Phenylethylamine derivatives possess a broad spectrum of biological activity and fulfill an important function in animal metabolism¹. Synthetic beta-phenylethylamines are the key substances in the synthesis of a number of isoquinoline alkaloids: 1-benzylisoquinolines, N-benzylisoquinolines, aporphines, and diisoquinolines². Despite the large number of publications devoted to the synthesis of beta-phenylethylamines, this problem has hitherto remained unsolved. In the present paper we give the results of a search for an effective and extremely accessible method of synthesizing substituted beta-phenylethylamines.

Of known methods, the greatest attention has been attracted by two fundamentally different schemes of obtaining amines: via nitriles (Scheme 1) and via nitrostyrenes (Scheme 2). Judging from information in the literature, neither possesses a clear advantage, and we have therefore performed the synthesis of a number of amines by both schemes, carrying out the optimization and modification of the individual processes.

The industrial production of papaverine includes the synthesis of 3,4-dimethoxyphenylacetonitrile (IVb) from veratrole (VI) in 38% yield³. The low yield of the desired nitrile induced us to use the aldehydes (1a-d) instead of the ether (VI) as the starting material.

The alcohols (II) were obtained by the method of reducing the aldehydes (I) with sodium borohydride which is widely used in the laboratory (yield 98%)⁴, and also by a method⁵ using copper chromite in a current of hydrogen, which enables the reaction to be performed on a large scale. The results of the reduction of piperonal over copper chromite are given below:

The best results were obtained on the hydrogenation of piperonal at 170°C under a pressure of 230 atm. Similar yields were given by the reduction of veratraldehyde (Ib), while it was impossible to obtain isovanillyl alcohol (IIc) by this method in satisfactory yields. The further transformation of the alcohols (II) into the nitriles (IV) was carried out as described in Ref. 4 with 65-81% yields calculated on the initial aldehydes. Thus, the yields of the nitriles (IV) from the aldehydes (I) were twice as great as the yield of nitrile (IVb) from veratrole (VI) (Scheme 1).

The subsequent reduction of the 3,4-methylenedioxyphenylacetonitrile (IVa) obtained to the amine (Va) was performed by analogy with the industrial hydrogenation of (IVb)³ over a skeletal nickel catalyst in alcohol and alcoholic ammonia at elevated pressures and temperatures. The results of the catalytic hydrogenation of homopiperonylonitrile are given below:

The best yield of homopiperonylamine (Va) was 68-73%, but the product obtained was contaminated with secondary amines, which complicated its purification and lowered the yield of the desired amine (Va). It was impossible to increase the yield either by varying the ratio of the reactants or by changing the other parameters.

We obtained good results by using as the reducing agent diisobutylaluminum hydride (DIBAH)⁶ and diisobutyllithioaluminum hydride (DILAH). With the reverse order of performing the reaction, when the DIBAH was added to the nitrile (IVa) the best yields were obtained with the use of ether and tetrahydrofuran (THF) as solvents at a ratio of nitrile (IVa) to DIBAH of 1:5 (Table 1). When a solution of the nitrile (IVa) was added dropwise to DIBAH (direct order), the yield of amine increased by 10-15% (Table 1). This is probably due to the fact that in the reverse order of performing the reaction the deficiency of the DIBAH at the beginning of the reaction leads to the formation of by-products from the N-alumoimine.

A synthesis of homoveratrylamine (Vb) based on the electrocatalytic reduction of the nitrile (IVb) with 96% yield has been proposed fairly recently. Such a yield of the amine (Vb) (96%, GLC) is comparable with the yield of homopiperonylamine [82-88% of the hydrochloride of (Va) was isolated] that we obtained on reduction with DIBAH.

Of other variants of the preparation of substituted beta-phenylethylamines attention is attracted by a route through the reduction of nitrostyrenes which is shorter than the first (Scheme 1) and avoids working with sodium cyanide.

