Cu/Pd-catalyzed C-2-H arylation of quinazolin-4(3H)-ones with (hetero)aryl halides

Article abstract of DOI:10.1002/ejoc.201501129

The regiospecific C-2-H arylation of N-3-substituted quinazolin-4(3H)-ones with a wide range of aryl or (hetero)aryl halides under microwave irradiation was studied. A ligand-dependent palladium/copper bicatalytic system was developed and allowed direct c

Full text of DOI:10.1002/ejoc.201501129

FULL PAPER
DOI: 10.1002/ejoc.201501129
Cu/Pd-Catalyzed C-2–H Arylation of Quinazolin-4(3H)-ones with (Hetero)aryl
Halides
Julien Godeau,[a] Marine Harari,[a] Sylvain Laclef,[a] Emmanuel Deau,[a] Corinne Fruit,*[a]
and Thierry Besson*[a]
Keywords: Nitrogen heterocycles / Microwave chemistry / C–H functionalization / Cross-coupling / Palladium
The regiospecific C-2–H arylation of N-3-substituted quin-
azolin-4(3H)-ones with a wide range of aryl or (hetero)aryl
halides under microwave irradiation was studied. A ligand-
dependent palladium/copper bicatalytic system was devel-
oped and allowed direct cross-coupling with a variety of (het-
motes the construction of C(sp2)–C(sp2) bonds from arenes or
(hetero)arenes and aryl or (hetero)aryl bromides and chlor-
ides in a time-efficient strategy. The extension of the reaction
to various N-3-substituted quinazolin-4(3H)-ones with iodo-
benzene as well as the scope and limitations of the method
ero)aryl halides. This useful and scalable procedure pro- were also investigated.
heteroarenes has also received significant attention and
Introduction
emerged as a useful route to complex molecular struc-
tures.[3] To date, despite the practical importance of 2-ar-
ylquinazolin-4(3H)-ones, C-2–H arylation reactions have
mostly been accomplished through intramolecular cycliza-
tions with palladium catalysts and limited to the synthesis
of luotonin derivatives (Figure 1).[4] In this regard, a general
transition-metal-catalyzed protocol appears to be particu-
larly attractive.
Recently, our research group demonstrated that substi-
tuted quinazolin-4(3H)-ones and pyridopyrimidin-4(3H)-
ones are convenient substrates for ligand-free palladium-
catalyzed and copper-assisted intermolecular C-2–H aryla-
tions with (hetero)aryl iodides.[5] Following our efforts on
the functionalization of quinazolin-4(3H)-one derivatives,[6]
we intended to enhance the procedure by extending the cou-
pling partners to bromo- and chloro(hetero)aryls.
2-Arylquinazolin-4(3H)-ones are a highly significant
class of heteroaromatic compounds that are widely found in
bioactive molecules, pharmaceuticals, and natural products
(Figure 1).[1] Therefore, their syntheses have attracted much
attention (Scheme 1).[2] Owing to the importance of the
quinazolinone core in many pharmaceutically active com-
pounds, the development of a simple method for their direct
functionalization is a highly desirable goal for chemists. In
this context, the transition-metal-catalyzed intermolecular
C–C coupling of quinazolin-4(3H)-one scaffolds through
direct C–H arylation represents an extremely attractive ap-
proach, which circumvents tedious multistep syntheses in
structure–activity relationship (SAR) studies. In the past
decade, the palladium-catalyzed C–H functionalization of
To the best of our knowledge, a unique example of inter-
molecular palladium-catalyzed C–H arylation of quinazol-
in-4(3H)-ones with aryl chlorides was reported for the syn-
thesis of Bouchardatine, a naturally occurring cytotoxic al-
kaloid.[7] We present here a detailed study of the C-2–H
arylation and heteroarylation of N-3-substituted quinazol-
in-4(3H)-ones through the direct incorporation of various
(hetero)aryl halides (Scheme 1).
Figure 1. Selected examples of bioactive quinazolin-4(3H)-ones ob-
tained through intra-[4] or intermolecular[7] C-2–H arylation reac-
tions.
Results and Discussion
[a] Normandie Univ, COBRA, UMR 6014 & FR 3038,
Univ Rouen; INSA Rouen; CNRS, IRCOF,
1 rue Tesnière, 76821 Mont St Aignan Cedex, France
E-mail: corinne.fruit@univ-rouen.fr
Firstly, the extension of the cross-coupling reaction of
quinazolin-4(3H)-one 1a was explored with bromobenzene.
According to the previously described procedure with iodo-
benzene derivatives,[5] the direct arylation of N-3-benzyl-
ated quinazolin-4(3H)-one 1a was attempted with LiOtBu
(2 equiv.), CuI (50 mol-%), Pd(OAc)2 (5 mol-%), and bromo-
thierry.besson@univ-rouen.fr
http://www.lab-cobra.fr
Supporting information and ORCID(s) from the author(s) for
this article are available on the WWW under http://dx.doi.org/
10.1002/ejoc.201501129.
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Scheme 1. Reported methods and the present strategy for the synthesis of quinazolin-4(3H)-ones.
benzene (2 equiv.) in N,N-dimethylformamide (DMF) at
Table 1. Ligand screening in the direct 2-arylation of 1a with phenyl
halides.[a]
120 °C. Unfortunately, this ligand-free methodology was
limited to iodobenzenes, and reactions with bromobenzene
failed, most certainly because of an ineffective oxidative ad-
dition of the Pd0 species to the C(sp2)–Br bond (Table 1,
Entry 2).
To verify this hypothesis, Pd(OAc)2 was combined with
a selection of electron-rich or electron-poor phosphine li-
gands as potential catalytic systems for the direct C–H aryl-
ation with bromobenzene (Table 1, Entries 3–6).
The addition of an electron-rich phosphine ligand such
Entry
PhX
Ligand (mol-%)
Yield [%][b]
91 (90)[c]
trace
82
83
80
[8]
as PPh3, PCy3, or PtBu3 (6 mol-%) increased the effi-
1
2
3
4
5
6
7
8
PhI
–
–
ciency of the reaction with bromobenzene dramatically, and
2a was obtained in 81% average yield (Table 1, Entries 3–
5). When the reaction was conducted with an electron-poor
phosphine ligand such as tris(pentafluorophenyl)phosphine,
the yield dropped to 68% (Table 1, Entry 6); therefore, the
direct C–H arylation of 1a requires an electron-rich ligand
to favor Pd0 insertion into the C(sp2)–Br bond.
We also investigated the variation of the reactant quanti-
ties, addition order, temperature, and reaction time without
the successful enhancement of the final result.
PhBr
PhBr
PhBr
PhBr
PhBr
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PCy3 (6)
PtBu3 (6)
PPh3 (6)
P(C6F5)3 (6)
PtBu3 (6)
PPh3 (6)
PPh3 (10)
dppp (6)
dCype (6)
dippp (6)
dippp (10)
dbpf (6)
Xantphos (6)
NiXantphos (6)
NiXantphos (10)
Pd-PEPPSI-IPent
68
trace
trace
trace
trace
trace
5
9
10
11
12
13
14
15
16
17
18
16
As described in our preceding report,[5] the order of the
addition of the reactants is crucial for a proper completion
of the cross-coupling: the copper source should first be
mixed and heated with lithium tert-butoxide and the quin-
azolin-4(3H)-one substrate for 10 min before the addition
of the rest of the reactants. Microwave irradiation[9] was
also used to provide an efficient and rapid heating of the
reaction medium and shorten the reaction time (30 min).
To confirm the utility of the copper(I)/palladium(II) bi-
trace
trace
37
93
trace
[a] Conditions: the reactions were performed in sealed tubes at
0.4 m with 1a (1 equiv.), LiOtBu (2 equiv.), and CuI (50 mol-%) pre-
mixed in a microwave reactor for 10 min at 120 °C before the ad-
dition of PhX (2 equiv.), Pd(OAc)2 (5 mol-%), and ligand (6–
10 mol-%) for 30 min at 120 °C. [b] Isolated yields. [c] Scale-up,
metallic catalyst, we also performed the reaction with one 8.5 mmol of 1a under optimized conditions.
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C-2–H Arylation of Quinazolin-4(3H)-ones with (Hetero)aryl Halides
of the two metals removed, and the lack of reaction indi- Table 2. Scope of aryl bromides in the direct 2-arylation of 1a.[a]
cated the pivotal role of both metal ions.
During our exploratory work, the efficient ligand-free
cross-coupling reaction of iodobenzene was performed on
an 8.5 mmol (2.4 g) scale (Table 1, Entry 1), and the suc-
cessful outcome highlights the achievability of the reaction
in larger quantities.
Under the optimized conditions for C–H phenylation
with bromobenzene and Pd(OAc)2/PtBu3 as the catalyst
(Table 1, Entry 4), less than 5% conversion of the final
product 2a was observed with chlorobenzene as the cou-
pling partner (Table 1, Entry 7). For chlorobenzene, Pd0
complexes with PPh3 or bidentate ligands such as 1,3-
bis(diphenylphosphanyl)propane (dppp), 1,3-bis(diisoprop-
ylphosphanyl)propane (dippp), 1,2-bis(dicyclohexylphos-
phanyl)ethane (dCype), 1,1Ј-bis(di-tert-butylphosphanyl)-
ferrocene (dbpf), or 4,5-bis(diphenylphosphanyl)-9,9-di-
methylxanthene (Xantphos) were all inactive (Table 1, En-
tries 8–15).[10] On the basis of the ability of palladium com-
plexes of 4,6-bis(diphenylphosphanyl)phenoxazine (the
NiXantphos ligand of Van Leeuwen) to effectively cross-
couple organometallics with aryl chlorides,[11] the reaction
was examined with 6 mol-% of this ligand. We were de-
lighted to find that the NiXantphos ligand afforded a better
conversion (Table 1, Entry 16), whereas the other ligands
were significantly less effective. An increased ligand loading
of 10 mol-% led to the complete consumption of 1a, and
the yield improved to 93% (Table 1, Entry 17). The opti-
mized 1/2 ratio of Pd(OAc)2 and NiXantphos was in agree-
ment with the results reported by Walsh for C(sp2)–H aryl-
ation.[11b] The dichloro[1,3-bis(2,6-di-3-pentylphenyl)imid-
azole-2-ylidene](3-chloropyridyl)palladium(II) precatalyst
(Pd-PEPPSI-IPent),[12] a palladium complex with an N-het-
erocyclic carbene ligand, only yielded trace amounts of the
cross-coupled product (Table 1, Entry 18).
Next, the scope of the C-2–H arylation of 1a was exam-
ined with sterically hindered electron-rich and electron-
poor bromobenzenes (Table 2). Among the three most ef-
fective ligands (PCy3, PtBu3, and PPh3; Table 1, Entries 3–
5) for the cross-coupling reaction with bromobenzene, PPh3
was selected as the optimum ligand for the C-2-arylation
owing to its availability and low cost. Gratifyingly, this ef-
ficient method was applicable to a large number of starting
bromobenzenes. 1-Bromo-4-tert-butylbenzene was tested
[a] Conditions: the reactions were performed in sealed tubes at
initially and led to the expected arylated product 2b in 74% 0.4 m with 1a (1 equiv.), LiOtBu (2 equiv.), and CuI (50 mol-%) pre-
mixed in a microwave reactor for 10 min at 120 °C before the ad-
dition of ArBr (2 equiv.), Pd(OAc)2 (5 mol-%), and PPh3 (6 mol-
%) for 30 min at 120 °C. The reported yields are isolated yields.
[b] Reaction performed with the corresponding aryl iodide as the
yield. A variety of para-substituted bromobenzenes, such
as those with chloro, methylsulfanyl, N,N-dimethylamino,
cyano, nitro, and tert-butyl ester substituents, were tolerated
under these reaction conditions and produced the corre-
coupling partner without ligand. [c] 10 mol-% of PPh3.
sponding compounds 2b–2h in good-to-excellent yields.
This optimized catalytic system also mediated the direct C– ene, 9-bromoanthracene, 1-bromo-2-methyl-3-nitrobenzene,
H arylation of 1a with meta-substituted and polyhalogen- and 1-bromo-2-chlorobenzene failed, whereas reactions
ated bromobenzene derivatives to yield products 2i–2n in with 1-bromo-2-methoxy-, 1-bromo-2-methyl- and 1-
moderate-to-excellent yields (38–93%).
bromo-2-methylsulfanylbenzene gave the corresponding C-
For the cross-coupling of ortho-substituted bromobenz- 2-arylated products 2o, 2p, and 2r in 90, 75, and 72% yield,
enes, steric hindrance and electronic effects strongly affected respectively (Table 2).
the course of the direct C–H arylation. Indeed, reactions
The enhancement of the reactivity of bromobenzenes
with 1-bromo-2-ethylbenzene, 1-bromo-2-methylnaphthal- with an electron-donating group at the ortho position could
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be related to the stabilization of the arylpalladium bromide Table 3. The direct arylation of 1a with heteroaryl bromides.[a]
intermediate.
