Controlling the Ambiphilic Nature of σ-Arylpalladium Intermediates in Intramolecular Cyclization Reactions

Controlling the Ambiphilic Nature of σ-Arylpalladium Intermediates in Intramolecular Cyclization Reactions DANIEL SOLÉ* AND ISRAEL FERNÁNDEZ* Laboratori de Química Orgànica, Facultat de Farmàci a, and Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028-Barcelona ( Spain) and Departamento de Química Orgánica I, Facultad de Cie nc as Químicas, Universidad Complutense de Madrid, 28040-Madrid (Spain). RECEIVED ON DATE GOES HERE.


Introduction
While the nucleophilic addition of main group organometallics to carbonyl compounds is a very common and useful reaction, the addition of organopalladiums to carbonyl derivatives represents an uncommon transformation. Indeed, the intermediacy of σ-aryl and σvinylpalladium species in C-C bond-forming processes is usually based on their electrophilic nature. Among the palladium-catalyzed annulation processes, the α-arylation of carbonyl compounds has emerged as an extremely powerful methodology for the synthesis of heterocyclic systems. Recent research, however, has demonstrated that in organopalladium complexes, switching the usual reactivity from electrophilic to nucleophilic is relatively simple since the same palladium intermediates can also react with carbon-heteroatom multiple bonds in a nucleophilic manner (Scheme 1). Although these addition reactions are still rare, they are growing in popularity because the increased diversity they give to organopalladium compounds is highly beneficial for organic synthesis. 1 Scheme 1. Ambiphilic character of σ-organopalladium species. Since the seminal report by Heck and co-workers describing a single example of palladium-catalyzed annulation of o-iodobenzaldehyde and alkynes to give indenones, 2 the number of publications on the intramolecular nucleophilic addition of σ-vinyl and σarylpalladium species to aldehydes 3 and ketones 4,5 has steadily increased. Their direct coupling with nitriles, 6 imines, 7 and isocyanates 8 has also led to the development of new reliable catalytic processes. In contrast, the nucleophilic attack of these species on the less electrophilic ester and amide carbonyls has been almost completely ignored. 9 Moreover, despite the inherent interest of being able to control the potential ambiphilic character of aryl and vinylpalladium intermediates, when we began our work in this field, to our knowledge, no attempts had been made to selectively promote both the electrophilic and nucleophilic reactivity from the same starting material. This Account describes our research on the ambiphilic character of σ-arylpalladium species in intramolecular palladium-catalyzed coupling reactions. Emphasis has been placed on a deeper understanding of the reaction mechanisms involved in these processes by using a combination of experimental and computational tools. The challenge was sequentially addressed through the following steps:

I. Intramolecular Pd-Catalyzed Reactions of Amino-Tethered Aryl Halides and Ketones
More than ten years ago, we decided to explore the intramolecular palladium-catalyzed coupling of aryl halides and ketones 10 as a methodology for the synthesis of aza-heterocycles.
Our initial efforts were focused on developing an optimum set of reaction conditions for the intramolecular coupling of (2-haloanilino)ketones. 11 We observed that these substrates show remarkable structure-dependent behavior when undergoing palladium-catalyzed cyclization. 12 Scheme 2. Pd(0)-Catalyzed Reactions of (2-Haloanilino)ketones. Thus, treatment of γ-(anilino)ketone 1 with PdCl 2 (PPh 3 ) 2 and Cs 2 CO 3 afforded the αarylation compound 2 (Scheme 2, eq 1). In contrast, under the same reaction conditions, α-(anilino)ketone 3 and β-(anilino)ketone 5a exclusively afforded alcohols 4 and 6a, respectively, as a result of the addition of the palladium intermediate to the ketone carbonyl group (Scheme 2, eq 2 and 3). In the case of β-(anilino)ketones, changing the substituent at the nitrogen from alkyl to alkoxycarbonyl resulted in a competition between the nucleophilic addition to the carbonyl and the α-arylation, regardless of the substrate structure (Scheme 2, eq 3 and 4). 13 Interestingly, both the intramolecular enolate arylation 14 and addition of aryl halides to ketones catalyzed by Pd(0) 5a had been previously reported in the carbocyclic series. However, these two reactions seemed to operate quite independently of each other, and no competition between the two processes had been observed. 15 It proved illuminating to compare the results obtained in our work with β-(anilino)ketones (Scheme 2, eq 4) with those reported by Muratake and co-workers in the carbocyclic series (Scheme 3). 14 It was immediately obvious that the change in the reaction pathway was strongly related to the presence of the nitrogen atom in our substrates.  To gain more insight into the above palladium-catalyzed cyclizations, we attempted the isolation of the σ-arylpalladium complexes, the purported intermediates in these reactions.
