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08-23-02 10:44
No 348137

Bull. Soc. Chim. Fr. (1993) 130, 459-466
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On the key precursor epoxides, aminoalcohols and aziridines in the asymmetric synthesis of (S)-fenfluramine

Introduction

During our studies on the asymmetric synthesis of (S)-fenfluramine 1 [1], we investigated the following scheme, using classical reactions and simple intermediates: alkenes, epoxides, aminoalcohols and aziridines:

The asymmetric center can for example be introduced using the alkene 2E using enantioselective epoxidation. This method is subject of lots of research and the yields are constantly improved [2]. The such obtained epoxide 3trans is then subjected to the action of a carefully selected nucleophile in order to give the enantiomerical pure aminoalcohol 4E. Hydrogenolysis of the hydroxyl in benzylic position will give (S)-fenfluramine 1. The aminoalcohol 4E and the aziridine 5trans could also be obtained starting with the alkene 2E using enantioselective hydroxyamination [3, 4] or enantioselective aziridination. This latter method, studied by multiple teams in the last years [5, 6] deserves being considered, because encouraging results have been obtained recently [7]. Another alternative would be the regiospecific reduction of the epoxide 3trans to the alcohol (R)-6, of which we have shown before that it can be used as precursor for (S)-fenfluramine in multiple processes.

We studied some of these possibilities starting with the alkenes 2E, 2Z and 7. Before embarking upon the asymmetric epoxidation, hydroxyamination and aziridination of these alkenes, we realised the synthesis of all compounds of the racemic series (schema 2). The results of these preliminary studies, which allowed us to characterise the different intermediates and to study the limits of each reaction, are presented in this paper. Then we studied the synthesis of (S)-fenfluramine 1 via the intermediate aminoalcohol (S)-9.

Results and discussion

Starting with the isomeric alkenes 2E, 2Z and 7 we have investigated three parallel reaction paths (schema 2).

We have pictured the optical active products, only which are of interest for the asymmetric synthesis of (S)-fenfluramine, but all the presented reactions were realised using racemic products, with the exception of the transformation 9 -> 12 -> 1.

Preparation of the epoxides and the aminoalcohols

The alkene 7 is obtained by condensation of 3-(trifluoromethyl)phenyl magnesium bromide with allyl chloride in refluxing ether, then isomerised by the action of sodium hydroxide in refluxing n-butanol into a mixture of the alkenes 2Z and 2E (2E/2Z : about 85/15), which are separated by distillation. The epoxides 3trans, 3cis and 8 were obtained by reacting 3-chloroperoxybenzoic acid (mCPBA) with the corresponding alkene and purification by distillation.

According to the literature [9] it seems rather difficult to obtain uniform ring opening of the epoxides favouring the aminoalcohols 4 and 10. In a first attempt we reacted the epoxides with ethylamine in ethanol during two days at 70?C, hoping to obtain and characterise the different aminoalcohols 4, 9, 10 and 11.

Starting with the epoxide 8 we have isolate the alcohol 9, pure according to GC, with a yield of 97% without purification. The regioisomer aminoalcohol 10 could not be detected.

The epoxide 3trans gives the aminoalcohols erythro 4E and 11E (4E/11E: 24/76) with 82% yield. The epoxide 3cis gives the epoxides threo 4T and 11T (4T/11T: 93/7) with 86% yield. This result was obtained by extrapolation because the sample used contained 8% of the epoxide 3trans. The products were separated by chromatography on silica. The configurations could be revealed using the 1H NMR coupling constants between the protons attached to the carbons attached to the heteroatoms and by comparison to the aminoalcohols with related structure [10].

The results show an inverse regioselectivity for the epoxides 3trans (4E/11E: 24/76) and 3cis (4T/11T: 93/7). Using the epoxide 3cis, one obtains better regioselectivity and further it gives the preferred product 4T. Ring opening in alpha position to the aromatic group predominates only in the case of the isomer 3trans where the conjugation of the aromatic group with the neighbouring carbon, carrying the oxygen, is possible.

