Original Synthesis of Substituted 6H-Benzo[c]chromene Derivatives Using a TDAE and Pd-Catalyzed Cyclization Strategy

Abstract

We report an efficient synthetic method for the preparation of 6H-benzo[c]chromenes from substituted 1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-phenylethanols. These intermediates were obtained via a TDAE-initiated reaction between new substituted 2′-bromo-[1,1′-biphenyl]-2-carbaldehyde derivatives and substituted nitrobenzylic chlorides. The second step involved a palladium-catalyzed intramolecular O-arylation of the alcohol intermediate under microwave irradiation (110 °C for 1.5 h). The structure of 6H-benzo[c]chromene derivatives was confirmed by X-ray crystallography of product 5c.

1. Introduction

Tetrakis(dimethylamino)ethylene (TDAE) is a reducing agent that reacts under mild conditions with activated halogenated derivatives to generate an anion via two sequential single electron transfers [1,2,3,4,5,6,7,8,9,10,11]. The first SET generates the radical and the second SET forms the anion. The carbanion generated by TDAE from o- or p-nitrobenzyl chloride can react with various electrophiles, such as aromatic aldehydes, ketones, α-keto esters, α-keto lactams, and diethyl oxomalonate, yielding the corresponding secondary alcohol [12,13,14]. Polycycles are fundamental scaffolds in organic compounds and are widely found in natural products, bioactive molecules, and synthetic drugs [15]. Their synthesis has been widely studied. Among these, fused heterocyclic compounds are of great importance and are broadly applied in different aspects [16]. Among the most important fused heterocycles found in several natural products, fused oxygen-containing heterocycles exhibit a wide range of biological activities. Among these compounds, cannabinol and its derivatives can be mentioned [17,18,19,20,21,22]. Many research groups have synthesized these compounds. Fagnou and co-workers have developed the synthesis via direct arylation [23,24,25,26], whereas Shen’s synthesis involves the use of palladium-catalyzed intramolecular decarboxylative coupling of arene carboxylic acids/esters with aryl bromides [27]. Shi and co-workers used transition metal-catalyzed direct functionalization of aromatic C–H bonds [28]. Herein, we report a new efficient synthesis of 6H-benzo[c]chromenes. Our strategy involves the activation of the alcohol using Cs₂CO₃ to generate alkoxide, followed by a Pd-catalyzed intramolecular C–O coupling of 1-(2′-bromo-[1,1′-biaryl]-2-yl)-2-(aryl)ethan-1-ol under microwave irradiation. The 1-(2′-bromo-[1,1′-biaryl]-2-yl)-2-(aryl)ethan-1-ols were obtained through the TDAE-mediated strategy using 2′-bromo-biaryl-2-carbaldehydes as electrophiles and nitrobenzyl chlorides, which serve as anion precursors, in moderate-to-good yields. The TDAE strategy offers the advantage of generating a nitrobenzyl carbanion under mild and practical conditions.

2. Results and Discussion

The starting materials 1a–i for the TDAE reactions were prepared by Suzuki–Miyaura cross-coupling [29,30] by the treatment of 2-bromocarboxaldehydes (1 equiv) with 2-bromophenylboronic acid (1.3 equiv) in the presence of Pd(PPh₃)₄ (0.0161 equiv) and Na₂CO₃ (3.9 equiv in 10 mL of H₂O) in toluene at 90 °C for 12 h (Scheme 1). After chromatographic separation, the desired 2′-bromo-biaryl-2-carbaldehydes 1a–i were isolated in moderate-to-good yields (48–87%).

The reaction of 2′-bromo-biaryl-2-carbaldehydes 1a–i (1 equiv) with activated benzylic halides such as 4-nitrobenzyl chloride 2a (1.3 equiv) under inert atmosphere (N₂), in anhydrous DMF in the presence of TDAE at −20 °C for one hour, followed by 2 h at room temperature, led to the corresponding alcohol products 3a–i in moderate-to-good yields (49–84%), as shown in Scheme 2 and

Table 1. Reaction of 4-nitrobenzyl chloride (2a) with 2′-bromo-biaryl-2-carbaldehydes 1a–i using TDAE.

Entry a	R1	Product	Yield b (%)
1	H	3a	84
2	4-OMe	3b	76
3	5-Me	3c	62
4	4,5-O-CH2-O	3d	58
5	5-OMe	3e	49
6	5-Cl	3f	69
7	4-F	3g	65
8	4-NO2	3h	78
9	5-F	3i	76

^a Reaction conditions: all the reactions were carried out under the following conditions: 2′-bromo-biaryl-2-carbaldehydes (1 equiv), 4-nitrobenzyl chloride (1.3 equiv), and TDAE (1.3 equiv) in anhydrous DMF stirred at −20 °C for 1 h and then warmed to rt for 2 h. ^b Yields refer to the isolated yields after purification through column chromatography.

.

We therefore extended this reaction to other nitrobenzyl chlorides 2b–k, which were either commercially available (2a,b) or prepared (2c–k) as shown in Scheme 3. Nitrobenzylic chlorides 2c–k were prepared in two steps from the corresponding aldehydes by the reduction of the aldehyde, followed by chlorination of the resulting alcohol. The corresponding nitrobenzylic chlorides 2c–k were isolated in good-to-excellent yields (70–92%).

These substituted benzyl chlorides 2b–k reacted with 2′-bromo-[1,1′-biphenyl]-2-carbaldehyde 1a under the usual conditions, 2′-bromo-[1,1′-biphenyl]-2-carbaldehyde (1a; 1 equiv) with substituted benzyl chlorides (2b–k; 1.3 equiv) in anhydrous DMF in the presence of TDAE at −20 °C for one hour, followed by 2 h at room temperature, yielding the corresponding alcohol 4b–k in good yields (64–93%), as shown in Scheme 4 and

Table 2. Reaction of 2′-bromo-[1,1′-biphenyl]-2-carbaldehyde (1a) with nitrobenzylic chlorides 2b–k using TDAE.

Entry a	R2	Product	Yield b (%)
1	2-NO2	4b	64
2	2-NO2; 4,5-O-CH2-O	4c	67
3	2-NO2; 4,5-OMe	4d	62
4	3-OMe; 4-NO2	4e	80
5	3-Me; 4-NO2	4f	64
6	2-NO2; 5-Me	4g	76
7	2-NO2; 5-OMe	4h	93
8	2-NO2; 4-C6H5	4i	75
9	3-F; 4-NO2	4j	67
10	4-(4-NO2-C6H5)	4k	82

^a Reaction conditions: all the reactions were carried out under the following conditions: 2′-bromo-[1,1′-biphenyl]-2-carbaldehyde (1a; 1 equiv), nitrobenzylic chloride (2b–k, 1.3 equiv), and TDAE (1.3 equiv) in anhydrous DMF stirred at −20 °C for 1 h and then warmed to rt for 2 h. ^b Yields refer to the isolated yields after purification through column chromatography.

.

The reaction of 2′-bromo-biaryl-2-carbaldehydes 1 with nitrobenzylic chlorides 2b–k led to a mixture of two isomers, easily separable by column chromatography. The first fraction corresponded to products with the Br and OH group “cis-substituted”, while the second fraction contained products with the Br and OH group “trans-substituted”, as shown in Scheme 5. However, evaporation of each separate fraction under reduced pressure at 40 °C resulted in the same mixture of the two isomers. This demonstrates the interconversion of the two isomers under the effect of heat during evaporation.

Compound 3a was used as the model substrate for synthesis of 6H-benzo[c]chromene 5. We investigated the influence of such parameters as the solvents (DMF, CH₃CN, or dioxane), the Pd-catalyst (Pd(PPh₃)₂Cl₂, Pd(OAc)₂ or Pd(PPh₃)₄), the ligand (PPh₃ or BINAP), the type and the amount of the base (2, 3, or 4 equiv) and the reaction time and temperature (

Table 3. Optimization conditions for the synthesis of 6-(4-nitrobenzyl)-6H-benzo[c]chromene 5a.

Entry a	Catalyst	Ligand	Base	Solvent	Temperature (°C)	Time (h)	Yield b (%)
1	Pd(PPh3)2Cl2	-	t-BuOK	CH3CN	80	1	-
2	Pd(OAc)2	PPh3	Cs2CO3 (3 equiv)	DMF	110	5	35
3	Pd(OAc)2	PPh3	Cs2CO3 (3 equiv)	Dioxane	90	5	42
4	Pd(PPh3)4	-	Cs2CO3 (3 equiv)	Toluene	110	5	83
5	Pd(PPh3)2Cl2	-	Cs2CO3 (3 equiv)	Toluene	110	5	81
6	Pd(OAc)2	BINAP	Cs2CO3 (3 equiv)	Toluene	110	5	-
7	Pd(OAc)2	PPh3	Cs2CO3 (2 equiv)	Toluene	110	5	59
8	Pd(OAc)2	PPh3	Cs2CO3 (3 equiv)	Toluene	110	5	87
9	Pd(OAc)2	PPh3	Cs2CO3 (4 equiv)	Toluene	110	5	71
10	Pd(OAc)2	PPh3	Cs2CO3 (3 equiv)	Toluene	110 (MW)	1	75
11	Pd(OAc)2	PPh3	Cs2CO3 (3 equiv)	Toluene	110 (MW)	1.5	88
12	Pd(OAc)2	PPh3	Cs2CO3 (3 equiv)	Toluene	110 (MW)	2	79

^a All the reactions were performed by using Pd-catalyst (0.04 equiv). ^b Yields refer to the isolated yields after purification through column chromatography.

). The first tests (Table 3, entries 1–4) carried out with standard solvents and bases for this method led us to choose toluene as the optimal solvent and Cs₂CO₃ as the best base (Table 3, entry 4). Then, we applied the reaction conditions with different catalysts (Pd(PPh₃)₂Cl₂, Pd(OAc)₂, Pd(PPh₃)₄), in the presence or the absence of ligand (PPh₃, BINAP) and different amounts of the base (Cs₂CO₃). An excess of base is necessary to deprotonate the alcohol forming the alkoxide, which then undergoes coupling. The best yield (87%) of 6-(4-nitrobenzyl)-6H-benzo[c]chromene (5a) was obtained with Pd(OAc)₂, PPh₃ as supporting ligand, and 3 equivalents of Cs₂CO₃ at 110 °C for 5 h (Table 3, entry 8). After optimizing the reaction conditions with a reaction time of 5 h, we wanted to determine whether we could carry out the reaction in a shorter time under microwave irradiation. We therefore reduced the reaction time to 1 h and then extended it to 1.5 h and 2 h (Table 3, entries 10–12). A similar best yield of 5a (88% vs. 87%) was obtained when the reaction was heated at 110 °C under microwave irradiation for only 1.5 h (Table 3, entry 11).

