Cobalt-catalysed reductive C-H alkylation of indoles using carboxylic acids and molecular hydrogen

Article abstract of DOI:10.1039/c7sc02117h

The direct CH-alkylation of indoles using carboxylic acids is presented for the first time. The catalytic system based on the combination of Co(acac)₃ and 1,1,1-tris(diphenylphosphinomethyl)-ethane (Triphos, L1), in the presence of Al(OTf)₃ as co-catalyst, is able to perform the reductive alkylation of 2-methyl-1H-indole with a wide range of carboxylic acids. The utility of the protocol was further demonstrated through the C3 alkylation of several substituted indole derivatives using acetic, phenylacetic or diphenylacetic acids. In addition, a careful selection of the reaction conditions allowed to perform the selective C3 alkenylation of some indole derivatives. Moreover, the alkenylation of C2 position of 3-methyl-1H-indole was also possible. Control experiments indicate that the aldehyde, in situ formed from the carboxylic acid hydrogenation, plays a central role in the overall process. This new protocol enables the direct functionalization of indoles with readily available and stable carboxylic acids using a non-precious metal based catalyst and hydrogen as reductant.

Full text of DOI:10.1039/c7sc02117h

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Cobalt-catalysed reductive C–H alkylation of
indoles using carboxylic acids and molecular
Cite this: Chem. Sci., 2017, 8, 6439
hydrogen†
Jose R. Cabrero-Antonino,
Rosa Adam,
Kathrin Junge
*
and Matthias Beller
The direct CH-alkylation of indoles using carboxylic acids is presented for the first time. The catalytic system
based on the combination of Co(acac)3 and 1,1,1-tris(diphenylphosphinomethyl)-ethane (Triphos, L1), in the
presence of Al(OTf)3 as co-catalyst, is able to perform the reductive alkylation of 2-methyl-1H-indole with
a wide range of carboxylic acids. The utility of the protocol was further demonstrated through the C3
alkylation of several substituted indole derivatives using acetic, phenylacetic or diphenylacetic acids. In
addition, a careful selection of the reaction conditions allowed to perform the selective C3 alkenylation of
some indole derivatives. Moreover, the alkenylation of C2 position of 3-methyl-1H-indole was also possible.
Control experiments indicate that the aldehyde, in situ formed from the carboxylic acid hydrogenation, plays
a central role in the overall process. This new protocol enables the direct functionalization of indoles with
readily available and stable carboxylic acids using a non-precious metal based catalyst and hydrogen as reductant.
Received 11th May 2017
Accepted 11th July 2017
DOI: 10.1039/c7sc02117h
rsc.li/chemical-science
CH activations are attractive.5n,7 While positions C2 and C3 are
the most activated ones, direct C3 alkylations are still limited.
Therefore, allylic alkylations,8 Baylis–Hillman9 and more
Introduction
Indoles are privileged scaffolds, acting as building blocks in
multiple natural products.1 In fact, the essential amino acid
tryptophan and the neurotransmitter serotonin contain the
indole moiety in their structure. Inspired by nature, chemists
have designed a myriad of indole based compounds with bio-
logical activities for its use as drugs or agrochemicals.2 For
example, indometacin, sumatriptan or uvastatin are currently
marketed as drugs for the treatment of inammation, migraine
or hipercholesterolemia, respectively (Fig. 1). Hence, the
development of new methodologies for the derivatization of this
class of heterocycles continues to be an important topic in
organic synthesis and catalysis.
Traditionally, the cyclisation of pre-functionalized benzoid
precursors is the method of choice for the synthesis of
substituted indoles.3 Since the development of the useful Fisher
indole synthesis in the 19th century,4 many other catalytic and
non-catalytic cyclisation protocols have been described along
the years.5 In contrast, the direct functionalization of indole has
emerged more recently as a preferred methodology as it is more
practical and step economical.6 Among the several approaches
to the direct substitution of indoles, transition metal catalysed
frequently Friedel–Cras type reactions10 have been especially
useful to achieve this transformation. Intimately related with
Friedel–Cras functionalizations are reductive alkylations.
Thus, reactions at indole C3 position have been successfully
performed employing aldehydes or ketones11 in the presence of
silanes,12 hydrogen13 or other reductants.14 Despite being
a practical transformation, the use of carbonyl compounds
limits its applicability as they are sometimes not easily available
or undergo unwanted side-reactions, e.g., aldol condensations.
Hence, the use of more stable carboxylic acids can be more
convenient. However, to the best of our knowledge, this strategy
has not been explored and only an example of a related indole
methylation using CO2 was described by our group in 2014.15
Selective hydrogenation of carboxylic acids is a challenging
transformation of interest for organic synthesis and catalysis.
The rst homogeneously catalysed examples of this reaction
¨
¨
Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Straße
29a, 18059 Rostock, Germany. E-mail: matthias.beller@catalysis.de
† Electronic supplementary information (ESI) available: General information
concerning experimental procedures, additional tables, gures, schemes,
characterization data and NMR spectra of the isolated compounds are available.
See DOI: 10.1039/c7sc02117h
Fig. 1 Examples of indole-based marketed drugs.
