One Pot Synthesis of γ-Benzopyranones via Iron-Catalyzed Aerobic Oxidation and Subsequent 4-Dimethylaminopyridine Catalyzed 6-endo Cyclization

Article abstract of DOI:10.1002/adsc.201700993

One-pot synthesis of γ-benzopyranones was realized in decent yields and excellent regioselectivities via iron-catalyzed aerobic oxidation and 4-dimethylaminopyridine-catalyzed cyclization of related propargylic alcohols. Derivatizations to aromatic substituted γ-benzopyranones and synthesis of naturally occurring 3′,4′-dimethoxyflavone have also been realized. (Figure presented.).

Full text of DOI:10.1002/adsc.201700993

Title: One Pot Synthesis of γ-Benzopyranones via Iron-Catalyzed
Aerobic Oxidation and Subsequent 4-Dimethylaminopyridine-
Catalyzed 6-endo Cyclization
Authors: Di Zhai, Lingzhu Chen, Minqiang Jia, and Shengming Ma
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700993
Link to VoR: http://dx.doi.org/10.1002/adsc.201700993

10.1002/adsc.201700993
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
One Pot Synthesis of γ-Benzopyranones via Iron-Catalyzed
Aerobic Oxidation and Subsequent 4-Dimethylaminopyridine-
Catalyzed 6-endo Cyclization
Di Zhai,a Lingzhu Chen,b Minqiang Jia,a* and Shengming Maa,b,c*
a
Research Center of Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan
Road, Shanghai 200433, P. R. China. E-mail: mqjia@fudan.edu.cn
Department of Chemistry, Laboratory of Molecular Recognition and Synthesis, Zhejiang University, 38 Zheda Road,
b
Zhejiang 310027, P. R. China.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
c
Sciences, 345 Lingling Road, Shanghai 200032, P. R. China.E-mail: masm@sioc.ac.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
adding an extra catalyst into the oxidation system, γ-
benzopyranones can be generated from propargylic
alcohols in a one-pot process. Herein, we report our
results on this topic.
Abstract. One-pot synthesis of γ-benzopyranones was
realized in decent yields and excellent regioselectivities via
iron-catalyzed
aerobic
oxidation
and
4-
dimethylaminopyridine-catalyzed cyclization of related
propargylic alcohols. Derivatizations to aromatic
substituted γ-benzopyranones and synthesis of naturally
occurring 3',4'-dimethoxyflavone have also been realized.
Keywords: one pot; iron catalysis; aerobic oxidation;
flavones; natural products
As a major class of polyphenolic natural products
commonly found in plants, γ-benzopyranones have
received a lot of attention due to their biological
activities such as anti-tumor and anti-inflammatory
activities.[1] In addition, the structure of conjugate
enone fragment and reactive fused phenyl have a
great synthetic potential in organic synthesis.[2] Thus,
much attention has been focused on the methods for
flavone synthesis. The reported literatures mainly
consist of five types of strategies (Scheme 1): a)
cyclization and dehydration of β-carbonyl
compounds.[3] b) Michael addition of chalcones and
subsequent oxidation.[4] c) Michael addition of
alkynones.[5] d) Palladium-catalyzed cyclization
reaction.[6] e) Palladium-catalyzed oxidative coupling
reaction.[7] Unfortunately, they all suffer from too
many steps, stoichiometric amount of oxidant, highly
toxic carbon monoxide, expensive palladium catalyst
or high temperature. The direct protocol using
propargylic alcohols as starting material remains quite
undeveloped.[8] Recently, our group developed an
iron-catalyzed oxidation of different alcohols at room
temperature in high yields and excellent
selectivities.[9] By using this method, the oxidation of
propargylic alcohols can be realized in excellent
yields and selectivities. We hypothesized that by
Scheme 1. The synthesis of γ-benzopyranones
To start our study, 2-(1-hydroxy-3-phenylprop-2-
yn-1-yl)phenol (1a) was selected as the model starting
material. First, different additives were screened after
the iron-catalyzed aerobic oxidation reaction.[9] When
K2CO3 and NaOH were used, both 2-phenyl-4H-
chromen-4-one (3a) and 2-benzylidenebenzofuran-
3(2H)-one (4a) were formed in moderate yields
(Table 1, entries 1 and 2).[10] Other additive such as
PCy3 (Table 1, entry 3) resulted in a poor selectivity
and low conversion. TfOH and t-BuOLi gave 86%
yield and 79% yield of alkynone 2a, respectively
(Table 1, entries 4 and 5). Running this reaction by
adding DMAP[11] gave the best result in 85% yield of
3a with an excellent selectivity and no starting
material was recovered (Table 1, entry 5).
