Edinburgh Research Explorer Iron-catalysed C(sp2)-H borylation enabled by carboxylate activation

: Arene C( sp 2 )-H bond borylation reactions provide rapid and e ﬃ cient routes to synthetically versatile boronic esters. While iridium catalysts are well established for this reaction, the discovery and development of methods using Earth-abundant alternatives is limited to just a few examples. Applying an in situ catalyst activation method using air-stable and easily handed reagents, the iron-catalysed C( sp 2 )-H borylation reactions of furans and thiophenes under blue light irradiation have been developed. Key reaction intermediates have been prepared and characterised, and suggest two mechanistic pathways are in action involving both C-H metallation and the formation of an iron boryl species. catalysis. and stability compared to the and dialkyl analogues. the in situ activation of dmpe FeCl and application to the )-H borylation reaction of heteroarenes 1b). 2 7 , as observed by 31 P-NMR spectroscopy (see Supplementary Materials, S16). Reaction of the activator, Na(2-EH), and HBpin in the absence of pre-catalyst showed ligand redistribution to a mixture of boron-containing species, including boron “ate” complexes, BH 3 and [BH 4 ] - , as observed by 11 B-NMR spectroscopy (see Supplementary Materials, S3). This reactivity is in accordance with that when using other nucleophiles such as alkoxide salts [39,41]. Taken together, these observations are indicative of an in situ activation process, whereby the added carboxylate reagent Na(2-EH) triggers hydride transfer from boron to iron to form the dihydride dmpe 2 FeH 2 7 . Once formed, the iron dihydride dmpe 2 FeH 2 7 can efficiently catalyse the C( sp 2 )-H borylation reaction.

Tatsumi and Ohki showed that arenes would undergo thermally promoted C(sp 2 )-H borylation using an N-heterocyclic carbene cyclopentadienyl iron(II) alkyl complex [NHC(Cp*)FeMe] as a catalyst in the presence of tert-butylethylene (Scheme 1a) [35]. Mankad applied heterobimetallic Fe-Cu and Fe-Zn complexes under continuous ultraviolet light irradiation to arene C(sp 2 )-H borylation [36]. Similarly, Darcel and co-workers reported the use of a bis(diphosphino) iron(II) dialkyl and dihydride complexes for arene C(sp 2 )-H borylation, again under continuous ultraviolet light irradiation [37]. While these landmark reports are highly significant developments, all require the prior synthesis of sensitive inorganic complexes which are synthetically challenging and difficult to handle for the non-specialist practitioner, thus limiting use by the broader synthetic community. To reduce the synthetic challenges, and need for organometallic reagents, we questioned whether the C(sp 2 )-H borylation chemistry reported previously could be simplified by in situ catalyst activation using only bench stable reagents. In the example reported by Darcel and co-workers the bis[1,2-bis(dimethylphosphino)ethane-P,P′]dimethyliron (II) pre-catalyst (dmpe2FeMe2) was generated by the addition of methyllithium to the corresponding iron(II) dichloride complex (dmpe2FeCl2) [37]. Similarly, the catalytically active bis[1,2-bis(dimethylphosphino)ethane-P,P′]iron(II) dihydride (dmpe2FeH2) could be accessed using either LiHBEt3 or LiAlH4 [37,38]. Given our previous work on the in situ generation of hydride donors formed by the combination of alkoxide salts and pinacolborane (HBpin) [39], we postulated that the active C(sp 2 )-H borylation pre-catalyst, dmpe2FeH2, may be accessible by the same method. Reaction of substoichiometric alkoxide salt with HBpin, the boron source used for this borylation, would generate a hydride reductant in situ to activate the dmpe2FeCl2 pre-catalyst to dmpe2FeH2, the active borylation catalyst, and thus initiate catalysis. Importantly, the dmpe2FeCl2 complex displays much greater air-and moisture stability compared to the dihydride and dialkyl analogues. Herein, we report the in situ activation of dmpe2FeCl2 and application to the C(sp 2 )-H borylation reaction of heteroarenes (Scheme 1b).

