Isothiocyanates nucleophilic additions

Nucleophilic addition of the peptide terminai amino group to p nenyi isothiocyanate (PITC) gives an /V-phenylthiourea derivative. 

An unusual reaction leading to the formation of 4-thioxopyrazolo[3,4-d]-pyrimidines has been reported. 1-Substituted 4-cyano-5-aminopyrazoles (103, R = H) react with phenyl isothiocyanate in dimethylformamide (DMF) saturated with hydrogen chloride to yield 1-substituted 4(5//)-pyrazolo[3,4-d]-pyrimidinethione (110). A proposed reaction sequence involved an initial nucleophilic addition of phenyl isothiocyanate to the protonated o-amino-nitrile to give an o-aminothioamide (108), followed by formylation by the dimethylformamide-hydrogen chloride mixture affording 109, which then cyclizes to the final product 110 (70MI1). 

Upon heating the diarylthiourea with concentrated hydrochloric acid, it is partly converted into the aryl isothiocyanate (e.g. phenyl isothiocyanate or phenyl mustard oil, Expt 6.98, Method 1). A little hydrogen sulphide is evolved in a side reaction forming diphenylcarbodi-imide (4) which undergoes nucleophilic addition of aniline to yield triphenylguanidine (5), isolated from the reaction mixture as the hydrochloride. 

Nucleophilic addition of the peptide terminal amino group to phenyl isothiocyanate (PITC) yields an N-phenylthiourca derivative. 

Alternatively, for A -monosubstituted thioamides, methods based on nucleophilic addition of hydride, carbanions, or cyanide to isothiocyanates are available, and, quite often, thionation of the corresponding amides provides a convenient route to thioamides (c/. Volume 6, Chapters 4.1 and 4.3). ... 

The reaction of monosaccharide isothiocyanates with enamines leads to the formation of a./J-u maturated thioamides4,169 (67), which can be cy-clized to isothiazole derivatives.4 Formation of additional products arising from attack of the amino group to the isothiocyanate functionality has also been observed, the outcome of the reaction being dependent on the nature of the enamine reagent and on reaction conditions. Thus, nucleophilic addition of a series of 3-amino-3-penten-2-ones (65) and ethyl 3-aminocroto-... 

Nucleophilic addition of diethyl malonate derivatives 68 to the glucosyl isothiocyanate 58 in the presence of sodium hydride afforded the corresponding A-thioacylglucosylamines 69 in 40-60% yields.170 Adducts incor-porting an a-phenacyl substituent (68, R Ar) were further cyclodehy-drated using phosphoric acid and acetic anhydride to give JV-nucleoside derivatives of 2-pyrroline 70. Under identical reaction conditions, the a-acetonyl derivative (68, R Me) led to the tetrahydropyridine helerocycle 71 (Scheme 21). 

Lithium enolate 329 and a nitrile-furnished enamino ester 330, which on condensation with isocyanates/isothiocyanates gave N-3 substituted 331 (X = O, S) through a tandem nucleophilic addition-intramolecular aza-Michael reaction (Scheme 126) (09JFC1145). 

Isothiocyanates, some of which derive from glucosinolates present in cruciferous vegetables, have been repeatedly shown to inhibit carcinogenesis [1,2]. Isothiocyanates are precursors of a wide range of N-thiocarbamoyl derivatives their tendency to imdergo nucleophilic additions and cycloadditions make them highly important intermediates in organic synthesis [3] for the preparation of thioureas and heterocyclic compoimds [4,5j. 

Nucleophilic Substitutions. 7V,7V-Dimethyldithiocarbamoyl-acetonitrile (1) serves as an active methylene compound, because its carbanion is stabilized by sulfur and cyano groups. It can be alkylated stepwise in aqueous sodium hydroxide under phase transfer catalysis (eq 1). The anion undergoes nucleophilic aromatic substitution to give nitroarenes, with elimination of the dithiocarbamate group (eq 2). Nucleophilic addition of (1) to phenyl isothiocyanate also occurs readily. ... 

Step 1 Make a new bond between a nucleophile and an electrophile Nucleophilic addition of the N-terminal amino group to the C=N bond of phenyl isothiocyanate gives a derivative of N-phenylthiourea. 

Mechanism 28.2 illustrates some of the key steps of the Edman degradation. The nucleophilic N-terminal NH2 group adds to the electrophilic carbon of phenyl isothiocyanate to form an A-phenylthiourea, the product of nucleophilic addition (Part [1]). Intramolecular cyclization followed by elimination results in cleavage of the terminal amide bond in Part [2] to form a new peptide with one fewer amino acid. A sulfur heterocycle, called a thiazolinone, is also formed, which rearranges by a multistep pathway (Part [3]) to form an A-phenylthiohydantoin. The R group in this product identifies the amino acid located at the N-terminal end. 

NDA derivatization has also been automated for analysis of amino acids in brain tissue and microdialysates (Shah et al, 1999). NDA reacts with primary amines in the presence of cyanide to form a highly stable N-substituted l-cyanobenz[/] isoindole (GBI) derivative. Addition of a nucleophile, such as cyanide, hydrogen sulphite, isothiocyanate, or 2-mercaptoethanol, is essential for the formation of the derivative. 

The carbon in the isothiocyanate grouping is highly susceptible to nucleophilic attack by the peptide s free amino group. Overall addition to the C=N creates a thiourea derivative. Making the conditions strongly acidic then promotes nucleophilic attack by the sulfur of the thiourea on to the carbonyl of the first peptide bond, producing a five-membered thiazoline heterocycle. Proton loss occurs from the nitrogen, and this creates an intermediate that is equivalent to the addition product in simple acid-catalysed amide... 

The amino group of 3-amino-1,2,4-oxadiazoles shows little nucleophilic character. For example, addition to phenyl isothiocyanate to give 3-(phenylthioureido) compounds requires heating of the components without solvent at 120-130 °C or the use of polar aprotic solvents (DMSO, DMF) and long reaction times (30 days at 23°C) <77JCS(P1)1616>. 3-(Thioureido)-1,2,4-oxadiazoles undergo fast ring transformations to thiadiazoles (see Section 4.04.5.1.1). 

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