Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic

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Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic Control of C(sp)-H Oxidative Addition Results in ortho-to-Fluorine Selectivity 2

Tyler P. Pabst, Jennifer V. Obligacion, Etienne Rochette, Iraklis Pappas, and Paul J. Chirik J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07984 • Publication Date (Web): 26 Aug 2019 Downloaded from pubs.acs.org on August 26, 2019

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Journal of the American Chemical Society

Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic Control of C(sp2)-H Oxidative Addition Results in ortho-to-Fluorine Selectivity Tyler P. Pabst, Jennifer V. Obligacion, Étienne Rochette, Iraklis Pappas, Paul J. Chirik* Department of Chemistry, Princeton University, Princeton, New Jersey, 08544, United States ABSTRACT: The mechanism of C(sp2)–H borylation of fluorinated arenes with B2Pin2 (Pin = pinacolato) catalyzed by bis(phosphino)pyridine (iPrPNP) cobalt complexes was studied to understand the origins of the uniquely high ortho-to-fluorine regioselectivity observed in these reactions. Variable time normalization analysis (VTNA) of reaction time courses and deuterium kinetic isotope effect measurements established a kinetic regime wherein C(sp2)–H oxidative addition is fast and reversible. Monitoring the reaction by in situ NMR spectroscopy revealed the intermediacy of a cobalt(I)–aryl complex that was generated with the same high ortho-to-fluorine regioselectivity associated with the overall catalytic transformation. Deuterium labeling experiments and stoichiometric studies established C(sp2)–H oxidative addition of the fluorinated arene as the selectivity-determining step of the reaction. This step favors the formation of orthofluoroaryl cobalt intermediates due to the ortho fluorine effect, a phenomenon whereby ortho fluorine substituents stabilize transition metal– carbon bonds. Computational studies provided evidence that the cobalt-carbon bonds of the relevant intermediates in (iPrPNP)Co-catalyzed borylation are strengthened with increasing ortho fluorine substitution. The atypical kinetic regime involving fast and reversible C(sp2)–H oxidative addition in combination with the thermodynamic preference for forming cobalt-aryl bonds adjacent to fluorinated sites are the origin of the high regioselectivity in the catalytic borylation reaction.

INTRODUCTION 2

The transition metal-catalyzed borylation of C(sp )–H bonds has emerged as a widely utilized and impactful application of C–H functionalization1-4 owing in part to the utility and versatility of the resulting aryl boronate ester products.5,6 Combination of the iridium(I) precursor, [Ir(COD)OMe]2 (COD = 1,5-cyclooctadiene) with a substituted bipyridine ligand, most typically dtbpy (4,4’-ditert-butyl-2,2’-bipyridine), and either B2Pin2 or HBPin (Pin = pinacolato) as the boron source constitutes the most commonly used method. The high activity, predictable sterically driven site selectivity, and complementarity to traditional aromatic substitution methods are responsible for the widespread application of the iridium catalysts. Both experimental7 and computational8 studies support a pathway involving rate-determining oxidative addition of a C(sp2)–H bond to an iridium(III) tris(boryl) intermediate followed by reductive elimination to form the arylboronate ester.7,8 Computational studies support late transition states with fully formed iridium-carbon bonds with regioselectivity determined by the difference in the interaction energies between the iridium and arene carbon at each possible site.9 Controlling the regioselectivity of C–H functionalization is of practical importance given the abundance of carbon-hydrogen bonds in organic molecules.10 In iridium-catalyzed C(sp2)–H borylation, the regioselectivity of the reaction is predominantly steric in origin, as the standard iridium catalysts do not readily activate aryl C–H bonds ortho to large substituents (methyl and larger).11-13 In cases where there are multiple sterically accessible C(sp2)–H bonds, statistical selectivity is typically observed; for example, the bipyridine-iridium catalyst was shown to borylate both toluene and trifluorotoluene with approximately 2:1 selectivity favoring the meta over the para product.12 Strategies to overcome

this inherent selectivity typically rely on directing groups – functionality designed to coordinate to the metal and activate a specific C(sp2)–H toward oxidative addition and ultimately borylation (Scheme 1).10 Introduction of hydridosilyl14 or benzylic tertiary amine15 groups on the arene substrate has been employed to promote ortho-directed borylation. Recent variants of this approach including hydrogen bonding interactions between the substrate and modified bipyridine ligands,16-18 ion pairing,19-21 electrostatic interactions,22,23 and others24,25 have been used to bias iridiumcatalyzed reactions away from statistical selectivity. Scheme 1. Directing group strategies for ortho-to-functional group C(sp2)–H borylation with bipyridine iridium catalysts (top) and origins of selectivity in (iPrPNP) cobalt-catalyzed C(sp2)–H borylation (bottom).

