N-Heterocyclic carbene catalyzed conjugate umpolung reactions leading to coumarin derivatives

Abstract

The NHC-catalyzed selective condensation reactions between cinnamaldehydes and salicylaldehydes viahomoenolate intermediates are described. A number of 3-benzyl-chromen-2-ones could be obtained in good yields. The reactions occurred in high yielding with low catalyst loading.

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Introduction

N-Heterocyclic carbene (NHC) catalyzed umpolung reactions have drawn great attention in the past decade and the mechanisms are well documented.¹ The adducts of aromatic aldehydes and some NHCs can be used as equivalents of acyl anions to participate in some umpolung reactions, such as nucleophilic addition towards carbon–hetero multi bonds² (benzoin condensation) and carbon–carbon multi bonds (Stetter Reaction),³ as well as nucleophilic substitution towards the carbon–halogen bond.⁴ Another type of umpolung reaction is the so-called “conjugate umpolung reaction”.⁵ As shown in Scheme 1, enamineII as an equivalent of homoenolateIII could be generated by exposing the appropriate NHCs to trans α,β-unsaturated aldehydes such as cinnamaldehyde (1a). Nucleophilic substitution of the homoenolate equivalents towards some electrophiles was used to form carbon–carbon bonds, carbon–nitrogen bonds and carbon–hydrogen bonds affording acyclic esters,^5c,6 acyclic amides,⁷ cyclopantenes,^5d,8lactones,^5a,9lactams.¹⁰

Fig. 1 Schematic illustration of the carbene precursors.

Scheme 1 The generation of a homoenolate equivalent from cinnamaldehyde.

Chromen-2-one (known as coumarin) and its derivatives are fundamental building blocks of many bioactive molecules, natural products, and organic materials.¹¹ Bräse and coworkers reported that 3-alkyl-chromen-2-ones could be prepared via an umpolung reaction of cinnamaldehydes,^12,13 however, the reaction requires stoichiometric NHCs relative to reactants as the promoters and restricted to electron rich substrates. In 2011, Shi and Bräse reported that catalytic amounts of in situ generated NHC catalyzed a one-pot redox esterification of α,β-unsaturated aldehydes with simultaneous aldol condensation, but it is only efficient for crotonaldehyde.¹⁴ Recently, Nair reported that 2H-chromene-3-carboxaldehydes undergo an intramolecular rearrangement mediated by NHC leading to 3-alkyl-chromen-2-ones.¹⁵ Herein, we describe an highly efficient synthetic procedure for 3-benzyl-chromen-2-ones using in situ generated NHC as a catalyst and commercially available salicylaldehydes and cinnamaldehydes as starting materials. 3-Ethyl-chromen-2-ones also can be synthesized using the same catalytic system in moderate yields.

Results and discussion

We envisioned that the nucleophilic attack of bulkier NHCs towards cinnamaldehyde would be preferable to that of salicylaldehyde. Bulky NHCs may suppress the formation of 2-hydroxybenzoyl anion derived from salicylaldehyde and promote subsequent “conjugate umpolung” reaction. Thus the condensation of cinnamaldehyde and salicylaldehyde would selectively afford chromen-2-one derivatives. The influences of solvents, bases, temperatures and NHCs on the reaction of cinnamaldehyde (1a) and salicylaldehyde (2a) were studied to optimize the reaction conditions, and the results are listed in Table 1. When the reaction was performed in toluene, the target product 4a could be obtained in a yield of 16% even when up to 20 mol% of 3a was used (Table 1, entry 1). The side product 5 was also observed due to the condensation of the homoenolate equivalent III with cinnamaldehydes (1a) which has already been noted.¹² The yield of 4a could be slightly improved when a large excess of 2a was used in the presence of 5 mol% of 3a (entry 2). Higher 2a/1a ratio is believed to suppress the self condensation of 1a. THF was a better solvent in which the reaction took place smoothly at 40 °C affording 4a in 31% yield (entry 3). Other solvents such as DCM, t-BuOH, THF/t-BuOH, toluene, and 1,4-dioxane are much less efficient than THF (entries 7-11). Among the bases examined, DBU (DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene) is more suitable to the generation of NHC than other bases (entry 4). The generation of water was expected in the intermolecular condensation of 1a and 2a, thus the presence of 4 Å molecular sieves as a water absorbent would facilitate the reaction. Actually, addition of 0.5 g of 4 Å molecular sieves sharply raised the yield of 4a to 74% (entry 6). The NHCs derived from the carbene precursors listed in Fig. 1 were all active for the condensation reaction of cinnamaldehyde and salicylaldehyde, but 3b-d showed much lower activity than 3a. Bulkier imidazolium salt 3b was reported to be the best NHC precursor for the condensation reaction of salicylaldehydes and crotonaldehyde, but 3b showed low catalytic activity for other bulky α, β-unsaturated aldehydes.¹⁴ In this study, the yield of 4a was also sharply reduced when 3b was used as (entry 16) catalyst precursor. It suggested that bulky homoenolates would require a less steric NHC catalyst. The saturated NHC deprotonated from 3c exhibited the poorest activity (entry 17). Triazolium salt 3d derived NHC was similar to the NHC derived from 3b (entry 18). Raising the temperature to 80 °C could significantly facilitate the reaction, and the yield of the target product was increased to 76% even within 6 h (entry 19).

