Singlet Oxygen Generation from a Water-Soluble Hypervalent Iodine(V) Reagent AIBX and H2O2: An Access to Artemisinin

Article abstract of DOI:10.1021/acs.joc.1c00596

Herein, we report an efficient method for the chemical generation of 1O2 by treatment of H2O2 with AIBX, a highly water-soluble, bench-stable, recyclable hypervalent iodine(V) reagent developed by our group. The generation of 1O2 was confirmed by the following results: (1) capture of 1O2 with the sodium salt of anthracene-9,10-bis(ethanesulfonate) produced the corresponding endoperoxide and (2) TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) produced by the oxidation of 2,2,6,6-tetramethylpiperidine with 1O2 generated using the AIBX/H2O2 system was detected by electron spin resonance spectroscopy. To illustrate the potential utility of this method for organic synthesis, we used the AIBX/H2O2 system to perform typical reactions of 1O2: [2 + 2]/[4 + 2] cycloadditions, Schenck ene reactions, and heteroatom oxidation reactions, which afforded the corresponding products in high yields. Moreover, we used the method to synthesize the antimalarial drug artemisinin. Finally, we demonstrated that AIBX could be regenerated after the reaction by means of a workup involving extraction and removal of water to obtain a precursor of AIBX, which could then be re-oxidized.

Full text of DOI:10.1021/acs.joc.1c00596

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Article
Singlet Oxygen Generation from a Water-Soluble Hypervalent
Iodine(V) Reagent AIBX and H2O2: An Access to Artemisinin
Hui-Jie Shen, Ze-Nan Hu, and Chi Zhang*
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ABSTRACT: Herein, we report an efficient method for the chemical
1
generation of O2 by treatment of H2O2 with AIBX, a highly water-
soluble, bench-stable, recyclable hypervalent iodine(V) reagent
1
developed by our group. The generation of O2 was confirmed by the
following results: (1) capture of 1O2 with the sodium salt of anthracene-
9,10-bis(ethanesulfonate) produced the corresponding endoperoxide
and (2) TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) produced by the
1
oxidation of 2,2,6,6-tetramethylpiperidine with O2 generated using the
AIBX/H2O2 system was detected by electron spin resonance spectros-
copy. To illustrate the potential utility of this method for organic
synthesis, we used the AIBX/H2O2 system to perform typical reactions
1
of O2: [2 + 2]/[4 + 2] cycloadditions, Schenck ene reactions, and
heteroatom oxidation reactions, which afforded the corresponding
products in high yields. Moreover, we used the method to synthesize the
antimalarial drug artemisinin. Finally, we demonstrated that AIBX could be regenerated after the reaction by means of a workup
involving extraction and removal of water to obtain a precursor of AIBX, which could then be re-oxidized.
arene endoperoxides,16 peracids,17 cholesterol hydroperox-
INTRODUCTION
■
ide,18 and dimethyldioxirane [DMDO]19) and triphenylphos-
1
Singlet oxygen, O2(1Δg), is the lowest excited electronic state
phite ozonide20 (Scheme 1d). However, because many
of molecular oxygen (22.4 kcal/mol above the triplet oxygen
[3O2], which is the ground state). Singlet oxygen participates
peroxides and the ozonide are thermally unstable, the
in reactions that distinguish it from 3O2, including [2 + 2]/[4 +
development of a safe, practical, efficient chemical method
1
for generating O2 would be desirable for both laboratory and
2] cycloadditions, Schenck ene reactions, and oxidation
reactions of various heteroatoms.1 As an important active
oxygen species and synthetic reagent, 1O2 is still at the
forefront of research due to its unique reactivity,2 and it has
been widely used for photodynamic therapy of tumors,3
wastewater treatment,4 and organic synthesis of natural
products including withanolide A and pandamarine and
pharmaceuticals such as milbemycin E, the antibiotic
( )-PS-5, and the antimalarial drug artemisinin.5
industrial applications.
We reasoned that the combination of H2O2 and a
hypervalent iodine reagent might be useful for this purpose.
