Pd-catalyzed C-H activation in water: Synthesis of bis(indolyl)methanes from indoles and benzyl alcohols

Article abstract of DOI:10.1039/c2ra21887a

A method for the synthesis of bis(indolyl)methanes via palladium-catalyzed domino reactions of indoles with benzyl alcohols was developed. This protocol involves C3-benzylation of indoles and benzylic C-H functionalization in water. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ra21887a

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Pd-catalyzed C–H activation in water: synthesis of
bis(indolyl)methanes from indoles and benzyl alcohols3
Cite this: RSC Advances, 2013, 3, 1061
Hidemasa Hikawa* and Yuusaku Yokoyama*
Received 22nd August 2012,
Accepted 17th November 2012
DOI: 10.1039/c2ra21887a
www.rsc.org/advances
A method for the synthesis of bis(indolyl)methanes via palladium-
catalyzed domino reactions of indoles with benzyl alcohols was
developed. This protocol involves C3-benzylation of indoles and
benzylic C–H functionalization in water.
Gong and co-workers reported the C–H-activation-based oxidative
coupling reaction of 3-arylmethylindoles with dibenzyl malonate.4a
Bis(indolyl)methanes 3 are key units in a wide range of relevant
pharmacophores with a broad spectrum of activities.5 While
condensation of aldehydes with indoles in the presence of acid is
the most practical method of synthesizing bis(indolyl)methanes
3,6 there are no examples of the synthesis of 3 from benzyl
alcohols 2.
First, we heated a mixture of 5-methoxyindole 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 60 uC for 16 h under air in a sealed tube. To
our surprise, indolyl product 3a was obtained in 81% yield in spite
of the possibility of forming the C3-benzylated 4a (Table 1, entry
1). Importantly, the reaction was completely C3-selective, with no
N-benzylated product formed. The reaction did not proceed in the
absence of both the palladium catalyst and the phosphine ligand
(entry 2), and the use of only Pd(OAc)2 resulted in a low yield (entry
3, 38%). With regard to the palladium catalyst, the use of PdCl2 or
Pd2(dba)3 also gave product 3a in good yields (entry 4, 82%; entry
5, 90%). Since the reaction did not occur when using PdCl2(PPh3)2
The development of methods for the direct conversion of C–H
bonds into C–C and C–N bonds has received significant attention
in organic chemistry.1 Palladium complexes are particularly
attractive catalysts for such transformations.
We are interested in unique strategies for the activation of C–H
bonds by palladium catalysts and benzyl alcohol in water. In our
previous work, palladium-catalyzed N-benzylation of anthranilic
acid with benzyl alcohol and benzylic C–H benzylation occurred
simultaneously to give dibenzylated product A.2a By replacing
anthranilic acid with o-aminobenzamide as the starting material,
the N-benzylated product undergoes benzylic C–H amidation to
give 2-phenylquinazolin-4(3H)-one B2b (Scheme 1: previous work).
Herein, we report a synthesis of bis(indolyl)methanes 3 via the
palladium-catalyzed domino reaction of indoles 1 with benzyl
alcohols 2 in water (Scheme 1: present work). This domino process
includes C–H activation/benzylation at the C3-position of the
indole and benzylic C–H functionalization. Recently, the synthesis
of C3-benzylated indoles from indoles 1 and benzyl alcohols 2 has
been reported.3 For example, Grigg and co-workers reported
iridium(III)-catalyzed cascade reactions using borrowing hydrogen
methodology.3f Additionally, Kobayashi and Shirakawa reported
dehydrative nucleophilic substitution using dodecylbenzenesulfo-
nic acid (DBSA) as a surfactant-type Brønsted acid catalyst in
water.3e However, to the best of our knowledge, the palladium-
catalyzed C–H activation/benzylation of indoles with benzyl
alcohol has not been described before. Benzylic C–H functiona-
lization of 3-benzylindole is also extremely rare.4 For example,
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi,
Chiba 274-8510, Japan. E-mail: hidemasa.hikawa@phar.toho-u.ac.jp;
yokoyama@phar.toho-u.ac.jp
Electronic supplementary information (ESI) available: Experimental procedures
3
and characterization data for all compounds. Copies of 1H and 13C NMR spectra for
the new compounds. See DOI: 10.1039/c2ra21887a
Scheme 1 Our concept of Pd-catalyzed benzylation/C–H functionalization.
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Table 1 Effect of catalysts and solventsa
Table 2 Scope of indoles 1 and alcohols 2a
Entry
Catalyst
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2–TPPMS
None
Pd(OAc)2
H2O
H2O
H2O
H2O
H2O
H2O
81
0
38
82
90
PdCl2–TPPMS
c
Pd2(dba)3 –TPPMS
PdCl2(PPh3)2
Pd(OAc)2–TPPMS
Pd(OAc)2–TPPMS
Trace
Trace
Trace
DMF, EtOH or THF
DMF–H2O (1 : 1)
a
Reaction conditions: 1a (0.5 mmol), Pd catalyst (5 mol%), ligand
(10 mol%), benzyl alcohol 2a (3 equiv.), solvent (2 mL), 60 uC, 16 h
b
under air in a sealed tube. Yield of isolated product.
instead of a water-soluble ligand (entry 6) or when using DMF,
EtOH or THF (entry 7) as the solvent, water must play an
important role in our catalytic system. In addition, the reaction in
DMF–H2O (1 : 1) did not proceed (entry 8). Thus, the hydrophobic
effect in water was also observed in our catalytic system.
