Nickel-catalysed chemoselective C-3 alkylation of indoles with alcohols through a borrowing hydrogen method

Article abstract of DOI:10.1039/d0cc07169b

An inexpensive, air-stable, isolable nickel catalyst is reported that can perform chemoselective C3-alkylation of indoles with a variety of alcohols following "borrowing hydrogen". A one-pot, cascade C3-alkylation starting from 2-aminophenyl ethyl alcohols, and thus obviating the need for pre-synthesized indoles, further adds to the broad scope of this method. The reaction is radical-mediated, and is significantly different from other examples, often dictated by metal-ligand bifunctionality. This journal is

Full text of DOI:10.1039/d0cc07169b

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DOI: 10.1039/D0CC07169B
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Nickel-catalysed chemoselective C-3 alkylation of indoles with
alcohols through borrowing hydrogen method
Received 00th January 20xx,
Accepted 00th January 20xx
Amreen K Bains, Ayanangshu Biswas and Debashis Adhikari*
DOI: 10.1039/x0xx00000x
www.rsc.org/
employ sustainable and less toxic base metals as the
replacement of noble metals in catalysis. Notably, the base
metal representatives for effective C3-alkylation of 1H-indole is
very scarce and limit to only few examples of iron complexes.
The groups of Piersanti,18 Morrill19 and Renaud20 have used an
iron phthalocyanine, and Knölker-type iron complexes for the
alkylation process.
An inexpensive, air-stable, isolable nickel catalyst is reported
that can perform chemoselective C3-alkylation of indoles with
a variety of alcohols following “borrowing hydrogen”. A one-
pot, cascade C3-alkylation starting from 2-aminophenyl ethyl
alcohols, and thus obviating the need for pre-synthesized
indoles, further adds to the broad scope of this method. The
reaction is radical-mediated, and is significantly different from
other examples, often dictated by metal-ligand bifunctionality.
a) C-3 alkylation of indole by borrowing hydrogen
R1
R2
R2
R1
OH
N
H
An indole is a privileged heterocycle that is found in a vast array
[M]
of natural products, fine chemicals, and pharmaceutically
2
important molecules.1,
Substituted indoles often exhibit
Noble metal : Ir, Ru, Pt, Pd
Base-metal : Fe
excellent binding activity to a large number of receptors with
high affinity.3 In this context, new methods toward their efficient
synthesis and selective functionalization have been drawing
great attention over many years. The earlier known pathway for
the alkylation of indoles is the Friedel-Crafts reaction with
haloalkanes and related alkyl agents mediated by Lewis acid.4, 5
Furthermore, several Pd catalysts have also been scrutinized to
steer C3-alkylation, where the alkyl halides, triflates and
[M]H2
R1
R2
R2
R1
O
N
H2O
N
H
b) This work: Ni- catalysed chemoselective C-3 alkylation
7
nonaflates have been used as the alkyl source.6, However,
N
N
O
these methods often become problematic owing to over
alkylation, toxic and mutagenic nature of many alkyl halides as
well as the production of large quantity of inorganic waste. As a
solution to this problem, methods relying on borrowing
hydrogen (BH) which is atom economic, hydrogen neutral, and
generates water as byproduct, has emerged as an extremely
versatile technique.8-11
Ni
O
N
R1
N
R2
1
R1
+
H2O
+
N
N
R2
OH
H
H
39 examples
Sole nickel example
Mild reaction conditions
Broad substrate scope
Radical promoted reactivity
Scheme 1: Alkylation of indole via BH method catalysed by 1
Utilizing BH-based technique, Grigg pioneered the C3-alkylation
of indoles with benzyl alcohols as the alkyl source in the
presence of an Ir-catalyst, [Cp*IrCl2]2.12 Several other
homogeneous and heterogeneous catalysts have been
developed further that primarily employ other precious metals
such as Pt, Pd and Ru for this alkylation reaction (Scheme 1a).13-
To this end, a significant opportunity remains for other base-
metal catalysts that can provide a sustainable and easy synthesis
method of this value-added product. Toward this goal, we chose
to explore the potential of a nickel catalyst since nickel is cheap,
it is the second most abundant transition metal present in the
earth’s crust, and fairly benign from toxicology side.21 Herein, we
wish to report a very inexpensive and air-stable, homogeneous
nickel catalyst that can synthesize a plethora of C3-alkylated
indoles under relatively mild reaction conditions. To the best of
our knowledge, this is the single example, where a nickel
catalyst monoalkylates indole in a chemoselective manner, and
can further do the same by a cascade reaction, starting from
amino alcohols. Furthermore, the reaction operates via a radical
17
In recent times, there is a significant shift of the focus to
Department of Chemical Sciences, Indian Institute of Science Education and
Research (IISER) Mohali, Sector-81, Knowledge City, Manauli-140306, India. E-
mail: adhikari@iisermohali.ac.in
Electronic Supplementary Information (ESI) available: Detailed synthetic
procedure, control experiments, characterization details, NMR spectra See
DOI: 10.1039/x0xx00000x
†
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mechanism, which is truly different from other catalysts
developed for this purpose, relying on metal-ligand cooperative
bond activation.
