Quinazoline-Directed C–H Bond Functionalization Catalyzed by Ruthenium(II) Carboxylate – Construction of Polyconjugated Aryl-Heteroaryl Systems

Article abstract of DOI:10.1002/ejoc.201700097

A series of coupling products have been prepared by a ruthenium(II)-catalyzed direct ortho-C–H arylation of 2-(aryl/heteroaryl)-substituted quinazolines with (hetero)aryl bromides. Tri(hetero)aryl-substituted alkenes were also prepared by olefinic C–H activation of 2-(2-arylvinyl)quinazoline derivatives. High conversions and selectivities were achieved by choosing the appropriate ruthenium(II) carboxylate catalyst system, solvent, and reaction temperature. The possibility of a C(sp³)–H functionalization by applying an arylation/reduction reaction sequence was also demonstrated.

Full text of DOI:10.1002/ejoc.201700097

A Journal of
Accepted Article
Title: Quinazoline-directed C-H bond functionalization catalyzed by
Ru(II)-carboxylate. Construction of polyconjugated aryl-heteroaryl
systems
Authors: Bogdan Štefane, Helena Brodnik Žugelj, Uroš Grošelj, Petra
Kuzman, Jurij Svete, and Franc Pozgan
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700097
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700097
Supported by

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
Quinazoline-directed C–H bond functionalization catalyzed by
Ru(II)-carboxylate. Construction of polyconjugated aryl-heteroaryl
systems
Bogdan Štefane,[a] Helena Brodnik Žugelj,[a] Uroš Grošelj,[a] Petra Kuzman,[a] Jurij Svete,[a] and Franc
Požgan*[a]
Dedicated to Prof. Dr. Miha Tišler on the occasion of his 90th birthday.
Abstract: A series of new coupling products of 2-(aryl, heteroaryl)-
substituted quinazolines with (hetero)aryl bromides were prepared
by ruthenium(II)-catalyzed direct ortho-C–H arylation. 2-(2-
arylvinyl)quinazoline derivatives as substrates gave rise to
tri(hetero)aryl-substituted alkenes through olefinic C–H activation.
High conversions and selectivities could only be achieved by subtle
choice of an appropriate in situ formed Ru(II)-carboxylate catalyst
system, solvent and reaction temperature. The possibility of
circumventing sp3C–H functionalization by applying arylation-
reduction sequence was also demonstrated.
The quinazoline skeleton is a common structural motif in many
natural products and synthetic compounds with various
pharmacological properties.9 For this reason, many synthetic
methods have been developed, especially for the construction of
2-substituted quinazolines,10 yet there is still a great demand for
the generation of novel quinazoline libraries. As part of our
ongoing interest in metal-catalyzed functionalization of
(hetero)arenes via C–H activation,11 we reasoned that
a
quinazoline nucleus could direct cleavage and further
functionalization of ortho-C–H bonds of the 2-aryl substituent
thus enabling the construction of highly conjugated quinazoline
derivatives. However, only very limited examples of the
quinazoline ring acting as
a
directing group in C–H
Introduction
functionalization have been demonstrated. Reddy and co-
workers reported the Pd-catalyzed ortho-selective direct
acetoxylation and methoxylation of 2-arylquinazolinones.12
Selective ortho-monoarylation of the 2-aryl group of 2,4-
diarylquinazolines with aryl iodides was achieved in the
presence of Pd(OAc)2 and Ag2CO3 in trifluoroacetic acid as
presented by Peng and co-workers.13 They also reported Rh-
catalyzed C–H amidation of 2,4-diarylquinazolines with sulfonyl
azides as an amine source.14 Similarly, transition-metal-
catalyzed activations of ortho-C–H bonds assisted by nitrogen
atom of 2-arylquinazolones and further functionalizations
associated with cyclization have also been documented. A Ru-
The catalytic direct functionalization of less reactive C–H bonds
in the presence of transition metals has brought innovation in
synthetic chemistry by enabling the rapid assembly of diversified
molecular architectures, particularly in the fields of medicinal and
material sciences, yet avoiding the use of prefunctionalized
coupling partners.1 Although Pd2 and Rh3 catalysts work very
well, the use of cheaper, easy-to-prepare, air stable, and
functional groups tolerant Ru(II)4 complexes have attracted
much interest in further development of efficient catalytic
systems for selective C–H bond activation. While the idea of
using C–H bonds as functional groups in chemical synthesis has
become prevalent, the sufficient reactivity of strong C–H bonds
and selective site reactivity still represent the main challenges.5
Regioselectivity can elegantly be controlled by bringing the
reactive metal centre into close proximity of a C–H bond by
chelation assistance of directing groups. From initial examples
of specific C–H bond functionalizations, a wide variety of
functional groups have been evaluated for the use as directing
catalyzed
oxidative
cross-coupling/annulation
of
2-
arylquinazolones with alkynes led to the fused polycyclic
heteroarenes,15 while 2-aryl-4-quinazolinones were coupled with
olefins in the presence of Ru(II) catalyst and Cu(OAc)2 as
oxidant to form a pyrrolo[2,1-b]quinazolin-9(1H)-one scaffold.16
Yang et al. developed a Pd-catalyzed intramolecular oxidative
C–H amination of 2-aryl-3-(arylamino)quinazolones to access
indazo[3,3-b]quinazolones.17
These results and our own work on successful ortho-arylation of
phenylpyrimidines11b in the presence of Ru(II)-carboxylate
catalytic system prompted us to explore direct arylation of
quinazoline derivatives via C–H bond cleavage of the C2-
(hetero)aryl substituent.
6
groups. A great number of them are based on nitrogen as
metal-coordinating atom, the pyridine ring being prevalent,
although other azaheterocycles, such as quinoline, pyrazole,
and oxazoline have also been successfully employed in
selective ortho-C–H functionalizations.7 The success of Ru(II)
catalysts is most likely ascribed to easy formation of
ruthenacyclic species via C–H bond cleavage with assistance of
directing groups.8
Results and Discussion
The starting 2-substituted quinazolines 1 were easily obtained
via condensation followed by cyclization and oxidation reaction
between 2-aminobenzylamine and the corresponding aldehydes
following the literature procedure.10l At the outset of this
investigation, the reaction of simple 2-phenylquinazoline (1a)
with 4-bromoacetophenone in the presence of [Ru(p-
cymene)Cl2]2 complex was selected as the model reaction to
[a]
Faculty of Chemistry and Chemical Technology, University of
Ljubljana,
Večna pot 113, SI-1000 Ljubljana, Slovenia
E-mail: franc.pozgan@fkkt.uni-lj.si
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
crude reaction mixture. [c]300 mol%. [d]Diarylated product with reduced
carbonyl group was isolated. [e]10 mol%. [f]Temperature 120 oC. [g]Isolated yield
is given. [h]EBDP = ethylenebis(diphenylphosphine).
determine the optimal reaction conditions. In order to compare
the catalytic results, temperature was set to 140 oC and
reactions were systematically quenched after 2 hours, while
solvents and additives were varied. Since it has been widely
documented that carboxylates coordinated to the metal centre
facilitate the C–H bond cleavage and significantly enhance the
efficiency of direct functionalizations,18 NaOAc was initially used
as an additive. While a variety of solvents, from nonpolar toluene
to polar NMP could be utilized (Table 1, entries 1–3), the Ru(II)-
catalyzed C–H arylation was the most effective in 1,4-dioxane
leading to 80% conversion in great favor of ortho-diarylated
product 2a (Table 1, entry 4). Isopropanol, however, gave
slightly higher conversion, but diarylated products with one or
both reduced carbonyl groups were formed.19 The activity of
ruthenium catalyst in 1,4-dioxane was further improved by
applying sterically more hindered carboxylate formed in situ from
PCCA (1-phenylcyclopentane-1-carboxylic acid), thus reaching
excellent 96% conversion with 93% selectivity towards the
diarylated product 2a (Table 1, entry 6). Finally, we found that
combination of PCCA and PPh3 (10 mol% of each) allowed the
exclusive formation of the diarylated product 2a in a quantitative
yield even at lower temperature of 120 oC, while the use of PPh3
as a sole ligand gave much lower conversion (Table 1, entries 7
vs. 8). It has been reported that C–H arylation is feasible in
aqueous medium in the presence of Ru(II)-carboxylate
catalyst.20 Indeed, our model reaction gave high conversion in
water, unfortunately with significantly affected product selectivity
(Table 1, entry 9). Interestingly, PPh3 as the ligand seemed to
favor monoarylation, while bidentate phosphine ligand turned the
catalyst totally inactive (Table 1, entries 7 vs. 10). The use of
other carboxylic acids as cocatalysts, such as 8-
quinolinecarboxylic acid, 1-naphthoic acid or hydroxyacetic acid
proved to be much less efficient.
With the optimized catalytic conditions ([Ru(p-cymene)Cl2]2 (5
mol%), PCCA (10 mol%), PPh3 (10 mol%), K2CO3 (3 equiv.),
1,4-dioxane, 120 oC) in hand we explored its versatility in ortho-
arylation of quinazolines 1 bearing different substituents at C2
with various (hetero)aryl bromides. In order to achieve a high
diarylation selectivity, 3 equivalents of arylating reagent were
used, and the reaction mixtures were heated for 24 hours.
Reactions of 2-phenylquinazoline (1a) with selected electron-rich
and electron-poor para-substituted aryl bromides (4-bromo-N,N-
dimethylaniline, 4-bromotoluene and 4-bromobenzonitrile)
proceeded smoothly with quantitative conversions and
diarylation selectivities (Table 2, entries 1–3). Functionalization
with 2-bromothiophene as electrophile also gave an excellent
91% yield of diheteroarylated product 2e (Table 2, entry 4).
