Exploiting the Distal Reactivity of Indolyl Methylenemalononitriles: An Asymmetric Organocatalyzed [4+2] Cycloaddition with Enals Enables the Assembly of Elusive Dihydrocarbazoles

Article abstract of DOI:10.1002/chem.201602793

An unprecedented technique for the in situ generation of indolyl ortho-quinodimethanes from 2-methylindole-based methylenemalononitriles by amine-mediated remote C(sp³)?H deprotonation was developed. These intermediates were efficiently trapped by diverse enals to provide a rapid entry to 2,9-dihydro-1H-carbazole-3-carboxyaldehyde structures through a formal asymmetric [4+2] eliminative cycloaddition governed by a α,α-diphenylprolinol trimethylsilyl ether catalyst.

Full text of DOI:10.1002/chem.201602793

A Journal of
Accepted Article
Title: Exploiting the Distal Reactivity of Indolyl- methylenemalononitriles: an Asym-
metric Organocatalyzed [4+2] Cycloaddition with Enals Enables the Assembly
of Elusive Dihydrocarbazoles
Authors: Claudio Curti; Gloria Rassu; Vincenzo Zambrano; Luigi Pinna; Nicoletta
Brindani; Giorgio Pelosi; Franca Zanardi
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To be cited as: Chem. Eur. J. 10.1002/chem.201602793
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Chemistry - A European Journal
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COMMUNICATION
Exploiting the Distal Reactivity of Indolyl-
methylenemalononitriles: an Asymmetric Organocatalyzed [4+2]
Cycloaddition with Enals Enables the Assembly of Elusive
Dihydrocarbazoles
Gloria Rassu,*[a] Claudio Curti,*[b] Vincenzo Zambrano,[a] Luigi Pinna,[c] Nicoletta Brindani,[b,d] Giorgio
Pelosi,[e] and Franca Zanardi[b]
Abstract: An unprecedented modality for in situ generation of
indole-ortho-quinodimethanes from 2-methylindole-based
enals under iminium ion-driven organocatalysis (Scheme 1,
section B).
methylenemalononitriles by amine-mediated remote C(sp3)-H
deprotonation was developed. These intermediates were efficiently
trapped by diverse enals to provide a rapid entry to 2,9-dihydro-1H-
carbazole-3-carboxyaldehyde structures via formal asymmetric [4+2]
eliminative cycloaddition governed by
trimethylsilyl ether catalyst.
-diphenylprolinol
Polycyclic indole architectures including carbazole and
hydrocarbazole skeletons represent privileged structural motifs
found in a number of natural alkaloids many of which displaying
interesting activities against a diverse set of biological targets.[1]
Accordingly, the search for efficient methods for the assembly of
these structures has drawn a great deal of attention by the
synthetic organic chemistry community.[2,3]
In 2011, Melchiorre[4] devised a reliable synthetic platform to
access tetrahydrocarbazoles by adopting a [4+2] strategy which
relies on in situ generation of active indole ortho-quinodimethane
intermediates in reactions with suitable dienophiles (e.g.
nitrostyrene or indolinone derivatives) under trienamine catalysis
(Scheme 1, section A). More recently, our research group[5]
discovered a direct [4+2] eliminative cycloaddition modality to
access carbocycles embedding fused cyclohexadiene frames
Scheme 1. Diarylprolinol silyl ether-catalyzed asymmetric [4+2] cycloaddition
strategies.
focused
on
the
use
of
remotely
enolizable
methylenemalononitriles as diene precursors in reactions with
Capitalizing on these inspiring studies, we now wondered
whether merging the distinctive issue of the malononitrile
activation strategy,[5,6] with the indole ortho-quinodimethane
modality[4,7] supported by the chiral iminium ion LUMO-lowering
concept,[8] 2,9-dihydro-1H-carbazole structures could be
[a]
[b]
Dr. G. Rassu, Dr. V. Zambrano
Istituto di Chimica Biomolecolare
Consiglio Nazionale delle Ricerche
Traversa La Crucca 3, 07100 Li Punti Sassari, Italy
E-mail: gloria.rassu@icb.cnr.it
Dr. C. Curti, Dr. N. Brindani, Prof. Dr. F. Zanardi
Dipartimento di Farmacia, Università degli Studi di Parma
Parco Area delle Scienze 27A, 43124 Parma, Italy
E-mail: claudio.curti@unipr.it; http://www.unipr.it/ugov/person/15926
Dr. L. Pinna
Dipartimento di Chimica e Farmacia
Università degli Studi di Sassari, Sassari, Italy
Dr. N. Brindani
Dipartimento di Scienze degli Alimenti
Università degli Studi di Parma, Parma, Italy
Prof. Dr. Giorgio Pelosi
accessed
by
reacting
2-methylindole-based
methylenemalononitriles with enals, as shown in section C of
Scheme 1. In this paper we describe the successful realization
of this idea, focusing on the organocatalytic, asymmetric [4+2]
eliminative
cycloaddition
between
2-methylindolyl
[c]
[d]
[e]
methylenemalononitriles 1 and enals 2 mediated by the popular
Hayashi-Jørgensen ,-diphenylprolinol trimethylsilyl ether
catalyst.[8,9] This chemistry offers a streamlined access to
hitherto elusive 2,9-dihydro-1H-carbazole 3-carboxaldehydes 3
with excellent levels of enantioinduction.
Dipartimento di Chimica,
Università degli Studi di Parma, Parma, Italy
At the outset, the designed N-Boc-protected 2-methylindolyl-
methylenemalononitrile 1a was easily prepared from
commercially available 2-methylindole-3-carboxaldehyde via N-
protection followed by high-yielding Knoevenagel condensation
with malononitrile (see Supporting Information for details). To
test the feasibility of the transformation described in Scheme 1C,
the reaction between 1a and cinnamaldehyde 2a was first
[**]
Financial support provided by the Università degli Studi di Parma is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.xxxxx

