Synthesis of hydantoins

Another method for the synthesis of hydantoins is the cyclization of A-(l-benzo-triazolylcarbonyl)phenylalanine butylamide.[147 ... 

Finally, another related study from the Sun laboratory concerned the synthesis of hydantoins utilizing acryloyl chloride to prepare a suitable polymer support [87]. All steps were carried out under reflux conditions in a dedicated microwave instrument utilizing 50-mL round-bottomed flasks. Identical reactions under classical thermal heating did not proceed in the same time period. 

A phase-transfer catalysed nucleophilic displacement reaction on chloro-acetanilides by cyanate ions, followed by ring-closure (Scheme 5.10), provides a simple and viable synthesis of hydantoins [41], The formation of the hydantoins is inhibited by substituents in the orf/to-position of the aryl ring, but the addition of potassium iodide, or tetra-n-butylammonium iodide, generally increases the overall rate of formation of the cyclic compounds, presumably by facilitating the initial nucleophilic substitution step. 

Kim80 reported recently a convenient synthesis of hydantoin derivatives (41) by PTC-catalyzed nucleophilic substitution, followed by cyclization. 

Cyclative cleavage to five- and six-membered ring heterocycles is dominated by the synthesis of hydantoins and diketopiperazines, respectively. In the seven-membered ring case, it is the benzodiazepine nucleus that has attracted attention, due to its status as a privileged structure in drug discovery. In the precombinatorial days, Camps et al,33 reported a... 

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

Dressman BA, Spangle LA, Kaldor SW, Solid phase synthesis of hydantoins using a carbamate linker and a novel cyclization/cleavage step, Tetrahedron Lett., 37 937-940, 1996. 

Scheme 1 Synthesis of hydantoins by cyclative cleavage of an ester bond on Merrifield resin.

Scheme 3 Synthesis of hydantoins with three dimensions of diversity.

A newer method [26] switched to N-terminal (rather than C-terminal) attachment of the amino acid building blocks and to a base- (rather than an acid-) catalyzed cyclative cleavage strategy. In contrast to the first published method for the solid-phase synthesis of hydantoins [12], which relied on isocyanates for derivatiza-... 

Habermeier also pointed out the ready synthesis of hydantoins from aldehydes or ketones the substituents in the 5-position of the ring were thus determined by the carbonyl compound used as starting material. Most of the examples cited had methyl, ethyl, or cyclopentamethylene substitution in the 5-position. Data were presented on the properties of cured resins with these substituents and with a broad variety of the other structural features mentioned. 

Figure 18 Synthesis of hydantoins 28 and thiohydantoins 29 from resin-bound dipeptides.

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). 

Finally, another related study achieved the synthesis of hydantoins by using acryloyl chloride to prepare a suitable polymer support under reflux conditions in a dedicated microwave instrument [88]. The soluble polymer support was dissolved in dichloromethane and treated with chloroacetyl chloride for 10 min under the action of microwave irradiation. Subsequent nucleophilic substitution using a variety of primary amines was carried out in N,N-dimethylformamide as solvent. The resulting PEG-bound amines were reacted with aryl or alkyl isothiocyanates in dichloromethane to furnish the polymer-bound urea derivatives after microwave irradiation for 5 min (Scheme 16.58). Finally, traceless release of the desired compounds by cyclative cleavage was achieved under mild basic conditions with micro-wave irradiation for 5 min. The 1,3-disubstituted hydantoins were obtained in varying yields but high purity. 

More recently, based on a Bucherer-Bergs protocol, Conway and coworkers have developed a one-pot gallium(III) triflate-catalyzed synthesis of 5-substituted and 5,5-disub-stituted hydantoins 31 from the corresponding aldehydes and ketones in CH Clj (Scheme 10.7) [30], This one-pot synthesis of hydantoins avoids the difficulty associated with the isolation and purification of the a-aminonitrile intermediate in these processes. 

SCHEME 10.9 Synthesis of hydantoins 2 using organolithium compound and Grignard reagents. 

A rapid and efficient microwave-assisted synthesis of hydantoins and thiolydan-toins was reported by Muccioli et al. [74], The reaction is known as Biltz synthesis and is the base-catalysed condensation of benzil and urea. It was observed that microwave irradiation reduced the reaction time as well as increased the yield of the product as compared to the conventional method. The reason behind this is the involvement of polar transition state, i.e. nucleophilic addition of a neutral NH2 group to a carbonyl site (Scheme 11.21). The yield via the conventional method was 36 % when heated for 2 h whereas the yield via microwave irradiation was 80 % when heated only for 30 min. 

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... 

Synthesis of Hydantoin Cores from UREAyTmouREA-LiKE Intermediates. There are many reports on the solid-phase synthesis of five-atom heterocycles having two nitrogen... 

---