Bifunctional Squaramide Organocatalysts for the Asymmetric Addition of Formaldehyde tert‐Butylhydrazone to Simple Aldehydes

Abstract

The nucleophilic addition of formaldehyde tert-butylhydrazone to simple aldehydes (a formal hetero-carbonyl-ene reaction) can be performed with good reactivity and excellent enantioselectivity by virtue of the dual hydrogen-bonding activation exerted by amide-squaramide organocatalysts. The resulting hydroxydiazenes (azo alcohols) were isolated in high yields as enantiomerically enriched azoxy compounds after a regioselective azo-to-azoxy transformation. Subsequent derivatization provides an entry to relevant amino alcohols, oxazolidinones, and derivatives thereof.

Asymmetric Organocatalytic Synthesis of Fluorinated β‐Hydroxy Diazenes

“…Cooling to 0 °C, the uncatalyzed reaction of 1a with 2a , b could not be inhibited (entries 7 and 13), highlighting the difficulties to overcome the background in the enantioselective catalytic reactions. In line with previous investigations,, N ‐anisyl derivative 1b showed no reactivity (entries 2 and 9). In conclusion, the thermal reactivity between 1 and 2 appears to be highly dependent on the reaction media and the structure of the reagent, thereby opening opportunities for the development of both uncatalyzed (racemic) and asymmetric catalytic versions.…”

“…The influence of the H ‐bond donor group was analysed next. A diminished H ‐bond donor capability of the catalysts (estimated from the chemical shifts of the NH protons in 1 H NMR spectra) in squaramides III (pentafluorophenyl derivative) and IV [bis(trifluoromethyl)benzyl derivative] correlates with a poorer catalytic activity and, hence, provided lower enantioselectivities (entries 4,5). The influence of the amino acid fragment was also evaluated: A significant decrease in enantioselectivity was observed when phenylalanine‐derived analogue V was used (entry 6), highlighting the better conformational control exerted by the tert ‐butyl group in the chiral amide fragment [ 1 H NMR spectra in DMSO at 303 K for I and V show (Z)/( E )‐amide rotamers in ratios of 6:1 and 4:1, respectively]…”

“…This surprising result suggests a cooperative assistance by the phenolic hydroxyl group, helping to fix the geometry of the catalysts/substrate complex while increasing the efficiency of the substrate activation. Further experiments (entries 10–15) served to identify two optimal catalytic systems: Squaramide I in α,α,α‐trifluorotoluene (TFT provides more homogeneous reaction media) at –20 °C and thiourea VIII in toluene at –30 °C. Reactions completed under such conditions, followed by in situ oxidation, yielded 5b in high yields (70–87 %) and enantioselectivities up to 68 % and 74 % ee , respectively (entries 11 and 15).…”

“…Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification. Formaldehyde tert ‐butyl hydrazone 1a and not commercially available ketones 2f , 2g , 2h , 2i , 2k and squaramide organocatalysts ( I , III , IV , V , VI , VII ) were synthesized according to literature procedures.…”

Organocatalysts Derived from Unnatural α‐Amino Acids: Scope and Applications

“…Very recently, the group of Fernández and Lassaletta reported a thorough study of bifunctional squaramide organocatalysts for the addition of formaldehyde tert ‐butyl hydrazone 164 to aromatic, heteroaromatic, and aliphatic aldehydes 17 (Scheme ). Of the tested derivatives, catalysts 163 exhibited the best results and led to the desired products with high yields and enantioselectivity with a catalyst loading of 10 mol %.…”