N-heterocyclic carbene-catalyzed [4 + 2] cycloaddition of ketenes and 3-aroylcoumarins: highly enantioselective synthesis of dihydrocoumarin-fused dihydropyranones

Abstract

The N-heterocyclic carbene-catalyzed [4 + 2] cyclization of ketenes and 3-aroylcoumarins has been developed to give the corresponding dihydrocoumarin-fused multisubstituted dihydropyranones in high yield with good diastereoselectivity and high enantioselectivity.

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Introduction

Compounds with two or more heterocycles fused play a vital role in natural and unnatural bioactive compounds.¹ Coumarins are present in large quantities in human diets and, more importantly, they are the active molecules in many traditional herbal medicines.² Thus the synthesis of coumarin and its derivatives attracts intensive attention.³ In this paper, we wish to report an N-heterocyclic carbene-catalyzed cycloaddition reaction of ketenes with aroylcoumarins for the construction of dihydrocoumarin-fused dihydropyranones.

Since Staudinger's discovery of ketenes in the early 1900s,⁴ their cycloaddition reactions have become a powerful methodology for the construction of cyclic compounds.^5,6 Over the past decades, N-heterocyclic carbene (NHC) catalysis has been very successful for a variety of reactions.⁷ We,⁸ independently with Smith et al.,⁹ demonstrated that N-heterocyclic carbenes (NHCs) were efficient catalysts for the formal cycloaddition reactions of ketenes. In 2008 and later, we reported the NHC-catalyzed enantioselective [4 + 2] cycloaddition of ketenes with activated enones, giving the corresponding dihydropyranones in good yield with high enantioselectivity.¹⁰ We envisaged that 3-aroylcoumarin may act as the oxodiene for the NHC-catalyzed [4 + 2] cycloaddition of ketenes, and thus provide a facile enantioselective access to coumarin-fused dihydropyranones.

Results and discussion

Initially, the reaction of phenyl(ethyl)ketene (1a) and 3-benzoyl-2H-chromen-2-one (2a) was investigated under NHC catalysis (Table 1). We were encouraged to find that the desired [4 + 2] cycloadduct 3aa was isolated in 49% yield with 29% ee and 8 : 1 dr in the presence of 10 mol% NHC 4a′,^8a,11 generated from L-pyroglutamic acid derived triazolium salt 4a and 20 mol% of Cs₂CO₃ (entry 1). NHC 4b′ with a less bulky TMS group and NHC 4c′ with a bulky N-(2-isopropyl)phenyl group resulted in better yields but decreased enantioselectivity (entries 2 and 3). NHC 4d′ with a free hydroxyl group¹² led to a reversed but high enantioselectivity (80% ee) for this reaction (entry 4). Tetracyclic NHC 5′, derived from aminoindanol, also worked well in the reaction, giving the cycloadduct 3aa in 88% yield with 67% ee and 8 : 1 dr (entry 5).

Table 1 Screening of NHC catalysts and optimization of reaction conditions

Entry	4–5 (X)^a	Cs2CO3 (Y)	Solvent	T (°C)	Yield^b (%)	ee^c (%)	dr^e
a NHC 4′–5′ was generated from its precursor 4–5 (10–12 mol%) in the presence of Cs2CO3 (10–20 mol%) in the noted solvent at room temperature for 30 min. b Isolated yield of pure cis-3aa. c Determined by HPLC. d ent-3aa was isolated as the major enantiomer for entries 1–3. e Determined by ^1H NMR (300 MHz) of the reaction mixture.
1	4a (10)	20	DCM	rt	49	29^d	8 : 1
2	4b (10)	20	DCM	rt	77	6^d	6 : 1
3	4c (10)	20	DCM	rt	82	18^d	7 : 1
4	4d (10)	20	DCM	rt	81	80	10 : 1
5	5 (10)	20	DCM	rt	88	67	8 : 1
6	4d (10)	20	THF	rt	67	10	8 : 1
7	4d (10)	20	Toluene	rt	89	87	8 : 1
8	4d (10)	20	Toluene	0 °C	91	83	10 : 1
9	4d (12)	10	Toluene	0 °C	87	91	12 : 1

