Microwave-assisted [3+2] cycloaddition and suzuki-miyaura cross-coupling for a concise access to polyaromatic scaffolds

Article abstract of DOI:10.1002/ejoc.201301014

Novel 3-(prop-2-ynyl)pyrido[2,3-d]pyrimidin-4(3H)-ones and 3-(prop-2-ynyl)quinazolin-4(3H)-ones have been synthesized in a high-yielding microwave-assisted one-pot procedure. The one-pot sequence was conveniently extended to the synthesis of commercially unavailable 6-bromo-N ³-propargylpyrido[2,3-d]pyrimidinone by a regiocontrolled bromination with NBS. The synthetic scaffolds were successfully converted into triazoles by copper(I)-catalyzed [3+2] cycloaddition and substituted at the 6-position by Suzuki-Miyaura cross-coupling in high overall yields. A microwave-assisted one-pot sequential synthesis involving esterification, formylation, bromination, and cyclization of anthranilic and 2-aminonicotinic acid derivatives provides access to N³-propargylquinazolinones or -pyridopyrimidinones in high overall yields. Functionalization by [3+2] cycloaddition and Suzuki-Miyaura cross-coupling rapidly led to 48 novel polyaromatic heterocycles.

Full text of DOI:10.1002/ejoc.201301014

FULL PAPER
DOI: 10.1002/ejoc.201301014
Microwave-Assisted [3+2] Cycloaddition[‡] and Suzuki–Miyaura Cross-
Coupling for a Concise Access to Polyaromatic Scaffolds
Damien Hédou,[a][‡‡] Emmanuel Deau,[a][‡‡] Carole Dubouilh-Benard,[a] Morgane Sanselme,[b]
Anthony Martinet,[c] Elizabeth Chosson,[a] Vincent Levacher,[a] and Thierry Besson*[a]
Keywords: Nitrogen heterocycles / Cycloaddition / Cross-coupling / Microwave chemistry / Polyaromatics
Novel 3-(prop-2-ynyl)pyrido[2,3-d]pyrimidin-4(3H)-ones and
3-(prop-2-ynyl)quinazolin-4(3H)-ones have been synthesized
in a high-yielding microwave-assisted one-pot procedure.
The one-pot sequence was conveniently extended to the syn-
thesis of commercially unavailable 6-bromo-N3-propargyl-
pyrido[2,3-d]pyrimidinone by a regiocontrolled bromination
with NBS. The synthetic scaffolds were successfully con-
verted into triazoles by copper(I)-catalyzed [3+2] cycload-
dition and substituted at the 6-position by Suzuki–Miyaura
cross-coupling in high overall yields.
This paper relates the development of a reliable and sim-
ple synthetic method involving [3+2] cycloaddition and
Introduction
As a continuation of our work on the synthesis of C,N,S- Suzuki–Miyaura cross-coupling reactions for the prepara-
containing heterocyclic precursors of kinase inhibitors, we tion of novel polyaromatic derivatives. The main part of
have reported the synthesis of various quinazoline deriva- the chemistry performed in this study was achieved under
tives.[1] Among the studied compounds, N3-substituted microwave irradiation as a continuation of our global strat-
quinazolines have been the focus of a large part of our ef- egy for the design of modified reactants and techniques
forts over the past 10 years.[2]
with operational, economic, and environmental benefits
The biological activities of such derivatives[3] has encour- over conventional methods.[6]
aged us to extend recent investigations to novel pyridopyr-
imidine analogues. In this context, we have reported a con-
venient microwave-assisted one-pot sequential synthesis of
Results and Discussion
the target molecules in good-to-excellent yields.[4] This reli-
Based on our previous one-pot cyclization of anthranilic
able and convenient methodology was applied to various
ring systems and aliphatic amines to form libraries of im-
portant heterocyclic scaffolds, which can be considered as
precursors of novel N3-substituted quinazolin-4(3H)-ones
and pyrido[2,3-d]pyrimidin-4(3H)-ones (Scheme 1) showing
an arrangement of cycles mimicking the structures of tris-
aromatic systems including a triazole core with high bio-
logical potential.[5]
acid and various aminonicotinic acid isomers into quinaz-
olin-4(3H)-ones and pyridopyrimidin-4(3H)-ones, respec-
tively,[4] we wished to use amines bearing a propargyl moi-
ety. Microwave irradiation of anthranilic acid (1a) or 2-
aminonicotinic acid (2) in the presence of N,N-dimethyl-
formamide dimethyl acetal (DMFDMA)[7] in DMF fol-
lowed by irradiation with propargylamine in acetic acid
gave the expected 3-(prop-2-ynyl)quinazolin-4(3H)-one (3)
and 3-(prop-2-ynyl)pyrido[2,3-d]pyrimidin-4(3H)-one (4) in
excellent overall yields (Scheme 2).
With compounds 3 and 4 in hand, we planned to per-
form a copper(I)-catalyzed [3+2] cycloaddition to give easy
access to triazoles 5 and 6, which would be subsequently
functionalized with a benzyl group. The absence of struc-
ture–activity relationship patterns for the studied N3-substi-
tuted quinazolin-4(3H)-one and pyrido[2,3-d]pyrimidin-
4(3H)-one series prompted us to employ the Topliss
scheme[8] for selecting substitution patterns on the triazole.
Microwave-assisted cycloaddition of the starting materials
3 and 4 in the presence of trimethylsilyl azide and copper
iodide in DMF/MeOH provided triazoles 5 and 6 in good
yields (70–76%).[9] Unfortunately, poor regioselectivity was
[a] Normandie Université, COBRA, UMR 6014 & FR 3038,
Université Rouen; INSA Rouen; CNRS; IRCOF
1 rue Tesnière, 76821 Mont St Aignan Cedex, France
E-mail: thierry.besson@univ-rouen.fr
http://ircof.crihan.fr/
[b] Laboratoire SMS - Unité de cristallogenèse, IRCOF,
1 rue Tesnière, 76821 Mont St Aignan Cedex, France
[c] Anton Paar France S.A.S.,
91967 Courtaboeuf Cedex, France
[‡] The term [3+2] cycloaddition, referring to the number of atoms
implicated in the reaction, should be more formally called
[π4s+π2s] cycloaddition. This official IUPAC nomenclature con-
cerns the number of π electrons participating in the cycload-
dition. For convenience, the more often used [3+2] nomencla-
ture is used in this paper.
[‡‡]These two authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301014.
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Scheme 1. Retrosynthetic pathways and access to novel N3,6-disubstituted quinazolin-4(3H)-ones and pyrido[2,3-d]pyrimidin-4(3H)-ones
from anthranilic acids (1a or 1b) or 2-aminonicotinic acid (2).
To best direct the regioselectivity of the cycloaddition,
para-substituted (azidomethyl)benzenes 7–9 were prepared
in excellent yields (91–97%) by the usual methods[11] from
the corresponding para-substituted benzyl chlorides and so-
dium azide in warm DMF (Scheme 4).
Scheme 2. One-pot sequential synthesis of 3-(prop-2-ynyl)quinaz-
olin-4(3H)-one (3) and 3-(prop-2-ynyl)pyrido[2,3-d]pyrimidin-
4(3H)-one (4) from anthranilic acid (1a) and 2-aminonicotinic acid
(2), respectively.
Scheme 4. Synthesis of para-substituted (azidomethyl)benzenes 7–
9.
observed during alkylation reactions with alkyl iodide un-
der basic conditions, which provided an inseparable mixture
of N-alkylated products. Also, failure of the regioselective
Copper(I)-catalyzed cycloaddition was then tested with
copper(I)-catalyzed [3+2] cycloaddition through the genera- (azidomethyl)benzenes 7–9 and copper sulfate in the pres-
tion of benzyl azide in situ[10] encouraged us to study an- ence of sodium ascorbate at 80 °C for 30 min in tBuOH and
other route involving the use of substituted azides water (Scheme 5). Two novel libraries of quinazolin-4(3H)-
(Scheme 3).
ones (10–13) and pyrido[2,3-d]pyrimidin-4(3H)-ones (14–
Scheme 3. Copper(I)-catalyzed [3+2] cycloaddition of azidotrimethylsilane with quinazolin-4(3H)-one (3) and pyrido[2,3-d]pyrimidin-
4(3H)-one (4).
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Access to Polyaromatic Scaffolds
Scheme 5. Optimized protocol for the microwave-assisted copper(I)-catalyzed [3+2] cycloaddition of 3-(prop-2-ynyl)quinazolin-4(3H)-one
(3) and pyrido[2,3-d]pyrimidin-4(3H)-ones (4) with p-substituted (azidomethyl)benzenes 7–9. For details of yields, see Table 1.
Table 1. Yields for the [3+2] cycloaddition-mediated synthesis of the 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones 10–
13 and pyrido[2,3-d]pyrimidin-4(3H)-ones 14–17.
[a] Isolated yield.
17) were isolated in good yields (77–88%) with perfect con-
To obtain the 6-bromo-3-(prop-2-ynyl)pyrido[2,3-d]pyr-
trol of the regioselectivity of the cycloaddition (Table 1). imidin-4(3H)-one analogue 20, a regioselective bromination
Given the isolated yields for the cycloaddition, the nature of commercial 2-aminonicotinic acid was necessary. The
of the aromatic moiety, whether quinazolinic or pyrido[2,3- starting compound 2 was treated with DMFDMA in the
d]pyrimidinic, did not seem to affect the click reaction. usual manner, followed by regiocontrolled bromination by
Also, the yields were not affected by the nature of the para- the addition of NBS at room temperature. Cyclization in
substituted (azidomethyl)benzenes employed.
Whilst we focused on the optimization of the conditions responding
of the [3+2] cycloaddition reaction, we envisioned ex- idin-4(3H)-one (20) in 86% overall yield (Scheme 6).
tending our polycyclic scaffolds by Suzuki–Miyaura cross- A short study of this new sequential one-pot reaction
the presence of propargylamine in acetic acid gave the cor-
6-bromo-3-(prop-2-ynyl)pyrido[2,3-d]pyrim-
coupling reaction starting from brominated intermediates. showed that bromination after the conversion of 2-amino-
This strategy was underpinned by the commercial availabil- nicotinic acid (2) into the amidino ester with DMFDMA
ity of 2-amino-5-bromobenzoic acid (1b). The latter was was crucial, otherwise the yields were significantly reduced.
easily converted into the corresponding 6-bromo-3-(prop-2- By applying the procedure described above, copper(I)-cata-
ynyl)quinazolin-4(3H)-one (19) in an excellent 94% yield by lyzed [3+2] cycloaddition of 6-bromo-3-(prop-2-ynyl)quin-
using the one-pot sequence previously described azolin-4(3H)-one (19) and its pyrido[2,3-d]pyrimidin-4(3H)-
(Scheme 6).
one analogue 20 in the presence of para-substituted benzyl
Scheme 6. One-pot sequential synthesis of 6-bromo-3-(prop-2-ynyl)quinazolin-4(3H)-one (19) and its pyrido[2,3-d]pyrimidin-4(3H)-one
analogue 20.
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Scheme 7. Optimized sequence for the microwave-assisted [3+2] cycloaddition and Pd-catalyzed Suzuki–Miyaura cross-coupling synthesis
of tris-aromatic N3,6-disubstituted quinazolin-4(3H)-ones 29–44 and pyrido[2,3-d]pyrimidin-4(3H)-ones 45–60. For the yields, see Tables 2
and 3.
Table 2. Yields for the [3+2] cycloaddition-mediated synthesis of the intermediate 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-bromoquin-
azolin-4(3H)-ones 21–24 and 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-bromopyrido[2,3-d]pyrimidin-4(3H)-ones 25–28.
[a] Isolated yield.
azides 7–9 (Scheme 7) gave the expected triazole derivatives lent yields (Table 3). During our efforts to optimize the re-
21–28 in yields ranging from 71 to 96% (Table 2). Function- action, attempts to achieve Suzuki–Miyaura cross-coupling
alization at the 6-position of the bicyclic unit by using prior to the [3+2] cycloaddition on intermediates 19 or 20
Suzuki–Miyaura cross-coupling was best achieved with the failed to give the expected aryl derivatives.
[1,1Ј-bis(diphenylphosphanyl)ferrocene]dichloropalladi-
In addition to the spectral characterization, the three-
um(II) dichloromethane complex as catalyst (Scheme 7). Ir- dimensional structure of compound 44 was confirmed by
radiation of the latter in the presence of brominated deriva- single-crystal X-ray diffraction. A single crystal of 44 was
tives 21–28, sodium carbonate, and the appropriate para- obtained from methanol/diethyl ether/dichloromethane
substituted phenylboronic acid in DMF at 150 °C for (1:1:1, v/v/v). The ORTEP representation is displayed in
90 min gave tris-aromatic products 29–60 in good-to-excel- Figure 1. Analysis revealed the perfectly planar structure of
Table 3. Yields for the Pd-catalyzed Suzuki–Miyaura cross-coupled synthesis of tris-aromatic N3,6-disubstituted quinazolin-4(3H)-ones
29–44 and pyrido[2,3-d]pyrimidin-4(3H)-ones 45–60.
