Pd-Catalyzed Ag(I)-Promoted C3-Arylation of Pyrido[1,2-a]pyrimidin-4-ones with Bromo/Iodo-Arenes

Article abstract of DOI:10.1021/acs.joc.5b01573

A regioselective Ag(I)-promoted Pd-catalyzed C3-H activation-arylation of pyrido[1,2-a]pyrimidin-4-ones with bromo/iodo-(hetero)arenes under aqueous conditions has been developed. It affords an efficient access to pharmaceutically important versatile 3-aryl-pyrido[1,2-a]pyrimidin-4-ones. Interestingly, the arylation undergoes via a pathway with an unusual feature involving the formation of cationic arylpalladium species promoted by halo-sequestering Ag salts enabling concerted C3-palladation-deprotonation, as explored by relevant experiments and spectroscopic studies. The present approach is step economical, good yielding, and compatible with various functionalities and applicable to a wide range of starting materials.

Full text of DOI:10.1021/acs.joc.5b01573

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Pd-Catalyzed Ag(I)-promoted C3-arylation of pyrido[1,2-a]pyrimidin-4-ones with
bromo/iodo-arenes
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Sankar K. Guchhait,*,† and Garima Priyadarshani†
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†Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), S. A. S. Nagar (Mohali) ꢀ 160062, Punjab, India, Fax: 91 (0)172 2214692;
Tel: 91 (0)172 2214683
Email: skguchhait@niper.ac.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
Abstract
A regioselective Ag(I)ꢀpromoted Pdꢀcatalyzed C3ꢀH activationꢀarylation of pyrido[1,2ꢀ
a]pyrimidinꢀ4ꢀones with bromo/iodoꢀ(hetero)arenes under aqueous conditions has been
developed. It affords an efficient access to pharmaceutically important versatile 3ꢀarylꢀ
pyrido[1,2ꢀa]pyrimidinꢀ4ꢀones. Interestingly, the arylation undergoes via a pathway with an
unusual feature involving the formation of cationic arylpalladium species promoted by haloꢀ
sequestering Agꢀsalts enabling concerted C3ꢀpalladationꢀdeprotonation, as explored by relevant
experiments and spectroscopic studies. The present approach is stepꢀeconomical, goodꢀyielding,
compatible with various functionalities and applicable to a wide range of starting materials.
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NꢀFused bicyclic heterocycles1ꢀ5 have emerged as one of the most important heterocyclic
frameworks because of their diverse applications in pharmaceuticals, agrochemicals and material
sciences.6,7 In this family, pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone is an interesting scaffold displaying
versatile biological activities,8ꢀ10 such as CXCR3 antagonism,11 MexABꢀOprM specific efflux
pump inhibition,12 acetylcholinesterase inhibition,13 and HLE inhibition.14 In particular, C3ꢀ
arylated pyrido[1,2ꢀa]pyrimidinꢀ4ꢀones are often found as a valuable structural motif of a wide
range of pharmaceutically active compounds, such as endothelial cell dysfunction inhibitors,15
phosphoinositide 3ꢀkinase inhibitors,16 CXCR3 antagonists11 and cell growth inhibitors (Figure
1).17 Also, they have been reported as mesoionic pesticides.18 Pemirolast19 is a marketed antiꢀ
allergic drug belonging to this class.
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OMe
N
N
OMe
N
N
N
NH
O
N
N
O
Pemirolast (anti-allergic drug)
endothelial cell dysfunction inhibitor
N
CF3
F
O
HN
N
EtO2S
N
N
O
N
H
N
N
N
F
N
O
PI3K inhibitor
CN
CXCR3 inhibitor
Figure 1. A representative examples of drugs/ agents that possess
3ꢀarylꢀpyrido[1,2ꢀa]ꢀpyrimidinꢀ4ꢀone motif.
Despite of enormous importance, surprisingly, a few synthetic approaches to access C3ꢀ
arylated pyrido[1,2ꢀa]pyrimidinꢀ4ꢀones have been documented so far (Figure 2). Hermecz
demonstrated an approach of classical intramolecular transꢀamidation of 2ꢀphenyl substituted
enamine ester.20 However, in the approach, a competing N→C acyl migration leading to
formation of thermodynamically relatively more stable 1,8ꢀnaphthridine as major side product
and requirement of harsh conditions and high heating were main limitations. The method of
[4+2] cycloaddition of chlorophenylketene precursor with aminopyridineꢀderived imines
providing 3ꢀphenylꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones is poor yielding.21 In approach of Suzukiꢀ
coupling reaction22 of C3ꢀbromo/chloro derivatives of pyridopyrimidinones with arene boronic
acids, the hydrodehalogenation reaction was found to compete in significant extent. In addition,
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the coupling required longer time upto 4 days and the use of a specific Pdꢀligand complex as
catalyst. The relative lower reactivity of C3ꢀchloro/bromo derivatives of pyridopyrimidinone has
been overcome later by using 3ꢀiodo derivatives,23 but the microwave irradiation for
considerably longer time (2 h) was mandatory.
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Remarkably, the pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone skeleton is known to possess several
unusual chemical characteristics. Pyrido[1,2ꢀa]pyrimidinones undergo thermal rearrangement via
carbonyl ketene intermediates,24 decomposition into aminopyridines in the harsh treatment with
acids or bases,20 and nucleophilic ring opening.25,26 These susceptibilityꢀfeatures of the skeleton
are obviously the impeding factors for convenient preparation/derivatization of this class of
compounds.