1
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10.1002/adsc.201700993
Advanced Synthesis & Catalysis
Table 1. The optimization of the reaction conditions.[a]
Finally, different loadings of DMAP were studied
in this one-pot synthesis. With 0.1 equivalent DMAP,
only 19% yield of 3a was detected together with 67%
yield of aerobic oxidation product 2-alkynone 2a
(Table 3, entry 1). When the loading of DMAP was
increased to 0.15 equiv, the yield of 3a was improved
to 72% with no 2a detected (Table 3, entry 2). The
best catalyst loading of DMAP was proved to be 0.2
equivalent with 85% NMR yield of 3a and no 2a was
detected (Table 3, entry 4). Further increasing the
loading of DMAP failed to improve the yield of 3a
(Table 3, entry 5).
Yield (%)[b]
Entry Additive Equiv.
t1/t2(h)
2a
3a
4a
1
2
3
4
5
6
K2CO3
NaOH
PCy3
TfOH
t-BuOLi
DMAP
2.0
2.0
0.2
0.2
0.2
0.2
3.0/4.0
3.0/2.5
3.0/2.5 29
2.3/2.5 86
3.2/14 79
0
0
40
15
12
0
0
85
52
61
19
0
0
0
Table 3. The effect of the DMAP loading.[a]
3.3/2.5
0
[a]
The reaction was conducted using 1a (1.0 mmol),
Fe(NO3)3·9H2O (0.05 mmol), NaCl (0.05 mmol),
TEMPO (0.05 mmol), and additive in MeCN (5 mL) with
an oxygen balloon at 25ꢀ°C.
Determined by H NMR analysis with dibromomethane
as the internal standard.
Yield (%)[b]
Entry
x
t1/t2 (h)
2a
3a
[b]
1
1
2
3
4
10
15
20
30
3.25/2.5
3.0/2.5
3.3/2.5
2.6/1.5
67
0
19
72
0
0
85 (81)[c]
83
[a]
Encouraged by these results, different solvents
were examined. DMF, dioxane, and THF gave
43~73% recovery of 1a (Table 2, entries1-3). When
DCM was used as the solvent, 8% yield of γ-
benzopyranone 3a was detected without recovery of
1a (Table 2, entry 4). When DCE was used, 58%
yield of 3a was obtained (Table 2, entry 5). Finally,
MeCN turned out to be the best solvent, providing γ-
benzopyranone 3a in 85% NMR yield and 81%
isolated yield (Table 2, entry 6).
The reaction was conducted using 1a (1.0 mmol),
Fe(NO3)3·9H2O (0.05 mmol), NaCl (0.05 mmol),
TEMPO (0.05 mmol) in MeCN (5 mL) with an oxygen
balloon at 25ꢀ°C. After the disappearance of 1a by TLC,
DMAP (0.2 mmol) was added into the resulting mixture.
[b]
1
Determined by H NMR analysis with dibromomethane
as the internal standard.
[c] The number in parenthesis represents isolated yield.
With the optimal conditions in hand (Table 3, entry
3), the reaction scope was further investigated. When
R1 is H, different aryl groups can be introduced into
the R2 position including electron withdrawing and
electron donating group substituted phenyl groups,
providing the desired γ-benzopyranones in good
yields (Table 4, entries 1-4, 3a-3d). Replacing R2
with H and n-Bu resulted in lower yields (Table 4,
entries 5-6, 3e and 3f). To understand the reason of
low yields for the substrates 1e and 1f, iron-catalyzed
oxidation and 6-endo cyclization were conducted
separately. Firstly, the oxidation of 1e provided the
desired product 2e in 83% NMR yield. The second
step of 6-endo cyclization gave only 33% NMR yield
of 3e. Thus, we reasoned that the low yield of 3e was
mainly due to the low yield of 6-endo cyclization step.