Table 1 Optimization of reaction conditions^a

Entry	3 (mol%)	Base	Solvent	T/°C	Yield (%)^b
a Reaction conditions: 1a, 1 mmol; 2a, 2 mmol; solvent, 2 mL; 24 h. b Isolated yield. c 1 eq. of 2a was used. d 40 °C, 12 h. e 80 °C, 6 h.
1	3a (20)	K2CO3 (3.0 eq)	toluene	100	16^c
2	3a (5)	K2CO3 (2.1 eq)	toluene	100	29
3	3a (5)	K2CO3 (2.1 eq)	THF	40	31
4	3a (5)	DBU (2.1 eq)	THF	40	52
5	3a (5)	t-BuOK (2.1 eq)	THF	40	6
6	3a (5)	DBU (2.1 eq)	THF + 4 Å MS	40	74
7	3a (5)	DBU (2.1 eq)	DCM + 4 Å MS	40	44
8	3a (5)	DBU (2.1 eq)	t-BuOH + 4 Å MS	40	11
9	3a (5)	DBU (2.1 eq)	THF/t-BuOH(9 : 1) + 4 Å MS	40	50
10	3a (5)	DBU (2.1 eq)	Toluene + 4 Å MS	40	63
11	3a (5)	DBU (2.1 eq)	1,4-dioxane + 4 Å MS	40	70
12	3a (5)	DBU (6 mol%)	THF + 4 Å MS	40	n.r.
13	3a (1)	DBU (2.1 eq)	THF + 4 Å MS	40	6
14	—	DBU (2.1 eq)	THF + 4 Å MS	40	—
15	3a (5)	DBU (2.1 eq)	THF + 4 Å MS	40	71^d
16	3b (5)	DBU (2.1 eq)	THF + 4 Å MS	40	36
17	3c (5)	DBU (2.1 eq)	THF + 4 Å MS	40	7
18	3d (5)	DBU (2.1 eq)	THF + 4 Å MS	40	37
19	3a (5)	DBU (2.1 eq)	THF + 4 Å MS	80	76^e

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Under the optimized reaction conditions described above, the condensation reaction of salicylaldehyde (2a) with a variety of cinnamaldehydes was investigated to examine the scope of the reaction (Table 2). The cinnamaldehyde derivatives having either electron-withdrawing or -donating groups worked well affording corresponding products in moderate to good yields when 5 mol% of 3a was used. Cinnamaldehydes containing an electron-donating group were more reactive towards salicylaldehyde (entries 1–5) than unsubstituted cinnamaldehyde. The results showed that the electron-donating substituents at meta- or para- positions of cinnamaldehydes play little influence on the reaction, and the yields of corresponding products were comparable to that of 4a. However, 1b having an ortho-methoxyl group gave higher yield of 4b. The electron-withdrawing groups substituted cinnamaldehydes were less reactive. The yield of 4g was 63%, lower than the yield of 4a (entry 6). Cinnamaldehyde containing a strong electron-withdrawing group has proven to be inert in the NHC catalyzed conjugate umpolung condensation reaction between cinnamaldehydes and salicylaldehydes. Actually, 1h containing a trifluoromethyl group showed quite low reactivity and the yield of 4h was only 5% when 5 mol% of 3a was used. Nevertheless, when the catalyst loading was increased to 10 mol%, the reaction could be significantly improved, and the yield was increased to 44%.

