Synthesis of Fused Pyrimidinone and Quinolone Derivatives in an Automated High-Temperature and High-Pressure Flow Reactor

Article abstract of DOI:10.1021/acs.joc.6b02520

Fused pyrimidinone and quinolone derivatives that are of potential interest to pharmaceutical research were synthesized within minutes in up to 96% yield in an automated Phoenix high-temperature and high-pressure continuous flow reactor. Heterocyclic scaffolds that are either hard to synthesize or require multisteps are readily accessible using a common set of reaction conditions. The use of low-boiling solvents along with the high conversions of these reactions allowed for facile workup and isolation. The methods reported herein are highly amenable for fast and efficient heterocycle synthesis as well as compound scale-ups.

Full text of DOI:10.1021/acs.joc.6b02520

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Article
Synthesis of Fused Pyrimidinone and Quinolone Derivatives in
an Automated High Temperature and High Pressure Flow Reactor
Jennifer Tsoung, Andrew R Bogdan, Stanislaw Kantor,
Ying Wang, Manwika Charaschanya, and Stevan W Djuric
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02520 • Publication Date (Web): 21 Dec 2016
Downloaded from http://pubs.acs.org on December 22, 2016
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Synthesis of Fused Pyrimidinone and Quinolone
Derivatives in an Automated High Temperature and
High Pressure Flow Reactor
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Jennifer Tsoung,1 Andrew R. Bogdan,1 Stanislaw Kantor,1 Ying Wang,*,1 Manwika
Charaschanya2 and Stevan W. Djuric1
1Discovery Chemistry and Technologies, AbbVie Inc., 1 North Waukegan Road, North Chicago,
Illinois, 60064
2Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, 66047
KEYWORDS: GouldꢀJacobs, Heterocycle formation, Flow chemistry
Abstract
Fused pyrimidinone and quinolone derivatives that are of potential interest to pharmaceutical
research were synthesized within minutes in up to 96% yield in an automated PhoenixTM highꢀ
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temperature and highꢀpressure continuous flow reactor. Heterocyclic scaffolds that are either
hard to synthesize or require multiꢀsteps, are readily accessible using a common set of reaction
conditions. The use of low boiling solvents along with the high conversions of these reactions
allowed for facile workꢀup and isolation. The methods reported herein are highly amenable for
fast and efficient heterocycle synthesis as well as compound scaleꢀups.
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Introduction
Heterocyclic compounds play a pivotal role in drug discovery, having a ubiquitous presence in
lead chemical series and marketed drugs. For this reason, heterocycle formation is one of the
most predominant reactions used by medicinal chemists.1 As such, new methodologies and
technologies that facilitate the generation of this class of compounds have a significant impact in
the pharmaceutical industry. In this context, thermal cyclization reactions are prevalent in the
synthesis of heterocycles. For example, a wellꢀknown reaction for the construction of 4ꢀ
quinolone scaffolds is the GouldꢀJacobs reaction,2 which is the key step in the synthesis of
antibacterial drugs, Nalidixic acid and Oxolinic acid, as well as in nonꢀsteroidal antiꢀ
inflammatory drugs (NSAID) Floctafenine and Glafenine (Figure 1). However, the Gouldꢀ
Jacobs reaction is a classical thermal cyclization reaction, typically requiring temperatures >200
°C with prolonged heating and high boiling solvents such as diphenyl ether or DowthermTM, thus
complicating workꢀup and product isolation. As a consequence, this powerful transformation is
underutilized in medicinal chemistry research.
Figure 1. Quinoloneꢀcontaining drug compounds
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Of recent interest is the ability to use continuous flow reactors to access novel process
windows such as chemical operations at high temperature and high pressure (>200oC/>50 bar).3
Under these conditions, many common solvents can be utilized near or at their supercritical state
to greatly accelerate chemical transformations. This area is still in its infancy for its application
within pharmaceutical industry, largely due to the lack of suitable instrumentation. In this
context, we have investigated and communicated efficient nucleophilic aromatic substitution
reactions and reagentꢀfree Boc deprotections in the high temperature and high pressure
PhoenixTM flow reactor.4 As part of our ongoing program to explore practical and relevant
synthetic transformations enabled by advanced flow technologies, herein we report a highly
efficient and selective synthesis of fused pyrimidinone and quinolone derivatives via the Gouldꢀ
Jacobs reaction enabled by an automated and modified PhoenixTM system at high temperatures
and pressures.
Results and Discussion
GouldꢀJacobs type reactions involve the condensation of an aryl amine with an
alkoxymethylene compound followed by thermal cyclization to form the corresponding
heterocyclic products (Scheme 1). This transformation normally requires high temperatures and
a short reaction time in order to avoid decomposition,5 thus making this ringꢀclosing reaction an
ideal protocol to adapt to high temperature synthesis in flow. Lengyel and coꢀworkers have
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previously disclosed the synthesis of GouldꢀJacobs and ConradꢀLimpach type products in both
an inꢀhouse built pyrolysis reactor and the XꢀCube Flash, a highꢀtemperature/highꢀpressure
mesoreactor;6 while the successful adaptation of these thermal reactions to high temperature,
high pressure reactors was highly promising, each product was separately optimized and
therefore lacked the generality and synthetic tractability for fast and reliable compound library
synthesis in drug discovery.
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Scheme 1. Reaction sequence leading to GouldꢀJacobs type products
O
Y
N
R
N
4a-j
when X = N
Y
H
CO2Et
Y
N
CO2Et
R
R
EtO
OH
X
X
NH2
Y
1
2
3
R
X = CH, N
Y = CO2Et, COMe, CN
N
5a-h
when X = CH
In order to rapidly screen and optimize reactions, and to facilitate synthesis of libraries of
heterocyclic compounds, we modified the existing PhoenixTM flow reactor to allow for robotic
liquid handling and rapid injections (Figure 2).
