Synthesis of Flavonols via Pyrrolidine Catalysis: Origins of the Selectivity for Flavonol versus Aurone

Article abstract of DOI:10.1021/acs.joc.0c01869

A novel synthetic method for flavonol from 2′-hydroxyl acetophenone and benzaldehyde promoted by pyrrolidine under an aerobic condition in water is established. This protocol was supported by efficient synthesis of 44 common examples and three natural products. The α, β-unsaturated iminium ion (enimine ion E) was proved to be the key intermediate in the reaction. H218O and 18O2 isotope tracking experiments demonstrated that both water and the aerobic atmosphere were necessary to ensure the transformation. The selectivity for flavonol or aurone was originated from solvent-triggered intermediates, which were determined by UV-visible spectra from isolated enimine. The phenol-iminium E-A is dominant in water and the ketoenamine intermediate E-B is prevalent in acetonitrile. In the presence of pyrrolidine and oxygen, E-A leads to flavonol through E-I, a zwitterionic-like phenoloxyl-iminium ion, following the key steps of cyclization and a [2 + 2] oxidation; E-B proceeds through path II, a radical process induced by photolysis of E-B with both pyrrolidine and oxygen, to afford aurone. Preliminary mechanistic studies are reported.

Full text of DOI:10.1021/acs.joc.0c01869

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Article
Synthesis of Flavonols via Pyrrolidine Catalysis:
Origins of the Selectivity for Flavonol versus Aurone
Wei Xiong, Xiaohong Wang, Xianyan Shen, Cuifang Hu, Xin Wang, Fei Wang, Guolin Zhang, and Chun Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01869 • Publication Date (Web): 24 Sep 2020
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The Journal of Organic Chemistry
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Synthesis of Flavonols via Pyrrolidine Catalysis: Origins of the
Selectivity for Flavonol versus Aurone
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Wei Xiong,†,‡,∥ Xiaohong Wang,†,‡,∥ Xianyan Shen,†,‡ Cuifang Hu,§ Xin Wang,§ Fei Wang,† Guolin
Zhang,†,* and Chun Wang†,*
† Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
‡ University of Chinese Academy of Sciences, Beijing 100049, China
§ College of Chemistry, Sichuan University, Chengdu 610064, China
* E-mail: wangchun@cib.ac.cn, Zhanggl@cib.ac.cn
Supporting Information Place hold
R'
R'
OH
O
O
O
OHC
Aerobic, H2O
O
R
R
R'
+
R
Pyrrolidine
OH
47 examples
up to 91% yield
O
Flavonol
Aurone
O
N
1) Cyclization
2) [2+2] Oxidation
R'
1) Radical Oxidation
2) Cyclization
O
N
R
R
R'
C-6 substituent substrates
Solvent Triggered

E-B in
CH3CN
E-I in H2
O
ABSTRACT: A novel synthetic method for flavonol from 2'-hydroxyl acetophenone and benzaldehyde promoted by pyrrolidine
under an aerobic condition in water is established. This protocol was supported by efficient synthesis of 44 common examples and
three natural products. The α, β-unsaturated iminium ion (enimine ion E) was proved to be the key intermediate in the reaction.
H218O and 18O2 isotope tracking experiments demonstrated that both water and the aerobic atmosphere were necessary to ensure the
transformation. The selectivity for flavonol or aurone was originated from solvent triggered intermediates, which were determined
by UV-visible spectra from isolated enimine. The phenol-iminium E-A is dominant in water and the ketoenamine intermediate E-B
is prevalent in acetonitrile. Under the presence of pyrrolidine and oxygen, E-A leads to flavonol through E-I, a zwitterionic-like
phenoloxyl-iminium ion, following the key steps of cyclization and a [2+2] oxidation; and E-B proceeds through Path II, a radical
process induced by photolysis of E-B with both pyrrolidine and oxygen, to afford aurone. Preliminary mechanistic studies are
reported.
■ INTRODUCTION
Flavonols (3-hydroxyflavones) are distributed widely in plant
kingdom and exist in a wide variety of natural plants. Besides
their plant physiological importance, they attract considerable
interest due to their biological effects, including antiviral,
antitumor and antibiotic activities.1 Most of the natural occurring
flavonols with therapeutic significance contain substituents at C-
5. For example, quercetin and kaempferol distinctly inhibit cancer
cell lipogenesis in both prostate and breast cancer cells.2 Icaritin
inhibits malignant growth of hepatocellular carcinoma-initiating
cells (HCICs) and may potentially be developed into an effective
therapeutic agent for the treatment of hepatocellular carcinoma
(HCC).3 The senolytic cocktail, dasatinib plus quercetin, can
selectively eliminate senescent cells and enhance remaining health
and lifespain in old mice.4 In spite of the biological importance of
flavonols, limited synthetic methods available include those with
key reactions such as Algar-Flynn-Oyamada (AFO) reaction,5
Baker-Venkataraman and
rearrangement6 Auwers7
dimethyldioxirane (DMDO) Oxidation.8 In addition to tedious
synthetic processes, harmful oxidants and solvents are also
involved. More vitally, these methods are not efficient for the
generation of C-5 substituted flavonols. The AFO reaction is the
most adapted method for synthesis of flavonols, which is through
the reaction of 2'-hydroxychalcone with alkaline hydrogen
peroxide. The major by-product aurone in the synthesis of 5-
substituted flavonol has been accounted for the 6'-substituent
directed cyclisation of phenolate in the postulated chalcone
epoxide intermediate to C-α rather than C-β of the carbonyl
group.9 By using weaker bases, such as sodium carbonate, the
yields of C-5 substituted flavonols could be moderately increased.
The over-oxidized by-products in the presence of hydrogen
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peroxide are still unavoidable.
the scope and the mechanism of reaction were not disclosed. Our
In terms of AFO reaction, two key steps are involved in the
transformation from 2'-hydroxylacetophenone and benzaldehyde
into flavonol, the aldol condensation (formation of chalcone) and
oxidative cyclization. Thus, a base (either inorganic alkali,
Scheme 1 (a) or amine, Scheme 1 (b)) and an oxidant would be
necessary. When we intended to use pyrrolidine as base to
catalyze the aldol condensation of 2'-hydroxy-6'- methoxyaceto-
preliminary experimental results show that 1) air is necessary for
the reaction, 2) flavonols were generated with poor selectivity in
ethanol. However, we found that the reaction could be
preferentially directed to flavonol by using water as solvent. On
the other hand, by switching the solvent to acetonitrile under
otherwise identical conditions would favor the generation of
aurone. 3) aurone was inhibited by addition of TEMPO, in the
meantime, generation of flavonol was not influenced. which
indicated that two different pathways were involved, in which one
was a non-radical pathway and the other was a radical pathway.
Motivated by this intriguing selectivity disparity, and the likely
interplay of the directing solvent influence to the selectivity, a
systematic study on the reaction and mechanism was carried out
to reveal the origin for the selectivity of flavonol versus aurone,
and to delineate the structural features of substrates responsible
for the reaction. We wish that our findings can reveal new and
fascinating reaction of α, β-unsaturated enamines or enimine salts.
3
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5
6
7
8
9
Scheme 1. Analysis of the formation of flavonol from
acetophenone and benzaldehyde: a) Through chalcone; b)
through iminium activation
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OH
H2O
2
Base
R'
R
OH
O
(a)
Previous work
R
O
Y
1
O
8
B
R'
7
A
2
C
A
R
6
OH
3
+
4
5
O
N
O
C
OHC
Pyrrolidine
R'
R
(b)
R'
This work
B
)
Air(O2
■ RESULTS AND DISCUSSION
E-I
The reaction of 2'-hydroxy-6'-methoxyacetophenone (A1) and
4-methoxybenzaldehyde (B1) was taking as the model reaction,
primary, secondary and tertiary amines were screened for the
synthesis of flavonols (Table 1). The reaction was promoted by
cyclic secondary amines. Piperidine is poorer than pyrrolidine
(Table 1, Entry 4, 5). Among the amines screened, pyrrolidine
provided the maximum yield of flavonol. Open-chain primary,
secondary and tertiary amines were unable to accomplish the
reaction and the reaction remained at flavonone step (Table 1,
Entry 1, 2, 8). Strong base like TBD resulted in chalcone (Table 1,
Entry 7). Next, we optimized the amount of pyrrolidine. Reducing
the equivalents of pyrrolidine from 10 to 4 resulted in slow down
of the reaction and reduced yield of C1. When 2-4 equivalents of
pyrrolidine were used, the reaction was extremely slow. On the
other hand, further increasing the amount of pyrrolidine to above
10 equivalents had no obvious influence on the reaction speed and
the yield of flavonols. Thus, the optimal amount of pyrrolidine
was found to be 10 equivalents. The effect of the solvent was also
evaluated. In the case of aprotic solvents like toluene, CH2Cl2,
THF, DMSO and acetonitrile (Figure 1 (a)), the reaction afforded
unsatisfactory results comparing to protic solvents like EtOH,
MeOH and water. Water could significantly enhance the yield of
flavonols (Table 1, Entry 11). Interestingly, the formation of
aurone was dominant (Table 1, Entry 10) in acetonitrile. It was
noticeable that water was always necessary for mediation of the
reaction, no products were detected without adding water, no
matter what solvent was used other than water. Heating the
phenone and 4-methoxybenzaldehyde under an aerobic condition
in methanol, we founded surprisingly that flavonol came out as
the major product whereas aurone was detected as minor product.
In addition, we confirmed the formation of iminium-ion
intermediate (E1: R=6'-OMe; R′=4-OMe) in the model reaction by
1
in situ H NMR measurement. Thus, we may reasonably assume
that the pyrrolidine not only worked as a base for catalyzing the
aldol condensation, but also activated the α, β-unsaturated ketone
through the formation of iminium-ion. The latter was converted
into flavonol and aurone involving oxidation by reactive oxygen
species (ROS) from the environment (air). The formation of
iminium-ion is known as the LUMO activation in amino catalysis,
which represents an important class of powerful and
straightforward approach for the construction of complex
molecules in a very efficient way.10 Many reactions are involved
in amino catalysis such as Michael reaction,11 [2+2] cyclization,12
Diels-Alder reaction,13 and singel-electron transfer (SET)
reaction.14 Oxidative reaction of the enimine ion or enamine is
less known, except the epoxidation of enimine with hydrogen
peroxide.15 To the best of our knowledge, the oxidation of enimine
catalysed by secondary amine under aerobic condition remains
unexplored.
The generation and properties of ROS are of great interest in
organic chemistry. It is well known that O2 can be photoactivated
through type I and type II processes to generate reactive oxygen
species (ROS).16 Type I undergoes photoinduced electron transfer
o
.
to form O2.- and HO2 ，consequently, a radical process is involved.
reaction to 50 C increased the yield of flavonol (Table 1, Entry
19 and 23, Figure 1, (b)), further elevation of the temperature
Type II is a sensitizer energy-transfer process to oxygen involved
the formation of singlet oxygen (1O2). Despite the types of ROS
exhibite varying lifetimes in different media, the rate of
oxygenated product formation can also vary widely; for example,
o
o
from 50 C to 80 C decreased the yield of flavonol (Table 1,
Entry 20-22, Figure 1, (b)). We noticed that air was necessary for
the reaction. Accomplishing the reaction in the absence of
oxygen, the reaction remained at the Claisen-Schmidt
condensation step, neither flavonol nor aurone was detected
except chalcone. On the other hand, the reaction under an oxygen-
balloon instead of an aerobic condition gave increased total yields
of flavonol and aurone. The careful exclusion of light completely
suppressed the formation of product, confirming the
photochemical nature of the process.
1
the rate constant for the reaction of methionine with O2 is ~60
mollion-fold greater than that with O2.-17. Although the use of
18
ROS to synthesize natural products are coming into use,
controlling of the types of ROS reaction is still challenging and its
use for manipulating the products selectivity is not known.
As part of our ongoing program on the methodology
development and mechnism implication of natural flavonol
synthesis, we have exploited the selective synthesis of flavonols
catalysized by pyrrolidine. Although Cao et al. described a
synthesis of flavonol from benzaldehyde and 2'-
hydroxylacetophenone in the existence of pyrrolidine in ethanol,19
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Table 1. Optimization of the Reaction Conditions a
(Table 2, C4, C19, C28, C37, C39), regardless of the types of A
2
used. B with 3-OH gave poorer yields than those with 4-OH
(Table 2, C10, C20). In addition, B with 3-OCH3, 4-OH or two
functional groups gave lower yields than those with 4-OH only
but gave higher yield than those with 4-OH and 3, 5-dimethoxyl
ones (Table 2, C11, C13, C22). We have also investigated B of
aliphatic aldehydes, formaldehyde, propanaldehyde and
valeraldehyde, but failed to obtain product. A with two electron-
donating groups at C-4 and C-6 gave higher yield than those with
single substituent at C-6 (Table 2, C17-C23). Fluorine, instead of
methoxy group at C-6 of A did not affect the yields of flavonol
significantly (Table 2, C15-C16). Although A with substituent at C-
4 or C-5 gave higher yields than those with functional group at C-
6, but still afforded poorer yields than those of unsubstituted A
(Table 2, C35-C42). When thiophenone was subjected for the
reaction, the presence or absence of C-6 on A had little effect on
the yields (Table 2, C14, C34). Comparing with the AFO reaction,
the yields of flavonol based on this protocol were enhanced about
20%-40%.
The efficiency of this method on a larger scale was next
investigated. It is noteworthy that this procedure can be scaled up
to gram quantities of the desired flavonols and aurones without
sacrificing yields. For example, 3.339 g of C1 and 4.293 g of D8
could be isolated in 62% and 80% yields respectively,
highlighting the synthetic utility of this method.