For the reaction of 1f, iron-catalyzed oxidation
provided 89% NMR yield of 2f, the second step of 6-
endo cyclizaion provided 86% NMR yield of 3f with
acetonitrile as solvent.[11] However, the 6-endo
cyclization under the catalysis of DMAP together
with the catalysts for the first step gave 3f in only
53% NMR yield. Based on these results, we proposed
that the low yield of 3f was also caused by the low
yield of 6-endo cyclization under the combined
conditions (Scheme 2).
Table 2. The scope of aldehydes.[a]
t1/ t2
(h)
Yield of
Recovery of
Entry Solvent
3a (%)[b]
1a (%)[b]
1
2
3
4
5
6
DMF
dioxane 2.7/2.4
2.8/1.7
0
0
0
8
58
73
43
49
0
0
0
THF
DCM
DCE
2.5/2.0
3.0/2.5
3.0/2.5
MeCN 3.3/2.5 85 (81)[c]
[a]
The reaction was conducted using 1a (1.0 mmol),
Fe(NO3)3·9H2O (0.05 mmol), NaCl (0.05 mmol), TEMPO
(0.05 mmol) in solvent (5 mL) with an oxygen balloon at
25ꢀ°C. After the disappearance of 1a by TLC, DMAP (0.2
mmol) was added into the resulting mixture.
[b]
1
Determined by H NMR analysis with dibromomethane
as the internal standard.
[c]
The number in parenthesis represents isolated yield.
DMAP: 4-dimethylaminopyridine.
2
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10.1002/adsc.201700993
Advanced Synthesis & Catalysis
R1 may also be 5-chloro with R2 being phenyl,
cyclopropyl, 2-thienyl, 3-thienyl, providing the
desired product in 52-86% isolated yields (Table 4,
entries 7-10, 3g-3j). It is worth noting that methyl,
bromo, nitro, and 3,5-dichloro on R1 position were all
tolerated in this reaction providing the corresponding
products in good to excellent yields (Table 4, entries
11-14, 3k-3n). However, when R1 is 5-methoxyl
group, the reaction provided the desired product 3o in
only 13% isolated yield (Table 4, entry 15, 3o).
Table 4. The substrate scope.[a]
Yield of 3
Entry
R1/R2
t1/ t2 (h)
(%)
1
2
H/Ph (1a)
H/p-MeC6H4 (1b)
H/p-MeOC6H4 (1c)
H/p-ClC6H4 (1d)
H/H (1e)
H/n-Bu (1f)
5-Cl/Ph (1g)
5-Cl/Cyclopropyl (1h) 3.5/3.5
3.3/2.5
3.0/3.0
3.75/5.5
3.3/11.6
4.0/3.0
3.0/3.0
3.5/3.0
82 (3a)
81 (3b)
81 (3c)
68 (3d)
20 (3e)
44 (3f)
78 (3g)
86 (3h)
52 (3i)
78 (3j)
67 (3k)
78 (3l)
85 (3m)
63 (3n)
13 (3o)
3[b]
4
5
6
7
8
Scheme 2. Reactions of 1e/2e and1f/2f
9
5-Cl/2-thienyl (1i)
5-Cl/3-thienyl (1j)
5-Me/Ph (1k)
3.5/3.5
3.5/4.0
3.5/3.0
3.75/13
3.75/13
12/7.0
Since γ-benzopyranones with multi-methoxy
substituents are core structure of nature products and
play an important role in pharmaceutical science, we
also tested 4-methoxy and 4,5-dimethoxy substituted
propargylic alcohols (1p-1q). Since 1p and 1q are
easily decomposed during the chromatographic
purification, we used the crude products directly for
the reaction. However, the one-pot process of
oxidation and cyclization for 1p provided only 10%
yield of 3p, and one-pot synthesis of 3q failed,
yielding a complex mixture-product 3q was not
observed from the crude NMR spectra. The poor
results were due to the oxidation steps (24% NMR
yield for 2p and 5% NMR yield for 2q). When 2q
was isolated and submitted for the cyclization process,
the reaction proceeded smoothly to provide the final
product 3q in 76% yield (Scheme 3).
