Selective Oxidation of Benzylic sp3C-H Bonds using Molecular Oxygen in a Continuous-Flow Microreactor

Oxygen in a Continuous-Flow Microreactor

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Selective Oxidation of Benzylic sp C−H Bonds using Molecular

Lei Yun, Jingnan Zhao, Xiaofei Tang, Cunfei Ma, Zongyi Yu, and QingWei Meng*

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sı Supporting Information

ABSTRACT: Selective aerobic oxidation of benzylic sp C−H bonds to generate the corresponding ketones was achieved under

continuous-ﬂow conditions. The catalysts N-hydroxyphthalimide (NHPI) and tert-butyl nitrite (TBN) as the precursor of the radical

under aerobic conditions motivated this process. Flow microreactors operating under optimized conditions enabled this oxidation

with higher eﬃciency and a shortened reaction time of 54 s (total time was 10 min), which was improved 466 times compared with

the batch parallel reaction (7.0 h). Notably, the catalyst and solvent recycling (92.6 and 94.5%) and scale-up experiments (0.87 g h⁻

in 28 h) demonstrated the practicability of the protocol. The high product selectivity and functional group tolerance of the process

allowed the production of ketones in yields of 41.2 to 90.3%. To reveal the versatility and applicability of this protocol, the late-stage

modiﬁcation of an antiepileptic drug to obtain oxcarbazepine was further conducted.

KEYWORDS: microreactor, oxidation, pharmaceuticals, scalable, ketones

INTRODUCTION

develop a safe and scalable system that can carry out benzylic

oxidation rapidly without the incorporation of a metal catalyst.

Currently, it is well established that microreactors can be

employed to enhance the chemical reaction eﬃciency and to

■

Direct benzylic oxidation has been applied extensively for the

synthesis of pharmaceuticals and ﬁne chemicals, and this

approach has enjoyed signiﬁcant commercial success. A wide

range of commercially available pharmaceutical drugs have one

or more oxidized benzylic positions involved in their structural

framework (Scheme 1). To date, considerable research

eﬀorts have been directed toward developing an environ-

mentally benign process for oxidizing benzylic sp C−H bonds

to obtain the corresponding ketones. Traditionally, benzylic

oxidation reactions require the introduction of metal catalysts

enable facile expansion and further commercialization of the

19−22

process.

Compared with tank reactors, continuous-ﬂow

synthesis in microchannels exhibits various advantages,

23,24

especially concerning safety and eﬃciency.

The enhanced

safety is a result of the eﬃcient heat-transfer performance and

low liquid-holding capacity. Speciﬁcally, the heat-transfer area

is focused and maximized on the ﬂat reaction module. This

reduces the risk of losing control because of the local

overheating that occurs when pure dioxygen interacts with a

ﬂammable solvent. In particular, ﬂow microreactors are

characterized by a high interfacial area and a unique internal

structure, which allow a state of continuous dispersion and

mixing, thus eliminating mass-transfer limitations in reactions

involving gas−liquid mixed ﬂow. The excellent gas−liquid

mass transfer and elevated reaction temperatures also impact

the reaction kinetics and signiﬁcantly reduce the reaction

−7

such as Co, Ru, Ni, Mn, and Cu.

An entirely metal-free

catalytic system must be established for the oxidation of

benzylic sp C−H bonds to avoid the problems involved in the

removal of residual toxic metals from the products. Such

impurities limit the applications of these systems for

pharmaceutical synthesis. Recently, Kang reported a N-

hydroxyphthalimide/tert-butyl nitrite (NHPI/TBN) system

that could generate benzyl radicals, thereby representing an

time.

eﬀective method for aromatic ketone synthesis.

Over the last several decades, these oxidative processes have

been modiﬁed by combining transition-metal catalysts or other

RESULTS AND DISCUSSION

■

The oxidation of 1,2,3,4-tetrahydronaphthalene (1a) to α-

tetralone (2a) using dioxygen as the oxidant was chosen as a

model reaction, and various potential solvents were optimized

at the very beginning, which involved the use of an extremely

additives with various oxidants, such as NaIO , 3-chloroper-

benzoic acid (m-CPBA), tert-butyl hydroperoxide (TBHP),

,10

and hydrogen peroxide.