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Solvent screening revealed that the reaction performed better in toluene than in DCM or THF in terms of enantioselectivity (87% ee vs. 80% ee or 10% ee, entries 4, 6–7). Lowering the reaction temperature to 0 °C benefits the yield but with decreased enantioselectivity (entry 8). Careful examination revealed that excess Cs₂CO₃ could also promote the reaction, giving the cycloadduct as a racemate. Thus the reaction employing 10 mol% of Cs₂CO₃ and 12 mol% triazolium NHC precursor 4d resulted in an improved enantioselectivity (91% ee) and diastereoselectivity (12 : 1 dr) (entry 9).

With the optimized reaction condition in hand, the reaction scope was then briefly investigated (Table 2). It was found that aryl(alkyl)ketenes with ethyl, methyl and n-propyl all worked well to give the corresponding cycloadduct (3aa, 3ba and 3ca) in high yield with high enantioselectivity and diastereoselectivity. However, ketenes with a bulky isobutyl group resulted in decreased yield and enantioselectivity (3da). Electron-withdrawing substituents (4-Br, 4-ClC₆H₄) are well tolerated, giving cycloadducts (3ea and 3fa) in high yield with high enantioselectivity, while an electron-donating group (4-MeC₆H₄) led to some loss of yield and enantioselectivity (3ga). It should be noted that reaction of ketene containing an o-chlorophenyl group gave only a trace of cycloaddduct (3ha). Interestingly, ketene 1i derived from cycloheptanecarbonyl chloride worked very well, giving the desired cycloadduct 3ia in 83% yield with 98% ee, while benzyl(ethyl)ketene (1j) resulted in decreased yield and low diastereo- and enantioselectivity (3ja).

Table 2 Variation of ketenes

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Several 3-aroylcoumarins were also tested for the reaction (Table 3). Both an electron-donating group (4-MeC₆H₄) and electron-withdrawing groups (4-BrC₆H₄, 4-ClC₆H₄) on the aroyl are tolerated, giving the desired cycloadduct in high yield with good diastereo- and enantioselectivity (3ab, 3ac and 3ad). However, aroyl groups with meta- or ortho-substituents (3-ClC₆H₄, 2-ClC₆H₄) led to decreased enantioselectivity albeit in high yield and good to high diastereoselectivity (3ae and 3af). 6-Halocoumarin derivatives (X = Cl, Br) also worked as well as the parent one (3ag and 3ah).

Table 3 Variation of 3-aroylcoumarins^a

a Reaction conditions as Table 2.

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The absolute stereochemistry of cycloadduct (+)-3fa was unambiguous established by the X-ray analysis† of its crystal (Fig. 1),¹³ and that of all other cycloadducts is proposed by analogy. The crystal of (+)-3fa was prepared from a solution in DCM–ether (90 : 10) with a trace of petroleum ether.

Fig. 1 X-ray structure of cycloadduct (+)-3fa.

Based on the dramatic effect of the free hydroxyl group of the NHC catalyst, and the diastereo- and enantioselectivity observed,¹⁴ a likely transition state is proposed as in Fig. 2. The enolate generated by addition of the NHC to ketene favors its Z-isomer, which minimizes the steric repulsion. The hydrogen-bonding between the hydroxy group of the NHC–ketene adduct and aroyl group of the coumarin derivative directs the facial selectivity. The endo transition state of the Diels–Alder reaction is favored and results in the cis-cycloadduct observed.

Fig. 2 Proposed model for stereochemical outcome.

