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Article

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

by
Hidemasa Hikawa
*,
Hideharu Suzuki
,
Yuusaku Yokoyama
* and
Isao Azumaya
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
*
Authors to whom correspondence should be addressed.
Catalysts 2013, 3(2), 486-500; https://doi.org/10.3390/catal3020486
Submission received: 27 March 2013 / Revised: 9 May 2013 / Accepted: 10 May 2013 / Published: 16 May 2013
(This article belongs to the Special Issue Palladium Catalysts for Cross-Coupling Reaction)
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Versions Notes

Abstract

:
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.

Graphical Abstract

1. Introduction

The (η3-benzyl)palladium catalysts are gaining increasing interest. The powerfulness of these complexes is still far from other well-established Tsuji–Trost reactions, merely due to a more recent development [1,2,3,4,5,6,7,8,9]. Palladium-catalyzed benzylations with benzylic alcohols via the (η3-benzyl)palladium intermediate are especially challenging, because the reactivity of benzylic alcohols towards Pd(0) is poor compared to benzylic halides, esters, carbonates and phosphates. 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] sp3 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 (η3-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 (η3-benzyl)palladium species, which can then undergo innovative direct transformation reactions. We became interested in further expanding the substrate scope of the (η3-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.
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Scheme 1. Our previous work.
Scheme 1. Our previous work.
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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.

