Selective ruthenium-catalyzed alkylation of indoles by using amines

Article abstract of DOI:10.1002/chem.200903261

(Chemical Equation Presented) Lend me your hydrogen! The first transition-metal-catalyzed alkylations of indoles with aliphatic amines proceeding under transfer hydrogenation conditions are developed (see scheme). This reaction is based on the borrowing h

Full text of DOI:10.1002/chem.200903261

COMMUNICATION
DOI: 10.1002/chem.200903261
Selective Ruthenium-Catalyzed Alkylation of Indoles by Using Amines
Sebastian Imm, Sebastian Bꢀhn, Annegret Tillack, Kathleen Mevius,
Lorenz Neubert, and Matthias Beller*[a]
Indoles belong to the important heterocyclic ring systems
in nature. Based on their significant structural diversity and
potent biological activity they have become key building
blocks for several pharmaceutical agents.[1] In the past, the
development of novel synthetic methodologies for the gen-
eration of the basic heterocyclic core, as well as functionali-
zation reactions on the aromatic ring system, have stimulat-
ed widespread utilization of indoles in life sciences.[2]
Among the numerous known bioactive indoles, C-3-alky-
lated derivatives, for example, naturally occurring serotonin
and melatonin, are of major importance. More recently de-
veloped efficient approaches for catalytic C-3-functionaliza-
tion of indoles are based on different types of Friedel–Crafts
reactions, which proceed, for example, in the presence of
Lewis and Brønsted acids as well as organocatalysts.[3] In
contrast to these alkylations, transition-metal-catalyzed
methodologies have been rarely exploited. In this respect,
the recent work of Grigg et al.[4] is noteworthy, they ach-
ieved good yields by applying mainly benzylic alcohols as al-
kylation reagents. This reaction is based on the so-called
“borrowing hydrogen methodology”.[5] Thereby, the alcohol
is initially dehydrogenated, then undergoes a functionaliza-
tion reaction, and finally, re-hydrogenated. Elegant applica-
tions of this general methodology came from the groups of
Williams,[6] Yus,[7] Fujita,[8] Grigg,[9] and us.[10]
Scheme 1. Possible alkylations of indole using amines. R=alkyl, aryl.
Notably, such an alkylation process would lead to ammo-
nia as the only side product and proceed under basic condi-
tions, which is quite different from the more general Lewis
acid catalyzed reactions.
As a starting point of our investigations, we examined the
alkylation of indole with di-n-hexylamine (DHA) as a
model system. At first, several catalysts, including the ruthe-
nium p-cymene/1,1’-bis(diphenylphosphano)ferrocene (dppf)
system of Williams and Hamid,[13] ruthenium p-cymene/N-
(4-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN)
system developed by Noyori et al.,[14] the iridium/h5-C5Me5
(Cp*) catalyst of Fujita[8] and our ruthenium carbonyl–phos-
phane system,[15] which are known to be highly active in
transfer hydrogenation reactions were tested at 1408C with-
out solvent in a sealed tube. Unfortunately, we obtained
only low to moderate conversions. Thus, the catalyst screen-
ing was repeated at 1608C by applying the five most active
catalysts of the initial screening (Table 1). From all catalysts
tested, the Shvo complex (1)[16,17] (Scheme 2) showed the
highest reactivity, giving 41% of 3-hexylindole (Table 1,
entry 4). To our delight, C-alkylation in the 3-position oc-
curred selectively and no formation of the N-alkylated prod-
uct took place. To the best of our knowledge, these reactions
represent the first examples of borrowing-hydrogen-cata-
lyzed alkylation of arenes with amines.[18]
Based on our continuing interest in the activation of
amines[11] and the synthesis of novel indoles,[12] we had the
idea to apply the former methodology for the derivatization
of this important class of natural products. As a result, the
reaction of indoles with amines was studied. In principle,
such alkylations might result in N- and C-alkylated products
(Scheme 1).
Intensive mechanistic studies on transfer hydrogenation
processes in the presence of 1 were performed by the
groups of Bꢀckvall[19] and Casey.[20] It was shown that 1 is
dissociated into two active species when exposed to higher
temperatures. The 16 electron complex 1a catalyzes the de-
hydrogenation reaction, while the 18 electron complex 1b is
active in the hydrogenation step. Based on the known reac-
[a] S. Imm, S. Bꢀhn, Dr. A. Tillack, K. Mevius, L. Neubert,
Prof. Dr. M. Beller
Leibniz-Institut fꢁr Katalyse an der Universitꢀt Rostock e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903261.