Conclusions

In summary, N-heterocyclic carbenes were found to be efficient catalysts for the [4 + 2] cycloaddition of ketenes and 3-aroylcoumarins. When the NHC derived from L-pyroglutamic acid and featuring a free hydroxyl group was used as the catalyst, the desired dihydrocoumarin-fused dihydropyranones were obtained in high yield with good to high diastereo- and enantioselectivity.

Experimental

Typical procedure for NHC-catalyzed [4 + 2] cycloaddition of ketenes with 3-aroylcoumarins

An oven-dried 50 mL Schlenk tube equipped with a stir bar was charged with triazolium salt 4d (27.3 mg, 0.06 mmol) and anhydrous Cs₂CO₃ (17 mg, 0.05 mmol). This tube was closed with a septum, evacuated, and back-filled with argon. To this mixture was added freshly distilled toluene (5 mL) and stirred for 30 min at room temperature. After stirring for 10 min at 0 °C, ketene 1a (146 mg, 1 mmol) and 3-aroylcoumarin 2a (125 mg, 0.5 mmol) were added. After stirring for 24 h, the reaction mixture was diluted with diethyl ether and passed through a short silica pad. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate–petroleum ether, typically 1 : 100) to give the desired product.

Racemic samples for the standard of chiral HPLC spectra were prepared using 2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolium chloride as the catalyst.

(1S,10bS)-1-Ethyl-1,4-diphenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3aa). Yield: 172.4 mg (87%), white solid, mp 130–132 °C, R_f = 0.67 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +158.4 (c 1.2, CHCl₃), HPLC analysis: 91% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 16.3 min (major), 25.9 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.48–7.42 (m, 3H), 7.40–7.37 (m, 4H), 7.25–7.24 (m, 1H), 7.19–7.02 (m, 3H), 7.04 (d, J = 8.1 Hz, 1H), 6.73 (dd, J = 6.6 Hz, J = 1.8 Hz, 2H), 4.67 (s, 1H), 2.40–2.32 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 170.0, 164.0, 158.1, 151.7, 136.5, 131.6, 131.4, 130.0, 129.9, 129.4, 128.9, 128.3, 127.9, 126.0, 124.1, 117.1, 116.8, 104.1, 56.5, 40.2, 29.6, 10.2. IR (KBr) ν 3044, 1951, 1774, 1612, 1321, 785, 515, 468. HRMS (EI) m/z: M⁺ Calc. for C₂₆H₂₀O₄, 396.1362, Found 396.1366.

(1S,10bS)-1-Methyl-1,4-diphenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ba). Yield: 161.4 mg (85%), white solid, mp 90–92 °C, R_f = 0.56 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +167.3 (c 1.0, CHCl₃), HPLC analysis: 87% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 12.3 min (major), 19.4 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.49–7.45 (m, 1H), 7.42–7.27 (m, 6H), 7.25–7.21 (m, 1H), 7.20–7.17 (m, 3H), 7.0–7.06 (m, 1H), 6.81–6.77 (m, 2H), 4.53 (s, 1H), 1.94 (s, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 170.8, 164.2, 157.9, 151.5, 137.4, 131.5, 131.3, 130.1, 129.8, 129.4, 129.0, 128.3, 127.9, 125.5, 124.1, 117.7, 116.7, 104.5, 52.0, 42.6, 25.0. IR (KBr) ν 3024, 1855, 1774, 1642, 1221, 775, 550, 468. HRMS (EI) m/z: M⁺ Calc. for C₂₅H₁₈O₄, 382.1205, Found 382.1212.