The regioselective C(sp2)–H borylation of fluorinated arenes is of practical interest as an enabling approach for the construction of

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fluorine-containing small molecules, a substructure prevalent in pharmaceuticals and agrochemicals.26 The energetics of C(sp2)–H activation and competing C(sp2)–F activation of fluorinated arenes have been analyzed by Eisenstein and Perutz in a comprehensive review.27 Braun and coworkers have also reported that a rhodium(I)-boryl (PEt3)3Rh(BPin) promoted the selective activation of C(sp2)–H bonds in fluorinated benzene and pyridine derivatives, and C(sp2)–F activation was only observed in the presence of perfluorinated substrates.28 From a fundamental perspective, the selective borylation of electronically distinct C(sp2)–H bonds without exploiting steric effects is an unmet challenge in C–H functionalization catalysis.10 Despite the ubiquity of fluorinated arenes, few methods for their selective C(sp2)–H borylation have been reported. With state-of-the-art iridium catalysts,12 borylation of various 3substituted fluoroarenes resulted in little deviation from statistical selectivity for the ortho and meta-borylated products (Table 1a).29 Platinum catalysts supported by N-heterocyclic carbene ligands30 or a [PSiN]-pincer31 exhibited higher ortho-to-fluorine selectivity (Table 1b) although elevated temperatures (typically between 80 and 150 °C) were required, and the origin of the improved selectivity remains unknown.

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ble 1c), and this selectivity was maintained even in the presence of functional groups that typically serve as directing groups in iridiumcatalyzed reactions; initially, the observed regioselectivity was attributed to the increased acidity of C(sp2)–H bonds ortho to fluorine substituents.29 Subsequent to these findings, Driess, Cui and coworkers reported that in situ activation of a bis(silylene) pyridine (SiNSi) cobalt(II) dibromide with NaBEt3H in the presence of cyclohexene afforded meta-to-fluorine selectivity in C(sp2)–H borylation of fluorinated arenes (Table 1d).33 Importantly, these findings demonstrate that first-row transition metals not only offer improved selectivity over precious metals but also the opportunity for inversion of selectivity with appropriate choice of pincer ligand. An understanding of the origins of these selectivities would inform the rational design of catalysts for a desired regioselectivity, perhaps extending to transformations beyond C(sp2)–H borylation. Scheme 2. Experimental Results of Previous Mechanistic Studies on (iPrPNP)Co-Catalyzed Borylation of (a) 2,6-lutidine with B2Pin2 and (b) Benzofuran with HPBin

Table 1. Selectivitya in the C(sp 2)–H Borylation of Fluorinated Arenes with (a) State-of-the-art Iridium Catalysts, (b) Platinum Catalysts, (c) (iPrPNP) Cobalt Catalysts, and (d) SiNSi Cobalt Catalysts.

a

The numbers in the table are the reported ratios of arylboronate product isomers resulting from the borylation of the substrate drawn. Our laboratory has reported that cobalt complexes bearing bis(phosphino)pyridine (iPrPNP) pincers are active for the C(sp2)– H borylation of arenes and heteroarenes.32 With fluorinated arenes, synthetically useful ortho-to-fluorine selectivity was observed (Ta-

