P-nitroalcohols

A very attractive method for the preparation of nitroalkenes, which is based on the reaction with NO, has been reported. Treatment of alkenes at ambient pressure of nitrogen monoxide (NO) at room temperature gives the corresponding nitroalkenes in fairly good yields along with P-nitroalcohols in a ratio of about 8 to 2. The nitroalcohol by-products are converted into the desired nitroalkenes by dehydration with acidic alumina in high total yield. This simple and convenient nitration procedure is applied successfully to the preparation of nitroalkenes derived from various terminal alkenes or styrenes (Eq. 2.27).53 This process is modified by the use of HY-zeolites instead of alumina. The lack of corrosiveness and the ability to regenerate and reuse the catalyst make this an attractive system (Eq. 2.28).54... 

To investigate the lipase enantiomeric specificity, HPLC was used to monitor the enantiomeric ratios of products 22C and 22A. From these analyses, 99% and 98% ee of ester products 22C and 22A, respectively, were obtained and shown to have -configuration. This revealed that lipase-catalyzed transesterification is an efficient resolution technique since only two products were selected from 20 p-nitroalcohol substrates. 

Angelin M, Vongvilai P, Fischer A, Ramstrom O (2010) Crystallization driven asymmetric synthesis of pyridine P-nitroalcohols via discovery-oriented self-resolution of a dynamic system. Eur J Org Chem 6315-6318... 

The Henry reaction or the nitroaldol is a classical reaction where the a-anion of an alkyinitro compound reacts with an aldehyde or ketone to form a p-nitroalcohol adduct. Over the decades, the Henry reaction has been used to synthesize natural products and pharmaceutical intermediates. In addition, asyimnetric catalysis has allowed this venerable reaction to contribute to a plethora of stereoselective aldol condensations. Reviews (a) Ballini, R. Bosica, G. Fiorini, D. Palmieri, A. Front. Nat. Prod. Chem. 2005, 1, 37-41. (b) Ono, N. In The Nitro Group in Organic Synthesis Wiley-VCH Weinheim, 2001 Chapter 3 The Nitro-Aldol (Henry) Reaction, pp. 30-69. (c) Luzzio, F. A. Tetrahedron 2001, 57, 915-945. 

The Henry (or nitro-aldol) reaction is one of the powerful carbon-carbon bond formation reactions frequently used in organic synthesis, providing access (via coupling between a carbonyl compound and an alkylnitro compound) to P-nitroalcohols, useful synthons in organic synthesis (Scheme 16.26) [160]. 

The Henry reaction is performed, in the presence of catalysts (organic or inorganic bases, quaternary ammonium salts, etc.), protic and aprotic organic solvents [161], water [162], supercritical fluids [163] or ionic liquids [164], Nitroalkenes can be obtained as by-products, via dehydration of p-nitroalcohols. Considerable efforts have been made to increase the yield and selectivity and to control the basicity of the medium and the reaction time. 

An electrochemical-induced Henry reaction has been achieved by Elinson et al. via electrolysis (undivided cell) of solutions of carbonyl compounds and nitromethane in methanol or in methanol-DMF mixture containing alkali metal iodide as supporting electrolyte. p-Nitroalcohols have been isolated in 60-75% yields. The authors suggest that the Henry reaction could be induced by the deprotonation of methanol at the cathode and by the oxidation of the iodide anion at the anode (Scheme 16.27) [165]. 

Finally, the electrosynthesis of P-nitroalcohols has been performed, under mild conditions and in high yields and selectivity, by stirring nitromethane and aldehydes in previously electrolyzed RTILs in total absence of VOCs and supporting electrolyte. The effects of the number of Faradays per mole of aldehyde supplied to the electrode, the reaction time, temperature and the stracture of the RTILs on the yield and selectivity have been extensively investigated. After the workup of the catho-lyte, RTILs were recovered and reused. In every case, P-nitroalcohols were isolated in good yields (81-92%) (Scheme 16.29) [171]. 