Figure 2. Reported approaches and the present route
The direct arylation via CꢀH bond activation has significantly grown in past decade and
become one of the most widely explored reactions by the organic chemists.27 These reactions are
featured with instinct attractive qualities, nonꢀrequirement of preꢀfunctionalization of arenes,
avoidance of preparing organometallic coupling partners, atomꢀeconomical and production of
less waste. In this area, of the particular interest is the development of approach accommodating
unexplored valuable heteroꢀarenes as CꢀH partners.28ꢀ30 Recently, Pdꢀcatalyzed regioselective
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direct arylations have been documented for pharmaceuticallyꢀimportant numerous Nꢀfused
heterocyclic motifs, for example, imidazo[1,2ꢀa]pyridines,31 indolizines,32 pyrazolo[1,5ꢀ
a][1,3,5]triazinꢀ4(3H)ꢀones,33 imidazo[1,2ꢀa]pyrazines34 and imidazo[1,2ꢀb]pyridazines.35 These
structural arylꢀmodulation of Nꢀfused bicycles have been found useful in the discovery of new
potent bioactive agents.36,37 To the best of our knowledge, pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone, a
privileged skeleton, has not been investigated yet for CꢀH bond functionalizationꢀarylation. In
the course of our continuous research on convenient and diversityꢀfeasible syntheses of
pharmaceutically promising heterocyclic compounds, we were interested in the preparation of 3ꢀ
arylꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones. Herein, we report a Pdꢀcatalyzed Ag(I)ꢀpromoted C3ꢀH
activationꢀarylation of pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone in aqueous coꢀsolvent, affording a novel
route to conveniently access versatile 3ꢀarylꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones. The mechanism
involving a distinctive feature has been explored with relevant studies.
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At the outset, the C3ꢀarylation reactions of pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone following
various Pdꢀ and Cuꢀcatalytic methods38,39 developed for arylation of structurally related
heterocycles with arene electrophiles (haloarenes and arene boronic acids) and a radicalꢀbased
direct arylation40 protocol were tried. However, the desired C3ꢀarylated product was obtained in
not more than 24% yield. Variation in reagents/conditions also could not improve the yield.
Next, following our previously reported Pdꢀcatalyzed method for direct arylation of imidazo[1,2ꢀ
a]pyrazines with boromoarenes a reaction of pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone with bromobenzene
was performed.34 The desired product was obtained in 13% yield only. Further studies with
variation of the reagents/conditions of Pdꢀcatalyzed method revealed that the use of cesium
carbonate, (tBu)2PMe.HBF4 and PivOH, gave the desired product in 26% yield. It also indicated
the use of pivalic acid indispensable for this transformation. Therefore, subsequent evaluations
were done using PivOH. The key results are summerized in the Table 1. The study of various
solvents ranging from weakly polar to polar aprotic or polar weakly protic showed a significant
effect on the reaction (entries 1ꢀ8). In polar aprotic or weakly protic solvents (DMA, NMP and
PEGꢀ400), the reaction completed within 2 h, but the side reactions were considerably high.
When moderately polar solvents (acetonitrile and THF) were used, trace reaction conversions
were observed. The side reactions were found to be little as a weakly polar solvent toluene was
used, although the desired product was obtained in 35% yield due to incomplete conversion.
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Table 1: Screening of solvents, ligands, bases and additives
N
N
Ph
Reaction conditiona
N
Br
H
N
Ph
O
O
9
#
Variable
Temp
(°C)
Time Yield
(h)
(%)b
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Pd(OAc)2 (10 mol %), Cs2CO3 (3 eq), PivOH (30
mol%), (tBu)2PMe.HBF4 (20 mol%), Solvent (2 mL)
1
2
3
4
5
6
7
8
DMF
DMA
NMP
MeCN
Toluene
1,4ꢀdioxane
THF
110
110
110
80
110
110
80
48
2
2
48
6
8
24
8
10
Trace
35
26
Trace
Trace
24
6
PEGꢀ400
110
Pd(OAc)2 (10 mol %), Cs2CO3 (3 eq), PivOH (30
mol%), Ligands (20 mol %), toluene
9
BINAP
Xantphos
DavePhos
DPPM
DPPP
(oꢀtol)3P
(Cy)3P
–
110
110
110
110
110
110
110
110
110
6
6
6
6
10
12
8
15
11
33
42
NR
12
10
11
12
13
14
15
16
6
12
12
12
24
17c Pd(PPh3)4
Pd(OAc)2 (10 mol %), (Cy)3P (20 mol%), PivOH
(30 mol%), Base (3 eq), toluene
18
19
20
K2CO3
Na2CO3
KOtBu
110
110
110
20
20
20
48
15
NR
Pd(OAc)2 (10 mol %), (Cy)3P (20 mol%), K2CO3 (3
eq), PivOH (30 mol%), Ag-salt (1 eq), toluene
21
22
23
24
AgOTf
AgOAc
Ag2O
110
110
110
110
20
20
20
20
65
61
25
68
Ag2CO3
aSubstrates, reagents and condtions: Pyridopyrimidineꢀ4ꢀone (0.5 mmol),
PhBr (2 equiv); byield for maximum conversion in optimum time;
cPd(OAc)2 and PCy3 were not used.
We then looked for evaluating different monoꢀ and biꢀdentate ligands (entries 9ꢀ15). Among the
ligands tested, monodentate ligands were proved to be better and triꢀcyclohexylphosphine was
the best, providing 42% yield. In the absence of a ligand, the reaction did not take place. Use of a
Pd(0) catalyst precursor, Pd(PPh3)4 lowered the yield. In screening of bases, potassium carbonate
was found to be more effective.