To elaborate the synthetic utility further, we then adapt the
method for natural flavonols synthesis. Three natural flavonols:
isorhamnetin, tamarixrtin, and kaempferide were successfully
synthesized in three steps: selective protection of acetophenol,
formation of flavonol and deprotection, with successive yields of
41%, 64% and 65%, (Scheme 2), corresponding to 15% (six
steps), 15% (six steps) and 25% (five steps) as reported with
protection-deprotection processes.20
3
4
5
6
7
8
9
O
Base
solvent
O
OH
O
O
+
H
temperature
air
OH
O
O
O
O
A1
B1
C1
Entry
Base
Solvent
MeOH
MeOH
T(°C
rt
Yield b (%)
n. d
1
2
n-propylamine
diethylamine
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rt
n. d
3
pyrrole
piperidine
pyrrolidine
L-proline
TBD
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
CH3CN
H2O
rt
rt
n. d.
trace
40
4
5
rt
6
rt
n. d
7
rt
trace
n. d
8
Et3N
rt
9
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
rt
35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
rt
8%(70%d)
63%(29%d)
11
rt
THF
rt
DMSO
Toluene
CH2Cl2
H2O
rt
15
rt
trace
trace
50
rt
20
30
40
50
60
70
80
50
H2O
56
H2O
61
H2O
73
H2O
65
H2O
68
H2O
70
81c
H2O
a
We then focused on the mechanism. The aerobic oxidation
without additional oxidant in which this reaction proceeds
suggested a distinct mechanism compared to previously reported
hydrogen peroxide procedures (AFO reaction).
Reaction conditions: A1 (10 mg, 0.0602 mmol), B1 (7.7 μL,
0.0632 mmol), base (0.6020 mmol), and solvent 1.0 mL. The
reaction was performed at the above temperature in air for 16 h. b
Yield determined by HPLC analysis. c Reaction performed under
an O2 balloon. n.d = not detected.d Yields of aurone.
We started with tracking the oxygen source of 3-OH in flavonol.
First, isotope oxygen 18O2 gas in balloon was used instead of air
for the model reaction. The products flavonol (69%) and aurone
(22%) were analyzed by high-resolution mass spectroscopy (HR-
ESI-MS), in which 18O containing flavonol was detected, but no
18O labelled aurone was found (Scheme 3 (a) and Figure S1).
Next, H218O was used as solvent in the model reaction. Indeed,
both 18O contained flavonol (61%) and aurone (28%) (Scheme 3
(b), Figure S2) were obtained. Furthermore, H218O and 18O2 gas
balloon were used together for the model reaction, two 18O
isotopes containing (18O)2-C1 (70%) and only one isotope
containing 18O-D1 (20%) were isolated (Scheme 3 (c), Figure S3).
The above isotope tracking experiments together revealed that
oxygen atom at C-3 of flavonol came from atmospheric oxygen in
the environment and the oxygen atom of the carbonyl in both
flavonol and aurone were from water.
Figure 1. Schematic demonstration of the influence of reaction conditions
on the model reaction: a) Solvents; b) Temperature.
Having identified an appropriate set of conditions, the
optimized one-pot protocol was further extended to synthesis of
different flavonol derivatives with/without 5-substituents, bearing
both electrons donating and withdrawing groups (Table 2). Most
2'-hydroxylacetophenone without substituent at C-6 were resulted
in good yields, regardless of aldehyde types (Table 2, C24-C42).
However, when 2'-hydroxylacetophenone (A) with substituent at
C-6 was subjected to the reaction, benzaldehydes (B) bearing
electron withdrawing group (-Cl, -Br, -NO2) afforded lower yields
of flavonols (Table 2, C6-C8), and aurones were turned to be the
major products. On the other hand, B bearing electron-donating
groups (-OH, -OCH3, -CH3 and -N(CH3)2) were favorable for
flavonol formation (Table 2, C1-C4, C9-C13, C15-C22).
Particularly, All B with 4-hydroxyl group resulted in good yields
Next, we turned to investigate the key intermediate(s) leading
1
to flavonol and aurone. We conducted in-situ H NMR monitor
for the model reaction. After 10 mins of the reaction, we found a
proton signal appeared at δ 7.33, which could be assigned to Hd
(Figure S4), the typical indicator of β-proton of α, β-unsaturated
imine. Prolonging the reaction to 30 mins, the signal at δ7.33 was
increased, showing that almost all starting materials converted
into this intermediate (Figure S4). This intermediate is quite stable
under the oxygen deficient condition in a capped NMR tube. It
took several hours before the intermediate changed. Thus, we
were able to do HMBC (Figure S8) and HSQC (Figure S7)
experiments to determine the structure of the intermediate. An α-
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deuterated eniminium ion (Since CD3OD and D2O were used),
addition of 2, 2, 6, 6-tetramethylpiperidine 1-oxyl (TEMPO, 2
could be assigned to the intermediate as E1 (Figure S4). During
the transformation from E1 to C1 and D1, a number of
intermediates were emerged which were unable to be identified
from in-situ 1H NMR measurement (Figure S5-6).
Being established that the eniminium E1 was the key
intermediate leading to flavonol and aurone, we next tried to
explore the origin in directing the selectivity from E1 to flavonol
and aurone. The first question arises to whether flavonol and
aurone generated through the same pathway or different pathways.
We found that the formation of aurone (D1) was ceased by the
equivalents) into the model reaction, in the meantime, the
generation of flavonol was not affected. This is indicative of a
radical mechanism for the formation of aurone and a non-radical
mechanism for the generation of flavonol. In other words, two
different pathways were involved in the reaction. To further
confirm that TEMPO inhibits the generation of aurone, we added
TEMPO to the reaction of A1, and B6, and A1 and B7, also found
that aurones (D6 and D7) were also inhibited, in the meantime, the
yields of C6 and C7 were remained unaffected. Thus, we could
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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49
50
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52
53
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55
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57
58
59
60
Table 2. Synthesis of Flavonols
R'
OH
O
Pyrrolidine (10 equiv.)
R'
R
R
H
+
air, H2O, 50 oC, 24h
OH
C1-C44
O
O
O
B1-B15
A1-A12
1: R=OCH3, 63% (29%)c
2: R=N(CH3)2, 85%
3: R=CH3, 60% (28%)c
4: R=OH, 85%
5: R=H, 35% (52%)c
6: R=Cl, 10% (72%)c
7: R=Br, trace (75%)c
8: R=NO2, trace (81%)c
C
C
C
C
C
C
C
C
R
R
O
O
O
O
C
17: R=OCH3, 85%
O
O
C
C
31: R=OCH3, 70%
32: R=OH, 91%
R
C
18: R=N(CH3)2, 90%
C
19: R=OH, 82%
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
R=CH3, 42% (47%)c
OH
C9
:
R
10:R=OH, 52% (44%)b
:
68% (19%)c
C
C20
C
33: 74%
OH
OH
O
R
O
R1
R2
S
O
O
O
O
O
O
O
C
C
C
C
11: R=OH, 83%
12: R=OCH3, 61% (31%)c
21: R1=R2=OCH3, 85%
22: R1=OH,R2=OCH3, 80%
C
34: 75%
OH
OH
O
O
O
OH
O
R
C
C
C
35: R=H, 72%
36: R=OCH3, 76%
37: R=OH, 85%
MOMO
O
O
O
O
O
O
O
13: 50% (30%)c
C
23: 88%
C
C
OH
OH
OH
OH
OH
MOMO
O
C
C
C
C
C
C
C
C
C
C
C
C
C
C
24: R=H, 78%
38: R'=OCH3, R=H, 75%
39: R'=OCH3, R=OH, 81%
40: R'=F, R=H, 78%
41: R'=Cl, R=H, 81%
42: R'=Br, R=H, 82%
R
R
25: R=CH3, 80%
26: R=N(CH3)2, 87%
27: R=OCH3, 89%
28: R=OH, 86%
29: R=Cl, 85%
S
O
O
O
O
O
O
14: 76%
R'
OH
43: R'=NO2, R=N(C2H5)2, 38%
44: R'=Br, R=N(C2H5)2, 45%
30: R=Br, 80%
O
R1
R2
R3
15: R1=R3=H, R2=OCH3, 81%
16: R1=R2=R3=OCH3, 78%
a Reaction conditions: Reactions were carried out with A (1.2 mmol, 1.0 equiv.), B (1.26 mmol , 1.05 equiv.),H2O 20 mL,
C
C
O
O
and pyrrolidine (12 mmol, 10 equiv.) at 50 oC in air for 24 h.
b Isolated yield of purified material.
c Aurone yields.
OH
F
Scheme 2. Convenient Synthesis of Natural Products
Scheme 3. H218O and 18O2 Tracking for the Model Reaction
O
1) Benzaldehyde
Pyrrolidine
H2O, air
R'
(a)
O
MOMO
OH
HO
O
HO
OH
O
OH
MOMCl
O
O
O
Pyrrolidine
18O2, H2
OH
+
+
2) 1 M HCl, MeOH
DIPEA, DCM
MOMO
O
18OH
HO
O
O
OHC
OH
O
O
50oC, 24h
O
O
C45-C47
O
O
A4
D1 22%
A1
B1
C1 69%
O
(b)
O
OH
O
O
O
Pyrrolidine
O
OH
O
O
+
+
air, H218O
50oC, 24h
OHC
OH
O
HO
O
O
HO
O
O
HO
OH
O
O
O
18O
18O
O
O
A1
B1
D1 28%
C1 61%
OH
OH
OH
O
OH
OH
OH
O
(c)
OH
O
O
C45: Isorhamnetin (41%)
C46: Tamarixetin (64%)
C47: Kaempferide (65%)
Pyrrolidine
O
+
+
18O2, H218O
50oC, 24h
18OH
OHC
O
O
18O
18O
O
O
C1 70%
A1
B1
D1 20%
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conclude that different pathways are involved in formation of
Scheme 5. Possible trajectories’ from E4 to C4: a) cyclization-
oxidation; b) oxidation-cyclization
2
flavonol or aurone. Since both flavonol and aurone were
generated in the model reaction, it is impossible to differentiate
intermediates of one path (for flavonol) from the other (for aurone)
within the same reaction. Fortunately, during the preparation of
C4 from A1 and B4 in water, we noticed some precipitates
generated when the first drops of pyrrolidines were added into the
aqueous solution of A1 and B4. The precipitate was isolated and
3
4
5
6
7
8
9
OH
OH
O
(a)
Cyclization
O
Oxidation
OH
O
N
O
O
C4
W4
E4
characterized by H NMR, 13C NMR, HSQC, HMBC, HR-ESI-
1
OH
O
OH
Cyclization
(b)
Oxidation
O
O
MS and elementary analysis. The data together indicate that this
precipitate is an aggregate of E4, with a formula of 2E4.H2O
(Figure S9-12) Addition of 9 equivalents of pyrrolidine into the
mixture of the isolated solids in water, flavonol C4 was generated
almost quantitatively, no aurones were detected in this reaction
(Scheme 4 (a)).
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13
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19
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O
N
OH
O
O
V4
F'4
Next, we investigate the pathway from E13 to aurone by the
following experiments: 1) The reaction of A1 and B13 (one-pot
reaction) under 9 equivalents of pyrrolidine in water produced
50% C13 and 30% D13. (Scheme 6, (a)); 2) On the other hand, the
reaction of E13HCl under the same condition did not give either
C13 or D13. (Scheme 6, (d)); 3) By switch the solvent to
acetonitrile, the reaction of Scheme 6 (a) and (d) under the
otherwise identical conditions, afforded D13 only with yield of
20% and 30%, respectively (Scheme 6, (b) and (e)); 4) Addition
of TEMPO into the reactions of Scheme 6 (a), (b) and (e)
inhibited the formation of D13; 5) Both the one-pot reaction and
the reaction of E13HCl in water with NaOH/H2O2 resulted in
dihydrogen flavonol V13 only, with yields of 85% and 80%
respectively. (Scheme 6, (c) and (f)) Interestingly, V13 could not
be converted into C13 by addition of pyrrolidines or H2O2.
In addition, during the reaction of A1 and B13 in acetonitrile, we
noticed some purple solid precipitated out from the solution when
4 equivalents of pyrrolidines were added. Further addition of
pyrrolidine into the suspension of the purple solids in water,
methanol or acetonitrile respectively, resulted in no product.
Neutralization of the purple solids with 3N of HCl solution, a
yellow powder was obtained by extraction with dichloromethane.
The structure of the yellow powder was proved to be the enimine
salt 2E13HCl.H2O from 1H NMR, 13C NMR, HR-ESI-MS (Figure
S15-16), element analysis and single X-ray crystallographic
analysis together. (Figure S17). Surprisingly, addition of 9
equivalents of pyrrolidines into the solution of E13HCl in
acetonitrile, only aurone was obtained.
With the two isolated enamine aggregate intermediates E4 and
E13HCl in hand, now we are able to investigate the path leading to
flavonol or aurone respectively. Two possible trajectories to
flavonol from E4 are assumed. One is the cyclization followed
oxidation and the other is the epoxidation-cyclization. (Scheme 5
(a) and (b)). To investigate the trajectory to flavonol, we
conducted the reactions of E4 catalysed by 9 equivalents of
pyrrolidine in water, methanol and acetonitrile, respectively, as
presented in Scheme 4, (a), (b) and (c). We found that flavonol C4
was generated with 80% yield in water (Scheme 4, (a)), 40% yield
in methanol (scheme 4, (b)), and trace C4 in acetonitrile (Scheme
4, (c)). Addition of TEMPO into the above reactions had no effect
on the yields of C4, indicating that the generation of flavonol is
not a radical mechanism.
However, addition of H2O2 into the suspension of E4 in water,
dihydrogenflavonol (V4) was obtained with 85% yield (Scheme 4,
(d)), which is known through an epoxide intermediate path21. Thus,
the epoxide path (Scheme 5(b)) could be excluded from E4 to C4
by pyrrolidine catalysis. We speculated that the cyclization-
oxidation process is accounted for the trajectory from E to C by
pyrrolidine catalysis.
Scheme 6. Reactivity of iminium ion E13•HCl; A1 and B13.
