Henry adduct

The catalyst screening experiments were performed in the asymmetric Henry addition of nitromethane (10 equiv.) to 4-nitrobenzaldehyde in the presence of DABCO (20mol %) as the base and (thio)ureas 157, 158, 163, and 170-175 (each 10mol% loading). After 12h in reaction time at room temperature and in THF as the solvent, the corresponding Henry adduct was obtained in excellent yields (99%) but with very low ee values (7-17%) nearly independently of the sterical hindrance of the axiaUy chiral backbone skeleton (e.g., 172 and 174 each 99% yield 11% ee). Thioureas appeared slightly more enantioselective (e.g., 163 83% yield, 33% ee 171 99% yield, 15% ee) than their urea counterparts probably due... 

The authors suggested that 222 operates in a bifunctional mode by hydrogenbonding activation of the nitroalkane and subsequent a-deprotonation through the basic oxazoline nitrogen providing a nucleophilic nitronate, which attacks the imine and give the observed aza-Henry adduct (Scheme 6.183) [345]. 

Scheme 16.28 Conversion of the chiral aza-Henry adducts to 1,2-diamines and a-amino acids.

The applieation of another bifunctional thiourea-secondary amine derived from trflHi-cyclohexane diamine to the asymmetric aza-Henry reaction of A-Boc imines with nitroalkanes was reported by Wang et al., providing the corresponding aza-Henry adducts with excellent enantioselectivities (96-99% ee) and high awti-selectivities (86-98% de) for a broad scope of substrates (Scheme 3.23). ... 

In addition, Wulff et al. have reported the first aza-Henry reaction catalysed by a bis-thiourea catalyst, which was based on the 2,2 -diaminobinaphthalene (BINAM) chiral scaffold.The aza-Henry adducts derived from A -Boc imines and nitromethane were isolated in moderate to good yields and good to high enantioselectivities of up to 91% ee (Scheme 3.25). 

Henry adduct The aldehyde (5 1 mmol) was added to a stirred mixture of nitrocompound (4 1 mmol) in a 10% water solution of hexadecyltrimethyl ammonium hydroxide (0.300 mL) at room-temperature under solvent-free conditions. The reaction progress was monitored by TLC. After completion of the reaction (within 2-6 h), the resulting solution was treated with brine (10 mL) and extracted by dichloromethane (3 x 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum to afford p-nitroalcohol 6, the Henry adduct, which was purified on flash chromatography using cyclohexane-ethyl acetate (yield 68-86%). 

Deng s strategy was successfully applied by Cossy and coworkers as the key step for the asymmetric synthesis of the antidepressant SSR 241586 chiral core 18 [21]. The Henry adduct 18 was further converted into the SSR 241586 19 in 14 steps in excellent enantiomeric excess (93% ee) and an overall yield of 4.6% (Scheme 29.7). 

Chiral ammonium betaines are a particular class of bifunctional BB-based catalysts that have been successfully applied in the aza-Henry reaction of N-Boc imines and a-substituted a-nitroesters [42]. The catalyst structure displays an intramolecular ion-pairing quaternary ammonium aryl-oxide and the mode of action may involve deprotonation of the pronucleophile by the basic anion to furnish and onium ion as its conjugate acid form. Catalyst loadings as low as lmol% produced the corresponding quaternary-tertiary aza-Henry adducts in excellent yields and enantioselectivities, albeit with low to moderate diastereoselectivities (Scheme 29.18). The lowest de s (up to 33%) were obtained with aliphatic N-Boc imines (R = CH2CH2Ph, -octyl). 

A particularly successfiil case of BB catalyzed aza-Henry reaction is the addition of arylnitromethanes to aryl N-Boc imines promoted by chiral bis(amidines) [44], Reactions carried out in toluene at —78 C employing 5mol% of catalyst 36 afford the corresponding aza-Henry adducts in good yields and enantioselectivities and high diastereoselectivities. The methodology has been appHed to the synthesis of (-)-nutlin-3, a potent p53/MDM2 inhibitor (Scheme 29.19). 

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