Metal-Free Aerobic Oxidation of Nitro-Substituted Alkylarenes to Carboxylic Acids or Benzyl Alcohols Promoted by NaOH

Article abstract of DOI:10.1021/acs.joc.8b00903

Efficient and selective aerobic oxidation of nitro-substituted alkylarenes to functional compounds is a fundamental process that remains a challenge. Here, we report a metal-free, efficient, and practical approach for the direct and selective aerobic oxidation of nitro-substituted alkylarenes to carboxylic acids or benzyl alcohols. This sustainable system uses O₂ as clean oxidant in a cheap and green NaOH/EtOH mixture. The position and type of substituent critically affect the products. In addition, this sustainable protocol enabled gram-scale preparation of carboxylic acid and benzyl alcohol derivatives with high chemoselectivities. Finally, the reactions can be conducted in a pressure reactor, which can conserve oxygen and prevent solvent loss. The approach was conducive to environmental protection and potential industrial application.

Full text of DOI:10.1021/acs.joc.8b00903

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Article
Metal-Free Aerobic Oxidation of Nitro-Substituted Alkylarenes
to Carboxylic Acids or Benzyl Alcohols Promoted by NaOH
Kun Fang, Guijie Li, and Yuanbin She
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00903 • Publication Date (Web): 15 Jun 2018
Downloaded from http://pubs.acs.org on June 15, 2018
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Metal-Free Aerobic Oxidation of Nitro-Substituted Alkylarenes to Carboxylic Acids or Benzyl
Alcohols Promoted by NaOH
Kun Fang, Guijie Li* and Yuanbin She*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014,
P. R. China.
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Eꢀmail: guijieli@zjut.edu.cn; sheyb@zjut.edu.cn
Efficient and selective aerobic oxidation of nitroꢀsubstituted alkylarenes to functional compounds is
a fundamental process that remains a challenge. Here, we report a metalꢀfree, efficient and practical
approach for the direct and selective aerobic oxidation of nitroꢀsubstituted alkylarenes to carboxylic
2
acids or benzyl alcohols. This sustainable system uses O as clean oxidant in a cheap and green
NaOH/EtOH mixture. The position and type of substituent critically affect the products. In addition,
this sustainable protocol enabled gramꢀscale preparation of carboxylic acid and benzyl alcohol
derivatives with high chemoselectivities. Finally, the reactions can be conducted in a pressure
reactor, which can conserve oxygen and prevent solvent loss. The approach was conducive to
environmental protection and potential industrial application.
INTRODUCTION
Aerobic oxidation of hydrocarbons is one of the most fundamental and critical processes
in the manufacture of functional compounds, such as carboxylic acids and benzyl alcohols,
which are essential materials for pharmaceutical, agricultural, dyestuff, and flavor industries
1
,2
3
(
Figure 1). Traditionally, stoichiometric amounts of hazardous oxidants, such as KMnO ,
4
4
5
6
7,8
2 2 7 2 3
Na Cr O , PdO , and HNO , or noble metal catalysts are required for the carboxylic
9–11
acids production; meanwhile, metalloporphyrin catalysts
are used in the synthesis of
benzyl alcohols. The use of these chemicals limit the applications of the methods because of
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substantial waste, high toxicity, intense corrosion, economic problems, or poor
chemoselectivities. Thus, development of environmentally friendly, mild, and cheap
approaches for the oxidation of hydrocarbons by using clean oxidants is highly desired and is
the focus of green chemistry.
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Figure 1. Selected pharmaceutical and pesticide molecules containing the nitroꢀbenzoyl or
aminoꢀbenzoyl motifs.
12ꢀ17
12
13
14
Several oxidants
,6ꢀdichloropyridine
the oxidation of hydrocarbons. Among oxidants, O
atomꢀeconomical; thus this oxidant has attracted considerable attention in past years and
,
such as
H
2
O
2
,
tertꢀbutyl hydroperoxide , oxone ,
1
5
16
2
Nꢀoxide , and 2,6ꢀdimethylbenzoquinone , have been investigated for
2
is ubiquitous, clean, and
1
8ꢀ27
gained notable progress
aerobic oxidation of eubstituted toluenes to aldehydes or carboxylic acids in the presence of
carboxylic acids ꢀhydroxyphthalimide (NHPI) or its derivatives and transition metal
. Ishii's group developed a series of efficient mothods for the
N
1
9
catalysts, like Co(II), Mn(II). In 2015, Li's group reported an efficient homogeneous
Ag(I)ꢀcatalyzed aerobic oxidation of aldehydes to carboxylic acids in water by using IPr as
2
5a
ligand (Scheme 1a). In 2016, Ma's group developed a practical and efficient aerobic
.
oxidation protocol of alcohols to carboxylic acids catalyzed by Fe(NO
3
)
3
9H
2
O (Scheme
26a
1
b). Recently, Pappo's group successfully developed an efficient approach for the highly
selective aerobic oxidation of methylarenes to benzaldehydes using NHPI and Co(OAc)
2
as
catalysts and hexafluoropropanꢀ2ꢀol as solvent, and up to 98% conversion with 99%
2
7
selectivity could be achieved. However, direct, selective aerobic oxidation of aromatic alkyl
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groups remain challenging because of the chemical inert of the C–H bonds and the poor
7d,9,22,28
chemoselectivity of alcohol, aldehyde, ketone, and carboxylic acid products.
Here, we
aim to report a metalꢀfree, efficient and practical approach for the direct and selective aerobic
oxidation of nitroꢀsubstituted alkylarenes to carboxylic acids or benzyl alcohols promoted by
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NaOH with O as clean oxidant.
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Scheme 1. Aerobic Oxidation of Aldehydes, Alcohols and Nitro-Substituted alkylarenes to
Carboxylic Acids.
RESULTS AND DISCUSSION
In the investigation of aerobic oxidation of 2ꢀnitrotoluene (1a) in a NaOH/MeOH system with
2
O as oxidant, we unexpectedly found that, without catalyst, 2ꢀnitrobenzoic acid (2a) can be obtained
in 13% yield with 68% conversion yield of 1a at room temperature (Table 1, entry 1). This result
motivated us to further explore the reaction in detail. Given the potential industrial application and
2
environmental protection issues, a pressure reactor was utilized for the reaction to conserve O and
prevent solvent loss. Initially, we investigated the reaction at different temperature (entries 2–4) and
found that 67% yield of 2a can be obtained with a 90% conversion yield of 1a in MeOH at 52 °C for
2
5
4 h (entry 3). Moreover, the addition of water to MeOH was unfavorable for the conversion (entries
, 6). However, the isolated yield of 2a can be improved with 80%EtOH as solvent (entry 7).
Furthermore, conversions and isolated yields can be increased by prolonging the reaction time
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(
entries 8–10). Anhydrous EtOH and PrOH can also serve as the solvents for the aerobic oxidation
(
entries 11–15); 2a can be separated in 76% yield with a 91% conversion yield of 1a in EtOH at 60
o
i
C for 24 h (entry 12) and 72% yield with 90% conversion if PrOH is used as solvent at a low
temperature (entry 15). A blank experimant was also carried out with the absence of NaOH, and no
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conversion of 1a was observed, indicating NaOH played a critical role in the raection.
Table 1. Metal-Free Aerobic Oxidation of 2-Nitrotoluene Using O as Oxidant Under Different
2
a
Conditions
a
c
b
Reaction was carried out in a pressure reactor on a 6.0 mmol scale in 10 mL of ROH/H O. Internal temperature.
2
d
e
Conversion yield was based on the recovery yield of the starting material 1a. Isolated yield. Without NaOH.
