Nitrones, synthesis nitro compounds

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

The required nitro compounds are easy to prepare, and are useful building blocks for synthesis. Treatment with an appropriate base—e.g. aqueous alkali—leads to formation of nitronates 2. Various substituted nitro compounds, such as nitro-ketones, -alcohols, -esters and -nitriles are suitable starting materials. 

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. 

Giomi s group developed a domino process for the synthesis of spiro tricyclic nitroso acetals using a, 3-unsaturated nitro compounds 4-163 and ethyl vinyl ether to give the nitrone 4-164, which underwent a second 1,3-dipolar cycloaddition with the enol ether (Scheme 4.35) [56]. The diastereomeric cycloadducts formed, 4-165 and 4-166 can be isolated in high yield. However, if R is hydrogen, an elimination process follows to give the acetals 4-167 in 56% yield. 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

I.2. Oxidation of Amines Oxidation of primary amines is often viewed as a particularly convenient way to prepare hydroxylamines. However, their direct oxidation usually leads to complex mixtures containing nitroso and nitro compounds and oximes. However, oxidation to nitrones can be performed after their conversion into secondary amines or imines. Sometimes, oxidation of secondary amines rather than direct imine oxidation seems to provide a more useful and convenient way of producing nitrones. In many cases, imines are first reduced to secondary amines which are then treated with oxidants (26). This approach is used as a basis for a one-pot synthesis of asymmetrical acyclic nitrones starting from aromatic aldehydes (Scheme 2.5) (27a) and 3,4-dihydroisoquinoline-2-oxides (27b). 

I. Condensation of N-Monosubstituted Hydroxylamines with Carbonyl Compounds Condensation of N -monosubstituted hydroxylamines with carbonyl compounds is used as a direct synthesis of many acyclic nitrones. The synthesis of hydroxylamines is being carried out in situ via reduction of nitro compounds with zinc powder in the presence of weak acids (NH4CI or AcOH) (14, 18, 132). The reaction kinetics of benzaldehyde with phenylhydroxylamine and the subsequent reaction sequence are shown in Scheme 2.21 (133). 

In 1981, it was demonstrated (70) that anions of nitro compounds can be involved in C,C-coupling with allyl acetates at the allylic carbon atom with the use of metal complex catalysis. For many years, this observation did not come to the attention of chemists interested in the synthesis of cyclic nitronates. However, Trost demonstrated (71) that this process can be used in the synthesis of five-membered cyclic nitronates from olefins (18) containing two acyl groups in the different allylic positions (Scheme 3.21). 

Analogous intramolecular cyclization can be carried out by performing the reaction of CAN with nitro olefin (20) (73) (Scheme 3.23). However, this reaction is unlikely to be useful in the synthesis of a broad range of cyclic nitronates because the starting nitro compounds (similar to (20)) are difficult to prepare. 

Recently, C,N condensation of salts of nitro compounds with the nitroso group has been discovered (251, 451) (Scheme 3.190). This reaction can be considered as a convenient procedure for the synthesis of nitrones from AN. The yields of the target products are 40 to 97 %. 

Nitro compounds, synthesis of, 12, 3 Nitrone-olefin cycloadditions, 36, 1 Nitrosation, 2, 6 7, 6 Nucleosides, synthesis of, 55, 1... 

E. Brener, Nitrones and Nitronic Acid Derivatives Their Structure and their Roles in Synthesis , in The Chemistry of Amino, Nitroso and Nitro Compounds and their Derivatives, Vol. 1, S. Patai ed., Wiley, Chichester, 1982, pp. 459-538. 

Nitrile oxide J -I- 2 cycloaddition.1 A key step in a recent stereospecific synthesis of biotin (6) from cycloheptene (1) is an intramolecular [3 + 2]cyclo-addition of a nitrile oxide (a), obtained by dehydration of a primary nitro compound (3), preferably with phenyl isocyanate. This cycloaddilion is more efficient than the well-known olefinic nitrone cycloaddition. The carbon atoms in 6 derived from cycloheptene are marked with asterisks. 

Many other functional groups are reduced by Sml. For example, sulfonyl halides are converted to disulfides. The reduction of nitro compounds by this reagent enables synthesis of 1,2-diamines based on a reaction sequence initiated by nitronate addition to aldimines, and in the presence of nitriles it furnishes amidines, and that of isothiocyanates in the presence of conjugated esters, the half thioamide derivatives of succinic esters. 

Polymer-supported enzymes have been combined with polymer-supported reagents in the synthesis of the bryostatins. The nitrone derived from the nitro compound 43 supported on a soluble aryl poly-ether polymer undergoes an efficient 1,3-dipolar cycloaddition with butenone to give the isoxazoline 44 and hence by reduction the racemic syn compound 45 required for the synthesis.16... 

Silylation as new strategy of using of aliphatic nitro compounds in organic synthesis (cyclic silyl nitronates, heterocyclization) 01IZV1850. 

As mentioned above, nitro compounds are obviously of great importance in organic chemistry and aryl nitro compounds are an important source of aniline derivatives (secs. 4.2.C.V, 4.8.D). Both amine oxides and nitrones have been synthetically exploited. Alkyl nitroso derivatives, however, usually cannot be isolated since they decompose in solution, although the aromatic derivatives are more stable in solution and can be used in synthesis (sec. 2.1 l.E). Treatment of a primary amine with excess peroxyacid is a useful preparative route to alkyl nitro compounds.588 Yields are highest for tertiary alkyl primary amines next come secondary, followed by primary alkyl. Peroxyacid oxidation of oximes also provides a route to alkyl nitro compounds.589 This method is convenient for preparing aromatic nitro compounds as in the oxidation of 2,6-dichloroaniline to 2,6-dichloronitrobenzene (441).590 Nitrones are 1,3-dipoles and have been used in 1,3-dipolar cycloaddition reactions (sec. ll.ll.D). 

Nowadays a broad range of different 1,3-dipoles, ozone, azides ° and diazoalkanes on the one hand as well as dipoles like nitrones, nitro compounds, carbonyl ylides, nitrile oxides, nitrile imines and ylides on the other hand, are well-established. The addition of these 1,3-dipoles to an alkene is one of the most frequently used cycloaddition reactions in organic synthesis. ... 

Jawdosiuk M, Ostrowska B, Makosza M (1971) A new synthesis of nitrones from aromatic nitro-compounds and carbanions by nucleophilic replacement of hydrogen. J Chem Soc D 1971 548-549. doi 10.1039/C29710000548... 

Lypkalo IM, Ioffe SL, Strelenko Y, Tartakovsky VA (1996) A novel general method for the synthesis of nitrones by reaction of nitroso compounds with anions of aliphatic nitro compounds. Russ Chem Bull 45(4) 856-862. doi 10.1007/BE01431312... 

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