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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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The Journal of Organic Chemistry

Synthesis of Fused Pyrimidinone and Quinolone Derivatives in an Automated High Temperature and High Pressure Flow Reactor Jennifer Tsoung,1 Andrew R. Bogdan,1 Stanislaw Kantor,1 Ying Wang,*,1 Manwika Charaschanya2 and Stevan W. Djuric1 1

Discovery Chemistry and Technologies, AbbVie Inc., 1 North Waukegan Road, North Chicago,

Illinois, 60064 2

Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, 66047

KEYWORDS: Gould-Jacobs, 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 high-

ACS Paragon Plus Environment

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temperature and high-pressure continuous flow reactor. Heterocyclic scaffolds that are either hard to synthesize or require multi-steps, 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 work-up and isolation. The methods reported herein are highly amenable for fast and efficient heterocycle synthesis as well as compound scale-ups. 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 well-known reaction for the construction of 4quinolone scaffolds is the Gould-Jacobs reaction,2 which is the key step in the synthesis of antibacterial drugs, Nalidixic acid and Oxolinic acid, as well as in non-steroidal antiinflammatory drugs (NSAID) Floctafenine and Glafenine (Figure 1). However, the GouldJacobs 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 work-up and product isolation. As a consequence, this powerful transformation is underutilized in medicinal chemistry research. Figure 1. Quinolone-containing drug compounds


2

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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 reagent-free 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 GouldJacobs reaction enabled by an automated and modified PhoenixTM system at high temperatures and pressures. Results and Discussion Gould-Jacobs 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 ring-closing reaction an ideal protocol to adapt to high temperature synthesis in flow. Lengyel and co-workers have


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previously disclosed the synthesis of Gould-Jacobs and Conrad-Limpach type products in both an in-house built pyrolysis reactor and the X-Cube Flash, a high-temperature/high-pressure 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. Scheme 1. Reaction sequence leading to Gould-Jacobs type products O R

Y

N N

H N

CO2Et R X

NH2

1 X = CH, N

EtO

R

Y

2 Y = CO2Et, COMe, CN

4a-j when X = N

Y CO2Et

OH

X

3

Y R 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


4

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A two-arm 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 β-diester 3a was selected as the model substrate for this study. We chose to use Design-of-Experiment software (Stat-Ease 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 temperatures (250 – 400 oC), 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 Design-of-Experiment 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)


5


H N Me

N

CO2Et CO 2Et

250 - 400 oC, 100 bar 0.5 - 4.0 mL/min, 2.0 mL loop 0.05 - 0.40 M in THF

a: Flow rate: 4.0 mL/min

N

N N

Me

3a

CO2 Et

Me

N

O

O

4a

6a

b: Flow rate: 0.5 mL/min

% 6a

% 4a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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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 ring-closing reaction on a preparative scale using the automated platform. Under the same reaction conditions, alkylidene β-diester 3a was aspirated through a three-way valve and injected alternately into two injection loops to allow near-continuous operation. The crude reaction mixture was collected in a roundbottom flask, and simple removal of THF and trituration of the residue in ethyl acetate allowed isolation of product 4a on a gram-scale (Scheme 2), equating to a production level of approximately 18.2 g/h. Scheme 2. Preparative-scale reaction in flow

This thermal ring-closing 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

Isolated yields in parentheses. b HPLC trace of crude reaction mixture shows a 68:32 ratio of 5a/6g. c HPLC trace of crude reaction mixture shows a 77:23 ratio of regioisomers (7-MeO/5MeO). Only 5c was isolated. d 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 keto-enol 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 meta-substituted anilines


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gave a mixture of regioisomeric products, with preferential formation of the 7-substituted 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 5-aminopyrazoles 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, 4-hydroxybenzoquinolones were also obtained in moderate to good yields (5g–h). 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 β-diesters. 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 ring-closing reaction of these precursors in the X-Cube 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 cyclization-hydrolysisdecarboxylation 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 oC, 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). Figure 4. Effect of pressure on ratio of products 6a vs 4a

90 80 70 60 % Yield

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50 % 6a

40

% 4a

30 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). Table 3. Gould-Jacobs/decarboxylation products 6a-ja