2. 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 PdCl2 or Pd2(dba)3 also gave the product 3a in excellent yields (entry 5, 91%; entry 6, 93%). Since the reaction did not occur when using PdCl2(PPh3)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 (η3-benzyl)palladium intermediate might be unstable under high temperature and strong basic conditions [34].
Results for the reaction of indole-5-carboxylic acid 1a with a number of benzyl alcohols 2 or several indole carboxylic acids 1 with benzyl alcohol 2a using Pd(OAc)2 and TPPMS are summarized in Figure 1. The benzyl alcohols with electron-donating methyl, ethyl and methoxy groups resulted in moderate to good yields (3b, 83%; 3c, 92%; 3d, 54%; 3e, 54%). The reaction of 4-fluorobenzyl alcohol also proceeded (3f, 52%). The benzyl alcohol with a chloro group produced desired 3g in good yield with the carbon–halogen moiety left intact, which could be employed for further manipulation (3g, 67%). A heteroaryl methyl alcohol, thienyl methanol, also resulted in a moderate yield (3h, 52%). To our surprise, aliphatic benzyl alcohol, 2-naphthalenemethanol, which is not very soluble in water, gave desired product 3i in 96% yield. The indoles with 4-, 6- and 7-carboxyl groups resulted in moderate to good yields (3j, 52%; 3k, 60%; 3l, 76%). Interestingly, the indole with 2-carboxyl groups was also tolerated in the reaction (3m, 45%), despite the weak nucleophilicity at the C3 position of indole due to the electron-withdrawing 2-carboxyl acid group. Therefore, synthesis without protecting groups is possible to prepare 3m with our catalytic system.
We monitored the C3–H activation reaction by 1H 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 (η3-benzyl)palladium(II) to form intermediate A, followed by formation of intermediate B, which reacted with D2O to give C3-D indole 1a’ (Scheme 2, path A). Indeed, treatment of indole-5-carboxylic acid 1a with Pd2(dba)3, TPPMS and benzyl alcohol 2a in D2O 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).
Table
Table 1. Effect of catalysts and solvents a. Catalysts 03 00486 i001
Table 1. Effect of catalysts and solvents a. Catalysts 03 00486 i001
EntryCatalystSolventTemp product (%) b
(°C)3a4a
1Pd(OAc)2/TPPMSH2O1208415
2Pd(OAc)2/TPPMSH2O6091 (92) ctrace
3Pd(OAc)2/TPPMSH2Orttrace0
4noneH2O6000
5PdCl2/TPPMSH2O6091trace
6Pd2(dba)3 d/TPPMSH2O6093trace
7PdCl2(PPh3)2H2O60tracetrace
8Pd(OAc)2/TPPMSDMSO, EtOH or THF6000
9Pd(OAc)2/TPPMSAcOH6093trace
10Pd(OAc)2/TPPMS1M NaOHaq.e6063trace
a Reaction conditions: 1a (0.5–1 mmol), Pd catalyst (5 mol%), ligand (10 mol%), benzyl alcohol 2a (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 1H NMR analysis of the crude product using p-nitroanisole as an internal standard. d 2.5 mol%. e 4 equiv were used.
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Figure 1. Scope of alcohols 2 and indole carboxylic acids 1 a. a Reaction conditions: 1a (0.5–1 mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%), benzyl alcohols 2 (3 equiv), H2O (2–4 mL), 60 °C, 16 h in a sealed tube. Yield of isolated product. b benzyl alcohols 2 (5 equiv), 80 °C.
Figure 1. Scope of alcohols 2 and indole carboxylic acids 1 a. a Reaction conditions: 1a (0.5–1 mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%), benzyl alcohols 2 (3 equiv), H2O (2–4 mL), 60 °C, 16 h in a sealed tube. Yield of isolated product. b benzyl alcohols 2 (5 equiv), 80 °C.
Catalysts 03 00486 g001
Catalysts 03 00486 g005 1024
Scheme 2. Possible mechanism of C–H bond activation.
Scheme 2. Possible mechanism of C–H bond activation.
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Table
Table 2. C–H bond activation at the C3-position of indole-5-carboxylic acid 1a a. Catalysts 03 00486 i002
Table 2. C–H bond activation at the C3-position of indole-5-carboxylic acid 1a a. Catalysts 03 00486 i002
EntryIndoles 1Benzylic alcohols 2D incorporation (%) b
1 Catalysts 03 00486 i003 1a Catalysts 03 00486 i004 2a65
21anone12
31a Catalysts 03 00486 i005 instead of 2a14
41a Catalysts 03 00486 i006 2b80
51a Catalysts 03 00486 i007 2c70
6 Catalysts 03 00486 i008 1b Catalysts 03 00486 i009 2a3
7 Catalysts 03 00486 i010 1c 2a81
a Reaction conditions: 1 (0.25 mmol), Pd2(dba)3 (2.5 mol%), TPPMS (10 mol%), benzyl alcohols 2 (3 equiv), D2O (0.75 mL), 60 °C, 3 h under Ar in a sealed tube. b D incorporation was calculated by NMR integration.
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Figure 2. Role of carboxylic acid as a directing group.
Figure 2. Role of carboxylic acid as a directing group.
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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.
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Scheme 3. Pd-catalyzed benzylation of indole 1a and 3-benzylindole 4.
Scheme 3. Pd-catalyzed benzylation of indole 1a and 3-benzylindole 4.
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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 (η3-benzyl)palladium 7 occurred to generate intermediate 8, which did not form 3-benzylated 4 through reductive elimination (see Scheme 3). Instead, intermediate 8 reacted with benzyl alcohol 2 to give C3-benzylated 10.
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Scheme 4. Proposed mechanism.
Scheme 4. Proposed mechanism.
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Furthermore, toluene 5 should be formed from the (η3-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.
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Scheme 5. 1H NMR experiments to monitor the reaction.
Scheme 5. 1H NMR experiments to monitor the reaction.
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Next, we utilized 1H NMR experiments to monitor the reaction using benzyl-α,α-d2 alcohol 15. The reaction afforded desired deuterated 20 (D/H = 96:4) and deuterated toluene 21 (D/H = 73:27) (Scheme 6). This observation clearly explained that β-D elimination of intermediate 17 occurred to generate intermediate 18, followed by addition of indole 12 to give desired deuterated 20 along with deuterated toluene 21 with regeneration of Pd(0) through reductive elimination.β
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Scheme 6. Pd-catalyzed reaction with benzyl-α,α-d2 alcohol 15.
Scheme 6. Pd-catalyzed reaction with benzyl-α,α-d2 alcohol 15.
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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 (η3-benzyl)palladium 7 [39,40]. As expected, 65% deuterium incorporation was observed using benzyl acetate 22 in D2O (Table 3, entry 1). To our surprise, the reaction did not afford 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 CD3OD instead of water were examined, which also did not afford desired product 3a (entry 2 and 3). Interestingly, 89% deuterium incorporation was observed when CD3OD 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 CD3OD, 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 sp3 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].
Table
Table 3. Use of benzyl acetate 12 a. Catalysts 03 00486 i011
Table 3. Use of benzyl acetate 12 a. Catalysts 03 00486 i011
EntrySolventAdditiveD incorporation (%) b
1D2Onone65
21,4-dioxanebenzyl alcohol 2a
(3 equiv)		-
3CD3ODbenzyl alcohol 2a
(3 equiv)		89
a Reaction conditions: 1a (0.5 mmol), Pd2(dba)3 (2.5 mol%), TPPMS (10 mol%), benzyl acetate 12 (3 equiv), solvent (1.5 mL), 60 °C, 16 h in a sealed tube. b D incorporation was calculated by NMR integration.
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Figure 3. Role of water for water-promoted sp3 C–O bond activation of benzyl alcohols 2.
Figure 3. Role of water for water-promoted sp3 C–O bond activation of benzyl alcohols 2.
Catalysts 03 00486 g003
Catalysts 03 00486 g010 1024
Scheme 7. Development of unprotected syntheses, new activated catalysts, and new reaction fields.
Scheme 7. Development of unprotected syntheses, new activated catalysts, and new reaction fields.
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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. Experimental Section

