Concise synthesis of substituted quinolizin-4-ones by ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201402648

The 4H-quinolizin-4-one scaffold is of significant pharmaceutical interest. This heterocyclic structure is predicted to have attractive physico-chemical properties and is present in a variety of biologically active molecules. Despite these interesting characteristics, 4H-quinolizin-4-ones are largely under-represented in current small molecule screening libraries, and, therefore, this scaffold has been poorly investigated. Herein, a new strategy is reported for the syntheses of these rare and biologically interesting 4H-quinolizin-4-ones. This modular route involves the regioselective N-alkylation of 6-halo-2-pyridones followed by a Stille cross-coupling, ring-closing metathesis, and palladium-catalyzed dehydrogenation reaction sequence. This method furnishes the target compounds in good yields and allows for access to unusual substitution patterns that are difficult to achieve by using other synthetic strategies.

Full text of DOI:10.1002/ejoc.201402648

FULL PAPER
DOI: 10.1002/ejoc.201402648
Concise Synthesis of Substituted Quinolizin-4-ones by Ring-Closing Metathesis
Thomas A. Alanine,[a] Warren R. J. D. Galloway,[a] Thomas M. McGuire,[b] and
David R. Spring*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Cross-coupling / Metathesis / Dehydrogenation
The 4H-quinolizin-4-one scaffold is of significant pharma- rare and biologically interesting 4H-quinolizin-4-ones. This
ceutical interest. This heterocyclic structure is predicted to
have attractive physico-chemical properties and is present in
a variety of biologically active molecules. Despite these inter-
esting characteristics, 4H-quinolizin-4-ones are largely un-
der-represented in current small molecule screening librar-
ies, and, therefore, this scaffold has been poorly investigated.
Herein, a new strategy is reported for the syntheses of these
modular route involves the regioselective N-alkylation of 6-
halo-2-pyridones followed by a Stille cross-coupling, ring-
closing metathesis, and palladium-catalyzed dehydrogena-
tion reaction sequence. This method furnishes the target
compounds in good yields and allows for access to unusual
substitution patterns that are difficult to achieve by using
other synthetic strategies.
become unwieldy and difficult to perform. Recently, Muir
et al. reported an elegant general route towards 4H-quinol-
izin-4-ones that proceeded through the construction of the
oxygenated ring.[2] This method allowed for the introduc-
tion of substituents at the 2-position of the bicyclic ring
system. However, the introduction of substituents at other
positions of the scaffold was not reported. Complementary
synthetic approaches that allow access to 4H-quinolizin-4-
ones with alternative substitution patterns would therefore
be of significant value. These would expand upon the range
Introduction
Heterocyclic drugs are found in all therapeutic areas of
medicinal chemistry, and heterocyclic rings are also the core
scaffold of numerous agrochemicals.[1,2] It is therefore not
surprising that there remains intense interest in the synthe-
sis of both new heterocyclic systems and heterocycles that
have been underexploited in drug and agrochemical re-
search. Quinolizinones are a class of heterocycles that have
attracted the attention of the pharmaceutical industry in
recent years. These bicyclic systems, which contain a nitro-
gen atom at the ring junction, are predicted to have favor-
able physico-chemical properties as a result of their polar
zwitterionic character (see Figure 1).[2,3] The 4H-quinolizin-
4-one scaffold has garnered particular attention. In ad-
dition to its predicted physico-chemical properties, this het-
erocyclic unit is present in a variety of molecules that have
interesting biological activities (see Figure 1).[2,4] Despite
these properties, 4H-quinolizin-4-ones are largely under-
represented in current small molecule screening libraries.
Overall, this scaffold has been poorly investigated. The rela-
tive paucity of these compounds can be attributed primarily
to their synthetic intractability. General methods to con-
struct this ring system are relatively scarce, with synthetic
approaches individually tailored for a particular target.
When their preparation is combined with the requirement
for substitution on the ring system, the syntheses typically
[a] Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, UK
E-mail: spring@ch.cam.ac.uk
Figure 1. The 4H-quinolizinone system and its dipolar canonical
form together with some examples of biologically active com-
pounds that contain this ring system. Compound 1 is a therapeutic
for immunoglobulin E related diseases.[5] Compound 2 has antibac-
terial activity,[6] and compound 3 is a hypnotic.[7]
http://www-spring.ch.cam.ac.uk
[b] AstraZeneca UK Ltd.,
Alderly Park, Macclesfield, Cheshire, SK10, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402648.
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T. A. Alanine, W. R. J. D. Galloway, T. M. McGuire, D. R. Spring
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of synthetically accessible derivatives of 4H-quinolizin-4-
ones and thus allow for further investigation of its bio-
logical usefulness.
The ring-closing metathesis (RCM) reaction has emerged
as a powerful tool for the construction of a variety of het-
erocyclic ring systems.[8] A number of RCM-based strate-
gies for the construction of quinolizidinones and related bi-
cyclic heterocyclic systems that contain a nitrogen atom at
the ring junction have been reported. For example, Ma et
al. described the syntheses of a range of bicyclic quinolizid-
ine alkaloid derivatives by employing a double RCM reac-
tion with N-alkynyl-N-(1,ω)-alkadienyl acrylamides (see
Scheme 1, A).[9] Nomura et al. reported the syntheses of
two unsaturated quinolizidinone frameworks by carrying
out the RCM reactions of two chiral unsaturated piperidine
building blocks that contain propenyl substituents (see
Scheme 1, B).[10] Donohoe et al. described the synthesis of
a 6,6-fused ring system with a nitrogen atom at the ring
junction by using a RCM reaction of a dihydropyridone
(see Scheme 1, C).[11] The Alvarez-Builla group developed
elegant RCM-based strategies for the syntheses of a variety
of cationic bicyclic heterocyclic systems that contain a ni-
trogen atom at the ring junction.[12] Of particular interest,
this group has reported a route for the preparation of quin-
olizinium salts by employing a RCM reaction with the acy-
clic precursors followed by the thermal dehydrogenation
(oxidation) of the resultant 3,4-dihydroquinolizinium salts
(see Scheme 2).[12b]
Scheme 2. RCM-based route to quinolizinium salts developed by
the Alvarez-Builla group.[12b]
We envisaged that a similar approach could be used in
the design of a new RCM-based strategy for the syntheses
of substituted 4H-quinolizin-4-ones that have 4 as the gene-
ral structure (see Scheme 3). By starting from readily avail-
able 2-pyridones 5, a selective N-alkylation reaction would
yield 6, and a subsequent Pd-catalyzed cross-coupling reac-
tion would furnish 7. The RCM reaction would furnish di-
hydroquinolizinones 8, and a subsequent dehydrogenation
would yield the final substituted 4H-quinolizin-4-ones 4.
The construction of the carbocyclic ring in this fashion
would represent an unprecedented approach towards the
4H-quinolizin-4-one scaffold. We anticipate that this route
would allow for facile access to new substitution patterns
at the 7- and 8-positions of the bicyclic architecture (which
is difficult to achieve with existing strategies) by varying the
building blocks that are used to prepare compounds 6 and
7. Furthermore, our RCM strategy would have the added
benefit of providing versatile dihydroquinolizinone interme-
diate 8. In principle, this could be manipulated to generate
our desired quinolizinone core 4 or reduced to provide ac-
cess to tetrahydroquinolizinone moieties, which are also of
interest in drug discovery efforts. Herein, we report the suc-
cessful realization of the RCM-based strategy that is out-
lined in Scheme 3. This approach has enabled concise access
to a range of new substituted 4H-quinolizin-4-ones from
readily available starting materials. The enrichment of
screening libraries with these compounds will allow for the
Scheme 1. Some notable examples of the syntheses of 6,6-fused bi-
cyclic ring systems that have a nitrogen atom at the ring junction:
(A) a double RCM approach by Ma et al.,[9] (B) a RCM approach
that uses propenyl-substituted piperidine derivatives by Nomura et
al.,[10] and (C) a RCM of a dihydropyridone by Donohoe et al.[11]
Scheme 3. Retrosynthetic strategy towards the 4H-quinolizin-4-one
scaffold {[M] = unspecified metal, X = unspecified halide}.
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Concise Synthesis of Substituted Quinolizin-4-ones
sampling of attractive heterocyclic compounds that are un-
derexploited in current drug and agrochemical discovery ef-
forts.[13]
Results and Discussion
Our studies began with the selective N-alkylation of 6-
bromo-2-pyridone (9) with a range of allylic halides to form
N-allylated pyridones 10a–10d (see Table 1).[14] In general,
the reactions proceeded smoothly and with a high level of
regioselectivity for the pyridone nitrogen over the pyridine
oxygen atom. This approach allowed for the introduction of
unsubstituted terminal alkene units as well as alkyl-, aryl-,
and ester-functionalized allylic chains at the pyridone core.
Alternative strategies were used to generate diester-substi-
tuted pyridone 10e and structurally related uracil derivative
10f (see Figure 2).[15]
Table 1. Synthesis of N-allylated pyridones 10a–10d.[a]
Scheme 4. Synthesis of bis(allylic) pyridones 12a–12j and uracil de-
rivatives 12k and 12l [dba = dibenzylideneacetone, TFP = tri(2-
furyl)phosphine].
