Synthesis of functionalized pyrimidouracils by ruthenium‐catalyzed oxidative insertion of (hetero)aryl methanols into N‐uracil amidines

Abstract

A dehydrogenative coupling of N‐uracil amidines with (hetero)aryl methanols has been developed, allowing for the facile synthesis of a broad range of structurally diverse pyrimidouracils. By applying [RuCl2(p‐cymene)]2/Cs2CO3 as an efficient catalytic system, the easily available, cheap (hetero)aryl methanols were firstly employed for oxidative insertion/CH amination into the N‐uracil amidines, providing highly functionalized pyrimido[4,5‐d]pyrimidine‐2,4‐diones. Due to the better stability of alcohols than aldehydes, this synthetic protocol is applicable to a broad range of alcoholic substrates and does not required any protection during the whole preparation process. The presented protocol has the potential to prepare valuable products which cannot be accessed presently or extremely arduous to procure by following regular procedure. Hence, this is a remarkably improved protocol compared with the existing methodologies. The overall reaction sequence is an effective oxidation‐imination‐cyclization tandem process catalyzed by ruthenium catalyst.

Recent Developments towards the Synthesis of Pyrimidopyrimidine and Purine Derivatives

“…From this elegant idea, recently we reported a dehydrogenative coupling between N-uracil amidines (88) and (hetero)aryl methanols (91) for the synthesis of structurally diverse pyrimidouracils. [90] The oxidative insertions of alcohols into the N-uracil amidines were achieved by applying 2.5 mol% of [RuCl 2 (p-cymene)] 2 as a catalyst and Cs 2 CO 3 as a base in DMSO at 110 °C (Scheme 28). A variety of functionalized pyrimido[4,5-d]pyrimidine-2,4-diones (89) were obtained in high yields utilizing commercially available and cheap (hetero)aryl methanols.…”

Synthesis of Amidines and Its Application to Pyrimidouracil Synthesis

“…In order to alleviate these shortcomings, we have developed another synthetic protocol for the preparation of 1,3,5,7tetrasubstituted pyrimido[4,5-d]pyrimidines via TBHP-mediated direct oxidative coupling of N-uracil amidines and under metal-free conditions [35]. Very recently, we also observed that pyrimidouracils synthesis could also be accomplished by ruthenium catalyzed oxidative insertion of aryl methanols into N-uracil amidines [36]. In continuation of our efforts towards the synthesis of nitrogen heterocycles, an efficient synthetic procedure for the synthesis of pyrimidouracils via PhI(OAc)2 mediated oxidation insertion of methylarenes into N-uracil amidines has been developed.…”