Nitromethane, nitroaldol reactions

Novel chiral thiolated amino alcohols have been recently synthesised and then evaluated by Vilaivan el al. as a potential new class of ligands for Cu-catalysed nitroaldol reactions. Amino alcohol ligands bearing Ai-(2-alkyl-thio)benzyl substituents provided only modest enantioselectivities (22-46% ee) while those carrying Al-2-thienylmethyl substituents provided better enantioselectivities of up to 75% ee for the nitroaldol reaction between p-nitro-benzaldehyde and nitromethane. A range of aromatic aldehydes were acceptable substrates giving moderate to high enantioselectivities of up to 88% ee, as shown in Scheme 10.32. 

The enantioselective nitroaldol reaction of phe-nylalaninals 45 with nitromethane was also promoted with the N-anthracenylmethyl ammonium fluorides in the presence of potassium fluoride.1411 Interestingly, as shown in Scheme 16, the major product was the (2R,3S)-isomer 46a when N,N-dibenzyl-(S)-phenylalaninal and 12 (R=benzyl, X=F) were used while the (2S,3S)-isomer 46b was major when N-tert-butoxycarbonyl derivative 45b and 12 (R=allyl, X=Br) together with potassium fluoride were used. The nitroalcohols 46a and 46b were respectively converted to amprenavir 47a, a HIV protease inhibitor, and its diastereomer 47b. The... 

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. 

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). 

Various nitro compounds have been condensed with carbonyl compounds in reactions catalyzed by alkaline earth metal oxides and hydroxides 145). It was found that the reactivities of the nitro compounds were in the order nitro-ethane > nitromethane > 2-nitropropane, and those of carbonyl compounds were propionaldehyde > isobutyraldehyde > pivalaldehyde > acetone > benzaldehyde > methyl propionate. Among the catalysts examined, MgO, CaO, Ba(OH)2, and Sr(OH)2, exhibited high activity for nitroaldol reaction of nitromethane with propionaldehyde. In reactions with these catalysts, the yields were between 60% (for MgO) and 26% (for Sr(OH)2) at 313 K after 1 h in a batch reactor. On Mg(OH)2, Ca(OH)2, and BaO, the yields were in the range of 3.8% (for BaO) and 17.5% (for Mg(OH)2). Investigation of the influence of the pre-treatment... 

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

Shibasaki et al. have reported an asymmetric nitroaldol reaction catalyzed by chiral lanthanum alkoxide 18 to produce an optically active 2-hydroxy-1-nitroalkane with moderate-to-high enantiomeric excesses (Scheme 8B1.10) [27]. Apparently this novel catalyst acts as Lewis base. The proposed reaction mechanism is shown in Scheme 8B1.11, where the first step of the reaction is the ligand exchange between binaphthol and nitromethane. This reaction is probably the first successful example of the catalytic asymmetric reaction promoted by a Lew i s base metal catalyst. Future application of this methodology is quite promising. 

Corey and Zhang utilized chiral quaternary ammonium fluoride 4d possessing a 9-anthracenylmethyl group on nitrogen for the face-selective nitroaldol reaction of nitromethane with protected (S)-phenylalaninal. This was directed toward the... 

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. 

The enantioselective nitroaldol reaction in the presence of alkaloid-based organo-catalysts has been investigated by the Matsumoto group [127]. A further focus of this study was investigation of the effect of high pressure on the course of the reaction. Addition of nitromethane to benzaldehyde at atmospheric pressure resulted in a low (4%) yield and 18% ee when a catalytic amount (3 mol%) quinidine was... 

C. Application of catalytic, asymmetric nitroaldol reactions using nitromethane... 

The lanthanoid and group 3 metals, the so-called rare earth elements, are generally regarded as a group of 17 elements with similar properties, especially with respect to their chemical reactivity. However, in the above-mentioned catalytic asymmetric nitroaldol reactions, pronounced differences were observed both in the reactivity and in the enantioselectivity of the various rare earth metals used.29 For example, when benzaldehyde (54) and nitromethane (12) were used as starting materials, the EuLB complex gave 55 in 72% ee (91% yield) compared to 37% ee (81% yield) in the case of LLB (-40 °C, 40 h). The unique relationship... 

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 polyhydroxylated azepane as potential glycosidase inhibitors, Dha-vale [28] described a short synthetic route utilizing the Henry approach. The nitroaldol reaction of l,2-0-isopropylidene-3-0-benzyl-a-D-xylo-pentodialdose 36 and nitromethane in the presence of triethylamine at room temperature afforded a-D-gluco- and /3-L-ido- nitroal-dose 37, the precursors to (2S, 3R, 4R, 5R) and (2S, 3R, 4R, 55) tetrahydroxyazepanes 38 and 39, in a 88 12 ratio in 95% yield (O Scheme 13). 

The asymmetric nitroaldol reaction between naphthoxyacetoaldehyde and nitromethane (1 50 ratio) is effected by the ( )-BINOL-La complex 67 to give 66 with 92% ee in 80% yield, an intermediate for (S)-Propranolol (Scheme 19) [65,66] (cf. Section 3.2.5). 

However, structural modification of the BINOL ligand system also plays an important role with regard to stereoselection in the asymmetric Henry reaction. Improved enantioselectivites were obtained using a number of (P)-BINOL derivatives 8 (3 mol equiv) in which the 6,6 -positions were substituted [21 ]. Their utility as asymmetric catalysts was assessed using the nitroaldol reaction of ni-tromethane with hydrocinnamaldehyde 1. Enantioselectivities up to 88% ee accompanied by chemical yields up to 85% were obtained using 3.3 mol % of various catalysts 9 and 10 equiv of nitromethane (-40 °C, 91 h) (Scheme 4). 

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