A green development of Bernthsen 9-substituted acridine synthesis in the absence of solvent catalyzed by p-toluenesulphonic acid (p-TSA)

Abstract

Bernthsen reaction has been carried out under microwave irradiation in the presence of p-TSA (10 mol%) as catalyst in a solventless reaction to provide 9-substituted acridines. In the present report, time economy and better yields as compared to conventional Bernthsen reaction are described.

Keywords:

• Bernthsen
• acridine
• p-toluenesulphonic acid (p-TSA)
• microwave

Introduction

Acridines represent an important class of nitrogen heterocycles 1 2 having several significant properties such as pigment and dye properties 3–5, photochemical/physical properties 6–8, electrochemical properties 9, potent anti-malarial activity 10, anticancer activity 11–16,1 antifungal activity 17–20, etc. Natural and synthetic acridines and their derivatives are effective DNA and RNA-binding compounds 21–24 owing to their intercalation abilities as well as being a lipophilic carrier molecule. It is the acridine chromophore that renders to the molecules a planar structure allowing them to bind DNA by stacking between base pairs. Recently, structure–activity relationship of acridine analogs as haspin and DYRK2 kinase inhibitors has been studied 25.

In one of our ongoing synthetic programs on bioactive molecules and organic synthesis involving microwave energy, which provides greener reaction condition coupled with increased yield and time economy, we came across Bernthsen reaction. Owing to the bioactivity of acridines, we became interested therein. Use of microwave energy for the enhancement of organic reactions, i.e. microwave organic reactions enhancement (MORE) is well known 26–28. That is why, we decided to explore the same in our ongoing program on bioactive molecules.

Acridine family members can be prepared by classical Bernthsen reaction by coupling an carboxylic acid (aromatic or aliphatic) and diphenylamine (DPA) in the presence of zinc chloride (Scheme 1) at a temperature of 200–210°C for about 20 hours 29 30. The conditions for this reaction tend to be quite vigorous coupled with very low yield. In addition, more than stoichiometric amounts of ZnCl₂ is required [1:5:1 (DPA:ZnCl₂:carboxylic acid)]. In 1962, Popp reported a modified Bernthsen reaction procedure by replacing the Lewis acid ZnCl₂ with polyphosphoric acid 31, which was more convenient in regard to reaction times despite the poorer yields. Toma et al. 32 and Seijas et al. 33 have reported an improved synthesis of acridine derivatives assisted by microwave and catalyzed by ZnCl₂. But, as compared to synthetic methodologies for other classes of compounds, this reaction has not been explored adequately as evidenced by reports of only two catalysts (ZnCl₂ and polyphosphoric acid) being employed.

short-legendScheme 1. Traditional Bernthsen acridine synthesis.

But none of these procedures were satisfactory in terms of yield and time economy. In this regard, hence, there is still need for looking at this reaction in order to have improved reaction conditions/superior catalysts so that better yields could be achieved. At the same time, we should not forget the cost, environment, etc. Accordingly, our main aim of this present investigation is to find alternative conditions/catalysts for Bernthsen reaction with the following objectives: (a) to search for milder reaction condition, (b) to reduce the reaction time, (c) to increase the yield, (d) to promote economical and environmentally friendly experimental procedures (green chemistry) by performing the reaction under microwave and solventless condition, and (e) to use cost-effective, easily available, mild, water tolerant, and economical catalysts alternative to ZnCl₂ and polyphosphoric acid.

In an effort to amend the situation above, in this communication, we report a simple and general solventless reaction for the synthesis of 9-substituted acridines, by a modification of classical Bernthsen reaction (Scheme 2), using p-TSA (p-toluenesulphonic acid) as the catalyst under microwave irradiation. This paves the way for an environmentally benign condition without compromising viability and speed. Our method is equally applicable to both aliphatic and aromatic carboxylic acids, thereby providing more generality and flexibility.

short-legendScheme 2. Synthesis of a 9-substituted acridines using catalyst under microwave radiation.