Entry
R
X
Product
Yield [%]
1
2
3
4
H
Me
Ph
CO2Me
I
10a
10b
10c
10d
84
65
39
87
Br
Br
Br
With bis(allylic) pyridones 12a–12j and bis(allylic) uracil
derivatives 12k and 12l in hand, we subjected our substrates
to the RCM reaction with Grubbs second-generation cata-
lyst in an attempt to access the corresponding dihydroquin-
olizinone derivatives 13 (see Scheme 5). Gratifyingly, the
compounds with unsubstituted allylic groups (such as 12a)
underwent rapid ring-closure by using a catalyst loading of
5 mol-% at room temperature. Compounds with an allylic
group that was monosubstituted at the 2-position (such as
12b) required heating to 50 °C. We were also able to form
sterically hindered tetrasubstituted olefin products (i.e., 13c,
13f, and 13h) by increasing both the catalyst loadings and
reaction times.[19] Some dihydroquinolizinones products 13
slowly degraded after isolation upon standing at room tem-
[a] DME = 1,2-dimethoxyethane, DMF = N,N-dimethylform-
amide.
Figure 2. Other N-allylated heterocycles that were prepared.[15]
Next, we sought to explore the palladium cross-coupling perature.[20] For this reason, the crude metathesis mixtures
reactions of 2-pyridones 10a–10e and uracil derivative 10f were directly submitted without further purification to the
as a mild and selective method to install the second allylic dehydrogenation step. The oxidation of related quinolizin-
unit (see Scheme 4). The cross-coupling reaction of 2-pyri- ium cations has been reported by using Pd/C and heat un-
dones with allylic coupling partners (such as 11) represents der solvent-free conditions (see Scheme 2).[12b] A screening
an unprecedented transformation. A variety of cross-cou- of conditions and reagents for the dehydrogenation step by
pling methods were investigated, and it was found that the starting from 12a revealed that 30 mol-% Pd/C at 150 °C
Stille cross-coupling conditions, which employ a palla- under solvent-free conditions gave good yields of the quin-
dium(0) source and tri(2-furyl)phosphine (TFP),[16] were olizinone product after only 1–2 h.[20] See Supporting Infor-
the most reliable. Under these conditions, the reaction with mation for details regarding the screening process. Pleas-
allyltributyltin or (2-methylallyl)tributyltin coupling part- ingly, these conditions proved to be applicable to a wide
ners used relatively modest catalyst and ligand loadings to range of substrates to yield the desired 4H-quinolizin-4-
furnish diene compounds 12a–12j in good yields ones 14a–14j and the structurally related pyridopyrimidine
(Scheme 4).[17,18] Similarly, compounds 12k and 12l could derivative 14k (see Scheme 5).[21] In the majority of cases,
be accessed from 10f.
compound 15 was obtained after workup and detected as a
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T. A. Alanine, W. R. J. D. Galloway, T. M. McGuire, D. R. Spring
FULL PAPER
minor byproduct in the crude product mixture. This pre-
sumably resulted from the rearrangement of the alkene moi-
ety that was generated in the RCM step.[22] In most cases,
15 could be readily separated from the desired products by
column chromatography.[23] Overall, the isolated yields of
the final analytically pure 4H-quinolizin-4-ones products 14
were typically good over the two steps. Alkyl, aryl, and
carbonyl functionalities could be introduced into the 4H-
quinolizin-4-one scaffold. Carbonyl groups are valuable, as
they provide possible synthetic handles for further modifi-
cations at the 4H-quinolizin-4-one core. A variety of substi-
tution patterns were accessible by using this approach,
which included substitution at the 7- and 8-positions. This
is rare and difficult to achieve by using other strategies.
Conclusions
In summary, we have developed a new strategy for the
synthesis of substituted 4H-quinolizin-4-ones from readily
available pyridone precursors. This represents a valuable ad-
vance in the synthesis of this rare and biologically interest-
ing class of compounds. We have also demonstrated that
this general RCM-based approach is suitable for the prepa-
ration of the structurally related pyridopyrimidine scaffold,
another synthetically challenging heterocyclic ring system
of pharmaceutical interest. There are several notable fea-
tures of our synthetic strategy. It is a step-efficient approach
and inherently modular in nature, which renders it highly
amenable to the preparation of analogues and allows for
the facile introduction of a range of substituents at the 4H-
quinolizin-4-one core (including unprecedented derivati-
zation). In addition, the modular nature of the strategy
should facilitate the systematic modification and optimiza-
tion of substitution and functionality at the core scaffold to
improve properties (as would be required in any hit-to-lead
optimization process). Furthermore, the strategy features
the cross-coupling reaction between 2-pyridones and allylic
coupling partners, a previously unreported synthetic trans-
formation that we foresee as useful in a wider synthetic con-
text. Overall, we envisage that the research described herein
will be of significant interest to medicinal chemists and the
wider synthetic community. The physico-chemical proper-
ties of the 4H-quinolizin-4-ones that are synthesized by this
method are currently being evaluated and will be reported
in due course.
Experimental Section
General Methods: All nonaqueous reactions were performed under
a constant stream of dry nitrogen using oven-dried glassware. Stan-
dard practices were employed when handling moisture and air-sen-
sitive materials. Room temperature refers to ambient temperature.
All temperatures below 0 °C are those of the external baths, and a
temperature of 0 °C was maintained by using an ice-water bath.
Temperatures below 0 °C were maintained by using an acetone-dry
ice bath. All reagents and solvents were used as received, unless
otherwise stated. Toluene, acetonitrile, dichloromethane, and meth-
anol were distilled from calcium hydride. Tetrahydrofuran was
dried with Na wire and distilled from a mixture of lithium alumin-
ium hydride and calcium hydride with triphenylmethane as an indi-
cator. Diethyl ether was distilled from a mixture of calcium hydride
and lithium aluminium hydride. Petroleum ether was distilled be-
fore use. Dichloromethane and methanol were distilled from cal-
cium hydride, yields refer to chromatographically and spectroscopi-
cally pure compounds, unless otherwise stated. When possible, re-
actions were monitored by thin layer chromatography, which was
performed on commercially prepared glass plates that were pre-
coated with Merck silica gel 60 F254 or aluminium oxide 60 F254.
Visualization was done was by quenching with UV fluorescence
Scheme 5. RCM and dehydrogenation steps. [a] Conditions A:
Grubbs second-generation catalyst (5 mol-%), CH2Cl2 (substrate
concentration 0.1 m), room temp., 2 h. [b] Conditions B: Grubbs
second-generation catalyst (5 mol-%), CH2Cl2 (substrate concen-
tration 0.1 m), 50 °C, 2 h. [c] Conditions C: Grubbs second-genera-
tion catalyst portionwise (3ϫ 5 mol-%), CH2Cl2 (substrate concen-
tration 0.1 m), 50 °C, 2 h. [d] Ratio determined by 1H NMR analy-
sis of crude product mixture. [e] Isolated yield of pure material.
[f] Ratio of 14h/15h/12h. [g] Ratio of 14k/15k/13k.
(ν
= 254 nm), by staining with potassium permanganate, or by
˜
max
using LC–MS analysis with an Agilent 1200 series LC system, an
ESCi Multi-Mode Ionization Waters ZQ spectrometer, and
MassLynx 4.0 software. Flash column chromatography was carried
out by using slurry-packed Merck 9385 Kieselgel 60 SiO2 (230–
400 mesh) under a positive pressure of compressed air. Preparative
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Concise Synthesis of Substituted Quinolizin-4-ones
HPLC purification was performed on an Agilent 1260 Infinity sys-
with N2, and the allylic tin reagent (1.1 equiv.) was then added. The
resulting mixture was heated to 80 °C until TLC indicated con-
sumption of the starting material. The solvent was removed under
reduced pressure, and the resulting residue was diluted with Et2O
(10 mL) and 10% aqueous KF (2 mL). The mixture was stirred at
room temperature for 10 min. The organic layer was then sepa-
rated, and the aqueous layer was extracted with Et2O (20 mL). The
organic layer was dried with MgSO4, and the solvent was removed
under reduced pressure. The resulting residue was purified by col-
umn chromatography (SiO2/KF, 9:1) according to the method of
Harrowven et al.[18] to yield the title compound.
tem that was fitted with
a Supelcosil ABZ+Plus column
(250ϫ21.2 mm, 5 μm) by using a linear gradient system [solvent
A: 0.1% (v/v) trifluoroacetic acid (TFA) in water, solvent B: 0.05%
(v/v) TFA in acetonitrile] at a flow rate of 20 mLmin–1. Melting
points were measured on a Büchi B-545 melting point apparatus.
Infrared spectra were recorded on a Perkin–Elmer Spectrum One
spectrometer with internal referencing. Selected absorption max-
ima (νmax) are reported in wavenumbers (cm–1) with the abbrevi-
˜
ations w (weak), med (medium), str (strong), and br. (broad). The
1H NMR spectroscopic data were recorded by using an internal
deuterium lock at ambient probe temperatures (unless otherwise
stated) with a Bruker DPX-400 (400 MHz), a Bruker Avance 400
QNP (400 MHz), or a Bruker Avance 500 Cryo Ultrashield
(500 MHz) spectrometer. Chemical shifts (δH) are reported in ppm,
to the nearest 0.01 ppm, and are referenced to the residual nondeu-
terated solvent peak. Coupling constants (J) are reported in Hertz
to the nearest 0.1 Hz. Data are reported in the order of chemical
shift, integration, multiplicity [br. (broad), s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), or a combination thereof],
coupling constant(s), and assignment. The numbering/lettering sys-
tems of selected structures do not follow IUPAC nomenclature
rules and are used for the assignment of the 1H and 13C NMR
spectra. Proton assignments were determined either on the basis of
unambiguous chemical shift, coupling patterns, by using patterns
observed in 2D experiments [1H-1H COSY, HMBC, and heteronuc-
lear multiple quantum coherence (HMQC)], or by analogy to fully
interpreted spectra of related compounds. The 13C NMR spectro-
scopic data were recorded by using broadband proton spin decou-
pling at ambient probe temperatures with an internal deuterium
lock with a Bruker DPX-400 (100 MHz), a Bruker Avance 400
QNP (100 MHz), or a Bruker Avance 500 Cryo Ultrashield
(125 MHz) spectrometer. Chemical shifts (δC) are reported in ppm,
to the nearest 0.1 ppm, and are referenced to the residual solvent
peak. Assignments were made on the basis of chemical shift, DEPT
editing, and where appropriate, HMQC and HMBC experiments,
or by analogy to fully interpreted spectra of related compounds.