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employed a ruthenium16 or an iridium17 based complex. functionalization of 2-substituted indoles is an interesting task for
Nowadays, the substitution of precious metals by earth abun- medicinal chemistry due to increased metabolic stability of the
dant non-noble metals, less toxic and expensive, is an exciting resulting products. Inspired by the previously known catalytic
goal in catalysis.18 In this direction, many examples of homo- systems vide supra, Co(BF4)2$6H2O and Co(acac)3 (4 mol%) in
geneous hydrogenation catalysts based on cobalt have been combination with 1,1,1-tris(diphenylphosphinomethyl)-ethane,
reported recently.19,20 In 2015, the groups of de Bruin and so-called Triphos ꢀ(ligand L1, 2 eq. to Co), were tested under 60
Elsevier described the rst base metal catalyst able to hydro- bar of H2, at 160 C, using THF as solvent during 18 h (Table 1,
genate carboxylic acids using a system composed by [Co(BF4)2- entries 1 and 2). Unfortunately, no activity was observed. Previous
$6H2O/Triphos (L1)].21 Later on, our group reported the CO2 works involving carboxylic acid derivatives hydrogenation cata-
hydrogenation to methanol using a modied related catalyst lysed by a Ru/Triphos system showed the crucial effect of an acid
[Co(acac)3/Triphos (L1)/HNTf2].22 Inspired by these precedents, additive for the catalytic activity.16a,23 Usually this additive provides
we envisaged the development of a methodology for the alkyl- a weakly coordinating counter anion, able to stabilize the active
ation of indole directly using carboxylic acids with a cobalt complex, as well as the optimal reaction medium pKa for the
based catalytic system. Here we describe the rst general hydrogenation events to take place. Recently, we showed a similar
reductive alkylation of indole C3 position with a variety of effect in the Co/Triphos catalysed CO2 hydrogenation to meth-
carboxylic acids).
anol, where the presence of HNTf2 is required to form the catalytic
active species.22 Hence, we decided to explore the reductive
alkylation of indole 1a with the Co/Triphos system in the presence
of an external acid additive.
Results and discussion
Gratifyingly, moderate yields of 3-ethyl-2-methyl-1H-indole
3a were detected when catalytic amounts of HNTf2 or Al(OTf)3
(10 mol%, 2.5 eq. to Co) were added to the [Co(acac)3/Triphos
(L1)] mixture (42–52%, Table 1, entries 3 and 4, respectively).
Surprisingly, no traces of N-alkylated products or bis(indole)
derivatives were observed in the reaction mixtures by GC
As a starting point of this project, we selected the reductive C–H
alkylation of 2-methyl-1H-indole 1a with acetic acid 2a (4 eq.
respect to 1a) as benchmark reaction (Table 1). Notably,
Table 1 Cobalt-catalysed reductive C–H alkylation of 2-methyl-1H-
indole (1a) with acetic acid (2a) and molecular hydrogen: initial analysis.
screening of the reaction conditions
Next, a more detailed investigation regarding the effect of
alkylating agent 2a amount, catalyst loading, pressure and
temperature on the catalytic activity was carried out (Table 1,
entries 5–15). In general, high conversions of 1a were detected,
although only moderate yields of the desired C3-alkylated
product 3a were obtained, indicating some degradation of the
indoles. Nevertheless, the yield of the desired C3-alkylated
indole derivative 3a could be improved to 70% using 1.75 eq.
of acetic acid 2a under 30 bar of hydrogen and 160 ꢀC (Table 1,
entry 13). Milder reaction temperatures or lower catalysts
loadings and hydrogen pressures did not afford better yields of
3a (Table 1, entries 6, 8, 9 and 15). In the absence of ligand L1,
no desired product was detected and only some degradation of
1a was observed (Table 1, entry 16).
b
Entrya 2a (eq.) [Co]
Additive Conv.b (%) 3a (%)
1
2
3
4
4
4
4
4
2
2
1.5
4
3
Co(BF4)2$6H2O
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
—
15
—
89
—
—
42
52
69
53
62
44
48
68
68
67
70
63
67
—
—
HNTf2
Al(OTf)3 >99
Al(OTf)3 >99
Al(OTf)3 74
Al(OTf)3 89
Al(OTf)3 >99
Al(OTf)3 91
Al(OTf)3 >99
Al(OTf)3 >99
Al(OTf)3 94
Al(OTf)3 >99
Al(OTf)3 90
Al(OTf)3 94
Al(OTf)3 35
5
6c
At this point we became interested in studying the inuence of
the acid co-catalyst. Fig. 2 (up) shows that, among the different
7
8d
9d
10e
11e
12e
13f
14f
15g
16h
¨
Bronsted and Lewis acid additives tested for the CH-alkylation of
2
the indole 1a, aluminium(III) triuoromethanesulfonate
[Al(OTf)3] afforded the best yield of 3a (70%). Other Lewis acid
additives such as In(OTf)3, Ga(OTf)3 or Sn(OTf)2 also promoted
the desired transformation and gave yields of alkylated product
3a above 60%. In order to improve the model reaction further on,
we varied the relative Al(OTf)3 amount (with respect to the cobalt
precatalyst). As shown in Fig. 2 (bottom) 10 mol% of Al(OTf)3 (2.5
1.75
1.5
1.75
1.5
1.75
1.75
a
Standard reaction conditions: 2-methyl-1H-indole 1a (67.0 mg, 0.5
mmol), Co precatalyst (0.02 mmol, 4 mol%), Triphos L1 (25.0 mg, 0.04 eq. to Co) gave the optimal yield (70% of 3a).
mmol, 8 mol%, 2 eq. to Co), additive (0.05 mmol, 10 mol%, 2.5 eq. to
Next, the inuence of the solvent was investigated in detail
(see ESI, Table S1†). The presence of water (10% v/v respect to
Co), THF (2 mL), acetic acid 2a (0.75–1.25 mmol, 1.5–2.5 eq.) and H2
b
(60 bar) at 160 ꢀC. Conversions of 1a and yields of product 3a were
c
calculated by GC using hexadecane as internal standard. Run with 2 THF) was detrimental for the activity of the catalytic system,
mol% of Co(acac)3, 4 mol% of ligand L1 (2 eq. to Co) and 5 mol% of
affording very poor yields of product 3a (7%, Table S1,† entry 2).
