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. 2018 Jun 27;140(25):8020-8026.
doi: 10.1021/jacs.8b04530. Epub 2018 May 24.

Site-Selective Switching Strategies to Functionalize Polyazines

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Site-Selective Switching Strategies to Functionalize Polyazines

Ryan D Dolewski et al. J Am Chem Soc. .
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Abstract

Many drug fragments and therapeutic compounds contain multiple pyridines and diazines. Developing site-selective reactions where specific C-H bonds can be transformed in polyazine structures would enable rapid access to valuable derivatives. We present a study that addresses this challenge by selectively installing a phosphonium ion as a versatile functional handle. Inherent factors that control site-selectivity are described along with mechanistically driven approaches for site-selective switching, where the C-+PPh3 group can be predictably installed at other positions in the polyazine system. Simple protocols, readily available reagents, and application to complex drug-like molecules make this approach appealing to medicinal chemists.

Figures

Scheme 1.
Scheme 1.
Mechanistic stages of phosphonium ion formation.
Scheme 2.
Scheme 2.. Effect of base on reactivity and site-selectivitya, b
aYields and ratios reported as in Table 1.bYields calculated by1H NMR spectroscopy of the crude reaction mixture.
Scheme 3.
Scheme 3.. Impact of reagent order on site-selectivitya,b,c,d,e
aYields and ratios reported as in Table 1.bYield calculated by1H NMR using 1,3,5-trimethoxybenzene as an internal standard.cx+y represents a bis-phosphonium salt.diso refers to an unidentified phosphonium salt isomer.eMixture of two undefinited isomers
Scheme 4.
Scheme 4.. Phosphine-dependent site-selectivitya,b
aYields and ratios reported as in Table 1.bYields calculated by1H NMR spectroscopy of the crude reaction mixture.
Scheme 5.
Scheme 5.. Derivatizations of phosphonium salt isomersa,b
aIsolated yields are shown and ratios are reported as in Table 1.bThe minor isomer is a 2-position pyridine phosphonium salt.

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