Highly Enantioselective Catalytic Addition of Grignard Reagents to N-Heterocyclic Acceptors

Article abstract of DOI:10.1002/anie.201906237

General methods to prepare chiral N-heterocyclic molecular scaffolds are greatly sought after because of their significance in medicinal chemistry. Described here is the first general catalytic methodology to access a wide variety of chiral 2- and 4-substituted tetrahydro-quinolones, dihydro-4-pyridones, and piperidones with excellent yields and enantioselectivities, utilizing a single catalyst system.

Full text of DOI:10.1002/anie.201906237

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Accepted Article
Title: Highly enantioselective catalytic addition of Grignard reagents to
N-heterocyclic acceptors
Authors: Syuzanna R. Harutyunyan and Yafei Guo
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10.1002/anie.201906237
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COMMUNICATION
Highly enantioselective catalytic addition of Grignard reagents to
N-heterocyclic acceptors
Yafei Guo, and Syuzanna R. Harutyunyan*
Abstract: General methods to prepare chiral N-heterocyclic
molecular scaffolds are greatly sought after due to their significance
in medicinal chemistry. Here we describe the first general catalytic
methodology to access a wide variety of chiral 2- and 4-substituted
tetrahydro-quinolones, dihydro-4-pyridones and piperidones with
excellent yields and enantioselectivities, utilizing a single catalyst
system.
pursuit of a catalytic asymmetric approach to a wide variety of
chiral N-heterocyclic compounds we were interested in
developing a single catalytic system capable of harnessing the
reactivity of various N-heterocyclic acceptors.
Herein, we describe the first general protocol for catalytic
asymmetric addition of various Grignard reagents to a wide
variety of N-heterocyclic acceptors with excellent yields and
enantioselectivities (Scheme 1, C), requiring a single catalytic
system based on copper salt and chiral diphosphine ligand.
Optically active piperidine and tetrahydroquinoline derivatives
are ubiquitous structural motifs in alkaloid-based natural
products, and bioactive and pharmaceutical compounds. Some
examples to be highlighted include Torcetrapib, a drug used to
treat elevated cholesterol levels, the antibiotic Helquinoline, as
well as various alkaloids such as the Angustureine, Coniine,
Myrtine, Solenopsin series and Indolizidine (Scheme 1, A).1
Accordingly, chiral piperidine and tetrahydroquinoline derivatives
represent important synthetic targets. General asymmetric
synthetic routes for their synthesis rely on several strategic
approaches (Scheme 1, B). Some of the most developed routes
to chiral substituted tetrahydroquinolines make use of catalytic
asymmetric hydrogenation of quinoline derivatives using chiral
transition metal complexes and transfer hydrogenations by chiral
Brønsted acids with Hantzsch esters.2 Efficient catalytic
asymmetric synthesis to access chiral hydroquinoline, quinolone
and piperidone derivatives using intramolecular aza-Michael and
aza-Diels-Alder reactions catalyzed by Lewis or Bronsted acids
have been also explored.3
Other potential alternative N-heterocyclic precursors for the
synthesis of chiral piperidine and tetrahydroquinoline derivatives
include piperidones, dihydropyridones and quinolones, which in
addition are often found as part of more complex biologically
active compounds.4 A common strategy that can access these
precursors is the asymmetric conjugate addition of
organometallics to N-heterocyclic acceptors using chiral
auxiliaries.5 However, catalytic enantioselective methodologies
for conjugate additions to for example quinolone, pyridone,
dihydropyridone and to acylpyridinium salts would constitute
more attractive routes. Several such methods for additions of
organometallics to 4-quinolones and dihydropyridone have been
developed to date, with the most successful examples focusing
on arylations.6 In contrast, for asymmetric alkylations there are
only few reports, which make use of dihydropyridone6f,g and
acylpyridinium salt.7,1a,8b These alkylation methods suffer from
limited product scope with either low yields or moderate
enantioselectivities. Furthermore, catalytic asymmetric alkylation
of 4-quinolones and catalytic asymmetric conjugate additions in
general to 2-quinolones as well as 4-pyridone8 are unknown. In
Scheme 1. (A) Examples of pharmaceuticals and natural products featuring
chiral N-heterocyclic core (B) State of the Art (C) This work.