In general, other ether-type solvents gave similar results
compared to THF (Table S1,† entries 2–8), being methyl
Al(OTf)3 (2.5 eq. to Co). d Run at 140 ꢀC. e Run at 40 bar of H2. f Run at
30 bar of H2. g Run at 15 bar of H2. h Run without ligand L1.
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Table 2 Cobalt-catalysed reductive C–H alkylation of 2-methyl-1H-
indole (1a) with acetic acid (2a) and molecular hydrogen: optimization
of the reaction conditions using MCPE as solvent
Entrya T (ꢀC) H2 (bar) 2a (eq.) [Co] (mol%) Conv.b (%) 3ab (%)
1
2
3
4
160
160
160
160
160
160
160
160
160
160
160
160
160
160
160
160
160
140
140
140
140
160
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
15
—
30
30
60
60
30
1.75
1.5
1.25
2.5
1.75
1.75
1.75
1.75
1.75
1.75
1.75
1.75
1.5
4
4
4
2
2
2
2
2
—
—
2
2
2
1
1
2
2
4
4
2
2
2
>99
>99
86
>99
>99
24
57
14
12
54
64
47
87
47
40
56
15
96
96
69
83
70
83
79
62
85
89
—
—
—
—
—
42
—
76
31
23
27
—
68
70
41
49
64
5
6c
7d
8e
9c
10d
11f
12g
13
14c
15d
16
17h
18
19
20
21
22i
2.5
1.75
1.75
1.75
1.75
2.5
1.75
2.5
1.75
a
Standard reaction conditions: 2-methyl-1H-indole 1a (67.0 mg, 0.5
mmol), Co(acac)3 (1–4 mol%), Triphos L1 (2–8 mol%, 2 eq. to Co),
Al(OTf)3 (2.5–10 mol%, 2.5 eq. to Co), MCPE (2 mL), acetic acid 2a
(0.75–1.25 mmol, 1.5–2.5 eq.) and H2 (15–60 bar) at 140–160 ꢀC.
b
Conversion of 1a and yield of product 3a were calculated by GC
c
Fig. 2 Up: Testing of additives in the cobalt-catalysed reductive C–H
alkylation of 2-methyl-1H-indole 1a with acetic acid 2a and molecular
hydrogen. Bottom: Influence of the Al(OTf)3 loading in the formation
of product 3a from 1a and 2a. Standard reaction conditions: 2-methyl-
1H-indole 1a (67.0 mg, 0.5 mmol), Co(acac)3 (7.2 mg, 0.02 mmol, 4
mol%), Triphos L1 (25.0 mg, 0.04 mmol, 8 mol%, 2 eq. to Co), additive
(2–12 mol%, 0.5–3 eq. to Co), THF (2 mL), acetic acid 2a (50.3 mL,
0.875 mmol, 1.75 eq.) and H2 (30 bar) at 160 ꢀC. The yields of product
3a were calculated by GC using hexadecane as internal standard.
using hexadecane as internal standard. Run without ligand L1 and
Al(OTf)3. Run without ligand L1. Run without Al(OTf)3. Run with
d
e
f
g
3 mol% of ligand L1 (1.5 eq. to Co). Run with 2 mol% of ligand L1
(1 eq. to Co). h Run with 30 bar of N2. i Run at 6 h.
Notably, the relative amounts of ligand L1 with respect to the
cobalt precursor had a signicant inuence on the product
yield. When the reaction was conducted using 1.5 and 1
cyclopentyl ether (MCPE) the one that gave the best result (Table equivalents of ligand, moderate yields (42%) of 3a or no product
S1,† entry 6, 83% yield 3a). Also in toluene a good yield of the were detected, respectively (Table 2, entries 11 and 12), showing
desired indole 3a was obtained (76%, Table S1,† entry 9). In that 2 eq. of Triphos (L1) are the minimum required to perform
contrast, the catalyst was totally inactive when DMF was used the reaction efficiently.
(Table S1,† entry 10).
Next, the catalytic activity of different metal pre-catalysts was
To our delight, the employment of MCPE allowed to use evaluated under the optimized reaction conditions (30 bar of
a lower catalyst loading (2 mol% of cobalt) with excellent results H2, 160 ꢀC, 1.75 eq. of 2a, 2 mol% of cobalt and 18 h; see Table 1
(Table 2, entry 5, 89% yield of 3a). Blank experiments revealed and ESI, Fig. S1†). Among the different Co(III), Co(II), Ru(III),
that the presence of all the three components of the catalytic Mn(III), Fe(III) and Cu(II) acetylacetonate complexes tested,
system, [Co(acac)3/Triphos (L1)/Al(OTf)3], are required for the Co(acac)3 was the one that gave the best yields of the desired
reductive alkylation of indole (Table 2, entries 6–10). In addi- alkylated indole 3a (89%, see ESI, Fig. S1†). In addition,
tion, these experiments showed that the partial degradation of Co(acac)2$H2O afforded a slightly lower yield (78% yield of 3a,
1a can be attributed mainly to the presence of the acid additive Fig. S1†), while other related metal salts were not active. These
(Table 2, entries 7 and 10).
results indicate that cobalt is unique for this reaction.
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Table 3 [Co/Triphos (L1)]-catalysed reductive C(3)–H alkylation of 2- Table 3 (Contd.)
methyl-1H-indole (1a) using different carboxylic acids and molecular
hydrogen
Entrya T (ꢀC) [Co] (mol%) Product 3
Yieldb (%)
Entrya T (ꢀC) [Co] (mol%) Product 3
Yieldb (%)
[80]
11c
12
160
160
3
3
[46]
1
2
160
140
2
2
[68]
[47]
[80]
3
4
160
160
2
2
[67]
[74]
13d
140
140
2
1
14
[35]
5c
140
160
160
2
2
2
[59]
[74]
[70]
6
15
16
17
140
140
160
2
2
3
[73]
[78]
[70]
7c
8
140
160
4
4
[75]
[64]
9c
10
140
2
[49]
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Table 3 (Contd.)