By employing the optimized conditions, a series of nitroꢀsubstituted alkylarenes were used to
investigate the substrate scope of the above aerobic reaction in pressure reactor, and the comparison
of various reaction conditions is shown in Table 2. The oxidation of 4ꢀnitrotoluene (1b) can proceed
smoothly with a conversion yield nearly quantitative in various solvents (entries 6–11), and
50%EtOH was demonstrated to be a superior solvent for obtaining a 95% yield of 2b (entry 11),
however, if this reaction was carried out in glass bottle using oxygen balloon either under light or in
dark, just obtained a litter desired product and a plenty of tarry product, which was insoluble in
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normal solvents. Then, the substrates bearing two methyl groups on the phenyl ring (1c–1f) were
investigated (entries 12–20). Notably, the methyl groups on the ortho or para positions of the nitro
group can be oxidized selectively to yield corresponding carboxylic acids (2c–2e) in a moderate to
good yield under various conditions, because of their stronge acidity; however, the methyl groups on
the meta positions remained unchanged (entries 12–18). Moreover, the molecular structure of 2c was
confirmed by singleꢀcrystal Xꢀray diffraction analysis (see Figure S9). As expected, both methyl
groups on the 2,4ꢀdimethylnitrobenzene (1f) can be converted into carboxyl groups with a
conversion yield of up to 97%, but the 4ꢀnitrobenzeneꢀ1,3ꢀdioic acid (2f) was separated in a low
yield owing to a large amount of oily tar formed (entry 20). The substrates containing methoxyl
group (1g, 1h) also yielded efficient results (entries 21–23). Unexpectedly, the nitrobenzene
substrates bearing the linear alkyl group on the para position (1i–1k) can be smoothly oxidized
involving C–C δꢀbond cleavage to generate the sole product 2b in 93%, 75%, and 91% yields
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(entries 24, 27, 29). Moreover, mixture of nitroꢀsubstituted alkylarenes can easily produce 2b,
indicating that a crude raw material can be used for the reaction and also keep reasonable yield
(entries 30, 31). We also tried to some substrates with other electronꢀwithdrawing group, like ꢀCl, ꢀBr,
ꢀ
F, or cyano group, only no reactions or hydrolysate were observed (see Scheme S1). The reactions
were very messy if 2ꢀchloroꢀ1ꢀmethylꢀ4ꢀnitrobenzene, 2ꢀchloroꢀ1ꢀmethylꢀ4ꢀnitrobenzene,
ꢀmethylꢀ1ꢀnitronaphthalene or 1ꢀmethylꢀ4ꢀ(methylsulfonyl)ꢀ2ꢀnitrobenzene were used as substrates
see Scheme S1), owing to the possible side reactions, like nucleophilic substitution, Aldol
2
(
condensation, oxidation of naphthalene ring et. al.
a
Table 2. Aerobic Oxidation of Nitro-Substituted Alkylarenes to Carboxylic Acids.
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a
All reactions were carried out in pressure reactors at concentrations of 0.6 M for the substrates unless noted, and
b
internal temperature was reported. Conversion yield was based on the recovery yield of the starting material.
c
d
e
f
Isolated yield. At 52 °C. 72 h. At 55 °C.
Surprisingly, if the linear alkyl groups were on the ortho position of the nitro group (1l–1n),
sole product benzyl alcohols (3a–3c) were obtained in 63%–89% yields under various conditions
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(
Table 3). These excellent chemoselectivities may be attributed to intramolecular hydrogen bonds
27
between nitro and hydroxyl groups, preventing the benzyl alcohols from being further oxidized.
Notably, the reaction can proceed smoothly using an O
5% yield (entry 4). Importantly, aerobic oxidation of nitrobenzene substrates with branched alkyl
group on the para position of the nitro group (1o, 1p) also produced the benzyl alcohol derivatives
2
balloon and achieved 98% conversion and
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d and 3e in good yields (entries 9–12). This approach can be highly efficient for the synthesis of
2
ꢀnitrobenzylalcohols , which are difficult to prepare from direct nucleophilic addition between
nitrobenzaldehydes and the corresponding Grignard or lithium reagents. Notably, the direct oxidation
of the benzyl C–H bond to benzyl alcohol remains challenging because of low yields or poor
7d, 9,22, 28
chemoselectivities.
a
Table 3. Aerobic Oxidation of Nitro-Substituted Alkylarenes to Benzyl Alcohols
a
All reactions were performed in pressure reactors with concentrations of 0.6 M for the substrates unless noted, and
b
intrnal temperature was reported. Conversion yield was based on the recovery yield of the starting material.
c
d
e
f
2
Isolated yield. O balloon was used. 48 h. At 80 °C.
In addition, the effect of substrate concentration on aerobic reaction was investigated based on
1l (Table 4). Decreased substrate concentration to 0.45 M could further increased the isolated yield to
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0% compared with that at 0.60 M under O balloon (entry 2). In general, increased substrate
concentration resulted in the decrease in both conversion yields of 1l and the isolated yields of 3a.
However, production efficiency is a critical parameter for potential application in industry, and the
isolated yield was not significantly reduced even at 1.2 M in the pressure reactor under the O
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balloon (entries 3,4). More than 60% yield can still be obtained even with the increase of substrate
concentration to 2.25 M (entries 6,7). It should be noted that some waste water were inevitable in the
treatment of the reaction, but not very much.
Table 4. Substrate Conversion at Various Concentrations
a
b
c
d
e
Conversion yield was based on the recovery yield of 1l. Isolated yield. At 60 °C. At 65 °C. 48 h.
For understanding the reaction process, the in situ NMR experiment was performed using 1l in
2 6
NaOD/D O/EtODꢀd (Figure 2aꢀd). Evidently, the changes in spectral sharps that the methylene
protons (2.85–3.00 ppm) was gradually deuterated. An extremely small amount of 1l remained after
o
3.5 h at 65 C under N
2
(Figure 2c), indicating the strong acidity of the methylene group and the
involvement of carbon anion in the reaction.
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Figure 2. H NMR spectrum of 1l in NaOD/D O/EtODꢀd for (a), at 65 °C under N for 1.0 h for (b), at 65 °C
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2
under N
2
for 3.5 h for (c), and at 65 °C under O
2
for 12.0 h for (d).
1
8
To further gain insight into the mechanism of the aerobic oxidation, the control and
Oꢀlabeling
o
experiments were also conducted as shown in Scheme 2. The oxidation of 1a in 80%MeOH at 60 C
for 11 h afforded 5% 2ꢀnitrobenzaldehyde (4a), 44% 2a, and a trace of 2ꢀnitrobenzenemethanol (5)
(Scheme 2, Eq 1). Compound 5 can be further oxidized in EtOH under similar conditions to provide
1
8
2a in 66% yield (Eq 2). In addition, the aerobic oxidation of 1l with the
O
2
gas yielded a sole
18
18
O
ꢀlabeled product 3a- O (see Figure S8), indicating that the oxygen atom in the hydroxyl group
.
ꢀ
exclusively originated from the molecular oxygen and not through OH from the OH of the NaOH.
Thus, the reaction was considerably different from the basedꢀcatalyzed anthranilate rearrangement in
29
2
the absence of O .
18
Scheme 2. Control and O-Labeling Experiments
CH3
CH2OH
NO2
CHO
COOH
NO2
O2 (1.8 MPa)
NaOH (4.5 M)
NO2
NO2
(1)
0%MeOH, 60 oC, 11 h
8
1a
CH OH
84% conv.
5, trace
COOH
NO2
4a, 5%
2a, 44%
2
O2 (1.8 MPa)
NaOH (4.5 M)
NO2
(2)
(3)
EtOH, 60 oC, 24 h
5
2a, 66%
18OH
H
OH
18O2 (balloon)
NaOH (4.5 M)
0%EtOH, 65 oC, 24 h
8
NO2
NO2
3a-18O, 77%
NO2
3a, not observed
1
l
82% conv.
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5
5
5
5
6
Scheme 3. Large-Scale Reactions and Application.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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6
7
8
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0
1
2
3
4
5
6
7
8
9
0
For further demonstrating the practicality of the metalꢀfree aerobic oxidation method,
largeꢀscale reactions and application in the synthesis of Procaine, one of anesthetics used commonly
2
in clinic, were conducted (Scheme 3). A 30 mmol reaction of 1l was performed under the O balloon,
resulting in 3.91 g of 3a in 78% yield (Scheme 3, Eq 1). The other gramꢀscale oxidation was carried
out for 1b on a 60 mmol scale, and 6.52 g of 2b can be separated in 65% yield (Eq 2). After
esterification of 2b with 2ꢀ(diethylamino)ethanol, Procaine can be efficiently synthesized through
the hydrogenation of the nitro group catalyzed with a recyclable Ni/celite catalyst with 91% yield by
using only two environmentally friendly organic solvents. This procedure can also be utilized for
synthesizing other anesthetics.
CONCLUSION
In summary, we developed an efficient, metalꢀfree approach for the aerobic oxidation of
nitroꢀsubstituted alkylarenes to carboxylic acids or benzyl alcohols with high chemoselectivities.