Table 2 The condensation reactions of substituted cinnamal-dehydes with salicylaldehyde^a

Entry	Substrate	Product	Yield (%) ^b
a Reaction conditions: 1, 1 mmol; 2a, 2 mmol; 3a, 0.05 mmol; DBU, 2.1 mmol; 4 Å MS, 0.5 g; THF, 2 ml; All reactions were carried out at 80 °C for 6 h. b Isolated yield. c 3a, 0.1 mmol.
1			84
2			73
3			75
4			77
5			75
6			63
7			5 (44^c)

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The reaction of a series of substituted salicylaldehydes with cinnamaldehyde was also tested under the optimized conditions (Table 3). The results showed that both electron-withdrawing and -donating groups could be tolerated. The electron-donating groups such as methoxyl and methyl on the phenyl ring had little influence on the condensation reaction (entries 1–3 and 9–11). However, the electron-withdrawing groups lowered the yields of corresponding products (entries 6–8). Compared to 4 or 5-substituted salicylaldehydes, 3-substituted salicylaldehydes were less reactive, even 3-methyl salicylaldehyde (2l) was inert. Probably the hindrance of the 3-substituted salicylaldehyde made it difficult to undergo nucleophilic substitution with the active carbonyl speies.^6a,6b The optimized reaction conditions had good tolerance towards some functional groups, such as ester groups (entry 12) and hydroxy groups (entry 13), and the corresponding products were suitable for further functionalization.

Table 3 Influences of substituent on salicylaldehyde^a

Entry	Substrate	Product	Yield (%) ^b
a Reaction conditions: 1a, 1 mmol; 2, 2 mmol; 3a, 0.05 mmol; DBU, 2.1 mmol; 4 Å MS, 0.5 g; THF, 2 ml; All reactions were carried out at 80 °C for 6 h. b Isolated yield.
1			71
2			72
3			62
4			68
5			76
6			50
7			48
8			62
9			68
10			69
11			trace
12			45
13			61

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The reactivity of aliphatic α,β-unsatuated aldehyde was investigated and the results are listed in Scheme 2. The catalytic generation of homoenolate anion was expected to be easier from cinnamaldehydes than from crotonaldehydes as the phenyl ring in cinnamaldehydes could lower the energy of III. Indeed, compared to cinnamaldehyde, crotonaldehyde is not so reactive towards salicylaldehydes. When 5 mol% of 3a was used, we found that the reaction between crotonaldehyde and salicylaldehydes gave 7a in only 5% yield. When the catalyst loading was increased to 30 mol%, 7a could be yielded in 50%. Other salicylaldehydes could also afford corresponding products in moderate yields. 2-Hydroxy-1-naphthaldehyde (2f) reacted as efficiently as 2a. Electron-donating substituents such as methyl and methoxyl could promote the reaction, affording 7b and 7c in 55% and 62% yields, respectively. Salicylaldehydes bearing electron-withdrawing groups such as 2g and 2i reacted less efficiently affording corresponding products in 38% and 43%, respectively.

Scheme 2 Reaction of salicylaldehydes with crotonaldehyde.

The proposed catalytic cycle is shown in Scheme 3. NHC species generated from deprotonation of IMes·HCl (3a) added to cinnamaldehyde (1a) leading to I. Further proton transfer resulted in the formation of intermediate II. Tautomerization of III would give its enolate form IV. Subsequent nucleophilic addition of IV to the carbonyl group of salicylaldehyde would afford V. Cyclization of V would give VI and release free IMes. Protonization and dehydration would be expected to form the final product 4a. Although γ-lactone 5 as a byproduct would also be expected from the reaction of III with another molecule of cinnamaldehyde. Using 2 equivalent of 2a has significantly suppressed the formation of 5. However, lactone 8, an outcome of III undergoes 1,2-addition to 2a, was not observed.

