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Stereoselective synthesis of β-fluoroenyne by the reaction of gem-difluoroalkenes with terminal alkynes
Journal of Fluorine Chemistry 168 (2014) 240–246
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Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
Stereoselective synthesis of b-fluoroenyne by the reaction of gem-difluoroalkenes with terminal alkynes Guanyi Jin a, Juan Zhang a, Wei Wu a, Song Cao a,b,* a b
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST), Shanghai 200237, China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 July 2014 Received in revised form 2 October 2014 Accepted 14 October 2014 Available online 24 October 2014
A mild and convenient method for the stereoselective synthesis of a series of conjugated b-fluoroenynes by the reaction of gem-difluoroalkenes with terminal alkynes with the assistance of n-butyllithium and K3PO4 is described. ß 2014 Elsevier B.V. All rights reserved.
Keywords: Conjugated b-fluoroenynes gem-Difluoroalkenes Terminal alkynes Potassium phosphate
1. Introduction Conjugated enyne motif is found in many natural products and biologically active compounds (Fig. 1) [1]. Moreover, the conjugated 1,3-enynes are an important class of versatile building blocks in organic synthesis [2]. Therefore, the synthesis of various functionalized enynes has received much attention in recent years. A large number of methods for the synthesis of these valuable synthetic intermediates have been developed so far [3]. Among the protocols for the preparation of conjugated enyne, the Pd or Cu catalyzed C(sp2)–C(sp) cross-coupling reactions between vinylic and acetylenic partners is the most reliable and straightforward methodology [4]. The dimerization of terminal alkynes is an alternate and atom-economical route to conjugated enyne compounds [5]. The fluorinated conjugated enynes are a kind of useful synthons in organic transformation [6]. However, compared to 1,3-enynes, the synthesis and application of fluoroenynes have not been thoroughly investigated [7]. The most common method for the synthesis of conjugated fluoroenynes is the palladium-catalyzed cross-coupling of fluorinated vinyl halides (X = Cl, Br, I) with
* Corresponding author at: Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST), Shanghai 200237, China. Tel.: +86 21 64253452; fax: +86 21 64252603. E-mail address: [email protected] (S. Cao). http://dx.doi.org/10.1016/j.jfluchem.2014.10.010 0022-1139/ß 2014 Elsevier B.V. All rights reserved.
terminal alkynes [8]. Another facile and practical alternative for the preparation of fluorinated conjugated enynes involves the reaction of fluorinated alkenes with alkynyllithiums via a nucleophilic addition–elimination reaction. However, examples of the above-mentioned addition–elimination reaction are very scarce. Most importantly, the necessity of using certain fluoroalkenes such as highly electron-deficient fluorinated alkenes limits the utility of the method (Fig. 2, compounds I–IV) [9]. Consequently, it is still highly desirable to develop a simple method to access fluorinated conjugated enynes. Herein, we report an efficient and practical protocol for the E-selective formation of conjugated fluoroenynes by the reaction of gem-difluoroalkenes with terminal alkynes in the presence of n-butyllithium with the assistance of K3PO4 (Scheme 1). 2. Results and discussion In continuation of our research on the reactivity of gemdifluoroalkenes [10], in this paper, we focused on the nucleophilic vinylic substitution (SNV) of gem-difluoroalkenes, which have relatively electron-rich carbon–carbon double bond, with terminal alkynes. We chose 1-(2,2-difluorovinyl)-4-methoxybenzene 1a as the model substrate to optimize suitable conditions (Table 1). Initially, we have studied the influence of base on the model reaction. In the absence of the base, the reaction hardly proceeded and only trace amount of expected product 3aa was observed (Table 1, entry 1). Among the various bases examined, K3PO4 was
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Scheme 1. Synthesis of b-fluoroenynes.
Fig. 1. Four examples of bioactive conjugated enynes.
Fig. 2. Electron poor fluoroalkenes described in literature.
best, and Na2CO3 or Ca(OH)2 were less effective (Table 1, entries 2–6). The yields were also significantly affected by the amount of K3PO4. The use of 3.0 equiv. of K3PO4 afforded an excellent yield of 3aa with good E-selectivity (entry 6), but if the amount of K3PO4
was decreased to 1.0 or 2.0 equiv., the yields of 3aa decreased dramatically (entries 7 and 8). Substrate 1a was completely recovered in the reaction in the absence of K3PO4, suggesting that the K3PO4 plays a crucial role in this reaction. Subsequent screening of alternate solvents revealed that only THF could give fluoroenyne in excellent yield (entry 6), while almost no product was formed when Et2O, DMF, CH3CN, CH2Cl2 were used as solvent (entries 9–12). Furthermore, the reaction could not proceed well at the lower temperature (20 or 40 8C) (entry 13 and 14). Decreasing the amount of n-butyllithium or terminal alkyne 2a obviously diminished the yields (entries 15–18). In addition, in order to avoid the reaction of n-butyllithium with 1-(2,2-difluorovinyl)-4-methoxybenzene 1a, the amount of n-butyllithium is slightly less than that of 2a. With the optimized reaction conditions in hand (Table 1, entry 6), we further explored the scope of the novel nucleophilic vinylic substitution reaction of different terminal alkynes with gemdifluoroalkenes (Table 2). It was found that gem-difluoroalkenes containing electron-donating group such as CH3O and OCH2O on the aromatic ring could afford the corresponding fluoroenynes in high yields and good to high stereoselectivity, whereas gemdifluoroalkenes containing electron-withdrawing group such as CN on the aromatic ring only provided fluoroenyne in moderate yield (3ea). The replacement of the aryl group with the thienyl group in difluoroalkene would lead to a decrease in yield (3fa).
Table 1 Optimization of the reaction conditions.a
Entry
Amt of 2a (equiv.)
Temp. (8C)
n-BuLi (equiv.)
Base (equiv.)
Solvent
Yield of 3aa (%)b
E/Zb
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1.5
65 65 65 65 65 65 65 65 65 65 65 65 40 20 65 65 65 65
1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 0 1 0.5 1.5
– NaOH (3) Ca(OH)2 (3) Na2CO3 (3) Et3N (3) K3PO4 (3) K3PO4 (2) K3PO4 (1) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3)
THF THF THF THF THF THF THF THF Et2O CH2Cl2 DMF CH3CN THF THF THF THF THF THF
5 0 20 29 0 98 65 17 0 8 0 0 16 5 0 64 47 70
88:12 – 88:12 85:15 – 88:12 87:13 85:15 – 88:12 – – 83:17 75:25 – 84:16 72:28 80:20
a
Reaction conditions: 1a (1.0 mmol), THF (6 mL), 6–8 h. Yields determined by GC analysis and based on 1a. The ratios of E/Z isomers in the crude reaction mixture were determined by 19F NMR. The configuration of E-isomer 3aa (after purification) was determined by its 3JHF coupling constant in 1H NMR spectrum. b
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Table 2 Reactions of gem-difluoroalkenes 1a–f with various terminal alkynes 2a–e.a,b,c
a
Reaction conditions: gem-difluoroalkenes 1a–f (1.0 mmol), 2a–e (2.0 mmol), n-BuLi (1.5 mmol), K3PO4 (3.0 mmol), THF (6 mL), 6–8 h, 65 8C. Isolated yields of an inseparable E/Z mixture of the products. c E/Z selectivity was determined by 19F NMR spectra. The configurations of E- and Z-isomers were determined by their 3JHF coupling constants in 1H NMR spectra (ca. 17.0 Hz for E-isomers and 35.0 Hz for Z-isomers) [7c]. b
In addition, the use of (E)-(4,4-difluorobuta-1,3-dien-1-yl)benzene resulted in an obvious decrease in yield (58%) and a poor E/Z selectivity (57:43, GC–MS and 19F NMR). Furthermore, when aliphatic difluoroalkene such as 1,1-difluoro-2-benzyl ethylene and terminal aliphatic alkyne such as pent-1-yne was used as substrate, the reaction did not proceed to completion and only a small amount of the expected fluoroenyne was observed. The effect of substituent on the aromatic ring of the terminal alkynes was also examined. The terminal alkynes bearing electrondonating groups (3ab and 3ac) gave higher yields than those containing electron-withdrawing groups (3ad and 3ae). Although the reaction proceeded well and gave fluoroenynes with good E-selectivity, unfortunately, (E)-isomers were not separated from the corresponding the (Z)-isomers at this stage due to their similarity in affinity to chromatographic silica gel. To avoid the formation of a mixture of E- and Z-isomers of products, symmetrical gem-difluoroalkenes (1g–i) were used as substrates to explore the limitations of the reaction (Table 3). As anticipated, both electron-donating and electron-withdrawing groups located in the aromatic rings of difluoroalkenes were found to be tolerated in this reaction, and these substrates furnished the corresponding symmetrical fluoroenynes in good to high yields (3ha and 3ia). We were delighted to find the terminal aliphatic alkynes could react with symmetrical gem-difluoroalkenes efficiently, however, the expected products were obtained in slightly lower yields (Table 3, 3gg, 3gh, 3gi and 3gj). Based on the above observations and earlier reports by Jeong and Konno et al. [9b,9c], a plausible mechanism for the formation of 3 is outlined in Scheme 2. First, gem-difluoroalkene reacts with terminal alkyne in the presence of n-butyllithium to give the key carbanion intermediate I. Subsequently, rotation of the intermediate I by 60 degrees would result in two conformational intermediates, II and IV, which is in equilibrium with III and V, respectively. The intermediate IV is unstable due to the existence of electronic repulsion between the aryl group and fluorine atom.
Finally, the elimination of a fluoride ion from the intermediates II with the assistance of K3PO4 affords (E)-3 in a high stereoselectivity. 3. Conclusions In conclusion, we have developed a novel and efficient method for the synthesis of conjugated b -fluoroenynes by the reaction of gem-difluoroalkenes with terminal alkynes via nucleophilic substitution of vinylic fluorine (SNV) in the presence of n-butyllithium and K3PO4. The reaction proceeds efficiently under mild reaction conditions affording the fluorinated enynes in good to excellent yields with good E selectivity. The addition of 3 equiv. of K3PO4 is essential for efficient transformation. The applications of this valuable building block (fluoroenyne) are currently underway in our laboratory. 4. Experimental All reagents were of analytical grade, and obtained from commercial suppliers and used without further purification. THF and other solvents were dried by standard method prior to use. Melting points were measured in an open capillary using Bu¨chi melting point B-540 apparatus and are uncorrected. 1H NMR and 13 C NMR spectra were recorded on a 400 spectrometer (400 MHz for 1H and 100 MHz for 13C NMR, respectively) using TMS as internal standard, The 19F NMR spectra were obtained using a 400 spectrometer (376 MHz). CDCl3 was used as the NMR solvent in all cases. High resolution mass spectra (HRMS) were recorded under electron impact conditions using a MicroMass GCT CA 055 instrument and recorded on a MicroMass LCTTM spectrometer. Silica gel (300–400 mesh size) was used for column chromatography. TLC analysis of reaction mixtures was performed using silica gel plates.
