Tuning Reactivity in Pd-catalysed C(sp 3 )-H Arylations via Directing Group Modifications and Solvent Selection

. The palladium-catalysed sp 3 C-H arylation of a selection of saturated amine scaffolds was investigated using substituted picolinamide directing groups. On the bornylamine scaffold, highly selective monoarylation takes place using unsubstituted picolinamide or 3-methylpicolinamide, whereas a double C-H arylation occurs with other substituents present, becoming a significant product with 3-trifluoromethylpicolinamide. DFT calculations were used to help rationalise the effect of directing groups on the C-H palladation steps which were found experimentally to be irreversible. The substituted picolinamide directing groups were also examined on acyclic amine scaffolds and in many cases increased yields and selectivity could be obtained using methylpicolinamides. For a selection of other amine scaffolds, the yield of C-H arylation could be improved significantly using 3-methylpicolinamide as the directing group and/or 3-methylpentan-3-ol as the solvent.


Introduction
Palladium-mediated C-H functionalisation reactions provide a powerful approach for selective transformation of individual C-H bonds on sp 3 -rich scaffolds. [1] Given the increasing importance of these compounds in medicinal chemistry, [2] the ability to selectively introduce novel functionality at particular locations in the molecular framework could provide a highly useful tool in drug development. Building upon pioneering work on the use of stoichiometric quantities of palladium(II) salts to mediate selective reactions of C-H bonds in sp 3 -rich scaffolds, [3] catalytic reactions employing a directing group to coordinate to the palladium(II) catalyst to control the site of reaction have proved to be especially effective. [4][5] In most cases, the directing group incorporates one or more heteroatoms which can act as ligands for the palladium and deliver it to an adjacent C-H bond. Nitrogen-rich scaffolds are of particular importance in a wide range of chemistry-related fields, so nitrogen-linked directing groups have been the focus of considerable attention. [5] In 2005 Daugulis introduced the 8aminoquinoline and picolinamide directing groups, [5a] and since then a number of nitrogen-linked directing groups for C-H activation have been reported (Figure 1). [5] Typically, these directing groups deliver the palladium catalyst to a nearby C-H bond via the formation of a 5-or 6-membered palladacycle, though transannular functionalisation reactions have been observed in some cases. [5e] Figure 1. Amide-linked directing groups employed in Pd-catalysed C-H functionalisation reactions of sp 3 -rich scaffolds. [5a-5e] Two major drawbacks of many of these reactions are the requirement for excess silver salt in the C-H activation reaction, as well as difficulty in removing the directing group from the product molecule to recover a free amine for use in further synthetic manipulation. In recent work we have shown that selective monoarylation of bicyclic amine scaffolds can be achieved efficiently under silver-free conditions using the 2-picolinamide directing group. [6] The picolinamide group can readily be removed under mild reductive conditions using Zn/HCl. [7] We envisaged (Fig. 2) that by manipulating the electronic and steric properties of the picolinamide directing group, it should be possible to enhance the efficiency and selectivity of Pd-catalysed C-H functionalisation reactions, as well as potentially enabling C-H functionalisation at different reaction sites within a molecule.