Reactions of fluoro- and chloro-quinazoline substrates 1b and
1c with p-bromotoluene proceeded with 100% conversions
providing the desired diarylated products 2f and 2g in good
isolated yields (Table 2, entries 5 and 6). In the reaction of 2-(4-
bromophenyl)quinazoline (1d) the conversion was still 100%, but
the diarylated product 2h (25% isolated yield) was accompanied
by significant amount of the monoarylated product 3h (12%
isolated yield) (Table 2, entry 7). The successful formation of the
expected ortho-arylated products from the halogenated
quinazoline substrates 1b–d suggests that the cleavage of their
C-halogen bond is not seriously affected under applied reaction
conditions. However, much lower isolated yields of 2h and 3h
might be at expense of the formation of side products arising
from C–H functionalizations with quinazolines acting not only as
substrates but also as arylating agents, although we were not
able to isolate any of such products. Next, quinazolines 1e–h
bearing electronically different para-substituents at the C2-
phenyl group were also reacted with p-bromotoluene (Table 2,
Table 1. Screening of reaction conditions.[a]
entries 8–11). Quinazoline 1e bearing
a strong electron-
withdrawing trifluoromethyl group gave only the diarylated
product 2i in an excellent 95% isolated yield. Surprisingly, the
reaction of the nitro-substituted analogue 1f attained much lower
conversion (62%) and furnished both mono- and diarylated
products 2j and 3j in a ratio of 45 : 55. On the other hand, 4-
(quinazolin-2-yl)benzonitrile (1g) completely reacted with p-
bromotoluene with higher diarylation selectivity to give di- and
monoarylated products 2k and 3k in 55% and 10% isolated
yields, respectively. Methyl-substituted quinazoline 1h reacted
quantitatively giving the diarylated product 2l in 75% yield. Our
method proved to be suitable also for functionalization of C2-
heteroaryl moiety of quinazolines 1i and 1j with p-
bromoacetophenone as arylating agent (Table 2, entries 12 and
13). Thus, 2-(thiophen-3-yl)quinazoline (1i) gave ortho-mono-
and ortho-diarylated products 3m and 2m in almost equal
isolated yields of ~30%, while 2-(furan-2-yl)quinazoline (1j) gave
the expected monoarylated product 3n in 61% isolated yield.
When 2-(pyridin-4-yl)quinazoline (1k) was reacted with 4-
bromoacetophenone no products were detected, suggesting that
more basic pyridine nitrogen competes for ruthenium
coordination thus preventing the ortho-C–H cleavage (Table 2,
COMe
Ar
Ar
N
N
N
[Ru(p-cymene)Cl2]2 (5 mol%)
+
+
N
N
K2CO3 (3 equiv.), additive
solvent, 140 oC, 2 h
N
Ar
Br
1a
2a
3a
(3 equiv.)
Ar = p-MeCOC6H4
Conv.
(%)b
23
(2a : 3a)[b]
Entry
solvent
Additive
1
NMP
NaOAc[c]
NaOAc[c]
NaOAc[c]
NaOAc[c]
NaOAc[c]
PCCA[e]
67 : 33
62 : 38
93 : 7
2
toluene
THF
67
3
82
4
1,4-dioxane
i-PrOH
80
92[d]
92 : 8
5
95 : 5
6
1,4-dioxane
1,4-dioxane
1,4-dioxane
H2O
96
93 : 7
[e]
7
PPh3
41
28 : 72
100 : 0 (98)[g]
68 : 32
–
8[f]
PCCA[e] /PPh3
NaOAc[c]
EBDP[e],[h]
100
93
[e]
9
10
1,4-dioxane
–
[a]Reaction conditions: 1a (0.5 mmol), 4-bromoacetophenone (1.5 mmol),
[Ru(p-cymene)Cl2]2 (0.025 mmol), K2CO3 (1.5 mmol), solvent (2 mL), argon.
[b]Conversion and ratio determined on the basis of 1H NMR analysis of the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
Me
entry 14). Successful arylations presented in Table 2 indicate
that electron-donating and electron-withdrawing groups, being
present at quinazoline 1 or aryl bromide, with slight exception of
a nitro group, do not have a significant influence on the catalytic
C–H functionalization process.
NO2
NO2
N
N
N
N
9
62
45 : 55
87 : 13
100 : 0
N
N
N
N
1f
2j (15%)
3j (19%)
Me
Me
Table 2. Scope of direct arylation of 2-substituted quinazolines.[a]
CN
CN
Products 2 and 3
(yield %)[c]
Conv.
(%)b
(2 : 3) [b]
N
Quinazoline 1
Entry
10
11
100
100
N
Me2N
1g
1h
1i
2k (55%)
3k (10%)
Me
N
N
N
Me
1
100
100
100 : 0
N
Me
Me
1a
N
2b (97%)
NMe2
N
Me
2l (75%)
Me
S
N
N
N
MeOC
2
100 : 0
N
S
1a
N
2c (97%)
N
12
100
45 : 55
Me
N
N
NC
2m (33%)
3m (31%)
COMe
N
N
N
MeOC
3
4
5
100
100
100 : 0
100 : 0
100 : 0
N
O
1a
N
N
2d (96%)
13
14
91
–
–
CN
N
N
N
O
1j
S
N
3n (61%)
N
N
N
N
N
–
–
S
1a
2e (91%)
1k
Me
F
F
[a]Reaction conditions: 1 (0.5 mmol), (hetero)aryl bromide (1.5 mmol), [Ru(p-
cymene)Cl2]2 (0.025 mmol), PCCA (0.05 mmol), PPh3 (0.05 mmol), K2CO3 (1.5
mmol), 1,4-dioxane (2 mL), 120 oC, 24 h, argon. [b]Conversion and ratio
determined on the basis of 1H NMR analysis of the crude reaction mixture.
[c]Isolated yield.
N
N
100
100
100
100
N
N
1b
2f (68%)
Me
Me
Cl
N
Cl
N
In continuation, we turned our attention to explore the possibility
of functionalization of readily accessible (E)-2-styrylquinazoline10l
(4a) via its olefinic C–H bond activation by favorable formation of
a 5-membered metallacyclic intermediate in the presence of a
ruthenium catalyst. Moreover, the reports on Ru-catalyzed
stereospecific direct arylation of heteroaryl-substituted olefins
are very scarce. For instance, the reaction of (E)-2-styrylpyridine
with aryl bromides in the presence of [Ru(η6-benzene)Cl2]2 gave
the corresponding β-arylated products with aryl moiety being
introduced cis to the pyridine ring acting as a directing group.21
Ackermann and co-workers reported on successful direct
arylation of 2-pyridinyl alkenes with aryl chlorides while using
Ru(IV) carbene catalyst to produce multisubstituted alkenes.22
Very recently, the synthesis of tri(hetero)aryl-substituted alkenes
with high levels of stereocontrol by employing phosphinous acid
Ru(II) catalysts in arylation of 2-styrylpyridine derivatives with
aryl bromides was presented by the same research group.23
There are, however, reports on the synthesis of heteroaryl
olefins through their C–H bond activation using other metals, but
6
7
8
100 : 0
80 : 20
100 : 0
N
N
1c
2g (62%)
Me
Me
Br
N
Br
N
N
N
1d
2h (25%)
3h (12%)
Me
Me
CF3
CF3
N
N
N
N
1e
2i (95%)
Me
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
usually more reactive organometallic reagents were required. As
one example, iron-catalyzed C–H functionalization of 2-pyridinyl-
substituted olefins required Grignard reagents as coupling
partners in the presence of 1,2-dichloro-2-methylpropane as the
oxidant.24
(E)-5e isomer which stereochemistry would have arisen from
Heck-type reaction. This may indicate that the newly introduced
heteroaryl moiety has greater influence on the in situ E/Z
isomerization than an aryl group in the products 5a,c,d.
With interesting results in hand, we continued to functionalize
the C=C double bond through its C–H activation in (E)-2-(furan-
2-yl)vinylquinazoline (4b) (Scheme 2). The reactions of 4b with
First, (E)-2-styrylquinazoline (4a) was reacted with 4-
bromoacetophenone
in
the
presence
of
[Ru(p-
cymene)Cl2]2/PCCA catalyst system, but heating the reaction
mixture in 1,4-dioxane even at 150 C for 21 h resulted in only
selected
bromobenzonitrile,
methoxypropoxy)benzene,
bromoacetophenone) proceeded smoothly in toluene at 130 C
to give selectively the E-products after 24 hours. It is worth
mentioning, that with 4b increased amounts of [Ru(p-
cymene)Cl2]2 (10 mol%)/PCCA (20 mol%) were required to
achieve satisfying conversions and selectivities. We also noticed
that quinazolinyl olefins bearing a furanyl moiety gradually
decomposed and isomerized, especially if not stored in the dark
(hetero)aryl
bromides
(4-bromotoluene,
4-bromo-1-methoxy-2-(3-
5-bromopyrimidine, 4-
4-
o
~40% conversion giving a mixture of products: reduced starting
quinazoline 4a-R, reduced arylated product 5a-R, and only small
amounts of Z and E isomers of the desired product 5a (Scheme
1). Notably, none of the analogous side products were reported
in above mentioned Ru-catalyzed arylation of 2-pyridinyl
alkenes.21,22,23 After varying different solvents (NMP, water,
DMAc, cyclohexane, i-PrOH, benzene, DMF, toluene), additives
(KOAc, PCCA, PPh3), and reaction temperatures (see Table SI)
we were pleased to find that, again, [Ru(p-cymene)Cl2]2/PCCA
catalyst system worked best, but in this case toluene as solvent
and 130 oC were decisive for attaining quantitative conversion of
4a into the desired (Z)-5a product (aryl group introduced cis to
the quinazoline ring). The importance of the Ru(II)-carboxylate
catalyst system was demonstrated in the reaction without added
PCCA, which led to a significant decrease of conversion (43%)
under otherwise identical conditions. It is worth mentioning, that
when the reaction was performed in the presence of N,N-
diisopropylethylamine as the base, only reduced starting
compound 4a-R was detected, while in the reaction without the
base, starting compounds were fully recovered. We were not,
however, able to find reaction conditions that would have
selectively led to the reduced arylated product 5a-R.
o
o
at low temperature (5 C). These processes were observed by
NMR analysis as well as by gradual change of product colour
and could explain the relatively low isolated yields of some of the
products 5.
The structures of alkenes 5 were determined by NMR analysis.
The structures of (Z)-5e and (E)-5e were unambiguously
confirmed by X-ray diffraction (see SI). The configuration around
the C=C double bond in (E)-5a, which is the unfavored product
under optimal reaction conditions (toluene, 130 oC), was
determined by NOESY spectroscopy, which revealed spatial
proximity between the olefinic proton and the p-acetylphenyl
protons (see SI). Consequently, the configuration of the
expected isomer 5a must be opposite, i.e Z. Similarly, the Z
configuration was also ascribed to 5c (see SI). Taking into
account the trans configuration of the starting compounds 4a
and 4b, the expected configuration (aryl moiety introduced cis to
the quinazoline ring) was ascribed to all other products 5. Finally,
the N^C cycloruthenated complexes successfully prepared in the
reaction of 4a and 4b with [Ru(p-cymene)Cl2]2 also confirmed
the selective C–H activation (see SI).
