Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water

A method for synthesis without protecting groups of bis(indolyl)methanes by the (η3-benzyl)palladium system generated from a palladium catalyst and benzyl alcohol in water is developed. This domino protocol involves C3–H bond activation/benzylation of indole–carboxylic acids and benzylic C–H functionalization. Mechanistic studies indicate that the (η3-benzyl)palladium(II) complex, which is formed via oxidative addition of benzyl alcohol 2 to a Pd(0) species, activates the C–H bond at the C3-position of indole 1. Notably, water plays an important role in our catalytic system for sp3 C–O bond activation and stabilization of OH− by hydration for the smooth generation of the activated Pd(II) cation species, as well as for nucleophilic attack of indoles to hydrated benzyl alcohols.


OPEN ACCESS
Therefore, the development of a direct catalytic substitution of benzylic alcohols, which produces the desired products along with water as the sole co-product, is highly desired in organic chemistry.Recently, direct application of benzyl alcohols as electrophiles in various reactions was achieved via Brønsted/Lewis acid [10][11][12], transition metal [13,14] or water-promoted [15][16][17] sp 3 C-O bond activation.
We have developed a unique strategy for benzylation and C-H activation [18][19][20][21][22][23][24] by the (η 3 -benzyl)palladium system from a palladium catalyst and benzyl alcohol in water [25][26][27][28].Water activates the benzyl alcohol via hydration of the hydroxyl group for generation of the (η 3 -benzyl)palladium species, which can then undergo innovative direct transformation reactions.We became interested in further expanding the substrate scope of the (η 3 -benzyl)palladium system to water-soluble unprotected indole carboxylic acids 1, since we have been studying the development of synthesis without protecting groups and selective reactions towards various reactive functional groups [29][30][31][32].In general, synthesis without protecting groups represents a distinct challenge and has been fraught with a number of difficulties such as chemoselectivity [33].One of the most effective ways for achieving synthesis without protecting groups is the development of selective reactions towards various reactive functional groups.Although the possibility of generating by the different coupling reactions the undesired products shown in parentheses exists, in our catalytic system, only the desired products were obtained selectively in excellent to good yields (Scheme 1).Oxygen nucleophilicity of the carboxyl group may be weak due to hydration under aqueous conditions.

R
In our previous paper [25], we reported a method for the synthesis of bis(indolyl)methanes via palladium-catalyzed domino reactions of indoles with benzyl alcohols in water and suggested a plausible mechanism for the formation of bis(indolyl)methanes.In the present study, we explore the synthesis without protecting groups of bis(indolyl)methanes 3 from indole-carboxylic acids 1 and propose a more detailed mechanism based on various control experiments.Herein, we report the development of synthesis without protecting groups of bis(indolyl)methanes 3 via palladium-catalyzed domino reactions of indole-carboxylic acids 1 with benzyl alcohols 2 in water.Based on observations made in this investigation, we can now provide strong support for the Pd-catalyzed C3-H activation and benzylation pathway.This paper describes mechanistic investigations aimed at providing a rational explanation for the formation of bis(indolyl)methanes 3.