Results & Discussion
We elected to study three different scaffolds which each contain two chemically distinct C-H bonds capable of undergoing C-H activation to yield a 5-membered palladacycle (Fig. 2). A wide range of picolinic acids are available commercially and we selected seven examples bearing both electrondonating (Me, MeO) and electron-withdrawing (CF3) substituents at a variety of positions around the ring, alongside the unsubstituted picolinic acid as a benchmark. In the case of the bornylamine scaffold, despite the proximity of the methyl C-H bond to the directing group, we had not observed C-H activation taking place at that site during our original study with an unsubstituted picolinamide directing group. [6] Interestingly, in our evaluation of the substituted picolinic acid directing groups, it rapidly became apparent that the substituent on the directing group exerts a significant effect on the reactivity of the methyl group (Table 1). As reported previously, the unsubstituted picolinamide 1a gives an excellent yield of monoarylated product 2a under our optimised reaction conditions, with no trace of methyl C-H activation. The 3-methylpicolinamide 1b also gives the monoarylated product 2b with complete selectivity and with the highest yield. Interestingly, upon changing the position of the methyl substituent to the 4 or 5 positions on the pyridine ring (1c/1d), a novel diarylated compound (3c/3d) was observed as a minor product, perhaps suggesting that the conformational or electronic effects of the substituent are able to facilitate C-H activation on the methyl group, although the C-H activation still evidently occurs preferentially at the CH2 in both substrates. [8] Introduction of an electron withdrawing CF3 group at the 3-position (1e) increased the quantity of diarylated product formed, giving almost equal amounts of monoarylated product 2e and diarylated product 3e. The 5-CF3 derivative 1f gave the lowest overall conversion, with a mixture of monoarylated 2f and diarylated 3f products being generated. The 4-and 5methoxypicolinamides 1g and 1h gave similar overall yields of product, with small quantities of diarylated product in both cases. [9] As a general rule, high overall yields were obtained with all of the picolinamides bearing the moderately electron-donating methyl group, with the 3methylpicolinamide giving the highest yield of monoarylated product 2b with no observable formation of the corresponding diarylated compound 3b. The 3-trifluoromethylpicolinamide 1e provided the largest quantity of diarylated product 3e as well as giving a high overall product yield. Control experiments (Scheme 1) demonstrated that the C-H insertion step for the initial methylene arylation reaction was not reversible as no deuterium exchange was observed at the methylene unit to give d1-1a upon heating 1a in the presence of Pd(OAc)2 and CsOAc in deuterated tert-butanol. [10] Furthermore, the palladated complex 1a-Pd (L=CD3CN) generated from 1a and Pd(OAc)2/CsOAc in acetonitrile [6] did not undergo deuteration upon treatment with either deuterated tert-butanol or deuterated acetic acid. In addition we observed that the monoarylated product 2e was not converted into the diarylated product 3e upon resubmission to the reaction conditions. This suggests that the selectivity in the Pd-catalysed C-H arylation is under kinetic control, and hence determined by the energy barriers of the C-H insertion steps. The diarylation product must be formed via two sequential C-H arylation processes, without dissociation of the palladium catalyst as dissociation of the palladium from the monoarylated product 2e seems to be irreversible.

Scheme 1. Control experiments.
On changing the coupling partner from an aryl iodide to an aryl bromide, [11] the formation of the diarylated product was no longer observed (Scheme 2). Electron withdrawing directing groups gave lower overall yields of the arylated products (2e and 2f) and higher yields were seen with the unsubstituted picolinamide and substrates bearing electron donating groups (2a-2c and 2h). This monoarylation reaction almost certainly provides a better reflection of the inherent reactivity of each directing group in terms of facilitating the catalytic cycle. The improved efficency of the reaction with 3-methylpicolinamide perhaps reflects conformational effects on the palladium complexation/decomplexation steps which enable better catalytic turnover. More generally, electrondonating substituents on the picolinamide are clearly preferable to electron-withdrawing substituents in terms of reaction efficiency. Again, the 3-methylpicolinamide 1b gave the highest yield of monoarylated product. Subsequent results (vide infra, Scheme 5) suggested that bromide ions could suppress C-H activation processes, so this is probably the reason why no arylation of the methyl group is observed in these reactions.
