2-Pyridinethiol

[2637-34-5]  · C5H5NS  · 2-Pyridinethiol  · (MW 111.18)

(reagent for the synthesis of thiolesters which acylate nucleophiles1 or yield ketones with organometallic reagents;2 utilized in protection and deprotection chemistry;3,4 glycoside coupling agent;5,6 component of a selective reducing agent;7 precursor of electrophilic sulfur reagents;8,9 applied to dienophile synthesis10)

Physical Data: mp 128-130 °C.

Solubility: sol most organic solvents; sol aqueous base.

Form Supplied in: crystalline solid, available from various suppliers.

Analysis of Reagent Purity: mp measurement is indicative of purity; values below 120 °C suggest an impure sample.

Purification: recrystallization from benzene.

Handling, Storage, and Precautions: demonstrates good stability if stored in a well sealed vial under an inert atmosphere at room temperature. On continued exposure to air the reagent becomes contaminated with moisture and disulfide. 2-Pyridinethiol is irritating to eyes and skin and imparts a stench.

Thiolester Synthesis and Utility.

Thiolesters represent a class of acylating agents.

Synthesis.

Pyridine-based thiolester generation utilizes carboxylic acids and 2-pyridinethiol under 1,3-Dicyclohexylcarbodiimide coupling conditions (EtOAc, 0 °C).11 Quantitative conversions of the carboxylic acid to the 2-pyridyl thiolester involve premixing 2-pyridinethiol and Phosgene before introduction of the acid.12 A mixed anhydride method (Trichloroacetyl Chloride, Triethylamine) of acid activation successfully generates the thiolester13 as does use of an acyl chloride.14 Other methods of acid activation provide routes to the 2-pyridyl thiolesters.15 Alternate methods are available from 2,2-Dipyridyl Disulfide.16 2-Pyridyl thiolesters may also be generated from ketenes17 using the tin(II) sulfides obtained from 2-pyridinethiol.18 This technique provides a tin(II) enolate which reacts with aldehydes with syn selectivity and provides a 3-hydroxy thiolester.

Acylation of Nucleophiles.

2-Pyridyl thiolesters and 2-pyridyl esters provide a coupling technique in peptide synthesis.11a Macrolactonization with a thiolester has been demonstrated.16 Alkylation of the 2-pyridylthiolester with nonthiophilic agents such as Triethyloxonium Tetrafluoroborate provides successful acylation of phenols, amines, and carboxylic acids.1 Using 2 equiv of Methylenetriphenylphosphorane, 2-pyridyl thiolesters provide a route to stabilized ylides.11d

Ketone Generation from a Carboxylic Acid Derivative.

An historical quest for organic chemists has been the generation of ketones from carboxylic acid derivatives. Carbon nucleophiles select the intermediate ketone in preference to the acid derivative, resulting in alcohol products. The stabilized intermediate provided by Grignard addition to a 2-pyridyl thiolester provides isolation of ketones from a carboxylic acid derivative.2 Successful application of this technique to complex molecules requires a tolerance for other functional groups. Ketone formation has been accomplished in the presence of imide,19 t-butoxycarbonyl, and ester11b,13 moieties. A comparison of acid activation agents used for ketone formation from Grignard reagents examined 2-pyridyl thiolesters.20 Investigations of ketone formation using alkynylmetals suggest that N-alkoxyamides may be better substrates for these organometallic reagents21 (see N,O-Dimethylhydroxylamine).

Protecting Group Chemistry.

2-Pyridinethiol provides reagents for facile protection of amines as the benzyloxycarbonyl or t-butoxycarbonyl protected species.3,22 2-Pyridinethiol protects the imide function of uridine and guanosine units in nucleotide synthesis and is displaced by nucleophiles such as amines.23 Deprotection of thiols24 and the azetidinone nitrogen4 is accomplished with 2-pyridinethiol as the reagent of choice.

Glycoside Synthesis.

Thioglycosides generated from 2-pyridinethiol provide important synthetic intermediates in glycoside chemistry. The synthesis of the thioglycosides utilizes an acid5,6,25 or Lewis acid catalyst.26 Silyl enol ethers react with the 2-pyridylthioglycosides generating C-glycosides. Using Silver(I) Trifluoromethanesulfonate (silver triflate) activation, the electrophilic glycoside center accomplishes electrophilic aromatic substitution of electron-rich aromatic rings.5 N-Alkylation of the 2-pyridyl thioglycoside provides the activation for facile glycosidic linkage formation.6

Selective Reducing Agent.

2-Pyridinethiol, Tin(II) Chloride, and Et3N produce a complex that provides selective reduction of azides to primary amines, primary and secondary nitro alkanes to oximes, and tertiary nitro alkanes and nitro aromatics to hydroxylamines.7 This complex tolerates ketone, sulfoxide, sulfone, nitrile, and ester functional groups. Applications to macrolactamization have been demonstrated.27

Synthesis of Electrophilic Agents.

The chloramine generated from Morpholine reacts with 2-pyridinethiol to generate an electrophilic sulfenylation agent.8 This reagent provides a mixed disulfide containing a 2-pyridyl unit (see also 2-Pyridinesulfonyl Chloride and 2-Pyridinesulfenyl Bromide) which is N-alkylated by nonthiophilic agents such as Triethyloxonium Tetrafluoroborate. The resulting salt is readily displaced to generate mixed disulfides (from thiols, thioamides, dithiocarbamates, thiocyanate), sulfenamides (from amines), or sulfides (from b-dicarbonyl nucleophiles).

2-Pyridinethiol is transformed into methyl 2-pyridinesulfinate using MeOH and N-Bromosuccinimide. Enolate sulfinylation with this reagent, followed by thermal elimination, provides a formal dehydrogenation to an enone with (E) selectivity. Generating this reagent from 2-pyridinethiol provides an internal buffering during the elimination step.9

Application to Diels-Alder Chemistry.

Conjugate addition of 2-pyridinethiol to menthol propiolate results in a cis-alkene which undergoes a diastereoselective oxidation of sulfur using m-Chloroperbenzoic Acid to yield a highly reactive dienophile. Subsequent application to cycloaddition chemistry has been demonstrated.10,28

Other Applications.

2-Pyridinethiol photochemically adds to alkenes to yield a bis(2-pyridylethyl) disulfide.29 2-Pyridinesulfenylation of 2,5-piperazinediones provides an opportunity for carbon-carbon bond formation using silver triflate activation in the presence of a silyl enol ether.30 Under nickel catalysis, 2-pyridinethiol provided a 2-pyridyl unit in an aryl-aryl coupling with subsequent loss of sulfur.31


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Edward J. Adams

E. I. DuPont de Nemours and Co., Newark, DE, USA



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