Ruthenium-catalyzed alkylation of indoles with tertiary amines by oxidation of a sp3 CH bond and lewis acid catalysis

Article abstract of DOI:10.1002/chem.200902387

Ruthenium porphyrins (particularly [Ru(2,6-Cl₂tpp)CO]; tpp = tetraphenylporphinato) and RuCl₃ can act as oxidation and/or Lewis acid catalysts for direct C-3 alkylation of indoles, giving the desired products in high yields (up to 82

Full text of DOI:10.1002/chem.200902387

FULL PAPER
DOI: 10.1002/chem.200902387
Ruthenium-Catalyzed Alkylation of Indoles with Tertiary Amines by
3
À
Oxidation of a sp C H Bond and Lewis Acid Catalysis
Ming-Zhong Wang,[a] Cong-Ying Zhou,[a] Man-Kin Wong,[a, b] and Chi-Ming Che*[a]
Abstract: Ruthenium porphyrins (par-
ticularly [Ru(2,6-Cl2tpp)CO]; tpp=tet-
raphenylporphinato) and RuCl3 can act
as oxidation and/or Lewis acid catalysts
for direct C-3 alkylation of indoles,
giving the desired products in high
yields (up to 82% based on 60–95%
substrate conversions). These rutheni-
um compounds catalyze oxidative cou-
pling reactions of a wide variety of ani-
lines and indoles bearing electron-with-
drawing or electron-donating substitu-
ents with high regioselectivity when
using tBuOOH as an oxidant, resulting
in the alkylation of N-arylindoles to 3-
{[(N-aryl-N-alkyl)amino]methyl}indoles
(yield: up to 82%, conversion: up to
95%) and the alkylation of N-alkyl or
N-H indoles to 3-[p-(dialkylamino)ben-
zyl]indoles (yield: up to 73%, conver-
sion: up to 92%). A tentative reaction
mechanism involving two pathways is
proposed: an iminium ion intermediate
catalyzed oxidative coupling reactions
of 4-X-substituted N,N-dimethylani-
lines with N-phenylindole (using
tBuOOH as oxidant), determined
through competition experiments, cor-
relate linearly with the substituent con-
stants s (R2 =0.989), giving a 1 value
of À1.09. This 1 value and the magni-
tudes of the intra- and intermolecular
deuterium isotope effects (kH/kD) sug-
gest that electron transfer most likely
occurs during the initial stage of the
oxidation of 4-X-substituted N,N-dime-
may be generated by oxidation of an
3
À
sp C H bond of the alkylated aniline
by an oxoruthenium species; this imini-
um ion could then either be trapped by
an N-arylindole (pathway A) or con-
verted to formaldehyde, allowing
a
subsequent three-component coupling
reaction of the in situ generated form-
aldehyde with an N-alkylindole and an
aniline in the presence of a Lewis acid
catalyst (pathway B). The results of
deuterium-labeling experiments are
consistent with the alkylation of N-al-
kylindoles via pathway B. The relative
reaction rates of [Ru(2,6-Cl2tpp)CO]-
thylanilines.
Ruthenium-catalyzed
three-component reaction of N-alkyl/
N-H indoles, paraformaldehyde, and
anilines gave 3-[p-(dialkylamino)benzyl]-
indoles in up to 82% yield (conversion:
up to 95%).
Keywords: alkylation
· indoles ·
Lewis acids · oxidation · ruthenium
Introduction
does not require pre-functionalization of the substrates and
does not produce undesired byproducts.[1] Oxidation of an
Transition metal-catalyzed cross-coupling reaction through
the oxidation of C H bonds has emerged as a highly effi-
cient and atom-economic organic transformation, which
sp3 C H bond adjacent to a nitrogen atom in a tertiary
À
À
amine, followed by attack of a carbon nucleophile, is a pow-
À
erful strategy for C C bond formation. In recent years, Mur-
ahashi and co-workers have reported the efficient construc-
[2]
À
À
tion of C CN bonds by RuCl3-catalyzed oxidation of C H
bonds of tertiary amines followed by attack of the carbon
nucleophile CNÀ, with molecular oxygen or hydrogen perox-
ide as an oxidant. Li and co-workers reported that copper(I)
salts could catalyze the oxidative a-alkylation of tertiary
amines with various carbon nucleophiles in the presence of
tert-butyl hydroperoxide (TBHP).[3] Doyle and co-workers
[a] M.-Z. Wang, C.-Y. Zhou, Dr. M.-K. Wong, Prof. C.-M. Che
Department of Chemistry and Open Laboratory of Chemical Biology
of the Institute of Molecular Technology for
Drug Discovery and Synthesis
The University of Hong Kong, Pokfulam Road, Hong Kong (China)
Fax : (+852)2857-1586
E-mail: cmche@hku.hk
[b] Dr. M.-K. Wong
reported an interesting dirhodiumACTHUNTGRNEUNG(II,II)-catalyzed Mannich
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University, Hung Hom, Kowloon
Hong Kong (China)
reaction of tertiary amines with 2-triisopropoxysilylfuran as
carbon nucleophile using TBHP as the oxidant.[4] Vogel and
À
co-workers reported an FeCl2-catalyzed oxidative C C
cross-coupling of tertiary amines with terminal alkynes
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902387.
Chem. Eur. J. 2010, 16, 5723 – 5735
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5723

using (tBuO)2 as an oxidant.[5] Despite these advances,[6] the
search for highly efficient and robust catalysts remains a
other ruthenium catalysts (5 mol%) such as [Ru
cis-[Ru(acac)2A(CH3CN)2] (acac=acetylacetone), and [Ru-
(salen)(OH2)2]PF6 (salen=N,N’-ethylenebis(salicylidene-
imine)) resulted in substrate conversions of 70–76% and
product yields of 60–70% (Table S2 in the Supporting Infor-
mation).
ACHTUGNERTN(NUNG PPh3)3Cl2],
G
CHTUNGTRENNUNG
À
challenge in the field of metal-catalyzed C C cross-coupling
A
ACHTUNGTRENNUNG
3
À
reactions through oxidation of an sp C H bond.
ACHTUNGTRENNUNG
Alkylated indoles occur widely in bioactive natural prod-
ucts and therapeutic drug molecules,[7] and are usually syn-
thesized by acid- or base-mediated alkylation reactions[8] re-
quiring the use of stoichiometric or excess amounts of
strong acid/base and air-/moisture-sensitive organometallic
reagents. Thus, there is a need to develop new methods for
the efficient synthesis of alkylated indoles under mild condi-
tions.[9] Herein, we describe the ruthenium porphyrin- and
RuCl3-catalyzed C-3 alkylation of indoles through oxidation
3
À
of an sp C H bond of tertiary amines, and a three-compo-
nent coupling reaction for the synthesis of 3-[p-(dialkylami-
no)benzyl]indoles from indoles, paraformaldehyde, and ani-
lines. In the latter, both ruthenium porphyrins and RuCl3 act
as Lewis acid catalysts. Although it is well documented that
Figure 1. Structures of ruthenium porphyrin catalysts 1a–d.
[2]
ruthenium porphyrins[10,11] and RuCl3 are efficient oxida-
tive catalysts, there have only been a few reports on the use
of ruthenium porphyrins as Lewis acid catalysts.[12,13] We
have employed ruthenium porphyrins as catalysts due to
their excellent stability and recyclability, features that are
often less than satisfactory with commercially available
ruthenium salts.
With 1 mol% [Ru(2,6-Cl2tpp)CO] (1a) or 5 mol% RuCl3
as the catalyst, the oxidative coupling reactions of N,N-di-
methylanilines 3a–f with various N-aryl-substituted indoles
2a–d afforded the corresponding alkylated indoles 4b–i in
up to 82% yield (entries 2–9, Table 1). N-(4-Methoxyphenyl)-
AHCTUNGTREGiNNNU ndole (2d) gave slightly higher substrate conversion and
product yield than N-p-tolylindole (2c) or N-phenylindole
(2a) (cf. entries 1, 3, and 4, Table 1). Substituted anilines
with electron-donating substituents (4-Me, 3-Me, 2-Me, and
4-OMe) displayed higher activities than those with electron-
withdrawing substituents (4-Br) (entries 5–9, Table 1). An
ortho substituent (2-Me) on the aniline, as in 3e, did not
lead to a remarkable change in the product yield and sub-
strate conversion compared with those from an aniline bear-
ing a meta or para substituent (entries 6–8, Table 1). In the
presence of other alkyl group(s), an N-methyl group in a ter-
tiary amine was selectively oxidized. For example, the reac-
tion of N-methyl-N-butyl-aniline (3g) gave N-butyl-N-[(1-
phenyl-1H-indol-3-yl)methyl]aniline (4j) in good yield with
no trace of the product derived from oxidation of the N-
butyl group (entry 10, Table 1). Cyclic amines such as
1,2,3,4-tetrahydroisoquinoline selectively underwent the oxi-
dative coupling reaction to give the a-indolylation product
in good yield (entries 11 and 12, Table 1). In no case was
any N-oxide of the N,N-dialkylaniline observed.