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Table 2: Synthesis of 3ꢀarylpyridopyrimidinonea
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9
N
N
O
N
O
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N
N
N
O
Cl
F
b
3a,
72%
3b,
70%
3c,
75%
N
N
N
N
F
N
N
O
O
O
CF3
OCF3
3d
3e
3f
, 71%
N
, 68%
, 73%
N
N
N
N
N
O
, 64%
O
, 67%
O
Me
COMe
CHO
OMe
3i
3g
3h
, 71%
N
N
N
N
OMe
OMe
N
N
O
O
, 72%
O
, 70%
OMe
OMe
3j
3l, 69%
3k
N
N
N
N
OMe
OMe
N
N
O
O
O
O
O
3o
, 65%
3m
, 65%
3n
, 70%
OMe
N
OMe
N
N
N
N
N
N
N
O
O
, 62%
O
3r
, 61%
3q
, 66%
3p
OBn
N
O
N
O
N
O
N
N
N
Me
Ph
Ph
Ph
Ph
3s
, 71%
3t
, 64%
3u
, 54%
aSubstrates, reagents and condtions: Pyridopyrimidineꢀ4ꢀone (0.5 mmol),
ArBr (2 equiv), Pd(OAc)2 (10 mol%), PCy3 (20 mol%), PivOH (1 equiv),
Ag2CO3 (1 equiv), K2CO3 ( 3equiv), toluene:water (3:1, 2 mL), 110 °C;
byield for maximum conversion in optimum time.
Fortunately, a significant improvement in the yield (65%) of the product was obtained by
addition of a silver salt, AgOTf. This prompted us to investigate various silver salts (entries 21ꢀ
24). Silver carbonate was found to be best (68% yield). When the reaction was performed in
aqueous coꢀsolvent (TolueneꢀH2O ꢀ 3:1) and with 1 equiv. of pivalic acid, the yield enhanced to
72%. The reaction without pivalic acid provided virtually no arylation, indicating pivalate anion
necessary for this arylation.
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With the developed protocol, we next investigated its generality towards generation of 3ꢀ
arylꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones with substitutions/functionalitiesꢀdiversities (Table 2). We
were pleased to find that protocol was flexible for versatile pyrido[1,2ꢀa]pyrimidinones and
bromoarenes and the products were obtained in good yields. Bromoarenes bearing electronꢀ
withdrawing as well as electronꢀdonating substituents and heteroaryl bromides were compatible.
Unfortunately, the reaction did not work with pyridopyrimidinones with C2ꢀsubstitutions, such
as phenyl and methyl moieties. The reaction method also was found to be nonꢀflexible to enable
the arylation of 4Hꢀpyrazino[1,2ꢀa]pyrimidinꢀ4ꢀone. Gratifyingly, the functional groups like
formyl, acetyl, benzyloxy, and dioxomethylene were tolerated under the reaction conditions.
This provides an opportunity of their further derivatization towards preparation of products with
elaborate substitution patterns. Importantly, the method did not produce any of regioꢀisomeric
arylated and polyꢀarylated products. The products that are known to be generated from ring
opening/rearrangement/degradation of the skeleton did not form in the present method, as
indicated by mass spectrometry of crude mixtures of several reactions. There was no oxidative
homoꢀcoupling of pyridopyrimidinone and the homoꢀcoupling of bromoꢀarenes occurred in
traces for some cases. Iodobenzene provided product yield (63%) as similar as that obtained
using bromoarenes, while, chlorobenzene was found to be nearly nonꢀreactive. Aromatic alcohol
derivatives, phenyl tosylate and phenyl triflate were less reactive (7ꢀ12 % yields). The reaction
performed at 2 mmol scale did not cause considerable decrease in the yield of the product
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We were then interested to gain inside the possible mechanism. The electronically varied
substituents linked to bromoarenes showed nonꢀsignificant influence on the reaction rate and
yields, which ruled out the possibility of eletrophilic aromatic palladation (SEAr) in the arylation.
The Heckꢀtype pathway would promote C2ꢀarylation of pyrido[1,2ꢀa]pyrimidinone due to more
electronꢀrich at C3 of the nucleus. The presence of pivalate was found mandatory for the
reaction. The observation is in accordance with the Pdꢀcatalyzed CꢀH functionalizationꢀarylation
that occur via concerted metalation deprotonation (CMD) pathway.41ꢀ45 The ESIꢀMS (see SI) of
three sets of reaction of pyridopyrimidinone with 4ꢀbromotoluene, pyridopyrimidinone with 4ꢀ
bromoanisole and 7ꢀmethylpyridopyrimidinone with 4ꢀbromobenzene suggested the formation of
CMD transition state (Figure 3, TS C). IR studies of crude reaction mixtures obtained after
intermediate times (2, 6, 10 h) were done and no shift in C=O stretching frequency (1693 cmꢀ1)
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was observed (SI, spectra), indicating nonꢀinvolvement of C=O oxygen or πꢀbond chelation to
Pd for C3ꢀpalladation or stabilization of TS.46ꢀ48 The present reaction required stoichiometric Agꢀ
salts, preferentially Ag2CO3. On the other hand, the reactions in the presence of oxidizing agents
commonly used for Pd(II)ꢀPd(0) catalysis, such as PhI(OAc)2, Cu(OAc)2 or K2S2O8 provided
traces or no arylation product. Therefore, in this case, Ag2CO3 plays not as oxidizing agent, but
as halogen scavenger and an important function in the generation of cationic
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Figure 3. Plausible Mechanism
arylpalladium species. The formation of such highly reactive cationic species has been essential
for reacting with pyridopyrimidinone in the presence of pivalate anion to enable CꢀH activation
and Cꢀpalladation via construction of CMD TS. This is also supported by the fact that both of
bromoꢀ and iodoꢀarene required Ag2CO3 and were found to be similarly reactive arylating agents,
although the poisoning49 of Pdꢀcatalyst is known to occur by iodide only. Based on these
characteristics of the present reaction, a plausible mechanism is outlined (Figure 3). It involves
the oxidative addition of ArBr to Pd(0), silverꢀpromoted generation of cationic arylpalladium
species, formation of CMD TS, and reductive elimination providing arylation product and
regeneration of Pd(0).
