Isothioureas guanidines

This section is new and only one article appeared in this area. The reaction of iV-/-butyl-iV -pyridazin-3-ylcarbodi-imide with amines, thiols, and alcohols was studied by Rakowitz and co-workers and yielded respectively novel guanidines, isothioureas, and isoureas <2002JHC695>. 

The lA4,2,5-thiadiazole 1-oxide 4 undergoes ring transformation with binucleophiles, e g. imidamides, guanidines, isothiourea, to give 1,2,4,6-thiatriazinc 1-oxides 5.64 The reactions of the 1-oxide 4 with binucleophiles are conducted in methanolic solution at room temperature. Thus, 5 (R = Ph) is obtained in a 40% yield by reaction of the 1-oxide 4 with benzimidamide hydrochloride. 

When cyanogen bromide was used instead of CS2, the corresponding guanidines 169 were obtained under analogous conditions [108]. Moreover, differently substituted guanidines 171 could be obtained in very good yields when the isothiourea 168 was alkylated with Mel under microwave irradiation and the product treated with a primary amine. An intramolecular version of this reaction was also described for the preparation of structure 172 present in several important natural products (Scheme 61). 

Preparation of guanidine from thioureas has been carried out. There are many ways to synthesize guanidines. Converting thioures and isothiourea moieties into guanidine is one of the most popular methods. 

Scheme 14 shows a typical example in a series of reactions in which a supported amino acid reacted with fluorenylmethoxycarbonyl isothiocyanate to give a supported (on Rink s amide)35 thiourea.36 Removal of the protection followed by 5-alkylation gave supported isothioureas. Reaction of these with amines, then cleavage from the resin, afforded substituted guanidines. For 10 examples the purities were between 40 and 92%. An aryl group separates the resin from the guanidine, just as in the sequences shown in Schemes 11 and 12. 

The guanidine moiety was incorporated by dimethyl (2,2,5,7,8-pentamethylchromane-6-sulfonyl N-alkylated amino) dithiocarbonate[264] (Pmc-dithiocarbonate) 91 in two steps. One methylsulfanyl group was replaced by the primary amino group of Bzl-Norn-OBzl in the presence of excess DIPEA and the isothiourea obtained was reacted with silver nitrate under basic conditions to yield the intermediate sulfonylcarbodiimide which reacts immediately with ammonia to yield the guanidine Bzl-Narg(Pmc)-OBzl 91. 

Several strategies enable the attachment of guanidines and amidines to insoluble supports (Figure 3.29, Table 3.28). These include attachment as A-benzyl, A-acyl, and A-alkoxycarbonyl derivatives. Furthermore, support-bound isothioureas can be used to convert amines into guanidines. The synthesis of support-bound guandines is considered in Section 14.3. 

Conversion of the diamine of 52 to a guanidine proved very challenging. Reaction of 52 with thiophosgene26 afforded cyclic thiourea 53 in only 40% yield and initial attempts to convert 53 to the guanidine were unsuccessful. Reaction with methyl iodide in MeOH at reflux afforded isothiourea 54, which did not form the desired guanidine on treatment with ammonia in MeOH. 

Thiadiazole S.S -dioxides (336) have been prepared by the cyclization of N-halomethylsulfonyl-amidines and -guanidines (335 Scheme 120) <70JCS(C)1429>. N-chloromethylsulfonyl-isoureas and -isothioureas (337) cyclize in the presence of base and chloroformate esters to yield the related S,S-dioxides (92) which easily undergo chlorinolysis to produce (93 Scheme 121) (see also Scheme 45) (74BSF1580). 

The guanidines 210 can be prepared from the corresponding primary amines by treatment with the 5-methyl isothiourea 211 and HgCl2/Et3N in DMF. The products... 

Oxo derivatives (43 and 44) can be prepared from isothioureas and guanidines with diketene.99-144 145... 

The reactions are often carried out in an alcohol at room temperature, and the amidine is generally liberated from its hydrochloride by treatment with one equivalent of a base. Reaction times are short and the yields are high. It is also possible to employ isoureas, isothioureas and guanidines as the amidine component. The unstable 2-phenylisoureas (R3 = OPh) are prepared in situ. 

Cyclocondensation of substituted isothiocyanates 24 with amidines, isoureas, isothioureas or guanidines provides 1,3,5-triazine-2(1 //j-thiones 25 in good yield.433 43s Generally, aroyl isothiocyanates and imidoyl isothiocyanates are employed. 

Similarly, ethoxycarbonyl isothiocyanate (26) reacts with amidines, isoureas, isothioureas and guanidines to yield the corresponding tautomeric 4-thioxo-3,4-dihydro-l,3,5-triazin-2(l//)-ones 27.434... 

Benzoxazonium cation (227) is obtained when disalicylimide (226) is treated with 70% perchloric acid and gives on reaction with guanidines or isothioureas 1,3,5-triazines (228) (Scheme 70) <83KGS406>. 

Sodium hydroxide Guanidines from amines and isothioureas s. 3, 392 NaOH /N N—C( N... 

The new examples reported include the preparation of antiviral, antibacterial, and antitumor agents by coupling sugar isothiocyanates and such biologically active amines as triazole derivatives,195 mitomycin,196 isothia-zolopyrimidines,40 and also platinum compounds.197 Other A -nuclcophiles such as hydrazine,37 isothiourea,198 and guanidine derivatives199 have been similarly coupled to sugar isothiocyanates. 

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