Scheme 1. Direct arylation of (E)-2-styrylquinazoline (4a).
After finding the optimal reaction conditions we extended the
scope of 4a functionalization with selected aryl bromides as well
as heterocylic bromide to construct triaryl-substituted olefins
(Scheme 2). Quinazoline 4a reacted with phenyl bromide to
produce diphenyl-quinazolinyl olefin 5b, while C–H arylation with
p-bromotoluene gave (Z)-5c with high stereoselectivity (~90%).
More electron-rich 4-bromoanisol gave the trisubstituted alkene
5d as a single diastereomer in excellent isolated yield. In the
latter three cases, the reaction time was prolonged to 72 h to
assure complete conversion of 4a. However, when 2-
bromothiophene was used as the arlylating agent, a 1 : 2
mixture of (Z)-5e and (E)-5e was obtained after 72 h.
Surprisingly, the stereoselectivity was in favor of the unexpected
Scheme 2. Direct arylation of quinazolinyl-alkenes 4.
Since we were not able to find suitable reaction conditions for
the selective hydroarylation of 4a, i.e. formation of 5-R (Table,
SI), and 2-phenethylquinazoline (4a-R) did not arylate under our
catalytic conditions (Scheme 3), we envisaged that sequential
arylation-reduction performed on 4a could be
a suitable
substitute for the direct sp3C–H arylation of its reduced form 4a-
R. Indeed, the reaction of 4a with p-bromotoluene gave first the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
arylated product 5c, which was without isolation further
transformed into 5c-R. After the arylation reaction, toluene was
simply replaced with i-PrOH, catalytic amounts of [Ru(p-
cymene)Cl2]2 (5 mol%) and PPh3 (10 mol%) were added, and
functionalization of 2-phenethylquinazoline. The obtained
quinazoline derivatives are being studied for further synthetic
explorations and for biological evaluations.
o
the reaction mixture was strired at 80 C for 24 h. Surprisingly,
NMR and MS analyses revealed that besides the expected 5c-R
also 5c-RR was formed (5c-R : 5c-RR = 15 : 85), in which
additionally to the C=C reduction a partial saturation of a
quinazoline ring occurred (Scheme 3). Even though we noticed
that 5c-RR is not stable enough in air and is gradually
transforming into 5c-R, we were able to sufficiently characterize
it. To accelerate transformation of 5c-RR into the desired
product 5c-R, the crude reaction mixture formed after the
reduction step was stirred under oxygen atmosphere (balloon) at
room temperature. After 4 days, complete aromatization of 5c-
RR occurred to give product 5c-R in 64% isolated yield. If no
oxygen was applied, the rearomatization was much slower.
Experimental Section
General Information
The reagents and solvents were used as received from commercial
suppliers. Toluene was dried with sodium and distilled. Melting points
were determined on a Kofler micro hot stage. The NMR spectra were
recorded at 302 K either on a Bruker Avance DPX 300 or Avance III 500
MHz spectrometer operating at 300 MHz or 500 MHz and 75.5 MHz or
126 MHz for 1H and 13C nuclei. The 1H NMR spectra in CDCl3 are
referenced with respect to TMS as the internal standard. The 1H NMR
spectra in CD3CN are referenced with respect to central line of quintet
(1.94 ppm) of residual solvent peak as the internal standard. The 13C
NMR spectra are referenced against the central line of the solvent signal
(CDCl3 triplet at δ = 77.0 ppm, CD3CN septet at δ = 1.32 ppm). The
coupling constants (J) are given in Hz. The multiplicities are indicated as
follows: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), m
(multiplet) and br (broad). IR spectra were obtained with a Bruker ALPHA
FT-IR spectrophotometer. MS spectra were recorded with an Agilent
6224 Accurate Mass TOF LC/MS instrument. Elemental analyses (C, H,
N) were performed with a Perkin-Elmer 2400 Series II CHNS/O Analyzer.
TLC was carried out on Fluka silica gel TLC-cards. Column
chromatography was performed on 230–400-mesh silica gel. Merck silica
gel 60 PF254 containing gypsum was used to prepare chromatotron
plates. Radial chromatography was performed with Harrison Research,
model 7924T chromatotron.
Me
N
Ph
[RuCl2(p-cymene)]2 (5 mol%)
+
no reaction
N
PCCA (10 mol%), K2CO3 (3 equiv.)
toluene, 130 °C, 48 h
4a-R
Br
1.) [RuCl2(p-cymene)]2 (5 mol%)
Me
Me
Me
Br
PCCA (10 mol%), K2CO3 (3 equiv.)
toluene, 130 °C, 72 h
H
N
O2
N
4a
+
r.t., 96 h
N
Ph
2.) [RuCl2(p-cymene)]2 (5 mol%)
N
Ph
i-PrOH 80 o
C
, 24 h
PPh3 (10 mol%),
,
5c-R
(64%)
5c-RR
Scheme 3. Arylation-reduction sequence as substitute for sp3C–H arylation.
Conclusions
In summary, we have developed
chelation-assisted functionalization of 2-substituted quinazolines
with (hetero)aryl bromides to construct conjugated
a ruthenium-catalyzed,
General procedure for the direct arylation of quinazolines 1a–k
A mixture of quinazoline derivative 1 (0.50 mmol), (hetero)aryl bromide
(1.50 mmol), [RuCl2(p-cymene)]2 (0.025 mmol, 15 mg), PCCA (0.05
mmol, 10 mg), PPh3 (0.05 mmol, 13 mg) and powdered K2CO3 (1.00
mmol, 138 mg) in 1,4-dioxane (2 mL) was stirred for 24 h at 120 oC under
argon in a sealed tube. DCM (10 mL) was added to the cold reaction
mixture, and the inorganic salts were filtered off and washed with a small
amount of DCM. The filtrate was concentrated under reduced pressure,
and the residue was purified by radial chromatography on silica gel to
yield the arylated product 2 (and 3).
heteroaromatic systems. The combination of catalytic amounts
of [RuCl2(p-cymene)]2, 1-phenyl-1-cyclopentanecarboxylic acid,
and PPh3 generates an active catalyst for the direct ortho- C–H
arylation of aryl and heteroaryl substitiuents at the position C2 of
a quinazoline ring. The arylation of 2-substituted quinazolines
was possible with electron-deficient as well as with electron-rich
aryl bromides and gave good-to-excellent yields, mainly of ortho-
disubstituted products. Direct arylation of quinazolinyl alkenes in
the presence of [RuCl2(p-cymene)]2 and 1-phenyl-1-
cyclopentanecarboxylic acid led to highly selective formation of
tris(heteroaryl)alkenes where an aryl group was introduced cis to
the quinazoline ring by favorable formation of a five-membered
ruthenacyclic intermediate. Careful inspection of the products
distribution in the reaction of (E)-2-styrylquinazoline and 4-
bromoacetophenone under different reaction conditions revealed,
that the choice of solvent and reaction temperature was crucial
for attaining highly stereoselective olefinic C–H functionalization.
Our method is compatible with different functional groups (cyano,
methoxy, halogen, nitro, acetyl, trifluoromethyl, dimethylamino)
either at the quinazoline derivative or at the arylating reagent.
Finally, we demonstrated, though in only one example, that an
arylation-reduction sequence performed at 2-styrylquinazoline
can replace the otherwise more difficult to achieve sp3C–H
2-(4,4''-Diacetyl-[1,1':3',1''-terphenyl]-2'-yl)quinazoline (2a): Radial
chromatography (eluting with petroleum ether/EtOAc; 5/1). White solid
(217 mg, 98%); m.p. = 201–202 °C. FT-IR (ATR, neat): 1674, 1603, 1582,
1555, 1484, 1395, 1362, 1264, 1180, 960, 829, 806, 784 cm-1. 1H NMR
(500 MHz, CDCl3): δ = 2.49 (s, 6H), 7.25–7.27 (m, 4H), 7.53–7.55 (m,
2H), 7.58–7.65 (m, 2H), 7.67–7.72 (m, 5H), 7.79–7.82 (m, 2H), 9.10 (d, J
= 0.61 Hz, 1H) ppm. 13C NMR (500 MHz, CDCl3): δ = 26.5, 122.2, 127.0,
127.9, 128.0, 128.1, 129.0, 129.3, 129.9, 134.3, 135.1, 137.7, 140.9,
146.2, 149.4, 159.4, 163.2, 197.8 ppm. HRMS (ESI+): calcd for
C30H23N2O2 [M+H]+ 443.1754; found 443.1757.
2-(4'-Acetyl-[1,1'-biphenyl]-2-yl)quinazoline
(3a):
Radial
chromatography (eluting with petroleum ether/EtOAc; 5/1, then 5/3).
White solid (12 mg, 7%); m.p.= 148–149 °C. FT-IR (ATR, neat): 1672,
1604, 1579, 1549, 1397, 1375, 1267, 1181, 1034, 849. 1H NMR (500
MHz, CDCl3): δ = 2.56 (s, 3H), 7.29 (AA’BB’, J = 8.5 Hz, 2H), 7.50–7.53
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
(m, 1H), 7.55–7.58 (m, 2H), 7.61–7.65 (m, 1H), 7.79 (AA’BB’, J = 8.5 Hz,
2H), 7.86–7.92 (m, 3H), 7.98–8.02 (m, 1H), 9.21 (s, 1H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 26.6, 122.7, 127.1, 127.7, 128.0, 128.2, 128.4,
129.4, 129.5, 130.6, 131.1, 134.2, 135.0, 138.5, 140.6, 147.1, 150.3,
159.8, 163.7, 197.9 ppm. HRMS (ESI+): calcd for C22H17N2O [M+H]+
325.1335; found 325.1329.
