Hydantoins isocyanates

Mass spectral fragmentation patterns of alkyl and phenyl hydantoins have been investigated by means of labeling techniques (28—30), and similar studies have also been carried out for thiohydantoins (31,32). In all cases, breakdown of the hydantoin ring occurs by a-ftssion at C-4 with concomitant loss of carbon monoxide and an isocyanate molecule. In the case of aryl derivatives, the ease of formation of Ar—NCO is related to the electronic properties of the aryl ring substituents (33). Mass spectrometry has been used for identification of the phenylthiohydantoin derivatives formed from amino acids during peptide sequence determination by the Edman method (34). 

Synthesis from OC-Amino Acids and Related Compounds. Addition of cyanates, isocyanates, and uiea derivatives to a-amino acids yields hydantoin piecuisois. This method is called the Read synthesis (2), and can be considered as the reverse of hydantoin hydrolysis. Thus the reaction of a-amino acids with alkaline cyanates affords hydantoic acids, which cyclize to hydantoins in an acidic medium. 

The use of an organic isocyanate instead of potassium isocyanate gives a A-substituted hydantoin. 

The silylated glycine derivative 1450 cyclizes spontaneously on heating to 85-140 °C to give the hydantoin derivative 1451 in 94% yield [20, 21]. The silylated hy-dantoin 1453 is obtained by reacting silylated N-carboxymethylglycine 1452 with trimethylsilyl isocyanate 327 and subsequent heating to 140°C [22] (Scheme 9.12). 

A hydantoin structure can be built by the reaction of a primary amine with CDI to an isocyanate (Section 8.1), followed by conversion with an amino acid [146]... 

The described fluorous-tag strategy has also been applied to the synthesis of biaryl-substituted hydantoins (Scheme 7.81) [94]. 4-Hydroxybenzaldehyde was converted into the corresponding perfluorinated species, which was then subjected to a reductive amination. The resulting amine was treated with an isocyanate to produce the fluorous-tagged urea, which spontaneously cyclized to form the corresponding hydantoin. Finally, the fluorous tag was detached by a Suzuki-type carbon-carbon bond formation to furnish the desired target structure in good yield. 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

The oxidation of phenylhydrazine and 1,2-disubstituted hydrazines to hydrazones and diazenes by CI2C proceeds via formation of unstable azomethine imines.95 The conversion of alcohols into alkyl halides is achieved by reaction with CCI4 (or CBr4) in DMF under electrochemical reduction.96 The reaction of dihalocarbene X2C with DMF to form a Vilsmaier reagent (93) is proposed as the key process. The reaction of simple isocyanates (RNCO) with dimethoxycarbene normally gives hydantoin-type products. In the reaction with vinyhsocyanates such as (94), however, hydroindoles (95) are formed in good yields.97... 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

A novel reaction of pyroglutamate (6) and an isocyanate promoted by NaH in THF leads to functionalized hydantoins (7) in good yields. The reaction involves the ring closure of intermediate (8) by a nucleophilic attack on the carbonyl of the ester function followed by expulsion of an alkoxide anion resulting in the formation of the bicyclic intermediate (9). The alkoxide anion in turn can open this bicyclic intermediate with formation of anions (10) and (11) leading to the final racemic hydantoins (7) (Scheme 3).8... 

The technique of parallel synthesis is best illustrated by means of an example. Consider the general theoretical steps that would be necessary for the preparation of a combinatorial library of hydantoins by the reaction of isocyanates with amino acids (Figure 6.7) using a 96 well array. 

Figure 6.7 The reaction of amino acids with isocyanates to form hydantoins...

Scheme 16 shows parallel syntheses of cyclic and acyclic amide compounds. Fluorous benzaldehydes were first subjected to reductive amination reactions. The resulting amines were then reacted with isocyanates to form substituted hydantoin rings 14 or with benzoyl chlorides to form amides 15. Purified F-sulfonates were used for palladium-catalyzed cross-coupling reactions to form corresponding biaryl 16 [31] and arylsulfide 17 [32] products, respectively. 

Resin-bouda-amino esters, besides being traditionally used for making peptides, have served as key intermediates for the construction of various heterocyclic scaffolds. Thus, they react smoothly with isocyanates to form ureas, which upon heating under acidic conditions cyclize to form hydantoins 53 [27]. A one-pot, three-component condensation of resin-bound a-amino esters with aldehydes and a-mercapto acids affords 4-thiazolidi-... 

