Nitrogen hydantoin

Bridgehead nitrogen hydantoins have been obtained from imidazole-, pyrrolidine-, and piperidine-2-carboxylates,19 as well as spirohydantoins, such as 15, derived from the aminolysis products of isatincarboxamides.20 Amino nitriles react in a similar manner.1,3,21,22... 

Hydantoins can react with electrophiles at both nitrogen atoms and at C-5. The electrophilic carbonyl groups can be attacked by nucleophiles, leading to hydrolysis of the ring or to partial or total reduction of the carbonyl system. Other reactions are possible, including photochemical cleavage of the ring. 

The imide proton N-3—H is more acidic than N-1—H and hence this position is more reactive toward electrophiles in a basic medium. Thus hydantoins can be selectively monoalkylated at N-3 by treatment with alkyl haUdes in the presence of alkoxides (2,4). The mono-A/-substituted derivatives (5) can be alkylated at N-1 under harsher conditions, involving the use of sodium hydride in dimethylform amide (35) to yield derivatives (6). Preparation of N-1 monoalkylated derivatives requires previous protection of the imide nitrogen as an aminomethyl derivative (36). Hydantoins with an increased acidity at N-1—H, such as 5-arylmethylene derivatives, can be easily monoalkylated at N-3, but dialkylation is also possible under mild conditions. 

One of the earliest preparations of this ring system starts with displacement of the hydroxyl of benzaldehyde cyanohydrin (125) by urea. Treatment of the product (126) with hydrochloric acid leads to addition of the remaining urea nitrogen to the nitrile. There is thus obtained, after hydrolysis of the imine (127), the hydantoin (128). Alkylation by means of ethyl iodide affords ethotoin (129)... 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

Hydantoin (5.2 g, 52 mmol) was added to piperidine (9.9 mL, 100 mmol) in a twonecked reaction flask equipped with a magnetic stirrer bar and heated to 130 °C under nitrogen flux. 4-Fluorobenzaldehyde (5 mL, 47 mmol) was added dropwise to the stirring mixture. The reaction was monitored by TLC (eluent ethyl acetate/cyclohex-ane, 1 4) and reached completion in 30 min. 

Attention. At room temperature hydantoin is insoluble in piperidine, but it will dissolve at approximately 80 °C. Nitrogen is required to remove any traces of oxygen, but the reaction does not need to be moisture-free. 

Alkylation of the hydantoin (89-2) from benzaldehyde with ethyl iodide takes place at the imide nitrogen to afford ethitoin (89-3) [93]. In much the same vein, treatment of the hydantoin (89-5) from propiophenone with methyl iodide (89-5) in the presence of a base affords mephenytoin (89-6) [94]. Replacement of the quite acidic imide proton by an aUcyl group is not required for activity the well-known anticonvulsant phenytoin (89-8) consists of simply the hydantoin obtained from benzophenone (89-7) [95] this is often formulated as its sodium salt. 

A variety of heterocyclic systems have been used for forming merocyanines. The more usual nitrogen-containing heterocycles involved include benzimidazole, quinoline, ben-zothiazole, benzoselenazole, thiazole, thiazoline and indolenine. Among the more useful carbonyl-containing heterocycles are derivatives of 2-pyrazolin-5-one, 2-thiobarbituric acid, rhodanine and hydantoin. 

Hydantoins are crystalline solids with high melting points, particularly those compounds in which nitrogen is unsubsUtutcd. because this allows intermolccular association by hydrogen bonds. Hydanloins are weak acids... 

The search for other amino acid-based catalysts for asymmetric hydrocyanation identified the imidazolidinedione (hydantoin) 3 [49] and the e-caprolactam 4 [21]. Ten different substituents on the imide nitrogen atom of 3 were examined in the preparation, from 3-phenoxybenzaldehyde, of (S)-2-hydroxy-2-(3-phenoxy-phenyl)acetonitrile, an important building block for optically active pyrethroid insecticides. The N-benzyl imide 3 finally proved best, affording the desired cyanohydrin almost quantitatively, albeit with only 37% enantiomeric excess [49]. Interestingly, the catalyst 3 is active only when dissolved homogeneously in the reaction medium (as opposed to the heterogeneous catalyst 1) [49]. With the lysine derivative 4 the cyanohydrin of cyclohexane carbaldehyde was obtained with an enantiomeric excess of 65% by use of acetone cyanohydrin as the cyanide source [21]. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

Analytical Properties Higher selectivity for nitrogen-containing racemates than fl-/V-(3,5-dinitrobenzoyl) phenylglycine examples of nitrogen-containing racemates include succinimides, hydantoins, and mandelates Reference 41... 

There were a number of new nitrogen sources for the AA introduced, such as tert-butylsulphonamide [17], primary amides [18] and N-bromobenzamide [19]. The combination of urethanes as the nitrogen and l,3-dichloro-5,5-dimethyl hydantoin as a co-oxidant/... 

In the second major class of amine derivatives, the amidic nitrogen atom can also be A-arylatcd when the sodium salt of the amides is treated with /wra-tolyllead triacetate 58 in CH2C12-DMF at 60-80 °C under mild conditions113,114 (Equations (91)-(93)). Amides as well as sulfonamides, imides, or hydantoins reacted with aryllead triacetates under copper(ll) catalysis, to afford good to excellent yields of the derived A-arylamidcs. In general, better yields were obtained when the sodium salt of the amide was used. For these amidic substrates, the reactions are... 

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