Alkylation nitroalkanes

Alan H. Haines, Methods for the Oxidation of Organic Compounds, Alcohols, Alcohol Derivatives. Alkyl Halides, Nitroalkanes, Alkyl Azides, Carbonyl Compounds, Hydroxyarenes and Amino-arene s, 1988... 

R -j-CHj—OR, Equation 4.13). The reaction is also competitive for many nitroalkanes, alkyl iodides, secondary and tertiary alkyl bromides, and tertiary alkyl chlorides, but not for RCH2—Y compounds of higher C—Y bond strengths, such as unbranched alkanols and alkyl chlorides for these [(M — HY)" ] > [(M — Y) ] as in Equation 4.23 (see Section 4.9). As is expected for an inductive effect, the influence of the charge site can affect a bond that is farther away if it has more polarizable electrons the loss of CH2CI is much larger in Equation 4.24 than in 4.23. 

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

Nitroparaffias (or nitroaLkanes) are derivatives of the alkanes ia which one hydrogen or more is replaced by the electronegative nitro group, which is attached to carbon through nitrogen. The nitroparaffins are isomeric with alkyl nitrites, RONO, which are esters of nitrous acid. The nitro group ia a nitroparaffin has been shown to be symmetrical about the R—N bond axis, and may be represented as a resonance hybrid ... 

Titanium alkyls, known as tamed Grignard reagents, do not add to esters, nitriles, epoxides, or nitroalkanes at low temperatures. Rather, they add exclusively ia a 1,2 fashion to unsaturated aldehydes (208—210). 

Reaction of various pyridazine derivatives with nitromethane or nitroethane in DMSO affords the corresponding 5-methyl and 5-ethyl derivatives. The reaction proceeds as a nucleophilic attack of the nitroalkane at the position 5. In this way, 3,6-dichloro-4-cyano-pyridazine, 4-carboxy- and 4-ethoxycarbonyl-pyridazin-3(2//)-ones and 4-carboxy- and 4-ethoxycarbonyl-pyridazin-6(lH)-ones can be alkylated at position 5 (77CPB1856). 

Nitroalkanes show a related relationship between kinetic acidity and thermodynamic acidity. Additional alkyl substituents on nitromethane retard the rate of proton removal although the equilibrium is more favorable for the more highly substituted derivatives. The alkyl groups have a strong stabilizing effect on the nitronate ion, but unfavorable steric effects are dominant at the transition state for proton removal. As a result, kinetic and thermodynamic acidity show opposite responses to alkyl substitution. 

Scheme 12.7. Carbon Alkylation via Nitroalkane Radical Anions Generated by...

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

The reaedvity of carbon is much enhanced by the double deprotonated intermediates of nitro compounds. Except for nitromuhane, other nitroalkanes are alkylated to give the C-alkylated products in 50-60% yield by this procedure fsee Eq. 5.4. ... 

Thus, the direct alkyladon of the anions derived from nitroalkanes v/ith alkyl hahdes has some chfficiddes, and such chfficuldes are partially overcome by the radicM reacdc raetM catMyzed reacdons, as discussed in Secdons 5 4 and 5 5... 

Alkyl mercury halides participate in a photo-sdmidated rathcM chain reacdon of the anion of nitroalkanes Isee Eq. 5.38 in which a 375-W sun lamp Is used." Primary, secondary, and ternary alkyl rathcMs generated from alkyl mercury halides react with the anion of ttitroalkanes to form new C-C bonds. 

Oxidadve cross-conphng reactions of alkylated derivatives of activated CH compounds, such as malonic esters, acetylacetone, cyanoacetates, and ceitain ketones, v/ithnitroalkanes promoted by silver nitrate or iodine lead to the formation of the nitroalkylated products. This is an alternative way of performing Spj l reactions using cr.-halo-nitroalkanes. 

Although this method is aot a geaeral procedure, bemg specific for ct-nitroketoues, k has several merits to avoid the use of toxic reageuts such as organodn compounds Functionalized ketones have been prepared by this denitration reaction, in which functionalized nitroalkanes are used as alkyl anion synthons For example, 3-nitropropanal ethylene acetal can be used as synthon of the 3-oxo-propyl anion and 1,4-dicarbonyl compounds are prepared, as shovm In Eq 7 88... 

AlkenyldQon using nitroalkanes foUowedby theselecQve reducQonof the double bends with NiCl and NdBbb, can be regarded as the addition of alkyl aruons to electron-deficient alkenes... 

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. 

The stereospecific base-cleavage of the trimethylsilyl group in 1,3-dithiane 1-oxides 499 enables to obtain the specifically deuteriated products 500 (equation 303), A nitro group in y-nitroalkyl sulphoxides 501 (obtained by the Michael addition of nitroalkanes to a, j8-unsaturated sulphoxides) is replaced by hydrogen by means of tributyltin hydride (equation 304). This reagent does not affect the sulphinyl function. The overall procedure provides an efficient method for the conjugate addition of alkyl groups to a, -unsaturated sulphoxides . ... 

Smith, R. M. and Finn, N., Comparison of retention index scales based on alkyl aryl ketones, alkan-2-ones and 1-nitroalkanes for polar drugs on re-versed-phase high-performance liquid chromatography,. Chromatogr., 537, 51,1991. 

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... 

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