Regioselective Synthesis of Coumarin-Annulated Polycyclic Heterocycles via Sequential Claisen Rearrangement and Radical Cyclization Reaction ^†

Abstract

Coumarin and its annulated heterocycles are mainly found in natural products, many of which show significant biological activities and are used extensively for the preparation of pharmaceutical products. Investigation revealed that many heterocyclic compounds fused with coumarin moiety exhibited antihelmentic, hypnotic, insecticidal, antifungal, and anti-coagulant properties. In industry, coumarin scaffolds are widely used for the preparation of drugs, agrochemicals, pesticides, and dyes. In recent studies, several coumarin derivatives have been used in materials science for the preparation of organic cell imaging materials, fluorescent biological probes, etc. Due to their immense application potential in biological science and material chemistry, much attention has been paid by researchers towards the synthesis of a new class of coumarin annulated heterocycles. In this paper, the synthesis of coumarin-annulated polycyclic heterocycles via sequential Claisen rearrangement and tin-hydride mediated radical cyclization is reported. The requisite starting materials 3-((4-chlorobut-2-yn-1-yl)oxy)-2H-chromen-2-one (1) was prepared from 3-hydroxycoumarin and 1,4-dichlorobut-2-yne. The Claisen rearrangement of 1 in refluxing chlorobenzene afforded 1-(chloromethyl)pyrano[2,3-c]chromen-5(3H)-one (2). Finally, radical cyclization reactions were carried out smoothly using ⁿBu₃SnH and AIBN in toluene at 110 °C, leading to the coumarin-annulated polycyclic heterocycles in high yields. The process is operationally simple and easy to work-up, making it convenient for the preparation of coumarin annulated heterocycles.

1. Introduction

Coumarin and its annulated molecules are largely found in natural products, many of which show significant physiological activities and are used for the preparation of drug molecules [1,2]. According to the literature, several coumarin derivatives have potential biological activities [3,4,5,6], including antihelmentic, hypnotic, insecticidal, antidiabetic, antifungal, antiviral, anti-HIV, antibacterial, and anti-coagulant properties [7,8,9]. Coumarin-annulated molecules are extensively used in industry for the preparation of various pesticides, agrochemicals, and dye molecules [10,11,12]. Due to its fluorescence properties, several coumarin derivatives have been used in materials science for the preparation of organic cell imaging materials and fluorescent biological probes [13,14]. Owing to their diverse applications, the synthesis of this class of compounds is a hot topic in modern research [15]. As a result, several methods have been developed for the synthesis of coumarin-annulated heterocycles.

Claisen rearrangement is a classical method applied for the construction of C-C bonds in organic synthesis with a high degree of regio-selectivity [16,17]. In our previous reports, we have synthesized a number of polycyclic heterocycles of biological interest using Claisen rearrangement [18,19]. Additionally, radical-mediated cyclization has been considered an important tool for the synthesis of carbo- and heterocycles via carbon-carbon and carbon-heteroatom bond forming reactions [20,21,22]. The intramolecular addition of a carbon centered-radical intermediate to aromatic heterocycles has emerged as an efficient method for the construction carbocycles, heterocycles, and spirocyclic compounds. This protocol has also been applied as an intermediate step in total synthesis of natural products [23]. In this paper, the synthesis of coumarin-annulated polycyclic heterocycles via sequential Claisen rearrangement and tin-hydride mediated radical cyclization is discussed, using 3-hydroxycoumarin and 1,4-dichlorobut-2-yne as starting materials. The development protocol is an operationally simple, easy work-up procedure that leads to high yields of the coumarin-fused polycyclic heterocycles.

2. Results and Discussion

The requisite starting material, 3-((4-chlorobut-2-yn-1-yl)oxy)-2H-chromen-2-one (1) was prepared from 3-hydroxycoumarin (A) and 1,4-dichlorobut-2-yne (B) in refluxing acetone for 7 h. The Claisen rearrangement of 1 in refluxing chlorobenzene for 5 h provided 1-(chloromethyl)pyrano[2,3-c]chromen-5(3H)-one (2). The radical precursors 3 were prepared by the nucleophile substitution reaction between compound 2 and 2-bromo anilines (C) in refluxing ethyl methyl ketone in the presence of K₂CO₃ and a catalytic amount of NaI. The treatment of radical precursors (3) with ⁿBuSnH (1.0 eq) and AIBN (0.5 eq.) in toluene at 110 °C leads to the formation of polyheterocyclic compounds 4 in 75–82% yields (Scheme 1).

