Acyl‐Directed ortho‐Borylation of Anilines and C7 Borylation of Indoles using just BBr3

Abstract Indoles are privileged heterocycles found in many biologically active pharmaceuticals and natural products. However, the selective functionalization of the benzenoid moiety in indoles in preference to the more reactive pyrrolic unit is a significant challenge. Herein we report that N‐acyl directing groups enable the C7‐selective C−H borylation of indoles using just BBr3. This transformation shows some functional‐group tolerance and notably proceeds with C6 substituted indoles. The directing group can be readily removed in situ and the products isolated as the pinacol boronate esters. Acyl‐directed electrophilic borylation can be extended to carbazoles and anilines with excellent ortho selectivity. 4‐amino‐indoles are amenable to this process, with acyl group installation and directed electrophilic C−H borylation enabling selective formation of C5‐BPin‐indoles.

Abstract: Indoles are privileged heterocycles found in many biologically active pharmaceuticals and natural products. However,t he selective functionalization of the benzenoid moiety in indoles in preference to the more reactive pyrrolic unit is as ignificant challenge.H erein we report that N-acyl directing groups enable the C7-selective C À Hb orylation of indoles using just BBr 3 .T his transformation shows some functional-group tolerance and notably proceeds with C6 substituted indoles.T he directing group can be readily removed in situ and the products isolated as the pinacol boronate esters.A cyl-directed electrophilic borylation can be extended to carbazoles and anilines with excellent ortho selectivity.4 -amino-indoles are amenable to this process,w ith acyl group installation and directed electrophilic C À Hb orylation enabling selective formation of C5-BPin-indoles.
CÀHborylationisapowerfulmethodologytoformsynthetically versatile C À Bb onds. [1] Numerous methods have been developed, with iridium-catalysed C À Hborylation one of the most notable. [1] This method functionalises the pharmaceutically important heteroarene indole at the C2-position. [2] Alternative indole CÀHb orylation methods include electrophilic borylation (dominated by electronic effects) [3] and CÀH lithiation/borylation (controlled by C À Hacidity). [4] However, these also functionalise the pyrrole unit (at C3 and C2, respectively,S cheme 1t op left). Indole C À Hb orylation that occurs selectively on the less reactive benzenoid unit is desirable,i ncluding for accessing C5 and C7-functionalised indoles which are motifs found in many biologically active natural products and pharmaceuticals (e.g.c hloropeptin I, teleocidins,h ippadine,t iplaxtinin). [5] To date the selective C5 À H/C7 À Hb orylation of indoles in the presence of C2 À H/ C3 À Hr equires prefunctionalised indoles (e.g.h alide at C5/ C7) or functionalisation of the more reactive C2ÀH/C3ÀH site prior to C5ÀH/C7ÀHb orylation and then unmasking of the C2 À H/C3 À H. [6] To the best of our knowledge,o ne example of directed iridium-catalysed C À Hb orylation [7] provides the only exception to these requirements (Scheme 1, middle left). [8] This process while notable uses ruthenium and iridium catalysts and substrates containing C6 substituents are not viable (6,7-disubstituted indoles are also bioactive motifs for example,i ndole isosteres of combrestatins). [5, 6c,9] Therefore as imple,p recious metal free route for the C À Hb orylation of indoles that is selective for:( i) C7 (over C2), including for C6 substituted indoles,a nd (ii)C5 (over C3), would be highly notable particularly if using areadily removed directing group. CÀHborylation using BX 3 (X = Cl or Br) is an attractive method to form organoboranes, [3a,b,10, 11] and directed borylation using BX 3 has proved to be apowerful route to form B À C bonds for organic materials applications. [12] Directed electrophilic CÀHb orylation is dominated by directing R 2 N-or Nheterocycle groups with borylation generally forming six membered boracycles preferentially over other ring sizes. [13] Thee xtension of CÀHb orylation using BX 3 to the C5/C7 positions of indoles would be highly attractive.However,this requires conditions that disfavour electrophilic C3 À Hb orylation (which is relatively facile) and ad irecting group that: (i)iscompatible with BX 3 ;(ii)enables selective borylation at the desired position;( iii)isr eadily deprotected post CÀH borylation. Tr ansition metal-catalysed C7ÀHindole function-Scheme 1. Select previous work on the borylation of indoles, specifically borylation reactions occurring at the C5 and C7 positions. Bottom inset, this work on acyl-directed electrophilicC ÀHborylation at C5 and C7 using BBr 3 . alisation often uses bulky phosphinyl directing groups installed at N1 which are challenging to remove (requiring refluxing with LiAlH 4 ), [5,6a, 14] however,i nl imited cases Nacyl directing groups also have been used [5,15] and these are more readily removed. Herein we demonstrate that N-acyl directing groups are compatible with BBr 3 and lead to C7ÀH borylation of indoles generating useful C7-BPin products on work up (Scheme 1, bottom). Notably,b orylation is compatible with C6 substituted indoles in contrast to the iridiumcatalysed process.F urthermore,a cyld irecting groups also enable ortho C À Hborylation of anilines using BBr 3 ,including of 4-amino indoles which affords C5-BPin indoles.