Unexpectedly, reaction of N-benzylindole (2e) with N,N-
dimethylaniline (3a) in the presence of TBHP and 1a
(1 mol%) gave 3-[p-(dimethylamino)benzyl]indole (5a) in
54% yield, while the oxidative coupling product 4m was ob-
tained in only 25% yield (entry 1, Table 2). Similarly, the re-
actions of N-ethylindole (2 f) and N-methylindole (2g) with
N,N-dimethylaniline (3a) afforded 3-[p-(dimethylamino)-
benzyl]indoles 5b and 5c, respectively, both in good yields,
and in each case only a trace amount of the oxidative cou-
pling product 4 was detected by analysis of the 1H NMR
spectrum of the crude reaction mixture (entries 2 and 3,
Table 2). Indole 2h, with a free NH group, could also be
converted into the corresponding 3-[p-(dimethylamino)ben-
Results
Ruthenium-catalyzed oxidative coupling reaction of tertiary
amines with indoles: The ruthenium porphyrin catalysts 1
employed in this work are shown in Figure 1. We examined
the catalytic properties of 1 for the reaction of N-arylindoles
2 with tertiary amines 3 using TBHP as an oxidant; the re-
sults are presented in Table 1, wherein the substrate conver-
sions correspond to the N-arylindoles and the product yields
are based on the amount of N-arylindole consumed in each
reaction. Excess tertiary amine and TBHP were used to op-
timize the conversions of the N-arylindoles. Treatment of N-
phenylindole (2a) (0.2 mmol) with N,N-dimethylaniline 3a
(0.6 mmol) and TBHP (0.6 mmol, 70% in H2O), using
1 mol% (relative to 2a) of [Ru(2,6-Cl2tpp)CO] (1a) as cata-
lyst, in toluene at 1108C for 6 h afforded the cross-coupling
product 4a in 67% yield with 83% conversion (entry 1,
Table 1).[14] Lower substrate conversions were obtained on
decreasing the reaction temperature to 808C (67% conver-
sion, 72% yield) and 508C (35% conversion, 75% yield), or
by changing the 2a/3a:TBHP ratio (1:3:3) to 1:2:2 (59%
conversion, 75% yield) and 1:1:1 (30% conversion, 62%
yield), as shown in Tables S2 and S3 in the Supporting Infor-
mation. Among the ruthenium porphyrins screened
(Figure 1), [Ru(2,6-Cl2tpp)CO] (1a) and [RuACTHNUTRGEN(UNG F20-tpp)CO]
(1b) were the most effective in terms of substrate conver-
sions and product yields (entry 1, Table 1). Under similar re-
action conditions, the use of 1 mol% of RuCl3 led to only
25% substrate conversion, which could be improved to
80% when 5 mol% of RuCl3 catalyst was used. The use of
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Ruthenium-Catalyzed C-3 Alkylation of Indoles
FULL PAPER
Table 1. Ruthenium-catalyzed oxidative coupling of tertiary amines with indoles.[a]
zyl]indole (5d) in 73% yield
(entry 4, Table 2). Both N-
alkyl- and N-H-indoles reacted
with unsymmetrical N-substi-
tuted anilines to give the cor-
responding 3-[p-(dialkylami-
no)benzyl]indoles 5 in good
yields (entries 5–8, Table 2).
Entry
1
Indole
Aniline
Product
Conv. [%][b]
Yield [%][c]
83
67
65
70
63
75
65
73
70
86[d]
65[e]
60[f]
25[g]
80[h]
85
We speculate that
5 was
formed due to the presence of
formaldehyde (Scheme 1), as
formaldehyde can be generat-
ed through N-demethylation
of N-methyl-N-alkylanilines by
82[h]
2
3
3a
3a
metal-catalyzed
oxidation
processes.[2d] Indeed, a three-
component reaction of N-
methylindole 2g, paraformal-
dehyde, and N,N-dimethylani-
line 3a in toluene in the pres-
ence of ruthenium porphyrin
catalyst (1 mol%) at 1108C
for 6 h gave 5c as the major
80
75
72
83[h]
91
78
82
95[h]
product
(Table 3).
in
good
yield
4
3a
Ruthenium-catalyzed
three-
80
70
67
component coupling reaction
of indoles, paraformaldehyde,
and anilines: Based on the
above observation, we devel-
oped a synthesis of 3-[p-(dia-
86[h]
5
6
2a
2a
89
82
75
92[h]
lkylamino)benzyl]indoles
by
metal-catalyzed three-compo-
nent coupling reaction of in-
doles, paraformaldehyde, and
anilines. In the literature, 3-[p-
(dialkylamino)benzyl]indoles
have hitherto been obtained
through nucleophilic substitu-
tion reaction of indoles with
85
79
74
90[h]
7
8
9
2a
2a
2a
86
76
75
88[h]
benzotriazole-linked
AHCTUNGTRENNUNG
anili-
nes,[15a] halogenated anilines,[15b]
or hydroxy-substituted anili-
nes,[15c] as well as by acid-cata-
lyzed condensation of 3-hy-
droxymethyl indoles with anili-
nes.[15d] All of these reported
methods require the prior in-
90
72
65
95[h]
60
64
71
65[h]
corporation
of
leaving
group(s) in either the anilines
or indoles. After completion of
this work and during revision
of this manuscript, a three-
component coupling reaction
of indoles, formaldehyde, and
anilines catalyzed by silica-sup-
10
2a
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5725

C.-M. Che et al.
indoles 2h–k with substituted
anilines in the presence of par-
aformaldehyde afforded alky-
lated indoles with good sub-
strate conversions (up to 95%)
and product yields (up to
82%) (entries 2–11, Table 4).
This three-component coupling
reaction tolerates functionali-
ties including phenol, chloro,
and methoxy groups. Low sub-
strate conversions were ob-
served for N-arylindoles 2a–d
(entries 12–15). Indoles having
an N-aryl moiety bearing an
electron-donating substituent
such as 4-Me (2c) or 4-OMe
(2d) displayed higher activities
than 2a with an N-phenyl
group. Indole dimers 6 (<5%)
were detected as byproducts in
all of the reactions presented
Table 1. (Continued)
Entry
Indole
Aniline
Product
Conv. [%][b]
Yield [%][c]
85
73
75
80[h]
11
2c
82
79
80
85[h]
12
2d
3h
[a] Indole (0.2 mmol), aniline (0.6 mmol), [Ru(2,6-Cl2tpp)CO] 1a (0.002 mmol), TBHP (0.6 mmol, 70% in
water), toluene (0.5 mL). [b] Conversion based on the recovery of indoles. [c] Yield based on conversion.
[d] [RuACHTUNGTRENNUNG(F20-tpp)CO] 1b (0.002 mmol). [e] [RuACHTUNRTGENN(GUN tpp)CO] (1c) (0.002 mmol). [f] [RuACHTNUGTREN(NUNG 4-MeOtpp)CO] (1d)
(0.002 mmol). [g] RuCl3 (0.002 mmol). [h] RuCl3 (0.01 mmol).
1
in Tables 3 and 4 by H NMR spectroscopic analyses of the
reaction mixtures.
We have examined the recyclability of 1a in the three-
component coupling reaction of N-methylindole (2g) with
paraformaldehyde and N,N-dimethylaniline (3a). High sub-
strate conversions (85–90%) and good product yields (68–
72%) were obtained in five consecutive reactions, with no
significant loss of catalytic activity (Table 5).
