Iron-Catalyzed Cross-Coupling of Bis-(aryl)manganese Nucleophiles with Alkenyl Halides: Optimization and Mechanistic Investigations

Various substituted bis-(aryl)manganese species were prepared from aryl bromides by one-pot insertion of magnesium turnings in the presence of LiCl and in situ trans-metalation with MnCl2 in THF at −5 °C within 2 h. These bis-(aryl)manganese reagents undergo smooth iron-catalyzed cross-couplings using 10 mol% Fe(acac)3 with various functionalized alkenyl iodides and bromides in 1 h at 25 °C. The aryl-alkenyl cross-coupling reaction mechanism was thoroughly investigated through paramagnetic 1H-NMR, which identified the key role of tris-coordinated ate-iron(II) species in the catalytic process.


Introduction
Transition-metal catalyzed cross-couplings are widely used in the development and production of pharmaceutical compounds [1]. The most versatile of them are palladium-catalyzed and nickelcatalyzed cross-couplings [2][3][4][5] as they tolerate a great variety of functionalities on both coupling partners. Yet, these metals have drawbacks such as toxicity [6,7] and high prices in the case of palladium [8]. That is one of the reasons why copper [9], iron [10][11][12][13], or cobalt [14] have been developed as alternative metal-catalysts.
Recently, we have developed a two-step preparation of functionalized bis-(aryl)manganese reagents by oxidative insertion of magnesium into the C-Br bond of aryl bromides, which is followed by a trans-metalation with MnCl2·2LiCl [31]. Herein, we wish to report an effective one-pot preparation of those functionalized bis-(aryl)manganese reagents (Ar2Mn•2MgX2•4LiCl, denoted as Ar2Mn (1), Scheme 1) starting from aryl bromides, which are followed by an iron-catalyzed crosscoupling of 1 with alkenyl iodides and bromides, and provide a range of polyfunctionalized alkenes (4, Scheme 1). These bis-(aryl)manganese reagents are generally stable at RT (25 °C) for several hours, which makes them suitable reagents for mild cross-coupling reactions [32]. Scheme 1. One-pot preparation of bis-(aryl)manganese reagents by in situ trans-metalation followed by iron-catalyzed cross-couplings with alkenyl iodides and bromides.