Hypervalent iodine reagents have drawn considerable attention
not only because of their richly varied reactivity but also
because they are stable, easy to handle, and environmentally
benign.21 In a previously reported work, H2O2 has been used
in combination with a hypervalent iodine reagent, either PhIO2
1O2 is typically generated by dye-sensitized photooxidation
of 3O2 (Scheme 1a),6 but scaling up this process for industrial
use is not a simple task.7 Therefore, chemical methods for
generating 1O2 without light have been developed as
alternatives to the photochemical method.8 The first chemical
method to be reported, in the early 1960s, involves the
oxidation of H2O2 with NaOCl (Scheme 1b).9 Subsequently,
22
1
or PhI(OCOCF3)2, for the generation of O2. However, the
1
yields of O2 (46% and 55%, respectively) are only moderate,
which limits the synthetic utility of these combinations.
1
Because the moderate yield of O2 obtained from H2O2/
PhIO2 might be due to the poor water solubility of PhIO2 in
aqueous H2O2, we speculated that the yield could be improved
1
methods for disproportionation of H2O2 to afford O2 with
catalysis by transition-metal ions such as CrVI, TiIV, MoVI, or
LaIII were developed.10 Moreover, 1O2 formation has also been
observed in reactions of ozone with amines, sulfides, phenols,
Received: March 12, 2021
and nucleophilic anions (NO2 , N3 , Br−, Cl−, and CN−;
Scheme 1c).11 Other reported chemical sources of 1O2 include
peroxides (KHSO5,12 CaO2·2H2O2,13 K3CrO8,14 Na2MoO8,15
−
−
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A

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1
available O2 to yield the corresponding stable endoperoxide
Scheme 1. Existing Methods for Generation of Singlet
Oxygen
16,18
2g,
(AESO2, 2; Scheme 2).
Scheme 2. Generation and Trapping of Singlet Oxygen
The formation of AESO2 can be easily monitored by means
1
of H and 13C{1H} NMR spectroscopy (Figures 2 and 3).
Comparison with the NMR spectrum of an authentic sample
24
of AESO2 showed that the AES in a reaction mixture
containing AIBX and H2O2 was completely converted into
AESO2 and that the AIBX was reduced to 2-iodo-5-
(trimethylammonio)benzoate (3, Scheme 2). Moreover,
when we used electron spin resonance (ESR) spectroscopy
to analyze an AIBX/H2O2 reaction mixture containing 2,2,6,6-
tetramethylpiperidine (TEMP) as a spin trap agent,25 we
observed the characteristic 1:1:1 three-line signal of TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) with a hyperfine cou-
pling constant (aN) of 16.6 G (Figure 4), which is identical to
the value reported in the literature.26 The formation of AESO2
and ESR detection of TEMPO unambiguously demonstrated
by using a more water-soluble hypervalent iodine reagent, such
as AIBX (Figure 1), a bench-stable, recyclable zwitterionic
1
that O2 was generated from the AIBX/H2O2 system.
Encouraged by these results, we next investigated the
influence of the amount of H2O2 on the yield of 1O2 using the
yield of AESO2 as a metric (Table 1). When the amount of
50% H2O2 was 100 μL (19.5 mol/L, 1.95 mmol), the yield of
AESO2 was 36% (entry 1). Increasing the amount to 200 μL
(3.9 mmol) resulted in a similar yield (35%, entry 2), but as
the amount was increased further, the AESO2 yield increased
substantially, reaching a maximum of 91% at 600 μL (entries
3−6). However, increasing the amount further (to 700 μL,
13.65 mmol) slightly decreased the yield (to 85%, entry 7).
Therefore, the optimal amount of 50% H2O2 (600 μL, 11.7
mmol, entry 6) was used in subsequent experiments.