1) pyrrolidine
H2O, air
O
C
D
13, 30%
13, 50%
+
OH
O
(a)
2) HCl
O
O
O
OH
O
1) pyrrolidine
CH3CN, air
(b)
(c)
OH
O
OH
O
D
V
13, 20%
+
2) HCl
O
OHC
O
C13
H2O2, NaOH
H2O, air
B13
A1
OH
13, 85%
O
O
1) pyrrolidine
H2O, air
X
O
O
O
O
(d)
2) HCl
O
OH
N
OH
D13
OH
O
1) pyrrolidine
CH3CN, air
(e)
(f)
O
O
O
D
13, 30%
O
2) HCl
Cl
OH
H2O2, NaOH
H2O, air
E13.HCl
V
V13
13, 80%
The above reactions demonstrate that the formation of both
flavonol and aurone in the presence of pyrrolidine is not from the
epoxide intermediate. A radical mechanism for the formation of
aurone can be confirmed. The selectivity of flavonol or aurone is
solvent dependent for a same substrate.
After knowing that the reaction pathways leading to flavonol
and aurone are heavily solvent dependent, it is necessary to
identify the intermediates involved in different solvents. The
advantage of UV-vis spectra lies in the fact that it can differentiate
between the multitude of reaction species. Thus, we turned to
investigate the solvent triggered formats of E4 and E13HCl by
UV-vis spectra. UV-vis absorption spectra of E4 (red), E4 with
equal molar HCl (break line) and E4 in the presence of 0-10
equivalents of pyrrolidine (plain lines) in water and acetonitrile
were recorded respectively, as presented in Figure 2 (2) and (3). It
is clear that the bands at 378 nm in water, and 380 nm in
acetonitrile of E4 were overlapped with those of E4HCl in
corresponding solvents, which was assigned to the enol-imine
intermediate E4-A (Figure 2 (1)). The structure of E4HCl was
confirmed by 1H NMR and 13C NMR (Figure S13-14). In addition,
during electrospray mass spectrometry (ESI_MS) spectra for in-
Scheme 4. Reactions of E4 with pyrrolidine catalysis in
different solvents: a) H2O, b) CH3OH, c) CH3CN, and (d) with
H2O2
1) pyrrolidine
H2O, air, r.t.
(a)
OH
OH
C4, 80%
C4, 40%
2) HCl
O
O
1) pyrrolidine
CH3OH, air, r.t.
OH
(b)
O
O
2) HCl
C4
E4
1) pyrrolidine
CH3CN, air, r.t.
O
O
C4, trace
V4, 85%
(c)
(d)
2) HCl
OH
V4
H2O2
H2O, air, r.t.
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situ analysis of the model reaction, the mass peaks at m/z
Benesi–Hildebrand expression, suggesting the 1 : 2 stoichiometry
338.1759 and 356.1758 corresponding to E1 and E1H2O are
clearly observed (Figure S24), which give solid evidence for the
formation of E1H2O.
between the pyrrolidine and E4-B with an association constant of
7.92 x 103 M-1 (Figure S22, (4)). Based on the UV-vis data, the
band at 499 nm could be assigned to E4-B. Due to E4 is not
soluble in acetonitrile, E4-B cannot be characterized by
spectroscopy methods.
The UV-vis spectrum of E4 in water with the gradual addition
of pyrrolidine is characterised by a new band centered at 448 nm,
at the same time the absorption at 378 nm (E4-A) decreased
sharply with no isosbestic point. (Figure 2, (2)). Such a
phenomenal implies that the band at 448 nm in water correspond
to a species which is not an isomer of E4-A, but a new species.
According to the linear Benesi-Hildebrand expression22, the
measured absorbance [1/(A-A0)] at 448 nm varied as a function of
1/[pyrrolidine] in a linear relationship (R=0.9955) (Figure S22,
(2)), indicating the 1 : 1 stoichiometry bewtween the pyrrolidine
and E4 with the associate constant of 9.06 x 103 M-1. On the basis
of UV-vis data in Figure 2 (2) and the fact that the reaction of E4
in water in the presence of pyrrolidine produces flavonol C4 only,
the band at 448 nm could be attributed to a solvated E4-I, which
could be cyclized to F4 and oxadized to G4 under the presence of
singlet oxygen through an electron transfer process23. Successive
ring open of G4 and hydrolysis afforded flavonol.
To understand the pathway involved in the formation of aurone,
the UV-vis spetra of E13HCl (break line) and E13HCl with an
increasing pyrrolidine amount from 0.2 to 10 equivalents in water
(Figure 3, (2))and acetonitrile (Figure 3, (3)) were recorded and
analyzed. The absorption spectra of E13HCl mesured in water
exhibit one band at 408 nm (Figure 3, (2)), which could be
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1
assigned to E13-A. The structure of E13-A was confirmed by H
NMR and 13C NMR. (Figure S15-16) from E13HCl and crstal
strucutre (Figure S17)
O
O
O
H
（1）
N
O
OH
O
OH
OH
O
O
N
OH
O
Protic solvents
Aprotic solvents
H
N
O
N
O
N
O
Cl
E13-A
E13-B
E13-I
(1)
X
H
O
N
OH
O
OH
O
N
OH
O
O
N
O
X=OH-, Cl-, CH3O-
E4-I
H2O, pyrrolidine
E4-A, in protic solvent
E4-B, in aprotic solvent
H
N
O
N
OH
H
OH
O
Figure 3 (1) The predicted formats of E13 from UV-visible spectra. (2)
UV-vis absorption spectra of E13HCl (1.7×10-5 M) and E13 plus 0-10 eq.
pyrrolidine in water and (3) in acetonitrile.
However, the absorption spectrum of E13HCl in acetonitrile
shows two bands at 419 nm and 550 nm (Figure 3, (3)). Further
addition of pyrrolidine into solution of E13HCl in acetonitrile did
not shift the two bands but leads to a continuous decrease in the
419 nm of the E13-A band, along with an increase in the 550 nm
band with an isosbestic point existed at 467nm. The measured
absorbance [1/(A-A0) at 550 in acetonitrile give a linear
relationship with
a
change of 1/[pyrrolidine]2 (R=0.999),
indicating a 1 : 2 stoichiometry between pyrrolidine and E13HCl,
with the associate constant of 1.46 x 104 M-1. (Figure S23, (4)).
On the basis of UV-vis data in Figure 3 (3) and the fact that the
reaction of E13 in acetonitrile in the presence of pyrrolidine
generates aurone D13 only, the band at 550 nm was assigned to
E13-B, which was associated with two molar of pyrrolidine.
(Figure 3 (1)). On the other hand, addition of pyrrolidine in water
shifted the band at 408 nm to a prevalent new band at 503 nm, but
no isosbestic point was observed (Figure 3, (2)) indicating that
this species is not a tautomer of either E13-A or E13-B. According
to the linear Benesi-Hidebrand expression, the measured
Figure 2 (1) The predicted formats of E4 from UV-visible spectra. (2) UV-
vis absorption spectra of E4 (1.7×10-5 M), E4 plus 1eq of HCl and E4 plus
0-10 eq. pyrrolidine in water and (3) in acetonitrile
On the other hand, the very intense band of E4 in acetonitrile at
499 nm arises as the increasing concentration of pyrrolidine, at the
same time the absorption at 380 nm (E4-A) decreased sharply
with an isosbestic point at 423 nm. (Figure 2 (3)), indicating that
the band at 499 nm and E4-A are two inter-changable isomers.
The measured absorbance [1/(A–A0)] at 499 nm varied as a
function of 1/[pyrrolidine]2 (R=0.9953) according to the linear
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absorbance [1/(A-A0)] in water at 503 shows a linear relashioship
2
3
4
5
6
7
8
9
Scheme 7. Intermediates involved in the transformations from
(a) E-A to Flavonol and (b) E-B to Aurone
with a change of 1/[pyrrolidine] (R=0.9953), indicating a 1 : 1
stoichiometry between pyrrolidine and E13HCl (Figure S23, (2))
with the association constant of 1.69 x 103 M-1.
On the basis of our preliminary experimental observations that
the format of intermediates depended on the solvent, and the
product selectivity as well, we anticipate that the solvent triggled
intermediate formats of enolimine (E-A) and ketoenamine (E-B)
determine the products selectivity.
a)
O
O
H
R'
[2+2] oxidation
O
N
R
R'
Pyrrolidine
R
R'
Cyclization
R
C
OH
H2
O
Hydrolysis
N
N
E-A
F
E-I
b)
H
O
1） In protic solvents, e.g. in water, E-A is dominant, which is
tend to form the zwitterionic-like intermediate (E-I) under
the presence of pyrrolidine, followed by cyclization to afford
F, [2+2] oxidation of F with singlet oxygen leading to
flavonol. (Scheme 7, a).
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60
O
N
OH
1O2
N
Pyrrolidine
CH3CN
R
R
R'
R'
R
R'
H
D
HOO
N
N
N
N
N
K
L
E-B
2） On the other hand, in aprotic solvent (e.g. acetonitrile) E-B is
prevalent, generating enamine K through the Michael
reaction with pyrrolidine., The radical pair of L and
hydrogenperoxide (Scheme 8 b) were initialized in the
presence of pyrrolidine and O2 under visible light.
Successive radical oxidation, cyclization, depyrrolidine and
hydrolysis affored aurone (Scheme 7, b).
The generation of phenoxyl radical under the presence of O2
and light was proposed by Novak et al.24. Thus, we can undertand
the phenominas: 1). E4 does not react in acetonitrile and only
produces flavonol in water, since there is no E4-B existed in the
reaction system. (Scheme 4, (c)) 2). E13HCl generates aurone
only in acetonitrile, because E13-B is existed as the only
intermediate specie. However, we could not understand why the
one-pot reaction could produce flavonol C13 but not from E13 or
E13HCl.
Scheme 8. Proposed mechanism
O
R
C, D
R'
R'
1O2
[2+2]
O
OH
N
N
N
R
1O2
R
R'
R'
O
O
N
L
O
N
N
Pyrrolidin
N
R
O
HOO
R
R'
e
R
R'
O
O
H2
O
Dismutation
F
N
e
CN
3
O
K
H2
N
F'
Pyrrolidin
CH
H2O2
G
M
O
N
O
N
H2O2
OH
R
R'
R
R'
OH
I
Path
Path II
O
N
R'
H2
O
CH3CN
OH
O
R'
R
R'
O
R'
R
E-B
A + B
E-I
R
OH
O
N
OOH
O
R
N
H2
O
H2
O
Pyrrolidine
O
C
N
R'
H
D
O
N
Pyrrolidine
R'
R
O
O
R
OH
R
R'
OH
R'
N
O
R
N
R
OH
O
O
J
H2
O
O
R
O
N
O
R'
OH
R'
R
N
I
N
H+
Q
P
A plausible two-pathway reaction mechanism for the formation
retention time 1.576 min). At this time point, there is no
detectable m/z signals belong to G4 was observed, probably due to
its very short lifetime. However, m/z signals that correlate to
peroxide intermediate H4 (ring opening of G4) and I4
(rearrangement of H) was detected as [H4+H]+ at m/z 356.1407.
m/z 338.1440 could be assigned to [I4]+ and its taotomeric form J4.
The final produc C4 was conformed by m/z 285.0745.
of flavonol and aurone can be proposed, as illustrated in Scheme 8.
The reaction in protic solvent, i.e. water, takes place through path
I that begins with the cyclization of the zwitterionic phenoxy-
iminium ion E-I, which was generated from E-A in the presence
of pyrrolidine, to afford F, successive [2+2] oxidation of the
1
cyclic enamine F by O2 form dioxetane G. Ring opening of G
gave peroxide intermediate H, rearrangement of H through I to J,
followed by hydrolysis finished flavonol C. The proposed
intermediates in Path I were identified by a set of LC-ESI-MS
experiments for the reaction of E4 in water proceeds in under 40
min (Scheme 4 (a), Figure S25). The intramolecular Michael
product F4 was detected at m/z 324.1606 with a retention time of
1.792 min which can be differentiate from E4-A (m/z 324.1652,
On the other hand, the reaction in aprotic solvent, i.e.
acetonitrile, takes place through Path II that starts from the
Michael reaction between E-B and pyrrolidine, and concomitant
generation of the radical pair precursors of L and HOO. to adducts
M arising by intramolecular electron transfer. HOO. would
conversion into H2O2 by dismutation under the presence of water,
the precursor of highly reactive OH.25. Photoaddition of M and
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HO. to afford N. Retro-Michael reaction of N resulted in O.
resulted in good yields, regardless of the substituent of B-ring
Tautomerization of O generates P, which proceeds through
cylization and dehydration to resulted in R. Aurone was finalized
by hydration of the iminium precursor R. The proposed
intermediates in Path II were identified by a set of LC-ESI-MS
experiments of E13HCl in acetonitrile (Scheme 6 (e)), Figure S26).
m/z 455.2200 ([K13+H]+) was detected, which could be assigned
to the Michael product of E-B. Although the radical species L13
and M13 could not be detected, the adduct N13 of M13 and the
hydroxyl radical was recognized ([N13+Na]+ m/z 493.3276). The
intermediate O13 resulted by the elimination of pyrrolidine from
N13, as well as its tautomeric format P13 and successive
cyclization intermediate Q13, were detected at m/z 400.2017). R13
(not detectable from LCMS) could be generated from dehydration
of Q13 and simultaneously hydrolyzed to D13. The final product
D13 was confirmed by the fragment at m/z 329.1019, of [D13+H]+.
It should be pointed out that for most substrates, both flavonol
and aurone were produced, since both E-A and E-B were existed
in either water or acetonitrile. The effects of different lifetime of
singlet oxygen in water and acetonitrile to the product selectivity
also could not be excluded. Since the lifetime of singlet oxygen in
water (3.1 μs) is much shorter than in acetonitrile (77.1 μs).26 The
activation energy of [2+2] oxidation in Path I might be higher
than that of the radical reaction in Path II. Therefore, typically,
higher reaction temperature is favored in preparation of flavonols.
