Supported cobalt complex-catalysed conjugate addition of indoles, amines and thiols to α,β-unsaturated compounds

Article abstract of DOI:10.1039/b926599f

A highly active and reusable supported Co(ii) complex on SBA-15 shows an excellent activity and selectivity to target products in aza- and thia-Michael conjugate additions of indoles, amines and thiols to α,β-unsaturated compounds under solventless mild reaction conditions. The Co-catalyst was also highly reusable and comparably more active than related catalysts in the reaction.

Full text of DOI:10.1039/b926599f

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Supported cobalt complex-catalysed conjugate addition of indoles, amines
and thiols to a,b-unsaturated compounds†
Fatemeh Rajabi,*a Sepideh Razavia and Rafael Luque*b
Received 17th December 2009, Accepted 16th February 2010
First published as an Advance Article on the web 3rd March 2010
DOI: 10.1039/b926599f
A highly active and reusable supported Co(II) complex on
SBA-15 shows an excellent activity and selectivity to target
products in aza- and thia-Michael conjugate additions of
indoles, amines and thiols to a,b-unsaturated compounds
under solventless mild reaction conditions. The Co-catalyst
was also highly reusable and comparably more active than
related catalysts in the reaction.
addition have also been reported to be promoted in polyethylene
glycol (PEG-400), but require relatively long times of reaction
to achieve good product yields.13 However, to the best of our
knowledge, indoles remained largely unexplored as substrates
in these Michael reactions due to difficulties in controlling
the reaction conditions (e.g. acidity) to prevent side reactions
including dimerisation and/or polymerization. Thus, an efficient
and versatile methodology able to grant access not only to
3-substituted indoles but also to related amino- and thio-
substituted compounds via Michael addition will be of high
interest in organic synthesis.
In some of our recent work, we have developed versatile
Co(II) catalysts supported on mesoporous SBA-15 that exhibited
remarkable activities in a wide range of processes including the
chemoselective deprotection of aryl acetates,14 the acetylation
and aerobic oxidation of alcohols15 and related oxidations of
cyclohexene16 and lignin model monomers.17
Introduction
Michael reactions of heteroatom nucleophiles to a,b-un-
saturated compounds are important strategies for the forma-
tion of carbon–carbon/heteroatom bonds (Scheme 1), opening
easy routes for the preparation of pivotal synthetic interme-
diates including bioactive compounds,1 fine chemicals2 and
pharmaceuticals.3
Following previous studies with Co(II) catalysts, we report
here a highly efficient solventless Michael addition of indoles,
amines and thiols to a,b-unsaturated compounds catalysed by
a Co(II) complex on SBA-15 under mild reaction conditions.
Experimental
Scheme
compounds.
1 Michael addition of nucleophiles to a,b-unsaturated
Materials: preparation and characterisation
Co(II) complex on SBA-15 material (subsequently denoted as
Co/SBA-15, Scheme 2) was prepared as previously reported.13,14
Previous studies have shown that this catalyst is highly stable
under a wide range of reaction conditions, providing excellent
activities in different processes.13–16 Cobalt loading achieved for
the catalyst employed in this work was found to be 0.3 mmol g-1.
Characterisation results of the Co/SBA-15 material have been
included in the ESI.† The catalyst had a surface area of
448 m2 g-1, with a pore size of 3.6 nm and 0.77 mL g-1 meso-
porous pore volume.