Although 1a and 1-bromo-2,4-dimethylbenzene were ex-
pected to react poorly, the corresponding cross-coupled
product 2q was obtained in an acceptable 65% yield. In this
case, the transmetalation step could be disfavored upon the
approach of both intermediate 1a–CuI and Ar–PdII–Br spe-
cies. Finally, the reactions of both isomers of bromonaphth-
alene and 9-bromophenanthrene with 1a proceeded
smoothly to produce the desired compounds 2s–2u in excel-
lent yields (Table 2).
As depicted in Table 3, the reactions of 1a with heterocy-
clic aryl bromides[13] under identical conditions resulted in
the formation of the corresponding products. Notably, 2-
bromopyridine derivatives were good substrates and fur-
nished the coupled 2-pyridinylquinazolin-4(3H)-one deriva-
tives 3a–3d, whereas 2-iodopyridine[5] failed to produce
compound 3a.
The broad scope of this arylation methodology was fur-
ther demonstrated with a range of heteroaromatics. Thus,
more challenging heteroaromatic bromides reacted success-
fully to produce C-2-heteroaryl-substituted quinazolin-
4(3H)-ones 3a–3n in moderate-to-good yields (Table 3). For
3-bromopyridine derivatives, the yields were improved by
switching from PPh3 to PCy3 as the ligand. Owing to the
prevalence of heteroaromatic rings in bioactive compounds,
we were delighted to find that substituted 2- or 3-bromo-
pyridines and quinolines as well as thiophene and benzo-
furan derivatives were acceptable coupling partners. Bromo-
pyrazine was a sluggish substrate, and the reaction afforded
3j in only 27% yield. When 3-bromothiophene, 5-bromopic-
olinonitrile, 2-, 4-, or 5-bromothiazole, and 4-bromo-1-
methylpyrazole were employed, no reaction occurred. When
3-bromothiophene or 3-bromofuran were tested as coupling
partners, unsatisfactory yields incited us to change the li-
gand source (PCy3 instead of PPh3) and the catalyst load.
Unfortunately, the alteration of these two parameters did
not modify the reaction outcome.
Owing to their cost, availability, and diversity, less reac-
tive aryl chlorides are arguably more attractive substrates
than the corresponding bromides and iodides. Therefore,
the extension of the palladium-catalyzed C–H arylation to
various substituted chlorobenzene derivatives was investi-
gated with NiXantphos, which was the most efficient ligand
with chlorobenzene as a coupling partner (Table 1, En-
try 17). On the basis of these results, the scope and limita-
[a] Conditions: the reactions were performed in sealed tubes at
0.4 m with 1a (1 equiv.), LiOtBu (2 equiv.), and CuI (50 mol-%) pre-
mixed in a microwave reactor for 10 min at 120 °C before the ad-
dition of HetArBr (2 equiv.), Pd(OAc)2 (5 mol-%), and ligand
tions of the reaction with LiOtBu (2 equiv.), CuI (50 mol-
%), Pd(OAc)2 (5 mol-%), and the NiXantphos ligand
(10 mol-%) in DMF at 120 °C were studied. Under these
conditions, various aryl and heteroaryl chlorides were iden-
tified as convenient substrates for direct arylation reactions.
(10 mol-%) for 30 min at 120 °C. The reported yields are isolated
yields. [b] PPh3 (10mol-%). [c] PCy3 (10mol-%). [d] Reaction time
of 1 h. [e] PPh3 (6mol-%).
With the optimized ligand–catalyst mixture, 1a was cou- ucts in 36–64% yields, whereas chlorobenzenes with elec-
pled with a set of aryl chlorides to furnish the desired C-2- tron-donating substituents led to the corresponding prod-
arylated and heteroarylated compounds 2f, 2i, 2v–y, 3a, 3e, ucts 2 in lower yields. Cyano and trifluoromethyl groups
3h, 3j, and 3o–3q in low-to-good yields (Tables 4 and 5).
were both well tolerated (2f and 2i). In addition, steric hin-
The nature of the substituent on the phenyl ring had a drance may have a strong influence, as the reactions with 1-
significant impact on the reaction yields. Chlorobenzenes chloro-2-methyl- and 1-chloro-2-methoxybenzene failed to
bearing electron-withdrawing groups gave the desired prod- provide the expected cross-coupled products (Table 4).
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C-2–H Arylation of Quinazolin-4(3H)-ones with (Hetero)aryl Halides
Table 4. The direct arylation of 1a with aryl chlorides.[a]
Table 5. Heteroaryl chloride scope in the direct arylation of 1a.[a]
[a] Conditions: the reactions were performed in sealed tubes at
0.4 m with 1a (1 equiv.), LiOtBu (2 equiv.), and CuI (50 mol-%) pre-
mixed in a microwave reactor for 10 min at 120 °C before the ad-
dition of HetArCl (2 equiv.), Pd(OAc)2 (5 mol-%), and NiXantphos
(10 mol-%) for 30 min at 120 °C. The reported yields are isolated
yields. [b] The reactions were performed with the corresponding
aryl bromide as the coupling partner and PPh3 or PCy3 as the
ligand.
[a] Conditions: the reactions were performed in sealed tubes at
0.4 m with 1a (1 equiv.), LiOtBu (2 equiv.), and CuI (50 mol-%) pre-
mixed in a microwave reactor for 10 min at 120 °C before the ad-
dition of ArCl (2 equiv.), Pd(OAc)2 (5 mol-%), and NiXantphos
(10 mol-%) for 30 min at 120 °C. The reported yields are isolated
yields. [b] Reaction performed with the corresponding iodobenzene
as the coupling partner without ligand. [c] Reaction performed
with the corresponding bromobenzene as the coupling partner with
PPh3 as the ligand (Table 2).
respectively) were treated with 1b, 1d, and 1g to yield the
desired products in lower but convenient yields. In this case,
Similarly to 2-bromopyridine, unsubstituted 2-chloropyr-
idine was successfully converted to 3a in 78% yield. 2-
Chloro-5-trifluoropyridine and 3-chloro-6-methoxypyridine
both underwent cross-coupling with 1a to afford the target
compounds 3p and 3h in moderate yields. When 2-chloro-
5-cyanopyridine was employed, compound 3o was obtained
in only 11% yield. Interestingly, 2-chloroquinoline, chloro-
pyrazine, and 2-chloropyrimidine were acceptable coupling
partners and afforded the corresponding products 3e, 3j,
and 3q in 38–51% yield. However, 3-chloro-6-methylpyrid-
azine failed to give the desired product (Table 5).
Table 6. C–H phenylation of 1b–1g with phenyl iodide.[a]
In the course of using quinazolin-4(3H)-one derivatives
as building blocks, we finally investigated the opportunity
for the direct C–H arylations of a small library of 3-
aryl- and 3-alkylquinazolin-4(3H)-ones synthesized in a
previous study.[14] In this context, the evaluation of the C–H
phenylation was examined with iodobenzene as a coupling
partner, according to the initial ligand-free procedure.
As shown in Table 6, a range of aryl- and alkylquinazo-
lin-4(3H)-ones 1b–1g were found to be suitable substrates
and underwent the C–H phenylation to give 4a–4f with high
efficiencies. However, for 1d–1g, complete conversions re-
quired 1 equiv. of CuI. To verify the robustness of our
methodology, less reactive bromobenzene or chlorobenzene
[a] Conditions: the reactions were performed in sealed tubes at
0.4 m with 1b–1g (1 equiv.), LiOtBu (2 equiv.), and CuI (50 mol-%)
premixed in a microwave reactor for 10 min at 120 °C before the
addition of PhI (2 equiv.) and Pd(OAc)2 (5 mol-%) for 30 min at
120 °C. [b] The reported yields are isolated yields. [c] Reaction per-
formed with 1 equiv. of CuI. [d] The reaction was performed with
bromobenzene as the coupling partner and PPh3 as the ligand. [e]
The reaction was performed with chlorobenzene as the coupling
and their adapted ligands (i.e., Ph3P and NiXantphos, partner and NiXantphos as the ligand.
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Scheme 2. Proposed mechanism for the C-2 (hetero)arylation of N-3-substituted quinazolin-4(3H)-ones.
the reactions of chloro derivatives were less efficient than
those of the iodo and bromo analogues (Table 6, Entries 1,
3, and 6).
With all these data in hand, we were able to propose a
mechanism for the microwave-assisted arylation in the pres-
ence of different (hetero)aryl halides.
Owing to the electron-withdrawing character of the quin-
azolin-4(3H)-one, an electrophilic metalation process can-
not be considered as a plausible mechanism. In addition,
direct arylation by a concerted metalation–deprotonation
process, which tends to be accelerated by an electron-poor
phosphine ligand,[15] was also ruled out. Indeed, phos-
phines bearing fluoro substituents, such as P(C6F5)3, did
not increase the activity of the palladium catalyst and did
not show any ligand acceleration effect (Table 1, En-
try 6).[16]
Conclusions
We have developed an efficient method for the function-
alization of N-3-substituted quinazolin-4(3H)-ones through
the direct C-2–H arylation of these heterocycles. The palla-
dium/copper catalyst system was applicable to various aro-
matic halides. A screening of ligands resulted in an improve-
ment of the reaction efficiency, depending on the halogen
atoms involved. In our case, the use of bromo- or chloroaryl
derivatives as coupling partners enhanced the possibility of
molecular diversity by extending the scope of functional
groups on the aryl coupling partner. Pyridine derivatives,
thiophenes, and diazines were also readily introduced at the
2-position of quinazolin-4(3H)-ones, a notable feature with
respect to the development of syntheses for medicinal
agents.
As previously suggested, a cross-coupling mechanism is
arguably the best hypothesis.[5] The active species CuOtBu
is first generated from CuI in the presence of the base Li-
OtBu. For a cooperative Pd/Cu system for the direct C–
Experimental Section
General Information: Materials were obtained commercially and
H bond arylation, the proposed mechanism relies on the used without further purification. All reactions were performed un-
der an inert atmosphere of argon or nitrogen and monitored by
thin-layer chromatography with silica gel 60 F254 precoated alu-
minium plates (0.25 mm). Visualization was performed with UV
light at wavelengths of 254 and 312 nm. Purifications were per-
formed with a flash column chromatography system equipped with
a dual UV/Vis spectrophotometer (200–600 nm), a fraction collec-
presence of a N-donor atom on the quinazolin-4(3H)-one,
which can coordinate to the copper center and rearrange
into a substrate–copper intermediate I.[17]
Nevertheless, the formation of a CuI–amide type com-
plex with the in situ generated dimethylamine resulting
from the degradation of DMF at 120 °C[18] could not be
ruled out. As depicted in Scheme 2, we assume that the sec-
ond step is an oxidative addition of the aryl halide through
the insertion of the Pd0[19] species into the C–X bond to
tor (176 tubes), a dual piston pump (1 to 200 mL/min, Pmax
=
15 bar), which allowed quaternary gradients, and an additional in-
let for air purge. Samples can be injected in liquid or solid mode.
The melting points of solid compounds were measured with a
give the arylpalladium halide intermediate II.[20] At this STUART Melting Point SMP3 instrument with a precision of
Ϯ1.5 °C. IR spectra were recorded with a PerkinElmer Spectrum
100 Series FTIR spectrometer. Liquids and solids were investigated
with a single-reflection attenuated total reflectance (ATR) access-
stage, the transmetalation step leads to the concomitant re-
generation of CuX and the formation of the quinazolin-
4(3H)-one–PdII–Ar intermediate III, which can release the
coupling product after reductive elimination to regenerate
the Pd0 catalyst. For (hetero)aryl bromide or chloride deriv-
atives as coupling partners, CuBr or CuCl is generated dur-
ing the catalytic cycle. As the transmetalation step was less
effective with CuBr or CuCl instead of CuI as the cocata-
lyst,[5] the C–H arylation is somewhat more efficient with
aryl iodide derivatives.
