Pyridone Functionalization: Regioselective Deprotonation of 6-Methylpyridin-2(1H)- and -4(1H)-one Derivatives

Article abstract of DOI:10.1002/ejoc.201601156

Selective functionalization at the α-methyl group of 1-substituted pyridin-2(1H)- and 4(1H)-ones (2- and 4-pyridones) can be achieved by appropriate choice of base. n-Butyllithium was found to effect clean 6(2)-methyl deprotonation of 1-benzyl-2- and -4-p

Full text of DOI:10.1002/ejoc.201601156

A Journal of
Accepted Article
Title: Pyridone Functionalization: Regioselective Deprotonation of 6-Methylpyridin-
2(1H)- and -4(1H)-one Derivatives
Authors: Beatriz Pilar Fernandez Diaz Ropero; Mark Elsegood; Gary Fairley; Gareth
Pritchard; George William Weaver
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601156
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601156
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COMMUNICATION
Pyridone Functionalization: Regioselective Deprotonation of 6-
Methylpyridin-2(1H)- and -4(1H)-one Derivatives
Beatriz P. Fernandez Diaz Ropero,[a] Mark R. J. Elsegood,*[a] Gary Fairley,[b] Gareth J. Pritchard,*[a] and
George W. Weaver*[a]
In memory of Russ Bowman
Abstract: Selective functionalization at the α-methyl group of 1-
substituted pyridin-2(1H)- and 4(1H)-ones (2- and 4-pyridones) can
be achieved by appropriate choice of base. n-Butyllithium was found
to effect clean 6(2)-methyl deprotonation of 1-benzyl 2- and 4-
pyridone derivatives, while potassium hexamethyldisilazide
(KHMDS) was the preferred reagent for methyl deprotonation of the
corresponding 1-methyl 2- and 4-pyridones. Deprotonation proceeds
smoothly at -78 °C and the resulting anions react readily with a wide
range of electrophiles (aldehydes, ketones, alkylating reagents, and
an azo compound) under precise temperature control to form
usefully functionalized 2- and 4-pyridones and quinolizinones.
side chain functionalization of N-alkyl 2- and 4-pyridones by
selective deprotonation of a 6- or 2-methyl substituent, along
with convenient methods for the preparation of the required N-
alkyl 6-methyl-2- and 2-methyl-4-pyridone substrates. Methyl
substituted 2- and 4-pyridones represent versatile building
blocks for elaboration to side chain functionalized derivatives,
and for construction of quinolizinones, bridgehead nitrogen
compounds of significant recent interest as bicyclic scaffolds in
medicinal chemistry.[7] While the addition of electrophiles to
lithiated methyl pyridines continues to be studied in depth,[8]
there is a lack of information on reactions of metalated 6-methyl-
2- and 2-methyl-4-pyridones. Only limited examples of alkylation
of 2-pyridone methyl substituents are reported in the literature,[9]
along with early pioneering work on ring and N-substituent
lithiation.[10] A heterocyclic methyl group represents a source of
diversity for ring functionalization,[11] while conditions to
selectively effect lithiation of a pyridine ring, but leaving a methyl
substituent intact, have also been developed.[12] Metalation of a
methyl substituent on the weakly aromatic pyridone system thus
Introduction
1(N)-Substituted 2(1H)- and 4(1H)-pyridinones (commonly
referred to as 2- and 4-pyridones) are widely employed in
medicinal chemistry,[1] occur as key fragments of natural
products[2] and as hydrogen bonding synthons in supramolecular
chemistry.[3] Pyridones are regarded as privileged heterocyclic
scaffolds,[4] and both synthesis and functionalization of the
pyridone ring system continue as intensive areas of research.[5]
Recently, CH activation of pyridones (Figure 1) has been
highlighted employing Ni, Pd or Fe catalysis.[6] In this
communication we wish to report an alternative approach for
represents
a significant challenge in synthetic carbanion
chemistry. Here we report the successful methyl deprotonation
of a range of 6-methylpyridin-2(1H)- and 2-methylpyridin-4(1H)-
ones, and reaction with a variety of electrophiles, including
aldehydes, ketones, diketones, alkylating reagents and an azo
compound to form highly functionalized pyridone derivatives
relevant to medicinal chemistry. Careful choice of base and
temperature control allows excellent regioselectivity and clean
product formation in moderate to excellent isolated yield.