Our previous studies on C(sp2)–H borylation catalyzed by cobalt complexes of iPrPNP have shown that mechanism and kinetic regime may vary with the identity of the substrate class examined. Mechanistic investigations into the borylation of 2,6-lutidine with B2Pin2 and [(iPrPNP)Co] precatalysts established a Co(I)-Co(III) redox cycle with oxidative addition of the C(sp2)–H to a cobalt(I)– boryl as the turnover limiting step (Scheme 2a). 34 This pathway is similar to the bipyridine-iridium catalysts that operate through an Ir(III)-Ir(V) cycle with rate-determining oxidative addition to a iridium(III) tris(boryl).7 For the borylation of heteroarenes with activated C(sp2)–H bonds such as benzofuran with HBPin, a different kinetic regime was observed whereby reductive elimination from (iPrPNP)Co(H)2BPin (1-(H)2BPin) to generate the cobalt(I)-boryl is slow and oxidative addition is fast (Scheme 2b).35 Computational studies on the borylation of benzene with B2Pin2 and [(iPrPNP)Co] established that pathways involving phosphine dissociation, -bond metathesis and ligand dearomatization were not kinetically competent, supporting the proposed Co(I)-Co(III) pathway.36 The flexibility and dynamics of the methylene linkers of the PNP pincer were found to be important as oxidative addition, isomerization, and reductive elimination steps occurred with con-


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comitant interconversion between cisoid and transoid conformations of the ligand. This mechanistic information combined with the enhanced regioselectivity observed in the [(PNP)Co]-catalyzed borylation of fluoroarenes with B2Pin2 raised questions pertaining to the origin of the unique selectivity as well as the kinetic regime operative. Here we describe a comprehensive study on the mechanism of these reactions, establish the reversibility of C(sp2)–H oxidative addition and demonstrate the role of cobalt-C(sp2) bond thermodynamics as the origin of selectivity.

RESULTS AND DISCUSSION Rate Law for the [(iPrPNP)Co]-Catalyzed Borylation of Fluorinated Arenes. Our studies commenced with determination of the experimental rate law for the borylation of fluorinated aryl sulfonamide 2a with B2Pin2 using 1-(H) 2BPin as the cobalt precatalyst. A 3-substituted fluoroarene was selected for these investigations in order to limit the number of possible borylation products; only two sterically accessible C(sp2)–H bonds are present in substrate 2a. Variable time normalization analysis (VTNA) of reaction time courses as described by Burés was applied37 where the initial concentrations of 1-(H)2BPin, 2a, B2Pin2 and HBPin, the stoichiometric boron-containing byproduct, were systematically varied. Analysis of the resulting overlay plots (Figure 1) established the rate law in eq. 1. Rate = k[1-(H)2BPin]1[2a]0[B2Pin2]0[HBPin]0.5

(1)

For the majority of the reaction’s time course, the reaction was found to be zeroth order in 2a, a result distinct from previous reports involving the borylation of 2,6-lutidine with B2Pin2 by [(iPrPNP)Co] precursors34 and the borylation of benzene or 1,2-

dichlorobenzene by bipyridine iridium precatalysts.7 In these previous studies, a first-order dependence on arene was observed, and mechanisms involving turnover-limiting C(sp2)–H oxidative addition to metal-boryl were proposed. In contrast to these established pathways, the zeroth order (or saturation38) behavior of the present reaction implies reversible C–H activation of 2a prior to the turnover limiting step. Another striking feature of the rate law in equation 1 is the half-order dependence on HBPin, the stoichiometric boron-containing byproduct from the C(sp2)–H functionalization. While half-order behavior is often attributed to monomer-dimer speciation, HBPin is monomeric in solution as are the cobalt pincer complexes. The origin of this fractional order will be discussed in a later section (see “Proposed Mechanism”). Deuterium Kinetic Isotope Effects. To further assay the possibility of C(sp2)–H oxidative addition as the turnover limiting step, deuterium kinetic isotope effect (KIE) measurements were conducted in two separate vessels at 50 °C with identical concentrations of 2a and 2a-d2 in the presence of 10 mol% of 1-(H)2BPin and superstoichiometric B2Pin2 (Scheme 3). KIE values of 1.1(1) and 0.9(1) were determined for borylation of the ortho and meta sites arising from formation of the major and minor isomers, respectively. The absence of a significant deuterium KIE supports a pathway wherein C(sp2)–H bond activation does not occur in the turnover-limiting step. These observations in combination with the rate law for the catalytic reaction demonstrate that the cobaltcatalyzed borylation of fluorinated arenes operates in a distinct kinetic regime from the borylation of 2,6-lutidine using (iPrPNP)CoCH2SiMe3, where C(sp2)–H oxidative addition to cobalt(I) is turnover limiting.



