Enantioselective catalytic dearomative addition of grignar reagents to 4-methoxypyridinium ions

Article abstract of DOI:10.1021/acscatal.1c01544

We describe a general catalytic methodology for the enantioselective dearomative alkylation of pyridine derivatives with Grignard reagents, allowing direct access to nearly enantiopure chiral dihydro-4-pyridones with yields up to 98%. The methodology involves dearomatization of in situ-formed N-Acylpyridinium salts, employing alkyl organomagnesium reagents as nucleophiles and a chiral copper (I) complex as the catalyst. Computational and mechanistic studies provide insights into the origin of the reactivity and enantioselectivity of the catalytic process.

Full text of DOI:10.1021/acscatal.1c01544

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Research Article
Enantioselective Catalytic Dearomative Addition of Grignard
Reagents to 4‑Methoxypyridinium Ions
̃
Yafei Guo, Marta Castineira Reis, Johanan Kootstra, and Syuzanna R. Harutyunyan*
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ABSTRACT: We describe a general catalytic methodology for the enantioselective dearomative alkylation of pyridine derivatives
with Grignard reagents, allowing direct access to nearly enantiopure chiral dihydro-4-pyridones with yields up to 98%. The
methodology involves dearomatization of in situ-formed N-acylpyridinium salts, employing alkyl organomagnesium reagents as
nucleophiles and a chiral copper (I) complex as the catalyst. Computational and mechanistic studies provide insights into the origin
of the reactivity and enantioselectivity of the catalytic process.
KEYWORDS: dihydro-4-pyridones, dearomatization, organomagnesium reagents, acylpyridiniums, copper catalysis
Scheme 1. State of the Art in Asymmetric Dearomatization
of Acylpyridinium Ions with Organometallics
yridine and its derivatives are among the most significant
Pheterocyclic units. Not only are they found in the
structures of many natural products and pharmaceuticals but
they also serve as building blocks for constructing other
common scaffolds such as six-membered aza-heterocycles.1
Prime examples are dihydropyridine and piperidine motives,
which are ubiquitous in numerous alkaloids and bioactive
molecules. As a result, extensive work has been directed toward
the synthesis of chiral dihydropyridine and piperidine
derivatives.2,3
Several methodologies relying on the conjugate addition of
organometallics to pyridine and dihydropyridones (commonly
synthesized from the corresponding pyridine-based precursors)
have been reported to date.4 At the same time, elegant
strategies that depend on the direct use of pyridinium salts as
substrates in addition reactions have been reported as well.5,6
Among literature precedence, the strategy that makes use of
Grignard reagents and relies on chiral pyridinium salts to
control the stereochemistry of the addition step has found the
broadest application and still remains the preferred option
(Scheme 1A).5 On the other hand, catalytic examples that
make use of prochiral acylpyridinium ions are especially
attractive in terms of atom economy and cost-efficiency. As a
result, several catalytic methods that utilize prochiral
acylpyridinium ions have also been reported,6 including
nickel-catalyzed arylations6h,i and copper-catalyzed alkyla-
tions,6j both using organozinc reagents (Scheme 1B). While
highly enantiopure products can be obtained using these
strategies, both reports are restricted to unsubstituted pyridine
Received: April 4, 2021
Revised: June 16, 2021
Published: June 28, 2021
© 2021 The Authors. Published by
American Chemical Society
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or 4-methoxypyridine and make use of expensive zinc reagents.