For green and sustainable

chemistry, molecular oxygen is considered as an ideal oxidant.

Therefore, it has been used increasingly for common oxidative

1,12

processes.

By implementing O as an oxidant for the direct

Received: March 2, 2021

Published: June 25, 2021

oxidation of benzylic sp C−H bonds, such systems have

established a green method for obtaining ketones from

benzylic compounds.

3−18

Additionally, the long reaction

time, which can range from dozens of hours to several days,

leads to low eﬃciency. Therefore, it is highly desirable to

2021 American Chemical Society

Org. Process Res. Dev. 2021, 25, 1612−1618

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Scheme 1. Benzylic C−H Oxygenated Pharmaceutical Compounds

thin pipe diameter. Reactant mixtures cannot contain any

solids that may cause a blockage in the microreactor.

dihydronaphthalene-1,4-dione (3a) increased from 5.8 to

18.4%. On the other hand, high temperature meant large

energy consumption and poor reaction safety. The optimal

reaction temperature was determined to be 100 °C (80.4%

yield of 2a; Figure 1 (1)).

There is an approximately linear relationship between the

quantity of TBN in the system and the conversion of 1a

(Figure 1 (2)). However, the selectivity associated with

converting 1a to 2a decreased as a result of further oxidation.

When the amount of TBN reached 1.75 equiv, the designed

product was quickly oxidized into diketone byproduct 3a.

Therefore, a TBN loading of 1.5 equiv was selected to optimize

the reaction selectivity.

Especially, it is diﬃcult for the solid-containing system to

pump into the microreactor through the liquid-phase pump.

Acetonitrile (MeCN) alone is not an eﬀective solvent for

dissolving NHPI. Therefore, MeCN was mixed with several

polar solvents to create two-solvent systems that were more

appropriate for the target oxidation reaction. According to the

order of polarity, a group of solvents was screened, including

dichloromethane (CH Cl ), tetrahydrofuran (THF), ethanol

(

EtOH), acetone (DMK), acetic acid (CH COOH), and

water (H O). The performances of the mixed solvent systems

were evaluated with O as the oxidant (Table 1, entries 2, 4−

Similarly, the eﬀect of NHPI loading on the oxidation of

Table 1. Solvent System Screening

benzylic sp C−H bonds was investigated in the range of 0.5−

1.5 equiv with respect to the substrate. As shown in Figure 1

(

3), the yield of 2a increased from 69.1 to 80.4% when the

amount of NHPI increased from 0.5 to 0.75 equiv. As the

amount of NHPI continued to increase, the yield augmenta-

tion was less than 2%.

entry

2a yield (%)

In addition, when the amount of NHPI was reduced to 0.2

equiv in the batch reaction, the reaction yield could still reach

75.3% (Supporting Information Section 5 ). At the same time,

NHPI can be almost completely recycled without being

consumed. These results proved that NHPI played a role of the

catalyst in the reaction. In contrast, TBN will form nitroxide

substitutes with the substrate under anaerobic conditions

(Table S1 Entry 10). During the entire reaction process, TBN

will be oxidized to tert-butanol and nitrogen oxides, so it is

only the precursor of radical.

