Thermo-promoted annulation of arylboronic acids with anthranils under catalyst-free conditions: Access to acridines

Abstract

Acridine derivatives have exhibited great application prospects in organic photovoltaic devices. An efficient and atomically economical synthetic method was developed for the production of acridines from anthranils using arylboronic acids. This protocol features no catalysts, good functional group tolerance, and operational simplicity. This catalyst-free process afforded various acridines in moderate to good yields, providing an efficient platform for the investigation of untapped reactions at high temperatures.

Keywords

acridines anthranil catalyst-free one-pot thermo-promoted

Introduction

Heterocyclic compounds are a class of structurally unusual but intriguing compounds encountered in a wide range of synthetic and biological applications.^1–3 Acridines are important nitrogen-containing compounds derived from anthracene with a pungent odor that can be embedded in DNA.^4,5 Owing to their unique aromatic structure, acridines have demonstrated exceptional antimicrobial, antiviral, and anticancer activities and can function as versatile biological probes.^6,7 The rigid planar conjugated structure of acridine imparts it with remarkable electrochemical and photophysical properties, rendering acridine derivatives highly promising for use in organic photovoltaic devices. Therefore, many efforts have been focused on developing synthetic methods for the construction of various acridine derivatives.^8–10 Among the established protocols for acridines, o-aminoaryl aldehydes/ketones have been coupled with cyclohexanones,^11,12 hypervalent iodonium salts,^13,14 and arylboronic acids.^15,16 In addition, a protocol for the production of acridines using aromatic azides with imines has been developed through a cascade process of Rh(III)-catalyzed amination, followed by intramolecular electrophilic aromatic substitution and aromatization.^17,18

Since the synthesis reported by Baum, who used anthranils and organozinc reagents as starting materials in a metal-catalyzed cross-coupling reaction, o-(substituted-amino)benzaldehydes have been synthesized, and acridine products were subsequently obtained under acidic conditions.¹⁹ Subsequently, Kim et al.²⁰ described Rh(III)-catalyzed C–H functionalization, followed by intramolecular electrophilic cyclization between benzaldehydes and anthranils to generate 4-acyl acridines. Li et al.²¹ reported cobalt-catalyzed amination using anthranils and organozinc pivalates to form condensed N-heterocycles. More recently, Gao et al.²² developed an efficient copper-catalyzed electrophilic amination of arylboronic acids and anthranils to produce N-aryl-2-aminophenones, which provided acridine derivatives via condensation in TFA (trifluoroacetic acid). Li et al.²³ established a Cu-catalyzed one-pot synthesis of acridines using aryl boronic acids and anthranils (Scheme 1).

Scheme 1.

Methods for the synthesis of acridines.

Over the past few decades, anthranils have gained great attention as valuable precursors for constructing diverse nitrogen-containing heterocycles that are difficult to obtain by other means.^24–28 Our earlier study successfully identified straightforward reaction conditions at high temperatures to produce benzoxazinones, amides, esters, and quinolines from anthranils without any catalyst or additive.²⁹ Inspired by this thermo-promoted reaction, we recently introduced a novel reaction between anthranils and arylboronic acids to construct acridines via heating.

Results and discussion

We began our investigation using anthranil (1a) and phenylboronic acid (2a) as model substrates. Solvents with high boiling points were required because acridines were to be obtained by heating without a catalyst. Six solvents with high boiling points were used (Table 1, Entries 1–6; triglyme: triethylene glycol dimethyl ether; tetraglyme: tetraethylene glycol dimethyl ether; DMI: 1,3-dimethyl-2-imidazolidinone; TEG: tetraethylene glycol; DPG: dipropylene glycol; DMA: dimethyl adipate). Owing to their water solubility, these solvents were easily removed by simple extraction after the reaction was complete. With the exception of DMI (Entry 3), the other five solvents (Entries 1, 2, and 4–6) could all deliver the desired product 3a. When the reaction was carried out in the commonly used solvents dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO), the process deteriorated, and no product was obtained (Entries 7 and 8). A survey of the amount of phenylboronic acid revealed that 1.5 equiv. was optimal for this procedure (Entries 9–11). Lowering the temperature slowed down the reaction and reduced the yield (Entries 12–15), and when the temperature was decreased to 150 °C, no reaction occurred.

