Angewandte
Communications
Chemie
Balz–Schiemann Reaction
Rapid Synthesis of Aryl Fluorides in Continuous Flow through the
Balz–Schiemann Reaction
Nathaniel H. Park+, Timothy J. Senter+, and Stephen L. Buchwald*
Abstract: The Balz–Schiemann reaction remains a highly
utilized means for preparing aryl fluorides from anilines.
However, the limitations associated with handling aryl diazo-
nium salts often hinder both the substrate scope and scalability
of this reaction. To address this, a new continuous flow
protocol was developed that eliminates the need to isolate the
aryl diazonium salts. The new process has enabled the
fluorination of an array of aryl and heteroaryl amines.
S
purred by the pharmaceutical and agrochemical signifi-
cance of fluorinated aromatic compounds,[1] there have been
À
significant advances in methods for aryl C F bond formation.
These include transition metal-catalyzed or mediated proto-
cols,[2] deoxyfluorination of phenols,[3] and fluorination of aryl
Grignard reagents.[4] Despite these advances, established
methods such as the Halex process[5] and the Balz–Schiemann
reaction[6,7] remain relevant routes for preparing aryl fluo-
rides. While the Halex process is limited to highly activated
substrates, the Balz–Schiemann reaction can utilize a variety
of aryl amine substrates making it a versatile method. As aryl
amines are readily accessible, this process has been utilized on
many advanced synthetic intermediates.[7] Unfortunately, the
Balz–Schiemann reaction suffers from the need to employ
harsh reaction conditions, and often provides modest yields,
and involves the generation of a potentially explosive aryl
diazonium salt.[7] Thus, the development of an improved
protocol that would provide rapid, scalable access to aryl
fluorides would be significant.
The Balz–Schiemann reaction involves converting the aryl
amine starting material into the corresponding diazonium
salt, which is typically isolated and dried prior to thermal or
photochemically-mediated dediazotization (Figure 1).[8]
Handling the aryl diazonium intermediates is a major safety
concern as they have the potential to undergo spontaneous
and violent decomposition.[9] To mitigate the potential safety
risks associated with the isolation of aryl diazonium salts,
several one-pot protocols have been utilized.[10] While effec-
tive, they still involve the generation of aryl diazonium salts
under batch conditions and in some cases require the use of
HF·pyridine as the solvent.[7c,f,10b] Alternatively, continuous
flow processing offers numerous safety advantages over batch
Figure 1. Summary of the advantages of this work.
reactors and is an attractive option for handling diazonium
salts.[11] A technique has been previously developed for the
Balz–Schiemann reaction where diazotization and subse-
quent thermal decomposition were conducted as two inde-
pendent continuous flow processes.[12] Unfortunately, this
protocol still necessitated the isolation and drying of the aryl
diazonium salt intermediate formed under aqueous condi-
tions. To overcome the current limitations of both the batch
and flow processes, we sought to develop a new continuous
flow process that overcomes the limitations of the previous
methods.
Adapting the Balz–Schiemann reaction to a continuous
flow process poses several challenges. One of the main issues
is the extensive formation of side products that are seen
during the thermal dediazotization process. These include the
parent arene, formed from H-atom abstraction of the solvent
by the aryl radical, or products including phenol and aryl
ethers formed from trapping of the cation intermediate by
other nucleophiles present in the reaction mixture
(Figure 2).[13] To avoid these side reactions, the thermal
dediazotization is often performed using the neat diazonium
salt[7b,8c] or in nonpolar solvents such as toluene,[7g] 1,2-
dichlorobenzene,[10a] or heptane[7c] after initial formation of
the diazonium salt in a polar or aqueous reaction medium.
The solvent switch required renders these procedures cum-
bersome to employ in a continuous process. Moreover, these
commonly used nonpolar solvents do not dissolve the aryl
diazonium salt readily and would lead to reactor clogging
under flow conditions. To overcome this, we focused our
[*] Dr. N. H. Park,[+] Dr. T. J. Senter,[+] Prof. Dr. S. L. Buchwald
Department of Chemistry
Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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