Three-Step One-Pot Process of 3-Methyl-5-Benzofuranol from Amine, Aldehydes, and p-Benzoquinone

Article abstract of DOI:10.1021/acs.oprd.0c00507

3-Methyl-5-benzofuranol was prepared by a one-pot process from morpholine, propionaldehyde, and p-benzoquinone in 85-87% isolated yields. Avoiding the tedious multistep isolation and purification operations, this practical and efficient process dramatically enhanced the production efficiency as well as reduced the amount of chemical wastes of reaction. The scale-up results showed that the performance was maintained, suggesting potential large-scale applications. Furthermore, the synthesis strategy showed high efficiency for a wide range of aliphatic aldehydes and ketone derivatives.

Full text of DOI:10.1021/acs.oprd.0c00507

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Article
Three-Step One-Pot Process of 3‑Methyl-5-Benzofuranol from
Amine, Aldehydes, and p‑Benzoquinone
§
§
Chaoming Liang, Maolin Sun, Xinyuan Shen, Chao Shan, Weijuan Wang, Ruihua Cheng,
and Jinxing Ye*
Cite This: Org. Process Res. Dev. 2021, 25, 810−816
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*
sı Supporting Information
ABSTRACT: 3-Methyl-5-benzofuranol was prepared by a one-pot process from morpholine, propionaldehyde, and p-benzoquinone
in 85−87% isolated yields. Avoiding the tedious multistep isolation and purification operations, this practical and efficient process
dramatically enhanced the production efficiency as well as reduced the amount of chemical wastes of reaction. The scale-up results
showed that the performance was maintained, suggesting potential large-scale applications. Furthermore, the synthesis strategy
showed high efficiency for a wide range of aliphatic aldehydes and ketone derivatives.
KEYWORDS: benzofuran, 3-methyl-5-benzofuranol, process development, one-pot synthesis
INTRODUCTION
process, suggesting the impracticability of the large-scale
production of 3-methyl-5-benzofuranol.
■
3
-Methyl-5-benzofuranol (1, Figure 1) is a useful compound
known as a key intermediate for the preparation of numerous
bioactive molecules, such as Caspase-3 inhibitor (2, Figure 1),
NAD(P)H: quinone oxidoreductase 1-directed antitumor
The “one-pot process” refers to conversion of starting
materials into the final target by a series of transformations,
even the changing reaction conditions, occurring in the same
1
9,10
reactor and avoiding the isolation of any intermediates. This
2
−5
quinone substrates (3, Figure 1),
tanshinone IIA (4, Figure
approach is very stimulating from the sustainable point of view
for the synthesis of 3-methyl-5-benzofuranol because it can be
processed without the separation of enamine and intermediate
6
7
1
3
) and its analogues, and TGR5 agonists (5, Figure 1). Also,
-methyl-5-benzofuranol can be used as additives in spices to
significantly enhance the aroma of perfumes, textiles, skincare
1
3 and it improves the repeatability. In some instances, the
8
products, and so on. Nowadays, because valuable natural
one-pot method may become feasible if the reactants,
products, solvents, and reagents do not interfere with each
other during the process. Herein, via the investigation of the
effects of solvent, the additive et al. of the route B, the
synthesis of 3-methyl-5-benzofuranol was carried out using a
practical and efficient one-pot process, which showed a
potential application in large-scale production.
fragrance resources are expensive and scarce, there is an urgent
need for new fine chemicals with a steady supply in the market.
Until now, in order to synthesize 3-methyl-5-benzofuranol
efficiently and rapidly, two main routes have been widely
developed (Scheme 1). Route A: using the expensive 2-acetyl-
4
-methoxyphenol (6) and ethyl bromoacetate (7) as starting
materials, 3-methyl-5-benzofuranol was prepared via subse-
quent condensation, hydrolysis, cyclization, and demethylation.
The intermediates had to be isolated and purified in several
steps through column chromatography purifications and
crystallizations. The toxic and hazardous ethyl bromoacetate
and boron tribromide brought difficulties in waste disposal.
