Metal free C–H functionalization of diazines and related heteroarenes with organoboron species and its application in the synthesis of a CDK inhibitor, meriolin 1

Abstract

Here, we report a metal-free cross-coupling reaction of diazines and related heteroarenes with organoboron species via C-H functionalization. The optimized conditions represent a metal-free method for the activation of aryl/heteroarylboronic acids, which undergo coupling with diazines and related heteroarenes. Optimized conditions also find application in the synthesis of a pyrimidine-based potent CDK inhibitor, meriolin1.

Iron-catalyzed cross-coupling of arylboronic acids with unactivated N-heterocycles and quinones under microwave heating

“…Singh and coworkers reported the coupling of N-heteroarenes and arylboronic acids in the absence of a metal catalyst or acid using a persulfate oxidant (Scheme 1.10). 67 Arylated products were obtained in moderate to good yields with more electron-deficient N-heteroarenes, but yields diminished with less electron-deficient heteroarenes. Arylboronic acid esters and aryltrifluoroborate salts were also examined, and gave moderately lower yields than arylboronic acids.…”

“…Arylboronic acid esters and aryltrifluoroborate salts were also examined, and gave moderately lower yields than arylboronic acids. 67 While a metal and acid-free reaction is desirable, the reaction required heating to 160 °C, and in most cases resulted in lower yields than most metal-catalyzed reactions. , which demonstrate the utility of the reaction in the synthesis of biologically active compounds.…”

“…The scope of N-heteroarene cross-coupling in the reaction has been examined several times, usually focussing on six-membered rings containing one or more nitrogen atom (Figure 1.8). [18][19][20][63][64][65][66][67] Unactivated N-heteroarenes such as quinoline, pyridine, pyrazine, or pyrimidine have been cross-coupled in good yields, but better results are obtained when a strong electron-withdrawing group, such as a cyano or trifluoromethyl group, is present on the N-heteroaryl. 18,20,63,64,66 Reactions with weakly electronwithdrawing halide substituents have been described with mixed results, with some groups reporting greatly diminished yields, and others reporting little difference between the halides and more strongly electron-withdrawing groups.…”

“…There are four accounts of coupling with arylboronic acid pinacol esters. 19,53,62,67 All accounts reported that the pinacol esters were more sluggish, and gave lower yields, than the corresponding arylboronic acid. 19,53,62,67 There are also 5 reports of coupling with potassium aryltrifluoroborate salts (Molander salts), with both quinones and Nheteroaryls.…”

“…19,53,62,67 All accounts reported that the pinacol esters were more sluggish, and gave lower yields, than the corresponding arylboronic acid. 19,53,62,67 There are also 5 reports of coupling with potassium aryltrifluoroborate salts (Molander salts), with both quinones and Nheteroaryls. 19,53,62,63,67 In all cases, the aryltrifluoroborate salt reacted with similar or slightly higher yield when compared to the corresponding arylboronic acids.…”