Aminocatalyzed Cascade Synthesis of Enantioenriched 1,7-Annulated Indoles from Indole-7-Carbaldehyde Derivatives and α,β-Unsaturated Aldehydes

Article abstract of DOI:10.1002/adsc.201500629

We report herein a new cascade strategy for the enantioselective synthesis of 1,7-annulated indoles based on iminium-enamine activation. A careful study of the indole substitution pattern revealed that a chloro substituent at the C-3 position was importan

Full text of DOI:10.1002/adsc.201500629

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DOI: 10.1002/adsc.201500629
Aminocatalyzed Cascade Synthesis of Enantioenriched
1,7-Annulated Indoles from Indole-7-Carbaldehyde Derivatives
and a,b-Unsaturated Aldehydes
Maxime Giardinetti,a Xavier Moreau,a,* Vincent Coeffard,a,* and Christine Grecka
a
Institut Lavoisier Versailles, UMR CNRS 8180, UniversitØ de Versailles-St-Quentin-en-Yvelines, 45 Avenue des
États-Unis, 78035 Versailles cedex, France
E-mail: xavier.moreau@uvsq.fr or vincent.coeffard@uvsq.fr
Received: June 30, 2015; Revised: September 17, 2015; Published online: November 17, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500629.
Abstract: We report herein a new cascade strategy
for the enantioselective synthesis of 1,7-annulated
indoles based on iminium-enamine activation. A
careful study of the indole substitution pattern re-
vealed that a chloro substituent at the C-3 position
was important to the implementation of the reac-
tion. Employing a diphenylprolinol silyl ether cata-
lyst, a range of 3-chloro-1H-indole-7-carbaldehyde
derivatives reacted with a,b-unsaturated aldehydes
to afford the corresponding 1,7-annulated indoles in
good yields (62–99%) and enantioselectivities (62–
92%). Besides the fluorescence properties of the
1,7-ring fused indoles prepared following our meth-
odology, these compounds contain a useful set of
functional groups which undergo various synthetic
transformations.
To the best of our knowledge, the asymmetric synthe-
sis of 1,7-annulated indoles (or pyrrolo[3,2,1-ij]quino-
lines) through an organocatalytic cascade approach
has not been reported although it is a key structural
unit found in natural products, therapeutic agents and
materials (Figure 1).[3] For instance, murrayazoline is
an alkaloid isolated from the genus Murraya which
shows a potent antiplatelet aggregation activity.[4] KC
11404 exhibits activities against histamine, platelet ac-
tivating factor (PAF) and leukotrienes which are in-
volved in chronic asthma.[5] In addition, the tricyclic
structure pyrrolo[3,2,1-ij]quinoline is the central core
of red-emitting dopants for organic light-emitting
diodes (OLEDs) such as DCQTB.[6] From a synthetic
standpoint, indoles bearing relevant functional groups
at the C-7 and/or N-1 positions have emerged as pow-
erful building blocks to reach 1,7-annulated indoles
through metal-catalyzed intramolecular processes.[7]
In sharp contrast, the synthesis of 1,7-ring fused in-
Keywords: asymmetric catalysis; domino reactions;
fused-ring systems; indoles; organocatalysis
The selective functionalization of indole skeletons is
a thriving field of research due to the ubiquity of this
framework in natural products, pharmaceuticals and
material science. The synthetic potential of asymmet-
ric organocatalysis through the generation of various
activation modes has fuelled the implementation of
numerous methodologies towards the functionaliza-
tion of indoles at the C-3 and C-2 positions while the
organocatalytic alkylation of the nitrogen atom has
been far less described.[1] The ever increasing power
of new synthetic methodologies has enabled the selec-
tive synthesis of ring-fused indole architectures
through the combination of asymmetric organocataly-
sis and cascade processes. Successful organocatalytic
methods have been recently described for the prepa-
Figure 1. Importance of the pyrrolo[3,2,1-ij]quinoline frame-
ration of chiral 1,2-, 2,3- and 3,4-annulated indoles.[2] work.
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Maxime Giardinetti et al.
