Synthesis of benzochromenes and dihydrophenanthridines with helical motifs using Garratt–Braverman and Buchwald–Hartwig reactions

Abstract

A simple strategy for the synthesis of 6H-benzo[c]chromenes and 5,6-dihydrophenanthridines through a judicious use of Garratt–Braverman (GB) cyclization and Buchwald–Hartwig (BH) coupling in moderate to good yield, has been reported. The uniqueness of the GB reaction is exemplified in providing the required biaryl intermediate which could be successfully converted to the target skeleton via functional group transformations followed by BH coupling. The presence of a dihydro-isofuran moiety assisted in inducing a helical motif in these molecules, which is also confirmed by single crystal X-ray structural analysis. The crystallographic data gives valuable insight into the role of the non-bonding interaction in regulating the helicity.

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Introduction

Over the last couple of decades, development of divergent synthetic methodology that leads to many useful products starting from a common intermediate has drawn the attention of synthetic organic chemists.¹ It provides a quick access to a large molecular library with skeletal diversity. The key to the success of such an approach relies on the ability of the common intermediate to undergo a variety of reactions. Additionally, the common intermediate should be easily accessible and the methodology becomes more relevant if the target skeletal core is present in molecules of biological and material importance. During the course of our work to synthesize polycyclic aromatic compounds,² our attention was drawn to the presence of angularly fused polynuclear heterocyclic moiety Z in several natural products where the central ring has a heteroatom (O/N) substitution.

Examples include 6H-benzo[c]chromenes,³ found in natural products like cannabinol and cannabinolic acid A and 5,6-dihydro-phenanthridines,⁴ another important core structure found in natural products like the ‘Amaryllidaceae’ alkaloids (Fig. 1). All these possess profound pharmacological activities. We realized that the same core skeleton Z along with a fused dihydro isofuran moieties may be accessed from the corresponding bis-propargyl ether by a combination of Garratt–Braverman⁵ (GB) cyclization and Buchwald–Hartwig⁶ (BH) coupling.

Fig. 1 Some of the well known natural products with the benzochromene and dihyrophenanthridine moiety.

The isofuran part may act as additional handle for functionalization and also may induce helicity⁷ in these classes of molecules. Helical cores, apart from finding applications in asymmetric synthesis,⁸ also constitute a design element in the development of chiroptical materials,⁹ photochromic materials,¹⁰ sensors,¹¹ molecular level devices,¹² organic electronics,¹³ NLO materials,¹⁴ etc. By the virtue of their inherent chirality, helicenes find profound applications in triggering certain biological activities. Molecules capable of structure-selective binding to DNA are of great importance, since they may have influence upon biological functions of genetic material.¹⁵ Thus investigation of the interactions of DNA with small molecules having helical motif is a highly potential area of research. Chirally selective binding of helicenes to DNA is well known.¹⁶ Thus apart from the synthesis and structural analysis, elementary DNA binding studies have been also carried out to study the variation in binding pattern of these molecules with change in their chemical and structural architecture. Our results on the synthesis, structural analysis and initial DNA binding studies of these classes of molecules are reported in this paper.

Results and discussion

Retrosynthetic analysis revealed that the biaryl¹⁷ alcohol C should act as the key intermediate. This can be directly converted to the benzochromenes A via BH coupling. Alternately, this can be converted to the sulphonamide D which can then be converted to the dihydrophenanthridines B via BH coupling. The alcohol should be derivable from the corresponding ester E which, in turn, may be obtained through a GB cyclization of a suitable bis-propargyl ether F (Scheme 1).

Scheme 1 Retrosynthesis leading to moiety ‘Z’.

It is worth comparing existing (apparently simple) alternative synthetic routes to biaryl systems with our method. Considering Suzuki coupling¹⁸ as the most obvious alternative to GBC, for synthesizing heterocycle fused biaryls, as presented here, one needs halo phthalan derivatives or phthalan boronic acids (Scheme 2). Literature survey revealed that their synthesis is not a straight forward process and suffers from problems like use of costly transition metal catalysts, poor yields and often leads to mixture of products.¹⁹ So GBC is likely to be a good alternative to such approaches for accessing heterocycle fused biaryls with helical motif.

Scheme 2 Possible synthetic alternatives.

The precursor bis-propargyl ether for the GB reaction was synthesized following a multistep synthetic protocol starting from various 1,2-dibromo benzene derivatives. Compounds 1a–d underwent Sonogashira coupling²⁰ with 2-(4-prop-2-ynyloxy-but-2-ynyloxy)-tetrahydro-pyran²¹ to give 2a–d, followed by PPTS mediated THP deprotection to give 3a–d. For 1b, major Sonogashira coupling product obtained was 2b (explainable on electronic grounds),²² along with the minor regioisomer formed in very less amount (upon carefully controlling the reaction time and temperature). 2b could be isolated in pure form via flash column chromatography. For 1c, the major Sonogashira coupling product was 2c, with the formation of other regioisomer in minor amount which was obtained as an inseparable mixture (3 : 1). The forward synthesis was carried on with this inseparable mixture.²³ The corresponding aldehydes 4a–d were synthesized using IBX as oxidant. These were then made to undergo Wittig reaction to give the precursor 5a–d for GB reaction. The crucial GB cyclization was done with DBU as base in refluxing benzene. The chemoselectivity of the GB reaction was of particular interest to us. The substrates 5a–d had the possibility of cyclizing either via the involvement of the double bond in conjugation with the ester, or the double bond which is a part of the aryl ring.²⁴ However, in majority of cases, the double bond in the unsaturated ester participated almost exclusively. This is most likely due to the involvement of loss of aromaticity when the aryl double participates in the process. The selectivity is much less in case of nitro analogue 5b, for which the two products were obtained in a ratio of ∼7 : 1. The reason for this reduced selectivity is possibly due to the stabilization of the radical via captodative effect²⁵ by both the aryl ring as well the α,β-unsaturated ester. However, loss of aromaticity was found to be the predominant factor in determining the overall chemoselectivity (Scheme 3).

Scheme 3 Mechanistic route for the two alternate GB cyclization pathways.

Biaryl esters 6a–d thus obtained were subjected to reduction (under various conditions and using a variety of reducing agents) to obtain the alcohols 8a–d directly, which however failed possibly due to steric reason. As a way out, the ester was first hydrolyzed to give the carboxylic acids 7a–d which were then reduced by borane to give the desired alcohols 8a–d. These were then subjected to Pd-mediated BH coupling to give the 6H-benzo[c]chromene derivatives 9a–d. The C (aryl)–O BH coupling of the alcohol involved the use of PdCl₂(PPh₃)₂ as the catalyst and ^tBuOK for 8a, b.²⁶ However for electron donating substituents in 8c-d, this reagent system gave very poor yields, which improved with Pd(OAc)₂, BINAP, ^tBuOK. The reactions proceeded under reflux with a varying time period of 1–2 h (Scheme 4). The results of GB and BH coupling are shown in Table 1. For synthesis of dihydrophenathrene derivatives, the alcohols 8a, 8c-d were first converted to the azide 11a, 11c-d via the corresponding bromide 10a, 10c-d, which was obtained using PBr₃. The azide was made to undergo PPh₃ mediated Staudinger reduction²⁷ to give the corresponding amine isolated as the Boc amides 12a, 12c-d. Deprotection of Boc followed by tosylation gave the sulfonamides 13a, 13c-d, the precursor for BH coupling. Finally Pd catalyzed BH coupling was done to get the desired 5,6-dihydro-phenanthridine derivatives 14a, 14c-d. Pd(OAc)₂, BINAP, dry K₂CO₃ were employed to accomplish C (aryl)–N BH coupling.²⁸ BINAP was the ligand chosen rather than cheaper PPh₃ as the latter is reported to assist β-hydride elimination and hence form phenanthridine.²⁹ The reaction under reflux took 3 h for completion for 13a. For substrates with electron donating functionality (13c-d), it took 8–12 h for complete consumption of starting material (Scheme 5). The GB cyclization and BH coupling results are compiled in Table 1.