Results
Guided by the work of Darcel and co-workers, we selected 2-methylfuran 2a as an ideal test substrate for our investigations. Darcel and co-workers showed that dmpe2FeMe2 could be used as a pre-catalyst for the borylation of furan 2a (3 equiv.) using HBpin (1 equiv.) under continuous Scheme 1. Iron-catalysed C-H borylation of arenes. (a) Prior approaches to iron-catalysed C(sp 2 )-H-bond borylation with pinacolborane (HBpin) using organoiron and iron/copper bimetallic catalysts. (b) This work: C(sp 2 )-H bond borylation using dmpe 2 FeCl 2 as a pre-catalyst, activated by exogenous nucleophiles, under blue light irradiation.
To reduce the synthetic challenges, and need for organometallic reagents, we questioned whether the C(sp 2 )-H borylation chemistry reported previously could be simplified by in situ catalyst activation using only bench stable reagents. In the example reported by Darcel and co-workers the bis[1,2-bis(dimethylphosphino)ethane-P,P ]dimethyliron(II) pre-catalyst (dmpe 2 FeMe 2 ) was generated by the addition of methyllithium to the corresponding iron(II) dichloride complex (dmpe 2 FeCl 2 ) [37]. Similarly, the catalytically active bis[1,2-bis(dimethylphosphino)ethane-P,P ]iron(II) dihydride (dmpe 2 FeH 2 ) could be accessed using either LiHBEt 3 or LiAlH 4 [37,38]. Given our previous work on the in situ generation of hydride donors formed by the combination of alkoxide salts and pinacolborane (HBpin) [39], we postulated that the active C(sp 2 )-H borylation pre-catalyst, dmpe 2 FeH 2 , may be accessible by the same method. Reaction of substoichiometric alkoxide salt with HBpin, the boron source used for this borylation, would generate a hydride reductant in situ to activate the dmpe 2 FeCl 2 pre-catalyst to dmpe 2 FeH 2 , the active borylation catalyst, and thus initiate catalysis. Importantly, the dmpe 2 FeCl 2 complex displays much greater air-and moisture stability compared to the dihydride and dialkyl analogues. Herein, we report the in situ activation of dmpe 2 FeCl 2 and application to the C(sp 2 )-H borylation reaction of heteroarenes (Scheme 1b).

Results
Guided by the work of Darcel and co-workers, we selected 2-methylfuran 2a as an ideal test substrate for our investigations. Darcel and co-workers showed that dmpe 2 FeMe 2 could be used as a pre-catalyst for the borylation of furan 2a (3 equiv.) using HBpin (1 equiv.) under continuous ultraviolet light irradiation to give a regioisomeric mixture of 5-and 4-borylated furans, 3a and 4a respectively (67%, 3a:4a = 82:18) [37]. Using our alkoxide activation strategy we found the use of ultraviolet light for this reaction was not necessary, instead operating with lower energy blue light (Kessil A160 WE, 40 W Blue LED). Additionally, we used an inverted stoichiometry of arene (1 equiv.) and HBpin (1.2 equiv) and a reduced catalyst loading. Using these reaction parameters, we assessed the ability of a selection of potential activators to initiate catalysis alongside the dmpe 2 FeCl 2 1 pre-catalyst. (Scheme 2).
Molecules 2020, 25, x FOR PEER REVIEW 4 of 12 of 2,3-dimethylfuran 2c gave the corresponding 5-boryl regioisomer 3c exclusively in good yield. 2-Ethylfuran 2d reacted similarly to the 2-methylfuran analogue 2a giving a mixture of 4-and 5substituted boronic esters 3d and 4d. Unfortunately, application to thiophenes demonstrated limited reactivity under the established reaction conditions, giving only low yields of boryl-arenes 3e-g and 4e-g, again as a mixture of regioisomers, and bis-borylated product when the parent thiophene was used [40].

Mechanistic Investigations
On the basis of successful catalysis we presumed that our in situ activation system provided access to the active iron(II) dihydride complex dmpe2FeH2 7, which had been shown to be catalytically active by Darcel and co-workers [37]. To support this, we combined each component in the absence of light or arene, i.e., the reaction of dmpe2FeCl2 1, Na(2-EH) and HBpin (Scheme 4a). This showed the formation of both the monohydride product dmpe2FeHCl 6 and the expected dihydride, dmpe2FeH2 7, as observed by 31 P-NMR spectroscopy (see Supplementary Materials, S16). Reaction of the activator, Na(2-EH), and HBpin in the absence of pre-catalyst showed ligand redistribution to a mixture of boron-containing species, including boron "ate" complexes, BH3 and [BH4] -, as observed by 11 B-NMR spectroscopy (see Supplementary Materials, S3). This reactivity is in accordance with that when using other nucleophiles such as alkoxide salts [39,41]. Taken together, these observations are indicative of an in situ activation process, whereby the added carboxylate reagent Na(2-EH) triggers hydride transfer from boron to iron to form the dihydride dmpe2FeH2 7. Once formed, the iron dihydride dmpe2FeH2 7 can efficiently catalyse the C(sp 2 )-H borylation reaction.