Table 1.

Optimization of the reaction conditions of anthranil and phenylboronic acid.^a.

Entry	Solvent	2a (equiv.)	Temperature (°C)	Yield (%)^b

1	Triglyme	1.2	216	55
2	Tetraglyme	1.2	216	48
3	DMI	1.2	216	<5
4	TEG	1.2	216	32
5	DPG	1.2	216	15
6	DMA	1.2	216	41
7	DMF	1.2	153	<5
8	DMSO	1.2	189	<5
9	Triglyme	1.0	216	35
10	Triglyme	1.5	216	64
11	Triglyme	2.0	216	50
12	Triglyme	2.0	rt	NR^c
13	Triglyme	2.0	100	NR^c
15	Triglyme	2.0	150	<5

Reaction conditions: A solution of anthranil 1a (0.2 mmol) and phenylboronic acid 2a (0.2–0.4 mmol) in solvent (1 mL) was stirred under the specified temperature conditions.

Isolated yield.

NR: no reaction.

The more than 4000 commercially available aryl boronic acids are among the most versatile building blocks for organic synthesis. The utility of substances in this family is largely derived from the myriad of carbon–carbon and carbon–heteroatom bond forming processes that are generally accomplished using transition-metal complexes. However, metal-free reactions with boronic acids are rare. The Petasis boronic acid–Mannich reaction is a representative example.³⁰ To the best of our knowledge, this metal-free reaction is the first case in which acridines were synthesized from boronic acids. After evaluating the reaction conditions, the generality of the reaction was examined. Initially, an array of para-substituted phenylboronic acids was used, affording the corresponding 2-substituted acridines in 49%–78% yields. Electron-donating methoxy, methyl, and methylthio groups afforded the corresponding acridines. Trifluoromethyl and cyano groups were also tolerated, affording 3g (49%) and 3h (51%), respectively; however, when the substituent was a nitro group, the target product could not be obtained. Halides, including Cl⁻, Br⁻, and F⁻, were compatible under these conditions. Notably, an aldehyde was compatible with the reaction conditions, furnishing acridine-2-carbaldehyde (3l). It is difficult to obtain this product by other methods because of the sensitivity of aldehydes. The acridine-2-carboxamide (3m) was also obtained under the conditions. We then examined the effect of substituents at different phenylboronic acid sites on the reaction, and the results showed that chlorine-substituted boronic acids could be formed at the 2-, 3-, and 4-positions. When 3-substituted boronic acids were used, the annulation could occur at two positions after site-specific C–N cross-coupling according to the literature.²³ However, 1-chloroacridine was not found possibly due to the steric hindrance of the Cl atom. When the polycyclic arylboronic acids, 1- and 2-naphthylboronic acids, were used, benzo[c]acridine and benzo[b]acridine were obtained in 62% and 71% yields, respectively (Table 2). Heteroaromatic substrates, such as isoquinoline-5-boronic acid, also gave good yields (3r, 68%), which could not be achieved under acidic conditions.

Table 2.

Substrate scope of arylboronic acids.^a.

Reaction conditions: anthranil 1a (0.2 mmol) and arylboronic acids 2 (0.3 mmol) in triglyme (1 mL) were stirred at 216 °C for 0.5–1 h. All yields are reported as isolated yields.

In addition, we examined anthranils bearing different substituents in reactions using 4-methylphenylboronic acid as a substrate. The electronic properties of the substituted anthranils did not significantly influence the isolated yields (Table 3). When the substituents were 5-F, 5-Cl, and 5-Br, the target products 4b, 4c, and 4e were obtained under the reaction conditions in 73%, 71%, and 71% yields, respectively. Whether the substituent was at the 4- or 5-position had no significant effect on the yield. 5-methoxy-2,1-benzoxazole was well tolerated under the optimal conditions, affording 4f in a 68% yield. Notably, 5-chloro-3-phenyl-2,1-benzisoxazole was compatible with the reaction conditions and furnished 2-chloro-7-methyl-9-phenylacridine 4g in a 21% yield. This relatively low yield could be attributed to the steric hindrance of the 3-phenyl group, which prevented the attack of boric acid. When a nitro group was used as a substituent, no reaction occurred.