10
11
12
13
14
15
5-Br/Ph (1l)
5-NO2/Ph (1m)
3-Cl, 5-Cl/Ph (1n)
5-MeO/Ph (1o)
13/4.0
[a]
The reaction was conducted using 1a (1.0 mmol),
Fe(NO3)3·9H2O (0.05 mmol), NaCl (0.05 mmol),
TEMPO (0.05 mmol) in MeCN (5 mL) with an oxygen
balloon at 25ꢀ°C. After the disappearance of 1a by TLC,
DMAP (0.2 mmol) was added into the resulting mixture.
[b] The reaction was conducted using 1c (0.5 mmol).
3
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10.1002/adsc.201700993
Advanced Synthesis & Catalysis
Finally,
the
naturally
occurring
3',4'-
dimethoxyflavone 3r was obtained in 78% yield
(Scheme 5).
Reagents and conditions: i) 2-methylbut-3-yn-2-ol (3.6
equiv), Pd(PPh3)2Cl2 (5 mol%), CuI (10 mol%), TEA, 90
o
oC, 24 h; ii) KOH (3 equiv), toluene, 110 C, 22 h; iii)
salicylic aldehyde (0.45 equiv), n-BuLi (0.95 equiv), THF,
-78 oC, 4 h; iv) Fe(NO3)3·9H2O (5 mol%), NaCl (5 mol%),
TEMPO (5 mol%), MeCN, oxygen balloon, 25ꢀ°C, 4.7 h
then DMAP (20 mol%), 25ꢀ°C, 6 h
Scheme 5. Synthesis of naturally occurring 3',4'-
dimethoxyflavone 3r.
Meanwhile, the Suzuki coupling reaction of 3n
with phenylboronic acid gave the desired γ-
benzopyranone 7n by using LB-Phos[13] as the ligand
in 71% isolated yield via simple recrystallization
(Scheme 6).
Scheme 3. Reactions of multi-methoxy substituted
substrates 1p and 1q
To demonstrate the practicality and efficiency of
this methodology, gram scale synthesis of γ-
benzopyranones were carried out. When 1l and 1n
were chosen to be the substrates, 1.53 g of 3l (85%
yield) and 1.07 g of 3n (61% yield) were successfully
prepared (Scheme 4).
Scheme 6. Synthetic application.
In conclusion, a green methodology consisting of
iron-catalyzed aerobic oxidation and DMAP-
catalyzed 6-endo cyclization to differently substituted
γ-benzopyranones in moderated to excellent yields
was developed. This eco-friendly one-pot synthesis
protocol may be easily executed on gram scale and
has been applied to the synthesis naturally occurring
3',4'-dimethoxyflavone 3r. Due to the importance of
these products, this method will be of high interest to
people who work in fine chemical and pharmaceutical
synthesis.
Scheme 4. Gram scale reactions.
At last, naturally occurring 3',4'- dimethoxyflavone
3r was chosen as the target and synthesized in four
steps from commercially available starting materials
(Scheme 4).[12] The first two steps including
Sonogashira coupling and subsequent Retro-Favorski
reaction gave 6r in 55% yield. Then, the reaction of
salicylic aldehyde with 6r-based lithium acetylide
gave the desired propargylic alcohol 1r in 85% yield.
Experimental Section
General Information. NMR spectra were taken with an
Agilent-400 spectrometer (400 MHz for 1H NMR, 100
1
MHz for 13C NMR). H NMR spectra were recorded using
TMS as an internal standard (δ 0 ppm), or using solvent
residual signal of acetone-d6 as an internal standard (δ 2.05
4
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10.1002/adsc.201700993
Advanced Synthesis & Catalysis
ppm), or using solvent residual signal of CD3CN as an cm-1; Anal. Calcd for C12H11ClO2: C 64.73, H 4.98; Found:
internal standard (δ 1.95 ppm) and coupling constants were C 64.84, H 4.98.
reported in Hz. 13C NMR spectra were recorded using
CDCl3 as an internal standard (δ 77.0 ppm), or using 2. Synthesis of γ-benzopyranones
acetone-d6 as an internal standard (δ 29.84 ppm), or using (1) Preparation of 2-(4-methylphenyl)-4H-chromen-4-one
CD3CN as an internal standard (δ 118.2 ppm). All reactions (3b)
were carried out in flame-dried Schlenk tubes.