An inspection of the literatures revealed that in Bernthsen reaction using ZnCl₂ and polyphosphoric acid, the stoichiometry used for DPA and carboxylic acid was not 1:1. The acid was taken always in excess. The catalyst used was also in stoichiometric amount or higher. In our green chemistry approach, we searched for the conditions where the substrates would be used in stoichiometric ratios and the catalyst used would be in minimum amount, e.g. (10 mol% or lower than that).

Results and discussion

Other than p-TSA, we studied the effects of several compounds as catalyst, e.g. basic Al₂O₃, cerric ammonium nitrate (CAN), ZrOCl₂ 8H₂O, K₂Cr₂O₇, anhydrous AlCl₃ in Bernthsen reaction (reaction of DPA and benzoic acid was chosen as the model reaction) under thermal as well as MWI in the absence of solvent. However, the best results in terms of yields and reaction time were obtained with p-TSA (Table 1) under MWI. CAN and basic alumina also afforded the products but yields were poorer. In order to demonstrate the scope of this reaction, differently substituted benzoic acids, aliphatic mono/dicarboxylic acids were taken up for the systematic study which is depicted in Table 2. However, in the conditions we explored, it was found that in the ratio of 1:1 (DPA and carboxylic acid), only entries 1 and 11 (Table 2) worked well; in all other cases the yields were not satisfactory. Too many products were observed in TLC and also we faced difficulty in separation by column chromatography. The best results were obtained when we used the acids in twofolds with respect to DPA. To our delight, we were successful in reducing the amount of catalyst from stoichiometric ratios to 10 mol%, a significant outcome in comparison to the classical methods. Aromatic anhydride also responded and showed reactivity under this condition (entry 11). p-Nitro (entry 4) and p-Amino benzoic acids (entry 5) also afforded acridine under the reaction condition. Overheating and increasing the reaction time did not increase the reaction yield; rather some polymeric products were obtained.

Table 1. Screening of catalysts for the synthesis of 9-(phenyl)acridine via Scheme 2.

		Under microwave irradiation		Thermal heating
Entry	Catalysts	Power/reaction time (min)	Yield (%)^a,b	Reaction time (hr)	Yield (%)^a,b
1	p-Toluenesulfonic acid	450/4	80	12	75
2	Ceric ammonium nitrate	600/12	31	20	30
3	Basic alumina	600/12	25	20	27
4	Zirconium oxychloride octahydrate	600/12	–	20	–
5	Potassium dichromate	600/12	–	20	–
6	Anhydrous aluminium chloride	600/12	–	20	–
^aIsolated yield.
^bAll the products were characterized by IR, ^1H NMR, ^13C NMR and mass spectrometry, elemental analysis, and mp.

Table 2. p-TSA catalyzed synthesis of acridine derivatives via Scheme 2.

			Under microwave irradiation		Thermal heating
Entry	Acid/acid anhydride	Stoichiometry (DPA:acid moiety)	Power/reaction time (min)	Yield (%)^a,b	Reaction time (hr)	Yield (%)^a,b
1	R = − C6H5	1:1	450/4	80	12	75
2	R = p-ClC6H4	1:2	600/2	84	10	73
3	R = o-ClC6H4	1:2	600/2.5	82	10	73
4	R = p-NO2C6H4	1:2	600/7	74	15	42
5	R= p-NH2C6H4	1:2	600/9	66	15	38
6	R = p-OHC6H4	1:2	450/7	49	12	20
7	R = o-C6H4COOH	1:2	450/3.5	84	10	64
8	R = − CH2COOH	1:2	600/5	48	10	31
9	R = −(CH2)2COOH	1:2	600/3	78	10	67
10	R = −(CH2)4COOH	1:2	300/2.5	88	10	71
11	C6H4(CO)2O	1:1	450/3	79	10	67
^aIsolated yield.
^bAll the products were characterized by IR, ^1H NMR, ^13C NMR and mass spectrometry, elemental analysis, and mp.