Scheme 1. Proposed reaction pathway for the formation of 5.
ported perchloric acid to give 3-[p-(dialkylamino)benzyl]-
ACHTUNGTRENNUNG
indoles was reported.[15e]
In initial experiments, a series of Lewis acid catalysts was
Discussion
screened (Table 3). Among these catalysts, 1a proved to be
the best for the three-component coupling reaction of
indole 2g with paraformaldehyde and aniline 3a, affording
5c in 72% yield with 90% conversion of 2g at a catalyst
loading of 1 mol% (entry 1, Table 3). In contrast, in the ab-
sence of 1a, <5% conversion of 2g was observed (entry 2,
Table 3). Lower product yield (60%) and substrate conver-
sion (68%) were obtained when 1 mol% of RuCl3 was used
as the catalyst (entry 6, Table 3). Using 5 mol% of RuCl3,
the substrate conversion (95%) and product yield (75%)
were comparable to those obtained with 1 mol% of 1a as
Transition metal-catalyzed oxidative cross-coupling of terti-
ary amines with carbon nucleophiles has emerged as a pow-
À
erful strategy for C C bond formation. In the literature,
there have been reports of extensive studies on the oxidative
demethylation of tertiary amines catalyzed by cytochro-
me P450 and its biomimetic model systems.[16] Murahashi
and co-workers proposed that RuCl3-catalyzed oxidative
coupling reactions of tertiary amines with sodium cyanide,
using molecular oxygen or H2O2 as oxidant, involve an oxor-
uthenium intermediate, which oxidizes the tertiary amine to
give an iminium ion.[2f–h] For the copper-catalyzed cross-de-
hydrogenation coupling reaction of tertiary amines with ter-
minal alkynes, nitromethane, or malonate in the presence of
TBHP, Li and co-workers proposed two types of reaction in-
termediates: an iminium ion coordinated to copper and a
tert-butyldioxygenated amine.[3c,e] Doyle and co-workers pro-
catalyst (cf. entries 1 and 7, Table 3). [Ru
[Ru(salen)(OH2)2]PF6 were also effective in catalyzing the
three-component reaction, but cis-[Ru(acac)2A(CH3CN)2]
ACHTUGNTNERN(UNG PPh3)3Cl2] and
A
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
gave <5% conversion (entries 8–10, Table 3). Only 45%
and 65% substrate conversions were obtained when Yb-
ACHTUNGTRENNUNG(OTf)3 (10 mol%) and TsOH (10 mol%) were used as the
catalyst, respectively (entries 11 and 12, Table 3).
posed that a dirhodiumACTHUGNTERN(UNG II,II)-catalyzed oxidative Mannich
The substrate scope of this ruthenium-catalyzed three-
component coupling reaction using 1a (1 mol%) or RuCl3
(5 mol%) as catalyst has been examined. The results are de-
picted in Table 4. With N-benzylindole (2e), good substrate
conversions (60–73%) were observed (entry 1, Table 4).
Coupling reactions of N-alkyl-indoles 2 f and 2g and N-H
reaction in MeOH proceeds via an intermediate a-methoxy-
lated amine.[4]
Mechanism of the ruthenium porphyrin- or RuCl3-catalyzed
oxidative coupling reaction of tertiary amines with indoles
using TBHP as oxidant: Based on the results presented in
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Ruthenium-Catalyzed C-3 Alkylation of Indoles
FULL PAPER
Table 2. Ruthenium-catalyzed oxidative coupling of anilines with N-alkylindoles.[a]
tions. We propose that nucleo-
philic attack of intermediate II
by N-arylindoles gives the cor-
responding alkylated indoles 4
(pathway A, Scheme 2). As tert-
butyldioxygenated amine III
was detected during the reac-
tion (see below), the intermedi-
ate II could also be trapped by
tBuOOH to give III.[2d] In the
presence of a Lewis acid, III
may decompose to regenerate
intermediate II.[2c] In view of
the results in Table 2, we pro-
Entry
Indole
Aniline
Product
Conv. [%][b]
Yield [%][c]
1
3a
92
5a/4m 54:25
pose
that
pathway B
(Scheme 2) is consistent with
the reactions of tertiary amines
with N-alkyl-indoles, probably
owing to the rapid reaction of
N-alkyl-indoles with formalde-
hyde. The formation of formal-
dehyde could be due to trap-
ping of intermediate II by coor-
dinated OH (analogous to the
2
3a
86
67
3
4
5
3a
3a
90
85
82
72
73
67
oxygen-rebound
mechanism
proposed by Groves and
McClusky for iron-catalyzed
aliphatic hydroxylation[18]), or
by water,[19] to give a-hydroxy-
lated amine IV, which subse-
quently decomposes to give
formaldehyde and the N-deme-
thylation product. This process
is reminiscent of the cytochro-
me P450-catalyzed N-dealkyla-
tion of tertiary amines.[16] The
proposed mechanism depicted
in Scheme 2 is supported by the
experiments described in the
following three subsections.
2h
2h
6
88
68
7
8
2 f
2g
3i
3i
85
90
66
69
[a] Indole (0.2 mmol), aniline (0.6 mmol), 1a (0.002 mmol), TBHP (0.6 mmol, 70% in water), toluene
(0.5 mL). [b] Conversion based on the recovery of indoles. [c] Yield based on conversion.
Oxidation of tertiary amines by
oxoruthenium
complexes:
Tables 1 and 2, a tentative reaction mechanism is proposed
(Scheme 2), which involves reaction of the ruthenium cata-
lyst with TBHP to form an oxoruthenium intermediate I,
presumably through pre-generation of an RuOOtBu inter-
Ruthenium porphyrin combined with 2,6-dichloropyridine
N-oxide (2,6-Cl2pyNO) is an oxidation system that is exten-
sively employed for the oxidation of alkenes, hydrocarbons,
and alcohols. In this system, a reactive oxoruthenium species
is generally believed to be responsible for the oxidation.[20]
We found this catalytic oxidation system to also be effective
for the oxidative coupling of N,N-dimethylaniline with N-
phenylindole, affording 4a in 75% yield with 95% substrate
conversion (Scheme 3), thus providing indirect support for
the involvement of a reactive oxoruthenium intermediate in
the ruthenium porphyrin-catalyzed oxidative coupling of ter-
tiary amines with indoles.
À
mediate with subsequent cleavage of the O O bond. This is
similar to the mechanism proposed by Murahashi and co-
workers for a related ruthenium-catalyzed oxidation with
TBHP[2a,17c] and the formation of an oxoiron species from
FeOOR observed by Groves and Watanabe[17a] (R=
C(O)Ar) and proposed by Balch and co-workers[17b] (R=
tBu). On the basis of a previous report by Murahashi and
co-workers,[2h] intermediate I could oxidize the tertiary
amine to give an iminium ion intermediate II, presumably
by electron transfer and subsequent hydrogen-transfer reac-
Previously, we prepared and structurally characterized the
cis-dioxoruthenium(VI) complex cis-[(tet-Me6)RuVIO2]-
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5727

C.-M. Che et al.
Table 3. Lewis acid-catalyzed three-component coupling reaction of 2g,
paraformaldehyde, and aniline 3a.[a]
AHCTUNGTRENNUNG
A
ACHTUNGTRENN(NUG ClO4)2 (1e) was ex-
AHCTUNGTRENNUNG
Entry
Catalyst (mol%)
Conv. [%][b]
Yield [%][c]
1
2
3
4
5
6
7
8
1a (1)
–
90
<5
85
57
65
68
95
88
85
<5
45
65
72
–
Scheme 4. Stoichiometric oxidation of N,N-dimethylaniline by cis-[(tet-
Me6)RuVIO2]
(ClO4)2 (1e).
1b (1)
1c (1)
1d (1)
RuCl3 (1)
RuCl3 (5)
70
61
62
60
75
65
60
–
AHCTUNGTRENNUNG
and cis-[(tet-Me6)RuVIO2]
ACTHUNRGTNEG(UN ClO4)2 1e in CH3CN was stirred
[Ru
[Ru
ACHTUNGTRENNUNG
for 15 h to give the demethylated product N-methylaniline
in 42% isolated yield and 4-(dimethylamino)phenol in 4%
isolated yield. This experiment demonstrated the direct oxi-
dation of N,N-dimethylaniline 3a to its demethylated prod-
uct by a structurally characterized oxoruthenium complex
containing a non-porphyrin ligand. We also prepared dioxor-
uthenium(VI) porphyrin [RuVI(2,6-Cl2tpp)O2] 1 f by the
method reported in a previous work[22a] and by reaction of
[Ru(2,6-Cl2tpp)CO] 1a with TBHP,[22b] and used 1 f as a stoi-
chiometric oxidant for the oxidation of N,N-dimethylaniline
3a at room temperature for 12 h; the demethylated product
N-methylaniline was isolated in 36% yield (Scheme 5). All
of these experiments support the view that the ruthenium-
catalyzed oxidative coupling reactions of tertiary amines
with indoles described in this work involve a reactive oxoru-
thenium intermediate, which may be generated by reaction
of the ruthenium porphyrin complex/RuCl3 with TBHP.