Scheme 4 Synthetic route for the synthesis of 6H-benzo[c]chromene derivatives.

Table 1 Synthesized 6H-benzo[c]chromene and N-tosyl-5,6-dihydrophenanthridine derivatives

Compounds	GBC yield (%)	BHC yield (%)
	70	85
	45	70
	70	83
	72	83
	70	80
	70	78
	72	78

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Scheme 5 Synthetic route for the synthesis of 5,6-dihydrophenanthridine derivatives.

The final compounds (chromenes/dihydrophenathridines) were characterized by NMR and HRMS studies. The C–O bond formation was confirmed from the ¹³C spectra of the cyclized product, by the disappearance of the peak for quaternary C containing the C (aryl)–Br bond (δ 113.0) and appearance of a new peak for quaternary C containing the C (aryl)–O bond (δ 114.7). The C–N bond formation was confirmed from the ¹H NMR by the disappearance of peak for the sulfonamide NH proton (δ 4.60) in the cyclized product (see spectra for comparison) (Fig. 2a and b). HRMS data also supported the C–O/C–N bond formation. Definitive proof came from single crystal X-ray structures of three of the products (Fig. 3).

Fig. 2 (a) Stacked ¹³C NMR spectra showing the disappearance and arrival of new peaks. (b) Stacked ¹H NMR spectra showing the disappearance sulfonamide NH proton.

Fig. 3 ORTEP diagram of the obtained crystals with 30% probability.

The X-ray structures did show certain amount of helicity as was expected. Interestingly, the dihydrophenathridines showed greater helicity as compared to the corresponding chromene analogue. This can be attributed to the intramolecular π-stacking between the sulfonamide tolyl (ring E) and the aryl ring B which tilted the latter more towards ring E thus causing greater helicity (Table 2). The interplanar distance of 3.6 Å between rings ‘E’ and ‘B’ for compounds 14c and 14d is conducive for such π-stacking³⁰ (Fig. 4). This proposition was also supported by the crystallographic data of analogous crystallographic studies for compounds reported in the literature (Fig. 5).^31,32

Table 2 Interplanar distance and angle of the synthesized crystals along with the reference compounds

Compound	Angle between mean planes containing rings ‘A’ and ‘D’	Angle between mean planes containing rings ‘E’ and ‘B’	Average distance between ring ‘E’ and ‘B’
14c	22.91°	12.48°	3.6 Å
14d	22.70°	14.88°	3.6 Å
15	17.11°	25.01°	4.0 Å
9d	14.73°	—	—
16	12.84°	—	—

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Fig. 4 Structural skeleton used for explaining the X-ray data with reference compounds 15 and 16.

Fig. 5 Crystal structures showing interplanar twisting of synthesized and reference compounds.

The synthesized chromenes/dihydrophenathridines were screened for their DNA-intercalating activity. For this, the known DNA intercalator ethidium bromide displacement assay was carried out. Thus the compounds, dissolved in acetonitrile-buffer were gradually added to a solution of calf thymus DNA in Tris–Cl buffer (pH 7.2) containing 40 mM NaCl, and fluorescence emission was measured at 600 nm (slit width 5 nm; 1 cm path length). Significant quenching of fluorescence intensity was observed for compounds 9a, 9b, 9c, out of which 9a showed maximum quenching (Fig. 6). The observed quenching supports the DNA intercalating property of these compounds.

Fig. 6 Fluorescence spectral overlay of DNA–EtBr complex under the presence of compound 9a. Relative fluorescence intensity reduced after EtBr replacement induced by compound 9a. A fixed concentration of DNA (6 μL of 1 mg mL⁻¹) and EtBr (3 μL of 0.5 mg mL⁻¹) was used to make a final volume of 3 mL solution. Fluorescence emission spectra (λ_max = 600 nm, excitation wavelength 546 nm) were recorded from each concentrations 0 μM (black line); 0.25 μM (red line); 0.5 μM (cyan line); 0.75 μM (blue line); 1.0 μM (navy line); 1.25 μM (violet line); 1.5 μM (olive line), 2.0 μM (magenta line) and the lower pink colour line indicates no fluorescence from only DNA–compound 9a complex (2.0 μM).

The rest of the compounds 14a, 14c, 9d and 14d did not show any quenching. The compound 9a was also studied for its DNA-binding by UV-spectroscopy. With gradual addition of the compound, characteristic hypochromicity was also observed (Fig. 7). The reduction in the UV/visible absorbance of DNA by the subsequent addition of compounds and quenching of DNA–EtBr fluorescence³³ revealed that compound 9a behaved as an ideal intercalating agent.

Fig. 7 Absorption spectral changes of calf-thymus DNA (5 μM) treated with 0, 5, 10, and 20 μM of compound 9a. Black line represent only compound in same buffer (20 μM). Inset: shows a fitting of the absorbance data used to obtain the binding constants. Plots of 1/(A − A₀) vs. 1/[compound] for the determination of binding constants of complex-DNA adducts.

Conclusions

We have developed a novel, simple, economically viable, moderate to high yielding synthetic protocol for the synthesis of 6H-benzo[c]chromene and N-tosyl 5,6-dihydrophenanthridine derivatives using GB cyclization and BH coupling as the key steps in our multistep synthetic route. With the confirmation of helicity by X-ray crystallography, we will try to further explore this aspect by imposing suitable steric constrains and tune the molecular geometry accordingly. Divergent synthesis on other suitable biaryl derivatives generated through GB to get important bioactive skeletons (like benzochromenones from the carboxylic acids 7a–d) is going on in our laboratory. Initial ethidium bromide displacement studies indicated DNA intercalative activity of benzochromene class of molecules.

Experimental

General information

All dry reactions were conducted with oven-dried glassware under an atmosphere of nitrogen (N₂). All common reagents were commercial grade reagents and used without further purification. Silica gel (60–120 and 230–400 mesh) was used for column chromatography. TLC was performed on aluminum-backed plates coated with silica gel 60 with F254 indicator. Locally available UV-lamp chamber and I₂-blower were used as the TLC spot indicator. HRMS were obtained using ESI-TOF mass spectrometer. The ¹H NMR spectra were recorded at 600, 400, 200 MHz and ¹³C NMR spectra were measured at 150, 100, 50 MHz using CDCl₃. Proton and carbon spectra were referenced internally to solvent signals, using values of δ = 7.26 ppm for proton and δ = 77.2 for carbon (middle peak) in CDCl₃ and the following abbreviations are used to describe peak patterns where appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs = broad signal, AB_q = AB quartet. All coupling constants (J) are given in Hz.

Compounds 1b–d were prepared following standard literature procedure.³⁴ Compounds 2a–d were prepared via Pd catalyzed Sonogashira reaction following standard reaction protocols. 2-(4-Prop-2-ynyloxy-but-2-ynyloxy)-tetrahydro-pyran was prepared following standard literature procedure.

