Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross‐Couplings in Flow

Abstract We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp2)–C(sp3) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2)–C(sp3) coupling method using boronic esters and cyano heteroarenes under flow conditions.

Visible light photoredox catalysis has emerged as apowerful tool to trigger and control carbon radical reactions under mild and environmentally benign conditions. [1] In particular, new CÀCbond forming reactions have been developed using this novel activation mode. [2] Classical palladium-catalyzed C(sp 2 )-C(sp 3 )c ross-coupling reactions are especially challenging owing to as low transmetallation step of C(sp 3 ) nucleophiles and competitive b-hydride elimination. [3] Concomitantly reported by Molander [4] and MacMillan [5] in 2014, dual photoredox/nickel catalysis has become ap owerful protocol to construct C(sp 2 )-C(sp 3 )b onds under mild conditions. [6] In particular, Molandersapproach makes use of the ability of highly oxidizing iridium photocatalysts to afford single-electron oxidation of organotrifluoroborate salts in order to produce carbon-centred radicals ( Figure 1). [7] These photo-generated C(sp 3 )radical species can then be used in the nickel catalytic cycle to afford av ariety of cross-coupled products. [4,8] Despite the elegance of these new methods, severe solubility issues associated with the use of charged trifluoroborate,carboxylate [9] or silicate [10] salts often require the use of polar aprotic solvents or solvent mixtures (such as DMF or DMSO) at low concentrations (typically < 0.1m). These diluted conditions result in long irradiation times (24 to 48 h), low throughput and are difficult to scale-up.Moreover, these water soluble,h igh boiling point solvents are not compatible with the REACH regulation and pose issues for downstream processing. [11] Am ore soluble source of organic radical precursor for use in amore acceptable solvent would therefore be beneficial. [12] Boronic esters are suitable precursors as they are widely available,b oth from commercial and synthetic sources. [13] Although organoboron species have been extensively described as tin-free source of alkyl radicals, [14] only al imited number of studies have focused on the use of boronic esters as alkyl radical precursors. [15] Despite the growing interest of generating carbon radicals using trifluoroborate salts,n o reports to date for the activation of boronic esters using photoredox catalysis have been made. [16] Therefore,w e anticipated that by the use of as uitable activating method, these species could be used as starting materials for photoredox activation and thereby expand the scope of carbon radical chemistry.
Finally,s olving solubility issues associated with these reactions would enable the use of continuous processing methods which could provide additional advantages.F or instance,more efficient irradiation with microchannel devices and shorter residence times often result in faster and cleaner photo-reactions in flow. [17] Moreover,d ue to the inherent limitation of light attenuation through absorbing media, resulting in as mall light penetration depth, [17a] batch photoreactors become inefficient when scaling up ar eaction. [18] Given our expertise in continuous processing [13e, 19] and with the recent availability of suitable equipment, [20] we aimed to develop aflow system using aphotoredox catalyst to activate boronic esters in order to achieve afast and scalable C(sp 2 )-C(sp 3 )c oupling process.
Using trifluoroborate salts,c logging issues were immediately observed in the flow equipment due to the rapid precipitation of insoluble potassium salts.W hens witching to the commercial boronic pinacol ester (2a), af ully homogeneous solution in acetone was obtained but we failed to observe any cross-coupling product with 4-cyanobromobenzene (1a). (Table 1, entry 2).
Initial investigations highlighted the dramatic effect of the nature of the pyridine-derived base additive on the yield of the reaction. In particular, without any base additive (entry 1) or using 2,6-lutidine (entry 2, used by Molander), no product formation was observed, while using the less sterically hindered pyridine or the more electron-rich 4-(dimethylamino)pyridine (DMAP) resulted in ag reatly enhanced formation of product (entries 3and 4). This behavior correlates with calculated equilibrium constants of the corresponding base complexing with 2a.Itwas postulated therefore that aLewis acid-base adduct [21] formed between the base additive and 2a served as ar eactive intermediate.N MR experiments confirmed af ast and reversible dynamic complex formation between DMAP and 2a (for more details see the Supporting Information (SI), Figure S1). Additionally,insilico studies of the resulting complexes confirmed that complexation favors the postulated single-electron oxidation process and the subsequent formation of the reactive benzylic radical from the pinacol ester 2a (Figure 4; for more details see the SI, Schemes S1-S3). Based on these promising preliminary results,w ed ecided to explore the scope of this method and compare it with the existing batch method [4] using trifluoroborate salts (Figure 2).
