Research Article

pubs.acs.org/journal/ascecg

Triphenylphosphine‑m‑sulfonate/Carbon Tetrabromide as an
Efficient and Easily Recoverable Catalyst System for Friedel−Crafts
Alkylation of Indoles with Carbonyl Compounds or Acetals
Congde Huo,* Chougu Sun, Cheng Wang, Xiaodong Jia, and Wenju Chang
Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education, College of Chemistry and Chemical
Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
*
S Supporting Information

ABSTRACT: A solid complex, conveniently prepared from commercially available sodium triphenylphosphine-m-sulfonate
(TPPMS) and carbon tetrabromide, can be used as an easily recoverable and reusable catalyst system for Friedel−Crafts
alkylation of indoles with carbonyl compounds or acetals to produce bis(indolyl)alkane products (BIAs).
KEYWORDS: Friedel−Crafts alkylation, Indoles, Carbonyl compounds, Recoverable catalyst

■ INTRODUCTION
Friedel−Crafts (FC) reaction is one of the cornerstone
and for the tetrahydropyranylation of alcohols.19 In these
reactions, as a solid complex, the TPPMS/CBr4 system is stable
and can be kept readily. The catalyst is soluble in relatively
reactions for carbon−carbon bond construction and has been
polar organic solvents such as methanol but can be easily and
widely used to generate important classes of building
quantitatively recovered from the reaction mixture by simply
blocks.1−10 However, the methods often suffer from drastic
adding a nonpolar organic solvent such as ether. The recovered
reaction conditions and more than stoichiometric amounts of
catalyst can be reused without loss of catalytic activity.
catalysts. With the recent increased environmental and As part of our ongoing program to develop highly efficient
economic awareness, the development of greener and/or and environmentally benign synthetic processes, we are
sustainable methods for this fundamental transformation has interested in exploring new catalytic activities for this solubility
emerged in recent years.5−10 controllable TPPMS/CBr4 complex. Herein, an efficient FC
3,3′-Bis(indolyl)alkanes (BIAs) were widely isolated from reaction of indoles with carbonyl compounds or acetals
various terrestrial and marine natural sources, which exhibit a catalyzed by TPPMS/CBr4 complex to achieve various BIAs
range of important biological activities.11 Therefore, there is a is introduced in this paper.

■
great deal of interest in the synthesis of this class of compounds
since it was first prepared by Fischer in 1886.12 The practical
synthetic method of this skeleton is the FC reaction between RESULTS AND DISCUSSION
indoles and carbonyl compounds, which generally require a The TPPMS/CBr4 complex used in this study was produced as
stoichiometric amount of the Lewis acids or Brönsted acid. follows. A mixture of TPPMS and carbon tetrabromide (1:1
Therefore, the development of green methods to construct molar ratio) was stirred at room temperature in methanol for 4
BIAs is still highly desired.13−15 h, and then the reaction mixture was concentrated and ether
Sodium triphenylphosphine-m-sulfonate (TPPMS) is a was added to precipitate the TPPMS/CBr4 complex as a white
commercially available reagent that is used industrially as a solid.
ligand for the Rh-catalyzed biphasic hydroformylation reac- Our investigations started with the reaction between p-
tions.16,17 Recently, we demonstrated that TPPMS can be used chlorobenzaldehyde (2i) and indole (1) (Table 1). The
as an ion-tagged reagent to mediate a facilitate Wittig solvents are crucial to the reaction, and the best result was
reaction.18 The product alkenes were often sufficiently pure
without chromatographic purification. Shortly afterward, we Received: February 6, 2013
developed the use of the TPPMS/CBr4 complex as a highly Revised: March 18, 2013
efficient catalyst for the preparation of acetals from aldehydes Published: March 20, 2013

© 2013 American Chemical Society 549 dx.doi.org/10.1021/sc400033t | ACS Sustainable Chem. Eng. 2013, 1, 549−553
ACS Sustainable Chemistry & Engineering Research Article

Table 1. Reaction Conditions Optimization Table 2. TPPMS/CBr4 Catalyzed FC Alkylation Reactions of

Indole with Aldehydes (isolated yields in parentheses)

entry conditions NMR yield of 3i (%)

1 10% TPPMS/CBr4, MeCN, rt, 4 h 95
2 10% TPPMS/CBr4, DCM, rt, 4 h 75
3 10% TPPMS/CBr4, THF, rt, 4 h 37
4 10% TPPMS/CBr4, Dioxane, rt, 4 h 30
5 10% TPPMS/CBr4, EtOAc, rt, 4 h 44
6 10% TPPMS/CBr4, Acetone, rt, 4 h 58
7 1% TPPMS/CBr4, MeCN, rt, 4 h 51
8 2% TPPMS/CBr4, MeCN, rt, 4 h 84
9 5% TPPMS/CBr4, MeCN, rt, 4 h 93
10 10% TPPMS, MeCN, rt, 4 h -
11 10% CBr4, MeCN, rt, 4 h -

