Reaction of Aldoximes with Sodium Chloride and Oxone under Ball-Milling Conditions

molecules

Article

Reaction of Aldoximes with Sodium Chloride and

Oxone under Ball-Milling Conditions

Kuan Chen ¹, Chuang Niu ¹and Guan-Wu Wang ^1,2,

*

1

Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry,

University of Science and Technology of China, Hefei 230026, Anhui, China; kuanc@mail.ustc.edu.cn (K.C.);

cniu@mail.ustc.edu.cn (C.N.)

State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Gansu, China

Correspondence: gwang@ustc.edu.cn; Tel.: +86-551-6360-7864

2

*

ꢀꢁꢂꢀꢃꢄꢅꢆꢇ

Academic Editor: Vjekoslav Štrukil

Received: 17 July 2020; Accepted: 11 August 2020; Published: 14 August 2020

ꢀꢁꢂꢃꢄꢅꢆ

Abstract: The solvent-free mechanochemical reaction has aroused increasing interest among scientists.

Mechanical ball-milling can implement reactions under mild conditions, shorten the reaction time,

and improve the reaction eﬃciency. Particularly, the most attractive characteristic of mechanochemistry

is that it can alter the reaction pathway. However, few such examples have been reported so far.

In this paper, we report the reaction of aldoximes with NaCl and Oxone under ball-milling conditions

to aﬀord N-acyloxyimidoyl chlorides, which are diﬀerent from those of the liquid-phase counterpart.

Keywords: mechanochemistry; aldoximes; sodium chloride; Oxone; N-acyloxyimidoyl chlorides

1. Introduction

Since the rise of modern chemistry in the 17th century, traditional solution-based methods have

dominated in most synthetic research laboratories and industries. Nevertheless, liquid-phase reactions

are characterized by using bulk toxic organic solvents and harsh reaction conditions. With the need for

cleaner, safer, and more sustainable chemical transformations, the use of mechanochemistry, which is

identiﬁed by IUPAC as one of the 10 world-changing technologies [1] in chemical synthesis, has boomed

over the past few decades and is rapidly becoming a powerful tool for environmentally friendly and

sustainable synthesis of molecules and materials, including coordination, supramolecular, and covalent

structures [2–14].

The mechanical ball-milling technique, an eco-friendly mechanochemical protocol, can not

only promote solvent-free reactions and increase the reaction eﬃciency [6–12], even more attractively,

but also alter chemical reactivity and selectivity compared to the solution-based counterparts, leading to

diﬀerent products, which draws forth the tantalizing hypothesis that some molecules can only be

obtained by mechanochemistry [13,14]. For instance, Wang et al. reported the reaction of [60]fullerene

(C₆₀) and KCN under high-speed vibration ball milling (HSVM) for 30 min to unexpectedly aﬀord

fullerene dimer C₁₂₀even after quenching with triﬂuoroacetic acid (TFA) [15], while the same reaction

in a mixture of 1,2-dichlorobenzene (ODCB) and N,N-dimethylformamidal (DMF) reported earlier by

Wudl and coworkers aﬀorded a diﬀerent fullerene product, C₆₀H(CN) [16]. Another example was the

mechanochemical reaction of C₆₀and N-benzhydryl sulfonamides in the presence of FeCl₃to give

fulleroindanes, which could not be obtained in ODCB or 1,1,2,2-tetrachloroethane (TCE) solution at

120 ^◦C [17]. A more recent example reported by Bolm, Hern

ández, and coworkers was the reaction of

aldehydes with amines and CaC₂under ball-milling conditions to give 1,4-diamino-2-butynes [18].

In contrast, terminal propargylamines were the major products by heating the same reaction

mixtures in undried acetonitrile [19]. The use of CaC₂, a solid replacement of hazardous and

diﬃcult-to-handle acetylene gas, in organic synthesis has been widely reported [20–24]. Nevertheless,

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its application is still limited because of its very poor solubility in organic solvents. Moreover, an Oxone

(2KHSO₅KHSO₄K₂SO₄)-NaCl-Na₂CO₃system could react with aldoximes to aﬀord nitrile oxides [25].

·

In this context, we attempted the reaction of CaC₂with (E)-4-methylbenzaldehyde oxime (1a), NaCl,

Oxone, and Na₂CO₃in order to obtain 3,4-di-p-tolyl-3a,6a-dihydroisoxazolo[4,5-d]isoxazole via double

[2 + 3] cycloadditions between the in situ generated acetylene and 1,3-dipolar nitrile oxide under

ball-milling conditions. Unexpectedly, (Z)-4-methyl-N-((4-methylbenzoyl)oxy)benzimidoyl chloride

(2a) was obtained as the major product with no participation of CaC₂(Scheme 1). To further investigate

this unexpected reaction pathway, we conducted the present work.

Scheme 1. The unexpected product 2a obtained from 1a without participation of CaC₂.