Scheme 3 A proposed catalytic cycle.

Conclusion

In summary, we described an NHC catalyzed intermolecular condensation reaction between salicylaldehydes and trans α,β-unsatuated aldehydes leading to 3-benzyl-chromen-2-ones in good to excellent yields. The low catalyst loading, good efficiency and good tolerance towards some functional groups made the procedure a promising way to synthesize chromen-2-one derivatives.

Experimental section

General information

All reactions were carried out under a nitrogen atmosphere. THF, 1,4-dioxane and toluene were dried and freshly distilled from sodium/benzophenone. t-BuOH and DCM were dried by distillation from calcium hydride and stored under nitrogen. Petroleum ether and ethyl acetate were distilled. Flash chromatography was carried out with silica gel (silica gel, 300–400 mesh). ¹H and ¹³C NMR spectra were recorded on Bruker AV-400 spectrometers with chloroform, methyl sulfoxide or acetone solutions of the compounds at a temperature of 300 K. Chemical shifts (δ) are expressed in ppm downfield to TMS at δ = 0 ppm and coupling constants (J) are expressed in Hz. IR spectra were recorded on a Bruker Vector-22 spectrophotometer and reported in cm⁻¹. EI mass spectra were recorded on GC-TOF.

Cinnamaldehyde and its derivatives were distilled under reduced pressure before use. All the carbene precursors were prepared according to known procedures.¹⁶ Other chemicals were used without further purification.

General procedure for NHC catalyzed synthesis of 3-alkyl-2H-chromen-2-one

Under an atmosphere of nitrogen, a mixture of trans α,β-unsaturated aldehyde (1.0 mmol), salicylaldehyde (2.0 mmol), 3a (17.1 mg, 0.05 mmol), DBU (320.0 mg, 2.1 mmol), and 0.5 g of 4 Å molecular sieves in 2 mL of THF was heated at 80 °C for 6 h. After cooling to room temperature the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography using petroleum ether/ethyl acetate (12 : 1) as the eluent.

3-Benzyl-2H-chromen-2-one (4a)¹²

Yield: 76%. White solid. Mp: 105–106 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.46 (t, J = 8.0 Hz, 1H), 7.36–7.27 (m, 8H), 7.23 (t, J = 8.0 Hz, 1H), 3.90 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.1, 153.1, 140.4, 138.7, 131.5, 129.3, 128.9, 128.7, 128.4, 126.9, 124.9, 119.6, 116.3, 36.4; IR (KBr): 1712, 1608, 1077, 1050, 754, 697 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₆H₁₂O₂, m/z 236.0837, found 236.0841.

3-(2-Methoxybenzyl)-2H-chromen-2-one (4b)¹⁴

Yield: 84%. White solid. Mp: 95–96 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.44 (dt, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.34–7.26 (m, 4H), 7.20 (m, 2H), 6.96 (dt, J = 7.4 Hz, J = 1.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.89 (s, 2H), 3.81 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.9, 157.7, 153.1, 138.8, 131.4, 130.5, 128.8, 128.4, 127.4, 126.0, 124.2, 120.8, 19.8, 116.4, 110.7, 55.5, 31.0; IR (KBr): 1709, 1607, 1276, 1048, 755 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₃, m/z 266.0943, found 266.0947.

3-(3-Methoxybenzyl)-2H-chromen-2-one (4c)

Yield: 73%. White solid. Mp: 92–94 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.46 (dt, J = 7.9 Hz, J = 1.4 Hz, 1H), 7.36 (dd, J = 7.8 Hz, J = 1 Hz, 1H), 7.33–7.26 (m, 3H), 7.23 (dt, J = 7.5 Hz, J = 1 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.84–6.82 (m, 2H), 3.87 (s, 2H), 3.81 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.8, 160.1, 153.3, 139.5, 139.4, 131.0, 129.9, 129.4, 127.6, 124.4, 121.9, 119.6, 116.6, 115.3, 112.3, 55.4, 36.7; IR (KBr): 1707, 1608, 1258, 1151, 1056, 761 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₃, m/z 266.0943, found 266.0948.

