"one-Pot" Synthesis of γ-Pyrones from Aromatic Ketones/Heteroarenes and Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.0c01924

Despite the various attractive properties of γ-pyrones, there are still some deficiencies in their synthetic approaches such as lower atom economy, multistep processes, and prefunctionalization of the reagents. In this work, an efficient and simple (CF3CO

Full text of DOI:10.1021/acs.joc.0c01924

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Article
“One-Pot” Synthesis of γ‑Pyrones from Aromatic Ketones/
Heteroarenes and Carboxylic Acids
Xiangyu Sun,§ Ming Gong,§ Mengmeng Huang, Yabo Li, Jung Keun Kim,* Vladimir Kovalev,*
Elvira Shokova, and Yangjie Wu*
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ACCESS
ABSTRACT: Despite the various attractive properties of γ-
pyrones, there are still some deficiencies in their synthetic
approaches such as lower atom economy, multistep processes,
and prefunctionalization of the reagents. In this work, an efficient
and simple (CF3CO)2O/CF3SO3H-mediated “one-pot” approach
was realized to produce γ-pyrones by applying aromatic ketones/
heteroarenes and carboxylic acids as the starting materials. The
target products were isolated in moderate to excellent yields. The
reaction mechanism was studied by density functional theory calculational methods. The results of experimental and theoretical
investigations not only helped us explain the reason of high selectivity formation of β-diketones but also proved that 1,3,5-ketones
might be important intermediates for the cyclization to afford γ-pyrones.
for the synthesis of organic compounds because of the high
atom efficiency, higher product yield, and facile work-up.20 On
the basis of this conception, “one-pot” synthesis could be
realized via the following processes: (1) the multicomponent
reaction;21 (2) the combination with multiapproaches (such as
thermocatalysis, photocatalysis, or/and electrocatalysis);22 (3)
the combination of stepwise reactions without any inter-
mediate separation.23 In order to avoid the application of the
multistep synthetic method, one-pot approach is necessary to
be introduced into the γ-pyrone synthesis. Herein, we
demonstrate a (CF3CO)2O/CF3SO3H-mediated “one-pot”
synthesis for the preparation of γ-pyrones from the reaction
of commercial aromatic ketones/heteroarenes with carboxylic
acids.
INTRODUCTION
■
γ-Pyrones as a class of heterocycles are found in some natural
chemical compounds such as chromone, maltol, and kojic
acid.1 γ-Pyrone derivatives have good pharmaceutical and
pharmacological properties.2 They could be used as anti-
tumor,3 antioxidant,4 anti-HIV,5 antibacterial,6 and antiproli-
ferative agents.7 In organic synthesis, γ-pyrones are also used as
intermediates to prepare α-pyrones, pyridinones, isoxazoles,
pyrazoles, and fused ring and 1,4-dihydropyridines that present
relevant pharmaceutical activity.8 Through structure modifica-
tion, γ-pyrone derivatives exhibit attractive optical activity in
the fields of fluorescent probes, photochromic materials,
organic light-emitting diodes, and organic sensitized solar
cells.9
Because of the above wide scope of applications, numerous
researchers devoted much effort to develop synthetic methods
of γ-pyrones (Scheme 1).10 The synthetic methods involve the
cyclocondensation of 1,3,5-tricarbonyls,11 hetero Diels−Alder
reaction,12 recyclization of α-pyrones,13 electrophilic cycliza-
tion of diynones,14 condensation of 1,3-dicarbonyl derivatives
or enaminones,15 [3 + 3] annulation of α,β-unsaturated alkynyl
carboxylic acids with 1,3-dicarbonyl compounds,16 [4 + 2]
cyclization of ketene dithioacetals with acyl chlorides,17 and
cyclization of carboxylic acids under polyphosphoric acid
medium.18 In these approaches, the main precursors are
usually prepared via multistep synthesis.19 The applications of
multistep synthetic methods not only have a lower atom
economy but also directly lead to a significant reduction in the
product yield.
RESULTS AND DISCUSSION
■
Based on our previous works,24 the reaction of p-
chloroacetophenone (1a) with isovaleric acid (2a) was chosen
as the model reaction. Fortunately, the model reaction could
be carried out in the presence of trifluoroacetic anhydride
(TFAA)/TfOH/CH2Cl2 mixture to give 1-(4-chlorophenyl)-
5-methylhexane-1,3-dione (3a) and 6-(4-chlorophenyl)-2-
isobutyl-3-isopropyl-4H-pyran-4-one (4a) in 39 and 58%
yield, respectively (Table 1, entry 1). It was found that the
Received: August 9, 2020
In contrast to multistep synthesis, “one-pot” method has
received considerable attention as a green chemistry approach
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Scheme 1. Synthetic Methods to Access γ-Pyrones
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
2a (equiv)
TfOH (equiv)
3a
39
14
trace
trace
4a
1
2
3
4
5
6
7
8
2
3
4
5
4
4
4
4
1
1
1
1
1.25
1.5
1.75
2
58
69
78
68
84
88
89
92
a
b
Reaction conditions: 1a (1 mmol), TFAA (6 equiv), 2a (2−5 equiv), TfOH (1−2 equiv), CH2Cl2 (1 mL), at room temperature, 9 h. Isolated
yield.
excess amount of isovaleric acid (2a) led to the complete
conversion of intermediate 3a (Table 1, entries 2−4). At the
same time, the transformation was improved with 2 equiv of
TfOH to give the desired product 4a in excellent yield (92%)
(Table 1, entries 5−8).
l) had poorer reactivity, and intermediates 3k−l were isolated
as coproducts. The two products were also observed in the
cases of benzocyclic ketones (1m−n). In comparison to 1-
indanone (1m), 1-tetralone (1n) reacted with isovaleric acid
(2a) to afford 2-isobutyl-3-isopropyl-5,6-dihydro-4H-benzo-
[h]chromen-4-one (4n) with a higher yield. Various aliphatic
carboxylic acids (such as acetic acid, propionic acid, phenyl-
acetic acid, 1-adamantaneacetic acid, t-BuCH2COOH, and
octanoic acid) were also suitable for the developed system. The
corresponding desired products were produced in moderate to
excellent yields (4o−t). Unlike other tested carboxylic acids,
the products of the reactions involving AdCH2COOH (2e) or
t-BuCH2COOH (2f) were unsubstituted on their C-3 position
(4r−s). It might be caused by the ipso-substitution of the tert-
butyl and adamantyl groups with protons under the superacidic
condition.25
With the optimized reaction conditions in hand, the scope of
the substrates was investigated (Scheme 2). Generally, there
was a clear difference in the reactivity of ketones. The activity
of acetophenones (1a−h) bearing electron-withdrawing
groups is higher than that of acetophenones with donating
groups (1k−l). The single products (4a−g) were detected in
good to excellent yields from the reaction between para-/
metasubstituted acetophenones and isovaleric acid (2a). To
improve the product yields, the reactions involving ortho-
chloroacetophenone (1h), para-phenyl acetophenone (1j),
parasubstituted acetophenones with donating groups (1k−l),
and benzocyclic ketones (1m−n) were carried out in the
presence of additional 2 (2 equiv)/TFAA (2 equiv)/CH2Cl2
(0.3 mL) mixture after 7 h. Despite the steric hindrance, ortho-
chloroacetophenone (1h) could still participate in this reaction
to give the target product in moderate yield (51%).
