Electrochemically induced cross-dehydrogenative coupling (CDC) reaction. An efficient electrochemical method for the synthesis of dicoumarols

Abstract

Electrochemical synthesis of dicoumarols as anticoagulant drugs was carried out by the electrochemical oxidation of N,N,N′,N′-tetramethyl-1,4-phenylenediamine in the presence of 4-hydroxycoumarin derivatives. Electrochemically generated radical cation participates in cross-dehydrogenative coupling (CDC) reaction with 4-hydroxycoumarins. The present work has led to the development of a facile catalyst-less, one-pot and environmentally friendly method under ambient conditions using a carbon electrode.

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Introduction

Dicoumarol is an anticoagulant drug that functions as a vitamin K antagonist.¹ It is metabolized from coumarin in the sweet clover by molds, such as penicillium nigricans and penicillium jensi and is considered to be a fermentation product and mycotoxin.² Coumarin was used as early as 1000 A.D as medicinal plant extract according to Persian literature.³ Latter, numerous reports were published about anti-proliferative and antitumor activities of coumarin and its derivatives such as 7-hydroxycumarin by interfering with mitotic spindle microtubule function.⁴ Dicoumarol was synthesized via a Knoevenagel–Michael reaction between 4-hydroxycoumarin and formaldehyde or aromatic aldehydes, which allows the attachment of a second 4-hydroxycoumarin molecule by linking the carbon atom of the aldehyde to the 3-position of the first 4-hydroxycoumarin molecule to obtain the semi-dimer, the motif of the drug class.⁵

The formation of C–C bonds is one of the most important reactions in organic synthesis. The direct coupling of two C–H bonds is the most efficient method for constructing C–C bonds.¹⁰ Transition metals, iron, Li and other alkali metals made a significant contribution to develop a series of synthetic method to directly form C–C bond from two C–H bonds under oxidative conditions.

This mechanism was characterized as cross-dehydrogenative-coupling (CDC).⁶ The biological importance of this drug influenced us to develop a facile and one-pot electrochemical method for the synthesis of dicoumarols. Therefore, the development of an efficient method for the synthesis of dicoumarol derivatives that overcome the drawbacks of reported methods would be appreciable. To the best of our knowledge, there are only two reports on the electrochemical synthesis of dicoumarol.⁷ These results influenced us to investigate the electrochemical oxidation of N,N,N′,N′-tetramethyl-1,4-phenylenediamine (TMPD) (Wurster's reagent) in the presence of 4-hydroxycoumarin (1a), 4-hydroxy-6-methylcoumarin (1b) and 4-hydroxy-6-methylpyron (1c). Finally, we have discovered an easy and one-pot electrochemical method for the synthesis of dicoumarol derivatives (3a–3c) in high yield and purity, using an environmentally friendly method. From green chemistry and waste management viewpoints, dicoumarol was synthesized via electrochemically CDC mechanism in absence of catalyst. Therefore, this method minimizes metallic catalyst consumption as a great pollutant, and on the other hand, catalyst recycling cost decreases particularly.

Results and discussion

The cyclic voltammogram of TMPD in water (phosphate buffer, c = 0.2 M, pH = 3.0)/ethanol mixture (70/30, v/v) is shown in Fig. 1 curve a. In this condition, the voltammogram exhibits two anodic (A₁ and A₂) in the positive-going scan and two cathodic peaks (C₁ and C₂) in the negative-going scan. Anodic peaks A₁ and A₂ correspond to the transformation of TMPD to the radical cation (TMPD˙⁺), and then TMPD˙⁺ to dication (TMPD⁺⁺), respectively, within two successive quasi-reversible one-electron processes (Scheme 1). Obviously, cathodic peaks C₂ and C₁ are related to the reduction of TMPD⁺⁺ to TMPD˙⁺ and TMPD˙⁺ to TMPD, respectively.⁸

Fig. 1 Cyclic voltammograms of TMPD at a glassy carbon electrode in a water (phosphate buffer, c = 0.2 M, pH = 3.0)/ethanol (70/30) mixture. Scan rate from (a) to (f) are 1000, 500, 250, 100, 25 and 5 mV s⁻¹. t = 25 ± 1 °C.

Scheme 1 Electrochemical oxidation of TMPD.