[*] Y. Guo, Prof. Dr. S. R. Harutyunyan
Our initial studies focused on the development of an efficient
catalytic methodology for the alkylation of 4-quinolones (Table 1).
To compensate for the relatively low reactivity of the 4-quinolone
acceptor, we decided to take advantage of the high reactivity of
Grignard reagents. For the screening of catalytic systems and
reaction conditions we chose the addition of EtMgBr to
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: s.harutyunyan@rug.nl
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document.((Please delete this text if not appropriate))
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carboxybenzyl-protected (Cbz) 4-quinolone 1a as model
reaction. Addition of EtMgBr in the absence of any catalyst did
not provide substrate conversion, even at room temperature
(entry 1).
Table 1. Optimization of reaction conditions for the addition of EtMgBr to N-
Cbz-4-quinolone 1a.a
mol%), (R,R)-L1 (6 mol%), Grignard reagent (2.0 equiv,), in
CH2Cl2 for 30 min at room temperature.
Next, we evaluated EtMgBr with quinolones featuring various
substituents at the N-atom (Scheme 2). We found that
quinolones with electron withdrawing groups such as Cbz and
Boc are well tolerated and give the corresponding products (2a
and 2b) with excellent yields and enantiomeric excess. However,
for less reactive Bn- and Me-protected quinolones the addition
products 2c and 2d can only be isolated in the presence of
Lewis acid (TMSBr) with good yields and moderate 42-43% ee.
Importantly, the addition of EtMgBr to unprotected quinolone
substrate in the presence of TMSBr provided the corresponding
product 2e with 52% yield and 96% ee).
Entry
T (oC) Time (h)
Ligand Yield (%)b
ee (%)c
0
1d
2
Rt
-78
-20
0
2
12
2
-
0
L1
L1
L1
L1
L2
L3
L4
L5
L6
99
99
99
98
21
78
82
32
71
99
99
98
98
28
27
57
0
3
4
5
6
7
8
9
10
2
Rt
Rt
Rt
Rt
Rt
Rt
0.5
0.5
0.5
0.5
0.5
0.5
0
aReaction conditions: N-Cbz-4-quinolone 1a (0.2 mmol), EtMgBr (2.0 equiv.),
Ligand L (6 mol%), CuBr·SMe2 (5 mol%) in CH2Cl2 (2 mL). bYields are those
c
for the isolated products. The enantiomeric excess was determined by HPLC
on a chiral stationary phase. dReaction without CuBr·SMe2 and ligand.
First we set out to identify promising chiral catalysts, using 5
mol% of CuBr·SMe2 and 6 mol% of various chiral diphoshine
(L1-L5) and phosphoarmidite (L6) ligand (Table 1). To our
delight, using chiral diphosphine ligand L1, developed by
Pilkington et al.,9 the reaction proceeded to completion in 12 h at
o
-78 C providing the isolated final product 2a in 99% yield and
with 99% of enantiomeric excess. Optimization of the reaction
temperature (entries 2-5) allowed us to establish highly practical
conditions in which the addition product can be obtained at room
temperature in only 20-30 min with a yield and enantiomeric
purity of 98% (entry 5). This result is remarkable in its own right,
as it represents the first example of highly enantioselective
catalytic conjugate addition of Grignard reagents at room
temperature.10
Further ligand screening revealed that none of the other
diphosphine-type ligands L2-L5, nor phosphoramidite-type
ligand L6, work for this chemistry both in terms of yield and
enantioselectivity (entries 6-10). This is rather surprising, as all
of these ligands are normally very efficient in Grignard additions
to more conventional Michael acceptors.11
Scheme 2. Scope of the reaction between N-Cbz-4-quinolone substrates 1
and organomagnesium reagents. Reaction conditions: N-Cbz-4-quinolones 1
(0.2 mmol), EtMgBr (2.0 equiv.), ligand L1 (6 mol%), CuBr·SMe2 (5 mol%) and
CH2Cl2 (2 mL) at room temperature for 0.5 h. a Reactions with quinolones 1c-
1e were carried out in the presence of TMSBr (2.0 equiv.) at -78 oC for 12 h.
Absolute configuration of 2k was established by X-ray crystallography.
bPhMgBr and pTolMgBr were added slowly via a syringe pump in 2 h at 0 oC.
