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Article

Assembly of Diverse 3-Methylenetetrahydrofurans via Palladium-Catalyzed Cascade Carboetherification of Buta-1,3-Dienes with Alkynols

by
Yin-Long Lai
1,2,*,
Yanan Niu
3,†,
Kaitong Zeng
3,†,
Huanfeng Jiang
3,
Huishi Guo
1,2,*,
Sheng-Ling Zhang
1,2 and
Jianxiao Li
3,4,*
1
College of Chemistry and Civil Engineering, Shaoguan University, Shaoguan 512005, China
2
Guangdong Provincial Engineering Technology Research Center for Eco-Environmental Protection and Solid Waste Utilization in Northern Guangdong, Shaoguan University, Shaoguan 512005, China
3
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
4
Guangdong Provincial Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region, Shaoguan University, Shaoguan 512005, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2025, 30(21), 4244; https://doi.org/10.3390/molecules30214244
Submission received: 13 October 2025 / Revised: 28 October 2025 / Accepted: 29 October 2025 / Published: 31 October 2025
(This article belongs to the Special Issue Feature Papers in Organic Chemistry—Third Edition)
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Abstract

Tetrahydrofuran scaffolds have found promising applications in both pharmaceutical chemistry and organic synthesis but remain underexplored owing to the challenges associated with their preparation. Herein, we have developed a robust synthetic strategy for the palladium-catalyzed cascade annulation reaction of buta-1,3-dienes with alkynols for the assembly of diverse 3-methylenetetrahydrofurans with excellent functional group compatibility and good regioselectivity. More importantly, this protocol features broad substrate scope, good functional group tolerance, and good step- and atom-economy. A diverse array of functional groups such as halogen atoms, aldehyde, nitro, ester, and several aromatic heterocycles were also nicely tolerated and provided the corresponding products in moderate to good yields. It is noteworthy that the practicability is further verified by gram-scale experiments and synthetic transformation to access organic functional molecules.

Graphical Abstract

1. Introduction

As an important branch of heterocyclic frameworks, oxygen-containing five-membered heterocyclic compounds such as tetrahydrofuran architectures have proven to be excellent scaffolds for the assembly of structurally diverse pharmaceutical and bioactive molecules [1,2,3]. As depicted in Figure 1, the (−)-trans-Kumausyne was isolated from the red alga Laurencia nipponica and further used as an antibiotic drug [4]. Moreover, trans-Oxylipid was reported as the inhibitor in parasitic nematodes in vitro [5]. In particular, the natural product (−)-Bisezakyne A, a halogenated C15-acetogenin, was isolated from the red algal genus Laurencia by Suzuki and co-workers in 1999 [6]. It is a remarkable fact that the integration of polysubstituted tetrahydrofuran moiety as the core structure into drug candidates may greatly enhance their biological activities [7]. As a result, the development of a practical and expeditious synthetic approach for the construction of polyfunctionalized tetrahydrofuran moieties using inexpensive and easily available raw materials is still highly desirable.
Given the importance of the five-membered heterocyclic building blocks, numerous synthetic approaches have been successfully exploited for the construction of these diverse structural skeletons in recent years. In this regard, Semmelhack and co-workers reported the first intramolecular alkoxypalladation/carbonylation of enol for constructing 5- or 6-membered oxygen-containing heterocyclic compounds (Scheme 1a) [8]. However, the regioselectivity of alkene was uncontrollable under the developed catalytic system. After that, transition-metal-catalyzed intramolecular cascade cyclization/functionalization reactions of 1,6-enynes emerged as a flourishing strategy for the synthesis of various high-added-value heterocyclic scaffolds (Scheme 1b) [9]. Among them, palladium-catalyzed protocols have been widely investigated in this field, owing to their good functional group tolerance and high regio- and stereoselectivity [10,11,12,13,14]. For example, Chegondi and colleagues developed an elegant palladium-catalyzed regioselective cascade cyclization of cyclohexadienones-containing 1,6-enynes to afford a variety of cis-fused bicyclic frameworks containing a tetrahydrofuran motif with excellent regio- and stereoselectivity [13]. Furthermore, other transition metal catalysts, such as Rh [15,16,17,18], Ru [19,20], Co [21,22,23,24], and others [25,26,27,28,29], have also been identified as the most effective catalysts for assembling more elaborated tetrahydrofuran scaffolds. For instance, Tian, Lin, and co-workers demonstrated a rhodium-catalyzed cross-addition of cyclohexadienone-tethered internal alkynes to an assembly of the cis-hydrobenzofuran frameworks, with good yields [15]. Then, RajanBabu and co-workers realized an extraordinary cobalt-catalyzed ligand-controlled regioselective tandem cycloisomerization-hydroarylation and cycloisomerization-hydroalkenylation of 1,6-enynes [24]. In 2014, we developed a palladium-catalyzed hydroxyl chelation-assisted carboetherification of alkynamides with olefins for the synthesis of oxygenated heterocycles (Scheme 1c) [30]. In 2017, we also developed a palladium-catalyzed cascade carboetherification of haloalkynes with enols for the straightforward preparation of four- to seven-membered functionalized oxetanes (Scheme 1d) [31]. To the best of our knowledge, there is no previous synthetic method for the synthesis of a polyfunctionalized tetrahydrofuran structural motif by palladium-catalyzed cascade cyclization reactions from readily available alkynol with alkenes. In continuation of our interests in palladium-catalyzed cross-coupling of alkynes [32,33,34,35] and of our previous studies on functionalized heteroaromatic motifs [36,37,38], we herein disclose an efficient and practical palladium-catalyzed cascade protocol for a tunable assembly of diversified tetrahydrofuran architectures (Scheme 1e).

