The phenethylamine scaffold represents a recurring motif among natural and synthetic drug molecules. The latter are mainly constituted by a varied class of substituted phenylethylamines exhibiting psychoactive properties, and typically employed for medical and recreational use . Representative examples include CNS stimulants (amphetamine), antidepressants and antiparkinson’s agents (e.g., ʟ-deprenyl) , hallucinogens and entactogens (e.g., 2,5-dimethoxy-4-iodoamphetamine (DOI) and 3,4-methylenedioxy-N-methylamphetamine (MDMA)) , nasal decongestants (e.g., levomethamphetamine), and appetite suppressants (e.g., phentermine) .

Phenethylamines can be produced via numerous different procedures . One of the oldest methods involves the reduction of benzyl cyanide with H2 in liquid ammonia with Raney-Nickel catalyst at 130 °C, and high pressure . Another known method is based on the reductive amination of phenyl-2-propanone by use of Al/Hg amalgam. The latter procedure involves numerous drawbacks, such as environmental concerns for the use of mercury, contamination of the final products, the need of special safety precautions, and adequate disposal techniques .

Scheme 1: Brief comparison between the main traditional synthetic routes for the preparation of substituted phenethylamines from β-nitrostyrene scaffolds and our work.

Differently from lithium aluminum hydride, sodium borohydride is a non-pyrophoric and easy-to-handle reducing agent. Since the first attempts in 1967, NaBH4 has been employed to reduce β-nitrostyrene scaffolds to the corresponding nitroalkanes . Several catalysts have been combined with NaBH4 to facilitate full reduction of β-nitrostyrenes to phenethylamines, however, to date, no effective method for converting α,β-unsaturated nitroalkenes into aminoalkanes have been developed using NaBH4 as reducing agent .

The number of procedures reported in the literature regarding the reduction of β-nitrostyrenes is limited, since a NaBH4/transition metal salt system is mostly used to reduce nitroarenes .

One of the reported methods takes advantage of titanium(IV) isopropoxide as a catalyst to prepare varied β-phenethylamine analogues. Despite its simplicity, the reaction time is quite prolonged (from 18 to 20 hours), and this procedure is not used to prepare α-phenethylamines .

Figure 1: The β-nitrostyrene analogues used in this work.

Table 1: The reduced β-nitrostyrene scaffolds with their corresponding products (entries 1–6). The isolated product yields were obtained by performing the reactions at 80 °C for the time indicated beside each product. For more details, see the experimental section below.

Scheme 2: Additional products obtained via this method: nitrobenzene and methyl benzoate are reduced in excellent yields.

Therefore, the NaBH4/CuCl2 system was proved to work on aromatic ester, nitro, and α,β-unsaturated nitroalkene functionalities.

Our work demonstrates that, up to 24 hours, this method shows some degree of functional group tolerance, as the amido and carboxylic acid functionalities of benzamide and benzoic acid, were left untouched, and the starting materials were finally fully recovered.

1-Bromo-4-nitrobenzene (8a) and 3-chlorophenol were used to test the potential effects on halogenated aromatic structures and no dehalogenation was detected up to 24 hours stirring. The retention of halogen atoms on aryl halides distinguishes this procedure from traditional techniques, such as those involving LiAlH4, which can cause dehalogenation .

The role of the CuCl2 salt is pivotal to the success of this method. Studies on the reduction of CuCl2 by NaBH4 suggest that copper(II) is promptly reduced to free Cu(0), composing up to 96% of the products. The remaining 4% consist of Cu2O and negligible amounts of other copper species . Consistently, once the chloride is added, the reduction to free Cu(0) is visually indicated by the immediate disappearance of the blue color of the copper(II) solution, and the formation of a fine suspended black powder. The latter, as metallic copper particles, acts as the actual catalyst.

Time plays a crucial role in the synthesis of phenethylamine analogues via this method. Dithering before the addition of the copper solution leads to the formation of Micheal adducts, which decrease the product yields. This phenomenon is due to the nature of β-nitrostyrenes, displaying considerable delocalization towards the nitro group, which makes them highly susceptible to Michael addition .

While being stirred with the borohydride, the substrate progressively forms an α-carbanion in the newly formed nitroalkane, which ultimately leads to Michael addition to the nitrostyrene.

Figure 2: Numerous masses (m/z) were detected by ESI-MS at T = 0 upon mixing all the reagents to produce 1b.

Figure 3: Structures of proposed adducts. Their masses, 254.2 and 242.2, respectively, were found at T = 0 by UPLC-MS investigation.

Scheme 3: Proposed mechanism for the formation of the hydroxylamine side product b. N-Phenethylhydroxylamine (d), originated during the reduction process, reacts with the acetaldehyde e resulting from the hydrolysis of the aldoxime precursor c.

Further research is required to clarify the formation of high molecular weight structures both prior to and following the production of the target compounds.

In summary, the presented procedure represents a simple, higher-yielding, and faster alternative to the conventional reductive methods used to date for the synthesis of substituted phenethylamines from their α,β-unsaturated nitroalkene analogues. Furthermore, the NaBH4/CuCl2 system is effective at reducing nitro and ester functionalities on aromatic structures, while leaving intact benzoic acid, amido- and halogenated aromatic compounds.

NMR spectra were recorded on Bruker Avance 400 MHz or Bruker Avance III HD 600 MHz spectrometers. Residual solvent peaks (CDCl3, D2O, CD3OD, (CD3)2SO) were used as internal standard (7.26, 4.79, 3.31, and 2.50 ppm for 1H, and 77.16, 49, and 39.52 ppm for 13C, respectively). UPLC-MS analyses were performed on a Waters Acquity H-class UPLC with a Sample Manager FTN and a TUV dual wavelength detector coupled to a QDa single quadrupole analyzer using electrospray ionization (ESI). UPLC separation was achieved with a C18 reversed-phase column (Acquity UPLC BEH C18, 2.1 mm × 50 mm, 1.7 µm) operated at 40 °C, using a linear gradient of the binary solvent system of buffer A (Milli-Q H2O/MeCN/formic acid, 95:5:0.1 v/v) to buffer B (MeCN/formic acid, 100:0.1 v/v) from 0 to 100% B in 3.5 min, then 1 min at 100% B, flow rate: 0.8 mL/min. Data acquisition was controlled by MassLynx ver. 4.1 and data analysis was done using Waters OpenLynx browser ver. 4.1.

Solvents were commercial HPLC grade and used without further purification. The substrates 2a, 7a, and 8a were commercially available and used without further purification. The substituted β-nitrostyrenes 1a and 3a–6a were prepared as described in the literature . 9a was prepared by modification of the literature .