Acetophenones with stronger electron-donating groups (1k−
Considering the stability of heteroaryl compounds in strong
acid, the activity of thiophene derivatives was investigated
(Scheme 3). It was found that 2-/3-halothiophenes (5u−w), 4-
bromobenzofuran (5x), and dibenzofuran (5y) could proceed
with stepwise multistep “one-pot” synthesis. The γ-pyrone
synthesis did not require prefunctionalization. The precursor
B
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ab
Scheme 2. Substrate Scope of γ-Pyrone Synthesis
a
Reaction conditions: 1 (1 mmol), 2a (4 equiv), TFAA (6 equiv), TfOH (2 equiv), CH2Cl2 (1 mL) in flask at room temperature for 9 h, isolated
b
yield. 1 (1 mmol), 2a (4 equiv), TFAA (6 equiv), TfOH (2 equiv), CH2Cl2 (1 mL), at room temperature for 7 h. Then, a mixture of 2a (2 equiv),
TFAA (2 equiv), and CH2Cl2 (0.3 mL) was added, and the reaction mixture was stirred for 11 h.
ab
Scheme 3. Substrate Scope of γ-Pyrone Synthesis
a
Reaction conditions: 5 (1 mmol), AcOH (1 equiv), TFAA (6 equiv), TfOH (2 equiv), and CH2Cl2 (1 mL) were stirred at room temperature for 1
h; then, 2a (4 equiv) was added to the reaction mixture. After 7 h, the mixture of 2a (2 equiv), TFAA (2 equiv), and CH2Cl2 (0.3 mL) was added
b
and stirred for 11 h. Isolated yield. NMR yield (mesitylene as the internal standard).
substance of acetyl thiophenes was obtained from the reaction
between 2-/3-halothiophenes (5) and acetic acid in the
presence of TFAA/TfOH/CH2Cl2 mixture. 3-Halothiophenes
(5u−v) were transformed into the corresponding γ-pyrones
(4u−v) in higher yields compared to 2-bromothiophenes
(5w). Because of the similar activity of 5-bromobenzofuran
C
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Figure 1. Density functional theory calculations. Computed Gibbs free energy profile for the cyclization of 1a with 2a and the spin density of TS.
Energies are given in kcal mol−1. Calculated by the Gaussian 16 program29 using B3LYP-D3BJ/6-311+G(d,p)/CH2Cl2 (PCM).30 RDG analysis
was carried out using Multiwfn Version 3.7(dev)27 and VMD version 1.9.3 programs.31
Scheme 4. Proposed Mechanism
D
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(5x) on its C2 and C3 positions, the ratio of corresponding
products (4xa and 4xb) was 3:2. The calculation of Fukui
index (f−) shows that the C-2 position (f− = 0.148) is more
active than the C-3 position (f− = 0.109) in our situation (see
Supporting Information Scheme S1).26 This calculated result is
well consistent with the experiments. In addition, dibenzofuran
(5y) could also be transformed into product 4y in moderate
yield (51%). However, the optimized reaction conditions were
not suitable for thiophene with electron-donating substitutions
(3z).
intermediate L. Molecular structure of γ-pyrone 4a was exactly
proved by X-ray diffraction (see Supporting Information).
CONCLUSIONS
■
In summary, we have developed an efficient and simple
(CF3CO)2O/CF3SO3H-mediated “one-pot” approach to
produce γ-pyrones from aryl methyl ketones and carboxylic
acids. A range of aryl acetophenones, benzocyclic ketones, and
aliphatic carboxylic acids were found to be compatible with
this system. The target products were obtained in moderate to
excellent yields. It is worth to mention that unfunctionalized
heterocyclic compounds such as thiophenes and (di)-
benzofuran could also be introduced into this system to
produce their corresponding γ-pyrones. The reaction mecha-
nism is verified by calculational methods using Gaussian 16
program. Based on the results of experimental and theoretical
investigations, the selectivity formation of β-diketones was first
explained. In addition, 1,3,5-ketones which were afforded from
the acylation of β-diketones might be the important
intermediates for the γ-pyrone synthesis.
In order to obtain more insight into the cyclization, the
reaction pathway was examined by density functional theory at
the level of B3LYP and 6-311+G(d,p) standard basis set
(Figure 1 and Supporting Information). Throughout the whole
reaction process, there are two unclear parts of the mechanism:
(1) the high selectivity of β-diketone production and (2) the
important intermediates for the γ-pyrones cyclization. It was
found that the reaction of isovaleric acid (2a) with TFAA
proceeds spontaneously (ΔG = −4.54 kcal/mol) to afford the
strong acylation agent B. With the help of TfOH, the active
intermediate B could be converted into complex (C) via the
hydrogen bond. The results of noncovalent interaction analysis
applying reduced density gradient (RDG) method27a showed
that a strong interaction of hydrogen bond exists between the
oxygen of carbonyl groups and the hydrogen atom of TfOH.28
Subsequently, the decomposition of complex C gives
formation of trifluoroacetyl cation (E), and more stable acyl
cation D can participate in further transformation with enol
(F) to afford diketone 3a and enol H. This result is consistent
with our proposal of previous work.24 In our synthetic process,
any other intermediate for γ-pyrone cyclization was not
detected. Compared to the formation energy of compound I,
1,3,5-triketone (J) is easier to obtain. The acylation of β-
diketone 3a might proceed on its C2- or C4-position giving
corresponding 1,3,3′-triketone (VII) or 1,3,5-triketone (J) (see
Supporting Information, Scheme S3). However, the deacyla-
tion of 1,3,3′-triketone (VII) could occur to form β-diketone
3a during the reaction process (see Supporting Information,
Scheme S2 for detailed information). It was found that the
reaction between 1,3,5-triketone (J) and TfOH is easily carried
out at the C5 carbonyl position to give intermediate K (ΔG =
−8.82 kcal/mol). The active intermediate L is afforded via the
process of isomerization. The protonation of intermediate L
takes place in the first step to form a more stable carbocation
M (−8.57 kcal/mol). Further cyclization might undergo
through transition state (TS) with a low-energy barrier
(20.15 kcal/mol). The target product 4a was obtained after
the proton cleavage with the help of TfO− (see Supporting
Information, Scheme S3). All calculated results are well
consistent with the experiments.