3-(4-Methoxybenzyl)-2H-chromen-2-one (4d)¹⁷

Yield: 75%. White solid. Mp: 119–120 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.46 (dt, J = 7.9 Hz, J = 1.4 Hz, 1H), 7.36 (dd, J = 7.8, 1.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26–7.20 (m, 4H), 6.90 (d, J = 8.4 Hz, 2H), 3.84 (s, 2H), 3.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.8, 158.6, 153.2, 139.1, 130.8, 130.5, 129.9, 129.7, 127.5, 124.4, 119.6, 116.5, 114.3, 55.4, 35.8; IR (KBr): 1723, 1608, 1512, 1244, 1166, 1036, 755 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₃, m/z 266.0943, found 266.0948.

3-(4-(Dimethylamino)benzyl)-2H-chromen-2-one (4e)

Yield: 77%. Pink solid. Mp: 135–136 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.70 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 3.67 (s, 2H), 2.84 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 161.2, 153.0, 149.6, 139.6, 131.3, 129.9, 129.7, 128.3, 125.8, 124.8, 119.7, 116.3, 113.0, 40.6, 35.5; IR (KBr): 1707, 1612, 1523, 1357, 1052, 752 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₈H₁₇NO₂, m/z 279.1259, found 279.1262.

3-(4-Methylbenzyl)-2H-chromen-2-one (4f)

Yield: 75%. White solid. Mp: 110 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.46 (t, J = 7.3 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.18–7.15 (m, 4H), 3.86 (s, 2H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.7, 153.1, 139.2, 136.5, 134.6, 130.8, 129.7, 129.5, 129.3, 127.4, 124.3, 119.6, 116.4, 36.2, 21.1; IR (KBr):1707, 1609, 1511, 1455, 1051, 752 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₂, m/z 250.0994, found 250.0994.

3-(4-Chlorobenzyl)-2H-chromen-2-one (4g)

Yield: 63%. White solid. Mp: 127–128 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.48 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.33–7.30 (m, 4H), 7.26–7.23 (m, 3H), 3.86 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.6, 153.2, 139.5, 136.3, 132.8, 131.1, 130.8, 129.0, 128.9, 127.5, 124.5, 119.4, 116.5, 36.1; IR (KBr): 1710, 1629, 1608, 1490, 1094, 1068, 1014, 757 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₆H₁₁ClO₂, m/z 270.0448, found 270.0450.

3-(3-(Trifluoromethyl)benzyl)-2H-chromen-2-one (4h)

Imidazolium salt 3a (34.2 mg, 0.1 mmol) was used as precatalyst. Yield: 44%. White solid. Mp: 100–101 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.55–7.45 (m, 5H), 7.41 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.26 (dt, J = 7.6 Hz, J = 0.8 Hz, 1H), 4.0 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.5, 153.3, 139.8, 139.0, 132.8, 131.2, 131.1 (q, J = 32.1 Hz), 129.3, 128.4, 127.6, 126.0 (q, J = 4.0 Hz), 124.5, 124.2 (q, J = 270.3 Hz), 123.8 (q, J = 3.9 Hz), 119.3, 116.5, 36.6; IR (KBr): 1718, 1609, 1331, 1163, 1121, 1072, 755, 703 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₁F₃O₂, m/z 304.0711, found 304.0709.

