2- - imidazolidine derivatives

The preparative value of this compound lies in the surprising fact that bis(l,3-diphenylimidazolidinylidenc-2) behaves in many reactions ie.g., with aromatic aldehydes,2,7 and with carbon acids 2 7-fJ) as if it dissociated to form a nucleophilic carbene. The hydrolytic cleavage of these derived imidazolidine derivatives makes possible the preparation of formyl compounds, so that the amino olefin can be considered as a potential carbonyla-tion reagent. In many reactions it is not necessary to isolate... 

Rogers, J. A. Choi, Y. W., The liposome partitioning system for correlating biological activities for imidazolidine derivatives, Pharm. Res. 10, 913-917 (1993). 

Niridazole Niridazole, l-(5-nitro-2-thiazolyl)-2-imidazolidinone (38.1.11), is made by reacting 2-amino-5-nitrothiazol with 2-chloroethylisocyanate to make the disubstituted urea (38.1.10). Heating this compound results in an intramolecular N-alkylation reaction to form the desired imidazolidine derivative, niridazole [7-11]. 

This strategy was further developed so as to prepare the quinolizidine polyol 155 (315), by separating the racemic furoisoxazoline acetals (21,82,293,294) derived from the imidazolidine derivatives, which in turn, were obtained from (15, 25)-diphenylethylenediamine (316) (see Scheme 6.78). Aminal hydrolysis led to aldehyde 153, and this was followed by aldehyde reduction and catalytic hydrogenation (221,313) to give (-l-)-deoxynojirimycin (natural). Its enantiomer was... 

Table 14. F Chemical Shift (C6D6) of the Two CFj-Signals of Diastereomeric Imidazolidines Derived from Selected Aldehydes (Data Adapted from ref 65)...

The optically pure bis-naphthalene ortho-methoxy amide 117 cyclized to the l,4-diazepin-5-one 118 in 86% yield and with >95% ee upon refluxing in ethylenediamine for 5 h to provide the first axially chiral 1,4-diazepine derivative (Scheme 64) <2000SL1616>. This example of a type g ring closure in which the leaving group is MeOH, proceeded in lower yield with an ot/ o-hydroxy substituent, with product distribution largely redirected toward an imidazolidine derivative in which the ethylenediamine reacted solely with the ester. In the structurally simpler salicylic acid ester series, activation of the phenol as the trifluoromethanesulfonate facilitated the SnAr reaction <1995TL7595>. 

When tetrahydropyridopyrimidine-3-carboxylate 562 (R = COOEt, R1 = H) was treated with carbon disulfide in the presence of potassium hydroxide at 25-30°C, salt 569 was obtained in good yield (79NEP79/ 3401 82USP4321377). The alkylation of569 with dimethyl sulfate and with ethylene dibromide in ethanol afforded 9-dithioester 570 and 9-(dithiolen-2-ylidene) derivative 571, respectively. When 569 was heated in acetic anhydride for 2 hours, bis product 572 was obtained in 57% yield. 9-Imidazolidine derivative 573 was prepared from both iminium chloride 563 (R = COOEt, R1 = H, R2 = Me) and 9-dithioester 570 by treatment with ethylenediamine (Scheme 37) (79NEP79/3401 82USP4321377 83MIP1). 

Literature reports on iron-catalyzed alkene diamination are scarce. Li et al. described the synthesis of imidazolidine derivatives with an FeCl3-PPh3 complex. As substrates, a, 3-unsaturated ketones and a,P-unsaturated esters were used. The products were obtained in good to high yields and with excellent stereoselectivity (Scheme 3.18). Interestingly, the iron catalyst system worked much better than a previously described rhodium catalyst. Furthermore, the iron catalyst is inexpensive and easier to handle because it is less hygroscopic [104],... 

Besonders reaktionsfahig sind 4.4-disubstituierte 2-Trifluormethyl-A2-oxazolinone-(5). Sie wurden von Kenner und seiner Schule los.ios.iis) zur Synthese von Peptiden sterisch stark gehinderter Aminosauren be-nutzt und reagieren selbst mit Inaminen oder Dicyclohexylcarbodiimid, wobei in einer Art Einschubreaktion N-Acyl-2.3-dihydropyrrolone-(3) (29) 175> oder Imidazolidin-Derivate (30) 85> entstehen ... 

Scheme 12.19 Formation of 1,3-d iacety 1-4-i m ida/.oline from imidazole and its hydrogenation to imidazolidine derivative.

Imidazolidine-derived organolithium compounds 468 have been prepared by deprotonation of the corresponding IV-acylated imidazolidines with two equivalents of s-BuLi at — 78 °C. The best results have been obtained with the fraws-l,2-diaminocyclohexane-derived imidazolidine 472, so its anion 473 reacted with different electrophiles to give compounds 474 in moderated yields, which gave the expected hydrazones 471 as described above (Scheme 124)676,677. Other imidazolidines suffered deprotonation at the 4-position... 

In an investigation by Wehner (2), imidazolidine derivatives, (II), were effective as integrin antagonists and used in treating rheumatoid arthritis or allergic diseases. 