Try at the hydrogenolysis of the benzylic hydroxyl function of the aminoalcohols 4

According to the literature [11], hydrogenation of an alcohol group in benzylic position is easy and is performed in mild conditions (5% Pd/C in alcohol at room temperature and standard pressure). However beta-aminated benzylic alcohols are much harder to hydrogenolyse: the yield is acceptable when the reaction is performed in acidic medium [12-14].

Our experiments, using a mixture of the aminoalcohols 4E + 4T + 11E + 11T and different conditions were not successful: when using mild conditions (ethanol-60?C-24h without activator), the reactants were isolated unchanged, and using harder conditions (acetic acid or water-100-110?C-1 to 16 h-in presence of concentrated hydrochloric and sulfuric acid), gives general degradation. The expected products, the amine 1 and the alcohol 6 could only be detected in trace amounts. We believe that the trifluoromethyl group renders the cutting in benzylic position difficult by deactivating the aromatic ring.

The regioselective opening of the epoxides on one hand and the difficulties of the hydrogenolysis of the aminoalcohols 4 and 11 on the other hand made us study a new strategy, going via the aziridines 5 and 12. One notes that the 2 aminoalcohols 4E and 11E give the same aziridine 5trans, likewise the aminoalcohols 4Z and 11Z giving the aziridine 5cis. A given epoxide is transformed into the aziridine with opposite configuration (see scheme 2).

Preparation of the aziridines

One finds in the literature multiple methods giving aziridines starting from aminoalcohols [15-19]. They all use phosphorus compounds, with the exception of the method by Wenker [19] which uses concentrated sulfuric acid in very hard conditions. Using phosphorus compounds, the transformation is realised in one step in mild conditions. One can use dibromo-triphenylphosphine in presence of triethylamine [15], triphenylphosphine in presence of triethylamine and carbon tetrachloride [16], tretraiodophoshporus [17] and (diethoxy triphenyl)phosphorane [18]. In two cases [15, 18], the conservation of the chiral centres by Walden inversion has clearly been established.

The method we retained used the simplest and most easily accessed reagents: triphenylphosphine, triethylamine and carbon tetrachloride [16]. Starting with the aminoalcohols 4, 11 and 9 we thus obtained the aziridines 5cis, 5trans and 12, which have never been described before. The yields after purification by distillation are between 70 and 75%.

For the preparation of the aziridine 12 we have also carried out multiple experiments with triethyl phosphite. The yield is a bit less (60%). This variation of the original method [16] has never been described as far as we know.

Going via these aziridines has the following advantages: it is unnecessary to separate the aminoalcohols 4 and 11, and the useless aminoalcohol 11 is such recycled in the reaction without any additional work. It is also a quick method for the valorisation of the aminoalcohol 9. Further, it is no longer necessary to bother with the regioselectivity of the nucleophilic attack on the epoxide, which allows the usage of the simplest method for the preparation of the aminoalcohols: ethylamine in ethanol.

Reduction of the aziridines

It remained to work out the transformation of the aziridines 5 and 12 into fenfluramine 1. The aziridines 5 can lead to the amines 1 and 13, the aziridine 12 to the amines 1 and 14 [20] (scheme 3).

In order to realise the ring opening of the aziridines 5 and 12 into fenfluramine 1, we used catalytic hydrogenation [11], peculiar to open the ring at the less substituted side, in the case of the aziridine 12, and benzylic hydrogenolysis in the case of the aziridines 5. The experiments were performed in ethanol at standard temperature and pressure (table I).

We noted that in all three cases the reaction is perfectly regioselective, the amines 13 and 14 could not be detected. The only observed side reaction is the formation of the diethylamine 15, especially when using palladium on calcium carbonate. We believe that, on contact with the catalyst, the ethanol is dehydrogenated into acetaldehyde [21] which gives the diethylamine by amination of the amine 1 formed during the reduction. Provided that the regioselectivity is preserved, the replacement of ethanol by another solvent should allow to obtain the pure amine 1.