[a] Isolated yield.
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Access to Polyaromatic Scaffolds
quaternary gradients, and an additional inlet for purging with air.
Samples can be injected in liquid or solid mode. Purification was
controlled and monitored on an integrated panel PC with a touch
screen controlled by Armen Glider Flash v3.1d software. Biotage
SNAP flash chromatography cartridges (KP-Sil, normal phase, 10–
340 g) were used for the purification process. Melting points of so-
lid compounds were measured with a WME Köfler hot-stage with
a precision of Ϯ2 °C. IR spectra were recorded with a PerkinElmer
Spectrum 100 Series FT-IR spectrometer by using a single reflec-
tion attenuated total reflectance (ATR) accessory.
the quinazolinone core and the aromatic moiety at the 6-
position. The presence of the methylene group at N-3 leads
to the 1,4-disubstituted triazole moiety being almost or-
thogonal to the quinazolin-4(3H)-one ring, with the second
methylene group promoting a stair-like three-dimensional
structure of the molecule.
1H and 13C NMR spectra were recorded with a Bruker DXP 300
spectrometer at 300 and 75 MHz, respectively. Abbreviations used
for peak multiplicities are as follows: s: singlet, d: doublet, t: triplet,
q: quartet, m: multiplet. Coupling constants J are in Hz and the
chemical shifts are given in ppm and calibrated with [D6]DMSO
(residual solvent signals) or CDCl3. Mass spectroscopy was per-
formed by the Mass Spectrometry Laboratory of the University of
Rouen. Mass spectra (EI) were recorded with a Waters LCP 1er
XR spectrometer.
Figure 1. ORTEP diagram of 44 (for details, see the Exp. Sect. and
additional data).
Some comments can be made concerning the microwave
procedure as well as the technical and practical aspects. In
the case of our microwave-assisted synthesis, DMF and ace-
tic acid have the advantage of good dielectric properties,
thus enabling an efficient heating of the reaction mixture.[12]
The one-pot reactions and [3+2] cycloadditions (with the
exception of compounds 5 and 6) were carried out at
amospheric pressure in a multimode cavity, and Suzuki–Mi-
yaura cross-coupling reactions were performed in pressur-
ized vials in a single-mode reactor (for details see Exp.
Sect.).
Microwave experiments were conducted in two different commer-
cial microwave reactors especially designed for synthetic chemistry.
1) RotoSYNTH™ (Milestone S.r.l. Italy) is a multimode cavity with
a microwave power delivery system ranging from 0 to 1200 W. Open
vessel experiments were carried out in round-bottomed flasks (from
25 mL to 4 L) fitted with a reflux condenser. The temperature was
monitored by means of a contactless IR pyrometer (IRT) and fiber-
optic contact thermometer (FO). Temperature, pressure and power
profiles were controlled and monitored through the EASY-Control
software provided by the manufacturer. 2) Anton Paar Monomode
300™ is a monomode cavity with a microwave power delivery sys-
tem ranging from 0 to 850 W allowing pressurized reactions (0–
30 bars) to be carried out in sealed glass vials (4–30 mL) equipped
with a snap cap and a silicon septum. The temperature (0–300 °C)
was monitored by means of a contactless IR sensor and was cal-
ibrated with a Ruby Thermometer. Temperature, pressure, and
power profiles were controlled and monitored through a touch-
screen control panel.
Conclusions
An innovative synthetic methodology for the rapid syn-
thesis of N3-substituted quinazolin-4(3H)-ones and pyr-
ido[2,3-d]pyrimidin-4(3H)-ones in a one-pot sequence has
been achieved. This one-pot sequential reaction was ex-
tended to the synthesis of variously functionalized pyr-
The crystal structure of 44 was determined by single-crystal X-
ray diffraction with a SMART APEX diffractometer (with Mo-Kα1
radiation: λ = 0.71073 Å). The cell parameters and the orientation
matrix of the crystal were preliminarily determined by using the
SMART software.[13] Data integration and global cell refinement
were performed with the SAINT software.[14] Intensities were cor-
rected for Lorentzian polarization, decay and absorption effects
(SAINT and SADABS software) and reduced to Fo2. The struc-
tures were solved by direct methods (SHELXS-97[15]). Anisotropic
displacement parameters were refined for all non-hydrogen atoms
by using SHELXL-97[16] available in the WinGX[17] package. All
hydrogen atoms were located by Fourier-difference synthesis and
fixed geometrically according to their environment with a common
isotropic factor.
ido[2,3-d]pyrimidinones by including
a
regioselective
bromination step. Copper(I)-catalyzed [3+2] cycloaddition
and Suzuki–Miyaura cross-coupling were optimized and
perfectly controlled to provide novel 3-[(1-benzyl-1H-1,2,3-
triazol-4-yl)methyl]-6-phenylquinazolin-4(3H)-ones 29–44
and phenylpyrido[2,3-d]pyrimidin-4(3H)-ones 45–60. Mi-
crowave technology proved to be a versatile tool allowing
rapid and clean reactions in all steps of the syntheses. This
approach is coherent with our overall strategy for the design
of new molecules with operational, economic, and environ-
mental benefits.
General Procedure for the Microwave-Mediated One-Pot Synthesis
of N3-Substituted Quinazolin-4(3H)-one and Pyrido[2,3-d]pyrimidin-
4(3H)-one Derivatives:
A stirred suspension of amino acid
Experimental Section
(7.24 mmol, 1 equiv.) in N,N-dimethylformamide dimethyl acetal
(DMFDMA; 1.92 mL, 18.1 mmol, 2.5 equiv.) and DMF (7.2 mL)
was heated at 100 °C for 15 min under microwave irradiation at
atmospheric pressure (RotoSYNTH™, time measured when the
mixture reached the programmed temperature after a ramp period
of 2 min under a power of 900 W). The solvents were removed in
vacuo and propargylamine (464 μL, 7.96 mmol, 1.1 equiv.) was
added followed by AcOH (7.2 mL). The mixture was irradiated at
General: All reactions were carried out under argon or nitrogen
and monitored by TLC with silica gel 60 F254 precoated alumin-
ium plates (0.25 mm). Visualization was performed with a UV light
at 254 and 312 nm. Purification was performed on an Armen In-
strument Spot 2 Flash System equipped with a dual UV/Vis spec-
trophotometer (200–600 nm), a fraction collector (192 tubes), a
dual piston pump (1–250 mL/min, pmax = 50 bar/725 psi) allowing
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T. Besson et al.
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100 °C for 15 min at atmospheric pressure (RotoSYNTH™, time
measured when the mixture reached the programmed temperature
after a ramp period of 2 min under a power of 900 W). Evaporation
of the solvent gave a crude product which was purified by flash
chromatography using petroleum ether/dichloromethane (100:0 to
0:100, v/v) as eluent for the quinazolinone series and dichlorometh-
ane/ethyl acetate (100:0 to 0:100, v/v) for the pyridopyrimidinone
series.
General Procedure for the Microwave-Assisted Click Chemistry of
N3-Propargylquinazolin-4(3H)-one and Pyrido[2,3-d]pyrimidin-
4(3H)-one Derivatives: In a sealed tube, a stirred suspension of al-
kyne (0.5 mmol, 1 equiv.), azidotrimethylsilane (0.75 mmol, 99 μL,
1.5 equiv.), and copper iodide (5 mg, 25 μmol, 0.05 equiv.) in a mix-
ture of DMF (972 μL) and MeOH (108 μL) was heated at 130 °C
for 40 min under microwave irradiation under ambient pressure
(Anton Paar Monomode 300™, time measured when the mixture
reached the programmed temperature after a ramp period of 2 min
under a power of 850 W). Evaporation of the solvents gave a crude
product which was purified by flash chromatography using dichlo-
romethane/ethyl acetate (100:0 to 0:100, v/v) as eluent for product
5 and ethyl acetate/methanol (100:0 to 95:5, v/v) for product 6.
3-(Prop-2-ynyl)quinazolin-4(3H)-one (3): Yield 90% (1.2 g); color-
less solid, m.p. 116–118 °C (ref.[18] 116 °C). 1H NMR (300 MHz,
[D6]DMSO): δ = 8.46 (s, 1 H, 2-H), 8.17 (dd, J = 8.0, 1.2 Hz, 1 H,
5-H), 7.88–7.82 (m, 1 H, 6-H), 7.70 (d, J = 8.0 Hz, 8-H), 7.60–7.54
(m, 1 H, 7-H), 4.84 (d, J = 2.5 Hz, 2 H, CH2), 3.44 (t, J = 2.5 Hz,
1 H, C-H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.5, 147.8,
147.1, 134.6, 127.4, 127.3, 126.1, 121.4, 78.6, 75.7, 35.2 ppm. IR:
3-[(1H-1,2,3-Triazol-4-yl)methyl]quinazolin-4(3H)-one (5): Yield
76% (86 mg); colorless solid, m.p. 196–198 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 15.0 (br. s, 1 H, NH), 8.54 (s, 1 H, 2-
H), 8.14 (dd, J = 1.3, 8.0 Hz, 1 H, 5-H), 7.83–7.70 (m, 1 H + 1 H,
triazole-H, 6-H), 7.68 (d, J = 7.7 Hz, 1 H, 8-H), 7.57–7.52 (m, 1
H, 7-H), 5.31 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 159.9, 147.9 (2 C), 134.5, 127.3 (2 C), 127.2 (2 C), 126.1, 121.6,
ν
= 3217, 1658, 1600, 1470, 1379, 1269, 1169, 767, 696 cm–1.
˜
max
3-(Prop-2-ynyl)pyrido[2,3-d]pyrimidin-4(3H)-one (4): Yield 97%
(1.3 g); colorless solid, m.p. 162–164 °C (ref.[19] 122–123 °C). 1H
NMR (300 MHz, [D6]DMSO): δ = 9.00 (dd, J = 4.6, 2.0 Hz, 1 H,
7-H), 8.69 (s, 1 H, 2-H), 8.58 (dd, J = 7.9, 2.0 Hz, 1 H, 5-H), 7.62
(dd, J = 7.9, 4.6 Hz, 1 H, 6-H), 4.84 (d, J = 2.5 Hz, 1 H, CH2), 3.48
(t, J = 2.5 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 160.1, 157.7, 156.1, 150.2, 135.9, 123.1, 116.8, 78.2, 76.0,
40.8 ppm. IR: ν
= 3139, 3082, 2917, 2860, 2817, 1673, 1613,
˜
max
1473, 1324, 1154, 771 cm–1. HRMS: calcd. for C11H10N50 [M +
H]+ 228.0885; found 228.0888.
3-[(1H-1,2,3-Triazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-4(3H)-one
(6): Yield 70% (80 mg); colorless solid, m.p. 194–196 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 14.90 (br. s, 1 H, NH), 8.98 (dd, J =
4.6, 1.9 Hz, 1 H, 7-H), 8.76 (s, 1 H, 2-H), 8.54 (dd, J = 7.9, 1.9 Hz,
1 H, 5-H), 7.81 (s, 1 H, triazole-H), 7.58 (dd, J = 7.9, 4.6 Hz, 1 H,
6-H), 5.31 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 160.5, 157.9, 156.0 (2 C), 151.1, 135.9 (2 C), 122.9, 116.9,
35.4 ppm. IR: ν
= 3222, 2972, 2939, 2123, 1675, 1566, 1432,
˜
max
1362, 1224, 1103, 938, 798, 709 cm–1. HRMS: calcd. for C10H8N3O
[M + H]+ 186.0667; found 186.0674.
6-Bromo-3-(prop-2-ynyl)quinazolin-4(3H)-one (19): Yield 94%
(1.7 g); colorless solid, m.p. 134–136 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 8.51 (s, 1 H, 2-H), 8.24 (d, J = 2.3 Hz, 1 H, 5-H),
8.00 (dd, J = 8.7, 2.3 Hz, 1 H, 7-H), 7.66 (d, J = 8.7 Hz, 1 H, 8-
H), 4.82 (d, J = 2.5 Hz, 1 H, CH2), 3.45 (t, J = 2.5 Hz, 1 H,
CH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 158.4, 147.6,
146.7, 137.4, 129.7, 128.1, 122.9, 119.8, 78.2, 75.9, 35.4 ppm. IR:
41.1 ppm. IR: ν
= 1685, 1619, 1562, 1369, 1224, 974, 795 cm–1.
