Synthesis of 4-trifluoromethanesulfonate substituted 3,6-dihydropyrans and their application in various C–C coupling reactions

Abstract

The triflic acid mediated Prins cyclization of homopropargylic alcohols with aldehydes afforded 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonates efficiently and highly regioselectively. The dihydropyran thus formed is transformed into different 4-alkyl and aryl substituted products using Suzuki, Heck, Stille and Sonogashira coupling reactions.

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Introduction

Substituted pyran motifs constitute the core structural unit in numerous biologically active natural products such as calixyn L,¹ ambruticin,² kendomycin³ (Fig. 1) and have diverse applications in cosmetics and agro chemicals as well.⁴ The dihydropyran skeleton of this family is distinctly important since functionalized dihydropyrans are versatile building blocks widely used in the synthesis of biologically active molecules⁵ and this structural moiety exists in many natural products such as laulimalide⁶ and aspergillide C (Fig. 1).⁷ The presence of double bond in cyclic system is not only responsible for their biological properties but also serve as a functional group for further manipulations in organic synthesis.⁸ They can also be used as building blocks in organic synthesis.⁹ Triflates, present at vinylic position, in general are valuable substrates for a number of organic reactions such as electrophilic aromatic substitution reaction¹⁰ and various metal catalyzed cross-coupling reactions such as Suzuki,¹¹ Heck,¹² Stille,¹³ and Sonogashira coupling.¹⁴ Therefore, the synthesis of such valuable units in an easier and economical method is of value to organic chemists. There are different methods towards the construction of dihydropyrans including hetero-Diels–Alder reactions,¹⁵ olefin metathesis,¹⁶ base promoted cyclizations of sulfenyl dienols,¹⁷ oxonium–ene reactions,¹⁸ [4 + 2] annulations,¹⁹ intramolecular C–C bond formation of alkyne-epoxide,²⁰ and Prins cyclization reactions.²¹

Fig. 1 Structures of natural products containing pyran ring.

Among various methods available, Prins cyclization is considered to be the most convenient tool as it provides the desired product in a single step with high diastereoselectivity. On the other hand, one pot, multi component and selective reactions are considered as green synthetic routes.²² Considering these and in continuation of our research on Prins cyclization reaction,²³ herein, we report a one pot, three component and highly selective Prins cyclization reaction for efficient synthesis of 3,6-dihydro-2H-pyran-4-yl trifluoromethane-sulfonates from homopropargylic alcohols and aldehydes mediated by triflic acid in which triflic acid acts as Brønsted acid as well as a nucleophile. Although there are several reports which illustrate the preparation of 4-halotetrahydropyran derivatives, there are only a couple of reports which demonstrated the preparation of 4-halo-3,6-dihydro-2H-pyrans mediated by Lewis acids. Use of Fe(III) salts by Martin and co-workers have resulted in 2-alkyl-4-halo-3,6-dihydro-2H-pyrans.^9g,21h,i The presence of the triflate group at the vinylic position of dihydropyran ring, which can be used in many coupling reactions, has not been reported so far.

Results and discussion

To start with homopropargyl alcohol 1 (1.5 equiv.) and benzaldehyde 2a (1.0 equiv.) were treated with 1.2 equivalents of triflic acid in dry dichloromethane at room temperature for 12 h and 3,6-dihydro-2-phenyl-2H-pyran-4-yl trifluoromethane-sulfonate 3a was obtained in 92% yield. The reaction is regioselective and only 3,6-dihydropyrans was formed in the reaction. The stereochemistry of the compounds was determined by ¹H, ¹³C, DEPT and HMQC analysis. Finally the structure is confirmed by X-ray crystallographic analysis (Fig. 2).²⁴ The scope of the reaction was examined with variety of aliphatic and aromatic aldehydes (Table 1). It was observed from the Table 1 that both aromatic and aliphatic aldehydes gave the good yields. Aromatic aldehydes are better substrates than the aliphatic substrates. There is no major role of electron withdrawing and donating groups on the aromatic rings, both groups are providing comparable yields. To study the steric effect, ortho-, meta- and para-chlorobenazaldehydes (entries 4–6) were reacted with alcohol 1, but the effect is not noticeable. On the other hand, highly sterically hindered 2,6-dichlorobenzaldehyde (entry 7) and 4-chloro-3-nitrobenzaldehyde (entry 12) gave low yields. 4-Methoxybenzaldehyde was found to be decomposed under these reaction conditions. Reaction of 2p gave two inseparable diastereomers with a ratio of 2 : 1, which was determined by ¹H NMR.

Fig. 2 X-ray crystallographic structure of 3n.