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H N R

390 oC, 0.5 mL/min 120 bar, 100:1 THF/H2O (0.05M) 0.2 mmol scale

CO2Et CO2Et

X

N

R

H N

R or

N O

3 X = CH, N

6a-f

N Me

O

Me

H N

N

6g-j

Me N

N N O

O

6a (82%)

N

F3C

O 6c (67%)

6b (48%)

N

MeO

N

N

O

O

O

6d (63%)

6f (73%)

6e (67%) H N

Cl

N

S

N

H N Br

O

O

6g (55%)

6h (84%)

Ph N N

N

Me

OH

H N

O 6i (46%) a

6j (59%)

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

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 ‘one-pot’ thermal cyclizationhydrolysis-decarboxylation process as compared to the two-step process described in Scheme 3 (55% in Table 3 compared to 27% in Scheme 3) while conserving time, energy and materials. A tandem thermal cyclization-hydrolysis-decarboxylation process could be applied to cyanoacetic acid esters (Table 4), yielding the 4-aminopyrazolopyridine (7a–b) and 4aminobenzoquinoline (7c) products in moderate yields as the free amine. Table 4. Intramolecular condensation/decarboxylation products 7a-ca


14

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a

Isolated yields in parentheses

Thermal cyclization of an alkylidene malonitrile gave the 4-amino-3-cyanoquinoline product 7d, with no evidence of hydrolysis of the nitrile group occurring under these reaction conditions. In all of these cases, an elevated temperature (400 oC) and a longer residence time of 8 minutes (0.25 mL/min, 2 mL loop) were required for full conversion. This Gould-Jacobs type protocol is the first reported to directly access 4-amino heterocyclic compounds in a ‘one-pot’ fashion. These highly desirable scaffolds are otherwise generally accessed through a tedious and harsh chlorination-substitution sequence from the hydroxyl moiety of typical Gould-Jacobs products.17 Conclusions In conclusion, we rapidly optimized general reaction conditions for synthesizing diverse scaffolds that are of high interest to pharmaceutical research via Gould-Jacobs type reaction enabled by a modified and automated PhoenixTM high-temperature and pressure continuous flow reactor and the Design-of-Experiment 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 preparative-scale synthesis was also demonstrated in good yield under nearcontinuous flow operation. Experimental Section General Experimental Methods Flash chromatography was performed using a Combiflash® Rf automated purification system. Preparative HPLC was performed on either an automated preparative-scale 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 (0-0.5 min 5% A, 0.5-6.5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10 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 (DMSO-d6) 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 Mid-infrared Spectroscopy (ATR/FT-MIR) using a Diamond internal reflection element (IRE). Starting Material Synthesis 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 Teflon-lined 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) The flow rate on the PhoenixTM reactor was set to 4.0 mL/min, the back-pressure regulator set to 100 bar, and the temperature set to 390 oC. Substrates (0.2 mmol) were added to 4 mL vials, dissolved in 500 µL 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

2-(((5-methylpyridin-2-

yl)amino)methylene)malonate (56 mg) according to procedure 1. The product was isolated as an off-white 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, 2H), 2.51 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C 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


yl)amino)methylene)malonate (56 mg) according to procedure 1. The product was isolated as


18

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white powder in 96% yield (45 mg). 1H NMR (400 MHz, CDCl3) δ 9.19 (dd, J = 7.0, 0.8 Hz, 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, 2H), 2.66 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.0, 158.4, 155.2, 152.9, 138.2, 135.8, 126.9, 116.8, 105.2, 61.1, 18.2, 14.5. HRMS (ESI/TOF-Q): 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

2-(((4-(trifluoromethyl)pyridin-2-

yl)amino)methylene)malonate (66 mg) according to procedure 1. The product was isolated as white crystalline solid in 87% yield (50 mg). m.p. (o C) = 146.6 – 148.0. 1H 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).

13

C 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.

19

F NMR (375 MHz, CDCl3) δ -65.61.

HRMS (ESI/TOF-Q): 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

2-(((5-methoxypyridin-2-

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


19


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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/TOF-Q) m/z: [M + Na]+ calcd for C12H12N2O4Na: 271.0689; found: 271.0696. Ethyl 5-oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (4e)

This compound was prepared from diethyl 2-((thiazol-2-ylamino)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).

13

C 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 2-((quinolin-2-ylamino)methylene)malonate (63 mg) according to procedure 1. The product was purified by prep-HPLC (3-30% 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


20

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= 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).