Urea- and L-aspartyl-L-glycine imidazolidine derivatives, (III) and (IV), prepared by Wehner (5,6), respectively, were effective as leukocytes inhibitors and used in treating rheumatoid arthritis and allergic diseases. 

Table 1 Selected imidazolidine derivatives and their corresponding melting points...

Additional 2-imidazolidine derivatives, (I), effective as a1L-adrenoreceptor agonists were prepared by the authors (1) in earlier investigations and used in the treatment of stress incontinence in women. 

Both the mechanism as well as the stereochemical course of the pho-tochcmically induced cyclization of a large series of phthalimide Mannich bases (331, Fig. 128) have been accurately investigated. It has been found that the main reaction is bond formation between the carbonyl and the C-a atom of the substituent linked to the amino group. This produces the imidazolidine derivative 332, although in some cases the formation of complex mixtures of products is observed. The phthalimide Mannich base 331 can be used in the synthesis of pcrhydrooxadiazole.s and perhydrobenzodiazepines as well. 

Sodium borohydride converts 4//-imidazole N-oxides into 1-hydroxy-imidazoline or -imidazolidine derivatives. Under the same conditions 1,3-dioxides form 1,3-dihydroxy-imidazolidines (76CHE1280). 

Ring-chain isomerism can be observed in some imidazolidine derivatives. This is the specific case of equilibrium between an imine and an aminol. Substituent influence on this isomerization has been investigated by various spectroscopic methods. 

It would not be imprudent to say that most imine cycloadditions have been discovered unexpectedly during investigations on the generation of azo-methine ylides. As already discussed (Section II,C), imines 60, formed by the condensations of diethyl aminomalonate with aromatic aldehydes, quickly isomerize into highly stabilized azomethine ylides 61, which are all trapped by the imine 60 to give imidazolidine derivatives 217 (80TL2197). It has also been described above (Section II,E) that the iminium salt 75 (R = OMe, EWG = CN), formed in the N-alkylation of 6,7-dimethoxy-3,4-dihydroiso-quinoline with chloroacetonitrile, quickly loses a proton generating stabilized... 

The oxide function can be removed using phosphorus trichloride, or phosphorus oxychloride, by reduction with hydrogen and Raney nickel" with sodium borohydride, and with hexachlorodisilane in chloroform. The reduction of 4H-imidazole N-oxides with borohydride leads to the 1-hydroxyimidazoline or imidazolidine derivatives under the same conditions 4if-imidazole JV,N -dioxides give 1,3-dihydroxy-imidazolidines. ... 

With phenyldiazomethane as a carbene precursor, a satisfactory yield of imidazolidine derivative 532 is achieved only in the reaction with N-benzylidenemethylamine (84T2569). Imidazole derivatives, albeit in very... 

In a analogous way, Leu-enkephalin and Met-enkepha-lin were rendered resistant to aminopeptidases by condensation with various aldehydes and ketones to form 4-imidazolidine derivatives (Figure 41.9). 

Imidazolidine derivative 9 was obtained by the borohydride reduction of the corresponding A2-imidazolinium cation precursor formed by the condensation of the acetonide of the ethyl ester of D,L-glyceric acid and 1,1-dimethyl-1,2-diamine followed by acetylation and methylation (80H947, 83T3987). 

The carbanion derived from methyl homophthalate adds to 3a to provide a mixture of imidazolidine derivative 14a and its enaminic (aminostyrene) acyclic tautomer 14b. Likewise, a mixture of homologous perhydropyrimidine 16a and enamine (aminostyrene) 16b was formed by addition of the same carbanion to l-methyl-3-tosyl-tetrahydropyrimidinium cation (15). The stereochemistry of the products has been adequately established (85T3355). 

One of the most interesting diaminomethanes that has been investigated is a model for the coenzyme tetrahydrofolate (3), a biological one-carbon transfer agent. The mechanism of its conversion into the imidazolidine derivative /V, yV °-methylenetetrahydrofolate (4) has been studied. The pH rate profile apparently results from a change in the rate-determining step with changing acidity. Secondary amines such as morpholine and imidazole catalyze the reaction between tetrahydrofolic acid and formaldehyde via a... 

A self-condensation of 2-(2-aminomethylarseno)benzaldehyde (protected by its imidazolidine derivative) gave the diarsenic-containing macrocyclic bis Schiff base as a pure diastereoisomer (method AD-2) (Martin et al., 1988). 

This type of cyclization has been used mainly to prepare imidazo[2,l-fe]thiazoles and imidazo[l,2-6]pyrazoles (Schemes 13 and 14). Base-catalyzed cyclizations of 2-(cyanoimino)thiazolidines (124) afforded imidazo[2,l-6]thiazoles (126) via intermediates (125). Cyclization of (124) only occurs when R is an electron withdrawing group <885261 >. Imidazo[l,2-6]pyrazoles have been prepared from suitably substituted imidazolidine derivatives <80JHC1413>. The imidazolidine (127), prepared in 5 stages from 2-imidazolidine thione, was subjected to a hydrazinolysis reaction initiated by 2,4-dinitrophenylhydrazine to give a mixture of imidazo[l,2-fe]pyrazoles (129) and (130) and the hydra-zone (128). 

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