Simple access to 5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones via domino acylative electrocyclization: the first three step total synthesis of the dihydronaphthopyran-4-one class of natural products

Abstract

Intermolecular domino C-acylation/6π-oxaelectrocyclization between β-ketoesters and α,β-unsaturated acid chlorides took place readily in the presence of CaCl₂ to afford a variety of polysubstituted 5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones, in good yields. The products were successfully exploited as precursors, for a simple and efficient construction of a naphthalene fused pyran-4-one ring system. This intramolecular Friedel–Crafts acylative aromatization approach was useful for the synthesis of the phytogrowth inhibiting dihydronaphthopyranone class of natural products.

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Introduction

Linear naphthalene fused pyran-4-one ring systems, such as naphtho-γ-pyrone (NGP),¹ 1,4-pyranonaphthoquinone (PNQ),² and bisnaphthopyranone (BNP)³ containing compounds are well known fungal metabolites. Some of the natural products rubrofusarin B (i),^1e–g 4-oxo-α-lapachone (ii),^2d,e cephalochromin,^3a,b chaetochromin A^3c and nigerone^3d,e belonging to this class exhibit important biological activities such as topoisomerase-II inhibition, toxin inhibition, anti-tumour, anti-bacterial and anti-proliferative activity. Similarly, linear dihydronaphthopyran-4-one (DHNP) natural products,⁴ trans-11b, cis-11b and 11c showing phytogrowth-inhibition activity, constitute another important sub-class of naphthalene fused pyran-4-ones. The presence or absence of a double bond in the pyranone ring and the hydroxyl or the 1,4-diketone functionality in the adjacent naphthalene ring gives rise to structural differences (Fig. 1).

Fig. 1 Linear naphthopyran-4-one class of natural products.

Although there are methods known for the synthesis of different naphthopyran-4-one class of compounds (B, Scheme 1a),^1–3 the synthesis of DHNP class of natural products,⁴ (D, Scheme 1b) remains virgin. These approaches are either based on construction of pyranone on a pre-existing naphthalene ring (A, Scheme 1a),^1–3 or reaction of orsellinate anion with pyrylium salt.^1g Moreover, these methods are difficult to be adopted for the synthesis of DHNPs (ref. 4) because of drawbacks such as, difficulty in chemoselective conjugate reduction of enone in NGP (B, Scheme 1a), need for the use of hard to handle intermediates such as pyrylium salt^1g and dimsyl anion,^3d,e formation of mixture of products,^1g and conversion of angular to linear naphthopyranone involving lengthy synthetic sequence.^3d,e Thus there is a need for development of a new and efficient method for the synthesis of DHNPs.

Scheme 1 Approaches for naphthopyran-4-one ring formation.

Designing simple but powerful domino reactions useful for construction of cyclic ring systems, especially natural products, is a challenging task.⁵ Strategic positioning of functional groups in a molecule allows tandem reactions to take place in one pot. Considering the advantages of domino reactions, and to overcome the drawbacks mentioned above, we envisaged to generate naphthalene fused dihydropyran-4-one ring system (D, Scheme 1b) in a shortest possible way, by intramolecular Friedel–Crafts acylative aromatization of 6-benzyl-5-carboalkoxy-2,3-dihydropyran-4-one (6-BCDHP, C, Scheme 1b), which in turn could be generated via domino C-acylation/6π-oxaelectrocyclization reaction between β-ketoesters and α,β-unsaturated acid chlorides.

Literature background shows that synthesis of 6-alkyl/aryl-5-carboalkoxy-2,3-dihydropyran-4-ones (6-ACDHPs) was reported independently by Gelin^6a and Takeda^6b as well as used as intermediate in the synthesis of natural products.^6b,7 Nevertheless, these methods does not cover synthesis of 6-BCDHP and has drawbacks such as need for the use of stoichiometric quantity of bases such as Mg(OEt)₂ (ref. 6a) and NaH,^6b high reaction temperature and limited substrate scope. Also, other methods known for the synthesis of substituted 2,3-dihydropyran-4-one (DHP) ring system without 5-carboalkoxy substituent was found not suitable for the synthesis of 5-carboalkoxy-2,3-dihydropyran-4-one (5-CDHP).^8–16 The presence of 5-carboalkoxy group in DHP ring system provides multitude of opportunities for further synthetic transformations. Thus we realised that development of a simple method for the synthesis of 6-ACDHP itself is desirable. To avoid the use of stoichiometric quantity of base,⁶ in C-acylation of β-keto esters with α,β-unsaturated acid chloride, to get DHPs, we thought of using a Lewis acid. Lewis acids are expected to work in catalytic quantity for the C-acylation reaction.¹⁷ CaCl₂ is a biocompatible, cost-effective, bifunctional (Lewis acid as well as Lewis base) catalyst and it has been exploited only to limited extent in organic synthesis,^18a,b for example, in aldol reaction,^18c Biginelli reaction,^18d synthesis of Mannich bases,^18e and aminophosphonic esters.^18f Thus in continuation of our interest on the use of CaCl₂,¹⁹ as Lewis acid catalyst we examined its utility in this reaction. Herein we present successful realisation of what we contemplated.

Results and discussion

Reaction optimization

To start with, reaction between ethylbenzoylacetate (1a) and 3,3-dimethylacrylolyl chloride (2a) was designed as a model, to check the feasibility of formation of 5-carboalkoxy-2,3-dihydro-4H-pyran-4-one (3aa, Table 1). When an equimolar mixture of 1a and 2a was stirred for 7 h at room temperature in the presence of CaCl₂ (5 mol%) and Et₃N (2.0 equiv.) in DCM, the expected dihydropyranone 3aa was obtained only in 60% yield (Table 1, entry 1). Gratifyingly, the yield of product 3aa improved to 80% when the quantity of the CaCl₂ was increased to 10 mol% (entry 1). Further, increasing the quantity of CaCl₂ to 20 mol% or decreasing the quantity of Et₃N did not improve the yield (entries 1 and 2). In the absence of Et₃N (entry 3) no reaction was observed and in the absence of CaCl₂ (entry 4) a mixture of product was formed.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (mol%)	Base	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), base (2.0 mmol) and solvent (5 mL) at room temperature.b Isolated yield.c 1.5 equiv. of Et3N was used.d NR = no reaction (β-ketoester 1a was recovered).e Not determined.
1.	CaCl2 (5), (10), (20)	Et3N	DCM	7, 7, 7	60, 80, 80
2.	CaCl2 (10)	Et3N	DCM	7	70^c
3.	CaCl2 (10)	—	DCM	15	NR^d
4.	—	Et3N	DCM	15	nd^e
5.	CaCl2 (10)	Et3N	DMF, toluene, THF	24	55, 40, 20
6.	CaCl2 (10)	DMAP, DBU	DCM	24	30, 20
7.	CaCl2 (10)	DABCO	DCM	24	nd^e
8.	MgCl2 (20)	Et3N	DCM	24	25
9.	BaCl2 (20)	Et3N	DCM	24	20
10.	ZnCl2 (20)	Et3N	DCM	24	15
11.	FeCl3 (20)	Et3N	DCM	24	nd^e
12.	CuCl2 (20), CeCl3 (20)	Et3N	DCM	24	Trace

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Change of solvent to DMF, toluene and THF only lead to decrease in the yield (entry 5). Similarly, change of base to DMAP, DBU or DABCO had either decreased the yield or led to the formation of mixture of products (entries 6 and 7). Making use of other alkaline earth metal chlorides (MgCl₂ and BaCl₂) and transition metal halides (ZnCl₂, FeCl₃, CuCl₂ and CeCl₃) had only negative impact on the reaction (entries 8–12). Based on these results, treatment of an equimolar mixture of β-ketoester and α,β-unsaturated acid chloride in the presence of 10 mol% of CaCl₂ and 2.0 equiv. of Et₃N in DCM at room temperature (entry 1) was identified as the optimum condition for further study.