General methods for the preparation of aldehyde (4a–d)

Alcohol (3.5 mmol) dissolved in 6 mL of dry DMSO was treated with IBX (1.2 eq.) and stirred for 3–4 h at room temperature. The reaction was quenched with water. The reaction mixture was partitioned between DCM (30 × 3 mL) and water (50 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

4-[3-(2-Bromo-phenyl)-prop-2-ynyloxy]-but-2-ynal (4a). State: viscous liquid; R_f = 0.6 (hexane/EtOAc 10/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 849 mg, 88%; ¹H NMR (600 MHz, chloroform-d) δ 9.26 (s, 1H), 7.59 (dd, J = 8.1, 1.2 Hz, 1H), 7.48 (dd, J = 7.7, 1.7 Hz, 1H), 7.29–7.26 (m, 1H), 7.20 (td, J = 7.8, 1.7 Hz, 1H), 4.60 (s, 2H), 4.57 (s, 2H); ¹³C NMR (50 MHz, chloroform-d) δ 176.4, 133.7, 132.7, 130.2, 127.3, 125.8, 124.5, 91.7, 88.2, 86.4, 86.1, 58.1, 56.5. HRMS: m/z [M + H]⁺ calcd for C₁₃H₉BrO₂ 276.9864; obtained 276.9860.

4-[3-(2-Bromo-4-nitro-phenyl)-prop-2-ynyloxy]-but-2-ynal (4b). State: gummy solid; R_f = 0.5 (hexane/EtOAc 7/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 1.0 g, 89%; ¹H NMR (200 MHz, chloroform-d) δ 9.26 (s, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.14 (dd, J = 8.5, 2.3 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 4.60 (s, 2H), 4.59 (s, 2H); ¹³C NMR (50 MHz, chloroform-d) δ 176.1, 147.2, 133.8, 130.7, 127.4, 125.7, 122.1, 93.8, 90.9, 85.9, 84.4, 57.7, 56.6. HRMS: m/z [M + H]⁺ calcd for C₁₃H₈BrNO₄ 321.9715; obtained 321.9718.

4-[3-(2-Bromo-5-methoxy-phenyl)-prop-2-ynyloxy]-but-2-ynal (major isomer) (4c). State: viscous liquid; R_f = 0.6 (hexane/EtOAc 6/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 952 mg, 89%; ¹H NMR (200 MHz, chloroform-d) δ 9.24 (s, 1H), 7.43 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 3.1 Hz, 1H), 6.76 (dd, J = 8.9, 3.1 Hz, 1H), 4.58 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 176.2, 158.5, 133.1, 124.8, 118.3, 116.9, 116.1, 91.5, 87.9, 86.2, 85.9, 57.9, 56.4, 55.6. HRMS: m/z [M + H]⁺ calcd for C₁₄H₁₁BrO₃ 306.9970; obtained 306.9964.

4-[3-(2-Bromo-4,5-dimethoxy-phenyl)-prop-2-ynyloxy]-but-2-ynal (4d). State: viscous liquid; R_f = 0.5 (hexane/EtOAc 4/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 7 : 1); yield: 1.184 g, 90%; ¹H NMR (200 MHz, chloroform-d) δ 9.25 (s, 1H), 7.02 (s, 1H), 6.94 (s, 1H), 4.59 (s, 2H), 4.55 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 176.2, 150.3, 148.1, 116.9, 116.0, 115.4, 115.1, 91.6, 86.4, 85.9, 58.0, 56.27, 56.33, 56.2. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₃BrO₄ 377.0075; obtained 377.0076.

General methods for the preparation of ester (5a–d)

Aldehyde (3.1 mmol) dissolved in 15 mL of dry benzene was treated with the phosphonium ylide (1.2 eq.) and stirred under refluxing conditions for 3–4 h, under nitrogen atmosphere. Benzene was removed under reduced pressure. The reaction mixture was partitioned between EtOAc (30 × 2 mL) and water (50 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by flash silica gel column chromatography with hexane–ethyl acetate as eluent.

6-[3-(2-Bromo-phenyl)-prop-2-ynyloxy]-hex-2-en-4-ynoic acid ethyl ester (5a). State: gummy solid; R_f = 0.7 (hexane/EtOAc 10/1); the reaction product was purified by column chromatography (Si-gel 230–400 mesh, hexane/EtOAc = 20 : 1); yield: 847 mg, 79%; ¹H NMR (600 MHz, chloroform-d) δ 7.59 (dd, J = 8.1, 1.2 Hz, 1H), 7.48 (dd, J = 7.7, 1.7 Hz, 1H), 7.27 (td, J = 7.5, 1.1 Hz, 1H), 7.19 (td, J = 7.8, 1.7 Hz, 1H), 6.80 (dt, J = 15.9, 1.9 Hz, 1H), 6.26 (d, J = 15.9 Hz, 1H), 4.56 (d, J = 2.0 Hz, 2H), 4.55 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 165.5, 133.5, 132.4, 131.1, 129.8, 127.0, 125.5, 124.5, 124.2, 93.6, 88.7, 85.6, 83.6, 60.8, 57.4, 57.1, 14.2. HRMS: [M + H]⁺ calcd for C₁₇H₁₅BrO₃ 347.0283; obtained 347.0280.

6-[3-(2-Bromo-4-nitro-phenyl)-prop-2-ynyloxy]-hex-2-en-4-ynoic acid ethyl ester (5b). State: gummy solid; R_f = 0.6 (hexane/EtOAc 7/1); the reaction product was purified by column chromatography (Si-gel 230–400 mesh, hexane/EtOAc = 20 : 1); yield: 945 mg, 78%; ¹H NMR (400 MHz, chloroform-d) δ 8.43 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 8.6, 2.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.76 (dt, J = 16.2, 2.0 Hz, 1H), 6.23 (d, J = 15.8 Hz, 1H), 4.55 (s, 2H), 4.52 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 165.4, 147.2, 133.8, 131.3, 130.9, 127.4, 125.8, 123.9, 122.1, 94.5, 93.2, 84.0, 83.9, 60.9, 57.5, 57.3, 14.2. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₄BrNO₅ 392.0134; obtained 392.0137.

6-[3-(2-Bromo-5-methoxy-phenyl)-prop-2-ynyloxy]-hex-2-en-4-ynoic acid ethyl ester (major isomer) (5c). State: gummy solid; R_f = 0.7 (hexane/EtOAc 7/1); the reaction product was purified by column chromatography (Si-gel 230–400 mesh, hexane/EtOAc = 20 : 1); yield: 909 g, 78%; ¹H NMR (400 MHz, chloroform-d) δ 7.41 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 3.0 Hz, 1H), 6.79–6.69 (m, 2H), 6.23 (d, J = 15.9 Hz, 1H), 4.53 (d, J = 1.7 Hz, 2H), 4.51 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 165.7, 158.5, 133.2, 131.2, 125.1, 124.3, 118.3, 116.9, 116.2, 93.7, 88.5, 85.8, 83.8, 60.9, 57.6, 57.3, 55.78, 14.3. HRMS: m/z [M + H]⁺ calcd for C₁₈H₁₇BrO₄ 377.0388; obtained 377.0382.

6-[3-(2-Bromo-4,5-dimethoxy-phenyl)-prop-2-ynyloxy]-hex-2-en-4-yoic acid ethyl ester (5d). State: gummy solid; R_f = 0.6 (hexane/EtOAc 4/1); the reaction product was purified by column chromatography (Si-gel 230–400 mesh, hexane/EtOAc = 15 : 1); yield: 1.0 g, 80%; ¹H NMR (600 MHz, chloroform-d) δ 7.00 (s, 1H), 6.93 (s, 1H), 6.77 (dt, J = 15.9, 1.9 Hz, 1H), 6.23 (d, J = 15.9 Hz, 1H), 4.52 (d, J = 2.1 Hz, 2H), 4.50 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 165.5, 150.1, 148.0, 131.1, 124.2, 116.8, 116.1, 115.3, 115.0, 93.7, 86.9, 85.8, 83.6, 60.8, 57.5, 57.1, 56.2, 56.1, 14.2. HRMS: m/z [M + H]⁺ calcd for C₁₉H₁₉BrO₅ 407.0494; obtained 407.0493.