The minor existence of epoxide, which leads to both flavonol and
aurone cannot be excluded, since dihydrogenflavonol was
detected from the model reaction. Density functional theory (DFT)
calculations for the cyclization of epoxide intermediate (G'1). The
results suggest that the barrier is higher for flavonol C1 formation
than that of aurone D1. (Figure S27). If flavonol and aurone are
developed mainly from the epoxide, aurone D1 should be obtained
as the major product rather than flavonol C1. This was in
controversial to our experimental observations. Thus, the
proposed mechanism of path I for flavonol and path II for aurone
was plausible.
At current state, although we are not sure of which species
works as the sensitizer to promote the reactive oxygen species
(ROS), but both the enamine E and pyrrolidine are responsible for
the generation of ROS, since no oxidation of E was observed in
the absence pyrrolidine or pyrrolidine was oxidized without E.
The requirements for light and 10 equivalents of pyrrolidine in
effecting the reaction are indicative of photochemical nature of
the reaction and the function of pyrrolidine in initiation of ROS.
Based on the mechanism, we could understand the influence of
both the steric and electronic property of substrates on the
selectivity of products. All substrates without a 5-substituent are
favorable in producing flavonols through cyclizarion of the
zwitterionic-like intermediate E-I, due to the easy formation of E-
A and co-planar effect of the phenoxide of A-ring with imine ion
(Table 2, C24-C42). In addition, substrates with electron donation
group(s), such as those of -OH, -OCH3, -CH3, and -N(CH3)2 on B-
ring, would stabilize the formation of E-A, which proceeded
favorably to generate the zwitterionic phenoxy-iminium
intermediate E-I in the presence of pyrrolidine, following path I to
afford flavonols (Table 2, C1-C4, C9-C13, C15-C23, C25-C28, C31-
C33, C36-C37, C39). Substrates with –OH group at C'-4 of B-ring
gave excellent yields (Table 2, C4 (85%), C19 (82%), C28 (86%),
C37 (85%), C39 (81%), regardless of the types of substituents on
A-ring. Whereas the substrates with 5-substituent on A-ring
and/or electron-withdrawing groups on B-ring, such as –Cl, -Br
and –NO2, would favor the formation of E-B, which would
successively going through path II to produce aurones (Table 2,
C6-C8). The stereoscopic effect is greater than the electronic
effect in the reaction. A-ring without substituent at C-5 were
(Table 2, C24-C42). A-ring with a group at C-5 and B-ring with
electron withdrawing group (-Cl, -Br, -NO2) afforded lower yields
of flavonols, and aurones were turned to be the major products.
(Table 2, D6 (72%), D7 (75%), and D8 (81%)).
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■ CONCLUSION
In summary, we have developed a one-pot aerobic oxidative
synthesis of flavonols from 2'-hydroxyl-acetophenone and
benzaldehyde in the presence of pyrrolidine in water under
atmospheric condition.
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Our preliminary mechanistic investigation demonstrates that
the selectivity for flavonol or aurone was originated from solvent
triggered intermediates, the phenol-iminium E-A and the
ketoenamine intermediate E-B. Consequently, formation of
flavonol was favored in the presence of pyrrolidine in water
through cyclization of the zwitterionic phenoxy-iminium ion E-I
followed by [2+2] reaction with 1O2, whereas the Michael
reaction between in-situ generated E-A and pyrrolidyl anion,
followed by a radical oxidation in the presence of pyrrolidine in
aprotic solvent, was accounted for the pathway leading to aurone.
Our results should provide valuable information not only for
optimization of synthetic methods for flavonols, but also for the
design of new amine catalyzed ROS reactions. Further studies are
underway in our group to elucidate the fundamental ROS
generations and the theoretical investigation of the reactivates of
solvent dependent intermediates toward the cyclization/ [2+2]
oxidation and the Michael /radical processes.
■ EXPERIMENTAL PART
General Information. All commercially available chemicals and
reagents were used without any further purification unless
mentioned otherwise. Melting Points were determined by X-6
apparatus without correction. Chromatographic purification was
performed on silica gel (200-300 mesh). Analytical thin layer
chromatography (TLC) was performed on silica gel 60-F254
1
(Qindao, China), which was detected by fluorescence. H NMR
spectra were recorded on 400 MHz, 600 MHz and 800 MHz. 13
C
NMR spectra were recorded at 101, 151 or 201 MHz.
Assignments of 1H NMR and 13C NMR signals were made, where
possible, using HSQC and HMBC experiments. The spectra were
recorded in CDCl3, DMSO-d6, CD3OD, or Acetone-d6 as the
solvent. The peaks around δ 7.26 (1H NMR) and 77.16 (13C
NMR) correspond to CDCl3. The peaks around δ 2.50 (1H NMR)
and 39.52 (13C NMR) correspond to DMSO-d6. The peaks around
δ 3.31 (1H NMR) and 49.01 (13C NMR) correspond to CD3OD.
The peaks around δ 2.05 (1H NMR), 29.84 (13C NMR) and 206.26
(13C NMR) correspond to Acetone-d6. Multiplicities are indicated
as follows: s (singlet), d (doublet), t (triplet), dd (doublet of
doublets), etc. Coupling constants (J) are given in hertz. Chemical
shifts (δ) are reported in parts per million relative to TMS as an
internal standard. The ESI-HRMS was carried out on a Bruker
Bio TOF IIIQ (quadrupole time of flight) mass spectrometer.
General Procedure for the Preparation of Flavonols.
Pyrrolidine (12.04 mmol, 10.0 equiv.) was added to a suspending
solution of acetophenone
A (1.204 mmol, 1.0 equiv.),
benzaldehyde B (1.26 mmol, 1.05 equiv.) in H2O (20 mL) under
an atmospheric condition. The resulting mixture was stirred at 50
°C (oil bath) for 24 h then cooled to room temperature. The
mixture was poured into ice-cold water and acidified with HCl
aqueous solution (30%, v/v) to pH=4. The produced precipitate
was filtered and washed with water and ethanol. The crude
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ethanol to afford 2'-hydroxy-4, 6'-dimethoxy chalcone Y1 (1.38 g,
82%) as a yellow solid.
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products were recrystallized from ethanol to afford flavonol C.
All products were similarly purified by crystallization, except C1,
C3, C5-C10, C12-C13, and C20, which were obtained by flash silica
gel column chromatography (PE/EA), since aurone (D1, D3, D5-
D10, D12 -D13, D20) was produced.
2-3-Dihydro-5-methoxy-2-(4-methoxyphenyl)-4H-1-
benzopyran-4-one (Z1): Sodium carbonate (1.06 g, 10 mmol)
was added to a solution of 2'-hydroxy-4, 6'-dimethoxychalcone Y1
(0.5 g, 1.758 mmol) in MeOH (10 mL) and H2O (10 mL). After
stirring at room temperature for 3 h, the reaction mixture was
diluted with water (10 mL) and extracted three times with diethyl
ether (40 mL). The organic layers were combined and dried over
anhydrous sodium sulfate. The organic solvent was removed in
vacuo. The crude product was purified by silica gel column
chromatography (PE/EA= 6/1) to afford a pale yellow solid Z1
(0.2 g, 35%).
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A Gram Scale Synthesis of C1: Pyrrolidine (14.817 mL, 10.0
equiv.) was added to a suspending solution of acetophenone A1
(3.000 g, 1.0 equiv.), benzaldehyde B1 (2.701 g, 1.1 equiv.) in
H2O (120 mL) and CH3OH (10 mL) under an atmospheric
condition. The resulting mixture was stirred at 50 °C (oil bath) for
24 h then cooled to room temperature. The mixture was poured
into ice-cold water and acidified with HCl aqueous solution (30%,
v/v) to pH=4. The purification process followed the general
procedure. The isolated products C1 (3.339 g, 62%) were obtained.
A Gram Scale Synthesis of D8 : Pyrrolidine (14.817 mL, 10.0
equiv.) was added to a suspending solution of acetophenone A1
(3.000 g, 1.0 equiv.), benzaldehyde B8 (3.001 g, 1.1 equiv.) in
CH3CN (120 mL) and H2O (10 mL) under an atmospheric
condition. The resulting mixture was stirred at 50 °C (oil bath) for
24 h then cooled to room temperature. The mixture was poured
into ice-cold water and acidified with HCl aqueous solution (30%,
v/v) to pH=4. The purification process followed the general
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2,3-Dihydro-3-hydroxy-5-methoxy-2-(4-methoxyphenyl)-4H-
1-benzopyran-4-on
(V1):
The
2′-hydroxy-4,
6′-
dimethoxychalcone Y1 (0.5 g, 1.758 mmol) was suspended in H2O
(30 mL), then sodium hydroxide (1.4 g, 35 mmol) and 30% H2O2
(0.9 mL, 8.79 mmol) were added at room temperature. After
stirring for 2 h, the suspension was filtered and washed with
water. The crude product was purified by silica gel column
chromatography (PE/EA= 6/1) to afford a white solid V1 (0.25 g,
46%).
4-Methoxy-2-(4-methoxybenzylidene) benzofuran-3(2H)-one
(D1): The 2'-hydroxy-4, 6'-dimethoxychalcone Y1 (0.5 g, 1.758
mmol) was dissolved in pyridine (10 mL), and mercuric acetate
(0.843 g, 2.64 mmol) was added to the solution. The reaction
mixture was stirred at 110 °C (oil bath) for 5 h then cooled to
room temperature. The resulting mixture was poured into ice-cold
water and acidified with HCl aqueous solution (30%, v/v) to
pH=6. The resulting mixture was extracted three times with
dichloromethane (20 mL), which was dried over sodium sulfate.
After evaporation, the residue was on recrystallization from
ethanol gave yellow needles of D1 (0.39 g, 85%).
procedure. The isolated products D8 (4.293 g, 80%) were obtained.
Isotope Oxygen Tracking for the Model Reaction: 18O2
Tracking. A Schlenk tube was charged with acetophenone A1 (30
mg, 0.18 mmol), benzaldehyde B1 (26 mg, 0.19 mmol),
pyrrolidine (150.0 μL, 1.8 mmol) and water (1 mL). The Schlenk
tube was filled with nitrogen, which was exchanged for isotope
oxygen with an isotope oxygen balloon (18O2). The mixture was
stirred at 50 °C (oil bath) for 24 h then cooled to room
temperature and quenched with 5 mL of HCl aqueous solution
(30%, v/v). The purification process followed the general
procedure. The isolated products C1 (37 mg, 69%) and D1 (11 mg,
22%) were subjected for HRMS analysis (Figure S1).
In-Situ 1H NMR Study of the Model Reaction in CD3OD.
Pyrrolidine (30.0 μL, 0.36 mmol) was added to a solution of
acetophenone A1 (6 mg, 0.036 mmol), benzaldehyde B1 (4.7 μL,
0.038 mmol) in CD3OD (0.5 mL) and H2O (5.2 μL, 0.288 mmol)
under an atmospheric condition. The mixture is stirred at room
temperature under an atmospheric condition. Then, the mixture
H218O Tracking. A Schlenk tube equipped with an oxygen
balloon was charged with acetophenone A1 (30 mg, 0.18 mmol),
benzaldehyde B1 (26 mg, 0.19 mmol), pyrrolidine (150.0 μL, 1.8
mmol) and H218O (1 mL). The resulting mixture was stirred at 50
°C (oil bath) for 24 h then cooled to room temperature and
quenched with 5 mL of HCl aqueous solution (30%, v/v). The
purification process followed the general procedure. The isolated
products C1 (33 mg, 61%) and D1 (14 mg, 28%) were subjected
for HRMS analysis (Figure S2).
1
1
was detected by H NMR in a time scale manner. The H NMR
spectra resulting was time-dependent (Figure S4).
(E)-3-Methoxy-2-(3-(4-Methoxyphenyl)-1-(Pyrrolidin-1-ium-
1-ylidene)allyl-2-d)phenolate (E1). Pyrrolidine (12.0 μL, 0.144
mmol) was added to a solution of acetophenone A1 (6 mg, 0.036
mmol), benzaldehyde B1 (4.7 μL, 0.038 mmol) in CD3OD (0.5
mL) and H2O (5.2 μL, 0.288 mmol) under an atmospheric
condition. The reaction mixture was stirred at room temperature
H218O and 18O2 Tracking. A Schlenk tube was charged with
acetophenone A1 (30 mg, 0.18 mmol), benzaldehyde B1 (26 mg,
0.19 mmol), pyrrolidine (150.0 μL, 1.8 mmol) and H218O (1 mL).
The Schlenk tube was filled with nitrogen, which was exchanged
for isotope oxygen with an isotope oxygen balloon (18O2). The
mixture is stirred at 50 °C (oil bath) for 24 h then cooled to room
temperature and quenched with 5 mL of HCl aqueous solution
(30%, v/v). The purification process followed the general
procedure. The isolated products C1 (38 mg, 70%) and D1 (10 mg,
20%) were subjected for HRMS analysis (Figure S3).
Preparation of the Reference Substances. 2'-Hydroxy-4, 6'-
dimethoxychalcone (Y1): sodium hydroxide (0.96 g, 24 mmol)
was added to a solution of acetophenone A1 (1 g, 6 mmol),
benzaldehyde B1 (0.86 g, 6.3 mmol) in ethanol (30 mL). The
reaction mixture was stirred at room temperature for 24 h. The
resulting mixture was acidified with HCl aqueous solution (30%,
v/v) to pH=4. The resulting precipitate was filtered and washed
with water and ethanol. The crude product was recrystallized from
1
for 1 h then detected by NMR. The H, 13C{1H}, HSQC, HMBC
1
NMR spectra of E1 were shown in Figure S5-8. H NMR (400
MHz, CD3OD) δ 7.73 - 7.62 (m, 2H), 7.33 (s, 1H), 7.19 (t, J = 8.3
Hz, 1H), 7.04 - 6.95 (m, 2H), 6.41 (dd, J = 8.5, 0.6 Hz, 1H), 6.21
(dd, J = 7.7 Hz, 1H), 4.22 (m, 2H), 3.87 (m, 4H), 3.71 (m, 4H),
2.36-2.19 (m, 2H), 2.16 - 1.99 (m, 2H). 13C{1H} NMR (101 MHz,
CD3OD) δ 174.8, 166.4, 163.4, 157.0, 153.2, 132.1, 131.6, 127.1,
117.3, 114.4, 114.4, 109.5, 95.1, 54.7, 54.6, 54.2, 51.9, 24.6, 23.9.