EXPERIMENTAL SECTION
■
General Experimental Information. 1H NMR spectra were
recorded on a Bruker DPX-400 (400 MHz) spectrometer at an
ambient temperature unless otherwise indicated. Chemical shifts are
reported in ppm from tetramethylsilane as the internal standard in
CDCl3. Abbreviations used in the NMR follow up experiments are as
follows: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; dd
= doublet−doublet, and m, multiplet. 13C NMR spectra were
recorded on a Bruker DPX-400 (100 MHz) spectrometer at an
ambient temperature and were proton decoupled. Chemical shifts are
reported in ppm from tetramethylsilane on the scale, with the solvent
resonance employed as the internal standard. 19F NMR spectra were
recorded on a Bruker DPX-400 (376 MHz) spectrometer at an
ambient temperature. Chemical shifts are reported in ppm from
CFCl3 as the internal standard. High-resolution mass spectra
(HRMS) were obtained on an Agilent LC-MSD-Trap-XCT
spectrometer with micromass MS software using electrospray
ionization (ESI). The LCD Digital Hotplate Magnetic Stirrer MS-
H-Pro+ and Digital Single Channel Adjustable Automatic Electronic
Pipette Micropipette dPettee+ were purchased from Dragon
Laboratory Instruments Limited. All reactions were performed
under air atmosphere. All reagents and solvents were purchased
from commercial suppliers and used without further purification
excluding TFAA and dichloromethane (DCM). TFAA was freshly
distilled from P2O5.32 Anhydrous DCM was dried by standard
methods before it was used. Reactions were monitored by thin-layer
chromatography (TLC). Silica gel was purchased from Qing Dao Hai
Yang Chemical Industry Co.
General Procedure A for the Synthesis of γ-Pyrones. Ketone
1 (1.0 mmol), CH2Cl2 (1.0 mL), carboxylic acid 2 (4.0 mmol, 4.0
equiv), and TFAA (6 mmol, 6.0 equiv) were stirred under room
temperature for 15 min, and then TfOH (2.0 mmol, 2 equiv) was
added. The homogeneous solution was stirred at room temperature
for 9 h. The reaction mixture was evaporated under reduced pressure.
After quenching with water, the residue was redissolved in DCM (5
mL). The mixture was washed with 5% NaHCO3 (2 × 3 mL) and
water (2 × 3 mL) and dried over Na2SO4. The solvent was removed
in vacuum, and the crude reaction mixture was purified by silica gel
chromatography (DCM; DCM/EtOH = 50/1−35/1).
General Procedure B for the Synthesis of γ-Pyrones. Ketone
1 (1.0 mmol), CH2Cl2 (1.0 mL), carboxylic acid 2 (4.0 mmol, 4.0
equiv), and TFAA (6 mmol, 6.0 equiv) were stirred under room
temperature for 15 min, and then TfOH (2.0 mmol, 2 equiv) was
added. The homogeneous solution was stirred at room temperature
for 7 h. Then, the mixture of 2a (2 equiv), TFAA (2 equiv), and
CH2Cl2 (0.3 mL) was added and stirred for 11 h. The reaction
Based on the results of computational analysis, a possible
mechanism is proposed (Scheme 4). Initially, isovaleric acid
(2a) reacts easily with TFAA in the presence of TfOH to give
2,2,2-trifluoroacetic 3-methylbutanoic anhydride (B) which
plays the role of the reaction initiator. To generate the acyl
cation D, the active acylation reagent B might undergo the
formation of complex C. Subsequently, product 3a and its
isomer H are formed from the reaction between the acyl cation
(D) and the enol isomer (F) of compound 1a. The precursor
compound of the cyclization might be 1,3,5-triketone (J)
because of its higher accessibility. In the presence of TfOH, the
desired product 4a could be obtained from the cyclization of
E
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mixture was evaporated under reduced pressure and quenched with
water. The residue was redissolved in DCM (5 mL). The mixture was
washed with 5% NaHCO3 (2 × 3 mL) and water (2 × 3 mL) and
dried over Na2SO4. The solvent was removed in vacuum, and the
crude reaction mixture was purified by silica gel chromatography
(DCM; DCM/EtOAc = 100/1−20/1).
General Procedure C for the Synthesis of γ-Pyrones.
Heteroarene 5 (1 mmol), acetic acid 2b (1 equiv), TFAA (6
equiv), and CH2Cl2 (1 mL) were stirred at room temperature for 15
min, and then TfOH (2.0 mmol, 2 equiv) was added. The resulting
solution was stirred at room temperature for 1 h (TLC monitoring).
Subsequently, 2a (4 equiv) was added to the reaction mixture for β-
diketone generation. After 7 h (TLC monitoring), the mixture of 2a
(2 equiv), TFAA (2 equiv), and CH2Cl2 (0.3 mL) was added, and the
reaction solution was stirred for 11 h. The reaction mixture was
evaporated under reduced pressure and quenched with water. The
residue was redissolved in DCM (5 mL). The mixture was washed
with 5% NaHCO3 (2 × 3 mL) and water (2 × 3 mL) and dried over
Na2SO4. The solvent was removed in vacuum, and the crude reaction
mixture was purified by silica gel chromatography (DCM; DCM/
EtOAc = 200/1−40/1).
6-(4-Chlorophenyl)-2-isobutyl-3-isopropyl-4H-pyran-4-one (4a).
General procedure A, purified by silica gel chromatography (DCM;
DCM/EtOH = 50/1−35/1). Yellow solid (278.9 mg, 92%), mp
111.9−112.3 °C. 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.7 Hz,
2H), 7.44 (d, J = 8.7 Hz, 2H), 6.61 (s, 1H), 2.98−2.91 (m, 1H), 2.60
(d, J = 7.5 Hz, 2H), 2.16−2.10 (m, 1H), 1.36 (d, J = 7.0 Hz, 6H),
1.04 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.8,
163.5, 160.5, 137.0, 130.2, 130.0, 129.3, 126.8, 111.1, 40.1, 28.0, 27.6,
22.5, 20.1. HRMS (ESI) m/z: [M + H]+ calcd for C18H22ClO2,
305.1303; found, 305.1306.
164.0, 159.0, 149.0, 137.6, 130.6, 126.4, 124.2, 113.0, 40.2, 28.1, 27.7,
22.5, 20.0. HRMS (ESI) m/z: [M + H]+ calcd for C18H22NO4,
316.1543; found, 316.1546.
6-(3-Chlorophenyl)-2-isobutyl-3-isopropyl-4H-pyran-4-one (4f).
General procedure A, purified by silica gel chromatography (DCM;
DCM/EtOH = 50/1−35/1). Yellow solid (256.8 mg, 84%), mp
69.5−70.1 °C. 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.60 (d,
J = 7.3 Hz, 1H), 7.46−7.38 (m, 2H), 6.62 (s, 1H), 3.00−2.91 (m,
1H), 2.61 (d, J = 7.5 Hz, 2H), 2.19−2.10 (m, 1H), 1.36 (d, J = 7.0
Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 179.7, 163.6, 160.1, 135.1, 133.5, 130.8, 130.3, 130.1,
125.6, 123.6, 111.5, 40.1, 28.0, 27.6, 22.5, 20.1. HRMS (ESI) m/z: [M
+ H]+ calcd for C18H22ClO2, 305.1303; found, 305.1305.