EtOH 10 mL

acetonitrile(MeCN) 10 mL, THF 1 mL

MeCN 10 mL, THF 1 mL

MeCN 10 mL, H O 1 mL

MeCN 10 mL, CH Cl 1 mL

MeCN 10 mL, CH COOH 1 mL

MeCN 5 mL, Acetone (DMK) 5 mL

MeCN 5 mL, DMK 5 mL

2,2′-azobis(2-methylpropionitrile)

tert-butyl hydroperoxide

42.5

35.1

trace

52.4

66.5

<10

75.1

trace

<10

trace

The resident time is another key factor that inﬂuences a

Unless otherwise noted, reactions were conducted with 1a (1.25

continuous reaction:

mmol), TBN (1.5 equiv), and NHPI (0.75 equiv) in MeCN (5.0 mL)

mixed with DMK (5.0 mL), which were heated at 160 °C under 10

Resident time (t ) = n ×

bar back pressure. Liquid ﬂow rate = 1.0 mL/min; O ﬂow rate = 20

v_l_i_q+ v_g_a_s

mL/min. Determined by H-NMR. Reaction was carried out with

N . Temperature was 120 °C.

T*×p

T × p*

× v_o₂

gas

), and the combination of MeCN and DMK exhibited the

greatest yield (75.1%), which was obtained within only 54 s

entry 7). Control experiments was carried out in the absence

Therefore,

(

Resident time = n × _v

of O (using MeCN and THF or MeCN and DMK solvent

T * ×p

T × p *

^×^vo2

mixtures; entries 3 and 8, respectively), which achieved a

negligible chemical yield and conﬁrmed that molecular oxygen

was the only oxygen source.

liq

Otherwise,

Obviously, the conversion of substrate 1a was positively

correlated with an increase in temperature. However, under

high temperature conditions, the yield of byproduct 2,3-

^vliq

total time (t ) =

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Figure 1. Screening experiment performed in an advanced ﬂow reactor.

V refers to the total volume of each reaction module, V = 2.7

mL. V* refers to the total volume of the reactants. n refers to

the number of reaction modules. v_l_i_qand v refer to the ﬂow

Scheme 2. Parallel Reactions for Mechanisms

rates of the reaction mixture and O , respectively. v = 1.0 mL/

liq

min. v_g_a_srefers to the ﬂow rate of the oxygen in the reactor

under pressure, and v = 20 mL/min. p is 1 atm (standard

state), p* is the reaction pressure, T is 298.15 K, and T* is the

reaction temperature.

Therefore, the gas−liquid ﬂow rate ratio signiﬁcantly

aﬀected the mass-transfer eﬃciency of the heterogeneous

reaction. To shorten the residence time and improve the yield,

the pumping speed of reactants was increased up to 2.0 mL/

min, while the oxygen ﬂow rate was 40 mL/min. However, this

condition actually made the gas−liquid mixing eﬀect less

favorable (Table 2, entries 4−7). Through the control

ethylene, to the standard reaction conditions, we found that

only a trace amount or even no desired product was detected.

In contrast, the equivalent amount of 1,4-diazabicyclo [2.2.2]-

octane (DABCO) did not aﬀect the reaction result. According

to the abovementioned results, this reaction should be a free

radical reaction pathway. Each free radical was captured in a

stable state in a high-resolution mass spectrometer, and a

possible reaction mechanism was proposed from this evidence

^T^a^b^l^e²^.^E^ﬀ^e^c^t^o^f^R^e^sⁱ^d^eⁿ^t^Tⁱ^m^e⁽^tR⁾

entry V_l(mL/min) V_g(mL/min)

t_R(s)

81.0

t_T(min) yield (%)

1.0

2.0

1.0

10.0

20.0

30.0

10.0

20.0

30.0

40.0

20.0

73.0

80.4

76.6

70.4

73.4

72.2

70.5

80.8

76.2

(

Figure 2).

54.0

40.5

54.0

40.5

32.4

27.0

Initially, a NO free radical (Figures S2 and S3) was formed

by thermal cracking of the ester bond of TBN. NO was

27−30

produced by the oxidation of NO with molecular oxygen.

31,32

Then, NHPI was activated by (CH ) O free radicals,

generating an intermediate N-oxyphthalimide radical (PINO).

