Design and synthesis of a hybrid framework of indanone and chromane: total synthesis of a homoisoflavanoid, brazilane

Abstract

A chemical backbone of tetracyclic homoisoflavanoid natural products such as brazilin inspired us to design a new chemical scaffold, 6a,11b-dihydroindeno[2,1-c]chromen-7(6H)-one, which is a hybrid structure of indanone and chromane. Pd-catalyzed Suzuki–Miyaura cross-coupling of 4-chloro-2H-chromene-3-carbaldehydes with (hetero)aryl boronic acids was employed as a means to introduce a wide variety of (hetero)aryl groups as the D ring and intramolecular Friedel–Crafts acylation was utilized to construct the C ring of this skeleton. Total synthesis of the natural product, brazilane, was also demonstrated via this new chemical framework.

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Introduction

Biologically active natural products have been a rich source for new drug development for the last several decades.¹ At an early stage of the research, it is critical to evaluate which functional groups in natural products are essential for desired pharmacological effects and to modulate the potency and/or toxicity. For this purpose, strategic design and construction to rapidly realize a number of synthetic analogues in a divergent manner are highly important for structure–activity relationship (SAR) studies in small-molecule drug discovery programs.²

In connection with our interest on homoisoflavanoid natural products (Fig. 1),³ we have developed several synthetic approaches to enable diverse analogues to be synthesized in a highly efficient manner.⁴ Structurally, tetracyclic homoisoflavanoids (1 in Scheme 1) can be viewed as a hybrid structure⁵ of indane and chromane, both of which are bicyclic frameworks embedded in many natural and synthetic products and are known to exhibit a wide variety of interesting biological functions depending on the substitution patterns of these basic cores. Inspired by this scaffold, we came up with a new structural analogue, 6a,11b-dihydroindeno[2,1-c]chromen-7(6H)-one (2), which has not been reported in the literature.⁶ Since it may have some intriguing biological properties as a hybrid molecule of indanone⁷ and chromane,⁸ we decided to develop a flexible synthetic route to this skeleton by which access to a number of analogues is feasible. Retrosynthetically, it was envisioned that the C ring of 2 could be formed via the intramolecular Friedel–Crafts acylation⁹ of 3. We chose the Suzuki–Miyaura cross-coupling reaction¹⁰ of 4 with (hetero)arylboronic acids as a means to introduce diverse D rings. The requisite β-halo-α,β-unsaturated aldehyde 4 could be easily derived from chromanone 5 by the known Vilsmeier–Haack reaction.¹¹

Fig. 1 Some representative homoisoflavanoids.

Scheme 1 Synthetic plan.

Results and discussion

Our approach commenced with the preparation of 4 by using the known procedure (Scheme 2). The Vilsmeier–Haack reaction of 5a–c ¹² provided the corresponding β-chloroenals (4a–c) in good to excellent yields. Although several Suzuki–Miyaura coupling reactions of β-halo-α,β-unsaturated enal systems have been known in the literature,¹³ the use of β-chloro-2H-chromene-3-carbaldehydes (4) as substrates for Suzuki–Miyaura cross-coupling reactions is rare.¹⁴

Scheme 2 Synthesis of β-chloro-2H-chromene-3-carbaldehydes (4).

Initially, we found that the Suzuki–Miyaura coupling of 4 with arylboronic acid in the presence of Pd(PPh₃)₄ and K₃PO₄ in EtOH at room temperature provided the desired β-aryl-α,β-unsaturated aldehyde 6 under mild conditions (Table 1). In some cases, however, yields were poor so coupling reactions were conducted in other catalytic systems where Pd₂dba₃ and SPhos were used as a Pd source and a ligand, respectively. Generally, electron-rich aromatic groups as well as electron-poor aromatic groups were installed in good yields under these conditions. The reactions with heteroarylboronic acids afforded the corresponding adducts in 72–81% yields (entries 15, 16, and 19).

