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.
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.
Pyridine and its derivatives
are among the most significant heterocyclic 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 A).[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 arylations[6h,6i] and copper-catalyzed alkylations,[6j] both
using organozinc reagents (Scheme B). While highly enantiopure products can be obtained
using these strategies, both reports are restricted to unsubstituted
pyridine 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]
Scheme 1
State of
the Art in Asymmetric Dearomatization of Acylpyridinium
Ions with Organometallics
Grignard reagents are one of the most attractive organometallics
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 C).[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.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 ). 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 commercially 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 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).
Table 1
Optimization of Reaction
Conditions
for the Addition of EtMgBr to 4-Methoxypyridine 1aa
entry
L-Cu (I)b
solvent
Conv. (%)c
ee (%)d
1
THF, Et2O, toluene
full
2
Cu (I)
THF
full
0
3
Cu (I)
toluene
0
4
Cu (I)
Et2O
0
5
L1-Cu (I)
THF
full
0
6
L1-Cu (I)
2-Me-THF
full
37
7
L1-Cu (I)
Et2O
full
88
8
L1-Cu (I)
toluene
full
94
9
L1-Cu (I)
CH2Cl2
full
93
Reaction conditions: 4-methoxypyridine 1a (0.2 mmol), phenylchloroformate (2.0 equiv), and EtMgBr
(2.0 equiv), in solvent (2 mL) at −78 °C, for 12 h.
Ligand L (6 mol %),
CuBr·SMe2 (5 mol %).
Conversions were determined by 1H NMR.
The ee was determined by HPLC on
a chiral stationary phase.
Reaction conditions: 4-methoxypyridine 1a (0.2 mmol), phenylchloroformate (2.0 equiv), and EtMgBr
(2.0 equiv), in solvent (2 mL) at −78 °C, for 12 h.Ligand L (6 mol %),
CuBr·SMe2 (5 mol %).Conversions were determined by 1H NMR.The ee was determined by HPLC on
a chiral stationary phase.With the optimized conditions in hand, we investigated the scope
of the reaction with respect to the acylating reagents (Scheme ). 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).
Scheme 2
Scope of Acylating
Reagents
Reaction conditions are the same
as in Table using
different acylating agents. The reported yields correspond to isolated
yields.
Scope of Acylating
Reagents
Reaction conditions are the same
as in Table using
different acylating agents. The reported yields correspond to isolated
yields.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 ). 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–2q) with moderate to high yields (58–94%)
and ees exceeding 98%.
Scheme 3
Scope of Grignard Reagents
Reaction
conditions are the same
as in Table using
different Grignard reagents. The reported yields correspond to isolated
yields.
Scope of Grignard Reagents
Reaction
conditions are the same
as in Table using
different Grignard reagents. The reported yields correspond to isolated
yields.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 , entry 8). However, under these conditions,
no conversion was observed. Suspecting that the steric hindrance introduced
by 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.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 , compare
entry 3 with entries 2 and 4–7).
Table 2
Optimization
of Reaction Conditions
for the Addition of EtMgBr to 3aa
The reported yields correspond to
isolated yields.
The ee
was determined by HPLC on
a chiral stationary phase.
Reaction conditions: 3a (0.2 mmol), chloroformate
reagent (2.0 equiv), EtMgBr (2.0 equiv),
ligand L1 (6 mol %), and CuBr·SMe2 (5
mol %) in solvent (2 mL).The reported yields correspond to
isolated yields.The ee
was determined by HPLC on
a chiral stationary phase.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 ),
obtaining addition products with various alkyl substituents (4a–d) with decent yields (51–66%) and good to
high enantioselectivities (80–97%).
Scheme 4
Scope of 4-Methoxypyridine
Derivatives as Substrates
Reaction conditions are the same
as in Table , using
different substituted 4-methoxypyridines. The reported yields correspond
to isolated yields. L1 (12
mol %) and CuBr·SMe2 (10 mol %) were used.
Scope of 4-Methoxypyridine
Derivatives as Substrates
Reaction conditions are the same
as in Table , using
different substituted 4-methoxypyridines. The reported yields correspond
to isolated yields. L1 (12
mol %) and CuBr·SMe2 (10 mol %) were used.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 product 4a (Scheme a). 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 b).[8] Other examples are the synthesis of alkaloid
precursor 6 with 92% yield as single trans diastereoisomer
after hydrogenation[9] and the synthesis
of product 7, a crucial precursor to access the natural
product (−)-epimyrtine (Scheme c).[10]
Scheme 5
Synthetic Applications
of the Methodology
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 chloroformate 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, 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 a). 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- 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- toward V- involves a transition state with an activation energy of
7.75 kcal/mol, whereas the analogous transition state in the case
of IV- 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 c). In TS-(IV-V)-, 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)-, 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 phosphorous–copper
bonds at TS-(IV-V)- 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 a) is very weak, particularly in V- (dCu–C-5( = 2.16 Å and dCu–C-5( = 2.40 Å), and the breaking of this complex is very favorable
(ΔG =
−82.46 kcal/mol). The release of the L1–CuCl complex ensures a new catalytic cycle.
Scheme 6
Proposed Mechanism
for the Cu-Catalyzed Enantioselective Addition
of Grignard Reagents to Substrate 1a
Calculations
were performed at
the PCM(CH2Cl2)[12]/B3LYP-D3/def2tzvpp//B3LYP-D3/def2svpp[13] 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.
Proposed Mechanism
for the Cu-Catalyzed Enantioselective Addition
of Grignard Reagents to Substrate 1a
Calculations
were performed at
the PCM(CH2Cl2)[12]/B3LYP-D3/def2tzvpp//B3LYP-D3/def2svpp[13] 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.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 d) 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 (Scheme ), 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 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.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6