The effect of the potential scan rate on the cyclic voltammogram of TMPD was also studied. It is seen that, upon decreasing the potential scan rate, the peak current ratios (I_pC1/I_pA1 and I_pC2/I_pA2) decrease, which is indicative of the presence of a following chemical reaction (such as hydroxylation) after the electron transfer step.⁹ It should also be noted that, the effect of potential scan rate on the I_pC2/I_pA2 is more than I_pC1/I_pA1. These data are consistent with the higher reactivity of TMPD⁺⁺ compared with that of TMPD˙⁺. The peak current ratios (I_pC1/I_pA1 and I_pC2/I_pA2) are also dependent on the pH of the solution. Our data show that I_pC1/I_pA1 and I_pC2/I_pA2 decrease with increasing pH. These data also indicate that I_pC2/I_pA2 is more sensitive to pH than I_pC1/I_pA1 such that the cathodic peak C₂ disappears in basic solutions. This confirms the instability of TMPD⁺⁺ compared with that of TMPD˙⁺.

Preparative scale electrolyses were performed in a mixture of phosphate buffer (c = 0.2 M, pH = 3.0)/ethanol (70/30, v/v), containing TMPD (0.5 mmol) and 1a (1.0 mmol) in an undivided cell at the first peak potential. The reaction product was isolated and identified as dicoumarol (3a) (yield 95%) (Scheme 2). The formation of this compound is explained as follows: oxidation of TMPD at 0.25 V (vs. Ag/AgCl) by the loss of an electron affords the corresponding radical cation (TMPD˙⁺), which further converts to hydrogen radical and the cation TMPD⁺. Subsequent intramolecular attack of 1a to TMPD⁺ gives intermediate 2a. In acidic media, 2a undergoes direct S_N2 substitution¹¹ by the second molecule of 1a to afford the final product (3a). This work has been extended with the use of 1b and 1c as a substrate and related semi-dimer products have been reported.

Scheme 2 Proposed mechanism for the electrochemical oxidation of TMPD in the presence of 1a–1c.

Galvanostatic studies

Constant current electrolysis was performed for improving the applicability of the procedure. To take the high product yield, some affecting electrosynthetic factors must be optimized. In this regards applied current density, charge passed and electrode material were investigated by setting all parameters to be constant and optimizing one each time. Among the electrochemical parameters for the synthesis of organic compounds, the current density is one of the most important factors influencing the yield and purity. This factor can also play an important role in determining the dominant reaction at the surface of the electrode. In this work, the current density varied from 0.05 to 1.20 mA cm⁻², while the other parameters (temperature = 298 K, charge passed = 50 C, TMPD, 0.5 mmol and 1a 1.0 mmol) are kept constant. The highest product yield was obtained at current density of 1.0 mA cm⁻² (Fig. 2, part I). The formation of TMPD⁺⁺ (two electron oxidation) at higher current densities and its participation in Michael addition reaction cause a decrease in the product yield. The product yield also depends on the amount of charge passed, as shown in Fig. 2, part II. The effect of charge passed was studied in the range of 10–60 C (theoretical amount is 50 C). As shown, the product yield decreases with increasing charge passed from theoretical amount. This may be because of the over-oxidation of 3a after the consumption of 1 F mol⁻¹. All the variables (anode = carbon, current density = 1.0 mA cm⁻², temperature = 298 K, TMPD, 0.5 mmol and 1a, 1.0 mmol) except the amount of charge passed were kept constant. The effect of anode material (carbon, platinum and gold) on the yield of 3a was also studied. Our data show that carbon is a suitable anode for the synthesis of 1a. The similar results are obtained by repeating the same experiments for 1b and 1c.

Fig. 2 Effect of current density and charge passed on the yield of 3a.

Conclusion

The results of this work show that TMPD is oxidized to its respective radical cation. The formed radical cation via the cross-dehydrogenative-coupling (CDC) converts to dicoumarols (3a–3c) in good yield and high purity without any metal catalysts. The prominent features of this paper, the synthesis of valuable compounds in aqueous/ethanol mixture instead of toxic solvents, room temperature conditions, high energy efficiency and using the electrode as an electron source instead of toxic reagents are in accordance with the principles of green chemistry.