Substrate scope

With the optimal reaction condition in hand, scope and limitation of the reaction was explored using fourteen different β-ketoesters and six different α,β-unsaturated acid chlorides such as, 3,3-dimethylacryloyl chloride (2a, or senecioyl chloride), (E)-2,3-dimethylacryloyl chloride (2b, or tigloyl chloride), crotonoyl chloride (2c), acryloyl chloride (2d), cinnamoyl chloride (2e) and (E)-pent-2-enoyl chloride (2f, Scheme 2). Comparison of the reactivity of the different β-ketoesters (1a–1d) with 3,3-dimethylacryloyl chloride (2a) revealed that the electron donating substituents such as 4–Me, 4-OMe and 3,4,5-OMe on the aromatic ring had no significant effect on the rate and yield of the reaction. The presence of chloro group, at sterically hindered ortho position in the β-ketoester 1f slowed down the reaction (see 3ea and 3fa) compared to para position in the β-ketoester 1e. Among the different acid chlorides, 2a gave high yield of the product (see 3aa, tc-3ab, 3ac) compared to 2b and 2c. The product tc-3ab was obtained as a separable trans–cis (dr 6 : 4) diastereomeric mixture, which was confirmed by ¹H NMR.

Scheme 2 Synthesis of 5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones. ^aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), CaCl₂ (0.1 mmol), triethylamine (2.0 mmol) in DCM (5 mL) at room temperature. ^bIsolated yield. ^ctrans–cis = 6 : 4 was confirmed by ¹H NMR of crude reaction mixture. ^dNot determined.

While thiophene and furan derived β-ketoesters, 1g and 1h gave the product 3ga and 3ha respectively in excellent yield, the expected product 3ia could not be obtained with pyridine derived β-ketoester 1i. Most likely, the pyridine nitrogen might have formed irreversible complex with acid chloride. Formation of 6-ACDHP ring structure was further confirmed using the X-ray crystal structure obtained for the compound 3ga (Fig. 2).²⁰ Acryloyl chloride (2d) and cinnamoyl chloride (2e) failed to react with 1a to provide the desired product 3ad and 3ae. This is similar to the failure of α,β-unsaturated 1,3-diketones, which has no substitution or phenyl group substitution at β position, to undergo cyclization to form DHPs.¹²

Fig. 2 ORTEP diagram of compound 3ga.

Further, the substrate scope was extended to aliphatic β-ketoesters. The acid chlorides 2a and 2c on reaction with ethyl acetoacetate (1j) produced 3ja and 3jc respectively in good yield. Similarly, methyl-3-oxo-pentanoate (1k) on reaction with acid chlorides 2a and 2b gave the expected product 3ka and 3kb respectively in very good yield. Compound 3lf, a potential intermediate for the synthesis of the natural product hepialone²¹ was obtained in moderate yield when compound 1l was treated with acid chloride 2f. Dihydropyranones 3ma and 3mc were obtained in moderate yield from the reaction of diethyl acetone dicarboxylate (1m) with acid chlorides 2a and 2c. Interestingly, 6-BCDHPs, 3na and 3nc, useful intermediates for the synthesis of DHNPs 8na and 8nc (Scheme 4), was obtained in good yield starting with ethyl 3-oxo-4-phenylbutyrate (1n). Thus, the domino acylative cyclization method was found useful for the synthesis of wide variety of polysubstituted 6-ACDHPs including 6-BCDHPs.

Under the optimized condition, reaction of cyclic active methylene compounds such as 4-hydroxycoumarin (4a) and 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (4b) with 3,3-dimethylacryloyl chloride (2a) was examined (Scheme 3). However, similar to the formation of O-acylated product in the case of Lewis acid, SmCl₃,¹⁷ only O-acylated products 5a (ref. 17) and 5b were obtained in good yield in the presence of CaCl₂. Increasing the temperature or the catalyst did not change the course.

Scheme 3 CaCl₂ catalyzed C-acylation vs. O-acylation of cyclic active methylene compounds.

Total synthesis of dihydronaphthopyran-4-one (DHNP) class of natural products and its analogs

As a part of our strategy, utility of 6-BCDHPs, 3na, 3nc and 10a-c, was examined as starting materials, for the synthesis of DHNP class of synthetic analogs 11na, 11nc and 11a, and natural products trans-11b, cis-11b and 11c. On treatment with PPA compounds 3na and 3nc (Scheme 2 and 4) underwent facile intramolecular Friedel–Crafts acylative aromatization to afford a separable mixture of 11na (50%)/11na′ (45%) and 11nc (45%)/11nc′ (40%) respectively in very high yield (Scheme 4). As a next step, synthesis of β-keto ester 9, starting material for the synthesis of 11a, trans-11b, cis-11b and 11c was initiated. 3,5-Dimethoxyacetophenone (7) was subjected to Willgerodt–Kindler reaction to get 3,5-dimethoxyphenyl acetic acid (8) in very good yield. Compound 8 was further coupled with Meldrum's acid using DCC/DMAP and refluxed with ethanol to get the β-ketoester 9. However, when compound 9, containing 3,5-dimethoxy benzene ring, was treated with acid chloride 2a, under the standard reaction condition using CaCl₂, a mixture of products, instead of the desired product 10a, was obtained. There was no change in the course of the reaction when the reaction temperature was lowered or increased; quantity of CaCl₂ was increased to 1.0 equiv.; solvent was changed to DMF. Similarly, when the reaction was tried with different Lewis acids such as Yb(OTf)₃, In(OTf)₃, Cu(OTf)₂, SmCl₃ (ref. 17) and InCl₃ an inseparable mixture of unidentifiable products was obtained. Thus we were bewildered to know that, while compound 1n could give rise to cyclised product 6-BCDHP (3n), compound 9 failed to give the desired product 10a in the presence of Lewis acids. Most likely, the electron rich 3,5-dimethoxy benzene ring, in the presence of Lewis acid, may undergo side reactions and play spoilsport. To overcome this problem in the preparation of compound 10a and to achieve our main goal of synthesis of compound 11a–c, we opted to use a base, Mg(OEt)₂,^6a instead of Lewis acid. To our delight, with Mg(OEt)₂ a facile acylation followed by 6π-oxaelectrocyclization took place readily to deliver dihydropyranone 10a. Similarly, other dihydropyranone derivatives tc-10b and 10c were prepared in good yield using Mg(OEt)₂.