Table 1 Synthesis of dihydropyrans^a

Entry	Aldehyde 2	Product 3	Yield^b (%)
a Yields refer to isolated yield. Compounds are characterized by IR, NMR and mass spectrometry. d = decomposed.b Two inseparable diastereomeric mixture with a ratio of 2 : 1 determined by ^1H NMR.
1			92
2			80
3			d
4			72
5			74
6			75
7			60
8			78
9			70
10			65
11			70
12			61
13			72
14			73
15			67
16			64^b

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The mechanism of the reaction can be explained as follows. The acidic proton activates the aldehyde for nucleophilic attack by homopropargylic alcohols to form oxocarbenium ion 5, which after Prins cyclization generates carbocation 6. The carbocation 6 is then attacked by triflate ion to give dihydropyran 3 (Scheme 1).

Scheme 1 Mechanism of the reaction.

The reaction is further utilized for the synthesis of 4-arylated dihydropyrans. It may be noted that 4-arylated tetrahydropyrans are found in many biologically active natural products.¹ Generally 4-aryl tetrahydropyrans are prepared by Prins–Friedel–Crafts reactions.^23b,c,25 The major drawback of the existing methods is that the electron deficient aromatic rings cannot participate in this reaction. Therefore, use of triflates 3 as an arylating unit via Suzuki coupling would be a better alternative for introduction of various aryl groups including both electron donating and electron withdrawing groups. Thus the reaction of 3a with different aryl and heteroaryl boronic acids 7a–f under Suzuki coupling conditions afforded 4-aryl-dihydropyrans 8a–f in good yields (Table 2). Similarly, Heck, Stille and Sonogashira coupling of 3a produce corresponding coupling products 9, 10 and 11, respectively, in excellent yields (Schemes 2–4).

Table 2 Suzuki coupling reaction

SI. No	boronic acid 7	Product 8	Yield^a (%)
a Yields refer to isolated yield. Compounds are characterized by IR, NMR spectroscopy and mass spectrometry.
1			95
2			93
3			94
4			91
5			90
6			92

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Scheme 2 Heck coupling reaction.

Scheme 3 Stille coupling reaction.

Scheme 4 Sonogashira coupling reaction.

Conclusions

In conclusion, we have developed one pot, three component, mild and efficient method for the synthesis of 4-trifluoromethanesulfonate substituted dihydropyrans via Prins cyclization reaction in good yields. The reaction is compatible with a wide range of functional groups such as ester, ether, nitro, and bromo. The aspect of this reaction is that it introduces trifluoromethanesulfonate group at 4-position of the dihydropyrans, which can be used for subsequent coupling reactions such as Suzuki, Heck, Stille and Sonogashira coupling reactions.

Experimental

General information

All the reagents were of reagent grade (AR grade) and were used as purchased without further purification. Silica gel (60–120 mesh size) was used for column chromatography. Reactions were monitored by TLC on silica gel GF₂₅₄ (0.25 mm). Melting points were recorded in an open capillary tube and are uncorrected. Fourier transform-infra red (FT-IR) spectra were recorded as neat liquid or KBr pellets. NMR spectra were recorded in CDCl₃ with tetramethylsilane as the internal standard for ¹H (600 MHz, 400 MHz) or ¹³C (150 MHz, 100 MHz) NMR. Chemical shifts (δ) are reported in ppm and spin–spin coupling constants (J) are given in Hz. HRMS spectra were recorded using Q-TOF mass spectrometer.

General procedure for the formation of 4-trifluoromethanesulfonate 3,6-dihydropyan

To a stirring solution of aldehyde (1.0 equiv.) and 3-butyn-1-ol (1.5 equiv.) in dry dichloromethane (5.0 mL) was added triflic acid (1.2 equiv.) dropwise at 0 °C. The reaction mixture was brought to room temperature and stirred for a specific time. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluents. After completion of the reaction, the reaction mixture was treated with saturated sodium bicarbonate solution (5.0 mL). The product was extracted with CH₂Cl₂ (2 × 10.0 mL) and washed with brine. Organic layer was separated and dried over anhydrous Na₂SO₄ and evaporated using rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane as eluents to afford the cyclic compounds.

