2-Aminoimidazole derivative

The chemistry of 2-aminoimidazole derivatives in the synthesis of pyrrole-imidazole alkaoids has been reviewed <2006SL965, 2003S1753, 2001EJ0237>. 

Van der Eycken s group [27] also recently reported a flexible synthesis toward polysubstituted 2-aminoimidazoles (see Scheme 9). A key step in their synthesis involved the use of silver (I) as a catalyst to heterocyclize guanidine derivatives to provide the desired 1,4,5-trisubstituted 2-aminoimidazole derivatives. 

This approach (Scheme 3) has been applied (53JCS1636) to the synthesis of 4(5)-aminoimidazole derivatives with potential antihistamine or anthelmintic properties. For example, 4(5)-amino-2-thymyloxymethylimidazole (47) was obtained from benzyl-thymyloxy acetothioimidate hydrochloride (42) (75%). Similarly, 4(5)-amino-2-phenylimidazole (48) and 4(5)-amino-2-(thiophen-3-yl)imidazole (49) were prepared (72CA19645) from benzyl-phenyl acetothioimidate hydrochloride (43) and benzyl-(thiophen-3-yl) acetothioimidate hydrochloride (44), respectively. 

Table II summarizes 4(5)-aminoimidazoles derivatives (25), which have been described as either the free base or a simple salt, or were generated in situ and used immediately without isolation.

With ethoxymethylenemalononitrile (136), C-addition appears to be the only mode of reaction with simple 5-aminoimidazole derivatives. Typically, reaction of 5-amino-1,2-dimethylimidazole (96 R = R2 = Me) with the reagent (136) in dioxane solution gave an 84% yield of the product (144 R = R2 = Me). In contrast, reaction of the same amine with diethyl ethoxymethylenemalonate (135) in dioxane solution gave exclusively an... 

V-Aminoimidazole derivatives, (IV), prepared by De Clercq (5) were effective as retroviral enzyme inhibitors and used in treating HIV. 

Restricted rotation (atropisomerism) about N-N single bonds in 1-aminoimidazole derivatives... 

IP 166 with a somewhat unusual structure formed in good yield when 3-amino-imidazo[l,2-a]pyridine 165 was condensed with acetylacetone, the former playing the part of a 4-aminoimidazole derivative (94H1527). 

B. V. Lichitsky, A. N. Komogortsev, A. A. Dudinov, M. M. Krayushkin, Rttss. Chem. Bull. 2012, 61, 1591-1595. Three-component condensation of 5-aminoimidazole derivatives with aldehydes and Meldrum s acid. Synthesis of 3,4,6,7-tetrahydroimidazo[4,5-<>]pyridin-5-ones. 

Substances of this type have hitherto received little attention. One of the reasons appears to be the limited possibilities of preparation. The only known method of preparation, described by Woolley et ai./ proceeds from the derivatives of 4-aminoimidazole-5-carboxylic acid. The amide of this acid (142) is treated with nitrous acid to yield 4-hydroxyimidazo [4,5-d]-i -triazine (2-azahypoxanthine) (143), the amidine (144) yielding the 4-amino derivative (2-azaadenine) (145) under the same conditions. 2-Azahypoxanthine was probably obtained in the same way earlier but was not identified. ... 

Fig. 4.5 The adenine synthesis can be varied to give other purine derivatives. Structures I-IX are those of I aminomalonitrile, II HCN tetramer, III aminoimidazole-carbonitrile, IV 4-aminoimidazole-5-carboxamide, V adenine, VI diaminopurine, VII xanthine, VIII guanine and IX hypo xanthine (Sanchez et al., 1966a)... 

An up-to-date summary of this class of aminoimidazoles (4) is contained in a recent review [92AHC(53)85]. The parent molecule (4 R1 = R2 = R3 = H) is unstable and has been isolated only as its hydrochloride salt (82S592). A number of substituted derivatives have been described, but studies of this class of heterocyclic amine remain limited. 

