Alkylation of Indoles with α,β-Unsaturated Ketones using Alumina in Hexanes

Article abstract of DOI:10.1002/adsc.201901037

We evaluated the influence of solvent on the alumina-promoted C3-alkylation of indoles with α,β-unsaturated ketones. We found that lipophilic solvents were generally superior to hydrophilic ones with hexanes offering the 3-alkyl indole products in high yields. Thus, we demonstrate an inexpensive and procedurally simple new process that pairs acidic alumina with hexanes to achieve this important Michael alkylation. The substrate scope includes twenty-four examples with reaction yields ranging from 61 to 96%. (Figure presented.).

Full text of DOI:10.1002/adsc.201901037

Title: Alkylation of indoles with α,β-unsaturated ketones using alumina
in hexanes.
Authors: Xiong Zhang, Ebenezer Jones-Mensah, Jackson Deobald,
and Jakob Magolan
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901037
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10.1002/adsc.201901037
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Alkylation of indoles with α,β-unsaturated ketones using alumina in hexanes.
Xiong Zhang,a Ebenezer Jones-Mensah,b Jackson Deobald,b Jakob Magolana*
a
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
Phone: (904) 525-9140 x 22268, Email: magolanj@mcmaster.ca
Department of Chemistry, University of Idaho, Moscow, ID, USA
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. We evaluated the influence of solvent on the
alumina-promoted C3-alkylation of indoles with α,β-
unsaturated ketones. We found that lipophilic solvents
were generally superior to hydrophilic ones with hexanes
offering the 3-alkyl indole products in high yields. Thus,
we demonstrate an inexpensive and procedurally simple
new process that pairs acidic alumina with hexanes to
achieve this important Michael alkylation. The substrate
scope includes twenty-four examples with reaction yields
ranging from 61 to 96 %.
observed that fifteen of seventeen Food and Drug
Administration (FDA)-approved indole-containing
drugs have substitution at the C3 position.[4]
Keywords: indoles; α,β-unsaturated ketones; alumina;
hexanes; Michael addition
Activated γ-aluminum oxides or “aluminas”, sold
ubiquitously for use in chromatography, have
Scheme 1. Lewis Acids used for alkylation of indoles with
α,β-unsaturated ketones.
amorphous surfaces with exposed acidic and basic
sites that also make them useful to synthetic chemists
as heterogeneous reagents, catalysts, or catalyst
supports, with the procedural convenience of easy
removal from reaction products via filtration.[1]
When a solvent is employed in an alumina-promoted
chemical transformation, dissolved substrates must
interact with the alumina surface at the alumina-
solvent interface. We have observed that only
minimal solvent screening is typically reported in
most of the published synthetic methods literature in
this field and this led us to consider whether solvent
may be an underappreciated variable in the context of
reactivity at alumina surfaces. With the pragmatic
aim of advantageous new synthetic methods that
benefit from inexpensive heterogeneous alternatives
to traditional homogeneous reagents[2] we decided to
investigate the effect of solvent on alumina activity.
The C3-alkylation of indoles with enones was first
shown to be induced by Ac2O in 1957,[5] and has
since been revisited and improved using a range of
Lewis Acid promoters including Yb(OTf)3,[6] InCl3,[7]
Bi(NO3)3, [8] I2,[9] SmI3,[10] and others[11] (Scheme 1).
To our knowledge, alumina has not been previously
used for this transformation. The analogous reaction
between indoles and nitroolefins to make 3-
nitroethylindoles has been reported with alumina, but
under solvent-free conditions.[12]
In our hands, treatment of indole (4) with methyl
vinyl ketone (5, 1.3 equiv.) and acidic alumina (2
g/mmol of indole) at room temperature for two hours
in twelve different solvents revealed a dramatic
solvent effect on the yield the corresponding 3-alkyl
indole 6 (Table 1, entries 1-12). These ranged from
<10 % in acetone and ethanol to >90 % in toluene
and hexanes. The highest product yield of 94 % was
observed in hexanes, along with complete
consumption of indole in two hours. Lipophilic
solvents (hexanes, n-hexane, heptanes, toluene,
chloroform) were generally superior to hydrophilic
solvents (acetone, ethanol, 2-butanol).
As a suitable system for this study, we chose the acid-
promoted Michael addition of indoles (1) to α,β-
unsaturated ketones (2) (Scheme 1). The indole
scaffold is common in natural products and medicinal
chemistry and has accordingly received much
attention from our synthetic community,[3] and C3-
substituted indoles are particularly significant as
highlighted by Njardarson and co-workers who
1
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10.1002/adsc.201901037
Advanced Synthesis & Catalysis
e)
equiv.). Amount of alumina was reduced to 0.5 g (1
g/mmol).
