Copper-Catalyzed Addition of Grignard Reagents to in situ Generated Indole-Derived Vinylogous Imines

Article abstract of DOI:10.1002/chem.202004232

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3-sec-alkyl-substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates.

Full text of DOI:10.1002/chem.202004232

Accepted Article
Accepted Article
Title: Copper Catalyzed Addition of Grignard Reagents to in situ
Generated Indole-Derived Vinylogous Imines
Authors: Syuzanna R. Harutyunyan, Luo Ge, and Mercedes Zurro
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To be cited as: Chem. Eur. J. 10.1002/chem.202004232
Link to VoR: https://doi.org/10.1002/chem.202004232
01/2020

10.1002/chem.202004232
Chemistry - A European Journal
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Copper Catalyzed Addition of Grignard Reagents to in situ
Generated Indole-Derived Vinylogous Imines
Luo Ge, Mercedes Zurro, and Syuzanna R. Harutyunyan*
Abstract: Chiral indole derivatives are ubiquitous motifs in
pharmaceuticals and alkaloids. Herein, we present the first protocol
for catalytic asymmetric conjugate addition of Grignard reagents to
various sulfonyl indoles, offering a straightforward approach for the
synthesis of chiral 3-sec-alkyl-substituted indoles in high yields and
enantiomeric ratios. This methodology makes use of a chiral catalyst
based on copper phosphoramidite complexes and in situ formation
of vinylogous imine intermediates.
The chiral 3-sec-alkyl-substituted indole motif is
ubiquitous in pharmaceuticals, natural alkaloids, and
agrochemicals (Scheme 1a),1 making optically active
derivatives important building blocks in both natural product
synthesis and drug discovery.
Various methods for the production of 3-sec-alkyl-
substituted indoles have emerged in recent years with
Friedel-Crafts reactions most commonly used (Scheme 1b).2
In 2006, a novel methodology was reported by Petrini and
co-workers that makes use of 3-(1-arylsulfonylalkyl)indoles
as electrophilic precursor.3 The sulfonyl moiety acts as a
good leaving group, allowing the reaction with a base to
generate vinylogous α, β-unsaturated imine intermediates in
situ, which subsequently are used as Michael acceptors for
the addition of nucleophiles. Using this strategy various
nucleophiles have been added to sulfonyl indoles,4 including
Scheme 1. a) Selected examples of natural products and bioactive molecules
containing the 3-sec-alkyl-substituted indoles framework. b) Catalytic
asymmetric Friedel-Crafts reaction with indoles. c) Catalytic asymmetric
several examples of enantioselective nucleophilic additions.
All enantioselective methods make use of soft nucleophiles
and the addition of an exogenous base to generate the
electrophilic species (vinylogous imines) (Scheme 1c).5 Even
though catalytic enantioselective additions of organometallics
to conventional carbonyl based Michael acceptors6, mostly
copper catalysed, have been well developed, no examples of
enantioselective additions of organometallics to indole
derived Michael acceptors have been reported to date. This
approach would, however, enable access to structurally new
chiral indoles, with the added advantage that no additional
base is needed since an organometallic can serve both as a
base to form the vinylogous imine intermediate and also as
nucleophile. However, although the copper catalysed
enantioselective conjugate addition of organometallics to
indole-derived Michael acceptors could be comparable to
additions to α, β-unsaturated imines, the examples reported
in the literature using of the latter are rare and limited to
organozinc reagents.7
addition of soft nucleophiles to arylsulfonylalkylindoles . d) This work.
On the other hand, over the past few years, our research
group has developed the synthesis of optically active
molecules using a methodology based on copper catalyzed
asymmetric addition of Grignard reagents to various Michael
acceptors.8 Building on this experience we pursue in this
work the development of a novel catalytic methodology to
obtain
enantioenriched
3-sec-alkyl-substituted
indole
derivatives, based on the conjugate addition of alkyl Grignard
reagents to vinylogous imines generated in situ from sulfonyl
indoles (Scheme 1d).
At the outset of this work, sulfonylindole 1a was chosen as
model substrate and EtMgBr as nucleophile (Table 1). We
immediately noticed that in the absence of any catalyst the
reaction proceeds with complete conversion to the racemic
desired product in CH2Cl2 at −78 °C, signifying it might be
