Synthesis of 2-Arylpyridopyrimidinones, 6-Aryluracils, and Tri- and Tetrasubstituted Conjugated Alkenes via Pd-Catalyzed Enolic C-O Bond Activation-Arylation

Article abstract of DOI:10.1021/acs.joc.5b00771

A new and efficient approach for the synthesis of biologically important 2-aryl-4H-pyrido[1,2-a]pyrimidin-4-ones and 6-aryluracils via previously unknown Pd-catalyzed enolic C-OH activation-arylation of pyridopyrimidin-2,4-diones and barbituric acids, res

Full text of DOI:10.1021/acs.joc.5b00771

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Article
Synthesis of 2-arylpyridopyrimidinones, 6-aryluracils
and tri- and tetra-substituted conjugated alkenes via
Pd-catalyzed enolic C–O bond activation-arylation
Sankar K. Guchhait, and Garima Priyadarshani
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00771 • Publication Date (Web): 21 May 2015
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Synthesis of 2-arylpyridopyrimidinones, 6-aryluracils and tri- and tetra-substituted
conjugated alkenes via Pd-catalyzed enolic C–O bond activation-arylation
Sankar K. Guchhait,*,† and Garima Priyadarshani†
9
†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
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Email: skguchhait@niper.ac.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
Abstract:
A new and efficient approach for synthesis of biologically important 2ꢀarylꢀ4Hꢀpyrido[1,2ꢀ
a]pyrimidinꢀ4ꢀones and 6ꢀaryluracils via previously unknown Pdꢀcatalyzed enolic C–OH
activationꢀarylation of pyridopyrimidinꢀ2,4ꢀdiones and barbituric acids, respectively with
boronic acids is reported. The starting materials are readily available and products are
obtained in high yields. An efficient and chemoꢀ and stereoꢀselective access to various triꢀ
and tetraꢀsubstituted conjugated alkenones and alkenoates is also obtained in this arylation
approach. Interestingly, the procedure for construction of such diverse molecular frameworks
is general and featured with excellent substrates scope, tolerance of a broad range of
functionalities, unusual viability of performing reaction under open air and in aqueous coꢀ
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solvent and the amenability to a scale up synthesis, which have been found to be common
limitations in the conventional/classical routes. The application of the protocol in a simple
oneꢀstep highꢀyielding route to pharmaceutically important polyꢀarylated pyridopyrimidinone
demonstrates its further synthetic utility.
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Introduction
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The importance of nitrogen heterocycles in drug discovery processes has long been known.
Major prescription drugs comprise of these scaffolds. Pyrimidinone motif is one of the
important Nꢀheterocycles that occupy privileged positions in drug discovery. In particular, its
pyridineꢀannulated analogs, pyrido[1,2ꢀa]pyrimidinꢀ4ꢀones have been found to possess
various biological activities.1 Risperidone2 and Paliperidone3 are used as atypical oral
antipsychotic drugs.4 The recent studies have explored a particular derivativeꢀset of this
structural motif 2ꢀaryl substituted pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone as medicinally valuable.
They have been attributed a diverse range of bioactivities, such as selective aldose reductase
inhibition,5 hepatitis C virus NS3 protease inhibition,6 improving the transcriptional
functions of estrogenꢀrelated receptors,7 Quorum sensing inhibition,8 and MexABꢀOprM
specific efflux pump inhibition.9 2ꢀArylpyridopyrimidinones are prepared by a classical
reaction of 2ꢀaminopyridine with 3ꢀarylꢀ3ꢀoxopropanoate, but the method is nonꢀflexible in
incorporating versatile aryl moieties and poor to moderate yielding in major cases.5 Another
approach involves the preparation of 2ꢀchloropyridopyrimidinone by deoxychlorination of
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pyridopyrimidinꢀ2,4ꢀdione using excess POCl3 or SOCl2 and subsequently the Suzuki
coupling with arylboronic acid. However, such deoxychlorination process is notorious and
hazardous, generating enormous waste materials, while, on the other hand, as part of the
current momentum of minimizing global environmentꢀconcern the research with
development of green synthesis has been realized as an essential practice by chemists in both
industry and academia.11,12 Moreover, the reaction in POCl3/SOCl2 solvent is detrimental for
tolerating numerous functionalities and, thus, limits the potential in generating the
substitutionsꢀdiversity in the productsꢀlibrary.
One more wellꢀknown important motif of pyrimidinones family is uracil. Its derivatives are
present in uridine nucleosides and naturally occurring thymidine, are used as probes in
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indentifying the interactions between nucleosides/nucleotides and proteins,13 and have
showed a wide range of biological activities.14,15 In recent years, C6ꢀarylated uracil
derivatives have received significant attention because of their various biological
applications.
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Figure 1: A representative bioactive a) pyridopyrimidinones and b) 6ꢀaryluracils
6ꢀAryluracils have been reported as versatile pharmacologically active agents, e.g., GnRH
antagonist,16 antiꢀinflamatory agents,17 dipeptidyl peptidase IV (DPPꢀ4) inhibitors18 antiviral
agents and sirtuin inhibitors.19ꢀ22 However, the synthetic methods of 6ꢀaryluracils are limited.
They include arylation of 6ꢀiodouracils by photochemical reaction,23 and Stille24 or Suzukiꢀ
Miyaura25 coupling. The limitations in preparation of 6ꢀiodouracils that are usually obtained
by lithiation of uracils using LDA and iodination,26 such as inflexibility, lowꢀyielding and
requirement of stringent anhydrous conditions,27 make these photochemical/coupling
methods nonꢀpractical. Therefore, towards development of an alternative approach devoid of
using 6ꢀiodouracil as precursor, recent efforts have been made for direct C6ꢀH arylation of
1,3ꢀdimethyluracil.28ꢀ30 Nevertheless, the methodologies suffer from low reaction conversions
and yields of products, feasibility of reactions limited to electronꢀrich arylating substrates
only, and the use of strong base. Ricart et al has documented an interesting approach towards
direct construction of C6ꢀaryluracils, which involves formal [3+3] cycloaddition of metal
carbene complexes with substituted ureas followed by oxidation.31
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In transitionꢀmetalꢀcatalyzed crossꢀcouplings, the recent attractive trend is, among others,
the discovery of new variants32,33 of reaction towards convenient preparation of versatile
molecular frameworks,34 not limiting to biaryl only. Significant attention on the catalyzed
arylation via C–O bond cleavage has been focussed for synthesis of biaryls,35,36 but its
conceptual variation in the direction of arylation via enolic C–O bond activation leading to
preparation of biologically important Nꢀheterocyclic motifs has not been yet documented.37,38
Herein, we report a new approach for synthesis of 2ꢀarylꢀ4Hꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones
and 6ꢀaryluracils from pyridopyrimidinꢀ2,4ꢀdiones and barbituric acids, respectively, via Pdꢀ
catalyzed enolic C–O bond activationꢀarylation (Figure 2). Notably, pyridopyrimidinꢀ2,4ꢀ
diones are easily accessible and barbituric acid is much economical compared to uracil39
used as synthetic precursor in previous methods. Moreover, this approach represents a oneꢀ
step strategy of converting an Nꢀheterocyclic scaffold to other. An efficient and chemoꢀ and
stereoꢀselective route to various triꢀ and tetraꢀsubstituted conjugated alkenone and alkenoate
has also been accomplished.
