Homogeneous gold catalysts continue to attract increasing levels of interest in organic chemistry because of the efficiency, mild nature and unique properties ^{[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]}. Our collective understanding of gold catalysis has been facilitated by the theories of frontier molecular orbitals ^[16], relativistic effects ^{[17, 18]} and π-acidity ^[19]. The unusual reactivity of gold catalysts, namely the activation of C-C triple bonds, has led to the development of a wide range of powerful methods for the efficient construction of diverse structural frameworks and molecular architectures ^{[20, 21]}. The strong σ-donor and weak π-acceptor properties of alkynes render gold-complexed alkynes electrophilic and therefore opens the door for the discovery of new reactions ^{[22, 23]}. In contrast to the vast majority of transition metal-catalyzed processes, the high oxidation potential of Au(I) to Au(III) allows most Au(I)-catalyzed reactions to proceed without the requirement for an inert atmosphere. We have initiated a program to exploit the unique reactivity of alkyne precursors towards gold catalysis for the synthesis of carbo- and heterocyclic compounds ^{[24, 25, 26, 27, 28, 29, 30]}. Furans fused to cycloalkyl ring systems (e.g., cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl rings) have found numerous applications in a variety of different areas ranging from natural products to medicinal chemistry ^{[31, 32, 33, 34, 35, 36, 37, 38]}. Consequently, contemporary synthetic chemistry has witnessed the development of a plethora of highly efficient synthetic strategies for the construction of these sub-structures ^{[39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56]}. However, despite significant advances in this area, there are still some challenging substrates for this reaction, including cyclooctyl derivatives. As part of our ongoing interest in the development of transition-metal catalysts for the synthesis of carbo- and heterocyclic systems ^{[24, 25, 26, 27, 28, 29, 30, 57, 58, 59, 60, 61, 62, 63]}, we recently reported the gold- catalyzed preparation of fused-furans containing five, six and seven member rings ^[24]. In a continuation of this work, it was envisaged that furans fused to an eight member ring could also be prepared in a similar manner. During our study towards the preparation of the requisite synthons, we found that the exposure of 2-bromocyclooct-2-enol to terminal acetylenes under Sonogashira conditions led to a sequential cross-coupling/ cycloisomerization process, which resulted in the formation of the fused furans. In other words, this process provided direct access to the desired cyclooctyl furans through a "gold-free" protocol. In this paper, we provide a detailed account of our work, including the synthetic elaboration of commercially available starting materials to give complex cyclooctyl furans, as well as the exploitation of tandem processes and the synthetic potential of these fused furan systems.

All of the commercially available solvents and reagents were used as supplied without further purification. Solutions in organic solvents were dried over anhydrous Na₂SO₄. Solvents were evaporated under reduced pressure. Melting points (MP) were obtained using open capillaries and have been reported as the uncorrected values. Infrared (IR) spectra were recorded on a Perkin-Elmer FTIR spectrophotometer (Hopkinton, MA, USA). The IR spectra were recorded as KBr pellets for solid compounds and neat sample for liquid compounds. ¹H and ¹³C NMR spectra were recorded on a JEOL spectrometer (Peabody, MA, USA) at 500 and 125 MHz, respectively. The samples for NMR spectroscopy were prepared in DMSO-d₆ and CDCl₃. The chemical shifts (d) for the ¹H NMR spectra have been reported relative to tetramethylsilane (TMS, d = 0.00), which was used as an internal reference standard, and expressed in parts per million (ppm). The number of protons (n) for a given resonance has been indicated as nH and the spin multiplicities have been given as follows: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets) and m (multiplet). The coupling constants (J) have been given in hertz. GC-MS spectra were recorded on a Perkin-Elmer system. Elemental analyses were recorded on a Thermo Finnigan FLASH EA 1112CHN analyzer (Niulab Equipments, Mumbai, India). All of the compounds analyzed in the current study gave C, H and N results that were within ±0.5% of the theoretical values. Purifications by column chromatography were conducted over silica gel (100-200 mesh, SRL, Mumbai, India) using a mixture of petroleum ether and ethyl acetate (EtOAc) as the eluent. Analytical thin-layer chromatography (TLC) was performed on pre-coated plastic sheets of silica gel G/UV-254 of 0.2 mm in thickness (Macherey-Nagel, Düren, Germany) using analytical grade solvents. The TLC plates were visualized with iodine spray (10% w/w I₂ in silica gel), UV light (λ = 254 and 365 nm) and alkaline KMnO₄ solution.

Dry triethylamine (5 mL) was added to a mixture of iodo compound 3 (1.0 mmol), Pd(PPh₃)₂Cl₂ (5 mol%) and CuI (5 mol%) in an oven-dried flask under N₂, and the resulting suspension was magnetically stirred for 5 min. Terminal alkyne 4 (1.2 mmol) was then added to the reaction in a drop-wise manner, and the resulting mixture was stirred at room temperature until TLC analysis showed the disappearance of the 2-iodo-cycloalk-2-enol starting material (~6 h). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4 × 15 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and the solvent was removed under reduced pressure to give the crude product as a residue. The residue was subsequently purified by column chromatography over silica gel eluting with a 9:1 (v/v) mixture of EtOAc and petroleum ether to afford the pure product ( 5a-5l ).

2-(Phenylethynyl)-cyclohept-2-enol ( 5a ). Brown oil; IR (CH₂Cl₂): 3395, 2923, 2354, 1595, 1438, 752 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.67-1.71 (m, 4H), 1.93-1.97 (m, 2H), 2.13-2.20 (m, 1H), 2.30-2.40 (m, 2H), 6.43 (t, 1H, J = 6.8 Hz), 7.29-7.30 (m, 4H), 7.42-7.44 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ_C 25.7, 27.2, 28.6, 35.1, 71.3, 87.6, 91.2, 123.1, 128.3, 128.4, 131.2, 131.5, 138.9. GC-MS: m/z = 212. Anal. Calcd. for C₁₅H₁₆O: C, 84.87%; H, 7.60%. Found: C, 84.80%; H, 7.64%.

2-(4-Pentylphenylethynyl)-cyclohept-2-enol ( 5b ). Brown oil; IR (CH₂Cl₂): 3435, 2927, 1679, 1595, 1438, 838 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.87 (t, 3H, J = 6.9 Hz), 1.28-1.32 (m, 5H), 1.51-1.68 (m, 5H), 1.93-1.95 (m, 2H), 2.15-2.18 (m, 2H), 2.25-2.30 (m, 1H), 2.58 (t, 2H, J = 8.4 Hz), 4.43 (brs, 1H), 6.40 (t, 1H, J = 6.1 Hz), 7.10 (d, 2H, J = 7.6 Hz), 7.34 (d, 2H, J = 8.4 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.1, 22.6, 26.0, 27.3, 28.5, 31.0, 31.5, 35.1, 35.9, 71.3, 86.8, 91.6, 120.1, 123.2, 128.6, 131.4, 138.4, 143.5. GC-MS: m/z = 282. Anal. Calcd. for C₂₀H₂₆O: C, 85.06%; H, 9.28%. Found: C, 84.98%; H, 9.30%.