Figure 1. Structures of PhIO2 and AIBX.
pseudocyclic iodylarene that we reported in 2011.23 AIBX,
which is air- and moisture-stable and can be stored at ambient
temperature for at least 3 months without decomposition,
bears a carboxylate anion and a trimethylammonium cation at
the ortho and para positions of the phenyl ring, respectively,
which make this compound highly water-soluble (up to 0.38 M
at room temperature). Herein, we report that treatment of
aqueous H2O2 with AIBX is an efficient method for the
We also screened the following other water-soluble hyper-
valent iodine reagents: PISA, HTIB, AIBA, PIBS, IBX-SO3K,
and mIBX (Scheme 3). Singlet oxygen was not detected when
PISA or HTIB was used. In contrast, the other reagents did
1
generate O2, but the yields were low or moderate.
1
chemical generation of O2.
To illustrate the potential synthetic utility of the present
method, we investigated [2 + 2]/[4 + 2] cycloaddition
reactions and heteroatom oxidation reactions of 1O2 generated
from the AIBX/H2O2 system (method A, Table 2). A mixed
solvent consisting of CH3CN and H2O was used to increase
the solubility of the organic substrates. Reaction of 2,2′-
bi(adamantanylidene) (4) afforded the corresponding per-
RESULTS AND DISCUSSION
■
1
To observe O2 formation in the AIBX/aq. H2O2 system, we
trapped 1O2 with the sodium salt of anthracene-9,10-
bis(ethanesulfonate) (AES, 1),22a a water-soluble compound
that undergoes a rapid [4 + 2] cycloaddition reaction with all
B
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Figure 2. H NMR spectra of AES, an authentic AESO2 sample, and an AIBX/H2O2/AES mixture.
Figure 3. 13C{1H} spectra of AES, an authentic AESO2 sample, and an AIBX/H2O2/AES mixture.
oxide 5 in 79% yield via a [2 + 2] cycloaddition (entry 1), and
reactions of 1,3-cyclohexadiene (6) and α-terpinene (8) gave
the endoperoxide products 7 and 927 in 62 and 87% yields,
respectively, via [4 + 2] cycloadditions (entries 2 and 3).
Endoperoxide 11 could be obtained from the relatively low
reactivity of diphenylanthracene (10), but the yield was 50%
because conversion of 10 was only moderate (55%, entry 4).
However, the electron-deficient substrate tropone (12) gave
disappointing results (entry 5). 1,3-Diphenylisobenzofuran
(14) was oxidized to 1,2-dibenzoylbenzene (15) in 84% yield
via [4 + 2] cycloaddition and subsequent ring opening (entry
6). Similarly, 2,5-dimethyl furan (16) was converted to (E)-3-
hexene-2,5-dione (17) in 50% overall yield via reduction of the
hydroperoxyl intermediate with PPh3 (entry 7).10f Dearoma-
tization of mesitol (18) was achieved in 40% yield (entry 8).
The oxygenation of 1-methyltryptophan derivative 20 provided
a 27% yield of 3-hydroxypyrroloindole derivative 21, which is
an important intermediate in the synthesis of the potent
anthelmintic natural product CJ-12663 (entry 9).28 Phospho-
rus- and sulfur-containing compounds could be oxidized with
C
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Scheme 3. Screening of Other Water-Soluble Hypervalent
Iodine Reagents
Figure 4. ESR spectra of TEMPO from the oxidation of TEMP with
the AIBX/aq. H2O2 system.
Table 1. Influence of the Amount of 50% H2O2 on the Yield
of Singlet Oxygen
a
b
1
1
1
ND = O2 was not detected. Yield of O2 was determined by H
NMR spectroscopy.
ester 27, we increased the amount of mAIBX to 8 equiv and
found that 28 could be obtained in 77% yield (entry 13).
For comparison, substrates were also subjected to the
conventional H2O2/NaOCl method (method B, Table 2). It
was found that only for two substrates 16 and 18, method B
could give better yields than method A. For substrates 8, 12,
and 22, these two methods yielded equal results. It was worth
noting that the remaining seven substrates performed much
better when using the current combination of AIBX/H2O2.