1
ory; the absorption bands are given in cm–1. The H and 13C{1H}
NMR spectra were recorded at 295 K with a Bruker AVANCE
300 MHz spectrometer at 300 and 75.4 MHz, respectively. The ab-
breviations used for peak multiplicities are s: singlet, d: doublet, t:
triplet, q: quadruplet, and m: multiplet. Coupling constants J are
in Hz, and chemical shifts are given in ppm and were referenced
to CDCl3 (residual solvent signals). Mass spectrometry was per-
formed by the Mass Spectrometry Laboratory of the University of
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C-2–H Arylation of Quinazolin-4(3H)-ones with (Hetero)aryl Halides
Rouen. The mass spectra [ESI, EI, and field desorption (FD)] were
recorded with a WATERS LCP 1er XR spectrometer. The micro-
3-Benzyl-2-(4-chlorophenyl)quinazolin-4(3H)-one (2c):[22] White
needles, yield 217 mg (74%); Rf = 0.42 (PE/AcOEt 8:2); m.p. 117–
wave experiments were conducted in a commercial ANTON-PAAR 118 °C (ref.[22] 170–172 °C). IR (neat): ν = 3061, 3033, 1679, 1584,
˜
Monowave 300® microwave reactor specially designed for synthetic
chemistry. The experiments were conducted in a monomode cavity
1555, 1470, 1356, 1256, 1088, 972, 830, 776, 726, 693 cm–1. 1H
NMR (CDCl3, 300 MHz): δ = 8.40 (dd, J = 8.0, 0.8 Hz, 1 H), 7.87–
with a microwave power delivery system ranging from 0 to 850 W, 7.73 (m, 2 H), 7.63–7.51 (m, 1 H), 7.40 (d, J = 8.6 Hz, 2 H), 7.34–
which allows pressurized reactions (0 to 30 bars) to be performed
in sealed glass vials (4 to 30 mL) equipped with snap caps and
silicon septa. The temperature (0 to 300 °C) was monitored by a
contactless infrared sensor and calibrated with a Ruby thermome-
ter. The temperature, pressure, and power profiles were edited and
monitored through a touch-screen control panel. The times indi-
cated in the various protocols are the times measured when the
mixtures reached the programmed temperature after a ramp period
of 2 min.
7.18 (m, 5 H), 7.01–6.91 (m, 2 H), 5.28 (s, 2 H) ppm. 13C{1H}
NMR (CDCl3, 75.4 MHz): δ = 162.5 (C), 155.4 (C), 147.4 (C),
136.5 (C), 136.3 (C), 134.8 (CH), 133.8 (C), 129.6 (2ϫCH), 128.9
(2ϫCH), 128.8 (2ϫCH), 127.7 (CH), 127.7 (CH), 127.5 (CH),
127.3 (CH), 126.9 (2ϫCH), 120.9 (C), 48.9 (CH2) ppm.
3-Benzyl-2-[4-(methylthio)phenyl]quinazolin-4(3H)-one (2d): White
powder; yield 226 mg (74%); Rf = 0.31 (PE/AcOEt 8:2); m.p. 118–
119 °C. IR (neat): ν = 2952, 2912, 1678, 1580, 1567, 1379, 1352,
˜
965, 811, 783, 712, 514 cm–1. 1H NMR (CDCl3, 300 MHz): δ =
8.29 (br. d, J = 7.9 Hz, 1 H), 7.75–7.63 (m, 2 H), 7.49–7.40 (m, 1
H), 7.24–7.10 (m, 7 H), 6.94–6.85 (m, 2 H), 5.21 (s, 2 H), 2.43 (s,
3 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.6 (C), 156.2
(C), 147.4 (C), 141.6 (C), 136.7 (C), 134.7 (CH), 131.8 (C), 128.7
(2ϫCH), 128.6 (2ϫCH), 127.7 (CH), 127.6 (CH), 127.3 (CH),
127.2 (CH), 127.0 (2ϫCH), 126.0 (2ϫCH), 120.9 (C), 49.1 (CH2),
15.5 (CH3) ppm. HRMS (TOF-ESI+): calcd. for C22H19N2OS [M
+ H]+ 359.1213; found 359.1208.
General Procedure for the Synthesis of 2a–2u from 1a: In a 10 mL
glass microwave vial, 1a (200 mg, 0.85 mmol, 1.0 equiv.), copper
iodide (81 mg, 0.42 mmol, 0.50 equiv.) and lithium tert-butoxide
(136 mg, 1.69 mmol, 2.0 equiv.) were mixed in dry DMF (2 mL)
and heated in a microwave oven at 120 °C for 10 min (2 min ramp).
After the mixture cooled to 60–70 °C, aryl bromide (1.7 mmol,
2.0 equiv.), PPh3 (0.051–0.085 mmol, 6–10 mol-%) and Pd(OAc)2
(9.6 mg, 0.042 mmol, 5.0 mol-%) were added successively. The reac-
tion mixture was heated at 120 °C by microwave irradiation for
30 min (2 min ramp). The resulting solution was diluted with Ac-
OEt (10 mL) and filtered through a small pad of silica gel. The
volatile compounds were evaporated, and the crude product was
purified by flash chromatography with petroleum ether/ethyl acet-
ate (PE/AcOEt) as the eluent to afford products 2b–2u.
3-Benzyl-2-[4-(dimethylamino)phenyl]quinazolin-4(3H)-one (2e):[23]
White powder; yield 187 mg (62%); Rf = 0.17 (PE/AcOEt 8:2); m.p.
144–145 °C (ref.[23] 150–151 °C). IR (neat): ν = 2898, 2811, 1673,
˜
1606, 1522, 1471, 1374, 1354, 1199, 1167, 945, 820, 771, 709, 694
1
cm–1. H NMR (CDCl3, 300 MHz): δ = 8.36 (br. d, J = 8.0 Hz, 1
H), 7.82–7.72 (m, 2 H), 7.52–7.44 (m, 1 H), 7.35 (d, J = 8.9 Hz, 2
H), 7.31–7.20 (m, 3 H), 7.12–7.04 (m, 2 H), 6.69 (d, J = 8.9 Hz, 2
H), 5.40 (s, 2 H), 3.00 (s, 6 H) ppm. 13C{1H} NMR (CDCl3,
75.4 MHz): δ = 162.8 (C), 157.1 (C), 151.3 (C), 147.6 (C), 137.0
(C), 134.3 (CH), 129.4 (2ϫCH), 128.5 (2ϫCH), 127.4 (CH), 127.2
(CH), 126.9 (CH), 126.7 (2ϫCH), 126.5 (CH), 122.5 (C), 120.5
(C), 111.4 (2ϫCH), 49.3 (CH2), 40.2 (2ϫCH3) ppm.
Aryl Chloride Partners (2a, 2f, and 2i): Compound 1a (100 mg,
0.43 mmol, 1.0 equiv.), copper iodide (41 mg, 0.21 mmol,
0.50 equiv.), and lithium tert-butoxide (68 mg, 0.85 mmol,
2.0 equiv.) were mixed in dry DMF (1 mL) and heated in a micro-
wave oven at 120 °C for 10 min (2 min ramp). After the mixture
cooled to 60–70 °C, NiXantphos, (23 mg, 0.043 mmol, 10 mol-%),
Pd(OAc)2 (4.8 mg, 0.02 mmol, 5.0 mol-%), and aryl chloride
(0.85 mmol, 2.0 equiv.) were added successively.
4-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzonitrile
(2f):[5]
White powder; yield 181 mg (63% from 4-bromobenzonitrile),
82 mg (82% from 4-chlorobenzonitrile); Rf = 0.17 (PE/AcOEt 8:2);
m.p. 129–130 °C (ref.[5] 66–69 °C). IR (neat): ν = 2993, 2902, 2227,
3-Benzyl-2-phenylquinazolin-4(3H)-one (2a):[21] Pale yellow powder;
yield 186 mg (80% from bromobenzene), 123 mg (93% from chlo-
robenzene); Rf = 0.35 (PE/AcOEt 8:2); m.p. 142–143 °C (ref.[21]
˜
1
1676, 1586, 1453, 1426, 1357, 1256, 972, 782, 697 cm–1. H NMR
(CDCl3, 300 MHz): δ = 8.39 (dd, J = 8.0, 1.0 Hz, 1 H), 7.86–7.77
(m, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.67 (d, J = 8.5 Hz, 2 H), 7.62–
7.53 (m, 1 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.24–7.17 (m, 3 H), 6.91–
6.82 (m, 2 H), 5.23 (s, 2 H) ppm. 13C{1H} NMR (CDCl3,
75.4 MHz): δ = 162.2 (C), 154.5 (C), 147.1 (C), 139.4 (C), 136.2
(C), 135.0 (CH), 132.4 (2ϫCH), 129.0 (2ϫCH), 128.9 (2ϫCH),
127.9 (CH), 127.9 (CH), 127.8 (CH), 127.4 (CH), 126.8 (2ϫCH),
121.0 (C), 118.1 (C), 113.9 (C), 48.7 (CH2) ppm.
131–133 °C). IR (neat): ν = 3059, 3033, 2959, 1675, 1584, 1567,
˜
1377, 1245, 1149, 1075, 966, 771, 696 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 8.38 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 3.6 Hz, 2 H),
7.55–7.31 (m, 6 H), 7.26–7.14 (m, 3 H), 6.99–6.84 (m, 2 H), 5.28
(s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 159.8 (C),
150.1 (CH), 147.0 (CH), 144.7 (C), 138.9 (C), 135.9 (CH), 135.3
(C), 129.1 (2ϫCH), 128.5 (CH), 128.4 (CH), 128.3 (2ϫCH), 49.7
(CH2) ppm.
3-Benzyl-2-(4-nitrophenyl)quinazolin-4(3H)-one (2g):[5] Yellow pow-
der; yield 142 mg (47%); Rf = 0.22 (PE/AcOEt 8:2); m.p. 121–
3-Benzyl-2-(4-tert-butylphenyl)quinazolin-4(3H)-one (2b): White
needles; yield 231 mg (74%); Rf = 0.51 (PE/AcOEt 8:2); m.p. 173–
123 °C (ref.[5] 121–122 °C). IR (neat): ν = 3069, 3033, 2961, 2934,
˜
2861, 1683, 1583, 1515, 1385, 1349, 1322, 1107 cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 8.41 (dd, J = 8.0, 1.5 Hz, 1 H), 8.29–8.19
(m, 2 H), 7.83 (ddd, J = 8.5, 7.0, 1.6 Hz, 1 H), 7.75 (dd, J = 8.1,
1.3 Hz, 1 H), 7.59 (ddd, J = 8.3, 7.0, 1.4 Hz, 1 H), 7.53–7.47 (m, 2
H), 7.26–7.18 (m, 3 H), 6.95–6.82 (m, 2 H), 5.24 (s, 2 H) ppm.
13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.1 (C), 154.1 (C), 148.4
(C), 146.9 (C), 141.0 (C), 136.0 (C), 134.9 (CH), 129.3 (2ϫCH),
128.8 (2ϫCH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.3 (CH),
126.6 (2ϫCH), 123.7 (2ϫCH), 120.9 (C), 48.6 (CH2) ppm.
174 °C. IR (neat): ν = 3066, 3033, 2966, 1680, 1590, 1376, 1349,
˜
967, 775, 727, 695 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 8.36 (d,
J = 7.8 Hz, 1 H), 7.79–7.75 (m, 2 H), 7.51 (ddd, J = 8.2, 5.4, 2.9 Hz,
1 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.5 Hz, 2 H), 7.23–
7.17 (m, 3 H), 6.99–6.91 (m, 2 H), 5.30 (s, 2 H), 1.34 (s, 9 H) ppm.
13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.6 (C), 156.7 (C), 153.4
(C), 147.5 (C), 136.9 (C), 134.6 (CH), 132.5 (C), 128.6 (2ϫCH),
127.9 (2ϫCH), 127.7 (CH), 127.5 (CH), 127.2 (CH), 127.1 (CH),
127.1 (2ϫCH), 125.7 (2ϫCH), 121.0 (C), 49.0 (CH2), 35.0 (C),
31.3 (3ϫCH3) ppm. HRMS (TOF-ESI+): calcd. for C25H25N2O
[M + H]+ 369.1961; found 369.1980.
tert-Butyl
4-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzoate
(2h): White crystals; yield 316 mg (90%); Rf = 0.43 (PE/AcOEt 8:2);
Eur. J. Org. Chem. 2015, 7705–7717
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7711

J. Godeau, M. Harari, S. Laclef, E. Deau, C. Fruit, T. Besson
FULL PAPER
m.p. 160–161 °C. IR (neat): ν = 3060, 3026, 2986, 2952, 1713, 1680,
(CH), 126.8 (2ϫCH), 124.5 (d, J = 3.3 Hz, CH), 120.9 (C), 117.8
˜
1584, 1562, 1301, 1125, 1112, 846, 774, 693 cm–1. 1H NMR (d, J = 24.4 Hz, CH), 114.1 (d, J = 23.2 Hz, CH), 48.7 (CH2) ppm.
