Fischer indole synthesis in DMSO/AcOH/H 2 O under continuous flow conditions

Abstract

A new continuous flow synthetic method for preparing indole and its derivatives are successfully developed to overcome the disadvantages of traditional batch methods, such as low conversion rates, long reaction times, and amplification effects. The method represents a sustainable and efficient preparation of indole and its derivatives without the need for additional catalysts. By investigating the effects of the reaction temperature, the solvent, the equivalence ratio, and the residence time, high conversion rates and excellent yields were simultaneously achieved within 20 min under optimized conditions. For the template reaction, DMSO/H₂O/AcOH = 2:1:1 is used as the solvent, the reaction temperature is 110 °C, and the ratio of phenylhydrazine hydrochloride to cyclopentanone is 1:1.05. Indole and a wide array of its derivatives are synthesized to verify the universality of the method, and most of the reactions exhibit satisfactory conversion rates and high yields are obtained. This new continuous flow method is more suitable for industrial scale-up relative to traditional batch methods.

Fischer indole synthesis under continuous flow conditions

Introduction

Indole, consisting of a benzene and a pyrrole ring, and its derivatives are widely found in various organisms and were originally isolated as degradation products of indigo. Indole-based structures are widely used in drugs. Indole and its derivatives show good biological activity for many applications, including anticancer, antibacterial, antiviral and antidiabetic activities. The design, synthesis, and biological evaluation of indole derivatives have attracted widespread attention in recent years, and many pharmaceuticals that contain indole skeletons have been successfully prepared. Three important indole-containing compounds—lysergic acid, indomethacin, and melatonin—are shown in Figure 1.

Figure 1.

Pharmaceuticals containing indole skeletons.

The traditional method for synthesizing indole and its derivatives is via Fischer’s method, which was developed in 1883; subsequently, a large number of researchers have explored the mechanism and its application. The general reaction procedure is shown in Scheme 1. In this method, (substituted) phenylhydrazine and aliphatic aldehydes or ketones are used as the raw materials. The corresponding phenylhydrazone derivatives are obtained by condensation in the first step, which then undergo rearrangement and acid catalyzed cyclization to give the indigo skeletons without isolation. ¹

Scheme 1.

The Fischer indole synthesis in batch mode.

Traditional Fischer indole synthesis has been widely used in industry; however, the batch mode has a natural drawback, namely, low efficiency. Continuous flow chemistry is characterized by high mixing and high conversion rates;^2–16 it has been widely used for many reactions but also has limitations because pipeline blockage can occur when insoluble solids are formed inside pipes. Unfortunately, the raw material for the reaction, the phenylhydrazine salt, and the ammonium salt byproduct formed during the Fischer indole synthesis have poor solubilities in most organic solvents, and the products, indole and its derivatives can only be dissolved in conventional organic solvents and water; this makes reaction homogenization challenging. The first continuous Fischer indole synthesis was reported by Watts; ¹⁷ the reaction of phenylhydrazine and a ketone was catalyzed by methanesulfonic acid (MSA) in ethanol, and the optimum yield and selectivity reached 86% and 98%, respectively; however, the process had a distinct disadvantage: the raw material phenylhydrazine was unstable and was easily oxidized in air. Furthermore, the purity of phenylhydrazine from commercial products only reached 95%, and the process was very expensive. In addition, the concentration of the products was too low to ensure homogeneity, which made the process difficult to scale up, so it was not an ideal continuous Fischer indole synthetic method. Another related example was the study by Kappe and colleagues; according to their method, phenylhydrazine and ketones were used as raw materials, and methanol was used as the solvent in a continuous mode; however, this process only proceeded under harsh conditions, for example, 200 °C and 75 bar, ¹⁸ and it also involved expensive and unstable materials.

