2-Methylindole as an indicative nucleophile for developing a three-component reaction of aldehyde with two different nucleophiles

Article abstract of DOI:10.1021/co500010x

2-Methylindole was used as an indicative nucleophile for rapid screening of MCRs of aldehydes with two different nucleophiles. By removal of some samples that have characteristic color associated with the generation of di(indolyl)methane derivatives the difficulties encountered in the product analysis were alleviated significantly.

Full text of DOI:10.1021/co500010x

Research Article
pubs.acs.org/acscombsci
2‑Methylindole as an Indicative Nucleophile for Developing a Three-
Component Reaction of Aldehyde with Two Different Nucleophiles
Dan Jiang,† Xiaojuan Pan,† Minghao Li,† and Yanlong Gu*,†,‡
†Key Laboratory for Large-Format Battery Materials and System, Ministry of Education, Huazhong University of Science and
Technology, Wuhan 430074, China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, P.R.
China
S
* Supporting Information
ABSTRACT: 2-Methylindole was used as an indicative nucleophile for rapid screening of
MCRs of aldehydes with two different nucleophiles. By removal of some samples that have
characteristic color associated with the generation of di(indolyl)methane derivatives the
difficulties encountered in the product analysis were alleviated significantly.
KEYWORDS: 2-methylindole, indicative nucleophile, three-component reaction
aldehyde should be closely associated with a distinctive
phenomenon that enabled us to realize its occurrence; (ii)
the reactivity of the indicative nucleophile should be much
higher than that of its partner nucleophile; this ensures the
indicative nucleophile has the priority to react with aldehyde
when the reaction conditions are inappropriate for the progress
of the expected MCR; (iii) the indicative nucleophile should be
representative of many other nucleophiles in terms of the
reactivity and stability; thus the obtained catalytic/synthetic
systems can be applied in developing other MCRs. All these
things put together tend to narrow the possibility of finding a
suitable indicative nucleophile. Thanks to the extensive studies
on the electrophilic alkylation of aldehydes with indole,5 we
found one. Herein, we report for the first time the use of 2-
methylindole as an indicative nucleophile for establishing the
concept. The aim of this work is to show that the
aforementioned difficulties associated with the analysis of
reaction products can be alleviated by removing some reaction
samples that have the characteristic color of the byproduct
generated through electrophilic alkylation of aldehyde with 2-
methylindole.
INTRODUCTION
■
Multicomponent reactions (MCRs) not only enable the flexible
assembly of three or more substrates in one-pot operation, but
also generates products that contain substantial elements of all
the reactants.1 Electrophilic reaction of aldehydes with two
different nucleophiles is known to be a common strategy for
developing MCRs.2 However, this strategy is often plagued by
side reactions of the aldehyde with the same nucleophile.
Therefore, in this area, most of the research efforts are paid to
rational design of substrate and catalysts to control the reaction
selectivity.3 For instance, an assistance of an intramolecular
cyclization or hydrogen bond has been well adopted in
designing substrates.4 Unfortunately, because of the intrinsic
sensitivities of these MCRs to catalyst, solvent and some other
parameters, exploration of this type three-component reaction
is now a labor-intensive and time-consuming task for
researchers. On this account, an effective method for rapid
screening of substrate, catalyst and other parameters is needed.
Because many components were involved in the reaction
mixture, the choke point for implementing the study of MCRs
is, in the most cases, analysis of the product. An ideal method
to solve this problem is to establish a convenient way to identify
the formation of the target compound. However, it is not easy
because in most cases the desired product is unknown and it is
hard to predict its properties. As an alternative method, we can
also use the generated byproduct, that is capable of indicating
its formation in a practically simple way, as a probe to monitor
whether side reactions occur extensively.
RESULTS AND DISCUSSION
■
During the course of investigating the synthetic reactions of
indole derivatives,6 we became aware of an extraordinary color
alteration in the electrophilic alkylation of aldehydes with
indoles. Once the reaction is initiated, the color of the reaction
To establish this concept, the choice of the indicative
nucleophile is the key. A suitable one should have the following
properties: (i) side reaction of the indicative nucleophile with
Received: January 19, 2014
Revised: February 14, 2014
© XXXX American Chemical Society
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Figure 1. Schematic representation of our work.
Figure 2. Libraries of the partner nucleophile, aldehyde, and catalyst.