Notably, another two methods were also tried to synthesize the
product 28. Reaction of 27 with KHSO5, a water-soluble
a
entry
volume of 50% H2O2 (μL)
yield of AESO2 (%)
1
2
3
4
5
6
7
100
200
300
400
500
600
36
35
53
65
72
91
85
1
inorganic peroxide that decomposes to generate O2, gave no
detectable 28; instead, a complex mixture was obtained, owing
to the strong acidity of the aqueous KHSO5 solution. 28 was
produced in 29% yield with the combination of the hypervalent
iodine(III) reagent PhI(OCOCF3)2 and H2O2; the yield of
recovered 27 was 52%.22c These results demonstrate the
superiority of our method to the other three methods.
To demonstrate the synthetic utility of the AIBX/H2O2
system, we used it in the key step of a synthesis of the
antimalarial drug artemisinin (29, Scheme 4).,7b,c,30,31
Specifically, the ester 27 was prepared from dihydroartemisinic
acid (DHAA), and then a Schenck ene reaction of 1O2 and 27
gave the crude hydroperoxide 28 in 77% yield after extraction
and concentration. Treatment of 28 with trifluoroacetic acid
under a balloon of O2 afforded a 70% yield of artemisinin. The
overall yield was 51%, which is higher than that reported for
the established photochemical method.7c
We also investigated the regeneration of AIBX (Figure 6).
Upon completion of the oxidation of PPh3 with the AIBX/
H2O2 system, any remaining AIBX was reduced to 3 by
addition of saturated aqueous sodium sulfite. Extraction of the
reaction mixture with EtOAc removed the triphenylphosphine
oxide, leaving 3 in the aqueous phase, owing to its high water
solubility. Evaporation of H2O afforded 3 in 95% yield. Finally,
AIBX could then be obtained in 91% yield by oxidation of the
recovered 3 with dimethyldioxirane, which was reduced to
acetone.
700
a
1
Determined by H NMR spectroscopy.
the AIBX/H2O2 system. For example, oxidation of PPh3 (22)
afforded triphenylphosphine oxide (23) in a quantitative yield
(entry 10), and oxidation of Fmoc-L-Met-OMe (24) gave a
1:3.88 mixture of sulfoxide 25 and sulfone 26. When 6.0 equiv
of AIBX was used instead of 2 equiv, the oxidation products
were obtained in a quantitative yield, and the ratio of 25 and
26 was 1:10.7 (entry 11); that is, the yield of sulfone 26
increased as the amount of AIBX was increased. Finally, we
1
carried out a Schenck ene reaction of O2 and dihydroarte-
misinic methyl ester (27) (for details, see Table S1 of the
Supporting Information), which smoothly gave tertiary hydro-
peroxide 28 in 48% yield (data not shown). The yield of 28
was determined by 1H NMR spectroscopy, owing to the
selective degradation of the hydroperoxide; the characteristic
peak was identical to that previously reported.29 In an attempt
to improve the yield of 28, we replaced AIBX with mAIBX, an
isomer bearing a trimethylammonium cation at the meta-
position of the phenyl ring (Figure 5; for details on the
synthesis of AIBX and mAIBX, see the Supporting
Information), and were pleased to find that the yield of 28
increased to 66% (entry 12). To increase the consumption of
D
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a
Table 2. Substrate Scope
a
Method A: AIBX (2 equiv), 50% H2O2 (600 μL), 4 mL of 3:1 (v/v) MeCN/H2O, rt. Method B: NaClO (90 μL), 50% H2O2 (600 μL) in 4 mL of
b
c
d
3:1 (v/v) MeCN/H2O, rt. Isolated yields. Performed in 1:1 (v/v) diglyme/H2O for 7 h. Performed with 4 equiv of AIBX and 300 μL of 50%
H2O2 in 3:1 (v/v) THF/H2O for 48 h. Performed in 3:1 (v/v) MeOH/H2O for 12 h. Performed with 6 equiv of AIBX and 300 μL of 50% H2O2
in 3:1 (v/v) CH3CN/tetraborate buffer (pH 9.18) for 36 h. Performed with 8 equiv of AIBX and 300 μL of 50% H2O2 in 3:1 (v/v) CH3CN/
e
f
g
h
i
j
tetraborate buffer for 72 h. Yield of the recovered substrate in the absence of H2O2. Performed with 6.0 equiv of AIBX for 7 h. Performed with
k
4.0 equiv of mAIBX in 3:1 (v/v) CH3CN/tetraborate buffer for 48 h. Determined by 1H NMR spectroscopy with 1,3,5-trimethoxybenzene as an
l
internal standard. Performed with 8.0 equiv of mAIBX in 3:1 (v/v) CH3CN/tetraborate buffer for 48 h.