hard to find a catalyst that can outcompete the background
reaction (Table 1, entry 1).
Since chiral copper (I) complexes are the most obvious
candidates to serve as catalysts in this chemistry, we started
the screening of different classes of chiral ligands L1-L6 (6
mol%) in combination with 5 mol% of Cu(I) salts (Table 1,
entries 2-7, selected examples). While in the presence of
copper complex with chiral diphosphine ligands L1 and L2
full conversion to nearly racemic product was observed
(Table 1, entries 2 and 3), the use of phosphoramidite
ligands L3-L5 (Table 1, entries 4-6) led to significant
[a]
L. Ge, Dr. M. Zurro, Prof. Dr. S. R. Harutyunyan
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: s.harutyunyan@rug.nl
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
1
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10.1002/chem.202004232
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enantioselectivity. The best result in terms of enantiomeric
ratio (93.5:6.5), however, was obtained with biaryl based
phosphoramidite ligand L6 (Table 1, entry 7). This
enantioselectivity could be further improved to 95:5 by slow
addition of EtMgBr within 1 hour (Table 1, entry 8). As
To kick off our study of the substrate scope we explored
different functionalized sulfonylindoles 1 in the addition with
EtMgBr (Scheme 2). Firstly, we evaluated the effect of the
R1-substituent on the reaction outcome. Different
substitutions with alkyl or phenyl groups led to excellent
results in most of the cases.
o
expected, increasing the reaction temperature to -50 C had
a negative effect, causing the enantiomeric ratio to drop to
91:9 (Table 1, entry 9).
Table 1. Optimization of the reaction conditions. [a]
Conversion
Entry
Ligand
Solvent
er (2a)[c]
[%][b]
>99
>99
>99
>99
>99
>99
>99
>99
>99
97
1
2
-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
tBuOMe
Toluene
2-Me-THF
-
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
48 : 52
47 : 53
71 : 29
84 : 16
85 : 15
93.5 : 6.5
95 : 5
3
4
5
6
7
8[d]
9[e]
10
11
12
Scheme 2. Scope of the reaction for sulfonylindoles 1 and EtMgBr. Reaction
conditions: Sulfonylindoles 1 (0.1 mol), CuBr·SMe2 (5 mol%), L6 (6 mol%),
EtMgBr (3.0 equiv, 0.13 M in CH2Cl2) in 1.0 ml CH2Cl2 at -78 oC for 16 h.
Absolute configuration of 2e was established by X-ray crystallography.9
91 : 9
89:11
98
84:16
Substituting the propyl group in 1a with a methyl group (1b)
afforded the addition product 2b with slightly decreased yield
and enantiomeric ratio, while α-branched, β-branched and
cyclic substituted sulfonylindoles 1c-1f unexpectedly showed
very similar results to 1a, which bears a linear alkyl
substituent. Benzyl substituted sulfonyl indole 1g and
sulfonyl indole 1h containing a terminal double bond afforded
the corresponding products with equally excellent e.r. and
only slightly lower yields. On the other hand, sulfonylindole 1i
bearing a phenyl group led to decreased enantioselectivity
(85.5:14.5 e.r.), but an excellent yield.
Next, we explored different substitution patterns of the
aromatic ring (R2) of the sulfonylindoles. Substrates with
either an electron-donating group (methoxy-substituent, 1j)
or an electron-withdrawing group (fluoro-substituent, 1k) at
the sterically demanding 4-position of the indole ring
81
52.5:47.5
[a] General conditions: 1a (0.1 mol), CuBr·SMe2 (5 mol%), Ligand (6 mol%),
EtMgBr (3 equiv.) in CH2Cl2 (1.0 ml) for 16 h. [b] The ratio was determined by
1H NMR of reaction crude. [c] Enantiomeric ratio(er) was determined by HPLC
on a chiral stationary phase. [d] EtMgBr (was diluted in 1.0 ml CH2Cl2) was
added over 1h. [e] In this case the reaction was performed at -50 oC.
Settling for L6 as the ligand of choice, we studied the effect
of the solvent, only to find all other tested solvents, including
tBuOMe, toluene and 2-methyltetrahydrofuran (2-Me-THF),
to afford product 2a with moderate to good conversion but
poor enantiomeric ratio. Based on these data the following
optimized reaction conditions were selected for the substrate
and Grignard reagent scope investigations: 5 mol % of
CuBr·SMe2, 6 mol % L6, 3.0 equiv. Grignard reagent in
CH2Cl2 at -78 oC for 16 hours.
2
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furnished the corresponding products (2j and 2k) in high
yields (≥75%) and excellent enantiomeric ratios (97:3 e.r.).
affording the corresponding products (4e and 4f) with high
yields and enantiomeric ratios. On the other hand racemic
product was obtained with PhMgBr. Importantly, Grignard