2. Results

At the outset of our study, 1a was selected as the representative substrate to screen the optimal

reaction conditions. When a mixture of 1a (0.2 mmol), NaCl (2 equiv.), CaC₂(1 equiv.), Oxone (2 equiv.),

and Na₂CO₃(2 equiv.) along with four stainless steel balls (5 mm in diameter) were introduced

into a stainless steel jar (5 mL) and milled vigorously at a frequency of 30 Hz in a Retsch MM400

mixer mill (Retsch GmbH, Haan, Germany) at room temperature for 30 min, an unexpected product

2a was isolated in 23% yield (Table 1, entry 1). The structure of product 2a was unambiguously

established by single-crystal X-ray diﬀraction analysis (see the Supplementary Materials for details).

Because CaC₂did not take part in the formation of 2a, the same reaction was repeated without

CaC₂. Similar results, that is, 24% yield for 2a, were obtained (entry 2). Encouraged by this initial

result, the employed oxidant and base, molar ratio of the reactants, reaction time, as well as the

liquid-assisted grinding (LAG) agent [26], were screened to attain the optimal conditions, and the

results are shown in Table 1. At ﬁrst, we tried to replace Oxone with K₂S₂O₈, Na₂S₂O₈, (NH₄)₂S₂O₈,

1,4-benzoquinone quinone (BQ), and PhI(OAc)₂, but all of these reactions failed and indicated that

Oxone was the best oxidant (entries 3–7). Then, the replacement of Na₂CO₃with other diﬀerent bases,

including NaHCO₃, NaOAc, NaO^tBu, KO^tBu, Cs₂CO₃, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),

4-dimethylaminopyridine (DMAP), and 1,4-diazabicyclo[2.2.2]octane (DABCO), gave inferior results

(entries 8–15). Subsequently, the amounts of the reactants were varied. The yield of 2a was only 7% if 1

equiv. of Oxone was used (entry 16), while a better yield of 41% was obtained by using 3 equiv. of

Oxone (entry 17). To our delight, the yield of 2a was increased to 57% when the amount of Oxone was

further increased to 4 equiv. (entry 18). Further screening the amounts of Na₂CO₃and NaCl revealed

that the best molar ratio of 1a, NaCl, Oxone, and Na₂CO₃was still 1:2:4:2 (entries 19–23 vs. entry 18).

Based on these results, the eﬀect of the reaction time on the product yield was investigated. However,

the yield by either shortening to 20 min or prolonging to 40 min was not improved (entries 24 and 25

vs. entry 18). The LAG protocol has been known as a powerful tool to promote mechanochemical

reaction [

were added to the reaction mixture as LAG agents. Unfortunately, the yield of 2a could not be improved

(entries 26–28). Therefore, the optimal reaction conditions were determined as follows: 0.2 mmol of 1a

1,13,14,26]. Therefore, several liquids including dichloromethane (DCM), EtOH, and H₂O

,

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2 equiv. of NaCl, 4 equiv. of Oxone, and 2 equiv. of Na₂CO₃at 30 Hz for 30 min under solvent-free

ball-milling conditions (entry 18).

Table 1. Optimization of the reaction conditions ^a.

Yield of 2a (%) ^b

Entry

NaCl (equiv.)

Oxidant (equiv.)

Base (equiv.)

1

2

3

4

5

6

7

8

9

2.0

1.0

3.0

2.0

Oxone (2.0)

K₂S₂O₈(2.0)

Na₂S₂O₈(2.0)

(NH₄)₂S₂O₈(2.0)

BQ (2.0)

Na₂CO₃(2.0)

NaHCO₃(2.0)

NaOAc (2.0)

NaO^tBu (2.0)

KO^tBu (2.0)

23 ^c

24

trace

0

trace

10

6

12

14

9

0

7

41

57

46

35

PhI(OAc)₂(2.0)

Oxone (2.0)

Oxone (1.0)

Oxone (3.0)

Oxone (4.0)

Oxone (5.0)

Oxone (4.0)

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24 ^d

25 ^e

26 ^f,g

27 ^f,h

28 ^f,i

Cs₂CO₃(2.0)

DBU (2.0)

DMAP (2.0)

DABCO (2.0)

Na₂CO₃(2.0)

Na₂CO₃(1.0)

Na₂CO₃(3.0)

Na₂CO₃(2.0)

29

39

43

48

37

40

trace

45

^aUnless otherwise noted, the reactions were carried out in a Retsch MM400 mixer mill with 0.2 mmol of 1a

.

^bIsolated

c

d

e

f

yields based on 1a

.

CaC₂(1 equiv.) was added. 20 min. 40 min. A liquid (100 µL, η = 0.17 µL/mg) was added

g

h

i

as a LAG agent. DCM was added. EtOH was added. H₂O was added.

With the optimized reaction conditions in hand, the substrate scope and functional group

tolerance of this reaction were then investigated with a range of aldoximes 1a (Scheme 2). In general,

benzaldehyde oximes 1a with both electron-donating and electron-withdrawing groups on the

–

o

–

o

phenyl ring were tolerated under our reaction conditions, aﬀording the corresponding products 2a–o

in moderate to good yields.

Firstly, the substrate 1b with no substituent was examined and aﬀorded 2b in 44% yield.