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Figure 2: Access to 2ꢀarylpyridopyrimidinones, 6ꢀaryluracils and triꢀ and tetraꢀsubstituted
conjugated alkenes
Results and Discussion
At the outset of our studies for a model enolic activationꢀarylation reaction of
pyridopyrimidinꢀ2,4ꢀdione with phenylboronic acid, we screened a number of Pdꢀcatalytic
conditions involving different solvents at varying temperatures with a few selected
inexpensive activating agents, pꢀTsCl, (EtO)2P(O)Cl, and tertꢀbutoxycarbonyl anhydride.
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Pd(PPh3)2Cl2 catalyst and pꢀTsCl in 1,4ꢀdioxane provided the desired product, although in
poor yield (maximally 11%), while other activating agents were found to be ineffective. Pdꢀ
sources were then examined (Figure 3). Varied yields of the product were obtained with
different Pdꢀcatalysts. Pd(PPh3)4 as catalyst was proved to be best and its 3 mol% quantity
was found to be optimal. The desired product did not form when the reaction was done in the
absence of Pdꢀcatalyst.
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aSubstrates, reagents and condtions: Pyridopyrimidineꢀ2,4ꢀdione (1 mmol), pTsCl (1.3 eq), K2CO3 (5 eq), 1,4ꢀdioxane (2 mL), H2O (0.8
mL), then ArB(OH)2 (2 eq), catalyst, 100 °C; bsolvent used as received commercially without further distillation; cyield for maximum
conversion in optimum time.
Figure 3 Evaluation of Pdꢀcatalysts
Among the bases tested, K2CO3 was most effective (Table 1). 1,4ꢀDioxane was found to be
superior than other evaluated solvents ranging from weakly polar to polar aprotic.
Remarkably, the reaction did not require any inert atmosphere and proceeded smoothly in the
presence of water as coꢀsolvent (optimal quantity) which was proved to be essential plausibly
for dissolving K2CO3 (entries 11ꢀ14).
To check the generality of the method, we investigated the reactions of various substituted
pyridopyrimidinones with different arene boronic acids (Table 2). Pleasingly, the method was
found to be flexible in accommodating the varied substrates. The successful synthesis of 2ꢀ
arylpyridopyrimidinꢀ4ꢀone prompted us to consider other enolizable motifꢀcontaining
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heterocyclic scaffold, barbituric acid, towards synthesis of biologically important 6ꢀarylated
uracils. Delightfully, barbituric acid underwent arylation smoothly with various arene boronic
acids and afforded 6ꢀaryluracils in high yields. Compared to the conventional/classical
methods known for synthesis of 2ꢀarylpyridopyrimidinꢀ4ꢀone and 6ꢀaryluracils, the present
enolic activationꢀarylation approach is stepꢀeconomical, convenient and highꢀyielding, uses
easily accessible or economical starting materials, and avoids hazardous reagents and
stringent anhydrous conditions.
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Table 1 Evaluation of base, additive and solventa
#
PhB(OH)2 Base (eq)
(eq)
Solventb
water Yield
(mL)
(%)c
55
NRd
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35
81
65
NRd
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90
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2
K3PO4 (5)
Et3N (5)
Na2CO3 (5) 1,4-dioxane 0.8
Cs2CO3 (5) 1,4-dioxane 0.8
K2CO3 (2.5) 1,4-dioxane 0.8
K2CO3 (1.5) 1,4-dioxane 0.8
K2CO3 (2.5) Toluene
K2CO3 (2.5) DMF
K2CO3 (2.5) MeCN
K2CO3 (2.5) THF
1,4-dioxane 0.8
1,4-dioxane 0.8
0.8
0.8
0.8
0.8
0
9
10e
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14
K2CO3 (2.5) 1,4-dioxane
K2CO3 (2.5) 1,4-dioxane 0.4
K2CO3 (2.5) 1,4-dioxane
K2CO3 (2.5) 1,4-dioxane 1.2
1
15 1.5
16 1.2
K2CO3 (2.5) 1,4-dioxane
K2CO3 (2.5) 1,4-dioxane
1
1
aSubstrates, reagents and condtions: Pyridopyrimidineꢀ2,4ꢀdione (1 mmol),
pTsCl (1.3 eq), base, solvent (2 mL), H2O, then ArB(OH)2,Pd(PPh3)4 (3 mol %),
100 °C;bsolvent used as received commercially without further distillation;
cyield for maximum conversion in optimum time;
dNo reaction; e80 °C;
We were pleased to find that our developed approach provided also a useful access to
acyclic/cyclic and alkyl/aryl triꢀ and tetraꢀsubstituted conjugated alkenes (carbonyl/ester)
(Table 2, 9aꢀd; 10a,b; 11a,b).40,41 Importantly, excellent stereoselectivity (90 to 100 : 5 to 0)
for acyclic alkenes was obtained.
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Table 2 Enolic–OH arylation of versatile motifsa
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Substrates
Products
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aSubstrate (1 mmol), pTsCl (1.3 eq), K2CO3 (2.5 eq), 1,4ꢀdioxane (2 mL), H2O
(1 mL), then RB(OH)2 (1.2ꢀ1.5 eq), Pd(PPh3)4 (3 mol %), 100 °C,1ꢀ1.5 h (24 h
for 9c and 9d); byield; cKOH (1.5 eq) replacing K2CO3 was added; dPd(PPh3)4
(10 mol %); eDABCO (1.5 eq) replacing K2CO3 was added; f Determined by 1H NMR.