(CDCl3, 300 MHz): δ = 8.38 (d, J = 7.3 Hz, 1 H), 8.01 (d, J =
HRMS (TOF-EI+): calcd. for C21H1335Cl19FN2O [M – H]+
8.3 Hz, 2 H), 7.85–7.71 (m, 2 H), 7.61–7.47 (m, 1 H), 7.40 (d, J = 363.07004; found 363.06980.
8.3 Hz, 2 H), 7.24–7.18 (m, 3 H), 6.97–6.88 (m, 2 H), 5.24 (s, 2 H),
3-Benzyl-2-(4-chloro-3-methoxyphenyl)quinazolin-4(3H)-one (2m):
White crystals; yield 244 mg (76%); Rf = 0.36 (PE/AcOEt 8:2); m.p.
1.61 (s, 9 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 165.0
(C), 162.4 (C), 155.7 (C), 147.3 (C), 138.9 (C), 136.4 (C), 134.8
(CH), 133.4 (C), 129.8 (2ϫCH), 128.8 (2ϫCH), 128.2 (2ϫCH),
127.8 (CH), 127.7 (CH), 127.6 (CH), 127.3 (CH), 126.9 (2ϫCH),
121.0 (C), 81.8 (C), 48.9 (CH2), 28.3 (3ϫCH3) ppm. HRMS (TOF-
ESI+): calcd. for C26H25N2O3 [M + H]+ 413.1860; found 413.1862.
151–152 °C. IR (neat): ν = 3073, 3033, 3013, 2939, 1688, 1584,
˜
1565, 1376, 1353, 1222, 1066, 825, 776, 694 cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 8.42 (d, J = 7.5 Hz, 1 H), 7.88–7.73 (m, 2
H), 7.65–7.53 (m, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 7.34–7.21 (m, 3
H), 7.04–6.93 (m, 3 H), 6.72 (d, J = 1.7 Hz, 1 H), 5.26 (s, 2 H),
3.56 (s, 3 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.5
(C), 155.6 (C), 154.9 (C), 147.3 (C), 136.9 (C), 134.9 (CH), 134.7
(C), 130.6 (CH), 128.9 (2ϫCH), 127.8 (CH), 127.6 (CH), 127.6
(CH), 127.3 (CH), 126.7 (2ϫCH), 124.5 (C), 120.9 (C), 120.7
(CH), 111.9 (CH), 55.9 (CH3), 49.2 (CH2) ppm. HRMS (TOF-
ESI+): calcd. for C22H1835ClN2O2 [M + H]+ 377.1051; found
377.1053.
3-Benzyl-2-[3-(trifluoromethyl)phenyl]quinazolin-4(3H)-one
(2i):
White needles; yield 299 mg [93% from 1-bromo-3-(trifluorometh-
yl)benzene], 103 mg [64% from 1-chloro-3-(trifluoromethyl)benz-
ene]; R = 0.34 (PE/AcOEt 8:2); m.p. 89–90 °C. IR (neat): ν = 3029,
˜
f
2951, 2982, 1684, 1582, 1568, 1452, 1377, 1328, 1237, 1171, 1116
1
cm–1. H NMR (CDCl3, 300 MHz): δ = 8.41 (dd, J = 8.0, 1.5 Hz,
1 H), 7.85–7.70 (m, 3 H), 7.63–7.48 (m, 4 H), 7.24–7.17 (m, 3 H),
6.91–6.81 (m, 2 H), 5.24 (s, 2 H) ppm. 13C{1H} NMR (CDCl3,
75.4 MHz): δ = 162.3 (C), 154.8 (C), 147.0 (C), 136.2 (C), 135.9
(C), 134.8 (CH), 131.2 (CH), 131.1 (q, J = 33.0 Hz, C) 129.1 (CH),
128.7 (2ϫCH), 127.7 (CH), 127.6 (CH), 127.2 (CH), 126.8
(2ϫCH), 126.6 (q, J = 3.5 Hz, CH), 125.2 (q, J = 3.5 Hz, CH),
123.4 (q, J = 368.0 Hz, C), 120.9 (C), 48.7 (CH2) ppm. HRMS
(TOF-EI+): calcd. for C22H1419F3N2O [M – H]+· 379.10582; found
379.10611.
3-Benzyl-2-(3,4,5-trimethoxyphenyl)quinazolin-4(3H)-one
(2n):
White crystals; yield 312 mg (92%); Rf = 0.10 (PE/AcOEt 8:2); m.p.
152–153 °C. IR (neat): ν = 2999, 2939, 2838, 1685, 1582, 1334,
˜
1235, 1123, 1001, 830, 783, 731, 696 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 8.43 (br. d, J = 8.1 Hz, 1 H), 7.88–7.76 (m, 2 H),
7.58 (ddd, J = 8.2, 6.2, 2.1 Hz, 1 H), 7.33–7.21 (m, 4 H), 7.05 (br.
d, J = 8.1 Hz, 1 H), 6.52 (s, 2 H), 5.28 (s, 2 H), 3.88 (s, 3 H), 3.64
(s, 6 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.7 (C),
156.4 (C), 153.3 (2ϫC), 147.3 (C), 139.3 (C), 137.2 (C), 134.8
(CH), 130.4 (C), 128.8 (2ϫCH), 127.7 (CH), 127.5 (CH), 127.4
(CH), 127.3 (CH), 126.7 (2ϫCH), 120.9 (C), 105.2 (2ϫCH), 61.0
(CH3), 56.0 (2ϫCH3), 49.4 (CH2) ppm. HRMS (TOF-ESI+):
calcd. for C24H23N2O4 [M + H]+ 403.1652; found 403.1660.
3-Benzyl-2-(3-chlorophenyl)quinazolin-4(3H)-one (2j): Brown pow-
der; yield 252 mg (86%); Rf = 0.34 (PE/AcOEt 8:2); m.p. 119–
120 °C. IR (neat): ν = 3063, 3022, 2948, 1679, 1562, 1470, 1374,
˜
1
1350, 1252, 971 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.44–8.27
(m, 1 H), 7.88–7.67 (m, 2 H), 7.61–7.48 (m, 1 H), 7.47–7.37 (m, 1
H), 7.36–7.26 (m, 2 H), 7.24–7.12 (m, 4 H), 7.00–6.82 (m, 2 H),
5.24 (s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.2
(C), 154.8 (C), 147.0 (C), 136.7 (C), 136.3 (C), 136.3 (C), 134.6 (C),
134.6 (CH), 130.0 (CH), 129.8 (CH), 128.6 (2ϫCH), 128.4 (CH),
127.6 (2ϫCH), 127.4 (CH), 127.1 (CH), 126.9 (2ϫCH), 126.0
(CH), 120.8 (C), 48.7 (CH2) ppm. HRMS (TOF-EI+): calcd. for
C21H1435ClN2O [M – H]+· 345.07947; found 345.08086.
3-Benzyl-2-(2-methoxyphenyl)quinazolin-4(3H)-one (2o):[5] White
powder; yield 193 mg (66%); Rf = 0.22 (PE/AcOEt 8:2); m.p. 135–
136 °C (ref.[5] 119–121 °C). IR (neat): ν = 3040, 2999, 1668, 1607,
˜
1428, 1255, 1158, 1023, 962, 764, 710, 691 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 8.45–8.33 (m, 1 H), 7.84–7.71 (m, 2 H), 7.60–7.38
(m, 2 H), 7.23–7.09 (m, 4 H), 7.02–6.82 (m, 4 H), 5.51 (d, J =
15.1 Hz, 1 H), 4.83 (d, J = 15.1 Hz, 1 H), 3.66 (s, 3 H) ppm.
13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.6 (C), 156.2 (C), 154.6
(C), 147.7 (C), 136.8 (C), 134.4 (CH), 131.6 (CH), 130.1 (CH),
128.3 (2ϫCH), 127.7 (CH), 127.6 (2ϫCH), 127.4 (CH), 127.2
(CH), 127.1 (CH), 124.6 (C), 121.2 (C), 121.0 (CH), 111.0 (CH),
55.5 (CH3), 48.3 (CH2) ppm.
3-Benzyl-2-(3,4-dichlorophenyl)quinazolin-4(3H)-one (2k): White
powder; yield 277 mg (86%); Rf = 0.40 (PE/AcOEt 8:2); m.p. 151–
152 °C. IR (neat): ν = 3029, 2942, 1682, 1586, 1470, 1385, 1243,
˜
1
1137, 1033 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.40 (dd, J =
7.9, 1.6 Hz, 1 H), 7.83 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.75 (dd, J
= 8.1, 1.3 Hz, 1 H), 7.58 (ddd, J = 8.1, 6.9, 1.4 Hz, 1 H), 7.48 (d,
J = 8.3 Hz, 1 H), 7.40 (d, J = 2.1 Hz, 1 H), 7.30–7.25 (m, 3 H),
7.17 (dd, J = 8.3, 2.1 Hz, 1 H), 6.99–6.90 (m, 2 H), 5.26 (s, 2 H)
ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.2 (C), 154.0 (C),
146.9 (C), 136.2 (C), 134.8 (C), 134.8 (CH), 134.5 (C), 133.0 (C),
130.5 (CH), 130.3 (CH), 128.8 (2ϫCH), 127.7 (CH), 127.6 (CH),
127.6 (CH), 127.2 (CH), 127.2 (CH), 126.7 (2ϫCH), 120.8 (C),
48.8 (CH2) ppm. HRMS (TOF-EI+): calcd. for C21H1535Cl2N2O
[M]+· 381.0556; found 381.0568.
3-Benzyl-2-o-tolylquinazolin-4(3H)-one, (2p):[5] White crystals; yield
209 mg (75%); Rf = 0.42 (PE/AcOEt 8:2); m.p. 112–113 °C (ref.[5]
106–107 °C). IR (neat): ν = 3060, 3033, 2952, 1667, 1607, 1585,
˜
1376, 960, 777, 767, 751, 709, 693 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 8.44 (d, J = 7.9 Hz, 1 H), 7.86–7.72 (m, 2 H), 7.62–
7.51 (m, 1 H), 7.73–7.35 (m, 1 H), 7.30–7.12 (m, 6 H), 6.94–6.82
(m, 2 H), 5.27 (d, J = 14.8 Hz, 1 H), 5.11 (d, J = 14.8 Hz, 1 H),
1.98 (s, 3 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.6
(C), 156.0 (C), 147.4 (C), 136.3 (C), 136.1 (C), 134.7 (C), 134.6
(CH), 130.7 (CH), 129.9 (CH), 128.4 (2ϫCH), 128.0 (CH), 127.8
(2ϫCH), 127.7 (CH), 127.6 (CH), 127.3 (CH), 127.2 (CH), 126.0
(CH), 121.1 (C), 48.2 (CH2), 19.0 (CH3) ppm.
3-Benzyl-2-(3-chloro-5-fluorophenyl)quinazolin-4(3H)-one
(2l):
White powder; yield 119 mg (38%); Rf = 0.55 (PE/AcOEt 8:2); m.p.
