Aryl Bromides and Aryl Chlorides for the Direct Arylation of Benzylic Amines Mediated by Ruthenium(II)

The ruthenium(II)-catalyzed sp3 C–H bond arylation of benzylic amines with aryl halides is reported. In the present method, aryl iodides and, more importantly, also the cheaper aryl bromides and aryl chlorides can be applied as aryl sources. Additionally, the method does not require elaborate manipulations in a glove box and can be carried out in simple screw cap vials. Potassium pivalate proved to be beneficial for the transformation with aryl bromides or iodides as aryl source, but was not required for aryl chlorides. In the latter case, the addition of PPh3 led to high conversion. 3-Methyl and 3-phenyl pyridine were established as directing groups, and the substituent in the 3-position represents a key structural feature for high conversion. The directing group can be cleaved after the transformation, which allows access to diarylmethylamines. Mechanistic studies were carried out and critically compared to mechanistic reports of related transformations.


Introduction
Carbon-carbon bond formation is a central part of many chemical syntheses, and nowadays there is a vast number of ways for the formation of this kind of bond. Transitionmetal catalyzed cross-coupling reactions are one of the most frequently applied methods for the creation of new C-C bonds. [1] However, the required organometallic nucleophilic reagents, particularly those that are functionalized, are often not commercially available or are relatively expensive. One way to overcome this problem is to introduce new functional groups directly through transformation of C-H bonds, which unlocks opportunities for markedly different synthetic strategies. Thus, transition-metal-catalyzed functionalization of hydrocarbons is one of the most frequently investigated but also one of the most challenging topics in modern organic synthesis. [2] The development of new synthetic methods and innovations in these types of reactions will profoundly improve overall synthetic efficiency. The possibility of direct formation of a new carboncarbon bond by C-H bond transformation is a highly attractive strategy in covalent synthesis, owing to the ubiquitous nature of C-H bonds in organic substances and the high atom economy of the process.
case, the addition of PPh 3 led to high conversion. 3-Methyl and 3-phenyl pyridine were established as directing groups, and the substituent in the 3-position represents a key structural feature for high conversion. The directing group can be cleaved after the transformation, which allows access to diarylmethylamines. Mechanistic studies were carried out and critically compared to mechanistic reports of related transformations.
Regioselective direct arylations are difficult to achieve because the arene reagents often contain several nonequivalent C-H bonds that can react with the metal center at a similar rate. This selectivity problem usually furnishes undesired side products. The electronic properties of the substrate can control the position of C-H bond cleavage. [3] These electronic properties can be difficult to override and limit the scope of reagents. There are several approaches to overcome this problem and the most common strategy for conducting regioselective direct arylations involves the use of substrates containing directing groups. Ligating substituents can direct the metal center to cleave a specific C-H bond to form a five-or six-membered metallacycle. [4] Despite the success in this area, there are relatively few studies on the direct functionalization of sp 3 carbon centers. [5] We recently reported a Ru 0 -catalyzed chelation-assisted method for the direct arylation of benzylic amines. [6] Our preliminary studies in this area focused on the identification of an appropriate directing group. Notably, we found that 3-substituted pyridine displayed the best activity owing to the steric properties of this group. However, this protocol was limited to boronic acid esters, and other aryl sources, most importantly aryl halides, were not tolerated. Hence, we were interested in the investigation of alternative methods suitable for aryl halides, and we developed a Ru II -catalyzed method that enabled the use of aryl bromides and aryl iodides as arylation reagents. [7] Aryl chlorides were not suitable for this kind of transformation. Within the present contribution, we describe the expansion of substrate scope of our previously reported method and disclose a new synthetic procedure, which also enables the use of aryl chlorides. Mechanistic investigations indicated that the two protocols proceed by different mechanistic pathways.