Table 1 Synthesis of diverse 6^a

Entry	4	Conditions	ArB(OH)2	6
a Conditions A: A mixture of 4, arylboronic acid (1.1 equiv.), Pd(PPh3)4 (0.1 equiv.), and K3PO4 (2 equiv.) in EtOH (1 mL) was stirred at rt. Conditions B: A mixture of 4, arylboronic acid (1.1 equiv.), Pd2dba3 (0.05 equiv.), SPhos (0.15 equiv.), and K3PO4 (2 equiv.) in THF (2 mL) was stirred at 100 °C. b Isolated yield (%).
1	4a	A			6a (52)
2	4a	A			6b (47)
3	4a	A			6c (69)
4	4a	A			6d (68)
5	4a	A			6e (66)
6	4a	A			6f (61)
7	4a	B			6g (85)
8	4b	B			6h (88)
9	4b	B			6i (88)
10	4b	B			6j (90)
11	4b	B			6k (92)
12	4b	B			6l (38)
13	4b	B			6m (88)
14	4b	B			6n (80)
15	4b	B			6o (72)
16	4b	B			6p (73)
17	4c	B			6q (80)
18	4c	B			6r (39)
19	4c	B			6s (81)

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Having secured a wide variety of 4-(hetero)aryl-2H-chromene-3-carbaldehydes (6) in hand, we next directed our attention to the elaboration of 6 to 2. Initial attempts including the intramolecular Friedel–Crafts alkylation with 6h under acidic conditions¹⁵ did not yield the desired cyclized product (Scheme 3). After some experimentation, we decided to reduce the olefin bond in 6h first by using catalytic hydrogenation conditions (H₂, 10% Pd/C), which reduced not only the double bond but also aldehyde in 6h to afford alcohol 7 in an 85% yield. The Dess–Martin periodinane oxidation¹⁶ of 7 proceeded smoothly to give 8, with which cyclization efforts in the presence of various acids did not lead to success. Finally, the Kraus–Pinnick oxidation¹⁷ of 8 delivered carboxylic acid which was exposed to POCl₃ at 80 °C (ref. 18) to furnish indanone (2h) in a 55% yield (for two steps).

Scheme 3 Synthesis of 2h.

In the meantime, the conversion of 2h to naturally occurring brazilane was attempted (Scheme 4). The diastereoselective reduction of 2h provided benzylic alcohol 9 which was dehydrated under acidic media to give alkene 10 instead of 10′ as a result of the facile acid-promoted isomerization of 10′ (trisubstituted) to 10 with the more stable double bond (tetrasubstituted and double conjugation with two aromatics). The catalytic hydrogenation of the olefin bond in 10 furnished the trimethyl ether analogue (11) of brazilane.^19,20 Alternatively, the carbonyl group in 2h was removed by the catalytic hydrogenation of 2h to directly deliver 11. Global deprotection with excess BBr₃ provided brazilane in a 64% yield. The spectral data of the synthetic brazilane matched the literature values.

Scheme 4 Total synthesis of brazilane.

In conclusion, a new chemical scaffold based on a hybrid structure of indanone and chromane, a tetracyclic isoflavanoid natural product analogue, was designed and synthesized. Suzuki–Miyaura cross-coupling and intramolecular Friedel–Crafts acylation were employed to construct the D and C rings of this motif, respectively. Further functionalization of this basic skeleton and biological tests of the synthesized compounds are currently in progress.

Experimental section

General methods

Unless specified, all reagents and starting materials were purchased from commercial sources and used as received without purification. “Concentrated” refers to the removal of volatile solvents via distillation using a rotary evaporator. “Dried” refers to pouring onto, or passing through, anhydrous magnesium sulfate followed by filtration. Flash chromatography was performed using silica gel (230–400 mesh) with hexanes, ethyl acetate, and dichloromethane as the eluent. All reactions were monitored by thin-layer chromatography on 0.25 mm silica plates (F-254) visualized with UV light. Melting points were measured using a capillary melting point apparatus. ¹H and ¹³C NMR spectra were recorded on a 400 MHz NMR spectrometer and were described as chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of protons. HRMS were measured with an electrospray ionization (ESI) and Q-TOF mass analyzer.

General procedure for the synthesis of 4

To a stirred solution of 5 (3.91 mmol) in CH₂Cl₂ (13 mL) was dropwise added a pre-mixed solution of POCl₃ (2.19 mL, 23.47 mmol) and DMF (2.26 mL, 29.34 mmol) at 0 °C. After being stirred at 0 °C for 17 h, the reaction mixture was quenched with H₂O (5 mL) at 0 °C and concentrated in vacuo to give the residue. The resulting residue was basified with aq. NaOH solution (pH ∼ 8) and the precipitated solid was filtered and dried to afford 4.

