DABCO-catalyzed regioselective cyclization reactions of β,γ-unsaturated α-ketophosphonates or β,γ-unsaturated α-ketoesters with allenic esters

Abstract

Highly efficient DABCO-catalyzed [4 + 2] cycloaddition of β,γ-unsaturated α-ketophosphonates or β,γ-unsaturated α-ketoesters with allenic esters gives the corresponding highly functionalized tetrahydropyran and dihydropyran derivatives in good to excellent yields and moderate to good regioselectivities under mild conditions.

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Introduction

Heterocycles are of great value in the design and discovery of new biologically active compounds.¹ The development of efficient processes to construct heterocycles, using metal-free catalysts, has been drawing much attention over the past decades.² Recently, nitrogen-containing Lewis base (LB) catalyzed cyclization reactions of allenoates have emerged as powerful synthetic tools in the rapid construction of cyclic molecular complexity.³ To our surprise, examples of β,γ-unsaturated α-ketophosphonates⁴ or β,γ-unsaturated α-ketoesters⁵ as the electrophiles were seldom mentioned in the construction of heterocycles. Herein, we wish to report a novel DABCO-catalyzed regioselective [4 + 2] cycloaddition of β,γ-unsaturated α-ketophosphonates or β,γ-unsaturated α-ketoesters with allenic esters to give the corresponding highly functionalized tetrahydropyran and dihydropyran derivatives, which are structural subunits in many natural products and biologically active molecules.⁶

Results and discussion

We initially utilized (E)-dimethyl cinnamoylphosphonate 1a (0.1 mmol, 1.0 equiv) and ethyl 2,3-butadienoate 2a (0.12 mmol, 1.2 equiv) as the substrates to investigate their cyclization behavior in tetrahydrofuran (THF) at room temperature in the presence of 20 mol% 1,4-diazabicyclo[2,2,2]octane (DABCO). It was found that the desired [4 + 2] cycloaddition reaction took place smoothly to give the corresponding cyclic products 3aa and 4aa in 87% combined yield but with low regioselectivity as the ratio of 3aa : 4aa was 2 : 1 within 24 h (Table 1, entry 1). Subsequently, we screened various nitrogen-containing Lewis base catalysts for this reaction, and the results are summarized in Table 1 (entries 2–7). 4-N,N-dimethylpyridine (DMAP) can also efficiently catalyze this reaction to give the product mixture of 3aa and 4aa in 84% combined yield with a ratio of 1 : 1 (Table 1, entry 2). Other weak nucleophilic nitrogen-containing Lewis base catalysts, such as 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), Et₃N and diisopropylethylamine (DIEA) did not catalyze this reaction (Table 1, entries 3–5). We next attempted to screen phosphane-containing Lewis base catalysts, such as PPh₃ and tributylphosphine (PBu₃), in this reaction, but it was found that no reactions occurred either (Table 1, entries 6 and 7). Of the catalysts examined, DABCO was found to be the best one. Using DABCO as the catalyst, various solvents were examined and dichloromethane (DCM) was found to be the solvent of choice, affording 3aa and 4aa in 90% combined yield with the ratio of 3 : 1 (Table 1, entries 8–16). Lowering the reaction temperature to 0 °C or −20 °C, similar results were obtained (Table 1, entries 17 and 18). At −40 °C, the corresponding cyclic adducts 3aa and 4aa were obtained in 86% combined yield along with a 5 : 1 ratio of 3aa : 4aa (Table 1, entry 19). Further reducing the reaction temperature did not improve the reaction outcomes (Table 1, entry 20). Thus, we have established the optimal reaction conditions for this reaction: using 20 mol % DABCO as a catalyst and DCM as a solvent to perform the reaction at −40 °C.

Table 1 Optimization of the reaction conditions of (E)-dimethyl cinnamoylphosphonate 1a and ethyl 2,3-butadienoate 2a^a

Entry	LB	T/°C	Solvent	Yield (%)^b	3aa : 4aa (%)^c
a All reactions were carried out using 1a (0.10 mmol) and 2a (0.12 mmol) in solvent (1.00 mL) for 24 h. b Isolated combined yield. c Determined by ^1H NMR spectroscopic data, and these regioisomers can not be easily separated by column chromatography.
1	DABCO	rt	THF	87	2 : 1
2	DMAP	rt	THF	84	1 : 1
3	DBU	rt	THF	NR	—
4	Et3N	rt	THF	NR	—
5	DIEA	rt	THF	NR	—
6	PPh3	rt	THF	NR	—
7	PBu3	rt	THF	NR	—
8	DABCO	rt	DCM	90	3 : 1
9	DABCO	rt	Et2O	80	1 : 1
10	DABCO	rt	Dioxane	82	2 : 1
11	DABCO	rt	CH3CN	81	2 : 1
12	DABCO	rt	Toluene	78	1 : 1
13	DABCO	rt	DCE	80	2 : 1
14	DABCO	rt	CHCl3	82	3 : 1
15	DABCO	rt	DMSO	trace	—
16	DABCO	rt	DMF	trace	—
17	DABCO	0	DCM	85	3 : 1
18	DABCO	−20	DCM	85	4 : 1
19	DABCO	−40	DCM	86	5 : 1
20	DABCO	−60	DCM	85	3 : 1

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Under the optimized reaction conditions, the reaction generality was investigated by using various cinnamoylphosphonates 1 in the reaction with several allenic esters 2, and the results of these experiments are summarized in Table 2. As can be seen from Table 2, changing the ester moiety of allenic esters 2 from OEt to OMe or OⁱPr provided similar reaction outcomes, affording the desired products in good combined yields (up to 90%) along with moderate regioselectivities (3 : 4 = 3 : 1) (Table 2, entries 2 and 3). However, we found that the R² substituent in the phosphonate moiety of cinnamoylphosphonates 1 can significantly affect the reaction outcomes, as that R²group can improve the regioselectivity of the products (up to 3 : 4 = 10 : 1) if it had a sterically bulky group, such as OⁱPr or O^tBu (Table 2, entries 4 and 5). As for substrates 1d–1h, electron-withdrawing or electron-donating substituents at the meta- or para-positions of the benzene ring of 1 were equally well-tolerated in the reaction, giving the corresponding products 3 and 4 in good combined yields along with high regioselectivities (up to 3 : 4 > 20 : 1) (Table 2, entries 6–10). The substrate 1i, in which R¹ is a 1-naphthyl group, was also able in this reaction to give the corresponding products in 85% combined yield along with good regioselectivity (3ia : 4ia = 14 : 1) (Table 2, entry 11). When R¹ is an alkyl group (1j, R¹ = Me), the reaction also proceeded smoothly to give the desired products 3ja and 4ja in 75% combined yield but with moderate regioselectivity (3ja : 4ja = 4 : 1) (Table 2, entry 12). The structures of 3 and 4 were determined by the 2-D NMR spectroscopic data (HMQC, HMBC, DEPT and NOESY spectra) of compounds 3ca and 4ca (see the Supporting Information for the details†).

Table 2 Substrate scope of the reactions of phosphonates 1 and allenic esters 2^a

Entry	No	R^1	R^2	R^3 (2)	Yield (%)^b	No	3 : 4^c
a All reactions were carried out using 1 (0.10 mmol) and 2 (0.12 mmol) in DCM (1.00 mL) at −40 °C for 24 h. b Isolated combined yield. c Determined by ^1H NMR spectroscopic data, and these regioisomers cannot be easily separated by column chromatography.
1	1a	C6H5	OMe	Et (2a)	86	3aa : 4aa	5 : 1
2	1a	C6H5	OMe	^i Pr (2b)	82	3ab : 4ab	3 : 1
3	1a	C6H5	OMe	Me (2c)	90	3ac : 4ac	3 : 1
4	1b	C6H5	O^tBu	Et (2a)	70	3ba : 4ba	9 : 1
5	1c	C6H5	O^iPr	Et (2a)	85	3ca : 4ca	10 : 1
6	1d	4-ClC6H4	O^iPr	Et (2a)	87	3da : 4da	10 : 1
7	1e	4-NO2C6H4	O^iPr	Et (2a)	80	3ea : 4ea	>20 : 1
8	1f	4-BrC6H4	O^iPr	Et (2a)	85	3fa : 4fa	13 : 1
9	1g	3-MeC6H4	O^iPr	Et (2a)	85	3ga : 4ga	10 : 1
10	1h	4-MeOC6H4	O^iPr	Et (2a)	75	3ha : 4ha	8 : 1
11	1i	1-naphthyl	O^iPr	Et (2a)	85	3ia : 4ia	14 : 1
12	1j	Me	O^iPr	Et (2a)	75	3ja : 4ja	4 : 1

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Encouraged by the above results, β,γ-unsaturated α-ketoesters were also examined under the optimal reaction conditions. Initially, we utilized (E)-ethyl 2-oxo-4-phenylbut-3-enoate 5a (0.10 mmol, 1.0 equiv) and ethyl 2,3-butadienoate 2a (0.12 mmol, 1.2 equiv) as the substrates in DCM (2.00 mL, 0.05 M) at room temperature in the presence of 20 mol% DABCO. We were pleased to find that the reaction proceeded smoothly to give the desired products 6aa and 7aa in 82% combined yield along with good regioselectivity (7aa : 6aa = 8 : 1) (Table 3, entry 1), which was contrary to the above results in Table 2. Reducing the concentration to 0.03 M by increasing the amount of solvent (DCM) employed to 3.00 mL can improve the reaction outcome, affording the corresponding products in 85% combined yield along with the 13 : 1 ratio of 7aa : 6aa (Table 3, entry 1). Inspired by this result, we next screened various nitrogen-containing Lewis base catalysts for this reaction in the optimized amount of solvent (3.00 mL, 0.03 M). DMAP can efficiently catalyze this reaction as well but with low regioselectivity. However, DBU and DIEA did not catalyze this reaction (Table 3, entries 2–4). Accordingly, DABCO was then used as the best catalyst for further investigation of solvent and temperature effects in this reaction. It was found that THF was the solvent of choice in comparison with those reactions carried out in other organic solvents, such as toluene, Et₂O, 1,2-dichloroethane (DCE), chloroform, 1,4-dioxane, CH₃CN, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) (Table 3, entries 5–13). The low temperature (−10 °C) can improve the combined yield of 6aa and 7aa (Table 3, entry 15), but further lowering the reaction temperature to −40 °C reduced the combined yield (Table 3, entry 16). Thus, we have identified the optimal reaction conditions for this reaction: using 20 mol% of DABCO as a catalyst and THF as a solvent to perform the reaction at −10 °C.