Interestingly, γ-(2-iodoanilino)ketone 1 reacted with equimolar amounts of zerovalent palladium sources in the presence of PPh 3 to give the four-membered palladacycle 11, whose structure was unambiguously confirmed by X-ray crystallography (Scheme 4). The intermediacy of azapalladacycle 11 in the α-arylation of ketone 1 was confirmed when the cyclization was promoted by treatment with Ag 2 CO 3 in THF at high temperature. 13 Similar reactions were observed starting from other γ-(anilino)ketones. In contrast, when both αand β-(anilino)ketones were treated with zerovalent palladium sources to obtain the corresponding azapalladacycles, their behavior was completely different. In both cases, the alcohols resulting from the nucleophilic addition to the carbonyl were directly obtained, while the corresponding fourmembered azapalladacycles were never isolated.  To support our hypotheses, the competition between the α-arylation and the nucleophilic addition reaction pathways of (2-haloanilino)ketones was explored by means of density functional theory (DFT) calculations. 16 Figure  Alternatively, the enolic species 1M-enol, formed from 1M in an endergonic process (∆G 298 = 7.2 kcal/mol), can coordinate the transition metal through its double bond to form the πcomplex 5M. This species evolves to the five-membered ring complex 6M through the transition state TS2 (activation barrier of ∆G ≠ 298 = 16.2 kcal/mol), which is associated with the α-arylation process, in an exergonic transformation (∆G 298 = -7.2 kcal/mol). Complex 6M would then be transformed into 7M (the analogue of the α-arylation product) via a base-mediated process.
Furthermore, the α-arylation reaction may also occur through the corresponding enolate complex 8M formed from 1M-enol. In this case, 7M is produced through TS3 with an activation barrier of 18.6 kcal/mol ( Figure 2).
Our calculations suggest that although the metallacyclobutane intermediate is formed under the reaction conditions, it does not directly lead to either of the two competitive processes.
Moreover, from the computed data, one would expect the exclusive formation of the nucleophilic addition product, as we experimentally observed in the reaction of 5a (Scheme 2, eq. 3). The high chemoselectivity of this reaction is mainly due to the energetic cost associated with the endergonic enolization process that hampers the pathways leading to the corresponding α-arylation product (via TS2 or TS3). In contrast, the α-arylation products are also formed in the reactions of substrates bearing a CO 2 Me group at the aniline nitrogen atom (Scheme 2). This is a consequence of the electron-withdrawing effect of this group, which avoids the π-delocalization of the lone-pair of the nitrogen atom into the aryl ring. As a result, the nucleophilicity of the reactive aryl carbon atom is dramatically reduced, making the addition reaction (via TS1) far more difficult (i.e. with a higher activation barrier). Under these conditions, the α-arylation is now competitive, and a mixture of reaction products is observed.
Finally, our calculations also confirm that the length of the tether joining the amino and carbonyl groups is decisive for the outcome of the process. Thus, for the analogous γ-   Continuing our research on this chemistry, we hypothesized that if we were able to stabilize the arylpalladium(II) moiety and also significantly increase the enolization of the ketone, we could overcome the nucleophilic attack at the carbonyl and favor the α-arylation reaction. Interestingly, we had observed the effectiveness of potassium phenoxide 17 as the base for promoting the palladium-catalyzed intramolecular coupling of amino-tethered vinyl or aryl halides with enolate-type nucleophiles. 18 So, we aimed to capitalize on the beneficial effect of the phenoxide anion to force the α-arylation reaction from β-(2-iodoanilino)ketone 5a, a substrate which exclusively undergoes the nucleophilic addition to the carbonyl.