2-(5'-Chloro-4,4''-dimethyl-[1,1':3',1''-terphenyl]-2'-yl)quinazoline
(2g): Radial chromatography (eluting with petroleum ether/DCM; 1/1 then
1/2). Grey solid (131 mg, 62 %); m.p.= 129–131 oC. FT-IR (ATR, neat):
3032, 2917, 1615, 1581, 1562, 1513, 1483, 1389, 1372, 1132, 1112,
1031, 870, 819, 813, 773, 763, 713 cm-1. 1H NMR (500 MHz, CDCl3): δ =
2.17 (s, 6H), 6.87 (AA'BB', J = 7.9 Hz, 4H), 7.03 (AA'BB', J = 8.1 Hz, 4H),
7.46 (s, 2H), 7.55–7.58 (m, 1H), 7.76–7.81 (m, 3H), 9.12 (s, 1H) ppm. 13
C
NMR (126 MHz, CDCl3): δ = 21.0, 122.2, 126.9, 127.6, 128.2, 128.6,
128.9, 129.0, 133.9, 134.1, 136.3, 136.4, 137.2, 143.4, 149.5, 159.3,
163.4 ppm. HRMS (ESI+): calcd for C28H22Cl35N [M+H]+ 421.1466; found
421.1464.
2-(4,4''-Bis(dimethylamino)-[1,1':3',1''-terphenyl]-2'-yl)quinazoline
(2b): Radial chromatography (eluting with petroleum ether/EtOAc; 5/1).
Yellow solid (215 mg, 97%); m.p.= 245–250 °C. FT-IR (ATR, neat): 2798,
1609, 1522, 1483, 1441, 1353, 1199, 1166, 1037, 943, 801, 770 cm-1. 1H
NMR (500 MHz, CDCl3): δ = 2.80 (s, 12H), 6.42–6.45 (m, 4H), 7.01–7.04
(m, 4H), 7.40–7.41 (m, 2H), 7.49 (dd, J = 8.3, 7.0 Hz, 1H), 7.54–7.57 (m,
1H), 7.76–7.79 (m, 2H), 7.82–7.84 (m, 1H), 9.18 (s, 1H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 40.4, 112.0, 122.2, 126.9, 127.1, 128.4, 128.5,
128.7, 129.8, 129.9, 133.5, 137.4, 141.6, 148.8, 149.7, 159.2, 165.0 ppm.
HRMS (ESI+): calcd for C30H29N4 [M+H]+ 445.2387; found 445.2379.
2-(5'-Bromo-4,4''-dimethyl-[1,1':3',1''-terphenyl]-2'-yl)quinazoline
(2h): Radial chromatography (eluting with petroleum ether/DCM; 1/1 then
1/2). Brownish solid (59 mg, 25%); m.p.= 75–77 oC. FT-IR (ATR, neat):
3027, 2821, 2855, 1617, 1576, 1562, 1512, 1484, 1392, 1375, 1110,
1031, 869, 820, 810, 862, 729, 656, 649 cm-1. 1H NMR (500 MHz,
CDCl3): δ = 2.18 (s, 6H), 6.87 (AA'BB', J = 8.0 Hz, 4H), 7.02 (AA'BB', J =
8.1 Hz, 4H), 7.56–7.59 (m, 1H), 7.61 (s, 2H), 7.75–7.81 (m, 3H), 9.12 (s,
1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 21.0, 122.2, 122.4, 126.9,
127.6, 128.2, 128.6, 128.9, 131.9, 133.9, 136.5, 136.7, 137.1, 143.6,
149.5, 159.3, 163.5 ppm. HRMS (ESI+): calcd for C28H22Br79N2 [M+H]+
465.0961; found 465.0953.
2-(4,4''-Dimethyl-[1,1':3',1''-terphenyl]-2'-yl)quinazoline (2c): Radial
chromatography (eluting with petroleum ether/EtOAc; 10/1).White solid
(189 mg, 97%); m.p.= 163–167 °C. FT-IR (ATR, neat): 3018, 2922, 1616,
1561, 1514, 1372, 1036, 819, 796, 770, 732 cm-1. 1H NMR (500 MHz,
CDCl3): δ = 2.18 (s, 6H), 6.86–6.87 (m, 4H), 7.03–7.06 (m, 4H), 7.45–
7.47 (m, 2H), 7.52–7.58 (m, 2H), 7.76–7.81 (m, 3H), 9.13 (s, 1H) ppm.
13C NMR (500 MHz, CDCl3): δ = 20.9, 122.1, 126.9, 127.4, 128.2, 128.4,
128.6, 129.0, 129.3, 133.7, 135.8, 137.7, 138.5, 141.6, 149.5, 159.1,
164.3 ppm. HRMS (ESI+): calcd for C28H23N2 [M+H]+ 387.1856; found
387.1856.
2-(5-Bromo-4'-methyl-[1,1'-biphenyl]-2-yl)quinazoline (3h): Radial
chromatography (eluting with petroleum ether/DCM; 1/1 then 1/2). Grey
solid (23 mg, 12 %); m.p.= 49–52 oC. FT-IR (ATR, neat): 3025, 2919,
2857, 1318, 1583, 1565, 1556, 1485, 1445, 1402, 1374, 1286, 1086,
1028, 1012, 869, 819, 803, 763, 747, 729, 708, 644 cm-1. 1H NMR (500
MHz, CDCl3): δ = 2.28 (s, 3H), 6.99 (AA'BB', J = 8.0 Hz, 2H), 7.05
(AA'BB', J = 8.1 Hz, 2H), 7.60–7.65 (m, 2H), 7.66 (d, J = 2.0 Hz, 1H),
7.79 (d, J = 8.2 Hz, 1H), 7.86–7.91 (m, 2H), 7.95–7.96 (m, 1H), 9.21 (s,
1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 21.1, 122.8, 123.5, 127.1,
127.7, 128.4, 128.8, 128.9, 130.2, 132.5, 133.5, 134.1, 136.7, 137.4,
137.4, 143.5, 150.3, 159.8, 163.6 ppm. HRMS (ESI+): calcd for
C21H16Br79N2 [M+H]+ 375.0491; found 375.0486.
2-(4,4''-Dicyanol-[1,1':3',1''-terphenyl]-2'-yl)quinazoline (2d): Radial
chromatography (eluting with petroleum ether/EtOAc; 3/1). White solid
(196 mg, 96%); m.p.= 266–270 °C. FT-IR (ATR, neat): 2225, 1616, 1555,
1482, 1392, 1376, 1178, 984, 857, 841, 805, 760 cm-1. 1H NMR (500
MHz, CDCl3): δ = 7.24–7.26 (m, 4H), 7.38–7.40 (m, 4H), 7.53–7.54 (m,
2H), 7.64–7.71 (m, 3H), 7.83–7.88 (m, 2H), 9.11 (s, 1H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 110.4, 118.7, 122.1, 127.1, 127.9, 128.4, 129.2,
129.7, 130.0, 131.6, 134.7, 137.7, 140.4, 145.9, 149.4, 159.5, 162.5 ppm.
HRMS (ESI+): calcd for C28H17N4 [M+H]+ 409.1448; found 409.1445.
2-(4,4''-Dimethyl-5'-(trifluoromethyl)-[1,1':3',1''-terphenyl]-2'-
yl)quinazoline (2i): Radial chromatography (eluting with petroleum
ether/DCM; 1/2). Yellow solid (217 mg, 95 %); m.p.= 124–127 oC. FT-IR
(ATR, neat): 3026, 2923, 1617, 1583, 1560, 1514, 1478, 1363, 1261,
1173, 1120, 1105, 1033, 893, 813, 778, 765, 713 cm-1. 1H NMR (500
MHz, CDCl3): δ = 2.18 (s, 6H), 6.89 (AA'BB', J = 7.9 Hz, 4H), 7.05
(AA'BB', J = 8.0 Hz, 4H), 7.56–7.59 (m, 1H), 7.72 (s, 2H), 7.76–7.82 (m,
3H), 9.14 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 21.0, 122.3,
124.0 (d, 1J = 272.5 Hz), 125.9 (q, 3J = 3.7 Hz), 127.0, 127.8, 128.3,
128.7, 128.9, 130.7 (q, 2J = 32.4 Hz), 134.0, 136.6, 137.1, 140.9, 140.6,
149.5, 159.3, 163.2 ppm. HRMS (ESI+): calcd for C29H22F3N2 [M+H]+
455.1730; found 455.1733.
2-(2,6-Di(thiophen-2-yl)phenyl)quinazoline
(2e):
Radial
chromatography (eluting with petroleum ether/EtOAc; 5/1). White solid
(168 mg, 91%); m.p.= 164–169 °C. FT-IR (ATR, neat): 1616, 1578, 1551,
1483, 1394, 1373, 1226, 1031, 841, 769, 701 cm-1. 1H NMR (500 MHz,
CDCl3): δ = 6.71–6.74 (m, 4H), 7.05–7.06 (m, 2H), 7.50–7.53 (m, 1H),
7.60–7.66 (m, 3H), 7.87–7.91 (m, 2H), 7.95–7.98 (m, 1H), 9.30 (d, J =
0.5 Hz, 1H) ppm. 13C NMR (500 MHz, CDCl3): δ = 122.9, 125.8, 126.7,
126.9, 127.1, 127.9, 128.5, 128.8, 130.1, 134.2, 134.3, 137.6, 142.3,
149.7, 159.8, 163.3 ppm. HRMS (ESI+): calcd for C22H15N2S2 [M+H]+
371.0671; found 371.0668.
2-(4,4''-Dimethyl-5'-nitro-[1,1':3',1''-terphenyl]-2'-yl)quinazoline (2j):
Radial chromatography (eluting with petroleum ether/DCM; 1/1, then 1/2).
Grey solid (33 mg, 15 %); mp = 211–214 oC. FT-IR (ATR, neat): 3027,
2821, 2855, 1617, 1576, 1562, 1512, 1484, 1392, 1375, 1110, 1031, 869,
820, 810, 862, 729, 656, 649 cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.19
(s, 6H), 6.91 (AA'BB', J = 8.0 Hz, 4H), 7.06 (AA'BB', J = 8.1 Hz, 4H),
2-(5'-Fluoro-4,4''-dimethyl-[1,1':3',1''-terphenyl]-2'-yl)quinazoline (2f):
Radial chromatography (eluting with petroleum ether/DCM; 1/1 then 1/2).