Fe(NO3)3·9H2O (98%) and Pd(OAc)2 (47.5% Pd) was
purchased from J&K Chemicals; NaCl (>99.5%), CuI
(>99.5%) and DMAP (>99%) was purchased from
Typical Procedure B: To a flame-dried Schlenk tube were
added Fe(NO3)3·9H2O (20.1 mg, 0.05 mmol) and NaCl (3.1
mg, 0.05 mmol) under argon. The Schlenk tube was then
degassed to remove the argon inside completely, and
refilled with O2 by a balloon of O2 for three times. Then, a
solution of TEMPO (8.2 mg, 0.05 mmol) in dry MeCN (3
mL) and the solution of 1b (239.4 mg, 1.0 mmol) in dry
MeCN (2 mL) were added sequentially. Then the mixture
was stirred at 25 oC with a balloon of O2 for 3.0 h. After the
disappearance of 1b by TLC, O2 balloon was removed and
DMAP (24.1 mg, 0.2 mmol) was added into the reaction
Sinopharm Chemical Reagent Co., Ltd; TEMPO (98%)
was purchased from Shanghai Darui Fine Chemical Co.,
Ltd.; Pd(PPh3)2Cl2 (98%) was purchased from Energy
Chemical; Dioxane, toluene and THF were dried over
sodium wire. MeCN was dried over CaH2 and distilled. All
the temperatures are referred to the oil baths, acetone/dry
ice bath or ice/water bath used. Recovery of substrates was
1
determined by H NMR analysis using dibromomethane as
the internal standard.
Experimental details and analytical data
1. Synthesis of propargylic alcohols[8]
o
mixture. Then the mixture was stirred at 25 C for 3.0 h as
monitored by TLC. After concentration under reduced
pressure, the residue was diluted with DCM. To the
solution was added 1M HCl (10 mL) and the resulting
mixture was washed with 20 mL of water. The organic
layer was separated and the aqueous solution was extracted
with DCM (3 x 30 mL). The combined organic layer was
dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. Then, the mixture was transferred
with DCM, filtered through a short column on silica gel (3
cm) (eluent: ethyl ether) until no product can be observed
by TLC, and concentrated under reduced pressure [the
(1)
Preparation
of
3-cyclopropyl-1-(2-hydroxy-5-
chlorophenyl)-2-propynol (1h)
Typical Procedure A: To a flame-dried Schlenk tube were
added cyclopropyl acetylene (1.18 g, 17.6 mmol) and THF
(40 mL) under Ar. The resulting mixture was cooled to -
78 °C. n-BuLi (2.4 M in hexanes, 7 mL, 16.8 mmol) was
slowly added at -78 °C within 15 min. The mixture was put
into an ice-water bath and stirred at 0 °C for 83 min. Then,
1
yield of 3b was determined by H NMR analysis of the
crude products using dibromomethane as the internal
standard (82%)]. The residue was purified by column
chromatography on silica gel to afford 3b[8] (193.5 mg,
81%) as a pale yellow solid [eluent: petroleum ether/ethyl
acetate = 8/1]: m.p. 112.5-113.4 °C (petroleum ether/DCM)
(Lit[6f] m.p.: 111 oC); 1H NMR (400 MHz, CDCl3): δ = 8.21
(dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1 H, ArH), 7.78 (d, J = 8.4 Hz,
2 H, ArH), 7.70- 7.62 (m, 1 H, Ar-H), 7.53 (d, J = 8.4 Hz, 1
H, ArH), 7.38 (t, J = 7.6 Hz, 1 H, ArH), 7.28 (d, J = 7.6 Hz,
2 H, ArH), 6.76 (s, 1 H, =CH), 2.40 (s, 3 H, CH3); 13C
NMR (100 MHz, CDCl3): δ = 178.3, 163.4, 156.1, 142.1,
133.5, 129.6, 128.8, 126.1, 125.5, 125.0, 123.8, 117.9,
106.8, 21.4; MS (70 eV, EI) m/z (%): 236 (M +, 100); IR
(neat): ν = 1634, 1604, 1567, 1510, 1464, 1414, 1370, 1124
cm-1.
o
the mixture was put into a dry ice-acetone bath at -78 C.
