Imidazole 5-cyanoimidazole

The photocyclization of cis-diaminomaleonitrile (372) to 4-amino-5-cyanoimidazole (373) has been shown to proceed via the trans isomer 374.308 4-Amino-3-cyanopyrazole does not seem to be an intermediate in this transformation.309 Analogous cyclizations have been reported in the imidazole 373 which undergoes further photoreaction to yield the bicycle 375, and in o-aminobenzonitrile which is converted into indazole.310 This photocyclization has been extended to include enaminonitriles 376 spectroscopic evidence for the intermediacy of iminoketenimes 377 in this311 and other similar transformations312 have been reported. 

Substituted imidazole 1-oxides 263 upon treatment with dimethyl or diethyl sulfate furnish l-alkoxy-3-subtituted imidazolium salts 283 that were converted to the tetrafluoroborate 283 (A- = BF4 ) or hexafluorophos-phates 283 (A = PF6-) by treatment with sodium tetrafluoroborate or hexa-fluorophosphate (2007ZN(A)295). The tetrafluoroborates 283 (A = BF4 ) reacted with cyanide ion to give 2-cyanoimidazoles 285 (1975JCS(P1)275). The reaction probably follows a mechanism similar to that suggested to be operative in the pyrazole series encompassing O-alkylation succeeded by nucleophilic addition and elimination of methanol (Scheme 85). 

Reaction of 4,5-disubstituted imidazole 1-oxide with trimethylsilyl cyanide (TMSCN) leads to 2-cyanoimidazole. If devoid of substituents at C4 and C5, the cyano (CN) group also enters these positions (1996JOC6971). The reactivity of the 2-, 4-, and 5-position is comparable and 245 reacts with TMSCN affording the isomeric cyanoimidazoles 296-298 in a ratio that depends on the nature of the 3-substituent, solvent polarity, and reaction temperature. These parameters could be optimized to give each of the three cyano compounds as the major product. Mechanisms (iii) and (iv) (Section 1.5.1.3 and 1.5.1.4) account for the formation of 296-298 (Scheme 88). 

Several novel IOji bicyclic imidazoles (63 or 65), obtained from polysubstituted imidazoles, were reported during this period. The first synthesis of an imidazo[4 ,5 4,5]thieno[3,2-d]pyri-midine commences with l-benzyl-2-(methylthio)-4-bromo-5-cyanoimidazole (62) [95TL12807]. Sequential metallation, sulfurization, S-alkyiation, and Thorpe cyclization of 62 afforded the thienoimidazole intermediate 63. Precursor 62 was obtained from 1 -benzyl-2,4,5-tribromoimida-zole in a series of metallation-electrophile trapping protocols. Nitroimidazo[l,5-a]imidazoles (65) were readily obtained from l-(acylmethyl)-2-methyl-4-nitro-5-bromoimidazoles (64) by sequential amination and cyclization [94KGS490]. 

The zwitterion, or carbene, derived from 4,5-dicyano-2-diazoimidazole reacts with acetic acid to give 4,5-dicyanoimidazolin-2-one (79JOC1717). Photolysis of 4-amino-5-cyanoimidazole gives l,6-dihydroimidazo[4,5-d]imidazole (207 Scheme 109) (74JA2010). 

Hydroxylamine-O-sulfonic acid converts an imidazole-2-aldehyde into a mixture of the carboximidamide and the 2-cyanoimidazole (79JHC871). 

Oxidation of the Schiff bases (22) of diaminomaleonitrile monoamide gives 4-cyanoimidazole-5-carboxamides with a variety of 2-substituents. When diaminomaleonitrile reacts with formamidine, the condensation product (23) can form imidazoles in two ways. Direct loss of ammonia gives 4,5-dicyanoimidazole, but isomerization, followed by cycliz-ation in which HCN is eliminated, gives 4-amino-5-cyanoimidazole. With further formamidine this latter product is converted into adenine (Scheme 11) (79JOC4532). 

A further example of a similar sequence of reactions is provided by the reactions of N-cyaniminodithiocarbonic esters (55) with a-cyanoammonium salts. The initial condensation product (56) cyclizes when heated with sodium ethoxide in DMF, again giving a 4-amino-5-cyanoimidazole. Related is the reaction of (55) with the hydrochloride salt of ethyl methylaminoacetate, which gives imidazoles directly perhaps this might be classified... 

