A rapid and highly efficient Michael addition of methoxybenzenes and indoles to α,β-unsaturated ketones using BF3·OEt2 as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2017.09.016

An efficient and general protocol is described for the Michael addition of α,β-unsaturated ketones with electron-rich arenes/indoles to give alkylated arenes/indoles under mild reaction condition at room temperature. Shorter reaction time, convenient and

Full text of DOI:10.1016/j.tetlet.2017.09.016

Accepted Manuscript
A rapid and highly efficient Michael addition of methoxybenzenes and indoles
to α,β-unsaturated ketones using BF3.OEt2 as a catalyst
A Swetha, M Raghavender Reddy, B Madhu Babu, H.M. Meshram
PII:
S0040-4039(17)31133-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.016
TETL 49286
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 July 2017
3 September 2017
7 September 2017
Please cite this article as: Swetha, A., Reddy, M.R., Babu, B.M., Meshram, H.M., A rapid and highly efficient
Michael addition of methoxybenzenes and indoles to α,β-unsaturated ketones using BF3.OEt2 as a catalyst,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.09.016
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A rapid and highly efficient Michael addition
of methoxybenzenes and indoles to α,β-
unsaturated ketones using BF3.OEt2 as a catalyst
Dr. A Swetha, Dr. M Raghavender Reddy, Dr. B Madhu Babu and Dr. H. M. Meshram*

Tetrahedron Letters
1
A rapid and highly efficient Michael addition of methoxybenzenes and indoles to
α,β-unsaturated ketones using BF3.OEt2 as a catalyst
Dr. A Swetha, Dr. M Raghavender Reddy, Dr. B Madhu Babu and Dr. H. M. Meshram*
Medicinal Chemistry and pharmacology division
Indian Institute of Chemical Technology, Hyderabad – 500 007, India
Tel.: +91-40-27191640, Fax: +91-40-27193275, E-mail address- hmmeshram@yahoo.com
Abstract— An efficient and general protocol is described for the Michael addition of α, β-unsaturated ketones with electron-rich
arenes/indoles to give alkylated arenes/indoles under mild reaction condition at room temperature. Shorter reaction time, convenient and
good isolated yields are the significant features of this protocol. Moreover, the procedure is environmentally benign in nature and
applicable to variety of arenes/indoles as well as α, β-unsaturated ketones.
Keywords: Michael reaction, Methoxybenzenes, Indole, α, β-unsaturated ketones, BF3.OEt2.
The Lewis acid catalyzed Friedel-Crafts-type alkylation and
Michael-type addition reactions are among the most
important synthetic tools available for C/C-bond forming
reactions and has wide synthetic applications in organic
synthesis.1 Among them the addition reactions of electron-
rich arenes/indoles to electron-deficient carbonyl compounds
has attracted much attention over the past few years. 2 In
addition, these reactions are involved in the total synthesis of
a class of biologically active indole alkaloids.3 Moreover, 3-
substituted indoles are important structural motifs that occur
in nature and in many natural and synthetic molecules with
significant biological activity such as antibacterial, antialgal
and antimycotic(Fig. 1).4 Due to distinct properties of 3-
substituted indoles, there is research interest to develop
convenient and efficient method for the synthesis of 3-
substituted indoles.
(MSSA).26 However, a plethora of synthetic strategies have
been developed, the use of excess amount of reagents,26
expensive catalysts,10,14-18 tedious preparation of catalysts,5,6,26
longer reaction times (48h),5,16 harsh reaction conditions (e.g.
ultrasonic irradiation, high temperatures),13 poor yields of the
desired product5 and cumbersome work-up procedures19 made
the various existing methodologies undesirable under the
aspect of sustainable synthesis. Although some of the
protocols are satisfactory, still there is a scope to develop
rapid, convenient and general protocols for the Michael
reaction of indoles with various α, β-unsaturated carbonyl
compounds under mild reaction condition.
Fig. 1: Representative examples of natural products and
biologically active 3-substituted indole derivatives.
Scheme 1: Optimization of the reaction conditions.
There are numerous methods for the Michael reaction of
indoles with various α, β-unsaturated carbonyl compounds in
the presence of either Lewis acids or protic acids such as
Sc(DS)3,5 clay-supported nickel bromide,6 Fe(BF4)2.6H2O,7
InBr3,8 InCl3,9 Gold(III) Chloride,10 GaI3,11 Bi(NO3)3,12
bismuthyl perchlorate,13 Bi(OTf)3,14 Os(NH3)5(OTf)3,15
zirconium triflate,16 Hf(OTf)4,17 triflic acid,18 Al2O3,19
rhodium complex,20 ruthenium complex,21 I2,22 HClO4/SiO2,23
PTSA,24 sulfamic acid,25 modified silica sulfuric acid
Recently, BF3.OEt2 has emerged as a powerful Lewis acid
catalyst and has been used for organic transformations
effectively under mild reaction conditions.27 To the best of
our knowledge, there is no report for the Micheal addition of
indoles and α, β-unsaturated ketone using BF3.OEt2 as a
catalyst. Hence, as a part of our28 ongoing research in the
applications of BF3.OEt2, herein we wish to report rapid,
highly efficient and operationally simple protocol for Micheal