(1S,10bS)-1,4-Diphenyl-1-propyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ca). Yield: 178.1 mg (87%), white solid, mp 122–124 °C, R_f = 0.70 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +241 (c 1.5, CHCl₃), HPLC analysis: 91% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 85 : 15, 1.0 mL min⁻¹, 254 nm, 11.5 min (major), 15.9 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.54–7.40 (m, 7H), 7.38–7.15 (m, 4H), 7.05 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 6.0 Hz, 2H), 4.66 (s, 1H), 2.35 (t, J = 8.7 Hz, 2H), 1.96–1.86 (m, 1H), 1.36–1.23 (m, 1H), 1.02 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 170.1, 164.0, 158.1, 151.6, 136.6, 131.6, 131.4, 130.0, 129.8, 129.3, 128.8, 128.2, 127.9, 125.9, 124.1, 117.7, 116.8, 104.1, 56.1, 40.5, 38.9, 18.7, 14.4. IR (KBr) ν 3030, 1961, 1834, 1644, 1331, 765, 545, 455. HRMS (EI) m/z: M⁺ Calc. for C₂₇H₂₂O₄, 410.1518, Found 410.1523.

(1S,10bS)-1-Isobutyl-1,4-diphenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3da). Yield: 166.7 mg (78%), white solid, mp 121–123 °C, R_f = 0.40 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +241.3 (c 1.0, CHCl₃), HPLC analysis: 70% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 85 : 15, 1.0 mL min⁻¹, 254 nm, 10.2 min (major), 15.5 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.47–7.35 (m, 7H), 7.26–7.20 (m, 4H), 7.10 (d, J = 8.7 Hz, 1H), 6.94–6.91 (m, 2H), 4.58 (s, 1H), 2.30–2.17 (m, 2H), 2.04–1.95 (m, 1H), 1.09 (d, J = 7.5 Hz, 3H), 0.33 (d, J = 6.6 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 170.4, 164.0, 158.5, 151.5, 136.1, 131.5, 131.3, 130.1, 130.0, 129.7, 128.9, 128.4, 127.9, 126.6, 124.0, 117.7, 117.2, 104.1, 54.8, 45.7, 42.3, 25.9, 25.5, 23.6. IR (KBr) ν 3030, 1871, 1674, 1512, 1221, 780, 535. HRMS (EI) m/z: M⁺ Calc. for C₂₈H₂₄O₄, 424.1675, Found 424.1682.

(1S,10bS)-1-(4-Bromophenyl)-1-ethyl-4-phenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ea). Yield: 206.4 mg (87%), white solid, mp 140–141 °C, R_f = 0.65 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +231.4 (c 1.5, CHCl₃), HPLC analysis: 91% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 15.6 min (major), 18.9 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.55–7.38 (m, 7H), 7.32–7.20 (m, 3H), 7.05 (d, J = 7.8 Hz, 1H), 6.61 (d, J = 5.7 Hz, 2H), 4.67 (s, 1H), 2.37–2.29 (m, 2H), 1.19 (t, J = 6.9 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.5, 164.0, 158.0, 151.65, 135.6, 132.0, 131.6, 131.3, 130.2, 129.9, 129.3, 128.0, 127.7, 124.3, 122.5, 117.8, 116.4, 103.9, 56.2, 39.9, 29.6, 10.1. IR (KBr) ν 2980, 1836, 1658, 1556, 1262, 755. HRMS (EI) m/z: M⁺ Calc. for C₂₆H₁₉Br⁷⁹O₄, 474.0467, Found 474.0475, M⁺ Calc. for C₂₆H₁₉Br⁸¹O₄, 476.0446, Found 474.0443.

(1S,10bS)-1-(4-Chlorophenyl)-1-ethyl-4-phenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3fa). Yield: 187.2 mg (87%), white solid, mp 119–122 °C, R_f = 0.70 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +211.3 (c 1.4, CHCl₃), HPLC analysis: 90% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 8.6 min (major), 10.7 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.55–7.51 (m, 2H), 7.50–7.48 (m, 2H), 7.44–7.39 (m, 3H), 7.27–7.22 (m, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.7 Hz, 2H), 4.67 (s, 1H), 2.38–2.29 (m, 2H), 1.20 (t, J = 6.9 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.6, 164.0, 158.1, 151.6, 135.1, 134.3, 131.6, 131.4, 130.2, 129.9, 129.4, 129.1, 128.0, 127.4, 124.3, 117.8, 116.4, 103.9, 56.1, 40.0, 29.7, 10.1. IR (KBr) ν 3010, 1856, 1648, 1556, 1262, 775. HRMS (EI) m/z: M⁺ Calc. for C₂₆H₁₉ClO₄, 430.0972, Found 430.0979.

