Development of Monofluoroalkenes as Molecular Platform for Diversity-Oriented Syntheses of Tertiary Aliphatic Fluorides via Nickel/Manganese-Dual Catalysis

Open AccessCCS ChemistryCOMMUNICATION5 Sep 2022Development of Monofluoroalkenes as Molecular Platform for Diversity-Oriented Syntheses of Tertiary Aliphatic Fluorides via Nickel/Manganese-Dual Catalysis Yanlin Li, Wei Liu, Zhi-Yuan Liu, Cheng-Yu Wang, Kang-Jie Bian, Jie Sheng and Xi-Sheng Wang Yanlin Li Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, Anhui 230026 , Wei Liu Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, Anhui 230026 , Zhi-Yuan Liu Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, Anhui 230026 , Cheng-Yu Wang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, Anhui 230026 , Kang-Jie Bian Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, Anhui 230026 , Jie Sheng Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, Anhui 230026 and Xi-Sheng Wang *Corresponding author: E-mail Address: [email protected] Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei, Anhui 230026 https://doi.org/10.31635/ccschem.021.202101395 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The selective introduction of fluorine atoms into drug candidates has long been used as a common strategy in drug discovery. Most methods used for the synthesis of tertiary aliphatic fluorides rely on C–F bond formation by fluorinating relatively stable tertiary carbon cation or radical intermediates, where the stoichiometric amounts of corrosive/expensive electrophilic fluorinating reagents were required; thus, limiting its potential in late-stage fluorination in pharmaceutical development. Moreover, it remains a considerable challenge to develop a rapid and efficient method for facile syntheses of tertiary aliphatic fluorides with regio- and chemo-selectively. Herein, we report the development of a dual catalytic system capable of generating diverse tertiary aliphatic fluorides through cross-coupling between alkyl and tertiary fluoroalkyl species under mild conditions. With monofluoroalkenes serving as a molecular platform, the protocol leverages Mn-catalyzed metal-hydride hydrogen atom transfer (MHAT) to generate tertiary fluoroalkyl radicals regioselectively, followed by Nickel-catalyzed C(sp3)–C(sp3) coupling, giving rise to fluorine-bearing quaternary carbons. The broad scope and utility of the method in synthesizing fluorine-containing pharmaceutical derivatives and biologically useful molecules were demonstrated. Download figure Download PowerPoint Introduction The introduction of fluorine atom(s) into drug candidates has long been used as a common strategy for drug discovery and development. The fluorine substitution imparts molecules with improved metabolic stability, lipophilicity, bioavailability, and binding affinity.1–5 For instance, studies have shown that replacing a hydrogen atom at the specific site of a drug-like molecule with single fluorine could improve its activity by avoiding undesired metabolic cycle, benefitted from the mimic effect, and blocking the effect of organofluorine compounds.6,7 Accordingly, the synthetic community has shown interest in developing new strategies to access fluorinated molecules. Compared with primary and secondary alkyl fluorides, the construction of tertiary aliphatic fluorides largely relies on C–F bond formation by fluorinating tertiary carbon cations8–14 (nucleophilic fluorination) or radicals15–33 (electrophilic fluorination) (Scheme 1a). Meanwhile, the elimination, solvolysis, and rearrangement of in situ generated carbocation intermediates undoubtedly hampered their synthetic utility; the radical fluorination of C–H bond15–18 or functionalized tertiary alkanes19–33 offered an alternative solution to the construction of fluorine-containing quaternary carbon center. However, the poor regiocontrol for multiple tertiary C–H centers in the substrate of radical fluorinations and the requirement of individually site-selective preinstallation of functional groups definitely impose limitations on their application prospects. Alternatively, it would be of greater appeal to synthetic chemists in modern drug discovery to establish methods that would allow diversity-oriented syntheses (DOS)34 of tertiary aliphatic