˜
max
HRMS: calcd. for C10H9N6O [M + H]+ 229.0838; found 229.0829.
General Procedure for the Synthesis of para-Substituted (Azi-
domethyl)benzenes: A stirred solution of para-substituted benzyl
chloride (12.42 mmol, 1 equiv.) and sodium azide (888 mg,
13.66 mmol, 1.1 equiv.) in DMF (12 mL) was gradually heated to
60 °C and stirred for 6 h. The cooled reaction mixture was parti-
tioned between diethyl ether and water. The organic layer was
washed with water and brine, and dried with magnesium sulfate.
Evaporation of the solvent under a flow of nitrogen yielded analyti-
cally pure para-substituted (azidomethyl)benzene.
ν
= 3292, 3178, 2120, 1669, 1597, 1468, 1367, 1317, 1259, 839,
˜
max
613, 495 cm–1. HRMS: calcd. for C11H879BrN2O [M + H]+
262.9820; found 262.9821.
6-Bromo-3-(prop-2-ynyl)pyrido[2,3-d]pyrimidin-4(3H)-one (20):
A
stirred suspension of 2-aminonicotinic acid (2; 1.0 g, 7.24 mmol) in
DMFDMA (1.92 mL, 18.1 mmol) and DMF (7.2 mL) was heated
at 100 °C for 15 min under microwave irradiation at atmospheric
pressure (RotoSYNTH™, time measured when the mixture reached
the programmed temperature after a ramp period of 2 min under
1-(Azidomethyl)-4-methylbenzene (7): Yield 93% (1.945 g); colorless
1
oil. H NMR (300 MHz, CDCl3): δ = 7.22 (s, 4 H, Ph-H), 4.30 (s,
power of 900 W). Freshly recrystallized NBS[20] (1.353 g,
2 H, CH2), 2.38 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
a
7.60 mmol, 1.05 equiv.) was added to the cooled solution, which
was vigorously stirred for 4 h at room temperature. The solvents
were removed in vacuo and propargylamine (464 μL, 7.96 mmol,
1.1 equiv.) was added followed by AcOH (7.2 mL). The mixture
was irradiated at 100 °C for 15 min at atmospheric pressure (Roto-
SYNTH™, time measured when the mixture reached the pro-
grammed temperature after a ramp period of 2 min under a power
of 900 W). The solvents were removed in vacuo. Purification of the
oily residue by flash chromatography using dichloromethane/ethyl
acetate (100:0 to 0:100, v/v) as eluent gave the desired compound
(1.644 g, 6.23 mmol) in 86% yield as a colorless solid; m.p. 148–
150 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.09 (d, J = 2.6 Hz,
1 H, 7-H), 8.72 (s, 1 H, 2-H), 8.70 (d, J = 2.6 Hz, 1 H, 5-H), 4.84
(d, J = 2.5 Hz, 1 H, CH2), 3.49 (t, J = 2.5 Hz, 1 H, CH) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 159.1, 156.7, 156.3, 150.6, 137.4,
δ = 137.2, 131.4, 128.6 (2 C), 127.3 (2 C), 53.2, 19.5 ppm. IR: ν
˜
max
= 3025, 2924, 2876, 2090, 1616, 1515, 1343, 1252, 801, 753, 664,
536, 467 cm–1. HRMS: calcd. for C8H9N3 [M]+ 147.0796; found
147.0777.
1-(Azidomethyl)-4-methoxybenzene (8): Yield 97% (2.024 g); color-
less oil. 1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.5 Hz, 2
H, Ph-H), 6.91 (d, J = 8.5, Hz, 2 H, Ph-H), 4.27 (s, 2 H, CH2),
3.82 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.2,
130.2 (2 C), 127.8, 114.5 (2 C), 55.3, 54.3 ppm. IR: ν
= 3003,
˜
max
2936, 2837, 2089, 1610, 1585, 1512, 1303, 1242, 1174, 1031, 811,
550, 514 cm–1. HRMS: calcd. for C8H9N3O [M]+ 163.0736; found
163.0745.
1-(Azidomethyl)-4-chlorobenzene (9): Yield 91% (1.882 g); colorless
oil. 1H NMR (300 MHz, CDCl3): δ = 7.36 (d, J = 8.5 Hz, 2 H, Ph-
H), 7.26 (d, J = 8.5 Hz, 2 H, Ph-H), 4.32 (s, 2 H, CH2) ppm. 13C
NMR (75 MHz, CDCl3): δ = 134.7, 134.3, 130.0 (2 C), 129.5 (2 C),
118.0, 117.8, 77.9, 76.1, 35.6 ppm. IR: ν
= 3116, 3067, 2125,
˜
max
1672, 1596, 1461, 1247, 1231, 1092, 920, 810 cm–1. HRMS: calcd.
for C10H779BrN3O [M + H]+ 263.9772; found 263.9767.
54.0 ppm. IR: ν
= 2935, 2091, 1597, 1492, 1408, 1341, 1246,
˜
max
7538
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7533–7545

Access to Polyaromatic Scaffolds
1089, 1015, 796, 516 cm–1. HRMS: calcd. for C7H6ClN3 [M]+
167.0250; found 167.0258.
νmax = 3135, 3052, 1669, 1609, 1474, 1382, 1312, 1294, 1226, 1053,
˜
1025, 780, 772, 698 cm–1. HRMS: calcd. for C18H15ClN5O [M +
H]+ 352.0965; found 352.0954.
General Procedure for the Microwave-Assisted [3+2] Cycloaddition
of N3-Propargylquinazolin-4(3H)-one and Pyrido[2,3-d]pyrimidin- 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]pyrido[2,3-d]pyrimidin-
4(3H)-one Derivatives: Copper sulfate pentahydrate (137 mg,
0.55 mmol, 0.1 equiv.) and sodium ascorbate (218 mg, 1.1 mmol,
0.2 equiv.) were added to a stirred suspension of alkyne (5.5 mmol,
1 equiv.) and the appropriate benzyl azide in tert-butanol (11 mL)
and water (11 mL) at room temperature. The mixture was heated
at 80 °C for 30 min under microwave irradiation at atmospheric
pressure (RotosynthTM, time measured when the mixture reached
the programmed temperature after a ramp period of 2 min under
a power of 900 W). Evaporation of the solvents gave a crude prod-
uct which was purified by flash chromatography using dichloro-
methane/ethyl acetate (100:0 to 0:100, v/v) as eluent for the quin-
azolinone series and ethyl acetate/methanol (100:0 to 95:5, v/v) for
the pyridopyrimidinone series.
4(3H)-one (14): Yield 88 % (1.54 g); colorless solid, m.p. 192–
194 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.99 (dd, J = 4.6,
1.9 Hz, 1 H, 7-H), 8.77 (s, 1 H, 2-H), 8.54 (dd, J = 7.9, 1.9 Hz, 1
H, 5-H), 8.21 (s, 1 H, triazole-H), 7.58 (dd, J = 7.9, 4.6 Hz, 1 H,
6-H), 7.37–7.29 (m, 5 H, Bn-H), 5.56 (s, 2 H, CH2), 5.28 (s, 2 H,
CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.5, 157.8,
155.9, 151.1, 142.4, 135.9, 128.8 (2 C), 128.2, 128.0 (2 C), 123.9,
122.9, 116.9, 52.9, 41.3 ppm. IR: ν
= 3076, 2934, 1674, 1600,
˜
max
1469, 1430, 1310, 1216, 1046, 796, 724 cm–1. HRMS: calcd. for
C17H15N6O [M + H]+ 319.1307; found 319.1293.
3-{[1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}pyrido[2,3-d]-
pyrimidin-4(3H)-one (15): Yield 77% (1.408 g); colorless solid, m.p.
1
206–208 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.97 (dd, J =
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one (10): 4.6, 2.0 Hz, 1 H, 7-H), 8.76 (s, 1 H, 2-H), 8.52 (dd, J = 7.9, 2.0 Hz,
Yield 88 % (1.54 g); colorless solid, m.p. 134–136 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.56 (s, 1 H, 2-H), 8.21 (s, 1 H, tri-
azole-H), 8.14 (dd, J = 1.3, 8.0 Hz, 1 H, 5-H), 7.86–7.80 (m, 1 H,
6-H), 7.69 (d, J = 8.0 Hz, 1 H, 8-H), 7.57–7.52 (m, 1 H, 7-H), 7.36–
7.30 (m, 5 H, Bn-H), 5.56 (s, 2 H, CH2), 5.27 (s, 2 H, CH2) ppm.
1 H, 5-H), 8.17 (s, 1 H, triazole-H), 7.57 (dd, J = 7.9, 4.6 Hz, 1 H,
6-H), 7.21 (d, J = 8.1 Hz, 2 H, Bn-H), 7.15 (d, J = 8.1 Hz, 2 H,
Bn-H), 5.50 (s, 2 H, CH2), 5.27 (s, 2 H, CH2), 2.26 (s, 3 H, Bn-
CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.4, 157.8,
155.9, 151.0, 142.3, 137.5, 135.8, 132.8, 129.2 (2 C), 128.1 (2 C),
13C NMR (75 MHz, [D6]DMSO): δ = 159.9, 147.9, 142.7, 135.9, 123.6, 122.8, 116.8, 52.6, 41.2, 20.6 ppm. IR: ν
= 3118, 1675,
˜
max
134.5, 128.8 (2 C), 128.2, 128.0 (2 C), 127.3, 127.2, 126.1, 123.8, 1604, 1562, 1473, 1431, 1361, 1214, 1096, 1052, 800, 794, 473 cm–1.
121.6, 52.8, 41.1 ppm. IR: ν
= 3161, 3142, 3057, 1670, 1611,
HRMS: calcd. for C18H17N6O [M + H]+ 333.1464; found 333.1468.
˜
max
1603, 1474, 1382, 1292, 1167, 1051, 931, 768, 727 cm–1. HRMS:
calcd. for C18H16N5O [M + H]+ 318.1355; found 318.1351.
3-{[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}pyrido[2,3-d]-
pyrimidin-4(3H)-one (16): Yield 83% (1.59 g); colorless solid, m.p.
1
3-{[1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}quinazolin-
4(3H)-one (11): Yield 78 % (1.42 g); colorless solid, m.p. 134–
222–224 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.98 (dd, J =
4.6, 1.9 Hz, 1 H, 7-H), 8.76 (s, 1 H, 2-H), 8.53 (dd, J = 7.9, 1.9 Hz,
1 H, 5-H), 8.16 (s, 1 H, triazole-H), 7.58 (dd, J = 7.9, 4.6 Hz, 1 H,
6-H), 7.28 (d, J = 8.6 Hz, 2 H, Bn-H), 6.92 (d, J = 8.6 Hz, 2 H,
Bn-H), 5.47 (s, 2 H, CH2), 5.26 (s, 2 H, CH2), 3.72 (s, 3 H, Bn-
OCH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.5, 159.2,
1
136 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.54 (s, 1 H, 2-H),
8.16–8.12 (m, 1H + 1H, triazole-H, 5-H), 7.89–7.79 (m, 1 H, 6-H),
7.69 (d, J = 7.7 Hz, 1 H, 8-H), 7.59–7.52 (m, 1 H, 7-H), 7.21 (d, J
= 8.2 Hz, 2 H, Bn-H), 7.16 (d, J = 8.2 Hz, 2 H, Bn-H), 5.50 (s, 2
H, CH2), 5.25 (s, 2 H, CH2), 2.27 (s, 3 H, Bn-CH3) ppm. 13C NMR 157.9, 156.0, 151.1, 142.4, 135.9, 129.7 (2 C), 127.8, 123.5, 122.9,
(75 MHz, [D6]DMSO): δ = 165.1, 153.2, 153.1, 147.9, 142.7, 139.6,
116.9, 114.1 (2 C), 55.1, 52.4, 41.2 ppm. IR: ν
= 3118, 1672,
˜
max
138.1, 134.5 (2 C), 133.3 (2 C), 132.5, 132.4, 131.3, 128.8, 126.8, 1605, 1589, 1515, 1360, 1307.1249, 1214, 1191, 1054, 1024, 800,
57.9, 46.2, 25.9 ppm. IR: νmax = 3137, 3064, 2917, 1674, 1608, 1472,
794, 782 cm–1. HRMS: calcd. for C18H17N6O2 [M + H]+ 349.1413;
found 349.1405.
˜
1321, 1291, 1154, 1052, 772, 697, 546, 474 cm–1. HRMS: calcd. for
C19H18N5O [M + H]+ 332.1511; found 332.1524.