Table 3 Optimization of the reaction conditions of (E)-ethyl 2-oxo-4-phenylbut-3-enoate 5a and ethyl 2,3-butadienoate 2a^a

Entry	LB	T/°C	Solvent	Yield (%)^b	7aa : 6aa (%)^c
a All reactions were carried out using 5a (0.10 mmol) and 2a (0.12 mmol) in solvent (3.00 mL, 0.03 M) for 24 h. b Isolated combined yield. c Determined by ^1H NMR spectroscopic data, and these regioisomers can not be easily separated by column chromatography. d The reaction was carried out in DCM (2.00 mL, 0.05 M).
1	DABCO	rt	DCM	85 (82)^d	13 : 1 (8 : 1)^d
2	DMAP	rt	DCM	80	2 : 1
3	DIEA	rt	DCM	NR	—
4	DBU	rt	DCM	NR	—
5	DABCO	rt	THF	90	>20 : 1
6	DABCO	rt	Toluene	75	5 : 1
7	DABCO	rt	Et2O	88	13 : 1
8	DABCO	rt	DCE	86	8 : 1
9	DABCO	rt	CHCl3	90	6 : 1
10	DABCO	rt	Dioxane	89	14 : 1
11	DABCO	rt	CH3CN	50	>20 : 1
12	DABCO	rt	DMSO	trace	—
13	DABCO	rt	DMF	trace	—
14	DABCO	0	THF	91	>20 : 1
15	DABCO	−10	THF	95	>20 : 1
16	DABCO	−40	THF	92	>20 : 1

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Having identified the optimal reaction conditions, we next set out to examine the scope and limitations of the [4 + 2] cycloaddition reaction catalyzed by DABCO using various β,γ-unsaturated α-ketoesters 5 with different substituents on the R⁴group, and the results are summarized in Table 4. As can be seen from Table 4, when R⁴ is an aromatic group, whether they have electron-withdrawing or electron-donating substituents at the ortho-, meta- or para-positions on the benzene rings, the reactions proceeded smoothly to give the desired products in good yields along with good regioselectivities (Table 4, entries 2–7). Heterocyclic substrates 5h and 5l were also suitable in this reaction to give the corresponding products in moderate combined yields and regioselectivities (Table 4, entries 8 and 9). The substrate 5j, in which R⁴ is a 2-naphthyl group, was also tolerable in this reaction to give the corresponding products in 82% combined yield along with good regioselectivity (7ja : 6ja = 8 : 1) (Table 4, entry 10). For substrate 5k, in which R⁴ is a cyclopropyl group, the reaction also proceeded smoothly to give the desired products in high combined yield (up to 90%) along with high regioselectivity (up to 7ka : 6ka = >20 : 1). The structure of 6ea was unambiguously determined by X-ray diffraction. The ORTEP drawing is shown in Fig. 1 and its CIF data are summarized in the Supporting Information.†⁷ The structure of 7 and the E-configuration of the double bond were assigned by the 2-D NMR spectroscopic data (HMQC, HMBC, DEPT and NOESY spectra) of compound 7aa (see the Supporting Information for the details†).

Table 4 Substrate scope of the reactions of β,γ-unsaturated α-ketoesters 5 and ethyl 2,3-butadienoate 2a^a

Entry	No	R^1	Yield (%)^b	No	7 : 6^c
a All reactions were carried out using 5 (0.10 mmol) and 2a (0.12 mmol) in solvent (3.00 mL, 0.03 M) for 24 h. b Isolated combined yield. c Determined by ^1H NMR spectroscopic data, and these regioisomers can not be easily separated by column chromatography.
1	5a	C6H5	95	7aa : 6aa	>20 : 1
2	5b	4-ClC6H4	86	7ba : 6ba	14 : 1
3	5c	4-BrC6H4	87	7ca : 6ca	10 : 1
4	5d	3-BrC6H4	83	7da : 6da	8 : 1
5	5e	2-BrC6H4	85	7ea : 6ea	8 : 1
6	5f	2,4-Cl2C6H3	87	7fa : 6fa	7 : 1
7	5g	4-MeC6H4	85	7ga : 6ga	12 : 1
8	5h	2-furyl	60	7ha : 6ha	3 : 1
9	5i	2-thiophene	57	7ia : 6ia	6 : 1
10	5j	2-naphthyl	82	7ja : 6ja	8 : 1
11	5k	cyclopropyl	90	7ka : 6ka	>20 : 1

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Fig. 1 An ORTEP drawing of 6ea.

The mechanism for the reactions has not been unequivocally established, but one reasonable explanation is shown in Scheme 1 based on earlier reports and our own investigations. Addition of DABCO to allenoate 2a delivers zwitterionic intermediate A, which coexists with its resonance form B.^3a,3c The zwitterionic intermediate A reacts with 1 or 5 to give intermediate C, which undergoes enolization to give intermediate E. Subsequent cyclization produces cyclic product G and regenerates the DABCO catalyst. Finally, G isomerizes to give the more stable adducts 3 or 6. At the same time, the zwitterionic intermediate B can also react with 1 or 5 to give intermediate D, which undergoes enolization to give intermediate F. Subsequent cyclization produces cyclic product 4 or 7 and regenerates the DABCO catalyst. We also assumed that the major products in the reaction might be mainly due to the steric interaction between intermediates C and D. When EWG = PO(OⁱPr)₂, which is sterically more bulky than an aromatic ring, the steric repulsion between CO₂Et and EWG is larger than that of CO₂Et and an aromatic ring. Therefore, intermediate C is more stable than intermediate D, affording 3 as the major product. When EWG = CO₂Et, which is sterically smaller than aromatic ring, the steric repulsion between CO₂Et and EWG is less than that of CO₂Et and aromatic ring. Therefore, intermediate D is more stable than intermediate C, leading to 7 as the major product.

Scheme 1 A plausible reaction mechanism.

In conclusion, we have established a novel DABCO-catalyzed [4 + 2] cycloaddition of β,γ-unsaturated α-ketophosphonates or β,γ-unsaturated α-ketoesters with allenic esters to give the corresponding highly functionalized tetrahydropyran and dihydropyran derivatives in good to excellent yields and moderate to good regioselectivities under mild conditions. The obtained multiple functionalized tetrahydropyran and dihydropyran derivatives are useful building blocks in the organic synthesis of biologically useful compounds. A plausible reaction mechanism has been also proposed on the basis of previous literature and our own investigations. Efforts are in progress to elucidate further mechanistic details of these reactions and to understand their scope and limitations.

Experimental section

General remarks

¹H NMR spectra were recorded on a Bruker AM-300 or AM-400 spectrometer for solution in CDCl₃ with tetramethylsilane (TMS) as internal standard; J-values are in Hz. Mass spectra were recorded with a HP-5989 instrument. All of the compounds reported in this paper gave satisfactory HRMS analytic data. Melting points were determined on a digital melting point apparatus and temperatures were uncorrected. Infrared spectra were recorded on a Perkin-Elmer PE-983 spectrometer with absorption in cm⁻¹. THF, toluene and Et₂O were distilled from sodium (Na) under argon (Ar) atmosphere. CH₃CN, 1,2-dichloroethane and dichloromethane were distilled from CaH₂ under argon (Ar) atmosphere. Commercially obtained reagents were used without further purification. All reactions were monitored by TLC with Huanghai GF254 silica gel coated plates. Flash column chromatography was carried out using 300–400 mesh silica gel at increased pressure. All the β,γ-unsaturated α-ketophosphonates and β,γ-unsaturated α-ketoesters were prepared according to the literature.^4b,8

General procedure for the preparation of 3 and 4 from the reaction of 1a with 2a using 3aa and 4aa as an example in the presence of DABCO

To a mixture of 1a (0.10 mmol, 24.0 mg), 2a (0.12 mmol, 13.6 μL) and DABCO (2.2 mg, 0.02 mmol) was added 2.0 mL of dichloromethane at −40 °C. The reaction solution was monitored by TLC. After the reaction was complete, the solution was concentrated under reduced pressure and the residue was further purified by silica gel column chromatography (EtOAc/PE = 1/6) to give the target products 3aa and 4aa.