7-(Benzyloxy)-4-chloro-2H-chromene-3-carbaldehyde (4a).
Yellow solid, mp: 78.3–79.9 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.41–7.34 (m, 5H), 6.68 (dd, J = 2.0, 8.8 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 5.09 (s, 2H), 5.00 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 187.6, 164.0, 158.6, 143.8, 136.0, 128.9, 128.5, 128.3, 127.6, 122.3, 114.0, 110.2, 102.4, 70.5, 64.8; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₇H₁₄ClO₃ 301.0626, found 301.0621.

4-Chloro-7-methoxy-2H-chromene-3-carbaldehyde (4b).
Yellow solid, mp: 83.2–85.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.11 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 6.61 (dd, J = 2.4, 8.8 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 5.01 (s, 2H), 3.84 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 187.7, 164.9, 158.7, 143.9, 128.3, 122.2, 113.8, 109.6, 101.5, 64.9, 55.8; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₁H₁₀ClO₃ 225.0313, found 225.0314.

6-(tert-Butyl)-4-chloro-7-methoxy-2H-chromene-3-carbaldehyde (4c).
Yellow solid, mp: 102.1–103.2 °C; ¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 7.57 (s, 1H), 6.43 (s, 1H), 4.99 (s, 2H), 3.87 (s, 3H), 1.37 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 187.6, 163.9, 157.2, 144.8, 133.2, 124.9, 121.7, 112.3, 99.8, 64.8, 55.6, 34.8, 29.8; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₅H₁₈ClO₃ 281.0939, found 281.0932.

General procedure for the synthesis of 6

Conditions A: To a stirred solution of 4 (0.10 mmol) in EtOH (1 mL) were added arylboronic acid (1.1 equiv.), K₃PO₄ (2 equiv.), and Pd(PPh₃)₄ (0.1 equiv.) at rt. After being stirred at rt for 16 h, the reaction mixture was suction-filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 20 : 1 : 2) to give 6.

Conditions B: To a stirred solution of 4 (0.10 mmol) in THF (2 mL) were added arylboronic acid (1.1 equiv.), K₃PO₄ (2 equiv.), Pd₂dba₃ (0.05 equiv.), and SPhos (0.15 equiv.) at rt. After being stirred at 100 °C for 16 h, the reaction mixture was suction-filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 10 : 1 : 2) to give 6.

7-(Benzyloxy)-4-(p-tolyl)-2H-chromene-3-carbaldehyde (6a).
Brown solid, mp: 114.5–116.1 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.41 (s, 1H), 7.41–7.35 (m, 5H), 7.28–7.26 (m, 2H), 7.20 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.07 (s, 2H), 5.06 (s, 2H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.4, 163.0, 158.3, 152.3, 139.4, 136.3, 130.4, 130.2, 130.1, 129.2, 128.8, 128.4, 127.6, 124.0, 117.0, 109.6, 102.5, 70.3, 63.8, 21.5; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₄H₂₁O₃ 357.1485, found 357.1485.

7-(Benzyloxy)-4-(3-(methylthio)phenyl)-2H-chromene-3-carbaldehyde (6b).
Brown solid, mp: 80.9–81.3 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.40 (s, 1H), 7.41–7.33 (m, 7H), 7.15 (s, 1H), 7.07 (d, J = 6.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.57 (s, 1H) 6.52 (d, J = 8.4 Hz, 1H), 5.07 (s, 4H), 2.50 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.0, 163.1, 158.2, 151.5, 139.6, 136.2, 133.9, 130.1, 128.9, 128.8, 128.4, 127.6, 127.4, 126.9, 126.8, 124.2, 116.6, 109.7, 102.6, 70.4, 63.7, 15.6; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₄H₂₁O₃S 389.1206, found 389.1201.

