Angewandte

Communications Chemie

International Edition: DOI: 10.1002/anie.201509693

Cycloaddition German Edition: DOI: 10.1002/ange.201509693

Enantioselective Formal [4+

+2] Cycloadditions to 3-Nitroindoles by
Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles
Yang Li+, Fernando Tur+, Rune Pagh Nielsen, Hao Jiang, Frank Jensen, and
Karl Anker Jørgensen*
Abstract: The first enantioselective formal [4+ +2] cycloaddi-
tions of 3-nitroindoles are presented. By using 3-nitroindoles in
combination with an organocatalyst, chiral dihydrocarbazole
scaffolds are formed in moderate to good yields (up to 87 %)
and enantioselectivities (up to 97 % ee). The reaction was
extended to include enantioselective [4++2] cycloadditions of 3-
nitrobenzothiophene. The reaction proceeds through a [4+ +2] Figure 1. The 4,9-dihydro-1H-carbazole alkaloid scaffold in natural
cycloaddition/elimination cascade under mild reaction condi- products.
tions. Furthermore, a diastereoselective reduction of an enan-
tioenriched cycloadduct is presented. The mechanism of the
reaction is discussed based on experimental and computational in good yields and high enantioselectivities. We demonstrate
studies. that the reaction concept can also be extended to 3-nitro-
benzothiophene.
The ubiquity of the indole heterocycle in natural products Different approaches for the formation of chiral dihydro-
and pharmaceuticals underscores the importance of this carbazole scaffolds can be envisioned. The most direct
privileged motif.[1] Therefore, the preparation of substituted approach would be the cycloaddition of a diene to 2,3-
indole derivatives has received significant attention over the indolyne (Scheme 1, top). However, 2,3-indolynes and related
years.[2] The vast majority of these methods involve the well-
known nucleophilic character of indole.[2] Exploiting the
umpolung[3] reactivity of indole would provide complemen-
tary synthetic methods to access complex indole derivatives.[4]
Recently, electrophilic indoles have been disclosed as prom-
ising electron-deficient alkenes in the asymmetric catalysis
area.[5] In this context, we hypothesized that combining
electrophilic indoles and trienamine catalysis[6] might provide
access to new highly functionalized indole scaffolds which are
difficult to obtain by conventional strategies.
The synthesis of a key heterocyclic moiety, such as
carbazole, has been broadly studied.[7] However, the synthe-
ses of the related tetrahydro-[8] and dihydrocarbazoles[9] have Scheme 1. Synthetic strategy for the formation of dihydrocarbazoles.
received less attention because of the limited synthetic LG = leaving group.
procedures available, even though, the unique dihydrocarba-
zole scaffold constitutes a compound class (dihydrotubingen-
sins A and B; Figure 1) which has been isolated from natural heteroarynes have, according to the best of our knowledge,
sources.[10] Consequently, asymmetric organocatalytic proto- not been generated and applied in catalytic asymmetric
cols providing access to these compounds are highly desirable reactions.[12]
for the development of reactions for skeletal diversity.[11] We envisioned that an electron-deficient indole[13] might
Herein, we disclose a catalytic enantioselective formal be a suitable candidate for reacting under organocatalytic
[4++2] cycloaddition/elimination cascade of 2,4-dienals with 3- asymmetric conditions with an electron-rich diene function-
nitroindoles, thus providing chiral dihydrocarbazole scaffolds ality, which is generated in situ, by using the trienamine
approach.[6] To be able to control the reaction course we
assumed that installing a nitro functionality at the 3-position
[*] Y. Li,[+] Dr. F. Tur,[+] R. P. Nielsen, Dr. H. Jiang, Prof. Dr. F. Jensen,
of the indole,[5] and use of a hydrogen-bonding organo-
Prof. Dr. K. A. Jørgensen
Department of Chemistry, Aarhus University catalyst[14] would direct the dienophile to approach the amino-
8000 Aarhus C (Denmark) activated diene functionality in a stereoselective manner
E-mail: kaj@chem.au.dk (Scheme 1, bottom). The strategy was expected to induce
[+] These authors contributed equally to this work. LUMO lowering of the dienophile, thus making it more
Supporting information for this article is available on the WWW reactive with the in situ generated diene. We anticipated that
under http://dx.doi.org/10.1002/anie.201509693. the role of the catalyst would be threefold: activation of both