General methods for the preparation of biaryl ester using Garratt–Braverman reaction (6a–d)

The bis-propargyl ether (2.4 mmol) dissolved in 60 mL of dry benzene was treated with DBU (2.0 eq.) and stirred under refluxing conditions for 6–8 h, under nitrogen atmosphere. Benzene was removed under reduced pressure. The reaction mixture was partitioned between EtOAc (30 × 2 mL) and water (50 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

4-(2-Bromo-phenyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid ethyl ester (6a). State: gummy solid; R_f = 0.6 (hexane/EtOAc 10/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 581 mg, 70%; ¹H NMR (600 MHz, chloroform-d) δ 8.02 (d, J = 7.9 Hz, 1H), δ 7.63 (d, J = 8.0 Hz, 1H),7.34 (td, J = 7.7, 1.3 Hz, 2H), 7.23 (td, J = 7.8, 1.7 Hz, 1H), 7.15 (dd, J = 7.5, 1.7 Hz, 1H), 5.22 (AB_q, Δν_AB = 13.9 Hz, J_AB = 13.2 Hz, 2H), 4.77 (AB_q, Δν_AB = 21.8 Hz, J_AB = 12.6 Hz, 2H), 4.10–4.04 (m, 2H), 0.98 (t, J = 7.1 Hz, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 166.7, 143.5, 140.7, 139.9, 136.1, 132.6, 130.6, 129.4, 129.3, 129.1, 127.4, 122.6, 120.6, 74.23, 73.4, 60.9, 13.8. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₅BrO₃ 347.0283; obtained 347.0285.

4-(2-Bromo-4-nitro-phenyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid ethyl ester (6b). State: gummy solid; R_f = 0.4 (hexane/EtOAc 7/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 7 : 1); yield: 422 mg, 45%; ¹H NMR (400 MHz, chloroform-d) δ 8.53 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 5.23 (s, 2H), 4.74 (s, 2H), 4.13 (qd, J = 7.1, 6.6, 2.0 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, chloroform-d) δ 165.9, 147.9, 147.8, 144.4, 139.3, 134.5, 130.9, 129.9, 128.6, 127.9, 123.2, 122.6, 121.6, 74.2, 73.0, 61.4, 14.0. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₄BrNO₅ 392.0134; obtained 392.0131.

4-(2-Bromo-5-methoxy-phenyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid ethyl ester (major isomer) (6c). State: gummy solid; R_f = 0.5 (hexane/EtOAc 7/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 8 : 1); yield: 640 mg, 71%; ¹H NMR (400 MHz, chloroform-d) δ 7.99 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.77 (dd, J = 8.8, 3.0 Hz, 1H), 6.70 (d, J = 3.1 Hz, 1H), 5.18 (s, 2H), 4.80 (s, 2H), 4.08 (q, J = 6.8 Hz, 2H), 3.75 (s, 3H), 1.01 (t, J = 7.1 Hz, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 166.5, 158.8, 143.5, 141.4, 139.7, 135.9, 133.1, 130.4, 129.3, 120.6, 114.9, 114.8, 112.9, 74.1, 73.3, 60.9, 55.6, 13.8. HRMS: m/z [M + H]⁺ calcd for C₁₈H₁₇BrO₄ 377.0388; obtained 377.0389.

4-(2-Bromo-4,5-dimethoxy-phenyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid ethyl ester (6d). State: gummy solid; R_f = 0.4 (hexane/EtOAc 4/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 7 : 1); yield: 701 mg, 72%; ¹H NMR (600 MHz, chloroform-d) δ 7.98 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.08 (s, 1H), 6.65 (s, 1H), 5.20 (AB_q, Δν_AB = 15.6 Hz, J_AB = 13.2 Hz, 2H), 4.82 (AB_q, Δν_AB = 21.1 Hz, J_AB = 12.6 Hz, 2H), 4.11 (qd, J = 7.1, 5.0 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 3H), 1.06 (t, J = 7.2 Hz, 1H); ¹³C NMR (50 MHz, chloroform-d) δ 166.7, 148.9, 148.4, 143.3, 140.2, 135.8, 132.3, 130.3, 129.8, 120.5, 115.2, 112.5, 111.9, 74.2, 73.4, 60.9, 56.2, 13.9. HRMS: m/z [M + H]⁺ calcd for C₁₉H₁₉BrO₅ 407.0494; obtained 407.0491.

General methods for the preparation of biaryl carboxylic acid (7a–d)

The biaryl ester (1.7 mmol) dissolved in 10 mL of MeOH was treated with aqueous NaOH (3 eq.) solution (2 mL) and stirred under refluxing conditions for 8 h. MeOH was removed under reduced pressure. The excess base was neutralized by N/10 HCl solution under at 0 °C under ice cold conditions (monitored by pH paper). Then the reaction mixture was partitioned between EtOAc (30 × 2 mL) and water (50 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure to furnish the acid which was used for the next step without further purification.

4-(2-Bromo-phenyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid (7a). State: gummy solid; R_f = 0.3 (hexane/EtOAc 1/1); yield: 511 mg, 95%; ¹H NMR (600 MHz, chloroform-d) δ 8.10 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.35–7.31 (m, 2H), 7.22 (td, J = 7.7, 1.7 Hz, 1H), 7.15 (dd, J = 7.5, 1.7 Hz, 1H), 5.23 (AB_q, Δν_AB = 13.2 Hz, J_AB = 13.8 Hz, 2H), 4.78 (AB_q, Δν_AB = 21.1 Hz, J_AB = 12.6 Hz, 2H); ¹³C NMR (50 MHz, chloroform-d) δ 171.3, 144.4, 140.0, 136.9, 132.6, 131.3, 129.2, 129.1, 127.8, 127.5, 122.2, 120.7, 74.2, 73.3. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₁BrO₃ 318.9970; obtained 318.9965.

4-(2-Bromo-4-nitro-phenyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid (7b). State: gummy solid; R_f = 0.3 (hexane/EtOAc 1/2); yield: 603 mg, 98%; ¹H NMR (400 MHz, chloroform-d) δ 8.51 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 5.24 (s, 2H), 4.74 (s, 2H); ¹³C NMR (150 MHz, chloroform-d) δ 169.9, 147.8, 147.4, 145.4, 139.6, 135.3, 131.8, 129.8, 127.9, 127.1, 123.0, 122.7, 121.8, 74.2, 73.0. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₀BrNO₅ 363.9821; obtained 363.9824.

4-(2-Bromo-5-methoxy-phenyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid (major isomer) (7c). State: gummy solid; R_f = 0.4 (hexane/EtOAc 1/2); yield: 567 mg, 96%; ¹H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 12.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.77 (dd, J = 8.9, 3.1 Hz, 1H), 6.69 (d, J = 3.0 Hz, 1H), 5.21 (s, 2H), 4.80 (s, 2H), 3.76 (s, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 171.1, 158.9, 144.5, 140.9, 140.0, 136.9, 133.3, 131.3, 127.9, 120.7, 115.1, 114.8, 112.9, 74.2, 73.4, 55.7. HRMS: m/z [M + H]⁺ calcd for C₁₆H₁₃BrO₄ 349.0075; obtained 349.0078.