Results for the reaction of 5-methoxyindole 1a with a number
of benzyl alcohols 2 or several indoles 1 with benzyl alcohol 2a
using Pd(OAc)2 and TPPMS are summarized in Table 2. Benzyl
alcohols with electron-donating methyl, ethyl and methoxy groups
resulted in moderate to good yields (3b, 60%; 3c, 97%; 3d, 65%;
3e, 94%). The use of 4-fluorobenzyl alcohol also resulted in a good
yield (3f, 73%). A sterically demanding ortho-methyl-substituted
benzyl alcohol was also tolerated in the reaction (3g, 87%).
2-Thiophenemethanol resulted in a moderate yield (3h, 56%).
Indole resulted in a moderate yield (3i, 58%). Indoles with
5-methyl, 5-fluoro and 5-cyano groups resulted in moderate to
good yields (3j, 74%; 3k, 56%; 3l, 90%). Methyl ester substituents
were also tolerated in the reaction (3m, 84%). Sterically demand-
ing 2-methylindole resulted in an excellent yield (3n, 98%).
1-Methylindole also afforded the desired 3o in good yield (73%).
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (5 mol%),
TPPMS (10 mol%), benzyl alcohols 2 (3 equiv.), H2O (2 mL),
b
60 uC, 16 h in sealed tube. Yield of isolated product. 48 h.
that indeed toluene 5 was obtained in the reaction mixture
(Scheme 3, A). In addition, the desired 3a, 3-benzylated indole 4a
and benzaldehyde
1 : 0.1 : 0.7 : 0.5 : 3). To confirm that 3-benzylindole 4b was the
intermediate in our catalytic system, we tested the reaction of 4b
(Scheme 3, B). To our surprise, the reaction afforded desired 3b
(78% from 1b), recovery of 3-benzylindole 4b (96%) and indole 1b
6 were detected (3a : 4a : 5 : 6 : 2a =
1
We monitored the reaction using H NMR experiments. First,
treatment of 5-methoxyindole 1a with Pd(OAc)2, TPPMS and
benzyl alcohol 2a in D2O at 60 uC for 30 min showed 97%
deuterium incorporation at the C3-position of indole (Scheme 2).
The reaction did not proceed in the absence of Pd(OAc)2, TPPMS
and benzyl alcohol 2a. The use of zero valent palladium, Pd2(dba)3,
instead of Pd(OAc)2 for 3
h resulted in 34% deuterium
incorporation. Hence, palladium-catalyzed activation of the C–H
bond at the C3-position of indole 1a is possible in our catalytic
system. C–H activation is usually conducted in organic solvents
and extrusion of moisture is essential. To the best of our
knowledge, palladium-catalyzed C–H functionalization of indoles
in water has not been described before.7 After the reaction, toluene
should be formed from the (g3-benzyl)palladium complex and
indoles 1 in our catalytic system. We were delighted to observe
Scheme 2 C–H bond acitvation at the C3-position of indole 1a.9
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same intermediate 9 might possibly form in our catalytic system.
Next, b-hydride elimination of C3-benzylated 9 occurs to generate
intermediate 10, followed by addition of indole 1 to give the
desired product 3 along with toluene 5, with regeneration of Pd0
through reductive elimination.
Notably, the (g3-benzyl)palladium system plays an important
role for benzyl transfer and C–H activation. In previous work, after
N-benzylation occurred, dibenzylated A was obtained by C–H
activation/C-benzylation (Scheme 1). In contrast, quinazolinone B
was formed by C–H activation/amidation. To our surprise, the role
of (g3-benzyl)palladium system was quite different in the present
work, and activated intermediate 8 might form C3-benzylated 9,
followed by intermediate 10. We are attracted to the versatile (g3-
benzyl)palladium system.
In summary, we have developed a method for achieving a
palladium-catalyzed domino reaction for the synthesis of bis(in-
dolyl)methanes 3. The domino reactions achieved C–H activation
of the C3-position of indole followed by benzylic C–H functiona-
lization. Our method provides a unique strategy for the activation
of C–H bonds by palladium catalyst and benzyl alcohol in water.
We are developing new C–H activation/functionalization reactions
using (g3-benzyl)palladium from benzyl alcohols in aqueous
media, which will be reported in due course.
Scheme 3 1H NMR experiments to monitor the reaction.9
(trace). This result suggested that 3-benzylindole 4b might not be
the intermediate in our catalytic system.
These results suggest the following mechanism of the
formation of bis(indolyl)methanes 3 from indole 1 and benzyl
alcohol 2 in water (Scheme 4). First, oxidative addition of benzyl
alcohol 2 to a Pd0 species affords (g3-benzyl)palladium complex 7.
Water may play an important role in the smooth generation of the
(g3-benzyl)palladium species 7 by hydration of the hydroxyl group
and stabilization of hydroxide ion by hydration, followed by
formation of an active PdII cation species, since the reaction does
not occur without water.8
Next, activation of the C–H bond at the C3-position of indole 1a
with (g3-benzyl)palladium 7 occurs to generate intermediate 8,
which does not form 3-benzylated 4 through reductive elimination
(see Scheme 3, B). Instead, intermediate 8 reacts with benzyl
alcohol 2a to give C3-benzylated 9. Rawal and Zhu reported the Pd-
catalyzed C3-benzylation of 3-substituted indoles using benzyl
carbonates, and the reaction between indole and excess benzyl-
carbonate afforded 3,3-dibenzylindole in high yield.3g Thus, the
Notes and references
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