2
This sustainable system can use O as clean oxidant in green NaOH/EtOH mixture under mild
conditions. The position and type of the alkyl substituent critically affected the product. Moreover,
this cheap and green protocol is suitable for gramꢀscale preparation. Furthermore, the reactions
conducted in the pressure reactor or under the balloon can conserve oxygen and avoid solvent loss,
which are all conducive to the environmental protection problem. Further studies on the mechanism
details and other potential applications are still under way in our laboratory.
EXPERIMENTAL SECTION
1
13
General Information. H NMR spectra were recorded at 400 or 500 MHz, and C NMR spectra
were recorded at 100 or 126 MHz NMR instruments in CDCl or DMSO– solutions and chemical
3
d
6
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shifts were referenced to tetramethylsilane (TMS) or residual protiated solvent. If CDCl
3
was used as
1
13
solvent, H NMR spectra were recorded with TMS (δ = 0.00 ppm) as internal reference; C NMR
spectra were recorded with CDCl
3
(δ = 77.00 ppm) as internal reference. If DMSO–
O (δ = 3.33 ppm) as
(δ = 39.52 ppm) as internal
6
d was used as
1
solvent, H NMR spectra were recorded with TMS (δ = 0.00 ppm) or residual H
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
internal reference; C NMR spectra were recorded with DMSO– 6
d
reference. All of the new compounds were analyzed for HRMS on an ESIꢀQTOF mass spectrometer
using electrospray ionization in positive ion mode. The following abbreviations (or combinations
1
thereof) were used to explain H NMR ultiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p
= quintet, m = multiplet, br = broad. Mass spectra were recorded on Thermo Fisher Scientific LTQ
FT Ultra mass spectrometer.
All the starting materials were purchased and used as received without further purification. The
Ni/celite (Ni: 50%) catalyst was from the donation of professor Jiantai Ma (Lanzhou University).
General Experimental Procedure A: Aerobic Oxidation of Nitro-Substituted Alkylarenes to
Carboxylic Acids in Pressure Reactor.
2 2
The nitro hydrocarbon, solvent (EtOH, EtOH/H O, MeOH or MeOH/H O) and NaOH were added to
a 100 mL pressure reactor equipped with a magnetic stir bar. The pressure reactor was filled with
oxygen (1.0 MPa), then the gas was deflated, this fill and deflation procedure was repeated another
twice. After that, the pressure reactor was refilled with oxygen (1.8 MPa), sealed, then stirred at 52 or
o
o
6
0 C for 24–72 h (oil bath temp. 55 or 65 C). Then the mixture was cooled down to ambient
temperature, and the excess oxygen was released slowly. The reaction mixture was transferred to a
round bottom flask and neutralized with concentrated hydrochloric acid to pH = 2–3. If EtOH or
MeOH as the solvent, the residue was diluted with ethyl acetate, dried over anhydrous Na
EtOH/H O or MeOH/H O as the solvent, the residue was extracted with ethyl acetate three times,
and the combined organic layer was then dried over anhydrous Na SO , filtered and concentrated
2 4
SO ; If
2
2
2
4
under reduced pressure. The residue was purified through column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent to afford the desired product.
General Experimental Procedure B: Aerobic Oxidation of Nitro-Substituted Alkylarenes to
Benzyl Alcohols in Pressure Reactor.
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2 2
The nitro hydrocarbon, solvent (EtOH, EtOH/H O, MeOH or MeOH/H O) and NaOH were added to
a 100 mL pressure reactor equipped with a magnetic stir bar. The pressure reactor was filled with
oxygen (1.0 MPa), then the gas was deflated, this fill and deflation procedure was repeated another
twice. After that, the pressure reactor was refilled with oxygen (1.8 MPa), sealed, then stirred at 60
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
o
C for 24–48 h(oil bath temp. 65 C). Then the mixture was cooled down to ambient temperature,
and the excess oxygen was released slowly. The reaction mixture was transferred to a round bottom
flask neutralized with concentrated hydrochloric acid to pH = 6–7. If EtOH or MeOH as the solvent,
the residue was diluted with ethyl acetate, dried over anhydrous Na
MeOH/H O as the solvent, the residue was extracted with ethyl acetate three times, and the
combined organic layer was then dried over anhydrous Na SO , filtered and concentrated under
2 4 2
SO ; If EtOH/H O or
2
2
4
reduced pressure. The residue was purified through column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent to afford the desired product.
General Experimental Procedure C: Aerobic Oxidation of Nitro-Substituted Alkylarenes to
Benzyl Alcohols Under Oxygen Balloon.
The nitro hydrocarbon, solvent (EtOH/H O=4:1) and NaOH were added to flask equipped with a
2
magnetic stir bar. The flask was then evacuated and backfilled with oxygen (0.1 MPa), this
evacuation and backfill procedure was repeated twice. Then the flask was placed in an oil bath (65
o
C) and stirred under a oxygen balloon for 24–48 h. Then the mixture was cooled down to ambient
temperature. The reaction mixture was transferred to a round bottom flask neutralized with
concentrated hydrochloric acid to pH=6–7. Then the organic solvent was removed under reduced
pressure, and the residue was extracted with ethyl acetate three times, and the combined organic
2 4
layer was then dried over anhydrous Na SO , filtered and concentrated under reduced pressure. The
residue was purified through column chromatography on silica gel using petroleum ether/ethyl
acetate as eluent to afford the desired product.
Aerobic oxidation of 2ꢀnitrotoluene (1a) to 2ꢀnitrobenzoic acid (2a):
Table 2, entry 1: Following the general experimental procedure A, the reaction mixture of 1a
(823 mg, 6.0 mmol), MeOH (10 mL) and NaOH (1800 mg, 45.0 mmol) in the pressure reactor was
o
o
stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2a (eluent: petroleum ether/ethyl acetate
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=
5:1–3:1) as a slight yellow solid, 673 mg in 67% yield, wherein 1a was recycled 99 mg in 10%
o
1
yield. Mp: 141.1–141.7 C. H NMR (500 MHz, DMSO–d6):
δ
7.75–7.81 (m, 2H), 7.85–7.87 (m,
1H), 7.97–7.99 (m, 1H), 13.84 (br, 1H). C NMR (126 MHz, DMSO– ): 123.7, 127.3, 129.9,
32,4, 133.1, 148.4, 165.9. The NMR data was in accordance with the literature. MS (DART
1
3
d
6
δ
30
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
–
Negative) m/z: 166.0 ([M–H] , 100%), 333.0 ([2M–H] , 46%). HRMS (DART Negative, LTQ FT):
–
calcd for C
7
H
4
O
4
N [M–H] : 166.0146, found 166.0144.
Table 2, entry 2: Following the general experimental procedure A, the reaction mixture of 1a
(823 mg, 6.0 mmol), EtOH (10 mL) and NaOH (1800 mg, 45.0 mmol) in the pressure reactor was
o
o
stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2a (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a slight yellow solid, 713 mg in 71% yield, wherein 1a was recycled 201 mg in 20%
1
yield. The structure of the product was confirmed by H NMR.
Table 2, entry 3: Following the general experimental procedure A, the reaction mixture of 1a
(823 mg, 6.0 mmol), 80%EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 52 C (oil bath temp.: 55 C) for 72 hours to afford 2a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 825 mg in 83% yield, wherein 1a
1
was recycled 62 mg in 7% yield. The structure of the product was confirmed by H NMR.
Table 2, entry 4: Following the general experimental procedure A, the reaction mixture of 1a
(823 mg, 6.0 mmol), EtOH (10 mL) and NaOH (1800 mg, 45.0 mmol) in the pressure reactor was
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2a (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a slight yellow solid, 757 mg in 76% yield, wherein 1a was recycled 73 mg in 9% yield.
1
The structure of the product was confirmed by H NMR.
Table 2, entry 5: Following the general experimental procedure A, the reaction mixture of 1a
i
(823 mg, 6.0 mmol), PrOH (10 mL) and NaOH (1800 mg, 45.0 mmol) in the pressure reactor was
o
o
stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2a (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a slight yellow solid, 724 mg in 72% yield, wherein 1a was recycled 99 mg in 10%
1
yield. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 4ꢀnitrotoluene (1b) to 4ꢀnitrobenzoic acid (2b):
Table 2, entry 6: Following the general experimental procedure A, the reaction mixture of 1b
(823 mg, 6.0 mmol), MeOH (10 mL) and NaOH (1800 mg, 45.0 mmol) in the pressure reactor was
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
o
stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2b (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a slight yellow solid, 719 mg in 72% yield, wherein 1b was recycled 34 mg in 4%
o
1
yield. Mp: 234.7–235.9 C. H NMR (500 MHz, DMSO–
d
6
):
δ
8.16 (dt,
J
= 9.5, 2.0 Hz, 2H), 8.32
): 123.7, 130.7, 136.4,
50.0, 165.8. The NMR data was in accordance with the literature. MS (DART Negative) m/z
1
3
(dt,
J
= 9.0, 2.0 Hz, 2H), 13.66 (br, 1H). C NMR (126 MHz, DMSO–
d
6
δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
1
1
:
–
–
66.0 ([M–H] , 100%), 333.0 ([2M–H] , 12%). HRMS (DART Negative, LTQ FT): calcd for
–
C
7
H
4
O
4
N [M–H] : 166.0146, found 166.0144.