3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
pyrido[2,3-d]pyrimidin-4(3H)-one (17): Yield 84% (1.64 g); colorless
solid, m.p. 224–226 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.98
(dd, J = 4.6, 2.0 Hz, 1 H, 7-H), 8.77 (s, 1 H, 2-H), 8.53 (dd, J =
3-{[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}quinazolin-
4(3H)-one (12): Yield 85 % (1.55 g); colorless solid, m.p. 174–
1
176 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.54 (s, 1 H, 2-H),
8.15 (s, 1 H, triazole-H), 8.15–8.12 (m, 1 H, 5-H), 7.86–7.82 (m, 1 7.9, 2.0 Hz, 1 H, 5-H), 8.23 (s, 1 H, triazole-H), 7.58 (dd, J = 7.9,
H, 6-H), 7.69 (d, J = 8.0 Hz, 8-H), 7.57–7.52 (m, 1 H, 7-H), 7.29 4.6 Hz, 1 H, 6-H), 7.44 (d, J = 8.6 Hz, 2 H, Bn-H), 7.34 (d, J =
(d, J = 8.8 Hz, 2 H, Bn-H), 6.91 (d, J = 8.8 Hz, 2 H, Bn-H), 5.47
8.6 Hz, 2 H, Bn-H), 5.57 (s, 2 H, CH2), 5.28 (s, 2 H, CH2) ppm.
(s, 2 H, CH2), 5.25 (s, 2 H, CH2), 3.72 (s, 3 H, Bn-OCH3) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 160.5, 157.9, 156.0, 151.1,
13C NMR (75 MHz, [D6]DMSO): δ = 159.8, 159.1, 147.9, 142.6, 142.5, 135.9, 134.9, 132.9, 130.0, 128.8, 123.9, 122.9, 116.9, 52.0,
134.4, 129.7 (2 C), 127.8, 127.2, 127.1, 126.0, 123.4, 121.5, 114.1 (2
C), 55.1, 52.3, 41.0 ppm. IR: ν = 3144, 3058, 2999, 2947, 1658,
41.2 ppm. IR: ν
= 3151, 3067, 1673, 1602, 1469, 1435, 1228,
˜
max
795, 788 cm–1. HRMS: calcd. for C17H14ClN6O2 [M + H]+
˜
max
1610, 1511, 1473, 1361, 1324, 1250, 1173, 1048, 1024, 779, 353.0918; found 353.0913.
768 cm–1. HRMS: calcd. for C19H18N5O2 [M + H]+ 348.1461;
found 348.1454.
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-bromoquinazolin-
4(3H)-one (21): Yield 96 % (2.09 g); colorless solid, m.p. 176–
1
3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}quinazolin-
4(3H)-one (13): Yield 88 % (1.70 g); colorless solid, m.p. 158–
178 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.59 (s, 1 H, 2-H),
8.20 (s, 1 H, triazole-H), 8.18 (d, J = 2.3 Hz, 1 H, 5-H), 7.95 (dd,
J = 8.7, 2.3 Hz, 1 H, 7-H), 7.62 (d, J = 8.7 Hz, 1 H, 8-H), 7.37–
1
160 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.56 (s, 1 H, 2-H),
8.22 (s, 1 H, triazole-H), 8.14 (dd, J = 8.0, 1.4 Hz, 1 H, 5-H), 7.81 7.27 (m, 5 H, Bn-H), 5.56 (s, 2 H, CH2), 5.26 (s, 2 H, CH2) ppm.
(m, 1 H, 6-H), 7.69 (d, J = 8.0 Hz, 8-H), 7.54 (m, 1 H, 7-H), 7.42
(d, J = 8.8 Hz, 2 H, Bn-H), 7.33 (d, J = 8.8 Hz, 2 H, Bn-H), 5.57
13C NMR (75 MHz, [D6]DMSO): δ = 159.5, 149.1, 147.6, 143.1,
137.9, 136.5, 130.2, 129.3 (2 C), 128.7, 128.6 (2 C), 124.4, 123.7,
(s, 2 H, CH2), 5.27 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]- 120.1, 52.9, 41.3 ppm. IR: ν
= 3129, 2922, 1667, 1600, 1465,
˜
max
DMSO): δ = 159.9, 147.9, 142.8, 134.9, 134.4, 132.9, 130.0 (2 C),
128.7 (2 C), 127.3, 127.2, 126.1, 123.9, 121.6, 52.0, 41.0 ppm. IR:
1318, 1223, 1049, 833, 786, 597 cm–1. HRMS: calcd. for
C18H1579BrN5O [M + H]+ 396.0460; found 396.0448.
Eur. J. Org. Chem. 2013, 7533–7545
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7539

T. Besson et al.
6-Bromo-3-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]- solid, m.p. 240–242 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.07
FULL PAPER
methyl}quinazolin-4(3H)-one (22): Yield 94% (2.12 g); colorless so-
(d, J = 2.6 Hz, 1 H, 7-H), 8.80 (s, 1 H, 2-H), 8.65 (d, J = 2.6 Hz,
1 H, 5-H), 8.15 (s, 1 H, triazole-H), 7.28 (d, J = 8.7 Hz, 2 H, Bn-
lid, m.p. 162–164 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.58
(s, 1 H, 2-H), 8.19 (d, J = 2.1 Hz, 1 H, 5-H), 8.15 (s, 1 H, triazole- H), 6.91 (d, J = 8.7 Hz, 2 H, Bn-H), 5.47 (s, 2 H, CH2), 5.26 (s, 2
H), 7.95 (dd, J = 8.7, 2.1 Hz, 1 H, 7-H), 7.62 (d, J = 8.7 Hz, 1 H,
8-H), 7.20 (d, J = 8.2 Hz, 2 H, Bn-H), 7.14 (d, J = 8.0 Hz, 2 H,
Bn-H), 5.50 (s, 2 H, CH2), 5.25 (s, 2 H, CH2), 2.25 (s, 3 H, Bn-
H, CH2), 3.72 (s, 3 H, Bn-OCH3) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 159.5, 159.2, 156.6, 156.5, 151.5, 142.1, 137.4, 129.7
(2 C), 127.8, 123.5, 118.2, 117.7, 114.1 (2 C), 55.1, 52.4, 41.4 ppm.
CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.5, 149.1, IR: ν
= 3115, 3059, 2841, 1671, 1601, 1515, 1459, 1249, 1213,
˜
max
147.6, 143.0, 138.1, 137.9, 133.4, 130.2, 129.8 (2 C), 128.7, 128.6 (2
C), 124.1, 123.7, 120.1, 52.7, 41.2, 20.5 ppm. IR: νmax = 3064, 2925,
1025, 813, 781 cm–1. HRMS: calcd. for C18H1679BrN6O2 [M +
H]+ 427,0518; found 427.0505.
˜
1662, 1600, 1465, 1317, 1222, 1049, 928, 832, 775, 596 cm–1
.
6-Bromo-3-{[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
pyrido[2,3-d]pyrimidin-4(3H)-one (28): Yield 71% (1.69 g); colorless
solid, m.p. 256–258 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.07
(d, J = 2.5 Hz, 1 H, 7-H), 8.82 (s, 1 H, 2-H), 8.64 (d, J = 2.5 Hz,
1 H, 5-H), 8.23 (s, 1 H, triazole-H), 7.43 (d, J = 8.3 Hz, 2 H, Bn-
H), 7.33 (d, J = 8.3 Hz, 2 H, Bn-H), 5.57 (s, 2 H, CH2), 5.28 (s, 2
H, CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.5, 156.6,
156.4, 151.5, 142.2, 137.4, 134.8, 132.9, 130.0 (2 C), 128.7 (2 C),
HRMS: calcd. for C19H1779BrN5O [M + H]+ 410.0616; found
410.0623.
6-Bromo-3-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
quinazolin-4(3H)-one (23): Yield 93% (2.18 g); colorless solid, m.p.
160–162 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.58 (s, 1 H, 2-
H), 8.21 (d, J = 2.3 Hz, 1 H, 5-H), 8.13 (s, 1 H, triazole-H), 7.98
(dd, J = 8.7, 2.3 Hz, 1 H, 7-H), 7.64 (d, J = 8.7 Hz, 1 H, 8-H), 7.28
(d, J = 8.7 Hz, 2 H, Bn-H), 6.91 (d, J = 8.7 Hz, 2 H, Bn-H), 5.46
(s, 2 H, CH2), 5.24 (s, 2 H, CH2), 3.72 (s, 3 H, Bn-OCH3) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 159.9, 159.5, 149.1, 147.5,
143.0, 137.8, 130.2 (2 C), 130.2, 128.7, 128.3, 124.0, 123.6, 120.1,
123.9, 118.1, 117.6, 52.0, 41.4 ppm. IR: ν
= 3140, 3057, 2990,
˜
max
1681, 1599, 1460, 1294, 1219, 1048, 811, 785 cm–1. HRMS: calcd.
for C17H1379BrClN6O [M + H]+ 431,0023; found 431.0025.
General Procedure for the Microwave-Mediated Suzuki–Miyaura
Cross-Coupling of N3-Substituted 6-Bromoquinazolin-4(3H)-ones
and 6-Bromopyrido[2,3-d]pyrimidin-4(3H)-ones: In a sealed tube, a
stirred solution of N3-substituted 6-bromoquinazolin-4(3H)-one or
6-bromopyrido[2,3-d]pyrimidin-4(3H)-one (200 μmol, 1 equiv.),
[1,1Ј-bis(diphenylphosphanyl)ferrocene]dichloropalladium(II)
complexed with dichloromethane (10 wt.-%), sodium carbonate
(400 μmol, 42 mg, 2 equiv.), the appropriate phenylboronic acid
(1.05 equiv.) in dry DMF (2 mL) was heated at 150 °C for 90 min
under microwave irradiation under ambient pressure (Anton Paar
Monomode 300™, time measured when the mixture reached the
programmed temperature after a ramp period of 2 min under a
power of 850 W).
114.5 (2 C), 55.2, 52.5, 41.2 ppm. IR: ν
= 3145, 2999, 2942,
˜
max
1653, 1609, 1511, 1459, 1358, 1323, 1302, 1248, 1214, 1179, 1029,
957, 876, 834, 776, 651, 597, 552, 490 cm–1. HRMS: calcd. for
C19H1779BrN5O2 [M + H]+ 426.0566; found 428.0580.
6-Bromo-3-{[1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
quinazolin-4(3H)-one (24): Yield 89% (2.11 g); colorless solid, m.p.
1
180–182 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.59 (s, 1 H),
8.21 (s, 1 H, triazole-H), 8.19 (d, J = 2.4 Hz, 1 H, 5-H), 7.95 (dd,
J = 8.7, 2.4 Hz, 1 H, 7-H), 7.62 (d, J = 8.7 Hz, 1 H, 8-H), 7.41 (d,
J = 8.5 Hz, 2 H, Bn-H), 7.32 (d, J = 8.5 Hz, 2 H, Bn-H), 5.57 (s,
2 H, CH2), 5.26 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 159.5, 149.2, 147.6, 143.1, 137.9, 135.4, 133.5, 130.5
(2 C), 130.2, 129.3 (2 C), 128.7, 124.4, 123.7, 120.1, 52.1, 41.3 ppm.
For the pyridopyrimidinone series, ice was added to the cooled
solution. The dark precipitate was filtered off and purified by flash
chromatography using ethyl acetate/methanol (100:0 to 95:5, v/v)
as eluent.
IR: ν
= 3137, 2958, 1669, 1601, 1465, 1366, 1318, 1222, 1054,
˜
max
801, 782 cm–1. HRMS: calcd. for C18H1479BrClN5O [M + H]+
430,0070; found 430.0091.
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-bromopyrido[2,3-d]-
pyrimidin-4(3H)-one (25): Yield 93% (2.03 g); colorless solid, m.p.
222–224 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.08 (d, J =
2.6 Hz, 1 H, 7-H), 8.81 (s, 1 H, 2-H), 8.66 (d, J = 2.6 Hz, 1 H, 5-
H), 8.21 (s, 1 H, triazole-H), 7.37–7.29 (m, 5 H, Bn-H), 5.56 (s, 2 H,
CH2), 5.28 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 159.5, 156.6, 156.4, 151.5, 142.1, 137.4, 135.8, 128.7 (2 C), 128.1,
For the quinazolinone series, the cooled solution was partitioned
between dichloromethane and water. The organic layer was dried
with magnesium sulfate and evaporated in vacuo. The dark residue
was purified by flash chromatography using dichloromethane/ethyl
acetate (100:0 to 0:100, v/v) as eluent.
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-phenylquinazolin-
4(3H)-one (29): Yield 86 % (68 mg); colorless solid, m.p. 166–
128.0 (2 C), 123.8, 118.1, 117.6, 52.8, 41.4 ppm. IR: ν
= 3129,
˜
max
2928, 1680, 1598, 1458, 1293, 1217, 1048, 799, 713 cm–1. HRMS:
calcd. for C17H1479BrN6O [M + H]+ 397.0412; found 397.0414.