101–102 °C. IR (neat): ν = 3070, 3029, 2955, 1682, 1585, 1567,
˜
1425, 1373, 1269, 928, 855, 772, 695 cm–1. 1H NMR (CDCl3,
3-Benzyl-2-(2,4-dimethylphenyl)quinazolin-4(3H)-one (2q): Brown
300 MHz): δ = 8.32–8.22 (m, 1 H), 7.75–7.57 (m, 2 H), 7.52–7.36 powder; yield 186 mg (65%); Rf = 0.41 (PE/AcOEt 8:2); m.p. 147–
(m, 1 H), 7.24–7.02 (m, 4 H), 7.01–6.94 (m, 1 H), 6.91–6.77 (m, 3 148 °C. IR (neat): ν = 3036, 2969, 1668, 1607, 1590, 1438, 1379,
H), 5.13 (s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 1332, 1236, 1153 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 8.40 (dd,
162.2 (d, J = 252.3 Hz, C), 162.1 (C), 153.68 (C), 146.86 (C), 137.7 J = 8.1, 1.7 Hz, 1 H), 7.81–7.71 (m, 2 H), 7.53 (ddd, J = 8.3, 6.3,
(d, J = 8.7 Hz, C), 136.22 (C), 135.6 (d, J = 10.6 Hz, C), 134.8 2.0 Hz, 1 H), 7.22–7.11 (m, 3 H), 7.09–7.00 (m, 3 H), 6.94–6.84 (m,
(CH), 128.8 (2ϫCH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 127.2 2 H), 5.25 (d, J = 14.7 Hz, 1 H), 5.08 (d, J = 14.8 Hz, 1 H), 2.37
˜
7712
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7705–7717

C-2–H Arylation of Quinazolin-4(3H)-ones with (Hetero)aryl Halides
(s, 3 H), 1.94 (s, 3 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ
= 162.5 (C), 156.1 (C), 147.3 (C), 139.7 (C), 136.3 (C), 135.7 (C),
134.4 (CH), 131.9 (C), 131.2 (CH), 128.3 (2ϫCH), 127.8 (CH),
127.6 (2ϫCH), 127.5 (CH), 127.0 (CH), 126.5 (CH), 120.9 (C),
48.1 (CH2), 21.3 (CH3), 18.9 (CH3) ppm. HRMS (TOF-EI+):
calcd. for C23H20N2O [M]+· 340.15756; found 340.15765.
General Procedure for the Synthesis of 2v–2y from 1a: In a 5 mL
glass microwave vial, 1a (100 mg, 0.43 mmol, 1.0 equiv.), copper
iodide (41 mg, 0.21 mmol, 0.50 equiv.), and lithium tert-butoxide
(68 mg, 0.85 mmol, 2.0 equiv.) were mixed in dry DMF (1 mL) and
heated in a microwave oven at 120 °C for 10 min (2 min ramp).
After the mixture cooled to 60–70 °C, NiXantphos, (23 mg,
0.043 mmol, 10 mol-%), Pd(OAc)2 (4.8 mg, 0.02 mmol, 5.0 mol-%),
and (hetero)aryl chloride (0.85 mmol, 2.0 equiv.) were added suc-
cessively. The reaction mixture was heated at 120 °C by microwave
irradiation for 30 min (2 min ramp). The resulting solution was di-
luted with AcOEt (10 mL) and filtered through a small pad of silica
gel. The volatile compounds were evaporated, and the crude prod-
uct was purified by flash chromatography with PE/AcOEt as the
eluent to afford products 2v–2y.
3-Benzyl-2-[2-(methylthio)phenyl]quinazolin-4(3H)-one (2r): Orange
crystals; yield 218 mg (71%); Rf = 0.26 (PE/AcOEt 8:2); m.p. 118–
119 °C. IR (neat): ν = 3063, 3029, 3009, 2921, 1669, 1595, 1581,
˜
1
1471, 1380, 960, 764, 752, 710, 697, 686 cm–1. H NMR (CDCl3,
300 MHz): δ = 8.43 (d, J = 8.0 Hz, 1 H), 7.82–7.77 (m, 2 H), 7.59–
7.51 (m, 1 H), 7.44 (td, J = 7.8, 1.5 Hz, 1 H), 7.35 (br. d, J =
7.7 Hz, 1 H), 7.21–7.09 (m, 4 H), 7.03 (dd, J = 7.6, 1.3 Hz, 1 H),
6.94–6.88 (m, 2 H), 5.65 (d, J = 15.2 Hz, 1 H), 4.76 (d, J = 15.2 Hz,
1 H), 2.38 (s, 3 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 3-Benzyl-2-p-tolylquinazolin-4(3H)-one (2v):[5] Yellow powder; yield
162.4 (C), 154.7 (C), 147.3 (C), 137.3 (C), 136.4 (C), 134.5 (CH),
134.2 (C), 130.3 (CH), 128.9 (CH), 128.3 (2ϫCH), 127.6 (CH),
127.5 (2ϫCH), 127.4 (CH), 127.3 (CH), 127.1 (CH), 126.5 (CH),
125.2 (CH), 121.2 (C), 48.2 (CH2), 16.0 (CH3) ppm. HRMS (TOF-
FD): calcd. for C22H18N2OS [M]+· 354.11344; found 354.11495.
102 mg (74%); Rf = 0.33 (PE/AcOEt 8:2); m.p. 127–128 °C (ref.[5]
124–125 °C). IR (neat): ν = 3045, 1674, 1584, 1472, 1354, 1249,
˜
1
1152 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.39 (d, J = 7.8 Hz,
1 H), 7.84–7.75 (m, 2 H), 7.55 (ddd, J = 8.1, 5.8, 2.4 Hz, 1 H),
7.29–7.23 (m, 6 H), 7.05–6.95 (m, 2 H), 5.31 (s, 2 H), 2.43 (s, 3 H)
ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.5 (C), 156.6 (C),
140.1 (C), 136.7 (C), 134.5 (CH), 132.4 (C), 129.2 (2ϫCH), 128.5
(2ϫCH), 127.9 (2ϫCH), 127.6 (CH), 127.4 (CH), 127.1 (CH),
126.9 (CH), 126.9 (2ϫCH), 120.8 (C), 48.9 (CH2), 21.4 (CH3)
ppm.
3-Benzyl-2-(naphthalen-1-yl)quinazolin-4(3H)-one (2s):[5] White
needles; yield 288 mg, (94%); Rf = 0.39 (PE/AcOEt 8:2); m.p. 148–
149 °C (ref.[5] 149–150 °C). IR (neat): ν = 3063, 3029, 2969, 1670,
˜
1
1581, 1567, 1456, 1376, 1338, 1289, 1142 cm–1. H NMR (CDCl3,
300 MHz): δ = 8.46 (dd, J = 7.8, 1.5 Hz, 1 H), 7.97 (d, J = 8.3 Hz,
1 H), 7.92 (d, J = 8.1 Hz, 1 H), 7.86–7.77 (m, 2 H), 7.59 (ddd, J =
Methyl 4-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzoate (2w):
8.2, 6.5, 1.9 Hz, 1 H), 7.55–7.48 (m, 2 H), 7.46–7.37 (m, 2 H), 7.28 White needles; yield 57 mg (36%); Rf = 0.18 (PE/AcOEt 8:2); m.p.
(dd, J = 7.0, 1.2 Hz, 1 H), 7.15–7.01 (m, 3 H), 6.80–6.68 (m, 2 H),
5.51 (d, J = 15.1 Hz, 1 H), 4.64 (d, J = 15.1 Hz, 1 H) ppm. 13C{1H}
NMR (CDCl3, 75.4 MHz): δ = 162.4 (C), 155.3 (C), 147.3 (C),
131–132 °C. IR (neat): ν = 3029, 2948, 1716, 1678, 1604, 1586,
˜
1
1455, 1329, 1377, 1281, 1105 cm–1. H NMR (CDCl3, 300 MHz):
δ = 8.39 (d, J = 8.0 Hz, 1 H), 8.06 (m, 2 H), 7.82–7.72 (m, 2 H),
136.5 (C), 134.6 (CH), 133.3 (C), 132.1 (C), 130.4 (C), 130.1 (CH), 7.58–7.52 (m, 1 H), 7.41 (m, 2 H), 7.24–7.16 (m, 3 H), 6.95–6.80
128.5 (CH), 128.2 (2ϫCH), 127.7 (CH), 127.4 (CH), 127.3 (CH),
127.3 (CH), 127.2 (2ϫCH), 127.1 (CH), 126.7 (CH), 126.5 (CH),
124.9 (CH), 124.1 (CH), 121.1 (C), 48.5 (CH2) ppm.
(m, 2 H), 5.24 (s, 2 H), 3.95 (s, 3 H) ppm. 13C{1H} NMR (CDCl3,
75.4 MHz): δ = 166.2 (C), 162.2 (C), 155.4 (C), 147.0 (C), 139.2
(C), 136.2 (C), 134.7 (CH), 131.3 (C), 129.7 (2ϫCH), 128.6
(2ϫCH), 128.2 (2ϫCH), 127.6 (CH), 127.6 (CH), 127.5 (CH),
127.2 (CH), 126.8 (2ϫCH), 120.8 (C), 52.4 (CH3), 48.6 (CH2)
ppm. HRMS (TOF-EI+): calcd. for C23H17N2O3 [M – H]+·
369.12392; found 369.12452.
3-Benzyl-2-(naphthalen-2-yl)quinazolin-4(3H)-one
(2t):[5]
Pale
orange powder; yield 282 mg (92%); Rf = 0.34 (PE/AcOEt 8:2);
m.p. 141–142 °C (ref.[5] 138–139 °C). IR (neat): ν = 3070, 3029,
˜
2921, 1674, 1600, 1580, 1561, 1471, 1418, 1363, 1235, 975 cm–1. 1H
NMR (CDCl3, 300 MHz): δ = 8.41 (d, J = 8.0 Hz, 1 H), 7.97–7.85 3-Benzyl-2-(4-methoxyphenyl)quinazolin-4(3H)-one (2x):[5] Brown
(m, 2 H), 7.85–7.77 (m, 3 H), 7.76–7.69 (m, 1 H), 7.61–7.50 (m, 3
powder; yield 20 mg (14%); Rf = 0.17 (PE/AcOEt 8:2); m.p. 114–
H), 7.44 (dd, J = 8.5, 1.7 Hz, 1 H), 7.24–7.12 (m, 3 H), 6.99–6.86
115 °C (ref.[5] 116–117 °C). IR (neat): ν = 3063, 3036, 2955, 1674,
˜
(m, 2 H), 5.31 (m, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): 1584, 1568, 1494, 1474, 1432, 1378, 1352, 1222, 1074 cm–1. 1H
δ = 162.5 (C), 156.4 (C), 147.3 (C), 136.6 (C), 134.5 (CH), 133.5
NMR (CDCl3, 300 MHz): δ = 8.36 (d, J = 7.7 Hz, 1 H), 7.82–7.70
(C), 132.5 (C), 132.4 (C), 128.5 (2ϫCH), 128.4 (CH), 128.4 (CH), (m, 2 H), 7.51 (ddd, J = 8.1, 5.8, 2.5 Hz, 1 H), 7.36–7.28 (m, 2 H),
128.2 (CH), 127.7 (CH), 127.6 (CH), 127.4 (CH), 127.3 (CH), 127.1 7.25–7.14 (m, 3 H), 7.01–6.94 (m, 2 H), 6.93–6.84 (m, 2 H), 5.30
(CH), 127.1 (CH), 126.9 (2ϫCH), 126.8 (CH), 124.7 (CH), 120.8
(C), 49.0 (CH2) ppm.
(s, 2 H), 3.84 (s, 3 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ
= 162.6 (C), 160.7 (C), 156.3 (C), 147.3 (C), 136.7 (C), 134.5 (CH),
129.6 (2ϫCH), 128.5 (2ϫCH), 127.7 (C), 127.5 (CH), 127.3 (CH),
127.0 (CH), 126.9 (CH), 126.8 (2ϫCH), 120.7 (C), 113.9 (2ϫCH),
55.4 (CH3), 48.9 (CH2) ppm.
3-Benzyl-2-(phenanthren-9-yl)quinazolin-4(3H)-one (2u):[5] White
crystals; yield 263 mg (75%); Rf = 0.46 (PE/AcOEt 8:2); m.p. 166–
167 °C (ref.[5] 160–161 °C). IR (neat): ν = 3066, 3033, 2925, 1681,
˜
1581, 1563, 1472, 1357, 1330, 941, 893, 769, 724, 695 cm–1. 1H
3-Benzyl-2-(3-methoxyphenyl)quinazolin-4(3H)-one (2y):[5] White
powder; yield 32 mg (22%); Rf = 0.24 (PE/AcOEt 8:2); m.p. 117–
NMR (CDCl3, 300 MHz): δ = 8.78 (d, J = 8.4 Hz, 1 H), 8.73 (d,
J = 8.3 Hz, 1 H), 8.49 (d, J = 7.8 Hz, 1 H), 7.88–7.78 (m, 2 H), 119 °C (ref.[5] 118–119 °C). IR (neat): ν = 3070, 3009, 2840, 1667,
˜
7.78–7.65 (m, 3 H), 7.64–7.48 (m, 5 H), 7.15–7.07 (m, 1 H), 7.07–
6.98 (m, 2 H), 6.76 (d, J = 7.2 Hz, 2 H), 5.64 (d, J = 15.1 Hz, 1
H), 4.60 (d, J = 15.1 Hz, 1 H) ppm. 13C{1H} NMR (CDCl3,
75.4 MHz): δ = 162.7 (C), 155.4 (C), 147.6 (C), 136.8 (C), 134.8
1558, 1472, 1423, 1360, 1223, 1040 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 8.38 (dd, J = 8.0, 1.8 Hz, 1 H), 7.84–7.72 (m, 2 H),
7.54 (ddd, J = 8.1, 5.9, 2.4 Hz, 1 H), 7.32 (dd, J = 8.0, 7.8 Hz, 1
H), 7.25–7.18 (m, 3 H), 7.03–6.90 (m, 4 H), 6.80–6.72 (m, 1 H), 5.26
(CH), 130.9 (C), 130.8 (C), 130.5 (C), 130.5 (C), 129.4 (CH), 129.2 (s, 2 H), 3.61 (s, 3 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ
(C), 128.7 (CH), 128.4 (2ϫCH), 128.1 (CH), 127.9 (CH), 127.7 = 159.4 (C), 156.2 (C), 147.2 (C), 136.8 (C), 136.2 (C), 134.6 (CH),
(CH), 127.6 (2ϫCH), 127.5 (2ϫCH), 127.5 (CH), 127.3 (CH),
127.3 (CH), 125.2 (CH), 123.4 (CH), 122.7 (CH), 121.4 (C), 48.7
(CH2) ppm.