Ethyl 6-(dimethoxyphosphoryl)-2-methyl-4-phenyl-4H-pyran-3-carboxylate 3aa. A colorless oil (16.7 mg, 70%); ¹H NMR (400 MHz, CDCl₃, TMS) δ 1.09 (t, J = 7.2 Hz, 3H), 2.39 (s, 3H), 3.78 (d, J = 11.2 Hz, 3H), 3.80 (d, J = 11.2 Hz, 3H), 3.96–4.07 (m, 2H), 4.45 (d, J = 5.2 Hz, ¹H), 6.12 (dd, J = 10.0 Hz, 5.2 Hz, 1H), 7.19–7.22 (m, 3H), 7.29–7.31 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.8, 19.0, 38.1 (d, J = 10.4 Hz), 53.3 (d, J = 6.7 Hz), 53.4 (d, J = 5.9 Hz), 60.1, 104.8, 122.0 (d, J = 20.9 Hz), 126.9, 127.8, 128.5, 137.4, 139.8, 144.0 (d, J = 2.2 Hz), 159.7 (d, J = 8.2 Hz), 166.6; ³¹P NMR (161.93 MHz, CDCl₃, 85% H₃PO₄): δ 9.734;. IR (CH₂Cl₂) ν 2966, 2902, 1715, 1659, 1473, 1373, 1260, 1176, 1105, 1026, 947, 800, 741, 700 cm⁻¹; MS (ESI) m/z 353.0 (M+H⁺). HRMS (ESI) Calcd for C₁₇H₂₂O₆P requires (M+H⁺): 353.1149, found: 353.1156.

(E)-Ethyl 2-(6-(dimethoxyphosphoryl)-4-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate 4aa. A colorless oil (5.5 mg, 16%); ¹H NMR (400 MHz, CDCl₃, TMS) δ 1.23 (t, J = 7.2 Hz, 3H), 3.10 (dd, J = 10.4 Hz, 6.8 Hz, 1H), 3.67–3.73 (m, 2H), 3.84 (d, J = 11.2 Hz, 3H), 3.85 (d, J = 11.2 Hz, 3H), 4.08–4.14 (m, 2H), 5.67 (s, 1H), 6.28 (dd, J = 10.4 Hz, 2.8 Hz, 1H), 7.19–7.22 (m, 2H), 7.26–7.28 (m, 1H), 7.31–7.35 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 14.1, 29.8, 35.6 (d, J = 11.9 Hz), 53.39 (d, J = 3.7 Hz), 53.40 (d, J = 6.2 Hz), 59.8, 100.8, 122.0 (d, J = 19.3 Hz), 127.0, 127.2, 128.8, 141.0 (d, J = 11.2 Hz), 143.4, 164.6 (d, J = 9.7 Hz), 166.6; ³¹P NMR (161.93 MHz, CDCl₃, 85% H₃PO₄): δ 9.180; IR (neat) ν 2966, 2902, 1712, 1656, 1494, 1449, 1374, 1261, 1172, 1111, 1026, 824, 764, 700 cm⁻¹; MS (ESI) m/z 353.1 (M+H⁺); HRMS (ESI) Calcd for C₁₇H₂₂O₆P requires (M+H⁺): 353.1149, found: 353.1159.

Isopropyl 6-(dimethoxyphosphoryl)-2-methyl-4-phenyl-4H-pyran-3-carboxylate 3ab. A slightly yellow liquid (22.0 mg, 60%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 0.91 (d, J = 6.0 Hz, 3H), 1.16 (d, J = 6.0 Hz, 3H), 2.39 (s, 3H), 3.78 (d, J = 11.2 Hz, 3H), 3.81 (d, J = 11.2 Hz, 3H), 4.44 (d, J = 4.8 Hz, 1H), 4.88 (sept, J = 6.0 Hz, 1H), 6.11 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 7.18–7.31 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 19.0, 21.3, 21.8, 38.3 (d, J = 10.6 Hz), 53.29 (d, J = 6.0 Hz), 53.35 (d, J = 6.0 Hz), 67.6, 105.0, 121.9 (d, J = 20.4 Hz), 126.9, 128.0, 128.5, 137.6, 139.9, 144.3, 159.5 (d, J = 9.1 Hz), 166.2; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 9.795; IR (CH₂Cl₂) ν 3061, 2980, 2902, 1713, 1659, 1628, 1374, 1262, 1177, 1104, 1047, 953, 803, 739, 701 cm⁻¹; MS (ESI) m/z 367.1 (M+H⁺); HRMS (ESI) Calcd for C₁₈H₂₃O₆PNa requires (M+Na⁺): 389.1125, found: 389.1110.

(E)-Isopropyl 2-(6-(dimethoxyphosphoryl)-4-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate 4ab. A slightly yellow liquid (8.1 mg, 22%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.19 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 3.10 (dd, J = 17.2 Hz, 10.4 Hz, 1H), 3.68–3.72 (m, 2H), 3.84 (d, J = 11.2 Hz, 3H), 3.85 (d, J = 11.2 Hz, 3H), 4.98 (sept, J = 6.4 Hz, 1H), 5.64 (s, 1H), 6.29 (dd, J = 10.0 Hz, 2.8 Hz, 1H), 7.20–7.27 (m, 3H), 7.31–7.34 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 21.8, 29.9, 35.7 (d, J = 11.9 Hz), 53.4 (d, J = 4.4 Hz), 67.1, 101.4, 121.5 (d, J = 19.3 Hz), 127.1, 127.2, 128.8, 141.1 (d, J = 16.4 Hz), 143.6, 164.4 (d, J = 9.7 Hz), 166.2; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 9.206; IR (CH₂Cl₂) ν 3062, 2979, 2905, 1706, 1655, 1452, 1374, 1260, 1170, 1100, 1023, 800, 761, 700 cm⁻¹; MS (ESI) m/z 367.2 (M+H⁺); HRMS (ESI) Calcd for C₁₈H₂₃O₆PNa requires (M+Na⁺): 389.1125, found: 389.1112.

Methyl 6-(dimethoxyphosphoryl)-2-methyl-4-phenyl-4H-pyran-3-carboxylate 3ac. A slightly yellow liquid (21.6 mg, 64%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 2.39 (s, 3H), 3.57 (s, 3H), 3.78 (d, J = 11.2 Hz, 3H), 3.80 (d, J = 11.2 Hz, 3H), 4.45 (d, J = 4.8 Hz, 1H), 6.13 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 7.20–7.22 (m, 3H), 7.28–7.32 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 19.1, 38.1 (d, J = 10.4 Hz), 51.3, 53.27 (d, J = 6.0 Hz), 53.34 (d, J = 5.9 Hz), 104.8, 121.9 (d, J = 20.0 Hz), 127.0, 127.8, 128.6, 137.8, 140.2, 144.0, 160.0 (d, J = 8.9 Hz), 167.2; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 9.654. IR (CH₂Cl₂) ν 3062, 2963, 2904, 1717, 1660, 1627, 1437, 1375, 1262, 1174, 1037, 840, 803, 702 cm⁻¹; MS (ESI) m/z 339.1 (M+H⁺); HRMS (ESI) Calcd for C₁₆H₁₉O₆PNa requires (M+Na⁺): 361.0812, found: 361.0801.

(E)-Methyl 2-(6-(dimethoxyphosphoryl)-4-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate 4ac. (8.8 mg, 26%): a slightly yellow liquid. ¹H NMR (CDCl₃, 400 MHz, TMS) δ 3.11 (dd, J = 17.6 Hz, 10.4 Hz, 1H), 3.65 (s, 3H), 3.68–3.73 (m, 2H), 3.85 (d, J = 11.2 Hz, 6H), 5.68 (s, 1H), 6.29 (dd, J = 10.4 Hz, 3.2 Hz, 1H), 7.19–7.27 (m, 3H), 7.33–7.35 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 19.1, 29.9, 35.6 (d, J = 11.9 Hz), 51.1, 53.4 (d, J = 5.2 Hz), 100.4, 122.1 (d, J = 19.4 Hz), 127.1, 127.3, 128.8, 141.1 (d, J = 20.0 Hz), 143.5, 164.5 (d, J = 9.7 Hz), 167.1; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 9.165; IR (CH₂Cl₂) ν 3061, 2963, 2904, 1714, 1655, 1372, 1262, 1168, 1114, 1028, 803, 764, 701, 651 cm⁻¹; MS (ESI) m/z 339.2 (M+H⁺); HRMS (ESI) Calcd for C₁₆H₂₀O₆P requires (M+H⁺): 339.1001, found: 339.0992.

Ethyl 6-(di-tert-butoxyphosphoryl)-2-methyl-4-phenyl-4H-pyran-3-carboxylate 3ba. A slightly yellow liquid (27.5 mg, 63%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.08 (t, J = 7.2 Hz, 3H), 1.46 (s, 9H), 1.51 (s, 9H), 2.40 (s, 3H), 3.96–4.06 (m, 2H), 4.42 (d, J = 4.8 Hz, 1H), 5.99 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 7.17–7.20 (m, 3H), 7.26–7.29 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 13.7, 19.2, 29.6–31.0 (m, 6C), 38.2 (d, J = 10.4 Hz), 60.1, 83.5, 104.6, 118.3 (d, J = 21.5 Hz), 126.7, 128.0, 128.3, 142.6, 144.6, 144.9, 160.2 (d, J = 8.2 Hz), 167.1; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ −2.515; IR (CH₂Cl₂) ν 2980, 2902, 2884, 1714, 1659, 1626, 1476, 1372, 1262, 1171, 1108, 1041, 992, 804, 700 cm⁻¹; MS (ESI) m/z 459.3 (M+Na⁺); HRMS (ESI) Calcd for C₂₃H₃₃O₆PNa requires (M+Na⁺): 459.1907, found: 459.1919.