General procedure: A mixture of indole carboxylic acid 1 (0.5–1 mmol), palladium(II) acetate (5 mol%), sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol%) and benzyl alcohol 2 (3–5 equiv) in H2O (2–4 mL) was heated at 60–80 °C for 16 h in a sealed tube. After cooling, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexanes/EtOAc) to give desired product 3.
3,3'-(Phenylmethylene)bis(1H-indole-5-carboxylic acid) 3a (Table 1, entry 2) Following the general procedure, 3a was obtained as a red solid. 93 mg (91%); mp 212–214 °C; IR (KBr) (cm−1) 3424, 1680; 1H NMR (400 MHz, DMSO-d6): δ 5.98 (s, 1H), 6.87 (s, 2H), 7.20 (t, J = 6.4 Hz, 1H), 7.30 (t, J = 7.2 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.69 (dd, J = 8.4 Hz, 2H), 8.01 (s, 2H), 11.2 (s, 2H), 12.3 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 111.3, 119.3, 120.8, 121.8, 122.4, 125.3, 126.1, 128.2, 139.1, 144.3, 168.3; MS (EI): m/z (%) 410 (M+, 100); Anal. Calcd for C25H18N2O4 0.6H2O: C, 71.28; H, 4.59; N, 6.65. Found: C, 71.22; H, 4.59; N, 6.37.
3,3'-(p-Tolylmethylene)bis(1H-indole-5-carboxylic acid) 3b Following the general procedure, 3b was obtained as a red solid. 88 mg (83%); mp 222–224 °C; IR (KBr) (cm−1) 3411, 1682; 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 5.93 (s, 1H), 6.85 (d, J = 1.6 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.69 (dd, J = 8.8, 1.6 Hz, 2H), 8.00 (d, J = 0.8 Hz, 2H), 11.2 (s, 2H), 12.3 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 20.6, 111.3, 119.5, 120.8, 121.9, 122.3, 125.2, 126.1, 128.1, 128.8, 134.9, 139.2, 141.3, 168.3; MS(EI): m/z (%) 424 (M+, 37.2), 161 (100); Anal. Calcd for C26H20N2O4 0.6H2O: C, 71.75; H, 4.91; N, 6.44. Found: C, 71.80; H, 4.80; N, 6.35.
3,3'-((4-Ethylphenyl)methylene)bis(1H-indole-5-carboxylic acid) 3c Following the general procedure, 3c was obtained as a red solid. 101 mg (92%); mp 206–208 °C; IR (KBr) (cm−1) 3414, 1679; 1H NMR (400 MHz, DMSO-d6): δ 1.16 (t, J = 7.6 Hz, 3H), 2.56 (q, J = 7.6 Hz, 2H), 5.94 (s, 1H), 6.87 (d, J = 2.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.68 (dd, J = 8.4, 1.2 Hz, 2H), 8.01 (d, J = 0.8 Hz, 2H), 11.2 (s, 2H), 12.3 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 15.4, 27.7, 111.2, 119.5, 120.8, 121.8, 122.3, 125.2, 126.1, 127.6, 128.1, 139.1, 141.2, 141.5, 168.3; MS(EI): m/z (%) 438 (M+, 13.6), 161 (100); Anal. Calcd for C27H22N2O4 0.6H2O: C, 72.18; H, 5.20; N, 6.24. Found: C, 72.25; H, 4.95; N, 6.18.
3,3'-((4-Methoxyphenyl)methylene)bis(1H-indole-5-carboxylic acid) 3d Following the general procedure, 3d was obtained as a red solid. 59 mg (54%); mp 241–243 °C; IR (KBr) (cm−1) 3400, 1681; 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H), 5.92 (s, 1H), 6.84 (d, J = 2.0 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.69 (dd, J = 8.4, 1.6 Hz, 2H), 8.01 (s, 2H), 11.2 (s, 2H), 12.3 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 38.3, 54.9, 111.2, 113.6, 119.7, 120.8, 121.9, 122.3, 125.2, 126.1, 129.1, 136.2, 139.2, 157.5, 168.3; MS(EI): m/z (%) 440 (M+, 12.5), 161 (100); Anal. Calcd for C26H20N2O5 0.7H2O: C, 68.93; H, 4.76; N, 6.18. Found: C, 68.92; H, 4.62; N, 6.05.