1
168 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.57 (s, 1 H, 2-H),
8.34 (d, J = 2.0 Hz, 1 H, 5-H), 8.16 (s, 1 H, triazole-H) 8.14 (dd,
J = 8.3, 2.0 Hz, 1 H, 7-H), 7.79–7.74 (m, 1 H + 2 H, 8-H, Ph-H),
7.53–7.32 (m, 3 H + 5H, Ph-H, Bn-H), 5.56 (s, 2 H, CH2), 5.29 (s,
2 H, CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.9, 147.9,
147.2, 142.6, 138.8, 138.7, 135.9, 132.9, 129.1 (2 C), 128.7 (2 C),
128.1, 128.0 (2 C), 126.8 (2 C), 123.7, 123.3, 121.9, 52.8, 41.1 ppm.
6-Bromo-3-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
pyrido[2,3-d]pyrimidin-4(3H)-one (26): Yield 90% (2.04 g); colorless
solid, m.p. 214–216 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.07
(d, J = 2.6 Hz, 1 H, 7-H), 8.80 (s, 1 H, 2-H), 8.65 (d, J = 2.6 Hz,
1 H, 5-H), 8.17 (s, 1 H, triazole-H), 7.21 (d, J = 8.2 Hz, 2 H, Bn-
H), 7.16 (d, J = 8.2 Hz, 2 H, Bn-H), 5.50 (s, 2 H, CH2), 5.26 (s, 2
H, CH2), 2.26 (s, 3 H, Bn-CH3) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 159.5, 156.6, 156.4, 151.5, 142.1, 137.5, 137.4, 132.8,
129.4 (2 C), 128.1 (2 C), 123.6, 118.1, 117.6, 52.6, 41.4, 20.7 ppm.
IR: ν
= 3121, 3064, 2917, 1674, 1607, 1477, 1364, 1222, 1163,
˜
max
1072, 844, 796, 764, 711, 693, 569 cm–1. HRMS: calcd. for
C24H20N5O [M + H]+ 394.1668; found 394.1658.
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-(p-tolyl)quinazolin-
4(3H)-one (30): Yield 88 % (72 mg); colorless solid, m.p. 180–
IR: ν
= 3129, 3058, 2926, 1676, 1600, 1459, 1293, 1219, 1049,
˜
max
1219, 1049, 812, 784 cm–1. HRMS: calcd. for C18H1679BrN6O [M
+ H]+ 411.0569; found 411.0559.
1
182 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.56 (s, 1 H, 2-H),
8.31 (d, J = 2.1 Hz, 1 H, 5-H), 8.20 (s, 1 H, triazole-H), 8.12 (dd,
J = 8.6, 2.1 Hz, 1 H, 7-H), 7.75 (d, J = 8.6 Hz, 1 H, 8-H), 7.65 (d,
J = 8.2 Hz, 2 H, Ph-H), 7.38–7.30 (m, 5 H + 2 H, Bn-H, Ph-H),
6-Bromo-3-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
pyrido[2,3-d]pyrimidin-4(3H)-one (27): Yield 84% (1.97 g); colorless
7540
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7533–7545

Access to Polyaromatic Scaffolds
5.56 (s, 2 H, CH2), 5.28 (s, 2 H, CH2), 2.36 (s, 3 H, Ph-CH3) ppm.
solid, m.p. 190–192 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.53
13C NMR (75 MHz, [D6]DMSO): δ = 159.9, 147.8, 147.0, 142.6, (s, 1 H, 2-H), 8.28 (d, J = 1.9 Hz, 1 H, 5-H), 8.15 (s, 1 H, triazole-
138.7, 137.5, 135.9, 135.8, 132.7, 129.7 (2 C), 128.7 (2 C), 128.1, H), 8.11 (dd, J = 8.5, 1.9 Hz, 1 H, 7-H), 7.76–7.69 (m, 1 H + 2 H,
128.0 (2 C), 126.6 (2 C), 123.7, 122.9, 121.9, 52.8, 41.1, 20.7 ppm.
8-H, Ph-H), 7.21 (d, J = 8.0 Hz, 2 H, Bn-H), 7.16 (d, J = 8.0 Hz,
2 H, Bn-H), 7.07 (d, J = 8.7 Hz, 2 H, Ph-H), 5.50 (s, 2 H, CH2),
5.27 (s, 2 H, CH2), 3.81 (s, 3 H, Ph-OCH3), 2.26 (s, 3 H, Bn-
CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.7, 160.1,
148.3, 147.3, 143.3, 139.2, 138.1, 133.5, 133.1, 131.6, 129.8 (2 C),
128.7 (2 C), 128.6 (2 C), 128.5, 124.1, 123.0, 122.4, 115.1 (2 C),
IR: ν
= 3129, 2926, 1680, 1606, 1482, 1335, 1255, 1162, 811,
˜
max
716 cm–1. HRMS: calcd. for C25H22N5O [M + H]+ 408.1824; found
408.1826.
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-(4-methoxyphenyl)-
quinazolin-4(3H)-one (31): Yield 84% (71 mg); colorless solid, m.p.
186–188 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.54 (s, 1 H, 2-
H), 8.28 (d, J = 2.1 Hz, 1 H, 5-H), 8.20 (s, 1 H, triazole-H), 8.11
(dd, J = 8.6, 2.3 Hz, 1 H, 7-H), 7.75–7.69 (m, 1 H + 2 H, 8-H, Ph-
H), 7.38–7.30 (m, 5 H, Bn-H), 7.06 (d, J = 8.8 Hz, 2 H, Ph-H),
5.56 (s, 2 H, CH2), 5.28 (s, 2 H, CH2), 3.81 (s, 3 H, Ph-OCH3) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 159.9, 159.3, 147.6, 146.7,
142.7, 138.5, 135.9, 132.5, 131.0, 128.7 (2 C), 128.1 (2 C), 128.0 (2
C), 127.9, 12.7, 122.5, 121.9, 114.6 (2 C), 55.2, 52.8, 41.1 ppm. IR:
55.3, 52.7, 41.1, 20.6 ppm. IR: νmax = 3120, 2964, 1675, 1605, 1483,
˜
1369, 1259, 1186, 825 cm–1. HRMS: calcd. for C26H24N5O2 [M +
H]+ 438.1930; found 438.1917.
6-(4-Chlorophenyl)-3-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-
yl]methyl}quinazolin-4(3H)-one (36): Yield 72% (64 mg); colorless
solid, m.p. 174–176 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.08
(s, 1 H, 2-H), 7.85 (d, J = 1.8 Hz, 1 H, 5-H), 7.71–7.62 (m, 1 H +1
H, triazole-H, 7-H), 7.34–7.27 (m, 1 H + 2 H, 8-H, Ph-H), 7.07 (d,
J = 8.4 Hz, 2 H, Ph-H), 6.72 (d, J = 8.0 Hz, 2 H, Bn-H), 6.67 (d,
J = 8.0 Hz, 2 H, Bn-H), 5.01 (s, 2 H, CH2), 4.79 (s, 2 H, CH2),
1.77 (s, 3 H, Bn-CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
160.6, 148.8, 148.1, 143.2, 138.2, 138.1, 138.0, 133.5, 133.4, 133.3,
129.8 (2 C), 129.6 (2 C), 129.2 (2 C), 128.6 (2 C), 124.1, 124.0,
ν
= 3129, 2942, 1680, 1605, 1482, 1337, 1259, 1164, 1031, 824,
˜
max
717 cm–1. HRMS: calcd. for C25H22N5O2 [M + H]+ 424.1773;
found 424.1766.
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-(4-chlorophenyl)quin-
azolin-4(3H)-one (32): Yield 56% (48 mg); colorless solid, m.p. 166–
1
122.4, 52.7, 41.1, 20.6 ppm. IR: ν
= 3129, 2917, 2852, 1662,
˜
max
168 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.58 (s, 1 H, 2-H),
1604, 1476, 1368, 1331, 1251, 1156, 1095, 1014, 819, 793, 742, 494,
452 cm–1. HRMS: calcd. for C25H21ClN5O [M + H]+ 442.1435;
found 442.1435.
8.32 (d, J = 2.1 Hz, 1 H, 5-H), 8.21 (s, 1 H, triazole-H), 8.12 (dd,
J = 8.6, 2.3 Hz, 1 H, 7-H), 7.79–7.75 (m, 1 H + 2 H, 8-H, Ph-H),
7.54 (d, J = 8.6 Hz, 2 H, Ph-H), 7.38–7.30 (m, 5 H, Bn-H), 5.56 (s,
2 H, CH2), 5.29 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 159.8, 148.1, 147.4, 142.6, 137.5, 137.4, 135.9, 132.9,
132.8, 129.1 (2 C), 128.7 (2 C), 128.6 (2 C), 128.12, 128.06, 128.0
3-{[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-phenyl-
quinazolin-4(3H)-one (37): Yield 77% (65 mg); colorless solid, m.p.
150–152 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.57 (s, 1 H, 2-
H), 8.34 (d, J = 2.2 Hz, 1 H, 5-H), 8.18–8.14 (m, 1 H +1 H, 7-H,
triazole-H), 7.81–7.74 (m, 1 H + 2 H, 8-H, Ph-H), 7.52 (t, J =
7.4 Hz, 2 H, Ph-H), 7.42 (t, J = 7.3 Hz, 1 H, Ph-H), 7.29 (d, J =
8.7 Hz, 2 H, Bn-H), 6.91 (d, J = 8.7 Hz, 2 H, Bn-H), 5.47 (s, 2 H,
CH2), 5.27 (s, 2 H, CH2), 3.72 (s, 3 H, Bn-OCH3) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 160.7, 159.9, 148.6, 147.9, 143.3, 139.4,
139.3, 133.5, 130.3 (2 C), 129.7 (2 C), 128.5, 128.3, 127.4 (2 C),
(2 C), 123.7, 123.4, 121.9, 52.8, 41.1 ppm. IR: ν
= 3078, 1668,
˜
max
1605, 1477, 1375, 1256, 1096, 821, 717 cm–1. HRMS: calcd. for
C24H19ClN5O [M + H]+ 428.1278; found 428.1273.
3-{[1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-phenylquin-
azolin-4(3H)-one (33): Yield 79% (64 mg); colorless solid, m.p. 156–
1
158 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.57 (s, 1 H, 2-H),
8.34 (d, J = 2.2 Hz, 1 H, 5-H), 8.16 (s, 1 H, triazole-H) 8.15 (dd,
J = 8.2, 2.2 Hz, 1 H, 7-H), 7.81–7.73 (m, 1 H + 2 H, 8-H, Ph-H),
7.52 (t, J = 7.3 Hz, 2 H, Ph-H), 7.42 (t, J = 7.3 Hz, 1 H, Ph-H),
7.22 (d, J = 8.1 Hz, 2 H, Bn-H), 7.16 (d, J = 8.1 Hz, 2 H, Bn-H),
5.50 (s, 2 H, CH2), 5.28 (s, 2 H, CH2), 2.26 (s, 3 H, Bn-CH3) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 160.7, 148.6, 147.9, 143.3,
139.4, 139.3, 138.1, 133.5, 133.4, 129.8 (2 C), 129.7 (2 C), 128.6 (2
C), 128.6, 127.4 (2 C), 124.1, 123.9, 122.4, 52.7, 41.1, 20.6 ppm.
124.0, 123.9, 122.4, 114.6 (2 C), 55.2, 52.5, 41.1 ppm. IR: ν
=
˜
max
3137, 3056, 2925, 2836, 1668, 1601, 1513, 1478, 1251, 1176, 1050,
1024, 934, 835, 793, 759, 693, 568, 546 cm–1. HRMS: calcd. for
C25H22N5O2 [M + H]+ 424.1774; found 424.1771.
3-{[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(p-tolyl)-
quinazolin-4(3H)-one (38): Yield 73% (64 mg); colorless solid, m.p.
156–158 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.55 (s, 1 H, 2-
H), 8.31 (d, J = 2.1 Hz, 1 H, 5-H), 8.17–8.09 (m, 1 H + 1 H, 7-H,
triazole-H), 7.76 (d, J = 8.5 Hz, 1 H, 8-H), 7.66 (d, J = 8.4 Hz, 2
H, Ph-H), 7.35–7.23 (m, 4 H, Bn-H), 6.91 (d, J = 8.4 Hz, 2 H, Ph-
H), 5.47 (s, 2 H, CH2), 5.27 (s, 2 H, CH2), 3.72 (s, 3 H, Bn-OCH3),
2.36 (s, 3 H, Ph-CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
160.7, 159.9, 148.5, 147.7, 143.3, 139.4, 138.1, 136.4, 133.3, 130.4
(2 C), 130.3 (2 C), 128.5, 128.4, 127.2 (2 C), 123.9, 123.5, 122.4,
IR: ν
= 3121, 3056, 2917, 1666, 1600, 1478, 1359, 1253, 1047,
˜
max
927, 837, 791, 759, 714, 568, 479 cm–1. HRMS: calcd. for
C25H22N5O [M + H]+ 408.1824; found 408.1829.