The para-halogen-substituted (E)-benzaldehyde oximes 1c also worked and aﬀorded the desired

products 2c in 35–48% yields. For the substrate 1f with the para-substituted CF₃group,

the corresponding product 2f could be isolated in 37% yield. As for the meta-substituted substrates

1g bearing Me, Br, and F, the desired products 2g were synthesized in 26–43% yields. Substrates

1j with the ortho-substituted Me, Br, and Cl groups were also compatible, resulting in products 2j

–

e

–

e

–i

–l

in 40–46% yields. Delightedly, the disubstituted substrates 1m and 1n performed well, furnishing

products 2m and 2n in 81% and 65% yields, respectively. The trisubstituted substrate 1o also underwent

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well to generate the desired product 2o in a good yield of 75%. Taking the multistep processes from

the aldoximes to N-acyloxyimidoyl chlorides (vide infra) into account, the yields of ~40–60% in most

cases were satisfactory.

a

Scheme 2. The reaction of aldoximes with NaCl and Oxone under ball-milling conditions ^a,b

.

Unless

otherwise noted, the reactions were performed with

1 (0.2 mmol), NaCl (0.4 mmol), Oxone (0.8 mmol),

and Na₂CO₃(0.4 mmol) together with four stainless steel balls (5 mm in diameter) in a stainless steel

c

d

jar (5 mL). ^bIsolated yields based on

1.

NaCl (0.6 mmol), Na₂CO₃(0.2 mmol). Na₂CO₃(0.8 mmol).

It was believed that hydroximoyl chloride

3 might be the key intermediate of this reaction.

To prove our assumption, control experiments were performed. The reaction of (Z)-N-hydroxy-

4-methylbenzimidoyl chloride (3a) (0.2 mmol) with Na₂CO₃(1 equiv.) and Oxone (2 equiv.) under

solvent-free ball-milling conditions indeed aﬀorded 2a in 78% yield (Scheme 3). However, 2a could not

be formed from 3a in the presence of just Na₂CO₃under the same ball-milling conditions, indicating that

Oxone was essential for the mechanochemical transformation of 3a to 2a.

Scheme 3. The reaction of 3a with Oxone and Na₂CO₃under ball-milling conditions.

Although the exact reaction mechanism towards the formation of

2 is not clear, a proposed

reaction pathway is shown in Scheme 4 based on the aforementioned experiments and previous

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literature [25

Next, undergoes chlorination reaction with

II or III 25]. The key precursor is then dimerized to IV in the presence of Na₂CO₃. Subsequently,

,

27,

28]. First, NaCl is oxidized to the chlorinating species

I

in the presence of Oxone [25].

I

1 to generate the hydroximoyl chloride 3 via intermediate

[

3

the deoximation of IV by Oxone [27] and/or a combination of excess Oxone and NaCl via the

gem-chloronitro intermediate V and following hydrolysis [28] provides the ﬁnal product 2.

Scheme 4. A plausible reaction pathway.

3. Discussion

The formation of 2b as a byproduct in 12% yield upon distillation of the chlorination product of

benzaldoxime in methylene chloride was previously reported by Chiang [29]. Subsequentl_◦y, the same

author disclosed that the thermolysis of N-hydroxybenzimidoyl chloride (3b) at 180 C (8 mm)

aﬀorded 70% of phenyl isocyanate and 21% of 2b

yield along with 4-chlorobenzonitrile from the pyrolysis of 4-chloro-N-hydroxybenzimidoyl chloride

3c) [30]. These product yields are lower than those from aldoximes (see Scheme 2) and should be

[30]. Similarly, product 2c was also isolated in 10%

(

much lower than those from the same hydroximoyl chlorides under our mechanochemical conditions

(see Scheme 3).

The oxidation reactions of aldoximes have been widely investigated in organic synthesis,

among which the most typical one is to be oxidized to 1,3-dipolar nitrile oxide, which undergoes

cyclization reaction with alkenes or alkynes to form isoxazolines [25]. When it comes to the

α

-chlorination of aldoximes, N-chlorosuccinimide (NCS) [31] is the most common chlorinating agent,

chlorine (Cl₂) [29 30] is also used, yet it is hard to handle. Compared to the other reagents utilized

for the -chlorination of aldoximes, including benzyltrimethylammonium tetrachloroiodate (BTMA

,

α

ICl₄) [32] and t-butyl hypochlorite (t-BuOCl) [33], NaCl-Oxone is more convenient, cheaper and easier

to handle. In the present work, when aldoximes were treated with NaCl, Oxone, and Na₂CO₃under our

solvent-free ball-milling conditions, N-acyloxyimidoyl chlorides were obtained unexpectedly. However,

when NaCl was replaced with NCS, NaBr, or NaI, neither the corresponding N-acyloxyimidoyl halides,

nor hydroximoyl halides could be isolated except for some yet-unidentiﬁed products.

For comparison purpose, the present reaction was also carried out under liquid-phase conditions.