E4. Pyrrolidine (118.6 μL, 1.44 mmol) was added to a solution of
acetophenone A1 (60 mg, 0.36 mmol), benzaldehyde B4 (44 mg,
0.36 mmol) in MeOH (5 mL) under an atmospheric condition.
Then, the reaction mixture was stirred at room temperature for 1 h,
intermediate E4 (105 mg, 90%) was generated as a precipitate,
which was isolated by filtration and washed with MeOH (10 mL)
1
three times. The H, 13C{1H}, HSQC, HMBC, NMR spectra of
1
E4 were shown in Figure S9-12. H NMR (800 MHz, CD3OD) δ
7.50 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 8.4 Hz, 1H), 7.12 (d, J = 14.6
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Hz, 1H), 7.02 (d, J = 14.7 Hz, 1H), 6.66 (d, J = 8.6 Hz, 2H), 6.57
The Reaction of E4 with H2O2.30% H2O2 (28 μL, 0.9 mmol) was
(dd, J = 8.5, 5.2 Hz, 2H), 4.13 – 4.06 (m, 2H), 3.77 (s, 3H), 3.66
(m, 1H), 3.55 (m, 1H), 2.23 (m, 2H), 2.07 – 2.01 (m, 2H). 13C{1H}
NMR (201 MHz, CD3OD) δ 161.8, 161.7, 161.5, 156.9, 155.6,
144.5, 138.8, 132.4, 122.4, 118.6, 110.3, 108.8, 100.1, 55.0, 53.4,
added to a solution of E4 (30 mg, 0.09 mmol ) in water (2 mL).
The resulting mixture was stirred at room temperature for 30 min.
Then, dihydrogenflavonol (V4 ) (21 mg, 80%) was generated as a
1
precipitate, which was isolated by filtration. The H and 13C{1H}
+
1
51.2, 24.5, 24.1. HRMS (ESI) m/z: [M+H]+ calcd for C20H21NO3
NMR spectra of V4 were shown in Figure S18-19. H NMR (400
324.1594; found 324.1594. Elementary analysis: calcd for
C40H44N2O7: C, 72.27; N, 4.24; H, 6.67; found: C, 72.26; N, 4.41;
H, 6.511. All data indicate that this precipitate is an aggregate of
E4, with a formula of 2E4.H2O.
MHz, DMSO-d6) δ 9.55 (s, 1H), 7.48 (t, J = 8.3 Hz, 1H), 7.32 (d,
J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.40 (d, J = 5.0 Hz, 1H),
5.07 (d, J = 11.4 Hz, 1H), 4.48 (dd, J = 11.3, 5.0 Hz, 1H), 3.84 (s,
2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 192.5, 162.5, 160.6,
158.1, 136.7, 129.8, 128.1, 115.3, 109.8, 109.7, 104.8, 82.9, 73.3,
56.4. HRMS (ESI) m/z: [M+Na]+ calcd for C16H14O5Na 309.0733;
found 309.0734.
The Reaction of E13•HCl with Pyrrolidine. Pyrrolidine (1 mL,
12.6 mmol) was added to a suspending solution of E13•HCl (52
mg, 0.126 mmol) in CH3CN (10 mL) under an atmospheric
condition. The resulting mixture was stirred at room temperature
for 24 h then cooled to room temperature. The mixture was
poured into ice-cold water and acidified with HCl aqueous
solution (30%, v/v) to pH=4. Then, the mixture extracted with
DCM (100 mL) three times, the organic layer was combined and
dried over sodium sulfate, filtered and concentrated. The crude
product was purified by flash silica gel column chromatography to
give D13 (12 mg, 30%) as a yellow solid.
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(E)-1-(1-(2-Hydroxy-6-methoxyphenyl)-3-(4-
Hydroxyphenyl)allylidene)pyrrolidin-1-ium chloride (E4-A). A
NMR tube was charged with E4 (10 mg), CD3OD (0.5 mL), and
HCl aqueous solution (36%, v/v) (20 μL). Then, the resulting
1
mixture was detected by NMR (Figure S13-14). H NMR (400
MHz, CD3OD) δ 7.66 (d, J = 8.7 Hz, 2H), 7.48 (t, J = 8.4 Hz,
1H), 7.37 (d, J = 15.1 Hz, 1H), 7.17 (d, J = 15.1 Hz, 1H), 6.90 (d,
J = 8.7 Hz, 2H), 6.75 (t, J = 7.8 Hz, 2H), 4.36 - 4.24 (m, 2H), 3.83
(s, 3H), 3.78 - 3.61 (m, 2H), 2.30 (p, J = 6.9 Hz, 2H), 2.11 (p, J =
6.9 Hz, 2H). 13C{1H} NMR (101 MHz, CD3OD) δ 171.0, 162.9,
156.8, 155.4, 154.8, 133.5, 132.7, 125.5, 116.2, 115.4, 108.7,
107.4, 102.6, 55.5, 54.7, 52.7, 24.5, 24.0. HRMS (ESI) m/z:
[M+H]+ calcd for C20H21NO3 324.1521; found 324.1642.
(E)-1-(3-(4-Hydroxy-3,5-dimethoxyphenyl)-1-(2-Hydroxy-6-
methoxyphenyl)allylidene)pyrrolidin-1-ium
chloride
The Reaction of E13•HCl with H2O2.30% H2O2 (51.0 μL, 2.4
mmol) and sodium hydroxide (9.6 mg, 0.24 mmol) was added to a
solution of E13•HCl (100 mg, 0.24mmol) in H2O (5.0 mL) under
an atmospheric condition. The resulting mixture was stirred at
room temperature for 2 h. Dihydroflavonol (V13) (21 mg, 80%)
was generated as a precipitate, which was isolated by filtration.
The 1H, 13C{1H} NMR spectra of V13 were shown in Figure S20-
(E13.HCl). Pyrrolidine (118.6 μL, 1.44 mmol) was added to a
solution of acetophenone A1 (60 mg, 0.36 mmol), benzaldehyde
B13 (60 mg, 0.36 mmol) in MeOH (5 mL) under an atmospheric
condition. Then, the reaction mixture was stirred at room
temperature for 4 h. the mixture was poured into ice-cold water
and acidified with HCl aqueous solution (30%, v/v) to pH=4. The
mixture was extracted with DCM (3 × 100 mL), the organic layer
was combined and dried over sodium sulfate, filtered and
concentrated. Yellow enimine salt intermediate E13∙HCl (121 mg,
1
21. H NMR (400 MHz, CDCl3) δ 7.48 (t, J = 8.4 Hz, 1H), 6.82
(s, 2H), 6.67 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 5.66 (s,
1H), 5.00 (d, J = 12.3 Hz, 1H), 4.55 (d, J = 12.3 Hz, 1H), 4.05 (s,
1H), 3.99 (s, 3H), 3.96 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3)
δ 192.6, 163.0, 160.7, 147.1, 137.2, 135.6, 127.3, 110.1, 108.5,
104.4, 104.2, 83.6, 73.1, 56.4, 56.3. HRMS (ESI) m/z: [M+Na]+
calcd for C18H18NaO7 369.0945; found 369.0945.
UV-visible Spectra Characterization of E4. The stock solution
with the final concentration of 5×10-4 M was prepared by
dissolving 16 mg of E4 in 50mL methanol, transfer the solution to
100 mL volumetric flask and set the volume to the scale for use.
Taking o.1 mL of stock solution using a Hamilton syringe into the
colourimeter, then adding 3 mL different solvents (water,
acetonitrile) and different concentrations of pyrrolidine, After
each of addition, the UV-vis absorption was measured in the
wavelength range of 300-600. All the titration experiments were
carried out on a Pgeneral TU-1900 spectrometer at 298K. UV-vis
absorption spectra of E4 (1.7×10-5 M), E4 with equal molar HCl
(break line) and E4 in the presence of 0.2-10 equivalents of
pyrrolidine (plain lines) in water and acetonitrile were recorded,
respectively (Figure S22, (1), (3)).
UV-visible Spectra Characterization of E13•HCl. The stock
solution with the final concentration of 5×10-4 M was prepared by
dissolving 10.5 mg of E13•HCl in 20 mL methanol, transfer the
solution to 50 mL volumetric flask and set the volume to the scale
for use. Taking o.2 mL of stock solution using a Hamilton syringe
into the colourimeter, then adding 3 mL different solvents (water,
acetonitrile) and different concentrations of pyrrolidine, After
each of addition, the UV-vis absorption was measured in the
wavelength range of 300-600. All the titration experiments were
carried out on a Pgeneral TU-1900 spectrometer at 298K. The
UV-vis spectra of E13.HCl (3.4×10-5 M, break line) and E13HCl
with an increasing pyrrolidine amount from 0.2 to 10 equivalents
in water and acetonitrile were recorded (Figure S23, (1), (3)).
1
80%) were obtain. The H, 13C{1H} NMR spectra and single-
1
crystal structure of E13.HCl were shown in Figure S15-17. H
NMR (400 MHz, D2O) δ 7.48 (t, J = 8.4 Hz, 1H), 6.87 (s, 2H),
6.70 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 12.0 Hz, 1H), 6.51 (s, 2H),
3.99 (m, 2H), 3.63 (s, 9H), 3.56 (m, 2H), 2.14 (m, 2H), 1.93 (m,
2H). 13C{1H} NMR (101 MHz, D2O) δ 167.0, 156.4, 155.7, 153.5,
147.4, 139.8, 133.9, 125.0, 115.7, 109.0, 107.6, 103.8, 56.0, 55.1,
52.7, 24.5, 24.0. HRMS (ESI) m/z: [M]+ calcd for C22H26NO5
384.1805; found 384.1840. Elementary analysis: calcd for
C44H54Cl2N2O11: C, 61.61; N, 3.27; H, 6.35; Cl, 8.27 found: C,
61.82; N, 2.81; H, 6.24; Cl, 8.12. All data indicate that this
precipitate is an aggregate of E13HCl, with a formula of 2E13
HCl.H2O.
X-ray crystallographic analysis of E13.HCl. In a sealable bottle,
the dried solids of E13HCl (20 mg) were dissolved in 10 mL
methanol and 1mL water. The X-ray-quality crystals were
obtained from the capped bottle after one week. The X-ray
crystallographic analysis of the intermediate E13.HCl was shown
in Figure S17.
The Reaction of E4 with Pyrrolidine. Pyrrolidine (1 ml, 12.6
mmol) was added to a suspending solution of E4 (40 mg, 0.126
mmol) in different solvents (10 mL) (H2O, CH3OH, CH3CN)
under an atmospheric condition. The resulting mixture was stirred
at room temperature for 24 h. The mixture was poured into ice-
cold water and acidified with HCl aqueous solution (30%, v/v) to
pH=4. The produced precipitate was filtered and then washed
with water and ethanol. The crude product were recrystallized
from ethanol to afford C4. The flavonol C4 was respectively
generated with 80% yield in water, 40% yield in methanol, and
trace C4 in acetonitrile.
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LCMS Study for the Model Reaction under 18O2. Method:
56.5, 55.4. HRMS (ESI) m/z: [M+Na]+ calcd for C17H14NaO5
2
3
4
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6
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Column: Waters X-Bridge-Shield-RP-C18 50 mm*4.6 mm 3.5
µm; Mobile Phase: A: 0.05% TFA Water B: 0.05% TFA CAN;
Gradient: B from 10% to 100% for 4.0 min and hold 100% for 1.0
min; Flow Rate: 2.5 mL/min; Column Temperature: 40 °C. Assay
conditions: A Schlenk tube was charged with acetophenone A1
(30 mg, 0.18 mmol), benzaldehyde B1 (26 mg, 0.19 mmol),
pyrrolidine (150.0 μL, 1.8 mmol) and water (2 mL). The Schlenk
tube is filled with nitrogen, which is exchanged for isotope
oxygen with an isotope oxygen balloon (18O2 ). The mixture was
stirred at 50 °C (oil bath) for 3 h and examined by LC-HRMS
(Figure S24).
321.0733; found 321.0720.
2-(4-(Dimethylamino)phenyl)-3-hydroxy-5-methoxy-4H-
chromen-4-one (C2): Yellow solid; yield: 85%; mp: 170-172 °C
1
(CH3OH-H2O); H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 9.1
Hz, 2H), 7.55 (t, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.15 (d, J = 8.5 Hz,
1H), 6.77-6.83 (m, 3H), 4.04 (s, 3H), 3.08 (s, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ 172.2, 159.4, 157.0, 151.2, 144.3, 137.2,
133.2, 128.9, 118.1, 111.6, 110.3, 104.7, 56.4, 40.1. HRMS (ESI)
m/z: [M+Na]+ calcd for C18H17NNaO4 334.1050; found 334.1045.
3-Hydroxy-5-methoxy-2-(p-Tolyl)-4H-chromen-4-one
(C3):Yellow solid; yield: 60%; mp: 165-167 °C (CH3OH-H2O);
1H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 8.3 Hz, 2H), 7.58 (t, J
= 8.4 Hz, 1H), 7.37 (s, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.16 (d, J =
8.5 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 4.03 (s, 3H), 2.43 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3) δ 172.8, 159.6, 157.3, 142.9,
140.3, 138.4, 133.8, 129.3, 128.2, 127.4, 111.5, 110.3, 104.9,
56.4, 21.5. HRMS (ESI) m/z: [M+Na]+ calcd for C17H14NaO4
305.0784; found 305.0773.
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LCMS Study for the Reaction of E4 with Pyrrolidine in Water.
Method: Column: Waters X-Bridge-Shield-RP-C18 50 mm*4.6
mm 3.5 um; Mobile Phase: A: Water B: MeOH; Gradient: B from
10% to 100% for 4.0 min and hold 100% for 1.0 min; Flow Rate:
2.5 mL/min; Column Temperature: 40 °C. Assay conditions:
Pyrrolidine (26.0 μL, 0.31 mmol) was added to a solution of
intermediate E4 (10 mg, 0.031 mmol) in H2O (2 mL). The mixture
was stirred at room temperature under an atmospheric condition.
