Cu(OTf)2‐Mediated Cross‐Coupling of Nitriles and N‐Heterocycles with Arylboronic Acids to Generate Nitrilium and Pyridinium Products**

Abstract Metal‐catalyzed C–N cross‐coupling generally forms C−N bonds by reductive elimination from metal complexes bearing covalent C‐ and N‐ligands. We have identified a Cu‐mediated C–N cross‐coupling that uses a dative N‐ligand in the bond‐forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a CuII complex bearing neutral N‐ligands, such as nitriles or N‐heterocycles. Subsequent generation of a putative CuIII complex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp2) precursors and can be applied to drug synthesis and late‐stage N‐arylation, and the limitations in the methodology are mechanistically evidenced.


Introduction
Tr ansition metal-mediated C-N cross-coupling is an essential synthetic method, used extensively throughout the chemical industry for the synthesis of pharmaceuticals,a gro-chemicals,n atural products,a nd materials. [1][2][3][4][5][6][7][8] Thed evelopment of new or improved processes for C À Nb ond construction remains acontinual inspiration for metal-based reaction development. Despite ab road diversity and subtlety in the mechanism of these methods,t he basic premise of the reaction involves as eries of individual mechanistic steps, e.g.,o xidative addition, transmetalation, and/or deprotonation, to allow access to akey metal complex bearing formally anionic, covalently bound C-and N-ligands (Scheme 1a). This complex undergoes reductive elimination to deliver aneutral product, which is produced regardless of whether the catalysis itself is electroneutral (e.g.,t he Buchwald-Hartwig or Ullmann-Goldberg reactions) or oxidative (e.g.,t he Chan-Lam reaction). [6][7][8][9] In these processes,the N-ligand originates from aprecursor amine or amine-derived substrate bearing at least one functionalizable NÀH, which undergoes deprotonation at some stage in the reaction mechanism to deliver the required anionic N-ligand. This limits the scope of established processes to substrates with at least one N À H. However,itshould be noted that the direct N-arylation of substrates without af unctionalizable site is known. Narylation of nitriles and N-heterocycles has been achieved with or without transition metal activators,for example,using diaryliodonium salts. [10,11] With Cu-promoted processes, [10,11] these are mechanistically ambiguous,w ith no evidence for Scheme 1. a) General approach to cross-coupling. b) This work:c rosscoupling to unconventional substrates.A r= aryl, TM = transition metal.
ametal-centered reductive elimination. These processes have also been rationalized as direct arylation using the increased electrophilicity of the aryl transfer reagent via Lewis acid activation. [12] More specifically,w hile Cu I has been shown to slightly accelerate aryl transfer with diaryliodoniums,t hese processes also proceed effectively without Cu I , [13,14] consistent with observed general reactivity of this class of reagents [15] and related reactive aryl transfer reagents,such as aryldiazonium salts. [16] Here,w er eport the discovery,m echanistic rationale, example scope,a nd limitations of aC u-mediated C-N crosscoupling method that promotes reductive elimination to neutral N-ligands,s uch as nitriles and N-heterocycles generating reactive cationic products (Scheme 1b).

Results and Discussion
During investigations to rationalize the reactivity of Cu II sources in standard Chan-Lam reactions,t he amide product 3a was identified in good yield when the reaction of arylboronic acid 1 with aniline was attempted with Cu(OTf) 2 in MeCN as solvent (Scheme 2a). As imilar observation was made by Sanford during studies of fluorodeboronation, which also used stoichiometric Cu(OTf) 2 (4 equiv) in MeCN (Scheme 2b). [17] We were intrigued by this observation since hydrolysis of MeCN to acetamide followed by Chan-Lamtype N-arylation seemed unlikely-we have previously attempted Chan-Lam arylations of amides using Cu(OTf) 2 and found this to be problematic (vide infra). Consequently,w e sought to understand the origin of this coupling process.
Control experiments indicated the possibility of an alternative pathway.T he Chan-Lam arylation of acetamide 6 using Cu(OTf) 2 in PhMe does not provide the N-aryl product. Instead, the products of aryl-boronic acid oxidation and protodeboronation were observed and represented the almost complete mass balance (Scheme 3a)-protodeboronation was also noted as an issue in Sanfordsstudy [17] and is ac ommon problem for Cu-mediated reactions of organoborons. [18,19] Separate experiments (Table S1) indicated that the same conditions did not lead to nitrile hydrolysis. [20] The competition reaction of 1 with acetamide and D 3 CCN in the presence of Cu(OTf) 2 led to the deuterated acetamide product 3b exclusively,f urther supporting the absence of aC han-Lam pathway and indicating selectivity for nitrile (Scheme 3b).
To rationalize these initial observations,w ec onsidered areaction pathway that proceeded via formation of anitrilium intermediate formed by Cu-mediated N-arylation of the nitrile.N -arylation of nitriles is known using highly reactive aryl transfer agents,s uch as iodonium and diazonium salts; [10,16] however,o xidative coupling of nitriles with arylboronic acids is unknown. Accordingly,wesought to establish if an oxidative coupling pathway was operational.