Brownish solid (137 mg, 68 %); m.p.= 141–143 oC. FT-IR (ATR, neat):
3027, 2921, 1617, 1592, 1564, 1515, 1484, 1391, 1374, 1339, 1264,
1164, 1037, 869, 824, 816, 763, 713, 675, 622 cm-1. 1H NMR (500 MHz,
CDCl3): δ = 2.18 (s, 6H), 6.87 (AA'BB', J = 8.0 Hz, 4H), 7.03 (AA'BB', J =
8.1 Hz, 4H), 7.18 (AA'BB', J = 9.3 Hz, 2H), 7.56–7.59 (m, 1H), 7.77–7.82
(m, 3H), 9.13 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 21.0, 115.9
(d, 2J = 21.6 Hz), 122.1, 127.0, 127.7, 128.1, 128.6, 128.8, 134.0, 136.5,
137.4 (d, 4J = 1.8 Hz) , 144.1 (d, 3J = 8.5 Hz), 149.4, 159.3, 162.2 (d, 1J =
248.5 Hz), 163.4 ppm. HRMS (ESI+): calcd for C28H22FN2 [M+H]+
405.1762; found 405.1759.
7.60–7.63 (m, 1H), 7.78–7.85 (m, 3H), 8.33 (s, 2H), 9.15 (s, 1H) ppm. 13
C
NMR (126 MHz, CDCl3): δ = 21.0, 122.4, 123.7, 127.0, 128.0, 128.2,
128.8, 128.9, 134.2, 136.4, 137.1, 143.4, 143.6, 147.5, 149.5, 159.4,
162.5 ppm. HRMS (ESI+): calcd for C28H22N3O2 [M+H]+ 432.1707; found
432.1709.
2-(4'-Methyl-5-nitro-[1,1'-biphenyl]-2-yl)quinazoline
(3j):
Radial
chromatography (eluting with petroleum ether/DCM; 1/1, then 1/2).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
Brown solid (33 mg, 19 %); m.p.= 125–127 oC. FT-IR (ATR, neat): 2923,
2853, 1618, 1582, 1567, 1554, 1524, 1512, 1485, 1374, 1339, 1033, 913,
816, 808, 776, 755, 734, 719, 707 cm-1. 1H NMR (500 MHz, CDCl3): δ =
2.30 (s, 3H), 7.03 (AA'BB', J = 8.0 Hz, 2H), 7.08 (AA'BB', J = 8.1 Hz, 2H),
7.67–7.70 (m, 1H), 7.90–7.95 (m, 2H), 7.98–7.99 (m, 1H), 8.07 (d, J =
8.5 Hz, 1H), 8.32 (dd, J = 2.3, J = 8.5 Hz, 1H), 8.38 (d, J = 2.3 Hz, 1H),
9.25 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 21.1, 121.9, 123.0,
125.6, 127.2, 128.2, 128.5, 128.9, 129.0, 132.1, 134.5, 136.6, 137.3,
143.3, 144.2, 148.2, 150.3, 160.0, 162.6 ppm. HRMS (ESI+): calcd for
C21H16N3O2 [M+H]+ 342.1237; found 342.1235.
7.85−7.89 (m, 3H), 7.90 (AA'BB', J = 8.5 Hz, 2H), 9.29 (s, 1H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 26.6, 123.1, 125.3, 127.1, 127.5, 128.0,
128.4, 129.8, 131.1, 134.2, 136.0, 137.3, 139.6, 143.5, 150.4, 159.3,
160.3, 197.7 ppm. FT-IR (ATR, neat): 1675, 1554, 1484, 1413, 1355,
1262, 1180, 828, 797, 763, 706 cm-1. HRMS (ESI+): calcd for
C20H15N2OS [M+H]+ 331.0900; found 331.0900.
2-(3-(4-Acetylphenyl)furan-2-yl)quinazoline
(3n):
Radial
chromatography (eluting with petroleum ether/DCM; 1/1, then 1/2, then
PE/EtOAc; 5/3). Brown-yellow solid (82 mg, 61 %); m.p.= 148−151 oC. 1H
NMR (500 MHz, CDCl3): δ = 2.66 (s, 3H), 6.73 (d, J = 1.8 Hz, 1H),
7.59−7.63 (m, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.76 (AA'BB', J = 8.4 Hz, 2H),
7.86−7.91 (m, 2H), 7.95−7.99 (m, 1H), 8.01 (AA'BB', J = 8.5 Hz, 2H),
9.32 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 26.7, 114.8, 123.4,
127.2, 127.6, 127.9, 128.5, 128.9, 129.8, 134.5, 136.0, 138.8, 144.2,
146.8, 150.3, 154.6, 160.4, 197.9 ppm. HRMS (ESI+): calcd for
C20H15N2O2 [M+H]+ 315.1128; found 315.1126.
2-(5'-Cyano-4,4''-dimethyl-[1,1':3',1''-terphenyl]-2'-yl)quinazoline (2k):
Radial chromatography (eluting with petroleum ether/DCM; 1/2). Light
yellow solid (113 mg, 55 %); m.p.= 89–92 oC. FT-IR (ATR, neat): 3028,
2922, 2227, 1618, 1564, 1512, 1485, 1392, 1376, 1037, 889, 815, 764,
731, 627 cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.19 (s, 6H), 6.89 (AA'BB',
J = 8.0 Hz, 4H), 7.01 (AA'BB', J = 8.1 Hz, 4H), 7.60–7.63 (m, 1H), 7.75 (s,
2H), 7.78–7.85 (m, 3H), 9.15 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ
= 21.0, 112.5, 118.6, 122.3, 127.1, 128.0, 128.2, 128.8, 128.8, 132.5,
134.3, 136.3, 137.0, 141.8, 143.1, 149.4, 159.4, 162.5 ppm. HRMS
(ESI+): calcd for C29H22N3 [M+H]+ 412.1808; found 412.1803.
General procedure for the direct arylation of quinazolines 4a,b
A mixture of quinazoline 4a (0.86 mmol, 200 mg) or 4b (0.25 mmol, 55.5
mg), (hetero)aryl bromide (0.91 mmol in combination with 4a or 0.5 mmol
in combination with 4b), [RuCl2(p-cymene)]2 (0.043 mmol (26.5 mg) in
combination with 4a or 0.025 mmol (15.5 mg) in combination with 4b),
PCCA (0.086 mmol (16.5 mg) in combination with 4a or 0.05 mmol (9.5
mg) in combination with 4b) and powdered K2CO3 (2.58 mmol (356 mg)
in combination with 4a or 0.75 mmol (104 mg) in combination with 4b) in
dry toluene (2–3 mL) was stirred for 24–72 h at 130 oC under argon in a
sealed tube. DCM (10 mL) was added to the cold reaction mixture, and
the inorganic salts were filtered off and washed with a small amount of
DCM. The filtrate was concentrated under reduced pressure, and the
residue was purified by radial chromatography on silica gel to yield the
arylated products 5a–j.
2-(5-Cyano-4'-methyl-[1,1'-biphenyl]-2-yl)quinazoline (3k): Radial
chromatography (eluting with petroleum ether/DCM; 1/2). Yellow solid
(16 mg, 10 %); m.p.= 47–49 oC. FT-IR (ATR, neat): 3028, 2920, 2228,
1617, 1567, 1547, 1483, 1404, 1376, 1034, 903, 817, 807, 768, 752, 727,
709, 619 cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.29 (s, 3H), 7.00–7.04 (m,
4H), 7.66–7.69 (m, 1H), 7.76 (dd, J = 1.6, 7.9 Hz, 1H), 7.80 (d, J = 1.3 Hz,
1H), 7.90–7.95 (m, 2H), 7.97–7.99 (m, 1H), 8.01 (d, J = 7.9 Hz, 1H), 9.23
(s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 21.1, 113.0, 118.6, 122.9,
127.1, 128.2, 128.5, 128.8, 129.0, 130.5, 131.7, 134.3, 134.5, 136.5,
137.2, 142.5, 142.8, 150.2, 160.0, 162.8 ppm. HRMS (ESI+): calcd for
C22H16N3 [M+H]+ 322.1339; found 322.1333.
2-(4,4'',5'-Trimethyl-[1,1':3',1''-terphenyl]-2'-yl)quinazoline (2l): Radial
chromatography (eluting with petroleum ether/DCM; 1/2). Light yellow
solid (165 mg, 75 %); m.p.= 196–199 oC. FT-IR (ATR, neat): 3027, 2918,
1616, 1603, 1564, 1555, 1513, 1390, 1372, 1185, 1037, 814, 774, 766,
714, 621 cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.18 (s, 6H), 2.49 (s, 3H),
6.88 (AA'BB', J = 8.0 Hz, 4H), 7.07 (AA'BB', J = 8.1 Hz, 4H), 7.30 (s, 2H),
7.51–7.54 (m, 1H), 7.74–7.79 (m, 3H), 9.12 (s, 1H) ppm. 13C NMR (126
MHz, CDCl3): δ = 20.9, 21.3, 122.0, 126.8, 127.2, 128.2, 128.3, 129.0,
130.0, 133.6, 135.0, 135.7, 138.2, 138.6, 141.5, 149.5, 159.0, 164.4 ppm.
HRMS (ESI+): m/z calcd for C29H25N2 [M+H]+ 401.2012; found 401.2008.
(Z)-2-(2-(4-Acetylphenyl)-2-phenylvinyl)quinazoline ((Z)-5a): Radial
chromatography (eluting with petroleum ether/EtOAc; 7/1, then 5/1, then
5/3). White solid (133 mg, 44%); m.p.= 140–142 °C. FT-IR (ATR, neat):
2960, 1680, 1603, 1579, 1550, 1484, 1398, 1378, 1357, 1265, 1016, 957,
758, 698 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.63 (s, 3H), 7.31–7.38 (m,
5H), 7.38 (s, 1H), 7.39–7.43 (m, 2H), 7.56 (m, 1H), 7.69 (m, 1H), 7.81 (m,
2H), 7.91 (m, 2H), 9.12 (d, J = 0.5 Hz, 1H) ppm. 13C NMR (75.5 MHz,
CDCl3) δ 26.6, 122.8, 127.0, 127.5, 127.9, 128.0, 128.19, 128.22, 128.4,
128.7, 130.4, 134.0, 136.0, 141.9, 145.8, 149.5, 150.1, 159.6, 161.2,
198.0 ppm. HRMS (ESI+): calcd for C24H19N2O [M+H]+: 351.1492;
351.1491. Elemental analysis calcd for C24H18N2O: C, 82.26; H, 5.18; N,
7.99; found: C, 81.98; H, 4.99; N, 7.91.