Table 1. Reaction optimization.[a]
doles via bimolecular multi-bond forming processes
starting from 1H-indoles has been scarcely reported
in the literature. In an important contribution to this
field, the group of Tønder reported in 2006 a tandem
metallation/palladium-catalyzed
cross-coupling/lac-
tamization strategy starting from 7-bromoindoles and
2-halobenzoate derivatives (Scheme 1).[8]
Entry
3
Solvent
Yield [%]
ee [%][b]
1
2
3
3a
3b
3c
3a
3a
3a
3a
3a
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
MeCN
toluene
1,2-DCE
99
64
36
98
99
100
82
93
82
57
61
30
37
45
26
78
4[c]
5[d]
6
7
8
[a]
Reactions were performed on a 0.3 mmol scale using
1 equiv. of 1a, 1.5 equiv. of 2a, 15 mol% of 3 and
1.1 equiv. of AcONa at 558C for 16 h unless otherwise
noted.
Enantiomeric excesses were determined by chiral HPLC.
In this case, no AcONa was added to the reaction mix-
ture.
[b]
[c]
Scheme 1. Catalyzed bimolecular strategies towards 1,7-an-
nulated indoles.
[d]
In this case, the reaction mixture was conducted at room
temperature for 64 h.
Further to this work, the groups of Hartwig[9] and
Banwell[10] extended the methodology to other targets
by using, in particular, C-7 borolated indoles and 2-
bromobenzoate derivatives. In this communication, possessing a bulkier silyl group (e.g., TBS) which
we wish to report a new access to functionalized 1,7- could improve the stability and lifetime of the catalyst
annulated indoles. Central to the implementation of (entries 2 and 3).[11g] Both catalysts 3b and 3c resulted
the methodology is the propensity of chiral secondary in a significant decrease of yields and enantioselectivi-
amines 3 to condense with a,b-unsaturated aldehydes ties. The reaction carried out without sodium acetate
2 and to promote the cyclization reaction through imi- gave rise to 4aa in 98% yield with a dramatic de-
nium-enamine activation.[11] This novel cascade reac- crease of the enantioselectivity (entry 4). A similar
tion lies in an aza-Michael addition starting from 1H- trend was observed by employing the reaction condi-
indole-7-carbaldehyde derivatives 1 followed by an tions at room temperature for 64 h. A brief solvent
intramolecular aldol condensation reaction to give the screening indicated that acetonitrile, toluene and 1,2-
architectures 4. Building upon previous works on or- dichloroethane are suitable solvents for the transfor-
ganocatalytic alkylation of indoles,[2a–c] we surmised mation even if the best enantiomeric excess was ob-
that the introduction of an electron-withdrawing tained for chloroform (entries 1, 6–8). The decrease
group at the C-3 position could prevent a possible of the enantioselectivity for the reaction performed at
side reaction at this site and could reduce the pKa room temperature for 64 h (ee=37%, entry 5 vs. ee=
À
value of the N H proton which is a crucial point for 82%, entry 1) prompted us to study the configuration-
the success of N-alkylation reaction.[12] To this aim, al stability of 4aa over time. A racemization of the
we chose the trifluoroacetyl group and subjected the chiral center (11% loss of ee) was observed after stor-
indole derivative 1a to the reaction with trans-cinnam- age for 6 days at À58C. The racemization was even
aldehyde 2a in the presence of an aminocatalyst 3[13] faster (40% loss of ee) by storing the compound 4aa
and AcONa as base (Table 1). The reaction of 1a with at room temperature as an isopropyl alcohol solution.
2a in the presence of the catalyst 3a afforded 4aa in Therefore, the use of indole 1a was precluded as the
99% yield and 82% ee determined by chiral HPLC resulting product 4aa racemized upon storage. In light
(entry 1).[14] The influence of the catalyst structure on of these observations, we assumed that the trifluoro-
the reaction was then investigated by using the 3,5- acetyl group could play a key role in the racemization
(CF3)2C6H3-derived catalyst 3b and the catalyst 3c process by increasing the acidity of the proton borne
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Aminocatalyzed Cascade Synthesis of 1,7-Annulated Indoles
Table 2. Influence of the functional group.[a]
Table 3. Scope and limitations.[a]
Entry
FG
4
Yield [%]
ee [%][b]
Entry
1
R2
4
Yield [%] ee [%][b]
1
2
-COCF3 (1a)
-CHO (1b)
-H (1c)
-Br (1d)
-Cl (1e)
4aa
4ba
4ca
4da
4ea
4ea
99
76
n.r.