obtained by the use of CH3CN as solvent. Encouraged by the

initial results, we went on to investigate the generality of this
procedure. We examined the reactivity of various aldehydes as
summarized in Table 2. In general, the TPPMS/CBr4 complex
was able to catalyze the FC reaction of both aryl and aliphatic
aldehydes with indole. The reaction conditions are usually quite
mild, simply stirring of the solution at room temperature. Aryl
aldehydes with electron-donating substituents and with
electron-withdrawing substituents were all well tolerant of the
reaction conditions (Table 2, 3a−3p). The aldehydes with ortho
or meta substituents delivered the corresponding alkylated
indoles in high yields (Table 2, 3g, 3h, 3j, 3k), illustrating that
steric hindrance played a poor role to the reaction. The
procedure was also successfully applied for heteroaromatic
aldehydes (Table 2, 3m), and their corresponding BIAs were
obtained at high yields. The reaction was tolerant of
unprotected phenols (Table 2, 3n) with the adduct of 4-
hydroxybenzaldehyde being isolated in 82% yield. Aliphatic
aldehydes also gave good yields of the corresponding BIAs
(Table 2, 3q−3s). Furthermore, the reaction of indole with
cinammaldehydes (Table 2, 3t, 3u) as α,β-unsaturated
aldehydes furnished moderate to excellent yields of the
corresponding BIAs. The N-substituted indole presented
equally high efficiency in respect to that of free indole to give
the adduct in high yields (Table 2, 3v). Ethyl bis-1H-indol-3-yl-
acetate, 3w, as the important intermediate for the synthesis of
pharmacologically interesting natural product Streptin-
dole,20−23 was prepared by our method in 83% yield, and
biologically interesting (chromon-3-yl)bis(indol-3-yl)-
methanes24,25 3X was also prepared in high yield. The ketones
failed to furnish the BIAs under the reaction conditions and
were recovered quantitatively. 4-Acetylbenzaldehyde reacted
with indole to give the BIA 3p in good yield, demonstrating Cyclic arenecarbaldehyde acetals have previously found use
high chemoselectivity. in Friedel−Crafts reactions, which proceed to give the alkylated
In the reaction, the separation and recovery of the catalyst products in high overall yield.26,27 The reaction catalyzed by the
system was simply carried out by precipitation with ether after TPPMS/CBr4 complex between indole and acetals were next
completion of the reaction. The recovered catalyst can be investigated. We were gratified to observe that reactions of
reused without loss of catalytic activity. We demonstrated this indole with acetals in acetonitrile gave efficient conversions to
with the FC reaction of p-chlorobenzaldehyde with indole using the desired products. In all cases, the reaction of dimethyl
recovered TPPMS/CBr4 system for 10 cycles without distinctly acetals derived from aldehydes provided the bisindolylalkane
diminished yield (Figure 1.). product in excellent yield in short reaction times (Table 3,
550 dx.doi.org/10.1021/sc400033t | ACS Sustainable Chem. Eng. 2013, 1, 549−553
ACS Sustainable Chemistry & Engineering Research Article

the direct conversion of aldehydes to acetals in the presence of

alcohols and diols without the requirement for additional
dehydrating agents.19 As an extension of this chemistry, we
envisioned that the TPPMS/CBr4 complex might also be
utilized to promote the tandem acetalization−FC reaction of
aldehydes and indoles in simple alcohols. It was expected that
after the acetalization of aldehydes, the acetals generated in situ
would undergo the FC alkylation to produce BIAs. We
investigated the reaction between indole and a few aldehydes in
Figure 1. Studying reusablility of TPPMS/CBr4 in the reaction of p-
methanol as shown in Table 4. The reaction performed
chlorobenzaldehyde with indole. smoothly, but not as effectively as the same reaction in
acetonitrile.
entries 1−5). Reactions involving other acetals (Table 3, entries
6−9) also proceeded efficiently, giving excellent isolated yields. Table 4. TPPMS/CBr4 catalyzed FC alkylation reactions in
methol (isolated yields in parentheses)
Table 3. TPPMS/CBr4 Catalyzed FC Alkylation Reactions of
Indole with Acetals

There is an increasing interest in solvent-free reactions. This

protocol leads to a clean, efficient, and economical technology
not only with the increment of safety, the simpleness of work
up, and the reduction of cost, but also increased amounts of
reactants can be achieved in the same equipment without huge
modifications.29−32 We then proceed to examine our method
under solvent-free conditions. We got very exciting results that
beside aldehydes, both aromatic and aliphatic ketones were also
transformed to the desired BIAs with good to excellent yield.
The ketones’ reactivity may be enhanced due to without
dilution in solvent-free condition. The results are shown in
Table 5.
To evaluate the practicability of our method,33,34 the reaction
Furthermore, Graham et al. reported last year on a between indole (1) and p-chlorobenzaldehyde (2i) has been
nanoporous aluminosilicate catalyzed tandem acetalization− performed on a large scale [11.6 g 1 (100 mmol) + 7 g 2i (50
FC protocol in which the acetal is generated in situ and mmol)] in a single batch, and to our delight, no yield loss was
undergoes subsequent FC reaction.28 The main benefit of this observed with even lower initiator loading (5 mol % TPPMS/
protocol is allowable of using environmentally preferable CBr4 in 25 mL MeCN at room temperature, finished in 4 h,
solvents, such as methanol. We have previously demonstrated 97% isolated yield). That is to say, here we present a practical
that the TPPMS/CBr4 complex is a highly efficient catalyst for and scalable synthetic entry to the BIA derivatives.
551 dx.doi.org/10.1021/sc400033t | ACS Sustainable Chem. Eng. 2013, 1, 549−553
ACS Sustainable Chemistry & Engineering

■
Research Article

Table 5. TPPMS/CBr4 Ctalyzed FC Alkylation Reactions of ASSOCIATED CONTENT

indole with Ketones (isolated yields in parentheses) *
S Supporting Information
Copies of 1H NMR and 13C NMR. This material is available
free of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected].
Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(21002080, 21262029) and the Specialized Research Fund for
the Doctoral Program of Higher Education (20106203120003)
of the Education Ministry for financially supporting this work.

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