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Table 3 Reactions of symmetrical gem-difluoroalkenes 1g–i with various terminal alkynes 2a–j.a,b
a b
Reaction conditions: gem-difluoroalkenes 1g–i (1.0 mmol), 2a–j (2.0 mmol), n-BuLi (1.5 mmol), K3PO4 (3.0 mmol), THF (6 mL), 6–8 h, 65 8C. Isolated yields.
Scheme 2. A plausible mechanism for the formation of 3.
4.1. Preparation of 1,1-difluoroalkenes 1a–f and symmetrical gemdifluoroalkenes 1g–i The 1,1-difluoroalkenes (1a–f) were prepared according to the reported procedure [11a,11b]. The symmetrical gem-difluoroalkenes (1g–i) were prepared according to the Hu’s reported procedure [12]. 4.2. General procedure for the target compounds 3 Under an argon atmosphere, n-BuLi (0.93 mL, 1.6 M in hexanes, 1.5 mmol) was added dropwise to a solution of terminal alkynes
2a–j (2.0 mmol) and anhydrous K3PO4 (3.0 mmol, 0.636 g) in 5 mL of dry THF at 0 8C. After stirring the reaction mixture at 0 8C for 30 min, a solution of gem-difluoroalkenes 1a–i (1.0 mmol) in 1 mL of dry THF was added dropwise to the mixture at 0 8C and then the mixture was stirred at 65 8C until the reaction was completed as monitored by TLC (usually about 6–8 h). The reaction mixture was allowed to cool to room temperature and quenched with H2O (5 mL). The aqueous phase was extracted with EtOAc (3 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography using n-hexane as eluent to afford the corresponding product 3.
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(E/Z)-1-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)-4-methoxybenzene (E/Z-3aa): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 3.89 (s, 3H, Z-isomer), 3.90 (s, 3H, E-isomer), 6.24 (d, J = 35.6 Hz, 1H, Z-isomer), 6.75 (d, J = 17.0 Hz, 1H, E-isomer), 6.97 (d, J = 8.8 Hz, 2H, Z-isomer), 7.04 (d, J = 8.8 Hz, 2H, E-isomer), 7.46–7.47 (m, 3H, Z-isomer), 7.49–7.50 (m, 3H, E-isomer), 7.59–7.63 (m, 4H, Z-isomer), 7.66–7.69 (m, 2H, E-isomer), 7.79 (d, J = 8.4 Hz, 2H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.3, 81.8 (d, 2JCF = 41.0 Hz), 97.7 (d, 3JCF = 7.0 Hz), 114.2, 117.5 (d, 2JCF = 33.0 Hz), 121.6 (d, 4JCF = 2.4 Hz), 124.7 (d, 3JCF = 8.9 Hz), 128.8, 129.6, 129.7, 131.8 (d, 4JCF = 2.3 Hz), 140.1 (d, 1 JCF = 227.7 Hz), 159.8 (d, 5JCF = 1.6 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 107.4 (d, J = 35.3 Hz, 1F, Z-isomer), 105.5 (d, J = 17.7 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C17H13FO [M]+: 252.0950, found: 252.0949. (E/Z)-1-(3-Fluoro-4-(4-methoxyphenyl)but-3-en-1-yn-1-yl)4-methylbenzene (E/Z-3ab): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 2.44 (s, 3H, Z-isomer), 2.46 (s, 3H, E-isomer), 3.86 (s, 3H, Z-isomer), 3.89 (s, 3H, E-isomer), 6.18 (d, J = 35.6 Hz, 1H, Z-isomer), 6.69 (d, J = 16.8 Hz, 1H, E-isomer), 6.94 (d, J = 8.8 Hz, 2H, Z-isomer), 6.99–7.02 (m, 2H, E-isomer), 7.21–7.26 (m, 2H, Z-isomer), 7.28 (d, J = 8.0 Hz, 2H, E-isomer), 7.50–7.51 (m, 2H, Z-isomer), 7.54 (d, J = 8.0 Hz, 2H, E-isomer), 7.60 (d, J = 8.8 Hz, 2H, Z-isomer), 7.75 (d, J = 8.8 Hz, 2H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 21.7, 55.3, 81.1 (d, 2JCF = 41.0 Hz), 97.9 (d, 3JCF = 7.0 Hz), 114.1, 117.0 (d, 2JCF = 33.3 Hz), 124.8 (d, 3 JCF = 9.0 Hz), 129.5 (d, 4JCF = 4.4 Hz), 131.7 (d, 4JCF = 2.3 Hz), 134.2, 140.0, 140.3 (d, 1JCF = 245.2 Hz), 141.4, 159.7 (d, 5 JCF = 2.0 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 107.1 (d, J = 35.7 Hz, 1F, Z-isomer), 105.1 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C18H15FO [M]+: 266.0743, found: 266.0742. (E/Z)-4,40 -(2-Fluorobut-1-en-3-yne-1,4-diyl)bis(methoxybenzene) (E/Z-3ac): White solid. 1H NMR (400 MHz, CDCl3): d = 3.84 (s, 3H, Z-isomer), 3.85 (s, 3H, both E- and Z-isomers), 3.86 (s, 3H, E-isomer), 6.15 (d, J = 35.5 Hz, 1H, Z-isomer), 6.66 (d, J = 17.0 Hz, 1H, E-isomer), 6.91–6.93 (m, 4H, Z-isomer), 6.96–7.00 (m, 4H, E-isomer), 7.52–7.54 (m, 4H, Z-isomer), 7.56 (d, J = 8.8 Hz, 2H, E-isomer), 7.73 (d, J = 8.7 Hz, 2H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.2, 55.3, 80.5 (d, 2 JCF = 40.8 Hz), 98.0 (d, 3JCF = 7.2 Hz), 114.1, 114.4, 116.6 (d, 2 JCF = 33.3 Hz), 124.8 (d, 3JCF = 8.9 Hz), 129.5 (d, 4JCF = 3.0 Hz), 133.4 (d, 4JCF = 2.5 Hz), 134.1, 140.3 (d, 1JCF = 226.9 Hz), 159.6 (d, 5 JCF = 2.2 Hz), 160.7 ppm; 19F NMR (376 MHz, CDCl3): d = 106.7 (d, J = 35.3 Hz, 1F, Z-isomer), 104.7 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (ESI): calc. for C18H15FO2 [M]+: 282.1056, found: 282.1053. (E/Z)-1-Fluoro-4-(3-fluoro-4-(4-methoxyphenyl)but-3-en-1yn-1-yl)benzene (E/Z-3ad): White solid. 1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3H, both E- and Z-isomers), 6.12 (d, J = 35.3 Hz, 1H, Z-isomer), 6.65 (d, J = 16.9 Hz, 1H, E-isomer), 6.93–6.96 (m, 2H, both E- and Z-isomers), 7.09–7.15 (m, 2H, both E- and Z-isomers), 7.53–7.58 (m, 2H, both E- and Z-isomers), 7.64–7.68 (m, 2H, both E- and Z-isomers) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.3, 81.2 (d, 2JCF = 41.0 Hz), 96.2 (d, 3JCF = 7.1 Hz), 114.1, 116.0 (d, 2JCF = 22.0 Hz), 117.3 (d, 2 JCF = 32.9 Hz), 124.6 (d, 3JCF = 8.8 Hz), 129.4 (d, 4JCF = 3.2 Hz), 133.2 (dd, 3JCF = 8.4 Hz, 5JCF = 2.4 Hz), 139.9 (d, 1JCF = 229.1 Hz), 159.6, 159.7, 163.2 (d, 1JCF = 250.2 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 109.2 to 109.1 (m, 1F, Z-isomer), 108.6 to 108.5 (m, 1F, E-isomer), 107.9 (d, J = 35.3 Hz, 1F, Z-isomer), 106.1 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C17H12F2O [M]+: 270.0856, found: 270.0857. (E/Z)-2-(3-Fluoro-4-(4-methoxyphenyl)but-3-en-1-yn-1yl)pyridine (E/Z-3ae): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3H, both E- and Z-isomers), 6.25 (d, J = 35.2 Hz, 1H,
Z-isomer), 6.71 (d, J = 16.8 Hz, 1H, E-isomer), 6.90–6.92 (m, 1H, Z-isomer), 6.93–6.95 (m, 2H, both E- and Z-isomers), 7.32–7.35 (m, 1H, both E- and Z-isomers), 7.52–7.53 (m, 1H, Z-isomer), 7.55–7.57 (m, 1H, both E- and Z-isomers), 7.69 (d, J = 8.8 Hz, 2H, E-isomer), 7.73–7.77 (m, 1H, both E- and Z-isomers), 8.65–8.66 (m, 1H, Z-isomer), 8.69–8.90 (m, 1H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.3, 80.9 (d, 2JCF = 41.2 Hz), 96.0 (d, 3JCF = 7.2 Hz), 114.2, 119.0 (d, 2JCF = 32.1 Hz), 123.7, 124.2 (d, 3 JCF = 8.7 Hz), 127.6, 129.7 (d, 4JCF = 3.1 Hz), 136.3, 139.4 (d, 1 JCF = 228.2 Hz), 142.0 (d, 4JCF = 2.3 Hz), 150.4, 159.8 ppm; 19F NMR (376 MHz, CDCl3): d = 110.3 (d, J = 35.3 Hz, 1F, Z-isomer), 108.1 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C16H12FNO [M]+: 253.0903, found: 253.0902. (E/Z)-5-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)benzo[d][1,3]dioxole (E/Z-3ba): White solid. 1H NMR (400 MHz, CDCl3): d = 6.01 (s, 2H, both E- and Z-isomers), 6.10 (d, J = 34.8 Hz, 1H, Z-isomer), 6.62 (d, J = 16.8 Hz, 1H, E-isomer), 6.83–6.86 (m, 1H, both E- and Z-isomers), 6.99–7.01 (m, 1H, Z-isomer), 7.08–7.10 (m, 1H, E-isomer), 7.22–7.23 (m, 1H, Z-isomer), 7.43–7.46 (m, 4H, both E- and Z-isomers), 7.55–7.56 (m, 1H, Z-isomer), 7.59–7.61 (m, 2H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 81.4 (d, 2JCF = 41.0 Hz), 98.0 (d, 3JCF = 6.9 Hz), 101.3, 107.3 (d, 5 JCF = 2.3 Hz), 108.4, 117.5 (d, 2JCF = 33.8 Hz), 121.4 (d, 4 JCF = 2.4 Hz), 123.2 (d, 4JCF = 4.0 Hz), 126.3 (d, 3JCF = 9.0 Hz), 128.6, 129.5, 131.7 (d, 4JCF = 2.3 Hz), 140.2 (d, 1JCF = 228.6 Hz), 147.7 (d, 5JCF = 2.1 Hz), 147.9 ppm; 19F NMR (376 MHz, CDCl3): d = 106.6 (d, J = 34.6 Hz, 1F, Z-isomer), 105.0 (d, J = 17. 