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

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.


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(sp 3 )-C(sp 2 ) 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.
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 PdCl 2 dppf as catalyst gave the desired product as a mixture of E/Z isomers in 95% yield (entries 1-3). Among the bases, Cs 2 CO 3 proved to be the most effective (entries 3-7). Subsequently, the solvents were screened, and the original biphasic mixture of toluene/H 2 O (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][14][15][16][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 Pd 2 (dba) 3 (2 mol%) with xantphos (2 mol%) as the catalyst and Cs 2 CO 3 as the base in a mixture of toluene/H 2 O (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.
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.

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).

Synthesis of Gem-Bromofluoroalkenes 1
Gem-bromofluoroalkenes 1a-n were synthesized according to known procedures reported by Pannecoucke's group 31 from the appropriate aldehyde and tribromofluoromethane.

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).

Synthesis of Gem-Bromofluoroalkenes 1
Gem-bromofluoroalkenes 1a-n were synthesized according to known procedures reported by Pannecoucke's group 31 from the appropriate aldehyde and tribromofluoromethane.

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.