Figure 2. Schematic view of automated PhoenixTM Flow Reactor platform
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A twoꢀarm Tecan MiniPrep was installed to handle the autosampler (2) and fraction collector
(5) functions. High pressure operations were provided by a Jasco HPLC pump (3), a
backpressure regulator (BPR) and a Valco injection valve. Modifications to the PhoenixTM
reactor itself included removal of the heat exchanger and pressure relief valve in order to reduce
the path length, and the addition of a temperature probe within the reactor body to better monitor
reaction temperatures.
Alkylidene βꢀdiester 3a was selected as the model substrate for this study. We chose to use
DesignꢀofꢀExperiment software (StatꢀEase Design Expert 7) to enable rapid optimization in
developing a general protocol for this reaction in continuous flow. A series of reactions were
designed and subsequently carried out in THF using a 2 mL stainless steel loop on the
PhoenixTM.7 In this investigation, three key parameters were screened, which included a range of
o
temperatures (250 – 400 C), concentrations (0.05 – 0.4 M in THF), and flow rates (0.5 – 4.0
mL/min).
Figure 3. Reaction optimization to obtain 4a using DesignꢀofꢀExperiment software at (a) flow
rate of 4.0 mL/min (residence time of 0.5 min), (b) 0.5 mL/min (residence time of 4 min)
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250 - 400 oC, 100 bar
N
CO2Et
CO2Et
N
H
N
0.5 - 4.0 mL/min, 2.0 mL loop
N
N
Me
0.05 - 0.40 M in THF
Me
CO2Et
N
Me
O
O
9
6a
3a
4a
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a: Flow rate: 4.0 mL/min
b: Flow rate: 0.5 mL/min
A contour plot of these results illustrated that elevated temperatures, higher concentrations and
fast flow rates were required to achieve high yields of product 4a (Figure 3a). Incomplete
conversion from 3a was observed when lower temperatures were used, while a longer residence
time resulted in a mixture of 4a and the decarboxylated product 6a (Figure 3b).8 Based on this
data, optimal conditions were predicted to require a reactor temperature of 390 oC, a flow rate of
4.0 mL/min (equivalent to a residence time of 0.5 min) and a reaction concentration of 0.4 M in
THF. Put into action, these conditions led to a 97% isolated yield of product 4a, completely
devoid of the decarboxylated product 6a (Table 1).
Table 1. Pyrimidinone products 4a-ia
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a Isolated yields in parentheses.
Using this procedure, a diverse array of substituted pyridopyrimidinones was synthesized in
high yields. Notably, these compounds could be isolated with high purity through a simple
trituration and filtration procedure. Various substitution patterns with both electron donating and
withdrawing groups were tolerated on the aminopyridine ring (4a–d). Other heteroaromatics
were also tenable, producing thiazolopyrimidines (4e), pyrimidoquinolines (4f) and
pyrazinopyrimidinones (4g) in equally high yields. Furthermore, the alkoxy methylenemalonic
ester could be replaced with condensation products of ꢀketo esters (4g–h) and cyanoacetic acid
esters (4i) to yield the corresponding polysubstituted fused pyrimidinone products.
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We were also able to demonstrate the application of this thermal ringꢀclosing reaction on a
preparative scale using the automated platform. Under the same reaction conditions, alkylidene
βꢀdiester 3a was aspirated through a threeꢀway valve and injected alternately into two injection
loops to allow nearꢀcontinuous operation. The crude reaction mixture was collected in a roundꢀ
bottom flask, and simple removal of THF and trituration of the residue in ethyl acetate allowed
isolation of product 4a on a gramꢀscale (Scheme 2), equating to a production level of
approximately 18.2 g/h.
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Scheme 2. Preparativeꢀscale reaction in flow
This thermal ringꢀclosing reaction procedure was also used to synthesize a variety of quinolone
derivatives, a motif also commonly found in many pharmaceutically relevant compounds (Table
2).9
Table 2. Synthesis of quinolone derivatives 5a–ha
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a
b
Isolated yields in parentheses. HPLC trace of crude reaction mixture shows a 68:32 ratio of
c
5a/6g. HPLC trace of crude reaction mixture shows a 77:23 ratio of regioisomers (7ꢀMeO/5ꢀ
d
MeO). Only 5c was isolated. HPLC trace of crude reaction mixture shows a 76:24 ratio of
5e/6j. e HPLC trace of crude reaction mixture shows a 62:38 ratio of 5g/6i.
Analysis by NMR and IR spectroscopy indicated that these structures exhibit ketoꢀenol
tautomerization. A range of substituents were tolerated on the aniline substrate, potentially
allowing for further derivatization of these heterocyclic frameworks (5a–d). In cases where
decarboxylation was possible, a mixture of products was obtained (5a, e and g). However, the
desired products were easily purified and isolated by a simple recrystallization and filtration
process. As in other cases reported in the literature, the cyclization of metaꢀsubstituted anilines
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gave a mixture of regioisomeric products, with preferential formation of the 7ꢀsubstituted
quinolone products (5c–d).10 Pyrazolopyridine derivatives have also been targets of organic
synthesis as potentially biologically active materials.11 These compounds were readily accessed
under our thermal cyclization conditions from the condensation product of 5ꢀaminopyrazoles
with diethyl ethoxymethylenemalonate (5e) or ethyl ethoxymethylenecyanoacetate (5f) in
moderate to high yields. In these cases, the enol form prevails over the keto form, confirmed
from NMR and IR characterizations. Finally, 4ꢀhydroxybenzoquinolones were also obtained in
moderate to good yields (5g–h).