Methyl 4-(7-(benzyloxy)-3-formyl-2H-chromen-4-yl)benzoate (6c).
Yellow solid, mp: 121.3–123.7 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.36 (s, 1H), 8.15 (d, J = 7.2 Hz, 2H), 7.42–7.35 (m, 7H), 6.71 (d, J = 8.8 Hz, 1H), 6.58 (s, 1H), 6.51 (d, J = 8.8 Hz, 1H), 5.08 (s, 4H), 3.97 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 189.6, 166.6, 163.2, 158.2, 150.9, 138.0, 136.1, 131.0, 130.4, 129.9, 129.8, 128.8, 128.4, 127.6, 124.3, 116.3, 109.8, 102.7, 70.4, 63.6, 52.6; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₅H₂₁O₅ 401.1384, found 401.1386.

3-(7-(Benzyloxy)-3-formyl-2H-chromen-4-yl)benzonitrile (6d).
Yellow solid, mp: 172.6–174.3 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.32 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.2 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.41–7.36 (m, 5H), 6.65 (d, J = 8.8 Hz, 1H), 6.59 (s, 1H), 6.54 (d, J = 8.8 Hz, 1H), 5.08 (s, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 188.9, 163.5, 158.3, 149.3, 136.0, 134.8, 134.6, 133.5, 132.9, 129.7, 129.6, 128.9, 128.5, 127.6, 124.7, 118.1, 116.0, 113.3, 110.0, 102.9, 70.5, 63.6; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₄H₁₈NO₃ 368.1281, found 368.1283.

7-(Benzyloxy)-4-(4-nitrophenyl)-2H-chromene-3-carbaldehyde (6e).
Brown solid, mp: 110.1–113.3 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.34 (s, 1H), 8.36 (d, J = 6.8 Hz, 2H), 7.53 (d, J = 6.8 Hz, 2H), 7.40–7.36 (m, 5H), 6.64 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.52 (d, J = 8.8 Hz, 1H), 5.09 (s, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 188.8, 163.5, 158.2, 149.5, 148.5, 140.2, 136.0, 131.3, 129.6, 128.9, 128.5, 127.6, 124.6, 123.9, 115.9, 110.1, 102.9, 70.5, 63.5; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₃H₁₈NO₅ 388.1179, found 388.1180.

7-(Benzyloxy)-4-(4-chlorophenyl)-2H-chromene-3-carbaldehyde (6f).
Yellow solid, mp: 89.2–92.1 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.39 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.42–7.33 (m, 5H), 7.27–7.25 (m, 2H), 6.76 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 2.4, 8.8 Hz, 1H), 5.07 (s, 2H), 5.06 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 189.7, 163.2, 158.3, 150.8, 136.2, 135.6, 131.7, 131.6, 129.9, 129.0, 128.8, 128.4, 127.6, 124.3, 116.5, 109.8, 102.7, 70.4, 63.7; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₃H₁₈ClO₃ 377.0939, found 377.0940.

7-(Benzyloxy)-4-(3,4-dimethoxyphenyl)-2H-chromene-3-carbaldehyde (6g).
Yellow solid, mp: 91.2–93.7 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.46 (s, 1H), 7.41–7.34 (m, 5H), 6.96 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 6.57 (s, 1H), 6.53 (d, J = 8.8 Hz, 1H), 5.08–5.02 (m, 4H), 3.95 (s, 3H), 3.86 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.4, 163.0, 158.4, 152.0, 150.0, 149.0, 136.3, 130.2, 128.8, 128.4, 127.6, 125.5, 124.0, 123.5, 117.0, 113.3, 111.0, 109.6, 102.5, 70.4, 63.9, 56.2, 56.1; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₅H₂₃O₅ 403.1540, found 403.1544.

4-(3,4-Dimethoxyphenyl)-7-methoxy-2H-chromene-3-carbaldehyde (6h).
Yellow solid, mp: 102.5–103.1 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.46 (s, 1H), 6.97–6.88 (m, 3H), 6.80 (s, 1H), 6.50 (s, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.06 (d, J = 30.8 Hz, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.4, 163.9, 158.5, 152.1, 150.0, 148.9, 130.2, 125.6, 123.9, 123.5, 116.8, 113.3, 110.9, 108.9, 101.6, 63.9, 56.2, 56.1, 55.7; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₁₉H₁₈NaO₅ 349.1046, found 349.1049.