(E)-ethyl 2-(6-(di-tert-butoxyphosphoryl)-4-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate 4ba. A slightly yellow liquid (3.1 mg, 7%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.24 (t, J = 7.2 Hz, 3H), 1.54 (s, 18H), 3.05 (dd, J = 13.6 Hz, 6.8 Hz, 1H), 3.61–3.70 (m, 2H), 4.09–4.14 (m, 2H), 5.65 (s, 1H), 6.19 (dd, J = 11.2 Hz, 2.8 Hz, 1H), 7.19–7.21 (m, 2H), 7.22–7.26 (m, 1H), 7.30–7.33 (m, 2H); ³¹P NMR (CDCl₃, 121 MHz, 85% H₃PO₄) δ −3.003; IR (CH₂Cl₂) ν 2977, 2903, 1713, 1655, 1373, 1261, 1170, 1114, 1042, 1014, 801, 739, 700 cm⁻¹; MS (ESI) m/z 459.2 (M+Na⁺); HRMS (ESI) Calcd for C₂₃H₃₃O₆PNa requires (M+Na⁺): 459.1907, found: 459.1915.

Ethyl 6-(diisopropoxyphosphoryl)-2-methyl-4-phenyl-4H-pyran-3-carboxylate 3ca. A slightly yellow liquid (31.4 mg, 77%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.09 (t, J = 6.8 Hz, 3H), 1.31 (d, J = 6.4 Hz, 6H), 1.35 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H), 2.40 (s, 3H), 3.97–4.06 (m, 2H), 4.44 (d, J = 4.8 Hz, 1H), 4.65–4.73 (m, 2H), 6.10 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 7.18–7.22 (m, 3H), 7.28–7.30 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 13.8, 19.0, 23.60 (d, J = 3.8 Hz), 23.65 (d, J = 4.4 Hz), 23.9 (d, J = 4.5 Hz), 38.2 (d, J = 9.9 Hz), 60.1, 71.8 (d, J = 4.9 Hz), 104.8, 120.7 (d, J = 19.8 Hz), 126.8, 127.9, 128.0, 128.4, 139.7, 142.0, 144.3, 159.9 (d, J = 9.4 Hz), 166.8; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.537; IR (CH₂Cl₂) ν 2982, 2905, 2876, 1769, 1720, 1658, 1376, 1261, 1098, 1009, 800, 701 cm⁻¹; MS (ESI) m/z 409.2 (M+H⁺); HRMS (ESI) Calcd for C₂₁H₂₉O₆PNa requires (M+Na⁺): 431.1594, found: 431.1595.

(E)-Ethyl 2-(6-(diisopropoxyphosphoryl)-4-phenyl-3,4-dihydro-2H-pyran-2-ylidene)acetate 4ca. A slightly yellow liquid (3.2 mg, 8%); ¹H NMR (CDCl₃, 300 MHz, TMS) δ 1.23 (t, J = 7.2 Hz, 3H), 1.35 (d, J = 6.3 Hz, 6H), 1.39 (d, J = 6.3 Hz, 6H), 3.10 (dd, J = 16.8 Hz, 9.9 Hz, 1H), 3.64–3.71 (m, 2H), 4.07–4.16 (m, 2H), 4.71–4.80 (m, 2H), 5.65 (s, 1H), 6.27 (dd, J = 10.2 Hz, 6.9 Hz, 1H), 7.19–7.26 (m, 3H), 7.30–7.35 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz, TMS) δ 14.2, 23.7 (d, J = 4.6 Hz), 24.0 (d, J = 3.5 Hz), 29.9, 35.6 (d, J = 11.4 Hz), 59.8, 71.9 (d, J = 5.7 Hz), 100.4, 120.6 (d, J = 19.4 Hz), 127.1, 127.2, 128.7, 141.3, 142.8, 145.9, 165.1 (d, J = 9.7 Hz), 166.8; ³¹P NMR (CDCl₃, 121.453 MHz, 85% H₃PO₄) δ 5.107; IR (CH₂Cl₂) ν 3063, 2980, 2937, 2902, 1711, 1654, 1352, 1259, 1170, 1110, 1044, 985, 886, 762, 700 cm⁻¹; MS (ESI) m/z 409.2 (M+H⁺); HRMS (ESI) Calcd for C₂₁H₂₉O₆PNa requires (M+Na⁺): 431.1594, found: 431.1579.

Ethyl 4-(4-chlorophenyl)-6-(diisopropoxyphosphoryl)-2-methyl-4H-pyran-3-carboxylate 3da. A slightly yellow liquid (34.9 mg, 79%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.11 (t, J = 7.2 Hz, 3H), 1.31 (d, J = 6.0 Hz, 6H), 1.36 (d, J = 6.0 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H), 2.40 (s, 3H), 4.00–4.08 (m, 2H), 4.43 (d, J = 4.8 Hz, 1H), 4.64–4.75 (m, 2H), 6.06 (dd, J = 10.0 Hz, 4.8 Hz, 1H), 7.14 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 7.2 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.2, 19.1, 23.0–24.5 (m, 4C), 37.6 (d, J = 10.4 Hz), 60.2, 71.8 (d, J = 5.2 Hz), 71.9 (d, J = 5.2 Hz), 104.4, 119.9 (d, J = 20.0 Hz), 128.6, 129.2, 132.6, 140.1, 142.4, 142.9, 160.2 (d, J = 8.9 Hz), 166.6; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.175; IR (CH₂Cl₂) ν 2980, 2942, 2904, 1714, 1663, 1625, 1488, 1376, 1259, 1176, 1104, 986, 946, 804, 685 cm⁻¹; MS (ESI) m/z 443.3 (M+H⁺); HRMS (ESI) Calcd for C₂₁H₂₈O₆PNa requires (M+Na⁺): 465.1204, found: 465.1193.

(E)-Ethyl 2-(4-(4-chlorophenyl)-6-(diisopropoxyphosphoryl)-3,4-dihydro-2H-pyran-2-ylidene)acetate 4da. A slightly yellow liquid (3.5 mg, 8%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.24 (t, J = 7.2 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.0 Hz, 6H); 3.16 (dd, J = 15.2 Hz, 7.6 Hz, 1H), 3.55 (dd, J = 15.2 Hz, 6.0 Hz, 1H); 3.64–3.67 (m, 1H), 4.09–4.13 (m, 2H), 4.73–4.79 (m, 2H), 5.65 (s, 1H), 6.22 (dd, J = 10.0 Hz, 4.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H); ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 3.723; IR (CH₂Cl₂) ν 2980, 2942, 2902, 1713, 1657, 1492, 1375, 1261, 1172, 1116, 1045, 994, 820, 739, 703 cm⁻¹; MS (ESI) m/z 443.2 (M+H⁺); HRMS (ESI) Calcd for C₂₁H₂₈O₆PNa requires (M+Na⁺): 465.1204, found: 465.1213.

Ethyl 6-(diisopropoxyphosphoryl)-2-methyl-4-(4-nitrophenyl)-4H-pyran-3-carboxylate 3ea. A slightly yellow liquid (36.2 mg, 80%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.11 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 6.4 Hz, 6H), 1.36 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H), 2.43 (s, 3H), 4.00–4.06 (m, 2H), 4.58 (d, J = 4.8 Hz, 1H), 4.67–4.74 (m, 2H), 6.04 (dd, J = 10.0 Hz, 4.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.0, 19.3, 23.7 (d, J = 4.6 Hz), 23.9 (d, J = 2.3 Hz), 38.3 (d, J = 9.9 Hz), 60.5, 72.1 (d, J = 5.3 Hz), 103.8, 118.6 (d, J = 19.5 Hz), 123.9, 128.7 141.1, 143.5, 146.9, 151.6, 161.2 (d, J = 8.3 Hz), 166.3; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 3.597; IR (CH₂Cl₂) ν 3074, 2981, 2906, 2874, 1715, 1662, 1626, 1521, 1375, 1347, 1176, 1105, 988, 854, 806, 700 cm⁻¹; MS (ESI) m/z 454.2 (M+H⁺); HRMS (ESI) Calcd for C₂₁H₂₈NO₈PNa requires (M+Na⁺): 476.1445, found: 476.1461.

Ethyl 4-(4-bromophenyl)-6-(diisopropoxyphosphoryl)-2-methyl-4H-pyran-3-carboxylate 3fa. A slightly yellow liquid (38.3 mg, 79%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.11 (t, J = 6.8 Hz, 3H), 1.31 (d, J = 6.4 Hz, 6H), 1.35 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H), 2.39 (s, 3H), 4.00–4.06 (m, 2H), 4.41 (d, J = 4.8 Hz, 1H), 4.65–4.73 (m, 2H), 6.05 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.0, 19.1, 23.64 (d, J = 2.3 Hz), 23.68 (d, J = 2.3 Hz), 23.9 (d, J = 3.8 Hz), 37.7 (d, J = 10.6 Hz), 60.3, 71.9 (d, J = 5.3 Hz), 104.4 (d, J = 1.5 Hz), 119.8 (d, J = 19.8 Hz), 120.8, 129.6, 131.6, 140.2, 142.5, 143.5 (d, J = 2.3 Hz), 160.2 (d, J = 8.4 Hz), 166.6; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.165; IR (CH₂Cl₂) ν 2979, 2934, 2906, 1713, 1657, 1488, 1448, 1261, 1170, 1111, 1010, 802, 740, 702, 668 cm⁻¹; MS (ESI) m/z 487.3 (M+H⁺); HRMS (ESI) Calcd for C₂₁H₂₈O₆PBrNa requires (M+Na⁺): 509.0699, found: 509.0705.