Usage of palladium on carbon minimises the formation of diethylamine 15 in the case of the aziridines 5trans and 12. On the other hand, the aziridine 5cis is less reactive and needs a reaction time of 3 days instead of one. Therefore the byproduct is present in non deniable amounts.

Reduction of the epoxides

The epoxide 3 can lead to the alcohols 6 and 16 and the epoxide to the alcohols 6 and 17.

Only the alcohol 6 is a potential precursor of the fenfluramine 1.

Given the satisfying results obtained using the aziridines, we realised the same type of study (table II).

The alcohol 16 was never detected. In the case of the epoxide 8, the alcohol 17, formed when using palladium on carbon, disappears when replacing the latter by palladium on calcium carbonate.

Among the byproducts one finds the deoxygenated product 18, when using palladium on carbon and the ketone 19, formed by dehydrogenation of the alcohol 6 on contact with the catalyst [21], particularly when using palladium on calcium carbonate.

Thus, like in the case of the aziridines, we were able to obtain a regioselective ring opening of the epoxides 3 and 8 by hydrogenolysis of the bond in benzylic position using palladium on carbon in the case of the epoxide 3 and by hydrogenation of the ring on the less substituted side by palladium on calcium carbonate in the case of the epoxide 8.

Asymmetric synthesis of the (S)-fenfluramine

From a stereochemical viewpoint, one could contemplate to access the many proposed precursors of the amine 1 (epoxide, aminoalcohol or aziridine) by totally different reactions than those we have described. Thus the validity of our reaction scheme for the asymmetric synthesis of (S)-fenfluramine has been shown starting with the aminoalcohol (S)-9. The latter was prepared using the epoxyalcohol (1R,2R)-20, which in turn was obtained by asymmetric epoxidation of the corresponding allyl alcohol according to the method of Sharpless and transformed into fenfluramine via the intermediate aziridine (R)-12 (schema) using the technique described above.

The comparison of the enantiomeric excesses of the epoxyalcohol 20 and the fenfluramine (S)-1 shows that there is no racemisation during the different reactions, notably during the cyclisation into aziridine. The detailed results of these transformations will be published later [22].

Conclusion

Regarding synthesis, we have prepared and characterised a number of intermediates: racemic epoxides, aminoalcohols and aziridines, and shown possible synthetic pathways to fenfluramine 1 using simple methods starting with the alkenes 2Z, 2E and 7.

Regarding stereochemistry, we have shown the validity of our reaction scheme to prepare (S)-fenfluramine starting with the aminoalcohol (S)-9. The enantioselective epoxidation, hydroxyamination and aziridination reactions can now be approached.

From a general point of view, given the large applicability of the presented reactions, the regiospecificity of the hydrogenation reactions and the hydrogenolysis, we believe that this work gives new perspectives for the synthesis of 2-(alkylamino)-1-arylpropanes and 1-arylpropane-2-ols which are potential precursors.

Experimental part

General indications

The 1H NMR spectra were recorded on an Perkin Elmer R 12 (60 Mhz) or a Bruker AW 80 (80 MHz), the 13C NMR spectra on a Varian CFT 20 (20 MHz). The chemical shifts are expressed in ppm. Unless otherwise noted, the solvent is deuterochloroform and the internal reference is TMS.

Concerning the 13C NMR spectra: the used spectrometer did not allow the recording of fluorine and proton decoupled spectra at the same time. The carbon of the CF3 group (q, 2JCF=271.7 Hz) and the carbon on alpha to the CF3 group (q, 2JCF=32.3 Hz) are only hardly or not at all visible. They were never indicated. On the other hand, the 2 carbons beta to the CF3 group are very characteristic (q, 3JCF=3.9 Hz).