Experimental

The working electrode used in the voltammetry experiments was a glassy carbon disc (1.8 mm² area), and platinum wire was used as counter electrode. The working electrode used in controlled-potential coulometry and macro-scale electrolysis was carbon plated (148 cm²) and large steel gauze constituted the counter electrode. The working electrode potential was measured versus Ag/AgCl. The electrochemical oxidations were performed under constant-current condition in a simple cell equipped with a magnetic stirrer. N,N,N′,N′-tetramethyl-1,4-phenylenediamine, 4-hydroxycoumarin, ethanol, phosphoric acid and phosphate salts were reagent-grade materials and obtained from commercial sources. These chemicals were used without further purification. The glassy carbon electrode was polished using alumina slurry (from Iran Alumina Co.). Reaction equipment is described in an earlier article.¹⁰ For more details see ESI.†

Electroorganic synthesis of 3a–3c

A solution of phosphate buffer (c = 0.2 M, pH = 3.0)/ethanol (70/30 v/v) mixture containing TMPD (0.5 mmol) and 1a, 1b or 1c (1.0 mmol) was electrolyzed in an undivided cell by a potentiostatic method at the first peak potential or galvanostatic method at current density 1.0 mA cm⁻². The electrolysis was terminated when the consumed charge was 52 C. At the end of the electrolysis, the precipitated solid was collected by filtration and washed with water/ethanol mixture (50/50 v/v). The products were characterized by: MS, FTIR, ¹H NMR and ¹³C NMR (see ESI†).

3,3′-Methylenebis(4-hydroxy-2H-chromen-2-one) or dicoumarol (3a). Creamy-white crystalline powder (yield 95%). mp = 286–289 °C (dec.) (lit. 289–292).^{11a 1}H NMR (400 MHz, DMSO-d₆) δ 3.79 (s, 2H, methylene), 7.34 (m, 4H, aromatic), 7.59 (t, J = 7.6, 2H, aromatic), 7.91 (d, J = 7.6, 2H, aromatic); ¹³C NMR (100 MHz, DMSO-d₆): δ 19.3, 102.2, 116.0, 116.8, 123.3, 123.8, 131.6, 151.8, 162.4, 163.6; IR (KBr, cm⁻¹): 770, 1110, 1309, 1349, 1454, 1601, 1628, 1651, 2612, 2729, 3067, 3436; MS (EI) (m/z) (relative intensity): 336 [M]⁺ (83), 290 (7), 215 (67), 187 (44), 175 (27), 162 (82), 121 (100), 65 (63).

4-Hydroxy-3-((4-hydroxy-6-methyl-2-oxo-2H-chromen-3-yl) methyl)-6-methyl-2H-chromen-2-one (3b). Creamy-white powder (yield 90%). mp = 273–275 °C (dec.) (lit. 273–275).^{11a,b 1}H NMR (400 MHz, DMSO-d₆): δ 2.38 (s, 6H, methyl), 3.77 (s, 2H, methylene), 7.24 (d, J = 8.4, 2H, aromatic), 7.39 (d, J = 8.4, 2H, aromatic), 7.71 (s, 2H, aromatic); ¹³C NMR (100 MHz, DMSO-d₆): δ 19.3, 20.4, 102.2, 115.8, 116.4, 123.0, 132.6, 133.1, 150.0, 164; IR (KBr, cm⁻¹): 816, 916, 1106, 1211, 1282, 1332, 1447, 1504, 1581, 1659, 2925, 3061, 3432; MS (EI) m/z (relative intensity): 364 [M]⁺ (85), 318 (11), 290 (3), 255 (3), 229 (58), 202 (32), 176 (69), 135 (100), 106 (30), 72 (32), 51 (15). Anal. calcd for C₂₁H₁₆O₆: C, 69.23; H, 4.43%. Found: C, 69.16; H, 4.60.

4-Hydroxy-3-((4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)methyl)-6-methyl-2H-pyran-2-one (3c). Black crystalline powder (yield 80%). mp = 245–247 °C (dec.) (lit. 250–251).^{11c 1}H NMR (400 MHz, DMSO-d₆): δ 2.13 (s, 6H, methyl), 3.33 (s, 2H, methylene), 5.96 (s, 2H, aromatic), 11.1 (s, 1H, OH). ¹³C NMR (100 MHz, DMSO-d₆): δ 17.2, 19.1, 99.3, 100.3, 159.7, 165.0, 165.6. IR (KBr, cm⁻¹): 525, 991, 1076, 1175, 1238, 1578, 1681, 2672, 2926, 3087, 3439. MS (EI) m/z (relative intensity): 264 [M]⁺ (100), 221 (14), 179 (85), 151 (50), 111 (21), 85 (42), 55 (18). Anal. calcd for C₁₃H₁₂O₆: C, 59.09; H, 4.58%. Found: C, 58.93; H, 4.67.

Acknowledgements

We acknowledge the Bu-Ali Sina University Research Council and Centre of Excellence in Development of Environmentally Friendly Methods for Chemical Synthesis (CEDEFMCS) for their support of this work.

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR, ¹³C NMR, FT-IR, MS of 3a–3c. See DOI: 10.1039/c4ra08181a

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