Phosphine/palladium-catalyzed one-pot synthesis of functionalized 6H-benzo[c]chromenes

Abstract

In this study, a one-pot, phosphine/palladium sequential catalysis reaction has been realized, and a series of functionalized alkenyl 6H-benzo[c]chromenes are synthesized in high yields and with good stereoselectivity.

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The rapid and efficient synthesis of complex molecular structures from simple substrates remains a great challenge in organic synthesis. A traditional one-catalyst one-reaction approach is less than ideal for the increasing demands of environmentally benign and economical synthetic processes. In recent years, one-pot multiple catalytic transformations, including tandem, cascade, and sequential-catalysis processes, have attracted more and more attention because they eliminate the need to isolate and purify intermediates, providing the desired products in more efficient ways.¹

Accordingly, many groups have developed multicatalyst systems that promote two or more chemical transformations in a single flask.² These multistep/singleflask operations minimize the time and cost of delivering complex molecular architectures from simple starting materials in a facile and efficient manner.

Tertiary phosphine is an important class of Lewis base catalysts,³ which has shown great potential for the catalysis of numerous reactions, such as the Morita–Baylis–Hillman reaction, Rauhut–Currier reaction, Michael addition, etc.⁴ Especially, nucleophilic phosphine-catalyzed reactions are among the most important methods available for ring construction,⁵ and show the application in natural products synthesis and medicinal chemistry.⁶ One the other hand, palladium-catalyzed Heck reaction is one of the most efficient method to form C–C bond and C-hetero bond.⁷ Recently, Kwon and co-workers reported a Michael–Heck sequential catalysis reaction to synthesize a series of highly functionalized (Z)-alkylidene phthalans.⁸

6H-Benzo[c]chromenes are one of the most important heterocycles because they have been found in several natural products.⁹ Some important bioactive molecules with these moieties are presented in Fig. 1.¹⁰ Recently, 6H-benzo[c]chromenes have been synthesized by many groups,¹¹ but the synthesis of functionalized alkenyl 6H-benzo[c]chromenes from simple substrates remains a challenge. Herein we report an efficient and highly stereoselective one-pot synthesis of functionalized alkenyl 6H-benzo[c]chromenes via phosphine/palladium sequential catalysis.

Fig. 1 Typical compounds of 6H-benzo[c]chromenes.

Before proceeding to the one-pot transformation, we investigated the efficiency of each reaction step. First, we chose 2-[2′-bromophenyl]phenol (1a) and methyl propiolate (2a) as the standard substrates to search for suitable reaction conditions of the phosphine-catalyzed nucleophilic Michael addition (Table 1). When PPh₃ was use as the catalyst, CH₃CN as the solvent, the desired product (E)-methyl-3-((2′-bromo-[1,1′-biphenyl]-2-yl)oxy)acrylate (3a) was obtained in 92% yield (Table 1, entry 1), and the Z isomer was not detected. When benzene, THF, toluene, CHCl₃, DMF and 1,4-dioxane were used as the solvent, the desired product was also obtained in good yield (Table 1, entries 2–7). Then, we used tributylphosphine as the catalyst, CH₃CN as the solvent, the yield was decreased to 63% (Table 1, entry 8). Then, we used 3a, which was isolated from the Michael addition reaction, as the starting material to search for suitable reaction conditions of the palladium-catalyzed Heck reaction (Table 2). When we introduced Pd(OAc)₂ as the catalyst (5 mol%), NaHCO₃ as the base, CH₃CN as the solvent, the desired product (4a) was isolated in less than 5% yield (Table 2, entry 1). Considering n-Bu₄NCl is known to improve the yields of Heck reactions,¹² we used 1.0 eq. of n-Bu₄NCl as an additive, and the yield of the desired product was greatly increased to 79% (Table 2, entry 2), and only E isomer was isolated (see the ESI,† NOESY spectrum of 4a). But when we used n-Bu₄NBr as the additive, the yield decreased to 30% (Table 2, entry 3). After that, several solvents were screened, and the desired product was obtained in good yields in 1,4-dioxane and CHCl₃ (Table 2, entries 4 and 6). But when DMF was used, the reaction did not occur (Table 2, entry 5). Further, a number of palladium catalysts were tested. When Pd(dppf)Cl₂ was used, the yield of the desired product increased to 85% (Table 2, entry 8). When PdCl₂, Pd(dppp)Cl₂ and Pd(dppe)Cl₂ were used, the desired product were also obtained in good yield (Table 2, entries 7, 9 and 10). However, the yield was only less than 10% when Pd(PPh₃)₄ was used as the catalyst (Table 2, entry 11). Then, Na₂CO₃, K₂CO₃ and Et₃N were surveyed to optimize the reaction conditions. Na₂CO₃ was found to be the best base and the yield of the product increased to 90% (Table 2, entry 13). When K₂CO₃ and Et₃N were used, the product was formed in moderate to good yields (Table 2, entries 12 and 14). In consideration of the optimization of two separated reaction steps, we future investigated the suitable conditions of this sequential catalysis (Table 3). After investigation of different solvents, palladium catalysts and base, the most efficient reaction conditions were confirmed (Table 3, entry 1).