Scheme 4 Total synthesis of dihydronaphthopyranone class of natural products and its analogs. ^aReagents and conditions: (a) S₈, TsOH/morpholine, 120–130 °C, 6 h; 20% aq. NaOH, TBAB, 100–110 °C, 6 h, 80%; (b) Meldrum's acid, DCC, DMAP, DCM, 25 °C, 5 h; EtOH, reflux, 10 h (50% for two steps); (c) 9, Mg(OEt)₂, dry toluene, 100 °C, 30 min; 2 (2a–c), ACN, r.t.; (d) 3n and 2 (2a and 2c), CaCl₂, Et₃N, DCM, r.t.; (e) PPA, 80 °C; ^ftrans–cis = 6 : 4 was confirmed by ¹H NMR of crude reaction mixture.

Further, 6-BCDHPs 10a, tc-10b and 10c were successfully converted to DHNPs 11a, tc-11b and 11c respectively, in excellent yield by following the procedure used for the conversion of compound 3na. The product tc-11b was obtained as a separable diastereomeric mixture of trans-11b and cis-11b isomer (dr 6 : 4). The constrained cis-geometry of the ester group favoured aromatic acylation. This forms the first ever, short, three step total synthesis of naturally occurring dihydronaphthopyranones trans-11b, cis-11b and 11c and its synthetic analogs 11a, 11na, 11na′, 11nc and 11nc′.

Mechanistic hypothesis

Based on our own observations and previous literature precedence,^12,17 a plausible reaction mechanism for the formation of 5-carboalkoxy-2,3-dihydropyran-4-one (3) is proposed (Scheme 5). The in situ generated γ,δ-unsaturated β-diketone (III) is expected to exist in fully conjugated and more stable enolic form IV,¹² instead of partly conjugated and less stable enolic form V. Intermediate III might undergo 6π-oxaelectrocylization instead of intramolecular oxa-Michael addition to form the product 3. The acid chlorides 2a, 2b, 2c and 2f substituted with alkyl groups at β-position reacted efficiently while 2d with no substitution and 2e with phenyl substitution failed to react. This shows that dialkyl or mono alkyl substituents at β-position of the acid chloride favours positive polarization for the 6π-oxaelectrocylization¹² to take place.

Scheme 5 Proposed mechanism.

This mechanism is further supported by the observation that the cyclic active methylene compounds (4a and 4b) did not undergo pyranone ring formation. These compounds are well known to exist in the enol form, thus the geometric constraints may not allow the catalyst to achieve cyclic coordination state similar to I. Thus, O-alkylation rather than C-alkylation took place.

Conclusions

In conclusion, we have developed a simple and efficient domino strategy for the synthesis of polysubstituted 5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones from acyclic β-ketoesters and α,β-unsaturated acid chloride in the presence of CaCl₂. Unlike the need for the stoichiometric quantity of bases such as Mg(OEt)₂ and NaH, the Lewis acid CaCl₂ worked effectively in catalytic quantity. The 6-benzyl-5-carboalkoxy-2,3-dihydro-4H-pyran-4-ones were successfully employed as intermediates for the first and concise total synthesis of dihydronaphthopyranone class of natural products and its synthetic analogs via intramolecular Friedel–Crafts acylative aromatization. This in situ generation of naphthalene ring system has potential for its extension to the synthesis of other naphthopyran-4-one class of compounds such as NGP, PNQ and BNP. Investigation in this direction is under progress in our laboratory. Also, studies on acylation of 1,3-diketones using the same strategy is under progress so that we did not present the results in this manuscript.

Experimental section

General remarks

Melting points were determined by the open capillary tube method using a Toshniwal melting point apparatus and are uncorrected. The ¹H and ¹³C NMR spectra were measured on a Bruker Avance 400 (400 MHz) NMR spectrometer. Chemical shifts are reported in ppm (δ) relative to internal standard tetramethylsilane (TMS, δ 0.00 ppm). Data are reported as follows: chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad resonance (br)], coupling constants [Hz], integration). All the NMR spectra were acquired at ambient temperature. ESI-MS was recorded on Agilent 1100 LC/MSD (70 eV) spectrometer. High resolution mass spectra (HRMS) were recorded on a Waters Q-Tof micro mass spectrometer. Elemental analyses were performed on a CHN analyser. X-ray crystallographic data were collected on a Bruker SMART APEX-II CCD diffractometer. Thin layer chromatography (TLC) was performed on Merck pre-coated silica gel 60F plates and visualized by exposure to UV light. ACME silica gel (100–200 mesh) was used for column chromatography. All commercially available reagents were used without purification unless otherwise indicated and were purchased from standard chemical supplier. The β-ketoesters 1b–1i,²² and 1n (ref. 23) was prepared according to literature procedure. Polyphosphoric acid (Sigma-Aldrich: catalogue no.: 208213) reagent grade, 115% H₃PO₄ basis was used for the reaction.

General method A: typical experimental procedure for the synthesis of 2,3-dihydro-4H-pyran-4-ones (3)

To a suspension of β-ketoester (1, 1.0 mmol), CaCl₂ (0.1 mmol) and Et₃N (2.0 mmol) in 5 mL of DCM was added acid chloride (2, 1.0 mmol) dropwise at 10 °C. After completion of the addition the reaction mixture was allowed to stir at room temperature for 3–10 h. The reaction mixture was quenched with water, neutralised by dil. HCl, extracted with CH₂Cl₂ (2 × 8 mL) and washed with brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc–hexane = 2 : 8) to afford pure 2,3-dihydro-4H-pyran-4-ones 3.

Ethyl 2,2-dimethyl-4-oxo-6-phenyl-2,3-dihydro-4H-pyran-5-carboxylate (3aa)

The reaction was carried out according to general method A using ethyl benzoylacetate (1a, 192 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 6 h gave 3aa (219 mg, 80%) as a colorless crystal. M.p. 78–80 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.53–7.51 (m, 2H), 7.49–7.45 (m, 1H), 7.40–7.37 (m, 2H), 4.05 (q, J = 7.2 Hz, 2H), 2.64 (s, 2H), 1.56 (s, 6H), 0.98 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.9, 170.7, 165.9, 133.9, 131.5, 128.3, 128.2, 111.4, 81.9, 61.0, 47.0, 26.1, 13.7 ppm; MS (ESI): m/z 274.1 (M)⁺. Anal. calcd for C₁₆H₁₈O₄: C, 70.06; H, 6.61. Found: C, 70.20; H, 6.65%.

Ethyl 2,2-dimethyl-6-(4-methylphenyl)-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3ba)

The reaction was carried out according to general method A using ethyl 3-(4-methylphenyl)-3-oxopropanoate (1b, 206 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 5 h gave 3ba (236 mg, 82%) as a yellow solid. M.p. 88–90 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.41 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.07 (q, J = 7.0 Hz, 2H), 2.62 (s, 2H), 2.36 (s, 3H), 1.54 (s, 6H), 1.01 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 187.9, 169.7, 165.2, 141.2, 129.9, 128.0, 127.2, 109.9, 80.5, 60.0, 45.9, 25.0, 20.5, 12.7; HRMS (ESI): [M + H]⁺ calcd for C₁₇H₂₁O₄, 289.1440; found, 289.1461.

