Nitroalkanes Mannich reaction

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

The Mannich reaction is an excellent route to polynitroaliphatic amines and their derivatives. /3-Nitroalkylamines are formed from the reaction of an amine and aldehyde in the presence of a nitroalkane (Equations 1.4 and A large number of these reactions... 

Primary and secondary nitroalkanes, dinitromethane, and terminal em-dinitroaliphatic compounds like 1,1-dinitroethane, all contain acidic protons and have been used to generate Mannich products. Formaldehyde is commonly used in these reactions although the use of other aliphatic aldehydes has been reported. The nitroalkane component is frequently generated in situ from its methylol derivative, a reaction which also generates formaldehyde. Ammonia, " aliphatic amines, " hydrazine, and even urea have been used as the amine component of Mannich reactions. 

Scheme 6.73 Typical products of the enantioselective aza-Henry (nitro-Mannich) reaction between nitroalkanes and N-phosphinoylimines proceeding in the presence of catalyst 12.

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

Deaminomethylation of Mannich bases (path a in Fig. 81), which is actually a retro-Mannich reaction, as it reproduces the same reactants employed in the direct synthesis, has been observed in practically every class of Mannich derivative (Table 22 and Figs. 186, 189 in Chap. V). C-Mannich bases are more stable than the corresponding derivatives, having the aminomethyl group linked to a heteroatom. This has been directly found, for example, in barbituric acid derivatives, although the C-Mannich bases deriving from particularly activated subsU atcs, such as nitroalkanes, also exhibit a remarkable tendency to decompose. "... 

N—X—A -linked bis- azacyclam cations (146)-(149) are formed by Mannich reactions (Section 1.20.5), with a,cu-diamine locking reagents. Triangular trismacrocycle analogues are similarly formed with triamino triazine linkers (Scheme 35).180 Extension of the nitroalkane/... 

Acdve methylene compounds ranging in acidity from -keto esters, malonates and nitroalkanes pK = 9-13) to ketones (pATa = 16-20) can be used in the Mannich reaction. The lack of examples using simple unactivated esters (p/iTa = 25) appears to be due to their weaker acidity or to transamination and/or hydrolysis side reactions. Enolizable aldehydes have also been used in certain instances however, side products arising from subsequent aldol condensation of the resulting -amino aldehyde often occur. Best results are achieved with a-branched aldehydes, which produce Mannich bases without enolizable protons. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

I. Aldolic addition and the Mannich reaction (Vol. I. p. 186) The aldolic I addition reaction of nitroalkanes with carbohydrates (specifically aldoses) continues to be an important reaction in sugar chemistry which according to Baer i ) in some respects surpasses in versatility limil Fischer s classical cyano-[hydrin syntliesis. Particularly noteworthy are publications by Baer and Kovaf 1144, 45], Funubaski. Yoshimura and co-workers (46 51] and other Japanese [workers (52], Russian workers [53, 54] and Bilik (55]. 

Yoon et al. [33] found that thiourea catalyst with an amine function promotes the stereoselective addition of a range of nitroalkanes to aromatic A-butoxycarbonyl (A-Boc) imines. In the Mannich reaction of nitroethane (Table 9.12) high enantioselectivity, but low yield, is observed when urea is used (run 1), whereas thiourea affords the adduct in >95% yield with 92% ee (run 2). It should be noted that addition of powdered molecular sieves is necessary for reproducible results. 

Nucleophilic addition to the C=N bond of imine derivatives is quite important in organic chemistry for the synthesis of functionalised amines and related nitrogen-containing compounds. This section introduces an enan-tioselective Mannich reaction, including an aza-Henry reaction that uses nitroalkanes as a nucleophile, via PTC catalysis in the presence of Cinchona-derived quaternary ammonium salts. 

The original Mannich reaction consisted in the reaction of a compound containing at least one active hydrogen atom (ketones, nitroalkanes, p-ketoesters, P-cyano acids etc.) with formaldehyde and primary or secondary amine or ammonia (in the form of its hydrochloride) to give products, p-aminoketone derivatives, known as mannich base (Scheme 153). ... 

Scheme 8.13 Nitro-Mannich reaction of isatin-derived iV-Boc-ketimines with nitroalkanes in the presence of an in situ generated nickel catalyst derived from a bis(imidazolidine)-pyridine ligand.

The Mannich reaction between an aldehyde (usually formaldehyde) and a primary or secondary amine in the presence of a third substance having an active hydrogen, e.g. ketones, nitroalkanes, malonic esters, bears close similarity to the Leuekart reaction (equation 40). The net... 

The nitro-Mannich reaction has been reviewed (266 references), covering a variety of its manifestations simple nitroalkane versus more functionalized nitro compounds, non-catalytic, metal ion- and organo-catalytic, conjugate and cycloadditions and so on. 0 New chiral modular bifimctional iminophosphorane superbase organocatalysts allow 0 metal-free enantioselective addition of nitromethane to otherwise unreactive ketone-derived imines. The readily scalable reaction yields -nitroamines (20) with a fully 0 substituted carbon atom, in up to 95% ee. 

N-Benzotriazole derivatives of quinine and quinidine were applied as phase-transfer catalysts for the nitro-Mannich reaction between a-amido-sulfones and nitroalkanes (Scheme 6.57) [119]. The products were formed in good yields and high enantioselechvihes and could be transformed efficiently into either a diamine... 

In 2007, Ooi and coworkers introduced chiral tetraaminophosphonium salts as a new class of Bronsted acids [166]. Similar to the guanidine/guanidinium case, these tetraaminophosphonium salts act as Bronsted bases in their neutral/ deprotonated (triaminoiminophosphorane) form, while they can also be used as mono-functional Bronsted acids in their protonated, phosphonium form. Phos-phonium salt 67, when neutralized in situ with KO Bu, was shown to be a highly effective catalyst in the enantioselective Henry reaction of nitroalkanes with various aromatic and aliphatic aldehydes (Scheme 10.65). The same strategy was further applied to the catalytic asymmetric Henry reaction of ynals [167] and hydrophosphonylation of ynones (Scheme 10.66) [168]. Brfunctional catalysis using this scaffold were also obtained using the carboxylate salts of tetraaminophosphoniums in the direct Mannich reaction of sulfonyl imines with azlactones (Scheme 10.67) [169]. 

Addition of Nitroalkanes to C=NR (The Aza-Henry or Nitro-Mannich Reaction) 851... 

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