2. Results and Discussion

Our investigation was initiated by using 4-phenylbut-3-yn-2-ol (1a) and buta-1,3-dien-1-ylbenzene (2a) as the model substrates to optimize this cascade cyclization approach. As outlined in Table 1, the desired product 3a was obtained in 86% GC yield (82% isolated yield) when this protocol was performed in the presence of 10 mol% of Pd(TFA)2, 4 equiv. of CuCl2, and 80 mol% of DIPEA in HOAc at room temperature for 24 h in open air (Table 1, entry 1). It is worth mentioning that the CuCl2 as the oxidant and chloride ion source was previously established for these trans-chloropalladation initiated cascade transformations of alkynes [39,40]. Various palladium catalysts were firstly screened, and Pd(TFA)2 proved to be optimal, producing the target product 3a in 86% GC yield, while the other palladium sources, such as PdCl2, Pd(OAc)2, Pd(Py)2Cl2, and Pd(MeCN)2Cl2, gave inferior results (Table 1, entries 1–5). Subsequently, several solvents, including DMSO, MeCN, DCE, acetone, and HOAc, were then examined, and the results suggested that HOAc as the solvent was the best choice in this transformation (Table 1, entries 6–9). Different bases were also evaluated, and we found that DIPEA was a suitable base in this cascade approach (Table 1, entries 10–13). In addition, the increase of the temperature from r.t. to 40 °C led to a diminishing yield and the ratio of Z/E (Table 1, entry 14). Control experiments indicated that both Pd(TFA)2 and CuCl2 played a vital role in this transformation (Table 1, entry 15).
With the optimal reaction conditions in hand, we next examined the substrate scope of this cascade carboetherification of alkynols, and several representative examples are summarized in Figure 2. Gratifyingly, both electron-donating (Me, tBu, OMe, OCF3) and electron-withdrawing (F, Cl, Br, CO2Me, CF3, CHO, NO2) substituents on the phenyl ring of alkynols were nicely amenable for these catalytic systems and generated the corresponding products 3a–3q with yields ranging from 50% to 82% with high regioselectivities. Additionally, alkynol substrates with halogen atoms such as Cl and Br at the ortho-, meta-, and para-position had little influence on the reaction, furnishing the desired products 3d, 3e, and 3l, 3m in similar yields. The configuration of 3c (CCDC 2448859) was determined by X-ray analysis (see Supplementary Materials). Notably, alkynol substrates with various sensitive functional groups, such as ester (3g), aldehyde (3h), trifluoromethyl (3j), and nitro (3n), were also well accommodated, offering the corresponding products in moderate to good yields. Delightfully, 2,4-, and 3,5-disubstituted alkynol substrates were perfectly compatible with our catalytic systems, giving the desired products 3p and 3q in 77% and 61% yields, respectively. Of particular interest is that the naphthyl and thienyl substituents were amenable to these reaction conditions, furnishing the corresponding products 3r and 3s in satisfactory yields. It is remarkable that alkyl alkynols also efficiently coupled with 2a and gave the target products 3t–3w in moderate to good yields. Of note, a great many structurally diverse alkynols, such as 3-phenylprop-2-yn-1-ol (1x), 4-phenylbut-3-yn-2-ol (1y), 1,3-diphenylprop-2-yn-1-ol (1aa), 1-(phenylethynyl)cyclopentan-1-ol (1ab), and 1-(phenylethynyl)cyclohexan-1-ol (1ac) can be applied as well in these catalytic systems, albeit in somewhat low yields.
Inspired by the good results we obtained, we then evaluated the substrate generality of a diverse array of alkenes under our developed conditions. As outlined in Figure 3, the alkenes with a wide variety of functional groups, such as methyl, tert-butyl, fluorine, chlorine, ester, and nitro, on the benzene ring worked well in our catalytic systems, giving the desired products 4a–4d in moderate to good yields (60–75%) and satisfactory Z/E ratio (96:4 to 90:10). Satisfactorily, the position of the substituent had little effect on the reaction outcomes, and the substrates with an ortho- or meta-substituent on the benzene ring gave similar outcomes of the desired products (4a–4c). Conjugated 1,3-dienes bearing a 1-naphthyl or 2-thienyl moiety were also amenable for these conditions and furnished the corresponding products 4j and 4k in 58% and 71% yields, respectively. The absolute configuration of 4j was unambiguously determined by X-ray crystallography (see Supplementary Materials). Moreover, substrate hexa-3,5-dien-1-ylbenzene could also be efficiently transformed into the desired product 4l in 59% yield. However, owing to the strong conjugative effect and coordination with the palladium catalyst, desired product 4n was not detected by GC-MS analysis. Unfortunately, the substrates of cyclopenta-1,3-diene, cyclohexa-1,3-diene, cycloocta-1,3-diene, and hex-1-ene were unsuccessful in our developed catalytic systems and failed to furnish the corresponding products 4o–4s.
To demonstrate the practicality of this cascade protocol, a gram-scale experiment and several synthetic transformations were carried out under our developed catalytic conditions. As shown in Scheme 2, when 6 mmol of 1a was utilized, 1.47 g of the desired product 3a was obtained in a 76% yield without erosion of the Z/E ratio (Scheme 2a). The carbon-carbon double bond offers a useful handle for further manipulation. Useful synthetic epoxides can be easily obtained through the epoxidation reaction of 3a, giving the target product 5a in a 75% yield [41]. In addition, in the presence of bromination reagents such as NBS and LiBr, the dibromination reaction was performed, and it delivered the corresponding product 5b in an 80% yield [42]. Finally, the Pd/C reduction reaction of 3a generated the corresponding 5c in a 72% yield [43]. In addition, alkynol derived from a menthol natural product consistently furnished the corresponding cyclization product 7a in a 65% yield (Scheme 2c).
On the basis of the obtained results and precedents from the literature, we proposed a plausible mechanism for this palladium-catalyzed cascade carboetherification of buta-1,3-dienes with alkynols for the efficient synthesis of diverse 3-methylenetetrahydrofurans. As depicted in Scheme 3, in the presence of excess chloride ions [44,45], trans-chloropalladation of the alkynols gives the vinyl palladium species int-I. Then, the buta-1,3-dienes undergo migratory insertion to the palladium species int-I, generating σ-alkyl-Pd species int-II [46]. Subsequently, six-membered palladacycle species int-III is formed in the presence of the basic conditions. After that, a reductive elimination of the palladacycle int-III delivers the desired product 3 and palladium(0) species. Finally, the oxidation of Pd(0) species to Pd(II) by Cu(II) and air completes this catalytic cycle.

3. Materials and Methods

3.1. Materials

All the reagents were obtained from commercial sources and used directly without further purification. Melting points were measured on an Electrothemal SGW-X4 microscopy digital melting point apparatus (Wagner & Münz, Munich, Germany) and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Bruker AVANCE III 400 MHz (Bruker, Billerica, MA, USA) using CDCl3 as a solvent. The chemical shifts are referenced to signals at 0 or 7.26 and 77.0 ppm and chloroform as the solvent, with TMS as the internal standard. Chemical shifts (δ) are reported in ppm, and coupling constants (J) are reported in Hertz (Hz). 19F NMR spectra were collected at 376 MHz on the same instrument and are referenced to internal C6H5F at δ −113.15. GC-MS data were obtained with a Thermo Scientific TRACE (Milan, Italy) 1300 & ISQ QD system equipped with a TG-5MS column. High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-600 spectrometer (Waters Corporation, Beijing, China). X-ray diffraction was measured on a ‘Bruker APEX-II CCD’ diffractometer (Bruker, Billerica, MA, USA) with Cu-Kα radiation. TLC analysis was performed on pre-coated, glass-backed silica gel plates (Qingdao Haiyang, Qingdao, China) and visualized with UV light. Flash column chromatography was performed on silica gel (200–300 mesh), with petroleum ether and ethyl acetate (Guanghua Corporation, Guangzhou, China) as eluents.