The IR spectra were recorded using a Perkin Elmer 377. The melting points were measured using a melting point microscope Reichert Jung. The microanalyses were performed by the common microanalysis service of the INSA of Rouen.

The gas chromatographs were realised with a Girdel series 30 chromatograph with a flame ionisation detector. The used columns are:
Column A: 30% SE 30 + 1% triethanolamine on chromosorb W AW 80-100 mesh (0.75 m) (maximum usage temperature: 150?C)
Column B: 2.5% SE 30 + 2.5% XE 60 on chromosorb W AW 80-100 mesh (1.50 m)
Column C: 5% carbowax 20M on chromosorb W AW 100-120 mesh (1.40 m)
Unless otherwise noted, column A was used.

The percentages of the components were measured using a Shimadzu C-R1B integrator.

The TLCs were realised on silica plates Merk Kieselgel 254GF with 0.25mm thickness. They were developed using UV (254 nm) or an ethanolic vanilline solution.

The silica used for purification is a Merck Kieselgel 60 230-400 mesh. It was used as is.

The anhydrous ether was distilled over sodium and benzophenone right before use. The dichloromethane was distilled and filtered over basic aluminium. The acetonitrile was dried and distilled over calcium hydride. The RPE anhydrous ethanol (Carlo Erba) was used as is.

None of the described reactions was optimised.

Preparation of the alkenes

- 3-[3-(Trifluoromethyl)phenyl]propene 7

The magnesium compound is prepared liked previously described [8] using 3-(trifluoromethyl)bromobenzene (50.2 g; 223 mmol) and fine magnesium turnings (5.55 g; 228 mmol). After 30 min at room temperature, the reaction is newly refluxed. Allyl chloride (17.6 g; 230 mmol) in ether (30 ml) is then added over 45 min. The reaction is refluxed for 2h then cooled and poured on ice (65g). The flask is rinsed with water (20 ml). The phases are separated and the aqueous phase extracted with ether (45 ml). The combined organic phases are dried over magnesium sulfate, filtered and evaporated. After distillation (bp = 54-54?C/13-14 mm Hg), the alkene 7 (33.8 g; 81% yield) is obtained.
IR(film): 1745 cm-1 (C=C)
1H NMR: 3.45 (d, J=10.0 Hz, 2H); 4.85-5.25 (m, 2H); 5.60-6.30 (m, 1H); 7.20-7.50 (m, 4H).
13C NMR: 39.8 (t); 116.5 (t); 122.9 (d); 125.2 (d); 128.7 (d); 131.9 (d); 136.3 (d); 141.0 (s).
Anal: C10H9F3; Calc % C 64.51; H 4.87; Found % C 64.5; H 4.5

- 1-[3-(trifluoromethyl)phenyl]propene 2 cis and 2 trans

Sodium hydroxide (392 mg 9.8 mmol) is added to 3-[3-(trifluoromethyl)phenyl]propene (33.1 g; 178 mmol) in n-butanol (33 ml). The reaction is refluxed for 7h, cooled and tranfered into a separatory funnel. It is washed with 3N hydrochloric acid (4 ml), water (2 x 3.5 ml), and distilled: first the n-butanol then the products (bp = 66-70?C/13-14 mm Hg). A mixture of both isomers is obtained (31.1g; 94% yield; cis/trans = 13/87 according to GC).

In order to separate both isomers, we have distilled 21g of the mixture at 15 mmHg through a Nester Faust spinning band column and obtained 3 main fractions:

63?C <= bp <= 65?C: 1.85g (yield = 9%) GC: 89% 2cis
65?C < bp < 73?C: 3.90 g (yield = 19%) GC: cis/trans = 24/76
bp = 73?C: 14.5g (yield = 71%) GC: 98.4% 2trans

Alkene 2cis (1st fraction): bp = 63-65?C/15 mm Hg. GC purity = 89% (8% 2trans and 3% impurities) (column B)
IR (film): 1650 cm-1 (C=C)
1H NMR: 1.85 (dd, J=0.9 and 6.7 Hz, 3H); 5.60-6.60 (m, 2H); 7.40-7.60 (m, 4H).
1C NMR: 14.1 (q); 123.0 (d); 125.4 (d); 128.5 (d); 131.9 (d); 138.3 (s).