Discussion
In order to rationalize some of the mechanistic features of the transformations reported in the first section, we focused our efforts on the coupling system involving various bis-(aryl)manganese nucleophiles (bis-mesitylmanganese and bis-phenylmanganese) with (2-bromovinyl)-trimethylsilane (3b). This choice has been motivated by the low cross-coupling yields obtained with this electrophile in the absence of the iron catalyst, which ascertains the requirement of an Fe-based catalysis for this coupling (see Table 2, entries 1, 3, 9 and 11).
The bis-(mesityl)manganese reagent was prepared by adding MesMgBr (2.0 equiv.) into a solution of MnCl2LiCl (1.0 equiv.) in THF at −5 °C within 1 h. 1 H-NMR showed no free MesMgBr left. The spectra presented high signal-to-noise ratios and broad signals, due to the high paramagnetism of manganese(II) species, which could not be attributed to a specific molecule ( Figure  1a) [33]. High-spin organomanganese compounds are often reported to be NMR silent [34] or without NMR characterization at all [35][36][37]. Yet, after addition of a catalytic load of FeCl2 (0.10 equiv.) to the Mes2Mn solution, the ate complex [Mes3Fe II ] − was detected by 1 H-NMR from the three signals at 127 ppm (s, 6H, meta-H of the Mes group), 110 ppm (s, 9H, para-CH3), and 26 ppm (bs, 18 H, ortho-CH3), as shown in Figure 1b. These signals attest to a strong paramagnetism, due to the high-spin (S = 2) configuration of this complex [38]. This proves a fast trans-metalation of the aryl groups from the manganese toward the iron(II) center. A similar result was obtained while adding an excess of the Mes2Mn solution onto Fe(acac)3 (0.10 equiv.) as an iron(III) precursor. [Mes3Fe II ] -was detected by 1 H-NMR, showing that, when an iron(III) precursor is used, a first 1-electron reduction of the latter by the nucleophile can take place, affording an iron(II) species. This is in agreement with recent reports by Neidig [39] and by some of us [40] regarding the reduction of iron(III) salts by Grignard reagents as MeMgBr and PhMgBr. Accordingly, all the mechanistic studies discussed thereafter were performed using an iron(II) precursor.
Upon addition of the electrophile 3b ((2-bromovinyl)trimethylsilane) to a mixture of FeCl2 and Mes2Mn at 25 °C, the signals corresponding to [Mes3Fe II ] − were observed to slowly decrease, affording [Mes2BrFe II ] − , characterized by new signals at 128 ppm (s, 4H, meta-H of the Mes group), 104 ppm (s, 6H, para-CH3), and 29 ppm (bs, 12 H, ortho-CH3) (see Figure 1c) (this tricoordinate ate species also presents a high-spin S = 2 configuration) [38]. The same reaction was run at 25 °C for 1 h, then quenched, and analyzed by GC-MS, which proved formation of the desired cross-coupling product with a low conversion (ca. 20%). This is in fair agreement with the result given in Table 2, entry 11 (due to the high paramagnetism of the NMR-analyzed solution and due to the presence of non-deuterated solvents (THF solutions of organometallics), NMR monitoring of the coupling product formation could not be efficiently performed). The following catalytic cycle (Scheme 2) can be suggested, which echoes recent reports by Neidig on the Fe-catalyzed alkyl-alkenyl coupling reactions [39], and by ourselves on the benzyl-alkenyl coupling [26]. Thanks to the steric hindrance in the ortho positions, the ate [Mes3Fe II ] -species remains stable for hours at 25 °C [38,41]. Thus, the use of a mesityl nucleophile in the mechanistic experiments discussed earlier prevents any degradation of the Fe II catalyst toward lower oxidation states. In order to delineate the influence of the formation of lower oxidation states on the system, additional investigations were, therefore, carried out using PhMgBr as a less hindered nucleophile [42].
First, [Ph3Fe II ] − was generated at −20 °C by stoichiometric trans-metalation between FeCl2 and 3.0 equiv. of PhMgBr, and characterized by its 1 H-NMR signals at 116 and −41 ppm. As we recently reported, [Ph3Fe II ] -is stable for more than 1 h at this temperature [40,41]. Its fate upon addition of an excess of the electrophile 3b (10 equiv.) was then monitored by paramagnetic 1 H-NMR. [Ph3Fe II ] − reacted rapidly, as attested by the decrease of its resonances (ca. 75% of the starting [Ph3Fe II ] − reacted after 10 min). The reaction was quenched after 1 h, and the GC-MS confirmed formation of the crosscoupling product, which confirms that [Ph3Fe II ] − was able to react with 3b in a cross-coupling process, akin to [Mes3Fe II ] − . Moreover, several transient resonances in the −15/−5 ppm area could also be detected in the course of the reaction (see Figure 2). These elusive resonances quickly disappeared, and were not detected after 30 min at −20 °C. These signals echo the formation of (η 2 -alkene)n-Fe 0 intermediates, as recently reported by Deng, which exhibit similar resonances [43]. This suggests that Fe 0 species are formed in situ by 2-electron reductive elimination from [Ph3Fe II ] − , which is in agreement with a recent report by some of us demonstrating that the evolution of [Ph3Fe II ] − led to the formation of a distribution of Fe 0 and Fe I oxidation states (identified as (η 4 -arene)2Fe 0 and [(η 6arene)Fe I (Ph)2] − , "arene" being an aromatic ligand present in the bulk medium (e.g., C6H6 or C6H5-C6H5 coming from the oxidation of PhMgBr). Fe 0 being preponderantly formed [40,41]). Those Fe 0 intermediates would then be trapped by alkene ligands present in the bulk medium, which leads to the observed resonances. Then, the reactivity of the low valent Fe 0 and Fe I oxidation states in the reaction medium was investigated. Following one of our recent procedures, reduction of Fe II into a distribution of Fe 0 and Fe I species was performed, by fast trans-metalation between FeCl2 and PhMgBr (2.0 equiv.) at room temperature [40,41]. After 10 min, 1.0 equiv. of MesMgBr was added. The 1 H-NMR spectrum showed no signal in the 100-150 ppm area, which attests to the absence of any Mes-Fe II species, which shows that all the starting Fe II was reduced by PhMgBr (Figure 3a). The addition of 3.0 equiv. of the electrophile 3b to the in situ generated solution of Fe 0 and Fe I species led to a color change of the sample, which turned from dark brown to yellow. The 1 H-NMR spectrum showed that, after 30 min, ca. 20% of the iron contained in the solution was converted into [Mes3Fe II ] − (Figure 3b). The presence of 3b, therefore, allows a re-oxidation of the reduced Fe 0 and/or Fe I species to the Fe II oxidation state, the latter being trapped by trans-metalation with MesMgBr to afford [Mes3Fe II ] − . The re-oxidation of low iron oxidation states by 3b to the Fe II stage was also confirmed by the observation of bis(trimethylsilyl)butadienes TMS-CH=CH-CH=CH-TMS (TMS-(CH)4-TMS, E/E; Z/E; Z/Z) in GC-MS, after catalytic reactions involving 10%mol of FeCl2, PhMgBr, and 3b as coupling partners. Formation of TMS-(CH)4-TMS undoubtedly comes from the sacrificial monoelectronic reduction of the electrophile that permits re-oxidation of the low Fe 0 and/or Fe I oxidation states. TMS-(CH)4-TMS, moreover, also appears as a suitable ligand for Fe 0 oxidation state, and a (η 4 -TMS-(CH)4-TMS)Fe 0 complex might, thus, contribute to the group of high field resonances in the in the −15/−5 ppm area (Figure 2). Quantity of detected TMS-(CH)4-TMS represents ca. 10% of the quantity of a detected coupling product, which shows that this off-cycle sacrificial reduction pathway is not preponderant. By comparison, no traces of TMS-(CH)4-TMS were detected when using mesityl nucleophiles (conditions of Figure 1), attesting that no sacrificial 1-electron reduction of 3b by oxidation states lower than Fe II formed in situ occurred.
Scheme 3 presents a summary of the competitive reactions that were observed in this work during the Fe-catalyzed coupling of Ph2Mn with (2-bromovinyl)-trimethylsilane (3b), taking into account the possibility of an off-cycle process involving in situ formed low iron oxidation states. Kinetic studies will further be pursued in order to determine the global kinetics of the arylalkenyl cross-coupling reaction, and to examine the possibility for the low Fe 0 and Fe I oxidation states involved in a cross-coupling catalytic cycle, in addition to the off-cycle sacrificial reduction of the alkenyl electrophile evidenced herein. Such studies will also help analyze the mechanism of the activation of the C-X bond of the alkenyl halide. Isomerization toward the sterically more stable E coupling products may suggest the implication of an iron-based radical activation of the alkenyl halide, as observed in the case of alkyl electrophiles [44], albeit formation of the Csp2-centered radical is generally more energetically-demanding. Additionally, it cannot be excluded in an alternative scenario that isomerization of the C=C bond occurs after the coupling step, akin to the observations made by Jacobi von Wangelin for the iron-catalyzed isomerization of Z-olefins to their E analogues [45].

