One-Pot Access to 2-Aryl-3-(arylmethyl)chromones

Abstract

Sodium hydroxide controlled intermolecular double aldol condensation of o-hydroxyacetophenones with 2 equivalents of aryl­aldehydes provides 2-aryl-3-(arylmethyl)chromones (a chimera of flavone and homoisoflavanone) in MeOH at 50 °C under mild conditions. The uses of various bases and solvents are investigated for one-pot facile and efficient transformation. A plausible mechanism is proposed.

Key words

aldol condensation - o-hydroxyacetophenones - aryl­aldehydes - chromones - homoisoflavanone - benzopyran-4-one

The structure of a 2-aryl-3-(arylmethyl)chromone, having α-arylmethyl and β-aryl-conjugated groups, is a chimera of flavone and homoisoflavanone. On the basis of the same benzopyran-4-one skeleton (black), both flavone (blue, 2-aryl) and homoisoflavanone (red, 3-arylmethyl) possess an aryl motif and are the key members of benzofused oxacycles (Scheme [1]). They are widely present in natural products and serve as multifunctionalized blocks in synthetic fields.[1] They exhibit diversified bioactive properties, such as antioxidant, anticancer, and antimicrobial activities­.[2] [3]

Scheme 1 Structures of 2-aryl-3-(arylmethyl)chromones

Therefore, a number of attempts to synthesize the skeletons of flavone and homoisoflavanone have been reported via various prepared protocols.[4] [5] Comparing two common core skeletons, however, there are fewer studies on the related synthetic works and pharmaceutical properties of 2-aryl-3-(arylmethyl)chromones. So far, there are three main groups that have demonstrated the unique biological activities of 2-aryl-3-(arylmethyl)chromones. The Bisi group[6a–c] reported that 2-phenyl-3-(imidazolylmethyl)chromones, e.g. 1a, are suitable to serve as flavonoid-based cytochrome P450 (CYP) inhibitors. Lee and co-workers described that 2-pyridyl-3-(pyridylmethyl)chromone 1b is an antioxidant agent.[7a]

On the other hand, two attractive examples of the synthesis of 2-aryl-3-(arylmethyl)chromones with the structural hybrid of flavone and homoisoflavanone were described as follows (Scheme [2]). They included: (1) Lee and co-workers investigated the ruthenium-catalyzed one-pot C–H activation of salicylaldehydes and decarboxylative coupling of alkynoic acids (eq 1),[7a] and (2) Liu and co-workers explored the palladium-catalyzed dehydrogenation of o-acylphenols (eq 2).[7b] They both showed novel transition-metal-promoted routes in the formation of 2-aryl-3-(arylmethyl)chromones. In spite of the advancements however, some problems exist, such as complicated catalytic conditions, lack of broad substrate generality, and prefunctionalized fragments. However, an operationally easy, inexpensive, open-vessel, and high-yield route for the preparation of 2-aryl-3-(arylmethyl)chromones with potential bioactive properties had not been reported until recently. As a result of the recent findings, further investigation of efficient synthetic methods for introducing both 2-aryl and 3-arylmethyl groups into the core scaffold of benzopyran-4-one is still highly desired. Herein, we present a one-pot synthesis of 2-aryl-3-(arylmethyl)chromones 4 via alkali-controlled intermolecular double aldol condensation of substituted o-hydroxyacetophenones 2 with arylaldehydes 3 (2 equiv) under warming alcoholic reaction conditions (eq 3).

Scheme 2 Synthetic routes toward 2-aryl-3-(arylmethyl)chromones

Continuing our synthetic research on the tandem aldol condensation/Michael addition of o-allylbenzaldehydes with different equivalents of substituted acetophenones (1, 2, and 3 equiv) for the preparation of diversified benzannulated molecules,[8] a convenient route for synthesizing 2-aryl-3-(arylmethyl)chromones 4 was explored next. Using equal equivalents of starting materials, aldol condensation of substituted o-hydroxyacetophenones 2 (1 equiv) with arylaldehydes 3 (1 equiv) provided o-hydroxychalcones 5 under alkali-mediated traditional conditions.[9] In particular, when the number of equivalents of arylaldehydes 3 was changed from 1 to 2 equiv, 2-aryl-3-(arylmethyl)chromones 4 displaced the expected o-hydroxychalcones 5 as the domain products in good yields (Scheme [3]). In fact, to the best of our knowledge, so far no examples of the double aldol condensation of acetophenones 2 with arylaldehydes 3 have been reported. On the basis of these observations, initially, we utilized 6-bromopicolinaldehyde (3a) as the starting substrate to screen the reaction conditions since the bromo group could introduce a variety of functionalized groups by transition-metal cross-coupling, and the pyridyl ring could perform as a specific pharmacophore.[10]

Scheme 3 Alkali-mediated condensation of 2 and 3

The study commenced with the treatment of model substrates 2a (Ar = Ph, 1.0 mmol) and 6-bromopicolinaldehyde (3a, 2 equiv) in the presence of NaOH (2 equiv) in MeOH (30 mL) at 25 °C for 10 h (Table [1], entry 1). Under these reaction conditions, only trace amounts (8%) of 4a were observed. Then, by controlling the temperature at 25 °C and increasing the time to 20, 30, and 40 h, 4a was still isolated in low yields (14%, 16%, 15%, entries 2–4). Next, elevating the temperature to 50 °C and controlling the time at 10 h, the yield of 4a was increased to 86% (entry 5). After increasing the time from 10 to 20 h, the yield (80%) of 4a decreased slightly (entry 6). From the results, we found that temperature is a more important factor than time when affecting the formation of 4a. To obtain better yields, we wanted to increase the temperature to reflux (65 °C), but this reflux condition provided a 71% yield of 4a (entry 7). Furthermore, adjusting the reaction concentrations (0.033 → 0.10, 0.02 M) was examined. We found that concentrated solution (0.1 M) provided 4a in a 25% yield along with major complex unknown products (entry 8). On the other hand, the diluted solution (0.02 M) could maintain the yield at 79% (entry 9). From the phenomenon, we understood that the factor of reaction concentration also affected the yield. Three alkalis with different basicity levels were examined next. Entries 10 and 11 show that no better yields were detected using LiOH and KOH (65% and 78%), respectively. Using K₂CO₃, the desired 4a could not be generated (entry 12). By controlling the combination of 50 °C and 10 h, the solvent was adjusted from MeOH to EtOH, however only a 58% yield of 4a was formed (entry 13). After elevating the temperature from 50 °C to 70 °C, the yield was still maintained at 68% (entry 14). Entries 15 and 16 show that iPrOH and tBuOH did not give better yields (37% and 12%) than MeOH (86%). By using H₂O as the solvent, no reaction was observed due to the poor solubility (entry 17). In entries 18 and 19, attempts to increase the number of equivalents (2 → 3 or 4) failed to afford higher yields (82% or 75%). Then, 1 equivalent of NaOH was tested, and only a 45% yield of 4a was detected (entry 20). From our observations, we concluded that NaOH was the optimal alkali to yield 4a under warming methanolic reaction conditions via one-pot facile intermolecular double condensation of 2a and 3a.

Table 1 Reaction Conditions^a

Entry	Alkali	Solvent (mL)	Temp (°C)	Time (h)	Yieldb (%)
1	NaOH	MeOH (30)	25	10	8
2	NaOH	MeOH (30)	25	20	14
3	NaOH	MeOH (30)	25	30	16
4	NaOH	MeOH (30)	25	40	15
5	NaOH	MeOH (30)	50	10	86
6	NaOH	MeOH (30)	50	20	80
7	NaOH	MeOH (30)	reflux (65)	10	71
8	NaOH	MeOH (10)	50	10	25c
9	NaOH	MeOH (50)	50	10	79
10	LiOH	MeOH (30)	50	10	65
11	KOH	MeOH (30)	50	10	78
12	K2CO3	MeOH (30)	50	10	–d
13	NaOH	EtOH (30)	50	10	71
14	NaOH	EtOH (30)	70	10	68
15	NaOH	iPrOH (30)	50	10	37
16	NaOH	tBuOH (30)	50	10	12
17	NaOH	H2O (30)	50	10	–d
18	NaOHe	MeOH (30)	50	10	82
19	NaOHf	MeOH (30)	50	10	75
20	NaOHg	MeOH (30)	50	10	45

^a Reaction conditions: 2a (1.0 mmol), 3a (2 equiv), alkali (2 equiv).