Table 1 Optimization of conditions for phosphine-catalyzed nucleophilic Michael addition^a

Entry	[P]	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), solvent (3 mL), 85 °C, 2 h.b Isolated yield.
1	PPh3	CH3CN	92
2	PPh3	Benzene	75
3	PPh3	THF	81
4	PPh3	Toluene	75
5	PPh3	CHCl3	88
6	PPh3	DMF	84
7	PPh3	1,4-Dioxane	90
8	(n-Bu)3P	CH3CN	63

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Table 2 Optimization of the palladium-catalyzed Heck reaction conditions^a

Entry	[Pd]	Additive	Base	Solvent	Yield^b (%)
a Reaction conditions: 3a (0.5 mmol), Pd-catalyst (0.025 mmol), additive (0.5 mmol), base (1 mmol), solvent (3.0 mL), under N2.b Isolated yield.c Et3N (4.0 eq.).
1	Pd(OAc)2	None	NaHCO3	CH3CN	<5%
2	Pd(OAc)2	n-Bu4NCl	NaHCO3	CH3CN	79%
3	Pd(OAc)2	n-Bu4NBr	NaHCO3	CH3CN	30%
4	Pd(OAc)2	n-Bu4NCl	NaHCO3	1,4-Dioxane	82%
5	Pd(OAc)2	n-Bu4NCl	NaHCO3	DMF	Neat
6	Pd(OAc)2	n-Bu4NCl	NaHCO3	CHCl3	56%
7	PdCl2	n-Bu4NCl	NaHCO3	CH3CN	70%
8	Pd(dppf)Cl2	n-Bu4NCl	NaHCO3	CH3CN	85%
9	Pd(dppp)Cl2	n-Bu4NCl	NaHCO3	CH3CN	71%
10	Pd(dppe)Cl2	n-Bu4NCl	NaHCO3	CH3CN	79%
11	Pd(PPh3)4	n-Bu4NCl	NaHCO3	CH3CN	<10%
12	Pd(dppf)Cl2	n-Bu4NCl	K2CO3	CH3CN	85%
13	Pd(dppf)Cl2	n-Bu4NCl	Na2CO3	CH3CN	90%
14^c	Pd(dppf)Cl2	n-Bu4NCl	Et3N	CH3CN	54%

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Table 3 Optimization of conditions for sequential catalysis^a

Entry	Solvent	[Pd] catalyst	Base	Yield^b (%)
a Reaction conditions: (1). 1a (0.5 mmol), 2a (0.55 mmol), solvent (3 mL), 85 °C, 2 h, under N2. (2). Pd-catalyst (0.025 mmol), n-Bu4NCl (0.5 mmol), base (1 mmol), 85 °C, 8 h, under N2.b Isolated yield.
1	CH3CN	Pd(dppf)Cl2	Na2CO3	80%
2	1,4-Dioxane	Pd(dppf)Cl2	Na2CO3	70%
3	CH3CN	Pd(OAc)2	Na2CO3	61%
4	CH3CN	Pd(dppe)Cl2	Na2CO3	59%
5	CH3CN	Pd(dppf)Cl2	NaHCO3	77%
6	CH3CN	Pd(dppf)Cl2	K2CO3	78%