Synthesis of 6-phenyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (3a). To a stirring solution of benzaldehyde (0.1 mL, 1 mmol) and 3-butyn-1-ol (0.11 mL, 1.5 mmol) in CH₂Cl₂ (5 mL) was added TfOH (0.1 mL, 1.2 mmol) dropwise at 0 °C. The reaction mixture was brought to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluents. After completion of the reaction, CH₂Cl₂ (10 mL) was added and the reaction mixture was washed with saturated sodium bicarbonate solution and brine solution. The organic layer was separated and dried over anhydrous Na₂SO₄ and evaporated using rotary evaporator to leave the crude product which was purified by column chromatography over silica gel using ethyl acetate and hexane as eluents to give 6-phenyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate 3a; colourless oil; R_f (hexane/EtOAc 50 : 1) 0.20; yield 292 mg, 92%; ¹H NMR (400 MHz, CDCl₃) δ 2.05 (dd, J = 16.0 and 6.0 Hz, 1H), 2.68–2.73 (m, 1H), 3.86 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.11 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.26 (d, J = 4.0 Hz, 1H), 5.93 (s, 1H), 7.34–7.38 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 28.5, 63.1, 75.8, 118.7 (q, J = 318.0 Hz), 120.2, 127.8, 128.9, 128.9, 139.0, 146.9; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.03 (s, –F); IR (KBr, neat) 2929, 2869, 1690, 1455, 1422, 1351, 1246, 1141, 1029, 894, 762 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₂F₃O₄S (M + H)⁺ 309.0403, found 309.0408.

6-(p-Tolyl)-3,6-dihydro-2H-pyran-4-yl trifluoromethane-sulfonate (3b). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.21; yield 257 mg, 80%; ¹H NMR (400 MHz, CDCl₃) δ 2.34 (s, 3H), 2.40 (dd, J = 12.0 and 4.0 Hz, 1H), 2.65–2.70 (m, 1H), 3.83 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.11 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.22 (d, J = 4.0 Hz, 1H), 5.91 (s, 1H), 7.18 (d, J = 7.2 Hz, 2H), 7.23 (d, J = 7.2 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 21.3, 28.5, 62.9, 75.5, 118.7 (q, J = 318.0 Hz), 120.3, 127.7, 129.6, 136.0, 138.8, 146.8; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 1.99 (s, –F); IR (KBr, neat) 2926, 2866, 1689, 1420, 1349, 1212, 1142, 1071, 899, 816 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₄F₃O₄S (M + H)⁺ 323.0559, found 323.0565.

6-(2-Chlorophenyl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (3d). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.2; yield 246 mg, 72%; ¹H NMR (400 MHz, CDCl₃) δ 2.38 (dd, J = 12.0 and 4.0 Hz, 1H), 2.70–2.76 (m, 1H), 3.88 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.16 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.70 (d, J = 4.0 Hz, 1H), 5.90 (s, 1H), 7.24–7.29 (m, 2H), 7.39 (dd, J = 7.2 and 4.0 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 28.4, 63.4, 72.4, 117.4 (q, J = 319.5 Hz), 119.7, 127.3, 128.9, 129.9, 130.0, 133.1, 136.4, 147.1; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.01 (s, –F); IR (KBr, neat) 2928, 2872, 1690, 1420, 1219, 1142, 1065, 764 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₁ClF₃O₄S (M + H)⁺ 343.0013, found 343.0010.

6-(3-Chlorophenyl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (3e). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.2; yield 253 mg, 74%; ¹H NMR (400 MHz, CDCl₃) δ 2.41 (dd, J = 12.0 and 4.0 Hz, 1H), 2.66–2.73 (m, 1H), 3.86 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.11 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.24 (d, J = 4.0 Hz, 1H), 5.90 (s, 1H), 7.21–7.23 (m, 1H), 7.31–7.32 (m, 2H), 7.35 (d, J = 7.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 28.4, 63.1, 75.0, 118.7 (q, J = 318.0 Hz), 119.7, 125.7, 127.9, 129.0, 130.2, 134.8, 141.1, 147.2; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.08 (s, –F); IR (KBr, neat) 2928, 2870, 1689, 1421, 1214, 1142, 1073, 875 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₁ClF₃O₄S (M + H)⁺ 343.0013, found 343.0035.

6-(4-Chlorophenyl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (3f). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.2; yield 256 mg, 75%; ¹H NMR (400 MHz, CDCl₃) δ 2.42 (dd, J = 12.0 and 6.0 Hz, 1H), 2.67–2.74 (m, 1H), 3.86 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.16 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.25 (d, J = 6.0 Hz, 1H), 5.89 (s, 1H), 7.28 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 28.3, 63.0, 74.9, 115.4 (q, J = 318.0 Hz), 120.2, 129.0 (2C), 134.6, 137.6, 147.1; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 1.97 (s, –F); IR (KBr, neat) 2929, 2869, 1692, 1421, 1213, 1148, 1091, 1066, 900, 765, 613 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₁ClF₃O₄S (M + H)⁺ 343.0013, found 343.0017.