Tr eatment of Cu(OTf) 2 with H 2 Oi nM eCN leads to as table and isolable complex Cu II (OTf) 2 (H 2 O) 2 (MeCN) 2 (10 a,S cheme 3c). [21] Heating this complex with 1 lead to the observed acetamide 3a,w hich we propose proceeds through nitrilium 11 a,s uggesting possible formation and involvement of 10 a in the reaction. [22] Nitrilium ions are highly reactive electrophiles capable of av ariety of bond forming processes with nucleophiles; [23] however, extensive experimentation to intercept the proposed nitrilium 11 a were unsuccessful and afforded amixture of amide and returned starting material (Tables S2 and S3). We therefore attributed amide formation to hydrolysis of the nitrilium with H 2 Op resent in the reaction mixture,a rising either from boroxine formation from 1 or Cu-bound H 2 Oi n 10 a-H 2 Oc ould not be excluded in preparation of stoichiometric Cu(OTf) 2 nitrile complexes as noted above.
Independent preparation of stable nitrilium 11 c [24] and treatment with 10 a led to instantaneous hydrolysis,h igh-  lighting the lability of Cu-bound H 2 O(Scheme 3d). To probe the origin of H 2 Oi nt he acetamide product, we undertook labelling experiments.A ddition of H 2 18 Ot ot he reaction of 10 a with 1 led to 41 % 18 Oi ncorporation in the product 3c, consistent with the 16 O: 18 Os toichiometry (Scheme 3e). Preparation of 18 O-labelled complex 10 b was successful; however, the 18 Oincorporation could not be quantified due to lability of the dative ligands.Indeed, despite obtaining crystal structure data of 10 a and 10 b (identical), HRMS analyses were uniformly unsuccessful. Use of 10 b in the absence of additional H 2 Ogave 3c in comparable yield to the reaction of 10 a and with 60 % 18 Oi ncorporation (Scheme 3f).
Theinability to trap the nitrilium by any nucleophile other than H 2 Osuggests that nitrilium quenching may be occurring from H 2 Oi ns olution, aC ua quo species (e.g., 10 a/10 b), or from aC u I complex liberated after reductive elimination (e.g., 13,Scheme 3f).
To further substantiate this nitrilium proposal, HRMS analysis of reaction mixtures identified as eries of mass ions that allowed the following mechanism to be proposed (Scheme 4). [25] We propose that Cu(OTf) 2 [26][27][28] allowing formation of the nitrilium product 11 (11 b found). Mass ions consistent with the proposed Cu I aquo complex 18 a were detected (18 b), consistent with the quenching proposal outlined in Scheme 3f.S toichiometric Cu(OTf) 2 was exclusively effective-other Cu sources failed to promote the reaction (Table S7). Extensive investigation failed to allow this process to operate with catalytic Cu(OTf) 2 -the addition of terminal oxidants led to issues of organoboron oxidation and rendering Cu turnover (Scheme 4, dotted line) irrelevant (Table S9). Thes ame turnover issues in systems using Cu-(OTf) 2 and CuOTf have been observed in C-F bond formation by Sanford [17] and Hartwig, [29] respectively,w here 3-4 equivalents of Cu were necessary for reaction efficiency. This problem remains unresolved for many Cu(OTf) 2 -based processes. [30] Thep roposed nitrilium ions were observable by HRMS; however, the inability to intercept the proposed nitrilium with other nucleophiles was unsatisfactory.Specifically,this invites further scrutiny of the proposed key CÀNbond forming event in Scheme 4-the potential for an on-metal hydrolysis cannot be excluded. We therefore sought to demonstrate the C À N bond forming process using as ystem that would allow unambiguous identification C À Nb ond formation produced from reductive elimination to aneutral N-ligand on Cu III .
Complex 19 is similar to the nitrile complex 10 a;however, this can be prepared without aquo ligands.U nder the same reaction conditions used in Scheme 3c, 19 leads to as imilar CÀNb ond formation giving N-aryl pyridinium 20 and in similar yield to the nitrile process. 20 was characterized unambiguously by spectroscopy and X-ray,p roviding strong support for C-N cross-coupling via Cu III .W ep ropose this reaction to follow as imilar course to that proposed in Scheme 4. Single electron pathways via oxidation of DMAP by Cu II were proposed to be unlikely based on oxidation potentials and EPR analysis (vide infra). [33][34][35] Despite evidence for the feasibility of reductive elimination from (aryl)Cu III complexes yielding N-aryl ammonium products, [36,37] the equivalent N(sp 3 )cross-coupling under the conditions reported here did not afford the desired C-N(sp 3 ) bond. We attribute this to competing amine oxidation by Cu II ; [38] this was substantiated by EPR studies,which showed quenching of Cu II and, in the case of N-methylpyrrolidine, aradical species could be observed (Scheme 6a). Addition of tertiary amines to the optimized DMAP N-arylation process had variable effects on the observed yield (Scheme 6b). For example,P hNMe 2 almost completely reduced Cu II and lowered yield of 21 by approximately half;h owever, nbutylaziridine reduced approx. 25 %ofCu II yet had no impact on the yield of 21.L ittle reduction of Cu II by TMEDAwas observed by EPR and the arylation reaction was instead impaired by formation of as eries of novel but unreactive bidentate complexes (Scheme S12). As expected, DMAP did not significantly reduce Cu II .
