Nitroalcohols aldehyde

Method A ct,ct-Donbly deprotonated nitroalkanes react with aldehydes to give intermediate nitronate alkoxides, which afford iyti-nitroalcohols as major products d8 7-47 3 by kmedc protonadon at -100 C in THF-HMPA. The carcinogenic hexamethylphosphorons triamide fHMPAi can be replaced by the ntea derivadve (T)MPU. ... 

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. 

The procedure described in Sect. 14.9.1 for addition of nitroalkane anions to activated alkenes can also be used for addition to aldehydes. The nitroalcohol formed can be dehydrated in almost quantitative yields in dilute H3PO4 in a subsequent step [130, 131]. Starting with... 

The DCL was generated from equimolar amounts of five different aromatic aldehydes (24, 26, 27, 36, and 37) and 2-nitropropane (38) to provide 10 3-nitroalcohol substrates including all enantiomers (DCL-E, Scheme 6.9). 

To initiate the equilibrium, triethylamine was added and the reaction followed frequently by H-NMR. Under these conditions, equilibrium was reached within 3 hours (Fig. 6.15). Following this, the full hbrary (DCL-F) including aldehyde (49) was constructed. This library initially behaved similarly to DCL-G, with several nitroaldoladducts forming competitively. A total of 20 individual (3-nitroalcohol adducts is possible including enantiomers and diastereoisomers. However, within 1 hour, a clear amplification of a single diastereomeric pair, supposedly iminolactone (56), became clearly visible. The amphfication effect then gradually continued until all... 

Figure 6.17 Reaction composition followed over time ( ) aldehyde (49), (O) nitroalcohol intermediate (55), and (A) product (57) (modified from Reference 6). Lines represent fitted data from kinetic model [49],...

Polynitroaliphatic alcohols are invaluable intermediates for the synthesis of energetic materials (see Section 1.11). The most important route to /i-nitroalcohols is via the Henry reaction where a mixture of the aldehyde and nitroalkane is treated with a catalytic amount of base, or the nitronate salt of the nitroalkane is used directly, in which case, on reaction completion, the reaction mixture is acidified with a weak acid. Reactions are reversible and in the presence of base the salt of the nitroalkane and the free aldehyde are reformed. This reverse reaction is known as demethylolation if formaldehyde is formed. 

C), various (hetero)aromatic aldehydes were transformed into nitroalcohols 1-6 in consistently high yields (90-99%) and ee values (86-92%) as shown in Scheme 6.146. The protocol failed for aliphatic aldehydes such as cyclohexanecar-boxaldehyde and isobutyraldehyde that displayed incomplete conversion to the respective nitroalcohols even after 1 week reaction time and gave low ee values (<20%) of the adducts. Catalyst 132, the pseudoenantiomer of 131, gave access to nitroalcohols with the opposite configuration and comparable enantiomeric excess, as exemplified for three aldehydes (e.g., (R)-adduct 3 87% yield 93% ee). 

Utilizing 10mol% of (R,R)-guanidine-thiourea catalyst 186 under optimized biphasic condihons for the Henry reaction [224] of (S)-a-amino aldehydes with nitromethane furnished the corresponding nitroalcohols 1-6 in yields ranging from 33 to 82% and with excellent diastereoselechvities (up to 99 1 anti/syn) and enanhoselectivihes of the major isomer (95-99% ee) (Scheme 6.171) [328]. 

Keywords aromatic aldehyde, nitromethane, nitroethane, Henry reaction, activated Si02, microwave irradiation, nitroalcohol... 

Nitroalcohols 3a-j were isolated in good yields when a mixture of aromatic aldehydes 1 (10 mmol) and nitro compound 2 (10 mmol) adsorbed on Si02 (finer than 200 mesh, 5 g) and taken in a open Pyrex test tube was subjected to micro-wave irradiation in a domestic microwave oven (BPL, BMO 700T) at an out-put of about 600 W. After cooling the reaction mass to room temperature, the products were isolated by extracting with dichloromethane and evaporation of the sol-... 

When a primary or secondary nitroparaffin is allowed to react with an aldehyde in the presence of a basic catalyst, the product is a nitroalcohol. 

The reduction of nitroalcohols to aminoalcohols is complicated to some extent by the instability of the nitroalcohols in the presence of bases due to the reversal of the aldehyde-nitroparaffin condensation reaction. This reduction can be carried out smoothly, however, with Raney nickel and hydrogen.21 Thus the interesting sugar aminoalcohols are readily available from the corresponding sugar nitroalcohols. 

The above method of producing a carbohydrate C-nitroalcohol is now of only minor interest since subsequent experiments have shown that substituted aldoses with a free reducing group as well as the unsubsti-tuted aldose sugars will undergo the aldehyde-nitroparaffin condensation reaction.29... 