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With the optimized reaction conditions established, various 2-[bromoaryl]phenols were subjected to the reactions, and representative results are summarized in Table 4. When 6-methyl-2-[2′-bromophenyl]phenol reacted with methyl propiolate, the desired product was obtained in a little lower yield, maybe because of the steric effect (4b). Normally, 2-[bromoaryl]phenols with electron-donating groups reacted well with methyl propiolate under the standard reaction conditions (4c, d and f). When 2-[bromoaryl]phenols with electron-withdrawing groups reacted with methyl propiolate, the desired products were isolated in moderate yields (4e and g). To expand the scope of the reaction, we further examined the heterocyclic substituted substrates. When 2-(3-bromopyridin-2-yl)phenol was used as the substrate, the desired product was gathered in good yield (4h). But when 2-(3-bromopyridin-4-yl)phenol was used, the yield of the cyclization product decreased to 57% (4i). And when we used 2-(4-bromothiophen-3-yl)phenol as the substrate, the desired product was obtained in a lower yield (4j).

Table 4 Sequential catalysis reactions of 2a with different 2-[bromoaryl]phenols^a,b

a (1) 2-[Bromoaryl]phenols (0.5 mmol), 2a (0.55 mmol), CH₃CN (3 mL), 85 °C, 2 h, under N₂. (2) Pd(dppf)Cl₂ (0.025 mmol), n-Bu₄NCl (0.5 mmol), Na₂CO₃ (1 mmol), 85 °C, 8 h, under N₂.b Isolated yield.

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After screening the 2-[bromoaryl]phenols, we also introduced an array of electron-deficient acetylenes to react with different 2-[bromoaryl]phenols (Table 5). When ethyl propiolate was used to react with 2-[2′-bromophenyl]phenol, we isolated the desired product in high yield (5a). When acetylacetylene was used as the substrate to react with different 2-[bromoaryl]phenols, we obtained a series of desired cyclization products in moderate to good yields (6a–d). In contrast with acetylacetylene, benzyl propiolate reacting with different 2-[bromoaryl]phenols afforded their corresponding products in higher yields (7a–e). Also, when benzoylacetylene was used, the desired products were obtained in good yields (8a and b).

Table 5 Sequential catalysis reactions of different 2-[bromoaryl]phenols with various electron-deficient acetylenes^a,b

a (1) 2-[Bromoaryl]phenols (0.5 mmol), electron-deficient acetylenes (0.55 mmol), CH₃CN (3 mL), 85 °C, 2 h, under N₂. (2) Pd(dppf)Cl₂ (0.025 mmol), n-Bu₄NCl (0.5 mmol), Na₂CO₃ (1 mmol), 85 °C, 8 h, under N₂.b Isolated yield.

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In addition, we investigated the 2-[2′-iodophenyl]phenol and 2-[2′-chlorophenyl]phenol to react with methyl propiolate (Scheme 1). When 2-[2′-iodophenyl]phenol was introduced, the desired product 4a was isolated in a very high yield. On the other hand, the desired product 4a was isolated in a low yield when 2-[2′-chlorophenyl]phenol was introduced.

Scheme 1 Synthesis of 4a with 2-[2′-iodophenyl]phenol (9a) and 2-[2′-chlorophenyl]phenol (10a). (1) 2-[2′-iodophenyl]phenol or 2-[2′-chlorophenyl]phenol (0.5 mmol), 2a (0.55 mmol), CH₃CN (3 mL), 85 °C, 2 h, under N₂. (2) Pd(dppf)Cl₂ (0.025 mmol), n-Bu₄NCl (0.5 mmol), Na₂CO₃ (1 mmol), 85 °C, 8 h, under N₂. Isolated yield.

According to literature,⁸ a possible mechanism was proposed in Scheme 2. First, nucleophilic addition of PPh₃ onto the electron-deficient acetylene 2a to afford phosphonium vinyl anion 11. Then, the phosphonium vinyl anion 11 deprotonates the pronucleophile 1a to provide the anion intermediate 12, which undergoes conjugate addition to another molecule of 2a to give the intermediate 13, the protonation of which gives 3a. The Michael adduct 3a can also be formed through an addition and elimination route involving 12 and 14 via 15.

Scheme 2 A possible mechanism.

In the second catalytic step, the palladium catalyst inserts into the aryl bromide of the Michael adduct 3a, generating the arylpalladium(II) complex 16. Then, 16 undergoes carbopalladation to form the intermediate 17. After hydride elimination, final product 4a and the palladium(II) halide 18 were generated. Then, 18 undergoes the reductive elimination of HBr, and regenerates the active Pd(0) species.