Materials and Instruments
All reactions, except otherwise noted, were carried out in flame-dried glassware equipped with magnetic stirring under an argon atmosphere using standard Schlenk techniques. To transfer solvents or reagents, syringes were used, which were purged three times with argon prior to use. After purification by flash column chromatography, products were concentrated using a rotary evaporator and, subsequently, dried under high vacuum. Indicated yields are isolated yields of compounds estimated to be >95% pure, as determined by 1 H-NMR (25 °C) and capillary GC.
To examine the reaction progress of the performed reactions, GC-analysis of quenched hydrolyzed and iodolyzed reaction aliquots relative to an internal standard was used. For this purpose, small amounts of the reaction mixture were hydrolyzed using a saturated aqueous solution of NH4Cl, subsequently extracted with EtOAc, dried over MgSO4 and gaschromatographically quantified. To monitor the process of directed metalations and oxidative insertion reactions, small amounts of the reaction mixture were iodolyzed. A small quantity of iodine was dissolved in freshly distilled THF (0.50 mL), charged with the reaction mixture, and added to a solution of Na2S2O3. The mixture was extracted with EtOAc, dried over MgSO4, and was then gas chromatographically measured.
To determine the concentration of the different synthesized metallic reagents, iodometric titration was used. For this purpose, a known amount of iodine was charged with freshly distilled THF (1.00 mL) to give a deep red solution. The metallic reagent was added dropwise at 2 °C to the iodine solution until the red coloration went colorless. The concentration of the organometallic reagent could be calculated via the consumed volume of the reaction mixture and the amount of used iodine.
Thin layer chromatography (TLC) was implemented on alumina plates coated with SiO2 (Merck 60, F-254, Merck, Darmstadt, Germany). To visualize the spots of the different products, UV light was used.
Mass spectroscopy: High resolution (HRMS) and low resolution (MS) spectra were recorded on a FINNIGAN MAT 95Q instrument (now Thermo Fisher company, Waltham, MA, USA). Electron impact ionization (EI) was conducted with an ionization energy of 70 eV. For coupled gas chromatography/mass spectrometry, a HEWLETT-PACKARD HP 6890 /MSD 5973 GC/MS system was used. Molecular fragments are reported starting at a relative intensity of 10%.
Infrared spectra (IR) were recorded from 4500 cm −1 to 650 cm −1 on a PERKIN ELMER Spectrum BX59343 instrument (Perkin Elmer, Wellesley, MA, USA). For detection, a SMITHS DETECTION DuraSamplIR IIDiamond ATR sensor (Smiths Detection, Hemel Hempstead, UK) was used. Wavenumbers are reported in cm −1 starting at an absorption of 10%.