Table 2, entry 7: Following the general experimental procedure A, the reaction mixture of 1b
(823 mg, 6.0 mmol), 80% MeOH (MeOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in
o
o
the pressure reactor was stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2b (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 767 mg in 77% yield, and 1b was
1
consumed completely. The structure of the product was confirmed by H NMR.
Table 2, entry 8: Following the general experimental procedure A, the reaction mixture of 1b
(
823 mg, 6.0 mmol), 50% MeOH (MeOH/H
2
O=5 mL/5 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2b (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 920 mg in 92% yield, and 1b was
1
consumed completely. The structure of the product was confirmed by H NMR.
Table 2, entry 9: Following the general experimental procedure A, the reaction mixture of 1b
(
823 mg, 6.0 mmol), EtOH (10 mL) and NaOH (1800 mg, 45.0 mmol) in the pressure reactor was
o
o
stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2b (eluent: petroleum ether/ethyl acetate
= 5:1–3:1) as a slight yellow solid, 698 mg in 70% yield, and 1b was consumed completely. The
1
structure of the product was confirmed by H NMR.
Table 2, entry 10: Following the general experimental procedure A, the reaction mixture of 1b
(
823 mg, 6.0 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2b (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 874 mg in 87% yield, and 1b was
1
consumed completely. The structure of the product was confirmed by H NMR.
Table 2, entry 11: Following the general experimental procedure A, the reaction mixture of 1b
(
2
823 mg, 6.0 mmol), 50% EtOH (EtOH/H O = 5 mL/5 mL) and NaOH (1800 mg, 45.0 mmol) in the
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o
o
pressure reactor was stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2b (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 947 mg in 95% yield, and 1b was
1
consumed completely. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1,4ꢀdimethylꢀ2ꢀnitrobenzene (1c) to 4ꢀmethylꢀ2ꢀnitrobenzoic acid (2c):
Table 2, entry 12: Following the general experimental procedure A, the reaction mixture of 1c
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
907 mg, 6.0 mmol), 80% MeOH (MeOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in
o
o
the pressure reactor was stirred at 60 C (oil bath temp.: 65 C) 24 hours to afford 2c (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 707 mg in 65% yield, wherein 1c
o
1
was recycled 207 mg in 23% yield. Mp: 156.6–157.3 C. H NMR (500 MHz, DMSO–
H), 7.59 (dd, = 8.0, 1.0 Hz, 1H), 7.76 (d, = 8.0 Hz, 1H), 7.78 (s, 1H) , 13.72 (br, 1H). C NMR
126 MHz, DMSO–
6
d ): δ 2.43 (s,
13
3
J
J
(
d
6
):
δ
20.6, 123.8, 123.8, 130.0, 133.1, 143.5, 148.9, 165.6. MS (DART Negative)
–
–
m/z: 180.0 ([M–H] , 100%), 361.1 ([2M–H] , 35%). HRMS (DART Negative, LTQ FT): calcd for
–
C
8
H
6
O
4
N [M–H] : 180.0302, found 180.0301.
Table 2, entry 13: Following the general experimental procedure A, the reaction mixture of 1c
(907 mg, 6.0 mmol), 80% EtOH (EtOH/H O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in the
2
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2c (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 811 mg in 75% yield, wherein 1c
1
was recycled 129 mg in 14% yield. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1,2ꢀdimethylꢀ3ꢀnitrobenzene (1d) to 2ꢀmethylꢀ6ꢀnitrobenzoic acid (2d):
Table 2, entry 14: Following the general experimental procedure A, the reaction mixture of 1d
(455 mg, 3.0 mmol), 80% EtOH (EtOH/H
2
O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2d (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a yellow solid, 247 mg in 46% yield, wherein 1d was
o
1
recycled 141 mg in 31% yield. Mp: 144.4–145.1 C. H NMR (500 MHz, DMSO–
.59 (t, = 7.5 Hz, 1H), 7.72 (d, = 7.5 Hz, 1H), 7.98 (d, = 8.0 Hz, 1H), 13.83 (br, 1H). C NMR
126 MHz, DMSO–
6
d ): δ 2.39 (s, 3H),
13
7
J
J
J
(
d
6
):
δ
18.7, 121.6, 129.9, 130.1, 136.3, 136.5, 145.7, 167.1. MS (DART Negative)
–
–
m/z: 180.0 ([M–H] , 100%), 361.1 ([2M–H] , 41%). HRMS (DART Negative, LTQ FT): calcd for
–
C
8
H
6
O
4
N [M – H] : 180.0302, found 180.0301.
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2, entry 15: Following the general experimental procedure A, the reaction mixture of 1d
(
455 mg, 3.0 mmol), EtOH (5 mL) and NaOH (900 mg, 22.5 mmol) in the pressure reactor was
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2d (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a yellow solid, 350 mg in 64% yield, wherein 1d was recycled 47 mg in 10% yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1,2ꢀdimethylꢀ4ꢀnitrobenzene (1e) to 2ꢀmethylꢀ4ꢀnitrobenzoic acid (2e):
Table 2, entry 16: Following the general experimental procedure A, the reaction mixture of 1e
(
907 mg, 6.0 mmol), 50% MeOH (MeOH/H
2
O = 5 mL/5 mL) and NaOH (1800 mg, 45.0 mmol) in
o
o
the pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2e (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 673 mg in 62% yield, wherein 1e
o
1
was recycled 72 mg in 8% yield. Mp: 140.5–141.6 C. H NMR (500 MHz, DMSO–
H), 7.98 (d, = 9.0 Hz, 1H), 8.09 (dd, = 8.5, 2.5 Hz, 1H), 8.16 (d, = 2.0 Hz, 1H), 13.55 (br, 1H).
C NMR (126 MHz, DMSO– ): 20.7, 120.8, 125.7, 131.2, 136.9, 140.7, 148.7, 167.5. MS
6
d ): δ 2.60 (s,
3
J
J
J
13
d
6
δ
–
–
(
DART Negative) m/z: 180.0 ([M–H] , 100%), 361.1 ([2M–H] , 10%). HRMS (DART Negative,
–
LTQ FT): calcd for C H O N [M–H] : 180.0302, found 180.0300.
8
6
4
Table 2, entry 17: Following the general experimental procedure A, the reaction mixture of 1e
(
907 mg, 6.0 mmol), 50% EtOH (EtOH/H
2
O = 5 mL/5 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2e (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a red solid, 580 mg in 53% yield, and 1e was consumed
1
completely. The structure of the product was confirmed by H NMR.
Table 2, entry 18: Following the general experimental procedure A, the reaction mixture of 1e
(
454 mg, 3.0 mmol), 80% EtOH (EtOH/H O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
2
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2e (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a red solid, 312 mg in 58% yield, and 1e was consumed
1
completely. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 2,4ꢀdimethylꢀ1ꢀnitrobenzene (1f) to 4ꢀnitrobenzeneꢀ1,3ꢀdioic acid (2f):
Table 2, entry 19: Following the general experimental procedure A, the reaction mixture of 1f
(
907 mg, 6.0 mmol), 50% EtOH (EtOH/H
2
O = 5 mL/5 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2f (eluent:
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petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 231 mg in 18% yield, wherein 1f
o
o
32
1
was recycled 367 mg in 40% yield. Mp: 259.9–260.8 C (literature reported: 260–263 C) . H
NMR (500 MHz, DMSO–
d
6
):
δ
7.77 (d,
J
= 8.5 Hz, 1H), 8.01 (dd,
J = 8.0, 2.0 Hz, 1H), 8.23 (d, J =
13
2
.0 Hz, 1H), 13.85 (br, 2H). C NMR (126 MHz, DMSO–
d
6
): 124.3, 126.7, 130.8, 133.5, 134.4,
δ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[
3]
1
51.0, 164.8, 165.1. The NMR data was in accordance with the literature. MS (DART Negative)
–
–
2
m/z: 166.0 ([MꢀHꢀCO ] , 24%), 210.0 ([M–H] , 100%). HRMS (DART Negative, LTQ FT): calcd for
–
C
8
H
4
O
6
N [M–H] : 210.0044, found 210.0042.
