Organocatalytic asymmetric synthesis of polyfunctionalized 3-(cyclohexenylmethyl)-indoles via a quadruple domino Friedel-Crafts-type/ Michael/Michael/aldol condensation reaction

Article abstract of DOI:10.1039/c002839h

A new organocatalytic quadruple domino Friedel-Crafts-type/Michael/Michael/ aldol condensation reaction has been developed. In this one-pot multi-component process acrolein, various indoles and nitroalkenes are used as starting materials. The diphenylprolinol TMS-ether catalysis provides a straightforward and efficient entry to 3-(cyclohexenylmethyl)-indoles bearing three stereogenic centers in moderate to excellent yields (23-82%) and excellent stereoselectivities (dr = 91 9 to >95 5, ee = 94 to >99%). The Royal Society of Chemistry.

Full text of DOI:10.1039/c002839h

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Organocatalytic asymmetric synthesis of polyfunctionalized
3-(cyclohexenylmethyl)-indoles via a quadruple domino
Friedel–Crafts-type/Michael/Michael/aldol condensation reactionw
Dieter Enders,* Chuan Wang, Meruyert Mukanova and Andreas Greb
Received (in Cambridge, UK) 10th February 2010, Accepted 24th February 2010
First published as an Advance Article on the web 8th March 2010
DOI: 10.1039/c002839h
A new organocatalytic quadruple domino Friedel–Crafts-type/
Michael/Michael/aldol condensation reaction has been developed.
In this one-pot multi-component process acrolein, various indoles
and nitroalkenes are used as starting materials. The diphenyl-
prolinol TMS-ether catalysis provides a straightforward and
efficient entry to 3-(cyclohexenylmethyl)-indoles bearing three
stereogenic centers in moderate to excellent yields (23–82%)
and excellent stereoselectivities (dr = 91 : 9 to >95 : 5,
ee = 94 to >99%).
Scheme 1 Retrosynthetic analysis of the domino Friedel–Crafts-type/
Michael/Michael/aldol condensation reaction.
Michael addition.8 After an intramolecular aldol-condensation,
four C–C bonds are formed and the domino product is
constructed bearing three stereogenic centers. To the best of
our knowledge, only three examples of an organocatalytic
quadruple cascade have been published so far.4o–q Additionally,
3-(1H-indol-3-yl)propanals are not commercially available and
are usually synthesized in two steps starting from indole-3-
acetic acids9a,b or in one step from tryptophans.9c Therefore,
involving these indolylpropanals as a component in our triple
cascade4e,j would necessitate additional manual operations.
Diphenylprolinol TMS-ether 510,11 shows good catalytic acti-
vity and excellent stereocontrol in the triple cascade reactions.4e,f,j
Thus, we used it as a catalyst again in the new quadruple
cascade. Initially, we performed the reaction of indole (1a),
acrolein (2) and b-nitrostyrene (3a) using toluene as solvent
(Scheme 2). The reaction provided the desired product 4a only
in a very low yield but with high diastereoselectivity (Table 1,
entry 1). It was observed that a large mount of polymer was
formed during the reaction. In addition, the analytical TLC
revealed that the conversion of indole (1a) was completed
within an hour. Furthermore, we carried out the reaction
involving only acrolein (2) and indole (1a) under the catalysis
of 5 or pyrrolidine, which also gave much polymer but only
traces of 3-(1H-indol-3-yl)propanal. The formation of the
polymer may be attributed to a competing Michael addition
with acrolein (2) as acceptor. To avoid the polymerisation we
In the last decade organocatalysis attracted much attention and
became a focal point of asymmetric synthesis.1 One develop-
ment is designing new cascade reactions, in which complex
molecules are constructed from simple precursors in one single
operation, thereby avoiding the isolation of reaction inter-
mediates and time-consuming protecting group manipulations.
Furthermore, these domino processes are often accompanied by
excellent stereoselectivities. Due to these advantages, organo-
catalytic domino reactions have been intensively investigated by
many research groups in recent years.2–4
Indole is a ubiquitous subunit present in a large number
of alkaloids with biological and pharmacological activities.5
Employing indole or its derivatives as a component in cascade,
tandem or one pot reactions provides direct access to complex
indole alkaloids. For example, Franzen and Fisher reported a
highly enantioselective one pot synthesis of indolo[2,3a]-
quinolidines using an organocatalytic Michael addition as
the initial step followed by an intramolecular acid-catalyzed
Friedel–Crafts-type reaction.4r Very recently, our group and
Wang et al. developed independently a domino aza-Michael/
aldol condensation reaction with indole-2-carbaldehydes and
enals as starting materials furnishing 3H-pyrrolo[1,2-a]indoles
in a highly enantioselective manner.4n,w 3-(Cyclohexylmethyl)-
1H-indole is a core structure of suaveolindole, which shows
activity against Gram-positive and methicillin-resistant bacteria.6
We envisaged a quadruple cascade using indoles (A), acrolein
(B), and nitroalkenes (C) as components to afford poly-
substituted functionalized 3-(cyclohexenylmethyl)-1H-indoles
(D) as the domino products (Scheme 1). This cascade is initiated
by a Friedel–Crafts reaction after an iminium activation mode,7
followed sequentially by an enamine- and an iminium-mediated
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
52074 Aachen, Germany. E-mail: enders@rwth-aachen.de;
Fax: +49-241-809-2127; Tel: +49-241-809-4676
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/c002839h
Scheme 2 Asymmetric synthesis of 3-(cyclohexenylmethyl)-indole 4