Alkene 2trans (3rd fraction): bp = 73?C/15 mm Hg. GC purity = 98.4% (1.6% 2cis and impurities < 0.1%) (column B)
IR (film): 1660 cm-1 (C=C)
1H NMR: 185 (d, J = 4.8 Hz, 3H); 5.70-6.40 (m, 2H); 7.25-7.60 (m, 4H).
13C NMR: 18.1 (q); 122.4 (d); 123.1 (d); 127.6 (d); 128.7 (d); 138.7 (s).

Preparation of the epoxides

- 2-[3-(Trifluoromethyl)benzyl]oxirane 8

Meta-chloroperoxybenzoic acid (80%; 5.8g; 27.0 mmol) is added over 5 min to dichloromethane (25 ml) at 20?C in small aliquots. The reaction is stirred for 5h30 at 20?C. Dichloromethane (20 ml) is added and the reaction is washed successively with 10% aqueous sulfite solution (10 ml), saturated sodium bicarbonate solution and water (10 ml). The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is taken up in petroleum ether (25 ml) and left standing at room temperature over night. Then the precipitate is removed by filtration, the solvent evaporated and the residue distilled (bp = 65-95?C / 13-14 mmHg). The epoxide 8 (2.12 g; 78% yield) is thus obtained.
1H NMR: 2.40-3.30 (m, 5H); 7.45-7.70 (m, 4H).
13C NMR: 38.2 (t); 46.4 (t); 51.7 (d); 123.3 (d); 125.5 (d); 128.7 (d); 132.3(d); 138.0 (s).

- 2-methyl-3-[3-(trifluoromethyl)phenyl]oxirane 3 (cis and trans)

The epoxides 3cis and 3trans were prepared like previously described, starting with the alkenes 2cis and 2trans.

Epoxide 3cis (85% yield; 89% GC (9% 3trans and 2% impurities) (column B)). Bp = 84-86?C/13 mm Hg.
1H NMR: 1.05 (d, J=5.6 Hz, 3H); 3.40 (qd, J=4.3 and 5.6 Hz, 1H); 4.10 (d, J=4.3 Hz, 1H); 7.45-7.70 (m, 4H).
13C NMR: 12.0 (q); 54.9 (d); 56.6 (d); 123.2 (d); 124.1 (d); 128.3 (d); 129.8 (d); 136.7 (s).

Epoxide 3trans (71% yield; 98% GC). bp = 70-90?C/13-14 mm Hg.
1H NMR: 1.42(d, J=51 Hz, 3H); 3.00(qd, J=2.3 and 5.1 Hz, 1H); 3.58 (d, J=2.3 Hz, 1H); 7.40-7.65 (m, 4H).
13C NMR: 17.4 (q); 58.5 (d); 59.1 (d); 122.1 (d); 124.5 (d); 128.7 (d); 138.9 (s).

Preparation of the amino alcohols

- 3-Ethylamine-1-[3-(trifluoromethyl)phenyl]propan-2-ol 9

Anhydrous ethylamine (5 ml; 76.6 mmol) is added at once to the epoxide 8 (2.11 g; 10.5 mmol) in absolute ethanol (50 ml). The reaction is heated to 70?C during 47h. After evaporation of the solvent and the excess ethylamine, one obtains the aminoalcohol 9 (2.52g; yield 97%; GC >99%). mp = 43-45?C (microscope).
1H NMR: 1.00 (t, J=7.3 Hz, 3H); 2.20-2.80 (m, 6H); 3.37 (s, 2H interchangeable with D2O); 3.60-4.05 (m, 1H); 7.35-7.60 (m, 4H).
13C NMR: 14.4 (q); 41.4 (t); 43.4 (t); 54.5 (t); 69.7 (d); 122.7 (d); 125.8(d); 128.3 (d); 132.6 (d); 139.7(s)
Anal: C12H16F3NO; calc % C 58.29; H 6.52; N 5.66; Found % C 58.7; H 6.4; N 5.5