In conclusion, nontraditional MORE of Bernthsen acridine synthesis is achieved in a simple, clean, fast, and solventless reaction catalyzed by p-TSA. Good time economy and better yields as compared to conventional Bernthsen reaction was observed. The reaction is applicable to aromatic as well as aliphatic acids (mono- and di-).

Considering the environmental issues that require the substitution of toxic catalysts by more friendly catalysts, our methodology is consistent with green chemistry philosophy 34. Moreover, p-TSA is easily available and can be easily removed from the reaction mixture being water-soluble.

Experimental

Melting points were determined on a Buchi 504 apparatus and are uncorrected. IR spectra were recorded in KBr pallets on a Nicolet (Impact 410) FT-IR spectrophotometer. ¹H NMR and ¹³C NMR spectra were recorded on a Varian Mercury Plus 400 MHz NMR spectrophotometer using tetramethylsilane (TMS) as internal standard. Coupling constants are expressed in hertz. Microwave synthesis system used was model CAT-2R from Catalyst^TM systems. The progress of the reaction was monitored by thin layer chromatography (TLC) run on silica gel G (Merck). All the chemicals were used as received. Elemental analysis was done in a Perkin Elmer CHN analyzer (2400 series II).

General procedure for the synthesis of 9-(phenyl)acridine

A mixture of N,N-DPA (169 mg, 1 mmol), benzoic acid (122 mg, 1 mmol), and pure p-TSA (19 mg, 10 mol%) was irradiated in a microwave oven (450 W) for 5 mins. The reaction was monitored by TLC. The crude product was extracted with chloroform (20 ml×2) and washed with 10% NaOH followed by distilled water. The organic layer was dried over Na₂SO₄, evaporated and the residue was subjected to column chromatography to give 9-phenylacridine (244.80 mg, 80% yield). The pure products were characterized by IR, ¹H-NMR, ¹³C-NMR spectroscopy and mass spectrometry, elemental analysis and mp.9-(phenyl)acridine (Table 2, entry 1)

IR (KBr) (v _max/cm⁻¹) 1652.64 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 7.42–7.46 (m, 4H, Ar-H), 7.59–7.61 (m, 3H, Ar-H), 7.71 (d, 2H, J=4.4 Hz, Ar-H), 7.76–7.80 (m, 2H, Ar-H), 8.28 (d, 2H, J=4.4 Hz, Ar-H); ¹³C NMR (100 MHz, CDCl₃) δ_c 125.2, 125.6, 126.9, 128.4, 128.5, 129.7, 130.0, 130.5, 135.9, 147.1, 148.7 ppm. MS, m/z 255 (M⁺). Elemental analysis for C₁₉H₁₃N: Calculated, C, 89.38; H, 5.13; N, 5.49. Found: C, 88.47; H, 5.09; N, 6.01. mp. 183–185°C (lit.¹⁶ mp. 184–185°C).

Similarly, the other products were also synthesized (Table 2) and characterized (supplementary information).

Supplementary information

Data for all the compounds are given as supplementary information.Supplementary information

Acknowledgement

AJT thanks Department of Science and Technology (DST), Govt. of India, New Delhi, for financial support to the project (SR/FTP/CS-58/2005) and UGC, New Delhi, for a Rajiv Gandhi National Fellowship to SD.

