Hydantoins and Thiohydantoins

To the fully derivatized product on the solid support was added excess TFA/CH2CI2 (90 10) and the cleavage reaction was allowed to proceed for 0.5 h at rt. The cleavage solution was then removed by filtration through a cannula and the resin was rinsed with an appropriate solvent (e.g., MeOH/ CH2CI2). Concentration of the combined filtrates provided the crude product 12 in yields 80% (56-67% isolated yields after purification by RP-HPLC). 

The same set of alkyl halides used for N -alkylation was also found to be suitable for Nhalkylation, with the notable expansion to include other alkyl iodides beyond methyl and ethyl iodide. No evidence was found for C- or O-alkylation. Some resin bleeding , which is not uncommon in the use of PEG-derived solid supports, was reported. This refers to the presence of PEG fragments (released during strong acid treatments) in the crude samples. 

A very extensive diversification of l,5-benzodiazepin-2-ones with the help of the radiofrequency tagged IRORI system (Discovery Partners International, San Diego, USA) was reported by Herpin et al. [24]. Here, the strategy of template preformation in solution and subsequent derivatization on a soHd phase was pursued. 

The 3-amino-l,5-benzodiazepin-2-one scaffold was attached via its benzamide nitrogen to a series of Rl-functionalized bromoacetamide resins. The sorted and recombined microreactors were further subjected to an alkylation and an acylation step. A 10,000-member library was produced. 

More recently, a novel resin-bound isonitrile has been reported to be suitable for synthesizing libraries of l,4-benzodiazepine-2,5-diones through Ugi multicomponent reactions [25]. The method produces solid-supported Ugi products, which are cleaved by base activation to form N-acyloxazolidone intermediates that can be further elaborated. The flexibility of the approach was demonstrated by an analogous preparation of 2,5-diketopiperazines by simply replacing the 2-aminobenzoyl building blocks with a-amino acids. 

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Figure 15.8. Strategies for the preparation of hydantoins and thiohydantoins on insoluble supports. X O, S.

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

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. 

Among radicals from diazoles, in the imidazole series hydantoin, methyl-hydantoin, and thiohydantoin have given various radicals e.g., 159, differing in degree of protonation, upon radiolysis of aqueous solutions.546 Values of... 

Spiro hydantoins, (III) prepared by Webb (4) and hydantoin and thiohydantoin, (IV), derivatives prepared by Poitout (5) were effective as somatostatin receptor agonists and were useful in treating hypersecretion disorders. 

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. 

Aloxidone and albutoine are anticonvulsivant V-allyl derivatives of hydantoin and thiohydantoin (Figure 20.21). The dibenzazepine azapetine is an a-adrenergic blocking agent used as peripheral vasodilator. 

Most X-ray diffraction studies have been undertaken to confirm the structure of hydantoins and thiohydantoins or their derivatives obtained by unusual methods.87,88,111,126,201,202 Many others have emphasized con-... 

As would be expected, hydantoins and thiohydantoins can react with nucleophilic and electrophilic as well as with other types of reagents. 

Hydantoins and thiohydantoins have been used as analytical reagents for heavy metals because of their capacity for complex formation.361-363... 

Condensation of urea with carbonyl compounds A rapid and efficient MW-assisted synthesis of hydantoins and thiohydantoins was described by Muccioli et al. [117]. The most straightforward conditions for synthesis of phenytoin are the base-catalyzed condensation using benzil and urea, known as the Biltz synthesis (Eq. 33). MW activation of the Biltz synthesis of phenytoin improved both yield and reaction time. The first step consists in MW activation of the reaction of benzil with (thio)urea the second includes the conversion of the resulting 2-(thio)hydantoin to hydantoin using hydrogen peroxide. When reactions were performed at the same temperature under both reaction conditions, yields were by far better under the action of MW and emphasized the evident specific MW effects. These are perfectly expected when one considers the polar TS involved in the first step (nucleophilic addition of neutral NH2 group on carbonyl moiety). 

A series of poly(amide-imide)s have been obtained by polycondensation of hydantoin and thiohydantoin derivatives of pyromellitic acid chlorides with [N,N -(4,4 -carbonyldiphthaloyl)] bisalanine diacid chloride [57], N,N -(pyromellitoyl)-bis-i-phenylalanine diacid chloride [58], and N,N -(4,4 -diphenyl ether) bistrimellitide... 

Muccioli GC, Poupaert JH, Wouters J, Norberg B, Poppitz W, Scriba GKE, Lambert DM (2003) A rapid and efiBcent microwave-assisted synthesis of hydantoins and thiohydantoins. Tetrahedron 59 1301-1307... 

The result is the formation of a stable amide linkage. Other acylations may be accomplished by classical methodology, such as acetylation with acetic anhydride. However, as was observed with alkylations and other reactions, acylations have been developed which readily occur under mild reaction conditions. For example, amino acids will react with isocyanates (R—N=C=0) and isothiocyanates (R—N=C=S) to form hydantoins and thiohydantoins. 

K. Eaghihi, K. Zamani, A. Mirsamie, M.R. Sangi, Microwave-assisted rapid synthesis of novel optically active poly(amide-imide)s containing hydantoins and thiohydantoins in main chain. Europ. Poly. J. 39, 247-254 (2003)... 

Figure 53 Polycondensation of hydantoin and thiohydantoins derivatives of pyromellitic acid chlorides.

Matl997 Matthews, J. and Rivero, R.A., Base-Promoted Solid-Phase Synthesis of Substituted Hydantoins and Thiohydantoins, J. Org. Chem., 62 (1997) 6090-6092. 

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