Organic letters: one pot synthesis of polysubstituted purines

In recent decades, purine skeleton has made great contribution to the development of biotechnology tools and bioactive molecules Since the approval of the antiviral drug vidarabine in 1976, purine analogues have been widely used in clinical practice Many drugs have been designed to have structures similar to those of natural purine nucleosides and nucleic acid bases In general, these compounds have different structures at the 9-position of purine skeleton, such as glycosyl group, carbocyclic group, alkyl group, etc (Fig 1) Figure 1 Source of bioactive purine compounds: there are still challenges in the diverse synthesis of purines in organic letters One representative example is the 9-arylation of purines, because such reactions often have problems such as low synthesis efficiency and narrow substrate range Generally, 9-arylation has two paths: (1) copper catalyzed C-N cross coupling of purines; (2) cyclization of aromatic amines and 5-amino-4-chloropyrimidine, adding orthoester derivatives, acyl chloride or adding additional methylation steps before ring closing All of the above methods have disadvantages, such as limited substrate, low yield and multi-step In addition to aromatization, the synthesis of 9-alkylpurines and the direct substitution of purine nucleosides are difficult, because the mixture of N 3 -, n 7 - and N 9 - substitutions is usually obtained in the reaction, which results in the loss of yield and affects the separation In addition, it is difficult to get 8-substituted products by the previous methods, and further Bromination and substitution reactions are needed Recently, Jean Luc decout team from the University of Grenoble Alps in France published a paper on organic letters, reporting a new method of one pot synthesis of purine without metal catalysis In the reaction, Vilsmeier reagent was used and purines were substituted at multiple positions with high yield Figure 2 New strategy source of purine synthesis: the author of organic letters envisages that purine can be obtained from 5-amino-4,6-dichloropyridine in two ways One route is to replace one chlorine at the 4 position with ammonia, then connect amidine group at the 5 position of amino group, and then close the intermediate ring under acid condition; the other method can be synthesized in one pot Similarly, first replace the 4 position chlorine with amine, and then add Vilsmeier reagent to form the ring together The two methods have the same result, and 9-substituted-6-chloropine is obtained (Fig 2) The one pot synthesis process is shown in Figure 3 The reaction goes through three steps: nucleophilic substitution, amidine formation and ring closing However, there is no need to separate and purify the intermediate, and there are few by-products generated, so the final product purine can be easily separated The control experiment shows that the presence of a small amount of water and oxygen will not affect the reaction, which shows the stability of the reaction In addition, the scale of the reaction was expanded from 50 mg to 1 g, and the reaction still proceeded smoothly Figure 3 One pot substrate development source: after organic letters studied various characteristics of the reaction, the author expanded the substrate (Figure 3) The experimental results show that the purine products (4-17) with 9 consecutive aryl substituents can be obtained by using compound 1 as the reaction substrate, most of which have excellent yields, and the yields of strong electron withdrawing aniline and heterocyclic benzidine are relatively low Two pyrimidines with different substituents, such as me, NH 2, Cl, react with substituted aniline, and the yield is also good (18 - 23) Aliphatic amines can also react under alkaline conditions, but the reaction activity is quite different (24 - 27) In addition, several 8-Position functionalized purines were synthesized After adjusting the reaction conditions, methyl, dimethylamine, phenyl, 4-chlorophenyl and the substrate with steric hindrance were all compatible with the reaction (28-32) Finally, 8-substituted ribonucleosides were synthesized from pyrimidine (Fig 4) Figure 4 Source of ribonucleoside synthesis: summary of organic letters: the jean Luc decout team has developed a general one pot synthesis method of multi substituted purines, which will provide strong chemical support for finding new biological tools and drugs Paper link: http://pubs.acs.org/doi/abs/10.1021/acs.orglett.7b03209