Ethyl 2,2-dimethyl-6-(4-methoxyphenyl)-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3ca)

The reaction was carried out according to general method A using ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (1c, 222 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 5 h gave 3ca (258 mg, 85%) as a yellow solid. M.p. 66–68 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.52 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 2.64 (s, 2H), 1.56 (s, 6H), 1.08 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.9, 170.3, 166.5, 162.4, 130.2, 125.9, 113.7, 110.4, 81.3, 61.1, 55.4, 47.0, 26.1, 13.8 ppm; HRMS (ESI): [M + Na]⁺ calcd for C₁₇H₂₀NaO₅, 327.1208; found, 327.1238.

Ethyl 2,2-dimethyl-4-oxo-6-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-pyran-5-carboxylate (3da)

The reaction was carried out according to general method A using ethyl 3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate (1d, 282 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 5 h gave 3da (309 mg, 85%) as a white solid. M.p. 128–130 °C; ¹H NMR (400 MHz, CDCl₃): δ 6.76 (s, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 6H), 2.63 (s, 2H), 1.56 (s, 6H), 1.06 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.8, 169.8, 166.3, 153.1, 141.1, 128.9, 111.3, 105.7, 81.8, 61.2, 60.9, 56.2, 46.9, 26.1, 13.8 ppm; HRMS (ESI): [M + Na]⁺ calcd for C₁₉H₂₄NaO₇, 387.1420; found, 387.1453.

Ethyl 6-(4-chlorophenyl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3ea)

The reaction was carried out according to general method A using ethyl 3-(4-chlorophenyl)-3-oxopropanoate (1e, 226 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 3 h gave 3ea (277 mg, 90%) as a white solid. M.p. 81–83 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.47 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 4.09 (q, J = 7.0 Hz, 2H), 2.65 (s, 2H), 1.56 (s, 6H), 1.06 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.7, 169.1, 165.8, 137.8, 132.2, 129.6, 128.7, 111.6, 82.1, 61.2, 47.0, 26.1, 13.7 ppm; HRMS (ESI): [M + H]⁺ calcd for C₁₆H₁₈ClO₄, 309.0894; found, 309.0921.

Ethyl 6-(2-chlorophenyl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3fa)

The reaction was carried out according to general method A using ethyl 3-(2-chlorophenyl)-3-oxopropanoate (1f, 226 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 7 h 3fa (246 mg, 80%) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.33–7.31 (m, 1H), 7.29–7.24 (m, 1H), 7.21–7.19 (m, 1H), 7.18–7.15 (m, 1H), 3.84 (q, J = 7.2 Hz, 2H), 2.58 (s, 2H), 1.47 (s, 6H), 0.75 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.4, 171.2, 164.2, 133.8, 132.6, 131.3, 129.8, 129.5, 126.5, 112.5, 83.3, 60.6, 47.5, 26.1, 13.5 ppm. HRMS (ESI): [M + H]⁺ calcd for C₁₆H₁₈ClO₄, 309.0894; found, 309.0895.

Ethyl 2,3-dimethyl-4-oxo-6-phenyl-2,3-dihydro-4H-pyran-5-carboxylate (tc-3ab)

The reaction was carried out according to general method A using ethyl benzoylacetate (1a, 192 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), tigloyl chloride (2b, 110 μL, 1.0 mmol) in DCM (4 mL). Condition: room temperature, 7 h. The crude diastereomeric mixture was purified through a silica gel column chromatography (hexane–EtOAc = 8 : 2). First eluted was compound trans-3ab (128 mg, 47%), obtained as a colourless solid and second eluted was cis-3ab (86 mg, 31%), obtained as pale yellow paste. The overall yield of tc-3ab was 78% (214 mg). Compound trans-3ab: M.p. 76–78 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.58–7.56 (m, 2H), 7.50–7.46 (m, 1H), 7.41–7.37 (m, 2H), 4.44–4.36 (m, 1H), 4.13–4.04 (m, 2H), 2.52–2.43 (m, 1H), 1.56 (d, J = 6.0 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 191.3, 171.4, 166.2, 133.2, 131.7, 128.4, 128.3, 111.8, 80.9, 61.2, 44.5, 19.1, 13.7, 10.0 ppm; MS (ESI): m/z 274.1 (M)⁺. Anal. calcd for C₁₆H₁₈O₄: C, 70.06; H, 6.61. Found: C, 70.18; H, 6.64%. Compound cis-3ab: ¹H NMR (400 MHz, CDCl₃): δ 7.58–7.55 (m, 2H), 7.50–7.46 (m, 1H), 7.41–7.37 (m, 2H), 4.83–4.78 (m, 1H), 4.12–4.02 (m, 2H), 2.56–2.50 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 7.2 Hz, 3H), 0.99 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 193.2, 171.7, 166.1, 133.2, 131.8, 128.4, 128.3, 110.9, 78.5, 61.1, 43.4, 15.7, 13.7, 8.9 ppm; MS (ESI): m/z 274.0 (M)⁺. Anal. calcd for C₁₆H₁₈O₄: C, 70.06; H, 6.61. Found: C, 70.22; H, 6.67%.

Ethyl 2-dimethyl-4-oxo-6-phenyl-2,3-dihydro-4H-pyran-5-carboxylate (3ac)

The reaction was carried out according to general method A using ethyl benzoylacetate (1a, 192 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), crotonoyl chloride (2c, 96 μL, 1.0 mmol) in DCM (4 mL) for 7 h gave 3ac (182 mg, 70%) as a colorless solid. M.p. 93–95 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.59–7.57 (m, 2H), 7.52–7.47 (m, 1H), 7.43–7.38 (m, 2H), 4.83–4.74 (m, 1H), 4.13–4.03 (m, 2H), 2.67–2.55 (m, 2H), 1.58 (d, J = 6.4 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.9, 172.4, 165.9, 133.2, 131.7, 128.4, 128.3, 112.4, 76.2, 61.1, 42.4, 20.3, 13.7 ppm; MS (ESI): m/z 261.3 (M + 1)⁺. Anal. calcd for C₁₅H₁₆O₄: C, 69.22; H, 6.20. Found: C, 69.40; H, 6.26%.

Ethyl 2,2-dimethyl-4-oxo-6-(thiophen-2-yl)-2,3-dihydro-4H-pyran-5-carboxylate (3ga)

The reaction was carried out according to general method A using ethyl 3-oxo-3-(thiophen-2-yl)propanoate (1g, 198 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 6 h gave 3ga (246 mg, 88%) as a pale yellow color crystal. M.p. 92–94 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.54 (d, J = 4.8 Hz, 1H), 7.44–7.43 (m, 1H), 7.05–7.02 (dd, J = 4.8, 4.0 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.57 (s, 2H), 1.49 (s, 6H), 1.19 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.8, 166.2, 161.5, 135.3, 131.7, 131.0, 128.0, 109.9, 81.8, 61.6, 46.9, 26.0, 13.9; HRMS (ESI): [M + H]⁺ calcd for C₁₄H₁₇O₄S, 281.0848; found, 281.0869. Single crystals suitable for X-ray studies were grown from a solution of 3ga in hexane–ethyl acetate (3 : 7).

