Iridium‐Catalysed C−H Borylation of Heteroarenes: Balancing Steric and Electronic Regiocontrol

Abstract The iridium‐catalysed borylation of aromatic C−H bonds has become the preferred method for the synthesis of aromatic organoboron compounds. The reaction is highly efficient, tolerant of a broad range of substituents and can be applied to both carbocyclic and heterocyclic substrates. The regioselectivity of C−H activation is dominated by steric considerations and there have been considerable efforts to develop more selective processes for less constrained substrates. However, most of these have focused on benzenoid‐type substrates and in contrast, heteroarenes remain much desired but more challenging substrates with the position and/or nature of the heteroatom(s) significantly affecting reactivity and regioselectivity. This review will survey the borylation of heteroarenes, focusing on the influence of steric and electronic effects on regiochemical outcome and, by linking to current mechanistic understandings, will provide insights to what is currently possible and where further developments are required.


Introduction
Compounds bearing heteroaromatic scaffolds feature prevalently in pharmaceuticals,b ioactive molecules,l igands for metal complexes,n atural products,a grochemicals,a nd other functional materials. [1][2][3][4][5][6][7] Therefore,a tom-economical, streamlined syntheses of these molecules are of commercial value.M ost heteroarenes are traditionally prepared by de novo synthesis and variation of substitution patterns can often require considerable synthetic effort. Consequently,methods that enable late-stage modification have become desirable.In particular,C À Ha ctivation strategies that improve overall atom-and step-economy have attracted the attention of many research groups in both academic and industrial settings,and numerous synthetic procedures for the formation of carboncarbon and carbon-heteroatom bonds based on CÀHb ond activation strategies have been developed. Reflecting the versatility enabled by aC ÀBb ond, iridium-catalysed CÀH borylation has become am ajor option for this chemistry. However,the regioselectivity of heteroarene C À Hborylation can be challenging to predict and rationalise,and this review summarises current understanding of this important transformation.

Introduction to Organoboron Compounds
Although organoboron compounds do not appear in nature,applications are emerging in radiochemistry,chemical biology,a nd medicinal chemistry as well as polymers and other functional materials (Figure 1). [8][9][10][11][12][13][14][15][16][17][18] However, the greatest use of these compounds resides in their use as reagents for synthesis.In1979, Suzuki and Miyaura reported that organoboron compounds could be cross-coupled with organohalides to form CÀCbonds with catalytic quantities of Pd. [19,20] This is now the second most practiced reaction in medicinal chemistry and natural product synthesis. [21] Subsequently, many other useful transformations of the CÀBb ond have been developed, [22][23][24][25][26][27] which has secured the status of organoboron compounds as important intermediates in synthesis. Av ariety of organoboron derivatives ( Figure 2) including boranes,b oronic acids,b oronic (boronate) esters,b orinic acids,b orinic esters,b oroxines,a nd trifluoroborates have been employed in these roles,w ith the boronate ester being the most frequently used. This reflects their ease of handling, good reactivity,a nd solubility and, when compared with alternative organometallic analogues,s uch as organostannane,o rganozinc and organocopper reagents,g reater air stability,l ower toxicity,a nd commercial availability. [28,29] Whilst alkyl and alkenyl boronate compounds are widely used and find growing application, the most important class of boronate esters are the aromatic derivatives.

Synthesis of Aromatic Organoboron Compounds
Tr aditionally,a romatic boronate esters have been synthesised by metalation of aC ÀHorC ÀXbond (X = Cl, Br,I) by ar epresentative organometallic reagent, followed by reaction with ab orate ester (Scheme 1a,b). [30,31] Whilst this strategy carries advantages,s uch as low reagent cost and operational simplicity,t here are limitations.F or instance,i n CÀHmetalation adirecting/activating group can be required to provide CÀHr eactivity and selectivity.T his is less The iridium-catalysed borylation of aromatic C À Hbonds has become the preferred method for the synthesis of aromatic organoboron compounds.The reaction is highly efficient, tolerant of abroad range of substituents and can be applied to both carbocyclic and heterocyclic substrates.T he regioselectivity of C À Ha ctivation is dominated by steric considerations and there have been considerable efforts to develop more selective processes for less constrained substrates. However,most of these have focused on benzenoid-type substrates and in contrast, heteroarenes remain muchd esired but more challenging substrates with the position and/or nature of the heteroatom(s) significantly affecting reactivity and regioselectivity.This review will survey the borylation of heteroarenes,focusing on the influence of   Scheme 1. Selected syntheses of aryl organoboron compounds;literature references given in square brackets. dppf = 1,1'-bis(diphenylphosphino)ferrocene, pin = pinacolyl, TMEDA = tetramethylethylenediamine.
problematic in metal-halogen exchange,w hich is typically faster than C À Hd eprotonation. However,p refunctionalisation is required to generate the haloarene precursor.F urthermore,the hard bases required offer poor functional group tolerance.I nt his context, transition metal catalysts are attractive because they can offer superior scope,m ilder reaction conditions,a nd improved atom economy (Scheme 1c). [27,[32][33][34] Whilst this approach is amenable to late-stage functionalisation, it remains limited by the requirement for aprefunctionalised aromatic halide.
As impler approach to borylation involves the direct transformation of aC ÀHt oaC ÀBb ond. To as ignificant extent, catalytic borylation of aromatic CÀHb onds has addressed many of the shortcomings of these other strategies.