^b Isolated yields of 4a.

^c Unknown mixture was isolated.

^d No product detected.

^e 3 equiv.

^f 4 equiv.

^g 1 equiv.

Table 2 Synthesis of 4a–4ab ^a

Entry	2 b Ar	3 c Ar′	Yield (%)d
1	2a, Ph	3a, 6-Br-2-pyridyl	4a, 86
2	2b, 4-FC6H3	3a, 6-Br-2-pyridyl	4b, 86
3	2c, 4-ClC6H3	3a, 6-Br-2-pyridyl	4c, 83
4	2d, 4-BrC6H3	3a, 6-Br-2-pyridyl	4d, 80
5	2e, 1-naphthyle	3a, 6-Br-2-pyridyl	4e, 76
6	2f, 5-MeOC6H3	3a, 6-Br-2-pyridyl	4f, 72
7	2g, 4-MeOC6H3	3a, 6-Br-2-pyridyl	4g, 80
8	2h, 3-MeOC6H3	3a, 6-Br-2-pyridyl	4h, 70
9	2i, 5-BuOC6H3	3a, 6-Br-2-pyridyl	4i, 83
10	2j, 4-BuOC6H3	3a, 6-Br-2-pyridyl	4j, 80
11	2k, 3-BuOC6H3	3a, 6-Br-2-pyridyl	4k, 64
12	2l, 5-BnOC6H3	3a, 6-Br-2-pyridyl	4l, 80
13	2m, 4-BnOC6H3	3a, 6-Br-2-pyridyl	4m, 73
14	2n, 3-BnOC6H3	3a, 6-Br-2-pyridyl	4n, 70
15	2o, 4,6-Cl2C6H2	3a, 6-Br-2-pyridyl	4o, 78
16	2p, 4,6-F2C6H2	3a, 6-Br-2-pyridyl	4p, 80
17	2q, 4-MeC6H3	3a, 6-Br-2-pyridyl	4q, 83
18	2r, 2-naphthylf	3a, 6-Br-2-pyridyl	4r, 67
19	2s, 4-PhC6H3	3a, 6-Br-2-pyridyl	4s, 80
20	2t, 4-(4-FC6H4)C6H3	3a, 6-Br-2-pyridyl	4t, 78
21	2u, 4-(4-MeOC6H4)C6H3	3a, 6-Br-2-pyridyl	4u, 78
22	2v, 4-(2-naphthyl)C6H3	3a, 6-Br-2-pyridyl	4v, 76
23	2w, 4-(4-PhC6H4)C6H3	3a, 6-Br-2-pyridyl	4w, 74
24	2a, Ph	3b, 2-pyridyl	4x, 70
25	2a, Ph	3c, 5-F-2-pyridyl	4y, 74
26	2a, Ph	3d, 6-Cl-2-pyridyl	4z, 74
27	2a, Ph	3e, 6-Me-2-pyridyl	4aa, 80
28	2a, Ph	3f, 6-MeO-2-pyridyl	4ab, 78

^a Reaction conditions: 2a–2w (1.0 mmol) 3a–3f (2 equiv), NaOH (80 mg, 2 equiv), MeOH (30 mL), 50 °C, 10 h.

^b Ar is the substituted arene ring in 2-formylaren-1-ol (numbering shown).

^c Ar′ is the substituted pyridine ring in 2-formylpyridine (numbering shown).

^d Isolated yields.

^e Substrate was 1-hydroxynaphthalene-2-carbaldehyde.

^f Substrate was 2-hydroxynaphthalene-1-carbaldehyde.

On the basis of our experimental results, a plausible mechanism for the formation of 4a is illustrated in Scheme [4]. Initially, NaOH (2 equiv) mediated deprotonation of 2a provided a dianion intermediate. Following, in situ formed α-carbanion which attacked the carbonyl group of 3a to lead to A. Then, an intramolecular proton exchange of A with two oxyanions yielded B. By the involvement of another 3a, B was converted into C via a second intermolecular aldol reaction. Subsequently, D having the delocalized α-carbanion, was generated again by the repeated intramolecular proton exchange of C. After releasing the hydroxide ion on D, E with a conjugated enone moiety was formed. Furthermore, the oxyanion promoted the oxy-Michael reaction to the enone moiety followed by elimination of another hydroxide ion, and afforded (E)- or (Z)-homoisoflavone skeleton F via an intramolecular ring-closure process. Finally, 1,3-hydride migration on F from trisubstituted exo-olefin to tetrasubstituted endo-olefin furnished the construction of 4a. On the other pathway, removal of the hydroxyl group of B provided G with a chalcone group. By intramolecular oxa-Michael annulation of G followed by intermolecular aldol condensation of the resulting H with 3a, F was achieved. Based on the above-mentioned procedure, 4a was constructed. From the possible mechanism, we found that NaOH efficiently organized the continuous sequence of intermolecular aldol reactions and intramolecular ring-closures­.

Scheme 4 Plausible mechanism

To study the scope and limitations of this approach, substituted o-hydroxyacetophenones 2a–2w and 2-formylpyridines 3a–3f were reacted with NaOH (2 equiv) to afford diversified 2-aryl-3-(arylmethyl)chromones 4a–4ab under warming methanol (50 °C/10 h) conditions, as shown in Table [2]. With optimal conditions established (Table [1], entry 5) and a plausible mechanism proposed (Scheme [4]), we found that this route allowed direct double aldol condensation in moderate to good yields (64–86%). Among entries 1–28, efficient formation of 4a–4ab showed that the two aryl substituents (2, Ar and 3, Ar′) did not affect the yields. The structures of 4a–4d, 4g, 4t, and 4z were determined by single-crystal X-ray crystallography.[11] For the electronic nature of aryl substituents (Ar) of 2, not only haloaryl (bromo, chloro, dichloro) groups but also electron-neutral (methyl), electron-withdrawing (fluoro, difluoro) and electron-donating­ (methoxy, butoxy, benzyloxy) groups were appropriate. For the pyridyl substituents (Ar′) of 3, 6-bromo, 5-fluoro, 6-methyl, 6-chloro, and 6-methoxy groups were well-tolerated. Based on the results, after replacing the pyridyl group of 3a–3f with benzaldehyde (3g) and 2-naphthaldehyde (3h), synthesis of 4ac–4ad was examined next (Scheme [5]). However, the desired 4ac and 4ad were formed in 43% and 36% yields, respectively. Next, when the monocyclic 2-formyl-heteroarenes were changed from 2-formylpyridines 3a–3f to 1-allyl-2-formyl-1H-pyrrole (3i), 2-formylfuran (3j), 2-formylthiophene (3k), and 3-formylpyridine (3l), 4af and 4ag were produced with moderate results (58% and 60% yields); surprisingly, the desired 4ae could be not isolated. The structure of 4ag was determined by single-crystal X-ray crystallography.[11] In particular, 4ah was provided in only a 27% yield. Then, changing to bicyclic 2-formylbenzofuran (3m), 2-formylbenzothiophene (3n), and 3-formyl-1-methyl-1H-indole (3o), 4ai and 4aj were obtained in 64%, and 63% yields, respectively. However, the desired 4ak could be not isolated, and only 15% yield of chalcone 4ak-1 was obtained. Furthermore, 2-formylquinoline (3p) produced 63% yield of 4al.