High resolution mass spectrometry measurements were recorded
with a Bruker Bioapex 4.7e FTICR or a Micromass LCT Premier
spectrometer. Mass values are reported within the error limits of
Ϯ5 ppm mass units. ToF ESI+ refers to the mass spectral ioniza-
tion technique. Microwave reactions were carried out in a CEM
Discover Microwave in microwave vials that were equipped with
clip-on caps.
General Procedure 3 – RCM and Dehydrogenation of Substrates
with Unsubstituted Allyl Groups: To a stirred solution of the diene
in anhydrous CH2Cl2 (10 mL/mmol) at room temperature was
added Grubbs second-generation catalyst (0.05 equiv.). The mix-
ture was stirred at room temperature for 1–3 h until TLC showed
consumption of the starting material. Then 10% Pd/C (0.3 equiv.)
was added, and the solvent was removed under reduced pressure.
The mixture was heated to 150 °C for 1–3 h until 1H NMR analysis
showed consumption of starting material. The mixture was cooled
to room temperature and then suspended in CH2Cl2 (10 mL). The
suspension was filtered through a short pad of Celite®, and the
filter cake was washed with CH2Cl2 (4ϫ 20 mL). The solvent was
removed under reduced pressure, and the resulting yellow residue
was then purified by column chromatography (SiO2) to yield the
title compound.
General Procedure 4 – RCM and Dehydrogenation of Substrates
with One Substituted Allyl Group: To a stirred solution of the diene
(0.3 mmol) in anhydrous CH2Cl2 (0.1 m) at room temperature was
added Grubbs second-generation catalyst (0.05 equiv.). The mix-
ture was stirred and heated at reflux (50 °C) for 1–3 h until TLC
showed consumption of the starting material. Then, 10% Pd/C
(0.3 equiv.) was added, and the solvent was removed under reduced
pressure. The mixture was heated to 150 °C for 1–3 h until 1H
NMR analysis showed consumption of the starting material. The
mixture was cooled to room temperature and then suspended in
CH2Cl2 (10 mL). The suspension was filtered through a short pad
of Celite®. The filter cake was washed with CH2Cl2 (4ϫ 20 mL),
and the solvent was removed under reduced pressure. The resulting
yellow residue was then purified by column chromatography (SiO2)
to yield the title compound.
General Procedure 5 – RCM and Dehydrogenation of Substrates
with Two Substituted Allyl Groups: To a stirred solution of the diene
(0.3 mmol) in anhydrous CH2Cl2 (0.1 m) at room temperature was
added Grubbs second-generation catalyst (0.05 equiv.). The mix-
ture was stirred and heated at reflux (50 °C) for 24 h. Additional
portions of catalyst (0.05 equiv.) were added after 6 and 14 h or
until TLC analysis showed consumption of the starting material.
Then, 10% Pd/C (0.3 equiv.) was added, and the solvent was re-
moved under reduced pressure. The mixture was then heated to
General Procedure 1 – N-Alkylation of 2-Pyridones: This procedure
was adapted from a reported method by Liu et al.[14] To a stirred
solution of the 2-pyridone (1 equiv.) in DME/DMF (4:1,
2.5 mLmmol–1) at 0 °C was added NaH (60% in mineral oil,
1.1 equiv.) portionwise. The reaction was stirred at 0 °C for 15 min
and then warmed to room temperature. LiBr (2 equiv.) was then
added, and the reaction was stirred at room temperature for
15 min. The allylic bromide or iodide (2 equiv.) was then added,
and the reaction mixture was heated to 65 °C for 16 h or until TLC
indicated conversion of the starting material. The reaction mixture
was then poured onto brine (30 mL), and the organic layer was
separated. The aqueous layer was then extracted with EtOAc (4ϫ
25 mL). The combined organic layers were dried with MgSO4, and
the solvent was removed under reduced pressure. The residue was
purified by column chromatography to yield the title compounds.
1
150 °C for 1–3 h until H NMR analysis showed consumption of
the starting material. The mixture was cooled to room temperature
and then suspended in CH2Cl2 (10 mL). The suspension was fil-
tered through a short pad of Celite®. The filter cake was washed
with CH2Cl2 (4ϫ 20 mL), and the solvent removed under reduced
pressure. The resulting yellow residue was then purified by column
chromatography (SiO2) to yield the title compound.
1-Allyl-6-bromopyridin-2(1H)-one (10a): General procedure 1 was
followed by using the allylic iodide. The crude reaction material
was purified by chromatography on a silica gel column (40–60 pe-
troleum ether/EtOAc, 4:1 then 7:3) to yield 10a (84% yield) as a
yellow solid; m.p. 54–55 °C. Rf = 0.49 (40–60 petroleum ether/
General Procedure 2 – Stille Coupling Procedure: To a stirred solu-
tion of the heteroaryl bromide (1 equiv.) and tri(2-furyl)phosphine
(0.05 equiv.) in anhydrous MeCN (0.1 m) at room temperature was
added Pd2(dba)3 (0.025 equiv.). The mixture was then degassed
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T. A. Alanine, W. R. J. D. Galloway, T. M. McGuire, D. R. Spring
itored by LC–MS analysis. Additional PBr3 (0.1 mL) was added
FULL PAPER
EtOAc, 1:1). IR (CDCl ): νmax = 1656 (str), 1583 (str), 1583 (med),
˜
3
1431 (med) cm–1. 1H NMR (400 MHz, CDCl3): δH = 7.12 (dd, J = every hour until no starting material was observed. The reaction
9.2, 7.2 Hz, 1 H), 6.50 (dd, J = 9.5, 1.1 Hz, 1 H), 6.45 (dd, J = 7.2, was then quenched at 0 °C by the addition of water. The organic
1.2 Hz, 1 H), 5.96–5.86 (m, 1 H), 5.23 (ddd, J = 10.4, 2.4, 1.2 Hz,
1 H), 5.14 (ddd, J = 17.2, 2.6, 1.6 Hz, 1 H), 4.89 (ddd, J = 5.2, 3.1,
1.5 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δC = 162.7, 139.2,
131.1, 127.2, 119.1, 118.0, 111.2, 51.1 ppm. HRMS (FTMS ESI+):
calcd. for C8H9NO79Br+ [M + H]+ 213.9862; found 213.9867; Δ =
2.4 ppm.
solvent was removed under reduced pressure, and the residue was
again dissolved in water (100 mL) and Et2O (50 mL). The organic
layer was separated, and the aqueous layer was washed with Et2O
(2ϫ 50 mL). The combined organic layers were dried with MgSO4,
and the solvent was removed under reduced pressure to yield a pale
yellow solid, which was purified by column chromatography (SiO2,
50 g; 40–60 petroleum/EtOAc, 9:1 then 4:1) to give 10e (0.91 g,
2.53 mmol, 80%) as a pale yellow solid; m.p. 82–85 °C. Rf = 0.42
6-Bromo-1-(2-methylallyl)pyridin-2(1H)-one (10b): General pro-
cedure 1 was followed by using the allylic bromide. The crude prod-
uct material was purified by chromatography on a silica gel column
(40–60 petroleum ether/EtOAc, 4:1) to give 10b (65% yield) as a
cream solid; m.p. 56–57 °C. Rf = 0.37 (40–60 petroleum ether/
(40–60 petroleum ether/EtOAc, 1:1). IR (neat): νmax = 2968 (med),
˜
2918 (med), 2850 (w), 1721 (med), 1697 (str), 1676 (str), 1596
(med), 1484 (med), 1424 (med), 1395 (w), 1365 (med), 1306 (med),
1268 (w), 1229 (str), 1155 (str), 1113 (med) cm–1. 1H NMR
(500 MHz, CDCl3): δH = 8.62 (s, 1 H), 5.92 (ddt, J = 17.1, 10.4,
5.6 Hz, 1 H), 5.34–5.24 (m, 2 H), 5.10 (d, J = 5.6 Hz, 2 H), 4.38
(q, J = 7.1 Hz, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 1.38 (app t, J =
7.2 Hz, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 164.1, 163.3,
158.3, 144.4, 137.6, 130.0, 119.6, 117.8, 111.8, 62.0, 61.7, 52.5, 14.2
(2 C) ppm. HRMS (TOF ESI+): calcd. for C14H17NO579Br+ [M +
H]+ 358.0290; found 358.0306; Δ = 4.5 ppm.
EtOAc, 1:1). IR (neat): ν
= 3082 (w), 2980 (w), 2936 (w), 2911
˜
max
(w), 1652 (str), 1575 (med), 1502 (str), 1444 (med), 1426 (str), 1406
(med), 1380 (w), 1362 (w), 1299 (w), 1240 (w), 1215 (w), 1182 (w),
1168 (med), 1144 (med), 1130 (str) cm–1. 1H NMR (500 MHz,
CDCl3): δH = 7.16 (dd, J = 9.0, 7.5 Hz, 1 H), 6.54 (dd, J = 9.0,
1.0 Hz, 1 H), 6.50 (dd, J = 7.5, 1.0 Hz, 1 H), 4.91–4.86 (m, 1 H),
4.81 (s, 2 H), 4.49–4.44 (m, 1 H), 1.82 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δC = 162.7, 139.2, 138.9, 127.6, 119.1, 111.2,
110.4, 53.4, 20.4 ppm. HRMS (FTMS ESI+): calcd. for
C9H11NO79Br+ [M + H]+ 228.0029; found 228.0021; Δ = –3.9 ppm.
