Nitromethane alkylation

Aluminum chloride dissolves readily in chlorinated solvents such as chloroform, methylene chloride, and carbon tetrachloride. In polar aprotic solvents, such as acetonitrile, ethyl ether, anisole, nitromethane, and nitrobenzene, it dissolves forming a complex with the solvent. The catalytic activity of aluminum chloride is moderated by these complexes. Anhydrous aluminum chloride reacts vigorously with most protic solvents, such as water and alcohols. The ability to catalyze alkylation reactions is lost by complexing aluminum chloride with these protic solvents. However, small amounts of these "procatalysts" can promote the formation of catalyticaHy active aluminum chloride complexes. 

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. 

Acetophenone enolate and nitromethane anions have also been used successfully in alkyl substitution. 

Tnfluoroacetic anhydnde in a mixture with sulfuric acid is an efficient reagent for the sulfonylation of aromatic compounds [44] The reaction of benzene with this system in nitromethane at room temperature gives diphenyl sulfone in 61% yield Alkyl and alkoxy benzenes under similar conditions form the corresponding diaryl sulfones in almost quantitative yield, whereas yields of sulfones from deactivated arenes such as chlorobenzene are substantially lower [44] The same reagent (tnfluoroacetic anhydride-sulfunc acid) reacts with adamantane and its derivatives with formation of isomeric adamantanols, adamantanones, and cyclic sultones [45]... 

Few other reactions of series of substituted pyridines have been investigated extensively. Dondoni, Modena, and Todesco have measured the rate of N-oxidation of a limited series of pyridines and found a good correlation with normal u-values with a p-value of — 2.23. The A-alkylation of pyridines with alkyl iodides in nitrobenzene has been studied by Brown and Cahn and by Clarke and Rothwell. Unfortunately, the only data available are for the parent compound and for alkyl derivatives, and, since the a-values for the various alkyl groups in a given position are substantially constant, this leaves a correlation of only three independent points. However, the rates of A-alkylation of the j8- and y-alkyl derivatives are so nearly equal that it appears as if no correlation existed. Clarke and Rothwell have also studied the alkylation with allyl bromide in nitromethane at various temperatures, and in this case a more extensive series is available. The authors state that no overall Hammett correlation is obtained however, the j8-substituted derivatives fall on one straight line and the y-derivatives on another one with a different slope. The data are shown in Fig. 2. The line for the j8-compounds, p = — 2.53 0.31, r = 0.95, is seen not to be very good the line for the y-derivatives, p = — 1.42 0.06, r = 0.99, is much more satisfactory. It does not seem likely that the discrepancy is due to the intervention of resonance effects, since in this case one would expect the correlation for the y-derivatives to be poorer than that for the j8-analogs. More extensive studies with a wider variety of substituents would seem very desirable. 

Fig. 2. A Hammett plot of the rates of alkylation of substituted pyridines with allyl bromide in nitromethane. Circles represent 4-substituted compounds and crosses 3-substituted compounds. Cf. ref. 54.

Dithio-l-nitroalkenes are prepared by the reacdon of nitromethane v/ith CS and KOH followed by alkyladonv/ith alkyl halides CEq. 10.84. They are important reagents forsynthesis... 

Studies of the relative rates of the zinc chloride-catalysed bromination of alkyl-and halogeno-benzenes in nitromethane at 25 °C have lead to the suggestion that the rate-determining step of the reaction is formation of Ji-complex, since low substrate selectivity was found to be coupled with high (i.e. normal) positional selectivity323. Under some conditions (column 1 in Table 75) the low selectivity... 

Alkylation with alkyl halides in organic solvents other than nitromethane The first reliable kinetic study of alkylation appears to have been that of... 

Low substrate selectivity accompanying high positional selectivity was also found in isopropylation of a range of alkyl and halogenobenzenes by /-propyl bromide or propene in nitromethane, tetramethylene sulphone, sulphur dioxide, or carbon disulphide, as indicated by the relative rates in Table 86. The toluene benzene reactivity ratio was measured under a wide range of conditions, and varied with /-propyl bromide (at 25 °C) from 1.41 (aluminium chloride-sulphur... 