9
A
ACHTUNGTRENNUNG
10
11
12
cis-[Ru
Yb
A
CHTUNGTRENNUNG
C
71
42
[a] Indole 2g (0.2 mmol), paraformaldehyde (0.6 mmol), 3a (0.6 mmol),
catalyst (1–10 mol%), toluene (2 mL). [b] Conversion based on the re-
covery of indoles. [c] Yield of 5 based on conversion.
Scheme 5. Stoichiometric oxidation of N,N-dimethylaniline by [RuVI(2,6-
Cl2tpp)O2] (1 f).
Scheme 2. Proposed reaction pathways for the ruthenium-catalyzed oxi-
dative coupling reaction of tertiary amines with indoles.
Hammett correlation and deuterium isotope effect studies:
The relative rates of oxidative coupling reactions of para-
substituted N,N-dimethylanilines (p-MeO, p-Me, H, p-Br)
with N-phenylindole using tBuOOH as oxidant and [Ru(2,6-
1
Cl2tpp)CO] as catalyst were examined by H NMR analysis
of the corresponding products (alkylated indoles 4). A Ham-
mett plot based on these relative rates is depicted in
Figure 2, which shows a linear correlation (R2 =0.989) with
a 1 value of À1.09, suggesting the build-up of positive
Scheme 3. Ruthenium-catalyzed oxidative coupling of 3a with 2a using
2,6-Cl2pyNO as oxidant.
5728
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Chem. Eur. J. 2010, 16, 5723 – 5735

Ruthenium-Catalyzed C-3 Alkylation of Indoles
FULL PAPER
Table 4. Ruthenium-catalyzed three-component coupling reactions of indoles, paraformaldehyde, and
anilines.[a]
charge on the aniline in the
transition state. Thus, the reac-
tion is accelerated by an elec-
tron-donating substituent but
retarded by an electron-with-
drawing substituent. The intra-
molecular and intermolecular
deuterium isotope effects for
[Ru(2,6-Cl2tpp)CO]-catalyzed
oxidative reaction of anilines
with N-phenylindole have been
examined. The kH/kD (intra)
values for the reactions of 4-X-
N-methyl-N-trideuteriomethyl-
Entry
1
Indole
Aniline
Product
Conv. [%][b]
Yield [%][c]
60
78
75
73[d]
AHCTUNGERTGaNNUN nilines (X=MeO, Me, H, Br)
were determined as 3.8, 3.2,
2.2, and 1.2, respectively, which
decrease on going from elec-
tron-donating to electron-with-
drawing substituents, suggesting
that electron transfer from the
tertiary amine to the oxoruthe-
86
70
65
90[d]
2
3
3a
3a
90
72
75
95[d]
nium
intermediate
occurs
80
65
75
during the initial stage.[23] The
kH/kD (inter) values for the re-
actions of 4-X-substituted N,N-
dimethyl- and N,N-bis(trideu-
teriomethyl)anilines (X=MeO,
Me, H) were measured as 2.5,
2.1, and 1.7, respectively. The
different values of kH/kD (inter)
and kH/kD (intra) are consistent
with an electron-transfer mech-
anism for the ruthenium por-
phyrin-catalyzed oxidation of
tertiary amines to iminium
ions.[23]
88[d]
4
5
6
3a
3i
85
68
71
82[d]
80
69
72
82[d]
3a
85
82
78
90[d]
7
8
3a
3a
82
62
40
80[d]
87
65
60
92[d]
Coupling reaction of tert-butyl-
dioxygenated amines with in-
doles: After the [Ru(2,6-
Cl2tpp)CO]-catalyzed oxidative
coupling reaction of N,N-dime-
thylaniline (3a) with N-phenyl-
indole (2a) (using TBHP as ox-
idant) had proceeded for 1 h,
we detected tert-butyldioxygen-
ated amine III (Scheme 2) in
the crude reaction mixture by
1H NMR analysis (see the Sup-
porting Information). In the ab-
sence of 2a, the reaction of 3a
with TBHP catalyzed by
[Ru(2,6-Cl2tpp)CO] at 508C for
5 h gave III in 90% isolated
yield. The following experi-
ments provide further evidence
9
2h
2h
75
40
70
78[d]
10
72
70
65
76[d]
11
12
2g
<10
–
–
<10[d]
–
Chem. Eur. J. 2010, 16, 5723 – 5735
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5729

C.-M. Che et al.
for the intermediacy of III in
the ruthenium-catalyzed oxida-
tive coupling reaction. Using
1a as catalyst, the reaction of
N-phenylindole 2a with III[24]
in toluene at 1108C for 4 h af-
forded 4a both in the absence
Table 4. (Continued)
Entry
Indole
Aniline
Product
–
Conv. [%][b]
Yield [%][c]
<5
–
–
<5[d]
13
20
90
85
and
presence
of
3a
25[d]
(Scheme 6); neither the 3-[p-
(dialkylamino)benzyl]indole
nor the indole dimer was de-
tected in the reaction mixtures.
These findings support the
view that the oxidative cou-
pling reactions of anilines with
14
15
30
87
85
32[d]
N-arylindoles
preferentially
afford 4a (via pathway A). In
contrast, the reaction of N-
methylindole 2g with III cata-
lyzed by 1a gave indole dimer
[a] Indole (0.2 mmol), paraformaldehyde (0.6 mmol), aniline (0.6 mmol), 1a (0.002 mmol), toluene (2 mL).
[b] Conversion based on the recovery of indoles. [c] Yield of 5 based on conversion. [d] RuCl3 (0.01 mmol).
Table 5. Recyclability of the [Ru(2,6-Cl2tpp)CO] catalyst for the three-
component reaction of indoles 2g with paraformaldehyde and 3a.[a]
Scheme 6. Reaction of 2a with III.
Entry
Conv. [%][b]
Yield [%]
1
2
3
4
5
90
90
88
86
85
72
70
70
71
68
6a in 89% yield (Scheme 7), while the same reaction in the
presence of 3a afforded 3-[p-(dimethylamino)benzyl]indole
(5c) in 72% yield along with a trace amount of 6a
(Scheme 7). The reaction of 2g with N,N-di(trideuterome-
thyl)aniline (3l) gave deuterated product 5q in 52% yield
(Scheme 8). These experiments reveal that N-alkyl-indoles
tend to form 3-[p-(dialkylamino)benzyl]indole 5, and that
the CH2 group of 5 comes from the N-CH3 group of the ani-
[a] A mixture of 2g (2 mmol), paraformaldehyde (6 mmol), 3a (6 mmol),
and 1a (0.02 mmol) in toluene (10 mL) was stirred at 1108C for 6 h.
[b] Conversion based on the recovery of indoles. [c] Yield of 5c based on
conversion.
Figure 2. Hammett plot derived for [Ru(2,6-Cl2tpp)CO]-catalyzed oxida-
tive coupling reaction of p-X-C6H4N
2a.
(CH3)2 (X=MeO, Me, H, Br) with
Scheme 7. Reaction of 2g with N-methyl-N-(tert-butyldioxymethyl)ani-
line.
5730
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Chem. Eur. J. 2010, 16, 5723 – 5735

Ruthenium-Catalyzed C-3 Alkylation of Indoles
FULL PAPER
line, consistent with the formation of 5 via pathway B de-
picted in Scheme 2.
Scheme 10. a) Ruthenium-catalyzed reaction of 2g with (HCHO)n and
b) ruthenium-catalyzed reaction of 3a with (HCHO)n.
Scheme 8. Reaction of 2g with N,N-di(trideuteromethyl)aniline (3l).
Mechanism of the ruthenium-catalyzed three-component
coupling reaction of indoles, paraformaldehyde, and ani-
lines: We propose that the three-component reaction of in-
doles with formaldehyde and anilines to form 3-[p-(dialkyl-
ACHTUNGTRENNUNGamino)benzyl]indoles 5 involves a 3-alkylidene-3H-indolium
cation (intermediate V, Scheme 9), which may be generated
the reaction mixtures for the ruthenium-catalyzed three-
component coupling of indoles, paraformaldehyde, and ani-
lines. Nor were these dimers detected in the reaction mix-
tures for the ruthenium-catalyzed oxidative coupling of terti-
ary amines with indoles. The three-component coupling re-
action of 2g with deuterated paraformaldehyde and aniline
(3a) gave deuterium-substituted product 5r in 78% yield
(Scheme 11), consistent with the mechanism depicted in
Scheme 11. Ruthenium-catalyzed three-component coupling reaction of
2g, deuterated paraformaldehyde, and 3a.