Aromatic C À HB orylation
Arene CÀHb orylation, the direct conversion of aC ÀH bond to aC ÀBb ond, can be achieved by electrophilic and frustrated Lewis pairs (FLP), or metal-catalysed pathways. Thefirst of these,involving the reaction of an arene with an in situ generated borenium ion, is generally limited to more nucleophilic arenes,i ncluding various heterocyclic systems such as carbazole 7 (Scheme 2a). [35] Aminoborane frustrated Lewis pairs (FLPs) enable the catalytic dehydrogenative CÀH borylation of electron-rich (hetero)arenes,w ith similar siteselectivities (Scheme 2b). [36] Sterically controlled electrophilic C À Hb orylation of arenes can also be accomplished using boron triiodide (Scheme 2c). [37] Much greater substrate scope has been achieved using an umber of transition metal catalysts.O ft hese,i ridium trisboryl complexes have become the catalyst system of choice and this review will focus on the application of these systems in the borylation of heterocyclic substrates.Whilst other transition metal complexes including those containing Pd, Co,F e, Zn, Ru, Ni, Pt, Rh, and Mn also promote similar transformations,these will only be discussed when they offer adistinct advantage in regiocontrol. [38][39][40][41][42][43][44][45][46] 3.1. Ir-Catalysed Arene C À HB orylation Building on earlier work using other iridium boryl complexes, [47][48][49] independent publications by Smith (Scheme 3a)a nd Hartwig,I shiyama, and Miyaura (Scheme 3b) described the catalytic borylation of aryl C À Hb onds with phosphine or bipyridine Ir III trisboryl complexes,r espectively. [50,51] Reflecting higher turnover numbers and more stable catalysts,m ost CÀHb orylations are now conducted with variations of the latter system using ac ombination of [Ir(cod)(OMe)] 2 ,4 ,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) or 3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) as the ligand and B 2 pin 2 or HBpin as the boron source. [51][52][53][54] Theg enerally accepted mechanism involves ac atalytic cycle that oscillates between Ir III /Ir V intermediates,w ith the key step involving the activation of the arene CÀHb ond by the pentacoordinate bipyridyl trisboryl complex 18 (Scheme 4). [55][56][57][58][59] Although early computational studies supported the intermediacyo fa no rganoiridium species formed by an oxidative addition pathway,ac oncerted s-bond metathesis pathway influenced by the basicity of the boryl ligands has yet to be ruled out. Consistent with this,c alculated transition state energies correlate well with developing negative charge during C À Hc leavage at unhindered sites in benzene derivatives. [60] However,Houk et al.,inmore recent work using distortion/interaction analysis,h as demonstrated that ab etter measure is IrÀCb ond strengths which give arobust predictor of regioselectivity. [61] Boryl-assisted reductive elimination from this highly sterically crowded intermediate 19 produces the aryl boronate and an Ir III bisboryl hydride 20.T he cycle is then completed via the oxidative addition of B 2 pin 2 or HBpin, followed by the reductive elimination of HBpin or H 2 ,respectively,toregenerate 18.As such, the catalysis can be divided into two distinct cycles according to the boron reagent involved, with B 2 pin 2 reacting  preferentially to HBpin. In general, electron-deficient arenes are more active than electron-rich counterparts and the reaction shows good functional group tolerance with aw ide range of functional groups being accepted.
Due to the sterically crowded nature of the catalytically active species,r egioselectivity is generally dominated by steric effects (Scheme 5), with the most accessible positions preferentially activated. Theb orylation of 1,2-disubstituted arenes and symmetrical 1,3-disubstituted arenes, 22 and 24, proceeds at the uncongested C À Hb onds (no ortho substituents) affording asingle product (Scheme 5a,b). If the catalyst is not offered an unhindered C À Hs ite,b orylation ortho to moderately sized substituents can occur, albeit with lower rates and conversions (Scheme 5c). [62] Substrates with multiple accessible sites give mixtures of products,with monosubstituted arenes such as toluene affording statistical product mixtures at elevated temperatures (Scheme 5d). [51] At lower temperatures,i somer distributions deviate from sterically determined statistical ratios,a lluding to an underlying electronic selectivity.I ng eneral, p-electron acceptors (ÀM) favour para borylation, and p-donors (+ M) (also s-acceptors) favour meta borylation. (Scheme 5e). [55] Borylation ortho to small strongly electron-withdrawing substituents (F,CN) is facile,p otentially reflecting an electronic activating effect (Scheme 5f). [63,64] Clearer evidence for intrinsic electronic selectivity is seen with benzodioxole 36,which borylates with near complete selectivity at the more hindered ortho position, despite the presence of uncongested C À Hs ites (Scheme 5g). [60] This is attributed to the enhanced acidity of these C À H bonds and relates to the intrinsic selectivity observed in many heterocyclic systems discussed below.Reflecting these observations,amajor challenge in CÀHb orylation has been to develop methodologies that afford good levels of control in sterically uncongested substrates,a nd an umber of elegant strategies have been reported which accomplish this.A comprehensive discussion of these is beyond the scope of this article and the interested reader is directed to more specialised reviews. [65][66][67] Fore xample,i ti sp ossible to use groups within the coordination sphere of the Ir complex to direct the borylation via chelation control. This may be achieved using both inner-sphere and outer-sphere directed processes ( Figure 3).
Ty pically,i ni nner-sphere directed borylation ( Figure 3a) asubstrate containing aligating element coordinates to the Ir  centre,t hereby orientating as pecific C À Hb ond for activation. Fore xample, ortho-selective borylation of 44 occurs on reaction with a[ Silica-SMAP]Ir(Bpin) 3 complex (Scheme 6a). [68][69][70][71] Whilst most of these approaches lead to borylation ortho to ac oordinating group,m ore remote CÀHa ctivation can occur in relay inner-sphere borylation (Figure 3b). In this process,t he substrate contains an additional reactive functional group which can ligate the metal centre,displacing one of the boron ligands.A ss uch, binding of the directing group with the metal centre does not necessarily require additional vacant coordination sites. [72][73][74][75][76] One such example involves the borylation of hydrosilyl arene 46,w hich undergoes selective ortho C À Ha ctivation following substrate binding to the Ir centre via addition of the Si À Hb ond (Scheme 6b). Outersphere directed borylation is ac omplementary process in which asubstrate interaction with aligand of the catalytically active species leads to regioselective CÀHa ctivation (Figure 3c). Fore xample,a ni ns itu N-borylated aniline 51 undergoes selective ortho C-borylation facilitated by ahydrogen bond between the aniline N À Ha nd an Oa tom of the boryl ligand on the active catalyst, as shown in 51 a (Scheme 6c). [77][78][79] Anilines protected with Boc show similar outer-sphere directing effects.

Borylation of Heteroarenes
TheI r-catalysed CÀHb orylation lends itself well to the late-stage functionalisation of heterocycles because,reflecting the higher C À Ha cidity of heteroarene C À Hb onds,t he reactivity of substituted heteroarenes is typically higher than the equivalent benzenoid systems.F or example,2 -phenylpyridine (64)i sexclusively borylated in the heterocyclic ring (Scheme 8). [93] In contrast to the sterically dominated selectivity observed in carbocyclic arenes,h eteroarenes can show ah igher degree of intrinsic electronic regiocontrol. It is frequently observed that sterically encumbered C À Hb onds can be activated over unencumbered ones,a nd the position and/or nature of constituent heteroatoms can significantly affect regioselectivity. [92,94,95] This review outlines the regioselectivity in the Ir-catalysed C À Hborylation of heteroarenes. It will focus on intrinsic substrate-based selectivity but highlight examples in which designer catalysts of the types discussed in Section 3.1 have been used to impose reagentbased regiocontrol. It is organised by substrate classes according to ring system (mono-, bi-, polycyclic), ring size (5/6), and number of heteroatoms.H eteroarenes that do not fit into these simple categories are discussed in Section 4.8. Compared to electron-rich carbocyclic arenes,p yrroles, thiophenes,and furans react much more rapidly and, even in the presence of 10 equivalents of arene,a fford am ixture of mono-and bisborylated products (Scheme 9a). Using excess arene leads to higher selectivity for the monoborylated product, but in the case of thiophene this is accompanied by lower efficiency,potentially due to an inhibitory coordinating effect of the sulfur atom on the catalyst. Borylation occurs preferentially at the a position (C-2 and C-5) owing to the enhanced CÀHa cidity associated with the adjacent heteroatom. Reflecting the more pronounced electronegativity of Oa nd hence enhanced reactivity of this heterocycle,l ower regioselectivity can be observed in reactions of furans,w ith small amounts of b-boryl isomers being detected (Scheme 9b). [96] All of these heterocycles display high reactivity at room temperature,a tw hich selectivity for furan is improved (Scheme 9c). [97] Substituents have asimilar steric influence as observed in carbocyclic substrates,w ith reaction occurring preferentially Scheme 7. Reagent-based regiocontrolled CÀHborylation.

