2-Imidazolines

The schemes for preparing imidazolines take advantage of the fact that this heterocyclic system in effect consists simply of a cyclic amidine of ethylenediamine. Thus, treatment of the iminoether (81-1) from phenylacetonitrile with ethylenediamine can be envisaged to result in the initial displacement of ethoxide to give a transient intermediate such as (81-2) internal addition-elimination by the remaining side chain 

A very lipophUic, highly substituted benzene ring provides the side chain for the nasal decongestant a-blocker xylometazoline (82-5). The synthesis of this compound starts with the chloromethylation of the mesitylene derivative (82-1) followed by the displacement of chlorine by cyanide there is thus obtained the arylacetonittile (82-3). This is then converted to the corresponding imidazoline via iminoether (82-4) [86] by the sequence outlined above. 

The a-blocker phentolamine (83-3) was used fairly extensively as an antihypertensive agent prior to the availability of more effective and far better tolerated drugs. Some of the most important side effects from use of this drug, such as fluid retention and tachycardia, were at that time attributed to compensatory mechanisms, casting a cloud on all a-blockers. The use of this class of agents for controlling elevated blood 

The frequently observed bioisosteric relation of benzene and thiophene applies to the clonidine series as well. Reaction of the thiophenyl thiourea (85-1), in which the amine group is flanked by substituents as in the prototype, with methyl iodide and a base gives the corresponding methyl thioether (85-2). Treatment of that intermediate with ethylene diamine leads to the formation of an imidazoline ring and the antihypertensive agent, tiamenidine (85-3) [90], shown as its imino tautomer. 

A compound that includes a carbonyl group on the imidazoline ring is described as sedative. Treatment of the guanidyl substituted amino acid creatine (87-1) with hydrochloric acid results in cyclization to the iminoimidazolinone creatinine (87-2). Condensation of that intermediate with meta-chlorophenylisocyanate (87-3) leads to the formation of a urea by condensation of the reactive function with the imidazole as its amino tautomer. There is thus obtained fenobam (87-4) [92]. 

Kong etaU US Patent 6,734,302 (May 11, 2004) Assignee Hoffman-La Roche Inc. 

Hydrogen chloride gas was passed through a solution of 2,4-dimethoxy benzonitrile (32 mmol) dissolved in 200 ml ethyl alcohol at 0°C 7 hours and the mixture stirred overnight at ambient temperature. The solvent was removed, the residue triturated in diethyl ether, and the product isolated in 57% and used without purification. 

5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-lH-imidazole 

Isobutyryl chloride (0.18 mmol) was added to a solution of triethylamine (0.18 mmol) containing the product from Step 2 (0.164 mmol) and the mixture stirred at ambient temperature 2 hours. It was then diluted with CH2CI2, washed with water and brine, dried, and concentrated. The residue was purified by chromatography using silica gel with 0.5-1% methyl alcohol/CH2Cl2 and the product isolated. MS data supplied. 

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In addition to their antiknock properties, organic lead compounds possess bactericidal properties and motor fuels with lead are known to inhibit bacterial growth during storage in contact with water. With the disappearance of lead-based compounds, it is necessary to incorporate biocides from the cyclic imine family, (piperidine, pyrrolidine, hexamethyleneimine), alkylpropylene diamines or imidazolines (Figure 9.2). 

METHOD 3 [109]—1 part guaiacol and 2.5 parts MesSiSNa in 1,3-dimethyl-2-imidazoline heated at 185°C in a sealed pipe bomb gives 80-96% catechol. 

Although acetonitrile is one of the more stable nitriles, it undergoes typical nitrile reactions and is used to produce many types of nitrogen-containing compounds, eg, amides (15), amines (16,17) higher molecular weight mono- and dinitriles (18,19) halogenated nitriles (20) ketones (21) isocyanates (22) heterocycles, eg, pyridines (23), and imidazolines (24). It can be trimerized to. f-trimethyltriazine (25) and has been telomerized with ethylene (26) and copolymerized with a-epoxides (27). 