6-(3-Bromophenyl)-2-isobutyl-3-isopropyl-4H-pyran-4-one (4g).
General procedure A, purified by silica gel chromatography (DCM;
DCM/EtOH = 50/1−35/1). Red-brown solid (269.0 mg, 77%), mp
1
64.1−65.1 °C. H NMR (400 MHz, CDCl3): δ 7.88−7.82 (m, 1H),
7.66−7.58 (m, 2H), 7.34 (t, J = 7.95 Hz, 1H), 6.61 (s, 1H), 2.98−
2.91 (m, 1H), 2.61 (d, J = 7.5 Hz, 2H), 2.18−2.08 (m, 1H), 1.36 (d, J
= 7.1 Hz, 6H), 1.05 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 179.7, 163.7, 160.0, 133.78, 133.75, 130.5, 130.2, 128.5,
124.1, 123.1, 111.6, 40.1, 28.0, 27.6, 22.5, 20.1. HRMS (ESI) m/z: [M
+ H]+ calcd for C18H22BrO2, 349.0798; found, 349.0801.
6-(2-Chlorophenyl)-2-isobutyl-3-isopropyl-4H-pyran-4-one (4h).
General procedure B, purified by silica gel chromatography (DCM;
1
DCM/EtOAc = 100/1−20/1). Red-brown oil (155.8 mg, 51%). H
NMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.6 Hz, 2H), 7.43−7.34 (m,
2H), 6.49 (s, 1H), 3.00−2.93 (m, 1H), 2.55 (d, J = 7.5 Hz, 2H),
2.19−2.08 (m, 1H), 1.38 (d, J = 7.0 Hz, 6H), 1.01 (d, J = 6.6 Hz,
6H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.6, 164.3, 160.9, 132.6,
131.7, 131.4, 130.7, 130.4, 129.9, 127.0, 116.4, 40.2, 27.7, 27.6, 22.4,
20.1. HRMS (ESI) m/z: [M + H]+ calcd C18H22ClO2, 305.1303;
found, 305.1306.
6-(4-Fluorophenyl)-2-isobutyl-3-isopropyl-4H-pyran-4-one (4b).
General procedure A, purified by silica gel chromatography (DCM;
DCM/EtOH = 50/1−35/1). Yellow solid (227.7 mg, 79%), mp
2-Isobutyl-3-isopropyl-6-phenyl-4H-pyran-4-one (4i). General
procedure A, purified by silica gel chromatography (DCM; DCM/
EtOH = 50/1−35/1). Yellow solid (233.4 mg, 86%), mp 85.8−86.5
1
86.5−87.8 °C. H NMR (400 MHz, CDCl3): δ 7.74−7.71 (m, 2H),
7.18−7.14 (m, 2H), 6.59 (s, 1H), 2.99−2.92 (m, 1H), 2.60 (d, J = 7.5
Hz, 2H), 2.17−2.10 (m, 1H), 1.36 (d, J = 7.1 Hz, 6H), 1.04 (d, J =
6.6 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.9, 164.3 (d, 1J
= 251.6 Hz), 163.5, 160.7, 129.9, 128.0 (d, 4J = 3.7 Hz), 127.6 (d, 3J =
1
°C. H NMR (400 MHz, CDCl3): δ 7.76−7.72 (m, 2H), 7.49−7.45
(m, 3H), 6.65 (s, 1H), 2.99−2.92 (m, 1H), 2.61 (d, J = 7.5 Hz, 2H),
2.20−2.10 (m, 1H), 1.37 (d, J = 7.0 Hz, 6H), 1.04 (d, J = 6.6 Hz,
6H). 13C{1H} NMR (100 MHz, CDCl3): δ 180.1, 163.5, 161.6, 131.8,
130.9, 129.9, 129.0, 125.5, 111.0, 40.2, 28.0, 27.5, 22.5, 20.1. HRMS
(ESI) m/z: [M + H]+ calcd for C18H23O2, 271.1693; found, 271.1695.
6-([1,1′-Biphenyl]-4-yl)-2-isobutyl-3-isopropyl-4H-pyran-4-one
(4j). General procedure B, purified by silica gel chromatography
(DCM; DCM/EtOAc = 100/1−20/1). Red-brown solid (285.7 mg,
82%), mp 77.5−78.3 °C. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J =
8.6 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 7.2 Hz, 2H), 7.48−
7.44 (m, 2H), 7.40−7.36 (m, 1H), 6.71 (s, 1H), 3.01−2.94 (m, 1H),
2.62 (d, J = 7.5 Hz, 2H), 2.22−2.11 (m, 1H), 1.38 (d, J = 7.1 Hz,
6H), 1.06 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ
180.0, 163.6, 161.4, 143.7, 139.9, 130.5, 129.9, 129.0, 128.1, 127.6,
127.1, 126.0, 110.8, 40.2, 28.0, 27.6, 22.6, 20.2. HRMS (ESI) m/z: [M
+ H]+ calcd for C24H27O2, 347.2006; found, 347.2009.
8.8 Hz), 116.2 (d, 2J = 22.0 Hz), 110.7, 40.2, 28.0, 27.5, 22.5, 20.1. 19
F
NMR (376 MHz, CDCl3): δ −108.8. HRMS (ESI) m/z: [M + H]+
calcd for C18H22FO2, 289.1598; found, 289.1601.
6-(4-Bromophenyl)-2-isobutyl-3-isopropyl-4H-pyran-4-one (4c).
General procedure A, purified by silica gel chromatography (DCM;
DCM/EtOH = 50/1−35/1). Yellow solid (337.0 mg, 97%), mp
99.3−100.1 °C. 1H NMR (400 MHz, CDCl3): δ 7.60 (s, 4H), 6.62 (s,
1H), 2.98−2.91 (m, 1H), 2.60 (d, J = 7.3 Hz, 2H), 2.18−2.07 (m,
1H), 1.36 (d, J = 7.0 Hz, 6H), 1.04 (d, J = 6.6 Hz, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 179.8, 163.5, 160.5, 132.2, 130.6, 130.0,
126.9, 125.4, 111.1, 40.1, 28.0, 27.6, 22.5, 20.1. HRMS (ESI) m/z: [M
+ H]+ calcd for C18H22BrO2, 349.0798; found, 349.0801.
2-Isobutyl-3-isopropyl-6-(4-(trifluoromethyl)phenyl)-4H-pyran-
4-one (4d). General procedure A, purified by silica gel chromatog-
raphy (DCM; DCM/EtOH = 50/1−35/1). Yellow solid (304.6 mg,
90%), mp 62.4−63.2 °C. 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J =
8.3 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 6.72 (s, 1H), 3.00−2.94 (m,
1H), 2.64 (d, J = 7.3 Hz, 2H), 2.21−2.11 (m, 1H), 1.38 (d, J = 7.0
Hz, 6H), 1.06 (d, J = 6.7 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 179.6, 163.8, 159.9, 135.1, 132.4 (q, J = 32.3 Hz), 130.3,
125.9 (q, J = 3.7 Hz), 125.8, 123.6 (d, J = 272.2 Hz), 112.1, 40.1,
28.0, 27.6, 22.4, 20.0. 19F NMR (376 MHz, CDCl3): δ −63.0. HRMS
(ESI) m/z: [M + H]+ calcd for C19H22F3O2, 339.1566; found,
339.1569.