Figure 3. A photo of reaction of Nu3, A1, and 2-methylindole over
different catalysts.
Figure 5. Sc(OTf)3-catalyzed reactions of Nu1 + A1 to Nu1 + A7 in
the presence of 2-methylindole.
Scheme 1. Three-Component Reaction of Nu3, A1, and 2-
Methylindole
Figure 4. ZnCl2-catalyzed electrophilic reactions of A1 + 2-
methylindole to A7 + 2-methylindole.
mixture becomes immediately red and, sometimes, even dark.
Particularly, in the reaction of 2-methylindole, this behavior is
acute and inevitable. Intriguingly, no significant color change
was observed if a three-component reaction occurs exclusively
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Figure 6. Proposed mechanism.
in the presence of a suitable nucleophile and an appropriate
catalyst.7 Similar tendencies were also observed in many other
indole-participated MCRs.8 This stimulated us to use it as an
indicative nucleophile in this work. The pKa value of 2-
methylindole is −0.3 at 25 °C.9 To maximize the evaluation
efficiency of our method, an overwhelming reactivity
predominance should be arranged to the indicative nucleophile.
For this reason, some nucleophiles that have much lower
reactivity toward aldehydes were selected as shown in Figure 2.
To facilitate selective assembly of all these three types of
substrates, first, some aldehydes that are able to assist the
assembly with an intramolecular interaction were selected. A
para-substituted aromatic aldehyde, an aliphatic aldehyde and
ethyl glyoxalate were also involved in the library of aldehydes. It
should be noted that aldehydes bearing dark colors cannot be
employed here, for example 2-pyridinecarboxaldehyde and
furfural. As for the catalysts, both strong and weak Lewis and
Brønsted acids were all included. By the same token, some acids
that can colorize the reaction solution, such as FeCl3 and I2,
were ruled out. Both organic and inorganic bases and an
amphoteric catalyst, L-proline, were also involved in this library.
Initially, electrophilic alkylation of the aldehydes and 2-
methylindole was examined in dichloroethane using ZnCl2 as
catalyst and the results verified that the colors of the reaction
mixtures changed to red or dark in all the cases (Figure 4). This
implies that 2-methylindole should be able to act as an
indicative nucleophile to cooperate with all the aldehydes in
Figure 2. We then started to scrutinize the performance of each
combination of the three components using Sc(OTf)3 as a
catalyst. To avoid the possible interference of over-reactions,
which also resulted in dark solution, the reactions were stopped
within 30 min at 80 °C. A significant color alteration was
observed in Sc(OTf)3-catalyzed reactions of Nu1 + A1 to Nu1
+ A8 in the presence of 2-methylindole. In these cases, the
combinations were considered as failure and eliminated without
analysis (Figure 5). Similarly, all the nucleophile−aldehyde
combinations associated with In(OTf)3, ZnCl2, TsOH, LiBr,
TFA, and AcOH catalysts resulted in either red or dark
solutions, implying the fact that all these reactions were
detrimentally affected by the side reaction of aldehyde and 2-
methylindole. To verify the reliability of our method, some
samples were also subjected to TLC analysis, and the results
were always in a good agreement with that the reaction color
indicated. When basic and amphoteric catalysts were employed,
the obtained solutions were generally yellow. In these cases,
further analysis is needed in order to know whether the
expected three-component reaction occurred. Although a
tedious TLC analysis is still needed, this method removed
more than 60% of the samples without TLC analysis, improving
significantly the efficiency of substrate- and condition-screen-
ing. Incidentally, in many cases, the reaction solution becomes
dark within only 5 min, allowing us to judge the reaction
outcome more quickly. This improved further the screening
efficiency.
With this method, a three-component reaction of salicy-
laldehyde (2a), acetophenone (3a) and 2-methylindole was
successfully discovered with the aid of the L-proline catalyst
(Scheme 1). A two-step method for the synthesis of 4a has
been reported,10 which involves (i) synthesis of 2-hydrox-
ychalcone through condensation of 2a and 3a under basic
conditions; (ii) tandem Michael addition/cyclization reaction
of 2-methylindole with 2-hydroxychalcone using iodine as
catalyst (the maximum yield is 69%). The MCR in Scheme 1
not only opened a straightforward route to access 4a-type 4H-
chromenes, but also improved the synthesis in terms of
enhancing the reaction yield and simplifying the operational
procedure.
