1,4,5-trisubstituted imidazoles

Analogously, 5-tributylstannylimidazole 29 was easily obtained from the regioselective deprotonation of 1,2-disubstituted imidazole 28 at C(5) followed by treatment with tributyltin chloride [24]. In the presence of 2.6 equivalents of LiCl, the Stille reaction of 29 with aryl triflate 30 afforded the desired 1,2,5-trisubstituted imidazole 31 with 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical scavenger. Reversal of the nucleophile and electrophile of the Stille reaction also provided satisfactory results. For example, the coupling reaction of 5-bromoimidazole 33, derived from imidazole 32 via a regioselective bromination at C(5), and vinylstannane 34 produced adduct 35 [24],... 

Polylithiation at both the 2- and 5-positions gives access to 1,2,5-trisubstituted imidazoles in yields dependent on the ability of the 2-anion to further deprotonate at C-5 (83JCR(S)i96). As the 5-anion is the more reactive, sequential quenching by different electrophiles becomes possible (84JCS(Pi)48l). 

TOSMIC can be converted into an A-tosylmethylimidic ester or thioester (10) which will react with an aldimine to form a 1,2,5-trisubstituted imidazole (Scheme 4.2.3). These esters (10) can be made from A-tosylmethylacetamidc (from the Mannich condensation of p-toluenesulfonic acid, formaldehyde and acetamide [10]), which is smoothly converted by P4S10 in DME into the thioamide which forms the 5-methylated imidate when treated with methyl fluorosulfonate in dichloromethane. Yields of the Al-tosylmethylimidic thioesters are good (65-93%) they are fairly stable crystalline solids which are best stored under nitrogen at —20°C. In reaction with an aldimine in the presence of sodium hydride or potassium t-butoxide (in DME -DMSO or... 

Lithiated imidazoles are good nucleophiles and can easily be converted into other species by treatment with an appropriate electrophile. For example AT-methylimidazole was converted into 332. r -butyllithium was then used to deprotonate at the 5-position for reaction with 333 leading to 334. Removal of the silyl group followed by installation of the second alkyl group at C-2, using -butyllithium and 336, then gave the 1,2,5-trisubstituted imidazole 337 (Scheme 80) <2005H(66)263>. 

Thus, in the presence of a dirhodium(II) tetraoctanoate catalyst, 1-sulfonyl triazoles react with nitriles, forming imidazoles [123]. The reaction proceeds at 60-80 °C with conventional heating or can be performed in a microwave reactor, and generally provides imidazoles in good to excellent yields (Scheme 7.11 A). The sufonyl group can be readily removed, revealing the parent NH-imidazole. Alternatively, sulfonyl imidazoles can be converted to 1,2,5-trisubstituted imidazoles by simple alkylation (Scheme 7.11B). 

Very recently, Wu and co-workers achieved a novel l2-mediated Radziszewski-type reaction of methyl ketones 8, anilines 9, and tosylmethyl isocyanide (TosMlC) 10 via [2 + 1+1 + 1] annulations for the assembly of 1,2,5-trisubstituted imidazoles 11 (Scheme 7.5) [60]. In this protocol, the methylketones 8 play dual roles as a-dicarbonyl compounds and aldehydes for the first time. Initial studies of the mechanism suggest that the reaction proceeds via a key C-acyfimine intermediate and I2 plays an important role in the self-sorting tandem reaction. 

Scheme 7.5 l2-mediated RadziszewsM-type reaction for the synthesis of 1,2,5-trisubstituted imidazoles... 

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-... 

An analogous approach starting from monoximes 44 derived from 1,2 diketo derivatives was described in 2004 [44]. Reaction with different aldehydes in the presence of NH4OAC in acetic acid at 200 °C under microwave irradiation for 20 min gave the corresponding trisubstituted imidazoles 45... 

Reaction of trisubstituted imidazole N-oxides such as l,4,5-trimethylimidazole-3-oxide 930 with 18/NEt3 in CH2CI2 at 0-5 °C affords the l,4,5-trimethyl-2-cyano-... 

