Angewandte
Communications
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À
Table 1: Substrate scope of the C C cross-coupling reaction between aryl
of organolithium species in continuous-flow synthesis was
pioneered by Yoshida and co-workers.[12,13] Several examples
demonstrated the successful transfer of organolithium reac-
tions from batch to continuous-flow conditions, resulting in
improvements of yield and functional-group compatibil-
ity.[13,14] Furthermore, modular cryo-flow reactors have been
developed.[15] Knochel and co-workers recently reported the
formation of (hetero)aryl zincates in flow followed by Negishi
cross-coupling under batch conditions.[16] Aside from this
semi-batch approach, a Negishi cross-coupling for the for-
fluorides and bromobenzene.[a]
2
3
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mation of C(sp ) C(sp ) bonds under flow conditions has also
been described.[17] Yet, the formation of biaryl compounds
through Negishi couplings using continuous-flow conditions
exclusively is still unknown. Herein, we describe the regio-
selective lithiation of fluoro- and trifluoromethyl-substituted
arenes and pyridines followed by zincation and Negishi cross-
coupling in a telescoped continuous-flow process.
We initiated our study by optimizing the reaction of
fluorobenzene with bromobenzene to provide biaryl 4a. A
three-stage reactor was assembled; stage 1: directed lithia-
tion, stage 2: zincation, stage 3: cross-coupling (Scheme 2).[18]
[a] 1.0 mmol scale; yields of isolated products are given (average of two
runs). See the Supporting Information for details. [b] Yield of isolated
product after conversion into the corresponding phenol. [c] Lithiation at
À608C for 240 s. [d] Yield of isolated product on 5.0 mmol scale.
resulted in further arylation to provide triaryl compound 4b.
Difluoro-substituted arenes[7c] gave the desired biaryls in high
yields (4c–4e). In the case of fluoro-substituted anisoles,[7e]
the fluoro substituent proved to be the stronger directing
group as demonstrated by the formation of 4 f–4h as single
regioisomers. The same applied to the use of trifluoromethyl-
substituted fluoroarenes (4i–4k).[7c] However, in the case of
3-fluorobenzotrifluoride, a small amount of the regioisomer
4l was isolated, which is likely due to the steric hindrance at
the ortho position next to the bulky CF3 group. Chloro-
substituted fluoroarenes[7f] were also suitable substrates,
giving the desired biaryl products in good yield (4m–4o)
without formation of either homocoupled or dechlorinated
side products. Furthermore, fluoro-substituted toluene[7d]
derivatives were well tolerated (4p–4r). In the case of
3-fluorotoluene, the methyl group directs the lithiation to
the para position (4r), presumably for steric reasons.
Given the importance of heterocyclic compounds in
medicinal chemistry,[21] we next examined the Negishi cou-
pling of 3a with heteroaryl bromides and other functionalized
bromoarenes (Table 2). Aryl bromides with electron-with-
drawing and electron-donating substituents were efficiently
coupled (4s–4u). Bromoferrocene could be employed under
our reaction conditions to give 4v. A variety of brominated
heterocycles, including pyridine (4w, 4x), pyrimidine (4y),
indole (4z), furan (4a’), thiophene (4b’), pyrazole (4c’),
thiazole (4d’), and benzothiophene (4e’), were efficiently
coupled to provide the desired biaryls. To demonstrate the
utility of our system, we were able to run experiments for
more than 2.5 h without any interruption to collect a total of
5 mmol of the product (Table 1, 4p; Table 2, 4s). These
examples highlight the ease of scale-up in continuous-flow
chemistry.
Scheme 2. Experimental setup for the synthesis of 2-fluorobiaryls by
directed lithiation, zincation, and Negishi cross-coupling.
We found that intermediate 2 was stable up to À308C. Above
this temperature, benzyne formation through LiF elimination
took place, as indicated by a strong discoloration of the
reaction mixture. To avoid undesired side reactions through
benzyne formation, lithiation and zincation were conducted
at À408C. Another challenge encountered during method
development was an undesired pulsation of flow caused by
gas generation in stage 3. This problem was mitigated by
utilizing a back-pressure regulator (BPR). The last challenge
of optimization was avoiding the clogging in stage 3, which is
due to the precipitation of inorganic salts. Thus the cross-
coupling portion of the flow reactor necessitated the use of
a heated ultrasonic bath to keep particles in suspension.[19,20]
The total residence time in the flow reactor was 15 min. The
biaryl products were obtained after aqueous workup and
chromatographic purification.
Using the reaction setup described above (Scheme 2), the
substrate scope was explored with a variety of fluoro-
substituted arenes (Table 1). Aside from bromo-substituted
arenes, aryl triflates and chlorides were also suitable cross-
coupling partners. Subjecting 4a to these reaction conditions
Next, we turned our attention to the arylation of fluoro-
substituted pyridines. The regioselective ortho lithiation of
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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