Imidazolines, alkylative cyclization

Deprotonation of amidinium salts gives 1,1-enediamines112 and the method is well suited for the preparation of simple cyclic 1,1-enediamines18, 41. 4,5-Dihydroimidazolium salts 99, prepared easily by alkylation of imidazolines or cyclization of ethylenediamine with orthoesters, react with sodium hydride to afford 2-alkylideneimidazolidines 100 in good to excellent yields (equation 34)18. 

A Cu(OTf)2-mediated highly regioselective S v2-type ring opening followed by C N alkylative cyclization of alkyl and substimted A-tosylaziridines 228 with nitriles to synthesize substituted imidazolines 229 with moderate-to-good yields has been reported by Ghorai et al. (Scheme 40.48). "... 

Imidazolines are also formed in silver cyanide-catalyzed cyclization of alkyl isocyanides with aliphatic diamines (Scheme 103).169 This simple synthesis can be applied in a general way with difunctional nucleophiles and has been used to prepare benzimidazoles, oxazoles, thiazoles, and oxazines.169 It is suggested that transient carbene complexes are formed in these reactions (cf. 87 in Scheme 103) but further work is required to ascertain the mechanism and scope of these processes. 

Nitrogen cationic surfactants can also be created by the use of difunctional small molecule amines which, after formation of an amide or ester bond, leave an amine residue which is suitable for quaternization as shown in eqs 6.1.9-6.1.11. The amine residue is then reacted with a suitable alkylating agent to form the cationic. Similarly, reaction of a triglyceride with diethylene triamine gives initially the diamide which, under appropriate conditions, can be cyclized to imidazoline [16] ... 

The earliest method of this type was the old Marckwald synthesis (1] in which a suitable a-aminocarbonyl compound is cyclized with cyanate, thiocyanate or isothiocyanatc. More recent modifications have employed the acetals of the a-amino aldehyde or ketone or an a-amino acid ester. The two-carbon fragment can also be provided by cyanamide, a thioxamate, a carbodiimidc or an imidic ester. When cyanates, thiocyanates or isothiocyanates are used, the imidazolin-2-ones or -2-thiones (1) are formed initially, but they can be converted into 2-unsubstituted imidazoles quite readily by oxidative or dehydrogenative means (Scheme 4.1.1). The chief limitations of the method arc the difficulty of making some a-aminocarbonyls and the very limited range of 2 substituents which are possible in the eventual imidazole products. The method is nonetheless valuable and widely used, and typically condenses the hydrochloride of an a-amino aldehyde or ketone (or the acetals or ketals), or an a-amino-)6-ketoester with the salt of a cyanic or thiocyanic acid. Usually the aminocarbonyl hydrochloride is warmed in aqueous solution with one equivalent of sodium or potassium cyanate or thiocyanate. An alkyl or aryl isocyanate or isothiocyanate will give an A-substituted imidazole product (2), as will a substituted aminocarbonyl compound (Scheme 4.1.1) [2-4]. 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

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). 

Other similar methods which involve cyclization of iV-substituted diaminoalkenes or -alkanes include the preparation of 2-alkyl- and 2-acyl-l-methylimidazole-4-carboxylates from methyl (Z)-j -dimethylamino-a-isocyanoacrylate (191) in reaction with an alkyl or acyl halide <82LA2093>, the preparation of perfluorinated 3-imidazolines (192) <83S169>, the high yield synthesis of 2-imidazolines by decay of phosphaza compounds (193) in a version of the intramolecular Staudinger reaction <85T793>, and the formation of 1,3-diaroylimidazolidines (34-71%) when bis-alkylidene-or -arylidene-ethylenediamines react with acid chlorides in polar solvents (Scheme 129)... 

The role of acid in influencing the cyclization of 14 with imines towards imidazolines products is at present unclear. One possibility is suggested by the work of Ferraccioli and Croce (16), who have shown that the electronic nature of the imine can have a significant influence upon its reactivity with Munchnone. In particular, while N-alkyl substituted imines react with Munchnones to form (3-lactams, more electron poor imines, such as the N-tosyl substituted substrates, have been found to undergo a 1,3-dipolar cyclization with 14 to form imidazoles. (16) In our case, the role of acid may be in protonation of the imine substrate, thereby creating a more electrophilic C=N which can undergo a dipolar cycloaddition with 14 (path A, Scheme 2). Subsequent heterolysis of the C-0 bond in 18, would yield the observed imidazoline-carboxylate 17. 

Nitrogen derivatives can be made directly from fatty acids and esters by reaction with polyamines and alcoholamines. Reaction of fatty acids with polyamines such as diethylenetriamine or aminoethylethanolamine leads to the formation of amidoamines, which can be cyclized through further condensation to give alkyl imidazolines [12-15]. Condensation with dimethylaminopropylamine affords alkylamidodimethylaminopropy-lamines, which are popular precursors to betaines and amine oxides (Figure 2.2). While imidazolines and amidoamine derivatives have lost ground to esterquats in fabric... 

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