Palladium ( II )-catalysed ortho-arylation of N-benzylpiperidines †

Cross-coupling reactions of aromatic compounds constitute one of the most versatile entries to compounds possessing a biaryl motif. Such transformations are usually performed by traditional cross coupling reactions of organohalides or pseudohalides with organometallic reagents. However, prefunctionalisation of substrates to form specific organohalides for cross coupling can be difficult and this has accordingly led many research groups to develop more direct routes to biaryl scaffolds. Over the last decade, a variety of direct, chelationassisted, C–H activation on arenes, mainly via [Pd], [Rh] and [Ru] catalysis, has been developed using a wide range of directing groups (DGs) such as amides, imines, oximes, ketones and other N-heterocycles. Expanding the scope of DGs to include simple amine derivatives that are commonly found in natural products and pharmaceutical compounds is highly desirable. In 2006, Daugulis and co-workers reported an ortho arylation of unsubstituted benzylamines directed by the free amine with iodobenzene under Pd catalysis. Meanwhile, Shi et al. demonstrated that N,N-di-alkyl amine is also an effective directing group for ortho-olefination and -carbonylation. More recently, Zhang and co-workers developed a Pd-catalysed orthoarylation of N,N-dimethylbenzylamines with iodobenzene (Fig. 1). Inspired by these findings we envisaged that saturated N-containing heterocycles could also serve as efficient DGs for C(sp)–H arylation; this would expand the range of DGs in the field (Fig. 1) and the new chemistry could be applied directly to the construction of biologically relevant motifs such as those present, for example, in known Bcl-2 antagonists, g-secretase modulators and 5-HT7-antagonists 13 (Fig. 2). Herein we report a Pd-catalysed ortho-arylation of a range of benzylic heterocycles with arylboronic acid pinacol esters leading directly to the biaryl product in one step. Initially we focused on the piperidine moiety as a potentially useful directing group for C(sp)–H activation/arylation. Inspired by Yu’s pioneering work, a preliminary experiment was conducted on the model substrate 1-(2-methylbenzyl)piperidine 1a and phenylboronic acid pinacol ester 2a in the presence of catalytic Pd(OAc)2, and Ag2CO3, Na2CO3 and 1,4-benzoquinone at 100 1C (Table 1). Encouragingly, ortho-arylated product 3a was observed in 55% NMR yield (entry 1). Fig. 1 Ortho-Arylation using benzylic heterocycles as directing groups.

tion to generate the desired biaryl products is reported. This methodology is efficient and applicable to a wide range of functionalised Ar-BPin and benzylic heterocycles, allowing the direct synthesis of important biaryl motifs in modest to good yield.
Cross-coupling reactions of aromatic compounds constitute one of the most versatile entries to compounds possessing a biaryl motif. 1 Such transformations are usually performed by traditional cross coupling reactions of organohalides or pseudohalides with organometallic reagents. 2 However, prefunctionalisation of substrates to form specific organohalides for cross coupling can be difficult and this has accordingly led many research groups to develop more direct routes to biaryl scaffolds. 3 Over the last decade, a variety of direct, chelationassisted, C-H activation on arenes, mainly via [Pd], 4 [Rh] 5 and [Ru] 6 catalysis, has been developed using a wide range of directing groups (DGs) such as amides, imines, oximes, ketones and other N-heterocycles. Expanding the scope of DGs to include simple amine derivatives that are commonly found in natural products and pharmaceutical compounds is highly desirable. In 2006, Daugulis and co-workers reported an ortho arylation of unsubstituted benzylamines directed by the free amine with iodobenzene under Pd catalysis. 7 Meanwhile, Shi et al. demonstrated that N,N-di-alkyl amine is also an effective directing group for ortho-olefination 8 and -carbonylation. 9 More recently, Zhang and co-workers 10a developed a Pd-catalysed orthoarylation of N,N-dimethylbenzylamines with iodobenzene ( Fig. 1). 10 Inspired by these findings we envisaged that saturated N-containing heterocycles could also serve as efficient DGs for C(sp 2 )-H arylation; this would expand the range of DGs in the field (Fig. 1) and the new chemistry could be applied directly to the construction of biologically relevant motifs such as those present, for example, in known Bcl-2 antagonists, 11 g-secretase modulators 12 and 5-HT 7 -antagonists 13 (Fig. 2). Herein we report a Pd II -catalysed ortho-arylation of a range of benzylic heterocycles with arylboronic acid pinacol esters leading directly to the biaryl product in one step.