RESULTS AND DISCUSSION
■
The Synthesis of Enamine 12a. In the first step reaction,
the method of the synthesis of enamine from morpholine and
2
,4
propionaldehyde was investigated. In You’s work, the mole
ratio of morpholine to propionaldehyde was 2.4. However, in
our experiment, the excess morpholine in the system was
incompletely removed via vacuum distillation, and the poor
stability of the resulted enamine led to the low yield. In the
subsequent treatment with PBQ, only a small amount of the
desired product was generated in the presence of residual
7
Thus, the total yield was only 31%. Route B: the enamine
(12a or 12b) was prepared from secondary amine (piperidine
and morpholine) and propionaldehyde and reacted with p-
benzoquinone (PBQ) in slow addition over 12 h to generate
intermediate 13. Finally, 3-methyl-5-benzofuranol was ob-
tained through the deamination of intermediate 13 in HCl. In
this long process, the intermediate enamine needed to be
purified by distillation. Also, the reported total yields ranged
from 25 to 76%, indicating that the reaction process was
Received: November 18, 2020
Published: March 12, 2021
1
,3,8
difficult to control and repeat.
Compared with route A,
route B was conducted using a mild reaction with cheaper raw
materials. However, both routes suffered from tedious
purification operations of several intermediates in the multistep
©
2021 American Chemical Society
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10

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Article
Figure 1. Structure of 3-methyl-5-benzofuranol and bioactive derivatives.
Scheme 1. Process Routes of 3-Methyl-5-Benzofuranol
morpholine in enamine. Thus, multiple distillation purifica-
tions were required. Even if the pure enamine was used, the
reaction was not satisfactory because of the formation of the
byproduct (p-phenol) in the system, and the yield of 13a was
only 80%.
Table 1. Effect of Different Additives on the Synthesis of
Enamine
a
To avoid the difficult separation, the problem from excess
morpholine must be solved. The amount of propionaldehyde
was increased to consume the morpholine completely.
However, a small amount of morpholine residue was still
observed with 1.5 equivalents of aldehyde. While the use of 3.0
equivalents of aldehyde led to no residual morpholine, the
product was accompanied by 20% impurities (Table S1).
Then, various additives on the synthesis of 12a were screened
under the condition of an equivalent amount of morpholine
and propionaldehyde in CHCl In Table 1, 4 Å molecular
yield of the product
yield of the
b
b
entry
additive
amount
(%)
byproduct (%)
1
2
3
4
5
6
7
8
4 Å MS
4 Å MS
4 Å MS
MgSO4
TiCl4
1.0 g
1.5 g
2.0 g
1.0 g
0.5 mmol
0.5 mmol
0.5 mmol
73
73
74
<50
0
69
87
97
70
1
13
3
K CO3
Ti(OPr )
Ti(OPr )4 0.75
2
i
4
3.
i
sieves (4 Å MS) and anhydrous MgSO were selected as water
4
mmol
1.0 mmol
adsorbents in the reaction. Though the performance of the
former was better than that of the latter, the increased amount
of 4 Å MS did not improve the yield, which was leveled around
Ti(OPri)
9
>99
0
4
a
Reaction conditions: morpholine (1 mmol) diluted with CHCl3,
propionaldehyde (1 mmol), and additives was added in the ice bath,
stirred at 0 °C for 30 min, then reacted at room temperature for 2 h.
The yield was determined with GC area normalization.
7
4% (entries 1−4, Table 1). No product was formed in the
presence of TiCl , while the yield was 69% over K CO
3
b
4
2
i
(entries 5, 6, Table 1). Ti(OPr ) was used in the preparation
4
1
1,12
i
of the imine.
In our reaction, using Ti(OPr ) as an
4
THF were proved to be the appropriate solvents for this
conversion (entries 1−8, Table 2). As shown in Tables S3−S4
and Table 2, both CH Cl and THF were investigated in
additive, the yield of enamine was up to 87% without residual
morpholine (entry 7, Table 1). To our delight, when 1.0 equiv.