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>. 

With )3-ketoesters, /3-ketoamides and )3-diketones, DAMN is converted into enamines, which can be cyclized purely by heating in an alcoholic solvent. The products are 2-substituted-4,5-dicyanoimidazoles (Scheme 2.1.5) [45], When DAMN reacts with formamidine, the initial condensation product (16)/(17) can form imidazoles either by loss of ammonia (when 4,5-dicyanoinnidazole is formed), or via an isomerization and subsequent cyclization which eliminates HCN to give 4-ainino-5-cyanoimidazole (18). With excess formamidine the latter product is converted into adenine. The intermediate amidines (16)/(17), as transient intermediates, react with aqueous ammonia to form (18), and with acetic acid to give (15) (R = R = H) [48, 50]. The transformation of (17) to (18) is a 1,5 bond formation (Scheme 2.1.6). 

There are a number of examples of photochemical transformations of DAMN which may have some synthetic applications. At first, irradiation isomerizes the cir-dinitrile to the rrani -dinitrile, which then forms 5-amino-4-cyanoimidazole (18). Both azctidine or azirine intermediates have been postulated for these cyclizations [54, 55]. Although yields are good the photolytic conditions require dilute solutions ( lO moll solutions of the enaminonitriles) and may not prove practicable for the synthesis of larger quantities of imidazoles. On a small scale, however, the method merits consideration particularly since the process works for a wide variety of enaminonitriles (Scheme 2.1.9) [56-58]. 

A similar reaction sequence condenses iV-cyanoiminodithiocarbamic esters (7) with a-cyanoammonium salts (e.g. sarcosine nitrile sulfate) (Scheme 2.3.2). The isothiourea product (8) readily cyclizes to give 4-amino-5-cyanoimidazoles when heated with sodium ethoxide in DMF solution. It is possible to convert the dithiocarbamic esters directly into imidazoles if they are heated in DMF solution with sarcosine ethyl ester hydrochloride or methylaminoacetophenone in the presence of triethyamine [3]. These direct cyclizations arc, however, examples of both 1,2 and 1,5 bond formation. (See also Section 3.2). 

Pyrazoles rearrange under photochemical conditions to imidazoles with yields as high as 30%. Frequently, however, mixtures of isomers are formed, decreasing the synthetic utility of the approach. Thus, photolysis of 1,5-dimethylpyrazole gives a mixture of 1,2-, 1,4- and 1,5-dimethylimidazoles [7] 3-cyanopyrazole gives 2- (25%) and 4-cyanoimidazoles (11%) [8] ... 

There are considerable data available on imidazole formation by ring contractions of pyrimidines, pyrazincs and triazines [15, 43, 59-61]. Few of the reactions, however, have synthetic potential except perhaps for the thermolytic conversions of azidopyrimidines and azidopyrazines into 1-cyano-substituled imidazoles, and the reactions of chloropyrimidines and chloropyrazines with potassium amide in liquid ammonia to give 4- and 2-cyanoimidazoles, respectively. Ring contractions of quinoxaline 1-oxides may also have some applications. 

Chloropyrazines undergo ring contraction when treated with potassium amide in liquid ammonia. The reactions resemble those of pyridines and pyrimidines, and may be useful for making 2-cyanoimidazoles despite the formation of product mixtures and low yields. For example, 2-chloropyrazine is converted into a mixture of 2-aminopyrazine (15%), imidazole (14-15%) and 2-cyanoimidazole (30-36%) [82]. In a similar experiment, 2-cyano-4-phenylimidazole (19%) can be obtained 83J. 

In 4-cyanoimidazole 838, the nitrile group undergoes addition to Grignard reagents to afford 4-acyl-l//-imidazoles... 

The reaction of 2potassium amide in liquid ammonia to give 2-cyanoimidazole, imidazole, and 2-aminopyridine has been investigated (911). It has been found that 2-chloropyrazine containing an excess of in position 1, on treatment with potassium amide in liquid ammonia at — 65° yields 2-aminopyrazine in which the exocyclic nitrogen contains all the excess and an addition-nucleophilic-ring opening-ring closure (ANRORC) mechanism was proposed (822). The mechanism of the conversions into imidazole (823) and... 

---