Notes

1. For chemotherapeutic effects of acridine derivatives, see (13).

Supplementary information

9-(4-chlorophenyl)acridine (Table 2, entry 2)

IR (KBr) (v _max/cm⁻¹) 1650.41 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 7.13 (d, 2H, J=3.25 Hz, Ar-H), 7.17 (t, 2H, J=3.05 Hz, Ar-H), 7.26 (d, 2H, J=3.28 Hz, Ar-H), 7.40–8.06 (m, 6H, Ar-H); ¹³C NMR (100 MHz, CDCl₃) δ_c 125.5, 126.2, 126.5, 127.4, 128.5, 129.6, 130.0, 133.4, 135.2, 142.6, 168.4 ppm. MS, m/z 289 (M⁺). Elemental analysis for C₁₉H₁₂ClN: Calculated, C, 78.76; H, 4.17; N, 4.83. Found: C, 79.07; H, 4.25; N, 4.76. mp. 245–248°C.

9-(2-chlorophenyl)acridine (Table 2, entry 3)

IR (KBr) (v _max/cm⁻¹) 1651.01 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 7.33–7.42 (m, 4H, Ar-H), 7.59–7.63 (m, 4H, Ar-H), 7.77–8.17 (m, 4H, Ar-H); ¹³C NMR (100 MHz, CDCl₃) δ_c 125.3, 126.3, 126.5, 127.2, 128.7, 129.8, 130.3, 132.2, 135.1, 144.1, 160.3 ppm. MS, m/z 289 (M⁺). Elemental analysis for C₁₉H₁₂ClN: Calculated, C, 78.76; H, 4.17; N, 4.83. Found: C, 79.07; H, 4.27; N, 4.84. mp. 269–271°C.

9-(4-nitrophenyl)acridine (Table 2, entry 4)

IR (KBr) (v _max/cm⁻¹) 1646.91 (C = N), 1523 (–NO₂); ¹H NMR (400 MHz, CDCl₃) δ_H 7.46 (t, 2H, J=3.09 Hz, Ar-H), 7.61–7.64 (m, 6H, Ar-H), 8.16 (d, 2H, J=3.17 Hz, Ar-H), 8.21 (d, 2H, J=3.17 Hz, Ar-H); ¹³C NMR (100 MHz, CDCl₃) δ_c 124.7, 125.1, 126.4, 128.1, 128.5, 129.7, 130.1, 135.8, 139.4, 146.9, 162.6 ppm. MS, m/z 300 (M⁺). Elemental analysis for C₁₉H₁₂N₂O₂: Calculated, C, 75.99; H, 4.03; N, 9.33. Found: C, 74.98; H, 4.01; N, 8.89. mp. 258–260°C.

9-(4-aminophenyl)acridine (Table 2, entry 5)

IR (KBr) (v _max/cm⁻¹) 3334 (–NH2), 1650.46 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 4.07 (br, s, 2H, NH₂), 7.26 (t, 2H, J=3.18 Hz, Ar-H), 7.61–7.64 (m, 6H, Ar-H), 8.14 (d, 2H, J=3.17 Hz, Ar-H), 8.23 (d, 2H, J=3.17 Hz, Ar-H); ¹³C NMR (100 MHz, CDCl₃) δ_c 124.9, 125.4, 126.7, 128.2, 128.6, 129.9, 130.2, 135.8, 137.7, 147.1, 148.5 ppm. MS, m/z 270 (M⁺). Elemental analysis for C₁₉H₁₄N₂: Calculated, C, 84.42; H, 5.22; N, 10.36. Found: C, 84.47; H, 5.31; N, 9.98. mp 270–272°C.

9-(4-hydroxyphenyl)acridine (Table 2, entry 6)

IR (KBr) (v _max/cm⁻¹) 3632 (–OH), 1650.46 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 7.05–7.35 (m, 6H, Ar-H), 7.56–7.97 (m, 6H, Ar-H), 8.68 (br, s, 1H, –OH); ¹³C NMR (100 MHz, CDCl₃) δ_c 124.9, 125.4, 126.7, 128.2, 128.6, 129.9, 130.2, 135.8, 137.7, 147.1, 148.5 ppm. MS, m/z 271 (M⁺). Elemental analysis for C₁₉H₁₃NO: Calculated, C, 84.11; H, 4.83; N, 5.16. Found: C, 84.10; H, 4.85; N, 5.07. mp >300°C.