In conclusion, we have developed for the first time a regioselective Pdꢀcatalyzed Ag(I)ꢀ
assisted direct C3ꢀH activationꢀarylation of pyrido[1,2ꢀa]pyrimidinꢀ4ꢀones with bromo/iodoꢀ
(hetero)arenes en route to biologically relevant versatile 3ꢀarylꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones.
Remarkably, the protocol is stepꢀeconomical, general for various coupling partners, devoid of
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usual side reactions, overcomes the known difficulties due to skeletonꢀsusceptibility and
effective for preparing products in good yields under aqueous conditions, which are common
limitations of the reported methods. Interestingly, in this direct arylation, the formation of
cationic arylpalladium species assisted by Ag2CO3 as haloꢀsequestering agent was found to be
essential for reaction with pyridopyrimidinone in the presence of pivalate anion and promoting
the C3ꢀpalladationꢀdeprotonation; an unusual feature for CMDꢀbased arylations and important
for studying new reactions. This work is resourceful for expanded application of arylꢀ
pyridopyrimidinones and will encourage for investigation of heteroarenes unexplored yet for Cꢀ
H activationꢀarylation.
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Experimental Section:
General information: Infrared (IR) spectra were recorded on a FTIR with ATR & IR
1
Microscope spectrometer. H NMR spectra were measured on a 400 MHz spectrometer. Data
were reported as follows: chemical shifts in ppm from tetramethylsilane as an internal standard
in CDCl3/CD3OD/DMSOꢀd6 integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, td = triplet of doublet, dt = doublet of triplet, ddd = doublet of doublet of
doublet, br = broad), and coupling constants (Hz). 13C NMR spectra were measured on a 100
MHz spectrometer with complete proton decoupling. Chemical shifts were reported in ppm from
the residual solvent as an internal standard. Highꢀresolution mass spectra (HRMS) were
performed on a high resolution LCMS/MS instrument with “QꢀTOF” mass analyser. For thin
layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica
gel 60 GF254, 0.25 mm) were used. The products were purified by column chromatography
silica gel 60ꢀ120 (Merck, silica gel 60ꢀ120 mesh, neutral, spherical).
The starting materials and solvents were used as received from commercial suppliers without
further purification.
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General experimental procedure for direct C3-arylation of pyrido[1,2-a]pyrimidinones:
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Pyridopyrimidinone (0.5 mmol), K2CO3 (1.5 mmol, 207 mg, 3 eq), Ag2CO3 (0.5 mmol, 137 mg,
1 eq), PCy3 (0.1 mmol, 28 mg, 0.2 eq), Pd(OAc)2 (0.05 mmol, 11 mg, 0.1 eq) were weighed in
air to a sealed tube equipped with magnetic stirring bar. PivOH (0.5 mmol, 0.06 mL, 1 eq) and
bromoarene (1 mmol, 2 eq) were added to the tube. The tube was purged with argon and toluene
(1.5 mL) and water (0.5 mL) were added to the resultant mixture. The mixture was heated at 110
°C for 18ꢀ24 h until complete consumption of the substrate as indicated by TLC. It was then
cooled to rt and concenterated under reduced pressure. The mixture was extracted with EtOAc
(2x50 mL) and washed with 10% aqueous ammonia solution (3x20 mL). The combined organic
solution was washed with water (2x5 mL) and brine (1x5 mL), dried with anhyd. Na2SO4, and
concentrated under reduced pressure. The column chromatographic purification of crude mass
was performed on silica gel partially deꢀacidified by passing triethylamine (1ꢀ2 mL) using
EtOAcꢀhexane (25ꢀ40%) as eluting solvent to afford the arylated products (3aꢀu).
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3-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one22 (3a): Yellow crystalline solid, 80 mg, 72%, m.p.
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167ꢀ169 °C; H NMR (400 MHz, CDCl3):
δ 9.20 (d, J = 7.1 Hz, 1H), 8.55 (s, 1H), 7.80 (d, J =
7.1 Hz, 2H), (m, 2H), 7.76ꢀ7.72 (m, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 7.8 Hz, J = 7.4
Hz, 2H), 7.36 (t, J = 6.7 Hz, 1H), 7.19 (dt, J = 7.2 Hz, J = 1.6 Hz, 1H) ppm; 13C{1H}NMR (100
MHz, CDCl3):
δ 156.8, 152.9, 150.7, 135.7, 134.3, 128.5, 127.8, 127.7, 126.5, 117.0, 115.9
ppm; IR: νmax 3136, 1668, 1630, 1494 cmꢀ1; HRMS (ESI) m/z: calcd. for C14H11N2O [M+H]+
223.0871, found: 223.0864.