Table 2, entry 20: Following the general experimental procedure A, the reaction mixture of 1f
(454 mg, 3.0 mmol), 80% EtOH (EtOH/H
2
O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2f (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 180 mg in 28% yield, wherein 1f
1
was recycled 16 mg in 3% yield. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 4ꢀmethoxyꢀ1ꢀmethylꢀ2ꢀnitrobenzene (1g) to 4ꢀmethoxyꢀ2ꢀnitrobenzoic acid
(2g):
Table 2, entry 21: Following the general experimental procedure A, the reaction mixture of 1g
501 mg, 3.0 mmol), 80%EtOH (EtOH/H2O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
(
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2g (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a white solid, 444 mg in 75% yield, and 1g was
o
1
consumed completely. Mp: 194.1–194.9 C. H NMR (500 MHz, DMSO–
dd, = 9.0, 2.5 Hz, 1H), 7.49 (d, = 2.5 Hz, 1H), 7.87 (d, = 9.0 Hz, 1H), 13.55 (br, 1H). C NMR
(126 MHz, DMSO– ): 56.4, 109.1, 117.0, 117.3, 132.2, 151.2, 162.2, 164.7. MS (DART Positive
Ion Mode) m/z: 136.0 ([MꢀNO ꢀCH ] , 2%), 149.0 ([MꢀH OꢀCH O+H] , 4%), 180.0 ([MꢀH O+H] ,
6
d ): δ 3.89 (s, 3H), 7.27
13
(
J
J
J
d
6
δ
+
+
+
2
3
2
3
2
+
+
1
2
7%), 198.0 ([M+H] , 42%), 215.1 ([M+H O] , 100%). HRMS (DART Positive Ion Mode, LTQ
+
FTICR): calcd for C
8
H
8
O
5
N [M+H] : 198.0397, found 198.0396.
Table 2, entry 22: Following the general experimental procedure A, the reaction mixture of 1g
(501 mg, 3.0 mmol), EtOH (5 mL) and NaOH (900 mg, 22.5 mmol) in the pressure reactor was
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2g (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a white solid, 336 mg in 57% yield, and 1g was consumed completely. The structure of
1
the product was confirmed by H NMR.
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Aerobic oxidation of 2ꢀmethoxyꢀ1ꢀmethylꢀ4ꢀnitrobenzene (1h) to 2ꢀmethoxyꢀ4ꢀnitrobenzoic acid
(2h):
Table 2, entry 23: Following the general experimental procedure A, the reaction mixture of 1h
(1003 mg, 6.0 mmol), 50% EtOH (EtOH/H
2
O = 5 mL/5 mL) and NaOH (900 mg, 22.5 mmol) in the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
o
pressure reactor was stirred at 52 C (oil bath temp.: 55 C) for 24 hours to afford 2h (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a red solid, 646 mg in 55% yield, and 1h was consumed
o
1
completely. Mp: 126.4.1–127.4 C. H NMR (500 MHz, DMSO–
d
6
):
.0 Hz, 1H), 7.84–7.86 (m, 2H), 13.36 (br, 1H). C NMR (126 MHz, DMSO–
115.1, 128.2, 130.9, 149.8, 157.9, 166.3. The NMR data was in accordance with the literature. MS
δ
3.95 (s, 3H), 7.82 (dd,
J = 7.5,
13
1
d
6
): 56.5, 107.1,
δ
33
+
+
(
DART Positive Ion Mode) m/z: 136.0 ([MꢀNO
2
ꢀCH
3
] , 5%), 149.0 ([MꢀH
2
OꢀCH
3
O+H] , 8%), 154.0
+
+
+
+
(
[MꢀH
2
OꢀCH
3
] , 21%), 180.0 ([MꢀH
2
O+H] , 23%), 198.0 ([M+H] , 100%), 215.1 ([M+H
2
O] , 8%),
+
2
44.1 ([M+NO +H] , 8%). HRMS (DART Positive Ion Mode, LTQ FTICR): calcd for C H O N [M
2
8
8
5
+
+
H] : 198.0397, found 198.0397.
Aerobic oxidation of 1ꢀethylꢀ4ꢀnitrobenzene (1i) to 4ꢀnitrobenzoic acid (2b):
Table 2, entry 24: Following the general experimental procedure A, the reaction mixture of 1i
(907 mg, 6.0 mmol), 50% EtOH (EtOH/H
2
O = 5 mL/5 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2b (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 929 mg in 93% yield, wherein 1i
1
was recycled 18 mg in 2% yield. The structure of the product was confirmed by H NMR.
Table 2, entry 25: Following the general experimental procedure A, the reaction mixture of 1i
(907 mg, 6.0 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2b (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 798 mg in 80% yield, wherein 1i
1
was recycled 27 mg in 3% yield. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1ꢀnitroꢀ4ꢀpropylbenzene (1j) to 4ꢀnitrobenzoic acid (2b):
Table 2, entry 26: Following the general experimental procedure A, the reaction mixture of 1j
(496 mg, 3.0 mmol), 80% EtOH (EtOH/H
2
O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2b (eluent:
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petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 205 mg in 41% yield, and 1j was
1
consumed completely. The structure of the product was confirmed by H NMR.
Table 2, entry 27: Following the general experimental procedure A, the reaction mixture of 1j
(496 mg, 3.0 mmol), EtOH ( 5 mL) and NaOH (900 mg, 22.5 mmol) in the pressure reactor was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2b (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a slight yellow solid, 375 mg in 75% yield, wherein 1j was recycled 10 mg in 2% yield.
1
The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1ꢀbutylꢀ4ꢀnitrotoluene (1k) to 4ꢀnitrobenzoic acid (2b):
Table 2, entry 28: Following the general experimental procedure A, the reaction mixture of 1k
(538 mg, 3.0 mmol), 80% EtOH (EtOH/H
2
O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2b (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 256 mg in 51% yield, and 1k was
1
consumed completely. The structure of the product was confirmed by H NMR.
Table 2, entry 29: Following the general experimental procedure A, the reaction mixture of 1k
(538 mg, 3.0 mmol), EtOH (5 mL) and NaOH (900 mg, 22.5 mmol) in the pressure reactor was
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2b (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a slight yellow solid, 456 mg in 91% yield, wherein 1k was recycled 11 mg in 2%
1
yield. The structure of the product was confirmed by H NMR.
Aerobic oxidation of a mixture of 1b+1i to 4ꢀnitrobenzoic acid (2b):
Table 2, entry 30: Following the general experimental procedure A, the reaction mixture of 1b
(411 mg, 3.0 mmol), 1i (453 mg, 3.0 mmol), 50%EtOH (EtOH/H
2
O = 5 mL/5 mL) and NaOH (1800
o
o
mg, 45.0 mmol) in the pressure reactor was stirred at 55 C (oil bath temp.: 60 C) for 24 hours to
afford 2b (eluent: petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 891 mg in 89%
1
yield. The structure of the product was confirmed by H NMR.
Aerobic oxidation of a mixture of 1j+1k to 4ꢀnitrobenzoic acid (2b):
Table 2, entry 31: Following the general experimental procedure A, the reaction mixture of 1j
(248 mg, 1.5 mmol), 1k (269 mg, 1.5 mmol), EtOH (5 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 2b (eluent:
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2
2
2
2
2
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5
6
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 325 mg in 65% yield. wherein
1
1
j+1k was recycled 50 mg. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1ꢀethylꢀ2ꢀnitrobenzene (1l) to 1ꢀ(2ꢀnitrophenyl)ethanol (3a):
Table 3, entry 1: Following the general experimental procedure B, the reaction mixture of 1l
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(907 mg, 6.0 mmol), MeOH (10 mL) and NaOH (1800 mg, 45.0 mmol) in the pressure reactor was
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent: petroleum ether/ethyl acetate
1
=
5:1–3:1) as a brown liquid, 631 mg in 63% yield, wherein 1l was recycled 30 mg in 3% yield. H
NMR (500 MHz, CDCl
= 8.0 Hz, 1H), 7.65 (t,
126 MHz, CDCl ):
accordance with the literature. HR (DART Positive, LTQ FT) m/z: 120.1 ([MꢀNO
3
):
= 7.5 Hz, 1H), 7.84 (d,
δ 24.2, 65.5, 124,3, 127.5, 128.1, 133.6, 140.9, 147.8. The NMR data was in
δ
1.58 (d,
J
= 6.5 Hz, 3H), 2.34 (s, 1H), 5.42 (q,
J = 6.0 Hz, 1H), 7.42 (t, J
13
J
J
= 8.0 Hz, 1H), 7.90(d, J = 8.0 Hz, 1H). C NMR
(
3
3
4
+
2
ꢀH] , 2%), 150.1
+
+
(
[MꢀH O+H] , 100%), 185.1 ([M+NH ] , 15%).