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substrates, induction of stereoselectivity, and promotion of results in various solvents and with various bases (entries 6–
the elimination of the nitro group. 13). The best results were obtained in CH2Cl2 with DABCO
Towards our aim, the model reaction was envisioned to as the base, with 4 a in 81 % ee (entry 6). It was notable that
proceed by reaction of the 3-nitroindole 1 a with (E)-5- the elimination of HNO2 was normally slow at 0 8C. However,
methylhexa-2,4-dienal (2 a) in the presence of a hydrogen- by increasing the temperature to 40 8C, after completion of
bond directing organocatalyst (3), which should have the the cycloaddition step, the elimination was accelerated with-
properties mentioned above (Table 1). Furthermore, a base out observing any deleterious effect on the enantioselectivity
additive would also be needed as the strategy is based on the of 4 a. Moreover, the multiple roles of the additive DABCO
elimination of HNO2 from 1 a.[15] Table 1 presents some were found to be essential in the reaction, thus preventing
representative screening results. The reaction was dependent potential self-aggregation of 3 c, and increasing conversion
on the additive as greater than 95 % conversion was obtained and enantioselectivity (entries 6 and 12). We also tested other
when a base was used, and no reaction took place when, for aminocatalysts for the model reaction and used, for example,
example, N,N-diethylacetamide (DEA) was present (entries 1 the TMS-protected diarylprolinol catalysts, which gave lower
and 2). A basic additive such as DABCO was required for the conversions and enantioselectivities, required longer reaction
reaction to take place, and in the presence of the squaramide- times, and higher reaction temperatures, thus verifying the
based catalyst 3 a high conversions were found in both toluene threefold role of 3 (see the Supporting Information).
and CH2Cl2 (entries 2–4). The catalyst 3 a gave up to 79 % ee To study the steric and electronic effects, the reaction of
of the cycloaddition product 4 a (entry 4), while the thiourea- the 3-nitroindoles 1 with 2 a was investigated with various N-
based catalyst 3 b gave the same enantioselectivity and protecting groups in 1 (Scheme 2). From the results, it appears
increased conversion to greater than 95 % (entry 5). The that the reaction is not dependent on the N-protecting group
corresponding urea-based catalyst 3 c showed promising in 1, as greater than 95 % conversion was observed and the
enantioselectivity was rather consistent (76–81 % ee) for all
four N-protecting groups studied.
Table 1: Screening and optimization of reaction conditions for the formal
+2] cycloaddition to 3-nitroindole 1 a.[a]
[4+

Scheme 2. Variation of the N-protecting group in the 3-nitroindoles 1.

Conversion of the limiting reagent was measured by 1H NMR analysis
of the crude reaction mixture. The ee values were determined by chiral-
phase UPC2 after reduction of 4 into the alcohol. Boc = tert-butoxycar-
bonyl, Cbz = carboxybenzyl, Ts = 4-toluenesulfonyl.

Entry Catalyst Additive Solvent T [88C] Conv. [%][b] ee [%][c]