In summary, we have developed an efficient one-pot phosphine/palladium sequential catalysis pathway to synthesize a series of functionalized alkenyl 6H-benzo[c]chromenes. This provides a wide scope of 6H-benzo[c]chromenes in scientific research.

Experimental section

General information

NMR spectra were recorded on AM400 instruments in CDCl₃. Chemical shifts were calibrated using a solvent peak or tetramethylsilane as an internal reference. Coupling constants are reported in Hertz (Hz). TLC was carried out with 0.2 mm thick silica gel plates (GF254). Visualization was accomplished by UV light. The columns were hand packed with silica gel 60 (200–300). All reactions were carried out in an over-dried Schlenk tube equipped with a magnetic stir bar under N₂ atmosphere. Unknown compound was additionally confirmed by HRMS. Mass spectra were obtained using EI ionization.

Experiment procedures

General procedure for products 3a. A sealed tube was charged with 2-[2′-bromophenyl]phenol (1a)¹³ (0.5 mmol), PPh₃ (0.1 mmol) and dry CH₃CN (1.5 mL). The mixture was stirred at 85 °C, under N₂ atmosphere. Methyl propiolate (2a) (0.55 mmol) mixed with dry CH₃CN (1.5 mL) and added dropwise to the reaction mixture over 2 h. The reaction was left to proceed until the pronucleophile was consumed, typically 2 h. The reaction mixture was concentrated. Column chromatography on silica gel (pure petroleum ether/EtOAc, 10 : 1), and the fraction with an R_f = 0.5 was collected to give the desired product.

Synthesis of product 4a from 3a. A sealed tube was charged with 3a (0.5 mmol), Pd-catalyst (0.025 mmol), n-Bu₄NCl (0.5 mmol), Na₂CO₃ (1.0 mmol) and CH₃CN (3 mL). The mixture was stirred at 85 °C under N₂ atmosphere, 8 h. The reaction mixture was concentrated. Column chromatography on silica gel (PE/EtOAc, 10 : 1), and the fraction with an R_f = 0.3 was collected to give the desired product.

General procedure for the sequential catalysis. A sealed tube was charged with 2-[2′-bromophenyl]phenol (1a) (0.5 mmol), PPh₃ (0.1 mmol) and dry CH₃CN (1.5 mL). The mixture was stirred at 85 °C, under N₂ atmosphere. Methyl propiolate (2a) (0.55 mmol) mixed with dry CH₃CN (1.5 mL) and added dropwise to the reaction mixture over 2 h. After the mixture was stirred for 2 h, Pd-catalyst (0.025 mmol), n-Bu₄NCl (0.5 mmol) and Na₂CO₃ (1.0 mmol) were added. Then the mixture was stirred for 8 more hours. The reaction mixture was concentrated. Column chromatography on silica gel (pure petroleum ether/EtOAc, 10 : 1), and the fraction with an R_f = 0.3 was collected to give the desired product.

When 2-[2′-iodophenyl]phenol (9a) and 2-[2′-chlorophenyl]phenol (10a) were used as the substrate, the procedures for the reactions are the same.

Characterization data

3a: (E)-methyl-3-((2′-bromo-[1,1′-biphenyl]-2-yl)oxy)acrylate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.63 (m, 2H), 7.44–7.21 (m, 6H), 7.14 (d, J = 8.0 Hz, 1H), 5.39 (d, J = 12.4 Hz, 1H), 3.68 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.3, 101.7, 118.5, 123.8, 125.1, 127.2, 129.4, 129.8, 131.4, 132.5, 132.7, 138.0152.8, 159.7, 167.6. MS (70 eV, EI) m/z = 332. HRMS (EI): m/z calcd for C₁₆H₁₃BrO₃ (M⁺): 332.0048. Found, 332.0045.

4a: (E)-methyl-2-(6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.58–7.54 (m, 1H), 7.41–7.32 (m, 3H), 7.19 (m, 1H), 5.85 (s, 1H), 3.71 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.0, 90.8, 117.4, 118.3, 121.9, 122.3, 123.7, 124.2, 124.9, 128.8, 129.5, 130.2, 131.9, 150.6, 159.0, 165.8. IR (neat): 3057, 2947, 1707, 1629, 1600, 1438, 1278, 1153, 810, 738 cm⁻¹. MS (70 eV, EI) m/z = 252. HRMS (EI): m/z calcd for C₁₆H₁₂O₃ (M⁺): 252.0786. Found, 252.0785.