By using the reaction of 1a with NaCl, Oxone, and Na₂CO₃as an example, a number of solvents and

diﬀerent reaction temperature were examined, hydroximoyl chloride 3a instead of 2a was obtained

in all cases. Our best result is shown in Scheme 5 . When a mixture of 1a (0.2 mmol), NaCl (2 equiv.),

Oxone (4 equiv.), and Na₂CO₃(2 equiv.) was stirred in N,N-dimethylformamide (DMF) at room

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temperature for 1 h, 3a was obtained in 94% yield. It is obvious that diﬀerent products, 2a and 3a

,

are formed under solvent-free mechanochemical conditions and liquid-phase conditions. The most

likely reason is that the possibility for the close contact of two neighboring molecules of 3a to

dimerize under solvent-free conditions is much higher than that under liquid-phase conditions [15].

This result provided another example to showcase the uniqueness of altering the reaction pathway

by the mechanochemical protocol [15,17,18]. It should be noted that the expected product shown in

Scheme 1 still could not be obtained from the reaction of 1a with CaC₂, NaCl, Oxone, and Na₂CO₃;

compound 3a was obtained in essentially the same yield as that without CaC₂after stirring for 1 h

(Scheme 1), while a similar complex mixture with no obvious predominant product was observed for

the reaction with or without CaC₂after 24 h. These results indicated that CaC₂did not participate

in the present liquid-phase reaction, and a longer reaction time could not aﬀord 2a, 3a, or any other

meaningful product.

Scheme 5. The reaction of 1a with NaCl, Oxone, and Na₂CO₃in DMF.

4. Experimental Section

4.1. General Information

All reagents were obtained from commercial sources and used without further puriﬁcation.

NMR spectra were recorded on a Bruker Advance III HD 400 NMR spectrometer (Bruker BioSpin

AG, Fällanden, Switzerland; 400 MHz for ¹H NMR; 101 MHz for ¹³C NMR; 376 MHz for ¹⁹F NMR)

and a Bruker Advance III HD 500 NMR spectrometer (Bruker BioSpin AG, Fällanden, Switzerland;

500 MHz for ¹H NMR; 126 MHz for ¹³C NMR; 471 MHz for ¹⁹F NMR). ¹H NMR chemical shifts were

determined relative to CDCl₃at

δ

7.26 ppm. ¹³C NMR chemical shifts were determined relative to

, ppm), multiplicity (s = singlet,

CDCl₃at 77.16 ppm. Data are reported as follows: chemical shift (

δ

d = doublet, t = triplet, m = multiplet, q = quartet). High-resolution mass spectra (HRMS) were

taken on a Waters Acquity UPLC-Xevo G2 QTof mass spectrometer (Waters, Milford, MA, USA)

with FTMS-ESI in positive mode. Ball-milling reactions were performed in a MM400 mixer mill

(Retsch GmbH, Haan, Germany), using a 5 mL stainless steel jar with four 5 mm diameter stainless

steel balls and were milled vigorously at a frequency of 1800 rounds per minute (30 Hz) at room

temperature. Aldoximes

1 were prepared according to the reported protocol [25]. Single crystals of 2a

were grown from dichloromethane/n-hexane at 4 ^◦C.

4.2. Synthesis and Characterization of Products 2

A mixture of

1 (0.2 mmol, 1.0 equiv.), NaCl (0.4 mmol, 2 equiv.), Oxone (0.8 mmol, 4.0 equiv.),

and Na₂CO₃(0.4 mmol, 2.0 equiv.) together with four stainless balls (5 mm in diameter) were

introduced into a stainless steel jar (5 mL). The reaction vessel and another identical vessel were closed

and ﬁxed on the vibration arms of a Retsch MM400 mixer mill, and were vibrated vigorously at a rate

of 1800 rounds per minute (30 Hz) at room temperature for 30 min. After completion of the reaction,

the resulting mixtures from the two runs were combined and extracted with dichloromethane and water.

The organic layer was decanted, and the aqueous layer was extracted by dichloromethane (2 × 20 mL).

The combined organic extracts were evaporated to remove the solvent in vacuo. The residue was

separated by ﬂash column chromatography on silica gel with ethyl acetate/petroleum ether as the

eluent to aﬀord 2.

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(Z)-4-Methyl-N-((4-methylbenzoyl)oxy)benzimidoyl chloride (2a). By following the general procedure,

the reaction of 1a (55.6 mg, 0.4 mmol) with NaCl (48.0 mg, 0.8 mmol), Oxone (987.3 mg, 1.6 mmol),

and Na₂CO₃(85.5 mg, 0.8 mmol) aﬀorded 2a (32.7 mg, 57% yield). White solid; ¹H NMR (400 MHz,

CDCl₃) δ 8.08 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H),

2.43 (s, 3H), 2.40 (s, 3H); ¹³C NMR (101 MHz, CDCl₃)

δ 162.9, 147.9, 144.8, 142.8, 130.2 (2C), 129.5 (2C),

129.4 (2C), 128.7, 128.3 (2C), 125.3, 21.9, 21.6; HRMS (FTMS-ESI) Calcd for C₁₆H₁₄³⁵ClNO₂Na [M +

Na]⁺310.0605; found 310.0613.

