Highly Nucleophilic Dipropanolamine Chelated Boron Reagents for Aryl-Transmetallation to Iron Complexes

New aryl- and heteroarylboronate esters chelated by dipropanolamine are synthesised directly from boronic acids. The corresponding anionic borates are readily accessible by deprotonation and demonstrate an increase in hydrocarbyl nucleophilicity in comparison to other common borates. The new borates proved competent for magnesium or zinc additive-free, direct boron-to-iron hydrocarbyl transmetallations with well-defined iron(II) (pre)catalysts. The application of the new borate reagents in representative C sp 2 -C sp 3 cross-coupling led to almost exclusive homocoupling unless coupling is performed in the presence of a zinc additive.


Introduction
Nucleophilic organoboron compounds are crucial in modern synthesis, particularly in transition metal catalysed carboncarbon bond formation such as the synthetically ubiquitous Suzuki-Miyaura (SM) reaction. [1][2][3] In the SM reaction the transfer of a hydrocarbyl group from boron to a transition metal is an essential step and one that has been extensively studied for palladium systems. 4 Extending the SM reaction from palladium catalysis to base metal catalysts, with a particular emphasis on iron is important to reduce our current reliance upon expensive and toxic palladium catalysts. [5][6] The unique reaction pathways accessible to iron catalysis [6][7][8][9][10] (both one and two electron manifolds) also represent a considerable driving force for the advancement of this area. Recent advances in iron catalysed SM type cross-coupling have been significant, particularly in the employment of anionic boronate nucleophiles, [B(Ar) 4 ] -, [11][12] [RB(pin)( t Bu)] -(pin = pinacolato, R = aryl/alkenyl) [13][14] and [R'BR 3 ] -(R' = Alkyl or Aryl). 15 However, in contrast to Pd catalysed SM, where ArB(OR) 2 and a range of bases in aqueous/ether media readily effect boron to Pd transmetallation, transmetallation to iron is more challenging and analogous conditions do not effect hydrocarbyl transfer. Instead boron to iron transmetallation requires organometallic activating agents (e.g. t BuLi or ArMgX) in examples employing pinacolboronate esters or triorganoboranes. [13][14][15] Furthermore, additives such as MgBr 2 , ZnCl 2 or Zn(Ar) 2 are required for good heterocoupling yields in the Fe catalysed SM reaction, with additive free systems providing inferior heterocoupling outcomes. 14 These additives are proposed to facilitate hydrocarbyl transmetallation, although their specific role(s) in this process have yet to be defined. Hydrocarbyl transmetallation from boron-to-iron 16 employing modular boronate reagents that are readily accessible, particularly from the widely available boronic acids, and are activated for transmetallation using simple bases (e.g., Group I M[OR] salts) would be attractive for iron catalysed SM protocols. 17 Herein, we describe our efforts toward this goal, principally through the design of highly nucleophilic borate reagents and their application in boron-to-iron hydrocarbyl transmetallation.

Results and Discussion
Our recent investigations on boron-to-iron hydrocarbyl transmetallation, employing [Fe(NHC) 2 X 2 ] (NHC = Nheterocyclic carbene, X = Cl or OMe) systems with arylborate nucleophiles afforded key observations of significance to our current investigation. 18 Specifically, that alkoxide transfer from arylborates of the general formulae, [ArB(eg)(OMe)] -(eg = ethylene glycolato) occurs in preference to aryl transfer ( Figure  1). Considering this, we set out to design a new class of highly nucleophilic borates that incorporate tethered, trianionic ligands and are accessible from boronic acids and Group I M[OR] salts, with the intention of facilitating hydrocarbyl transfer in preference to alkoxide transfer (Fig. 1).