Results and Discussion
The initial inspiration for the development of an arylation protocol that uses aryl halides came from a publication of Ackermann and co-workers who reported a ruthenium-catalyzed cyclometalation method for the direct arylation of sp 2 carbon centers with aryl halides. [8] [RuCl 2 (pcymene)] 2 is a frequently used catalyst for the direct functionalization of unactivated sp 2 C-H bonds and a variety of catalytic reactions have been developed during recent years. [9] We envisaged that this method would also be applicable to our benzylic system, although direct sp 3 arylation was unprecedented with this catalyst at that time. We initiated our optimization studies with 1 equiv. of N-benzyl-3methylpyridin-2-amine (1a), 1.5 equiv. of bromobenzene, 2.5 mol-% of [RuCl 2 (p-cymene)] 2 , and 3 equiv. of K 2 CO 3 in 2 mL of toluene. The reaction mixture was stirred for 24 h at 140°C. Under these conditions, the desired product 3a was formed (Table 1, Entry 1), but only in 34 % yield. Interestingly, we could also detect the corresponding dehydrogenated imine derivative 4 as a major side product, although the reaction was performed under an inert atmosphere in the absence of an oxidant. We also tested other catalysts known to undergo C-H activation in combination with different additives (Table 1, Entries 2-7). [10] Products 3a and 4a were detected simultaneously in reactions that gave noteworthy conversions ( Table 1, Entries 1-3), however in different amounts. The ratio of amine to imine product was obviously dependant on the reaction conditions, in particular on the catalyst species. Amongst the investigated complexes, the initially used [RuCl 2 (p-cymene)] 2 showed the best activity and also the highest amine-to-imine ratio. In a first series of experiments, we tested whether additives such as potassium pivalate (KOPiv) and PPh 3 showed beneficial effects on the yields and also if they suppressed imine formation. The addition of carboxylates can facilitate C-H bond activation by promoting a concerted metalation deprotonation (CMD) mechanism. [11] Indeed, the addition of KOPiv led to a significant higher yield of 75 % (Table 1, Entry 8). PPh 3 also increased the activity of the catalyst, but we decided to continue with KOPiv owing to its slightly better performance. Bromo-and iodobenzene showed good conversion but chlorobenzene was not suitable for this method.

Entry Catalyst
Ligand X Conv. [b]  phenyl substituent at the 3-position of pyridine 1b showed slightly better yields at a higher temperature (150°C, see Table 2, Entries 23-33). By employing this bulky group, even the electron-withdrawing 4-MeCO substituent in the aryl donor was converted with 41 % yield ( Table 2, Entry 31). Next, we were interested in the influence of the electronic effects of functional groups incorporated into the benzylic group. Thus, we varied the benzylic group of our starting material and performed the reaction under the above outlined standard conditions. To exclude steric effects, functional groups were only installed at the para position. The results are in accordance with those with the ruthenium(0) series and indicate that electron-neutral groups perform best (Table 3, Entry 4). [6] However, this method gives better results with electron-withdrawing substituents than with electron-donating substituents, which is contrary to the ruthenium(0) method. [6] We could not detect any decarboxylation with starting material 1h (Table 3, Entry 7), as was the case within the ruthenium(0) method. [6] Competition experiments between differently substituted starting materials were carried out to validate the results presented in Table 3. We used an equimolar mixture of unsubstituted and para-substituted starting material with our optimized reaction conditions; this mixture was treated with 1 equiv. of bromobenzene, a decreased amount of aryl source in comparison to previous experiments to ensure incomplete conversion of both substrates. Only then does the obtained product distribution give meaningful results, which are shown in Table 4. Weak electron-withdrawing substituents such as F or CF 3 ( Table 4, Entries 4 and 5) react faster than strong electron-donating and -withdrawing groups (Table 4, Entries 1, 2, and 6). These findings corroborate the results shown in Table 3, and the overall performance of the systems is complementary to the results with Ru 0 catalysis. [6] In the next step, we wanted to investigate the role of the nitrogen atom adjacent to the C-H bond. Therefore, we substituted the nitrogen atom with a CH 2 group (5) or oxygen atom (6). In the ruthenium(0) protocol, the presence of an oxygen center was detrimental, but CH 2 gave a good yield. In the ruthenium(II) protocol, both substituents were not suitable for this transformation, which indicates that the ruthenium(II) mechanism is completely different from the ruthenium(0) mechanism and requires a nitrogen atom in this position (Scheme 1).  