3-Benzyl-6-methoxy-2H-chromen-2-one (4i)¹²

Yield: 71%. White solid. Mp: 129–130 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.38–7.35 (m, 2H), 7.30–7.27 (m, 3H), 7.24 (d, J = 9.2 Hz, 1H), 7.21 (s, 1H), 7.04 (dd, J = 9.6 Hz, J = 2.8 Hz, 1H), 6.79 (d, J = 3.2 Hz, 1H), 3.90 (s, 2H), 3.80 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.9, 156.1, 147.5, 139.2, 137.8, 129.8, 129.5, 128.8, 126.9, 119.8, 118.6, 117.4, 109.6, 55.8, 36.6; IR (KBr): 1708, 1577, 1492, 1451, 1284, 1066, 1038, 815, 702 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₃, m/z 266.0943, found 266.0945.

3-Benzyl-7-methoxy-2H-chromen-2-one (4j)¹²

Yield: 72%. White solid. Mp: 106–107 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.37–7.33 (m, 2H), 7.30–7.22 (m, 5H), 6.81–6.78 (m, 2H), 3.86 (s, 2H), 3.85 (s, 3H) ; ¹³C NMR (100 MHz, CDCl₃) δ: 162.1, 162.0, 154.8, 139.5, 138.2, 129.4, 128.8, 128.4, 126.8, 125.8, 113.1, 12.4, 100.6, 55.8, 36.5; IR (KBr): 1709, 1616, 1251, 1150, 1051, 1022, 827 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₃, m/z 266.0943, found 266.0947.

3-Benzyl-8-methoxy-2H-chromen-2-one (4k)¹²

Yield: 62%. White solid. Mp: 86–89 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.37–7.34 (m, 2H), 7.30–7.27 (m, 3H), 7.23 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 6.93 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 2H) ; ¹³C NMR (100 MHz, CDCl₃) δ: 161.2, 147.1, 142.8, 139.5, 137.8, 129.7, 129.5, 128.8, 126.9, 124.2, 120.2, 119.0, 112.9, 56.3, 36.6; IR (KBr): 1719, 1609, 1580, 1481, 1281, 1110, 1060, 976, 783, 749, 729 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₃, m/z 266.0943, found 266.0945.

3-Benzyl-2H-benzo[h]chromen-2-one (4l)¹⁸

Yield: 68%. White solid. Mp: 129–130 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.55–8.53 (m, 1H), 7.86–7.84 (m, 1H), 7.65–7.60 (m, 3H), 7.40–7.28 (m, 7H), 3.97 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.8, 150.0, 140.1, 138.0, 134.4, 129.5, 129.0, 128.9, 128.3, 127.9, 127.1, 127.0, 124.3, 123.6, 123.0, 122.2, 114.9, 36.7; IR (KBr): 1709, 1614, 1061, 815, 761, 700 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₂₀H₁₄O₂, m/z 286.0994, found 286.0996.

2-Benzyl-3H-benzo[f]chromen-3-one (4m)¹²

Yield: 76%. White solid. Mp: 156–158 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.11 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.62 (dt, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.41–7.29 (m, 5H), 4.01 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.8, 152.5, 138.0, 135.2, 132.1, 130.3, 129.4, 129.0, 128.9, 128.8, 128.5, 128.0, 127.0, 125.9, 121.5, 116.7, 113.4, 37.0; IR (KBr): 1709, 1065 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₂₀H₁₄O₂, m/z 286.0994, found 286.0997.

3-Benzyl-6-chloro-2H-chromen-2-one (4n)¹⁹

Yield: 50%. White solid. Mp: 143 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.40 (dd, J = 8.8 Hz, 2Hz, 1H), 7.39–7.27 (m, 7H), 7.17 (s, 1H), 3.90 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.1, 151.5, 138.0, 137.3, 130.9, 130.7, 129.6, 129.5, 129.0, 127.1, 126.8, 120.6, 117.9, 36.7; IR (KBr): 1722, 1481, 1079, 1048, 849,817, 757, 704 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₆H₁₁O₂Cl, m/z 270.0448, found 270.0450.