(1S,10bS)-1-Ethyl-4-phenyl-1-p-tolyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ga). Yield: 157.2 mg (77%), white solid, mp 121–123 °C, R_f = 0.60 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +153.3 (c 1.1, CHCl₃), HPLC analysis: 66% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 85 : 15, 1.0 mL min⁻¹, 254 nm, 14.9 min (major), 18.5 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.55–7.37 (m, 8H), 7.25–7.23 (m, 1H), 7.05–6.95 (m, 2H), 6.61 (d, J = 7.5 Hz, 2H), 4.64 (s, 1H), 2.35–2.30 (m, 2H), 2.22 (s, 3H), 1.19 (t, J = 6.9 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 170.3, 164.1, 158.4, 151.8, 138.1, 133.5, 131.8, 131.5, 130.0, 129.7, 129.5, 128.0, 126.0, 124.2, 117.8, 117.0, 104.2, 56.3, 40.3, 29.8, 21.1, 10.3. IR (KBr) ν 3026, 1851, 1674, 1512, 1221, 765, 565, 480. HRMS (EI) m/z: M⁺ Calc. for C₂₇H₂₂O₄, 410.1518, Found 410.1523.

(S)4′-Phenyl-2′H-spiro[cycloheptane-1,1′-pyrano[3,4-c]chromene]-2′,5′(10b′H)-dione (3ia). Yield: 155.4 mg (83%), white solid, mp 95–97 °C, R_f = 0.50 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +142.1 (c 1.0, CHCl₃), HPLC analysis: 98% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 16.9 min (major), 28.5 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.64 (d, J = 7.2 Hz, 2H), 7.50–7.32 (m, 5H), 7.16–7.09 (m, 2H), 4.27 (s, 1H), 2.32–2.24 (m, 1H), 2.04–2.02 (m, 1H), 2.02–2.00 (m, 1H), 1.80–1.08 (m, 8H), 0.87–0.85 (m, 1H). ¹³C NMR (300 MHz, CDCl₃) δ 172.0, 160.0, 151.8, 131.7, 131.4, 130.2, 129.7, 129.5, 128.3, 127.9, 124.0, 117.7, 103.0, 49.2, 43.4, 34.8, 30.6, 30.5, 28.8, 24.8, 23.1. IR (KBr) ν 3030, 1816, 1658, 1356, 1262, 760. HRMS (EI) m/z: M⁺ Calc. for C₂₄H₂₂O₄, 374.1518, Found 374.1526.

(1R,10bS)-1-Benzyl-1-ethyl-4-phenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ja). Yield: 155.1 mg (76%), white solid, mp 89–91 °C, R_f = 0.60 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +173.1 (c 1.0, CHCl₃), HPLC analysis: 48% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 85 : 15, 1.0 mL min⁻¹, 254 nm, 12.9 min (major), 15.4 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.47 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 6.9 Hz, 2H), 7.40–7.09 (m, 10H), 7.02 (d, J = 7.8 Hz, 1H), 4.33 (s, 1H), 4.04 (d, J = 15.0 Hz, 1H), 3.11 (d, J = 15.3 Hz, 1H), 2.01–1.91 (m, 1H), 1.88–1.75 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.3, 161.1, 160.9, 151.3, 135.9, 132.1, 131.1, 129.8, 129.3, 129.1, 128.8, 128.1, 127.9, 127.3, 124.1, 118.9, 118.1, 101.4, 49.6, 39.2, 37.0, 26.0, 8.7. IR (KBr) ν 2990, 1766, 1556, 1455, 1262, 779. HRMS (EI) m/z: M⁺ Calc. for C₂₇H₂₂O₄, 410.1518, Found 410.1523.