Scheme 4. Synthesis of Artemisinin (29)
Figure 5. Structures of AIBX and mAIBX.
CONCLUSIONS
In summary, we have developed an efficient and practical
method for chemical generation of O2 by treatment of H2O2
■
1
with AIBX, a highly water-soluble, bench-stable, recyclable
E
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The ESR Measurement. To a solution of TEMP (14 mg, 0.1
mmol) and AIBX (68 mg, 0.2 mmol) in 1:1 (v/v) CH3CN/H2O (4
mL) was added 50% H2O2 (19.5 mol/L, 600 μL) dropwise at room
temperature. The reaction mixture was stirred for 18 h, and then the
ESR spectra were measured.
Procedure for Reactions Using the AIBX/Aq. H2O2 System.
To a solution of the desired substrate (0.2 mmol) and AIBX (0.4
mmol, 135 mg) in 3:1 (v/v) CH3CN/H2O (4 mL) was added 50%
aqueous H2O2 (19.5 mol/L, 600 μL) dropwise at room temperature.
The reaction mixture was stirred for 24 h and monitored by TLC.
After the substrate was completely consumed, 5 mL of saturated
sodium sulfite aqueous solution was added. The reaction mixture was
then extracted with dichloromethane (3 × 10 mL), and the combined
organic layers were dried over anhydrous MgSO4. After filtration, the
solvent was evaporated from the filtrate, and the residue was purified
by column chromatography to afford the target product.
2-Iodo-5-(trimethylammonio)benzoate (3).23a Colorless solid,
Figure 6. Procedure for AIBX regeneration.
1
m.p. 193−195 °C; H NMR (400 MHz, D2O) δ 8.06 (d, J = 8.9
Hz, 1H), 7.71 (d, J = 3.2 Hz, 1H), 7.49 (dd, J = 8.9, 3.3 Hz, 1H), 3.61
(s, 9H); 13C{1H} NMR (100 MHz, D2O) δ 175.2, 148.2, 146.7,
141.3, 120.6, 117.9, 92.9, 57.0.
hypervalent iodine(V) reagent. The formation of 1O2 from this
system was confirmed by chemical trapping of O2 with AES
1
Adamantylideneadamantane 1,2-Dioxetane (5).33 Colorless
and by ESR detection of TEMPO generated by the oxidation
1
solid, 47 mg, 79% yield; m.p. 161−163 °C; H NMR (400 MHz,
1
1
CDCl3) δ 2.64 (s, 4H), 2.06−1.49 (m, 24H); 13C{1H} NMR (100
MHz, CDCl3) δ 99.9, 95.8, 37.3, 34.6, 32.8, 31.9, 26.7, 26.5.
2,3-Dioxabicyclo[2.2.2]oct-5-ene (7).22d Colorless oil, 14 mg, 62%
yield; 1H NMR (400 MHz, CDCl3) δ 6.69 (dd, J = 4.4, 3.3 Hz, 2H),
4.69−4.66 (m, 2H), 2.30−2.27 (m, 2H), 1.50−1.47 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 132.2, 70.9, 21.6.