Having established the effect of the substituents at the nitrogen
atom of the quinolone we explored the scope of Grignard
reagents with N-Cbz-4-quinolone 1a. We were pleased to find
Based on these results we adopted the following optimized
conditions for further substrate scope studies: CuBr·SMe2 (5
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10.1002/anie.201906237
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that our catalytic system enables the addition of a wide variety of
alkyl Grignard reagents, including linear, α-, β- and γ-substituted,
functionalized PhMgBr and pTolMgBr, providing products 2f-2n
all with excellent results. This even extended to the markedly
less reactive MeMgBr, for which product 2o was obtained with
93% yield and 97% enantiomeric excess.
Subsequently we examined the scope of the N-Cbz-4-quinolone
substrates and found that substrates bearing functional groups
such as Me, Br, CF3, ether, amide or ester at the 5, 6, and 7-
position, were all converted to the corresponding final products
(2p-2v) successfully. In all cases, our optimized system afforded
the products in excellent yields (66% to 99%) and
enantioselectivities (ees 94% to 99%). However, when 2-Me-N-
Cbz-4-quinolone was used as a substrate, a lack of reactivity
prevented the formation of addition product 2w with quaternary
stereocenter.
To expand this strategy towards the synthesis of chiral dihydro-
pyridones and piperidones, we hypothesised that this protocol
could also enable addition reactions to N-Cbz-4-pyridone 3
(Scheme 3). This substrate is more challenging for applications
in catalysis as its aromatic character reduces the reactivity
towards nucleophilic additions. As a result, pyridones have been
hardly explored in asymmetric catalysis,8 even though there is
major potential in the application of these substrates in chemical
synthesis: after the initial conjugate addition reaction the
resulting chiral N-heterocyclic product with remaining Michael
acceptor functionality can subsequently undergo further
stereoselective functionalisations to provide 2,6-substituted
chiral pyridines that can be very useful for natural product
synthesis. We initially evaluated the reactivity of substrate 3
towards nucleophilic addition of EtMgBr using the reaction
conditions optimized for N-Cbz-4-quinolones (Table 1, entry 2).
addition product 4a, we decided to introduce Lewis acids.8a,b
With BF3·OEt2 as Lewis acid the best possible results, with 95%
yield and more than 99% enantiomeric purity, were obtained
(Scheme 3).13 With this reaction conditions we assessed the
scope of organomagnesium reagents for this reaction system
(Scheme 3). A number of chiral 2-substituted 2,3-dihydro-4-
pyridone products derived from the addition of linear (4a-4d), β-,
and γ-branched (4e-4f) and functionalized (4g-4i) Grignard
reagents were synthesized with high yields. In all cases
excellent enantioselectivities were observed as well (ees 94% to
>99%).
Although asymmetric conjugate addition of arylboronic acid, aryl
and dialkylzinc nucleophiles to N-substituted-2,3-dihydro-4-
pyridones has been well explored in recent years5,6f,g we were
interested to investigate the behavior of our catalytic system
when applied to these substrates. Given their substantially
higher reactivity than N-Cbz-4-pyridone we anticipated that
Lewis acids are not needed and that low temperatures will most
likely be required to avoid non catalyzed addition of Grignard
reagents. Indeed, quick screening of several Grignard reagents,
namely MeMgBr, EtMgBr and nPrMgBr supported this notion
and the corresponding chiral 2-substituted 4-piperidones (6a-6c)
were obtained with excellent yields and enantiomeric excesses
above 90% (Scheme 4).
Scheme 4. Scope of the reaction of N-Cbz-2,3-dihydro-4-pyridone 5 with
organomagnesium reagents. Reaction conditions: N-Cbz-2,3-dihydro-4-
pyridone 5 (0.2 mmol), EtMgBr (2.0 equiv.), Ligand L1 (6 mol%), CuBr·SMe2
(5 mol%) and CH2Cl2 (2 mL), -78 oC for 12 h.
Our next quest was to access chiral products derived from
additions to N-substituted-2-quinolones that are formally cyclic
α,β-conjugated amides and expected to be less reactive than 4-
quinolones (Scheme 5). We were pleased to find that when
using 2-quinolones with an OMe protecting group at the N-atom
the corresponding deprotected products 8a-8h were obtained
with excellent enantiomeric excess and chemical yields.