Scheme 5 Synthesis of 4ac–4al and 4ak–1; ND = not detected

From the results, we understand that hetero-mono­cyclic 2-azaarenes could produce better yields than benzaldehyde and naphthaldehyde, especially with substituted 2-formylpyridines. The putative explanations for the differences are that the aggregated intermediate adopts a bidentate coordination of the sodium ion by the nitrogen lone-pair of 2-formylpyridine and the alkoxy anion such that this resulting complexation would necessitate the intermediate to coordinate with the second equivalent of 2-formyl­pyridine via the aldol reaction process.[12]

To elongate the side arm on the pyridyl ring of 4a, Suzuki–Miyaura coupling of 4a with 3,4-dimethoxyphenylboronic acid provided 4am in a 75% yield along with a 10% yield of 4am-1, as shown in Scheme [6]. With the results, we envisioned that different aryl substituents could be installed into the 6-position of pyridine ring on 4a to afford diversified aryl-pyridyl-conjugated homoisoflavanones.

Scheme 6 Suzuki–Miyaura coupling of 4a

On the other hand, a macrocyclic isoflavanone was examined (Scheme [7]). Under the above conditions, a one-pot NaOH-controlled reaction of 2a and 3q with the o-allyl side chain provided flavone 4an in a 40% yield. In particular, no desired homoisoflavanone was detected. The possible reason should be that the o-allyl group on 3q exhibited a bulkier steric hindrance such that the second aldol condensation could not be generated. For the formation of 4an, we thought that in situ generated I could trap molecular oxygen­ (from air) to lead II. Following, by the peroxyanion-mediated intramolecular deprotonation of II, 4an was accomplished.

Scheme 7 Synthesis of 4an

In summary, we have developed an NaOH-controlled synthesis of 2-aryl-3-(arylmethyl)chromones via intermolecular double aldol condensation of o-hydroxyacetophenones with 2 equivalents of an arylaldehyde under warming MeOH reaction conditions in moderate to good yields. The process provides a cascade pathway of C–C and then, C–O bond formations. The uses of various bases and solvents are investigated for one-pot facile and efficient transformation. Related plausible mechanisms have been proposed. The structures of the key products were confirmed by X-ray crystallography. Further investigations regarding the synthetic applications of o-hydroxyacetophenones will be conducted and published in due course.

All reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry air with magnetic stirring. The heating mantle is used to provide a stable heat source. Products in organic solvents were dried with anhydrous MgSO₄ before concentration in vacuo. Melting points were determined with a SMP3 melting apparatus. ¹H and ¹³C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 400 and at 100 MHz, respectively. HRMS were measured with a mass spectrometer Finnigan/Thermo Quest MAT 95XL. X-ray crystal structures were obtained with an Enraf-Nonius FR-590 diffractometer (CAD4, Kappa CCD).

For the starting compounds 2a–2w and 3a–3r, these reagents were obtained from commercial sources and used without further purification.

2-Aryl-3-(arylmethyl)chromen-4-ones 4a–4ad, 4af–4aj, 4ak-1, and 4al; General Procedure

NaOH (80 mg, 2.0 mmol) was added to a solution of 2a–2w (1.0 mmol) in MeOH (30 mL) at 25 °C. The mixture was stirred at 25 °C for 10 min. Arylaldehyde 3a–3p (2.0 mmol) was added to the mixture at 25 °C and it was stirred at 50 °C for 10 h. The mixture was cooled to 25 °C and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried (MgSO₄), filtered and evaporated to afford crude product under reduced pressure. The remaining mixture was separated by column chromatography (silica gel, hexanes/EtOAc 20:1–3:1) affording the title compounds.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-chromen-4-one (4a)

Colorless solid; yield: 404 mg (86%); mp 179–180 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.21 (dd, J = 8.0, 1.6 Hz, 1 H), 8.06 (dd, J = 8.0, 0.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.69 (dd, J = 8.8, 2.0 Hz, 1 H), 7.56 (dd, J = 8.0, 0.8 Hz, 1 H), 7.51 (dd, J = 8.8, 0.8 Hz, 1 H), 7.42 (dt, J = 8.0, 1.2 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.23 (dd, J = 8.0, 0.4 Hz, 1 H), 7.21 (dd, J = 8.0, 0.4 Hz, 1 H), 4.32 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.2, 161.2, 158.4, 155.8, 152.1, 141.4, 141.0, 138.9, 138.8, 134.0, 129.3, 126.0, 125.2, 125.2, 123.2, 122.8, 121.8, 120.4, 118.1, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₃Br₂N₂O₂: 470.9344; found: 470.9338.

Single-crystal X-ray diagram: crystal of compound 4a was grown by slow diffusion of EtOAc into a solution of compound 4a in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group Pbca, a = 11.6446(3) Å, b = 14.7976(4) Å, c = 19.6780(6) Å, V = 3390.76(16) ų, Z = 8, d _calcd = 1.850 g/cm³, F(000) = 1856, 2θ range 2.070–26.456°, R indices (all data) R1 = 0.0233, wR2 = 0.0499.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-fluorochromen-4-one (4b)

Colorless solid; yield: 420 mg (86%); mp 190–191 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.05 (d, J = 7.2 Hz, 1 H), 7.81 (dd, J = 8.0, 3.2 Hz, 1 H), 7.71 (t, J = 8.0 Hz, 1 H), 7.55 (dd, J = 8.0, 0.8 Hz, 1 H), 7.51 (dd, J = 9.2, 4.0 Hz, 1 H), 7.43–7.36 (m, 2 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 4.31 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.5 (d, J = 2.3 Hz), 160.9, 159.5 (d, J = 245.6 Hz), 158.2, 152.0 (d, J = 1.5 Hz), 151.8, 141.4, 141.0, 139.0, 138.5, 129.4, 125.3, 123.8 (d, J = 8.6 Hz), 123.3, 122.2 (d, J = 25.7 Hz), 121.9, 120.3 (d, J = 7.6 Hz), 119.8, 110.7 (d, J = 23.5 Hz), 32.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₂Br₂FN₂O₂: 488.9250; found: 488.9244.

Single-crystal X-ray diagram: crystal of compound 4b was grown by slow diffusion of EtOAc into a solution of compound 4b in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P2 ₁ /c, a = 14.5142(8) Å, b = 19.8390(9) Å, c = 12.2505(6) Å, V = 3521.0(3) ų, Z = 4, d _calcd = 1.849 g/cm³, F(000) = 1920, 2θ range 1.406–26.451°, R indices (all data) R1 = 0.0658, wR2 = 0.01105.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-chlorochromen-4-one (4c)

Colorless solid; yield: 418 mg (83%); mp 188–189 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.15 (d, J = 2.8 Hz, 1 H), 8.06 (dd, J = 8.0, 0.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.62 (dd, J = 8.8, 2.8 Hz, 1 H), 7.56 (dd, J = 8.0, 0.8 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 1 H), 4.31 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.1, 160.8, 158.6, 154.1, 151.8, 141.4, 141.1, 139.0, 138.5, 134.2, 131.1, 129.5, 125.4, 125.3, 123.7, 123.3, 122.0, 120.6, 119.9, 32.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₂Br₂ClN₂O₂: 504.8954; found: 504.8950.

Single-crystal X-ray diagram: crystal of compound 4c was grown by slow diffusion of EtOAc into a solution of compound 4c in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P 1, a = 7.5481(3) Å, b = 10.3357(4) Å, c = 13.1031(5) Å, V = 896.64(6) ų, Z = 2, d _calcd = 1.876 g/cm³, F(000) = 496, 2θ range 1.682–26.413°, R indices (all data) R1 = 0.0208, wR2 = 0.0475.

6-Bromo-2-(6-bromopyridin-2-yl)-3-(6-bromopyridin-2-yl­methyl)chromen-4-one (4d)

Colorless solid; yield: 438 mg (80%); mp 175–176 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.33 (d, J = 2.4 Hz, 1 H), 8.08 (dd, J = 7.6, 0.8 Hz, 1 H), 7.77 (dd, J = 8.8, 2.4 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.58 (dd, J = 8.0, 0.4 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 4.30 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 176.9, 160.8, 158.6, 154.6, 151.8, 141.5, 141.1, 139.0, 138.5, 136.9, 129.5, 128.6, 125.4, 124.1, 123.4, 122.0, 120.7, 120.1, 118.6, 32.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₂Br₃N₂O₂: 548.8449; found: 548.8446.