Initially we focused on the piperidine moiety as a potentially useful directing group for C(sp 2 )-H activation/arylation. Inspired by Yu's pioneering work, 14 a preliminary experiment was conducted on the model substrate 1-(2-methylbenzyl)piperidine 1a and phenylboronic acid pinacol ester 2a in the presence of catalytic Pd(OAc) 2 , and Ag 2 CO 3 , Na 2 CO 3 and 1,4-benzoquinone at 100 1C (Table 1). Encouragingly, ortho-arylated product 3a was observed in 55% NMR yield (entry 1).  Further optimisation was then carried out, starting with an investigation of the performance of different bases. Potassium bases, KF and K 2 HPO 4 , resulted in a reduced yield (entries 2 & 3). Pleasingly, however, NaHCO 3 was found to be optimal for this transformation; full conversion of 1a to the arylated product 3a was observed after 18 hours (entry 4). Replacement of Pd(OAc) 2 with other Pd sources such as PdCl 2 , PdCl 2 (PPh 3 ) 2 and PdCl 2 (CH 3 CN) 2 did not result in the formation of any arylated product (entry 5). Decreasing the catalyst loading to 5 mol% resulted in a decrease in yield and therefore, 10 mol% of catalyst was deemed necessary (entry 6). Other oxidants such as Cu(OAc) 2 and CuF 2 , were found to give inferior yields (entries 7 & 8) and although AgOAc was found to perform reasonably well (entry 10), Ag 2 CO 3 proved optimal (entry 9). 1,4-Benzoquinone was also essential as a promoter; in its absence no reaction was observed in agreement with literature findings relating to its importance in the reductive elimination step. 14b,15 A decline in yield was also observed without the addition of H 2 O and DMSO (see the ESI †). t-Amyl alcohol was found to be the most suitable solvent for this transformation, followed by 1,4-dioxane and MeCN. Other aryl boronic acid derivatives were investigated, but arylboronic acid pinacol esters, were by far the best in this reaction (see the ESI †).
After attaining the optimised conditions, the scope of this methodology was assessed using different functionalized arylboronic acid pinacol esters (Ar-BPins) with 1-(2-methylbenzyl)piperidine (Scheme 1). Generally, a wide range of para-substituted Ar-BPin substrates was tolerated and the corresponding biaryl products were obtained in modest 16 to good yields. Ar-BPins substituted with functional groups, such as cyano, nitro and fluorine were suitable substrates under these reaction conditions affording the desired products in respectable yields. Chlorine substituents on Ar-BPin were also well-tolerated, giving rise to biaryl products poised for further transformations. In the case of ortho-substituted Ar-BPin substrates, the reaction worked well using the ester 2l affording the biaryl product 3l in a yield of 76% but, unfortunately, poor conversions were obtained for other substituents such as fluoro (3m) and methyl (3n). This methodology was also amenable to meta-substituted and 3,5-disubstituted Ar-Bpin derivatives, giving rise to the corresponding products in 43-77% yield. In agreement with related studies 14f heteroarylboronates that contained pyridine-(3u), thiophene-(3v) were unreactive under these conditions. Similarly, under the optimised conditions attempted ortho alkylation using cyclohexylboronic acid pinacol ester failed to yield any desired product.
In line with previous studies, 14 we propose this C-H activation cross-coupling reaction proceeds via a Pd(II)/Pd(0) catalytic cycle (Fig. 3). The palladium species activates the ortho C-H of 1, forming a 5-membered palladacycle intermediate A. Subsequently, addition of base is necessary for the transmetallation of Ar-Bpin to proceed to generate intermediate B. 1,4-benzoquinone then facilitates reductive elimination of the biaryl product 3 forming the Pd(0) species. 14b,15 Reoxidation of Pd(0) by an oxidant, in this case Ag 2 CO 3 , is necessary for regeneration of the active Pd(II) species for further turnovers.
In conclusion, we have demonstrated that a range of saturated nitrogen-containing heterocycles attached via the nitrogen atom to benzylic substrates serve as effective directing groups for palladium catalysed C(sp 2 )-H activation/arylation. Under palladium catalysis, the coupling of a range of arylboronic acid pinocol esters to the ortho position of N-benzylated pyrrolidines, piperidines, morpholine and piperazine substrates giving direct access, under relatively mild reaction conditions, to important biaryls motifs, was demonstrated. Investigations to develop the related direct ortho alkylation reaction are ongoing and our findings will be reported in due course.
The authors acknowledge the University of Oxford and the Agency of Science, Technology and Research (A*STAR) Singapore for a predoctoral fellowship. We also thank Dr Jayasree Seayad and Dr Vaibhav Mehta for their invaluable suggestions.