Synthesis thiohydantoins

In analogy to the thiohydantoin synthesis, the PEG-bound diamines have also been treated with various alkyl and aryl isothiocyanates and, after applying traceless cyclative cleavage, the desired thioxotetrahydropyrimidinones were obtained in excellent yields. In contrast to the thiohydantoin synthesis, purification of the products was more complicated if the excess of isothiocyanate amounted to more than 2.2 equivalents [85],... 

Shalaby. A. F. A.. Daboun, H. A., and Aziz, M. A. A.. Reactions with 2-thiohydantoin synthesis of imidazothiazolone derivatives and Mannich bases of 5-arylidenc-2-thiohy-dantoin, Z. Numrforsch. Teil B, 3IB, 111,... 

In a procedure similar to the thiohydantoin synthesis, the PEG-bound diamines... 

In 1875, Mulder (43) extended the synthesis reaction of thiohydantoine to the ethyl ester and amide of chloroacetic acid. Claus (44) demonstrated the acidic properties of thiohydantoin and its ability to form metallic salts. 

Synthesis from Thiohydantoins. A modification (71) of the Bucherer-Bergs reaction consisting of treatment of an aldehyde or ketone with carbon disulfide, ammonium chloride, and sodium cyanide affords 2,4-dithiohydantoias (19). 4-Thiohydantoias (20) are available from reaction of amino nitriles with carbon disulfide (72). Compounds (19) and (20) can be transformed iato hydantoias. 

A one-pot synthesis of thiohydantoins has been developed using microwave heating [72]. A small subset of p-substituted benzaldehydes, prepared in situ from p-bromobenzaldehyde by microwave-assisted Suzuki or Negishi reactions, was reacted in one pot by reductive amination followed by cyclization with a thioisocyanate catalyzed by polystyrene-bound dimethyl-aminopyridine (PS-DMAP) or triethylamine, all carried out under microwave irradiation, to give the thiohydantoin products in up to 68% isolated yield (Scheme 16). 

Muccioli, G.G., Poupaert, J.H., Wouters, J. etal. (2003) A Rapid and Efficient Microwave-Assisted Synthesis ofHydantoins and Thiohydantoins. Tetrahedron, 59, 1301-1307. 

In a separate study, Ohberg and Westman applied the same PS-DMAP in a one-pot microwave-induced base-catalyzed reaction of N-aryl and N-alkyl amino acids (or esters) and thioisocyanates for the library synthesis of thiohydantoins (Scheme 7.115) [136]. Thiohydantoins are of interest due to their ease of preparation and the range of biological properties associated with this heterocyclic ring system. The use of PS-DMAP as the base in this reaction gave slightly lower yields compared to when triethylamine (TEA) was used, but it resulted in a cleaner reaction mixture and an easier purification procedure. Cyclizations of a number of N-substituted... 

A-Thiazolyl a-amino acids 56 have been prepared. The preferred route to these compounds would utilise the Hantzsch synthesis, however in this case the in situ formation of the required thiourea derivatives of a-aminoacids 52 failed. A variety of isothiocyanate reagents were tried, with the result being either no reaction, decomposition or the corresponding thiohydantoin 53. A modified version of the Hantzsch synthesis was developed. If the bromoketone 54 is initially treated with sodium thiocyanate an a-thiocyanatoketone 55 is formed, subsequent addition of the amino acid ester 51 yields A-thiazolyl a-amino acids 56 <00T3161>. 

Microwave-induced imine formation, subsequent reduction with NaBH(OAc)3 and cyclisation of the resulting amino acid with isothiocyanates was used in an efficient one-pot multi-step synthesis of thiohydantoins (Scheme 4.26). The reductive animation was conducted as a two-step procedure to avoid direct reduction of the aldehyde at high temperatures48. 

Fig. 3. Solid-phase synthesis of hydantoin and thiohydantoin libraries from resin-bound dipeptides.

To increase the number of diversities, the hydantoin (or thiohydantoin) formation reaction was performed starting from N-alkylated dipeptides (Fig. 3). In the last synthesis step, the hydantoin (or thiohydantoin) ring was alkylated followed by the cleavage from the resin. Using 54 different amino acids for the first position of diversity (R1), 60 different amino acids for the second position of diversity (R2), and four different alkylating... 

An efficient solid-phase protocol for the synthesis of substituted (5-biphenyltetrazolyl)-hydantoins and -thiohydantoins has been developed. Suzuki cross-coupling between resin-bound 2-(tetrazol-5-yl)-phenylborinane 333 and 4-bromobenzaldehyde gave the corresponding tetrazolylbiphenyl aldehyde 334 (Equation 59) <2004BML317>. 

Nefzi, A., Giulianotti, M Truong, L., Rattan, S Ostresh, J. M and Houghten, R. A., (2002) Solid-phase synthesis of linear ureas tethered to hydantoins and thiohydantoins. / Comb. Chem. 4, 175-178. 

The selected example by Sim and Ganesan [19] reported the design of a 3078-member discrete thiohydantoin library, prepared without purification of intermediates, with a three-step synthesis, which is shown in Figure 7.2. Nine amino acid esters were reacted with eighteen aromatic aldehydes to produce imines, which were reduced by sodium triacetoxyborohydride. The resulting amines were treated with nineteen isothiocyanates in the presence of triethylamine (TEA), producing intermediate isoureas, which eventually cyclized to the final thiohydantoins. 

FIGURE 7.2 Three step synthesis of 3078-membered discrete thiohydantoin library. 

Sim and Ganesan (56) have recently reported the partial synthesis of a 3078-member thiohydantoin library in solution (L2, Fig. 8.11). The initial studies were aimed at the preparation of a library of thiohydantoins in SP based on the adaptation of a previously... 

Figure 8.12 Synthesis of the solution-phase, discrete thiohydantoin library L2 structure of the monomer sets M1-M3.

A fluorous catch and release method was used by Zhang in the synthesis of di-substituted pyrimidines.A fluorous route to hydantoins and thiohydantoins was also reported by the same group. 

The earliest method of this type, developed by Marckwald, employed the reaction of a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates to give 3//-imidazoline-2-thiones. These compounds can be converted readily into imidazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and the limited range of 2-substituents which are introduced. The reduction of a-amino acids with aluminum amalgam provides one source of starting materials. The method has been applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone (70AHC(12)103), and to the synthesis of pilocarpine (84 Scheme 47) (80AHC(27)24l). If esters of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and 2-thiohydantoins, respectively. 

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