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Figure 1. Overlay plots obtained from VTNA for the determination of the rate law for the borylation of 2a with B2Pin2 with 1-(H)2BPin as the precatalyst. CF3

Scheme 3. Determination of Deuterium Kinetic Isotope Effects (KIE) for the Borylation of 2a and 2a-d2 with 1-(H)2BPin in Two Separate Vessels. SO2NMe2

SO2NMe2 B2Pin2

THF, 50 oC - HBPin

F

2b

C6 D 6, 23 o C, time - HBPin

F

F BPin ortho -3b

BPin meta -3b

SO2NMe2

F

BPin

BPin

2a SO2NMe2

SO2NMe2 B2Pin2

F

B 2Pin 2 1 equiv.

F

CF3

10 mol% 1-(H)2BPin

1.7 equiv.

F

CF3 20 mol% 1-(H) 2BPin

D

SO2NMe2

10 mol% 1-(H)2BPin

1.7 equiv.

D

THF, 50 oC - DBPin

F

D BPin

F

BPin D

2a-d2

KIE(50 oC)ortho = 1.1 ± 0.1

KIE(50 oC)meta = 0.9 ± 0.1 (two separate vessels)

Determination of the Catalyst Resting State as a Function of Time. The borylation of 3-fluoro-α,α,α-trifluorotoluene (2b) promoted by 1-(H)2BPin was monitored by 1H, 19F and 31P NMR spectroscopies in an attempt to gain insight into the resting state(s) of the cobalt catalyst. A higher precatalyst loading of 20 mol% was used to facilitate observation of metal-containing products. Substrate 2b was selected over 2a due to its slower turnover. We previously reported that 2b undergoes borylation with 95:5 selectivity favoring the ortho-to-fluorine isomer and this ratio was unperturbed with variations in temperature, catalyst loading or reaction time.29

Figure 2. The benzene-d6 31P NMR spectra of the borylation of 2b with 20 mol % 1-(H)2BPin and B2Pin2 at 23 °C over time. The 31P NMR spectra recorded over time for the borylation of 2b at 23 °C are depicted in Figure 2. At the earliest time point (5 min, 48% conversion), two major 31P signals were observed at 103.9 ppm and 53.2 ppm, corresponding to 1-(H)2BPin and a new, unidentified cobalt species, respectively. The observed 31P


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NMR shift of the new cobalt species is similar to those of previously reported cobalt(I) methyl (50.6 ppm)34 and benzofuranyl (54.7 ppm)39 compounds supported by the PNP pincer. Over the course of 60 minutes at which point the reaction reached 89% conversion, the 31P NMR signal corresponding to the unidentified species gradually diminished. The 19F NMR spectra collected during this time period exhibit two signals (in addition to those of 2b and its borylation products) at -60.4 ppm and -82.1 ppm that integrate in a 3:1 ratio. Based on these NMR data and independent syntheses (vide infra), the new cobalt species was identified as cobalt(I) aryl complex ortho-4b (Scheme 4). The 31P and 19F NMR spectra were also collected throughout the time course for the borylation of 2a catalyzed by 1-(H)2BPin at 50 oC in THF-d8. While the reaction reached complete conversion in 15 minutes, cobalt species with similar spectroscopic features were observed (see the Supporting Information for additional details and spectroscopic data). Scheme 4: Mechanism of (iPrPNP) Cobalt Aryl Complex Formation Supported by Previous Computational Study34 and the Experimental Observation of ortho-4b During Catalysis H3C

H3C

Ar

Co P

Scheme 5: Proposed Mechanism for the Formation of ortho4b from 1-CH3 and Excess 2a Following Exposure to 1 atm H2

H3C Ar

PiPr2

N

results support oxidative addition of benzene to (iPrPNP)CoBPin to generate a Co(III) boryl-hydride-aryl complex with mutually trans boryl and aryl ligands as the most favorable pathway (Scheme 4). Reductive elimination of HBPin then generates (iPrPNP)CoPh, which can then react with HBPin or B2Pin2 to produce the arylboronate product. The observation of cobalt(I) aryl resting states by 31P and 19F NMR spectroscopy provide evidence that these events occur in the borylation of fluoroarenes 2a and 2b. As we reported in our previous investigation of cobalt-catalyzed borylation of 2,6-lutidine, dihydride boryl 1-(H)2BPin is also observed spectroscopically throughout the course of the reaction, and at later conversion it becomes the predominant cobalt species in solution by 31P NMR. This suggests that as the concentration of HBPin increases, it reacts with cobalt hydride intermediates to regenerate the precatalyst, an off-cycle resting state.