6-(2,6-Dichlorophenyl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (3g). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.19; yield 225 mg, 60%; ¹H NMR (400 MHz, CDCl₃) δ 2.38 (dd, J = 12.0 and 4.0 Hz, 1H), 2.81–2.91 (m, 1H), 3.88 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.24 (dd, J = 12.0 and 4.0 Hz, 1H), 5.78 (s, 1H), 5.97 (s, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 28.1, 65.2, 72.7, 118.6 (q, J = 318.0 Hz), 119.7, 129.6, 130.5, 133.1, 136.1, 146.9; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 1.91 (s, –F); IR (KBr, neat) 2923, 2857, 1659, 1437, 1219, 1119, 1052, 775 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₀Cl₂F₃O₄S (M + H)⁺ 376.9623, found 376.9627.

6-(3-Bromophenyl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (3h). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.18; yield 301 mg, 78%; ¹H NMR (400 MHz, CDCl₃) δ 2.42 (dd, J = 12.0 and 4.0 Hz, 1H), 2.66–2.74 (m, 1H), 3.87 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.11 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.24 (d, J = 4.0 Hz, 1H), 5.90 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.46–7.51 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 28.4, 63.1, 74.9, 118.6 (q, J = 319.5 Hz), 119.7, 122.9, 126.2, 130.5, 130.8, 131.9, 141.4, 147.2; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.04 (s, –F); IR (KBr, neat) 2871, 1690, 1420, 1213, 1141, 1072, 784 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₁BrF₃O₄S (M + H)⁺ 386.9508, found 386.9520.

6-(4-Fluorophenyl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (3i). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.19; yield 228 mg, 70%; ¹H NMR (600 MHz, CDCl₃) δ 2.41 (dd, J = 12.0 and 6.0 Hz, 1H), 2.67–2.74 (m, 1H), 3.86 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 4.11 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 5.25 (d, J = 6.0 Hz, 1H), 5.90 (s, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 28.4, 63.0, 75.0, 115.7, 118.7 (q, J = 318.0 Hz), 119.9, 129.4, 134.9, 147.0, 163.0 (q, J = 246.0 Hz); ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.06 (s, –F); IR (KBr, neat) 2925, 2869, 1690, 1421, 1219, 1141, 1071, 897, 775 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₁F₄O₄S (M + H)⁺ 327.0309, found 327.0313.

6-(4-(Trifluoromethyl)phenyl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (3j). Pale yellow oil; R_f (hexane/EtOAc 50 : 1) 0.20; yield 244 mg, 65%; ¹H NMR (600 MHz, CDCl₃) δ 2.42 (dd, J = 18.0 and 6.0 Hz, 1H), 2.69–2.76 (m, 1H), 3.90 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 4.14 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 5.33 (d, J = 6.0 Hz, 1H), 5.92 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 28.4, 63.3, 75.1, 118.7 (q, J = 319.5 Hz), 119.5, 121.9, 124.1 (q, J = 270.0 Hz), 126.0, 128.0, 130.3, 143.0, 147.3; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.20 (s, –F), 13.27 (s, –F); IR (KBr, neat) 2928, 2872, 1622, 1421, 1327, 1216, 1130, 1069, 858, 792 cm⁻¹; HRMS (ESI) calcd for C₁₃H₁₁F₆O₄S (M + H)⁺ 377.0277, found 377.0249.

6-(2-Nitrophenyl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (3k). Yellow oil; R_f (hexane/EtOAc 50 : 1) 0.25; yield 247 mg, 70%; ¹H NMR (600 MHz, CDCl₃) δ 2.39 (dd, J = 18.0 and 6.0 Hz, 1H), 2.79–2.85 (m, 1H), 3.91 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 4.22 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 5.86 (d, J = 6.0 Hz, 1H), 6.02 (s, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 28.3, 63.9, 71.4, 118.6 (q, J = 318.0 Hz), 119.9, 124.8, 129.3, 129.4, 133.9, 134.6, 147.1, 148.2; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 1.97 (s, –F); IR (KBr, neat) 2929, 2873, 1689, 1531, 1419, 1353, 1211, 1141, 1073, 901, 789, 751 cm⁻¹; HRMS (ESI) calcd for C₁₂H₁₁F₃NO₆S (M + H)⁺ 354.0259, found 354.0259.

6-(4-Chloro-3-nitrophenyl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (3l). Yellow oil; R_f (hexane/EtOAc 50 : 1) 0.25; yield 236 mg, 61%; ¹H NMR (600 MHz, CDCl₃) δ 2.44 (dd, J = 18.0 and 6.0 Hz, 1H), 2.70–2.76 (m, 1H), 3.90 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 4.13 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 5.33 (d, J = 4.0 Hz, 1H), 5.90 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 28.3, 63.3, 74.0, 118.6, 118.7 (q, J = 318.0 Hz), 124.6, 127.3, 131.9, 132.5, 139.8, 147.8, 148.2; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.1 (s, –F); IR (KBr, neat) 2927, 2873, 1690, 1539, 1421, 1353, 1214, 1141, 1073, 888, 792 cm⁻¹; HRMS (ESI) calcd for C₁₂H₉F₃NO₆SNa (M + Na)⁺ 409.9689, found 409.9691.