After optimization of the conditions (Table 3, entry 11), we generalized the cyclization with different alcohol derivatives. The corresponding 6H-benzo[c]chromenes 5a–s were obtained in moderate-to-good yields (37–91%,

Table 4. Generalization of the synthesis of 6H-benzo[c]chromene.

Entry a	Substrate	Product	R1	R2	Yield b (%)
1	3a	5a	H	4-NO2	88
2	3b	5b	8-OMe	4-NO2	47
3	3c	5c	9-Me	4-NO2	37
4	3d	5d	1,3-O-CH2-O	4-NO2	80
5	3e	5e	9-OMe	4-NO2	55
6	3f	5f	9-Cl	4-NO2	77
7	3g	5g	8-F	4-NO2	80
8	3h	5h	8-NO2	4-NO2	79
9	3i	5i	9-F	4-NO2	91
10	4b	5j	H	2-NO2	79
11	4c	5k	H	2-NO2; 4,5-O-CH2-O	68
12	4d	5l	H	2-NO2; 4,5-OMe	87
13	4e	5m	H	3-OMe; 4-NO2	71
14	4f	5n	H	3-Me; 4-NO2	69
15	4g	5o	H	2-NO2; 5-Me	66
16	4h	5p	H	2-NO2; 5-OMe	49
17	4i	5q	H	2-NO2; 4-C6H5	75
18	4j	5r	H	3-F; 4-NO2	45
19	4k	5s	H	4-(4-NO2-C6H5)	70

^a Reaction conditions: all the reactions were carried out under the following conditions: alcohol derivatives (3a–i, 4b–k; 1 equiv), Pd(OAc)₂ (0.04 equiv), PPh₃ (0.25 equiv), and Cs₂CO₃ (3 equiv), in toluene heated at 110 °C for 1.5 h under microwave irradiation. ^b Yields refer to the isolated yields after purification through column chromatography.

). The optimal reaction time is 1.5 h (88% yield), as the yield is lower at 1 h (75%, incomplete reaction) and decreases to 79% at 2 h (product degradation).

It is quite difficult to establish clear relationships between the nature of the substituents (at R¹ and R²) and the obtained yields, as there are many parameters involved (substituent position, stability and solubility of the final product). The only noticeable effect is that when R¹ is a halogen (Cl, F) or a nitro group, the yield is very high (77–91%).

The structure of product 5c was confirmed by X-ray crystallography, and an ORTEP view is reported in Figure 1 [31]. Crystal data for C₂₁H₁₇NO₃ (M = 331.36 g/mol): monoclinic, space group P2₁/c (no. 14), a = 17.0030(19) Å, b = 10.1693(11) Å, c = 9.6214(12) Å, β = 92.347(10)°, V = 1662.2 (3) ų, Z = 4, T = 295 K, μ(Mo Kα) = 0.089 mm⁻¹, Dcalc = 1.324 g/cm³, 11,226 reflections measured (7.196° ≤ 2Θ ≤ 59.016°), 3896 unique (R_int = 0.0615, R_sigma = 0.0883), which were used in all calculations. The final R₁ was 0.0667 (I > 2σ(I)), and wR₂ was 0.1731 (all data).

3. Materials and Methods

3.1. General Chemistry Information

TDAE is commercially available. All melting points were determined on a Stuart melting point apparatus SMP3, and are uncorrected. The ¹H-NMR spectra were recorded on a Bruker Avance III spectrometer operating at 400 MHz (¹H) or 100 MHz (¹³C) (Bruker, Billerica, MA, USA). ¹H- and ¹³C-NMR chemical shifts were reported in parts per million (ppm) and were referenced to the residual proton peaks in a deuterated solvent, CDCl₃ (7.26 ppm for ¹H and 77.16 ppm for ¹³C). Multiplicities are represented by s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), dt (doublet of triplets), and m (multiplet). TLC was performed on 5 cm × 10 cm aluminum plates coated with silica gel 60F-254 (Merck) in an appropriate eluent. HRMS was performed out at the Spectropole, Faculte des Sciences et Techniques de Saint-Jérôme, Marseille. HRMS spectra were recorded on a SYNAPT G2 HDMS mass spectrometer (Waters, Milford, MA, USA) equipped with an electrospray ionization (ESI) source. All anhydrous solvents used were purchased commercially and used without further purification. Microwave reactions were performed with a Biotage^® Initiator Microwave oven (Uppsala, Sweden) using 10–20 mL sealed vials; temperatures were measured with an IR sensor, and reaction times are given as hold times. Column chromatography was performed with puriFlash^® 5.020 (Advion, Interchim Scientific, Montluçon, France) (solid injection mode, column (IR-20SI-F0012), 3 racks, 132 test tubes (18 × 150 mm). Single-crystal X-ray diffraction data were collected on a SuperNova, Dual, Cu at home/near, AtlasS2 diffractometer (Rigaku Oxford Diffraction, Tokyo, Japan). All commercial reagents were used without purification.

3.2. General Procedure for the Synthesis of 2′-Bromo-biaryl-2-carbaldehydes (1a–i)

A vial was charged with Pd(PPh₃)₄ (0.0161 equiv), (2-bromophenyl)boronic acid (1.4 equiv), and 2-bromocarboxaldehydes (1 equiv). The test tube was sealed with a cap lined with a disposable silicone septum, evacuated, and purged with N₂ (×3). To the vial were added toluene (10 mL) and a solution of Na₂CO₃ (3.9 equiv) in 10 mL of water. The test tube was evacuated and purged with N₂ (×3) a second time; then the reaction was heated at 90 °C for 12 h. The reaction mixture was allowed to cool to room temperature, then transferred to a separatory funnel. The layers were separated, and the organic layer was extracted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate, and filtered, and then the solvent was removed under reduced pressure. The resulting oil was purified by silica gel column chromatography (elution with petroleum ether/dichloromethane: 5/5).

2′-bromo-[1,1′-biphenyl]-2-carbaldehyde (1a). Yield: 48%; Mp: 80 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 7.28–7.34 (m, 3H, H_arom), 7.40–7.44 (m, 1H, H_arom), 7.53–7.57 (m, 1H, H_arom), 7.64–7.71 (m, 2H, H_arom), 8.04 (dd, J = 7.80, 1.4 Hz, 1H, H_arom), 9.79 (s, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 123.98 (C₆), 127.50 (C_2′), 127.53 (C₃), 128.70 (C₄), 129.94 (C₅), 130.96 (C_4′), 131.72 (C_5′), 132.90 (C_3′), 133.78 (C₁), 133.82 (C₅), 139.01 (C_1′), 144.61 (C₂), 191.66 (CHO). HRMS (ESI): m/z [M+Na]⁺ calcd for C₁₃H₉BrO: 282.9729; found: 282.9728.

2′-bromo-4-methoxy-[1,1′-biphenyl]-2-carbaldehyde (1b). Yield: 73%; Mp: oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.90 (s, 3H, H_arom), 7.19–7.23 (m, 2H, H_arom), 7.28–7.32 (m, 2H, H_arom), 7.40 (td, J = 7.40, 1.30 Hz, 1H, H_arom), 7.52 (dd, J = 2.6, 0.6 Hz, 1H, H_arom), 7.68 (dd, J = 8.00, 1.20 Hz, 1H, H_arom), 9.74 (s, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 55.72 (C_b), 109.92 (C₃), 121.28 (C₅), 124.59 (C_2′), 127.48 (C₁), 129.78 (C_5′), 132.13 (C₆), 132.22 (C_4′), 132.87 (C_6′), 134.71 (C_3′), 137.64 (C_1′), 138.68 (C₂), 159.73 (C₄), 191.52 (CHO). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₄H₁₁BrO₂: 290.0015; found: 291.0011.

2′-bromo-5-methyl-[1,1′-biphenyl]-2-carbaldehyde (1c). Yield: 57%; Mp: oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.46 (s, 3H, H_arom), 7.11 (d, J = 7.11 Hz, 1H, H_arom), 7.29–7.42 (m, 4H, H_arom), 7.68 (dd, J = 7.68 Hz, 1H, H_arom), 7.94 (d, J = 7.94 Hz, 1H, H_arom), 9.73 (s, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 21.96 (C_b), 123.95 (C_2′), 127.45 (C₅), 127.60 (C₄), 129.53 (C_4′), 129.80 (C₃), 131.45 (C_6′), 131.53 (C_3′), 131.64 (C₁), 132.80 (C_1′), 139.20 (C₂), 144.68 (C₆), 144.85 (C₅), 191.33 (CHO). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₄H₁₁BrO: 275.0066; found: 275.0072.

6-(2′-bromophenyl)benzo[d][1,3]dioxole-5-carbaldehyde (1d). Yield: 65%; Mp: 93 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 6.11 (s, 2H, CH₂), 6.72 (s, 1H, H_arom), 7.27–7.31 (m, 2H, H_arom), 7.37–7.41 (m, 1H, H_arom), 7.46 (s, 1H, H_arom), 7.67 (d, J = 7.67 Hz, 1H, H_arom), 9.53 (s, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 102.38 (C₂), 106.10 (C₇), 110.55 (C₄), 124.28 (C_2′), 127.43 (C₁), 129.01 (C_5′), 130.00 (C_4′), 131.95 (C_6′), 132.95 (C_3′), 138.55 (C₅), 141.98 (C_1′), 148.37 (C_3a), 152.24 (C_7a), 189.89 (CHO). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₁₄H₉BrO₃: 304.9808; found: 304.9810.