The last experiments inspired us to test whether a free NH group is essential for this transformation. We performed the reaction with the NMe-benzylic amine 7a (Scheme 1). In contrast to the ruthenium(0) system, only the free amines showed any conversion, and all other substrates were not tolerated. Hence, we conclude that the free amine function is essential for the ruthenium(II)-catalyzed transformation. This conclusion is also supported by the findings presented in Scheme 2. Tetrahydroisoquinoline (THIQ) substrates 7b and 7c did not show any conversion. Hence, the predominant geometry of substrate 7a, which Scheme 1. Direct arylation of 5, 6, and 7a. disfavors arylation, can be excluded as the reason for substrate 7a to fail in this reaction. If this were the case, compounds 7b and 7c would react at least to some extent. One explanation for the mandatory presence of a free NH group could be that the mechanism does not proceed by direct sp 3 C-H insertion of the metal center but rather by dehydrogenation of the amine to the corresponding imine. The imine formed can further react in a subsequent arylation step to form imine product 4, which is most likely in equilibrium with the desired product. This equilibrium explains the detection of imine 4 in the reaction. We conducted an experiment with the already dehydrogenated benzylic imine 12 to investigate this hypothesis. As expected, we isolated the imine compound 4 (67 % yield, Scheme 3). The fact that 4 was not reduced to 3 in this experiment suggests that the hydrogen required for reduction originates from a [RuH 2 ] species. This species is produced by the dehydrogenation of 11 to form 12. It seems that [RuH 2 ] stays closely associated with 4 and immediately induces the reduction to 3. Furthermore, Jun and coworkers have shown that 12 can be arylated with Ru 3 -(CO) 12 and phenyl boronic acid ester. [12] We were also interested in a comparison of the rate of both the arylation of amine 1a and of imine 12. To this end, we performed kinetic studies for both derivatives. We found that the rate of arylation of imine 12 was in the same range as that of the arylation of amine 1a. This could either be coincidental or be due to a fast (not rate determining) formation of imine 12 from amine 1a. In the latter case, the reduction of 4 to 3a also has to be fast (i.e., not rate determining). Alternatively, 4 could be formed after arylation from 3a by metal-catalyzed dhydrogenation; this could be tested by submitting 1a and 3a to the reaction conditions in the absence of bromobenzene. Interestingly, in both cases only trace amounts of the corresponding imines were formed. Evidently, the aryl halide is also involved in the dehydrogenation process. Based on these results, we cannot determine whether the arylation takes place on the amine or imine compound; at this stage of our studies we favor mechanisms that do not include imine formation (Scheme 4).
Finally, we performed the reaction under different atmospheres as this could provide mechanistic information. We have found the catalyst to be stable under air in the ruthenium(0) protocol and that it performs even better under a H 2 atmosphere. [6] In the ruthenium(II) case, the catalyst performs slightly worse under air and significantly worse under hydrogen (Table 5, Entries 2 and 4). Eventually, H 2 partially transforms the catalyst to an inactive species. Alternatively, the oxidation of the amine to the imine might be hindered under a H 2 atmosphere if the reaction proceeds by initial imine formation and arylation thereof. Furthermore, the reaction does not proceed under CO, which can be attributed to the strong binding character of the CO ligand (Table 5, Entry 3), which leads to catalyst inactivation. The reaction can be carried out under microwave irradiation, which significantly decreases the reaction time from 24 h to 2.5 h with similar yield. We also performed kinetic isotope effect (KIE) experiments to determine whether the C-H activation step is ratelimiting. A KIE of 1.3 was found, which indicates that C-H insertion of the metal center is not the rate-determining step in this reaction, as otherwise a much higher KIE would be expected. [13] This result is in contrast to the previously observed Ru 3 (CO) 12 /phenylboronic acid ester protocol, which displays a KIE of 3.3. [6] Consequently, we also carried out an intramolecular competition experiment. Here, the KIE was found to be 1, which is again in contrast to the Ru 3 (CO) 12 protocol (KIE = 0.43) and indicates again that C-H insertion is not rate-determining and is most likely also irreversible. As experiments to form imine 12 from substrate 1a failed, we hypothesize that the mechanism does not include imine formation prior to arylation. However, at present only a speculative discussion of the reaction mechanism is possible, which is in line with the work of Ackermann [11b] and Jutand and Dixneuf. [11c] The most probable mechanism involves the carboxylatoruthenium(II) complex 14, which is formed from [RuCl 2 (p-cymene)] 2 in the presence of KOPiv. This complex undergoes cyclometalation with 1 to form intermediate 15. Subsequent CMD via transition state 16 delivers the ruthenium(II) complex 17, followed by oxidative addition of the aryl halide to the ruthenium(IV) species 18. Final reductive elimination yields product 3, and the ruthenium(II) complex 14 is regenerated; complex 14 can now reenter the next catalytic cycle (Scheme 5). Scheme 5. Proposed mechanism for the ruthenium(II)-catalyzed reaction.