To gain further insight into the regioselectivity of the arylation processes, we undertook computational studies of the various possible C-H activation steps. Density functional theory (DFT) calculations were carried out with the M06 functional, [12] using the 6-31+G(d) basis set for C, H, N, O and F atoms and the LANL2DZ basis set for Pd. All optimised structures were confirmed by the presence of zero or one imaginary frequencies for minima and transition states respectively, and transition states were shown to link the correct minima through IRC calculations. [13] Calculated free energies were corrected to the reaction temperature of 413 K. [14] Initially, we modelled an adduct Ia in which a palladium atom with a bidentate acetate ligand was chelated by the two nitrogens of a deprotonated molecule of 1a (Scheme 3). Transition states for a concerted metalation-deprotonation (CMD) mechanism could then be located for both methylene and methyl groups (IIa and IIIa respectively; Scheme 3 and Table 2). As expected, these calculations indicated that insertion into the methylene group had a much lower energy barrier (G ‡ = 18.1 kJ mol -1 ). A second insertion step was then investigated, starting from the monophenylated adduct VIIa. From this complex, the free energy of activation for insertion into a C-H bond of the methyl group (transition state VIIIa) was found to be considerably lower than that for methyl group activation in the initial complex Ia via transition state IIIa (93.1 kJ mol -1 vs. 101.7 kJ mol -1 ). The corresponding calculations were repeated for the remaining picolinamide substrates 1b-1h. The free energy of activation for each of the C-H insertion steps is shown in Table 2 For all compounds, the activation energy for initial CH3 insertion is considerably higher than for CH2 insertion (G ‡ = 15.9 kJ mol -1 on average), explaining why monoarylation at the CH3 is not observed. In all cases except for 1g, arylation of the CH2 leads to a lowering of the transition state energy for a subsequent CH3 insertion with this effect being most pronounced for substrates 1e and 1f (G ‡ = 10.3 kJ mol -1 and 11.0 kJ mol -1 respectively) which notably were the substrates which yielded the largest proportion of diarylated product. Given the fact that decomplexation of the monoarylated product 2 from the palladium appears to be irreversible (Scheme 1), the quantity of the diarylated product 3 obtained from each substrate probably reflects the relative rates of the CH3 insertion step and the decomplexation. In the case of substrate 1e, where the largest proportion of diarylated product was observed, the activation energy of the second CH3 insertion step (VIIIe) from the arylated palladium complex VIIe is comparable to that of the initial CH2 insertion (IIe) from complex Ie. In the case of substrates 1a and 1b, the decomplexation of the monoarylated product 2 from palladium is presumably much more rapid than C-H insertion into the methyl group so only monoarylated product is formed, even though the C-H insertion into the methyl group has a lower activation energy in the arylated product. To discover whether such calculations could be used to predict the selectivity for an untested directing group, we calculated the corresponding energy barriers for reactions of the 3-phenylpicolinamide derivative 1i (Scheme 4). Similar values (88.2, 103.0 and 94.0 kJ mol -1 respectively for the three C-H insertion transition states as shown in table 2) were obtained to the methyl derivatives 1c/1d so we expected that this substrate would provide ~10% of the diarylated product. 3-Phenylpicolinamide was synthesised according to a modified literature procedure, [15] and coupled to bornylamine to give 1i. In the event, the arylation reaction of 1i gave 13% of diarylated product 3i alongside 65% of 2i (Scheme 4). We can conclude that the calculated energy barriers for the C-H insertion steps can only provide a qualitative guide to the likely reaction outcomes. This is a consequence of the difficulties of accurately modelling the decomplexation step which is in competition with the second C-H insertion reaction. Further work will be required to understand the complexation/decomplexation mechanisms in order to make more accurate predictions of the effect of different directing groups on the C-H insertion selectivity. We then set out to explore whether these directing group effects could be observed with other substrates. In contrast to the bornylamine framework, most acyclic scaffolds show a preference for methyl C-H activation over methylene C-H activation. [8] The unsubstituted picolinamide 4a derived from (1-methylcyclohexyl)methylamine [16] gives a ~3:1 ratio of monoarylated product 5a and diarylated product 6a with the monoarylation occurring exclusively on the methyl group (Table 3). Analysis of the 1 H and 13 C NMR spectra of 6a and comparison with calculated 1 H and 13 C NMR shifts was used to assign the stereochemistry of the major isomer of 6a as the syn compound ( Figure 3). Interestingly, the 3-methylpicolinamide undergoes a more selective reaction with 57% of the monoarylated product 5b being isolated, alongside traces of diarylated compound 6b, with the balance of the material being unreacted starting material. The 4-and 5-methyl derivatives 4c and 4d give similar levels of selectivity with the former giving a high overall yield of arylated products (5c and 6c) which was comparable to the unsubstituted system 4a. On this amine scaffold, the trifluoromethyl derivatives (4e/4f) gave relatively low yields in the arylation reaction, as did the 4-methoxy derivative 4h. The 4-methoxy derivative 4g gave a good overall yield with reasonable selectivity for the monoarylated product.
