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Synthesis
DOI: 10.1055/a-2593-4458
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Chitosan-Promoted Reduction of Nitroaromatics by B2(NMe2)4 under Wet Ball Milling Conditions

Yuhang Su
a   School of Materials and Packaging Engineering, Fujian Polytechnic Normal University, Fuzhou, Fujian 350300, P. R. of China
,
Jingyan Chen
b   Department of Chemistry and Materials Science, Xi’an Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, P. R. of China
,
Hui Lin
a   School of Materials and Packaging Engineering, Fujian Polytechnic Normal University, Fuzhou, Fujian 350300, P. R. of China
,
Conglong Lin
a   School of Materials and Packaging Engineering, Fujian Polytechnic Normal University, Fuzhou, Fujian 350300, P. R. of China
,
Yuanzhi Lin
a   School of Materials and Packaging Engineering, Fujian Polytechnic Normal University, Fuzhou, Fujian 350300, P. R. of China
,
Xiuqiang Lu∗
a   School of Materials and Packaging Engineering, Fujian Polytechnic Normal University, Fuzhou, Fujian 350300, P. R. of China
c   Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
› Author Affiliations

We are grateful to National Natural Science Foundation of China (No. 51503037), Natural Science Foundation of Fujian Province (No. 2024J01968), and the Project of Fujian Provincial Science and Technology Department (No. 2024H6018, No.2024Y0030) for financial support.
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Abstract

The environmentally friendly reduction of nitro compounds to their corresponding amino compounds has been a practical and challenging task. In this paper, a method has been developed for the reduction of nitroaromatics to aromatic amines by ball milling. The method uses cheap and available tetrakis(dimethylamino)diboron as the reducing agent and NaOH as the base, and the reduction reaction can be achieved by wet ball milling assisted by chitosan. A range of nitroaromatic compounds containing a variety of alkyl, halogen, polynitro, and other groups were chemoselectively reduced to the corresponding anilines in good yields. This protocol will enrich functional group transformations of nitroaromatics to amines.


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Key words

nitroaromatic - chitosan - tetrakis(dimethylamino)diboron - ball-milling - reduction

Aromatic amines are recognized as essential intermediates in synthesizing dyes, pharmaceuticals, agrochemicals, and synthetic polymers.[1] The highly selective reduction of nitro groups to amino groups is a worthwhile transformation for preparing valuable amines. Abundant strategies and protocols have been developed to achieve this transformation. Generally, the transformation has been realized mainly by several diverse methods: (1) Metal-based traditional classic methods: The reactions using a large excess of metal powder (Fe, Zn, Sn, Al, and so on), stannous chloride, or titanium trichloride with acidic solutions are usually considered to be the reduction methods;[2] (2) Metal-catalyzed methods: The metal (mainly composed of transition metals) catalytic hydrogenation in the presence of hydrogen or hydrogen source reagents (H2NNH2, HCO2H, H3N·BH3, metal hydrides, and so on) can also reduce nitro groups;[3] (3) Metal-free traditional methods: These commonly used methods include adopting stoichiometric Na2S, (NH4)2S, NH4HS, or other polysulfides as reducing agents;[4] (4) Metal-free novel methods: These available methods incorporate the use of 9,10-dihydroanthracene,[5] HSiCl3 with triethylamine,[6] fullerene (C60 or C70)/H2,[7] and graphene oxide/H2NNH2.[8] So far, very many methods of nitro reduction to amines have been developed, but with the rise of green chemistry, it is imperative to develop new green methods of nitro reduction, which can further enrich the methods of nitro reduction, suit new chemical needs, and expand new uses.

