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Communication

Palladium-Catalyzed Cross-Coupling of Gem-Bromofluoroalkenes with Alkylboronic Acids for the Synthesis of Alkylated Monofluoroalkenes

by
Laëtitia Chausset-Boissarie
*,
Nicolas Cheval
and
Christian Rolando
*
Univ. Lille, CNRS, USR 3290—MSAP—Miniaturisation Pour la Synthèse, l’Analyse et la Protéomique, F-59000 Lille, France
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(23), 5532; https://doi.org/10.3390/molecules25235532
Submission received: 15 October 2020 / Revised: 13 November 2020 / Accepted: 19 November 2020 / Published: 25 November 2020
(This article belongs to the Special Issue Organofluorine Chemistry)
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Abstract

:
Monofluoroalkenes are versatile fluorinated synthons in organic synthesis, medicinal chemistry and materials science. In light of the importance of alkyl-substituted monofluoroalkenes efficient synthesis of these moieties still represents a synthetic challenge. Herein, we described a mild and efficient methodology to obtain monofluoroalkenes through a stereospecific palladium-catalyzed alkylation of gem-bromofluoroalkenes with primary and strained secondary alkylboronic acids under mild conditions. This novel strategy gives access to a wide range of functionalized tri- and tetrasubstituted monofluoroalkenes in high yield, with good functional group tolerance, independently from the gem-bromofluoroalkenes geometry.

Graphical Abstract

1. Introduction

The incorporation of fluorine atoms into bioactive molecules hugely impacts their physicochemical and pharmacokinetic properties, prevents oxidative metabolism and, more important, modulates their overall biological activities [1,2]. Accordingly, fluorinated compounds are abundant scaffolds found in a large variety of materials, agrochemicals and pharmaceuticals [3,4,5,6,7,8]. In particular, monofluoroalkenes are highly valuable fluorinated synthons in organic synthesis, in high-performance materials and in medicinal chemistry as they are excellent peptide bond mimics with enhanced stability towards proteases and stable conformation, improving the molecule stability and lipophilicity [9,10]. Despite the importance of alkylated monofluoroalkenes, limited methodologies have been developed for their modular synthesis. Pioneering studies to obtain alkyl-substituted monofluoroalkenes were focused on classical olefination (Wittig, Horner-Wadsworth-Emmons or Julia Kocienski reaction) [11,12], electrophilic fluorination or fluorination of alkynes [13,14,15,16]. More recently, transition metal-catalyzed defluorinative alkylation of gem-difluoroalkenes [17,18,19,20,21] or gem-difluorocyclopropanes [22,23,24] with various carbon nucleophiles has proven to be efficient strategies to access alkylated monofluoroalkenes. In the meantime, photoredox monofluoroalkenylation of gem-difluoroalkenes has also been successfully applied for their syntheses [25,26,27,28]. Despite these remarkable achievements, defluorinative cross-coupling towards the C(sp3)-C(sp2) bond formation is still limited by the use of expensive catalytic systems, moderate Z/E selectivity, air-sensitive reagents or specific alkyl sources bearing a heteroatom at the α-position. Gem-bromofluoroalkenes, which are easily accessible, starting materials from aldehyde or ketones via a Wittig-Burton reaction, can also be efficient substrates for the selective formation of alkyl-substituted monofluoroalkenes [29,30]. In this regard, Pannecoucke’s group reported the selective synthesis of stereo-defined butylated Z-(fluoro)alkene by Pd-catalyzed cross-coupling of (E/Z)-gem-bromofluoroalkenes with an in situ-generated organozinc intermediate [31]. Following up, the group of Wnuk reported an elegant pallado-catalyzed Negishi cross-coupling of gem-bromofluoroalkenes with alkyl organozinc derivatives as coupling partners to selectively produce (Z)-monofluoroalkenes [32]. Nevertheless, one of the drawbacks of these pathways is a low functional group tolerance and the use of sensitive reagents. Therefore, despite great successes achieved, the development of mild and practical methodologies to monofluoroalkenes, especially 2-fluoroalkyl scaffolds, remains an appealing task. Continuing our research directed towards the development of new methodology for the synthesis of functionalized monofluoroalkenes [33,34,35,36] Herein, we report the first example of a stereospecific Suzuki-Miyaura-cross-coupling reaction with readily available alkyl boronic acids that is adaptable across a range of gem-bromofluoroalkenes providing a large array of alkylated monofluoroalkenes with retention of configuration and in good yields under mild conditions.

2. Results and Discussion

At the outset of the study, coupling reactions were investigated with the easily accessible (E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a [31] and butylboronic acid 2a.
To establish the best reaction conditions, a broad range of palladium catalyst precursors, bases, solvents, temperatures and phosphine ligands were evaluated (Table 1). An initial survey demonstrated that the use of PdCl2dppf as catalyst gave the desired product as a mixture of E/Z isomers in 95% yield (entries 1–3). Among the bases, Cs2CO3 proved to be the most effective (entries 3–7). Subsequently, the solvents were screened, and the original biphasic mixture of toluene/H2O (9:1) was the best of choice (entries 3, 8–10). Further examination revealed that a decrease in the reaction temperature reduces the reaction efficiency (entries 11–12). Common ligands of palladium were tested (entries 13–17), and bidentate bisphosphines and, above all, those with large P-Pd-P bite angles appeared to be essentials [37]. Under some conditions, (E)-isomer reacts faster than the corresponding (Z)-isomers in Pd-catalyzed coupling reactions (entries 3, 5, 16). The best catalytic system was found to be Pd2(dba)3 (2 mol%) with xantphos (2 mol%) as the catalyst and Cs2CO3 as the base in a mixture of toluene/H2O (9:1) at 80 °C under nitrogen affording the desired product in almost quantitative yield (entry 15).
With the optimized conditions in hand, we investigated the substrate scope of the cross-coupling reaction on the gem-bromofluoroalkene part (Scheme 1). A large range of (E/Z)-gem-bromofluoroalkenes was successfully cross-coupled to afford the related Z and E monofluoroalkenes in good to excellent isolated yield. The electronic effects of the substituents on the aromatics rings showed no obvious influence on this transformation since (E/Z)-gem-bromofluoroalkenes possessing electron neutral (3ba–ca), electron-donating (3da) and electron-withdrawing groups (3ea–ga) provided the (E/Z)-monofluoroalkenes in high yields. Several sensitive or valuable functional groups, notably for further post-functionalizations, such as esters, trifluoromethyl and nitro groups, were well tolerated throughout the coupling reactions. In all cases, no sterodifferentiation was observed since a mixture of the corresponding E/Z isomers was obtained with the same isomeric composition of the starting material. The cross-coupling reaction of isomerically pure (Z)-1-bromo-1-fluoroalkene 1a led stereospecifically to a corresponding (E)-monofluoroalkene 3aa with complete retention of the stereochemistry confirming the stereospecificity of the reaction. Interestingly, gem-bromofluoroalkene that are meta-substituted (3ha) or sterically hindered at the ortho position (3ia) were suitable coupling partners for the reaction albeit, aryl gem-bromofluoroalkenes bearing substituents in the para position showed better reactivity. Gratifyingly, in the case of symmetric and unsymmetric gem-bromofluoroalkenes derived from ketones, the corresponding tetrasubstituted monofluoroalkenes 3ja and 3ka are obtained in excellent isolated yield. Unfortunately, the reaction is not compatible with nitrogen or sulfur hetaryl gem-bromofluoroalkenes (3la–ma) mainly due to the degradation of the starting material. In addition, when alkylated gem-bromofluoroolefin 1n was used as the substrate, the reaction also failed to give any coupling product.
We then examined the coupling reactions with different primary and secondary alkyl boronic acids and (E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a using the same set of reaction conditions developed (Scheme 2). All of the primary aliphatic alkyl boronic acids 2a–e provided the desired product 3aa-ae in good to excellent isolated yields. In the case of secondary alkyl substituents such as isopropyl or cyclohexyl boronic acids 2f–g, no reaction occurred; only starting materials were recovered. Cyclopropyl boronic acid 2 h was shown to undergo a cross-coupling reaction giving the product in 83% yield. This could be due to the geometry of the substrate, which suppresses β-hydride elimination.

