Heterocycles from ureas

The classical Biginelli synthesis of heterocycles from /3-diketones, urea, and aldehydes has been extended by the replacement of the dione with a cycloalkanone.343 The... 

Heterocycles. Many different heterocycles are synthesized via a carbonylation process hydantoins from aldehydes and urea, flavones from ethynylarenes and o-iodophenol acetates, and a-substituted a,p-unsaturated lactones from iodoalkenols. ... 

One of the extensively investigated applications of enamines to heterocyclic syntheses is based on the bifunctional character of enamine acylation products. Thus the vinylogous ureas and thiorueas obtained from enamines and phenylisocyanate and phenylisothiocyanate (-433) have been converted to aminopyrazoles and thiouracils with hydrazine (566) and phenylisocyanate (567). 

Heterocyclic rings can be produced from the reaction of a chalcone 203 under basic conditions with urea or thiourea, generating the corresponding diaryl guanidinium structure 204a or 204b as displayed in Scheme 56 by Kidwai and... 

No new calculations were specifically devoted to this heterocylic system since CHEC-II(1996). Redox properties of chalcogeno-ureas possessing this heterocyclic skeleton and resulting from the reaction of Arduengo carbenes such as 108 with sulfur or selenium was investigated through semi-empirical calculations <2000EJI1935>. 

The traditional synthesis of miinchnones involves the cyclodehydration of N-acylamino acids usually with acetic anhydride or another acid anhydride. Potts and Yao (3) were apparently the first to employ dicyclohexylcarbodiimide (DCC) to generate mesoionic heterocycles, including miinchnones. Subsequently, Anderson and Heider (4) discovered that miinchnones can be formed by the cyclodehydration of N-acylamino acids using Ai-ethyl-Ai -dimethylaminopropylcarbodiimide (EDC) or silicon tetrachloride. The advantage of EDC over DCC is that the urea byproduct is water soluble and easily removed, in contrast to dicyclohexylurea formed from DCC. Although the authors conclude that the traditional Huisgen method of acetic anhydride is still the method of choice, these two newer methods are important alternatives. Some examples from the work of Anderson and Heider are shown. The in situ generated miinchnones (not shown) were trapped either with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate. 

Ganellin et al. [23] have combined histamine or its sulfur analog with nitrogen containing heterocycles ( urea equivalent strategy) to prepare a unique series of potent H3 antagonists related to UCL 1283 16. Examples of compounds from these efforts are the pyridine 18 (K,= 17 nM) and UCL 1199 19 (Ki = 4.8 nM) (Figure 9). 

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. 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

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. 

An impressive range of nucleophiles was successful for arylboronic acids in the presence of Cu(OAc)2 and base, which included amine, anilines, amides, imines, ureas, carbamates, sulfonamides, and aromatic heterocycles (e.g., imidazoles, pyrazoles, triazoles, tetrazoles, benzimidazoles, and indazoles) (Equation (226)) 996 997 1000-1011 For all the reactions investigated with A-nucleophiles, the use of Et3N resulted in yields superior to those obtained with pyridine, but pyridine was the base of choice for the preparation of imidazole derivatives from heteroarenes. For the tetrazole, NMO and DBU were studied as alternative bases. There are mechanistic studies.999,1002-1013... 

For anions of organic compounds, like thiols (i), derivatives of urea and thiourea (ii) such as barbituric and thiobarbituric acids and their derivatives, as well as for some heterocyclic compounds, the reaction product Hg2(X) is slightly soluble. In such cases the anodic wave is a linear function of concentration only until a concentration is reached, when the surface is covered by Hg2(X) . With a further increase in concentration the limiting current of the anodic wave becomes independent of concentration of X. Such limiting current is controlled by adsorption and is a linear function of the height of the mercury column (h). From the concentration at which the electrode surface is covered by Hg2 (X) it is possible to calculate the surface area covered by the species Hg2(X) . 

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