Asymmetric Synthesis of Chiral Primary Amines by Transfer Hydrogenation ofN-(tert-Butanesulfinyl)ketimines

Abstract

The diastereoselective reduction of (R)-N-(tert-butanesulfinyl)ketimines by a ruthenium-catalyzed asymmetric transfer hydrogenation process in isopropyl alcohol, followed by desulfinylation of the nitrogen atom, is an excellent method to prepare highly enantiomerically enriched alpha-branched primary amines (up to >99% ee) in short reaction times (1-4 h). (1S,2R)-1-Amino-2-indanol has been shown to be a very efficient ligand to perform this transformation. Ketimines bearing either an aryl or a heteroaryl group and an alkyl group as substituents of the iminic carbon atom are very good substrates for this process. The reduction of a dialkyl ketimine could also be achieved, affording the expected amine with moderate optical purity (69% ee). Some amines which are precursors of very interesting biologically and pharmacologically active compounds have been prepared in excellent yields and enantiomeric excesses.

Chiral β-Amino Alcohols as Ligands for the Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of N-Phosphinyl Ketimines

“…Therefore, it seems that the rigidity of the β-amino alcohol seems to be very convenient for achieving good enantioselectivities in this ATH process. Finally, in agreement with our observations in the ATH of sulfinylimines [38][39][40][41], a ligand with a free primary amino group led to higher enantioselectivities than other ligands bearing secondary amino groups: when the ligands with a prolinol backbone L4 and L5 were tested, either no reduction product or only traces of it could be detected after working-up the reaction (Table 2, entries 4 and 5). After having established that L1 was the ligand of choice, we tested two more imines as substrates.…”

“…Since those ligands have shown to give excellent results in the ruthenium-catalyzed asymmetric transfer hydrogenation of ketones [12][13][14][15][16][17][18][19] and N-sulfinylimines [38][39][40][41] in isopropyl alcohol, we decided to investigate if they could also be applied to the reduction of N-phosphinyl ketimines by the same methodology. One of the most noteworthy chiral β-amino alcohols in the ATH of both ketones and N-sulfinyl imines is cis-1-amino-2-indanol [50].…”

“…A slight improvement of both yield and enantioselectivity were observed when the initial temperature was −20 °C instead of 0 °C (Table 1, entry 12). Since in our previous studies concerning the ATH of N-(tert-butylsulfinyl)imines [38][39][40][41] we found that potassium tert-butoxide was a more convenient base than potassium hydroxide, we decided to evaluate the former in the ATH of phosphinylimine 1a and we obtained a further improvement, giving 87% yield and 82% ee (Table 1, entry 13). A decrease of the initial temperature to −40 °C slightly reduced both the yield and the enantiomeric excess (Table 1, entry 14).…”

“…Although the transfer hydrogenation protocol has been already applied to the reduction of different iminic substrates bearing alkyl [18], benzyl [17,18], aryl [17,18], sulfonyl [13,18,37] or sulfinyl [38][39][40][41] groups attached to the nitrogen atom, there are only a few examples on the use of N-phosphinyl imines as substrates [18,42]. In the last years, we have been interested in the use of β-amino alcohols as ligands for ruthenium complexes used as catalysts for the ATH of imines, especially N-(tert-butylsulfinyl)imines [38][39][40][41].…”

“…In the last years, we have been interested in the use of β-amino alcohols as ligands for ruthenium complexes used as catalysts for the ATH of imines, especially N-(tert-butylsulfinyl)imines [38][39][40][41]. Since, to the best of our knowledge, the use of β-amino alcohols as chiral ligands has not been reported so far for the ATH of N-(diphenylphosphinyl)imines, we became interested in trying to apply our methodology to those substrates.…”