Scheme 9. The low substrate conversions (5–32%) in the
three-component reactions of N-arylindoles, paraformalde-
hyde, and anilines (Table 4, entries 12–15) might suggest
that N-arylindoles are reluctant to react with paraformalde-
hyde to form 3-alkylidene-3H-indolium cation V under the
ruthenium-catalyzed conditions. This could rationalize the
finding that ruthenium-catalyzed oxidative coupling reac-
tions of tertiary amines with N-arylindoles using TBHP as
oxidant did not give 3-[p-(dialkylamino)benzyl]indoles 5
(via pathway B, Scheme 2).
Scheme 9. Possible pathways for the ruthenium-catalyzed three-compo-
nent reaction.
by ruthenium-catalyzed condensation of indoles with form-
Conclusion
aldehyde.[25] The formation of
5 via intermediate VI
(Scheme 9), as proposed for the three-component coupling
reaction of N-methyl or N-H indoles, formaldehyde, and
anilines in methanol catalyzed by silica-supported perchloric
acid,[15e] cannot be excluded, but is evidently less favored in
the ruthenium-catalyzed reactions in the light of the follow-
ing observations (Scheme 10): i) in the presence of 1a
(1 mol%) or RuCl3 (5 mol%), N-methylindole (2g) reacted
with paraformaldehyde to give indole dimer 6a in 85–95%
yield; ii) no reaction was observed between aniline 3a and
paraformaldehyde under similar reaction conditions. More-
over, aniline dimers 7[26] (Scheme 9) were not detected in
We have developed two types of ruthenium-catalyzed reac-
tion for the C-3 alkylation of indoles in high yields: i) oxida-
tive coupling of tertiary amines with indoles using TBHP as
oxidant, and ii) three-component coupling of indoles, paraf-
ormaldehyde, and anilines. Through ruthenium-catalyzed re-
action i), N-arylindoles were alkylated to afford 3-{[(N-aryl-
N-alkyl)amino]methyl}indoles, whereas N-alkylindoles were
alkylated to give 3-[p-(dialkylamino)benzyl]indoles. The
same 3-[p-(dialkylamino)benzyl]indoles could be obtained
from N-alkylindoles through ruthenium-catalyzed reaction
ii).
Chem. Eur. J. 2010, 16, 5723 – 5735
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5731

C.-M. Che et al.
(d, J=8.1 Hz, 2H), 7.12–7.18 (m, 2H), 7.24 (s, 2H), 7.28–7.31 (m, 3H),
7.44–7.51 (m, 4H), 7.54–7.60 ppm (m, 2H); 13C NMR (100 MHz, CDCl3):
d=38.71, 49.17, 108.95, 111.19, 114.26, 114.42, 114.98, 119.78, 120.76,
123.22, 124.71, 126.56, 126.89, 128.48, 130.09, 132.28, 136.88, 149.40 ppm;
MS (EI): m/z: 390 [M+]; HRMS (EI): m/z: calcd for C22H19N2Br:
390.0732; found 390.0735.
Experimental Section
General: Ruthenium porphyrins were prepared according to the litera-
ture.[10] Solvents (AR grade) were used as received unless otherwise
specified. NMR spectra were recorded on Bruker AMX-300/400 spec-
trometers from solutions in CDCl3. Chemical shifts are expressed in ppm
and coupling constants are given in Hz. 1H NMR data are recorded as
follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet;
m, multiplet), coupling constant (Hz), integration. 13C NMR data are re-
ported in terms of chemical shift (d, ppm). Lower resolution mass spectra
and high-resolution mass spectra (HRMS) were obtained on Finnigan
GC-MS 4021 and Finnigan MAT-8430 instruments, respectively, using the
electron-impact ionization technique (70 eV).
N,4-Dimethyl-N-[(1-phenyl-1H-indol-3-yl)methyl]benzenamine
(4 f):
Yellow oil, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
0.52; 1H NMR (300 MHz, CDCl3): d=2.28 (s, 3H), 2.97 (s, 3H), 4.67 (s,
2H), 6.81 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 7.15–7.24 (m, 4H),
7.45–7.47 (m, 4H), 7.47 (d, J=8.1 Hz, 1H), 7.54 ppm (d, J=7.8 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=20.26, 38.23, 49.09, 110.57, 113.48, 114.53,
118.15, 119.47, 120.11, 122.55, 124.17, 126.00, 126.21, 128.28, 129.53,
129.66, 136.31, 139.69, 148.19 ppm; MS (EI): m/z: 326 [M+]; HRMS (EI):
m/z: calcd for C23H22N2: 326.1783; found 326.1786.
General procedure for ruthenium porphyrin-catalyzed oxidative coupling
of tertiary amines with N-arylindoles (Table 1): tert-Butyl hydroperoxide
(0.6 mmol, 77 mL, 70% in water) was added to a mixture of tertiary
amine (0.6 mmol), [Ru(2,6-Cl2tpp)CO] (1a) (2.1 mg, 0.002 mmol), and
the requisite indole (0.2 mmol) in toluene (0.5 mL) at room temperature
in a flask open to the air. The reaction mixture was heated at 1108C for
6 h. After cooling, the mixture was diluted with ethyl acetate (30 mL)
and washed successively with water (3ꢁ10 mL), saturated NaHCO3 solu-
tion (5 mL), and brine (5 mL), and then dried over anhydrous sodium
sulfate. After filtration of the organic phase through a short pad of
Celite, the solvent was removed under reduced pressure and the residue
was purified by flash column chromatography on silica gel (hexane/
EtOAc, 30:1) to afford the corresponding coupling product.
N,3-Dimethyl-N-[(1-phenyl-1H-indol-3-yl)methyl]benzenamine
(4g):
Yellow oil, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
0.51; 1H NMR (400 MHz, CDCl3): d=2.28 (s, 3H), 2.99 (s, 3H), 4.70 (s,
2H), 6.55 (d, J=7.8 Hz, 1H), 6.71 (d, J=6.1 Hz, 2H), 7.16–7.36 (m, 5H),
7.45–7.47 (m, 1H), 7.55–7.57 (m, 3H), 7.63 (d, J=8.0 Hz, 1H), 7.68 ppm
(d, J=7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=22.45, 38.50, 49.25,
110.76, 111.12, 114.23, 117.90, 118.15, 119.32, 119.95, 120.65, 123.09,
124.69, 126.65, 126.75, 128.23, 129.96, 130.06, 131.86, 140.19, 150.75 ppm;
MS (EI): m/z: 326 [M+]; HRMS (EI): m/z: calcd for C23H22N2: 326.1783;
found 326.1779.
N,2-Dimethyl-N-[(1-phenyl-1H-indol-3-yl)methyl]benzenamine
(4h):
Yellow oil, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
0.50; 1H NMR (400 MHz, CDCl3): d=2.33 (s, 3H), 2.68 (s, 3H), 4.35 (s,
2H), 6.99 (t, J=7.2 Hz, 1H), 7.13–7.25 (m, 6H), 7.27–7.31 (m, 1H), 7.49–
7.51 (m, 4H), 7.54 (d, J=8.0 Hz, 1H), 7.63 ppm (d, J=7.9 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=18.45, 41.19, 51.77, 110.44, 114.71, 119.88,
120.00, 120.04, 122.42, 122.94, 124.18, 126.20, 126.39, 126.93, 128.94,
129.57, 131.09, 133.08, 136.22, 139.98, 152.55 ppm; MS (EI): m/z: 326 [M+
]; HRMS (EI): m/z: calcd for C23H22N2: 326.1783; found 326.1780.
N-Methyl-N-[(1-phenyl-1H-indol-3-yl)methyl]benzenamine (4a): Yellow
solid, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =0.51;
1H NMR (300 MHz, CDCl3): d=3.02 (s, 3H), 4.73 (s, 2H), 6.73 (t, J=
7.2 Hz, 1H), 6.88 (d, J=7.9 Hz, 2H), 7.17–7.31 (m, 6H), 7.41–7.51 (m,
4H), 7.55 (d, J=8.2 Hz, 1H), 7.62 ppm (d, J=7.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=30.19, 49.42, 110.13, 113.74, 117.78, 119.85, 120.68,
123.11, 123.97, 124.59, 124.69, 126.79, 128.68, 129.67, 129.97, 130.05,
136.82, 140.12 ppm; MS (EI): m/z: 312 [M+]; HRMS (EI): m/z: calcd for
C22H20N2: 312.1626; found 312.1621.