Ethyl 6-(furan-2-yl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3ha)

The reaction was carried out according to general method A using ethyl 3-(furan-2-yl)-3-oxopropanoate (1h, 182 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 7 h gave 3ha (227 mg, 86%) as a yellow solid. M.p. 70–72 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.53–7.52 (dd, J = 1.6, 0.8 Hz, 1H), 6.98–6.97 (dd, J = 3.6, 0.4 Hz, 1H), 6.52–6.51 (dd, J = 3.4, 1.8 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 2.61 (s, 2H), 1.52 (s, 6H), 1.28 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.7, 165.5, 156.8, 146.9, 146.1, 116.1, 112.3, 109.2, 81.6, 61.4, 47.1, 26.1, 14.1; HRMS (ESI): [M + H]⁺ calcd for C₁₄H₁₇O₅, 265.1076; found, 265.1097.

Ethyl 2,2,6-trimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3ja)

The reaction was carried out according to general method A using ethyl acetoacetate (1j, 130 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 7 h gave 3ja (159 mg, 75%) as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 4.24 (q, J = 7.0 Hz, 2H), 2.49 (s, 2H), 2.16 (s, 3H), 1.41 (s, 6H), 1.29 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.2, 175.4, 165.8, 110.8, 81.5, 60.9, 47.1, 26.2, 20.8, 14.2 ppm; MS (ESI): m/z 212.1 (M)⁺. Anal. Calcd for C₁₁H₁₆O₄: C, 62.25; H, 7.60. Found: C, 62.46; H, 7.68%.

Ethyl 2,6-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3jc)

The reaction was carried out according to general method A using ethyl acetoacetate (1j, 130 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), crotonoyl chloride (2c, 96 μL, 1.0 mmol) in DCM (4 mL) for 8 h gave 3jc (119 mg, 60%) as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 4.61–4.48 (m, 1H), 4.27 (q, J = 7.0 Hz, 2H), 2.48–2.46 (m, 2H), 2.19 (s, 3H), 1.46 (d, J = 6.4 Hz, 3H), 1.31 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.1, 176.7, 165.5, 112.4, 75.6, 60.9, 42.3, 20.2, 20.1, 14.1 ppm; MS (ESI): m/z 198.1 (M)⁺. Anal. calcd for C₁₀H₁₄O₄: C, 60.59; H, 7.12. Found: C, 60.78; H, 7.18%.

Methyl 6-ethyl-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3ka)

The reaction was carried out according to general method A using methyl 3-oxo-pentanoate (1k, 130 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 6 h gave 3ka (170 mg, 80%) as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 3.79 (s, 3H), 2.52 (s, 2H), 2.47 (q, J = 7.4 Hz, 2H), 1.43 (s, 6H), 1.16 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.6, 179.5, 166.3, 109.9, 81.4, 52.0, 47.0, 27.5, 26.0, 11.2; HRMS (ESI): [M + H]⁺ calcd for C₁₁H₁₇O₄, 213.1127; found, 213.1140.

Methyl 6-ethyl-2,3-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (tc-3kb)

The reaction was carried out according general method A using methyl 3-oxo-pentanoate (1k, 130 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), tigloyl chloride (2b, 110 μL, 1.0 mmol) in DCM (4 mL). Condition: room temperature, 7 h. The crude diastereomeric mixture was purified through a silica gel column chromatography (hexane–EtOAc = 8 : 2). First eluted was compound trans-3kb (99 mg, 47%), obtained as a pale yellow liquid and second eluted was cis-3kb (66 mg, 31%), obtained as a pale yellow liquid. The overall yield of tc-3kb was 78% (165 mg). Compound trans-3kb: ¹H NMR (400 MHz, CDCl₃): δ 4.20–4.13 (m, 1H), 3.80 (s, 3H), 2.52–2.42 (m, 2H), 2.36–2.26 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.17 (t, J = 7.4 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 191.0, 180.0, 166.5, 110.6, 80.5, 52.1, 44.4, 27.2, 19.0, 11.2, 10.3 ppm; MS (ESI): m/z 212.0 (M)⁺. Anal. calcd for C₁₁H₁₆O₄: C, 62.25; H, 7.60. Found: C, 62.42; H, 7.66. Compound cis-3kb: ¹H NMR (400 MHz, CDCl₃): δ 4.61–4.55 (m, 1H), 3.79 (s, 3H), 2.51–2.41 (m, 3H), 1.36 (d, J = 6.4 Hz, 3H), 1.18 (t, J = 7.6 Hz, 3H), 1.07 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 192.9, 180.2, 166.4, 109.9, 80.5, 52.1, 43.3, 27.1, 15.5, 11.3, 9.1 ppm; MS (ESI): m/z 212.0 (M)⁺. Anal. calcd for C₁₁H₁₆O₄: C, 62.25; H, 7.60. Found: C, 62.46, H, 7.69.

Methyl 2-ethyl-6-methyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3lf)

The reaction was carried out according to general method A using methyl acetoacetate (1l, 116 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), trans-2-pentenoyl chloride (2f, 114 μL, 1.0 mmol) in DCM (4 mL) for 10 h gave 3lf (99 mg, 50%) as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 4.33–4.26 (m, 1H), 3.74 (s, 3H), 2.44–2.41 (m, 2H), 2.17 (s, 3H), 1.82–1.64 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.3, 177.7, 166.1, 111.9, 80.4, 52.0, 40.3, 27.2, 20.4, 9.0 ppm; MS (ESI): m/z 198.1 (M)⁺. Anal. calcd for C₁₀H₁₄O₄: C, 60.59; H, 7.12. Found: C, 60.81; H, 7.19%.

Ethyl 6-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3ma)

The reaction was carried out according to general method A using diethyl 1,3-acetonedicarboxylate (1m, 202 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 10 h gave 3ma (128 mg, 45%) as a yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 4.25 (q, J = 7.0 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.57 (s, 2H), 2.57 (s, 2H), 1.46 (s, 6H), 1.32–1.24 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 188.3, 171.7, 167.6, 164.9, 111.2, 82.6, 61.4, 61.1, 47.4, 40.5, 25.9, 14.1, 14.0 ppm; MS (ESI): m/z 284 (M)⁺. Anal. calcd for C₁₄H₂₀O₆: C, 59.14; H, 7.09. Found: C, 59.33; H, 7.16%.

Ethyl 6-(2-ethoxy-2-oxoethyl)-2-methyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3mc)

The reaction was carried out according to general method A using diethyl 1,3-acetonedicarboxylate (1m, 202 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), crotonoyl chloride (2c, 96 μL, 1.0 mmol) in DCM (4 mL) for 10 h gave 3mc (81 mg, 30%) as a yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 4.69–4.62 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 3.66–3.52 (m, 2H), 2.54–2.52 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H), 1.31–1.24 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 188.3, 173.1, 167.5, 164.8, 112.8, 76.4, 61.6, 61.2, 42.6, 40.2, 20.0, 14.1, 14.0 ppm; MS (ESI): m/z 270 (M)⁺. Anal. calcd for C₁₃H₁₈O₆: C, 57.77; H, 6.71. Found: C, 58.06; H, 6.82%.