3 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C17H11FO2 [M]+: 266.1107, found: 266.1108. (E/Z)-4-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)-1,2-dimethoxybenzene (E/Z-3ca): White solid. 1H NMR (400 MHz, CDCl3): d = 3.84 (s, 3H, both E- and Z-isomers), 3.89 (s, 3H, both E- and Z-isomers), 6.10 (d, J = 34.8 Hz, 1H, Z-isomer), 6.61 (d, J = 16.8 Hz, 1H, E-isomer), 6.85–6.87 (m, 1H, both E- and Z-isomers), 7.04–7.10 (m, 2H, Z-isomer), 7.14–7.16 (m, 1H, both E- and Z-isomers), 7.37– 7.39 (m, 3H, E-isomer), 7.45–7.46 (m, 1H, E-isomer), 7.53–7.55 (m, 2H, E-isomer), 7.62 (d, J = 8.4 Hz, 2H, Z-isomer), 7.73–7.78 (m, 2H, Z-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.7, 55.8, 81.6 (d, 2JCF = 41.0 Hz,), 97.7 (d, 3JCF = 7.0 Hz), 110.3 (d, 4JCF = 2.3 Hz), 111.1, 117.6 (d, 2JCF = 33.2 Hz), 121.3 (d, 4 JCF = 2.5 Hz), 121.9 (d, 4JCF = 3.9 Hz), 124.9 (d, 3JCF = 9.0 Hz), 128.7, 129.6, 131.6 (d, 5JCF = 2.2 Hz), 140.0 (d, 1JCF = 228.2 Hz), 148.8, 149.3 (d, 5JCF = 2.1 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 107.4 (d, J = 35.0 Hz, 1F, Z-isomer), 105.4 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C18H15FO2 [M]+: 282.1056, found: 282.1057. (E/Z)-2-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)naphthalene (E/Z-3da): White solid. 1H NMR (400 MHz, CDCl3): d = 6.91 (d, J = 32.8 Hz, 1H, Z-isomer), 7.33 (d, J = 15.6 Hz, 1H, E-isomer), 7.35–7.36 (m, 1H, both E- and Z-isomers), 7.37–7.39 (m, 2H, both E- and Z-isomers), 7.42–7.45 (m, 2H, both E- and Z-isomers), 7.52– 7.61 (m, 3H, both E- and Z-isomers), 7.86–7.92 (m, 2H, E-isomer), 7.92–7.97 (m, 2H, Z-isomer), 8.04–8.07 (m, 2H, E-isomer), 8.13 (d, J = 8.4 Hz, 2H, Z-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 80.9 (d, 2JCF = 41.5 Hz), 95.7 (d, 3JCF = 6.7 Hz), 114.6 (d, 2JCF = 32.1 Hz), 121.3, 123.8, 125.3, 126.0, 126.4, 126.5, 126.6, 128.5, 128.7, 128.8, 129.1 (d, 3JCF = 8.2 Hz), 129.4, 131.7 (d, 4 JCF = 2.2 Hz), 133.6, 142.5 (d, 1JCF = 233.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 104.6 (d, J = 32.7 Hz, Z-isomer), 100.7 (d, J = 15.3 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C20H13F [M]+: 272.1001, found: 272.0988. (E/Z)-4-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)benzonitrile (E/ Z-3ea): White solid. 1H NMR (400 MHz, CDCl3): d = 6.10 (d, J = 33.6 Hz, 1H, Z-isomer), 6.58 (d, J = 16.0 Hz, 1H, E-isomer), 7.34–7.39 (m, 3H, both E- and Z-isomers), 7.49–7.51 (m, 2H, both E- and Z-isomers), 7.56–7.59 (m, 2H, both E- and Z-isomers),
G. Jin et al. / Journal of Fluorine Chemistry 168 (2014) 240–246
7.71–7.73 (m, 2H, both E- and Z-isomers); 13C NMR (100 MHz, CDCl3): d = 80.6 (d, 2JCF = 40.5 Hz), 98.8 (d, 3JCF = 5.9 Hz), 111.3 (d, 5 JCF = 1.8 Hz), 116.0 (d, 2JCF = 34.4 Hz), 118.8, 120.6 (d, 4 JCF = 2.1 Hz), 128.5 (d, 4JCF = 3.1 Hz), 128.8, 130.2, 131.9 (d, 5 JCF = 1.9 Hz), 132.2, 137.1 (d, 3JCF = 10.1 Hz), 142.9 (d, 1 JCF = 237.3 Hz); 19F NMR (376 MHz, CDCl3): d = 98.2 (d, J = 33.8 Hz, 1F, Z-isomer), 95.6 (d, J = 15.8 Hz, 1F, E-isomer); HRMS (EI): calc. for C17H10FN [M]+: 247.0797, found: 247.0796. (E/Z)-2-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)thiophene (E/Z3fa): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 6.37 (d, J = 34.0 Hz, 1H, Z-isomer), 6.82 (d, J = 13.6 Hz, 1H, E-isomer), 6.86–6.89 (m, 1H, Z-isomer), 6.93–6.95 (m, 1H, E-isomer), 7.03– 7.08 (m, 2H, Z-isomer), 7.09–7.10 (m, 1H, E-isomer), 7.15–7.17 (m, 1H, Z-isomer), 7.19–7.20 (m, 1H, E-isomer), 7.25–7.26 (m, 2H, Zisomer), 7.30–7.31 (m, 3H, E-isomer), 7.42–7.45 (m, 2H, Z-isomer), 7.54–7.56 (m, 2H, E-isomer); 13C NMR (100 MHz, CDCl3): d = 81.4 (d, 2JCF = 40.8 Hz), 101.3 (d, 3JCF = 6.6 Hz), 112.9 (d, 2JCF = 37.3 Hz), 121.6 (d, 5JCF = 2.1 Hz), 126.4 (d, 4JCF = 4.6 Hz), 127.1, 128.8, 129.3 (d, 5JCF = 6.9 Hz), 129.8, 131.8 (d, 5JCF = 2.1 Hz), 135.4 (d, 3 JCF = 8.3 Hz), 140.3 (d, 1JCF = 231.5 Hz); 19F NMR (376 MHz, CDCl3): d = 108.9 (d, J = 13.5 Hz, 1F, E-isomer), 102.7 (d, J = 36.0 Hz, 1F, Z-isomer); HRMS (EI): calc. for C14H9FS [M]+: 228.0409, found: 228.0408. (2-Fluorobut-1-en-3-yne-1,1,4-triyl)tribenzene (3ga): White solid. mp: 88.9–89.6 8C. 1H NMR (400 MHz, CDCl3): d = 7.43– 7.60 (m, 13H), 7.68–7.69 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 82.8 (d, 2JCF = 40.7 Hz), 95.8 (d, 3JCF = 6.3 Hz), 121.8, 121.9, 128.3, 128.4, 128.6, 129.3, 130.2, 130.3, 130.4 (d, 2JCF = 16.9 Hz), 130.8 (d, 4JCF = 2.9 Hz), 131.6 (d, 4JCF = 2.2 Hz), 136.7 (d, 3 JCF = 3.6 Hz), 137.8 (d, 3JCF = 4.2 Hz), 139.1 (d, 1JCF = 240.3 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 107.2 (s, 1F) ppm; HRMS (EI): calc. for C22H15F [M]+: 298.1158, found: 298.1157. (2-Fluoro-4-(p-tolyl)but-1-en-3-yne-1,1-diyl)dibenzene (3gb): White solid. mp: 89.5–89.9 8C. 1H NMR (400 MHz, CDCl3): d = 2.86 (s, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.44–7.55 (m, 8H), 7.64 (dd, J = 6.9, 1.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 21.7, 82.2 (d, 2JCF = 40.5 Hz), 96.1 (d, 3JCF = 5.8 Hz), 118.8 (d, 5 JCF = 2.1 Hz), 128.0, 128.1, 128.2, 128.3, 129.3, 129.8 (d, 2 JCF = 18.5 Hz), 130.2 (d, 3JCF = 5.1 Hz), 130.7 (d, 4JCF = 2.9 Hz), 131.5 (d, 4JCF = 2.4 Hz), 136.7 (d, 4JCF = 3.6 Hz), 137.8 (d, 3 JCF = 4.1 Hz), 139.1 (d, 1JCF = 240.1 Hz), 139.6 ppm; 19F NMR (376 MHz, CDCl3): d = 106.9 (s, 1F) ppm; HRMS (EI): calc. for C23H17F [M]+: 312.1314, found: 312.1315. (2-Fluoro-4-(4-methoxyphenyl)but-1-en-3-yne-1,1-diyl)dibenzene (3gc): White solid. mp: 91.0–91.6 8C. 1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3H), 6.94 (d, J = 8.7 Hz, 2H), 7.39–7.45 (m, 3H), 7.47–7.54 (m, 7H), 7.64 (dd, J = 7.4, 1.7 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 55.4, 81.6 (d, 2JCF = 40.6 Hz), 96.0 (d, 3 JCF = 6.5 Hz), 113.7, 113.8, 114.3, 128.1, 128.2, 128.3, 129.4 (d, 2 JCF = 18.9 Hz), 130.2 (d, 3JCF = 5.1 Hz), 130.8 (d, 4JCF = 2.6 Hz), 133.2 (d, 4JCF = 2.4 Hz), 136.8 (d, 4JCF = 3.5 Hz), 137.9 (d, 3JCF = 4.3 Hz), 139.2 (d, 1JCF = 239.9 Hz), 160.5 ppm; 19F NMR (376 MHz, CDCl3): d = 106.7 (s, 1F) ppm; HRMS (EI): calc. for C23H17FO [M]+: 328.1263, found: 328.1262. (2-Fluoro-4-(4-fluorophenyl)but-1-en-3-yne-1,1-diyl)dibenzene (3gd): White solid. mp: 95.9–96.8 8C. 1H NMR (400 MHz, CDCl3): d = 6.90–6.94 (m, 2H), 7.20–7.35 (m, 10H), 7.41–7.44 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 82.4 (d, 2JCF = 40.8 Hz), 94.6 (d, 3JCF = 6.3 Hz), 115.9 (d, 2JCF = 22.2 Hz), 117.9 (dd, 3 JCF = 3.4 Hz, 5JCF = 2.3 Hz), 128.2, 128.3, 130.1, 130.2, 130.3 (d, 2 JCF = 17.7 Hz), 130.7 (d, 3JCF = 2.9 Hz), 133.5 (d, 4JCF = 2.3 Hz), 113.6 (d, 4JCF = 2.2 Hz), 136.5 (d, 3JCF = 3.6 Hz), 137.6, 138.8 (d, 1 JCF = 235.7 Hz), 163.0 (d, 1JCF = 249.8 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 108.9 to 108.8 (m, 1F), 107.8 (s, 1F) ppm; HRMS (EI): calc. for C22H14F2 [M]+: 316.1064, found: 316.1065.