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Table 1. Alkylation of indole with di-n-hexylamine in the presence of dif-
sults in the formation of intermediate 2, which is finally hy-
drogenated to give the desired product. Clearly, the hydro-
gen required for the final hydrogenation step is generated
completely by dehydrogenation of the amine in the first re-
action step. Hence, there is no need for additional hydrogen.
The discrepancy between conversion and yield (Table 1,
entry 4) is mainly explained by the formation of two side
products. On the one hand, reaction of intermediate 2 with
a second molecule of indole leads to the bis(3-indolyl)me-
thane species 3,[21] also reported by the group of Grigg.[4] On
the other hand, the formation of small amounts of 2,3’-biin-
dole are observed.
ferent catalysts.[a]
Entry
Catalyst[b]
Conv.[c] [%]
Yield[c] [%]
1
2
3
4
5
6
–
–
–
[Ru{(+)-binap}Cl2]
55
33
78
63
53
15
14
41
30
22
ACHTUNGTRENNUNG
[Ru3(CO)12]/CataCXiumꢃPCy
Shvo (1)
[{Rh(Cp*)Cl2}2]
[{Ir(Cp*)Cl2}2], NaHCO3
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Next, we investigated the influence of various reaction pa-
rameters on the model reaction (Table 2). Most importantly,
we discovered that the addition of catalytic amounts of po-
[a] Reaction conditions: di-n-hexylamine (0.5 mmol), indole (1 mmol),
catalyst (2 mol% metal with respect to indole), 1608C, 24 h.
[b] BINAP=2,2’-bis(diphosphano)-1-1’-binaphthyl, CataCXiumꢃPCy
=
N-phenyl-2-(dicyclohexylphosphanyl)pyrrole. [c] Conversion and yield
are determined by GC analysis with hexadecane as internal standard.
Conversions and yields are based on indole.
Table 2. Alkylation of indole with di-n-hexylamine under different reac-
tion conditions.[a]
Entry DHA/indole K2CO3 [mol%] T [8C] Conv.[b] [%] Yield[b] [%]
1
2
3
4
5
6
7
8
2
2
2
2
1
0.5
2
10
10
10
10
10
10
5
110
130
150
170
130
130
130
130
37
93
99
99
75
52
92
94
31
87
96
96
70
44
88
89
Scheme 2. Dissociation of 1.
2
2.5
tivity of 1, we propose the typical borrowing hydrogen
[a] Reaction conditions: indole (1 mmol), Shvo catalyst 1 (1 mol%), 24 h.
[b] Conversion and yield are determined by GC analysis with hexadecane
as internal standard. Conversions and yields are based on indole.
mechanism for this novel reaction (Scheme 3).
tassium carbonate increased the yield and selectivity for the
main product to a synthetically useful level. As shown in
Table 2 the product yield is increased to 87 and 96% in the
presence of potassium carbonate at 130 or 1508C, respec-
tively (Table 2, entries 2 and 3). Best results are obtained by
applying two equivalents of di-n-hexylamine (Table 2,
entry 2, 5, and 6). The excess of secondary amine undergoes
transalkylation side reactions to give also the corresponding
primary and tertiary amines. Interestingly, the amount of po-
tassium carbonate can be reduced to 2.5 mol% without any
decrease in the yield of the main product (Table 2, entry 8).
Finally, we were interested in the general applicability of
1 for this reaction. To demonstrate the scope of the process,
both various alkyl amines and indoles were investigated
(Tables 3 and 4).
In general, catalytic experiments were performed with
1 mol% of 1 in the presence of 4 equiv of the alkyl chain of
the amine. To achieve high yields even with less reactive
substrates, a reaction temperature of 1408C and an amount
of 5 mol% of potassium carbonate were chosen. The varia-
tion of the amines is summarized in Table 3. We were
pleased to find that different amines, including those with
Scheme 3. Borrowing hydrogen mechanism for the alkylation of indoles
with amines.