4-(2-Bromo-4,5-dimethoxy-phenyl)-1,3-dihydro-isobenzofuran-5-carboxylic acid (7d). State: gummy solid; R_f = 0.2 (hexane/EtOAc 1/2); yield: 616 mg, 96%; ¹H NMR (600 MHz, chloroform-d) δ 8.02 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.63 (s, 1H), 5.18 (AB_q, Δν_AB = 16.5 Hz, J_AB = 13.5 Hz, 2H), 4.78 (AB_q, Δν_AB = 16.0 Hz, J_AB = 12.6 Hz, 2H), 3.87 (s, 3H), 3.77 (s, 3H); ¹³C NMR (150 MHz, chloroform-d) δ 171.1, 148.9, 148.3, 144.1, 140.3, 136.6, 131.8, 131.2, 128.2, 120.5, 115.3, 112.3, 111.8, 74.1, 73.3, 56.1. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₅BrO₅ 379.0181; obtained 379.0180.

General methods for the preparation of biaryl benzyl alcohol (8a–d)

The carboxylic acid (1.6 mmol) dissolved in 15 mL of dry THF was treated with borane dimethyl sulfide (solution in THF) (3.5 eq.) at 0 °C under ice cold conditions, under nitrogen atmosphere. The temperature was gradually brought to room temp and stirred for 30 h at 40 °C. The reaction mixture was quenched with saturated NaHCO₃ solution at 0 °C under ice cold conditions. The reaction mixture was partitioned between EtOAc (20 × 2 mL) and water (30 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

[4-(2-Bromo-phenyl)-1,3-dihydro-isobenzofuran-5-yl]-methanol (8a). State: gummy solid; R_f = 0.5 (hexane/EtOAc 3/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 4 : 1); yield: 437 mg, 90%; ¹H NMR (600 MHz, chloroform-d) δ 7.68 (dd, J = 8.0, 1.3 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.38 (td, J = 7.4, 1.3 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.26 (td, J = 7.8, 1.6 Hz, 1H), 7.21 (dd, J = 7.5, 1.6 Hz, 1H), 5.19 (AB_q, Δν_AB = 14.3 Hz, J_AB = 12.3 Hz, 2H), 4.77 (AB_q, Δν_AB = 37.5 Hz, J_AB = 12.6 Hz, 2H), 4.41 (AB_q, Δν_AB = 42.6 Hz, J_AB = 12.6 Hz, 2H); ¹³C NMR (50 MHz, chloroform-d) δ 138.9, 138.7, 138.6, 137.9, 133.7, 133.1, 130.5, 129.8, 127.9, 127.6, 123.2, 121.00, 74.2, 73.3, 62.7. HRMS: m/z [M + Na]⁺ calcd for C₁₅H₁₃BrO₂Na 326.9997; obtained 326.9995.

[4-(2-Bromo-4-nitro-phenyl)-1,3-dihydro-isobenzofuran-5-yl]-methanol (8b). State: gummy solid; R_f = 0.3 (hexane/EtOAc 3/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 4 : 1); yield: 418 mg, 75%; ¹H NMR (400 MHz, chloroform-d) δ 8.57 (d, J = 2.2 Hz, 1H), 8.25 (dd, J = 8.4, 2.3 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 5.20 (s, 2H), 4.75 (AB_q, Δν_AB = 30.5 Hz, J_AB = 12.6 Hz, 2H), 4.41 (AB_q, Δν_AB = 39.4 Hz, J_AB = 12.6 Hz, 2H); ¹³C NMR (100 MHz, chloroform-d) δ 148.3, 146.1, 139.5, 138.4, 137.3, 132.2, 131.4, 128.3, 128.2, 124.1, 122.8, 121.9, 74.1, 73.0, 62.8. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₂BrNO₄ 350.0028; obtained 350.0029.

[4-(2-Bromo-5-methoxy-phenyl)-1,3-dihydro-isobenzofuran-5-yl]-methanol (8c). State: gummy solid; R_f = 0.6 (hexane/EtOAc 5/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 5 : 1); yield: 426 mg, 80%; ¹H NMR (400 MHz, chloroform-d) δ 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 6.81 (dd, J = 8.8, 3.0 Hz, 1H), 6.74 (d, J = 3.0 Hz, 1H), 5.17 (s, 2H), 4.78 (AB_q, Δν_AB = 15.8 Hz, J_AB = 12.6 Hz, 2H), 4.42 (AB_q, Δν_AB = 28.0 Hz, J_AB = 12.8 Hz, 2H), 3.77 (s, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 159.1, 139.7, 138.4, 137.8, 133.6, 133.5, 130.8, 127.4, 120.9, 115.8, 115.5, 113.4, 74.1, 73.2, 62.5, 55.6. HRMS: m/z [M + H]⁺ calcd for C₁₆H₁₅BrO₃ 335.0283; obtained 335.0280.

[4-(2-Bromo-4,5-dimethoxy-phenyl)-1,3-dihydro-isobenzofuran-5-yl]-methanol (8d). State: gummy solid; R_f = 0.4 (hexane/EtOAc 3/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 4 : 1); yield: 465 mg, 80%; ¹H NMR (600 MHz, chloroform-d) δ 7.46 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.08 (s, 1H), 6.67 (s, 1H), 5.13 (AB_q, Δν_AB = 17.4 Hz, J_AB = 12.3 Hz, 2H), 4.77 (AB_q, Δν_AB = 35.6 Hz, J_AB = 12.6 Hz, 2H), 4.40 (AB_q, Δν_AB = 43.8 Hz, J_AB = 12.6 Hz, 2H), 3.88 (s, 3H), 3.78 (s, 3H); ¹³C NMR (150 MHz, chloroform-d) δ 149.3, 148.6, 138.9, 138.4, 138.2, 133.5, 130.6, 127.4, 120.8, 115.5, 113.0, 112.7, 74.1, 73.3, 62.6, 56.3, 56.2. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₇BrO₄ 365.0388; obtained 365.0385.

General methods for the preparation of benzochromene using Buchwald–Hartwig coupling reaction (9a–d)

For 9a-b. The biaryl benzyl alcohol (0.3 mmol) dissolved in 10 mL of dry CH₃CN was treated with PdCl₂(PPh₃)₂ (0.02 eq.) and ^tBuOK (2 eq.) sequentially, stirred under refluxing conditions for 2 h, under nitrogen atmosphere. The reaction was quenched with water. The reaction mixture was partitioned between EtOAc (15 × 2 mL) and water (20 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

For 9c-d. The biaryl benzyl alcohol (0.3 mmol) dissolved in 10 mL of dry toluene was treated with BINAP (0.2 eq.), Pd(OAc)₂ (0.1 eq.) and dry ^tBuOK (2 eq.) sequentially, stirred under refluxing condition for 1–1.5 h, under nitrogen atmosphere. The reaction was quenched with water. The reaction mixture was partitioned between EtOAc (15 × 2 mL) and water (20 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

3,6-Dihydro-1H-2,7-dioxa-cyclopenta[c]phenanthrene (9a). State: white solid; R_f = 0.6 (hexane/EtOAc 10/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 57 mg, 85%; ¹H NMR (400 MHz, chloroform-d) δ 7.28–7.25 (m, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.12–7.03 (m, 3H), 5.42 (s, 2H), 5.14 (s, 2H), 5.09 (s, 2H); ¹³C NMR (100 MHz, chloroform-d) δ 155.7, 140.5, 134.6, 131.2, 129.6, 126.0, 125.4, 124.4, 123.1, 122.3, 119.9, 117.7, 74.2, 73.2, 68.7. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₂O₂ 225.0916; obtained 225.0913.

