Modular Synthesis of Highly Substituted Pyridines via Enolate α-Alkenylation

Article abstract of DOI:10.1021/acs.orglett.5b01312

A novel methodology for the synthesis of highly substituted pyridines based on the palladium-catalyzed enolate α-alkenylation of ketones is presented; the formation of aromatic compounds is a new direction for this catalytic C-C bond forming reaction. In the key step, a protected β-haloalkenylaldehyde participates in α-alkenylation with a ketone to afford a 1,5-dicarbonyl surrogate, which then undergoes cyclization/double elimination to the corresponding pyridine product, all in one pot. The β-haloalkenylaldehyde starting materials can be obtained from the corresponding methylene ketone via Vilsmeier haloformylation. Using this concise route, a variety of highly substituted pyridines were synthesized in three steps from commercially available compounds. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01312

Letter
pubs.acs.org/OrgLett
Modular Synthesis of Highly Substituted Pyridines via Enolate
α‑Alkenylation
Leo A. Hardegger, Jacqueline Habegger, and Timothy J. Donohoe*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: A novel methodology for the synthesis of highly
substituted pyridines based on the palladium-catalyzed enolate
α-alkenylation of ketones is presented; the formation of
aromatic compounds is a new direction for this catalytic C−C
bond forming reaction. In the key step, a protected β-
haloalkenylaldehyde participates in α-alkenylation with a
ketone to afford a 1,5-dicarbonyl surrogate, which then
undergoes cyclization/double elimination to the correspond-
ing pyridine product, all in one pot. The β-haloalkenylaldehyde
starting materials can be obtained from the corresponding methylene ketone via Vilsmeier haloformylation. Using this concise
route, a variety of highly substituted pyridines were synthesized in three steps from commercially available compounds.
he regioselective formation of multiply substituted
pyridines remains an important synthetic challenge. In
We decided to explore a haloformylation approach to make the
α-alkenylation precursor 2; therefore pyridines 4 all contain
hydrogen in the C6 position. Efforts at developing reaction
conditions giving access to pyridines with five substituents are
underway, and their results will be reported in due course.
Alkenyl derivatives 6a−l can be obtained in one step from
methylene ketones 5 in a Vilsmeier haloformylation reaction
(Scheme 1).5,6 The yields of this transformation were generally
T
view of the scale of production of various pyridine compounds
and the importance of pyridines in the pharmaceutical,
agrochemical, and material sciences, a concise synthetic route
to highly and selectively substituted pyridines is very desirable.1
We have previously reported several modular routes to pyridines
in which the N-heterocycle was formed either by ring-closing
metathesis of a diene or by cyclization of a 1,5-dicarbonyl,
prepared by cross-metathesis, with a nitrogen source.2 As part of
a research program designed to utilize new catalytic reactions in
arene synthesis, we envisioned that the Pd-catalyzed enolate α-
alkenylation reaction3 of ketone 1 and protected β-haloalkeny-
laldehyde 2 could lead to masked 1,5-dicarbonyl compound 3
capable of forming pyridine 4 after treatment with a nitrogen
source (Figure 1). This proposed synthesis takes advantage of
Scheme 1. Vilsmeier Haloformylation of Ketones
good, and highest when the reactions were carried out in the
presence of 6 equiv of DMF without using any other solvent.
Both alkenyl chlorides and alkenyl bromides could be accessed
using POCl3 or POBr3, respectively. In our hands, POCl3 was
easier to handle and resulted in a more homogeneous reaction
mixture leading to higher yields as compared to POBr3. As
detailed below, both alkenyl chlorides and bromides can be
employed in the enolate α-alkenylation. While most β-
haloalkenylaldehydes 6 were obtained as a mixture of stereo-
isomers, the stereochemistry of the intermediate is incon-
sequential to the success of subsequent reactions, vide infra.
As suspected, the reaction of the parent aldehyde 6a (R4 = 4-
MeO-Ph, R5 = Me, X = Br) with propiophenone under
alkenylation conditions gave a complex mixture of compounds
Figure 1. Enolate α-alkenylation approach to pyridines.
the Pd-catalyzed enolate α-alkenylation reaction which has
remained under-utilized in chemical synthesis and is almost
unknown in applications such as the de novo synthesis of aromatic
compounds.4 In addition to expanding the scope of the method,
our approach provides complete regioselectivity and omits the
problem of isomer formation that is often encountered in
pyridine syntheses.