We found that annulation reactions of 5a using Pd(PPh 3 ) 4 as the catalyst in the presence of phenol invariably afforded mixtures of alcohol 6a and indole 12, the latter arising from the palladium-catalyzed dehydrogenation of the initially formed indoline. The best ratio of arylation/nucleophilic addition products (2:1) was obtained with KO t Bu as the base in the presence of an excess of phenol in THF (Scheme 6). 19 Scheme 6. Pd(0)-Catalyzed α-Arylation of Ketone 5a. This result indicates that a different α-arylation reaction mechanism, which efficiently competes with the nucleophilic addition, must occur in the presence of phenol. Indeed, DFT calculations show that the enolization process from 1M-OPh, formed by the exergonic phenoxyiodide ligand exchange in 1M, becomes much more favorable (∆∆G 298 = -9.7 kcal/mol, Figure   3). From the enolic species 1M-OPh-enol, the α-arylation reaction occurs through TS2-OPh to produce 6M-OPh, which would be transformed into indoline 7M, the precursor of the experimentally observed indole, via a base-mediated process. Nevertheless, we located an alternative and more favorable pathway from 1M-OPh-enol on the potential energy surface. This species finally evolves to indoline 7M via the transition state TS4. Once the role of the phenoxy additive was established, further exploration showed that a complete reversal in chemoselectivity to favor the α-arylation reaction from ketone 5a could be achieved by simply changing the ligand on palladium. When PPh 3 was replaced by xantphos, ketone 12 was obtained in 80% yield in a highly chemoselective transformation (i.e., 6a/12 = 1:14.5). Similarly, the use of binap also favored the α-arylation product (6a/12 = 1:3.9). 19 Interestingly, the competition between α-arylation and the nucleophilic attack on the ketone carbonyl was also observed in the palladium-catalyzed cyclization of α-aminoketone 13a ( Thus, the use of binap for the cyclization of iodoindole 13a resulted in the formation of a nearly equimolar mixture of ketone 14a and alcohol 15. Although we were unable to increase the ratio of the α-arylation product, the nucleophilic addition to the carbonyl became the only apparent reaction when using dppe as the ligand. As mentioned above, in 2-iodoanilines the delocalization of the nitrogen lone-pair in the aryl π-system increases the nucleophilicity of the reactive carbon atom, thus favoring the attack at the carbonyl group. 16 As a similar delocalization operates in 3-haloindoles, we realized that by significantly decreasing the nucleophilicity of the indole C-3 position, the α-arylation process could be favored instead. Indeed, the nucleophilic addition to the ketone carbonyl was not observed in the reactions of N-phenylsulfonylindole 13b, which exclusively afforded 14b (Table 1).

II. Pd-Catalyzed Reactions of (2-Iodoanilino) Aldehydes
We expanded our work on the ambiphilic character of σ-arylpalladium species by exploring the reactions of amino-tethered aryl halides and aldehydes. Both the intramolecular palladium-catalyzed α-arylation of aldehydes 21 and acylation of aryl halides by aldehydes 22 had also been previously reported in the carbocyclic series. However, although one example of competition between the two processes had been reported, 21a the switch from one reaction mode to the other starting from the same precursor had not been explored prior our report. 23 In these palladium-catalyzed cyclization reactions, we chose β-(anilino)aldehyde 16 as a model for investigating the control over chemoselectivity. It was found that the acylation process was the preferred reaction pathway in the presence of bulky monodentate phosphines, with a direct correlation between the phosphine cone angle and the observed chemoselectivity ( Table   2). 23 Interestingly, the best acylation-to-α-arylation ratio was obtained with dtpf, which afforded ketone 18 in 65% yield in a highly chemoselective transformation. Although it contains two phosphorus donors, dtpf is probably ligated to the metal in a κ 1 -fashion, thus also acting as a sterically hindered monophosphine. 24 xantphos ---17 +18 (1:0.9) ---While we found that the palladium-catalyzed nucleophilic addition of aryl halides to ketones was quite sensitive to the length of the tether connecting the nitrogen atom and carbonyl group, the acylation reaction with aldehydes was successfully promoted starting from α-, β-, or γ-(anilino)aldehydes ( Figure 4). As expected, the aminoaldehydes without hydrogen atoms α to the carbonyl group smoothly underwent acylation to give the corresponding ketones in high yields. Similar to the reaction profiles depicted in Figure 1, our calculations suggest that the nucleophilic addition reaction is favored over the corresponding pathways leading to the αarylation products. 