4b: (E)-methyl-2-(4-methyl-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.58–7.53 (m, 1H), 7.40–7.36 (m, 1H), 7.26–7.22 (m, 1H), 7.08 (t, J = 7.6 Hz, 1H), 5.86 (s, 1H), 3.80 (s, 3H), 2.56 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.7, 50.9, 90.7, 117.9, 122.2, 123.1, 124.0, 124.8, 127.0, 128.6, 129.9, 131.5, 131.6, 148.9, 159.0, 166.0. IR (neat): 2947, 2924, 2852, 1712, 1627, 1593, 1153, 1138, 808, 861 cm⁻¹. MS (70 eV, EI) m/z = 266. HRMS (EI): m/z calcd for C₁₇H₁₄O₃ (M⁺): 266.0943. Found, 266.0944.

4c: (E)-methyl-2-(8,9-dimethyl-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.87 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.54 (s, 1H), 7.35–7.32 (m, 2H), 7.20–7.15 (m, 1H), 5.81 (s, 1H), 3.78 (s, 3H), 2.38 (s, 3H), 2.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.9, 20.2, 50.8, 89.4, 117.3, 118.4, 121.9, 122.0, 122.7, 123.6, 125.5, 127.2, 129.5, 138.0, 141.6, 150.4, 159.3, 166.1. IR (neat): 3055, 2987, 2906, 1869, 1734, 1647, 1541, 1419, 1265, 869, 738 cm⁻¹. MS (70 eV, EI) m/z = 280. HRMS (EI): m/z calcd for C₁₈H₁₆O₃ (M⁺): 280.1099. Found, 280.1100.

4d: (E)-methyl-2-(8,9-dimethoxy-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.79 (d, J = 7.6 Hz, 1H), 7.36–7.34 (m, 2H), 7.21–7.18 (m, 1H), 7.12 (s, 1H), 5.67 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H), 3.79 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 50.8, 56.1, 88.4, 106.1, 117.3, 118.2, 121.6, 122.3, 123.6, 124.1, 128.8, 129.4, 150.0, 150.2, 153.0, 159.1, 166.0. IR (neat): 3055, 2985, 2852, 1701, 1600, 1587, 1517, 1265, 1149, 852, 738 cm⁻¹. MS (70 eV, EI) m/z = 312. HRMS (EI): m/z calcd for C₁₈H₁₆O₅ (M⁺): 312.0998. Found, 312.0999.

4e: (E)-methyl-2-(8,9-difluoro-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.64–7.59 (m, 2H), 7.50–7.44 (m, 1H), 7.34–7.10 (m, 3H), 5.60 (s, 1H), 3.71 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.1, 91.7, 110.8, 113.7, 116.8, 117.5, 121.3, 122.3, 124.0, 127.6, 130.9, 149.3, 150.5, 154.4, 156.9, 165.3. IR (neat): 3055, 2987, 2908, 1770, 1602, 1516, 1423, 1265, 896, 738 cm⁻¹. MS (70 eV, EI) m/z = 288. HRMS (EI): m/z calcd for C₁₆H₁₀F₂O₃ (M⁺): 288.0598. Found, 288.0593.

4f: (E)-methyl-2-(4,8,9-trimethyl-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.64–7.60 (m, 2H), 7.44 (s, 1H), 7.19–7.16 (m, 1H), 7.06–7.03 (m, 1H), 5.75 (s, 1H), 3.79 (s, 3H), 2.53 (s, 3H), 2.31 (s, 3H), 2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.7, 19.9, 20.2, 50.8, 89.1, 117.9, 119.4, 121.5, 122.8, 122.9, 125.3, 126.8, 127.5, 130.8, 137.7, 141.5, 148.7, 159.3, 166.3. IR (neat): 3053, 2985, 1674, 1593, 1421, 1265, 1611, 894, 740, 705 cm⁻¹. MS (70 eV, EI) m/z = 294. HRMS (EI): m/z calcd for C₁₉H₁₈O₃ (M⁺): 294.1256. Found, 294.1258.