Borate reagents incorporating tethered, trianionic ligands are known, 19 with the triolborates particularly noteworthy, 20 however these are non-productive in Fe catalysed SM couplings. 12 Borates incorporating a trianionic 6,6-bicyclic chelate are rare, 21 but are attractive as they will afford a reduction in ring strain in the conjugate 3-coordinate boronate ester formed post hydrocarbyl transfer relative to 5,5-bicyclic and 6,6,6-tricyclic (e.g. triolboronate) systems. This would facilitate the planarisation of the neutral 3-coordinate boronate ester by-product and thus its stabilisation through increased π-orbital overlap, an outcome enhanced further by the greater multiple bond character present in B-NR 2 relative to B-OR; both factors were envisaged to enhance the nucleophilicity of the anionic hydrocarbyl-borate.
Combining dipropanolamine (which can be easily prepared on multi-gram scales from cheap, commercially available reagents) 22 with phenylboronic acid (0.9 equiv.) in THF afforded the desired neutral boronate ester 1a within 10 minutes at ambient temperature. The poor solubility of 1a in THF allows for its isolation by filtration and subsequent recrystallisation from hot acetone affords analytically pure 1a in 89% yield (9.74g) ( Figure 2). The rigid nature of the 6,6bicyclic chelate is evident in the 1 H NMR spectra of 1a through the diastereotopic nature of the CH 2 protons within the chelate backbone, a feature also observed in related 5,5bicyclic systems. 23 It is noteworthy that 5,5-bicyclic analogues demonstrate fluxional behaviour at temperatures above 40°C, whereas 1a is considerably more conformationally rigid, demonstrating no fluxional behaviour up to 110°C (in d 6 -DMSO), analogous to the extremely robust MIDA boronate esters. 24 This simple esterification protocol can be extended to a number of aryl-or heteroarylboronic acids, affording neutral boronate esters 1a-1q in good to excellent isolated yields (97-72%) ( Figure 2  Generation of the anionic borates is simple as exemplified by the formation of K[2a] which can be achieved in quantitative yield via deprotonation of 1a with a variety of bases (KH, t BuOK, KOMe) in anhydrous THF. 25 The employment of KOH leads only to the recovery of neutral boronate ester, 1a. This observation correlates with the fact that K[2a] slowly hydrolyses to 1a (and presumably KOH) with prolonged storage in the solid or solution state under air. With methods for the generation of the anionic borates in hand, we next focused upon calculating relative phenyl ion affinities (PhIAs) to assess the relative nucleophilicity of K[2a] and other common borate anions. PhIAs were calculated from the isodesmic reactions between tetraphenylborate and the appropriate neutral boron Lewis acid (Table 1). This methodology is analogous to previous approaches for calculating hydride and chloride ion affinities (HIAs and CIAs) of boron Lewis acids, where calculations of HIA correlated well with hydride transfer reactivity. [26][27] Analysis of the calculated PhIA values revealed neutral borane 3 to have a substantially lower PhIA (hence K[2a] will provide a better source of Ph -) than other common borate reagents tested ( Table 1). The alleviation of ring strain in 3 relative to the 5,5-bicyclic analogue derived from diethanolamine (5,5-ONO, entry 4) and to a greater extent the 6,6,6-tricyclic containing triolborane (entry 1) does indeed have a considerable effect on PhIA and thus the energetics of aryl transfer. It is more significant in the context of this investigation to experimentally benchmark the PhIA of 3 against boron Lewis acids whose Ph-borate anions transmetallate to Fe (with or without additives). However, attempts to experimentally confirm the relative PhIA of BPh 3  would translate to facile boron-to-iron hydrocarbyl transmetallation with common iron(II) (pre)catalysts. We began this investigation with the (pre)catalyst, [Fe(dppe)Cl 2 ] n 4 (dppe = 1,2-bis(diphenylphosphino)ethane) (4 was found by Xray diffraction studies to exist as a 1D coordination polymer in the solid state on recrystallisation from THF). 