Furthermore, the alkylation protocol suffers from a limited
scope of nucleophiles and low yields.6j
Table 1. Optimization of Reaction Conditions for the
Addition of EtMgBr to 4-Methoxypyridine 1a
a
Grignard reagents are one of the most attractive organo-
metallics in terms of their availability, cost-efficiency, and
reactivity. However, the high reactivity of both acylpyridinium
ions and Grignard reagents leads to fast non-catalyzed
background reactions, which results in racemic products and
is difficult to outcompete for a chiral catalyst. As a result, the
only known example that makes use of Grignard reagents relies
on stereoselective synthesis using acylpyridinium ions and a
chiral auxiliary. Recently, we reported the enantioselective
catalytic synthesis of chiral dihydro-4-pyridones via asymmetric
addition of Grignards to pyridones, the low reactivity of which
is beneficial to achieve asymmetric induction in catalytic
conditions (Scheme 1C).4i Despite good yields and excellent
enantioselectivities, this procedure has its own drawbacks: the
substrate must be prepared from 4-MeO-pyridines in two low
yielding additional steps and, as in the case of the
abovementioned catalytic additions of organozinc reagents,
this methodology is limited to a single pyridone substrate.
Herein, we disclose a highly enantioselective catalytic
dearomatization of in situ-generated N-acylpyridinium salts
using highly reactive Grignard reagents and a chiral copper
catalyst. What sets this method apart is the use of readily
available Grignard reagents, a broader scope that includes
substituted pyridines, and operational simplicity. This allows
straightforward access to enantioenriched derivatives of
dihydropyridone, enabling the further generation of multiple
stereocenters.
b
c
d
entry
L-Cu (I)
solvent
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
THF, Et2O, toluene
THF
toluene
full
full
0
Cu (I)
Cu (I)
Cu (I)
0
Et2O
THF
0
L1-Cu (I)
L1-Cu (I)
L1-Cu (I)
L1-Cu (I)
L1-Cu (I)
full
full
full
full
full
0
2-Me-THF
Et2O
toluene
37
88
94
93
CH2Cl2
We started off our investigations using 4-methoxypyridine
1a as the starting material, phenyl chloroformate as the
acylating agent, and EtMgBr as the Grignard reagent (Table
1). Anticipating a background reaction between the highly
reactive acylpyridinium ion and the Grignard reagent, we chose
−78 °C as the reaction temperature for the optimization
studies. First, we investigated the rate of the uncatalyzed
reaction in different solvents, namely, THF, Et2O, and toluene.
In all cases, full conversion of 1a to the addition product 2a
was observed (entry 1), indicating that a catalyst with very high
turnover frequency is needed to outcompete the uncatalyzed
addition reaction. Based on our recent experience in
combining copper catalysis with Grignard reagents,4i,7 we
employed a Cu (I) salt as a potential catalyst for this reaction.
In the presence of CuBr·SMe2 (5 mol %), full conversion to
the product was obtained in THF, but to our surprise, no
product was formed when performing the reaction in toluene
or Et2O (entries 3−4). A subsequent ligand screening in
combination with CuBr·SMe2 involved a variety of commer-
cially available chiral ligands L1−L7, including bidentate
ferrocenyl- and biaryl-based diphosphines and monodentate
phosphoramidite. The only chiral ligand that showed
promising results in combination with the Cu (I) salt was
diphosphine ligand L1. While using L1 in combination with a
copper salt in THF still results in racemic 2a, some
enantioenrichment (37% ee) was observed when the reaction
was carried out in 2-Me-THF (entries 5 and 6). Moreover,
when the reaction was performed in other solvents (Et2O,
CH2Cl2, and toluene, entries 7−9), the L1-Cu (I) catalyst
system provided good results with full conversion to product
2a and enantiomeric excess (ee) values between 88 and 94%.
In contrast, the catalytic system with bidentate ligands L2−L6
provided racemic products, whereas monodentate L7 gave no
a
Reaction conditions: 4-methoxypyridine 1a (0.2 mmol), phenyl-
chloroformate (2.0 equiv), and EtMgBr (2.0 equiv), in solvent (2 mL)
b
at −78 °C, for 12 h. Ligand L (6 mol %), CuBr·SMe2 (5 mol %).
c
d
Conversions were determined by 1H NMR. The ee was determined
by HPLC on a chiral stationary phase.
conversion. Consequently, we adopted the following reaction
conditions as the optimal ones for further studies: L1 (6 mol
%), CuBr·SMe2 (5 mol %), and Grignard reagent (2.0 equiv)
in toluene at −78 °C for 12 h (entry 8).