In the last decade, reagents, normally used as borylating reagents, have been used in cleaning processes for highly efficient nitro reduction.[9] These diboron agents have enabled new protocols toward amine derivatives containing various reducible functional groups that avoid adopting high-pressure hydrogen gas or toxic hydrazines. Remarkably, several methods employing diboron performed well under metal-free conditions in the presence of Lewis bases or an aqueous solution. For example, an efficient reduction using bis(pinacolato)diboron (B2pin2) and KOtBu in propan-2-ol was discovered by Wu’s group.[10a] Qin developed a method for the rapid reduction using B2pin2 and NaOH at 50 °C in MeOH/H2O.[10b] Other facile methods have also been developed that utilize tetrahydroxydiboron [B2(OH)4] as a reductant. Uozumi’s group extended an efficient reduction method in which the nitro group reacts with B2(OH)4 at 80 °C in water.[11] Du et al. extended a DNA-compatible nitro reduction using B2(OH)4 in NaOH aqueous solution; inevitably, dehalogenation took place under the reaction conditions.[12] Lately, Hosoya et al. reported the analogous reduction using bis(neopentylglycolato)diboron (B2nep2), organic-catalyzed by bipyridyl.[13] While these diboron-based protocols can reduce nitro groups under metal-free conditions, there still exist several restrictions that require high temperatures or produce volatile organic solvents in processes. Development of other eco-friendly methods is gaining in importance.[14] In recent years, mechanochemistry by ball-milling has become more powerfully applied in synthetic chemistry, which is recognized as an excellent green method.[15] Chemists will find the prospect of carrying out various reactions in a unique manner highly appealing.[16] Various organic transformations can be efficiently realized in this way.[17] In the last decade, some groups have combined the advantages of boron reagents and mechanochemistry to effectively realize the reduction of nitroxide.[18] Although several diboron reagents exist for the efficient reduction of nitroaromatics, some of them are expensive or require several steps of conversion to realize their synthesis, and it is of higher economic value to search for easily available and cheaper diboron reagents [e.g., tetrakis(dimethylamino)diboron]. Using new diboron reagents [e.g., tetrakis(dimethylamino)diboron] and combining them with mechanochemistry, we are exploring solvent-free or solvent-reduced green pathways to open up new synthetic methods for nitro reduction.

Nitrobenzene (1a) was selected first as the substrate for the template reaction and the reaction conditions were optimized as shown in Table [1], with 5.0 equivalent of B2(NMe2)4, 4.0 equivalents of solid sodium hydroxide, chitosan (95% deacetylated) as reaction promoter (0.5 g), α-Al2O3 milling additives (2.0 g), and deionized water (0.5 mL) as a liquid additive, and the time for wet ball milling was 3 hours. The corresponding product aniline was obtained in 88% isolated yield (Table [1], entry 1). Meanwhile, in the comparison experiment without chitosan as a promoter, the yield of the corresponding product was only 27% (entry 2). Thus, it can be seen that chitosan plays an important role in this reduction reaction, which is reflected in its reaction promoter function. When we tried to increase the addition of chitosan, we found that the yield did not effectively increase but decreased slightly (entry 4). To further test the role of chitosan, without the addition of B2(NMe2)4 and relying on chitosan alone, no reduction reaction occurred, and the corresponding products were not obtained (entry 18). So, it is clearly shown that chitosan is only a reaction promoter and not a reducing agent. Solvents (liquid additives) play significant roles in reduction reactions, and we investigated the effect of solvents (liquid additives) on the reaction. Water and common alcohols are excellent solvents for reduction reactions because they are both polar solvents and provide a source of hydrogen in the reaction. The yields of aniline (2a) in the presence of the same base (sodium hydroxide) were 88%, 54%, 51%, and 47% when water, methanol, ethanol, and isopropyl alcohol, respectively, were used as solvents (entries 1, 9–11). When tetrahydrofuran was used as a liquid additive, the yield of aniline was only 21%, which may be related to the inability of tetrahydrofuran to provide a large source of hydrogen (entry 8). The effect of the base on the reaction was then investigated. The results showed that the stronger the inorganic base was, the more favorable the reduction reaction was. On the contrary, organic bases (DBU, pyridine, and triethylamine) or the absence of bases did not induce the reaction (entries 14–17). The effect of additive amounts of B2(NMe2)4 and NaOH on the reaction were briefly screened. When the amount of B2(NMe2)4 was increased to 10 equivalents, the yield was 91% (entry 3). When attempting to increase the amount of NaOH from 4.0 to 8.0 equivalents, the yield was 90% (entry 5). Overall, increasing the amount of B2(NMe2)4 or NaOH did not have a significant effect on the product yield.

Table 1 Optimization of the Reaction Conditionsa

Entry

B2(NMe2)4 (equiv.)

Base (equiv.)

Chitosan (g)

Liquid additive (mL)

Yield of 2a (%)b

 1

 5

NaOH (4.0)

0.5

H2O (0.5)

88

 2

 5

NaOH (4.0)

–

H2O (0.5)

27

 3

10

NaOH (4.0)

0.5

H2O (0.5)

91

 4

 5

NaOH (4.0)

1.0

H2O (0.5)

87

 5

 5

NaOH (8.0)

0.5

H2O (0.5)

90

 6

 5

K2CO3(4.0)

0.5

H2O (0.5)

79

 7

 5

NaOEt (4.0)

0.5

H2O (0.5)

82

 8

 5

NaOH (4.0)

0.5

THF (0.5)

21

 9

 5

NaOH (4.0)

0.5

MeOH (0.5)

54

10

 5

NaOH (4.0)

0.5

EtOH (0.5)

51

11

 5

NaOH (4.0)

0.5

i-PrOH (0.5)

47

12

 5

NaOH (4.0)

0.5

toluene (0.5)

n. r.

