Imidazoles, reduction aldehydes

The ideas for delocalization of nitrogen lone pair electron density into an aromatic or heteroaromatic system were pursued through reduction of acylated pyrazoles and imidazoles to aldehydes in high yield. 3,5-Dimethyl-A -acylpyrazoles are easy to prepare and afford 77-96% yields of aldehydes with LiAlH4 in diethyl ether at 0 Further examples of this reaction have appeared.Although these later publications commented unfavorably on the ability of LiAlH4 to reduce acyl imidazoles to aldehydes (low yields), other workers have demonstrated that yields of 60-80% could be attained at temperatures of -20 to 4-20 °C in diethyl ether.It was considered that the earlier failure may have been caused by the presence of impurities in the acyl imidazoles. The latter are easy to prepare from the parent carboxylic acid and A jV -carbonyldiimidazole. 

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

Reduction of the carboxylic acid group passes through the intermediate aldehyde. For a number of examples in the heterocyclic series, the aldehyde becomes a major product because it is trapped as the hydrated vfc.-diol form. Examples include imidazole-2-caiboxylic acid [139], thiazole-2-carboxylic acid [140] and pyridine-4-carboxylic acid [141] reduced in dilute aqueous acid solution. Reduction of imidazole-4-carboxylic acid proceeds to the primary alcohol stage, the aldehyde intermediate is not isolated. Addition of boric acid and sodium sulphite to the electrolyte may allow the aldehyde intermediate to be trapped as a non-reducible complex, Salicylaldehyde had been obtained on a pilot plant scale in this way by... 

Aldehyde groups in C-formylazoles can participates in intramolecular cyclizations. Thus, reduction of l-(2-nitrophenyl)-imidazole-2-carbaldehyde (557) with sodium dithionite leads via amine (558) to imidazo[l,2-fl]quinoxaline (519) with good yield (71KGS570). 

Carboxylic acids can be reduced in acid solution to alcohols, aldehydes, or hydrocarbons 7<9 Polarographic and epe studies on the cathodic reduction of isonicotinic acid in weakly acid solution (pH about 3.1 M aqueous potassium chloride) have shown that the product, 4-pyridinealdehyde, exists as a hydrate in aqueous medium and that the hydrate does not undergo further cathodic reduction 137 The same applies to reduction of picolinic acid 137 imidazole-2-car-boxylic acid 138 and 2-thiazolecarboxylic acid 13 9. In the last case the yield of aldehyde was fairly low, probably due to competing reduction of the thiazole ring. It was concluded 139 that the following requirements must be fulfilled for the facile reduction of a carboxylic acid to the aldehyde stage to take place ... 

The synthesis of substrates 88-96 for the IMDA reaction is depicted in Schemes 14 and 15. Treatment of 74 with I2, PPh3, and imidazole [91] provided iodide 75. The substitution of the iodo group in 75 by an anion generated from 2-methylpropionitrile [56-60] provided a hepta-nitrile derivative 76 in 95% yield. Then the secondary hydroxyl group in 76 was protected as an MOM ether to provide 77. Reduction of 77 with DIBALH followed by acidic hydrolysis gave aldehyde 78. The Horner-Emmons reaction of 78 with triethyl 4-phosphonocrotonate in the presence of LiOHH20 and molecular sieves 4A powder [68]... 

Other methods of preparing imidazoles on solid-supports have been reported. Solid-supported amino acid 71 underwent sequential reductive amination with aldehydes, benzotriazole-mediated cyclizations and acidic cleavage to give 1,2,5-trisubstituted-4-... 

Imidazole carboxylic acids are readily converted into hydrazides,436 acid halides,437 amides,437-439 and esters,439-440 and they may be reduced to alcohols with lithium aluminum hydride,441 and to aldehydes by controlled potential reduction.442 Anodic oxidation of l-methylimidazole-5-acetic acid (94) using cooled platinum electrodes yields l,2-bis(l-methylimidazol-5-yl)ethane (95).443... 

Mulzer (Scheme 8 upper left) obtained the a,/(-unsaturated ester 33 with Z configuration from aldehyde 26a via a Still-Gennari olefination with phosphonate ester 34. Reduction of the ester with DIBAH and application of L-imidazole-PPhj gives allylic iodide 35. This acts as electrophile on the -anion of sulfone 36. After reductive removal of the phenylsulfone, group 28b is obtained [23]. 

The usual range of carboxylic acid derivatives can be prepared and interconverted. Both carboxylic acid and ester functions are capable of reduction by lithium aluminum hydride to alcohols, or by controlled potential reduction to aldehydes. Attempts to form the anhydride from imidazole-4,5-dicarboxylic acid by heating with acetic anhydride failed. Instead, compound (199) is formed. This product forms the monoester (200) when heated with methanol and the hydrazide (201) when treated similarly with hydrazine (Scheme 107) (75S162). The corresponding l-methyl-4,5-dicarboxylic acid loses the 4-carboxyl group when heated with acetic anhydride, but in boiling aniline it is transformed into the 1-methyl-4-carboxanilide (79H(12)186). 

Most usual oxidizing agents act normally with imidazole aldehydes and ketones but l-benzylimidazole-2-carbaldehyde is reportedly somewhat resistant to selenium dioxide oxidation. Reduction of ketone functions under Clemmensen and Wolfi-Kischner conditions is usually successful. Zinc dust and acetic acid reduce acetyl groups to a mixture of secondary alcohol and ethyl borohydride gives the alcohol exclusively (B-76MI40701). 

The reactions of 2-lithio- and 2-sodio-imidazoles and -benzimidazoles are not particularly novel. The compounds do, however, prove a means of introducing a variety of functional groups into the 2-position of the heterocyclic ring. Such metalation reactions at C-2 can only occur readily when there is no alternative site for the metal. Therefore, only N-substituted imidazoles are of synthetic utility, and it may be necessary to select an N-substituent which can be removed later. For this reason, benzyl (removed by reductive or oxidative methods), benzenesulfonyl (removed by ammoniacal ethanol), trityl (hydrolyzed by mild acid treatment) and alkoxymethyl (easily hydrolyzed in acid or basic medium) groups have proved useful in this context. A typical reaction sequence is shown in Scheme 136 <78JOC438l, 77JHC517). In addition, reactions with aldehydes and ketones (to form alcohols), with ethyl formate (to form the alcohol) and with carbon dioxide (to form carboxylic acids) have found application (B-76MI40701). 

There has been considerable research into the electrolytic reduction of aromatic carboxylic acids to the corresponding aldehydes. A general procedure has been described in which key elements are the use of the ammonium salt of the acid, careful control of the pH and the presence of an organic phase (benzene) to extract the aldehyde and thus minimize overreduction. The method appears to work best for relatively acidic substrates for example, salicylaldehyde was obtained in 80% yield. Danish workers have shown that, under acidic conditions, controlled electrolytic reductions are possible for certain pyridine-, imidazole- and thiazole-carboxylic acids. In these cases, it is thought that the product aldehydes are protected by geminal diol formation. A chemical method which is closely related to electrolysis is the use of sodium amalgam as reductant. Although not widely used, it was successfully employed in the synthesis of a fluorinated salicylaldehyde. ... 

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