(Z)-N-(Benzoyloxy)benzimidoyl chloride (2b). By following the general procedure, the reaction of 1b

(44

0.8 mmol) aﬀorded 2b (22.8 mg, 44% yield). White solid; ¹H NMR (400 MHz, CDCl₃)

7.5 Hz, 2H), 8.06 (d, J = 7.5 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.57–7.43 (m, 5H); ¹³C NMR (101 MHz,

µL, 0.4 mmol) with NaCl (48.5 mg, 0.8 mmol), Oxone (993.5 mg, 1.6 mmol) and Na₂CO₃(86.8 mg,

δ

8.21 (d, J =

CDCl₃) δ 162.8, 148.1, 134.0, 132.3, 131.5, 130.2 (2C), 128.82 (2C), 128.76 (2C), 128.4 (2C), 128.1; HRMS

(FTMS-ESI) Calcd for C₁₄H₁₀³⁵ClNO₂Na [M + Na]⁺282.0292; found 282.0299.

(Z)-4-Chloro-N-((4-chlorobenzoyl)oxy)benzimidoyl chloride (2c). By following the general procedure,

the reaction of 1c (62.8 mg, 0.4 mmol) with NaCl (47.2 mg, 0.8 mmol), Oxone (983.6 mg, 1.6 mmol)

and Na₂CO₃(85.4 mg, 0.8 mmol) aﬀorded 2c (22.9 mg, 35% yield). White solid; ¹H NMR (500 MHz,

CDCl₃) δ 8.12 (d, J = 8.6 Hz, 2H), 7.98 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.7 Hz,

2H); ¹³C NMR (126 MHz, CDCl₃)

δ 161.8, 147.3, 140.7, 138.8, 131.5 (2C), 129.8, 129.6 (2C), 129.3 (2C),

129.1 (2C), 126.3; HRMS (FTMS-ESI) Calcd for C₁₄H₉³⁵Cl₃NO₂[M + H]⁺327.9693; found 327.9685.

(Z)-4-Bromo-N-((4-bromobenzoyl)oxy)benzimidoyl chloride (2d). By following the general procedure,

the reaction of 1d (80.7 mg, 0.4 mmol) with NaCl (48.0 mg, 0.8 mmol), Oxone (984.9 mg, 1.6 mmol)

and Na₂CO₃(86.3 mg, 0.8 mmol) aﬀorded 2d (37.2 mg, 45% yield). White solid; ¹H NMR (500 MHz,

CDCl₃)

δ 8.04 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H);

¹³C NMR (126 MHz, CDCl₃)

δ

162.0, 147.5, 132.3 (2C), 132.1 (2C), 131.6 (2C), 130.3, 129.8 (2C), 129.5,

127.3, 126.8; HRMS (FTMS-ESI) Calcd for C₁₄H₉⁷⁹Br₂³⁵ClNO₂[M + H]⁺415.8683; found 415.8683.

(Z)-4-Fluoro-N-((4-ﬂuorobenzoyl)oxy)benzimidoyl chloride (2e). By following the general procedure,

the reaction of 1e (57.2 mg, 0.4 mmol) with NaCl (47.3 mg, 0.8 mmol), Oxone (985.0 mg, 1.6 mmol) and

Na₂CO₃(86.3 mg, 0.8 mmol) aﬀorded 2e (28.6 mg, 48% yield). White solid; ¹H NMR (400 MHz, CDCl₃)

δ

8.21 (dd, J = 8.9, 5.4 Hz, 2H), 8.06 (dd, J = 9.0, 5.2 Hz, 2H), 7.24–7.12 (m, 4H); ¹³C NMR (101 MHz,

CDCl₃)

δ 166.4 (d, J_C-F= 255.9 Hz), 165.31 (d, J_C-F= 254.2 Hz), 161.8, 147.2, 132.8 (d, J_C-F= 9.5 Hz, 2C),

130.7 (d, J_C-F= 9.0 Hz, 2C), 127.5 (d, J_C-F= 3.3 Hz), 124.2 (d, J_C-F= 3.0 Hz), 116.2 (d, J_C-F= 22.2 Hz,

2C), 116.1 (d, J_C-F= 22.2 Hz, 2C); ¹⁹F NMR (376 MHz, CDCl₃)

δ –103.35 to –103.43 (m, 1F), –106.51 to

–106.59 (m, 1F); HRMS (FTMS-ESI) Calcd for C₁₄H₉³⁵ClF₂NO₂[M + H]⁺296.0284; found 296.0289.

(Z)-4-(Triﬂuoromethyl)-N-((4-(triﬂuoromethyl)benzoyl)oxy)benzimidoyl chloride (2f). By following the

general procedure, the reaction of 1f (76.3 mg, 0.4 mmol) with NaCl (48.8 mg, 0.8 mmol), Oxone (987.0 mg,

1.6 mmol) and Na₂CO₃(85.3 mg, 0.8 mmol) aﬀorded 2f (29.5 mg, 37% yield). White solid; ¹H NMR

(500 MHz, CDCl₃)

7.75 (d, J = 8.2 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃)

(q, J_C-F= 32.9 Hz), 131.1, 130.7 (2C), 128.9 (2C), 126.0 (q, J_C-F= 3.8 Hz, 2C), 125.9 (q, J_C-F= 3.7 Hz, 2C),

δ

8.32 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H),

δ

161.4, 147.5, 135.6 (q, J_C-F= 32.9 Hz), 134.6, 134.1

123.5 (q, J_C-F= 272.6 Hz), 123.4 (q, J_C-F= 272.9 Hz); ¹⁹F NMR (471 MHz, CDCl₃)

δ –63.09 (s, 3F), –63.26

(s, 3F); HRMS (FTMS-ESI) Calcd for C₁₆H₈³⁵ClF₆NO₂Na [M + Na]⁺418.0040; found 418.0060.

