Imidazolines, 2-amino— from

Catalysts In the last decade, several catalysts have been developed based on the concept of chiral secondary amines bearing a bulky substituent. MacMillan and coworkers have developed a family of chiral imidazolines derived from a-amino acids (Scheme 33.3). 

A-Acetimidoyl groups have been found in several LPS from Pseudomonas species. It is generally N-3 of a 2,3-diamino-2,3-dideoxyhexuronic acid residue, as in 43, that carries this group, which was originally mistaken for an imidazoline grouping. It has also been found linked to 2-amino-2,6-di-... 

Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have been widely reported in the literature. Bazureau showed that imidates derived from a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-additions with imino-alcohols 121 in the absence of solvent under microwave irradiation. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122 (Scheme 9.36) [87]. 

The one-step synthesis of further tri- and tetracyclic pteridine derivatives from 2-aminopyrazine 153 has also been described <2001JHC1173>. Cyclic analogues of A -[bis(methylthio)methylene]amino reagents such as 2-(methylthio)-2-thiazoline, 5,6-dihydro-2-(methylthio)-4//-l,3-thiazine, 2-(methylthio)-2-imidazoline, 2-(methylthio)-l,4,5,6-tetrahydro-pyrimidine, 2-(methylthio)-2-pyrazine, and 2-chloropyrimidine reacted with aminopyrazine 153 to afford thiazolo/thia-zino[2,3-3]- 159 ( = 1 (53%), n = 2 (42%)), imidazo/pyrimidino[2,l-/ ]- 160 ( = 1 (53%), = 2 (57%)), pyrazino[2,l-/ ]-161 (21%), and pyrimido[2,l-/ ]-pteridine 162 (42%) derivatives, respectively. 

Schollkopf et al.187) synthesized a-alkyl-a-amino acids (186) by the alkylation of chiral 1-substituted 2-imidazolin-5-ones (185), which can be prepared from a-amino acid (S)-phenylethylamides and orthoformic esters. The optical yields of the products (186) were in many cases higher than 95 %. 

Support-bound 1,2-diamines can be readily converted into imidazolidinones by treatment with carbonyl diimidazole [128,129]. The required diamines have been prepared on cross-linked polystyrene by reduction of peptides bound to MBHA resin with borane. Similarly, bicyclic imidazolines have been prepared from triamines and thiocarbonyl diimidazole (Entry 10, Table 14.3). Dehydration of polystyrene-bound monoacyl ethylene-1,2-diamines yields 4,5-dihydroimidazoles (cyclic amidines, Entry 5, Table 13.18). Several groups have reported the synthesis of 2-aminoimidazol-4-ones from resin-bound amino acid derivatives (e.g., Entry 6, Table 15.11). Most of these compounds are, however, unstable, and slowly decompose if dissolved in DMSO (Jesper Lau, private communication). 

Due to the interaction between the two amino groups, 1,1-enediamine 4 would adopt a perpendicular conformation which impairs attack on the rc-system from both sides of 4. If 1,1-enediamine 4 would have a planar configuration, it would show greater reactivity than ketene N,S- or JV, 0-acetals. This has been convincingly demonstrated by comparing the reactivity of l,3-dimethyl-2-(methylene)imidazoline (3) with 4, and with ketene N,S- or N, 0-acetals. 

Recently a new bromo compound was isolated from the Red Sea sponge Acanthella auzantiaca. X-ray analysis established the structure 4-(2-amino- 4-oxo-2- imidazolin-5-ylidene)-2-bromo- 4,5,6,7-tetrahydropyrrolo [2,3-c]azepin-8-one which shows structural relationship with (mono-bromo)oroidin (182b). 

Aminoimidazole has been isolated from the seeds of Mundulea sericea (Willd.) A. Chev., a leguminous shrub from tropical Africa and Asia (233). The alanyl derivative of 2-aminoimidazole, enduracididine (165), and 2-[2-amino-2-imidazolin-4-yl]acetic acid have been obtained from the seeds of the legume Lonchocarpus sericeus (Poir) H.B. and K., native to the West Indies, tropical America, and West Africa (234). 

The earliest method of this type, developed by Marckwald, employed the reaction of a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates to give 3//-imidazoline-2-thiones. These compounds can be converted readily into imidazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and the limited range of 2-substituents which are introduced. The reduction of a-amino acids with aluminum amalgam provides one source of starting materials. The method has been applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone (70AHC(12)103), and to the synthesis of pilocarpine (84 Scheme 47) (80AHC(27)24l). If esters of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and 2-thiohydantoins, respectively. 

Racemization of Amino Acids. The synthesis of (7 )-alanine was achieved starting from (S)-alanine via formation of the imidazoline with (S)-proline. This result can he explained in terms of epimerization and stereoselective protonation with asymmetric induction hy the chiral center originating from (S)-proline. 

The isomeric 1-suhstituted imidazole-5-carboxylates are made by cyclization of 3-amino-2-alkylaminopropanoic acids with triethyl orthoformate followed by active manganese dioxide oxidation of the imidazoline product (see Section 3.1.1), or from IV-substituted glycine esters, which are formylated, converted into the enolates and then condensed with potassium thiocyanate... 

In the uncondensed imidazoles the standard method reacts an a-aminocarbonyl compound with a thiocyanate (see Section 4.1 and Table 4.1.1). If a 2-alkylthioimidazole is required directly, one can combine an N-alkyT or A -arylcarbonimidodithioate in refluxing acetic acid with the aminocarbonyl substrate (see Section 4.1 and Scheme 4.1.3). Alternatively, reaction between thiourea and a two-carbon synthon (ot-hydroxy-, a-halogeno-, a-dicarbonyl) leads to imidazoline-2-thiones (see Section 4.3). In sulfuric acid, 3-butynylthiourea cyclizes to 4,5-dimethylimidazolin-2-thione (see Section 2.2.1). 1-Substituted 2-methylthioimidazoles can be made, albeit in rather poor yields, from appropriately substituted 2-azabutadienes (see Section 3.2 and Scheme 3.2.3), and 2-arylthioimidazoles are available in moderate yields from benzyl isocyanides and arylsulfenyl chlorides (see Section 4.2 and Scheme 4.2.12). Ring transformations of 5-amino-2-alkylaminothiazoles and 2-acylamino-5-aminothiazoles may have occasional applications (see Section 6.1.2.7). The ease with which a thiol group or imidazole or benzimidazole can be alkylated, in comparison with the annular nitrogens, usually makes it more convenient to prepare alkylthioimidazoles from the thiols (or thiones). 

Enantiopure 1,4-disubstituted 2-imidazolines 1179 can be prepared from chiral P-amino alcohols 1175. The acylated alcohols, iV-hydroxyethylamides 1176, are reacted with excess thionyl chloride (or with thionyl chloride followed by phosphorus pentachloride) to yield A -chloroethylimidoyl chlorides 1177. Treatment of 1177 with amines or anilines produces iV-chloroamidines 1178, which were converted into imidazolines 1179 upon work-up with aqueous hydroxide (Scheme 287) <2002JOC3919>. 

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