- 1-Ethylamino-1-[3-(trifluoromethyl)phenyl)propan-2-ol 11 and 2-ethylamino-1-[3-(trifluoromethyl)phenyl]propan-1-ol 4

* With erythro configuration 4E and 11E
Reacting the epoxide 3trans with the same conditions as the epoxide 8 gives a mixture of the two aminoalcohols 4E and 11E with erythro structure. After two fruitless distillations under vacuum (bp = 90-100?C/0.3-0.4 mm Hg), we were able to separate the mixture using chromatography over silica (eluant: ether then acetone) giving 11E (yield = 62%) and 4E (yield = 20%) (global yield = 82%).

Aminoalcohol 4E (eluant: ether). mp = 65-67?C (microscope).
1H NMR: 0.80 (d, J=6.7 Hz, 3H); 1.05 (t, J=7.3 Hz, 3H); 2.50-3.00 (m, 3H); 3.22 (s, 2H exchangeable with D2O); 4.80 (d, J=3.6 Hz, 1H); 7.40-7.75 (m, 4H).
13C NMR: 13.7 (q); 15.1 (q); 41.2 (t); 58.1 (d); 72.4 (d); 122.7 (d); 123.5 (d); 128.2 (d); 129.3 (d); 143.1 (s).
Anal: C12H16F3NO; Calc % C 58.29; H 6.52; N 5.66; Found % C 57.9; H 6.3; N 5.6

Aminoalcohol 11E (eluant: ether then acetone): very thick oil.
1H NMR: 0.90-1.30 (m, 6H); 2.40 (s, 2H exchangeable with D2O); 2.55 (q, J=6.7 Hz, 2H); 3.68 (d, J=4.0 Hz, 1H); 4.02 (qd, J=4.0 and 6.7 Hz, 1H); 7.45-7.70 (m, 4H).
13C NMR: 15.1 (q); 18.4 (q); 41.7 (t); 67.7 (d); 68.8 (d); 124.0 (d); 124.8 (d); 128.5 (d); 131.5 (d); 140.9 (s).
Anal: C12H16F3NO; Calc % C 58.29; H 6.52; N 5.66; Found % C 58.1; H 6.5; N 5.9.

* With threo configuration 4T and 11T
We operated in the same manner starting with 1.20g epoxide 3cis (containing 8% epoxide 3trans) and obtained a mixture of the aminoalcohols 4T and 11T (containing some erythro aminoalcohols), which we were able to separate by chromatography (global yield = 86%).

11: Yield = 11% (about 50% erythro and 50% threo),
4: Yield = 75% (threo, only 2-3% erythro).

Aminoalcohol 4T: mp = 54-56?C (microscope)
1H NMR: 0.80-1.25 (m, 6H); 2.30-3.20 (m, 5H whereof 2H exchangeable with D2O); 4.20 (d, J=8.3 Hz, 1H); 7.40-7.70 (m, 4H)
13C NMR: 15.1 (q); 15.8 (q); 41.2 (t); 59.5 (d); 76.8 (d); 123.7 (d); 124.3 (d); 128.5 (d); 130.5 (d); 144.1 (s).
Anal: C12H16F3NO; Calc % C 58.29; H 6.52; N 5.66; Found % C 58.4; H 6.7; N 5.8

Aminoalcohol 11T: very thick oil.
1H NMR: 0.85-1.20 (m, 6H); 2.44 (q, J=6.8 Hz, 2H); 3.85 (s, 2H exchangeable with D2O); 3.33 (d, J=8.7 Hz, 1H); 3.40-4.10 (m, 1H); 7.40-7.60 (m, 4H).
13C NMR: 15.0 (q); 19.6 (q); 41.5 (t); 70.0 (d); 70.3 (d); 124.2 (d + d); 128.8 (d); 130.9 (d); 142.2 (s).
Anal: C12H16F3NO; Calc % C 58.29; H 6.52; N 5.66; Found % C 57.9; H 6.5; N 5.5.