28 In-situ generation of K[2a] with KH (1 equiv.) in anhydrous THF followed by the addition of 4 (0.5 equiv.) and dppe (0.5 equiv.) then agitation at ambient temperature led to no observable reaction (by 11   [Fe(dpbz) 2 Cl 2 ], 6 (0.5 equiv.) (dpbz = 1,2bis(diphenylphosphino)benzene) reacted analogously with K[2a] or K[2b], with two equivalents of borate consumed per Fe centre (by 11 B NMR spectroscopy) and significant biphenyl or bi-tolyl (ca. 0.5 equiv. by GC-MS) formed again indicating significant transmetallation from boron to iron. The previously reported iron(I) complex, [Fe(dpbz) 2 (p-Tol)] 7 30 (Figure 3) was observed from this reaction mixture by X-band continuouswave EPR measurements at 120 K further confirming successful boron to Fe transmetallation. The spectrum of 7 is in excellent agreement with previous X-band CW-EPR measurements obtained for 7 by Bedford and co-workers 30 and with an independently prepared sample of 7 obtained from the reaction of 6 with p-TolMgBr (2 equiv.) (Figure 3). Whilst the presence of EPR and NMR spectroscopy silent Fe complexes cannot be precluded from these reactions combined the formation of significant quantities of the homocoupled biaryl compounds and the observation of 7 by EPR spectroscopy do confirm significant boron to iron hydrocarbyl transmetallation using [2x].   Diarylzinc co-catalysts are used widely in Fe SM catalysis, but it is important to note that species formulated as aryl 2 Zn are actually often ionic zincates, and this can significantly impact reactivity in cross-coupling. 32 For example, the previously reported attempted synthesis of (p-tol) 2 Zn led instead to the zincate [Mg(THF) 4 Br 2 (Zn(p-tol) 2 ) 2 ] n , 8 (on recrystallisation, Scheme 2, inset). 33 Using 10 mol% of a stock solution of 8 (equating to a total of 0.08 mmol of tolyl nucleophile) and 5 mol% 4 / dppe resulted in the heterocoupling product from K[2a] and cyclo-heptylbromide being the major product (Scheme 2). However, the product distribution from this reaction is significantly less selective towards heterocoupling than cross coupling cycloheptylbromide using [  Li shifts are referenced relative to external BF 3 -etherate, hexafluorobenzene and LiCl, respectively. Coupling constants J are given in Hertz (Hz) as positive values regardless of their real individual signs. The multiplicity of the signals are indicated as "s", "d", "t" "pent", "sept" or "m" for singlet, doublet, triplet, pentet, septet or multiplet, respectively. High resolution mass spectra (HRMS) were recorded on a Waters QTOF mass spectrometer. GC-MS analysis was performed on an Agilent Technologies 7890A GC system equipped with an Agilent Technologies 5975C inert XL EI/CI MSD with triple axis detector. The column employed was an Agilent J&W HP-5ms ((5%-Phenyl)-methylpolysiloxane) of dimensions: length, 30 m; internal diameter, 0.250 mm; film, 0.25 μm. Microanalysis was performed by Mr Stephen Boyer at the London Metropolitan University microanalytical service. Xband CW-EPR spectra were recorded at 120K on a Bruker EMXmicro spectrometer operating at 9.35 GHz field modulation, 2 mW microwave power and equipped with a high sensitivity Bruker cavity (ER 4119HS).
General Procedure for the Synthesis of 1a-1q: Under ambient conditions, with no additional precautions taken to exclude air or moisture, a round bottom flask was charged with 3,3'azanediylbis(propan-1-ol) (1.1 equiv.) and tetrahydrofuran. To this stirred solution was added the appropriate boronic acid (1 equiv.) and the reaction mixture stirred at ambient temperature. Typically, the desired products 1a-1q began to deposit from solution after stirring for between 5 and 30 minutes, however in examples where this was not the case, stirring was continued at ambient temperature for 16h. Isolation of the insoluble material by filtration followed by washing with cold tetrahydrofuran typically afforded 1a-1q as colourless free-flowing solids of sufficient purity to be used without further purification. Alternatively, 1a-1q can be recrystallized from hot acetone.