To guide our selection of appropriate acyl directing groups initially we probed the thermodynamic outcome from indole borylation at C2 and C7 computationally.N otably,t he C7 borylated isomer is calculated to be thermodynamically favoured over the C2 (Scheme 2) isomer in all cases,t his is attributed to (i)the differing degrees of steric clash between R and the C7 À Hand C2 À Hhydrogens (as previously noted); [16] (ii)the differing bond angles in 5and 6-membered boracycles, with the former leading to compressed O-B-C angles relative to the latter (which approaches the ideal for tetrahedral boron, Scheme 2). C7-borylation is also calculated to be the kinetic outcome (for R = t Bu) based on borylation proceeding via acyl!BBr 3 formation, [acyl!BBr 2 ] + formation and then S E Ar (see SI).
While BCl 3 resulted in no borylation of 1a and 2a,w ith BBr 3 C À Bbond formation proceeded with both these indoles, forming products with d 11B % 0ppm (distinct to amide-BBr 3 adducts for which d 11B is ca. À10 ppm). Subsequent addition of pinacol/Et 3 Nl ed to formation of the pinacol boronate esters 3a-5a (Scheme 4). Thed isparity between BCl 3 /B Br 3 also has been observed in N-heterocycle directed borylation and the origin of this has been examined previously. [18] The regioselectivity of borylation using BBr 3 was assessed by NMR spectroscopy in situ and post pinacol protection. This revealed that borylation of 1a led to C7 and C2 borylation products (with 3a and 4a formed in a4:1 ratio). Borylation of 2a with BBr 3 led to more selective C7 borylation, with compound 5a-BBr 2 the major borylated product observed in situ (in ca. 85-90 %conversion, see SI). 5a-BBr 2 and 6a-BBr 2 are more soluble (than benzoyl congeners) enabling in situ reaction monitoring.N otably,w hile minor amounts of 6a-BBr 2 were observed in situ no 6a was observed after pinacol protection. To confirm regioselectivity ZnPh 2 was added to the reaction mixture from 2a/BBr 3 to form predominantly 7 (right, Scheme 4) which has a d 11B of 8.6 ppm indicating af our-coordinate boron centre (in contrast 5a has ab road d 11B at 26 ppm consistent with aw eaker PinB-O pivaloyl interaction). 7 was isolated in 42 %y ield and subsequently crystallised with X-ray diffraction studies confirming the formulation as the C7-borylated regioisomer.T he solid state structure of 7 revealed aB ÀOdistance of 1.610(2) and aO-B-C angle of 104.3(1)8 8 that deviates from that calculated for 5a-BBr 2 presumably due to the different steric demand of BPh 2 vs.B Br 2 .T he complete absence of C3-borylation is consistent with the requirement for boranes more electrophilic than BBr 3 (e.g. borenium salts) to effect intermolecular indole C3 borylation. [3b, 17] Scheme 2. Relative energy of C2 and C7 borylated isomers calculated at the M06-2X/6-311G(d,p)l evel with apolarizable continuum model of DCM.  (hydrogens omitted and ellipsoids at the 50 %p robability level). [24] Thes ubstrate scope was explored next and notably C6 substituted N-pivaloyl-indoles were amenable to C À Hb orylation using BBr 3 in moderate to good yields (e.g., 5c and 5d)( Table 1). The6-methoxy derivative 2e was also aviable substrate,h owever,i tu nderwent competitive ether cleavage with BBr 3 producing two C7-borylated products (5e and 5f) in varying amounts depending on the amount of BBr 3 used. Conditions for one-pot CÀHb orylation, pinacol protection and pivaloyl deprotection simply required the addition of methanol after BPin formation and heating to 60 8 8C. The removal of the pivaloyl group occurs without any observable CÀBcleavage.This enables three steps to be achieved in onepot with no solvent switches with 8a formed in 71 %isolated yield. These conditions were applicable to indoles substituted at C2, C3, C4, C5 and C6 (8g-8l), and containing electron withdrawing and donating groups.T he reaction was performed on a3mmol scale to provide 0.82 go f8g in 86 % yield. However,5 -SMe,5 -NO 2 and 4-CN substituted indoles did not furnish isolable C-BPin products,while attempts with abulkier group at C6, 6-(p-tolyl)-N-pivaloyl-indole,led to C2 borylation dominating (35:65 C7:C2). Compounds 8x are useful in Suzuki-Miyaura cross couplings,a llylations and halogenations, [8] and we note that 8a readily undergoes oxidation with H 2 O 2 /NaOH to form 7-hydroxy-indole.
During substrate screening minor C2ÀBBr 2 borylation (forming 6x-BBr 2 )often was observed. Attempts to form the C7ÀBBr 2 products (5x-BBr 2 )selectively by heating (in sealed tubes so HBr does not leave the system) failed to change the C2:C7 ratio suggesting that C À Hborylation of these indoles is irreversible under these conditions.However,itwas observed that the ratio of C2:C7 BBr 2 products was different to that of the C2:C7 BPin products (with C7-BPin increasing). Furthermore,inanumber of cases the amount of 5x/8x isolated was greater than that possible based on the observed 5x-BBr 2 :6x-BBr 2 ratio (precluding C2-selective protodeborylation during pinacol addition as the only origin of ratio changes). Fore xample,s ubstrate 2k borylates to form a 5k-BBr 2 :6k-BBr 2 ratio of ca. 55:45 (by 1 HNMR spectroscopy), however, post work up 8k was isolated in 75 %y ield. This indicates that addition of pinacol enables C2ÀBp rotodeborylation and C7ÀHborylation. As the BBr 2 products are stable to isomerisation in the presence of HBr this suggests that it is aC À B(OR)Br or C À B(OR) 2 species that is undergoing protodeborylation and leading to more selective C7 À H borylation. [19] While the species undergoing C2!C7 isomerisation on pinacol addition is unknown Lewis/Brønsted acid initiated isomerisation of (RO) 2 B-Aryl has been previously observed. [17] To expand the utility of acyl-directed electrophilic borylation other N-heterocyclic frameworks were explored. However, N-pivaloyl-carbazole did not undergo CÀHb orylation using BBr 3 (even on heating). This is attributed to steric crowding between the two proximal CÀHunits (at C1 and C8, Scheme 5, top left) and the pivaloyl t Bu group that presumably results in large B-O-C-N dihedral angles in the pivaloyl analogue of 10.B enzoyl contains as maller Rg roup (phenyl relative to t Bu), therefore N-benzoyl carbazole, 9,w as combined with BBr 3 .T his did not lead to C À Hb orylation at room temperature,instead the Lewis adduct, 10,was formed which was poorly soluble in DCM facilitating isolation and characterisation (including by X-ray diffraction, Scheme 5).