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The decarboxylated variants of these quinolone compounds are also of great synthetic interest,
and are commonly prepared via multiple sequential steps of thermal cyclization, hydrolysis, and
decarboxylation from alkylidene βꢀdiesters. Alternatively, these products can be accessed using
classical flash vacuum pyrolysis conditions from enamine starting materials obtained by
condensation of aryl amines with ketene precursors such as Meldrum’s acid.12 Lengyel and
coworkers have previously reported the thermal ringꢀclosing reaction of these precursors in the
XꢀCube Flash.6b From our earlier optimization studies, we observed that we could favor the
formation of the decarboxylated product 6a from 3a by decreasing the reaction concentration,
extending the residence time and maintaining an elevated temperature in the flow reactor
(Figure 3b). We hypothesized that by fine tuning the existing reaction conditions, it would be
possible to obtain product 6a exclusively from a tandem thermal cyclizationꢀhydrolysisꢀ
decarboxylation process in flow. This is particularly attractive from the viewpoint that both types
of scaffolds could be conveniently accessed via a common precursor compound 3. As the
reagents and solvent in our reaction system are likely near or in supercritical state,13 there was
potential for variation in reaction pressure to have a significant influence on the reaction outcome
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due to fluid compressibility. Starting from previously determined conditions (390 C, 0.5
mL/min), a 0.05M solution of 3a in THF was injected into the PhoenixTM flow reactor at varying
pressures regulated by the backpressure regulator (Figure 4).
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Figure 4. Effect of pressure on ratio of products 6a vs 4a
90
80
70
60
50
% 6a
% 4a
40
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20
10
0
80 bar
100 bar
120 bar
140 bar
Reaction Pressure
a 0.05M solution of 3a in THF (0.2 mmol) was injected into PhoenixTM flow reactor at 390 oC,
0.5 mL/min and 100 – 140 bar. Ratios of 6a/4a were determined by HPLC analysis of the crude
reaction mixture.
A significant correlation between increasing pressure and increasing conversion to 6a was
observed, with a ratio of 83:17 6a/4a at 140 bar. Higher conversion due to increased pressure can
either be a result of increased residence time,14 or concentration, or both. However, our DOE
results (see SI) show minimal change in conversion to 6a with increased residence time (from
0.5 – 2 minutes) and thus appears to be a less significant factor. Increased concentration can only
be a factor if the decarboxylation process is occurring through a bimolecular process, most likely
catalyzed by H2O present in the solvent. Our earlier observations also showed that more dilute
reactions (where higher amounts of H2O are present) resulted in higher ratios of 6a/4a (Figure
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3b). Based on these results, we imagined that addition of water to the reaction mixture would
accelerate the decarboxylation process. Gratifyingly, the use of a 100:1 THF/H2O ratio as the
solvent system at 0.05M concentration at 390 oC, 120 bar and 0.5 mL/min afforded 6a cleanly as
the sole product, which could be isolated in 87% yield (Table 3).
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Table 3. GouldꢀJacobs/decarboxylation products 6a-ja
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390 oC, 0.5 mL/min
H
N
N
O
R
R
120 bar, 100:1 THF/H2O
(0.05M)
CO2Et
CO2Et
5
6
7
8
H
N
or
N
0.2 mmol scale
R
X
O
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3
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6a-f
6g-j
X = CH, N
H
N
Me
N
O
Me
N
N
O
N
Me
N
O
6a (82%)
6b (48%)
6c (67%)
N
S
F3C
N
O
N
O
N
N
N
MeO
O
6f (73%)
6d (63%)
6e (67%)
H
H
N
Cl
N
Br
O
O
6g (55%)
6h (84%)
Ph
H
N
N
N
N
Me
OH
O
6i (46%)
6j (59%)
a Isolated yields in parentheses.
Applying these conditions to a select number of alkylidene
ꢀdiesters yielded the
complementary decarboxylated pyridopyrimidinone (6a–f), quinolone (6g–i) and
pyrazolopyridine (6j) products in moderate to good yields.
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To evaluate the reaction pathways at play in this process, intermediate products 5a and 815
were synthesized and subjected to the same reaction conditions (Scheme 3).
Scheme 3. Reaction pathway to access 6ga
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a
5a and 8 were individually injected into the PhoenixTM flow reactor as 0.05M solutions in
100:1 THF/H2O at 390 oC, 120 bar, 0.5 mL/min. Isolated yields are reported.
Product 6g could be obtained cleanly from decarboxylation of quinolone 5a, while no product
was observed from the reaction with acrylate 8 under our reaction conditions.16 This exercise
also showed that better yields could be obtained through our ‘oneꢀpot’ thermal cyclizationꢀ
hydrolysisꢀdecarboxylation process as compared to the twoꢀstep process described in Scheme 3
(55% in Table 3 compared to 27% in Scheme 3) while conserving time, energy and materials.
A tandem thermal cyclizationꢀhydrolysisꢀdecarboxylation process could be applied to
cyanoacetic acid esters (Table 4), yielding the 4ꢀaminopyrazolopyridine (7a–b) and 4ꢀ
aminobenzoquinoline (7c) products in moderate yields as the free amine.
