Thioureas cyclic

Hyperthyroidism may be treated in several ways. One of these is interference with the synthesis of the thyroid hormones, possibly by removal of iodine. Thiourea and cyclic thioureas have this effect and of such cyclic compounds, thiouracil (1030 R = H), its 6-alkyl derivatives (1030 R = Me or Pr) and thiobarbital (1031) are effective thyroid drugs. Today only propylthiouracil (1030 R = Pr) is widely used, probably because it has fewer side effects than the others (71MI21302). The thiouracils are made by the Principal Synthesis from a /3-oxo ester (1032 R = H, Me, Pr, etc.) and thiourea (45JA2197) their fine structures are experimentally based (64AF1004). 

Except this particular example, the other possibilities such as the desulfurization of cyclic thioureas or the vacuum thermolysis of methoxy derivatives [1-5], has never been used for the preparation of chiral diaminocar-... 

Benzopyranothiazolopyrimidines such as 175 can be prepared by the reaction between the appropriate cyclic thiourea and chloroacetic acid (Equation 45) <2005IJB1887>. 

Triazoloimidazo- and -imidazolinothiazinopyrimidines have been prepared by reaction of the dichloropyrimidine-carbaldehyde 192 with substituted five-membered cyclic thioureas in DMF (Scheme 48) <1996CHE371,... 

Cyclic thiourea derivatives having three different types of cyclophane structure (ortho-meta, meta-meta and meta-para) and a lariat-type thiourea have been synthesized, using reaction of isothiocyanate with amine.230 Cyclic thioureas have been obtained from formaldehyde aminals and sulfur (Sg) (Scheme 77).231... 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

Cyclic thiourea derivatives like l,3,4,5-tetramethylimidazole-2(3H)-thione— prepared by condensation of substituted thioureas with a-hydroxyketones—can be converted into the corresponding imidazolin-2-ylidene by desulfurization with sodium or potassium [Eq. (23)]. This method was used to prepare and isolate l,3-bis-neo-pentylbenzimidazolin-2-ylidene with Na/K. With LDA as the base it is also possible to generate free benzimidazolin-2-ylidenes in solution. ... 

Cyclic thioureas such as 2-thiouracil 1118 (R = H), its 6-methyl 1118 (R = Me) and 6-propyl derivatives 1118 (R = Pr), as well as thiobarbital 1119 are effective agents against hyperthyroidism, while thiamylal 1120 is used as an anesthetic. A large number of barbituric acid derivatives have hypnotic or sedative effects, and allobarbital 1121 (R = R = allyl), aprobarbital 1121 (R = allyl, R = r-Pr), cyclobarbital 1121 (R = Et, R = 1-cyclohexenyl), pentobarbital 1121 (R = Et, R = 2-pentyl), phenobarbital 1121 (R = Et, R = Ph), propallyonal 1121 (R = isopropyl, R = 2-bromoallyl), and secobarbital 1121 (R = allyl, R = 2-pentyl) are all examples of N-unsubstituted barbiturates, while hexobarbital 1122 represents an N-methylated derivative. 

A number of annelated 1,3,4,6-thiatriazepines (613) have been prepared by the reactions of the sodium salts of cyclic thioureas with dichlorodiazabutadienes (612). Acyclic thioureas take an alternative reaction path via the elimination of a carbodiimide to give only 2,5-diphenyl-l,3,4-thiadiazole (80CC156). An X-ray structure determination on (613 n = 2) shows that the seven-membered ring has the expected boat conformation and that ring fusion does not appear to strain the five-membered ring <81AX(B)486>. 

A small group of cyclic thioureas have been used in the treatment of excessive thyroid function. They include 6-n-propylthiouracil (176 R1 = H, R2 = Prn), 5-iodo-2-thiouracil (176 R1 = I, R2 = H), l-methyl-2-mercaptoimidazole (methimazole) and its ethoxycarbonyl derivative carbimazole (177), which lacks the bitter taste of the unacylated compound. These compounds block the synthesis of thyroxin by inhibiting the oxidation of iodide to iodine and the oxidative coupling of iodotyrosine residues. 

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. 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

Fig. 11. Solid-phase synthesis of bis-cyclic thioureas and bis-cychc guanidines from resin-bound reduced tripeptides.

There have been investigations of the reaction of cyclic thioureas with unsaturated carbonyls. For example, interactions involving imidazolidine-2-thione 64 (n = 1) or tetrahydropyrimidine-2-thione 64 (n = 2) with ketones 65 (k = 1-3) in the presence of the catalyst boron trifluoroetherate yielded only one stereoisomer 66 according to Perjesi et al. [70] (Scheme 3.20). 

Another cyclic thiourea—4,5-dihydrothiazole-2-ylamine 67—reacted with unsaturated heterocyclic carbonyls 68, yielding tricyclic compounds 69 [71] (Scheme 3.21). 

In 1993, Kuhn reported that cyclic thiourea derivatives like 1,3,4,5-tetramethyl-2(3H)-thione can be used as NHC precursors [62]. In most cases the thione affords an easy access to the free carbenes by treatment with sodium or potassium [62-71]. This method provides an efficient way to prepare unsymmetrically substituted saturated NHCs (Scheme 16) [35,72],... 

Reaction of an amino-substituted heterocyclic thiol such as 84 with acylating agents gives compounds 85, which are cyclized by POCl3 to form the respective imidazo[2,l- ][l,3,4]thiadiazoles 86 (Scheme 51) (for a review see <1998CHE1003>). Bromine oxidation of the cyclic thiourea 87 forms 2,3,5,6-tetrahydroimidazo[l,2- /][l,2,4]thiadia-zol-3-ones 88 (Scheme 52) <1973JPR539>. 

Nair and Desai113 described another synthetic route to conjugated cyclic 1,1-enediamines such as 8. Condensation of cyclic thiourea component 101 with arylacyl bromide furnishes arylacylmethylisothioureas 102, which are converted to products 8 when treated with triphenylphosphine in the presence of base (equation 35). 1,1-Enediamines having other diamine moieties are obtained similarly. Although this... 

The bicyclic nine membered ring carbodiimide 11 is stable at room temperature. Also 12 is obtainable in the dehydrosulfurization of the corresponding cyclic thiourea, and 13 is a stable solid, but the tricyclic carbodiimide 14 has only been postulated as an intermediate. ... 

The homocyclic carbodiimides 16 were first synthesized by Behringer and Meier in 1957 by dehydrosulfurization of cyclic thioureas 15 with HgO. 

The cyclic thiourea 19, upon reaction with HgO affords the cyclic carbodiimide 20, but the compound has not been isolated in pure form. ... 

Thiourea (98) was first prepared in 1870 by heating ammonium thiocyanate (99) (Scheme 54). The reaction is analogous to the historic preparation of urea (Wohler, 1828) which involved heating ammonium cyanate. Thioureas generally are stable crystalline solids which are useful in the synthesis of heterocyclic compounds. Symmetrical thioureas (100) may be obtained by the action of amines on carbon disulfide, and the procedure can be extended to the synthesis of cyclic thioureas (101) (Scheme 55). The reaction occurs via the intermediate (102) which on subsequent treatment with either ammonia or an amine yields the corresponding... 

Cyclic thioureas react predictably with COClj [2083a]. In the following example, the chloroimidazolidinium chloride is formed, accompanied by the production of carbonyl sulfide ... 

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