3,3'-((3-Methoxyphenyl)methylene)bis(1H-indole-5-carboxylic acid) 3e Following the general procedure, 3e was obtained as a pale brown solid. 60 mg (54%); mp 258–260 °C; IR (KBr) (cm−1) 3425, 3291, 1697; 1H NMR (400 MHz, DMSO-d6): δ 3.68 (s, 3H), 5.96 (s, 1H), 6.78 (dd, J = 8.0, 2.0 Hz, 1H), 6.85–6.95 (m, 4H), 7.22 (dd, J = 7.6, 7.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 8.02 (s, 2H), 11.2 (s, 2H), 12.3 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 54.9, 111.0, 111.3, 114.5, 119.2, 120.7, 120.9, 121.9, 122.4, 125.3, 126.1, 129.2, 139.1, 146.0, 159.2, 168.4; MS (EI): m/z (%) 440 (M+, 17.0), 161 (100); Anal. Calcd for C26H20N2O5 0.5H2O: C, 69.48; H, 4.71; N, 6.23. Found: C, 69.50; H, 4.57; N, 6.20.
3,3'-((4-Fluorophenyl)methylene)bis(1H-indole-5-carboxylic acid) 3f Following the general procedure, 3f was obtained as a red solid. 56 mg (52%); mp 210–212 °C; IR (KBr) (cm−1) 3428, 1680; 1H NMR (400 MHz, DMSO-d6): δ 6.02 (s, 1H), 6.86 (d, J = 2.0 Hz, 2H), 7.12 (dd, J = 8.8, 8.8 Hz, 2H), 7.38 (dd, J = 8.8, 5.6 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.69 (dd, J = 8.4, 1.6 Hz, 2H), 8.00 (s, 2H), 11.2 (s, 2H), 12.3 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 38.3, 111.3, 114.9 (J = 22 Hz), 119.3, 120.9, 121.8, 122.4, 125.3, 126.0, 130.0 (J = 7 Hz), 139.2, 140.4 (J = 3 Hz), 160.6 (J = 242 Hz), 168.3; MS (EI): m/z (%) 428 (M+, 48.7), 252 (100); Anal. Calcd for C25H17FN2O4 0.8H2O: C, 67.81; H, 4.23; N, 6.33. Found: C, 67.96; H, 4.12; N, 6.41.
3,3'-((4-Chlorophenyl)methylene)bis(1H-indole-5-carboxylic acid) 3g Following the general procedure, 3g was obtained as a pale brown solid. 75 mg (67%); mp 211–213 °C; IR (KBr) (cm−1) 3435, 1679; 1H NMR (400 MHz, DMSO-d6): δ 6.03 (s, 1H), 6.87 (d, J = 2.0 Hz, 2H), 7.36 (s, 4H), 7.42 (d, J = 8.4 Hz, 2H), 7.69 (dd, J = 8.4, 1.2 Hz, 2H), 8.00 (s, 2H), 11.2 (brs, 2H), 12.4 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 38.4, 111.3, 118.9, 120.9, 121.7, 122.4, 125.4, 126.0, 128.2, 130.1, 130.6, 139.1, 143.4, 168.3; MS(EI): m/z (%) 446 (M++2, 17.3), 444 (M+, 45.2), 252 (100); Anal. Calcd for C25H17ClN2O4 0.3H2O: C, 66.69; H, 3.94; N, 6.22. Found: C, 66.56; H, 3.97; N, 6.20.
3,3'-(Thiophen-2-ylmethylene)bis(1H-indole-5-carboxylic acid) 3h Following the general procedure, 3h was obtained as a brown solid. 54 mg (52%); mp 228–230 °C; IR (KBr) (cm−1) 3392, 1682; 1H NMR (400 MHz, DMSO-d6): δ 6.29 (s, 1H), 6.90–7.00 (m, 2H), 7.09 (s, 2H), 7.34 (dd, J = 4.8, 1.2 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 8.09 (s, 2H), 11.3 (brs, 2H), 12.4 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 34.5, 111.3, 119.3, 120.9, 121.9, 122.4, 124.1, 124.9, 125.0, 125.8, 126.6, 139.1, 148.8, 168.3; MS(EI): m/z (%) 416 (M+, 18.7), 161 (100); Anal. Calcd for C23H16N2O4S 1.0H2O: C, 63.58; H, 4.18; N, 6.45. Found: C, 63.86; H, 4.08; N, 6.18.
3,3'-(Naphthalen-2-ylmethylene)bis(1H-indole-5-carboxylic acid) 3i Following the general procedure, 3i was obtained as a pale brown solid. 110 mg (96%); mp 222–224 °C; IR (KBr) (cm−1) 3419, 1676; 1H NMR (400 MHz, DMSO-d6): δ 6.17 (s, 1H), 6.91 (s, 2H), 7.40–7.48 (m, 4H), 7.56 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.76–7.88 (m, 4H), 8.05 (s, 2H), 11.2 (brs, 2H), 12.3 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 111.3, 119.2, 120.9, 121.8, 122.4, 125.5, 125.9, 126.0, 126.1, 127.4, 127.5, 127.6, 127.7, 131.8, 133.1, 139.2, 142.0, 168.3; MS (EI): m/z (%) 460 (M+, 98.1), 161 (100); Anal. Calcd for C29H20N2O4 1.0H2O: C, 72.79; H, 4.63; N, 5.85. Found: C, 72.75; H, 4.49; N, 5.75.