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Reviews 2802 www.angewandte.org at positions lacking ortho substituents. [63,97,98] Consequently,2and 3-and 2,3-substituted heterocycles undergo CÀHb orylation a to the heteroatom at C-5 (Scheme 10 a-c). However, reflecting expanded bond angles relative to benzene derivatives, ortho substituents are more readily tolerated. For example,s ome borylation ortho to the methyl group in 76 was observed at room temperature,with the major site of CÀ Ha ctivation occurring ortho to the nitrile group owing to its lower steric requirement (Scheme 10 d).
TheC À Hb orylation of substituted thiophenes has been thoroughly investigated and these also can undergo reactions at C À Hsites that are sterically congested (Scheme 11). [99] For example,t he catalyst does not distinguish between the hindered and unhindered a sites in 3-cyanothiophene (Scheme 11 a). Furthermore,w hen at andem CÀHs ilylation/ borylation sequence is used, C-3 borylation of 82 can occur ortho to an ethyl group (Scheme 11 b). [100] Given that protodesilylation is straightforward, as equence involving silylation/borylation/protodesilylationpotentially provides aroute for formal selective ortho borylation of a2 -substituted thiophene (see also Section 4.4). As with other arenes, reactivity is highly dependent on both the size and electronic nature of the substituents.F or example,2 ,5-dibromothiophene (84)reacts at room temperature to afford 85 (Scheme 11 c), whereas the more hindered (A Me % 7kJmol À1 , A Br % 2kJmol À1 )a nd electron-rich dimethylthiophene (86) requires more forcing conditions for efficient borylation (Scheme 11 d). [99,101] Unsymmetrical 2,5-disubstituted thio-phenes undergo borylation with selectivities that reflect the size of their substituents (Scheme 11 e).
Pyrrole is unique in that the N-substituent can influence the regioselectivity of the borylation reaction. Whilst the parent heterocycle borylates at C-2, N-methylpyrrole (91 a) affords amixture of the 2-and 3-borylated products in a76:24 ratio (Scheme 12 a), substrates with larger N-substituents (TIPS,B oc, Bpin) exclusively give b-borylated pyrroles (Scheme 12 a,b). [78,96,102,103] Whilst TIPS and Boc need to be introduced in ad iscrete step,B pin may be installed and removed in situ to provide a" traceless" b-directed pyrrole borylation (Scheme 12 c). [78] Alternative C À Hb orylation selectivities in pyrrole,t hiophene,a nd furan may be obtained using inner-a nd outersphere directing effects (Scheme 13). Most use specifically designed ligands,a lthough an otable exception is the use of the dithiane-containing substrate 98.T his ligand-free process affords the 3-borylated thiophene in the presence of an unhindered a C À Hb ond (Scheme 13 a), with the dithiane acting as both substrate and ligand. [104] Good levels of ortho selectivity in the borylation of pyrrole,thiophene,and furanyl ketones,e sters,a nd amides can be achieved using innersphere directing effects,enabled by specific ligands including AsPh 3 , [105] silyl/phosphorus donor chelates, [106] and Silica-SMAP, [71] (Scheme 13 b-e). Control experiments indicated that the use of AsPh 3 provides complementary regioselectivity to that observed with dtbpy,a nd this method probably relies on the lability of the ligand to produce an open coordination site and enable inner-sphere direction. This hypothesis is supported by the observation that ac hloro Scheme 10. CÀHborylation of substituted pyrroles, thiophenes, and furans. dba = dibenzylideneacetone, Q-phos = 1'-[bis(1,1-dimethylethyl)phosphino]-1,2,3,4,5-pentaphenylferrocene. Scheme 9. C-2 selective CÀHborylation of pyrrole, thiophene, and furan using a) excess heterocycle (* C-3-borylated furan also observed), b) stoichiometric heterocycle, c) room temperature. substituent, ak nown inner-sphere director, [68] leads to lower selectivity,w hen AsPh 3 is used, than that observed with the equivalent methyl substituent (Scheme 13 b,c). Similarly,with ligand L8 ac oordinatively unsaturated active catalyst is produced, permitting ligation of ester 106 and facilitating C-3 borylation in the presence of an otherwise highly reactive a CÀHs ite (Scheme 13 d). With Silica-SMAP,t he directing effect is pronounced enough to facilitate borylation ortho to two substituents in the presence of an uncongested a position. However,a sa bove,t he enhanced C À Ha cidity observed in furan ester 108 b led to some competitive a reactivity (Scheme 13 e).

