Transition-Metal-Free Redox-Neutral One-Pot C3-Alkenylation of Indoles Using Aldehydes

Article abstract of DOI:10.1021/acs.orglett.6b03612

The synthesis of sensitive β-alkyl 3-vinylindoles having diverse functional groups with good selectivity remains a challenging task. Keeping the synthetic utility of 3-alkenylindoles in mind, we explored a unique approach to synthesize them from unprotected indoles in a domino fashion. A transition-metal-free C3-alkenylation of indole is reported by using sequential Br?nsted acid/base catalysis. Several β-substituted 3-alkenylindoles and conjugated 1,3-dienes are synthesized by direct coupling of indole and readily available aliphatic aldehydes. Excellent scalability and recycling of benzenesulfinic acid for successive alkenylation reactions up to five times make this method economically viable.

Full text of DOI:10.1021/acs.orglett.6b03612

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Redox-Neutral One-Pot C3-Alkenylation of
Indoles Using Aldehydes
Samrat Sahu, Ankush Banerjee, and Modhu Sudan Maji*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
S
* Supporting Information
ABSTRACT: The synthesis of sensitive β-alkyl 3-vinylindoles
having diverse functional groups with good selectivity remains a
challenging task. Keeping the synthetic utility of 3-alkenylindoles in
mind, we explored a unique approach to synthesize them from
unprotected indoles in a domino fashion. A transition-metal-free C3-
alkenylation of indole is reported by using sequential Brønsted acid/
base catalysis. Several β-substituted 3-alkenylindoles and conjugated
1,3-dienes are synthesized by direct coupling of indole and readily
available aliphatic aldehydes. Excellent scalability and recycling of
benzenesulfinic acid for successive alkenylation reactions up to five times make this method economically viable.
ynthesis of functionalized indoles has gained considerable
1)14 and 1,4-addition followed by either oxidation or
Sattention in recent years due to their presence in various elimination15 are largely limited to the activated alkenes.
bioactive natural products, drugs, and other alkaloids.1 C3-
Alkenylindoles are one of the key building blocks and play a
pivotal role in synthesizing these materials. Their diverse
synthetic utility has been demonstrated in [4 + 2] cycloaddition
reactions,2 acid-catalyzed dimerization reactions,3 and 1,4-
addition reactions,4 and they have also been used as vinylogous
indole nucleophiles.5 In addition, 3-alkenylindoles show their
bioactivities as various anticancer, antibacterial, and antiviral
agents.6 Natural products having 3-alkenylindole moieties are
also well documented in the literature (Figure 1).7 In addition,
they are important precursors for the synthesis of many
important, biologically relevant molecules such as indole
alkaloids,8 carbolines,9 and carbazoles.10
Scheme 1. Literature Survey
Fe(III)-catalyzed direct alkenylation of indole using aldehydes
is limited to 2-substituted indoles, and only β-aryl alkenes can be
synthesized.16 Brønsted acid mediated alkenylation of indoles
requires relatively harsh reaction conditions and N-alkyl-
protected indoles, and by this method only β,β-disubstituted
alkenes can be synthsized.17 Keeping the broad synthetic utility
of 3-alkenylindoles and the above-mentioned limitations to
synthesize them in mind, herein we report a highly efficient,
transition metal and protecting group free method to access 3-
alkenylated indoles using readily available aliphatic aldehydes as
an alkenylating agent via one-pot sequential Brønsted acid/base
catalysis.18,19
Figure 1. Natural products having a 3-alkenylindole moiety.
Despite the considerable number of methods reported in the
literature,11 syntheses of β-alkyl-substituted C3-alkenylindoles in
particular are extremely limited. Wittig olefination is a well-
practiced method to avail them.12 However, this approach
requires two to four consecutive steps starting from unprotected
indole2,13 and is often plagued by poor yields, limited scope, and
low selectivity between geometrical isomers, resulting in
difficulty in purification.2,12b Alkenylation protocols based on
transition-metal-catalyzed cross-coupling reactions (Scheme
Brønsted acid plays a crucial role to activate aldehydes for
achieving several unique transformations.20 Reaction of indole
Received: December 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03612
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Organic Letters
Letter
a
with aldehydes in the presence of a catalytic amount of Brønsted
acid gives bis-indolylmethanes as the major product.21 There-
fore, direct C3-alkenylation of unprotected indole with aliphatic
aldehydes, in particular, is challenging under the Brønsted acid or
Lewis acid catalysis. To circumvent this problem, we envisioned
that the presence of a phenylsulfonyl group, which can be
installed under acidic conditions and can also be removed under
basic conditions, will help us to solve this long-standing
problem.22 We hypothesized that, on treatment with base, 3
generates vinylogous imine intermediate 4 which in the presence
of a non-nucleophilic base might facilitate β-proton abstraction
from intermediate 4, leading to the formation of 3-alkenylindole
5−7.
