A safe and convenient synthesis of 4-benzyloxy-3-chloroaniline 1

A convenient, safe, large-scale synthesis of the title compound 4-benzyloxy-3-chloroaniline is described. The commercially available 4-benzyloxy-3-chloronitrobenzene is reduced conveniently using SnCl 2 to afford 4-benzyloxy-3-chloroaniline in high yield, high purity, and free of tin residues. This process is suitable for kilogram-scale synthesis of the title compound.


Introduction
4-Benzyloxy-3-chloroaniline has been frequently used as a building block in the construction of potential anti-cancer, [2][3][4][5][6][7] anti-diabetes 6 and anti-viral 8 agents.Despite the widespread use of this compound, its preparation has not been thoroughly discussed in the literature except for a few limited examples involving small scale (milligrams to grams) preparations.The methods currently reported in the literature include: (1) reduction of 2-chloro-4-nitrophenol to 3-chloro-4hydroxyaniline using Zn/NH 4 Cl in MeOH/H 2 O, followed by Boc protection of the amine, benzylation of the hydroxy group and deprotection of the Boc group, 9 (2) reduction of 4benzyloxy-3-chloronitrobenzene by either Raney Ni 10 or Pd/C 4 catalyzed hydrogenation, and (3) reduction of 4-benzyloxy-3-chloronitrobenzene mediated by Fe powder in acetic acid 8 or NH 4 Cl solution. 11,12In connection with one of our development projects, we needed quick access to large amounts of this compound.
Although 4-benzyloxy-3-chloroaniline is commercially available, we quickly found that its purity did not always meet our specifications and could not be used directly.Some commercially available samples were contaminated with 4-amino-2-chlorophenol (4), most likely due to poor control during a hydrogenation step involving 4-benzyloxy-3-chloronitrobenzene (vide infra).
Following a brief survey of the reported procedures, we chose to avoid any large-scale process using hydrogenation conditions involving Raney nickel due to safety concerns associated with its use and the possibility of residual nickel being left in the final product.The reduction of 4-benzyloxy-3-chloronitrobenzene using traditional Pd/C catalyzed hydrogenation conditions has been reported for the preparation of 4-benzyloxy-3-chloroaniline but without detailed experimental procedures. 4Although this approach was attractive to us, we envisioned that careful control of the reaction conditions would be needed to avoid the possible debenzylation and/or dechlorination.
In order to test this reduction, we reacted 4-benzyloxy-3-chloronitrobenzene in ethanol:THF co-solvents (1:1 v/v) with 0.5 mol% of Pd on activated carbon under 20 psi of H 2 at ambient temperature.The reaction proceeded rapidly to afford, within 30 min, a reaction mixture containing compounds 2, 3 and 4 with compound 4 as the major product.Only a trace amount of the desired compound 5 was detected (LC-MS and 1 H NMR analyses, Scheme 1).Based on these findings we decided to explore preparing the title compound using nonhydrogenation conditions, starting with the commercially available 4-benzyloxy-3chloronitrobenzene.We required the process to be simple and safe, and amenable for further scale-up.We first tried to reduce 4-benzyloxy-3-chloronitrobenzene in acetic acid with Fe powder since Fe powder in acetic acid has been known to reduce the nitro compounds successfully to their corresponding amines. 3,8,13As expected, when 4-benzyloxy-3chloronitrobenzene was heated with Fe powder in refluxing acetic acid, the nitrobenzene starting material was quickly consumed.However, to our surprise the only product isolated was acetylaniline 6: the acetylation product of the aniline intermediate (Scheme 2).Although we believed that the formation of this by-product could be controlled by adjusting the reaction conditions we chose not to pursue this route further because of the difficulty of removing acetic acid on large scale and the expected exothermic feature of this reaction. 13cheme 2. Reduction of nitrobenzene 1 using Fe in acetic acid.
Reduction of 4-benzyloxy-3-chloronitrobenzene by powdered Fe in NH 4 Cl solution 11,12 is also known and could be used for large scale preparation of 4-benzyloxy-3-chloroaniline.However, its workup requires tedious multiple extractions and filtrations.We therefore chose not to pursue this method.Stannous chloride is well known to reduce an aromatic nitro compound to the corresponding aniline under very mild reaction conditions, while a benzyl group and a chlorine functionality is stable under these conditions. 14Further more, stannous chloride reduction of aromatic nitro compounds can usually be performed under homogeneous conditions, and we believed that one could precipitate the aniline products as their hydrochlorides directly from the reaction mixture.In fact, Bellamy et.al. 14 reported the reduction of 4benzyloxynitrobenzene to 4-benzyloxyaniline using stannous chloride under neutral conditions.Under the conditions reported we encountered a thick suspension that made isolation of the product by extraction very difficult.We were glad to find that using acidic conditions afforded a more practical process for the preparation of the title compound.Thus when 4-benzyloxy-3chloronitrobenzene was treated with 4 equivalent of SnCl 2 (or SnCl 2 •H 2 O) in acidic aqueous ethanol, the reduction proceeded smoothly and quickly to generate 4-benzyloxy-3-chloroaniline (5) without formation of any detectable debenzylated or dechlorinated side-products.Within one and a half hours, HPLC analysis and TLC analysis indicated that the starting material was completely consumed.Water was then added to the reaction mixture and the aniline hydrochloride precipitated as an easily filterable off-white solid.The solid was collected by simple filtration and washed with water to remove soluble inorganic salts.The wet cake was dried to afford the hydrochloride of the title compound in nearly quantitative yield.
To prepare the free base form of the title compound, the solid was treated with a 2N NaOH solution and extracted with dichloromethane or ethyl acetate.Alternatively, the wet cake was treated without drying with a 2N NaOH solution to pH 12, and the mixture extracted with dichloromethane or ethyl acetate, washed with brine, dried (Na 2 SO 4 ), filtered and concentrated to afford the free base form of 4-benzyloxy-3-chloroaniline as an off-white solid.The purity of the product prepared in this method was satisfactory for our use (>99% by HPLC area analysis), and the amount of residual Sn in the material was at the level of 1 ppm (Scheme 3). 15If desired, the material can be further purified by recrystallization in ethyl acetate/heptane to generate 4benzyloxy-3-chloroaniline as an off-white crystalline solid free of any tin residues.In summary, we have reported here that SnCl 2 effectively reduced 4-benzyloxy-3chloronitrobenzene to form 4-benzyloxy-3-chloroaniline in excellent yield without cleaving either the benzyl group or the chlorine group.The process is simple, safe and can be easily scaled-up to provide larger amount of material in excellent purity and yield.