2-(acridin-9-yl)benzoic acid (Table 2, entries 7 & 11)

IR (KBr) (v _max/cm⁻¹) 3456 (OH), 1737.41 (C = O), 1652.64 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 7.55 (t, 2H, J=3.01 Hz, ArH), 7.70 (t, 2H, J=3.01 Hz, ArH), 8.14–8.28 (m, 4H, ArH); ¹³C NMR (100 MHz, CDCl₃) δ_c 119.3, 125.9, 126.8, 127.4, 128.1, 128.3, 128.7, 132.8, 138.1, 141.3, 147.9, 191.9 ppm. MS, m/z 299 (M⁺). Elemental analysis for C₂₀H₁₃NO₂: Calculated, C, 80.25; H, 4.38; N, 4.68. Found: C, 81.01; H, 4.54; N, 4.31. mp. 265–266°C.

2-(acridin-9-yl)acetic acid (Table 2, entry 8)

IR (KBr) (v _max/cm⁻¹) 3446 (OH), 1731.83 (C = O), 1637.76 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 2.85 (s, 2H, CH₂), 7.51 (t, 2H, J=2.98 Hz, ArH), 7.67 (t, 2H, J=2.99 Hz, ArH), 8.10–8.23 (m, 4H, ArH); ¹³C NMR (100 MHz, CDCl₃) δ_c 54.0, 124.3, 125.5, 127.5, 128.5, 129.3, 135.4, 147.5, 200.3 ppm. MS, m/z 237 (M⁺). Elemental analysis for C₁₅H₁₁NO₂: Calculated, C, 75.94; H, 4.67; N, 5.90. Found: C, 75.86; H, 4.78; N, 5.79. mp. Decomp.

3-(acridin-9-yl)propanoic acid (Table 2, entry 9)

IR (KBr) (v _max/cm⁻¹) 3440 (OH), 1732.96 (C = O), 1638.91 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 2.50 (t, 2H, J=3.01 Hz, CH₂), 2.71 (t, 2H, J= 3.02 Hz, CH₂COOH), 7.54 (t, 2H, J= 2.93 Hz, ArH), 7.66 (t, 2H, J=2.93 Hz, ArH), 8.00–8.17 (m, 4H, ArH); ¹³C NMR (100 MHz, CDCl₃) δ_c 27.0, 35.6, 124.9, 125.8, 127.6, 128.8, 129.3, 135.3, 147.1, 200.7 ppm. MS, m/z 251 (M₊). Elemental analysis for C₁₆H₁₃NO₂: Calculated, C, 76.48; H, 5.21; N, 5.57. Found: C, 77.13; H, 5.23; N, 5.61. mp 305–3078°C.

5-(acridin-9-yl)pentanoic acid (Table 2, entry 10)

IR (KBr) (v _max/cm⁻¹) 3442 (OH), 1731.61 (C = O), 1637.13 (C = N); ¹H NMR (400 MHz, CDCl₃) δ_H 1.24–1.20 (m, 4H, 2CH₂), 1.98 (t, 2H, J=2.99 Hz, CH₂-COOH), 2.11 (t, 2H, J= 2.97 Hz, ArCH₂), 7.58 (t, 2H, J=2.97 Hz, ArH), 7.69 (t, 2H, J=2.96 Hz, ArH), 8.05–8.07 (m, 4H, ArH); ¹³C NMR (100 MHz, CDCl3) δ_c 22.8, 27.0, 35.6, 54.0, 124.9, 125.8, 127.4, 128.6, 129.5, 135.3, 147.1, 200.3 ppm. MS, m/z 279 (M⁺). Elemental analysis for C₁₉H₂₁NO₂: Calculated, C, 77.40; H, 6.13; N, 5.0. Found: C, 77.27; H, 5.98; N, 4.91. mp. 265–69°C.