of TEMP by O2. In addition, the O2 generated with the
AIBX/H2O2 system was used to carry out three typical
reactions: [2 + 2]/[4 + 2] cycloaddition reactions to afford
endoperoxides, oxidation of heteroatomic compounds to afford
heteroatom oxides, and a Schenck ene reaction to afford an
allylic hydroperoxide. Moreover, we used the method for the
synthesis of the antimalarial drug artemisinin. Finally, AIBX
could be efficiently regenerated by means of a simple workup
and re-oxidation with dimethyldioxirane. Our findings
demonstrate that the AIBX/H2O2 system is an attractive
Ascaridole (9).22c Colorless oil, 44 mg, 87% yield; H NMR (400
1
MHz, CDCl3) δ 6.50 (d, J = 8.5 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H),
2.07−1.98 (m, 2H), 1.96−1.89 (m, 1H), 1.53−1.50 (m, 2H), 1.38 (s,
3H), 1.00 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
136.3, 133.0, 79.7, 74.3, 32.1, 29.5, 25.6, 21.4, 17.2, 17.1.
1
9,10-Diphenyl-9,10-dihydro-9,10-epidioxyanthracene (11).22d
Colorless solid, 36 mg, 50% yield; m.p. 192−195 °C; 1H NMR
(400 MHz, CDCl3) δ 7.71−7.69 (m, 4H), 7.65−7.61 (m, 4H), 7.56−
7.53 (m, 2H), 7.26−7.19 (m, 8H); 13C{1H} NMR (100 MHz,
CDCl3) δ 140.2, 132.9, 128.3, 128.2, 127.6, 127.5, 123.5, 84.0.
1,2-Dibenzoylbenzene (15).22d Colorless solid, 36 mg, 84% yield;
chemical source of O2.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under an air
atmosphere without any special protections. Distilled CH3CN,
diglyme THF, and deionized water were used as solvents. Some
known chemicals (4, 6, 8, 10, 12, 14, 16, and 18) were available from
commercial suppliers. Known compounds (1,22a 13,7d 20,28 24,32 and
2729) were synthesized using the reported procedures and were
identified by comparison of their NMR spectra with literature data.
1
m.p. 145−147 °C; H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.1
Hz, 4H), 7.62 (s, 4H), 7.52 (t, J = 7.0 Hz, 2H), 7.38 (t, J = 7.6 Hz,
4H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.6, 140.0, 137.2, 133.0,
130.3, 129.8, 129.7, 128.3.
The H NMR spectra were recorded at 400 MHz and the 13C{1H}
(E)-Hex-3-ene-2,5-dione (17).10f Colorless solid, 11 mg, 50% yield;
m.p. 75−77 °C; 1H NMR (400 MHz, CDCl3) δ 6.79 (s, 2H), 2.37 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.5, 137.8, 28.0.
4-Hydroxy-2,4,6-trimethylcyclohexa-2,5-dien-1-one (19).10f Col-
orless solid, 12 mg, 40% yield; m.p. 45−47 °C; 1H NMR (400 MHz,
CDCl3) δ 6.62 (s, 2H), 1.87 (s, 6H), 1.43 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 186.7, 147.2, 133.4, 67.1, 27.0, 15.8.
1-(tert-Butyl) 2-Methyl 3a-Hydroxy-8-methyl-3,3a,8,8a-
tetrahydropyrrolo[2,3-b] Indole-1,2(2H)-dicarboxylate (21).28 Col-
1
NMR spectra were measured at 100 MHz using a Bruker AV 400 as a
spectrometer; CDCl3 was used as the solvent. The H NMR spectra
1
are reported as follows: chemical shift in ppm (δ) relative to the
chemical shift of CDCl3 at 7.26 ppm, multiplicities, coupling
constants (Hz), and integration values. The 13C{1H} NMR spectra
are reported in ppm (δ) relative to the central line of CDCl3 triplet at
77.00 ppm. The IR spectra were recorded with a Fourier transform IR
Bruker EQUINOX55 spectrometer in KBr pellets. High-resolution
mass spectroscopy (HRMS) was performed with a high-resolution
electrospray ionization Fourier transform ion cyclotron resonance
mass spectrometer (Varian 7.0T). ESR measurements were
performed with a Bruker E580-10/12 instrument.
