Radical C−N Borylation of Aromatic Amines Enabled by a Pyrylium Reagent

Abstract Herein, we report a radical borylation of aromatic amines through a homolytic C(sp2)−N bond cleavage. This method capitalizes on a simple and mild activation via a pyrylium reagent (ScPyry‐OTf) thus priming the amino group for reactivity. The combination of terpyridine and a diboron reagent triggers a radical reaction which cleaves the C(sp2)−N bond and forges a new C(sp2)−B bond. The unique non‐planar structure of the pyridinium intermediate, provides the necessary driving force for the aryl radical formation. The method permits borylation of a wide variety of aromatic amines indistinctively of the electronic environment.

Primary aromatic amines represent ac lass of relevant functionalities present in aw idev ariety of contexts-from natural sourcessuch as DNA or vitamins to synthetic molecules as part of their structure. [1] Despite their potential as anchor points for furtherm anipulation, direct functionalization of primary amino groups in (hetero)aromatic compounds has been at remendous challenge in catalysis [2] due to high energy of the C(sp 2 )À NH 2 bonds (BDE of C 6 H 5 -NH 2 :1 02.6 AE 1.0 kcal mol À1 ), [3] coordination of the lone pair of the nitrogen to metalc atalysts, and acid-base interactions with polarf unctionalities. To circumvent such drawbacks, approaches to cleave CÀNb onds have relied on the preactivation of the amino group,c onverting them into virtuousl eaving groups, for example by diazotization, [4] polyalkylation [5] and others [6] (Figure1A). However,d espite the wealth of reportsi nt his area, severalc hallenges remain. For example, diazotization reactions require the use of strong oxidants and acids,t og enerate the correspondingd iazonium salts, which are thermally unstable and explosive ( Figure 1A, path a). [4] The use of an excess of toxic alkylating reagents restrictst he functional group tolerancei nc omplex settings for polyalkylation strategies ( Figure 1A, path b). [5] Although limited in functional group tolerance and scope, approaches based on transition metals have recently appeared, enabling the cleavage and functionalization of aniline derivatives (Figure 1, path c). [6] Seminal work by Katritzky demonstrated the possibility of converting amino groups into good leavinggroups by condensation with ap yrylium salt (Figure1A, path d). [7] This strategy is characterized by the remarkable stability of the pyridinium salt intermediates,h igh selectivity for the amino groups and benefits from the high practicality and simplicity.Indeed, pyridinium salts have recently been employed to unlock SET processes based on transition-metal or photoredox catalysis, and have been shown to be ap owerfult ool for constructingamyriad of chemicalb onds. [8][9][10][11] However,t he wealth of literature in this area has been focusedo nt he generation of alkyl radicals (Figure 1B,t op). Yet, methods which capitalizeo np yridinium salts to generate aryl radicals through SET are largely underdeveloped. ( Figure 1B,b ottom), [12] mainly due to the disfavored thermodynamics for the aryl radicalf ormation. Althoughe xamples of this approachh ave been reported in the past (3 exam-   ples), [12] pyrolysis of the reagents is required (ca. 200 8C), obtaining low yields for very specific substrates, thus relegating these approaches to proof of concept examples with limited synthetic applicability.B ased on our recent interest on pyrylium reagents, [13] we set out to explore this approachinthe context of radicalb orylations using diboron reagents, as they have been shown to be excellent radical acceptors. [14][15][16][17] Herein, we report ap rotocol for the borylation of (hetero)aromatic amines throughaS ET process, enabled by the use of atethered pyrylium salt ( Sc Pyry-OTf). [18] The structure of this pyrylium reagent provedu nique in assistingt he cleavage of the C(sp 2 )ÀNb ond, af eature beyondt he capabilities of other common pyrylium activators. Moreover,t he choice of the solventw as also crucial to achieve high yields of the correspondingo rganoboron compounds.T he protocol has been demonstrated to be scalable and tolerant to aw ide varietyo ffunctionalities.