2′-bromo-5-methoxy-[1,1′-biphenyl]-2-carbaldehyde (1e). Yield: 68%; Mp: 92 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.90 (s, 3H, CH₃), 6.77 (d, J = 6.77 Hz, 1H, H_arom), 7.04 (ddd, J = 8.70, 2.61, 0.80 Hz, 1H, H_arom), 7.28–7.34 (m, 2H, H_arom), 7.41 (m, 1H, H_arom), 7.68 (dd, J = 8.00, 0.90 Hz, 1H, H_arom), 8.02 (d, J = 8.02 Hz, 1H, H_arom), 9.63 (s, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 55.79 (C_b), 114.54 (C₄), 115.68 (C₆), 123.76 (C_2′), 127.41 (C_5′), 127.43 (C_4′), 129.89 (C_6′), 129.92 (C₃), 131.51 (C₅), 132.86 (C₂), 138.96 (C₁), 146.93 (C_1′), 163.75 (C₅), 190.29 (CHO). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₄H₁₁BrO₂: 291.0015; found: 291.0019.

2′-bromo-5-chloro-[1,1′-biphenyl]-2-carbaldehyde (1f). Yield: 72%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 7.31–7.35 (m, 3H, H_arom), 7.46 (td, J = 8.40, 1.3, Hz, 1H, H_arom), 7.52 (ddd, J = 8.40, 2.0, 0.80 Hz, 1H, H_arom), 7.69–7.71 (m, 1H, H_arom), 7.98 (d, J = 7.98 Hz, 1H, H_arom), 9.72 (s, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 123.72 (C_2′), 127.69 (C₆), 128.96 (C₄), 129.10 (C_5′), 130.40 (C_4′), 130.96 (C_6′), 131.53 (C_3′), 132.20 (C₃), 133.02 (C_1′), 137.60 (C₁), 140.11 (C₂), 145.86 (C₅), 190.33 (CHO). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₈BrClO: 296.9; found: 296.9500.

2′-bromo-4-fluoro-[1,1′-biphenyl]-2-carbaldehyde (1g). Yield: 75%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 7.30–7.44 (m, 5H, H_arom), 7.69–7.72 (m, 2H, H_arom), 9.72 (d, J = 9.71 Hz, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 113.61 (d, J = 22.50 Hz, C₃), 120.98 (d, J = 22.00 Hz, C₅), 124.18 (C_2′), 127.64 (C_5′), 130.20 (C_4′), 131.89 (C_3′), 132.94 (d, J = 8.07, C₆), 132.99 C_6′), 135.52 (d, J = 6.50 Hz,C₂), 137.91 (C_1′), 140.58 (d, J = 3.50 Hz, C₁), 162.66 (d, J = 240.94 (C₄), 190.34 (d, J = 2.10 Hz, CHO). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₈BrFO: 277.0; found: 276.9673.

2′-bromo-4-nitro-[1,1′-biphenyl]-2-carbaldehyde (1h). Yield: 78%; Mp: 85 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 7.33 (dd, J = 7.52, 1.77 Hz, 1H, H_5′), 7.39 (td, J = 7.52, 1.77 Hz, 1H, H_4′) 7.49 (td, J = 7.52, 1.2 Hz, 1H, H_6′), 7.55 (d, J = 8.40 Hz, 1H, H₆), 7.74 (dd, J = 8.03, 1.26 Hz, 1H, H_3′), 8.48 (dd, J = 8.40, 2.46 Hz, 1H, H₅), 8.84 (d, J = 2.46 Hz, 1H, H₃), 9.79 (s, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) =116.15 (C₄), 117.94 (C₆), 123.58 (C_2′), 127.63 (C_5′), 130.35 (C_4′), 130.44 (C_6′), 131.45 (C_1′), 133.01 (C_3′), 137.71 (C₃), 147.21 (C₁), 164.34 (C₂), 166.90 (C₅), 189.93 (CHO). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₈BrNO₃: 303.9615; found: 303.9614.

2′-bromo-5-fluoro-[1,1′-biphenyl]-2-carbaldehyde (1i). Yield: 87%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 7.02 (dd, J = 7.02 Hz, 1H, H_arom), 7.23 (td, J = 8.20, 2.51 Hz, 1H, H_arom), 7.31–7.35 (m, 2H, H_arom), 7.42 (td, J = 7.43, 1.61 Hz, 1H, H_arom), 7.70 (d, J = 8.20 Hz, 1H, H_arom), 8.07 (dd, J = 8.07, 2.51 Hz, 1H, H_arom), 9.69 (s, 1H, CHO); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 116.15 (d, J = 21.8 Hz (C₄), 117.95 (d, J = 22.13 Hz) (C₆), 123.58 (C_2′), 127.63 (C_5′), 130.35 (C_4′), 130.44(d, J = 9.23 Hz) (C₃), 130.47 (C_1′), 131.45 (C_6′), 133.01 (C_3′), 137.71(d, J = 1.96 Hz) (C₂), 147.16(d, J = 9.47 Hz) (C₁), 164.65 (d, J = 257.18 Hz) (C₅), 189.93 (CHO). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₃H₈BrFO: 278.9815; found: 278.9813.

3.3. General Procedure for the Synthesis of 1-(2′-Bromo-[1,1′-biaryl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3a–i)

To a 100 mL round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a nitrogen inlet, containing 2′-bromo-biaryl-2-carbaldehydes (300 mg, 1 equiv), 10 mL of anhydrous DMF was added. The solution was stirred at −20 °C for 10 min; then TDAE (1.3 equiv) was added. To the round-bottom flask, 10 mL of anhydrous DMF solution of 4-nitrobenzyl chloride (1.3 equiv) was added dropwise with a syringe. A red color immediately developed, with the formation of a fine white precipitate (octamethyloxamidinium dichloride, TDAECl₂). The mixture was stirred at −20 °C for 1 h, then warmed to room temperature over 2 h. Then water was added to quench the reaction. The solution was extracted with ethyl acetate (3 × 30 mL), and the combined organic layers were washed with brine (3 × 50 mL), and dried over Na₂SO₄. The crude product was then obtained after evaporation of the solvent under reduced pressure. Purification by silica gel chromatography (dichloromethane/cyclohexane: 7/3) yielded the corresponding compounds 3a–i as “cis-substituted” and “trans-substituted” forms.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3a). Yield: 84%; Mp: 101 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.87–3.13 (m, 2H, CH₂), 4.69–4.79 (m, 1H, CH), 6.77–7.75 (m, 10H, H_arom), 8.07 (d, J = 8.71 Hz, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.15/44.89 (C₂), 71.63/72.14 (C₁), 123.45/123.67 (C_3″), 123.57/124.07 (C_5″), 125.63/125.79 (C_2′), 127.55/127.58 (C₃), 127.62 (C₆), 128.03 (C₅), 128.78/128.97 (C₄), 129.28/129.53 (C_5′), 129.34/130.25 (C_4′), 130.34/130.37 (C_2″), 131.13/131.34 (C_6″), 132.63 (C_6′), 133.12 (C₁), 139.21/139.27 (C_3′), 140.98/141.13 (C_1′), 141.19/141.40 (C₂), 146.21/146.71 (C_1″), 146.78/146.85 (C_4″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₁₆BrNO₃: 422.0188; found: 422.0182.

1-(2′-bromo-4-methoxy-[1,1′-biphenyl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3b). Yield: 76%; Mp: 68 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.85–3.09 (m, 2H, CH₂), 3.87/3.89 (s, 3H, CH₃), 4.67–4.78 (m, 1H, CH), 6.69–8.08 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.15/44.89 (C₂), 55.49–55.52 (C_a), 71.78/72.32 (C₁), 110.72/110.87 (C₃), 113.27/113.64 (C₅), 123.48/123.59 (C_2′), 124.42/124.79 (C_3″,5″), 127.59 (C₁), 129.23/129.43 (C_5′), 130.33/130.36 (C₆), 130.52 (C_4′), 131.52/131.61 (C_2″/6″), 131.64/131.80 (C_6′), 132.63/133.15 (C_3′), 140.95/141.03 (C_1′), 142.53/143.01 (C₂), 146.22/146.75 (C_1″), 146.82/146.85 (C_4″), 159.88/160.08 (C₄). HRMS (ESI): m/z [M ⁺Na]⁺ calcd for C₂₁H₁₈BrNO₄:452.0294; found: 452.0294.

1-(2′-bromo-5-methyl-[1,1′-biphenyl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3c). Yield: 62%; Mp: 67 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.38/3.40 (s, 3H, CH₃), 2.85–3.12 (m, 2H, CH₂), 4.65–4.73 (m, 1H, CH), 6.73–8.07 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 21.22/21.24 (CH₃), 44.16/44.90 (C₂), 71.52/72.02 (C₁), 123.43/123.67 (C_2′), 123.56/124.02 (C₆), 125.57/125.72 (C_3″,5″), 127.49/127.53 (C₃), 129.22/129.43 (C₄), 129.54/129.74 (C_5′), 129.84/130.36 (C_4′), 130.38/130.73 (C_2″,6″), 131.17/131.34 (C_6′), 132.56/133.02 (C₁), 137.42/137.79 (C_3′), 138.06/138.39 (C_1′), 139.23 (C₂), 141.30/141.34 (C₅), 146.32/146.68 (C_1″), 146.76/147.01 (C_4″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₈BrNO₃: 436.0345; found: 436.0344.

1-(6-(2-bromophenyl)benzo[d][1,3]dioxol-5-yl)-2-(4-nitrophenyl)ethan-1-ol (3d). Yield: 58%; Mp: 168 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.82–3.07 (m, 2H, CH₂), 4.55–4.64 (m, 1H, CH), 6.02–6.05 (m, 2H, H₂), 6.49–8.08 (m, 10H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.35/44.81 (C₂), 71.61/72.06 (C₁), 101.57/101.60 (C₂), 106.82/106.96 (C₇), 109.23/110.09 (C₄), 123.49/124.12 (C_2′), 123.64/124.49 (C_3″,5″), 127.54/127.67 (C₆), 129.34/129.58 (C_5′), 130.33/130.37 (C_4′), 131.46/131.57 (C_2″,6″), 132.68/132.89 (C_6′), 133.11 (C₅), 135.00/135.22 (C_3′), 140.92/140.93 (C_1′), 146.09 (C_1″), 146.75/146.81 (C_4″), 146.90/147.19 (C_3a), 148.08/148.24 (C_7a). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₆BrNO₅: 466.0087; found: 466.0081.