Table 3.

Substrate scope of anthranils.^a.

Reaction conditions: anthranil 1 (0.2 mmol) and 4-methylphenylboronic acid 2i (0.3 mmol) in triglyme (1 mL) were stirred at 216 °C for 0.5–1 h. All yields are reported as isolated yields.

According to the above results and the previous literature,^23,24,31 a possible mechanism is proposed as shown in Scheme 2. Anthranils can be converted into nitrenes through a thermolytic N–O cleavage at high temperature. The N atom can then bond to boric acid to give a zwitterionic intermediate II. Migration of the aryl group on II could then lead to intermediate III followed by cyclization to give the acridine 3a.

Scheme 2.

A possible mechanistic pathway.

Conclusion

In summary, we discovered novel reaction conditions for the synthesis of acridines that allowed for direct condensation between anthranil and arylboronic acids without the use of any catalyst or additive, producing acridines in moderate to good yields. This strategy is characterized by atom economy, operational simplicity, and low cost, and it is particularly appealing for both academic and industrial laboratories to pursue new synthetic strategies. This method is a beneficial complement to existing methods.

Experiment

General materials and methods

¹H and ¹³C NMR spectra were obtained from a solution in CDCl₃ or d₆-DMSO with TMS (tetramethylsilane) as internal standard using a 500/125 MHz (¹H/¹³C) or 400/101 MHz (¹H/¹³C) spectrometer. The chemical shifts were reported in δ (ppm) using the δ 7.26 signal of CDCl₃ and δ 2.50 signal of DMSO-d₆ (¹H NMR), the δ 77.16 signal of CDCl₃ and δ 39.52 signal of DMSO-d₆ (¹³C NMR) as internal standards. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Mass spectra were acquired on a Finnigan SSQ7000 (EI/CI) spectrometer and high-resolution mass spectra on a Finnigan MAT 95 (EI/CI) or on a Thermo Fisher Scientific LTQ Orbitrap XL or Thermo Scientific Q Exactive Plus. Melting points were determined using a Büchi 510 apparatus and are uncorrected. The isotope recorded in for the m/z data was ³⁵Cl and ⁷⁹Br. All commercially available reagents were used without further purification, purchased from Acros or Aldrich and used without further purification unless otherwise noted. Solvents were predistilled according to standard laboratory methods. The progress of the reactions was monitored by analytical thin-layer chromatography (TLC) from Jiangyou Chemical Co., Ltd (Yantai, China). Visualization of the developed TLC plates was performed with ultraviolet irradiation (254 nm) or by staining with basic potassium permanganate solution. In addition, silica gel (200–300 mesh) for column chromatography was purchased from Haiyang Chemical Co., Ltd (Qingdao, China), particle size 0.040–0.063 mm (230–240 mesh, flash).

General procedure for synthesis of acridines

Anthranil 1 (1.0 mmol) and arylboronic acid 2 (1.5 mmol) were dissolved in triglyme (5.0 mL). The reaction mixture was stirred at 216 °C using an oil bath for 0.5–1 h and monitored via TLC. Upon completion, the reaction mixture was cooled to room temperature and poured into water. The product was extracted with ethyl acetate (EtOAc) twice, the combined organic phases were washed with water, brine solution, dried over Na₂SO₄, and filtered. The solution was removed under vacuum and the residue was purified by column chromatography. The crude reaction mixture was purified on silica gel using hexanes/EtOAc as the eluent to afford the desired product 3.

The substituted anthranils were prepared according to the literature methods with minor modifications.³² All arylboronic acids were all commercially purchased without further purification.

Acridine (3a). The title compound was prepared according to the general procedure.³³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as an orange powder (114 mg, yield 64%); m.p. 110 °C–112 °C (literature³³ 112 °C–113 °C); R_f 0.50 (10:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 8.24 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.78 (t, J = 8.0 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 149.1, 136.1 × 2, 130.3 × 2, 129.4 × 2, 128.2 × 2, 126.6 × 2, 125.7 × 2. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₃H₁₀N 180.0813, found 180.0835.