4-Benzyloxy-3-chloroaniline (5).
In a 5 L, 3-necked round bottom flask equipped with an overhead stirrer, a thermal couple and a water-cooled reflux condenser was added tin(II) chloride dihydrate (427.8g,1.90 mol), ethanol (1250 mL) and concentrated HCl (250 mL).The mixture was stirred and heated to 70 °C to become a clear solution.To this hot solution was added portion-wise 3-chloro-4-benzyloxynitrobenzene (129.0 g, 0.48 mol, 5 portions over 30 min).The solution was kept slightly refluxing during the addition.After the addition, the mixture was heated for 1.5 hours at which time TLC and HPLC analysis indicated that no starting material remained.Water (1250 mL) 15 was added and the resulting solution was allowed to cool to room temperature.The product precipitated as a white solid during cooling.The mixture was further cooled and stirred for 30 min at 15 °C and the precipitation was collected by vacuum filtration through a Medium-sintered glass funnel, washed with water (2 x 250 mL then 500 mL), suction dried thoroughly and further dried in a vacuum oven at 50 °C under house vacuum until constant weight to afford 4-benzyloxy-3-chloroaniline hydrochloride as an off-white powder (131.1g,99%).Mp (by DSC): 224.4 °C.For the preparation of the free base form of 4-benzyloxy-3-chloroaniline, the drying step is not necessary.The wet solid was transferred to a 1 L 3-necked round bottom flask equipped with an overhead stirrer and dichloromethane (200 mL) was added.The suspension was cooled with an ice-water bath.NaOH solution (2 N) was added with stirring to adjust the solution to pH ~12 (300 mL of NaOH solution added).The mixture was transferred to a separatory funnel and the organic phase was separated.The aqueous phase was extracted with dichloromethane (2 x 200 mL).The combined organic phase was washed with brine (100 mL) and dried (MgSO 4 ), filtered ARKAT USA, Inc. and concentrated in vacuo to afford the product as an off-white solid (90.0g, 79%). 1