Mechanistic Investigations
On the basis of successful catalysis we presumed that our in situ activation system provided access to the active iron(II) dihydride complex dmpe 2 FeH 2 7, which had been shown to be catalytically active by Darcel and co-workers [37]. To support this, we combined each component in the absence of light or arene, i.e., the reaction of dmpe 2 FeCl 2 1, Na(2-EH) and HBpin (Scheme 4a). This showed the formation of both the monohydride product dmpe 2 FeHCl 6 and the expected dihydride, dmpe 2 FeH 2 7, as observed by 31 P-NMR spectroscopy (see Supplementary Materials, S16). Reaction of the activator, Na(2-EH), and HBpin in the absence of pre-catalyst showed ligand redistribution to a mixture of boron-containing species, including boron "ate" complexes, BH 3 and [BH 4 ] -, as observed by 11 B-NMR spectroscopy (see Supplementary Materials, S3). This reactivity is in accordance with that when using other nucleophiles such as alkoxide salts [39,41]. Taken together, these observations are indicative of an in situ activation process, whereby the added carboxylate reagent Na(2-EH) triggers hydride transfer from boron to iron to form the dihydride dmpe 2 FeH 2 7. Once formed, the iron dihydride dmpe 2 FeH 2 7 can efficiently catalyse the C(sp 2 )-H borylation reaction.  As the dihydride complex dmpe 2 FeH 2 7 was readily formed using our in situ hydride transfer method, and was observable by 1 H and 31 P-NMR spectroscopy, we next investigated the fundamental steps of this borylation reaction with the aim of identifying key reaction intermediates. Reaction of the in situ generated dmpe 2 FeH 2 7 with excess HBpin under blue light irradiation led to the formation of both cis-dmpe 2 FeH(Bpin) 8 and trans-dmpe 2 FeH(Bpin) 9 boryl iron complexes, as observed by 1 H, 11 B, and 31 P NMR spectroscopy (see Supplementary Materials, S17-19). These complexes were previously reported by Darcel and co-workers, where they were formed from the reaction of the related dialkyl complex, dmpe 2 FeMe 2 , with HBpin [37]. Addition of 2-methylfuran 2a to the mixture of cis-dmpe 2 FeH(Bpin) 8 and trans-dmpe 2 FeH(Bpin) 9 under blue light irradiation gave the formation Molecules 2020, 25, 905 6 of 11 of the regioisomeric furyl boronic esters 3a and 4a (3a:4a = 71:29), notably in a different ratio to that observed during catalysis (vide supra, 3a:4a = 81: 19).

Conclusions
In summary, we have investigated the applicability of several alkoxide, carboxylate and other, common bench stable reagents towards the in situ activation of an iron(II) pre-catalyst for C(sp 2 )-H bond borylation. We found a sodium carboxylate salt Na(2-EH) in combination with HBpin to be a potent pre-catalysts activator generating the iron dihydride dmpe 2 FeH 2 7 in situ. The validity of this method was demonstrated by the generation of catalytically relevant species that were used as mechanistic probes. These suggest two C-H borylation pathways are operating to give the aryl boronic ester products; C-H metallation followed by borylation, and formation of an iron boryl species followed by arylation.

General Information
All compounds reported in the manuscript are commercially available or have been previously described in the literature unless indicated otherwise. All experiments involving iron were performed using standard Schlenk techniques under argon or nitrogen atmosphere. All yields refer to yields determined by 1 H-NMR spectroscopy of crude reaction mixtures using an internal standard. All product ratios refer to product ratios determined by 1 H-NMR spectroscopy of the crude reaction mixtures. 1 H-NMR and 13 C-NMR data are given for all compounds when possible in the experimental section for characterisation purposes. Spectroscopic data matched those reported previously.

Tetra-n-butylammonium 2-ethylhexanoate TBA(2-EH)
A suspension of KH (80 mg, 2 mmol) in anhydrous THF (20 mL) was prepared under an N 2 atmosphere, 2-ethylhexanoic acid (0.32 mL, 2 mmol) was added dropwise whilst stirring. n.b. gas evolution (H 2 ). The solution was stirred for 3 h at room temperature, and the THF removed in vacuo to give an amorphous colourless solid. The solid was re-dissolved in MeOH (20 mL) and tetra-n-butylammonium chloride (556 mg, 2 mmol) was added, the solution was stirred for 16 h, filtered through a glass frit and dried in vacuo without further purification to give tetra-n-butylammonium 2-ethylhexanoate (0.72 g, 1.86 mmol, 93%) as an amorphous white solid.

Pre-catalyst Synthesis
Anhydrous iron dichloride (0.21 g, 1.67 mmol) was charged to a Schlenk flask and dissolved in anhydrous THF (10 mL), dmpe [(bis(dimethylphosphino)ethane]; 0.50 g, 3.33 mmol) were added to the flask under an Ar atmosphere and the solution left to stir for 48 h at room temperature. The solvent was removed in vacuo, and in an argon-filled glove box, the residue was re-dissolved in dichloromethane (5 mL) and filtered through glass wool. The filtrate was reduced in vacuo to produce a green amorphous solid (0.549 g, 1.29 mmol, 77%).