Aldehydes nitroaldol reactions with

The nitroaldol reaction of methyl nitroacetate (199, Scheme 38) with 1,2 3,4-di-0-isopropylidene-a-D-ga/acfo-hexodialdo-l,5-pyranose (200) and 2,3-O-isopropyli-dene-D-glyceraldehyde (202) catalyzed by silica gel proceeded in almost quantitative yield, with high selectivity for attack on the aldehyde carbonyl group, giving derivatives 201 and 203, respectively. Two of the four possible diastereomers were detected as main products, and were obtained as a mixture. For the nitroaldol reaction with 200 gave similar results in either the presence or absence of silica gel, whereas the reaction with 202 did not proceed in its absence, showing that catalytic action of silica is mandatory in this case.176... 

Lanthanum catalysts were generated by Shibasaki and coworkers from lithium binaphthoxide and LaCl3 in the presence of NaOH and water [847, 848, 849], These reagents catalyze asymmetric nitroaldol reactions with a good enantioselec-tivity, but are less efficient in promoting asymmetric additions of dialkylphosphites to aldehydes [850],... 

Regio- and Stereo-selectivity in the Nitroaldol Reaction with afi-Unsaturated Aldehydes and Ketones 330... 

Bases lb. Id, and 9b catalyze the nitroaldol reaction with ketones and aldehydes at room temperature in the presence of MgS04 in generally superior yields [Eq. (14)] [123]. Moreover, ketone self-condensation was not problematic under our conditions. In a comparison of the effectiveness of Id with le and If in these reactions, le and If were more efficacious [71]. 

The catalytic activity of a lanthanum (R)-BINOL complex tethered either on silica (62a) or MCM-41 (62b) was evaluated for the enantioselective nitroaldol reaction of cyclohexanecarboxaldehyde (Se), hexanal (Sf), iso-butyraldehyde (Sg) and hydro-cinnamaldehyde (Sh) with nitromethane inTHF (Scheme 12.22) [166]. The silica-anchored lanthanum catalyst 62a gave 55-76% e.e. and yields up to 87%, while the PMS-immobilized catalyst 62b revealed slightly higher e.e.s (57-84%) for the same aldehydes. The homogeneous counterparts showed similar catalytic performance, albeit within a shorter reaction time. The increased enantioselectivity observed for the MCM-41 hybrid catalyst 62b was explained by transformations inside the channels, which is also reflected by lower yields due to hindered diffusion. The recyclability of the immobilized catalysts 62b was checked with hydrocin-namaldehyde (Ph). It was found that the reused catalyst gave nearly the same enantioselectivities after the fourth catalytic run, although the time period for achieving similar conversion increased from initially 30 to 42 h. 

Scheme 12.22 Asymmetric nitroaldol (Henry) reaction of various aldehydes (Pe-h) with nitromethane.

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by Hiemstra [76], Based on their earlier studies with Cinchona alkaloid derived catalysts, they were able to achieve moderate enantioselectivities between aromatic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reactions displayed poor selectivities. Based on prior reports by Sods [77], an activated thionrea tethered to a Cinchona alkaloid at the quinoline position seemed like a good catalyst candidate. Hiemstra incorporated that same moiety to their catalyst. Snbsequently, catalyst 121 was used in the nitroaldol reaction of aromatic aldehydes to generate P-amino alcohols in high yield and high enantioselectivities (Scheme 27). 

Scheme 6.166 Product range of the asymmetric Henry (nitroaldol) reaction of aldehydes with various nitroalkanes in the presence of (S,S)-configured catalyst 183.

Scheme 6.171 Product range of the 186-catalyzed anti-diastereoselective Henry (nitroaldol) reaction of a-chiral aldehydes with nitromethane.

Though not available commercially, trifluoronitroethane shows some interesting chemistry consistent with the powerful electron-withdrawing effect exerted by the nitro group. Fluoride-mediated nitroaldol reactions were reported [144] with aldehydes affording a valuable entry to trifluoromethyl amino alcohols... 

The compound 3 can be easily prepared, in one pot, through a solvent-free procedure by nitroaldol reaction of nitroalkane 1 (2.2 mmol) and aldehyde 2 (2.2 mmol, freshly distilled), on activated neutral alumina (0.6 g, the alumina was added to a mechanically stirred solution of 1 and 2, at 0°C, then at room temperature for 20 h). Then, in situ addition (0°C) of wet-alumina supported chro-mium(VI) oxide (0.88 g (8.8 mmol) of C1O3 and 2.64 g of wet alumina). After standing for additional 20 h, the product was extracted with diethyl ether and passed through a bed of alumina. Evaporation of the organic solvent and flash chromatographic purification afforded the pure a-nitro ketone 3 in good yields (68-86%). 