product 2p in 66% yield. Also, a gram scale reaction resulted 2a
in 68% yield, proving that the scaling up DoOf tI:h1e0.r1e0a3Vc9ite/iDwo0nACrtpiCcrl0eo7Ot1on6cl9inoBel
is feasible. Encouragingly, our reaction conditions employed
lower temperature and lesser reaction time compared to many
catalysts that alkylate indoles from alcohols. Of note, our
catalyst is advantageous to the iron catalysts based on Knölker’s
system, where pre-activation by sacrificial reagent Me3NO or UV
exposure is necessary.
In our continuing interest on base-metal catalysed BH or
dehydrogenative coupling reactions, we recently discovered a
nickel azophenolate complex, 1 which is highly active in reducing
the polarized C=N bond to result alkylation of amines.22 Based
on both experimental results and supporting DFT calculations,
we delineated the key features of the catalyst where a facile 2e-
/2H+ redox conversion between azo-hydrazo functionality plays
a preponderant role in the dehydrogenation reactions. The
dehydrogenating ability of the catalyst promises the generation
of a more active and electrophilic carbonyls in a controlled
manner, such that alkylation of indoles can be envisaged
(Scheme 1b). To examine the catalytic ability of 1 toward C-3
alkylation of indole, various reaction parameters were screened
with indole and benzyl alcohol as model substrates. When a
mixture of indole (1 mmol), benzyl alcohol (2 mmol), 1 (2.5
mol%) and KOtBu (0.25 eq) in 2 mL toluene was heated at 110
oC, 3-benzyl-1H-indole (2a) was obtained in only 16% yield. In an
attempt to improve the yield of 2a, catalyst loading was
increased to 5 mol% and the amount of base loading was also
screened (entries 2-4, Table S1). The reaction gave best yield
when the catalyst loading was 5 mol% and the reaction was
performed at 110 oC (entry 4). Surveying the scope of other
bases like KOH, NaOH and K2CO3 resulted poor conversion to
product under similar reaction conditions (entry 6-8, Table S1).
While the use of NaOtBu offered moderate yield (entry 9),
further screening of the reaction conditions revealed KOtBu was
an effective base, and the reaction was complete in 12 h with its
sub-stoichiometric (0.7 equiv) loading. Notably, the necessity of
KOtBu to promote the reaction was originated from its ability as
a mild reductant that is required to initiate the azo-radical
Table 1: Substrate scope for C-3 alkylation of indole with
primary alcohols
OH
R
1 (5 mol%), KOtBu
+
Toluene, 110 oC, 12 h
(2a-2q)
N
N
R
H
H
R
R
(2e, R - Me, 73%)
(2f, R - OMe, 76%)
(2g, R - Et, 69%)
(2h, R - iPr, 65%)
R
N
H
N
H
(2a, 79%)
(2b, R - Me, 74%)
(2c, R - OMe, 81%)
(2d, R - Cl, 73%)
N
H
N
H
(2i, 75%)
N
H
(2j, 76%)
(2k, R - F, 64%)
(2l, R - Cl, 79%)
(2m, R - Br, 71%)
N
H
O
N
N
N
H
N
H
N
H
(2n, 77%)
(2o, 76%)
(2p, 66%)
H
Ph
Ph
N
(2q, 72%)
N
H
Reaction conditions: 1 (5 mol%, with respect to indole), indole (1 mmol),
o
primary alcohol (2 mmol), KOtBu (0.7 mmol), toluene (2 mL), 110 C (oil
generation and further hydrogenation following
a radical
bath), 12 h.
pathway.22 Control reactions in the absence of any base and
catalyst 1 completely failed to deliver the product, supporting
the necessity of both components for the reaction (entries 10-
11, Table S1). Only metal precursor, NiCl2 was also unable to
promote the reaction proving the unique catalytic activity of the
complex 1 (entry 12, Table S1).