3. Materials and Methods

3.1. General Methods

All reagents were purchased from commercial suppliers and were used without further purification unless otherwise indicated. Thin-layer chromatography (TLC) was performed on silica gel 60 F254 plates (Merck, Pfizer, Sanofi) and visualized under UV (254 nm) or by staining with potassium permanganate or phosphomolybdic acid. The purification of the obtained products was performed by flash chromatography using silica gel (230–400 mesh, 0.040–0.063 mm).
NMR spectra were recorded on a Bruker AVANCE 300 spectrometer (Bruker Corporation, Billerica, MA, USA) at 300 MHz (75 MHz). Chemical shifts are given in parts per million relative to the solvent signal. Multiplicities of the signals are reported using the standard abbreviations: singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). Coupling constants are reported in hertz (Hz). Coupling constants (J) are reported in hertz (Hz). High-resolution mass spectra (HRMS) were performed on a ThermoFisher Scientific LTQ Orbitrap XL mass spectrometer (Thermo Fischer Scientific, Bremen, Germany) using electrospray ionization (ESI).

3.2. Synthesis of Gem-Bromofluoroalkenes 1

Gem-bromofluoroalkenes 1a–n were synthesized according to known procedures reported by Pannecoucke’s group31 from the appropriate aldehyde and tribromofluoromethane.

3.3. General Procedure for the Synthesis of Monofluoroalkenes 3

In a Schlenk tube, gem-bromofluoroalkene 1 (1.0 equiv), boronic acid 2 (1.2 equiv), Pd2dba3·CHCl3 (2 mol%), xantphos (2 mol%) and Cs2CO3 (3 equiv) were added. The vial was flushed under nitrogen, then filled with a mixture of toluene/H2O (9:1) (0.09 M). The reaction mixture was heated for 6 h at 80 °C then cooled to r.t., filtered through Celite® and washed with EtOAc. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 100:0 to 95:5) to afford the pure product 3. 1H-, 13C- and 19F-NMR spectra of products can be found in Supplementary Materials.

3.3.1. (E/Z)-1-(2-fluorohex-1-en-1-yl)-4-nitrobenzene (3aa)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a (0.23 mmol, 56.32 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3aa in 99% yield (50.80 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.09 (t, J = 9.1 Hz, 2.0H), 7.51 (d, J = 8.9 Hz, 0.8 H), 7.26 (d, J = 8.4 Hz, 1.2H), 6.15 (d, JEH-F = 21.1 Hz, 0.6H), 5.49 (d, JZH-F = 38.1 Hz, 0.4H), 2.47–2.23 (m, 2.0H), 1.59–1.50 (m, 2.0H), 1.37–1.27 (m, 2.0H), 0.90–0.81 (m, 3.0H). 13C NMR (75 MHz, CDCl3): δ 164.1 (d, 1JEC-F = 257.5 Hz), 163.6 (d, 1JZC-F = 271.8 Hz), 145.3 (2), 140.5 (d, 3JEC-F = 14.8 Hz), 139.6 (d, 3JZC-F = 2.7 Hz), 127.9 (2), 127.7, 127.6, 122.8 (2), 122.7 (2), 106.1 (d, 2JZC-F = 31.0 Hz), 103.5 (d, 2JEC-F = 8.2 Hz), 31.9 (d, 2JZC-F = 25.6 Hz), 28.0 (d, 2JEC-F = 26.6 Hz), 27.3 (2), 21.2, 21.0, 12.7 (2). 19 F NMR (282.5 MHz, CDCl3): δ − 99.23 (q, JE = 23.2 Hz), −101.65 (dt, JZ = 39.7, 18.1 Hz). HRMS (ESI): m/z [M + H]+ calc. for C12H15FNO2, 224.1081 found 224.1080.

3.3.2. (E)-1-(2-fluorohex-1-en-1-yl)-4-nitrobenzene (E-3aa)

(Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a (0.23 mmol, 56.32 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound E-3aa in 99% yield (50.80 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.09 (t, J = 9.1 Hz, 2.0H), 7.51 (d, J = 8.9 Hz, 2.0 H), 6.15 (d, JEH-F = 21.1 Hz, 1.0H), 2.47–2.23 (m, 2.0H), 1.59–1.50 (m, 2.0H), 1.37–1.27 (m, 2.0H), 0.90–0.81 (m, 3.0H). 13C NMR (75 MHz, CDCl3): δ 164.1 (d, 1JEC-F = 257.5 Hz), 145.3, 140.5 (d, 3JEC-F = 14.8 Hz), 127.9, 127.7, 122.8, 122.7, 103.5 (d, 2JEC-F = 8.2 Hz), 28.0 (d, 2JEC-F = 26.6 Hz), 27.3, 21.2, 12.7. 19 F NMR (282.5 MHz, CDCl3): δ − 99.23 (q, JE = 23.2 Hz). HRMS (ESI): m/z [M + H]+ calc. for C12H15FNO2, 224.1081 found 224.1082.

3.3.3. (E/Z)-(2-fluorohex-1-en-1-yl)benzene (3ba)

(E/Z)-1-(2-bromo-2-fluorovinyl)-benzene 2b (0.23 mmol, 46.39 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ba in 95% yield (39.25 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.43–7.34 (m, 1.00H), 7.28–7.20 (m, 2.00H), 7.16–7.05 (m, 2.00H), 6.10 (d, JEH-F = 22.0 Hz, 0.53H), 5.38 (d, JZH-F = 39.5 Hz, 0.47H), 2.43–2.19 (m, 2.00H), 1.57–1.46 (m, 2.00H), 1.31 (ddd, J = 15.1, 9.5, 7.4 Hz, 2.00H), 0.87 (t, J = 6.3 Hz, 1.40H), 0.82 (t, J = 6.4 Hz, 1.60H). 13C NMR (75 MHz, CDCl3): δ 162.8 (d, 1JEC-F = 251.3 Hz), 161.3 (d, 1JZC-F = 265.1 Hz), 134.5 (d, 3JEC-F = 14.1 Hz), 134.0 (d, 3JZC-F = 2.5 Hz), 128.6, 128.6 (3), 128.5 (2), 128.4, 128.3, 126.7 (2), 108.1 (d, 2JZC-F = 28.6 Hz), 105.7 (d, 2JEC-F = 8.8 Hz), 32.8 (d, 2JZC-F = 26.3 Hz), 28.7 (d, 2JEC-F = 29.2 Hz), 28.5 (2), 22.3, 22.1, 13.8 (2).19 F NMR (282 MHz, CDCl3): δ − 98.35 (dd, JE = 45.7, 23.4 Hz), −100.61 (dt, JZ = 39.4, 18.0 Hz). HRMS (ESI): m/z [M + H]+ calc. for C12H16F 179.1230, found 179.1233.