Based on recent reports on the borylationo fa lkyl pyrydinium salts, [11] we started our investigationso nt he borylation of pyridinium salts using B 2 cat 2 (bis(catecholato)diboron). After screening of the reactionp arameters, terpyridine (terpy) was identified as the Lewis-base of choice, performing the reaction at 130 8C, using i Pr 2 NC(O)Me as solvent. [19] Interestingly,u nder the optimized conditions, none of the classical pyridiniums alts commonlye mployed provede fficient in the borylation reaction (Table 1A, 1-3). Then, we turned our attentiont othe teth-ered pyrylium reagent initially reported by Katritzky in the context of alkyl amine activation. [20] It was the pyridinium 4-OTf that delivered excellent yields of CÀBb ond formation 5 (Table 1A,e ntry 1, 82 %). When the counterion in 4 was replaced by BF 4 (4-BF 4 ), al ower yield was obtained (57 %). The effect of the solventw as also remarkable: whereas DMFa nd DMAc failed to deliver good yields of product (entries 2a nd 3), the use of am ore sterically hindered amide sucha s i Pr 2 NC(O)Me provedt ob ec rucial for obtaining high yields. Althoughi nt he absence of Lewis-base the reactiona fforded only 10 %o f5 (entry 4), the use of bipyridine derivatives did not reacht he levels of reactivity of terpy (entries 5a nd 6). Althoughb orylation strategies based on B 2 pin 2 and aromatic Lewis bases have recently appeared in the literature, [16b] the use of this diboron reagent resulted in no conversion of 4-OTf (entry 7). Heating the reaction further had no effect on the reactivity (entry 8) and 120 8Cp roved insufficientt oo btain high yields of 5 (entry 9). Isolation of 5 proceeded through the conversion of the sensitive ArÀB(cat) into the corresponding ArÀ Bpin reagent, by as imple quenchw ith pinacol andE t 3 N. However,aq uenching protocol based on MIDA resulted in slightly higher yields and afforded am ore robust organoboron compound (6). [21,22] Of note, the synthesis of the Sc Pyry-OTf ( 7) could be conducted similarly to the parent2 ,4,6-triphenylpyrylium reagent. [20a] Commercially available tetralone ($0.26 g À1 ), [23] condenses with benzaldehyde,w hich upon addition of TfOH, pure 7 precipitates as ab right-yellow solid. The protocolc ould be scaled-up to > 30 grams in one run, without any complicated setup (Table 1B).
With the optimal protocol in hand, we explored the scope of this new borylation strategy.I ti sw orth notingt hat condensation of aromatic amines with 7 proceeded smoothly across the whole range of substrates w ith an average yield of > 85 %. [19] As shown in Table 2A,t he borylation protocol bodedw ell with anilines substituted at the meta-( 33)a nd para-positions (34, 35). The presence of electron-deficient fluorinated moieties such as CF 3 (36), OCF 3 (37)o rF( 38, 39)d id not affect the reactivity and provided good yields of product. The reaction could also be performed in ao ne-pot fashion as exemplified by 39;albeit in moderate yield.
Electron-releasing substituents in the aniline were also amenable,a se xemplified by the presence of thioethers (40), tertiary amines (41), amides (42)a nd ethers (43-45). Notably,n o Claisen rearrangementb y-products were observed for product 44.B romo-( 46)a nd chloroanilines (47, 48)w ere also compatible under the reactionc onditions, thus providing boronic acid derivatives bearing orthogonal handles for further derivatization. Boronic acid derivatives of p-extended anilines such as naphthyl (49), fluorenyl (50)o ra nthracenyl (51)c ould also be synthesized in high yields. The presence of oxygen-(52)o r sulfur-containing heterocycles( 53)d id not affect the formation of the CÀBb ond. Anilines bearing aliphatic esters (54)o ra benzoate motif, such as the anesthetic drug benzocaine, could also be borylated (55)i ng ood yields. Finally,h eterocyclic Ncontaining compounds such as pyridine (56)a nd indole (57) were amenable for borylationu nder the optimal conditions. As depicted in Ta ble 2B,b oth the condensation and the boryla- [a] 1-4 (0.1 mmol), B 2 cat 2 (0.3 mmol), terpy (20 mol %), i Pr 2 NC(O)Me (0.5 mL) at 130 8Cfor 24 h; then pinacol(0.6 mmol) and Et 3 N( 0.5 mL) were added and stirred for additional 2h at 25 8C. At this point, we set out to explore the remarkable effects for both the solventa nd the structure of the pyrylium. As shown in Ta ble 1, when 3 was subjected to the optimized conditions using DMAc,n ob orylation was obtained and > 90 %o f startingp yridinium salt 3 was recovered (Figure 2A). When i Pr 2 NC(O)Me was used instead, am inimal yield of 5 waso btained (12 %). However,t he conversion was low and the reaction wasp lagued with several unidentified by-products. In stark contrast, when 4-OTf was subjected to the borylation conditions in DMAc, acceptable yields of borylation were obtained (49 %, Table 1, entries 3). Analysis of the reaction mixture revealed the formation of am ajor by-product, which was identified as the reduced compound 59. [24] Gratifyingly,w hen the solventw as replaced by the optimal i Pr 2 NC(O)Me, formation of by-product 59 was suppressed (< 5%), and excellent yields of 5 were obtained (82 %, Table 1, entry 1). As suggested by Katritzky's report,[12c] 59 possibly resulted from HATf rom solventmolecules. [24] Motivated by the striking differences in reactivity between 3 and 4-OTf,w ei nitially interrogated their electronic properties. Cyclic voltammetry experiments