Benzyl radicals from the substrate underwent hydrogen

abstraction to give a trace amount of compound 1,2-

dihydronaphthalene, which was observed by high-resolution

54.0 * 2

54.0 * 3

Unless otherwise noted, reactions were conducted with 1a (1.25

mmol), TBN (1.5 equiv), and NHPI (0.75 equiv) in MeCN (5.0 mL)

mass spectrometry (HRMS). With the participation of

molecular oxygen, peroxy free radicals were generated and

ﬁnally converted to product 2a. In this process, NHPI

underwent two hydrogen proton transfers to achieve self-

circulation. No water was detected during the entire reaction.

The reaction condition screening and the proposed radical

reaction mechanism both indicated that NHPI would not be

consumed in the reaction. NHPI was collected after further

experiments to verify whether it could be used in recycling

experiments (Table 3). The observed yield was expected to

drop slightly after each cycle; however, after 4 cycles, the yield

was still higher than 78%. This experiment conﬁrmed the role

of NHPI as a radical transport agent and further indicated that

this process has the potential to be scaled for commercial

recycling to eﬀectively reduce costs.

mixed with DMK (5.0 mL), which were heated at 100 °C under 10

bar back pressure. Determined by H-NMR. Added reaction

modules to achieve the purpose of extending the resident time.

experiments, the optimal ratio of the liquid−gas ﬂow rate

was 1:20 (entries 1−3). Additional reaction modules were

incorporated in the attempt to achieve higher yields. However,

the exponential increase in the residence time resulted in worse

selectivity and additional equipment costs (entries 8−9). As a

result, 1.0 mL/min was selected as the liquid ﬂow rate (V ),

and 20 mL/min was chosen as the oxygen ﬂow rate (V_g).

To gain more insights into the possible reaction mechanism,

we conducted a series of parallel reactions (Scheme 2). When

we tested the eﬀect of radical scavengers, including 2,2,6,6-

tetramethyl-1-piperdiny-l-oxy (TEMPO) and 1,1-diphenyl-

Additionally, the scalability of the reaction was conﬁrmed in

gram-scale and run for 28 h continuously. Product 2a was in

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Org. Process Res. Dev. 2021, 25, 1612−1618

mL), the liquid was divided into two bottles, and they were

Article

pumped into the reaction module (each bottle took 7 h to

complete the pumping, Table S2 entries 1−14). The reaction

solution for the ﬁrst 7 h was collected, and 360.6 g of solvent

was recovered by vacuum distillation. These recovered solvents

were used to reconﬁgure 0.125 M reaction solution (480 mL,

supplemented with 8.5 g of MeCN and 12.4 g of DMK, entries

5−21). The 8−14 h of reaction solution was collected, and

the same amount of 1a and TBN was added to conﬁgure a 0.25

M solution (with 1.8 g of MeCN and 2.5 g of DMK, entries

2−28). The byproduct 3a in this batch of reaction liquid

increased signiﬁcantly, resulting in a decrease in the total yield

of 2a.

Finally, the substrate scope was investigated under the

optimized conditions (Table 4). Ultimately, a wide range of

ketones that were prepared from the corresponding benzylic

compounds was selectively. 2,3-Dihydroindene, similar to 1a,

was selectively converted to 1-indanone (2b) in 75.1% yield.

When the benzylic position is substituted with another

benzene ring, the yield increases, as observed for benzophe-

none (2c) and 9-ﬂuorenone (2d). If the substituent is an

electron-donating group like alkane groups or methoxy (1e, 1f,

j, and 1i), the yield drops signiﬁcantly. In particular, the

selectivity of product 2j is higher than 99%, which proved that

this process selectively oxidizes the benzyl position. On the

other side, if the substituent is an electron-donating group

Figure 2. Proposed Mechanism.

(

1g), the product yield is slightly higher than that of the

Table 3. NHPI Recycling Experiments

electron-withdrawing group (1h). We also tried heterocyclic

substrates and obtained totally diﬀerent results (1k and 1l).

