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

Abstract

Ac ontinuous-flowm ethod for the regioselective arylation of fluoroarenes and fluoropyridines has been developed. The telescoped procedure reported here consists of at hree-step metalation, zincation, and Negishi cross-coupling sequence,p roviding efficient access to av ariety of functionalized 2-fluorobiaryl products.Precise temperature control of the metalation step,made possible by continuous-flowtechnology, allowed for the efficient preparation of the arylated products in high yields and short residence times.A dditionally,s everal examples of the regioselective arylation of benzotrifluoride derivatives are also provided.

Synthesis of Polyfunctional Diorganomagnesium and Diorganozinc Reagents through In Situ Trapping Halogen–Lithium Exchange of Highly Functionalized (Hetero)aryl Halides in Continuous Flow

“…[3] The scope of halogen-lithium exchange reactions is limited by the presence of sensitive functional groups in these unsaturated substrates, [2,3] which precludes the presence of an ester, an itro,a na zide,o ra ni sothiocyanato group. [6] Continuous-flow setups have emerged as ap owerful tool for solving synthetic problems. [6] Continuous-flow setups have emerged as ap owerful tool for solving synthetic problems.…”

“…[15] Ther esulting products 4i-k were obtained in 68-85 %y ield (entries 8-10). [2][3][4][5][6] Notably,only halogen-lithium exchanges of o-nitroarenes [2,6] and an alkenyl iodide containing an aliphatic azide [6] at À100 8 8Cu nder batch conditions are known, as well as several flow methods for ester-, ketone-, and nitrocontaining arenes that involve applying ultrafast micromixing and residence times down to 0.0015 s. [8] Again, we found that in the absence of am etal salt, 4-iodophenyl azide [17] (5a) decomposes completely when performing the reaction in flow. [16] To further demonstrate the broad applicability of in situ trapping exchange reactions in flow,w ei nvestigated the compatibility of these exchanges with aryl halides bearing challenging functional groups such as ester, ketone,nitro,and heterocumulene groups,f or example,a na zide or isothiocyanate.…”

“…Thus,b is-(nitroaryl)zinc compounds 6c-f were generated from the corresponding aryl halides 5c-f. Allylation, acylation, and addition to indole aldehyde 3m or ketone 3f in batch furnished the desired functionalized nitroarenes 7c-g in 60-78 %yield (entries [2][3][4][5][6]. Thus,b is-(nitroaryl)zinc compounds 6c-f were generated from the corresponding aryl halides 5c-f. Allylation, acylation, and addition to indole aldehyde 3m or ketone 3f in batch furnished the desired functionalized nitroarenes 7c-g in 60-78 %yield (entries [2][3][4][5][6].…”

“…[4] These drawbacks were avoided to some extent by the use of cryogenic temperatures, [2a] special protecting groups, [5] or fast consecutive transmetalations to less reactive organometallics. [6] Continuous-flow setups have emerged as ap owerful tool for solving synthetic problems. [6b, 7] Thus,Yoshida and others have utilized ultra-fast mixing and precise reaction-time control of custom-made flow setups for achieving the generation of lithiated arenes bearing ester,i sothiocyanate,c yano,o rn itro groups.…”

“…[16] To further demonstrate the broad applicability of in situ trapping exchange reactions in flow,w ei nvestigated the compatibility of these exchanges with aryl halides bearing challenging functional groups such as ester, ketone,nitro,and heterocumulene groups,f or example,a na zide or isothiocyanate. [2][3][4][5][6] Notably,only halogen-lithium exchanges of o-nitroarenes [2,6] and an alkenyl iodide containing an aliphatic azide [6] at À100 8 8Cu nder batch conditions are known, as well as several flow methods for ester-, ketone-, and nitrocontaining arenes that involve applying ultrafast micromixing and residence times down to 0.0015 s. [8] Again, we found that in the absence of am etal salt, 4-iodophenyl azide [17] (5a) decomposes completely when performing the reaction in flow. However,s creening of various in situ trapping exchange conditions,f or example,a ddition of soluble metal salts,f low rate,a nd temperature, [13] led to the desired allylated phenyl azide 7a in 72 %yield of isolated product (Scheme 3).…”