Table 4. Intramolecular condensation/decarboxylation products 7a-ca
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a Isolated yields in parentheses
Thermal cyclization of an alkylidene malonitrile gave the 4ꢀaminoꢀ3ꢀcyanoquinoline product
7d, with no evidence of hydrolysis of the nitrile group occurring under these reaction conditions.
o
In all of these cases, an elevated temperature (400 C) and a longer residence time of 8 minutes
(0.25 mL/min, 2 mL loop) were required for full conversion. This GouldꢀJacobs type protocol is
the first reported to directly access 4ꢀamino heterocyclic compounds in a ‘oneꢀpot’ fashion.
These highly desirable scaffolds are otherwise generally accessed through a tedious and harsh
chlorinationꢀsubstitution sequence from the hydroxyl moiety of typical GouldꢀJacobs products.17
Conclusions
In conclusion, we rapidly optimized general reaction conditions for synthesizing diverse
scaffolds that are of high interest to pharmaceutical research via GouldꢀJacobs type reaction
enabled by a modified and automated PhoenixTM highꢀtemperature and pressure continuous flow
reactor and the DesignꢀofꢀExperiment software. These otherwise hard to access heterocycles are
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obtained in good to high yields within 0.5 – 8 minutes with operational simplicity in low boiling
point solvents. Access to various fused pyrimidines and quinolone derivatives and their
corresponding decarboxylated products are achieved with high efficiency and specificity, notably
from one common starting material through slight variation of the reaction conditions.
Furthermore, a preparativeꢀscale synthesis was also demonstrated in good yield under nearꢀ
continuous flow operation.
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Experimental Section
General Experimental Methods
Flash chromatography was performed using a Combiflash® Rf automated purification system.
Preparative HPLC was performed on either an automated preparativeꢀscale purification system
equipped with a Waters Sunfire C8 5m column (150 x 30 mm) or on a Phenomenex Luna C8 5m
100Å AXIA column (50mm × 21.2mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic
acid in water (B) was used, at a flow rate of 30 mL/min (0ꢀ0.5 min 5% A, 0.5ꢀ6.5 min linear
gradient 5ꢀ100% A, 6.5ꢀ8.5 min 100% A, 8.5ꢀ9.0 min linear gradient 100ꢀ5% A, 9.0ꢀ10 min 5%
A). Proton nuclear magnetic resonance spectra (1H NMR, 500 or 400 MHz), fluorine nuclear
magnetic resonance spectra (19F NMR, 375 MHz) and proton decoupled carbon nuclear magnetic
resonance spectra (13C NMR, 125 or 100 MHz) were obtained in deuterochloroform (CDCl3) or
deuterodimethylsulfoxide (DMSOꢀd6) with residual solvent as the internal standard unless
otherwise noted. Data for NMR are reported as follows: chemical shift as parts per million
(ppm), coupling constants as scalar values in Hz and integration. Mass spectra (MS) were
obtained by ionizing samples via positive electron spray ionization (ESI) or desorption chemical
ionization (DCI) with TOF as the mass analyzer. Infrared spectra (IR) were obtained with
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Attenuated Total Reflectance Fourier Transform Midꢀinfrared Spectroscopy (ATR/FTꢀMIR)
using a Diamond internal reflection element (IRE).
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Starting Material Synthesis
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The aminomethylene adducts 3 were prepared through adaptation of literature procedures
using commercially available starting materials.5a,10,18 General procedure: A 2.0 – 5.0 mL
microwave vial was charged with aryl amine (1.0 equiv,
2
mmol), diethyl
ethoxymethylenemalonate or ethyl ethoxymethylenecyanoacetate (1.05 equiv, 2.1 mmol), and
1.0 mL of EtOH. The reaction vessel was sealed with a Teflonꢀlined cap and subjected to
microwave irradiation at 130 oC for 10 minutes. Reaction mixture temperature was monitored by
an external surface sensor. Upon cooling, the products precipitated out of the solution, and were
collected by filtration as crystalline solids. Yields: 39 – 92%. Purity was confirmed by 1H NMR.
Characterization data was compared and fully concordant with that already reported in the
literature.
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Experimental Procedure 1 (Tables 1 and 2)
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The flow rate on the PhoenixTM reactor was set to 4.0 mL/min, the backꢀpressure regulator set
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to 100 bar, and the temperature set to 390 C. Substrates (0.2 mmol) were added to 4 mL vials,
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dissolved in 500 ꢀL of the feed solvent, and injected into the Phoenix using the autosampler. The
crude reaction mixtures were collected in 20 mL scintillation vials, concentrated, and purified by
trituration with ethyl acetate unless otherwise noted.
Characterization data (Table 1)
Ethyl 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (4a)
This
compound
was
prepared
from
diethyl
2ꢀ(((5ꢀmethylpyridinꢀ2ꢀ
yl)amino)methylene)malonate (56 mg) according to procedure 1. The product was isolated as an
offꢀwhite powder in 96% yield (45 mg). 1H NMR (500 MHz, CDCl3) δ 9.10 (app dt, J = 2.1, 1.0
Hz, 1H), 9.03 (s, 1H), 7.81 (dd, J = 8.9, 2.1 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 4.43 (q, J = 7.1 Hz,
13
2H), 2.51 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl3) δ 164.9, 158.8, 154.8,
152.3, 141.9, 128.0, 126.6, 126.4, 105.2, 61.1, 18.6, 14.5. HRMS (ESI): m/z: [M + Na]+ calcd
for C12H12N2O3Na: 255.0740; found: 255.0741.