2-Thiophen-2-ylethynyl-cyclohept-2-enol ( 5c ). Brown oil; IR (CH₂Cl₂): 3421, 2925, 2842, 1654, 1444, 1079, 850, 698 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.35-1.40 (m, 1H), 1.58-1.72 (m, 3H), 1.77-1.83 (m, 1H), 1.90-1.98 (m, 2H), 2.28-2.40 (m, 2H), 4.43 (brs, 1H), 6.41 (t, 1H, J = 1.5 Hz), 6.94 (t, 1H, J = 5.3 Hz), 7.16 (d, 1H, J = 3.8 Hz), 7.23 (d, 1H, J = 5.3 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 25.7, 27.1, 28.6, 35.0, 71.4, 84.0, 91.6, 123.2, 127.1, 127.2, 131.0, 131.8, 139.4. GC-MS: m/z = 218. Anal. Calcd. for C₁₃H₁₄OS: C, 71.52%; H, 6.46%. Found: C, 71.40%; H, 6.50%.

2-Hex-1-ynyl-cyclohept-2-enol ( 5d ). Colorless oil; IR (CH₂Cl₂): 3368, 2928, 2851, 1707, 1447, 1065, 909, 732 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.96 (t, 3H, J = 6.8 Hz), 1.28-1.34 (m, 6H), 1.36-1.48 (m, 4H), 1.97-2.10 (m, 4H), 2.50 (m, 1H), 4.17 (brs, 1H), 6.07 (t, 1H, J = 3.8 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 13.5, 18.3, 19.1, 22.5, 24.7, 25.8, 29.8, 30.1, 69.4, 80.0, 92.0, 130.2, 137.5. GC-MS:m/z = 192. Anal. Calcd. for C₁₃H₂₀O: C, 81.20%; H, 10.48%. Found: C, 81.31%; H, 10.54%.

2-(1-Hydroxy-cyclohexylethynyl)-cyclohept-2-enol ( 5e ). Colorless oil; IR (CH₂Cl₂): 3500, 3450, 2930, 1640, 1435, 1199, 799 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.12-1.18 (m, 4H), 1.35-1.51 (m, 6H), 1.59-1.65 (m, 4H), 1.69-1.77 (m, 4H), 1.91-1.99 (m, 1H), 3.30 (brs, 1H), 4.20 (brs, 1H), 6.16 (t, 1H, J = 3.9 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.1, 18.2, 22.6, 24.6, 25.2, 25.6, 30.5, 39.0, 67.3, 69.4, 75.1, 82.9, 93.0, 124.4, 139.0. GC-MS: m/z = 234. Anal. Calcd. for C₁₅H₂₂O₂: C, 76.88%; H, 9.46%. Found: C, 77.00%; H, 9.44%.

2-(Phenylethynyl)-cyclohex-2-enol ( 5f ). Brown oil; IR (CH₂Cl₂): 3383, 2928, 1592, 1053, 755 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.60-1.62 (m, 1H), 1.75-1.78 (m, 3H), 1.87-1.90 (m, 1H), 2.12-2.21 (m, 2H), 4.26 (brs, 1H), 6.30 (t, 1H, J = 4.6 Hz), 7.28-7.29 (m, 3H), 7.43-7.44 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ_C 18.1, 26.0, 30.6, 66.9, 88.4, 89.3, 123.2, 124.2, 128.2, 128.3, 131.6, 137.8. GC-MS: m/z = 198. Anal. Calcd. for C₁₄H₁₄O: C, 84.81%; H, 7.12%. Found: C, 84.91%; H, 7.09%.

2-(4-Pentylphenylethynyl)-cyclohex-2-enol ( 5g ). Brown oil; IR (CH₂Cl₂): 3400, 2928, 2363, 1509, 1461, 1047, 980 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.87 (t, 3H, J = 6.9 Hz), 1.25-1.32 (m, 4H), 1.57-1.60 (m, 3H), 1.74-1.76 (m, 2H), 1.88-1.90 (m, 1H), 2.11-2.22 (m, 3H), 2.57 (t, 2H, J = 7.6 Hz), 4.22 (brs, 1H), 6.28 (t, 1H, J = 4.6 Hz), 7.11 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.1, 18.2, 22.6, 26.0, 30.6, 31.0, 31.5, 35.9, 67.0, 87.5, 89.6, 120.2, 124.4, 128.5, 131.5, 137.3, 143.4. GC-MS: m/z = 268. Anal. Calcd. for C₁₉H₂₄O: C, 85.03%; H, 9.01%. Found: C, 85.18%; H, 8.96%.

2-Pyridin-2-ylethynyl-cyclohex-2-enol ( 5h ). Yellow oil; IR (CH₂Cl₂): 3450, 3398, 2929, 2369, 1500, 1450, 1055, 977 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.58-1.60 (m, 1H), 1.75-1.77 (m, 2H), 1.86-1.88 (m, 1H), 2.12-2.18 (m, 2H), 2.21-2.24 (m, 1H), 4.31 (brs, 1H), 6.41 (t, 1H, J = 4.6 Hz), 7.17 (t, 1H, J = 7.6 Hz), 7.39 (d, 1H, J = 6.8 Hz), 7.61 (t, 1H, J = 7.6 Hz), 8.53 (d, 1H, J = 5.3 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 18.1, 26.2, 30.7, 66.5, 88.3, 89.1, 122.6, 124.1, 127.0, 136.2, 139.6, 143.4, 149.8. GC-MS: m/z = 199. Anal. Calcd. for C₁₃H₁₃NO: C, 78.36%; H, 6.58%; N, 7.03%. Found: C, 78.47%; H, 6.56%; N, 7.00%.

2-Hex-1-ynyl-cyclohex-2-enol ( 5i ). Colorless oil; IR (CH₂Cl₂): 3430, 2930, 1501, 1455, 990, 803 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.96 (t, 3H, J = 6.8 Hz),, 1.32-1.44 (m, 4H), 1.60-1.79 (m, 4H), 1.90-2.15 (m, 5H), 4.09 (brs, 1H), 5.91 (t, 1H, J = 4.3 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 13.6, 19.2, 21.5, 25.0, 28.4, 31.2, 36.8, 69.9, 78.7, 90.3, 132.3, 137.8. GC-MS: m/z = 178. Anal. Calcd. for C₁₂H₁₈O: C, 80.85%; H, 10.18%. Found: C, 80.99%; H, 10.12%.

2-(1-Hydroxy-cyclohexylethynyl)-cyclohex-2-enol ( 5j ). Colorless oil; IR (CH₂Cl₂): 3505, 3451, 2929, 1513, 1219, 782 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.18-1.23 (m, 2H), 1.43-1.59 (m, 6H), 1.63-1.73 (m, 3H), 1.79-1.91 (m, 3H), 2.00-2.05 (m, 1H), 2.08-2.15 (m, 1H), 2.80-2.99 (m, 1H), 3.35 (brs, 1H), 4.14 (brs, 1H), 6.15 (t, 1H, J = 3.8 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 18.3, 23.5, 25.2, 25.7, 25.8, 30.7, 40.0, 68.9, 83.3, 92.9, 123.9, 129.9. GC-MS: m/z = 220. Anal. Calcd. for C₁₄H₂₀O₂: C, 76.33%; H, 9.15%. Found: C, 76.44%; H, 9.12%.