4-Chloroacridine (3b). The title compound was prepared according to the general procedure.¹⁰ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (123 mg, yield 58%); m.p. 83 °C–85 °C; R_f 0.50 (20:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.79 (s, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 4.0 Hz, 1H), 7.91 (d, J = 3.0 Hz, 1H), 7.84-7.81 (m, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 149.5, 145.2, 136.9, 133.5, 130.9, 130.3, 130.0, 128.1, 127.6, 127.6, 127.0, 126.7, 125.3. HRMS (ESI) m/z [M+H]⁺calcd for C₁₃H₉ClN 214.0424, found 214.0462.

3-Chloroacridine (3c). The title compound was prepared according to the general procedure.³³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (106 mg, yield 50%); m.p. 119 °C–121 °C (literature³³ 119 °C–120 °C); R_f 0.60 (10:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.24 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 149.5, 148.9, 136.3, 136.2, 130.9, 129.5, 129.3, 129.2, 128.2, 127.9, 126.5, 126.0, 124.8. HRMS (ESI) m/z [M+H]⁺calcd for C₁₃H₉ClN 214.0424, found 214.0458.

2-Chloroacridine (3d). The title compound was prepared according to the general procedure.³³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (149 mg, yield 73%); m.p. 173 °C–175 °C (literature³³ 172 °C–173 °C); R_f 0.50 (10:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 9.6 Hz, 1H), 8.01–7.99 (m, 2H), 7.81 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 149.1, 147.2, 135.1, 131.6, 131.5, 131.1, 130.7, 129.4, 128.1, 126.9, 126.7, 126.4, 126.3. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₃H₉ClN 214.0424, found 214.0447.

2-Bromoacridine (3e). The title compound was prepared according to the general procedure.³³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a brown powder (179 mg, yield 70%); m.p. 148 °C–150 °C (literature³³ 147 °C–148 °C); R_f 0.50 (10:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 6.8 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 149.2, 147.3, 135.0, 133.9, 131.1, 130.8, 129.8, 129.5, 128.2, 127.3, 126.8, 126.5, 119.7. HRMS (ESI) m/z [M+H]⁺calcd for C₁₃H₉BrN 257.9918, found 257.9935.

2-Fluoroacridine (3f). The title compound was prepared according to the general procedure.³³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as an orange powder (149 mg, yield 76%); m.p. 119 °C–121 °C (literature³³ 120 °C–121 °C); R_f 0.50 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.65 (s, 1H), 8.24–8.19 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.59–7.51 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 159.8 (d, J = 250 Hz), 148.7, 146.6, 135.2, 132.3 (d, J = 5.0 Hz), 130.2, 129.7, 127.9, 126.8, 126.6, 126.4, 122.2 (d, J = 28.75 Hz), 109.8 (d, J = 22.5 Hz). ¹⁹F NMR (470 MHz, CDCl₃) δ −113.28. HRMS (ESI) m/z [M+H]⁺calcd for C₁₃H₉FN 198.0719, found 198.0759.

2-(Trifluoromethyl)acridine (3g). The title compound was prepared according to the general procedure.²³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a brown powder (121 mg, yield 49%); m.p. 129 °C–131 °C (literature²³ 130 °C–133 °C); R_f 0.40 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.88 (s, 1H), 8.35–8.37 (m, 2H), 8.27 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.91 (dd, J = 9.0, 1.5 Hz, 1H), 7.88–7.85 (m, 1H), 7.62–7.59 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 150.5, 149.3, 137.8, 131.7, 131.1, 129.8, 128.5, 127.8, 126.8 (q, J = 5.0 Hz), 126.7, 126.1 (q, J = 258.5 Hz), 125.5 (q, J = 2.5 Hz), 125.1, 123.1. ¹⁹F NMR (470 MHz, CDCl₃) δ −62.75. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₉F₃N 248.0687, found 248.0696.

