Solvent-free zinc-mediated Béchamp reduction using mechanochemistry

Abstract

In this study, we report the first mechanochemical protocol for highly efficient solvent-free Béchamp reduction using inexpensive Zn metal as a reductant in combination with NH₄Cl. This reaction is considerably faster than previous solution-based reactions. Herein, a variety of nitroarenes were chemoselectively reduced to the corresponding primary aromatic amines in good yields within 30 min. Notably, the present solvent-free protocol does not require an organic solvent or air-sensitive and/or expensive reagents, and all synthetic operations can be performed under ambient conditions, greatly enhancing its practical utility. Furthermore, the feasibility of the gram-scale reaction as well as the synthesis of an important intermediate of the muscle relaxant tizanidine were demonstrated.

---

The chemoselective reduction of nitroarenes is an important transformation in the synthesis of many aromatic amines, which are indispensable components of pharmaceutical drugs and bioactive molecules.¹ Numerous methods for reducing nitroarenes have been reported previously.¹ Among these, zero-valent-metal-mediated reduction under acidic conditions, also known as the Béchamp reduction, has been widely used in academic and industrial settings.^1,2 Typical metals used in these reductions are Fe,³ Sn,⁴ In,⁵ and Zn⁶ in combination with several proton sources. Although many useful Béchamp conditions have been developed, conventional reductions are commonly performed in potentially harmful organic solvents and often require corrosive HCl, high temperatures, and prolonged reaction times. Recently, several modified procedures for the Béchamp reduction in the presence of NH₄Cl as a mild proton source have been developed; however, these require expensive reagents such as surfactants or ionic liquids.^6e,f Therefore, the development of a highly efficient, time-saving, cost-effective, and sustainable Béchamp process remains an important challenge in synthetic chemistry.

Mechanochemistry using ball milling has attracted significant attention as a promising alternative to solution-based organic synthesis.^7,8 The effectiveness of mechanochemical methods is reflected in the minimal solvent use, high efficiency, short reaction times, operational simplicity, low energy consumption, and cost efficiency; however, despite recent advances in this field, the development of a mechanochemical protocol for Béchamp reduction remains unexplored. Other mechanochemical methods for the reduction of nitroarenes, such as palladium-catalyzed⁹ or base-mediated transfer hydrogenation¹⁰ and gold-nanoparticle-catalyzed hydride reduction,¹¹ have been reported (Scheme 1A). However, these methods require precious metal catalysts,^9,11 liquid additives,⁹ potentially hazardous reductants such as hydrazine,¹⁰ and highly basic conditions.¹⁰ Therefore, the development of a simple and mild mechanochemical protocol for the Béchamp reduction can offer a more practical choice for the synthesis of aromatic amines and address the aforementioned limitations associated with traditional solution-based Béchamp processes.^1–6

Scheme 1 Mechanochemical protocols for reduction of nitroarenes.

Herein, we report a highly efficient mechanochemical Béchamp reduction method using inexpensive Zn metal as the reductant (Scheme 1).¹² These reactions are rapid, and various nitroarenes can be reduced to afford the desired aromatic amines in good yields within 30 min. Notably, this simple and mild mechanochemical method does not require bulk solvents or even small amounts of liquid additives and air-sensitive and/or expensive reagents. Additionally, all synthetic operations can be performed under ambient conditions. The practical utility of this protocol was further demonstrated by an efficient gram-scale reaction as well as by the synthesis of the intermediate tizanidine.^13,14