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The stereoselectivity (E/Z) of tosylꢀintermediates in a representative example (11a) was
found to retain in the final arylated products. This as well as the requirement of a Pdꢀcatalyst
indicates that the additionꢀelimination pathway is not involved in the reaction. These triꢀ and
tetraꢀsubstituted conjugated alkenꢀones/oates have been, in general, prepared by classical
approach of addition of Grignard reagent to 1,3ꢀdicarbonyl followed by dehydration,42 and
later by Heck coupling,43 diarylation of αꢀoxoꢀ ketene dithioacetal,44 or MeyerꢀSchuster
rearrangement of propargylic alcohol.45 In comparison, the present approach represents a
simple and high yielding methodology, enables the incorporation of versatile aryl units in
products, and is functional compatible.
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Next, we investigated the flexibility of the method for versatile boronic acids (Table
3). We found that a variety of aryl, heteroaryl and arylalkenyl boronic acids containing both
electronꢀdonating and electronꢀwithdrawing functionalities were feasible substrates in the
arylation of pyridopyrimidinꢀ2,4ꢀdione. The reaction conversions were complete and the
products were obtained in high to excellent yields. The tolerance of several functional groups
on both aryl boronic acids and pyridopyrimidinꢀ2,4ꢀdiones, including aldehyde, acetyl, and
phenolic and alcoholic hydroxyl groups in the reaction is remarkable (Tables 2 and 3). In the
Table 3 Arylation with various boronic acidsa
aSubstrates, reagents and condtions: Pyridopyrimidineꢀ2,4ꢀdione (1 mmol), pTsCl
(1.3 eq), K2CO3 (2.5 eq), 1,4ꢀdioxane (2 mL), H2O (1 mL), then RB(OH)2 (1.2ꢀ1.5 eq),
Pd(PPh3)4 (3 mol %), 100 °C, 1ꢀ1.5 h; byield
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previously known methods, the preparation of 2ꢀarylpyridopyrimidinones with numerous
substitutions/funtionalities on fused pyridine ring46 (e.g., methyl, benzyloxy) or 2ꢀaryl
moieties45 have been found to be poorꢀyielding. In contrast, our developed approach has
comfortably accommodated these variations in the scaffold, affording high yields. The
protocol has showed excellent substrates scope, tolerance of a broad range of functionalities
and highꢀyielding access of products. The reaction conditions proved also amenable to a
scaleꢀup synthesis (investigated upto 20 mmol).
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Polyꢀarylated pyridopyrimidinones are known to enhance the transcriptional functions
of nuclear estrogenꢀrelated receptor α (ERRα).7 These compounds have been prepared before
via multiꢀreaction steps,7 whereas, interestingly, can now be readily accessible in high yields
using the present approach via oneꢀpot chemoselective polyꢀarylation. The reaction of 7ꢀ
bromoꢀpyridopyrimidinꢀ2,4ꢀdione with two similarly reactive arylboronic acids proceeded
chemoselective arylations and provided 2,7ꢀdiaryl substituted pyrido[1,2ꢀa]pyrimidinꢀ4ꢀone
in high yield (Scheme 1). This demonstrates the further synthetic utility of our developed
method. The arylation takes place chemoselectively first at C7ꢀBr and subsequently at C2ꢀ
OH. The only intermediate formed was isolated from the resultant mixture obtained by
stopping the reaction at intermediate time (after 40 min). It was found to be 7ꢀPhenylꢀ2ꢀ(4ꢀ
methylbenzenesulphonyloxy)ꢀ4Hꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀone (7c1).
Scheme 1 Oneꢀpot synthesis of multiꢀarylated heterocycle
In conclusion, a new and efficient method for the synthesis of biologically important 2ꢀarylꢀ
4Hꢀpyrido[1,2ꢀa]pyrimidinꢀ4ꢀones and 6ꢀaryluracils from pyridopyrimidinꢀ2,4ꢀdiones and
barbituric acids, respectively, via Pdꢀcatalyzed enolic C–OH activationꢀarylation with
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boronic acids has been established. This method opens up a practical strategy of generating a
valuable Nꢀheterocyclic unit in high yield from readily available scaffold of completely
different class of Nꢀheterocycle that contains enolizable moiety. In this approach, versatile
cyclic/acyclic aryl/alkyl triꢀ and tetraꢀsubstituted conjugated carbonyls/esters are accessible in
high yields with chemoꢀ and stereoꢀselectivities. The method has also been successfully
applied to a simple highꢀyielding synthesis of pharmaceutically important polyꢀarylated
pyridopyrimidinone. This protocol is quite resourceful in broad applications to the synthesis
of biologically/synthetically important motifs.
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Experimental Section:
General information: Infrared (IR) spectra were recorded on a FTIR with ATR & IR
Microscope spectrometer. 1H 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) or neutral alumina column chromatography.
The starting materials and solvents were used as received from commercial suppliers without
further purification.
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Typical experimental procedure for direct C-OH bond arylation of
enolizable/tautomerizable motifs: pꢀTsCl (1.3 eq, 124 mg, 0.65 mmol) was added to a
mixture of the substrate (0.5 mmol), and K2CO3 (2.5 eq, 173 mg, 1.25 mmol) in 1,4ꢀdioxane
(2 mL) and H2O (1 mL) taken in a roundꢀbottomed flask. The mixture was stirred under open
air for 1h at rt (25ꢀ28 °C). The boronic acid (1.2 eq, 0.6 mmol) and Pd(PPh3)4 (3 mol %, 17
mg, 0.015 mmol) were subsequently added and the mixture was heated at 100 °C under open
air. For compounds (8aꢀ8d) KOH (1.5 eq, 42 mg, 0.65 mmol) and for compounds (10aꢀ11b)
DABCO (1.5 eq, 84 mg, 0.65 mmol) in place of K2CO3 (2.5 eq) was added after substrate and
K2CO3 (1 eq, 69 mg, 0.5 mmol) was added after Pdꢀcatalyst. Upon completion of reaction as
indicated by TLC (1ꢀ1.5 h), the resultant mixture was cooled to rt and extracted with EtOAc
(2x25 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 neutral alumina (for
compounds 7aꢀ7s, 8a-8d) using EtOAcꢀhexane (30ꢀ40%) as eluting solvent and on silica gel
(for compounds 9aꢀ11b) eluting with EtOAcꢀhexane (2ꢀ10%) to afford the arylated products.
