Heterocyclic syntheses from thioureas

The present volume encompasses a wide range of heterocyclic chemistry. Syntheses of heterocycles from thioureas are reviewed by T. S. Criffin, T. S. Woods, and 1). L. Klayman, while S. W. Schneller describes the chemistry of benzothiins and their derivatives (thiochromans, thiochromones, and thio-chromanones). Developments in chrom-3-ene chemistry are reviewed by L. Merlini. F. D. Popp contributes a chapter on the isatins. A discussion of theoretical aspects of the tautomerism of pyrimidines, by J. S. Kwiatkowski and B. Pullman, follows up a corresponding earlier contribution (Vol. 13) on tautomeric purines. In the final chapter P. and D. Cagniant describe the natural occurrence and synthesis of the benzofurans. 

Nefzi A, Ostresh JM, Meyer JP, Houghten RA, Solid phase synthesis of heterocyclic compounds from linear peptides cyclic ureas and thioureas, Tetrahedron Lett., 38 931-934, 1997. 

Nefl997c Nefzi, A., Ostresh, J.M., Meyer, J.-P. and Houghten, R.A., Solid Phase Synthesis of Heterocyclic Compounds from Linear Peptide Cyclic Ureas and Thioureas, Tetrahedron Lett., 38(1997) 931-934. 

There is an enormous literature on thiocarbonyl compounds, due in part to the technical and industrial importance of many of them, including thioamides, thioureas, xanthates, dithiocarbamates and so forth. An excellent, and recent, general review is available.107 There are also specialized reviews germane to the present chapter Griffin, Woods, and Klayman2 discussed the use of thioureas in the synthesis of heterocycles the preparation of thiazoles from thioamides is included in a three-part volume on Thiazoles 108 the use of carbon disulfide in the synthesis of trithiones and related heterocycles has been reviewed by Mayer109 and Huisgen110 has reported numerous examples of 1,3-dipolar cycloadditions in which carbon disulfide was used. 

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. 

Stannyl ketyl radicals were generated from an amide carbonyl group and when incorporated in cinnamic enamides, indolizidinone rings can be assembled [37]. Du and Curran have shown that a-thioaminoalkyl radicals such as 24 resulting from the addition of a tris(trimethylsilyl)radical onto N-aryl thiocarbamates, thioamides or thioureas 22, can be exploited in the context of the synthesis of carbocyclic and heterocyclic fused quinolines 23 (Scheme 8) [38]. 

The reagents used for the completion of the purine heterocycle are essentially the same as those used for the Traubc synthesis. The purine ring is formed by condensation with derivatives of formic acid or other carboxylic acids. Alternatively, formylation of the amino group is accomplished by a mixture of formic acid and acetic anhydride followed by cyclization. Alkyl esters or trialkyl ortho esters are also versatile synthons for ring closure. Moreover, heating in formamide or cyclization with urea or thiourea provides a satisfactory route. Condensations with isothiocyanates show unusual versatility leading to 2-sulfanylpurin-6-ols. From carbonic acid derivatives, cyclization is reported with chlorocarbonic esters, diethyl carbonate or carbon disulfide. 

Figure 15 Synthesis of positional scanning heterocyclic libraries (diethyltriamines 24, cyclic ureas 25, and cyclic thioureas 26) derived from dipeptides.

Many biologically active compounds contain cyclic ureas, including inhibitors of human immunodeficiency virus (HIV) protease and HIV replication [70]. Kim et al. [71] presented an illustration of the synthesis of oligomeric cyclic ureas as nonnatural biopolymers. Applying the libraries from libraries [72] concept, triamines [65] such as those described earlier were used as templates for the generation of different heterocyclic compounds such as cyclic ureas, cyclic thioureas, and bicyclic guanidines [65]. The cyclizations to obtain the five-membered ring cyclic ureas and cyclic thioureas were... 

With the increasing importance of the need to discover new dmgs, considerable effort has been directed to identify a convenient method for rapidly preparing a large number of diverse molecules. To satisfy such keen demand, polymer-supported synthesis offers tremendous utility, and several methods have been developed to derive heterocyclic compounds based on a heterocyclization strategy. For example, Habermann et al. described a convenient method for preparing 2-amino-1,3-thiazole derivatives from a-bromoketone precursors by direct treatment with thiourea in refluxing THF in the presence of PS-TBD [63] (Scheme 6.15). 

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. 

The most common method for the preparation of thioureas is, however, based on the reaction of isothiocyanates with amines, and, not unexpectedly, the majority of papers deal with this particular reaction. 6-2 1 Among the N-substituent groups thus introduced into thiourea are 3-cyclo-pentenyl, 1-adamantyl, furfuryl, diphenylphosphinoyl, diphenyl-phosphinothioyl, AW-9,10-diacetyldihydro-2-phena2inyl, and variously substituted aryls. - If the isothiocyanate or the amine contains other reactive groups, cyclization to heterocyclic compounds containing the thiourea grouping may occur, either spontaneously or promoted by external influence, as recently demonstrated in the synthesis of thiones derived from imidazoline, pyrimidine, - and j-triazine. - ... 

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