Nitromethane alkylation with

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. 

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

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. 

Dithio-l-nitroalkenes are prepared by the reaction of nitromethane with CS2 and KOH followed by alkylation with alkyl halides (Eq. 10.84).43 They are important reagents for synthesis... 

Alkylation with Oxonium Salts Oxonium salts are the most efficient alkylating agents and can react with both activated and nonactivated AN, including nitromethane and 2-nitropropane (Scheme 3.4). 

Commercially available ethyl nitroacetate is an interesting pronucleophile, because it can serve as the synthetic equivalent of either nitromethane or glycine. The ethoxycarbonyl group can also be considered as a protecting group against dialkylation. The allylic alkylation with ethyl nitroacetate did not require an additional base (salt-free conditions). As a consequence of the high acidity of the chirality center a to N, 1 1 mixtures of epimers were formed. 

The quaternary salt 366 was not obtained from 9-hydroxyl-2-methyl-4 -pyrido[ 1,2-a]pyrimidin-4-one 365 and benzyl chloride by heating in nitromethane (92KGS1660). The hydroxy group of 9-hydroxylpyridopy-rimidin-4-one 365 was alkylated with methyl iodide in dimethyl sulfoxide at 40°C for 30 hours to give 9-methoxy derivative 367 in 9% yield. 

Condensation reaction between active methyl and methylene compounds and S-alkylated thioureas provides another useful synthetic pathway to the 1,1-enediamines. Rajappa and coworkers20 reported that nitromethane condensed with S-methylated thioureas 72, prepared from the reaction of amines and methyl isothiocyanate followed by S-methylation, to form asymmetric nitro 1,1-enediamines 73 (Scheme 5). 

Ammonium salts with two different alkyl chains were prepared directly via subsequent alkylations of dimethylamine with primary bromides and crystallization. Commercial hexadecyl-methylamine can be conveniently applied in the same way in order to convey functionality to cationic synkinons. A recent example describes subsequent alkylations with a small functional and a long-chain primary bromide (Scheme 2.4). A-acylated / -phenylenediamine was also alkylated at the second nitrogen atom which had two different alkyl chains, with or without extra functionality . After deacylation, this head group can be diazotized or coupled oxidatively with various heterocycles in water (Scheme 2.4). Photoactive and coloured membrane surfaces are thus obtained. Phenylene-diamine, pyridine and in particular A-methyl-4,4-bipyridinium chloride are relatively weak nucleophiles. Substitution of bromides is slow and the more reactive iodides can rarely be obtained commercially, but the selection of nitromethanes as solvent for bromide substitution is of great help as well as the addition of sodium iodide to enforce a Finkelstein reaction or a combination of both. 

The alkylation of aromatic 1,2,4-triazines has been studied by various groups.251 -259 Alkylation with iodomethane affords the red 1-methyl-1,2,4-triazinium salts 4c-j predominantly and in a few cases yields the colorless 2-methyl-l,2,4-triazinium salts 5. The best results are obtained when nitromethane is used as the solvent for the alkylation. Similar results are obtained when trialkyloxonium tetrafluoroborates or dialkyl sulfates are used as alkylation agents. The formation of either the 1- or the 2-isomers depends on the substituents bound to the 1,2,4-triazine ring. In cases with a bulky substituent in the 3-position, alkylation occurs exclusively at Nl, in other cases mixtures of N1 and N2 alkylated triazinium salts are obtained. Introduction of a more bulky substituent, such as isopropyl or aryl substituents, in the 6-posi-tion hinders quaternization at Nl. 

S-Alkylation. A stirred soln. of mer/-bicyclo-3,5-epidithio-l,4-diphenyl-2,4-penta-diene-l-thione in nitromethane treated with methyl iodide, and refluxed overnight 3-(2-methylthio-l-phenylvinyl)-5-phenyl-l,2-dithiolium iodide. Y 90%. F. e., also N-analogs, s. E. Klingsberg, J. Org. Chem. 33, 2915 (1968). 

Exclusive alkylation of normally unfavored positions in (po/y-N)-heterocyclics can be achieved by using acyl (acetyl, benzoyl, carbethoxy) as N-protective groups. - E Trimethyloxonium fiuoroborate in nitromethane dropped rapidly under anhydrous conditions into a cooled soln. of l-acetyl-1,2,4-triazole in the same solvent, methanol added to hydrolyze the acyl cation to the protonated salt, and the aq. soln. of the latter neutralized with Na-carbonate -> 4-methyl-l,2,4-triazole. Y 88%. F. e., also alkylation with carboxonium salts, s. R. A. Olofson and R. V. Kendall, J. Org. Chem. 55, 2246 (1970). 

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). 

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]... 

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.

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... 

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... 

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). 

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... 

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... 

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... 

Very interesting transformations were reported in terminal alkynes RC=CH (R = alkyl, aryl, alkoxy, carboxylate, etc.). They react readily with nitric acid, in aqueous nitromethane (1 1) and in the presence of catalytic amounts of tetra-butylammonium tetrachloroaurate to give 3,5-disubstituted isoxazoles 15 in 35% to 50% isolable yield (92). The reaction might proceed via a nitrile oxide intermediate by attack of an electrophile (AuCh or H+) and of a nucleophile (N02 ) on the triple bond to form a vinyl nitrite, which is converted to a nitrile oxide by the action of gold(III) or of nitric acid (Scheme 1.8). 

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