Organic reaction in water. Part 5. Novel synthesis of anilines by zinc metal-mediated chemoselective reduction of nitroarenes

Abstract

Nitroarenes can be reduced in high yields to the corresponding anilines using zinc metal and NH₄Cl in water without any organic solvent at 80 °C with a simple procedure at low cost. The procedure is powerful enough to reduce sterically hindered 2,6-dimethylnitrobenzene and is chemoselective for nitro groups; ester, amide and halide substituents on aromatic rings are unaffected.

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Green Context

The reduction of aromatic nitro compounds to anilines is a very important synthetic transformation since the nitro group is often used to activate the aromatic nucleus to nucleophilic substitution but the amino group is often used for further derivitisation towards valuable products such as pharmaceuticals. There are many methods for carrying out this reaction and these are generally hazardous to the environment due to the use of organic solvents and can suffer from the need for expensive and sensitive metallic reagents. Here both of these problems are dealt with by using water as the solvent and the relatively benign and inexpensive reagents zinc with ammonium chloride. The procedure is versatile, quick and enables easy separation of the products from the inorganic reagents.

JHC

Introduction

Reduction of nitroarenes leading to aromatic amines is an important key step in the industrial syntheses of dyes, medicinal supplies and agricultural chemicals. Furthermore, the primary aromatic amines are readily converted into diazonium salts, which can be substituted for many other functional groups. Therefore, a variety of methods for the reduction of nitro groups have been developed.² The methods employed generally are catalytic hydrogenation³ such as with Raney Ni, Pd/C and PtO₂, or dissolving metal reduction, for example, with Fe/HCl⁴ and Sn/HCl.⁵ In addition, recently, chemoselective reduction of nitro groups using metallic reducing reagents such as Sm,⁶ In⁷ and B₁₀H₁₄⁸ was reported. However, these reactions require an expensive and/or a moisture-sensitive reagent and an organic solvent, and for catalytic hydrogenation, it is necessary to pressurize the reactor with hydrogen gas. In these methods, there is little consideration given to the environment, cost, safety, or simplicity of operation. On the other hand, recently, in view of human health and environmental concerns, much attention is being paid to ‘Green Chemistry’, which is a chemical methodology to decrease or eliminate the use or generation of hazardous substances in the design, preparation and application of chemical production.⁹ In this area of investigation, there is growing interest in synthetic organic reactions in environmentally friendly water.¹⁰ We have demonstrated a facile reductive coupling of aromatic imines by zinc metal and NH₄Cl in water.¹ In continuation of our progressive investigation into the application of this methodology, we are strongly interested in the development of the chemoselective reduction of nitro groups using a cheap reagent with easy operation in water without any organic solvent, a methodology which would have some advantages in terms of cost, safety, simple operation, human health and environmental concerns as compared with use of an organic solvent. Here, we wish to report that in water without any organic solvent, aromatic amines can be obtained in high yields by an operationally easy chemoselective reduction of aromatic nitro compounds facilitated by cheap zinc metal.

Results and discussion

In preliminary work, we investigated the influence of additives and solvent on reduction of nitrobenzene 1 using zinc metal (Scheme 1 and Table 1). Some zinc and ammonium salts, except for ammonium nitrate, were effective for the reduction of nitrobenzene using zinc metal in water to give aniline 2 in high yield without any other coupling products such as azo- and hydrazo-benzenes (runs 1–9).¹¹ Furthermore, when using α-amino acids as an additive, the reduction of 1 proceeds readily at a neutral pH (runs 10 and 11). We found that an additive was necessary because the reduction did not occur in the presence of zinc metal and methanol, ethanol, or water only. As a solvent for the reduction of 1, water was superior to alcohols such as methanol and ethanol in terms of reaction time (runs 1–3). Reduction of 1 occurred with other metals such as bismuth and magnesium; however, these methods were inferior in terms of the yield of 2 or reaction times compared with that using zinc metal.¹²

Scheme 1

Table 1 Reduction of nitrobenzene under various conditions^a

Run	Additive	Solvent	Reaction time/h	Isolated yield(%)
a 1: 2 mmol, Zn: 14.5 mmol, additive: 4 mmol, solvent: 15 ml.
1	NH4Cl	MeOH	1	79
2	NH4Cl	EtOH	6	80
3	NH4Cl	Water	0.5	84
4	NH4NO3	Water	No reaction	—
5	(NH4)2SO4	Water	1	87
6	MeCO2NH4	Water	0.5	89
7	HCOONH4	Water	0.5	81
8	ZnCl2	Water	0.5	81
9	ZnSO4	Water	1	82
10	L-Alanine	Water	0.5	87
11	L-Glutamine	Water	0.5	78

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On the basis of these results, reduction of other nitroarenes were carried out by using zinc metal and NH₄Cl in water without any organic solvent at 80 °C under atmospheric pressure (Table 2). We found that the reduction of nitroarenes took place smoothly and chemoselectively to afford the corresponding anilines in high yields (entries 4–8). These results demonstrate that reduction-sensitive substituents such as ester (entry 4), amido (entry 5), and halide (entries 6–8) groups are unaffected during this reaction. In addition, the sterically hindered 2,6-dimethylnitrobenzene was readily reduced to the 2,6-dimethylaniline in excellent yield (95%) by this method, which did not require any drastic conditions (entry 3).