Preparation of the aziridines

- 1-Ethyl-2-[3-(trifluoromethyl)benzyl]aziridine 12

* Method using triphenylphosphine

Triethylamine (491 mg; 1 eq), tetrachloromethane (747 mg; 1 eq) and triphenylphosphine (1.46 g; 1.15 eq) are added to the aminoalcohol 9 (1.2 g; 4.85 mmol) in acetonitrile (5 ml). The reaction is heated to 42?C for 3h30. The precipitate is filtered off and washed with acetonitrile (5 ml). The solvent is evaporated and the residue taken up 4 times in petroleum ether (10 ml). The organic phases are combined and the solvent evaporated. The residue is distilled (bp = 70-75?C/0.5 mm Hg) giving the aziridine 12 (817 mg; 73% yield; GC >99%)

1H NMR: 1.00 (t, J=6.7 Hz, 3H); 1.20-1.80 (m, 3H); 1.95-2.55 (m, 2H); 2.75 (d, J=5.3 Hz, 2H); 7.40-7.70 (m, 4H).
13C NMR: 14.0 (q); 33.2 (t); 38.9 (t); 39.9 (d); 54.9 (t); 122.8 (d); 125.1 (d); 128.5 (d); 131.9 (d); 140.5 (s).

* Method using triethyl phosphite

Triethylamine (208 mg; 1 eq), tetrachloromethane (316 mg; 1 eq) and triethylphosphite (0.49 ml; 1.15 eq) are added to the aminoalcohol 9 (508 mg; 2.05 mmol) in acetonitrile (2 ml). The reaction is heated to 45?C for 5h20. After cooling, first 1N hydrochloric acid (10 ml) then ether (20 ml) are added. The phases are separated and the aqueous phase is washed with ether (2 x 20 ml). It is basified with 10N sodium hydroxide (2 ml) and reextracted with ether (2 x 20ml). The two etherical phases are combined, washed with water, dried over magnesium sulfate, filtered and evaporated. The aziridine 12 (341 mg; 73% yield; GC about 80%) is thus obtained.

- 1-Ethyl-2-methyl-3-[3-(trifluoromethyl)phenyl]aziridine 5

We proceeded in the same way as for the aziridine with the triphenylphosphine route.

Aziridine 5trans: Reacting the aminoalcohol 11E (1.27 g; 5.12 mmol) for 6h at 40?C gives after distillation (bp = 105-107?C/14-15 mm Hg) the aziridine 5trans (882 mg, 75% yield; GC 98%).
1H NMR (CCl4): 1.18 (t, J = 7.3 Hz, 3H); 1.40 (d, J = 7.0 Hz, 3H); 1.80-2.10 (m, 2H); 2.30-2.80 (m, 2H); 7.30-7.50 (m, 4H)
13C NMR (CCl4): 11.6 (q); 15.9 (q); 44.3 (d); 46.7 (d); 47.9 (t); 123.7 (d + d); 129.0 (d); 130.0 (d); 143.6 (s).
Anal: C12H14F3N; Calc % C 62.87; H 6.16; N 6.11; Found % C 62.5; H 6.0; N 6.1.