2-(Phenylethynyl)-cyclopent-2-enol ( 5k ). Brown oil; IR (CH₂Cl₂): 3368, 2924, 2363, 1485, 1309, 1048, 756 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.82-1.84 (m, 1H), 2.14 (s, 1H), 2.34-2.37 (m, 2H), 2.58-2.60 (m, 1H), 4.87 (brs, 1H), 6.29 (t, 1H, J = 3.05 Hz), 7.29-7.31 (m, 2H), 7.45-7.46 (m, 3H). ¹³C NMR (125 MHz, CDCl₃): δ_C 31.0, 32.9, 77.1, 84.7, 92.1, 123.1, 128.2, 128.4 (2C), 131.7, 140.5. GC-MS: m/z = 184. Anal. Calcd. for C₁₃H₁₂O: C, 84.75%; H, 6.57%. Found: C, 84.80%; H, 6.55%.

2-(4-Pentylphenylethynyl)-cyclopent-2-enol ( 5l ). Brown oil; IR (CH₂Cl₂): 3377, 2914, 2363, 1491, 1313, 1041, 759 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.87 (t, 3H, J = 6.9 Hz), 1.27-1.34 (m, 4H), 1.58-1.63 (m, 2H), 1.80-1.84 (m, 1H), 2.03 (s, 1H), 2.33-2.37 (m, 2H), 2.56-2.62 (m, 3H), 4.86 (s, 1H), 6.26 (s, 1H), 7.11 (d, 2H, J = 7.6 Hz), 7.36 (d, 2H, J = 8.4 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.1, 22.6, 30.9, 31.0, 31.5, 32.9, 35.9, 79.1, 83.9, 92.5, 120.2, 128.4, 128.5, 131.6, 139.9, 143.5. GC-MS: m/z = 254. Anal. Calcd. for C₁₈H₂₂O: C, 84.99%; H, 8.72%. Found: C, 84.85%; H, 8.78%.

Experimental procedure for the synthesis of compound ( 5m ). A mixture of compound 3a (205 mg, 1 mmol), phenylethynylcopper(I) (164 mg, 1 mmol) and dry Et₃N (5 mL) was heated at 80 °C under an atmosphere of N₂ for 6 h. The mixture was then poured into ice-cold water (25 mL) and extracted with Et₂O (3 × 10 mL). The combined organic extracts were washed sequentially with 2M HCl (5 mL), 5% NaHCO₃ (5 mL) and water (10 mL), and then dried over anhydrous MgSO₄. The solvent was removed under reduced pressure to afford the crude product, which was purified by column chromatography over silica gel eluting with a 1:4 (v/v) mixture of EtOAc and petroleum ether to afford the pure product 5m as a light yellow solid. IR (KBr): 3390, 2921, 2352, 1595, 1431, 748 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.62-1.77 (m, 6H), 1.99-2.08 (m, 2H), 2.17-2.23 (m, 1H), 2.34-2.43 (m, 2H), 6.45 (t, 1H, J = 6.9 Hz), 7.32-7.40 (m, 4H), 7.48-7.52 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ_C 24.3,25.9, 27.5, 28.9, 35.4, 71.7, 87.9, 91.6, 123.6, 128.5, 128.9, 131.7, 131.9, 140.4. GC-MS: m/z = 226. Anal. Calcd. for C₁₆H₁₈O: C, 84.80%; H, 8.02%. Found: C, 84.95%; H, 7.96%.

AuBr₃ (5 mol%) was added a stirred solution of 2-acetylenic alcohol 5 (1.0 mmol) in dichloroethane (1 mL) under N₂, and the resulting mixture was stirred at the specified temperature and the specified time (see Table 2 and Schemes 2 and 7). Upon completion of the reaction, as indicated by TLC, the reaction mixture was quenched with 10 mL of water and extracted with dichloromethane (3 × 5 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography over silica gel (100-200 mesh) eluting with a mixture of cyclohexane and EtOAc to afford pure product ( 6a-6l and 6q ).

Table 2 Synthesis of furans 6a-6l . Entry 5 6 a Yield b (%) 1 5a 6a 90 2 5b 6b 91 3 5c 6c 89 4 5d 6d 95 5 5e 6e 79 6 5f 6f 86 7 5g 6g 88 8 5h 6h 70 9 5i 6i 92 10 5j 6j 83 11 5k 6k 60 12 5l 6l 66 a All of these products were characterized by IR, 1H NMR, 13C NMR and GC-MS analyses b Isolated yield after column chromatography.

Table 2 Synthesis of furans 6a-6l .

Scheme 2. Synthesis of cyclooctylfurans 6m-6o .

Scheme 7. AuBr3 catalyzed cyclization of acyclic substrates.

2-Phenyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan ( 6a ). Colorless oil; IR (CH₂Cl₂): 2924, 2851, 1676, 1450, 803 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.75-1.82 (m, 6H), 2.53 (t, 2H, J = 5.3 Hz), 2.86 (t, 2H, J = 6.1 Hz), 6.45 (s, 1H), 7.21 (t, 1H, J = 7.6 Hz), 7.36 (t, 2H, J = 8.4 Hz), 7.63 (d, 2H, J = 7.6 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 26.3, 26.7, 28.8, 29.1, 30.9, 108.8, 123.0, 123.2, 126.5, 128.6, 131.4, 149.8, 153.4. GC-MS: m/z = 212. Anal. Calcd. for C₁₅H₁₆O: C, 84.87%; H, 7.60%. Found: C, 85.00%; H, 7.55%.

2-(4-Pentylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan ( 6b ). Colorless liquid; IR (CH₂Cl₂): 2926, 2851, 1676, 1450, 803 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.90 (t, 3H, J = 6.9 Hz), 1.33-1.36 (m, 5H), 1.62 (t, 2H, J = 7.6 Hz), 1.72-1.79 (m, 5H), 2.51 (t, 2H, J = 6.1 Hz), 2.59 (t, 2H, J = 7.6 Hz), 2.83 (t, 2H, J = 6.1 Hz), 6.37 (s, 1H), 7.15 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 7.6 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.1, 22.6, 26.3, 26.7, 28.8, 29.1, 30.9, 31.2, 31.6, 35.7, 108.0, 122.8, 123.2, 128.6, 128.9, 141.3, 150.1, 152.9. GC-MS: m/z = 282. Anal. Calcd. for C₂₀H₂₆O: C, 85.06%; H, 9.28%. Found: C, 85.00%; H, 9.30%.

2-Thiophen-2-yl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan ( 6c ). Brown oil; IR (CH₂Cl₂): 2921, 2847, 1663, 1573, 1443, 1218, 1080, 840, 691 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.72-1.73 (m, 4H), 1.77-1.79 (m, 2H), 2.49 (t, 2H, J = 6.1 Hz), 2.81 (t, 2H, J = 6.1 Hz), 6.29 (s, 1H), 7.00 (dd, 1H, J₁ = 3.8 Hz, J₂ = 3.8 Hz), 7.14-7.15 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ_C 26.2, 26.6, 28.7, 29.0, 30.8, 108.8, 121.3, 122.9, 123.1, 127.6, 134.5, 145.5, 153.0. GC-MS: m/z = 218. Anal. Calcd. for C₁₃H₁₄OS: C, 71.52%; H, 6.46%. Found: C, 71.58%; H, 6.45%.

2-Butyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan ( 6d ). Colorless liquid; IR (CH₂Cl₂): 2919, 2850, 1660, 1565, 1435, 1211, 1075, 850 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.95 (t, 3H, J = 6.8 Hz), 1.27-1.34 (m, 4H), 1.55-1.65 (m, 6H), 2.31-2.55 (m, 6H), 6.03 (s, 1H). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.0, 20.2, 20.3, 24.4, 29.9, 30.1, 31.2, 32.6, 32.8, 106.4, 112.8, 149.8, 152.0. GC-MS: m/z = 192. Anal. Calcd. for C₁₃H₂₀O: C, 81.20%; H, 10.48%. Found: C, 81.30%; H, 10.44%.