Received: May 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01312
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Letter
probably arising from aldol-type chemistry. In order to find
optimal reaction conditions, various protected derivatives of the
aldehydes 6, such as oximes and imines, were subjected to
palladium catalysis under conditions described previously (base,
(Dt-BPF)PdCl2, THF).3c,7 This work showed that employing
tert-butylimines 2 as the carbonyl surrogates was optimal for
yields, and this group was adopted for further study. Note that
imines 2 are readily available by the addition of t-BuNH2 to
aldehydes 6 and stirring the reaction mixture with molecular
sieves in CH2Cl2; after evaporation, no purification was
necessary. In the reaction of 2a and propiophenone 1a, chosen
as a model, the acyclic coupled intermediate 3a could not be
isolated since it reacted in situ to yield pyridine 4a directly in 43%
(Table 1, entry 1) in 6.5 h.
the mixture was increased gradually for each step of the cascade
reaction (see Supporting Information (SI)). Monitoring the
reaction progress by MS showed that the enolate α-alkenylation
cross-coupling between alkenyl halide 2a and propiophenone 1a
to the acyclic intermediate 3a occurred at 70 °C, cyclization and
elimination to pyridinium 7a were optimal at 90 °C, and finally
elimination of t-Bu at 120 °C gave pyridine 4a. Simply running
the whole reaction at 110 °C from the beginning led mostly to
the dehalogenated alkenyl derivative.
Weaker bases such as LiOt-Bu (27%, Table 1, entry 4) or
NaOt-Bu (39%, Table 1, entry 5) gave low yields. Commercial
NaHMDS (37%, Table 1, entry 6) also performed poorly
compared to in situ prepared LDA (69%, Table 1, entry 7), which
gave pyridine 4a in a similar yield to LiHMDS (71%, Table 1,
entry 8). Later studies showed that, for aromatic ketones 1 (R2 =
aromatic), in situ prepared LiHMDS was the base of choice,
whereas, for the less acidic aliphatic ketones 1 (R2 = aliphatic), in
situ prepared LDA gave the best results.
Table 1. Optimization of the Alkenylation and Cyclization/
Aromatization Protocol
No conversion of alkenyl halide 2a was observed in the
absence of palladium (Table 1, entry 9). When (Dt-BPF)PdCl2
was exchanged for a Pd(0) species (Pd2dba3, Qphos), the yield
dropped to 31% (Table 1, entry 10). Applying conditions which
have recently been shown to catalyze enolate α-alkenylations
even at 0 °C did not lead to pyridine formation (Table 1, entry
11), and only traces of α-alkenylation product 3a were observed
by MS.3b Moreover, the use of an N-heterocyclic carbene ligand
(PEPPSI) afforded pyridine 4a in moderate yield (51%, Table 1,
entry 12). When moving to the preformed catalyst with bulky
monodentate phosphine ligands (Amphos)2PdCl2, the yield of
4a could be increased to 76% with fewer side products observed
(Table 1, entry 13).
It is important to note that at least 2 equiv of base are required
for this transformation, presumably because the coupling
product is more acidic than the starting ketone. With only 1.2
equiv of base added, the reaction did not reach completion and,
instead, a mixture of the desired product and intermediates was
observed. However, the yields were comparable if 2.1, 2.5, or 3.0
equiv of LiHMDS were used. The only byproduct that we were
able to observe in the sequence was the dehalogenated analogue
of imine 2a.
With the optimal conditions in hand, modification at the
pyridine positions R2/R3 (C2 and C3) was then achieved using
different ketone enolates 1 (Figure 2). The conditions for the
enolate α-alkenylation reaction are compatible with electron-
deficient (4b) and -rich (4c) aromatic substituents. Hetero-
aromatic substituents give the desired pyridines (4e, 4f) in
reasonable yields. Using a methyl ketone (R3 = H) gives the
corresponding trisubstituted pyridine 4g in 58% yield; increasing
the steric bulk at position R3 leads to lower product formation for
pyridines 4h and 4i. Interestingly, elimination of the t-Bu group
from pyridinium 7g (R2 = Ph, R3 = H) occurs at 70 °C, a
temperature much lower than that for the corresponding
pyridines with R3 ≠ H. This observation may be explained by
considering the increased steric congestion present at the
pyridine nitrogen when the aromatic ring at R2 is in conjugation
with the pyridine π-system. For the synthesis of the aliphatic
substituted pyridines 4j and 4k, a slightly modified procedure
using LDA gave the best results. Pyridine 4l, in which the ketone
is part of a six-membered ring, could be synthesized in 26% yield.
Substituents R4 and R5 (C4 and C5) are introduced via
different alkenyl derivatives 6, and this feature was examined next
(Figure 3). Aromatic substituents at R4 can be decorated with
electron-donating (4a, 4d, 4m) and electron-withdrawing (4n)
a
b
Yield of 4a over two steps based on aldehyde 6a. Prepared in situ.
Amphos = di-tert-butyl(4-dimethylaminophenyl)phosphine.