Single-crystal X-ray diagram: crystal of compound 4d was grown by slow diffusion of EtOAc into a solution of compound 4d in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P 1, a = 7.5768(5) Å, b = 10.4119(7) Å, c = 13.2517(9) Å, V = 915.93(11) ų, Z = 2, d _calcd = 1.998 g/cm³, F(000) = 532, 2θ range 1.666–26.479°, R indices (all data) R1 = 0.0292, wR2 = 0.0593.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-benzo­[h]chromen-4-one (4e)

Colorless solid; yield: 395 mg (76%); mp 223–224 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.50 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.81–7.65 (m, 4 H), 7.60 (dd, J = 8.0, 0.4 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 4.44 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.9, 161.2, 157.7, 152.2, 141.5, 141.1, 139.1, 138.5, 138.7, 136.0, 129.4, 129.3, 128.2, 127.2, 125.5, 125.2, 123.9, 123.2, 122.4, 121.90, 121.88, 121.0, 119.2, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₄H₁₅Br₂N₂O₂: 520.9500; found: 520.9496.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-7-methoxy­chromen-4-one (4f)

Colorless solid; yield: 360 mg (72%); mp 198–199 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.12 (d, J = 8.8 Hz, 1 H), 8.07 (dd, J = 7.6, 0.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.56 (dd, J = 8.0, 0.8 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.25 (d, J = 8.8 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 6.98 (dd, J = 8.8, 2.4 Hz, 1 H), 6.91 (d, J = 2.0 Hz, 1 H), 4.28 (s, 2 H), 3.91 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.4, 164.4, 161.3, 158.1, 147.7, 152.2, 141.5, 141.0, 138.9, 138.5, 129.3, 127.4, 125.2, 123.3, 121.9, 120.3, 116.9, 114.9, 100.1, 55.9, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₁H₁₅Br₂N₂O₃: 500.9450; found: 500.9444.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-methoxy­chromen-4-one (4g)

Colorless solid; yield: 400 mg (80%); mp 177–178 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 7.6 Hz, 1 H), 7.68 (t, J = 7.6 Hz, 1 H), 7.52–7.50 (m, 2 H), 7.41 (d, J = 9.2 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.25 (dd, J = 8.8, 2.8 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 2 H), 4.32 (s, 2 H), 3.84 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.9, 161.3, 158.0, 156.9, 152.0, 150.6, 141.2, 140.9, 138.9, 138.4, 129.2, 125.1, 124.1, 123.2, 123.1, 121.7, 119.50, 119.45, 104.7, 55.8, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₁H₁₅Br₂N₂O₃: 500.9450; found: 500.9444.

Single-crystal X-ray diagram: crystal of compound 4g was grown by slow diffusion of EtOAc into a solution of compound 4g in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P21/c, a = 4.4683(4) Å, b = 22.3901(19) Å, c = 18.7910(16) Å, V = 1879.6(3) ų, Z = 4, d _calcd = 1.774 g/cm³, F(000) = 992, 2θ range 1.415–26.411°, R indices (all data) R1 = 0.0443, wR2 = 0.0972.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-5-methoxy­chromen-4-one (4h)

Colorless solid; yield: 350 mg (70%); mp 187–188 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 7.6 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.07 (dd, J = 8.4, 0.8 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 1 H), 4.23 (s, 2 H), 3.97 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.7, 161.4, 159.8, 157.9, 156.8, 152.0, 141.4, 140.9, 138.9, 138.5, 134.0, 129.2, 125.1, 123.3, 122.1, 121.5, 113.6, 110.1, 106.2, 56.4, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₁H₁₅Br₂N₂O₃: 500.9450; found: 500.9445.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-7-butoxy­chromen-4-one (4i)

Colorless solid; yield: 450 mg (83%); mp 140–141 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 9.2 Hz, 1 H), 8.06 (dd, J = 8.0, 0.8 Hz, 1 H), 7.71 (t, J = 8.0 Hz, 1 H), 7.56 (dd, J = 8.0, 0.8 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.24 (t, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 6.97 (dd, J = 8.8, 2.4 Hz, 1 H), 6.89 (d, J = 2.4 Hz, 1 H), 4.28 (s, 2 H), 4.05 (t, J = 6.4 Hz, 2 H), 1.86–1.79 (m, 2 H), 1.56–1.49 (m, 2 H), 0.99 (t, J = 7.6 Hz, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.4, 163.9, 161.4, 158.1, 157.7, 152.2, 141.4, 141.0, 138.9, 138.5, 129.2, 127.3, 125.2, 123.3, 121.9, 120.3, 116.7, 115.3, 100.5, 68.5, 32.9, 31.0, 19.2, 13.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₄H₂₁Br₂N₂O₃: 542.9919; found: 542.9916.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-butoxy­chromen-4-one (4j)

Colorless solid; yield: 434 mg (80%); mp 124–125 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.05 (d, J = 8.4 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.56 (d, J = 8.8 Hz, 1 H), 7.55 (s, 1 H), 7.45 (d, J = 9.2 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.29 (dd, J = 9.2, 3.2 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), 4.32 (s, 2 H), 4.05 (t, J = 6.4 Hz, 2 H), 1.83–1.76 (m, 2 H), 1.55–1.45 (m, 2 H), 0.98 (t, J = 7.6 Hz, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.1, 161.4, 158.2, 156.6, 152.3, 150.6, 141.4, 141.0, 139.9, 138.5, 129.3, 125.2, 124.6, 123.4, 123.3, 121.8, 119.6, 119.5, 106.5, 68.4, 33.0, 31.1, 19.2, 13.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₄H₂₁Br₂N₂O₃: 542.9919; found: 542.9916.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-5-butoxy­chromen-4-one (4k)

Colorless solid; yield: 347 mg (64%); mp 170–171 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.4 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 6.80 (d, J = 8.4 Hz, 1 H), 4.29 (s, 2 H), 4.10 (t, J = 6.4 Hz, 2 H), 1.95–1.88 (m, 2 H), 1.60–1.50 (m, 2 H), 0.98 (t, J = 7.6 Hz, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.4, 161.6, 159.4, 157.8, 156.4, 152.1, 141.3, 140.9, 138.8, 138.4, 133.9, 129.1, 125.0, 123.0, 121.8, 121.3, 113.8, 109.7, 107.3, 69.3, 32.7, 31.0, 19.2, 13.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₄H₂₁Br₂N₂O₃: 542.9919; found: 542.9915.

7-Benzyloxy-2-(6-bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)chromen-4-one (4l)

Colorless solid; yield: 461 mg (80%); mp 216–217 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 9.2 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 7.71 (t, J = 8.0 Hz, 1 H), 7.56 (dd, J = 8.0, 0.8 Hz, 1 H), 7.46–7.34 (m, 6 H), 7.24 (d, J = 7.6 Hz, 2 H), 7.06 (dd, J = 8.8, 2.4 Hz, 1 H), 6.98 (d, J = 2.4 Hz, 1 H), 5.17 (s, 2 H), 4.28 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.4, 163.4, 161.3, 158.2, 157.6, 152.1, 141.4, 141.0, 138.9, 138.5, 135.6, 129.3, 128.8 (2 ×), 128.4, 127.52, 127.47 (2 ×), 125.2, 123.3, 121.9, 120.4, 117.0, 115.4, 101.1, 70.5, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₇H₁₉Br₂N₂O₃: 576.9763; found: 576.9757.