3.3.4. (E/Z)-1-(2-fluorohex-1-en-1-yl)-4-methylbenzene (3ca)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-methylbenzene 2c (0.23 mmol, 49.64 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ca in 96% yield (42.79 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.39 (d, J = 8.2 Hz, 1.00H), 7.21–7.08 (m, 3.00H), 6.18 (d, JEH-F = 22.1 Hz, 0.51H), 5.45 (d, JZH-F = 39.8 Hz, 0.49H), 2.54–2.29 (m, 2.00H), 2.36 (s, 1.47H), 2.35 (s, 1.53H), 1.64–1.56 (m, 2.00H), 1.47–1.37 (m, 2.00H), 0.98 (t, J = 5.5 Hz, 1.47H), 0.93 (t, J = 5.5 Hz, 1.53H). 13C NMR (75 MHz, CDCl3): δ 162.5 (d, 1JEC-F = 250.2 Hz), 160.9 (d, 1JZC-F = 263.9 Hz), 136.4 (2), 131.6 (d, 3JEC-F = 14.0 Hz), 131.3 (d, 3JZC-F = 2.5 Hz), 129.3 (3), 129.2, 128.5, 128.4, 128.3, 128.2, 108.0 (d, 2JZC-F = 28.6 Hz), 105.6 (d, 2JEC-F = 9.0 Hz), 32.9 (d, 2JZC-F = 26.4 Hz), 28.9 (d, 2JEC-F = 28.6 Hz), 28.7 (2), 22.5, 22.2, 21.3, 21.2, 13.9 (2).19 F NMR (282 MHz, CDCl3): δ − 99.23 (q, JE = 23.2 Hz), −101.65 (dt, JZ = 39.7, 18.1 Hz). HRMS (ESI): m/z [M + H]+ calc. for C13H18F 193.1387, found 193.1388.

3.3.5. (E/Z)-1-(2-fluorohex-1-en-1-yl)-4-methoxybenzene (3da)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-methoxybenzene 2d (0.23 mmol, 53.35 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3da in 96% yield (46.35 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.42 (d, J = 8.9 Hz, 0.96H), 7.13 (d, J = 8.3 Hz, 1.04H), 6.90–6.84 (m, 2.00H), 6.14 (d, JEH-F = 22.0 Hz, 0.52H), 5.41 (d, JZH-F = 39.8 Hz, 0.48H), 3.81 (s, 3.00H), 2.49–2.28 (m, 2.00H), 1.64–1.56 (m, 2.00H), 1.45–1.36 (m, 2.00H), 0.96 (t, J = 5.4 Hz, 1.44H), 0.92 (t, J = 5.5 Hz, 1.56H). 13C NMR (75 MHz, CDCl3): δ 162.1 (d, 1JEC-F = 249.3 Hz), 160.1 (d, 1JZC-F = 262.2 Hz), 158.6, 158.4, 129.7, 129.6 (2), 129.5, 126.9 (d, 3JEC-F = 13.9 Hz), 126.8 (d, 3JZC-F = 2.3 Hz), 114.0 (4), 107.6 (d, 2JZC-F = 28.9 Hz), 105.1 (d, 2JEC-F = 9.2 Hz), 55.4 (2), 32.9 (d, 2JZC-F = 26.5 Hz), 28.8 (d, 2JEC-F = 27.1 Hz), 28.7 (2), 22.4, 22.2, 13.9 (2). 19 F NMR (282 MHz, CDCl3): δ − 100.27 (dd, JE = 45.9, 23.2 Hz), −103.58 (dt, JZ = 39.8, 18.3 Hz). HRMS (ESI): m/z [M + H]+ calc. for C13H18FO, 209.1336 found 209.1336.

3.3.6. (E/Z)-methyl 4-(2-fluorohex-1-en-1-yl)benzoate (3ea)

(E/Z)-methyl 4-(2-bromo-2-fluorovinyl)benzoate 2e (0.23 mmol, 59.84 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ea in 89% yield (48.75 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 7.90 (dd, J = 8.4, 6.0 Hz, 2.00H), 7.43 (d, J = 8.5 Hz, 0.92H), 7.17 (d, J = 8.1 Hz, 1.08H), 6.12 (d, JEH-F = 21.6 Hz, 0.54H), 5.43 (d, J = 38.9 Hz, 0.46H), 3.83 (s, 1.62H), 3.82 (s, 1.38H), 2.44–2.21 (m, 2.00H), 1.57–1.48 (m, 2.00H), 1.36–1.24 (m, 2.00H), 0.87 (t, J = 7.0 Hz, 1.38H), 0.81 (t, J = 7.3 Hz, 1.62H). 13C NMR (75 MHz, CDCl3): δ 167.0 (2), 164.2 (d, 1JEC-F = 254.7 Hz), 163.3 (d, 1JZC-F = 269.0 Hz), 139.5 (d, 3JEC-F = 14.3 Hz), 138.7 (d, 3JZC-F = 2.6 Hz), 129.9 (3), 129.8 (3), 128.4 (2), 128.2, 128.1, 107.8 (d, 2JZC-F = 29.7 Hz), 105.3 (d, 2JEC-F = 8.5 Hz), 52.2, 52.1, 33.0 (d, 2JZC-F = 26.0 Hz), 29.0 (d, 2JEC-F = 26.8 Hz), 28.5 (2), 22.4, 22.2, 13.9, 13.8. 19 F NMR (282 MHz, CDCl3): δ − 94.29 (dd, JE = 45.3, 23.4 Hz), −96.35 (dt, JZ = 38.8, 18.3 Hz). HRMS (ESI): m/z [M + H]+ calc. for C14H18FO2, 237.1285 found 237.1287.

3.3.7. (E/Z)-1-(2-fluorohex-1-en-1-yl)-4-(trifluoromethyl)benzene (3fa)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-trifluoromethylbenzene 2f (0.23 mmol, 62.16 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3fa in 95% yield (54.24 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 7.35–7.26 (m, 3.00H), 7.00 (d, J = 8.6 Hz, 1.00H), 5.93 (t, JEH-F = 15.5 Hz, 0.47H), 5.22 (d, JZH-F = 38.6 Hz, 0.53H), 2.20–2.00 (m, 2.00H), 1.38–1.28 (m, 2.00H), 1.17–1.06 (m, 2.00H), 0.67 (t, J = 6.6 Hz, 1.41H), 0.62 (t, J = 6.6 Hz, 1.59H). 13C NMR (75 MHz, CDCl3): δ 164.2 (d, 1JEC-F = 254.7 Hz), 163.3 (d, 1JZC-F = 268.2 Hz), 138.4 (d, 3JEC-F = 15.2 Hz), 137.7 (d, 3JZC-F = 1.2 Hz), 129.7, 129.3, 128.8 (4), 128.5 (2), 128.4 (2), 125.5 (dq, J = 7.7, 3.8 Hz, 2), 107.4 (d, 2JZC-F = 30.0 Hz), 104.9 (d, 2JEC-F = 8.5 Hz), 33.0 (d, 2JZC-F = 25.9 Hz), 29.0 (d, 2JEC-F = 26.8 Hz), 28.5 (2), 22.4, 22.2, 13.9 (2). 19 F NMR (282 MHz, CDCl3): δ −62.54 (s), −94.83 (dd, JE = 44.9, 23.2 Hz), −97.08 (dt, JZ = 36.8, 18.1 Hz). HRMS (ESI): m/z [M + H]+ calc. for C13H15F4, 247.1104 found 247.1103.