Additionally, we were also interested in the expansion of the arylation reaction to aryl chlorides. These precursors showed very little conversion under the standard conditions developed for aryl bromides and iodides. Further fine tuning of the protocol was attempted to make this compound class also accessible for direct sp 3 arylation. The reactions of aryl chlorides have already been the target of catalyst development in cross-coupling chemistry because they are less expensive than aryl bromides and more derivatives are commercially available. [14] In the field of direct arylations of sp 3 C-H bonds, only a few examples have been reported that take advantage of aryl chlorides, usually in combination with Pd catalysts. [15] We started our screening with our initial conditions and changed the ligand in a first series of experiments. A low yield of 12 % was achieved in the absence of carboxylate (Table 6, Entry 1), whereas only 4 % yield was detected in the presence of carboxylate (Table 6,  Entries 2 and 3). Next, we tested different kinds of phosphane ligands as Oi and co-workers had already demonstrated their favorable effect on the [RuCl 2 (p-cymene)] 2 catalyst system. [16] In these cases, an increased yield for all investigated phosphanes ( Table 6, Entries 4-12) was observed. The best result was obtained when using simple PPh 3 , however in this case a 38 % GC yield ( Table 6, Entry 4) could not be surpassed. Other electron-rich, electronpoor, or sterically-demanding phosphanes also showed an enhancement of GC yield but were less effective ( Table 6, Entries 5-12). The addition of bidentate BINAP ligand decreased the conversion ( Table 6, Entry 13). The N-heterocyclic carbene (NHC) ligand IMes·HCl did not show a significant positive effect ( Table 6, Entry 14). Hence, we decided to continue optimization with PPh 3 as ligand. One main problem for the transformation of aryl chlorides has been the high concomitant imine formation. This imine formation can be explained by ruthenium-catalyzed dehydrogenation of the product. [17] Unfortunately, when using aryl chlorides we could not get a better amine-to-imine ratio Table 6. Optimization studies for the direct arylation of benzylic amine 1a with aryl chlorides. [a] Entry Ligand Additive Conv. [b] 3a/4 [c] Yield of than 2.9 ( Table 6, Entry 10) which is significantly lower than that obtained with aryl bromides (6.0, Table 1, Entry 8). In the ruthenium(0) reaction, we found the dissociated hydrogen to be successfully scavenged by the ketone with concomitant reduction to the alcohol. [6] Hence, we hypothesized the possibility of a reverse pathway: the addition of an alcohol should deliver the required hydrogen, which might reduce the imine in situ (Scheme 6). Scheme 6. Role of secondary alcohol.
We were pleased to discover that the addition of secondary alcohols led to a high amine-to-imine ratio ( Table 6, Entries 15-18). Cyclohexanol was more effective (38 %, Table 6, Entry 18) than other alcohols such as iPrOH and 3-pentanol (Table 6, Entries 15 and 16). Although this additive did not improve the overall transformation (cf. Table 6, Entry 4), its presence led to the exclusive formation of amine product 3a. Notably, we could detect the corresponding cyclohexanone by GC-MS analysis. Finally, conducting the reaction at 160°C for 30 h (with o-xylene as solvent) furnished 70 % yield of product 3a (Table 6, Entry 19).
Furthermore, this catalytic system is not restricted to halides, and triflates were also accepted, which was not the case in the presence of KOPiv (tosylates were in both cases not tolerated, Scheme 7). Unfortunately, the GC yield was only modest, and the procedure requires additional optimization for synthetic utilization. The corresponding aryl chlorides showed analogous substrate scope to the bromide/iodide protocol, albeit the reaction conditions are harsher ( Table 7, Entries 1-5). In this case, the reaction is obviously again sensitive to electronwithdrawing substituents (Table 7, Entries 6 and 7). Interestingly, phenyl-substituted pyridine precursor 1b showed lower conversion for this specific method (Table 7, Entries [8][9][10][11][12][13][14][15][16]. We assume that the more bulky phenyl substituent is less tolerated by the in-situ-formed complex in this case. Notably, the corresponding imine starting material 12 was not converted under these conditions, which indicates that the arylation process occurs directly on the C-H bond of the starting material 1a, and the imine compound 4 is subsequently formed from amine product 3a by dehydrogenation. The mechanism of the [RuCl 2 (p-cymene)PPh 3 ] catalyst is obviously not exactly the same as for the [Ru(pcymene)(OPiv) 2 ] complex (the lack of carboxylate allows no CMD mechanism). Finally, we also wanted to conduct intermolecular and intramolecular KIE experiments with the [RuCl 2 (p-cymene)] 2 /PPh 3 /chlorobenzene/cyclohexanol system to obtain more information about the mechanism of the reaction. However, we observed a high rutheniumcatalyzed H/D exchange of the substrates under these conditions. In an intermolecular competition experiment, only an arylated product that contained hydrogen atoms but not deuterium atoms was detected. The same result was found in the intramolecular competition experiment. This would mean that only the C-D bond is broken, which is highly unlikely. We also isolated the substrates from these experiments, which also contained only hydrogen atoms and no deuterium atoms. Most likely, the exchange is caused by the cyclohexanol present in the reaction mixture. Performing the reaction with deuterated cyclohexanol instead would also not give a meaningful result as in this case H/D exchange has to be expected and, hence, the measured values would also be misleading. As a control experiment, we subjected only the deuterated starting material 19 to the reaction conditions (Scheme 8). This experiment delivered exwww.eurjoc.org clusively the H-containing product. This proves that KIE studies are not possible for the aryl chloride protocol. Scheme 8. KIE control experiment with 19.