9-Nitro-3,6-dihydro-1H-2,7-dioxa-cyclopenta[c]phenanthrene (9b). State: yellow solid; R_f = 0.4 (hexane/EtOAc 5/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 7 : 1); yield: 56 mg, 70%; ¹H NMR (400 MHz, chloroform-d) δ 7.94 (dd, J = 8.7, 2.4 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.43 (s, 2H), 5.19 (s, 2H), 5.17 (s, 2H); ¹³C NMR (100 MHz, chloroform-d) δ 156.1, 148.1, 141.3, 135.9, 131.7, 129.3, 126.4, 124.9, 123.8, 122.2, 117.4, 113.3, 74.2, 73.3, 69.1. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₁NO₄ 270.0766; obtained 270.0765.

10-Methoxy-3,6-dihydro-1H-2,7-dioxa-cyclopenta[c]phenanthrene (9c). State: white solid; R_f = 0.5 (hexane/EtOAc 10/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 63 mg, 83%; ¹H NMR (400 MHz, chloroform-d) δ 7.18 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.84–6.82 (m, 2H), 5.44 (s, 2H), 5.14 (s, 2H), 5.05 (s, 2H), 3.83 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) δ 154.9, 149.9, 140.6, 134.7, 131.9, 125.6, 124.6, 123.8, 120.3, 118.1, 114.8, 111.6, 74.2, 73.3, 69.1, 55.9. HRMS: m/z [M + H]⁺ calcd for C₁₆H₁₄O₃ 255.1021; obtained 255.1013.

9,10-Dimethoxy-3,6-dihydro-1H-2,7-dioxa-cyclopenta[c]phenanthrene (9d). State: white solid; R_f = 0.5 (hexane/EtOAc 8/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 70 mg, 83%; ¹H NMR (600 MHz, chloroform-d) δ 7.10 (d, J = 7.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.79 (s, 1H), 6.61 (s, 1H), 5.44 (s, 2H), 5.14 (s, 2H), 5.06 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H); ¹³C NMR (150 MHz, chloroform-d) δ 150.6, 150.5, 144.5, 140.6, 133.3, 130.3, 125.8, 124.5, 119.2, 114.7, 109.3, 101.6, 74.1, 73.4, 69.2, 56.8, 56.2. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₆O₄ 285.1127; obtained 285.1129.

General methods for the preparation of biaryl benzyl bromide (10a, 10c-d)

The biaryl benzyl alcohol (0.8 mmol) dissolved in 30 mL of dry DCM was treated with PBr₃ (0.6 eq.) solution in DCM (slowly and dropwise) at 0 °C under ice cold condition, under nitrogen atmosphere. The temperature was gradually brought to room temperature and stirred for 6 h. The reaction was quenched with water. The reaction mixture was partitioned between DCM (15 × 2 mL) and water (20 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

5-Bromomethyl-4-(2-bromo-phenyl)-1,3-dihydro-isobenzofuran (10a). State: gummy solid; R_f = 0.6 (hexane/EtOAc 10/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 249 mg, 85%; ¹H NMR (600 MHz, chloroform-d) δ 7.69 (dd, J = 8.1, 1.2 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.42 (td, J = 7.5, 1.2 Hz, 1H), 7.33 (dd, J = 7.6, 1.8 Hz, 1H), 7.31–7.27 (m, 2H), 5.18 (AB_q, Δν_AB = 12 Hz, J_AB = 12.6 Hz, 2H), 4.81 (d, J = 12.6 Hz, 1H), 4.72 (d, J = 12.6 Hz, 1H), 4.40 (d, J = 10.2 Hz, 1H), 4.15 (d, J = 10.2 Hz, 1H); ¹³C NMR (100 MHz, chloroform-d) δ 139.9, 139.5, 138.1, 134.9, 134.8, 133.1, 130.8, 130.1, 130.0, 127.8, 123.2, 121.4, 74.2, 73.4, 31.2. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₂Br₂O 366.9333; obtained 366.9331.

4-(2-Bromo-5-methoxy-phenyl)-5-bromomethyl-1,3-dihydro-isobenzofuran (major isomer) (10c). State: gummy solid; R_f = 0.5 (hexane/EtOAc 9/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 285 mg, 90%; ¹H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 3.0 Hz, 1H), 6.86 (dd, J = 8.8, 3.0 Hz, 1H), 5.18 (s, 2H), 4.81 (AB_q, Δν_AB = 35.2 Hz, J_AB = 12.6 Hz, 2H), 4.43 (d, J = 10.2 Hz, 1H), 4.15 (d, J = 10.2 Hz, 1H), 3.82 (s, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 159.0, 139.9, 139.4, 138.9, 134.8, 133.8, 130.2, 121.4, 116.4, 115.8, 113.9, 113.4, 74.2, 73.4, 55.8, 31.3. HRMS: m/z [M + H]⁺ calcd for C₁₆H₁₄Br₂O₂ 396.9439; obtained 396.9435.

4-(2-Bromo-4,5-dimethoxy-phenyl)-5-bromomethyl-1,3-dihydro-isobenzofuran (10d). State: gummy solid; R_f = 0.6 (hexane/EtOAc 7/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 8 : 1); yield: 306 mg, 90%; ¹H NMR (600 MHz, chloroform-d) δ 7.46 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.12 (s, 1H), 6.86 (s, 1H), 5.18 (AB_q, Δν_AB = 15.4 Hz, J_AB = 12.9 Hz, 2H), 4.88 (d, J = 12.6 Hz, 1H), 4.75 (d, J = 12.6 Hz, 1H), 4.43 (d, J = 10.1 Hz, 1H), 4.16 (d, J = 10.1 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H); ¹³C NMR (150 MHz, chloroform-d) δ 149.6, 148.6, 139.9, 139.9, 135.3, 134.9, 130.2, 129.9, 121.4, 115.6, 113.2, 113.2, 74.3, 73.5, 56.4, 56.4, 31.6. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₆Br₂O₃ 426.9544; obtained 426.9543.

General methods for the preparation of biaryl benzyl azide (11a, 11c-d)

The biaryl benzyl bromide (0.7 mmol) dissolved in 6 mL of dry DMF was treated with NaN₃ (2.5 eq.) and stirred for 8 h, under nitrogen atmosphere. The reaction was quenched with water. The reaction mixture was partitioned between EtOAc (15 × 3 mL) and water (20 mL), washed with brine. The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

5-Azidomethyl-4-(2-bromo-phenyl)-1,3-dihydro-isobenzofuran (11a). State: gummy solid; R_f = 0.6 (hexane/EtOAc 10/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 202 mg, 88%; ¹H NMR (600 MHz, chloroform-d) δ 7.69 (dd, J = 8.0, 1.2 Hz, 1H), 7.42–7.39 (m, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.28 (td, J = 7.8, 1.7 Hz, 1H), 7.23 (dd, J = 7.6, 1.7 Hz, 1H), 5.20 (AB_q, Δν_AB = 12 Hz, J_AB = 12.6 Hz, 2H), 4.79 (AB_q, Δν_AB = 35.0 Hz, J_AB = 12.6 Hz, 2H), 4.17 (d, J = 13.8 Hz, 1H), 4.05 (d, J = 13.8 Hz, 1H); ¹³C NMR (50 MHz, chloroform-d) δ 139.6, 139.4, 138.4, 134.7, 133.1, 132.6, 130.6, 129.9, 128.6, 127.9, 123.2, 121.1, 74.1, 73.3, 52.2. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₂BrN₃O 330.0242; obtained 330.0243.