3.3.8. (E/Z)-1-chloro-4-(2-fluorohex-1-en-1-yl)benzene (3ga)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-chlorobenzene 2g (0.23 mmol, 54.27 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ga in 88% yield (43.29 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 7.30 (d, J = 8.6 Hz, 1.00H), 7.19 (dd, J = 11.7, 4.6 Hz, 2.00H), 7.03 (d, J = 8.3 Hz, 1.00H), 6.04 (d, JEH-F = 21.5 Hz, 0.55H), 5.34 (d, JZH-F = 39.0 Hz, 0.45H), 2.40–2.20 (m, 2.00H), 1.56–1.47 (m, 2.00H), 1.38–1.26 (m, 2.00H), 0.87 (t, J = 6.5 Hz, 1.35H), 0.81 (d, J = 7.3 Hz, 1.65H). 13C NMR (75 MHz, CDCl3): δ 163.3 (d, 1JEC-F = 252.7 Hz), 161.9 (d, 1JZC-F = 265.9 Hz), 133.1 (d, 3JEC-F = 14.3 Hz), 132.6 (d, 3JZC-F = 2.4 Hz), 132.3, 132.2, 129.9, 129.8, 129.7, 129.6, 128.7 (2), 128.6 (2), 107.3 (d, 2JZC-F = 29.5 Hz), 104.8 (d, 2JEC-F = 8.8 Hz), 32.9 (d, 2JZC-F = 26.0 Hz), 28.8 (d, 2JEC-F = 27.0 Hz), 28.6 (2), 22.4, 22.2, 13.9 (2). 19 F NMR (282 MHz, CDCl3): δ − 97.15 (dd, JE = 45.0, 23.2 Hz), −99.62 (dt, JZ = 39.0, 18.2 Hz). HRMS (ESI): m/z [M + H]+ calc. for C12H15ClF, 213.0841 found 213.0842.

3.3.9. (E/Z)-1-(2-fluorohex-1-en-1-yl)-3-nitrobenzene (3ha)

(E/Z)-1-(2-bromo-2-fluorovinyl)-3-nitrobenzene 2h (0.23 mmol, 56.82 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ha in 99% yield (51.24 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 8.30 (s, 0.49H), 8.14–7.99 (m, 1.50H), 7.76 (d, J = 7.8 Hz, 0.51H), 7.51–7.43 (m, 1.50H), 6.22 (d, JEH-F = 20.8 Hz, 0.51H), 5.55 (d, JZH-F = 37.8 Hz, 0.49H), 2.54–2.32 (m, 2.00H), 1.66–1.57 (m, 2.00H), 1.42 (dd, J = 15.2, 7.8 Hz, 2.00H), 0.96 (t, J = 6.5 Hz, 1.50H), 0.91 (t, J = 6.5 Hz, 1.50H). 13C NMR (75 MHz, CDCl3): δ 164.7 (d, 1JEC-F = 256.0 Hz), 163.7 (d, 1JZC-F = 269.1 Hz), 148.6 (2), 136.4 (d, 3JEC-F = 14.9 Hz), 135.7 (d, 3JZC-F = 2.2 Hz), 134.5 (d, JC-F = 2.7 Hz), 134.1 (d, JC-F = 7.9 Hz), 129.5, 129.3, 123.2 (d, JC-F = 2.8 Hz), 123.0 (d, JC-F = 8.1 Hz), 121.6, 121.4 (d, JC-F = 1.9 Hz), 106.7 (d, 2JZC-F = 31.3 Hz), 104.2 (d, 2JEC-F = 8.4 Hz), 32.9 (d, 2JZC-F = 25.8 Hz), 28.9 (d, 2JEC-F = 26.9 Hz), 28.4 (2), 22.4, 22.2, 13.9 (2). 19 F NMR (282 MHz, CDCl3): δ −93.83 (td, JE = 23.2, 20.9 Hz), −96.00–−96.53 (m). HRMS (ESI): m/z [M + H]+ calc. for C12H15FNO2, 224.1081 found 224.1079.

3.3.10. (E/Z)-1-(2-fluorohex-1-en-1-yl)-2-methoxybenzene (3ia)

(E/Z)-1-(2-bromo-2-fluorovinyl)-2-methoxybenzene 2i (0.23 mmol, 53.35 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ia in 81% yield (39.11 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3) δ 7.67 (dt, J = 8.2, 4.1 Hz, 0.41H), 7.18–7.05 (m, 1.59H), 6.86–6.71 (m, 2.00H), 6.15 (d, JEH-F = 21.9 Hz, 0.59H), 5.79 (d, JZH-F = 40.6 Hz, 0.41H), 3.74 (s, 3.00H), 2.38–2.23 (m, 2.00H), 1.53 (ddd, J = 8.2, 7.2, 5.2 Hz, 2.00H), 1.31 (dd, J = 14.9, 7.6 Hz, 2.00H), 0.87 (t, J = 7.3 Hz, 1.23H), 0.81 (t, J = 7.3 Hz, 1.77H). 13C NMR (75 MHz, CDCl3): δ 162.6 (d, 1JEC-F = 250.6 Hz), 161.4 (d, 1JZC-F = 264.4 Hz), 157.2 (d, JC-F = 2.7 Hz), 156.0, 129.9 (d, JC-F = 12.7 Hz), 129.7 (d, JC-F = 1.6 Hz), 128.3, 127.8 (d, JC-F = 1.7 Hz), 123.5 (d, 3JEC-F = 13.8 Hz), 122.8 (d, 3JZC-F = 2.7 Hz), 120.7, 120.5, 110.6 (2), 103.7 (d, 2JZC-F = 30.4 Hz), 99.1 (d, 2JEC-F = 7.4 Hz), 55.7, 55.6, 33.2 (d, 2JZC-F = 26.7 Hz), 28.9 (d, 2JEC-F = 27.2 Hz), 28.7 (2), 22.5, 22.2, 13.9 (2). 19 F NMR (282 MHz, CDCl3): δ − 98.74 (q, JE = 22.7 Hz), −102.28 (dt, JZ = 40.6, 18.0 Hz). HRMS (ESI): m/z [M + H]+ calc. for C13H18FO, 209.1336 found 209.1333.