4g: (E)-methyl-2-(2-fluoro-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.60–7.51 (m, 2H), 7.45–7.40 (m, 1H), 7.32–7.26 (m, 1H), 7.10–7.04 (m, 1H), 5.85 (s, 1H), 3.78 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.0, 91.1, 108.4, 117.2, 118.8, 119.5, 122.2, 124.4, 124.9, 128.7, 129.5, 132.0, 146.8, 158.6, 160.1, 165.7. IR (neat): 3053, 2987, 1662, 1548, 1417, 1205, 1138, 896, 738 cm⁻¹. MS (70 eV, EI) m/z = 270. HRMS (EI): m/z calcd for C₁₆H₁₁FO₃ (M⁺): 270.0692. Found, 270.0691.

4h: (E)-methyl-2-(5H-chromeno[4,3-b]pyridin-5-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.73 (q, J = 4.8 Hz, 1H), 8.37 (q, J = 8.0 Hz, 1H), 7.79 (q, J = 8.4 Hz, 1H), 7.47–7.41 (m, 1H), 7.31–7.20 (m, 3H), 5.78 (s, 1H), 3.79 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.0, 92.2, 116.8, 119.5, 120.1, 123.4, 124.0, 124.2, 131.9, 132.1, 147.0, 152.6, 158.1, 165.2. IR (neat): 3055, 2987, 1550, 1419, 1338, 1265, 1205, 1138, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 253. HRMS (EI): m/z calcd for C₁₅H₁₁NO₃ (M⁺): 253.0739. Found, 253.0741.

4i: (E)-methyl-2-(5H-chromeno[3,4-c]pyridin-5-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 9.01 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.84 (q, J = 8.0 Hz, 1H), 7.71 (d, J = 5.6 Hz, 1H), 7.48–7.43 (m, 1H), 7.33–7.28 (m, 1H), 7.23–7.18 (m, 1H), 5.93 (s, 1H), 3.80 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.1, 92.1, 115.0, 116.1, 117.7, 119.9, 123.0, 124.0, 132.6, 136.2, 147.0, 151.5, 151.7, 165.1. IR (neat): 3055, 2987, 1558, 1419, 1338, 1265, 1139, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 253. HRMS (EI): m/z calcd for C₁₅H₁₁NO₃ (M⁺): 253.0739. Found, 253.0738.

4j: (E)-methyl-2-(4H-thieno[3,4-c]chromen-4-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.79–7.64 (m, 3H), 7.37–7.32 (m, 2H), 7.18–7.13 (m, 1H), 5.68 (s, 1H), 3.79 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 51.0, 90.8, 117.0, 117.5, 123.3, 123.8, 124.0, 128.4, 129.5, 131.8, 150.0, 151.2, 155.5, 165.7. IR (neat): 3055, 2987, 2906, 1683, 1541, 1419, 1265, 1147, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 258. HRMS (EI): m/z calcd for C₁₄H₁₀O₃S (M⁺): 258.0351. Found, 258.0358.

5a: (E)-ethyl-2-(6H-benzo[c]chromen-6-ylidene)acetate. Light yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 8.0 Hz, 1H), 7.88 (m, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.59–7.54 (m, 1H), 7.41–7.31 (m, 3H), 7.20–7.16 (m, 1H), 5.85 (s, 1H), 4.26 (q, J = 14.4 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.5, 59.5, 91.4, 117.4, 118.3, 121.9, 122.2, 123.6, 124.4, 124.9, 128.8, 129.4, 130.2, 131.8, 150.7, 158.8, 165.5. IR (neat): 3055, 2985, 1734, 1541, 1419, 1373, 1265, 1138, 1045, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 266. HRMS (EI): m/z calcd for C₁₇H₁₄O₃ (M⁺): 266.0943. Found, 266.0945.

6a: (E)-1-(6H-benzo[c]chromen-6-ylidene)propan-2-one. Light yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ = 7.95 (d, J = 8.0 Hz, 1H), 7.91–7.88 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.58 (q, J = 7.2 Hz, 1H), 7.42–7.35 (m, 2H), 7.24–7.18 (m, 2H), 6.10 (s, 1H), 2.61 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 31.9, 103.6, 116.7, 118.5, 121.9, 122.6, 124.0, 124.3, 125.2, 129.0, 129.5, 130.2, 132.0, 150.3, 157.5, 196.9. IR (neat): 3055, 2985, 1732, 1598, 1438, 1373, 1247, 1047, 997, 846, 740 cm⁻¹. MS (70 eV, EI) m/z = 236. HRMS (EI): m/z calcd for C₁₆H₁₂O₂ (M⁺): 236.0837. Found, 236.0839.