The reaction mixture was examined by LCMS at 0min, 40 min,
2h, 4h, 8h, 12h, 24h. (Figure S25).
3-Hydroxy-5-methoxy-2-(4-Hydroxyphenyl)-4H-chromen-4-
one (C4): Yellow needles; yield: 85%; mp: 240-242 °C (CH3OH-
1
H2O); H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.95 (s,
LCMS Study for the Reaction of E13.HCl with Pyrrolidine in
Acetonitrile. Method: Column: Waters X-Bridge-Shield-RP-C18
50 mm*4.6 mm 3.5 um; Mobile Phase: A: Water B: MeOH;
Gradient: B from 10% to 100% for 4.0 min and hold 100% for 1.0
min; Flow Rate: 2.5 mL/min; Column Temperature: 40 °C. Assay
conditions: Pyrrolidine (20 μL, 0.24 mmol) was added to a
solution of intermediate E13.HCl (10 mg, 0.024 mmol) in CH3CN
(2 mL). The mixture was stirred at room temperature under an
atmospheric condition. The reaction mixture was examined by
LCMS at 0 h, 2 h, 4 h, 8 h, 12 h, and 24 h. (Figure S26).
1H), 8.07 (d, J = 8.9 Hz, 2H), 7.66 (t, J = 8.4 Hz, 1H), 7.24 (d, J =
8.3 Hz, 1H), 6.99 – 6.89 (m, 3H), 3.90 (s, 3H), 3.38 (s, 14H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 172.2, 159.5, 159.3,
156.8, 143.4, 138.3, 134.2, 129.6, 122.2, 115.9, 112.1, 110.4,
106.1, 56.6. HRMS (ESI) m/z: [M+H]+ calcd for C16H13O5
285.0760; found 285.0757.
3-Hydroxy-5-methoxy-2-phenyl-4H-chromen-4-one
(C5):
1
Yellow solid; yield: 35%; mp: 169-171 °C (CH3OH-H2O); H
NMR (400 MHz, Acetone-d6) δ 8.33 – 8.27 (m, 2H), 8.11 (s, 1H),
7.71 (t, J = 8.4 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.51 (t, J = 7.3
Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 3.98
(s, 3H). 13C{1H} NMR (101 MHz, Acetone-d6) δ 172.1, 159.7,
157.3, 141.6, 138.9, 134.2, 131.4, 129.6, 128.5, 127.3, 111.5,
110.0, 105.5, 55.7. HRMS (ESI) m/z: [M+Na]+ calcd for
C16H12NaO4 291.0628; found 291.0619.
Calculation Methods. Density functional theory (DFT)
calculations were performed with Gaussian 03 program.27 The
M06-2X functional by Zhao and Truhlar was used, with the
standard 6-31+G (d) basis set. The geometries of reactants,
transition states (TS), and products were fully optimized, followed
by vibrational frequency calculations at the same levels of theory
to obtain the zero-point energies (ZPE) and verify whether it is a
minimum or a transition state on the potential energy surfaces
(PES).28 To estimate the bulk solvent effects on the reaction, all
structures were optimized in methanol solvent with the polarized
continuum model using the integral equation formalism variant
(IEFPCM).29 The temperature-dependent enthalpy corrections and
the entropy effects are computed at 298K and 1 atmosphere of
pressure. As shown in Figure S27, the reaction would prefer to the
reaction channel via transition state TS-A for the process via TS-
A has lower Gibbs free energy barrier. The transition state TS-B
is 3.3 kcal mol-1 less stable than TS-A. Thus, the product with
five-membered ring structures would be the major product.
1-[2-Hydroxy-4,6-bis(Methoxymethoxy)phenyl]ethanone (A4):
Colorless oil; yield 76%; 1H NMR (400 MHz, CDCl3) δ 13.73 (s,
1H), 6.26 (dd, J = 6.5, 2.3 Hz, 2H), 5.26 (s, 2H), 5.18 (s, 2H),
3.53 (s, 3H), 3.48 (s, 3H), 2.66 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 203.2, 166.8, 163.5, 160.4, 106.9, 97.1, 94.5, 94.0, 56.7,
56.4, 33.0. HRMS (ESI) m/z: [M+Na]+ calcd for C12H16NaO6
279.0839; found 279.0841.
2-(4-Chlorophenyl)-3-hydroxy-5-methoxy-4H-chromen-4-one
(C6): Yellow solid; yield: 10%; mp: 195-197 °C (CH3OH-H2O);
1H NMR (600 MHz, CDCl3) δ 8.22 (d, J = 8.7 Hz, 2H), 7.63 (t, J
= 8.4 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.46 (s, 1H), 7.18 (d, J =
8.5 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.06 (s, 3H). 13C{1H} NMR
(150 MHz, CDCl3) δ 172.8, 159.7, 157.3, 141.4, 138.7, 135.9,
134.1, 129.5, 128.9, 128.7, 111.4, 110.3, 105.1, 56.5. HRMS (ESI)
m/z: [M+Na]+ calcd for C16H1135ClNaO4 325.0238; found
325.0229; [M+Na]+ calcd for C16H1137ClNaO4 327.0227; found
327.0227.
3-Hydroxy-5-methoxy-2-(m-tolyl)-4H-chromen-4-one
(C9):
White solid; yield: 42%; mp: 142-144 °C (CH3OH-H2O); 1H
NMR (400 MHz, Acetone-d6) δ 8.10 (d, J = 9.3 Hz, 2H), 7.71 (t, J
= 8.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H),
7.27 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 3.98 (s, 3H),
2.46 (s, 3H). 13C{1H} NMR (101 MHz, Acetone-d6) δ 172.0,
159.7, 157.3, 141.8, 138.8, 138.0, 134.1, 131.3, 130.4, 128.4,
127.7, 124.6, 115.9, 111.4, 110.0, 105.4, 55.7. HRMS (ESI) m/z:
[M+Na]+ calcd for C17H14NaO4 305.0784; found 305.0772.
3-Hydroxy-5-methoxy-2-(3-Hydroxyphenyl)-4H-chromen-4-
one (C10): Yellow solid; yield: 52%; mp: 267-269 °C (EtOH-
3-Hydroxy-5-methoxy-2-(4-Methoxyphenyl)-4H-chromen-4-
one (C1):Yellow solid; yield: 63%; mp: 168-170 °C (EtOH-H2O);
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.8 Hz, 2H), 7.59 (t, J
= 8.3 Hz, 1H), 7.37 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.06 (d, J =
8.8 Hz, 2H), 6.80 (d, J = 8.1 Hz, 1H), 4.05 (s, 3H), 3.91 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 172.7, 160.9, 159.5, 157.2,
143.0, 137.9, 133.7, 129.2, 123.4, 114.1, 111.4, 110.3, 104.9,
1
H2O); H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.19 (s,
1H), 7.74 – 7.57 (m, 3H), 7.36 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.4
Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 8.0, 2.4 Hz, 1H),
3.91 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.5,
159.6, 157.8, 156.9, 142.5, 139.6, 134.6, 132.7, 130.0, 118.5,
117.2, 114.6, 112.1, 110.4, 106.2, 56.7. HRMS (ESI) m/z:
[M+Na]+ calcd for C16H12NaO5 307.0577; found 307.0575.
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2-(3-Methoxy-4-hydroxyphenyl)-3-hydroxy-5-methoxy-4H-
2-(4-(Dimethylamino)phenyl)-5,7-dimethoxy-3-hydroxy-4H-
chromen-4-one (C11): Yellow needles; yield: 83%; mp: 248-250
chromen-4-one (C18): Yellow solid; yield: 90%; mp: 210-212 °C
1
1
°C (EtOH-H2O); H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H),
(EtOH-H2O); H NMR (400 MHz, CDCl3) δ8.13 (d, J = 9.2 Hz,
8.99 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.5, 2.0 Hz,
1H), 7.67 (t, J = 8.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.97 (d, J =
7.7 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 172.2, 159.5, 156.8, 148.9, 147.9, 143.2, 138.5,
134.2, 122.6, 121.7, 116.0, 112.0, 111.8, 110.5, 106.1, 56.6, 56.2.
HRMS (ESI) m/z: [M+H]+ calcd for C17H15O6 315.0863; found
315.0859.
2-(3,4-Dimethoxyphenyl)-3-hydroxy-5-methoxy-4H-chromen-
4-one (C12): Yellow solid; yield: 61%; mp: 175-177 °C (CH3OH-
H2O); 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.80 (m, 2H), 7.60 (t,
J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.04 (d, J
= 9.1 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 4.06 (s, 3H), 4.01 (s, 3H),
3.99 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.7, 159.5,
157.2, 150.5, 148.8, 142.8, 138.0, 133.8, 123.6, 121.0, 110.9,
110.4, 105.0, 56.5, 56.0. HRMS (ESI) m/z: [M+Na]+ calcd for
C18H16NaO6 351.0839; found 351.0827.
1H), 7.34 (s, 1H), 6.80 (d, J = 9.2 Hz, 1H), 6.55 (d, J = 2.2 Hz,
1H), 6.34 (d, J = 2.2 Hz, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.07 (s,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 163.9, 160.4,
158.7, 151.0, 143.5, 136.7, 128.5, 118.3, 111.6, 106.3, 95.4, 92.4,
56.4, 55.8, 40.1. HRMS (ESI) m/z: [M+Na]+ calcd for
C19H19NNaO5 364.1155; found 364.1155.
9
5,7-Dimethoxy-3-hydroxy-2-(4-Hydroxyphenyl)-4H-chromen-
4-one (C19): Yellow solid; yield: 82%; mp: 263-265 °C (EtOH-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
H2O); H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.78 (s,
1H), 8.06 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.82 (d, J
= 2.1 Hz, 1H), 6.48 (d, J = 2.1 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 171.5, 164.1, 160.6,
159.1, 158.5, 142.7, 137.9, 129.3, 122.3, 115.9, 106.7, 96.1, 93.2,
56.6, 56.4. HRMS (ESI) m/z: [M+Na]+ calcd for C17H14NaO6
337.0683; found 337.0683.
5,7-Dimethoxy-3-hydroxy-2-(3-Hydroxyphenyl)-4H-chromen-
4-one (C20): Yellow solid; Yield: 68%; mp: 267-269 °C (EtOH-
H2O); 1H NMR (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.63 (d, J =
7.9 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H),
6.80 (s, 1H), 6.49 (s, 1H), 3.91 (s, 3H), 3.88 (s, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 171.7, 164.3, 160.6, 158.6, 157.8,
141.8, 139.2, 132.8, 129.9, 118.2, 117.0, 114.4, 106.7, 96.2, 93.1,
56.7, 56.4. HRMS (ESI) m/z: [M+Na]+ calcd for C17H14NaO6
337.0681; found 337.0683.
3-Hydroxy-2-(4-Hydroxy-3,5-dimethoxyphenyl)-5-methoxy-
4H-chromen-4-one (C13): Yellow solid; yield: 50%; mp: 178-180
1
°C (EtOH-H2O) H NMR (400 MHz, CDCl3) δ 7.64 – 7.56 (m,
3H), 7.19 (d, J = 8.5 Hz, 1H), 6.85 – 6.80 (m, 1H), 5.87 (s, 1H),
4.06 (s, 3H), 4.03 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
172.6, 159.6, 157.1, 147.0, 142.8, 138.0, 136.7, 133.8, 122.1,
111.4, 111.4, 110.3, 105.0, 104.8, 77.3, 77.2, 77.0, 76.7, 56.5,
56.5. HRMS (ESI) m/z: [M+Na]+ calcd for C18H16NaO7
367.0794; found 367.0793.
2-(3,4-Dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-
chromen-4-one(C21): Yellow solid; Yield: 85%; mp: 267-269 °C
3-Hydroxy-5-methoxy-2-(Thiophen-2-yl)-4H-chromen-4-one
(C14): Yellow solid; yield: 76%; mp: 204-206 °C (CH3OH-H2O);
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 3.8 Hz, 1H), 7.60 (dd,
J = 10.2, 6.7 Hz, 2H), 7.25 (m, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.81
(d, J = 8.2 Hz, 1H), 4.05 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 172.1, 159.6, 157.0, 140.3, 136.5, 133.9, 132.8, 129.4,
128.8, 128.1, 111.7, 110.3, 105.2, 56.5. HRMS (ESI) m/z:
[M+Na]+ calcd for C14H10NaO4S 297.0192; found 297.0182.
5-Fluoro-3-hydroxy-2-(4-Methoxyphenyl)-4H-chromen-4-one
(C15): Yellow solid; yield: 81%; mp: 198-200 °C (CH3OH-H2O);
1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.6 Hz, 2H), 7.64 (dd,
J = 13.4, 7.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 6.99-7.23 (m, 4H),
3.93 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.3 (d, J=1.01
Hz), 161.2, 160.3 (d, J = 264.62 Hz), 159.0, 156.1, 156.1, 144.5,
137.9, 133.3 (d, J = 11.11 Hz), 129.5, 123.0, 114.2, 114.1, 110.7
(d, J = 19.19Hz), 55.4 HRMS (ESI) m/z: [M+Na]+ calcd for
C16H11FNaO4 309.0534; found 309.0523.
5-Fluoro-3-hydroxy-2-(3,4,5-Trimethoxyphenyl)-4H-chromen-
4-one(C16): Yellow solid; yield: 78%; mp: 187-189 °C (EtOH);
1H NMR (400 MHz, CDCl3) δ 7.66 (td, J = 8.3, 5.6 Hz, 1H), 7.54
(s, 2H), 7.43 (d, J = 8.6 Hz, 1H), 7.25 (s, 1H), 7.10 (dd, J = 10.3,
8.1 Hz, 1H), 3.99 (s, 6H), 3.97 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 171.5, 160.3 (d, J= 265.63 Hz), 156.1, 156.1, 153.3,
143.9, 140.1, 138.4, 133.6 (d, J = 10.1 Hz), 125.7, 114.2 (d, J =
4.04 Hz), 111.3 (d, J = 11.11Hz), 110.9 (d, J = 20.2 Hz), 105.4,
61.0, 56.3 HRMS (ESI) m/z: [M+H]+ calcd for C18H16FO6
347.0925; found 347.0937.