23 Again, this is ascribed to the computed lower barrier for the acylation and to the energetic cost associated with the endergonic enolization process. Moreover, the competition between the nucleophilic addition and the alternative C−H insertion was also computed starting from the palladacycle 11M, which lacks hydrogen atoms placed at the α-position to the carbonyl group and is therefore unable to undergo α-arylation. As clearly seen in Figure 5, the nucleophilic addition reaction is kinetically and thermodynamically favored over the insertion of the σ-arylpalladium(II) species 15M into the formyl C−H bond. Once complex 13M is formed via TS5, it evolves to the corresponding alcohol by protonolysis of the O-Pd bond or alternatively it can undergo a β-hydride elimination process to produce complex 14M via TS6.
The latter reaction pathway is very likely to occur in view of the very low barrier energy (∆G ≠ 298 20 = 0.7 kcal/mol) and high exergonicity (∆G 298 = -19.8 kcal/mol) computed for this process.
Complex 14M will be finally converted into the corresponding ketone by the simple decoordination of the carbonyl group regenerating the palladium-catalyst. While we were able to efficiently effect the acylation from aldehydes, the possibility of selectively promoting the enolate arylation proved to be a more challenging task. To date, starting from aldehyde 16, we have only managed to obtain equimolar amounts of 17 and 18 using xantphos as the ligand ( Table 2). The use of strong bases like KO t Bu or PhOK, which could favor the α-arylation reaction, is completely hampered by the retro-Michael degradation of the β-amino aldehyde moiety. In contrast, the α-arylation was the only reaction pathway observed in the cyclizations of aldehydes 20 and 21 when using xantphos and PhOK.
Interestingly, aldehyde 22 was not isolated as it was directly transformed into ketone 24 under the reaction conditions (Scheme 8).

III. Pd-Catalyzed Reactions of β-(2-Iodoanilino)esters and β-(2-Iodoanilino)carboxamides
The ester and carboxamido groups have been traditionally considered inert toward organopalladium reagents. The scarcely reported palladium-catalyzed reactions resulting in the modification of an ester functionality do not involve the carbopalladation of the carbonyl group but the attack of the oxygen atom at the carbon-palladium bond. 2,27 In this context, we thought that we could take advantage of the high nucleophilicity of the palladium(II) species derived from 2-haloanilines to force the nucleophilic attack at the low electrophilic ester and amide carbonyl groups, therefore manipulating their dual reactivity.
After some optimization studies, we found that the substitution reaction at the alkoxycarbonyl group on ester 25 can be successfully promoted by using Pd(PPh 3 ) 4 and K 3 PO 4 in toluene at high temperature (Scheme 9). 28 Scheme 9. Pd(0)-Catalyzed Nucleophilic Substitution at the Alkoxycarbonyl Group. A range of differently substituted dihydroquinolin-4-ones was synthesized under the optimized reaction conditions. In general, the acylation was largely unaffected by the aromatic ring substituents, whose electronic properties do not influence the nucleophilicity of the aryl palladium species. The reaction of amino esters without hydrogen atoms α to the carbonyl group proceeded smoothly to give the corresponding ketones in high yields. Moreover, no competition between the nucleophilic attack at the carbonyl and the α-arylation was observed in the reactions of esters containing hydrogen atoms placed at the α-position to the carbonyl group. Our calculations on model compounds indicate that although the activation barriers for the αarylation process are feasible, these reaction pathways are not competitive with the nucleophilic addition because of the required highly endergonic (ca. 30 kcal/mol) enolization process. 19 The acylation reaction with esters proceeds through a mechanism involving carbopalladation between the σ-arylpalladium moiety and the alkoxycarbonyl group to give a Pd(II) alkoxide, followed by β-alkoxide elimination to give the ketone and a Pd(II) methoxide complex, which would finally undergo β-hydride elimination to regenerate the palladium-catalyst with simultaneous loss of formaldehyde. In agreement with our chemical intuition that an ester group is less electrophilic than a ketone, the computed barrier for the nucleophilic addition at the alkoxycarbonyl group is higher than at the ketone. 19 It should be noted that the above reaction represents the first example of a palladium-catalyzed acylation of aryl halides by an ester group.