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2-(3-Fluoro-4,4-diphenylbut-3-en-1-yn-1-yl)pyridine (3ge): White solid. mp: 66.1–66.8 8C. 1H NMR (400 MHz, CDCl3): d = 7.13–7.21 (m, 2H), 7.31–7.40 (m, 8H), 7.48–7.56 (m, 3H), 8.54–8.56 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): d = 81.9 (d, 2 JCF = 40.7 Hz), 94.4 (d, 3JCF = 6.3 Hz), 123.5, 127.5, 127.6, 128.3, 128.4, 128.5, 130.2 (d, 3JCF = 5.1 Hz), 130.6 (d, 4JCF = 2.9 Hz), 131.9 (d, 2JCF = 17.6 Hz), 136.1, 136.2 (d, 4JCF = 3.8 Hz), 137.1 (d, 3 JCF = 4.0 Hz), 138.3 (d, 1JCF = 240.9 Hz), 142.0 (d, 4JCF = 2.0 Hz), 150.2 ppm; 19F NMR (376 MHz, CDCl3): d = 108.7 (s, 1F) ppm; HRMS (EI): calc. for C21H14FN [M]+: 299.1110, found: 299.1107. (4-(4-Ethylphenyl)-2-fluorobut-1-en-3-yne-1,1-diyl)dibenzene (3gf): White solid. mp: 63.3–63.8 8C. 1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.6 Hz, 3H), 2.69 (q, J = 7.6 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.37–7.44 (m, 8H), 7.52–7.54 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 15.3, 28.9, 81.9 (d, 2 JCF = 40.0 Hz), 95.9 (d, 3JCF = 6.3 Hz), 118.8 (d, 5JCF = 2.0 Hz), 127.8, 127.9, 128.0, 128.1, 128.2, 129.7 (d, 2JCF = 18.8 Hz), 130.1 (d, 3 JCF = 7.0 Hz), 130.7 (d, 4JCF = 3.0 Hz), 131.5 (d, 4JCF = 2.1 Hz), 136.6 (d, 4JCF = 3.5 Hz), 137.7 (d, 3JCF = 4.4 Hz), 139.0 (d, 1JCF = 240.0 Hz), 145.8 ppm; 19F NMR (376 MHz, CDCl3): d = 107.2 (s, 1F) ppm; HRMS (EI): calc. for C24H19F [M]+: 326.1471, found: 326.1472. (2-Fluorohept-1-en-3-yne-1,1-diyl)dibenzene (3gg): White solid. mp: 37.6–38.0 8C. 1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7.6 Hz, 3H), 1.51–1.60 (m, 2H), 2.32–2.37 (m, 2H), 7.31–7.43 (m, 8H), 7.45–7.47 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 13.4, 21.4, 21.5, 74.0 (d, 2JCF = 40.3 Hz), 97.5 (d, 3JCF = 6.0 Hz), 127.7, 127.8, 128.0, 128.1, 128.2 (d, 2JCF = 19.3 Hz), 130.0 (d, 3JCF = 5.0 Hz), 130.5 (d, 4JCF = 2.8 Hz), 136.7 (d, 5JCF = 3.5 Hz), 137.8, 138.5 (d, 1 JCF = 243.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 104.4 (t, J = 4.1 Hz, 1F) ppm; HRMS (EI): calc. for C19H17F [M]+: 264.1314, found: 264.1315. (4-Cyclopropyl-2-fluorobut-1-en-3-yne-1,1-diyl)dibenzene (3gh): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 0.84–0.88 (m, 2H), 0.93–0.98 (m, 2H), 1.45–1.52 (m, 1H), 7.44–7.54 (m, 8H), 7.59–7.61 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 0.0 (d, 4 JCF = 2.5 Hz), 8.5 (d, 5JCF = 1.6 Hz), 68.6 (d, 2JCF = 40.6 Hz), 100.5 (d, 3JCF = 6.1 Hz), 127.5, 127.6, 127.7, 127.8, 128.1 (d, 2 JCF = 19.5 Hz), 129.7 (d, 3JCF = 4.9 Hz), 130.1 (d, 4JCF = 2.9 Hz), 136.4 (d, 4JCF = 3.3 Hz), 137.5 (d, 3JCF = 4.4 Hz), 138.7 (d, 1 JCF = 239.9 Hz); 19F NMR (376 MHz, CDCl3): d = 104.2 (d, J = 3.8 Hz, 1F); HRMS (EI): calc. for C19H15F [M]+: 262.1158, found: 262.1156. (2-Fluoro-5,5-dimethylhex-1-en-3-yne-1,1-diyl)dibenzene (3gi): White solid. mp: 58.3–59.1 8C. 1H NMR (400 MHz, CDCl3): d = 1.14 (s, 9H), 7.24–7.31 (m, 8H), 7.36–7.38 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 28.2 (d, 4JCF = 1.8 Hz), 30.2 (d, 5JCF = 1.6 Hz), 72.8 (d, 2JCF = 41.1 Hz), 105.2 (d, 3JCF = 6.5 Hz), 127.7, 127.8, 128.0 (d, 2JCF = 21.0 Hz), 128.3, 128.5, 130.0 (d, 3JCF = 4.9 Hz), 130.5 (d, 4 JCF = 2.9 Hz), 136.8 (d, 3JCF =3.3 Hz), 137.9, 139.1 (d, 1 JCF = 234.4 Hz); 19F NMR (376 MHz, CDCl3): d = 105.1 (s, 1F); HRMS (EI): calc. for C20H19F [M]+: 278.1471, found: 278.1474. (2-Fluoronon-1-en-3-yne-1,1-diyl)dibenzene (3gj): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 1.17 (t, J = 6.8 Hz, 3H), 1.52– 1.55 (m, 4H), 1.67–1.74 (m, 2H), 2.49–2.54 (m, 2H), 7.48–7.60 (m, 8H), 7.67–7.69 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 14.2, 19.6 (d, 4JCF = 2.1 Hz), 22.5, 27.9 (d, 5JCF = 1.7 Hz), 31.1, 74.4 (d, 2 JCF = 40.3 Hz), 97.9 (d, 3JCF = 6.1 Hz), 128.0, 128.1, 128.2, 128.3, 128.5 (d, 2JCF = 19.2 Hz), 136.9, 137.0, 138.0, 138.1, 139.3 (d, 1 JCF = 240.3 Hz); 19F NMR (376 MHz, CDCl3): d = 103.9 (t, J = 4.5 Hz, 1F); HRMS (EI): calc. for C21H21F [M]+: 292.1627, found: 292.1626. 4,40 -(2-Fluoro-4-phenylbut-1-en-3-yne-1,1-diyl)bis(methylbenzene) (3ha): White solid. mp: 67.6–68.7 8C. 1H NMR (400 MHz, CDCl3): d = 2.31 (s, 3H), 2.34 (s, 3H), 7.10–7.15 (m, 4H), 7.22–7.24 (m, 5H), 7.27–7.30 (m, 2H), 7.32–7.34 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 21.4, 21.5, 83.0 (d, 2JCF = 40.5 Hz), 95.4 (d, 3JCF = 6.4 Hz),
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G. Jin et al. / Journal of Fluorine Chemistry 168 (2014) 240–246
122.0 (d, 5JCF = 2.2 Hz), 128.5, 128.9 (d, 2JCF = 10.5 Hz), 129.1, 130.2 (d, 3JCF = 5.0 Hz), 130.6 (d, 4JCF = 2.9 Hz), 131.5 (d, 4JCF = 2.3 Hz), 133.9 (d, 4JCF = 3.5 Hz), 134.8 (d, 3JCF = 4.1 Hz), 135.8, 138.0, 138.1, 138.4 (d, 1JCF = 238.4 Hz), 141.5; 19F NMR (376 MHz, CDCl3): d = 108.3 (s, 1F); HRMS (EI): calc. for C24H19F [M]+: 326.1471, found: 326.1469. 4,40 -(2-Fluoro-4-phenylbut-1-en-3-yne-1,1-diyl)bis(fluorobenzene) (3ia): White solid. mp: 85.9–86.5 8C. 1H NMR (400 MHz, CDCl3): d = 6.96–7.05 (m, 4H), 7.22–7.29 (m, 7H), 7.36–7.39 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 82.3 (d, 2JCF = 40.5 Hz), 96.1 (d, 3 JCF = 6.3 Hz), 115.3 (d, 2JCF = 21.5 Hz), 115.4 (d, 2JCF = 21.4 Hz), 121.6 (d, 4JCF = 2.6 Hz), 128.6, 129.4, 131.5 (d, 4JCF = 2.3 Hz), 131.9 (d, 3JCF = 5.4 Hz), 132.0 (d, 3JCF = 5.4 Hz), 132.5 (d, 2JCF = 18.2 Hz), 132.5 (dd, 3JCF = 8.1 Hz, 4JCF = 3.0 Hz), 133.5 (d, 3JCF = 7.7 Hz), 139.0 (d, 1JCF = 240.8 Hz), 162.5 (d, 1JCF = 247.6 Hz), 162.8 (d, 1 JCF = 246.9 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 112.7 to 112.6 (m, 1F), 112.4 to 112.3 (m, 1F), 107.1 (s, 1F), ppm; HRMS (EI): calc. for C22H13F3 [M]+: 334.0969, found: 334.0968.
[3]
Acknowledgments
[4]
We are grateful for financial supports from the National Natural Science Foundation of China (Grant Nos. 21472043, 21272070 and 21072057), the National Basic Research Program of China (973 Program, 2010CB126101), and the Key Project in the National Science & Technology Pillar Program of China in the twelfth fiveyear plan period (2011BAE06B05).
