Thioamides secondary amines

Cyanopyridazines add ammonia, primary and secondary amines and hydroxylamine to give amidines or amidoximes. Substituted amides, thioamides and carboximidates can be also prepared. With hydrazine, 3-pyridazinylcarbohydrazide imide is formed and addition of methylmagnesium iodide with subsequent hydrolysis of the imine affords the corresponding pyridazinyl methyl ketone. 

Thioamides can be synthesized by reacting thioazolides with primary or secondary amines in cyclohexane, THF, or CH2CI2, or without solvent at 20-50 °C.[164Mi6S]... 

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

The reaction of thioaldehydes, generated from phosphonium ylides and sulphur with secondary amines such as dimethylamine, leads to thioamides. If the thioaldehydes possess a a-hydrogen atom enamines are produced (equation 103)326. 

Thioamides of secondary amines are deprotonated with isopropyhnagnesium to give (Z)-enolates. Thioamides of primary amines react with two equivalents of /-PrMgBr to afford dianions that have been shown to have the (Z)-configuration. These magnesium species are versatile intermediates in stereoselective aldol reaction (equation 50, Table 5 ... 

The products obtained after treatment of thioamides with magnesium bromide diiso-propylamide (BMDA) and subsequent aldol condensation are presented in equation 111. The difference in the stereochemistry between thioamides of secondary amines and primary amines should be noted (Table 15). Although, in each case, the metallation leads to... 

If thioamide enolates are prepared by conjugate addition of Grignard reagents to a,/3-unsaturated thioamides of secondary amines, the reaction of these enolates with aldehydes affords anti aldols. These results are rationalized by the formation of a boat-like, chelate transition state" Representative examples are provided in equation 112 and Table 16. 

With primary and secondary amines, the aminolysis of a trifluoromethyl group to a carbonitrile group is not possible nevertheless, under these reaction conditions, analogs of carboxylic acids, c.g. amidines,51,52 amides29,53 - 55 or thioamides,56 are formed. 

The reaction of phosphorus ylides with elemental sulfur gave thioaldehydes, which were trapped in situ by treatment with secondary amines to afford the corresponding thioamides (equation 17)237. 

The reaction of thioketenes, generated by flash-vacuum pyrolysis (Section IU.C.l.b), with secondary amines affords the corresponding thioamides and is the standard trapping procedure for these unstable compounds288 (equation 114). 

As described above, the reduction of imines often proceeds via iminium ions particularly in acidic media, since protonation enhances the electrophilicity of the imine carbon. Thus, as expected, preformed iminium salts generated from carbonyls and secondary amines are also readily reduced by most hydride reagents. Several examples of synthetic applications with a variety of reagents are illustrated in Table 4. Entries 9-12 illustrate the use of iminium intermediates for the reductive removal of amide carbonyls. Thus, treatment of amides with POCI3 affords the iminium derivatives (e.g. 9 Scheme 3), which are reduced by NaBHt to the corresponding amines (Table 4, entries 9, 10). Likewise, reaction of amides witii trialkyloxonium salts to give imidic esters (entry 12) or thioamides with methyl iodide to give... 

Meanwhile, there are many substrates of FMO already known, including tertiary and secondary amines, hydroxyamines, thiols, sulfides, thiocar-bamides, and thioamides (for a review, see Ziegler, 1991). Compounds accepted by this mono-oxygenase have one chemical properly in common All are soft nucleophiles readily oxidized by per-adds. Apparently, the nudeophilic centers are oxidized by an ionic r er than a radical mechanism in an active site requiring more than one point of contact (Ziegler, 1991). 

The Kindler modification of the Willgerodt reaction uses sulfur and dry amines, ammonia, primary amines or secondary amines, which leads to the formation of thioamides (conversion of thioamides to amides cf Section 2.3.1.7). This reaction can also be extended to aldehydes, hydrocarbons and heterocyclic ketones. Due to the usually low to moderate yields this reaction has not found general application. 

Nucleophilic attack of ammonia or of a primary or secondary amine on an O-alkyl thiocarboxylate (2) provides a formally straightforward approach to thioamides and a number of examples have been reported (equation l). - However, some limitations should be noted. Thus, there is a tendency of esters (2) to rearrange to their 5-alkyl isomers on heating (cf. Volume 6, Chapter 2.5) and these yield amides with amines rather than thioamides. Besides, excess primary amine will lead to amidine formation, or the tetrahedral intermediate of the substitution reaction may break down to an imidate rather than a thioamide (cf. Volume 6, Chapter 2.7). These unwanted side reactions are favoured in polar, protic solvents such as ethanol. In contrast, THF has proven to be particularly useful in the synthesis of tertiary thioamides according to equation (1). For improved reactivity in the preparation of V-aryl derivatives and milder reaction conditions, it is advantageous to employ the amine in the form of its Mg salt. ... 

Thioketenes (34) are highly electrophilic and give a smooth reaction with ammonia or amines. In fact, addition of a secondary amine offers the best way to scavenge a suspected thioketene. But the approach also deserves interest from the point of view of thioamide synthesis as it allows very mild and nonreducing conditions, tolerating the presence of sensitive additional functional groups such as cyano, nitro, or sulfonyl residues (equation... 

DMF is recommended as diluent in the Ullmann synthesis of diaryls from aryl halides and as solvent for the Beckmann rearrangement of steroidal enone oximes. The Willgerodt-Kindler reaction (a carbonyl compound with a secondary amine and sulfur to give a thioamide) can be carried out in good yield at 50-60 if DMF is... 

The reaction of pyruvic or benzoylformic acids with primary or secondary amines will generate imino acids that can be decarboxylated in benzene at 80 °C, or in CH2CI2 to the corresponding iraines via a 1,2-ylide that can be trapped by a tenfold excess of elementary sulfur, providing thioamides in good yields. The mechanism of trapping suggests that the sulfur serves the role of electrophile (equation 18). 

The yields of trifluoropyruvic thioamides 6 with common secondary amines are mostly fair and do not exceed 65 %. The reduction products - trifluorolactic thioamides 7 are formed in certain cases as by-products (about 5 %). Trifluoroacetone yields under the Willgerodt-Kindler conditions only 7 (30-35 %), besides other products. These lactic products 7 are therefore formed more expediently by reduction of 6 using ammonium formate at 100°C. 

In Chart 2 are depicted various poly-valent donor building blocks such as thiols, secondary amines, phosphotyl imines and ylids which serve both the purposes of diversification and cleavage as well as of construction of the central core stmctures. Bidentate nucleophiles such as thioamides, thioureas, ureas, isothioureas, amidines, guanidines, 1,2-dihydroxybenzenes, 2-aminothiophenols and others (see Chart 2) were exclusively employed for the synthesis of the cores as exemplified in Chapter 3 and 4 (the indicated references refer to these examples)... 

The reaction of Sc-phenylp-toluenecarboselenothioate (31 R=Tol, Ar=Ph) with aniline gave thioamide 59 and PhSeSePh, while that with aliphatic secondary amines yielded the ammonium dithioates 60 (Scheme 6) [12]. The formation mechanism of 60 was not clarified [12]. On the other hand, the reaction of Se-methyl selenothioates 32 with dimethylamine in dichloromethane provided the corresponding thioamides 61 and MeSeSeMe in quantitative yields (Eq. 15) [13]. 

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