Acridine-2-carbonitrile (3h). The title compound was prepared according to the general procedure.²³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (104 mg, yield 51%); m.p. 198 °C–201 °C (literature²³ 200 °C–202 °C); R_f 0.30 (5:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.82 (s, 1H), 8.42 (s, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.89–7.86 (m, 1H), 7.82 (dd, J = 9.0, 1.5 Hz, 1H), 7.62 (t, J = 8.0, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 150.8, 148.8, 137.4, 135.7, 132.3, 129.8, 129.6, 128.6, 127.2, 127.1, 125.3, 125.3, 118.8, 109.6. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₉N₂ 205.0766, found 205.0745.

2-Methylacridine (3i). The title compound was prepared according to the general procedure.³³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as an off-white powder (142 mg, yield 74%); m.p. 127 °C–129 °C (literature³³ 126 °C–128 °C); R_f 0.50 (20:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.62 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.74 (t, J = 7.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.50 (t, J = 7.0 Hz, 1H), 2.56 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 148.7, 148.2, 135.6, 135.0, 133.4, 129.9, 129.5, 129.2, 128.2, 126.9, 126.9, 126.3, 125.7, 21.9. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₂N 194.0970, found 194.0943.

2-Methoxyacridine (3j). The title compound was prepared according to the general procedure.²³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (146 mg, yield 70%); m.p. 92 °C–95 °C; R_f 0.50 (20:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.71 (s, 1H), 7.51–7.46 (m, 2H), 7.14 (s, 1H), 3.97 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 157.0, 147.3, 146.1, 133.7, 130.8, 129.2, 129.1, 127.6, 127.4, 126.9, 125.8, 125.6, 103.0, 55.5. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₂NO 210.0919, found 210.0934.

2-(Methylthio)acridine (3k). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (146 mg, yield 65%); m.p. 94 °C–97 °C; R_f 0.50 (20:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 6.8 Hz, 1H), 7.63–7.61 (m, 2H), 7.52 (t, J = 7.2 Hz, 1H), 2.63 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 148.4, 147.6, 136.7, 133.9, 130.4, 129.8, 129.4, 129.3, 128.0 × 2, 127.0, 126.0, 121.1, 15.4. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₂NS 226.0690, found 226.0652.

Acridine-2-carbaldehyde (3l). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (107 mg, yield 52%); m.p. 150 °C–152 °C; R_f 0.40 (10:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 8.96 (s, 1H), 8.52 (s, 1H), 8.31–8.22 (m, 3H), 8.07 (d, J = 7.6 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 6.4 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 191.3, 150.6, 150.5, 138.6, 136.2, 133.8, 132.1, 130.7, 129.5, 128.6, 126.9, 126.7, 126.3, 125.5. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₀NO 208.0762, found 208.0738.

Acridine-2-carboxamide (3m). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (117 mg, yield 53%); m.p. 167 °C–169 °C; R_f 0.40 (10:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 9.47 (s, 1H), 8.63 (d, J = 6.8 Hz, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.93–7.89 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.59–7.53 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 161.1, 160.5, 150.8, 138.1, 134.1, 133.9, 130.6, 128.7 × 2, 128.6, 128.6, 127.3, 127.2, 123.6. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₁NO₂ 223.0871, found 223.0917.

Benzo[c]acridine (3n). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (141 mg, yield 62%); m.p. 110 °C–112 °C; R_f 0.40 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 9.53 (d, J = 7.5 Hz, 1H), 8.64 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.84–7.81 (m, 1H), 7.79–7.76 (m, 1H), 7.76–7.72 (m, 2H), 7.71–7.69 (m, 1H), 7.60 (t, J = 7.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 148.0, 147.9, 135.1, 134.1, 131.8, 129.9, 129.8, 129.2, 128.0, 127.9, 127.8, 127.4, 127.2, 126.1, 125.9, 125.4, 125.3. HRMS (ESI) m/z [M+H]⁺calcd for C₁₇H₁₂N 230.0970, found 230.0934.