1
(EtOH-H2O); H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz,
2H), 7.43 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.55 (s, 1H), 6.36 (s,
1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 171.9, 164.3, 160.5, 158.8, 150.3,
148.8, 142.1, 137.5, 123.8, 120.6, 110.9, 110.4, 106.2, 95.7, 92.4,
56.4, 56.0, 55.9, 55.8. HRMS (ESI) m/z: [M+Na]+ calcd for
C19H18NaO7 381.0945; found 381.0935.
3-Hydroxy-2-(4-Hydroxy-3-Methoxyphenyl)-5,7-dimethoxy-
4H-chromen-4-one (C22): Yellow solid; Yield: 80%; mp: 267-
1
269 °C (EtOH-H2O); H NMR (400 MHz, DMSO-d6) δ 9.26 (s,
1H), 8.84 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.6, 2.0
Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 1.7 Hz, 1H), 6.48
(d, J = 1.7 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 171.5, 164.1, 160.6,
158.5, 149.3, 146.7, 142.3, 138.3, 124.2, 119.4, 114.7, 112.3,
106.7, 96.1, 93.1, 56.6, 56.4, 56.1. HRMS (ESI) m/z: [M+H]+
calcd for C18H17O7 345.0969; found 345.0965.
5,7-Bis(Methoxymethoxy)-2-(4-(Dimethylamino)
phenyl)-3-
hydroxy-4H-chromen-4-one (C23): Yellow solid; yield: 88%;
mp: 170-172 °C (EtOH-H2O); 1H NMR (400 MHz, CDCl3) δ 8.21
(d, J = 9.0 Hz, 2H), 7.34 (s, 1H), 7.05 (d, J = 9.0 Hz, 2H), 6.87 (d,
J = 2.2 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 5.40 (s, 2H), 5.29 (s,
2H), 3.91 (s, 3H), 3.60 (s, 3H), 3.55 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 171.9, 161.5, 160.7, 158.3, 157.8, 142.6, 137.4,
129.0, 123.5, 114.0, 107.4, 100.7, 96.6, 95.3, 94.4, 56.6, 56.6,
55.4. HRMS (ESI) m/z: [M+H]+ calcd for C20H21NaO8 411.1050;
found 411.1047.
5,7-Dimethoxy-3-hydroxy-2-(4-Methoxyphenyl)-4H-chromen-
4-one (C17): Yellow solid; yield: 85%; mp: 155-157 °C (EtOH-
3-Hydroxy-2-phenyl-4H-chromen-4-one (C24): Yellow solid;
1
1
H2O); H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 9.0 Hz, 2H),
yield: 78%; mp: 170-172 °C (EtOH-H2O); H NMR (400 MHz,
7.38 (s, 1H), 7.04 (d, J = 9.0 Hz, 2H), 6.56 (d, J = 2.1 Hz, 1H),
6.36 (d, J = 2.1 Hz, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 164.3, 160.6, 160.5,
158.8, 142.2, 137.4, 128.9, 123.6, 114.0, 106.2, 95.7, 92.4, 56.4,
55.8, 55.4. HRMS (ESI) m/z: [M+Na]+ calcd for C16H12NaO5
307.0577; found 307.0575.
CDCl3) δ 8.29 (d, J = 7.5 Hz, 3H), 7.78 - 7.71 (m, 1H), 7.66 - 7.54
(m, 3H), 7.54 - 7.41 (m, 2H), 7.06 (s, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 173.5, 155.4, 144.9, 138.5, 133.7, 131.1, 130.2,
128.6, 127.8, 125.5, 124.5, 120.7, 118.3. HRMS (ESI) m/z: [M-
H]- calcd for C15H9O3 237.0547; found 237.0549.
3-Hydroxy-2-(p-Tolyl)-4H-chromen-4-one (C25): Yellow solid;
1
yield: 80%; mp: 191-193 °C (EtOH-H2O); H NMR (400 MHz,
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CDCl3) δ 8.25 (dd, J = 8.0, 1.5 Hz, 1H), 8.16 (d, J = 8.3 Hz, 2H),
DMSO-d6) δ 173.4, 157.7, 155.0, 145.7, 139.5, 134.2, 132.9,
2
7.70 (ddd, J = 8.6, 7.1, 1.6 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.45
- 7.38 (m, 1H), 7.35 (d, J = 8.2 Hz, 2H), 6.99 (s, 1H), 2.44 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 155.4, 145.3, 140.6,
138.1, 133.5, 129.4, 128.3, 127.7, 125.4, 124.5, 120.7, 118.3,
21.6. HRMS (ESI) m/z: [M-H]- calcd for C16H11O3 251.0703;
found 251.0708.
2-(4-(Dimethylamino)phenyl)-3-hydroxy-4H-chromen-4-one
(C26): Yellow solid; yield: 87%; mp: 184-186 °C (EtOH-H2O); 1H
NMR (400 MHz, CDCl3) δ 8.26 - 8.16 (m, 3H), 7.69 - 7.62 (m,
1H), 7.56 (d, J = 8.4 Hz, 1H), 7.38 (t, J =7.5 Hz, 1H), 6.92 (s, 1H),
6.81 (d, J = 8.0 Hz, 2H), 3.07 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 172.5, 155.1, 151.4, 146.7, 137.0, 132.8, 129.2, 125.2,
124.2, 120.9, 118.2, 118.0, 111.5, 40.1. HRMS (ESI) m/z: [M-H]-
calcd for C17H14NO3 280.0969; found 280.0962.
130.0, 125.3, 125.0, 121.7, 118.9, 118.8, 117.5, 115.0. HRMS
(ESI) m/z: [M+H]+ calcd for C15H11O4 255.0650; found 255.0652.
3-Hydroxy-2-(3,4,5-Trimethoxyphenyl)-4H-chromen-4-one
(C33): Yellow solid; yield: 74%; mp: 180-182 °C (EtOH-H2O); 1H
NMR(400 MHz, CDCl3) δ 8.26 (dd, J = 8.0, 1.5 Hz, 1H), 7.72
(ddd, J = 8.6, 7.1, 1.6 Hz, 1H), 7.61 (d, J =8.4 Hz, 1H), 7.55 (s,
2H), 7.46 – 7.40 (m, 1H), 7.04 (s, 1H), 3.98 (s, 6H), 3.94 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 155.3, 153.3, 144.7,
140.0, 138.2, 133.6, 126.3, 125.5, 124.6, 120.6, 118.3, 105.5,
61.0, 56.3. HRMS (ESI) m/z: [M-H]- calcd for C18H15O6
327.0864; found 327.0868.
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3-Hydroxy-2-(Thiophen-2-yl)-4H-chromen-4-one
(C34):
Yellow solid; yield: 75%; mp: 201-203 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.27 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 3.7 Hz,
1H), 7.72 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 5.0 Hz, 1H), 7.60 (d, J =
8.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.28 – 7.21 (m, 1H), 7.11 (s,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 155.0, 142.6,
136.3, 133.5, 132.9, 129.9, 129.5, 128.1, 125.4, 124.6, 121.0,
118.2. HRMS (ESI) m/z: [M+H]+ calcd for C13H9O3S 245.0267;
found 245.0278.
3-Hydroxy-2-(4-Methoxyphenyl)-4H-chromen-4-one
(C27):
Yellow solid; yield: 89%; mp: 232-234 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.27 (dd, J = 9.5, 2.5 Hz, 3H), 7.72 (ddd, J =
8.6, 7.1, 1.6 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.44 (t, J = 7.5 Hz,
1H), 7.08 (dd, J = 9.5, 2.5 Hz, 2H), 3.93 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 173.1, 161.1, 161.1, 155.3, 145.3, 137.6,
133.4, 129.5, 125.4, 124.4, 123.6, 120.7, 118.2, 114.1, 55.4.
HRMS (ESI) m/z: [M-H]- calcd for C16H11O4 267.0652; found
267.0647.
3-Hydroxy-7-methoxy-2-phenyl-4H-chromen-4-one
(C35):
Yellow solid; yield: 72%; mp: 180-182 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.26 - 8.21 (m, 2H), 8.14 (d, J = 8.9 Hz,
1H), 7.57 - 7.41 (m, 3H), 7.08 - 6.94 (m, 3H), 3.94 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 172.8, 164.3, 157.4, 144.2,
138.1, 131.2, 129.9, 128.6, 127.5, 126.8, 114.9, 114.6, 99.9, 77.3,
77.0, 76.7, 55.9. HRMS (ESI) m/z: [M-H]- calcd for C16H11O4
267.0652; found 267.0647.
3-Hydroxy-2-(4-Hydroxyphenyl)-4H-chromen-4-one
(C28):
Yellow solid; yield: 86%; mp: 168-170 °C (EtOH-H2O); 1H NMR
(400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.38 (s, 1H), 8.12 (t, J =
7.5 Hz, 3H), 7.77 (dt, J = 15.4, 7.7 Hz, 2H), 7.46 (t, J = 7.1 Hz,
1H), 6.96 (d, J = 8.8 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-
d6) δ 173.0, 159.6, 154.8, 146.5, 138.3, 133.8, 130.0, 125.2, 124.9,
122.4, 121.8, 118.7, 115.9. HRMS (ESI) m/z: [M+H]+ calcd for
C15H11O4 255.0640; found 255.0652.
3-Hydroxy-7-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-
one (C36): Brown solid; yield: 76%; mp: 192-193 °C (EtOH-
1
H2O); H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.6 Hz, 2H),
2-(4-Chlorophenyl)-3-hydroxy-4H-chromen-4-one
(C29):
8.14 (d, J = 8.8 Hz, 1H), 7.16 - 6.96 (m, 4H), 3.95 (s, 3H), 3.91 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.6, 164.1, 160.8,
157.2, 144.6, 137.3, 129.2, 126.7, 123.7, 114.7, 114.0, 99.8, 55.8,
55.4. HRMS (ESI) m/z: [M+H]+ calcd for C17H15O5 229.0903;
found 229.0914.
3-Hydroxy-7-methoxy-2-(4-hydroxyphenyl)-4H-chrom en-4-
one (C37): Yellow solid; yield: 85%; mp: 277-279 °C (EtOH-
H2O); 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 7.7 Hz, 2H),
7.69 (d, J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H),
6.95 (d, J = 7.8 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 172.5, 159.5, 156.3, 149.8, 146.4, 137.9, 130.0,
123.5, 122.5, 122.3, 120.3, 115.9, 104.3, 56.1. HRMS (ESI) m/z:
[M+H]+ calcd for C16H13O5 285.0760; found 285.0757.
Yellow solid; yield: 85%; mp: 198-200 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.28 - 8.19 (m, 3H), 7.72 (ddd, J = 8.7, 7.1,
1.7 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.43
(ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.07 (s, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ173.4, 155.4, 143.8, 138.5, 136.2, 133.9, 129.6,
129.0, 128.9, 125.5, 124.7, 120.6, 118.3. HRMS (ESI) m/z: [M-
H]- calcd for C15H835ClO3 271.0157; found 271.0156; [M-H]-
calcd for C15H837ClO3 273.0127; found 273.0122.
2-(4-Bromophenyl)-3-hydroxy-4H-chromen-4-one
(C30):
Yellow solid; yield: 80%; mp: 189-190 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.28 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.6 Hz,
2H), 7.75 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.62 (d, J =
8.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.09 (s, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 173.4, 155.4, 143.8, 138.6, 133.9, 131.9,
130.0, 129.2, 128.9, 125.5, 124.7, 120.6, 118.3. HRMS (ESI) m/z:
[M+H]+ calcd for C15H1079BrO3 316.9710; found 316.9735;
[M+H]+ calcd for C15H1081BrO3 318.9732; found 318.9734.
3-Hydroxy-6-methoxy-2-phenyl-4H-chromen-4-one
(C38):
Yellow solid; yield: 75%; mp: 204-206 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.25 (d, J = 7.4 Hz, 2H), 7.60 – 7.43 (m,
5H), 7.31 (dd, J = 9.2, 3.1 Hz, 1H), 7.05 (s, 1H),3.92 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 173. 2, 156.5, 150.6, 144.8,
138.2, 131.2, 130.1, 128.6, 127.7, 124.5, 121.1, 119.8, 103.8,
56.0. HRMS (ESI) m/z: [M-H]- calcd for C16H11O4 267.0652;
found 267.0649.
3-Hydroxy-2-(3-Methoxyphenyl)-4H-chromen-4-one
(C31):
Yellow solid; yield: 70%; mp: 130-132 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.28 (dd, J = 8.0, 1.6 Hz, 1H), 7.91 – 7.84
(m, 2H), 7.74 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H),7.62 (d, J = 8.5 Hz,
1H), 7.52 – 7.41 (m, 2H), 7.06 (dd, J = 8.3, 2.2 Hz, 2H), 3.93 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.5, 159.7, 155.4,
144.6, 138.6, 133.7, 132.3, 129.7, 125.5, 124.6, 120.6, 120.3,
118.3, 116.0, 113.2, 55.4. HRMS (ESI) m/z: [M+H]+ calcd for
C16H11O4 267.0652; found 267.0649.
3-Hydroxy-6-methoxy-2-(4-hydroxyphenyl)-4H-chrom-en-4-
one (C39): Brown solid; yield: 81%; mp: 278-280 °C (EtOH-
1
H2O); H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.27 (s,
1H), 8.11 (d, J = 8.9 Hz, 2H), 7.98 (d, J = 8.9 Hz, 1H), 7.24 (d, J
= 2.3 Hz, 1H), 7.03 (dd, J = 8.9, 2.3 Hz, 1H), 6.95 (d, J = 8.9 Hz,
2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.4, 163.9, 159.3,
156.7, 145.8, 137.9, 129.7, 126.5, 122.6, 115.8, 115.6, 114.9,
100.7, 56.5. HRMS (ESI) m/z: [M+H]+ calcd for C16H13O5
285.0760; found 285.0757.
