[(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 (
The hydrazine [(R)-(-)-4] was transformed into the hydrazone [(R)-(-)-5] upon reaction with benzaldehyde in the presence of anhydrous MgSO4 in dichloromethane (
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
Following the reaction scheme (
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).
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