Unlike the bornylamine scaffold above, resubmission of 5c to the reaction conditions gave a 26% yield of the diarylated compound 6c (Scheme 5), indicating that the monoarylated compound 5c can effectively form a reactive complex with palladium, perhaps because the picolinamide is less hindered than in 2e. In contrast to bornylamine above, arylation of the (1-methylcyclohexyl)methylamine scaffold with aryl bromides was ineffective. Furthermore, the arylation reaction with an aryl iodide could be suppressed by the addition of 30 mol% tetrabutylammonium bromide to the reaction mixture. [17] It seems that the presence of bromide in the reaction mixture retards the C-H activation step, presumably by outcompeting acetate as a ligand on the intermediate palladium complex. This may also explain why only monoarylation of the bornylamine scaffolds is seen when aryl bromides are employed (Schemes 2 & 4)  Next we explored the effect of the eight different picolinamide directing groups on the flexible openchain scaffold 2-methylbut-1-ylamine (Table 4). [18] As anticipated, arylation of the methyl group occurs preferentially, followed by a second arylation on the ethyl group. Reaction of the unsubstituted amide 7a gives 72% yield of monoaryl product 8a and 21% of the diaryl compound 9a. Complete control over the formation of mono or diarylation products is more challenging in this case, but once again the 3methylpicolinamide gives the highest levels of selectivity yielding only 5% of diaryl compound 9b alongside a synthetically useful 73% yield of monoarylated compound 8b. Good selectivity was also observed with the 5-methyl (7d) and 5-methoxy (7h) derivatives which both also gave improved yields of the monoaryl derivatives 8d and 8h respectively. The 4-methylpicolinamide gave a poor overall yield as well as showing no selectivity in the arylation reaction with equal amounts of 8c and 9c being produced. In this latter reaction, it was possible to detect a third product 10c in which diarylation had taken place on the two methyl groups ( Figure 5). Trifluoromethyl picolinamides 7e and 7f gave high selectivity for the monoarylated products 8e and 8f but in only moderate yield. 4-Methoxypicolinamide 7g gave a similarly low overall yield but with high selectivity for monoarylation. [b] Ratio of products 8:9 determined from crude 1 H NMR; it was not possible to accurately determine this ratio for all reactions. [c] A mixture of two diarylated products was obtained including 10c ( Figure 5); see SI for further details. As a final example, we explored the arylation of substrates 11a/11b derived from isobutylamine, in which two equivalent methyl groups are present (Scheme 6). [19] Switching from the unsubstituted picolinamide 11a to the 3-methylpicolinamide 11b led to a slightly increased selectivity for monoarylation (12b vs 13b), albeit with the diarylated compound being the major product in both cases. The overall arylation yield with the 3-methylpicolinamide was also slightly higher.

Scheme 6. Arylation of isobutylamine picolinamides 11
The directing group effects in the above reactions are not trivial to fully disentangle, but broadly speaking one or more of the methyl-substituted picolinamides appear to be advantageous in terms of improving the selectivity of arylation reactions, and typically leading to slightly higher overall yields of the C-H arylation products than the unsubstituted picolinamide. There was no observable benefit to employing systems with the more electron-donating methoxy group, and the electron-withdrawing trifluoromethyl group generally led to lower-yielding reactions. The arylation reaction of bornylamine with aryl bromides perhaps provides the most useful insight into the inherent efficiency of each directing group for mediating catalytic arylation. This likely involves several effects including the efficiency of complexation to/decomplexation from the palladium catalyst as well as the C-H insertion and arylation steps themselves. Some combinations of directing group and scaffold led to greater promiscuity in the terms of the C-H activation site (1e, 7c), but none of these combinations led to a complete change in the initial reaction site. We envisaged that these insights may prove useful for enhancing the yield of more challenging C-H arylation reactions in which the overall conversion under our previously developed conditions is low. In particular, the 3-methylpicolinamide often provided enhanced yield and selectivity in the C-H arylation reactions, which can potentially be attributed to the steric effect of the methyl group accelerating decomplexation from the monoarylated product. The DFT calculations for the bornylamine scaffold suggest that there is little difference in the activation energies for the C-H insertion steps between 3-methylpicolinamide and the unsubstituted system. With this in mind, we then went onto examine other sp3 C-H arylation reactions to see if improved conditions could be identified. Reaction of cyclohexyl [20] picolinamide 14a and p-fluoroiodobenzene under our standard conditions led to the formation of the arylated product 15a in 70% yield (Scheme 7). By changing the solvent to 3-methylpentan-3-ol (tHxOH, bp 123 °C), [21] without changing the external temperature, the yield of 15a was increased to 80%. 3-Methylpentan-3-ol is available commercially in reasonably large quantities, but has rarely been used as a reaction solvent for C-H activation. [22] Changing the directing group to 3-methylpicolinamide 14b led to a further improvement in reaction yield (91%, 15b). These conditions could also be used to improve the arylation yield of the same substrate with p-anisyl iodide from 68% to 85% (15c/15d). We also extended the reaction to a small selection of other substrates including cyclohexylmethylamine 16 [16] (to give diarylated product 17a, along with small quantities of monoarylated derivative 18a), cycloheptylamine 19 (to give 20), [23] and 4-aminotetrahydropyran 21 (to give 22). [24] In all cases, the combination of 3-methylpicolinamide as the directing group and t HxOH as solvent gave an improved yield of the arylation product. In the reaction to form 17a only, the use of CsOPiv as base was beneficial.