13

 5

NaOH (4.0)

0.5

MeCN (0.5)

n. r.

14

 5

DBU (4.0)

0.5

H2O (0.5)

n. r.

15

 5

pyridine (4.0)

0.5

H2O (0.5)

n. r.

16

 5

Et3N (4.0)

0.5

H2O (0.5)

n. r.

17

 5

–

0.5

H2O (0.5)

n. r.

18

 –

NaOH (4.0)

0.5

H2O (0.5)

n. r.

19

 5c

NaOH (4.0)

–

H2O (0.5)

36

20

 5c

NaOH (4.0)

0.5

H2O (0.5)

91

a Reaction conditions: 1a (2.0 mmol), B2(NMe2)4 (5.0–10.0 equiv.), chitosan (95% deacetylated) reaction promoter (0.5 g), base (4.0–8.0 equiv.), liquid additive (0.5 mL), α-Al2O3 grinding auxiliary (2.0 g), miniature planetary ball mill (produced by Shenzhen Jitong Technology Co.), stainless steel beaker (25 mL), six stainless steel balls (∅ = 5 mm), 600 rpm, 3 h.

b Isolated yield of 2a. n. r. = No reaction.

c B2(NMe2)4 was replaced by B2(OH)4.

After determining the optimal reaction conditions, a series of reduction reactions were carried out on p-nitroaromatic compounds as shown in Scheme [1]. First, we examined the compatibility of this reduction system with some common functional groups using p-nitroaromatic compounds as the substrates. When the substituents were halogens (fluorine, chlorine, and bromine), the yields of the target compounds 2g–i obtained by this method were high (89–93%) and without dehalogenation. No debromination products were also found when a representative tribromo-substituted nitroaromatic was used as substrate and the yield of 2j was 87%. With p-trifluoromethylnitrobenzene as substrate, the product amine 2f was isolated in 95% yield. The yields of the nitro reduction reactions were all higher when the substituent was an electron-withdrawing group; when the substituent was an electron-donating group (e.g., methyl, ethyl, or isopropyl), the yields of the reaction products 2b–e were slightly lower than those of the substrates with electron-withdrawing groups. For a polynitro substrate such as p-dinitrobenzene, an increase of the reducing agent can also lead to an isolated yield of the product 2k to 80%.

Zoom Image
Scheme 1 Reduction of nitroarenes. Reagents and conditions: nitroaromatic (2.0 mmol), B2(NMe2)4 (5.0 equiv.), chitosan reaction promoter (0.5 g), NaOH (4.0 equiv.), α-Al2O3 grinding auxiliary (2.0 g), deionized H2O (0.5 mL), miniature planetary ball mill, stainless steel beaker (25 mL), six stainless steel balls (∅ = 5 mm), 600 rpm, 3 h. Isolated yields of 2 are shown. Conditions for the synthesis of the product 2k: B2(NMe2)4 (10.0 equiv.), NaOH (8.0 equiv.), other conditions are the same.

To preliminarily verify the reaction mechanism, we performed mass spectrometry and NMR analysis on the aqueous phase after the reaction. From the mass spectra (Figure [1]), it can be found that there is a molecular ion peak of dimethylamine, indicating that the diboron reagent B2(NMe2)4 was hydrolyzed, and dimethylamine was produced. From 11B NMR spectra (Figure [2]), the NMR chemical shift of boric acid at 19.36 ppm indicates that boric acid is generated in the reaction by-product. To better validate the hydrolysis mechanism of B2(NMe2)4, B2(NMe2)4 was replaced by B2(OH)4, and without the participation of chitosan in the reaction, the yield was only 36% (Table [1], entry 19); while the reaction with the addition of chitosan, the yield could reach 91% (entry 20). From Table [1] (entries 2, 19, and 20), it can be inferred that chitosan accelerated the hydrolysis of B2(NMe2)4 to B2(OH)4, and that chitosan is also effective in assisting the reduction of nitro groups by B2(OH)4. B2(NMe2)4 is also easily hydrolyzed in an aqueous solution containing alcohols, which is reported in the literature.[19] Chitosan has a large number of reactive hydroxyl groups, which, in the presence of water, act in a similar way to alcohols and promote hydrolysis reactions to occur. Inspired by the mechanism from a combined B2pin2/base for amination reaction of nitroarenes,[10] a possible reaction mechanism is shown in Scheme [2]. First, B2(NMe2)4 was hydrolyzed by the combined action of chitosan and sodium hydroxide to form B2(OH)4. Sodium hydroxide further reacted with B2(OH)4 to form the nucleophilic diboron reactive intermediate B2(OH)5 – (A). Intermediate A undergoes a nucleophilic reaction on the electron-deficient N atom on nitroaromatic 1 to form intermediate B, which undergoes an intramolecular rearrangement reaction to form intermediate C, followed by the elimination of a molecule of boric acid by the intermediate to form the nitroso compound D. Then, the active intermediate A continues the nucleophilic reaction on the electron-deficient N atom on the nitroso compound to produce the intermediate E, which is hydrolyzed to produce the hydroxylamine F. The hydroxylamine continues to react with the active intermediate A to eliminate a molecule of boric acid to produce the boronic acid amine G. Finally, G is hydrolyzed to produce the corresponding arylamine 2.