42
49
87
82
78
n.d.
87
91
1
2
3
4
5
6
7
8
1e Ph (2a)
4ea 87
92
79
87
84
72
73
88
81
84
62
82
82
79
80
3
1e 4-MeOC6H4 (2b) 4eb 62
1e 3-MeOC6H4 (2c) 4ec 83
1e 2-MeOC6H4 (2d) 4ed 84
4[c]
5
6[c]
-Cl (1e)
92
1e 4-MeC6H4 (2e)
1e 4-ClC6H4 (2f)
1e 3-ClC6H4 (2g)
1e 4-NO2C6H4 (2h)
1e 2-NO2C6H4 (2i)
1e 2-naphthyl (2j)
1e 2-thienyl (2k)
1f Ph (2a)
4ee 87
4ef 88
4eg 95
4eh 76
[a]
Reactions were performed on a 0.3 mmol scale using
1 equiv. of 1a–e, 1.5 equiv. of 2a, 15 mol% of 3a and
1.1 equiv. of AcONa at 558C for 16 h in chloroform
unless otherwise noted. n.r.=no reaction. n.d.=not de-
termined.
9
4ei
71
10
11
12
13
14
4ej 90
4ek 99
4fa 95
4ga 79
4ha 80
[b]
[c]
Enantiomeric excesses were determined by chiral HPLC.
Reaction time was 40 h.
1g Ph (2a)
1h Ph (2a)
[a]
Reactions were performed on 0.3 mmol scale using
1 equiv. of 1, 1.5 equiv. of 2, 15 mol% of 3a and 1.1 equiv.
of AcONa at 558C for 40 h in chloroform.
by the chiral center. As a result, the influence of the
functional group at C-3 position was investigated
(Table 2).[15] The introduction of a formyl group at
C-3 position gave similar results to those obtained
with the trifluoroacetyl group. The product 4ba was
[b]
Enantiomeric excesses were determined by chiral HPLC.
produced in 76% yield and 78% ee (entry 2). It is ities slightly lower than the result obtained with trans-
worthwhile noting that no reaction occurred starting cinnamaldehyde (entries 1–4). The compound 4ee was
from 1H-indole-7-carbaldehyde under our reaction obtained in 87% yield and 72% ee (entry 5). Similar
conditions (entry 3). We then turned our attention to results were obtained for the compound 4ef while an
halogen substituents because they are weakly elec- increase of both the yield and the enantioselectivity
tron-withdrawing due to inductive effects and the cor- was observed starting from aldehydic compound 2g
responding products 4da and 4ea could undergo (entries 6 and 7). The nitro substituent was well toler-
cross-coupling reactions for further transformations ated, leading to the compounds 4eh and 4ei in 76%
(entries 4–6). While a dramatic decrease of reactivity yield, 81% ee and 71% yield, 84% ee, respectively
was observed with 1d (FG=Br, 40 h reaction time), (entries 8 and 9). A decrease of enantiomeric excess
the introduction of a chloro substituent gave rise to compared to the results obtained with trans-cinnamal-
4ea in 49% yield and 91% ee after 16 h of reaction dehyde was observed on reacting 1e and 2j (entry 10).
(entry 5). Extending the reaction time to 40 h in- The a,b-unsaturated aldehyde 2k was amenable to
creased the yield of 4ea to 87% while maintaining the aza-Michael/cascade cyclization sequence by pro-
a high enantioselectivity (ee=92%). Regardless of viding the compound 4ek in 99% yield and 82% ee
the storage conditions, no racemization of 4ea was ob- (entry 11). Unfortunately, no reaction took place be-
served, thus demonstrating the influence of the C-3 tween the indole 1e and crotonaldehyde. Variations to
substituent on the racemization process. With the op- the indole scaffold were next investigated (entries 12–
timized conditions in hand (Table 2, entry 6), the 14). The indoles 4fa and 4ga were produced in excel-
scope and limitations with respect to the nature of R1 lent yields and good enantioselectivities (entries 12
and R2 were assessed (Table 3). Initially, changes to and 13). The reaction of 1h with trans-cinnamalde-
the R2 group on the a,b-unsaturated aldehydes 2 were hyde 2a gave rise to 4ha in 80% yield and 80% ee
investigated (2a–k). Regardless of the nature of R2, (entry 14). Based on the above results and literature
good-to-excellent yields of the desired 1,7-annulated reports, a plausible catalytic cycle is shown in Sche-
indoles 4 were obtained. The reaction with a,b-unsa- me 2.[2a–c]
turated aldehydes 2b–d bearing a methoxy group on
The catalytic cycle would start by the formation of
the aromatic ring gave the corresponding products in the iminium A. The attack of the indole 1 to the less
yields ranging from 62% to 84% with enantioselectiv- hindered face of the iminium A would afford the en-
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Maxime Giardinetti et al.