7-Methoxy-4-(3-methoxyphenyl)-2H-chromene-3-carbaldehyde (6i).
Yellow solid, mp: 93.9–95.7 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.42 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.01 (dd, J = 2.4, 8.4 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.85–6.82 (m, 2H), 6.49 (d, J = 2.8 Hz, 1H), 6.44 (dd, J = 2.4, 8.8 Hz, 1H), 5.07 (d, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.3, 164.0, 159.6, 158.3, 151.9, 134.6, 130.2, 129.7, 123.9, 122.8, 116.5, 115.8, 114.8, 109.0, 101.6, 63.7, 55.7, 55.5; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₁₈H₁₆NaO₄ 319.0948, found 319.0945.

4-(3,5-Dimethoxyphenyl)-7-methoxy-2H-chromene-3-carbaldehyde (6j).
Orange solid, mp: 100.3–101.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.46 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.55 (t, J = 2.2 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.46–6.43 (m, 3H), 5.06 (s, 2H), 3.81 (m, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 190.2, 163.9, 160.8, 158.2, 151.9, 135.2, 130.1, 123.8, 116.3, 108.9, 108.4, 101.6, 101.1, 63.7, 55.7, 55.6; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₁₉H₁₈NaO₅ 349.1067, found 349.1064.

7-Methoxy-4-(3,4,5-trimethoxyphenyl)-2H-chromene-3-carbaldehyde (6k).
Yellow solid, mp: 130.2–132.5 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.48 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.53 (s, 2H), 6.50–6.46 (m, 2H), 5.06 (s, 2H), 3.93 (s, 3H), 3.85 (s, 6H), 3.83 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.2, 164.0, 158.3, 153.3, 152.0, 138.6, 130.1, 128.7, 123.8, 116.4, 109.0, 107.6, 101.6, 63.7, 61.1, 56.4, 55.7; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₂₀H₂₀NaO₆ 379.1152, found 379.1148.

3-(3-Formyl-7-methoxy-2H-chromen-4-yl)benzonitrile (6l).
Orange solid, mp: 135.6–137.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.65–7.61 (m, 2H), 7.59–7.57 (m, 1H), 6.65 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 2.4, 8.8 Hz, 1H), 5.08 (d, J = 2.8 Hz, 2H), 3.83 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 188.9, 164.4, 158.4, 149.5, 134.8, 134.6, 133.5, 132.9, 129.7, 129.6, 124.6, 118.1, 115.8, 113.3, 109.4, 101.9, 63.6, 55.8; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₁₈H₁₃NNaO₃ 314.0788, found 378.0786.

Methyl 3-(3-formyl-7-methoxy-2H-chromen-4-yl)benzoate (6m).
Yellow solid, mp: 99.3–102.2 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.45 (dd, J = 2.4, 8.4 Hz, 1H), 5.09 (d, J = 1.6 Hz, 2H), 3.94 (s, 3H), 3.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 189.6, 166.5, 164.2, 158.4, 151.0, 134.6, 133.7, 131.3, 130.8, 130.4, 129.9, 128.8, 124.4, 116.3, 109.1, 101.7, 63.7, 55.8, 52.6; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₁₉H₁₆NaO₅ 347.0898, found 347.0897.

4-(4-Acetylphenyl)-7-methoxy-2H-chromene-3-carbaldehyde (6n).
Yellow solid, mp: 119.6–121.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.36 (s, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 2.6, 8.6 Hz, 1H), 5.09 (s, 2H), 3.82 (s, 3H), 2.68 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 197.5, 189.5, 164.2, 158.3, 150.9, 138.2, 137.6, 130.7, 129.8, 128.5, 124.2, 116.1, 109.2, 101.8, 63.6, 55.8, 26.9; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₁₉H₁₆NaO₄ 331.0945, found 331.0941.

4-(Furan-3-yl)-7-methoxy-2H-chromene-3-carbaldehyde (6o).
Yellow solid, mp: 146.4–148.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.69 (s, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 6.53–6.49 (m, 3H), 5.02 (s, 2H), 3.83 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 189.6, 164.0, 158.5, 143.9, 143.5, 143.2, 129.7, 125.1, 117.5, 115.9, 112.7, 109.1, 101.7, 63.7, 55.7; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₁₅H₁₂NaO₄ 279.0630, found 279.0628.