A screen of bases and their loadings, solvents, catalysts, and
reaction temperatures resulted in optimized conditions for the
enolate α-alkenylation cross-coupling/aromatization reaction
cascade (Table 1). Changing the solvent from THF to toluene
facilitated cleavage of the t-Bu from pyridinium intermediate 7a
and increased the yield of 4a to 69% (Table 1, entry 2).
Conversely, performing the reaction in 1,4-dioxane resulted in
the formation of only 12% pyridine 4a (Table 1, entry 3) even
after a prolonged reaction time. From screening different
reaction temperatures in toluene, it was found that greater yields
of the pyridine product were obtained when the temperature of
B
DOI: 10.1021/acs.orglett.5b01312
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Letter
groups and may be heteroaromatic (4o). We were pleased to find
that cyclic alkenyl derivatives can be employed under the reaction
conditions and the aromatic, R4−R5-fused pyridines 4p and 4q
could be obtained in moderate yields, as well as the seven-
membered aliphatic pyridine 4r. The reaction conditions are also
compatible with R5 = H, and trisubstituted pyridine 4s was
obtained in good overall yield. The crystal structures of
substituted pyridines 4o and 4s were obtained, confirming the
formation of pyridines through enolate α-alkenylation (see SI for
details).8 Steric repulsion appears to have a smaller influence on
R5 than on R3, and pyridine 4t with R5 = Ph could be synthesized
in 50% yield. Alkenyl derivatives in which the double bond was
part of a five- or six-membered ring, or when the alkenyl halide
was substituted with OMe or CF3, gave the corresponding
pyridines in <25% yield.
Generally, we found that both alkenyl bromides and alkenyl
chlorides could be used in the key transformation, although as
expected the alkenyl bromides tended to couple more rapidly
than their chloride counterparts. This result is in agreement with
a similar observation made for related enolate α-arylations and
can be explained by the higher preference of Pd(0) to insert into
C−Br bonds than C−Cl bonds.9 Once the enolate is coupled to
the alkenyl halide, the cyclization was completed within 3 h for
both types of substrate. For example, the yield of product 4d was
similar when starting from the bromide (63%) and the chloride
derivative (61%).
Finally, we studied the role of alkene geometry in the alkenyl
halide coupling partner and found that the (E)- and (Z)-isomer
of alkenyl chlorides 6l could be separated by MPLC (these were
unambiguously assigned by using the nuclear Overhauser effect,
SI). The aldehydes were converted into the corresponding
imines and subjected to the optimized reaction conditions
(Scheme 2). While the enolate α-alkenylation for both the (Z)-
Figure 2. Variation in the ketone component. Yields over two steps: (i)
6, t-BuNH2, 3 Å MS, CH2Cl2; (ii) ketone (2 equiv), LiHMDS (2.5
equiv), (Amphos)2PdCl2 (5 mol %), toluene, 70−120 °C. LDA used for
4j, 4k. a X = Br. b X = Cl. c (Dt-BPF)PdCl2 (5 mol %) cat.
Scheme 2. Studies on Alkenyl Halide Geometry
and the (E)-isomer was slow (16 h at 70 °C), the following
cyclization of the (Z)-isomer was almost instantaneous as judged
by MS analysis. The coupled intermediate immediately cyclizes
and aromatizes, and an m/z = 392.2 was observed for the
pyridinium intermediate. In the case of the (E)-isomer, on the
other hand, double bond isomerization and subsequent
cyclization appear to be slow and only occur at elevated
temperatures and longer reaction times (24 h at 120 °C). Note
1
that the isomer (Z)-6l was unstable as judged by H NMR
spectroscopy, which could explain the reduced yield for the
transformation into pyridine 4t.
Figure 3. Variation in the halide component. Yields over two steps: (i) 6,
t-BuNH2, 3 Å MS, CH2Cl2; (ii) ketone (2 equiv), LiHMDS (2.5 equiv),
(Amphos)2PdCl2 (5 mol %), toluene, 70−120 °C. LDA used for 4r. a X
= Br. b X = Cl.
A catalytic cycle for the enolate α-alkenylation reaction is
proposed which is similar to the one published for the enolate α-
arylation reaction.10 The Pd(0) catalyst undergoes oxidative
addition into the C−X bond of the alkenyl halide 2 to give
complex A (Scheme 3). The Li-enolate, formed from ketones 1,
C
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commercially available compounds with complete regiocontrol
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are given in the Supporting Information (CIF). Crystallographic data
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obtained via www.ccdc.cam.ac.uk/data_request/cif.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data for all new
compounds; copies of 1H and 13C NMR spectra. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01312.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: timothy.donohoe@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the EPSRC for support (Established Career
Fellowship, T.J.D.). This work was also supported by the Swiss
National Science Foundation and Marie Curie actions fellow-
ships (L.A.H.) and a Berrow Foundation Lord Florey scholarship
(J.H.).
REFERENCES
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