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3-(4-Chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3b): Yellow solid, 89 mg, 70%, m.p.
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198ꢀ200 °C; 1H NMR (400 MHz, CDCl3):
δ 9.20 (ddd, J = 7.2 Hz, J = 1.5 Hz, J = 0.8 Hz, 1H),
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8.54 (s, 1H), 7.80ꢀ7.73 (m, 3H), 7.71 (ddd, J = 8.9 Hz, J = 1.4 Hz, J = 0.8 Hz, 1H), 7.43 (d, J =
8.7 Hz, 2H), 7.23 (dt, J = 7.2 Hz, J = 1.5 Hz, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
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δ
156.6,
152.8, 150.8, 135.9, 133.7, 132.7, 129.7, 128.7, 127.7, 126.6, 116.1, 115.8 ppm; IR: νmax 3136,
1668, 1630, 1494, 764 cmꢀ1; HRMS (ESI) m/z: calcd. for C14H10ClN2O [M(35Cl)+H]+ 257.0481,
found: 257.0474.
3-(4-Fluorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3c): Yellow solid, 102 mg, 75%, m.p.
>200 °C; 1H NMR (400 MHz, CDCl3):
δ 9.19 (ddd, J = 7.1 Hz, J = 1.4 Hz, J = 0.8 Hz, 1H), 8.52
(s, 1H), 7.80ꢀ7.74 (m, 3H), 7.70 (ddd, J = 8.9 Hz, J = 1.4 Hz, J = 0.8 Hz, 1H), 7.21 (dt, J = 7.2
Hz, J = 1.6 Hz, 1H), 7.15 (t, J = 8.8 Hz, 2H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
162.4 (d,
JCꢀF = 246 Hz), 156.8, 152.7, 150.7, 135.7, 130.23 (d, JCꢀCꢀCꢀF = 8 Hz), 130.23, 127.7, 126.6,
116.1, 115.9, 115.5 (d, JCꢀCꢀF = 21 Hz) ppm; IR: νmax 2924, 1672, 1634, 1484, 1298 cmꢀ1; HRMS
(ESI) m/z: calcd. for C14H10FN2O [M+H]+ 241.0777, found: 241.0774.
3-(3-Fluorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3d): Light yellow solid, 85 mg, 71%,
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m.p. 170ꢀ172 °C; H NMR (400 MHz, CDCl3):
δ 9.21 (ddd, J = 7.2 Hz, J = 1.4 Hz, J = 0.7 Hz,
1H), 8.56 (s, 1H), 7.78 (dt, J = 6.6 Hz, J = 1.6 Hz, 1H), 7.71 (ddd, J = 8.8 Hz, J = 1.2 Hz, J =
0.8 Hz, 1H), 7.61ꢀ7.55 (m, 2H), 7.44ꢀ7.40 (m, 1H), 7.23 (dt, J = 7.1 Hz, J = 1.5 Hz, 1H), 7.15
(ddd, J = 8.4 Hz, J = 2.6 Hz, J = 0.9 Hz, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 162.8 (d,
JCꢀF = 244 Hz), 156.6, 153.1, 150.9, 136.4 (d, JCꢀCꢀCꢀF = 9 Hz), 136.1, 129.9 (d, JCꢀCꢀCꢀF = 8 Hz),
127.8, 126.6, 123.9 (d, JCꢀCꢀCꢀCꢀF = 3 Hz), 116.1, 115.5 (d, JCꢀCꢀF = 23 Hz), 114.6 (d, JCꢀCꢀF = 21
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Hz) ppm; IR: νmax 3136, 3057, 1675, 1628, 1476, 1293 cmꢀ1; HRMS (ESI) m/z: calcd. for
C14H10FN2O [M+H]+ 241.0777, found: 241.0767.
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3-(4-(Trifluoromethyl)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one22 (3e): Light yellow solid,
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98 mg, 68%, m.p. >200 °C; 1H NMR (400 MHz, CDCl3):
δ 9.22 (ddd, J = 7.2 Hz, J = 1.4 Hz, J
= 0.8 Hz, 1H), 8.58 (s, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.82 (dt, J = 6.6 Hz, J = 1.5 Hz, 1H), 7.74ꢀ
7.70 (m, 3H), 7.27ꢀ7.23 (m, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
156.6, 153.3, 151.1,
137.9, 136.4, 129.6 (q, JCꢀCꢀF = 32 Hz), 128.6, 127.8, 126.6, 125.4 (q, JCꢀCꢀCꢀF = 4 Hz), 124.2 (q,
JCꢀF = 270 Hz), 116.3, 115.4 ppm; IR: νmax 3108, 1666, 1633, 1492, 1102, 1071 cmꢀ1; HRMS
(ESI) m/z: calcd. for C15H10F3N2O [M+H]+ 291.0745, found: 291.0745.
3-(4-(Trifluoromethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3f): Light yellow solid,
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111 mg, 73%, m.p. 175ꢀ177 °C; H NMR (400 MHz, CDCl3):
δ 9.21 (ddd, J = 7.2 Hz, J = 1.4
Hz, J = 0.8 Hz, 1H), 8.55 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.79 (ddd, J = 8.9 Hz, J = 6.5 Hz, J =
1.5 Hz, 1H), 7.71 (dd, J = 8.8 Hz, J = 0.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.24 (dt, J = 7.1 Hz,
J = 1.5 Hz, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 156.7, 152.9, 150.9, 148.7, (d, JCꢀOꢀCꢀF
= 2 Hz), 136.0, 133.0, 129.9, 127.7, 126.6, 121.0, 120.5 (q, JCꢀF = 256 Hz), 116.1, 115.6 ppm;
IR: νmax 3108, 1669, 1632, 1497, 1295, 1203, 1146 cmꢀ1; HRMS (ESI) m/z: calcd. for
C15H10F3N2O2 [M+H]+ 307.0694, found: 307.0688.