Moreover,i nt he presence of unsubstituted anilines,a n alternative oxidative coupling pathway becomes evident via formation of 1,2-diarylhydrazines (22)a nd azobenzenes (23) (Scheme 6c). This is clearly mechanistically related to previously reported Cu-mediated N-N coupling reactions. [44,45] Consistent with these previous reports,our EPR data suggests that these processes proceed via single electron oxidation of the aniline by Cu II ;h owever,i mportantly,t he resulting aminium radical does not appear to be free in solution and attempts to intercept these species were universally unsuccessful (Table S6). In contrast to ap reviously proposed mechanism, [44] our data suggests formation of the NÀNb ond at the metal or within the solvent cage.This would deliver the symmetrical hydrazine product, consistent with previous observations. [44,45] As an adjunct to the main work described here,a dditional control experiments have shown facile oxidation of the hydrazine to the azobenzene by Cu(OTf) 2 aligning with the experimental data observed across these separate studies (Scheme S14). [44,45] Following optimization (Tables S7-S11), ageneral process was developed for the coupling of arylboronic acids with nitriles and N-heterocycles-a selection of products is provided in Scheme 7( for additional substrates see Scheme S15). [46] Thep rocess tolerates av ariety of functional groups on both the nitrile and arylboronic acid, with standard structural and electronic variations examined in this example scope.The nitrilium process is an unusual amidation protocol (essentially an aryl Ritter reaction) providing anew approach to this ubiquitous motif;however, the heterocycle N-arylation process allows access to products that cannot be made easily using any established method, providing novel opportunities for synthetic design. In general, the scope of the boronic acid was very good for arylboronic acids,w ith some lower yields observed using heteroaromatic species consistent with established limitations with these substrates. [47] Alkylboronic acids were tolerated only in the N-heterocycle process (e.g., product 45); no desired products were observed in the equivalent nitrilium reactions.F or the nitrilium process,t he C-N cross-coupling could be achieved using the nitrile as solvent where practical (e.g., for MeCN,E tCN), otherwise PhMe was the preferred medium for both the nitrilium and Nheterocycle processes.W hile generally effective,s olubility issues can present with certain arylboronic acids in PhMe resulting in lower yields (e.g., [29][30][31]. With regards the Nheterocycle process,t he reaction was broadly tolerant to the nature of the heterocycle,a lthough higher yields were obtained with more electron-rich compounds,w hich may be expected based on the oxidative coupling process.The issue of lower yields with substrates bearing ortho-substitution was replicated (e.g., 27 and 40)a nd is again consistent with observations in Cu-mediated oxidative coupling processes. [9] As discussed above for the nitrile process,s toichiometric Cu(OTf) 2 was also needed for the heterocycleprocess,which perhaps offers some explanation for the lack of observable reinsertion into the N-aryl pyridinium products.A dditional demonstrations of utility are provided in Scheme 7c-g. TheC-Ncoupling process can be applied to the N-arylation of nonaryl N(sp 2 )including the common organic base DBUaswell as the Lewis base organocatalyst (À)-tetramisole to afford compounds 52 and 53,r espectively (Schemes 7c and d).
Theability to induce direct N-arylation of N-heterocycles allows asignificantly shorter route to non-symmetrical NHCs by N-arylation of N-aryl imidazoles such as 54,w hich proceeds via the expected complex 55 to deliver imidazolium salt 56 (Scheme 7e;see also 50 and 51 in Scheme 7b for alkyl/ aryl imidazolium). [11] Lastly,t he process can be used in synthesis,f or example using the nitrilium process to access pharmaceutically relevant amides,s uch as the Tolvaptan intermediate 57 (Scheme 7f)a nd for late-stage functionalization, for example N-arylation of the agrochemical Pyriproxyfen, giving product 58 (Scheme 7g).

Conclusion
In summary,t he data provided establishes af ramework for oxidative C-N cross-coupling of arylboronic acids with neutral N-ligands.I mportantly,m echanistic data supports [ a] vs. Fc +/0 . [39] [b] vs. SCE. [40] [c] vs. SCE. [41] [d] vs. SCE. [42] [e] vs. SCE. [43] [f]Determined by 1 HNMR analysis. Fc = ferrocene, SCE = saturated calomel electrode. aC u III -based process and is distinct from Lewis acid-assisted N-arylations using reactive aryl transfer electrophiles (e.g., iodoniums). This expands the scope of oxidative coupling, allowing access to new products.The broader implications are that, assuming specific metal-centered mechanistic events can be appropriately controlled, neutral N-ligands may be effective partners for cross-coupling more generally within transition metal catalysis,p roviding new opportunities for reaction design. [48]