Reactions nitroaldol

Sequential radical cyclizations are also featured in an efficient and clever synthesis of the cedrane framework 83 (see Scheme 15).30 Compound 81, the product of a regioselective Diels-Alder reaction between isoprene (79) and nitroethylene (80), participates in a nitroaldol reaction (Henry reaction) with 5-methyl-4-hexenal in the presence of a basic resin to give 82. Because the nitro group in... 

Due to the reversibility of this nitroaldol reaction, the easy epimerization at the nitro-sub-stituted carbon, and the often low yields in reactions with nitro compounds other than ni-tromethane, few stereoselective additions have been reported. Highly stereoselective reactions are known for the synthesis of cyclic systems (see Section 1.3.5.6.6.). 

To achieve reproducible (R. . ) selectivities in these nitroaldol reactions pure, distilled /m-butyldimcthylsilylnitronates and anhydrous tetrabutylammonium fluoride should be used22. The corresponding trimethylsilylnitronates furnish mixtures of (R, S )- and (R, R )-isomers22. 

A variety of 1,5-dialdehydes 9 react in a double nitroaldol reaction with nitroalkanes to give 6-membered carbo- and heterocyclic owMran. -2-nitro-l,3-diols 10 which can be transformed into the enantiomcrically pure derivatives via enantiosclcctive saponification of their diacetates with pig liver esterase5. 

Intermolecular reaction of the mannose-derived 2,3-0-isopropylideiie-a-D-/y.vc>-pentodialdo-l,4-furanoside 13 affords a diastereomeric mixture of nitroalcohols 14. Upon fluoride-catalyzed desilylation, a stereoisomerically pure nitrocyclitol 15 was obtained from a successive intramolecular nitroaldol reaction as a consequence of the reversibility of the nitroaldol reaction which, in this case, allows the equilibration of isomers through open-chain intermediates33. 

The nitroaldol reaction or Henry reaction is a powerful and highly versatile carbon-carbon bond-forming reaction, allowing a plethora of key molecular frameworks, such as p-hydroxynitroalkanes, 1,2-amino alcohols or a-hydroxy carboxylic acids to be synthesised in a straightforward manner. Therefore, the development of practical catalytic asymmetric versions of this reaction is still largely desirable. The first catalytic asymmetric nitroaldol reaction was reported in 1992, " but despite its long history, relatively few chiral ligands have... 

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. 

In addition, highly enantioselective nitroaldol reactions were performed by Bandini et al. by using a new class of C2-symmetric oligothiophene ligands, in 2007. Thus, associated to copper, these C2-symmetric bis(amino) ligands allowed the synthesis of a wide range of enantiomerically enriched nitroalcohols... 

The Henry (nitroaldol) reaction was reported under very mild reaction conditions, in aqueous media using a stoichiometric amount of a nitroalkane and an aldehyde, in NaOH 0.025 M and in the presence of cetyltrimethylammonium chloride (CTAC1) as cationic surfactant (Eq. 8.94) 240 Good to excellent yields of (i-nitroalkanol are obtained. Under these conditions several functionalities are preserved, and side-reactions such as retro-aldol reaction or dehydration of 2-nitroalcohols are avoided. 

Scheme 30 Reductive intramolecular Henry reaction, nitroaldol reaction, mediated by Cu H...

Molecular modeling studies revealed a similar binding mode for (5)-2-nitro-1 -phenylethanol in the catalytic center of ///)HNL as was determined experimentally for (5)-mandelonitrile, preserving all mechanistically important polar interactions with active-site residues. This implies that the mechanism for the cyanohydrin reaction applies to the nitroaldol reaction as well. 

Purkarthofer, T., Gruber, K., Gruber-Khadjawi, M,et al. (2006) A biocatalytic Henry reaction - the hydroxynitrile lyase from Hevea brasiliensis also catalyzes nitroaldol reactions. Angewandte Chemie (International Edition in English), 45, 3454-3456. 

Verkade and co-workers have shown the usefulness of their phosphazanes in various stoichiometric as well as catalytic reactions <1999PS(144)101>. Compound 290 was used to promote the cyanohydration of benzaldehyde with trimethylsilyl cyanide (TMSCN). The cyanohydrin was isolated in 95% yield, but no enantioselectivity was noticed <2002JOM(646)161>. Compounds 291 and 292 were attached to dendrimers and shown to be effective in the catalysis of Michael reactions, nitroaldol reactions, and aryl isocyanate trimerizations <2004ASC1093>. 

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... 

SCHEME 38. Nitroaldol reaction of methyl nitroacetate with hexodialdo-l,5-pyranose 200 and 2,3-0-isopropylidene-D-glyceraldehyde (202) catalyzed by silica gel. 

Table 1. syn-Selective catalytic asymmetric nitroaldol reaction. 

In order to remove a proton from I, we added almost 1 equiv of base to the LLB catalyst. After many attempts, we were finally pleased to find that 1 mol% of second-generation LLB (LLB-II), prepared from LLB, 1 mol equiv of H20, and 0.9 mol equiv of butyllithium efficiently promoted the catalytic asymmetric nitroaldol reactions. Moreover, we also found that the use of LLB-II (3.3 mol%) accelerated these reactions. The use of other bases such as NaO-t-Bu, KO-t-Bu and Ca(0-i-Pr)2 gave less satisfactory results. The results are shown in Table 2 The structure of LLB-II has not yet been unequivocally determined. We propose here, however, that it is a complex of LLB and LiOH a proposed reaction course for its use in an improved catalytic asymmetric nitroaldol reaction is shown at the bottom of Scheme 4. Industrial application of a catalytic asymmetric nitroaldol reaction is being examined. 

H. Sasai, T. Suzuki, S. Arai, T. Arai, M Shibasaki, Basic Character of Rare Earth Metal Alkoxides. Utilization in Catalytic C-C Bond-Forming Reactions and Catalytic Asymmetric Nitroaldol Reactions, J. Am. Chem. Soc 1992,114, 4418-4420. 

H. Sasai, S. Watanabe, M. Shibasaki, A New Practical Preparation Method for Lanthanum-Lithium-Binaphtol Catalysts (LLBs) for Use in Asymmetric Nitroaldol Reactions, Enantiomer, 1997,2,267-271. 

H. Sasai, T. Suzuki, N. Itoh, K. Tanaka, T. Date, K. Oka-mura, M Shibasaki, Catalytic Asymmetric Nitroaldol Reaction Using Optically Active Rare Earth BINOL Complex Investigation of the Catalyst Structure, J. Am Chem Soc 1993,115,10372-10373. 

H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shibasaki, Efficient Diastereoselective and Enantiose-lective Nitroaldol Reactions from Prochiral Starting MaterialsStUtilization of La-Li-6,6 -Disubstituted BINOL Complexes as Asymmetric CatalystsUtJ. Org Chem 1995, 60, 7388-7389. 

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... 

Intramolecular nitroaldol reactions are a useful choice for the conversion of sugars into polyhydroxylated nitro cyclopentanes, nitro cyclohexanes and their derivatives.46 Baer et al. in the course of their studies on the cyclization of 6-deoxy-6-nitrohexoses under kinetic and thermodynamic control,47 established the reaction pathway involved in the formation of nitroinositols mediated by intramolecular Henry reactions. Firstly, a nitronate is formed and then, under thermodynamic control conditions, an epimerization occurs before cyclization. But, under kinetic controlled conditions, the cyclization occurs first.48... 

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