(Z)-3-Methyl-N-((3-methylbenzoyl)oxy)benzimidoyl chloride (2g). By following the general procedure,

the reaction of 1g (55.5 mg, 0.4 mmol) with NaCl (71.1 mg, 1.2 mmol), Oxone (985.7 mg, 1.6 mmol)

and Na₂CO₃(43.2 mg, 0.4 mmol) aﬀorded 2g (24.7 mg, 43% yield). White solid; ¹H NMR (500 MHz,

CDCl₃) δ 8.03–7.99 (m, 2H), 7.88 (s, 1H), 7.85–7.81 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.9 Hz,

1H), 7.37–7.33 (m, 2H); ¹³C NMR (126 MHz, CDCl₃)

δ 163.1, 148.3, 138.7, 138.6, 134.8, 133.1, 131.4, 130.7,

128.8, 128.71, 128.65, 128.0, 127.3, 125.8, 21.5, 21.4; HRMS (FTMS-ESI) Calcd for C₁₆H₁₅³⁵ClNO₂[M +

H]⁺288.0786; found 288.0787.

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(Z)-3-Bromo-N-((3-bromobenzoyl)oxy)benzimidoyl chloride (2h). By following the general procedure,

the reaction of 1h (88.4 mg, 0.4 mmol) with NaCl (48.6 mg, 0.8 mmol), Oxone (987.0 mg, 1.6 mmol)

and Na₂CO₃(85.8 mg, 0.4 mmol) aﬀorded 2h (22.0 mg, 26% yield). White solid; ¹H NMR (400 MHz,

CDCl₃)

δ 8.31 (s, 1H), 8.19 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.9 Hz,

1H), 7.68 (d, J = 7.9 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃)

δ

161.4, 147.2, 137.1, 135.4, 133.2, 133.1, 131.2, 130.5, 130.3, 129.8, 128.8, 127.1, 122.97, 122.95; HRMS

(FTMS-ESI) Calcd for C₁₄H₈⁷⁹Br₂³⁵ClNO₂Na [M + Na]⁺437.8503; found 437.8503.

(Z)-3-Fluoro-N-((3-ﬂuorobenzoyl)oxy)benzimidoyl chloride (2i). By following the general procedure,

the reaction of 1i (59.3 mg, 0.4 mmol) with NaCl (47.3 mg, 0.8 mmol), Oxone (986.0 mg, 1.6 mmol)

and Na₂CO₃(85.8 mg, 0.8 mmol) aﬀorded 2i (23.6 mg, 40% yield). White solid; ¹H NMR (400 MHz,

CDCl₃)

1H), 7.46 (td, J = 8.1, 5.8 Hz, 1H), 7.36 (td, J = 8.2, 2.2 Hz, 1H), 7.29–7.22 (m, 1H); ¹³C NMR (101 MHz,

CDCl₃) 162.74 (d, J_C-F= 248.1 Hz), 162.71 (d, J_C-F= 247.6 Hz), 161.6 (d, J_C-F= 3.2 Hz), 147.3 (d, J_C-F

δ 8.00 (d, J = 7.8 Hz, 1H), 7.90–7.84 (m, 2H), 7.77 (dt, J = 9.5, 1.9 Hz, 1H), 7.52 (td, J = 8.0, 5.6 Hz,

δ

= 3.3 Hz), 133.4 (d, J_C-F= 8.4 Hz), 130.6 (d, J_C-F= 7.8 Hz), 130.5 (d, J_C-F= 8.1 Hz), 130.0 (d, J_C-F= 7.5

Hz), 126.0 (d, J_C-F= 3.2 Hz), 124.2 (d, J_C-F= 3.1 Hz), 121.3 (d, J_C-F= 21.3 Hz), 119.5 (d, J_C-F= 21.2 Hz),

117.1 (d, J_C-F= 23.5 Hz), 115.6 (d, J_C-F= 24.7 Hz); ¹⁹F NMR (376 MHz, CDCl₃)

δ –111.26 to –111.35

(m, 1F), –111.56 to –111.65 (m, 1F); HRMS (FTMS-ESI) Calcd for C₁₄H₉³⁵ClF₂NO₂[M + H]⁺296.0284;

found 296.0291.

