Nitromethane synthesis preparation

In order to treat influenza infections, the development of neuraminidase inhibitors is required. The currently available compounds are not potent enough, and they have a number of side effects. The stereoselective total synthesis of one potent inhibitor, BXC-1812 (RWJ-270201), was achieved by M.J. Muller and co-workers. The key intermediate substituted nitromethane was prepared via a Pd-catalyzed allylation of nitromethane under basic conditions. The transformation of this nitroalkane to the corresponding carboxylic acid methyl ester was carried out in two steps. The Nef reaction was conducted in DMF instead of the usual DMSO because DMSO as the solvent caused extensive epimerization of the product. The initially formed carboxylic acid was then esterified. 

Peptide synthesis [before references]. Zervas and his group9 have found benz-hydryl esters useful in peptide synthesis. They prepared the esters either by the reaction of the silver salt of an N-protected amino acid with diphenylmethyl chloride or by reaction of diphenyldiazomethane with the N-protected amino acid. Cleavage of the protective group was accomplished by treatment with 0.2 N hydrogen chloride in nitromethane. They prepared both the a- and y-benzhydryl esters of L-glutamic acid.10... 

In a reapplication of the cyanohydrin synthesis to L-rhamnose, the crystalline T-deoxy-L-jfZj/cero-L-gfalacto-heptose was further characterized as the pentaacetates and methyl glycosides. The heptoses derived from D-galactose and n-mannose have been prepared by the nitromethane synthesis, and this can be the method of choice for sugars which are not preferred epimers in cyanohydrin synthesis. 

Preparation. L-Mannose can be prepared by chain elongation methods, starting from L-arabinose. Both L-glucose and L-mannose are obtained. The nitromethane synthesis leads to a mixture of the nitroalditols that are separated by fractional crystallization and converted individually into the L-monosaccharides.130... 

Preparation (4, 4S). D-Ribose may be synthesized from D-arabinose by alkaline isomerization, by the glycal synthesis, or through the pyridine-catalyzed epimerization of D-arabonic acid followed by reduction. The sugar also has been prepared by the oxidative degradation of calcium D-altronate (44) and by the nitromethane synthesis from D-erythrose (4 ). 

The nitromethane synthesis is illustrated by the preparation of L-glucose and L-mannose from L-arabinose (149),... 

In addition to L-glucose and L-mannose, other sugars that have been prepared conveniently by the nitromethane synthesis include L-gulose (150), the aldoheptoses from D-mannose (151), and D-erythro-h-manno-octose (152),... 

Amino-2,6-dideoxy-D-allose and -altrose hydrochlorides have been prepared by application of the Kuhn modification of the cyanohydrin synthesis to 5-deoxy-D-ribose, the overall yields of the two amino-sugars being roughly the same as those obtained using the nitromethane synthesis. ... 

This class was first reported in 1924 and was formed 62HC(17)l) by cyclization of a-bromo-/3-aryl-y-nitroketones. The direct synthesis by oxygenation of 2-isoxazolines has not been reported. To date only 3-substituted derivatives have been prepared. Aryl-nitromethanes react with nitrostilbene to form isoxazoline A-oxide by a nitrile ion displacement (Scheme 138) <62HC(17)1, 68TL3375). 

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... 

Nitroacetaldehyde diethyl acetal is prepared by the reaction of nitromethane with triethyl orthoformate in the presence of ZnCl2 (Eq. 5.8).17 Jager and coworkers have used this reagent for the synthesis of amino sugars via nitro-aldol reaction.18 Preparation of this useful reagent is now described in volume 74 of Organic Synthesis.19... 

Ono and coworkers have extended the radical elimination of v/c-dinitro compounds to P-nitro sulfones151 and P-nitro sulfides.138,152 As P-nitro sulfides are readily prepared by the Michael addition of thiols to nitroalkenes, radical elimination of P-nitrosulfides provides a useful method for olefin synthesis. For example, cyclohexanone is converted into allyl alcohol by the reaction shown in Eq. 7.110. Treatment of cyclohexanone with a mixture of nitromethane, PhSH, 35%-HCHO, TMG (0.1 equiv) in acetonitrile gives ahydroxymethylated-P-nitro sulfide in 68% yield, which is converted into the corresponding allyl alcohol in 86% yield by the reaction with Bu3SnH.138 Nitro-aldol and the Michael addition reactions take place sequentially to give the required P-nitro sulfides in one pot. 

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... 

Zard and coworkers have developed a synthesis of substituted dienes by reductive elimination of allylic nitroacetates (equation 33)66. Allylic nitroacetates can be prepared by condensation of nitromethane with the carbonyl compound followed by addition of formaldehyde and acetylation67. Reductive elimination can be carried out by employing either chromous acetate or samarium iodide. 

An interesting example of the effectiveness of different reagents for 0-nitration can be seen during the synthesis of neo-inositol-based nitrate ester explosives. l,4-Dideoxy-l,4-dinitro-neo-inositol (15), a compound readily prepared from the condensation of nitromethane and glyoxal in the presence of base,undergoes conversion to the tetranitrate ester (16) on... 

Over the last decade, dialdehyde-nitromethane cyclization has established itself as a generally applicable and preparatively satisfactory method for the synthesis of nitrocyclanols, nitrosugars and nitrosugar nucleosides which on hydrogenation are easily converted to the corresponding amino-derivatives... 