In general, the flow process using boronic esters resulted in slightly lower yields than the previously reported examples (3a to 3c). However,t he reaction time is dramatically decreased, from 24 hi nb atch (with trifluoroborate salts) [4] to 50 min in flow,t hus significantly increasing the productivity. [22] As an example,s pace-time-yield (STY) of 3a with regard to the batch conditions is 2mmol h À1 L(reactor) À1 whereas the use of af low photo reactor, allows us to reach an impressive 100 mmol h À1 L(reactor) À1 of 3a.T his clearly shows the massive intensification of the process due to the solubility improvement, more efficient light absorption and elevated pressure of the flow system enabling reactions which involve association. [23] Ther eaction scope revealed that electron-rich organoboron compounds were converted in good to excellent yields (3a,b,e)w hereas compounds bearing electron-withdrawing substituents were associated to lower isolated yields of coupled products (3c,d,f). This is consistent with the putative single-electron oxidation mechanism, since higher electron density will make the boronates more reactive towards oxidation. Thea ryl bromide coupling partners could be  [c] Experimental value observed is K eq = 0.8 (for more details see the SI, Figure S1).
[d] NMR yields calculated versus CH 2 Br 2 as an internal standard in the crude 1 H-NMR.
[e] Isolated yield. Figure 2. Scope of the dual Ir/Ni-catalyzed benzyl boronic ester arylation in flow (0.5 mmol scale, 0.1 m in acetone). Isolated yields, aslug containing all the premixed reaction mixture was eluted through the photo-reactora t100 mLmin À1 ,c ollected, filtered through ap lug of Celite and concentrated before being purified by flash column chromatography.
[a] Isolated yield reported by Molander for the product. [4] [b] Isolated as the phenol after oxidation of the aryl boronic pinacol ester with H 2 O 2 /NaOH.
varied tolerating the presence of sensitive aldehyde (3h), alkene (3j)a nd alkyne (3k)g roups.R emarkably an orthosubstituent (3i)i sa lso well tolerated. Theu se of ab oronic ester containing aryl bromide (3l)s erved to confirm the orthogonality between the C(sp 2 )a nd the C(sp 3 )c oupling events as previously described with trifluoroborate salts. [24] Despite the benefits proved by the replacement of benzylic trifluoroborate salts by their boronic ester counterparts,l arge amount of additives is still necessary and the use of Ni(COD) 2 (COD = cyclooctadienyl) required the preparation in aglovebox. Since these issues arise from the specific activation of aryl bromides,w ee nvisaged that using other electrophiles could greatly simplify the reaction conditions.In particular,the MacMillan group reported elegant photoredox arylation methods using electron-deficient cyanoarenes as single-electron acceptors. [25] These cyanoarenes could receive an electron from aphotoredox catalyst to generate persistent radical anions [26] that can couple with other transiently generated radicals via ap ostulated radical-radical coupling pathway. [24a,d] Therefore,a st he boronic esters should require as ingle-electron oxidation and the cyanoarenes as ingleelectron reduction, anet neutral photoredox coupling process could ensue with only ap hotoredox catalyst. [1a] Among the cyanoarenes employed by MacMillan, the 4cyanopyridine scaffold was of particular interest since it would also serve as aL ewis base that could bind to boronic esters and potentially circumvent the use of DMAP additive. Thei nvestigation commenced using 4-cyanopyridine (4a)a s am odel substrate.S light modifications of the previous reaction conditions were required to couple 4a and 2a (see SI, Figure S3). As expected, ag ood yield of 5a was achieved within 100 min of irradiation at 60 8 8Cusing 1mol %ofcat(1) without the use of DMAP or any other additives.T hese conditions highlighted again the advantages of the flow setup for photomediated reactions where temperature could be precisely controlled. Although al onger residence time was necessary to achieve good yields,the concentration in starting material could be raised from 0.1m to 0.25 m thus allowing similar STYs to the previous process using aryl bromides.