Scheme 2. Scope of Aldehydes
During the optimization study, we were pleased to discover
that simple PTSA·H2O and DBU were suitable catalysts for this
transformation.23 Unlike Wittig olefination, this method
provided 5e in excellent yield having exclusive (E)-selectivity.
Lowering the PTSA·H2O loading to 5 mol % did not affect the
formation of 3e or the yield of 5e (Table 1, entry 4). The
a
a
Reaction conditions: indole 1 (1.0 equiv), aldehyde 2 (1.0 equiv),
PhSO2H (1.0 equiv), PTSA·H2O (5 mol %), THF, 60 °C; NaH (2.5
Table 1. Optimization of Reaction Conditions
b
equiv), DBU (5 mol %) in THF at 60 °C under N2; isolated yield. In
the case of aryl acetaldehydes 2a−d, minor alkenylated products 5a−d
c
d
and 6a−d were observed in the first step. EtOAc as solvent. Reaction
was conducted after the corresponding 3 was isolated.
Aldehydes bearing ester, amide, and ether functional groups were
also well tolerated under these reaction conditions and provided
the alkenylated products 5j−l in good to excellent yields (74−
91% yields). Despite the basic reaction medium and high
temperature, no double-bond-isomerized product was detected
for 5j. Trisubstituted alkenes 5m,n were also synthesized in
moderate yields (44−61%) using 2,2-disubstituted acetalde-
hydes. Thiophene-2-acetaldehyde also reacted under these
optimized conditions (5o, 33%), although the yield was lower
due to the incomplete conversion of bis-indole to sulfonyl indole.
For indoles having no substitution at the 2-position, a similar
one-pot strategy was applied. As observed before, different aryl
acetaldehydes provided alkenes 6a−d in moderate to good yields
(44−70%). However, in the case of aliphatic aldehydes, a
stepwise strategy was adopted due to the difficulties in product
purification as well as incomplete conversion of bis-indole to
sulfonyl indole 3. Using this stepwise strategy, products 6e−h
were isolated in 67−98% yields.
a
b
c
1.5 mmol scale; butanal (1.0 equiv). Isolated yield. 1.1 equiv of
d
e
PhSO2H. 1.0 equiv of PhSO2H. 3,3′-(butane-1,1-diyl)bis(2-methyl-
1H-indole) was also isolated in 26% yield.
Next, the scope of the reaction was further investigated using
various functionalized indoles. Sterically hindered 2-phenyl-
indole and 2-tert-butylindole were reactive enough, and products
5ea,eb were isolated in excellent yields (89−90%, Scheme 3). In
general, indoles having electron-withdrawing CO2Me, CON-
(OMe)Me, and Br functional groups at the 2-position were also
suitable substrates for this transformation (5ec−ef, 50−80%).
Even the presence of a sterically hindered carboxymenthyl group
at the 2-position did not deter the reactivity of the indole. Indoles
having various electron-withdrawing groups such as Br, NO2, and
CN at the 5-position underwent smooth conversion and gave the
corresponding alkenes 5eg−ei in moderate to excellent yields
(67−87% yields). An indole having pinacolatoboron substitu-
tion, which might not be a suitable substrate for transition-metal-
catalyzed alkenylation reactions, also underwent smooth
conversion to provide 5aj in 74% yield. Alkyl-substituted indoles
such as 6,7-dimethylindole and 4,7-dimethylindole also gave the
desired alkenes 6i,j in 68% and 57% yields, respectively.
presence of PTSA·H2O catalyst was essential to convert
intermediate bis-indolylmethane to 3 (entry 10). To confirm
this, in a control experiment when bis-indolylmethane was
subjected with PhSO2H (1.0 equiv) and PTSA·H2O (5.0 mol %)
in THF, 60% of 3e was isolated along with 24% of 1a.23 Both
NaH and DBU were essential for the reaction as no 5e was
formed in their absence (entries 11 and 12). No alkenylated
product was detected for 8 under identical reaction conditions.24
At first, we explored the scope of this alkenylation reaction
with various aliphatic aldehydes. Arylacetaldehydes containing
electron-withdrawing and -donating groups did not affect the
outcome of the reaction, and 5a−d were isolated in 67−96%
yields (Scheme 2). Aldehydes, having normal as well as branched
aliphatic chains, reacted smoothly to provide alkenylated
products 5e−h in 63−98% yields. Simple acetaldehyde was
also found to be a suitable substrate for our reaction (5i, 63%).