1-(2′-bromo-5-methoxy-[1,1′-biphenyl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3e). Yield: 49%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.85–3.11 (m, 2H, CH₂), 4.61–4.68 (m, 1H, CH_k), 3.82/3.83 (s, 3H, CH₃), 6.56–8.07 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.27/44.96 (C₂), 55.48/55.54 (C_a), 71.29/71.78 (C₁), 114.24/114.59 (C₄), 114.76/115.21 (C₆), 123.44/123.52 (C_2′), 123.58/123.87 (C₃), 127.05/127.22 (C_3″,5″), 127.49/127.57 (C_5′), 129.36/129.57 (C_4′), 130.40 (C_2″,6″), 131.07/131.20 (C_6′), 132.61/133.48 (C_3′), 133.07/133.27 (C₂), 140.60 (C₁), 141.06/141.07 (C_1′), 146.28/146.69 (C_1″), 146.78/146.97 (C_4″), 158.73/159.02 (C₅). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₈BrNO₄: 452.0294; found: 452.0290.

1-(2′-bromo-5-chloro-[1,1′-biphenyl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3f). Yield: 69%; Mp: 116 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.82–3.09 (m, 2H, CH₂), 4.65–4.74 (m, 1H, CH), 6.77–8.07 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.07/44.84 (C₂), 71.17/71.71 (C₁), 123.25/123.53 (C_2′), 123.63/123.75 (C_3″,5″), 127.37/127.47 (C₄), 127.73 (C₆), 128.91/129.12 (C_5′), 129.22/129.81 (C₃), 129.99/130.12 (C_4′), 130.34–130.39 (C_2″,6″), 130.96/131.18 (C_6′), 132.80/133.27 (C_3′), 133.32/133.61 (C₁), 139.62/139.83 (C₅), 139.81/140.16 (C_1′), 140.64 (C₂), 145.79/146.40 (C_1″), 146.80/146.88 (C_4″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₁₅BrClNO₃: 455.9795; found: 455.9796.

1-(2′-bromo-4-fluoro-[1,1′-biphenyl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3g). Yield: 65%; Mp: 150 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.82–3.07 (m, 2H, CH₂), 4.66–4.76 (m, 1H, HCH), 6.81–8.08 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.07/44.81 (C₂), 71.50/72.04 (C₁), 112.75 (d, J = 22.81 kHz)/112.86 (d, J = 22.53 Hz) (C₃), 114.69 (d, J = 21.69 Hz)/115.10 (d, J = 21.65 Hz) (C₅), 123.56/123.67 (C_3″,5″), 123.93/124.36 (C_2′), 127.72 (C_5′), 129.62/129.80 (C_4′), 130.32/130.34 (C_2″,6″), 131.11 (d, J = 8.03 Hz) (C₆), 131.35/131.57(C_6′), 132.12 (d, J = 7.99 Hz (C₆), 132.80/133.31 (C_3′), 134.85 (d, J = 3.58 Hz)/135.00 (d, J = 3.03 Hz) (C₁), 140.26/140.31 (C_1′), 143.69 (d, J = 6.63 Hz)/144.26 (d, J = 6.60 Hz) (C₂), 145.83/146.42 (C_1″), 146.84/146.91 (C_4″), 162.97 (d, J = 247.27 Hz)/163.18 (d, J = 247.73 Hz) (C₄). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₁₅BrFNO₃: 440.0094; found: 440.0095.

1-(2′-bromo-4-nitro-[1,1′-biphenyl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3h). Yield: 78%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.84–3.09 (m, 2H, CH₂), 4.76–4.86 (m, 1H, CH), 6.89–8.64 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.07/44.88 (C₂), 71.20/71.78 (C₁), 121.54 (C₅), 122.47/122.70 (C_2′), 122.96/123.17 (C₃), 123.69/123.79 (C_3″,5″), 128.00 (C_5′), 130.29/130.39 (C₆), 130.45/130.53 (C_4′), 130.71/130.79 (C_2″,6″), 131.75 (C_6′), 133.12/133.57 (C_3′), 139.17/139.22 (C_1′), 143.45/144.21 (C₁), 145.08/145.15 (C₂), 145.38/145.87 (C_1″), 146.95/147.02 (C_4″), 148.31/148.56 (C₄). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₁₅BrN₂O₅: 467.0039; found: 467.0038.

1-(2′-bromo-5-fluoro-[1,1′-biphenyl]-2-yl)-2-(4-nitrophenyl)ethan-1-ol (3i). Yield: 76%; Mp: 112 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.83–3.09 (m, 2H, CH₂), 4.65–4.74 (m, 1H, CH), 6.75–8.08 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.27/44.99 (C₂), 71.15/71.66 (C₁), 115.78 (d, J = 19.1 Hz)/115.97 (d, J = 17.5 Hz) (C₄), 116.18 (d, J = 20.0 Hz)/117.08 (d, J = 21.8 Hz) (C₆), 123.31 (C_2′), 123.53 (C_3″,5″), 123.65 (C_2′), 127.69/127.73 (C_5′), 127.76 (d, J = 6.0 Hz)/127.89 (d, J = 8.3 Hz) (C₃), 129.76/129.95 (C_4′), 130.37/130.39 (C_2″,6″), 130.91/131.11 (C_6′), 132.81/133.26 (C_3′), 136.97 (d, J = 3.1 Hz)/137.43 (d, J = 3.3 Hz) (C₂), 140.01 (C_1′), 140.98 (d, J = 2.2 Hz)/141.06 (d, J = 2.2 Hz) (C₁), 145.92/146.54 (C_1″), 146.80/146.89 (C_4″), 160.60 (d, J = 27.1 Hz)/163.07 (d, J = 27.2 Hz) (C₅). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₁₅BrFNO₃: 440.0094; found: 440.0092.