This data is in accordance with that previously reported.[24]
1-Allyl-3-benzyl-6-bromopyrimidine-2,4(1H,3H)-dione (10f): To a
stirred solution of 3-benzyl-6-bromopyrimidine-2,4(1H,3H)-dione
(0.30 g, 1.07 mmol) in CH2Cl2 (2.0 mL) at room temperature was
added 10% aqueous NaOH (2 mL) followed by tetrabutylammo-
nium bromide (0.14 g, 0.43 mmol) and allyl iodide (0.29 mL,
3.20 mmol). The mixture was then heated to 40 °C for 19 h. TLC
(40–60 petroleum ether/EtOAc, 7:3) showed consumption of start-
ing material. The mixture was then cooled to room temperature
and diluted with H2O (20 mL). The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (2ϫ 20 mL). The
combined organic layers were dried with MgSO4, and the solvent
6-Bromo-1-(2-phenylallyl)pyridin-2(1H)-one (10c): General pro-
cedure 1 was followed by using the allylic bromide. The crude reac-
tion material was purified by chromatography on a silica gel col-
umn (40–60 petroleum ether/EtOAc, 4:1) to give 10c (39% yield)
as a red crystalline solid; m.p. 88–91 °C. Rf = 0.33 (40–60 petro-
leum ether/EtOAc, 4:1). IR (neat): νmax = 3090 (w), 3060 (w), 3035
˜
(w), 2949 (w), 1660 (str), 1648 (str), 1628 (str), 1581 (str), 1547 (w),
1508 (str), 1496 (str), 1431 (str), 1411 (med), 1393 (med), 1337 (w),
1302 (w), 1292 (w), 1268 (w), 1218 (med), 1168 (med), 1128 (str), was removed under reduced pressure to yield an orange oil, which
1105 (med) cm–1. 1H NMR (500 MHz, CDCl3): δH = 7.50–7.47 (m, was purified by column chromatography (SiO2, 20 g; 40–60 petro-
2 H), 7.39–7.30 (m, 3 H), 7.20 (dd, J = 9.2, 7.2 Hz, 1 H), 6.58 (dd,
J = 9.2, 1.2 Hz, 1 H), 6.53 (dd, J = 7.1, 1.3 Hz, 1 H), 5.37 (t, J =
1.8 Hz, 1 H), 5.27 (app s, 2 H), 4.64 (t, J = 2.0 Hz, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δC = 162.7, 141.9, 139.3, 138.9, 128.5 (2
C), 128.2, 127.6, 126.2 (2 C), 119.1, 111.3 (2 C), 51.8 ppm. HRMS
(TOF ESI+): calcd. for C14H13NO79Br+ [M + H]+ 290.0181; found
290.0190; Δ = 3.1 ppm.
leum ether/EtOAc, 4:1) to give 10f (0.31 g, 0.98 mmol, 91%) as a
white solid; m.p. 103–104 °C. Rf = 0.39 (40–60 petroleum ether/
EtOAc, 7:3). IR (neat): ν
= 3095 (w), 3065 (w), 3028 (w), 2961
˜
max
(w), 1704 (str), 1647 (str), 1597 (str), 1526 (w), 1496 (w), 1425 (str),
1385 (med), 1351 (med), 1336 (med), 1284 (med), 1205 (w), 1178
(w), 1158 (w), 1129 (w), 1105 (w) cm–1. 1H NMR (400 MHz,
CDCl3): δH = 7.43 (dt, J = 8.2, 1.3 Hz, 2 H), 7.32–7.21 (m, 3 H),
6.14 (s, 1 H), 5.86 (ddt, J = 17.2, 10.4, 5.1 Hz, 1 H), 5.30–5.19 (m,
2 H), 5.08 (s, 2 H), 4.68 (dt, J = 5.5, 1.5 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δC = 160.6, 150.3, 136.3 (2 C), 130.9, 129.0 (2
C), 128.5 (2 C), 127.8, 118.7, 106.7, 51.5, 44.9 ppm. HRMS (TOF
ESI+): calcd. for C14H14N2O279Br+ [M + H]+ 321.0239; found
321.0246; Δ = 2.2 ppm.
Methyl 2-{[6-Bromo-2-oxopyridin-1(2H)-yl]methyl}acrylate (10d):
General procedure 1 was followed by using the allylic bromide. The
crude reaction material was purified by chromatography on a silica
gel column (40–60 petroleum ether/EtOAc, 4:1) to give 10d (87%
yield) as a brown solid; m.p. 69–70 °C. Rf = 0.10 (40–60 petroleum
ether/EtOAc, 4:1). IR (CDCl ): ν
= 3113 (w), 2953 (w), 1718
˜
3
max
(str), 1665 (str), 1589 (med), 1510 (str) cm–1. H NMR (500 MHz,
CDCl3): δH = 7.21 (dd, J = 9.3, 7.2 Hz, 1 H), 6.57 (dd, J = 9.3,
1.2 Hz, 1 H), 6.53 (dd, J = 7.2, 1.2 Hz, 1 H), 6.30 (t, J = 1.9 Hz, 1
H), 5.20 (t, J = 1.9 Hz, 1 H), 5.16 (t, J = 1.9 Hz, 2 H), 3.83 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δC = 165.6, 162.6, 139.5,
134.1, 127.2, 124.3, 119.2, 111.4, 52.1, 49.0 ppm. HRMS (FTMS
ESI+): calcd. for C10H10NO379BrNa+ [M + Na]+ 293.9742; found
293.9750; Δ = 2.7 ppm.
1
1,6-Diallylpyridin-2(1H)-one (12a): General procedure 2 was fol-
lowed by using 1-allyl-6-bromopyridin-2(1H)-one (10a) and allyltri-
butyltin. The crude reaction material was purified by column
chromatography (silica/KF, 9:1; 40–60 petroleum ether/EtOAc, 7:3
then 6:4) to yield 12a (91% yield) as a yellow solid; m.p. 38–41 °C.
R = 0.25 (40–60 petroleum ether/EtOAc, 1:1). IR (neat): ν
=
˜
f
max
2960 (w), 1657 (str), 1582 (str), 1550 (str), 1429 (med), 1146
1
(med) cm–1. H NMR (400 MHz, CDCl3): δH = 7.24 (dd, J = 9.1,
Diethyl 1-Allyl-6-bromo-2-oxo-1,2-dihydropyridine-3,5-dicarboxyl-
ate (10e): To a stirred solution of diethyl 1-allyl-6-hydroxy-2-oxo-
6.9 Hz, 1 H), 6.49 (dd, J = 9.2, 1.1 Hz, 1 H), 6.03 (app dt, J = 6.9,
0.6 Hz, 1 H), 5.98–5.80 (m, 2 H), 5.21 (app dq, J = 10.2, 1.4 Hz, 1
1,2-dihydropyridine-3,5-dicarboxylate (1.00 g, 3.15 mmol) in anhy- H), 5.18–5.11 (m, 1 H), 5.07 (app dq, J = 17.2, 1.4 Hz, 1 H), 4.98–
drous DMF (47.3 mL) at 0 °C was added PBr3 (0.50 mL,
4.73 mmol) dropwise. The mixture was stirred at 0 °C for 1 h and
then warmed to room temperature over 8 h. The reaction was mon-
4.90 (m, 1 H), 4.69 (ddd, J = 4.7, 2.0, 1.8 Hz, 2 H), 3.33 (d, J =
6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δC = 163.4, 147.6,
138.9, 133.1, 132.6, 118.5, 118.3, 116.2, 106.6, 45.6, 36.8 ppm.
5772
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5767–5776

Concise Synthesis of Substituted Quinolizin-4-ones
HRMS (TOF ESI+): calcd. for C11H14NO+ [M + H]+ 176.1075;
found 176.1070; Δ = –2.8 ppm.
17.1, 10.3, 6.0 Hz, 1 H), 5.34 (t, J = 1.6 Hz, 1 H), 5.19 (dd, J =
10.3, 1.3 Hz, 1 H), 5.14–5.00 (m, 3 H), 4.56 (t, J = 1.9 Hz, 1 H),
3.32 (app d, J = 6.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δC = 163.5, 147.8, 142.7, 139.0, 138.8, 133.2, 128.6 (2 C), 128.3,
126.0 (2 C), 118.5, 118.4, 110.9, 106.8, 46.2, 37.0 ppm. HRMS
(TOF ESI+): calcd. for C17H18NO+ [M + H]+ 252.1388; found
252.1396; Δ = 3.2 ppm.
1-Allyl-6-(2-methylallyl)pyridin-2(1H)-one (12b): General procedure
2 was followed by using 1-allyl-6-bromopyridin-2(1H)-one (10a)
and 2-methylallyltributyltin. The crude reaction material was puri-
fied by column chromatography (silica/KF, 9:1; 40–60 petroleum
ether/EtOAc, 7:3 then 6:4) to give 12b (72% yield) as a pale yellow
oil; Rf = 0.17 (40–60 petroleum ether/EtOAc, 1:1). IR (CH2Cl2):
6-(2-Methylallyl)-1-(2-phenylallyl)pyridin-2(1H)-one (12f): General
ν
= 3082 (w), 2926 (w), 1656 (str), 1582 (str), 1549 (str), 1430 procedure 2 was followed by using 6-bromo-1-(2-phenylallyl)pyr-
˜
max
(med), 1377 (w), 1336 (w), 1291 (w), 1242 (w), 1146 (med) cm–1.