2-(2,4-Bis(4-acetylphenyl)thiophen-3-yl)quinazoline
(2m):
Radial
chromatography (eluting with petroleum ether/DCM; 1/1, then 1/2, then
PE/EtOAc; 5/3). Grey solid (74 mg, 33 %); m.p.= 172−176 oC. FT-IR
(ATR, neat): 1674, 1598, 1555, 1354, 1264, 1181, 1014, 959, 828, 760
cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.52 (s, 3H), 2.53 (s, 3H), 7.26
(AA'BB', 2H), 7.35 (AA'BB', J = 8.4 Hz, 2H), 7.52 (s, 1H), 7.66−7.70 (m,
1H), 7.75 (AA'BB', J = 8.4 Hz, 2H), 7.77 (AA'BB', J = 8.4 Hz, 2H),
7.83−7.93 (m, 3H), 9.30 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ =
26.52, 26.54, 122.9, 124.6, 127.2, 128.2, 128.37, 128.39, 128.5, 129.1,
134.5, 135.4, 136.0, 136.9, 138.5, 141.1, 143.1, 143.4, 150.1, 160.0,
160.4, 197.5, 197.7 ppm. HRMS (ESI+): calcd for C28H21N2O2S [M+H]+
449.1318; found 449.1319.
2-(2,2-Diphenylvinyl)quinazoline (5b): Radial chromatography (eluting
with petroleum ether/EtOAc; 7/1, then 5/1, then 5/3). Yellow solid (214
mg, 77%); m.p.= 139–141 °C. FT-IR (ATR, neat): 2988, 2901, 1624,
1608, 1550, 1481, 1441, 1395, 1375, 1074, 880, 752, 693 cm-1. 1H NMR
(300 MHz, CDCl3): δ = 7.18–7.24 (m, 2H), 7.27–7.37 (m, 7H), 7.41–7.47
(m, 2H), 7.50–7.56 (m, 1H), 7.70–7.82 (m, 3H), 9.12 (d, J = 0.5 Hz, 1H)
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 122.7, 126.9, 127.0, 127.2, 127.4,
127.8, 128.19, 128.22, 128.35, 128.43, 130.2, 133.8, 140.3, 142.6, 150.2,
150.7, 159.5, 161.8 ppm. HRMS (ESI+): calcd for C22H17N2 [M+H]+
309.1386; found 309.1387. Elemental analysis calcd for C22H16N2: C,
85.69; H, 5.23; N, 9.08; found: C, 85.81; H, 5.27; N, 9.07.
2-(2-(4-Acetylphenyl)thiophen-3-yl)quinazoline
(3m):
Radial
chromatography (eluting with petroleum ether/DCM; 1/1, then 1/2, then
PE/EtOAc; 5/3). Grey solid (52 mg, 31 %); m.p.= 123−124 oC. FT-IR
(ATR, neat): 3091, 1671, 1583, 1484, 1381, 1272, 952, 833, 761 cm-1. 1H
NMR (500 MHz, CDCl3): δ = 2.62 (s, 3H), 7.44 (d, J = 5.3 Hz, 1H), 7.52
(AA'BB', J = 8.4 Hz, 2H), 7.60−7.63 (m, 1H), 7.83 (d, J = 5.3 Hz, 1H),
(Z)-2-(2-Phenyl-2-(p-tolyl)vinyl)quinazoline
((Z)-5c):
Radial
chromatography (eluting with petroleum ether/EtOAc; 7/1, then 5/1, then
5/3). White solid (132 mg, 48%); m.p.= 71–74 °C. FT-IR (ATR, neat):
3053, 2919, 1606, 1579, 1561, 1547, 1483, 1441, 906, 821, 754, 727,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
695 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.37 (s, 3H), 7.09 (m, 4H),
7.29–7.36 (m, 4H), 7.40–7.46 (m, 2H), 7.49–7.55 (m, 1H), 7.75–7.80 (m,
3H), 9.14 (s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 21.3, 122.7,
126.8, 126.9, 127.1, 128.1, 128.2, 128.3, 128.4, 128.5, 130.2, 133.7,
137.09, 137.15, 143.0, 150.2, 150.7, 159.5, 162.0 ppm. HRMS (ESI+):
calcd for C23H19N2 [M+H]+ 323.1543; found 323.1542. Elemental analysis
calcd for C23H18N2: C, 85.68; H, 5.63; N, 8.69; found: C, 85.40; H, 5.59; N,
8.66.
J = 8.0, 7.0, 1.0 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.73−7.76 (AA'BB', J =
8.4 Hz, 2H), 7.84 (ddd, J1 = 8.5, 7.0, 1.4 Hz, 1H), 7.89 (m, 1H), 9.15 (s,
1H) ppm. 13C NMR (126 MHz, CD3CN): δ = 111.9, 113.3, 113.6, 119.9,
123.6, 124.8, 128.3, 128.6, 128.7, 131.6, 132.7, 135.2, 138.1, 144.1,
145.4, 150.7, 155.2, 160.7, 161.3 ppm. HRMS (ESI+): calcd for
C21H14N3O [M+H]+ 324.1131; found 324.1128.
(E)-2-(2-(Furan-2-yl)-2-(4-methoxy-3-(3-
methoxypropoxy)phenyl)vinyl)quinazoline
((E)-5h):
Radial
(Z)-2-(2-(4-Methoxyphenyl)-2-phenylvinyl)quinazoline ((Z)-5d): Radial
chromatography (eluting with petroleum ether/EtOAc; 10/1, then 5/1).
Yellow solid (268 mg, 92%); m.p.= 58–62 °C. FT-IR (ATR, neat): 3054,
3024, 1612, 1589, 1555, 1483, 1447, 1419, 1392, 1354, 1315, 1199,
1153, 1141, 1079, 970, 902, 860, 790, 744, 715, 688 cm-1. 1H NMR (500
MHz, CDCl3): δ = 3.82 (s, 3H), 6.81 (m, 2H), 7.13 (m, 2H), 7.22 (s, 1H),
7.32–7.36 (m, 3H), 7.42–7.46 (m, 2H), 7.52–7.56 (m, 1H), 7.77–7.83 (m,
3H), 9.15 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 55.2, 113.2,
122.7, 126.5, 126.9, 127.1, 128.11, 128.15, 128.4, 128.6, 131.7, 132.4,
133.8, 143.1, 150.2, 150.5, 159.2, 159.5, 162.1 ppm. HRMS (ESI+): calcd
for C23H19N2O [M+H]+ 339.1492; found 339.1493.
chromatography (eluting with petroleum ether/EtOAc; 7/1 then 5/3).
Orange oil (30 mg, 29%). FT-IR (ATR, neat): 2928, 2873, 2834, 1511,
1396, 1251, 1226, 1115, 1020, 750 cm-1. 1H NMR (500 MHz, CD3CN): δ
= 1.82 (qn, J = 6.5 Hz, 2H), 3.18 (s, 3H), 3.35 (t, J = 6.5 Hz, 2H), 3.84 (t,
J = 6.5 Hz, 2H), 3.84 (s, 3H), 6.22 (d, J = 3.5 Hz, 1H), 6.48−6.52 (m, 1H),
6.83−6.89 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.55−7.67 (m,
3H), 7.81−7.91 (m, 2H), 9.15 (s, 1H) ppm. 13C NMR (126 MHz, CD3CN):
δ = 30.1, 56.4, 58.7, 66.7, 69.6, 112.2, 113.1, 113.4, 116.7, 123.4, 123.6,
123.9, 128.22, 128.25, 128.7, 130.9, 135.0, 139.3, 144.9, 148.6, 150.3,
151.0, 156.4, 160.5, 162.3 ppm. HRMS (ESI+): calcd for C25H25N2O4
[M+H]+ 417.1809; found 417.1807.
(Z)-2-(2-Phenyl-2-(thiophen-2-yl)vinyl)quinazoline ((Z)-5e): Radial
chromatography (eluting with petroleum ether/EtOAc; 7/1, then 5/1, then
5/3). White solid (35 mg, 13%); m.p.= 126–128 °C. FT-IR (ATR, neat):
2987, 1620, 1600, 1552, 1396, 1380, 1225, 1076, 1054, 891, 755, 722,
700 cm-1. 1H NMR (300 MHz, CDCl3): δ = 6.97 (m, 2H), 7.19 (s, 1H), 7.30
(m, 1H), 7.34–7.40 (m, 3H), 7.50–7.60 (m, 3H), 7.81–7.91 (m, 3H), 9.25
(s, 1H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 122.9, 126.5, 126.7, 127.0,
127.4, 128.12, 128.16, 128.24, 128.5, 128.6, 129.7, 133.9, 141.3, 142.7,
142.9, 150.2, 159.7, 161.4 ppm. HRMS (ESI+): calcd for C20H15N2S
[M+H]+: 315.0950; found 315.0952. Elemental analysis calcd for
C20H14N2S: C, 76.40; H, 4.49; N, 8.91; found: C, 76.28; H, 4.29; N, 8.91.
(E)-2-(2-(Furan-2-yl)-2-(pyrimidin-5-yl)vinyl)quinazoline
Radial chromatography (eluting with petroleum ether/EtOAc; 7/1 then
1/1). Brownish solid (42 mg, 56%); m.p.= 109 111 °C. FT-IR (ATR, neat):
((E)-5i):
̶
3018, 2925, 1574, 1481, 1373, 1302, 1188, 1050, 882, 802, 739, 731,
711, 630 cm-1. 1H NMR (500 MHz, CD3CN): δ = 6.26 (d , J = 3.5 Hz, 1H),
6.55 (dd , J = 3.5, 2 Hz, 1H), 7.51 (s, 1H), 7.56 (dd, J = 8.5, 1.0 Hz, 1H),
7.60 (ddd, J = 8.0, 7.09, 1.0 Hz, 1H), 7.68 (d, J = 2, 1H), 7.85 (ddd, J =
8.5, 7.0, 1.5 Hz, 1H), 7.89−7.92 (m, 1H), 8.71 (s, 2H), 9.18 (s, 1H), 9.21
(s, 1H) ppm. 13C NMR (126 MHz, CD3CN): δ = 113.5, 113.8, 123.8, 126.3,
128.4, 128.68, 128.72, 132.96, 132.98, 135.3, 145.7, 150.7, 155.0, 158.0,
158.4, 160.9, 161.1 ppm. HRMS (ESI+): calcd for C18H13N4O [M+H]+:
301.1048 ; found 301.1079.