3.4. General Procedure for the Synthesis of 1-(2′-Bromo-[1,1′-biphenyl]-2-yl)-2-(aryl)ethan-1-ol (4b–k)

The appropriate substituted benzylic chloride (1.3 equiv) in anhydrous DMF (10 mL) was added dropwise with a syringe under nitrogen to a sealed round-bottom flask containing 2′-bromo-[1,1′-biphenyl]-2-carbaldehyde (1a, 300 mg, 1 equiv) and TDAE (1.3 equiv). The solution was cooled to −20 °C, maintained at this temperature for 1 h, and then kept at room temperature for 2 h. The solution was then extracted with ethyl acetate (3 × 30 mL), and the extracts were washed with brine (3 × 50 mL), dried (Na₂SO₄), and evaporated under reduced pressure. Purification by silica gel chromatography (dichloromethane/cyclohexane: 7/3) gave the corresponding compounds 4b–k as “cis-substituted” and “trans-substituted” forms.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(2-nitrophenyl)ethan-1-ol (4b). Yield: 64%; Mp: 95 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.03–3.39 (m, 2H, CH₂), 4.79–4.85 (m, 1H, CH), 6.76–7.80 (m, 12H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.24/41.26 (C₂), 71.28/71.63 (C₁), 123.60/124.17 (C_2′), 124.56/124.59 (C₃), 125.91/126.14 (C₆), 127.45/127.50 (C_4″), 127.54 (C_6″), 127.91 (C_5″), 127.74/128.91 (C₄), 129.22/129.38 (C₅), 130.26 (C_5′), 131.17/131.36 (C_4′), 132.44/132.53 (C_6′), 132.75/132.88 (C₁), 132.99/133.13 (C_3′), 133.32/133.35 (C_3″), 139.34/139.54 (C_1″), 141.18/141.21 (C_1′), 141.59 (C₂), 150.19/150.67 (C_2″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₁₆BrNO₃: 422.0188; found: 422.0182.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(6-nitrobenzo[d][1,3]dioxol-5-yl)ethan-1-ol (4c). Yield: 67%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.99–3.34 (m, 2H, CH₂), 4.77–4.85 (m, 1H, CH₂), 6.02–6.05 (m, 2H, H_2″), 6.26/6.35 (s, 1H, H_4″), 6.96–7.74 (m, 9H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 40.85/41.71 (C₂), 71.32/71.73 (C₁), 102.82/102.84 (C_2″), 105.53/105.57 (C_4″), 111.23/111.78 (C_2′), 123.63/124.15 (C₃), 125.90/126.07 (C₆), 127.47/127.56 (C₄), 127.93 (C₅), 128.77/128.93 (C_5′), 129.30/129.34 (C_5″), 129.41/130.22 (C_7″), 130.31/130.40 (C_4′), 131.24/131.48 (C_6′), 132.51/133.15 (C_3′), 139.32/139.51 (C₁), 141.17/141.21 (C_1′), 141.26/141.67 (C₂), 143.78/144.22 (C_6″), 146.71/146.74 (C_9″), 151.23/151.49 (C_8″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₆BrNO₅: 466.0087; found: 466.0085.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(4,5-dimethoxy-2-nitrophenyl)ethan-1-ol (4d). Yield: 67%; Mp: 76 °C; ¹H NMR (400 MHz, CDCl₃, 25) δ (ppm) = 3.01–3.45 (m, 2H, H₂), 3.68/3.69 (s, 3H, CH₃), 3.89/3.90 (s, 3H, CH₃), 4.84–4.87 (m, 1H, H₁), 6.17/6.20 (s, 1H, H_6″), 6.66–7.77 (m, 9H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 40.36/41.83 (C₂), 56.34 (C_a), 56.43/56.46 (C_b), 71.40/71.99 (C₁), 107.92/107.97 (C_6″), 114.24/114.55 (C_2′), 123.73/124.15 (C₃), 126.23/126.25 (C₆), 127.28/127.32 (C₅), 127.55/127.86 (C₄), 128.00/128.15 (C_5′), 128.59/128.84 (C_1″), 129.15/129.31 (C_3″), 129.20/130.36 (C_4′), 131.44/131.53 (C_6′), 132.44/133.07 (C₁), 139.10/139.72 (C_3′), 141.11/141.26 (C_1′), 141.30/141.78 (C₂), 142.14/142.69 (C_4″), 147.55/147.59 (C_2″), 152.48/152.72 (C_5″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₂H₂₀BrNO₅: 482.0400; found: 482.0399.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(3-methoxy-4-nitrophenyl)ethan-1-ol (4e). Yield: 80%; Mp: 76 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.80–3.06 (m, 2H, H₂), 3.71/3.81 (s, 3H, CH₃), 4.67–4.80 (m, 1H, H₁), 6.32–7.81 (m, 11H, H₁); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.52/45.40 (C₂), 56.13/56.43 (C_a), 71.69/72.32(C₁), 114.40/114.53 (C_2″), 131.26/121.29 (C_6″), 123.60/124.02 (C_2′), 125.60/125.65 (C₃), 125.74/125.86 (C_5″), 127.47/127.56 (C₆), 127.96 (C₄), 128.69/128.92 (C₅), 129.13/129.16 (C_5′), 129.42/130.19 (C_4′), 131.24/131.45 (C_6′), 132.44/133.00 (C₁), 137.87/137.90 (C_3′), 1138.99/139.30 (C_1′), 140.95/141.14 (C_4″), 141.16/141.39 (C₂), 145.85/146.77 (C_1″), 152.83/153.01 (C_3″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₈BrNO₄: 452.0294; found: 452.0297.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(3-methyl-4-nitrophenyl)ethan-1-ol (4f). Yield: 64%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.58 (s, 3H, CH₃), 3.02–3.34 (m, 2H, CH₂), 4.75–4.82 (m, 1H, CH), 6.88–7.76 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 40.17 (C_a), 40.90/41.00 (C₂), 71.15/71.34 (C₁), 123.56/124.12 (C_2′), 125.80 (C_5″), 125.97/125.98 (C₃), 127.49/127.56 (C₆), 127.58/127.65 (C_6″), 128.07 (C₄), 128.73/128.96 (C₅), 129.31/129.33 (C_5′), 129.50/130.32 (C_4′), 131.10/131.35 (C_2″), 132.53/132.83 (C_6′), 133.20 (C₁), 135.21/135.61 (C_3″), 138.66/138.79 (C_3′), 139.24/139.38 (C_1′), 141.00/141.08 (C₂), 141.27 (C_1″), 148.37/148.79 (C_4″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₈BrNO₃: 436.0345; found: 436.0341.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(5-methyl-2-nitrophenyl)ethan-1-ol (4g). Yield: 64%; oil; ¹H NMR (400 MHz, CDCl₃, 25) δ (ppm) = 2.26/2.27 (2s, 3H, CH₃), 3.02–3.34 (m, 2H, H₂), 4.77–4.85 (m, 1H, H₁), 6.83–7.75 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 21.32/21.39 (C_a), 41.04/41.37 (C₂), 71.45/71.83 (C₁), 123.62/124.20 (C_2′), 124.74/124.77 (C_3″), 125.88/126.10 (C₃), 127.29/127.46 (C₆), 127.40/127.78 (C_4″), 128.03/128.08 (C₄), 128.63/128.82 (C₅), 129.11/129.26 (C_5′), 129.14/130.22 (C_4′), 131.27/131.42 (C_6″), 132.39/133.11 (C_6′), 133.14/133.42 (C₁), 133.56/133.90 (C_3′), 139.17/139.46 (C_1″), 141.24/141.45 (C_1′), 141.71 (C₂), 143.61/143.84 (C_5″), 147.78/148.19 (C_2″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₈BrNO₃: 436.0345; found: 436.0346.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(5-methoxy-2-nitrophenyl)ethan-1-ol (4h). Yield: 93%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.04–3.46 (m, 2H, CH₂), 3.68/3.70 (s, 3H, CH₃), 4.82–4.91 (m, 1H, CH), 6.28–7.90 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 40.85/40.96 (C₂), 55.81/55.87 (C_a), 71.22/71.81 (C₁), 113.25/113.37 (C_4″), 116.93/117.32 (C_6″), 123.62/124.11 (C_2′), 126.06/126.17 (C₃), 127.33/127.34 (C₆), 127.39/127.46 (C_3″), 127.82/128.62 (C₄), 128.83/129.31 (C₅), 129.16/130.26 (C_5′), 131.34/131.39 (C_4′), 132.39/133.06 (C_6′), 136.21/136.56 (C₁), 139.17/139.62 (C_3′), 141.17/141.21 (C_1′), 141.24 (C_1″), 141.68 (C₂), 142.99/143.47 (C_2″), 162.57/162.76 (C_5″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₈BrNO₄: 452.0294; found: 452.0294.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(3-nitro-[1,1′-biphenyl]-4-yl)ethan-1-ol (4i). Yield: 75%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.07–3.42 (m, 2H, CH₂), 4.83–4.89 (m, 1H, CH), 6.81–8.02 (m, 16H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 40.95/41.08 (C₂), 71.35/71.58 (C₁), 122.90 (C_2″), 123.62/124.18 (C_2′), 125.91/126.16 (C₃), 127.03/127.07 (C₆), 127.45/127.52 (C_4‴), 127.49/127.94 (C₄), 128.43/128.48 (C_2‴,6‴), 128.75/128.94 (C₅), 129.19/129.24 (C_5′), 129.22/129.38 (C_5″), 130.28 (C_3‴,5‴), 130.83/131.11 (C_4′), 131.18/131.40 (C_6′), 131.62/131.94 (C₁), 132.45/133.14 (C_3′), 133.36/133.80 (C_6″), 138.51/138.55 (C_4″), 139.38/139.53 (C_1″), 140.91/140.94 (C_1′), 141.19/141.22 (C₂), 141.63 (C_1‴), 150.48/150.95 (C_3″). HRMS (ESI): m/z [M+ Na]⁺ calcd for C₂₆H₂₀BrNO₃: 498.0502; found: 498.0504.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(3-fluoro-4-nitrophenyl)ethan-1-ol (4j). Yield: 75%; oil; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.80–3.06 (m, 2H, CH₂), 4.69–4.78 (m, 1H, CH), 6.67–7.90 (m, 11H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 43.96/44.74(C₂), 71.22/71.82 (C₁), 119.16 (d, J = 20.73 Hz)/119.25 (d, J = 20.42 Hz) (C_2″), 123.62/123.99 (C_2′), 125.55 (d, J = 3.63 Hz)/125.64 (d, J = 6.69 Hz) (C_5″), 125.66/125.68 (C₃), 125.81 (d, J = 2.33 Hz)/125.89 (d, J = 2.67 Hz) (C_6″), 127.62/127.65(C₆), 128.13 (C₄), 128.77/129.00 (C₅), 129.34 (C_5′), 129.46/129.58(C_4′), 130.28 (C_1′), 131.11/131.29 (C_6′), 132.73/133.14 (C_3′), 135.68/135.76(C₁), 139.12/139.15 (C_2′), 140.95 (d, J = 10.84 Hz)/141.17 (d, J = 14.51 Hz) (C_4″), 148.17 (d, J = 8.52 Hz)/148.85 (d, J = 8.27 Hz) (C_1″), 155.29 (d, J = 264.60 Hz)/155.36 (d, J = 264.50 Hz) (C_3″). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₁₅BrFNO₃: 440.0094; found: 440.0095.

1-(2′-bromo-[1,1′-biphenyl]-2-yl)-2-(4′-nitro-[1,1′-biphenyl]-4-yl)ethan-1-ol (4k). Yield: 82%; Mp: 138 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.86–3.12 (m, 2H, CH₂), 4.71–4.81 (m, 1H, CH), 6.82–8.28 (m, 16H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 44.28/45.01 (C₂), 72.01/72.53 (C₁), 123.74/124.17 (C_2′), 124.21/124.24 (C₃), 125.73/125.86 (C_3‴,5‴), 127.30/127.38 (C₆), 127.46/127.51 (C_2″,6″), 127.61/127.65 (C₄), 127.72 (C₅), 128.72/128.66 (C_5′), 129.16/129.19 (C_2‴,6‴), 129.37/130.13 (C_3″,5″), 130.29/130.31 (C_4′), 131.23/131.49 (C_6′), 132.51/133.05 (C₁), 136.83/136.97 (C_3′), 139.28/139.34 (C_4″), 139.51/140.07 (C_1′), 141.36/141.38 (C_1″), 141.42/141.95 (C₂), 147.05 (C_1‴), 147.47/147.49 (C_4‴). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₆H₂₀BrNO₃: 498.0502; found: 498.0504.

3.5. General Procedure for the Synthesis of 6H-Benzo[c]chromene (5a–s)

A mixture of 1-(2′-bromo-[1,1′-biaryl]-2-yl)-2-(aryl)ethan-1-ol (3a–i, 4b–k) (100 mg, 1 equiv), Pd(OAc)₂ (0.04 equiv), PPh₃ (0.25 equiv), and Cs₂CO₃ (3 equiv) was added to a Biotage microwave vial and the vial sealed, evacuated, and purged with N₂ (×3). The toluene (4 mL) was added to the mixture under nitrogen. The reaction was then heated at 110 °C under microwave irradiation for 1.5 h. After cooling, H₂O (50 mL) was added, and the solution was extracted with ethyl acetate (3 × 30 mL) and washed with brine (3 × 50 mL). The combined organic layers were dried over Na₂SO₄ and evaporated. The crude product was purified by column chromatography (silica gel, cyclohexane/CH₂Cl₂: 7/3).

6-(4-nitrobenzyl)-6H-benzo[c]chromene (5a). Yield: 88%; Mp: 113 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.93 (dd, J = 13.95, 4.80 Hz, 1H, CH₂), 3.19 (dd, J = 13.95, 9.08 Hz, 1H, CH₂), 5.31 (dd, J = 9.08 Hz, 4.80 1H, CH), 6.83 (dd, J = 8.07 Hz, 1H, H_arom), 6.91 (d, J = 7.14 Hz, 1H, H_arom), 7.07 (td, J = 7.50, 1.2 Hz, 1H, H_arom), 7.24–7.28 (m, 4H, H_arom), 7.39 (td, J = 7.66, 1.35 Hz, 1H, H_arom), 7.75 (d, J = 7.76 Hz, 2H, H_arom), 8.13 (d, J = 8.66 Hz, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.43 (C_a), 78.00 (C₆), 118.33 (C₄), 122.22 (C₂), 122.37 (C_10b), 122.49 (C_3′,5′), 123.25 (C₇), 123.58 (C₁₀), 125.23 (C₈), 127.87 (C₉), 128.81 (C₃), 128.99 (C_2′,6′), 129.98 (C₁), 130.52 (C_10a), 133.22 (C_6a), 145.47 (C_1′), 146.92 (C_4′), 151.96 (C_4a). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₀H₁₅NO₃: 340.0944; found: 340.0944.