1-(5,6,7,8-Tetrahydro-4H-cyclohepta[b]furan-2-yl)-cyclo-hexanol ( 6e ). Colorless liquid; IR (CH₂Cl₂): 3477, 2940, 2935, 1652, 1439, 1231, 799, 702 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.19-1.26 (m, 2H), 1.55-1.63 (m, 6H), 1.72-1.79 (m, 4H), 1.75-1.81 (m, 4H), 1.92-2.15 (m, 4H), 3.99 (brs, 1H), 6.49 (s, 1H). ¹³C NMR (125 MHz, CDCl₃): δ_C 16.9, 17.3, 18.5, 18.9, 19.9, 20.1, 22.8, 31.2, 35.3, 105.9, 117.8, 140.7, 151.0. GC-MS: m/z = 234. Anal. Calcd. for C₁₅H₂₂O₂: C, 76.88%; H, 9.46%. Found: C, 77.01%; H, 9.44%.

2-Phenyl-4,5,6,7-tetrahydro-benzofuran ( 6f ). Colorless liquid; IR (CH₂Cl₂): 2934, 2851, 1669, 1447, 1247, 760, 690 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.75-1.78 (m, 2H), 1.84-1.89 (m, 2H), 2.46 (t, 2H, J = 6.1 Hz), 2.67 (t, 2H, J = 6.1 Hz), 6.47 (s, 1H), 7.20 (t, 1H, J = 7.6 Hz), 7.35 (t, 2H, J = 7.6 Hz), 7.62 (d, 2H, J = 6.9 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 22.2, 23.1, 23.2, 23.4, 106.1, 119.0, 123.3, 126.6, 128.6, 131.5, 150.9. GC-MS: m/z = 198. Anal. Calcd. for C₁₄H₁₄O: C, 84.81%; H, 7.12%. Found: C, 84.75%; H, 7.15%.

2-(4-Pentylphenyl)-4,5,6,7-tetrahydro-benzofuran ( 6g ). Colorless liquid; IR (CH₂Cl₂): 2928, 2851, 2354, 1495, 1452, 909, 838 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.92 (t, 3H, J = 6.8 Hz), 1.30-1.36 (m, 5H), 1.64-1.66 (m, 3H), 1.80-1.88 (m, 2H), 1.99-2.28 (m, 2H), 2.59-2.77 (m, 4H), 6.35 (s, 1H), 7.18 (d, 1H, J = 8.4 Hz), 7.25 (d, 1H, J = 7.6 Hz), 7.52-7.57 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.2, 22.1, 22.9, 23.1, 23.5, 30.7, 31.2, 31.6, 35.8, 105.2, 118.8, 123.3, 126.6, 141.5, 147.7, 150.1, 152.1. GC-MS: m/z = 268. Anal. Calcd. for C₁₉H₂₄O: C, 85.03%; H, 9.01%. Found: C, 84.98%; H, 9.03%.

2-(4,5,6,7-Tetrahydro-benzofuran-2-yl)-pyridine ( 6h ). Yellow oil; IR (CH₂Cl₂): 3400, 2930, 2850, 1680, 1450, 823 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.65-1.74 (m, 3H), 2.21-2.24 (m, 2H), 2.38-2.40 (m, 1H), 2.44 (t, 1H, J = 7.6 Hz), 2.66 (t, 1H, J = 6.1 Hz), 6.36 (s, 1H), 7.14-7.17 (m, 1H), 7.56 (t, 1H, J = 7.6 Hz), 7.63-7.65 (m, 1H), 8.57 (d, 1H, J = 3.8 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 19.7, 24.6, 27.7, 29.7, 82.9, 104.2, 113.7, 120.1, 123.0, 136.4, 143.2, 149.6, 160.1. GC-MS: m/z = 199. Anal. Calcd. for C₁₃H₁₃NO: C, 78.36%; H, 6.58; N, 7.03%. Found: C, 78.25%; H, 6.60%; N, 7.07%.

2-Butyl-4,5,6,7-tetrahydrobenzofuran ( 6i ). Colorless oil; IR (CH₂Cl₂): 2935, 2853, 1675, 1447, 799, 763 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.93 (t, 3H, J = 6.9 Hz), 1.33-1.69 (m, 8H), 2.35-2.60 (m, 6H), 6.01 (s, 1H). ¹³C NMR (125 MHz, CDCl₃): δ_C 13.4, 20.9, 21.2, 29.5, 31.1, 32.3, 35.4, 36.0, 106.3, 112.6, 149.5, 151.1. GC-MS:m/z = 178. Anal. Calcd. for C₁₂H₁₈O: C, 80.85%; H, 10.18%. Found: C, 80.74%; H, 10.22%.

1-(4,5,6,7-Tetrahydro-benzofuran-2-yl)-cyclohexanol ( 6j ). Colorless oil; IR (CH₂Cl₂): 3480, 2935, 2929, 1669, 1447, 1250, 800, 713 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.20-1.25 (m, 2H), 1.49-1.61 (m, 6H), 1.65-1.69 (m, 4H), 1.72-1.75 (m, 2H), 1.89-2.10 (m, 4H), 3.95 (brs, 1H), 6.51 (s, 1H). ¹³C NMR (125 MHz, CDCl₃): δ_C 17.2, 17.4, 18.0, 18.2, 19.0, 20.1, 22.6, 35.7, 105.2, 118.0, 141.9, 151.2. GC-MS: m/z = 220. Anal. Calcd. for C₁₄H₂₀O₂: C, 76.33%; H, 9.15%. Found: C, 76.25%; H, 9.17%.

2-Phenyl-5,6-dihydro-4H-cyclopenta[b]furan ( 6k ). Colorless oil; IR (CH₂Cl₂): 2935, 2859, 1681, 1453, 810 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.79-1.83 (m, 2H), 1.95 (t, 2H, J = 6.3 Hz), 2.56 (t, 2H, J = 6.2 Hz), 6.50 (s, 1H), 7.15 (t, 1H, J = 7.6 Hz), 7.34 (t, 2H, J = 8.4 Hz), 7.63 (d, 2H, J = 7.6 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 23.5, 23.7, 24.2, 105.1, 118.0, 122.3, 125.5, 127.6, 130.5, 150.7, 151.9. GC-MS: m/z = 184. Anal. Calcd. for C₁₃H₁₂O: C, 84.75%; H, 6.57%. Found: C, 84.86%; H, 6.54%.

2-(4-Pentylphenyl)-5,6-dihydro-4H-cyclopenta[b]furan ( 6l ). Colorless oil; IR (CH₂Cl₂): 2931, 2856, 1680, 1455, 892, 800 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.94 (t, 3H, J = 6.8 Hz), 1.36-1.41 (m, 5H), 1.68-1.71 (m, 3H), 1.76-1.80 (m, 2H), 1.93 (t, 2H, J = 6.2 Hz), 2.56 (t, 2H, J = 6.3 Hz), 6.43 (s, 1H), 7.22 (d, 2H, J = 7.6 Hz), 7.34 (d, 2H, J = 7.6 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.3, 22.0, 22.8, 23.0, 30.6, 31.1, 31.6, 35.8, 104.9, 117.9, 123.4, 123.8, 128.7, 148.0, 150.0, 152.0. GC-MS: m/z = 254. Anal. Calcd. for C₁₈H₂₂O: C, 84.99%; H, 8.72%. Found: C, 85.10%; H, 8.67%.