4-Methoxy-N-methyl-N-[(1-phenyl-1H-indol-3-yl)methyl]benzenamine
(4i): Yellow solid, analytical TLC (silica gel 60) (5% EtOAc in hexane),
N-Methyl-N-[(1-o-tolyl-1H-indol-3-yl)methyl]benzenamine (4b): Yellow
solid, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =0.50;
1H NMR (400 MHz, CDCl3): d=2.08 (s, 3H), 3.08 (s, 3H), 4.89 (s, 2H),
6.69 (t, J=7.2 Hz, 1H), 6.90 (d, J=8.0 Hz, 2H), 7.00 (s, 1H), 7.09 (d, J=
6.8 Hz, 1H), 7.18–7.23 (m, 2H), 7.25–7.30 (m, 2H), 7.31–7.35 (m, 2H),
7.36–7.41 (m, 2H), 7.71 ppm (d, J=7.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=17.59, 37.98, 48.70, 110.61, 113.06, 113.13, 116.61, 118.09,
119.16, 119.61, 122.23, 126.68, 127.09, 128.01, 129.06, 129.22, 131.15,
135.68, 137.69, 145.62, 149.88 ppm; MS (EI): m/z: 326 [M+]; HRMS (EI):
m/z: calcd for C23H22N2: 326.1783; found 326.1780.
1
Rf =0.35; H NMR (400 MHz, CDCl3): d=2.92 (s, 3H), 3.76 (s, 3H), 4.66
(s, 2H), 6.86–6.88 (m, 4H), 7.17–7.46 (m, 4H), 7.48–7.53 (m, 4H), 7.57
(d, J=8.0 Hz, 1H), 7.63 ppm (d, J=7.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=39.10, 50.69, 55.75, 110.62, 114.73, 116.04, 116.97, 119.35,
120.27, 122.60, 124.22, 126.37, 127.01, 128.35, 128.44, 129.57, 136.23,
139.58, 157.82 ppm; MS (EI): m/z: 342 [M+]; HRMS (EI): m/z: calcd for
C23H22N2O: 342.1732; found 342.1734.
N-Butyl-N-[(1-phenyl-1H-indol-3-yl)methyl]benzenamine (4j): Yellow
oil, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =0.55;
1H NMR (400 MHz, CDCl3): d=0.93 (t, J=8.1 Hz, 3H), 1.33–1.39 (m,
2H), 1.65–1.68 (m, 2H), 3.43 (t, J=7.2 Hz, 2H), 4.73 (s, 2H), 6.66 (t, J=
7.2 Hz, 1H), 6.80 (d, J=7.8 Hz, 2H), 7.18–7.30 (m, 6H), 7.42–7.48 (m,
4H), 7.50 (d, J=8.0 Hz, 1H), 7.72 ppm (d, J=7.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=13.96, 20.37, 29.32, 46.76, 50.48, 110.64, 112.51,
114.48, 115.83, 119.20, 120.07, 122.57, 124.18, 124.38, 125.97, 126.20,
127.94, 129.13, 129.51, 136.75, 148.83 ppm; MS (EI): m/z: 354 [M+];
HRMS (EI): m/z: calcd for C25H26N2: 354.2096; found 354.2093.
N-Methyl-N-[(1-p-tolyl-1H-indol-3-yl)methyl]benzenamine (4c): White
solid, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =0.50;
1H NMR (300 MHz, CDCl3): d=2.35 (s, 3H), 3.05 (s, 3H), 4.75 (s, 2H),
6.77 (t, J=7.2 Hz, 1H), 6.92 (d, J=8.0 Hz, 2H), 7.18–7.21 (m, 2H), 7.23–
7.38 (m, 7H), 7.55 (d, J=8.2 Hz, 1H), 7.66 ppm (d, J=7.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=21.55, 38.53, 49.25, 111.15, 113.55,
114.51, 117.16, 119.89, 120.53, 121.57, 122.72, 124.66, 124.85, 128.58,
129.59, 130.62, 136.67, 137.66, 150.66 ppm; MS (EI): m/z: 326 [M+];
HRMS (EI): m/z: calcd for C23H22N2: 326.1783; found 326.1781.
1,2,3,4-Tetrahydro-2-phenyl-1-(1-p-tolyl-1H-indol-3-yl)isoquinoline (4k):
White solid, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
0.48; 1H NMR (400 MHz, CDCl3): d=2.39 (s, 3H), 2.85 (ddd, J=15.1,
4.2, 4.2 Hz, 1H), 3.07 (ddd, J=15.1, 7.6, 7.6 Hz, 1H), 3.55–3.68 (m, 2H),
6.23 (s, 1H), 6.75 (s, 1H), 6.81 (t, J=7.5 Hz, 1H), 7.05–7.10 (m, 3H),
7.15–7.22 (m, 4H), 7.23–7.30 (m, 6H), 7.31–7.38 (m, 1H), 7.40 (d, J=
8.3 Hz, 1H), 7.63 ppm (d, J=7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=21.12, 42.51, 55.81, 57.60, 111.34, 112.58, 113.63, 117.85, 120.16,
121.64, 121.95, 122.38, 123.35, 125.56, 125.86, 126.72, 127.23, 128.07,
128.29, 128.91, 129.81, 132.26, 133.15, 134.65, 137.28, 150.02 ppm; MS
(EI): m/z: 414 [M+]; HRMS (EI): m/z: calcd for C30H26N2: 414.2096;
found 414.2092.
N-{[1-(4-Methoxyphenyl)-1H-indol-3-yl]methyl}-N-methylbenzenamine
(4d): White solid, analytical TLC (silica gel 60) (5% EtOAc in hexane),
1
Rf =0.38; H NMR (400 MHz, CDCl3): d=2.99 (s, 3H), 3.83 (s, 3H), 4.70
(s, 2H), 6.71 (t, J=7.2 Hz, 1H), 6.89 (d, J=8.0 Hz, 2H), 6.97 (d, J=
6.8 Hz, 2H), 7.09 (s, 1H), 7.15–7.27 (m, 4H), 7.33 (d, J=6.7 Hz, 2H),
7.45 (d, J=8.0 Hz, 1H), 7.63 ppm (d, J=7.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=37.95, 48.65, 55.52, 110.43, 112.99, 113.65, 114.64,
115.68, 119.28, 122.36, 125.76, 126.49, 127.80, 129.10, 132.66, 136.78,
150.09, 158.08 ppm; MS (EI): m/z: 342 [M+]; HRMS (EI): m/z: calcd for
C23H22N2O: 342.1732; found 342.1731.
4-Bromo-N-methyl-N-[(1-phenyl-1H-indol-3-yl)methyl]benzenamine
(4e): White solid, analytical TLC (silica gel 60) (5% EtOAc in hexane),
Rf =0.52; H NMR (400 MHz, CDCl3): d=3.00 (s, 3H), 4.69 (s, 2H), 6.97
1,2,3,4-Tetrahydro-1-[1-(4-methoxyphenyl)-1H-indol-3-yl]-2-phenylisoqui-
noline (4l): White solid, analytical TLC (silica gel 60) (5% EtOAc in
hexane), Rf =0.37; 1H NMR (400 MHz, CDCl3); d=2.85 (ddd, J=15.8,
1
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Chem. Eur. J. 2010, 16, 5723 – 5735

Ruthenium-Catalyzed C-3 Alkylation of Indoles
FULL PAPER
4.3, 4.3 Hz, 1H), 3.07 (ddd, J=15.8, 7.5, 7.5 Hz, 1H), 3.66 (d, J=3.2 Hz,
1H), 3.67 (d, J=12.0 Hz, 1H), 3.84 (s, 3H), 6.24 (s, 1H), 6.72 (s, 1H),
6.80 (t, J=7.2 Hz, 1H), 6.95 (d, J=8.9 Hz, 2H), 7.05–7.07 (m, 3H), 7.16–
7.19 (m, 4H), 7.20–7.26 (m, 4H), 7.26–7.27 (m, 1H), 7.28 (d, J=8.8 Hz,
1H), 7.70 ppm (d, J=7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
26.52, 42.35, 55.57, 56.60, 110.34, 113.55, 114.62, 115.84, 118.16, 119.64,
119.95, 120.37, 122.33, 125.76, 125.91, 126.72, 127.12, 128.08, 128.19,
128.90, 129.24, 132.16, 135.64, 137.26, 149.98, 160.12 ppm; MS (EI): m/z:
430 [M+]; HRMS (EI): m/z: calcd for C30H26N2O: 430.2045; found
430.2042.
264 [M+]; HRMS (EI): m/z: calcd for C18H20N2: 264.1626; found
264.1626.