N

H

PiPr2

P

BPin

BPin

PiPr2

N

HBPin

Co

Co P

H

Ar

H3C Ar =

Ar =

PiPr2

N Co CF3

F

computational (ref. 34)

P F

experimental (this work)

CF3

ortho-4b

The intermediacy of cobalt(I) aryl complexes is consistent with recently reported computational results on the borylation of benzene with 1-(H)2BPin.36 The density functional theory (DFT) Scheme 6. Synthesis and selected spectroscopic data for ortho -4b and meta-4b, as well as solid-state molecular structures of ortho4b and meta-4b at 30% probability ellipsoids. Hydrogen atoms, except for those on the methylene units, are omitted for clarity. H3C

H 3C

CF3 1) 1 atm H2, C6H6, 23 oC, 1 h - CH4

PiPr2

N

Co P

CH3

91% yield

20 equiv. 1-CH3

Co

=

P

2) freeze-pump-thaw (5x)

F

PiPr2

N

CF3

F

2b

ortho-4b 31P

NMR: d 53.2 19F NMR: -60.4 (CF ), -82.1 (ArF) d 3 H3C

H 3C

CF3 PiPr2

N Co P

Br

PiPr2

N F

MgBr

Co

PhMe, -95 to 23 oC, 16 h - MgBr2

F

P

=

95% yield CF3 meta-4b NMR: d 49.2 19F NMR: -61.9 (CF ), -119.6 (ArF) d 3

1-Br

31P

Independent Syntheses of Cobalt Aryl Complexes. To establish the identity of the cobalt(I) aryl intermediates unequivocally, diamagnetic ortho-4b and meta-4b were synthesized independently. An initial attempt to prepare ortho-4b by reaction of 1-CH334 with excess 2b in THF-d8 at room temperature was unsuccessful, as the cobalt methyl complex failed to promote C(sp2)–H oxidative addi-

tion under these conditions. Subsequently, an experiment designed to generate 1-H in the presence of 2b was attempted. Exposure of a benzene-d6 solution containing 1-CH3 and 20 equivalents of 2b to 1 atm H2 for one hour at 23 °C resulted in quantitative conversion to cobalt trihydride 1-H3 as judged by 1H NMR spectroscopy. Conducting repeated freeze-pump-thaw cycles on this mixture



resulted in complete conversion to a product with spectroscopic features identical to those observed when the borylation of 2b catalyzed by 1-(H)2BPin was monitored in situ. This species, assigned as ortho-4b, likely arises from in situ generation of cobalt(I) hydride 1-H, which undergoes C(sp2)–H oxidative addition of 2a followed by loss of H2 (Scheme 5). Notably, only the ortho fluorinated isomer of this compound was observed by 19F and 31P NMR spectroscopies. Single crystals suitable for X-ray diffraction were obtained from slow evaporation of a pentane solution of the compound over the course of one week and the solid-state structure confirmed the identity of ortho-4b (Scheme 6). The selective formation of the ortho isomer of the cobalt(I) aryl complex demonstrates that C(sp2)–H oxidative addition maintains high ortho site selectivity in the absence of carbon-boron bond-forming processes. The meta isomer of 4b was also synthesized to evaluate its competency and propensity for isomerization in cobalt-catalyzed borylation. This complex was successfully prepared from straightforward transmetallation of the cobalt(I) bromide, 1-Br with the appropriate aryl Grignard reagent. The desired cobalt aryl complex, meta-4b was obtained in 95% yield and exhibited a broad 31P NMR signal at 49.2 ppm, similar to but distinct from the value of 53.2 ppm for ortho-4b. While the 19F NMR resonance corresponding to the aryl fluoride substituent of ortho-4b appears at -82.1 ppm, the corresponding 19F NMR shift in the meta isomer appears at -118.1 ppm. The independent synthesis and characterization of the cobalt aryl compounds confirmed the identity of ortho-4b as one of the resting states observed during the catalytic borylation of 2b. Observation of ortho-4b by in situ 31P and 19F NMR spectroscopy provides additional support for rapid C(sp2)–H oxidative addition, as observation of this intermediate would be unlikely if this step was turnover-limiting. Furthermore, meta-4b was not present in detectable quantities during catalysis, suggesting that the formation of the cobalt aryl intermediate or a prior step is selectivity determining. Stoichiometric Reactivity Studies. The intermediacy of ortho-4b in catalysis prompted study of its reactivity with both B2Pin2 and HBPin. Addition of one equivalent of B2Pin2 to a benzene-d6 solution of ortho-4b resulted in immediate formation of 1-(N2)BPin and ortho-borylated fluoroarene ortho-3b by 19F NMR (Scheme 7a). The meta-borylated product meta-3b was not detected by 19F NMR. This result is consistent with a possible pathway involving oxidative addition of B2Pin2 to the cobalt(I)–aryl followed by C–B reductive elimination of the aryl boronate product.