129.8 (CH), 128.5 (2ϫCH), 127.6 (CH), 127.4 (CH), 127.2 (CH),
127.1 (CH), 126.9 (2ϫCH), 120.1 (CH), 116.5 (CH), 112.7 (CH),
55.1 (CH3), 48.9 (CH2) ppm.
Eur. J. Org. Chem. 2015, 7705–7717
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7713

J. Godeau, M. Harari, S. Laclef, E. Deau, C. Fruit, T. Besson
FULL PAPER
General Procedure for the Synthesis of 3a–3n from 1a: In a 5 mL
glass microwave vial, 1a (200 mg, 0.85 mmol, 1.0 equiv.), copper
iodide (81 mg, 0.42 mmol, 0.50 equiv.), and lithium tert-butoxide
(136 mg, 1.69 mmol, 2.0 equiv.) were mixed in dry DMF (2 mL)
3-Benzyl-2-(5-chloropyridin-2-yl)quinazolin-4(3H)-one (3d): White
powder; yield 183 mg (62%); Rf = 0.40 (PE/AcOEt 8:2); m.p. 116–
117 °C. IR (neat): ν = 3060, 1677, 1586, 1567, 1471, 1436, 1385,
˜
1105, 1015, 952, 850, 775, 690 cm–1. 1H NMR (CDCl3, 300 MHz):
and heated in a microwave oven at 120 °C for 10 min (2 min ramp). δ = 8.64 (d, J = 2.3 Hz, 1 H), 8.39 (d, J = 7.9 Hz, 1 H), 7.84–7.70
After the mixture cooled to 60–70 °C, PPh3 or PCy3, (0.085 mmol, (m, 2 H), 7.67 (dd, J = 8.4, 2.3 Hz, 1 H), 7.56 (t, J = 7.4 Hz, 1 H),
10 mol-%), Pd(OAc)2 (9.6 mg, 0.042 mmol, 5.0 mol-%), and (het- 7.42 (d, J = 8.4 Hz, 1 H), 7.17–7.09 (m, 3 H), 6.92–6.81 (m, 2 H),
ero)aryl bromide (1.7 mmol, 2.0 equiv.) were added successively.
The reaction mixture was heated by microwave irradiation at
120 °C for 30 min (2 min ramp). The resulting solution was diluted
with AcOEt (10 mL) and filtered through a small pad of silica gel.
The volatile compounds were evaporated, and the crude product
was purified by flash chromatography with PE/AcOEt as the eluent
to afford products 3a–3n.
5.67 (s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.4
(C), 152.8 (C), 151.9 (C), 147.4 (CH), 147.1 (C), 137.0 (C), 137.0
(CH), 134.7 (CH), 133.3 (C), 128.6 (2ϫCH), 127.8 (CH), 127.8
(CH), 127.5 (CH), 127.5 (CH), 127.2 (2ϫCH), 125.9 (CH), 121.3
(C), 46.9 (CH2) ppm. HRMS (TOF-ESI+): calcd. for
C20H1535ClN3O [M + H]+ 348.0898; found 348.0908.
3-Benzyl-2-(quinolin-2-yl)quinazolin-4(3H)-one (3e): Yellow powder;
(Hetero)aryl Chloride Partners (3a, 3e, 3h, and 3j): Compound 1a
yield 211 mg (68% from 2-bromoquinoline), 78 mg (51% from 2-
(100 mg, 0.43 mmol, 1.0 equiv.), copper iodide (41 mg, 0.21 mmol, chloroquinoline); Rf = 0.34 (PE/AcOEt 8:2); m.p. 110–111 °C. IR
0.50 equiv.), and lithium tert-butoxide (68 mg, 0.85 mmol,
2.0 equiv.) were mixed in dry DMF (1 mL) and heated in a micro-
(neat): ν = 3053, 3006, 2932, 2892, 1673, 1581, 1386, 1152, 947,
˜
845, 759, 717, 691 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 8.41 (d,
wave oven at 120 °C for 10 min (2 min ramp). After the mixture J = 7.8 Hz, 1 H), 8.14 (d, J = 8.5 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1
cooled to 60–70 °C, NiXantphos, (23 mg, 0.043 mmol, 10 mol-%),
Pd(OAc)2 (4.8 mg, 0.02 mmol, 5.0 mol-%), and (hetero)aryl chlor-
ide (0.85 mmol, 2.0 equiv.) were added successively.
H), 7.85–7.70 (m, 4 H), 7.62–7.55 (m, 2 H), 7.51 (ddd, J = 8.2, 5.8,
2.5 Hz, 1 H), 7.11–6-97 (m, 3 H), 6.83 (br. d, J = 6.4 Hz, 2 H), 5.80
(s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.4 (C),
153.6 (C), 153.2 (C), 147.1 (C), 146.6 (C), 137.2 (CH), 137.1 (C),
134.4 (CH), 130.4 (CH), 129.5 (CH), 128.3 (2ϫCH), 127.9 (CH),
127.8 (C), 127.7 (2ϫCH), 127.5 (CH), 127.3 (2ϫCH), 127.2
(2ϫCH), 121.6 (CH), 121.2 (C), 47.1 (CH2) ppm. HRMS (EI+):
calcd. for C24H17N3O [M]+· 363.13716; found 363.13672.
3-Benzyl-2-(pyridin-2-yl)quinazolin-4(3H)-one (3a): White powder;
yield 120 mg (from 2-bromopyridine), 104 mg (79% from 2-chloro-
pyridine); R = 0.11 (PE/AcOEt 8:2); m.p. 105–106 C. IR (neat): ν
˜
f
= 3053, 2951, 1669, 1591, 1563, 1471, 1446, 1383, 1331, 1151, 974,
1
779, 721, 692 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.67 (br. d,
J = 4.8 Hz, 1 H), 8.38 (d, J = 7.9 Hz, 1 H), 7.77–7.71 (m, 2 H), 3-Benzyl-2-(quinolin-3-yl)quinazolin-4(3H)-one (3f): Brown powder;
7.68 (td, J = 7.8, 1.7 Hz, 1 H), 7.52 (ddd, J = 8.2, 5.4, 2.9 Hz, 1
H), 7.42 (d, J = 7.8 Hz, 1 H), 7.35 (ddd, J = 7.6, 4.9, 0.6 Hz, 1 H),
7.13–7.04 (m, 3 H), 6.89–6.78 (m, 2 H), 5.67 (s, 2 H) ppm. 13C{1H}
NMR (CDCl3, 75.4 MHz): δ = 162.4 (C), 153.7 (C), 153.6 (C),
yield 157 mg (51%); Rf = 0.35 (PE/AcOEt 8:2); m.p. 124–125 °C.
IR (neat): ν = 3060, 3026, 2919, 1668, 1603, 1558, 1337, 1130, 923,
˜
1
766, 737, 694 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.92 (d, J =
2.1 Hz, 1 H), 8.43 (d, J = 7.6 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H),
148.5 (CH), 147.1 (C), 137.2 (CH), 137.0 (2ϫC), 134.5 (CH), 128.3 8.02 (d, J = 2.0 Hz, 1 H), 7.89–7.73 (m, 3 H), 7.68 (d, J = 7.1 Hz,
(2ϫCH), 127.6 (CH), 127.5 (CH), 127.3 (CH), 127.2 (2ϫCH), 1 H), 7.64–7.55 (m, 2 H), 7.25–7.15 (m, 3 H), 6.96–6.82 (m, 2 H),
124.8 (CH), 124.5 (CH), 121.2 (C), 46.8 (CH2) ppm. HRMS (TOF- 5.32 (s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.5
ESI+): calcd. for C20H16N3O [M + H]+ 314.1288; found 314.1284.
(C), 154.0 (C), 148.7 (CH), 148.1 (C), 147.3 (C), 136.4 (C), 136.1
(CH), 135.0 (CH), 131.2 (CH), 129.5 (CH), 128.9 (2ϫCH), 128.5
(C), 128.4 (CH), 127.9 (CH), 127.8 (3ϫCH), 127.4 (CH), 126.9
(2ϫCH), 126.6 (C), 121.0 (C), 49.1 (CH2) ppm. HRMS (TOF-
EI+): calcd. for C24H17N3O [M]+· 363.13661; found 363.13819.
3-Benzyl-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one (3b): White
powder; yield 183 mg (66%); Rf = 0.18 (PE/AcOEt 8:2); m.p. 111–
112 °C. IR (neat): ν = 3066, 3035, 2912, 1673, 1590, 1564, 1454,
˜
1381, 1163, 960, 774, 707, 692 cm–1. 1H NMR (CDCl3, 300 MHz):
δ = 8.37 (d, J = 7.9 Hz, 1 H), 7.74 (br. d, J = 3.8 Hz, 2 H), 7.57 (t,
J = 7.8 Hz, 1 H), 7.53–7.46 (m, 1 H), 7.25–7.18 (m, 2 H), 7.13–
7.07 (m, 3 H), 6.91–6.83 (m, 2 H), 5.59 (s, 2 H), 2.58 (s, 3 H) ppm.
13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.4 (C), 157.7 (C), 153.8
3-Benzyl-2-(pyridin-3-yl)quinazolin-4(3H)-one (3g):[24] Yellow pow-
der; yield 144 mg (54%); Rf = 0.12 (PE/AcOEt 8:2); m.p. 129–
130 °C (ref.[24] 124–125 °C). IR (neat): ν = 3060, 3033, 2966, 2932,
˜
1680, 1585, 1474, 1381, 1327, 771, 711, 696 cm–1. 1H NMR
(C), 152.9 (C), 147.1 (C), 137.4 (CH), 137.0 (C), 134.4 (CH), 128.3 (CDCl3, 300 MHz): δ = 8.71 (dd, J = 4.9, 1.6 Hz, 1 H), 8.64 (d, J
(2ϫCH), 127.6 (CH), 127.4 (CH), 127.3 (2ϫCH), 127.3 (CH), = 1.9 Hz, 1 H), 8.40 (br. d, J = 8.0 Hz, 1 H), 7.86–7.73 (m, 2 H),
127.1 (CH), 124.1 (CH), 121.6 (CH), 121.2 (C), 47.1 (CH2), 24.3 7.61–7.55 (m, 2 H), 7.30 (dd, J = 7.7, 4.9 Hz, 1 H), 7.25–7.19 (m, 3
(CH3) ppm. HRMS (TOF-ESI+): calcd. for C21H18N3O [M + H]+ H), 6.94–6.84 (m, 2 H), 5.28 (s, 2 H) ppm. 13C{1H} NMR (CDCl3,
328.1444; found 328.1451.
75.4 MHz): δ = 162.4 (C), 153.8 (C), 151.0 (CH), 148.8 (CH), 147.2
(C), 136.2 (C), 135.6 (CH), 135.0 (CH), 131.6 (C), 128.9 (2ϫCH),
127.9 (CH), 127.8 (2ϫCH), 127.4 (CH), 126.9 (2ϫCH), 123.2
(CH), 121.0 (C), 48.8 (CH2) ppm.