8-methoxy-6-(4-nitrobenzyl)-6H-benzo[c]chromene (5b). Yield: 47%; Mp: 130 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.00 (dd, J = 13.99, 4.59 Hz, 1H, CH₂), 3.26 (dd, J = 13.99, 9.16 Hz, 1H, CH₂), 3.80 (s, 3H, CH₃), 5.34 (dd, J = 9.16, 4.59 Hz, 1H, CH), 6.54 (d, J = 2.59 Hz, 1H, H_arom), 6.89 (dd, J = 8.02, 1.24 Hz, 1H, H_arom), 6.94 (dd, J = 8.62, 2.61 Hz, 1H, H_arom), 7.05 (dt, J = 7.52, 1.25 Hz, 1H, H_arom), 7.19 (dt, J = 7.52, 1.59 Hz, 1H, H_arom), 7.30 (d, J = 8.68 Hz, 2H, H_arom) 7.67–7.70 (m, 2H, H_arom), 8.15 (d, J = 8.68 Hz, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.39 (C_a), 55.55 (C_b), 78.09 (C₆), 110.61 (C₇), 114.36 (C₉), 118.21 (C₄), 121.83 (C₂), 122.32 (C_10b), 122.39 (C_3′,5′), 122.61 (C_10a), 123.59 (C₃), 124.02 (C₁₀), 128.96 (C_2′,6′), 130.54 (C₁), 134.86 (C_6a), 145.55 (C_1′), 146.93 (C_4′), 151.10 (C_4a), 159.50 (C₈). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₁H₁₇NO₄: 365.1496; found: 365.1499.

9-methyl-6-(4-nitrobenzyl)-6H-benzo[c]chromene (5c). Yield: 37%; Mp: 133 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.42 (s, 3H, CH₃), 3.00 (dd, J = 13.94, 4.80 Hz, 1H, CH₂), 3.26 (dd, J = 13.94, 8.98 Hz, 1H, CH), 5.37 (dd, J = 8.98, 4.80 Hz, 1H, CH), 6.89 (d, J = 7.59 Hz, 2H, H_arom) 7.06–7.09 (m, 2H, H_arom), 6.24–7.30 (m, 3H, H_arom), 7.57 (s, 1H, H_arom), 7.75 (dd, J = 7.77, 1.61 Hz, 1H, H_arom), 8.14 (d, J = 8.69 Hz, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 21.65 (C_b), 41.59 (C_a), 77.94 (C₆), 118.31 (C₄), 122.28 (C₂), 122.33 (C_10b), 123.08 (C_3′,5′), 123.19 (C₃), 123.59 (C_10a), 125.14 (C₇), 128.64 (C_2′,6′), 128.81 (C₁), 129.82 (C₉), 130.46 (C₁₀), 130.55 (C₈), 138.51 (C_6a), 145.62 (C_1′), 146.91 (C_4′), 152.06 (C_4a). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₇NO₃: 354.1101; found: 354.1096.

6-(4-nitrobenzyl)-6H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-c]chromene (5d). Yield: 80%; Mp: 186 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.88 (dd, J = 13.98, 4.60 Hz, 1H, CH₂), 3.26 (dd, J = 13.98, 9.10 Hz, 1H, CH₂), 5.37 (dd, J = 9.10, 4.60 Hz, 1H, CH), 6.54 (s, 2H, CH₂), 6.94 (dd, J = 8.11, 1.23 Hz, 1H, H_arom), 7.10 (td, J = 7.57, 1.25 Hz, 1H, H_arom), 7.30 (dd, J = 7.60, 1.59 Hz, 1H, H_arom), 7.33 (s, 1H, H_arom), 7.35 (d, J = 8.68 Hz, 2H, H_arom) 7.63 (dd, J = 7.84, 1.56 Hz, 1H, H_arom), 8.20 (d, J = 8.65 Hz, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.46 (C_a), 78.05 (C₆), 101.49 (C₉), 103.08 (C₇), 105.60 (C₁₁), 118.15 (C₄), 122.38 (C₂), 122.41 (C_11b), 122.75 (C_3′,5′), 123.38 (C_11a), 123.61 (C₃), 127.34 (C_2′,6′), 129.23 (C₁), 130.48 (C_6a), 145.45 (C_1′), 146.93 (C_4′), 147.50 (C_7a), 148.42 (C_10a), 151.14 (C_4a). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₅NO₅: 384.0842; found: 384.0840.

9-methoxy-6-(4-nitrobenzyl)-6H-benzo[c]chromene (5e). Yield: 55%; Mp: 123 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.00 (dd, J = 13.88, 5.00 Hz, 1H, CH₂), 3.25 (dd, J = 13.88, 8.80 Hz, 1H, CH₂), 3.88 (s, 3H, CH₃), 5.37 (dd, J = 8.80, 5.00 Hz, 1H, CH), 6.80 (dd, J = 8.38, 2.50 Hz, 1H, H_arom), 6.89–6.93 (m, 2H, H_arom), 7.07 (td, J = 7.52, 1.24 Hz, 1H, H_arom), 7.25–7.29 (m, 4H, H_arom), 7.71 (dd, J = 7.76, 1.62 Hz, 1H, H_arom), 8.13 (d, J = 8.70 Hz, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.73 (C_a), 55.57 (C_b), 77.77 (C₆), 107.86 (C₈), 113.40 (C₁₀), 118.36 (C₄), 122.16 (C₂), 122.28 (C_10b), 123.29 (C₇), 123.58 (C_3′,5′), 125.75 (C₃), 126.42 (C_2′,6′), 130.10 (C₁), 130.30 (C_6a), 130.56 (C_10a), 145.57 (C_1′), 146.91 (C_4′), 152.13 (C_4a), 160.11 (C₉). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₇NO₄: 370.1050; found: 370.1046.

9-chloro-6-(4-nitrobenzyl)-6H-benzo[c]chromene (5f). Yield: 77%; Mp: 138 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.00 (dd, J = 13.90, 5.00 Hz, 1H, CH₂), 3.26 (dd, J = 13.90, 8.89 Hz, 1H, CH₂), 5.38 (dd, J = 8.89, 5.00 Hz, 1H, CH), 6.90 (d, J = 8.13 Hz, 1H, CH), 6.91 (dd, J = 8.13, 1.22 Hz, 1H, CH), 7.09 (td, J = 7.53, 1.22 Hz, 1H, H_arom), 7.23 (dd, J = 8.08, 2.04 Hz, 1H, H_arom), 7.26–7.32 (m, 3H, H_arom), 7.70 (dd, J = 7.79, 1.61 Hz, 1H, H_arom), 7.72 (d, J = 2.04 Hz, 1H, H_arom), 8.13–8.16 (m, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.29 (C_a), 77.54 (C₆), 118.47 (C₄), 121.10 (C₂), 122.58 (C_10b), 122.68 (C_3′,5′), 123.40 (C₈), 123.68 (C₁₀), 126.63 (C₃), 127.74 (C₇), 130.52 (C_2′,6′), 130.75 (C₁), 130.90 (C_10a), 131.45 (C₉), 134.83 (C_6a), 144.99 (C_1′), 147.03 (C_4′), 152.02 (C_4a). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₁₄ClNO₃: 369.1000; found: 369.1000.

8-fluoro-6-(4-nitrobenzyl)-6H-benzo[c]chromene (5g). Yield: 80%; Mp: 132 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.02 (dd, J = 14.03, 4.57 Hz, 1H, CH₂), 3.27 (dd, J = 14.03, 9.21 Hz, 1H, CH₂), 5.36 (dd, J = 9.21, 4.57 Hz, 1H, CH), 6.75 (dd, J = 8.54, 2.63 Hz, 1H, H_arom), 6.91 (dd, J = 8.09, 1.20 Hz, 1H, H_arom), 7.06–7.13 (m, 2H, H_arom), 7.24–7.32 (m, 3H, H_arom), 7.68 (dd, J = 7.90, 1.73 Hz, 1H, H_arom), 7.72 (dd, J = 8.85, 5.47 Hz, 1H, H_arom), 8.15 (d, J = 8.68 Hz, 1H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.09 (C_a), 77.55 (C₆), 112.18 (d, J = 22.50 Hz, C₇), 115.89 (d, J = 21.77 Hz, C₉), 118.38 (C₄), 121.60 (C₁₀), 122.59 (C₁), 123.05 (C_10b), 123.68 (C_3′,5′), 124.53(d, J = 8.17 Hz, C_10a), 125.34(d, J = 2.98 Hz, C₃), 125.37 (C_2′,6′), 129.90 (C₁), 130.49 (C_1′), 135.41 (d, J = 7.22 Hz, C_6a), 145.04 (C_4′), 147.03 (C_4a), 151.46 (C₈), 162.20 (d, J = 248.46 Hz, C₈). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₁₄FNO₃: 353.1296; found: 353.1296.

8-nitro-6-(4-nitrobenzyl)-6H-benzo[c]chromene (5h). Yield: 79%; Mp: 235 °C; ¹H NMR (400 MHz, DMSO-_d6) δ (ppm) = 3.14–3.22 (m, 2H, CH₂), 5.80 (dd, J = 8.32, 5.5 Hz, 1H, CH), 6.91 (dd, J = 8.13, 1.17 Hz, 1H, H_arom), 7.16 (td, J = 7.55, 1.19 Hz, 1H, H_arom), 7.42 (ddd, J = 8.17, 7.32, 1.56 Hz, 1H, H_arom), 7.52 (d, J = 8.75 Hz, 2H, H_arom), 8.04 (dd, J = 7.88, 1.60 Hz, 1H, H_arom), 8.15–8.20 (m, 3H, H_arom), 8.26 (dd, J = 8.63, 2.40 Hz, 1H, H_arom), 8.33 (dd, J = 2.38 Hz, 1H, H_arom); ¹³C NMR (100 MHz, DMSO-_d6) δ (ppm) = 40. 15 (C_a), 76.20 (C₆), 118.32 (C₄), 120.05 (C₂), 121.15 (C_10b), 122.66 (C₉), 123.24 (C_3′,5′), 123.62 (C₇), 123.70 (C₃), 124.85 (C₁₀), 130.77 (C_2′,6′), 132.17 (C₁), 134.58 (C_10a), 134.78 (C_6a), 145.50 (C_1′), 146.30 (C_4′), 146.56 (C₈), 152.20 (C_4a). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₁₄N₂O₅: 380.1241; found: 380.1234.