Initially, we conducted a study to optimize the mechanochemical conditions for Béchamp reduction (Table 1). With 3-nitro-1,1′-biphenyl (1a) as the model substrate, all reactions were performed in a Retsch MM400 mixer mill (stainless-steel milling jar: 5 mL; stainless-steel ball: 10 mm in diameter). We used a commercially available temperature-controllable heat gun placed directly above the ball-milling jar to control the reaction temperature.^8e Based on traditional solution-based conditions,⁶ the mechanochemical reaction was initially conducted for 30 min using Zn (5 equiv.) and NH₄Cl (5.0 equiv.) as proton sources. All reactions were conducted under atmospheric conditions, and all reagents were purchased from common commercial suppliers and used as received. Under the applied conditions, the desired product (2a) was obtained in excellent yield (95%) with a heat gun preset to 70 °C (entry 1). The internal temperature of the reaction mixture (50 °C) was confirmed using thermography immediately after the milling jar was opened. Without external heating, the reaction was slow, and 2a was obtained in a lower yield (18%, entry 2). Decreasing the amount of Zn or NH₄Cl yielded poor results (entries 3–6). Next, other metal reductants were tested (entries 7–10). Fe metal, which is most widely used in Béchamp reduction,³ did not yield the desired product (2a) (entry 7). Other metals such as Mn and Sn also showed poor reactivity under the applied mechanochemical conditions (entries 8 and 9). The reaction with In resulted in low product yield (22%), despite the high conversion of the starting materials (entry 10). These results suggest that the use of Zn is crucial for achieving a highly efficient mechanochemical Béchamp reduction. Traditional solution-based conditions for Béchamp reduction typically require several hours to complete,^1–6 whereas the proposed mechanochemical protocol significantly accelerates the reaction, achieving completion within 30 min. Moreover, this reaction does not require air-sensitive or expensive reagents, significantly enhancing its practical utility.

Table 1 Optimization study on the solvent-free Béchamp reduction under mechanochemical conditions^a

Entry	Deviation from “standard conditions”	Conv. of 1a^b(%)	Yield (%) of 2a^b
a Conditions: 1a (0.5 mmol), Zn (2.5 mmol), and NH4Cl (2.5 mmol) were added to a stainless-steel ball mill jar (5 mL) with a stainless steel ball (diameter: 10 mm). b Determined by ^1H NMR analysis of the crude reaction mixture using an internal standard.
1	None	>99	95
2	Room temperature	34	18
3	Zn (1.0 equiv.)	5	9
4	Zn (3.0 equiv.)	63	51
5	NH4Cl (1.0 equiv.)	32	16
6	NH4Cl (3.0 equiv.)	65	63
7	Fe instead of Zn	5	<1
8	Mn instead of Zn	21	3
9	Sn instead of Zn	40	11
10	In instead of Zn	95	22

---

Subsequently, the effect of the proton sources was investigated (Table 2). The use of NH₄OAc^6f instead of NH₄Cl also afforded 2a in excellent yield (95%). Next, we tested other solid, easy-to-handle Brønsted acid reagents, such as (+)-10-camphorsulfonic acid (3a) and BINOL-based phosphoric acid (3b), although these have not been previously used in Béchamp reduction in solution. The reaction with 3a proceeded and produced a considerably low yield of 2a (10%). No reaction was observed when 3b was used. These results suggest that the use of ammonium salts is essential for efficient reduction. Given the high moisture sensitivity of NH₄OAc, we used NH₄Cl, which can be easily handled in air, as the optimal proton source.

Table 2 Effect of proton sources^a,b

a Conditions: 1a (0.5 mmol), Zn (2.5 mmol), and a proton source (2.5 mmol) were added to a stainless-steel ball mill jar (5 mL) with a stainless-steel ball (diameter: 10 mm). b Determined by ¹H NMR analysis of the crude reaction mixture using an internal standard.

---

Using the optimized mechanochemical conditions, we explored the substrate scope of the mechanochemical solvent-free Béchamp reduction (Table 3). Overall, the scope of this mechanochemical method is comparable to that of the solution protocols for Béchamp reduction. The reactions of methyl-, methoxy-, and benzyloxy-substituted substrates (1b–1f) proceeded smoothly to afford the desired products (2b–2f) in moderate to good yields (61–79%). The position of the methoxy group on the benzene ring did not affect the reactivity. Substrates containing terminal alkene (1g), bromo group (1h), and silyl ether moiety (1i) did not interfere with the reduction process, affording the corresponding products (2g–2i) in moderate to good yields (84%, 48%, and 86%, respectively). This protocol is suitable for the synthesis of diamine compounds (2j and 2k) in good yields (53% and 77%, respectively). The reactions of substrate bearing electron-withdrawing substituents, such as fluoro (1l–1n), chloro (1o), and ester (1p) groups, afforded the desired products (2l–2p) in good to high yields (65–89%). Sterically hindered nitro compound (1q) underwent efficient reduction to produce the corresponding aniline (2q) in high yield (84%).

Table 3 Substrate scope^a,b

a Conditions: 1 (0.5 mmol), Zn (2.5 mmol), and NH₄Cl (2.5 mmol) were added to a stainless-steel ball mill jar (5 mL) with a stainless-steel ball (diameter: 10 mm). b ¹H NMR yield. c 60 min. d 6.0 equivalents of Zn were used. e Zn (5.0 mmol) and NH₄Cl (5.0 mmol) were used.