Aziridine 5cis: Reacting the aminoalcohol 4T (489 mg; 1.98 mmol) for 3h at 45?C gives after distillation (bp = 93-96?C/15 mm Hg) the aziridine 5cis (317 mg; 70% yield; GC 95%).
1H NMR: 0.88 (d, J=5.6 Hz, 3H); 1.18 (t, J=7.2 Hz, 3H); 1.77 (quintuplet, J=6.0 Hz, 1H); 2.10-2.95 (m, 3H); 7.40-7.60 (m, 4H).
13C NMR: 12.8 (q); 14.0 (q); 41.5 (d); 45.5 (d); 55.0 (t); 123.2 (d); 124.5 (d); 128.2 (d); 131.2 (d); 139.3(s).

Reduction of the aziridines: typical procedure

Palladium on carbon 5% (35 mg; 10% per weight) is added to the aziridine 12 (332 mg; 1.45 mmol) in ethanol (5 ml). The reaction is stirred for 16 h at 19?C under hydrogen atmosphere at standard pressure. The catalyst is filtered off, rinsed with ethanol (20 ml) and the solvent evaporated. The amine 1 is thus obtained (305 mg; 91% yield; 95% GC).

Catalytic reduction of the epoxides

- Reference alcohols 16 and 17

* 3-[3-(trifluoromethyl)phenyl]propan-1-ol 17

Palladium on carbon 5% (46 mg; 10% per weight) is added to 3-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (452 mg) [22] in ethanol (10 ml). The reaction is vigorously stirred for 26 h at 20?C under hydrogen atmosphere at standard pressure. The catalyst is filtered off, rinsed with ethanol (20 ml) and the solvent evaporated. The raw product (342 mg) is chromatographied over 6 g silica (eluant: petroleum ether-ether 100:0 to 75:25) to give the alcohol 17 (263 mg; 57% yield; 98% GC).
IR(film): 3340 cm-1 (intense O-H)
1H NMR: 1.60-2.15 (m, 3H whereof 1H exchangeable with D2O); 2.60-2.95 (m, 2H); 3.60 (t, J=6.0 Hz, 2 H); 7.30-7.50 (m, 4H).
13C NMR: 31.7 (t); 33.6 (t); 61.5 (t); 122.6 (d); 124.8 (d); 128.6 (d); 131.7 (d); 142.6 (s).
Anal: C10H11F3O: Calc % C 58.82; H 5.43; Found % C 58.5; H 5.4.

* 1-[3-(Trifluoromethyl)phenyl]propan-1-ol 16

Platinum oxide (4 mg; 1% per weight) is added to 1-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (407 mg; 2.01 mmol) [22] in ethanol (5 ml). The reaction is vigorously stirred for 24 h at 20?C under hydrogen atmosphere at standard pressure. The catalyst is filtered off, rinsed with ethanol (5 ml) and the solvent evaporated. The raw product (390 mg) is chromatographied over 6 g silica (eluant: petroleum ether-ether 100:0 to 95:5) to give the alcohol 16 (333 mg; 81% yield; 95% GC).
IR(film): 3360 cm-1 (intense O-H).
1H NMR: 0.88 (t, J=7.5 Hz, 3H); 1.50-20.00 (m, 2H); 2.20 (s, 1H exchangeable with D2O); 4.62 (t, J=6.7 Hz, 1H); 7.50-7.75 (m, 4H).
13C NMR: 9.4 (q); 31.6 (t); 75.1 (d); 122.6 (d); 124.0 (d); 128.6 (d); 129.2 (d); 145.5 (s).

- Catalytical reduction of the epoxides

The reaction time and the quantity of catalyst were not optimised.
Typical procedure: Palladium on carbon 10% (102 mg; 39% per weight) is added to the epoxide 3 (260 mg; 1.28 mmol; trans/cis=83/17) in ethanol (5 ml). The reaction is vigorously stirred for 28h30 at 22?C under hydrogen atmosphere at standard pressure. The catalyst is filtered off, rinsed with ethanol (20 ml) and the solvent evaporated. The alcohol 6 (205 mg; 78% yield; 96% GC (column C)) is such obtained.