3,3'-(Phenylmethylene)bis(1H-indole-4-carboxylic acid) 3j Following the general procedure, 3j was obtained as a red solid. 53 mg (52%); mp 266–268 °C; IR (KBr) (cm−1) 3413, 3063, 1682; 1H NMR (400 MHz, DMSO-d6): δ 6.24 (s, 2H), 6.86 (s, 1H), 7.00 (d, J = 4.0 Hz, 2H), 7.05–7.15 (m, 4H), 7.18 (dd, J = 8.0, 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 11.0 (d, J = 4.0 Hz, 2H), 12.0 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 41.4, 115.0, 119.6, 120.3, 121.0, 123.4, 125.1, 126.2, 126.9, 127.5, 129.2, 138.1, 146.7, 168.9; MS(ESI): m/z (%) 410 (M+); Anal. Calcd for C25H18N2O4 0.3H2O: C, 72.21; H, 4.51; N, 6.74. Found: C, 72.29; H, 4.44; N, 6.62.
3,3'-(Phenylmethylene)bis(1H-indole-6-carboxylic acid) 3k Following the general procedure, 3k was obtained as a pale brown solid. 62 mg (60%); mp 280–283 °C; IR (KBr) (cm−1) 3376, 3011, 1672; 1H NMR (400 MHz, DMSO-d6): δ 5.91 (s, 1H), 7.07 (d, J = 2.0 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.26–7.40 (m, 7H), 7.49 (dd, J = 8.4, 1.2 Hz, 2H), 8.02 (s, 2H), 11.2 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 113.7, 118.4, 118.6, 119.3, 123.2, 126.0, 127.3, 128.2, 129.7, 135.9, 144.4, 168.4; MS (EI): m/z (%) 410 (M+, 56.5), 161 (100); Anal. Calcd for C25H18N2O4 0.4H2O: C, 71.90; H, 4.54; N, 6.71. Found: C, 71.81; H, 4.50; N, 6.47.
3,3'-(Phenylmethylene)bis(1H-indole-7-carboxylic acid) 3l Following the general procedure, 3l was obtained as a pink solid. 78 mg (76%); mp 198–200 °C; IR (KBr) (cm−1) 3453, 3035, 1668; 1H NMR (400 MHz, DMSO-d6): δ 5.94 (s, 1H), 6.79 (s, 2H), 6.99 (dd, J = 7.6, 7.6 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.30 (dd, J = 7.2, 7.2 Hz, 2H), 7.35 (d, J = 7.2 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 7.6 Hz, 2H), 10.9 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 113.5, 117.9, 118.3, 123.9, 124.5, 125.3, 126.1, 128.1, 128.2, 128.3, 135.3, 144.3, 168.0; MS (EI): m/z (%) 410 (M+, 100); Anal. Calcd for C25H18N2O4 0.7H2O: C, 70.98; H, 4.62; N, 6.62. Found: C, 70.86; H, 4.55; N, 6.51.
3,3'-(Phenylmethylene)bis(1H-indole-2-carboxylic acid) 3m Following the general procedure, 3m was obtained as a purple solid. 46 mg (45%); mp 231–234 °C; IR (KBr) (cm−1) 3390, 3063, 1677; 1H NMR (400 MHz, DMSO-d6): δ 6.50 (d, J = 8.0 Hz, 2H), 6.61 (dd, J = 8.0, 8.0 Hz, 2H), 7.05–7.10 (m, 4H), 7.20–7.25 (m, 3H), 7.39 (d, J = 8.4 Hz, 2H), 7.46 (s, 1H), 11.6 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 112.6, 119.0, 121.8, 123.4, 123.6, 125.2, 125.8, 127.2, 127.9, 128.7, 136.0, 144.7, 162.9; MS (EI): m/z (%) 410 (M+, 15.5), 252 (100); Anal. Calcd for C25H18N2O4•1.0H2O: C, 70.08; H, 4.71; N, 6.54. Found: C, 69.85; H, 4.59; N, 6.24.
3-Benzyl-1H-indole-5-carboxylic acid 4a (Table 1, entry 1) Following the general procedure, 4a was obtained as an off-white solid. 38 mg (15%); mp 184–186 °C; IR (KBr) (cm−1) 3442, 2966, 2640, 1673; 1H NMR (400 MHz, DMSO-d6): δ 4.08 (s, 2H), 7.10–7.20 (m, 1H), 7.20–7.35 (m, 5H),7.39 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 11.2 (brs, 2H), 12.3 (brs, 2H); 13C NMR (100 MHz, DMSO-d6): δ 30.7, 111.1, 115.2, 120.8, 121.2, 122.3, 124.8, 125.7, 126.5, 128.2, 128.3, 138.9, 141.4, 168.3; MS (EI): m/z (%) 251 (M+, 100); HRMS(EI): m/z calcd for C16H13NO2 [M+], 251.0946 found 251.0944.