13

C 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. 3-Acetyl-4H-pyrazino[1,2-a]pyrimidin-4-one (4g)

This compound was prepared from ethyl 3-oxo-2-((pyrazin-2-ylamino)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.

1

H NMR (400 MHz, DMSO-d6) 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, DMSO-d6) δ 195.3, 157.4, 155.2, 153.1, 146.2, 134.5, 118.7, 115.2, 30.8. HRMS (ESI/TOF-Q): 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 2-(((5-chloropyridin-2-yl)amino)methylene)-3oxobutanoate (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, DMSO-d6) 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, DMSO-d6) δ 195.7, 157.4, 155.9, 152.4, 141.5, 128.4, 127.1, 125.8, 112.3,


21


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Page 22 of 40

40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.3, 31.2. HRMS (ESI/TOF-Q): m/z: [M + Na]+ calcd for C10H7ClN2O2Na: 245.0088; found:245.0093. 8-Bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (4i)

This compound was prepared from ethyl 3-((4-bromopyridin-2-yl)amino)-2-cyanoacrylate (53 mg) according to procedure 1. The product was isolated as a red-ochre powder in 77% yield (35 mg). 1H NMR (400 MHz, DMSO-d6) 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, DMSO-d6) δ 160.6, 156.4, 152.9, 137.0, 129.8, 128.9, 122.7, 116.2, 89.9. HRMS (ESI/TOF-Q): 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 2-(((3-chlorophenyl)amino)methylene)malonate (60 mg) according to procedure 1. The product was isolated as light beige powder in 32% yield (16 mg). The product was extremely insoluble in most common solvents, therefore no

13

C NMR

spectrum is available. Characterization data was compared and fully concordant with that already reported in the literature. 20 1H NMR (500 MHz, DMSO-d6) 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.


22

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6-bromo-4-hydroxyquinoline-3-carbonitrile (5b)

This compound was prepared from ethyl 3-((4-bromophenyl)amino)-2-cyanoacrylate (50 mg) according

to

procedure

1.

The

product

was

purified

by

prep-HPLC

(15-45%

ACN/H2O+NH4OAc) and isolated as an off-white 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, DMSO-d6) 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, DMSO-d6) 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 2-cyano-3-((3-methoxyphenyl)amino)acrylate (49 mg) according to procedure 1. Both regioisomers (~8:2 ratio) were observed by LC-MS and the main product was purified by prep-HPLC (5-100% ACN/H2O+TFA) and isolated as an off-white 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, DMSO-d6) 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, DMSO-d6) 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.


23


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Page 24 of 40

6- and 8-chloro- 4-hydroxyquinoline-3-carbonitrile (5d) These compounds were prepared from ethyl 3-((3-chlorophenyl)amino)-2-cyanoacrylate (50 mg) according to procedure 1. Both regioisomers (~2.5:1 ratio) were observed by LC-MS and the products were purified by prep-HPLC (15-45% NH4OAc/ACN method). 7-chloro-4-hydroxyquinoline-3-carbonitrile

This compound was isolated in 35% yield (14 mg) as a white powder. 1H NMR (400 MHz, DMSO-d6) 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/TOF-Q): m/z: [M + Na]+ calcd for C10H5ClN2ONa: 226.9983; found: 226.9986. 5-chloro-4-hydroxyquinoline-3-carbonitrile

This compound was isolated in 13% yield (6 mg) as a white powder. 1H NMR (400 MHz, DMSO-d6) 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, DMSO-d6) δ 173.5, 146.3, 141.9, 133.0, 132.2, 128.0, 121.5, 118.9, 116.7, 95.7. HRMS (ESI/TOF-Q): 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)


24

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This

compound

was

prepared

from

diethyl

2-(((3-methyl-1-phenyl-1H-pyrazol-5-

yl)amino)methylene)malonate (69 mg) according to procedure 1. The product was isolated as yellow crystalline solid in 68% yield (40 mg). m.p. (o C) = 150.0 – 151.2.

