Imidazoline, basicity

A -Imidazolines (294 Z = NH) are cyclic amidines and exhibit the characteristic resonance stabilization and high basicity. A -Oxazolines (294 Z = 0) are cyclic imino ethers, and A"-thiazolines (294 Z = S) are imino thioethers both are consequently easily hydrolyzed by dilute acid. 

Quite recently [71] an expeditious solvent-free synthesis of imidazoline derivatives, using basic or neutral alumina under microwave irradiation, was reported. The reaction time was reduced from hours to minutes with improved yield compared with conventional heating. 

The most practical approach is the direct treatment of azolium salts with metal complexes under neutral or basic conditions [39,154-159]. Alternatively, the free carbenes can be generated in the presence of a suitable metal complex by reduction of a carbene precursor, e.g. a thiourea [160]. Stable, uncomplexed imidazoline-2-ylidenes, isolated for the first time in 1991 by Arduengo [161] (for further examples see [162-166]), are also convenient starting materials for the preparation of carbene complexes [167,168]. The corresponding diaminocarbene complexes can be obtained by treatment of the stable diaminocarbenes with transition metal complexes. Finally, at high temperatures many transition metal complexes catalyze the carbon-carbon bond scission of tetraaminoethylenes, forming carbene complexes [169-171]. Examples of such preparations are given in Table 2.8. 

Other (less acidic) ot-substituted isocyano acetates (1, R = H, Me, /Bu, /Pr) [159]. Silver(l) salts (AgOAc) were found to accelerate the reaction, probably by coordination of the terminal NC carbon atom to Ag which increases the a-acidity and NC electrophilicity (Fig. 22). Remarkably, unlike most other reactions reported with a-acidic isonitriles, no additional base or acid is required for the three-component coupling to 2//-2-imidazolines 65. Most likely, the intermediate imine is basic enough to deprotonate the isocyanide. 

The unmodified pyridine ring, in contrast to imidazole or imidazoline rings, is seldom associated with any specific pharmacophoric activity. It does, however, appear in a number of therapeutic agents due to the fact that benzene rings in biologically active compounds can often be replaced by pyridines in spite of the presence of the basic nitrogen atom. The relatively small number of pyridines discussed below thus do not reflect the frequency of their occurrence in therapeutic agents instead, examples have been selected that illustrate some facet of pyridine chemistry. 

Nowadays new imidazolin-2-ylidene substituted Ru-catalysts like 35 are under investigation, which show increasing activity even at low temperatures. Advantageously they show no sensitivity to air or to moisture. Potential activity is expected to result from higher Lewis basicity and steric demand. They give good results even in the synthesis of tetrasubstituted cycloalkenes.12... 

Imidazoline is a simple cyclic amidine and its pKaH value is just what we expect, around 11. Imidazole, on the other hand, is less basic (p.fQtH 7.1) because both nitrogens are attached to an electron-withdrawing sp2 carbon. However, imidazole, with its two nitrogen atoms, is more basic than pyridine (pKaH 3.2) because pyridine only has one nitrogen on which to stabilize the positive... 

It is a general rule that imidazoles and benzimidazoles are resistant to Friedel-Crafts reactions. This is not surprising since such basic compounds must be markedly deactivated in the presence of Lewis acids. Imidazolin-2-ones appear to be an exception and apparently possess sufficient activation to react. Reactions between imidazoles and Af-methylfor-manilide and phosphoryl chloride are also unproductive. With 4,5-diphenylimidazole, phenyl isocyanate at 80 °C gives products of both N- and C-substitution, but in boiling nitrobenzene only the latter (86) is formed. 2-Methyl-4-phenylimidazole gives (87) under the same conditions, and 1,3-diphenylimidazolium perchlorate is transformed by potassium t-butoxide into a ylide which reacts at C-2 with phenyl isothiocyanate. Sufficient activation is present in l-methyl-2-phenyl-4-phenylaminoimidazole for it to react by substitution at C-5 with acetic anhydride (71JOC3368). 

The related Mannich reaction is not common. Under the usual acidic reaction conditions TV-substitution occurs, but this is a reversible reaction in the presence of base. Therefore, in basic medium, C- substituted products accumulate, and all positions can be substituted. 2-Methylimidazole gives 1,4,5-tri, 4,5-di- and 4-mono-substituted products. The observation that with formaldehyde and hydrochloric acid histamine gave (98) is at variance with the apparent requirement for basic medium. Since 1-substituted imidazoles do not react it is likely that the imidazole conjugate base is the reactive species. Unless imidazoles contain activating substituents they are not very susceptible to reaction with aldehydes (except HCHO) and ketones. An exception appears to be the product (99) of interaction between imidazole and hexane-2,4-dione. An activated compound such as 4-methylimidazoline-2-thione gives the 5-dimethylamino compound (100) imidazoline-2-thione gave only the (V-hydroxymethyl product under the same reaction conditions. Imidazolin-4-ones with a free 5-position readily form benzylidene derivatives (B-76MI40701). 

Imidazolines can exist as three possible structures 2-imidazolines (171), 3-imidazolines (172) or 4-imidazolines (173) (Scheme 83). The first-named can exist as a pair of tautomers, but any proton shift in (172) will give (173) by rearrangement. In fact the hydrolysis of Af-unsubstituted 3-imidazolines to a-aminoketones occurs presumably via the 4-imidazoline. 2-Imidazolines are cyclic amidines, and as such exhibit the characteristic resonance stabilization and strongly basic natures of these compounds. Protonation occurs on the unsubstituted nitrogen to give a resonance-stabilized imidazolinium ion. Examples of p/fa... 

The strongly basic 2-imidazolines dissolve in water to give basic solutions and form salts with acids. Although the hydrochlorides tend to be hydroscopic the picrates are well-developed crystalline compounds. 3-Imidazolines, too, form hydrochloride salts readily in anhydrous medium, but these are hydrolyzed with some facility to ring-opened products. The picrates are more stable. 

Imino-4,4-bis(trifluoromethyl)imidazoline 542, obtained from amide 541, undergoes Dimroth rearrangement upon basic work-up giving the less congested isomer 543 that is also stabilized due to extended conjugation (Scheme 124) <1996T11153>. 

Deprotection of the A -alloc group of A -imidazoline 1056 with Pd(PPh3)4 catalyst gives cleanly the desired product 1075 if a basic allyl acceptor is used. In contrast, a mixture of 1057 and 1058 is formed when the acidic allyl acceptor dimedone is used (Scheme 254) <1997TL4359>. 

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