Table 3 (Contd.)
Entrya T (ꢀC) [Co] (mol%) Product 3
Yieldb (%) Entrya T (ꢀC) [Co] (mol%) Product 3
Yieldb (%)
18
140
2
[55]
24
140
2
[55]
a
Standard reaction conditions: 2-methyl-1H-indole 1a (67.0 mg, 0.5
mmol), Co(acac)3 (1–4 mol%), Triphos L1 (2–8 mol%, 2 eq. to Co),
Al(OTf)3 (2.5–10 mol%, 2.5 eq. to Co), MCPE (2 mL), carboxylic acid
(0.875 mmol, 1.75 eq.) and H2 (30 bar) at 140–160 ꢀC. The selectivity
to the desired product was >95% in all cases. In some examples
19
160
3
[72]
b
degradation problems were observed. Yield of isolated product aer
c
column chromatography on silica. Run with (1.75 mmol, 2.5 eq.) of
carboxylic acid. d Run at 5 h.
Among the different cobalt-based precatalysts containing
counteranions such as [BF4ꢁ], [ClO4ꢁ], [OAcꢁ], [Fꢁ], [NO3ꢁ] and
[SO42ꢁ] (see ESI, Fig. S1†) tested for the alkylation of indole 1a,
only Co(BF4)2$6H2O and Co(SO4)$7H2O promoted the forma-
tion of the product 3a, albeit in lower yields (21% and 8% yield
of 3a, respectively, Fig. S1†).
20
160
2
[42]
With regard to the ligand, we compared the activity of Tri-
phos L1 with several multidentate (L2–L11) and one mono-
dentate ligands (L11) (see ESI, Scheme S1†). All the other tested
ligands showed lower activities than Triphos (L1), and only the
tridentate ligands L2 and L3 or the tetradentate L5 afforded 3-
ethyl-2-methyl-1H-indole 3a, though in low yields (18%, 17%
and 3%, respectively, Scheme S1†).
21
140
2
[64]
At this point, we decided to explore the general applicability
of the cobalt-based system in the C3-alkylation of 2-methyl-1H-
indole 1a using a wide range of carboxylic acids (Table 3). In
some cases, higher catalyst loadings (up to 4 mol%) or excess of
the alkylating agent (up to 2.5 eq.) were needed in order to
achieve a total conversion of indole 1a.
22
23
140
140
2
2
[70]
[72]
Aliphatic carboxylic acids 2a–g, including examples con-
taining heteroatoms such as oxygen-(2e) or uorine-(2f and 2g),
afforded the corresponding C3-alkylated indoles 3a–g in good to
very good isolated yields (59–80%, Table 3, entries 1–7). More-
over, benzoic acid 2h and different o-, m- and p-substituted
benzoic acids containing chloro (2i), triuoromethyl (2j) or
methoxy groups (2k–m), could also be used as alkylating agents
giving good isolated yields of the C3-benzylated indole deriva-
tives 3h–m (46–75%, Table 3, entries 8–13). Gratifyingly, per-
uorinated benzoic acid 2n and naphthoic acid 2o also gave the
desired functionalized indole derivatives 3n and 3o in moderate
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to good yields aer isolation (36 and 73%, Table 3, entry 14 and
15, respectively). In addition, more sensitive phenylacetic acid
2p, naphthaleneacetic acid 2u as well as 2-hydroxy-(2q), 2-
methoxy-(2r), 2,4-dichloro-(2s) and peruoro-(2t) substituted
phenylacetic acids were successfully employed as alkylating
agents of indole 1a (42–78%, Table 3, entries 16–21). In general,
no clearly correlation between the reactivity and the electronic
character of the substituent attached to the benzene ring of the
carboxylic acid could be observed. Finally, diphenylacetic acid
2v, 3-(3-(triuoromethyl)phenyl)propanoic acid 2w and 9-
xanthene carboxylic acid 2x, as an example of (hetero)aromatic
acid, exhibited good activity (55–70%, Table 3, entries 22–24).
These examples illustrate the potential of the base metal cata-
lysed methodology as a practical tool for introducing molecular
diversity in the indole core using readily available carboxylic
acids as alkylating agents.
Aer showing the reductive alkylation using different
carboxylic acids, we investigated the reaction of several
substituted indole derivatives (Scheme 1). Using the optimized
conditions, a variety of indoles were reacted with acetic acid 2a,
phenylacetic acid 2p or diphenylacetic acid 2v. In general, for the
same indole, 2p was the most reactive carboxylic acid followed
by 2v and 2a, as the less reactive one. As shown in Scheme 1,
several 5-substituted 2-methyl-1H-indole derivatives – some of
them previously synthetized by us (see ESI† for experimental
details) – containing methyl, hydroxy, methoxy, chloro, amino,
phenylamino, triuoromethyl and thiophenyl groups were well
tolerated. The desired C3-alkylated products 3y-ah were ob-
tained in moderate to good yields aer isolation (38–74%,
Scheme 1). Interestingly, in the case of 5-amino-2-methyl-1H-
indole reacting with acetic acid, the main product was the one
corresponding to the simultaneous C3 alkylation and amida-
tion, being possible to isolate the amide 3ad in moderate yields
(38%, Scheme 1). This result indicates that the [Co(acac)3/Tri-
phos (L1)/Al(OTf)3] catalysts exhibits selectivity towards the
hydrogenation of a carboxylic acid in the presence of an amide.
Moreover, 6-substituted as well as 5,7-substituted indole
substrates were also successfully alkylated giving products 3ai–
ak in 63–80% isolated yields. At this point it was interesting to
explore the tolerance of our protocol towards different alkyl and
aryl substituents in the C2 position as well as in the nitrogen
atom of the indole. To our delight, the reductive alkylation of
this indoles class was successfully achieved under different
reaction conditions using phenylacetic acid 2p and diphenyl-
acetic acid 2v as alkylating agents. Thus, the desired C3-alkylated
products 3al–ap could be isolated in 49–70% yields (Scheme 1).