The interface between a lipophilic solvent and the
hydroxyl-rich alumina surface may be considered
somewhat analogous to an oil-water interface.
Accordingly, we hypothesize that the rationale for the
reactivity observed upon pairing of lipophilic
solvents with alumina may be analogous to that
offered for rate enhancement seen for reactions “on
water”.[13] These are reactions run in oil-water
emulsions that demonstrate rate acceleration
explained by a combination of 1) increased
We chose hexanes as our preferred solvent for small
scale reactions because of its ubiquity and low cost.
For preparative scale reactions, heptanes or n-heptane
would be a better option because of lower volatility
and toxicity relative to hexanes and n-hexane (see
Scheme 3 below). We observed no background
reaction in hexanes in the absence of alumina (Table
1, entry 15), reduced yields with neutral and basic
aluminas (entries 16 & 17), and comparable yields
with acidic aluminas from two other manufacturers
(entries 18 & 19, see Supporting Information for
details). Lowering the relative amount of methyl
vinyl ketone from 1.3 to 1.1 equiv. slightly
concentration of reactants at the oil-water interface,
and 2) the enhanced hydrogen bonding capacity of
unbound, or “dangling”, –OH groups that protrude
from the aqueous phase into the organic phase.[14]
Table 1. Optimization of reaction conditions.
diminished yield (entry 20) while reducing the
alumina loading from 2 to 1 g/mmol of indole,
increased the yield to 96 % (entry 21).
Our subsequent expansion of the substrate scope to
other α,β-unsaturated ketones showed that methyl
vinyl ketone was the most reactive electrophile while
most others benefited from heating of the reaction
mixture to reflux temperature (68 °C) as well as
employment of 2 g of alumina per 1 mmol of indole.
Thus our preferred general set of conditions for this
reaction ultimately became: indole (1.0 equiv.), enone
(1.3 equiv.), alumina (2 g/mmol), and hexanes (5
mL/mmol), stirred at reflux temperature, and
Entry
Solvent
Alumina
type
Yield of 6
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
ethanol
acetone
THF
acidic
acidic
acidic
acidic
acidic
acidic
acidic
acidic
acidic
acidic
acidic
acidic
acidic
acidic
none
1
8
13
44
66
77
80
81
81
84
90
94
95
95
0
41
66
96
92
94d
96e
2-butanol
acetonitrile
diethyl ether
DCM
ethyl acetate
MTBE
chloroform
toluene
hexanes
n-hexane
heptane
hexanes
hexanes
hexanes
hexanes
hexanes
hexanes
hexanes
monitored by thin layer chromatography (TLC) for
disappearance of indole (2 - 24 hours).
As summarized in Scheme 2, we demonstrated the
substrate scope of this reaction by applying it to a
range of indole and α,β-unsaturated ketone substrates
to generate a library of twenty-four 3-alkyl indoles
(compounds 10 – 33). First methyl vinyl ketone was
paired with six substituted indoles to yield 3-alkyl
indoles containing a second alkyl (11, 12, 16), alkoxy
(13, 15), or halogen (14) substituent in good yields.
Next, indole was paired with nine phenyl vinyl
ketones to yield compounds 17 - 25 with a range of
substituents including a hydroxyl moiety, which was
well tolerated with phenol 25 obtained in 82 % yield.
Indole was also alkylated with six chalcone
neutral
basic
acidic 2c
acidic 3c
acidic
acidic
derivatives to yield compounds 26 – 33 in high yields
ranging from 86 % – 96 %. Finally, indole was
reacted with 2-chloro-1-phenylpropenone resulting in
the α-chloro ketone 32 in 61% yield and with 1,2-
diphenylprop-2-en-1-one to offer 33 in 62 % yield.
a)
Procedure: indole (0.5 mmol), alumina (1 g; acidic; see
Supporting Information), solvent (5 mL) and methyl vinyl
ketone (0.65 mmol, 1.3 equiv.), stirred at r.t. for 2 hours;
mixture was filtered and washed with EtOAc (3 x 5 mL);
solvent was removed and crude residue was analyzed by
NMR. b) Determined by 1H NMR with dibromomethane as
the internal standard. c) Alumina purchased from a different
supplier was used (see Supporting Information). d) Amount
of methyl vinyl ketone was reduced to 0.55 mmol (1.1
2
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10.1002/adsc.201901037
Advanced Synthesis & Catalysis
Finally, we demonstrated larger scale preparations of
compounds 10 and 26 by making 17.7 g and 27.7 g of
these respectively using our protocol (Scheme 3). For
these substrates (indole, methyl vinyl ketone, and
chalcone) three modifications to the typical procedure were
tolerated well: 1) the use of heptanes instead of hexanes, 2)
less alumina, 0.5 g/mmol of indole, and 3) reaction at room
temperature rather than reflux. Compounds 10 and 26
were obtained in 94 % and 85 % yields respectively.