fluorides with excellent site-selectivity derived from prevalent organic feedstock, while design and facile syntheses of such molecular platforms remain underdeveloped. Scheme 1 | Synthesis of tertiary aliphatic fluorides (R, R′, R″ = alkyl). (a) C–F bond formation via nucleophilic or radical fluorination. (b) Ni/Mn-dual catalyzed C(sp3)–C(sp3) bond-forming cross-coupling. Download figure Download PowerPoint Indeed, retrosynthetic analysis of tertiary alkyl fluorides indicated that such moiety could be obtained from the C(sp3)–C(sp3) bond-forming cross-coupling between alkyl and tertiary fluoroalkyl species. Considering that the tertiary fluoroalkyl partner generated in situ bore no activating group on the tertiary carbon center, the frequently-used carbon anion, thus, is clearly excluded for this transformation. As part of our continuous efforts35–40 in nickel-catalyzed fluoroalkylation, we envisioned that monofluorinated tertiary radical could serve as an appropriate candidate in cross-coupling with alkyl halides to give the desired tertiary aliphatic monofluorides. Inspired by Shenvi's hydroalkylation methodology,41 which was featured with high Markovnikov regioselectivity via metal-hydride hydrogen atom transfer (MHAT) process,42–55 we reckoned that monofluoroalkene56 might act as a promising radical precursor (Scheme 1b) with the usage of manganese as a co-catalyst to give the fluoroalkyl radical in Markovnikov's fashion. Then the fluoroalkyl radical, in turn, would enter nickel-catalyzed C(sp3)–C(sp3) bond-forming cycle, affording the final tertiary aliphatic fluorides. Herein, we described C(sp3)–C(sp3) bond cross-coupling between alkyl and tertiary fluoroalkyl radicals via nickel/manganese dual catalysis, giving diverse tertiary alkyl fluorides that are unattainable with traditional fluorination methods. The key to success is matching rates between the Ni- and Mn-catalysis cycles, with a monofluoroalkene serving as a molecular platform to enable the DOS of tertiary aliphatic fluorides. Nickel was used as a catalyst for the cross-coupling cycle; manganese played a crucial role in controlling the regioselective outcome and improved the reactivity. Broad scope, mild conditions, and eligibility for late-stage construction of fluorine-containing pharmaceutical derivatives and biologically functional molecules were also demonstrated. Notably, the monofluoroalkenes were prepared from cheap, general alkenes or obtained directly from commercially available methyl 2-fluoroacrylate. Experimental Methods Preparation of catalyst solution A. To a 25 mL dry Schlenk tube, Na2SO4 (28.4 mg, 0.2 mmol), Ag (0.5–1 μm, 21.6 mg, 0.2 mmol), and K3PO4 (6.3 mg, 0.03 mmol) were added and heated with a heat gun under vacuum for 5 min. Then the solid mixture was cooled to room temperature in an Ar atmosphere, and NiCl2.DME (DME = glyme) (1.1 mg, 0.005 mmol), 4,4′-bis(trifluoromethyl)-2,2′-bipyridine (1.8 mg, 0.006 mmol), and 1,2-dichloroethane (DCE) (1 mL) were added under Ar atmosphere. The tube was sealed with a rubber plug; then the mixture was stirred at room temperature for 30 min. The solution A obtained was used immediately. The Schlenk tube was opened, and Mn(dpm)3 (0.04 mmol, 24 mg) was added quickly to solution A (1.0 mL), and the tube was sealed again. The mixture was stirred, and monofluoroalkene (0.3 mmol) and hexafluoroisopropanol (HFIP) (21 μL, 0.2 mmol) were added dropwise. Afterward, the reaction mixture was stirred for 3 min, and the Schlenk tube was placed in a EtOH cooling bath at 0 °C and equipped with an approximately 1.5 L balloon (8% O2 in Ar) through a vent needle (pink, 1.2 × 30 mm). Finally, alkyl iodide (RI) (0.1 mmol) and PhSiH3 (62 μL, 0.5 mmol) dissolved in DCE (0.1 mL) were added dropwise (1 drop/∼5 s), then the reaction mixture was stirred for 4 h at 0 °C. After the reaction was completed, the mixture was filtrated (3 cm silica gel) and concentrated. Then the residue was purified by silica gel chromatography with petroleum ether and ethyl acetate to afford the product 3- 55. Results and Discussion Based on Shenvi's reaction conditions,41 our study commenced with methyl 4-(4-iodobutoxy)benzoate ( 1) as the initial substrate and 2-fluoroallyl benzoate ( 2) as the coupling partner in the presence of a catalytic