Phenylhydrazine hydrochloride is one of the raw materials used for the Fischer indole synthesis in traditional batch mode, and it is more stable and easier to obtain from commercial suppliers at lower prices and higher purities of up to 99%. Thus, the major obstacles for realizing the continuous flow synthesis of indoles could be overcome if we could find a suitable solvent system that dissolves all the compounds involved in the Fischer indole synthesis, including phenylhydrazine hydrochloride, at high concentrations. Therefore, we have developed a new and benign method for preparing indole and its derivatives by continuous flow technology.^19,20

Results and discussion

As described above, it was necessary to screen suitable reaction factors to avoid pipe blockage. In this study, phenylhydrazine hydrochloride and cyclopentanone were used as template substrates for reaction screening. The experimental setup is shown in Figure 2. The tubular microreactor was made of polytetrafluoron (polytetrafluoroethylene = PTFE, inner diameter = 1.06 mm, length = 96 m), and two reactant channels delivered materials A and B through two syringe pumps. Pump A delivered a phenylhydrazine hydrochloride solution, while pump B delivered an aldehyde or a ketone solution, and the concentrations of A and B were 0.90 mol L⁻¹ and 0.90–1.08 mol L⁻¹, respectively.

Figure 2.

Structural diagram of the continuous flow reactor.

In addition, AcOH, as a Lewis acid, has been widely used as a solvent in the Fischer indole reactions because of its acid-catalyzing effect.^21,22 However, it was found that acetic acid was unable to dissolve the products produced, especially NH₄Cl, at 110 °C or higher temperatures, so it could not resolve the clogging problem. Water is an inexpensive, green, noncombustible, and renewable solvent that has received increasing attention;^23,24 in addition, it is an excellent solvent for NH₄Cl. Therefore, we tried the reaction in AcOH/H₂O and NH₄Cl dissolved, but 2,3,4,9-tetrahydro-1H-carbazole precipitated. We also tried EtOH/H₂O because EtOH is a polar and environmentally friendly solvent, and it can be recovered easily from the mixture by distillation. Unfortunately, the mixed solvent could not homogenize the reaction system, even at different ratios. We also attempted the reaction in DMSO/H₂O for 30 min and obtained a good conversion rate, while a small amount of a solid precipitate was formed. ²⁵ Based on this encouraging preliminary result, we screened different solvents and their combinations. Finally, we utilized a mixture of acetic acid, water, and DMSO in the same volume ratio, and surprisingly, the reaction proceeded smoothly (Table 1). We also explored the conversion rate and the yield from the systems that yielded a homogeneous reaction.

Table 1.

Screening different solvent combinations ^a .

Entry	Solvent b	Homogeneous	Conversion (%) c	Yield (%) d
1	DMSO/H2O = 4:1	Yes	85.4	70.1
2	DMSO/AcOH = 1:1	No	81.2	67.8
3	AcOH/H2O = 1:1	No	72.4	63.1
4	THF	No	84.9	72.0
5	EtOH	No	79.6	68.6
6	EtOH/H2O = 1:1	No	78.4	63.9
7	EtOH/H2O = 2:1	No	80.1	64.1
8	PhMe	No	66.3	48.7
9	Acetone	No	78.4	59.6
10	DMF	Yes	67.3	53.2
11	DMSO/H2O/AcOH = 1:1:1	Yes	95.8	85.8

a

Raw materials were added to the solvent and sonicated for 30 min before use. Residence time = 20 min; reaction temperature = 120 °C; material A = 0.90 mol L⁻¹, material B = 0.95 mol L⁻¹.

b

All solvent ratios are volume ratios.

c

Determined by HPLC peak area integration.

d

Overall yield of 2,3,4,9-tetrahydro-1H-carbazole.

Since the solvent mixture of acetic acid, water, and DMSO was successful, we continued to explore various ratios of these three solvents (Figure 3(a)). The results showed that the ratio of the mixed solvents was not a key factor that affected the conversion rate and yield. The ratio of DMSO/H₂O/AcOH = 1:1:1 gave the highest conversion rate. Due to the high proportion of acetic acid in the solvent, some clogging occurred when the residence time (RT) was increased. The reaction proceeded smoothly when the solvent ratio was 1:1:1 (v/v) and 2:1:1 (v/v); furthermore, the conversion rates of the raw materials and the yields of the crude product were high. By comparing the data, it can be seen that the two results were almost the same. However, a small amount of precipitate formed when the solvent ratio was 1:1:1 (v/v). When the solvent ratio was 2:1:1 (v/v), the reaction was completely homogeneous. Therefore, we selected a solvent ratio of 2:1:1 (v/v) as the optimum. On this basis, we continued to explore the effect of the RT on the reaction.