3-(4-Acetylphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3g): Light yellow solid, 88 mg, 67%,
m.p. >200 °C; 1H NMR (400 MHz, CDCl3):
δ 9.23 (ddd, J = 7.1 Hz, J = 1.4 Hz, J = 0.7 Hz, 1H),
8.61 (s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.84ꢀ7.79 (m, 1H), 7.73 (d, J =
8.8 Hz, 1H), 7.28ꢀ7.24 (m, 1H), 2.65 (s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
197.7,
156.5, 153.4, 151.1, 139.2, 136.4, 136.0, 128.6, 128.4, 127.8, 126.7, 116.3, 115.6, 26.7 ppm; IR:
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νmax 3073, 1672, 1630, 1491 cmꢀ1; HRMS (ESI) m/z: calcd. for C16H13N2O2 [M+H]+ 265.0977,
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found: 265.0973.
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3-(4-Formylphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3h): Yellow crystalline solid, 88 mg,
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71%, m.p. 165ꢀ167 °C; H NMR (400 MHz, CDCl3):
δ 10.05 (s, 1H), 9.24 (d, J = 6.9 Hz, 1H),
8.63 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.85ꢀ7.81 (m, 1H), 7.75 (d, J =
8.8 Hz, 1H), 7.27 (ddd, J = 8.3 Hz, J = 6.8 Hz, J = 1.2 Hz, 1H) ppm; 13C{1H}NMR (100 MHz,
CDCl3):
δ 191.9, 156.5, 153.5, 151.2, 140.7, 136.6, 135.3, 129.9, 128.8, 127.9, 126.7, 116.4,
115.3 ppm; IR: νmax 3047, 2835, 2733, 1694, 1668, 1632, 1484 cmꢀ1; HRMS (ESI) m/z: calcd. for
C15H11N2O2 [M+H]+ 251.0820, found: 251.0818.
3-(4-Methylphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3i): Yellow crystals, 75 mg, 64%
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yield, m.p. 142ꢀ144 °C; H NMR (400 MHz, CDCl3):
δ 9.19 (ddd, J = 7.2 Hz, J = 1.4 Hz, J =
0.8 Hz, 1H), 8.54 (s, 1H), 7.74ꢀ7.66 (m, 4H), 7.27 (d, J = 7.9 Hz, 2H), 7.20ꢀ7.16 (m, 1H), 2.40
(s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
156.8, 152.6, 150.5, 137.7, 135.4, 131.3, 129.2,
128.4, 127.7, 126.5, 117.1, 115.7, 21.3 ppm; IR: νmax 3136, 3027, 2920, 1668, 1630, 1485 cmꢀ1;
HRMS (ESI) m/z: calcd. for C15H13N2O [M+H]+ 237.1028, found: 237.1022.
3-(4-Methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one22 (3j): Yellow crystals, 90 mg, 72%
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yield, m.p. 142ꢀ144 °C; H NMR (400 MHz, CDCl3):
δ 9.18 (dd, J = 7.2 Hz, J = 1.1 Hz, 1H),
8.52 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.73ꢀ7.69 (m, 1H), 7.67 (ddd, J = 8.9 Hz, J = 1.5 Hz, J =
0.8 Hz, 1H), 7.19ꢀ7.15 (m, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H) ppm; 13C{1H}NMR (100
MHz, CDCl3):
δ 159.3, 156.9, 152.2, 150.3, 135.3, 129.7, 127.6, 126.6, 126.5, 116.9, 115.7,
114.0, 55.4 ppm; IR: νmax 2955, 2924, 1674, 1632, 1482, 1245, 1179 cmꢀ1; HRMS (ESI) m/z:
calcd. for C15H13N2O2 [M+H]+ 253.0977, found: 253.0974.
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3-(3-Methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3k): Yellow solid, 88 mg, 70% yield,
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m.p. 130ꢀ132 °C; H NMR (400 MHz, CDCl3):
δ 9.18 (d, J = 7.2 Hz, 1H), 8.56 (d, J = 1.6 Hz,
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1H), 7.75 (dt, J = 6.6 Hz, J = 1.5 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.40ꢀ7.35 (m, 3H), 7.19 (dt, J
= 6.5 Hz, J = 1.5 Hz, 1H), 6.93ꢀ6.90 (m, 1H), 3.86 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3):
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δ
159.6, 156.7, 153.0, 150.7, 135.7, 135.6, 129.5, 127.7, 126.5, 120.9, 116.8, 115.9, 114.1, 113.6,
55.3 ppm; IR: νmax 3080, 2937, 1674, 1497, 1282, 1041 cmꢀ1; HRMS (ESI) m/z: calcd. for
C15H13N2O2 [M+H]+ 253.0977, found: 253.0971.