5-Azidomethyl-4-(2-bromo-5-methoxy-phenyl)-1,3-dihydro-isobenzofuran (major isomer) (11c). State: gummy solid; R_f = 0.5 (hexane/EtOAc 9/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 10 : 1); yield: 226 mg, 90%; ¹H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.84 (dd, J = 8.8, 3.1 Hz, 1H), 6.76 (d, J = 3.0 Hz, 1H), 5.19 (s, 2H), 4.81 (AB_q, Δν_AB = 14.2 Hz, J_AB = 12.6 Hz, 2H), 4.13 (AB_q, Δν_AB = 42.5 Hz, J_AB = 13.4 Hz, 2H), 3.80 (s, 3H); ¹³C NMR (50 MHz, chloroform-d) δ 159.22, 139.6, 139.23, 139.2, 134.7, 133.8, 132.6, 128.7, 121.2, 116.1, 115.9, 113.50, 74.2, 73.4, 55.8, 52.2. HRMS: m/z [M + H]⁺ calcd for C₁₆H₁₄BrN₃O₂ 360.0348; obtained 360.0347.

5-Azidomethyl-4-(2-bromo-4,5-dimethoxy-phenyl)-1,3-dihydro-isobenzofuran (11d). State: gummy solid; R_f = 0.6 (hexane/EtOAc 7/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 8 : 1); yield: 245 mg, 90%; ¹H NMR (600 MHz, chloroform-d) δ 7.37 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.12 (s, 1H), 6.70 (s, 1H), 5.18 (AB_q, Δν_AB = 13.7 Hz, J_AB = 12.6 Hz, 2H), 4.82 (AB_q, Δν_AB = 31.8 Hz, J_AB = 12.6 Hz, 2H), 4.13 (AB_q, Δν_AB = 51.9 Hz, J_AB = 13.5 Hz, 2H), 3.91 (s, 3H), 3.82 (s, 3H); ¹³C NMR (150 MHz, chloroform-d) δ 149.6, 148.7, 139.7, 139.6, 134.7, 132.9, 130.1, 128.8, 121.1, 115.6, 113.2, 112.9, 74.2, 73.4, 56.4, 56.3, 52.2. HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₆BrN₃O₃ 390.0453; obtained 390.0454.

General methods for the preparation of N-Boc biaryl benzyl amine (12a, 12c-d)

The biaryl benzyl azide (0.6 mmol) dissolved in 6 mL of distilled THF–H₂O (10 : 1) was treated with PPh₃ (1.1 eq.) and stirred for 18 h. Solvent was dried under reduced pressure. To the dried reaction mixture, Et₃N (1.1 eq.) followed by Boc anhydride (1.3 eq.) were added at 0 °C under ice cold condition under nitrogen atmosphere. The temperature was gradually brought to room temperature and stirred for 8 h under nitrogen atmosphere. The reaction was quenched with water. The reaction mixture was partitioned between EtOAc (15 × 3 mL) and water (20 mL), washed with brine. The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

[4-(2-Bromo-phenyl)-1,3-dihydro-isobenzofuran-6-ylmethyl]-carbamic acid tert-butyl ester (12a). State: gummy solid; R_f = 0.5 (hexane/EtOAc 5/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 7 : 1); yield: 157 mg, 65%; ¹H NMR (600 MHz, chloroform-d) δ 7.67 (d, J = 8.1 Hz, 1H), 7.40–7.32 (m, 2H), 7.27–7.25 (m, 2H), 7.19 (dd, J = 7.5, 1.7 Hz, 1H), 5.17 (AB_q, Δν_AB = 15.0 Hz, J_AB = 12.0 Hz, 2H), 4.75 (AB_q, Δν_AB = 41.3 Hz, J_AB = 12.6 Hz, 2H), 4.66 (bs, 1H), 4.10 (dd, J = 15.0, 6.1 Hz, 1H), 4.03 (dd, J = 14.9, 5.5 Hz, 1H), 1.40 (s, 9H); ¹³C NMR (100 MHz, chloroform-d) δ 155.8, 139.1, 138.9, 138.5, 135.9, 134.2, 133.2, 130.4, 129.8, 128.1, 127.9, 123.3, 121.0, 79.6, 74.2, 73.4, 42.2, 28.6. HRMS: m/z [M + Na]⁺ calcd for C₂₀H₂₂BrNO₃Na 426.0681; obtained 426.0684.

[4-(2-Bromo-5-methoxy-phenyl)-1,3-dihydro-isobenzofuran-6-ylmethyl]-carbamic acid tert-butyl ester (major isomer) (12c). State: gummy solid; R_f = 0.4 (hexane/EtOAc 5/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 7 : 1); yield: 179 mg, 69%; ¹H NMR (400 MHz, chloroform-d) δ 7.53 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.81 (dd, J = 8.8, 3.0 Hz, 1H), 6.73 (d, J = 3.1 Hz, 1H), 5.16 (s, 2H), 4.82–4.66 (m, 3H), 4.14 (dd, J = 15.3, 6.6 Hz, 1H), 4.03 (dd, J = 14.7, 5.0 Hz, 1H), 3.78 (s, 3H), 1.40 (s, 9H); ¹³C NMR (100 MHz, chloroform-d) δ 159.2, 155.8, 139.8, 138.8, 138.5, 135.8, 134.2, 133.8, 127.8, 121.0, 115.8, 115.6, 113.5, 79.5, 74.2, 73.3, 55.7, 42.1, 28.6. HRMS: m/z [M + H]⁺ calcd for C₂₁H₂₄BrNO₄ 434.0967; obtained 434.0963.

[4-(2-Bromo-4,5-dimethoxy-phenyl)-1,3-dihydro-isobenzofuran-6-ylmethyl]-carbamic acid tert-butyl ester (12d). State: gummy solid; R_f = 0.5 (hexane/EtOAc 4/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 6 : 1); yield: 195 mg, 70%; ¹H NMR (600 MHz, chloroform-d) δ 7.37 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.11 (s, 1H), 6.68 (s, 1H), 5.17 (AB_q, Δν_AB = 16.0 Hz, J_AB = 12.6 Hz, 2H), 4.79 (AB_q, Δν_AB = 35.6 Hz, J_AB = 12.6 Hz, 2H), 4.69 (s, 1H), 4.16 (dd, J = 14.8, 6.2 Hz, 1H), 4.04 (dd, J = 14.5, 4.8 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz, chloroform-d) δ 155.8, 149.5, 148.9, 139.4, 138.5, 136.3, 134.2, 130.8, 127.9, 120.9, 115.7, 113.2, 112.7, 79.6, 74.2, 73.5, 56.4, 56.4, 42.2, 28.6. HRMS: m/z [M + Na]⁺ calcd for C₂₂H₂₆BrNO₅Na 486.0892; obtained 486.0891.

General methods for the preparation of N-tosylbiaryl benzyl amine (13a, 13c-d)

N-Boc biaryl benzyl amine (0.4 mmol) dissolved in 10 mL of dry DCM, was treated with TFA (5 eq.) at 0 °C under ice cold condition. The temperature was gradually brought to room temperature and stirred for 6 h. TFA and the solvent were removed under reduced pressure adopting the necessary precautions. The dried reaction mixture was treated with Et₃N (1.1 eq.) followed by tosyl chloride (1.3 eq.) at 0 °C under ice cold condition, under nitrogen atmosphere. The temperature was gradually brought to room temperature and stirred for 3 h. The reaction was quenched with water. The reaction mixture was partitioned between EtOAc (15 × 3 mL) and water (20 mL), washed with brine. The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

N-[4-(2-Bromo-phenyl)-1,3-dihydro-isobenzofuran-5-yl methyl]-4-methyl-benzenesulfonamide (13a). State: white solid; R_f = 0.5 (hexane/EtOAc 2/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 4 : 1); yield: 146 mg, 80%; ¹H NMR (400 MHz, chloroform-d) δ 7.59–7.54 (m, 3H), 7.34–7.18 (m, 6H), 7.06 (dd, J = 7.6, 1.6 Hz, 1H), 5.14 (d, J = 14 Hz, 2H), 4.73 (AB_q, Δν_AB = 21.6 Hz, J_AB = 12.6 Hz, 2H), 4.38 (d, J = 5.2 Hz, 1H), 3.90 (dd, J = 13.2, 6.8 Hz, 1H), 3.79 (dd, J = 13.0, 4.6 Hz, 1H), 2.42 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) δ 143.5, 139.5, 139.2, 138.5, 136.7, 134.6, 133.2, 133.1, 130.3, 129.9, 129.8, 129.2, 128.0, 127.3, 123.0, 121.3, 74.2, 73.3, 44.8, 21.7. HRMS: m/z [M + Na]⁺ calcd for C₂₂H₂₀BrNO₃SNa 480.0245; obtained 480.0246.