As expected, in case of 2,3-dimethyl-1H-indole S1 (Scheme
S2,† eqn (A)), no products were detected aer its reaction with
acetic acid 2a, discarding a possible N-alkylation catalysed by
our system. In agreement with this observation, for 3-methyl-
1H-indole 1b where the C3 position is blocked, only very low
amounts of C2-ethylated product S3 (<2%) were detected
(Scheme S2,† eqn (B)), conrming the lower nucleophilicity of
C2 position in comparison with C3. Finally, when simple indole
Scheme 1 Standard reaction conditions: indole (0.5 mmol), Co(acac)3
(1–4 mol%), Triphos L1 (2–8 mol%, 2 eq. to Co), Al(OTf)3 (2.5–10 mol%,
2.5 eq. to Co), MCPE (2 mL), carboxylic acid (0.875–1.75 mmol, 1.75–
3.5 eq.) and H2 (30 bar) at 140–160 ꢀC during 18–60 h. Yield of isolated
product after column chromatography on silica are given. The selec-
tivity to the desired product, calculated by GC-MS, was >90% in all
cases. In some examples degradation problems were observed.
Specific reaction conditions for substrate 3y and 3ak: Co(acac)3 (4
mol%), carboxylic acid (0.875 mmol, 1.75 eq.), 160 ꢀC, 18 h; for
substrate 3z: Co(acac)3 (2 mol%), carboxylic acid (0.875 mmol, 1.75
eq.), 160 ꢀC, 18 h; for substrates 3aa and 3ai: Co(acac)3 (2 mol%),
carboxylic acid (0.875 mmol, 1.75 eq.), 140 ꢀC, 18 h; for substrate 3ab:
Co(acac)3 (3 mol%), carboxylic acid (0.875 mmol, 1.75 eq.), 160 ꢀC,
48 h; for substrate 3ac: Co(acac)3 (6 mol%), carboxylic acid (1.5 mmol,
3.5 eq.), 160 ꢀC, 18 h; for substrates 3ad–ae: Co(acac)3 (4 mol%),
carboxylic acid (1.5 mmol, 3 eq.), 160 ꢀC, 18 h; for substrate 3af:
Co(acac)3 (3 mol%), carboxylic acid (0.875 mmol, 1.75 eq.), 160 ꢀC,
18 h; for substrates 3ag–ah and 3aj: Co(acac)3 (5 mol%), carboxylic
acid (1.25 mmol, 2.5 eq.), 160 ꢀC, 18 h; for substrate 3al: Co(acac)3 (2
mol%), carboxylic acid (1.25 mmol, 2.5 eq.), 160 ꢀC, 18 h; for substrate
3am: Co(acac)3 (6 mol%), carboxylic acid (1.25 mmol, 2.5 eq.), 160 ꢀC,
18 h; for substrate 3an: Co(acac)3 (3 mol%), carboxylic acid (1.25 mmol,
2.5 eq.), 160 ꢀC, 18 h; for substrate 3ao: Co(acac)3 (6 mol%), carboxylic
acid (0.875 mmol, 1.75 eq.), H2 (60 bar), 160 ꢀC, 60 h; for substrate 3ap:
Co(acac)3 (6 mol%), carboxylic acid (1.25 mmol, 2.5 eq.), 160 ꢀC, 18 h.
[a] 2-Methyl-1H-indol-5-amine was used as starting material.
1c or N-methyl derivative 1d were used, low conversions (<20%) and (D)). Interestingly, in these two cases small amounts of
and poor yields of the desired C3-ethylated products S3 and S5 bis(indole) compounds S4 and S6 (<2 and <5%, respectively,
were observed (10 and 8%, respectively, Scheme S2,† eqn (C) Scheme S2,† eqn (C) and (D)) were detected.
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During the development of the alkylation reactions of unreactive towards alkylation when acetic acid was used (vide
different indoles using diphenylacetic acid 2v (see Scheme 1), supra), were also successfully vinylated in C3 position using
we observed alkenylation of selected substrates as a side reac- diphenylacetic acid 2v. In these cases only traces of C2-
tion.24 A ne control of the reaction parameters (temperature, alkenylated products were detected (<2%), observing a full
pressure of hydrogen, catalyst loading, amount of alkylating selectivity to C3 vs. C2-position. In fact, C3-alkenylated products
agent and reaction time) allowed us to selectively stop the 4g and 4h were isolated in moderate to good yields (58 and 67%,
reaction at the alkene stage (Scheme 2). For example, 5-methyl- respectively, Scheme 2) with selectivities alkene vs. alkane
and 6-uoro-2-methyl-1H-indole derivatives were selectively between 87–89%. Finally, despite the lower nucleophicility of
alkenylated (selectivity alkene vs. alkane >85%) affording the the indole C2 position, it was possible to perform the cobalt
desired tri-substituted alkenes 4a and 4b in very good isolated catalysed C2 alkenylation of 3-methyl-1H-indole 1b by using an
yields (70 and 88%, respectively, Scheme 2). To the best of our excess of diphenylacetic acid 2v as alkylating source. The
knowledge such alkenylations using carboxylic acids have not desired C2-alkenylated product 4i could be isolated in 56%
described, yet.