3-Hydroxy-2-(3-Hydroxyphenyl)-4H-chromen-4-one
(C32):
Yellow solid; yield: 91%; mp: 235-237 °C (EtOH-H2O); 1H NMR
(400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.59 (s, 1H), 8.13 (dd, J =
8.0, 1.4 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.75 (d, J = 8.3 Hz, 1H),
7.72 - 7.64 (m, 2H), 7.51 - 7.45 (m, 1H), 7.37 (t, J = 8.0 Hz, 1H),
6.92 (ddd, J = 8.1, 2.4, 0.8 Hz, 1H). 13C{1H} NMR (101 MHz,
6-Fluoro-3-hydroxy-2-phenyl-4H-chromen-4-one
(C40):
Yellow solid; yield: 78%; mp: 164-166 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.24 (d, J = 7.9 Hz, 2H), 7.88 (dd, J = 8.0,
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3.0 Hz, 1H), 7.66 – 7.40 (m, 5H), 7.01 (s, 1H). 13C{1H} NMR
(s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H), 6.47 (d,
(101 MHz, CDCl3) δ 172.9 (d, J = 2.7 Hz), 159.1 (d, J = 246.6
Hz), 151.8, 145.4, 138.2, 130.8, 130.4, 128.7, 127.8, 122.3 (d, J =
25.9 Hz), 121.6 (d, J = 8.1 Hz), 120.5 (d, J= 8.3 Hz), 109.9 (d, J =
23.7 Hz). HRMS (ESI) m/z: [M-H]- calcd for C15H8FO3
255.0452; found 255.0455.
J = 1.7 Hz, 1H), 6.21 (d, J = 1.7 Hz, 1H), 3.85 (s, 2H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 176.5, 164.4, 161.2, 160.9, 156.7,
146.7, 136.5, 129.8, 123.7, 114.5, 103.6, 98.7, 94.0, 55.8. HRMS
(ESI) m/z: [M+H]+ calcd for C16H13O6 301.0712; found 301.0723.
(Z)-2-(4-Bromobenzylidene)-4-Methoxybenzofuran-3(2H)-one
1
6-Chloro-3-hydroxy-2-phenyl-4H-chromen-4-one
(C41):
(D7) Yellow solid; yield: 75%; mp: 161-164 °C (EtOH-H2O); H
Yellow solid; yield: 81%; mp: 162-164 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.26 – 8.20 (m, 3H), 7.65 (dd, J = 9.0, 2.6
Hz, 1H), 7.59 – 7.46 (m, 4H), 7.00 (s, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 172.4, 153.7, 145.4, 138.6, 133.9, 130.7, 130.5,
130.5, 128.7, 127.8, 124.7, 121.6, 120.0. HRMS (ESI) m/z: [M-
H]- calcd for C15H835ClO3 271.0157; found 271.0151; [M-H]-
calcd for C15H837ClO3 273.0152; found 273.0141.
NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.59 (m, 3H),
6.91 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 6.66 (d, J = 8.3 Hz, 1H),
4.03 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 158.6,
147.1, 138.6, 132.6, 132.1, 131.4, 124.0, 110.5, 105.4, 104.8,
56.3. HRMS (ESI) m/z: [M+Na]+ calcd for C16H1179BrNaO3
352.9789; found 352.9784; [M+Na]+ calcd for C16H1181BrNaO3
354.9769; found 352.9784.
(Z)-4-Methoxy-2-(4-Nitrobenzylidene)benzofuran-3(2H)-one
(D8): Yellow solid; yield: 81%; mp: 170-173 °C (EtOH-H2O); 1H
NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 8.06 (d, J =
8.8 Hz, 2H), 7.66 (t, J = 8.3 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H),
6.85 (s, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.05 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO) δ 164.6, 136.2, 135.7, 134.1, 132.7, 131.8,
130.5, 129.5, 129.4, 129.4, 113.6, 67.4. HR-ESIMS: 298.0637;
[M+H]+ (calc. for C16H12NO5, 298.0715).
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6-Bromo-3-hydroxy-2-phenyl-4H-chromen-4-one
(C42):
Yellow solid; yield: 82%; mp: 181-183 °C (EtOH-H2O); 1H NMR
(400 MHz, CDCl3) δ 8.38 (d, J = 2.4 Hz, 1H), 8.27 – 8.20 (m,
2H), 7.77 (dd, J = 9.0, 2.4 Hz, 1H), 7.60 – 7.45 (m, 4H), 7.01 (s,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.3, 154.1, 145.4,
138.6, 136.6, 130.7, 130.5, 128.7, 128.0, 127.8, 122.0, 120.2,
117.9. HRMS (ESI) m/z: [M-H]- calcd for C15H879BrO3 314.9652;
found 314.9655; [M-H]- calcd for C15H881BrO3 316.9722; found
316.9735.
(Z)-2-(4-Hydroxy-3,5-Dimethoxybenzylidene)-4-
2-(4-(Diethylamino)phenyl)-3-Hydroxy-6-nitro-4H-chromen-
4-one (C43): Yellow solid; yield: 38%; mp: 181-183 °C (EtOH-
H2O); 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.78 (d, J =
2.3 Hz, 1H), 8.54 – 8.48 (m, 1H), 8.14 (d, J = 8.9 Hz, 2H), 7.97
(d, J = 9.2 Hz, 1H), 6.82 (d, J = 9.0 Hz, 2H), 3.45 (q, J = 6.6 Hz,
4H), 1.15 (t, J = 6.8 Hz, 6H). 13C{1H} NMR (101 MHz, DMSO-
d6) δ 171.3, 157.5, 149.3, 144.0, 137.9, 130.0, 127.4, 122.0, 121.3,
120.7, 116.7, 111.3, 44.2, 12.9. HRMS (ESI) m/z: [M+H]+ calcd
for C19H19 N2O5 355.1214; found 355.1215.
6-Bromo-2-(4-(Diethylamino)phenyl)-3-Hydroxy-4H-
chromen-4-one (C44): Yellow solid; yield: 45%; mp: 181-183 °C
(EtOH-H2O); 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.14
(d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.9 Hz, 2H), 7.88 (dd, J = 8.9, 2.1
Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.43
(q, J = 6.8, 4H), 1.14 (t, J = 6.9 Hz, 6H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 170.9, 153.5, 149.1, 148.1, 137.7, 135.9,
129.9, 127.0, 123.6, 121.2, 117.1, 117.0, 111.2, 44.2, 12.9. HRMS
(ESI) m/z: [M+H]+ calcd for C19H1879BrNO3 387.0432; found
387.0470; [M+H]+ calcd for C19H1881BrNO3 389.0438; found
389.0442.
Methoxybenzofuran-3(2H)-one (D13): Yellow solid; yield: 30%;
1
mp: 160-162 °C H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 8.0
Hz, 1H) 7.22 (s, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 6.58
(dd, J = 17.5, 8.3 Hz, 1H), 3.93 (s, 1H), 3.86 (s, 2H). 13C{1H}
NMR (101 MHz, MeOD) δ 195.1, 162.0, 161.8, 160.3, 143.8,
141.0, 134.3, 130.0, 127.7, 125.1, 114.1, 113.0, 109.6, 101.8,
55.1, 54.5. HRMS (ESI) m/z: [M+Na]+ calcd for C18H16NaO6
351.0845; found 351.0839.
(E)-1-(2-hydroxy-6-methoxyphenyl)-3-(4-
methoxyphenyl)prop-2-en-1-one (Y1): Yellow solid; yield: 82%;
1H NMR (400 MHz, CD3OD) δ 7.70 – 7.52 (m, 4H), 7.37 (t, J =
8.3 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.58 (dd, J = 17.5, 8.3 Hz,
1H), 3.93 (s, 1H), 3.86 (s, 2H). 13C{1H} NMR (101 MHz,
CD3OD) δ 195.1, 162.0, 161.8, 160.3, 143.8, 141.0, 134.3, 130.0,
127.7, 125.1, 114.1, 113.0, 109.6, 101.8, 55.1, 54.5. HRMS (ESI)
m/z: [M+H]+ calcd for C17H17O4 285.1052; found 285.1048.
3-hydroxy-5-methoxy-2-(4-methoxyphenyl)chroman-4-one
1
(V1): White solid; yield: 46%; H NMR (400 MHz, CD3OD) δ
7.54 – 7.41 (m, 3H), 7.00 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.4 Hz,
1H), 6.62 (d, J = 8.4 Hz, 1H), 5.08 (d, J = 11.9 Hz, 1H), 4.54 (d, J
= 12.0 Hz, 1H), 3.92 (s, 2H), 3.85 (s, 1H). 13C{1H} NMR (101
MHz, CD3OD) δ 193.2, 162.9, 160.7, 160.2, 136.7, 129.1, 128.8,
113.4, 109.5, 103.9, 100.0, 83.0, 73.4, 55.1, 54.4. HRMS (ESI)
m/z: [M+H]+ calcd for C17H17O5 301.1012; found 301.0998.
5-methoxy-2-(4-methoxyphenyl)chroman-4-one (Z1): Yellow
solid; yield: 35%; 1H NMR (400 MHz, CD3OD) δ 7.44 (d, J =
8.7Hz, 1H), 6.98 (d, J = 8.7Hz 1H), 6.67 (dd, J = 11.9, 8.4 Hz,
1H), 5.44 (dd, J = 12.9, 2.9 Hz, 1H), 3.89 (s, 2H), 3.83 (s, 2H),
3.13 (dd, J = 16.6, 12.9 Hz, 1H), 2.78 (dd, J = 16.6, 3.0 Hz, 1H).
13C{1H} NMR (101 MHz, CD3OD) δ 192.2, 163.5, 160.8, 160.0,
136.4, 130.9, 127.5, 113.6, 110.7, 109.8, 103.8, 78.6, 55.0, 54.4,
45.2. HRMS (ESI) m/z: [M+H]+ calcd for C17H17O4 285.1056;
found 285.1049.
(Z)-4-methoxy-2-(4-methoxybenzylidene)benzofuran-3(2H)-
one (D1): Yellow needles; yield: 85%; 1H NMR (400 MHz,
CDCl3) δ 7.97 – 7.83 (m, 2H), 7.65 – 7.49 (m, 1H), 7.08 – 6.95
(m, 2H), 6.94 – 6.73 (m, 2H), 6.63 (d, J = 8.3 Hz, 1H), 4.03 (s,
3H), 3.89 (s 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 182.3,
166.8, 160.8, 158.5, 145.9, 138.0, 133.2, 125.2, 114.4, 112.2,
111.2, 104.9, 104.8, 56.3, 55.4. HRMS (ESI) m/z: [M+H]+ calcd
for C17H15O4 283.0965; found 283.0967.
3,5,7-trihydroxy-2-(4-hydroxy-3-methoxyphenyl)-4H-
chromen-4-one (C45): Yellow solid; yield: 41%; mp: 305-307 °C
1
(EtOH-H2O); H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H),
9.78 (s, 1H), 9.47 (s, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.70 (dd, J =
8.5, 2.1 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.49 (d, J = 2.1 Hz,
1H), 6.21 (d, J = 2.1 Hz, 1H), 3.85 (s, 2H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 176.3, 164.4, 161.1, 156.6, 149.2, 147.8,
147.1, 136.3, 122.4, 122.2, 116.0, 112.1, 103.5, 98.7, 94.1, 56.2.
HRMS (ESI) m/z: [M+H]+ calcd for C16H13O7 317.0661; found
317.0646.
3,5,7-trihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-
chromen-4-one (C46): Yellow solid; yield: 64%; mp: 266-267 °C
1
(EtOH-H2O); H NMR (400 MHz, DMSO-d6) δ12.47 (s, 1H),
10.81 (s, 1H), 9.41 (d, J = 48.6 Hz, 2H), 7.70 – 7.63 (m, 2H), 7.09
(d, J = 8.6 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 6.21 (d, J = 2.1 Hz,
1H), 3.86 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 176.4,
164.4, 161.2, 156.6, 149.8, 146.7, 146.6, 136.6, 123.9, 120.2,
115.1, 112.3, 103.5, 98.7, 93.9, 56.1. HRMS (ESI) m/z: [M+H]+
calcd for C16H13O7 317.0661; found 317.0632.
3,5,7-trihydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one
(C47): Yellow solid; yield: 65%; mp: 276-277 °C (EtOH-H2O); 1H
NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), δ 10.86 (s, 1H) 9.56
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(4) Xu, M.; Pirtskhalava, T.; Farr, J. N.; Weigand, B. M.; Palmer,
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■ ASSOCIATED CONTENT
A. K.; Weivoda1, M. M.; Inman, C. L.; Ogrodnik, M. B.;
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Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental details, spectroscopic data and analytical data
(PDF)
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■ AUTHOR INFORMATION
9
Corresponding Author
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* wangchun@cib.ac.cn
* zhanggl@cib.ac.cn
ORCIDID:
Chun Wang: 0000-0001-8553-1182
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Present Addresses
†If an author’s address is different than the one given in the
affiliation line, this information may be included here.
Author Contributions
∥ Wei Xiong and Xiaohong Wang contributed equally.
Funding Sources
Any funds used to support the research of the manuscript should
be placed here (per journal style).
Notes
The authors declare no competing financial interest.
Regioselective
hydroxylation
of
2-hydroxychalcones
by
dimethyldioxirane towards polymethoxylated flavonoids. Tetrahedron
2004, 60, 2647-2655.
■ ACKNOWLEDGMENT
(9) Adams, C. J.; Main, L. Cyclisation and subsequent reactions of
2'-hydroxy-6'-methoxychalcone epoxide and related compounds.
Tetrahedron 1991, 47, 4979-4990.
Financial supports from the National Natural Science Foundation
of China (No. 21561142003 and No. 21977092), the National
New Drug Innovation Major Project of China (2018ZX09711001-
001-006), and Science and Technology Department of Sichuan
Province (2019YFS0106), are gratefully acknowledged.
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