6b: (E)-1-(4-methyl-6H-benzo[c]chromen-6-ylidene)propan-2-one. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.98–7.95 (m, 1H), 7.82–7.75 (m, 2H), 7.59–7.54 (m, 1H), 7.42–7.37 (m, 1H), 7.25–7.23 (m, 1H), 7.14–7.09 (m, 1H), 6.18 (s, 1H), 2.59 (s, 3H), 2.50 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.1, 32.2, 102.7, 118.2, 120.1, 122.1, 123.4, 124.0, 125.1, 126.3, 128.9, 130.0, 131.8, 132.0, 149.0, 157.5, 196.3. IR (neat): 3053, 2985, 1635, 1419, 1265, 1217, 1139, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 250. HRMS (EI): m/z calcd for C₁₇H₁₄O₂ (M⁺): 250.0994. Found, 250.0995.

6c: (E)-1-(8,9-dimethoxy-6H-benzo[c]chromen-6-ylidene)propan-2-one. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.82 (q, J = 8.0 Hz, 1H), 7.38–7.33 (m, 2H), 7.27–7.20 (m, 2H), 7.13 (s, 1H), 5.96 (s, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 2.63 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 31.7, 56.1, 101.9, 103.3, 106.4, 116.6, 117.2, 118.5, 121.9, 123.9, 124.1, 128.6, 129.4, 150.0, 150.2, 153.1, 157.9, 197.0. IR (neat): 3055, 2987, 2904, 1843, 1558, 1541, 1419, 1265, 1207, 1136, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 296. HRMS (EI): m/z calcd for C₁₈H₁₆O₄ (M⁺): 296.1049. Found, 296.1055.

6d: (E)-1-(5H-chromeno[4,3-b]pyridin-5-ylidene)propan-2-one. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.78 (dd, J = 4.8 Hz, 1H), 8.44 (dd, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.0 Hz, 1H), 7.50–7.45 (m, 1H), 7.36–7.23 (m, 3H), 6.06 (s, 1H), 2.63 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 31.9, 104.7, 116.2, 119.8, 120.3, 123.7, 124.4, 124.6, 132.0, 132.5, 147.0, 152.4, 153.0, 156.8, 196.5. IR (neat): 3053, 2987, 1749, 1539, 1419, 1265, 1220, 1138, 896, 740, 705 cm⁻¹. MS (70 eV, EI) m/z = 237. HRMS (EI): m/z calcd for C₁₅H₁₁NO₂ (M⁺): 237.0790. Found, 237.0794.

7a: (E)-benzyl-2-(6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 8.0 Hz, 1H), 7.88 (q, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.59–7.54 (m, 1H), 7.48–7.16 (m, 9H), 5.91 (s, 1H), 5.26 (s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 65.5, 90.9, 117.4, 118.3, 121.9, 122.3, 123.7, 124.2, 124.9, 128.0, 128.2, 128.5, 128.8, 129.5, 130.2, 133.0, 136.8, 150.6, 159.2, 165.2. IR (neat): 3053, 2985, 1683, 1629, 1600, 1436, 1419, 1265, 1145, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 328. HRMS (EI): m/z calcd for C₂₂H₁₆O₃ (M⁺): 328.1099. Found, 328.1095.

7b: (E)-benzyl-2-(8,9-dimethyl-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.53 (s, 1H), 7.48–7.25 (m, 8H), 5.85 (s, 1H), 5.25 (s, 2H), 2.36 (s, 3H), 2.30 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.9, 20.2, 65.4, 89.4, 117.3, 118.4, 121.8. 122.0, 122.7, 123.6, 125.6, 127.2, 127.9, 128.2, 128.5, 129.5, 136.9, 138.0, 141.7, 150.4, 159.6, 165.5. IR (neat): 3055, 2987, 1419, 1265, 1138, 894, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 356. HRMS (EI): m/z calcd for C₂₄H₂₀O₃ (M⁺): 356.1412. Found, 356.1421.