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Characterization data for arylated products (7a-11b)
2-(4-Methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one5 (7a): Light yellow solid, 116 mg,
1
92% yield, m.p. 148ꢀ150 °C; H NMR (400 MHz, CDCl3):
δ 9.06 (d, J = 7.1 Hz, 1H), 8.09
(d, J = 8.7 Hz, 2H), 7.76ꢀ7.70 (m, 2H), 7.11 (dd, J = 6.8 Hz, J = 5.8 Hz, 1H), 7.02 (d, J = 8.7
Hz, 2H), 6.87 (s, 1H), 3.89 (s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
161.8, 161.5,
158.6, 150.9, 136.0, 129.5, 128.9, 127.2, 126.6, 114.9, 114.1, 98.7, 55.4 ppm; IR: νmax 3037,
1667, 1637, 1253, 1027 cmꢀ1; HRMS (ESI) m/z: calcd. for C15H13N2O2 [M+H]+ 253.0977,
found: 253.0979.
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2-(4-Chlorophenyl)-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (7b): Light yellow solid,
119 mg, 88%, m.p. 210ꢀ212 °C; 1H NMR (400 MHz, CDCl3):
δ 8.84 (s, 1H), 8.00 (d, J = 8.5
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8
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Hz, 2H), 7.64ꢀ7.58 (m, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.83 (s, 1H), 2.43 (s, 3H) ppm;
13C{1H}NMR (100 MHz, CDCl3):
δ
160.2, 158.4, 149.9, 139.3, 136.7, 135.7, 128.9, 128.6,
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126.1, 125.7, 124.7, 99.5, 18.4 ppm; IR: νmax 2924, 1686, 1645, 823 cmꢀ1; HRMS (ESI) m/z:
calcd. for C15H12ClN2O [M(35Cl)+H]+ 271.0638, found: 271.0639.
2-(4-Chlorophenyl)-7-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (7c): Greenishꢀyellow
1
solid, 139 mg, 84%, m.p. 195ꢀ197 °C; H NMR (400 MHz, CDCl3):
δ 9.26 (d, J = 1.9 Hz,
1H), 8.06ꢀ8.02 (m, 3H), 7.77 (d, J = 9.2 Hz, 1H), 7.68ꢀ7.64 (m, 2H), 7.53ꢀ7.49 (m, 2H), 7.48ꢀ
7.44 (m, 3H), 6.88 (s, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
160.4, 158.6, 150.1,
136.9, 136.3, 135.6, 135.4, 129.40, 129.36, 129.0, 128.9, 128.7, 126.88, 126.79, 124.2, 99.8
ppm; IR: νmax 3071, 2922, 1682, 1633, 822 cmꢀ1; HRMS (ESI) m/z: calcd. for
C20H13ClN2ONa [M(35Cl)+Na]+ 355.0614, found: 355.0609.
2,7-bis(4-Chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7d): Greenishꢀyellow solid,
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143 mg, 78%, m.p. 208ꢀ210 °C; H NMR (400 MHz, CDCl3):
δ 9.22 (d, J = 1.9 Hz, 1H),
8.02 (d, J = 8.6 Hz, 2H), 7.97 (dd, J = 9.3 Hz, J = 2.2 Hz, 1H), 7.77 (dd, J = 9.2 Hz, J = 0.4
Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.50ꢀ7.43 (m, 4H), 6.88 (s, 1H) ppm; 13C{1H}NMR (100
MHz, CDCl3):
δ 160.5, 158.4, 149.9, 137.0, 135.9, 135.5, 135.2, 133.8, 129.6, 129.0, 128.7,
128.13, 128.09, 127.0, 124.2, 99.9 ppm; IR: νmax 3089, 1690, 1634, 813 cmꢀ1; HRMS (ESI)
m/z: calcd. for C20H13Cl2N2O [M(35Cl35Cl)+H]+ 367.0405, found: 367.0399.
9-(Benzyloxy)-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (7e): White solid, 116 mg, 71%,
m.p. 180ꢀ184 °C; 1H NMR (400 MHz, CDCl3):
δ 8.70 (dd, J = 7.1 Hz, J = 1.3 Hz, 1H), 8.18ꢀ
8.14 (m, 2H), 7.54ꢀ7.34 (m, 8H), 7.05 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 6.98ꢀ6.95 (m, 2H),
5.38 (s, 2H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
160.7, 158.9, 151.5, 145.8, 137.3,
135.7, 130.6, 128.80, 128.78, 128.3, 127.5, 127.1, 119.6, 114.3, 114.1, 100.6, 71.7 ppm; IR:
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νmax 1687, 1376, 1275, 1171 cmꢀ1; HRMS (ESI) m/z: calcd. for C21H17N2O2 [M+H]+
5
6
329.1280, found: 329.1282.
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6-(4-methoxyphenyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione28 (8a): Light yellow
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1
solid, 108 mg, 88%, m.p. 107ꢀ109 °C; H NMR (400 MHz, CDCl3):
δ 7.26 (d, J = 8.7 Hz,
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2H), 6.98 (d, J = 8.7 Hz, 2H), 5.68 (s, 1H), 3.87 (s, 3H), 3.40 (s, 3H), 3.25 (s, 3H) ppm;
13C{1H}NMR (100 MHz, CDCl3):
δ
162.5, 160.9, 154.6, 152.8, 129.3, 125.6, 114.3, 102.4,
55.4, 34.6, 28.0 ppm; IR: νmax 2956, 1697, 1645, 1249, 1177 cmꢀ1; HRMS (ESI) m/z: calcd.
for C13H14N2O3Na [M+Na]+ 269.0902, found: 269.0906.
1,3-Dimethyl-6-phenylpyrimidine-2,4(1H,3H)-dione28 (8b): White solid, 84 mg, 78%, m.p.
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142ꢀ145 °C; H NMR (400 MHz, CDCl3):
δ
7.50ꢀ7.46 (m, 3H), 7.34ꢀ7.32 (m, 2H), 5.70 (s,
162.5, 154.6, 152.7,
1H), 3.41 (s, 3H), 3.22 (s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
133.4, 130.2, 129.0, 127.8, 102.5, 34.6, 28.0 ppm; IR: νmax 3057, 1689, 1637 cmꢀ1; HRMS
(ESI) m/z: calcd. for C12H12N2O2Na [M+Na]+ 239.0797, found: 239.0791.
