Imidazoles preparation

Scheme 14). The diversity of the collection of imidazoles prepared was relatively high, and yields ranged from 17 to 83%. It is interesting to observe that the intermediate N-hydroxyimidazole 46 was obtained when the reaction was carried out at temperature lower than 200 °C. 

With neutral phosphoric monoimidazolides, which are more reactive than the ionic species the reaction time for phosphorylation of an alcohol is reduced. A one-flask synthesis of unsymmetrical phosphoric diesters from N-( 1,2-dimethylethylenedioxy-phosphoryl)imidazole, prepared from di(l,2-dimethylethylene)pyrophosphate and imidazole, is presented below [103,[11]... 

Solid state 15N NMR has also been used103 to study lyophilized powders of 15N-enriched histidine and imidazole, prepared from aqueous solutions with pH ranging... 

The reaction between a suitable imidatc and an a-aminoaldehyde or a-aminoacetal to form an amidine, which cyclizes to an imidazole, rests largely on the availability of the aminoaldehydes from a-amino acids, which are readily reduced using the Akabori method [2], Dimethyl or diethyl acetals frequently replace the aldehydes in these reactions 13,4]. Table 2.2.1 lists some 2,5-disub.stituted imidazoles prepared (ultimately) from amino acids. It is not possible to introduce a range of substituents at both the 4- and 5-positions by this method unless the amino acid is converted into a ketone rather than an aldehyde (see Section 2.1.1) (Scheme 2.2.2). 

Table 4.2.3 lists some representative examples of 4,5-disubstituted imidazoles prepared using those methods. 

Imidazoles and benzimidazoles with a free NH group are weak acids, but sufficiently acidic to be able to form anions in the presence of strong bases <87AHC(4l)l87,88CHE469). This property becomes important in transformations sueh as 7V-alkylation and metallation. Whereas most metal salts hydrolyze very readily in aqueous media, they can be prepared and isolated from anhydrous aprotic solvents. Thus, Af-lithiated imidazoles, prepared under such conditions, react in turn with copper(I) cyanide and an alkyllithium to give cuprates [R(Im)Cu(CN)Li2] which are useful carbanion sources <92TL1041>. Some determined acid values appear in Table 6. 

Imidazole can be A -allylated. The A -glycosylimidazole 299 is prepared by regiospecific amination at the anomeric center with retention of configuration. Phenoxy is a good leaving group in this reaction[181]. Heterocyclic amines such as the purine base 300 are easily allylatedfl 82]. 

These compounds are easily prepared from the appropriate 2-aminothiazole and acyl chloride (see Section III.2.D) or by general heterocydization methods. Acyl chlorides may be replaced by the corresponding anhydrides (471). Acids themselves may be used as acylating agents provided that the imidazole-triphenyl phosphine mixture is used as a catalyst (472). The Curtius degradation of 247 yields 2-acetamido-4-phenylthiazole (248) (Scheme 149) (473). 

Selenium heterocycles receive far less mention in the literature than do such homologs as oxazole, thiazole, or imidazole. In fact, preparative methods of selenium heterocycles are much more limited than for the other series, mainly because of manipulatory difficulties arising from the toxicity of selenium (hydrogen selenide is even more toxic) that can produce severe damage to the skin, lungs, kidneys, and eyes. Another source of difficulty is the reactivity of the heterocycle itself, which can easily undergo fission, depending on the reaction medium and the nature of the substituents. 

Several biologically and pharmacologically active compounds have been prepared from the condensation of the acid chloride of 1-naphthoxyacetic acid with carbazole, iadole, or pyrrole ia 2A[ NaOH solution ia ethanol (63). Also, naphthyloxy derivatives of imidazole, benzimidazole, and benzotriazoles have been synthesized and screened for their antimicrobial, analgesic, and antiinflammatory activities. 2-Naphthyloxy derivatives are comparatively more active than 1-naphthyloxy derivatives (64). 

A/-Chloroamidines are usehil for preparation of biocidal imidazoles (106) and thiadiazolines (107). Ai-Chloroguanidines, RNHC(=NC1)NHR, serve as starting materials for synthesis of imidazoles, oxadiazoles, and thiadiazoles (108,109). 

Pyrazoles and imidazoles carrying a substituent on nitrogen, as well as oxazoles, thiazoles, etc., are converted by alkyl halides into quaternary salts. This is Illustrated by the preparation of thiamine (89) from components (87) and (88). 

N-Arylation of azoles is achieved either by using arynes, activated halobenzenes (e.g. dinitro) or under Ullmann conditions. Thus benzyne reacts with imidazoles to give N-arylimidazoles (70AHC(12)103), and these compounds have also been prepared under modified Ullmann conditions. 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

Attempted diazotization in dilute acid sometimes yields primary nitroso compounds. Reactions of 3- and 5-amino-1,2,4-thiadiazoles with sodium nitrite and acid give primary nitrosamines (e.g. 432->433) (65AHC(5)n9) which can be related to the secondary nitrosamines (434) prepared in the normal way. 1-Substituted 5-aminotetrazoles with nitrous acid give stable primary nitrosamines (435). Primary nitrosamines have been isolated in the imidazole series. 

Fluorenylmethyl esters of A -protected amino acids were prepared using the DCC/ DMAP method (50-89% yield) or by imidazole-catalyzed transesterification of... 

The piperonyl ester can be prepared from an amino acid ester and the benzyl alcohol (imidazole/dioxane, 25°, 12 h, 85% yield) or from an amino acid and the benzyl chloride (Et3N, DMF, 25°, 57-95% yield). It is cleaved, more readily than a p-methoxybenzyl ester, by acidic hydrolysis (CF3COOH, 25°, 5 min, 91% yield). ... 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

The THP derivative of the imidazole nitrogen in purines has been prepared by treatment with dihydropyran (TsOH, 55°, 1.5 h, 50-85% yield). It is cleaved by acid hydrolysis. ... 

Acyloins are useful starting materials for the preparation of a wide variety of heterocycles (e.g., oxazoles and imidazoles ) and carbocyclic compounds (e.g., phenols ). Acyloins lead to 1,2-diols by reduction, and to 1,2-diketones by mild oxidation. 

The aldehyde functionality present in 3-phenyl-2H-azirine-2-carbox-aldehyde reacts selectively with amines and with Qrignard and Wittig reagents to give a variety of substituted azirines. These azirines have been used, in turn, to prepare a wide assortment of heterocyclic rings such as oxazoles, imidazoles, pyrazoles, pyrroles, and benzazepins. ... 

C=N, C=S, C=C, and N N containing substrates. Thus oxa2oles, imidazoles, thiazoles, p rrroles, and 1,2,4-triazoles have been prepared, respectively. Furthermore, p-tolylsulfonylmethyl isocyanide has found use in a one-step conversion of ketones into cyan-idea and in a two-step synthesis of a-hydroxyaldehydes from ketones. ... 

This technique has been applied to the synthesis of fluormated dopamine and other compounds of biological significance Fluoroheterocycles such as fluoro-imidazoles [JJ, 36] and fluoropyrazoles [37] can also be prepared by the photo Balz-Schiemann technique (equation 9) Photochemically induced in situ fluoro dediazoniation can also be applied to arenediazonium fluorides in hydrogen fluo nde-pyndine media Thus, o-fluoroanisole is obtained in 73% yield at 20 °C after I8h [dS]... 

The piperonyl ester can be prepared from an amino acid ester and the benzyl alcohol (imidazole/dioxane, 25°, 12 h, 85% yield) or from an amino acid and the... 

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