Benzo[b]acridine (3o). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (160 mg, yield 71%); m.p. 298 °C–300 °C. R_f 0.40 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 9.36 (s, 1H), 8.71 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 9.5 Hz, 1H), 8.01 (d, J = 9.5 Hz, 1H), 7.93 (d, J = 9.5 Hz, 1H), 7.87 (dd, J = 8.0, 1.0 Hz, 1H), 7.83–7.79 (m, 1H), 7.71–7.68 (m, 1H), 7.64 (td, J = 7.5, 1.0 Hz, 1H), 7.61–7.57 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 149.5, 148.3, 132.6, 131.4, 130.6, 130.2, 130.1, 129.2, 129.0, 128.6, 128.4, 127.8, 127.6, 126.6, 126.2, 124.3, 123.0. HRMS (ESI) m/z [M+H]⁺calcd for C₁₇H₁₂N 230.0970, found 230.0946.

[1,3]Dioxolo[4,5-b]acridine (3p). The title compound was prepared according to the general procedure.²³ The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/40) to provide the product as a yellow powder (118 mg, yield 53%); m.p. 158 °C–161 °C (literature²³ 159 °C–162 °C); R_f 0.40 (20:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.74 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 6.26 (s, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 152.8, 148.2, 148.1, 147.2, 134.3, 129.8, 128.6, 128.3, 125.7, 125.6, 124.5, 103.6, 102.7, 101.9. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₀NO₂ 224.0712, found 224.0735.

1,3-Dimethoxyacridine (3q). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/40) to provide the product as a yellow powder (117 mg, yield 49%); m.p. 116 °C–118 °C; R_f 0.40 (20:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 9.02 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.09 (s, 1H), 6.44 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.5, 156.2, 150.8, 149.1, 131.7, 130.7, 128.8, 128.1, 124.8, 124.5, 117.4, 97.7, 97.6, 55.9, 55.8. HRMS (ESI) m/z [M+H]⁺calcd for C₁₅H₁₄NO₂ 240.1025, found 240.1058.

Benzo[b][1,8]phenanthroline (3r). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/2) to provide the product as a yellow powder (156 mg, yield 68%); m.p. 236 °C–239 °C; R_f 0.30 (2:1 hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 9.07 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 7.6 Hz, 1H), 8.46 (d, J = 7.6 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.87-7.83 (m, 1H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 7.67–7.62 (m, 2H), 7.53–7.49 (m, 1H), 7.02 (d, J = 7.6 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 159.5, 147.6, 146.2, 134.8, 132.9, 132.2, 128.5, 127.5, 127.5, 127.3, 127.3, 126.5, 125.8, 121.9, 117.8, 113.2. HRMS (ESI) m/z [M+H]⁺calcd for C₁₆H₁₁N₂ 231.0922, found 231.0946.

6-Fluoro-2-methylacridine (4a). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/10) to provide the product as a yellow powder (158 mg, yield 75%); m.p. 124 °C–127 °C; R_f 0.50 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.59 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.92 (t, J = 9.0 Hz, 1H), 7.78 (dd, J = 11.5, 2.0 Hz, 1H), 7.68 (s, 1H), 7.61 (dd, J = 9.0, 1.0 Hz, 1H), 7.33–7.29 (m, 1H), 2.55 (s, 3H).¹³C NMR (125 MHz, CDCl₃) δ 163.4 (d, J = 250 Hz), 149.2 (d, J = 12.5 Hz), 148.7, 135.6, 135.3, 133.9, 130.5 (d, J = 11.25 Hz), 128.8, 126.5, 126.3, 124.1, 117.7 (d, J = 27.5 Hz), 117.7 (d, J = 20.0 Hz), 21.8. ¹⁹F NMR (470 MHz, CDCl₃) δ −107.76. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₁FN 212.0876, found 212.0889.

2-Fluoro-7-methylacridine (4b). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/20) to provide the product as a yellow powder (154 mg, yield 73%); m.p. 156 °C–159 °C; R_f 0.50 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.56 (s, 1H), 8.21 (dd, J = 10.0, 5.5 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.56–7.52 (m, 2H), 2.57 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 169.8 (d, J = 250 Hz), 147.8, 146.1, 136.4, 134.1 (d, J = 7.5 Hz), 133.3, 132.3 (d, J = 10.0 Hz), 129.3, 127.1, 126.9 (d, J = 10.0 Hz), 125.9, 121.6 (d, J = 28.75 Hz), 109.7 (d, J = 21.25 Hz), 22.0. ¹⁹F NMR (470 MHz, CDCl₃) δ −113.64. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₁FN 212.0876, found 212.0897.