Heating combinations of 9/BBr 3 led to high yielding C À H borylation at the C1 position. TheC À Hborylated product, 11, could be isolated (and structurally characterised by X-ray diffraction studies) or protected at boron in situ to furnish the pinacol boronate ester 12 in excellent yield (96 %). For 10 and 11,t he C=O( 1.284(3) and 1.296(7) )a nd OÀBd istances (1.485(3) and 1.504(8) )reveal minimal difference,while the O-B-C angle in 11 (109.9(5)8 8)iscomparable to that calculated for 5a-BBr 2 and is close to ideal for four coordinate boron centres.N otably the B À Od istance in 11 is significantly shorter than in 7 indicative of the greater Lewis acidity of the BBr 2 moiety relative to BPh 2 . We next explored the ortho borylation of anilines (Scheme 6). In previous work, borenium mediated electrophilic borylation of anilines proceeded at the para position. [17] Ortho borylated anilines are accessible e.g.,b yd irected lithiation of carbamate functionalised anilines, [20] however, this approach has functional group limitations (e.g., CÀBr). Both N-pivaloyl and N-benzoyl anilines were found to undergo selective ortho borylation using BBr 3 ,w ith no paraborylation observed.
This methodology was applicable to o-, m-a nd psubstituted anilines,f orming 13 c-e in good yield, including for abromo containing derivative (13 d). Directed borylation with BBr 3 also can be applied to tertiary amides with the N-Me derivative, 13 f,f ormed in good yield (83 %). Smith, Chattopadhyay and co-workers have recently developed directed iridium-catalysed ortho-borylation of anilines using B 2 eg 2 (eg = ethylene glycolate). [21] This report is notable,b ut while excellent for NÀHsystems it is low yielding with N-Me substituted anilines (< 25 %), [21] in contrast to the high yielding formation of 13 f using just commercially available DCM solutions of BBr 3 .
N-Bn-indol-4-yl-2,2-dimethylpropanamide, 14,n ext was investigated with it hypothesised that borylation would occur at C5 instead of C3 (the preferred site for S E Ar in indoles) due to the preference for the formation of six membered boracycles over seven. [13c] Functionalisation of the C5ÀHo f indoles is important for accessing pharmaceuticals such as C4-amino-C5-functionalised indoles (e.g.B ranebrutinib). [5,22] Thet hermodynamics of C5 vs.C 3b orylation again was probed by DFT calculations which showed the C5 isomers 15A to be more stable than the C3 isomers 15B (inset, Scheme 7) for both halide and pinacol substituents.C 5 borylation of 14 was achieved in high selectivity with the pinacol boronate ester 16 formed in moderate yield (77 %in situ and 40 %p ost purification). Attempts to monitor the borylation of 14 at the BBr 2 stage were prevented by this intermediate being poorly soluble.F inally,t he ability to perform aC 5/C7 double CÀHb orylation using BBr 3 was demonstrated using 17 (made in one step from 4-aminoindole). This formed 18 selectively post pinacol protection. Notably,i ns itu NMR spectra prior to pinacol addition show that the C3, C7 diborylated compound, 19,was formed as the major product and this does not isomerise on standing. However,a ddition of pinacol induces isomerisation of the C3ÀBm oiety to form the thermodynamically favoured C5-BPin unit and yield the desired C5/C7 product in good conversion (72 %).
In summary, N-pivaloyl is an effective and readily removed directing group enabling C7 borylation of indoles and ortho borylation of anilines simply using commercial solutions of BBr 3 .The process is complementary to borylation with [(amine)BBr 2 ] + and to iridium-catalyzed directed borylation as C6-substituted indoles are tolerated using BBr 3 , while it has complementary functional group tolerance to directed lithiation methods.N otably,i nanumber of cases pinacol induced isomerisation of the initial borylated regioisomer is essential to access the desired products containing C5ÀBa nd C7ÀBu nits.D ue to the simplicity of this process and the many heterocycles containing NÀHgroups we believe acyl-directed borylation with BBr 3 will be applicable to many other systems. Scheme 7. Top, relative energy of C3 and C5 borylated isomers at the M06-2X/6-311G(d,p) level, PCM (DCM). Bottom, borylation of 14 and 17.Insitu yields versus an internals tandard, isolated yields are provided in parentheses. [23] . Scheme 6. Directed ortho electrophilic borylation of NÀHa nd NÀMe anilines. Pivaloyl-directed CÀHborylation proceeds at 20 8 8C(over the course of 3-16 h), whereas as the benzoyl congener requires heating at 60 8 8Cf or 16 h.