3-(3,4-Dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3l): Yellow solid, 97 mg, 69%
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yield, m.p. 155ꢀ157 °C; H NMR (400 MHz, CDCl3):
δ 9.19 (d, J = 7.1 Hz, 1H), 8.55 (s, 1H),
7.74 (dt, J = 6.4 Hz, J = 1.5 Hz, 1H), 7.69 (dd, J = 8.8 Hz, J = 0.6 Hz, 1H), 7.47 (d, J = 2 Hz,
1H), 7.32 (dd, J = 8.3 Hz, J = 2 Hz, 1H), 7.19 (dt, J = 7.3 Hz, J = 1.6 Hz, 1H), 6.97 (d, J = 8.4
Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 156.9, 152.4, 150.3,
148.9, 148.8, 135.3, 127.5, 126.9, 126.5, 120.9, 116.8, 115.8, 111.9, 111.3, 55.9 ppm; IR: νmax
2956, 1672, 1630, 1479, 1277, 1024 cmꢀ1; HRMS (ESI) m/z: calcd. for C16H15N2O3 [M+H]+
283.1082, found: 283.1078.
3-(3,5-Dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3m): Yellow solid, 91 mg, 65%
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yield, m.p. 135ꢀ137 °C; H NMR (400 MHz, CDCl3):
δ 9.19 (ddd, J = 7.2 Hz, J = 1.3 Hz, J =
0.8 Hz, 1H), 8.56 (s, 1H), 7.76 (ddd, J = 8.9 Hz, J = 6.5 Hz, J = 1.6 Hz, 1H), 7.69 (ddd, J = 8.9
Hz, J = 1.3 Hz, J = 0.8 Hz, 1H), 7.20 (ddd, J = 7.1 Hz, J = 6.5 Hz, J = 1.5 Hz, 1H), 6.97 (d, J =
2.3 Hz, 2H), 6.49 (t, J = 2.3 Hz, 1H), 3.85 (s, 6H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
160.8, 156.6, 153.0, 150.7, 136.2, 135.8, 127.7, 126.5, 116.8, 115.9, 106.7, 100.2, 55.4 ppm; IR:
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νmax 2936, 1681, 1632, 1485, 1158, 1046 cmꢀ1; HRMS (ESI) m/z: calcd. for C16H15N2O3 [M+H]+
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283.1082, found: 283.1077.
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3-(Benzo[d][1,3]dioxol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (3n): Yellow solid, 93 mg,
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70%, m.p. >200 °C; H NMR (400 MHz, CDCl3):
δ 9.19 (dd, J = 7.2 Hz, J = 0.4 Hz, 1H), 8.49
(s, 1H), 7.74 (ddd, J = 8.9 Hz, J = 6.4 Hz, J = 1.5 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.34 (d, J =
1.7 Hz, 1H), 7.24 (dd, J = 8.1 Hz, J = 1.7 Hz, 1H), 7.19 (dt, J = 7.2 Hz, J = 1.6 Hz, 1H), 6.91 (d,
J = 8.1 Hz, 1H), 6.00 (s, 2H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 156.8, 152.4, 150.4, 147.8,
147.4, 135.4, 128.1, 127.6, 126.5, 122.3, 116.9, 115.8, 109.1, 108.5, 101.2 ppm; IR: νmax 3029,
2905, 1677, 1633, 1498, 1448, 1251, 1035 cmꢀ1; HRMS (ESI) m/z: calcd. for C15H11N2O3
[M+H]+ 267.0769, found: 267.0765.
3-(3,4,5-Trimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (3o): Yellow solid, 101 mg,
65%, m.p. 170ꢀ172 °C; 1H NMR (400 MHz, CDCl3):
δ 9.19 (ddd, J = 7.1 Hz, J = 1.5 Hz, J = 0.8
Hz, 1H), 8.56 (s, 1H), 7.76 (ddd, J = 8.9 Hz, J = 6.4 Hz, J = 1.5 Hz, 1H), 7.71 (ddd, J = 8.9 Hz, J
= 1.5 Hz, J = 0.8 Hz, 1H), 7.22 (ddd, J = 8.0 Hz, J = 6.5 Hz, J = 1.6 Hz, 1H), 7.05 (s, 2H), 3.93
(s, 6H), 3.90 (s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 156.8, 153.2, 152.7, 150.6, 137.9,
135.7, 129.8, 127.6, 126.9, 116.9, 115.9, 105.9, 60.9, 56.2 ppm; IR: νmax 2996, 1666, 1632, 1485,
1246, 1120 cmꢀ1; HRMS (ESI) m/z: calcd. for C17H17N2O4 [M+H]+ 313.1188, found: 313.1184.
3-(Naphthalen-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (3p): Yellow solid, 87 mg, 62% yield,
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m.p. 123ꢀ125 °C; H NMR (400 MHz, CDCl3):
δ 9.21 (d, J = 7.1 Hz, 1H), 8.49 (s, 1H), 7.94ꢀ
7.90 (m, 2H), 7.82ꢀ7.74 (m, 3H), 7.58ꢀ7.43 (m, 4H), 7.22 (dt, J = 7.2 Hz, J = 1.9 Hz, 1H) ppm;
13C{1H}NMR (100 MHz, CDCl3):
δ
157.1, 154.9, 151.3, 136.0, 133.8, 132.1, 132.0, 128.9, 128.5,
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128.4, 127.9, 126.6, 126.2, 125.9, 125.6, 125.5, 117.1, 115.9 ppm; IR: νmax 3036, 2926, 1678,
1638, 1483 cmꢀ1; HRMS (ESI) m/z: calcd. for C18H13N2O [M+H]+ 273.1028, found: 273.1025.