(Scheme 3). Hence, this novel non-precious metal based meth-
In addition, different C2-phenyl and/or nitrogen-alkyl odology opens the way to the development of further trans-
substituted indole derivatives gave the corresponding alkene formations for the C2 and C3-functionalization of indoles.
products 4c–f with high selectivities towards alkene vs. alkane
To gain insight into the mechanism of the cobalt-catalysed
(>94%) and good isolated yields (63–80%, Scheme 2). Notably, reductive alkylation of indoles, some kinetic studies
the simple indole 1c and the N-methyl substituted 1d, (see Fig. 3 and 4) and control experiments were performed
(see Schemes 4–6). Fig. 3 and 4 show the concentration/time
proles for the reductive alkylation of 2-methyl-1H-indole 1a
with acetic acid 2a and phenylacetic acid 2p, respectively
(optimized reaction conditions for each acid). It should be
noted that no induction periods were observed in any of the
experiments, indicating that the active catalytic species is easily
formed. Interestingly, in the case of the reaction with phenyl-
acetic acid 2p it is possible to detect low amounts of the inter-
mediate (E)-alkene 3p0, observed in slightly higher
concentrations at initial reaction times (see Fig. 4). This
observation indicates that the hydrogenation of the alkene 3p0
is not the rate determining step of the process.
Next, we carried out the reaction under the optimized
conditions for phenylacetic acid 2p but in the absence of any
indole (Scheme 4A). This experiment revealed that our catalytic
system is able to hydrogenate the carboxylic acid to the corre-
sponding alcohol in moderate yields (14% of 2-phenylethanol 5
and 17% of 2-phenetyl phenylacetate 8 were detected, Scheme
4A). The experiment at shorter reaction times and using phe-
nylacetaldehyde 9 as starting material, afforded 2-phenyl-
ethanol 5 in good yields (76%, Scheme 4B).
At this point it was interesting to compare the reactivity of
several possible alkylating agents, all of them being related
derivatives of phenylacetic acid 2p. Thus, reactions of indole 1a
Scheme 2 Cobalt-catalysed reductive selective C(3)–H diphenylvi-
nylation of different indoles using diphenylacetic acid 2v and molec-
ular hydrogen. Standard reaction conditions: indole (0.5 mmol),
Co(acac)3 (1–6 mol%), Triphos L1 (2–12 mol%, 2 eq. to Co), Al(OTf)3
(2.5–15 mol%, 2.5 eq. to Co), MCPE (2 mL), diphenylacetic acid 2v
(1.25–1.75 mmol, 2.5–3.5 eq.) and H2 (30 bar) at 120–160 ꢀC over 18 h.
Yield of isolated products after column chromatography on silica are
given between brackets. Between parentheses is shown the selectivity
to the desired alkene vs. alkane by-product, calculated by GC-MS. In
some examples degradation problems were observed. Specific reac- Scheme 3 Cobalt-catalysed reductive C(2)–H diphenylvinylation of
tion conditions for substrate 4a: Co(acac)3 (2 mol%), carboxylic acid 3-methyl-1H-indole 1b using diphenylacetic acid 2v and molecular
(1.75 mmol, 3.5 eq.), 120 ꢀC; for substrate 4b: Co(acac)3 (2 mol%), hydrogen. Standard reaction conditions: 3-methyl-1H-indole 1b
carboxylic acid (1.75 mmol, 3.5 eq.), 130 ꢀC; for substrates 4c–e: (67.0 mg, 0.5 mmol), Co(acac)3 (3.6 mg, 0.01 mmol, 2 mol%), Triphos
Co(acac)3 (4 mol%), carboxylic acid (1.25 mmol, 2.5 eq.), 160 ꢀC; for L1 (12.5 mg, 0.02 mmol, 4 mol%, 2 eq. to Co), Al(OTf)3 (11.9 mg,
substrate 4f: Co(acac)3 (6 mol%), carboxylic acid (1.75 mmol, 3.5 eq.), 0.025 mmol, 5 mol%, 2.5 eq. to Co), MCPE (2 mL), diphenylacetic acid
160 ꢀC; for substrate 4g: Co(acac)3 (1 mol%), carboxylic acid 2v (486.0 mg, 2.25 mmol, 4.5 eq.) and H2 (30 bar) at 140 ꢀC over 18 h.
(2.25 mmol, 4.5 eq.), 140 ꢀC; for substrate 4h: Co(acac)3 (4 mol%), Yield of isolated product after column chromatography on silica is
carboxylic acid (1.75 mmol, 3.5 eq.), 120 ꢀC.
given. The selectivity to the alkene product 4i was 97%.
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were performed in the presence of the [Co(acac)3/Triphos (L1)/
Al(OTf)3] system at 140 ꢀC and 30 bar of H2, using phenylacetic
acid 2p, phenylacetaldehyde 9, phenethyl alcohol 5 and methyl
phenylacetate 6 (usually formed from phenylacetic acid and
methanol coming from MCPE cleavage) (Scheme 5A–D). Under
these conditions, the best alkylating agent was the acid deriv-
ative (Scheme 5A), while the ester 6 and the alcohol 5 only
afforded only traces of the alkylated product 3p (Scheme 5C and
D, respectively). The aldehyde 9 gave the alkylated indole 3p in
low yield (21%) together with traces of the alkenylated product
3p0 (Scheme 5B). This latter result is especially surprising
considering the general use and high reactivity of aldehydes as
alkylating agents. At milder reaction temperatures of 100 and
ꢀ
60 C, a decrease in the catalytic activity was observed for phe-
nylacetic acid 2p, while phenethyl alcohol 5 and methyl phe-
nylacetate 6 were totally unreactive (Scheme 5A, C and D,
respectively). Interestingly, the reaction with phenyl-
acetaldehyde 9 at 100 and 60 ꢀC gave moderate and good yields
of the alkenylated product 3p0, respectively (Scheme 5B). This
Fig. 3 Concentration/time profile for 2-methyl-1H-indole 1a (blue
line) and 3-ethyl-2-methyl-1H-indole 3a (red line) in the reductive observation suggests that the aldehyde could be an important
C–H alkylation of 1a with acetic acid 2a at 160 ꢀC and 30 bar of
molecular hydrogen. Standard reaction conditions: 2-methyl-1H-
indole 1a (3.0 mmol, 402.0 mg), Co(acac)3 (21.6 mg, 0.06 mmol, 2
mol%), Triphos L1 (75.0 mg, 0.12 mmol, 4 mol%, 2 eq. to Co), Al(OTf)3
(71.4 mg, 0.15 mmol, 5 mol%, 2.5 eq. to Co), MCPE (12.0 mL), acetic
acid 2a (301.8 mL, 5.25 mmol, 1.75 eq.) and H2 (30 bar) at 160 ꢀC. 140 C, are partially explained by the aldehyde fast hydrogena-
reaction intermediate that, when formed slowly from the
carboxylic acid at the optimized conditions, is able to afford the
alkylated product in good yields. The low yields of 3p obtained
when the reaction was performed starting from the aldehyde at
ꢀ
Percentages of 1a and 3a were calculated by GC using hexadecane as
internal standard.