(Z)-1-Hydroxy-5-methyl-1-(p-tolyl)hex-1-en-3-one (3k). General
procedure B, purified by silica gel chromatography (PE/DCM = 10/
1−3/1). Red-brown oil (10.9 mg, 10%). 1H NMR (400 MHz,
CDCl3): keto−enol (1:12), enol tautomer δ 7.79 (d, J = 8.2 Hz, 2H),
7.24 (d, J = 8.1 Hz, 2H), 6.13 (s, 1H), 2.40 (s, 3H), 2.26 (d, J = 7.0
Hz, 2H), 2.20−2.12 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 194.8, 184.6, 143.0, 132.5, 129.3, 127.1,
96.5, 48.0, 26.5, 22.6, 21.6. HRMS (ESI) m/z: [M + H]+ calcd for
C14H19O2, 219.1380; found, 219.1379.
2-Isobutyl-3-isopropyl-6-(p-tolyl)-4H-pyran-4-one (4k). General
procedure B, purified by silica gel chromatography (DCM; DCM/
EtOAc = 100/1−20/1). Yellow solid (112.3 mg, 73%), mp 70.2−70.9
°C. 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.2 Hz, 2H), 7.26 (d,
J = 8.2 Hz, 2H), 6.63 (s, 1H), 2.99−2.92 (m, 1H), 2.60 (d, J = 7.5 Hz,
2H), 2.40 (s, 3H), 2.17−2.11 (m, 1H), 1.37 (d, J = 7.1 Hz, 6H), 1.04
(d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 180.1,
163.4, 161.8, 141.4, 129.7, 128.9, 125.4, 110.3, 40.2, 28.0, 27.5, 22.5,
2-Isobutyl-3-isopropyl-6-(4-nitrophenyl)-4H-pyran-4-one (4e).
General procedure A, purified by silica gel chromatography (DCM;
DCM/EtOH = 50/1−35/1). Yellow solid (270.2 mg, 86%), mp
127.6−128.5 °C. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 9.0 Hz,
2H), 7.92 (d, J = 9.0 Hz, 2H), 6.76 (s, 1H), 2.99−2.92 (m, 1H), 2.65
(d, J = 7.5 Hz, 2H), 2.19−2.12 (m, 1H), 1.37 (d, J = 7.0 Hz, 6H),
1.07 (d, J = 6.7 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.4,
F
https://dx.doi.org/10.1021/acs.joc.0c01924
J. Org. Chem. XXXX, XXX, XXX−XXX

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pubs.acs.org/joc
Article
21.5, 20.2. HRMS (ESI) m/z: [M + H]+ calcd for C19H25O2,
285.1849; found, 285.1851.
6-(4-Chlorophenyl)-2-ethyl-3-methyl-4H-pyran-4-one (4p). Gen-
eral procedure A, purified by silica gel chromatography (DCM;
DCM/EtOH = 50/1−35/1). Light yellow solid (150.3 mg, 60%), mp
(Z)-1-Hydroxy-1-(4-methoxyphenyl)-5-methylhex-1-en-3-one
1
(3l). General procedure B, purified by silica gel chromatography (PE/
96.8−97.5 °C. H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.8 Hz,
1
DCM = 10/1−3/1). Orange oil (198.4 mg, 85%). H NMR (400
2H), 7.44 (d, J = 8.8 Hz, 2H), 6.69 (s, 1H), 2.74 (q, J1 = 7.7 Hz, J2 =
15.3 Hz, 2H), 2.01 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 179.9, 165.2, 161.2, 137.1, 130.2, 129.3, 126.8,
120.5, 109.4, 24.9, 11.5, 9.41. HRMS (ESI) m/z: [M + H]+ calcd for
C14H14ClO2, 249.0677; found, 249.0680.
MHz, CDCl3): keto−enol (1:8), enol tautomer δ 7.87 (d, J = 9.0 Hz,
2H), 6.93 (d, J = 8.9 Hz, 2H), 6.09 (s, 1H), 3.84 (s, 3H), 2.25 (d, J =
7.0 Hz, 2H), 2.19−2.11 (m, 1H), 0.98 (d, J = 6.5 Hz, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 193.4, 185.0, 163.1, 129.2, 127.9, 113.9,
96.0, 55.4, 47.7, 26.5, 22.6. HRMS (ESI) m/z: [M + H]+ calcd for
C14H19O3, 235.1329; found, 235.1327.
2-Benzyl-6-(4-chlorophenyl)-3-phenyl-4H-pyran-4-one (4q).
General procedure B, purified by silica gel chromatography (DCM;
DCM/EtOAc = 100/1−20/1). Yellow solid (122.4 mg, 33%), mp
118.8−119.7 °C. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.3 Hz,
2H), 7.48−7.38 (m, 5H), 7.33−7.25 (m, 5H), 7.17 (d, J = 7.2 Hz,
2H), 6.82 (s, 1H), 3.90 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3):
δ 178.7, 163.4, 161.7, 137.5, 136.0, 132.1, 130.3, 129.9, 129.4, 128.9,
128.8, 128.7, 128.3, 127.9, 127.3, 127.0, 110.8, 38.0. HRMS (ESI) m/
z: [M + H]+ calcd for C24H18ClO2, 373.0990; found, 373.0989.
2-(Adamantan-1-ylmethyl)-6-(4-chlorophenyl)-4H-pyran-4-one
(4r). General procedure B, purified by silica gel chromatography
(DCM; DCM/EtOAc = 100/1−20/1). Red-brown solid (79.8 mg,
90%), mp 161.7−162.6 °C. 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J
= 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 6.72 (s, 1H), 6.13 (s, 1H),
2.36 (s, 2H), 2.00 (br s, 3H), 1.75−1.69 (m, 3H), 1.65−1.57 (m,
9H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.9, 166.5, 162.3, 137.5,
129.9, 129.4, 127.0, 116.2, 111.0, 48.5, 42.5, 36.6, 33.9, 28.6. HRMS
(ESI) m/z: [M + H]+ calcd for C22H24ClO2, 355.1459; found,
355.1460.
2-Isobutyl-3-isopropyl-6-(4-methoxyphenyl)-4H-pyran-4-one
(4l). General procedure B, purified by silica gel chromatography
(DCM; DCM/EtOAc = 100/1−20/1). Yellow solid (15.2 mg, 5%),
1
mp 55.2−56.1 °C. H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 9.0
Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.57 (s, 1H), 3.86 (s, 3H), 2.99−
2.92 (m, 1H), 2.59 (d, J = 7.3 Hz, 2H), 2.19−2.08 (m, 1H), 1.36 (d, J
= 7.0 Hz, 6H), 1.04 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 180.1, 163.2, 161.8, 161.7, 129.6, 127.1, 124.1, 114.4,
109.6, 55.4, 40.2, 28.0, 27.4, 22.5, 20.2. HRMS (ESI) m/z: [M + H]+
calcd for C19H25O3, 301.1798; found, 301.1801.