6-(4-Chlorophenyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione30 (8c): White solid, 96 mg,
76%, m.p. 122ꢀ124 °C; 1H NMR (400 MHz, CDCl3):
8.4 Hz, 2H), 5.68 (s, 1H), 3.40 (s, 3H), 3.22 (s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 7.48 (d, J = 8.3 Hz, 2H), 7.29 (d, J =
δ
162.2, 153.4, 152.6, 136.6, 131.7, 129.4, 129.2, 102.7, 34.6, 28.1 ppm; IR: νmax 3084, 1697,
1651, 838 cmꢀ1; HRMS (ESI) m/z: calcd. for C12H11ClN2O2Na [M+Na]+ 273.0407, found:
273.0400.
6-(4-Acetylphenyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (8d): Off-white solid, 86
mg, 67%, m.p. 126ꢀ128 °C; 1H NMR (400 MHz, CDCl3):
J = 8.4 Hz, 2H), 5.69 (s, 1H), 3.39 (s, 3H), 3.20 (s, 3H), 2.64 (s, 3H) ppm; 13C{1H}NMR (100
δ 8.06 (d, J = 8.4 Hz, 2H), 7.45 (d,
MHz, CDCl3):
δ 192.2, 157.4, 148.7, 147.7, 133.5, 132.8, 124.1, 123.4, 97.9, 29.8, 23.3, 21.9
ppm; IR: νmax 3060, 2959, 1697, 1682, 1650 cmꢀ1; HRMS (ESI) m/z: calcd. for C14H15N2O3
[M+H]+ 259.1082, found: 259.1079.
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3-(4-Methoxyphenyl)-5,5-dimethylcyclohex-2-enone48 (9a): Yellow oil, 106 mg, 92%, H
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NMR (400 MHz, CDCl3):
δ 7.52 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.39 (t, J = 1.3
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8
Hz, 1H), 3.85 (s, 3H), 2.62 (d, J = 1.2 Hz, 2H), 2.32 (s, 2H), 1.13 (s, 6H) ppm; 13C{1H}NMR
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(100 MHz, CDCl3):
δ 200.1, 161.2, 156.9, 135.0, 131.1, 128.1, 126.8, 122.6, 114.1, 55.4,
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50.9, 42.1, 33.7, 28.5 ppm; IR: νmax 2956, 1653, 1596, 1239, 1179 cmꢀ1; HRMS (ESI) m/z:
calcd. for C15H19O2 [M+H]+ 231.1385, found: 231.1389.
3-(4-Formylphenyl)-5,5-dimethylcyclohex-2-enone (9b): Light yellow solid, 97 mg, 85%,
m.p. 111ꢀ113 °C; 1H NMR (400 MHz, CDCl3):
δ 10.05 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 6.68
(d, J = 8.3 Hz, 2H), 6.46 (s, 1H), 2.67 (d, J = 1.2 Hz, 2H), 2.37 (s, 2H), 1.15 (s, 6H) ppm;
13C{1H}NMR (100 MHz, CDCl3):
δ
199.7, 191.5, 155.9, 144.9, 136.9, 130.0, 126.8, 126.2,
50.9, 42.3, 33.8, 28.4 ppm; IR: νmax 3103, 1689, 1637 cmꢀ1; HRMS (ESI) m/z: calcd. for
C15H17O2 [M+H]+ 229.1228, found: 229.1221.
3-(4-Methoxyphenyl)-5,5-(dimethyl)-2-phenylcyclohex-2-enone (9c): White solid, 84 mg,
55%, m.p. 120ꢀ122 °C; 1H NMR (400 MHz, CDCl3):
δ 7.19ꢀ7.12 (m, 3H), 6.96ꢀ6.93 (m, 4H),
6.66 (d, J = 8.9 Hz, 2H), 3.72 (s, 3H), 2.71 (s, 2H), 2.51 (s, 2H), 1.19 (s, 6H) ppm;
13C{1H}NMR (100 MHz, CDCl3):
δ
198.5, 159.1, 155.0, 136.1, 135.8, 133.1, 131.0, 130.0,
129.8, 127.7, 126.6, 113.3, 55.2, 51.7, 47.0, 33.0, 28.2 ppm; IR: νmax 3010, 2958, 1655, 1605,
1252, 1175 cmꢀ1; HRMS (ESI) m/z: calcd. for C21H23O2 [M+H]+ 307.1698, found: 307.1698.
2,3-(Diphenyl)-5,5-(dimethylcyclohex-2-enone (9d): White solid, 86 mg, 62%, m.p. 150ꢀ
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152 °C; H NMR (400 MHz, CDCl3):
δ
7.16ꢀ7.11 (m, 6H), 7.01ꢀ6.99 (m, 2H), 6.93ꢀ6.91 (m,
198.5,
2H), 2.72 (s, 2H), 2.53 (s, 2H), 1.20 (s, 6H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
155.5, 141.0, 136.7, 135.4, 130.9, 128.0, 127.9, 127.7, 127.6, 126.8, 51.7, 47.1, 33.2, 28.22
ppm; IR: νmax 3031, 2949, 1658 cmꢀ1; HRMS (ESI) m/z: calcd. for C20H21O [M+H]+
277.1592, found: 277.1592.
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(E)-4-(4-Methoxyphenyl)pent-3-en-2-one49 (10a): White solid, 71 mg, 75%, m.p. 69ꢀ71 °C;
1H NMR (400 MHz, CDCl3):
0.6 Hz, 1H), 3.83 (s, 3H), 2.52 (d, J = 1.1 Hz, 1H), 2.27 (s, 3H) ppm; 13C{1H}NMR (100 MHz,
δ 7.46 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 6.49 (d, J =
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CDCl3):
δ 198.8, 160.6, 153.3, 134.5, 127.9, 122.9, 113.9, 55.3, 32.2, 18.0 ppm; IR: νmax
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2925, 1673, 1584, 1246, 1172 cmꢀ1; HRMS (ESI) m/z: calcd. for C12H14O2Na [M+ Na]+
213.0892, found: 213.0891.
