Imidazoles, 2,4,5-trialkyl

Vom praparativen Standpunkt interessanter ist die Herstellung symmetrisch substituierter 2,4,5-Trialkyl-imidazole in Ausbeuten von 50-60% aus Olefinen, Ammoniak und Koh-lenmonoxid mit Rhodium-Katalysatoren in waBrigem Methanol bei Temperaturen von 130-150° und Drucken von 150-250 bar11. 

Aus zwei Aquivalenten Benzonitril werden mit Trialkyl-aluminium und Tetrachlor- bzw. Te-trabrommethan 2-substituierte 4,5-Diphenyl-imidazole erhalten (s.Bd. XIII/4, S. 250). Zur Umsetzung von Blausaure in fliissigem Ammoniak zu 4,5-Dicyan-imidazol s. Bd. E5/2, S. 1555. 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

It should be recalled here that the alcoholic hydroxyl of serine does not possess a dissociation constant within the pH range, accessible to enzymic reactions. Therefore, this amino acid cannot influence the pH-activity curve. On the other hand, it is well known that DFP inhibition is initially reversible and becomes only slowly irreversible. This has been demonstrated for true ChE from electric eel by Nachmansohn and associates (46) and for plasma ChE by Mackworth and Webb (47). Similarly, a stepwise reaction with inhibitors, containing the diethyl phosphoryl moiety, has been made probable by Hobbiger (34)- Therefore, it appears possible that phosphates are first attacked by the imidazol moiety of the esteratic site, in conformity with the catalytic influence of free imidazol on phosphate hydrolysis (48). This step is followed by transfer to serine. The final product is a trialkyl phosphate XV, which is not split by imidazol (scheme F). 

When urea (or thiourea) reacts with a-hydroxy ketones or a-diketones the products are imidazolin-2-ones (or -thiones) (70AHC(12)103,66RCR122). The reaction is limited to the preparation of 4,5-alkyl(or aryl)- or l,4,5-trialkyl(or triaryl)-imidazoles since an oxygen or sulfur function appears at C-2. Benzoin condenses with iV-phenylthiourea in hexanol in the presence of catalytic quantities of HCl to give l,4,5-triphenylimidazoline-2-thione (131) in 50-60% yield (Scheme 69). While 1-methylurea can also take part in the reaction. 

Although all of these methods suffered from deficiencies (difficulties of synthesis of starting materials, low yields, and more often than not the formation of mixtures of products requiring tedious separation procedures), they still find ample application for the preparation of many C-substituted imidazoles (e.g. 4-alkyl, 4,5-dialkyl, 2,4,5-trialkyl). The old Debus (or Radziszewski) method is still useful for preparing such compounds as 4-methyl- (132) and 2,4-dimethyl-imidazoles (133) using pyruvaldehyde (Scheme 71). However, alkaline fission of the pyruvaldehyde can result in a mixture of products. When pyruvaldehyde is treated alone with aqueous ammonia there are three main products (132), (133) and 2-acetyl-4-methylimidazole. Reversed aldol condensations cause degradation of the pyruvaldehyde, and subsequent cyclization of the fragments as in Schemes 71 and 72 accounts for the products. 

It is convenient to combine these two synthetic approaches because they are formally similar. Both condense an a-functionalized ketone or aldehyde (C-4-C-5 synthon) with an amine or ammonia (N-1, N-3) and an aldehyde (C-2). "Die alternative Bredereck modification uses formamide as the source of the C-2-N-3 bond and of N-1. The older (Radziszewski or Weidenhagen) methods give 4-mono-, 4,5-di- and 2,4,5-trialkyl or -triaryl imidazoles the Bredereck formamide synthesis is largely restricted to the preparation of imidazoles with no 2 substituent. 

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... 

Weak bases can assist the reaction. Naturally, the only useful W-acyl substituents of use in lithiation sequences are the acetals (e.g. dialkoxymethyl), which can be made quite readily by treating the imidazole with a trialkyl orthoformate with p-toluenesulfonic acid as a catalyst. The groups are easily removed again, but have the drawback of also being unstable under dilithiation conditions [25, 55]. 

There have been reports of a novel synthesis of 2,4,5-trialkyl-imidazoles by the rhodium-catalyzed reactions of alkenes with carbon monoxide and ammonia. Yields are 50-60%. Benzylamine and derivatives react with carbon tetrachloride in the presence of a catalytic amount of metal carbonyls to yield 2,4,5-triarylimidazoles and -imidazolines. The suggested reaction mechanism implicates an initially formed radical species which coordinates with the metal carbonyl. 

Carrington who repeated this work 76 though found that N-substituted a-amino nitriles (CLXIa) do not yield 1,5,5-trialkyl imidazol-idine-2,4 dithiones (CLIX) with carbon disulfide but rather 3,4,4-triaIkyl-5-imino thiazohdine-2-thione.s (CLXII). On hydrolysis with dilute acid these are changed into 3,4,4-trialkyl thiazolidin-5-one-2-thiones (CLXIII). 

From the up-to-date literature and patent review of catalysts used In anhydride and phenolic cured epoxy molding compounds, It Is evident that Imidazoles and their derivatives predominate (Table I). Metal complex, trialkyl or triaryl phosphines and their complexes, Lewis acids such as zinc or stannous octoate are used to a much lesser extent (Table II). There are a few examples of tertiary amines and urea derivatives used. 

Titanium tetrachloride is an efficient reagent for the conversion of trialkyl phosphites and dialkyl hydrogen phosphonates into dialkyl phosphorochloridates. Imidazolides and dialkyl or diaryl phosphoric acids react with acyl fluorides - benzoyl fluoride and oxalyl difluoride being the reagents of choice - to give quantitative yields of the phosphoryl fluorides. The procedure is adaptable to the preparation of fluorides of carbohydrate phosphates in this field, the reaction between the ceu bohydrate and tris-l//-imidazolylphosphine oxide or sulphide with the replacement of one imidazole... 

The same is true for X=Br, OR, SR, or aryl (39). Recently, both van der Kerk et al. (39) and Ourselves (19S) found a procedure with which trialkyl hydrides can be prepared in situ (X=halogen). In the cases where X is an acetate, imidazole (39), OH (respectively OPbR3), and allyl (198), the equilibrium is shifted more to the side of R3FbH. 

The groups of Siebert " and Erker " studied the reactivity toward a strong base of imidazole-borane adducts, showing that for the BH3 moiety the anionic 3-boraneimidazol-2-yhdene could be isolated (structure 25 in Scheme 31), whereas migration of BR3 (R = Et, C Fs) groups to the carbene carbon atom was observed for trialkyl- or triarylborane reagents (complex 26 in Scheme 31). 

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