2
2
i
of Ti(OPr ) was employed, enamine could be obtained in
4
subsequent experiments, and the latter was more acceptable in
the process. In THF, the yield could reach over 99% in 10 min
at 0 °C (entry 10, Table 2). However, elevated temperature or
prolonged reaction time decreased the yield because of the
formation of side products (entries 11−14, Table 2).
The Synthesis of 13a. With the optimum conditions for
the synthesis of enamine 12a in hand, PBQ (1.0 equiv.) was
directly added to the above mentioned enamine solution
(entry 1, Table 2). The mixture was stirred for 20 min, and
then the black precipitate was filtered and washed with
more than 99% yield (entry 9, Table 1). In addition, the
feeding sequence influenced the yield of enamine synthesis,
i
and adding the mixture of propionaldehyde and Ti(OPr ) in a
4
dropwise manner to the solution of morpholine in an ice bath
(
Table S2) presented the best yield.
Considering the toxic CHCl and its limitation in the
3
industry, several solvents including EtOAc, CH Cl , tetrahy-
2
2
drofuran (THF), 2-Me-THF, dimethylformamide (DMF),
CH CN, toluene, and n-hexane were tested. CH Cl and
3
2
2
8
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Table 2. Optimization of Reaction Conditions for the
Table 4. Optimization of Reaction Conditions for
Deamination
i
Synthesis of Enamine with Ti(OPr ) as the Additive
4
T
time
yield of the
yield of the a
byproduct (%)
a
entry
solvent
EtOAc
(°C) (min)
product (%)
a
entry
solvent
HCl (eq)
time (h)
yield (%)
1
2
3
4
0
0
0
0
30
30
30
30
88
93
92
80
8
4
3
8
1
2
3
4
5
6
7
8
9
THF
5.0
5.0
5.0
5.0
1.0
1.5
2.0
3.0
10
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
1.0
1.5
97
83
2
CH Cl2
acetone
EtOAc
toluene
THF
THF
THF
THF
THF
THF
THF
THF
2-Me-
THF
81
89
97
97
96
51
74
90
5
6
7
8
9
DMF
0
0
0
0
0
0
0
0
30
30
30
30
5
10
15
20
10
10
58
50
83
85
93
99
97
94
97
85
12
20
6
5
0
1
3
6
3
CH CN
3
toluene
n-hexane
THF
THF
THF
THF
THF
THF
1
1
1
0
1
2
2.0
2.0
2.0
1
1
1
1
1
0
1
2
3
4
THF
a
Isolated yields.
25
40
15
a
(entry 1, Table 4). Compared with the case of THF as the
solvent, the yield of 1 decreased slightly in acetone (entry 2,
Table 4). Unfortunately, the resulted mixture was a two-phase
system when toluene or ethyl acetate was used as the solvent,
and only a trace amount of the product was obtained because
of the limited mass transfer (entries 3 and 4, Table 4). In THF,
using 2.0 equivalents of HCl (2 M) afforded 1 in comparable
yield (entry 7, Table 4). Furthermore, a reaction time of 2 h
was essential because shortening the reaction time made the
conversion of 13a incomplete, resulting in a decreased yield
(entries 10−12, Table 4).
One-Pot Synthesis of 3-Methyl-5-Benzofuranol. En-
couraged by these results, three-step one-pot synthesis of 3-
methyl-5-benzofuranol was investigated. As a result, in Table 5,
the ″one-pot method″ experiment was carried out on the scale
of 10 mmol with the total yield of 89% (entry 1), which was
higher than the overall yield of the step-by-step reaction.
Moreover, the ″one-pot method″ dramatically enhanced the
production efficiency through avoiding the tedious multistep
isolation and purification operations. In order to verify the
scale-up effect and industrial value of the one-pot process for
The yield was determined with GC area normalization.
dichloromethane. The solvent was distilled, and the residue
was purified by column chromatography to obtain product 13a
with 88% isolated yields. As seen from Table 3, the amount of
PBQ changing in the range of 1.0 to 1.5 equivalents had a little
influence on the yield (entries 1−3, Table 3). When the
reaction was conducted at −10, 25, and 50 °C, the reaction
performance was not as good as at 0 °C. The reaction at room
temperature or above led to the formation of p-phenol and
decrease of yield (entries 1 and 5−6, Table 3). Based on the
optimization, the reaction could be completed in 20 min with
1
.0 equivalent PBQ in 88% yield (entry 1, Table 3), and the
yield remained the same even after further increasing of the
reaction time.