Results and Discussion
Our study started with the synthesis of the required 1-substituted
6-methylpyridin-2-ones 2a-g (Scheme 1) via direct alkylation of
Figure 1. Functionalization of pyridone scaffolds.[6]
[a]
Department of Chemistry, Loughborough University
Loughborough LE11 3TU, UK
E-mails: m.r.j.elsegood@lboro.ac.uk, g.j.pritchard@lboro.ac.uk,
g.w.weaver@lboro.ac.uk,
http://www.lboro.ac.uk/departments/chemistry/staff/academic-
research/mark-elsegood/,
http://www.lboro.ac.uk/departments/chemistry/staff/academic-
research/gareth-pritchard/,
http://www.lboro.ac.uk/departments/chemistry/staff/academic-
research/george-weaver/
[b]
AstraZeneca R&D  Oncology iMed, Darwin Building (310),
Cambridge Science Park, Milton Road, Cambridge CB4 0WG, (UK)
Scheme 1. Synthesis of 2-pyridone precursors
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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2-methoxy-6-methylpyridine
1
adapting
a
method for 2-
pyridone 3k, the low yield of 19% was attributed to the poor
solubility of the dibromobenzil electrophile, while addition of an
unsaturated aldehyde gave a 33% yield of 3d together with a
low yield of the unstable 3e formed by conjugate addition. In an
attempt to synthesize pyridone 3f, with propionaldehyde as
electrophile, a 26% yield of the ring alkylated product 4 (addition
at C-3) was obtained, together with starting material, as the
pyridone anion was basic enough to deprotonate the α position
of the aldehyde.
methoxypyridine.[13] Reaction with alkyl bromides proceeded in
good to excellent yield in the absence of solvent, despite the ring
nitrogen being flanked on both sides by the methoxy and methyl
substituents. Demethylation occurred concomitantly, presumably
by attack by bromide ion and loss of the volatile MeBr,
generating the 1-substituted pyridones 2a-g. We were also able
to generate a 1:1 mixture of 1,6-dimethyl pyridine-2(1H)-one 2a
and 1-benzyl-6-methylpyridin-2(1H)-one 2e by treating 1 with 0.5
equivalents of benzyl bromide. The two compounds could be
separated readily by chromatography.
N-Alkylation-O-
dealkylation is an effective method for conversion of
alkoxypyridines to pyridones[14] and avoids the frequent
heteroatom selectivity problem associated with attempts to
alkylate ambident pyridones.[15]
With the 2-pyridone derivatives 2a-g in hand, we studied
the deprotonation of the 6-methyl substituent to synthesize new
N-alkyl-6-substituted 2-pyridones. Initially we focused on 2a and
2e as test compounds and a study of reactivity towards n-BuLi
was undertaken (Scheme 2). 1-Benzyl-6-methyl-2-pyridone 2e
was treated with n-BuLi in THF at –78 °C → 0 °C → –78 °C
resulting in an intense blue solution. Quenching the mixture with
D2O at –78 °C led to clean recovery of the mono-deuterated
pyridone 3a (>98% by NMR; 87% isolated) substituted on the
methyl group (C-7 position). The location of the label was
1
established by H and 13C NMR spectroscopy [(H 2.23 (2H, bs)
1
and C 19.6 (t, JCD = 20 Hz)]. Treatment of 1,6-dimethyl-2-
pyridone 2a with 1 equivalent of n-BuLi under the same
conditions however, resulted in formation of an orange solution,
and quenching with D2O at –78 °C produced a mixture of
starting material and inseparable products.