(E)-Ethyl 2-(4-(4-bromophenyl)-6-(diisopropoxyphosphoryl)-3,4-dihydro-2H-pyran-2-ylidene)acetate 4fa. A slightly yellow liquid (3.1 mg, 6%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.24 (t, J = 7.2 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 6H); 3.16 (dd, J = 15.2 Hz, 7.6 Hz, 1H), 3.57 (dd, J = 15.2 Hz, 6.4 Hz, 1H), 3.62–3.66 (m, 1H), 4.09–4.14 (m, 2H), 4.72–4.79 (m, 2H), 5.65 (s, 1H), 6.21 (dd, J = 10.0 Hz, 4.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H); ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 3.697; IR (CH₂Cl₂) ν 2980, 2939, 2902, 1714, 1661, 1626, 1485, 1376, 1260, 1176, 1106, 992, 805, 740, 664 cm⁻¹; MS (ESI) m/z 487.3 (M+H⁺); HRMS (ESI) Calcd for C₂₁H₂₈O₆PBrNa requires (M+Na⁺): 509.0699, found: 509.0708.

Ethyl 6-(diisopropoxyphosphoryl)-2-methyl-4-m-tolyl-4H-pyran-3-carboxylate 3ga. A slightly yellow liquid (32.6 mg, 77%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.11 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 6.4 Hz, 6H), 1.35 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H), 2.31 (s, 3H), 2.39 (s, 3H), 4.00–4.07 (m, 2H), 4.40 (d, J = 4.8 Hz, 1H), 4.66–4.73 (m, 2H), 6.09 (dd, J = 10.0 Hz, 4.8 Hz, 1H), 7.00–7.02 (m, 3H), 7.17 (t, J = 8.0 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 13.9, 19.0, 21.3, 23.6 (d, J = 5.2 Hz), 23.7 (d, J = 5.9 Hz), 24.0 (d, J = 3.7 Hz), 38.1 (d, J = 9.7 Hz), 60.1, 71.7 (d, J = 5.2 Hz), 104.9, 120.8 (d, J = 20.1 Hz), 125.0, 127.6, 128.3, 128.7, 138.0, 139.7, 142.0, 144.3, 159.8 (d, J = 8.2 Hz), 166.9; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 5.259; IR (CH₂Cl₂) ν 2979, 2901, 2884, 1715, 1660, 1626, 1475, 1376, 1261, 1171, 1107, 1011, 801, 739, 703 cm⁻¹; MS (ESI) m/z 423.3 (M+H⁺); HRMS (ESI) Calcd for C₂₂H₃₁O₆PNa requires (M+Na⁺): 445.1751, found: 445.1743.

(E)-Ethyl 2-(6-(diisopropoxyphosphoryl)-4-m-tolyl-3,4-dihydro-2H-pyran-2-ylidene)acetate 4ga. A slightly yellow liquid (3.3 mg, 8%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.24 (t, J = 7.2 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H), 1.39 (d, J = 6.4 Hz, 6H), 2.33 (s, 3H), 3.03 (dd, J = 15.2 Hz, 8.4 Hz, 1H), 3.62–3.64 (m, 1H), 3.70 (dd, J = 15.2 Hz, 6.0 Hz, 1H), 4.08–4.14 (m, 2H), 4.73–4.79 (m, 2H), 5.64 (s, 1H), 6.26 (dd, J = 10.4 Hz, 3.6 Hz, 1H), 6.99–7.00 (m, 2H), 7.06 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H); ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.008; IR (CH₂Cl₂) ν 2979, 2903, 1713, 1656, 1375, 1260, 1175, 1112, 1044, 1013, 800, 739, 703 cm⁻¹; MS (ESI) m/z 423.3 (M+H⁺); HRMS (ESI) Calcd for C₂₂H₃₁O₆PNa requires (M+Na⁺): 445.1751, found: 445.1744.

Ethyl 6-(diisopropoxyphosphoryl)-4-(4-methoxyphenyl)-2-methyl-4H-pyran-3-carboxylate 3ha. A slightly yellow liquid (29.2 mg, 67%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.12 (t, J = 7.2 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H), 2.37 (s, 3H), 3.78 (s, 3H), 4.00–4.08 (m, 2H), 4.38 (d, J = 4.8 Hz, 1H), 4.65–4.73 (m, 2H), 6.08 (dd, J = 10.0 Hz, 4.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.0, 19.0, 23.6 (d, J = 1.4 Hz), 23.7 (d, J = 1.4 Hz), 24.0 (d, J = 4.6 Hz), 37.3 (d, J = 9.9 Hz), 55.2, 60.1, 71.7 (d, J = 5.3 Hz), 105.1 (d, J = 2.3 Hz), 113.8, 120.8 (d, J = 19.8 Hz), 129.0, 136.7 (d, J = 2.3 Hz), 139.6, 141.9, 158.5, 159.6 (d, J = 9.2 Hz), 167.0; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.631; IR (CH₂Cl₂) ν 2980, 2937, 2906, 1714, 1626, 1510, 1376, 1259, 1176, 1106, 1070, 991, 946, 805, 745 cm⁻¹; MS (ESI) m/z 439.3 (M+H⁺); HRMS (ESI) Calcd for C₂₂H₃₁O₇PNa requires (M+Na⁺): 461.1700, found: 461.1699.

(E)-ethyl 2-(6-(diisopropoxyphosphoryl)-4-(4-methoxyphenyl)-3,4-dihydro-2H-pyran-2-ylidene)acetate 4ha. A slightly yellow liquid (3.7 mg, 8%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.24 (t, J = 7.2 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 6.0 Hz, 6H), 3.11 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 3.57–3.63 (m, 2H), 3.79 (s, 3H), 4.08–4.14 (m, 2H), 4.72–4.78 (m, 2H), 5.64 (s, 1H), 6.24 (dd, J = 10.4 Hz, 4.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H); ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.061; IR (CH₂Cl₂) ν 2968, 2902, 2839, 1713, 1657, 1513, 1474, 1447, 1375, 1172, 1109, 1046, 1016, 803, 738, 702 cm⁻¹; MS (ESI) m/z 439.3 (M+H⁺); HRMS (ESI) Calcd for C₂₂H₃₁O₇PNa requires (M+Na⁺): 461.1700, found: 461.1694.

Ethyl 6-(diisopropoxyphosphoryl)-2-methyl-4-(naphthalen-1-yl)-4H-pyran-3-carboxylate 3ia. A slightly yellow liquid (36.2 mg, 79%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 0.74 (t, J = 7.2 Hz, 3H), 1.25 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 5.2 Hz, 3H), 1.30 (d, J = 6.0 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H), 2.49 (s, 3H), 3.85 (q, J = 7.2 Hz, 2H), 4.53–4.62 (m, 1H), 4.65–4.73 (m, 1H), 5.34 (d, J = 4.8 Hz, 1H), 6.21 (dd, J = 10.4 Hz, 4.8 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.47–7.56 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 13.6, 18.9, 23.5 (d, J = 4.4 Hz), 23.6 (d, J = 5.2 Hz), 23.87 (d, J = 4.4 Hz), 23.91 (d, J = 4.4 Hz), 33.1 (d, J = 10.5 Hz), 60.0, 71.66 (d, J = 5.2 Hz), 71.72 (d, J = 6.0 Hz), 104.3 (d, J = 1.5 Hz), 120.2 (d, J = 21.1 Hz), 122.5, 125.60, 125.61, 126.3, 127.3, 128.7, 130.4, 133.7, 139.5, 140.8 (d, J = 2.2 Hz), 141.8, 160.4 (d, J = 8.2 Hz), 166.8; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.637; IR (CH₂Cl₂) ν 3059, 2980, 2939, 1713, 1665, 1627, 1375, 1327, 1258, 1106, 984, 798, 776, 740, 702 cm⁻¹; MS (ESI) m/z 459.3 (M+H⁺); HRMS (ESI) Calcd for C₂₅H₃₁O₆PNa requires (M+Na⁺): 481.1751, found: 481.1760.

(E)-Ethyl 2-(6-(diisopropoxyphosphoryl)-4-(naphthalen-1-yl)-3,4-dihydro-2H-pyran-2-ylidene)acetate 4ia. A slightly yellow liquid (2.6 mg, 6%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.16 (t, J = 7.2 Hz, 3H), 1.38 (d, J = 6.0 Hz, 6H), 1.40 (d, J = 6.0 Hz, 6H), 3.22 (dd, J = 15.2 Hz, 8.4 Hz, 1H), 3.87 (dd, J = 15.2 Hz, 5.6 Hz, 1H), 4.00–4.08 (m, 2H), 4.47–4.50 (m, 1H), 4.77–4.84 (m, 2H), 5.68 (s, 1H), 6.38 (dd, J = 10.4 Hz, 3.6 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.49–7.58 (m, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H); ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 3.937; IR (CH₂Cl₂) ν 2981, 2901, 1712, 1657, 1474, 1374, 1261, 1175, 1116, 1046, 1013, 88, 801, 739 cm⁻¹; MS (ESI) m/z 459.3 (M+H⁺); HRMS (ESI) Calcd for C₂₅H₃₁O₆PNa requires (M+Na⁺): 481.1751, found: 481.1743.