3.2. General Methods for the Preparation of 3-Methylenetetrahydrofuran Derivatives

A mixture of Pd(TFA)2 (10 mol %), CuCl2 (4 equiv.), DIPEA (80 mol%), and HOAc (2 mL) was added to a tube equipped with a stir bar. Then, propargyl alcohols (1, 0.2 mmol) and alkenes (2, 0.3 mmol) were added to the tube under air and stirred at room temperature for 24 h. After the reaction was finished, the reaction was quenched by saturated aqueous NH4Cl and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under a vacuum. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether/ethyl acetate) to afford the desired products.
(Z)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-((E)-styryl)tetrahydrofuran (3a): Alkynol 1a (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3a (82%, 53.2 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.47–7.43 (m, 2H), 7.42–7.38 (m, 4H), 7.37–7.31 (m, 3H), 7.30–7.26 (m, 1H), 6.66 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 7.0 Hz, 1H), 4.59–4.47 (m, 1H), 2.79–2.64 (m, 2H), 1.76 (s, 3H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.6, 140.0, 136.5, 132.4, 128.8, 128.5, 128.3, 128.3, 128.2, 127.8, 126.6, 121.3, 83.6, 42.1, 26.1, 24.0; HRMS (ESI, m/z): calcd for C21H21ClO, [M+H]+: 325.1184, found: 325.1179.
(Z)-3-(chloro(p-tolyl)methylene)-2,2-dimethyl-5-((E)-styryl)tetrahydrofuran (3b): Alkynol 1b (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3b (80%, 54.4 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.42–7.37 (m, 2H), 7.37–7.31 (m, 2H), 7.27 (td, J = 10.7, 8.7, 2.4 Hz, 4H), 7.15 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 15.9 Hz, 1H), 6.24 (dd, J = 15.9, 7.0 Hz, 1H), 4.57–4.49 (m, 1H), 2.71 (d, J = 9.3 Hz, 2H), 2.40 (s, 3H), 1.74 (s, 3H), 1.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.3, 139.9, 138.0, 136.5, 132.4, 129.0, 128.9, 128.8, 128.5, 128.2, 127.8, 126.6, 125.4, 121.4, 83.6, 76.4, 42.1, 26.1, 24.0, 21.4; HRMS (ESI, m/z): calcd for C22H23ClO, [M+H]+: 339.1340, found: 339.1345.
(Z)-3-((4-(tert-butyl)phenyl)chloromethylene)-2,2-dimethyl-5-((E)-styryl)tetrahydrofuran (3c): Alkynol 1c (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3c (76%, 57.5 mg) as a yellow solid, mp = 117.9–118.6 °C; 1H NMR (400 MHz, CDCl3) δ 7.45–7.37 (m, 5H), 6.65 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 7.0 Hz, 1H), 4.58–4.48 (m, 1H), 2.83–2.66 (m, 2H), 1.75 (s, 3H), 1.70 (s, 3H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 151.3, 144.1, 137.0, 136.5, 132.4, 128.9, 128.5, 128.0, 127.8, 126.6, 125.1, 121.4, 83.7, 76.4, 42.2, 34.7, 31.3, 26.2, 24.1; HRMS (ESI, m/z): calcd for C25H29ClO, [M+H]+: 381.1245, found: 381.1246.
(Z)-3-(chloro(4-chlorophenyl)methylene)-2,2-dimethyl-5-((E)-styryl)-tetrahydrofuran (3d): Alkynol 1d (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3d (66%, 47.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 6.2 Hz, 7H), 7.32–7.27 (m, 2H), 6.64 (d, J = 15.9 Hz, 1H), 6.22 (dd, J = 15.9, 7.0 Hz, 1H), 4.56–4.49 (m, 1H), 2.68 (d, J = 4.5 Hz, 2H), 1.72 (s, 3H), 1.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.4, 138.3, 136.4, 134.1, 132.6, 129.7, 128.6, 128.5, 127.9, 126.6, 120.1, 83.7, 76.4, 42.1, 26.0, 23.9; HRMS (ESI, m/z): calcd for C21H20Cl2O, [M+H]+: 359.0794, found: 359.0789.
(Z)-3-((4-bromophenyl)chloromethylene)-2,2-dimethyl-5-((E)-styryl)-tetrahydrofuran (3e): Alkynol 1e (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3e (68%, 55.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.54–7.49 (m, 2H), 7.41–7.37 (m, 2H), 7.36–7.26 (m, 5H), 6.64 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.0 Hz, 1H), 4.56–4.47 (m, 1H), 2.73–2.63 (m, 2H), 1.72 (s, 3H), 1.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.4, 138.8, 136.4, 132.5, 131.5, 130.0, 128.5, 128.5, 127.9, 126.6, 122.3, 120.2, 83.7, 76.4, 42.1, 26.0, 23.9; HRMS (ESI, m/z): calcd for C21H20BrClO, [M+H]+: 403.0296, found: 403.0293.
4-((Z)-chloro-2,2-dimethyl-5-((E)-styryl)dihydrofuran-3(2H)-ylidene)methyl)-phenyl acetaten (3f): Alkynol 1f (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3f (62%, 47.9 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.46–7.25 (m, 7H), 7.16–7.06 (m, 2H), 6.64 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.0 Hz, 1H), 4.57–4.47 (m, 1H), 2.79–2.62 (m, 2H), 2.33 (s, 3H), 1.72 (s, 3H), 1.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.3, 150.3, 145.0, 137.5, 136.4, 132.5, 129.6, 128.6, 128.5, 127.8, 126.6, 121.4, 120.5, 83.7, 76.4, 42.1, 26.1, 23.9, 21.2; HRMS (ESI, m/z): calcd for C23H23ClO3, [M+H]+: 383.1411, found: 383.1408.
methyl 4-((Z)-chloro(2,2-dimethyl-5-((E)-styryl)dihydrofuran-3(2H)-ylidene) methyl)benzoate (3g): Alkynol 1g (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3g (60%, 45.8 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 6.9 Hz, 2H), 7.32 (t, J = 7.7 Hz, 3H), 6.64 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.0 Hz, 1H), 4.57–4.49 (m, 1H), 3.95 (s, 3H), 2.71 (d, J = 7.7 Hz, 2H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 146.1, 144.2, 132.6, 129.8, 129.6, 128.5, 128.4, 127.9, 126.6, 120.2, 83.8, 76.4, 52.3, 42.1, 26.1, 23.9; HRMS (ESI, m/z): calcd for C23H23ClO3, [M+H]+: 383.1410, found: 383.1408.
4-((Z)-Chloro(2,2-dimethyl-5-((E)-styryl)dihydrofuran-3(2H)-ylidene)methyl) benzaldehyde (3h): Alkynol 1h (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3h (58%, 41.1 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 7.95–7.87 (m, 2H), 7.64–7.58 (m, 2H), 7.41–7.36 (m, 2H), 7.34–7.28 (m, 2H), 7.28–7.20 (m, 1H), 6.64 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.0 Hz, 1H), 4.57–4.50 (m, 1H), 2.72 (d, J = 7.6 Hz, 2H), 1.74 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 191.5, 146.7, 145.6, 136.3, 135.8, 132.7, 129.7, 129.1, 128.6, 128.3, 127.9, 126.6, 120.0, 83.9, 42.1, 26.1, 23.8; HRMS (ESI, m/z): calcd for C22H21ClO2, [M+H]+: 353.1306, found: 353.1303.
(Z)-3-(chloro(4-(trifluoromethoxy)phenyl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3i): Alkynol 1i (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3i (56%, 45.5 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 7.4 Hz, 2H), 7.29–7.22 (m, 3H), 6.65 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.1 Hz, 1H), 4.57–4.48 (m, 1H), 2.74–2.65 (m, 2H), 1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.7, 145.6, 138.5, 136.4, 132.6, 129.9, 128.5, 128.5, 127.9, 126.6, 120.8, 119.9, 83.7, 42.1, 26.0, 23.9; 19F NMR (376 MHz, CDCl3) δ −57.80; HRMS (ESI, m/z): calcd for C22H20ClF3O2, [M+H]+: 409.1000, found: 409.1002.
(Z)-3-(chloro(4-(trifluoromethyl)phenyl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3j): Alkynol 1j (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3j (55%, 42.8 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.7 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.29–7.25 (m, 1H), 6.64 (d, J = 15.9 Hz, 1H), 6.22 (dd, J = 15.9, 7.0 Hz, 1H), 4.58–4.49 (m, 1H), 2.70 (d, J = 7.6 Hz, 2H), 1.74 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.3, 143.3, 136.3, 132.7, 128.8, 128.5, 128.4, 127.9, 126.6, 125.3 (dd, J = 8.3, 4.0 Hz), 83.8, 42.1, 26.0, 23.8; 19F NMR (376 MHz, CDCl3) δ −62.75; HRMS (ESI, m/z): calcd for C22H20ClF3O, [M+H]+: 393.1053, found: 393.1054.
(Z)-3-(chloro(3-methoxyphenyl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3k): Alkynol 1k (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3k (69%, 48.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.39 (dt, J = 6.6, 1.4 Hz, 2H), 7.36–7.25 (m, 4H), 7.06–6.93 (m, 2H), 6.88 (ddd, J = 8.3, 2.7, 1.1 Hz, 1H), 6.64 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.0 Hz, 1H), 4.57–4.48 (m, 1H), 3.85 (s, 3H), 2.80–2.62 (m, 2H), 1.73 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 144.7, 141.2, 136.5, 132.4, 129.3, 128.7, 128.5, 127.8, 126.6, 121.1, 120.7, 114.0, 113.9, 83.6, 76.4, 55.3, 42.1, 26.1, 23.9; HRMS (ESI, m/z): calcd for C22H23ClO2, [M+H]+: 355.1291, found: 355.1284.
