Direct Catalytic Enantioselective Vinylogous Aldol Reaction of Allyl Ketones to Pyrazole-4,5-diones

Abstract

The first catalytic enantioselective vinylogous nucleophilic addition to pyrazole-4,5-diones is reported. Using quinine-derived bifunctional tertiary amino-amide as the catalyst, this direct aldol reaction of allyl ketones is shown to proceed exclusively in γ- and E-selective manner to generate pyrazolone derivatives, bearing an oxygen-containing quaternary stereogenic center, in good yields with moderate to high enantioselectivities (up to 97:3 er).

Noncovalent Catalysis for Enantioselective Direct Aldol Reaction of 3‐Acetylcoumarins to Pyrazole‐4,5‐diones

“…(entry 7). Relatively lower catalytic activity of VI compared to the corresponding urea III and squaramide IV is presumably due to the number of H-bond donor sites, as observed in our previous studies [13] and explained through DFT calculations by Hatanaka and co-workers. [15a] The exact reason for this dramatic improvement in enantioselectivity observed for amino-amide catalyst VI requires further investigation.…”

“…Disubstituted 3-acetylcoumarins could also be used as the substrate and furnished the products with similar level of e.r. (entries [13][14][15][16][17][18].…”

“…Enders and co-workers have recently explored the C-4 electrophilicity of pyrazole-4,5-diones for catalytic enantioselective addition reactions. [12] Inspired by the applications of pyrazolones in pharmaceutical, analytical and dye chemistry, and following our own studies in vinylogous nucleophilic addition to pyrazole-4,5-diones, [13] we became interested in developing a hitherto unknown direct aldol reaction of 3acetylcoumarins to pyrazole-4,5-diones. We envisioned that the aldol products, bearing two biologically relevant scaffolds (coumarin and pyrazolone), if synthesized in enantiomerically enriched form, may exhibit interesting biological properties.…”

Recent Advances in Catalytic Enantioselective Synthesis of Pyrazolones with a Tetrasubstituted Stereogenic Center at the 4-Position

“…Mukherjee and co-workers described the first regio-() and stereoselective (E-selective and enantioselective) vinylogous nucleophilic addition of allyl ketones to pyrazole-4,5-diones catalyzed by a quinine-derived bifunctional catalyst (Scheme 17). 46 Vinylogy is the extension of electronic behavior due to conjugation in a molecule, and sometimes it is challenging to control the regioselectivity in vinylogous reactions. 47 In this report, they solved the problem of regioselectivity (-and -mixtures) by using a bulky substituent (R 1 = t-Bu) attached to the nitrogen atom of the pyrazolone.…”

Asymmetric Vinylogous Aldol-type Reactions of Aldehydes with Allyl Phosphonate and Sulfone

“…Asymmetric vinylogous aldol reaction (VAR) has been one of the most important reactions in the synthesis of complex natural products, especially in the synthesis of polyketides. In the past decades, catalytic asymmetric VAR of aldehydes or ketones has evolved from classical Mukaiyama vinylogous aldol reaction (Denmark et al., 2005, Casiraghi et al., 2011; Pansare and Paul, 2011, Bisai, 2012, Kalesse et al., 2014, Hosokawa, 2018a, Hosokawa, 2018b) to direct vinylogous aldol reaction (DVAR) (Li and Yin, 2018, Otsuka et al., 2013, Zhu et al., 2013, Li et al., 2014, Han and Chang, 2016, Jing et al., 2016, Ray and Mukherjee, 2018), which enjoys the advantages of easy reaction protocol and high atom economy (Trost, 1991, Anastas and Crabtree, 2009, Newhouse et al., 2009). However, the nucleophiles in DVAR were mainly limited to unsaturated carbonyl compounds and their close derivatives (Bai et al., 2017).…”