N-Ethyl-4-[(1-ethyl-1H-indol-3-yl)methyl]-N-methylbenzenamine (5g):
White solid, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
1
0.52; H NMR (300 MHz, CDCl3): d=1.13 (t, J=7.1 Hz, 3H), 1.48 (t, J=
7.2 Hz, 3H), 2.89 (s, 6H), 3.40 (q, J=7.1 Hz, 3H), 4.04 (s, 2H), 4.13 (q,
J=7.3 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.83 (s, 1H), 7.08 (t, J=7.1 Hz,
1H), 7.16–7.24 (m, 3H), 7.31 (d, J=8.2 Hz, 1H), 7.57 ppm (d, J=7.9 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=11.20, 15.48, 30.46, 37.57, 40.68,
47.05, 109.08, 112.76, 115.32, 119.17, 119.39, 121.76, 125.17, 128.09, 129.03,
136.18, 147.51 ppm; MS (EI): m/z 292 [M+]; HRMS (EI): m/z: calcd for
C20H24N2: 292.1939; found 292.1937.
N-[(1-Benzyl-1H-indol-3-yl)methyl]-N-methylbenzenamine (4m): Yellow
oil, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =0.45;
1H NMR (300 MHz, CDCl3): d=2.94 (s, 3H), 4.65 (s, 2H), 5.20 (s, 2H),
6.68 (t, J=7.2 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.94 (s, 1H), 7.04–7.18
(m, 4H), 7.21–7.25 (m, 6H), 7.58 ppm (d, J=7.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=37.92, 48.72, 49.97, 109.83, 112.41, 113.21, 116.65,
119.34, 121.94, 126.66, 126.82, 127.54, 127.63, 127.84, 129.12, 129.21,
137.62, 138.69, 149.50 ppm; MS (EI): m/z: 326 [M+]; HRMS (EI): m/z:
calcd for C23H22N2: 326.1783; found 326.1774.
N-Ethyl-N-methyl-4-[(1-methyl-1H-indol-3-yl)methyl]benzenamine (5h):
White solid, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
0.51; 1H NMR (300 MHz, CDCl3): d=1.14 (t, J=7.1 Hz, 3H), 2.90 (s,
3H), 3.40 (q, J=7.1 Hz, 2H), 3.74 (s, 3H), 4.05 (s, 2H), 6.70 (d, J=
8.7 Hz, 2H), 6.76 (s, 1H), 7.17 (t, J=8.1 Hz, 1H), 7.24 (d, J=8.6 Hz,
2H), 7.26–7.32 (m, 2H), 7.59 ppm (d, J=7.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=11.18, 30.38, 32.50, 37.56, 47.03, 108.99, 112.76,
115.32, 119.05, 119.27, 121.39, 127.07, 127.92, 128.89, 129.35, 137.15,
147.52 ppm; MS (EI): m/z: 278 [M+]; HRMS (EI): m/z: calcd for
C19H22N2: 278.1783; found 278.1780.
General procedure for ruthenium porphyrin-catalyzed oxidative coupling
of tertiary amines with N-alkylindoles (Table 2): tert-Butyl hydroperoxide
(0.6 mmol, 77 mL, 70% in water) was added to a mixture of the tertiary
amine (0.6 mmol), [Ru(2,6-Cl2tpp)CO] 1a (2.1 mg, 0.002 mmol), and the
N-alkylindole (0.2 mmol) in toluene (0.5 mL) at room temperature in a
flask open to the air. The reaction mixture was heated at 1108C for 6 h.
After cooling, the mixture was diluted with ethyl acetate (30 mL) and
washed successively with water (3ꢁ10 mL), saturated NaHCO3 solution
(5 mL), and brine (5 mL), and then dried over anhydrous sodium sulfate.
After filtration of the organic phase through a short pad of Celite, the
solvent was removed under reduced pressure and the residue was puri-
fied by flash column chromatography on silica gel (hexane/EtOAc, 30:1)
to afford the corresponding coupling product.
General procedure for ruthenium porphyrin-catalyzed three-component
coupling reaction of indoles, paraformaldehyde, and anilines (Tables 3
and 4): Paraformaldehyde (0.6 mmol) was added to a mixture of tertiary
amine (0.6 mmol), [Ru(2,6-Cl2tpp)CO] 1a (2.1 mg, 0.002 mmol), and
indole (0.2 mmol) in toluene (2 mL) at room temperature in a flask open
to the air. After heating at 1108C for 6 h, the solvent was removed under
reduced pressure. The residue was diluted with ethyl acetate (30 mL) and
washed successively with water (3ꢁ10 mL), saturated NaHCO3 solution
(5 mL), and brine (5 mL), and then dried over anhydrous sodium sulfate.
After filtration of the organic phase through a short pad of Celite, the
solvent was removed under reduced pressure and the residue was puri-
fied by flash column chromatography on silica gel (hexane/EtOAc, 20:1
or hexane/EtOAc, 10:1) to afford the corresponding coupling product.
4-[(1-Benzyl-1H-indol-3-yl)methyl]-N,N-dimethylbenzenamine
(5a):
Yellow oil, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
0.41; 1H NMR (300 MHz, CDCl3): d=2.86 (s, 6H), 3.96 (s, 2H), 5.18 (s,
2H), 6.62 (d, J=8.6 Hz, 2H), 6.77 (s, 1H), 7.07–7.11 (m, 6H), 7.17–7.30
(m, 4H), 7.50 ppm (d, J=7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
30.46, 40.89, 49.85, 109.53, 112.51, 112.99, 116.10, 118.89, 119.40, 121.62,
126.41, 126.51, 126.67, 127.41, 128.65, 129.23, 129.46, 137.85, 149.68 ppm;
MS (EI): m/z: 340 [M+]; HRMS (EI): m/z: calcd for C24H24N2: 340.1939;
found 340.1936.
4-[(5-Chloro-1H-indol-3-yl)methyl]-N,N-dimethylbenzenamine
(5i):
White solid, analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf =
0.42; 1H NMR (400 MHz, CDCl3): d=2.92 (s, 6H), 3.97 (s, 2H), 6.70 (d,
J=6.7 Hz, 2H), 6.91 (s, 1H), 7.11–7.15 (m, 3H), 7.23 (d, J=8.6 Hz, 1H),
7.51 (s, 1H), 7.98 ppm (brs, NH, 1H); 13C NMR (100 MHz, CDCl3): d=
30.83, 41.40, 112.47, 113.54, 117.09, 119.22, 122.71, 124.05, 125.48, 129.15,
129.36, 129.69, 135.30, 149.68 ppm; MS (EI): m/z: 283 [M+]; HRMS (EI):
m/z: calcd for C17H16ClN2: 283.1002; found 283.1000.
4-[(1-Ethyl-1H-indol-3-yl)methyl]-N,N-dimethylbenzenamine
(5b):
White solid, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
0.55; 1H NMR (300 MHz, CDCl3): d=1.45 (t, J=7.3 Hz, 3H), 2.93 (s,
6H), 4.09 (s, 2H), 4.13 (q, J=7.3 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 6.83
(s, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.21–7.22 (m, 3H), 7.33 (d, J=8.1 Hz,
1H), 7.58 ppm (d, J=7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
16.01, 31.01, 41.39, 41.45, 109.63, 113.33, 115.78, 119.09, 122.29, 125.71,
128.59, 129.61, 129.75, 136.71, 149.59 ppm; MS (EI): m/z: 278 [M+];
HRMS (EI): m/z: calcd for C19H22N2: 278.1783; found 278.1776.
4-[(5-Ethoxy-1H-indol-3-yl)methyl]-N,N-dimethylbenzenamine
(5j):
White solid, analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf =
0.38; 1H NMR (300 MHz, CDCl3): d=1.41 (t, J=7.0 Hz, 3H), 2.89 (s,
6H), 3.97 (s, 2H), 4.05 (q, J=7.0 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 6.82
(d, J=8.0 Hz, 1H), 6.85 (s, 1H), 6.98 (s, 1H), 7.15 (d, J=8.7 Hz, 2H),
7.21–7.24 (m, 1H), 7.80 ppm (brs, NH, 1H); 13C NMR (100 MHz,
CDCl3): d=15.23, 30.69, 41.14, 64.38, 102.51, 111.79, 112.76, 113.26,
114.85, 119.18, 123.16, 129.44, 129.50, 129.81, 131.85, 149.82 ppm; MS
(EI): m/z: 294 [M+], 265 [M+ÀC2H5]; HRMS (EI): m/z: calcd for
C19H22N2O: 294.1732; found 294.1724.