1
orless oil, 18 mg, 27% yield; H NMR (400 MHz, CDCl3) δ 7.19−
7.26 (m, 4H), 6.78 (t, J = 7.2 Hz, 1H), 6.54−6.49 (m, 1H), 5.44 (s,
0.5H), 4.45 (t, J = 9.1 Hz, 1H), 4.18 (s, 0.5H), 3.84−3.82 (m, 2H),
3.67 (s, 0.5H), 3.02 (s, 1.5H), 2.92 (s, 1H), 2.48−2.25 (m, 2H),
1.55−1.46 (m, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.4,
175.9, 154.7, 149.6, 130.1, 129.9, 129.7, 121.9, 118.8, 118.7, 109.9,
108.3, 108.1, 93.4, 93.3, 86.9, 85.9, 81.9, 81.3, 61.1, 53.0, 52.7, 42.4,
35.4, 31.9, 29.7, 28.3, 28.2. HRMS (ESI): m/z calcd for C18H24N2O5
[M + Na]+: 371.1577; found: 371.1580.
1
Trapping of O2 with AES. To a solution of AES (47.4 mg, 0.1
mmol) and AIBX (67.4 mg, 0.2 mmol) in D2O (2 mL) was added
50% H2O2 (19.5 mol/L, 200 μL) dropwise at room temperature. The
reaction mixture was stirred for 24 h and monitored by H NMR.
Preparation of the Authentic AESO2 Sample. To a solution of
AES (23 mg, 0.05 mmol) and 5.84% NaClO (20 μL) in D2O (2 mL)
was added 50% H2O2 (19.5 mol/L, 10 μL) dropwise at room
temperature. The reaction mixture was stirred for 30 min, and then
1
Triphenylphosphine Oxide (23).10f Colorless solid, 56 mg,
1
quantitative yield; m.p. 155−157 °C; H NMR (400 MHz, CDCl3)
δ 7.69−7.64 (m, 6H), 7.58−7.52 (m, 3H), 7.50−7.43 (m, 6H);
1
0.5 mL of the reaction mixture was placed in an NMR tube for H
13C{1H} NMR (100 MHz, CDCl3) δ 133.0, 132.1, 132..0, 131.9,
NMR and 13C{1H} NMR spectroscopy.
131.9, 128.5, 128.4.
AESO2 (2).24 Known compound; H NMR (400 MHz, D2O) δ
1
Methyl (2S)-2-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]-4-
7.39−7.32 (m, 8H), 3.27−3.10 (m, 8H). 13C{1H} NMR (100 MHz,
D2O) δ 138.9, 128.2, 121.7, 81.3, 45.4, 23.3.
(methylsulfinyl)butanoate (25). Colorless solid, 6.8 mg, 8.5% yield;
1
m.p. 157−159 °C; H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5
F
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Article
Hz, 2H), 7.59 (d, J = 6.7 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.33 (td, J
= 7.0, 2.5 Hz, 2H), 5.49 (d, J = 6.6 Hz, 1H), 4.45 (d, J = 6.3 Hz, 3H),
4.22 (t, J = 6.6 Hz, 1H), 3.79 (s, 3H), 3.08 (d, J = 45.0 Hz, 2H), 2.92
(s, 3H), 2.47 (s, 1H), 2.21 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 171.3, 156.0, 143.7, 143.5, 141.3, 127.8, 127.1, 125.0, 120.1,
67.1, 53.0, 52.4, 51.0, 47.1, 40.8, 25.6; IR (KBr) ν = 3332, 2957, 2926,
1721, 1527, 1447, 1295, 1264, 1220, 1130, 1048, 965, 797, 740 cm−1;
HRMS (ESI): m/z calcd for C21H23NO5S [M + Na]+: 424.1189;
found: 424.1193.