With the optimized conditions in hand, we investigated the
scope of the reaction with respect to the acylating reagents
(Scheme 2). With the exception of isopropyl chloroformate,
for which the corresponding product 2f was not formed, all
tested acylating reagents, including aliphatic and aromatic
chloroformates, provided high isolated yields (82 to 98%) and
enantioselectivities (81 to >99% ee).
The reaction using benzyl chloroformate, for which product
(2d) was obtained with the highest ee at −78 °C (>99%), was
also attempted at room temperature. The increase in the
reaction temperature was detrimental for the stereoselectivity,
with the enantiomeric purity decreasing from >99% to 52%.
Based on the described results, benzyl chloroformate was
selected as the acylating reagent for the investigation of the
scope of Grignard reagents. We were pleased to find that a
wide variety of alkyl Grignards, including β- and γ-branched
reagents, were tolerated and gave the corresponding products
(2d, 2j−m) with good yields and high ees (Scheme 3). The
addition of secondary Grignard reagents (cyclopentyl and
isopropyl magnesium bromide), however, led to the racemic
products. Various functionalized Grignard reagents were also
evaluated which delivered their corresponding products (2n−
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a
Scheme 2. Scope of Acylating Reagents
a
Reaction conditions are the same as in Table 1 using different acylating agents. The reported yields correspond to isolated yields.
a
Scheme 3. Scope of Grignard Reagents
a
Reaction conditions are the same as in Table 1 using different Grignard reagents. The reported yields correspond to isolated yields.
2q) with moderate to high yields (58−94%) and ees exceeding
98%.
the additional substituent might impede the pyridinium salt
formation, we decided to exchange benzyl chloroformate for
methyl chloroformate to stimulate the formation of pyridinium
ions.
The next important question to assess was whether
derivatives of 4-methoxypyridine are amenable to our catalytic
system because if successful, this would represent a
straightforward route to chiral precursors that are highly
valuable for generating molecules with multiple stereocenters.
Literature precedence reveals that the substituted derivatives of
4-methoxypyridine are often not successful candidates for
nucleophilic additions due to a diminished tendency to form
pyridinium ions, which is crucial for the reactivity toward
nucleophiles. We opted for the addition of EtMgBr to 4-
methoxy-2-methylpyridine 3a as a model reaction under the
optimal reaction conditions found for substrate 1a (Table 1,
entry 8). However, under these conditions, no conversion was
observed. Suspecting that the steric hindrance introduced by
Optimization of the reaction conditions with this substrate
revealed that a synthetically useful yield (66%) of the desired
addition product with 97% ee can be obtained with CH2Cl2 as
the solvent (Table 2, compare entry 3 with entries 2 and 4−7).
On the other hand, in the same solvent, no substrate
conversion was observed for benzyl and phenyl acylpyridinium
salts (entries 8−9). Encouraged by these results, we
synthesized several 2-substituted 4-methoxypyridine substrates
and evaluated them in the reaction with EtMgBr (Scheme 4),
obtaining addition products with various alkyl substituents
(4a−d) with decent yields (51−66%) and good to high
enantioselectivities (80−97%).
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product 4a (Scheme 5a). Furthermore, the products accessed
in this work are important building blocks for the synthesis of
alkaloids. For example, our method allows access to compound
2q, which upon deprotection gives product 5, a key compound
in the synthesis of Barrenazine A and B (Scheme 5b).8 Other
examples are the synthesis of alkaloid precursor 6 with 92%
yield as single trans diastereoisomer after hydrogenation9 and
the synthesis of product 7, a crucial precursor to access the
natural product (−)-epimyrtine (Scheme 5c).10
To gain more insights into the origin of the stereoselectivity,
we have initially conducted density functional theory
calculations.11 In line with the experimental data, we posit
that the overall transformation consists of two stages: (i)
formation of a pyridinium ion upon acylation and (ii)
interaction of the resulting salt with the chiral copper complex,
leading to the final chiral product.