(Z)-3-((3-bromophenyl)chloromethylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3l): Alkynol 1l (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3l (65%, 52.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 1.9 Hz, 1H), 7.47 (dt, J = 8.1, 1.5 Hz, 1H), 7.41–7.30 (m, 5H), 7.26 (t, J = 7.7 Hz, 2H), 6.65 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.1 Hz, 1H), 4.58–4.48 (m, 1H), 2.76–2.62 (m, 2H), 1.72 (s, 3H), 1.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.9, 141.8, 136.4, 132.6, 131.4, 131.3, 129.9, 128.6, 128.5, 127.9, 127.0, 126.6, 122.3, 119.7, 83.7, 77.4, 77.1, 76.7, 76.4, 42.1, 26.0, 23.9; HRMS (ESI, m/z): calcd for C21H20BrClO, [M+H]+: 403.0297, found: 403.0293.
(Z)-3-(chloro(3-chlorophenyl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3m): Alkynol 1m (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3m (60%, 43.2 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.45–7.37 (m, 3H), 7.36–7.25 (m, 6H), 6.66 (d, J = 15.9 Hz, 1H), 6.24 (dd, J = 15.9, 7.1 Hz, 1H), 4.57–4.48 (m, 1H), 2.77–2.65 (m, 2H), 1.74 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.8, 141.5, 136.4, 134.2, 132.6, 129.6, 128.6, 128.5, 128.4, 127.8, 126.6, 126.6, 120.2, 83.7, 76.4, 42.1, 26.1, 23.9; HRMS (ESI, m/z): calcd for C21H20Cl2O, [M+H]+: 359.0794, found: 359.0789.
(Z)-3-(chloro(3-nitrophenyl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3n): Alkynol 1n (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3n (53%, 39.2 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.31 (t, J = 2.0 Hz, 1H), 8.22–8.14 (m, 1H), 7.80–7.74 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.40–7.36 (m, 2H), 7.35–7.26 (m, 3H), 6.65 (d, J = 15.9 Hz, 1H), 6.23 (dd, J = 15.9, 7.1 Hz, 1H), 4.56–4.46 (m, 1H), 2.78–2.67 (m, 2H), 1.74 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.1, 147.3, 141.4, 136.3, 134.4, 132.9, 129.4, 128.6, 128.2, 127.9, 126.6, 123.5, 123.1, 118.7, 83.8, 76.4, 42.0, 25.9, 23.8; HRMS (ESI, m/z): calcd for C21H20ClNO3, [M+H]+: 370.1036, found: 370.1029.
(Z)-3-(chloro(2-chlorophenyl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3o): Alkynol 1o (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3o (50%, 35.6 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.48–7.43 (m, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.33–7.28 (m, 5H), 7.25 (d, J = 7.0 Hz, 1H), 6.62 (dd, J = 15.9, 5.6 Hz, 1H), 6.26–6.17 (m, 1H), 4.64–4.52 (m, 1H), 2.54–2.33 (m, 2H), 1.75 (s, 3H), 1.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.5, 136.5, 132.4, 130.0, 128.7, 128.5, 127.8, 127.3, 126.5; HRMS (ESI, m/z): calcd for C21H20Cl2O, [M+H]+: 359.0792, found: 359.0789.
(Z)-3-(chloro(3,5-dimethylphenyl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3p): Alkynol 1p (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3p (77%, 54.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.3 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.29–7.24 (m, 1H), 7.05 (s, 2H), 6.98 (s, 1H), 6.66 (d, J = 15.9 Hz, 1H), 6.26 (dd, J = 15.9, 7.0 Hz, 1H), 4.59–4.49 (m, 1H), 2.80–2.66 (m, 2H), 2.37 (s, 6H), 1.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.1, 139.9, 137.9, 136.5, 132.3, 129.9, 128.9, 128.5, 127.8, 126.6, 126.0, 121.6, 83.6, 76.4, 42.1, 26.2, 24.1, 21.3; HRMS (ESI, m/z): calcd for C23H25ClO, [M+H]+: 353.1666, found: 353.1667.
(Z)-3-((4-bromo-2-fluorophenyl)chloromethylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3q): Alkynol 1q (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3q (61%, 50.6 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.39–7.36 (m, 2H), 7.35–7.31 (m, 3H), 7.31–7.24 (m, 3H), 6.64 (d, J = 15.9 Hz, 1H), 6.26–6.13 (m, 1H), 4.60–4.52 (m, 1H), 2.59–2.48 (m, 2H), 1.72 (s, 3H), 1.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7 (d, J = 254.2 Hz), 148.6, 136.4, 132.6, 131.7 (d, J = 3.3 Hz), 128.5 (d, J = 3.5 Hz), 127.9, 127.8 (d, J = 3.7 Hz), 126.6, 126.5, 123.0 (d, J = 9.3 Hz), 119.8 (d, J = 25.1 Hz), 113.5, 83.5, 76.3, 41.3, 41.2, 26.1, 23.8; 19F NMR (376 MHz, CDCl3) δ -110.71; HRMS (ESI, m/z): calcd for C21H19BrClFO, [M+H]+: 421.0363, found: 421.0365.
(Z)-3-(chloro(naphthalen-1-yl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3r): Alkynol 1r (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3r (40%, 54.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.0 (d, J = 8.2 Hz, 1H), 7.9 (d, J = 8.2 Hz, 4H), 7.6–7.4 (m, 3H), 7.3–7.2 (m, 4H), 6.6 (d, J = 16.0 Hz, 1H), 6.25–6.12 (m, 1H), 4.61–4.53 (m, 1H), 2.60–2.49 (m, 2H), 1.90 (s, 3H), 1.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.9, 137.4, 136.4, 134.0, 132.3, 130.0, 129.0, 128.7, 128.6, 128.5, 127.8, 127.0, 126.8, 126.4, 126.3, 125.6, 124.6, 119.2, 83.4, 76.4, 41.5, 41.1, 26.4, 24.0; HRMS (ESI, m/z): calcd for C25H23ClO, [M+H]+: 375.1340, found: 375.1335.
(Z)-3-(chloro(thiophen-2-yl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3s): Alkynol 1s (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3s (77%, 51.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.46–7.41 (m, 2H), 7.41–7.31 (m, 3H), 7.31–7.21 (m, 2H), 7.06 (dd, J = 5.1, 3.8 Hz, 1H), 6.72 (d, J = 15.9 Hz, 1H), 6.31 (dd, J = 15.9, 7.1 Hz, 1H), 4.67–4.59 (m, 1H), 3.13 (dd, J = 16.2, 5.4 Hz, 1H), 2.82 (dd, J = 16.2, 5.4 Hz, 1H), 1.74 (s, 3H), 1.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.6, 142.2, 136.5, 132.6, 128.7, 128.6, 127.9, 127.4, 126.76, 126.6, 126.2, 116.1, 84.5, 76.4, 42.7, 26.2, 23.9; HRMS (ESI, m/z): calcd for C19H19ClOS, [M+H]+: 331.0747, found: 331.0743.
(Z)-3-(chloro(cyclopropyl)methylene)-2,2-dimethyl-5-((E)-styryl) tetrahydrofuran (3t): Alkynol 1t (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3t (59%, 34.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 6.70 (d, J = 15.9 Hz, 1H), 6.29 (dd, J = 15.9, 7.0 Hz, 1H), 4.64–4.56 (m, 1H), 3.01 (dd, J = 15.6, 5.4 Hz, 1H), 2.65 (dd, J = 15.5, 5.4 Hz, 1H), 1.75 -1.69 (m, 1H), 1.61 (s, 3H), 1.54 (s, 3H), 0.92–0.81 (m, 2H), 0.78–0.70 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 141.1, 136.6, 132.3, 129.2, 128.5, 127.8, 126.6, 124.4, 83.5, 76.19, 40.2, 26.4, 24.0, 16.6, 5.6, 5.4; HRMS (ESI, m/z): calcd for C18H21ClO, [M+H]+: 289.1355, found: 289.1354.
(Z)-3-(1-chlorobutylidene)-2,2-dimethyl-5-((E)-styryl)tetrahydrofuran (3u): Alkynol 1u (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3u (75%, 43.1 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.46–7.39 (m, 2H), 7.37–7.31 (m, 2H), 7.29–7.24 (m, 1H), 6.69 (d, J = 15.9 Hz, 1H), 6.26 (dd, J = 15.9, 7.1 Hz, 1H), 4.61–4.51 (m, 1H), 2.86 (dd, J = 15.4, 5.5 Hz, 1H), 2.55 (dd, J = 15.5, 10.2 Hz, 1H), 2.34 (t, J = 7.2 Hz, 2H), 1.74–1.64 (m, 2H), 1.63 (s, 3H), 1.52 (s, 3H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 141.6, 136.5, 132.3, 129.1, 128.5, 127.8, 126.6, 124.1, 83.2, 76.0, 40.4, 39.9, 26.4, 23.9, 20.4, 13.0; HRMS (ESI, m/z): calcd for C18H23ClO, [M+H]+: 291.1511, found: 291.1510.
(Z)-3-(1-chlorohexylidene)-2,2-dimethyl-5-((E)-styryl)tetrahydrofuran (3v): Alkynol 1v (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3v (80%, 50.9 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.43–7.39 (m, 2H), 7.36–7.30 (m, 2H), 7.29–7.25 (m, 1H), 6.67 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 7.1 Hz, 1H), 4.62–4.52 (m, 1H), 3.02 (dd, J = 16.6, 5.7 Hz, 1H), 2.74–2.57 (m, 1H), 2.44–2.31 (m, 2H), 1.70–1.57 (m, 3H), 1.53 (s, 3H), 1.45 (s, 3H), 1.42–1.28 (m, 5H), 0.95 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.6, 136.6, 132.2, 129.2, 128.5, 127.7, 127.4, 126.6, 81.8, 75.7, 42.0, 35.3, 31.3, 28.2, 27.9, 26.2, 22.5, 14.0, 14.0; HRMS (ESI, m/z): calcd for C20H27ClO, [M+H]+: 319.1826, found: 319.1823.