2 4
Table 3, entry 2: Following the general experimental procedure B, the reaction mixture of 1l
(907 mg, 6.0 mmol), 80% MeOH (MeOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in
o
o
the pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 629 mg in 63% yield, wherein 1l was
1
recycled 23 mg in 3% yield. The structure of the product was confirmed by H NMR.
Table 3, entry 3: Following the general experimental procedure B, the reaction mixture of 1l
(907 mg, 6.0 mmol), 80 % EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 878 mg in 88% yield, wherein 1l was
1
recycled 47 mg in 5% yield. The structure of the product was confirmed by H NMR.
Table 3, entry 4: Following the general experimental procedure C, the reaction mixture of 1l
(907 mg, 6.0 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) under
o
o
an oxygen balloon was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 856 mg in 85% yield, wherein 1l was
1
recycled 17 mg in 2 % yield. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1ꢀnitroꢀ2ꢀpropylbenzene (1m) to 1ꢀ(2ꢀnitrophenyl)propanꢀ1ꢀol (3b):
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Table 3, entry 5: Following the general experimental procedure B, the reaction mixture of 1m
(
496 mg, 3.0 mmol), 80% EtOH (EtOH/H O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
2
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3b (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow liquid, 464 mg in 85% yield, wherein 1m
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
was recycled 57 mg in 11 % yield. H NMR (500 MHz, DMSO–d6):
δ 0.92 (t, J = 7.5 Hz, 3H),
1
.51–1.60 (m, 1H), 1.64–1.72 (m, 1H), 4.86–4.89 (m, 1H), 5.51 (d,
H), 7.72 (td, = 7.5, 2.0 Hz, 1H), 7.78 (dd,
J
= 4.5 Hz, 1H), 7.47–7.50 (m,
13
1
J
J
= 7.5, 2.0 Hz, 1H), 7.87 (dd,
J
= 8.5, 1.5 Hz, 1H). C
NMR (126 MHz, DMSO–
TOF): calcd for C NO
d
6
):
δ
10.5, 31.5, 68.8, 123.6, 127.9, 128.2, 133.1, 140.7, 147.7. HRMS (EI,
+
7
H
6
3
[MꢀC
2
H
5
] : 152.0348, found 152.0346.
Table 3, entry 6: Following the general experimental procedure B, the reaction mixture of 1m
(
496 mg, 3.0 mmol), EtOH (5 mL) and NaOH (900 mg, 22.5 mmol) in the pressure reactor was
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3b (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a brown liquid, 382 mg in 70% yield, wherein 1m was recycled 30 mg in 6 % yield.
1
The structure of the product was confirmed by H NMR.
Aerobic oxidation of1ꢀbutylꢀ2ꢀnitrobenzene (1n) to 1ꢀ(2ꢀnitrophenyl)butanꢀ1ꢀol (3c):
Table 3, entry 7: Following the general experimental procedure B, the reaction mixture of 1n
(
538 mg, 3.0 mmol), 80% EtOH (EtOH/H
2
O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3c (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow liquid, 522 mg in 89% yield, wherein 1n
1
was recycled 43 mg in 8 % yield. H NMR (500 MHz, DMSO–
d
6
):
δ
0.88 (t,
J
= 7.5 Hz, 3H),
= 5.0 Hz,
= 8.0, 1.0 Hz, 1H), 7.87 (dd, J =
1.35–1.40 (m, 1H), 1.44–1.50 (m, 1H), 1.51–1.59 (m, 2H), 4.94–4.98 (m, 1H), 5.49 (d,
J
1
8
1
H), 7.47–7.50 (m, 1H), 7.71(td,
J
= 7.5, 1.0 Hz, 1H), 7.79 (dd,
J
13
.0, 1.5 Hz, 1H). C NMR (126 MHz, DMSO–
d
6
):
δ
13.6, 18.8, 40.7, 67.0, 123.6, 127.9, 128.1,
+
33.1, 141.1, 147.6. HRMS (EI, TOF): calcd for C
7
H
6
NO
3
[MꢀC
3
H
7
] : 152.0348, found 152.0358.
Table 3, entry 8: Following the general experimental procedure B, the reaction mixture of 1n
538 mg, 3.0 mmol), EtOH (5 mL) and NaOH (900 mg, 22.5 mmol) in the pressure reactor was
(
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3c (eluent: petroleum ether/ethyl acetate
=
5:1ꢀ3:1) as a slight yellow liquid, 396 mg in 68% yield, wherein 1n was recycled 76 mg in 7 %
1
yield.The structure of the product was confirmed by H NMR.
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Aerobic oxidation of 1ꢀisopropylꢀ4ꢀnitrobenzene (1o) to 2ꢀ(4ꢀnitrophenyl)propanꢀ2ꢀol (3d):
Table 3, entry 9: Following the general experimental procedure B, the reaction mixture of 1o
(496 mg, 3.0 mmol), 80 %EtOH (EtOH/H
2
O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3d (eluent:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
petroleum ether/ethyl acetate = 5:1ꢀ3:1) as a brown liquid, 411 mg in 76% yield, wherein 1o was
1
recycled 115 mg in 23 % yield. H NMR (500 MHz, DMSO–
d
6
):
δ
1.46 (s, 6H), 5.36 (s, 1H),
): 31.2, 70.8, 123.0, 125.9,
] : 166.0504, found 166.0512.
Table 3, entry 10: Following the general experimental procedure B, the reaction mixture of 1o
496 mg, 3.0 mmol), EtOH (5 mL) and NaOH (900 mg, 22.5 mmol) in the pressure reactor was
13
7
.23–7.76 (m, 2H), 8.16–8.18 (m, 2H). C NMR (126 MHz, DMSO–
d
6
δ
+
1
8 8 3 3
45.9, 158.4. HRMS (EI): calcd for C H NO [MꢀCH
(
o
o
stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3d (eluent: petroleum ether/ethyl acetate
=
5:1–3:1) as a brown liquid, 474 mg in 87% yield, wherein 1o was recycled 17 mg in 3 % yield.
1
The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1ꢀsecꢀbutylꢀ4ꢀnitrobenzene (1p) to 2ꢀ(4ꢀnitrophenyl)butanꢀ2ꢀol (3e):
Table 3, entry 11: Following the general experimental procedure B, the reaction mixture of 1p
(538 mg, 3.0 mmol), 80 %EtOH (EtOH/H
2
O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 48 hours to afford 3e (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow liquid, 398 mg in 68% yield, wherein 1p
1
was recycled 118 mg in 29 % yield. H NMR (400 MHz, DMSO–
d
6
):
= 8.8 Hz, 2H), 8.17 (d,
8.1, 29.5, 36.1, 73.2, 122.9, 126.5, 145.8, 157.1. HRMS (EI, TOF): calcd
δ
0.67 (t,
J = 9.0 Hz, 3H), 1.43
13
(
s, 3H), 1.66–1.80 (m, 2H), 5.17 (s, 1H), 7.69 (d,
J
J
= 8.8 Hz, 2H). C NMR
(100 MHz, DMSO–
d
6
):
δ
+
for C H NO [M–H O] : 177.0790, found 177.0797.
10 11
2
2
Table 3, entry 12: Following the general experimental procedure B, the reaction mixture of 1p
(538 mg, 3.0 mmol), 80% EtOH (EtOH/H
2
O = 4 mL/1 mL) and NaOH (900 mg, 22.5 mmol) in the
o
o
pressure reactor was stirred at 73 C (oil bath temp.: 80 C) for 24 hours to afford 3e (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow liquid, 459 mg in 78% yield, wherein 1p
1
was recycled 102 mg in 19 % yield. The structure of the product was confirmed by H NMR.