4-(5-Acetylthiophen-2-yl)-7-methoxy-2H-chromene-3-carbaldehyde (6p).
Yellow solid, mp: 129.2–130.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.61 (s, 1H), 7.73 (d, J = 3.6 Hz, 1H), 7.20 (d, J = 3.6 Hz, 1H), 7.02–7.00 (m, 1H), 6.51–6.48 (m, 2H), 5.04 (s, 2H), 3.83 (s, 3H), 2.62 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.5, 188.9, 164.4, 158.2, 146.8, 143.5, 141.4, 132.1, 131.6, 129.6, 126.1, 115.9, 109.4, 101.8, 63.6, 55.8, 27.0; HRMS (ESI-QTOF) m/z [M + Na]⁺ calcd for C₁₇H₁₄NaO₄S 337.0503, found 337.0505.

Methyl 4-(6-(tert-butyl)-3-formyl-7-methoxy-2H-chromen-4-yl)benzoate (6q).
Yellow solid, mp: 122.4–123.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.68 (s, 1H), 6.50 (s, 1H), 5.08 (s, 2H), 3.98 (s, 3H), 3.87 (s, 3H), 1.18 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 189.5, 166.6, 163.1, 156.7, 151.7, 138.2, 132.6, 130.9, 130.5, 129.7, 126.6, 123.7, 114.7, 100.1, 63.6, 55.5, 52.5, 34.6, 29.7; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₃H₂₅O₅ 381.1697, found 381.1696.

4-(4-Acetylphenyl)-6-(tert-butyl)-7-methoxy-2H-chromene-3-carbaldehyde (6r).
Brown solid, mp: 81.3–83.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.68 (s, 1H), 6.50 (s, 1H), 5.08 (s, 2H), 3.87 (s, 3H), 2.69 (s, 3H), 1.18 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 197.6, 189.5, 163.1, 156.8, 151.6, 138.4, 137.6, 132.7, 130.7, 128.4, 126.6, 123.8, 114.6, 100.1, 63.6, 55.5, 34.6, 29.7, 26.9; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₃H₂₅O₄ 365.1747, found 365.1752.

4-(5-Acetylthiophen-2-yl)-6-(tert-butyl)-7-methoxy-2H-chromene-3-carbaldehyde (6s).
Brown solid, mp: 63.2–65.6 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.60 (s, 1H), 7.74 (d, J = 3.6 Hz, 1H), 7.21 (d, J = 4.0 Hz, 1H), 6.99 (s, 1H), 6.49 (s, 1H), 5.03 (s, 2H), 3.87 (s, 3H), 2.63 (s, 3H), 1.24 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 190.6, 188.9, 163.4, 156.7, 146.8, 144.2, 141.7, 132.9, 132.1, 131.7, 126.3, 125.5, 114.4, 100.1, 63.6, 55.5, 34.7, 29.8, 27.0; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₂₁H₂₃O₄S 371.1312, found 371.1317.

(4-(3,4-Dimethoxyphenyl)-7-methoxychroman-3-yl)methanol (7).
A solution of 6h (1091 mg, 3.34 mmol) in ethyl acetate (11 mL) was hydrogenated under H₂ balloon pressure in the presence of Pd–C (10% by weight, 35.58 mg) for 16 h. The reaction mixture was suction-filtered through a pad of Celite and the filtrate was concentrated to give the crude product which was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 10 : 1 : 2 to 5 : 1 : 2) to give 7. White solid, mp: 79.6–80.8 °C; ¹H NMR (400 MHz, CDCl₃) δ 6.85 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.45–6.43 (m, 2H), 4.23–4.19 (m, 2H), 4.08 (t, J = 10.4 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.53–3.48 (m, 1H), 3.40–3.34 (m, 1H), 2.50–2.42 (m, 1H), 1.22 (t, J = 4.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 159.5, 155.6, 148.7, 148.0, 134.7, 131.4, 122.0, 116.5, 113.1, 111.0, 108.0, 101.1, 64.4, 61.7, 56.1, 56.0, 55.4, 42.2, 40.1; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₉H₂₃O₅ 331.1540, found 331.1541.