Scheme 2. Proposed catalytic cycle.
amine intermediate B which would form C via an in-
tramolecular aldol reaction. The hydrolysis of C to re-
lease the catalyst 3a followed by a dehydration reac-
tion would give rise to the desired target 4.
Scheme 3. Synthetic transformations.
hol 5 was obtained in 87% yield with a slight racemi-
An interesting feature is the fluorescence of the zation of the chiral center (92% ee to 90% ee). Pro-
1,7-annulated indoles 4 as shown with the absorption tection of the alcohol furnished the product 6 in 79%
and fluorescence spectra of 4ea (Figure 2).[16] The yield which underwent a cross-coupling reaction in
compound 4ea presents a maximum of absorption at the presence of PhB(OH)2 and the catalytic system
400 nm and the fluorescence spectrum recorded at Pd(OAc)2/SPhos (2-dicyclohexylphosphino-2’,6’-dime-
this wavelength exhibits a maximum at 500 nm. How- thoxybiphenyl). This allowed the formation of 7 in
ever, the alcohol 5 prepared by reduction of the alde- 59% yield.
hyde function of 4ea had no fluorescent properties,
demonstrating the importance of the enal moiety in tion of an unprecedented strategy for the enantiose-
the fluorescence process. lective synthesis of 1,7-annulated indoles which are
In conclusion, we have described the implementa-
In addition to providing a tricyclic key structure key motifs found in biologically relevant compounds.
motif, the compounds 4 contain a useful set of func- This represents the first synthesis of enantioenriched
tional groups. In particular, the chloro substituent at 1,7-annulated indoles through an aminocatalyzed N-
the C-3 position is prone to cross-coupling reactions alkylation/cyclization cascade. Optimization studies
of the Suzuki–Miyaura type as exemplified in the performed on a range of C-3-functionalized indole-7-
Scheme 3.[17] The sequence started from 4ea by the re- carbaldehydes revealed the influence of the C-3 func-
duction of the aldehydic function in the presence of tional group on the reaction outcome and the configu-
NaBH4 in ethanol. Under these conditions, the alco- rational stability of the products. Starting from 3-
chloro-1H-indole-7-carbaldehyde derivatives and a,b-
unsaturated aldehydes, a series of 1,7-ring fused in-
doles was prepared in yields ranging from 62% to
99% with good enantioselectivities (62–92%). In addi-
tion, the indole-containing target compounds which
exhibit fluorescence properties include various func-
tionalities which can undergo synthetic transforma-
tions.
Experimental Section
General Experimental Procedure of Table 3
Indole 1 (0.31 mmol, 1 equiv.), a,b-unsaturated aldehyde 2
(0.47 mmol, 1.5 equiv.), catalyst 3a (15.1 mg, 0.047 mmol,
0.15 equiv.), AcONa (27.8 mg, 0.34 mmol, 1.1 equiv.) and
Figure 2. Absorption and fluorescence spectra of 4ea in
CHCl3 (1”10À5 M).
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Aminocatalyzed Cascade Synthesis of 1,7-Annulated Indoles
CHCl3 (1.5 mL) filtered over alumina were introduced in
a capped flask. The mixture was stirred for 40 h at 558C.
The solvent was removed under reduced pressure. The
crude compound was purified by column chromatography
on silica gel.
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Acknowledgements
The authors thank University of Versailles-St-Quentin-en-
Yvelines for a Ph.D. grant (M.G.).
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