2,3-Dimethylfuran ( 6q ). Colorless liquid; IR (neat): 3150, 3115, 1501, 1164, 1075, 801 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.91 (s, 3H), 2.29 (s, 3H), 6.19 (d, 1H, J = 6.0 Hz), 7.41 (d, 1H, J = 6.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 9.3, 11.0, 113.3, 114.5, 140.5, 147.9. GC-MS: m/z = 96. Anal. Calcd. for C₆H₈O: C, 74.97%; H, 8.39%. Found: C, 75.15%; H, 8.26%.

Dry triethylamine (5mL) was added to a mixture of 2-bromo-cyclooct-2-enol 3d (1.0 mmol), Pd(PPh₃)₂Cl₂ (5 mol%) and CuI (5 mol%) in an oven-dried flask under N₂, and the resulting suspension was stirred for 5 min. Terminal alkyne 4 (1.2 mmol) was then added to the reaction in a dropwise manner, and the resulting mixture was stirred at room temperature until it reached completion, indicated by the disappearance of 2-bromo-cyclooct-2-enol by TLC (~6 h). The reaction was diluted with water (50 mL) and extracted with ethyl acetate (4 × 15 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude was then purified by column chromatography over silica gel eluting with a 1:9 (v/v) mixture of EtOAc and petroleum ether to afford the pure product ( 6m-6o ). Compound 6m was synthesized in the way using the catalyst and conditions depicted in Scheme 3.

Scheme 3. Cyclization of 5m by several transition metal catalysts.

2-Phenyl-4,5,6,7,8,9-hexahydrocycloocta[b]furan ( 6m ). Colorless oil; IR (CH₂Cl₂): 3081, 3055, 2927, 2844, 1625, 1606, 1541, 1485, 1455, 1351, 895, 797 cm^-1.¹H NMR (500 MHz, CDCl₃): δ_H 1.49-1.55 (m, 4H), 1.65-1.70 (m, 2H), 1.75-1.80 (m, 2H), 2.55 (t, 2H, J= 6.2 Hz), 2.85 (t, 2 H, J = 6.2 Hz), 6.41 (s, 1H), 7.15-7.20 (m, 1H),7.30-7.35 (m, 2H), 7.60-7.64 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ_C 23.8, 25.3, 26.1, 27.4, 28.9, 108.1, 120.5, 123.1, 126.4, 128.5, 131.3, 150.5, 151.7. GC-MS: m/z = 226. Anal. Calcd. for C₁₆H₁₈O: C, 84.91%; H, 8.02%. Found: C, 85.11%; H, 7.98%.

2-Pentyl-4,5,6,7,8,9-hexahydrocycloocta[b]furan ( 6n ). Colorless oil; IR (CH₂Cl₂): 2927, 2860, 1733, 1520, 1455, 1345, 1257, 1165, 1090, 1010, 930, 850 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 0.89 (t, 3H, J = 6.4 Hz), 1.30-1.35 (m, 4H), 1.44-1.68 (m, 10 H), 2.44-2.55 (m, 4H), 2.70 (m, 2H), 5.69 (s, 1H). ¹³C NMR (125 MHz, CDCl₃): δ_C 14.1, 22.3, 23.8, 25.3, 26.0, 26.1, 27.5, 28.0, 28.1, 28.9, 31.5, 107.5, 118.5, 149.5, 152.9. GC-MS: m/z = 220. Anal. Calcd. for C₁₅H₂₄O: C, 81.76%; H, 10.98%. Found: C, 81.91%; H, 10.92%.

2-(3-(Benzyloxy)propyl)-4,5,6,7,8,9-hexahydrocycloocta[b] furan ( 6o ). Colorless oil; IR (CH₂Cl₂): 2925, 2853, 1572, 1495, 1476, 1450, 1410, 1361, 1305, 1280, 1250, 1210, 1145, 1100, 1074, 1025, 983, 960, 905, 881, 858, 800 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.35-1.70 (m, 8H), 1.85 (q, 2H, J = 6.7 Hz), 2.39 (t, 2H, J = 6.3 Hz), 2.55-2.65 (m, 6H), 3.45 (t, 2H, J = 6.7 Hz), 5.65 (s, 1H),7.20-7.29 (m, 5H). ¹³C NMR (125 MHz, CDCl₃): δ_C 23.7, 24.6, 25.3, 25.8, 26.0, 27.3, 28.2, 28.7, 69.4, 73.0, 108.0, 118.6, 127.5, 127.6, 127.7, 128.4, 128.5, 138.5, 149.7, 152.0. GC-MS: m/z = 321. Anal. Calcd. for C₂₀H₂₆O₂: C, 80.50%; H, 8.78%. Found: C, 80.21%; H, 8.85%.

Dry triethylamine (50 mL) was added to a mixture of 2-bromo-cyclooct-2-enol 3d (10.0 mmol), Pd(PPh₃)₂Cl₂ (5 mol%), and CuI (5 mol%) in an oven-dried flask under N₂, and the resulting suspension was stirred for 5 min. Phenylacetylene 4a (1.2 eq.) was then added to the reaction in a dropwise manner, and the resulting mixture was stirred at room temperature for 6 h. Molecular iodine (1.0 eq.) was then added to the reaction, and the resulting mixture was stirred for further 2 h. The mixture was then quenched with a saturated solution of sodium thiosulfate and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography over silica gel (100-200 mesh) eluting cyclohexane/EtOAc to afford pure 8a as a colorless liquid. IR (neat): 3084, 3059, 2929, 2851, 1635, 1610, 1549, 1489, 1449 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.65-1.79 (m, 4H); 1.81-1.92 (m, 4H); 2.37 (t, 2H, J = 6.1 Hz); 2.72 (t, 2H, J = 6.2 Hz); 7.34 (t, 1H, J = 7.6 Hz); 7.48 (t, 2H, J = 7.6 Hz); 8.02 (d, 2H, J = 7.6 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 20.7, 21.9, 22.9, 23.4, 23.6, 66.9, 123.7, 126.5, 128.0, 128.9, 129.0, 131.2, 150.1, 151.5. GC-MS: m/z = 352. Anal. Calcd. for C₁₆H₁₇IO: C, 54.56%; H, 4.86%. Found: C, 53.91%; H, 4.95%.

A solution of organozinc reagent 7a (1.05 eq.) in THF was added to a stirred solution of 8a (1.0 mmol) and Pd(Ph₃P)₄ (10 mol%) in dry dioxane at 0 °C, and the resulting mixture was stirred at 25 °C for 30 min. The reaction was quenched with 0.5 mol/L HCl and extracted with Et₂O. The combined organic extracts were then washed sequentially with saturated NaHCO₃ solution and brine, and dried over anhydrous Na₂SO₄. The solvent was then removed under reduced pressure to give the crude product, which was purified by column chromatography over silica gel (100-200 mesh) eluting with a mixture of hexane and EtOAc to give the pure product 9a as a colorless solid. MP 72-74 °C; IR (KBr): 3069, 3025, 2935, 1519, 1489, 1449, 1375, 781 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.34-1.45 (m, 4H), 1.67-1.77 (m, 4H). 2.36 (s, 3H), 2.47 (t, 2H, J = 7.6 Hz), 2.89 (t, 2H,J = 8.1 Hz), 6.95-7.04 (m, 2H), 7.12 (t, 1H, J = 7.6 Hz), 7.29-7.40 (m, 4H), 7.51-7.67 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ_C 21.5, 22.9, 24.1, 25.5, 27.0, 30.5, 57.4, 115.1, 116.5, 119.5, 120.2, 124.1, 127.9, 129.8, 130.4, 132.5, 131.9, 146.7, 150.9, 160.1. GC-MS: m/z = 316. Anal. Calcd. for C₂₃H₂₄O: C, 87.30%; H, 7.64%. Found: C, 88.11%; H, 7.55%.