In the initial attempt to cause the radical cyclization, substrate 3a was used as a radical precursor. The treatment of compound 3a with ⁿBu₃SnH (1.0 eq) and 0.5 eq. of azobisisobutyronitrile (AIBN) in dry toluene at 80 °C for 5 h under N₂ atmosphere afforded cyclized product tetrahydrochromeno[4′,3′:5,6]pyrano[4,3-c]quinolin-1(6cH)-one (4a) in 52% yield. However, the yield of the product was increased to 75% by increasing the temperature to 110 °C (Scheme 1). Changing the solvent to benzene, xylene, and tetrahydrofuran did not achieve any improvement in the yield. Under the same reaction conditions (ⁿBu₃SnH (1.0 eq), AIBN (0.5 eq.), toluene, 110 °C, N₂ atm, 5 h), other substrates (3b and 3c) also gave the desired products 4b and 4c at yields of 82% and 80%, respectively. The structure of product 4 was determined using ¹H NMR spectroscopy. The ¹HNMR (400 MHz, CDCl₃) spectra of compound 4a showed one proton at a ring juncture, a double triplet (dt) at δ = 2.13 (J = 3.2 Hz and 14.4 Hz), and another one proton doublet triplet at δ = 2.34 (J = 2.9 Hz and 15.3 Hz). This indicates that radical cyclization proceeded with the formation of a trans-ring juncture with coupling constant >14 Hz of the ring juncture protons. The mass spectrum of compound 4a showed a molecular ion peak at m/z [M⁺+H] = 320.1012.

The formation of the product 4 from the radical precursor 3 can be explained by the generation of aryl radical 5, which may undergo a 6-endo-trig radical cyclization with the nearest double bond of pyran ring to produce a resonance stabilized allyl radical (6) followed by the abstraction of hydrogen from ⁿBu₃SnH to afford the desired cyclic product 4. An alternative route may also be possible, in which a 5-exo-trig cyclization may give a spiro-cyclic radical intermediate, followed by neophyl rearrangement and abstraction of hydrogen from tin-hydride to give [6,6]-fused cyclic product 4 (Scheme 2).

3. Conclusions

In conclusion, we have successfully synthesized coumarin-annulated pentacyclic heterocycles via sequential Claisen rearrangement and tin-hydride mediated radical cyclization. The radical cyclization reaction proceeded smoothly in the presence of ⁿBu₃SnH and AIBN in toluene, leading to the regioselective synthesis of coumarin-annulated polycyclic heterocycles in high yields. The process is an operationally simple, easy work-up procedure, thereby making it more convenient for the preparation of coumarin annulated polyheterocycles.

4. Experimental

Open capillaries were used to determine the melting points and are uncorrected. TLC plates were purchased from Merck and used for thin-layer chromatography (TLC). Petroleum ether refers to the fraction boiling between 60 °C to 80 °C. ¹H NMR spectra were recorded on a Bruker Ascend 400 MHz spectrometer (Bruker, Berlin, Germany) at 400 MHz using CDCl₃ solvents and TMS as internal standard. Chemical shifts values are given in parts per million (ppm, δ) with reference to an internal standard and coupling constants are reported in Hertz (Hz).

(a) 

General procedure for the radical cyclization of substrates 3 to cyclized product 4.

A suspension of compound 3 (0.5 mmol), ⁿBu₃SnH (0.5 mmol, 1.0 eq., 0.14 mL), and AIBN (40 mg, 0.25 eq) in dry toluene was refluxed at 110 °C under N₂ atmosphere for 5 h. After completion of the reaction, the solvent was removed under reduced pressure. The residue was dissolved with DCM (15 mL) and washed with water (2 × 10 mL). Finally, DCM was washed with brine and dried over anhy Na₂SO₄. The solvent was removed and the residual mass was purified with column chromatography over silica gel using petroleum/ethyl acetate as eluent.

(b) 

Spectral analysis:

• 1-(((2-Bromophenyl)(methyl)amino)methyl)pyrano[2,3-c]chromen-5(3H)-one (3a)

White solid; R_f = 0.50 (SiO₂, petroleum ether/ethyl acetate = 50:50); Yield: 74% (147 mg, 0.37 mmol), mp 155–157 °C. ¹H NMR (400 MHz, CDCl₃) δ = 2.71 (s, 3H), 4.13 (s, 2H), 4.76 (d, J = 4.8 Hz, 2H), 6.41 (t, J = 4.7 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H) 7.23–7.38 (m, 3H), 7.51 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H). HRMS (ESI): m/z calcd for C₂₀H₁₇BrNO₃ [M⁺+H]: 398.0314; found: 398.1202.

• 1-(((2-Bromo-4-methylphenyl)(methyl)amino)methyl)pyrano[2,3-c]chromen-5(3H)-one (3b)

White solid; R_f = 0.50 (SiO₂, petroleum ether:ethyl acetate = 50:50); Yield: 70% (144 mg, 0.35 mmol), mp 172–174 °C. ¹H NMR (400 MHz, CDCl₃) δ = 2.25 (s, 3H), 2.67 (s, 3H), 4.07 (s, 2H), 4.72 (d, J = 4.7 Hz, 2H), 6.34 (t, J = 4.7 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 7.01 (dd, J = 1.3 Hz, 8.1 Hz, 1H), 7.14–7.19 (m, 1H), 7.27–7.30 (m, 2H), 7.33–7.37 (m, 1H), 7.69 (dd, J = 1.2 Hz, and 8.1 Hz, 1H). HRMS (ESI): m/z calcd for C₂₁H₁₉BrNO₃ [M⁺+H]: 412.0470; found: 412.0498.