Methyl 4-(4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-2-yl)benzoate (3m). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.23; yield 263 mg, 72%; ¹H NMR (600 MHz, CDCl₃) δ 2.41 (dd, J = 16.0 and 6.0 Hz, 1H), 2.68–2.74 (m, 1H), 3.88 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 3.91 (s, 3H), 4.12 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 5.31 (s, 1H), 5.91 (s, 1H), 7.42 (d, J = 7.2 Hz, 2H), 8.04 (d, J = 7.2 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 28.4, 52.4, 63.2, 75.2, 118.6 (q, J = 319.5 Hz), 119.7, 127.5, 130.2, 130.6, 144.0, 147.1, 166.8; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.07 (s, –F); IR (KBr, neat) 2925, 2850, 1725, 1690, 1418, 1282, 1213, 1142, 1113, 1072, 860, 771 cm⁻¹; HRMS (ESI) calcd for C₁₄H₁₄F₃O₆S (M + H)⁺ 367.0458, found 367.0465.

6-(Naphthalen-2-yl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (3n). Colourless solid; mp 71–73 °C R_f (hexane/EtOAc 50 : 1) 0.20; yield 261 mg, 73%; ¹H NMR (600 MHz, CDCl₃) δ 2.42 (dd, J = 12.0 and 4.0 Hz, 1H), 2.67–2.83 (m, 1H), 3.86 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.10 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.39 (d, J = 4.0 Hz, 1H), 5.99 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.47–7.50 (m, 2H), 7.77 (s, 1H), 7.81–7.85 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 28.5, 62.9, 75.7, 118.7 (q, J = 318.0 Hz), 120.1, 125.2, 126.5, 126.6, 127.0, 127.9, 128.3, 128.9, 133.3, 133.5, 136.4, 147.0; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.04 (s, –F); IR (KBr, neat) 2976, 2868, 1689, 1464, 1422, 1244, 1114, 1058, 886, 757 cm⁻¹; HRMS (ESI) calcd for C₁₆H₁₄F₃O₄S (M + H)⁺ 359.0559, found 359.0564.

6-Isobutyl-3,6-dihydro-2H-pyran-4-yl trifluoromethane-sulfonate (3o). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.20; yield 193 mg, 67%; ¹H NMR (600 MHz, CDCl₃) δ 0.93 (s, 3H), 0.94 (s, 3H), 1.27–1.32 (m, 1H), 1.55–1.60 (m, 1H), 1.79–1.87 (m, 1H), 2.26 (dd, J = 12.0 and 4.0 Hz, 1H), 2.58–2.64 (m, 1H), 3.71 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 4.09 (ddd, J = 12.0, 6.0 and 6.0 Hz, 1H), 4.27 (d, J = 6.0 Hz, 1H), 5.72 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 22.1, 23.3, 24.5, 28.6, 43.8, 63.2, 71.9, 117.6 (q, J = 318.0 Hz), 121.2, 146.4; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 2.05 (s, –F); IR (KBr, neat) 2960, 2872, 1690, 1442, 1211, 1143, 1072, 884, 614 cm⁻¹; HRMS (ESI) calcd for C₁₀H₁₆F₃O₄S (M + H)⁺ 289.0721, found 289.0715.

6-(1-Phenylethyl)-3,6-dihydro-2H-pyran-4-yl trifluoro-methanesulfonate (diastereomeric mixture, 2 : 1, 3p). Colourless oil; R_f (hexane/EtOAc 50 : 1) 0.20; yield 215 mg, 64%; ¹H NMR (400 MHz, CDCl₃) δ 1.30 (d, J = 4.0 Hz, 3H, minor), 1.35 (d, J = 8.0 Hz, 3H, major), 2.07–2.12 (m, 1H, minor), 2.16–2.24 (m, 1H, major), 2.56–2.64 (m, 1H), 2.82–2.89 (m, 1H, major), 3.08–3.15 (m, 1H, minor), 3.62–3.71 (m, 1H), 4.09–4.13 (m, 1H), 4.24–4.26 (m, 1H, major), 4.36–4.37 (m, 1H, minor), 5.54 (s, 1H, major), 5.68 (s, 1H, minor), 7.20–7.26 (m, 3H), 7.29–7.35 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 15.0, 17.0, 28.4, 43.6, 44.7, 63.4, 63.8, 78.1, 78.2, 118.6 (q, J = 319.5 Hz), 119.7, 126.9, 127.0, 128.0, 128.1, 128.6, 128.7, 142.1, 142.9, 147.0, 147.3; ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ 1.9 (s, –F); IR (KBr, neat) 2972, 2873, 1690, 1420, 1213, 1143, 1073, 891, 763 cm⁻¹; HRMS (ESI) calcd for C₁₄H₁₆F₃O₄S (M + H)⁺ 337.0716, found 337.0722.