In view of the ability of nitromethane to undergo a cyclizing bis-aminoalkylation when reacted with dialdehydes in the presence of amines 80,61) its application to other nitromethylene compounds seems an obvious extension. This reaction has already been verified when glutar-aldehyde is allowed to react with nitromethane and benzylamine in a 1 2 4 molar ratio in water, lr-methyl-l-nitro-2c,6c-bis-benzylamino-cyclohexane (110) is obtained in 56% yield 2) xhe same product is isolated in even higher yield (83%) on treatment of the nitroethane-glutaraldehyde cyclization product (6) with benzylamine However, further work is required to evaluate the preparative utility of this reaction principle for the synthesis of C-methyl branched triaminosugars. 

PhenyUhlo)nitromethane is a convenient reagent for the synthesis of derivatives of 3-methylfuranfor the preparation of a-substituted phenylthio esters via the homologation of aldehydes, and for the preparation of bicyclic... 

The class of nitrolic acids (nitro-oximes) was introduced by Victor Mayer as early as 1873 with the simplest representative methylnitroUc acid (HC(N02)=N0H) °. Tscher-niak, a student of Mayer, was the first to isolate the very labile methylnitroUc acid at low temperatures, while Wieland improved the synthesis by detailing the exact reaction conditions to increase the low yields. MethylnitroUc acid can be prepared as crystalline solid from nitromethane and KNO2/H2SO4 in situ generation of nitrous acid) in water at low temperatures, followed by extraction from this weak acidic solution into ether (Scheme 17). Removal of ether yields the pme, highly unstable free acid. Salts of methylnitroUc acid, NNtM, can be generated by extracting the acid into sodium carbonate solution. ... 

Dimethylaminonitroethylene is prepared from the anion of nitromethane and the salt prepaffed from dimethylformamide and dimethyl sulfate. The condensation step is general for other types of active methylene compounds, indicating further potential for pyrrole synthesis. A related process involves the condensation of ketones with the moao-N,N-dimethylhydrazone of glyoxal base-catalyzed condensation affords the hydrazones of a conjugated 1,4-dicarbonyl system, and sodium thiosulfate reduction then affords 2,3-disubstituted pyrroles (equation 85) (77CB491). 

An alternative method to prepare p-formyl esters uses different building blocks to assemble the 1,4-dicarbonyl system and is complementary in many cases.10 Base-catalyzed addition of nitromethane to a,p-unsaturated esters, followed by a variation of the Nef reaction, provides y-dialkoxy-substituted esters. The scope of this sequence has not yet been explored. Another approach involves cuprate additions to norephedrine-derived 2-alkenyloxazolidines this process allows small-scale synthesis of several p-formyl esters in optically active form (ee up to 95%).11... 

EXTENSIONS AND COMMENTARY This is pretty sparse information upon which to build a picture of biological activity. First, the synthesis was done by someone else and, as I have not been able to find where the notes are, this will be the one recipe in the footnote without explicit directions incorporated. The procedure used was exactly the same as that described for DMMDA, except that the starting material was dillapiole rather than apiole. The dillapiole was obtained by the careful fractionation of Oil of Dill (as opposed to the isolation of apiole from the careful fractionation of Oil of Parsley). Isomerization to isodillapiole, nitration with tetra-nitromethane to give 1 -(2,3-dimethoxy-4,5-methylenedioxyphenyl)-2-nitropropene, and its reduction with LAH in ether to give 2,3-dimethoxy-4,5-methylenedioxyamphetamine hydrochloride (DMMDA-2) proceeded in a precisely analogous manner to the preparation of DMMDA. 

SYNTHESIS A solution of 50 g myristicinaldehyde (3-methoxy-4,5-methylenedioxybenzaldehyde, see under MMDA for its preparation) in 200 mL acetic acid was treated with 33 mL nitromethane and 17.4 g anhydrous ammonium acetate and held on the steam bath for 5 h. The reaction mixture was diluted with a little H,0 and cooled in an external ice-acetone bath. A heavy crop of yellow crystals formed, which were removed by filtration, washed with cold acetic acid, and dried to constant weight. There was thus obtained 19.3 g 3-methoxy-4,5-methylene-dioxy-fi-nitrostyrene with a mp of 210-212 °C. 

The reaction is thought to proceed by a radical chain mechanism (SRJV1), probably first involving a charge transfer complex between cationic species (3) and the anionic species (4). The illustrative example is the synthesis of 2-phenylnitro-ethane from nitromethane and 1-benzyl-2,4,6-triphenylpyridinium tetrafluoroborate (Expt 5.192) this latter compound is prepared from benzylamine and 2,4,6-triphenylpyrylium tetrafluoroborate (Expt 8.31). 

The final step in the synthesis—replacement of the amino group in XI by a hydroxyl group—was carried out by Posternak28 by treatment with nitrous acid. Inversion occurred, giving a 10-15% yield of myo-inositol the other products of the reaction could not be identified. A much better yield (71 %) was achieved by the nitrous acid deamination of the penta-acetate ester of XI, rather than by deamination of the free inosamine.30,31 This method has been utilized30,31 for the preparation of myo-inositol- -C14 from nitromethane-C 14. 

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