Trisubstituted imidazoles have been synthesized from 1,2-diketones or a-hydroxyketones with ammonium acetate in very short reaction times with excellent yields in the presence of l,l,3,3-VAr V ,(V -tetramethylguanidinium trifluoroacetate as an ionic liquid <06SC65>. Iodine acted as an efficient catalyst in the synthesis of 1,2,4,5-tetraarylimidazoles 93 using benzoin 91,... 

A broad choice of 1,4,5-trisubstituted imidazoles can be prepared with the aid of the novel synthon BETMIP (68) and primary amines, as shown in Scheme 55. The resulting intermediate 139 reacts without isolation directly with a-diarylketones (140) to afford 1-substituted 4,5-diarylim-idazoles (141). Cycloheptylamine, benzylamine, dodecylamine, and 4-dimethylaminoaniline can be employed as amines. Reactive 1,2-diketones include benzil, 4-chlorobenzil, and 9,10-phenanthrenequinones (90H2187). 

The imidazole ring is often found in biologically active molecules and is as such important in medicinal chemistry [16]. An interesting route for the production of substituted imidazoles is the Debus-Radziszewski reaction. This is a three-component reaction of a diketone, an amine and an aldehyde to form trisubstituted imidazoles (Scheme 3). 

Technically, the 1,4,5-trisubstituted imidazoles are the side products of the above mentioned isothiazoles production. However, the results are reproducible (confirmed in a series of trials) and the reported bifurcation is an interesting method of extrapolating the microflow applications. 

Condensation of 1,2-diketones with aldehydes in the presence of NH4OH constitutes an efficient approach towards trisubstituted imidazoles. Impressively, under dielectric heating conditions (180 °C), the cyclocondensation reaction required merely 5 min to go to completion [39]. Moreover, analytically pure products were easily isolated from the reaction mixture by a neutralization-filtration sequence. The high speed of the reaction combined with the ease of product isolation rendered the cyclocondensation especially suitable for the generation of imidazole libraries (Scheme 15). 

Biologically interesting 4,5-disubstituted and 2,4,5-trisubstituted imidazoles have been prepared by the Suzuki reaction (Eq. (37)) [68]. 

Various trisubstituted imidazoles (xix) have been synthesized in good yields by Shaabani et al. [19] via the condensation of 1,2-diketone or a-hydroxyketone or a-ketoxime with various aromatic aldehydes and ammonium acetate using a solid acid catalysis. 

Shaabani A, Rahmati A, Farhangi E et al (2007) Silica sulfuric acid promoted the one-pot synthesis of trisubstituted imidazoles under conventional heating conditions or using microwave irradiation. Catal Commun 8 1149-1152... 

When K2CO3 was used as base in DME, trisubstituted imidazole 180 was alkylated by benzyl bromide 181 with a 2 1 ratio in favor of 182 (Scheme 48) <2003JOC5168>. 

A -Alkyl-A -(/3-keto)amides 1216 have been prepared using a traceless linker strategy starting from resin-bound benzylamines 1215. The ketoamides 1217 released from the resin react with an ammonium salt to afford 1,2,4-trisubstituted imidazoles 1218 in good yields and high purities (Scheme 297) <20000L323>. 

Many modified Marckwald procedures are available to prepare structurally diverse imidazoles most of them are focused on the preparation of an oe-aminoketone or its equivalents. For example, a regiospecific synthesis of trisubstituted imidazoles has been developed. Thus, treatment of BOC-protected a-amino acids 1265 with malonic monoester leads to a-aminoketones. After removal of the BOC protecting group, the resulted a-aminoketone salt 1266 will condense with isothiocyanates to form thioureas 1267. The intermediates 1285 undergo cyclodehydration under acidic conditions, yielding imidazole-2-thiones 1268 in good yields. Both reductive and oxidative desulfonation have been used to convert the imidazole-2-thiones 1268 into imidazoles (1269 or 1270) (Scheme 321) <2005TL7315>. 

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