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3-(Pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (3q): Yellow solid, 73 mg, 66%, m.p. 170ꢀ
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172 °C; 1H NMR (400 MHz, CDCl3):
δ 9.21 (ddd, J = 7.2 Hz, J = 1.4 Hz, J = 0.8 Hz, 1H), 8.97
(dd, J = 2.2 Hz, J = 0.6 Hz, 1H), 8.60 (dd, J = 4.8 Hz, J = 1.6 Hz, 1H), 8.59 (s, 1H), 8.22 (ddd, J
= 7.9 Hz, J = 2.2 Hz, J = 1.7 Hz, 1H), 7.82 (ddd, J = 8.8 Hz, J = 6.6 Hz, J = 1.5 Hz, 1H), 7.74
(ddd, J = 8.8 Hz, J = 1.4 Hz, J = 0.8 Hz, 1H), 7.40 (ddd, J = 7.9 Hz, J = 4.8 Hz, J = 0.7 Hz, 1H),
7.28ꢀ7.24 (m, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 156.7, 152.9, 151.1, 149.0, 148.7,
136.4, 135.9, 130.3, 127.7, 126.7, 123.3, 116.3, 113.7 ppm; IR: νmax 3115, 1682, 1632, 1573,
1503 cmꢀ1; HRMS (ESI) m/z: calcd. for C13H10N3O [M+H]+ 224.0824, found: 224.0819.
3-(Pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (3r): Yellow solid, 68 mg, 61%, m.p. 160ꢀ
1
162 °C; H NMR (400 MHz, CDCl3):
δ 9.40 (s, 1H), 9.28 (ddd, J = 7.2 Hz, J = 1.3 Hz, J = 0.8
Hz, 1H), 8.69 (ddd, J = 4.7 Hz, J = 1.7 Hz, J = 0.8 Hz, 1H), 8.54 (dd, J = 8.1 Hz, J = 0.8 Hz,
1H), 7.84ꢀ7.75 (m, 3H), 7.28ꢀ7.22 (m, 2H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
156.6,
155.2, 152.3, 151.3, 149.3, 136.4, 127.9, 126.8, 123.5, 122.2, 116.3, 114.1 ppm; IR: νmax 3106,
3031, 1678, 1631, 1567, 1485 cmꢀ1; HRMS (ESI) m/z: calcd. for C13H10N3O [M+H]+ 224.0824,
found: 224.0818.
7-Methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3s): Yellow solid, 84 mg, 71%, m.p.
110ꢀ113 °C; 1H NMR (400 MHz, CDCl3):
δ 9.01 (s, 1H), 8.52 (s, 1H), 7.79 (d, J = 7.3 Hz, 2H),
7.64ꢀ7.58 (m, 2H), 7.46 (dd, J = 7.8 Hz, J = 7.5 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 2.46 (s, 3H)
ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
156.5, 152.6, 149.6, 138.6, 134.5, 128.52, 128.49,
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127.6, 126.2, 125.9, 125.1, 116.6, 18.4 ppm; IR: νmax 3057, 1677, 1636, 1478 cmꢀ1; HRMS (ESI)
m/z: calcd. for C15H13N2O [M+H]+ 237.1028, found: 237.1024.
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3,7-Diphenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3t): Yellow solid, 95 mg, 64%, m.p. 166ꢀ168
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°C; 1H NMR (400 MHz, CDCl3):
δ 9.41 (dd, J = 2.0 Hz, J = 0.4 Hz, 1H), 8.56 (s, 1H), 8.02 (dd,
J = 9.2 Hz, J = 2.1 Hz, 1H), 7.81 (d, J = 7.1 Hz 2H), 7.77 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 7.1
Hz 2H), 7.55ꢀ7.51 (m, 2H), 7.49ꢀ7.44 (m, 3H), 7.46 (dd, J = 7.5 Hz, J = 7.3 Hz, 1H) ppm;
13C{1H}NMR (100 MHz, CDCl3):
δ 156.9, 152.7, 149.7, 135.7, 135.5, 134.3, 129.9, 129.4, 128.9,
128.5, 127.8, 126.9, 126.6, 124.7, 117.0 ppm; IR: νmax 3056, 1675, 1635, 1477 cmꢀ1; HRMS
(ESI) m/z: calcd. for C20H14N2ONa [M+Na]+ 321.1004, found: 321.0997.
9-(Benzyloxy)-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (3u): Light yellow solid, 88 mg,
54%, m.p. 150ꢀ152 °C; 1H NMR (400 MHz, CDCl3):
δ 8.81 (ddd, J = 4.1 Hz, J = 3.5 Hz, J = 0.9
Hz, 1H), 8.60 (s, 1H), 7.80 (d, J = 7.2 Hz, 2H), 7.49ꢀ7.44 (m, 4H), 7.41ꢀ7.32 (m, 4H), 7.03ꢀ6.99
(m, 2H), 5.40 (s, 2H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
156.9, 151.7, 151.2, 145.1, 135.2,
134.2, 128.9, 128.6, 128.5, 127.9, 127.2, 119.7, 117.8, 114.7, 112.9, 71.7 ppm; IR: νmax 3159,
3058, 2926, 1670, 1634, 1480, 1297, 1266, 1144 cmꢀ1; HRMS (ESI) m/z: calcd. for C21H17N2O2
[M+H]+ 329.1290, found: 329.1288.
Acknowledgement: We gratefully acknowledge financial support from DST, New Delhi for this
investigation. GP is thankful to NIPER, Mohali for her fellowship
Supporting Information Available: Scanned H and 13C spectra for products 3aꢀ3u. This
1
material is available free of charge via the Internet at http://pubs.acs.org.
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