6-Benzyloxy-2-(6-bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)chromen-4-one (4m)

Colorless solid; yield: 420 mg (73%); mp 184–185 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.05 (dd, J = 7.6, 0.4 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.68 (d, J = 2.8 Hz, 1 H), 7.56 (dd, J = 8.0, 0.8 Hz, 1 H), 7.48–7.34 (m, 8 H), 7.24 (d, J = 7.6 Hz, 2 H), 5.14 (s, 2 H), 4.33 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.0, 161.3, 158.3, 156.1, 152.2, 150.8, 141.4, 141.0, 138.9, 138.5, 136.2, 129.3, 128.6 (2 ×), 128.2, 127.7 (2 ×), 125.2, 124.7, 123.4, 123.3, 121.8, 119.7, 119.6, 106.1, 70.6, 33.0.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₇H₁₉Br₂N₂O₃: 576.9763; found: 576.9757.

5-Benzyloxy-2-(6-bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)chromen-4-one (4n)

Colorless solid; yield: 403 mg (70%); mp 203–204 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.03 (dd, J = 7.6, 0.4 Hz, 1 H), 7.70 (t, J = 8.0 Hz, 1 H), 7.57–7.53 (m, 3 H), 7.51 (t, J = 8.0 Hz, 1 H), 7.40–7.36 (m, 3 H), 7.29 (t, J = 7.2 Hz, 1 H), 7.23 (dt, J = 8.0, 0.4 Hz, 1 H), 7.07 (dd, J = 8.4, 0.4 Hz, 2 H), 6.83 (d, J = 8.0 Hz, 1 H), 5.30 (s, 2 H), 4.32 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.4, 161.5, 158.6, 157.9, 156.5, 152.1, 141.4, 140.9, 138.9, 138.5, 136.4, 133.8, 129.2, 128.6 (2 ×), 127.7, 126.7 (2 ×), 125.1, 123.1, 121.9, 121.5, 114.2, 110.4, 108.4, 70.9, 32.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₇H₁₉Br₂N₂O₃: 576.9763; found: 576.9758.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6,8-dichlorochromen-4-one (4o)

Colorless solid; yield: 420 mg (78%); mp 216–217 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.13 (dd, J = 7.6, 0.8 Hz, 1 H), 8.11 (d, J = 2.4 Hz, 1 H), 7.76 (t, J = 8.0 Hz, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.57 (dd, J = 8.0, 0.8 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.20 (dd, J = 7.6, 0.8 Hz, 1 H), 4.51 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 176.7, 160.7, 157.8, 151.7, 150.1, 141.22, 141.16, 139.2, 138.4, 134.0, 130.9, 129.7, 125.3, 124.4, 124.3, 124.2, 123.1, 121.7, 121.1, 32.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₁Br₂Cl₂N₂O₂: 538.8564; found: 538.8560.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6,8-difluorochromen-4-one (4p)

Colorless solid; yield: 405 mg (80%); mp 155–156 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.09 (dd, J = 7.6, 0.8 Hz, 1 H), 7.74 (t, J = 8.0 Hz, 1 H), 7.65 (dt, J = 8.0, 2.8 Hz, 1 H), 7.57 (dd, J = 8.0, 0.8 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.27 (dt, J = 8.0, 2.8 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 2 H), 4.41 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 176.5 (t, J = 3.1 Hz), 160.6, 158.3 (dd, J = 9.8, 247.9 Hz), 158.0, 151.6, 151.4 (dd, J = 11.4, 256.2 Hz), 141.4 (d, J = 2.3 Hz), 141.3, 141.1, 139.1, 138.5, 129.7, 125.3, 124.8 (d, J = 8.3 Hz), 123.2, 121.8, 120.6, 109.3 (dd, J = 20.5, 28.8 Hz), 106.2 (dd, J = 4.6, 23.5 Hz), 32.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₁Br₂F₂N₂O₂: 506.9155; found: 506.9151.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-methylchromen-4-one (4q)

Colorless solid; yield: 402 mg (83%); mp 163–164 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.02 (d, J = 7.6 Hz, 1 H), 7.97 (t, J = 0.4 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.49 (dd, J = 8.4, 2.0 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 4.32 (s, 2 H), 2.43 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.2, 161.3, 158.2, 154.1, 152.1, 141.3, 141.0, 138.9, 138.4, 135.23, 135.20, 129.2, 125.2, 125.1, 123.2, 122.4, 121.7, 120.2, 117.8, 32.9, 20.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₁H₁₅Br₂N₂O₂: 484.9500; found: 484.9493.

3-(6-Bromopyridin-2-yl)-2-(6-bromopyridin-2-ylmethyl)-benzo­[f]chromen-1-one (4r)

Colorless solid; yield: 348 mg (67%); mp 177–178 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 10.03 (d, J = 8.0 Hz, 1 H), 8.14 (dd, J = 8.4, 0.8 Hz, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.75 (t, J = 8.0 Hz, 1 H), 7.74 (t, J = 8.0 Hz, 1 H), 7.63 (dt, J = 8.0, 1.2 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 1 H), 7.58 (dd, J = 7.6, 0.8 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 1 H), 4.42 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 179.5, 161.4, 157.1, 156.3, 152.0, 141.5, 141.1, 139.0, 138.6, 135.9, 130.6, 130.4, 129.4, 129.3, 128.3, 127.1, 126.7, 125.2, 123.3, 123.0, 121.8, 117.6, 116.2, 33.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₄H₁₅Br₂N₂O₂: 520.9500; found: 520.9495.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-phenylchromen-4-one (4s)

Colorless solid; yield: 437 mg (80%); mp 174–175 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.43 (d, J = 2.4 Hz, 1 H), 8.09 (dd, J = 7.6, 0.8 Hz, 1 H), 7.94 (dd, J = 8.4, 2.4 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.67–7.64 (m, 2 H), 7.583 (t, J = 8.0 Hz, 1 H), 7.580 (t, J = 8.0 Hz, 1 H), 7.48–7.44 (m, 2 H), 7.42–7.36 (m, 2 H), 7.26 (d, J = 8.4 Hz, 1 H), 7.24 (dd, J = 8.0, 0.4 Hz, 1 H), 4.36 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.2, 161.2, 158.4, 155.3, 152.1, 141.4, 141.1, 139.2, 139.0, 138.5, 138.4, 132.9, 129.4, 129.0 (2 ×), 127.8, 127.1 (2 ×), 125.2, 123.8, 123.3, 122.9, 121.9, 120.5, 118.6, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₆H₁₇Br₂N₂O₂: 546.9657; found: 546.9652.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-(4-fluorophenyl)chromen-4-one (4t)

Colorless solid; yield: 440 mg (78%); mp 191–192 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.37 (d, J = 2.4 Hz, 1 H), 8.09 (dd, J = 7.6, 0.8 Hz, 1 H), 7.88 (dd, J = 8.4, 2.4 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.62–7.56 (m, 4 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.18–7.13 (m, 2 H), 4.35 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.2, 162.7 (d, J = 246.3 Hz), 161.1, 158.5, 155.2, 152.0, 141.4, 141.1, 139.0, 138.5, 137.4, 135.4 (d, J = 3.1 Hz), 132.7, 129.4, 128.8 (d, J = 8.4 Hz, 2 ×), 125.3, 123.7, 123.3, 122.9, 121.9, 120.5, 118.7, 115.9 (d, J = 21.2 Hz, 2 ×), 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₆H₁₆Br₂FN₂O₂: 564.9563; found: 564.9557.

Single-crystal X-ray diagram: crystal of compound 4t was grown by slow diffusion of EtOAc into a solution of compound 4t in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P 1, a = 7.4478(6) Å, b = 10.0187(8)Å, c = 15.9674(13) Å, V = 1079.68(15) ų, Z = 2, d _calcd = 1.742 g/cm³, F(000) = 560, 2θ range 1.315–26.402°, R indices (all data) R1 = 0.0221, wR2 = 0.0517.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-(4-methoxyphenyl)chromen-4-one (4u)

Colorless solid; yield: 449 mg (78%); mp 162–163 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.36 (d, J = 2.4 Hz, 1 H), 8.07 (d, J = 7.2 Hz, 1 H), 7.89 (dd, J = 8.4, 2.4 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.60–7.53 (m, 4 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.24 (t, J = 7.6 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 4.36 (s, 2 H), 3.85 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.3, 161.3, 159.5, 158.3, 154.8, 152.1, 141.3, 141.0, 138.9, 138.5, 138.0, 132.5, 131.7, 129.3, 128.2 (2 ×), 125.2, 123.2, 123.0, 122.9, 121.8, 120.4, 118.5, 114.4 (2 ×), 55.3, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₇H₁₉Br₂N₂O₃: 576.9763; found: 576.9756.