Porphyrins and Corroles
Porphyrins and corroles are closely related macrocycles consisting of four modified pyrrole units,a nd therefore they share aspects of borylation regioselectivity with 2,5-disubstituted pyrroles.F or example,the borylation of porphyrin 119, with limiting boron reagent, occurs at the least hindered pyrrole position minimising peri interactions,affording major monoborylated isomer 120 a alongside two minor bisborylated isomers 120 b and 120 c in a1 :1 ratio (Scheme 14 a). Notably,the borylation also tolerates Ni-and Cu-coordinated analogues of 119,a ffording products with similar selectivities. [107] Judicious meso substitution blocks the corresponding peri positions,p ermitting ad egree of regiochemical control in iterative borylation reactions.One borylation event occurs in the reaction of corrole 121 because the other CÀHs ites are sterically hindered by the meso pentafluorophenyl substituents (Scheme 14 b). Substitution at all four meso positions in aporphyrin blocks reaction in the macrocyclic ring. [108,109] Scheme 11. CÀHborylationo fsubstituted thiophenes. Thep resence of ac arbocyclic ring in indole,b enzothiophene,a nd benzofuran introduces the potentiality for borylation at multiple sites.H owever,i na ll three heterocycles there is amarked preference for borylation in the heterocyclic ring. As with non-benzofused analogues,t he parent heterocycle undergoes borylation selectively a to the heteroatom with excess heteroarene at elevated temperature,w ith benzofuran 123 c displaying slightly lower selectivity in analogy to the CÀHb orylation of furan (Section 4.1; Scheme 15 a). [51] Reducing the arene equivalency and temperature leads to similar product outcomes in these three heterocycles.T his contrasts with the electrophilic borylation that occurs in metal-free systems,w hich gives the complementary C-3 functionalised products (Section 3). Interestingly,t he borylation of 5-furylbenzofuran with as ilyldimesitylborane reagent occurs selectively at C-2 of the benzofused heterocycle (Scheme 15 b). [110] Whilst comparison to the traditional CÀHb orylation systems are challenged by the very different ligand, catalyst and reagents involved, this experiment warrants further investigation into the relative reactivities of benzofused heterocycles and their monocyclic counterparts,a nd could suggest ah igher reactivity of the former ring system. Owing to the prevalence of indole in pharmaceutical agents,t he Ir-catalysed CÀHb orylation of many substituted indole derivatives has been well documented and this discussion will focus on this,e mphasising differences with the other heterocycles where relevant. [111][112][113][114][115][116][117][118] Bisborylation of indole affords the 2,7-disubstituted product 128,and other C-2s ubstituted indoles,s uch as 2-phenylindole,a lso undergo selective borylation at C-7. Significantly,r eaction of 2phenylindole is selective for the fused arene ring, leaving the phenyl substituent intact (Scheme 15 c,d). [117] Polyborylation of 2-substituted indole 131 occurs initially at C-7 and then preferentially at C-4. Thel atter presumably reflecting the para directing effect of aB pin group (Scheme 15 e). [63,115] Reflecting the lower steric demands in af ive-membered ring, 3-substituted indoles also show good levels of C-2 selectivity,further emphasising the electronic activating effect of the heteroatom (Scheme 15 f). [119] With higher stoichiometries of B 2 pin 2 ,i terative borylation of 3-substituted indoles such as 3-methylindole (136)can occur,with C À Ha ctivation occurring at, successively,C-2, C-7, and C-5 (Scheme 15 g). [120] Formal selective C-7 mono-borylation of indole is possible by blocking C-2 with al abile group,w hich is subsequently removed. Forexample,a2-silyl substituent can be selectively cleaved using TBAF after having sterically directed borylation to C-7 (Scheme 15 h). [117] Smith has suggested that the C-7 selectivity observed with indole originates from substrate ligation to the catalyst, which may promote chelation-controlled C À Ha ctivation. This model can potentially account for the C-1,8 bisborylation of carbazole 140 (Scheme 16 a). However,t he high degree of peri steric hindrance at Nf rom the boryl group and the carbocycle might be expected to hinder metal complexation for the second borylation event, suggesting the involvement of an electronic directing effect. [118] Further support for this proposal comes from the borylation of benzofuran, which also shows selectivity for C-7, albeit with some leakage to the 2,6bisborylated product (Scheme 16 b). Whilst the latter observation is consistent with the poorer coordinating nature of the oxygen atom, the possibility for simple intrinsic activation of these positions by the heteroatom is supported by the calculated relative free energies of the anions in 2-phenylindole (129). These indicate that C-7 (À10.96 kcal mol À1 ) should be the most reactive CÀHs ite when contrasted to other uncongested CÀHsites,which range between À9.4 and 0kcal mol À1 . [121] Moreover,t he selectivities observed with benzofuran are comparable with the ortho selectivity observed in the C À Hb orylation of benzodioxole (36; Section 3.1). [60] In analogy to the C À Hborylation of pyrrole,the use of Nsubstituents can modify the regiochemical outcome,a s observed in the borylation of N-methylindole (145), which affords am ixture of C-2 and C-3 functionalised products Scheme 15. CÀHborylation of indoles. IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazolium.

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Reviews 2806 www.angewandte.org (Scheme 16 c). Independent reports give different selectivities for this process and potentially reflect the use of varying solvents,ligands,and reaction times.This collectively suggests that subtly different catalytic cycles/species may exist. [96,122] As with their pyrrole analogues,i ndoles with the bulkier N protecting groups TIPS,B pin and Boc are borylated with complete b selectivity.The NBpin substrate 148 is prepared in situ in as imilar manner to NBpin pyrrole 97 (Section 4.1.1; Scheme 16 d). [78,96,103,123] Interestingly,the corresponding reaction with B 2 eg 2 (eg = ethylene glycolato) affords the aborylated product via ap rocess involving an electrostatic outer-sphere interaction between the NBeg group and the ancillary ligand (Scheme 16 e). [124] If borylation in the heterocyclic ring is sterically inhibited, then borylation in the carbocyclic ring occurs,o ften with sterically controlled regioselectivity.F or example,t he borylation of N-TIPS indole 151 in which C-2, C-4, and C-7 are sterically congested, leads to relatively non-selective borylation at C-5 and C-6. Site-selectivity can be enhanced by switching the ligand from dtbpy/tmphen to 1,10-phenanthroline (phen) in indoles and carbazoles,a si so bserved in the borylation of 151 and 154 (Scheme 16 f,g). This ligandmediated selectivity is almost certainly electronically con-trolled, although further studies are required to determine its origin. [125] Notably,these substrates possess astructure that is comparable to a1 ,2-disubstituted arene,i nw hich electronic effects also contribute significantly to the selectivity observed in reactions run at room temperature. [55] As observed with their monocyclice quivalents,t he intrinsic selectivities of indole,b enzothiophene,b enzofuran, and carbazoles can be altered using various directing effects. Forexample,the dithiane-directed borylation of 2-substituted benzothiophene 157 leads to an ortho functionalised product 158 (Scheme 17 a). [104] Likewise,using Silica-SMAP,2-, 3-and N-substituted carbonyl derivatives of these heterocycles undergo ortho or peri borylation, as exemplified by the efficient C-1 borylation of N-substituted carbazole 159 (Scheme 17 b). [71] Relay direction provides an alternative mode of regiocontrol in polycyclic heterocycles.T his can be achieved using ah ydrosilyl group that is either generated in situ or preinstalled. Fore xample,t he borylation of chloroindole 161 is completely C-7 selective (Scheme 17 c), whilst 3-hydrosilyl benzothiophene and indole 163 a and 163 b undergo periselective borylation at C-4 (Scheme 17 d). [72,75] In both cases, the bulky nature of the silyl group presumably helps to reduce competing C-2 borylation.
Outer-sphere systems can also alter the selectivity in substituted indole derivatives.F or example,i on-pair recognition enables C-6 meta borylation to compete with C-7 functionalisation of ammonium indole 165 using ligand L11 (Scheme 18 a), [82] whilst CÀHborylation with L-shaped ligand L9 leads to enhanced a selectivity in indole ester 168 and indole amide 170 (Scheme 18 b,c). [85,126]

Indazoline
Indazoline is structurally related to indole and may be employed as ab ioisostere.W hilst the CÀHb orylation of the parent heterocycle is slow,s ubstitution with electron-withdrawing groups enhances reactivity. [127] In analogy to the C À H borylation of pyrrole,c yanoindazoline 173 undergoes C-3 borylation a to the heteroatom, and additionally displays reactivity at C-6, and this is similarly observed for indazoline diester 176 (Scheme 19). Curiously,i nt his latter transformation the 5,6-bisarylated 179 was also produced, indicative of an unusual C À Hb orylation occurring ortho to aB pin substituent.