Dry triethylamine (5mL) was added to a mixture of compound 8a (1.0 mmol), Pd(PPh₃)₂Cl₂ (5 mol%) and CuI (5 mol%) were placed in an oven-dried flask under N₂, and the resulting suspension was stirred for 5 min. Phenylacetylene 4a (1.1 eq.) was added to the reaction in a dropwise manner, and the resulting mixture was stirred at room temperature for 3 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (4 × 15 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to dryness to give the crude product, which was purified by column chromatography over silica gel eluting with a mixture of EtOAc and petroleum ether to afford the pure product 10a as a yellow solid. MP 110-112 °C; IR (KBr): 3060, 3018, 2939, 2855, 2219, 1642, 1608, 1556, 1499, 1351 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.66-1.79 (m, 4H), 1.85-1.93 (m, 4H), 2.55 (t, 2H, J = 6.7 Hz), 2.69 (t, 2H, J = 6.4 Hz), 7.29 (t, 1H, J = 7.6 Hz), 7.35-7.41 (m, 5H), 7.51-7.55 (m, 2H), 8.05 (d, 2H, J = 8.1 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 20.7, 21.0, 21.3, 22.8, 23.1, 23.4, 84.1, 97.5, 105.2, 123.6, 124.5, 124.9, 127.9, 128.4, 128.8, 129.6, 131.5, 132.2, 151.1, 153.4. GC-MS: m/z = 326. Anal. Calcd. for C₂₄H₂₂O: C, 88.31%; H, 6.79%. Found: C, 88.91%; H, 6.65%.

To a stirred solution of iodofuran 8a (1.0 mmol) in dimethoxyethane at room temperature was added phenylboronic acid 11a (1.0 eq.), Pd(PPh₃)₄ (10 mol%) and Cs₂CO₃ (1.0 eq.), and the resulting mixture was stirred at 60 °C for 1 h. The mixture was cooled to room temperature and filtered through a sintered crucible. The filtrate was collected and concentrated to dryness under reduced pressure to give the crude product, which was purified by column chromatography over silica gel eluting with a mixture of EtOAc and petroleum ether to afford the pure product 12a as a colorless solid. MP 88-90 °C; IR (KBr): 3068, 3025, 2932, 1515, 1475, 1381, 763 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.65-1.78 (m, 4H), 1.83-1.92 (m, 4H), 2.39 (t, 2H, J = 6.7 Hz), 2.75 (t, 2H, J = 6.6 Hz),6.78-6.89 (m, 2H), 7.17-7.35 (m, 5H), 7.44-7.55 (m, 3H). ¹³C NMR (125 MHz, CDCl₃): δ_C 20.9, 21.3, 22.7, 22.9, 23.1, 23.4, 55.7, 114.1, 114.2, 119.8, 122.1, 125.6, 126.5, 126.6, 127.4, 128.5, 130.8, 131.9, 146.8, 150.5, 158.9. GC-MS: m/z = 302. Anal. Calcd. for C₂₂H₂₂O: C, 87.38%; H, 7.33%. Found: C, 86.97%; H, 7.45%.

To a stirred solution of iodofuran 8a (1.0 mmol) in dry THF (10 mL) at room temperature was added Pd(PPh₃)₄ (10 mol%), LiCl (3.0 eq.) and tributyl(vinyl)tin (2.0 eq.), and the resulting mixture was stirred at room temperature for 12 h. The mixture was filtered through a pad of Celite and the filtrate was concentration under reduced pressure to give a residue, which was purified by column chromatography over silica gel (100-200 mesh) eluting with a mixture of hexane and EtOAc to afford 14a as a colorless liquid. IR (neat): 3091, 3061, 3035, 2935, 2849, 1631, 1614, 1591, 1471, 1455, 1425, 1345, 781 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.65-1.79 (m, 4H), 1.85-1.94 (m, 4H), 2.55-2.67 (m, 4H), 5.35 (dd, 1H, J₁ = 12.2 Hz; J₂ = 2.1 Hz), 5.47 (dd, 1H, J₁ = 18.4 Hz; J₂ = 12.2 Hz), 6.91 (dd, 1H, J₁ = 18.2 Hz, J₂ = 12.2 Hz), 7.29-7.34 (m, 1H), 7.40-7.45 (m, 2H), 7.67 (t, 2H, J = 7.6 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 21.5, 22.6, 22.9, 23.4, 115.2, 118.3, 127.1, 128.8, 129.6, 130.1, 130.3, 131.9, 149.5, 150.6. GC-MS: m/z = 252. Anal. Calcd. for C₁₈H₂₀O: C, 85.67%; H, 7.99%. Found: C, 86.07%; H, 7.87%.

To a stirred solution of iodofuran 8a (1.0 mmol) in DMAc (1.5 mL) at room temperature was added ethylacrylate (1.1 eq.), Pd(OAc)₂ (5 mol%), nBu₃P (25 mol%) and pyridine (3.0 eq.), and the resulting mixture was stirred at 50 °C for 1 h. The mixture was then diluted with brine (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (20 mL) and dried over anhydrous MgSO₄. The solvent was then removed under reduced pressure to give a residue, which was purified by column chromatography over silica gel eluting with a mixture of hexane and EtOAc to give 16a as a pale yellow liquid. IR (neat): 3095, 3061, 2941, 2841, 1717, 1635, 1621, 1542, 1480, 1455, 1425, 1341, 781 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.29 (t, 3H, J = 7.6 Hz), 1.66-1.78 (m, 4H), 1.81-1.92 (m, 4H), 2.67-2.75 (m, 4H), 3.96 (q, 2H, J = 7.6 Hz), 6.52 (d, 1H, J = 16.4 Hz), 7.30 (t, 1H, J = 7.6 Hz), 7.45 (t, 2H, J = 7.6 Hz), 7.65 (t, 2H, J = 7.6 Hz), 7.95 (d, 1H, J = 16.4 Hz). ¹³C NMR (125 MHz, CDCl₃): δ_C 13.8, 21.8, 22.4, 22.7, 23.0, 23.3, 51.5, 61.7, 117.1, 117.5, 117.9, 127.2, 128.0, 128.6, 130.8, 137.5, 151.8, 153.8, 167.1. GC-MS: m/z = 324. Anal. Calcd. for C₂₁H₂₄O₃: C, 77.75%; H, 7.46%. Found: C, 77.57%; H, 7.53%.