3-{[1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(p-tolyl)-
quinazolin-4(3H)-one (34): Yield 81% (68 mg); colorless solid, m.p.
168–170 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.54 (s, 1 H, 2-
H), 8.31 (d, J = 2.0 Hz, 1 H, 5-H), 8.15 (s, 1 H, triazole-H), 8.12
(dd, J = 8.6, 2.2 Hz, 1 H, 7-H), 7.75 (d, J = 8.5 Hz, 1 H, 8-H), 7.65
(d, J = 8.1 Hz, 1 H, Ph-H), 7.31 (d, J = 7.9 Hz, 2 H, Ph-H), 7.21
(d, J = 8.0 Hz, 2 H, Bn-H), 7.15 (d, J = 8.0 Hz, 2 H, Bn-H), 5.50
(s, 2 H, CH2), 5.27 (s, 2 H, CH2), 2.36 (s, 3 H, Ph-CH3), 2.26 (s, 3
H, Bn-CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.7,
148.4, 147.7, 143.3, 139.4, 138.1, 138.1, 136.4, 133.5, 133.3, 130.3
(2 C), 129.8 (2 C), 128.6 (2 C), 128.5, 127.2 (2 C), 124.1, 123.4,
114.6 (2 C), 55.2, 52.5, 41.1, 20.6 ppm. IR: νmax = 3137, 2925, 2852,
˜
1665, 1603, 1514, 1483, 1372, 1336, 1252, 1177, 1050, 810,
777 cm–1. HRMS: calcd. for C27H26N5O2 [M + H]+ 438.1930;
found 438.1932.
3-{[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(4-meth-
oxyphenyl)quinazolin-4(3H)-one (39): Yield 65% (59 mg); colorless
solid, m.p. 150–152 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.54
(s, 1 H, 2-H), 8.27 (d, J = 2.2 Hz, 1 H, 5-H), 8.16 (s, 1 H, triazole-
H), 8.08 (dd, J = 8.5, 2.2 Hz, 1 H, 7-H), 7.72 (d, J = 8.5 Hz, 1 H,
8-H), 7.68 (d, J = 8.8 Hz, 2 H, Ph-H), 7.29 (d, J = 8.6 Hz, 2 H,
Bn-H), 7.05 (d, J = 8.8 Hz, 2 H, Ph-H), 6.90 (d, J = 8.6 Hz, 2 H,
Bn-H), 5.47 (s, 2 H, CH2), 5.27 (s, 2 H, CH2), 3.80 (s, 3 H, Ph-
122.4, 52.7, 41.1, 20.6 (2 C) ppm. IR: ν
= 3129, 3015, 2917,
˜
max
1677, 1606, 1483, 1335, 1262, 1157, 949, 810, 781 cm–1. HRMS:
calcd. for C26H24N5O [M + H]+ 422.1981; found 422.1984.
6-(4-Methoxyphenyl)-3-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-
yl]methyl}quinazolin-4(3H)-one (35): Yield 74% (65 mg); colorless
Eur. J. Org. Chem. 2013, 7533–7545
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7541

T. Besson et al.
FULL PAPER
OCH3), 3.71 (s, 3 H, Bn-OCH3) ppm. 13C NMR (75 MHz, [D6]- 3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(4-chloro-
DMSO): δ = 160.7, 160.1, 159.9, 148.3, 147.3, 143.3, 139.1, 133.1, phenyl)quinazolin-4(3H)-one (44): Yield 67% (62 mg); colorless so-
131.6, 130.3 (2 C), 128.5 (2 C), 128.4, 128.3, 123.9, 123.0, 122.4, lid, m.p. 188–190 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.58
115.1 (2 C), 114.6 (2 C), 55.3, 55.2, 52.5, 41.1 ppm. IR: ν
=
(s, 1 H, 2-H), 8.33 (d, J = 2.1 Hz, 1 H, 5-H), 8.22 (s, 1 H, triazole-
H), 8.14 (dd, J = 8.6, 2.3 Hz, 1 H, 7-H), 7.80–7.76 (m, 3 H, 8-H,
Ph-H), 7.42 (d, J = 8.5 Hz, 2 H, Bn-H), 7.33 (d, J = 8.5 Hz, 2 H,
Bn-H), 5.57 (s, 2 H, CH2), 5.29 (s, 2 H, CH2) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 159.8, 148.1, 147.4, 142.6, 137.5, 137.4,
134.9, 132.92, 132.86, 132.80, 130.0 (2 C), 129.1 (2 C), 128.7 (2 C),
˜
max
3129, 2925, 2836, 1674, 1604, 1514, 1481, 1368, 1331, 1247, 1179,
1028, 823, 778, 550, 497 cm–1. HRMS: calcd. for C26H24N5O3 [M
+ H]+ 454.1879; found 454.1877.
6-(4-Chlorophenyl)-3-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
yl]methyl}quinazolin-4(3H)-one (40): Yield 75% (69 mg); colorless
solid, m.p. 176–178 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.57
(s, 1 H, 2-H), 8.31 (d, J = 2.2 Hz, 1 H, 5-H), 8.16 (s, 1 H, triazole-
H), 8.11 (dd, J = 8.5, 2.2 Hz, 1 H, 7-H), 7.76 (d, J = 8.6 Hz, 2 H,
Ph-H), 7.75 (d, J = 8.5 Hz, 1 H, 8-H), 7.53 (d, J = 8.6 Hz, 2 H,
Ph-H), 7.29 (d, J = 8.7 Hz, 2 H, Bn-H), 6.90 (d, J = 8.7 Hz, 2 H,
Bn-H), 5.47 (s, 2 H, CH2), 5.26 (s, 2 H, CH2), 3.71 (s, 3 H, Bn-
OCH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.6, 159.9,
148.8, 148.1, 143.2, 138.1, 138.0, 133.5, 133.4, 130.3 (2 C), 129.6 (2
C), 129.2 (2 C), 128.6, 128.3, 123.9, 122.4, 114.6 (2 C), 55.2, 52.5,
128.6 (2 C), 128.1, 123.8, 123.4, 121.9, 52.0, 41.1 ppm. IR: ν
=
˜
max
3120, 3068, 1672, 1607, 1477, 1366, 1102, 818 cm–1. HRMS: calcd.
for C24H18Cl2N5O [M + H]+ 462.0888; found 462.0886.
Crystal Structure Data for 44: C24H17Cl2N5O, M = 462.33, mono-
clinic, P21/n (Nr 14), a = 17.9326(17), b = 5.3129(5), c =
23.655(2) Å, β = 104.194(2)°, V = 2184.9(4) Å3, Z = 4, dcalcd.
=
2
1.405. The final cycle of full-matrix least-squares refinement on Fo
was based on 4480 observed reflections and 289 variable param-
eters and converged with unweighted and weighted agreement fac-
tors of R1 = 0.0829 and wR2 = 0.1805 for 3106 reflections with I
Ͼ 2σI, and R1 = 0.1166 and wR2 = 0.1982 for all data.
41.1 ppm. IR: ν
= 3148, 3121, 3066, 1668, 1604, 1517, 1477,
˜
max
1252, 1025, 817, 794 cm–1. HRMS: calcd. for C25H21ClN5O2 [M +
H]+ 458.1384; found 458.1393.
CCDC-948758 (for 44) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-phenylquin-
azolin-4(3H)-one (41): Yield 67% (57 mg); colorless solid, m.p. 178–
1
180 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.57 (s, 1 H, 2-H),
8.34 (d, J = 2.1 Hz, 1 H, 5-H), 8.22 (s, 1 H, triazole-H), 8.15 (dd,
J = 8.5, 2.1 Hz, 1 H, 7-H), 7.81–7.74 (m, 1 H + 2 H, 8-H, Ph-H),
7.51 (t, J = 7.4 Hz, 2 H, Ph-H), 7.43 (m, 1 H + 2 H, Ph-H, Bn-H),
7.34 (d, J = 8.5 Hz, 2 H, Bn-H), 5.57 (s, 2 H, CH2), 5.29 (s, 2 H,
CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.9, 157.9,
147.2, 142.7, 138.8, 138.7, 134.9, 132.9, 132.8, 129.9 (2 C), 129.2 (2
C), 128.7 (2 C), 128.0, 126.8 (2 C), 123.8, 123.3, 121.9, 52.0,
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-phenylpyrido[2,3-d]pyr-
imidin-4(3H)-one (45): Yield 68 % (79 mg); colorless solid, m.p.
188–190 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.32 (d, J =
2.6 Hz, 1 H, 7-H), 8.80 (s, 1 H, 2-H), 8.68 (d, J = 2.6 Hz, 1 H, 5-
H), 8.23 (s, 1 H, triazole-H), 7.88–7.85 (m, 2 H, Ph-H), 7.58–7.47
(m, 3 H, Ph-H), 7.37–7.29 (m, 5 H, Ph), 5.56 (s, 2 H, Bn-H), 5.28
(s, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.6,
157.1, 154.3, 151.0, 142.4, 135.9, 135.8, 132.5, 129.4 (2 C), 128.8 (2
C), 128.7, 128.2, 128.1 (2 C), 127.2 (2 C), 123.8, 116.7, 52.9,
41.1 ppm. IR: ν
= 3129, 1671, 1607, 1478, 1373, 1337, 1052,
˜
max
792, 763 cm–1. HRMS: calcd. for C24H19ClN5O [M + H]+
428.1278; found 428.1278.
41.3 ppm. IR: ν
= 3032, 2934, 2838, 1663, 1595, 1469, 1256,
˜
max
1225, 1048, 814 cm–1. HRMS: calcd. for C23H19N6O [M + H]+
3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(p-tolyl)-
quinazolin-4(3H)-one (42): Yield 66% (58 mg); colorless solid, m.p.
174–176 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.55 (s, 1 H, 2-
H), 8.31 (d, J = 2.1 Hz, 1 H, 5-H), 8.21 (s, 1 H, triazole-H), 8.12
(dd, J = 8.6, 2.3 Hz, 1 H, 7-H), 7.75 (d, J = 8.6 Hz, 1 H, 8-H), 7.64
(d, J = 8.1 Hz, 2 H, Ph-H), 7.43 (d, J = 8.5 Hz, 2 H, Bn-H), 7.35–
7.30 (m, 2 H + 2 H, Bn-H, Ph-H), 5.57 (s, 2 H, CH2), 5.29 (s, 2 H,
CH2), 2.35 (s, 3 H, Ph-CH3) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 159.9, 147.8, 147.0, 142.7, 138.7, 137.5, 135.8, 134.9,
132.9, 132.7, 129.9 (2 C), 129.7 (2 C), 128.7, (2 C), 127.9, 126.6 (2
395.1620; found 395.1623.
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-(p-tolyl)pyrido[2,3-d]-
pyrimidin-4(3H)-one (46): Yield 64% (52 mg); colorless solid, m.p.
196–198 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.31 (d, J =
2.6 Hz, 1 H, 7-H), 8.78 (s, 1 H, 2-H), 8.66 (d, J = 2.6 Hz, 1 H, 5-
H), 8.23 (s, 1 H, triazole-H), 7.76 (d, J = 8.2 Hz, 2 H, Ph-H), 7.37–
7.29 (m, 5 H + 2 H, Bn-H, Ph-H), 5.57 (s, 2 H, CH2), 5.30 (s, 2 H,
CH2), 2.38 (s, 3 H, Ph-CH3) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 160.5, 156.8, 154.0, 150.8, 142.4, 138.2, 135.9, 134.2,
132.8, 132.0, 129.9 (2 C), 128.7 (2 C), 128.1, 128.0 (2 C), 126.9 (2
C), 123.8, 122.9, 121.9, 52.0, 41.1, 20.6 ppm. IR: νmax = 3120, 3068,
˜
2921, 1656, 1605, 1483, 1365, 1233, 818, 777 cm–1. HRMS: calcd.
for C25H21ClN5O [M + H]+ 442.1435; found 442.1433.
C), 123.8, 116.6, 52.8 41.3, 20.7 ppm. IR: νmax = 3048, 2941, 2834,
˜
1665, 1599, 1469, 1256, 1225, 1050, 828, 815 cm–1. HRMS: calcd.
for C24H21N6O [M + H]+ 409.1777; found 409.1789.