Conclusions
Acyclic sp 3 C-H bonds adjacent to a free N-H group were readily arylated by cyclometalation by employing [RuCl 2 (p-cymene)] 2 and carboxylates with aryl bromides and iodides. Improvements in the conversion in the presence of carboxylates can be explained by a CMD mechanism. Furthermore, the protocol was expanded to cheaper aryl chlorides by using phosphanes as ligands and secondary alcohols as the hydrogen source. The synthetic utility of this approach was demonstrated by the synthesis of various arylated benzylic amines. A wide range of substituents were used in the reaction, and moderate-to-good yields were achieved. The electronic nature of the substituents affects the electron density of the benzylic C-H bond, which has a significant impact on the C-H functionalization rate. Electron-withdrawing and coordinating substituents inhibited the reaction. A free N-H group was mandatory for the arylation, which indicates that imine formation is a crucial step in this reaction. KIE experiments of the Ru II protocol revealed that the oxidative addition step is not the rate-determining step for aryl bromides and aryl iodides. For the aryl chloride protocol, no KIE measurements could be undertaken owing to a competing H-D exchange. The establishment of these conditions should provide a valuable starting point for subsequent examinations of direct arylation in C-C bond synthesis and may facilitate the discovery of other new cross-coupling partners in this type of chemistry.

Experimental Section
General Methods: All reactions were carried out under argon, unless otherwise mentioned. Argon was purified by passage through Drierite. Unless otherwise noted, chemicals were purchased from commercial suppliers and were used without further purification. HRMS for literature unknown compounds were analyzed by hybrid ion trap/time-of-flight MS coupled with liquid chromatography (LC-IT-TOF-MS) in positive ion detection mode with the recording of MS and MS/MS spectra. NMR spectra were recorded in CDCl 3 with TMS as internal standard and chemical shifts are reported in ppm. GC-MS runs were performed with a standard capillary column (BGB 5, 30 m ϫ 0.32 mm i.d.). Microwave reactions were performed with a BIOTAGE Initiator sixty microwave unit (max pressure 20 bar, IR temperature sensor). Analytical data for all new compounds are given below. Compounds 12 [18] and 19 [6] were prepared according to the literature procedures.

General Procedure I for the Preparation of Benzylic Amines:
The 2choloro-3-substituted pyridine (1 equiv.), amine (1.2 equiv.), K 2 CO 3 (3.5 equiv.), Pd(OAc) 2 (2 mol-%), and BINAP (2 mol-%) were placed in an oven-dried 6 mL vial with septum screw cap and a magnetic stirring bar. The vial was evacuated and flushed with argon (three times). Dry toluene was added to the reaction mixture, and the vial was closed with a fully covered solid Teflon ® -lined cap. The reaction vial was then heated in a reaction block at 130°C for 16 h. The suspension was cooled to room temp., and the solid material was removed by filtration and washed with CH 2 Cl 2 (10 mL). The combined organic layers were evaporated, and the resulting crude product was purified by flash column chromatography (PE/ EtOAc = 10:1). General Procedure II for the Preparation of Tertiary Amines: The 2-bromo-3-substituted pyridine (1 equiv.), amine (1.4 equiv.), Na-OtBu (2 equiv.), bis(dibenzylideneacetone)palladium [Pd 2 (dba) 2 , 2 mol-%], and DPPP [1,3-bis(diphenylphosphanyl)propane, 2 mol-%] were placed in an oven-dried 6 mL vial with a septum screw cap and a magnetic stirring bar. The vial was evacuated and flushed with argon (three times). Dry toluene was added to the reaction mixture, and the vial was closed with a fully covered solid Teflon ®lined cap. The reaction vial was then heated in a reaction block at 75°C for 16 h. The suspension was cooled to room temp., and the solid material was removed by filtration and washed with CH 2 Cl 2 (10 mL). The combined organic layers were evaporated, and the resulting crude product was purified by flash column chromatography (PE/EtOAc = 15:1/10:1).