Zoom Image
Figure 1 Mass spectra of the by-product dimethylamine
Zoom Image
Figure 2 11B NMR spectra of by-product boric acid in D2O
Zoom Image
Scheme 2 Proposed mechanism

In summary, we have developed an eco-friendly method for nitroaromatics to amines using cheap and readily available B2(NMe2)4. This reaction does not require any rare and precious metals, higher-pressure reactors, or hydrogen gas. Although more additives and reagents are used, most of the additives are cheap and available chemicals, especially chitosan – a biomass – which is used as a reaction additive to avoid the use of metal catalysts. In addition, the addition of a small amount of water as a solvent completely avoids the use of other organic solvents and reduces the emission of organic volatiles. The reduction of nitroaromatics by milling without the addition of organic solvents using the unreported diboron reagent as a reducing agent provides another new green method. Further mechanistic studies and synthetic applications of this method are underway in our laboratory.

NMR spectra were recorded on a Bruker Avance III 400 MHz spectrometer for 1H spectra. Deuterated solvents for 1H NMR and 13C NMR were purchased from J & K chemical or Acros. MS were recorded on GC/MS Agilent 7890A spectrometer. TLC analyses were performed on silica gel plate and column chromatography over silica gel (mesh 300–400), which were both obtained from Qingdao Ocean Chemicals. Unless otherwise noted, reagents were commercially available and used as received. Ball-milling reactions were performed in PBM-0.2A miniature planetary ball mill (produced by Shenzhen Jitong), using a stainless steel jar (25 mL) along with 6 stainless steel balls (∅ = 5 mm) and milled at a rate of 600 rounds per minute (rpm) at room temperature.


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Reduction of Nitroaromatics 1 to Amines 2 under Ball-Milling Conditions; General Procedure

Six stainless steel balls (∅ = 5.0 mm) were placed into stainless steel beaker (25 mL) in air. Then nitroaromatic 1 (2.0 mmol), B2(NMe2)4 (5.0–10.0 equiv.), chitosan (95% deacetylated) reaction promoter (0.5 g), NaOH (4.0–8.0 equiv.), α-Al2O3 grinding auxiliary (2.0 g), and deionized H2O (0.5 mL) were added into the stainless steel beaker. After the beaker was closed by purging with inert gas argon, the beaker was placed in the ball mill (600 rpm, 3 h). After grinding for 3 h, the reaction material system was extracted with EtOAc (3 × 30 mL). The EtOAc liquid mixture was filtered through a Büchner funnel to remove the solids. The filtrate was collected, and the corresponding reduced amine was obtained by removing the solvent under reduced pressure. After that, the crude product was purified by silica gel column chromatography using the EtOAc/petroleum ether mixture (v/v = 1:20).


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3,5-Dimethylaniline (2b)

Light yellow oil; yield: 198 mg (82%).

1H NMR (400 MHz, CDCl3): δ = 6.62 (s, 1 H), 6.46 (s, 2 H), 3.66 (s, 2 H), 2.43 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 146.35, 138.38, 119.92, 112.86, 20.96.

MS (EI): C8H11N; m/z = 121.1 (M+, 100%).


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2,3-Dimethylaniline (2c)

Light yellow oil; yield: 196 mg (81%).

1H NMR (400 MHz, CDCl3): δ = 7.19 (t, J = 7.7 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H), 3.74 (s, 2 H), 2.53 (s, 3 H), 2.28 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 144.44, 136.63, 125.71, 120.48, 120.17, 112.93, 20.13, 12.21.

MS (EI): C8H11N; m/z = 121.1 (M+, 100%).


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4-Ethylaniline (2d)

Yellow oil; yield: 208 mg (86%).