[5]
[6]
Appendix A. Supplementary data [7]
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jfluchem. 2014.10.010. [8]
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Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
Stereoselective synthesis of b-fluoroenyne by the reaction of gem-difluoroalkenes with terminal alkynes Guanyi Jin a, Juan Zhang a, Wei Wu a, Song Cao a,b,* a b
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST), Shanghai 200237, China Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 July 2014 Received in revised form 2 October 2014 Accepted 14 October 2014 Available online 24 October 2014
A mild and convenient method for the stereoselective synthesis of a series of conjugated b-fluoroenynes by the reaction of gem-difluoroalkenes with terminal alkynes with the assistance of n-butyllithium and K3PO4 is described. ß 2014 Elsevier B.V. All rights reserved.
Keywords: Conjugated b-fluoroenynes gem-Difluoroalkenes Terminal alkynes Potassium phosphate
1. Introduction Conjugated enyne motif is found in many natural products and biologically active compounds (Fig. 1) [1]. Moreover, the conjugated 1,3-enynes are an important class of versatile building blocks in organic synthesis [2]. Therefore, the synthesis of various functionalized enynes has received much attention in recent years. A large number of methods for the synthesis of these valuable synthetic intermediates have been developed so far [3]. Among the protocols for the preparation of conjugated enyne, the Pd or Cu catalyzed C(sp2)–C(sp) cross-coupling reactions between vinylic and acetylenic partners is the most reliable and straightforward methodology [4]. The dimerization of terminal alkynes is an alternate and atom-economical route to conjugated enyne compounds [5]. The fluorinated conjugated enynes are a kind of useful synthons in organic transformation [6]. However, compared to 1,3-enynes, the synthesis and application of fluoroenynes have not been thoroughly investigated [7]. The most common method for the synthesis of conjugated fluoroenynes is the palladium-catalyzed cross-coupling of fluorinated vinyl halides (X = Cl, Br, I) with
* Corresponding author at: Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST), Shanghai 200237, China. Tel.: +86 21 64253452; fax: +86 21 64252603. E-mail address: [email protected] (S. Cao). http://dx.doi.org/10.1016/j.jfluchem.2014.10.010 0022-1139/ß 2014 Elsevier B.V. All rights reserved.
terminal alkynes [8]. Another facile and practical alternative for the preparation of fluorinated conjugated enynes involves the reaction of fluorinated alkenes with alkynyllithiums via a nucleophilic addition–elimination reaction. However, examples of the above-mentioned addition–elimination reaction are very scarce. Most importantly, the necessity of using certain fluoroalkenes such as highly electron-deficient fluorinated alkenes limits the utility of the method (Fig. 2, compounds I–IV) [9]. Consequently, it is still highly desirable to develop a simple method to access fluorinated conjugated enynes. Herein, we report an efficient and practical protocol for the E-selective formation of conjugated fluoroenynes by the reaction of gem-difluoroalkenes with terminal alkynes in the presence of n-butyllithium with the assistance of K3PO4 (Scheme 1). 2. Results and discussion In continuation of our research on the reactivity of gemdifluoroalkenes [10], in this paper, we focused on the nucleophilic vinylic substitution (SNV) of gem-difluoroalkenes, which have relatively electron-rich carbon–carbon double bond, with terminal alkynes. We chose 1-(2,2-difluorovinyl)-4-methoxybenzene 1a as the model substrate to optimize suitable conditions (Table 1). Initially, we have studied the influence of base on the model reaction. In the absence of the base, the reaction hardly proceeded and only trace amount of expected product 3aa was observed (Table 1, entry 1). Among the various bases examined, K3PO4 was
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Scheme 1. Synthesis of b-fluoroenynes.
Fig. 1. Four examples of bioactive conjugated enynes.
Fig. 2. Electron poor fluoroalkenes described in literature.
best, and Na2CO3 or Ca(OH)2 were less effective (Table 1, entries 2–6). The yields were also significantly affected by the amount of K3PO4. The use of 3.0 equiv. of K3PO4 afforded an excellent yield of 3aa with good E-selectivity (entry 6), but if the amount of K3PO4
was decreased to 1.0 or 2.0 equiv., the yields of 3aa decreased dramatically (entries 7 and 8). Substrate 1a was completely recovered in the reaction in the absence of K3PO4, suggesting that the K3PO4 plays a crucial role in this reaction. Subsequent screening of alternate solvents revealed that only THF could give fluoroenyne in excellent yield (entry 6), while almost no product was formed when Et2O, DMF, CH3CN, CH2Cl2 were used as solvent (entries 9–12). Furthermore, the reaction could not proceed well at the lower temperature (20 or 40 8C) (entry 13 and 14). Decreasing the amount of n-butyllithium or terminal alkyne 2a obviously diminished the yields (entries 15–18). In addition, in order to avoid the reaction of n-butyllithium with 1-(2,2-difluorovinyl)-4-methoxybenzene 1a, the amount of n-butyllithium is slightly less than that of 2a. With the optimized reaction conditions in hand (Table 1, entry 6), we further explored the scope of the novel nucleophilic vinylic substitution reaction of different terminal alkynes with gemdifluoroalkenes (Table 2). It was found that gem-difluoroalkenes containing electron-donating group such as CH3O and OCH2O on the aromatic ring could afford the corresponding fluoroenynes in high yields and good to high stereoselectivity, whereas gemdifluoroalkenes containing electron-withdrawing group such as CN on the aromatic ring only provided fluoroenyne in moderate yield (3ea). The replacement of the aryl group with the thienyl group in difluoroalkene would lead to a decrease in yield (3fa).
Table 1 Optimization of the reaction conditions.a
Entry
Amt of 2a (equiv.)
Temp. (8C)
n-BuLi (equiv.)
Base (equiv.)
Solvent
Yield of 3aa (%)b
E/Zb
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1.5
65 65 65 65 65 65 65 65 65 65 65 65 40 20 65 65 65 65
1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 0 1 0.5 1.5
– NaOH (3) Ca(OH)2 (3) Na2CO3 (3) Et3N (3) K3PO4 (3) K3PO4 (2) K3PO4 (1) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3) K3PO4 (3)
THF THF THF THF THF THF THF THF Et2O CH2Cl2 DMF CH3CN THF THF THF THF THF THF
5 0 20 29 0 98 65 17 0 8 0 0 16 5 0 64 47 70
88:12 – 88:12 85:15 – 88:12 87:13 85:15 – 88:12 – – 83:17 75:25 – 84:16 72:28 80:20
a
Reaction conditions: 1a (1.0 mmol), THF (6 mL), 6–8 h. Yields determined by GC analysis and based on 1a. The ratios of E/Z isomers in the crude reaction mixture were determined by 19F NMR. The configuration of E-isomer 3aa (after purification) was determined by its 3JHF coupling constant in 1H NMR spectrum. b
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Table 2 Reactions of gem-difluoroalkenes 1a–f with various terminal alkynes 2a–e.a,b,c
a
Reaction conditions: gem-difluoroalkenes 1a–f (1.0 mmol), 2a–e (2.0 mmol), n-BuLi (1.5 mmol), K3PO4 (3.0 mmol), THF (6 mL), 6–8 h, 65 8C. Isolated yields of an inseparable E/Z mixture of the products. c E/Z selectivity was determined by 19F NMR spectra. The configurations of E- and Z-isomers were determined by their 3JHF coupling constants in 1H NMR spectra (ca. 17.0 Hz for E-isomers and 35.0 Hz for Z-isomers) [7c]. b
In addition, the use of (E)-(4,4-difluorobuta-1,3-dien-1-yl)benzene resulted in an obvious decrease in yield (58%) and a poor E/Z selectivity (57:43, GC–MS and 19F NMR). Furthermore, when aliphatic difluoroalkene such as 1,1-difluoro-2-benzyl ethylene and terminal aliphatic alkyne such as pent-1-yne was used as substrate, the reaction did not proceed to completion and only a small amount of the expected fluoroenyne was observed. The effect of substituent on the aromatic ring of the terminal alkynes was also examined. The terminal alkynes bearing electrondonating groups (3ab and 3ac) gave higher yields than those containing electron-withdrawing groups (3ad and 3ae). Although the reaction proceeded well and gave fluoroenynes with good E-selectivity, unfortunately, (E)-isomers were not separated from the corresponding the (Z)-isomers at this stage due to their similarity in affinity to chromatographic silica gel. To avoid the formation of a mixture of E- and Z-isomers of products, symmetrical gem-difluoroalkenes (1g–i) were used as substrates to explore the limitations of the reaction (Table 3). As anticipated, both electron-donating and electron-withdrawing groups located in the aromatic rings of difluoroalkenes were found to be tolerated in this reaction, and these substrates furnished the corresponding symmetrical fluoroenynes in good to high yields (3ha and 3ia). We were delighted to find the terminal aliphatic alkynes could react with symmetrical gem-difluoroalkenes efficiently, however, the expected products were obtained in slightly lower yields (Table 3, 3gg, 3gh, 3gi and 3gj). Based on the above observations and earlier reports by Jeong and Konno et al. [9b,9c], a plausible mechanism for the formation of 3 is outlined in Scheme 2. First, gem-difluoroalkene reacts with terminal alkyne in the presence of n-butyllithium to give the key carbanion intermediate I. Subsequently, rotation of the intermediate I by 60 degrees would result in two conformational intermediates, II and IV, which is in equilibrium with III and V, respectively. The intermediate IV is unstable due to the existence of electronic repulsion between the aryl group and fluorine atom.
Finally, the elimination of a fluoride ion from the intermediates II with the assistance of K3PO4 affords (E)-3 in a high stereoselectivity. 3. Conclusions In conclusion, we have developed a novel and efficient method for the synthesis of conjugated b -fluoroenynes by the reaction of gem-difluoroalkenes with terminal alkynes via nucleophilic substitution of vinylic fluorine (SNV) in the presence of n-butyllithium and K3PO4. The reaction proceeds efficiently under mild reaction conditions affording the fluorinated enynes in good to excellent yields with good E selectivity. The addition of 3 equiv. of K3PO4 is essential for efficient transformation. The applications of this valuable building block (fluoroenyne) are currently underway in our laboratory. 4. Experimental All reagents were of analytical grade, and obtained from commercial suppliers and used without further purification. THF and other solvents were dried by standard method prior to use. Melting points were measured in an open capillary using Bu¨chi melting point B-540 apparatus and are uncorrected. 1H NMR and 13 C NMR spectra were recorded on a 400 spectrometer (400 MHz for 1H and 100 MHz for 13C NMR, respectively) using TMS as internal standard, The 19F NMR spectra were obtained using a 400 spectrometer (376 MHz). CDCl3 was used as the NMR solvent in all cases. High resolution mass spectra (HRMS) were recorded under electron impact conditions using a MicroMass GCT CA 055 instrument and recorded on a MicroMass LCTTM spectrometer. Silica gel (300–400 mesh size) was used for column chromatography. TLC analysis of reaction mixtures was performed using silica gel plates.