Deamination. In Table 4, the effects of solvents, amount of
acid, and reflux time on the reaction were investigated.
13
According to Snyder’s work, the compound 13a could
smoothly convert to the desired product 1 in an excellent yield
in THF with 5.0 equivalents amount of 2 M aqueous HCl
Table 3. Optimization of Reaction Conditions of Enamine with PBQ
a
entry
PBQ (mmol)
T (°C)
time (min)
yield (%)
1
2
3
4
5
6
7
8
9
1.0
1.25
1.5
1.0
1.0
1.0
1.0
1.0
1.0
0
0
0
−10
25
50
0
0
0
20
20
20
20
20
20
10
30
60
88
87
88
59
84
75
79
87
85
a
Isolated yields.
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Table 5. One-Pot Process for the Preparation of 3-Methyl-5-
Benzofuranol (1)
EXPERIMENTAL SECTION
■
a
General. All reagents were commercially available and used
without any further purification unless otherwise noted. H
1
NMR spectra were recorded on a Bruker 400 MHz instrument.
1
3
C NMR spectra were recorded on the same instrument at
1
00 MHz. Chemical shifts for protons are reported in parts per
million downfield from tetramethylsilane or referenced to
residual solvent. Chemical shifts for carbon are reported in
parts per million downfield from tetramethylsilane or
referenced to residual solvent. Data are represented as follows:
chemical shift, integration, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), and coupling
constants in Hertz (Hz). High-resolution mass spectrometry
(electrospray ionization, ESI) were carried out using a Waters
Quatro Macro triple quadrupole mass spectrometer Mass
spectra (EI) were measured on a Waters Micromass GCT
spectrometer. GC analysis was performed on an Echrom A90
gas chromatograph equipped with a flame ionization detector
using a fused silica capillary column. Analytical HPLC
(Shimadzu LC20) analysis was carried out on a C18
reversed-phase analytical column (150 mm × 4.6 mm, particle
b
entry
scale (mol)
yield (%)
1
2
3
4
5
0.01
0.1
1.0
1.0
1.0
89
88
85
87
87
a
Reaction conditions: a solution of propionaldehyde in THF added
dropwise to the solution of morpholine in THF at 0 °C and stirred for
0 min. A solution of PBQ in THF was dropped into the reaction
1
mixture with stirring for 20 min at 0 °C. Then, HCl aqueous was
added to the reaction mixture over 15 min, and the reaction mixture
size 5 μm) at 30 °C using mobile phases 68% (pure water) and
3
b
was heated to 90 °C and stirred for 2 h. Isolated yields.
−1
2% (acetonitrile) at a flow rate of 1.0 mL min . Inductively
coupled plasma−optical emission spectrometry (ICP-OES)
analysis was carried out on Agilent 725 ICP-OES.
One-Pot Preparation of 3-Methyl-5-benzofuranol (1).
the preparation of 3-methyl-5-benzofuranol, the scale of the
reaction was enlarged to 1.0 mol, and 85−87% isolated yields
for parallel batches were obtained (entries 3−5, Table 5).
Almost no obvious scale-up effect occurred in the one-pot
process under the current scale, which showed potential in
industrial scale-up. Furthermore, the recovery rate of solvent
THF was still more than 90%, which greatly reduced the cost
of the solvent and the production of chemical wastes.