1H NMR (400 MHz, CDCl3): δ = 6.83–6.69 (m, 2 H), 6.68–6.53 (m, 2 H), 3.95 (q, J = 7.0 Hz, 2 H), 3.48 (s, 2 H), 1.38 (t, J = 7.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 151.40, 140.02, 115.96, 115.23, 63.58, 14.60.

MS (EI): C8H11N; m/z = 121.1 (M+, 100%).


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4-Isopropylaniline (2e)

Clear liquid; yield: 230 mg (85%).

1H NMR (400 MHz, CDCl3): δ = 7.21–7.14 (m, 2 H), 6.78–6.70 (m, 2 H), 3.60 (s, 2 H), 2.97 (hept, J = 6.9 Hz, 1 H), 1.38 (d, J = 7.0 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 144.23, 138.78, 126.98, 115.14, 33.13, 24.18.

MS (EI): C9H13N; m/z = 135.1 (M+, 100%).


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4-Aminobenzotrifluoride (2f)

Clear liquid; yield: 306 mg (95%).

1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.3 Hz, 2 H), 6.68 (d, J = 8.4 Hz, 2 H), 3.98 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 149.91, 149.90, 129.33, 126.72, 126.69, 126.65, 126.61, 123.96, 121.27, 120.11, 119.79, 119.47, 119.15, 114.51, 114.23, 113.90.

19F NMR (376 MHz, CDCl3): δ = –61.3.

MS (EI): C7H6F3; m/z = 161.0 (M+, 100%).


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4-Fluoroaniline (2g)

Light yellow oil; yield: 207 mg (93%).

1H NMR (400 MHz, CDCl3): δ = 6.98–6.81 (m, 2 H), 6.69–6.51 (m, 2 H), 3.58 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 157.15, 154.82, 142.69, 142.67, 115.85, 115.78, 115.44, 115.22.

19F NMR (376 MHz, CDCl3) : δ = –126.9.

MS (EI): C6H6FN; m/z = 111.0 (M+, 100%).


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4-Chloroaniline (2h)

White solid; yield: 230 mg (90%).

1H NMR (400 MHz, CDCl3): δ = 7.15–7.07 (m, 1 H), 6.63–6.54 (m, 1 H), 3.65 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 145.11, 128.99, 122.71, 116.20.

MS (EI): C6H6ClN; m/z = 127.0 (M+, 100%).


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4-Bromoaniline (2i)

White solid; yield: 306 mg (89%).

1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.3 Hz, 2 H), 6.68 (d, J = 8.4 Hz, 2 H), 3.98 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 145.50, 131.89, 116.73, 109.91.

MS (EI): C6H6BrN; m/z = 170.9 (M+, 100%).


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2,4,6-Tribromoaniline (2j)

White solid; yield: 574 mg (87%).

1H NMR (400 MHz, CDCl3): δ = 7.50 (s, 1 H), 4.56 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 141.50, 133.97, 108.99.

MS (EI): C6H4Br3N; m/z = 328.8 (M+, 100%).


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p-Phenylenediamine (2k)

White solid; yield: 173 mg (80%).

1H NMR (400 MHz, CDCl3): δ = 6.57 (s, 4 H), 3.33 (s, 4 H).

13C NMR (100 MHz, CDCl3): δ = 138.78, 116.89.

MS (EI): C6H8N2; m/z = 108.1 (M+, 100%).


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2593-4458.
  • Supporting Information

Corresponding Author

Xiuqiang Lu
Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190
P. R. of China   

Publication History

Received: 07 February 2025

Accepted after revision: 23 April 2025

Accepted Manuscript online:
23 April 2025

Article published online:
12 May 2025

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Zoom Image
Scheme 1 Reduction of nitroarenes. Reagents and conditions: nitroaromatic (2.0 mmol), B2(NMe2)4 (5.0 equiv.), chitosan reaction promoter (0.5 g), NaOH (4.0 equiv.), α-Al2O3 grinding auxiliary (2.0 g), deionized H2O (0.5 mL), miniature planetary ball mill, stainless steel beaker (25 mL), six stainless steel balls (∅ = 5 mm), 600 rpm, 3 h. Isolated yields of 2 are shown. Conditions for the synthesis of the product 2k: B2(NMe2)4 (10.0 equiv.), NaOH (8.0 equiv.), other conditions are the same.
Zoom Image
Figure 1 Mass spectra of the by-product dimethylamine
Zoom Image
Figure 2 11B NMR spectra of by-product boric acid in D2O
Zoom Image
Scheme 2 Proposed mechanism