The preparation of the nitrostyrene (VII) is described in detail in the literature^8-11 and information is given on the advantage of the method using ammonium acetate⁸; however, the results of other authors^1,9 contradict these conclusions. We have compared the yields of nitrostyrenes that we obtained in the condensation of aldehydes (Ia) and (Ib) with nitromethane catalyzed by methylamine (method A)⁸, by ethylamine (method B)⁹, by a solution of caustic soda (method C)¹⁰, and by ammonium acetate (method D)^8,11. The most stable results were obtained when the reaction was performed by method D (Table 2). In spite of the high yields of reaction products, methods A, B, and C were inefficient. The substances (VIIa) and (VIIb) synthesized by these methods were contaminated to different degrees by high-melting polymeric products which interfered with their purification. Method D gave the required nitrostyrene with a yield of 70-80% without perceptible contamination by high-molecular-mass products.

According to the literature, the passage from the nitrostyrenes (VII) to amines can be effected by reduction with lithium aluminium hydride^11,12, sodium bis(2-methoxyethoxy)aluminum hydride¹³, amalgamated zinc dust¹⁴, and hydrogenation over Raney nickel¹⁵ or a palladium catalyst^1,16, etc. We have performed a series of experiments (more than 50) on the hydrogenation of the nitrostyrenes (VIIa) and (VIIb) over Raney nickel at elevated temperatures (50-70°C) and pressures (110-120 atm) in various solvents (acetic acid, methanol, and mixtures of methanol and acetic acid in ratios of 4:1, 3:1, and 2:1). The results of the experiments showed that the yields of amines obtained by this method range from 30 to 60%.

We obtained good results in the reduction of nitrostyrenes by LiAlH₄ in ether-tetrahydrofuran solution¹⁷. However, these yields were not stable [for (VIIa) they ranged from 25 to 70%, and for (VIIb) from 50 to 85%]. The use of THF alone as solvent lowered the yields of the amines (Va) and (Vb) to 30%, while in benzene, because of pronounced resinification, the yields did not exceed 10-15%. Performing the reaction in dioxane⁹ shortened it from 12-20 h to 3 h and gave the amine (Va) with a yield of 50%.

Attempting to find another method of reducing nitrostyrenes, we carried out a number of search investigations. Attempts to reduce the nitrostyrenes (VIIa) and (VIIb) by means of sodium borohydride with the addition both of nickel chloride¹⁸ and Raney nickel did not give satisfactory results. When the reaction was performed in an ammoniacal medium with ferrous sulfate, pronounced resinification took place [the yield amounted to 10% for the amine (Va)]. When the nitrostyrene (VIIa) was reduced with Raney alloy¹⁹ in 10 and 15% aqueous caustic soda, the amine (Va) was obtained with yields of 15 and 10%, respectively. The use of 20% aqueous caustic soda in methanol did not increase the yield of amine. An effective reagent for the reduction of nitrostyrenes proved to be diisobutylaluminum hydride, which we are the first to have used for these purposes.

In the search for the optimum conditions of performing the reaction, we used the direct (DO) and reverse (RO) orders of adding the DIBAH. This was dictated by the poor solubility of the nitrostyrenes (VII) in organic solvents. The reverse order is convenient technologically, since a solution of the reducing agent is added to a suspension. However, a detailed investigation of the reaction products (Table 3) showed that this method gives a mixture of primary and secondary amines.

With the direct order of performing the reaction, the desired amine (Va) was obtained with a yield that depended directly on the solubility of the initial nitrostyrene in the solvent. The best yield (at an equal ratio of the reactants) was obtained in dioxane (Table 3). Under similar conditions, in THF the amine (Va) was obtained in 60% yield while an increase in the amount of DIBAH (1:10) led to an 85% yield.

Similar results (80%) were obtained on the reduction by DIBAH of 3,4-dimethoxynitrostyrene (VIIb). The yields of amines containing phenolic hydroxy groups (Vc) and (Vd) did not exceed 45-50%, which is connected with difficulties in the isolation of the amines from the reaction mixture.

The use of DILAH enabled the amount of reducing agent used to be decreased both in the reactions with nitriles (Table 1) and with nitrostyrenes (Table 3).

An analysis of the experimental results given above shows that the proposed method of obtaining amines by Scheme 2 through the stage of reducing nitrostyrenes with DIBAH has advantages over other methods - a stable 60-65% yield, calculated on the initial aldehyde, and a relatively short time of each reaction in the two-stage process.