Amphoteric Detergents. These surfactants, also known as ampholytics, have both cationic and anionic charged groups ki thek composition. The cationic groups are usually amino or quaternary forms while the anionic sites consist of carboxylates, sulfates, or sulfonates. Amphoterics have compatibihty with anionics, nonionics, and cationics. The pH of the surfactant solution determines the charge exhibited by the amphoteric under alkaline conditions it behaves anionically while ki an acidic condition it has a cationic behavior. Most amphoterics are derivatives of imidazoline or betaine. Sodium lauroamphoacetate [68647-44-9] has been recommended for use ki non-eye stinging shampoos (12). Combkiations of amphoterics with cationics have provided the basis for conditioning shampoos (13). 

Baby Shampoos. These shampoos, specifically marketed for small children, feature a non-eye stinging quaHty. The majority of the products in this category are based on an amphoteric detergent system a system combining the use of an imidazoline amphoteric with an ethoxylated nonionic surfactant has been successfiiUy marketed (15,16). The sulfosuccinates also have been suggested for baby shampoo preparation because of thek mildness... 

The reaction of ethyleneimine with nittiles in the presence of HBF gives A -imidazolines (229). If trichloroacetonitrile [545-06-2] (R = Cl) is used as the nitrile component, the intermediate amidine can be isolated (230). 

Oil field uses are primarily imidazolines for surfactant and corrosion inhibition (see Petroleum). Besides the lubrication market for metal salts, the miscellaneous market is comprised of free acids used ia concrete additives, motor oil lubricants, and asphalt-paving applications (47) (see Asphalt Lubrication AND lubricants). Naphthenic acid has also been studied ia ore flotation for recovery of rare-earth metals (48) (see Flotation Lanthanides). 

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... 

Fats, Oils, or Fatty Acids. The primary products produced direcdy from fats, oils, or fatty acids without a nitrile iatermediate are the quatemized amidoamines, imidazolines, and ethoxylated derivatives (Fig. 3). Reaction of fatty acids or tallow with various polyamines produces the iatermediate dialkylarnidoarnine. By controlling reaction conditions, dehydration can be continued until the imidazoline is produced. Quaternaries are produced from both amidoamines and imidazolines by reaction with methyl chloride or dimethyl sulfate. The amidoamines can also react with ethylene oxide (qv) to produce ethoxylated amidoamines which are then quaternized. 

Fig. 3. Quatemaiies fiom amidoamines and imidazolines where R is a fatty alkyl group.

These compounds and their derivatives can be manufactured using relatively simple equipment compared to that required for the fatty nitrile derivatives. Cyclization of amidoamines to imidazolines requires higher reaction temperatures and reduced pressures. Prices of imidazolines are therefore high. 

Table 5. Application Rates of Sulfonylurea and Imidazoline Herbicides...

Another class of herbicides, the imida zolines, was discovered at American Cyanamid in the early 1980s. Extensive research has led to the development of four commercial compounds imazapyr, imazamethahenz-methyl, imazethapyr, and imazaquin (see Table 5). Like the sulfonylureas, the imidazolines are extremely active at low rates. 

In addition to the mono- and dialkylamines, representative stmctures of this class of surfactants include /V-alkyltrimethylene diamine, RNH(CH2)3NH2, where the alkyl group is derived from coconut, tallow, and soybean oils or is 9-octadecenyl, 2-aLkyl-2-imidazoline (3), where R is heptadecyl, heptadecenyl, or mixed alkyl, and l-(2-aniinoethyl)-2-aLk5l-2-imidazoline (4), where R is heptadecyl, 8-heptadecenyl, or mixed alkyl. 

Oxygen-Cont iiningAmines. This group includes amine oxides, ethoxylated alkylamines, l-(2-hydroxyethyl)-2-imidazolines, and alkoxylates of ethylenediamine. Oxygen-containing amines are steadily increasing in economic importance. 