Aerobic oxidation of 1ꢀethylꢀ2ꢀnitrobenzene (1l) to 1ꢀ(2ꢀnitrophenyl)ethanol (3a) at different
concentrations:
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Table 4, entry 1: Following the general experimental procedure C, the reaction mixture of 1l
(
454 mg, 3.0 mmol), 80 %EtOH (EtOH/H O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) under
2
o
an oxygen balloon was placed in an oil bath (65 C) and was stirred for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1ꢀ3:1) as a brown liquid, 419 mg in 84% yield, and 1l was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
consumed completely. The structure of the product was confirmed by H NMR.
Table 4, entry 2: Following the general experimental procedure B, the reaction mixture of 1l
(
680 mg, 4.5 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 590 mg in 78% yield, wherein 1l was
1
recycled 18 mg in 3 % yield. The structure of the product was confirmed by H NMR.
Following the general experimental procedure C, the reaction mixture of 1l (680 mg, 4.5 mmol), 80%
EtOH (EtOH/H O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) under an oxygen balloon was
2
o
placed in an oil bath (65 C) and was stirred for 24 hours to afford 3a (eluent: petroleum ether/ethyl
acetate = 5:1–3:1) as a brown liquid, 669 mg in 90% yield, wherein 1l was recycled 7 mg in 1 %
1
yield. The structure of the product was confirmed by H NMR.
Table 4, entry 3: Following the general experimental procedure B, the reaction mixture of 1l
(
907 mg, 6.0 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in the
o
o
pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 878 mg in 88% yield, wherein 1l was
1
recycled 47 mg in 5 % yield. The structure of the product was confirmed by H NMR.
Following the general experimental procedure C, the reaction mixture of 1l (907 mg, 6.0 mmol), 80%
EtOH (EtOH/H O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) under an oxygen balloon was
2
o
placed in an oil bath (65 C) and was stirred for 24 hours to afford 3a (eluent: petroleum ether/ethyl
acetate = 5:1–3:1) as a brown liquid, 856 mg in 85% yield, wherein 1l was recycled 17 mg in 2 %
1
yield. The structure of the product was confirmed by H NMR.
Table 4, entry 4: Following the general experimental procedure B, the reaction mixture of 1l
(1814 mg, 12.0 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in
o
o
the pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 1733 mg in 86% yield, wherein 1l was
1
recycled 190 mg in 10 % yield. The structure of the product was confirmed by H NMR.
Following the general experimental procedure C, the reaction mixture of 1l (1814 mg, 12.0
mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) under an oxygen
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
balloon was placed in an oil bath (65 C) and was stirred for 24 hours to afford 3a (eluent: petroleum
ether/ethyl acetate = 5:1–3:1) as a brown liquid, 1339 mg in 67% yield, wherein 1l was recycled 99
1
mg in 5 % yield. The structure of the product was confirmed by H NMR.
Table 4, entry 5: Following the general experimental procedure B, the reaction mixture of 1l
(2268 mg, 15.0 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in
o
o
the pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 1734 mg in 69% yield, wherein 1l was
1
recycled 211 mg in 9 % yield. The structure of the product was confirmed by H NMR.
Following the general experimental procedure C, the reaction mixture of 1l (2268 mg, 15.0
mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) under an oxygen
o
balloon was placed in an oil bath (65 C) and was stirred for 24 hours to afford 3a (eluent: petroleum
ether/ethyl acetate = 5:1–3:1) as a brown liquid, 1494 mg in 60% yield, wherein 1l was recycled 183
1
mg in 7 % yield. The structure of the product was confirmed by H NMR.
Table 4, entry 6: Following the general experimental procedure B, the reaction mixture of 1l
(3401 mg, 22.5 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in
o
o
the pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 2334 mg in 62% yield, wherein 1l was
1
recycled 673 mg in 20 % yield. The structure of the product was confirmed by H NMR.
Following the general experimental procedure C, the reaction mixture of 1l (3401 mg, 22.5
mmol), 80%EtOH (EtOH/H
2
O=8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) under an oxygen
o
balloon was placed in an oil bath (65 C) and was stirred for 24 hours to afford 3a (eluent: petroleum
ether/ethyl acetate = 5:1–3:1) as a brown liquid, 2216 mg in 59% yield, wherein 1l was recycled 765
1
mg in 22% yield. The structure of the product was confirmed by H NMR.
Table 4, entry 7: Following the general experimental procedure B, the reaction mixture of 1l
2
(3401 mg, 22.5 mmol), 80% EtOH (EtOH/H O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in
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o
o
the pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 48 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 2368 mg in 63% yield, wherein 1l was
1
recycled 391 mg in 11 % yield. The structure of the product was confirmed by H NMR.
Following the general experimental procedure C, the reaction mixture of 1l (3401 mg, 22.5 mmol),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
0% EtOH (EtOH/H O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) under an oxygen balloon
2
o
was placed in an oil bath (65 C) and was stirred for 48 hours to afford 3a (eluent: petroleum
ether/ethyl acetate = 5:1–3:1) as a brown liquid, 2595 mg in 69% yield, wherein 1l was recycled 291
1
mg in 9 % yield. The structure of the product was confirmed by H NMR.
Table 4, entry 8: Following the general experimental procedure B, the reaction mixture of 1l
(
4535 mg, 30.0 mmol), 80% EtOH (EtOH/H
2
O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in
o
o
the pressure reactor was stirred at 60 C (oil bath temp.: 65 C) for 24 hours to afford 3a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 2398 mg in 48% yield, wherein 1l was
1
recycled 1251 mg in 25 % yield. The structure of the product was confirmed by H NMR.
Following the general experimental procedure C, the reaction mixture of 1l (4535 mg, 30.0
mmol), 80% EtOH (EtOH/H O = 8 mL/2 mL) and NaOH (1800 mg, 45.0 mmol) in under an oxygen
2
o
balloon was placed in an oil bath (65 C) and was stirred for 24 hours to afford 3a (eluent: petroleum
ether/ethyl acetate = 5:1–3:1) as a brown liquid, 2272 mg in 45% yield, wherein 1l was recycled
1
1
687 mg in 37 % yield. The structure of the product was confirmed by H NMR.
Control Experiments.
Scheme 2, eq 1 : The 1ꢀmethylꢀ2ꢀnitrobenzene 1a (1646 mg, 12.0 mmol), 80% MeOH
2
(MeOH/H O = 16 mL/4 mL) and NaOH (3600 mg, 90.0 mmol) were added to a pressure reactor
equipped with a magnetic stir bar. The pressure reactor was filled with oxygen (1.0 MPa), then the
gas was deflated, this fill and deflation procedure was repeated another twice. After that, the pressure
o
reactor was refilled with oxygen (1.8 MPa), sealed, then the mixture was stirred at 60 C (oil bath
o
temp.: 65 C) for 11 h, cooled down to ambient temperature, and the excess oxygen was released
slowly. The reaction mixture was transferred to a round bottom flask and the organic solvent was
removed under reduced pressure. The residue was extracted with ethyl acetate three times, and the
combined organic layer was then dried over anhydrous Na
2 4
SO , filtered and concentrated. The
residue was purified through column chromatography on silica gel using petroleum ether/ethyl
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
acetate = 5:1ꢀ3:1 as eluent to afford 4a as a slight yellow solid, 91 mg in 5% yield; and a trace of
(2ꢀnitrophenyl)methanol 5 was also observed; 2a as a slight yellow solid, 873 mg in 44% yield,
1
wherein 1a was recycled 262 mg in 16% yield. The structure of the product 2a was confirmed by H
1
NMR. 4a: H NMR (500 MHz, CDCl
3
):
δ
7.75–7.82 (m, 2H), 7.96 (dd,
J
= 7.5, 1.5 Hz, 1H), 8.13
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(dd,
J
= 8.0, 1.0 Hz, 1H), 10.43 (s, 1H).
Scheme 2, eq 2: The (2ꢀnitrophenyl)methanol 5 (367 mg, 3.0 mmol), EtOH (5 mL) and NaOH
(900 mg, 22.5 mmol) were added to a pressure reactor equipped with a magnetic stir bar. The
pressure reactor was filled with oxygen (1.0 MPa), then the gas was deflated, this fill and deflation
procedure was repeated another twice. After that, the pressure reactor was refilled with oxygen (1.8
o
o
MPa), sealed. The mixture was stirred at 60 C (oil bath temp.: 65 C) for 24 h, cooled down to
ambient temperature, the excess oxygen was released slowly. The reaction mixture was transferred to
2 4
a round bottom flask, dried over anhydrous Na SO , filtered and concentrated under reduced
pressure. The residue was purified through column chromatography on silica gel to afford 2a (eluent:
petroleum ether/ethyl acetate = 5:1–3:1) as a slight yellow solid, 268 mg in 66% yield, and 1a was
1
consumed completely. The structure of the product was confirmed by H NMR.