General procedure of Suzuki coupling reaction

To a solution of 3 (1.0 mmol) in THF (4.0 mL) were added PPh₃ (5 mol%), PdCl₂ (5 mol%), boronic acid 7 (1.56 mmol) and 2 M aqueous solution of Na₂CO₃ (2.0 mL) under inert atmosphere. The reaction mixture was stirred at 40 °C for 1 h. Then water was added to reaction mixture and extracted with EtOAc (3 × 10 mL). Combined organic layer was dried and concentrated under reduced pressure. Residue obtained was purified by silica gel column chromatography using EtOAc/hexane as eluent to furnish the compound 8.

Synthesis of 4,6-diphenyl-3,6-dihydro-2H-pyran (8a). To a solution of 3,6-dihydro-2-phenyl-2H-pyran-4-yl trifluoromethanesulfonate 3a (308 mg, 1 mmol) in THF (4.0 mL) were added PPh₃ (14 mg, 5 mol%), PdCl₂ (9 mg, 5 mol%), phenyl boronic acid 7a (183 mg, 1.56 mmol) and 2 M aqueous solution of Na₂CO₃ (2.0 mL) under inert atmosphere. The reaction mixture was stirred at 40 °C for 1 h. Then water was added to reaction mixture and extracted with EtOAc (3 × 10 mL). Combined organic layer was dried and concentrated under reduced pressure. Residue obtained was purified by silica gel column chromatography using EtOAc/hexane as eluent to furnish the 2,4-diphenyl-3,6-dihydro-2H-pyran as a yellow oil; R_f (hexane/EtOAc 50 : 1) 0.3; yield 224 mg, 95%; ¹H NMR (400 MHz, CDCl₃) δ 2.49 (dd, J = 12.0 and 4.0 Hz, 1H), 2.71–2.80 (m, 1H), 2.92 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.19 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.31 (d, J = 4.0 Hz, 1H), 6.22 (s, 1H), 7.27–7.39 (m, 6H), 7.41–7.45 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 27.2, 63.6, 76.9, 125.1, 125.5, 127.7, 127.8, 128.2, 128.6, 128.7, 135.0, 140.2, 141.5; IR (KBr, neat) 2924, 2853, 1600, 1493, 1263, 1120, 1029, 771 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₇O (M + H)⁺ 237.1274, found 237.1277.

4-(4-Chlorophenyl)-6-phenyl-3,6-dihydro-2H-pyran (8b). Pale yellow oil; R_f (hexane/EtOAc 50 : 1) 0.28; yield 251 mg, 93%; ¹H NMR (400 MHz, CDCl₃) δ 2.44 (dd, J = 12.0 and 4.0 Hz, 1H), 2.67–2.76 (m, 1H), 3.91 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.19 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.29 (d, J = 4.0 Hz, 1H), 6.20 (s, 1H), 7.29–7.42 (m, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 27.2, 63.5, 76.8, 126.1, 126.4, 127.7, 128.2, 128.8 (2C), 133.5, 134.0, 138.6, 141.2; IR (KBr, neat) 2924, 2853, 1598, 1493, 1368, 1177, 1074, 762 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₆ClO (M + H)⁺ 271.0884, found 271.0886.

4-(4-Fluorophenyl)-6-phenyl-3,6-dihydro-2H-pyran (8c). Pale yellow oil; R_f (hexane/EtOAc 50 : 1) 0.25; yield 238 mg, 94%; ¹H NMR (400 MHz, CDCl₃) δ 2.45 (dd, J = 16.0 and 4.0 Hz, 1H), 2.68–2.77 (m, 1H), 3.92 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.19 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.30 (d, J = 4.0 Hz, 1H), 6.16 (s, 1H), 7.03 (t, J = 8.0 Hz, 2H), 7.29–7.43 (m, 7H); ¹³C NMR (100 MHz, CDCl₃) δ 27.3, 63.6, 76.9, 115.5 (d, J = 21.0 Hz), 125.4, 126.3 (d, J = 8.0 Hz), 127.8, 128.2, 128.7, 134.1, 136.3 (d, J = 3.3 Hz), 141.3, 162.5 (d, J = 245.1 Hz); ¹⁹F NMR (376 MHz, CDCl₃/TFA) δ −39.2 (s, –F); IR (KBr, neat) 2925, 2854, 1601, 1451, 1275, 1231, 1160, 1071, 836, 700 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₆FO (M + H)⁺ 255.1180, found 255.1185.