1

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/TOF-Q) 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 cm-1. 4-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (5f)

This compound was prepared from ethyl 2-cyano-3-((3-methyl-1-phenyl-1H-pyrazol-5yl)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, DMSO-d6) 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, DMSOd6) 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/TOF-Q) 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,


25


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Page 26 of 40

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 cm-1. Ethyl 4-hydroxybenzo[h]quinoline-3-carboxylate (5g)

This compound was prepared from diethyl 2-((naphthalen-1-ylamino)methylene)malonate (63 mg) according to procedure 1. The product was purified by prep-HPLC (30-60% 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, DMSO-d6) 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 cm-1. 4-hydroxybenzo[h]quinoline-3-carbonitrile (5h)


26

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This compound was prepared from ethyl 2-cyano-3-(naphthalen-1-ylamino)acrylate (53 mg) according to procedure 1. The product was isolated as a white chalky powder in 82% yield (36 mg). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 8.74 (s, 1H), 8.71 (dt, J = 6.3, 3.4 Hz, 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, DMSO-d6) 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 cm-1.

Bulk mode – Preparative scale synthesis of ethyl 7-methyl-4-oxo-4H-pyrido[1,2a]pyrimidine-3-carboxylate (4a)

A

25

mL

conical

flask

was

charged

with

diethyl


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 back-pressure regulator set to 100 bar, and the temperature set to 390° C. Sample was aspirated from the conical flask by way of the 3-way 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 near-continuous

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 offwhite powder in 82% yield (1.36 g).


27


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Page 28 of 40

Experimental Procedure 2 (Table 3) The flow rate on the PhoenixTM reactor was set to 0.5 mL/min, the back-pressure regulator set to 120 bar, and the temperature set to 390 oC. Substrates (0.2 mmol) were added to 4 mL vials, 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 prep-HPLC unless otherwise noted. Characterization data (Table 3) 7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6a)

This

compound

was

prepared

from

diethyl


yl)amino)methylene)malonate (56 mg) according to procedure 2. The product was isolated as a cream-coloured powder in 82% yield (26 mg). 1H NMR (400 MHz, DMSO-d6) 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, DMSO-d6) δ 156.3, 151.7, 149.3, 141.6, 127.4, 124.8, 123.7, 103.3, 17.7. HRMS (ESI/TOF-Q) 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


yl)amino)methylene)malonate (56 mg) according to procedure 2. The product was purified by prep-HPLC (3-30% ACN/H2O+NH4OAc) to give the title compound as a white powder in 48%


28

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yield (16 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 2.57 (s, 3H).

13

C NMR (100 MHz,

DMSO-d6) δ 177.8, 162.9, 150.7, 140.4, 135.2, 120.3, 118.6, 110.1, 24.8. HRMS (ESI/TOF-Q) m/z: [M+H]+ calcd for C9H9N2O: 161.0709; found: 161.0712. 9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6c)

This

compound

was

prepared

from

diethyl


yl)amino)methylene)malonate (56 mg) according to procedure 2. The product was isolated as a white powder in 67% yield (21 mg). 1H 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).

13

C NMR (100 MHz, CDCl3) δ 158.4, 154.0, 151.6, 135.1, 125.6, 115.2,

104.8, 18.4. HRMS (ESI/TOF-Q) 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 8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (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, DMSO-d6) 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, DMSOd6) 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


29


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Page 30 of 40

Hz), 110.7 (q, J = 3.0 Hz), 106.5. 19F NMR (375 MHz, DMSO-d6) δ -64.22. HRMS (ESI/TOFQ) m/z: [M+H]+ calcd for C9H6F3N2O: 215.0427; found: 215.0436. 7-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (6e)

This

compound

was

prepared

from

diethyl


yl)amino)methylene)malonate (56 mg) according to procedure 2. The product was purified by column chromatography to give the title compound as an off-white powder in 67% yield (22 mg). 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.8 Hz, 1H), 8.26 (d, J = 6.2 Hz, 1H), 7.62 (d, J = 9.6 Hz, 1H), 7.53 (dd, J = 9.6, 2.8 Hz, 1H), 6.44 (d, J = 6.2 Hz, 1H), 3.96 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.7, 153.5, 151.0, 148.9, 131.6, 127.3, 106.9, 104.1, 56.6. HRMS (ESI/TOF-Q) m/z: [M+H]+ calcd for C9H9N2O2: 177.0659; found: 177.0662. 5H-thiazolo[3,2-a]pyrimidin-5-one (6f)

