[(2R)-[211987-91-6]]  · C5H14N2O  · (MW 118.14)

(chiral reagent for the synthesis of enantiomerically enriched a-arylalkanamines)

Physical Data: colorless oil, [a]D20 -21.6(c 1.1, MeOH).

Solubility: soluble in CH2Cl2, THF, alcohols.

Purification: none; immediate use is recommended following its preparation because of the inherent instability of the reagent.

Handling, Storage, and Precautions: unstable compound, must be used without purification. Probably toxic.


The enantioselective addition of organometallic reagents to chiral hydrazones, followed by hydrogenolytic cleavage of the N-N bond of the resulting hydrazine, constitutes an attractive method for the preparation of optically active amines. The general synthetic strategy disclosed by Takahashi and his coworkers1 as early as 1979 is still in use: the chiral hydrazones are most generally derived from an enantiopure secondary amine by N-nitrosation followed by reduction of the NO group to an NH2 group and reaction with an appropriate aldehyde.1-5

Racemic 2-aminobutan-1-ol (1) is a cheap chemical which can be easily resolved into both its enantiomers on an industrial scale. The asymmetric synthesis of chiral amines from hydrazines derived from (R)-(-)-2-aminobutan-1-ol [(R)-(-)-1], using the general strategy disclosed in early works,1 is summarized here. The title hydrazine (4) is prepared as follows (1). Treatment of the amino alcohol [(R)-(-)-1] with excess ethyl formate followed by LAH reduction of the intermediate formamide gives the N-methylamine [(R)-(-)-2].6 N-Nitrosation of the latter afforded (R)-(+)-3 which is next reduced to the hydrazine [(R)-(-)-4] by means of LAH.7 Being unstable, the hydrazine (4) must be used immediately without purification.

Chiral a-phenylalkanamines

The hydrazine [(R)-(-)-4] was transformed into the hydrazone [(R)-(-)-5] upon reaction with benzaldehyde in the presence of anhydrous MgSO4 in dichloromethane (2). The hydrazone (5) was next treated with a tenfold molar excess of various n-alkyl Grignard reagents in refluxing ether for 15 h. This led to the corresponding seven trisubstituted liquid hydrazines [(R,R)-6a-g] in yields ranging between 70 and 89% in all cases but one. The use of smaller quantities of Grignard reagents (i.e. fivefold molar excess) gave mixtures of starting hydrazone (5) and trisubstituted hydrazine (6), the latter having rather average diastereomeric excesses. Examination of the high resolution 1H and 13C NMR spectra of the hydrazines (6a-g) (prepared with a tenfold excess of Grignard reagents) revealed that they were diastereomerically pure (de = 100% in all cases). The absolute R,R configuration of the hydrazines (6a-g) was assigned on the basis of the tentative mechanistic proposal depicted in 2.

Being rather unstable, the hydrazines (6a-g) were used directly in the following step without purification. Thus, hydrogenolysis of the crude colorless hydrazines (6a-g) was carried out in the presence of concentrated HCl and 10% Pd-C catalyst under hydrogen (6 bars) at ca. 60 °C for 16 h. This afforded the crude amines [(R)-7a-g)] which were purified by chromatography over silica gel in the presence of triethylamine in order to avoid racemization.7 The amines (R)-(+)-7a,8 (S)-(-)-7b,9 and (S)-(-)-7c10 are known compounds, which made it possible to confirm the R,R absolute configuration allotted to the starting hydrazines (6). It is assumed that the other amines (7d-g) also have the R configuration. The latter amines have been described in racemic form only.11 Gas chromatography using a chiral column revealed that the ees of the amines (7a,c-g) were in the range 90-92%, which implies that some racemization must have occurred during the final hydrogenolysis step.1a

Chiral Ring-substituted a-arylalkanamines

Following the reaction scheme (3), the hydrazones [(R)-(-)-8-15] (pure anti-isomers) were prepared in 63-86% yields from the hydrazine [(R)-(-)-4] and the corresponding substituted aromatic aldehydes, using the previously described experimental conditions (anhydrous MgSO4/TsOH/CH2Cl2/20 °C/17 h).The addition of Grignard reagents to the hydrazones (8-15) was carried out as above (10 equiv RMgX/Et2O/reflux/17 h). The eight trisubsituted hydrazines [(R,R)-16a-h] (4) were thus obtained in 51-83% yields and with a de = 100% in all cases (as evidenced by 1H and 13C NMR). The addition of EtMgBr to the hydrazones (14 and 15) could not be carried out to completion and gave inseparable mixtures of trisubstituted hydrazine and starting hydrazone.