This process was also applied for drug synthesis, and it

demonstrated rapid oxidation to produce oxcarbazepine (2m)

in a yield of 35.7%.

cycle

remaining NHPI

addition

yield (%)

CONCLUSIONS

0.143 g (93.5%)

0.139 g (90.8%)

0.141 g (92.2%)

0.144 g (94.1%)

0.012 g

0.014 g

0.012 g

78.5

78.8

79.4

78.6

■

This study describes the selective aerobic oxidation of benzylic

sp C−H bonds to generate the corresponding ketones,

catalyzed by NHPI and TBN in a mixture solvent of MeCN

and DMK in a microreactor. The reaction time was only 54 s,

which was much lower than that of batch processes. NHPI was

proved to be capable of being recycled through the recycling

experiments. The yield of multiple cycles changed within 1%,

and the recovery rate of NHPI was also above 90%. The

recycling of NHPI also makes this process more eﬃcient,

environmentally friendly, and cost eﬀective, which is conducive

to its widespread applications. When the parameters are set,

the system runs continuously for 28 h without manual

operation. Not only the solvent could be recovered by vacuum

distillation but also the equivalent amount of the substrate and

TBN could be directly added to react again to obtain the

corresponding product. A series of valuable ketones were

obtained from benzylic methylene in yields of 41.2 to 90.3%.

This rapid oxidation in a microreactor has a broad potential for

commercialization, especially for the synthesis of pharmaceut-

icals and ﬁne chemicals, because the developed process is

widely applicable and signiﬁcantly reduces labor and energy

costs.

Unless otherwise noted, the reactions were conducted with 1a (1.25

mmol), TBN (1.5 equiv), and NHPI (0.75 equiv) in MeCN (5.0 mL)

mixed with DMK (5.0 mL), which were heated at 100 °C under 10

bar back pressure in the module. Liquid ﬂow rate = 1.0 mL/min; O

ﬂow rate = 20 mL/min. The weight of recycling NHPI, as

determined by H-NMR against internal standards. Determined by

H-NMR.

9.5% overall yield (by H-NMR), and the production rate was

−

.87 g h (Figure 3).

a (120 mmol) was conﬁgured into a 0.125 M solution (960

EXPERIMENTAL SECTION

■

Because of the limitations of the microreactor material, the

reaction conditions were not exactly the same as those of the

batch. The substrate (1.25 mmol), TBN (1.88 mmol), and

NHPI (0.937 mmol) were dissolved in 5 mL of MeCN and 5

mL of DMK. In the pump, the organic-phase ﬂow rate was 1.0

Figure 3. Scaled-up continuous-ﬂow benzyl carbonylation.

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Table 4. Rapid Oxidation of Benzylic sp C−H Bonds To

The residue was puriﬁed by column chromatography on silica

gel to aﬀord the product.

a b

Obtain the Corresponding Ketones

Preparation of α-Tetralone (2a). α-Tetralone (2a) was

prepared according to the general procedure and puriﬁed by

ﬂash column chromatography. Pale yellow liquid was obtained

(

0.139 g,76.2%). H NMR (400 MHz, chloroform-d) δ 8.03

d, J = 1.5 Hz, 1H), 7.45 (td, J = 7.5, 1.5 Hz, 2H), 7.26 (ddd, J

24.0, 7.6, 1.2 Hz, 4H), 2.94 (t, J = 6.1 Hz, 4H), 2.63 (dd, J =

.3, 5.8 Hz, 4H), 2.12 (p, J = 6.5 Hz, 4H). 13C NMR (126

MHz, CDCl3) δ 198.2, 144.5, 133.4, 132.6, 128.8, 127.1,

26.6, 77.4, 77.2, 76.9, 39.1, 29.7, 23.3.

Preparation of 1-Indanone (2b). 1-Indanone (2b) was

prepared according to the general procedure and puriﬁed by

ﬂash column chromatography. Pale yellow liquid was obtained

(

0.124 g,75.1%). H NMR (400 MHz, chloroform-d) δ 7.76

d, J = 7.6 Hz, 1H), 7.58 (td, J = 7.4, 1.3 Hz, 1H), 7.48 (dt, J =

.7, 0.9 Hz, 1H), 7.42−7.32 (m, 1H), 3.19−3.10 (m, 2H),

.75−2.64 (m, 2H). C NMR (101 MHz, CDCl3) δ 207.1,

55.2, 137.1, 134.6, 127.3, 126.7, 123.7, 77.4, 77.1, 76.7, 36.2,

5.8.