Ethyl 6-benzyl-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3na)

The reaction was carried out according to general method A using ethyl 3-oxo-4-phenylbutanoate (1n, 206 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 6 h gave 3na (225 mg, 78%) as pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.30–7.24 (m, 5H), 4.29 (q, J = 7.2 Hz, 2H), 3.78 (s, 2H), 2.52 (s, 2H), 1.33 (s, 6H), 1.31 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.7, 174.8, 165.7, 135.5, 129.0, 128.5, 127.0, 111.5, 81.6, 61.2, 47.2, 39.6, 25.9, 14.2 ppm; HRMS (ESI): [M + H]⁺ calcd for C₁₇H₂₁O₄, 289.1440; found, 289.1460.

Ethyl 6-benzyl-2-methyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3nc)

The reaction was carried out according to general method A using ethyl 3-oxo-4-phenylbutanoate (1n, 206 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), crotonoyl chloride (2c, 96 μL, 1.0 mmol) in DCM (4 mL) for 10 h gave 3nc (192 mg, 70%) as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.31–7.27 (m, 5H), 4.56–4.47 (m, 1H), 4.29 (q, J = 7.0 Hz, 2H), 3.84–3.73 (m, 2H), 2.48 (d, J = 8.0 Hz, 2H), 1.41 (d, J = 6.4 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.7, 176.5, 165.6, 135.4, 129.0, 128.6, 127.1, 112.9, 75.9, 61.3, 42.4, 39.4, 20.1, 14.2 ppm; MS (ESI): m/z 275.3 (M + 1)⁺. Anal. calcd for C₁₆H₁₈O₄: C, 70.06; H, 6.61. Found: C, 70.29; H, 6.67%.

General method B: typical experimental procedure for the O-acylation of cyclic active methylene compounds (5)

To a suspension of cyclic active methylene compounds (4, 1.0 mmol), CaCl₂ (0.1 mmol) and Et₃N (2.0 mmol) in 4 mL of DCM was added senecioyl chloride (2a, 1.0 mmol) dropwise at 10 °C. After completion of the addition the reaction mixture was allowed to stir at room temperature for 3–6 h. The reaction mixture was quenched with water, neutralised by dil. HCl, extracted with CH₂Cl₂ (2 × 8 mL) and washed with brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane–EtOAc = 9 : 1) to afford pure O-acylated product 5a-b.

2-Oxo-2H-chromen-4-yl 3-methylbut-2-enoate (5a)

The reaction was carried out according to general method B using 4-hydroxy-2H-chromen-2-one (4a, 162 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a,112 μL, 1.0 mmol) in DCM (4 mL) for 3 h gave 5a (232 mg, 95%) as a white solid. M.p. 78–80 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.66 (dd, J = 8.0, 1.2 Hz, 1H), 7.59–7.55 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 8.4 Hz, 1H), 6.53 (s, 1H), 6.01–6.00 (m, 1H), 2.28 (s, 3H), 2.07 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 164.6, 161.8, 161.7, 158.7, 153.7, 132.6, 124.2, 122.9, 116.9, 115.9, 113.7, 104.8, 27.9, 20.9 ppm; MS (ESI): m/z 244.1 (M)⁺. Anal. calcd for C₁₄H₁₂O₄: C, 68.85; H, 4.95. Found: C, 68.97; H, 4.99%.

3-Methyl-1-phenyl-1H-pyrazol-5-yl 3-methylbut-2-enoate (5b)

The reaction was carried out according to general method B using 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (4b, 174 mg, 1.0 mmol), CaCl₂ (11 mg, 0.1 mmol), Et₃N (278 μL, 2.0 mmol), senecioyl chloride (2a, 112 μL, 1.0 mmol) in DCM (4 mL) for 6 h gave 5b (218 mg, 85%) as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 6.11 (s, 1H), 5.80 (s, 1H), 2.32 (s, 3H), 2.18 (s, 3H), 1.95 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 163.2, 161.3, 148.9, 144.7, 138.3, 128.9, 126.8, 122.9, 113.7, 95.8, 27.7, 20.7, 14.5 ppm; MS (ESI): m/z 256.0 (M)⁺. Anal. calcd for C₁₅H₁₆N₂O₂: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.38; H, 6.33; N, 11.06%.

3,5-Dimethoxyphenylacetic acid (8)

3,5-Dimethoxyphenylacetic acid (8) was prepared from 3,5-dimethoxtacetophenone (7) according to the literature procedure.²⁴ Spectral data and melting points are matched with literature procedure. M.p. 101–103 °C; ¹H NMR (400 MHz, CDCl₃): δ 6.43 (d, J = 2.0 Hz, 2H), 6.38 (t, J = 2.2 Hz, 1H), 3.77 (s, 6H), 3.57 (s, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 177.4, 160.9, 135.3, 107.5, 99.4, 55.3, 41.3 ppm.

Ethyl 4-(3,5-dimethoxyphenyl)-3-oxobutanoate (9)

To 3,5-dimethoxyphenylacetic acid (8, 196 mg, 1.0 mmol) in DCM solution at 25 °C Meldrum's acid (144 mg, 1.0 mmol), DCC (227 mg, 1.1 mmol) and DMAP (134 mg, 1.1 mmol) were added, and the solution was stirred at 25 °C for 10 h. The insoluble DCC by-product was then filtered off and the remaining solution was concentrated. The crude extract was then dissolved in EtOH (5 mL) and refluxed for 8 h. Following concentration in vacuo, the crude material was purified by column chromatography (hexane–EtOAc = 9 : 1) to yield the pure product 9 (133 mg, 50%) as colorless liquid. 9 : 1 keto–enol mixture was identified by ¹H NMR. ¹H NMR keto tautomer (400 MHz, CDCl₃): δ 6.37 (t, J = 2.4 Hz, 1H), 6.35 (d, J = 2.0 Hz, 2H), 4.17 (q, J = 7.0 Hz, 2H), 3.77 (s, 6H), 3.74 (s, 2H), 3.44 (s, 2H), 1.26 (t, J = 7.2 Hz, 3H); ¹³C NMR keto tautomer (100 MHz, CDCl₃): δ 200.4, 167.1, 161.1, 161.0, 135.3, 107.6, 99.4, 61.4, 55.3, 50.3, 48.0, 14.1 ppm; MS (ESI): m/z 267.3 (M + 1)⁺. Anal. calcd for C₁₄H₁₈O₅: C, 63.15; H, 6.81. Found: C, 63.34; H, 6.88%.