Figure 2. Functionalized 1-benzyl 2-pyridones prepared.
Scheme 2. Lithiation of 1-benzyl 2-pyridones
In studying the reactivity of the 1,6-dimethylpyridin-2(1H)-one 2a,
deprotonation took place efficiently when KHMDS was used as
base (Scheme 3). To exploit the methyl anion of the pyridone
synthetically we employed aldehyde, ketone, and alkylating
agents as electrophiles. The reactions, forming compounds 5a-
5e, occurred in good to excellent yield, except when 5-bromo-1-
pentene was used. Due to its low reactivity, reaction at –78 °C or
–35 °C returned only starting material, while reaction with 2.5 eq.
of base and electrophile addition at 0 °C afforded the ring
alkylated (5f; E=1-penten-5-yl, 8%), dialkylated (5g; 8%) and
methyl dialkylated (5h; 18%) pyridones. Use of 1.0 eq. of base
and electrophile addition at –10 °C was required to form the
desired product 5d cleanly with isolation in a low 20% yield, as
found by Sammes[9] who obtained 6.6% yield operating at –
23 °C. In comparison, 5a and 5b were obtained in significantly
lower yields of 37% and 38% respectively when n-BuLi was
employed as base.
Treatment of pyridone 2a with KHMDS as base, led to
clean formation of the monodeuterated pyridone (98% by NMR;
55% isolated), with no by-product formation. In the subsequent
experiments with 2a, we thus chose to employ KHMDS as base,
since n-BuLi appeared to attack the unhindered pyridone ring.
The lithiated benzyl 2-pyridones 2e and 2f were then exposed to
a range of electrophiles at –78 °C to produce compounds 3b-o
(Figure 2). Subsequent optimization steps demonstrated that the
best yields for direct methyl alkylation of the 1-benzyl-6-methyl-
2-pyridone anion occurred with 1 eq. of n-BuLi. Use of 1.2 → 2
eq. afforded products in which the benzylic position was also
alkylated, as observed by Katritzky.[10b,c] Pleasingly, the
conditions developed operated effectively for all electrophiles
tested (aldehyde, ketone, diketone, ketoester, alkylating agent,
azo compound) possessing a range of functionality, proceeding
in general in high yield with few exceptions. In the synthesis of
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The next part of the study investigated methyl deprotonation
of the corresponding 1-alkyl 2-methylpyridin-4(1H)-one
derivatives. These were considered more challenging
substrates due to the high polarity of the 4-pyridone system
(dipole moment ≥ 7.3 D for N-alkyl derivatives[16] compared
with ~ 4.0 for 2-pyridones.[17] 4-Pyridones are more
susceptible to attack by nucleophiles,[18] which could
compete with metalation. The higher polarity also resulted
in lower isolated yields due to difficult extraction and
chromatography. The substrates 9a and 9b were prepared
by alkylation of 2-methyl-4-alkoxypyridines (Scheme 4).
Scheme 4. Synthesis of 4-pyridones.
Base catalyzed hydrolysis (NaOH/H2O/THF) of the resulting
N-methyl and N-benzyl pyridinium salts was found a
convenient method of conversion to the pyridones, as the
salts were easily isolated by precipitation, and did not
undergo dealkylation as had occurred in the 2-pyridone
series under solvent-free conditions.
The 1-benzyl 4-pyridone 9b was investigated first, and
found to behave well using the lithiation conditions developed for
benzyl 2-pyridones (Scheme 5). Clean reaction was observed
using n-BuLi, although isolated yields were only moderate. The
methyl-lithiated 9b reacted successfully with aldehyde, diketone,
allyl halide and azo electrophiles forming 10a-d.
Scheme 3. Functionalization of pyridinone 2a
Figure 3. X-ray crystal structure of 5e[19]
The 4-benzyloxy derivative
reaction of 4-chloropyridine
7
was easily prepared by SNAr
6
, using NaH in DMSO.
