Our investigation began with a series of preliminary batch experiments using sealed vessels with the goal of obtaining an initial set of reaction conditions for our flow experiments. The gem-dichlorocyclopropanation of cyclohexene 1, providing 7,7-dichlorobicyclo[4.1.0]heptane 2 (Scheme 2), was chosen as a model reaction. Thus, in a 3 mL vial cyclohexene and 3 mol% benzyltriethylammonium chloride (BTEA-Cl) were dissolved in chloroform. An aqueous solution of sodium hydroxide 40 wt% was added and the mixture was vigorously stirred. Notably, the silicone septa ruptured (pressure ca. 6 bar) in most cases due to the formation of CO gas. The presence of this gas could be confirmed by approaching a CO detector to the reaction mixture. Under batch conditions, 97% conversion (GC-FID) to the desired product 2 was achieved after 1 h.

Scheme 2 gem-Dichlorocyclopropanation of cyclohexene utilized as model reaction Full size image

We then directly moved to continuous flow conditions. A simple continuous flow setup consisting of a Y-mixer (0.5 mm i.d.) and PFA tubing was initially tested. The setup consisted of three streams (Table 1). Aqueous NaOH (40 wt%) and the organic phase consisting of cyclohexene (1.95 M) and the PTC (3 mol%) in chloroform were pumped using a peristaltic and a syringe pump, respectively (see Supporting Information), and mixed using the Y-mixer. After the residence time coil (PFA tubing, 0.8 mm i.d.), the reaction was quenched with an aqueous stream, using a syringe pump. The system was pressurized at 5 bar. Utilizing this simple setup and mixer a segmented flow pattern was obtained. A series of phase transfer catalysts was examined at room temperature using a residence time of 10 min. Apart from the usual ammonium salts, secondary and tertiary amines were also evaluated as catalysts (Table 1). The use of amines as catalysts for dichlorocarbene reactions using the chloroform/aqueous hydroxide system, first reported by Isagawa et al [27], follows a different mechanism involving formation of ylides between the carbene and the amines in the aqueous phase [24, 28, 29]. Once the ylide is extracted to the organic phase it releases the carbene. Notably, conversions obtained using several inexpensive tertiary amines (Table 1, entries 2–8) were analogous to those for BTEA-Cl (entry 1). Other more bulky tertiary amines and secondary amines (entries 3, 6, and 9–11) gave poor results, in analogy to the reactivity described by Isagawa [27]. Best results were obtained using dimethylethylamine and diethylmethylamine (entries 4 and 5). Et 2 MeN was selected as catalyst for subsequent experiments due to its low boiling point (63–65 °C) [30] which simplifies the reaction workup as it can be removed by simple evaporation.

Table 1 Catalyst screening utilizing a PFA tubing reactor Full size table

Monitoring of the reaction conversion after a series of flow experiments with increasing residence time (Fig. 2) at 40 °C revealed that, while the reaction is relatively fast during the initial 2–3 min, it then becomes exceedingly slow. Nearly 50% conversion was observed after 5 min residence time. Increase of the residence time to 10 min only produced an increase of conversion of 6%. This effect was ascribed to the above mentioned aggregation of the phases in the residence time PFA tube, producing longer segments of liquid and significantly decreasing the surface contact area between the immiscible liquids (Fig. 2). Temperature had a positive effect in the reaction outcome. Keeping the residence time constant at 1 min, the reaction temperature was gradually increased from room temperature to 80 °C. The conversion increased from <10% to 40% (Fig. 3). No side products were observed by GC or NMR analysis. However, a significant amount of tar was produced at higher temperatures, presumably due to the polymerization of the excess of carbene (the same tarry material was observed when running the reaction in the absence of cyclohexene). Tar precipitation eventually caused clogging of the reactor and irreproducible results [31]. Clogging could not be avoided by applying ultrasound.

Fig. 2 Effect of the residence time on the formation of 2 at 40 °C (left). The continuous flow setup depicted in Table 1 was used. Conversion was determined by GC-FID analysis. Image of the reaction mixture at the end of the residence time coil. Long liquid segments can be observed (right) Full size image

Fig. 3 Effect of the reaction temperature on the gem-dichlorocyclopropanation of cyclohexene. The reactor depicted in Table 1 was used. Conversion was determined by GC-FID analysis Full size image

To ensure active mixing during the complete residence time and avoid aggregation of the liquid phases, a glass reactor plate with an active mixing geometry was also evaluated. Unfortunately, appropriate mixing was only achieved at relatively high flow rates (Fig. 4). Gradual increase of the flow rates of a biphasic water/chloroform mixture revealed that the desired dispersion is only achieved at a total flow rate of 1.5 mL/min. This resulted in a residence time for a 4 mL plate below 3 min and poor conversions were observed for the model reaction. Analogous problems were observed with a 3 mm inner diameter static Kenics type mixer.