(Z)-3-(4-methoxyphenyl)-1,3-diphenylprop-2-en-1-one50 (10b): Fluorescent yellow oil,
114 mg, 73%; 1H NMR (400 MHz, CDCl3):
δ 7.91 (d, J = 7.1 Hz, 2H), 7.47 (tt, J = 7.4 Hz, J
= 1.3 Hz, 1H), 7.41ꢀ7.34 (m, 7H), 7.11 (d, J = 8.8 Hz, 2H), 7.00 (s, 1H), 6.77 (d, J = 8.8 Hz,
2H), 3.77 (s, 3H), ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
192.9, 159.9, 154.8, 141.9, 138.4,
132.6, 131.5, 131.2, 129.7, 128.84, 128.76, 128.40, 128.36, 123.4, 113.5, 55.2 ppm; IR: νmax
3057, 1655, 1598, 1579, 1246, 1174 cmꢀ1; HRMS (ESI) m/z: calcd. for C22H18O2Na [M+Na]+
337.1205, found: 337.1205.
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(E)-Ethyl 3-(4-chlorophenyl)but-2-enoate51 (11a): Clear oil, 94 mg, 84%; H NMR (400
MHz, CDCl3):
δ 7.40 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 6.11 (q, J = 1.2 Hz, 1H),
4.22 (q, J = 7.1 Hz, 2H), 2.54 (d, J = 1.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}NMR
(100 MHz, CDCl3):
δ 166.7, 154.0, 140.6, 134.9, 128.7, 127.6, 117.5, 59.9, 17.8, 14.3 ppm;
IR: νmax 2929, 1712, 1629, 827 cmꢀ1; HRMS (ESI) m/z: calcd. for C12H14ClO2 [M+H]+
225.0682, found: 225.0673.
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Ethyl 3,3-diphenylacrylate52 (11b): Clear oil, 94 mg, 75%; H NMR (400 MHz, CDCl3):
δ
7.39ꢀ7.36 (m, 3H), 7.35ꢀ7.27 (m, 5H), 7.23ꢀ7.19 (m, 2H), 6.36 (s, 1H), 4.04 (q, J = 7.1 Hz,
2H), 1.10 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
166.2, 156.5, 140.8,
139.0, 129.4, 129.1, 128.4, 128.3, 128.1, 127.9, 117.5, 60.1, 14.0 ppm; IR: νmax 3028, 2979,
1720, 1700, 1262, 1149 cmꢀ1; HRMS (ESI) m/z: calcd. for C17H17O2 [M+H]+ 253.1228,
found: 253.1225.
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2-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one5 (7f): Light yellow solid, 100 mg, 90%, m.p.
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141ꢀ143 °C; H NMR (400 MHz, CDCl3):
δ 9.07 (d, J = 7.1 Hz, 1H), 8.10ꢀ8.08 (m, 2H),
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7.74ꢀ7.73 (m, 2H), 7.53ꢀ7.49 (m, 3H), 7.14ꢀ7.11 (m, 1H), 6.92 (s, 1H) ppm; 13C{1H}NMR
(100 MHz, CDCl3): 162.0, 158.6, 151.0, 137.3, 136.1, 130.6, 128.8, 127.4, 127.3, 126.8,
δ
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115.2, 100.1 ppm; IR: νmax 3131, 1678, 1634 cmꢀ1; HRMS (ESI) m/z: calcd. for C14H10N2ONa
[M+Na]+ 245.0691, found: 245.0687.
2-(3,4,5-Trimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7g): Light yellow solid,
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144 mg, 92%, m.p. 188ꢀ200 °C; H NMR (400 MHz, CDCl3):
δ 9.07 (dt, J = 7.1 Hz, J = 1.1
Hz, 1H), 7.76ꢀ7.75 (m, 2H), 7.35 (s, 2H), 7.16ꢀ7.12 (m, 1H), 6.87 (s, 1H), 3.98 (s, 6H), 3.92
(s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
161.6, 158.6, 153.4, 150.9, 140.4, 136.2,
132.6, 127.3, 126.7, 115.2, 104.7, 99.7, 60.9, 56.3 ppm; IR: νmax 2917, 2849, 1674, 1629,
1230, 1119 cmꢀ1; HRMS (ESI) m/z: calcd. for C17H17N2O4 [M+H]+ 313.1188, found:
313.1189.
2-(4-Acetylphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7h): Offꢀwhite solid, 112 mg, 85%,
1
m.p. 205ꢀ207 °C; H NMR (400 MHz, CDCl3):
δ 9.08 (d, J = 7.1 Hz, 1H), 8.18 (d, J = 8.0
Hz, 2H), 8.08 (d, J = 8.0 Hz, 2H), 7.81ꢀ7.75 (m, 2H), 7.17 (dd, J = 6.8 Hz, J = 5.8 Hz, 1H),
6.95 (s, 1H), 2.66 (s, 3H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
197.6, 160.6, 158.5, 151.1,
141.5, 138.3, 136.5, 128.7, 127.6, 127.3, 126.8, 115.6, 100.8, 26.8 ppm; IR: νmax 3124, 1685,
1669, 1634 cmꢀ1; HRMS (ESI) m/z: calcd. for C16H12N2O2Na [M+Na]+ 287.0797, found:
287.0799.
2-(4-Formylphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7i): Offꢀwhite solid, 112 mg,
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90%, m.p. >200 °C; H NMR (400 MHz, CDCl3+DMSOꢀd6):
δ 10.1 (s, 1H), 9.09 (d, J = 7.0
Hz, 1H), 8.26 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H), 7.86ꢀ7.79 (m, 2H), 7.23 (dd, J =
6.3 Hz, J = 6.2 Hz, 1H), 6.97 (s, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3+DMSOꢀd6):
δ
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192.1, 160.7, 158.7, 151.1, 142.8, 137.5, 136.8, 130.1, 128.1, 127.3, 126.8, 115.9, 101.0 ppm;
IR: νmax 3118, 2852, 2755, 1699, 1685, 1632, 1605 cmꢀ1; HRMS (ESI) m/z: calcd. for
C15H10N2O2Na [M+Na]+ 273.0640, found: 273.0642.