This

compound

was

prepared

from

diethyl


yl)amino)methylene)malonate (54 mg) according to procedure 2. The product was isolated as an off-white powder in 73% yield (22 mg). Characterization data was compared and fully concordant with that already reported in the literature.2b, 23 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 4.9 Hz, 1H), 8.03 (d, J = 6.4 Hz, 1H), 7.57 (d, J = 4.9 Hz, 1H), 6.25 (d, J = 6.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 164.0, 158.1, 153.6, 122.4, 114.1, 105.5. MS (ESI) m/z: [M+H]+ calcd for C9H7N2OS: 153.2; found: 153.1. 7-chloroquinolin-4-ol (6g)


30

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


This compound was prepared from diethyl 2-(((3-chlorophenyl)amino)methylene)malonate (60 mg) according to procedure 2. The product was isolated as a white powder in 55% yield (20 mg). Characterization data was compared and fully concordant with that already reported in the literature.15 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 8.7, 2.1 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 176.7, 141.3, 140.5, 136.6, 127.8, 124.8, 123.9, 117.9, 109.7. MS (ESI) m/z: [M+H]+ calcd for C9H7ClNO: 180.0; found: 180.3. 6-bromoquinolin-4-ol (6h)

This compound was prepared from diethyl 2-(((4-bromophenyl)amino)methylene)malonate (68 mg) according to procedure 2. The product was isolated as a white powder in 84% yield (38 mg). Characterization data was compared and fully concordant with that already reported in the literature.24 1H NMR (400 MHz, DMSO-d6) δ 12.02 (br s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 7.4 Hz, 1H), 7.79 (dd, J = 8.8, 2.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 6.11 (d, J = 7.4 Hz, 1H). 13

C NMR (100 MHz, DMSO-d6) δ 175.3, 140.1, 138.9, 134.5, 127.0, 127.0, 121.0, 115.9, 108.9.

MS (DCI) m/z: [M+NH4]+ calcd for C9H10N2OBr: 240.1; found: 240.9. benzo[h]quinolin-4(1H)-one (6i)


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This compound was prepared from diethyl 2-((naphthalen-1-ylamino)methylene)malonate (63 mg) according to procedure 2. The product was isolated as a white powder in 46% yield (18 mg). Characterization data was compared and fully concordant with that already reported in the literature.23 1H NMR (400 MHz, DMSO-d6) δ 8.78 – 8.70 (m, 1H), 8.24 (d, J = 7.1 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.08 (dd, J = 6.2, 3.4 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.79 (dt, J = 6.5, 3.6 Hz, 2H), 6.62 (d, J = 7.1 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 174.6, 140.8, 138.2, 134.7, 129.6, 129.3, 127.8, 125.5, 124.0, 122.7, 121.6, 121.2, 110.5. MS (ESI) m/z: [M+H]+ calcd for C13H10NO: 196.1; found: 196.2. 3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol (6j)

This

compound

was

prepared

from

diethyl

2-(((3-methyl-1-phenyl-1H-pyrazol-5-

yl)amino)methylene)malonate (34 mg) according to procedure 2. The product was isolated as a beige powder in 58% yield (13 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.28 – 8.19 (m, 3H), 7.61 – 7.45 (m, 2H), 7.31 – 7.22 (m, 1H), 6.60 (d, J = 5.5 Hz, 1H), 2.63 (s, 3H). 13C NMR (100 MHz, DMS-d6O) δ 161.4, 152.6, 150.2, 142.2, 139.4, 128.9, 125.1, 120.0, 107.6, 103.6, 14.3. HRMS (ESI/TOF-Q) m/z: [M+H]+ calcd for C13H12N3O: 226.0975; found: 226.0979. (E)-ethyl 3-((3-chlorophenyl)amino)acrylate (8)


