Imidazole ring expansion

Scheme 24.—Correspondence between the carbon atoms of AIR and those of pyramine, and the mode of opening of the imidazole ring in the ring expansion in the synthesis of pyramine.

Related redox transformations allow the conversion of ynals to a,P-nnsaturated esters [33], as well as the ring expansion of formyl P-lactams [34], oxacycloalkane-2-carboxaldehydes [35], and 2-acyl-1-formyIcyclopropanes [36], Farther developments allow the synthesis of amides from a range of a-fnnctionalised compounds, but require an additive (imidazole, HO At or HOBt) for efficient amidation [37],... 

Some of the ring expansion reactions discussed in Section 2.03.3.3.1 can be extended to five-membered heterocycles containing two or more heteroatoms. Reaction of imidazoles and pyrazoles with dichlorocarbene, for example, gives chloropyrimidines together with small amounts of chloro-pyrazines or -pyridazines, and oxidative ring expansion of 1-aminopyrazole with nickel peroxide gives 1,2,3-triazine (this, in fact, constitutes the only known synthesis of the unsubstituted triazine). There are, however, a number of interesting and useful transformations which are unique to five-membered polyheteroatom systems. 

At that time it was suggested that the isomerization occurred by way of an initial photo-ring contraction to an undetected 2-(A-methylimino)-2//-azirine intermediate (2) and subsequent ring expansion to the observed product, 1-methylimidazole (3). Although the intermediacy of acylazirines has been adequately demonstrated in the analogous isoxazole-to-oxazole phototransposition, such iminoazirines have not been detected in a pyrazole to imidazole isomerization, and thus, this mechanistic suggestion has never been experimentally substantiated. 

Imidazoles react with chloroform at high temperature to form azines by carbene insertion and trichloromethyl radicals behave similarly, but carbenes do not always induce ring expansion. In alkaline medium, chlorodifluoromethane converts benzimidazole and its 2-methyl analogue into the 1-difluoromethyl derivatives 365. Dichlorocarbene under basic conditions N-alkylates benzimidazole, and 1-methylbenzimidazole couples under the influence of the same reagent (Scheme 69), perhaps involving initial attack of the carbene at N(3). 

There have also been a few examples of ring expansions involving azetines. One such instance, which follows a pericyclic mechanism, is the thermolysis of 4-cyano-l-t-octyl-3-t-octylamino-2-t-octyliminoazetine (160), producing the 4-amino-5-cyanoimidazole (Scheme 89). Such azetine species have been implicated as intermediates in the photolysis of enaminonitriles to imidazoles (Section 4.08.1.1.1 Scheme 17). In strongly basic medium the azetidinone (161), which possesses a lactam group, is ring expanded to the 4H-imidazolinone (163), probably via the anionic acylic species (162 Scheme 89) <80AHC(27)241>. 

Ring expansion by reaction with dichlorocarbenes noted in the pyrazole and imidazole series does not appear to occur with 1,2,4-triazoIes but leads to the formation of tristriazole (51) (69JCS(C)2251) or bistriazole (52 Scheme 18) (72BRP1269619). The first of these reactions is induced by a free radical reagent but the mechanism of the second one is in doubt. 

An interesting example of a ring expansion of an azetine, involving a pericyclic mechanism, is the thermolysis of 4-cyano-l-c-octyl-3-c-octylamino-2-t-octyliminoazetine (51) into the imidazole (Eq. 15). Compound 52... 

Shah et al. carried out a Monte-Carlo simulation in the isothermal-isobaric (NPT) ensemble of [C4mim][PF6] [12]. The authors calculated the molar volume, cohesive energy density, isothermal compressibility, cubic expansion coefficient, and liquid structure as a function of temperature and pressure. A united atom force field was developed using a combination of ab initio calculations and literature parameter values were also developed. Calculated molar volumes were within 5% of experimental values, and a reasonable agreement was obtained between calculated and experimental values of the isothermal compressibility and cubic expansion coefficient. [PF6] anions were found to cluster preferentially in two favorable regions near the cation, namely around the C2 carbon atom, both below and above the plane of the imidazole ring [12],... 

Reactions of Imidazoles. The action of sodamide on the chloro(ethynyl)-imidazole (413 R = Cl, = H) results in the formation of the isomer (413 R = H, R = Cl) similar transhalogenations have been observed for chloro(ethynyl)-pyrazoles and -1,2,4-triazoles. The imidazolium salt (414) undergoes base-induced ring-expansion to the pyrazine derivative (415). 2,4,5-Tribromo-l-methylimidazole reacts with xenon difluoride to give the imidazolidinetrione (416). Low-temperature H n.m.r. studies of the sensitized photo-oxygenation of imidazoles (417 R, R, R = H or Me) give direct evidence for the formation of unstable enr/o-peroxides (418) 2-methyl-4,5-diphenylimidazole yields the peroxy-derivative (419) in this reaction.Irradiation of the N-oxide (420) produces the diamine (422) by way of the oxaziridine (421)."" ... 

Mechanistic studies have been carried out on the formation of diazines by ring expansion of azolyl-1-methyl radicals formed upon FVP of 1-aryloxy-methylpyrazoles and 1-aryloxymethylimidazoles at 700 °C (2015UP1). The pyrazole compound 368 gives exclusively pyrimidine, while the imidazole compound 369 gives both pyrazine and pyrimidine in the ratio shown in Scheme 74 (2015UP1). The effect of methyl substituents is demonstrated by the results for the imidazoles 370 and 371 (Scheme 74). 

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