2-Chloro-2-methylacridine (4c). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/30) to provide the product as a yellow powder (161 mg, yield 71%); m.p. 216 °C–218 °C; R_f 0.60 (10:1 hexane/EtOAc).¹H NMR (500 MHz, CDCl₃) δ 8.49 (s, 1H), 8.13 (d, J = 9.5 Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.64 (dd, J = 9.5, 2.5 Hz, 1H), 7.61 (dd, J = 9.0, 2.0 Hz, 1H), 2.56 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 148.3, 146.9, 136.4, 133.9, 133.7, 131.4, 131.3, 131.1, 129.3, 127.1, 127.0, 126.3, 126.2, 21.9. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₁ClN 228.0580, found 228.0572.

6-Bromo-2-methylacridine (4d).³³ The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/30) to provide the product as a yellow powder (189 mg, yield 70%); m.p. 187 °C–189 °C (literature³³ 188 °C–189 °C); R_f 0.60 (10:1 hexane/EtOAc).¹H NMR (500 MHz, CDCl₃) δ 8.57 (s, 1H), 8.40 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.68 (s, 1H), 7.62 (dd, J = 9.0, 1.5 Hz, 1H), 7.55 (dd, J = 9.0, 2.0 Hz, 1H), 2.56 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 148.8, 148.6, 136.1, 135.2, 134.0, 131.6, 129.4, 129.4, 129.2, 126.9, 126.4, 125.2, 124.3, 21.9. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₁BrN 272.0075, found 272.0085.

2-Bromo-2-methylacridine (4e). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/10) to provide the product as a brown powder (189 mg, yield 71%); m.p. 254 °C–258 °C; R_f 0.30 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.50 (s, 1H), 8.11–8.09 (m, 2H), 8.06 (d, J = 9.5 Hz, 1H), 7.76 (dd, J = 9.0, 2.0 Hz, 1H), 7.69 (s, 1H), 7.62 (dd, J = 9.0, 1.5 Hz, 1H), 2.57 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 148.3, 147.0, 136.5, 133.9, 133.8, 133.4, 131.3, 129.9, 129.3, 127.6, 127.1, 126.3, 119.7, 21.9. HRMS (ESI) m/z [M+H]⁺calcd for C₁₄H₁₁BrN 272.0075, found 272.0096.

2-Methoxy-7-methylacridine (4f). The title compound was prepared according to the general procedure. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/10) to provide the product as a yellow powder (151 mg, yield 68%); m.p. 130 °C–133 °C; R_f 0.30 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.44 (s, 1H), 8.09 (dd, J = 9.0, 4.0 Hz, 2H), 7.65 (s, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 9.5 Hz, 1H), 7.10 (s, 1H), 3.95 (s, 3H), 2.55 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 157.1, 146.6, 145.8, 135.7, 132.7, 132.2, 131.0, 129.2, 127.7, 127.1 125.9, 125.1, 103.2, 55.6, 21.9. HRMS (ESI) m/z [M+H]⁺calcd for C₁₅H₁₄NO 224.1075, found 224.1039.

2-Chloro-7-methyl-9-phenylacridine (4g). The title compound was prepared according to the general procedure. The reaction mixture was stirred at 216 °C using an oil bath for 6 h. The crude compound was purified by flash column chromatography over silica gel (EtOAc/n-hexane = 1/10) to provide the product as a yellow powder (63 mg, yield 21%); m.p. 235 °C–237 °C; R_f 0.30 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.65–7.60 (m, 6H), 7.41 (dd, J = 7.5, 2.0 Hz, 2H), 7.39 (s, 1H), 2.45 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 147.9, 146.5, 145.2, 136.3, 135.5, 133.2, 131.4, 131.3, 130.7, 130.4 × 2, 129.4, 128.7 × 2, 128.6, 125.7, 125.4, 125.0, 124.7, 22.0. HRMS (ESI) m/z [M+H]⁺calcd for C₂₀H₁₅ClN 304.0893, found 304.0911.