Table 2 Reduction of nitroarenes with Zn/NH₄Cl in water^a

Entry	Substrate	Reaction time/h	Product	Isolated yield(%)
a Substrate: 2 mmol, Zn: 14.5 mmol, NH4Cl: 4 mmol, water: 15 ml.
1	2-MeC6H4NO2	0.5	2-MeC6H4NH2	94
2	4-MeC6H4NO2	0.5	4-MeC6H4NH2	93
3	2,6-Me2C6H3NO2	1	2,6-Me2C6H3NH2	95
4	4-MeCO2C6H4NO2	0.5	4-MeCO2C6H4NH2	97
5	4-MeCONHC6H4NO2	1	4-MeCONHC6H4NH2	82
6	4-FC6H4NO2	0.5	4-FC6H4NH2	81
7	4-ClC6H4NO2	0.5	4-ClC6H4NH2	92
8	4-BrC6H4NO2	0.5	4-BrC6H4NH2	90

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For reduction of nitroarenes leading to aromatic amines with zinc metal, methods employing Zn/HCl,¹³ Zn/aq. NaOH/EtOH,¹⁴ Zn/NH₃,¹⁵ Zn/CaCl₂/EtOH¹⁶ and Zn/near-critical H₂O¹⁷ have been reported. However, since the conventional methods require an organic solvent and/or drastic conditions using an irritant reagent such as NH₃, concentrated HCl or 20% aq. NaOH, it is difficult to contend that these methods are environmentally harmonious. In addition, the reaction time is prolonged (24 h) for Zn/NH₃, whilst using Zn/CaCl₂/EtOH, a substantial amount of zinc metal is required (39 equiv.). On the other hand, special apparatus is required when using near-critical water. The greatest advantage of our method compared with other methods is that handling is very easy, and the reaction in water is safe, and cost is low because zinc metal and water as a solvent are cheap.

In conclusion, we have demonstrated an environmentally friendly method for the synthesis of anilines by the chemoselective reduction of nitroarenes with zinc metal in water.

Notes and references

1. Part 4, see: T. Tsukinoki, S. Nagashima, Y. Mitoma and M. Tashiro, Green Chem., 2000, 2, 117.
2. R. C. Larock, Comprehensive Organic Transformations: a Guide to Functional Group Preparations, Wiley-VCH, New York, 2nd edn., 1999, pp. 823–827..
3. G. V. Smith and F. Notheisz, Heterogeneous Catalysis in Organic Chemistry, Academic Press, New York, 1999, pp. 71–79..
4. C. A. Merlic, S. Motamed and B. Quinn, J. Org. Chem., 1995, 60, 3365.
5. 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.
6. B. K. Banik, C. Mukhopadhyay, M. S. Venkattaman and F. F. Becker, Tetrahedron Lett., 1998, 39, 7243; L. Wang, L. Zhou and Y. Zhang, Synlett, 1999, 1065.
7. C. J. Moody and M. R. Pitts, Synlett, 1998, 1028.
8. J. W. Bae, Y. J. Cho, S. H. Lee and C. M. Yoon, Tetrahedron Lett., 2000, 41, 175.
9. P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford, New York, 1998, pp. 1–129; P. T. Anastas and T. C. Williamson, Green Chemistry: Frontiers in Benign Chemical Syntheses and Processes, Oxford, New York, 1998, pp. 1–360..
10. C.-J. Li and T.-H. Chan, Organic Reactions in Aqueous Media, John Wiley & Sons, New York, 1997, pp. 1–189; P. A. Grieco, Organic Synthesis in Water, Blackie Academic & Professional, London, 1998, pp. 1–305; Mordern Solvents in Organic Synthesis, ed. P. Knochel, Springer, Berlin, 1999, pp. 41–59..
11. General procedure: to a stirred mixture of nitrobenzene (246 mg, 2 mmol) and water (15 ml), NH₄Cl (214 mg, 4 mmol) and zinc metal (950 mg, 14.5 mmol, powder) were added at room temperature. After the reaction mixture was stirred for 30 min at 80 °C, the insoluble materials were filtered off and the filtrate was extracted with ethyl acetate. The extract was washed with water, dried (MgSO₄) and evaporated in vacuo to give a residue, which was distilled on a Kugelrohr apparatus (oven temperature: 94–95 °C) under reduced pressure (16 Torr), to afford aniline (156 mg, 84%)..
12. Bi (14.5 mmol): reaction time: 24 h, yield: 33%; Mg (39 mmol): reaction time: 6 h, yield: 28%..
13. E. Kock, Chem. Ber., 1887, 20, 1567.
14. E. L. Martin, Org. Synth., 1943, Coll. Vol. II, 501..
15. A. Burawoy and J. P. Critchley, Tetrahedron, 1959, 5, 340.
16. R. Shundberg and W. Pitts, J. Org. Chem., 1991, 56, 3048.
17. C. Boix and M. Poliakoff, J. Chem. Soc., Perkin Trans. 1, 1999, 1487.

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