2-(6-Bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)-6-(naphthalen-2-yl)chromen-4-one (4v)

Colorless solid; yield: 453 mg (76%); mp 182–183 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.56 (d, J = 2.0 Hz, 1 H), 8.11 (dd, J = 8.0, 1.6 Hz, 1 H), 8.08 (s, 1 H), 8.07 (d, J = 8.8, 2.4 Hz, 1 H), 7.96–7.76 (m, 4 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.57 (dd, J = 8.0, 0.8 Hz, 1 H), 7.53–7.46 (m, 2 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.23 (d, J = 8.8 Hz, 1 H), 4.38 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.3, 161.2, 158.4, 155.3, 152.1, 141.4, 141.1, 139.0, 138.5, 138.3, 136.5, 133.6, 133.0, 132.8, 129.4, 128.7, 128.3, 127.6, 126.5, 126.3, 126.1, 125.3, 125.1, 124.0, 123.3, 123.0, 121.9, 120.5, 118.7, 33.0.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₀H₁₉Br₂N₂O₂: 596.9813; found: 596.9816.

6-(Biphenyl-4-yl)-2-(6-bromopyridin-2-yl)-3-(6-bromopyridin-2-ylmethyl)chromen-4-one (4w)

Colorless solid; yield: 460 mg (74%); mp 212–213 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.47 (d, J = 2.4 Hz, 1 H), 8.08 (d, J = 7.6 Hz, 1 H), 7.98 (dd, J = 8.8, 2.4 Hz, 1 H), 7.74–7.55 (m, 9 H), 7.48–7.35 (m, 4 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.25 (t, J = 8.0 Hz, 1 H), 4.38 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.2, 161.2, 158.3, 155.2, 152.0, 141.4, 141.1, 140.6, 140.3, 138.9, 138.5, 138.0, 137.8, 132.7, 129.3, 128.8 (2 ×), 127.6 (2 ×), 127.5, 127.4 (2 ×), 127.0 (2 ×), 125.2, 123.6, 123.3, 122.9, 121.9, 120.5, 118.7, 32.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₂H₂₁Br₂N₂O₂: 622.9970; found: 622.9974.

2-(Pyridin-2-yl)-3-(pyridin-2-ylmethyl)chromen-4-one (4x)

Colorless solid; yield: 220 mg (70%); mp 145–146 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (dd, J = 4.8, 0.8 Hz, 1 H), 8.40 (dd, J = 4.8, 0.8 Hz, 1 H), 8.19 (dd, J = 8.4, 1.2 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.78 (dt, J = 8.0, 1.6 Hz, 1 H), 7.64 (dt, J = 8.4, 1.6 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.49 (dt, J = 8.0, 1.6 Hz, 1 H), 7.35 (dt, J = 8.4, 1.2 Hz, 1 H), 7.33 (dt, J = 8.8, 1.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.00 (dd, J = 8.0, 1.2 Hz, 1 H), 4.37 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.4, 159.9, 159.8, 155.9 (2 ×), 151.6, 149.4, 148.8, 136.6, 136.0, 133.6, 125.9, 124.9, 124.5, 124.3, 122.8, 120.8, 120.6, 118.0, 33.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₅N₂O₂: 315.1134; found: 315.1129.

2-(5-Fluoropyridin-2-yl)-3-(5-fluoropyridin-2-ylmethyl)-chromen-4-one (4y)

Colorless solid; yield: 259 mg (74%); mp 149–150 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.55 (d, J = 2.8 Hz, 1 H), 8.27 (d, J = 2.8 Hz, 1 H), 8.21 (dd, J = 8.0, 1.6 Hz, 1 H), 8.15 (ddd, J = 8.8, 4.4, 0.4 Hz, 1 H), 7.69 (dt, J = 8.4, 1.6 Hz, 1 H), 7.56 (ddd, J = 8.8, 7.6, 2.8 Hz, 1 H), 7.52 (dd, J = 8.8, 0.8 Hz, 1 H), 7.40 (dt, J = 8.0, 1.2 Hz, 1 H), 7.30 (dt, J = 8.4, 4.4 Hz, 1 H), 7.26 (dt, J = 8.8, 2.8 Hz, 1 H), 4.36 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.4, 159.6 (d, J = 260.0 Hz), 158.8, 158.0 (d, J = 251.7 Hz), 155.9, 155.8 (d, J = 3.8 Hz), 147.9 (d, J = 4.6 Hz), 138.0 (d, J = 23.5 Hz), 136.8 (d, J = 22.8 Hz), 133.9, 126.1, 125.8 (d, J = 5.3 Hz), 125.1, 123.9 (d, J = 3.7 Hz), 123.5, 123.2 (d, J = 25.0 Hz), 122.9 (d, J = 1.5 Hz), 120.7, 118.0, 32.6 (d, J = 1.5 Hz).

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₃F₂N₂O₂: 351.0945; found: 351.0938.

2-(6-Chloropyridin-2-yl)-3-(6-chloropyridin-2-ylmethyl)-chromen-4-one (4z)

Colorless solid; yield: 283 mg (74%); mp 164–165 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.15 (dd, J = 8.0, 1.6 Hz, 1 H), 7.997 (dd, J = 7.6, 0.4 Hz, 1 H), 7.77 (t, J = 8.0 Hz, 1 H), 7.63 (dt, J = 8.8, 1.6 Hz, 1 H), 7.45 (dd, J = 8.0, 1.6 Hz, 1 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.35 (dt, J = 8.0, 0.8 Hz, 1 H), 7.33 (dt, J = 8.0, 1.2 Hz, 1 H), 7.16 (dt, J = 7.2, 0.4 Hz, 1 H), 7.02 (dd, J = 8.0, 0.8 Hz, 1 H), 4.33 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.0, 160.6, 158.2, 155.6, 151.5, 150.7, 150.1, 139.3, 138.6, 133.8, 125.8, 125.4, 125.1, 122.7, 122.6, 121.3, 121.2, 120.3, 117.9, 32.7.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₃Cl₂N₂O₂: 383.0354; found: 383.0348.

Single-crystal X-ray diagram: crystal of compound 4z was grown by slow diffusion of EtOAc into a solution of compound 4z in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P 1, a = 8.0551(5) Å, b = 10.7878(6) Å, c = 11.1421(6) Å, V = 815.63(8) ų, Z = 2, d _calcd = 1.560 g/cm³, F(000) = 392, 2θ range 2.043–26.470°, R indices (all data) R1 = 0.0404, wR2 = 0.1033.

2-(6-Methylpyridin-2-yl)-3-(6-methylpyridin-2-ylmethyl)-chromen-4-one (4aa)

Colorless solid; yield: 274 mg (80%); mp 77–78 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.22 (dd, J = 8.0, 1.6 Hz, 1 H), 7.76 (dd, J = 8.0, 0.4 Hz, 1 H), 7.68 (t, J = 7.6 Hz, 1 H), 7.65 (dd, J = 8.4, 0.8 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 4.30 (s, 2 H), 2.49 (s, 3 H), 2.46 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.6, 160.4, 159.4, 158.4, 157.2, 156.0, 150.9, 136.7, 136.4, 133.6, 126.0, 124.9, 124.2, 123.0, 121.3, 120.4, 120.2, 119.1, 118.0, 33.6, 24.4, 24.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₂H₁₉N₂O₂: 343.1447; found: 343.1442.