(Z)-3-(1-chlorononylidene)-2,2-dimethyl-5-((E)-styryl)tetrahydrofuran (3w): Alkynol 1w (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3w (77%, 55.0 mg) as a yellow solid, mp = 69.4–70.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.1 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.29–7.25 (m, 1H), 6.67 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 7.1 Hz, 1H), 4.63–4.53 (m, 1H), 3.02 (dd, J = 16.6, 5.6 Hz, 1H), 2.69–2.57 (m, 1H), 2.46–2.31 (m, 2H), 1.65–1.58 (m, 2H), 1.45 (s, 3H), 1.39–1.29 (m, 10H), 0.92 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.6, 136.6, 132.2, 129.2, 128.5, 127.7, 127.4, 126.6, 81.8, 75.7, 42.0, 35.3, 31.9, 29.5, 29.2, 29.2, 28.3, 28.2, 26.2, 22.7, 14.1; HRMS (ESI, m/z): calcd for C23H33ClO, [M+H]+: 361.2294, found: 361.2293.
(Z)-4-(chloro(phenyl)methylene)-2-((E)-styryl)tetrahydrofuran (3x): Alkynol 1x (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3x (57%, 34.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.55–7.48 (m, 2H), 7.41 (dd, J = 7.9, 2.8 Hz, 4H), 7.34 (t, J = 7.5 Hz, 3H), 7.30–7.26 (m, 1H), 6.66 (d, J = 15.9 Hz, 1H), 6.27 (dd, J = 15.9, 6.7 Hz, 1H), 4.84–4.74 (m, 1H), 4.70–4.54 (m, 2H), 3.00–2.85 (m, 1H), 2.76–2.62 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 138.1, 137.9, 136.4, 132.2, 128.6, 128.4, 128.3, 128.2, 127.9, 127.9, 126.6, 121.9, 81.4, 72.1, 39.5; HRMS (ESI, m/z): calcd for C19H17ClO, [M+H]+: 297.1043, found: 297.1041.
(Z)-3-(chloro(phenyl)methylene)-2-methyl-5-((E)-styryl)tetrahydrofuran (3y): Alkynol 1y (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3y (53%, 33.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.3 Hz, 4H), 7.34 (dd, J = 8.8, 6.1 Hz, 5H), 7.28 (d, J = 5.5 Hz, 1H), 6.71 (d, J = 15.9 Hz, 1H), 6.32 (dd, J = 15.9, 6.1 Hz, 1H), 4.59–4.52 (m, 1H), 4.50–4.44 (m, 1H), 2.77–2.67 (m, 1H), 2.57–2.49 (m, 1H), 1.59 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 139.4, 136.5, 132.3, 131.5, 129.8, 128.6, 128.5, 128.3, 128.1, 127.8, 127.6, 126.6, 38.8, 20.3; HRMS (ESI, m/z): calcd for C20H19ClO, [M+H]+: 311.1199, found: 311.1197.
(Z)-3-(chloro(phenyl)methylene)-2-phenyl-5-((E)-styryl)tetrahydrofuran (3aa): Alkynol 1aa (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3aa (47%, 35.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65–7.53 (m, 3H), 7.53–7.43 (m, 8H), 7.42–7.31 (m, 4H), 7.30 (dd, J = 2.9, 1.5 Hz, 1H), 6.74 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 6.2 Hz, 1H), 5.50 (s, 1H), 4.56–4.49 (m, 1H), 2.99–2.91 (m, 1H), 2.76–2.73 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 139.4, 139.1, 139.0, 138.2, 136.5, 134.3, 133.8, 131.7, 131.5, 129.3, 128.8, 128.7, 128.6, 128.5, 128.4, 128.4, 128.2, 128.1, 128.1, 127.9, 127.9, 127.8, 126.6, 126.5, 125.8, 81.5, 78.7, 68.1, 38.8, 38.2; HRMS (ESI, m/z): calcd for C25H21ClO, [M+H]+: 373.1356, found: 373.1354.
(Z)-4-(chloro(phenyl)methylene)-2-((E)-styryl)-1-oxaspiro[4.4]nonane (3ab): Alkynol 1ab (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3ab (55%, 39.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.48–7.42 (m, 2H), 7.41–7.36 (m, 4H), 7.35–7.29 (m, 3H), 7.29–7.24 (m, 1H), 6.63 (d, J = 15.9 Hz, 1H), 6.26 (dd, J = 15.9, 7.1 Hz, 1H), 4.43–4.35 (m, 1H), 2.72–2.68 (m, 2H), 2.44–2.34 (m, 1H), 2.06–1.80 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 143.7, 140.0, 136.5, 132.4, 128.7, 128.5, 128.3, 128.2, 128.2, 127.8, 126.6, 121.1, 93.9, 76.9, 42.4, 37.6, 36.5, 25.9, 25.5; HRMS (ESI, m/z): calcd for C23H23ClO, [M+H]+: 351.1336, found: 351.1335.
(Z)-4-(chloro(phenyl)methylene)-2-((E)-styryl)-1-oxaspiro[4.5]decane (3ac): Alkynol 1ac (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3ac (50%, 36.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44–7.35 (m, 6H), 7.34–7.28 (m, 3H), 7.25 (d, J = 7.2 Hz, 1H), 6.61 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 6.8 Hz, 1H), 4.50–4.39 (m, 1H), 2.71–2.59 (m, 2H), 2.57–2.47 (m, 1H), 2.39–2.29 (m, 1H), 1.82–1.62 (m, 7H), 1.36–1.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 144.5, 140.5, 136.6, 131.8, 129.3, 128.5, 128.4, 128.3, 128.1, 127.7, 126.5, 121.1, 85.1, 76.1, 42.3, 33.5, 29.8, 25.2, 22.3, 22.1; HRMS (ESI, m/z): calcd for C24H25ClO, [M+H]+: 365.1492, found: 365.1494.
(Z)-3-(chloro(naphthalen-1-yl)methylene)-2-methyl-5-((E)-styryl)tetrahydrofuran (3ae): Alkynol 1ae (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3ae (45%, 34.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 4H), 7.53–7.42 (m, 5H), 7.39–7.33 (m, 2H), 7.32–7.27 (m, 1H), 6.65 (d, J = 15.9 Hz, 1H), 6.28 (dd, J = 15.9, 6.8 Hz, 1H), 4.53–4.42 (m, 1H), 2.82–2.57 (m, 2H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.7, 140.4, 138.3, 138.1, 136.6, 131.9, 131.6, 131.5, 130.9, 130.0, 129.6, 128.8, 128.6, 128.6, 128.5, 128.5, 127.9, 127.4, 127.1, 127.0, 127.0, 126.6, 126.6, 74.3, 72.7, 68.6, 38.7, 38.2, 20.3, 18.4; HRMS (ESI, m/z): calcd for C25H23ClO, [M+H]+: 375.1319, found: 375.1324.
(Z)-4-(chloro(4-chlorophenyl)methylene)-2-((E)-styryl)-1-oxaspiro[4.4]nonane (3af): Alkynol 1af (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3af (44%, 34.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.39–7.35 (m, 5H), 7.34–7.30 (m, 2H), 7.29–7.27 (m, 1H), 6.63 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 7.0 Hz, 1H), 4.46–4.34 (m, 1H), 2.72–2.66 (m, 2H), 2.64–2.59 (m, 1H), 2.41–2.30 (m, 1H), 2.00–1.83 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 144.5, 138.4, 136.4, 134.0, 132.5, 129.7, 128.5, 128.5, 127.8, 126.6, 119.9, 93.9, 76.8, 42.4, 37.6, 36.4, 25.9, 25.5; HRMS (ESI, m/z): calcd for C23H22Cl2O, [M+H]+: 385.0945, found: 385.0944.
(Z)-4-(chloro(4-chlorophenyl)methylene)-2-((E)-styryl)-1-oxaspiro[4.5]decane (3ag): Alkynol 1ag (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3ag (48%, 38.4 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.41–7.38 (m, 2H), 7.36–7.33 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.28–7.25 (m, 1H), 6.62 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 6.9 Hz, 1H), 4.49–4.41 (m, 1H), 2.68–2.58 (m, 2H), 2.54–2.45 (m, 1H), 2.36–2.26 (m, 1H), 1.81- 1.65 (m, 7H), 1.36–1.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 145.3, 138.8, 136.5, 133.9, 131.9, 129.8, 129.1, 128.5, 127.8, 126.6, 119.9, 85.2, 76.1, 42.3, 33.4, 29.7, 25.2, 22.3, 22.1; HRMS (ESI, m/z): calcd for C24H25ClO, [M+H]+: 399.1106, found: 399.1102.
(Z)-4-((4-bromophenyl)chloromethylene)-2-((E)-styryl)-1-oxaspiro[4.5]decane (3ah): Alkynol 1ah (0.20 mmol) with buta-1,3-dien-1-ylbenzene 2a (0.30 mmol, 1.5 equiv.) gave compound 3ah (45%, 40.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.55–7.47 (m, 2H), 7.41–7.37 (m, 2H), 7.34–7.27 (m, 4H), 6.62 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 6.8 Hz, 1H), 4.49–2.41 (m, 1H), 2.69–2.55 (m, 2H), 2.53–2.43 (m, 1H), 2.36–2.26 (m, 1H), 1.83–1.63 (m, 7H), 1.36–1.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 145.3, 139.3, 136.5, 131.9, 131.5, 130.1, 129.1, 128.5, 127.8, 126.6, 122.2, 119.9, 85.2, 76.1, 42.3, 33.4, 29.7, 25.2, 22.3, 22.1; HRMS (ESI, m/z): calcd for C24H24BrClO, [M+H]+: 443.0607, found: 443.0606.
(Z)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-((E)-4-methylstyryl) tetrahydrofuran (4a): 1-(Buta-1,3-dien-1-yl)-4-methylbenzene 2b (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4a (75%, 51.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.46–7.33 (m, 5H), 7.29 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 15.9 Hz, 1H), 6.19 (dd, J = 15.9, 7.1 Hz, 1H), 4.55–4.48 (m, 1H), 2.71 (dd, J = 7.8, 3.2 Hz, 2H), 2.36 (s, 3H), 1.74 (s, 3H), 1.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.7, 139.9, 137.6, 133.7, 132.4, 129.2, 128.3, 128.3, 128.2, 127.7, 126.5, 121.2, 83.6, 76.5, 42.2, 26.1, 24.0, 21.2; HRMS (ESI, m/z): calcd for C22H23ClO, [M+H]+: 339.0754, found: 339.0755.