conducted in both compoundsr evealed ar eversibleb ehavior and as imilarf irst reduction potential( E red (3) = À1.39 Vv s. Fc/Fc + in DMF, E red (4-OTf) = À1.30 Vv s. Fc/Fc + in DMF). [19] This result suggests that the oxidation capabilities of both pyridinium salts are similar, and reduction through SET processes should be equally facile using the terpy/B 2 cat 2 system. [11b, 25] However,X -ray analysiso f the crystal structure for 3 and 4-BF 4 was far more revealing. The pyridine moiety in 3 is planar,w ith almost no torsion observed in the pyridinium ring ( Figure 3A,l eft). On the other Table 2. Scope of the radical borylation of (hetero)aromatic amines enabled by the pyrylium salt 7. [a] [a] Reactionc onditions:S tep 1: aromatic amine (1.05-1.50 equiv), 7 (1.0 equiv), NaOPiv (0-1.0 equiv) in EtOH (0.2 m)a t8 58C; Step 2: pyridinium salt (0.25mmol), B 2 cat 2 (0.75mmol), terpyridine( 20 mol%)i n   Chem.E ur.J. 2020, 26,3738 -3743 www.chemeurj.org 2020 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim hand, the ethane-bridged moiety in 4-BF 4 ,r enders am uch more constraint environmentand results in aheavilytensioned aromatic pyridinium motif, [20c] as judged by the remarkable 11.28, À174.48 and 5.88 of torsion for the three different angles explored ( Figure 3A,r ight). Based on all the experimental data, ap utative mechanism for this transformation is depicted in Figure 3B.I na ni nitiation phase, the combination of B 2 cat 2 , terpy and amide solventa ffords the highly reducing int-2 radical species, as suggested in previous Lewis-base-promoted borylation strategies ( Figure 3B). [11a] Int-2 would then engage in the reduction of the pyridiniumm oiety to generate int-1. The high degree of distortion of the aromatic ring in 4-OTf led us to postulate that int-1 would be highly unstable, and ho-molyticC ÀNc leavage occurs at high temperatures. We speculate that the restoration of the planarity renders ah igher degree of conjugation and aromaticity for the leavingp yridine 61 [26] and providest he necessary driving force for the homolysiso ft he CÀNb ond. As aforementioned, when DMAc was used competing formation of 59 occurs. Yet, the use of i Pr 2 NC(O)Me circumventsH AT,a nd aryl radical formation through CÀNs cission is largely operative. Although the nature of this difference in reactivity is still under investigation, we propose that the success of this solventh inges on providing an adequate balance for as uccessful radical chain towards productiver adicalb orylation. The aryl radicalf ormed, is then rapidly trapped by B 2 cat 2 ,d elivering the desired CÀBb ond, with concomitantg eneration of the reducing solvent-ligated boron radical int-2. [16g] The involvement of radical intermediates in the reactionw as verifiedb yc ontinuous wave (CW) electron paramagnetic resonance (EPR) experiments. Sample 1( Figure 4A-1) was extracted from the reaction mixture of 4-OTf with B 2 cat 2 and terpy in DMAc. According to the proposed mechanism ( Figure 3B), two long-lived radical intermediates can occur: the solvent-ligated boron radical int-2 as well as int-1 formed from the SET reduction of 4-OTf. Int-2 would be boron-centeredw hereas the latter is expected to be carbon centered. The dominantb oron isotope 11 B( 80 %) has nuclear spin I = 3/2, potentially giving rise to aq uartet hyperfine pattern in the EPR. Carbon, on the other hand, has no dominant isotope with nuclear spin ( 13 C with I = 1/2 has 1.1 %n aturala bundance). Therefore, no strong hyperfine interaction (HFI) pattern is expected for int-1.T he two proposed radical intermediates were separately generated. The int-2 was expected in am ixture of B 2 cat 2 with terpy in DMAc, that is, the reaction mixture without 4-OTf ( Figure 4A-2). Indeed, the EPR spectrums howed well resolved hyperfine lines but more than am ereq uartet. Possibly,a lso 1 Ha nd/or 14 Nh yperfine interactions contribute to this multiline (12) pattern. In any case, sample 1s howeda nE PR spectrum virtually identicalt ot hat of the sample 2. In contrast, sample 3w hich was generated by direct reduction of 4-OTf with TDAE, showedastrong EPR signal with weak HFI features containing very small splitting not resembling the EPR spectrum of sample 1. It therefore can be concluded that the reactionm ixture is dominated by the species int-2 generated from sample 2, which is consistentw ith int-2.I na ddition, performing the borylation reactioni nt he presence of 1,1-diphenyl-ethener esulted in the formation of 5 (53 %) and the radical addition product 60 (22 %) ( Figure 4B). This result offersa dditional evidencef or the homolytic cleavageo ft he CÀNb ond and the generation of aryl radicals in solution.
In summary,w eh ave developed an ovel strategy for the CÀ Nb orylation of aromatic amines, capitalizing on the mild and selective condensation of Sc Pyry-OTf (7)w ith amino groups. Additionally,t he rationally designed solventp ermits the smooth generation of highly reactive aryl radicals to engage in aC ÀBb ond forming event. The borylation protocol is demonstratedt ob es calablea nd is tolerant to various functional groups.T he ability of pyridinium salts derived from Sc Pyry-OTf (7)t os uccessfully generate aryl radicals, represents an ew approach in the area of CÀNf unctionalization.R esearch exploiting Sc Pyry-OTf (7)f or other applicationsi no rganic synthesis is currently ongoing in our research laboratories.