4-[(1H-Indol-3-yl)methyl]-N-butyl-N-methylbenzenamine (5e): White
solid, analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf =0.41;
1H NMR (400 MHz, CDCl3): d=0.95 (t, J=7.6 Hz, 3H), 1.42 (m, 2H),
1.71 (m, 2H), 2.90 (s, 3H), 3.28 (q, J=7.6 Hz, 2H), 4.05 (s, 2H), 6.71 (d,
J=8.7 Hz, 2H), 6.78 (s, 1H), 7.15 (t, J=8.1 Hz, 1H), 7.16–7.22 (m, 3H),
7.45 (d, J=7.9 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.90 ppm (brs, NH,
1H); 13C NMR (100 MHz, CDCl3): d=14.52, 20.89, 29.31, 30.96, 38.91,
53.33, 111.46, 112.90, 117.36, 119.69, 128.08, 129.02, 129.83, 136.98,
148.29 ppm; MS (EI): m/z: 292 [M+]; HRMS (EI): m/z: calcd for
C20H24N2: 292.1939; found 292.1941.
3-[4-(Dimethylamino)benzyl]-1H-indol-5-ol (5k): White solid, analytical
TLC (silica gel 60) (50% EtOAc in hexane), Rf =0.35; 1H NMR
(300 MHz, CDCl3): d=2.88 (s, 6H), 3.95 (s, 2H), 6.68 (d, J=7.9 Hz, 2H),
6.73 (d, J=7.2 Hz, 1H), 6.89 (s, 2H), 7.13–7.18 (m, 3H), 7.80 ppm (brs,
NH, 1H); 13C NMR (100 MHz, CDCl3): d=29.66, 40.91, 103.79, 110.05,
111.56, 111.58, 113.03, 123.34, 128.98, 129.17, 136.78, 145.12, 146.78,
150.12 ppm; MS (EI): m/z: 266 [M+]; HRMS (EI): m/z: calcd for
C17H18N2O: 266.1419; found 266.1415.
4-[(1H-Indol-3-yl)methyl]-N-ethyl-N-methylbenzenamine (5 f): White
solid, analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf =0.42;
1H NMR (400 MHz, CDCl3): d=1.12 (t, J=7.0 Hz, 3H), 2.89 (s, 3H),
3.37 (q, J=7.0 Hz, 2H), 4.05 (s, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.89 (s,
1H), 7.12 (t, J=8.1 Hz, 1H), 7.13–7.21 (m, 3H), 7.34 (d, J=7.5 Hz, 1H),
7.58 (d, J=7.9 Hz, 1H), 7.90 ppm (brs, NH, 1H); 13C NMR (75 MHz,
CDCl3): d=11.06, 30.47, 37.59, 47.08, 110.95, 112.64, 116.78, 119.23,
121.85, 122.14, 127.57, 128.06, 129.36, 136.47, 147.52 ppm; MS (EI): m/z:
4-[(1H-Indol-3-yl)methyl]-N,N,3-trimethylbenzenamine (5l): Pale-yellow
solid, analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf =0.39;
1H NMR (400 MHz, CDCl3): d=2.31 (s, 3H), 2.93 (s, 6H), 4.01 (s, 2H),
6.56 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.72 (s, 1H), 7.05–7.13 (m, 2H),
7.20 (d, J=7.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H),
7.90 ppm (brs, NH, 1H); 13C NMR (100 MHz, CDCl3): d=20.01, 26.38,
28.68, 40.94, 110.67, 110.96, 111.58, 114.99, 116.16, 119.09, 119.16, 121.85,
Chem. Eur. J. 2010, 16, 5723 – 5735
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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C.-M. Che et al.
122.25, 127.61, 130.09, 136.45, 136.95, 149.34 ppm; MS (EI): m/z: 264
[M+]; HRMS (EI): m/z: calcd for C18H10N2: 264.1626; found 264.1625.
S.-I. Murahashi, Chem. Rev. 1998, 98, 2599–2660; f) S.-I. Murahashi,
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4-[(1H-Indol-3-yl)methyl]-N,N-diethylbenzenamine (5m): White solid,
analytical TLC (silica gel 60) (20% EtOAc in hexane), Rf =0.45;
1H NMR (400 MHz, CDCl3): d=1.13 (t, J=7.0 Hz, 6H), 3.30 (q, J=
7.0 Hz, 4H), 4.01 (s, 2H), 6.61 (d, J=8.4 Hz, 2H), 6.90 (s, 1H), 7.07–7.15
(m, 4H), 7.32 (d, 1H), 7.55 (d, 1H), 7.88 ppm (brs, NH, 1H); 13C NMR
(100 MHz, CDCl3): d=13.08, 30.91, 44.93, 111.43, 112.75, 117.32, 119.68,
119.76, 122.37, 122.62, 127.05, 129.92, 131.12, 137.08, 149.72 ppm; MS
(EI): m/z: 278 [M+]; HRMS (EI): m/z: calcd for C19H22N2: 278.1783;
found 278.1785.
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3-[4-(Piperidin-1-yl)benzyl]-1-methyl-1H-indole (5n): Yellow solid, ana-
lytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =0.51; 1H NMR
(300 MHz, CDCl3): d=1.55–1.58 (m, 2H), 1.72–1.75 (m, 4H), 3.12 (t, J=
5.7 Hz, 4H), 3.72 (s, 3H), 4.03 (s, 2H), 6.73 (s, 1H), 6.89 (d, J=8.5 Hz,
2H), 7.17 (t, J=6.7 Hz, 1H), 7.23–7.27 (m, 4H), 7.52 ppm (d, J=7.9 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=20.78, 24.18, 30.30, 32.53, 51.28,
109.03, 114.91, 116.89, 118.62, 118.85, 119.24, 121.44, 126.99, 127.85,
129.21, 137.15 ppm; MS (EI): m/z: 304 [M+]; HRMS (EI): m/z: calcd for
C21H24N2: 304.1939; found 304.1941.
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N,N-Dimethyl-4-[(1-p-tolyl-1H-indol-3-yl)methyl]benzenamine
(5o):
White solid, analytical TLC (silica gel 60) (5% EtOAc in hexane), Rf =
0.49; 1H NMR (300 MHz, CDCl3): d=2.41 (s, 3H), 2.90 (s, 6H), 4.06 (s,
2H), 6.69 (d, J=8.2 Hz, 2H), 7.01 (s, 1H), 7.11–7.17 (m, 1H), 7.19 (d, J=
8.5 Hz, 2H), 7.22–7.28 (m, 3H), 7.33 (d, J=8.3 Hz, 2H), 7.52 (d, J=
8.3 Hz, 1H), 7.58 ppm (d, J=7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=29.67, 30.44, 40.89, 110.39, 113.01, 117.46, 119.45, 119.63, 122.18,
123.18, 123.99, 126.06, 127.81, 128.03, 129.33, 129.98, 135.74, 136.28,
138.19 ppm; MS (EI): m/z: 340 [M+]; HRMS (EI): m/z: calcd for
C24H24N2: 340.1939; found 340.1936.
4-{[1-(4-Methoxyphenyl)-1H-indol-3-yl]methyl}-N,N-dimethylbenzena-
mine (5p): White solid, analytical TLC (silica gel 60) (5% EtOAc in
hexane), Rf =0.32; 1H NMR (300 MHz, CDCl3): d=2.90 (s, 6H), 3.86 (s,
3H), 4.06 (s, 2H), 6.69 (d, J=6.9 Hz, 2H), 6.96–6.98 (m, 3H), 7.00–7.18
(m, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.37 (d, J=
8.1 Hz, 1H), 7.65 ppm (d, J=7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=30.44, 40.89, 55.54, 110.23, 113.01, 114.59, 117.68, 119.41, 119.51,
122.11, 125.66, 126.29, 128.35, 128.67, 129.33, 133.15, 137.18, 148.55,
147.82 ppm; MS (EI): m/z: 356 [M+]; HRMS (EI): m/z: calcd for
C24H24N2O: 356.1888; found 356.1878.
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Acknowledgements
This work was supported by The University of Hong Kong (University
Development Fund), the Hong Kong Research Grants Council
(HKU7009/06P), and the Area of Excellence Scheme (AoE/P-10-01) es-
tablished under the University Grants Committee (HKSAR).
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5734
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Ruthenium-Catalyzed C-3 Alkylation of Indoles
FULL PAPER
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Received: August 28, 2009
Revised: January 21, 2010
Published online: April 13, 2010
Chem. Eur. J. 2010, 16, 5723 – 5735
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www.chemeurj.org
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