Cu-Catalyzed [3 + 3] Annulation for the Synthesis of Pyrimidines via β-C(sp³)–H Functionalization of Saturated Ketones

Abstract

A novel, efficient, and facile approach for the synthesis of structurally important pyrimidines has been successfully developed by Cu-catalyzed and 4-HO-TEMPO-mediated [3 + 3] annulation of commercially available amidines with saturated ketones. This method provides a new protocol for the synthesis of pyrimidines by a cascade reaction of oxidative dehydrogenation/annulation/oxidative aromatization via direct β-C(sp)-H functionalization of saturated ketones followed by annulation with amidines.

Base-promoted cyclocondensation of (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones with guanidine hydrochloride: facile synthesis of E-2-amino-4-aryl-6-(2-arylethenyl)pyrimidines

“…Product isolation from the reaction mixture with each of 1a-d through work up in the usual way (vide Experimental) followed by purification by column chromatograpy over silica gel furnished a single product in good yield (Scheme 3) ( Table 1). Analytical and spectral data of the products definitely showed that only 1:1 cyclocondensation took place resulting in the formation of the hitherto unknown compounds E-2amino-4-aryl-6-(2-arylethenyl) pyrimidines (3). The reaction of the unsymmetrical compounds 2a-c with guanidine hydrochloride was then studied by using the similar reaction conditions (Scheme 4).…”

“…A considerable attention has been focused on synthesis of various substituted pyrimidines due to their interesting biological activities. [1][2][3] Aminopyrimidines constitute one of the important classes of pyrimidines. The pharmaceutical importance of these compounds lies on the fact that they can be effectively used as analgesics, anti-inflammatory, anticonvulsant, insecticidal, herbicidal, antitubercular, anticancer and antidiabetic agents.…”

Metal‐Free, TBHP‐Mediated, [3+2+1]‐Type Intermolecular Cycloaddition Reaction: Synthesis of Pyrimidines from Amidines, Ketones, and DMF through C(sp3)−H Activation

“…Organic bases, such as (CH 3 ) 3 COK, CH 3 ONa, DABCO, pyridine, DBU, and Et 3 N, were also employed as the base;h owever,t hese weren ot as effective as Cs 2 CO 3 ( Table 1, entries 5-10). Screening different oxidants did not lead to an improved yield, with either low yields or no reaction observedi na ll cases ( Table 1, entries [11][12][13][14][15][16][17]. Decreasing or increasing the reactiont emperature also caused the reactiony ield to decrease ( Table 1, entries 18-20).…”

“…[10] Han and co-workers developed copper-catalyzed C(sp 3 )ÀHo xidative and annulation processes for the synthesis of pyrimidines from amidines and ketones. [11] Herein, we report an ew method for the formation of CÀC/CÀNb onds in pyrimidines through aT BHP-mediated [3+ +2+ +1]-type intermolecularc ycloaddition process from amidines, ketones, and DMF, in which the C(sp 3 )ÀHb onds of ketones and DMF are all activated (Scheme 1). This transformation also constitutes an ew example of employing DMF as ao ne-carbon synthon.…”

Recent Approaches to the Synthesis of Pyrimidine Derivatives

“…A very recent report by Han demonstrated that enones can be produced in situ from ketones 11 under oxidative coppercatalyzed conditions and subsequently condensed with amidines to deliver the corresponding 2,4-disubstituted and 2,4,6trisubstituted pyrimidines (Scheme 12). [19] The oxidation of the starting ketone to the corresponding enone is likely to proceed through a single-electron transfer from a copper enolate. The reaction is rather general, with a wide range of propiophenones, as well as aliphatic ketones, being tolerated, and is equally efficient with aromatic and aliphatic amidines.…”