2-(6-Methoxypyridin-2-yl)-3-(6-methoxypyridin-2-ylmethyl)-chromen-4-one (4ab)

Colorless solid; yield: 292 mg (78%); mp 124–125 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.23 (dd, J = 8.0, 1.6 Hz, 1 H), 7.71–7.62 (m, 3 H), 7.51 (dd, J = 8.4, 0.4 Hz, 1 H), 7.38 (dt, J = 8.0, 0.8 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 6.80 (dd, J = 8.0, 0.8 Hz, 1 H), 6.76 (d, J = 6.8 Hz, 1 H), 6.45 (d, J = 8.4 Hz, 1 H), 4.53 (s, 2 H), 3.73 (s, 3 H), 3.65 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.6, 163.2, 163.1, 159.2, 157.7, 155.8, 149.3, 138.8, 138.5, 133.6, 126.0, 124.8, 122.8, 120.2, 117.8, 116.9, 114.7, 112.6, 10.3, 53.4, 52.9, 32.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₂H₁₉N₂O₄: 375.1345; found: 375.1337.

3-Benzyl-2-phenylchromen-4-one (4ac)

Colorless solid; yield: 134 mg (43%); mp 82–83 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.27 (dd, J = 8.0, 1.6 Hz, 1 H), 7.67 (dt, J = 8.4, 1.6 Hz, 1 H), 7.58–7.56 (m, 2 H), 7.52–7.46 (m, 3 H), 7.41 (dt, J = 8.0, 0.8 Hz, 1 H), 7.25–7.21 (m, 2 H), 7.17–7.13 (m, 4 H), 3.98 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.2, 162.9, 156.2, 140.1, 133.5, 133.2, 130.4, 128.6 (2 ×), 128.5 (2 ×), 128.4 (2 ×), 128.1 (2 ×), 126.1, 125.9, 124.9, 123.0, 120.6, 117.9, 31.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₂H₁₇O₂: 313.1229; found: 313.1221.

2-(Naphthalen-2-yl)-3-(naphthalen-2-ylmethyl)chromen-4-one (4ad)

Colorless solid; yield: 148 mg (36%); mp 144–145 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.34 (dd, J = 8.0, 1.6 Hz, 1 H), 8.06 (s, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.81–7.67 (m, 6 H), 7.61–7.52 (m, 4 H), 7.47–7.35 (m, 4 H), 4.20 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.4, 163.2, 156.3, 138.0, 133.9, 133.6, 132.5, 132.1, 130.4, 129.1, 128.7, 128.4, 128.0, 127.8, 127.6 (3 ×), 127.5, 127.1, 126.8, 126.2 (2 ×), 125.8, 125.18, 125.17, 125.0, 123.1, 120.8, 118.0, 31.6.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₀H₂₁O₂: 413.1542; found: 413.1536.

2-(Furan-2-yl)-3-(furan-2-ylmethyl)chromen-4-one (4af)

Colorless solid; yield: 169 mg (58%); mp 111–112 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.21 (dd, J = 8.0, 1.6 Hz, 1 H), 7.66 (dd, J = 1.6, 0.4 Hz, 1 H), 7.64 (dt, J = 8.8, 1.2 Hz, 1 H), 7.46 (dd, J = 8.4, 0.8 Hz, 1 H), 7.37 (dt, J = 8.0, 0.8 Hz, 1 H), 7.27 (dd, J = 1.6, 0.8 Hz, 1 H), 7.17 (dd, J = 3.6, 0.8 Hz, 1 H), 6.60 (dd, J = 3.6, 1.6 Hz, 1 H), 6.23 (dd, J = 3.2, 1.6 Hz, 1 H), 6.05 (dd, J = 3.2, 0.8 Hz, 1 H), 4.31 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.6, 155.5, 153.2, 152.2, 146.7, 145.4, 140.9, 133.6, 126.0, 124.8, 122.7, 117.7, 116.0, 115.3, 112.1, 110.3, 105.8, 23.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₁₃O₄: 293.0814; found: 293.0809.

2-(Thiophen-2-yl)-3-(thiophen-2-ylmethyl)chromen-4-one (4ag)

Colorless solid; yield: 194 mg (60%); mp 138–139 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.25 (dd, J = 8.0, 1.6 Hz, 1 H), 7.68 (dd, J = 7.2, 1.6 Hz, 1 H), 7.64 (dd, J = 8.0, 1.2 Hz, 1 H), 7.61 (dd, J = 8.8, 0.8 Hz, 1 H), 7.50 (dd, J = 8.0, 0.8 Hz, 1 H), 7.40 (dt, J = 8.0, 0.8 Hz, 1 H), 7.16 (dd, J = 4.8, 4.0 Hz, 1 H), 6.12 (dd, J = 4.8, 1.2 Hz, 1 H), 6.90–6.87 (m, 2 H), 4.36 (d, J = 0.8 Hz, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.6, 156.6, 155.7, 142.0, 134.4, 133.7, 130.6, 130.1, 127.9, 126.8, 126.1, 125.0, 124.7, 123.6, 122.6, 119.0, 117.8, 26.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₁₃O₂S₂: 325.0357; found: 325.0352.

Single-crystal X-ray diagram: crystal of compound 4ag was grown by slow diffusion of EtOAc into a solution of compound 4ag in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P21/n, a = 9.1253(10) Å, b = 9.1493(10) Å, c = 18.386(2) Å, V = 1512.1(3) ų, Z = 4, d _calcd = 1.425 g/cm³, F(000) = 672, 2θ range 2.249–26.551°, R indices (all data) R1 = 0.0339, wR2 = 0.0734.

2-(Pyridin-3-yl)-3-(pyridin-3-ylmethyl)chromen-4-one (4ah)

Colorless gum; yield: 85 mg (27%).

¹H NMR (400 MHz, CDCl₃): δ = 8.78 (dd, J = 1.6, 0.8 Hz, 1 H), 8.73 (dd, J = 4.8, 1.6 Hz, 1 H), 8.35 (d, J = 3.6 Hz, 1 H), 8.26 (d, J = 1.6 Hz, 1 H), 8.20 (dd, J = 8.0, 1.6 Hz, 1 H), 7.79 (dt, J = 8.0, 2.4 Hz, 1 H), 7.67 (dt, J = 8.4, 1.6 Hz, 1 H), 7.45–7.38 (m, 4 H), 7.10 (dd, J = 8.0, 4.8 Hz, 1 H), 3.91 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.5, 160.1, 156.0, 151.4, 149.2, 149.0, 147.5, 135.8, 135.6, 135.0, 134.0, 128.9, 125.9, 125.3, 123.3 (2 ×), 122.7, 120.6, 117.9, 28.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₅N₂O₂: 315.1134; found: 315.1136.

2-(Benzofuran-2-yl)-3-(benzofuran-2-ylmethyl)chromen-4-one (4ai)

Colorless solid; yield: 251 mg (64%); mp 186–187 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.27 (dd, J = 8.4, 1.6 Hz, 1 H), 7.72 (dt, J = 8.4, 1.6 Hz, 1 H), 7.69 (dd, J = 8.0, 0.8 Hz, 1 H), 7.59 (dd, J = 8.0, 0.8 Hz, 1 H), 7.58 (s, 1 H), 7.56 (dd, J = 8.4, 0.8 Hz, 1 H), 7.45–7.39 (m, 4 H), 7.32 (dt, J = 8.0, 0.8 Hz, 1 H), 7.17 (dt, J = 8.8, 1.6 Hz, 1 H), 7.12 (dt, J = 8.0, 1.6 Hz, 1 H), 6.47 (d, J = 1.2 Hz, 1 H), 4.61 (d, J = 0.8 Hz, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.5, 156.5, 155.7, 155.6, 154.7, 152.5, 148.2, 134.0, 128.9, 127.3, 126.9, 126.1, 125.2, 123.9, 123.1, 122.7, 122.4, 122.2, 120.3, 117.8, 117.3, 111.9, 111.5, 110.8, 102.9, 23.9.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₆H₁₇O₄: 393.1127; found: 393.1122.