Scheme 5. Functionalization of 4-pyridinone derivatives
Attempts to mono-metalate the 1,2-dimethylpyridin-4(1H)-
one analogue 9a met initially with less success. Different
reaction conditions were therefore systematically investigated in
order to find a set of conditions that would favour mono-
alkylation. The standard conditions of 1 eq. of KHMDS at –78 °C,
warming to 0 °C, and quenching with the electrophile at –78 °C,
unfortunately gave no alkylated pyridone. Screening the quantity
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European Journal of Organic Chemistry
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COMMUNICATION
eq. of n-BuLi gave modest yields of the quinolizinones 16-18.
Dehydration to the fully unsaturated ring system did not occur
under the reaction conditions, but 16 and 17 could be converted
to quinolizinone 19 and the 6,7-dihydro compound 20 on heating
with pTSA.
of base from 1 to 2.5 equiv. was studied, while the temperature
of the electrophile addition (–78 °C) and reaction time of 2 h
were held constant, but again only a high recovery of starting
material was obtained. Only by adding 2.5 equiv. of base to the
pyridone at –78 °C, equilibrating to 0 °C, and electrophile
addition at 0 °C (2 h) could alkylated products be obtained with a
limited range of electrophiles. Reaction with pivaldehyde was
found to proceed well giving pyridone 11a in a moderate 15%
yield. Isolation of the unsaturated product 11b (17%) formed by
elimination, indicated a greater degree of alkylation. Use of allyl
bromide gave a low yield (10%) of alkylated pyridone 11c, but
the reaction was complicated by the subsequent deprotonation
of the product, leading to further alkylation, delivering the
dialkylated compound 11d in 39% yield. Although the yields
were modest, we have demonstrated it is possible to
successfully manipulate the sensitive 4-pyridone anion in a
synthetically useful way.
Conclusions
In conclusion we have optimised deprotonation conditions for
the selective methyl activation of 6-methylpyridin-2(1H)-ones
and 2-methylpyridin-4(1H)-ones, and demonstrated these
intermediates can be manipulated in a synthetically useful way
to
prepare
side-chain
functionalized
pyridones
and
quinolizinones, important scaffolds in medicinal chemistry. n-
BuLi is a suitable base for N-benzyl substituted pyridones, while
KHMDS is preferable for N-methyl analogues.
Finally, we investigated the metalation reaction as a method
to form quinolizinone derivatives, compounds of interest as
bicyclic drug scaffolds.[7] As shown in Scheme 6, we were able
to generate this ring system using the chemistry developed
giving bicyclic heterocycles in modest yield. Treatment of
pyridone 2c with KHMDS and reaction with 4,4’-dimethylbenzil
gave 12 (10%) in which the ester group was lost. Addition of 1
eq. of n-BuLi, and adding the electrophile at –78 C, gave 13
showing the N-substituent was alkylated prior to the methyl. Use
of LDA to deprotonate benzyl pyridone 2e gave 14 in low yield
together with 15, also indicating lithiation of the N-alkyl group
occurs first with this base.[10b]
Acknowledgements
We thank AstraZeneca and Loughborough University for
financial support, the EPSRC UK National Mass Spectrometry
Facility at Swansea for mass spectra, and are grateful to Dr.
Mark Edgar for NMR spectroscopy and Mr. J. Alastair Daley for
technical support.
Keywords: heterocycles • pyridone • quinolizinone • scaffold •
side chain metalation
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Heterocycles
Beatriz P. Fernandez Diaz Ropero, Mark
R. J. Elsegood*, Gary Fairley, Gareth J.
Pritchard*, and George W. Weaver*
Page No. – Page No.
Text for Table of Contents
Pyridone Functionalization:
Regioselective Deprotonation of 6-
Methylpyridin-2(1H)- and -4(1H)-one
Derivatives
Base controlled regioselective methyl
deprotonation: functionalized pyridone
and quinolizinone scaffolds: 40
examples
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