Authors
Hui-Jie Shen − State Key Laboratory of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Ze-Nan Hu − State Key Laboratory of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00596
Methyl (2S)-2-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]-4-
(methylsulfonyl)butanoate (26). Colorless solid, 76.3 mg, 91.5%
yield; m.p. 57−59 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.5
Hz, 2H), 7.60 (s, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.2 Hz,
2H), 5.71 (dd, J = 36.5, 7.1 Hz, 1H), 4.51−4.41 (m, 3H), 4.22 (t, J =
6.6 Hz, 1H), 3.78 (s, 3H), 2.89−2.62 (m, 2H), 2.57 (s, 3H), 2.46−
2.33 (m, 1H), 2.29−2.06 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 171.7, 156.0, 143.7, 143.6, 141.3, 127.7, 127.0, 125.0, 120.0,
67.0, 53.0, 52.7, 50.2, 47.1, 38.5, 26.1; IR (KBr) ν = 3238, 2952, 2923,
1719, 1536, 1446, 1260, 1216, 1036, 739 cm−1; HRMS (ESI): m/z
calcd for C21H23NO6S [M + Na]+: 440.1138; found: 440.1142.
General Procedure for the Synthesis of the Crude Hydro-
peroxide 28. To a solution of 27 (0.2 mmol) and AIBX (135 mg,
0.4 mmol) in 3:1 (v/v) CH3CN/tetraborate buffer (4 mL) was added
50% H2O2 (19.5 mol/L, 600 μL) dropwise at room temperature.
After the reaction mixture was stirred for 24 h, another portion of
AIBX (135 mg, 0.4 mmol) was added, and the reaction mixture was
stirred for an additional 24 h. Upon completion of the reaction, 5 mL
of H2O was added, and the resulting mixture was extracted with
dichloromethane (3 × 10 mL). The combined organic layers were
dried over anhydrous MgSO4, and CH2Cl2 was removed at 30 °C on a
rotary evaporator to afford crude hydroperoxide 28 as a colorless,
sticky, oily residue. 1H NMR (400 MHz, CDCl3) δ 5.21 (s, 1H), 3.67
(s, 3H), 2.54−2.46 (m, 2H), 2.02−1.74 (m, 3H), 1.69−1.50 (m, 6H),
1.46−1.36 (m, 1H), 1.25 (dd, J = 10.9, 3.1 Hz, 2H), 1.13 (d, J = 6.9
Hz, 3H), 1.07 (dd, J = 12.5, 3.1 Hz, 1H), 0.94 (dd, J = 12.0, 3.3 Hz,
1H), 0.86 (d, J = 6.5 Hz, 3H).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by The National Natural
Science Foundation of China (22071116 and 21772096) and
t h e N a t i o n a l K e y R & D P r o g r a m o f C h i n a
(2017YFD020030202).
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General Procedure for the Synthesis of Artemisinin (29). To
a solution of the crude hydroperoxide 28 in dichloromethane (5 mL)
was added CF3CO2H (600 μL). The solution was stirred at room
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Artemisinin (29).10f Colorless solid, 31 mg, 70% yield; m.p. 153−
154 °C; [α]2D7 : +60.2 (c = 0.97, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.86 (s, 1H), 3.40 (m, 1H), 2.43 (td, J = 13.5, 3.7 Hz, 1H),
2.07−1.98 (m, 2H), 1.90−1.87 (m, 1H), 1.80−1.73 (m, 2H), 1.58 (s,
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19.7, 12.5; HRMS (ESI): m/z calcd for C15H23O5 [M + H]+:
283.1540; found: 283.1545.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00596.
1
Optimization of Schenck ene reaction conditions, H
and 13C{1H} NMR spectra, and HRMS spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
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E. Evaluation of advanced oxidation processes for water and
wastewater treatment−A critical review. Water Res. 2018, 139,
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materials for point-of-use water disinfection with solar reactors.
Chi Zhang − State Key Laboratory of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China; orcid.org/0000-0001-9050-076X;
Email: zhangchi@nankai.edu.cn
G
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NOTE ADDED AFTER ASAP PUBLICATION
A new reference 31a was added May 28, 2021.
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