2
Tetrahedron Letters
addition of indoles and α, β-unsaturated ketones using
BF3.OEt2 under mild reaction condition.
the effect of solvent for this reaction using various solvents
such as THF, MeCN and toluene.
In a preliminary experiment, we performed the reaction of
methyl vinyl ketone (1a, 1 mmol) and indole (2a, 1 mmol)
in the presence of BF3.OEt2 (1 equiv) in DCM (5 mL) at room
temperature (Scheme 1). The progress of the reaction was
moniterd by TLC. After completion of the reaction, the
reaction mixture was quenched with solid NaHCO3.Then
silica gel is added to the rection mixture, solvent is
evaporated and directly loaded on column chromatography
by avoiding aqueous work up-extraction step. After
purification 3a was obtained as a sole product, which was
confirmed by 1H NMR, 13C NMR, IR and Mass spectrometry
analysis (Table 2, entry 1).
Table 2: Synthesis of new 3-substituted indoles.a
Table 1: Optimization of the reaction conditions.a
Entry Lewis acid
(equiv)
Solvent Time
Yieldb
(%)
96
1. BF3.OEt2 (1.0) DCM
2 min
2 min
15 min
2. BF3.OEt2 (3.0)
3. BF3.OEt2 (1.0)
4. BF3.OEt2 (1.0)
5. BF3.OEt2 (1.0)
6. Sc(OTf)3 (1.0)
7. Ti(OTf)3 (1.0)
THF
94
MeCN
85
Toluene 10 min
81
THF
10 min
60 min
80 min
50 min
5 min
68
EtOH
DCE
38
51
8. Yb(OTf)3 (1.0) DCE
39
9. FeCl3 (1.0)
10. AlCl3 (1.0)
11. TMSCl (1.0)
12. TiCl4 (1.0)
13. SnCl4 (1.0)
DCM
MeCN
MeCN
DCM
DCM
18
3 min
82
6 min
56
8 min
10 min
67
-
a All the reactions were conducted with Methyl vinyl ketone 1a (1
equiv), indole 2a (1 equiv) in the presence of BF3.OEt2 in 5 mL
solvent at room temperature. b Isolated yield.
a All products exhibited physical and spectral (NMR, Mass and IR)
properties in accordance with the assigned structure. b Isolated Yield
The effect of other acid catalysts such as Bi(OTf)3, Sc(OTf)3,
Ti(OTf)3, Yb(OTf)3, FeCl3, AlCl3, TMSCl, TiCl4, SnCl4
(Table 1, entries 1-13) were also studied for this conversion.
However, the best results were achieved using BF3.OEt2. The
control experiment without BF3.OEt2 was also performed, but
the formation of the product 3a was not observed even after
stretching the reaction time upto 24h.The reaction was also
carried out using different amounts of the reagent ranging
from a catalytic to stoichiometric. BF3.OEt2 (1 equiv) was
found suitable for optimum conversion. We further examined
After extensive screening we found DCM as most suitable
solvent for maximum conversion interms of reaction time and
isolated yield.

