Asymmetric Synthesis of γ-Secondary Amino Alcohols via a Borrowing-Hydrogen Cascade

Abstract

The borrowing-hydrogen (or hydrogen autotransfer) process, where the catalyst dehydrogenates a substrate and formally transfers the H atom to an unsaturated intermediate, is an atom-efficient and environmentally benign transformation. Described here is an example of an asymmetric borrowing-hydrogen cascade for the formal anti-Markovnikov hydroamination of allyl alcohols to synthesize optically enriched γ-secondary amino alcohols. By exploiting the Ru-(S)-i PrPyme catalyst with minimal stereogenicity, a cascade process including dehydrogenation, conjugate addition, and asymmetric reduction was developed. The mild conditions, functional group tolerance, and broad substrate scope (54 examples) demonstrate the synthetic practicality of the catalytic system.

Manganese Catalyzed Anti-Markovnikov Hydroamination of Allyl Alcohols via Hydrogen Borrowing Catalysis

“…Based on the above experimental findings and previous literature, [13][14]18,20 a plausible mechanism is proposed (Scheme 3f). The base mediated dehydrobromination of Mn1 generates the amido complex I, which activates allyl alcohol 1 to produce the intermediate II.…”

“…12 Subsequently, Wang et al reported an alkyl phosphine-based iron catalyst for the anti-Markovnikov amino functionalization of allylic alcohols. 13 Recently, Xing 14 and Wang 15 group independently reported asymmetric hydroamination of arylvinyl alcohols utilizing ruthenium catalysts. While preparing this manuscript, Beller et al reported alkyl phosphine-based manganese catalyzed formal hydroamination of allyl alcohols using pyrophoric sodium triethylborohydride as catalyst activator.…”

Manganese-Catalyzed Anti-Markovnikov Hydroamination of Allyl Alcohols via Hydrogen-Borrowing Catalysis

“…The allyl alcohols (1h-o) were prepared according to the modified literature procedure. 2 To a solution of the aldehyde (5 mmol) in dry THF (10 mL) vinylmagnesium bromide (6 mL, 1M in THF) was added dropwise under nitrogen keeping the temperature at 0 o C. The mixture was slowly warmed at room temperature and stirred for 6-8 h. The reaction was quenched by the addition of saturated NH4Cl solution (5 mL), the organic part was extracted with DCM, dried over Na2SO4, and evaporated under reduced pressure. The crude mixture was purified with silicagel column chromatography using a mixture of EtOAc/hexane as eluent.…”

Highly Efficient Kinetic Resolution of Aryl-Alkenyl Alcohols by Ru-Catalyzed Hydrogen Transfer

“…Other amine-based nucleophiles, including proline t-butyl ester 2d and morpholine 2e, were then surveyed, and both provided excellent enantioselectivities and selectivity factors, respectively (Scheme 1, entry 6 and 7). We further explored other Ru-catalysts of minimal stereogenicity [41][42][43][44]. Catalysts B and C, both with R 1 as the electron-donating group (Scheme 1, entry 8: R 1 = 4-OMe-C 6 H 4 for B; Scheme 1, entry 9: R 1 = OMe for C), produced decreased enantioselectivities of 1 at around 50% conversion, but still affording successful kinetic resolutions.…”

“…By either way, the less reactive enantiomer would be recovered with high enantiomeric excesses (ees). According to the excellent performances of our recently developed Ru-catalysts of minimal stereogenicity (i.e., merely a single chirality element) in transfer hydrogenations [41][42][43][44], we envisioned that kinetic resolution of the aryl-alkenyl (sp 2 vs. sp 2 ) secondary alcohols (aryl substituted allylic alcohols) could be realized via the Ru-catalyzed hydrogen transfer, with or without an external nucleophile. Herein, a highly efficient kinetic resolution of aryl-alkenyl alcohols is described (Figure 1D).…”