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Figure 7. Substrate scope of the three-component reaction.
Scheme 2. Utilization of L-Proline Catalyst in the Other MCRs
Initial event of the reaction might be the formation of imine
ion (I),11 which is followed by a nucleophilic attack of an
enolize acetophenone with the aid of intermolecular hydrogen
bond that produced a Mannich-type intermediate (II). A
competition of both carboxylic and ketocarbonyl groups as a
hydrogen bond acceptor allowed the proline fragment in the
intermediate (II) to be a good leaving group (Figure 6).7b
Finally, substitution of 2-methylindole to proline and the
subsequent dehydration resulted in the formation of 4a. Figure
7 shows substrate scope of the three-component reaction.
Acetophenones with both electron-donating and electron-
withdrawing groups worked well. No significant steric effect
was observed in acetophenone as both 2-fluoroacetophenone
and 2-bromoacetophenone can be used uneventfully. 1-
Tetralone and 2-acetonaphthone and some aryl methyl ketones
with a heterocyclic fragment, such as furanyl, thienyl and
benzofuranyl, also participated readily in this reaction.
Substituted indoles with methyl, methoxy, fluoro, bromo and
phenyl groups can all be used in this system, producing the
desired products in fairly good yields. The scope of
salicylaldehyde was proved to be good as well, and the
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substrates possessing both electron-donating and electron-
withdrawing groups participated readily in the reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectroscopic data for the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
One of the main aims of utilizing the indicative nucleophile
was to develop other new MCRs with the aid of the obtained
catalytic/synthetic system. We then replaced 2-methylindole
with other nucleophiles in the L-proline system. Both
thiophenol and 1H-benzotriazole can be used as nucleophile
to react with 2a and 3a (Scheme 2). These results not only
offered an effective way for the synthesis of 4H-chromenes,12
but also demonstrated that the use of an indicative nucleophile
is indeed able to help the implementation of MCR study.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: (0)86-(0)27-87 54 45 32. E-mail: klgyl@hust.edu.cn.
Funding
Financial support from National Natural Science Foundation of
China for the financial support (21373093 and 21173089), the
Cooperative Innovation Center of Hubei Province and Chutian
Scholar Program of the Hubei Provincial Government are
greatly appreciated.
CONCLUSIONS
■
A novel method for the rapid screening of MCRs was
developed by using 2-methylindole as an indicative nucleophile.
In electrophilic reaction of aldehydes with two different
nucleophiles, this method improved the analytical efficiency
by removing some samples that have red or dark color, which
was ascribed to the extensive formation of “ABB” type
byproduct. With this strategy, three-component reactions of
salicylaldehyde, acetophenone and a carbon-, sulfur-, or
nitrogen-based nucleophile were developed, opening an
effective and a straightforward way for the synthesis of 4H-
chromene derivatives.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are also grateful for all the staff members in the
Analytical and Testing Center of HUST.
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EXPERIMENTAL PROCEDURES
■
1H, 13C, and 19F NMR spectra were recorded on a Bruker AV-
400. Chemical shifts are expressed in ppm relative to Me4Si in
CDCl3. HRMS was recorded on a Bruker micrOTOF-Q II
instrument. IR spectra were recorded on a FT-IR Bruker
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Procedure of Screening Three-Component Reactions
of Aldehyde, Nucleophile, and 2-Methylindole with the
Aid of a Catalyst. First, nucleophile Nu1(3.0 mmol) was
mixed with aldehyde A1 to A7 (3.0 mmol), respectively, in
dichloroethane (12.0 mL). Then, 2-methylindole (6.0 mmol)
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Typical Procedure for Three-Component Reaction of
Acetophenone, Salicylaldehyde, and Indole. All reactions
were conducted in a 10 mL of V-type flask equipped with
triangle magnetic stirring. In a typical reaction, 1,2-dichloro-
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(91.5 mg, 0.75 mmol), 3a (60.0 mg, 0.5 mmol), and L-proline
(5.8 mg, 10 mol %) under air. The mixture was stirred for 8 h at
80 °C. After reaction, the mixture was cooled to room
temperature and the desired product 4a was obtained by
preparative TLC using a mixed solution of ethyl acetate and
petroleum ether as eluting solvent (the ratio of ethyl acetate/
petroleum ether is 1/8 v/v). Tests for substrate scope and the
reaction of using other nucleophiles were all performed
according to an analogous procedure.
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