Preparation of Benzophenone (2c). The product (2c)

was prepared according to the general procedure and puriﬁed

by ﬂash column chromatography. Yellow solid (0.201

g,87.9%). H NMR (400 MHz, chloroform-d) δ 7.84−7.76

(

m, 4H),7.61−7.54 (m, 2H), 7.47 (dd, J = 8.4, 7.0 Hz, 4H).

C NMR (101 MHz, CDCl3) δ 196.8, 137.6, 130.1, 128.3,

7.4, 77.1, 76.8.

Preparation of 9-Fluorenone (2d). The product (2d)

was prepared according to the general procedure and puriﬁed

by ﬂash column chromatography. A yellow solid was obtained

(

0.204 g,90.7%). H NMR (400 MHz, chloroform-d) δ 7.64

dt, J = 7.3, 1.0 Hz, 2H), 7.52−7.42 (m, 4H), 7.30−7.24 (m,

H). C NMR (101 MHz, CDCl3) δ 193.9, 144.4, 134.7,

34.2, 129.1, 124.3, 120.3, 77.4, 77.0, 76.7.

Preparation of Acetophenone (2e). The product (2e)

was prepared according to the general procedure and puriﬁed

by ﬂash column chromatography. Pale yellow liquid was

obtained (0.088 g,58.6%). H NMR (400 MHz, chloroform-d)

δ 7.92−7.84 (m, 2H), 7.52−7.44 (m, 1H), 7.38 (dd, J = 8.2,

.8 Hz, 2H), 2.52 (s, 3H). C NMR (101 MHz, CDCl3) δ

98.1, 137.1, 133.1, 128.6, 128.3, 77.4, 77.1, 76.8, 26.6.

Preparation of Isobutyrophenone (2f). The product

(

2f) was prepared according to the general procedure and

puriﬁed by ﬂash column chromatography. Pale yellow liquid

was obtained (0.101 g,54.3%). H NMR (400 MHz,

chloroform-d) δ 8.00−7.91 (m, 2H), 7.59−7.51 (m, 1H),

.51−7.41 (m, 2H), 3.56 (hept, J = 6.9 Hz, 1H), 1.22 (d, J =

.8 Hz, 6H). C NMR (101 MHz, CDCl3) δ 204.5, 136.2,

32.8, 128.6, 128.3, 77.4, 77.0, 76.7, 35.4, 19.2.

Preparation of 4-Methoxyacetophenone (2g). The

product (2g) was prepared according to the general procedure

with 1 g of 2.5 mmol and puriﬁed by ﬂash column

chromatography. A yellow solid was obtained (0.268

g,71.4%). H NMR (400 MHz, chloroform-d) δ 8.03−7.84

Isolated yields are shown. Determined by H-NMR with nitro-

(

m, 2H), 6.97−6.87 (m, 2H), 3.94−3.78 (m, 3H), 2.62−2.49

methane as an internal standard.

(

m, 3H). C NMR (101 MHz, CDCl3) δ 196.8, 163.5, 130.6,

13.7, 77.4, 77.1, 76.8, 55.5, 26.3.

Preparation of p-Bromoacetophenones (2h). The

mL/min. The O ﬂow rate was 20 mL/min. The reaction

pressure was 10 bar. The reaction was carried out at 100 °C.