1 3a DEA[d] toluene RT <1 – Next, a variety of 3-nitro-1H-indole-1-carboxylates (1)
2 3a DABCO toluene RT > 95 ¢72 and 2,4-dienals (2) were tested to study the scope of the
3[e] 3a DABCO toluene 0 68 ¢55 reaction (Table 2). It was observed that better yields and
4 3a DABCO CH2Cl2 0 85 ¢79 enantioselectivities were obtained when 2,4-dienals other
5 3b DABCO CH2Cl2 0 > 95 79 than 2 a were used for the reaction with 1 a (products 4 e–h).
6 3c DABCO CH2Cl2 0 > 95 81 Notably, 4-phenylhepta-2,4-dienal gave excellent enantiose-
7 3c DABCO CHCl3 0 > 95 79
lectivity (97 % ee) and a nearly pure diastereoisomer (4 h).
8 3c DABCO ClCH2CH2Cl 0 > 95 75
9 3c DEA[d] CH2Cl2 0 <1 – Installing a methyl substituent at the 6-position of 1 a had
10[e] 3c DIPEA CH2Cl2 0 37 – a small effect on the outcome of the reaction (4 i). Substrates
11[e] 3c Et3N CH2Cl2 0 > 95 79 with an electron-withdrawing substituent at the 5-position
12 3c DABCO[f] CH2Cl2 0 85 69 showed consistent reactivity and stereoselectivity when
13[g] 3c DABCO CH2Cl2 ¢10 > 95 76 reacting with different 2,4-dienals and provided 89–90 % ee
[a] All reactions were performed using 1 a (0.05 mmol), 2 a (0.1 mmol), (4 j–n). During the process of expanding the substrate scope,
0.2 mL solvent, reaction time: 24 h. Then, the reaction mixture was we observed that 4-phenylhepta-2,4-dienal gave a better yield
heated up to 40 8C to complete the elimination of HNO2. [b] Conversion and enantioselectivity than 2 a, which we used for optimizing
of limiting reagent was measured by 1H NMR analysis of the crude the reaction conditions. Therefore, we tested the reaction
reaction mixture after 24 h. [c] The ee value was determined by chiral-
between 3-nitroindoles, bearing N-Boc and N-Cbz protecting
phase UPC2 after reduction of 4 a into the corresponding alcohol.
[d] DEA = N,N-diethylacetamide. [e] Reaction time: 72 h. [f ] 20 mol % groups, and 4-phenylhepta-2,4-dienal. As it appears from
DABCO was used. [g] Reaction time: 48 h. DABCO = 1,4-diazobicyclo- Table 2, the N-Boc- and N-Cbz-protected 3-nitroindole gave
[2.2.2]octane, TFA = trifluoroacetic acid. nearly the same enantioselectivity.

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+2] cycloaddition of the 3-nitroindoles 1.[a]

Table 2: Scope of the formal [4+ the presence of 3 c and DABCO, the results presented in
Table 3 show similar results to those obtained for the
reactions employing 1 a as the substrate. The highest enantio-
selectivities were found for the products 6 c and 6 d, with
98 %and 95 % ee, respectively.
The utility of the enantioenriched cycloadducts 4 is
outlined in Scheme 3. The diastereoselective reduction of

+2] cycloaddition of 5.[a]

Table 3: Scope of the formal [4+

[a] All reactions were performed using 5 (0.1 mmol), 2 (0.2 mmol), 3 c
(0.02 mmol), DABCO (0.1 mmol) in 0.4 mL CH2Cl2. All ee values were
determined by chiral-phase UPC2. The absolute configuration was
assumed to be identical to the cycloadducts obtained for 1 as the
substrate. See the Supporting Information. [b] Product isolation and
determination of the ee value were carried out by converting the
cycloadduct into the alcohol. [c] Product isolation and determination of
the ee value were carried out by converting the cycloadduct into the
Wittig adduct 6 c. The d.r. value was determined by 1H NMR analysis of
the crude reaction mixture.

the olefin and cleavage of the Cbz-group in 4 p were

performed in a single step, thus affording the cycloadduct 7
[a] All reactions were performed using 1 (0.1 mmol), 2 (0.2 mmol), 3 c
in high yield and excellent stereocontrol. Notably, the cyclo-
(0.02 mmol), DABCO (0.1 mmol) in 0.4 mL CH2Cl2. All ee values were
determined by chiral-phase UPC2. Absolute configuration was deter- adduct 7 is similar to the core structure of the natural
mined by X-ray crystallography analysis of 4 k and the remaining compound aristolasicone, which has only been synthesized in
structures were assigned by analogy. See the Supporting Information. racemic form.[17]
[b] Product isolation and determination of the ee value were carried out Experimental observations and computational investiga-
by converting the cycloadduct into the alcohol. [c] The ee value was tions have provided some insight into the mechanism for the
determined by converting 4 h into the alcohol. The d.r. was determined by
1
cycloaddition of 3-nitroindoles and 3-nitrobenzothiophene.
H NMR spectroscopy of the crude reaction mixture. [d] Product
isolation and determination of the ee value were carried out by
During the optimization of the reaction conditions (Table 1),
converting the cycloadduct into the Wittig adduct 4 o. we observed an intermediate as a diastereoisomeric mixture
(Scheme 1, lower left). For the reactions described in Tables 2
and 3, and Scheme 2, this intermediate was also observed by
To evaluate the practicality of the present synthetic NMR spectroscopy for several of the reactions, while for the 5
methodology we performed reactions on scales ranging the intermediate was observed for 6 a,b,d in about a 1:1 d.r.
from 0.1 to 1.0 mmol. These experiments gave the following
results for 4 h (d.r. > 20:1): 0.1 mmol: 76 % yield, 97 % ee;
0.5 mmol: 84 % yield, 97 % ee and 1.0 mmol: 85 % yield, 97 %
ee. These scale-up experiments thus demonstrate the reli-
ability of the method.
To our surprise, the reaction proceeded successfully with
3-nitrobenzothiophene (5) as the dienophile[16] under mild
reaction conditions, which are in striking contrast to the only
previous reaction conditions for the [4++2] cycloaddition to 3-
nitrobenzothiophene, where up to 180 8C were required.[16a] Scheme 3. Diastereoselective reduction and cleavage of the Cbz group
For the reaction of 5 with four different types of 2,4-dienals in in the enantioenriched cycloadduct 4 p.