Figure 3.

Influence of different solvents, residence times, and temperatures. Molarity of phenylhydrazine = 0.903 mol L⁻¹; molarity of cyclopentanone = 0.948 mol L⁻¹. (a) Reaction temperature = 110 °C; yields are calculated for reactions with a solvent ratio of 2:1:1. (b) Solvent ratio = 2:1:1 and residence time = 20 min.

The RT was controlled by adjusting the feed flow rates of the two pumps, which ranged from 3.43 to 16.64 mL min⁻¹. The conversion rates of the starting materials under different conditions were calculated based on the high-performance liquid chromatography (HPLC) analysis, and the crude product yield was obtained via further separation and purification. The relationship between the conversion rate, yield, and RT is shown in Figure 3(b). In this experiment, the molarity of the ketone was 5% greater than that of phenylhydrazine hydrochloride.

According to Figure 3(a), when the RT was 5 min, the conversion rate was very low. The longer the RT was, the higher the conversion rate was up to an RT of 20 min. It was found that phenylhydrazone intermediates began to be generated a short time after the raw materials were pumped in, and the concentration of the byproduct NH₄Cl also increased as the reaction proceeded. The conversion rate showed no noticeable change when the RT was between 20 and 25 min. The results showed that the reaction was essentially complete in 20 min under the applied continuous conditions.

As shown in Figure 3(b), the temperature also had a significant influence on the reaction. When the temperature was 70 °C, the conversion was only 32%, and it increased to 43% when the temperature reached 90 °C. However, the conversion increased exponentially when the temperature was further increased to 100 °C. The conversion was almost the same in the range of 110 and 120 °C, so the optimal temperature was 110 °C. On the basis of these preliminary research results, DMSO/H₂O/AcOH = 2:1:1 was selected as the solvent, and 20 min was used as the optimal RT for the subsequent material equivalence research.

As shown in Table 2, when the substance ratio of phenylhydrazine hydrochloride to cyclohexanone was less than 1:1.1, the product yield increased with the amount of cyclopentanone; when the equivalence ratio of phenylhydrazine hydrochloride to cyclopentanone was increased to 1:1.1, the product yield reached a maximum. A further increase in the amount of cyclopentanone did not improve the yield further; in fact, it gave a lower yield relative to that of the 1:1.1 ratio. When the equivalence ratio of phenylhydrazine hydrochloride to cyclopentanone was between 1:1.05 and 1:1.1, little difference in the product yield was observed. Ultimately, we chose an equivalence ratio of 1:1.05 for phenylhydrazine hydrochloride and cyclopentanone.

Table 2.

The effect of different equivalence ratios ^a .

Entry	Cyclopentanone equivalent	Conversion (%)	Yield (%)
1	1	90	80
2	1.05	97	90
3	1.1	97	89
4	1.2	97	84

a

Phenylhydrazine hydrochloride = 1 equiv., reaction temperature = 110 °C, solvent ratio = 2:1:1, and residence time (RT) = 20 min.

Having optimized the procedure with respect to phenylhydrazine hydrochloride and cyclopentanone, the solvent, the RT, the temperature, and the material equivalence ratio, we next investigated the scope with substituted phenylhydrazine hydrochlorides and different aldehydes or ketones under flow conditions (Scheme 2). Most of the reactions achieved satisfactory results, and the yields varied from 13% to 92%.

Scheme 2.

Continuous flow Fischer reactions between substituted phenylhydrazine hydrochloride and aliphatic aldehydes or ketones.

