Isothiocyanates with 2-aminothiazoles

The reaction of 2-aminothiazoles with alkyl isothiocyanates yields 2-thiazolylthioureas (30.3, 490), otherwise usually obtained by direct heterocyclization (Chapter II. Section II.4). Other synthetic methods... 

Isopropanol, with aminothiazoles, 47 Isothiocyanates, 58 with 2-aminobenzothiazoles, 59 with 2-aminothiazoles, 65 with azirines, 15... 

This type of synthesis, which was investigated initially by Cook and Heilbron in 1947, gives 5-aminothiazoles with various substituents in the 2-position by reacting an a-aminonitrile with salts and esters of dithioacids, carbon disulfide, carbon oxysulfide, and isothiocyanates under exceptionally mild conditions (47JCS1594). 

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). 

Isothiocyanates of general formula 221 condensed with a-aminonitriles lead to 2-substituted 5-aminothiazoles (223) (Table 11-36) through an acyclic intermediate (222) (Scheme 116). 

Amongst the more unusual reactions, 2,3-thiazolo fused pyrido[3,2-d]pyrimidines have been prepared from 3-aminopicolinic acid and 2-bromothiazoles, whilst a similar derivative resulted with allyl isothiocyanate (221 222) <72IJC602). Similar products are also produced in [3 + 3] reactions of 2-aminothiazoles (Section 2.15.5.7.1). 

The synthesis of 5-aminothiazoles via the reaction of isocyanate derivatives with aminomalononitrile p-toluenesulfonate (AMNT) has been investigated. It was found that AMNT 12 reacted with alkyl and aryl isothiocyanates in l-methyl-2-pyrrolidine (NMP) to furnish 5-amino-2-(alkylamino)-4-cyanothiazoles (13a) and 5-amino-2-(arylamino)-4-cyanothiazoles (13b-c) in 44-81 % yields. " ... 

Thioureas serve as a convenient starting material for 2-aminothiazoles. Reaction of (3-phenethylamine (103-1) with ammonium isothiocyanate gives the thiourea (103-2). Treatment of that product with phenacyl bromide (103-3) leads to the corresponding thiazole. That compound, fanetizole (102-4) [114], shows immuno-regulating activity. 

Aminomalonitrile p-toluensulfonate (279) reacts with alkyl and aryl isothiocyanates yielding 2-alkylamino and 2-arylamino-4-cyano-5-aminothiazoles (280) in good yields (Equation (47)) <91JOC4645>. 

Supports 3e and 3f derived from a related linker with only one me-thoxy group ortho to the aldehyde have been reported [140] to have a more reactive aldehyde group than 3c or 3d due to lower steric hindrance. Resin 3e was used to synthesize aminothiazoles, which were cleaved under acidic conditions [141]. Thus, amines were anchored reductively to 3e and converted to resin-bound thioureas by reaction with Fmoc-isothiocyanate followed by deprotection. Cyclization by reaction with a-bromomketones gave the desired heterocycles, which were cleaved from the resin by treatment with TFA-H2O (19 1) (Scheme 4). 

Suppose a case where the reactive building blocks 1-5 (three of each) would be available. Thioureas 1 are polyvalent donor molecules, isothiocyanates 2 and nitriles 3 can be viewed as acceptor-donor molecules, 2-bromoketones 4 are typical bis-acceptors whereas alkyl halides are mono-acceptors. In the typical Hantzsch synthesis of aminothiazoles, 1 is condensed with 4 to give thiazoles 6 which subsequently can be alkylated with 5 to give the final products 7 (27 aminothiazoles). 

Aminothiazol-5-ylmethyl)isothiourea (229) reacted with 3-chloropro-pionitrile in basic conditions to give the nitrile (230) which with benzoyl isothiocyanate gave the adduct (231). Basic hydrolysis, 5-methylation and ammonolysis afforded the guanidine (232) which underwent the Pinner reaction with sulphamide to give famotidine (233) Scheme 5.55.) [295]. The... 

The interaction of enamines with sulphur in conjunction with carbon disulphide, isocyanates, or isothiocyanates results in the production of sulphur-containing heterocyclics. Cyanamide has now been shown to participate in this reaction. Treatment of enamines of type (24) with sulphur and cyanamide at room temperature in ethanol produces a range of 2-aminothiazoles (27) in 30—70% yield no catalyst is required. Initial formation of the thiolated intermediate (25) is probably followed by addition of cyanamide, yielding (26) elimination of amine finally produces the observed thiazoles (27). Since AW-dialkylcyanamides do not undergo this reaction, cyanamide may react as the tautomeric carbodi-imide. An actual example of the reaction employing the enamine derived from cyclohexanone and morpholine is also shown [(28) - (29)]. ... 

Thiazolo[3,2-a][l,3,5]triazines [C3NS-C3N3].—A further report of the synthesis of compound (73) from 2-aminothiazole (see Vol. 3, p. 645) has appeared, whilst the structure of the major product from the reaction of 2-amino-A -thiazoline with ethoxycarbonyl isothiocyanate has been confirmed as being 2,3,6,7-tetra-... 

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