Ethyl 9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (4b)
This
compound
was
prepared
from
diethyl
2ꢀ(((3ꢀmethylpyridinꢀ2ꢀ
yl)amino)methylene)malonate (56 mg) according to procedure 1. The product was isolated as
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white powder in 96% yield (45 mg). H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 7.0, 0.8 Hz,
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1H), 9.08 (s, 1H), 7.81 (app dt, J = 7.0, 1.4 Hz, 1H), 7.25 (t, J = 7.0 Hz, 1H), 4.43 (q, J = 7.1 Hz,
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2H), 2.66 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl3) δ 165.0, 158.4, 155.2,
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152.9, 138.2, 135.8, 126.9, 116.8, 105.2, 61.1, 18.2, 14.5. HRMS (ESI/TOFꢀQ): m/z: [M + Na]+
calcd for C12H12N2O3Na: 255.0740; found: 255.0744.
Ethyl 4-oxo-8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (4c)
This compound was prepared from diethyl 2ꢀ(((4ꢀ(trifluoromethyl)pyridinꢀ2ꢀ
yl)amino)methylene)malonate (66 mg) according to procedure 1. The product was isolated as
1
white crystalline solid in 87% yield (50 mg). m.p. (o C) = 146.6 – 148.0. H NMR (400 MHz,
CDCl3) δ 9.35 (d, J = 7.4 Hz, 1H), 9.10 (s, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 7.4, 1.9
Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
164.1, 159.5, 154.2, 153.0, 134.0 (q, J = 35.4 Hz), 130.6, 124.9 (q, J = 4.5 Hz), 121.7 (q, J =
273.9 Hz), 112.2 (q, J = 2.7 Hz), 108.0, 61.6, 14.5. 19F NMR (375 MHz, CDCl3) δ ꢀ65.61.
HRMS (ESI/TOFꢀQ): m/z: [M + Na]+ calcd for C12H9F3N2O3Na: 309.0457; found: 309.0462.
Ethyl 7-methoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (4d)
This
compound
was
prepared
from
diethyl
2ꢀ(((5ꢀmethoxypyridinꢀ2ꢀ
yl)amino)methylene)malonate (59 mg) according to procedure 1. The product was isolated as
beige fluffy powder in 96% yield (48 mg). 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.80 (dd,
J = 2.5, 0.8 Hz, 1H), 7.76 – 7.65 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.42 (t, J = 7.1
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Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1, 157.8, 154.7, 152.2, 150.1, 133.7, 127.6, 108.8,
104.7, 61.2, 56.8, 14.5. HRMS (ESI/TOFꢀQ) m/z: [M + Na]+ calcd for C12H12N2O4Na:
271.0689; found: 271.0696.
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Ethyl 5-oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (4e)
This compound was prepared from diethyl 2ꢀ((thiazolꢀ2ꢀylamino)methylene)malonate (54 mg)
according to procedure 1. The product was isolated as beige powder in 94% yield (42 mg).
Characterization data was compared and fully concordant with that already reported in the
literature.19 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.19 (d, J = 4.9 Hz, 1H), 7.17 (d, J = 4.9
Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
166.6, 164.3, 158.4, 155.1, 123.4, 113.1, 107.9, 61.2, 14.4. MS (ESI) m/z: [M+H]+ calcd for
C9H9N2O3S: 225.2; found: 225.3.
Ethyl 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carboxylate (4f)
This compound was prepared from diethyl 2ꢀ((quinolinꢀ2ꢀylamino)methylene)malonate (63
mg) according to procedure 1. The product was purified by prepꢀHPLC (3ꢀ30%
ACN/H2O+TFA) and isolated as a yellow powder in 94% yield (50 mg). Characterization data
was compared and fully concordant with that already reported in the literature. 2a 1H NMR (400
MHz, CDCl3) δ 11.75 (br s, 1H), 9.68 (d, J = 8.9 Hz, 1H), 8.87 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H),
7.86 (dd, J = 7.8, 1.6 Hz, 1H), 7.80 (ddd, J = 8.9, 7.1, 1.7 Hz, 1H), 7.72 – 7.64 (m, 2H), 4.43 (q, J
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= 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 163.2, 158.9, 153.6,
141.6, 134.9, 131.7, 129.1, 128.5, 125.5, 122.5, 121.4, 111.2, 61.7, 14.4. MS (DCI) m/z: [M+H]+
calcd for C15H12N2O3: 268.1; found: 268.9.
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3-Acetyl-4H-pyrazino[1,2-a]pyrimidin-4-one (4g)
This compound was prepared from ethyl 3ꢀoxoꢀ2ꢀ((pyrazinꢀ2ꢀylamino)methylene)butanoate
(40 mg) according to procedure 1. The crude reaction mixture was concentrated and purified by
column chromatography. The product was isolated as a white crystalline solid in 91% yield (29
mg). m.p. (o C) = 160.4 – 161.4. 1H NMR (400 MHz, DMSOꢀd6) δ 9.29 (d, J = 1.2 Hz, 1H),
8.93 (dd, J = 4.7, 1.2 Hz, 1H), 8.89 (s, 1H), 8.47 (d, J = 4.7 Hz, 1H), 2.63 (s, 3H). 13C NMR (100
MHz, DMSOꢀd6) δ 195.3, 157.4, 155.2, 153.1, 146.2, 134.5, 118.7, 115.2, 30.8. HRMS
(ESI/TOFꢀQ): m/z: [M + Na]+ calcd for C9H7N3O2Na: 212.0430; found: 212.0431.