For the computational studies, we selected CuBr in
combination with L1 as the chiral copper complex, 4-
methoxy-2-methylpyridine 3a activated with methyl chlor-
oformate as the substrate, and EtMgBr·2Et2O as the Grignard
reagent. Prior to the exploration of the reaction of the
acylpyridinium salt with the Grignard reagent in the presence
of the copper catalyst, we explored the direct addition of the
Grignard reagent to II. We found that the activation energy for
the direct addition of the Grignard reagent to II is 14.70 kcal/
mol (Figure S3). Then, we explored the copper salt speciation
in the presence of ligand L1 and the Grignard reagent.
We found that both the formation of the L1−CuBr complex
from [Cu2Br2(SMe2)2] and the subsequent transmetallation
upon addition of EtMgBr leading to organocopper species L1−
CuEt are highly exergonic processes (ΔG = −37.90 and
−39.21 kcal/mol, respectively, Figure S4). With this in mind,
we envisioned that the resulting organocopper species L1−
CuEt can coordinate to II either via the carbonyl moiety,
Table 2. Optimization of Reaction Conditions for the
Addition of EtMgBr to 3a
a
b
c
entry
R
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
Bn
toluene
THF
CH2Cl2
Et2O
2-Me-THF
toluene
MTBE
CH2Cl2
CH2Cl2
0
Nd
13
97
82
31
Nd
90
Nd
Nd
Me
Me
Me
Me
Me
Me
Ph
<10
66
15
15
<5
30
0
Bn
0
a
Reaction conditions: 3a (0.2 mmol), chloroformate reagent (2.0
equiv), EtMgBr (2.0 equiv), ligand L1 (6 mol %), and CuBr·SMe2 (5
b
mol %) in solvent (2 mL). The reported yields correspond to
c
isolated yields. The ee was determined by HPLC on a chiral
stationary phase.
Also, 4-methoxyquinoline 3e shows potential for this
catalytic system, providing product 4e with 75% yield and
97% ee, whereas 2-phenyl- and 2-bromo-4-methoxypyridines
3f and 3g did not result in any conversion. Finally, a
substituent at the 3-position of the methoxypyridine was also
tolerated, providing the corresponding product 4h with 62%
yield and 82% ee.
To demonstrate the utility of our catalytic system, a gram-
scale reaction was performed, using only 1 mol % of the
catalyst, maintaining 68% yield and 97% ee in the formation of
a
Scheme 4. Scope of 4-Methoxypyridine Derivatives as Substrates
a
Reaction conditions are the same as in Table 2, using different substituted 4-methoxypyridines. The reported yields correspond to isolated yields.
bL1 (12 mol %) and CuBr·SMe2 (10 mol %) were used.