Compared with the previous method, this one-pot process
represented a 52% reduction in the Process Mass Intensity
i
A solution of propionaldehyde (58 g, 1.0 mol) and Ti(OPr )
4
(
284 g, 1.0 mol) in THF (500 mL) was added dropwise to the
solution of morpholine (86 g, 1.0 mol) in THF (500 mL) at 0
C and stirred for 10 min. A solution of PBQ (108 g, 1.0 mol)
°
in THF (500 mL) was dropped into the reaction mixture with
stirring for 20 min at 0 °C. Then, HCl aqueous (2 M, 1 L) was
added to the reaction mixture over 15 min, and the reaction
mixture was heated to 90 °C and stirred for 2 h. After the
reaction was complete, the white suspension formed (of TiO2)
was filtered through Celite. The residue was concentrated via a
rotatory evaporator in vacuo to recover THF. Then, the
residue reaction solution was extracted with ethyl acetate (500
mL × 3), The organic layers were combined and concentrated
to give a light purple solid, which was further purified by
recrystallization from dichloromethane to give the product (1)
(
PMI) (Table S5).
Substrates Scope of the One-Pot Process. To test the
generality of the established method, the substrate scope was
investigated. In Table 6, various aliphatic aldehydes could
convert to corresponding 3-substituted-5-benzofuranol with
the isolated yields of 79−84% (entries 1−4, Table 6).
Interestingly, aliphatic ketones were also acceptable in this
protocol. Acetone could be successfully transformed to 2-
methyl-5-benzofuranol (15e), and cyclic ketones, such as
cyclohexanone and cycloheptanone, could also be well
converted to the desired products with moderate yields
as a white solid (129 g, 87% for three steps). The purity was
1
9
(
8
1
9.4%, as determined by HPLC. m.p. 91−93 °C. H NMR
400 MHz, CDCl ) δ = 7.38 (d, J = 0.6 Hz, 1H), 7.30 (d, J =
3
.8 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 8.8, 2.5 Hz,
1
3
H), 5.37 (s, 1H), 2.16 (d, J = 1.0 Hz, 3H). C NMR (101
MHz, CDCl ) δ = 151.1, 150.3, 142.5, 130.0, 115.5, 112.7,
3
(
entries 5−8, Table 6). This one-pot process provided a
1
18.8, 104.7, 7.9. HRMS (ESI) m/z calcd for C H O [M +
9 8 2
promising method for the synthesis of the derived compounds.
+
H] : 148.0524, found: 148.0558.
Procedure for Synthesis of 15a-h. A solution of
aldehydes or ketones (2.0 mmol) and Ti(OPr ) (568 mg,
4
CONCLUSIONS
i
■
We have developed an efficient and scalable one-pot process
for the preparation of 3-methyl-5-benzofuranol with 85−87%
isolated yields. The complicated workup procedure and
reaction time were optimized comprehensively. More
importantly, the production of liquid waste was dramatically
reduced in the current process. Moreover, various aliphatic
aldehydes and aliphatic ketones could convert to the
corresponding products smoothly in this protocol. Compared
with the previously reported methods, the newly developed
process was of low cost and had a simple operation and high
efficiency.
2.0 mol) in THF (1 mL) was added dropwise to the solution
of morpholine (172 mg, 2.0 mmol) in THF (1 mL) at 0 °C
and stirred for 10 min. A solution of PBQ (216 mg, 2.0 mmol)
in THF (1 mL) was dropped into the reaction mixture with
stirred for 20 min at 0 °C. Then, HCl aqueous (2 M, 2 mL)
was added to the reaction mixture, and the reaction mixture
was heated to 90 °C and stirred for 2 h. After the reaction was
complete, water (5 mL) and ethyl acetate (10 mL) were
added, and the white suspension formed (of TiO ) was filtered
2
through Celite. The residue was washed with ethyl acetate (2
× 10 mL). The organic layers were combined and
8
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a
Table 6. Substrates Scope of the One-Pot Process
a
b
The reagent dosage and reaction conditions are the same as the one-pot process for the preparation of 3-methyl-5-benzofuranol. Isolated yields.
concentrated to give the crude product, which was further
purified by silica column chromatography (petroleum ether/
ethyl acetate = 5:1) to afford 15a-h.
8.7, 2.6 Hz, 1H), 5.24 (s, 1H), 2.57−2.61 (m, 2H), 1.62−1.69
13
(m, 2H), 1.36−1.43 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H).