4-(3,4-Dimethoxyphenyl)-7-methoxychromane-3-carbaldehyde (8).
To a stirred solution of 7 (920 mg, 2.80 mmol) in dry CH₂Cl₂ (10 mL) was added Dess–Martin periodinane (1426 mg, 3.36 mmol) at 0 °C. After being stirred at rt for 4 h, the reaction mixture was suction-filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 10 : 1 : 2 to 5 : 1 : 2) to give compound 8. Yellow solid, mp: 54.9–56.2 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.75 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 6.49–6.47 (m, 2H), 4.65 (d, J = 5.2 Hz, 1H), 4.43 (dd, J = 2.6, 11.4 Hz, 1H), 4.30 (t, J = 10.6 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 6H), 3.19–3.16 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 200.9, 159.9, 155.4, 149.0, 148.4, 133.7, 131.2, 121.8, 115.1, 112.7, 111.2, 108.5, 101.3, 62.1, 56.0, 56.0, 55.5, 50.2, 41.3; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₉H₂₁O₅ 329.1384, found 329.1386.

3,9,10-Trimethoxy-6a,11b-dihydroindeno[2,1-c]chromen-7(6H)-one (2h).
To a stirred solution of 8 (743 mg, 2.26 mmol) in THF (20 mL) were added NaClO₂ (2047 mg, 22.63 mmol), NaH₂PO₄ (3123 mg, 22.63 mmol) in H₂O (10 mL), and 2-methyl-2-butene (5 mL) at rt. After being stirred at rt for 4 h, the reaction mixture was concentrated under reduced pressure and diluted with CH₂Cl₂ (20 mL) and H₂O (20 mL). The water layer was extracted with CH₂Cl₂ (10 mL × 2) two more times. The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give a crude acid. To a solution of the crude acid (30 mg, 0.087 mmol) in CHCl₃ (2 mL) was dropwise added POCl₃ (0.041 mL, 0.44 mmol) at 0 °C. After being stirred at 80 °C for 7 h, the reaction mixture was cooled down to rt, and diluted with CH₂Cl₂ (3 mL) and H₂O (3 mL). The water layer was extracted with CH₂Cl₂ (3 mL × 2) two more times. The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give a crude mixture which was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 10 : 1 : 2 to 5 : 1 : 2) to give 2h. White solid, mp: 147.2–148.1 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.98 (s, 1H), 6.63 (dd, J = 2.4, 8.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 4.61 (dd, J = 2.8, 11.2 Hz, 1H), 4.55 (d, J = 7.6 Hz, 1H), 4.07 (dd, J = 4.6, 11.0 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H), 3.23–3.19 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 215.8, 168.3, 159.5, 156.8, 156.1, 152.2, 129.4, 128.3, 117.5, 109.5, 107.0, 104.2, 103.0, 67.3, 56.4, 56.3, 55.5, 49.6, 37.9; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₉H₁₉O₅ 327.1227, found 327.1225.

3,9,10-Trimethoxy-6,6a,7,11b-tetrahydroindeno[2,1-c]chromen-7-ol (9).
To a solution of 2h (34 mg, 0.104 mmol) in THF/MeOH (1/1, 2 mL) was added NaBH₄ (5.91 mg, 0.156 mmol) at 0 °C. After being stirred at rt for 1 h, the reaction mixture was quenched with sat. NH₄Cl (1 mL) and concentrated under reduced pressure. The residue was diluted with CH₂Cl₂ (3 mL) and H₂O (3 mL). The water layer was extracted with CH₂Cl₂ (3 mL × 2) two more times. The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give 9. White solid, mp: 157.3–158.9 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 6.85 (s, 1H), 6.62 (dd, J = 2.0, 8.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 5.51 (t, J = 7.0 Hz, 1H), 4.37 (dd, J = 4.4, 11.2 Hz, 1H), 4.10 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.86–3.80 (m, 1H), 3.77 (s, 3H), 3.14–3.07 (m, 1H), 2.08 (d, J = 7.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 159.4, 155.8, 149.8, 149.2, 136.4, 134.1, 130.4, 116.0, 108.3, 107.3, 107.0, 102.1, 76.6, 64.5, 56.2, 55.5, 42.5, 40.6; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₉H₂₁O₅ 329.1384, found 329.1386.