The nitroaldol (Henry) reaction involves the addition of nitronates to aldehydes and ketones to give a P-nitroalcohol. These products are usefrd synthetic building blocks as the nitro group can be transformed into a range of other functional groups, and this has stimulated some recent research into the development of a catalytic asymmetric variant. Some of the catalyst systems used in the asymmetric aldol rection have been successfully employed in the catalytic asymmetric nitroaldol process. 

Henry reaction can occur between nitroalkane and aldehyde to form P-nitroal-cohol. Lower nitroalkanes can react with formaldehyde through addition reaction to form P-nitroalcohol. 

Lipases are a family of enzymes that, in addition to their hydrolytic activity on triglycerides, also catalyze (trans)esterification reactions. They recognize a broad range of unnatural substrates in either aqueous or nonaqueous phase, have a high commercial availability, do not require expensive cofactors, and are easily recoverable. These factors make lipases especially interesting and they have been used extensively in, for example, asymmetric synthesis. The lipase from Pseudomonas cepacia was also targeted in a dynamic combinatorial resolution-type protocol [36]. Based on the efficient nitroaldol (Henry) reaction, DCLs of aldehydes, nitroal-kanes, and P-nitroalcohols could be easily generated (Scheme 5.9). 

In the DCR protocol using lipase as selector, selective P-nitroalcohol acylation was subsequently performed, yielding the corresponding acetylated products. Two products from the DCL were resolved by the process, where the major product proved to be the ester produced from 3-nitrobenzaldehyde and 2-nitropropane. The nitroaldol-lipase DCR process could, however, not only ampHfy specific P-nitroalcohol derivatives, but also lead to their asymmetric discrimination. The enantioselectivity of the process proved very high, resulting in high enantiomeric purity of the products. The (R)-enantiomer of the ester was thus resolved to 99% enantiomeric excess. 

Keywords Nitroalkanes, a,p-unsaturated ketones, aldehydes, CTAOH, solvent-free, room temperature, Michael reaction, Henry reaction, p-nitroalcohols... 

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%). 

A series of mono- and dialkylated, chiral 1,2-amino-phosphinamide ligands (752) have been successfully applied in the chiral phosphinamide-Zn(ii) catalysed asymmetric Henry reaction between benzaldehyde and nitromethane (Scheme 210). The effects of the N-substituent sizes of chiral ligands (752) on the enantioselectivities in this reaction have been correlated using a predictive quantitative structure-activity relationship (QSAR) mathematical model. A quantitative correlation model has been also established based on subtractive Sterimol parameters. Ligand optimisation based on the QSAR model led to chiral 1,2-amino-phosphinamide ligand (752a), which produced (R)-p-nitroalcohol (753) in excellent yield (99%) and enantioselectivity (92% ee). ... 

The Henry reaction is a base-catalyzed C-C bond-forming reaction between nitroalkanes and aldehydes or ketones. It is similar to the aldol addition, and is also referred to as the nitroaldol reaction. Since its discovery in 1895 [1] the Henry reaction has become one of the most useful reactions for the formation of C-C bonds, and most particularly for the synthesis of P-nitroalcohol derivatives [2]. The general features of this reaction are (i) the potential offered by the nitro and hydroxyl groups on the products for transformation into other compound families such as P-amino alcohols, P-amino acids, or nitroalkenes (ii) only a catalytic amount of base is required (iii) up to two contiguous stereogenic centers may be created in a single step concomitantly to the C-C bond formation. Several recent reviews with a focus on the asymmetric Henry reaction and its applications have appeared [3j. 

Pitchumani and coworkers have found that per-6-amino-P-cyclodextrin (per-6-ABCD) catalyzes efficiently the Henry reaction in aqueous media [12], Thus, a series of aldehydes react with nitromethane or nitroethane to afford the corresponding P-nitroalcohol derivatives in excellent yields (88-99%) and selectivities (dr > 15 1 and 79-99% ee) when using aromatic aldehydes, whereas aliphatic aldehydes afforded variable results (72-88% yield, 52-79% ee). 

Conjugated nitroalkenes were also synthesized by the reaction between aromatic aldehydes and nitroalkenes in the presence of catalytic amount of ammonium acetate by microwave-assisted Henry reaction in solvent-free conditions (Varma et al, 1997b). The p-nitroalcohols were formed as intermediates. 

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