3-Benzyl-8-chloro-2H-chromen-2-one (4o)

Yield: 48%. White solid. Mp: 110–113 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.52 (dd, J = 8.2 Hz, 1H), 7.38–7.34 (m, 2H), 7.30–7.27 (m, 3H), 7.25–7.24 (m, 2H), 7.16 (t, J = 7.8 Hz, 1H), 3.91 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.7, 148.9, 138.9, 137.4, 131.3, 130.5, 129.5, 129.0, 127.1, 126.0, 124.6, 121.4, 120.8, 36.6; IR (KBr): 1726, 1450, 1073, 1041, 794, 695 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₆H₁₁ClO₂, m/z 207.0448, found 207.0444.

3-Benzyl-6-bromo-2H-chromen-2-one (4p)

Yield: 62%. White solid. Mp: 143–144 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.54 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.31–7.28 (m, 3H), 7.19 (d, J = 9.2 Hz, 1H), 7.16 (s, 1H), 3.89 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.0, 151.9, 137.9, 137.3, 133.5, 130.9, 129.8, 129.5, 129.0, 127.1, 121.0, 118.2, 116.9, 36.7; IR (KBr): 1720, 1477, 1050, 823, 752, 726, 700 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₆H₁₁BrO₂, m/z 313.9942, found 313.9943.

3-Benzyl-6-methyl-2H-chromen-2-one (4q)^18,20

Yield: 68%. White solid. Mp: 123–128 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.37–7.34 (m, 2H), 7.30–7.25 (m, 4H), 7.22–7.20 (m, 2H), 7.15 (s, 1H), 3.89 (s, 2H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.9, 151.3, 139.3, 137.9, 134.0, 131.8, 129.5, 129.3, 128.8, 127.3, 126.9, 119.2, 116.2, 36.6, 20.8; IR (KBr): 1711, 1492, 1058, 821, 756, 702 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₂, m/z 250.0994, found 250.0998.

3-Benzyl-7-methyl-2H-chromen-2-one (4r)

Yield: 69%. White solid. Mp: 103–105 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.53 (s, 1H), 7.37–7.27 (m, 6H), 7.16 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 6.8 Hz, 1H), 3.92 (s, 2H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.7, 153.7, 138.1, 136.4, 135.6, 130.6, 129.3, 128.8, 128.7, 126.9, 125.7, 118.2, 114.5, 37.0, 18.3; IR (KBr): 1710, 1602, 1462, 1073, 1039, 790, 757, 733, 702 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₇H₁₄O₂, m/z 250.0994, found 250.0995.

Ethyl 3-benzyl-2-oxo-2H-chromene-6-carboxylate (4t)

Yield: 45%. White solid. Mp: 140–142 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.13 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.39–7.34 (m, 3H), 7.32–7.28 (m, 4H), 4.38 (q, J = 7.6 Hz, 2H), 3.90 (s, 2H), 1.39 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.4, 161.1, 155.9, 139.0, 137.3, 131.9, 130.5, 129.6, 129.5, 129.0, 127.1, 126.9, 119.2, 116.7, 61.5, 36.7, 14.4; IR (neat): 1725, 1705, 1606, 1271, 1242, 1217, 1170, 1101, 1046, 765, 707 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₉H₁₆O₄, m/z 308.1049, found 308.1047.

3-Benzyl-6-hydroxy-2H-chromen-2-one (4u)

4.1 eq of DBU (624 mg, 4.1 mmol) was used. After cooling to room temperature, the reaction mixture was neutralized by dilute hydrochloric acid. The organic layer was separated. Aqueous layer was extracted by ethyl acetate (10 ml × 3). The organic layer was collected and dried over MgSO₄. After concentrated under reduced pressure, the residue was purified by flash chromatography using petroleum ether/ethyl acetate (4 : 1) as the eluent. Yield: 61%. Pale yellow solid, Mp: 180–182 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.37–7.33 (m, 2H), 7.29–7.26 (m, 3H), 7.20–7.18 (m, 2H), 6.97 (dd, J = 8.6 Hz, J = 3.0 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 5.53 (br, 1H), 3.89 (s, 2H); ¹³C NMR (100 MHz, Acetone-d₆) δ: 161.5, 154.3, 147.4, 139.7, 139.1, 129.8, 129.6, 128.9, 126.9, 120.6, 119.3, 117.3, 112.6, 38.8; IR (neat): 3433, 3199, 1699, 1666, 1580, 1449, 1228, 1143, 975, 715, 697, 589 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₆H₁₂O₃, m/z 252.0786, found 252.0782.