1H NMR (400 MHz, CDCl3): δH = 7.20 (dd, J = 9.1, 6.8 Hz, 1 H),
6.43 (dd, J = 9.1, 1.3 Hz, 1 H), 5.98 (dd, J = 6.8, 1.3 Hz, 1 H), 5.87
(ddt, J = 17.2, 10.4, 4.8 Hz, 1 H), 5.09 (dq, J = 10.5, 1.7 Hz, 1 H),
4.89 (dq, J = 17.2, 1.6 Hz, 1 H), 4.87 (m, 1 H), 4.60 (dt, J = 4.8,
1.8 Hz, 2 H), 4.56 (m, 1 H), 3.20 (s, 2 H), 1.70 (d, J = 0.5 Hz, 3
idin-2(1H)-one (10c) and 2-methylallyltributyltin. The crude reac-
tion material was purified by column chromatography (silica/KF,
9:1; 40–60 petroleum ether/EtOAc, 4:1 then 3:1) to give 12f (52%
yield) as a yellow oil; Rf = 0.10 (40–60 petroleum ether/EtOAc,
1:1). IR (neat): ν
= 3067 (w), 2967 (w), 2945 (w), 1653 (str),
˜
max
1575 (str), 1545 (str), 1493 (w), 1443 (w), 1426 (med), 1399 (w),
H) ppm. 13C NMR (100 MHz, CDCl3): δC = 163.5, 147.2, 142.3, 1377 (w), 1353 (w), 1320 (w), 1304 (w), 1251 (w), 1169 (w), 1143
138.8, 132.8, 118.3, 116.0, 113.5, 107.6, 45.6, 41.1, 22.6 ppm.
HRMS (FTMS ESI+): calcd. for C12H16ON+ [M + H]+ 190.1226;
found 190.1222; Δ = –2.2 ppm.
(med) cm–1. 1H NMR (400 MHz, CDCl3): δH = 7.48–7.26 (m, 2
H), 7.40–7.26 (m, 4 H), 6.54 (dd, J = 9.2, 1.1 Hz, 1 H), 6.08 (dd,
J = 6.8, 1.4 Hz, 1 H), 5.34 (t, J = 1.7 Hz, 1 H), 5.05 (br. s, 2 H),
4.91 (t, J = 1.2 Hz, 1 H), 4.60 (app s, 1 H), 4.57 (t, J = 1.9 Hz, 1
H), 3.23 (s, 2 H), 1.71 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δC = 163.6, 147.4, 143.0, 141.4, 139.0, 138.4, 128.6 (2 C), 128.2,
126 (2 C), 118.5, 113.6, 110.8, 107.7, 46.2, 41.4, 22.6 ppm. HRMS
(FTMS ESI+): calcd. for C18H20ON+ [M + H]+ 266.1539; found
266.1538; Δ = –0.6 ppm.
1,6-Bis(2-methylallyl)pyridin-2(1H)-one (12c): General procedure 2
was followed by using 6-bromo-1-(2-phenylallyl)pyridin-2(1H)-one
(10c) and 2-methylallyltributyltin. The crude reaction material was
purified by column chromatography (silica/KF, 9:1; 40–60 petro-
leum ether/EtOAc, 7:3 then 6:4) to yield 12c (75% yield) as an
orange oil; Rf = 0.13 (40–60 petroleum ether/EtOAc, 1:1). IR
(neat): ν
= 3080 (w), 2973 (w), 2937 (w), 1656 (str), 1582 (str), Methyl 2-{[6-Allyl-2-oxopyridin-1(2H)-yl]methyl}acrylate (12g): Ge-
˜
max
1549 (str), 1432 (med), 1403 (w), 1377 (w), 1309 (w), 1260 (w), 1239
neral procedure 2 was followed by using methyl 2-{[6-bromo-2-
(w), 1142 (med) cm–1. 1H NMR (400 MHz, CDCl3): δH = 7.22 (dd, oxopyridin-1(2H)-yl]methyl}acrylate (10d) and allyltributyltin. The
J = 9.2, 6.8 Hz, 1 H), 6.46 (dd, J = 9.1, 1.0 Hz, 1 H), 6.01 (dd, J
= 6.8, 1.0 Hz, 1 H), 4.89 (t, J = 1.2 Hz, 1 H), 4.78 (t, J = 1.2 Hz,
1 H), 4.58 (s, 1 H), 4.55 (app s, 2 H), 4.33 (s, 1 H), 3.18 (s, 2 H),
crude reaction material was purified by column chromatography
(silica/KF, 9:1; 40–60 petroleum ether/EtOAc, 3:2) to give 12g (82%
yield) as a yellow oil; R = 0.30 (EtOAc). IR (neat): ν
= 2953
˜
f
max
1.75 (s, 3 H), 1.71 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δC (w), 1717 (med), 1659 (str), 1583 (med), 1548 (str), 1435 (med),
1
= 163.6, 147.4, 141.4, 140.3, 138.8, 118.3, 113.5, 109.5, 107.5, 48.0,
41.2, 22.6, 20.5 ppm. HRMS (FTMS ESI+): calcd. for C13H18ON+
[M + H]+ 204.1383; found 204.1382; Δ = –0.5 ppm.
1369 (w), 1299 (med), 1268 (med), 1195 (med), 1134 (str) cm–1. H
NMR (400 MHz, CDCl3): δH = 7.29 (dd, J = 9.1, 6.9 Hz, 1 H),
6.52 (dd, J = 9.0 Hz, 1 H), 6.08 (dd, J = 6.8 Hz, 1 H), 5.84 (ddt, J
= 17.1, 10.2, 6.1 Hz, 1 H), 6.23 (t, J = 1.6 Hz, 1 H), 5.20 (app dq,
J = 10.2, 6.1 Hz, 1 H), 5.13 (t, J = 1.9 Hz, 1 H), 5.08 (app dq, J =
17.1, 1.2 Hz, 1 H), 4.93 (dd, J = 1.9, 1.6 Hz, 2 H), 3.78 (s, 3 H),
3.24 (d, J = 6.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δC
= 165.8, 163.3, 147.4, 139.1, 134.9, 132.8, 124.3, 118.7, 118.4, 106.9,
52.2, 43.6, 37.0 ppm. HRMS (FTMS ESI+): calcd. for
C13H16O3N+ [M + H]+ 234.1136; found 234.1127; Δ = –3.9 ppm.
6-Allyl-1-(2-methylallyl)pyridin-2(1H)-one (12d): General procedure
2 was followed by using 6-bromo-1-(2-methylallyl)pyridin-2(1H)-
one (10b) and allyltributyltin. The crude reaction material was puri-
fied by column chromatography (silica/KF, 9:1; 40–60 petroleum
ether/EtOAc, 7:3 then 6:4) to yield 12d (92% yield) as a yellow oil;
R = 0.24 (40–60 petroleum ether/EtOAc, 1:1). IR (neat): ν
=
˜
f
max
3085 (w), 2938 (w), 1655 (str), 1580 (med), 1548 (str), 1431 (br.,
med), 1377 (w), 1311 (w), 1235 (w), 1142 (med) cm–1. 1H NMR
Methyl 2-{[6-(2-Methylallyl)-2-oxopyridin-1(2H)-yl]methyl}acrylate
(400 MHz, CDCl3): δH = 7.25 (dd, J = 9.1, 6.9 Hz, 1 H), 6.51 (d, (12h): General procedure 2 was followed by using methyl 2-{[6-
J = 9.0 Hz, 1 H), 6.03 (d, J = 6.8 Hz, 1 H), 5.86 (ddt, J = 17.1, bromo-2-oxopyridin-1(2H)-yl]methyl}acrylate (10d) and methylall-
10.2, 6.1 Hz, 1 H), 5.20 (dd, J = 10.2, 1.3 Hz, 1 H), 5.07 (dd, J =
17.2, 1.5 Hz, 1 H), 4.82 (t, J = 0.9 Hz, 1 H), 4.61 (app s, 2 H), 4.36
(t, J = 0.7 Hz, 1 H), 3.29 (d, J = 6.1 Hz, 2 H), 1.78 (s, 3 H) ppm.
yltributyltin. The crude reaction material was purified by column
chromatography (silica/KF, 9:1; 40–60 petroleum ether/EtOAc, 3:2)
to give 12h (62% yield) as an orange oil; Rf = 0.16 (40–60 petro-
13C NMR (100 MHz, CDCl3): δC = 163.4, 147.8, 140.0, 138.9, leum ether/EtOAc, 1:1). IR (CH Cl ): ν
= 2922 (w), 2850 (w),
˜
max
2
2
133.2, 118.4, 118.2, 109.7, 106.6, 48.0, 36.8, 20.4 ppm. HRMS
(TOF ESI+): calcd for C12H16NO+ [M + H]+ 190.1232; found
190.1238; Δ = 3.2 ppm.
1724 (str), 1663 (str), 1583 (str), 1553 (str), 1435 (med), 1408 (w),
1392 (w), 1298 (w), 1268 (str), 1197 (w), 1170 (w), 1147 (str) cm–1.
1H NMR (500 MHz, CDCl3): δH = 7.30 (dd, J = 9.2, 6.8 Hz, 1 H),
6.53 (dd, J = 9.2, 1.2 Hz, 1 H), 6.24 (t, J = 1.8 Hz, 1 H), 6.08 (dd,
J = 6.7, 1.2 Hz, 1 H), 5.15 (t, J = 1.9 Hz, 1 H), 4.95 (s, 1 H), 4.92
(t, J = 1.8 Hz, 2 H), 4.65 (s, 1 H), 3.81 (s, 3 H), 3.17 (s, 2 H), 1.74
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 165.8, 163.5,
147.0, 141.0, 139.0, 135.1, 124.2, 118.5, 113.9, 107.8, 52.1, 43.7,
41.4, 22.5 ppm. HRMS (TOF ESI+): calcd. for C14H17NO3Na+ [M
+ Na]+ 270.1106; found 270.1119; Δ = 4.8 ppm.
