Imidazoles, cyanation

Azoles can form stable compounds in which metallic and metalloid atoms are linked to nitrogen. For example, pyrazoles and imidazoles Af-substituted by B, Si, P and Hg groups are made in this way. Imidazoles with a free NH group can be Af-trimethylsilylated and Af-cyanated (with cyanogen bromide). Imidazoles of low basicity can be Af-nitrated. 

Acetylation of the hydroxymethyl imidazole 63 affords the corresponding ester (64), nitration (65) followed by hydrolysis gives intermediate 66, and reaction of this alcohol with potassium cyanate in hydrogen fluoride gives the carbamate ronidazole (67).16... 

Early studies on 4(5)-aminoimidazole (25 R=H) gave a stable urea derivative (37BJ488). Thus, treatment of a solution of 4(5)-aminoimidazole (25 R = H), made slightly acidic by addition of acetic acid, with potassium cyanate gave AMmidazol-4-yl-urea (31) (8%). TV-Imidazol-4-yl-urea (31) was similarly obtained using the dihydrochloride salt of 4(5)-aminoimidazole (25 R = H) (41MI1). 

It becomes apparent when one is faced with a synthetic problem in imidazole chemistry that there is no single, widely applicable synthetic procedure. Even the methods devised by Bredereck (Section II, A) and the reaction of a-aminoketones with cyanates or thiocyanates (Section II, F) have limitations. 

The Marckwald synthesis116 employed the reaction of a-amino-ketones with cyanates, thiocyanates, and isothiocyanates to yield 3 -imidazol-2-ones or AH-imidazole-2-thiones which are readily converted into imidazoles. The chief limitation of this method, which has been discussed adequately in earlier reviews,1-3 is in the synthesis of the a-aminocarbonyl compounds. The most convenient procedure is by reduction with sodium amalgam of a-amino acids.117 Among recent applications of the method118 119 is the synthesis118 of 4,5-... 

Direct Af-cyanation is possible when cyanogen bromide reacts with an imidazole or benzimidazole having a free NH group (Scheme 28) (80H(14)1963). 

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. 

Treatment of the imidoyl chloride (106) with triethylamine yields the nitrile ylide (107), which undergoes cycloaddition with a variety of reagents giving imidazole products. With ethyl cyanoformate a mixture of esters is obtained with 2,4-xylyl cyanate the 4-aryloxy... 

Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. BusSnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and BuaSnCN proceed smoothly in the presence of a catalytic amoimt of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions) again the dehydration process (imine formation) proceeded smoothly in water. 

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]. 

Electrophilic attack in imidazole is usually most facile at an annular nitrogen, and there are many examples of Af-aUcylation, -protonation, -acylation, cyanation, -arylation and -silylation. A-Nitration is much less common A-oxidation is virtually non-existent. When an annular nitrogen becomes substituted, tautomerism in the molecules is blocked, and mixtures of isomers are usually formed with substituted benzimidazoles and 4(5)-substituled imidazoles. 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

If the 2-position is blocked, cyanation occurs at the 3-position. Similarly, cyanation of 1-methylpyrazole gives a mixture of the 4- and 5-carbonitrile [228]. The efficient substitution observed for many pyrroles, imidazoles [229], and indoles contrasts markedly the addition reactions observed for furans (cf. Chapter 16) and thiophenes [230]. However, this difference may only be apparent. At least for two of the cases already cited [226], it has been demonstrated [231] that the cyanosubstituted pyrroles arise as a result of elimination during workup of the 2,5-addition product originally formed. For benzo[b]thiophenes, cyanation leads predominantly to substitution products [232] ... 

The reaction of proteins with cyanate has been exploited in the development of a method for the quantitative determination of NH2-terminal residues (Stark 1967a), as well as in a variety of interesting structure-function studies exemplified by those of Smyth (1967) on oxytocin, and Cerami and Manning (1971), as well as Lee and Manning (1973), on sickle cell hemoglobin. Whereas cyanate reacts with a-NH2, -NH2, thiol, imidazole, and phenolic OH groups of proteins, only the amino group derivatives are stable at alkaline pH. 

In another application, iV-acyl-imidazoles react with lithium alnminium hydride at 0 °C to give aldehydes, providing a ronte from the acid oxidation level. In a similar way, 1-cyanoimidazole acts as a mild and efficient N-, S- and C-cyanating agent. 

Cyanation. This reagent is prepared from imidazole and cyanogen bromide. It donates the cyano group to various nucelophiles such as amines, thiols, and RMgX (or RLi). 

This synthetic principle (Marckwald synthesis) can be applied in various ways cyanates yield imida-zole-2(3//)-ones, thiocyanates imidazole-2(37 /)"thiones and alkylisothiocyanates 1-alkylimidazole-2(3//)-thiones. 

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