A Scalable Balz-Schiemann Reaction Protocol in a Continuous Flow Reactor

Summary

A detailed scalable continuous flow protocol is presented to synthesize an aryl fluoride from an aryl amine through the Balz-Schiemann reaction.

Abstract

The demand for aromatic fluorides is steadily increasing in the pharmaceutical and fine chemical industries. The Balz-Schiemann reaction is a straightforward strategy for preparing aryl fluorides from aryl amines, via the preparation and conversion of diazonium tetrafluoroborate intermediates. However, significant safety risks exist in handling the aryl diazonium salts when scaling up. In order to minimize the hazard, we present a continuous flow protocol that has been successfully performed at a kilogram scale that eliminates the isolation of aryl diazonium salts while facilitating efficient fluorination. The diazotization process was performed at 10 °C with a residence time of 10 min, followed by a fluorination process at 60 °C with a residence time of 5.4 s with about 70% yield. The reaction time has been dramatically reduced by introducing this multi-step continuous flow system.

Introduction

The Balz−Schiemann reaction is a classic method for replacing the diazonium group with fluorine by heating ArN₂⁺BF₄⁻ without a solvent^1,2. The reaction can be applied to a wide variety of aryl amine substrates, making it a generally applicable approach to synthesize aryl amines, which are frequently utilized for advanced intermediates in pharmaceutical or fine chemical industries^2,3. Unfortunately, harsh reaction conditions are often employed in the Balz-Schiemann reaction, and the reaction genera....

Protocol

CAUTION: Carefully check the properties and toxicities of the chemicals described here for the appropriate chemical handling of the relevant material as per the material safety data sheets (MSDS). Some of the chemicals used are detrimental to health, and special care must be taken. Avoid inhalation and contact with skin of these materials. Please wear the proper PPE during the whole process.

1. Preparation of feeds for continuous flow protocol

1. Purchase BF₃·Et₂O with a concentration of 8.1 mmol/mL. Label the glass bottle with 2.5 kg of BF₃·Et₂O as Feed A.
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Results

The model reaction is shown in Figure 2. 2-Methylpyridin-3-amine (compound 1 in Figure 2) was chosen as the starting material to prepare 2-methylpyridin-3-fluoride (compound 3 in Figure 2) via the Balz-Schiemann reaction. The experimental parameters were systematically investigated by varying reaction temperature and residence time. Feed A is 0.35 M 2-methylpyridin-3-amine in THF. Feed B is pure BF₃·Et₂

Discussion

A continuous flow protocol of the Balz-Schiemann reaction has been successfully performed through a combination of a micro-channel flow reactor and a dynamically mixed flow reactor. This strategy features several advantages compared with the batch process: (i) it is safer with controlled diazonium salt formation; (ii) it is more amenable to a higher reaction temperature, 10 °C versus -20 °C; and (iii) it is more efficient without isolation of the diazonium intermediate, two steps in one continuous process. Spec.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
2-Methylpyridin-3-amine	Raffles Pharmatech Co. Ltd	C2021236-SM5-H221538-008	HPLC: >98%, Water by KF ≤0.5%
316L piston constant flow pump	Oushisheng (Beijing) Technology Co.,Ltd	DP-S200
BF3.Et2O	Whmall.com	B802217
Citric acid	Titan Technology Co., Ltd	G83162G
con.HCl	Foshang Xilong Huagong	1270110101601M
Dynamically mixed flow reactor	Autichem Ltd	DM500	316L reator with 500 mL of internal volume
Heptane	Shenzhen Huachang	HCH606	Water by KF ≤0.5%
Micro flow reactor	Corning Reactor Technology Co.,Ltd	G1 Galss AFR	Glass module with 9 mL of internal volume
PTFE piston constant flow pump	Sanotac China	MPF1002C
Sodium hydroxide	Foshang Xilong Huagong	1010310101700
tert-Butyl methyl ether	Titan Technology Co., Ltd	01153694
tert-Butyl nitrite	Whmall.com	XS22030900060
Tetrahydrofuran	Titan Technology Co., Ltd	1152930	Water by KF ≤0.5%