Imidazoles from TOSMIC

A two-step synthesis of 1,4-disubstituted imidazoles (8) from TOSMIC (1) plus an aldehyde, followed by reaction with ammonia or a primary amine, proceeds via a 4-tosyloxazoline (11). The reaction sequence could be classified as 1,2 and 1,5 bond formation, 1,5 bond formation, or transformation of another heterocycle. There are, however, analogies to the aldimine reactions, and so the process is detailed at this stage. Certainly the synthesis is carried out in two steps often with isolation of the oxazoline (see also Chapter 6). Heating (11) with a saturated solution of methanolic ammonia gives a 4-substituted imidazole with methanolic methylamine a 1,4-disubstituted product is isolated as a single regioisomer (Scheme 4.2.4). Some of the oxazolines cannot be isolated as they are unstable oils which have to be heated immediately with the amino compound [12]. Related is the synthesis of 2-carbamoyl-4-(2 -deoxy- 0-D-ribofuranosyl)imidazole [13]. 

Imidazoles (8) made from TOSMIC with aldehydes and amino compounds [12]... 

The most recent synthetically useful modification of TOSMIC reactions involves the cycloaddition of Af-trimethylsilylimines with lithiotosylmethyl isocyanides. This allows the preparation of 4-mono- and 4,5-disubstituted imidazoles from readily accessible aldehydes and organolithium compounds in a one-pot reaction. Although yields are only moderate, there are advantages which accrue from the easy availability of the starting... 

Tosylmethyl isocyanide (TosMIC) (75 R = H), a versatile reagent in synthesis, can also be used as an acyl anion equivalent. For instance symmetrical and unsymmetrical diketones were prepared by using this TosMIC synthon (equation 40). Ketones are homologated to enones by alkylating the condensation product derived from TosMIC, followed by acid hydrolysis (Scheme 46). 1-Isocyano-l-tosyl-l-alkenes (76), formed by the reaction of TosMIC with an aldehyde or ketone, react with a primary amine or ammonia to give 1,5-disubstituted (or 5-monosubstituted) imidazoles in high yield (Scheme 47). ... 

Tosylmethylisocyanide (TOSMIC) has been used only rarely in syntheses of this type. One example though is the preparation of 2-carbamoyl-4-(2 -deoxy- -D-ribofuranosyl)imidazole from the deoxyribosylaldehyde <91TL6915>. 

Fusion of the imidazole ring to pyrrolo-benzothiadiazepine 340 can be achieved by straightforward TosMIC cycloaddition approach (Scheme 72, Section 4.2 (1994JHC1033)). An alternative sequence starts with the addition of nitromethane to the C-N double bond on the thiadiazepine ring, nitro group reduction and manganese oxide oxidation of the intermediate dihydroimidazole derived from amine 342 and tiiethyl ortho formate. 

From the interaction at low temperatures in basic medium of an aldehyde or ketone and tosylmethyl isocyanide ( tosmic ), iV-(l-tosyl-l-alkenyl)formamides are formed. When these are dehydrated they produce 1-isocyano-l-tosylalkenes (66) which react with primary amines to form imidazoles in high yields (Scheme 35) (79RTC258). 

The dianion of TOSMIC will react readily by a [An -(- 2n] cycloaddition with nitriles to give A -unsubstituted 4-substituted imidazoles (7) (Scheme 4.2.1). These reactions also occur with other C—N multiple bonds with much more facility than with the monoanion, while other isocyanides susceptible to a-metallation can also take part [8, 9]. As mentioned above, the dilithiated derivative of TOSMIC is much more reactive than the monolithio derivative. It is also considerably more stable, e.g. the half-life of the monoanion at 20°C under nitrogen in THF-hexane is about 3h under the same conditions the dianion is still 80% recoverable after 24 h. It is possible, therefore, to prepare 4-phcnyl-5-tosylimidazole quite rapidly in 33% yield from the dianion and benzonitrile. The same product is formed only reluctantly from the monoanion. The dianion will also react even with azaaromatics (e.g. isoquinoline) with weakly electrophilic C=N bonds [9]. 

Such reactions can be extended to other isocyanides which are prone to a-metallation (Scheme 4.2.2). Thus, p-tolylthiomethyl isocyanide, which forms a more nucleophilic anion than TOSMIC, reacts with a variety of nitriles to give imidazole products [8]. Nitriles are added at —75°C to the monoanions formed from a variety of thiomethyl isocyanides (butyl lithium in THF-hexane at —75°C). The process is completed by allowing the reaction mixtures to come to 0°C, followed by treatment with water (method A). Alternatively, a THF solution of equimolar proportions of the isocyanide and the nitrile... 

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... 

Variants of TosMIC and imines have also been utilized for imidazole synthesis. For example, benzotriazol-1-ylmethyl isocyanide (BetMIC), 1320, reacts with aldimines 1321, like TosMIC, to form imidazoles 1322. In this case, the benzotriazolyl group stabilizes the anion formed in the first step and is spontaneously eliminated from the intermediate imidazoline. BetMIC derivatives are found to be unstable in the presence of strong bases such as LDA, -BuLi, and NaH. The most effective conditions for all of these reactions are found to be potassium /i t/-butoxide in DMSO or THF (Scheme 337) <1997H(44)67>. 

The condensation of the imine, derived from 2-fluoro-3-methylbut-2-enal and benzylamine, with tosyhnethyl isocyanide (TosMIC) prodnced A -benzyl-5-(l-fluoro-2-methylpropenyl)imidazole (Scheme 54) [69]. However, a similar condensation between the imine from 4,4,4-triflnoro-3-methyl-bnt-2-enal and benzylamine with TosMIC was ineffective, presumably due to the strong-electron withdrawing effect of the CFj group which caused unfavorable charge distribution in the a,p-unsaturated Systran of the imine. This prevents the initial TosMIC attack on the iminic C-position and leads to self-decomposition of TosMIC under the reaction conditions. 

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