Among them, aza- and thia-Michael reactions are able to
provide access to a considerable range of compounds containing
new C–N and C–S bonds. There are several reports of aza-
and thia-Michael reactions that can be performed under mild
reaction conditions (normally at room temperature for a few
minutes/hours). Catalysts employed in such reactions include
sulfated zirconia,4 silica-supported Lewis acids,5,6 polystyrene-
sulfonic acid,7 Si–Cu core–shell nanoparticles,8 ionic liquids9
and related acidic surfactants,10,11 and more recently by a ferrite-
anchored glutathione catalyst.12 Uncatalysed intramolecular
cyclisation of hydroxy/aminochalcones as well as aza-Michael
aDepartment of Science, Payame Noor University, PO Box 878, Qazvin,
Iran. E-mail: f_rajabi@pnu.ac.ir; Fax: +98 2813344081; Tel: +98
2813336366
bDpto. Qu´ımica Orga´nica, Universidad de Co´rdoba, Campus de
Rabanales, Edif. Marie Curie, Ctra Nnal IV, Km 396, E14014, Co´rdoba,
Spain. E-mail: q62alsor@uco.es; Fax: +34 957212066; Tel: +34
957212065
Scheme 2 Structure of the supported Co(II) complex on SBA-15.
† Electronic supplementary information (ESI) available: Experimen-
tal, full characterisation of the catalyst and products. See DOI:
10.1039/b926599f
Metal content in the materials was determined using in-
ductively coupled plasma (ICP) in a Philips PU 70000
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Table 1 Solventless Michael addition of indoles to a,b-unsaturated
compounds catalysed by Co/SBA-15
Table 2 Solventless Michael addition of amines to a,b-unsaturated
compounds catalysed by Co/SBA-15
Entry Substrate Enone
1
Product
Time/h Yield (%)a
Entry Substrate
1
Enone Product
Time/h Yield (%)a
1.5
1.0
3.0
90
94
88
1.0
98
2
3
1.0
1.5
91
94
2
3
4
5
1.5
1.5
92
95
4
5
1
2
94
82
6
7
3
3
80
84
6
3
80
a Isolated yields.
8
9
3
1
82
99
sequential spectrometer equipped with an Echelle monochro-
mator (0.0075 nm resolution). Samples were digested in HNO3
and subsequently analysed by ICP.
a Isolated yields.
Catalytic experiments
A typical Michael reaction was performed as follows: 1 mmol
indole, amine or thiol was added to a mixture of Co/SBA-15
(0.005 mmol, 0.017 g) and methyl vinyl ketone (1 mmol). The
reaction mixture was then stirred at room temperature (RT)
for the appropriate time. After reaction completion, CH2Cl2
(20 mL) was added and the cobalt catalyst was removed from
the reaction mixture by filtration, rinsed twice with CH2Cl2
(10 mL) and reused. The filtrate was washed with water, the
solvent evaporated off and the final product was isolated, in
most cases in almost pure form. Further purification was carried
out by column chromatography on silica gel, eluting with ethyl
acetate/petroleum ether. All compounds were characterized by
IR, NMR, and MS spectra (see ESI for more details†).
Steric effects related to the methylation in the ortho-position
with respect to the N from the indole did not seem to be
important for the Michael reaction as the corresponding product
was also obtained in excellent yields at reasonable times of
reaction (3 h, Table 1, entry 3).
This versatile methodology could also be extended to the
use of different amines (Table 2), including secondary amines
(Table 2, entries 7, 8) and pyrrole (Table 2, entry 9) acting
as nucleophiles in the reaction. Excellent yields of products
were obtained in all cases regardless of the nature of the
amine (aliphatic or aromatic, Table 2, entries 1, 3 and 5) in
1–2 h reaction at RT. Due to the high reactivity of pyrrole, the
substituted product in positions 2 and 5 was obtained as only
product.
Furthermore, thiophenol as well as aliphatic mercaptans were
employed as substrates to further extend the scope of the
protocol to thia-Michael additions. Results included in Table 3
prove the catalyst was also highly active in the Michael addition
of thiophenol/aliphatic mercaptans to methyl vinyl ketone, with
quantitative yields of products typically achieved after 1 h of
reaction (Table 3, entry 1).
