Koch–Haaf reaction of adamantanols in an acid-tolerant hastelloy-made microreactor

The Koch–Haaf reaction of adamantanols was successfully carried out in a microflow system at room temperature. By combining an acid-tolerant hastelloy-made micromixer, a PTFE tube, and a hastelloy-made microextraction unit, a packaged reaction-to-workup system was developed. By means of the present system, the multigram scale synthesis of 1-adamantanecarboxylic acid was achieved in ca. one hour operation.

Carbonylation reactions are a powerful tool for the introduction of carbon monoxide into organic molecules, and we also reported that Pd-catalyzed carbonylation [13] and radical carbonylation [16] could be successfully carried out in a continuous microflow system with higher efficiency than in a batch autoclave system. In this study, we focused on the carbonylation of carbocation intermediates carried out in a continuous microflow system [22][23][24]. The Koch-Haaf reaction [25], that is the carbonylation of alcohols or olefins with formic acid in the presence of a strong acid, is an important reaction for the preparation of carboxylic acids, which are widely used in organic synthesis [26][27][28][29][30][31]. Since the Koch-Haaf reaction is highly exothermic, the reaction is typically carried out at controlled temperature by means of a cooling bath, such as an ice bath, and with carefully controlled slow addition of reagents through an addition funnel. The temperature control causes a serious problem especially for large scale synthesis. Herein, we report that the Koch-Haaf reaction in a microflow reactor can be carried out at room temperature without any cooling equipment. The employed hastelloy-made microreactor system was compatible with corrosive (strongly acidic) conditions and confirmed for gram scale (7.1 g) synthesis of 1-adamantanecarboxylic acid in ca. 1 h operation.

Results and Discussion
The carbonylation reaction of 1-adamantanol (1a) was investigated in a microflow system as a model reaction. Since the Koch-Haaf reaction requires the use of concentrated sulfuric acid, an acid-tolerant system is essential. For this study, we employed a combination of a hastelloy-made micromixer (MiChS, β-150H) having 150 μm reactant inlet holes and 200 μm × 300 μm channels (Figure 1), and a PTFE tube (1.0 mm i.d. × 3 m, inner volume: 2.36 mL) as a residence time unit. To this reactor system, a hastelloy-made microextraction unit (a flow-workup system) was attached ( Figure 2 and Figure 3). The microextraction unit has three inlets and one outlet (channel size: 1 mm i.d. × 14 cm). The reaction mixture was mixed at T-shaped junctions with Et 2 O and water, and a biphasic mixture was collected from the outlet. 1-Adamantanol (1a) dissolved in HCOOH (flow rate: 0.30 mL/min) and 98% H 2 SO 4 (flow rate: 0.88 mL/min) were mixed in the micromixer at room temperature, and the resulting reaction mixture was fed into the PTFE tube and then into the extraction unit, in which Et 2 O (flow rate: 2.5 mL/min) and water (2 mL/min) were introduced to extract the carbonylation  product and remove excess acids (Scheme 1). The biphasic mixture was collected in a flask and the ether layer was concentrated in vacuo. 1-Adamantanecarboxylic acid (2a) was obtained in 89% isolated yield after purification by silica gel column chromatography. While the residence time was a priori expected to be 2 min based on the total flow rate of the reagents and inner volume of the residence time unit, the observed Scheme 1: Synthesis of 1-adamantanecarboxylic acid (2a) in a microflow system. residence time was 1.5 min due to a plug flow by the CO gas generated.
For comparison, we also carried out the batch reaction in a 50 mL glass flask on 4 mmol scale to give 2a in 92% yield. In the batch reaction, the careful addition of a solution of 1a in formic acid over a period of 5 min and cooling in an ice bath were necessary to achieve good results. Indeed, without a cooling bath, we observed that the temperature of the reaction mixture rose up to 50-60 °C. It is therefore remarkable that the reaction in the microflow system can be performed successfully at room temperature without any cooling unit.
Multigram scale synthesis of 2a from 1a was carried out in a continuous flow reaction. When the reaction of 1a (45 mmol) was performed for 55 min, 7.1 g of 2a was obtained in 88% yield, demonstrating that the present microflow system can be used for multigram scale synthesis without any problems (Scheme 3).

Conclusion
In this work, we demonstrated that the Koch-Haaf reaction of adamantanols was successfully carried out in an acid-tolerant microflow system comprising a hastelloy-made micromixer, a PTFE tube, and a hastelloy-made microextraction unit. Unlike in the batch system, the reaction could be carried out at room temperature without any cooling equipment. The employed reaction-to-workup system was useful for the multigram scale  synthesis of 1-adamantanecarboxylic acid (2a). We are now expanding the system to other cationic systems and the results will be published in due course.

Experimental
Typical procedure for Koch-Haaf reaction in a microflow system. Multigram scale synthesis of 1-adamantanecarboxylic acid (2a Typical procedure for Koch-Haaf reaction in a batch reaction system In a 50 mL two-necked round bottom flask, 99% H 2 SO 4 (80 mmol, 7.85 g) was placed. A solution of 1-adamantanol (1a, 4 mmol, 613 mg) in 96% HCOOH (24 mmol, 1.01 g) was added through a dropping funnel over a period of 5 min, while the temperature of the reaction mixture was maintained at 15-20 °C in an ice/water bath. The reaction mixture was stirred at 15-20 °C for an additional 2 min, poured into ice/water and extracted with Et 2 O. The ethereal layer was washed with 1.4 N KOH aq, and the aqueous layer was acidified with 1 N HCl and extracted with Et 2 O. The organic layer was dried over MgSO 4 , evaporated and purified by column chromatography on SiO 2 . Compound 2a was obtained in 92% yield (667 mg). The reaction of 1b and 1c was carried out by a similar procedure.