Six-Membered Monocyclic Heterocycles with One Heteroatom 4.3.1. Introduction
Heteroarenes that contain basic azinyl nitrogen atoms represent ad istinctive challenge for borylation chemistry.I n contrast to the selective a borylation observed in azole Ncontaining rings,borylation is electronically disfavoured a to an azinyl Na tom. This can crudely be likened to the steric inhibitory effect of as ubstituent but is best attributed to dipolar repulsion between the azinyl lone pair and the developing negative charge on the a carbon atom in the CÀ Ha ctivation transition state.Inagiven substrate,the degree to which a-azinyl borylation occurs is dependent on the electron density at N, and on steric constraints in the rest of the molecule.D FT calculations of the reaction pathway for the C-2 borylation of pyridine show ca. 1kcal mol À1 higher barrier compared to borylation at the other sites. [128] As this is arelatively small difference,the lack of a-azinyl products can also be attributed to the poor stability of 2-azaarylboronates. These are known to decompose via several pathways,including protodeborylation. [129] However,t he introduction of ab oryl group in the a-azinyl position may be promoted by stabilising groups,and these are typically electron-withdrawing groups such as other Nr ing atoms,s ulfonyl or trifluoromethyl groups,and halides.

Pyridine
In the original report on the Ir-catalysed CÀHborylation of heteroarenes,p yridine 180 stands out as an unusually Scheme 17. ortho-and peri-directed borylation of benzofused heterocycles.

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Reviews 2808 www.angewandte.org inactive substrate,r equiring increased temperature and affording as tatistical mixture of C-3 and C-4 borylated products in low yield (Scheme 20). [96] C-2 borylated products were not observed, and this is due to the inhibitory effect of the azinyl nitrogen. In contrast, borylation of various 2substituted pyridines occurs readily at room temperature with the expected sterically controlled selectivity (Scheme 21). Thec omplete selectivity for reaction in the heterocyclic ring observed with 2-phenyl pyridine provides further illustration of the higher reactivity of heterocyclic vs.carbocyclic arenes. Although the low yields in the borylation of pyridine may be attributed to the rapid decomposition of in situ C-2 borylated products,amore likely explanation is the reversible inhibition of the active catalyst through substrate ligation. Evidence for this is seen in the relative borylation of 2,6-lutidine (183) and 4-tert-butylpyridine (184). Thelatter,lacking unhindered nonazinyl C À Hbonds,isinert, whilst the former undergoes facile CÀHb orylation selectively at the sterically uninhibited 4position (Scheme 21 a). However,t he addition of small amounts of 184 into the borylation reaction of 183 efficiently inhibits the reaction through coordination to the vacant site on the catalytically active iridium trisboryl complex. [93] Whilst sterically blocked substrates such as 2,4-disubstituted pyridines generally display poor reactivity,Chirikspincer-ligated cobalt complexes can smoothly promote CÀHb orylation of 2,4-lutidine (186) a to the azinyl nitrogen, with C-2 functionalised pyridine 187 being detectable in 79 %G CMS yield (Scheme 21 b). [45] It is more difficult to activate this position using Ir (see Scheme 22 b), and this likely suggests that ad ifferent mechanistic pathway is operating with this Cocatalyst. In the Ir-catalysed CÀHborylation of azinyl heterocycles,the impact of substrate inhibition can be reduced by an electronegative substituent that lowers the basicity of the azinyl nitrogen, weakening the interaction with the catalyst. Forexample,the C À Hborylation of 2-fluoropyridine is facile at room temperature and gives rise to five isomeric pyridyl boronates.Electron density is reduced at NbyFto asufficient extent such that the a-azinyl borylated product 192 is observable (Scheme 21 c).
Other substituted pyridines show as electivity that is ab alance of sterics and electronics.F or example,2 ,3disubstituted pyridines borylate largely with steric control at C-5 but more strongly electron-deficient systems display enhanced reactivity at the a azinyl position (Scheme 22 a). Similar trends are observed with 2,4-disubstituted pyridines, with the inhibitory effect of the azinyl nitrogen leading to borylation occurring at C-5 providing that the bulk of the C-4 substituent can be tolerated. As with 188,p yridine 197 a is sufficiently electron-deficient and C À Hborylation is selective for C-2 even at room temperature.I nc ontrast, electron-rich and sterically congested pyridine 197 b requires more forcing conditions and is selective for C-5 (Scheme 22 b). Interestingly,dtbpy 207 undergoes CÀHborylation under more forcing conditions at the a azinyl positions,although this was not observed in the absence of excess dtbpy,s uggesting that ligand dissociation does not readily occur during catalysis (Scheme 23 a). [53,130] Theregioselectivity was confirmed using ao ne-pot Suzuki-Miyaura cross-coupling to deliver arylated product 208 and this ability to directly use borylated products is av aluable strategy for these less stable boronate esters. Given that the related 4-tert-butylpyridine 184 is unreactive (vide supra), the 2-pyridyl unit in 207 likely facilitates activity by functioning both as as teric blocker and an electronwithdrawing (activating) group.S teric effects remain the dominating influence in this transformation, as the corresponding 4,4'-dimethoxybipyridine analogue 209 gives the ortho methoxy functionalised products 210 and 211 (Scheme 23 b), in which borylation occurs remote to both the azinyl nitrogen and the pyridyl substituent. Borylation of 2,5disubstituted pyridines is only viable with moderately sized substituents and, given the inhibitory effect of the azinyl nitrogen, will occur preferentially at C-3 or C-4 in aratio that reflects the competing steric and electronic influences of the substituents.F or example,t he borylation of 2-cyano-5-bromopyridine (200)p roceeds efficiently to afford C-3 and C-4 boronates 201 and 202 in a2:1 ratio (Scheme 22 c), [63] whilst 2,5-lutidine (203)s hows poor conversion under comparable conditions (Scheme 22 d). Finally,2,6-disubstituted pyridines, for which the inhibitory effect of the azinyl nitrogen is blocked, react as electron-deficient arenes and generally have good activities exhibiting C-4 selectivity,and ligands based on the bipyridine scaffold such as L12 also promote this transformation (Scheme 22 e). [131] Outer-sphere directing effects have been exploited to override these selectivities.F or instance,a minopyridines undergo rapid NH borylation to form the corresponding NHBpin adduct. This intermediate facilitates ortho-selective borylation in 2-substituted 4-and 5-aminopyridines,a nd this may be seen in the borylation of 212,via the initial formation of 214 in situ (Scheme 24 a). In addition, the borylation of 5hydroxypyridine (215)i sortho (to OH) selective following traceless O-borylation with HBpin to afford C-4 functionalised 216 (Scheme 24 b). [78,124] However,i ti su nclear to what extent the regiochemical outcomes of these processes differ from intrinsic regioselectivity.I np articular,i tc an be argued that, given the relatively similar size of each substituent, the selectivity is ameasure of ortho activation due the competing