After the completion of the reaction, the mixture was diluted

with EtOAc (50 mL), washed with water (3 × 20 mL), dried

over anhydrous Na SO , ﬁltered, and concentrated in vacuo.

product (2h) was prepared according to the general procedure

and puriﬁed by ﬂash column chromatography. Yellow liquid

was obtained (0.17 g, 68.6%). H NMR (400 MHz,

chloroform-d) δ 7.82 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6

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Complete contact information is available at:

Article

Hz, 2H), 2.59 (s, 3H). C NMR (101 MHz, CDCl3) δ 197.0,

Engineering, Dalian University of Technology, Dalian

116024, P.R. China

35.8, 131.9, 129.8, 128.3, 77.3, 77.0, 76.7, 26.5.

Preparation of Methyl Benzoate (2i). The product (2i)

Xiaofei Tang − Xi’an Modern Chemistry Research Institute,

was prepared according to the general procedure and puriﬁed

by ﬂash column chromatography. Pale yellow liquid was

Xi’an, Shanxi 710065, P.R. China

Cunfei Ma − State Key Laboratory of Fine Chemicals,

Department of Pharmaceutical Sciences, School of Chemical

Engineering, Dalian University of Technology, Dalian

116024, P.R. China

Zongyi Yu − State Key Laboratory of Fine Chemicals,

Department of Pharmaceutical Sciences, School of Chemical

Engineering, Dalian University of Technology, Dalian

116024, P.R. China

obtained (0.07 g, 41.2%). H NMR (400 MHz, chloroform-d)

δ 8.08−8.00 (m, 2H), 7.58−7.50 (m, 1H), 7.46−7.38 (m, 2H),

.90 (s, 3H). C NMR (101 MHz, CDCl3) δ 167.1, 132.9,

30.2, 129.6, 128.3, 77.4, 77.1, 76.8, 52.0.

Preparation of Propiophenone (2j). The product (2j)

was prepared according to the general procedure and puriﬁed

by ﬂash column chromatography. Colorless liquid was

obtained (0.40 g, 60.6%). H NMR (400 MHz, chloroform-

https://pubs.acs.org/10.1021/acs.oprd.1c00080

d) δ 8.03−7.89 (m, 2H), 7.58−7.51 (m, 1H), 7.48−7.42 (m,

H), 2.96 (t, 2H), 1.80−1.68 (m, 2H), 1.36 (m, J = 3.9 Hz,

H), 0.98−0.84 (m, 3H).13C NMR (101 MHz, CDCl3) δ

00.6, 137.1, 132.9, 128.5, 128.1, 77.3, 77.0, 76.7, 38.6, 31.6,

4.1, 22.5, 14.0.

Author Contributions

The manuscript was written through contributions of all

authors. All authors have given approval to the ﬁnal version of

the manuscript.

Preparation of 1-(Thiophen-2-yl)Butan-1-One (2l).

The product (2L) was prepared according to the general

procedure and puriﬁed by ﬂash column chromatography. Pale

Notes

yellow liquid was obtained (0.13 g, 74.3%). H NMR (400

The authors declare no competing ﬁnancial interest.

MHz, chloroform-d) δ 7.71 (dd, J = 3.8, 1.1 Hz, 1H), 7.62 (dd,

J = 4.9, 1.1 Hz, 1H), 7.12 (dd, J = 5.0, 3.8 Hz, 1H), 2.88 (t, J =

ACKNOWLEDGMENTS

■

.3 Hz, 2H), 1.79 (q, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).

C NMR (101 MHz, CDCl3) δ 193.4, 144.6, 133.3, 131.6,

28.0, 77.3, 77.2, 77.0, 76.7, 41.3, 18.2, 13.9.

We are grateful for the ﬁnancial support from the National

Natural Science Foundation of China (U20A20143 and

1633006), Major Projects of Key Disciplines in Dalian

2019J11CY006), and the State Key Laboratory of Fine

(

Preparation of Oxcarbazepine (2m). The product (2M)

was prepared according to the general procedure and puriﬁed

by ﬂash column chromatography. A pale yellow solid was

Chemicals for their support.

obtained (0.11 g, 35.7%). H NMR (400 MHz, chloroform-d)

δ 8.10 (dd, J = 8.0, 1.7 Hz, 1H), 7.61−7.30 (m, 7H), 5.00 (s,

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