Glyoxal, reaction with primary amines

In order to introduce other substituents at the 1- and 3-positions of the imidazolium salt the reaction of primary amines with glyoxal and formaldehyde in the presence of acid can be used [Eq. (3)]. ° Variation of the amine allows the preparation of imidazolium salt libraries which can be diversified by using... 

Condensation of 1 with glyoxal derivatives or 1,3-dichloroacetone gave the Ws(dimedonyl)methane 40 whose fusion with an equimolar amount of ammonium acetate or heating with primary amines in chlorobenzene gave 4,5,6,7-tetrahydroindole 41 (89IJC(B)326). Reaction of 41 (R1 = Ph) with diazomethane or amino-alkylchloride afforded ethers 42, and with hydrazine gave the disubstituted hydrazine 43 as the major product and the indole derivative 44 as a minor one (89IJC(B)326) (Scheme 6). 

Preparation of the key tropine is achieved by any one of several variations on the method first developed by Robinson, which involves reaction of a primary amine with dihydroxyacetone and glyoxal. Reduction of the carbonyl group in the product (86) followed by acylation affords the aminoester (88). Transesterification with ester aldehyde 89... 

H). On the other hand, the synthesis of unsymmetricaUy iV,iV -substituted congeners is less straightforward as a functionalised imidazole has to be isolated prior to alkylation or arylation. Two main methods are available for imidazole functionaU-sation deprotonation with metalUc Na or K leading to an imidazoUde (I) followed by reaction with RX or reaction of glyoxal with a primary amine, an ammonium salt and formaldehyde (J). Al-functionalised imidazole can then be alkylated or... 

Reaction of glyoxal with aromatic primary amines [63]. 

The reaction of amines with 1,2-diketo substrates led to a variety of substituted imidazole derivatives. Treatment of various substituted anilines 88 with glyoxals 89 gave the imine intermediate 90, which was then cyclized to the 1-arylimidazoles 91 with paraformaldehyde and ammonium chloride under acidic conditions <0382661>. A one-pot, three-component condensation of benzil 92, benzonitrile derivatives and primary amines on the surface of silica gel under solvent-free conditions and microwave irradiation provided tetrasubstituted imidazoles 93<03TL1709>. 

This reaction was first reported by Hinsberg in 1888. It is the synthesis of N-alkyl-oxindole from IV-alkyl aniline and the glyoxal-bisulfite adduct after hydrolysis by hydrochloric acid. Similarly, the reaction of A -alkyl naphthylamine with glyoxal-bisulfite adduct leads to benzo-oxindole. In contrast, the reaction between primary aryl amines and... 

In general, Radziszewski reaction is the synthesis of an imidazole derivative 4 by the condensation of an a-dicarbonyl compound 1 (e.g., glyoxal, pyruvaldehyde, porphyrin-2,3-diones, and benzil), an aldehyde 2, and two equivalents of dry ammonia in alcohol. Interestingly, the replacement of one equivalent of ammonia with a primary amine 3 results in the formation of 1-substituted imidazoles 4 (Scheme 12.1). 

Other routes construct the heterocycle in a one-pot reaction (routes B, C). 1-Substituted imidazoles are formed when an aqueous solution of glyoxal is treated with alkyl amine, formaldehyde, and ammonium salt (route B). The reaction proceeds in acidic media [26]. When 2equiv of the primary amine... 

Investigation of the mechanism of these reactions has suggested ways in which the yields can be improved. Acidic conditions (pH 2) will prevent Cannizzaro rearrangement of any glyoxal-type species and also serve to hydrolyse any Schiff bases which result from side reactions of aldehyde and amine. Conditions should be adjusted so that the rate of hydrolysis of linear products is equal to the rate of cyclocondensation, allowing accumulation of the imidazole products. From glyoxal, formaldehyde and ammonium chloride the yield of imidazole can be inereased to 85% by careful control of the conditions. With an appropriate alkylammonium chloride, 1-substituted imidazoles are also accessible (e.g. 1-methyl (56%), 1-isopropyl (46%), 1-cyclohexyl (49%), 1-n-butyl (55%), 1-t-butyl (25%)). The process may have some applications, but yields drop off with branched alkyl compounds [22 j. Imidazolium salts are also available under similar conditions when two molar equivalents of a primary alkylamine are used [23]. 

The new condensation reactions of amines with glyoxal to yield hexa-azaisowurtzitane derivatives 51 appear to be limited to benzylamine and certain phenyl-substituted benzylamines. Primary aliphatic amines and anilines usually form dicarbinolamines 52 or diimines 53 (Refs. 108-112). With certain arylamines, such as 2-chloroaniline or aniline itself, one may obtain 52 or l,r,2,2 -tetrakis(arylamino)ethanes (Ref. 109). The condensation of benzylamine with glyoxal was apparently not described in the literature prior to our report (Ref. 107). However, condensations of a-methylbenzylamine and a,o -dimethylbenzyiamine with glyoxal have been reported to produce diimines (53, R = QHjCHCHj and QH5C(CH3)2, respectively) (Refs. 111,112). 

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