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Reviews 2810 www.angewandte.org electron-withdrawing effect of the nitrogen and oxygen substituents,r espectively.I ns upport of this,t raceless ortho direction is not displayed with 2,6-aminopyridine derivatives, and sterically mediated C-4 borylation analogous to the borylation of 205 occurs instead. [78] Other outer-sphere (ligand-mediated) directing systems can also influence the regioselectivity of the borylation of pyridines.F or example, when ionic ligand L11 is employed, the C-4 selectivity in pyridyl amides and trialkylammoniums is increased, and this can be observed in the borylation of 218. [82][83][84] Following C-4 borylation, the powerful electron-withdrawing capacity of the trimethylammonium group can facilitate borylation at C-6, affording bisborylated 220 selectively (Scheme 25 a). Alternative selectivities can also be obtained using ligand-based complexation to direct borylation of pyridine amides and esters (Scheme 25 b-e). [80,85,126] Control experiments using dtbpy indicate that the C-2 substituents in each substrate possess modulating effects on intrinsic site selectivities which deviate from simple steric control. Notably,the complexation of isonicotinamide 224 to L-shaped ligand L9 outcompetes the intrinsic inhibitory effect of the unhindered azinyl nitrogen, affording meta borylated product 225 (Scheme 25 c). The Lewis basicity of the azinyl Nc an also be used for outersphere direction in conjunction with aL ewis acid that is directly coupled to the bipyridine ligand, for example, L13 (Scheme 25 e). Presumably,s ubstrate coordination to these ligands outcompetes catalyst coordination, and this enables complementary C3 (meta)b orylation of the parent pyridine scaffold at room temperature.S ubstituted pyridines are also viable substrates for this process.I nterestingly,a ss hown by this example,aC-2 substituent does not seem to block complexation, giving selective access to 2,5-disubstituted pyridine products (Scheme 25 e). [86] Thea zinyl nitrogen can also coordinate directly to the Ir metal centre in inner-sphere systems enabling the selective borylation of pendant arene substituents (Scheme 26). Similar directed C À Ha ctivation processes of 2-aryl pyridines are common with other metal catalysts,such as Ru. [41] Using this approach, the electronic preference for borylation at the pyridine can be overcome in favour of reaction at the carbocyclic moiety. [106,132] Fore xample,h emilabile ligand L14 efficiently facilitates borylation at the ortho position of the phenyl ring in 2-phenylpyridine 64,p roducing N-B ylide 232 (Scheme 26 a). [132] Likewise 2-phenoxypyridine (233) undergoes borylation in the carbocyclic ring mediated by B-Si ligand L15,( Scheme 26 b). [133] In ar elated approach, 2benzyl pyridines act as as ubstrate,l igand, and inner-sphere director and are selectively borylated in the carbocycle ring. Notably,f luorinated arene 234 selectively affords 236, overcoming both the intrinsic reactivity of the pyridyl ring and the activating effect of af luorine substituent toward ortho C À H activation. (Scheme 26 c). [64,134] Nakao has exploited the coordinating ability of the azinyl nitrogen to direct the borylation to C-4 using bulky aluminium Lewis acids which hinder access to the meta position. Surprisingly this still functions well in the presence of C-2 substituents which appear not to hinder the crucial substrate Lewis acid binding (Scheme 26 d). [87] 4.4. Six Membered, Polycyclic, One Heteroatom (Quinolines and Isoquinolines) Although an azinyl heterocycle,u nsubstituted quinoline 241 is an active substrate in the CÀHb orylation because the peri C-8 CÀHb ond of the carbocyclic ring blocks inhibitory ligation to the active catalyst. As with other benzofused heteroarenes,q uinoline is preferentially activated in the heteroaromatic ring. In the presence of excess heteroarene, selective monosubstitution at C-3 can be obtained (Scheme 27 a), reflecting acombination of steric inhibition by the peri hydrogen at C-5 and the inhibitory effect of the azinyl lone pair on activation at C-2. [96] In the presence of excess boron reagent, quinoline undergoes bisborylation at C-3 and C6/C7 in a1 :1 ratio (Scheme 27 b). [55] Unlike benzofused azoles, which show selectivity for reaction at C-7, the analogous C-8 position in quinoline is normally unreactive,providing further evidence for the repressive effect of aproximal azinyl Nlone pair on CÀHa ctivation. As with other (hetero)arenes,t he introduction of substituents leads to sterically controlled regioselectivity.F or simple 2-substituted quinolines the unhindered nature of the carbocyclic rings means that polyborylation is facile and the nature of the C-2 substituent can affect the regiochemical outcome,w ith an increasing electron-withdrawing ability leading to an increased degree of C-7 substitution (Scheme 27 c). [55] Substitution in the carbocyclic ring leads to ag reater degree of control and further reveals the underlying role of electronic effects in these reactions.For example,whilst 2,6-disubstituted quinolines are borylated exclusively at C-4 (Scheme 27 d), which can be attributed to simple steric direction, 2,7-disubstituted quinolines show varying selectivity,w ith more electron-withdrawing groups leading to increased amounts of the C-5 boronate ester 252 b (Scheme 27 e). Since these positions are sterically equivalent this must reflect an electronic influence,and this is likely caused by the enhanced C À Ha cidity at C-5 of the carbocyclic ring in the CF 3 -containing substrate, 250 b. Indeed, the calculated CÀHa cidities at C-4 (38.6) and C-5 (39.7) in 250 b provide qualitative correlation with experimental site-selectivity.A sw ith other arenes,c ongested quinolines are viable substrates but require more forcing conditions,a lthough the preference for reaction in the heteroaromatic ring remains.F or example,a ll C À Hs ites in 4,7-disubstituted quinolines are encumbered, so borylation is completely selective for C-3 but the reaction of 253 a bearing ac hloro group at C-4 is significantly more efficient than for the C-4 methyl analogue (Scheme 27 f). As noted previously (see Section 4.2.1) as imple approach to deliver selective borylation in heteroarenes is to undertake sequential silylation, borylation and desilylation. Subjecting 2-methyl quinoline to this process affords exclusively the 6-borylated isomer 256 via silylated arene 255.S ince the corresponding 2,8dimethyl quinoline affords ac omplex mixture of mono-and diborylated products under the same conditions,this seems to reflect ac ombination of electronically and sterically driven selectivity.T he silyl group may be selectively removed to afford aformal, selective,and otherwise difficult to achieve C-6borylation process (Scheme 27 g). [100] Scheme 26. Inner-sphere directed CÀHborylation of 2-substituted pyridines.

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Reviews 2812 www.angewandte.org By replacing dtbpy with the silica-immobilised monodentate phosphine ligand Silica-SMAP,S awamura and co-workers have elegantly exploited inner-sphere coordination to selectively activate the C-8 position in arange of 2-substituted quinolines (Scheme 28 a). [70] Silica-SMAP directs borylation to the otherwise unreactive C-8 position in alibrary of mono-, di-, and trisubstituted quinolines.R emarkably,t he system affords C-8 regioselectivity even in congested substrates,such as 257,with asubstituent at C-7. Other groups can be used to direct regioselectivity;f or example,a minoquinoline 259 has been shown to undergo ortho-selective borylation at C-7 via NHBeg intermediate 267 (Scheme 28 b). [124] To date,t he various other ingenious ligand-controlled borylations have not been applied to quinoline and this may reflect the challenge of preparing suitably functionalised substrates.
Isoquinoline CÀHb orylation remains relatively unexplored, with the intrinsic regioselectivity undefined. This is probably attributable to catalyst inhibition by the heteroarene unless substituted at C-1 and/or C-3. However,s ome examples of directed borylation have been described. In as imilar fashion to 2-arylpyridines,h emilabile ligands facilitate selective remote borylation of 1-aryl isoquinolines (Scheme 28 c), [132] whilst hydrosilyl relay direction enables peri borylation of suitable 1-substituted isoquinolines (Scheme 28 d). [73] Curiously,similar chemistry using 2-chloro-4-hydrosilylquinoline 265 was not viable (Scheme 28 e) and this result highlights the degree of substrate specificity that exist in these more complex systems that have multiple influences on reaction outcomes.