After
10
min,
the
solution
of
5-chloro-2-
hydroxybenzaldehyde (1.20 g, 8 mmol) in dry THF (20
mL) was slowly added within 10 min. After being stirred at
-78 °C for 6.5 h, the resulting mixture was placed in an
ice/water bath, quenched with
a saturated aqueous
ammonium chloride solution (40 mL). The organic layer
was separated and the aqueous solution was extracted with
ethyl ether (3 x 30 mL). The combined organic layer was
dried over anhydrous Na2SO4. After filtration and
concentration under reduced pressure, the crude product
was purified by column chromatography on silica gel to
afford 1h (1.0735 g, 63%) as a white solid [DCM (100 mL)
to DCM/ethyl ether = 15/1 afforded impure 3h, which was
further purified with chromatography (eluent: petroleum
ether/ethyl acetate = 3/1)]: m.p. 74.0-74.9 °C (petroleum
(2) Preparation of 6-chloro-2-(thiophen-3-yl)-4H-chromen-
4-one (3j)
1
ether/dichloromethane); H NMR (400 MHz, CDCl3): δ =
7.36 (s, 1 H, ArOH), 7.31 (d, J = 2.4 Hz, 1 H, ArH), 7.18
(dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1 H, ArH), 6.83 (d, J = 8.8 Hz,
1 H, ArH), 5.59 (d, J = 4.0 Hz, 1 H, OCH), 2.68 (d, J = 5.2
Hz, 1 H, OH), 1.40-1.30 (m, 1 H, CH from cyclopropane),
0.90-0.72 (m, 4 H, CH2-CH2); 13C NMR (100 MHz,
CDCl3): δ = 153.9, 129.7, 127.4, 126.2, 124.8, 118.4, 93.3,
72.3, 63.8, 8.5, -0.5; MS (70 eV, EI) m/z (%): 224
(M+(37Cl), 2.55), 222 (M+(35Cl), 8.51), 176 (100); IR (neat):
ν = 3394, 2232, 1602, 1494, 1424, 1358, 1326, 1271, 1113
Typical Procedure C: To a flame-dried Schlenk tube were
added Fe(NO3)3·9H2O (20.2 mg, 0.05 mmol) and NaCl (2.7
mg, 0.05 mmol) under argon. The Schlenk tube was then
degassed to remove the argon inside completely, and
refilled with O2 by a balloon of O2 for three times. Then, a
solution of TEMPO (8.1 mg, 0.05 mmol) in dry MeCN (2
5
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10.1002/adsc.201700993
Advanced Synthesis & Catalysis
mL) and the solution of 1j (264.7 mg, 1.0 mmol) in dry (petroleum ether/DCM) (Lit[7e] m.p.: 154-156 oC); 1H NMR
MeCN (3 mL) were added sequentially. Then the mixture (400 MHz, CDCl3): δ = 8.23 (dd, J1 = 8.2 Hz, J2 = 1.4 Hz,
was stirred at 25 oC with a balloon of O2 for 3.5 h. After the 1 H, ArH), 7.89 (d, J = 9.2 Hz, 2 H, ArH), 7.73-7.65 (m, 1
disappearance of 1j by TLC, O2 balloon was removed and H, ArH), 7.56 (d, J = 8.0 Hz, 1 Hz, ArH), 7.45-7.37 (m, 1
DMAP (24.4 mg, 0.2 mmol) was added into the reaction H, ArH), 7.03 (d, J = 9.2 Hz, 2 H, ArH), 6.76 (s, 1 H, =CH),
o
mixture. Then the mixture was stirred at 25 C for 4 h as 3.90 (s, 3 H, OCH3); 13C NMR (100 MHz, CDCl3): δ =
monitored by TLC. After concentration under reduced 178.4, 163.4, 162.4, 156.1, 133.5, 128.0, 125.6, 125.0,
pressure, the residue was diluted with DCM. To the 123.9, 123.8, 117.9, 114.4, 106.1, 55.5; MS (70 eV, EI)
solution was added 1M HCl (10 mL) and the resulting m/z (%): 252 (M+, 100); IR (neat): ν = 1644, 1604, 1570,
mixture was washed with 20 mL of water. The organic 1512, 1464, 1426, 1376, 1314, 1264, 1251, 1192, 1122,
layer was separated and the aqueous solution was extracted 1023 cm-1.