Experimental details corresponding to these reactions,
including photographs, are presented in the Supporting
Information document.
In summary, we have reported a procedurally simple new
method for C3-alkylation of indoles with α,β-unsaturated
ketones that employs acidic alumina in hexanes or
heptanes. An evaluation of solvents in this reaction
showed that lipophilic solvents are superior to hydrophilic
solvents. Based on our informal analysis of reagent costs
listed on the websites of common suppliers, we are
confident that the cost of alumina (0.5 g/mmol of substrate,
or approximately $0.04 USD) is favourable relative to
other reagents that are similarly efficacious for this
transformation including InCl3 (0.1 mmol, approximately
$0.25), SmI3 (0.1 mmol, approximately $12) and Bi(NO3)3
(0.15 mmol, approximately $0.13). Due to this cost benefit
and the facile removal of alumina by filtration, we believe
that our new process is competitive with all previously
reported alternatives for this important transformation.
Finally, we hope this work might inspire the development
of additional synthetic tools that leverage the pairing of
alumina surfaces with lipophilic solvents.
Experimental Section
General procedure for the alkylation of indoles
with α,β-unsaturated ketones: To a round bottom
flask equipped with a stir bar were added: the indole
derivative (1.0 equiv.), α, β-unsaturated ketone (1.3
equiv.), Al2O3 (acidic, 2 g/mmol of indole), and
hexanes (5 mL/mmol of indole). The flask was
equipped with a reflux condenser and heated in a
sand bath at reflux temperature. The top of the
condenser was open to the air. The reaction was
monitored periodically by TLC. Upon complete
disappearance indole (2-24 hours), the reaction
mixture was cooled and filtered through filter paper.
The solids were rinsed with EtOAc (x 3), and the
combined filtrate was concentrated in vacuo and
purified by flash column chromatography using
hexanes and EtOAc as eluent to yield the 3-alkyl
indole products.
Scheme 2. Substrate Scope a
a)
Reaction conditions: indole substrate (1 equiv.), α,β-
unsaturated ketone (1.3 equiv.) Al2O3 (acidic, 2 g/mmol of
indole), and hexanes (10 mL/mmol of indole) was heated
to reflux for 4-16 h.; Reported yields are for isolated
products after chromatography.
Representative example, Compound 18: The
general procedure was used with 1-(4-
fluorophenyl)prop-2-en-1-one (97.6 mg, 0.65 mmol),
acidic alumina (1g), indole (58.6 mg, 0.5 mmol), and
Scheme 3. Preparative Scale Reactions
3
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10.1002/adsc.201901037
Advanced Synthesis & Catalysis
hexanes (5 mL). TLC analysis at 12 hours indicated
complete consumption of indole. Compound 18 was
isolated as a white solid (120.4 mg, 0.45 mmol, 90 %
yield); Rf = 0.56 (EA/Hex = 30:70 v/v); MP = 121-
122 °C; 1H NMR (500 MHz, Chloroform-d) δ 8.00 –
7.96 (m, 2H), 7.95 (s, 1H), 7.65 – 7.62 (m, 1H), 7.37
(dt, J = 8.1, 0.9 Hz, 1H), 7.21 (ddd, J = 8.1, 7.0, 1.2
Hz, 1H), 7.16 – 7.13 (m, 1H), 7.13 – 7.08 (m, 2H),
7.05 (dt, J = 2.0, 0.8 Hz, 1H), 3.38 – 3.33 (m, 2H),
3.25 – 3.20 (m, 2H); 13C NMR (126 MHz,
Chloroform-d) δ 198.4, 166.8, 164.8, 136.5, 133.6,
130.8, 130.8, 127.4, 122.3, 121.7, 119.5, 118.8, 115.9,
115.7, 115.6, 111.3, 39.4, 19.9; FTIR (νmax,
cm‐ 1):3308, 3063, 2909, 2852, 1669, 794, 760;
HRMS: calculated for C14H14FNO (M+H)+
286.1137; found 286.1125.
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This work was made possible by support from the National
Science Foundation, Grant # 1301506. X.Z. was funded by a
fellowship from the Chinese Scholarship Council. J.D. received
support from an IDeA award from the NIGMS, Grant
#P20GM103408. We are grateful for generous contributions to
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4
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10.1002/adsc.201901037
Advanced Synthesis & Catalysis
COMMUNICATION
Alkylation of indoles with α,β-unsaturated ketones
using alumina in hexanes.
Adv. Synth. Catal. Year, Volume, Page – Page
Xiong Zhang, Ebenezer Jones-Mensah, Jackson
Deobald, Jakob Magolan*
5
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