After the successful alkylation with primary alcohols, we
examined the scope of secondary alcohols (Table 2). As can be
anticipated,
Table 2: Substrate scope of C-3 alkylation of indole with
secondary alcohols
After having the optimized reaction conditions in hand, we
attempted to test the generality of the developed protocol. As
described in Table 1, a wide array of primary benzyl alcohols
bearing both electron-donating and electron withdrawing
groups was used as the source of alkyl group, resulting in 3-
substituted indoles in good to excellent yield. Several ortho-
substituted benzyl alcohols ranging from -Me, -OMe, -Cl offered
the respective alkylated product (2b, 2c, 2d) in 73-81% yields.
Similarly, the para-substituted benzyl alcohols ranging from
alkyls (2e, 2g, 2h), alkoxy (2f), and halides (2k-2m) were also
equally applicable as alkylating partner and the corresponding
indoles were isolated in good yield. Similarly, 3-naphthylindole
(2i) was constructed in 75% yield, using 1-naphthol as the
alkylating agent under this reaction protocol.
OH
R
1 (5 mol%), KOtBu
+
Toluene, 110 oC, 12 h
(3a-3j)
N
N
R
H
H
Me
OMe
N
H
N
H
N
H
(3a, 73%)
(3d, 64%)
(3b, 69%)
(3c, 71%)
Cl
Br
N
H
N
H
N
H
(3e, 61%)
(3f, 70%)
R
Furthermore, a biphenyl group was installed at the 3-position of
the indole (2j) starting from 4-phenyl benzyl alcohol.
Intriguingly, alcohols with heterocyclic rings such as pyridine and
furan survived well through the reaction conditions and
furnished 2n and 2o in 76-77% yields. Similarly, a diol substrate,
such as 1,4-phenylenedimethanol furnished the bisindole
N
H
N
H
N
H
(3i, 51%)
OMe
(3g, R - H, 61%)
(3h, R - Me, 65%)
(3j, 59%)
Reaction conditions: 1 (5 mol%, with respect to indole), indole (1 mmol),
secondary alcohol (2.2 mmol), KOtBu (0.7 mmol), toluene (2 mL), 110 C
o
(oil bath), 12 h.
2 | Chem. Commun., 2020, 56, 1-3
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secondary alcohols are less amenable to both condensation and
hydrogenation steps compared to primary alcohols and
regarded as challenging substrates for alkylation reactions.
Accordingly, when a test substrate 1-phenyl ethanol was chosen,
the C-3 alkylated 1H-3-(1-phenylethyl)-indole, 3a was isolated in
73% yield under the same reaction conditions. Moreover, other
secondary alcohols with p-Me and -OMe groups also assembled
the 3-alkylated indole products (3b-3c) in 69-71% yields.
The first part is the oxidative cyclization of the amino alcohol,
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while the second one is the C-3 alkylation of the in situ
DOI: 10.1039/D0CC07169B
generated indole (Scheme 2d).
As shown in Table 3, the model substrates under optimized
reaction conditions assembled 3-benzyl-1H-indole in 69% yield.
The ortho-substituted alcohols bearing electron-donating groups
such as -Me, -OMe offered the respective alkylated product (2b,
2c) in good yields. Subsequently, the alcohols with an electron
donating group at para-position were equally efficient in
alkylating the in situ generated indole (2e-2h) in 64-71% yields.
Notably, 1-naphthol and 4-phenyl benzyl alcohol were also used
as alkylating partners to give the corresponding indole (2i-2j) in
65-72% yields. Encouragingly, alcohols with halide substitution
survived well under this reaction protocol to give 2k-2m, in 51-
68% yields.