7c: (E)-benzyl-2-(8,9-dimethoxy-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.79–7.75 (m, 1H), 7.49–7.26 (m, 9H), 7.10 (s, 1H), 5.71 (s, 1H), 5.25 (s, 2H), 4.02 (s, 3H), 3.94 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 56.10, 56.12, 65.4, 88.4, 103.3, 106.1, 117.3, 118.2, 121.6, 123.6, 124.1, 128.0, 128.3, 128.4, 128.6, 129.4, 136.9, 150.0, 150.2, 153.0, 159.4, 165.5. IR (neat): 3055, 2987, 1541, 1419, 1338, 1265, 1211, 1138, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 388. HRMS (EI): m/z calcd for C₂₄H₂₀O₅ (M⁺): 388.1311. Found, 388.1314.

7d: (E)-benzyl-2-(8,9-difluoro-6H-benzo[c]chromen-6-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.65 (m, 2H), 7.55–7.50 (m, 1H), 7.46–7.16 (m, 8H), 5.71 (s, 1H), 5.24 (s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 65.7, 91.8, 110.7, 110.9, 113.7, 113.9, 116.8, 117.5, 121.3, 122.3, 124.0, 127.5, 128.1, 128.6, 130.9, 149.3, 150.5, 154.4, 157.2, 164.7. IR (neat): 3055, 2987, 1600, 1516, 1419, 1265, 1145, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 364. HRMS (EI): m/z calcd for C₂₂H₁₄F₂O₃ (M⁺): 364.0911. Found, 364.0912.

7e: (E)-benzyl-2-(5H-chromeno[4,3-b]pyridin-5-ylidene)acetate. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.76 (q, J = 4.8 Hz, 1H), 8.39 (q, J = 8.0 Hz, 1H), 7.99 (q, J = 8.0 Hz, 1H), 7.47–7.22 (m, 9H), 5.85 (s, 1H), 5.26 (s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 65.7, 92.3, 116.8, 119.6, 120.1, 123.5, 124.1, 124.2, 128.1, 128.2, 128.6, 131.9, 132.2, 136.6, 147.1, 152.7, 153.0, 158.4, 164.7. IR (neat): 2983, 2941, 1741, 1604, 1448, 1244, 1047, 846, 738 cm⁻¹. MS (70 eV, EI) m/z = 329. HRMS (EI): m/z calcd for C₂₁H₁₅NO₃ (M⁺): 329.1052. Found, 329.1057.

8a: (E)-2-(6H-benzo[c]chromen-6-ylidene)-1-phenylethanone. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.03–7.90 (m, 5H), 7.65–7.18 (m, 8H), 6.86 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ = 97.1, 117.6, 118.4, 122.1, 122.2, 123.9, 125.0, 127.9, 128.3, 128.9, 130.0, 130.1, 130.3, 131.6, 132.2, 140.8, 150.4, 158.7, 189.1. IR (neat): 2983, 2086, 1743, 1446, 1373, 1246, 1047, 937, 846, 634, 607 cm⁻¹. MS (70 eV, EI) m/z = 298. HRMS (EI): m/z calcd for C₂₁H₁₄O₂ (M⁺): 298.0994. Found, 298.0997.

8b: (E)-2-(8,9-dimethyl-6H-benzo[c]chromen-6-ylidene)-1-phenylethanone. Light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (dd, J = 8.4 Hz, 2H), 7.85 (dd, J = 8.0 Hz, 1H), 7.71–7.66 (m, 2H), 7.53–7.15 (m, 6H), 6.79 (s, 1H),. 2.37 (s, 3H), 2.35 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.0, 20.3, 95.8, 117.5, 118.5, 121.9, 122.0, 122.8, 123.8, 125.6, 127.8, 128.3, 129.6, 131.4, 138.1, 141.1, 142.2, 159.2, 188.9. IR (neat): 3055, 2985, 1616, 1550, 1419, 1265, 1213, 1147, 896, 738, 705 cm⁻¹. MS (70 eV, EI) m/z = 326. HRMS (EI): m/z calcd for C₂₃H₁₈O₂ (M⁺): 326.1307. Found, 326.1304.

Acknowledgements

This work was financially supported by the Natural Science Foundation of China (No. 21272169, 21302135) and the Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ15B020001.

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Footnote

† Electronic supplementary information (ESI) available: Characterization data; copies of ¹H, ¹³C, and NOSEY NMR spectra for all compounds; representative experimental procedures. See DOI: 10.1039/c5ra10550a

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