4-(3-Nitrophenyl)-6-phenyl-3,6-dihydro-2H-pyran (8d). Yellow oil; R_f (hexane/EtOAc 50 : 1) 0.30; yield 255 mg, 91%; ¹H NMR (400 MHz, CDCl₃) δ 2.51 (dd, J = 16.0 and 4.0 Hz, 1H), 2.76–2.85 (m, 1H), 3.96 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.25 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.34 (d, J = 4.0 Hz, 1H), 6.38 (s, 1H), 7.31–7.43 (m, 5H), 7.52 (t, J = 8.0 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 27.0, 63.4, 76.8, 119.9, 122.4, 127.6, 128.4, 128.8, 129.6, 130.9, 133.1, 140.8, 141.8, 148.7; IR (KBr, neat) 2924, 2855, 1528, 1453, 1349, 1269, 1121, 1063, 892, 737 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₆NO₃ (M + H)⁺ 282.1125, found 282.1130.

Synthesis of 4-(4-methoxyphenyl)-6-phenyl-3,6-dihydro-2H-pyran (8e). A mixture of 3a (308 mg, 1.0 mmol), aqueous sodium carbonate (1.4 mL, 2.80 mmol), lithium chloride (125 mg, 2.98 mmol), Pd(Ph₃P)₄ (23 mg, 0.02 mmol), 4-methoxyphenylboronic acid (166 mg, 1.09 mmol), and THF (5 mL) was refluxed for 3 h. After completion of the reaction the solvent was removed by evaporation; water was added and the mixture was extracted with ethyl acetate (2 × 10 mL). Combined organic layer was dried and concentrated under reduced pressure. The product was purified by column chromatography on silica gel (ethyl acetate/hexane, 1/4) to give 8e as a pale yellow oil; R_f (hexane/EtOAc 50 : 1) 0.40; yield 239 mg, 90%; ¹H NMR (600 MHz, CDCl₃) δ 2.51 (dd, J = 16.0 and 6.0 Hz, 1H), 2.68–2.74 (m, 1H), 3.80 (s, 3H), 3.91 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.17 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.29 (d, J = 4.0 Hz, 1H), 6.12 (s, 1H), 6.88 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.34–7.38 (m, 4H), 7.42 (d, J = 8.0 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 27.3, 55.5, 63.7, 76.9, 114.0, 123.8, 126.2, 127.8, 128.1, 128.7, 132.8, 134.4, 141.7, 159.4; IR (KBr, neat) 2957, 2836, 1607, 1456, 1309, 1248, 1180, 1062, 1034, 832, 761, 700 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₉O₂ (M + H)⁺ 267.1385, found 267.1385.

6-Phenyl-4-(thiophen-2-yl)-3,6-dihydro-2H-pyran (8f). Yellow oil; R_f (hexane/EtOAc 50 : 1) 0.30; yield 222 mg, 92%; ¹H NMR (400 MHz, CDCl₃) δ 2.49 (dd, J = 16.0 and 4.0 Hz, 1H), 2.71–2.78 (m, 1H), 3.90 (ddd, J = 16.0, 8.0 and 4.0 Hz, 1H), 4.15 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.28 (d, J = 4.0 Hz, 1H), 6.20 (s, 1H), 6.99 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.32–7.42 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 27.6, 63.3, 76.6, 122.5, 124.1, 127.5, 127.8, 128.2, 128.7, 129.7, 141.1, 144.8; IR (KBr, neat) 2924, 2854, 1639, 1453, 1361, 1263, 1116, 1062, 879, 698 cm⁻¹; HRMS (ESI) calcd for C₁₅H₁₅OS (M + H)⁺ 243.0844, found 243.0851.

(E)-6-Phenyl-4-styryl-3,6-dihydro-2H-pyran (9). To a solution of 3 (308 mg, 1.0 mmol) in DMF (10 mL) were added Pd(OAc)₂ (11 mg, 5 mol%) and AcOK (196 mg, 2 mmol) under inert atmosphere. The reaction mixture was stirred at 60 °C for overnight. Then water was added to reaction mixture and extracted with EtOAc (3 × 10 mL). Combined organic layer was dried and concentrated under reduced pressure. Residue obtained was purified by silica gel column chromatography using EtOAc/Pet. ether as eluent to furnish the compound 9 as yellow oil; R_f (hexane/EtOAc 50 : 1) 0.35; yield 222 mg, 85%; ¹H NMR (400 MHz, CDCl₃) δ 2.38 (dd, J = 12.0 and 4.0 Hz, 1H), 2.53–2.62 (m, 1H), 3.87 (ddd, J = 16.0, 8.0 and 4.0 Hz, 1H), 4.15 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.27 (d, J = 4.0 Hz, 1H), 5.92 (s, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.81 (d, J = 16.0 Hz, 1H), 7.20–7.25 (m, 1H), 7.30–7.43 (m, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 25.0, 63.4, 76.9, 126.5, 127.3, 127.6, 127.7, 128.2, 128.7, 128.8, 130.2, 130.5, 134.2, 137.4, 141.3; IR (KBr, neat) 2924, 2853, 1593, 1492, 1274, 1118, 1092, 1012, 830, 699 cm⁻¹; HRMS (ESI) calcd for C₁₉H₁₉O (M + H)⁺ 263.1430, found 263.1436.