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Table 3 Reactions of symmetrical gem-difluoroalkenes 1g–i with various terminal alkynes 2a–j.a,b
a b
Reaction conditions: gem-difluoroalkenes 1g–i (1.0 mmol), 2a–j (2.0 mmol), n-BuLi (1.5 mmol), K3PO4 (3.0 mmol), THF (6 mL), 6–8 h, 65 8C. Isolated yields.
Scheme 2. A plausible mechanism for the formation of 3.
4.1. Preparation of 1,1-difluoroalkenes 1a–f and symmetrical gemdifluoroalkenes 1g–i The 1,1-difluoroalkenes (1a–f) were prepared according to the reported procedure [11a,11b]. The symmetrical gem-difluoroalkenes (1g–i) were prepared according to the Hu’s reported procedure [12]. 4.2. General procedure for the target compounds 3 Under an argon atmosphere, n-BuLi (0.93 mL, 1.6 M in hexanes, 1.5 mmol) was added dropwise to a solution of terminal alkynes
2a–j (2.0 mmol) and anhydrous K3PO4 (3.0 mmol, 0.636 g) in 5 mL of dry THF at 0 8C. After stirring the reaction mixture at 0 8C for 30 min, a solution of gem-difluoroalkenes 1a–i (1.0 mmol) in 1 mL of dry THF was added dropwise to the mixture at 0 8C and then the mixture was stirred at 65 8C until the reaction was completed as monitored by TLC (usually about 6–8 h). The reaction mixture was allowed to cool to room temperature and quenched with H2O (5 mL). The aqueous phase was extracted with EtOAc (3 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography using n-hexane as eluent to afford the corresponding product 3.
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(E/Z)-1-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)-4-methoxybenzene (E/Z-3aa): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 3.89 (s, 3H, Z-isomer), 3.90 (s, 3H, E-isomer), 6.24 (d, J = 35.6 Hz, 1H, Z-isomer), 6.75 (d, J = 17.0 Hz, 1H, E-isomer), 6.97 (d, J = 8.8 Hz, 2H, Z-isomer), 7.04 (d, J = 8.8 Hz, 2H, E-isomer), 7.46–7.47 (m, 3H, Z-isomer), 7.49–7.50 (m, 3H, E-isomer), 7.59–7.63 (m, 4H, Z-isomer), 7.66–7.69 (m, 2H, E-isomer), 7.79 (d, J = 8.4 Hz, 2H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.3, 81.8 (d, 2JCF = 41.0 Hz), 97.7 (d, 3JCF = 7.0 Hz), 114.2, 117.5 (d, 2JCF = 33.0 Hz), 121.6 (d, 4JCF = 2.4 Hz), 124.7 (d, 3JCF = 8.9 Hz), 128.8, 129.6, 129.7, 131.8 (d, 4JCF = 2.3 Hz), 140.1 (d, 1 JCF = 227.7 Hz), 159.8 (d, 5JCF = 1.6 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 107.4 (d, J = 35.3 Hz, 1F, Z-isomer), 105.5 (d, J = 17.7 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C17H13FO [M]+: 252.0950, found: 252.0949. (E/Z)-1-(3-Fluoro-4-(4-methoxyphenyl)but-3-en-1-yn-1-yl)4-methylbenzene (E/Z-3ab): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 2.44 (s, 3H, Z-isomer), 2.46 (s, 3H, E-isomer), 3.86 (s, 3H, Z-isomer), 3.89 (s, 3H, E-isomer), 6.18 (d, J = 35.6 Hz, 1H, Z-isomer), 6.69 (d, J = 16.8 Hz, 1H, E-isomer), 6.94 (d, J = 8.8 Hz, 2H, Z-isomer), 6.99–7.02 (m, 2H, E-isomer), 7.21–7.26 (m, 2H, Z-isomer), 7.28 (d, J = 8.0 Hz, 2H, E-isomer), 7.50–7.51 (m, 2H, Z-isomer), 7.54 (d, J = 8.0 Hz, 2H, E-isomer), 7.60 (d, J = 8.8 Hz, 2H, Z-isomer), 7.75 (d, J = 8.8 Hz, 2H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 21.7, 55.3, 81.1 (d, 2JCF = 41.0 Hz), 97.9 (d, 3JCF = 7.0 Hz), 114.1, 117.0 (d, 2JCF = 33.3 Hz), 124.8 (d, 3 JCF = 9.0 Hz), 129.5 (d, 4JCF = 4.4 Hz), 131.7 (d, 4JCF = 2.3 Hz), 134.2, 140.0, 140.3 (d, 1JCF = 245.2 Hz), 141.4, 159.7 (d, 5 JCF = 2.0 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 107.1 (d, J = 35.7 Hz, 1F, Z-isomer), 105.1 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C18H15FO [M]+: 266.0743, found: 266.0742. (E/Z)-4,40 -(2-Fluorobut-1-en-3-yne-1,4-diyl)bis(methoxybenzene) (E/Z-3ac): White solid. 1H NMR (400 MHz, CDCl3): d = 3.84 (s, 3H, Z-isomer), 3.85 (s, 3H, both E- and Z-isomers), 3.86 (s, 3H, E-isomer), 6.15 (d, J = 35.5 Hz, 1H, Z-isomer), 6.66 (d, J = 17.0 Hz, 1H, E-isomer), 6.91–6.93 (m, 4H, Z-isomer), 6.96–7.00 (m, 4H, E-isomer), 7.52–7.54 (m, 4H, Z-isomer), 7.56 (d, J = 8.8 Hz, 2H, E-isomer), 7.73 (d, J = 8.7 Hz, 2H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.2, 55.3, 80.5 (d, 2 JCF = 40.8 Hz), 98.0 (d, 3JCF = 7.2 Hz), 114.1, 114.4, 116.6 (d, 2 JCF = 33.3 Hz), 124.8 (d, 3JCF = 8.9 Hz), 129.5 (d, 4JCF = 3.0 Hz), 133.4 (d, 4JCF = 2.5 Hz), 134.1, 140.3 (d, 1JCF = 226.9 Hz), 159.6 (d, 5 JCF = 2.2 Hz), 160.7 ppm; 19F NMR (376 MHz, CDCl3): d = 106.7 (d, J = 35.3 Hz, 1F, Z-isomer), 104.7 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (ESI): calc. for C18H15FO2 [M]+: 282.1056, found: 282.1053. (E/Z)-1-Fluoro-4-(3-fluoro-4-(4-methoxyphenyl)but-3-en-1yn-1-yl)benzene (E/Z-3ad): White solid. 1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3H, both E- and Z-isomers), 6.12 (d, J = 35.3 Hz, 1H, Z-isomer), 6.65 (d, J = 16.9 Hz, 1H, E-isomer), 6.93–6.96 (m, 2H, both E- and Z-isomers), 7.09–7.15 (m, 2H, both E- and Z-isomers), 7.53–7.58 (m, 2H, both E- and Z-isomers), 7.64–7.68 (m, 2H, both E- and Z-isomers) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.3, 81.2 (d, 2JCF = 41.0 Hz), 96.2 (d, 3JCF = 7.1 Hz), 114.1, 116.0 (d, 2JCF = 22.0 Hz), 117.3 (d, 2 JCF = 32.9 Hz), 124.6 (d, 3JCF = 8.8 Hz), 129.4 (d, 4JCF = 3.2 Hz), 133.2 (dd, 3JCF = 8.4 Hz, 5JCF = 2.4 Hz), 139.9 (d, 1JCF = 229.1 Hz), 159.6, 159.7, 163.2 (d, 1JCF = 250.2 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 109.2 to 109.1 (m, 1F, Z-isomer), 108.6 to 108.5 (m, 1F, E-isomer), 107.9 (d, J = 35.3 Hz, 1F, Z-isomer), 106.1 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C17H12F2O [M]+: 270.0856, found: 270.0857. (E/Z)-2-(3-Fluoro-4-(4-methoxyphenyl)but-3-en-1-yn-1yl)pyridine (E/Z-3ae): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3H, both E- and Z-isomers), 6.25 (d, J = 35.2 Hz, 1H,
Z-isomer), 6.71 (d, J = 16.8 Hz, 1H, E-isomer), 6.90–6.92 (m, 1H, Z-isomer), 6.93–6.95 (m, 2H, both E- and Z-isomers), 7.32–7.35 (m, 1H, both E- and Z-isomers), 7.52–7.53 (m, 1H, Z-isomer), 7.55–7.57 (m, 1H, both E- and Z-isomers), 7.69 (d, J = 8.8 Hz, 2H, E-isomer), 7.73–7.77 (m, 1H, both E- and Z-isomers), 8.65–8.66 (m, 1H, Z-isomer), 8.69–8.90 (m, 1H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.3, 80.9 (d, 2JCF = 41.2 Hz), 96.0 (d, 3JCF = 7.2 Hz), 114.2, 119.0 (d, 2JCF = 32.1 Hz), 123.7, 124.2 (d, 3 JCF = 8.7 Hz), 127.6, 129.7 (d, 4JCF = 3.1 Hz), 136.3, 139.4 (d, 1 JCF = 228.2 Hz), 142.0 (d, 4JCF = 2.3 Hz), 150.4, 159.8 ppm; 19F NMR (376 MHz, CDCl3): d = 110.3 (d, J = 35.3 Hz, 1F, Z-isomer), 108.1 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C16H12FNO [M]+: 253.0903, found: 253.0902. (E/Z)-5-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)benzo[d][1,3]dioxole (E/Z-3ba): White solid. 1H NMR (400 MHz, CDCl3): d = 6.01 (s, 2H, both E- and Z-isomers), 6.10 (d, J = 34.8 Hz, 1H, Z-isomer), 6.62 (d, J = 16.8 Hz, 1H, E-isomer), 6.83–6.86 (m, 1H, both E- and Z-isomers), 6.99–7.01 (m, 1H, Z-isomer), 7.08–7.10 (m, 1H, E-isomer), 7.22–7.23 (m, 1H, Z-isomer), 7.43–7.46 (m, 4H, both E- and Z-isomers), 7.55–7.56 (m, 1H, Z-isomer), 7.59–7.61 (m, 2H, E-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 81.4 (d, 2JCF = 41.0 Hz), 98.0 (d, 3JCF = 6.9 Hz), 101.3, 107.3 (d, 5 JCF = 2.3 Hz), 108.4, 117.5 (d, 2JCF = 33.8 Hz), 121.4 (d, 4 JCF = 2.4 Hz), 123.2 (d, 4JCF = 4.0 Hz), 126.3 (d, 3JCF = 9.0 Hz), 128.6, 129.5, 131.7 (d, 4JCF = 2.3 Hz), 140.2 (d, 1JCF = 228.6 Hz), 147.7 (d, 5JCF = 2.1 Hz), 147.9 ppm; 19F NMR (376 MHz, CDCl3): d = 106.6 (d, J = 34.6 Hz, 1F, Z-isomer), 105.0 (d, J = 17. 