tion to the corresponding alcohol (Scheme 4B) and/or its
degradation at this temperature. Notably, when the reaction
was performed at low hydrogen pressure or in its total absence,
low yields of the alkylated and alkenylated products were
observed with phenethyl alcohol 5 and phenylacetaldehyde 9 as
alkylating agents (Scheme 5B and C, respectively). This indi-
cates that dehydrogenation pathways could also be partially
contributing to the formation of the alkylated product, either by
forming the aldehyde from the alcohol or by abstracting
hydrogen from water or alcohols in the reaction media.
In addition, it was demonstrated that the presence of the
three components of the catalytic system, [Co(acac)3/Triphos
(L1)/Al(OTf)3], was required for the hydrogenation of the (E)-
styryl indole 3p0 to the alkylated product 3p (Scheme 6A).
Surprisingly, when 3p0 was submitted to the optimized reaction
conditions, 2-methyl-1H-indole 1a was formed in 68% yield. In
the presence of 0.75 eq. of phenylacetic acid 2p, lower amounts
of indole 1a were detected (Scheme 6B).
Finally, to obtain some information about the catalytic
system, the resting state of the reaction mixture aer standard
conditions was studied by 31P NMR (Fig. S2a†). In addition, the
same experiment was repeated for several mixtures to see the
Fig. 4 Concentration/time profile for 2-methyl-1H-indole 1a (blue
line), 2-methyl-3-phenethyl-1H-indole 3p (red line) and (E)-2-methyl-
3-styryl-1H-indole 3p0 (green line) in the reductive C–H alkylation of
1a with phenylacetic acid 2p at 140 ꢀC and 30 bar of molecular
hydrogen. Standard reaction conditions: 2-methyl-1H-indole 1a
(3.0 mmol, 402.0 mg), Co(acac)3 (21.6 mg, 0.06 mmol, 2 mol%), Tri-
phos L1 (75.0 mg, 0.12 mmol, 4 mol%, 2 eq. to Co), Al(OTf)3 (71.4 mg,
0.15 mmol, 5 mol%, 2.5 eq. to Co), MCPE (12.0 mL), phenylacetic acid
2p (720.0 mg, 5.25 mmol, 1.75 eq.) and H2 (30 bar) at 140 ꢀC.
Percentages of 1a, 3p and 3p0 were calculated by GC using hex-
adecane as internal standard.
effect of indole 1a, acetic acid 2a and Al(OTf)3 in the nature of
resting state (Fig. S2b–d†). In all these experiments it was
possible to detect signals between 18–32 ppm, corresponding to
phosphine ligands coordinated to cobalt,25 and similar to the
spectra obtained for the [Co(acac)3/Triphos (L1)/HNTf2]
system.22 Interestingly, when the [Co(acac)3/Triphos (L1)/
Al(OTf)3] system was employed, signals in the ranges of 18.7–
20.2 ppm and 28.7–31.5 ppm were detected (Fig. S2a–c†).
However, in the absence of Al(OTf)3 (Fig. S2d†), only signals
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Scheme 4 Control experiments in the hydrogenation of phenylacetic acid 2p (A) or phenylacetaldehyde 9 (B) in the absence of 2-methyl-1H-
indole 1a. Standard reaction conditions: phenylacetic acid 2p or phenylacetaldehyde 9 (0.875 mmol), Co(acac)3 (3.6 mg, 0.01 mmol, 1.2 mol%),
Triphos L1 (12.5 mg, 0.02 mmol, 2.4 mol%, 2 eq. to Co), Al(OTf)3 (11.9 mg, 0.025 mmol, 3 mol%, 2.5 eq. to Co), MCPE (2 mL) at 140 ꢀC during 3–
18 h. [a] Conversion of 2p and 9 and yield of products 5, 6, 7 and 8 were calculated by GC using hexadecane as internal standard.
around 30 ppm were observed, clearly indicating a main role of
the additive in the formation of some of the active complexes.
With all these observations in hand, a plausible mechanism
can be proposed for the cobalt catalysed reductive alkylation of
indoles (Fig. 5). The major pathway involves in rst place the
hydrogenation of the carboxylic acid 2 to the corresponding
aldehyde A or hemiacetal, which would react at the C3 nucleo-
philic position of indole 1 to afford the alkylated indole B.