Ethyl 6-(diisopropoxyphosphoryl)-2,4-dimethyl-4H-pyran-3-carboxylate 3ja. A slightly yellow liquid (20.8 mg, 60%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.16 (d, J = 6.4 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.30 (d, J = 6.0 Hz, 3H), 1.34 (d, J = 6.0 Hz, 3H), 1.36 (d, J = 6.0 Hz, 3H), 1.38 (d, J = 6.0 Hz, 3H), 2.27 (s, 3H), 3.29–3.35 (m, 1H), 4.16–4.26 (m, 2H), 4.64–4.76 (m, 2H), 6.07 (dd, J = 10.0 Hz, 5.2 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.2, 19.1, 23.4 (d, J = 2.7 Hz), 23.6 (d, J = 4.5 Hz), 24.0 (d, J = 3.8 Hz), 26.7 (d, J = 10.2 Hz), 60.1, 71.6 (d, J = 5.3 Hz), 71.7 (d, J = 5.3 Hz), 106.4, 122.6 (d, J = 20.1 Hz), 140.5, 142.8, 160.0 (d, J = 8.4 Hz), 167.3; ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.672; IR (CH₂Cl₂) ν 2980, 2937, 2905, 2874, 1713, 1665, 1625, 1375, 1259, 1163, 1056, 989, 945, 801, 662, 611 cm⁻¹; MS (ESI) m/z 347.2 (M+H⁺); HRMS (ESI) Calcd for C₁₆H₂₇O₆PNa requires (M+Na⁺): 369.1438, found: 369.1439.

(E)-Ethyl 2-(6-(diisopropoxyphosphoryl)-4-methyl-3,4-dihydro-2H-pyran-2-ylidene)acetate 4ja. A slightly yellow liquid (5.2 mg, 15%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.13 (d, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H), 1.37 (d, J = 5.6 Hz, 6H), 2.45–2.92 (m, 1H), 2.68 (dd, J = 14.8 Hz, 8.4 Hz, 1H), 3.44 (dd, J = 14.8 Hz, 5.6 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 4.66–4.74 (m, 2H), 5.61 (s, 1H), 6.08 (dd, J = 10.4 Hz, 4.0 Hz, 1H); ³¹P NMR (CDCl₃, 161.93 MHz, 85% H₃PO₄) δ 4.380; IR (CH₂Cl₂) ν 2978, 2906, 1713, 1657, 1375, 1351, 1261, 1114, 1048, 1014, 803, 739, 703 cm⁻¹; MS (ESI) m/z 347.2 (M+H⁺); HRMS (ESI) Calcd for C₁₆H₂₇O₆PNa requires (M+Na⁺): 369.1438, found: 369.1421.

General procedure for the preparation of 6 and 7 from the reaction of 5a with 2a using 6aa and 7aa as an example in the presence of DABCO

To a mixture of 1a (0.10 mmol, 20.4 mg), 2a (0.12 mmol, 13.6 μL) and DABCO (2.2 mg, 0.02 mmol) was added 3.0 mL of THF at −10 °C. The reaction solution was monitored by TLC. After the reaction was complete, the solution was concentrated under reduced pressure and the residue was further purified by silica gel column chromatography (EtOAc/PE = 1/6) to give the target products 6aa and 7aa.

Diethyl 6-methyl-4-phenyl-4H-pyran-2,5-dicarboxylate 6aa. A slightly yellow liquid (2.7 mg, 7%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.08 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.44 (s, 3H), 3.99–4.06 (m, 2H), 4.21–4.30 (m, 2H), 4.51 (d, J = 5.2 Hz, 1H), 6.26 (d, J = 5.2 Hz, 1H), 7.20–7.24 (m, 3H), 7.29–7.33 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 13.9, 14.1, 19.1, 38.9, 60.2, 61.5, 104.6, 116.2, 127.0, 128.1, 128.6, 138.9, 144.4, 159.8, 161.1, 166.9; IR (CH₂Cl₂) ν 2980, 2903, 1736, 1714, 1658, 1448, 1374, 1260, 1118, 1018, 860, 802, 761, 739, 700 cm⁻¹; MS (ESI) m/z 317.2 (M+H⁺); HRMS (ESI) Calcd for C₁₈H₂₀O₅Na requires (M+Na⁺): 339.1203, found: 339.1206.

(E)-Ethyl 2-(2-ethoxy-2-oxoethylidene)-4-phenyl-3,4-dihydro-2H-pyran-6-carboxylate 7aa. A slightly yellow liquid (30.0 mg, 95%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.23 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 3.11 (dd, J = 8.0 Hz, 4.8 Hz, 1H), 3.68–3.72 (m, 2H), 4.07–4.14 (m, 2H), 4.28–4.34 (m, 2H), 5.75 (s, 1H), 6.45 (d, J = 4.8 Hz, 1H), 7.20–7.22 (m, 2H), 7.26–7.28 (m, 1H), 7.31–7.35 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.1, 14.2, 29.7, 35.8, 59.8, 61.6, 101.0, 116.5, 127.2, 128.8, 141.3, 141.7, 161.1, 164.6, 166.9; IR (CH₂Cl₂) ν 2981, 2903, 2875, 1736, 1711, 1660, 1493, 1373, 1258, 1170, 1118, 1046, 1015, 821, 760 cm⁻¹; MS (ESI) m/z 317.2 (M+H⁺). HRMS (ESI) Calcd for C₁₈H₂₀O₅ requires (M+Na⁺): 339.1203, found: 339.1206.

Diethyl 4-(4-chlorophenyl)-6-methyl-4H-pyran-2,5-dicarboxylate 6ba. A slightly yellow liquid (2.0 mg, 6%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.11 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 2.44 (s, 3H), 4.00–4.08 (m, 2H), 4.22–4.31 (m, 2H), 4.49 (d, J = 4.8 Hz, 1H), 6.21 (d, J = 4.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.00, 14.04, 19.2, 38.4, 60.3, 61.6, 104.3, 115.5, 128.7, 129.4, 132.8, 139.1, 142.9, 160.1, 161.0, 166.7; IR (CH₂Cl₂) ν 2981, 2904, 1739, 1715, 1629, 1488, 1372, 1327, 1268, 1106, 1049, 1015, 946, 805, 739 cm⁻¹; MS (ESI) m/z 373.2 (M+Na⁺); HRMS (ESI) Calcd for C₁₈H₁₉ClNaO₅ requires (M+Na⁺): 373.0816, found: 373.0813.

(E)-Ethyl 4-(4-chlorophenyl)-2-(2-ethoxy-2-oxoethylidene)-3,4-dihydro-2H-pyran-6-carboxylate 7ba. A slightly yellow liquid (28.1 mg, 80%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.24 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 3.18 (dd, J = 15.2 Hz, 7.6 Hz, 1H), 3.57 (dd, J = 15.2 Hz, 6.0 Hz, 1H), 3.68–3.72 (m, 1H), 4.08–4.14 (m, 2H), 4.29–4.35 (m, 2H), 5.75 (s, 1H), 6.40 (d, J = 4.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.1, 14.2, 29.5, 35.2, 59.9, 61.7, 101.3, 115.6, 128.6, 128.9, 133.1, 139.7, 142.0, 161.0, 164.0, 166.8; IR (CH₂Cl₂) ν 2981, 2903, 2875, 1736, 1711, 1660, 1493, 1373, 1258, 1170, 1118, 1046, 1015, 821, 760 cm⁻¹; MS (ESI) m/z 373.2 (M+Na⁺); HRMS (ESI) Calcd for C₁₈H₁₉ClO₅ requires (M+Na⁺): 373.0813, found: 373.0821.

Diethyl 4-(4-bromophenyl)-6-methyl-4H-pyran-2,5-dicarboxylate 6ca. A slightly yellow liquid (3.1 mg, 8%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.12 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 2.44 (s, 3H), 3.99–4.08 (m, 2H), 4.23–4.30 (m, 2H), 4.48 (d, J = 5.2 Hz, 1H), 6.21 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.0, 14.1, 19.2, 38.4, 60.3, 61.6, 104.2, 115.4, 120.9, 129.8, 131.7, 139.1, 143.4, 160.1, 160.9, 166.6; IR (CH₂Cl₂) ν 2979, 2902, 1716, 1660, 1373, 1263, 1173, 1107, 1048, 1013, 803, 762, 738, 703 cm⁻¹; MS (ESI) m/z 395.2 (M+H⁺); HRMS (ESI) Calcd for C₁₈H₁₉BrO₅Na requires (M+Na⁺): 417.0308, found: 417.0320.

(E)-Ethyl 4-(4-bromophenyl)-2-(2-ethoxy-2-oxoethylidene)-3,4-dihydro-2H-pyran-6-carboxylate 7ca. A slightly yellow liquid (31.2 mg, 80%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.24 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 3.18 (dd, J = 15.2 Hz, 7.2 Hz, 1H), 3.56 (dd, J = 15.2 Hz, 6.4 Hz, 1H), 3.66–3.71 (m, 1H), 4.09–4.13 (m, 2H), 4.30–4.34 (m, 2H), 5.75 (s, 1H), 6.40 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.1, 14.2, 29.4, 35.3, 59.9, 61.7, 101.3, 115.4, 121.1, 129.0, 131.9, 140.2, 142.0, 161.0, 164.0, 166.8; IR (CH₂Cl₂) ν 3084, 2982, 2904, 1736, 1711, 1659, 1489, 1394, 1300, 1167, 1117, 1011, 859, 818, 760 cm⁻¹; MS (ESI) m/z 417.2 (M+Na⁺); HRMS (ESI) Calcd for C₁₈H₁₉BrO₅Na requires (M+Na⁺): 417.0308, found: 417.0315.