N-[4-(2-Bromo-5-methoxy-phenyl)-1,3-dihydro-isobenzofuran-5-ylmethyl]-4-methyl-benzenesulfonamide (major isomer) (13c). State: white solid; R_f = 0.4 (hexane/EtOAc 2/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 4 : 1); yield: 163 mg, 84%; ¹H NMR (400 MHz, chloroform-d) δ 7.59 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.9 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.23–7.21 (m, 3H), 6.75 (dd, J = 8.8, 3.0 Hz, 1H), 6.59 (d, J = 3.0 Hz, 1H), 5.15 (s, 2H), 4.73 (AB_q, Δν_AB = 13.8 Hz, J_AB = 12.8 Hz, 2H), 4.46 (dd, J = 7.1, 4.7 Hz, 1H), 3.92 (dd, J = 13.1, 7.2 Hz, 1H), 3.81 (dd, J = 13.2, 4.6 Hz, 1H), 3.75 (s, 3H), 2.42 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) δ 159.2, 143.5, 139.5, 139.3, 139.1, 136.6, 134.6, 133.8, 133.0, 129.8, 129.2, 127.3, 121.3, 116.0, 115.4, 113.2, 74.2, 73.3, 55.8, 44.8, 21.8. HRMS: m/z [M + Na]⁺ calcd for C₂₃H₂₂BrNO₄SNa 510.0351; obtained 510.0354.

N-[4-(2-Bromo-4,5-dimethoxy-phenyl)-1,3-dihydro-isobenzofuran-5-ylmethyl]-4-methyl-benzenesulfonamide (13d). State: white solid; R_f = 0.3 (hexane/EtOAc 2/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 3 : 1); yield: 176 mg, 85%; ¹H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.7 Hz, 1H), 7.21–7.20 (m, 3H), 7.00 (s, 1H), 6.53 (s, 1H), 5.13 (AB_q, Δν_AB = 18.8 Hz, J_AB = 12.6 Hz, 2H), 4.72 (AB_q, Δν_AB = 38.17 Hz, J_AB = 12.6 Hz, 2H), 4.60 (dd, J = 7.5, 4.5 Hz, 1H), 3.91–3.82 (m, 5H), 3.75 (s, 3H), 2.41 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) δ 149.6, 148.8, 143.6, 139.5, 139.3, 136.5, 134.5, 133.5, 130.2, 129.7, 129.1, 127.2, 121.2, 115.5, 112.9, 112.4, 74.2, 73.3, 56.4, 56.3, 44.8, 21.7. HRMS: m/z [M + H]⁺ calcd for C₂₄H₂₄BrNO₅S 518.0637; obtained 518.0636.

General methods for the preparation of N-tosyl dihydrophenanthridine using Buchwald–Hartwig coupling reaction (14a, 14c-d)

The N-tosylbiaryl benzyl amine (0.2 mmol) dissolved in 12 mL of dry toluene was treated with BINAP (0.4 eq.), Pd(OAc)₂ (0.2 eq.) and dry K₂CO₃ (2.5 eq.) sequentially, stirred under refluxing condition for 3–12 h, under nitrogen atmosphere. The reaction was quenched with water. The reaction mixture was partitioned between EtOAc (15 × 2 mL) and water (20 mL). The organic layer was dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and product was purified by silica gel column chromatography with hexane–ethyl acetate as eluent.

8-Propenyl-7-(toluene-4-sulfonyl)-1,3,6,7-tetrahydro-furo[3,4-f]isoquinoline (14a). State: white solid; R_f = 0.5 (hexane/EtOAc 3/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 6 : 1); yield: 60 mg, 80%; ¹H NMR (600 MHz, chloroform-d) δ 7.82 (dd, J = 7.9, 1.4 Hz, 1H), 7.43 (td, J = 7.7, 1.5 Hz, 1H), 7.37 (td, J = 7.6, 1.4 Hz, 1H), 7.11 (dd, J = 7.7, 1.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 8.3 Hz, 2H), 6.67 (d, J = 8.0 Hz, 2H), 4.97 (s, 2H), 4.95 (s, 2H), 4.82 (s, 2H), 2.19 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) δ 143.4, 140.3, 137.2, 136.2, 135.4, 134.1, 131.3, 130.8, 128.8, 128.1, 127.8, 127.0, 126.3, 126.1, 125.9, 120.3, 73.8, 73.2, 50.5, 21.4. HRMS: m/z [M + H]⁺ calcd for C₂₂H₁₉NO₃S 378.1164; obtained 378.1171.

10-Methoxy-7-(toluene-4-sulfonyl)-1,3,6,7-tetrahydro-2-oxa-7-aza-cyclopenta[c]phenanthrene (14c). State: white solid; R_f = 0.4 (hexane/EtOAc 3/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc C = 5 : 1); yield: 63 mg, 78%; ¹H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 9.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.96 (dd, J = 8.8, 1.6 Hz, 1H), 6.77 (d, J = 8.0, 2H), 6.61 (d, J = 8.0, 2H), 4.96 (s, 4H), 4.79 (s, 2H), 3.86 (s, 3H), 2.19 (s, 3H); ¹³C NMR (100 MHz, chloroform-d) δ 158.9, 143.3, 140.2, 135.4, 133.9, 131.8, 131.3, 130.0, 129.9, 128.1, 127.1, 126.4, 126.2, 120.4, 113.6, 111.5, 77.6, 73.7, 73.2, 55.7, 50.8, 21.3. HRMS: m/z [M + H]⁺ calcd for C₂₃H₂₁NO₄S 408.1270; obtained 408.1259.

9,10-Dimethoxy-7-(toluene-4-sulfonyl)-1,3,6,7-tetrahydro-2-oxa-7-aza-cyclopenta[c]phenanthrene (14d). State: white solid; R_f = 0.3 (hexane/EtOAc 3/1); the reaction product was purified by column chromatography (Si-gel 60–120 mesh, hexane/EtOAc = 5 : 1); yield: 68 mg, 78%; ¹H NMR (600 MHz, chloroform-d) δ 7.35 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 8.2 Hz, 2H), 6.68 (d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 4.96 (s, 4H), 4.78 (s, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 2.20 (s, 3H); ¹³C NMR (150 MHz, chloroform-d) δ 149.6, 148.8, 143.6, 139.5, 139.3, 136.5, 134.5, 133.5, 130.2, 129.7, 129.1, 127.2, 121.2, 115.5, 112.9, 112.4, 74.2, 73.3, 56.4, 56.3, 44.8, 21.7. HRMS: m/z [M + Na⁺] calcd for C₂₄H₂₃NO₅S 460.1195; obtained 460.1200.

Acknowledgements

Author A. B. is grateful to CSIR, Govt. of India, for funding and to DST, Govt. of India, for the JC Bose fellowship. P. B. and K. C. thank CSIR, Govt. of India for a research fellowship (NET). We thank IIT Kharagpur and DST for the 600 and 400 MHz facilities respectively.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1041542, 1041544 and 1041545. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra12512j

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