3.3.11. (2-Bromo-2-fluoroethene-1,1-diyl)dibenzene (3ja)

1-(2-bromo-2-fluorovinyl)-2-methoxybenzene 2j (0.23 mmol, 64.03 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ja in 90% yield (53.06 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 7.39–7.13 (m, 10H), 2.40–2.21 (m, 2H), 1.64–1.52 (m, 2H), 1.31 (dt, J = 14.6, 7.4 Hz, 2H), 0.85 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 158.5 (d, 1JEC-F = 261.1 Hz), 139.3 (d, 3JC-F = 8.3 Hz), 137.9, 130.4 (d, JC-F = 2.6 Hz), 129.7 (d, JC-F = 4.9 Hz), 128.5 (3), 128.1 (3), 127.2, 126.8, 120.4 (d, 2JC-F = 15.2 Hz), 30.3 (d, 2JC-F = 27.4 Hz), 29.0, 22.3, 13.9. 19 F NMR (282 MHz, CDCl3): δ − 106.14 (t, J = 23.0 Hz). HRMS (ESI): m/z [M + H]+ calc. for C18H20F, 255.1543 found 255.1541.

3.3.12. (E/Z)-1-(3-fluorohept-2-en-2-yl)-4-methoxybenzene (3ka)

(E/Z)-1-(1-bromo-1-fluoroprop-1-en-2-yl)-4-methoxybenzene 2k (0.23 mmol, 56.60 mg), butyl boronic acid 2a (0.28 mmol, 28.45 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ka in 90% yield (43.80 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 7.31 (dd, J = 8.9, 1.1 Hz, 1.0H), 7.11 (d, J = 8.6 Hz, 1.0H), 6.87 (dd, J = 8.9, 2.2 Hz, 2.0H), 3.82 (s, 1.5H), 3.81 (s, 1.5H), 2.40 (dt, J = 24.0, 7.3 Hz, 1.0H), 2.28–2.07 (m, 1.0H), 2.07–1.81 (m, 3.0H), 1.60–1.26 (m, 4.0H), 0.96 (t, J = 7.2 Hz, 1.5H), 0.85 (t, J = 7.3 Hz, 1.5H). 13C NMR (75 MHz, CDCl3): 158.5, 158.3, 157.1 (d, 1JEC-F = 248.6 Hz), 155.6 (d, 1JEC-F = 248.7 Hz), 133.0 (d, 3JEC-F = 9.3 Hz), 131.2, 129.6 (d, JC-F = 2.7 Hz, 2), 129.4 (d, JC-F = 4.2 Hz, 2), 113.8 (2), 113.5 (2), 111.3, (d, 2JC-F = 13.8 Hz, 2), 55.4 (2), 29.3 (d, JC-F = 19.6 Hz), 29.0 (d, J = 2.9 Hz), 29.0, 28.9, 22.3 (2), 17.4 (d, 3JZC-F = 4.7 Hz), 16.4 (d, 3JEC-F = 7.9 Hz), 14.0, 13.9. 19 F NMR (282 MHz, CDCl3): δ −107.87–−108.18 (m), −109.64 (ddd, J = 26.7, 19.6, 3.6 Hz). HRMS (ESI): m/z [M + H]+ calc. for C14H20FO, 223.1492 found 223.1490.

3.3.13. 1-(2-Fluoroprop-1-en-1-yl)-4-nitrobenzene (3ab)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a (0.23 mmol, 56.32 mg), methyl boronic acid 2b (0.28 mmol, 16.71 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ab in 86% yield (36.12 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 8.26–8.11 (m, 2.00H), 7.56 (t, J = 8.5 Hz, 1.26H), 7.35 (d, J = 8.6 Hz, 0.76H), 6.25 (d, J = 20.7 Hz, 0.37H), 5.58 (d, J = 37.4 Hz, 0.63H), 2.22–2.09 (m, 3.00H). 13C NMR (75 MHz, CDCl3): δ 164.1 (d, 1JEC-F = 257.5 Hz), 163.6 (d, 1JZC-F = 271.8 Hz), 145.3 (2), 140.5 (d, 3JEC-F = 14.8 Hz), 139.6 (d, 3JZC-F = 2.7 Hz), 129.2 (2), 129.1, 129.0, 124.2 (2), 123.9 (2), 111.8 (d, 2JZC-F = 6.0 Hz), 110.7 (d, 2JEC-F = 26.1 Hz), 19.40 (d, 2JZC-F = 2.5 Hz), 18.9 (d, 2JEC-F = 24.9 Hz). 19 F NMR (282 MHz, CDCl3): δ − 81.75 (tt, J = 36.1, 18.0 Hz), −87.75 (dq, J = 37.5, 17.1 Hz). HRMS (ESI): m/z [M + H]+ calc. for C9H8FNO2, 182.0612 found 182.0619.

3.3.14. 1-(2-Fluoropent-1-en-1-yl)-4-nitrobenzene (3ac)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a (0.23 mmol, 56.32 mg), pentyl boronic acid 2c (0.28 mmol, 24.51 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ac in 95% yield (46.08 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 8.24–8.12 (m, 2.00H), 7.62–7.56 (m, 1.24H), 7.36–7.31 (m, 0.76H), 6.24 (d, JEH-F = 21.1 Hz, 0.38H), 5.57 (d, JZH-F = 38.1 Hz, 0.62H), 2.51–2.30 (m, 2.00H), 1.67 (ddd, J = 14.8, 7.4, 5.7 Hz, 2.00H), 1.00 (dd, J = 15.7, 7.7 Hz, 3.00H). 13C NMR (75 MHz, CDCl3): δ 164.1 (d, 1JEC-F = 257.5 Hz), 163.6 (d, 1JZC-F = 271.8 Hz), 143.5 (2), 139.7 (d, 3JEC-F = 14.9 Hz), 138.8 (d, 3JZC-F = 2.5 Hz), 127.1 (2), 126.9, 126.8, 121.9 (4), 105.5 (d, 2JZC-F = 31.1 Hz), 102.8 (d, 2JEC-F = 8.1 Hz), 33.3 (d, 2JZC-F = 25.7 Hz), 29.3 (d, 2JEC-F = 26.8 Hz), 17.7 (2), 11.7, 11.5. 19 F NMR (282 MHz, CDCl3): δ − 91.24 (dd, JE = 44.6, 23.2 Hz), −93.61–−94.11 (m). HRMS (ESI): m/z [M + H]+ calc. for C11H13FNO2, 210.0925 found 210.0920.