1-(3-Hydroxy-1H-inden-2-yl)-3-methylbutan-1-one (3m).33 Gen-
eral procedure B, purified by silica gel chromatography (PE/DCM =
1
10/1−3/1). Colorless oil (170.7 mg, 79%). H NMR (400 MHz,
CDCl3): keto−enol (1:12), enol tautomer δ 7.82−7.78 (m, 1H),
7.59−7.33 (m, 3H), 3.56 (s, 2H), 2.30−2.18 (m, 3H), 1.00 (d, J = 6.1
Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 192.7, 179.0, 147.8,
138.4, 132.9, 127.3, 125.8, 123.2, 110.7, 43.4, 30.2, 26.6, 22.7. HRMS
(ESI) m/z: [M + H]+ calcd for C14H17O2, 217.1223; found, 217.1220.
2-Isobutyl-3-isopropylindeno[1,2-b]pyran-4(5H)-one (4m). Gen-
eral procedure B, purified by silica gel chromatography (DCM;
DCM/EtOAc = 100/1−20/1). Red-brown solid (60.4 mg, 21%), mp
(Z)-1-(4-Chlorophenyl)-1-hydroxy-5,5-dimethylhex-1-en-3-one
(3s). General procedure B, purified by silica gel chromatography (PE/
DCM = 10/1−3/1). Yellow solid (88.3 mg, 35%), mp 46.5−47.5 °C.
1H NMR (400 MHz, CDCl3): keto−enol (1:49), enol tautomer δ
7.82 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 6.07 (s, 1H), 2.27
(s, 2H), 1.06 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 193.9,
184.1, 138.6, 134.0, 128.9, 128.5, 98.0, 52.2, 32.0, 30.0. HRMS (ESI)
m/z: [M + H]+ calcd for C14H18ClO2, 253.0990; found, 253.0988.
2-(4-Chlorophenyl)-6-neopentyl-4H-pyran-4-one (4s). General
procedure B, purified by silica gel chromatography (DCM; DCM/
EtOAc = 100/1−20/1). Colorless solid (159.7 mg, 58%), mp 110.6−
1
69.9−70.5 °C. H NMR (400 MHz, CDCl3): δ 7.69−7.67 (m, 1H),
7.58−7.56 (m, 1H), 7.43−7.41 (m, 2H), 3.70 (s, 2H), 3.04−2.97 (m,
1H), 2.65 (d, J = 7.5 Hz, 2H), 2.21−2.10 (m, 1H), 1.41 (d, J = 7.1
Hz, 6H), 1.04 (d, J = 6.7 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 177.4, 162.9, 162.8, 143.0, 135.5, 130.0, 129.2, 127.1,
125.5, 124.6, 119.8, 40.3, 31.5, 28.1, 22.5, 20.3. HRMS (ESI) m/z: [M
+ H]+ calcd for C19H23O2, 283.1693; found, 283.1695.
1
111.5 °C. H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.7 Hz, 2H),
1-(1-Hydroxy-3,4-dihydronaphthalen-2-yl)-3-methylbutan-1-
7.46 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 2.2 Hz, 1H), 6.17 (d, J = 2.1 Hz,
1H), 2.49 (s, 2H), 1.06 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ 179.8, 167.3, 162.3, 137.4, 129.8, 129.4, 127.0, 116.0, 111.0, 47.6,
31.9, 29.6. HRMS (ESI) m/z: [M + H]+ calcd for C16H17ClO2,
277.0990; found, 277.0989.
one (3n). General procedure B, purified by silica gel chromatography
1
(PE/DCM = 10/1−3/1). Red-brown oil (86.8 mg, 38%). H NMR
(400 MHz, CDCl3): keto−enol (1:24), enol tautomer δ 7.95 (d, J =
6.6 Hz, 1H), 7.41−7.37 (m, 1H), 7.33−7.29 (m, 1H), 7.19 (d, J = 6.8
Hz, 1H), 2.86−2.83 (m, 2H), 2.64−2.60 (m, 2H), 2.37 (d, J = 7.1 Hz,
2H), 2.20−2.14 (m, 1H), 1.00 (d, J = 6.6 Hz, 6H). 13C{1H} NMR
(100 MHz, CDCl3): δ 194.5, 178.8, 141.0, 131.9, 131.6, 127.6, 126.9,
126.0, 106.2, 44.6, 28.4, 26.2, 22.8, 22.7. HRMS (ESI) m/z: [M + H]+
calcd for C15H19O2, 231.1380; found, 231.1378.
6-(4-Chlorophenyl)-2-heptyl-3-hexyl-4H-pyran-4-one (4t). Gen-
eral procedure A, purified by silica gel chromatography (DCM;
DCM/EtOH = 50/1−35/1). Yellow solid (284 mg, 73%), mp 46.5−
1
47.5 °C. H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.8 Hz, 2H),
7.45 (d, J = 8.5 Hz, 2H), 6.69 (s, 1H), 2.70−2.66 (m, 2H), 2.46−2.43
(m, 2H), 1.80−1.69 (m, 2H), 1.52−1.20 (m, 16H), 0.95−0.84 (m,
6H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.7, 164.8, 161.1, 137.2,
130.3, 129.3, 126.8, 125.7, 110.0, 31.73, 31.70, 31.2, 29.5, 29.3, 29.01,
29.00, 27.7, 24.4, 22.65, 22.62, 14.10, 14.07. HRMS (ESI) m/z: [M +
H]+ calcd for C24H34ClO2, 389.2242; found, 389.2241.
2-Isobutyl-3-isopropyl-5,6-dihydro-4H-benzo[h]chromen-4-one
(4n). General procedure B, purified by silica gel chromatography
(DCM; DCM/EtOAc = 100/1−20/1). Light yellow solid (169.1 mg,
1
57%), mp 101.3−102.1 °C. H NMR (400 MHz, CDCl3): δ 7.71−
7.69 (m, 1H), 7.36−7.28 (m, 2H), 7.23 (d, J = 6.4 Hz, 1H), 2.97 (m,
1H), 2.91−2.84 (m, 2H), 2.84−2.73 (m, 2H), 2.60 (d, J = 7.5 Hz,
2H), 2.20−2.10 (m, 1H), 1.38 (d, J = 7.1 Hz, 6H), 1.04 (d, J = 6.7
Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 178.6, 162.3, 156.3,
138.5, 130.3, 128.9, 128.5, 128.2, 126.8, 122.8, 119.7, 40.2, 28.0, 27.9,
27.1, 22.5, 20.2, 18.5. HRMS (ESI) m/z: [M + H]+ calcd for
C20H25O2, 297.1849; found, 297.1848.