In 1937 Hunter and Hlynka were able to reduce a methanolic solution of 4(5)-nitroimidazole (27 R = H) with sodium amalgam and trap the 4(5)-aminoimidazole (25 R = H) with cyanic acid giving the urea derivative (31) (37BJ488). Other reducing agents gave inferior results. Subsequently, 4(5)-aminoimidazole (25 R = H) was obtained as either its dihydrochloride (30%) or dipicrate salt but the isolation procedures were lengthy and difficult (41 Mil). 

However, in a later study, Cohen and Kirk described a successful hydrolysis of the f-butyl derivative (34 R = rBu) using tetrafluoro-boric acid (73JA4619, 73JOC3647). The resulting 4(5)-aminoimidazole (25 R = H) was diazotized in situ, and the solution irradiated to give 4-fluoroimidazole (yield 41%). This carbamate (34 R=fBu) was also hy-... 

Early studies on 4(5)-aminoimidazole (25 R=H) gave a stable urea derivative (37BJ488). Thus, treatment of a solution of 4(5)-aminoimidazole (25 R = H), made slightly acidic by addition of acetic acid, with potassium cyanate gave AMmidazol-4-yl-urea (31) (8%). TV-Imidazol-4-yl-urea (31) was similarly obtained using the dihydrochloride salt of 4(5)-aminoimidazole (25 R = H) (41MI1). 

An improved procedure for preparing urea derivatives involves reaction of isocyanates or isothiocyanates with 4(5)-aminoimidazole (25 R = H) in tetrahydrofuran solution [92JCS(P1)2779]. A THF solution of 4(5)-aminoimidazole (25 R=H) generated in situ and then treated with the appropriate reagent gave either lV-imidazole-4-yl-AT-phenylurea (56 X = 0) (32%) or AT-imidazoM-yl-A/ -phenylthiourea (56 X = S) (21%). 

An unusual observation was noted when ethanolic solutions of 2-alkyl-4(5)-aminoimidazoles (25 R = alkyl) were allowed to react with diethyl ethoxymethylenemalonate (62 R = H) [92JCS(P1)2789]. In addition to anticipated products (70), which were obtained in low yield ( 10%), the diimidazole derivatives (33 R = alkyl) were formed in ca.30% yield. The mechanism of formation of the diimidazole products (33) has been interpreted in terms of a reaction between the aminoimidazole (25) and its nitroimidazole precursor (27) during the reduction process. In particular, a soft-soft interaction between the highest occupied molecular orbital (HOMO) of the aminoimidazole (25) and the lowest unoccupied molecular orbital (LUMO) of the nitroimidazole (27) is favorable and probably leads to an intermediate, which on tautomerism, elimination of water, and further reduction, gives the observed products (33). The reactions of amino-imidazoles with hard and soft electrophiles is further discussed in Section VI,C. 

Treatment of a methanolic solution of the nitrile derivatives (81 R1 = CH2CN, R2 = CONH2) [prepared in two steps from the calcium antagonist compound (81 R1 = R2 = H)] with sodium hydride resulted in facile cyclization, giving the 4-aminoimidazol-2-one derivative (82) (53%) (90JMC1805). 

Cyclization of a-cyanoalkyl cyanamides (74) with hydrogen bromide gave 4-aminoimidazoles (77) as their hydrobromide salts. These compounds (77) were found to be unstable as the free base but gave stable (V-acetyl derivatives (84 R2 = Br, R3 = COCH3) (33-82%) when treated with acetic anhydride in pyridine (64JOC153 66CA12211). 

The instability of 5-aminoimidazoles (96) has led to in situ acylation being used to obtain stable compounds and using this approach several derivatives have been prepared. For example, a solution of the appropriate 5-nitroimidazole (97) in ethyl acetate was reduced with Raney nickel, and the resulting solution of 5-aminoimidazole (96) then treated with an acid chloride to give the amides (118 R1 = Me, R2 = S02Me, COPh, R3 = alkyl, aryl, hetaryl) (25-45%) [82IJC(B)1087],... 

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