9-fluoro-6-(4-nitrobenzyl)-6H-benzo[c]chromene (5i). Yield: 91%; Mp: 144 °C; ¹H NMR (400 MHz, DMSO-_d6) δ (ppm) = 3.00 (dd, J = 13.91, 5.00 Hz, 1H, CH₂), 3.26 (dd, J = 13.91, 8.88 Hz, 1H, CH₂), 5.39 (dd, J = 8.88, 5.00 Hz, 1H, CH), 6.92–6.96 (m, 3H, H_arom), 7.09 (td, J = 7.56, 1.23 Hz, 1H, H_arom), 7.25–7.32 (m, 2H, H_arom), 7.42 (dd, J = 10.78, 1.70 Hz, 1H, H_arom), 7.67 (dd, J = 7.78, 1.60 Hz, 1H, H_arom), 8.15 (d, J = 8.67 Hz, 1H, H_arom); ¹³C NMR (100 MHz, DMSO-_d6) δ (ppm) = 41.47 (C_a), 77.57 (C₆), 109.41 (d, J = 109.42 Hz, C₈), 114.67 (d, J = 114.67 Hz, C₁₀), 118.42 (C₄), 121.37 (d, J = 2.27 Hz, C_10b), 122.51 (C₂), 123.46 (C_3′,5′), 123.64 (C₃), 126.96 (d, J = 8.60 Hz, C₇), 128.89 (d, J = 2.93 Hz, C_10a), 130.71 (C₁), 130.52 (C_2′,6′), 131.31 (d, J = 8.54 Hz, C_6a), 145.13 (C_1′), 146.99 (C_4′), 151.96 (C_4a), 163.23 (d, J = 245.71 Hz, C₉). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₁₄FNO₃: 353.1296; found: 353.1290.

6-(2-nitrobenzyl)-6H-benzo[c]chromene (5j). Yield: 79%; Mp: 154 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.26 (dd, J = 13.84, 9.66 Hz, 1H, CH₂), 3.25 (dd, J = 13.84, 3.52 Hz, 1H, CH₂), 5.64 (dd, J = 9.66, 3.52 Hz, 1H, CH), 6.93 (dd, J = 8.07, 1.26 Hz, 1H, H_arom), 7.10 (td, J = 7.56, 1.26 Hz, 1H, H_arom), 7.20 (dd, J = 7.57, 1.54 Hz, 1H, H_arom), 7.27–7.34 (m, 3H, H_arom), 7.38–7.45 (m, 2H, H_arom), 7.53 (td, J = 7.56, 1.40 Hz, 1H, H_arom), 7.77 (dd, J = 7.79, 1.19 Hz, 1H, H_arom), 7.80 (dd, J = 7.77, 1.61 Hz, 1H, H_arom), 8.04 (dd, J = 8.21, 1.41 Hz, 1H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 38.84 (C_a), 77.36 (C₆), 118.48 (C₄), 122.20 (C₂), 122.26 (C_10b), 122.32 (C₇), 123.32 (C₁₀), 125.16 (C_4′), 125.59 (C_6′), 127.97 (C_5′), 128.16 (C₈), 128.59 (C₉), 128.67 (C₃), 129.87 (C₁), 132.95 (C_10a), 133.22 (C_3′), 133.80 (C_1′), 134.03 (C_6a), 149.40 (C_2′), 151.96 (C_4a). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₁₅NO₃: 335.1390; found: 335.1385.

6-((6-nitrobenzo[d][1,3]dioxol-5-yl)methyl)-6H-benzo[c]chromene (5k). Yield: 68%; Mp: 234 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.12 (dd, J = 13.88, 9.96 Hz, 1H, CH₂), 3.36 (dd, J = 13.88, 2.96 Hz, 1H, CH₂), 5.61 (dd, J = 9.99, 2.96 Hz, 1H, CH), 6.12 (d, J = 7.74 Hz, 1H, CH₂), 6.57 (s, 1H, H_arom), 6.95 (d, J = 8.07 Hz, 1H, H_arom), 7.09 (t, J = 7.49 Hz, 1H, H_arom), 7.30–7.41 (m, 4H, H_arom), 7.60 (s, 1H, H_arom), 7.78 (dd, J = 16.58, 7.72 Hz, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 39.52 (C_a), 77.36 (C₆), 103.03 (C_2′), 106.02 (C_4′), 112.40 (C₄), 118.45 (C₂), 122.17 (C_10b), 122.30 (C₇), 122.39 (C₁₀), 123.39 (C₈), 125.66 (C₉), 128.27 (C₃), 128.51 (C_5′), 128.68 (C₁), 129.95 (C_10a), 130.78 (C_6a), 133.86 (C_6′), 147.13 (C_7′a), 151.73 (C_4a), 151.91 (C_3′a). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₁H₁₅NO₅: 379.1288; found: 379.1286.

6-(4,5-dimethoxy-2-nitrobenzyl)-6H-benzo[c]chromene (5l). Yield: 87%; Mp: 170 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.16 (dd, J = 13.69, 9.88 Hz, 1H, CH₂), 3.44 (dd, J = 13.7, 3.43 Hz, 1H, CH₂), 3.85 (s, 3H, CH₃), 3.96 (s, 3H, CH₃), 5.65 (dd, J = 9.88, 3.43 Hz, 1H, CH), 6.45 (s, 1H, H_arom), 6.907.40 (dd, J = 8.11, 1.23 Hz, 1H, H_arom), 7.09 (td, J = 7.7, 1.0 Hz, 1H, H_arom), 7.24–7.35 (m, 3H, H_arom), 7.40 (td, J = 7.81, 1.90 Hz, 1H, H_arom), 7.70 (s, 1H, H_arom), 7.76 (d, J = 7.30 Hz, 1H, H_arom), 7.81 (dd, J = 7.78, 1.62 Hz, 1H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 39.61 (C_a), 56.38 (C_c), 56.46 (C_b), 77.27 (C₆), 108.38 (C_6′), 115.31 (C₄), 118.27 (C₂), 122.15 (C_10b), 122.23 (C₇), 122.44 (C₁₀), 123.45 (C₈), 125.74 (C₉), 128.19 (C₃), 128.45 (C_1′), 128.52 (C_3′), 128.60 (C₁), 129.64 (C_10a), 133.95 (C_6a), 141.28 (C_4′), 147.84 (C_2′), 152.02 (C_4a), 152.86 (C_5′). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₂H₁₉NO₅: 395.1601; found: 395.1596.

6-(3-methoxy-4-nitrobenzyl)-6H-benzo[c]chromene (5m). Yield: 71%; Mp: 84 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.97 (dd, J = 13.91, 4.94 Hz, 1H, CH₂), 3.21 (dd, J = 13.91, 8.82 Hz, 1H, CH₂), 3.87 (s, 3H, CH₃), 5.40 (dd, J = 8.82, 4.94 Hz, 1H, CH), 6.75 (d, J = 1.74 Hz, 1H, H_arom), 6.81 (dd, J = 8.29, 1.65 Hz, 1H, H_arom), 6.92 (dd, J = 8.11, 1.24 Hz, 1H, H_arom), 7.01 (dd, J = 8.11, 0.5 Hz, 1H, H_arom), 7.07 (td, J = 7.52, 1.24 Hz, 1H, H_arom), 7.24–7.30 (m, 2H, H_arom), 7.40 (td, J = 7.72, 1.30 Hz, 1H, H_arom), 7.76 (dd, J = 7.72, 1.55 Hz, 2H, H_arom), 7.81 (d, J = 8.27 Hz, 1H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.87 (C_a), 56.54 (C_b), 77.94 (C₆), 114.93 (C_2′), 118.25 (C₄), 121.50 (C₂), 122.20 (C_6′), 122.36 (C_10b), 122.47 (C₇), 123.30 (C_5′), 125.36 (C₁₀), 125.97 (C₈), 127.85 (C₉), 128.81 (C₃), 129.01 (C₁), 129.90 (C_10a), 133.19 (C_4′), 138.12 (C_6a), 145.28 (C_1′), 152.01 (C_3′), 153.07 (C_4a). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₁H₁₇NO₄: 365.1496; found: 365.1495.

6-(3-methyl-4-nitrobenzyl)-6H-benzo[c]chromene (5n). Yield: 69%; Mp: 77 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.58 (s, 3H, CH₃), 2.94 (dd, J = 13.96, 4.73 Hz, 1H, CH₂), 3.20 (dd, J = 13.9, 9.11 Hz, 1H, CH₂), 5.38 (dd, J = 9.11, 4.73 Hz, 1H, CH), 6.92 (dd, J = 8.10, 1.24 Hz, 1H, H_arom), 6.99–7.03 (m, 1H, H_arom), 7.05–7.11 (m, 3H, H_arom), 7.25–7.30 (m, 2H, H_arom), 7.40 (td, J = 7.62, 1.24 Hz, 1H, H_arom), 7.76 (td, J = 7.77, 1.41 Hz, 2H, H_arom), 7.92 (d, J = 8.16 Hz, 1H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 20.82 (C_b), 41.27 (C_a), 78.07 (C₆), 118.34 (C₄), 122.26 (C₂), 122.32 (C_10b), 122.45 (C_5′), 123.25 (C₇), 124.94 (C₁₀), 125.27 (C_6′), 127.84 (C₈), 128.12 (C₉), 128.77 (C₃), 128.99 (C₁), 129.94 (C_2′), 133.38 (C_10a), 133.86 (C_3′), 134.06 (C_6a), 143.68 (C_1′), 147.78 (C_4′), 152.02 (C_4a). HRMS (ESI): m/z [M+Na]⁺ calcd for C₂₁H₁₇NO₃: 349.1547; found: 349.1554.

