Selective Functionalization of 2-Fluoropyridine, 2,3-Difluoropyridine, and 2,5-Difluoropyridine at Each Vacant Position

Abstract

The concept of "regioexhaustive substitution" has been successfully applied to 2-fluoro-, 2,3-difluoro-, and 2,5-difluoropyridine. All vacant positions were amenable to regioselective metalation and subsequent carboxylation by employing either chlorine as a neighboring site activating protective group or trimethylsilyl as a neighboring site screening protective group. In this way, approximately half a dozen fluorinated pyridinecarboxylic acids were derived from each starting material.

Metalation and Derivatization of All Six Dichlorobenzotrifluorides:Site Selectivities

“…The main component 11, isolated in 19 % yield, was purified by fractional crystallization. The other isomers were identified after reductive dechlorination [11,[21][22][23] by gas chromatographic comparison with authentic 3-and 4-(trifluoromethyl)benzoic acid. The same 1:7:2 mixture (83 %) was obtained when butyllithium was employed as the base whereas sec-butyllithium gave a 3:2:6 mixture (57 %) of the acids 10, 11, and 12.…”

“…1,2,3-trichlorobenzene, [6,26] 1,2,3,4-tetrachlorobenzene, [26] and hexachlorobenzene [27] ) have been documented. 2,4-Dichloro-3-(trifluoromethyl)benzoic acid (25) is the expected "ortho-metalation" product derived from an intermediate bearing the metal atom at a chlorineadjacent position whereas the isomeric 3,5-dichloro-4-(trifluoromethyl)benzoic acid (26; identified by NMR spectroscopy as a byproduct after reductive dechlorination [11,[21][22][23] of the crude reaction mixture) is obviously the result of a "meta-directed metalation" reaction. Such an anomalous regioselectivity of organometallic attack has so far been observed with trialkyl(2,6-dichlorophenyl)-and trialkyl(2,6-dibromophenyl)silanes for which "meta metalation" was found to be the preferred if not exclusive reaction mode.…”

Continuous‐Flow Synthesis of Biaryls by Negishi Cross‐Coupling of Fluoro‐ and Trifluoromethyl‐Substituted (Hetero)arenes

“…The regioselective ortho-lithiation of halopyridines with lithium diisopropylamide (LDA) and other amide bases is well established. [22] Since pyridines are considerably more acidic than arenes, we were able to lithiate them under milder reaction conditions using LDA. However, we encountered significant salt formation after addition of zinc chloride.…”

“…Hence, the lithiation with LDA could be performed at 0 °C under continuous flow conditions within seconds, which is in strong contrast to previously reported batch conditions (−78 °C for several hours). [22] The optimized flow process for 2-fluoropyridine is depicted in Scheme 3. The total residence time for this process was less than 11 min.…”

The Reactivity of 2‐Fluoro‐ and 2‐Chloropyridines toward Sodium Ethoxide: Factors Governing the Rates of Nucleophilic (Het)Aromatic Substitutions

“…Starting Materials. The preparations of 2,3-, 2,4-, and 2,5-difluoropyridine (1f, 1e, and 1b) [28], 2,3,6-and 2,4,6-trifluoropyridine (3b and 3g) [28], 3-chloro-2-fluoro-and 4-chloro-2-fluoropyridine (1h and 1g) [29], 3-bromo-2,6-difluoro-, 3-chloro-2,6-difluoro-, 2,6-difluoro-3-iodo-, 2,6-difluoro-4-iodo-, 2,6-difluoro-3-(trimethylsilyl)-, 3-bromo-2,6-difluoro-5-(trimethylsilyl)-, 2,6-difluoro-3,5-bis(trimethylsilyl)-, and 3,5-dibromo-2,6-difluoropyridine (3e, 3d, 3f, 3h, 3a, 10, 9, and 11) [1], 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (12) [30], and 2-fluoro-5-(trifluoromethyl)pyridine (1i) [31] have already been described. All other starting materials, except one, are commercially available; 2-fluoropyridine (1c) and 2,6-difluoropyridine (1d3c) were purchased from Apollo Scientific (UK-SK6-2QR Stockport), and 2-chloropyridine (7a), 2,6-dichloro-, 2,6-dichloro-3-(trifluoromethyl)-, 2-chloro-3-(trifluoromethyl)-, and 2-chloro-5-(trifluoromethyl)pyridine (7b, 13, 7c, and 7d) from Acros Organics (B-2440 Geel).…”