Thes cope of this new reaction was then explored (Figure 3). Electronic effects of the pinacol boronic esters followed the same reactivity trend as in the previous reaction, with more electron-rich substrates providing higher yields. Secondary benzylic boronic esters proceeded in higher yields than their primary counterparts due to the higher stability of secondary alkyl radicals. Para-, meta-(5j and 5l)and even bis ortho-substituted (5k)b enzyl boronic esters could also be successfully arylated using this method. Screening the cyanoarene partner revealed that only nitrogen-containing heteroaromatic nitriles could be successfully coupled. Interestingly,N -heterocycles are generally seen as catalyst inhibitors but proved to be crucial in our reaction. Forexample,the commonly employed 1,4-dicyanobenzene was ineffective under these conditions,p robably because this substrate could not activate the boronic ester due to al ack of coordination. [27] As already observed by MacMillan, 4-cyanopyridine was one of the most successful cyanoarene of those examined (5a to 5d). Pleasingly,i na ddition to cyanopyridine,o ur transformation was successfully applied to several N-heterocycles (5e to 5r,F igure 3). Va riations around the 4-cyanopyridine scaffold were also possible with 4cyanoquinoline (5n)and other nitrile substituted 4-cyanopyridines derivatives (5o and 5p)giving very interesting coupled products with selective coupling at the most electron-poor 4position (the rest of the mass balance being unreacted cyanoarene). Interestingly,t he reaction could tolerate the unprotected 4-cyano-7-azaindole (5m).
In the effort to increase the methodsd iversity,w ew ere able to extend the standard reaction conditions for the allylation of N-heterocycles (e.g. 5s to 5u)u sing the commercially available allylboronic acid pinacol ester. To rationalize the mechanism of this last protocol, calculations of equilibrium constants for Lewis acid-base adducts and their corresponding single-electron reduction and oxidation potentials were performed at DFT level (for more details see the SI, Schemes S2 and S3). These results suggest that, as in the case of DMAP,4 -cyanopyridine (4a) and the boronic ester 2a are likely to form ac omplex 6 ( Figure 4). This complex formation facilitates the singleelectron oxidation of 2a (E 1/2 (6) = 0.73 Vv s. E 1/2 (2a) = 1.57 V). [28] This value makes this SET event possible within ar eductive quenching cycle of cat(1) (= Ir III ), [29] in agreement with that postulated by Molander. [4] Based on our assumption, the excited [Ir III ]* species (E 1/2 III*/II = 1.21 V) [30] is first quenched by 6 (E 1/2 = 0.73 V) leading, after rapid CÀB bond cleavage (1.7 kcal mol À1 barrier), to ac arbon-centered radical 7 and the pyridinium 40.The Ir II (E 1/2 III/II = À1.37 V) [30] species thus generated can immediately reduce the activated pyridinium 40 (E 1/2 = À0.32 V), [28] generating the radical 8 that quickly couples with 7 to form an intermediate that eliminates cyanide to give the coupled product 5a.
In summary,w eh ave demonstrated an ew activation mode of boronic esters that allow them to react under photoredox conditions by formation of ac omplex with ap yridine-like Lewis base.T his modification not only enhanced the existing chemistry with trifluoroborate salts but also facilitated its application using flow chemistry.These results enabled the development of an efficient new C(sp 2 )-C(sp 3 )p hotoredox coupling process using heteroaromatic nitriles and pinacol boronic esters,whereby no additive other than the photoredox catalyst was required as the nitrogencontaining heteroarene served as an activator of the boronic ester partner.