reagents containing a terminal double bond or a chloro
substituent, which are interesting derivatives for potential
further transformations, provided the corresponding addition
products (4g, 4h and 4i respectively) in good yields and
enantiomeric ratios.
In order to demonstrate the practicality of our catalytic
system several additional experiments were conducted
(Scheme 4). The reaction with sulfonylindole 1a and EtMgBr
was carried out in 1.3 g scale using only 1 mol% of chiral
catalyst L6-Cu(I), leading to the addition product 2c without
deterioration of the yield (89% yield) or the enantiomeric ratio
(95.5:4.5 e.r.). Furthermore, product 2c was subjected to
subsequent transformations, namely reduction with Et3SiH to
get product 2ca, and the oxidation of the indole derivative
using DMSO and concentrated HCl obtaining the amide
product 2cb.
Scheme 3. Scope of the reaction for sulfonylindole 1a with Grignard reagents.
Reaction conditions: Sulfonylindole 1a (0.1 mol), CuBr·SMe2 (5 mol%), L6 (6
mol%), Grignard reagents (3.0 equiv, 0.1 M-0.13 M in CH2Cl2) in 1.0 ml CH2Cl2
at -78 oC for 16 h. [a] CuBr·SMe2 (10 mol%) and L6 (12 mol%) were used in
this case.
Sulfonylindoles 1l and 1m, bearing a weakly electron-
donating (methyl) group and an electron-withdrawing group
at the 5-position of the indole ring, provided addition products
2l and 2m with very good yields and very high enantiomeric
ratios (95:5 e.r. and 97.5:2.5 e.r.). Varying the electronic
properties of the indole moiety had little effect: similar results
were obtained for substrate with either chloro- (1n), bromo-
(1o) or methoxy- (1p) substituents at the C6-position of the
indole ring. Finally, an electron-withdrawing substituent at the
C7-position led to the indole product (2q) with in excellent
yield (96%) and enantiomeric ratio (97.5:2.5 e.r.) where the
electron-rich MeO-substituent at the same position provided
product 2r with significantly decreased enantiomeric ratio
(88.5:11.5 e.r.). The latter might be attributed not only to the
electronic properties but also to increased sterics at the C7-
position.
After exploring the substrate scope we investigated the
Grignard scope (Scheme 3), which determines the variety of
chiral indole derivatives that the catalytic transformation
allows to synthesize. We were delighted to observe that our
methodology is not only valid for the addition of EtMgBr, but
that longer alkyl and branched Grignard reagents can be
employed, obtaining excellent enantioselectivities. Using
pentyl and butyl magnesium bromide as nucleophiles, the
corresponding indole derivatives (4a and 4b, respectively)
were obtained with high yields and enantiomeric ratios.
Scheme 4. Gram-scale reaction and transformations of 2c.
In conclusion, we have developed the first protocol for
catalytic asymmetric conjugate addition of Grignard reagents
to various vinylogous imines, generated in situ from sulfonyl
indoles. The importance of this work is reflected by the
number of biologically active products and natural products
which possess a chiral indole scaffold. This methodology
offers a simple and straightforward approach for the
synthesis of chiral 3-sec-alkyl-substituted indoles in high
yields and enantiomeric ratios. Furthermore, it is possible to
scale up the reaction using a minimum amount of catalyst (1
mol%) without any loss of yield or enantiomeric ratio. Further
work is currently underway in order to unravel the
mechanism of this transformation.
Acknowledgements
Financial support from The Netherlands Organization for
Scientific Research (NWO-VICI to S. R. H.), the China
Scholarship Council (CSC, to L. G.), and the Ramón Areces
Postdoctoral Fellowship (to M. Z.) are acknowledged. We are
grateful to Folkert de Vries and Beibei Guo for X-ray analysis.
Gratifyingly
methylmagnesium
bromide
and
cyclopentylmagnesium bromide also can be added to indole
derivatives leading to the corresponding products in excellent
yields albeit with a slightly decreased enantioselectivity (4c
and 4d, respectively). Furthermore γ-branched Grignard
reagents were well tolerated for this reaction as well,
Keywords: alkylation • asymmetric addition • copper catalysis •
Grignard reagents • indoles
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Conflict of interest ((optional))
The authors declare no conflict of interest.
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CCDC 1942935 (2e) contain the supplementary crystallographic data
for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
5
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