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Asymmetric Synthesis IX1:
Preparation of Chiral α-Substituted Phenethylamines

J.L. Marco, J. Royer & H.-P. Husson
Synth. Commun. 17(6), 669-676 (1987)

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Abstract

(S)-N-methyl-α-methyl-phenethylamines 5a-d were obtained in 56-62% e.e. from the chiral synthon (-)-N-cyanomethyl-4-phenyl-1,3-oxazolidine-1.

Despite their simple structure and important biological activities the asymmetric synthesis of amphetamines has not been the subject of many published work2. The recent publication of Takahashi3 describing the synthesis of chiral 1-alkyl-2-phenylethylamines from 4-phenyl-1,3-oxazolidines prompts us to report the results of our investigations in this area.

ln conjunction with our interest in preparation of optically active amines, aminoalcohols and aminoacids we have designed a new N-cyanomethyl-1,3-oxazolidine synthon 14. In recent years, α-aminonitriles have been demonstrated to be useful for alkylation of the α-position of the amino group leading to α-substituted amines after decyanation5. Our strategy for the synthesis of α-substituted phenethylamines 5 is based upon the double alkylation of the aminoritrile 1 followed by a stereoselective decyanation.

Thus, sequential dialkylation of 1 under the conditions previously described4 afforded 1,3-oxazolidines 3a-e (Scheme) that, without isolation were subjected to reductive decyanation in EtOH using NaBH4 at room temperature. The separation of the diastereomers 3a-e was possible but not helpful since the decyanation reaction which is an elimination-addition process was proved to be non-stereospecific. Compounds 4a-e, isolated as viscous oils, consist of two diastereomers. The d.e.s. were measured by integration of the two methyl signals in the 1H-NMR spectra of the crude mixture (Table). In the course of this work no separation of the diastereomers 4a-e was achieved and the chiral appendage of 4a-e was removed by hydrogenolysis (Pd/C, 10 MeOH, rt, 12h) giving (S)-N-methyl-α-methyl-phenethylamines 5a-d6 in 56-62% e.e. (Table). The e.e. values for compounds 5 were determined by polarimetry in the case of 5a and 5c and by the 1H-NMR spectra of the Mosher's amides7 in the case of 5b and 5d. The good agreement of d.e.s. for 4 and e.e. for 5 demonstrated that no racemization occurred in the hydrogenolysis step.

Diastereomeric excesses and
chemical shifts of the CH3 and
N-CH3 signals in the 1H-NMR
spectra of the diastereomeric
mixture of 4 (CDCl3, 200 MHz).

-CH3
N-CH3
Cpd.
d.e.
major
minor
major
minor
4a
66%
0.86
0.71
2.22
2.40
4b
64%
0.83
0.69
2.21
2.37
4c
66%
0.85
0.72
2.21
2.37
4d
64%
0.83
0.70
2.20
2.35
4e
66%
0.84
0.72
2.19
2.34

a) X=H, b) X=4-OMe, c) X=3-OMe, d) X=4-Me, e) X=4-Cl

In conclusion, the procedure described here should be valuable for the synthesis of various α-alkyl-phenethylamines since alkylation of synthon 1 can be achieved with a series of alkyl and benzyl halides. Separation of the diastereomers 4 would lead after hydrogenolysis of the chiral auxiliary to optically pure R- or S-amphetamines 5.

Experimental

Preparation of 3a

Typical preparation of 3 (used without purification for the next step):

To a stirred solution of LDA/HMPA (1:1; 5 mmol, prepared from 3.12 mL of BuLi 1.6 M and 0.75 mL of diisopropylamine at -10°C/-30°C under a nitrogen atmosphere) in THF (20 mL) was added 24 (0.909g, 4.5 mmol, THF, -78°C) via syringe over 5 min. After 20 min, the resultant anion solution was added benzyl bromide (2 equiv.) and the mixture was stirred at -78°C for 1 h, quenched by NH4Cl then extracted with ether dried and concentrated to dryness. Flash chromatography of the residual oil (SiO2, hexane-AcOEt, 80:20) yielded compound 3a as a mixture of diastereomers.

Cpd.
Yield
(From 1)
4a
30%
4b
29%
4c
25%
4d
21%
4e
26%

Preparation of 4

NaBH4 (1.1 eq.) was added portionwise to a solution of 3 in EtOH (~0.4 M); stirring was continued at room temperature overnight.

The solvent was removed and the residue taken up in DCM, washed with H2O and brine, dried over Na2SO4 and evaporated to dryness. The oily residue was purified by flash-chromatography (DCM-MeOH, 95:5).

Preparation of 5

α-Alkyl-Phenethylamines 5a-d: Properties & Yields
Comp.
mp°C
Optical Rotation
e.e.
Yield
Note
5a
35-37
-
-
-
90%
The product
solidifies
on standing
5a
HCl
170
172
[α]D25 2.0°
[α]D25 19.3°
H2O, c=1.2
H2O, c=1.2
62%
-
Green =
lit. ref 2c
5b
oil
[α]D25 1.2°
CHCl3, c=1.6
56%
55%
-
5c
oil
[α]D25 5.8°
[α]D23 9.7°
CH2Cl2, c=1.98
CH2Cl2, c=2
60%
42%
Green =
lit. ref 2a
5d
oil
[α]D25 2.7°
CHCl3, c 0.6
62%
45%
-

A methanolic solution (~0.2 M) of 4 was hydrogenolysed overnight at room temp, using 1 atm. H2 in the presence of 10% Pd/C. The reaction mixture was then filtered through a celite bed and the filtrate evaporated in vacuo to yield an oily residue which was purified by flash chromatography on silica (DCM-MeOH). Yields and properties of the products are found in the adjacent table.


References and Notes

  1. For part VIII, see: Bonin, M.; Royer, J.; Grierson, D.S. & Husson, H.-P., Tetrahedron Lett. 27, 1569 (1986)
  2. See for instance:
    1. Weinges, F. and Graab, G., Chem. Ztg. Chem. Appl. 94, 728 (1970)
    2. Nichols, DE.; Barfknecht, C.F. and Rusterholz, D.B., J. Med. Chem. 16, 480 (1973)
    3. Buckley III, T.F. and Rapoport, H., J. Am. Chem. Soc. 103, 6157 (1981)
    4. Chanut, F.; Hoa, H.A. and Guette, J.P., Fourth European Symposium on Organic Chemistry,
      Poster Session, Aix-en-Provence (France), Sept. 2-6 (1985)
  3. H. Takahashi, Y. Chida, K. Higashiyama, H. Onishi, Asymmetric α-Substituted Phenethylamines. V.
    Synthesis of Chiral 1-Alkyl-2-phenylethylamines via Grignard Reaction of 4-Phenyl-1,3-oxazolidines    , Chem. Pharm. Bull. 33(11), 4662-4670 (1985)
  4. Marco, J.L.; Royer, J. and Husson, H.-P., Asymmetric Synthesis IV. Preparation of Chiral α-Aminonitriles from a new N-Cyanomethyl-1,3-Oxazolidine Synthon, Tetrahedron Lett. 26, 3567 (1985)
  5.  
    1. Grierson, D.S.; Harris, M. and Husson, H.-P., J. Am. Chem. Soc. 102, 1064 (1980)
    2. Guerrier, L.; Royer, J.; Grierson, D.S. and Husson, H.-P., J. Am. Chem. Soc. 105, 7754 (1983)
  6. In the case of 4e, dehalogenation occurred simultaneously and compound 5a was obtained in quantitative yield.
  7. Dale, J.A. and Mosher, H.S., J. Am. Chem. Soc. 95, 512 (1973)