6-(5-methyl-2-nitrobenzyl)-6H-benzo[c]chromene (5o). Yield: 66%; Mp: 187 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.40 (s, 3H, CH₃), 3.20 (dd, J = 13.71, 9.90 Hz, 1H, CH₂), 3.36 (dd, J = 13.7, 3.28 Hz, 1H, CH₂), 5.63 (dd, J = 9.90, 3.28 Hz, 1H, CH), 6.91 (dd, J = 8.09, 1.23 Hz, 1H, H_arom), 6.96 (d, J = 1.95 Hz, 1H, H_arom), 7.10 (td, J = 7.50, 1.24 Hz, 1H, H_arom), 7.21 (ddd, J = 8.35, 1.84, 0.78 Hz, 1H, H_arom), 7.28–7.34 (m, 3H, H_arom), 7.40 (td, J = 7.81, 1.83 Hz, 1H, H_arom), 7.76 (dd, J = 7.78, 1.17 Hz, 1H, H_arom), 7.81 (dd, J = 7.76, 1.60 Hz, 1H, H_arom), 7.98 (d, J = 8.33 Hz, 1H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 21.50 (C_b), 39.10 (C_a), 77.39 (C₆), 118.43 (C₄), 122.17 (C₂), 122.22 (C_10b), 122.41 (C_3′), 123.36 (C₇), 125.43 (C₁₀), 125.65 (C_4′), 128.16 (C₈), 128.55 (C₉), 128.63 (C₃), 129.81 (C₁), 133.34 (C_6′), 133.95 (C_1′), 134.73 (C_6a), 144.16 (C_5′), 146.99 (C_2′), 152.03 (C_4a). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₁H₁₇NO₃: 349.1547; found: 349.1550.

6-(5-methoxy-2-nitrobenzyl)-6H-benzo[c]chromene (5p). Yield: 49%; Mp: 170 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.19 (dd, J = 13.62, 10.0 Hz, 1H, CH₂), 3.45 (dd, J = 13.6, 3.12 Hz, 1H, CH₂), 3.84 (s, 3H, CH₃), 5.66 (dd, J = 10.0, 3.10 Hz, 1H, CH), 6.58 (d, J = 2.80 Hz, 1H, H_arom), 6.88 (dd, J = 9.16, 2.80 Hz, 1H, H_arom), 6.94 (dd, J = 8.02, 1.27 Hz, 1H, H_arom), 7.09 (td, J = 7.52, 1.23 Hz, 1H, H_arom), 7.26–7.32 (m, 1H, H_arom), 7.33 (d, J = 3.89 Hz, 2H, H_arom), 7.40 (dt, J = 7.77, 4.32 Hz, 1H, H_arom), 7.77 (d, J = 7.71 Hz, 1H, H_arom), 7.81 (dd, J = 7.79, 1.60 Hz, 1H, H_arom), 8.16 (d, J = 9.13 Hz, 1H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 39.81 (C_a), 55.94 (C_b), 77.21 (C₆), 113.43 (C_4′), 118.43 (C_6′), 118.46 (C₄), 122.16 (C₂), 122.27 (C_10b), 122.45 (C₇), 123.41 (C₁₀), 125.70 (C_3′), 128.07 (C₈), 128.23 (C₉), 128.51 (C₃), 128.64 (C₁), 129.79 (C_10a), 133.97 (C_1′), 136.58 (C_6a), 142.15 (C_2′), 151.96 (C_4a), 163.06 (C_5′). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₁H₁₇NO₄: 365.1496; found: 365.1497.

6-((3-nitro-[1,1′-biphenyl]-4-yl)methyl)-6H-benzo[c]chromene (5q). Yield: 75%; Mp: 140 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 3.30 (dd, J = 13.88, 9.63 Hz, 1H, CH₂), 3.38 (dd, J = 13.88, 3.59 Hz, 1H, CH₂), 5.68 (dd, J = 9.63, 3.59 Hz, 1H, CH), 6.97 (dd, J = 8.02, 1.21 Hz, 1H, H_arom), 7.11 (dt, J = 7.56, 1.27 Hz, 1H, H_arom), 7.26 (t, J = 4.00 Hz, 1H, H_arom), 7.28–7.36 (m, 3H, H_arom), 7.39–7.46 (m, 2H, H_arom), 7.48–7.52 (m, 2H, H_arom), 7.60–7.66 (m, 2H, H_arom), 7.74–7.80 (m, 2H, H_arom), 7.82 (dd, J = 7.78, 1.60 Hz, 1H, H_arom), 8.27 (d, J = 1.94 Hz, 1H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 39.68 (C_a), 77.44 (C₆), 118.50 (C₄), 122.22 (C₂), 122.28 (C_2′), 122.35 (C_10b), 123.35 (C₇), 123.50 (C₁₀), 125.63 (C_4″), 127.17 (C₈), 128.21 (C_2″,6″), 128.56 (C₉), 128.61 (C₃), 128.70 (C_5′), 129.28 (C_3″,5″), 129.90 (C₁), 131.30 (C_10a), 131.85 (C_6′), 133.83 (C_4′), 134.49 (C_1′), 138.57 (C_6a), 141.41 (C_1″), 149.72 (C_3′), 151.98 (C_4a). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₆H₁₉NO₃: 411.1703; found: 411.1707.

6-(3-fluoro-4-nitrobenzyl)-6H-benzo[c]chromene (5r). Yield: 71%; Mp: 91 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.99 (dd, J = 14.07, 4.47 Hz, 1H, CH₂), 3.25 (dd, J = 14.1, 9.2 Hz, 1H, CH₂), 5.40 (dd, J = 9.21, 4.47 Hz, 1H, CH), 6.92 (dd, J = 8.10, 1.24 Hz, 1H, H_arom), 7.02–7.12 (m, 4H, H_arom), 7.26–7.33 (m, 2H, H_arom), 7.42 (td, J = 7.66, 1.36 Hz, 1H, H_arom), 7.76 (dt, J = 7.75, 1.46 Hz, 2H, H_arom), 7.99 (dd, J = 8.73, 7.69 Hz, 1H, H_arom).

¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.31 (C_a), 77.63 (C₆), 118.31 (C₄), 119.43 (d, J = 20.9 Hz) (C_2′), 122.16 (C₂), 122.56 (d, J = 5.0 Hz) (C₇), 123.32 (C₈), 125.13 (C₉), 125.78 (d, J = 3.8 Hz) (C_5′), 126.09 (d, J = 2.6 Hz) (C_6′), 128.02 (C₁₀), 129.01 (d, J = 2.2 Hz) (C₁), 130.11 (C_10a), 132.94 (C_6a), 147.36 (d, J = 8.4 Hz) (C_4′), 151.80 (C_1′), 155.54 (d, J = 264.9 Hz) (C_3′). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₀H₁₄FNO₃: 353.1296; found: 353.1300.

6-((4′-nitro-[1,1′-biphenyl]-4-yl)methyl)-6H-benzo[c]chromene (5s). Yield: 70%; Mp: 157 °C; ¹H NMR (400 MHz, CDCl₃) δ (ppm) = 2.96 (dd, J = 14.01, 4.88 Hz, 1H, CH₂), 3.25 (dd, J = 14.0, 9.13 Hz, 1H, CH₂), 5.41 (dd, J = 9.1, 4.9 Hz, 1H, CH), 6.97 (dd, J = 8.11, 1.22 Hz, 1H, H_arom), 7.03 (d, J = 7.52 kHz, 1H, H_arom), 7.09 (td, J = 7.51, 1.24 Hz, 1H, H_arom), 7.24–7.32 (m, 4H, H_arom), 7.40 (dt, J = 7.66, 1.29 Hz, 1H, H_arom), 7.57 (d, J = 8.25 Hz, 2H, H_arom), 7.69–7.82 (m, 4H, H_arom), 8.29 (d, J = 8.83 Hz, 2H, H_arom); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) = 41.30 (C_a), 78.71 (C₆), 118.50 (C₄), 122.17 (C₂), 122.41 (C_10b), 122.43 (C₇), 123.23 (C_3″,5″), 124.27 (C₁₀), 125.42 (C_2′,6′), 127.41 (C₈), 127.76 (C₉), 128.59 (C_2″,6″), 129.02 (C_3′,5′), 129.86 (C₁), 130.50 (C_10a), 133.91 (C_4′), 137.06 (C_1′), 138.88 (C_6a), 147.12 (C_4″), 147.57 (C_1″), 152.25 (C_4a). HRMS (ESI): m/z [M+NH₄]⁺ calcd for C₂₆H₁₉NO₃: 411.1703; found: 411.1708.

4. Conclusions

Two new series of 1-(2′-bromo-[1,1′-biaryl]-2-yl)-2-(aryl)ethan-1-ols were synthesized using the TDAE strategy. This method employs TDAE (tetrakis(dimethylamino)ethylene) as a metal-free organic reductant for the initial formation of 1-(2′-bromo-[1,1′-biaryl]-2-yl)-2-(aryl)ethan-1-ols, avoiding the use of stoichiometric metals at this stage. However, the subsequent cyclization step to synthesize 6H-benzo[c]chromenes requires a palladium catalyst (Pd(OAc)₂/PPh₃), introducing a metal-dependent process in the overall synthetic route. In the presence of TDAE, the reactions of 2′-bromo-biaryl-2-carbaldehydes with 4-nitrobenzyl chloride or of substituted benzyl chlorides with 2′-bromo-[1,1′-biphenyl]-2-carbaldehyde gave the corresponding alcohol in 62–93% yields. The obtained alcohol derivatives thus formed were good candidates for the synthesis of 6H-benzo[c]chromenes via an intramolecular cyclization in the presence of Pd(OAc)₂/PPh₃ and Cs₂CO₃ at 110 °C under microwave irradiation for 1.5 h. Regarding the two isomers of compounds 3 and 4 (the “cis-substituted” and “trans-substituted” forms), we demonstrated their interconversion (thermodynamic barrier) under the effect of heat during evaporation. The final step yields compounds 5a–s as racemates.