No abstract

5-Amino imidazole 4-substituted carboxamidines and 4-substituted imidoyl cyanides were selectively obtained under mild experimental conditions from reaction of the easily accessible 5-amino-4-cyanoformimidoyl imidazoles with primary aliphatic and aromatic amines, ammonia, and amino acids in a one-pot reaction. When alcohols were used, the corresponding 5-aminoimidazole 4-carboximidates were isolated. An equally simple reaction occurred when the starting imidazoles were combined with water to give 5-aminoimidazole 4-acyl cyanides.Imidazoles are key components in a large number of biomolecules and pharmacologically active compounds. They can be considered important scaffolds in heterocyclic synthesis and drug discovery. 1,2 Examples include the essential amino acid histidine and related compounds, biotin, imidazole alkaloids, antifungal ketoconazole, antiulcerative agent cimetidine, and the proton-pump inhibitor omeprazole. 1,2dThe a-iminonitriles (also referred to as imidoyl cyanides) are an important class of functionalized compounds used as precursors for a-keto acids, amides, N-alkylketene imines, cyanoenamides, amidines, etc. 3 These compounds are usually obtained through multistep processes, with limited application scope.Amidines, important synthons in heterocyclic chemistry, are mostly prepared from nitriles (Pinner synthesis) via imidates and usually require activated nitriles or forcing conditions. 4 The synthesis of a series of triazolo-3-(Nsubstituted) carboxamidines incorporating different alkyl amines and amino acids has been reported and involves a carboximidate as a key intermediate, prepared from the corresponding carbonitrile. 5The chemistry of 5-aminoimidazoles has not received much attention and this has been attributed to their lower stability, as compared to other classes of aminoazoles. 2e,6,7 Nevertheless, the synthesis of 5-aminoimidazole 4-carboxamidine from a carbonitrile via a carboximidate has been reported. 8 Herein we describe a new, more facile, and versatile synthesis of 5-aminoimidazole 4-carboxamidines from 5-amino-4-cyanoformimidoyl imidazoles 1.Imidazoles 1 are easily prepared following a previously developed method. 9 These imidazoles react with secondary amines at the imine carbon atom of the cyanoformimidoyl substituent with subsequent elimination of HCN. 9d We now report the incorporation of primary amines, amino acids, ammonia, alcohols, and water into the substituent in the 4-position of the imidazole ring using trifluoroacetate and hydrochloride salts of imidazoles 1 as key intermediates.During studies on the reaction of imidazoles 1 with anhydrides, 9c,10b,c we realized that imidazolium trifluoroacetate 1a·TFA was generated in 95% yield from trifluoroacetic anhydride (TFAA) and not the desired imidazole 2a ( Table 1). The reaction of 1a with trifluoroacetic acid (TFA) led to the same salt in 88% yield. From preliminary studies on the reactivity of 1a·TFA, two important results emerged. In the presence of methanol the carboximidate 3a·TFA was isolated in 76% yield after...

New fluorescent nucleobase analogues (FBAs) are emerging as extraordinarily useful tools for DNA labelling technologies. The highly fluorescent adenine analogue 2-aminopurine (2AP) is still the most used within the few hundreds of newly FBAs synthesized, but its excitation in the UV region demands for high energy sources endangering living cells. New and highly fluorescent 2AP derivatives, 2-amino-6-cyanopurines, were obtained using simpler but efficient synthesis method. All the new compounds exhibit advantageous photophysical proper-ties over 2AP, showing absorption and emission bands ranging the visible region (blue-green region), high fluorescence quantum yields and Stokes' shifts, especially in non-protic organic solvents. Density Functional Theory calculations (DFT) of electronic and vibrational structure were performed, allowing to predict absorption and emission spectra. In addition, these 2amino-6-cyanopurines exhibit little to no toxicity in assays using yeast cells.

S y n t h e s i s o f 3 -I m i d a z o l y l 1 , 2 , 4 -T r i a z o l e s a n d 1 , 2 , 4 -O x a d i a z o l o n e s

A series of 2,6,9-substituted adenines were obtained from the easily accessible 5-amino-4-cyanoformimidoyl imidazoles, acetic and benzoic anhydrides, and primary alkyl amines in a three-step sequence. Acylation of 5-amino-4-cyanoformimidoyl imidazoles followed by addition of the amine led to the intermediates 5-amino-4-(N-acyl)formamidino imidazoles under mild conditions. Cyclization of 5-amino-4-(N-acyl)formamidino imidazoles under reflux in ethanol led to the desired substituted adenine. A preliminary stepwise study led to the development of three general and efficient one-pot methods for the synthesis of adenine derivatives. The one-pot, three-step reaction in the presence of DMAP was the most convenient synthetic approach.Adenine is one of the most important naturally occurring nitrogen heterocycles. This purine nucleobase plays a fundamental role in the nucleic acid chemistry and cellular biochemistry. 1 In fact, the function of a remarkable number of proteins is governed by adenine nucleotides as cofactors or co-substrates. 1,2 Moreover, the increasing number of reports describing new biological activities of synthetic adenine derivatives reveals the great potential of these compounds as new chemical-biological tools and therapeutic target as enzyme inhibitors or receptor agonists/antagonists. 2,3 For instance, adenines, adenine nucleosides, and their analogues have found potential therapeutic application against cancer, 4 autoimmune disease, 5 viral infections, 6 and microbial infections. 7 The natural catalytic role and supramolecular assembly capacity of adenine inspired intense research on the field of organocatalysis and other applications ranging from coordination chemistry to the synthesis of new materials. 1,8 The most common synthetic method to prepare 2-and 6-substitued adenines involves nucleophilic substitution of a suitable leaving group from commercially available 2-halo and 6-chloro, 6-amino or 6-sulfonyl purines with amines or carbon nucleophiles and metal-catalyzed couplings. [2][3][4][5][6][7] To introduce functionality at the 9-position, N-alkylation(arylation) of adenine or 6-chloropurine has been accessed by treatment with alkyl halides, by a Mitsunobu reaction with an appropriate alcohol, or the coupling of purine bases with aryl boronic acids. 2,9 These methods suffer from several drawbacks including the use of toxic, expensive, and explosive reagents. An alternative route is amination of the 5-amino-4,6-dihalopyrimidine, followed by a ring-closing reaction with triethyl orthoformate or acid derivatives. 2,4b,9c To the best of our knowledge, there are few reports on the synthesis of adenines from 5-amino-4-carboxamidino imidazoles, prepared from ring opening of N1-alkoxyadenines or from 5-amino-4-cyano imidazoles, mostly involving multistep, low-yield processes. 10