However, to reach full conversion and high yields it is necessary
to use a Lewis acid, with TMSBr performing best. Importantly,
the methoxy substituent at the N-atom is removed upon reaction
work up. Using this reaction protocol we obtained a variety of
products using various Grignard reagents as well as substrates
with different substituents in the aromatic ring. It is noteworthy
that this catalytic system tolerates 2-quinolone substrates with
various protecting groups at the N-atom such as Me, Bn and
Allyl. The products 8i-8k, derived from conjugate addition of
EtMgBr to these substrates, were obtained with enantiomeric
purities above 93% and yields above 72%.
Scheme 3. Scope of the reaction of N-Cbz-4-pyridone
3
with
organomagnesium reagents. Reaction conditions: N-Cbz-4-pyridone 3 (0.2
mmol), Grignard reagents (2.0 equiv.), Ligand L1 (6 mol%), BF3·OEt2 (2.0
equiv.), CuBr·SMe2 (5 mol%) and CH2Cl2 (2 mL) at -78 oC for 12 h.
Unfortunately the corresponding addition product 4a was not
obtained, but instead the side products derived from the addition
of EtMgBr to the carboxybenzyl moiety were found.12 In order to
steer the chemoselectivity of the reaction towards conjugate
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10.1002/anie.201906237
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COMMUNICATION
derivatives of chiral 2- and 4-substituted tetrahydroquinolones
and
dihydro-4-pyridones
in
excellent
yields
and
enantioselectivities. Significantly, addition reactions to N-
substituted-4-quinolones can be carried out at room temperature,
while consecutive alkylation of pyridone and the resulting 2,3-
dihydro-4-pyridones allows for a convenient catalytic access to
2,6-substituted diastereomerically and enantiomerically pure
piperidones. We anticipate that this methodology will be a
valuable synthetic tool and find practical application in the
synthesis of complex building blocks and natural and
pharmaceutical compounds.
Acknowledgements
Financial support from the European Research Council (ERC
Consolidator to S.R.H.; Grant No. 773264, LACOPAROM ) and
the China Scholarship Council (CSC, to Y.G). We thank Dr.
Beibei Guo and Folkert de Vries for X-ray analysis.
Scheme 5. Scope of conjugate addition reactions of organomagnesium
reagents to N-protected 2-quinolones 7. Reaction conditions: 2-quinolone 7
(0.2 mmol), EtMgBr (2.0 equiv.), Ligand L1 (6 mol%), TMSBr (2.0 equiv.),
CuBr·SMe2 (5 mol%) and CH2Cl2 (2 mL), -78 oC for 12 h. Absolute
configuration of 8j was established by X-ray crystallography.
Keywords: asymmetric catalysis • Grignard reagent • copper •
alkaloid synthesis• alkylation
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Scheme 6. Gram-scale reaction and useful derivatisations.
In summary, we have developed the first general protocol for the
alkylation of various classes of N-heterocyclic electrophiles with
organomagnesium, utilizing one catalytic system based on Cu(I)
complex with (R,R)-Ph-BPE. Alkylation of 2-quinolones, 4-
quinolones and 4-pyridones provides easy access to various
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10.1002/anie.201906237
Angewandte Chemie International Edition
COMMUNICATION
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4-Pyridones have been explored in addition reactions with various
organometallics only for non-asymmetric reactions (see the references
below). In reference (b) however one example of catalytic asymmetric
addition was reported for the addition of Et2Zn to 4-pyridone, furnishing
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
General catalytic protocol to access
various derivatives of chiral 2- and 4-
substituted tetrahydroquinolones,
dihydro-4-pyridones and 2,6-
substituted piperidones has been
developed.
Yafei Guo, and Syuzanna R.
Harutyunyan*
Page No. – Page No.
Highly enantioselective catalytic
addition of Grignard reagents to N-
heterocyclic acceptors
Layout 2:
COMMUNICATION
Yafei Guo, and Syuzanna R.
Harutyunyan*
Page No. – Page No.
Highly enantioselective catalytic
addition of Grignard reagents to N-
heterocyclic acceptors
ext for Table of Contents
General catalytic protocol to access various derivatives of chiral 2- and 4-substituted
tetrahydroquinolones, dihydro-4-pyridones and 2,6-substituted piperidones has been developed.
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