---

To demonstrate the synthetic utility of this reaction, we investigated the synthesis of the important intermediate 2r of the muscle relaxant tizanidine (Scheme 2).^13,14 The reaction of 1r under the optimized conditions afforded the desired product 2r in good yield (70%). 2r can be converted into tizanidine in seven steps.¹⁴ This result showcases the potential of this solvent-free protocol for the preparation of bioactive compounds in a more sustainable manner.

Scheme 2 Mechanochemical Béchamp reduction for the synthesis of the intermediate 2r of tizanidine. Details of the reaction conditions are provided in the ESI.†

To demonstrate the practical utility of this reaction, we investigated the gram-scale synthesis of 2a (Scheme 3). A 7 mmol-scale reaction was conducted in a 25 mL stainless-steel jar with two 10 mm stainless-steel balls. The gram-scale reaction proceeded smoothly to afford 2a in 88% yield (1.04 g), which was comparable to the yield obtained in the small-scale reaction. This result emphasizes the practical utility of the solvent-free Zn-mediated Béchamp reduction protocol.

Scheme 3 Solvent-free mechanochemical Béchamp reduction on a gram scale. Details of the reaction conditions are provided in the ESI.†

To quantify the environmental benefits of this mechanochemical approach, we compared the E-factor of the present mechanochemical conditions to that of the previously reported representative solution-based conditions (Table 4).¹⁵ The E-factor is an index for the quantitative evaluation of the environmental impact of a chemical process.¹⁶ For our mechanochemical reduction of 1p, the E-factor is 4.1 (entry 1), whereas the E-factor of the representative solution-based method using acetone/H₂O (4 : 1, 0.1 M)¹⁵ is 60.9 (entry 2). This difference is primarily attributed to the absence of bulk solvents under our mechanochemical conditions. Based on these results, the current mechanochemical approach is significantly more eco-friendly than traditional solution-based methods.

Table 4 Comparison of E-factors^a

Entry	Conditions	E-factor
a For details of the E-factor calculations, see the ESI.
1	Zn (5 equiv.), NH4Cl (5 equiv.) 50 °C, 30 min	4.1
2	Zn (5 equiv.), NH4Cl (10 equiv.) 40 °C, acetone/H2O (4 : 1, 0.1 M), 24 h	60.9

---

In conclusion, we demonstrated a simple mechanochemical protocol that enables highly efficient and rapid solvent-free Zn-based Béchamp reduction without the use of bulk solvents or a complicated reaction setup involving inert gases. Notably, most nitroarenes were reduced within 30 min to produce the desired aromatic amines in good to high yields. A gram-scale reaction under mechanochemical conditions was also demonstrated. Compared to existing mechanochemical reduction protocols for nitroarenes,^9–11 this new method uses inexpensive, safe, and easy-to-handle Zn metal as the reductant and eliminates the need for transition metal catalysts. These results suggest that this study serves as an important proof of concept, demonstrating the feasibility of sustainable, solvent-free Béchamp reduction through mechanochemistry. However, it is important to highlight that the key limitations of this method include the need for external heating, as well as the use of excess Zn metal and NH₄Cl to achieve efficient nitroarene reduction. Further studies toward the development of a room-temperature version of the mechanochemical Béchamp reduction without using excessive reagents are currently underway in our laboratory.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the Japan Society for the Promotion of Science (JSPS) via KAKENHI grants 22H00318, 22K18333, 24H00453, 24H01832, and 24H01050 by the JST via CREST grant JPMJCR19R1 and FOREST grant JPMJFR201I and by the Institute for Chemical Reaction Design and Discovery (ICReDD) established by the World Premier International Research Initiative (WPI), MEXT, Japan. We thank Mr. Taiga Takeda for his help in cross-checking the experiments.