6-Allyl-1-(2-phenylallyl)pyridin-2(1H)-one (12e): General procedure
2 was followed by using 6-bromo-1-(2-phenylallyl)pyridin-2(1H)-
one (10c) and allyltributyltin. The crude reaction material was puri-
fied by column chromatography (silica/KF, 9:1; 40–60 petroleum
ether/EtOAc, 4:1 then 7:3) to give 12e (88% yield) as a yellow oil;
R = 0.21 (40–60 petroleum ether/EtOAc, 1:1). IR (neat): ν
=
˜
f
max
2951 (w), 1658 (str), 1581 (med), 1548 (str), 1495 (w), 1429 (med),
1290 (w), 1238 (w), 1165 (w), 1143 (med) cm–1. 1H NMR Diethyl
(400 MHz, CDCl3): δH = 7.52–7.42 (m, 2 H), 7.40–7.22 (m, 4 H), (12i): General procedure 2 was followed by using diethyl 1-allyl-6-
6.54 (d, J = 9.1 Hz, 1 H), 6.08 (d, J = 6.8 Hz, 1 H), 5.87 (ddt, J = bromo-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate (10e) and allyl-
1,6-Diallyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate
Eur. J. Org. Chem. 2014, 5767–5776
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5773

T. A. Alanine, W. R. J. D. Galloway, T. M. McGuire, D. R. Spring
(w), 1703 (med), 1655 (str), 1620 (med), 1496 (w), 1444 (str), 1391
FULL PAPER
tributyltin. The crude reaction material was purified by column
chromatography (silica/KF, 9:1; 40–60 petroleum ether/EtOAc,
85:15, 82:18, and then 80:20) to give 12i (74% yield) as a white
crystalline solid; m.p. 37–38 °C. Rf = 0.33 (40–60 petroleum ether/
1
(med), 1342 (med), 1292 (w), 1212 (w) cm–1. H NMR (400 MHz,
CDCl3): δH = 7.48–7.42 (m, 2 H), 7.31–7.20 (m, 3 H), 5.86 (ddt, J
= 17.2, 10.4, 4.9 Hz, 1 H), 5.64 (s, 1 H), 5.19 (dq, J = 10.4, 0.7 Hz,
EtOAc, 1:1). IR (neat): ν
= 3248 (w), 3082 (w), 2979 (w), 2923 1 H), 5.12 (s, 2 H), 5.06 (dq, J = 17.2, 0.7 Hz, 1 H), 4.99 (t, J =
˜
max
(w), 1742 (med), 1703 (str), 1672 (str), 1603 (w), 1528 (med), 1432 1.2 Hz, 1 H), 4.77 (t, J = 1.2 Hz, 1 H), 4.43 (dt, J = 4.8, 1.7 Hz, 2
(med), 1413 (med), 1399 (med), 1380 (med), 1365 (med), 1309
(med), 1290 (med), 1229 (str), 1199 (med), 1172 (med), 1144
H), 3.12 (s, 2 H), 1.76 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δC = 162.3, 152.6, 152.2, 139.4, 136.9, 132.5, 128.9 (2 C), 128.4 (2
(med) cm–1. 1H NMR (400 MHz, CDCl3): δH = 8.71 (s, 1 H), 5.99– C), 127.5, 116.7, 115.0, 102.5, 46.5, 44.5, 40.4, 22.5 ppm. HRMS
5.89 (m, 2 H), 5.23 (app d, J = 11.0 Hz, 1 H), 5.20 (dd, J = 11.3, (TOF ESI+): calcd. for C18H20O2N2Na+ [M + Na]+ 319.1422;
0.8 Hz, 1 H), 5.04 (d, J = 17.3 Hz, 1 H), 4.98 (dd, J = 17.4, 0.7 Hz,
1 H), 4.82 (d, J = 4.7 Hz, 2 H), 4.38 (q, J = 7.1 Hz, 2 H), 4.31 (q,
J = 7.1 Hz, 2 H), 4.02 (d, J = 5.2 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3
H), 1.36 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δC = 164.8, 164.4, 159.2, 158.6, 144.9, 132.4, 131.7, 117.7, 117.6,
117.3, 108.8, 61.4, 61.3, 46.7, 34.2, 14.3, 14.2 ppm. HRMS (TOF
ESI+): calcd. for C17H22NO5+ [M + H]+ 320.1498; found 320.1511;
Δ = 4.1 ppm.
found 319.1438; Δ = 5.0 ppm.
4H-Quinolizin-4-one (14a): General procedure 3 was followed by
using 1,6-diallylpyridin-2(1H)-one (12a). The crude reaction mix-
ture was purified by chromatography on a silica gel column (40–60
petroleum ether/EtOAc, 2:3) to give 14a (68% yield over 2 steps)
as a yellow solid, m.p. 54–56 °C (Et2O/hexane); ref.[2] m.p. 71–
72 °C. Rf = 0.22 (EtOAc/40–60 petroleum ether, 4:1). IR (CDCl3):
ν
= 1663 (med), 1633 (med), 1546 (med), 1475 (str) cm–1. 1H
˜
max
NMR (500 MHz, CDCl3): δH = 9.13 (dd, J = 7.6, 0.6 Hz, 1 H),
7.64 (app dd, J = 8.5, 7.6 Hz, 1 H), 7.47 (app d, J = 8.9 Hz, 1 H),
7.35–7.31 (m, 1 H), 7.00 (dd, J = 6.7, 1.1 Hz, 1 H), 6.68–6.63 (m,
2 H) ppm. 13C NMR (125 MHz, CDCl3): δc = 158.7, 142.6, 138.1,
129.3, 127.3, 125.4, 115.1, 109.1, 103.5 ppm. HRMS (FTMS
ESI+): calcd. for C9H8NO+ [M + H]+ 146.0600; found 146.0600;
Δ = 0.1 ppm. This data is in accordance with that previously re-
ported.[25]
Diethyl 1-Allyl-6-(2-methylallyl)-2-oxo-1,2-dihydropyridine-3,5-di-
carboxylate (12j): General procedure 2 was followed by using di-
ethyl 1-allyl-6-bromo-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate
(10e) and methylallyltributyltin. The crude reaction material was
purified by column chromatography (silica/KF, 9:1; 40–60 petro-
leum ether/EtOAc, 17:3 then 4:1) to give 12j (16% yield) as a yellow
oil; R = 0.38 (40–60 petroleum ether/EtOAc, 1:1). IR (neat): ν
˜
f
max
= 2980 (w), 2931 (w), 1742 (med), 1709 (str), 1672 (str), 1603 (w),
1530 (str), 1434 (w), 1407 (w), 1377 (w), 1367 (w), 1307 (med), 1278
8-Methyl-4H-quinolizin-4-one (14b): General procedure 4 was fol-
lowed by using 1-allyl-6-(2-methylallyl)pyridin-2(1H)-one (12b).
The crude product material was purified by chromatography on a
silica gel column (40–60 petroleum ether/EtOAc, 2:3) to give 14b
(33% yield over 2 steps) as a yellow/brown crystalline solid, m.p.
132–133 °C; ref.[26] m.p. 135 °C. Rf = 0.11 (40–60 petroleum ether/
(w), 1228 (str), 1143 (str) cm–1. 1H NMR (500 MHz, CDCl3): δH
=
8.73 (s, 1 H), 5.94 (ddt, J = 17.4, 10.5, 4.9 Hz, 1 H), 5.22 (dq, J =
10.4, 0.6 Hz, 1 H), 5.04 (dq, J = 17.4, 0.6 Hz, 1 H), 4.86 (s, 1 H),
4.74 (d, J = 4.8 Hz, 2 H), 4.38 (q, J = 7.0 Hz, 2 H), 4.32–4.27 (m,
3 H), 3.95 (s, 2 H), 1.87 (s, 3 H), 1.39 (t, J = 7.0 Hz, 3 H), 1.35 (t,
J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 164.8,
164.4, 159.2, 158.8, 144.9, 141.0, 131.9, 117.6, 117.2, 111.5, 109.1,
61.4, 61.2, 47.1, 37.6, 23.5, 14.3, 14.2 ppm. HRMS (TOF ESI+):
calcd. for C18H23NO5Na+ [M + Na]+ 356.1474; found 356.1474; Δ
= 0.0 ppm.
EtOAc, 3:7). IR (neat): ν
= 3044 (w), 2918 (w), 1660 (med),
˜
max
1634 (str), 1529 (med), 1481 (str), 1451 (med), 1431 (med), 1367
(w), 1342 (med), 1260 (w), 1179 (w), 1165 (med), 1144 (med) cm–1.
1H NMR (500 MHz, CDCl3): δH = 9.01 (d, 1 H, J = 7.6 Hz), 7.58
(dd, J = 8.5, 7.6 Hz, 1 H), 7.21 (s, 1 H), 6.82 (app dd, J = 7.6,
1.8 Hz, 1 H), 6.51 (d, J = 7.6 Hz, 1 H), 6.50 (d, J = 8.6 Hz, 1 H),
2.38 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 158.6, 142.9,
140.6, 138.2, 126.8, 123.3, 117.8, 107.5, 102.1, 21.1 ppm. HRMS
(FTMS ESI+): calcd. for C10H10ON+ [M + H]+ 160.0757; found
160.0756; Δ = –0.6 ppm. This data is in accordance with that pre-
viously reported.[26]
1,6-Diallyl-3-benzylpyrimidine-2,4(1H,3H)-dione (12k): General
procedure 2 was followed by using 1-allyl-3-benzyl-6-bromopyr-
imidine-2,4(1H,3H)-dione (10f) and allyltributyltin. The crude re-
action material was purified by column chromatography (silica/KF,
9:1; 40–60 petroleum ether/EtOAc, 9:1 then 4:1) to give 12k (74%
yield) as a yellow oil; Rf = 0.23 (40–60 petroleum ether/EtOAc,
7:3). IR (neat): νmax = 2983 (w), 1702 (med), 1655 (str), 1619 (med),
˜
7,8-Dimethyl-4H-quinolizin-4-one (14c): General procedure 5 was
followed by using 1,6-bis(2-methylallyl)pyridin-2(1H)-one (12c).