3.3.15. 1-(2-Fluoro-4-phenylbut-1-en-1-yl)-4-nitrobenzene (3ad)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a (0.23 mmol, 56.32 mg), phenethylboronic acid 2d (0.28 mmol, 41.78 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ad in 87% yield (54.71 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 8.16 (d, J = 9.0 Hz, 1.24H), 8.08 (d, JEH-F = 8.9 Hz, 0.76H), 7.57 (d, JZH-F = 8.9 Hz, 1.24H), 7.35–7.15 (m, 5.00H), 7.07–7.00 (m, 0.76H), 6.25 (d, JEH-F = 20.9 Hz, 0.38H), 5.53 (d, JZH-F = 38.0 Hz, 0.62H), 2.95 (dd, J = 8.8, 6.9 Hz, 2.00H), 2.70 (ddd, J = 16.2, 10.9, 7.4 Hz, 2.00H). 13C NMR (75 MHz, CDCl3): δ 163.4 (d, 1JEC-F = 261.0 Hz), 163.2 (d, 1JZC-F = 266.8 Hz), 146.2, 146.1, 141.1, 140.9, 140.3 (d, 3JZC-F = 2.4 Hz), 140.0 (d, 3JEC-F = 10.6 Hz), 129.0, 128.9, 128.8, 128.7 (2), 128.6 (4), 128.5, 128.4 (2), 126.6, 126.5, 123.7 (2), 123.7 (2), 108.1 (d, 2JZC-F = 30.3 Hz), 105.3 (d, 2JEC-F = 7.9 Hz), 35.2 (d, 2JZC-F = 25.8 Hz), 32.3 (d, 2JEC-F = 36.5 Hz), 31.5, 31.2. 19 F NMR (282 MHz, CDCl3): δ − 93.83 (dd, JE = 43.3, 22.6 Hz), −95.15 (dt, JZ = 36.5, 18.0 Hz). HRMS (ESI): m/z [M + H]+ calc. for C16H15FNO2, 272.1081 found 272.1082.

3.3.16. 1-(2-Fluoro-4-methylpent-1-en-1-yl)-4-nitrobenzene (3ae)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a (0.23 mmol, 56.32 mg), isobutylboronic acid 2e (0.28 mmol, 28.42 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ae in 77% yield (39.85 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 8.18 (d, J = 7.4 Hz, 0.84H), 8.15 (d, J = 7.5 Hz, 1.16H), 7.59 (d, J = 9.0 Hz, 1.16H), 7.34 (d, J = 8.4 Hz, 0.84H), 6.27 (d, JEH-F = 21.6 Hz, 0.42H), 5.56 (d, JZH-F = 37.9 Hz, 0.58H), 2.35 (dd, J = 23.4, 7.2 Hz, 0.84H), 2.23 (dd, J = 21.4, 7.1 Hz, 1.16H), 2.08–1.95 (m, 1.00H), 1.00 (dd, J = 6.6, 0.5 Hz, 3.48H), 0.96 (dd, J = 6.7, 0.6 Hz, 2.52H). 13C NMR (75 MHz, CDCl3): 164.3 (d, 1JEC-F = 257.5 Hz), 163.8 (d, 1JZC-F = 272.2 Hz), 141.5 (d, 3JEC-F = 15.1 Hz), 140.6 (d, 3JZC-F = 2.6 Hz), 129.1 (d, JC-F = 2.7 Hz, 2), 128.7 (d, JC-F = 8.3 Hz, 2), 123.8 (4), 108.0 (d, 2JZC-F = 31.1 Hz), 105.7 (d, 2JEC-F = 8.3 Hz), 42.5 (d, 2JEC-F = 25.0 Hz), 38.0 (d, 2JZC-F = 25.9 Hz), 26.2, 26.1, 22.3, 22.2. 19 F NMR (282 MHz, CDCl3): δ − 89.63 (q, JE = 22.9 Hz), −93.10 (dt, JZ = 37.9, 21.4 Hz). HRMS (ESI): m/z [M + H]+ calc. for C12H15FNO2, 224.1081 found 224.1080.

3.3.17. 1-(2-Cyclopropyl-2-fluorovinyl)-4-nitrobenzene (3ah)

(E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a (0.23 mmol, 56.32 mg), cyclopropylboronic acid 2h (0.28 mmol, 23.95 mg), Pd2dba3·CHCl3 (4.710−3 mmol, 4.25 mg), xantphos (4.710−3 mmol, 2.69 mg), Cs2CO3 (0.70 mmol, 227.10 mg), toluene/H2O (2.53 mL) were reacted according to general procedure. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 100:0 to 95:5) affording compound 3ah in 83% yield (39.87 mg) as a yellow solid.1H NMR (300 MHz, CDCl3): δ 8.12 (d, J = 8.9 Hz, 0.84H), 8.07 (d, J = 9.0 Hz, 1.16H), 7.47 (d, J = 9.0 Hz, 1.16H), 7.41 (d, J = 8.4 Hz, 0.84H), 6.16 (d, JEH-F = 19.9 Hz, 0.42H), 5.58 (d, JZH-F = 37.9 Hz, 0.58H), 1.93–1.77 (v-1Hm, 0.42H), 1.69–1.54 (m, 0.58H), 0.92 (dt, J = 8.9, 3.2 Hz, 0.84H), 0.87–0.78 (m, 3.16H). 13C NMR (75 MHz, CDCl3): 164.2 (d, 1JZC-F = 266.7 Hz), 164.0 (d, 1JEC-F = 252.9 Hz), 146.1, 147.5, 141.8 (d, 3JEC-F = 14.7 Hz), 140.8 (d, 3JZC-F = 3.3 Hz), 129.1 (d, JC-F = 2.7 Hz, 2), 128.4 (d, JC-F = 8.2 Hz, 2), 123.(4),.106.2 (d, 2JZC-F = 32.9 Hz), 102.9 (d, 2JEC-F = 9.9 Hz), 13.4 (d, 2JZC-F = 28.1 Hz), 10.3 (d, 2JEC-F = 26.6 Hz), 6.2, 6.1, 5.8 (2). 19 F NMR (282 MHz, CDCl3): δ − 108.50 (dd, J = 37.9, 22.7 Hz). HRMS (ESI): m/z [M + H]+ calc. for C11H11FNO2, 208.0768 found 208.0765.

4. Conclusions

In conclusion, an efficient palladium-catalyzed carbon–carbon coupling reaction of readily available gem-bromofluoroalkenes with primary and strained secondary alkyl boronic acid derivatives was successfully achieved under mild conditions. This methodology demonstrates its applicability for the synthesis of alkyl trisubstituted or tetrasubstituted monofluoroalkenes with a broad range of gem-bromofluoroalkenes and alkyl boronic acids with good group compatibility, stereospecificity and excellent yields. Such reactions may be useful for the synthesis of fluoroolefins of interest for life and material sciences.

Supplementary Materials

1H-, 13C- and 19F-NMR spectra of products associated with this article are available online.

Author Contributions

L.C.-B. and N.C. performed the experiments, L.C.-B. and C.R. designed and supervised the study and wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

