Imidazolines reduction

Some of these compounds show antibacterial activity. Reduction gives 2-[(2-aminoethyl)amino]ethanols which react with organic acids to form amides that, on further heating, cyclize to imidazolines (6). For example, the diamine obtained by reducing (1) reacts with an organic acid (R"COOH) to give... 

Reduction of nitrone groups to hydroxylamines occurs readily with sodium borohydride (201). In particular, the action of NaBHj on l-hydroxy-3-imidazoline-3-oxides (268) leads to 1,3-dihydroxyimidazolidines (269), which on subsequent treatment with hydroxylamine hydrochloride afford 1,2-bishydroxyl-amines (270) (Scheme 2.99) (478). 

Lastly, the electrochemical reduction of 3-imidazolin-5-thiones in an AN solution showed a rather unexpected migration of the aryl group from nitrogen to sulfur [196] occurring under electron transfer, although the mechanism was not strictly proven by the authors (Scheme 40). 

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. 

For example, complex 37 with an imidazolin-2-ylidene and a methyl ligand in cis-position to each other decomposes to yield the 1,2,3-trimethylimidazolium salt 38, Pd°, and cod (Fig. 13) [124], Additional examples for the reductive elimination of 2-alkyl and 2-aryl substituted azohum salts from palladium or nickel NHC complexes have been reported [125, 126]. Today, reductive elimination reactions have been established as one important reaction pathway for the deactivation of catalytically active metal NHC complexes [126, 127]. 

Additional factors which lead to an increased stability of the carbene complexes towards reductive ehmination are the type of NHC ligand and the NA -substitution pattern. The stability of NHC complexes depends strongly on the electronic situation at the carbene center. The oxidative addition of p-tolyl chloride to linear Pd° complexes bearing two unsaturated imidazolin-2-ylidenes (type 5, Fig. 6) or two saturated imidazolidin-2-ylidenes (t3q>e 7, Fig. 6) proceeds readily. The Pd complex with the imidazolin-2-yhdene ligands is stable, while the one with the imida-zolidin-2-ylidene ligands reductively ehminates the C2-arylated imidazolidinium salt [134]. 

A comparative study of the reduction of 4ff-imidazoles and their iV-oxides is shown in Scheme 33. ° Reduction stops at the imidazoline stage even with a large excess (2 1 mol ratio) of borohydride unless a 1-oxide group is present in this case it may proceed further to give an imidazolidine. 

One method used for the control of hypertension is reduction of the impulses flowing from the CNS to the sympathetic nervous system which controls the tone of the cardiovascular system. The veratrum alkaloids do this at doses that are near the emetic dose, and reserpine acts both centrally and peripherally. The imidazoline clonidine (175) and some analogues in which the chlorine is replaced by fluorine or methyl groups decrease sympathetic outflow and cause vasomotor relaxation. However, they cause sedation, lack of saliva and renewed hypertension on withdrawal of the drug. 

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). 

Imidazoline-2,5-dione, 1 -methyl-4-phenyl-reduction, 5, 415 Imidazolines acylation, 5, 425-426 alkylation, 5, 425 corrosion inhibitors, 1, 408 as drugs, 5, 498 lH NMR, 5, 353 hydrolysis, 5, 426 N -oxides synthesis, 5, 463 polymers, 1, 280, 305 reactions... 

Alternatively, the remaining sulfate ester of 70 may serve as a leaving group for a second nucleophilic displacement reaction. When this displacement is by an intramolecular nucleophile, a new ring is formed, as was first shown in the synthesis of a cyclopropane with malonate as the nucleophile [68] and of aziridines with amines as the nucleophiles [76]. The concept is further illustrated in the double displacement on (/J,/ )-stilbenediol cyclic sulfate (72) by benzamidine (73) to produce the chiral imidazoline 74 [79]. Conversion of the imidazoline (74) to (.V,.S )-stilbenediaminc 75 demonstrates an alternative route to optically active 1,2-diamines. Acylation of 75 with chloroacetyl chloride forms a bisamide, which, after reduction with diborane, is cyclized to the enantiomerically pure trans-2,3-diphenyl- 1,4-diazabicy-clo[2.2.2]octane (76) [81],... 

Phentolamine, an imidazoline derivative, is a potent competitive antagonist at both and 2 receptors (Table 10-1). Phentolamine causes a reduction in peripheral resistance through blockade... 

Resistance to reduction processes seems to be a general characteristic as most catalytic methods (as well as sodium in ethanol) reduce only the ring. However hydantoin can be reduced by diisobutylaluminum hydride to imidazolin-2-one (81TL2063), and imidazoline-2-thiones can be prepared from 2-thiohydantoins (70AHC(12)103). Oxidative procedures often result in ring opening (B-76MI4070i). 

When l-hydroxy-3-imidazoline 3-oxides (263) are treated with HCl they dehydrate forming imidazole 3-oxides (Scheme 153) (73CHE1175). Reduction of 4//-imidazole N-oxides with borohydride leads to either 1-hydroxy-imidazolines or -imidazolidines, depending on the position of the oxide function. Under the same conditions 4//-imidazole 1,3-dioxides give 1,3-dihydroxyimidazolidines (76CHE1280). The 4iT-imidazole AT-oxides are prepared by heating 5,5-disubstituted l-acyloxy-3-imidazoline 3-oxides in vacuo. 

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. 

When the dihydro-1,2,4-triazinone (194) is heated at 180 °C under reducing conditions there is rupture of the 1,2-bond followed by ring closure, producing 4,5-diphenyl-imidazolinone (195). Such reductive ring closures of benzotriazine 1-oxides (196) can give benzimidazoles, in particular 2-(4-thiazolyl)benzimidazoles (197) ( thiabendazole ). Similar reactions take place with 1,3,5-triazines. In fact, primary amines cleave the compounds completely with evolution of ammonia and formation of iV.iV -disubstituted formamidines. With suitable primary amines, though, this reaction can be designed to produce imidazolines or benzimidazoles (Scheme 113). 

Reduction of imidazole thiones 940 with Na/K in THF leads to carbenes 941 (Scheme 228) <2003AGE5243>. Under similar conditions, imidazoline 943 is formed from 942 <1999CEJ1931>. The carbene 944 can be obtained if the reaction is conducted in toluene. The intermediacy of a carbene has been proposed for the reaction of 4,4,5,5-tetramethylimidazolidine-2-thione and ( )-valine in the presence of Cso fullerene that leads to the formation of an open [5,6] adduct <1997TL6613>. 

Aldehydes have been used to condense with o-phenylenediamines, o-nitroanilines, or ethylene diamines to afford benzimidazoles and imidazolines. Either an oxidation or a reduction process may be required during the annelation depending on the oxidation state of the starting material. To prepare imidazolines or benzimidazoles from aldehydes and diamines under anaerobic conditions, the system I2/KI/K2CO3/H2O can be used to oxidize a C-N single bond to a double bond (Scheme 302) <2006TL79>. Oxidant K3Fe(CN)5 has also been used to promote similar processes... 

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