(Z)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-((E)-3-methylstyryl) tetrahydrofuran (4b): 1-(Buta-1,3-dien-1-yl)-3-methylbenzene 2c (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4b (72%, 49.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44–7.29 (m, 5H), 7.24–7.15 (m, 3H), 7.07 (dd, J = 6.9, 2.3 Hz, 1H), 6.60 (d, J = 15.9 Hz, 1H), 6.22 (dd, J = 15.9, 7.1 Hz, 1H), 4.59–4.45 (m, 1H), 2.81–2.66 (m, 2H), 2.35 (s, 3H), 1.73 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.6, 139.9, 138.0, 136.4, 132.5, 128.6, 128.6, 128.4, 128.3, 128.3, 128.2, 127.3, 123.7, 121.3, 83.6, 76.4, 42.1, 26.1, 24.0, 21.4; HRMS (ESI, m/z): calcd for C22H23ClO, [M+H]+: 339.1339, found: 339.1335.
(Z)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-((E)-2-methylstyryl) tetrahydrofuran (4c): 1-(Buta-1,3-dien-1-yl)-2-methylbenzene 2d (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4c (68%, 45.3 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49–7.32 (m, 6H), 7.22–7.15 (m, 3H), 6.87 (d, J = 15.7 Hz, 1H), 6.14 (dd, J = 15.7, 7.3 Hz, 1H), 4.60–4.53 (m, 1H), 2.79–2.68 (m, 2H), 2.36 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.7, 140.0, 135.5, 135.5, 130.4, 130.3, 130.1, 128.4, 128.3, 128.3, 127.7, 126.1, 125.8, 121.3, 83.7, 76.8, 42.2, 26.2, 24.1, 19.8; HRMS (ESI, m/z): calcd for C22H23ClO, [M+H]+: 339.1337, found: 339.1335.
(Z)-5-((E)-4-(tert-Butyl)styryl)-3-(chloro(phenyl)methylene)-2,2-dimethyltetrahydro-furan (4d): 1-(Buta-1,3-dien-1-yl)-4-(tert-butyl)benzene 2e (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4d (73%, 55.3 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 8.5, 2.1 Hz, 4H), 7.35 (dd, J = 8.4, 6.6 Hz, 2H), 7.29 (dd, J = 7.8, 5.9 Hz, 3H), 6.71 (d, J = 16.0 Hz, 1H), 6.33 (dd, J = 16.0, 6.0 Hz, 1H), 4.66–4.59 (m, 1H), 2.71 (dd, J = 16.8, 10.6 Hz, 1H), 2.51 (dd, J = 16.8, 3.2 Hz, 1H), 1.62 (s, 6H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 150.3, 136.8, 136.7, 133.0, 131.3, 131.2, 129.1, 128.6, 127.8, 127.8, 126.6, 125.1, 77.0, 69.1, 39.2, 34.6, 31.4, 28.6, 24.3; HRMS (ESI, m/z): calcd for C25H29ClO, [M+H]+: 381.1976, found: 381.1980.
(Z)-3-(chloro(phenyl)methylene)-5-((E)-3,5-difluorostyryl)-2,2-dimethyltetrahydro-furan (4e): 1-(Buta-1,3-dien-1-yl)-3,5-difluorobenzene 2f (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4e (60%, 43.0 mg) as a yellow oil. Yield: 60% (43 mg) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.44–7.30 (m, 6H), 6.88–6.76 (m, 2H), 6.72 (d, J = 16.1 Hz, 1H), 6.25 (dd, J = 16.1, 7.0 Hz, 1H), 4.57–4.47 (m, 1H), 2.78–2.65 (m, 2H), 1.73 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.6 (d, J = 12.1 Hz), 161.3 (dd, J = 45.5, 12.0 Hz), 159.0 (d, J = 12.0 Hz), 144.4, 139.9, 131.0 (dd, J = 4.8, 2.2 Hz), 128.4 (dd, J = 5.8, 3.7 Hz), 123.9, 121.4, 120.6 (dd, J = 12.0, 3.9 Hz), 111.5 (dd, J = 21.4, 3.7 Hz), 104.0 (d, J = 25.8 Hz), 83.8, 42.0, 26.1, 24.0; 19F NMR (376 MHz, CDCl3) δ -110.56, -110.58, -113.59, -113.61; HRMS (ESI, m/z): calcd for C21H19ClF2O, [M+H]+: 361.0997, found: 361.0990.
(Z)-3-(chloro(phenyl)methylene)-5-((E)-4-chlorostyryl)-2,2-dimethyltetrahydro-furan (4f): 1-(Buta-1,3-dien-1-yl)-4-chlorobenzene 2g (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4f (66%, 47.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.45–7.36 (m, 4H), 7.35–7.26 (m, 5H), 6.60 (d, J = 15.9 Hz, 1H), 6.21 (dd, J = 15.9, 7.0 Hz, 1H), 4.56–4.44 (m, 1H), 2.80–2.62 (m, 2H), 1.74 (s, 3H), 1.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 139.9, 134.9, 133.5, 131.1, 129.4, 128.7, 128.3, 127.7, 121.4, 83.7, 76.2, 42.0, 26.1, 24.0; HRMS (ESI, m/z): calcd for C21H20Cl2O, [M+H]+: 359.0795, found: 359.0789.
(Z)-3-(chloro(phenyl)methylene)-5-((E)-3-chlorostyryl)-2,2-dimethyltetrahydrofuran (4g): 1-(Buta-1,3-dien-1-yl)-3-chlorobenzene 2h (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4g (68%, 49.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44–7.33 (m, 6H), 7.24 (d, J = 3.6 Hz, 3H), 6.58 (d, J = 15.9 Hz, 1H), 6.25 (dd, J = 15.9, 6.8 Hz, 1H), 4.56–4.47 (m, 1H), 2.76–2.63 (m, 2H), 1.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.3, 139.9, 138.4, 134.5, 130.9, 130.4, 129.8, 128.3, 127.8, 126.5, 124.7, 121.4, 83.8, 76.1, 42.0, 26.1, 24.0; HRMS (ESI, m/z): calcd for C21H20Cl2O, [M+H]+: 359.0797, found: 359.0789.
Methyl 4-((E)-2-((Z)-4-(chloro(phenyl)methylene)-5,5-dimethyltetrahydrofuran-2-yl)vinyl)benzoate (4h): Methyl (E)-4-(buta-1,3-dien-1-yl)benzoate 2i (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4h (62%, 47.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.2 Hz, 2H), 7.46–7.31 (m, 7H), 6.67 (d, J = 15.9 Hz, 1H), 6.35 (dd, J = 15.9, 6.8 Hz, 1H), 4.58–4.50 (m 1H), 3.92 (s, 3H), 2.78–2.64 (m, 2H), 1.73 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 144.3, 140.9, 139.9, 131.5, 131.2, 129.9, 129.2, 128.3, 126.4, 121.5, 83.8, 52.1, 42.0, 26.1, 24.0; HRMS (ESI, m/z): calcd for C23H23ClO3, [M+H]+: 383.1410, found: 383.1408.
(Z)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-((E)-4-nitrostyryl)tetrahydrofuran (4i): 1-(Buta-1,3-dien-1-yl)-4-nitrobenzene 2j (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4i (60%, 46.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.24–8.11 (m, 2H), 7.53–7.46 (m, 2H), 7.44–7.31 (m, 5H), 6.71 (d, J = 15.9 Hz, 1H), 6.43 (dd, J = 15.9, 6.5 Hz, 1H), 4.62–4.50 (m, 1H), 2.84–2.64 (m, 2H), 1.74 (s, 3H), 1.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.1, 143.9, 142.9, 139.8, 133.8, 129.7, 128.4, 128.3, 128.3, 126.7, 123.9, 121.7, 84.4, 75.8, 41.9, 26.1, 24.0; HRMS (ESI, m/z): calcd for C21H20ClNO3, [M+H]+: 370.1206, found: 370.1204.
(Z)-3-(Chloro(phenyl)methylene)-2,2-dimethyl-5-((E)-2-(naphthalen-1-yl)vinyl)-tetrahydrofuran (4j): 1-(Buta-1,3-dien-1-yl)naphthalene 2k (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4j (58%, 43.0 mg) as a yellow solid, mp = 114.8–115.2 °C. 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 9.0, 6.8 Hz, 3H), 7.74 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 8.6, 1.7 Hz, 1H), 7.49–7.33 (m, 7H), 6.80 (d, J = 15.9 Hz, 1H), 6.37 (dd, J = 15.9, 7.0 Hz, 1H), 4.62–4.54 (m, 1H), 2.81–2.71 (m, 2H), 1.71 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 144.6, 139.9, 133.9, 133.5, 133.1, 132.5, 129.1, 128.3, 128.3, 128.3, 128.2, 128.0, 127.7, 126.7, 126.3, 125.9, 123.6, 121.3, 83.7, 76.6, 42.2, 26.1, 24.0; HRMS (ESI, m/z): calcd for C25H23ClO, [M+H]+: 375.1338, found: 375.1335.
(Z)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-((E)-2-(thiophen-2-yl)vinyl)-tetrahydrofuran (4k): 2-(Buta-1,3-dien-1-yl)thiophene 2l (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4k (71%, 48.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44–7.43 (m, 2H), 7.42–7.32 (m, 3H), 7.30–7.21 (m, 2H), 7.04 (dd, J = 5.1, 3.8 Hz, 1H), 6.70 (d, J = 15.9 Hz, 1H), 6.30 (dd, J = 15.9, 7.1 Hz, 1H), 4.67–4.59 (m, 1H), 3.14 (dd, J = 16.2, 5.3 Hz, 1H), 2.83 (dd, J = 16.2, 10.1 Hz, 1H), 1.72 (s, 3H), 1.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.6, 142.2, 136.5, 132.6, 128.7, 128.6, 127.9, 127.4, 126.8, 126.6, 126.2, 116.1, 84.5, 42.7, 26.2, 24.0; HRMS (ESI, m/z): calcd for C19H19ClOS, [M+H]+: 331.0821, found: 331.0819.
(Z)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-((E)-4-phenylbut-1-en-1-yl)tetrahydrofuran (4l): Hexa-3,5-dien-1-ylbenzene 2m (0.30 mmol, 1.5 equiv.) with alkynol 2-methyl-4-phenylbut-3-yn-2-ol 1a (0.20 mmol) gave compound 4l (59%, 42.0 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44–7.28 (m, 7H), 7.22–7.15 (m, 3H), 5.85–5.75 (m, 1H), 5.58–5.50 (m, 1H), 4.34–4.26 (m, 1H), 2.74–2.66 (m, 2H), 2.64–2.54 (m, 2H), 2.42–2.32 (m, 2H), 1.69 (s, 3H), 1.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.9, 141.7, 140.0, 133.7, 129.9, 128.4, 128.3, 128.2, 128.2, 125.9, 121.0, 83.4, 76.4, 42.0, 35.4, 34.2, 26.1, 23.9; HRMS (ESI, m/z): calcd for C23H25ClO, [M+H]+: 353.1403, found: 353.1402.