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2-(Benzo[d][1,3]dioxol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (7j): Offꢀwhite solid, 112
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mg, 84%, m.p. 213ꢀ215 °C; H NMR (400 MHz, CDCl3):
δ 9.05 (d, J = 7.1 Hz, 1H), 7.74
(ddd, J = 9.0 Hz, J = 6.2 Hz, J = 1.6 Hz, 1H), 7.69 (ddd, J = 9.0 Hz, J = 1.7 Hz, J = 0.9 Hz,
1H), 7.66 (dd, J = 8.2 Hz, J = 1.8 Hz, 1H), 7.61(d, J = 1.8 Hz, 1H), 7.12 (ddd, J = 6.3 Hz, J =
1.7 Hz, J = 0.9 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.81 (s, 1H), 6.05 (s, 2H) ppm; 13C{1H}NMR
(100 MHz, CDCl3):
δ 161.4, 158.6, 150.9, 149.9, 148.3, 136.2, 131.5, 127.3, 126.6, 122.2,
115.0, 108.5, 107.6, 101.6, 99.1 ppm; IR: νmax 2912, 1682, 1629, 1478, 1249, 1036 cmꢀ1;
HRMS (ESI) m/z: calcd. for C15H11N2O3 [M+H]+ 267.0769, found: 267.0763.
2-(3-Hydroxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7k): Offꢀwhite solid, 109 mg,
1
92% yield, m.p. 242ꢀ244 °C; H NMR (400 MHz, DMSOꢀd6):
δ 8.98 (d, J = 6.8 Hz, 1H),
7.98 (dt, J = 6.8 Hz, J = 1.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.64ꢀ7.60 (m, 2H), 7.38ꢀ7.34
(m, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.94 (dd, J = 7.9 Hz, J = 1.9 Hz, 1H), 6.91 (s, 1H), ppm;
13C{1H}NMR (100 MHz, DMSOꢀd6):
δ 160.9, 158.15, 158.13, 151.0, 138.5, 138.1, 130.3,
127.4, 126.6, 118.5, 118.2, 116.6, 114.4, 99.0 ppm; IR: νmax 3296, 1673, 1633, 1454, 1280
cmꢀ1; HRMS (ESI) m/z: calcd. for C14H11N2O2 [M+H]+ 239.0820, found: 239.0818.
2-(4-(Hydroxymethyl)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7l): White solid, 115
mg, 91% yield, m.p. 190ꢀ192 °C; 1H NMR (400 MHz, CDCl3+DMSOꢀd6):
δ 9.01 (d, J = 6.9
Hz, 1H), 8.10 (d, J = 7.7 Hz, 2H), 7.87 (dd, J = 8.0 Hz, J = 7.3 Hz, 1H), 7.73 (d, J = 8.8 Hz,
1H), 7.48 (d, J = 7.7 Hz, 2H), 7.25 (dd, J = 6.8 Hz, J = 6.7 Hz, 1H), 6.86 (s, 1H), 5.18 (t, J =
5.6 Hz, OH), 4.65 (d, J = 5.6 Hz, 2H) ppm; 13C{1H}NMR (100 MHz, CDCl3+DMSOꢀd6):
δ
161.9, 158.7, 151.6, 146.1, 137.6, 136.2, 127.9, 127.8, 127.5, 127.3, 116.4, 99.6, 64.0 ppm;
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IR: νmax 3315, 3115, 1652, 1629, 1471, 1444 cmꢀ1; HRMS (ESI) m/z: calcd. for
C15H12N2O2Na [M+Na]+ 275.0803, found: 275.0803.
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7
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2-(4-Chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one53 (7m): White solid, 113 mg, 88%,
9
1
m.p. 195ꢀ197 °C; H NMR (400 MHz, CDCl3):
δ 9.07 (d, J = 7.1 Hz, 1H), 8.05 (d, J = 8.6
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Hz, 2H), 7.79ꢀ7.71 (m, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.15 (ddd, J = 6.0 Hz, J = 5.8 Hz, J =
1.4 Hz, 1H), 6.88 (s, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
160.7, 158.5, 151.0, 136.9,
136.4, 135.6, 129.0, 128.7, 127.3, 126.7, 115.3, 99.8 ppm; IR: νmax 2916, 1679, 1625, 819
cmꢀ1; HRMS (ESI) m/z: calcd. for C14H9ClN2ONa [M(35Cl)+Na]+ 279.0301, found: 279.0300.
2-(4-Fluorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one53 (7n): White solid, 114 mg, 95%,
1
m.p. 185ꢀ187 °C; H NMR (400 MHz, CDCl3):
δ 9.06 (d, J = 7.1 Hz, 1H), 8.09 (dd, J = 8.8
Hz, J = 5.4 Hz, 2H), 7.75 (dt, J = 8.8 Hz, J = 1.4 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.17 (t, J
= 8.8 Hz, 2H), 7.12 (d, J = 6.2 Hz, 1H), 6.85 (s, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
164.5 (d, JCꢀF = 249 Hz), 160.9, 158.5, 151.0, 136.3, 133.3 (d, JCꢀCꢀCꢀCꢀF = 3 Hz), 129.5 (d, JCꢀ
= 9 Hz), 127.3, 126.7, 115.8 (d, JCꢀCꢀF = 21 Hz), 115.3, 99.6 ppm; IR: νmax 3042, 1681,
CꢀCꢀF
1633, 1233 cmꢀ1; HRMS (ESI) m/z: calcd. for C14H9FN2ONa [M+Na]+ 263.0597, found:
263.0601.
2-(4-(Trifluoromethyl)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one10 (7o): Crystal white
solid, 131 mg, 90%, m.p. 196ꢀ198 °C; 1H NMR (400 MHz, CDCl3):
δ 9.08 (dd, J = 6.1 Hz, J
= 0.9 Hz, 1H), 8.20 (d, J = 8.1 Hz, 2H), 7.81ꢀ7.74 (m, 4H), 7.18 (ddd, J = 6.4 Hz, J = 1.8 Hz,
J = 0.8 Hz, 1H), 6.93 (s, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
160.3, 158.4, 151.1,
140.6, 136.5, 132.1 (q, JCꢀCꢀF = 32 Hz), 127.7, 127.3, 126.8, 125.6 (q, JCꢀCꢀCꢀF = 4 Hz), 123.9
(q, JCꢀF = 271 Hz), 115.6, 100.6 ppm; IR: νmax 3055, 1692, 1637, 1107 cmꢀ1; HRMS (ESI)
m/z: calcd. for C15H9F3N2ONa [M+Na]+ 313.0565, found: 313.0561.