• 1-(((2-Bromo-4-ethylphenyl)(methyl)amino)methyl)pyrano[2,3-c]chromen-5(3H)-one (3c)

White solid; R_f = 0.45 (SiO₂, petroleum ether/ethyl acetate = 50:50); Yield: 82% (174 mg, 0.41 mmol), m.p.: 137–139 °C. ¹H NMR (400 MHz, CDCl₃) δ = 1.21 (t, J = 7.6 Hz, 3H), 2.56 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 4.09 (s, 2H), 4.74 (d, J = 4.4 Hz, 2H), 6.38 (t, J = 4.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H) 7.27–7.38 (m, 3H), 7.67 (d, J = 8.0 Hz, 1H). HRMS (ESI): m/z calcd for C₂₂H₂₁BrNO₃ [M⁺+H]: 426.0627 found: 426.0634.

• (6cR,12bR)-8-methyl-7,8,12b,13-tetrahydrochromeno[4′,3′:5,6]pyrano[4,3-c]quinolin-1(6cH)-one (4a)

Brown solid; R_f = 0.50 (SiO₂, petroleum ether/ethyl acetate = 65:35); Yield: 75% (120 mg, 0.375 mmol), m.p.: 182–183 °C. ¹H NMR (400 MHz, CDCl₃) δ = 2.13 (dt, J = 3.2 Hz, 14.4 Hz, 1H), 2.34 (dt, J = 2.9 Hz, 15.3 Hz, 1H), 2.92 (s, 3H), 3.46 (d, J = 9.7 Hz, 1H), 3.82 (d, J = 9.7 Hz, 1H), 4.26 (dt, J = 1.8 Hz, 11.4 Hz, 1H), 4.53 (dt, J = 3.5 Hz, 11.3 Hz, 1H), 6.58–6.62 (m, 2H), 6.69–6.70 (m, 2H), 6.90 (t, J = 7.1 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 7.15–7.28 (m, 2H). HRMS (ESI): m/z calcd for C₂₀H₁₈NO₃ [M⁺+H]: 320.1208, found: 320.1012.

• (6cR,12bR)-8,11-Dimethyl-7,8,12b,13-tetrahydrochromeno[4′,3′:5,6]pyrano[4,3-c]quinolin-1(6cH)-one (4b)

Brown solid; R_f = 0.48 (SiO₂, petroleum ether/ethyl acetate = 70:30); Yield: 82% (136 mg, 0.41 mmol), m.p. 162–164 °C. ¹H NMR (400 MHz, CDCl₃) δ = 2.11 (dt, J = 2.8 Hz, 14.9 Hz, 1H), 2.13 (s, 3H), 2.33 (dt, J = 2.8 Hz, 14.2 Hz, 1H), 2.90 (s, 3H), 3.45 (d, J = 9.7 Hz, 1H), 3.78 (d, J = 9.7 Hz, 1H), 4.26 (dt, J = 2.0 Hz, 11.3 Hz, 1H), 4.55 (dt, J = 3.7 Hz, 11.3 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.91–6.94 (m, 1H), 6.97 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 7.22–7.24 (m, 1H), 7.28 (dd, J = 1.1 Hz, 8.1 Hz, 1H). HRMS (ESI): m/z calcd for C₂₁H₂₀NO₃ [M⁺+H]: 334.1365 found: 334.1134.

• (6cR,12bR)-11-ethyl-8-methyl-7,8,12b,13-tetrahydrochromeno[4′,3′:5,6]pyrano[4,3-c]quinolin-1(6cH)-one (4c)

Brown solid; R_f = 0.48 (SiO₂, petroleum ether/ethyl acetate = 65:35); Yield: 80% (139 mg, 0.4 mmol), mp 155–157 °C. ¹H NMR (400 MHz, CDCl₃) δ = 1.02 (t, J = 7.7 Hz, 3H), 2.09 (dt, J = 2.8 Hz, 14.2 Hz, 1H), 2.34 (dt, J = 2.2 Hz, 14.2 Hz, 1H), 2.41 (q, J = 7.5 Hz, 2H), 2.89 (s, 3H), 3.43 (t, J = 9.7 Hz, 1H), 3.75 (d, J = 9.7 Hz, 1H), 4.25 (dt, J = 1.96 Hz, 12.3 Hz, 1H), 4.53 (dt, J = 3.6 Hz, 11.3 Hz, 1H), 6.56 (d, J = 8.04 Hz, 1H), 6.88–6.92 (m, 1H), 6.98–7.05 (m, 2H), 7.20–7.33 (m, 3H). HRMS (ESI): m/z calcd for C₂₂H₂₂NO₃ [M⁺+H]: 348.1521, found: 348.0986.