Notes and references

1. For selected reviews on the reduction of nitro compounds to amines, see: (a) M. Orlandi, D. Brenna, R. Harms, S. Jost and M. Benaglia, Org. Process Res. Dev., 2018, 22, 430; (b) V. Aggarwal, E. Bala, S. Saima, S. Pathan, S. Guleria, S. Sharma, M. Selvaraj and P. K. Verma, Synlett, 2024, 35, 245; (c) G. Haydar, S. Hakan, K. Benan and S. Fatih, Curr. Org. Chem., 2017, 27, 794; (d) A. M. Tafesh and J. Weiguny, Chem. Rev., 1996, 96, 2035; (e) H.-U. Blaser, H. Steiner and M. Studer, ChemCatChem, 2009, 1, 210.
2. A. J. Béchamp, Ann. Chim. Phys., 1854, 42, 186.
3. The selected examples of Fe-mediated Béchamp reduction: (a) C. A. Merlic, S. Motamed and B. Quinn, J. Org. Chem., 1995, 60, 3365; (b) S. Chandrappa, T. Vinaya, T. Ramakrishnappa and K. S. Rangappa, Synlett, 2010, 2010, 3019; (c) K. Ramadas and N. Srinivasan, Synth. Commun., 1992, 22, 3189; (d) D. G. Desai, S. S. Swami, S. K. Dabhade and M. G. Ghagare, Synth. Commun., 2001, 31, 1249; (e) A. B. Gamble, J. Garner, C. P. Gordon, S. M. J. O'Conner and P. A. Keller, Synth. Commun., 2007, 37, 2777; (f) N. R. Lee, A. A. Bikovtseva, M. Cortes-Clerget, F. Gallou and B. H. Lipshutz, Org. Lett., 2017, 19, 6518; (g) S. Chandrappa, T. Vinaya, T. Ramakrishnappa and K. S. Rangappa, Synlett, 2010, 3019.
4. The selected example of Sn-mediated Béchamp reduction: K. M. Doxsee, M. Feigel, K. D. Stewart, J. W. Canary, C. B. Knobler and D. J. Cram, J. Am. Chem. Soc., 1987, 109, 3098.
5. The selected examples of In-mediated Béchamp reduction: (a) C. J. Moody and M. R. Pitts, Synlett, 1998, 1998, 1028; (b) Y. S. Cho, B. K. Jun, S. Kim, J. H. Cha, A. N. Pae, H. Y. Koh, M. H. Chang and S.-Y. Han, Bull. Korean Chem. Soc., 2003, 24, 653.
6. The selected examples of Zn-mediated Béchamp reduction: (a) V. S. Sadavarte, S. S. Swami and D. G. Desai, Synth. Commun., 1998, 28, 1139; (b) R. J. Sundberg and W. J. Pitts, J. Org. Chem., 1991, 56, 3048; (c) D. G. Desai, S. S. Swami and S. B. Hapase, Synth. Commun., 1999, 29, 1033; (d) H. Mahdavi and B. Tamami, Synth. Commun., 2005, 35, 1121; (e) S. M. Kelly and B. H. Lipshutz, Org. Lett., 2014, 16, 98; (f) F. A. Khan, J. Dash, C. Sudheer and R. K. Gupta, Tetrahedron Lett., 2003, 44, 7783.
7. For selected reviews on reaction development using mechanochemistry, see: (a) S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friščić, F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L. Maini, A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed and D. C. Waddell, Chem. Soc. Rev., 2012, 41, 413; (b) G.-W. Wang, Chem. Soc. Rev., 2013, 42, 7668; (c) J.-L. Do and T. Friščić, ACS Cent. Sci., 2017, 3, 13; (d) J. G. Hernández and C. Bolm, J. Org. Chem., 2017, 82, 4007; (e) J. G. Hernández, Chem.–Eur. J., 2017, 23, 17157; (f) T. K. Achar, A. Bose and P. Mal, Beilstein J. Org. Chem., 2017, 13, 1907; (g) J.