Results and Discussion
First, we heated a mixture of indole-5-carboxylic acid 1a and benzyl alcohol 2a (3 equiv) in the presence of Pd(OAc) 2 (5 mol%) and sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol%) in water at 120 °C for 16 h in a sealed tube.Bis(indolyl) product 3a was obtained in 84% yield along with C3-benzylated 4a in 15% yield (Table 1, entry 1).Importantly, the reaction was completely C3-selective, with no C2-or N-benzylated product formed.When 1a was consumed completely at 60 °C in 16 h, the reaction afforded only desired 3a in excellent yield (entry 2, 91%).In contrast, the reaction at room temperature did not occur (entry 3).The reaction also did not proceed in the absence of the palladium catalyst and phosphine ligand (entry 4).With regard to the palladium catalyst, the use of PdCl 2 or Pd 2 (dba) 3 also gave the product 3a in excellent yields (entry 5, 91%; entry 6, 93%).Since the reaction did not occur when using PdCl 2 (PPh 3 ) 2 instead of a water-soluble ligand (entry 7) or when using DMSO, EtOH or THF (entry 8) as a solvent, water must play an important role in our catalytic system.AcOH also resulted in excellent yield (entry 9, 93%).To our surprise, the reaction proceeded when 1 M NaOH aq. was used as a solvent at 60 °C (entry 10).In our previous work, benzylation of anthranilic acid did not occur at 120 °C in 1 M NaOH aq [28].Thus, the (η 3 -benzyl)palladium intermediate might be unstable under high temperature and strong basic conditions [34].
We monitored the C3-H activation reaction by 1 H NMR spectroscopy (Table 2).In general, a C-H bond activation mechanism is used to describe the substitution of indoles by electrophilic metals such as Pd(II) [35][36][37][38].Thus, indole 1a reacted with (η 3 -benzyl)palladium(II) to form intermediate A, followed by formation of intermediate B, which reacted with D 2 O to give C3-D indole 1a' (Scheme 2, path A).Indeed, treatment of indole-5-carboxylic acid 1a with Pd 2 (dba) 3 , TPPMS and benzyl alcohol 2a in D 2 O at 60 °C for 3 h showed 65% deuterium incorporation at the C3-position of indole (entry 1).In contrast, in the absence of benzyl alcohol 2a, or when using toluene instead of 2a, only a trace amount of deuterium was incorporated (entry 2; 12%, entry 3; 14%).Use of 4-methylbenzyl alcohol 2b or 4-chlorobenzyl alcohol 2c instead of 2a resulted in good yields (entry 4; 80%, entry 5; 70%).These results suggested that the palladium(II) complex which was formed via oxidative addition of benzyl alcohol 2 to a Pd(0) species activated the C-H bond at the C3-position of 1a.While the indole with 2-carboxylic acid ethyl ester 1b resulted in no reaction (entry 6; 3%), the indole with 2-carboxylic acid 1c showed 81% deuterium incorporation (entry 7).This observation suggested that the 2-carboxylic acid moiety plays an important role as a directing group in C3-H palladation to afford the desired product 3m (Figure 2).In addition, 1,2-migration of intermediate A did not occur to give C2-palladated C (Scheme 2, path B).To confirm that 3-benzylindole 4a was not the intermediate in our catalytic system, we tested the reaction of 4a (Scheme 3, A).The reaction afforded desired 3a (71% from 1a) and recovery of 3-benzylated 4a (90%).Use of 3-benzylindole 4b instead of 4a also resulted in recovery of 3-benzylated 4b (90%) (Scheme 3, B).These results suggested that 3-benzylated 4a is not the intermediate in our catalytic system.Scheme 3. Pd-catalyzed benzylation of indole 1a and 3-benzylindole 4.These results and our previous report [25][26][27][28] suggest the following mechanism for the formation of bis(indolyl)methanes 3 from indole carboxylic acid 1 and benzyl alcohol 2 in water (Scheme 4).Notably, activation of the C-H bond at the C3-position of indole carboxylic acid 1 with (η 3  Furthermore, toluene 5 should be formed from the (η 3 -benzyl)palladium complex through reductive elimination in our catalytic system (see Scheme 4).We were delighted to observe that indeed toluene 5 was obtained in the reaction mixture (Sceme 5, A).In contrast, the reaction of benzyl alcohol 2a in the absence of indole 12 gave benzaldehyde 14 (14%) and recovery of SM 2a (68%) with no toluene 5 detected (Scheme 5, B).This observation suggested that benzaldehyde 14 should not be the intermediate in our catalytic system.Scheme 5. 1 H NMR experiments to monitor the reaction.Finally, we investigated the reaction using benzyl acetate 22 instead of benzyl alcohol 2 because oxidative addition of the benzylic ester to a Pd(0) species could occur to form (η 3 -benzyl)palladium 7 [39,40].As expected, 65% deuterium incorporation was observed using benzyl acetate 22 in D 2 O (Table 3, entry 1).To our surprise, the reaction did not desired product 3a.These results suggested that the C3-palladated indole could not react with benzyl acetate 22 (Figure 3, intermediate 23).It is known that the reactivity of benzyl acetate 22 with nucleophiles is high compared with benzyl alcohols 2. Next, the reactions using benzyl acetate 22 and benzyl alcohol 2a in organic solvents such as 1,4-dioxane or CD 3 OD instead of water were examined, which also did not afford desired product 3a (entry 2 and 3).Interestingly, 89% deuterium incorporation was observed when CD 3 OD was used.These results suggested that C3-palladated indole could not react with benzyl alcohol 2a after C-H activation of indole 1 occurred in CD 3 OD, and organic solvents could not activate the benzyl alcohol 2a (Figure 3, intermediate 24).Therefore, we have demonstrated an important role of water for water-promoted sp 3 C-O bond activation of benzyl alcohols 2 in our catalytic system (Figure 3, intermediate 9) [15][16][17].
This domino process includes C-H activation/benzylation at the C3-position of the indole-carboxylic acid and benzylic C-H functionalization.C3-Benzylation of unprotected indole carboxylic acids is extremely rare.Carter and co-workers reported the only reaction of indole-5-carboxylic acid with 4-methoxybenzylbromide using EtMgBr to afford 3-benzylated indole-5-carboxylic acid [41].Synthesis of bis(indolyl)methanes having carboxylic acids from benzyl alcohol and indole is also extremely rare.Itoh and co-workers reported the only one-pot synthesis from indole-3-butyric acid with benzyl alcohols using catalytic iodine and oxygen under visible light irradiation [42].Indole carboxylic acids and their analogs are key units in a wide range of relevant pharmacophores with a broad spectrum of activities [41][42][43][44][45][46].In general, almost all of the compounds that have been synthesized based on protection/deprotection steps and known organic transformations tend to be inefficient in organic solvents.To enable efficient synthesis for improvement of organic chemistry, it is essential to develop synthesis without protecting groups, newly activated catalysts that work for activating unreactive bonds such as C-H bonds, and new reaction fields.In our catalytic system, water plays an important role in activation of unreactive molecules and stabilization of hydroxide ion by hydration, followed by formation of activated Pd(II) cation species [47].Nucleophilic attack of indoles to hydrated benzyl alcohols also could occur (Scheme 7).In organic solvents, elimination of naked hydroxide ion is unfavorable.Thus, our catalytic system should have a broad impact on Pd-catalyzed reactions.

( 3
equiv), solvent (1-2 mL), rt-120 °C, 16 h in a sealed tube.b Yield of isolated product.cThe yield was determined by 1 H NMR analysis of the crude product using p-nitroanisole as an internal standard.d 2.5 mol%.e 4 equiv were used.

Figure 2 .
Figure 2. Role of carboxylic acid as a directing group.

Figure 3 .Scheme 7 .
Figure 3. Role of water for water-promoted sp 3 C-O bond activation of benzyl alcohols 2.

Table 1 .
Effect of catalysts and solvents a .

Table 3 .
Use of benzyl acetate 12 a .