3.3. General Procedure for the Preparation of 5a

A 25 mL round-bottomed flask was charged with 3a (0.20 mmol) and 3-chloroperbenzoic acid (182.6 mg, 0.6 mmol, 3.0 equiv.). Then, the mixture was dissolved in DCM (5.0 mL) and stirred at r.t. for 8 h. The solvent was removed by rotary evaporation, and the residue was purified by flash column chromatography (PE/EA = 20:1) to give the product 5a in a 75% yield.
(E)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-(3-phenyloxiran-2-yl)tetrahydrofuran (5a): Yield: 75% (49 mg) as a white solid, mp = 120.8–121.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.45–7.32 (m, 9H), 7.29 (d, J = 1.9 Hz, 1H), 4.08–4.00 (m, 1H), 3.76 (d, J = 2.0 Hz, 1H), 3.19 (dd, J = 4.4, 2.0 Hz, 1H), 2.79–2.66 (m, 2H), 1.72 (s, 3H), 1.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.4, 139.9, 136.7, 128.5, 128.4, 128.3, 128.3, 125.8, 121.7, 84.3, 62.9, 56.7, 37.3, 26.0, 24.1; HRMS (ESI, m/z): calcd for C21H21ClO2, [M+H]+: 326.1605, found: 326.1604.

3.4. General Procedure for the Preparation of 5b

A 25 mL round-bottomed flask was charged with 3a (0.20 mmol), NBS (53.4 mg, 0.3 mmol, 1.0 equiv.), and LiBr (34.7 mg, 0.4 mmol, 2.0 equiv.). Then, the mixture was dissolved in CH3CN (2.0 mL) and stirred at r.t. for 10 h. The solvent was removed by rotary evaporation, and the residue was purified by flash column chromatography (PE/EA = 15:1) to give the product 5b in an 80% yield.
(E)-3-(Chloro(phenyl)methylene)-5-(1,2-dibromo-2-phenylethyl)-2,2-dimethyltetrahydrofuran (5b): Yield: 80% (75 mg) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.54–7.44 (m, 2H), 7.42–7.29 (m, 8H), 5.29 (d, J = 6.9 Hz, 1H), 4.65 (t, J = 6.8 Hz, 1H), 4.09–3.93 (m, 1H), 2.84–2.62 (m, 2H), 1.72 (s, 3H), 1.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.7, 139.7, 137.7, 128.9 (d, J = 4.3 Hz), 128.4 (d, J = 3.6 Hz), 128.3, 128.2, 85.0, 61.5, 52.3, 38.6, 26.0, 24.3; HRMS (ESI, m/z): calcd for C21H21Br2ClO, [M+H]+: 470.5906, found: 470.5904.

3.5. General Procedure for the Preparation of 5c

To a glass test tube (10 mL) was added 3a (0.20 mmol, 1.0 equiv.), Pd/C (10 w%, 5.4 mg), and MeOH (1 mL). The tube was placed in a stainless-steel autoclave (Synthware, Beijing, China). After being sealed, the autoclave was purged three times with argon, and the final pressure of hydrogen was adjusted to 5 atm. The mixture was stirred at room temperature for 24 h, followed by release of the remaining gas. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using PE/EA (20:1) as the eluent to give the product 5c in a 72% yield.
(E)-3-(chloro(phenyl)methylene)-2,2-dimethyl-5-phenethyltetrahydrofuran (5c): Yield: 72% (47 mg) as a white solid, mp = 110.3–111.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.42–7.35 (m, 4H), 7.34–7.27 (m, 3H), 7.19 (d, J = 8.2 Hz, 3H), 3.95–3.83 (m, 1H), 2.80–2.61 (m, 2H), 2.56 (dd, J = 15.6, 5.0 Hz, 1H), 2.40 (dd, J = 15.6, 10.1 Hz, 1H), 2.06–1.95 (m, 1H), 1.86–1.77 (m, 1H), 1.69 (s, 3H), 1.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.1, 141.8, 140.1, 128.4, 128.3, 128.2, 128.1, 125.8, 120.9, 83.3, 41.3, 36.5, 32.1, 26.2, 23.9; HRMS (ESI, m/z): calcd for C21H23ClO, [M+H]+: 326.8607, found: 326.8609.