(Z)-2-Methyl-N-((2-methylbenzoyl)oxy)benzimidoyl chloride (2j). By following the general procedure,

the reaction of 1j (59.1 mg, 0.4 mmol) with NaCl (48.3 mg, 0.8 mmol), Oxone (987.6 mg, 1.6 mmol) and

Na₂CO₃(86.3 mg, 0.8 mmol) aﬀorded 2j (22.8 mg, 40% yield). White solid; ¹H NMR (400 MHz, CDCl₃)

δ

8.12 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.42–7.25 (m, 5H), 2.71 (s, 3H),

2.56 (s, 3H); ¹³C NMR (101 MHz, CDCl₃)

δ 163.4, 147.2, 141.5, 137.5, 133.1, 132.2, 132.1, 131.2, 131.1

(2C), 130.0, 127.2, 126.1 (2C), 22.0, 20.7; HRMS (FTMS-ESI) Calcd for C₁₆H₁₄³⁵ClNO₂Na [M + Na]⁺

310.0605; found 310.0612.

(Z)-2-Bromo-N-((2-bromobenzoyl)oxy)benzimidoyl chloride (2k). By following the general procedure,

the reaction of 1k (81.7 mg, 0.4 mmol) with NaCl (49.3 mg, 0.8 mmol), Oxone (985.0 mg, 1.6 mmol)

and Na₂CO₃(87.7 mg, 0.8 mmol) aﬀorded 2k (38.5 mg, 46% yield). White solid; ¹H NMR (500 MHz,

CDCl₃)

δ

7.98 (dd, J = 7.3, 2.1 Hz, 1H), 7.74 (dd, J = 7.6, 1.4 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.55 (dd,

162.0,

J = 7.6, 1.6 Hz, 1H), 7.47–7.39 (m, 3H), 7.36 (td, J = 7.7, 1.6 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃)

δ

147.2, 134.8, 133.9, 133.69, 133.67, 132.4, 132.0, 131.3, 129.6, 127.6, 127.5, 122.6, 122.1; HRMS (FTMS-ESI)

Calcd for C₁₄H₈⁷⁹Br₂³⁵ClNO₂Na [M + Na]⁺437.8503; found 437.8511.

(Z)-2-Chloro-N-((2-chlorobenzoyl)oxy)benzimidoyl chloride (2l). By following the general procedure,

the reaction of 1l (64.4 mg, 0.4 mmol) with NaCl (50.3 mg, 0.8 mmol), Oxone (986.0 mg, 1.6 mmol)

and Na₂CO₃(85.9 mg, 0.8 mmol) aﬀorded 2l (28.5 mg, 43% yield). White solid; ¹H NMR (400 MHz,

8.02 (d, J = 8.0 Hz, 1H), 7.60–7.33 (m, 7H); ¹³C NMR (101 MHz, CDCl₃)

CDCl₃) δ δ 161.6, 146.3, 134.7,

133.7, 133.4, 132.3, 132.1, 131.9, 131.5, 131.3, 130.6, 127.7, 127.1, 126.9; HRMS (FTMS-ESI) Calcd for

C₁₄H₈³⁵Cl₃NO₂Na [M + Na]⁺349.9513; found 349.9519.

(Z)-N-((3,4-Dimethylbenzoyl)oxy)-3,4-dimethylbenzimidoyl chloride (2m). By following the general

procedure, the reaction of 1m (62.6 mg, 0.4 mmol) with NaCl (51.1 mg, 0.4 mmol), Oxone (986.1 mg,

1.6 mmol) and Na₂CO₃(86.9 mg, 0.8 mmol) aﬀorded 2m (50.9 mg, 81% yield). White solid; ¹H NMR

(400 MHz, CDCl₃)

δ 7.95 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H),

7.26 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 2.35 (s, 6H), 2.32 (s, 6H); ¹³C NMR (101 MHz, CDCl₃)

δ

163.2, 148.1, 143.6, 141.6, 137.3, 137.2, 131.2, 130.1, 130.0, 129.2, 129.1, 127.7, 126.1, 125.6, 20.3, 20.0, 19.9,

19.8; HRMS (FTMS-ESI) Calcd for C₁₈H₁₈³⁵ClNO₂Na [M + Na]⁺338.0918; found 338.0922.

(Z)-4-Fluoro-N-((4-ﬂuoro-3-methylbenzoyl)oxy)-3-methylbenzimidoyl chloride (2n). By following the general

procedure, the reaction of 1n (63.9 mg, 0.4 mmol) with NaCl (48.4 mg, 0.8 mmol), Oxone (986.8 mg,

1.6 mmol) and Na₂CO₃(86.9 mg, 0.8 mmol) aﬀorded 2n (41.8 mg, 65% yield). White solid;

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¹H NMR (500 MHz, CDCl₃)

δ

8.07–8.00 (m, 2H), 7.91 (d, J = 7.1 Hz, 1H), 7.87–7.82 (m, 1H),

7.15–7.05 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ 165.0 (d, J_C-F= 254.5

Hz), 163.9 (d, J_C-F= 252.7 Hz), 162.1, 147.3, 133.9 (d, J_C-F= 6.7 Hz), 131.7 (d, J_C-F= 6.1 Hz), 130.1 (d, J_C-F

= 9.5 Hz), 128.1 (d, J_C-F= 9.0 Hz), 127.2 (d, J_C-F= 3.5 Hz), 125.9 (d, J_C-F= 18.1 Hz), 125.8 (d, J_C-F= 18.1

Hz), 123.8 (d, J_C-F= 3.3 Hz), 115.7 (d, J_C-F= 23.3 Hz), 115.6 (d, J_C-F= 23.3 Hz), 14.67 (d, J_C-F= 4.8 Hz),

14.65 (d, J_C-F= 4.7 Hz); ¹⁹F NMR (471 MHz, CDCl₃)

δ –107.66 to –107.74 (m, 1F), –110.77 to –110.85 (m,

1F); HRMS (FTMS-ESI) Calcd for C₁₆H₁₂³⁵ClF₂NO₂Na [M + Na]⁺346.0417; found 346.0421.