Chemicals, Solvents, and Typical Procedures
All chemicals were purchased from commercial sources and were used without any further purification unless otherwise noted.
THF was continuously refluxed and freshly distilled from benzophenone ketyl under nitrogen. The freshly distilled THF was stored over a molecular sieve (4 Å) under argon. Solvents for column chromatography were distilled prior to use.

Typical Procedure for the One-Pot Preparation of Bis-(aryl)manganese Reagents 1a-g
A dry and argon-flushed Schlenk-tube, equipped with a magnetic stirring bar and a rubber septum, was charged with LiCl (0.610 g, 14.4 mmol, 2.4 equiv.), heated to 450 °C under high vacuum, and then cooled to room temperature. After being switched to argon, the same procedure was applied after MnCl2 was added (453 mg, 3.60 mmol, 0.6 equiv.). After cooling to room temperature, magnesium turnings were added (0.350 g, 14.4 mmol, 2.4 equiv.), which was followed by freshly distilled THF (12 mL). After the reaction mixture was cooled to −5 °C, the aryl bromides 2a-g were then added dropwise using 1 mL syringes (6.0 mmol, 1.0 equiv., addition time: 1 min) and the reaction mixture was stirred until a complete conversion of the starting material was observed. The reaction progress was monitored by GC-analysis of hydrolyzed and iodolyzed aliquots.
When the metalation was completed, the concentration of the bis-(aryl)manganese species was determined by titration against iodine in freshly distilled THF. The black solutions of the aryl reagents 1a-g were then separated from the magnesium turnings using a syringe and, subsequently, transferred into another pre-dried and argon-flushed Schlenk-tube, which was cooled to −5 °C. After a titration against iodine in freshly distilled THF was performed, the reagent was ready to use for Cross-Couplings.