B
DOI: 10.1021/acs.orglett.6b03612
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a
yields. We found that the β-alkyl-substituted compounds 5−7, in
particular, are highly unstable in the presence of trace acid.12b
Next, a few structurally unique aldehydes were subjected to
standard reaction conditions, and their compatibility with the
method were tested. Direct 2-fold alkenylation was also
successfully performed on glutaraldehyde 2p to furnish skipped
diene 5p in 48% yield (Scheme 5). Even highly functionalized
Scheme 3. Scope of Indoles
Scheme 5. Scope of Structurally Unique Aldehydes
a
Reaction conditions: indole 1 (1.0 equiv), aldehyde 2 (1.0 equiv),
PhSO2H (1.0 equiv), PTSA·H2O (5 mol %), THF, 60 °C; NaH (2.5
equiv), DBU (5 mol %) in THF at 60 °C under N2; isolated yield.
b
c
acetate-protected cholic acid derived aldehyde 2q was also
compatible enough to provide the corresponding alkene 5q in
54% yield. Last, aldehyde 2r gave the corresponding skipped
diene 5r in 58% yield as a 2.5:1 mixture of E/Z isomers.
To demonstrate the scalability of this one-pot protocol, 10 g of
2-methylindole 1a was reacted with 10.2 g of 3-phenyl-
propionaldehyde. The corresponding alkene 5f was isolated in
17.9 g (95% yield, Scheme 6). Keeping in mind that the major
CH2Cl2 as solvent. EtOAc as solvent.
1,3-Dienes are considered to be among the most powerful
building blocks in organic synthesis and served as valuable
precursors for a wide range of reactions.25 3-Indolyl-1,3-diene
has been used for the synthesis of structurally unique indole
alkaloids yuehchukene and murrapanine.26 Intrigued by our
method’s mildness and wide functional group tolerability, we
next aimed to install a 1,3-diene moiety at the C3-position of
indole. Despite the fact that the preparation of functionalized
alkenes 5 and 6 is well documented, syntheses of 1,3-dienes 7 are
very scarce in the literature.27 At first, 3-methyl-3-buten-1-al was
subjected to the standard conditions, and 1,3-diene 7a was
isolated in 64% yield (Scheme 4). Similarly, 3-phenylbut-3-enal
Scheme 6. Gram-Scale Synthesis of 5f and Recycling of
Benzenesulfinic Acid
Scheme 4. Scope of 1,3-Dienes
byproduct of this method is sodium benzenesulfinate, which in
turn can be acidified easily to isolate benzenesulfinic acid, next we
investigated the economical aspect of this method. For this gram-
scale reaction, 12.7 g of benzenesulfinic acid was recovered by
acidification of the aqueous layer with 1 N HCl. No PTSA·H2O
was detected in the recovered benzenesulfinic acid as confirmed
by 1H NMR analysis.
To check the activity of recovered benzenesulfinic acid for
successive alkenylation, a 15 mmol scale reaction was conducted,
and 5f was isolated in 94% yield along with 99% recovery of
benzenesulfinic acid (Scheme 6). Successive repetition of the
alkenylation−recycling procedure revealed that even after five
consecutive cycles the activity of benzenesulfinic acid remained
unchanged as the alkenyl indole 5f was isolated in excellent yields
(93−96%). The fact that one can get up to 60 mmol of alkene
from 15 mmol of benzenesulfinic acid after five cycles proves the
economic advantages of this method.
gave the corresponding 1,3-diene 7b in 68% yield. Aldehydes
having aromatic groups such as phenyl and 4-methoxyphenyl at
the 4-position of aldehyde underwent smooth conversion, and
the corresponding 1,3-dienes 7c,d were isolated in good yields
(60−69%). In a similar fashion, benzyl- and isopropyl-
substituted 1,3-dienes 7e,f were also prepared in 61−67% yields.
Simple 3-indolyl-1,3-diene 7g and terminally dimethyl sub-
stituted 1,3-diene 7h were also synthesized in 45% and 41%
In summary, C3-alkenylation of unprotected indoles has been
developed using readily available aliphatic aldehydes through
C
DOI: 10.1021/acs.orglett.6b03612
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: msm@chem.iitkgp.ernet.in.
ORCID
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Modhu Sudan Maji: 0000-0001-9647-2683
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.S.M. gratefully acknowledges SERB, Department of Science
and Technology, New Delhi, India (Sanction No. EMR/2015/
000994), and DST/INSPIRE Faculty Award/2013/DST/
INSPIRE/04/2013/000681 for funding. S.S. thanks CSIR,
India, and A.B. thanks UGC, India, for fellowships.
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