-L. Do and T. Friščić, Synlett, 2017, 28, 2066; (h) D. Tan and T. Friščić, Eur. J. Org Chem., 2018, 18, 18; (i) J. L. Howard, Q. Cao and D. L. Browne, Chem. Sci., 2018, 9, 3080; (j) J. Andersen and J. Mack, Green Chem., 2018, 20, 1435; (k) N. R. Rightmire and T. P. Hanusa, Dalton Trans., 2016, 45, 2352; (l) M. Leonardi, M. Villacampa and J. C. Menéndez, Chem. Sci., 2018, 9, 2042; (m) D. Tan, L. Loots and T. Friščić, Chem. Commun., 2016, 52, 7760; (n) D. Tan and F. García, Chem. Soc. Rev., 2019, 48, 2274; (o) C. Bolmm and J. G. Hernández, Angew. Chem., Int. Ed., 2019, 58, 3285; (p) T. Friščić, C. Mottillo and H. M. Titi, Angew. Chem., Int. Ed., 2020, 59, 1018; (q) I. N. Egorov, S. Santra, D. S. Kopchuk, I. S. Kovalev, G. V. Zyryanov, A. Majee, B. C. Ranu, V. L. Rusinov and O. N. Chupakhin, Green Chem., 2020, 22, 302; (r) A. Pocheddu, E. Colacino, L. D. Luca and F. Delogu, ACS Catal., 2020, 10, 8344; (s) K. Kubota and H. Ito, Trends Chem., 2020, 2, 1066; (t) P. Ying, J. Yu and W. Su, Adv. Synth. Catal., 2021, 363, 1246; (u) K. J. Ardila-Fierro and J. G. Hernández, ChemSusChem, 2021, 14, 2145; (v) V. Martinez, T. Stolar, B. Karadeniz, I. Brekalo and K. Užarević, Nat. Rev. Chem., 2023, 7, 51; (w) N. Fantozzi, J.-N. Volle, A. Porcheddu, D. Virieux, F. García and E. Colacino, Chem. Soc. Rev., 2023, 52, 6680; (x) K. Kubota, Bull. Chem. Soc. Jpn., 2023, 96, 913.
8. For selected works on mechanochemical synthesis using ball milling, see: (a) K. Kubota, T. Seo, K. Koide, S. Hasegawa and H. Ito, Nat. Commun., 2019, 10, 111; (b) K. Kubota, Y. Pang, A. Miura and H. Ito, Science, 2019, 366, 1500; (c) T. Seo, K. Kubota and H. Ito, J. Am. Chem. Soc., 2020, 142, 9884; (d) Y. Pang, J. Lee, K. Kubota and H. Ito, Angew. Chem., Int. Ed., 2020, 59, 22570; (e) T. Seo, N. Toyoshima, K. Kubota and H. Ito, J. Am. Chem. Soc., 2021, 143, 6165; (f) K. Kubota, N. Toyoshima, D. Miura, J. Jiang, S. Maeda, M. Jin and H. Ito, Angew. Chem., Int. Ed., 2021, 60, 16003; (g) R. Takahashi, A. Hu, P. Gao, Y. Gao, Y. Pang, T. Seo, S. Maeda, J. Jiang, H. Takaya, K. Kubota and H. Ito, Nat. Commun., 2021, 12, 6691; (h) T. Seo, K. Kubota and H. Ito, Angew. Chem., Int. Ed., 2023, 62, e202311531; (i) T. Seo, K. Kubota and H. Ito, J. Am. Chem. Soc., 2023, 145, 6823; (j) K. Kubota, J. Jiang, Y. Kamakura, R. Hisazumi, T. Endo, D. Miura, S. Kubo, S. Maeda and H. Ito, J. Am. Chem. Soc., 2024, 146, 1062.
9. T. Portada, D. Margetić and V. Śtrukil, Molecules, 2018, 23, 3163.
10. K. Martina, F. Baricco, S. Tagliapietra, M. J. Moran, G. Cravotto and P. Cintas, New J. Chem., 2018, 42, 18881.
11. S. Menuel, B. Léger, A. Addad, E. Monflier and F. Hapiot, Green Chem., 2016, 18, 5500.
12. Examples of mechanochemical organic reactions using Zn metal: (a) Q. Cao, J. L. Howard, E. Wheatley and D. L. Browne, Angew. Chem., Int. Ed., 2018, 57, 11339; (b) A. C. Jones, W. I. Nicholson, J. A. Leitch and D. L. Browne, Org. Lett., 2021, 23, 6337; (c) A. C. Jones, M. T. J. Williams, L. C. Morrill and D. L. Browne, ACS Catal., 2022, 12, 13681; (d) J. Yin, R. T. Stark, I. A. Fallis and D. L. Browne, J. Org. Chem., 2020, 85, 2347.
13. D. M. Coward, Neurology, 1994, 44, S6.
14. K. A. Ali and E. A. Ragab, Preparations methods of tizanidine (API) and related compounds: A Review, Appl. Chem. Eng., 2023, 6, 12.
15. T.-H. Tsang and D. A. Gubler, Tetrahedron Lett., 2012, 53, 4243.
16. R. A. Sheldon, Green Chem., 2007, 9, 1273.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4mr00138a

---