(E)-2-(2-Phenyl-2-(thiophen-2-yl)vinyl)quinazoline ((E)-5e): Radial
chromatography (eluting with petroleum ether/EtOAc; 7/1, then 5/1, then
5/3). Pink solid (71 mg, 26%); m.p.= 86–89 °C. FT-IR (ATR, neat): 2988,
1617, 1575, 1559, 1548, 1395, 1376, 1225, 1073, 828, 758, 747, 697 cm-
1. 1H NMR (300 MHz, CDCl3): δ = 6.93 (dd, J = 3.7, 1.2 Hz, 1H), 6.99 (dd,
J = 5.1, 3.7 Hz, 1H), 7.30–7.38 (m, 6H), 7.41 (s, 1H), 7.50 (m, 1H), 7.66
(m, 1H), 7.72–7.80 (m, 2H) 9.08 (d, J = 0.5 Hz, 1H) ppm. 13C NMR (75.5
MHz, CDCl3): δ = 122.5, 124.9, 126.7, 126.9, 127.1, 127.5, 127.6, 127.8,
128.2, 128.3, 129.6, 133.8, 139.7, 144.2, 147.1, 150.2, 159.4, 161.2 ppm.
HRMS (ESI+): calcd for C20H15N2S [M+H]+ 315.0950; found 315.0952.
Elemental analysis calcd for C20H14N2S: C, 76.40; H, 4.49; N, 8.91;
found: C, 76.45; H, 4.32; N, 8.81.
(E)-2-(2-(4-Acetylphenyl)-2-(furan-2-yl)vinyl)quinazoline
Radial chromatography (eluting with petroleum ether/EtOAc; 7/1).
Yellowish solid (32 mg, 38%); m.p.= 120 122 °C. FT-IR (ATR, neat):
((E)-5j):
̶
3148, 3123, 1677, 1598, 1547, 1484, 1394, 1377, 1312, 1072, 987, 947,
882, 823, 750, 662, 629 cm-1. 1H NMR (500 MHz, CD3CN): δ = 2.62 (s,
3H), 6.12 (d, J = 3.4 Hz, 1H), 6.51 (m, 1H), 7.40−7.46 (m, 3H), 7.52−7.61
(m, 2H), 7.65 (s, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H),
7.97 (d, J = 8.0 Hz, 2H), 9.13 (s, 1H) ppm. 13C NMR (126 MHz, CD3CN):
δ = 27.1, 113.2, 113.5, 123.6, 124.6, 128.2, 128.5, 128.68, 128.74, 130.9,
135.1, 137.3, 143.9, 145.2, 150.8, 155.6, 160.6, 161.6, 198.8 ppm.
HRMS (ESI+): calcd for C22H17N2O2 [M+H]+ 341.1285; found 341.1277.
(E)-2-(2-(Furan-2-yl)-2-(p-tolyl)vinyl)quinazoline
((E)-5f):
Radial
2-(2-Phenyl-2-(p-tolyl)ethyl)quinazoline
(5c-R):
A
mixture
of
chromatography (eluting with petroleum ether/EtOAc; 10/1). Yellowish oil
(30 mg, 39%). FT-IR (ATR, neat): 3025, 2919, 1600, 1547, 1482, 1395,
1376, 1235, 1219, 143, 961, 912, 815, 749, 631 cm-1. 1H NMR (500 MHz,
CD3CN): δ = 2.38 (s, 3H), 6.12 (d , J = 3.4 Hz, 1H), 6.48 (dd, J = 3.4, 1.9,
1H), 7.14−7.19 (m, 4H), 7.35 (s, 1H), 7.56 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H),
7.59−7.62 (m, 2H), 7.81 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.86 (m, 1H),
9.09 (s, 1H) ppm. 13C NMR (126 MHz, CD3CN): δ = 21.4, 113.1, 113.3,
123.6, 124.1, 128.18, 128.23, 128.6, 129.3, 130.6, 135.0, 135.5, 138.4,
139.5, 144.9, 150.9, 156.4, 160.4, 162.1 ppm. HRMS (ESI+): calcd for
C21H17N2O [M+H]+ 313.1335; found 313.1329.
quinazoline 4a (0.25 mmol, 58 mg), 4-bromotoluene (0.503 mmol, 86 mg),
[RuCl2(p-cymene)]2 (0.013 mmol, 8 mg), PCCA (0.026 mmol, 5 mg),
K2CO3 (0.747 mmol, 103 mg) in dry toluene (2 mL) was stirred for 72 h at
130 oC under argon in a sealed tube. After arylation toluene was
replaced with i-PrOH (5 mL), and [RuCl2(p-cymene)]2 (0.013 mmol, 8 mg),
and PPh3 (0.027 mmol, 7 mg) were added. The mixture was stirred for 24
h at 80 oC under inert atmosphere. Then, the reaction mixture was stirred
under O2 atmosphere (baloon) for 4 days at room temperature. DCM (10
mL) was added to the reaction mixture, and the inorganic salts were
filtered off and washed with a small amount of DCM. The filtrate was
concentrated under reduced pressure, and the residue was purified by
radial chromatography on silica gel (petroleum ether/EtOAc; 7/1 then
DCM/MeOH; 25/1).
(E)-2-(2-(4-Cyanophenyl)-2-(furan-2-yl)vinyl)quinazoline
((E)-5g):
Radial chromatography (eluting with petroleum ether/EtOAc; 10/1).
Yellowish oil (14 mg, 18%). FT-IR (ATR, neat): 3058, 2227, 1601, 1579,
1550, 1484, 1403, 1224, 1020, 884, 834, 756, 630 cm-1. 1H NMR (500
MHz, CD3CN): δ = 6.11 (d, J = 3.4 Hz, 1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H),
7.42 (s, 1H), 7.45−7.49 (AA'BB', J = 8.4 Hz, 2H), 7.54 (m, 1H), 7.59 (ddd,
White solid (52 mg, 64%); m.p.= 120–124 °C. FT-IR (ATR, neat): 3022,
2854 2919, 1618, 1568, 1513, 1485, 1451, 1406, 1377, 970, 823, 759,
730, 721, 690 cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.24 (s, 3H), 3.86 (d,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
J = 8 Hz, 2H), 5.01 (t, J = 8 Hz, 1H), 7.02 (m, 2H), 7.09 (m, 1H), 7.18–
7.24 (m, 4H), 7.32 (m, 2H), 7.55 (m, 1H), 7.82–7.86 (m, 2H), 7.93 (m,
1H), 9.27 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3): δ = 21.0, 45.5, 49.4,
123.0, 126.0, 126.97, 127.03, 127.90, 127.92, 128.0, 128.3, 129.0, 133.9,
135.5, 141.3, 144.6, 150.3, 160.1, 165.6 ppm. HRMS (ESI+): calcd for
C23H21N2 [M+H]+ 325.1699; found 325.1707.
c) G.-F. Zha, H.-L.Qin, E. A. B. Kantchev, RSC Adv., 2016, 6, 30875–
30885; d) C. Bruneau, P. H. Dixneuf in Top. Organomet. Chem., Vol.
55 (Eds.: P. H. Dixneuf, H. Doucet), Springer, Cham, 2016, pp.137–
188; e) B. Li, P. H. Dixneuf in Top. Organomet. Chem., Vol. 48 (Eds.: P.
H. Dixneuf, C. Bruneau), Springer, Cham, 2014, 119–193; f) S. De
Sarkar, W Liu, S. I. Kozhushkov, L. Ackermann, Adv. Synth. Catal.,
2014, 356, 1461–1479; g) F. Juliá-Hernández, M. Simonetti, I. Larrosa,
Angew. Chem. Int. Ed., 2013, 52, 11458–11460; h) P. B. Arockiam, C.
Bruneau, P. H. Dixneuf, Chem. Rev., 2012, 112, 5879–5918; i) S. Oi, S.
Fukita, N. Hirata, N. Watanuki, S. Miyano, Y. Inoue, Org. Lett., 2001, 3,
2579–2581.
2-(2-Phenyl-2-(p-tolyl)ethyl)-1,4-dihydroquinazoline (5c-RR). Isolated
directly after reduction step by radial chromatography on silica gel
(petroleum ether/EtOAc; 7/1 then DCM/MeOH; 25/1). Brownish solid (36
mg, 44%); m.p.= 50–60 °C. FT-IR (ATR, neat): 3056, 2919, 2859, 1618,
1582, 1485, 1450, 1405, 1377, 1327, 1296, 1268, 1171, 1117, 748, 721,
696 cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.24 (s, 3H), 3.12 (d, J = 7.9
Hz, 2H), 4.36 (s, 2H), 4.58 (t, J = 7.9 Hz, 1H), 6.80 (m, 1H), 6.91–7.31 (m,
12H) ppm. HRMS (ESI+): calcd for C23H23N2 [M+H]+ 327.1856; found
327.1853.
[5]
[6]
a) J. F. Hartwig, M. A. Larsen, ACS Cent. Sci., 2016, 2, 281–292; b) T.
Iwai, M. Sawamura, ACS Catal., 2015, 5, 5031–5040; c) L. Ackermann,
J. Li, Nat. Chem., 2015, 7, 686–687.
a) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang, Org. Chem.
Front., 2015, 2, 1107–1295; b) G. Rouquet, N. Chatani, Angew. Chem.
Int. Ed., 2013, 52, 11726–11743; c) C. Wang, Y. Huang, Synlett, 2013,
24, 145–149; d) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem.
Res., 2012, 45, 788–802; e) Z. Huang, H. N. Lim, F. Mo, M. C. Young,
G. Dong, Chem. Soc. Rev., 2015, 44, 7764–7786; f) P. Gandeepan, C.-
H. Cheng, Chem. Asian J., 2015, 10, 824–838.
Acknowledgements
[7]
[8]
M. Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li, W. Su, Org. Chem. Front.,
2014, 1, 843–895.
We thank the Slovenian Research Agency for the financial
support through grant P1-0179. We also thank S. Gašparin, D.
Smodiš, and Š. Trafela for laboratory assistance.
a) W.-G. Jia, T. Zhang, D. Xie, Q.-T. Xu, S. Ling, Q. Zhang, Dalton
Trans., 2016, 45,14230–14237; b) A. S. Lima Barbosa, C. Werlé, C. O.
Oliva Colunga, C. Franco Rodríguez, R. A. Toscano, R. Le Lagadec, M.
