Imidazoles as Substrates

Imidazoles have proved to be quite useful as substrates for the preparation of pyrazines. Various routes are illustrated in the following examples  

1 - [ a-Methoxycarbonyl- a-(phenylhydrazono)methyl]-3 -methylimidazolium chloride (38) gave 4-methyl-3-oxo-2-phenylhydrazono-l,2,3,4-tetrahydro-l-pyrazinecarbaldehyde (40) by rearrangement of the isolable intermediate ylide (39) (NaOH, H20—EtOH, 20°C, 12 h 55%) 2 likewise, 4-amino-5-car-bamoyl-3-diphenylmethyl-l-phenacylimidazolium bromide gave 3- /V-(diphcnylmethyl)amidino]-6-phenyl-2( I //)-pyrazinonc (41) (NaOH, MeOH, reflux, 10 h 65%).151 

2-(a-Diazo-a-ethoxycarbonylmethyl)-l,3-diphenylimidazolidine (42, R = Et) gave among other products ethyl l,4-diphenyl-l,4,5,6-tetrahydro-2-pyrazinecarboxylate (43, R = Et) (2-methylnaphthalene, 160°C, 90 min 40%) 478 the substrate methyl ester (42, R = Me) gave methyl 1,4-diphenyl-l,4,5,6-tetrahydro-2-pyrazinecarboxylate (43, R = Me) by irradiation (hv, Et20, 20°C, 12 h 11% after separation from other products).478 

Primary Syntheses from Other Heterocyclic Systems 

4-(2-Ethoxycarbonylethyl-2-isopropyl-3-imidazoline (46) gave a separable mixture of 2,5-bis(2-ethoxycarbonylethyl)pyrazine (48, Q = H) and its 3-iso-propyl derivative (48, Q = IV) [trace TsOH, xylene, reflux, 1 h 21 and 38%, respectively postulated mechanism formation of dimer (47) and loss of FVC (=NH)H to give a dihydropyrazine that in part undergoes oxidation to product (48, R = H) and in part adds one of the foregoing fragments with subsequent oxidation to product (48, R = FV)].542 

2-Methylimidazole (51) with chloroform in the vapor phase gave, among other products, 2-chloro-3-methylpyrazine (52) (550°C, flow system —17%) other such reactions with imidazole, methylimidazoles, and methylimidazo- 

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An attractive alternative is to study intramolecular reactions. These are generally faster than the corresponding intermolecular processes, and are frequently so much faster that it is possible to observe those types of reaction involved in enzyme catalysis. Thus groups like carboxyl and imidazole are involved at the active sites of many enzymes hydrolysing aliphatic esters and amides. Bimolecular reactions in water between acetic acid or imidazole and substrates such as ethyl acetate and simple amides are frequently too slow to... 

As previously explored by Bode, other a-reducible substrates, such as a,P-epoxy aldehyde and aziridinylaldehyde, are competent partners for redox reactions. (Scheme 33) [109], Various amines are compatible nucleophiles in this methodology in which P-hydroxy amides are furnished in good yield and excellent diastereose-lectivity. A similar reaction manifold was discovered concurrently by Bode and co-workers using imidazole as co-catalyst [117],... 

Sulfotransferase activity is not restricted to minoxidil. The ability of other pyrimidine-, as well as pyridine-, triazine- and imidazole N-oxides to serve as substrates was investigated using soluble liver preparation and PAPS. The variety of structures studied indicated that heteroaromatic N-oxides are generally metabolized by sulfotransferases183. Presumably, all of the heterocycles tested were conjugated via their N-oxide oxygens. 

In an attempt to synthesize a component 50 of exochelin MN (51), the regioin-versed AA of imidazol acrylates 49 under the influence of the (DHQD)2AQN ligand was investigated (Scheme 9). While hydroxyphenyl-substituted substrates such as 48a and 48b gave satisfactory yields (45-55%), regioselectivities (3 1 — 1 0), and enantioselectivities (84-86% ee), no reaction was observed with imidazole-substituted substrates like 48c [71], However, the synthesis of the indole-substituted amino acid 52, a component of cyclomarin A (53), was achieved in 36% yield (Scheme 9) [72], The diastereoselectivity of the AA reaction was determined to be 95 5. 

A somewhat related, highly stable catalyst system was obtained from PdCl2 immobilised in a imidazole-imidazolium ionic liquid which serves both as solvent and ligand. 114 In the reaction solution a bis-imidazole complex, 26, is formed, which has also been synthesised and characterised separately (see Scheme 6.7). In this system catalyst immobilisation appears to be very efficient and after 11 runs with three different substrates high conversion was observed even with chlorobenzene as substrate. 