Disubstituted imidazoles have been N- and C-acylated by aryl isocyanates, leading to imidazo[l,2-c]hydantoins (equation 24) (59CB550,77JOC3925). 

Monosubshtuted hydantoins are a-amino acids cyclically protected at both the carboxyl- and the a-amino group. They can be easily prepared from an aldehyde and isocyanate or by the Bucherer-Bergs synthesis and similar methods. Indeed, the hydantoin synthesis is also a prachcal method for the preparahon of the racemic amino acid. Enzymes belonging to the dihydro-pyrimidinase family hydrolyze hydantoins to the carbamoyl amino acid. The latter can be hydrolyzed in turn to the amino acid by a second enzyme, a carbamoylase. Both enzymes can discriminate between enantiomers and, if their action is cooperative, either the L- or the D-amino acid can be obtained (Scheme 13.10) [36]. What makes the system of special interest is that the proton in the 5-position of the hydantoin ring (it will become the a-hydrogen in the a-amino acid) is considerably more acidic than conventional protons in amino acid esters or amides and much more acidic than the amino acid itself. Thus, the hydantoin can be often racemized in situ at slightly basic pH where the enzymes are stiU stable and active. If these condihons are met. 

The utility of urca.s and thioureas as substrates for making imidazoles is limited by the fact that the imidazole 2-substituent can only be an oxygen or sulfur function. Synthetic methods involving ureas and thioureas will also be discussed in Section 4.1, but some cyclizations of suitably functionalized species fall under the present heading. Appropriately substituted ureas and thioureas can be made from isocyanates and primary amines [36-38], from isocyanates and hydrazines [39] or thiocyanates and hydrazines [40], from or-aminonitrilcs and carbon dioxide [41] and by heating l,3,4-oxadiazol-2-oncs with amino acids [42]. Some of the substrates prepared in these ways, though, lead ultimately to reduced imidazoles such as hydantoins. Cyclizations arc usually acid catalysed, but they can also be thermal [43]. 

Treatment of a-azido esters 1290 with triphenylphosphine gives -phosphazides 1291, which subsequently react with isothiocyanates to afford thiohydantoins 1292 after aqueous work-up. The cyclization conditions can also be adapted to hydantoin synthesis when isocyanates are used (Scheme 328) <2004TL1655>. 

The amino acid ester forms the hydantoin 33 with the isocyanate 41. The free amine 32 attacks the isocyanate carbon and the nucleophilic isocyanate nitrogen in 42 then reacts with the electrophilic ester moiety. The carbonate base prevents protonation of the amine. 

A conceptual alternative way to the activation of the carboxylic acid function is the reaction of carboxylic acids with amino groups activated as isocyanates - and isothiocyanates (equation 16). Preparation of these derivatives is racemization free. The reaction proceeds via mixed acid anhydrides in aromatic hydrocarbon solvents at elevated temperatures, and decarboxylation leads to the V-substituted amide. Pyridine as solvent enhances the conversion rate but increases also the amount of the urea side product via disproportionation. Application to peptide chemistry is limited, because peptide ester fragments tend to form hydantoins. ... 

The formahon of hydantoins represents an early application of the cyclahve cleavage strategy. The group of Hobbs DeWitt presented a synthesis starhng from Merrifield resin-bound amino acid derivahves 1 (Scheme 1). These were N-deprotected and subsequently converted to ureas 2 by reachon with an isocyanate. Treatment with 6 M HCl (83-100 °C, 2 h) gave hydantoins 3 in yields of 4-81%, with two dimensions of diversity [1]. 

A third dimension of diversity in the generation of hydantoins can be introduced as shown in Scheme 3. After coupling of an Fmoc-amino acid to Wang resin and N-deprotection to give 7, a reductive alkylation sequence using aromatic aldehydes was performed (8) before the coupling of an isocyanate (9, X = O). The cleavage... 

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-... 

See Tables of Compounds in Ellis and Honeyman for data on glycosyl isocyanates and isothiocyanates, and glycosyl-urethans, -thiourethans, -hydantoins, -thiohydantoins, and related compounds. 

Thiazoles may also be intermediate in some other imidazole syntheses <87CJC282>. Dimroth rearrangement of 5-aminothiazoles ((255), (256)) gives hydantoin analogues <86BSBll29>. While 2,4-disubstituted thiazole A(-oxides are converted by aryl isocyanates into imidazoles, the 2,5-isomers are unreactive (Scheme 191) <82CPB1722>. 

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