Subsequent dehydration leads to the captured alkene interme-
diate D, that nally gets hydrogenated to afford the alkylated
indole. Minor pathways would involve the formation of an ester
Scheme 5 Control experiments in the C–H phenethylation of 2-
methyl-1H-indole 1a using phenylacetic acid 2p (A), phenylacetaldehyde
9 (B), phenethyl alcohol 5 (C) and methyl phenylacetate 6 (D) as alky-
lating agent. Standard reaction conditions: 2-methyl-1H-indole 1a
(67.0 mg, 0.5 mmol), Co(acac)3 (3.6 mg, 0.01 mmol, 2 mol%), Triphos L1
(12.5 mg, 0.02 mmol, 4 mol%, 2 eq. to Co), Al(OTf)3 (11.9 mg,
0.025 mmol, 5 mol%, 2.5 eq. to Co), MCPE (2 mL), alkylating agent
(0.875 mmol, 1.75 eq.) and H2 (10–30 bar) or N2 (30 bar) at 60–140 ꢀC
during 18 h. [a] Conversion of 1a and yield of products 3p and 3p0 were
calculated by GC using hexadecane as internal standard. Between
brackets is shown the isolated yield of the product after column chro-
matography on silica. [b] Run without Al(OTf)3. [c] Run without Co(acac)3
and Triphos L1. [d] Run without Co(acac)3, Triphos L1 and Al(OTf)3.
Scheme
6 Control experiments in the hydrogenation of (E)-2-
methyl-3-styryl-1H-indole 3p0 in the absence (A) or in the presence (B)
of phenylacetic acid 2p. Standard reaction conditions: (E)-2-methyl-3-
styryl-1H-indole 3p0 (116.7 mg, 0.5 mmol), phenylacetic acid 2p or not
(25.7 mg, 0.375 mmol, 0.75 eq.), Co(acac)3 (3.6 mg, 0.01 mmol, 2
mol%), Triphos L1 (12.5 mg, 0.02 mmol, 4 mol%, 2 eq. to Co), Al(OTf)3
(11.9 mg, 0.025 mmol, 5 mol%, 2.5 eq. to Co), MCPE (2 mL) at 140 ꢀ
during 3–18 h. [a] Conversion of 3p0 and yield of products 3p and 1a
C
were calculated by GC using hexadecane as internal standard.
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Co(acac)3 (3.6 mg, 0.01 mmol, 2 mol%), Triphos L1 (12.5 mg,
0.02 mmol, 4 mol%, 2 eq. to Co), Al(OTf)3 (11.9 mg, 0.025 mmol,
5 mol%, 2.5 eq. to Co), n-hexadecane (50.0 mg) as an internal
standard, MCPE (2.0 mL) as solvent and acetic acid 2a (50.3 mL,
0.875 mmol, 1.75 eq.). Aerwards, the reaction vial was capped
with a septum equipped with a syringe and set in the alloy plate,
which was then placed into a 300 mL autoclave. Once sealed,
the autoclave was purged three times with 30 bar of hydrogen,
then pressurized to 30 bar and placed into an aluminium block,
which was preheated at 160 ꢀC. Aer 18 h, the autoclave was
cooled in an ice bath, and the remaining gas was carefully
released. Finally, the reaction mixture was diluted with ethyl
acetate and analysed by GC.
General experimental procedure for the reductive C–H
alkylation of indoles with carboxylic acids
Fig. 5 Possible reaction mechanism for the [Co/L1/Al(OTf)3]-cata-
lysed reductive alkylation of indoles with carboxylic acids (simplified
version). The extended version of the overall mechanism containing
additional possible minor pathways and secondary transformations is
depicted in Scheme S6 (see ESI†).
A 8 mL glass vial containing a stirring bar was sequentially charged
with the indole substrate (0.5 mmol), Co(acac)3 (2–6 mol%), Tri-
phos L1 (4–12 mol%, 2 eq. to Co), Al(OTf)3 (5–15 mol%, 2.5 eq. to
Co), MCPE (2.0 mL) as solvent and the carboxylic acid (0.875–
1.75 mmol, 1.75–3.5 eq.). Aerwards, the reaction vial was capped
with a septum equipped with a syringe and set in the alloy plate,
which was then placed into a 300 mL autoclave. Once sealed, the
autoclave was purged three times with 30–60 bar of hydrogen, then
pressurized to 30 bar and placed into an aluminium block, which
was preheated at 120–160 ꢀC. Aer 18–48 h, the autoclave was
cooled in an ice bath, and the remaining gas was carefully
released. Finally, the reaction mixture was diluted with ethyl
acetate and puried by silica gel column chromatography (n-
heptane/ethyl acetate mixtures) obtaining the desired C3-
substituted indole derivatives.
that can be also hydrogenated to the aldehyde, as well as
a dehydrogenation mechanism from the formed alcohol.
Scheme S6 (see ESI†) shows the extended version of the reaction
mechanism containing additional possible minor pathways and
secondary transformations involved in the overall process.
Conclusions
For the rst time, a general reductive C–H alkylation of indoles
using carboxylic acids as alkylating agents is presented. This
cobalt-catalysed methodology allows functionalization of
different indoles at C3 in a straightforward manner. Using the
[Co(acac)3/Triphos (L1)] system in combination with Al(OTf)3 as
acid co-catalyst a wide range of carboxylic acids can be
employed as alkylating agents in the presence of molecular
hydrogen. In addition to alkylations, selective alkenylations of
some substrates have been successfully performed. Control
experiments revealed that the major reaction pathway involves
the in situ formation of the corresponding aldehyde from the
hydrogenation of the carboxylic acid, able to react with the
indole. This novel protocol complements previously described
reductive alkylations of indoles, mainly employing carbonyl
compounds as alkylating agents. Advantageously, the use of
carboxylic acids enlarges the potential molecular diversity
introduced in the indole scaffold, due to the availability and
stability of this class of compounds. Furthermore, the use of
a catalyst based on a non-precious metal increases the interest
of this transformation.
Acknowledgements
J. R. C.-A. and R. A. thanks Ramon Areces Foundation for
a postdoctoral fellowship. This work was supported by the state
of Mecklenburg-Vorpommern and the BMBF.
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6450 | Chem. Sci., 2017, 8, 6439–6450
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