amount of Mn(dpm)3 (40 mol %) and NiCl2·DME (5 mol %) with 4,4′-bis(trifluoromethyl) bipyridine (6 mol %), PhSiH3 (4 equiv), HFIP (2 equiv) and K2CO3 (1 equiv) in DCE at 0 °C under 1 atm atmosphere of N2 with 10% O2 (Table 1, entry 1). To our delight, the desired tertiary aliphatic monofluoride 3 was afforded in 22% of yield (Table 1, entry 1). In contrast, the use of Fe(dpm)3 and CoIISalt-Bu,t-Bu as MHAT catalyst failed to give 3, possibly due to an unusual reactivity of monofluoroalkene in ligand association and producing fluorinated radical (Table 1, entries 2 and 3). Further optimization did not give higher yields, while a large amount of 1 was found to be the leftover (∼40%). We then sought to activate alkyl iodide with some silver species. To our delight, the use of Ag2CO3 (1.2 equiv) as an additive improved the yield to 36%, with 1 consumed completely (Table 1, entry 4), which gave us a chance to improve the yield of 3 through more optimization efforts. Table 1 | Optimization of Reaction Conditionsa Entry Cat. M Base (equiv) Add. (equiv) 3b (%) 1 Mn(dpm)3 K2CO3 (1.0) None 22 2 Fe(dpm)3 K2CO3 (1.0) None 0 3 CoIISalt-Bu,t-Bu K2CO3 (1.0) None 0 4 Mn(dpm)3 K2CO3 (1.0) Ag2CO3 (1.2) 36 5 Mn(dpm)3 K2CO3 (0.5) Ag2CO3 (1.2) 44 6 Mn(dpm)3 K2CO3 (0.3) Ag2CO3 (1.2) 20 7 Mn(dpm)3 K3PO4 (0.3) Ag2CO3 (1.2) 62 8 Mn(dpm)3 K3PO4 (0.2) Ag2CO3 (1.2) 46 9 Mn(dpm)3 K3PO4 (0.3) Ag2O (1.2) 60 10c Mn(dpm)3 K3PO4 (0.3) Ag2O (1.2) 68 11c Mn(dpm)3 K3PO4 (0.3) Ag (0.5–1 μm) (2.0) 50 12c,d Mn(dpm)3 K3PO4 (0.3) Ag (0.5–1 μm) (2.0) 62 13c,e Mn(dpm)3 K3PO4 (0.3) Ag (0.5–1 μm) (2.0) 80 14c,e Mn(dpm)3 K3PO4 (0.3) None 22 15c,e Mn(dpm)3 K3PO4 (0.3) Ag2CO3 (1.2) 76 16c,e Mn(dpm)3 K3PO4 (0.3) Ag2O (1.2) 78 17c,e Mn(dpm)3 K3PO4 (0.3) Cu (0.5–1.5 μm) (2.0) 56 18c,e,f Mn(dpm)3 K3PO4 (0.3) Ag (0.5–1 μm) (2.0) 75 L = 4,4′-bis(trifluoromethyl)-2,2′-bipyridine. CoIISalt-Bu,t-Bu = (1S,2S)-(+)-1,2-Cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)cobalt(II). aReaction conditions: 1 (0.1 mmol, 1.0 equiv), 2 (2.0 equiv), cat. M (40 mol %), NiCl2·DME (5 mol %), L (6 mol %), PhSiH3 (4 equiv), HFIP (2 equiv), base (0.3–1.0 equiv), Na2SO4 (2 equiv), DCE (1.0 mL), 0 °C, 4 h, 10% O2 in N2 as mixed-gas. bIsolated yield. c 2 (3.0 equiv), PhSiH3 (5.0 equiv) were added. d10% O2 in Ar as mixed-gas. e8% O2 in Ar as mixed-gas. f Mn(dpm)3 (30 mol %) was used. To further improve the yield, we next carried out a careful examination of bases (Table 1, entries 4–8), which indicated that K3PO4 (0.3 equiv) was confirmed as the optimum base (62%; Table 1, entry 7). Considering that silver played a vital role in this catalytic process, silver from different sources, including Ag2O and Ag powder (0.5–1 μm), were examined (for more details, see the Supporting Information). Ag2O afforded a similar yield of Ag2CO3 (60%, Table 1, entry 9), while Ag powder (0.5–1 μm) gave a slightly lower yield (50%, Table 1, entry 11). Since the rate of MHAT was closely related to the amount of oxidant (O2), different ratios of mixed-gas were also investigated (Table 1, entries 12 and 13). Notably, when 8% O2 in Ar was used as the mixed-gas atmosphere, the yield was improved to 80% if Ag powder (0.5–1 μm) was used as the additive (Table 1, entry 13). Only a 22% yield of product was obtained in the absence of silver additive (Table 1, entry 14), indicating its irreplaceable role in this transformation; other additives all provided lower yields (Table 1, entries 15–17). Finally, reducing the Mn(dpm)3 to 30 mol % could also give a comparable yield of 75% (Table 1, entry 18). With the optimized conditions (Table 1, entry 13) in hand, different kinds of monofluoroalkenes were synthesized and examined in this Ni/Mn-dual catalytic system. First, the length of alkyl chains on monofluoroalkenes was investigated, which showed that the length of the alkyl chain had almost no effect on the reaction (Table 2, 3–6), even up to eight carbon atoms on the alkyl substituent; the corresponding product could be afforded in a comparative yield of 70% ( 7). Collectively, these results indicated that our system circumvented the cumbersome introduction of a "chelating group" required in previous allylic alcohol transformation.56 Second, monofluoroalkenes with various lactam substituents gave moderate to good yields with a