Nitroalkanes reactions with

Equation 26. Electron-deficient flavins will also oxidize nitroalkane anions in model reactions (12). The observation (11) that nitromethane anion and FloXEt yield a stable 4a-adduct is evidence that 4a-adducts are not on the reaction path for nitroalkane oxidation. That the blocking of the N(5)-position of flavin (i.e., FloxEt) prevents oxidation of nitromethane would, however, be in accord with the requirement for an N(5)-adduct (11). The nitroalkane reaction with flavoenzyme has been used to implicate N(5)-adducts as intermediates in the oxidation mechanism of amino acid oxidases. However, it must be understood that nitroalkane anions differ significantly from the carbanions generated from a normal substrate. The nitroalkane anion on loss of its pair of electrons would provide an impossibly unstable carbonium ion, whereas in the case of the amino acid anion an internal electron release obviates carbonium ion formation. 

This reaction can also be applied to tertiary nitroalkanes lacking any additional functional group. The reactions with nitro compounds lacking additional anion-stabilizing groups are carried out in DMSO solution ... 

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. 

A proof for the formation of alkyl radicals was found by their addition to the aci-nitromethane anion (CH2=N02 ) and by their reaction with p-benzoquinone to give the optically active nitroalkane radical-anion and the semiquinone radicals, respectively. In the case of di-r-butyl sulfoxide the f-butyl radical was observed directly by its absorption spectra. 

Both overt carbanions and organometallic compounds, such as Grignard reagents, are powerful nucleophiles as we have seen in their addition reactions with C=0 (p. 221 et seq.) they tend therefore to promote an SN2 pathway in their displacement reactions. Particularly useful carbanions, in preparative terms, are those derived from CH2(C02Et)2, (3-ketoesters, l,3-( 3-)diketones, e.g. (55), a-cyanoesters, nitroalkanes, etc.—the so-called reactive methylenes ... 

The reaction of alkyl halides with metal nitrites is one of the most important methods for the preparation of nitroalkanes. As a metal nitrite, silver nitrite (Victor-Meyer reaction), potassium nitrite, or sodium nitrite (Kornblum reaction) have been frequently used. The products are usually a mixture of nitroalkanes and alkyl nitrites, which are readily separated by distillation (Eq. 2.47). The synthesis of nitro compounds by this process is well documented in the reviews, and some typical cases are listed in Table 2.3.92a Primary and secondary alkyl iodides and bromides as well as sulfonate esters give the corresponding nitro compounds in 50-70% yields on treatment with NaN02 in DMF or DMSO. Some of them are described precisely in vol 4 of Organic Synthesis. For example, 1,4-dinitrobutane is prepared in 41 -46% yield by the reaction of 1,4-diiodobutane with silver nitrite in diethyl ether.92b 1-Nitrooctane is prepared by the reaction with silver nitrite in 75-80% yield. The reaction of silver nitrite with secondary halides gives yields of nitroalkanes of about 15%, whereas with tertiary halides the yields are 0-5%.92c Ethyl a-nitrobutyrate is prepared by the reaction of ethyl a-bromobutyrate in 68-75% yield with sodium nitrite in DMF.92d Sodium nitrite is considerably more soluble in DMSO than in DMF as a consequence, with DMSO, much more concentrated solutions can be employed and this makes shorter reaction times possible.926... 

Thus, the reaction of alkyl halides and a-halo esters with sodium nitrite provides a very useful synthetic method for nitroalkanes and a-nitro esters. However, ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate on treatment with sodium nitrite.93 This is due to the acidic hydrogen of the ethyl nitroacetate, which undergoes a further reaction with sodium nitrite to give the oxidized products (see Section 6.1, which discusses the Nef reaction). In a similar way, the reaction of benzyl bromide with sodium nitrite at 25 °C gives benzoic acid predominantly. To get phenylnitromethane, the reaction must be carried out at low temperature (-16 °C) (Eq. 2.48).93... 

Another method for improving the reactivity of nitro compounds is provided by the double deprotonation of nitroalkanes. In this case, the reaction with ketones affords P-nitro alcohols in 40-60% yield (Eq. 3.19).30... 

Proazaphosphatrane, P(RNCH2CH2)3N, is an efficient catalyst for the Henry reaction, and various ketones give nitro-aldols by the reaction with nitromethane and other nitroalkanes (Eq. 3.20).21... 

Gem-nitro imidazolyl alkanes undergo Sjy l reactions with the anion of various nitroalkanes, as shown in Eq. 5.36.54 The nitro group is replaced by hydrogen in 80-90% yield on treatment with Bu3SnH (see Chapter 7, which discusses radical denitration). 

Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the a.a-dianions of primary nitro compounds and radial reactions are described. Palladium-catalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuj i and Trost have developed the carbon-carbon bond forming reactions using 7t-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.6811-1 Nitro compounds can participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals. 

The Nef reaction can also be carried out with reducing agents. Aqueous titanium chloride reduces nitro compounds to imines, which are readily hydrolyzed to carbonyl compounds (Eq. 6.17).28 The Michael addition of nitroalkanes to enones followed by reaction with TiCl3 provides an excellent route to 1,4-diketones and hence to cyclopentenones. For example, cw-jasmone is readily obtained,28 as shown in Eq. 6.18. 

I. reactions of BENA with C-nucleophiles Russian researchers performed comprehensive studies on C,C-coupling reactions of terminal BENAs A with anions of nitro compounds (516, 517). This process enables one to assemble 3-substituted oximes from two different AN ((441) and 442). It should be noted that compound (442) must have the methyl group at the a-C atom necessary for generation of terminal BENA. Both nitroalkanes should be prepared for C,C-coupling, that is, AN (441) is transformed into the anion C by the reaction with DBU, while AN (442) is successively transformed into BENA A and nitrosoalkene B. The C,C-coupling reaction B + C is shown in Scheme 3.238. 

Silylation of AN (528b,c,e) with another silylating agent (Me3SiCl/Et3N) gives poorly separable mixtures of unidentified products. However, the reaction of AN (528a) under these conditions produces the silyl derivative of bis-oxime (533), which can be subjected to desilylation to prepare free bis-oxime (534) (491, 497). The stereoselectivity of the reaction with respect to the new C,C double bond is low (E/Z 1.3 1). Silylation of sterically more hindered nitroalkane (528 d)... 

Reduction of nitroalkanes RNO2 with samarium(II) iodide, obtained from samarium and 1,2-diiodoethane, yields either alkylhydroxylamines RNHOH or alkylamines RNH2, depending on the amount of the reagent434. The base-catalysed reaction of nitroalkanes with phenyl(vinyl) sulphoxide (399) yields the conjugate adducts 400, which fragment to allylic nitro compounds 401 on thermolysis435. 

Addition of nitroalkanes 402 (R = Me, Bu, Ph etc.) to methyl acrylate without a solvent in the presence of Amberlyst-21 gives good yields of the esters 403436. An analogous reaction with electrophilic acetylenes, e.g. dimethyl acetylenedicarboxylate, in the presence of potassium fluoride and tetrabutylammonium chloride yields adducts 404 as mixtures of geometrical isomers437. 

A review of the reaction of nitroalkanes RNO2 with carbon and heteroatom nucleophiles X to yield RX has appeared438. The nucleophilic displacement of a nitro group in benzylic and tertiary nitroalkanes by a thiophenyl group is exemplified in equation 130439. 

Nitroalkanes react with Jt-deficient alkenes, for example, p-nitro ketones are produced from a,P-unsaturated ketones [41], whereas allylic nitro compounds have been prepared via the Michael-type addition of nitroalkanes with electron-deficient alkynes (Table 6.19). The reaction in either dimethylsulphoxide [42] or dimethyl-formamide [43] is catalysed by potassium fluoride in the presence of benzyltriethyl-ammonium chloride the reaction with dimethyl acetylenedicarboxylate is only successful in dimethylsulphoxide [42], Primary nitroalkanes produce double Michael adducts [42,44], A-Protected a-aminoacetonitriles react with alkynes under catalysed solidiliquid conditions to produce the Michael adducts [45] which, upon treatment with aqueous copper(Il) sulphate, are converted into a,p-unsaturated ketones. 

The reaction is usually carried out in acid solution, but may also be base catalysed. This is the condensation between aldehydes, ammonia or a primary or secondary amine and a compound containing at least one active hydrogen atom e.g., ketones, b-ketoesters, b-cyanoesters, nitroalkanes, alkynes with C°H). For example. 

Nitroalkanes (Tables 12 and 13) These are possibly among the most useful substrates for reaction with the superoxide/dioxygen reagent, and the loss of nitrite, according to Scheme 21, has been confirmed. Secondary nitroalkanes are efficiently converted into ketones (Table 12), and the reaction may prove to be of especial value for the preparation of 1,4-diketones. 

An elegant extension of this approach is the combination of the nitroalkanes to ketone reaction with prior EGB-catalysed Michael condensation involving nitronate anions. Azobenzene works well as the catalyst probase and the condensation and... 

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