(1S,10bS)-1-Ethyl-1-phenyl-4-p-tolyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ab). Yield: 178.5 mg (87%), white solid, mp 95–97 °C, R_f = 0.61 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +256.4 (c 1.5, CHCl₃), HPLC analysis: 87% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 85 : 15, 1.0 mL min⁻¹, 254 nm, 12.3 min (major), 16.2 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.49–7.46(m, 3H), 7.42–7.36 (m, 1H), 7.25–7.15 (m, 6H), 7.03 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 6.6 Hz, 2H), 4.64 (s, 1H), 2.39–2.31 (m, 3H), 1.18 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 170.2, 164.2, 158.3, 151.6, 142.2, 136.4, 130.0, 129.9, 129.4, 128.8, 128.6, 128.5, 128.2, 126.0, 124.0, 117.6, 116.8, 103.2, 56.8, 40.2, 29.5, 21.7, 10.1. IR (KBr) ν 3030, 1851, 1674, 1512, 1322, 775, 525, 458. HRMS (EI) m/z: M⁺ Calc. for C₂₇H₂₂O₄, 410.1518, Found 410.1522.

(1S,10bS)-4-(4-Bromophenyl)-1-ethyl-1-phenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ac). Yield: 205.5 mg (87%), white solid, mp 127–129 °C, R_f = 0.61 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +163 (c 1.0, CHCl₃), HPLC analysis: 80% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 15.2 min (major), 21.7 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.54–7.48 (m, 3H), 7.43–7.37 (m, 3H), 7.27–7.16 (m, 4H), 7.04 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 6.6 Hz, 2H), 4.64 (s, 1H), 2.39–2.31 (m, 3H), 1.18 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.7, 162.7, 158.0, 151.5, 136.3, 131.4, 131.2, 130.3, 130.0, 129.4, 128.9, 128.3, 126.1, 125.9, 124.2, 117.7, 116.5, 104.6, 56.4, 40.2, 29.5, 10.1. IR (KBr) ν 3030, 1851, 1774, 1542, 1221, 785, 468. HRMS (EI) m/z: C₂₆H₁₉Br⁷⁹O₄, 474.0467, Found 474.0475, M⁺ Calc. for C₂₆H₁₉Br⁸¹O₄, 476.0446, Found 474.0443.

(1S,10bS)-4-(4-Chlorophenyl)-1-ethyl-1-phenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ad). Yield: 191.5 mg (89%), white solid, mp 127–129 °C, R_f = 0.62 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +189.7 (c 1.3, CHCl₃), HPLC analysis: 87% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 16.2 min (major), 25.8 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.46–7.41 (m, 3H), 7.40–7.36 (m, 3H), 7.28–7.14 (m, 4H), 7.05 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 6.6 Hz, 2H), 4.66 (s, 1H), 2.40–2.32 (m, 3H), 1.19 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.8, 162.7, 158.1, 151.5, 137.7, 136.3, 131.3, 130.1, 130.2, 129.4, 128.9, 128.4, 128.3, 125.9, 124.3, 117.7, 116.6, 104.6, 56.5, 40.2, 29.6, 10.2. IR (KBr) ν 3040, 1851, 1674, 1512, 1221, 760, 545, 480. HRMS (EI) m/z: M⁺ Calc. for C₂₆H₁₉ClO₄, 430.0972, Found 430.0979.