3-Benzyl-2-(5-methylpyridin-2-yl)quinazolin-4(3H)-one (3c): Yellow
solid; yield 93 mg (33%); Rf = 0.56 (PE/AcOEt 1:1); m.p. 99–
100 °C. IR (neat): ν = 3039, 2999, 2932, 1674, 1580, 1557, 1470,
˜
1354, 1147, 972, 834, 778, 697, 690 cm–1. 1H NMR (CDCl3,
3-Benzyl-2-(6-methoxypyridin-3-yl)quinazolin-4(3H)-one
(3h):
300 MHz): δ = 8.51 (s, 1 H), 8.37 (d, J = 7.8 Hz, 1 H), 7.79–7.70
White powder; yield 246 mg (85% from 5-bromo-2-methoxypyr-
(m, 2 H), 7.56–7.45 (m, 2 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.14–7.05 idine), 52 mg (36% from 5-chloro-2-methoxypyridine); Rf = 0.20
(m, 3 H), 6.92–6.83 (m, 2 H), 5.67 (s, 2 H), 2.38 (s, 3 H) ppm.
(PE/AcOEt 8:2); m.p. 125–126 °C. IR (neat): ν = 2952, 1683, 1601,
˜
13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.4 (C), 153.7 (C), 151.1
1584, 1496, 1372, 1289, 1013, 966, 841, 778, 720, 695 cm–1. 1H
(C), 148.9 (CH), 147.2 (C), 137.6 (CH), 137.1 (C), 134.6 (C), 134.4 NMR (CDCl3, 300 MHz): δ = 8.35 (br. d, J = 8.0 Hz, 1 H), 8.23
(CH), 128.3 (2ϫCH), 127.6 (CH), 127.4 (CH), 127.3 (CH), 127.3 (d, J = 2.5 Hz, 1 H), 7.82–7.69 (m, 2 H), 7.56–7.43 (m, 2 H), 7.25–
(2ϫCH), 127.2 (CH), 124.4 (CH), 121.1 (C), 46.9 (CH2), 18.5 7.18 (m, 3 H), 6.98–6.90 (m, 2 H), 6.71 (dd, J = 8.6, 0.5 Hz, 1 H),
(CH3) ppm. HRMS (TOF-ESI+): calcd. for C21H18N3O [M + H]+ 5.29 (s, 2 H), 3.95 (s, 3 H) ppm. 13C{1H} NMR (CDCl3,
328.1444; found 328.1448.
75.4 MHz): δ = 164.8 (C), 162.5 (C), 154.1 (C), 147.2 (C), 146.8
7714
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7705–7717

C-2–H Arylation of Quinazolin-4(3H)-ones with (Hetero)aryl Halides
(CH), 138.2 (CH), 136.4 (C), 134.7 (CH), 128.8 (2ϫCH), 127.7
7.19–7.13 (m, 2 H), 5.69 (s, 2 H) ppm. 13C{1H} NMR (CDCl3,
(CH), 127.6 (CH), 127.4 (CH), 127.2 (CH), 126.7 (2ϫCH), 124.9 75.4 MHz): δ = 162.5 (C), 155.1 (C), 148.8 (C), 147.4 (C), 146.8
(C), 120.8 (C), 110.6 (CH), 53.9 (CH3), 48.9 (CH2) ppm. HRMS (C), 136.8 (C), 134.8 (CH), 128.7 (2ϫCH), 128.0 (CH), 127.7
(TOF-ESI+): calcd. for C21H18N3O2 [M + H]+ 344.1393; found
344.1395.
(CH), 127.6 (CH), 127.4 (2ϫCH), 126.9 (2ϫCH), 126.6 (CH),
123.9 (CH), 122.3 (CH), 121.1 (C), 111.9 (CH), 111.5 (CH), 48.5
(CH2) ppm. HRMS (TOF-EI+): calcd. for C23H16N2O2 [M]+·
352.12118; found 352.12238.
3-Benzyl-2-(6-chloropyridin-3-yl)quinazolin-4(3H)-one (3i): Yellow
crystals; yield 99 mg (34%); Rf = 0.22 (PE/AcOEt 8:2); m.p. 108–
109 °C. IR (neat): ν = 3063, 3033, 2972, 2899, 1674, 1547, 1471,
˜
3-Benzyl-2-(quinolin-5-yl)quinazolin-4(3H)-one (3n): Yellow powder;
yield 211 mg (68%); Rf = 0.34 (PE/AcOEt 8:2); m.p. 163–164 °C.
1
1353, 735, 694 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.42 (d, J
= 2.4 Hz, 1 H), 8.39 (d, J = 8.0 Hz, 1 H), 7.86–7.78 (m, 1 H), 7.74
(d, J = 7.9 Hz, 1 H), 7.62–7.49 (m, 2 H), 7.32 (d, J = 8.2 Hz, 1 H),
7.28–7.19 (m, 3 H), 6.97–6.83 (m, 2 H), 5.27 (s, 2 H) ppm. 13C{1H}
NMR (CDCl3, 75.4 MHz): δ = 162.1 (C), 152.8 (C), 152.7 (C),
148.8 (CH), 147.0 (C), 138.3 (CH), 136.0 (C), 134.9 (CH), 130.4
(C), 129.0 (2ϫCH), 127.9 (2ϫCH), 127.7 (CH), 127.3 (CH), 126.6
(2ϫCH), 123.9 (CH), 120.8 (C), 48.7 (CH2) ppm. HRMS (TOF-
EI+): calcd. for C20H1335ClN3O [M – H]+ 346.07471; found
346.07431.
IR (neat): ν = 3059, 2986, 2898, 1668, 1586, 1564, 956, 800, 769,
˜
717, 694 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 8.89 (dd, J = 4.2,
1.7 Hz, 1 H), 8.47 (ddd, J = 8.0, 1.5, 0.5 Hz, 1 H), 8.24 (dt, J =
8.6, 0.9 Hz, 1 H), 7.86–7.79 (m, 1 H), 7.78–7.67 (m, 3 H), 7.61
(ddd, J = 8.2, 7.0, 1.4 Hz, 1 H), 7.42 (dd, J = 7.1, 1.1 Hz, 1 H),
7.22 (dd, J = 8.5, 4.2 Hz, 1 H), 7.10–6.94 (m, 3 H), 6.69–6.60 (m,
2 H), 5.20 (d, J = 15.1 Hz, 1 H), 5.01 (d, J = 15.1 Hz, 1 H) ppm.
13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.5 (C), 154.1 (C), 151.0
(CH), 147.9 (C), 147.2 (C), 136.4 (C), 134.9 (CH), 132.7 (CH),
132.5 (C), 131.8 (CH), 128.7 (CH), 128.4 (2ϫCH), 127.8 (CH),
127.8 (CH), 127.7 (CH), 127.4 (CH), 127.3 (2ϫCH), 127.0 (CH),
126.2 (C), 122.1 (CH), 121.2 (C), 48.6 (CH2) ppm. HRMS (TOF-
EI+): calcd. for C24H17N3O [M – H]+ 362.12934; found 362.12958.
3-Benzyl-2-(pyrazin-2-yl)quinazolin-4(3H)-one (3j): Yellow powder;
yield 73 mg (27%); Rf = 0.55 (PE/AcOEt 1:1); m.p. 142–143 °C. IR
(neat): ν = 3059, 3026, 2945, 1674, 1591, 1376, 1155, 1019, 781,
˜
723, 709, 698 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 8.71 (s, 1 H),
8.66–8.60 (m, 2 H), 8.41 (d, J = 7.3 Hz, 1 H), 7.88–7.72 (m, 2 H),
7.64–7.52 (m, 1 H), 7.16–7.06 (m, 3 H), 6.88–6.78 (m, 2 H), 5.69
(s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.3 (C),
151.1 (C), 149.6 (C), 147.0 (C), 146.0 (CH), 145.2 (CH), 142.6
(CH), 136.8 (C), 134.8 (CH), 128.7 (2ϫCH), 128.2 (CH), 128.0
(CH), 127.7 (CH), 127.5 (CH), 127.0 (2ϫCH), 121.3 (C), 46.7
(CH2) ppm. HRMS (TOF-EI+): calcd. for C19H14N4O [M]+·
314.11676; found 314.11762.
General Procedure for the Synthesis of 3o–3q from 1a: The same
procedure as that described above for 2v–2y was used.
6-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)nicotinonitrile
(3o):
White powder; yield 15 mg (11%); Rf = 0.18 (PE/AcOEt 8:2); m.p.
152–153 °C. IR (neat): ν = 3063, 2962, 2227, 1675, 1584, 1473,
˜
1386, 1143, 1075, 957, 855, 776, 693 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 8.94 (dd, J = 1.9, 0.7 Hz, 1 H), 8.42 (dd, J = 8.0,
0.9 Hz, 1 H), 7.94 (dd, J = 8.2, 2.1 Hz, 1 H), 7.86–7.72 (m, 2 H),
7.64–7.54 (m, 2 H), 7.17–7.09 (m, 3 H), 6.86–6.78 (m, 2 H), 5.70
(s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.1 (C),
156.6 (C), 151.9 (C), 151.0 (CH), 146.8 (C), 140.3 (CH), 136.7 (C),
134.8 (CH), 128.6 (2ϫCH), 128.2 (CH), 127.8 (CH), 127.6 (CH),
127.5 (CH), 127.0 (2ϫCH), 125.0 (CH), 121.2 (C), 116.1 (C), 110.5
(C), 46.6 (CH2) ppm. HRMS (TOF-EI+): calcd. for C21H14N4O
[M]+· 338.11676; found 338.11743.
3-Benzyl-2-(5-chlorothiophen-2-yl)quinazolin-4(3H)-one (3k): Yel-
low powder; yield 116 mg (39%); Rf = 0.56 (PE/AcOEt 8:2); m.p.
152–153 °C. IR (neat): ν = 3087, 3026, 2999, 1673, 1547, 1432,
˜
1246, 1008, 983, 803, 763, 741, 695 cm–1. 1H NMR (CDCl3,
300 MHz): δ = 8.32 (d, J = 8.0 Hz, 1 H), 7.83–7.69 (m, 2 H), 7.51
(t, J = 7.3 Hz, 1 H), 7.38–7.27 (m, 3 H), 7.13 (d, J = 7.2 Hz, 2 H),
6.95 (d, J = 4.0 Hz, 1 H), 6.80 (d, J = 4.0 Hz, 1 H), 5.53 (s, 2 H)
ppm. 13C{1H} NMR (CDCl3, 75.4 MHz): δ = 162.5 (C), 149.2 (C),
147.3 (C), 136.4 (C), 135.8 (C), 135.0 (C), 134.9 (CH), 129.2
(2ϫCH), 129.0 (CH), 127.7 (CH), 127.7 (CH), 127.5 (CH), 127.3
(CH), 126.8 (CH), 126.0 (2ϫCH), 120.4 (C), 49.4 (CH2) ppm.
3-Benzyl-2-[5-(trifluoromethyl)pyridin-2-yl]quinazolin-4(3H)-one
(3p): White powder; yield 68 mg (42%); Rf = 0.50 (PE/AcOEt 8:2);
m.p. 88–89 °C. IR (neat): ν = 3036, 2962, 2928, 1671, 1591, 1568,
˜
HRMS (TOF-ESI+): calcd. for C19H1435ClN2OS [M
353.0510; found 353.0510.
+
H]+
1474, 1456, 1399, 1327, 1150, 1128, 1078, 1018 cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 8.95 (dd, J = 1.3, 1.3 Hz, 1 H), 8.41 (dd,
J = 8.1, 1.4 Hz, 1 H), 7.91 (dd, J = 8.2, 2.2 Hz, 1 H), 7.80 (dd, J
= 6.9, 1.5 Hz, 1 H), 7.74 (dd, J = 8.3, 1.3 Hz, 1 H), 7.66–7.46 (m,
2 H), 7.11 (m, 3 H), 6.83 (m, 2 H) 5.67 (s, 2 H) ppm. 13C{1H}
NMR (CDCl3, 75 MHz): δ = 162.1 (C), 156.8 (C), 152.4 (C), 146.8
(C), 145.3 (CH), 145.3 (CH), 136.7 (C), 134.6 (C), 134.3 (CH),
134.2 (CH), 128.5 (2ϫCH), 127.9 (CH), 127.7 (CH), 127.4 (CH),
127.4 (CH), 127.0 (2 ϫ CH), 124.7 (CH), 121.2 (C), 46.7 (CH2)
ppm. HRMS (TOF-EI+): calcd. for C21H1419F3N3O [M]+·
381.10890; found 381.10888.