1
8
O-labeling Experiment.
Scheme 2, eq 3: The 1ꢀethylꢀ2ꢀnitrobenzene 1l (181 mg, 1.2 mmol), and NaOH (360 mg, 9.0
mmol) were added to a 10 mL round bottom flask equipped with a magnetic stir bar. The flask was
18
evacuated and backfilled with
O
2
gas (balloon). Then EtOH (1.6 mL) and H
2
O (0.4 mL) were
18
o
added through a syringe. The mixture was stirred under
O
2
gas balloon in an oil bath at 65 C for
24 h, cooled down to ambient temperature and neutralized with concentrated hydrochloric acid to pH
=
6–7. The reaction mixture was diluted with ethyl acetate, dried over anhydrous Na SO , filtered
2
4
and concentrated under reduced pressure. The residue was purified through column chromatography
18
on silica gel to afford 3a- O (eluent: petroleum ether/ethyl acetate = 5:1–3:1) as a brown liquid, 153
1
mg in 77% yield, wherein 1l was recycled 33 mg in 18% yield. H NMR (500 MHz, CDCl
3
):
δ
1.58
(d,
J
= 6.5 Hz, 3H), 2.30 (d,
= 8.0, 1.0 Hz, 1H), 7.85 (dd,
126 MHz, CDCl ):
J
= 3.5 Hz, 1H), 5.43 (qd,
J
= 6.5, 3.0 Hz 1H), 7.41–7.44 (m, 1H), 7.66
1
3
(td,
J
J
= 8.0, 1.5 Hz, 1H), 7.91 (dd, J = 8.5, 1.5 Hz, 1H). C NMR
(
3
δ
24.2, 65.5, 124.3, 127.5, 128.1, 133.6, 140.9, 147.8. HR (DART Positive) m/z
:
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+
+
1
50.1 ([MꢀH
2
O+H] , 100%), 185.1 ([M+NH
4
] , 4%). HRMS (DART Positive, LTQ FT): calcd for
18
+
C H NO O [M+NH ] 187.0963, found 187.0963. The 3a was not observed from the mass
8
9
2
4
spectrum of the product (Figure S8, bottom), see the spectra comparison in Figure S8.
Large-scale Reactions.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3, eq 1: The 1ꢀethylꢀ2ꢀnitrobenzene 1l (4535 mg, 12.0 mmol) and NaOH (9000 mg, 225
mmol) were added to a flask equipped with a magnetic stir bar. The flask was evacuated and
2
backfilled with O gas (balloon). This evacuation and backfill procedure were repeated for twice.
Then EtOH (40 mL) and H O (10 mL) were added through a syringe. Then the flask was stirred
2
o
under a oxygen balloon in an oil bath at 65 C under a oxygen balloon for 48 h. Then the reaction
mixture was cooled down to ambient temperature and neutralized with concentrated hydrochloric
acid to pH = 6–7. Then the organic solvent was removed under reduced pressure, and the residue was
extracted with ethyl acetate three times, and the combined organic layer was then dried over
anhydrous Na
2 4
SO , filtered and concentrated under reduced pressure. The residue was purified
through column chromatography on silica gel to afford 3a (eluent: petroleum ether/ethyl acetate =
5
:1–3:1) as a brown liquid, 3928 mg in 78% yield, wherein 1l was recycled 91 mg in 2% yield. The
1
structure of the product was confirmed by H NMR.
Application of the Aerobic Oxidation in the Synthesis of Procaine.
Scheme 3, eq 2: The 1ꢀmethylꢀ4ꢀnitrobenzene 1b (8.23 g, 60 mmol), 50% EtOH (EtOH/H O =
2
5
0 mL/50 mL) and NaOH (18.00 g, 450 mmol) were added to a pressure reactor equipped with a
magnetic stir bar. The pressure reactor was filled with oxygen (1.0 MPa), then the gas was deflated,
this fill and deflation procedure was repeated another twice. After that, the pressure reactor was
o
o
refilled with oxygen (1.8 MPa), sealed, then the mixture was stirred at 52 C (oil bath: 55 C) for 72
h, cooled down to ambient temperature, and the excess oxygen was released slowly. The reaction
mixture was transferred to a round bottom flask and the organic solvent was removed under reduced
pressure. The residue was extracted with ethyl acetate three times, and the combined organic layer
was then dried over anhydrous Na
2 4
SO , filtered and concentrated. The residue was purified through
column chromatography on silica gel to afford 2b (eluent: petroleum ether/ethyl acetate = 5:1–3:1) as
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1
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a yellow solid, 6.52 g in 65% yield, and 1b was consumed completely. The structure of the product
1
was confirmed by H NMR.
The 4ꢀnitrobenzoic acid 2b (10.11g, 60.5 mmol),
N,Nꢀdiethyletholamine (6.65 g, 55.0 mmol),
HCOOH (95 mg, 2.1 mmol) and xylene (45 mL) were added to a 100 mL threeꢀnecked flask
equipped with a magnetic stir bar, a water separator and a condenser. The mixture was stirred at
refluxed temperature for 24 h until about 1.0 mL water was separated. The reaction mixture was then
cooled down to ambient temperature, and diluted with xylene (40 ml), and then transferred into a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
250ml separating funnel, washed with 5%wt NaOH solution (50ml), dried with anhydrous sodium
sulfate, filtered and concentrated until 40–50ml xylene left in a glass bottle. The obtained solution
was then transferred into a 250 mL pressure reactor equipped with a magnetic stir bar, the glass
bottle washed with xylene (50 mL) and the mixture was also transferred into the pressure reactor.
Then catalyst Ni/celite (825 mg) was added. The pressure reactor was filled with hydrogen (1.0 MPa),
then the gas was deflated, this fill and deflation procedure was repeated another twice. After that, the
o
pressure reactor was refilled with hydrogen (2.8 MPa), sealed, then the mixture was stirred at 130 C
o
(
oil bath: 160 C) for 4 h until the pressure of the reactor was no longer down, then kept at that
3
5
temperature for another 1 h. The mixture was cooled down to ambient temperature, and the excess
hydrogen was released slowly. The mixture was filtered and washed with ethyl acetate. The filtrate
was concentrated under reduced pressure and the residue was purified through column
chromatography on silica gel, which was pretreated with petroleum ether/Et N = 100:0.5, to afford
3
Procaine (eluent: petroleum ether/ethyl acetate = 5:1, then petroleum ether/ethyl acetate/MeOH =
1
75:25:10) as a slight yellow liquid, 11.87 g in 91% total yield. H NMR (500 MHz, CDCl
3
):
= 6.5 Hz,
12.0, 47.8,
δ 1.07 (t,
J
2
5
= 7.5 Hz, 6H), 2.63 (q,
J
= 7.0 Hz, 4H), 2.84 (t,
J = 6.5 Hz, 2H), 4.04 (brs, 2H), 4.34 (t, J
13
H), 6.64 (d, = 8.5 Hz, 2H), 7.85 (d,
J
J
= 8.5 Hz, 2H). C NMR (126 MHz, CDCl
3
):
δ
36
1.1, 62.7, 113.8, 119.9, 131.6, 150.8, 166.6. The NMR data was in accordance with the literature.
+
HRMS (EI, TOF): calcd for C12
H
17
N
2
O
2
[MꢀCH
3
] 221.1285, found 221.1295.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Details of condition optimization of aerobic oxidation of 1a, 1b, 1l; In situ NMR experiment for 1l;
Stepwise synthesis of Procaine; Xꢀray molecular structure of 2c and the crystal data (CCDC
1553779); NMR and HRMS spectra of new compounds (PDF).
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The Journal of Organic Chemistry
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: guijieli@zjut.edu.cn; sheyb@zjut.edu.cn.
ORCID
Guijie Li: 0000ꢀ0002ꢀ0740ꢀ2235
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We gratefully acknowledge the National Natural Science Foundation of China (21776259, 21602198
and 21476270) for financial support. We also thank Prof. Jiantai Ma (Lanzhou University) for his
donation of the Ni/celite catalyst.
REFERENCES
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