32

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H N

OEt O

Cl

A mixture of 3-chloroaniline (51 mg, 0.4 mmol) and ethyl propiolate (55 µL, 0.48 mmol) in 1,2-DCE (4 mL) was stirred at 60 oC for 12 hours. Solvent was removed under reduced pressure, and the residue purified by column chromatography to give the title compound as a pale yellow oil (12 mg, 13%). Characterization data was compared and fully concordant with that already reported in the literature. 25 1H NMR (400 MHz, CDCl3) δ 9.91 (d, J = 12.5 Hz, 0H), 7.28 – 7.12 (m, 1H), 6.98 – 6.92 (m, 1H), 6.82 (ddd, J = 8.1, 2.2, 1.1 Hz, 0H), 4.88 (d, J = 8.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 1H), 1.30 (t, J = 7.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 170.0, 142.0, 135.2, 130.4, 122.1, 114.9, 113.4, 88.6, 59.3, 14.2. Experimental Procedure 3 (Table 4) The flow rate on the PhoenixTM reactor was set to 0.25 mL/min, the back-pressure regulator set to 120 bar, and the temperature set to 400 oC. Substrates (0.2 mmol) were added to 4 mL vials and dissolved in 4.0 mL of the feed solvent. The sample injected into the PhoenixTM using the autosampler. The crude reaction mixtures were collected in 20 mL scintillation vials, concentrated, and purified by prep-HPLC unless otherwise noted. Characterization data (Table 4) 3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-amine (7a)

This compound was prepared from ethyl 2-cyano-3-((3-methyl-1-phenyl-1H-pyrazol-5yl)amino)acrylate (30 mg) according to procedure 3. The product was isolated as a beige powder


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in 58% yield (18 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.35 – 8.21 (m, 2H), 7.99 (d, J = 5.5 Hz, 1H), 7.56 – 7.41 (m, 2H), 7.27 – 7.16 (m, 1H), 6.59 (br s, 2H), 6.31 (d, J = 5.5 Hz, 1H), 2.65 (s, 3H).

13

C NMR (100 MHz, DMSO-d6) δ 152.9, 150.5, 149.5, 141.9, 139.8, 128.8, 124.5,

119.6, 104.8, 101.4, 14.9. HRMS (ESI/TOF-Q) m/z: [M+H]+ calcd for C13H13N4: 225.1135; found: 225.1138. IR (neat): 3481, 3314, 3194, 3078, 2982, 2920, 2852, 1632, 1590, 1574, 1506, 1492, 1446, 1406, 1389, 1364, 1326, 1303,1290, 1263, 1137, 1096, 1064, 1015, 902, 821, 777, 747, 708, 687, 650, 614, 578, 543 cm-1. 1-benzyl-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-amine (7b)

This compound was prepared from (E)-ethyl 3-((1-benzyl-3-methyl-1H-pyrazol-5-yl)amino)2-cyanoacrylate (62 mg) according to procedure 3. The product was isolated as a creamcoloured powder in 76% yield (36 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 5.4 Hz, 1H), 7.32 – 7.14 (m, 5H), 6.43 (s, 2H), 6.17 (d, J = 5.4 Hz, 1H), 5.40 (s, 2H), 2.54 (s, 3H). 13C NMR (100 MHz, DMSO) δ 153.0, 150.3, 149.2, 139.5, 138.2, 128.3, 127.4, 127.1, 103.2, 99.9, 49.1, 14.7. HRMS (ESI/TOF-Q) m/z: [M+H]+ calcd for C14H15N4: 239.1291; found: 239.1298. IR (neat): 3467, 3301, 3099, 3029, 2955, 2921, 2851, 2800, 1645, 1598, 1575, 1505, 1492, 1461, 1448, 1417, 1397, 1363, 1328, 1290, 1243, 1151, 1133, 1090, 1025, 1009, 967, 948, 889, 815, 792, 729, 708, 692, 667, 587, 560 cm-1. benzo[h]quinolin-4-amine (7c)


34

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This compound was prepared from ethyl 2-cyano-3-(naphthalen-1-ylamino)acrylate (53 mg) according to procedure 3. The product was isolated as a white powder in 28% yield (11 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.91 (br s, 2H), 8.91 – 8.80 (m, 1H), 8.46 (d, J = 6.9 Hz, 1H), 8.27 (d, J = 9.1 Hz, 1H), 8.23 – 8.14 (m, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.96 – 7.84 (m, 2H), 7.01 (d, J = 6.9 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 151.8, 148.8, 146.3, 133.2, 131.3, 127.6, 127.5, 126.2, 124.4, 123.8, 120.1, 114.4, 104.9. HRMS (ESI/TOF-Q) m/z: [M+H]+ calcd for C13H11N2: 195.0917; found: 195.0922. 4-amino-7-methoxyquinoline-3-carbonitrile (7d)

