Electrophiles isothiocyanates

Apparently, when these agents are bound to p receptors, the electrophilic isothiocyanate group is not oriented in proper juxtaposition to a receptor nucleophile for covalent bond formation to occur. Incorporation of the electrophilic isothiocyanate into the structure of the highly k receptor-selective arylacetamides has provided affinity labeling agents (UPHIT and DIPPA) for k receptors (54,55). 

The reactivity of electrophilic isothiocyanates towards inorganic and organic azides is well known. The conversion of hydrazoic acid with aryl isothiocyanates 175 provides 5-amino-substituted 1,2,3,4-thiatriazoles 177 by addition of hydrazoic acid to the C=S bond of the isothiocyanate moiety, probably via unstable thiocarbamoyl azides 176 [132]. Benzoyl isothiocyanate (179, R = CeHs), for example, reacts with hydrazoic acid to benzoylcyanamide (180, R = CeHs). hi contrast, the reaction of sodium azide with isothiocyanates 175 occurs at the C=N bond of the isothiocyanate moiety and gives l-substituted-A -tetrazoHne-5-thiones, also known as l-substituted-5-mercaptotetrazoles 178 (Scheme 35) [133-135]. 

Treatment of 2-imino-3-phenyl-4-amino-(5-amido)-4-thiazoline with isocyanates or isothiocyanates yields the expected product (139) resulting from attack of the exocyclic nitrogen on the electrophilic center (276). Since 139 may be acetylated to thiazolo[4,5-d]pyrimidine-7-ones or 7-thiones (140). this reaction provides a route to condensed he erocycles (Scheme 92). 

The problem is more complicated when the ambident nucleophile. 2-aminothiazole, reacts with an ambident electrophilic center. Such an example is provided by the reaction between 2-amino-5-R-thiazole and ethoxycarbonyl isothiocyanate (144), which has been thoroughly studied by Nagano et al. (64, 78, 264) the various possibilities are summarized in Scheme 95. At 5°C, in ethyl acetate, the only observed products were 145a, 148. and 150. Product 148 must be heated to 180°C for 5 hr to give in low yield (25%) the thiazolo[3.2-a]-s-tnazine-2-thio-4-one (148a) (102). This establishes that attack 1-B is probably not possible at -5°C. When R = H the percentages of 145a. 148. and 150 are 29, 50, and 7%, respectively. These results show that ... 

Formamidinoyl isothiocyanates (157) combine with 2-aminothiazoles the ring nitrogen attacks the spC part of the electrophilic reagent (312) further reaction then yields aza-condensed thiazolo-s-triazines (158) (Scheme 99) (313). Mesoionic S-alkvlthiazolo[3.2-fl]-i-tria2ine-5,7-diones (159) are obtained when 2-alkylaminothiazoles react with phenoxycar-bonyl isocyanate (304). 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

Azaindolizine, 5-chloro-nucleophilic substitution, 4, 458 8-Azaindolizine, 7-chloro-nucleophilic substitution, 4, 458 Azaindolizines basicity, 4, 454 electronic spectra, 4, 445 electrophilic substitution, 4, 453 halogenation, 4, 457 hydrogen/deuterium exchange, 4, 458 NMR, 4, 447, 449 nucleophilic attack, 4, 458 protonation, 4, 453 reaction with isothiocyanates, 4, 513 reactions, 5, 267 reviews, 4, 444 UV spectra, 4, 446, 449 Azaindolizines, amino-tautomerism, 4, 452... 

The isothiocyanate (21) reacted with dienes to give the phosphoranes (22) more rapidly than did the corresponding fluoride and chloride, but less rapidly than did the bromide. The rates of reactions of (21) with various dienes were in the order isoprene > butadiene > piperylene > chloroprene. These data support the previous suggestion that attack on the diene is an electrophilic process. 

Isothiocyanates react with nucleophiles such as amines, sulfhydryls, and the phenolate ion of tyrosine side chains (Podhradsky et al., 1979). The only stable product, however, is with primary amine groups, and so TRITC is almost entirely selective for modifying s- and N-terminal amines in proteins. The reaction involves attack of the nucleophile on the central, electrophilic... 

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). 

Additions of lithiated alkoxyallenes to alkyl-substituted isocyanates and isothiocyanates as electrophiles were recently disclosed by Nedolya and co-workers [87-91]. A short route to N-[2(5H)-furanylidene]amines 133 consists in the addition of lithiated methoxyallene 42 to alkyl isocyanates 132 and silver acetate-mediated cydi-zation of the intermediate (Scheme 8.33) [87]. 

An interesting variation of this quinoxaline synthesis is outlined by the synthesis of sydnoquinoxalines shown in Scheme 103. The starting material is phenylsydnone 288 with an iminophosphorane group in an o-position. With isocyanate or isothiocyanate carbodiimide intermediates 289 are formed by an electrophilic aromatic substitution at the sydnone ring (4 position), the 4-(arylamino)sydno[3,4-a]quinoxalines (290) are obtained (91S745). 

PS-BEMP). The reaction gave 4,5-disubsituted isothiazole in 58% yield. What was interesting was that an additional washing of the immobilized base with an electrophile (in a typical setup, 2,4 -dibromoacetophenone) gave the corresponding 1,4,5-trisubstimted imidazole in 38% yield and >95% purity. Additional efforts were done to produce only the imidazole structure by using the premixed electrophile and ethyl isothiocyanate, however, without success. 

Isothiocyanate 23 (X = CO), when treated with AICI3 in nitromethane undergoes ring closure by an intramolecular electrophilic substitution between C3 of the pyrrole ring and the isothiocyanate group to afford pyrrolo[3,2-c][l]benzazepine-10(lH)-one-4(5H)-thione 24 (Scheme 2 (2005BMCL3220, 1998MI197)). 

Alkyl or aryl aminothiatriazoles (330) in contrast react with cyanates even at — 70°C to give 5-amidino substituted 1,2,4-thiadiazoles (331) weaker electrophiles, such as isothiocyanates, thiocyanates, and cyanamide do not react with aminothiatriazoles <85JOCl295>. 

Bis(benzimidazol-2-yl)disulfide (214) treated with phenyl isothiocyanate gives the 1,2,4-dithiazole derivative (215) as a result of electrophilic attack by the isothiocyanate group on the nitrogen atom... 

Only two syntheses use different approaches from the reaction of N-C-C-S and C-C fragments. In the first one, an isothiocyanate was used to supply a C-S fragment (Scheme 67) <1988ZC58>. In the second synthesis, compound 286 reacted three times as an electrophile (Scheme 68) <2006EJOI555>. 

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