The nitroaldol reaction of silyl nitronates with aldehydes promoted by ammonium fluorides, which was originally introduced by Seebach and Colvin in 1978 [24], is a useful method for the preparation of 1,2-functionalized nitroalkanols. Recently, the present authors have succeeded in developing an asymmetric version of high efficiency and stereoselectivity by using a designer chiral quaternary ammonium bifluoride of type 6 as catalyst, which was readily prepared from the corresponding bromide by the modified method C in Scheme 9.5 [25]. 

During the course of studies on these asymmetric nitroaldol reactions catalyzed by chiral ammonium bifluorides 6 (X= HF2), the reaction of 23a was attempted with trans-cinnamaldehyde, a representative a,P-unsaturated aldehyde, under the influence of (R,R)-6c (X = HF2, 2mol%) in THF at — 78 °C. The starting aldehyde was consumed within 30 min at this temperature and, surprisingly, the 1,4-addition product 25 was obtained predominantly as a diastereomeric mixture with concomitant formation of the initially expected nitroaldol (1,2-addition product) 26 [72% combined yield, 25/26 = 17 1, syn/antiof25 = 85 (4% ee) l 5 (25% ee)] (Scheme 9.13). 

The catalytic asymmetric Henry reaction has been reviewed.42 Mild and efficient enantioselective nitroaldol reactions of nitromethane with various aldehydes have been catalysed by chiral copper Schiff-base complexes yielding the corresponding adducts with high yields and good enantiometric excess.43,44... 

The asymmetric catalytic nitroaldol reaction, also known as the asymmetric Henry reaction, is another example of an aldol-related synthesis of high general interest. In this reaction nitromethane (or a related nitroalkane) reacts in the presence of a chiral catalyst with an aldehyde, forming optically active / -nitro alcohols [122], The / -nitro alcohols are valuable intermediates in the synthesis of a broad variety of chiral building blocks, e.g. / -amino alcohols. A highly efficient asymmetric catalytic nitroaldol reaction has been developed by the Shibasaki group, who used multifunctional lanthanoid-based complexes as chiral catalysts [122-125],... 

In addition to this highly enantioselective metal-catalyzed approach, several orga-nocatalytic versions of the asymmetric nitroaldol reaction have recently been reported. The Najera group used enantiomerically pure guanidines with and without C2 symmetry as chiral catalysts for the addition of nitromethane to aldehydes [126], When the reaction was conducted at room temperature yS-nitro alcohols of type 120 were obtained in yields of up to 85% but enantioselectivity, 26% ee or below, was low. A selected example is given in Scheme 6.52. Higher enantioselectivity, 54% ee, can be obtained at a low reaction temperature of —65 °C, but the yield (33%) is much lower. 

Nitroaldol reactions of enantiomerically pure a-amino aldehydes with nitromethane using a catalytic amount of LLB were found to proceed in a highly diastereoselective manner.35 The adducts (3-amino-2-hydroxy-l-nitro derivatives) are attractive intermediates for the synthesis of unnatural erythro-amino-2-hydroxy acids, which are important components of several biologically active compounds. As an example, the promising HIV-protease inhibitor KNI-272 (65)36 37... 

In the preparation of dynamic nitroaldol systems, different aldehydes and nitroalkanes were first evaluated for reversible nitroaldol reactions in the presence of base to avoid any side- or competitive reactions, and to investigate the rate of the reactions. 1H-NMR spectroscopy was used to follow the reactions by comparison of the ratios of aldehyde and the nitroalcohols. Among various bases, triethylamine was chosen as catalyst because its reactions provided the fastest exchange reaction and proved compatible with the enzymatic reactions. Then, five benzaldehydes 18A-E and 2-nitropropane 19 (Scheme 9) were chosen to study dynamic nitroaldol system (CDS-2) generation, because of their similar individual reactivity and product stabilities in the nitroaldol reaction. Ten nitroaldol adducts ( )-20A-E were generated under basic conditions under thermodynamic control, showing... 

Nitroalkanes are the key starting precursors for the formation of C-C bond by reactions with aldehydes (nitroaldol-Henry reaction) and electron-poor alkenes (Michael... 

Nitroalkanes having an a-hydrogen atom undergo aldol-type condensation with aldehydes and ketones in the presence of a base to give p-hydroxy nitro compounds or nitroethylene compounds. The reaction is known as the Henry reaction " or nitroaldol reaction. 

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