AuBr₃ (5 mol%) was added to a solution of compound 6f (1.0 mmol) in dichloroethane (1 mL) under N₂ at room temperature, and the resulting mixture was heated at 70 °C for 30 min. Butenone 17a (1.2 eq.) was then added to the reaction, and the resulting mixture was stirred for 20 min. Upon completion of the reaction, as indicated by TLC, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 × 5 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography over silica gel (100-200 mesh) eluting with a mixture of cyclohexane and EtOAc to afford pure product 18a as a yellow liquid. IR (neat): 3098, 3055, 2946, 1685, 1586, 1355 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.78-1.85 (m, 2H), 1.88-1.95 (m, 2H), 2.19 (s, 3H), 2.45 (t, 2H, J = 6.9 Hz), 2.61 (t, 2H, J = 6.7 Hz), 2.81 (t, 2H, J = 3.4 Hz), 2.95 (t, 2H, J = 2.8 Hz), 7.29 (t, 1H, J = 7.6 Hz),7.45 (t, 2H, J = 7.6 Hz), 7.66-7.77 (m, 2H). ¹³C NMR (125 MHz, CDCl₃): δ_C 19.5, 20.5, 21.4, 22.9, 23.6, 30.1, 44.2, 118.2, 119.1, 120.1, 121.1, 123.5, 124.3, 128.5, 150.3, 151.4, 208.8. GC-MS: m/z = 268. Anal. Calcd. for C₁₈H₂₀O₂: C, 80.56%; H, 7.51%. Found: C, 81.07%; H, 7.39%.

To a mixture of AuBr₃ (5 mol%) and AgSbF₆ (5 mol%) in dry dichloroethane (1 mL) under N₂ was added a solution of compound 6f (1.0 mmol) in dichloroethane (1 mL), and the resulting mixture was heated at 70 °C for 30 min. Phenylacetylene 4a (1.2 eq.) was added to the reaction, and the resulting mixture was stirred for 3 h. The reaction was then cooled to room temperature and quenched with water (10 mL). The resulting mixture was extracted with dichloromethane (3 × 5 mL) and the combined organic layers were dried over anhydrous Na₂SO₄. The solvent was then removed under reduced pressure to afford the crude product, which was purified by column chromatography over silica gel (100-200 mesh) eluting with a mixture of cyclohexane and EtOAc to afford pure product 19a as colorless liquid. IR (neat): 3095, 3054, 2941, 1685, 1609, 1450, 1355, 898, 747 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ_H 1.77-1.85 (m, 2H), 1.89-1.96 (m, 2H), 2.65 (t, 2H, J = 6.4 Hz), 2.78 (t, 2H, J = 6.6 Hz), 5.41 (d, 1H, J = 2.3 Hz), 5.67 (d, 1H, J = 2.0 Hz), 7.15-7.29 (m, 4H), 7.35-7.48 (m, 5H), 7.49-7.54 (m, 1H). ¹³C NMR (125 MHz, CDCl₃): δ_C 19.5, 22.5, 23.4, 23.9, 105.5, 120.1, 121.2, 124.4, 127.5, 127.9, 128.1, 128.3, 128.6, 129.3, 141.2, 145.8, 150.4, 150.6. GC-MS: m/z = 300. Anal. Calcd. for C₂₂H₂₀O: C, 87.96%; H, 6.71%. Found: C, 88.17%; H, 6.63%.

We previously reported a convenient method for the synthesis of fused furans via AuBr₃-catalyzed cycloisomerization of 2-alkynyl-cycloalk-2-enols (Scheme 1) ^[24]. The requisite 2-alkynyl-cycloalk-2-enols were synthesized via the α-iodination of the corresponding cycloalken-2-ones 1 with I₂/pyridine, which afforded the 2-iodocycloalk-2-enones 2 ^{[64, 65, 66]}. Subsequent 1,2-reduction of these 2-iodocycloalk-2-enones 2 with a stoichiometric mixture of NaBH₄ and CeCl₃·7H₂O gave the 2-iodoenols 3 ^{[67, 68]}. These iodoenols were then treated with a variety of terminal alkynes 4 under Sonogashira conditions ^{[69, 70]} to give the hitherto unknown 2-alkynyl-cyclo-alk-2-enols 5 in excellent yields. A wide range of coupling products were successfully synthesized under these conditions, including those bearing aliphatic, aromatic and heteroaromatic substituents, with yields ranging from good to excellent (Table 1).

Scheme 1. AuBr3-catalyzed synthesis of furans 6a - 6l .

Table 1 Synthesis of acetylenic alcohols. Entry n R 4 5 a Yield b (%) 1 3 phenylacetylene (4a) 5a 90 2 3 1-ethynyl-4-pentylbenzene (4b) 5b 92 3 3 2-ethynylthiopene (4c) 5c 88 4 3 1-hexyne (4d) 5d 89 5 3 1-ethynylcyclohexanol (4e) 5e 77 6 2 phenylacetylene (4a) 5f 91 7 2 1-ethynyl-4-pentylbenzene (4b) 5g 94 8 2 2-ethynylpyridine (4f) 5h 79 9 2 1-hexyne (4g) 5i 89 10 2 1-ethynylcyclohexanol (4e) 5j 79 11 1 phenylacetylene (4a) 5k 80 12 1 1-ethynyl-4-pentylbenzene (4b) 5l 81 a All of the products were characterized by IR, 1H NMR, 13C NMR and GC-MS analyses. b Isolated yield after column chromatography.

Table 1 Synthesis of acetylenic alcohols.

The results of a series of optimization studies revealed that all of the substrates underwent the desired cycloisomerization reaction in the presence of 5 mol% AuBr₃ in 1,2-dichloroethane (Table 2). As shown in Table 2, the yields of the fused furans varied from good to excellent depending on the nature of the substituent attached to the alkyne moiety and the reaction temperature. Furthermore, the results indicated that the efficiency of the cyclization was dependent on the nature and the size of the ring attached to the alkyne moiety for substrates 5a-5l . For example, substrates bearing a cycloheptyl ring, the reaction proceeds smoothly over a short reaction time, even at room temperature (Table 2, entries 1-5). Substrates bearing a cyclohexyl ring also reacted rapidly to produce the desired products in good yields when the reaction was carried out for 30 min at 70 °C (Table 2, entries 6-10). However, substrates with a cyclopentyl ring reacted slowly to give low yields of the desired products, even when the reaction time was extended to 45 min (Table 2, entries 11 and 12). These observations can be rationalized in terms of the greater degree of strain associated with the resulting cyclopenta[b]furan products compared with the cyclohexa[b]furan and cyclohepta[b]furan products. The results of these experiments also revealed that the nature of the substituent on the alkyne of the 2-alkynylcycloalk-2-enol substrate did not play a significant role in determining the success of the cyclization, because aliphatic, aromatic and heteroaromatic groups were well tolerated at this position to give almost identical yields of the products. The formation of the products was confirmed by the appearance of a singlet peak in their ¹H NMR spectra in CDCl₃ with a δ_H value in the range of 6.20-6.30 ppm, which was attributed to the C3-H of the furan ring. Moreover, the ¹³C NMR spectra of these products all contained a peak with a δ_C value in the range of 104-109 ppm, which confirmed the presence of the C3 carbon of the furan ring.