Encouragingly,
bulky
secondary
alcohols
such
as
diphenylmethanol gave 3d in 64% yield. In comparison, the
halide substituted 1-phenyl ethanols furnished the respective
substituted indoles (3e-3f) in 61-70% yields. Notably, alicyclic
alcohols such as cyclohexanols were alkylating indoles
successfully to offer products 3g-3h in 61-65% yields.
Additionally, cycloheptanol alkylated indole to give 3i in
moderate yield.
Mechanistically, the dehydrogenation of an alcohol to generate
electrophilic carbonyls, follows a radical pathway. To prove that
the reaction is radical mediated, we added a radical quencher,
TEMPO (1 equiv) to the reaction mixture and found the reaction
was fully prohibited (Scheme 2a). As a compelling proof for the
radical-driven hydrogen atom transfer step from alcohol, we
were able to intercept a resulting ketyl radical as its BHT adduct
(Scheme 2b). The ketyl-BHT product was identified by high-
resolution mass spectrometry (Figure S2). Additionally, a radical
clock substrate, phenyl-(2-phenylcyclopropyl) methanol offered
major amount of ring-opened product (39%) during the
dehydrogenation reaction, further substantiating the radical
mechanism. Significantly, the adoption of radical mechanism is
distinctly different from other metal catalysed C3-alkylation of
indoles.
We further reason, since
1 competently dehydrogenates
alcohols, the final product will likely be assembled even starting
from amino alcohols that would prepare indole in situ. Starting
with an amino alcohol will further increase the applicability of
the alkylation protocol. The groups of Grigg and Yamaguchi have
assembled indoles starting from amino alcohols employing the
iridium catalyst.12, 23 Henceforth, we started the reaction with 2-
(2-aminophenyl) ethanol and benzyl alcohol as the model
substrates. Notably, the N-heterocyclization of 2-(2-
aminophenyl) ethanol and its derivatives is an attractive
method, since such alcohols are easily obtained from 2-nitro
toluene derivatives and formaldehyde.24 To our delight, the final
product 2a was obtained in 69% yield via this one-pot synthesis
protocol, with a 5% loading of the catalyst. A quick optimization
for this reaction suggested that the reaction can perform well at
o
110 C, under essentially same reaction conditions. A thorough
a) Radical quenching experiment:
OH
literature survey reveals that, this is the only example of
homogeneous nickel catalyst that performs oxidative N-
heterocyclization of amino alcohols, followed by
1 (5 mol%), KOtBu
+
+
TEMPO
N
Toluene, 110 oC, 12 h
N
H
trace
a
H
(1 equiv)
chemoselective C3-alkylation of the in situ generated indole.
b) Intercepted ketyl-BHT adduct:
Applying this protocol, we have synthesized an array of 3-
susbtituted indoles (Table 4), which are identical to the products
from alkylation of prefabricated indoles. To our delight, in this
one-pot cascade reaction, a large number of substituted benzyl
OH
OH
OH
O
1 (5 mol%), KOtBu
Toluene, 60 oC, 2 h
+
O2
N
NO2
BHT-ketyl radical
adduct
BHT
Table 3: Table 1: Substrate scope for the synthesis of C-3
c) Radical-clock reaction:
alkylated indole from 2-(2-aminophenyl) ethanol
O
O
OH
1 (5 mol%), KOtBu
Toluene, 60 oC, 2 h
OH
+
R
OH
1 (5 mol%), KOtBu
+
(39% yield)
(10% yield)
Toluene, 110 oC, 12 h
(2a-2m)
NH2
N
d) Mechanism for the formation of C-3 alkylated indole
R
H
R
O
R
O
+
NH2
N
H
2
(2e, R - Me, 71%)
(2f, R - OMe, 64%)
(2g, R - Et, 68%)
(2h, R - iPr, 70%)
(2a, 69%)
(2b, R - Me, 64%)
(2c, R - OMe, 70%)
N
H
N
H
-H2O
HN
NH
N
H
5
Path A
O
+
Path B
R
N
H
+
N
N
H
4
(2k, R - F, 66%)
(2l, R - Cl, 51%)
(2m, R - Br, 68%)
N
H
Scheme 2: a)-c) Experiments supporting radical mechanism. d)
Proposed mechanism for the formation of C-3 alkylated indole
from 2-(2-aminophenyl) acetaldehyde, and formation of 5.