higher turnover for larger rings ( 8– 12). To our delight, phthalimide ( 13) and carbonic esters ( 14, 16) on the monofluoroalkenes were also compatible with this catalytic system giving synthetically useful yield. Fortunately, a malonate bearing monofluoroalkene containing an active hydrogen atom was hydroalkylated smoothly with a moderate yield (59%, 15). It should be noted that both electron-withdrawing groups such as CF3 ( 18, 21), CO2Me ( 19), CN ( 20), and electron-donating groups, including Me ( 22), i-Pr ( 23), OMe ( 24), and Ph ( 17), were all well tolerated under the standard conditions with acceptable yields. The electron neutral alkene ( 26) was conducted to examine the reaction conditions; we obtained a target product with a 63% yield. Table 2 | Scope of Monofluoroalkenesa aReaction conditions: RI (0.1 mmol), monofluoroalkene (0.3 mmol), Mn(dpm)3 (0.04 mmol), NiCl2·DME (0.005 mmol), L (0.006 mmol), PhSiH3 (0.5 mmol), HFIP (0.2 mmol), K3PO4 (0.03 mmol), Ag powder (0.5–1 μm) (0.2 mmol), DCE (1.0 mL), 8% O2 in Ar at 0 °C for 4 h. b30 mol % cat. Mn was used. cBuI was used as alkyl iodide. L = 4,4′-bis(trifluoromethyl)-2,2′-bipyridine. Next, we further investigated the scope of the catalytic hydroalkylation for the diverse synthesis of tertiary alkyl fluorides and a variety of alkyl iodides. Examination of the length of alkyl chains on the alkyl iodides showed that chain length has no noticeable effect on the reactivity of this reaction. For example, phenol ether-derived alkyl iodide with only one carbon atom shorter chain than 1 reacted smoothly under the optimized conditions (Table 3, 27), and an ester-derived linear alkyl chain containing nine carbon atoms was transformed successfully under this catalytic system ( 46). An investigation of the substituent effect on the phenyl ring indicated that several electron-withdrawing and -donating groups were compatible with this transformation. Importantly, not only stable aryl, phenol ether, ester, CF3 groups but also relatively active groups, including Cl ( 43), CN ( 45), and silyl ester ( 41), linked directly to the alkyl chain were compatible as well. It should be noted that diverse, active functional groups installed on the alkyl chain or the phenyl rings offered the potential for further synthetic derivation to more complex fluorine-containing molecules. For our interest, the simple alkyl iodide, MeI ( 31), and a long-chain alkyl iodide ( 47) also worked well in this reaction system. Table 3 | Scope of Alkyl Iodidesa aReaction conditions: RI (0.1 mmol), monofluoroalkene (0.3 mmol), Mn(dpm)3 (0.04 mmol), NiCl2·DME (0.005 mmol), L (0.006 mmol), PhSiH3 (0.5 mmol), HFIP (0.2 mmol), K3PO4 (0.03 mmol), Ag powder (0.5–1 μm) (0.2 mmol), DCE (1.0 mL), 8% O2 in Ar at 0 °C for 4 h. L = 4,4′-bis(trifluoromethyl)-2,2′-bipyridine. b30 mol % cat. Mn was used. c 17s was used as monofluoroalkene. d 20s was used as monofluoroalkene. e 55s was used as monofluoroalkene. To further demonstrate the functional group tolerance and synthetic potential, we attempted to use this novel Ni/Mn-dual catalytic system for the late-stage construction of fluorine-containing quaternary carbon centers in complex pharmaceutical or biological molecule derivatives. To our satisfaction, estrone ( 48), isoxepac ( 49), dehydrocholic acid ( 50), indomethacin ( 51), sesamol ( 52), gemfibrozil ( 53), flurbiprofen ( 54)-derived alkyl iodides were modified smoothly to tertiary aliphatic fluorides using monofluoroalkenes as the source for fluoroalkylation. It is worth mentioning that tertiary alkyl fluoride 55, bearing two different pharmaceutical moieties, could also be synthesized successfully with our catalytic method used as the connection strategy. These successful late-stage constructions of monofluorinated quaternary centers consistently proved that this new catalytic system offered an efficient and rapid method for selective modification of biologically active drug candidates. To gain some insights into the mechanism of this Ni/Mn-dual catalytic transformation, we next performed some control experiments: First, we subjected 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO) as a radical scavenger into the standard conditions, which completely quenched the reaction (Scheme 2a). Moreover, bisallylic