(Z)-1-(3-Chlorothiophen-2-yl)-1-hydroxy-5-methylhex-1-en-3-
one (3u). General procedure C, purified by silica gel chromatography
1
(PE/DCM = 10/1−3/1). Yellow oil (12.4 mg, 5%). H NMR (400
MHz, CDCl3): keto−enol (1:10), enol tautomer δ 15.94 (s, 1H), 7.52
(d, J = 5.2 Hz, 1H), 7.02 (d, J = 5.2 Hz, 1H), 6.49 (s, 1H), 2.28 (d, J =
7.2 Hz, 2H), 2.19−2.11 (m, 1H), 1.00 (d, J = 6.6 Hz, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 193.1, 179.1, 134.3, 130.6, 130.3, 127.0,
98.2, 47.3, 26.6, 22.5. HRMS (ESI) m/z: [M + H]+ calcd for
C11H14ClO2S, 245.0398; found, 245.0399.
2-(4-Chlorophenyl)-6-methyl-4H-pyran-4-one (4o).11 General
procedure B, purified by silica gel chromatography (DCM; DCM/
EtOAc = 100/1−20/1). Yellow solid (136.3 mg, 62%), mp 110.8−
111.7 °C (lit.11 111−112.5 °C). 1H NMR (400 MHz, CDCl3): δ 7.69
(d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 2.2 Hz, 1H),
6.18 (s, 1H), 2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
179.9, 165.4, 162.3, 137.4, 129.7, 129.3, 127.0, 114.4, 110.9, 19.9.
HRMS (ESI) m/z: [M + H]+ calcd for C12H10ClO2, 221.0364; found,
221.0361.
6-(3-Chlorothiophen-2-yl)-2-isobutyl-3-isopropyl-4H-pyran-4-
one (4u). General procedure C, purified by silica gel chromatography
(DCM; DCM/EtOAc = 200/1−40/1). Yellow solid (205.5 mg,
66%), mp 63.4−64.2 °C. 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J =
5.4 Hz, 1H), 7.03 (d, J = 5.4 Hz, 1H), 6.97 (s, 1H), 2.97−2.90 (m,
1H), 2.55 (d, J = 7.3 Hz, 2H), 2.17−2.07 (m, 1H), 1.35 (d, J = 7.1
G
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Article
Hz, 6H), 1.03 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 179.4, 163.4, 155.4, 130.4, 130.0, 127.52, 127.47, 125.5,
112.3, 40.0, 27.8, 27.5, 22.5, 20.1. HRMS (ESI) m/z: [M + H]+ calcd
for C16H20ClO2S, 311.0867; found, 311.0869.
6.24 (s, 1H), 2.31 (d, J = 7.0 Hz, 2H), 2.26−2.11 (m, 1H), 1.02 (d, J
= 6.6 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 194.0, 185.2,
158.6, 156.8, 130.4, 127.9, 126.6, 124.7, 123.7, 123.3, 121.0, 120.3,
111.9, 111.7, 96.6, 47.9, 26.6, 22.6. HRMS (ESI) m/z: [M + H]+
calcd for C19H19O3, 295.1329; found, 295.1327.
(Z)-1-(3-Bromothiophen-2-yl)-1-hydroxy-5-methylhex-1-en-3-
one (3v). General procedure C, purified by silica gel chromatography
6-(Dibenzo[b,d]furan-2-yl)-2-isobutyl-3-isopropyl-4H-pyran-4-
one (4y). General procedure C, purified by silica gel chromatography
(DCM; DCM/EtOAc = 200/1−40/1). Yellow solid (184.2 mg,
1
(PE/DCM = 10/1−3/1). Red-brown oil (5.1 mg, 2%). H NMR
(400 MHz, CDCl3): keto−enol (1:10), enol tautomer δ 15.91 (s,
1H), 7.50 (d, J = 5.1 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H), 6.54 (s, 1H),
2.28 (d, J = 7.2 Hz, 2H), 2.19−2.11 (m, 1H), 1.00 (d, J = 6.6 Hz,
6H). 13C{1H} NMR (100 MHz, CDCl3): δ 192.9, 179.4, 135.8, 133.5,
130.8, 112.6, 98.1, 47.3, 26.6, 22.6. HRMS (ESI) m/z: [M + H]+
calcd for C11H14BrO2S, 288.9892; found, 288.9893.
1
51%), mp 109.0−109.8 °C. H NMR (400 MHz, CDCl3): δ 8.26 (s,
1H), 7.99 (d, J = 7.5 Hz, 1H), 7.85−7.74 (m, 1H), 7.65−7.57 (m,
2H), 7.52−7.44 (m, 1H), 7.43−7.33 (m, 1H), 6.72 (s, 1H), 3.02−
2.91 (m, 1H), 2.65 (d, J = 7.3 Hz, 2H), 2.27−2.10 (m, 1H), 1.40 (d, J
= 6.9 Hz, 6H), 1.08 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 180.0, 163.5, 161.8, 157.5, 156.8, 129.8, 128.0, 126.7,
124.9, 124.8, 123.5, 123.3, 120.9, 118.1, 112.2, 111.9, 110.7, 40.2,
28.1, 27.6, 22.6, 20.2. HRMS (ESI) m/z: [M + H]+ calcd for
C24H25O3, 361.1798; found, 361.1799.
6-(3-Bromothiophen-2-yl)-2-isobutyl-3-isopropyl-4H-pyran-4-
one (4v). General procedure C, purified by silica gel chromatography
(DCM; DCM/EtOAc = 200/1−40/1). Yellow solid (257.9 mg,
73%), mp 64.1−65.0 °C. 1H NMR (400 MHz, CDCl3): δ 7.46 (d, J =
5.3 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H), 7.03 (s, 1H), 2.97−2.90 (m,
1H), 2.56 (d, J = 7.5 Hz, 2H), 2.19−2.08 (m, 1H), 1.35 (d, J = 7.1
Hz, 6H), 1.03 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 179.2, 163.6, 155.7, 133.0, 130.0, 129.3, 128.4, 112.4,
110.9, 40.0, 27.8, 27.5, 22.5, 20.1. HRMS (ESI) m/z: [M + H]+ calcd
for C16H20BrO2S, 355.0362; found, 355.0363.
5-Methyl-1-(3-methylthiophen-2-yl)hexane-1,3-dione (3z). Gen-
eral procedure C, purified by silica gel chromatography (PE/DCM =
1
10/1−3/1). Yield 12% (27.0 mg), yellow oil. H NMR (400 MHz,
CDCl3) keto−enol (1:7.6), enol tautomer δ 7.40 (d, J = 4.9 Hz, 1H),
6.92 (d, J = 5.0 Hz, 1H), 5.89 (s, 1H), 2.40 (s, 3H), 2.21 (d, J = 7.5
Hz, 2H), 2.16−2.07 (m, 1H), 0.99 (d, J = 6.5 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 190.0, 183.2, 143.7, 133.8, 132.8, 129.3, 98.4,
46.8, 26.6, 22.5, 16.9. HRMS (ESI) m/z: [M + H]+ calcd for
C12H17O2S, 225.0944; found, 225.0945.