Diethyl 4-(3-bromophenyl)-6-methyl-4H-pyran-2,5-dicarboxylate 6da. A slightly yellow liquid (3.6 mg, 9%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.12 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H), 2.44 (s, 3H), 4.00–4.09 (m, 2H), 4.25–4.30 (m, 2H), 4.48 (d, J = 5.2 Hz, 1H), 6.21 (d, J = 5.2 Hz, 1H), 7.16–7.18 (m, 2H), 7.34–7.26 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.0, 14.1, 19.2, 38.7, 60.3, 61.7, 104.1, 115.3, 122.7, 126.8, 130.1, 130.2, 131.2, 139.3, 146.7, 160.4, 160.9, 166.5; IR (CH₂Cl₂) ν 3058, 2980, 2873, 1714, 1627, 1590, 1472, 1328, 1267, 1096, 964, 839, 764, 739, 696 cm⁻¹; MS (ESI) m/z 395.2 (M+H⁺); HRMS (ESI) Calcd for C₁₈H₁₉BrO₅Na requires (M+Na⁺): 417.0308, found: 417.0315.

(E)-Ethyl 4-(3-bromophenyl)-2-(2-ethoxy-2-oxoethylidene)-3,4-dihydro-2H-pyran-6-carboxylate 7da. A slightly yellow liquid (29.2 mg, 74%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.24 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 3.12 (dd, J = 14.8 Hz, 6.8 Hz, 1H), 3.61–3.69 (m, 2H), 4.09–4.14 (m, 2H), 4.29–4.35 (m, 2H), 5.76 (s, 1H), 6.39 (d, J = 3.6 Hz, 1H), 7.13–7.16 (m, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.39–7.41 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.1, 14.2, 29.5, 35.6, 59.9, 61.8, 101.4, 115.3, 122.8, 126.0, 130.38, 130.41, 130.5, 142.1, 143.6, 161.0, 164.0, 166.8; IR (CH₂Cl₂) ν 3082, 2981, 2903, 2873, 1710, 1658, 1593, 1475, 1393, 1349, 1256, 1111, 1045, 1021, 855, 790, 676 cm⁻¹; MS (ESI) m/z 419.1 (M+Na⁺); HRMS (ESI) Calcd for C₁₈H₁₉BrO₅Na requires (M+Na⁺): 417.0308, found: 417.0307.

Diethyl 4-(2-bromophenyl)-6-methyl-4H-pyran-2,5-dicarboxylate 6ea. A white solid (3.7 mg, 9%); m.p. 122–124 °C; ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.00 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.50 (s, 3H), 3.93–4.03 (m, 2H), 4.20–4.29 (m, 2H), 5.06 (d, J = 4.8 Hz, 1H), 6.27 (d, J = 4.8 Hz, 1H), 7.05–7.10 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.27–7.30 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 13.8, 14.1, 19.0, 38.3, 60.2, 61.6, 103.6, 114.4, 122.7, 128.2, 128.4, 130.0, 132.7, 139.2, 143.4, 161.0, 161.2, 166.5; IR (CH₂Cl₂) ν 3058, 2980, 2873, 1714, 1627, 1590, 1472, 1328, 1267, 1096, 964, 839, 764, 739, 696 cm⁻¹; MS (ESI) m/z 395.2 (M+H⁺); HRMS (ESI) Calcd. for C₁₈H₁₉BrO₅Na requires (M+Na⁺): 417.0308, Found: 417.0315.

(E)-Ethyl 4-(2-bromophenyl)-2-(2-ethoxy-2-oxoethylidene)-3,4-dihydro-2H-pyran-6-carboxylate 7ea. A slightly yellow liquid (29.8 mg, 76%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.23 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 3.20 (dd, J = 15.6 Hz, 7.6 Hz, 1H), 3.59 (dd, J = 15.6 Hz, 6.4 Hz, 1H), 4.07–4.14 (m, 2H), 4.18–4.23 (m, 1H), 4.29–4.35 (m, 2H), 5.75 (s, 1H), 6.42 (d, J = 4.4 Hz, 1H), 7.13–7.17 (m, 2H), 7.27–7.30 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.09, 14.14, 28.1, 35.2, 59.9, 61.7, 101.5, 115.1, 124.0, 127.9, 128.4, 128.8, 133.1, 140.0, 142.4, 161.1, 163.8, 166.6; IR (CH₂Cl₂) ν 3060, 2980, 2902, 1711, 1659, 1470, 1372, 1298, 1258, 1197, 1108, 1022, 856, 803, 754, 670 cm⁻¹; MS (ESI) m/z 395.0 (M+H⁺); HRMS (ESI) Calcd for C₁₈H₁₉BrO₅Na requires (M+Na⁺): 417.0308, found: 417.0312.

Diethyl 4-(2,4-dichlorophenyl)-6-methyl-4H-pyran-2,5-dicarboxylate 6fa. A slightly yellow liquid (4.2 mg, 11%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.05 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 2.49 (s, 3H), 3.97–4.03 (m, 2H), 4.22–4.29 (m, 2H), 5.03 (d, J = 4.8 Hz, 1H), 6.22 (d, J = 4.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 13.8, 14.1, 19.1, 35.1, 60.4, 61.7, 103.0, 113.9, 127.8, 129.1, 130.7, 132.8, 133.2, 139.4, 140.4, 160.8, 161.6, 166.3; IR (CH₂Cl₂) ν 3086, 2982, 2906, 1716, 1630, 1586, 1561, 1372, 1270, 1189, 1172, 1097, 1074, 964, 918, 767 cm⁻¹; MS (ESI) m/z 385.3. (M+H⁺); HRMS (ESI) Calcd for C₁₈H₁₈Cl₂NaO₅ requires (M+Na⁺): 407.0424, found: 407.0435.

(E)-Ethyl 4-(2,4-dichlorophenyl)-2-(2-ethoxy-2-oxoethylidene)-3,4-dihydro-2H-pyran-6-carboxylate 7fa. A slightly yellow liquid (29.2 mg, 76%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.23 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 3.30 (dd, J = 15.2 Hz, 6.8 Hz, 1H), 3.47 (dd, J = 15.2 Hz, 6.4 Hz, 1H), 4.07–4.19 (m, 3H), 4.30–4.36 (m, 2H), 5.76 (s, 1H), 6.37 (d, J = 4.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.11, 14.15, 27.7, 32.2, 60.0, 61.8, 101.8, 114.2, 127.5, 129.1, 129.6, 133.7, 134.1, 136.9, 142.7, 160.9, 163.5, 166.6; IR (CH₂Cl₂) ν 3086, 2982, 2905, 1660, 1587, 1561, 1474, 1372, 1299, 1256, 1170, 1104, 1020, 861, 818, 760 cm⁻¹; MS (ESI) m/z 385.3. (M+H⁺); HRMS (ESI) Calcd for C₁₈H₁₈Cl₂NaO₅ requires (M+Na⁺): 407.0424, found: 407.0435.

Diethyl 6-methyl-4-p-tolyl-4H-pyran-2,5-dicarboxylate 6ga. A slightly yellow liquid (2.2 mg, 7%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.11 (t, J = 7.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 2.43 (s, 3H), 3.98–4.07 (m, 2H), 4.21–3.31 (m, 2H), 4.46 (d, J = 4.8 Hz, 1H), 5.74 (s, 1H), 6.25 (d, J = 4.8 Hz, 1H), 7.08–7.13 (m, 4H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.0, 14.1, 19.1, 21.0, 38.5, 60.2, 61.5, 104.8, 116.4, 128.0, 129.3, 136.7, 138.9, 141.5, 159.6, 161.2, 167.0; IR (CH₂Cl₂) ν 2979, 2902, 1715, 1659, 1629, 1511, 1446, 1373, 1324, 1263, 1172, 1106, 1021, 865, 803, 739 cm⁻¹; MS (ESI) m/z 353.1 (M+Na⁺); HRMS (ESI) Calcd for C₁₉H₂₂O₅Na requires (M+Na⁺): 353.1359, found: 353.1371.

(E)-Ethyl 2-(2-ethoxy-2-oxoethylidene)-4-p-tolyl-3,4-dihydro-2H-pyran-6-carboxylate 7ga. A slightly yellow liquid (25.9 mg, 78%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.23 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 2.33 (s, 3H), 3.06–3.13 (m, 1H), 3.62–3.69 (m, 2H), 4.08–4.14 (m, 2H), 4.27–4.33 (m, 2H), 5.74 (s, 1H), 6.43 (d, J = 4.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.1, 14.2, 21.0, 29.7, 35.5, 59.8, 61.6, 100.9, 116.8, 127.1, 129.5, 136.9, 138.3, 141.6, 161.2, 164.8, 166.9; IR (CH₂Cl₂) ν 2980, 2902, 1736, 1712, 1658, 1514, 1373, 1297, 1167, 1113, 1045, 1020, 847, 808, 762 cm⁻¹; MS (ESI) m/z 353.1 (M+Na⁺); HRMS (ESI) Calcd for C₁₉H₂₂O₅Na requires (M+Na⁺): 353.1359, found: 353.1371.

Diethyl 4-(furan-2-yl)-6-methyl-4H-pyran-2,5-dicarboxylate 6ha. A slightly yellow liquid (4.6 mg, 15%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.18 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H), 2.41 (s, 3H), 4.06–4.18 (m, 2H), 4.25–4.31 (m, 2H), 4.67 (d, J = 5.2 Hz, 1H), 6.05 (d, J = 5.2 Hz, 1H), 6.28–6.29 (m, 2H), 7.27–7.29 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.06, 14.12, 19.1, 32.3, 60.3, 61.6, 102.2, 106.1, 110.5, 112.9, 140.1, 141.6, 156.1, 160.5, 160.9, 166.7; IR (CH₂Cl₂) ν 2980, 2903, 2857, 1738, 1716, 1660, 1475, 1372, 1266, 1173, 1107, 1048, 1020, 798, 763, 739 cm⁻¹; MS (ESI) m/z 329.1 (M+Na⁺); HRMS (ESI) Calcd for C₁₆H₁₈O₆Na requires (M+Na⁺): 329.0996, found: 329.1000.