Chemistry - A European Journal
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COMMUNICATION
carried out in CH2Cl2 at room temperature in the presence of 20
mol% (S)-configured TMS-prolinol (S)-C1 and 20 mol% Et3N,
using the previously established catalytic conditions.[5] We were
pleased to find that, under these conditions, 1a underwent the
desired eliminative cycloaddition with enal 2a giving
dihydrocarbazole 3aa with exceptional enantioselectivity (99%
ee), albeit in only moderate yields (Table 1, entry 1). With this
promising result in hand, we proceeded to optimize the reaction
aiming at increasing the efficiency, while maintaining the almost
perfect enantiocontrol of the lead conditions. Variation of
solvents indicated that, except for toluene, other solvents such
as THF, acetonitrile, and ethanol furnished very low yield, if any,
of the desired product 3aa (entries 2-5). No substantial
improvement on yield was observed under higher or lower
reaction concentration (entries 6 and 7), while the yield dropped
to ca 20% when reducing the catalyst loading to 10 mol% (entry
8).
or amine co-catalyst, entirely suppressed the process (entries 13
and 14), and how the use of the parent N-Boc-protected 2-
methylindole-3-carboxaldehyde in lieu of the malononitrile
derivative 1a was inapplicable in this cyclization process (entry
15). As such, optimum conditions were established as in entry
12 of Table 1 namely, use of 1.0 equiv 1a, 1.2 equiv 2a, 20
mol% (S)-C1, and 50 mol% DIPEA in 0.2 M CH2Cl2 at 35 °C.
Table 2. Enantioselective iminium ion-mediated [4+2] eliminative
cycloaddition: indolylmalononitrile and enal scope.[a]
Table 1. Asymmetric eliminative [4+2] cycloaddition catalyzed by -
diphenylprolinol trimethylsilyl ether (S)-C1: effect of the reaction parameters.[a]
[a] All reactions were performed using 1 (0.39 mmol), 2 (0.47 mmol), prolinol
(S)-C1 (0.078 mmol), DIPEA (0.19 mmol) in 1.95 mL CH2Cl2 in air at 35 °C
over 24 h. All the reactions were also performed using (R)-C1 as the catalyst
to afford the opposite enantiomers of 3. Yields of the isolated products 3 are
given. Enantiomeric excess (ee) values were determined via HPLC analysis
on commercially available chiral stationary phase columns. [b] Performed on a
8× scale.
[a] Reactions performed on a 0.3-0.4 mmol scale (1a), using 2a (1.2 equiv), in
air. [b] Determined by 1H NMR analysis of the crude reaction mixture. Values
in parentheses represent isolated yields after column chromatography. [c]
Determined by HPLC analysis using
opposite enantiomer of 3aa formed. DIPEA= N,N-diisopropylethylamine.
a chiral stationary phase. [d] The
With these conditions in hand, we next examined the
generality, scope and limitations of this [4+2] eliminative
A screening of base co-catalysts revealed that inorganic
salts such as K2CO3 or Cs2CO3 are not beneficial for this
annulative reaction (entries 9 and 10), whereas use of DIPEA
instead of Et3N gratifyingly improved the productivity of the
process[10] consigning 3aa in 81-88% yields (70-75% isolated),
again with a superb level of enantiocontrol (99% ee, entries 11
and 12). Finally, it may mentioned that under the optimized
conditions of entry 12, control experiments revealed how the
exclusion of any of the reaction promoters, i.e., prolinol catalyst
cycloaddition
utilizing
diversely
substituted
methylenemalononitriles 1 and enals 2 (Table 2). Gratifyingly,
we found that the core structure of the formed formyl
dihydrocarbazoles 3 could be readily decorated at different
positions and the reactions proceeded smoothly with excellent
levels of enantioinduction for a broad range of substrates. First,
we elected to examine reactions of substituted indole substrates
1a-g. In contrast to the excellent results with N-Boc protected
malononitrile 1a leading to 3aa, unprotected indole 1b proved