Five-Membered, Monocyclic, TwoH eteroatoms (Imidazoles, Pyrazole, Oxazole)
Mirroring the effects observed with both pyrrole and pyridine,s ubject to steric accessibility,t he borylation of imidazole,p yrazole,a nd oxazole generally occurs a to the oxygen atom or azole nitrogen and remote from the azinyl nitrogen atom. In general, the higher reactivity of these heterocycles together with the less congested relationship between substituents in five-membered rings mean that steric effects are less pronounced, enabling positions with ortho substituents and even moderately sized doubly ortho substituted sites to be borylated (vide infra). Thep arent unprotected imidazole is not borylated, which is perhaps due to rapid N-borylation to form the corresponding N-Bpin adduct, leaving all CÀHs ites either sterically hindered or inhibited by the azinyl nitrogen. However,N -methylated imidazoles undergo borylation efficiently at C-5, and this is exemplified by the borylation of 268 in the presence of 1.5 equivalents of HBpin (Scheme 29 a). Interestingly,u sing 2.5 equivalents of HBpin, 268 undergoes asecond borylation event at the ortho CÀHsite on the phenyl ring (Scheme 29 b), likely mediated by an outer-sphere directing effect involving the azinyl Na tom. [135] As with 2-subsituted pyridines, a-azinyl borylation is normally disfavoured, although ac ombination of steric bulk and reduction of the azinyl electron density can allow this to occur. Fore xample,b locking the azole Nw ith either aB oc carbamate or dimethylsulfamoyl group enables a-azinyl boronates 272 and 274 to be generated (Scheme 29 c,d). [103] Whilst the Boc-protected boronate was unstable,t he higher electron-withdrawing capacity of asulfamoyl group rendered boronate 274 isolable.
In contrast to imidazole,unprotected pyrazole undergoes borylation at the b position owing to the rapid formation of bulky N-Bpin species 277,which sterically blocks a borylation (Scheme 30 a). [78] Unlike indole,the lower pK a of the pyrazole NH means that this does not require exogenous base as illustrated by the fact that 275 undergoes N-borylation without catalysis.O ther large nitrogen protecting groups such as Boc similarly direct borylation to the b position (Scheme 30 b), and recent results suggest that the b selectivity observed with 278 has an element of electronic control as the smaller methyl carbamate also leads to reaction at this position. [103,136] Other small azole nitrogen substituents,f or example, N-methyl pyrazole (280 a)a re selectively borylated at the a position reflecting the higher intrinsic reactivity of this CÀHb ond (Scheme 30 c). This selectivity is sustained even in the presence of an ortho bromine substituent (280 b). C-5 substituted pyrazoles such as 282 also undergo Nborylation and C-borylation is selective for C-4 (Scheme 30 d). [135] However, tautomerisation in pyrazoles is strongly modulated by the substituents and, in contrast to free N À Hi midazoles,3 -trifluoromethylpyrazole 284 is borylated

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Reviews 2814 www.angewandte.org at C-5 and not at C-4, with steric and electronic selectivity working in parallel (Scheme 30 e). [128] Significantly fewer oxazole derivatives have been reported as substrates for C À H borylation, although some examples are shown in Scheme 31. In these substrates,there is anormal preference for borylation at the most acidic site a to the Oa tom. [135] Somewhat surprisingly,d irected borylation, inner-o ro uter-sphere,o f imidazole,p yrazole,o ro xazole derivatives has yet to be described.

4.6.
Five-Membered Polycyclic Heterocycles with Two Heteroatoms 4.6.1. Indazole As with imidazole,t he borylation of unprotected NH indazole is not effective.T his is surprising,asthe structurally similar heteroarene pyrazole is an active substate and is borylated at C-4 following initial N À Hborylation. Thelack of indazole borylation has been suggested to be due to the inhibitory effect of the azinyl No nt he catalyst. [137,138] Alternatively,the parallels with imidazole might also suggest it is either an inability to N-borylate or, more likely,a n instability of the N-borylated species that is critical. In support of this latter idea, the more stable N-substituted indazole derivatives undergo facile borylation. Significantly, both N-methyl-1H-indazole (288)and N-methyl-2H-indazole (290)s how complete selectivity for the heteroaromatic moiety (Scheme 32 a,b). Moving from N-Me to larger substituents,s uch N-Boc, N-tetrahydropyranyl (N-THP), N-2-(trimethylsilyl)ethoxymethyl (N-SEM) or N-3,5-dimethylbenzyl does not alter this regioselectivity for either 1H-o r 2H-indazoles (Scheme 33). This provides further evidence for ad ifference in five-and six-membered heterocycles,w ith borylation occurring adjacent to both the peri C-4 substituent and azinyl nitrogen (Scheme 33 b). This reflects both the lower steric demand of ortho substituents and al ower inhibitory effect of the azinyl nitrogen which is strongly influenced by the electron-withdrawing effect of the azole nitrogen (pK a (indazolium) = 1.25).
Thea zinyl nitrogen effect is not completely ablated, as borylation of the 2H-indazole isomers,w hich avoid this inhibitory interaction, is much more rapid and the corresponding C-3 boronates undergo protodeborylation more slowly.The latter issue can be ameliorated through the use of the more electron-withdrawing N-Ms group,asin292,which stabilises boronate 293,p ermitting isolation following silica gel column chromatography in 62 %y ield (Scheme 32 c). As with pyridines,t he introduction of blocking groups (e.g. halogens) enables more complex sequences involving polyborylation and selective reaction, for example,cross-coupling and deborylation, giving access to other regioisomers.F or example,atelevated temperature in the presence of 2equivalents of B 2 pin 2 , N-SEM-2H-indazole (294)iteratively undergoes bisborylation, initially at C3 and then at C-5/C-6, to afford a5:1 mixture of products (Scheme 33 a). Substitution at C-4, as in 297 leads to the second CÀHactivation occurring exclusively at C-6 (Scheme 33 b). In this case,e xploiting the destabilising effect of the azinyl nitrogen enables selective protodeborylation at C-3 leading to af ormal C-6 monoborylation affording 299.