3 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C17H11FO2 [M]+: 266.1107, found: 266.1108. (E/Z)-4-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)-1,2-dimethoxybenzene (E/Z-3ca): White solid. 1H NMR (400 MHz, CDCl3): d = 3.84 (s, 3H, both E- and Z-isomers), 3.89 (s, 3H, both E- and Z-isomers), 6.10 (d, J = 34.8 Hz, 1H, Z-isomer), 6.61 (d, J = 16.8 Hz, 1H, E-isomer), 6.85–6.87 (m, 1H, both E- and Z-isomers), 7.04–7.10 (m, 2H, Z-isomer), 7.14–7.16 (m, 1H, both E- and Z-isomers), 7.37– 7.39 (m, 3H, E-isomer), 7.45–7.46 (m, 1H, E-isomer), 7.53–7.55 (m, 2H, E-isomer), 7.62 (d, J = 8.4 Hz, 2H, Z-isomer), 7.73–7.78 (m, 2H, Z-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 55.7, 55.8, 81.6 (d, 2JCF = 41.0 Hz,), 97.7 (d, 3JCF = 7.0 Hz), 110.3 (d, 4JCF = 2.3 Hz), 111.1, 117.6 (d, 2JCF = 33.2 Hz), 121.3 (d, 4 JCF = 2.5 Hz), 121.9 (d, 4JCF = 3.9 Hz), 124.9 (d, 3JCF = 9.0 Hz), 128.7, 129.6, 131.6 (d, 5JCF = 2.2 Hz), 140.0 (d, 1JCF = 228.2 Hz), 148.8, 149.3 (d, 5JCF = 2.1 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 107.4 (d, J = 35.0 Hz, 1F, Z-isomer), 105.4 (d, J = 16.9 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C18H15FO2 [M]+: 282.1056, found: 282.1057. (E/Z)-2-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)naphthalene (E/Z-3da): White solid. 1H NMR (400 MHz, CDCl3): d = 6.91 (d, J = 32.8 Hz, 1H, Z-isomer), 7.33 (d, J = 15.6 Hz, 1H, E-isomer), 7.35–7.36 (m, 1H, both E- and Z-isomers), 7.37–7.39 (m, 2H, both E- and Z-isomers), 7.42–7.45 (m, 2H, both E- and Z-isomers), 7.52– 7.61 (m, 3H, both E- and Z-isomers), 7.86–7.92 (m, 2H, E-isomer), 7.92–7.97 (m, 2H, Z-isomer), 8.04–8.07 (m, 2H, E-isomer), 8.13 (d, J = 8.4 Hz, 2H, Z-isomer) ppm; 13C NMR (100 MHz, CDCl3) for the major E-isomer: d = 80.9 (d, 2JCF = 41.5 Hz), 95.7 (d, 3JCF = 6.7 Hz), 114.6 (d, 2JCF = 32.1 Hz), 121.3, 123.8, 125.3, 126.0, 126.4, 126.5, 126.6, 128.5, 128.7, 128.8, 129.1 (d, 3JCF = 8.2 Hz), 129.4, 131.7 (d, 4 JCF = 2.2 Hz), 133.6, 142.5 (d, 1JCF = 233.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 104.6 (d, J = 32.7 Hz, Z-isomer), 100.7 (d, J = 15.3 Hz, 1F, E-isomer) ppm; HRMS (EI): calc. for C20H13F [M]+: 272.1001, found: 272.0988. (E/Z)-4-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)benzonitrile (E/ Z-3ea): White solid. 1H NMR (400 MHz, CDCl3): d = 6.10 (d, J = 33.6 Hz, 1H, Z-isomer), 6.58 (d, J = 16.0 Hz, 1H, E-isomer), 7.34–7.39 (m, 3H, both E- and Z-isomers), 7.49–7.51 (m, 2H, both E- and Z-isomers), 7.56–7.59 (m, 2H, both E- and Z-isomers),
G. Jin et al. / Journal of Fluorine Chemistry 168 (2014) 240–246
7.71–7.73 (m, 2H, both E- and Z-isomers); 13C NMR (100 MHz, CDCl3): d = 80.6 (d, 2JCF = 40.5 Hz), 98.8 (d, 3JCF = 5.9 Hz), 111.3 (d, 5 JCF = 1.8 Hz), 116.0 (d, 2JCF = 34.4 Hz), 118.8, 120.6 (d, 4 JCF = 2.1 Hz), 128.5 (d, 4JCF = 3.1 Hz), 128.8, 130.2, 131.9 (d, 5 JCF = 1.9 Hz), 132.2, 137.1 (d, 3JCF = 10.1 Hz), 142.9 (d, 1 JCF = 237.3 Hz); 19F NMR (376 MHz, CDCl3): d = 98.2 (d, J = 33.8 Hz, 1F, Z-isomer), 95.6 (d, J = 15.8 Hz, 1F, E-isomer); HRMS (EI): calc. for C17H10FN [M]+: 247.0797, found: 247.0796. (E/Z)-2-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)thiophene (E/Z3fa): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 6.37 (d, J = 34.0 Hz, 1H, Z-isomer), 6.82 (d, J = 13.6 Hz, 1H, E-isomer), 6.86–6.89 (m, 1H, Z-isomer), 6.93–6.95 (m, 1H, E-isomer), 7.03– 7.08 (m, 2H, Z-isomer), 7.09–7.10 (m, 1H, E-isomer), 7.15–7.17 (m, 1H, Z-isomer), 7.19–7.20 (m, 1H, E-isomer), 7.25–7.26 (m, 2H, Zisomer), 7.30–7.31 (m, 3H, E-isomer), 7.42–7.45 (m, 2H, Z-isomer), 7.54–7.56 (m, 2H, E-isomer); 13C NMR (100 MHz, CDCl3): d = 81.4 (d, 2JCF = 40.8 Hz), 101.3 (d, 3JCF = 6.6 Hz), 112.9 (d, 2JCF = 37.3 Hz), 121.6 (d, 5JCF = 2.1 Hz), 126.4 (d, 4JCF = 4.6 Hz), 127.1, 128.8, 129.3 (d, 5JCF = 6.9 Hz), 129.8, 131.8 (d, 5JCF = 2.1 Hz), 135.4 (d, 3 JCF = 8.3 Hz), 140.3 (d, 1JCF = 231.5 Hz); 19F NMR (376 MHz, CDCl3): d = 108.9 (d, J = 13.5 Hz, 1F, E-isomer), 102.7 (d, J = 36.0 Hz, 1F, Z-isomer); HRMS (EI): calc. for C14H9FS [M]+: 228.0409, found: 228.0408. (2-Fluorobut-1-en-3-yne-1,1,4-triyl)tribenzene (3ga): White solid. mp: 88.9–89.6 8C. 1H NMR (400 MHz, CDCl3): d = 7.43– 7.60 (m, 13H), 7.68–7.69 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 82.8 (d, 2JCF = 40.7 Hz), 95.8 (d, 3JCF = 6.3 Hz), 121.8, 121.9, 128.3, 128.4, 128.6, 129.3, 130.2, 130.3, 130.4 (d, 2JCF = 16.9 Hz), 130.8 (d, 4JCF = 2.9 Hz), 131.6 (d, 4JCF = 2.2 Hz), 136.7 (d, 3 JCF = 3.6 Hz), 137.8 (d, 3JCF = 4.2 Hz), 139.1 (d, 1JCF = 240.3 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 107.2 (s, 1F) ppm; HRMS (EI): calc. for C22H15F [M]+: 298.1158, found: 298.1157. (2-Fluoro-4-(p-tolyl)but-1-en-3-yne-1,1-diyl)dibenzene (3gb): White solid. mp: 89.5–89.9 8C. 1H NMR (400 MHz, CDCl3): d = 2.86 (s, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.44–7.55 (m, 8H), 7.64 (dd, J = 6.9, 1.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 21.7, 82.2 (d, 2JCF = 40.5 Hz), 96.1 (d, 3JCF = 5.8 Hz), 118.8 (d, 5 JCF = 2.1 Hz), 128.0, 128.1, 128.2, 128.3, 129.3, 129.8 (d, 2 JCF = 18.5 Hz), 130.2 (d, 3JCF = 5.1 Hz), 130.7 (d, 4JCF = 2.9 Hz), 131.5 (d, 4JCF = 2.4 Hz), 136.7 (d, 4JCF = 3.6 Hz), 137.8 (d, 3 JCF = 4.1 Hz), 139.1 (d, 1JCF = 240.1 Hz), 139.6 ppm; 19F NMR (376 MHz, CDCl3): d = 106.9 (s, 1F) ppm; HRMS (EI): calc. for C23H17F [M]+: 312.1314, found: 312.1315. (2-Fluoro-4-(4-methoxyphenyl)but-1-en-3-yne-1,1-diyl)dibenzene (3gc): White solid. mp: 91.0–91.6 8C. 1H NMR (400 MHz, CDCl3): d = 3.86 (s, 3H), 6.94 (d, J = 8.7 Hz, 2H), 7.39–7.45 (m, 3H), 7.47–7.54 (m, 7H), 7.64 (dd, J = 7.4, 1.7 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 55.4, 81.6 (d, 2JCF = 40.6 Hz), 96.0 (d, 3 JCF = 6.5 Hz), 113.7, 113.8, 114.3, 128.1, 128.2, 128.3, 129.4 (d, 2 JCF = 18.9 Hz), 130.2 (d, 3JCF = 5.1 Hz), 130.8 (d, 4JCF = 2.6 Hz), 133.2 (d, 4JCF = 2.4 Hz), 136.8 (d, 4JCF = 3.5 Hz), 137.9 (d, 3JCF = 4.3 Hz), 139.2 (d, 1JCF = 239.9 Hz), 160.5 ppm; 19F NMR (376 MHz, CDCl3): d = 106.7 (s, 1F) ppm; HRMS (EI): calc. for C23H17FO [M]+: 328.1263, found: 328.1262. (2-Fluoro-4-(4-fluorophenyl)but-1-en-3-yne-1,1-diyl)dibenzene (3gd): White solid. mp: 95.9–96.8 8C. 1H NMR (400 MHz, CDCl3): d = 6.90–6.94 (m, 2H), 7.20–7.35 (m, 10H), 7.41–7.44 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 82.4 (d, 2JCF = 40.8 Hz), 94.6 (d, 3JCF = 6.3 Hz), 115.9 (d, 2JCF = 22.2 Hz), 117.9 (dd, 3 JCF = 3.4 Hz, 5JCF = 2.3 Hz), 128.2, 128.3, 130.1, 130.2, 130.3 (d, 2 JCF = 17.7 Hz), 130.7 (d, 3JCF = 2.9 Hz), 133.5 (d, 4JCF = 2.3 Hz), 113.6 (d, 4JCF = 2.2 Hz), 136.5 (d, 3JCF = 3.6 Hz), 137.6, 138.8 (d, 1 JCF = 235.7 Hz), 163.0 (d, 1JCF = 249.8 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 108.9 to 108.8 (m, 1F), 107.8 (s, 1F) ppm; HRMS (EI): calc. for C22H14F2 [M]+: 316.1064, found: 316.1065.