Ethyl 6-(3,5-dimethoxybenzyl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (10a)

To ethyl 4-(3,5-dimethoxyphenyl)-3-oxobutanoate (9, 266 mg, 1.0 mmol) in dry toluene (5 mL) solution Mg(OEt)₂ (114 mmol, 1.0 mmol) was added and refluxed for 30 min under N₂ atm. Then senecioyl chloride (2a, 112 μL, 1.0 mmol) in dry ACN (1 mL) was added dropwise at 10 °C. After completion of the addition the reaction mixture was allowed to stir at room temperature for 10 h. The reaction mixture was quenched with water, neutralised by dil. HCl, extracted with EtOAc (2 × 8 mL) and washed with brine. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude material was purified by column chromatography (hexane–EtOAc = 8 : 2) to afford pure 10a (261 mg, 75%) as pale yellow solid. M.p. 40–42 °C; ¹H NMR (400 MHz, CDCl₃): δ 6.44 (d, J = 2.4 Hz, 2H), 6.34 (t, J = 2.2 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.76 (s, 6H), 3.70 (s, 2H), 2.52 (s, 2H), 1.35 (s, 6H), 1.31 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.7, 174.4, 165.7, 160.8, 137.6, 111.6, 107.2, 99.1, 81.6, 61.2, 55.3, 47.2, 39.7, 26.0, 14.2 ppm; MS (ESI): m/z 347.3 (M − 1)⁺. Anal. calcd for C₁₉H₂₄O₆: C, 65.50; H, 6.94. Found: C, 65.66; H, 6.98%.

In the same manner, 5-carboalkoxy-2,3-dihydro-4H-pyranones tc-10b (trans-10b and cis-10b) and 10c were synthesized.

Ethyl 6-(3,5-dimethoxybenzyl)-2,3-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (tc-10b)

The reaction was carried out similar to compound 10a using ethyl 4-(3,5-dimethoxyphenyl)-3-oxobutanoate (9, 266 mg, 1.0 mmol), Mg(OEt)₂ (114 mg, 1.0 mmol) in dry toluene (5 mL) and tigloyl chloride (2b, 110 μL, 1.0 mmol) in ACN (1 mL) for 10 h. The crude diastereomeric mixture was purified through a silica gel column chromatography (hexane–EtOAc = 8 : 2). First eluted was compound trans-10b (146 mg, 42%), obtained as a pale yellow paste and second eluted was cis-10b (98 mg, 28%), obtained as a pale yellow paste. The overall yield of tc-10b was 70% (244 mg). Compound trans-10b: ¹H NMR (400 MHz, CDCl₃): δ 6.38 (d, J = 2.4 Hz, 2H), 6.30–6.27 (m, 1H), 4.22 (q, J = 7.0 Hz, 2H), 4.11–4.04 (m, 1H), 3.71 (s, 2H), 3.70 (s, 6H), 2.31–2.23 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 190.9, 175.1, 165.8, 160.9, 137.6, 112.3, 107.2, 99.1, 80.7, 61.2, 55.3, 44.6, 39.4, 19.0, 14.2, 10.2 ppm; MS (ESI): m/z 347.3 (M − 1)⁺. Anal. calcd for C₁₉H₂₄O₆: C, 65.50; H, 6.94. Found: C, 65.68; H, 6.99%. Compound cis-10b: ¹H NMR (400 MHz, CDCl₃): δ 6.43 (d, J = 2.0 Hz, 2H), 6.34 (s, 1H), 4.59–4.53 (m, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.76 (s, 6H), 3.70 (d, J = 4.0 Hz, 2H), 2.48–2.42 (m, 1H), 1.32–1.24 (m, 6H), 1.04 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 191.7, 174.2, 164.8, 159.8, 136.6, 110.6, 106.0, 98.1, 77.3, 60.2, 54.3, 42.3, 38.4, 14.3, 13.2, 8.0 ppm; MS (ESI): m/z 347.4 (M − 1)⁺. Anal. calcd for C₁₉H₂₄O₆: C, 65.50; H, 6.94. Found: C, 65.72; H, 7.02%.

Ethyl 6-(3,5-dimethoxybenzyl)-2-methyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (10c)

The reaction was carried out similar to compound 10a using ethyl 4-(3,5-dimethoxyphenyl)-3-oxobutanoate (9, 266 mg, 1.0 mmol), Mg(OEt)₂ (114 mg, 1.0 mmol) in dry toluene (5 mL) and crotonoyl chloride (2c, 96 μL, 1.0 mmol) in ACN (1 mL) for 10 h. The title compounds 10c (210 mg, 63%) was obtained as pale yellow paste after passing through a silica gel column chromatography (hexane–EtOAc = 8 : 2). ¹H NMR (400 MHz, CDCl₃): δ 6.46 (d, J = 2.4 Hz, 2H), 6.37 (t, J = 2.2 Hz, 1H), 4.58–4.49 (m, 1H), 4.3 (q, J = 7.2 Hz, 2H), 3.78 (s, 8H), 2.50–2.48 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 188.7, 176.2, 165.6, 160.8, 137.5, 113.0, 107.2, 99.0, 75.9, 61.3, 55.3, 42.4, 39.5, 20.1, 14.2 ppm; MS (ESI): m/z 333.4 (M − 1)⁺. Anal. calcd for C₁₈H₂₂O₆: C, 64.66; H, 6.63. Found: C, 64.83; H, 6.69%.

5-Hydroxy-6,8-dimethoxy-2,2-dimethyl-4H-2,3-dihydronaphtho[2,3-b]-pyran-4-one (11a)

To ethyl 6-(3,5-dimethoxybenzyl)-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (10a, 348 mg, 1.0 mmol) in PPA (2.0 mL) mixture was heated at 80 °C for 15 min. The reaction mixture was quenched by crushed ice and extracted with EtOAc (3 × 10 mL). Finally organic layer was neutralised by 10% NaHCO₃ solution and EtOAc layer separated, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude was purified by column chromatography (hexane–EtOAc = 9 : 1) to afford pure 11a (287 mg, 95%) as yellow colour solid. M.p. 153–155 °C; ¹H NMR (400 MHz, CDCl₃): δ 14.36 (s, 1H), 6.47 (s, 1H), 6.42 (d, J = 2.0 Hz, 1H), 6.27 (d, J = 2.0 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 2.76 (s, 2H), 1.45 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 197.5, 164.9, 162.4, 161.4, 154.8, 143.6, 107.0, 103.3, 102.2, 98.3, 96.4, 77.8, 56.0, 55.4, 48.3, 26.9 ppm; MS (ESI): m/z 303.1 (M + 1)⁺. Anal. calcd for C₁₇H₁₈O₅: C, 67.54; H, 6.00. Found: C, 67.62; H, 6.05%.

In the same manner, dihydronaphthopyran-4-ones tc-11b (trans-11b and cis-11b), 11c, 11na, 11na′, 11nc and 11nc′ were synthesized.