3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(4-meth-
oxyphenyl)quinazolin-4(3H)-one (43): Yield 69% (63 mg); colorless
solid, m.p. 208–210 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.54
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-(4-methoxyphenyl)-
pyrido[2,3-d]pyrimidin-4(3H)-one (47): Yield 66% (56 mg); colorless
(s, 1 H, 2-H), 8.29 (d, J = 2.1 Hz, 1 H, 5-H), 8.21 (s, 1 H, triazole- solid, m.p. 180–182 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.28
H), 8.12 (dd, J = 8.6, 2.3 Hz, 1 H, 7-H), 7.75 (d, J = 8.6 Hz, 1 H,
8-H), 7.71 (d, J = 8.8 Hz, 2 H, Ph-H), 7.43 (d, J = 8.5 Hz, 2 H,
Bn-H), 7.34 (d, J = 8.5 Hz, 2 H, Bn-H), 7.07 (d, J = 8.8 Hz, 2 H,
Ph-H), 5.57 (s, 2 H, CH2), 5.28 (s, 2 H, CH2), 3.81 (s, 3 H, Ph-
OCH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.9, 159.3,
(d, J = 2.6 Hz, 1 H, 7-H), 8.77 (s, 1 H, 2-H), 8.62 (d, J = 2.6 Hz,
1 H, 5-H), 8.23 (s, 1 H, triazole-H), 7.80 (d, J = 8.8 Hz, 2 H, Ph-
H), 7.37–7.30 (m, 5 H, Bn-H), 7.08 (d, J = 8.8 Hz, 2 H, Ph-H),
5.57 (s, 2 H, CH2), 5.30 (s, 2 H, CH2), 3.82 (s, 3 H, Ph-OCH3) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 160.5, 159.7, 156.5, 153.8,
147.6, 146.7, 142.7, 138.5, 134.9, 132.9, 132.5, 131.0, 129.9 (2 C), 150.5, 147.9, 142.4, 135.9, 134.0, 131.4, 128.7 (2 C), 128.3, 128.1 (2
128.7 (2 C), 128.0 (2 C), 127.9, 123.8, 122.5, 121.9, 114.6 (2 C), C), 128.0 (2 C), 127.9, 123.8, 116.6, 114.7, 55.3, 52.8, 41.3 ppm.
55.2, 52.0, 41.1 ppm. IR: νmax = 3124, 3085, 3011, 2838, 1671, 1605,
IR: ν
= 3048, 2940, 2832, 1666, 1599, 1470, 1257, 1225, 1050,
˜
˜
max
1483, 1368, 1259, 1029, 826, 777 cm–1. HRMS: calcd. for
C25H21ClN5O2 [M + H]+ 458.1384; found 458.1363.
829, 809 cm–1. HRMS: calcd. for C24H21N6O2 [M + H]+ 425.1726;
found 425.1722.
7542
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7533–7545

Access to Polyaromatic Scaffolds
3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-(4-chlorophenyl)- 133.1, 132.1, 131.5, 131.3, 131.2, 127.7 (2 C), 127.6 (2 C), 127.4 (2
pyrido[2,3-d]pyrimidin-4(3H)-one (48): Yield 61% (52 mg); colorless
C), 126.6 (2 C), 122.1, 115.0, 50.7, 39.2, 18.4 ppm. IR: νmax = 3064,
2917, 1669, 1597, 1466, 1421, 1226, 1097, 1109, 928, 813, 746, 522,
˜
solid, m.p. 212–214 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.32
(d, J = 2.4 Hz, 1 H, 7-H), 8.80 (s, 1 H, 2-H), 8.69 (d, J = 2.5 Hz, 475, 458 cm–1. HRMS: calcd. for C24H20ClN6O [M + H]+
1 H, 5-H), 8.23 (s, 1 H, triazole-H), 7.90 (d, J = 8.5 Hz, 2 H, Ph-
H), 7.59 (d, J = 8.4 Hz, 2 H, Ph-H), 7.41–7.26 (m, 5 H, Bn-H),
5.57 (s, 2 H, CH2), 5.31 (s, 2 H, CH2) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 160.4, 157.1, 154.1, 151.1, 142.3, 135.8, 134.6,
133.6, 133.0, 132.7, 129.2 (2 C), 128.9 (2 C), 128.7 (2 C), 128.1,
443.1387; found 443.1375.
3-{[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-phenyl-
pyrido[2,3-d]pyrimidin-4(3H)-one (53): Yield 72% (61 mg); colorless
solid, m.p. 192–194 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.32
(d, J = 2.3 Hz, 1 H, 7-H), 8.79 (s, 1 H, 2-H), 8.67 (d, J = 2.3 Hz,
1 H, 5-H), 8.18 (s, 1 H, triazole-H), 7.85 (d, J = 7.4 Hz, 2 H, Ph-
H), 7.59–7.42 (m, 3 H, Ph-H), 7.29 (d, J = 8.4 Hz, 2 H, Bn-H),
6.91 (d, J = 8.4 Hz, 2 H, Bn-H), 5.48 (s, 2 H, CH2), 5.29 (s, 2 H,
CH2), 3.72 (s, 3 H, Bn-OCH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 161.3, 159.9, 157.8, 155.0, 151.7, 143.0, 136.3,
134.9, 133.1, 130.3 (2 C), 129.9 (2 C), 129.2, 128.3, 127.7 (2 C),
128.0 (2 C), 123.8, 116.6, 52.8, 41.3 ppm. IR: ν
= 3063, 1672,
˜
max
1600, 1468, 1227, 1043, 815, 717 cm–1. HRMS: calcd. for
C23H18ClN6O [M + H]+ 429.1231; found 429.1233.
3-{[1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-phenyl-
pyrido[2,3-d]pyrimidin-4(3H)-one (49): Yield 56% (46 mg); colorless
solid, m.p. 222–224 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.32
(s, 1 H, 7-H), 8.78 (s, 1 H, 2-H), 8.68 (d, J = 1.5 Hz, 1 H, 5-H),
8.18 (s, 1 H, triazole-H), 7.85 (d, J = 7.7 Hz, 2 H, Ph-H), 7.57–
7.44 (m, 3 H, Ph-H), 7.22 (d, J = 7.5 Hz, 2 H, Bn-H), 7.16 (d, J =
7.8 Hz, 2 H, Bn-H), 5.50 (s, 2 H, CH2), 5.29 (s, 2 H, CH2), 2.26 (s,
3 H, Bn-CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 161.3,
157.7, 154.9, 151.6, 143.0, 138.1, 136.3, 134.9, 133.4, 133.1, 129.9
(2 C), 129.8 (2 C), 129.2, 128.7 (2 C), 127.6 (2 C), 124.2, 117.2,
124.0, 117.2, 114.6 (2 C), 55.2, 52.5, 41.3 ppm. IR: ν
= 3120,
˜
max
3068, 2842, 1671, 1598, 1515, 1472, 1249, 1023, 1054, 814,
766 cm–1. HRMS: calcd. for C24H21N6O2 [M + H]+ 425.1726;
found 425.1728.
3-{[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(p-tolyl)-
pyrido[2,3-d]pyrimidin-4(3H)-one (54): Yield 62% (54 mg); colorless
solid, m.p. 210–212 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.29
(d, J = 2.7 Hz, 1 H, 7-H), 8.76 (s, 1 H, 2-H), 8.64 (d, J = 2.7 Hz,
1 H, 5-H), 8.16 (s, 1 H, triazole-H), 7.75 (d, J = 8.2 Hz, 2 H, Ph-
H), 7.35 (d, J = 7.9 Hz, 2 H, Ph-H), 7.29 (d, J = 8.7 Hz, 2 H, Bn-
H), 6.91 (d, J = 8.7 Hz, 2 H, Bn-H), 5.47 (s, 2 H, CH2), 5.29 (s, 2
H, CH2), 3.72 (s, 3 H, Bn-OCH3), 2.37 (s, 3 H, Ph-CH3) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 161.3, 159.9, 157.5, 154.7, 151.4,
144.0, 138.8, 134.8, 133.4, 132.6, 130.5 (2 C), 130.3 (2 C), 128.3,
127.4 (2 C), 123.9, 117.1, 114.6 (2 C), 55.2, 52.5, 41.3, 20.6 ppm.
52.8, 41.3, 20.6 ppm. IR: νmax = 3064, 3039, 2917, 2960, 1668, 1597,
˜
1467, 1327, 1226, 1050, 941, 813, 762, 689, 584, 521, 469 cm–1
.
HRMS: calcd. for C24H21N6O [M + H]+ 409.1777; found 409.1790.
3-{[1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(p-tolyl)-
pyrido[2,3-d]pyrimidin-4(3H)-one (50): Yield 63% (53 mg); colorless
solid, m.p. 198–200 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.30
(d, J = 2.7 Hz, 1 H, 7-H), 8.77 (s, 1 H, 2-H), 8.64 (d, J = 2.7 Hz,
1 H, 5-H), 8.18 (s, 1 H, triazole-H), 7.75 (d, J = 8.1 Hz, 2 H, Ph-
H), 7.35 (d, J = 8.1 Hz, 2 H, Ph-H), 7.21 (d, J = 8.3 Hz, 2 H, Bn-
H), 7.16 (d, J = 8.3 Hz, 2 H, Bn-H), 5.50 (s, 2 H, CH2), 5.29 (s, 2
H, CH2), 2.37 (s, 3 H, Ph-CH3), 2.26 (s, 3 H, Bn-CH3) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 161.3, 157.5, 154.7, 151.4, 143.0,
138.8, 138.1, 134.8, 133.4, 133.3, 132.5, 130.5 (2 C), 129.8 (2 C),
128.6 (2 C), 127.4 (2 C), 124.2, 117.1, 52.8, 41.3, 20.6, 20.5 ppm.
IR: ν
= 3115, 2983, 1672, 1597, 1249, 1024, 812, 782 cm–1
.
˜
max
HRMS: calcd. for C25H23N6O2 [M + H]+ 439.1882; found
439.1860.
3-{[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(4-meth-
oxyphenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (55): Yield 71 %
(65 mg); colorless solid, m.p. 200–202 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 9.28 (d, J = 2.6 Hz, 1 H, 7-H), 8.75 (s, 1 H, 2-H),
8.61 (d, J = 2.6 Hz, 1 H, 5-H), 8.17 (s, 1 H, triazole-H), 7.81 (d, J
= 8.6 Hz, 2 H, Ph-H), 7.29 (d, J = 8.5 Hz, 2 H, Bn-H), 7.09 (d, J
= 8.6 Hz, 2 H, Ph-H), 6.91 (d, J = 8.5 Hz, 2 H, Bn-H), 5.47 (s, 2
H, CH2), 5.28 (s, 2 H, CH2), 3.82 (s, 3 H, Ph-OCH3), 3.72 (s, 3 H,
Bn-OCH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 161.3,
160.6, 159.9, 157.2, 154.6, 151.3, 143.0, 134.7, 132.1, 130.3 (2 C),
128.9 (2 C), 128.5, 128.3, 124.0, 117.2, 115.3 (2 C), 114.6 (2 C),
IR: ν
= 3088, 3056, 1677, 1600, 1474, 1364, 1209, 1051, 961,
˜
max
811, 475 cm–1. HRMS: calcd. for C25H23N6O [M + H]+ 423.1933;
found 423.1922.
6-(4-Methoxyphenyl)-3-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-
yl]methyl}pyrido[2,3-d]pyrimidin-4(3H)-one (51): Yield 61 %
(53 mg); colorless solid, m.p. 198–200 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 9.28 (d, J = 2.5 Hz, 1 H, 7-H), 8.75 (s, 1 H, 2-H),
8.61 (d, J = 2.5 Hz, 1 H, 5-H), 8.18 (s, 1 H, triazole-H), 7.80 (d, J
= 8.7 Hz, 2 H, Ph-H), 7.21 (d, J = 8.0 Hz, 2 H, Bn-H), 7.16 (d, J
= 8.0 Hz, 2 H, Bn-H), 7.09 (d, J = 8.7 Hz, 2 H, Ph-H), 5.50 (s, 2
H, CH2), 5.29 (s, 2 H, CH2), 3.82 (s, 3 H, Ph-OCH3), 2.26 (s, 3 H,
Bn-CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.2, 158.4,
155.1, 152.4, 149.1, 140.9, 136.0, 132.5, 131.3, 129.9, 127.7 (2 C),
126.8 (2 C), 126.6 (2 C), 126.4 (2 C), 122.1, 115.0, 113.1, 53.3, 50.6,
55.4, 55.2, 52.5, 41.3 ppm. IR: νmax = 3120, 2936, 1668, 1597, 1474,
˜
1249, 1191, 813, 782 cm–1. HRMS: calcd. for C25H23N6O3 [M +
H]+ 455.1832; found 455.1827.