The reaction mixture contained, in a final volume of 250 fiL, imidazole-HC1 (pH 6.8) as the buffer, either 250 nmol AMP or the formycin analog formycin 5 -AMP (FoMP) as substrate, and the activators ATP and KCl. The reaction was started by the addition of the enzyme, and at intervals samples were withdrawn from the reaction tube and injected directly onto the HPLC column for analysis. 

Studies of nucleosides and the corresponding heterocyclic bases predominate, although nucleotides are also investigated. The synthesis of these compounds, based on the chemistry of Mannich bases, is reported by few papers, as in the case of the ring closure of imidazole (364 in Chap. II, E.2) however, the functionalization of nucleosides and nucleotides, using these molecules as substrates or amine reagents in aminomethylation reactions, is more diffusely reported. 

Electrophilic substitution reactions of 1-phenylimidazoles frequently involve substitution on the benzene rihg. When 1-phenylimidazole is nitrated with a mixed nitric-sulfuric acid reagent the major product is l-(p-nitrophenyl)imidazole. Such nitration has been shown to involve the imidazolium species as substrate. Nitration in acetic anhydride yields only the nitrate salt. 

We created a mimic of the cleavage of the cyclic phosphate by this enzyme by attaching two imidazole groups to a cyclodextrin molecule in well-defined positions (18). In water, the cyclodextrin bound a cyclic phosphate substrate—not, however, one derived from RNA—and performed the cleavage of the cyclic phosphate by using the two imidazoles as the enzyme does. That is, one functioned as a base, which delivered water... 

Using Co as the metal centre, 1-vinyl imidazole as the functional monomer and amino acids as the templates, Leonhardt and Mosbach prepared imprinted metal-complexing polymers [14]. These polymers were aimed at being used as enzyme-like substrate specific catalysts (for more details, see Section 6.5.3.). 

The utility of urca.s and thioureas as substrates for making imidazoles is limited by the fact that the imidazole 2-substituent can only be an oxygen or sulfur function. Synthetic methods involving ureas and thioureas will also be discussed in Section 4.1, but some cyclizations of suitably functionalized species fall under the present heading. Appropriately substituted ureas and thioureas can be made from isocyanates and primary amines [36-38], from isocyanates and hydrazines [39] or thiocyanates and hydrazines [40], from or-aminonitrilcs and carbon dioxide [41] and by heating l,3,4-oxadiazol-2-oncs with amino acids [42]. Some of the substrates prepared in these ways, though, lead ultimately to reduced imidazoles such as hydantoins. Cyclizations arc usually acid catalysed, but they can also be thermal [43]. 

When carbanions are generated from the products of reaction between az.irines and foimamidine, a similar process also leads to imidazoles in moderate yields. Azirincs are, however, rather too exotic as substrates to make this an appealing synthetic approach [4]. Treatment of perhydro-l,3-thiazine-2-thione wilh trifluoracetic anhydride gives an imidazothiazine [5]. 

Many of the classical methods grew out of the earliest synthesis of imidazole, which was achieved in 1858 by Debus [1] when he allowed glyoxal, formaldehyde and ammonia to react together. Although the earliest modifications of this method used a-diketones or a-ketoaldehydes as substrates [2, by the 1930s it was well established that a-hydroxycarbonyl compounds could serve equally well, provided that a mild oxidizer (e.g. ammoniacal copper(ll) acetate, citrate or sulfate) was incorporated [3. A further improvement was to use ammonium acetate in acetic acid as the nitrogen source. All of these early methods have deficiencies. There are problems associated with the synthesis of a wide range of a-hydroxyketones or a-dicarbonyls, yields are invariably rather poor, and more often than not mixtures of products are formed. There are, nevertheless, still applications to the preparation of simple 4-alkyl-, 4,5-dialkyl(diaryl)- and 2,4,5-trialkyl(triaryl)imidazoles. For example, pymvaldehyde can be converted quite conveniently into 4-methylimidazole or 2,4-dimethylimidazole. However, reversed aldol reactions of pyruvaldehyde in ammoniacal solution lead to other imidazoles (e.g. 2-acetyl-4-methylimidazole) as minor products [4]. Such... 

The imidazole product also has a 2-methyl substiment o -Bromoketal as substrate. 

The dimetallic receptor [Zn 2(43)] + is expected to act as a good and selective host for imidazole-containing substrates. Imidazole (imH) is a protic acid but, owing to its very high pK value (14.4), does not deprotonate in water. However, in the presence of two appropriately positioned metal ions, imH may deprotonate and form the imidazolate ion, im , which simultaneously bridges the two metal centers. An aqueous solution containing the dimetallic host [Zn"2(43)] + and adjusted to pH = 9.6 exhibits the typical anthracene fluorescent emission. On addition of imH, fluorescence is quenched substantially, and the Ip versus equivalents of imH profile points towards the formation of a 1 1 adduct ([Zn 2(43)(im)] +, log== 3.65),... 

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