3-Acetyl-7-chloro-4H-pyrido[1,2-a]pyrimidin-4-one (4h)
This compound was prepared from ethyl 2ꢀ(((5ꢀchloropyridinꢀ2ꢀyl)amino)methylene)ꢀ3ꢀ
oxobutanoate (54 mg) according to procedure 1. The crude reaction mixture was concentrated
and purified by column chromatography. The product was isolated as a pale yellow fluffy
powder in 96% yield (43 mg). 1H NMR (400 MHz, DMSOꢀd6) δ 9.20 (dd, J = 2.4, 0.7 Hz, 1H),
8.80 (s, 1H), 8.27 (dd, J = 9.3, 2.4 Hz, 1H), 7.87 (dd, J = 9.3, 0.7 Hz, 1H), 2.60 (s, 3H). 13C
NMR (100 MHz, DMSOꢀd6) δ 195.7, 157.4, 155.9, 152.4, 141.5, 128.4, 127.1, 125.8, 112.3,
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40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.3, 31.2. HRMS (ESI/TOFꢀQ): m/z: [M + Na]+ calcd for
C10H7ClN2O2Na: 245.0088; found:245.0093.
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8-Bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (4i)
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This compound was prepared from ethyl 3ꢀ((4ꢀbromopyridinꢀ2ꢀyl)amino)ꢀ2ꢀcyanoacrylate (53
mg) according to procedure 1. The product was isolated as a redꢀochre powder in 77% yield (35
mg). 1H NMR (400 MHz, DMSOꢀd6) δ 8.94 (d, J = 7.5 Hz, 1H), 8.80 (s, 1H), 8.27 (d, J = 2.1
Hz, 1H), 7.78 (dd, J = 7.5, 2.1 Hz, 1H). 13C NMR (100 MHz, DMSOꢀd6) δ 160.6, 156.4, 152.9,
137.0, 129.8, 128.9, 122.7, 116.2, 89.9. HRMS (ESI/TOFꢀQ): m/z: [M + Na]+ calcd for
C9H4BrN3ONa: 271.9430; found: 271.9432.
Ethyl 7-chloro-4-hydroxyquinoline-3-carboxylate (5a)
This compound was prepared from diethyl 2ꢀ(((3ꢀchlorophenyl)amino)methylene)malonate (60
mg) according to procedure 1. The product was isolated as light beige powder in 32% yield (16
13
mg). The product was extremely insoluble in most common solvents, therefore no C NMR
spectrum is available. Characterization data was compared and fully concordant with that already
reported in the literature. 20 1H NMR (500 MHz, DMSOꢀd6) δ 8.16 (d, J = 8.6 Hz, 1H), 8.00 (d, J
= 7.7 Hz, 1H), 7.84 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.6, 1.9 Hz, 1H), 6.08 (d, J = 7.7 Hz, 1H),
4.27 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). MS (ESI) m/z: [M+H]+ calcd for
C12H11ClNO3: 252.0; found: 252.0.
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6-bromo-4-hydroxyquinoline-3-carbonitrile (5b)
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This compound was prepared from ethyl 3ꢀ((4ꢀbromophenyl)amino)ꢀ2ꢀcyanoacrylate (50 mg)
according to procedure 1. The product was purified by prepꢀHPLC (15ꢀ45%
ACN/H2O+NH4OAc) and isolated as an offꢀwhite powder in 92% yield (39 mg).
Characterization data was compared and fully concordant with that already reported in the
literature. 21 1H NMR (400 MHz, DMSOꢀd6) δ 12.99 (br s, 1H), 8.77 (s, 1H), 8.20 (d, J = 2.4 Hz,
1H), 7.93 (dd, J = 8.8, 2.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz, DMSOꢀd6) δ
173.2, 147.2, 138.2, 136.0, 127.1, 126.54, 121.9, 118.2, 116.5, 93.9. MS (ESI) m/z: [M+H]+
calcd for C10H6BrN2O: 249.0; found: 249.1.
4-hydroxy-7-methoxyquinoline-3-carbonitrile (5c)
This compound was prepared from ethyl 2ꢀcyanoꢀ3ꢀ((3ꢀmethoxyphenyl)amino)acrylate (49
mg) according to procedure 1. Both regioisomers (~8:2 ratio) were observed by LCꢀMS and the
main product was purified by prepꢀHPLC (5ꢀ100% ACN/H2O+TFA) and isolated as an offꢀwhite
powder in 45% yield (18 mg). Characterization data was compared and fully concordant with
that already reported in the literature. 22 1H NMR (400 MHz, DMSOꢀd6) δ 10.79 (s, 1H), 8.70 (s,
1H), 8.05 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 8.8, 2.1 Hz, 1H), 6.94 (d, J = 2.1 Hz, 1H), 3.79 (s,
3H). 13C NMR (100 MHz, DMSOꢀd6) δ 173.2, 162.1, 151.0, 142.0, 127.8, 118.8, 116.7, 115.4,
101.7, 92.8, 40.9. MS (ESI) m/z: [M+H]+ calcd for C11H9N2O2: 201.1; found: 201.3.
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6- and 8-chloro- 4-hydroxyquinoline-3-carbonitrile (5d)
5
6
7
8
These compounds were prepared from ethyl 3ꢀ((3ꢀchlorophenyl)amino)ꢀ2ꢀcyanoacrylate (50
mg) according to procedure 1. Both regioisomers (~2.5:1 ratio) were observed by LCꢀMS and
the products were purified by prepꢀHPLC (15ꢀ45% NH4OAc/ACN method).
7-chloro-4-hydroxyquinoline-3-carbonitrile
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This compound was isolated in 35% yield (14 mg) as a white powder. 1H NMR (400 MHz,
DMSOꢀd6) δ 12.91 (br s, 1H), 8.76 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H),
7.51 (dd, J = 8.7, 2.0 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 173.8, 147.5, 140.1, 137.8, 127.3,
125.8, 123.8, 118.6, 116.5, 94.2. HRMS (ESI/TOFꢀQ): m/z: [M + Na]+ calcd for
C10H5ClN2ONa: 226.9983; found: 226.9986.