In light of their biological significance and their prevalence as the core substructures in numerous crenulide diterpenoid natural products, we became interested in extending the scope of our study to cyclooctyl-fused furan ring systems ^{[71, 72]}. Using the optimized reaction conditions, we initially explored the general scope of our methodology by investigating the synthesis of a series of cyclooctyl furans (Scheme 2). According to the literature, the precursors for this cyclization reaction could be synthesized from commercially available cycloheptene ( 1d ) ^{[73, 74]}. Thus, the cyclopropanation of 1d with CHBr₃ afforded cycloadduct 2d , which underwent a ring expansion reaction with AgClO₄ in aqueous acetone to furnish the 2-bromoenol 3d ^[75]. Surprisingly, the subsequent alkynylation of 3d under the standard Sonogashira conditions did not lead to the expected alkynylated product 5 . In contrast to other ring systems (n = 1, 2, 3), we found that the eight-membered ring 3d reacted rapidly under the Sonogashira condition to afford the cyclized product 6 directly without the isolation of the cross-coupled intermediate 5 .

At this stage in the study, the identity of the catalytic species involved in this one-pot operation was unknown. As well as playing an important role in oxidative addition reactions ^{[76, 77]}, palladium salts can catalyze the intramolecular cyclization reactions of alkynes bearing a hydroxyl tether ^{[78, 79, 80, 81]}. Prompted by this literature survey, we assumed that palladium was the catalyst involved in this tandem process. To test this hypothesis, we investigated the synthesis and isolation of alkyne 5m , which was readily prepared by the Castro-Stephens coupling of 2-bromoenol 3d with phenylethynylcopper(I) ^[82] (Scheme 3). This reaction led to the stable alkyne 5m in excellent yield without the formation of any of the corresponding cyclized product 6m , which suggested that Et₃N and CuBr (formed as by-product) were not acting as catalysts for the cyclization. We subsequently investigated the cyclization of 5m using 5 mol% PdCl₂(Ph₃P)₂ and found that the reaction proceeded smoothly to afford the cyclization product 6m in excellent yield. PdCl₂ also gave the cyclized product 6m in excellent yield, which indicated that this reaction did not require a neutral phosphine ligand. These two test reactions clearly indicated that Pd(II) was the active catalytic species involved in this transformation. Notably, the reaction of 5m with CuI (co-catalyst in the Sonogashira reaction) under the same conditions led to only trace quantities of the cyclization product 6m with 80% of starting material being recovered unchanged. This result therefore precluded the participation of CuI in the cyclization reaction. Finally, the reaction of 5m with a catalytic amount of AuBr₃ also afforded a clean conversion to product 6m , which suggested that our gold-based methodology was indeed applicable to cyclooctyl systems.

Based on these results, we proposed a mechanism for the formation of fused furans, which is shown in Scheme 4. Thus, the initial coordination of the soft Lewis acidic metal [M] to alkyne 5 would lead to π-complex 5I . The increased electrophilicity of the alkyne would allow for the nucleophilic attack of the adjoining hydroxyl group to give the cyclized intermediate 5II . The subsequent proto-deauration of 5II would results in the formation of 5III , which would undergo an isomerization reaction to produce the fused furan 6 .

Scheme 4. Tentative mechanism for the formation of furans 6 .

At this stage in the study, we decided to delineate the scope of our chemistry through a series of synthetic elaborations. Keeping in mind the versatility of the iodide functionality in organometallic transformations, we attempted the one-pot synthesis of 3-iodofuran 8a (Scheme 5). Pleasingly, this sequential process provided the desired iodide 8a in 84% yield. The subsequent Negishi coupling reaction of compound 8a with the arylzinc reagent 7a in the presence of 10 mol% Pd(Ph₃P)₄ allowed for the introduction of an aryl group, with the tetra-substituted furan product 9a being isolated in 79% yield ^{[83, 84]}. Furthermore, the Sonogashira reaction of 8a with phenylacetylene ( 4a ) provided the functionalized alkyne 10a in 88% yield ^[69]. The Suzuki-Miyaura coupling reaction of 8a with phenylboronic acid 11a afforded the 2,3-diphenyl substituted furan 12a in 90% yield ^[85]. Lastly, compound 8a also underwent Stille and Heck coupling reactions with tributyl(vinyl)tin ( 13a ) and ethylacrylate ( 15a ), respectively, to give the corresponding 3-vinyl derivatives 14a and 16a in moderate to good yields ^{[86, 87]}.

Scheme 5. Pd-catalyzed organometallic transformations of 8a .

Having demonstrated the catalytic application of this newly developed palladium-catalyzed tandem process, we turned our attention back towards the possibility of using AuBr₃ to facilitate other interesting one-pot procedures with particular emphasis on Michael- ^[88] and Friedel-Crafts-type reactions ^[89] (Scheme 6). For example, the cyclization of substrate 5f under the optimized conditions followed by the in situ addition of methyl vinyl ketone 17a resulted in the formation of the Michael adduct 18a in 80% yield. Furthermore, the tandem Friedel-Crafts alkenylation of 5f with phenylacetylene ( 4a ) in the presence of a silver co-catalyst resulted in product 19a bearing a C=C bond, albeit in a low yield of 22%. It is noteworthy, however, that this reaction proceeded regioselectively, with the addition only occurring at the internal carbon of alkyne 4a , as indicated by NMR analysis of the crude mixture. This observation was consistent with those of previous studies, in that the Au π-acid drove the addition of an arene/heteroarene to the internal carbon of the terminal acetylene ^[89].

Scheme 6. AuBr3-catalyzed sequential processes.

Finally, we were intrigued by the prospect of applying this methodology to acyclic acetylenic alcohols for the synthesis of non-fused furan rings (see Scheme 7). The requisite (Z)-iodoallylic alcohol 3e was prepared by the reaction of commercially available butyn-1-ol ( 20a ) with Red-Al [NaAlH₂(OCH₂CH₂OMe)₂], followed by quenching of the resulting carbanion with I₂ ^[90]. Subsequent Sonogashira coupling of 3e with ethynyltrimethylsilane 4h gave alkyne 5p ^[91]. Disappointingly, the reaction of silylated alkyne 5p under our validated conditions did not provide the expected product 6p , even under reflux conditions. This result was attributed to the reduced aurophilicity of alkyne 5p as a result of the deactivating effect of the silyl group. However, substrate 5q bearing an unsubstituted terminal alkyne underwent a 5-exo-dig cyclization exclusively to give furan 6q as the only product. The regioselectivity of this reaction was attributed to the greater electrophilicity of the remote sp-hybridized carbon of the alkyne.

The use of AuBr₃ as a catalyst allowed for the smooth and effective cycloisomerization of 2-alkynylcycloalk-2-enols to give the corresponding cycloalkyl-fused furans. A detailed study of this methodology as a synthetic strategy for the formation of a diverse range of furan derivatives has also been provided in terms of its scope and limitations towards ring-free substrates. We also observed the in situ cross-coupling/cycloisomerization of α-bromocyclooct-2-enols with terminal alkynes under Sonogashira conditions and showed that Pd(II) was the active catalytic species involved in this process. This methodology was also applied to a series of tandem processes, which provided access to a wide range of functionalized furan molecules. Given that most of these substrates are commercially available or synthetically accessible this new method could be used for the synthesis of furan-based libraries for detailed SAR studies in medicinal chemistry. Further studies towards identifying new applications for this process to generate furan-based chemical libraries of potential pharmacological interest are currently underway.

C. Praveen acknowledges the Department of Science and Technology for providing INSPIRE faculty award. C. Praveen also thanks Dr. Vijayamohanan K. Pillai and Dr. D. Jeyakumar of CSIR-CECRI for providing infrastructure facilities.