Benzoxazole, Benzothiazole, and Benzimidazole
Theb orylation of benzoxazoles,b enzothiazoles,a nd benzimidazoles requires as ubstituent at C-2, potentially to prevent substrate ligation to the catalyst through the azinyl nitrogen. Thereasons for this are not immediately obvious,as oxazole itself is an active substrate (see Section 4.5), although this may further reflect the higher reactivity of heterocyclic C À Hbonds when compared with those in carbocyclic rings.In 2-methylbenzoxazole (301), borylation selectively occurs at C-7 ortho to the Oatom (Scheme 34 a), and other derivatives with substituents at C-4 or C-5 also show this regioselectivity. [128] This is consistent with the ortho selectivity observed in benzodioxole 36 (see Section 3.1), and correlates to the enhanced C À Ha cidity of this site.M irroring the lower electronegativity of sulfur, 2-methylbenzothiazole (303)i s comparably less active towards C À Hb orylation and displays poorer selectivity (Scheme 34 b). Ther equirement for elevated temperature and catalyst loadings likely reflects the catalyst-deactivating effect of sulfur,a nd parallels can be drawn with thiophenes,which are less active than pyrrole and furan for this reason (see Section 4.1.1). In contrast to both these heterocycles,2 -methylbenzimidazole (305)e fficiently undergoes distal borylation at C-5 (Scheme 34 c). Thelack of ortho (C-4/C-7) reactivity can be attributed to an azinyl N effect in analogy to the inhibition of C-8 activation in quinoline,a lthough the contribution of an N-Bpin adduct, which also sterically hinders the peri position, cannot be discounted. Thelatter possibility is supported by the requirement for increased equivalents of B 2 pin 2 for efficient borylation of benzimidazoles. Thep resence of two Nr ing atoms renders diazines less basic than pyridine.T his,c oupled with the enhanced C À H acidity,a ffords greater intrinsic activity.I ndeed, parent pyrimidine 307 is borylated at room temperature using tmphen as al igand, albeit in low (NMR) conversion. [128] In analogy to the CÀHb orylation of other azinyl systems,t he catalyst avoids the a-azinyl positions and delivers C-5 functionalised boronate 308 selectively (Scheme 35 a). Blocking ligation of diazine substrates with substituents improves reactivity,a nd this may be seen in the comparably more efficient borylation of 2-substituted pyrimidines (Scheme 35 b,c). As with other heterocycles,a nd exemplified by the reaction of 2-phenylpyrimidine (311;Scheme 35 c), activation of C À Hb onds within the heterocyclic ring occurs more rapidly than in carbocyclic arenes.Likewise,the borylation of 6-methylpyridazine 313 is efficient and selective for C-4 (Scheme 35 d). In contrast to pyridines,s ubstituted pyridazines have been shown to undergo borylation at the a-azinyl CÀHb ond without necessarily requiring electron-withdrawing substituents.F or example,p yridazine 315 is efficiently borylated at C-6, despite the presence of both an ortho azinyl Nand an ortho methyl group (Scheme 35 e). Interestingly,the 2-chloro-3-methylpyridazine (317)ispreferentially borylated meta to the chlorine atom, as this nitrogen carries lower electron density (Scheme 35 f). [93] Finally,inparallel with the transformation of quinolines,t he borylation of quinoxaline has been reported with Silica-SMAP,a ffording bisborylated product 321 via inner-sphere coordination of the azinyl N atoms (Scheme 35 g). [70]

Azaborine and Borazaronaphthalene
Boron-nitrogen heterocycles such as borazine and 2,1borazaronaphthalene are isostructural with classical arenes and can undergo Ir-catalysed C À Hb orylation. In analogy to other azoles,b orazine 322 undergoes borylation selectively a to Na tC -6 (Scheme 36 a). [139] Under these conditions,a n aryl substituent on the boron atom is not affected and this selectivity correlates well with calculated gas-phase acidity (Scheme 36 b). 2,1-Borazaronaphthalenes are benzofused analogues of borazine,a nd this motif differs from other benzofused heteroarenes in that C À Hb orylation exhibits selectivity for the carbocyclic ring.F or instance,t he carbocycle of 326 is more reactive than both the azaborine and benzothiophene rings and undergoes selective borylation at C-8 (Scheme 36 c). [121] In parallel to the chemistry observed with indole, [116] it is possible that the NÀHgroup plays arole in enabling directed borylation through an inner-sphere effect. However,c alculations have shown that this site has the greatest anionic charge stabilisation, suggesting that the selectivity may be intrinsic in origin. Moreover,t he notion that, in borazaronaphthalenes,t he carbocyclic ring is more reactive is reinforced by the fact that both bisborylation of 328 and borylation of the N-methylated analogue 330 occurs in the carbocyclic and not the heterocyclic ring, albeit at what are the most accessible C À Hbonds (Scheme 36 d,e).

Fused Heterocyclic Rings with Multiple Heteroatoms
Borylation of fused heterocycles containing multiple heteroatoms is possible,a lthough fewer examples have been reported. In general, as imilar profile of reactivity can be established in which selectivity is ab alance of accessibility and intrinsic CÀHa ctivity (CÀHa cidity/CÀIr bond strength) countered by the inhibitory effect of aproximal and or Lewis basic azinyl nitrogen.
Mirroring the regioselectivity of other azoles,C -5 functionalisation a to the azole-like N-4 nitrogen is most favoured. With excess boron reagent, C-7 functionalisation occurs more rapidly than at C-8, presumably reflecting abalance between steric accessibility,inhibition by the N-1 azinyl lone pair, and activation by the para C-5 Bpin group.I nterestingly,t he borylation of 336 was far more efficient in CH 2 Cl 2 than in THF or MTBE despite the fact that chlorinated solvents are seldom employed in iridium C À Hb orylation as they are generally inferior to alkanes and ethers.

Summary
Organoboron compounds are versatile intermediates and the selective generation of these is paramount for many applications.A lmost twenty years after its inception, Ircatalysed aromatic C À Hb orylation remains the state-of-theart methodology for the regioselective installation of arene CÀBb onds.I ng eneral, the crowded nature of the catalyst permits sterically controlled borylation of carbocyclic CÀH bonds,a nd the least hindered sites are generally the most reactive.E lectronic effects,a lthough contributing to the reaction outcome,a re ar elatively minor component and, generally,o nly observed at lower temperatures.I nc ontrast, although the site-selectivity observed in the borylation of heteroarenes carries ad egree of steric control, as ignificant contribution from electronic effects is apparent, as evidenced by the observation that more congested CÀHb onds can undergo selective borylation. Factors such as Ir À Cb ond strength, relative anionic stabilisation, and C À Ha cidity,i n conjunction with sterics,a ll contribute more overtly to the outcome of this transformation and should be considered in order to predict and understand heterocycle borylation selectivities.M oreover,w hilst the intrinsic steric-regulated selectivities of carbocyclic aromatic C À Hb orylation can be altered using ligand-based directing effects,t he multiple factors observed in many heterocyclic systems complicate the application of these strategies to such substrates.
In conclusion, the increasing number of reports describing the application of Ir CÀHb orylation to new heterocyclic systems demonstrate the importance of this methodology. Selectivity remains achallenging aspect and we hope that this review shall serve as au seful resource for predicting the intrinsic borylation regioselectivity of these and related heterocyclic systems.L ooking forward, much of this chemistry has been achieved using arelatively limited set of ligands and boron reagents,and the development of new systems that enable greater scope and control in these transformations remains an important synthetic objective. [92]