For 7a–c, 3a (102.3 mg, 0.3 mmol) and DBU (365 mg, 2.4 mmol) were used.

3-Ethyl-2H-chromen-2-one (7a)¹⁴

Yield: 50%. White solid. Mp: 72–73 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.49–7.44 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.26 (dt, J = 7.3 Hz, J = 0.8 Hz, 1H), 2.61 (dq, J = 7.5 Hz, J = 1.0 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.8, 153.1, 137.6, 131.4, 130.4, 127.3, 124.3, 119.7, 116.4, 24.0, 12.4; IR (KBr): 1718, 1605, 1175, 1081, 1053, 766, 714 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₁H₁₀O₂, m/z 174.0681, found 174.0679.

3-Ethyl-6-methyl-2H-chromen-2-one (7b)

Yield: 55%. White solid. Mp: 54–55 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.43 (s, 1H), 7.27–7.20 (m, 3H), 2.60 (q, J = 7.2 Hz, 2H), 2.4 (s, 3H), 1.25 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.1, 151.2, 137.6, 133.9, 131.5, 131.2, 127.1, 119.4, 116.1, 24.0, 20.8, 12.4; IR (KBr): 1710, 1182, 1088, 1053, 818 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₂H₁₂O₂, m/z 188.0837, found 188.0841.

3-Ethyl-6-methoxy-2H-chromen-2-one (7c)

Yield: 62%. White solid. Mp: 106–107 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.43 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.84–6.82 (m, 2H), 3.86 (s, 3H), 5.71 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.2, 161.9, 154.7, 137.7, 128.1, 127.7, 113.3, 112.3, 100.6, 55.8, 23.8, 12.5; IR (KBr): 1705, 1615, 1506, 1238, 1155, 1087, 1053, 1025 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₂H₁₂O₃, m/z 204.0786, found 204.0785.

6-Chloro-3-ethyl-2H-chromen-2-one (7d)

Yield: 38%. White solid. Mp: 130–131 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.43–7.40 (m, 3H), 7.27–7.25 (m, 1H), 2.61 (dq, J = 7.4 Hz, J = 1.1 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.2, 151.5, 136.3, 132.8, 130.5, 129.5, 126.5, 120.8, 117.9, 24.1, 12.3; IR (KBr): 1716, 1631, 1480, 1248, 1180, 1087, 1058, 817 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₁H₉ClO₂, m/z 208.0291, found 208.0294.

6-Bromo-3-ethyl-2H-chromen-2-one (7e)^14,15

Yield: 43%. White solid. Mp: 113–114 °C. ¹H NMR (400 MHz, CDCl₃) δ: 7.59 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.40 (s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 2.62 (dq, J = 7.8 Hz, J = 1.1 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.2, 152.0, 136.2, 133.3, 132.8, 129.6, 121.3, 118.2, 116.9, 24.1, 12.3; IR (KBr): 1719, 1091, 1065, 814, 650 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₁H₉BrO₂, m/z 251.9786, found 251.9782.

2-Ethyl-3H-benzo[f]chromen-3-one (7f)²¹

Yield: 51%. White solid. Mp: 108–109 °C. ¹H NMR (400 MHz, CDCl₃) δ: 8.82 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 6.8 Hz, 1H), 7.68 (dt, J = 7.2 Hz, J = 1.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 2.73 (m, 2H), 1.35 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.9, 152.4, 133.3, 131.6, 130.5, 130.3, 129.0, 128.8, 127.9, 125.8, 121.5, 116.8, 113.5, 24.4, 12.6; IR (KBr): 1710, 1576, 1212, 1086, 965, 814 cm⁻¹; HRMS (TOF MS EI⁺) calcd. for C₁₅H₁₂O₂, m/z 224.0837, found 224.0841.

Acknowledgements

The authors thank the National Science Foundation of China for financial support through project No. 21072170.

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Footnote

† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/c1ra00916h/

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