5-chloro-4-hydroxyquinoline-3-carbonitrile
1
This compound was isolated in 13% yield (6 mg) as a white powder. H NMR (400 MHz,
DMSOꢀd6) δ 8.67 (s, 1H), 7.71 – 7.62 dd, J = 8.3, 7.8 Hz, 1H), 7.56 (dd, J = 8.3, 1.1 Hz, 1H),
7.44 (dd, J = 7.8, 1.1 Hz, 1H). 13C NMR (100 MHz, DMSOꢀd6) δ 173.5, 146.3, 141.9, 133.0,
132.2, 128.0, 121.5, 118.9, 116.7, 95.7. HRMS (ESI/TOFꢀQ): m/z: [M + Na]+ calcd for
C10H5ClN2ONa: 226.9983; found: 226.9987.
Ethyl 4-hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (5e)
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This compound was prepared from diethyl 2ꢀ(((3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀ
yl)amino)methylene)malonate (69 mg) according to procedure 1. The product was isolated as
1
yellow crystalline solid in 68% yield (40 mg). m.p. (o C) = 150.0 – 151.2. H NMR (400 MHz,
CDCl3) δ 12.22 (br s, 1H), 8.87 (s, 1H), 8.14 (dd, J = 8.6, 1.2 Hz, 2H), 7.49 (dd, J = 8.6, 7.4 Hz,
2H), 7.30 (t, J = 7.4 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.74 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 170.4, 165.1, 154.3, 151.9, 144.3, 138.9, 129.1, 126.3, 121.6, 106.6,
102.9, 77.4, 77.3, 77.1, 76.7, 61.8, 14.4, 14.2. HRMS (ESI/TOFꢀQ) m/z: [M + H]+ calcd for
C16H15N3O3: 298.1186; found: 298.1195. IR (neat): 3073 (br), 2992, 2981, 2925, 2906, 2767,
1677, 1631, 1594, 1562, 1507, 1488, 1439, 1404, 1372, 1331, 1282, 1268, 1215, 1141, 1120,
1110, 1074, 1026, 934, 891, 804, 787, 760, 720, 691, 672, 639, 623, 556 cmꢀ1.
4-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (5f)
This compound was prepared from ethyl 2ꢀcyanoꢀ3ꢀ((3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀ
yl)amino)acrylate 56 mg) according to procedure 1. The product was isolated as light beige
powder in 95% yield (45 mg). 1H NMR (400 MHz, DMSOꢀd6) δ 8.37 (s, 1H), 7.69 (d, J = 7.8
Hz, 2H), 7.62 – 7.51 (m, 2H), 7.51 – 7.41 (m, 1H), 2.52 (s, 3H). 13C NMR (100 MHz, DMSOꢀ
d6) δ 146.2, 137.4, 130.0, 128.6, 124.1, 116.8, 40.6, 40.3, 40.1, 39.92, 39.7, 39.5, 39.3, 13.9.
HRMS (ESI/TOFꢀQ) m/z: [M + Na]+ calcd for C14H10N4ONa: 273.0747; found: 273.0751. IR
(neat): 3219, 3153, 3057, 3046
,
2989, 2966, 2928, 2879, 2226, 1637, 1588, 1531, 1502, 1482,
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1457, 1421, 1352, 1326, 1269, 1211, 1180, 1162, 1096, 1083, 1069, 1032, 1012, 1004, 961, 927,
908, 870, 787, 759, 732, 709, 679, 642, 613 cmꢀ1.
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Ethyl 4-hydroxybenzo[h]quinoline-3-carboxylate (5g)
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This compound was prepared from diethyl 2ꢀ((naphthalenꢀ1ꢀylamino)methylene)malonate (63
mg) according to procedure 1. The product was purified by prepꢀHPLC (30ꢀ60%
ACN/H2O+TFA method) and isolated as white powder in 48% yield (25 mg). Characterization
data was compared and fully concordant with that already reported in the literature.9 1H NMR
(400 MHz, DMSOꢀd6) δ 8.70 – 8.62 (m, 2H), 8.60 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.16 – 8.06
(m, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.81 (dt, J = 6.3, 3.5 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.33 (t,
J = 7.1 Hz, 3H). 13C NMR (100 MHz, DMSO_D2O) δ 165.5, 144.4, 134.9, 129.5, 129.2, 127.9,
125.6, 122.5, 122.1, 112.4, 60.5, 14.7. MS (DCI) m/z: [M + H]+ calcd for C16H14NO3: 268.1;
found: 268.7. IR (neat): 3231, 3188, 3136, 3096, 3059, 2991, 2967, 2928, 2869, 1705, 1636,
1607, 1562, 1539, 1504, 1463, 1463, 1426, 1391, 1374, 1360, 1284, 1275, 1228, 1207, 1185,
1167, 1125, 1094, 1076, 1037 995, 945, 917, 859, 836, 800, 778, 749, 731, 713, 696, 652, 625,
600, 581, 553 cmꢀ1.