None of the ring-substituted hydrazines (16a-h) could be hydrogenolyzed under the conditions which were previously developed for the hydrazines (6a-g) (H2, 6 bar/HCl/EtOH/60 °C/17 h). The temperature proved to be the determining factor: indeed, hydrogenolysis of the hydrazines (16a-f) at 110-120 °C, in the presence of a 10% Pd-C catalyst and concentrated HCl in EtOH under 6 bar for 5 h, afforded the corresponding (R)-a-arylalkanamines [(R)-(+)-17a-f] in 35-47% yield after purification by chromatography. Under the same conditions, hydrogenolysis of the hydrazines (16g and 16h) gave inseparable mixtures. The enantiomeric excesses of the three amines (17a,d,f) were found to be within the range 90-93% by means of chiral GPC using a Restek b dex column. The other three amines (17b,c,e) could not be resolved using this or other chiral columns, or by running the 1H NMR spectra in the presence of the chiral shift reagent Eu(hfc)3. It can be assumed that the enantiomeric excesses of the amines (17b,c,e) are also in the range 90-93%, and that the six amines (17a-f) all belong to the R-series, analogous with the a-phenylalkanamines (7a-g), and in agreement with the addition mechanism which was previously put forth. The a-arylalkanamines [(R)-17a-d] were known in racemic form only. The amines [(R)-17e,f] are new compounds.12

Since 2-aminobutan-1-ol (1) is readily available in both enantiomeric forms on an industrial scale, the above strategy can be applied to the synthesis of a-arylalkanamines belonging to both the R- and S-series.

The final hydrogenolysis step leading to the required a-arylalkanamine also yields N-methyl-2-aminobutan-1-ol (2) which can be recovered and distilled in view of recycling via its transformation into the hydrazine (4).

Related Reagents.

RAMP; SAMP; (-)-N-aminoephedrine.

1. (a) Takahashi, H.; Tomita, K.; Otomasu, H., J. Chem. Soc., Chem. Commun. 1979, 668. (b) Takahashi, H.; Tomita, K.; Noguchi, H., Chem Pharm. Bull. 1981, 29, 3387. (c) Takahashi, H.; Inagaki, H., Chem. Pharm. Bull. 1982, 30, 922.
2. Takahashi, H.; Suzuki, Y., Chem. Pharm. Bull. 1983, 31, 4295.
3. (a) Enders, D.; Schubert, H.; Nübling, C., Angew. Chem. 1986, 98, 1118. (b) Enders, D.; Reinhold, U., Tetrahedron: Asymmetry 1997, 8, 1895. (c) Enders, D.; Nübling, C.; Schubert, H., Liebigs Ann. Recueil 1997, 1089.
4. (a) Denmark, S. E.; Weber, T.; Piotrowski, D. W., J. Am. Chem. Soc. 1987, 109, 2224. (b) Denmark, S. E.; Nicaise, O.; Edwards, J. P., J. Org. Chem. 1990, 55, 6219.
5. Kim, Y. H.; Choi, J. Y., Tetrahedron Lett. 1996, 37, 5543.
6. Touet, J.; Baudouin, S.; Brown, E., Tetrahedron: Asymmetry 1992, 3, 587.
7. Bataille, P.; Paterne, M.; Brown, E., Tetrahedron: Asymmetry 1998, 9, 2181.
8. Nohira, H.; Nohira, M.; Yoshida, S.; Osaka, A.; Terunuma, D.; Bull. Chem. Soc. Jpn 1988, 61, 1395.
9. Tanaka, H.; Inoue, K.; Pokorski, U.; Taniguchi, M.; Torii, S., Tetrahedron Lett. 1990, 31, 3023.
10. Yang, T. K.; Chen, R. Y.; Lee, D. S.; Peng, W. S.; Jiang, Y. Z., J. Org. Chem. 1994, 59, 914.
11. de Roocker, A.; de Radzitzky, P., Bull. Soc. Chim. Belg. 1963, 72, 202.
12. Bataille, P.; Paterne, M.; Brown, E., Tetrahedron: Asymmetry 1999, 10, 1579.

Eric Brown, Patricia Bataille & Michel Paterne

Laboratoire de Synthése Organique (UMR-CNRS 6011) Faculté des Sciences, Avenue Olivier Messiaen, Francé

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