In situ dehydrogenation of the amine gives the corre-
sponding imine, which reacts with indole to form the amino-
alkylated product. Subsequent elimination of ammonia re-
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Ruthenium-Catalyzed Alkylation
COMMUNICATION
Table 3. Alkylation of indole with different amines.[a]
nonactivated alkyl chains are converted to the C-3-alkylated
indoles in good yields (85–96%). High yields were observed
by applying secondary amines like di-n-hexylamine or di-
benzylamine (Table 3, entries 2 and 8), but also with primary
amines at slightly higher temperature (Table 3, entries 1 and
7), which is in line with previous investigations in our
group.[22] These results constitute a significant improvement
compared with the work of Grigg and co-workers, who ach-
ieved a maximum yield of 35% using non-benzylic alco-
hols.[4]
Entry Amine
Product
Conv.[b] Yield[b]
[%]
[%]
1[c]
97
85
When considering the stability of tertiary amines, it is
noteworthy that the reaction of tri-n-hexylamine with indole
proceeded smoothly and resulted in a good yield of the al-
kylated indole (Scheme 4).
2
97
98
96
89 (83)
96 (78)
90 (61)
3
4
5[c]
6[d]
7[d]
94
95
88
85 (78)
77 (56)
86
Scheme 4. Alkylation of indole using tri-n-hexylamine.
Apparently, this process proceeds through the generation
of an iminium cation in the dehydrogenation step of the bor-
rowing hydrogen mechanism. After variation of the amines,
different indoles were tested in the reaction with di-n-hexyl-
amine. Here, we focused on commercially available 5-substi-
tuted indoles. Electron-rich and -deficient indoles are con-
verted in very good yields and selectivities to the desired
products (Table 4, entries 1–4). Due to the steric hindrance
of the methyl group, 2-methylindole showed somewhat
lower reactivity and a higher reaction temperature was re-
quired to give the corresponding product in 89% yield
(Table 4, entry 5).
In summary, we have demonstrated for the first time that
transition-metal-catalyzed C-alkylation of indoles with easily
available aliphatic amines is possible. This novel atom effi-
cient and selective method for indole alkylation proceeds in
the presence of 1 under basic conditions. It constitutes a
complementary and valuable method for alkylations and
benzylations. Hence, various substrates, including primary,
secondary, and even tertiary amines, react in good to excel-
lent yield with the C-alkylated indoles.
8
95
96
94
89
82
91 (84)
94 (83)
92 (90)
87 (85)
74
9[c]
10[d]
11[d]
12[d]
Experimental Section
13
90
89 (80)
General procedure for the Shvo-catalyzed alkylation of indoles: In an
ACE pressure tube under an argon atmosphere, catalyst 1 (10.8 mg,
0.01 mmol), indole (117.2 mg, 1 mmol), potassium carbonate (6.9 mg,
0.05 mmol), and dibenzylamine (394.6 mg, 2 mmol) were stirred at 1408C
for 24 h. Then, the volatile compounds were removed under vacuum and
the residue was purified in the first step by column chromatography
(heptane/ethyl acetate=4:1). In the second step the pre-cleaned product
was dissolved in methanol and purified by using an Isolute SCX-2
column (2 g/15 mL, Biotage) to remove remaining amines, which were
[a] Reaction conditions: indole (1 mmol), alkyl chain of the amine
(4 equiv), Shvo catalyst 1 (1 mol%), K2CO3 (5 mol% with respect to
indole), 1408C, 24 h. [b] Conversion and yield are determined by GC
analysis with hexadecane as internal standard. Conversions and yields are
based on indole. Isolated yields in brackets. [c] 1508C. [d] 1608C.
Chem. Eur. J. 2010, 16, 2705 – 2709
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M. Beller et al.
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Entry
1
Indole
Product
Conv.[b]
[%]
Yield[b]
[%]
100
100
100
95 (89)
90 (56)
92 (78)
2
3
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4
100
95
85 (58)
89 (68)
5[c]
[a] Reaction conditions: indole (1 mmol), di-n-hexylamine (2 mmol),
Shvo catalyst 1 (1 mol%), K2CO3 (5 mol% with respect to indoles),
1408C, 24 h. [b] Conversion and yield are determined by GC analysis
with hexadecane as internal standard. Conversions and yields are based
on the indole. Isolated yields in brackets. [c] 1608C.
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kept back by the SPE column and the product passed through. After-
wards methanol was removed under vacuum to afford 3-benzyl-1H-
indole (174.8 mg, 84%) as a white solid (m.p.=1088C).
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This work has been supported by the BMBF (Bundesministerium fꢁr Bil-
dung und Forschung) and the Deutsche Forschungsgemeinschaft (DFG
BE 1931/16-1, Leibniz-price).
Keywords: alkylation
transfer · indoles
· amines · catalysis · hydrogen
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Received: November 29, 2009
Published online: January 29, 2010
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