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 Angewandte
Communications Chemie

The role of 3 c acting also as a hydrogen-bonding donor is roles of the hydrogen-bonding catalyst 3 c: it activates both
supported experimentally, as the installation of competing substrates in the addition step and promotes the elimination
hydrogen-bonding functionalities, such as nitro and cyano of the nitro group in the second step, thus reforming the
groups at the 5-position of 3-nitroindole resulted in no double bond.
reaction, even at 40 8C. In conclusion, the first enantioselective formal [4+ +2]
DFT calculations[18] (see the Supporting Information) cycloaddition to 3-nitroindoles is reported to proceed by using
were performed to account for the role of the catalyst for the organocatalysis. The combination of 3-nitroindoles and 2,4-
activation of the dienophile (5 was used to reduce the number dienals in the presence of an organocatalyst leads to the
of conformers). The electronic interaction leading to the formation of chiral dihydrocarbazole scaffolds in moderate to
reaction is that between the LUMO of 5 and the HOMO of good yields (up to 87 %) and enantioselectivities (up to 97 %
the trienamine, represented as an s-cis-diene (Figure 2, top ee) under mild reaction conditions. This novel approach is
applicable to the enantioselective cycloaddition reactions for
3-nitrobenzothiophene, thereby providing the cycloaddition
products in up to 98 % ee. Synthetic manipulation of the chiral
cycloadducts by a diastereoselective reduction of the olefin in
the product is also presented. Mechanistic studies based on
experimental observations and computational studies point
towards an asynchronous/stepwise addition followed by an
elimination in which the hydrogen-bonding catalyst plays
a pivotal role. The present development provides an alter-
native reaction concept for cycloaddition reactions of 2,3-
indolynes and 2,3-benzothiophynes, as the generation of these
heteroarynes have not yet been possible.

Acknowledgements

Figure 2. Selected results from the computational studies of the This work was financially supported by Aarhus University
transition states for the simplified model for the formal cycloaddition and the Carlsberg Foundation. Y.L. acknowledges the Chi-
of 5. Values within brackets are those for the uncatalyzed reactions. nese Scholarship Council for a Ph.d. fellowship. F.T. acknowl-
edges the European Commission for a Marie Curie Intra
European Fellowship for Career Development (PIEF-GA-
left).[19] Calculations have shown that the terminal carbon 2013-622413) within the 7th European Community Frame-
atom in the s-cis-diene moiety has the largest HOMO work Programme. Magnus E. Jensen is gratefully acknowl-
amplitude and might point towards an asynchronous or edged for performing X-ray analysis. Thanks are expressed to
stepwise mechanism.[20] By activating 5 by hydrogen bonding a reviewer for suggesting that we perform computational
to 3 c the LUMO is calculated to be lowered by 0.84 eV studies.
compared to that of the uncatalyzed system. We used the
transition state for the addition of butadiene as a model for Keywords: asymmetric catalysis · cycloaddition · heterocycles ·
the s-cis-diene moiety of the trienamine (Figure 2, top right). organocatalysis · synthetic methods
The role of the hydrogen-bonding activation of 5 by 3 c is
supported by the calculations as the activation energy is How to cite: Angew. Chem. Int. Ed. 2016, 55, 1020 – 1024
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