Supplemental Material

sj-docx-1-chl-10.1177_17475198241228252 – Supplemental material for Thermo-promoted annulation of arylboronic acids with anthranils under catalyst-free conditions: Access to acridines

Supplemental material, sj-docx-1-chl-10.1177_17475198241228252 for Thermo-promoted annulation of arylboronic acids with anthranils under catalyst-free conditions: Access to acridines by Jing Jiang, Peng Xie, Yue Gao, Chenqi Wu and Jingcheng Song in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Doctoral Promotion Program Research Initiation Fund of Suzhou Polytechnic Institute of Agriculture (grant no. BS[2022]22).

ORCID iD

Jing Jiang

Supplemental material

Supplemental material for this article is available online.

References

Zhang

Zhao

Hou

, et al. Chem Rev 2012; 112: 5271–5316.

Vitaku

Smith

Njardarson

JT.

J Med Chem 2014; 57: 10257–10274.

Bunz

UH.

Acc Chem Res 2015; 48: 1676–1686.

Denny

Baguley

BC.

Curr Top Med Chem 2003; 3: 339–353.

Belmont

Bosson

Godet

, et al. Anticancer Agents Med Chem 2007; 7: 139–169.

Gensicka-Kowalewska

Cholewiński

Dzierzbicka

RSC Adv 2017; 7: 15776–15804.

Mandal

Chhetri

Bhuyan

, et al. Green Chem 2020; 22: 3178–3185.

Zeghada

Bentabed-Ababsa

Mongin

, et al. Tetrahedron 2020; 76: 131435.

, et al. Org Lett 2014; 16: 18–21.

10.

Wang

Chen

, et al. Org Biomol Chem 2015; 13: 6580–6586.

11.

W-L

Wang

H-J

, et al. Adv Syn Catal 2017; 359: 4250–4257.

12.

Senadi

Dhandabani

W-P

, et al. Green Chem 2016; 18: 6241–6245.

13.

Pang

Lou

, et al. Eur J Org Chem 2015; 2015: 3361–3369.

14.

Zhang

, et al. Chem Commun (Camb) 2021; 57: 5442–5445.

15.

Zhang

, et al. J Org Chem 2018; 83: 12880–12886.

16.

Cao

Zhu

, et al. J Org Chem 2020; 85: 10167–10174.

17.

Lian

Hummel

Bergman

, et al. J Am Chem Soc 2013; 135: 12548–12551.

18.

Shen

Liu

Wang

, et al. Synth Commun 2018; 48: 1354–1362.

19.

Baum

Condon

Shook

DA.

J Org Chem 1987; 52: 2983–2988.

20.

Kim

Han

Mishra

, et al. Org Lett 2018; 20: 4010–4014.

21.

Tan

Keller

, et al. J Am Chem Soc 2019; 141: 98–103.

22.

Gao

Yang

, et al. J Org Chem 2020; 85: 10222–10231.

23.

Wei

Org Biomol Chem 2022; 20: 9742–9745.

24.

Gao

Nie

Huo

, et al. Org Chem Front 2020; 7: 1177–1196.

25.

Hirano

Miura

J Am Chem Soc 2022; 144: 648–661.

26.

Gao

Nie

, et al. Org Lett 2020; 22: 2600–2605.

27.

Cai

, et al. RSC Adv 2020; 10: 8989–8993.

28.

Shao

Zhao

Ding

, et al. Chem Commun (Camb) 2022; 58: 4771–4774.

29.

Jiang

Cai

, et al. J Org Chem 2019; 84: 2022–2031.

30.

Follmann

Graul

Schäfer

, et al. Synlett 2005; 2005: 1009–1011.

31.

Barluenga

Tomas-Gamasa

Aznar

, et al. Nat Chem 2009; 1: 494–499.

32.

Wang

, et al. Org Lett 2018; 20: 2204–2207.

33.

Zheng

Sun

, et al. Chem Commun (Camb) 2017; 53: 6263–6266.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

3.20 MB