The crude product material was purified by chromatography on a
silica gel column (40–60 petroleum ether/EtOAc, 1:3) to yield 14c
(75% yield over 2 steps) as a green/brown crystalline solid; m.p.
1586 (w), 1496 (w), 1444 (str), 1393 (med), 1341 (med), 1292 (w),
1
1267 (w), 1211 (w), 1197 (w), 1157 (w), 1107 (w) cm–1. H NMR
(500 MHz, CDCl3): δH = 7.45 (dd, J = 7.2, 3.5 Hz, 2 H), 7.31–7.21
(m, 3 H), 5.92–5.76 (m, 2 H), 5.66 (s, 1 H), 5.29 (dq, J = 9.0,
1.3 Hz, 1 H), 5.24–5.16 (m, 2 H), 5.15 (s, 2 H), 5.08 (dq, J = 17.3,
0.7 Hz, 1 H), 4.49 (dt, J = 4.9, 1.8 Hz, 2 H), 3.21 (ddd, J = 6.3,
2.2, 1.4 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 162.2,
152.1, 152.1, 136.9, 132.3, 131.2, 128.9 (2 C), 128.4 (2 C), 127.5,
120.0, 116.8, 110.7, 46.3, 44.7, 35.9 ppm. HRMS (FTMS ESI+):
126–129 °C. R = 0.23 (EtOAc). IR (neat): ν
= 2957 (w), 2924
˜
f
max
(w), 1731 (w), 1656 (str), 1637 (str), 1566 (w), 1529 (str), 1504 (w),
1482 (str), 1441 (med), 1420 (med), 1402 (med), 1389 (w), 1372
(med), 1322 (med), 1220 (w), 1180 (med), 1149 (med), 1130
1
(med) cm–1. H NMR (500 MHz, CDCl3): δH = 8.88 (s, 1 H), 7.52
+
calcd. for C17H11O2N2 [M + H]+ 283.1452; found 283.1444; Δ =
(dd, J = 8.7, 7.7 Hz, 1 H), 7.19 (s, 1 H), 6.48 (d, J = 7.6 Hz, 1 H),
6.45 (d, J = 8.8 Hz, 1 H), 2.30 (s, 3 H), 2.24 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δC = 158.2, 142.1, 141.8, 137.4, 125.9,
124.6, 123.5, 106.9, 101.8, 19.2, 16.9 ppm. HRMS (FTMS ESI+):
calcd. for C11H12ON+ [M + H]+ 174.0913; found 174.0912; Δ =
–0.7 ppm.
–2.8 ppm.
1-Allyl-3-benzyl-6-(2-methylallyl)pyrimidine-2,4(1H,3H)-dione
(12l): General procedure 2 was followed by using 1-allyl-3-benzyl-
6-bromopyrimidine-2,4(1H,3H)-dione (10f) and methylallyltri-
butyltin. The crude reaction mixture was purified by column
chromatography (silica/KF, 9:1; 40–60 petroleum ether/EtOAc, 4:1)
to give 12l (80% yield) as a colorless oil; Rf = 0.54 (40–60 petro-
7-Methyl-4H-quinolizin-4-one (14d): General procedure 4 was fol-
lowed by using 6-allyl-1-(2-methylallyl)pyridin-2(1H)-one (12d).
The crude reaction material was purified by chromatography on a
leum ether/EtOAc, 1:1). IR (neat): νmax = 3083 (w), 3031 (w), 2967
˜
5774
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5767–5776

Concise Synthesis of Substituted Quinolizin-4-ones
silica gel column (40–60 petroleum ether/EtOAc, 2:3) to give 14d
(62% yield over 2 steps) as a yellow crystalline solid; m.p. 93–94 °C.
2-oxopyridin-1(2H)-yl]methyl}acrylate (12h). The crude reaction
material was purified by chromatography on a silica gel column
(40–60 petroleum ether/EtOAc, 4:1 then 3:2) to give 14h (25% yield
R = 0.19 (40–60 petroleum ether/EtOAc, 1:3). IR (neat): ν
=
˜
f
max
3090 (w), 3066 (w), 2921 (w), 2858 (w), 1656 (str), 1634 (str), 1536 over 2 steps) as a yellow solid; m.p. 144–146 °C. Rf = 0.50 (EtOAc).
(str), 1505 (w), 1476 (str), 1458 (str), 1394 (med), 1378 (med), 1328 IR (neat): ν = 2954 (w), 2926 (w), 1723 (str), 1666 (str), 1624
˜
max
(w), 1264 (w), 1244 (w), 1209 (w), 1175 (w), 1151 (med), 1122 (med), 1543 (med), 1451 (str), 1456 (med), 1444 (med), 1419 (med),
1
(med) cm–1. H NMR (500 MHz, CDCl3): δH = 8.94 (s, 1 H), 7.58 1402 (med), 1380 (med), 1315 (w), 1280 (str), 1247 (med), 1200
1
(dd, J = 8.7, 7.7 Hz, 1 H), 7.38 (d, J = 9.0 Hz, 1 H), 7.18 (app dd, (w), 1187 (w), 1163 (med), 1109 (med) cm–1. H NMR (500 MHz,
J = 9.0, 1.6 Hz, 1 H), 6.60 (d, J = 7.6 Hz, 1 H), 6.58 (app dd, J =
CDCl3): δH = 9.71 (s, 1 H), 7.64 (dd, J = 8.9, 7.6 Hz, 1 H), 7.21 (s,
8.8, 1.0 Hz, 1 H), 2.36 (app d, J = 1.1 Hz, 3 H) ppm. 13C NMR 1 H), 6.54 (app dd, J = 9.0, 1.1 Hz, 1 H), 6.50 (d, J = 7.6 Hz, 1
(125 MHz, CDCl3): δC = 158.4, 141.4, 137.3, 132.4, 125.0, 124.9,
124.6, 108.7, 103.1, 18.6 ppm. HRMS (FTMS ESI+): calcd. for
C10H10ON+ [M + H]+ 160.0757; found 160.0760; Δ = 1.8 ppm.
H), 3.93 (s, 3 H), 2.62 (app d, J = 0.7 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δC = 165.2, 158.5, 142.5, 139.9, 139.7, 132.6,
125.4, 119.0, 108.9, 101.7, 52.3, 21.1 ppm. HRMS (FTMS ESI+):
calcd. for C12H12O3N+ [M + H]+ 218.0812; found 218.0808; Δ =
–1.7 ppm.
7-Phenyl-4H-quinolizin-4-one (14e): General procedure 4 was fol-
lowed by using 6-allyl-1-(2-phenylallyl)pyridin-2(1H)-one (12e).
The crude reaction material was purified by chromatography on a
silica gel column (40–60 petroleum ether/EtOAc, 2:3) to yield 14e
(72% yield over 2 steps) as a yellow crystalline solid; m.p. 99–
101 °C. Rf = 0.33 (40–60 petroleum ether/EtOAc, 1:3). IR (neat):
Diethyl 4-Oxo-4H-quinolizine-1,3-dicarboxylate (14i): General pro-
cedure 3 was followed by using diethyl 1,6-diallyl-2-oxo-1,2-di-
hydropyridine-3,5-dicarboxylate (12i). The crude reaction material
was purified by chromatography on a silica gel column (40–60 pe-
troleum ether/EtOAc, 1:1 then 2:3) to give 14i (81% yield over 2
steps) as a yellow solid, m.p. 122–124 °C; ref.[27,28] m.p. 131–132
and 135–138 °C. Rf = 0.34 (40–60 petroleum ether/EtOAc, 1:3). IR
ν
= 3059 (w), 2926 (w), 1664 (str), 1616 (str), 1543 (str), 1501
˜
max
(w), 1457 (str), 1392 (str), 1336 (w), 1290 (w), 1266 (w), 1245 (w),
1180 (w), 1156 (med), 1132 (med) cm–1. 1H NMR (500 MHz,
CDCl3): δH = 9.34 (d, J = 0.7 Hz, 1 H), 7.66–7.58 (m, 4 H), 7.52
(d, J = 9.1 Hz, 1 H), 7.46 (dd, J = 7.9, 7.3 Hz, 2 H), 7.39 (tt, J =
7.3, 1.0 Hz, 1 H), 6.65 (d, J = 7.6 Hz, 1 H), 6.62 (app dd, J = 8.8,
0.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 158.7, 141.5,
137.8, 136.2, 129.4, 129.2 (2 C), 128.8, 128.5, 126.8 (2 C), 125.6,
124.4, 109.2, 103.1 ppm. HRMS (FTMS ESI+): calcd. for
C15H12ON+ [M + H]+ 222.0913; found 222.0912; Δ = –0.8 ppm.
