Doubly Stereocontrolled Asymmetric Aza‐Henry Reaction with in situ Generation of N‐Boc‐Imines Catalyzed by Novel Rosin‐Derived Amine Thiourea Catalysts

Abstract

Abstract:The doubly stereocontrolled organocatalytic aza-Henry reaction of nitroalkanes to N-Bocimines generated in situ from a variety of substituted a-amido sulfones was investigated for the first time, in general, affording the corresponding products with high to excellent yields (up to 93% yield) and enantioselectivities (up to 98% ee), and satisfactory diastereoselectivies (anti/syn up to 98:2). Furthermore, these organocatalysts based on rosin have been proved to be the very effective promoters for this catalytic asymmetric process along side the Cinchona alkaloid-derived catalysts.Keywords: a-amido sulfones; asymmetric synthesis; aza-Henry reaction; imines; rosin-derived thioureaThe catalytic asymmetric aza-Henry reaction [1] constitutes one of the most versatile and attractive approaches for accessing optically active chiral b-nitro-A C H T U N G T R E N N U N G amines, which can be readily converted into valuable synthetic building blocks or biologically active vicinal diamines [2] and a-amino carbonyl compounds, [3] and could effectively be obtained by only two asymmetric catalytic ways to date (a: starting from N-protected imines; b: starting from a-amido sulfones, Scheme 1). Since Shibasaki reported the first catalytic asymmetric aza-Henry reaction of nitromethane to N-protected imines, [4] impressive progress has been made on the development of more selective and efficient catalytic systems involving metallic [5] and organic [6] catalysts for this asymmetric version. However, the preparation of these imines, such as N-carbamoylimines requires harsh conditions and their purification and storage are rather troublesome because of their inherent instability. To the best of our knowledge, only the two groups of Palomo [7a] and Ricci [7b] have independently reported catalytic asymmetric aza-Henry reactions with in situ generation of carbamate-protected imines from a-amido sulfones using the same chiral quaternary ammonium salt catalyst based on a Cinchona alkaloid by phase-transfer catalysis (PTC). Nevertheless, this more convenient and useful catalytic version remains a much less developed field and a practical asymmetric aza-Henry reaction with in situ generation of carbamate-protected imines catalyzed by other catalysts based on new chiral scaffolds has not yet been reported. Furthermore, except for a recently reported example, [8] Cinchona alkaloid derivatives were employed as exclusive efficient catalysts in all of the related asymmetric Mannich reactions with in situ generation of carbamate-protected imines from a-amido sulfones. [9] We recently reported [10] a new class of thiourea-derived bifunctional catalysts [11,12] based on rosin, which have successfully been applied to the doubly stereocontrolled synthesis of g-nitro heteroaromatic ketones. Herein, we describe our contribution to the progress of the catalytic asymmetric aza-Henry reaction and report the first doubly stereocontrolled Scheme 1. Two asymmetric catalytic ways.

Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry

“…For example, photochemically active thioxanthone was attached to thiourea moiety with various chiral linkers and the resulting catalysts were employed in the photocyclization of 2-aryloxycyclohex-2-enones (Figure 30) [334]. Wang and co-workers reported a preparation of bifunctional rosin-derived catalysts (prepared from chiral dehydroabietic amine) and used it in a doubly stereocontrolled addition reactions, including the stereoselective synthesis of chiral cyclic thioureas (Figure 31) [51,171,[335][336][337][338][339][340][341]]. Wang's group modified the original structure of their catalyst with Cinchona alkaloids as well to provide a double stereocontrol [342][343][344].…”

Advances in Rosin-Based Chemicals: the Latest Recipes, Applications and Future Trends

“…Moreover, rosin-derived thioureas can be used as enantioselective catalysts for many reactions [12]. In recent years these were: Michael addition [223,224], tandem Michael/cyclization sequence [225], asymmetric Michael/hemiketalization [226], asymmetric aza-Henry reaction [227], asymmetric tandem reaction [228], Mannich reaction [229,230], Friedel–Crafts alkylation [231], enantio- and diastereoselective asymmetric addition [232], as well as synthesis of chiral amines [233] or N -protected β-amino malonates [234]. In recent studies rosin-derived thioureas are dominant majority of all investigated rosin-derived catalysts.…”

Asymmetric Michael Addition of Malononitrile with Chalcones via Rosin-Derived Bifunctional Squaramide

“…Known adducts 4b, 4e, and 4j were assigned as R-configuration by HPLC comparisons with the reported data [23], respectively, and the absolute configurations of other products were confirmed by analogy with compounds 4b, 4e, and 4j. All the rosin-derived chiral squaramide organocatalysts I-IX were synthesized according to the literature procedures [25,28,29,46]. All 1 H NMR and HPLC spectra of compounds 4a-q could be found in Supplementary Materials.…”

“…Rosin-derived bifunctional thiourea organocatalysts, originated from the abundantly available natural rosin, were revealed to be highly efficient for some catalytic asymmetric reactions, including Aza-Henry [28], Mannich reaction [29,30], Aldol reaction [31,32], Michael addition [33][34][35][36], and Friedel-Crafts alkylation [37]. The thiourea moiety of those organocatalysts is usually introduced at position C-4 of rosin skeleton, while the tertiary amine moiety is either 1,2-diaminocyclohexane 1 or cinchona alkaloid 2 (Figure 1).…”