Sulfur compounds reactions with amides

The biochemical basis for the toxicity of mercury and mercury compounds results from its ability to form covalent bonds readily with sulfur. Prior to reaction with sulfur, however, the mercury must be metabolized to the divalent cation. When the sulfur is in the form of a sulfhydryl (— SH) group, divalent mercury replaces the hydrogen atom to form mercaptides, X—Hg— SR and Hg(SR)2, where X is an electronegative radical and R is protein (36). Sulfhydryl compounds are called mercaptans because of their ability to capture mercury. Even in low concentrations divalent mercury is capable of inactivating sulfhydryl enzymes and thus causes interference with cellular metaboHsm and function (31—34). Mercury also combines with other ligands of physiological importance such as phosphoryl, carboxyl, amide, and amine groups. It is unclear whether these latter interactions contribute to its toxicity (31,36). 

An interesting bridged-sulfur compound, which is a natural constituent of Iranian oil, has been synthesized 478) by the reaction of a bicyclic bis-enamine with sulfur dichloride and subsequent Wolff-Kishner reduction of an initial sulfur-bridged diketone. Sulfur dichloride has also been added to a number of vinylogous amides 479). 

Notice in the list of Lewis bases just given that some compounds, such as carboxylic acids, esters, and amides, have more than one atom ivith a lone pair of electrons and can therefore react at more than one site. Acetic acid, for example, can be protonated either on the doubly bonded oxygen atom or on the singly bonded oxygen atom. Reaction normally occurs only once in such instances, and the more stable of the two possible protonation products is formed. For acetic add, protonation by reaction with sulfuric acid occurs on... 

In the late 1960s, methods were developed for the synthesis of alkylated ketones, esters, and amides via the reaction of trialkyl-boranes with a-diazocarbonyl compounds (50,51), halogen-substituted enolates (52), and sulfur ylids (53) (eqs. [33]-[35]). Only one study has addressed the stereochemical aspects of these reactions in detail. Masamune (54) reported that diazoketones 56 (Ri = CH3, CH2Ph, Ph), upon reaction with tributylborane, afford almost exclusively the ( )-enolate, in qualitative agreement with an earlier report by Pasto (55). It was also found that E) - (Z)-enolate isomerization could be accomplished with a catalytic amount of lithium phenoxide (CgHg, 16 hr, 22°C) (54). 

One of the first compounds to be introduced to the clinic, aztreonam (40-9), has been produced by total synthesis. Constmction of the chiral azetidone starts with amide formation of L-threonine (40-1) via its acid chloride treatment with ammonia leads to the corresponding amide (40-2). The primary amino group in that product is then protected as its carbobenzyloxy derivative (40-3). Reaction of that product with methanesulfonyl chloride affords the mesylate (40-4). Treatment of that intermediate with the pyridine sulfur trioxide complex leads to the formation of the A -sulfonated amide (40-5). Potassium bicarbonate is sufficiently basic to ionize the very acidic proton on the amide the resulting anion then displaces the adjacent mesylate to form the desired azetidone the product is isolated as its tetrabutyl ammonium salt (40-6). Catalytic hydrogenation over palladium removes the carbobenzyloxy protecting group to afford the free primary amine (40-7). The... 

There is the raw stuff potentially available to answer this question. There are a couple of compounds known with the sulfur in the 4-position, which is the location of the oxygen atom in psilocybin. The 4-thio analogues have been synthesized from 4-methylthio-indole, via the oxalyl chloride method and reaction with the appropriate amine. With dimethylamine, the indoleglyoxylamide was made in a 43% yield and had a mp 163-164 °C. With diisopropylamine, the amide was made in a 27% yield and had a mp 190-192 °C. The final amines were prepared by the reduction of these amides with LAH in THF. N,N-Dimethyl-4-thiotryptamine (4-MeS-DMT) was obtained in a 68% yield and melted at 108-110 °C N,N-diisopropyl-4-methylthiotryptamine (4-MeS-DIPT) was obtained in a 61% yield and melted at 92-94 °C. In animal studies of behavioral disruption with these three compounds, there was systematic drop of potency in going from the 5-MeS-DMT to 4-MeS-DMT to 4-MeS-DIPT. 

However, most nucleophiles attack 5-oxazolones at the carbonyl group and the products are derivatives of a-amino acids formed by acyl-oxygen fission. Thus the action of alcohols, thiols, ammonia and amines leads, respectively, to esters, thioesters and amides orthophosphate anion gives acyl phosphates (Scheme 18). The use of a-amino acids in this reaction results in the establishment of a peptide link. Cysteine is acylated at the nitrogen atom in preference to the sulfur atom. Enzymes, e.g. a-chymotrypsin and papain, also readily combine with both saturated and unsaturated azlactones. A useful reagent for the introduction of an a-methylalanine residue is compound (202). Both the trifluoroacetamido and ester groups in the product are hydrolyzed by alkali to give a dipeptide. The alkaline hydrolyzate may be converted into the benzyloxycarbonyl derivative, which forms a new oxazolone on dehydration. Reaction with an ester of an amino acid then yields a protected tripeptide (equation 45). 

The reaction of amides with sulfur tetrafluoride or with carbonyl difluoride leads to fluorinated compounds with a nitrogen substituent at the difluoromethylene or trifluoromcthyl group and thus these reactions are not covered here. 

This is a new reaction for the preparation of N-alkyl amides. Nitriles and various substituted cyano compounds are treated with active olefins in the presence of sulfuric acid. Reaction occurs at room temperature in glacial acetic acid or dibutyl ether solution. The use of hydrogen cyanide in the reaction leads to the formation of N-alkylformamides. /-Butyl alcohol and sodium cyanide are used in place of the olefin and hydrogen cyanide in the preparation of N-/-butylfotmamide (50%). The reaction has been extended to the synthesis of N-alkyl diamides from dinitriles and olefins or alcohols. ... 

Many of these solutions are quite stable and the organic compound can be recovered unchanged simply by diluting the sulfuric acid solution with water. In other cases subsequent reactions ensue, such as hydrolysis, in the case of some esters (35, 70 and amides (14), for example,... 

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