.2 (d, JC-F = 8.1 Hz), 110.7 (d, JC-F = 23.6
Hz), 105.9, 101.6, 64.4, 30.7, 29.7, 19.2, 13.7; HRMS (ESIꢀquadrupole) m/z: [M + 1]+
calcd for C24H22O6F 425.1395; Found 425.1392.
Butyl
(E)-3-(6-((6-chloro-4-oxo-4H-chromen-3-yl)methyl)benzo[d][1,3]dioxol-5-yl)acrylate
(3o). White solid; yield: 352 mg (80%); Rf = 0.65 (EtOAc/hexanes = 1:4); mp 140ꢀ142 oC;
IR (KBr) νmax 3421, 1647, 1465, 1259, 1174, 1038 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ
8.18 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 15.6 Hz, 1H), 7.57 (dd, J = 9.0, 2.4 Hz, 1H), 7.83 (s,
1H), 7.35 (d, J = 9.0 Hz, 1H), 7.07 (s, 1H), 6.78 (s, 1H), 6.21 (d, J = 15.6 Hz, 1H), 5.97 (s,
2H), 4.14 (t, J = 6.6 Hz, 2H), 3.87 (s, 2H), 1.63ꢀ1.60 (m, 2H), 1.38ꢀ1.33 (m, 2H), 0.89 (t,
J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 176.1, 167.0, 154.7, 153.5, 149.7, 147.3,
140.8, 133.8, 132.3, 131.0, 127.1, 125.3, 124.5, 123.9, 119.8, 118.2, 110.8, 106.0, 101.6,
64.4, 30.7, 28.9, 19.2, 13.7; HRMS (ESIꢀquadrupole) m/z: [M + 1]+ calcd for C24H22O6Cl
441.1099; Found 441.1100.
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(E)-3-(2,3,4-trimethoxy-6-((7-methoxy-4-oxo-4H-chromen-3-yl)methyl)phenyl)acrylate
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(3p). Yellow solid; yield: 312 mg (71%); Rf = 0.35 (EtOAc/hexanes = 1:2); mp 148ꢀ150
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oC; IR (KBr) νmax 2923, 2359, 1713, 1610, 1439, 1168, 1128 cmꢀ1; H NMR (600 MHz,
CDCl3) δ 8.10 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 16.2 Hz, 1H), 7.34 (s, 1H), 6.92 (dd, J =
6.6, 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.67 (s, 1H), 6.58 (d, J = 16.2 Hz, 1H), 3.86 (s,
2H), 3.84 (s, 3H), 3.83 (s, 6H), 3.82 (s, 3H), 3.79 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
176.6, 168.2, 163.9, 158.1, 154.4, 153.8, 152.9, 141.2, 138.2, 134.4, 127.2, 123.3, 120.7,
120.3, 117.5, 114.5, 110.0, 100.0, 60.8, 60.4, 55.9, 55.7, 51.5, 29.6; HRMS
(ESIꢀquadrupole) m/z: [M + 1]+ calcd for C24H25O8 441.1544; Found 441.1546.
Ethyl
(E)-3-(2,3,4-trimethoxy-6-((7-methoxy-4-oxo-4H-chromen-3-yl)methyl)phenyl)acrylate
(3q). Yellow solid; yield: 331 mg (73%); Rf = 0.32 (EtOAc/hexanes = 1:2); mp 117ꢀ119
oC; IR (KBr) νmax 2925, 1610, 1440, 1170, 1128 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.10
(d, J = 9.0 Hz, 1H), 7.70 (d, J = 16.2 Hz, 1H), 7.35 (t, J = 1.2 Hz, 1H), 6.92 (dd, J = 9.0,
2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.68 (s, 1H), 6.56 (d, J = 16.2 Hz, 1H), 4.17 (q, J =
7.2 Hz, 2H), 3.86 (s, 2H), 3.85 (s, 3H), 3.84 (s, 6H), 3.83 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 176.6, 167.8, 163.9, 158.0, 154.3, 153.8, 153.0, 141.2,
137.9, 134.4, 127.2, 123.3, 121.2, 120.3, 117.5, 114.5, 110.0, 100.0, 60.8, 60.5, 60.3, 55.9,
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