(2i, 65%)
(2j, 72%)
N
H
N
H
Reaction conditions:
1 (5 mol%, with respect to indole), 2-(2-
aminophenyl) ethanol (1 mmol), primary alcohol (2.2 mmol), KOtBu (0.7
mmol), toluene (2 mL), 110 oC (oil bath), 12 h.
After alcohol oxidation, the nucleophilic attack of the indole
to the carbonyl of an aldehyde or ketone generates an
alkylideneindolenine, 4 (this is a vinylogous imine, Scheme
alcohols were converted to alkylated indoles in good yields. The
overall catalytic cascade consists of two consecutive steps by 1.
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2d) upon dehydration. Often alkylation of indole is marred
with byproduct, bis(3-indolyl) methane (5) which
Authors thank Mr. Matt Gordon (IU, Bloomington) for proof-
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a
reading the manuscript. AKB and AB thank IISER Mohali for
DOI: 10.1039/D0CC07169B
originates from the Michael addition of an indole to 4 (Path
B).25 Interestingly, our optimized reaction conditions
supressed the formation of 5, offering the alkylated indoles
as the sole product. Since, the azo group in the catalyst
backbone can be reversibly converted to the hydrazo
moiety, the borrowed hydrogens from the alcohol
substrates remain stored in the ligand backbone. This
hydrazo will hydrogenate further the in situ generated
vinylogous imine 4 to produce C-3 alkylated indole (Path A).
To prove unambiguously that the alcohol was the source of
hydrogen during the hydrogenation of 4, we took 1 equiv of
benzaldehyde and benzyl alcohol each, and the product 2a
was isolated in 66% yield (section 5c, ESI). This suggests that
4 forms the direct reaction of the aldehyde with indole and
the borrowed hydrogens from benzyl alcohol
dehydrogenation, hydrogenates it to form the alkylated
indole. To further examine whether the activated indole
ring has an influence on the reactivity, we started with an
N-methylated indole, so that no deprotonation by a base is
research fellowships.
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indole, 2a in 62% yield. This result implicates that the base
deprotonates the indole and makes it activated further for
the electrophilic substitution reaction (Scheme 3a).
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a)
1 (5 mol%), KOtBu
Ph
OH
+
5
+
+
+
N
N
H
Toluene, 110 oC, 12 h
N
N
H
1 mmol
1 mmol
1 mmol
62%
Not observed Trace
b)
c)
D
D/H
1 (5 mol%), KOtBu
Toluene, 110 oC, 12 h
D
D
+
N
H
Ph
OH
N
30 %
14.
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H
1 (5 mol%), KOtBu
Toluene, 110 oC, 12 h
+
OH
No reaction
N
H
Scheme 3: Control experiments for the synthesis of C-3
alkylated indole.
To establish that the reaction is truly a borrowing hydrogenation
catalysis, we studied the reaction further with d2-benzyl alcohol.
Significant amount of deuterium incorporation (30%) in the final
product 2a affirms the process to be BH in nature (Scheme 3b).
To ensure further, that no alkylation happens through the
formation of carbocation, we chose t-butanol as the alkylating
substrate and observed only starting indole remained intact
(Scheme 3c). Notably, under our reaction conditions, the C3-
alkylation is exclusive and no formation of N-alkylated product is
detected.
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In conclusion, we described herein an efficient nickel catalyst
that can effectively conduct the selective C3-alkylation of 1H-
indoles with a variety of alcohols. The ease of the process
prompted us further to perform C3-alkylation starting from 2-(2-
aminophenyl) ethanol, rather than prefabricated indoles. The
radical mechanism for the reaction is distinctly different from
multiple other catalysts explored in this direction.
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We thank SERB (DST), India (Grant No. ECR/2017/001764) for
financial support and IISER Mohali for seed funding. Authors
further thank IISER Mohali central facility for analytical data.
4 | Chem. Commun., 2020, 56, 1-3
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DOI: 10.1039/D0CC07169B
TOC (Table of Content)
A nickel catalysed chemoselective C3-alkylation of indole is reported that follows a borrowing hydrogen method promoted by a radical.
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Chem. Commun., 2020, 56, 1-3 | 5
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DOI: 10.1039/D0CC07169B
A nickel catalysed chemoselective C3-alkylation of indole is reported, that follows a borrowing hydrogen method promoted by a radical.