2-(Benzo[b]thiophen-2-yl)-3-(benzo[b]thiophen-2-yl)methylchromen-4-one (4aj)

Colorless solid; yield: 267 mg (63%); mp 195–196 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.29 (dd, J = 8.0, 1.6 Hz, 1 H), 7.89 (dd, J = 8.0, 2.0 Hz, 1 H), 7.88 (s, 1 H), 7.83 (dd, J = 8.4, 1.6 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.72 (dt, J = 8.8, 2.0 Hz, 1 H), 7.63 (dd, J = 8.8, 1.6 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.46–7.39 (m, 3 H), 7.29 (dt, J = 8.4, 1.2 Hz, 1 H), 7.25 (dt, J = 8.4, 1.2 Hz, 1 H), 7.12 (s, 1 H), 4.49 (d, J = 0.8 Hz, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 177.5, 156.9, 155.8, 143.1, 140.8, 140.1, 139.6, 138.9, 134.0, 133.9, 127.8, 126.3, 126.2, 125.3, 125.0 (2 ×), 124.1, 123.6, 123.0, 122.6, 122.2, 122.1, 121.3, 119.7, 117.9, 27.2.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₆H₁₇O₂S₂: 425.0670; found: 425.0678.

1-(2-Hydroxyphenyl)-3-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (4ak-1)

Colorless solid; yield: 42 mg (15%); mp 208–209 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 13.30 (s, 1 H), 8.19 (d, J = 15.2 Hz, 1 H), 8.03–8.00 (m, 1 H), 7.96 (dd, J = 8.4, 1.6 Hz, 1 H), 7.65 (d, J = 15.2 Hz, 1 H), 7.50 (s, 1 H), 7.48 (dt, J = 7.6, 2.0 Hz, 1 H), 7.41–7.33 (m, 3 H), 7.03 (dd, J = 8.4, 0.8 Hz, 1 H), 6.96 (dt, J = 8.0, 1.2 Hz, 1 H), 3.85 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 193.6, 163.5, 139.4, 138.4, 135.6, 135.4, 129.3, 126.1, 123.4, 121.9, 120.8, 120.3, 118.6, 115.5, 114.5, 113.1, 110.3, 33.4.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₁₆NO₂: 278.1181; found: 278.1188.

2-(Quinolin-2-yl)-3-(quinolin-2-ylmethyl)chromen-4-one (4al)

Colorless solid; yield: 145 mg (35%); mp 122–123 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.27 (dd, J = 8.0, 1.6 Hz, 1 H), 8.25 (d, J = 9.2 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.92 (dd, J = 8.4, 3.2 Hz, 1 H), 7.80 (dd, J = 8.0, 0.8 Hz, 1 H), 7.71–7.53 (m, 7 H), 7.46 (d, J = 8.8 Hz, 1 H), 7.43–7.38 (m, 2 H), 4.71 (s, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.6, 160.7, 160.1, 156.0, 151.5, 147.7, 147.3, 136.7, 135.9, 133.7, 130.0, 129.9, 128.9, 128.8, 127.9, 127.8, 127.4, 127.3, 126.7, 126.1, 125.4, 125.1, 123.0, 121.2, 121.0, 120.8, 118.0, 34.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₈H₁₉N₂O₂: 415.1447; found: 415.1446.

2-[6-(3,4-Dimethoxyphenyl)pyridin-2-yl]-3-[6-(3,4-dimethoxyphenyl)pyridin-2-ylmethyl]chromen-4-one (4am)

3,4-Dimethoxyphenylboronic acid (180 mg, 1.0 mmol), Pd(OAc)₂ (45 mg, 20 mol%), PPh₃ (130 mg, 0.5 mmol), and Na₂CO₃ (53 mg, 0.5 mmol) were added stepwise to a solution of 4a (235 mg, 0.5 mmol) in EtOH (15 mL) at 25 °C. The mixture was stirred at reflux for 8 h (TLC monitoring). The mixture was cooled to 25 °C, concentrated, and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried, filtered, and evaporated to afford the crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc 8:1–2:1) afforded 4am as a colorless gum; yield: 220 mg (75%).

¹H NMR (400 MHz, CDCl₃): δ = 8.24 (dd, J = 8.0, 1.6 Hz, 1 H), 7.93 (dd, J = 7.6, 0.8 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.76 (dd, J = 8.0, 0.8 Hz, 1 H), 7.70 (dt, J = 8.4, 1.6 Hz, 1 H), 7.56–7.52 (m, 4 H), 7.45–7.37 (m, 4 H), 7.17 (d, J = 7.6 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 4.70 (s, 2 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.71 (s, 3 H), 3.70 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.7, 159.7, 159.6, 156.6, 156.0, 155.8, 151.7, 150.2, 149.5, 149.1, 148.9, 137.3, 136.8, 133.7, 132.6, 131.2, 126.0, 124.9, 122.9, 121.7, 121.0, 120.5 (2 ×), 119.6, 119.0, 117.9, 116.8, 111.0, 110.7, 110.0, 109.9, 55.84, 55.81, 55.7, 55.5, 33.5.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₆H₃₁N₂O₆: 587.2182; found: 587.2188.

2-(6-Bromopyridin-2-yl)-3-[6-(3,4-dimethoxyphenyl)pyridin-2-ylmethyl]chromen-4-one (4am-1)

Colorless solid; yield: 26 mg (10%); mp 188–190 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.20 (dd, J = 8.0, 1.6 Hz, 1 H), 7.89 (dd, J = 7.6, 1.2 Hz, 1 H), 7.84 (d, J = 7.6 Hz, 1 H), 7.73 (dd, J = 7.6, 1.2 Hz, 1 H), 7.67 (dt, J = 8.4, 1.2 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.26 (dd, J = 8.4, 2.0 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.14 (d, J = 7.6 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 4.60 (s, 2 H), 3.89 (s, 3 H), 3.78 (s, 3 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 178.4, 161.8, 159.9, 156.5, 155.8, 151.2, 150.2, 149.0, 141.0, 138.4, 137.4, 133.8, 131.0, 125.8, 125.0 (2 ×), 122.7, 121.6, 120.9, 120.7, 119.7, 119.5, 117.9, 111.0, 109.7, 55.8, 55.7, 33.3.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₈H₂₂BrN₂O₄: 529.0763; found: 529.0769.

2-(2-Allyl-3,4-dimethoxyphenyl)chromen-4-one (4an)

NaOH (80 mg, 2.0 mmol) was added to a solution of 2a (136 mg, 1.0 mmol) in MeOH (30 mL) at 25 °C and the mixture was stirred at 25 °C for 10 min. Compound 3q (412 mg, 2.0 mmol) was added to the mixture at 25 °C and then the mixture was stirred at 50 °C for 10 h. The mixture was cooled to 25 °C and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford the crude product under reduced pressure. Purification (silica gel, hexanes/EtOAc 10:1–4:1) afforded 4an as a colorless solid; yield: 129 mg (40%); mp 208–209 °C (hexanes/EtOAc).

¹H NMR (400 MHz, CDCl₃): δ = 8.28 (dd, J = 8.0, 1.6 Hz, 1 H), 7.69 (dt, J = 8.4, 1.6 Hz, 1 H), 7.49 (dd, J = 8.4, 0.8 Hz, 1 H), 7.43 (dt, J = 8.0, 0.8 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 6.42 (s, 1 H), 5.95–5.85 (m, 1 H), 4.91–4.82 (m, 2 H), 3.94 (s, 3 H), 3.87 (s, 3 H), 3.51 (dt, J = 6.4, 1.6 Hz, 2 H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 173.2, 155.6, 154.4, 147.8, 147.7, 138.4, 136.6, 133.9, 133.5, 126.5, 125.5, 124.5, 123.0, 121.2, 118.4, 115.2, 110.2, 60.8, 55.8, 31.8.

HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₁₉O₄: 323.1283; found: 323.1288.

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