Conclusion

In summary, we have developed a practical continuous flow method for the synthesis of indole and its derivatives in moderate to high yield. The new method is efficient and facile, does not involve any expensive or unstable materials or harsh conditions, and can operate at high concentrations without leading to congestion. Notably, the method displayed good universality and tolerated a wide range of functional groups, such as halogen, alkoxy, and nitro. This method overcomes the disadvantages of previously reported methods and could be easily scaled up for industrialization.

Experimental section

Materials and methods

Phenylhydrazine hydrochloride (Shanghai Macklin Biochemical Co., Ltd., Shanghai, China), cyclopentanone (Sinopharm Chemical Reagent Co., Ltd., Shanghai, China), and anhydrous sodium sulfate and ethyl acetate (Aladdin Reagents Co., Ltd., Shanghai, China) were of analytical grade.

Unless otherwise stated, commercially available reagents and solvents were used directly from the supplier without further purification. An advection pump (Shanghai Tongtian Biotechnology Co., Ltd., Shanghai, China) was used for flow experiments. Pipes and machine parts were made of perfluoroalkyl (PFA) or PTFE plastic with ceramic pump heads. The unit was capable of pumping high concentrations of corrosive acids. The inner diameter of all PTFE tubing was 1.06 mm. The system was rinsed with the experimental solvent before reaction initiation. The structures of the target compounds were analyzed by nuclear magnetic resonance (NMR) (varian 400 and 300 MHz).

HPLC conditions

Analyses were performed on a Supersil AQ-C18 column (250 mm × 4.6 mm, 5 μm) with the mobile phase V (MeCN): V(H₂O) = 65:35 (containing 1 g L⁻¹ ammonium dihydrogen phosphate (MAP)) at a flow rate of 1 mL min⁻¹. The detection wavelength was 254 nm, and the injection volume was 20 μL.

Characterization data of compounds 3a and 3b selected as examples.

1,2,3,4-Tetrahydrocyclopenta[b]indole (3a): Beige powder; m.p.: 100.5–105.5 °C; yield: 91%; ¹H NMR (400 MHz, CDCl₃): δ 7.76 (s, 1H), 7.41–7.30 (m, 1H), 7.23 (dd, J = 5.9, 3.0 Hz, 1H), 7.08–6.95 (m, 2H), 2.84–2.69 (m, 4H), 2.47 (dt, J = 13.9, 7.0 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d₆): δ 144.6, 141.4, 124.6, 120.0, 118.9, 118.2, 117.9, 112.0, 28.8, 25.7, 24.5. HRMS (ESI-MS): m/z [M + H]⁺ calcd for C₁₁H₁₁N: 158.0870; found: 158.0968.

7-Chloro-1,2,3,4-tetrahydrocyclopenta[b]indole (3b): Dark brown solid; yield: 83%; ¹H NMR (400 MHz, DMSO-d₆): δ 11.05 (s, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 8.6, 2.1 Hz, 1H), 2.84 (t, J = 7.1 Hz, 2H), 2.73 (dd, J = 8.5, 5.3 Hz, 2H), 2.46 (dd, J = 14.0, 6.8 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d₆): δ 146.8, 139.8, 125.6, 123.5, 119.7, 117.9, 117.5, 113.3, 28.6, 25.7, 24.3.

Typical procedure for continuous flow synthesis of indole and its derivatives

The ketone or aldehydes and phenylhydrazine hydrochloride were dissolved in DMSO/H₂O/AcOH = 2:1:1, and gas was removed by ultrasonic treatment for 10 min. The two raw materials were pumped into the system using advection pumps. The feed streams converged in a T-mixer before entering the tubular reactor, which was preheated to 110 °C. The eluting reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and evaporated to remove the solvent and residue was recrystallized with 95% ethanol or purified by column chromatography to give the pure product.

Supplemental Material

sj-docx-1-chl-10.1177_17475198221150384 – Supplemental material for Fischer indole synthesis in DMSO/AcOH/H2O under continuous flow conditions

Supplemental material, sj-docx-1-chl-10.1177_17475198221150384 for Fischer indole synthesis in DMSO/AcOH/H2O under continuous flow conditions by Mei Wang, Shenghu Yan, Yue Zhang and Shunlin Gu in Journal of Chemical Research