from indoles 1, acrolein (2) and nitroalkenes 3.
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Table 1 Optimization of reaction conditions for the quadruple
cascadea
the substrate spectrum was observed in the case of the
aliphatic nitroalkene 3e, which did not lead to the desired
product. Next several substituted indoles 1b–f were examined
for the quadruple cascade. In general, the reactions occurred
with various indoles bearing electron-withdrawing or donating
groups in different positions, yielding the corresponding pro-
ducts 4f–j in moderate to good yields (23–54%) and excellent
stereoselectivities (dr = 91 : 9 to >95 : 5, ee = 97 to >99%).
The higher diastereomeric ratios in comparison to our pre-
vious triple cascade may be attributed to the more sterically
demanding intermediates bearing the indol moiety.
Entry
Solvent
t/d
Yieldb (%)
drc
eed (%)
1
2
3
4
Toluene
Toluene
THF
1
3
3
1
o5
54
48
55
>95 : 5
>95 : 5
>95 : 5
>95 : 5
n.d.e
91
93
94
CHCl3
a
Reactions were performed on a 1 mmol scale of b-nitrostyrene
(3a) using 1.5 equiv. of indole (1a), 3.0 equiv. acrolein (2) and
b
10 mol% catalyst 5 at RT in 4.0 mL solvent. Yield of isolated product.
c
d
Determined on isolated product by 1H-NMR-spectroscopy. Deter-
e
mined by HPLC analysis on a chiral stationary phase. Not determined.
A plausible catalytic cycle for the domino reaction is
described in Scheme 3. In the first step acrolein (2) is activated
by the chiral amine catalyst (S)-5 through the formation of the
vinylogous iminium ion 6, with which the indoles (1) perform
an intermolecular Friedel–Crafts-type reaction. The resulting
enamines 7 subsequently undergo an intermolecular Michael
addition to the nitroalkenes 3 affording the intermediates 8.
Next hydrolysis of 8 leads to aldehydes 9, which react with the
iminium ion 6 to give the enamine intermediates 10. After an
conducted the reaction in toluene by slowly adding acrolein (2)
within 12 h with the assistance of syringe pump. Encoura-
gingly, the polymerisation was effectively hampered and the
reaction was completed after 3 days affording the domino
product 4a in a yield of 54% and very high stereoselectivity
(dr >95 : 5, ee = 91%, Table 1, entry 2).12 The yield is quite
good considering that it is a quadruple cascade with three
intermolecular reactions where many side-reactions could
compete. Next a brief solvent screening was undertaken.
Employing THF as solvent no improved results with respect
to yield and stereoselectivity were achieved (Table 1, entry 3).
Performing the reaction in chloroform, the reaction time was
shortened to one day and the product was obtained with a
better yield (55%). Importantly, the stereoselectivity remained
excellent (dr >95 : 5, ee = 94%, Table 1, entry 4).
The scope of this domino reaction was evaluated by varying
the structure of both indoles 1 and nitroalkenes 3. Firstly, we
reacted indole (1a) and acrolein (2) with different nitroalkenes
3. Employing electron-deficient o-bromo nitrostyrene (3b) as
substrate, the product 4b was obtained in good yield (55%)
and excellent stereoselectivity (dr >95
: 5, ee > 99%)
(Table 2). In the case of the electron-rich piperonyl nitro-
alkene (3c), the reaction proceeded with an excellent yield
(82%) and stereocontrol (dr >95 : 5, ee > 99%). Further-
more, the heteroaromatic nitro-olefin 3d turned out to be a
reactive component for this domino reaction, too, furnishing
the product 4d in a moderate yield (30%) and excellent
stereoselectivity (dr >95 : 5, ee > 99%). One limitation of
Table 2 Yields and stereoselectivities of the organocatalytic quadruple
cascadea
4
R1
R2
Yieldb (%) drc
eed (%)
94
a
b
c
d
e
f
g
h
i
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
1-Me (1b)
5-Br (1c)
4-Br (1d)
6-F (1e)
Ph (3a)
55
48
82
30
0
54
50
23
54
32
>95 : 5
>95 : 5 >99
>95 : 5 >99
>95 : 5 >99
—
>95 : 5
2-BrC6H4 (3b)
Piperonyl (3c)
2-Furyl (3d)
Br–(CH2)4– (3e)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
—
97
>95 : 5 >99
>95 : 5 >99
>95 : 5
91 : 9e
97
99
j
5-OMe (1f) Ph (3a)
a
Reactions were performed on a 1 mmol scale of nitroalkene 3 using
1.5 equiv. of indole 1, 3.0 equiv. acrolein (2) and 10 mol% catalyst 5 at
b
c
RT in 4.0 mL solvent. Yields of isolated product. Determined on
isolated product by 1H-NMR-spectroscopy. Determined by HPLC
d
e
chiral stationary phase. Determined on isolated
analysis on
product by 13C-NMR-spectroscopy.
a
Scheme 3 Proposed catalytic cycle of the quadruple organo-cascade.
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intramolecular enamine-mediated aldol reaction, intermediates
11 are formed, which undergo dehydration and hydrolysis to
afford the title indoles 4 as products, while the catalyst is
regenerated for the next catalytic cycle.
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In summary, we have developed a novel organocatalytic
quadruple cascade reaction of indoles, acrolein and nitro-
alkenes under diphenylprolinol TMS-ether catalysis following an
iminium/enamine/iminium/enamine activation sequence. This
multi-component domino process provides an efficient and
direct asymmetric synthesis of polysubstituted functionalized
3-(cyclohexenylmethyl)-indoles controlling three stereogenic
centers in moderate to high yields (23–82%) and excellent
stereoselectivities (dr = 91 : 9 to >95 : 5, ee = 94 to >99%).
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12 The relative configuration was assigned by NOE-measurements.
The absolute configuration was deduced based on the results of our
triple cascade (see ref. 4e,f,j).
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