3.6. General Procedure for the Preparation of 7a

A mixture of Pd(TFA)2 (10 mol %), CuCl2 (4 equiv.), DIPEA (80 mol%) and HOAc (2 mL) was added to a tube equipped with a stir bar. Then, propargyl alcohols (6a, 0.2 mmol), and alkene (2a, 0.3 mmol) were added to the tube under air and stirred at room temperature for 24 h. After the reaction was finished, the reaction was quenched by saturated aqueous NH4Cl and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under a vacuum. The residue was purified by flash column chromatography on silica gel (eluting with petroleum ether/ethyl acetate) to afford the desired product 7a.
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-((Z)-chloro(2,2-dimethyl-5-((E)-styryl)dihydrofuran-3(2H)-ylidene)methyl)benzoate (7a): Yield: 65% (65 mg) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.3 Hz, 2H), 7.34–7.24 (m, 3H), 6.64 (d, J = 15.9, 1H), 6.22 (dd, J = 15.9, 6.8 Hz, 1H), 5.02–4.92 (m, 1H), 4.53 (q, J = 7.3 Hz, 1H), 2.78–2.65 (m, 2H), 2.15 (dt, J = 12.5, 3.8 Hz, 1H), 2.01–1.91 (m, 1H), 1.78 (t, J = 2.8 Hz, 1H), 1.74 (s, 3H), 1.68 (s, 3H), 1.63–1.54 (m, 2H), 1.20–1.08 (m, 2H), 1.04–0.97 (m, 1H), 0.95 (t, J = 6.2 Hz, 6H), 0.82 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 146.0, 146.0, 144.0, 144.0, 136.4, 132.5, 132.5, 130.5, 130.5, 129.6, 129.6, 128.5, 128.3, 127.8, 126.6, 120.3, 83.8, 83.7, 76.4, 75.1, 47.3, 42.1, 42.1, 41.0, 34.3, 31.5, 26.6, 26.5, 26.1, 23.9, 23.7, 23.7, 22.0, 20.7, 16.6, 16.5; HRMS (ESI, m/z): calcd for C32H39ClO3, [M+H]+: 507.2488, found: 507.2486.

4. Conclusions

In summary, we have developed a robust synthetic strategy for the palladium-catalyzed cascade annulation reaction of buta-1,3-dienes with alkynols under mild reaction conditions. The catalytic strategy provides an effective and practical synthetic methodology for the assembly of diverse 3-methylenetetrahydrofurans with excellent functional group compatibility and good regioselectivity. A library of functional groups such as halogen atoms, aldehyde, nitro, ester, and several aromatic heterocycles was also nicely tolerated and provided the corresponding products in moderate to good yields. More importantly, the practicability is further verified by gram-scale experiments and synthetic transformation to access organic functional molecules. Studies of the detailed mechanism of this protocol and the asymmetric synthesis for the construction of chirality3-methylenetetrahydrofurans are ongoing in our laboratory.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30214244/s1, X-ray Crystallographic analysis of 3c and 4j; the NMR spectra and HRMS spectra of the catalytic products.

Author Contributions

Conceptualization, Y.-L.L., Y.N. and J.L.; methodology, Y.N. and K.Z.; investigation, Y.-L.L., Y.N. and K.Z.; writing—original draft preparation, Y.-L.L. and Y.N.; writing—review and editing, H.G., J.L. and H.J.; supervision, H.J. and J.L.; project administration, J.L.; funding acquisition, Y.-L.L., S.-L.Z. and J.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Key Research and Development Program of China (2022YFB4101800), the Education Department of Guangdong Province (2023KTSCX135, 2023ZDZX2059), the “Hundreds of Counties, Thousands of Towns, and Myriads of Villages” Project of Shaoguang city in 2024, and the National Training Program of Innovation and Entrepreneurship for undergraduates (202510561040).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 04244 g001
Figure 1. Examples of biologically active tetrahydrofuran derivatives.
Figure 1. Examples of biologically active tetrahydrofuran derivatives.
Molecules 30 04244 g001
Molecules 30 04244 sch001
Scheme 1. Strategies for the synthesis of tetrahydrofuran derivatives.
Scheme 1. Strategies for the synthesis of tetrahydrofuran derivatives.
Molecules 30 04244 sch001
Molecules 30 04244 g002
Figure 2. Substrate scope of alkynols. All reactions were performed with 1 (0.20 mmol), 2a (0.30 mmol), Pd(TFA)2 (10 mol%), CuCl2 (4 equiv.), DIPEA (80 mol%), and HOAc (2 mL) stirred at room temperature for 24 h. Yields refer to isolated yield. The Z/E ratio was determined by GC-MS analysis of the crude material.
Figure 2. Substrate scope of alkynols. All reactions were performed with 1 (0.20 mmol), 2a (0.30 mmol), Pd(TFA)2 (10 mol%), CuCl2 (4 equiv.), DIPEA (80 mol%), and HOAc (2 mL) stirred at room temperature for 24 h. Yields refer to isolated yield. The Z/E ratio was determined by GC-MS analysis of the crude material.
Molecules 30 04244 g002
Molecules 30 04244 g003
Figure 3. Substrate scope of alkenes. All reactions were performed with 1a (0.20 mmol), 2 (0.30 mmol), Pd(TFA)2 (10 mol%), CuCl2 (4 equiv.), DIPEA (80 mol%), and HOAc (2 mL) stirred at room temperature for 24 h. Yields refer to isolated yield. The Z/E ratio was determined by GC-MS analysis of the crude material.
Figure 3. Substrate scope of alkenes. All reactions were performed with 1a (0.20 mmol), 2 (0.30 mmol), Pd(TFA)2 (10 mol%), CuCl2 (4 equiv.), DIPEA (80 mol%), and HOAc (2 mL) stirred at room temperature for 24 h. Yields refer to isolated yield. The Z/E ratio was determined by GC-MS analysis of the crude material.
Molecules 30 04244 g003
Molecules 30 04244 sch002
Scheme 2. The gram-scale experiment and synthetic transformations.
Scheme 2. The gram-scale experiment and synthetic transformations.
Molecules 30 04244 sch002
Molecules 30 04244 sch003
Scheme 3. Plausible mechanistic pathways.
Scheme 3. Plausible mechanistic pathways.
Molecules 30 04244 sch003
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 30 04244 i001
EntryVariation from Standard ConditionsYield bZ/E b
1none86 (82)96:4
2PdCl2 instead of Pd(TFA)25796:4
3Pd(OAc)2 instead of Pd(TFA)25895:5
4Pd(Py)2Cl2 instead of Pd(TFA)23678:22
5Pd(MeCN)2Cl2 instead of Pd(TFA)25290:10
6DMSO instead of HOAcN.D.-
7MeCN instead of HOAcN.D.-
8DCE instead of HOAc3894:6
9Acetone instead of HOAc4383:17
10Na2CO3 instead of DIPEA5490:10
11DABCO instead of DIPEA5880:20
12NEt3 instead of DIPEA3990:10
13Cs2CO3 instead of DIPEAtrace-
1440 °C instead of rt8490:10
15without Pd(TFA)2 or CuCl2N.D.-
a Conditions: All reactions were performed with 1a (0.10 mmol), 2a (0.15 mmol), Pd(TFA)2 (10 mol%), CuCl2 (4 equiv.), DIPEA (80 mol%), and HOAc (2 mL) stirred at room temperature for 24 h. The Z/E ratio was determined by GC-MS analysis of the crude material. N.D. = not detected. b Determined by GC-MS using dodecane as the internal standard. The value in parentheses is the yield of the isolated product.
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Lai, Y.-L.; Niu, Y.; Zeng, K.; Jiang, H.; Guo, H.; Zhang, S.-L.; Li, J. Assembly of Diverse 3-Methylenetetrahydrofurans via Palladium-Catalyzed Cascade Carboetherification of Buta-1,3-Dienes with Alkynols. Molecules 2025, 30, 4244. https://doi.org/10.3390/molecules30214244

AMA Style

Lai Y-L, Niu Y, Zeng K, Jiang H, Guo H, Zhang S-L, Li J. Assembly of Diverse 3-Methylenetetrahydrofurans via Palladium-Catalyzed Cascade Carboetherification of Buta-1,3-Dienes with Alkynols. Molecules. 2025; 30(21):4244. https://doi.org/10.3390/molecules30214244

Chicago/Turabian Style

Lai, Yin-Long, Yanan Niu, Kaitong Zeng, Huanfeng Jiang, Huishi Guo, Sheng-Ling Zhang, and Jianxiao Li. 2025. "Assembly of Diverse 3-Methylenetetrahydrofurans via Palladium-Catalyzed Cascade Carboetherification of Buta-1,3-Dienes with Alkynols" Molecules 30, no. 21: 4244. https://doi.org/10.3390/molecules30214244

APA Style

Lai, Y.-L., Niu, Y., Zeng, K., Jiang, H., Guo, H., Zhang, S.-L., & Li, J. (2025). Assembly of Diverse 3-Methylenetetrahydrofurans via Palladium-Catalyzed Cascade Carboetherification of Buta-1,3-Dienes with Alkynols. Molecules, 30(21), 4244. https://doi.org/10.3390/molecules30214244

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