(1S,10bS)-4-(3-Chlorophenyl)-1-ethyl-1-phenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ae). Yield: 184.5 mg (86%), white solid, mp 99–101 °C, R_f = 0.61 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +241.2 (c 1.5, CHCl₃), HPLC analysis: 66% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 85 : 15, 1.0 mL min⁻¹, 254 nm, 9.4 min (major), 13.4 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.52–7.46 (m, 3H), 7.44–7.36 (m, 3H), 7.28–7.14 (m, 4H), 7.05 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 6.6 Hz, 2H), 4.65 (s, 1H), 2.40–2.31 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.9, 162.8, 158.2, 151.6, 140.3, 137.8, 136.4, 131.5, 131.4, 130.2, 130.0, 129.5, 129.0, 128.5, 128.4, 126.0, 124.4, 117.8, 116.7, 104.7, 56.6, 40.3, 29.7, 10.3. IR (KBr) ν 3034, 1851, 1774, 1512, 1221, 790, 515, 468. HRMS (EI) m/z: M⁺ Calc. for C₂₆H₁₉ClO₄, 430.0972, Found 430.0979.

(1S,10bS)-4-(2-Chlorophenyl)-1-ethyl-1-phenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3af). Yield: 174.1 mg (81%), white solid, mp 107–109 °C, R_f = 0.71 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +106.8 (c 1.0, CHCl₃), HPLC analysis: 42% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 85 : 15, 1.0 mL min⁻¹, 254 nm, 19.0 min (major), 22.4 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J = 7.8 Hz, 1H), 7.43–7.28 (m, 3H), 7.27–7.23 (m, 5H), 7.08 (d, J = 5.1 Hz, 1H), 6.92–6.82 (br, 2H), 4.80 (s, 1H), 2.41–2.35 (t, J = 6.0 Hz, 3H), 1.25–1.23 (br, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.2, 159.9, 157.4, 151.6, 136.8, 133.7, 132.2, 131.2, 130.0, 129.7, 129.3, 128.9, 128.3, 127.9, 126.7, 126.2, 124.3, 116.7, 55.8, 38.8, 30.2, 10.3. IR (KBr) ν 3030, 1871, 1772, 1642, 1221, 780, 548, 468. HRMS (EI) m/z: M⁺ Calc. for C₂₆H₁₉ClO₄, 430.0972, Found 430.0979.

(1S,10bS)-9-Chloro-1-ethyl-1,4-diphenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ag). Yield: 187.5 mg (87%), white solid, mp 120–122 °C, R_f = 0.61 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +251.4 (c 1.5, CHCl₃), HPLC analysis: 91% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 14.8 min (major), 19.0 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.54–7.48 (m, 4H), 7.47–7.31 (m, 3H), 7.25–7.18 (m, 3H), 6.99 (d, J = 8.7 Hz, 1H), 6.76–6.73 (m, 2H), 4.62 (s, 3H), 2.36 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.5, 164.5, 157.6, 150.2, 136.1, 131.6, 131.3, 130.1, 129.9, 129.2, 129.0, 128.95, 128.4, 127.9, 125.9, 119.0, 118.5, 103.1, 56.5, 40.2, 29.4, 10.1. IR (KBr) ν 3040, 1972, 1774, 1610, 1221, 780, 468. HRMS (EI) m/z: M⁺ Calc. for C₂₆H₁₉ClO₄, 430.0972, Found 430.0979.

(1S,10bS)-9-Bromo-1-ethyl-1,4-diphenyl-1,10b-dihydropyrano[3,4-c]chromene-2,5-dione (3ah). Yield: 201.4 mg (85%), white solid, mp 131–133 °C, R_f = 0.60 (petroleum ether–ethyl acetate, 5 : 1); [α]²⁵_D +213.3 (c 1.0, CHCl₃), HPLC analysis: 82% ee [Daicel CHIRALPAK AD-H column, 20 °C, 254 nm hexane–i-PrOH = 90 : 10, 1.0 mL min⁻¹, 254 nm, 16.1 min (major), 25.8 min (minor)]. ¹H NMR (300 MHz, CDCl₃) δ 7.62 (s, 1H), 7.61–7.34 (m, 6H), 7.25–7.17 (m, 3H), 6.93 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 6.0 Hz, 2H), 4.61 (s, 1H), 2.35 (q, J = 6.9 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 169.5, 164.5, 157.5, 150.7, 136.0, 133.0, 132.0, 131.6, 131.3, 129.9, 128.9, 128.4, 127.9, 125.9, 119.4, 118.9, 116.5, 103.0, 56.4, 40.1, 29.4, 10.1. IR (KBr) ν 3030, 1816, 1658, 1556, 1462, 775. HRMS (EI) m/z: C₂₆H₁₉Br⁷⁹O₄, 474.0467, Found 474.0475, M⁺ Calc. for C₂₆H₁₉Br⁸¹O₄, 476.0466, Found 474.0460.