(Z)-2,4,5-Trimethyl-N-((2,4,5-trimethylbenzoyl)oxy)benzimidoyl chloride (2o). By following the general

procedure, the reaction of 1o (67.2 mg, 0.4 mmol) with NaCl (53.5 mg, 0.8 mmol), Oxone (996.0 mg,

1.6 mmol) and Na₂CO₃(178.1 mg, 1.6 mmol) aﬀorded 2o (51.5 mg, 75% yield). White solid; ¹H NMR

(500 MHz, CDCl₃)

δ

7.88 (s, 1H), 7.36 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 2.63 (s, 3H), 2.48 (s, 3H),

163.7, 147.2, 142.5, 140.0, 138.9, 134.7,

2.30 (s, 6H), 2.27 (s, 3H), 2.26 (s, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ

134.3, 133.5, 132.5, 132.1, 131.0 (2C), 129.6, 124.4, 21.6, 20.3, 20.0, 19.8, 19.4, 19.3; HRMS (FTMS-ESI)

Calcd for C₂₀H₂₂³⁵ClNO₂Na [M + Na]⁺366.1231; found 366.1239.

4.3. Liquid-Phase Synthesis and Characterization of 3a

To a stirred solution of 2a (0.2 mmol) in DMF (2 mL) were added NaCl (23.8 mg, 0.4 mmol),

Na₂CO₃(42.6 mg, 0.4 mmol) and Oxone (493.1 mg, 0.8 mmol). The reaction mixture was allowed

to stir at room temperature for 1 h. Then, the reaction mixture was ﬁltered through a silica gel plug

with ethyl acetate as the eluent, and subsequently the solvent was removed under reduced pressure.

The residue was puriﬁed by ﬂash chromatography on silica gel with petroleum ether/ethyl acetate as

eluent to give product 3a (31.9 mg, 94% yield).

(Z)-N-Hydroxy-4-methylbenzimidoyl chloride (3a). Pale yellow solid; ¹H NMR (500 MHz, CDCl₃)

δ 8.43

(s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 2.39 (s, 3H); ¹³C NMR (126 MHz, CDCl₃)

δ

141.3, 140.5, 129.8, 129.4 (2C), 127.3 (2C), 21.5; HRMS (FTMS-ESI) Calcd for C₈H₉³⁵ClNO [M + H]⁺

170.0367; found 170.0367.

4.4. Mechanochemical Synthesis of 2a from 3a

A mixture of 3a (0.1 mmol, 17.2 mg), Oxone (0.2 mmol, 125.4 mg), and Na₂CO₃(0.1 mmol,

11.1 mg) together with four stainless balls (5 mm in diameter) were introduced into a stainless steel

jar (5 mL). The reaction vessel and another same vessel were closed and ﬁxed on the vibration arms

of a Retsch MM400 mixer mill, and were vibrated vigorously at a rate of 1800 rounds per minute

(30 Hz) at room temperature for 30 min. After completion of the reaction, the resulting mixtures from

the two runs were combined and extracted with dichloromethane and water. The organic layer was

decanted, and the aqueous layer was extracted by dichloromethane (2

×

20 mL). The combined organic

extracts were evaporated to remove the solvent in vacuo. The residue was separated by ﬂash column

chromatography on silica gel with ethyl acetate/petroleum ether as the eluent to aﬀord 2a (22.4 mg,

78% yield).

5. Conclusions

In summary, we have disclosed the unexpected formation of N-acyloxyimidoyl chlorides

from the solvent-free reaction of aldoximes with NaCl and Oxone under ball-milling conditions,

while hydroximoyl chlorides are obtained from the liquid-phase counterparts. The present work

provides another veriﬁcation that mechanochemistry can alter the reaction pathways leading to

diﬀerent products compared to the solution-based counterparts.

Supplementary Materials: The following are available online, ¹H and ¹³C NMR spectra of

and crystal data of 2a.

2, 3a, X-ray structure

Molecules 2020, 25, 3719

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Author Contributions: K.C. did experiments and provided a draft; C.N. characterized X-ray structure of 2a

.

G.-W.W. supervised the project, analyzed data, discussed with K.C. and wrote the manuscript; all authors

contributed to the revision. All authors have read and agreed to the published version of the manuscript.

Funding: This research was funded by National Natural Science Foundation of China, grant number 21372211.

Conﬂicts of Interest: The authors declare no conﬂict of interest.

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Sample Availability: Not available.

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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access

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(CC BY) license (http://creativecommons.org /licenses /by /4.0 /).

Article Doi

Reaction of Aldoximes with Sodium Chloride and Oxone under Ball-Milling Conditions

DOI: 10.3390/molecules25163719

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