C
NMR (101 MHz, CDCl ) δ = 151.1, 150.4, 142.1, 129.3,
3
3
-Ethyl-5-benzofuranol (15a). White solid. m.p. 102−
120.5, 112.6, 111.8, 104.8, 31.1, 23.2, 22.5, 13.9. HRMS (ESI)
1
+
1
04 °C. H NMR (400 MHz, CDCl ) δ = 7.35 (s, 1H), 7.28
m/z calcd for C H O [M + H] : 190.0994, found:
3
12 14
2
(
2
d, J = 8.8 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.8,
.4 Hz, 1H), 6.13 (s, 1H), 2.57−2.63 (m, 2H), 1.28 (t, J = 7.4
190.0975.
3-(3-Chloropropyl)-5-benzofuranol (15d). White solid.
1
3
1
Hz, 3H). C NMR (101 MHz, CDCl ) δ = 151.4, 150.3,
1
(
1
m.p. 140−142 °C. H NMR (400 MHz, CDCl ) δ = 7.39 (s,
1H), 7.28 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.82
(dd, J = 8.7, 2.4 Hz, 1H), 3.54 (t, J = 6.3 Hz, 2H), 2.75 (t, J =
3
3
41.6, 129.1, 122.2, 112.7, 111.7, 104.7, 21.0, 16.9. HRMS
+
ESI) m/z calcd for C H O [M + H] : 162.0681, found:
10 10 2
1
3
62.0652.
-(tert-Butyl)-5-benzofuranol (15b). White solid. m.p.
7.1 Hz, 2H), 2.05−2.11 (m, 2H). C NMR (101 MHz,
3
CDCl ) δ = 151.6, 150.3, 142.5, 128.8, 118.6, 113.0, 111.9,
3
1
1
7
8
24−126 °C. H NMR (400 MHz, CDCl ) δ = 7.31 (s, 1H),
104.6, 44.3, 31.6, 20.5. HRMS (ESI) m/z calcd for
3
+
.30 (d, J = 7.1 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.80 (dd, J =
C H ClO [M + H] : 210.0448, found: 210.0490.
1
1
11
2
.7, 2.4 Hz, 1H), 5.53 (s, 1H), 1.38 (s, 9H). 1 C NMR (101
3
2-Methyl-5-benzofuranol (15e). White solid. m.p. 102−
1
MHz, CDCl ) δ = 150.0, 149.6, 139.4, 129.0, 126.6, 111.3,
104 °C. H NMR (400 MHz, CDCl ) δ = 7.23 (d, J = 8.7 Hz,
3
3
1
10.9, 105.9, 29.8, 28.7 (3C). HRMS (ESI) m/z calcd for
1H), 6.88 (d, J = 2.6 Hz, 1H), 6.70 (dd, J = 8.7, 2.6 Hz, 1H),
6.27 (s, 1H), 5.02 (s, 1H), 2.42 (d, J = 0.8 Hz, 3H). C NMR
+
13
C H O [M + H] : 190.0994, found: 190.0962.
1
2
14
2
3
-Butyl-5-benzofuranol (15c). Pale yellow solid. m.p.
(101 MHz, CDCl ) δ = 155.5, 150.3, 148.7, 129.0, 110.3,
3
1
1
7
21−123 °C. H NMR (400 MHz, CDCl ) δ = 7.36 (s, 1H),
.29 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.79 (dd, J =
109.9, 104.3, 101.5, 13.1. HRMS (ESI) m/z calcd for C H O
3
9
8
2
+
[M + H] : 148.0524, found: 148.0501.
8
14
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Organic Process Research & Development
,7,8,9-Tetrahydrodibenzo[b,d]furan-2-ol (15f). Pale
pubs.acs.org/OPRD
Article
6
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Weijuan Wang − Engineering Research Centre of
Pharmaceutical Process Chemistry, Ministry of Education,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
1
yellow solid. m.p. 97−99 °C. H NMR (400 MHz, CDCl )
3
δ = 7.23 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 2.6 Hz, 1H), 6.69
(
dd, J = 8.6, 2.6 Hz, 1H), 4.98 (s, 1H), 2.69−2.72 (m, 2H),
2
.54−2.57 (m, 2H), 1.89−1.93 (m, 2H), 1.80−1.86 (m, 2H).