The authors gratefully acknowledge the CNRS for financial support. The NMR facilities used in this study were funded by the European Community (FEDER), Région Haut de France (France), the CNRS and Lille University.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hagmann, W.K. The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359–4369. [Google Scholar] [CrossRef] [PubMed]
  2. Gillis, E.P.; Eastman, K.J.; Hill, M.D.; Donnelly, D.J.; Meanwell, N.A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315–8359. [Google Scholar] [CrossRef] [PubMed]
  3. Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881–1886. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320–330. [Google Scholar] [CrossRef]
  5. Wang, J.; Sánchez-Roselló, M.; Aceña, J.L.; Del Pozo, C.; Sorochinsky, A.E.; Fustero, S.; Soloshonok, V.A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001–2011). Chem. Rev. 2014, 114, 2432–2506. [Google Scholar] [CrossRef]
  6. Fujiwara, T.; O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluor. Chem. 2014, 167, 16–29. [Google Scholar] [CrossRef]
  7. Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J. Organic fluorine compounds: A great opportunity for enhanced materials properties. Chem. Soc. Rev. 2011, 40, 3496–3508. [Google Scholar] [CrossRef]
  8. Meanwell, N.A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822–5880. [Google Scholar] [CrossRef]
  9. Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Chiral dipeptide mimics possessing a fluoroolefin moiety: A relevant tool for conformational and medicinal studies. Org. Biomol. Chem. 2007, 5, 1151–1157. [Google Scholar] [CrossRef]
  10. Osada, S.; Sano, S.; Ueyama, M.; Chuman, Y.; Kodama, H.; Sakaguchi, K. Fluoroalkene modification of mercaptoacetamide-based histone deacetylase inhibitors. Bioorganic Med. Chem. 2010, 18, 605–611. [Google Scholar] [CrossRef]
  11. Zajc, B.; Kumar, R. Synthesis of Fluoroolefins via Julia-Kocienski Olefination. Synthesis 2010, 2010, 1822–1836. [Google Scholar] [CrossRef] [Green Version]
  12. Zhao, Y.; Jiang, F.; Hu, J. Spontaneous Resolution of Julia-Kocienski Intermediates Facilitates Phase Separation to Produce Z- and E-Monofluoroalkenes. J. Am. Chem. Soc. 2015, 137, 5199–5203. [Google Scholar] [CrossRef] [PubMed]
  13. Akana, J.A.; Bhattacharyya, K.X.; Mueller, P.; Sadighi, J.P. Reversible C-F Bond Formation and the Au-Catalyzed Hydrofluorination of Alkynes. J. Am. Chem. Soc. 2007, 129, 7736–7737. [Google Scholar] [CrossRef]
  14. Gorske, B.C.; Mbofana, C.T.; Miller, S.J. Regio- and Stereoselective Synthesis of Fluoroalkenes by Directed Au(I) Catalysis. Org. Lett. 2009, 11, 4318–4321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Liu, T.-L.; Wu, J.; Zhao, Y. Divergent reactivities in fluoronation of allylic alcohols: Synthesis of Z-fluoroalkenes via carbon-carbon bond cleavage. Chem. Sci. 2017, 8, 3885–3890. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Gauthier, R.; Mamone, M.; Paquin, J. Gold-Catalyzed Hydrofluorination of Internal Alkynes Using Aqueous HF. Org. Lett. 2019, 21, 9024–9027. [Google Scholar] [CrossRef] [PubMed]
  17. Dai, W.; Shi, H.; Zhao, X.; Cao, S. Sterically Controlled Cu-Catalyzed or Transition-Metal-Free Cross-Coupling of gem-Difluoroalkenes with Tertiary, Secondary, and Primary Alkyl Grignard Reagents. Org. Lett. 2016, 18, 4284–4287. [Google Scholar] [CrossRef]
  18. Lu, X.; Wang, Y.; Zhang, B.; Pi, J.-J.; Wang, X.-X.; Gong, T.-J.; Xiao, B.; Fu, Y. Nickel-Catalyzed Defluorinative Reductive Cross-Coupling of gem-Difluoroalkenes with Unactivated Secondary and Tertiary Alkyl Halides. J. Am. Chem. Soc. 2017, 139, 12632–12637. [Google Scholar] [CrossRef]
  19. Yang, L.; Ji, W.-W.; Lin, E.; Li, J.-L.; Fan, W.-X.; Li, Q.; Zhang, S.-S. Synthesis of Alkylated Monofluoroalkenes via Fe-Catalyzed Defluorinative Cross-Coupling of Donor Alkenes with gem-Difluoroalkenes. Org. Lett. 2018, 20, 1924–1927. [Google Scholar] [CrossRef]
  20. Yu, L.; Tang, M.-L.; Si, C.-M.; Meng, Z.; Liang, Y.; Han, J.; Sun, X. Zinc-Mediated Decarboxylative Alkylation of gem-Difluoroalkenes. Org. Lett. 2018, 20, 4579–4583. [Google Scholar] [CrossRef]
  21. Zhou, L.; Zhu, C.; Bi, P.; Feng, C. Ni-catalyzed migratory fluoro-alkenylation of unactivated alkyl bromides with gem-difluoroalkenes. Chem. Sci. 2019, 10, 1144–1149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Xu, J.; Ahmed, E.-A.; Xiao, B.; Lu, Q.-Q.; Wang, Y.-L.; Yu, C.-G.; Fu, Y. ChemInform Abstract: Pd-Catalyzed Regioselective Activation of gem-Difluorinated Cyclopropanes: A Highly Efficient Approach to 2-Fluorinated Allylic Scaffolds. Angew. Chem. 2015, 46, 8231–8235. [Google Scholar] [CrossRef] [PubMed]
  23. Wenz, J.; Rettenmeier, C.A.; Wadepohl, H.; Gade, L.H. ChemInform Abstract: Catalytic C-F Bond Activation of Geminal Difluorocyclopropanes by Nickel(I) Complexes via a Radical Mechanism. Angew. Chem. 2016, 47, 202–205. [Google Scholar] [CrossRef]
  24. Ahmed, E.-A.M.A.; Suliman, A.M.Y.; Gong, T.-J.; Fu, Y. Palladium-Catalyzed Stereoselective Defluorination Arylation/Alkenylation/Alkylation of gem-Difluorinated Cyclopropanes. Org. Lett. 2019, 21, 5645–5649. [Google Scholar] [CrossRef]
  25. Xie, J.; Yu, J.; Rudolph, M.; Rominger, F.; Hashmi, A.S.K. Monofluoroalkenylation of Dimethylamino Compounds through Radical-Radical Cross-Coupling. Angew. Chem. Int. Ed. 2016, 55, 9416–9421. [Google Scholar] [CrossRef] [PubMed]
  26. Li, J.; Lefebvre, Q.; Yang, H.; Zhao, Y.; Fu, H. Visible light photocatalytic decarboxylative monofluoroalkenylation of α-amino acids with gem-difluoroalkenes. Chem. Commun. 2017, 53, 10299–10302. [Google Scholar] [CrossRef] [Green Version]
  27. Yang, H.; Tian, C.; Qiu, D.; Tian, H.; An, G.-H.; Li, G.-M. Organic photoredox catalytic decarboxylative cross-coupling of gem-difluoroalkenes with unactivated carboxylic acids. Org. Chem. Front. 2019, 6, 2365–2370. [Google Scholar] [CrossRef]