5-Hydroxy-6,8-dimethoxy-2,3-dimethyl-4H-2,3-dihydronaphtho[2,3-b]-pyran-4-one (tc-11b)

The reaction was carried out similar to compound 11a using ethyl 6-(3,5-dimethoxybenzyl)-2,3-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (tc-10b, 348 mg, 1.0 mmol) in PPA (2.0 mL) for 15 min. The crude diastereomeric mixture was purified through a silica gel column chromatography (hexane–EtOAc = 9 : 1). First eluted was compound trans-11b (168 mg, 56%), obtained as a yellow solid and second eluted was cis-11b (112 mg, 37%), obtained as a yellow solid. The overall yield of tc-11b was 93% (280 mg). Compound trans-11b: M.p. 168–170 °C; ¹H NMR (400 MHz, CDCl₃): δ 14.47 (s, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 6.28 (s, 1H), 4.23–4.16 (m, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 2.69–2.61 (m, 1H), 1.50 (d, J = 6.0 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 200.0, 165.1, 162.3, 161.3, 156.0, 143.3, 107.2, 103.0, 101.2, 98.3, 96.4, 78.0, 56.0, 55.4, 46.5, 19.8, 10.5 ppm. MS (ESI): m/z 303.1 (M + 1)⁺. Anal. calcd for C₁₇H₁₈O₅: C, 67.54; H, 6.00. Found: C, 67.69; H, 6.06%. Compound cis-11b: M.p. 113–115 °C; ¹H NMR (400 MHz, CDCl₃): δ 14.40 (s, 1H), 6.50 (s, 1H), 6.44 (d, J = 2.0 Hz, 1H), 6.28 (d, J = 1.6 Hz, 3H), 4.61–4.55 (m, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 2.72–2.65 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 201.8, 165.5, 162.4, 161.4, 155.8, 143.3, 107.3, 102.5, 101.3, 98.3, 96.5, 75.3, 56.0, 55.4, 44.9, 16.5, 9.6 ppm; MS (ESI): m/z 303.0 (M + 1)⁺. Anal. calcd for C₁₇H₁₈O₅: C, 67.54; H, 6.00. Found: C, 67.75; H, 6.10%.

5-Hydroxy-6,8-dimethoxy-2-methyl-4H-2,3-dihydronaphtho[2,3-b]-pyran-4-one (11c)

The reaction was carried out similar to compound 11a using ethyl 6-(3,5-dimethoxybenzyl)-2-methyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (10c, 334 mg, 1.0 mmol) in PPA (2.0 mL) for 15 min gave 11c (259 mg, 90%) as yellow colour solid. M.p. 176–178 °C; ¹H NMR (400 MHz, CDCl₃): δ 14.40 (s, 1H), 6.50 (s, 1H), 6.44 (d, J = 2.0 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 4.56–4.49 (m, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 2.81–2.67 (m, 2H), 1.50 (d, J = 6.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 197.7, 165.2, 162.5, 161.4, 156.3, 143.4, 107.2, 103.7, 101.5, 101.4, 98.4, 96.5, 73.1, 56.0, 55.4, 55.3, 43.9, 21.0 ppm; MS (ESI): m/z 289.0 (M + 1)⁺. Anal. calcd for C₁₆H₁₆O₅: C, 66.66; H, 5.59. Found: C, 66.82; H, 5.64%.

5-Hydroxy-2,2-dimethyl-4H-2,3-dihydronaphtho[2,3-b]-pyran-4-one (11na) and 4-hydroxy-2,2-dimethyl-2H-benzo[g]chromen-5(3H)-one (11na′)

The reaction was carried out similar to compound 11a using ethyl 6-benzyl-2,2-dimethyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3na, 288 mg, 1.0 mmol) in PPA (2.0 mL) at 80 °C for 45 min. The crude mixture was purified through a silica gel column chromatography (hexane–EtOAc = 9 : 1). First eluted was compound 11na (121 mg, 50%), obtained as a yellow solid and second eluted was 11na′ (109 mg, 45%), obtained as a yellow solid. Compound 11na: M.p. 78–80 °C; ¹H NMR (400 MHz, CDCl₃): δ 13.35 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.53–7.46 (m, 2H), 7.30–7.26 (m, 1H), 6.66 (s, 1H), 2.78 (s, 2H), 1.45 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 198.9, 162.4, 153.6, 139.0, 130.8, 126.5, 124.4, 123.5, 120.3, 104.4, 102.7, 77.9, 48.6, 27.0 ppm; MS (ESI): m/z 240.7 (M − 1)⁺. Anal. calcd for C₁₅H₁₄O₃: C, 74.36; H, 5.82. Found: C, 74.44; H, 5.85%. Compound 11na′: M.p. 70–72 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.12 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.56–7.48 (m, 2H), 7.28–7.24 (m, 1H), 6.72 (s, 1H), 2.86 (s, 2H), 1.59 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 197.9, 159.4, 155.6, 139.4, 130.7, 126.4, 123.9, 123.1, 119.5, 105.3, 102.6, 80.4, 47.9, 26.5 ppm; MS (ESI): m/z 240.7 (M − 1)⁺. Anal. calcd for C₁₅H₁₄O₃: C, 74.36; H, 5.82. Found: C, 74.53; H, 5.88%.

5-Hydroxy-2-methyl-4H-2,3-dihydronaphtho[2,3-b]-pyran-4-one (11nc) and 4-hydroxy-2-methyl-2H-benzo[g]chromen-5(3H)-one (11nc′)

The reaction was carried out similar to compound 11a using ethyl 6-benzyl-2-methyl-4-oxo-2,3-dihydro-4H-pyran-5-carboxylate (3nc, 274 mg, 1.0 mmol) in PPA (2.0 mL) at 80 °C for 45 min. The crude mixture was purified through a silica gel column chromatography (hexane–EtOAc = 9 : 1). First eluted was compound 11nc (103 mg, 45%), obtained as a yellow solid and second eluted was 11nc′ (91 mg, 40%), obtained as a yellow solid. Compound 11nc: M.p. 74–76 °C; ¹H NMR (400 MHz, CDCl₃): δ 13.39 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.58–7.50 (m, 2H), 7.32 (t, J = 7.4 Hz, 1H), 6.72 (s, 1H), 4.61–4.53 (m, 1H), 2.84–2.74 (m, 2H), 1.53 (d, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 199.0, 162.7, 155.1, 138.8, 130.9, 126.6, 124.4, 123.6, 120.4, 104.8, 102.0, 73.3, 44.3, 21.0 ppm. MS (ESI): m/z 226.7 (M − 1)⁺. Anal. calcd for C₁₄H₁₂O₃: C, 73.67; H, 5.30. Found: C, 73.79; H, 5.35%. Compound 11nc′: M.p. 66–68 °C; ¹H NMR (400 MHz, CDCl₃): δ 11.13 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.57–7.49 (m, 2H), 7.29–7.26 (m, 1H), 6.75 (s, 1H), 4.83–4.77 (m, 1H), 2.91–2.75 (m, 2H), 1.67 (d, J = 6.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 198.0, 161.1, 155.8, 139.2, 130.7, 126.4, 123.8, 123.2, 118.9, 106.1, 103.1, 75.1, 43.5, 20.7 ppm. MS (ESI): m/z 226.7 (M − 1)⁺. Anal. calcd for C₁₄H₁₂O₃: C, 73.67; H, 5.30. Found: C, 73.83; H, 5.39%.

Acknowledgements

P.S. thanks UGC-RFSMS, New Delhi for the award of fellowship. We thank DST-FIST, New Delhi for NMR and XRD facilities at School of Chemistry, Bharathidasan University, Tiruchirappalli, India. We also thank P. Venkatesan, School of Chemistry, Bharathidasan University, Tiruchirappalli, India for his help in X-ray structure determination.

References

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra for all compounds and X-ray structural information of 3ga (CIF). CCDC 1019144. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra11174e

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