Scheme 7. Reactivity of Cobalt(I) Aryl Complexes Towards Boron Reagents

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(a) H3C

CF3 PiPr2

N

B2Pin2

Co

C6D6, 23 oC, 5 min

P CF3

F ortho-4b

F

1 atm N2

BPin

- 1-(N2)BPin >98% conv.

exclusive

(b) H3C

CF3

CF3 PiPr2

N

HBPin (4 equiv.)

Co

C6D6, 23 oC, 5 min

P CF3

F

- 1-(H)2BPin

+ BPin

>98% conv.

ortho-4b (c) H3C PiPr2

N

91%

9%

CF3

CF3

DBPin (4 equiv.)

Co

C6D6, 23 oC, 5 min

P CF3

F

F

F

- 1-(D)2BPin >98% conv.

ortho-4b

+ F

F

D

BPin 95%

5%

(d) H3C CF3

PiPr2

N Co

CF3

P

meta-4b

F

HBPin (4 equiv.) C6D6, 23 oC, 5 min - 1-(H)2BPin >98% conv.

BPin

F

exclusive

An analogous single turnover experiment was also conducted with HBPin (Scheme 7b). Addition of 4 equivalents of HBPin to ortho-4b produced ortho-3b in 91% yield along with 9% of 2b. Regeneration of the arene, 2b provides insight into the course of B– H oxidative addition to the cobalt(I) aryl complex where the arrangement of the ligands in the Co(III) product determines reaction outcome. To further explore this hypothesis, an analogous experiment was conducted using DBPin in place of HBPin (Scheme 7c). In this case, the recovered fluoroarene was deuterated in the position ortho to fluorine, confirming that C(sp2)–H oxidative addition occurred to generate mutually cis deuteride and aryl ligands resulting in deuterium incorporation, albeit to a minor extent. Addition of four equivalents of HBPin to meta-4b yielded meta-3b exclusively, with no 2b observed by 19F NMR spectroscopy (Scheme 7d). The selectivity of the oxidative addition of fluorinated arene 2b was explored with other (iPrPNP)Co(I)–X derivatives (Scheme 8). Because in a previous report34 the isolation of cobalt(I)–boryl complex 1-(N2)BPin proved to be recalcitrant, the more easily isolated pyrrolidinyl-substituted pincer complex 5-(N2)BPin was chosen to examine the reactivity of a well-defined cobalt(I)–boryl towards 2b. Importantly, the analogous dihyride boryl complex 5(H)2BPin exhibited similar activity and regioselectivity to 1(H)2BPin in the catalytic borylation of 2b (see the Supporting Information). Addition of 2.1 equivalents of 2b to a benzene-d6 solution of 5-(N2)BPin at 23 °C rapidly produced a mixture of the cobalt(I)–aryl complex ortho-6b and 5-(H)2BPin (Scheme 8a). This result demonstrates that cobalt(I)-aryl species can be generated by oxidative addition of a fluoroarene to a cobalt(I)–boryl followed by reductive elimination of HBPin. Moreover, observation of the 5-(H) 2BPin demonstrates that HBPin can react with cobalt(I) intermediates to generate the dihydride boryl resting state. Analysis of the organic products 24 hours after the addition of 2b revealed that the ortho- and meta-borylated products were produced in a 9:1 ratio, consistent with the regioselectivity of the catalytic reaction. The reactivity of 2b towards a cobalt alkyl complex supported


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by the pincer was also investigated. When five equivalents of 2b were added to a benzene-d6 solution of 1-CH3, ortho- and meta4b were produced in a 94:6 ratio upon heating to 60 C for one hour. Scheme 8. Formation of Cobalt(I) Aryl Complexes from C(sp2)–H Oxidative Addition. (a) N

CF3 PiPr2

N Co P N2

BPin

F

5-(N2)BPin

2b (2.1 equiv.) o

C6D6, 23 C 5 min

N

N PiPr2

N

N

Co

H

CF3

PiPr2

Co

P

P H

BPin

F

BPin

CF3

F ortho-6b

5-(H)2BPin

3b

62% conv.