Synthesis of 4-allyl-6-phenyl-3,6-dihydro-2H-pyran (10). A dried reaction tube was charged with triflate 3 (308 mg, 1 mmol). To this PPh₃ (14 mg, 5 mol%), PdCl₂ (9 mg, 5 mol%) was added and reaction tube was evacuated. Then LiCl (126 mg, 3 mmol), dry DMF (10 mL) and allyltributylstannane (397 mg, 1.21 mmol) were added under nitrogen atmosphere. Reaction mixture was heated at 80 °C for 2 h. Reaction was quenched with saturated NH₄Cl solution and extracted with EtOAc (4 × 5 mL). Combined organic layer was dried and concentrated under reduced pressure. Residue obtained was purified by silica gel column chromatography using EtOAc/hexane as eluent to furnish 4-allyl-3,6-dihydro-2-phenyl-2H-pyran 10 (174 mg, 87%) as yellow oil; R_f (hexane/EtOAc 50 : 1) 0.35; yield 174 mg, 87%; ¹H NMR (400 MHz, CDCl₃) δ 1.98 (dd, J = 16.0 and 4.0 Hz, 1H), 2.25–2.33 (m, 1H), 2.80 (d, J = 8.0 Hz, 2H), 3.78 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.02 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.05–5.12 (m, 3H), 5.56 (s, 1H), 5.76–5.87 (m, 1H), 7.27–7.37 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 28.4, 41.7, 63.5, 76.4, 116.8, 124.0, 127.6, 127.9, 128.6, 135.3, 135.7, 141.9; IR (KBr, neat) 2924, 2854, 1689, 1450, 1364, 1220, 1075, 771 cm⁻¹; HRMS (ESI) calcd for C₁₄H₁₇O (M + H)⁺ 201.1274, found 201.1277.

Synthesis of 6-phenyl-4-(phenylethynyl)-3,6-dihydro-2H-pyran (11). A dried reaction flask was charged with triflate 3 (308 mg, 1.0 mmol). To this PPh₃ (14 mg, 5 mol%), PdCl₂ (9 mg, 5 mol%), CuI (19 mg, 1 mol%) were added and the reaction flask was evacuated. Then Et₃N (2.5 mL, 18 mmol), dry DMF (10 mL) and phenyl acetylene (0.17 mL, 1.58 mmol) were added under nitrogen atmosphere. Reaction mixture was heated at 80 °C for 2 h. Reaction was quenched with saturated NH₄Cl solution and extracted with EtOAc (4 × 5 mL). Combined organic layer was dried and concentrated under reduced pressure. Residue obtained was purified by silica gel column chromatography using EtOAc/hexane as eluent to furnish the 6-phenyl-4-(phenylethynyl)-3,6-dihydro-2H-pyran 11 (247 mg, 95%) as yellow oil; R_f (hexane/EtOAc 50 : 1) 0.35; yield 247 mg, 95%; ¹H NMR (400 MHz, CDCl₃) δ 2.28 (dd, J = 12.0 and 4.0 Hz, 1H), 2.53–2.62 (m, 1H), 3.83 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 4.06 (ddd, J = 12.0, 8.0 and 4.0 Hz, 1H), 5.23 (d, J = 4.0 Hz, 1H), 6.25 (s, 1H), 7.28–7.32 (m, 4H), 7.33–7.40 (m, 4H), 7.42–7.45 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 29.2, 63.2, 76.6, 89.1, 89.2, 119.6, 123.3, 127.7, 128.3, 128.4, 128.5, 128.8, 131.7, 135.2, 140.6; IR (KBr, neat) 2919, 2850, 1597, 1490, 1450, 1253, 1120, 1062, 756, 699 cm⁻¹; HRMS (ESI) calcd for C₁₉H₁₇O (M + H)⁺ 261.1274, found 261.1279.

Acknowledgements

PG gratefully acknowledges Council of Scientific and Industrial Research (CSIR), New Delhi for her fellowship. Authors are grateful to Council of Scientific and Industrial Research (CSIR), New Delhi, for financial support (Grant No. 02/0159/13/EMR-II). Authors are also thankful to Central Instrument Facility (CIF) of IIT Guwahati for NMR and XRD facilities.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, ¹H, ¹³C and HRMS spectra of all new compounds. CCDC 1433323. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra02343f

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