2-(4-(Trifluoromethoxy)phenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (7p): Crystal white
1
solid, 125 mg, 82%, m.p. 152ꢀ154 °C; H NMR (400 MHz, CDCl3):
δ 9.08 (d, J = 7.1 Hz,
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1H), 8.14 (d, J = 8.8 Hz, 2H), 7.80ꢀ7.72 (m, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.16 (dt, J = 7.1
Hz, J = 1.7 Hz, 1H), 6.88 (s, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 160.6, 158.5,
7
8
9
151.0 (dd, JCꢀOꢀCꢀF = 8 Hz, JCꢀOꢀCꢀF = 2 Hz), 136.4, 135.8, 129.1, 127.3, 126.8, 120.9, 120.2
(q, JCꢀF = 270 Hz), 115.4, 100.0 ppm; IR: νmax 3081, 1683, 1633, 1250, 1209, 1144 cmꢀ1;
HRMS (ESI) m/z: calcd. for C15H9F3N2O2Na [M+Na]+ 329.0514, found: 329.0520.
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2-(Pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one10 (7q): Offꢀwhite solid, 100 mg, 90%,
1
m.p. 212ꢀ214 °C; H NMR (400 MHz, CDCl3):
δ 9.10 (d, J = 7.1 Hz, 1H), 8.78 (d, J = 5.7
Hz, 2H), 7.95 (dd, J = 4.6 Hz, J = 1.5 Hz, 2H), 7.84ꢀ7.80 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H),
7.21 (dt, J = 7.2 Hz, J = 1.6 Hz, 1H), 6.96 (s, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ
159.4, 158.5, 151.3, 150.6, 144.6, 136.7, 127.4, 126.9, 121.3, 115.9, 100.9 ppm; IR: νmax
3119, 1697, 1630 cmꢀ1; HRMS (ESI) m/z: calcd. for C13H10N3O [M+H]+ 224.0824, found:
224.0821.
2-(Furan-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (7r): Cream solid, 91 mg, 86%, m.p. 130ꢀ
1
132 °C; H NMR (400 MHz, CDCl3):
δ 9.03 (dd, J = 6.6 Hz, J = 0.4 Hz, 1H), 8.16 (dd, J =
1.4 Hz, J = 0.8 Hz, 1H), 7.74ꢀ7.70 (m, 1H), 7.63 (td, J = 8.9 Hz, J = 0.9 Hz, 1H), 7.52 (t, J =
1.7 Hz, 1H), 7.10 (dt, J = 7 Hz, J = 1.4 Hz, 1H), 6.87 (dd, J = 1.8 Hz, J = 0.8 Hz, 1H), 6.61
(s, 1H) ppm; 13C{1H}NMR (100 MHz, CDCl3):
δ 158.4, 156.7, 151.3, 144.3, 143.8, 136.2,
127.3, 126.3, 125.7, 114.9, 108.5, 99.4 ppm; IR: νmax 2916, 1676, 1628, 1442, 1115 cmꢀ1;
HRMS (ESI) m/z: calcd. for C12H8N2O2Na [M+Na]+ 235.0484, found: 235.0470.
(E)-2-Styryl-4H-pyrido[1,2-a]pyrimidin-4-one (7s): Light yellow solid, 109 mg, 88%,
m.p. 139ꢀ141 °C; 1H NMR (400 MHz, CDCl3):
δ 9.01 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 15.8
Hz, 1H), 7.71 (dt, J = 6.6 Hz, J = 1.4 Hz, 1H), 7.66ꢀ7.61 (m, 3H), 7.42ꢀ7.33 (m, 3H), 7.07 (dt,
J = 7.2 Hz, J = 1.4 Hz, 1H), 7.02 (d, J = 15.8 Hz, 2H), 6.49 (s, 1H) ppm; 13C{1H}NMR (100
MHz, CDCl3):
δ
160.1, 158.5, 150.9, 137.3, 136.2, 135.8, 129.3, 128.8, 127.7, 127.3, 126.33,
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126.28, 114.7, 102.4 ppm; IR: νmax 3081, 1683, 1633, 1607 cmꢀ1; HRMS (ESI) m/z: calcd. for
C16H12N2ONa [M+Na]+ 271.0848, found: 271.0852.
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Spectral data for the intermediates 7c1 and 11a1
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7-Phenyl-2-(4-methylbenzenesulphonyloxy)-4H-pyrido[1,2-a]pyrimidin-4-one
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(7c1): Yellow solid, 161 mg, 82%, m.p. >200 °C; 1H NMR (400 MHz, CDCl3):
δ 9.24 (d, J =
2.0 Hz, 1H), 8.10 (dd, J = 9.1 Hz, J = 2.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.66-7.62 (m,
3H), 7.54-7.47 (m, 3H), 7.38 (d, J = 8.2 Hz, 2H), 6.13 (s, 1H), 2.47 (s, 3H) ppm;
13C{1H}NMR (100 MHz, CDCl3):
δ 161.8, 159.2, 149.3, 145.8, 138.0, 134.9, 133.6, 130.5,
129.8, 129.5, 129.2, 128.8, 126.9, 125.9, 124.8, 91.6, 21.8 ppm; IR: •max 1704, 1637, 1371,
1165 cm-1; HRMS (ESI) m/z: calcd. for C21H17N2O4S [M+H]+ 393.0909, found: 393.0902.
1
(E)-Ethyl 3-(tosyloxy)but-2-enoate54 (11a1): Colorless oil, 122 mg, 86%; H NMR (400
MHz, CDCl3):
4.14 (q, J = 9.1 Hz, 2H), 2.47 (s, 3H), 2.27 (d, J = 0.9 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H)
ppm; 13C{1H}NMR (100 MHz, CDCl3):
165.4, 162.3, 145.7, 132.9, 130.0, 128.2, 111.0,
δ 7.82 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 5.71 (q, J = 0.9 Hz, 1H),
δ
60.5, 21.7, 18.6, 14.1 ppm; IR: •max 2926, 1717, 1657, 1367, 1177 cm-1; HRMS (ESI) m/z:
calcd. for C13H16O5SNa[M+Na]+ 307.0616, found: 307.0615.
Acknowledgement: We gratefully acknowledge financial support from DST, New Delhi for
this investigation.
1
Supporting Information Available: scanned H and 13C spectra for products 7aꢀ11b. This
material is available free of charge via the Internet at http://pubs.acs.org.
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