(E)-Ethyl 2-(2-ethoxy-2-oxoethylidene)-4-(furan-2-yl)-3,4-dihydro-2H-pyran-6-carboxylate 7ha. A slightly yellow liquid (13.8 mg, 45%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.27 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 3.36 (dd, J = 15.2 Hz, 8.0 Hz, 1H), 3.56 (dd, J = 15.2 Hz, 5.2 Hz, 1H), 3.78–3.83 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H), 5.76 (s, 1H), 6.13–6.14 (m, 1H), 6.30–6.31 (m, 1H), 6.45 (d, J = 4.0 Hz, 1H), 7.35–7.36 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.1, 14.3, 26.3, 29.7, 59.9, 61.7, 101.4, 105.7, 110.3, 113.4, 141.8, 142.1, 153.4, 161.1, 164.1, 166.9; IR (CH₂Cl₂) ν 2980, 2906, 2874, 1737, 1712, 1660, 1446, 1373, 1298, 1174, 1120, 1046, 1017, 801, 761, 739 cm⁻¹; MS (ESI) m/z 329.1 (M+Na⁺); HRMS (ESI) Calcd for C₁₆H₁₈O₆Na requires (M+Na⁺): 329.0996, found: 329.1007.

Diethyl 6-methyl-4-(thiophen-2-yl)-4H-pyran-2,5-dicarboxylate 6ia. A slightly yellow liquid (2.6 mg, 8%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.19 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H), 2.41 (s, 3H), 4.07–4.17 (m, 2H), 4.25–4.31 (m, 2H), 4.83 (d, J = 5.2 Hz, 1H), 6.34 (d, J = 5.2 Hz, 1H), 6.86–6.87 (m, 1H), 6.91 (dd, J = 4.8 Hz, 3.2 Hz, 1H), 7.17 (dd, J = 4.8 Hz, 1.2 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.03, 14.1, 19.1, 33.4, 60.4, 61.6, 104.8, 115.1, 124.6, 124.9, 126.9, 139.4, 148.3, 159.7, 161.0, 166.7; IR (CH₂Cl₂) ν 2980, 2903, 2857, 1738, 1716, 1660, 1475, 1372, 1266, 1173, 1107, 1048, 1020, 798, 763, 739 cm⁻¹; MS (ESI) m/z 345.1 (M+Na⁺); HRMS (ESI) Calcd for C₁₆H₁₈O₅SNa requires (M+Na⁺): 345.0767, found: 345.0775.

(E)-Ethyl 2-(2-ethoxy-2-oxoethylidene)-4-(thiophen-2-yl)-3,4-dihydro-2H-pyran-6-carboxylate 7ia. A slightly yellow liquid (15.7 mg, 49%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.25 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 3.41 (dd, J = 15.2 Hz, 8.0 Hz, 1H), 3.56 (dd, J = 15.2 Hz, 5.2 Hz, 1H), 3.99–4.03 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 5.77 (s, 1H), 6.48 (d, J = 4.0 Hz, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.95 (dd, J = 4.8 Hz, 3.6 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.15, 14.24, 29.8, 31.2, 59.9, 61.7, 101.7, 115.7, 124.4, 124.5, 126.9, 141.5, 144.1, 161.2, 163.9, 166.8; IR (CH₂Cl₂) ν 3075, 2966, 2934, 1736, 1713, 1660, 1373, 1259, 1173, 1259, 1119, 1046, 1020, 802, 762, 738, 701 cm⁻¹; MS (ESI) m/z 345.2 (M+Na⁺); HRMS (ESI) Calcd for C₁₆H₁₈O₅SNa requires (M+Na⁺): 345.0767, found: 345.0777.

Diethyl 6-methyl-4-(naphthalen-2-yl)-4H-pyran-2,5-dicarboxylate 6ja. A slightly yellow liquid (3.3 mg, 9%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.07 (t, J = 7.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H), 2.48 (s, 3H), 3.98–4.00 (m, 2H), 4.24–4.27 (m, 2H), 4.68 (d, J = 5.2 Hz, 1H), 6.31 (d, J = 5.2 Hz, 1H), 7.38 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.44–7.47 (m, 2H), 7.65 (s, 1H), 7.78–7.80 (m, 3H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.0, 14.1, 19.2, 39.1, 60.2, 61.6, 104.6, 116.0, 125.8, 126.1, 126.3, 126.9, 127.6, 127.8, 128.3, 132.6, 133.5, 139.0, 141.8, 159.9, 161.1, 166.9; IR (CH₂Cl₂) ν 3057, 2980, 2902, 1715, 1474, 1373, 1262, 1106, 1048, 1021, 956, 859, 801, 746, 702, 667 cm⁻¹; MS (ESI) m/z 389.2 (M+Na⁺); HRMS (ESI) Calcd for C₂₂H₂₂O₅Na requires (M+Na⁺): 389.1359, found: 389.1374.

(E)-ethyl 2-(2-ethoxy-2-oxoethylidene)-4-(naphthalen-2-yl)-3,4-dihydro-2H-pyran-6-carboxylate 7ja. A slightly yellow liquid (26.7 mg, 73%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 1.21 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H), 3.27 (dd, J = 14.8 Hz, 8.4 Hz, 1H), 3.71 (dd, J = 14.8 Hz, 5.2 Hz, 1H), 3.86–3.89 (m, 1H), 4.05–4.12 (m, 2H), 4.31–4.36 (m, 2H), 5.76 (s, 1H), 6.54 (d, J = 4.0 Hz, 1H), 7.34 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.46–7.49 (m, 2H), 7.64 (s, 1H), 7.78–7.83 (m, 3H); ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 14.17, 14.20, 29.6, 36.0, 59.8, 61.7, 101.3, 116.3, 125.5, 125.8, 125.9, 126.3, 127.6, 127.7, 128.7, 132.6, 133.4, 138.6, 142.0, 161.2, 164.5, 166.9; IR (CH₂Cl₂) ν 3056, 2982, 2904, 1734, 1709, 1659, 1508, 1474, 1445, 1372, 1298, 1254, 1172, 1115, 854, 817, 760 cm⁻¹; MS (ESI) m/z 389.2 (M+Na⁺); HRMS (ESI) Calcd for C₂₂H₂₂O₅Na requires (M+Na⁺): 389.1359, found: 389.1364.

(E)-Ethyl 4-cyclopropyl-2-(2-ethoxy-2-oxoethylidene)-3,4-dihydro-2H-pyran-6-carboxylate 7ka. A slightly yellow liquid (27.3 mg, 90%); ¹H NMR (CDCl₃, 400 MHz, TMS) δ 0.23–0.26 (m, 2H), 0.52–0.56 (m, 2H), 0.70–0.76 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.72–1.79 (m, 1H), 2.92 (dd, J = 15.2 Hz, 8.4 Hz, 1H), 3.48 (dd, J = 15.2 Hz, 5.6 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 4.27–4.32 (m, 2H), 5.70 (s, 1H), 6.32 (d, J = 4.0 Hz, 1H). ¹³C NMR (CDCl₃, 100 MHz, TMS) δ 3.2, 3.6, 14.1, 14.3, 15.3, 27.7, 34.9, 59.8, 61.5, 100.4, 117.1, 141.1, 161.3, 165.7, 167.2. IR (CH₂Cl₂) ν 3081, 2982, 2903, 1737, 1713, 1659, 1372, 1335, 1298, 1256, 1120, 1048, 1021, 854, 761, 740 cm⁻¹. MS (ESI) m/z 281.1 (M+H⁺). HRMS (ESI) Calcd for C₁₅H₂₀O₅Na requires (M+Na⁺): 303.1203, found: 303.1209.

Acknowledgements

Financial support from the National Basic Research Program of China (973)-2010CB833302, the Fundamental Research Funds for the Central Universities and the National Natural Science Foundation of China for financial support (21072206, 20472096, 20902019, 20872162, 20672127, 20821002, 20732008, 20772030 and 20702059) is greatly acknowledged.

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7. The crystal data of compound 6ea have been deposited in CCDC with number 833190. Empirical Formula: C₁₈H₁₉BrO₅; Formula Weight: 395.24; Crystal Color, Habit: colorless; Crystal Dimensions: 0.28 × 0.15 × 0.10 mm; Crystal System: Triclinic; Lattice Type: Primitive; Lattice Parameters: a = 8.5579(17) Å, b = 9.7108(19) Å, c = 11.568(3) Å, = 73.985(4)°, β = 68.692(3)°, γ = 73.448(3)°, V = 842.4(3) ų; Space group: P1̄; Z = 2; D_c = 1.558 g cm⁻³; F₀₀₀ = 404; Final R indices [I > 2σ(I)]: R₁ = 0.0438; wR₂ = 0.1321.
8. (a) A. Kumar, S. Sharma, V. D. Tripathi, R. A. Maurya, S. P. Srivastava, G. Bhatia, A. K. Tamrakar and A. K. Srivastava, Bioorg. Med. Chem., 2010, 18, 4138.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, NMR charts for all compounds and X-ray crystal data of 6ea. CCDC reference numbers 833190. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1ob06507f

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