Organocatalytic Enantioselective Transfer Hydrogenation of β‐Amino Nitroolefins

Abstract

Thea symmetric organocatalytic transfer hydrogenation of b-acylamino and b-tert-butyloxycarbonylamino nitroolefins has been successfully realised in excellent enantioselectivities and yields (up to > 99% ee,9 7% yield) with as imple thiourea catalyst and aH antzsch ester as hydrogens ource, giving ad irect access to enantiomerically pure bamino nitroalkanes.Keywords: alkenes;a symmetric synthesis;h ydrogen bonds;organocatalysis;r eduction Enantiomerically pure b-amino nitroalkanes are versatile intermediates in organic synthesis,o wing to their easy conversion into av ariety of useful compounds [1] such as a-amino acids, [2] 1,2-diamines, [3] monoamines, [4] a-amino carbonyls and to various moieties present in biologically active molecules [5] and pharmaceuticals such as clopidogrel, [6] oseltamivir, [7] and asimadoline.[8]Tr aditionally,t he preparation of chiral b-amino nitroalkanes mainly counts on asymmetric aza-Henry (nitro-Mannich) reactions, [9] in which chiral metal complexes ando rganocatalystsw ere utilised to afford moderate to high enantio-/diastereoselectivities.Suitable alternative approaches are represented by the asymmetric aza-Michael addition of amines to nitroalkenes, [10] and by the addition of aldehydes to b-amino nitroalkenes proceeding via enamine catalysis. [11] Thea symmetric catalytic reductiono fb-amino nitroolefins constitutes ac omplementary straightforward pathwayt of orm chiral b-amino nitroalkanes, owingt ot he easy availability of starting materials.I n this context, in 2012t he asymmetric hydrosilylation of b-p-methoxyphenylamino nitroolefins using 10 to 20 mol% of as imple N-sulfinylurea as ab ifunctional catalyst was reported (Scheme 1).[12] b-Amino nitroalkanesw ith good to high enantioselectivities( 79-97% ee)w ere obtained.More recently,e nantioselective metal-catalysed asymmetric hydrogenations [13] of b-acylamino nitroolefins have been developed. In 2013, Wang andZ hang used aR h-Tangphos complexa chievingh igh enantioselectivities for b-aryl b-aminon itroalkenes( up to 93% ee)b ut rather poore nantioselectivities for alkyl substrates (only 8-22% ee)[ Scheme 2, (i)].[14] Afterward, ah ighly efficient enantioselective hydrogenation of b-acylamino nitroolefins hasb eens uccessfully accomplishede mploying an Ir-spiroPhosc omplex and 20 atm H 2 as reported by Hou [15] [Scheme 2, (ii)] and by ar hodium/bifunctional bisphosphine-thioureal i-

A Continuous-Flow, Two-Step, Metal-Free Process for the Synthesis of Differently Substituted Chiral 1,2-Diamino Derivatives

“…Therefore, we turned our attention to the enantioselective reduction developed by Bernardi and Fochi, that relies on the use of a bifunctional, thiourea-based organocatalyst B (Scheme 3). 4 We initially studied the feasibility of the method in a continuous-flow process by screening some experimental conditions in a commercially available Chemtrix Labtrix® Start Standard platform that can be used at temperatures ranging from -20 °C to 195 °C and under pressures up to 25 bar. The results are reported in Table 1.…”

“…(CH 2 Cl 2 /petroleum ether 3:1, R f = 0.46) gave nitroenamine 3e (0.695 g, 50%) as a pale yellow solid with spectroscopic data in agreement with the literature. 4 1 H NMR (300 MHz, CDCl 3 ): δ = 10.30 (s, 1 H, NH), 7.33-7.31 (m, 2 H, Ar), 7.28-7.24 (m, 2 H, Ar), 6.66 (s, 1 H, CHNO 2 ), 2.43 (s, 3 H, CH 3 ), 1.43 (s, 9 H, CCH 3 ).…”

“…All analytical data are in agreement with the literature. 4 The enantiomeric excess was determined by HPLC (chiral stationary phase, Phenomenex Lux-Cellulose-3 column, eluent hexane/i-PrOH 9:1, flow rate 0.75 mL/min, λ = 210 nm): t R = 18 (minor), 15 min (major).…”

“…1 The possibility to modify the two amino groups of a chiral scaffold in different moments of the synthetic sequence is a highly desirable and powerful tool for the organic chemist; in this regard, the catalytic, stereoselective reduction of nitroenamines, readily prepared starting from a suitable aldehyde, is an efficient approach that leads to the formation of enantiomerically pure 2-nitro amines, easily converted into the corresponding diamine derivatives by reduction of the nitro group [Scheme 1 (a)]. 2 Recently, this transformation has been successfully performed enantioselectively by exploiting two organocatalytic methodologies, involving the use of trichlorosilane 3 or Hantzsch ester 4 as stoichiometric reducing agents. 5 Based on our previous experiences both with dihydropyridine derivatives 6 and with HSiCl 3 7 in the organocatalytic synthesis of chiral fluorinated amines, we decided to assess the possibility to perform the nitroenamine reduction under continuous-flow conditions.…”

Asymmetric Bioreduction of β‐Acylaminonitroalkenes: Easy Access to Chiral Building Blocks with Two Vicinal Nitrogen‐Containing Functional Groups

“…The synthetic strategies to chiral derivatives 1 reported to date consist mainly of asymmetric aza‐Henry (nitro‐Mannich) reactions, asymmetric aza‐Michael addition of amines to nitroalkenes and the addition of aldehydes to β‐amino nitroolefins catalysed by enamines . The enantioselective reduction of N‐substituted‐β‐amino nitroolefins 2 has been considered by using the following methods: i) hydrosilylation catalysed by a N ‐sulfinyl urea, ii) hydrogenations under H 2 pressure in the presence of Rh and Ir chiral complexes and iii) catalytic transfer hydrogenation with Hantzsch esters and a commercially available Jacobsen thiourea catalyst . However, the reduction of these intermediates by bio‐catalytic means has not been explored yet.…”