This compound was prepared from 2-(((3-methoxyphenyl)amino)methylene)malononitrile (40 mg) according to procedure 3. The product was isolated as a pale pink powder in 41% yield (16 mg). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 3H), 9.05 (s, 1H), 8.50 (d, J = 9.3 Hz, 1H), 7.41 (dd, J = 9.3, 2.5 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 3.96 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 164.3, 157.1, 148.0, 140.8, 126.3, 118.5, 114.6, 110.2, 101.7, 85.4, 56.3. HRMS (ESI/TOF-Q) m/z: [M+H]+ calcd for C11H10N3O: 200.0818; found: 200.0823.

ASSOCIATED CONTENT


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Supporting Information. Optimization data from DOE study (Figure 3), 1H and 13C NMR spectral data for all prepared compounds and a detailed description of modifications to the PhoenixTM flow reactor are provided. AUTHOR INFORMATION Corresponding Author •

[email protected]

Author Contributions All authors are employees or former employees of AbbVie. This study was sponsored by AbbVie. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the manuscript. Notes The authors declare no completing financial interest. ACKNOWLEDGMENT We thank the staff in the structural chemistry group for structural chemistry support, the staff in the analytical and purification sciences group for purification support, Maurice Pheil for IR support and Jeff Pan for helpful discussions on the PhoenixTM. We also thank IMSERC Mass Spectrometry at Northwestern University for assistance with HRMS. All authors are employees or former employees of AbbVie. AbbVie contributed to the study design, research, interpretation of data, writing, reviewing and approving the manuscript. The financial support for this research was provided by AbbVie.


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1

a) Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med. Chem. 2009, 52, 2952–2963;

b) Brown, D. G.; Boström, J. J. Med. Chem. 2016, 59, 4443–4458. 2

Gould, R.G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890–2895.

3

Razzaq, T.; Kappe, C. O. Chem-Asian J. 2010, 5, 1274 –1289.

4

a) Bogdan, A. R.; Charaschanya, M.; Dombrowski, A. W.; Wang, Y., Djuric, S. W. Org. Lett.

2016, 18, 1732–1735; b) Charaschanya, M.; Bogdan, A. R.; Wang, Y.; Djuric, S. W. Tetrahedron Lett. 2016, 57, 1035–1039. 5

a) Struass, C. R. Aust. J. Chem. 1999, 52, 83–96; b) Cablewski, T.; Gurr, P. A.; Pajalic, P. J.;

Strauss, C. R. Green Chem. 2000, 2, 25–28; c) Černuchová, P.; Vo-Thanh, G.; Milata, V.; Loupy, A. Heterocycles 2004, 64, 177–191. 6

a) Lengyel, L. C.; Nagy, T. Z.; Sipos, G.; Jones, R.; Dormán, G.; Ürge, L.; Darvas, F.

Tetrahedron Lett. 2012, 53, 738–743; b) Lengyel, L. C.; Sipos, G.; Sipócz, T.; Vagó, T.; Dormán, G.; Gerencsér, J.; Makara, G.; Darvas, F. Org. Proc. Res. Dev. 2015, 19¸ 399–409. 7

A screen of common organic solvents showed little effect on the reaction outcome.

Tetrahydrofuran was selected as the optimal solvent due to its low boiling point, and its use in previous preparations on the PhoenixTM flow reactor in literature (see ref 6a). 8

Lengyel and co-workers also observe similar results in their pyrolysis reactor in their

synthesis of a thiazolopyrimidinone (see ref 6b). 9

For a review, see: Heeb, S.; Fletcher, M. P.; Chhabra, S. R.; Diggle, S. P.; Williams, P.;

Cámara, M. FEMS Microbiol. Rev. 2011, 35, 247–274.