Pfeffer, Inorg. Chem., 2015, 54, 7617–7626; c) B. Li, C. Darcel, T.
Roisnel, P. H. Dixneuf, J. Organomet. Chem., 2015, 793, 200–209; d) X.
Xie, H. V. Huynh, Org. Chem. Front., 2015, 2, 1598–1603; e) B. Li, T.
Roisnel, C. Darcel, P. H. Dixneuf, Dalton Trans., 2012, 41, 10934–
10937; f) Y. Boutadla, D. L. Davies, R. C. Jones, K. Singh, Chem. Eur.
J., 2011, 17, 3438–3448; g) J.-P. Djukic, J.-B. Sortais, L. Barloy, M.
Pfeffer, Eur. J. Inorg. Chem., 2009, 817–853.
Keywords: quinazolines • C–H activation • ruthenium • direct
arylation • trisubstituted olefins
[1]
a) H. Sun, N. Guimond, Y. Huang, Org. Biomol. Chem., 2016, 14,
8389–8397; b) C. G. Frost, P. Marce, P. M. Liu, Organomet. Chem.,
2016, 40, 54–87; c) D. E. Stephens, O. V. Larionov, Tetrahedron, 2015,
71, 8683–8716; d) W. Zhang, N.-X. Wang, Y. Xing, Synlett, 2015, 26,
2088–2098; e) J. Yang, Org. Biomol. Chem., 2015, 13, 1930–1941; f) Y.
Liu, J. Kim, J. Chae, Curr. Org. Chem., 2014, 18, 2049–2071; g) J.
Schranck, A. Tlili, M. Beller, Angew. Chem. Int. Ed., 2014, 53, 9426–
9428; h) M. E. Farmer, B. N. Laforteza, J.-Q. Yu, Bioorg. Med. Chem.,
2014, 22, 4445–4452; i) A. R. Kapdi, Dalton Trans., 2014, 43, 3021–
3034; j) K. Okamoto, J. Zhang, J. B. Housekeeper, S. R. Marder, C. K.
Luscombe, Macromolecules, 2013, 46, 8059–8078; l) S. Rousseaux, B.
Liégault, K. Fagnou in Modern Tools in the Synthesis of Complex
Bioactive Molecules (Eds.: J. Cossy, S. Arseniyadis), John Wiley &
Sons, 2012, pp. 1–32; m) J. Yamaguchi, A. D. Yamaguchi, K. Itami,
Angew. Chem. Int. Ed., 2012, 51, 8960–9009; n) R. Jazzar, J. Hitce, A.
Renaudat, J. Sofack-Kreutzer, O. Baudoin, Chem. Eur. J., 2010, 16,
2654–2672.
[9]
a) V. G. Ugale, S. B. Bari, Eur. J. Med. Chem., 2014, 80, 447–501; b) T.
P. Selvam, P. V. Kumar, Res. Pharm., 2011, 1, 1–21; c) J. P. Michael,
Nat. Prod. Rep., 2008, 25, 166–187; d) A. Lüth, W. Löwe, Eur. J. Med.
Chem., 2008, 43, 1478–1488; e) A. Witt, J. Bergman, Curr. Org. Chem.,
2003, 7, 659–677; f) J. Jampilek, R. Musiol, J. Finster, M. Pesko, J.
Carroll, K. Kralova, M. Vejsova, J. O'Mahony, A. Coffey, J. Dohnal, J.
Polanski, Molecules, 2009, 14, 4246–4265; g) J. H. Park, H.-Y. Min, S.
S. Kim, J. Y. Lee, S. K. Lee, Y. S. Lee, Arch. Pharm. Pharm. Med.
Chem., 2004, 337, 20–24.
[10] a) I. M. Abdou, S. S. Al-Neyadi, Heterocycl. Commun., 2015, 21, 115–
132; b) T. Truong, T. M. Hoang, C. K. Nguyen, Q. T. N. Huynh, N. T. S.
Phan, RSC Adv., 2015, 5, 24769–24776; c) Z. Zhang, M. Wang, C.
Zhang, Z. Zhang, J. Lu, F. Wang, Chem. Commun., 2015, 51, 9205–
9207; d) S. D. Gawande, M. R. Zanwar, V. Kavala, C.-W. Kuo, R. R.
Rajawinslin, C.-F. Yao, Adv. Synth. Catal., 2015, 357, 168–176; e) S. M.
Saad, K. M. Khan, S. Perveen, W. Voelter, M. Taha, Monatsh. Chem.,
2015, 146, 1877–1880; f) D. Zhao, Q. Shen, J.-X. Li, Adv. Synth. Catal.,
2015, 357, 339–344; g) X. Fan, B. Li, S. Guo, Y. Wang, X. Zhang,
Chem. Asian J., 2014, 9, 739–743; h) J. Chen, K. Natte, H. Neumann,
X.-F. Wu, RSC Adv., 2014, 4, 56502–56505; i) J. Ju, R. Hua, J. Su,
Tetrahedron, 2012, 68, 9364–9370; j) C. C. Malakar, A. Baskakova, J.
Conrad, U. Beifuss, Chem. Eur. J., 2012, 18, 8882–8885; k) B. Han, X.-
L.Yang, C. Wang, Y.-W. Bai, T.-C. Pan, X. Chen, W. Yu, J. Org. Chem.,
2012, 77, 1136–1142; (l) C. U. Maheswari, G. S. Kumar, M.
Venkateshwar, R. A. Kumar, M. L. Kantam, K. R. Reddy, Adv. Synth.
Catal., 2010, 352, 341–346.
[2]
Selected reviews on Pd-catalyzed C-H activation: a) F. Bellina in Top.
Organomet. Chem., Vol. 55 (Eds.: P. H. Dixneuf, H. Doucet), Springer,
Cham, 2016, pp. 77–102; b) J. J. Topczewski, M. S. Sanford, Chem.
Sci., 2015, 6, 70–76; c) M. Ángeles Fernández-Ibáñez, ChemCatChem,
2014, 6, 2188–2190; d) K. Ramachandiran, T. Sreelatha, N. V. Lakshmi,
T. H. Babu, D. Muralidharan, P. T. Perumal, Curr. Org. Chem.,
2013, 17, 2001–2024; e) T. W. Lyons, M. S. Sanford, Chem. Rev.,
2010, 110, 1147–1169.
[3]
[4]
Selected reviews on Rh-catalyzed C-H activation: a) S.-S. Li, L. Qin, L.
Dong; Org. Biomol. Chem., 2016, 14, 4554–4570; b) J. Wencel-Delord,
F. W. Patureau, F. Glorius, Top. Organomet. Chem., Vol. 55 (Eds.: P. H.
Dixneuf, H. Doucet), Springer, Cham, 2016, pp. 1–28; c) G. Song, X. Li,
Acc. Chem. Res., 2015, 48, 1007–1020; d) M. Fultz in C−H Bond
Activation in Organic Synthesis, (Ed.: J. J. Li), CRC Press, Boca Raton,
2015, pp. 95–112.
[11] a) H. Brodnik, F. Požgan, B. Štefane, Org. Biomol. Chem., 2016, 14,
1969–1981; b) J. Fabris, B. Štefane, F. Požgan, Eur. J. Org. Chem.,
2011, 3474–3481; c) J. Roger, F. Požgan, H. Doucet, Adv. Synth.
Catal., 2010, 352, 696–710; d) F. Požgan, P. H. Dixneuf, Adv. Synth.
Catal., 2009, 351, 1737–1743; e) F. Požgan, J. Roger, H. Doucet,
ChemSusChem, 2008, 1, 404–407.
Selected reviews and examples on Ru-catalyzed C-H activation a) A.
Molnar, A. Papp, Curr. Org. Chem., 2016, 20, 381–458; b) S. Ruiz, P.
Villuendas, E. P. Urriolabeitia, Tetrahedron Lett., 2016, 57, 3413–3574;
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
[12] B. V. S. Reddy, G. Narasimhulu, N. Umadevi, J. S. Yadav, Synlett,
2012, 23, 1364–1370.
[13] Y. Peng, M. Zeng, H. Wang, J. Zhu, Q. Yang, Z. Deng, C. Yu,
Tetrahedron, 2015, 71, 9457–9462.
[14] C. Zhang, Y. Zhou, Z. Deng, X. Chen, Y. Peng, Eur. J. Org. Chem.,
2015, 1735–1744.
[15] H. Lu, Q. Yang, Y. Zhou, Y. Guo, Z. Deng, Q. Ding, Y. Peng, Org.
Biomol. Chem., 2014, 12, 758–764.
[16] Y. Zheng, W.-B. Song, S.-W. Zhang, L.-J. Xuan, Org. Biomol. Chem.,
2015, 13, 6474–6478.
[17] W. Yang, J. Chen, X. Huang, J. Ding, M. Liu, H. Wu, Org. Lett., 2014,
16, 5418–5421.
[18] L. Ackermann, Chem. Rev., 2011, 111, 1315–1345.
[19] The keto group of the arylated product 2a was reduced to a secondary
alcohol, presumably with i-PrOH as reductant in the presence of Ru(II)
catalyst.
[20] P. B. Arockiam, C. Fischmeister, C. Bruneau, P. H. Dixneuf, Angew.
Chem. Int. Ed., 2010, 49, 6629–6632.
[21] S. Oi, K. Sakai, Y. Inoue, Org. Lett., 2005, 7, 4009–4011.
[22] L. Ackermann, R. Born, P. Álvarez-Bercedo, Angew. Chem. Int. Ed.,
2007, 46, 6364–6367.
[23] D. Zell, S. Warratz, D. Gelman, S. J. Garden, L. Ackermann, Chem. Eur.
J., 2016, 22, 1248–1252.
[24] L. Ilies, S. Asako, E. Nakamura, J. Am .Chem. Soc., 2011, 133, 7672–
7675.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700097
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Key Topic*
Arylation of (hetero)aryl-substituted
quinazolines and quinazolinyl alkenes
through C–H bond activation is
feasable with Ru(II)-carboxylate
catalyst system thus offering a simple
method for construction of conjugated
heteroaromatic systems.
Bogdan Štefane, Helena Brodnik Žugelj,
Uroš Grošelj, Petra Kuzman, Jurij Svete,
Franc Požgan*
Page No. – Page No.
Title
*C–H activation
This article is protected by copyright. All rights reserved.