Disubstituted 2-Imidazolin-5-ones

In the unsubstituted imidazolin-4(5)-ones the number of possible structures is greatly increased. Although there are only three possible forms (41-43 X = 0) for the 5,5-disubstitufed compounds, there are eight alternative forms (44-51 X = 0) for the 2,4-disubstituted imidazolin-5-ones (Scheme 17). 2-Methyl-5,5-diphenyl- and 2,5,5-triphenyI-imidazoIin-4-one both have IR spectra in the solid state which show absorptions belonging... 

In many cases the synthesis of NHC complexes starts from iV,A/ -disubstituted azolium salts. Imidazolium salts as precursors for imidazolin-2-ylidenes are generally accessible by two ways complementing each other (i) nucleophilic substitution at the imidazole heterocycle or (ii) a multicomponent reaction building up the heterocycle with the appropriate substituents in a one-pot reaction. 

The organolithium compounds, formed by deprotonation of Af-benzylic-Af-Boc p-anisole carbamates, react with imines to yield tran5-4,5-disubstituted 1,3-imidazolin-2-ones in good yield and excellent stereoselectivity (Scheme 52). Benzaldehydes gave poor stereoselectivity, and the nse of imines as electrophiles is critical. The stereoselectivity can be explained by the transition states shown, in which the aryl and R substituents on the 4-membered ring are trans to one another. 

Disubstituted thiohydantoins can be oxidized by permanganate to 5//-2-imidazolin-4-ones. 

A modification of this method, which produces 2-aminoimidazoles in up to 90% yield, utilizes benzoins and diguanylhydrazine. The 2,2 -azoimidazoles (123) can be catalytically hydrogenated to the 2-amino compounds (Scheme 66) (66RCR122). When the disubstituted guanidine (124) is treated with phenacyl bromide the first product formed is the expected 2-( l-pyrazolyl)imidazole (125), but subsequent hydrolysis of this occurs to give a 57% yield of l-isopropyl-4-phenylimidazolin-2-one (Scheme 66) (70AHC(12)103). Benzamidine hydrochloride reacts with monosubstituted glyoxals to form 2-imidazolin-4-ones. 

A synthetic strategy which leads to 2,4(5)-disubstituted imidazoles utilizes the reaction between 2-aminonitriles and aldehydes. The aldehyde provides the 2-substituent [31, 32]. Thus, 2-methylaminophenylacetonitrile reacts with benzaldehyde to give l-mcthyl-2,5-diphenylimidazoIc (76%) [32]. With orthoformates the products are 2-imidazolin-4(5)-ones. Thus, when aminoacetonitrile hydrochloride is refluxed for 30 min with trimethyl orthoformatc, some 2-imidazolin-4(5)-one is formed (although the reaction is not very efficient — the major product is N-formylacetonitrile) (Scheme 3.1.8) [33, 34]. A rapid method for making //-substituted a-aminonitriles under mild conditions in a one-pot reaction uses an aldehyde, a primary or secondary amine, and trimcthylsilyl cyanide in methanol [35]. 

The previous cycloaddition reaction discussed is believed to proceed through an aldimine anion (19). Such delocalized anions can also be generated by treatment of suitable aldimines with a strong base. Subsequent cyclocondensation with a nitrile produces imidazoles [25-28]. The 2-azaallyl lithium compounds (19) are made by treatment of an azomethine with lithium diiso-propylamide in THF-hexane ( 5 1) (Scheme 4.2.9) [29. To stirred solutions of (19) one adds an equimolar amount of a nitrile in THF at —60°C. Products are obtained after hydrolysis with water (see also Section 2.3). If the original Schiff base is disubstituted on carbon, the product can only be a 3-imidazoline, but anions (19) eliminate lithium hydride to give aromatic products (20) in 37-52% yields (Scheme 4.2.9). It is, however, not possible to make delocalized anions (19) with R = alkyl, and aliphatic nitriles react only veiy reluctantly. Examples of (20) (Ar, R, R, yield listed) include Ph, Ph, Ph, 52% Ph, Ph, m-MeCeUi, 50% Ph, Ph, p-MeCeUi, 52% Ph, Ph, 3-pyridyl, 47% Ph, Ph, nPr, 1% [25]. Closely related is the synthesis of tetrasubstituted imidazoles (22) by regioselective deprotonation of (21) and subsequent reaction with an aryl nitrile. Even belter yields and reactivity are observed when one equivalent of potassium t-butoxide is added to the preformed monolithio anion of (21) (Scheme 4.2.9) [30]. 

Another recent asymmetric amino acid synthesis involves the reaction of a methyl 2-isocyanoalkanoate (5) with I in the presence of -butyllithium or potassium t-butoxide to form the metalated imidazolinones 6 in situ. Alkylation of 6 results in chiral 4,4-disubstituted imidazolinones (7) often in optical yields of 90-1007o. The highest optical yields are obtained when R has a higher priority than R. In this case 7 has the (R)-configuration. Reversal of the priority results in the (S)-configuration. Hydrolysis of 7 to the chiral amino acid 8 requires rather drastic conditions and is best conducted with base. This method was reported for the synthesis of twenty 2-imidazoline-5-ones of type 7. ... 

Chiral imidazoUdin-2-thione or 2-one were prepared from o-glucoseamine by reaction with o,o -disubstituted arylisothiocyanates to give 39 which can be cycHzed to 40 [76]. Thus, a variety of derivatives were prepared carrying different aryl groups and as a consequence of hindered rotation, some of them exist as stable rotamers (Fig. 7). Treatment of 39 with acetic anhydride in pyridine at low temperature gave the respective per-O-acetyl derivative imidazolidine thione, which upon elimination of acetic acid gave the imidazoline thion 41 as a mixture of atropisomers [76]. 

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