Further investigation on the palladium-catalyzed reactions of 25 revealed that the addition of a catalytic amount of phenol to otherwise the same reaction conditions previously used for the acylation, avoided the nucleophilic attack at the alkoxycarbonyl group and promoted the αarylation 29 to give indoline 27 (Scheme 10). Indoline 27 was obtained in good yield by using KOtBu in the presence of phenol. We also observed that the use of the couple K 3 PO 4 /PhOH in DMF resulted in the direct formation of indole 28. 30 This α-arylation reaction was successfully applied to the preparation of differently substituted indoles and indolines, as shown in Scheme 10. The moderate yields obtained in the synthesis of 3-monosubstituted indolines are mainly due to their high tendency to undergo aerobic oxidation to give the corresponding indoles.  The satisfactory results obtained using esters as initial substrates encouraged us to investigate the palladium-catalyzed reactions of carboxamides. We found that amide 29 can undergo either enolate arylation 31 to give indoline 30 or acylation to form 31, using the same reaction conditions employed in the α-arylation or acylation reactions of esters, respectively (Scheme 11, eq 1). 32 Scheme 11. Pd(0)-Catalyzed Reactions of β-(Anilino)carboxamides.
Both reactions were extended to Weinreb amides (Scheme 11, eq 2). 32 Interestingly, under the reaction conditions of the enolate arylation, Weinreb amide 32 afforded indole 33, which results from the demethoxylation and aromatization of the initially formed indoline.
Following this methodology, a variety of differently substituted indolines and indoles was prepared in acceptable yields ( Figure 6). The acylation with amides also showed a broad substrate scope (Figure 7). This reaction very likely proceeds through a mechanism similar to that proposed for the palladium-catalyzed acylation with esters. 19 Interestingly, Weinreb amides afforded better results than N,N-dimethyl amides in the acylation reaction. This is probably due to the chelation ability of the second oxygen atom, which would both facilitate the carbopalladation step and stabilize the resulting Pd(II) alkoxide intermediate. Notably, this acylation reaction also constitutes the first example of nucleophilic substitution at the carboxamido group by a σ-arylpalladium species.

Summary and Outlook
In this Account, we have summarized our studies on the ambiphilic character of σarylpalladium species derived from amino-tethered aryl halides and carbonyl compounds. These palladium intermediates act as electrophiles in α-arylation reactions and as nucleophiles in the transformations that involve a direct attack of the C−Pd bond at the different carbonyl groups.
Our joint computational and experimental efforts to elucidate the mechanism of these palladiumcatalyzed reactions suggest that two major factors are involved in the control of the dual character of these intermediates. First, the high nucleophilicity of the palladium(II) intermediates derived from 2-haloanilines, which modifies the interaction of the metal center with the carbonyl group and second, the additive phenol, which has a beneficial effect on the arylation by exchanging the iodide ligand to give an arylpalladium(II) phenoxide complex. The formation of this transient intermediate not only stabilizes the arylpalladium moiety, thus preventing the nucleophilic attack at the carbonyl group, but also assists the enolization reaction, which takes place in a more favorable intramolecular manner. Although the ability to modulate the ambiphilic character of organopalladium species has exciting potential, our study is one of the few reported attempts to switch from one reaction mode to the other starting from the same precursor. 15,33 We hope that the contents of this paper will motivate further research in the synthetic applications as well as the reaction mechanisms of related processes. In our opinion, this area will experience tremendous growth and activity in the future.