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10

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Zaman, A. U.; Khan, M. A.; Munawar, M. A.; Athar, M. M.; Pervaiz, M.; Pervais, A.;

Mahmood, A. Asian J. Chem. 2015, 27, 2823–2826. 11

(a) Hardy, C. R. Adv. Heterocycl. Chem. 1984, 36, 343–409; (b) Lynch, B. M.; Khan, M. A.;

Teo, H. C.; Pedrotti, F. Can. J. Chem. 1988, 66, 420–428. 12

a) Cantillo, D.; Sheibani, H.; Kappe, O. C. J. Org. Chem. 2012, 77, 2463–2473; b) Lipson,

V.V.; Gorobets, N. Y. Mol. Diversity 2009, 13, 399–419; c) Gaber, A.E.M.; McNab, H. Synthesis 2001, 14, 2059–2073. 13

a) Tilstam, U.; Defrance, T.; Giard, T. Org. Process. Res. Dev. 2009, 13, 312–232; b)

Nursanto, E. B.; Nugroho, A.; Hong, S.-A.; Kim, S. J.; Chung, K. Y.; Kim, J. Green Chem. 2011, 13, 2714–2718 14

Alanine et al. have previously demonstrated that effective residence time of toluene at

elevated temperatures is shorter than calculated due to the thermal expansion of solvent. As THF is likely near or in supercritical state at 390 oC, fluid compressibility under pressure may play a role in effective residence time. See: Martin, R. E.; Morawitz, F.; Kuratli, C.; Alker, A. M.; Alanine, A. I. Eur. J. Org. Chem. 2011, 1, 47–52. 15

Product 8 was prepared from Cu-catalyzed hydroamination of ethyl propriolate with 3-

chloroaniline. See Supporting Information for further details. 16

β-anilino- and β-m-chloroanilino-acrylates were reported to cyclize to form the 4-

hydroxyquinoline product at very high dilutions at 250 oC in diphenyl ether. See: Price, C. C.; Leonard, N. J.; Reitsema, R. H. J. Am. Chem. Soc. 1946, 68, 1256–1258.


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17

Selected examples: a) Foster, R. E.; Lipscomb, R. D.; Thompson, T. J.; Hamilton, C. S. J.

Am. Chem. Soc. 1946, 68, 1327–1330; b) Dow, R. L.; Koch, K.; Schulte, G. R. 4Aminopyrazolo(3,4-D)Pyrimidine

and

4-Aminopyrazolo(3,4-D)pyridine

Tyrosine

Kinase

Inhibitors. US Patent 4493996, January 14, 1997. 18

a) Singh, G. R. Synthesis 2005, 35, 2315–2320; b) Smith, R. B.; Faki, H.; Leslie, R.; Synth.

Comm. 2011, 41, 1492–1499. 19

a) Richardson Jr., A.; McCarty, F. J. J. Med. Chem. 1972, 15, 1203-1206; b) Allen, C. F. H.;

Beilfuss, H. R.; Burness, D. M.; Reynolds, G. A.; Tinker, J. F.; VanAllan, J. A. J. Org. Chem. 1959, 24, 787–793. 20

Agui, H.; Komatsu, T.; Nakagome, T. J. Heterocyclic Chem. 1975, 12¸ 557-563.

21

Hu, Y.; Green, N.; Gavrin, L. K.; Janz, K; Kaila, N.; Li, H.-Q.; Thomason, J. R; Cuozzo, J.

W.; Hall, J. P.; Hsu, S.; Nickerson-Nutter, C.; Telliez, J.-B.; Lin, L.-L.; Tam, S. Bioorg. Med. Chem. Lett. 2006, 16, 6067–6072. 22

Vincetti, P.; Caporuscio, F.; Kaptein, S.; Gioiello, A.; Mancino, V.; Suzuki, Y.; Yamamoto,

N.; Crespan, E.; Lossani, A.; Maga, G.; Rastelli, G.; Castagnolo, D.; Neyts, J.; Leyssen, P.; Costantio, G.; Radi, M. J. Med. Chem. 2015, 58, 4964–4975. 23

Cassis, R.; Tapia, R.; Valderrama, J. A. Synth. Commun. 1985, 15, 125–134.

24

Lavrado, J.; Ohnmacht, S. A.; Correia, I.; Leito, C.; Pisco, S.; Gunaratnam, M.; Moreira, R.;

Neidle, S.; Dos Santos, D. J.V.A.; Paulo, A. ChemMedChem 2015, 10, 836–849.


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Sirijindalert, T.; Hansuthirakul, K.; Rashatasakhon, P.; Sukwattanasinitt, M.; Ajavakom, A.

Tetrahedron 2010, 66, 5161-5167.


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Synthesis of Fused Pyrimidinone and Quinolone ... - ACS Publications

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