Fig. 4 Visual aspect of a biphasic water/chloroform system in a glass plate with active mixing geometry at (a) 0.5 mL/min and (b) 1.5 m/min Full size image

We next turned our attention towards a packed bed reactor filled with inert material (beads). This strategy has previously been utilized to provide biphasic systems with excellent mixing even at low flow rates [16, 32,33,34,35,36]. Thus, an Omnifit glass column (12 mL) was utilized as reactor, and heated in a commercially available column heater (Syrris). Several inert materials, namely glass, stainless steel and PFTE beads, and particle sizes were tested as stationary phase for comparison. Pressure drop, reaction conversion and reactor dead volume were examined in all cases (Table 2). As expected, highest conversions were achieved when the smallest particles where utilized (entries 4–6), under otherwise analogous conditions. These results clearly demonstrate the importance of effective mixing for this reaction. The flow regime within the packed-bed reactor could not be visually inspected. This type of static mixers are known to produce droplet/dispersion regimes for biphasic liquid-liquid system [37,38,39]. Indeed, an excellent dispersion of the aqueous phase in the organic phase could be visually observed in the tubing at the mixer output by adding a dye to the water solution (Fig. 5c). PTFE particles provoked the lowest pressure drop in the system (entry 6) and, more importantly, a constant pressure profile over time even for long run reactions (> 4 h). In contrast, the system pressure gradually increased when using stainless steel and sand particles, probably due to the accumulation of polymeric material within the packed-bed. These results could be ascribed to the very low van-der-Waals forces characteristic of PTFE, which prevent materials to easily stick to its surface [40]. Moreover, this material is fully inert under most reaction conditions. PTFE was therefore selected as packing material for subsequent optimization studies.

Table 2 Comparison of packed bed reactors using different stationary phase materials Full size table

Fig. 5 a Schematic view of the optimal continuous flow setup for the dichlorocarbene gem-dichlorocyclopropanation of alkenes utilizing a (b) column reactor packed with PTFE beads. c Visual aspect of the droplets of aqueous solutions in chloroform at the reactor output Full size image

Further optimization of the reaction conditions using the packed bed reactor was carried out by varying the catalyst loading, NaOH concentration, temperature and residence time for the reaction (Table 3). Initially, a solution of 0.5 M cyclohexene in chloroform containing 3 mol% of catalyst was used. Increasing the amount of the catalyst up to 10 mol% improved the conversion significantly (Table 3, entries 1–3). Higher catalyst loading only showed minor improvement (entry 4). Temperature had an important influence in the reaction outcome. While decreasing the temperature resulted in much lower conversions, increase to 90 °C provoked clogging of the reactor (entries 5 and 6). The conversion increased when higher concentrations of sodium hydroxide were applied (entry 7). This may be attributed to the fact that hydroxide anions are less solvated by water and therefore the reactivity increases [41]. Increasing the concentration of the sodium hydroxide solution to 40 wt% led to clogging of the reactor (entry 8). The optimal concentration was 35 wt% of sodium hydroxide in water. To extend the residence time, an additional column was added to enlarge the reactor volume by 50%, providing a total volume of 6.9 mL. Excellent conversion could finally be achieved by gradually increasing the NaOH/CHCl 3 ratio (entries 10–11). Under optimal conditions 97% conversion of the substrate and > 99% selectivity for the desired product 2 was obtained (entry 11).

Table 3 Optmization of the reaction conditions for the gem-dichlorocyclopropanation of cyclohexene Full size table

The continuous flow procedure was then applied for the synthesis of Ciprofibrate, a gem-dichlorocyclopropane-containing drug used as lipid-lowering agent (Fig. 6) [42,43,44,45]. Precursor 3 was prepared according to the literature [46]. Using the optimized conditions (Table 3, entry 11) full conversion of 3 and complete selectivity for the desired Ciprofibrate 4 was observed by GC-FID analysis. Notably, the high purity with which 4 was obtained permitted a very simple workup consisting in extraction of the product with DCM/water and evaporation of the organic phase. Using this protocol, the reaction was run for 4 h. 18.8 g of Ciprofibrate 4 (98% yield) was isolated, corresponding to a productivity of ca. 5 g/h.