1
3
C NMR (101 MHz, CDCl ) δ = 154.2, 150.1, 148.2, 128.7,
3
1
11.7, 110.0, 109.9, 102.9, 22.5, 21.9, 21.6, 19.4. HRMS (ESI)
Ruihua Cheng − School of Chemical Engineering, East China
University of Science and Technology, Shanghai 200237,
China
+
m/z calcd for C H O [M + H] : 188.0837, found:
1
2
12
2
1
88.0881.
,8-Dimethyl-6,7,8,9-tetrahydrodibenzo[b,d]furan-2-
8
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00507
1
ol (15 g). Pale yellow solid. m.p. 117−119 °C. H NMR (400
MHz, CDCl ) δ = 7.20 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 2.5 Hz,
3
1
H), 6.68 (dd, J = 8.6, 2.5 Hz, 1H), 5.58 (s, 1H), 2.66−2.69
Author Contributions
C.L. and M.S. contributed equally to this work.
Notes
§
(
m, 2H), 2.29 (s, 2H), 1.64 (t, J = 6.4 Hz, 2H), 1.01 (s, 6H).
1
3
C NMR (101 MHz, CDCl ) δ = 154.1, 151.2, 149.7, 130.1,
3
1
12.2, 111.1, 111.0, 103.9, 35.9, 34.3, 30.2, 28.0 (2C), 21.0.
The authors declare no competing financial interest.
+
HRMS (ESI) m/z calcd for C H O [M + H] : 216.1150,
14
16
2
found: 216.1103.
,8,9,10-Tetrahydro-6H-cyclohepta[b]benzofuran-2-
ACKNOWLEDGMENTS
■
7
1
This work was partially supported by the Engineering Research
Center of Pharmaceutical Process Chemistry, Ministry of
Education; National Natural Science Foundation of China
(22071056); and the Fundamental Research Funds for the
Central Universities.
ol (15h). Dark gray solid. m.p. 99−101 °C. H NMR (400
MHz, CDCl ) δ = 7.18 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 2.5 Hz,
3
1
H), 6.70 (dd, J = 8.6, 2.5 Hz, 1H), 5.70 (s, 1H), 2.88 (t, J =
.5 Hz, 2H), 2.59 (t, J = 5.4 Hz, 2H), 1.77−1.85 (m, 6H). C
1
3
5
NMR (101 MHz, CDCl ) δ = 157.6, 151.2, 148.2, 131.4,
3
1
15.8, 111.1, 110.8, 103.7, 30.5, 29.2, 28.2, 26.3, 23.2. HRMS
+
REFERENCES
(
2
ESI) m/z calcd for C H O [M + H] : 202.0994, found:
02.0958.
■
13
14
2
(
1) Zhang, J.; Guo, Y.; Gao, C.; Wang, E.; Ren, Z.; Fang, X.; Wang,
J. Design, Synthesis and Molecular Docking of a Novel Small-
Molecule Inhibitor of Caspase-3. Chem. Res. Chin. Univ. 2010, 26,
256−258.
(2) Bian, J.; Deng, B.; Xu, L.; Xu, X.; Wang, N.; Hu, T.; Yao, Z.; Du,
J.; Yang, L.; Lei, Y.; Li, X.; Sun, H.; Zhang, X.; You, Q. 2-Substituted
3-Methylnaphtho[1,2-b]furan-4,5-diones as Movel L-shaped Ortho-
quinone Substrates for NAD(P)H:Quinone Oxidoreductase
ASSOCIATED CONTENT
■
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00507.
Experiment optimization, one-pot protocol, PMI calcu-
(
NQO1). Eur. J. Med. Chem. 2014, 82, 56−67.