(Z)-1-(5-Bromothiophen-2-yl)-1-hydroxy-5-methylhex-1-en-3-
one (3w). General procedure C, purified by silica gel chromatography
1
(PE/DCM = 10/1−3/1). Red-brown oil (103.3 mg, 36%). H NMR
(400 MHz, CDCl3): keto−enol (1:9), enol tautomer δ 15.49 (s, 1H),
7.42 (d, J = 4.0 Hz, 1H), 7.08 (d, J = 3.9 Hz, 1H), 5.89 (s, 1H), 2.20
(d, J = 7.0 Hz, 2H), 2.16−2.08 (m, 1H), 0.98 (d, J = 6.5 Hz, 6H).
13C{1H} NMR (100 MHz, CDCl3): δ 189.0, 181.6, 143.7, 131.3,
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01924.
130.2, 120.9, 96.0, 46.3, 26.6, 22.5. HRMS (ESI) m/z: [M + H]+
calcd for C11H14BrO2S, 288.9892; found, 288.9891.
1H, 13C, 19F NMR spectra, HRMS spectra, computa-
tional details, and X-ray analysis (PDF)
6-(5-Bromothiophen-2-yl)-2-isobutyl-3-isopropyl-4H-pyran-4-
one (4w). General procedure C, purified by silica gel chromatography
(DCM; DCM/EtOAc = 200/1−40/1). Yellow solid (105.4 mg,
30%), mp 77.9−78.8 °C. 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J =
4.0 Hz, 1H), 7.08 (d, J = 3.9 Hz, 1H), 6.42 (s, 1H), 2.96−2.89 (m,
1H), 2.55 (d, J = 7.3 Hz, 2H), 2.14−2.04 (m, 1H), 1.33 (d, J = 7.0
Hz, 6H), 1.03 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz,
CDCl3): δ 179.3, 163.1, 156.3, 136.3, 131.2, 130.1, 126.9, 116.6,
109.3, 40.0, 27.9, 27.5, 22.5, 20.1. HRMS (ESI) m/z: [M + H]+ calcd
for C16H20BrO2S, 355.0362; found, 355.0364.
Accession Codes
CCDC 2004056 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
6-(5-Bromobenzofuran-2-yl)-2-isobutyl-3-isopropyl-4H-pyran-4-
one (4xa). General procedure C, purified by silica gel chromatog-
raphy (DCM; DCM/EtOAc = 200/1−40/1). Red-brown solid (106.3
AUTHOR INFORMATION
1
■
mg, 27%), mp 127.6−128.8 °C. H NMR (400 MHz, CDCl3): δ
Corresponding Authors
7.76−7.74 (m, 1H), 7.49−7.46 (m, 1H), 7.41 (d, J = 8.8 Hz, 1H),
7.15 (s, 1H), 6.74 (s, 1H), 2.98−2.91 (m, 1H), 2.59 (d, J = 7.3 Hz,
2H), 2.18−2.08 (m, 1H), 1.36 (d, J = 7.0 Hz, 6H), 1.05 (d, J = 6.7
Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 179.1, 163.4, 154.1,
153.2, 149.1, 130.6, 129.7, 129.4, 124.4, 116.8, 113.2, 111.3, 106.3,
40.1, 28.0, 27.7, 22.5, 20.1. HRMS (ESI) m/z: [M + H]+ calcd for
C20H22BrO3, 389.0747; found, 389.0745.
Jung Keun Kim − College of Chemistry, Henan Key Laboratory
of Chemical Biology and Organic Chemistry, Key Laboratory of
Applied Chemistry of Henan Universities, Zhengzhou
University, Zhengzhou 450052, China; Email: kim@
zzu.edu.cn
Vladimir Kovalev − Department of Chemistry, Moscow State
University, Moscow 119991, Russia; Email: kovalev@
petrol.chem.msu.ru
Yangjie Wu − College of Chemistry, Henan Key Laboratory of
Chemical Biology and Organic Chemistry, Key Laboratory of
Applied Chemistry of Henan Universities, Zhengzhou
University, Zhengzhou 450052, China; orcid.org/0000-
0002-0134-0870; Email: wyj@zzu.edu.cn
6-(5-Bromobenzofuran-3-yl)-2-isobutyl-3-isopropyl-4H-pyran-4-
one (4xb). General procedure C, purified by silica gel chromatog-
raphy (DCM; DCM/EtOAc = 200/1−40/1). Red-brown solid (71.7
mg, 18%), mp 85.4−86.2 °C. 1H NMR (400 MHz, CDCl3): δ 8.06 (s,
1H), 8.00 (s, 1H), 7.46 (dd, J1 = 8.8 Hz, J2 = 8.8 Hz, 2H), 6.57 (s,
1H), 2.99−2.92 (m, 1H), 2.61 (d, J = 7.3 Hz, 2H), 2.18−2.08 (m,
1H), 1.38 (d, J = 7.0 Hz, 6H), 1.06 (d, J = 6.6 Hz, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 179.3, 163.5, 156.1, 154.5, 145.8, 130.1,
128.5, 125.4, 123.6, 117.3, 114.8, 113.5, 112.0, 40.2, 28.1, 27.7, 22.5,
20.1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H21BrO3Na,
411.0566; found, 411.0565.
Authors
Xiangyu Sun − College of Chemistry, Henan Key Laboratory of
Chemical Biology and Organic Chemistry, Key Laboratory of
Applied Chemistry of Henan Universities, Zhengzhou
University, Zhengzhou 450052, China
Ming Gong − College of Chemistry, Henan Key Laboratory of
Chemical Biology and Organic Chemistry, Key Laboratory of
(Z)-1-(Dibenzo[b,d]furan-2-yl)-1-hydroxy-5-methylhex-1-en-3-
one (3y). General procedure C, purified by silica gel chromatography
(PE/DCM = 10/1−3/1). Light yellow solid (82.3 mg, 28%), mp
1
59.9−60.8 °C. H NMR (400 MHz, CDCl3): keto−enol (1:10.1),
enol tautomer δ 16.46 (s, 1H), 8.50 (s, 1H), 7.98 (t, J = 7.5 Hz, 2H),
7.56 (d, J = 8.6 Hz, 2H), 7.50−7.46 (m, 1H), 7.38−7.30 (m, 1H),
H
https://dx.doi.org/10.1021/acs.joc.0c01924
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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Elvira Shokova − College of Chemistry, Henan Key Laboratory
of Chemical Biology and Organic Chemistry, Key Laboratory of
Applied Chemistry of Henan Universities, Zhengzhou
University, Zhengzhou 450052, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01924
Author Contributions
§X.S. and M.G. authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation (NSF) of China (21172200 and
21302172) and the Basic Research Training Project of
Zhengzhou University (JC2020053021).
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