Results and discussion
Results of the solventless Co/SBA-15 catalysed Michael addi-
tion of indoles to a,b-unsaturated compounds are summarised
in Table 1. A range of 3-substituted indoles were successfully
obtained in high yields under mild reaction conditions at
short times of reaction (typically 1–2 h), regardless of the
substrate and the use of methyl vinyl ketone or the corresponding
aldehyde or ester (Table 1).
The protocol was also amenable to a range of enones, that
provided moderate to very good yields of target products under
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Table 3 Activity of the Co/SBA-15 material in the solventless Michael
addition of thiols to a range of enones
Table 4 Activity comparison of results obtained in this work using the
Co/SBA15 catalyst with related literature reports
Entry Thiol
1
Enone
Product
Time/h Yield (%)a
Yield
Substrate
Enone
Product
Time/h (%) Reference
1
99
65
71
78
95
82
65
1.5
1.0
90a
93b
This work
Ref. 11
2
3
4
5
6
7
1
1.5
0.8
92a
90c
This work
Ref. 4
1.5
1
1.0
0.8
98a
90c
This work
Ref. 4
1
1.5
2.0
95a
78d
This work
Ref. 6
1.5
2
1.0
0.1
99
This work
Ref. 5
78e
1.0
0.2
95a
78f
This work
Ref. 5
8
9
0.75
0.75
99
99
Reaction conditions for the different reports: a 0.5 mol% Co/SBA-15,
RT. b 4 mol% SDS·HCl, RT. c 2 mol% SO42-/ZrO2, RT. d 10 mol%
AlCl3/SiO2, 60 ◦C. e 1 mol% HBF4/SiO2, RT. f 1 mol% HBF4/SiO2,
0 ◦C.
a Isolated yields.
similar reaction conditions (Table 3, entries 2 to 7). Most
importantly, the Co/SBA-15 catalyst was also stable and highly
reusable under the investigated reaction conditions, preserving
over 90% of their initial activity after 5 reaction cycles (Fig. 1).
reaction (2–3 h compared to 1 h) to achieve yields of 90+%.
However, no detectable metal traces in solution (<0.5 ppm)
were determined by ICP of the final reaction mixture, con-
firming the strong coordination and stability of cobalt in
the catalyst that prevented metal leaching during/after the
reaction.
These results were further compared with related literature
reports. Results in Table 4 show that the reported protocol,
apart from being simple, versatile and environmentally sound,
provides comparable and even superior yields of products in
most cases under milder reaction conditions (e.g. less quantity
of catalyst added, milder temperature of reaction, safer and more
environmentally compatible catalyst, etc.).
This protocol is also greener compared to non-metallic meth-
ods as these normally employ significantly larger catalys◦t quan-
tities and solvents,4 high or very low temperatures (80 C and
above7,12 or 0 ◦C5), pressures (40–180 psi7,13) and/or long times
of reaction (>5 h) to achieve moderate yields,13 thus offering
for the first time a unique approach to the transformation of
a wide range of chemically different substrates. Furthermore,
the majority of such reported protocols are restricted to aza-
or thia-conjugated additions with restrictions in the scope
of the reaction (e.g. only amines, thiophenols but not linear
mercaptans, etc.) compared to the significant range of substrates
explored in this contribution.
Fig. 1 Reuses of the Co/SBA-15 catalyst in the Michael addition
of thiophenol to methyl vinyl ketone. Reaction conditions: 1 mmol
thiophenol, 1 mmol methylvinyl ketone, 0.017 g catalyst, RT, 1 h
reaction.
Further uses of the catalyst showed that, from the 6th cycle,
the catalyst slightly deactivated and needed longer times of
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and thiols to various a,b-unsaturated compounds. This novel
methodology may pave the way to the utilisation of highly active
and reusable mesoporous material-supported metal complexes
in multiple chemical processes.
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FR is grateful to Payame Noor University for funding and
support. RL gratefully acknowledges Ministerio de Ciencia e
Innovacio´n for a Ramon y Cajal contract (RYC-2009-04199).
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