3) Zhang, X.; Bian, J.; Li, X.; Wu, X.; Dong, Y.; You, Q. 2-
1
13
lation, HPLC and ICP-OES analysis, and H and
C
(
NMR spectra (PDF)
Substituted 3,7,8-Trimethylnaphtho[1,2-b]furan-4,5-diones as Specif-
ic L-shaped NQO1-mediated Redox Modulators for the Treatment of
Non-Small Cell Lung Cancer. Eur. J. Med. Chem. 2017, 138, 616−629.
AUTHOR INFORMATION
■
(
4) Bian, J.; Li, X.; Wang, N.; Wu, X.; You, Q.; Zhang, X. Discovery
Corresponding Author
of Quinone-Directed Antitumor Agents Selectively Bioactivated by
NQO1 over CPR with Improved Safety Profile. Eur. J. Med. Chem.
2017, 129, 27−40.
Jinxing Ye − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China; School of Biomedical and
Pharmaceutical Sciences, Guangdong University of
(
5) Zhang, X.; You, Q.; Bian, J.; Qian, X.; Wang, N. Preparation of
o-naphthoquinone compounds and their application as antitumor
agents. Patent WO2017035982A1, 2017.
6) Liu, W.; Zhou, J.; Geng, G.; Shi, Q.; Sauriol, F.; Wu, J. H.
(
Technology, Guangzhou 510006, China; orcid.org/0000-
Antiandrogenic, Maspin Induction, and Antiprostate Cancer Activities
of Tanshinone IIA and its Novel Derivatives with Modification in
Ring A. J. Med. Chem. 2012, 55, 971−975.
0
003-3319-6807; Email: yejx@ecust.edu.cn, jinxingye@
gdut.edu.cn
(
7) Shen, J.; Leng, Y.; Zou, Q.; Ning, M. Amide compounds as
Authors
TGR5 agonist useful in treatment of various diseases and their
preparation. Patent WO2014117292A1, 2014.
8) Geng, F.; Monteleone, M. G.; Narula, A. P. S.. 3-Methyl-
benzofuran-5-ol and its use in perfume compositions. Patent
EP2862918A1, 2015.
(9) Tietze, L. F.; Beifuss, U. Sequential Transformations in Organic
Chemistry: a Synthesis Strategy with a Future. Am. Ethnol. 1993, 32,
Chaoming Liang − Engineering Research Centre of
Pharmaceutical Process Chemistry, Ministry of Education,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
Maolin Sun − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education, School of
Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
Xinyuan Shen − Engineering Research Centre of
Pharmaceutical Process Chemistry, Ministry of Education,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
(
1
(
2
(
31−163.
10) Hayashi, Y. Pot Economy and One-Pot Synthesis. Chem. Sci.
016, 7, 866−880.
11) Muslehiddinog
̈
̆
lu, J.; Li, J.; Tummala, S.; Deshpande, R. Highly
Diastereoselective Hydrogenation of Imines by a Bimetallic Pd-Cu
Heterogeneous Catalyst. Org. Process Res. Dev. 2010, 14, 890−894.
12) Blacker, A. J.; Roy, M.; Hariharan, S.; Headley, C.; Upare, A.;
Jagtap, A.; Wankhede, K.; Mishra, S. K.; Dube, D.; Bhise, S.;
Vishwasrao, S.; Kadam, N. Convenient Method for Synthesis of N-
(
Chao Shan − Engineering Research Centre of Pharmaceutical
Process Chemistry, Ministry of Education, School of
8
15
https://dx.doi.org/10.1021/acs.oprd.0c00507
Org. Process Res. Dev. 2021, 25, 810−816

Organic Process Research & Development
pubs.acs.org/OPRD
Article
Protected α-Amino Epoxides: key Intermediates for HIV Protease
Inhibitors. Org. Process Res. Dev. 2011, 15, 331−338.
(
13) Lee, J.; Tang, J.; Snyder, J. K. Preparation and Dienophilicity of
3
-Methyl-4,5-benzofurandione. Tetrahedron Lett. 1987, 28, 3427−
3
430.
8
16
https://dx.doi.org/10.1021/acs.oprd.0c00507
Org. Process Res. Dev. 2021, 25, 810−816