Chemistry - A European Journal
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COMMUNICATION
totally unreactive, with no 3ba detected after 24 h, possibly due
to unproductive NH-induced tautomerization within the transient
o-quinodimethane structure, as suggested by Melchiorre et al.[4]
Also, a substituent with a different electronic nature at the N-
position of the indole substrate severely altered the reactivity of
the system, and N-methyl indole-derived malononitrile 1c, in
which an electron-withdrawing group was replaced by an
electron-donating methyl, does not react with cinnamaldehyde,
suggesting that the presence of a withdrawing group at indole
nitrogen is needed for the reaction to occur.
carbon of the indole o-quinodimethane intermediate as shown in
Scheme 2. In particular, it is reasonable to assume that initial
formation of the indole o-quinodimethane A and iminium ion B
from respectively malononitrile 1a and aldehyde 2a takes place
under the assistance of the binary prolinol/DIPEA catalytic
system. The chiral environment in the resulting donor/acceptor
complex A-B makes the subsequent bis-vinylogous Michael
attack[12] to proceed stereoselectively to form the chiral enamine
C. Next, this intermediate undergoes an intramolecular Michael
ring closure to substituted tetrahydrocarbazole D which, upon
hydrolysis and release of both the catalyst and the malononitrile
handle[5,13], finally furnishes the (R)-configured dihydrocarbazole
3aa.
As for the N-Boc representative 1a providing 3aa, N-Moc-
and N-Ts-substituted substrates 1d and 1e efficiently reacted
with cinnamaldehyde providing dihydrocarbazoles 3da and 3ea,
respectively, with high levels of enantioinduction. Different
substituents on the indole core of 1 were also tolerated, since
electronic modification of the aromatic ring could be
accomplished without affecting the reactivity of the system. Thus,
substitution at the indole C-5 position with methoxy- or chloro-
groups provided useful pronucleophilic substrates 1f and 1g for
the highly enantioselective coupling with cinnamaldehyde, giving
3fa and 3ga, respectively, with very good enantioselectivity.
Concerning the scope of the olefinic aldehyde derivatives 2,
varied substituents at the aromatic moiety were tolerated,
regardless of their position and electronic properties. The para-
substituted fluoro, chloro, and bromo aldehydes 2b-d were all
combined with 1a without incident, providing the halo-substituted
dihydrocarbazoles 3ab, 3ac, and 3ad, respectively, in fairly good
yields and with 92 - >99% ees. The functional group tolerance of
this reaction was further demonstrated by the use of ortho- and
para-methyl-substituted cinnamaldehydes 2e and 2f to give
highly enantioenriched carbazole products in good yields (3ae
and 3af). The reaction was also compatible with methoxy- and
nitro-derivatives 2g and 2h, rendering the expected products
Scheme 2. Possible mechanism of the formal catalytic asymmetric [4+2]
cycloaddition of methylenemalononitrile 1a with enal 2a assisted by catalyst
(S)-C1.
3ag
and
3ah,
respectively,
again
with
excellent
enantioselectivity albeit with lower efficiency in the case of 3ah.
In addition, the indole substrate 1a was partnered with naphthyl
aldehyde 2i to give the carbazole product 3ai in very good yield
and enantioselectivity. Regrettably, aliphatic enals showed only
very poor reactivity with this protocol; we made efforts to perform
such reactions by elongating the reaction time or elevating the
catalyst loading, but some unidentified by-products were only
observed, which were deduced to be decomposed from the
indole substrates.
One feature of this vinylogous cycloaddition/elimination is
that it provides direct access to chiral substituted 2,9-dihydro-
1H-carbazoles 3 while installing the -unsaturated aldehyde
system. This moiety could be exploited to vary the structure of
the molecule by simple transformations.
To showcase the practicality of the process, we performed a
gram-scale reaction using 1a and enal 2a. Pleasingly, the
conditions did not impact the outcome of the reaction and 3aa
was obtained with comparable efficiency and enantioselectivity.
The (2S) absolute configuration of ent-3ad derived from p-
bromocinnamaldehyde 2d using catalyst (R)-C1 was
unambiguously established by X-ray crystallographic analysis[11]
and, as a consequence, the opposite 2R-configuration was
assigned to all compounds 3 listed in Table 2.
To account for the stereochemical outcome of the reaction,
we propose a transition state where the Si-face of the iminium
ion derived from covalent association of enal 2 to the prolinol
catalyst (S)-C1 is engaged with the nucleophilic methylene
Scheme 3. Elaboration of dihydrocarbazole 3aa.