The selectivity in the arylation of 16a is noteworthy in that the monoarylated product 18a is formed almost exclusively as the trans isomer, whereas the diarylated product 17a is formed exclusively as the all cis isomer. This can be rationalised (Scheme 7) by assuming that the directing group can more effectively mediate the C-H activation step when it occupies an axial position, giving cis selectivity. Thus, arylation cis to the directing group gives a disubstituted cyclohexane cis-18a with one substituent is axial and one equatorial. This effectively lowers the energy of the conformation in which the directing group is axial, promoting a second C-H insertion reaction. In contrast, the formation of trans-18a presumably involves some distortion of the chair in the intermediate Pd complex trans-23.
The conformation of trans-18a in which both substituents are equatorial is likely to be overwhelmingly favoured and this will make the molecule more rigid, preventing further C-H insertion steps from taking place. It is possible that trans-18a is formed via epimerisation of the intermediate palladium complex from cis-23 to trans-23 prior to the arylation reaction with the iodoarene. Similarly, monoarylation of 14 and 21 almost certainly occurs selectively due to the requirement for the directing group to be axial in order for the palladium to reach the C-3 hydrogen atom. In the products 15/22, the conformation with both substituents axial is likely to be energetically unfavourable, so no second arylation takes place.

Scheme 7.
Improved yields of C-H arylation products were obtained using t HxOH as solvent and 3methylpicolinamide as the directing group. * CsO2CtBu was used in place of CsOAc.

Scheme 8.
Potential explanation of the stereoselectivity observed in arylation of 16a to give 17a and trans-18a.

Conclusions
In summary, it has been shown that the substituents on the picolinamide directing group can have a significant effect on the yield and selectivity of C-H functionalisation reactions conducted under silverfree conditions. A variety of electron rich and electron poor picolinamides were investigated on a range of amine substrates, with the latter generally leading to lower yielding reactions. Highest yields were obtained with a methylpicolinamide directing group which gave some improvements over the unsubstituted system. Most notably, the use of 3-methylpicolinamide typically led to increased yields of C-H arylation reactions in most cases, and also to reduced quantities of diarylation products. The beneficial effect of this directing group can perhaps tentatively be explained by accelerated decomplexation from the palladium leading to more efficient catalytic turnover, and deceleration of overarylation reactions due to the increased steric hindrance. Further improvements in reaction yields could often be obtained by performing reactions in 3-methyl-3-pentanol (tHxOH) as solvent. These conditions enabled us to obtain synthetically useful yields of arylation products from a range of substrates.
A tube was charged with a picolinamide (1 eq), CuBr2 (10 mol%), Pd(OAc)2 (5 mol%), CsOAc (4 eq), tAmOH (1 M) and an aryl iodide or bromide (4 eq). The tube was sealed with a PTFE lined cap and heated to 140 °C for 24 hours. The reaction mixture was then cooled and filtered through a pad of Celite®, washing with EtOAc. The filtrate was concentrated in vacuo and the resulting crude residue purified by flash column chromatography.