Ammonium acetate and sodium methoxide are effective catalysts for the ammonolysis of soybean oil (49). Polyfunctional amines and amino alcohols such as ethylenediamine, ethanolamine, and diethanolamine react to give useful intermediates. Ethylenediamine can form either a monoamide or a diamide depending on the mole ratio of reactants. With an equimolar ratio of reactants and a temperature of >250° C, a cyclization reaction occurs to give imidazolines with ethylenediamine (48) ... 

Hydrogen cyanide (HCN) and aliphatic nittiles (RCN) can be used to form imidazolines. For example, EDA and HCN form 2-imidazoline (38). In the presence of sulfur or polysulfides as catalysts, 2-aIkyl-2-imidazolines can be prepared from ahphatic nitriles and EDA (39,40). 

Fabric Softeners, Surfactants and Bleach Activators. Mono- and bisamidoamines and their imidazoline counterparts are formed by the condensation reaction of one or two moles of a monobasic fatty acid (typically stearic or oleic) or their methyl esters with one mole of a polyamine. Imidazoline formation requires that the ethyleneamine have at least one segment in which a secondary amine group Hes adjacent to a primary amine group. These amidoamines and imidazolines form the basis for a wide range of fabric softeners, surfactants, and emulsifiers. Commonly used amines are DETA, TETA, and DMAPA, although most of the polyethylene and polypropane polyamines can be used. 

Many of the surfactants made from ethyleneamines contain the imidazoline stmcture or are prepared through an imidazoline intermediate. Various 2-alkyl-imidazolines and their salts prepared mainly from EDA or monoethoxylated EDA are reported to have good foaming properties (292—295). Ethyleneamine-based imida zolines are also important intermediates for surfactants used in shampoos by virtue of their mildness and good foaming characteristics. 2- Alkyl imidazolines made from DETA or monoethoxylated EDA and fatty acids or their methyl esters are the principal commercial intermediates (296—298). They are converted into shampoo surfactants commonly by reaction with one or two moles of sodium chloroacetate to yield amphoteric surfactants (299—301). The ease with which the imidazoline intermediates are hydrolyzed leads to arnidoamine-type stmctures when these derivatives are prepared under aqueous alkaline conditions. However, reaction of the imidazoline under anhydrous conditions with acryflc acid [79-10-7] to make salt-free, amphoteric products, leaves the imidazoline stmcture essentially intact. Certain polyamine derivatives also function as water-in-oil or od-in-water emulsifiers. These include the products of a reaction between DETA, TETA, or TEPA and fatty acids (302) or oxidized hydrocarbon wax (303). The amidoamine made from lauric acid [143-07-7] and DETA mono- and bis(2-ethylhexyl) phosphate is a very effective water-in-od emulsifier (304). 

The derivatives used in corrosion inhibitor formulations for down-hole use constitute a significant industrial appHcation for polyamines. Again, mono- and bisarnidoamines, imidazolines, and polyamides made from the higher polyamines are the popular choices. The products made from DETA and fatty acids have been widely used (308). A wide variety of other polyamine-based, corrosion inhibiting derivatives have been developed, generally incorporating some form of oil-soluble or od-dispersible residue. Sulfur and its derivatives are also used in these polyamine-based corrosion inhibitors on... 

Imidazole and imidazoline derivatives have provided some useful antimicrobial compounds (Fig. 7). Metronidazole [433-48-1]... 

A -Imidazolines, -oxazolines and -thiazolines (291), and their benzo derivatives (292), are very easily aromatized (292 293), and syntheses which might be expected to yield... 

Dehydrogenation of A -imidazolines (294 Z = NR) gives imidazoles, but requires quite high temperatures and a catalyst such as nickel or platinum. Alternatively, hydrogen acceptors such as sulfur or selenium can be used (70AHC(12)103). 

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