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2-(3-Fluoro-4,4-diphenylbut-3-en-1-yn-1-yl)pyridine (3ge): White solid. mp: 66.1–66.8 8C. 1H NMR (400 MHz, CDCl3): d = 7.13–7.21 (m, 2H), 7.31–7.40 (m, 8H), 7.48–7.56 (m, 3H), 8.54–8.56 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): d = 81.9 (d, 2 JCF = 40.7 Hz), 94.4 (d, 3JCF = 6.3 Hz), 123.5, 127.5, 127.6, 128.3, 128.4, 128.5, 130.2 (d, 3JCF = 5.1 Hz), 130.6 (d, 4JCF = 2.9 Hz), 131.9 (d, 2JCF = 17.6 Hz), 136.1, 136.2 (d, 4JCF = 3.8 Hz), 137.1 (d, 3 JCF = 4.0 Hz), 138.3 (d, 1JCF = 240.9 Hz), 142.0 (d, 4JCF = 2.0 Hz), 150.2 ppm; 19F NMR (376 MHz, CDCl3): d = 108.7 (s, 1F) ppm; HRMS (EI): calc. for C21H14FN [M]+: 299.1110, found: 299.1107. (4-(4-Ethylphenyl)-2-fluorobut-1-en-3-yne-1,1-diyl)dibenzene (3gf): White solid. mp: 63.3–63.8 8C. 1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.6 Hz, 3H), 2.69 (q, J = 7.6 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.37–7.44 (m, 8H), 7.52–7.54 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 15.3, 28.9, 81.9 (d, 2 JCF = 40.0 Hz), 95.9 (d, 3JCF = 6.3 Hz), 118.8 (d, 5JCF = 2.0 Hz), 127.8, 127.9, 128.0, 128.1, 128.2, 129.7 (d, 2JCF = 18.8 Hz), 130.1 (d, 3 JCF = 7.0 Hz), 130.7 (d, 4JCF = 3.0 Hz), 131.5 (d, 4JCF = 2.1 Hz), 136.6 (d, 4JCF = 3.5 Hz), 137.7 (d, 3JCF = 4.4 Hz), 139.0 (d, 1JCF = 240.0 Hz), 145.8 ppm; 19F NMR (376 MHz, CDCl3): d = 107.2 (s, 1F) ppm; HRMS (EI): calc. for C24H19F [M]+: 326.1471, found: 326.1472. (2-Fluorohept-1-en-3-yne-1,1-diyl)dibenzene (3gg): White solid. mp: 37.6–38.0 8C. 1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7.6 Hz, 3H), 1.51–1.60 (m, 2H), 2.32–2.37 (m, 2H), 7.31–7.43 (m, 8H), 7.45–7.47 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 13.4, 21.4, 21.5, 74.0 (d, 2JCF = 40.3 Hz), 97.5 (d, 3JCF = 6.0 Hz), 127.7, 127.8, 128.0, 128.1, 128.2 (d, 2JCF = 19.3 Hz), 130.0 (d, 3JCF = 5.0 Hz), 130.5 (d, 4JCF = 2.8 Hz), 136.7 (d, 5JCF = 3.5 Hz), 137.8, 138.5 (d, 1 JCF = 243.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 104.4 (t, J = 4.1 Hz, 1F) ppm; HRMS (EI): calc. for C19H17F [M]+: 264.1314, found: 264.1315. (4-Cyclopropyl-2-fluorobut-1-en-3-yne-1,1-diyl)dibenzene (3gh): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 0.84–0.88 (m, 2H), 0.93–0.98 (m, 2H), 1.45–1.52 (m, 1H), 7.44–7.54 (m, 8H), 7.59–7.61 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 0.0 (d, 4 JCF = 2.5 Hz), 8.5 (d, 5JCF = 1.6 Hz), 68.6 (d, 2JCF = 40.6 Hz), 100.5 (d, 3JCF = 6.1 Hz), 127.5, 127.6, 127.7, 127.8, 128.1 (d, 2 JCF = 19.5 Hz), 129.7 (d, 3JCF = 4.9 Hz), 130.1 (d, 4JCF = 2.9 Hz), 136.4 (d, 4JCF = 3.3 Hz), 137.5 (d, 3JCF = 4.4 Hz), 138.7 (d, 1 JCF = 239.9 Hz); 19F NMR (376 MHz, CDCl3): d = 104.2 (d, J = 3.8 Hz, 1F); HRMS (EI): calc. for C19H15F [M]+: 262.1158, found: 262.1156. (2-Fluoro-5,5-dimethylhex-1-en-3-yne-1,1-diyl)dibenzene (3gi): White solid. mp: 58.3–59.1 8C. 1H NMR (400 MHz, CDCl3): d = 1.14 (s, 9H), 7.24–7.31 (m, 8H), 7.36–7.38 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 28.2 (d, 4JCF = 1.8 Hz), 30.2 (d, 5JCF = 1.6 Hz), 72.8 (d, 2JCF = 41.1 Hz), 105.2 (d, 3JCF = 6.5 Hz), 127.7, 127.8, 128.0 (d, 2JCF = 21.0 Hz), 128.3, 128.5, 130.0 (d, 3JCF = 4.9 Hz), 130.5 (d, 4 JCF = 2.9 Hz), 136.8 (d, 3JCF =3.3 Hz), 137.9, 139.1 (d, 1 JCF = 234.4 Hz); 19F NMR (376 MHz, CDCl3): d = 105.1 (s, 1F); HRMS (EI): calc. for C20H19F [M]+: 278.1471, found: 278.1474. (2-Fluoronon-1-en-3-yne-1,1-diyl)dibenzene (3gj): Yellow liquid. 1H NMR (400 MHz, CDCl3): d = 1.17 (t, J = 6.8 Hz, 3H), 1.52– 1.55 (m, 4H), 1.67–1.74 (m, 2H), 2.49–2.54 (m, 2H), 7.48–7.60 (m, 8H), 7.67–7.69 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 14.2, 19.6 (d, 4JCF = 2.1 Hz), 22.5, 27.9 (d, 5JCF = 1.7 Hz), 31.1, 74.4 (d, 2 JCF = 40.3 Hz), 97.9 (d, 3JCF = 6.1 Hz), 128.0, 128.1, 128.2, 128.3, 128.5 (d, 2JCF = 19.2 Hz), 136.9, 137.0, 138.0, 138.1, 139.3 (d, 1 JCF = 240.3 Hz); 19F NMR (376 MHz, CDCl3): d = 103.9 (t, J = 4.5 Hz, 1F); HRMS (EI): calc. for C21H21F [M]+: 292.1627, found: 292.1626. 4,40 -(2-Fluoro-4-phenylbut-1-en-3-yne-1,1-diyl)bis(methylbenzene) (3ha): White solid. mp: 67.6–68.7 8C. 1H NMR (400 MHz, CDCl3): d = 2.31 (s, 3H), 2.34 (s, 3H), 7.10–7.15 (m, 4H), 7.22–7.24 (m, 5H), 7.27–7.30 (m, 2H), 7.32–7.34 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 21.4, 21.5, 83.0 (d, 2JCF = 40.5 Hz), 95.4 (d, 3JCF = 6.4 Hz),
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122.0 (d, 5JCF = 2.2 Hz), 128.5, 128.9 (d, 2JCF = 10.5 Hz), 129.1, 130.2 (d, 3JCF = 5.0 Hz), 130.6 (d, 4JCF = 2.9 Hz), 131.5 (d, 4JCF = 2.3 Hz), 133.9 (d, 4JCF = 3.5 Hz), 134.8 (d, 3JCF = 4.1 Hz), 135.8, 138.0, 138.1, 138.4 (d, 1JCF = 238.4 Hz), 141.5; 19F NMR (376 MHz, CDCl3): d = 108.3 (s, 1F); HRMS (EI): calc. for C24H19F [M]+: 326.1471, found: 326.1469. 4,40 -(2-Fluoro-4-phenylbut-1-en-3-yne-1,1-diyl)bis(fluorobenzene) (3ia): White solid. mp: 85.9–86.5 8C. 1H NMR (400 MHz, CDCl3): d = 6.96–7.05 (m, 4H), 7.22–7.29 (m, 7H), 7.36–7.39 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 82.3 (d, 2JCF = 40.5 Hz), 96.1 (d, 3 JCF = 6.3 Hz), 115.3 (d, 2JCF = 21.5 Hz), 115.4 (d, 2JCF = 21.4 Hz), 121.6 (d, 4JCF = 2.6 Hz), 128.6, 129.4, 131.5 (d, 4JCF = 2.3 Hz), 131.9 (d, 3JCF = 5.4 Hz), 132.0 (d, 3JCF = 5.4 Hz), 132.5 (d, 2JCF = 18.2 Hz), 132.5 (dd, 3JCF = 8.1 Hz, 4JCF = 3.0 Hz), 133.5 (d, 3JCF = 7.7 Hz), 139.0 (d, 1JCF = 240.8 Hz), 162.5 (d, 1JCF = 247.6 Hz), 162.8 (d, 1 JCF = 246.9 Hz) ppm; 19F NMR (376 MHz, CDCl3): d = 112.7 to 112.6 (m, 1F), 112.4 to 112.3 (m, 1F), 107.1 (s, 1F), ppm; HRMS (EI): calc. for C22H13F3 [M]+: 334.0969, found: 334.0968.
[3]
Acknowledgments
[4]
We are grateful for financial supports from the National Natural Science Foundation of China (Grant Nos. 21472043, 21272070 and 21072057), the National Basic Research Program of China (973 Program, 2010CB126101), and the Key Project in the National Science & Technology Pillar Program of China in the twelfth fiveyear plan period (2011BAE06B05).
[5]
[6]
Appendix A. Supplementary data [7]
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jfluchem. 2014.10.010. [8]
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