with DCM (3 x 30 mL). The combined organic layer was
dried over anhydrous Na2SO4, filtered and concentrated to
remove most of DCM. Then, the mixture was filtered
Acknowledgements
through a short column on silica gel (3 cm) (eluent: ethyl
ether) until no product may be collected as indicated by
Financial support from National Basic Research Program
(2015CB856600) is greatly appreciated. We thank Shihua Song of
our group for reproducing the results of entry 4, entry 5 and
entry 14 in Table 4 represented in this study.
TLC, and concentrated under reduced pressure [the yield of
3j was determined by 1H NMR analysis of the crude
products using dibromomethane as the internal standard
(83%)]. The residue was purified by column
chromatography on silica gel to afford 3j[14] (207.2 mg,
78%) as a white solid [eluent: petroleum ether/ethyl acetate
References
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[1] For selected examples on the bioactivity and
acetate
= 15/2/1]: m.p. 155.5-156.4 °C (petroleum
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ether/ethyl ether) (Lit[14] m.p.: 160 oC); 1H NMR (400 MHz,
CDCl3): δ = 8.14 (d, J = 2.4 Hz, 1 H, ArH), 8.00 (t, J = 2.2
Hz, 1 H, ArH), 7.60 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1 H,
ArH), 7.51-7.41 (m, 3 H, ArH), 6.64 (s, 1 H, =CH); 13C
NMR (100 MHz, CDCl3): δ = 177.1, 159.7, 154.3, 133.83,
133.77, 131.1, 127.5, 127.1, 125.1, 125.0, 124.9, 119.6,
107.0; MS (70 eV, EI) m/z (%): 264 (M+(37Cl), 37.29), 262
(M+(35Cl), 100); IR (neat): v = 1649, 1616, 1603, 1567,
1434, 1410, 1380, 1332, 1258, 1042 cm-1
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(3) Preparation of 2-(4-methoxyphenyl)-4H-chromen-4-one
(3c)
Typical Procedure D: To a flame-dried Schlenk tube were
added Fe(NO3)3·9H2O (10.4 mg, 0.025 mmol) and NaCl
(1.5 mg, 0.025 mmol) under argon. The Schlenk tube was
then degassed to remove the argon inside completely, and
refilled with O2 by a balloon of O2 for three times. Then, a
solution of TEMPO (3.9 mg, 0.025 mmol) in dry MeCN
(1.5 mL) and the solution of 1c (127.5 mg, 0.5 mmol) in
dry MeCN (1 mL) were added sequentially. Then the
mixture was stirred at 25 oC with a balloon of O2 for 3.75 h.
After the disappearance of 1c by TLC, O2 balloon was
removed and DMAP (12.3 mg, 0.1 mmol) was added into
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o
the reaction mixture. Then the mixture was stirred at 25 C
for 5.5 h as monitored by TLC. After concentration under
reduced pressure, the residue was transferred with DCM,
filtered through a short column on silica gel (3 cm) (eluent:
ethyl ether) until no product can be observed by TLC, and
concentrated under reduced pressure [the yield of 3c was
1
determined by H NMR analysis of the crude products
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residue was purified by column chromatography on silica
gel to afford 3c[8] (102.5 mg, 81%) as a pale yellow solid
(eluent: petroleum ether/ethyl acetate = 10/1 (210 mL) to
petroleum ether/ethyl acetate = 5/1): m.p. 155.0-156.1 °C
6
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10.1002/adsc.201700993
Advanced Synthesis & Catalysis
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7
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10.1002/adsc.201700993
Advanced Synthesis & Catalysis
UPDATE
One Pot Synthesis of γ-Benzopyranones via Iron-
Catalyzed Aerobic Oxidation and Subsequent 4-
Dimethylaminopyridine-Catalyzed 6-endo
Cyclization
Adv. Synth. Catal.Year, Volume, Page – Page
Di Zhai, Lingzhu Chen, Wenxiao Lu, Minqiang
Jia* and Shengming Ma*
8
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