Methylenation amides

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

As a further application of the reaction, the conversion of an endocyclic double bond to an c.xo-methylene is possible[382]. The epoxidation of an cWo-alkene followed by diethylaluminum amide-mediated isomerization affords the allylic alcohol 583 with an exo double bond[383]. The hydroxy group is eliminated selectively by Pd-catalyzed hydrogenolysis after converting it into allylic formate, yielding the c.ro-methylene compound 584. The conversion of carvone (585) into l,3-disiloxy-4-methylenecyclohexane (586) is an example[382]. 

Reduction of amides (Section 22 9) Lithi um aluminum hydride reduces the car bonyl group of an amide to a methylene group Primary secondary or tertiary amines may be prepared by proper choice of the starting amide R and R may be ei ther alkyl or aryl... 

Acryhc esters dimerize to give the 2-methylene glutaric acid esters catalyzed by tertiary organic phosphines (37) or organic phosphorous triamides, phosphonous diamides, or phosphinous amides (38). Yields of 75—80% dimer, together with 15—20% trimer, are obtained. Reaction conditions can be varied to obtain high yields of trimer, tetramer, and other polymers. 

Solubility. Acryhc fibers are insoluble in methanol, acetone, and methylene chloride and soluble in dimethylform amide, dimethyl acetamide, and... 

Apparently the alkoxy radical, R O , abstracts a hydrogen from the substrate, H, and the resulting radical, R" , is oxidized by Cu " (one-electron transfer) to form a carbonium ion that reacts with the carboxylate ion, RCO - The overall process is a chain reaction in which copper ion cycles between + 1 and +2 oxidation states. Suitable substrates include olefins, alcohols, mercaptans, ethers, dienes, sulfides, amines, amides, and various active methylene compounds (44). This reaction can also be used with tert-huty peroxycarbamates to introduce carbamoyloxy groups to these substrates (243). 

Other Applications. Hydroxylamine-O-sulfonic acid [2950-43-8] h.2is many applications in the area of organic synthesis. The use of this material for organic transformations has been thoroughly reviewed (125,126). The preparation of the acid involves the reaction of hydroxjlamine [5470-11-1] with oleum in the presence of ammonium sulfate [7783-20-2] (127). The acid has found appHcation in the preparation of hydra2ines from amines, aUphatic amines from activated methylene compounds, aromatic amines from activated aromatic compounds, amides from esters, and oximes. It is also an important reagent in reductive deamination and specialty nitrile production. 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

Quinoxalin-2-ones are in tautomeric equilibrium with 2-hydroxy-quinoxalines, but physical measurements indicate that both in solution and in the solid state they exist as cyclic amides rather than as hydroxy compounds. Thus quinoxalin-2-one and its A -methyl derivative show practically identical ultraviolet absorption and are bases of similar strength. In contrast, the ultraviolet spectra of quinoxalin-2-one and its 0-methyl derivative (2-methoxyquinoxaIine) are dissimilar. The methoxy compound is also a significantly stronger base (Table II). Similar relationships also exist between the ultraviolet absorption and ionization properties of 3-methylquinoxalin-2-one and its N- and 0-methyl derivatives. The infrared spectrum of 3- (p-methoxy-benzyl)quinoxalin-2-one (77) in methylene chloride shows bands at 3375 and 1565 cm" which are absent in the spectrum of the deuterated... 

I he diaryImethanes (105). The protons on the methylene group of lliese compounds are sufficiently acidic to be removed by strong b.ises such as sodium amide or butyl lithium. Alkylation of the resulting carbanion with w-C2-chloroethyl)dimethylamine affords,... 

Interposition of a methylene group between the phenyl ring and the heterocycle leads to the benzyldiami nopyrimidines, a class of compounds notable for their antibacterial activity. Condensation of hydrocinnamate 54 with ethyl formate leads to the hydroxymethylene derivative 55. In this case, too, the heterocyclic ring is formed by reaction with guanidine. This sequence probably involves initial addition-elimination to the forniyl carbon to form 56 cyclization in this case involves simple amide formation. Tautomerization then affords the hydroxy derivative 57. This is converted to tetroxoprim (58) by first... 

The structural feature of ceforanide that is of particular interest is the movement of the C-7 side chain amino moiety from the position a to the amide carbonyl, where it normally resides in ampicillin/cephalexin analogues, to lodgement on a methylene attached to the ortho position on the aromatic ring. 

Diisopropylamino-a.a-diphenvlbutyronitriie (60 g) was added in several portions to a mixture of sulfuric acid (150 ml) and water (15 ml) and the solution was heated 3 /i hours on the steam bath and then poured on ice and made basic with NH4OH. The 7-diisopropyl-amino-o. a-diplienylbutyramide precipitated as a solid, which was taken up in methylene chloride from an aqueous slurry. The methylene chloride was separated and dried by filtering through anhydrous KjCOj. The solvent was removed by distillation, leaving the amide which was crystallized from Skellysolve B five times and found then to have MP 87.0° to BB.5°C. 

Conversion of Amides into Amines Reduction Like other carboxylic acid derivatives, amides can be reduced by LiAlH.4. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction reaction is thus the conversion of the amide carbonyl group into a methylene group (C=0 —> CTbV This kind of reaction is specific for amides and does not occur with other carboxylic acid derivatives. 

The method outlined here works well for amides of primary carbinamines. For amides of secondary carbinamines, lower temperatures must be used, and solvents such as methylene chloride are used in place of the acetic acid (the amide need not be completely soluble in the solvent) the procedure of White and Aufdermarsh6 used for a trimethylacetamide is recommended in such a case. Nitrosoamides of tertiary carbinamines are very unstable, and the salt method of preparation is suggested for these compounds 6... 

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