38% conv.

12% conv. (9:1 o/m)

(b)

H3C PiPr2

N Co P

H3C CF3

i

P Pr2

N P

CH3

C6D6, 60 oC, 1 h

F 1-CH3

CF3

F ortho-4b 94%

Co

2b (5 equiv.)

H3C PiPr2

N Co

CF3

P

meta-4b 6%

F

Deuterium Labeling Experiments. The observation and isolation of cobalt(I) aryl complexes, the rate law for the catalytic borylation reaction and the absence of significant deuterium kinetic isotope effects support a pathway involving facile oxidative addition of the C(sp2)–H bond to the cobalt(I)-boryl. To gain insight into the origins of ortho-to-fluorine selectivity, deuterium labeling experiments were conducted. The catalytic borylation of 2-fluoro-α,α,αtrifluorotoluene (2c) with 5 mol% of 1-CH3 was performed with DBPin rather than B2Pin2 as the boron source. It should be noted that the rate of the reaction was much slower when HBPin was used in place of B2Pin2 (see SI for additional details). Substrate 2c was chosen due to its inferior ortho-to-fluorine selectivity compared to 2a and 2b – 80:18:2 o/m/p versus 95:5 o/m.29 A less selective reaction was studied to enable the reliable detection of minor deuteration and borylation products by NMR spectroscopy. In addition, the volatility of 2c allowed for facile separation of the borylated products from natural abundance and deuterated arenes enabling deconvolution of NMR spectra for definitive characterization.

The borylation of 2c in the presence of two equivalents of DBPin and 5 mol% of 1-CH3 produced the arylboronate ester in 22% yield after 24 hours with an 82:18 ratio of ortho to meta products (Scheme 9a). Conversion and product ratios were determined by 19F NMR spectroscopy, and deuterium incorporation was quantified using 1H, 2H and 19F NMR spectroscopies.40 Analysis of the meta-borylated product revealed 42% deuterium incorporation at the site ortho to fluorine. No deuterated isotopologue of the ortho aryl boronate ester was detected, but this may be a result of low concentrations below the detection limits of the NMR experiment. Analysis of the recovered arene, 2c established deuterium incorporation at both the ortho (62% incorporation) and meta (13%) sites, an 82:18 ratio. No evidence for deuteration or borylation of the position para to the fluorine substituent was observed. That the observed selectivity for both borylation and deuteration are identical supports the hypothesis that C(sp2)–H oxidative addition is the selectivity-determining step. A proposed pathway for the observed hydrogen isotope exchange reaction with 2c is illustrated in Scheme 9b. Oxidative addition of DBPin to the cobalt(I) aryl intermediate (4b) generates two isomers of the cobalt(III) product depending on the approach of the borane. In one isomer, the deuteride and aryl groups are cis, and are capable of undergoing productive C–D reductive elimination to generate ortho-d1-2c. In the second isomer, the boryl and deuteride ligands are inverted such that the deuteride and aryl groups are trans, and this isomer can undergo C–B reductive elimination to generate the aryl boronate ester. It is by the latter pathway that hydrogen isotope exchange occurs when DBPin is used as the boron source. To determine whether hydrogen isotope exchange occurs under conditions more similar to those of the catalytic reaction, an additional labeling experiment was conducted in which both B2Pin2 (one equivalent to 2c) and DBPin (two equivalents) were present (Scheme 9c). The reaction was quenched with air at 40% conversion to arylboronate products and the volatiles were then separated by vacuum distillation. Analysis of the aryl boronate esters (82:18 ortho:meta) by 19F and 13C NMR spectroscopies established no detectable deuterium incorporation while the volatile component, containing the fluorinated arene, exhibited only trace (

Cobalt-Catalyzed Borylation of Fluorinated Arenes: Thermodynamic

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