3,9,10-Trimethoxy-6,7-dihydroindeno[2,1-c]chromene (10).
To a solution of 9 (10 mg, 0.031 mmol) in acetone (1 mL) was added a drop of 15% HCl solution at rt. After being stirred at 50 °C for 1 h, the reaction mixture was quenched with Et₃N (0.5 mL) at 0 °C and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 10 : 1 : 2) to furnish 10. White solid, mp: 137.9–139.4 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.10 (s, 1H), 6.60 (dd, J = 2.4, 8.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 5.17 (s, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.82 (s, 3H), 3.38 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 160.1, 155.2, 148.2, 147.3, 136.2, 134.4, 133.0, 131.8, 123.5, 114.8, 108.5, 107.0, 104.9, 102.7, 67.4, 56.6, 56.4, 55.5, 37.6; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₉H₁₉O₄ 311.1278, found 311.1273.

3,9,10-Trimethoxy-6,6a,7,11b-tetrahydroindeno[2,1-c]chromene (11).
From 10: A solution of 10 (13 mg, 0.04 mmol) in ethyl acetate/acetone (2 mL, 1/1) was hydrogenated under H₂ balloon pressure in the presence of Pd–C (10% by weight, 1.3 mg) at rt for 2 h. The reaction mixture was suction-filtered through a pad of Celite and the filtrate was concentrated to give the crude product which was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 10 : 1 : 2) to afford 11.

From 2h: A solution of 2h (66 mg, 0.20 mmol) in ethyl acetate (5 mL) was hydrogenated under H₂ balloon pressure in the presence of Pd–C (10% by weight, 2.13 mg) at rt for 16 h. The reaction mixture was suction-filtered through a pad of Celite and the filtrate was concentrated to give the crude product which was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 10 : 1 : 2) to afford 11. White solid, mp: 55.1–56.5 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.76 (s, 1H), 6.60 (dd, J = 2.6, 8.6 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 4.22 (d, J = 6.8 Hz, 1H), 4.12 (dd, J = 4.6, 11.0 Hz, 1H), 3.84 (s, 6H), 3.77 (s, 3H), 3.62 (t, J = 10.6 Hz, 1H), 3.17 (dd, J = 7.2, 15.6 Hz, 1H), 2.95–2.88 (m, 1H), 2.60 (dd, J = 1.8, 15.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 159.2, 155.6, 148.5, 148.3, 137.4, 132.7, 130.8, 116.0, 108.5, 108.1, 108.0, 101.9, 67.0, 56.2, 56.2, 55.4, 43.3, 37.0, 34.1; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₉H₂₁O₄ 313.1434, found 313.1430.

6,6a,7,11b-Tetrahydroindeno[2,1-c]chromene-3,9,10-triol (brazilane).
To a stirred solution of 11 (18 mg, 0.058 mmol) in CH₂Cl₂ (3 mL) was dropwise added BBr₃ (1 M in CH₂Cl₂, 0.29 mL, 0.29 mmol) at −78 °C. After being stirred at −78 °C for 1 h, the reaction mixture was stirred at rt for an additional 1 h. After being quenched with MeOH (3 mL), the mixture was concentrated under reduced pressure and diluted with ethyl acetate (3 mL) and H₂O (3 mL). The water layer was extracted with ethyl acetate (3 mL × 2) two more times. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes/ethyl acetate/dichloromethane = 3 : 1 : 1 to 1 : 1 : 1) to give brazilane. Red solid, mp: 152.1–153.7 °C; ¹H NMR (400 MHz, acetone-d₆) δ 8.16 (s, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H), 6.70 (s, 1H), 6.49 (dd, J = 2.6, 8.2 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 4.10 (d, J = 6.8 Hz, 1H), 4.06 (dd, J = 4.4, 10.8 Hz, 1H), 3.50 (t, J = 10.6 Hz, 1H), 3.05 (dd, J = 7.2, 15.6 Hz, 1H), 2.84–2.79 (m, 1H), 2.52 (dd, J = 2.0, 15.6 Hz, 1H); ¹³C NMR (100 MHz, acetone-d₆) δ 157.5, 156.4, 145.0, 144.7, 137.9, 132.8, 131.8, 116.2, 112.6, 112.3, 109.4, 104.0, 67.2, 43.6, 37.8, 34.2; HRMS (ESI-QTOF) m/z [M + H]⁺ calcd for C₁₆H₁₅O₄ 271.0965, found 271.0971.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2017R1A2A2A05069364).

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra of synthesized compounds. See DOI: 10.1039/c7ob02758c

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