Acknowledgements

Financial support from the Ministry of Science and Technology of China (2011CB808600), National Natural Science Foundation of China (No. 21072195, 20932008), and the Chinese Academy of Sciences is gratefully acknowledged.

Notes and references

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3. For examples of enantioselective synthesis of coumarins, see: (a) E. Alden-Danforth, M. T. Scerba and T. Lectka, Org. Lett., 2008, 10, 4951; (b) H. Alper and C. Dong, J. Org. Chem., 2004, 69, 5011; (c) T. Matsuda, M. Shigeno and M. Murakami, J. Am. Chem. Soc., 2007, 129, 12086; (d) H. Lv, L. You and S. Ye, Adv. Synth. Catal., 2008, 350, 2715; (e) X. Y. Lu and X. L. Han, Org. Lett., 2010, 12, 108.
4. (a) H. Staudinger, Ber. Dtsch. Chem. Ges., 1905, 38, 1735; (b) H. Staudinger, Justus Liebigs Ann. Chem., 1907, 356, 51.
5. For review, see: (a) T. T. Tidwell, Angew. Chem., Int. Ed., 2005, 44, 5778; (b) R. K. Orr and M. A. Calter, Tetrahedron, 2003, 59, 3545; (c) D. H. Paull, A. Weatherwax and T. Lectka, Tetrahedron, 2009, 65, 6771.
6. For examples, see: (a) A. E. Taggi, A. M. Hafez, H. Wack, B. Young, W. J. Drury III and T. Lectka, J. Am. Chem. Soc., 2000, 122, 7831; (b) J. Cabrera, T. Hellmuth and R. Peters, J. Org. Chem., 2010, 75, 4326–4329; (c) K. A. Morris, K. M. Arendt, S. H. Oh and D. Romo, Org. Lett., 2010, 12, 3764–3767; (d) M. Dochnahl and G. C. Fu, Angew. Chem., Int. Ed., 2009, 48, 2391–2393.
7. For reviews of NHC-catalyzed reactions, see: (a) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007, 107, 5606; (b) N. Marion, S. Díez-González and S. P. Nolan, Angew. Chem., Int. Ed., 2007, 46, 2988; (c) J. L. Moore and T. Rovis, Top. Curr. Chem., 2010, 291, 77.
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10. (a) Y.-R. Zhang, H. Lv, D. Zhou and S. Ye, Chem.–Eur. J., 2008, 14, 8473; (b) Bode et al. reported an NHC-catalyzed synthesis of dihydropyranone from α-chloroaldehydes and oxodienes: M. He, G. J. Uc and J. W. Bode, J. Am. Chem. Soc., 2006, 128, 15088.
11. D. Enders and J. Han, Tetrahedron: Asymmetry, 2008, 19, 1367.
12. L. He, Y.-R. Zhang, X.-L. Huang and S. Ye, Synthesis, 2008, 2825.
13. The crystal was prepared from the solution of cis-3fa in DCM–ether (90 : 10) with a trace of petroleum ether. CCDC 901312† contains the supplementary crystallographic data for this paper.
14. (a) C. E. Cannizzaro, T. Strassner and K. N. Houk, J. Am. Chem. Soc., 2001, 123, 2668; (b) C. E. Cannizzaro and K. N. Houk, J. Am. Chem. Soc., 2004, 126, 10992.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 901312. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ob26804c

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