sulfonamide 56s was added into the reaction system, affording 5-exo-trig cyclization products 56, 57, and 58, albeit in pretty low yields (Scheme 2b). Both results indicated a radical pathway was possible and that a tertiary monofluoro-carbon radical was generated in situ in the reaction system. Furthermore, the replacement of nickel salt with Ni(cod)2 gave the desired product 3 in a comparative yield (64%, Scheme 2c), which proved that Ni(cod)2 could also serve as a competent catalyst or precatalyst. Notably, internal olefin 59s (Scheme 2d) was also designed and subjected to this reaction, with only tertiary aliphatic monofluoride affording 16% yield, which illustrated that a complete reversal of the typical reactivity occurred on monofluoroalkene via the Mn catalytic cycle.55 Scheme 2 | Mechanistic studies of nickel/manganese-dual catalyzed hydroalkylation of monofluoroalkenes. (a) Radical trapping experiment. (b) 5-exo-trig cyclization reaction. (c) Control experiments using Ni(0)(cod)2. (d) Exploration for regioselectivity of MHAT. Download figure Download PowerPoint To further understand the distinct roles of the reactants, monofluoroalkene and relative methyl alkene analogue, and Ag powder (0.5–1 μm) in this reaction, we examined the relative consumption rate of both reactants. The monofluoroalkene showed an apparent higher reactivity than the corresponding methyl alkene analogue under the standard conditions (see the Supporting Information Figure S1). Meanwhile, the addition of Ag powder (0.5–1 μm) remarkably increased the consumption rate of alkyl iodide 1 (see the Supporting Information Figure S2). The above result revealed that Ag powder (0.5–1 μm) might act as an activating reagent to alkyl iodide so that the fluorinated tertiary carbon radical generation through Mn-catalyzed MHAT could synchronize with the Ni-catalyzed alkylation with alkyl iodide.57 Based on our mechanistic exploration results and previous report,41,58,59 a possible reaction mechanism was proposed as shown in Scheme 3: The Mn-catalytic cycle starts with the generation of H-MnIIIX2 species A with phenylsilane, which then reacts with monofluoroalkene 2 to give the regioselective tertiary carbon radical B. Oxidation of MnIIIX3 by molecular oxygen closes the Mn-cycle. Meanwhile, single-electron-oxidation of Ni0 catalyst by radical B could generate NiI species C, which undergoes oxidative addition with alkyl iodide to give NiIII species D. Finally, reductive elimination of D gives the corresponding 3, with concurrent regeneration of lower-valent nickel, followed by reduction to give Ni (0), with excessive phenylsilane to enter the next catalytic cycle. Scheme 3 | Proposed mechanism. Download figure Download PowerPoint Conclusion A nickel/manganese-dual-catalyzed cross-coupling of alkyl and tertiary fluoroalkyl species for DOS of tertiary aliphatic fluorides has been described. Nickel was used to catalyze the cross-coupling cycle, and manganese was responsible for high Markovnikov's regioselectivity demonstrated in the transformations. The matched rate of each cycle guarantees that monofluoroalkenes could be developed as a molecular platform to enable the facile synthesis of diverse tertiary aliphatic fluorides. This transformation demonstrated broad scope, good functional group tolerance under mild conditions and was used successfully for late-stage construction of fluorine-containing quaternary centers in complex biologically active molecule derivatives. Further exploration of the detailed mechanism and diverse synthesis of more complex tertiary aliphatic fluorides for drug design and screening is still underway in our laboratory. Supporting Information Supporting Information is available and includes parts of the complementary optimization of conditions, detailed experimental procedures, mechanistic studies, analytical data, and copies of 1H, 13C, and 19F NMR spectra for new compounds. Conflict of Interest There is no conflict of interest to report. Funding Information We gratefully acknowledge the National Science Foundation of China (nos. 21971228 and 21772187) for financial support. References 1. Purser S.; Moore R. P.; Swallow S.; Gouverneur V.Fluorine in Medicinal Chemistry.Chem. Soc. 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