Typical Procedure for the Cross-Coupling Reactions of Bis-(aryl)manganese Reagents 1a-g with Different Electrophiles 3a-e
A pre-dried and argon-flushed Schlenk-tube equipped with a magnetic stirring bar and a rubber septum was charged with Fe(acac)3 (35 mg, 0.10 mmol, 10 mol%), the corresponding electrophile (3ae, 1.0 mmol, 1.0 equiv.), tetradecane as internal standard (50 µL) and freshly distilled THF (1.0 mL) as solvent. The reaction mixture was cooled to 0 °C and the bis-(aryl)manganese solution (1a-g, 0.6 equiv.) was added dropwise whereupon a color change to dark brown could be recognized. After the addition was complete, the reaction mixture was stirred for a given time at room temperature and the completion of the cross-coupling reaction was monitored by GC-analysis of hydrolyzed aliquots. Thereupon, a saturated aqueous solution of NH4Cl was added and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the crude products by flash column chromatography afforded the desired cross-coupling reaction products (4a-k, 4m, 4n).

Studies on the Catalytically Active Species and Catalytic Cycle
All the samples were prepared in a recirculating JACOMEX inert atmosphere (Ar) drybox and vacuum Schlenk lines. Glassware was dried overnight at 120 °C before use. NMR spectra were obtained using a Bruker DPX 400 MHz spectrometer (Bruker, Billerica, MA, USA). Chemical shifts for 1 H-NMR spectra were referenced to solvent impurities (herein, THF). NMR tubes were equipped with a J. Young valves were used for all 1 H-NMR experiments and catalytic tests. The GC-MS analysis was performed using n-decane as an internal standard. The reaction media aliquots were quenched by the addition of distilled water under air. The organic products were extracted using DCM, and injected into the GC-MS. Mass spectra were recorded on a Hewlett-Packart HP 5973 mass spectrometer (Hewlett Packard, Palo Alto, CA, USA) via a GC-MS coupling with a Hewlett-Packart HP 6890 chromatograph (Hewlett Packard, Palo Alto, CA, USA) equipped with a capillary column HP-5MS (50 m × 0.25 mm × 0.25 µm, Hewlett Packard, Palo Alto, CA, USA). Ionisation was due to an electronic impact (EI, 70 eV).

Conclusions
In summary, various functionalized bis-(aryl)manganese species have been readily prepared in one-pot conditions from the corresponding aryl bromides by inserting magnesium in the presence of LiCl and in situ trans-metalation with MnCl2 in THF at −5 °C within 2 h. These bis-(aryl)manganese reagents have been allowed to undergo smooth iron-catalyzed cross-couplings using 10 mol% Fe(acac)3 and various functionalized alkenyl iodides and bromides at 25 °C for 1 h. Mechanistic investigations carried out by 1 H-NMR showed that ate-iron(II) species [Ar3Fe II ] − are formed by transmetalation of the bis-(aryl)manganese reagent with the iron catalyst, and that they can react with alkenyl bromides to afford the expected cross-coupling product. Low-valent Fe 0 and Fe I oxidation states can also be formed by the reduction of the ate-iron(II) catalyst under these conditions. This leads to the sacrificial reduction of the alkenyl electrophile via an off-cycle pathway, which partly regenerates the Fe II oxidation state, where the latter is able to enter a new catalytic cycle.
Supplementary Materials: Additional synthesis and characterization (NMR, IR, HRMS, m.p.) data are available online.
Author Contributions: Conceptualization, G.L. and P.K. Methodology, A.D. and L.R. Writing-original draft preparation, G.L., L.R., and A.D. Writing-review and editing, G.L. and P.K. Supervision, G.L. and P.K. Project administration, G.L. and P.K. Funding acquisition, G.L. and P.K. All authors have read and agreed to the published version of the manuscript.