Regioselective C–F Bond Activation/C–C Bond Formation between Fluoropyridines and Cyclopropyl Groups at Zirconium

Abstract

This paper addresses the problem of the strong and inert C−F bond activation of various fluoropyridines by zirconocene derivatives. Dicyclopropylzirconocene, [Cp 2 Zr(c-C 3 H 5 ) 2 ], thermally eliminates cyclopropane, giving the transient intermediate zirconabicyclobutane [Cp 2 Zr(η 2 -c-C 3 H 4 )] that cleaves a C−F bond of pentafluoropyridine selectively at position 2, forming new Zr−F and C−C bonds stereoselectively to give [Cp 2 ZrF{c-cis-CHCH 2 CH(2-NC 5 F 4 )}]. DFT computations indicate the selectivity results from the initial formation of an azazirconacycle intermediate that undergoes ring opening and C−F bond cleavage. Transmetalation with a variety of cyclopropyl donors yields [Cp 2 Zr(c-C 3 H 5 ){c-cis-CHCH 2 CH(2-NC 5 F 4 )}] with the selectivity depending on the nature of the donor. A synthetic cycle is realized when [Cp 2 Zr(c-C 3 H 5 ){c-cis-CHCH 2 CH(2-NC 5 F 4 )}] reacts with pentafluoropyridine, yielding 2-(c-C 3 H 5 )NC 5 F 4 and [Cp 2 ZrF{c-cis-CHCH 2 CH(2-NC 5 F 4 )}] with C−F bond activation. Attempts at converting this reaction sequence to a catalytic version failed due to either decomposition of the active species or multiple C−F bond substitutions by the transmetalating agent.

Halogenated Phenylpyridines Possessing Chemo-Selectivity for Diverse Molecular Architectures

“…Work by Chambers et al has reported one of the most comprehensive studies with C -nucleophile addition-substitutions using PFP demonstrating, in some cases, unique substitution patterns not otherwise observed with O -, S -, and N -nucleophiles . This work was further supported with studies reporting C -nucleophile additions using cyclopropane anion salts of Mg that showed exclusive regioselective addition to the 4-position of PFP while Zn­( c -C 3 H 5 ) 2 and Li­( c -C 3 H 5 ) afforded a distribution of 2- or 4-substituted PFP . In addition, Li­( c -C 3 H 5 ) also produced 2,4-substituted PFP on the heterofluoroaromatic ring limiting substrate diversity with C -nucelophiles.…”

“…M p maxima at 125 and 130 °C. m/z (% relative intensity) 580 ([M] + , 100), 500 (15), 420 (15), 339 (15), 319 (15), 238 (20), 207 (15).…”

“…The combined organic fractions were washed with saturated brine (1 × 100 mL), dried with magnesium sulfate, vacuum filtered over a dual plug of silica/ Celite, concentrated using rotary evaporation, and dried under high vacuum affording a yellow solid (389 mg, 67%). 1 (20). Network (N3).…”

“… 19 This work was further supported with studies reporting C -nucleophile additions using cyclopropane anion salts of Mg that showed exclusive regioselective addition to the 4-position of PFP while Zn( c -C 3 H 5 ) 2 and Li( c -C 3 H 5 ) afforded a distribution of 2- or 4-substituted PFP. 20 In addition, Li( c -C 3 H 5 ) also produced 2,4-substituted PFP on the heterofluoroaromatic ring limiting substrate diversity with C -nucelophiles. Other examples of high yielding, diverse C -nucleophile additions have included aryl/alkyl Grignard reagents, 21 alkyl transfer from phosphonium ylides, 22 and via mild tetramethylsilylacetylene deprotection 23 all with regio-controlled substitution limited to the PFP 4-position.…”