4. Conclusions

In summary, we have demonstrated a novel method for the direct construction of C–C bonds of unprotected indole carboxylic acid 1 and various benzyl alcohols 2 by Pd-catalyzed domino reactions in water. In our (η3-benzyl)palladium system, the domino reactions achieved C–H activation of the C3-position of indole, nucleophilic attack of indoles to hydrated benzyl alcohols, and benzylic C–H functionalization. Notably, water activated unreactive molecules such as hydroxyl groups and stabilized hydroxide ions by hydration, followed by formation of activated Pd(II) cation species.

Conflict of Interest

The authors declare no conflict of interest.

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MDPI and ACS Style

Hikawa, H.; Suzuki, H.; Yokoyama, Y.; Azumaya, I. Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water. Catalysts 2013, 3, 486-500. https://doi.org/10.3390/catal3020486

AMA Style

Hikawa H, Suzuki H, Yokoyama Y, Azumaya I. Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water. Catalysts. 2013; 3(2):486-500. https://doi.org/10.3390/catal3020486

Chicago/Turabian Style

Hikawa, Hidemasa, Hideharu Suzuki, Yuusaku Yokoyama, and Isao Azumaya. 2013. "Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water" Catalysts 3, no. 2: 486-500. https://doi.org/10.3390/catal3020486

APA Style

Hikawa, H., Suzuki, H., Yokoyama, Y., & Azumaya, I. (2013). Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water. Catalysts, 3(2), 486-500. https://doi.org/10.3390/catal3020486

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