  28. Du, H.-W.; Sun, J.; Gao, Q.-S.; Wang, J.-Y.; Wang, H.; Xu, Z.; Zhou, M. Synthesis of Monofluoroalkenes through Visible-Light-Promoted Defluorinative Alkylation of gem-Difluoroalkenes with 4-Alkyl-1,4-dihydropyridines. Org. Lett. 2020, 22, 1542–1546. [Google Scholar] [CrossRef]
  29. Chelucci, G. ChemInform Abstract: Synthesis and Metal-Catalyzed Reactions of gem-Dihalovinyl Systems. Angew. Chem. 2012, 43, 1344–1462. [Google Scholar] [CrossRef]
  30. Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F. Synthetic approaches to monofluoroalkenes. Chem. Soc. Rev. 2011, 40, 2867–2908. [Google Scholar] [CrossRef]
  31. Lei, X.; Dutheuil, G.; Pannecoucke, X.; Quirion, J.-C. A Facile and Mild Method for the Synthesis of Terminal Bromofluoroolefins via Diethylzinc-Promoted Wittig Reaction. Org. Lett. 2004, 6, 2101–2104. [Google Scholar] [CrossRef] [PubMed]
  32. Andrei, D.; Wnuk, S.F. Synthesis of the Multisubstituted Halogenated Olefins via Cross-Coupling of Dihaloalkenes with Alkylzinc Bromides. J. Org. Chem. 2006, 71, 405–408. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Zemmouri, R.; Kajjout, M.; Castanet, Y.; Eddarir, S.; Rolando, C. Palladium-Catalyzed Stereoconvergent Formylation of (E/Z)-β-Bromo-β-fluorostyrenes: Straightforward Access to (Z)-α-Fluorocinnamic Aldehydes and (Z)-β-Fluorocinnamic Alcohols. J. Org. Chem. 2011, 76, 7691–7698. [Google Scholar] [CrossRef] [PubMed]
  34. Eddarir, S.; Kajjout, M.; Rolando, C. Stereoselective cyanation of β-bromo-β-fluorostyrenes using potassium cyanide and promoted by (CH3CN)4Cu+ BF4−. Tetrahedron 2012, 68, 603–607. [Google Scholar] [CrossRef]
  35. Kajjout, M.; Zemmouri, R.; Eddarir, S.; Rolando, C. An efficient access to (Z)-β-fluoroallyl alcohols based on the two carbon homologation of aromatic aldehydes by Horner-Wadsworth-Emmons reaction with 2-(diethoxyphosphinyl)-2-fluoro-ethanethioic acid, S-ethyl ester followed by reduction with sodium borohydride. Tetrahedron 2012, 68, 3225–3230. [Google Scholar] [CrossRef]
  36. Kajjout, M.; Smietana, M.; Leroy, J.; Rolando, C. A new approach to the synthesis of (Z)-2-fluoro-2-alkenals via Wittig-type carbonyl condensation reactions of 2-(fluoromethyl)-4,4,6-trimethyl-1,3-oxazine phosphonium bromide. Tetrahedron Lett. 2013, 54, 1658–1660. [Google Scholar] [CrossRef]
  37. Tan, Z.; Negishi, E.-I. Widely Applicable Pd-Catalyzed trans-Selective Monoalkylation of Unactivated 1,1-Dichloro-1-alkenes and Pd-Catalyzed Second Substitution for the Selective Synthesis of (E)- or (Z)- Trisubstituted Alkenes. Angew. Chem. 2006, 37, 762–765. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds are available from the authors.
Molecules 25 05532 sch001 550
Scheme 1. Palladium-catalyzed cross-coupling of butylboronic acid 2a with various gem-bromofluoroalkenes 1a–n.
Scheme 1. Palladium-catalyzed cross-coupling of butylboronic acid 2a with various gem-bromofluoroalkenes 1a–n.
Molecules 25 05532 sch001
Molecules 25 05532 sch002 550
Scheme 2. Palladium-catalyzed cross-coupling of (E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a with various alkyl boronic acids 2a–i.
Scheme 2. Palladium-catalyzed cross-coupling of (E/Z)-1-(2-bromo-2-fluorovinyl)-4-nitrobenzene 1a with various alkyl boronic acids 2a–i.
Molecules 25 05532 sch002
Table
Table 1. Optimization of the cross-coupling between E/Z-1a and butylboronic acid 2a a.
Table 1. Optimization of the cross-coupling between E/Z-1a and butylboronic acid 2a a.
Molecules 25 05532 i001
EntryE/Z 1a b[Pd]LigandBaseSolventT (°C)Z/E 3aa bYield (%) c
155:45Pd(Ph3)4-Cs2CO3toluene/H2O80--
255:45Pd2dba3 CHCl3-Cs2CO3toluene/H2O80--
356:44PdCl2dppf-Cs2CO3toluene/H2O8058:4295
455:45PdCl2dppf-K2CO3toluene/H2O8046:5476
555:45PdCl2dppf-Na2CO3toluene/H2O8057:4344
655:45PdCl2dppf-K3PO4toluene/H2O8051:4993
755:46PdCl2dppf-Ba(OH)2toluene/H2O80--
839:61PdCl2dppf-Cs2CO3toluene8038:6289
939:61PdCl2dppf-Cs2CO3Dioxane80--
1039:61PdCl2dppf-Cs2CO3THF80--
1155:45PdCl2dppf-Cs2CO3toluene/H2ORT--
1255:45PdCl2dppf-Cs2CO3toluene/H2O6045:5551
1355:45Pd2dba3.CHCl3DppfCs2CO3toluene/H2O8051:4991
1448:52Pd2dba3 CHCl3DppeCs2CO3toluene/H2O8048:5241
1548:52Pd2dba3 CHCl3XantphosCs2CO3toluene/H2O8049:5199
1648:52Pd2dba3 CHCl3XphosCs2CO3toluene/H2O8060:4035
1748:52Pd2dba3 CHCl3TFPCs2CO3toluene/H2O8042:5878
a All reactions unless specified were carried out using 1a (1 eq), 2a (1.2 eq), Pd source (2 mol%), ligand (2 mol%) and base (3 eq), in solvent (0.09 M) under N2 for 6 h. b Ratio determined by 1H NMR. c Yield was determined using 1,3,5-trimethoxybenzene as an internal standard. Pd2dba3 = tris(dibenzylideneacetone)dipalladium. Dppf = 1,1′-bis(diphenylphosphino)ferrocene. Dppe = 1,2-bis(diphenylphosphino)ethane. Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Xphos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. TFP = tri(2-furyl)phosphine.
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Chausset-Boissarie, L.; Cheval, N.; Rolando, C. Palladium-Catalyzed Cross-Coupling of Gem-Bromofluoroalkenes with Alkylboronic Acids for the Synthesis of Alkylated Monofluoroalkenes. Molecules 2020, 25, 5532. https://doi.org/10.3390/molecules25235532

AMA Style

Chausset-Boissarie L, Cheval N, Rolando C. Palladium-Catalyzed Cross-Coupling of Gem-Bromofluoroalkenes with Alkylboronic Acids for the Synthesis of Alkylated Monofluoroalkenes. Molecules. 2020; 25(23):5532. https://doi.org/10.3390/molecules25235532

Chicago/Turabian Style

Chausset-Boissarie, Laëtitia, Nicolas Cheval, and Christian Rolando. 2020. "Palladium-Catalyzed Cross-Coupling of Gem-Bromofluoroalkenes with Alkylboronic Acids for the Synthesis of Alkylated Monofluoroalkenes" Molecules 25, no. 23: 5532. https://doi.org/10.3390/molecules25235532

APA Style

Chausset-Boissarie, L., Cheval, N., & Rolando, C. (2020). Palladium-Catalyzed Cross-Coupling of Gem-Bromofluoroalkenes with Alkylboronic Acids for the Synthesis of Alkylated Monofluoroalkenes. Molecules, 25(23), 5532. https://doi.org/10.3390/molecules25235532

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