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[4]
[5]
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2011, 133, 15212.
To illustrate this synthetic potential, 3aa was first subjected
to selective NaBH4 reduction of the aldehyde group, giving rise
to unsaturated carbinol 4 in very good yield. Next, hydrogenation
using 10% Pd on carbon in methanol ensured reduction of both
the -double bond and the aldehyde carbonyl of 3aa,
rendering enantiopure tetrahydrocarbazole 5, which was isolated
in 51% overall yield after acetylation and N-deprotection.[14]
Finally, a HWE olefination with triethyl phosphonoacetate was
performed, and this resulted in almost quantitative formation of
E-configured carbazole 6, with complete aromatization of the
tricyclic skeleton.
N. Brindani, G. Rassu, L. Dell’Amico, V. Zambrano, L. Pinna, C. Curti,
A. Sartori, L. Battistini, G. Casiraghi, G. Pelosi, D. Greco, F. Zanardi,
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In summary,
a
mild and highly enantioselective
organocatalytic [4+2] eliminative cycloaddition of 2-methylindolyl
methylenemalononitriles with enals has been developed as the
first direct and asymmetric entry to hitherto elusive 2,9-dihydro-
1H-carbazoles. Good levels of reaction efficiency and excellent
enantioselectivity were achieved across a diverse range of
indole and enal substrates using the chiral -diphenylprolinol
TMS-ether catalyst in combination with a tertiary amine (DIPEA).
The ability of the malononitrile handle to enable the remote
enolization of the 2-methylindole component to form an active
indole ortho-quinodimethane intermediate is emphasized, and
further studies to apply this nucleophilic activation mode in the
vinylogous reactivity scenario is ongoing in our laboratories and
will be disclosed in due course.
[8]
[9]
a) Y. Hayashi, D. Okamura, T. Yamazaki, Y. Ameda, H. Gotoh, S.
Tsuzuki, T. Uchimaru, D. Seebach, Chem. Eur. J. 2014, 20, 17077; b)
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[10] For
a recent review on the use of additives in asymmetric
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[11] CCDC 1480537 (ent-3ad) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Keywords:
heterocycles • organocatalysis • vinylogy
• asymmetric synthesis • cycloaddition •
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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[14] A 2,3-cis configuration was assigned to 5, based on COSY and NOESY
NMR measurements. This stereochemistry is a consequence of H2
addition from the less congested olefinic -face of 3aa.

Chemistry - A European Journal
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Layout 2:
COMMUNICATION
Gloria Rassu,* Claudio Curti,* Vincenzo
Zambrano, Luigi Pinna, Nicoletta
Brindani, Giorgio Pelosi, and Franca
Zanardi
Page No. – Page No.
Exploiting the Distal Reactivity of
Indolyl-methylenemalononitriles: an
Asymmetric Organocatalyzed [4+2]
Cycloaddition with Enals Enables the
Assembly of Elusive
Merging Issues. The formal asymmetric [4+2] eliminative cycloaddition between 2-
methylindolyl-methylenemalononitriles and aromatic enals leads to the formation of
highly enantioenriched dihydrocarbazole products. Three merging issues are
highlighted, the malononitrile activation strategy, the indole ortho-quinodimethane
modality, and the chiral iminium ion LUMO-lowering technique.
Dihydrocarbazoles