Tetrahedron Letters
3
Table 3: Synthesis of new 3-substituted arenes.a
indole 2f reacted analogously and gave 3-substituted indole
3m in good yield (Table 2, entry 13).
The efficiency of the reaction was further strengthened by the
participation of α, β-unsaturated ketones 1 with methoxy
benzenes 4 and the results are summarized in Table 3. The
reaction of 1,3-dimethoxybenzene 4a and 1,3,5-
trimethoxybenzene 4b reacted rapidly with methyl vinyl
ketone 1a to afford the corresponding products 5a and 5b
respectively in excellent yields (Table 3, entries 1-2).
Similarly, ethyl vinyl ketone 1b and arenes like 1,3-
dimethoxybenzene 4a, 1,2,4-trimethoxybenzene 4c, 1,3,5-
trimethoxybenzene 4b and 1-bromo-3,5-dimethoxybenzene
4d also underwent smoothly in the standard reaction
condition to furnish the desired product in a high yield (Table
3, entries 3-6). It was found that even cyclopent-2-enone 1d
as fairly sterically demanding precursors reacted with
corresponding arenes 4b in a similar fashion to afford the
respective product in acceptable yields (Table 3, entry 7). It is
worthy to mention that the method is also applicable for
cyclohex-2-enone 1c. For example the reaction of cyclohex-2-
enone 1c with 1,3,5-trimethoxybenzene 4b and 1,2,4-
trimethoxybenzene 4c also proceeded same way and afforded
corresponding product 5h and 5i in good yield (Table 3,
entries 8 and 9).
In conclusion, we have proven a rapid, highly efficient and an
operationally facile method for the synthesis of 3-substituted
indoles and arenes. Moreover, the method is applicable for a
variety of acyclic and cyclic α, β-unsaturated ketones as well
as substituted indoles and methoxybenzenes. The developed
protocol is general, mild and offers easy access for the
Michael reaction of indoles and arenes with various α, β-
unsaturated ketone.
Acknowledgments
a All products exhibited physical and spectral (NMR, Mass and IR)
properties in accordance with the assigned structure. b Isolated Yield.
The authors A S and B M B thank CSIR-UGC for the award
of a fellowship and to Dr. Ahmed Kamal (Outstanding
Scientist), Head, Medicinal Chemistry and Pharmacology
Division, IICT, for his support and encouragement.
For the general validity of the reaction, the optimized
reaction29 was tested on several α, β-unsaturated ketones as
well as indoles and the results are summarized in Table 2
(Scheme 2). The substituents on indoles either electron
withdrawing (cyano, bromo) or electron donating (methoxy,
methyl) has no substantial effect on the reaction (Table 2,
entries 2-5, 7-9 and 11-14). The reaction of indoles such as
indole 2a, 5-bromoindole 2b, 5-cyano indole 2c, 5-methoxy
indole 2d and 4-bromoindole 2e with methyl vinyl ketone 1a
underwent smoothly in optimised reaction condition and
furnished the desired products 3a-3e in a high yield (Table 2,
entries 1-5). Similarly, ethyl vinyl ketone 1b is also reacted
with indole 2a, 5-bromoindole 2b, 5-cyanoindole 2c and 5-
methoxyindole 2d to afford the corresponding products 3f-3i
in good yield (Table 2, entries 6-9). It is worthy to mention
that the developed protocol is also applicable for cyclic α, β-
unsaturated ketone like cyclohex-2-enone 1c (Table 2, entries
10-14). For example cyclohex-2-enone 1c with 1-methyl
The authors thank CSIR, New Delhi for financial support as
part of XII Five Year plan program under title ACT (CSC-
0301).
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