(neat): νmax = 3139 (w), 2984 (w), 2905 (w), 1713 (med), 1674 (str),
˜
1622 (str), 1582 (str), 1518 (med), 1494 (str), 1437 (med), 1390 (w),
1373 (med), 1350 (med), 1324 (w), 1295 (med), 1255 (w), 1203 (str),
1169 (med), 1149 (str), 1110 (med) cm–1. 1H NMR (500 MHz,
CDCl3): δH = 9.52 (d, J = 7.1 Hz, 1 H), 9.36 (d, J = 9.1 Hz, 1 H),
9.15 (s, 1 H), 7.87 (app ddd, J = 9.1, 6.8, 1.4 Hz, 1 H), 7.35 (app
td, J = 7.0, 1.3 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 4.38 (q, J =
7.1 Hz, 2 H), 1.45–1.38 (m, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δC = 165.4, 164.8, 155.5, 147.0, 144.4, 136.8, 130.3, 124.4,
117.6, 105.6, 101.9, 61.3, 61.2, 14.4 (2 C) ppm. HRMS (TOF
ESI+): calcd. for C15H16NO5+ [M + H]+ 290.1028; found 290.1035;
Δ = 2.4 ppm. This data is consistent with that previously re-
ported.[28]
8-Methyl-7-phenyl-4H-quinolizin-4-one (14f): General procedure 5
was followed by using 6-(2-methylallyl)-1-(2-phenylallyl)pyridin-
2(1H)-one (12f). The crude reaction mixture was purified by
chromatography on a silica gel column (40–60 petroleum ether/
EtOAc, 3:2 then 1:1) to give 14f (36% yield over 2 steps) as a yellow
wax; R = 0.50 (EtOAc). IR (neat): νmax = 3057 (w), 2958 (w), 2925
˜
f
(w), 2854 (w), 1719 (w), 1659 (med), 1626 (str), 1603 (w), 1540
(med), 1498 (w), 1475 (str), 1419 (w), 1401 (med), 1378 (w), 1319
(w), 1260 (w), 1181 (w), 1154 (str) cm–1. 1H NMR (500 MHz,
CDCl3): δH = 9.02 (s, 1 H), 7.63 (dd, J = 8.8, 7.7 Hz, 1 H), 7.49–
7.37 (m, 6 H), 6.58 (d, J = 7.6 Hz, 1 H), 6.54 (d, J = 8.8 Hz, 1 H),
2.30 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 158.6, 142.1,
140.3, 138.0, 136.3, 131.6, 129.4 (2 C), 128.5 (2 C), 128.2, 126.2,
124.4, 107.6, 101.7, 20.3 ppm. HRMS (TOF ESI+): calcd. for
C16H14ON+ [M + H]+ 236.1075; found 236.1082; Δ = 3.0 ppm.
Diethyl 8-Methyl-4-oxo-4H-quinolizine-1,3-dicarboxylate (14j): Ge-
neral procedure 4 was followed by using diethyl 1-allyl-6-(2-methyl-
allyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxylate (12j). The crude
reaction material was purified by chromatography on a silica gel
column (40–60 petroleum ether/EtOAc, 3:2 then 1:1) to give 14j
(22% yield over 2 steps) as a yellow wax; Rf = 0.25 (40–60 petro-
leum ether/EtOAc, 1:1). IR (neat): νmax = 3084 (w), 2979 (w), 2926
˜
(w), 2854 (w, C–H), 1739 (med), 1691 (str), 1670 (str), 1634 (med),
1584 (med), 1517 (med), 1501 (str), 1461 (med), 1390 (w), 1367
Methyl 4-Oxo-4H-quinolizine-7-carboxylate (14g): General pro-
cedure 4 was followed by using methyl 2-{[6-allyl-2-oxopyridin-
1(2H)-yl]methyl}acrylate (12g). The crude reaction mixture was
purified by chromatography on a silica gel column (40–60 petro-
leum ether/EtOAc, 2:3) to give 14g (40% yield over 2 steps) as a
(med), 1320 (med), 1294 (med), 1259 (w), 1215 (str), 1174 (med),
1
1140 (med), 1108 (med) cm–1. H NMR (500 MHz, CDCl3): δH
=
9.44 (d, J = 7.0 Hz, 1 H), 9.19 (s, 1 H), 9.15 (s, 1 H), 7.21 (dd, J =
7.0, 0.9 Hz, 1 H), 4.44 (q, J = 7.3 Hz, 2 H), 4.39 (q, J = 7.3 Hz, 2
H), 2.58 (s, J = 0.9 Hz, 3 H, d), 1.45–1.40 (m, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δC = 165.6, 165.0, 155.6, 149.7, 146.8, 144.6,
129.9, 123.1, 120.0, 104.4, 101.0, 61.1, 60.9, 22.1, 14.5, 14.4 ppm.
HRMS (TOF ESI+): calcd. for C16H18O5N+ [M + H]+ 304.1185;
yellow solid; m.p. 121–122 °C. R = 0.53 (EtOAc). IR (neat): ν
˜
f
max
= 3078 (w), 2924 (w), 2850 (w), 1718 (str), 1664 (str), 1630 (str),
1619 (str), 1554 (str), 1489 (str), 1451 (str), 1438 (str), 1397 (str),
1369 (med), 1327 (med), 1293 (str), 1261 (str), 1240 (str), 1197
(med), 1179 (med), 1145 (med), 1116 (str) cm–1. 1H NMR
(500 MHz, CDCl3): δH = 9.76 (s, 1 H), 7.74 (app dd, J = 9.0,
1.0 Hz, 1 H), 7.68 (dd, J = 9.0, 7.5 Hz, 1 H), 7.42 (d, J = 9.0 Hz,
1 H), 6.65 (d, J = 9.0 Hz, 1 H), 6.62 (d, J = 7.5 Hz, 1 H), 3.97 (s,
3 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 164.8, 158.8, 142.5,
139.5, 131.8, 127.5, 125.3, 118.3, 110.7, 103.3, 52.5 ppm. HRMS
(FTMS ESI+): calcd. for C11H10O3N+ [M + H]+ 204.0655; found
204.0655; Δ = –0.1 ppm.
found 304.1199,
Δ =
4.6 ppm; calcd. for C16H17O5NNa+
[M + Na]+ 326.1004; found 326.1018, Δ = 4.3 ppm.
2-Benzyl-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione (14k): General
procedure 3 was followed by using 1,6-diallyl-3-benzylpyrimidine-
2,4(1H,3H)-dione (12k). The crude reaction material was purified
by HPLC (30–45% solvent B, 20 min, 200 μL injections of
30 mgmL–1 sample) to give 14k (30% yield) as a crystalline yellow
solid; m.p. 158–160 °C. Rf = 0.18 (40–60 petroleum ether/EtOAc,
Methyl 8-Methyl-4-oxo-4H-quinolizine-7-carboxylate (14h): Gene-
1:1). IR (neat): ν
= 3081 (w), 2926 (w), 1704 (med), 1662 (str),
˜
max
ral procedure 5 was followed by using methyl 2-{[6-(2-methylallyl)-
1639 (str), 1579 (str), 1543 (str), 1493 (med), 1455 (w), 1424 (med),
Eur. J. Org. Chem. 2014, 5767–5776
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5775

T. A. Alanine, W. R. J. D. Galloway, T. M. McGuire, D. R. Spring
FULL PAPER
[12] For examples, see: a) A. Núñez, A. M. Cuadro, J. Alvarez-
Builla, J. J. Vaquero, Chem. Commun. 2006, 25, 2690–2692; b)
A. Núñez, B. Abarca, A. M. Cuadro, J. Alvarez-Builla, J. J. Va-
quero, J. Org. Chem. 2009, 74, 4166–4176; c) A. Núñez, A. M.
Cuadro, J. Alvarez-Builla, J. J. Vaquero, Org. Lett. 2007, 9,
2977–2980.
1407 (med), 1385 (med), 1362 (w), 1336 (med), 1265 (med), 1207
(w), 1161 (w), 1137 (w), 1116 (w) cm–1. 1H NMR (500 MHz,
CDCl3): δH = 8.19 (d, J = 7.5 Hz, 1 H), 7.51 (d, J = 8.3 Hz, 2 H),
7.33–7.22 (m, 3 H), 6.97 (app ddd, J = 9.1, 7.5, 1.0 Hz, 1 H), 6.79
(d, J = 9.2 Hz, 1 H), 6.33 (app dt, J = 1.2, 7.6 Hz, 1 H), 5.70 (s, 1
H), 5.26 (s, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δC = 160.9,
149.3, 146.3, 136.5, 132.9, 129.1 (2 C), 128.4 (2 C), 127.9, 127.7,
122.7, 110.8, 92.0, 45.0 ppm. HRMS (FTMS ESI+): calcd. for
[13] For recent discussions of chemical space coverage and bioac-
tive compound discovery, see: a) W. R. Pitt, D. M. Parry, B. G.
Perry, C. R. Groom, J. Med. Chem. 2009, 52, 2952–2963; b)
W. R. J. D. Galloway, A. Isidro-Llobet, D. R. Spring, Nature
Commun. 2010, 1, 80; c) J.-L. Reymond, R. van Deursen, L. C.
Blum, L. Ruddigkeit, Med. Chem. Commun. 2010, 1, 30–38.
[14] H. Liu, S.-B. Ko, H. Josien, D. P. Curran, Tetrahedron Lett.
1995, 36, 8917–8920.
+
C15H13O2N2 [M + H]+ 253.0972; found 253.0968; Δ = –1.4 ppm.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra, synthetic routes towards pyridone
10e and uracil derivative 10f, and optimization studies for the RCM
and dehydrogenation steps.
[15] See Supporting Information for details.
[16] V. Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585–
9595.
[17] The allyltributyltin resulted in a high conversion of starting
material after 16 h, whereas the more sterically demanding 2-
methylallyltin coupling partner required significantly longer re-
action times (4 to 6 days) to give acceptable yields.
[18] Tin residues were effectively removed from products 12 by
aqueous extraction with KF solution (10% w/v) and
chromatography on SiO2/KF (9:1) as the stationary phase. For
details, see: D. C. Harrowven, I. L. Guy, Chem. Commun. 2004,
17, 1968–1969.
Acknowledgments
The authors thank AstraZeneca, the European Union (EU), the
Engineering and Physical Sciences Research Council (EPSRC), the
Biotechnology and Biological Sciences Research Council (BBSRC),
the Medical Research Council (MRC), and the Wellcome Trust for
funding.
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Received: May 28, 2014
Published Online: July 25, 2014
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