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Scheme 5. Synthetic Applications of the Methodology
yielding III, or via the pyridine ring, specifically at position C-
5-C-6, rendering IV. These two species are very close in energy
and therefore likely in equilibrium. For the formation of IV, the
coordination of the metallic center to the substrate is
accompanied by the release of one of the phosphine groups
at the ligand from the copper center in order to allow copper
to accommodate the pyridinium substrate in its first
coordination sphere (Scheme 6a). Although decoordination
of the phosphine moiety is enthalpically disfavored, this is
partially balanced by the coordination of the substrate to the
copper center. At this point, the delivery of the Et group from
the copper complex to the substrate can take place from
complexes III or IV. However, the path from III toward the
product is energetically more demanding than that from IV
(Scheme S1). Therefore, continuing with complex IV, the
approach of the copper can take place on either side of the two
faces of the pyridine ring. Our calculations show that the proS
diastereomeric complex is 2.04 kcal/mol more stable than the
proR counterpart. Once species IV-proS is formed, it can
further progress via nucleophilic addition of the ethyl moiety to
form species V. The release of Et is facilitated by the approach
of the dangling phosphorous to the metallic center, which
ensures that the copper center remains tetracoordinated in this
step. The evolution of IV-proS toward V-S involves a transition
state with an activation energy of 7.75 kcal/mol, whereas the
analogous transition state in the case of IV-proR involves an
activation energy of 22.05 kcal/mol, rendering it non-
competitive under the working conditions. The striking energy
difference between these two transition states can be
rationalized from the analysis of their structures (Scheme
6c). In TS-(IV-V)-R, one of the P−Cu bonds is significantly
elongated (dCu−P‑5 = 3.38 Å) in order to accommodate the
substrate. The reason behind the need of dissociation of the
phosphorous atom resides in the clash between one of the
phenyl rings of the ligand and the substrate. On the contrary,
in the TS-(IV-V)-S, the phenyl group is now replaced by a
hydrogen atom, thus significantly reducing the steric
interaction between the substrate and the substituents in the
ligand. Furthermore, the weakening of one of the phospho-
rous−copper bonds at TS-(IV-V)-R results in slightly
shortened Cu−C bond distances (dCu−C‑5 = 2.13 Å and
dCu−C‑6 = 2.14 Å), creating an earlier and also energetically
more demanding transition state. Once Et is transferred from
the organocopper to the 4-methoxy-2-methyl-pyridine, the
counterion can behave as a new ligand, yielding V (R: −78.21
and S: −71.21 kcal/mol). In V, the interaction between the
metal and the substrate at position 5 (Scheme 6a) is very weak,
particularly in V-S (dCu−C‑5(V‑R) = 2.16 Å and dCu−C‑5(V‑S)
=
2.40 Å), and the breaking of this complex is very favorable
(ΔGL1−CuCl = −82.46 kcal/mol). The release of the L1−CuCl
complex ensures a new catalytic cycle.
The computational data highlight the importance of the
bidentate character of ligand L1, as well as the presence of a
flexible linkage between the two phosphine moieties in its
structure for the reactivity of the catalytic system and its
enantiodifferentiating ability. To corroborate these results
experimentally, we synthesized three chiral ligands L8−L10
(Scheme 6d) that lack either the flexible linkage (L8 and L9)
or have a less pronounced bidentate character (L9 and L10).
These ligands were tested in combination with Cu(I) salt in
the reaction of the synthesis of 2d under optimized reaction
conditions. In stark contrast to the results obtained with L1
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a
Scheme 6. Proposed Mechanism for the Cu-Catalyzed Enantioselective Addition of Grignard Reagents to Substrate 1a
a
Calculations were performed at the PCM(CH2Cl2)12/B3LYP-D3/def2tzvpp//B3LYP-D3/def2svpp13 computational level using the Gaussian 09
program.14 The thermochemistry was obtained at 1 atm and 298.15 K. The pyridinium species and the L1 ligand are depicted in black, the
protecting group in blue, and the ethyl group in red. (a) Left: proposed reaction mechanism. Right: reaction profile of the diastereoselective-
determining step. (b) Structural analysis of the minima IV (proR and proS). (c) Structural analysis of the transition states TS-(IV-V). For
visualization purposes, additional color coding is used in sections (b) and (c), showing the pyridinium species in light gray and blue, the L1 ligand
in black, and the ethyl group in red. (d) Results of the catalytic addition of EtMgBr to 1a using Cu(I) salt in combination with chiral ligands L8−
L10 under optimized reaction conditions.