2-(Benzo[b]thiophen-2-yl)-3-benzylquinazolin-4(3H)-one (3l): Yellow
powder; yield 111 mg (35%); Rf = 0.48 (PE/AcOEt 8:2); m.p. 141–
142 °C. IR (neat): ν = 3060, 3026, 3006, 2952, 1673, 1547, 1472,
˜
1
1207, 982, 738, 725, 717, 693 cm–1. H NMR (CDCl3, 300 MHz):
δ = 8.39 (d, J = 7.7 Hz, 1 H), 7.94–7.77 (m, 2 H), 7.72 (d, J =
7.8 Hz, 1 H), 7.62–7.49 (m, 2 H), 7.49–7.20 (m, 6 H), 7.16 (br. d,
J = 7.0 Hz, 2 H), 5.57 (s, 2 H) ppm. 13C{1H} NMR (CDCl3,
75.4 MHz): δ = 162.5 (C), 150.6 (C), 147.3 (C), 140.6 (C), 139.1
(C), 136.7 (C), 136.3 (C), 134.8 (CH), 129.0 (2ϫCH), 127.9 (CH),
127.7 (2ϫCH), 127.3 (CH), 126.5 (CH), 126.5 (2ϫCH), 126.2
(CH), 125.0 (CH), 124.9 (CH), 122.3 (CH), 120.8 (C), 49.5 (CH2)
ppm. HRMS (TOF-EI+): calcd. for C23H16N2OS [M]+· 368.09834;
found 368.09747.
3-Benzyl-2-(pyrimidin-2-yl)quinazolin-4(3H)-one (3q): White pow-
der; yield 51 mg (38%); Rf = 0.22 (PE/AcOEt 6:4); m.p. 49–50 °C.
IR (neat): ν = 3078, 2922, 2852, 1677, 1600, 1560, 1467, 1425, 1379,
˜
1
1154, 774, 694 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.83 (br. s,
2-(Benzofuran-2-yl)-3-benzylquinazolin-4(3H)-one (3m): White pow-
2 H), 8.39 (d, J = 8.0 Hz, 1 H), 7.93–7.71 (m, 2 H), 7.63–7.51 (m,
der; yield 158 mg (53%); Rf = 0.50 (PE/AcOEt 8:2); m.p. 158– 1 H), 7.45–7.32 (m, 1 H), 7.21–7.07 (m, 3 H), 6.98–6.85 (m, 2 H),
159 °C. IR (neat): ν = 3060, 3033, 2952, 1674, 1551, 1158, 839, 753,
5.56 (s, 2 H) ppm. 13C{1H} NMR (CDCl3, 75 MHz): δ = 161.7
˜
1
695 cm–1. H NMR (CDCl3, 300 MHz): δ = 8.40 (d, J = 8.0 Hz, 1 (C), 160.9 (C), 157.1 (CH), 151.5 (C), 146.8 (C), 136.0 (2 ϫC),
H), 7.87–7.81 (m, 2 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.62–7.52 (m, 2 134.3 (CH), 128.2 (2 ϫ CH), 127.8 (CH), 127.6 (CH), 127.2
H), 7.48–7.38 (m, 1 H), 7.36–7.29 (m, 1 H), 7.29–7.21 (m, 4 H),
(2 ϫ CH), 126.9 (2 ϫ CH), 126.9 (CH), 121.2 (CH), 46.9 (CH2)
7715
Eur. J. Org. Chem. 2015, 7705–7717
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

J. Godeau, M. Harari, S. Laclef, E. Deau, C. Fruit, T. Besson
FULL PAPER
ppm. HRMS (TOF-EI+): calcd. for C19H14N4O [M]+· 314.11676;
found 314.11794.
3-Isopropyl-2-phenylquinazolin-4(3H)-one (4e):[28] White powder;
yield 152 mg (68%); Rf = 0.51 (PE/AcOEt 8:2); m.p. 135–136 °C
(ref.[28] 130–131 °C). IR (neat): ν = 3055, 2973, 2934, 1668, 1606,
˜
General Procedure for the Synthesis of 4a–4f from 1b–1g: In a
10 mL glass microwave vial, 1b–1g (0.85 mmol, 1.0 equiv.), copper
iodide (for N-aryl: 81 mg, 0.42 mmol, 0.50 equiv.; for N-alkyl:
162 mg, 0.85 mmol, 1 equiv.), and lithium tert-butoxide (136 mg,
1.69 mmol, 2.0 equiv.) were mixed in dry DMF (2 mL) and heated
in a microwave oven at 120 °C for 10 min (2 min ramp). After the
mixture cooled to 60–70 °C, aryl iodide (1.7 mmol, 2.0 equiv.) and
Pd(OAc)2 (9.6 mg, 0.042 mmol, 5.0 mol-%) were added success-
ively. The reaction mixture was heated at 120 °C by microwave irra-
diation for 30 min (2 min ramp). The resulting solution was diluted
with AcOEt (10 mL) and filtered through a small pad of silica gel.
The volatile compounds were evaporated, and the crude product
was purified by flash chromatography with PE/AcOEt as the eluent
to afford products 4a–4f.
1588, 1572, 1473, 1345, 1333, 1177, 1070, 1021 cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 8.30 (d, J = 8.2 Hz, 1 H), 7.77–7.68 (m, 2
H), 7.52–7.46 (m, 6 H), 4.34 (sept, J = 6.8 Hz, 1 H), 1.59 (d, J =
6.8 Hz, 6 H) ppm. 13C NMR (CDCl3, 75.4 MHz): δ = 162.6 (C),
156.6 (C), 146.8 (C), 136.4 (C), 134.1 (CH), 129.7 (CH), 128.9
(2ϫCH), 127.2 (3ϫCH), 126.9 (CH), 126.4 (CH), 122.2 (C), 54.0
(CH), 16.6 (2ϫCH3) ppm.
3-Cyclopropyl-2-phenylquinazolin-4(3H)-one (4f):[29] White powder;
yield 187 mg (84%); Rf = 0.31 (PE/AcOEt 8:2); m.p. 112–114 °C.
IR (neat): ν = 3058, 2923, 1673, 1602, 1588, 1558, 1472, 1410, 1332,
˜
1261, 1107, 1047, 1021 cm–1. 1H NMR (CDCl3, 300 MHz): δ =
8.28 (d, J = 7.9 Hz, 1 H), 7.74–7.67 (m, 4 H), 7.51–7.42 (m, 4 H),
3.15–3.07 (m, 1 H), 0.90 (q, J = 7.0 Hz, 2 H), 0.50–0.44 (m, 2 H)
ppm. 13C NMR (CDCl3, 75.4 MHz): δ = 163.8 (C), 156.8 (C), 147.0
(C), 136.1 (C), 134.1 (CH), 129.7 (CH), 128.3 (2 ϫ CH), 128.1
(2 ϫ CH), 127.3 (CH), 126.8 (CH), 126.4 (CH), 120.8 (C), 30.2
(CH), 11.2 (2 ϫ CH2) ppm. HRMS (TOF-ESI+): calcd. for
C17H15N2O [M + H]+ 263.1184; found 263.1180.
2-Phenyl-3-(p-tolyl)quinazolin-4(3H)-one (4a):[25] White powder;
yield 228 mg (86%); Rf = 0.39 (PE/AcOEt 8:2); m.p. 179–180 °C
(ref.[25] 180–181 °C). IR (neat): ν = 3034, 2919, 1677, 1603, 1588,
˜
1564, 1511, 1473, 1342, 1328, 1269, 1210, 1158, 1108 cm–1 1H
.
NMR (CDCl3, 300 MHz): δ = 8.37 (d, J = 7.8 Hz, 1 H), 7.86–7.79
(m, 2 H), 7.54 (ddd, J = 8.1, 6.2, 2.1 Hz, 1 H), 7.38 (dd, J = 7.5,
1.8 Hz, 2 H), 7.30–7.21 (m, 3 H), 7.13 (d, J = 8.3 Hz, 2 H), 7.13
(d, J = 8.3 Hz, 2 H), 2.32 (s, 3 H) ppm. 13C NMR (CDCl3,
75.4 MHz): δ = 162.3 (C), 155.3 (C), 147.4 (C), 138.2 (C), 135.5
(C), 134.9 (C), 134.5 (CH), 129.6 (2 ϫ CH), 129.1 (CH), 128.8
(2 ϫ CH), 128.7 (2 ϫ CH), 127.9 (2 ϫ CH), 127.6 (CH), 127.1
(2ϫCH), 120.9 (C), 21.1 (CH3) ppm.
Acknowledgments
Financial support from the French Ministère de l’Enseignement
Supérieur & de la Recherche (MESR) is gratefully acknowledged
for the doctoral fellowships to M. H. The authors thank the
LABEX SynOrg (ANR-11-LABX-0029) for financial support (S. L
and J. G.). We also acknowledge Anton-Paar GmbH (Graz, Aus-
tria) for the provision of single-mode microwave reactor
(Monowave 300) and for technical support.
3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2-phenylquinazolin-4(3H)-
one (4b): White powder; yield 248 mg (82%); Rf = 0.16 (PE/AcOEt
8:2); m.p. 100–102 °C. IR (neat): ν = 3066, 2988, 2880, 1682, 1587,
˜
1563, 1504, 1471, 1309, 1279, 1155, 1121, 1064 cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 8.36 (d, J = 7.9 Hz, 1 H), 7.82 (d, J =
4.3 Hz, 2 H), 7.58–7.50 (m, 1 H), 7.40–7.36 (m, 2 H), 7.30–7.24 (m,
3 H), 6.77 (d, J = 8.6 Hz, 1 H), 6.72 (d, J = 2.5 Hz, 1 H), 6.60 (dd,
J = 8.6, 2.5 Hz, 1 H), 4.22 (s, 4 H) ppm. 13C NMR (CDCl3,
75.4 MHz): δ = 162.5 (C), 155.4 (C), 147.4 (C), 143.5 (2ϫC), 135.5
(C), 134.7 (CH), 130.6 (C), 129.3 (CH), 128.8 (2 ϫ CH), 128.0
(2ϫCH), 127.7 (CH), 127.2 (CH), 127.2 (CH), 122.1 (CH), 120.9
(C), 118.2 (CH), 117.4 (CH), 64.2 (CH2), 64.1 (CH2) ppm. HRMS
(TOF-ESI+): calcd. for C22H17N2O3 [M + H]+ 357.1239; found
357.1240.
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3-Methyl-2-phenylquinazolin-4(3H)-one (4c):[26] White powder; yield
183 mg (91%); Rf = 0.31 (PE/AcOEt 8:2); m.p. 128–129 °C (ref.[26]
130–132 °C). IR (neat): ν = 3059, 3007, 1675, 1609, 1588, 1562,
˜
1
1474, 1354, 1261, 1208, 1144, 1048, 1021 cm–1. H NMR (CDCl3,
300 MHz): δ = 8.34 (d, J = 8.0 Hz, 1 H), 7.80–7.73 (m, 2 H), 7.59–
7.49 (m, 6 H), 3.50 (s, 3 H) ppm. 13C NMR (CDCl3, 75.4 MHz): δ
= 162.7 (C), 156.1 (C), 147.3 (C), 135.4 (C), 134.3 (CH), 130.1
(CH), 128.9 (2 ϫCH), 128.0 (2ϫCH), 127.5 (CH), 127.0 (CH),
126.7 (CH), 120.5 (C), 34.3 (CH3) ppm.
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2-Phenyl-3-propylquinazolin-4(3H)-one (4d):[27] White powder; yield
161 mg (72%); Rf = 0.45 (PE/AcOEt 8:2); m.p. 99–100 °C (ref.[27]
98–100 °C). IR (neat): ν = 2985, 2959, 1679, 1604, 1584, 1567,
˜
1473, 1464, 1437, 1361, 1249, 1236, 1173, 1144, 1074, 1025 cm–1.
1H NMR (CDCl3, 300 MHz): δ = 8.33 (d, J = 8.0 Hz, 1 H), 7.78–
7.71 (m, 2 H), 7.52–7.47 (m, 6 H), 3.94 (m, 2 H), 1.63 (sext, J =
7.7 Hz, 2 H), 0.76 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (CDCl3,
75.4 MHz): δ = 162.1 (C), 156.2 (C), 147.2 (C), 135.6 (C), 134.3
(CH), 129.8 (CH), 128.7 (2ϫCH), 127.7 (2ϫCH), 127.4 (CH),
126.9 (CH), 126.7 (CH), 120.9 (C), 47.4 (CH2), 22.1 (CH2), 11.1
(CH3) ppm.
7716
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Eur. J. Org. Chem. 2015, 7705–7717

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Received: August 31, 2015
Published Online: November 6, 2015
don, S. Ramdeehul, J. M. Brown, A. Cowley, K. K. Hii, A.
Eur. J. Org. Chem. 2015, 7705–7717
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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