A very characteristic feature of primary and secondary nitro compounds is their ability to add on aldehydes in a weak basic medium to form nitroalcohols (X, XI). Formaldehyde is particularly readily added ... 

Bulbule, V. J., Deshpande, V. H., Velu, S., Sudalai, A., Sivasankar, S. and Sathe, V. T. (1999). Heterogeneous Henry reaction of aldehydes diastereoselective synthesis of nitroalcohol derivatives over Mg-Al hydrotalcites. Tetrahedron 55, 9325. 

The nitroaldol (Henry) reaction, first described in 1859, is a carbon-carbon bondforming reaction between an aldehyde or ketone and a nitroalkane, leading to a nitroalcohol adduct [29]. The nitroalcohol compounds, synthetically versatile functionalized structural motifs, can be transformed to many important functional groups, such as 1,2-amino alcohols and a-hydroxy carboxylic acids, common in chemical and biological structures [18, 20, 30, 31]. Because of their important structural transformations, new synthetic routes using transition metal catalysis and enzyme-catalyzed reactions have been developed to prepare enantiomerically pure nitroaldol adducts [32-34]. 

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... 

In order to increase the exchange rate, ten equivalents of triethylamine were added, and the dynamic system was generated at 40 °C. Figure 5 shows 1H-NMR spectra of the dynamic nitroaldol system at different reaction times. In the absence of any catalyst, none of the nitroalcohol adducts was observed, but addition of triethylamine resulted in efficient equilibrium formation (Fig. 5a). The aldehyde protons of compounds 18A-E were easily followed (10.0-10.5 ppm), as well as the a-protons of 2-nitropropane 19 and adducts 20A-E (4.5-6.5 ppm). The selected dynamic nitroaldol reaction proved to be stable without producing any side reactions within several days. 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

The oxidation of the alcohol was performed with supported perruthenate (8.48, Fig. 8.46) to produce clean aldehydes 8.91 after filtration. The Henry reaction was performed in the presence of a commercially available, supported strong base 8.92 and an excess of volatile nitroalkenes, giving clean nitroalcohols 8.93 after filtration and evaporation. The reaction mixtures from the trifluoroacetylation/elimina-tion steps were purified with commercially available amino PS resin 8.58 to scavenge the trifluoroacetates and with acidic ion-exchange resin 8.76 to remove the TEA-derived salts. Again, the nitrostyrenes 8.94 were obtained cleanly after filtration and evaporation. Cycloaddition with isocyanoacetate was promoted by the commercially available, supported guanidine base 8.95, while the subsequent N-alkylation of the pyrroles 8.96 was performed with an excess of halide in the presence of the commercially available, supported phosphazene 8.97. In this case, the excess halide was removed by treatment with supported 8.58, and filtra-... 

Henry reaction. Formation of nitroalcohols by an aldol-type condensation of nitroparaffins with aldehydes in the presence of base (Henry) or by the condensation of sodium salts of aci nitroparaffi ns with the sodium bisulfite addition products of aldehydes in the presence of a trace of alkali or weak acid (Kamlet). Widely used in sugar chemistry. 

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. 

Concerning the reaction mechanism, the transformation of an aldehyde into a nitroalkene can occur via two different pathways the first involves nitroalcohol formation through a traditional Henry reaction, which is then followed by water elimination to form the double bond the second proceeds through an imine intermediate rather than the nitroalcohol. The authors predicted that nitroalkene formation goes through an imine intermediate (Scheme 3.9) rather than the nitroalcohol as they did not observe nitroalcohol formation at any point in the reaction. In addition, when the nitroalcohol is placed in the presence of swollen capsules, no nitroalkene formation is observed this inability to... 

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]. 

First encouraging results for a stereoselective synthesis in general were reported by Seebach in 1982, who investigated the syn/anti-diastereoselectivity starting from achiral aldehydes and nitroalkanes [4,5]. Barrett et al. examined the influence of nonchiral Lewis acids on the syn/anti diastereoselectivity [6]. Stoichiometric amounts of an enantiomerically pure aldehyde were used in a di-astereoselective reaction with 3-nitropropionate by Hanessian et al. [7]. However, an approach to enantioselective synthesis of nitroalcohols via the route of the asymmetric Henry reaction could not be carried out until almost one hundred years after the discovery of the nitroaldol reaction. 

In 1992, Shibasaki et al. reported for the time an application of chiral heterobimetallic lanthanoid complexes (LnLB) as chiral catalysts in asymmetric catalysis, namely the catalytic asymmetric nitroaldol reaction (Henry reaction), which is one of the most classical C-C bond forming processes [11]. Additionally, this work represents the first enantioselective synthesis of (3-nitroalcohol compounds by the way of enantioselective addition of nitroalkanes to aldehydes in the presence of a chiral catalyst. The chiral BINOL based catalyst was prepared starting from anhydrous LaCl3 and an equimolar amount of the dialkali metal salt of BINOL in the presence of a small amount of water [9]. 

---