Relative rates of alkylation of toluene and benzene using a mixture of nitro-sonium hexafluorophosphate, nitromethane (or acetonitrile) and aliphatic amine as the alkylations agent have been determined at 25 °C as follows360 1.5 (ethyl-amine), 2.5 (i-propylamine) and 3.5 (benzylamine) nothing more as yet is known about the kinetics of alkylation with these new alkylating reagents. 

Phenylsulfonyl)nitromethane is preferentially C-alkylated by benzylic halides and primary alkyl iodides, affording secondary a-nitrosulfones338. 

The transformation of l-methylthio-l-(methylsulfonyl)alkanes (254) to methyl esters can be efficiently carried out by oxidation or by a-chlorination followed by methanolysis (equation 152)145. The lithium or the sodium salt of (phenylsulfonyl)nitromethane (256) is a very useful reagent for the preparation of higher homologues of nitromethanes by alkylation since the salts are air insensitive, non-hygroscopic, and easily handled without decomposition. The oxidation of the resulting secondary a-nitro sulfone (257) gives... 

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 condensation of arylsulfonyl acetonitriles 369a-c with 22a proceeds via addition of the in-situ formed anion 370 to the arylsulfonyl acetonitriles 369 to afford the dimers 371, in 69-94% yield, and hexamethyldisiloxane 7 [136]. Furthermore, y9-dicarbonyl compounds such as ethyl acetoacetate 372 a or ethyl benzoyl-acetate 372b are O-silylated by 22 a or 22 c to rather stable alkyl 3-O-trimethylsilyl-oxycrotonoate 373a and alkyl 3-0-trimethylsilyloxy-3-phenyl acrylate 373b [130]. Aliphatic nitro compounds such as nitromethane are O-trimethylsilylated and further transformed into oligomers [132] (cf Section 7.6) and are thus unsuitable reactants for silylation-C-substitutions (Scheme 4.50). 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

Novel chiral thiolated amino alcohols have been recently synthesised and then evaluated by Vilaivan el al. as a potential new class of ligands for Cu-catalysed nitroaldol reactions. Amino alcohol ligands bearing Ai-(2-alkyl-thio)benzyl substituents provided only modest enantioselectivities (22-46% ee) while those carrying Al-2-thienylmethyl substituents provided better enantioselectivities of up to 75% ee for the nitroaldol reaction between p-nitro-benzaldehyde and nitromethane. A range of aromatic aldehydes were acceptable substrates giving moderate to high enantioselectivities of up to 88% ee, as shown in Scheme 10.32. 

MISCELLANEOUS BENZOHETEROCYCLES Partial reduction of lactone 166 (using for example diisobutylaluminum hydride in the cold) affords lactol 167. Condensation with nitromethane leads to the corresponding alkylated tetrahydrobenzopyran 170. The sequence probably starts by aldol reaction of the hydroxylactone form of the lactol (168) with nitrome thane to give the vinyl nitro intermediate 169 ... 

C-Alkylation takes place in the reaction of methyl nitroacetate with alkyl halides the products are useful intermediates for preparing amino acids (Eq. 5.1).2 The requisite nitro acetate is prepared by self condensation of nitromethane.3... 

The reactivity of carbon is much enhanced by the double deprotonated intermediates of nitro compounds. Except for nitromethane, other nitroalkanes are alkylated to give the C-alkylated products in 50-60% yield by this procedure (see Eq. 5.4).9 10... 

Couplings of nitroalkyl radicals with nucleophiles such as CN-, N, N02, and other nitrogen nucleophiles provides a useful method for the preparation of nitro compounds with such groups at the a-position.49 65 The alkylation of nitromethane with trialkylborane is possible by electrolysis, in which alkyl radicals may be involved (Eq. 5.46).66... 

Phenylsulfonyl)nitromethane is preferentially C-alkylated by ally lie acetates in the presence of Pd(PPh3)4 (5 mol%) to give various a-nitro sulfones as shown in Eq. 5.53.76... 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

The hydrogenation in the presence of Pd/C is also effective for the conversion of nitro compounds to amines.94 The Michael addition of nitromethane to 2-alkenoic esters followed by catalytic hydrogenation using 10% Pd/C in acetic acid and hydrolysis is a convenient method for the preparation of 3-alkyl-4-aminobutanoic acids, which are important y-amino acids for biological study (Eq. 6.48).94b The reduction can be carried out at room temperature and atmospheric pressure. 

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