4-hydroxybenzo[h]quinoline-3-carbonitrile (5h)
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This compound was prepared from ethyl 2ꢀcyanoꢀ3ꢀ(naphthalenꢀ1ꢀylamino)acrylate (53 mg)
according to procedure 1. The product was isolated as a white chalky powder in 82% yield (36
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mg). H NMR (400 MHz, DMSOꢀd6) δ 13.04 (s, 1H), 8.74 (s, 1H), 8.71 (dt, J = 6.3, 3.4 Hz,
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1H), 8.10 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.79 (dt, J = 6.4, 3.5 Hz, 2H). 13C NMR
(100 MHz, DMSOꢀd6) δ 174.1, 145.8, 136.5, 134.7, 129.3, 128.8, 127.6, 125.9, 123.4, 122.3,
122.3, 120.8, 116.5, 96.2. HRMS (ESI/TOF-Q) m/z: [M + Na]+ calcd for C14H8N2ONa:
243.0529; found: 243.0533. IR (neat): 3223, 3205, 3149, 3104, 3066, 3001, 2229, 1633, 1611,
1540, 1501, 1424, 1381, 1353, 1266, 1255, 1219, 1206, 1170, 1148, 962, 948, 925, 830, 793,
754, 721, 700, 657, 584 cmꢀ1.
Bulk mode – Preparative scale synthesis of ethyl 7-methyl-4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carboxylate (4a)
A
25 mL conical flask was charged with diethyl 2ꢀ(((5ꢀmethylpyridinꢀ2ꢀ
yl)amino)methylene)malonate (2.00 g, 7.2 mmol) and 18 mL of THF. The flow rate on the
HPLC pump was set to 4 mL/min, the backꢀpressure regulator set to 100 bar, and the temperature
set to 390° C. Sample was aspirated from the conical flask by way of the 3ꢀway valve and
injected alternately into the two injection loops of the Valco valve with the output going to a
larger collection flask. This use of two sample injection loops allowed nearꢀcontinuous
operation. The crude reaction mixture was collected in a 250 mL round bottom flask,
concentrated and purified by trituration with ethyl acetate to afford the title compound as an offꢀ
white powder in 82% yield (1.36 g).
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Experimental Procedure 2 (Table 3)
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The flow rate on the PhoenixTM reactor was set to 0.5 mL/min, the backꢀpressure regulator set
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to 120 bar, and the temperature set to 390 C. Substrates (0.2 mmol) were added to 4 mL vials,
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dissolved in 4.0 mL of the feed solvent, and injected into the PhoenixTM using the autosampler.
The crude reaction mixtures were collected in 20 mL scintillation vials, concentrated, and
purified by prepꢀHPLC unless otherwise noted.
Characterization data (Table 3)
7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6a)
This
compound
was
prepared
from
diethyl
2ꢀ(((5ꢀmethylpyridinꢀ2ꢀ
yl)amino)methylene)malonate (56 mg) according to procedure 2. The product was isolated as a
creamꢀcoloured powder in 82% yield (26 mg). 1H NMR (400 MHz, DMSOꢀd6) δ 8.87 (d, J = 2.1
Hz), 8.30 (d, J = 6.6 Hz, 1H), 7.97 (dd, J = 9.0, 2.1 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 6.41 (d, J
= 6.6 Hz, 1H), 2.42 (s, 3H). 13C NMR (100 MHz, DMSOꢀd6) δ 156.3, 151.7, 149.3, 141.6, 127.4,
124.8, 123.7, 103.3, 17.7. HRMS (ESI/TOFꢀQ) m/z: [M+H]+ calcd for C9H9N2O: 161.0709;
found: 161.0714.
7-methyl-1,8-naphthyridin-4-ol (6b)
This
compound
was
prepared
from
diethyl
2ꢀ(((6ꢀmethylpyridinꢀ2ꢀ
yl)amino)methylene)malonate (56 mg) according to procedure 2. The product was purified by
prepꢀHPLC (3ꢀ30% ACN/H2O+NH4OAc) to give the title compound as a white powder in 48%
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yield (16 mg). H NMR (400 MHz, DMSOꢀd6) δ 8.32 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.5 Hz,
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1H), 7.26 (d, J = 8.1 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 2.57 (s, 3H). C NMR (100 MHz,
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DMSOꢀd6) δ 177.8, 162.9, 150.7, 140.4, 135.2, 120.3, 118.6, 110.1, 24.8. HRMS (ESI/TOFꢀQ)
m/z: [M+H]+ calcd for C9H9N2O: 161.0709; found: 161.0712.
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9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6c)
This
compound
was
prepared
from
diethyl
2ꢀ(((3ꢀmethylpyridinꢀ2ꢀ
yl)amino)methylene)malonate (56 mg) according to procedure 2. The product was isolated as a
1
white powder in 67% yield (21 mg). H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 7.0 Hz, 1H),
8.33 (d, J = 6.3 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.07 (t, J = 7.0 Hz, 1H), 6.46 (d, J = 6.3 Hz,
1H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.4, 154.0, 151.6, 135.1, 125.6, 115.2,
104.8, 18.4. HRMS (ESI/TOFꢀQ) m/z: [M+H]+ calcd for C9H9N2O: 161.0709; found: 161.0714.
8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (6d)
This compound was prepared from 8ꢀ(trifluoromethyl)ꢀ4Hꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀone (63
mg) according to procedure 2. The product was purified by column chromatography
(DCM/MeOH) to give the title compound as a white powder in 63% yield (26 mg). 1H NMR
(400 MHz, DMSOꢀd6) δ 9.07 (d, J = 7.5 Hz, 1H), 8.39 (d, J = 6.4 Hz, 1H), 8.07 (dd, J = 2.1, 1.1
Hz, 1H), 7.54 (dd, J = 7.5, 2.1 Hz, 1H), 6.56 (d, J = 6.4 Hz, 1H). 13C NMR (100 MHz, DMSOꢀ
d6) δ 156.7, 155.0, 150.7, 135.9 (q, J = 34.1 Hz), 129.6, 124.6 (q, J = 4.7 Hz), 122.3 (q, J = 273.4
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