6-(4-Chlorophenyl)-3-{[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
yl]methyl}pyrido[2,3-d]pyrimidin-4(3H)-one (56): Yield 69 %
(63 mg); colorless solid, m.p. 222–224 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 9.32 (d, J = 2.6 Hz, 1 H, 7-H), 8.80 (s, 1 H, 2-H),
8.70 (d, J = 2.6 Hz, 1 H, 5-H), 8.16 (s, 1 H, triazole-H), 7.91 (d, J
= 6.6 Hz, 2 H, Ph-H), 7.60 (d, J = 6.6 Hz, 2 H, Ph-H), 7.29 (d, J
= 8.5 Hz, 2 H, Bn-H), 6.92 (d, J = 8.5 Hz, 2 H, Bn-H), 5.48 (s, 2
H, CH2), 5.29 (s, 2 H, CH2), 3.73 (s, 3 H, Bn-OCH3) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 160.5, 159.2, 157.2, 154.2, 151.2,
142.3, 134.6, 133.6, 133.1, 132.7, 129.7 (2 C), 129.3 (2 C), 129.0 (2
39.2, 18.5 ppm. IR: ν
= 3057, 2927, 1678, 1603, 1468, 1254,
˜
max
1226, 1179, 1052, 809 cm–1. HRMS: calcd. for C25H23N6O2 [M +
H]+ 439.1882; found 439.1898.
6-(4-Chlorophenyl)-3-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-
yl]methyl}pyrido[2,3-d]pyrimidin-4(3H)-one (52): Yield 64 %
(57 mg); colorless solid, m.p. 214–216 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 9.32 (d, J = 2.7 Hz, 1 H, 7-H), 8.79 (s, 1 H, 2-H),
8.69 (d, J = 2.7 Hz, 1 H, 5-H), 8.18 (s, 1 H, triazole-H), 7.90 (d, J
= 8.6 Hz, 2 H, Ph-H), 7.59 (d, J = 8.6 Hz, 2 H, Ph-H), 7.22 (d, J
= 8.2 Hz, 2 H, Bn-H), 7.16 (d, J = 8.2 Hz, 2 H, Bn-H), 5.50 (s, 2
C), 127.8, 123.5, 116.7, 114.1 (2 C), 55.2, 52.4, 41.3 ppm. IR: ν
˜
max
= 3120, 1672, 1602, 1469, 1249, 1053, 814, 782 cm–1. HRMS: calcd.
for C24H20ClN6O2 [M + H]+ 459.1336; found 459.1336.
H, CH2), 5.29 (s, 2 H, CH2), 2.26 (s, 3 H, Bn-CH3) ppm. 13C NMR 3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-phenyl-
(75 MHz, [D6]DMSO): δ = 159.1, 155.8, 152.7, 149.7, 140.9, 136.1, pyrido[2,3-d]pyrimidin-4(3H)-one (57): Yield 72% (62 mg); colorless
Eur. J. Org. Chem. 2013, 7533–7545
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7543

T. Besson et al.
FULL PAPER
solid, m.p. 206–208 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.32
toral fellowship to D. H. The authors thank LABEX SynOrg
(d, J = 2.6 Hz, 1 H, 7-H), 8.79 (s, 1 H, 2-H), 8.69 (d, J = 2.6 Hz, (ANR-11-LABX-0029) and the AI-Chem. Channel program for fi-
1 H, 5-H), 8.24 (s, 1 H, triazole-H), 7.86 (d, J = 7.0 Hz, 2 H, Ph-
H), 7.57–7.49 (m, 3 H, Ph-H), 7.46 (d, J = 8.4 Hz, 2 H, Bn-H),
nancial support. We also acknowledge Anton Paar GmbH (Graz,
Austria) for provision of the single-mode microwave reactor
7.34 (d, J = 8.4 Hz, 2 H, Bn-H), 5.58 (s, 2 H, CH2), 5.31 (s, 2 H, (Monowave 300) and Milestone S.r.l. (Italy) for technical support.
CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 161.3, 157.7,
154.9, 151.7, 143.1, 136.3, 135.5, 134.9, 133.5, 133.1, 130.6 (2 C),
129.9 (2 C), 129.3 (2 C), 129.2, 127.7 (2 C), 124.4, 117.2, 41.3 ppm.
[1] For our recent work, see: a) Y. Loidreau, P. Marchand, C. Du-
bouilh-Benard, M.-R. Nourrisson, M. Duflos, N. Loaëc, L.
Meijer, T. Besson, Eur. J. Med. Chem. 2013, 59, 283–295; b) Y.
Loidreau, P. Marchand, C. Dubouilh-Benard, M.-R. Nourris-
son, M. Duflos, N. Loaëc, L. Meijer, T. Besson, Eur. J. Med.
Chem. 2012, 58, 171–183.
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IR: ν
= 3287, 3057, 1678, 1646, 1598, 1501, 1451, 1313, 1222,
˜
max
1048, 817, 693 cm–1. HRMS: calcd. for C23H18ClN6O [M + H]+
429.1231; found 429.1232.
3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(p-tolyl)-
pyrido[2,3-d]pyrimidin-4(3H)-one (58): Yield 67% (59 mg); colorless
solid, m.p. 186–188 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 9.30
(d, J = 2.7 Hz, 1 H, 7-H), 8.78 (s, 1 H, 2-H), 8.65 (d, J = 2.7 Hz,
1 H, 5-H), 8.23 (s, 1 H, triazole-H), 7.75 (d, J = 8.0 Hz, 2 H, Ph-
H), 7.43 (d, J = 8.4 Hz, 2 H, Bn-H), 7.35 (d, J = 8.0 Hz, 2 H, Ph-
H), 7.33 (d, J = 8.4 Hz, 2 H, Bn-H), 5.57 (s, 2 H, CH2), 5.30 (s, 2
H, CH2), 2.37 (s, 3 H, Ph-CH3) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 161.3, 157.5, 154.8, 151.5, 143.1, 138.8, 135.5, 134.9,
133.5, 133.4, 132.6, 130.6 (2 C), 130.5 (2 C), 129.3 (2 C), 127.5 (2
C), 124.4, 117.2, 52.1, 41.3, 20.6 ppm. IR: νmax = 3265, 1680, 1603,
˜
1469, 1313, 1230, 1052, 814, 751 cm–1. HRMS: calcd. for
C24H20ClN6O [M + H]+ 443.1387; found 443.1366.
[4] E. Deau, D. Hédou, E. Chosson, V. Levacher, T. Besson, Tetra-
hedron Lett. 2013, 54, 3518–3521.
3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(4-meth-
oxyphenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (59): Yield 66 %
(61 mg); colorless solid, m.p. 222–224 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 9.27 (d, J = 2.3 Hz, 1 H, 7-H), 8.76 (s, 1 H, 2-H),
8.59 (d, J = 2.3 Hz, 1 H, 5-H), 8.24 (s, 1 H, triazole-H), 7.78 (d, J
= 8.8 Hz, 2 H, Ph-H), 7.42 (d, J = 8.5 Hz, 2 H, Bn-H), 7.33 (d, J
= 8.5 Hz, 2 H, Bn-H), 7.07 (d, J = 8.8 Hz, 2 H, Ph-H), 5.58 (s, 2
H, CH2), 5.30 (s, 2 H, CH2), 3.81 (s, 3 H, Ph-OCH3) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 161.3, 160.5, 157.2, 154.6, 151.2,
143.1, 135.5, 134.6, 133.5, 132.0, 130.6 (2 C), 129.3 (2 C), 128.9 (2
[5] For reviews on triazoles as bioactive agents, see: a) N. Siddiqui,
W. Ahsan, M. S. Alam, R. Ali, S. Jain, B. Azad, J. Akhtar, Int.
J. Pharm. Sci. Rev. Res. 2011, 8, 161–169; b) S. G. Agalave,
S. R. Maujan, V. S. Pore, Chem. Asian J. 2011, 6, 2696–2718.
[6] For the latest advances in microwave-assisted organic synthesis
(MAOS), see: A. de la Hoz, A. Loupy (Eds.), Microwaves in
Organic Synthesis 3rd ed., Wiley-VCH, Weinheim, Germany,
2013, vol. 1 and 2.
[7] H. Vorbrüggen, Synlett 2008, 11, 1603–1617.
[8] J. G. Topliss, J. Med. Chem. 1972, 15, 1006–1011. In this paper,
proposals were presented for the stepwise selection for the syn-
thesis of analogues of an active compound. The diagrams are
based on a fundamental assumption of the Hansch method
that a particular substituent may modify the activity relative
to the parent compound by virtue of the resulting changes in
hydrophobic, electronic and steric effects. In our study, the use
of the Topliss scheme allowed us to choose certain reagents to
verify the validity of our methodology and at the same time
to start to build a list of molecules with potential biological
interest.
C), 128.5, 124.4, 117.1, 115.2 (2 C), 55.4, 52.1, 41.3 ppm. IR: ν
˜
max
= 3051, 2834, 1668, 1603, 1469, 1226, 1180, 1052, 1011, 807 cm–1.
HRMS: calcd. for C24H20ClN6O2 [M + H]+ 459.1336; found
459.1349.
3-{[1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl]methyl}-6-(4-chloro-
phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (60): Yield 55% (51 mg);
colorless solid, m.p. 232–234 °C. 1H NMR (300 MHz, [D6]DMSO):
δ = 9.32 (d, J = 2.7 Hz, 1 H, 7-H), 8.80 (s, 1 H, 2-H), 8.70 (d, J =
2.7 Hz, 1 H, 5-H), 8.23 (s, 1 H, triazole-H), 7.90 (d, J = 8.6 Hz, 2
H, Ph-H), 7.59 (d, J = 8.6 Hz, 2 H, Ph-H), 7.43 (d, J = 8.5 Hz, 2
H, Bn-H), 7.34 (d, J = 8.5 Hz, 2 H, Bn-H), 5.57 (s, 2 H, CH2), 5.31
(s, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.5,
157.2, 154.1, 151.1, 142.4, 134.9, 134.6, 133.6, 133.1, 132.9, 132.7,
130.0 (2 C), 129.2 (2 C), 129.0 (2 C), 128.8 (2 C), 123.9, 116.7, 52.0,
[9] T. Jin, S. Kamijo, Y. Yamamoto, Eur. J. Org. Chem. 2004,
3789–3791.
[10] For selected examples, see: a) J. Andersen, S. Bolvig, X. Liang,
Synlett 2005, 19, 2941–2947; b) A. K. Feldman, B. Colasson,
V. V. Fokin, Org. Lett. 2004, 6, 3897–3899; c) K. A. Dururgkar,
R. G. Gonnade, C. V. Ramana, Tetrahedron 2009, 65, 3974–
3979; d) T. Miao, L. Wang, Synthesis 2008, 3, 363–368.
[11] Although some substituted benzyl azides are commercially
available, most are provided, in: small quantities in solutions
of TBME or DCM, hence, they were freshly prepared, in: pure
form according to known methods, see: J. McNulty, K. Keskar,
R. Vemula, Chem. Eur. J. 2011, 17, 14727–14730; for a compre-
hensive review on the chemistry and synthesis of organic az-
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Chem. 2005, 117, 5320; Angew. Chem. Int. Ed. 2005, 44, 5188–
5240.
[12] The lost dissipation factor (tanδ) expresses the capacity of a
molecule or a material to transform electromagnetic energy
into thermal energy. A very high susceptibility to microwaves
is characterized by a high value (Ͼ0.5) of tanδ. tanδ (acetic
acid): δ = 0.174 at 2.45 GHz. For more details, see: C. Gabriel,
S. Gabriel, E. H. Grant, B. S. J. Halstead, D. M. P. Mingos,
Chem. Soc. Rev. 1998, 27, 213–224.
41.3 ppm. IR: ν
= 1679, 1605, 1466, 1406, 1229, 1095, 1052,
˜
max
943, 823 cm–1. HRMS: calcd. for C23H17Cl2N6O [M + H]+
463.0841; found 463.0860.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental methods, general experimental pro-
cedures and characterization data, 1H and 13C NMR spectra of
compounds, ORTEP diagram of compound 44 and crystallo-
graphic data.
Acknowledgments
Financial support from the Ministère de lЈEnseignement Supérieur
et de la Recherche (MESR) is gratefully acknowledged for a doc-
7544
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7533–7545

Access to Polyaromatic Scaffolds
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46, 467–473.
were observed in the crude mixture. Freshly recrystallized NBS
was obtained according to known procedures. For more details,
see: W. L. F. Armarego, C. L. L. Chai, Purification of Labora-
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Received: July 17, 2013
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Published Online: October 9, 2013
Eur. J. Org. Chem. 2013, 7533–7545
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7545