Thiophenols from amines

It is synthesized by reaction of the diazonium salt from amine 1 with potassium ethyl xanthate, followed by alkaline hydrolysis to afford thiophenol 2. 

Thioesters (2) are obtained starting from thioalcohols or thiophenols and carboxylic acid amides starting from amines (3). 

The synthesis of the promazine 444 class of antipsychotics was pursued by medicinal chemists firom Lundbeck Pharmaceuticals (Deerfield, EL). Although the C—N and C S bond formations have been separately developed and optimized to practical use, the formation of multiple carbon-heteroatom bonds has been challenging. To this end, the researchers developed a palladium-catalyzed, three-component cross-coupling reaction in which the formation of one C—S bond from thiophenol 441 and aromatic halogenide 443 and two C—N bonds from amines 442 were accomplished in a one-pot tandem reaction fashion (Scheme 46.50). 

A-Protected amines were assembled on solid-phase via sulfonamide-based handle 58 (Scheme 27) [67]. Tertiary sulfonamides were generated upon reaction with allylic, benzylic and primary alcohols under Mitsu-nobu conditions. Secondary amines were released from the support using mild nucleophilic conditions such as treatment with thiophenol and potassium carbonate. 

A versatile approach for the solid-phase synthesis of aminopyr-idazines used the anchoring of 3,6-dichloropyridazine to resin-bound thiophenol 59 (Scheme 28) [68]. Treatment with nucleophilic amines released the aminopyridazine products from the solid support without further oxidation. 

It is well-established that the molecular and electronic structures of metal complexes of azamacrocycles are greatly affected upon N-alkylation (197). This is mainly due to two factors (a) the decrease of the ligand field strength and (b) the increase in the steric requirements upon going from a secondary to a tertiary amine donor function (251). To examine whether the properties of the dinuclear amine-thiophenolate complexes are affected by the N-alkyl substituents, analogous complexes of the... 

Related (diisopropoxyphosphoryl)- and (diisobutoxyphosphoryl)formonitrile oxides (114), generated in basic media from the corresponding oximes react in situ with alcohols, phenols, alkanethiols, thiophenols, aliphatic and aromatic primary amines, hydrazines and hydrazides as well as 4-aminoantipyryne to give hydroxymates, thiohydroxymates, and amidoximes, respectively. It is important to note that the addition is stereoselective and gives E-adducts with the exception of (i-Pr0)2P(0)C( N0H)0Me, which is formed as a 1 1 mixture of E and Z isomers. 

The Marshall Unker [23] has been widely used to synthesize compounds that can be cleaved by primary and secondary amines to afford the corresponding amides. Marshall linker was used in the synthesis of three or more diversity-site hbraries because it allowed the addition of one more diversity element at the cleavage step. While the original reported linker [23] involved the oxidation of the Unker before cleavage, the efficient release of the resin-bound compounds using nucleophiles from the unoxidized linker has been reported [16, 24]. Similarly to the acid-labile linkers, the kinetics of the cleavage reaction and time required for this reaction directly affect the synthesis efficiency, purity and yield of the final products. A cleavage study was carried out on seven resin-bound thiophenol esters (34—40) on Marshall Unker with 3 amines (41-43) (Scheme 12.11 and Tab. 12.4). 

The synthesis of the active site analogue 206 that combines two essential features of the P450 enzymes has recently been accomplished (Fig. 34) [111]. The design involves the attachment of the thiophenolate ligand to the porphyrin 207 prepared very efficiently (> 80% yield) from the aldehyde 208 and the pyrromethane 209. Condensation of the free amine 210 with the acid chloride of Kemp s acid 211 furnished 206 containing a substrate binding site at the porphyrin face opposite to the thiolate ligand. Preliminary experiments with this... 

Dialkylaminomethyl alkyl (and aryl) sulfides result from the treatment of a-halogeno-amines with mercaptans (thiophenols).325 Dehydrogenation of amino-alcohols with mercuric acetate182,328 is accompanied by the intramolecular nucleophilic addition of the alkoxyl group when formation of a five- or six-membered ring is possible, e.g. ... 

In this case, carboxylic acid fragment 12a was prepared from benzoate 14 and amine 15 in 82% overall yield. Likewise, benzothiophene 13 was generated from thiophenol 16 and bromoketone 17 in 55% overall yield. 

The p-thiophenol linker 1.18 (75), prepared from aminomethyl PS resin and 3-(4-thiophenyl)-propionic acid, was used to support a chloropyridazine and to release after SPS decorated aminopyridazines by treatment with primary or secondary amines and anilines for 24-48 h at 90 °C. 

The replacement of an amino group by a mercapto group on an aromatic nucleus is effected by treating the diazotized amine with potassium ethyl xanthate and hydrolyzing the resulting aryl ethyl xanthate (Leuckart). Yields of 40-80% are reported for thiophenols containing methyl, halo, and methoxyl groups. Potassium ethyl xanthate is readily prepared from alcoholic potassium hydroxide and carbon disulfide. ... 

Sodium enolates of ketones and disodium enediolates of substituted phenylacetic acids reacted with activated aziridines to afford 7-amido ketones and 7-amidobutyric acids, respectively (Scheme 72). Aziridine-2-carboxylic acid esters can be utilized as versatile precursors for amino acid derivatives. Although the product distribution resulting from the reaction of activated aziridine-2-carboxylates with amines depends on the structure of the reactants, the reactions with alcohols or thiols in the presence of acidic cabilysts generally gave the a-amino acid derivatives (Scheme 73). ° On the other hand, free 3-methyl-2-aziridinecarboxylic acids (168) reacted with thiophenol, cysteine and glutathione to afford P-amino acid derivatives with sulfur substituents at the a-position as the main product (Scheme 73). ... 

Methylation is rarely of quantitative importance in the metabolism of xenobiotics. The methyl group is transferred from the nucleotide S-adenosyl-L-methionine (SAM) by means of a methyltransferase. The functional groups that undergo methylation include primary, secondary and tertiary amines, pyridines, phenols, catechols, thiophenols. The aza-heterocycle pyridine is metabolized to the A-methylpyridin-ium ion, which is more toxic than pyridine itself (Figure 33.18). The binding properties of the ionized metabolite are disturbed by the loss of its hydrophobic feature, resulting from the polarity inversion. 

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