(Scheme 3), no substrate conversion was observed when
ligands L8−L10 were used. Next, we carried out NMR
spectroscopic studies of the copper complexes formed upon
mixing of the copper salt with chiral ligands L9 and L10,
aiming to see the binding mode of these mono-oxidized ligands
to copper (Figures S6 and S7 in Supporting Information). The
results obtained confirmed the bidentate complexation of the
rigid mono-oxidized ligand L9 to the copper, while mono-
oxidized ligand L10 with the flexible link behaved as a
monodentate ligand. In an attempt to further understand the
influence of the binding angle and the ligand rigidity, we
recomputed the stereo-determining step using L8 (Scheme S2)
and found that enantiodiscrimination is in principle possible,
but that the difference in energy between the paths leading to
the R and S enantiomers of the product is smaller than that in
the case when using our optimal catalyst (with ligand L1). The
less pronounced enantiodiscrimination is caused by the rigidity
of the ligand that impedes the release of one of the phosphine
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arms. Importantly, the energy of the complexes IV with this
ligand, as well as the subsequent transition states, is quite high,
explaining the fruitless attempts to make this reaction work
experimentally and emphasizing the importance of flexible
bidentate ligands for the current transformation.
In conclusion, we have developed highly efficient catalytic
asymmetric addition of Grignard reagents to in situ-formed N-
acylpyridinium salts, with high yields and ees. The reaction is
operationally simple and tolerates a wide range of pyridine
derivatives and Grignard reagents and thus has a potential for
applications in the synthesis of alkaloids and other complex
building blocks. Finally, mechanistic studies revealed that
certain structural motives, namely, the bidentate character and
the flexible linkage between two binding arms, are responsible
for the reactivity of the catalyst and for the transfer of chiral
information from the catalyst to the final product.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c01544.
General experimental protocols, mechanistic studies, and
full characterization of all the species reported; 1H NMR
and 13C NMR spectra of all the reported compounds;
HPLC traces and HRMS data of new compounds;
computational details; electronic energies; stability and
imaginary frequencies of each stationary point; and
Cartesian coordinates (PDF)
AUTHOR INFORMATION
■
Corresponding Author
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Esters and Related Organic Hydride Donors. Chem. Soc. Rev. 2012,
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Iridium-Catalyzed Intramolecular Asymmetric Allylic Dearomatiza-
tion Reaction of Pyridines, Pyrazines, Quinolines, and Isoquinolines. J.
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M. W., Jr; Guo, S.; Buchwald, S. L. Asymmetric Cu-Catalyzed 1,4-
Dearomatization of Pyridines and Pyridazines without Preactivation
of the Heterocycle or Nucleophile. J. Am. Chem. Soc. 2018, 140,
5057−5060. (e) Bertuzzi, G.; Bernardi, L.; Fochi, M. Nucleophilic
Dearomatization of Activated Pyridines. Catalysts 2018, 8, 632−665.
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Synthesis of 2-Aryl-4-Piperidones. J. Am. Chem. Soc. 2004, 126,
Syuzanna R. Harutyunyan − Stratingh Institute for
Chemistry, University of Groningen, Groningen 9747 AG,
The Netherlands; orcid.org/0000-0003-2411-1250;
Email: s.harutyunyan@rug.nl
Authors
Yafei Guo − Stratingh Institute for Chemistry, University of
Groningen, Groningen 9747 AG, The Netherlands
Marta Castineira Reis − Stratingh Institute for Chemistry,
̃
University of Groningen, Groningen 9747 AG, The
Netherlands
Johanan Kootstra − Stratingh Institute for Chemistry,
University of Groningen, Groningen 9747 AG, The
Netherlands
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c01544
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the European Research Council
(S.R.H. grant no. 773264, LACOPAROM), The Netherlands
Organization for Scientific Research (NWO-VICI to S.R.H.),
and the China Scholarship Council (CSC, to Y.G.) are
acknowledged. M.C.R. thanks the Centro de Supercomputa-
ción de Galicia (CESGA) for the free allocation of computa-
tional resources and the Xunta de Galicia (Galicia, Spain) for
financial support through the ED481B-Axudas de apoio á etapa
de formación posdoutoral (modalidade A) fellowship.
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